The use of corticosteroid [both dexamethazon and methylprednisolon], was shown to improve survival rate and recovery for patients infected with Covid-19 causing severe pneumonia leading to respiratory failure treated with assisted ventilation particularly those in need for endotracheal intubation and ventilatory support.
in Recovery trial , adminstration of dexamethazon of 6 mg for 10 days was associated with improvement of 28 days mortality rate for patient on ventilatory support and endotracheal intubation.
However, it was reported to be linked to worse outcome with higher mortality for patients with covid pneumia without respiratory failure.
This conclusion might be reflecting the incidence and impotence of immunologic hyper-reactive syndrome with detrimental consequences in patients on ventilators. hence the maximum benefit gained from using steroid therapy.
On the contrary, in patients with Covid pneumonia without respiratory failure are featuring normal response of immune system, therefore, administration of steroid is of no use, or negatively impacting the immune system, rendering the patient at higher risk of propagation and worsening of the outcome.
The common recommendations stemmed from several studies were consistent on adminstering Corticosteroid for patients who are diagnosed with covid 19 pneumonia, and in need for
1] high O2 flow.
2] Non invasive ventilation.
3] mechanical ventilation.
4] ECMO.
In an article published in JAMA 2023, Ahmed Murad et al concluded the same finding discovered by Recovery study. with main conclusion of reducing the odds associated with COVID 19 pneumonia of mortality and discharge to hospice in those on need for O2 supply and ventilatory support.
1. Please do your own search and summarise the outcome of the different arms of the recovery trial.The RECOVERY trail was the world’s largest clinical trial into treatment for COVID, there are >40000 participants across 185 trails sites in the UK. It was demonstrated that dexa saved around 22000 COVID infected patients.The trail has identified four treatment for sever COVID patients, For COVID Sotrovimab, that is anti-spike protein monoclonal antibody and two other antiviral treatment (molnupiravir and paxlovid).For influenza, the Osltamivir and Baloxavir and low dose of steroids. It was demonstrated that web-based randomization to give treatment for COVID.Patient were allocated randomly to treat the eligible COVID proven patients. The collected data using a web- based case report and included demographic data.Eligible and consenting patient were assigned in a 2:1 ratio.One with standard dose of dexa for up-to 10 days, while other until admitted and discharged from hospital.The primary outcomes was all cause mortality within 28 days after randomization, and further analysis were extended at six months.Secondary outcomes, the dexa group had shorter duration of hospitalization, other clinical outcomes decrease need of mechanical ventilation.2. Please summarise this article.Background; coronavirus disease is associated with diffuse lung damage.Method; this is a controlled open label trail comparing a range of possible treatment in patient infected with COVID, patient were randomly assigned to receive oral or IV dexamethasone. Primary outcomes was 28-day mortality.Result ; total of 2104 patient were assigned to receive dexa and 4321 to receive usual care, in 482 in the dexa, and 1110 from usual group died with in the 28 days after randomization.Conclusion; those patient hospitalized with infected COVID, primary outcome was 28 days mortality, those who were receiving mechanical ventilation alone or oxygen alone. 3. What is the level of evidence provided by this article?Level I
1. Please do your own search and summarise the outcome of the different arms of the recovery trial. The recovery trial(Randomized Evaluation of Covid-19 Therapy) examined various treatments outcomes in hospitalized COVID-patients. 22.9% of those received dexamethasone died within 28 days. 25.7% of those received the normal standard of care passed away within 28 days of the randomization.
2. Please summarise this article. RCT , oper label trial, of patients with COVID19 who were randomly assigned to receive oral or intravenous dexamethasone or to receive usual care alone. 2104 patients in the dexamethasone group and 4321 in the usual care group . In the dexamethasone group, the incidence of death was lower than that in the usual care group among patients receiving invasive mechanical ventilation or oxygen without invasive mechanical ventilation 3. What is the level of evidence provided by this article? RCT is level 1
Please do your own search and summarise the outcome of the different arms of the recovery trial
The RECOVERY Study has identified 4 treatments for severe COVID-19, & it is presently evaluating the following suggested treatments to see if they are more successful at promoting recovery than the standard therapy that all patients receive: For COVID-19
Sotrovimab, an anti-spike protein monoclonal antibody, & 2 other antiviral treatments (molnupiravir & paxlovid).
For influenza
Oseltamivir & baloxavir & low doses of corticosteroids.
Data are periodically reviewed in order to swiftly identify & make all patients eligible for any effective treatments.
Randomized allocation of treatment for COVID-19
A web-based randomization was used to give treatments to eligible SARS-CoV-2 proven patients in addition to their routine care.
Eligible patients randomly assigned to =/> 1 treatment arms at once.
Randomization part E
Eligible patients (adult ≥18 years old without suspected or confirmed influenza coinfection) & requiring ventilatory support are randomized in a 1:1 ratio to 1 of the arms below:
No additional treatment
High-dose corticosteroids: dexamethasone 20 mg OD (PO, NGT, or IV) for 5 days, then 10 mg OD for 5 days.
Randomization part F:
Eligible patients (adult patients ≥18 years old) may be randomized in a 1:1 ratio to 1 of the below arms:
No additional treatment
Empagliflozin 10 mg OD PO for 28 days (or until discharge, if earlier).
Randomization part J (UK only):
Eligible patients (patients ≥12 years old) may be randomized in a 1:1 ratio to 1 of these arms:
No additional treatment
Sotrovimab 1000 mg in 100 mL 0.9% NaCl or D5% IV infusion.
Randomization part K:
Eligible patients (patients ≥18 years old) may be randomized in a 1:1 ratio to one of these arms:
No additional treatment
Molnupiravir 800 mg BID/5 d PO
Randomization part L (UK only):
Eligible patients (patients ≥18 years old) may be randomized in a 1:1 ratio to one of the arms listed below.
No additional treatment
Paxlovid (nirmatrelvir/ritonavir) 300/100 mg BID/5 d PO
The RECOVERY trial was created to assess the effects of potential treatments in patients hospitalized with Covid-19 at 176 NHS organizations in the UK.
Patients are no longer being randomized to receive tocilizumab, lopinavir-ritonavir, hydroxychloroquine, azithromycin, or convalescent plasma.
The trial is still randomizing participants to other therapies, such as REGN-COV2 (monoclonal antibodies against the SARS-CoV-2 spike protein), aspirin, colchicine, or standard medical therapy alone.
Eligibility for the trial
Suspected or confirmed SARS-CoV-2 infection.
Any age (age limit removed from May 9, 2020
Pregnant or breast-feeding women were eligible.
Data (demographic data, level of respiratory support, major coexisting illnesses, suitability of the trial treatment) were collected using a Web-based case-report form.
Eligible & consenting patients were randomized (2:1) to either the usual standard of care alone or the usual standard of care plus oral or IV dexamethasone (6 mg OD for up to 10 days (or until hospital discharge if sooner) or to receive 1 of the other suitable & available treatments that were being evaluated in the trial.
Primary outcome:
All-cause mortality within 28 days after randomization
Secondary outcomes:
The time until discharge from the hospital
Receipt of invasive mechanical ventilation (for those not receiving it at the time of randomization) or death.
Other pre-specified clinical outcomes:
Cause-specific mortality
Receipt of renal dialysis or hemofiltration
Major cardiac arrhythmia
Receipt & duration of ventilation
Results
11,303 patients underwent randomization (March 19 to June 8, 2020)
9355 (83%) were eligible to dexamethasone (drug available & no contraindication)
6425 randomized to either dexamethasone (2104) or usual care alone (4321)
The remaining patients were randomized to 1 of the other treatments in the trial.
Mean age: 66.1 +/-15.7 years
Female: 36%
18% Black, Asian, or from a minor ethnicity.
H/O diabetes: 24%
Heart disease: 27%
Chronic lung disease: 21%
56% have at least 1 major coexisting illness recorded
Laboratory-confirmed SARSCoV-2: 89%
16%: invasive mechanical ventilation or extracorporeal membrane oxygenation
Oxygen only: 60%
Primary Outcome
Dexamethasone group’s 28-day mortality rate was considerably reduced compared to the standard care group.
A trend towards greatest benefit those receiving invasive mechanical ventilation
In mechanical ventilated patients, the rate of death was lower in the dexamethasone group than it was in the usual care group.
No obvious impact of dexamethasone in those not receiving any respiratory support at the randomization
Patients getting invasive mechanical ventilation at randomization were 10 years younger than those not receiving any respiratory support & had symptoms for around 7 days longer before randomization.
Secondary Outcomes
Shorter duration of hospitalization in the dexamethasone group
A higher likelihood of discharge alive within 28 days in the dexamethasone arm
Other pre-specified outcomes
Transition to mechanical ventilation was lower in the dexamethasone arm among patients who were not receiving mechanical ventilation at randomization.
Cessation of invasive mechanical ventilation was more likely in the dexamethasone group.
Need for RRT was lower in dexamethasone group
The majority of deaths were caused by Covid-19, less fatalities in the dexamethasone group.
Deaths from other causes similar in both arms
Discussion
Dexamethasone led to lower 28-day mortality in those receiving invasive mechanical ventilation at randomization.
No proof of benefit of dexamethasone in those not receiving respiratory support at randomization
A subsequent meta-analysis (7 trials of glucocorticoids for critically ill patients with Covid-19, including RECOVERY), has confirmed the findings of this trial.
Dexamethasone linked to a lower risk of invasive ventilation among those who were getting oxygen or, for those who were already receiving invasive mechanical ventilation, a higher likelihood of successful discontinuation.
Dexamethasone increased the chance of discharge from the hospital alive within 28 days.
What is the level of evidence provided by this article?
Level 1b (Evidence obtained from at least one Randomized Trial)
RECOVERY Trial (Randomised Evaluation of Covid-19 Therapy)
Background SARS-CoV-2 infection cause diffuse alveolar injury, inflammatory infiltrates, and microvascular thrombosis. Glucocorticoids modulates inflammation-mediated lung injury, and may slow progression to respiratory failure and mortality.
Methods The study examined various treatments outcomes in hospitalized COVID-patients in UK. Clinically suspected SARS-CoV-2 infection or RTPCR-confirmed cases were enrolled, randomized to receive standard care alone or oral / intravenous dexamethasone 6mg OD for up to 10 days (or until discharge from hospital, whichever is earlier). Primary outcome: death (from any cause) within 28 days of randomization.
Secondary outcomes include length of hospital stay; requirement of invasive mechanical ventilation (IMV), including ECMO; and mortality.
Additional predetermined clinical outcomes, included cause-specific mortality, receiving HD or hemofiltration, experiencing severe cardiac arrhythmias, and duration of ventilator dependence.
Results: · 482 of 2104 patients (22.9%) in the dexamethasone arm died within 28 days. · 1110 out of 4321 (25.7%) among the patients in the normal standard of care arm, passed away within 28 days of the randomization. · 89% had laboratory-confirmed SARS-CoV-2 infection, mean (SD) age 66.1 15.7 years, 36% female, 18% black, 24% diabetes, 27% heart disease, 21% chronic lung illness, 16% on invasive mechanical ventilation or ECMO, 60% on oxygen alone (non-invasive ventilation), and 24% not on either. · In the dexamethasone group, the median length of treatment was 7 days, and 95% of the patients got at least one dose of glucocorticoid. 8% of the patients in the group receiving conventional care also received glucocorticoids.
· Azithromycin use was comparable across the two groups.
· Level of respiratory support the patient was getting at the time of randomization affected mortality.
· Mortality at 28 days in Dexamethasone group was lower than standard of care group. (22.9% vs 25.7%).
· Patients receiving ventilation (IMV) and those receiving oxygen without IMV experienced lower incidence of death in the dexamethasone group compared to the usual care group, but not among patients who were not receiving any respiratory support at the time of randomization.
· Patients on IMV at randomization had symptoms for a longer period of time and were 10 years younger than those who weren’t on respiratory assistance. · Those on IMV and those with longer-lasting symptoms benefited from dexamethasone. · Among individuals who had symptoms for longer than 7 days, dexamethasone was linked to a lower 28-day mortality rate. · Dexamethasone was linked to shorter hospital stay. · Following randomization, patients receiving dexamethasone were less likely to need IMV and renal replacement therapy. · Both groups’ incidence of new cardiac arrhythmias was comparable. Discussion Dexamethasone use (about 10 days) reduced 28-day mortality in hospitalized patients with Covid-19 by 12.3 age-adjusted percentage points (proportional reduction of about one third) in patients receiving invasive mechanical ventilation at randomization and by 4.2 age-adjusted percentage points (a proportional reduction of about one third) in patients receiving oxygen without invasive mechanical ventilation. Level of evidence: 1
Trial Design and Oversight
The RECOVERY trial was designed to evaluate the effects of potential treatments in patients hospitalizedwithCovid-19at176NationalHealth Service organizations in the United Kingdom and was supported by the National Institute for Health Research Clinical Research Network.
Hospitalized patients were eligible for the trial if they had clinically suspected or laboratory- confirmed SARS-CoV-2 infection and no medical history that might, in the opinion of the attend- ing clinician, put patients at substantial risk if they were to participate in the trial. Initially, re- cruitment was limited to patients who were at least 18 years of age, but the age limit was re- moved starting on May 9, 2020. Pregnant or breast-feeding women were eligible.
The initial version of the manuscript was drafted by the first and last authors, developed by the writing committee, and approved by all members of the trial steering committee. The funders had no role in the analysis of the data, in the preparation or approval of the manu- script, or in the decision to submit the manu- script for publication. The first and last mem- bers of the writing committee vouch for the completeness and accuracy of the data and for the fidelity of the trial to the protocol and sta- tistical analysis plan. Randomization
We collected baseline data using a Web-based case-report form that included demographic data, the level of respiratory support, major coexisting illnesses, suitability of the trial treatment for a particular patient, and treatment availability at the trial site. Randomization was performed with the use of a Web-based system with con- cealment of the trial-group assignment. Eligible and consenting patients were assigned in a 2:1 ratio to receive either the usual standard of care alone or the usual standard of care plus oral or intravenous dexamethasone (at a dose of 6 mg once daily) for up to 10 days (or until hospital discharge if sooner) or to receive one of the other suitable and available treatments that were being evaluated in the trial.
Procedures
A single online follow-up form was to be com- pleted by the local trial staff when each patient was discharged or had died or at 28 days after randomization, whichever occurred first. Infor- mation was recorded regarding the patients’ adherence to the assigned treatment, receipt of other treatments for Covid-19, duration of ad- mission, receipt of respiratory support (with duration and type), receipt of renal dialysis or hemofiltration, and vital status (including the cause of death). In addition, we obtained routine health care and registry data, including informa- tion on vital status (with date and cause of death), discharge from the hospital, and respira- tory and renal support therapy.
Outcome Measures
The primary outcome was all-cause mortality within 28 days after randomization; further analyses were specified at 6 months. Secondary outcomes were the time until discharge from the hospital and, among patients not receiving inva- sive mechanical ventilation at the time of ran- domization, subsequent receipt of invasive me- chanical ventilation (including extracorporeal membrane oxygenation) or death. Other prespeci- fied clinical outcomes included cause-specific mortality, receipt of renal dialysis or hemofiltra- tion, major cardiac arrhythmia (recorded in a subgroup), and receipt and duration of ventila- tion. Patients
Of the 11,303 patients who underwent random- ization from March 19 to June 8, 2020, a total of 9355 (83%) were eligible to receive dexametha- sone (i.e., the drug was available in the hospital at the time and the patient had no known indica- tion for or contraindication to dexamethasone). Of these patients, 6425 underwent randomiza- tion to receive either dexamethasone (2104 pa- tients) or usual care alone (4321 patients) (Fig. 1). The remaining patients were randomly assigned to one of the other treatment groups being evalu- ated in the trial.
Secondary Outcomes
Patients in the dexamethasone group had a shorter duration of hospitalization than those in the usual care group (median, 12 days vs. 13 days) and a greater probability of discharge alive within 28 days (rate ratio, 1.10; 95% CI, 1.03 to 1.17)
The greatest effect regarding discharge within 28 days was seen among pa- tients who were receiving invasive mechanical ventilation at randomization
Other Prespecified Clinical Outcomes
Among patients who were not receiving invasive mechanical ventilation at randomization, the risk of progression to invasive mechanical ventilation was lower in the dexamethasone group than in the usual care group (risk ratio, 0.79; 95% CI, 0.64 to 0.97)
Among those who were receiving invasive mechanical ventilation at ran- domization, successful cessation of invasive me- chanical ventilation was more likely in the dexa- methasone group than in the usual care group (rate ratio, 1.47; 95% CI, 1.20 to 1.78)
Our results show that among hospitalized pa- tients with Covid-19, the use of dexamethasone for up to 10 days resulted in lower 28-day mor- tality than usual care in patients who were re- ceiving invasive mechanical ventilation at ran- domization (by 12.3 age-adjusted percentage points, a proportional reduction of approximate- ly one third) and those who were receiving oxy- gen without invasive mechanical ventilation (by 4.2 age-adjusted percentage points, a proportional reduction of approximately one fifth).
The RECOVERY trial was designed to pro- vide a rapid and robust assessment of the effect of readily available potential treatments for Covid-19 on 28-day mortality. Approximately 10% of all hospitalized patients with Covid-19 in the United Kingdom were enrolled in the trial, and mortality in the usual care group was con- sistent with the overall case fatality rate for hospitalized patients with Covid-19 in the United Kingdom at the time that the dexamethasone comparison was active.7 Only essential data were collected at hospital sites, with additional infor- mation (including longer-term mortality) ascer- tained through linkage with routine data sources. We did not collect information on physiologic, laboratory, or virologic measures.
Glucocorticoids have been widely used in syndromes closely related to Covid-19, including SARS,MiddleEastrespiratorysyndrome(MERS), severe influenza, and community-acquired pneu- monia. However, the evidence to support or discourage the use of glucocorticoids under these conditions has been weak owing to the lack of data from sufficiently powered random- ized, controlled trials. In addition, the evi- dence base has suffered from heterogeneity in glucocorticoid doses, medical conditions, and disease severity.
Summary of the outcome of the different arms of the recovery trial;
Regarding hydroxychloroquine no benefits were suggested clinically, whereas dexamethasone proved to reduce mortality especially in hospitalized patients requiring either invasive mechanical ventilation or oxygen support. As for antivirals as Lopinavir or ritonavir or colchicine no significant advantages were added. By mentioning azithromycin or convalescent plasma proved to have no value as well. Both Tocilizumab and Baricitinib had proved to improve mortality, respiratory support and hospital discharge.
Introduction
The emergence of COVID disease in 2019 resulted in worldwide mortality being higher in immunosuppressed population. The pathological explanation was detected in autopsies by the presence of diffuse alveolar damage, inflammatory infiltrates, and microvascular thrombosis.
As the host immune response is believed to be the key player in the pathophysiology of organ failure, the levels of some inflammatory markers like C-reactive protein, ferritin, interleukin-1, and interleukin-6 were increased confirming severe systemic inflammation. Therefore, the value of glucocorticoids has been widely debated.
The results of the controlled, open-label Randomized Evaluation of Covid-19 Therapy (RECOVERY) trial of dexamethasone in patients hospitalized with Covid-19 were important as it included a large scale population for study.
Methods
The aim was to evaluate the effects of potential treatments in patients hospitalized with Covid-19 at 176 National Health Service organizations in the United Kingdom. The randomization of patients was to receive dexamethasone, hydroxychloroquine, lopinavir–ritonavir, azithromycin, convalescent plasma, tocilizumab as well as other treatments as REGN-COV2 (a combination of two monoclonal antibodies directed against the SARS-CoV-2 spike protein), aspirin, colchicine, or usual care alone.
The study group involved all hospitalized patients who had clinically suspected or laboratory confirmed SARS-CoV-2 infection. There was no age limit to the study after May 2020, even pregnant and breast-feeding women were eligible.
Randomization
Eligible and consenting patients were assigned in a 2:1 ratio to receive either the usual standard of care alone or the usual standard of care plus oral or IV dexamethasone (at a dose of 6 mg once daily) for up to 10 days (or until hospital discharge if sooner) or to receive one of the other suitable and available treatments that were being evaluated in the trial.
Data included demographic data, the level of respiratory support, major coexisting illnesses, suitability of the trial treatment for a particular patient, and treatment availability at the trial site.
Cases were dexamethasone was unavailable at the hospital at the time of enrollment or was confirmed by the managing physician to be either definitely indicated or definitely contraindicated were excluded from the study.
Procedures
Follow-up form was single, online, done for each patient at either discharge or death or at 28 days after randomization, whichever occurred first.
Important information as the patients ‘adherence to the assigned treatment, receipt of other treatments for Covid-19, duration of admission, receipt of respiratory support (with duration and type), receipt of renal dialysis or hemofiltration, and vital status (including the cause of death) were all reported.
Outcome Measures
The primary outcome was all-cause mortality within 28 days after randomization.
Other outcomes involved the time until discharge from the hospital, patients not receiving invasive mechanical ventilation at the time of randomization, subsequent receipt of invasive mechanical ventilation (including extracorporeal membrane oxygenation), receipt of renal dialysis or hemofiltration, major cardiac arrhythmia and receipt and duration of ventilation or death. Statistical Analysis
For the primary and secondary outcomes, the hazard ratio from Cox regression was used.
Kaplan–Meier survival curves were constructed to show cumulative mortality over the 28-day period.
The mean age was 1.1 years older among patients in the dexamethasone group than among those in the usual care group.
Characteristics at randomization: age, sex, race, level of respiratory support, days since symptom onset, and predicted 28-day mortality risk.
Chi-square tests for heterogeneity or linear trends were used. P values were significant when less than 0.005.
Results
11,303 patients who underwent randomization from March 19 to June 8, 2020, a total of 9355 (83%) were eligible to receive dexamethasone.
The mean SD age of the patients in this comparison was 66.1±15.7 years, 36% of the patients were female, and 18% were Black, Asian, or from a minority ethnic group.
Any reported history of diabetes was present in 24% of the patients, heart disease in 27%, and chronic lung disease in 21%, with 56% having at least one major coexisting illness was recorded. Laboratory-confirmed SARSCoV-2 infection in this analysis were 89% of the patients.
At randomization, 16% were receiving invasive mechanical ventilation or extracorporeal membrane oxygenation, 60% were receiving oxygen only (with or without noninvasive ventilation), and 24% were receiving neither.
In the dexamethasone group, 95% of the patients received at least one dose of glucocorticoid. The median duration of treatment was 7 days (interquartile range, 3 to 10). In the usual care group, 8% of the patients received a glucocorticoid as part of their clinical care.
The use of azithromycin or another macrolide antibiotic during the follow-up period was similar in the dexamethasone group and the usual care group (24% vs. 26%), and 0 to 3% of patients received hydroxychloroquine, lopinavir–ritonavir, or interleukin-6 antagonists during follow-up.
After May 26, 2020, the remdesivir drug was administered to 3 patients before randomization and 2 patients during the follow-up period.
Primary Outcome
Mortality at 28 days was significantly lower in the dexamethasone group than in the usual care group where deaths reported in 482 of 2104 patients (22.9%) and in 1110 of 4321 patients (25.7%), respectively (rate ratio, 0.83; 95% confidence interval [CI], 0.75 to 0.93; P<0.001).
In the dexamethasone group, the incidence of death was less than the usual care group among patients receiving invasive mechanical ventilation (29.3% vs. 41.4%; rate ratio, 0.64; 95% CI, 0.51 to 0.81).
Also the incidence of death was lower in the dexamethasone group than the usual care group receiving oxygen support without mechanical ventilation (23.3% vs. 26.2%; rate ratio, 0.82; 95% CI, 0.72 to 0.94).
Fortunately, there was no clear effect of dexamethasone among patients who were not receiving any respiratory support at randomization (17.8% vs. 14.0%; rate ratio, 1.19; 95% CI, 0.92 to 1.55).
Finally, the administration of dexamethasone was associated with a reduction in 28-day mortality among those with symptoms for more than 7 days.
Secondary Outcomes
Patients in the dexamethasone group had a shorter duration of hospitalization than those in the usual care group (median, 12 days vs. 13 days). Also, they had a higher probability of being discharged alive within 28 days (rate ratio, 1.10; 95% CI, 1.03 to 1.17).
Regarding those patients who were not receiving invasive mechanical ventilation, the number of patients who progressed to either invasive mechanical ventilation or death was lower in the dexamethasone group than in the usual care group (risk ratio, 0.93; 95% CI, 0.85 to 1.01).
Among those who were receiving invasive mechanical ventilation at randomization, successful cessation of invasive mechanical ventilation was more likely in the dexamethasone group than in the usual care group (rate ratio, 1.47; 95% CI, 1.20 to 1.78).
Among the patients who were not receiving renal-replacement therapy (renal dialysis or hemofiltration) at randomization, the number of patients who received this treatment within 28 days was lower in the dexamethasone group than in the usual care group (risk ratio, 0.61; 95% CI, 0.48 to 0.76).
Most deaths were due to Covid-19, and such deaths were less frequent in the dexamethasone group than in the usual care group.
The incidence of new cardiac arrhythmia was similar in the dexamethasone group and the usual care group.
Only four reports of serious adverse reaction related to dexamethasone were documented: two of hyperglycemia, one of gastrointestinal hemorrhage, and one of psychosis (all recognized adverse effects of glucocorticoids).
Discussion
The study results showed that among hospitalized patients with Covid-19, the use of dexamethasone proportional reduction of approximately one third of 28-day mortality than usual care patients group who were receiving invasive mechanical ventilation at randomization. While more reduction was noticed compared to those who received oxygen therapy in usual group by approximately one fifth.
Yet, no clear evidence that dexamethasone provided any benefit among patients who were not receiving respiratory support at randomization. Meanwhile there was advantage in patients who were being treated more than 7 days after symptom onset, when inflammatory lung damage is likely to be confirmed. This was also confirmed by RECOVERY trial.
Favourable data results included that among the patients who were receiving oxygen, the use of dexamethasone was associated with a lower risk of invasive mechanical ventilation as well as also for those already receiving invasive mechanical ventilation, they had a greater chance of successful cessation. In summary, both groups after the use of dexamethasone had better chance of being discharged from the hospital alive within 28 days.
As in epidemic conditions, trials are designed to get rapid results but facing many difficulties manipulating the evidence base due to heterogeneity in glucocorticoid doses, medical conditions, and disease severity. It is also necessary to mention that the beneficial effect of glucocorticoids in severe viral respiratory infections is mainly dependent on the selection of the right dose, at the right time, in the right patient.
The higher mortality benefit of dexamethasone in patients with Covid-19 who are receiving respiratory support and among those recruited after the first week of their illness suggests that at that stage the disease may be dominated by immunopathological elements prior to active viral replication playing a secondary role.
The RECOVERY trial demonstrated evidence of treatment with dexamethasone at a dose of 6 mg once daily for up to 10 days reduces 28-day mortality in patients with Covid-19 who are receiving respiratory support.
Severe COVID-19 induces a systemic inflammatory response that can lead to lung injury and multisystem organ dysfunction.
It has been proposed that the potent anti-inflammatory effects of corticosteroids might prevent or mitigate these harmful effects.
Hospitalized patients in the United Kingdom showed that patients who were randomized to receive dexamethasone had a reduced rate of mortality compared to those who received SOC.
This benefit was observed in patients with severe COVID-19,those who required supplemental oxygen and was best in those who required mechanical ventilation at enrollment. No benefit of dexamethasone was observed in patients who did not require supplemental oxygen.
In the RECOVERY trial, patients were not enrolled into the dexamethasone study arm (or included in the analysis) if their physicians decided that they were not suitable for corticosteroid therapy for any reason.
Before initiating dexamethasone, clinicians should review the patient’s medical history and assess the potential risks and benefits
Closely monitor patients with COVID-19 who are receiving dexamethasone for adverse effects (e.g., hyperglycemia, secondary infections).
Using systemic corticosteroids may increase the risk of reactivation of latent infections (e.g., hepatitis B virus, herpesviruses, strongyloidiasis, tuberculosis).
Dexamethasone is a moderate cytochrome P450 (CYP) 3A4 inducer, which may reduce the concentration and potential efficacy of concomitant medications that are CYP3A4 substrates.
It is not known whether other corticosteroids, such as prednisone, methylprednisolone, or hydrocortisone, will have a similar benefit to dexamethasone. Of note, the dose equivalencies for dexamethasone 6 mg daily are prednisone 40 mg, methylprednisolone 32 mg, and hydrocortisone 160 mg.
Hydroxychloroquine
does not provide a medical benefit for hospitalized patients with COVID-19.
randomized trials for the treatment of hospitalized patients with COVID-19 has not been shown to have a benefit in reducing death.
FDA, NIH and WHO recommend against use of HCQ as a treatment for hospitalized patients with COVID-19 based on studies showing a lack of effect and possible serious side effects.
Studies are still ongoing looking at use in early COVID disease, but prospective, randomized, controlled studies are not yet available.
Doxycycline
easily available and low-cost medication, should be considered as a COVID-19 therapy in all patients in the first days of symptoms of SARS-CoV-2 infection.
Due to its immunomodulatory, anti-inflammatory, cardioprotective and antiviral effects, it seems to be an ideal drug for patients with mild, moderate and severe type of COVID-19.
A large multicentre study to evaluate the effects of this medication is needed.
Azithromycin
did not substantially shorten the time to first self-reported recovery or decrease the risk of hospitalisation.
should not be used routinely to treat COVID-19 in the community in older adults, in the absence of additional indications.
Favipiravir
might be crucial for ensuring an efficient treatment, decrease mortality and allow early discharge in relation to Covid-19.
However more clinical studies are urgently needed to evaluate the efficacy and safety of this antiviral nucleoside for COVID-19 treatment.
Summaryof the article.
SARS-CoV-2 the cause of Covid-19, emerged in China in late 2019 from a zoonotic source.
The pathophysiological features of severe Covid-19 are dominated by an acute pneumonic process with extensive radiologic opacity and, on autopsy, diffuse alveolar damage, inflammatory infiltrates, and microvascular thrombosis.
Although one small trial has reported improved clinical outcomes in patients with Covid-19 who were given methylprednisolone,17 the absence of reliable evidence from large-scale randomized clinical trials means there is uncertainty about the effectiveness of glucocorticoids in patients with Covid-19.
Methods
open-label controlled, trial
Compared a range of possible treatments in patients who were hospitalized with Covid-19,
Patients randomized to receive oral or IV dexamethasone for up to 10 days or to receive the usual care.
Inclusion: hospitalized patients if clinically suspected or laboratory confirmed SARS-CoV-2 infection, No medical prevent them from participating, no restriction for, pregnant and breastfeeding women included.
The primary outcome was all-cause mortality within 28 days after randomization; further analyses were specified at 6 months.
Secondary outcomes were the time until discharge from the hospital and, among patients not receiving invasive mechanical ventilation at the time of randomization, subsequent receipt of invasive mechanical ventilation (including extracorporeal membrane oxygenation) or death.
Results
11,303 patients who underwent randomization from March 19 to June 8, 2020, a total of 9355 (83%) were eligible to receive dexamethasone
6425 underwent randomization to receive either dexamethasone (2104 patients) or usual care alone (4321 patients).
89% of the patients had laboratory-confirmed SARSCoV-2 infection.
At randomization, 16% were receiving invasive mechanical ventilation or extracorporeal membrane oxygenation, 60% were receiving oxygen only (with or without noninvasive ventilation), and 24% were receiving neither.
In the dexamethasone group, 95% of the patients received at least one dose of a glucocorticoid.
In the usual care group, 8% of the patients received a glucocorticoid as part of their clinical care.
The use of azithromycin or another macrolide antibiotic during the follow-up period was similar in the dexamethasone group and the usual care group (24% vs. 26%), and 0 to 3% of patients received hydroxychloroquine, lopinavir–ritonavir, or interleukin-6 antagonists during followup .
Discussion
showed that among hospitalized patients with Covid-19, the use of dexamethasone for up to 10 days resulted in lower 28-day mortality than usual care in patients who were receiving invasive mechanical ventilation at randomization (by 12.3 age-adjusted percentage points, a proportional reduction of approximately one third) and those who were receiving oxygen without invasive mechanical ventilation (by 4.2 age-adjusted percentage points, a proportional reduction of approximately one fifth)
no evidence that dexamethasone provided any benefit among patients who were not receiving respiratory support at randomization, and the results were consistent with possible harm in this subgroup.
What is the level of evidence provided by this article?
1 B
RECOVERY Trial (Randomised Evaluation of Covid-19 Therapy) Background
Infection with SARS-CoV-2 is linked to diffuse alveolar injury, inflammatory infiltrates, and microvascular thrombosis. By modulating the inflammation-mediated lung injury, glucocorticoids may slow the progression to respiratory failure and mortality. Methods
The study examined the outcomes of the various treatments given to patients with COVID-19 who were hospitalized in the UK.
Inpatient patients with a clinical suspicion of SARS-CoV-2 infection or a test confirmation were enrolled in the study.
Participants were randomized to receive standard care alone or oral or intravenous dexamethasone 6mg OD for up to 10 days (or until hospital release, whichever occurred first).
Death from any cause within 28 days of randomization was the primary outcome.
Secondary outcomes include the length of stay in the hospital, the number of patients who had invasive mechanical ventilation (IMV), including ECMO, after randomization and mortality.
Additional clinical outcomes that were predetermined in advance included cause-specific mortality, receiving HD or hemofiltration, experiencing severe cardiac arrhythmias, and the duration of ventilator dependance. Results
· 482 individuals (22.9%) who were in the dexamethasone arm out of 2104 patients died within 28 days of the randomization.
· Among the 4321 patients in the normal standard of care arm, 1110 patients (or 25.7%) passed away within 28 days of the randomization.
· 89% had laboratory-confirmed SARS-CoV-2 infection, mean (SD) age 66.1 15.7 years, 36% female, 18% black, 24% diabetes, 27% heart disease, 21% chronic lung illness, 16% on invasive mechanical ventilation or ECMO, 60% on oxygen alone (noninvasive ventilation), and 24% not on either.
· In the dexamethasone group, the median length of treatment was 7 days, and 95% of the patients got at least one dose of glucocorticoid.
· 8% of the patients in the group receiving conventional care also received glucocorticoids.
· Azithromycin use was comparable across the two groups.
· The level of respiratory support a patient was getting at the time of randomization affected mortality.
· Dexamethasone group mortality at 28 days was lower than typical standard of care group mortality (22.9% vs 25.7%, respectively).
· Patients receiving invasive mechanical ventilation and patients receiving oxygen without invasive mechanical ventilation experienced a lower incidence of death in the dexamethasone group compared to the usual care group, but not among patients who were not receiving any respiratory support at the time of randomization.
· Patients on IMV at randomization had symptoms for a longer period of time and were 10 years younger than those who weren’t on respiratory assistance.
· Those on IMV and those with longer-lasting symptoms benefited from dexamethasone.
· Among individuals who had symptoms for longer than 7 days, dexamethasone was linked to a lower 28-day mortality rate.
· Dexamethasone was linked to a shorter hospital stay time.
· Following randomization, patients receiving dexamethasone were less likely to need IMV and renal replacement therapy.
· Both groups’ incidence of new cardiac arrhythmias was comparable. Discussion
Dexamethasone use for up to 10 days reduced 28-day mortality in hospitalized patients with Covid-19 by 12.3 age-adjusted percentage points (a proportional reduction of about one third) in patients receiving invasive mechanical ventilation at randomization and by 4.2 age-adjusted percentage points (a proportional reduction of about one third) in patients receiving oxygen without invasive mechanical ventilation.
Population: Patients who hospitalized for COVID-19
Intervention: Oral or IV dexamethasone 6 mg daily up to 10 days
Comparison: Oral or IV dexamethasone 6 mg daily up to 10 days (2104) vs usual care (4321)
Outcome: 28-day mortality (22.9% dexamethasone vs 25.7% usual care died) and the incidence of death lower among those receiving mechanical ventilation and receiving oxygen (no difference in patient who were not on any respiratory support)
RECOVERY TRIAL
uk -nhs
LOW DOSE 6 MG DAILY DEXAMETHASONE upto 10 days LOWERS THE MORTALITY
covid patients with invasive ventilation and o2 therapy were included
all age group
28 day mortality was reported
following is found not to benefit study population
lopinavir–ritonavir
hydroxychloroquine
azithromycin
there was no clear effect of dexamethasone among patients who were not receiving any respiratory support at randomization
Coronavirus disease 2019 (Covid-19) is associated with diffuse lung damage. Glucocorticoids may modulate inflammation-mediated lung injury and thereby reduce progression to respiratory failure and death.
In patients hospitalized with Covid-19, the use of dexamethasone resulted in lower 28-day mortality among those who were receiving either invasive mechanical ventilation or oxygen alone at randomization but not among those receiving no respiratory support.
Although remdesivir has been shown to shorten the time until recovery in hospitalized patients, no therapeutic agents have been shown to reduce mortality.
The pathophysiological features of severe Covid-19 are dominated by an acute pneumonic process with extensive radiologic opacity and, on autopsy, diffuse alveolar damage, inflammatory infiltrates, and microvascular thrombosis.
Inflammatory organ injury may occur in severe Covid-19, with a subgroup of patients having markedly elevated levels of inflammatory markers, including C-reactive protein, ferritin, interleukin-1, and interleukin-6.
Randomization was performed with the use of a Web-based system with concealment of the trial-group assignment. Eligible and consenting patients were assigned in a 2:1 ratio to receive either the usual standard of care alone or the usual standard of care plus oral or intravenous dexamethasone (at a dose of 6 mg once daily) for up to 10 days (or until hospital discharge if sooner) or to receive one of the other suitable and available treatments that were being evaluated in the trial.
Primary Outcome
Mortality at 28 days was significantly lower in the dexamethasone group than in the usual care group.
Patients with a longer duration of symptoms (who were more likely to have been receiving invasive mechanical ventilation at randomization) had a greater mortality benefit in response to treatment with dexamethasone. The receipt of dexamethasone was associated with a reduction in 28-day mortality among those with symptoms for more than 7 days but not among those with a more recent symptom onset.
There were four reports of a serious adverse reaction that was deemed by the investigators to be related to dexamethasone: two of hyperglycemia, one of gastrointestinal hemorrhage, and one of psychosis (all recognized adverse effects of glucocorticoids).
the evidence to support or discourage the use of glucocorticoids under these conditions has been weak owing to the lack of data from sufficiently powered randomized, controlled trials. 28-31 In addition, the evidence base has suffered from heterogeneity in glucocorticoid doses, medical conditions, and disease severity. It is likely that the beneficial effect of glucocorticoids in severe viral respiratory infections is dependent on the selection of the right dose, at the right time, in the right patient. High doses may be more harmful than helpful, as may such treatment given at a time when control of viral replication is paramount and inflammation is minimal. Slower clearance of viral RNA has been observed in patients with SARS, MERS, and influenza who were treated with systemic glucocorticoids, but the clinical significance of these findings is unknown.
The RECOVERY trial provides evidence that treatment with dexamethasone at a dose of 6 mg once daily for up to 10 days reduces 28-day mortality in patients with Covid-19 who are receiving respiratory support. We found no benefit (and the possibility of harm) among patients who did not require oxygen. Before the completion of the trial, many Covid-19 treatment guidelines stated that the use of glucocorticoids was either contraindicated or not recommended. Dexamethasone is on the list of essential medicines of the World Health Organization and is readily available worldwide at low cost. Guidelines issued by the U.K. chief medical officers, the European Medicines Agency, the World Health Organization, and the National Institutes of Health in the United States have been updated to recommend the use of glucocorticoids in patients hospitalized with Covid-19 requiring oxygen with or without ventilatory support.
Dexamethasone in Hospitalized Patients with Covid-19 Q1- Please do your own search and summarize the outcome of the different arms of the recovery trial.
v Aspirin: dose not improve survival for hospitalized patients with COVID-19 found by recovery trial.
v Azithromycin : no benefit from azithromycin in patients hospitalized with COVID-19 .
v Baricitinib : reduces deaths in patients hospitalized with COVID-19 .
v Colchicine : recovery trial closes recruitment to colchicine treatment for patients hospitalized with COVID-19.
v Convalescent Plasma: closes by recovery trial
v Dexamethasone : Low-cost dexamethasone reduces death by up to one third in hospitalized patients with severe respiratory complications of COVID-19.
v Dimethyl Fumarate: does not improve recovery for patients hospitalized with COVID-19
v Hydroxychloroquine: No clinical benefit from use of hydroxychloroquine in hospitalized patients with COVID-19.
v Lopinavir-Ritonavir : No clinical benefit from use of lopinavir-ritonavir in hospitalized COVID-19 patients studied in RECOVERY .
v Regeneron’s monoclonal antibody combination : recovery trial finds that reduces deaths for hospitalized COVID-19 patients who have not mounted their own immune response.
v Tocilizumab : reduces deaths in patients hospitalized with COVID-19 Q2- Please summarize this article Introduction:
Coronavirus disease 2019 (Covid-19) is associated with diffuse lung damage. Glucocorticoids may modulate inflammation-mediated lung injury and thereby reduce progression to respiratory failure and death. patients may presented with mild or severe symptoms that appear in elevated inflammatory markers and opacity radiologically corticosteroid recommended in severe cases but it role is controversial. Methods:
Patients randomly receive oral or intravenous dexamethasone at a dose of 6 mg once daily for up to 10 days.
The primary outcome was 28-day mortality. Result:
A total of 2104 patients were assigned to receive dexamethasone and 4321 to receive usual care. Overall, 482 patients (22.9%) in the dexamethasone group and 1110 patients (25.7%) in the usual care group died within 28 days after randomization (age-adjusted rate ratio, 0.83; 95% confidence interval [CI], 0.75 to 0.93; P<0.001). In the dexamethasone group, the incidence of death was lower than that in the usual care group among patients receiving invasive mechanical ventilation (29.3% vs. 41.4%; rate ratio, 0.64; 95% CI, 0.51 to 0.81) and among those receiving oxygen without invasive mechanical ventilation (23.3% vs. 26.2%; rate ratio, 0.82; 95% CI, 0.72 to 0.94) but not among those who were receiving no respiratory support at randomization (17.8% vs. 14.0%; rate ratio, 1.19; 95% CI, 0.92 to 1.55). Conclusion:
In patients hospitalized with Covid-19, the use of dexamethasone resulted in lower 28-day mortality among those who were receiving either invasive mechanical ventilation or oxygen alone at randomization but not among those receiving no respiratory support. Q3- What is the level of evidence provided by this article? Randomized control trial – LEVEL 1b
Severe COVID-19 induces a systemic inflammatory response that can lead to lung injury and multisystem organ dysfunction.
It has been proposed that the potent anti-inflammatory effects of corticosteroids might prevent or mitigate these harmful effects.
Hospitalized patients in the United Kingdom showed that patients who were randomized to receive dexamethasone had a reduced rate of mortality compared to those who received SOC.
This benefit was observed in patients with severe COVID-19,those who required supplemental oxygen and was best in those who required mechanical ventilation at enrollment. No benefit of dexamethasone was observed in patients who did not require supplemental oxygen.
In the RECOVERY trial, patients were not enrolled into the dexamethasone study arm (or included in the analysis) if their physicians decided that they were not suitable for corticosteroid therapy for any reason.
Before initiating dexamethasone, clinicians should review the patient’s medical history and assess the potential risks and benefits
Closely monitor patients with COVID-19 who are receiving dexamethasone for adverse effects (e.g., hyperglycemia, secondary infections).
Using systemic corticosteroids may increase the risk of reactivation of latent infections (e.g., hepatitis B virus, herpesviruses, strongyloidiasis, tuberculosis).
Dexamethasone is a moderate cytochrome P450 (CYP) 3A4 inducer, which may reduce the concentration and potential efficacy of concomitant medications that are CYP3A4 substrates.
It is not known whether other corticosteroids, such as prednisone, methylprednisolone, or hydrocortisone, will have a similar benefit to dexamethasone. Of note, the dose equivalencies for dexamethasone 6 mg daily are prednisone 40 mg, methylprednisolone 32 mg, and hydrocortisone 160 mg.
Hydroxychloroquine
does not provide a medical benefit for hospitalized patients with COVID-19.
randomized trials for the treatment of hospitalized patients with COVID-19 has not been shown to have a benefit in reducing death.
FDA, NIH and WHO recommend against use of HCQ as a treatment for hospitalized patients with COVID-19 based on studies showing a lack of effect and possible serious side effects.
Studies are still ongoing looking at use in early COVID disease, but prospective, randomized, controlled studies are not yet available.
Doxycycline
easily available and low-cost medication, should be considered as a COVID-19 therapy in all patients in the first days of symptoms of SARS-CoV-2 infection.
Due to its immunomodulatory, anti-inflammatory, cardioprotective and antiviral effects, it seems to be an ideal drug for patients with mild, moderate and severe type of COVID-19.
A large multicentre study to evaluate the effects of this medication is needed.
Azithromycin
did not substantially shorten the time to first self-reported recovery or decrease the risk of hospitalisation.
should not be used routinely to treat COVID-19 in the community in older adults, in the absence of additional indications.
Favipiravir
might be crucial for ensuring an efficient treatment, decrease mortality and allow early discharge in relation to Covid-19.
However more clinical studies are urgently needed to evaluate the efficacy and safety of this antiviral nucleoside for COVID-19 treatment.
Summaryof the article.
SARS-CoV-2 the cause of Covid-19, emerged in China in late 2019 from a zoonotic source.
The pathophysiological features of severe Covid-19 are dominated by an acute pneumonic process with extensive radiologic opacity and, on autopsy, diffuse alveolar damage, inflammatory infiltrates, and microvascular thrombosis.
Although one small trial has reported improved clinical outcomes in patients with Covid-19 who were given methylprednisolone,17 the absence of reliable evidence from large-scale randomized clinical trials means there is uncertainty about the effectiveness of glucocorticoids in patients with Covid-19.
Methods
open-label controlled, trial
Compared a range of possible treatments in patients who were hospitalized with Covid-19,
Patients randomized to receive oral or IV dexamethasone for up to 10 days or to receive the usual care.
Inclusion: hospitalized patients if clinically suspected or laboratory confirmed SARS-CoV-2 infection, No medical prevent them from participating, no restriction for, pregnant and breastfeeding women included.
The primary outcome was all-cause mortality within 28 days after randomization; further analyses were specified at 6 months.
Secondary outcomes were the time until discharge from the hospital and, among patients not receiving invasive mechanical ventilation at the time of randomization, subsequent receipt of invasive mechanical ventilation (including extracorporeal membrane oxygenation) or death.
Results
11,303 patients who underwent randomization from March 19 to June 8, 2020, a total of 9355 (83%) were eligible to receive dexamethasone
6425 underwent randomization to receive either dexamethasone (2104 patients) or usual care alone (4321 patients).
89% of the patients had laboratory-confirmed SARSCoV-2 infection.
At randomization, 16% were receiving invasive mechanical ventilation or extracorporeal membrane oxygenation, 60% were receiving oxygen only (with or without noninvasive ventilation), and 24% were receiving neither.
In the dexamethasone group, 95% of the patients received at least one dose of a glucocorticoid.
In the usual care group, 8% of the patients received a glucocorticoid as part of their clinical care.
The use of azithromycin or another macrolide antibiotic during the follow-up period was similar in the dexamethasone group and the usual care group (24% vs. 26%), and 0 to 3% of patients received hydroxychloroquine, lopinavir–ritonavir, or interleukin-6 antagonists during followup .
Discussion
showed that among hospitalized patients with Covid-19, the use of dexamethasone for up to 10 days resulted in lower 28-day mortality than usual care in patients who were receiving invasive mechanical ventilation at randomization (by 12.3 age-adjusted percentage points, a proportional reduction of approximately one third) and those who were receiving oxygen without invasive mechanical ventilation (by 4.2 age-adjusted percentage points, a proportional reduction of approximately one fifth)
no evidence that dexamethasone provided any benefit among patients who were not receiving respiratory support at randomization, and the results were consistent with possible harm in this subgroup.
What is the level of evidence provided by this article?
1 B
Please do your own search and summarise the outcome of the different arms of the recovery trial.
The Recovery trial was a randomised controlled open-label trial that evaluated various treatments for patients admitted with severe Covid 19 in the UK.
It was later expanded to Indonesia, Nepal and Vietnam.
It was a multi-arm adaptive clinical trial that allowed addition of other drugs into the trial and closure of some treatment arms.
The primary objective was to provide reliable estimates of the effect of study treatments on all-cause mortality at 28 days after first randomization.
Findings:
HCQS: there was no clinical benefit.
Dexamethasone reduced mortality in patients admitted with severe respiratory complications.
Lopinavir-ritonavir: there was no clinical benefit.
Colchicine: had no benefits.
Azithromycin: there was no clinical benefit.
Tocilizumab: reduces the risk of death, the time to discharge and need for mechanical ventilation in hospitalised patients.
Barictinib: reduces the risk of death and its benefit was additional to other treatments that dampen the immune system eg dexamethasone and tocilizumab. This thus allows the use of combination anti-inflammatory drug to reduce the risk of death.
Convalescent plasma: there was no significant difference in the primary end point.
Please summarise this article. Introduction:
Remdesvir has been shown to shorten the time to recovery, however no drug had shown a mortality benefit.
Small trials has reported benefit with methylprednisolone however, there were no large scale randomised clinical trial that evaluated the benefits of glucocorticoids.
Methodology: Randomised controlled open label trial Study Population: Initially it was restricted to adults admitted with Covid 19 in the UK, however this was later expanded to include all patients. Inclusion criteria: Patients with clinical suspected or laboratory confirmed Sars-cov2.
Primary outcome: All-cause mortality within 28 days after randomization. Secondary outcome: Time until discharge from the hospital and, among patients not receiving invasive mechanical ventilation at the time of randomization, subsequent receipt of invasive mechanical ventilation or death. Treatment: Patients were randomised 2:1 to receive either usual care alone or usual care plus IV or oral dexamethasone at a dose of 6mg OD for 10 days.
Results
2104 patients in the dexamethasone arm and 4321 patients in the usual care.
Overall patients characteristics:
24% had diabetes, 27% had heart disease, 21% had chronic lung disease and 56% had at least one major co- existing illness recorded.
16% were receiving invasive mechanical ventilation or extra- corporeal membrane oxygenation, 60% were receiving oxygen only (with or without noninvasive ventilation), and 24% were receiving neither.
Primary outcome: Low dose dexamethasone reduced mortality rate by nearly a third in hospitalised patients with severe Covid 19 needing invasive ventilation and by fifth in patients needing supportive oxygen therapy.
There was no benefit in patient who didn’t require oxygen. Secondary outcome: Patients in the dexamethasone group had a shorter duration of hospitalization than those in the usual care group
Patients not receiving invasive mechanical ventilation the risk of progression was lower in the dexamethasone arm.
Discussion
Use of dexamethasone for 10 days was associated with lower 28day mortality in patients receiving invasive mechanical ventilation and in those receiving supplemental oxygen.
Patients not receiving any respiratory support use of dexamethasone was associated with possible harm than benefit.
Use of dexamethasone increased once chances of being discharged and reduced the risk of progression.
Thus the benefits of glucocorticoid in respiratory illness is dependent on the selection of the right dose, right time and the right patient.
What is the level of evidence provided by this article?
Level 1
Dexamethasone in Hospitalized Patients with Covid-19
Q1- Please do your own search and summarise the outcome of the different arms of the recovery trial.
1- Aspirin: RECOVERY trial finds aspirin does not improve survival for patients hospitalized with COVID-19 .
2- Azithromycin results : RECOVERY trial finds no benefit from azithromycin in patients hospitalised with COVID-19 .
3- Baricitinib results : New RECOVERY trial result: Baricitinib reduces deaths in patients hospitalised with COVID-19 .
4- Colchicine results: RECOVERY trial closes recruitment to colchicine treatment for patients hospitalized with COVID-19. 5- Convalescent Plasma results: RECOVERY trial closes recruitment to convalescent plasma treatment for patients hospitalised with COVID-19.
6- Dexamethasone results :Low-cost dexamethasone reduces death by up to one third in hospitalised patients with severe respiratory complications of COVID-19.
7- Dimethyl Fumarate results: RECOVERY trial finds that dimethyl fumarate does not improve recovery for patients hospitalised with COVID-19
8- Hydroxychloroquine results : No clinical benefit from use of hydroxychloroquine in hospitalised patients with COVID-19.
9- Lopinavir-Ritonavir results : No clinical benefit from use of lopinavir-ritonavir in hospitalised COVID-19 patients studied in RECOVERY .
10- Regeneron’s monoclonal antibody combination results : RECOVERY trial finds Regeneron’s monoclonal antibody combination reduces deaths for hospitalised COVID-19 patients who have not mounted their own immune response.
11- Tocilizumab results : Tocilizumab reduces deaths in patients hospitalised with COVID-19
Q2- Please summarise this article
Introduction:
Coronavirus disease 2019 (Covid-19) Covid 19 that first appeared in China is associated with diffuse lung damage. Glucocorticoids may modulate inflammation-mediated lung injury and thereby reduce progression to respiratory failure and death.
The extensive radiologic opacity with elevated inflammatory markers may reflect sever lung damage.
But steroids role in these patient was controversial. These drug ( corticosteroid ) is only recommended in sever cases. Most patient with COVID19 are asymptomatic or presented with mild symptoms.
Proportion of these patient may need hospital admission.
METHODS
This is a controlled, open-label trial
Are randomly assigned to receive oral or intravenous dexamethasone (at a dose of 6 mg once daily) for up to 10 days or to receive usual care alone.
The primary outcome was 28-day mortality.
RESULTS
A total of 2104 patients were assigned to receive dexamethasone and 4321 to receive usual care.
Overall, 482 patients (22.9%) in the dexamethasone group and 1110 patients (25.7%) in the usual care group died within 28 days after randomization (age-adjusted rate ratio, 0.83; 95% confidence interval [CI], 0.75 to 0.93; P<0.001).
The proportional and absolute between-group differences in mortality varied considerably according to the level of respiratory support that the patients were receiving at the time of randomization.
In the dexamethasone group, the incidence of death was lower than that in the usual care group among patients receiving invasive mechanical ventilation (29.3% vs. 41.4%)
and among those receiving oxygen without invasive mechanical ventilation (23.3% vs. 26.2%) but not among those who were receiving no respiratory support at randomization (17.8% vs. 14.0%)
CONCLUSIONS :
In patients hospitalized with Covid-19, the use of dexamethasone resulted in lower 28-day mortality among those who were receiving either invasive mechanical ventilation or oxygen alone at randomization but not among those receiving no respiratory support.
Q3- What is the level of evidence provided by this article?
RCT – LEVEL 1b
W 9 j2
Dexamethasone in Hospitalized Patients with Covid-19
Q1- Please do your own search and summarise the outcome of the different arms of the recovery trial.
1- Aspirin: RECOVERY trial finds aspirin does not improve survival for patients hospitalized with COVID-19 .
2- Azithromycin results : RECOVERY trial finds no benefit from azithromycin in patients hospitalised with COVID-19 .
3- Baricitinib results : New RECOVERY trial result: Baricitinib reduces deaths in patients hospitalised with COVID-19 .
4- Colchicine results: RECOVERY trial closes recruitment to colchicine treatment for patients hospitalized with COVID-19. 5- Convalescent Plasma results: RECOVERY trial closes recruitment to convalescent plasma treatment for patients hospitalised with COVID-19.
6- Dexamethasone results :Low-cost dexamethasone reduces death by up to one third in hospitalised patients with severe respiratory complications of COVID-19.
7- Dimethyl Fumarate results: RECOVERY trial finds that dimethyl fumarate does not improve recovery for patients hospitalised with COVID-19
8- Hydroxychloroquine results : No clinical benefit from use of hydroxychloroquine in hospitalised patients with COVID-19.
9- Lopinavir-Ritonavir results : No clinical benefit from use of lopinavir-ritonavir in hospitalised COVID-19 patients studied in RECOVERY .
10- Regeneron’s monoclonal antibody combination results : RECOVERY trial finds Regeneron’s monoclonal antibody combination reduces deaths for hospitalised COVID-19 patients who have not mounted their own immune response.
11- Tocilizumab results : Tocilizumab reduces deaths in patients hospitalised with COVID-19
Q2- Please summarise this article
Introduction:
Coronavirus disease 2019 (Covid-19) Covid 19 that first appeared in China is associated with diffuse lung damage. Glucocorticoids may modulate inflammation-mediated lung injury and thereby reduce progression to respiratory failure and death.
The extensive radiologic opacity with elevated inflammatory markers may reflect sever lung damage.
But steroids role in these patient was controversial. These drug ( corticosteroid ) is only recommended in sever cases. Most patient with COVID19 are asymptomatic or presented with mild symptoms.
Proportion of these patient may need hospital admission.
METHODS
This is a controlled, open-label trial
Are randomly assigned to receive oral or intravenous dexamethasone (at a dose of 6 mg once daily) for up to 10 days or to receive usual care alone.
The primary outcome was 28-day mortality.
RESULTS
A total of 2104 patients were assigned to receive dexamethasone and 4321 to receive usual care.
Overall, 482 patients (22.9%) in the dexamethasone group and 1110 patients (25.7%) in the usual care group died within 28 days after randomization (age-adjusted rate ratio, 0.83; 95% confidence interval [CI], 0.75 to 0.93; P<0.001).
The proportional and absolute between-group differences in mortality varied considerably according to the level of respiratory support that the patients were receiving at the time of randomization.
In the dexamethasone group, the incidence of death was lower than that in the usual care group among patients receiving invasive mechanical ventilation (29.3% vs. 41.4%)
and among those receiving oxygen without invasive mechanical ventilation (23.3% vs. 26.2%) but not among those who were receiving no respiratory support at randomization (17.8% vs. 14.0%)
CONCLUSIONS :
In patients hospitalized with Covid-19, the use of dexamethasone resulted in lower 28-day mortality among those who were receiving either invasive mechanical ventilation or oxygen alone at randomization but not among those receiving no respiratory support.
Q3- What is the level of evidence provided by this article?
RCT – LEVEL 1b
Please do your own search and summarise the outcome of the different arms of the recovery trial.
Only Dexamethasone shows benefit in patient with severe Covid ,those with oxygen nd mechanical ventilation .Other medication shows no effect like aspirin Colchicine.
Abstract:
Coronavirus disease is associated with diffuse lung damage. Glucocorticoids may modulate inflammation-mediated lung injury and thereby reduce progression to respiratory failure and death. Methods:
Controlled, open-label trial comparing patient received CS OR NOT. The results of the controlled, open-label Randomized Evaluation of Covid-19 Therapy (RECOVERY) trial of dexamethasone in patients hospitalized with Covid-19 Primary outcome was 28-day mortality. RESULTS:
the dexamethasone group, the incidence of death was lower than that in the usual care group among patients receiving invasive mechanical ventilation (29.3% vs. 41.4%; rate ratio, 0.64; 95% CI, 0.51 to 0.81) and among those receiving oxygen without invasive mechanical ventilation (23.3% vs. 26.2%; rate ratio, 0.82; 95% CI, 0.72 to 0.94) but not among those who were receiving no respiratory support at randomization (17.8% vs. 14.0%; rate ratio, 1.19; 95% CI, 0.92 to 1.55). Other Prespecified Clinical Outcomes:
Among patients who were not receiving invasive mechanical ventilation at randomization,
The risk of progression to invasive mechanical ventilation was lower in the dexamethasone group than in the usual care group.
Among those who were receiving invasive mechanical ventilation at randomization, successful cessation of invasive mechanical ventilation was more likely in the dexamethasone group than in the usual care group.
Among the patients who were not receiving renal-replacement therapy at randomization, the number of patients who received this treatment within 28 days was lower in the dexamethasone group than in the usual care group.
Most deaths were due to Covid-19, and such deaths were less frequent in the dexamethasone group than in the usual care group.
CONCLUSIONS:
The use of dexamethasone resulted in lower 28-day mortality among those who were receiving either invasive mechanical ventilation or oxygen alone at randomization but not among those receiving no respiratory support. Discussion:
Results show that among hospitalized patients with Covid-19, the use of dexamethasone for up to 10 days resulted in lower 28-day mortality than usual care in patients who were receiving invasive mechanical ventilation at randomization and those who were receiving oxygen without invasive mechanical ventilation.
No evidence that dexamethasone provided any benefit among patients who were not receiving respiratory support at randomization, and the results were consistent with possible harm in this subgroup.
Results also show that among the patients who were receiving oxygen, the use of dexamethasone was associated with a lower risk of invasive mechanical ventilation.
Or, for those already receiving invasive mechanical ventilation, a greater chance of successful cessation.
In both these groups, the use of dexamethasone increased the chance of being discharged from the hospital alive within 28 days.
The RECOVERY trial provides evidence that treatment with dexamethasone at a dose of 6 mg once daily for up to 10 days reduces 28-day mortality in patients with Covid-19 who are receiving respiratory support.
Please do your own search and summarise the outcome of the different arms of the recovery trial.RECOVERY Collaborative group trial was conducted to assess effect of dexamethasone, hydroxychloroquine, lopinavir-ritonavir, azithromycin, convalescent plasma, or Tocilizumab in hospitalized COVID-19 patients.The following conclusions were derived from different arms of the trial:
Hydroxychloroquine: No clinical benefit.Dexamethasone: Reduced mortality in patients requiring respiratory support.Lopinavir-ritonavir: No significant mortality benefit.Colchicine: No benefit.Azithromycin: No benefit.Tocilizumab: Reduced risk of death, length of hospital stay, and need for ventilator support.Baricitinib: Reduces death in hospitalized COVID-19 patients by 20%.Aspirin: No benefit.Convalescent plasma: No clinical benefit. 2. Please summarise this article.
The article deals with one arm of the RECOVERY Collaborative group trial, related to dexamethasone use in hospitalized patients with COVID-19.
Introduction: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19 presenting in most cases with either symptomatic or mild disease presentation. But the case fatality rate is high among hospitalized patients having diffuse lung damage, especially in those requiring mechanical ventilation. Inflammatory organ injury, characterized by elevated CRP, IL-1, IL-6 and ferritin, may occur in severe COVID-19. Glucocorticoids may modulate the lung injury associated with inflammation, decreasing progression to respiratory failure and death. The study was conducted to evaluate the effect of dexamethasone on such patients’ outcomes with respect to mortality.
Methods: Randomized Evaluation of Covid-19 Therapy (RECOVERY) trial was designed to evaluate effects of potential therapies in hospitalized patients with COVID-19, who were randomized to be given either usual care alone or dexamethasone (oral or intravenous, 6 mg per day for up to 10 days) in addition to the usual care in 2:1 ratio. All cause 28-day mortality was assessed in the 2 groups with time until discharge from the hospital as secondary outcome.
Results: Out of total 11303 patients undergoing randomization, 9355 were eligible to receive dexamethasone. Total 6425 underwent randomization in the dexamethasone arm of RECOVERY trial, out of which 2104 patients received dexamethasone while 4321 patients received the usual care alone. In the dexamethasone group 95% received at least 1 dose of dexamethasone, with median duration of treatment being 7 days. Mortality at 28 days was significantly reduced in the dexamethasone group (22.9%) as compared to the usual care alone group (25.7%), with trend of greatest benefit in patients receiving invasive mechanical ventilation (29% versus 41.4%) as well those requiring oxygen therapy without ventilator support (23.3% versus 26.2%). Effect of dexamethasone was not seen in those who did not require oxygen support. There was 12.3 and 4.2 percentage point age-adjusted absolute reduction in 28-day mortality with dexamethasone use in patients receiving mechanical ventilation and oxygen therapy respectively. Patients with longer duration of symptoms had greater mortality benefit with dexamethasone. Dexamethasone use was associated with reduced length of stay in hospital, and increased probability of discharged alive from the hospital within 28 days. Successful mechanical ventilation cessation was more in the dexamethasone group.
Discussion: Dexamethasone use upto 10 days in COVID-19 resulted in lower 4-week mortality in patients receiving oxygen therapy or mechanical ventilation. Dexamethasone use in COVID-19 patients requiring respiratory support led to reduced chances of renal replacement therapy use, reduced progression to ventilator support, increased chances of ventilator removal, and reduced COVID-19 associated mortality.
Conclusion: Dexamethasone use in hospitalized COVI-19 patients requiring respiratory support is associated with lower 28-day mortality.
3. What is the level of evidence provided by this article?
◇ Please do your own search and summarise the outcome of the different arms of the recovery trial
● The RECOVERY trial is a multi-center randomized control trial testing multiple treatments in patients hospitalized with Covid-19 at the same time
☆ Hydroxychloroquine has no clinical benefits
☆ Dexamethasone reduces deaths by up to one third
☆ No significant mortality impact for lopinavir
☆ Colchicine and aspirin add no benefits for patients
☆ Azithromycin has no clinical benefits
☆ Tocilizumab reduces deaths in patients hospitalised with COVID-19 and shortens the time taken for patients to discharged and reduces the need for a mechanical ventilator.
☆ Baricitinib reduces deaths in hospitalised patients also it reduced the chance of progressing to invasive mechanical ventilation.
◇ Please summarise this article
● Some patients with COVID19 have a respiratory illness requiring hospital care or critical illness with hypoxemic respiratory failure requiring prolonged ventilatory support.
● Mortality in Covid-19 hospitalized patients was 26% and 37% among patients with mechanical ventilation
● Inflammatory organ injury may occur in severe Covid-19, with elevated levels of
C-reactive protein, ferritin, IL-1, and IL-6 .
● Many guidelines have stated that glucocorticoids were either contraindicated or not recommended
● controlled, open-label Randomized Evaluation of Covid-19 Therapy (RECOVERY) trial of dexamethasone in patients hospitalized with Covid-19.
Methods
Trial Design and Oversight
● The RECOVERY trial was designed to evaluate the effects of potential treatments in patients hospitalized with Covid-19
● Randomiz patients to receive dexamethasone, hydroxychloroquine, lopinavir–ritonavir, azithromycin, convalescent plasma, or tocilizumab has now been stopped, the trial continues randomization to other treatments, as REGN-COV2 , aspirin, colchicine, or usual care alone.
Outcome Measures
● The primary outcome was all-cause mortality within 28 days and further analyses at 6 months.
● Secondary outcomes :
☆ Time until discharge from the hospital
☆ Receipt invasive mechanical ventilation
☆ Cause-specific mortality
☆ Receipt renal dialysis or hemofiltration
☆ Major cardiac arrhythmia
☆ Receipt and duration of ventilation.
☆ Outcome of successful cessation of invasive mechanical ventilation among who receiving it
Results
● 11,303 patients under randomization
● from March 19 to June 8, 2020
● 9355 (83%) were eligible to receive dexa
● 6425 under randomization to receive either dexamethasone or usual care alone
● The remaining patients were randomly assigned to one of the other treatment
● The mean age was 66.1±15.7 years
● 36% were female
● 18% were Black, Asian, or from a minority ethnic group
● Diabetes was present in 24%
● Heart disease in 27%
● Chronic lung disease in 21%
● 56% having major coexisting illness
● 89%had laboratory-confirmed SARS CoV-2 infection.
● 16% were receiving invasive mechanical ventilation or extracorporeal membrane oxygenation
● 60% were receiving oxygen only
● 24% were receiving neither.
☆ In the dexamethasone group 95% received at least one dose of a glucocorticoid with median duration 7 days
☆ In the usual care group, 8% of the patients received a glucocorticoid as part of their clinical care.
☆ Use of macrolide antibiotic during the follow-up period was similar in the dexamethasone group and the usual care group (24% vs. 26%), and 0 to 3% of patients received hydroxychloroquine, lopinavir–ritonavir, or interleukin-6 antagonists during follow-up
☆ remdesivir was administered to 3 patients before randomization and 2 patients during the follow-up period
Primary Outcome
● Mortality at 28 days was significantly lower in the dexamethasone group (22.9%) than in the usual care group (25.7%)
● There was no clear effect of dexamethasone among patients who were not receiving any respiratory support
● Patients who were receiving invasive mechanical ventilation were on average 10 years younger than those not receiving any respiratory support and had a history of symptoms for an average of 7 days longer
● Patients with a longer duration of symptoms (who were more likely to have been receiving invasive mechanical ventilation ) had a greater mortality benefit in response to treatment with dexa
● The receipt of dexamethasone was associated with a reduction in 28-day mortality among those with symptoms for more than 7 days but not among those with a more recent symptom onset
Secondary Outcomes
● Patients in the dexamethasone group had a shorter duration of hospitalization than those in the usual care group and a greater probability of discharge alive within 28 days especially among patients who were receiving invasive mechanical ventilation
● The risk of progression to invasive mechanical ventilation was lower in the dexamethasone group than in the usual care group among patients who were not receiving invasive mechanical ventilation
● Successful cessation of invasive mechanical ventilation was more in the dexamethasone group than in the usual care group among who were receiving invasive mechanical ventilation
● patients who received RRT within 28 days was lower in the dexamethasone group than in the usual care group
● Deaths due to Covid-19 were less frequent in the dexamethasone group than in the usual care group
● The incidence of death from other causes was similar in the dexamethasone group and the usual care group
● Incidence of cardiac arrhythmia was similar in the dexamethasone group and the usual care group
● Adverse effects of glucocorticoids were hyperglycemia, gastrointestinal hemorrhage, and psychosis
Discussion
● Use of dexamethasone for 10 days resulted in lower 28-day mortality than usual care and in patients with invasive mechanical ventilation
● There was no evidence that dexamethasone provided any benefit among patients who were not receiving respiratory support with possible harm
● A mong patients who were receiving oxygen, the use of dexamethasone was associated with a lower risk of invasive mechanical ventilation or, for those already receiving invasive mechanical ventilation, a greater chance of successful cessation.
● In both these groups, the use of dexamethasone increased the chance of being discharged from the hospital alive within 28 days.
● The RECOVERY trial was designed to provide a rapid and robust assessment of the effect of readily available potential treatments for Covid-19 on 28-day mortality
● Protocol combines methods used in treatments for acute myocardial infarction
● Glucocorticoids have been widely used in syndromes closely related to Covid-19, including SARS, MERS, severe influenza, and community-acquired pneumonia.
● Limitations :
☆ lack of randomized,controlled trials
☆ Heterogeneity in glucocorticoid doses, medical conditions, and disease severity.
● Beneficial effect of glucocorticoids in severe viral respiratory infections is dependent on the selection of the right dose, at the right time, in the right patient.
● Unlike with SARS, in which viral replication peaks in the second week of illness, viral shedding in SARS-CoV-2 appears to be higher early in the illness and declines thereafter.
● The greater mortality benefit of dexamethasone in patients with Covid-19 who are receiving respiratory support and among those recruited after the first week of their illness suggests that at that stage the disease may be dominated by immunopathological elements, with active viral replication playing a secondary role.
● This hypothesis would caution against extrapolation of the effect of dexamethasone in patients with Covid-19 to patients with other viral respiratory diseases with a different natural history.
● The RECOVERY trial provides that treatment with dexamethasone at a dose of 6 mg once daily for up to 10 days reduces 28-day mortality in patients with Covid-19 who are receiving respiratory support.
● We found no benefit (and possibility of harm) among patients who did not require oxygen.
● Before the completion of the trial, many Covid-19 treatment guidelines stated that the use of glucocorticoids was either contraindicated or not recommended.
● Dexamethasone is on the list of essential medicines of the World Health Organization and is readily available worldwide at low cost.
What is the level of evidence provided by this article?
1b
II. Dexamethasone in Hospitalized Patients with Covid-19
Summarise the outcome of the different arms of the recovery trial
Drugs/ biologics recommended in the treatment of Covid-19 infection include:
– Remdesivir
– Tocilizumab
– Nirmatrelvir/ ritonavir
– Baricitinib (JAK inhibitors)
– Systemic corticosteroids
– anticoagulants
Drugs not recommended because of proven lack of efficacy include:
– Hydroxychloroquine/ chloroquine
– Ivermectin
– Fluvoxamine
– Lopinavir/ ritonavir
– Colchicine
– Interferons
– Convalescent plasma
– Lactoferrin
Drugs with insufficient evidence to recommend for or against include:
– Nitazoxanide
– GMCSF inhibitors
– Anakinra
– Vitamin C and D
Summarise this article
Background
– SARS-CoV-2 infection is associated with diffuse alveolar damage, inflammatory infiltrates and microvascular thrombosis
– use of glucocorticoids may reduce progression to respiratory failure and death by modulating the inflammation-mediated lung injury
Methods
– open label RCT, RECOVERY Trial (Randomised Evaluation of Covid-19 Therapy)
– compared the effects of the various treatment options offered to patients admitted with Covid-19 in the UK
– recruited hospitalized patients who had clinically suspected or laboratory confirmed SARS-CoV-2 infection
– in a 2:1 ratio, patients were randomly assigned to receive oral or IV dexamethasone 6mg OD for up to 10 days (or until hospital discharge if sooner) or to receive usual standard of care alone
– primary outcome: all-cause mortality within 28 days after randomization
– secondary outcomes: time until discharge from the hospital, subsequent receipt of invasive mechanical ventilation (IMV) including ECMO in patients who were not on IMV at the time of randomization, death
– other prespecified clinical outcomes included: cause-specific mortality, receipt of HD or hemofiltration, major cardiac arrythmias, receipt and duration of ventilation
Results
– dexamethasone arm: 2104 patients, 482 patients (22.9%) died within 28 days after randomization
– usual standard of care alone arm: 4321 patients, 1110 patients (25.7%) died within 28 days after randomization
– mean (± SD) age 66.1 ± 15.7 years, 36% female, 18% black, 24% diabetes, 27% heart disease, 21% chronic lung disease, 89% had laboratory-confirmed SARS-CoV-2 infection, 16% were on invasive mechanical ventilation or ECMO, 60% were on oxygen only (± noninvasive ventilation), 24% were not on either
– in the dexamethasone group, 95% of the patients received at least one dose of glucocorticoid, median duration of treatment was 7 days
– in the usual standard of care group, 8% of the patients received a glucocorticoid as well
– use of azithromycin was similar in both groups (24% in the dexamethasone group, 26% usual standard of care group 26%), 0-3% of patients were on HCQ, LPV/r or IL-6 antagonists during follow up
– mortality varied according to the level of respiratory support the patient was receiving at the time of randomization
– mortality at 28 days was lower in the dexamethasone group than in the usual standard of care group (22.9% vs 25.7% respectively)
– incidence of death was lower in the dexamethasone group compared to the usual care group among patients on invasive mechanical ventilation and patients on oxygen without invasive mechanical ventilation but not among patients who were not on any respiratory support at randomization
– patients on IMV at randomization were 10 years younger than those not on respiratory support and had a longer duration of symptoms prior to randomization
– dexamethasone was beneficial to patients who had a longer duration of symptoms and patients on IMV
– dexamethasone was associated with a reduction in 28-day mortality among patients who had symptoms for more than 7 days
– dexamethasone was associated with a shorter duration of hospitalization
– patients on dexamethasone were less likely to require IMV after randomization and they were also less likely to require kidney replacement therapy
– the incidence of new cardiac arrythmias was similar in both groups
Discussion
– use of dexamethasone resulted in lower 28-day mortality in patients on IMV, patients on oxygen, patients with a long duration of symptoms but no benefit among patients not on respiratory support
– dexamethasone use was associated with lower risk for the need of IMV in patients on oxygen and improved mortality outcomes as well
– dexamethasone use among patients on IMV was associated with an increased the chance of successful cessation of IMV and hospital discharge alive within 28 days
– the beneficial effect of glucocorticoids therefore depends on selection of the right dose at the right time for the right patient
Conclusion
– use of dexamethasone 6mg OD for up to 10 days reduces 28-day mortality in patients with Covid-19 requiring oxygen with or without respiratory support
II. Dexamethasone in Hospitalized Patients with Covid-19
Please do your own search and summarise the outcome of the different arms of the recovery trial.
Patients with severe COVID-19 develop a systemic inflammatory response that can lead to lung injury and multisystem organ dysfunction.
It has been proposed that the potent anti-inflammatory effects of corticosteroids might prevent or mitigate these harmful effects.
hospitalized patients in the United Kingdom showed that patients who were randomized to receive dexamethasone had a reduced rate of mortality compared to those who received standard of care.
This benefit was observed in patients with severe COVID-19 (defined as those who required supplemental oxygen) and was greatest in those who required mechanical ventilation at enrollment. No benefit of dexamethasone was observed in patients who did not require supplemental oxygen at enrollment.
The results of the RECOVERY trial have not yet been published.
In the RECOVERY trial, patients were not enrolled into the dexamethasone study arm (or included in the analysis) if their physicians decided that they were not suitable for corticosteroid therapy for any reason.
Before initiating dexamethasone, clinicians should review the patient’s medical history and assess the potential risks and benefits of administering corticosteroids to the patient.
Should closely monitor patients with COVID-19 who are receiving dexamethasone for adverse effects (e.g., hyperglycemia, secondary infections).
Using systemic corticosteroids may increase the risk of reactivation of latent infections (e.g., hepatitis B virus, herpesviruses, strongyloidiasis, tuberculosis).
Dexamethasone is a moderate cytochrome P450 (CYP) 3A4 inducer, which may reduce the concentration and potential efficacy of concomitant medications that are CYP3A4 substrates.
Should review a patient’s medication regimens to assess potential interactions.
At this time, it is not known whether other corticosteroids, such as prednisone, methylprednisolone, or hydrocortisone, will have a similar benefit to dexamethasone. Of note, the dose equivalencies for dexamethasone 6 mg daily are prednisone 40 mg, methylprednisolone 32 mg, and hydrocortisone 160 mg. HCQ
Multiple studies provide data that hydroxychloroquine (brand name: Plaquenil) does not provide a medical benefit for hospitalized patients with COVID-19. Hydroxychloroquine, an FDA-approved prescription drug used for malaria, rheumatoid arthritis and lupus erythematosus, has been suggested as a possible treatment or preventive for COVID-19 based on demonstrated antiviral or immune system activity.
The use of hydroxychloroquine in randomized trials for the treatment of hospitalized patients with COVID-19 has not been shown to have a benefit in reducing death.
In addition, concerns exist over the benefit of the drug compared to its safety risk, especially with regard to abnormal heart rhythms.
Multiple worldwide public health organizations, including the FDA, NIH and WHO recommend against use of hydroxychloroquine as a treatment for hospitalized patients with COVID-19 based on studies showing a lack of effect and possible serious side effects. Studies are still ongoing looking at use in early COVID disease, but prospective, randomized, controlled studies are not yet available.
#Doxycycline
Doxycycline, as an easily available and low-cost medication, should be considered as a COVID-19 therapy in all patients in the first days of symptoms of SARS-CoV-2 infection.
Due to its immunomodulatory, anti-inflammatory, cardioprotective and antiviral effects, it seems to be an ideal drug for patients with mild, moderate and severe type of COVID-19.
A large multicentre study to evaluate the effects of this medication is needed. #Azithromycin
azithromycin plus usual care did not substantially shorten the time to first self-reported recovery or decrease the risk of hospitalisation.
azithromycin should not be used routinely to treat COVID-19 in the community in older adults, in the absence of additional indications. #Favipiravir
Favipiravir might be crucial for ensuring an efficient treatment, decrease mortality and allow early discharge in relation to Covid-19. However more clinical studies are urgently needed to evaluate the efficacy and safety of this antiviral nucleoside for COVID-19 treatment. Please summarise this article.
Introduction
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (Covid-19), emerged in China in late 2019 from a zoonotic source.
However, in a substantial percentage of patients, a respiratory illness requiring hospital care develops, and such infections can progress to critical illness with hypoxemic respiratory failure requiring prolonged ventilatory support.
The pathophysiological features of severe Covid-19 are dominated by an acute pneumonic process with extensive radiologic opacity and, on autopsy, diffuse alveolar damage, inflammatory infiltrates, and microvascular thrombosis.
Although one small trial has reported improved clinical outcomes in patients with Covid-19 who were given methylprednisolone,17 the absence of reliable evidence from large-scale randomized clinical trials means there is uncertainty about the effectiveness of glucocorticoids in patients with Covid-19. Methods
Controlled, open-label trial.
-Compared a range of possible treatments in patients who were hospitalized with Covid-19,
-Patients randomized to receive oral or IV dexamethasone for up to 10 days or to receive the usual care.
– Eligibility: hospitalized patients if clinically suspected or laboratory confirmed SARS-CoV-2 infection, No medical prevent them from participating, no restriction for, pregnant and breastfeeding women included. The primary outcome was all-cause mortality within 28 days after randomization; further analyses were specified at 6 months. Secondary outcomes were the time until discharge from the hospital and, among patients not receiving invasive mechanical ventilation at the time of randomization, subsequent receipt of invasive mechanical ventilation (including extracorporeal membrane oxygenation) or death. Results
Total 11,303 patients who underwent randomization from March 19 to June 8, 2020, a total of 9355 (83%) were eligible to receive dexamethasone Of these patients, 6425 underwent randomization to receive either dexamethasone (2104 patients) or usual care alone (4321 patients).
In this analysis, 89% of the patients had laboratory-confirmed SARSCoV-2 infection.
At randomization, 16% were receiving invasive mechanical ventilation or extracorporeal membrane oxygenation, 60% were receiving oxygen only (with or without noninvasive ventilation), and 24% were receiving neither.
In the dexamethasone group, 95% of the patients received at least one dose of a glucocorticoid.
In the usual care group, 8% of the patients received a glucocorticoid as part of their clinical care.
The use of azithromycin or another macrolide antibiotic during the follow-up period was similar in the dexamethasone group and the usual care group (24% vs. 26%), and 0 to 3% of patients received hydroxychloroquine, lopinavir–ritonavir, or interleukin-6 antagonists during followup . Discussion
Results show that among hospitalized patients with Covid-19, the use of dexamethasone for up to 10 days resulted in lower 28-day mortality than usual care in patients who were receiving invasive mechanical ventilation at randomization (by 12.3 age-adjusted percentage points, a proportional reduction of approximately one third) and those who were receiving oxygen without invasive mechanical ventilation (by 4.2 age-adjusted percentage points, a proportional reduction of approximately one fifth)
no evidence that dexamethasone provided any benefit among patients who were not receiving respiratory support at randomization, and the results were consistent with possible harm in this subgroup.
What is the level of evidence provided by this article?1 b.
Introduction. · SARS-CoV-2, the cause of coronavirus disease 2019 (Covid-19), emerged in China in late 2019 from a zoonotic source. · It is characterized by an acute pneumonic process with extensive radiologic opacity and diffuses alveolar damage, inflammatory infiltrates, and microvascular thrombosis. · Inflammatory organ injury may occur in severe Covid-19, with a subgroup of patients having markedly elevated levels of inflammatory markers. · Several therapeutic interventions have been proposed to mitigate inflammatory organ injury in viral pneumonia, but the value of glucocorticoids has been widely debated.
Trial Design and Oversight
· The RECOVERY trial evaluated the effects of potential treatments in patients hospitalized with Covid-19, with randomization to REGN-COV2, aspirin, colchicine, or usual care. · Hospitalized patients eligible for SARS-CoV-2 trial if they had suspected or laboratory-confirmed infection and no medical history that could put them at risk. · The trial was approved by the U.K. Medicines and Health- care Products Regulatory Agency and the Cambridge East Research Ethics Committee.
Randomization
· Randomization was conducted using a Web-based system with concealment of the trial-group assignment, with eligible and consenting patients assigned to either the usual standard of care or dexamethasone for up to 10 days.
· The randomly assigned treatment was prescribed by the treating clinician and patients and local members of the trial staff were aware of the assigned treatments.
Procedures
· A single online follow-up form was completed to record adherence to treatment, receipt of other treatments, duration of admission, respiratory support, and vital status.
Outcome Measures
· Primary outcome was all-cause mortality within 28 days after randomization; secondary outcomes were time until discharge, subsequent receipt of invasive mechanical ventilation, cause-specific mortality, renal dialysis or hemofiltration, major cardiac arrhythmia, and receipt and duration of ventilation.
· Information is complete for 99.9% of trial participants.
Patients
· Patients randomized to either dexamethasone or usual care alone were randomly assigned to one of the other treatment groups.
· The mean (±SD) age of the patients in this comparison was 66.1±15.7 years, 36% were female, and 18% were Black, Asian, or from a minority ethnic group. 89% had laboratory-confirmed SARS-CoV-2 infection, 16% were receiving invasive mechanical ventilation or extracorporeal membrane oxygenation, 60% were receiving oxygen only, and 24% were receiving neither. 95% of the patients received at least one dose of glucocorticoid, and the median duration of treatment was 7 days.
· The use of azithromycin or another macrolide antibiotic during the follow-up period was similar in the dexamethasone group and the usual care group and 0 to 3% of patients received hydroxychloroquine, lopinavir–ritonavir, or interleukin-6 antagonists.
Primary Outcome
· Mortality at 28 days was significantly lower in the dexamethasone group than in the usual care group, with deaths reported in 482 of 2104 patients (22.9%) and 1110 of 4321 patients (25.7%). In a prespecified analysis according to the level of respiratory support that the patients were receiving at randomization, there was a trend showing the greatest absolute and proportional benefit among patients who were receiving invasive mechanical ventilation (11.3% vs. 14.4%; rate ratio, 0.83; 95% confidence interval [CI], 0.75 to 0.93; P<0.001).
· Post hoc exploratory analysis restricted to 5744 patients with a positive SARS-CoV-2 test result showed similar findings.
· Exposure to dexamethasone reduced 28-day mortality by an average of 7 days.
· Dexamethasone was associated with a reduction in 28-day mortality among those with symptoms for more than 7 days, but not among those with more recent symptom onset.
Secondary Outcomes · Patients in the dexamethasone group had a shorter duration of hospitalization and a greater probability of discharge alive within 28 days than those in the usual care group, with the greatest effect seen among those receiving invasive mechanical ventilation at randomization. Other prespecified Clinical Outcomes · The risk of progression to invasive mechanical ventilation was lower in the dexamethasone group than in the usual care group, with successful cessation of invasive mechanical ventilation more likely in the dexamethasone group. · The incidence of death from other causes was similar, and the incidence of new cardiac arrhythmia was similar. · There were four reports of serious adverse reactions, two of hyperglycemia, one of gastrointestinal hemorrhage, and one of psychosis, all recognized adverse effects of glucocorticoids.
Discussion
· The RECOVERY trial found that the use of dexamethasone for up to 10 days resulted in lower 28-day mortality than usual care in patients who were receiving invasive mechanical ventilation at randomization and those who were receiving oxygen without invasive mechanical ventilation.
· The benefit was also clear in patients being treated more than 7 days after symptom onset when inflammatory lung damage is likely to have been more common.
· A subsequent meta-analysis of seven trials of glucocorticoids for critically ill patients with Covid-19 confirmed the findings of the trial.
· The protocol combines the methods used in large, simple trials of treatments for acute myocardial infarction in the 1980s with the opportunities provided by digital health care in the 2020s. Preliminary results for dexamethasone were announced on June 16, 2020, and were adopted into the U.K.
· The views expressed in this article are those of the authors and do not necessarily reflect those of the National Health Service, the National Institute for Health Research, the Medical Research Council of United Kingdom Research and Innovation, or the Department of Health and Social Care.
· Guidelines issued by the U.K. chief medical officers, the European Medicines Agency, the World Health Organization, and the National Institutes of Health have been updated to recommend the use of glucocorticoids in patients hospitalized with Covid-19 requiring oxygen with or without ventilatory support.
· Tocilizumab was provided free of charge for this study by Roche, AbbVie contributed supplies of lopinavir–ritonavir, Regeneron contributed supplies of REGN-COV2, and the National Health Service supplied dexamethasone.
Conclusion
· In patients hospitalized with Covid-19, the use of dexamethasone resulted in lower 28-day mortality
among those who were receiving either invasive mechanical ventilation or oxygen
alone at randomization but not among those receiving no respiratory support.
============================== Level of Evidence
Ib
Different arms of Recovery trial
The RECOVERY Trial has found four treatments that are effective for severe COVID-19 and is currently testing the following suggested treatments to find out whether they are more effective in helping people recover than the standard care that all patients receive:
For COVID-19
sotrovimab (a monoclonal antibody treatment against the spike protein)
molnupiravir (an antiviral treatment)
paxlovid (an antiviral treatment)
For influenza
oseltamivir (an antiviral treatment)
baloxavir (an antiviral treatment)
low dose corticosteroids
Data from the trial are regularly reviewed so that any effective treatment can be identified quickly and made available to all patients.
SUMMARY
Recovery trial was a land mark trial which confirmed the utility of dexamethasone as treatment modality reducing mortality in deadly Covid 19
METHODS
In this controlled, open-label trial comparing a range of possible treatments in patients who were hospitalized with Covid-19, we randomly assigned patients to receive oral or intravenous dexamethasone (at a dose of 6 mg once daily) for up to 10 days or to receive usual care alone.
A total of 2104 patients were assigned to receive dexamethasone and 4321 to receive usual care. Overall, 482 patients (22.9%) in the dexamethasone group and 1110 patients (25.7%) in the usual care group died within 28 days after randomization (age-adjusted rate ratio, 0.83; 95% confidence interval [CI], 0.75 to 0.93; P<0.001).
In the dexamethasone group, the incidence of death was lower than that in the usual care group among patients receiving invasive mechanical ventilation (29.3% vs. 41.4%; rate ratio, 0.64; 95% CI, 0.51 to 0.81) and among those receiving oxygen without invasive mechanical ventilation (23.3% vs. 26.2%; rate ratio, 0.82; 95% CI, 0.72 to 0.94) but not among those who were receiving no respiratory support at randomization.
CONCLUSIONS
In patients hospitalized with Covid-19, the use of dexamethasone resulted in lower 28-day mortality among those who were receiving either invasive mechanical ventilation or oxygen alone at randomization but not among those receiving no respiratory support.
Secondary Outcomes
Patients in the dexamethasone group had a shorter duration of hospitalization than those in the usual care group (median, 12 days vs. 13 days) and a greater probability of discharge alive within 28 days.
Among the patients who were not receiving invasive mechanical ventilation at randomiza- tion, the number of patients who progressed to the prespecified composite secondary outcome of invasive mechanical ventilation or death was lower in the dexamethasone group than in the usual care group.
Among those who were receiving invasive mechanical ventilation at ran- domization, successful cessation of invasive me- chanical ventilation was more likely in the dexa- methasone group than in the usual care group
Among the patients who were not receiving renal-replacement therapy (renal dialy- sis or hemofiltration) at randomization, the num- ber of patients who received this treatment within 28 days was lower in the dexamethasone group than in the usual care group
LEVEL OF EVIDENCE
RCTs are given the highest levelbecause they are designed to be unbiased and have less risk of systematic errors.
Dexamethasone in Hospitalized Patients with Covid-19: Introduction;
-Coronavirus disease 2019 (Covid-19) is associated with diffuse lung damage.
-Glucocorticoids may modulate inflammation-mediated lung injury and thereby reduce progression to respiratory failure and death.
-Glucocorticoids have been widely used in syndromes closely related to Covid-19, including SARS, Middle East respiratory syndrome (MERS), severe influenza, and community-acquired pneumonia . Aim;
-This controlled, open-label Randomized trial for evaluation of Covid-19 Therapy (RECOVERY) trial of dexamethasone in patients hospitalized with Covid-19. Methodology;
-In this controlled, open-label trial comparing a range of possible treatments in patients who were hospitalized with Covid-19, we randomly assigned patients to receive oral or intravenous dexamethasone (at a dose of 6 mg once daily) for up to 10 days or to receive usual care alone.
-The primary outcome was 28-day mortality. Results;
-A total of 2104 patients were assigned to receive dexamethasone and 4321 to receive usual care. Overall, 482 patients (22.9%) in the dexamethasone group and 1110 patients (25.7%) in the usual care group died within 28 days after randomization . Conclusion;
-In patients hospitalized with Covid-19, the use of dexamethasone resulted in lower 28-day mortality among those who were receiving either invasive mechanical ventilation or oxygen alone at randomization but not among those receiving no respiratory support.
-This open –label trial with Level of evidence: 1b
Dexamethasone in Hospitalized Patients with Covid-19
The RECOVERY Collaborative Group
published in the new England journal of medicine February 25, 2021
Methodology
It is a open-labeled randomized controlled trial (The level of evidence is 1B)
COVID-19 infection patients divided into two main groups one received oral or I.V glucocorticoid for treatment, and the other one received usual care
The primary outcome is 28-day mortality, and the secondary outcome is the time until discharge from the hospital
Results
6425 underwent randomization to receive either dexamethasone (2104 patients) or usual care alone (4321 patients)
Primary outcomes (mortality at 28 days): 482 of 2104 patients (22.9%) and in 1110 of 4321 patients (25.7%), respectively which were statistically significant
Secondary outcomes (a shorter duration of hospitalization): median, 12 days in dexamethasone group vs. 13 days in standard care group.
Among patients on invasive mechanical ventilation results were favored on the dexamethasone arm in the form of successful weaning.
Discussion
The use of 6mg dexamethasone reduced the 28-day mortality.
There was no statistically significance of adding dexamethasone for patients on no respiratory support.
Summary of outcome of the different arms of the recovery trial:
This international clinical trial is identifying treatments that may be beneficial for people hospitalized with suspected or confirmed COVID-19. A total of 48465 Participants from 195 Active sites were included. Azithromycin and standard care, no clinical benefit Aspirin was not associated with improved 28 days mortality Baricitinib for 10 days and standard care reduced the risk of death Colchicine and standard care, no improvement in survival Hydroxychloroquine did not improve survival Lopinavir/Rotinavir did not improve survival as compared to standard care alone Tocilizumab improve outcomes in patients with hypoxia and inflammation
Please summarise this article
Introduction: SARS-CoV-2, the cause of severe acute respiratory syndrome (Covid-19), emerged in China in late 2019. The majority of Covid-19 cases either are asymptomatic or result in only mild disease. Covid-19 is associated with diffuse lung damage. Glucocorticoids may modulate inflammation-mediated lung injury and thereby reduce progression to respiratory failure and death.
Methods:
In this controlled, open-label trial comparing a range of possible treatments in patients who were hospitalized with Covid-19, we randomly assigned patients to receive oral or intravenous dexamethasone (at a dose of 6 mg once daily) for up to 10 days or to receive usual care alone. The primary outcome was 28-day mortality.
Result: A total of 2104 patients received dexamethasone. 4321 patients received usual care. 482 patients (22.9%) in the dexamethasone group died and 1110 patients (25.7%) in the usual care group. In the dexamethasone group, the incidence of death was lower than that in the usual care group among patients receiving invasive mechanical ventilation and among those receiving oxygen without invasive mechanical ventilation but not among those who were receiving no respiratory support at randomization . Conclusion: In patients hospitalized with Covid-19, the use of dexamethasone resulted in lower 28-day mortality among those who were receiving either invasive mechanical ventilation or oxygen alone at randomization.
Please do your own search and summarise the outcome of the different arms of the recovery trial.
ASCARD – 150mg OD until discharge + usual care vs usual care ;No benefit.
Baricitinib – 4mg OD -10/7 + usual care vs usual care ;Decreased risk of death.
Azithromycin – 500mg OD -10/7 + usual care vs usual care ; No benefit.
Colchicine – 1Tab BD +Usual care vs usual care ; No benefit.
HCQs -200mg OD +Usual care vs usual care ; No benefit.
Convalscent plasma ; convalscent plasma + usual care vs usual care ; No benefit.
Lopinavir/Ritonavir ;400/100mg OD + usual care vs usual care ; No benefit.
DMF ;120mg OD -2/7 then 240mg BD – 8/7 +usual care vs usual care ; No benefit.
Tocilizumab ; 400-800mg OD 1-2/7 +usual care vs usual care;Improved survival with less inflammation and oxygen dependance.
Rengen-COV -Stat of 8mg IV + usual care vs usual care; decreased 28/7 death rate.
Please summarise this article.
SARS COV2 1st seen in china in late 2019 and resulted in lung damage and mortality.
Tx approach differed worldwide in 1st 6/12,Recovery trial was to evaluate different tx options and outcomes in 176 centres in the UK.
All those with Covid 19 without a medical contraindication participated in the study.
Pt received usual care or usual care + Dexamethasone 6 mg for ten days or until discharge, whichever came faster.
The dexamethasone group had lower mortality than the usual group (22.9 vs 25.7%,P < 0.001) and this was more pronounced in those receiving invasive ventilation without a clear benefit on those on no resp support.
Dexamethasone has a mortality benefit and less hospital stay in covid pts on some form of resp support but this benefit was not extended to those on no resp support.
What is the level of evidence provided by this article?
1b
Summary
· The current RCT compared IV dexamethasone to usual care
· Primary outcome was mortality at 6 months from randomization, and secondary outcomes were need for mechanical ventilation or ECMO, duration of MV, occurrence of arrhythmia, the need to dialysis and duration of hospital stay.
· The current study concluded that low dose dexa (6 mg/day) for 3-10 days was beneficial in reducing the mortality in cases with severe disease (on oxygen or invasive mechanical ventilation).
· However, dexa had no added benefits in those not requiring respiratory support.
· Steroid use need meticulous decision (right dose, at the right time, in the right patient)…usually start at later stage of the disease (at least 7 days from the onset of symptoms, only in severe cases who are oxygen dependent or need MV)
· Remdisivir may fasten recovery but did not decrease mortality.
· Lung autopsy in severe cases shows extensive infiltration by inflammatory cells and microvascular thrombosis. In addition, high levels of inflammatory markers as g C-RP, ferritin, interleukin-1 and -6 which raise the possibility o steroid use in severe cases.
· Trial of dexamethasone, hydroxychloroquine, lopinavir–ritonavir, azithromycin, convalescent plasma, or tocilizumab has now been stopped. Level of evidence: RCT (level II)
The outcome of the different arms of the recovery trial
The RECOVERY trial(1)was designed to evaluate the effects of potential treatments in patients hospitalized with Covid-19 at 176 National Health Service organizations in the United Kingdom and was supported by the National Institute for Health Research Clinical Research Network.
1. The randomization of patients to receive dexamethasone, hydroxychlo- roquine, lopinavir–ritonavir, azithromycin, convalescent plasma, or tocilizumab has now been stopped.
· Hydroxychloroquine has no clinical benefits.
· No significant mortality impact for lopinavir.
· Azithromycin has no clinical benefits.
· Aspirin was added to the trial because it is used to prevent blood clots, patients with COVID-19 are at higher risk of blood clots forming in their blood vessels. It is also cheap and widely available, which make it a good candidate. · Tocilizumab reduces deaths in patients hospitalized with COVID-19.The study also showed that tocilizumab shortens the time taken for patients to be successfully discharged from hospital, and reduces the need for a mechanical ventilator. · Baricitinib reduces deaths in hospitalized patients.The RECOVERY team found that treatment with baricitinib reduced deaths by 13%. It also reduced the chance of progressing to invasive mechanical ventilation.
· Dexamethasone reduces deaths by up to one third.
2. The trial continues randomization to other treatments, including REGN-COV2 (a combination of two monoclonal antibodies directed against the SARS-CoV-2 spike protein), aspirin, colchicine, or usual care alone.
· In March 2021, the trial closed the colchicine arm of the trial, as it had found no benefit to patients.
Summary of the article
Dexamethasone in Hospitalized Patients with Covid-19
This is a controlled, open-label trial comparing a range of possible treatments in patients who were hospitalized with Covid-19, randomly assigned to receive oral or intravenous dexamethasone (at a dose of 6 mg once daily) for up to 10 days or to receive usual care alone. The primary outcome was 28-day mortality.
The use of dexamethasone resulted in lower 28-day mortality among those who were receiving either invasive mechanical ventilation or oxygen alone at randomization but not among those receiving no respiratory support.
The level of evidence provided by this article:
This is a controlled, open-label trial. It is a prospective cohort study with level of evidence grade 2.
The RECOVERY trial: Hydroxychloroquine : Has no clinical benefitDexamethazone : : Dexamethasone is proven to improve survival in COVID-19. lopinavir : Had no significant mortality benefits Cholchicine and aspirine : Acholchicine: is a commonly used anti-inflammatory treatment. Inflammation is a key component of severe COVID-19 and can lead to lung damage, the need for mechanical ventilation and death.But unfortunately it had no benefit to patients . Aspirin : Was added to the trial because it is used to prevent blood clots, but it did not reduce the 28-day mortality rate in COVID-19 patients who were hospitalized, the risk of dying or moving to invasive mechanical ventilation, but it did slightly raise the percentage of patients who were discharged alive after 28 days.
Azithromycin : Azithromycin is a widely-used antibiotic that also reduces inflammation, a key feature of severe COVID-19 but unfortunately has no clinical benefits. Tocizumab: It reduces the risk of death for hospitalized patients with severe COVID-19, also shortens the time of stay in the hospital, and reduces the need for a mechanical ventilator. Baricitinib: : Is an anti-inflammatory drug normally used to treat rheumatoid arthritis , it is found to improve survival for patients with severe COVID-19.
Please summarise this article.
Introduction :
SARS-CoV-2, the cause of severe acute respiratory syndrome (Covid-19), emerged in China in late 2019 from a zoonotic source. The majority of Covid-19 cases either are asymptomatic or result in only mild disease It is characterized by an acute pneumonic process with extensive radiologic opacity and diffuse alveolar damage, inflammatory infiltrates, and microvascular thrombosis. Several therapeutic interventions have been proposed to mitigate inflammatory organ injury, but the value of glucocorticoids has been widely debated.
Methods and result :
11,303 patients underwent randomization from March 19 to June 8, 2020 to receive dexamethasone or usual care alone. The mean age of the patients was 66.1±15.7 years, 36% were female, and 18% were Black, Asian, or from a minority ethnic group. 89% had laboratory-confirmed SARSCoV-2 infection, 16% were receiving invasive mechanical ventilation or extracorporeal membrane oxygenation, 60% were receiving oxygen only, and 24% were receiving neither. 95% of the patients received at least one dose of a glucocorticoid, and the median duration of treatment was 7 days. The use of azithromycin or another macrolide antibiotic during the follow-up period was similar.
Outcome : Primary outcome : The dexamethasone group had a significantly lower incidence of death at 28 days than the usual care group, with the greatest absolute and proportional benefit among those receiving invasive mechanical ventilation. Secondary outcome : The dexamethasone group had a shorter duration of hospitalization and a greater probability of discharge alive within 28 days than the usual care group.
Conclusion :
The RECOVERY trial found that treatment with dexamethasone at a dose of 6 mg once daily for up to 10 days reduces 28-day mortality in patients with Covid-19 who are receiving respiratory support
What is the level of evidence provided by this article?
Please do your own search and summarise the outcome of the different arms of the recovery trial. 1- trial is supported by grants to the University of Oxford
The RECOVERY Trial has found four treatments that are effective for severe COVID-19 and is currently testing the following suggested treatments to find out whether they are more effective in helping people recover than the standard care that all patients receive:
For COVID-19
sotrovimab (a monoclonal antibody treatment against the spike protein)
molnupiravir (an antiviral treatment)
paxlovid (an antiviral treatment)
2-Sponsor:
University of Oxford RECOVERY is a randomised trial investigating whether treatment with Lopinavir-Ritonavir, Hydroxychloroquine, Corticosteroids, Azithromycin, Colchicine, IV Immunoglobulin (children only), Convalescent plasma, Casirivimab+Imdevimab, Tocilizumab, Aspirin, Baricitinib, Infliximab, Empagliflozin, Sotrovimab, Molnupiravir, Paxlovid or Anakinra (children only) prevents death in patients with COVID-19.
Please summarise this article. randomly assigned patients to receive oral or intravenous dexamethasone (at a dose of 6 mg once daily) for up to 10 days or to receive usual care alone.
The primary outcome was 28-day mortality.
RESULTS
2104 patients were assigned to receive dexamethasone and 4321 to receive usual care. Overall, 482 patients (22.9%) in the dexamethasone group and 1110 patients (25.7%) in the usual care group died within 28 days after randomization
In patients hospitalized with Covid-19, the use of dexamethasone resulted in lower 28-day mortality among those who were receiving either invasive mechanical ventilation or oxygen alone at randomization but not among those receiving no respiratory support.
Covid-19 were admitted to hospitals in the United Kingdom in the first half of 2020, the case fatality rate was approximately 26% overall and more than 37% among patients who were undergoing invasive mechanical ventilation.
Although remdesivir has been shown to shorten the time until recovery in hospitalized patients,8 no therapeutic agents have been shown to reduce mortality.
Several therapeutic interventions have been proposed to mitigate inflammaory organ injury in viral pneumonia, but the value of glucocorticoids has been widely debated
Although one small trial has reported improved clinical outcomes in patients with Covid-19 who were given methylprednisolone,the absence of reliable evidence from large-scale randomized clinical trials means there is uncertainty about the effectiveness of glucocorticoids in patients with Covid-19.
Many guidelines for the treatment of such patients have stated that glucocorticoids were either contraindicated or not recommended,
although in China, glucocorticoids have been recommended for severe cases
However, in the first 6 months of the pandemic, practice varied widely across the world: in some series, as many as 50% of patients were treated with glucocorticoids.
Here, we report the results of the controlled, open-label Randomized Evaluation of Covid-19 Therapy (RECOVERY) trial of dexamethasone in patients hospitalized with Covid-19.
Methods Trial Design and Oversight The RECOVERY trial
was designed to evaluate the effects of potential treatments in patients hospitalized with Covid-19 at 176 National Health Service organizations in the United Kingdom and was supported by the National Institute for Health Research Clinical Research Network.
. Although the randomization of patients to receive dexamethasone, hydroxychloroquine, lopinavir–ritonavir, azithromycin, convalescent plasma, or tocilizumab has now been stopped,
the trial continues randomization to other treatments, including REGN-COV2 (a combination of two monoclonal antibodies directed against the SARS-CoV-2 spike protein), aspirin, colchicine, or usual care alone.
Procedures
A single online follow-up form was to be completed by the local trial staff when each patient was discharged or had died or at 28 days after randomization, whichever occurred first
Information was recorded regarding the patients’
adherence to the assigned treatment, receipt of other treatments for Covid-19, duration of admission, receipt of respiratory support (with duration and type), receipt of renal dialysis or hemofiltration, and vital status (including the cause of death). routine health care and registry data, including information on vital status (with date and cause of death), discharge from the hospital, and respiratory and renal support therapy
Outcome Measures
The primary outcome was all-cause mortality within 28 days after randomization; further analyses were specified at 6 months
. Secondary outcomes were the time until discharge from the hospital and, among patients not receiving invasive mechanical ventilation at the time of randomization, subsequent receipt of invasive mechanical ventilation (including extracorporeal membrane oxygenation) or death.
Consequently, on June 8, 2020, the steering committee closed recruitment to the dexamethasone group, since enrollment had exceeded 2000 patients. For the primary outcome of 28-day mortality, the hazard ratio from Cox regression was used to estimate the mortality rate ratio.
The RECOVERY trial provides evidence that treatment with dexamethasone at a dose of 6 mg once daily for up to 10 days reduces 28-day mortality in patients with Covid-19 who are receiving respiratory support.
We found no benefit (and the possibility of harm) among patients who did not require oxygen.
What is the level of evidence provided by this article?A1b Individual randomized controlled trials
Please do your own search and summarise the outcome of the different arms of the recovery trial.
Recovery Trial
Coronavirus disease 2019 (Covid-19) is associated with diffuse lung damage. Glucocorticoids may modulate inflammation-mediated lung injury and thereby reduce progression to respiratory failure and death.
Methodology
In this controlled, open-label trial comparing a range of possible treatments in patients who were hospitalized with Covid-19, we randomly assigned patients to receive oral or intravenous dexamethasone (at a dose of 6 mg once daily) for up to 10 days or to receive usual care alone. The primary outcome was 28-day mortality.
Azithromycin
Standard Care + Azithromycin 500 mg OD 10 days VS Standard care
Azithromycin did not improve outcomes
Aspirin
Aspirin 150 mg OD plus standard care VS Standard Care
Aspirin was not associated with improved 28 days mortality
Baricitinib
Baricitinib for 10 days and standard care VS Standard care
Baricitinib reduced the risk of death
Colchicine
Colchicine + Standard care VS Standard care
No improvement in survival
Hydroxychloroquine -HCQ
HCQ + standard care VS Standard care
HCQ did not improve survival
Lopinavir/Rotinavir
It did not improve survival as compared to standard care alone
Rengen COV
Rengen COV 8 mg and standrad care VS standard care
Rengen COV did improve 28 days mortality
Tocilizumab
It improved outcomes in patients with hypoxia and inflammation
Please summarise this article.
Introduction
Coronavirus disease is associated with diffuse lung damage. Glucocorticoids may modulate inflammation-mediated lung injury and thereby reduce progression to respiratory failure and death.
METHODOLOGY
In this trial comparing a range of possible treatments in patients who were hospitalized with Covid-19 patients received oral or intravenous dexamethasone (at a dose of 6 mg once daily) for up to 10 days or to receive usual care alone.
The primary outcome- 28-day mortality.
RESULTS
Total of 2104 patients received dexamethasone
4321 to received usual care
482 patients (22.9%) in the dexamethasone group died
1110 patients (25.7%) in the usual care group died
In the dexamethasone group, the incidence of death was lower than that in the usual care group among patients receiving invasive mechanical ventilation and among those receiving oxygen without invasive mechanical ventilation but not among those who were receiving no respiratory support at randomization .
CONCLUSIONS
In patients hospitalized with Covid-19, the use of dexamethasone resulted in lower 28-day mortality among those who were receiving either invasive mechanical ventilation or oxygen alone at randomization but not among those receiving no respiratory support.
1. What is the level of evidence provided by this article
This article is focussed around the usage of Dexamethasone in COVID 19 patients in the hospital setting. The reasoning behind using dexamethasone is that it is a glucocorticoid, and this group of drugs modulate inflammation mediated lung injury, and thereby reduce progression to respiratory failure and death.
Discussion
This article is based on a controlled open label trial where different treatments of COVID 19 patients in the hospital setting have been compared and contrasted by randomly assigning patients to receive either oral or intravenous dexamethasone 6 mg OD for a period of 10 days.
Inflammatory lung damage is more prominent a week after the onset of symptoms, and dexamethasone benefit can also be seen more clearly after this period. Patients requiring oxygen support have benefited greatly with this drug regimen, with a greater chance of cessation of the need for mechanical support for ventilation. Patients also have a decreased risk of the need for mechanical ventilation when on this regimen. The use of dexamethasone has greatly increased the chance of such patients being discharged from the hospital alive within a time frame of 28 days.
The exact treatment dosage and frequency used in this trial is beneficial, with higher doses leading to possible harm to the patient. In addition, different glucocorticoids can have different effects in patients with other viral replication diseases, and thus caution is to be observed.
Conclusion
Dexamethasone, administered either in the oral or IV form, can reduce 28-day mortality rates in patients infected with COVID-19. The drug is administered to in-patients and includes those who receive invasive mechanical ventilation, just oxygen alone, and those who do not need respiratory support of any kind. However, with those who do not need respiratory support of any kind, this drug may cause possible harm instead of benefit.
The findings of this trial have been confirmed by a meta-analysis of six other trials of using glucocorticoids for critically ill patients with COVID 19.
Level of evidence
Level of evidence is 1 since this article is based on a randomized controlled trial.
This study is level 1A – randomized controlled trial.
Reference :
Kapoor MC. Types of studies and research design. Indian J Anaesth. 2016 Sep;60(9):626-630. doi: 10.4103/0019-5049.190616. PMID: 27729687; PMCID: PMC5037941.
The RECOVERY Trial:
The RECOVERY trial is a randomized, open-label, adaptive platform trial that is looking at several treatments compared with usual standard of care in patients admitted in hospitals in the UK with COVID 19. The primary outcome is 28 day mortality with other secondary prespecified outcomes of length of hospital stay and progression to mechanical ventilation. There were several treatments evaluated:
Azithromycin:
Azithromycin 500 mg once daily for 10 days plus usual standard of care versus usual standard of care
The results showed that azithromycin did not improve survival or other pre-specified clinical outcomes
Aspirin:
Aspirin 150 mg once daily until discharge plus usual standard of care versus usual standard of care
The results showed that aspirin was not associated with a reduction in 28 day mortality
Baricitinib:
Baricitinib 4 mg mg once daily for 10 days plus usual standard of care versus usual standard of care
The results showed that baricitinib significantly reduced the risk of death but the size of benefit was somewhat smaller than that suggested by previous trials
Colchicine:
Colchicine twice daily plus usual standard of care versus usual standard of care
The results showed that colchicine did not improve survival
Convalescent Plasma:
Convalescent plasma plus usual standard of care versus usual standard of care
The results showed that high-titer convalescent plasma did not improve survival or other pre-specified clinical outcomes
Dimethylfuroate (DMF):
DMF 120 mg twice daily for 2 days followed by 240 mg twice daily for eight days plus usual standard of care versus usual standard of care
The results showed that DMF did not improve survival or other pre-specified clinical outcomes
Hydroxychloroquine (HCQ):
Hydroxychloroquine daily for 10 days plus usual standard of care versus usual standard of care
The results showed that HCQ did not improve survival or other pre-specified clinical outcomes
Lopinavir/Ritonavir:
Lopinavir/Ritonavir (400mg/100mg) once daily plus usual standard of care versus usual standard of care
The results showed that Lopinavir/Ritonavir did not improve survival or other pre-specified clinical outcomes
RENGEN-COV:
RENGEN COV 8 gm intravenously as a single dose plus usual standard of care versus usual standard of care
The results showed that RENGEN-COV reduced 28 day mortality
Tocilizumab: Tocilizumab 400-800 mg once given intravenously as a single dose or 2 doses depending on the response plus usual standard of care versus usual standard of care
The results showed that tocilizumab improved survival and other outcomes in patients with hypoxia and inflammation
Summary Of The Article:
Introduction
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in China in 2019, and caused coronavirus disease 2019 (COVID-19). Many patients had mild disease, unfortunately a substantial percentage of patients developed critical illness requiring hospital care. The pathophysiological features of severe COVID-19 included an acute pneumonic process with extensive radiologic opacity, diffuse alveolar damage, inflammatory infiltrates and microvascular thrombosis. It is thought that the host immune response may result in inflammatory organ injury. This study reports the results of the trial of dexamethasone in patients hospitalized with COVID-19.
Methods
The study, a controlled, open-label Randomized Evaluation of COVID-19 Therapy (RECOVERY) trial was designed to evaluate the effects of potential treatment in patients hospitalized with COVID-19 infection. It involved 176 National Health Service organizations in the United Kingdom. Patients were randomized to receive either the usual standard of care alone, or the usual standard of care plus oral or intravenous dexamethasone for up to 10 days. The primary outcome was all cause mortality within 28 days of randomization. Secondary outcomes included the time until discharge from the hospital, progression to invasive mechanical ventilation or death. Other pre-specified clinical outcomes included cause-specific mortality, requirement of renal dialysis or hemofiltration, major cardiac arrhythmias and duration of ventilation.
Results
11,303 patients underwent randomization from 19th March to 8th June 2020. A total of 9355 were eligible to receive dexamethasone, out of which 6425 underwent randomization to receive either dexamethasone, or usual care alone. 36% of the patients were female and 18% were black Asian or from a minority ethnic group. The mean age was 66.1+/-15.7 years. 24% of the patient had diabetes, 27% had heart disease, 21% had chronic lung disease and 56% had at least one major coexisting illness.
The mortality at 28 days was significantly lower in the patients receiving dexamethasone compared to that in the usual care group. In patients receiving dexamethasone, there was a great benefit seen among those on invasive ventilation.
A shorter duration of hospital stay was seen in those patients who receive dexamethasone. The risk of progressing to invasive mechanical ventilation was lower in the dexamethasone group. Among patients who were not receiving dialysis or hemofiltration, the number of patients who progressed to renal replacement therapy was lower in the dexamethasone group. The deaths due to COVID-19 infection was less frequent in the dexamethasone group. There was no difference in the incidence of new cardiac arrhythmias in both groups.
Discussion
The results showed that the use of dexamethasone for up to 10 days resulted in a lower 28 day mortality than usual care in patients hospitalized and on mechanical ventilation with COVID-19 infection. However, there was no evidence that dexamethasone was of any benefit among patients who were not receiving respiratory support. It was noted that high doses may be more harmful than helpful due to the possible risk of infections
Level Of Evidence: This was a randomized controlled trial – Level I
Please do your own search and summarize the outcome of the different arms of the recovery trial.
RECOVERY trial:
Evaluate the effects of potential treatments in hospitalized patient with Covid-19 on 28-day mortality Aspirin:
-Aspirin 150 mg once daily
-It was not associated with reductions in 28-day mortality or in the risk of progressing to invasive mechanical ventilation or death.
-Although there was a small increase in the likelihood of being discharged alive this does not seem to be sufficient to justify its widespread use for patients hospitalized with COVID-19. Azithromycin:
-Azithromycin 500 mg OD for 10 days.
-There was also no evidence of beneficial effects on the risk of progression to mechanical ventilation or length of hospital stay. Colchicine:
-There has been no convincing evidence of the effect of colchicine on clinical outcomes in patients admitted to hospital with COVID-19 Baricitinib (JAK inhibitors):
-The dose 4mg tablet once daily for 10 days (or until discharge from hospital if sooner).
– The result confirms and extends earlier findings in other trials.
– Treatment significantly reduced deaths: a reduction of 13%
– It is also reduced the chance of progressing to invasive mechanical ventilation or death
– The benefit of baricitinib was consistent regardless of which other COVID-19 treatments the patients were also receiving, including corticosteroids, tocilizumab, or remdesivir. Hydroxychloroquine:
-Enrollment stooped.
-There was no significant difference in the primary endpoint of 28-day mortality
-There was also no evidence of beneficial effects on hospital stay duration or other outcomes Convalescent plasma:
– Shows no significant difference in the primary endpoint of 28-day mortality
– Follow-up of patients is ongoing and final results will be published as soon as possible. Dexamethasone:
-Low dose 6 mg once per day PO/ IV for 10 days
-It reduced deaths by one-third in ventilated patients (rate ratio 0.65) and by one fifth in other patients receiving oxygen only (0.800)
There was no benefit among those patients who did not require respiratory support -High dose 20 mg once daily for 5 days followed by 10 mg once daily for 5 days or until discharge if sooner. -Higher dose corticosteroids significantly increased the risk of death compared to usual care, which included low dose corticosteroids. lopinavir–ritonavir:
– No significant difference in the primary endpoint of 28-day mortality
– No evidence of beneficial effects on the risk of progression to mechanical ventilation or length of hospital stay Dimethyl fumarate DMF
– Dose:120 mg by mouth every 12 hours for the first four doses followed by 240mg every 12 hours for the total treatment duration of 10 days or until hospital discharge, whichever was sooner.
-Treatment with DMF was not associated with an improvement in this measure compared with usual care alone Tocilizumab.
-Treatment with tocilizumab significantly reduced deaths, increased the probability of discharge alive within 28 days and significantly reduced the chance of progressing to invasive mechanical ventilation or death
-There was no evidence that tocilizumab had any effect on the chance of successful cessation of invasive mechanical ventilation.
– In hospitalized COVID-19 patients with hypoxia and systemic inflammation, tocilizumab improved survival and other clinical outcomes. These benefits were seen regardless of the amount of respiratory support and were additional to the benefits of systemic corticosteroids. REGN-COV2 –a combination of two monoclonal antibodies directed against the SARS-CoV-2 spike protein.
-seronegative: had not mounted a natural antibody response of their own.
-seropositive : had already developed natural antibodies.
-Among seronegative patients at baseline treatment reduced the primary outcome of 28-day mortality by one-fifth but not in seropositive. Please summarize this article. Introduction:
– Covid-19 infection caused severe respiratory illness and diffuse lung injury with high fatality rate.
– Several therapeutic interventions have been proposed to mitigate inflammatory organ injury in viral pneumonia, but the value of glucocorticoids has been widely debated.
Method:
-Controlled, open-label trial
-Compared a range of possible treatments in patients who were hospitalized with Covid-19,
-Patients randomized to receive oral or IV dexamethasone (at a dose of 6 mg once daily) for up to 10 days or to receive the usual care.
– Eligibility: hospitalized patients if clinically suspected or laboratory confirmed SARS-CoV-2 infection, No medical prevent them from participating, no restriction for, pregnant and breastfeeding women included.
Primary outcome was 28-day all causes of mortality. Secondary outcomes: Time until discharge from the hospital. Cessation from mechanical ventilation (MV). In nonventilated patient, subsequent receipt of invasive MV or death. Results:
– Total of 6425 randomized to receive either dexamethasone (2104 patients) or usual care alone (4321 patients)
– At randomization: 16% were receiving invasive mechanical ventilation or ECMO, 60% were receiving oxygen only (with or without noninvasive ventilation), and 24% were receiving neither.
– Overall, 28 days mortality (22.9%) in the dexamethasone group and (25.7%) in the usual care group.
-The proportional and absolute differences in mortality varied according to the level of respiratory support
at the time of randomization.
– The greatest benefit among patients who were receiving invasive MV.
-In the dexamethasone group, the incidence of death was lower than that in the usual care group among patients receiving:
– Invasive mechanical ventilation (29.3% vs. 41.4)
– Oxygen without invasive mechanical ventilation (23.3% vs. 26.2%)
– Not among patients with no respiratory support at randomization (17.8% vs. 14.0%)
– Secondary Outcomes: dexamethasone group had a shorter duration, lower risk for progression to MV and less need for dialysis.
Level of evidence: 1b evidence obtained from single RCT.
Summarise this article. METHODS
Open-label trial comparing a range of possible treatments in patients who were hospitalized with Covid-19, we randomly assigned patients to receive oral or intravenous dexamethasone for up to 10 days or to receive usual care alone.
The primary outcome was 28-day mortality.Here, we report the final results of this assessment RESULTS
A total of 2104 patients were assigned to receive dexamethasone and 4321 to receive usual care.
482 patients (22.9%) in the dexamethasine group and 1110 patients (25.7%) in the usual care group died within 28 days after randomization.
The proportional and absolute between-group differences in mortality varied considerably according to the level of respiratory support that the patients were receiving at the time of randomization.
The incidence of death was lower than that in the usual care group among patients receiving invasive mechanical ventilation CI, 0.51 to 0.81) and among those receiving oxygen without invasive mechanical ventilation (23.3% vs 26.2%; rate ratio, 0.82; 95% CI, 0.72 to 0.94) but not among those who were receiving no respiratory support at randomization (17.8% vs 14.0%; rate ratio, 1.19; 95% CI, 0.92 to 1.55) CONCLUSIONS
In patients hospitalized with Covid-19, the use of dexamethasine resulted in lower 28-day mortality among those who were receiving either invasive mechanical ventilation or oxygen alone at randomization but not among those receiving no respiratory support.
We report the results of the controlled, open-label Randomized Evaluation of Covid-19 Therapy (RECOVERY) trial of dexamethasone in patients hospitalized with Covid-19.
The RECOVERY trial was designed to evaluate the effects of potential treatments in patients hospitalized with Covid-19 at 176 National Health Service organizations in the United Kingdom and was supported by the National Institute for Health Research Clinical Research Network.
Randomization We collected baseline data using a Web-based case-report form that included demographic data,the level of respiratory support, major coexisting illnesses, suitability of the trial treatment for a particular patient, and treatment availability at the trial site.
The randomly assigned treatment was prescribed by the treating clinician.Patients and local members of the trial staff were aware of the assigned treatments Procedures
A single online follow-up form was to be completed by the local trial staff when each patient was discharged or had died or at 28 days after randomization, whichever occurred first.
Through the play of chance in the unstratified randomization, the mean age was 1.1 years older among patients in the dexamethasine group than among those in the usual care group (Table 1)
To account for this imbalance in an important prognostic factor, estimates of rate and risk ratios were adjusted for the baseline age in three categories (<70 years, 70 to 79 years, and ≥80 years).
Among the patients who were not receiving invasive mechanical ventilation at randomization, the number of patients who progressed to the prespecified composite secondary outcome of invasive mechanical ventilation or death was lower in the dexamethasine group than in the usual care group (Table 2).
There were four reports of a serious adverse reaction that was deemed by the investigators to be related to dexamethasone two of hyperglycemia, one of gastrointestinal hemorrhage, and one of psychosis Discussion
Our results show that among hospitalized patients with Covid-19, the use of dexamethasine for up to 10 days resulted in lower 28-day mortality than usual care in patients who were receiving invasive mechanical ventilation at randomization and those who were receiving oxygen without invasive mechanical ventilation The greater mortality benefit of dexamethasone in patients with Covid-19 who are receiving respiratory support and among those recruited after the first week of their illness suggests that at that stage the disease may be dominated by immunopathological elements, with active viral replication playing a secondary role.
The RECOVERY trial provides evidence that treatment with dexamethasone at a dose of 6 mg once daily for up to 10 days reduces 28-day mortality in patients with Covid-19 who are receiving respiratory support.
summarise the outcome of the different arms of the recovery trial.
Tocilizmumab
Tocilizumab increased survival and other clinical outcomes in COVID-19 hospitalized patients with hypoxia and systemic inflammation.
These advantages were noted in addition to those of systemic corticosteroids and were independent of the level of respiratory support.
Azithromycine
Azithromycin did not enhance clinical outcomes such as survival or other predetermined clinical outcomes in patients admitted to hospitals with COVID-19.
Only patients with a clear antibacterial indication should receive azithromycin when they are hospitalized with COVID-19. Hydroxycholowuinine
The rate of death at 28 days was not any lower among Covid-19 hospitalized patients who got hydroxychloroquine compared to those who received standard therapy. Aspirin
Aspirin did not reduce the 28-day mortality rate in COVID-19 patients who were hospitalized, the risk of dying or progressing to invasive mechanical ventilation, but it did slightly raise the percentage of patients who were released alive after 28 days. Colchicines
Colchicine was not linked to decreased 28-day mortality, length of hospital stay, likelihood of advancing to invasive mechanical ventilation, or risk of death in persons hospitalized with COVID-19.
I like your well-structured summary, and conclusions. I appreciate level of evidence that you have allocated to this open labelled trial usage of steroids in patients of COVID19 requiring respiratory support. Any further sub-classification of level I? However, spellings of many drugs are incorrect.
1. Please do your own search and summarise the outcome of the different arms of the recovery trial.
Aspirin dose 150 mg/d
It does not reduce 28-day mortality, invasive mechanical ventilation, or death. It was linked to a little increase in 28-day survival.
Azithromycin Dose 500 mg oral or IV daily for 10 days or till discharge.
no increase in survival or clinical outcomes.
JAK inhibitors—primarily baricitinib —reduce COVID-19 hospitalized mortality by roughly 20%.
Colchicine Dosage 1 mg once, 500 μg 12 h later, 500 μg twice a day by mouth or nasogastric tube for 10 days or until discharge.
It did not reduce 28-day mortality, hospital stay, invasive mechanical ventilation, or death.
Convalescent Plasma:
Survival and other clinical outcomes were unaffected by high-titer convalescent plasma.
Hydroxychloroquine:
The hydroxychloroquine group had a lower rate of hospital discharge within 28 days than the usual-care group. The hydroxychloroquine group had more invasive mechanical ventilation or death in non-mechanically ventilated patients.
lopinavir–ritonavir(400 mg and 100 mg) orally for 10 days or till discharge:
did not reduce 28-day mortality, hospital stay, risk of invasive mechanical ventilation, or death.
Intravenous tocilizumab 400–800 mg (weight-dependent). If the patient’s condition didn’t improve, a second dose could be administered 12–24 h later.
Tocilizumab enhanced survival and other outcomes in COVID-19 patients with hypoxia and systemic inflammation (C-reactive protein >75 mg/L)used in addition to steroids & , regardless of respiratory support.
2. Please summarise this article.
Randomized control open-label multicentre trial, comparing the effect of the use of dexamethasone in hospitalized covid-19 patients with the usual care without steroids
it indicated that dexamethasone ( oral or intravenous dose of 6 mg once daily for up to 10 days) lowered mortality rates by one-third among patients requiring mechanical ventilation and by one-fifth among patients requiring oxygen therapy.
however, it shows little advantage for those who did not require respiratory support. Primary outcome Death at 28 days Secondary outcomes Discharged from the hospital within 28 days, Invasive mechanical ventilation, or death Subsidiary clinical outcomes: Use of ventilation, Noninvasive ventilation, Invasive mechanical ventilation), Successful cessation of invasive mechanical &renal-replacement therapy
3. What is the level of evidence provided by this article?
Level 1 RCT
I like your well-structured summary, and conclusions. I appreciate level of evidence that you have allocated to this open labelled trial usage of steroids in patients of COVID19 requiring respiratory support.
Any further sub-classification of level I?
Dexamethasone in Hospitalized Patients with Covid-19 Please do your own search and summarise the outcome of the different arms of the recovery trial. Aspirin 1 Dose used 150 mg daily. It not associated with reductions in 28-day mortality or in the risk of progressing to invasive mechanical ventilation or death. It was associated with a small increase in the rate of being discharged alive within 28 days. (Median 8 days, IQR 5 to >28, vs 9 days, IQR 5 to >28) subtle difference Aspirin didn’t improve survival. Azithromycin 2 Dose: azithromycin 500 mg once per day by mouth or intravenously for 10 days or until discharge It did not improve survival or other prespecified clinical outcomes. Azithromycin has no clinical benefit. Baricitinib 3 Baricitinib significantly reduced the risk of death, but the size of benefit was somewhat smaller than that suggested by previous trials. The total randomised evidence to date suggests that JAK inhibitors (chiefly baricitinib) reduce mortality in patients hospitalised for COVID-19 by about one-fifth. Baricitinib reduce death and reduce progression of invasive mechanical ventilator (IMV). Colchicine 4 Dose 1 mg after randomisation followed by 500 μg 12 h later and then 500 μg twice a day by mouth or nasogastric tube for 10 days in total or until discharge. It was not associated with reductions in 28-day mortality, duration of hospital stays, or risk of progressing to invasive mechanical ventilation or death. Colchicine has no benefit. Convalescent Plasma 5 high-titre convalescent plasma did not improve survival or other prespecified clinical outcomes. Convalescent plasma didn’t improve survival or another clinical outcome. Dexamethasone small dose 6
PO or intravenous dexamethasone at a dose of 6 mg once daily for up to 10 days
The use of dexamethasone resulted in lower 28-day mortality among those who were receiving either invasive mechanical ventilation or oxygen alone at randomization but not among those receiving no respiratory support.
Dexamethasone high dose 7
(Dexamethasone 20 mg once daily for 5 days followed by 10 mg once daily for 5 days or until discharge if sooner) clinical hypoxia but requiring either no oxygen or simple oxygen only, higher dose corticosteroids significantly increased the risk of death compared to usual care, which included low dose corticosteroids.
Dimethyl fumarate 8
DMF 120mg twice daily for 2 days followed by 240mg twice daily for 8 days, or until discharge if sooner. It was not associated with an improvement in clinical outcomes.
Hydroxychloroquine 9
The results suggest that patients in the hydroxychloroquine group were less likely to be discharged from the hospital alive within 28 days than those in the usual-care group (59.6% vs. 62.9%; rate ratio, 0.90; 95% CI, 0.83 to 0.98). Among the patients who were not undergoing mechanical ventilation at baseline, those in the hydroxychloroquine group had a higher frequency of invasive mechanical ventilation or death. Hydroxychloroquine: has no clinical benefit Lopinavir-Ritonavir results 10
lopinavir–ritonavir (400 mg and 100 mg, respectively) by mouth for 10 days or until discharge lopinavir–ritonavir was not associated with reductions in 28-day mortality, duration of hospital stays, or risk of progressing to invasive mechanical ventilation or death. These findings do not support the use of lopinavir–ritonavir for treatment of patients admitted to hospital with COVID-19. Lopinavir has no significant mortality benefit.
It is non-competing monoclonal antibodies that bind to two different sites on the receptor binding domain of the SARS-CoV-2 spike glycoprotein, blocking viral entry into host cells. Dose: casirivimab 4 g and imdevimab 4 g administered together in a single intravenous infusion. It reduced 28-day mortality in patients who were seronegative (and therefore had not mounted their own humoral immune response) at baseline but not in those who were seropositive at baseline. Regenerons monoclonal antibodies combination reduce death for hospitalized patients who have not mounted their own immune response. Tocilizumab 12
Dose tocilizumab at a dose of 400 mg–800 mg (depending on weight) given intravenously. A second dose could be given 12–24 h later if the patient’s condition had not improved. COVID-19 patients with hypoxia and evidence of systemic inflammation (C-reactive protein ≥75 mg/L), tocilizumab improved survival and other clinical outcomes. These benefits were seen regardless of the amount of respiratory support and were additional to the benefits of systemic corticosteroids. Tocilizumab reduce death in hospitalized severe COVID-19 patients. Summary this article Introduction
Covid 19 that first appeared in China presented with acute pneumonic features that can lead to respiratory failure with high fatality rate. The extensive radiologic opacity, diffuse alveolar damage, inflammatory infiltrates, and microvascular thrombosis revealed the severe inflammatory response confirmed with elevated inflammatory markers. Meanwhile steroids role was controversial. Glucocorticoids use was not recommended except in severe cases. Majority of COVID-19 patients either asymptomatic or presented with mild symptoms. Large percentage of patient need hospital admission mainly due to respiratory symptoms which can progressed to hypoxia & respiratory failure & need for IMV. IN UK 2020, mortality was 26% and >37% of patients need IMV. Remdesivir reduce hospital stay, but no drug reduce mortality. CRP, ferritin, IL-1 & IL-6 were high in COVID-19 patients. Method
Controlled open-label randomized trial. 9355 patients underwent randomization between dexamethasone & other treatment. 6425 patients randomized between dexamethasone and usual care alone (2104 patients in dexamethasone group & 4321 in usual care group). Included suspected or diagnosed COVID-19 hospitalized patient including pregnant and breast-feeding females. Patients assigned with 2:1 ratio to receive usual standard care alone or usual standard care with oral or IV dexamethasone (6 mg for 10 days) or receive one of other citable and available treatment evaluated in trial. Patient didn’t receive dexamethasone (due to unavailability) excluded from randomization. Primary outcome was all cause mortality within 28 days after randomization (other analysis specified at 6 months). Secondary outcome: time until discharge from hospital and among patients do not receive IMV at time of randomization, subsequent receipt of IMV or death. Other pre-specified clinical outcome includes cause specific mortality, receipt of renal dialysis or hemofiltration, major cardiac arrhythmia and recent and duration of ventilation. Result & discussion
28 days mortality reduced in patients used dexamethasone for 10 days (in patients on IMV or patients need oxygen with or without IMV). No evidence of benefit from steroid among patients do not receive respiratory support & it may cause harm. Benefit was clear in patients who use steroid >7 days after symptoms onset (common lung damage). Dexamethasone used to reduce risk of IMV in patients receive oxygen & in patients on IMV increase chance of cessation & discharge from hospital life within 28 days. Mortality in usual care group was consistent with over all case fatality rate for hospitalized COVID-19 patients in UK at time of dexamethasone comparison was active. Dexamethasone results released at June16,2020(<100 days after protocol first drafted) & adopted in UK practice at same day. Corticosteroid widely used in SARS, MERS, severe influenza & community acquired pneumonia. Beneficial effect of steroid depends on right dose, right time & right patients. High dose steroids may be more harmful than helpful. Viral replication of COVID-19 high in early stage of disease, so beneficial effect of steroid after 1 week may be due to immunopathological element. Guidelines update to recommend use of steroids in hospital patients with COVID-19 need O2 with or without need of IMV. Conclusion
Dexamethasone intake resulted in lower 28-day mortality in hospitalized cases among those who had either invasive mechanical ventilation or oxygen alone but not among those without respiratory support but dexamethasone did not show any benefit for cases who did not need respiratory support . What is the level of evidence provided by this article? Level of evidence is 1. References:
1)Abani, Obbina, et al. “Aspirin in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial.” The Lancet 399.10320 (2022): 143-151.
2)Abaleke, Eugenia, et al. “Azithromycin in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial.” The Lancet 397.10274 (2021): 605-612.
3)Abani, Obbina, et al. “Baricitinib in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial and updated meta-analysis.” The Lancet 400.10349 (2022): 359-368.
4)RECOVERY Collaborative Group. “Colchicine in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial.” The Lancet Respiratory Medicine 9.12 (2021): 1419-1426.
5)Abani, Obbina, et al. “Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial.” The Lancet 397.10289 (2021): 2049-2059.
6)RECOVERY Collaborative Group. “Dexamethasone in hospitalized patients with Covid-19.” New England Journal of Medicine 384.8 (2021): 693-704.
7)RECOVERY Collaborative Group, et al. “Higher dose corticosteroids in hospitalised COVID-19 patients with hypoxia but not requiring ventilatory support (RECOVERY): a randomised, controlled, open-label, platform trial.” medRxiv (2022): 2022-12.
8)RECOVERY Collaborative Group, et al. “Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial.” medRxiv (2022): 2022-09.
9)RECOVERY Collaborative Group. “Effect of hydroxychloroquine in hospitalized patients with Covid-19.” New England Journal of Medicine 383.21 (2020): 2030-2040.
10)Horby, Peter W., et al. “Lopinavir–ritonavir in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial.” The Lancet 396.10259 (2020): 1345-1352.
11)RECOVERY Collaborative Group. “Casirivimab and imdevimab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial.” Lancet (London, England) 399.10325 (2022): 665.
12)RECOVERY Collaborative Group. “Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial.” Lancet (London, England) 397.10285 (2021): 1637.
I like your well-structured summary in great details and conclusions with a long list in relevant references. I appreciate level of evidence that you have allocated to this open labelled trial usage of steroids in patients of COVID19 requiring respiratory support.
Any further sub-classification of level I?
Dexamethasone
Reduced deaths of hospitalised COVID-19 patients with severe respiratory complications by up to one third
Dexamethasone is the first drug to be shown to improve survival in COVID-19. It is inexpensive, on the shelf, and can be used immediately to save lives worldwide
Lopinavir–ritonavir
1183 Were assigned to receive lopinavir–ritonavir
No significant mortality benefit in hospitalised COVID-19 patients
Colchicines
In March 2021, the trial closed the colchicine arm of the trial, as it had found no benefit to patients
Aspirin
o 7351 patients were randomly allocated (1:1) to receive aspirin and 7541 patients to receive usual care alone
o Slightly shorter duration of hospitalisation and a higher proportion were discharged from hospital alive within 28 days
o Among patients not on invasive mechanical ventilation at baseline, there was no significant difference
Azithromycin
575 were assigned to receive azithromycin
In December 2020, the RECOVERY teamreleased preliminary results showing it has no effect on clinical outcomes in COVID-19
Tocilizumab Reduces the risk of death for hospitalised patients with severe COVID-19, shortens the time taken for patients to be successfully discharged from hospital, and reduces the need for a mechanical ventilator
Baricitinib
In March 2022, the RECOVERY trial reported that baricitinib reduces the risk of death when given to hospitalised patients with severe COVID-19 (reduced deaths by 13%)
It also reduced the chance of progressing to invasive mechanical ventilation
Remdesivir
Superior to placebo in shortening the time to recovery in adults who were hospitalized with Covid-19 and had evidence of lower respiratory tract infection
Convalescent plasma
No convincing evidence of the effect of convalescent plasma on clinical outcomes in patients admitted to hospital with COVID-19
Regeneron monoclonal antibody combination
Reduces the risk of death when given to patients hospitalised with severe COVID-19 who have not mounted a natural antibody response of their own
Promising treatments:
sotrovimab (a monoclonal antibody treatment against the spike protein)
molnupiravir (an antiviral treatment)
paxlovid (an antiviral treatment)
Please summarise this article. Introduction
o Covid-19 can be associated with severe pneumonia with high mortality rate. Glucocorticoids may reduce progression to respiratory failure and death
o One small trial has reported improved clinical outcomes in patients recieving methylprednisolone (no large-scale randomized clinical trials)
Methods
o Clinically suspected or laboratory confirmed SARS-CoV-2 infection were eligible. Also pregnant or breast-feeding women were eligible
o This is an open-label controlled trial of patients hospitalized with Covid-19. They randomly receive oral or intravenous dexamethasone (at a dose of 6 mg once daily) for up to 10 days or to receive usual care alone
o The primary outcome: death at 28 days
o Secondary outcomes: discharged from hospital within 28 days/ Invasive mechanical ventilation or death
Results
o 6425 underwent randomization to receive either dexamethasone (2104 patients) or usual care alone (4321 patients)
o In the dexamethasone group, 95% of the patients received at least one dose of a glucocorticoid (The median duration of treatment was 7 days)
o Mortality at 28 days was significantly lower in the dexamethasone group than in the usual care group, with deaths reported in 482 of 2104 patients (22.9%) and in 1110 of 4321 patients (25.7%), respectively
o In the dexamethasone group, the incidence of death was lower than that in the usual care group among patients receiving invasive mechanical ventilation (29.3% vs. 41.4%) and among those receiving oxygen without invasive mechanical ventilation (23.3% vs. 26.2%) but not among those who were receiving no respiratory support at randomization (17.8% vs. 14.0%)
o Patients in the dexamethasone group had a shorter duration of hospitalization than those in the usual care group (median, 12 days vs. 13 days) and a greater probability of discharge alive within 28 days
Discussion
o The RECOVERY trial provides evidence that treatment with dexamethasone at a dose of 6 mg once daily for up to 10 days reduces 28-day mortality in patients with Covid-19 who are receiving respiratory support
o Guidelines issued by the U.K. chief medical officers, the European Medicines Agency, the WHO, and the National Institutes of Health in the United States have been updated to recommend the use of glucocorticoids in patients hospitalized with Covid-19 requiring oxygen with or without ventilatory support
Conclusions
The use of dexamethasone in patients hospitalized with Covid-19 resulted in lower 28-day mortality among those who were receiving respiratory supports (invasive mechanical ventilation or oxygen alone) but not among those receiving no respiratory support
What is the level of evidence provided by this article?Level I (open-label randomized control trial)
I like your well-structured summary in great details, and conclusions. I appreciate level of evidence that you have allocated to this open labelled trial usage of steroids in patients of COVID19 requiring respiratory support. Any further sub-classification of level I?
Study design
This is a controlled open liable trial of two arms of the clinical intervention in hospitalized covid 19 patients on different o2 therapy support, the dexamethasone arm 6mg iv, oral for 10 days, and the usual care arm. A recovery trial was published in NEJM with an IF of 176.082 for 2023. Primary outcome
Compare the 28 days mortality between the two intervention groups Please summarize this article. Introduction
Severe acute respiratory SRAS-2 COVID-19 viral pneumonia with pandemic effect happening in China and spread globally from zoonotic infection in late 2019. the disease has a very variable clinical presentation from asymptomatic or mild illness in the majority of cases to severe acute respiratory distress syndrome requiring hospitalization and in some percentage, invasive ventilation in intensive care complicated with Multiple organ dysfunction with death in UK case fatality reported up to 26% in those requiring invasive ventilation, antiviral like remidesvir shows benefit in term of hasten the recovery in severe cases but not affect the overall mortality risk based reports from many studies no therapeutic agents have been shown to reduce mortality with sever Sars 2 covid 19 pneumonia. the main finding includes a pneumonic process with extensive radiologic opacity and, on autopsy, diffuse alveolar damage, inflammatory infiltrates, and microvascular thrombosis. Method Setting
Open liable RCT with treatment intervention in hospitalized patients with Covid-19 at 176 National Health Service organizations in the United Kingdom were supported by the National Institute for Health Research Clinical Research Network consent formed was taken from the patients or their representatives including all cases with clinical suspicion or diagnosed with covid 19, earlier age limited 18 and above however after may 2020 they removed the age limit, web-based data collection including patients demographics and clinical characteristics, comorbid, level of o2 therapy and support, treatment in each arm eligible and consented patients were assigned into 2;1 ratio One arm for the standard of care and another group standard of care with oral or IV dexamethasone 6 mg for 10 days or till discharge. Both the patient and the staff member from the trial are aware of the assigned treatment, however, some patients did not receive the dexamethasone assigned treatment because of not available or contraindicated so those patients are excluded from the randomization. The data of a single FU chart was documented by the allocated trial staff upon discharge or the date of the death or at 28 days after randomization whichever occur first. The primary outcome
Death at 28 days
Secondary outcome
1. hospital discharge within 28 days in patients not received ventilatory support at the time of randomization
2. Successful cessation from mechanical invasive ventilatory support including ECMO support or death within 28 days. Subgroup analysis
Receipt of renal dialysis or hemofiltration.
major cardiac arrhythmia
receipt and duration of ventilation. Among those receiving invasive mechanical ventilation at the time of randomization use measured death
outcome of successful cessation of invasive mechanical ventilation was defined as cessation within (and survival till) 28 days
The data was completed for all patients 99.9%
Results
11,303 enrolled
3% (370) excluded not received Dexamethasone and an additional 15% are not fit for dexa therapy 83% underwent randomization > 9350 patients
2930 Were assigned to receive other active treatment
1183 Were assigned to receive lopinavir-ritonavir
1172 Were assigned to receive hydroxychloroquine
575 Were assigned to receive azithromycin
6425 (57%) underwent randomization between dexamethasone and usual care alone
2104 (100%) Were assigned to receive dexamethasone
1996/2095 (95%) Received dexamethasone, 2 dropped the consent.
4321 (100%) Were assigned to receive usual care alone,47/4306 (8%) Received dexamethasone Primary outcome
Figure 2 shows Kaplan Meier the survival at 28 days for all patients according to the type of oxygen support ( primary outcome ) which is not adjusted to age while the rate ratio adjusted to age ( 3 groups < 70, 70-79, > 80 )
There is a better survival rate seen in the group with invasive ventilatory support and dexamethasone as shown in fig 3 (29.3% vs. 41.4%; rate ratio, 0.64; 95% CI,
0.51 to 0.81). However, there was no clear effect of dexamethasone among patients who were not receiving any respiratory support at randomization (17.8% vs. 14.0%; rate ratio, 1.19; 5% CI, 0.92 to 1.55), patients with longer duration of symptoms > 7 days they benefit from the addition of dexamethasone Secondary outcome All secondary outcomes result in favor of the dexamethasone treatment arm compared to the usual care arm as shown in Table 2
show that among the patients who were receiving oxygen, the use of dexamethasone was associated with a lower risk of invasive mechanical ventilation or, for those already receiving
invasive mechanical ventilation, a greater chance of successful cessation Conclusion
The RECOVERY trial provides evidence that treatment with dexamethasone at a dose of 6 mg once daily for up to 10 days reduces 28-day mortality in patients with Covid-19 who are receiving respiratory support. We found no benefit (and the possibility of harm) among patients who did not require oxygen
What is the level of evidence provided by this article?
RCT with level 1A of evidence
please do your own search and summarise the outcome of the different arms of the recovery trial. 1. RECOVERY Collaborative Group. Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomized controlled, open-label, platform trial. Lancet. 2021 May 29;397(10289):2049-2059. doi: 10.1016/S0140-6736(21)00897-7. Epub 2021 May 14. PMID: 34000257; PMCID: PMC8121538.
Clarification: In patients hospitalized with COVID-19, high-titer convalescent plasma did not improve survival or other prespecified clinical outcomes
2. RECOVERY Collaborative Group. Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomized, controlled, open-label, platform trial. Lancet. 2021 May 1;397(10285):1637-1645. doi: 10.1016/S0140-6736(21)00676-0. PMID: 33933206; PMCID: PMC8084355.
Eligible criteria for inclusion are all patients with ever covid pneumonia with O2 saturation < 92% in RA and requiring o2 support with high inflammatory markers CRP> 75, randomization ratio 1:1 one arm standard of care therapy, and the daclizumab arm 400mg or 800mg plus standard of care The primary outcome was 28-day mortality, assessed in the intention-to-treat population
this trial in favor of the tocilizumab arm with better survival at 28 days, patients allocated to tocilizumab were more likely to be discharged from hospital within 28 days (57% vs 50%; rate ratio 1·22; 1·12-1·33; p<0·0001).
The Conclusion of this trial, tocilizumab improved survival and another clinical outcome in patients with severe covid -19 pneumonia (hypoxic and high inflammatory response)
3. RECOVERY Collaborative Group. Colchicine in patients admitted to hospital with COVID-19 (RECOVERY): a randomized, controlled, open-label, platform trial. Lancet Respir Med. 2021 Dec;9(12):1419-1426. doi: 10.1016/S2213-2600(21)00435-5. Epub 2021 Oct 18. PMID: 34672950; PMCID: PMC8523117.
Interpretation: In adults hospitalized with COVID-19, colchicine was not associated with reductions in 28-day mortality, duration of hospital stay, or risk of progressing to invasive mechanical ventilation or death.
4. RECOVERY Collaborative Group. Aspirin in patients admitted to hospital with COVID-19 (RECOVERY): a randomized, controlled, open-label, platform trial. Lancet. 2022 Jan 8;399(10320):143-151. doi: 10.1016/S0140-6736(21)01825-0. Epub 2021 Nov 17. PMID: 34800427; PMCID: PMC8598213.
The aspirin arm did not show survival benefits over the standard-of-care group. Aspirin was not associated with reductions in 28-day mortality or in the risk of progressing to invasive mechanical ventilation or death but was associated with a small increase in the rate of being discharged alive within 28 days. 5. RECOVERY Collaborative Group. Azithromycin in patients admitted to hospital with COVID-19 (RECOVERY): a randomized, controlled, open-label, platform trial. Lancet. 2021 Feb 13;397(10274):605-612. doi: 10.1016/S0140-6736(21)00149-5. Epub 2021 Feb 2. PMID: 33545096; PMCID: PMC7884931.
Azithromycin did not improve survival or other prespecified clinical outcomes. Azithromycin use in patients admitted to hospitals with COVID-19 should be restricted to patients in whom there is a clear antimicrobial indication.
6. RECOVERY Collaborative Group. Lopinavir-ritonavir in patients admitted to hospital with COVID-19 (RECOVERY): a randomized, controlled, open-label, platform trial. Lancet. 2020 Oct 24;396(10259):1345-1352. doi: 10.1016/S0140-6736(20)32013-4. Epub 2020 Oct 5. PMID: 33031764; PMCID: PMC7535623.
lopinavir-ritonavir was not associated with reductions in 28-day mortality, duration of hospital stay, or risk of progressing to invasive mechanical ventilation or death. These findings do not support the use of lopinavir-ritonavir for the treatment of patients admitted to hospitals with COVID-19.
in summary, only dexamethasone and tocilizumab did show survival benefits among different arms of clinical interventions of recovery trial platfrom based RCT
Dexamethasone in Hospitalized Patients with Covid-19.
COVID 19 infection has been emerging on 2019 in China, mortality rate was approximately 26% overall and more than 37% among patients who were undergoing invasive mechanical ventilation. It cause severe acute pneumonic
process with extensive radiologic opacity and, on autopsy, diffuse alveolar damage, inflammatory infiltrates, and microvascular thrombosis, this sever inflammatory process may be propagate and cause multi-organ failure and the main role is to mitigate this inflammatory process to avoid further systems damage which is the role of glucocorticoids that still dose not have strong evident based but here, this controlled, open-label Randomized Evaluation of Covid-19 Therapy (RECOVERY) trial of dexamethasone in patients hospitalized with Covid-19 will discuss this issue. Methods:
Controlled, open-label trial comparing a range of possible treatment in patients who were hospitalized with Covid-19 patients at 176 National Health service organizations in the United Kingdom, we randomly assigned patients to receive oral or intravenous dexamethasone (at a dose of 6 mg once daily) for up to 10 days or to receive usual care alone. The primary outcome was 28-day mortality. Results:
A total of 2104 patients were assigned to receive dexamethasone and 4321 to receive usual care with total number 6425 underwent randomization.
Overall, 482 patients (22.9%) in the dexamethasone group and 1110 patients (25.7%) in the usual care group died within 28 days after randomization.
The proportional and absolute between-group differences in mortality varied considerably according to the level of respiratory support that the patient were receiving at the time of randomization. (at randomization, 16% were receiving invasive mechanical ventilation or extracorporeal membrane oxygenation, 60% were receiving oxygen only (with or without noninvasive ventilation), and 24% were receiving neither.
In the dexamethasone group (95% of the patients received at least one dose of a glucocorticoid with median duration of treatment was 7 days), the incidence of death was lower than that in the usual care group (with deaths reported in 482 of 2104 patients (22.9%) and in 1110 of 4321 patients (25.7%), respectively )among patient receiving invasive mechanical ventilation and among those receiving oxygen without invasive mechanical ventilation but not among those who were receiving no respiratory support at randomization.
Patients in the dexamethasone group had a shorter duration of hospitalization than those in the usual care group (median, 12 days vs. 13 days) and a greater probability of discharge alive within 28 days and decrease the incidence of shifting to invasive ventilation from non-invasive group on dexamethasone, also successful cessation of invasive mechanical ventilation was more likely in the dexamethasone group than in the usual care group. Conclusion:
The study shown evidence that treatment with dexamethasone at a dose of 6 mg once daily for up to 10 days reduces 28-day mortality in patients with Covid-19 who are receiving respiratory support and found that no benefit among patients who did not require oxygen. Before the completion of the trial, many Covid-19 treatment guidelines stated that the use of glucocorticoids was either contraindicated or not recommended and this study give strong evident with large sample size. Level of evidence: I b (individual RCT)
1.Please do your own search and summarize the outcome of the different arms of the recovery trial. The RECOVERY Study has identified 4 treatments for severe COVID-19, & it is presently evaluating the following suggested treatments to see if they are more successful at promoting recovery than the standard therapy that all patients receive: For COVID-19
Sotrovimab, an anti-spike protein monoclonal antibody, & 2 other antiviral treatments (molnupiravir & paxlovid).
For influenza
Oseltamivir & baloxavir & low doses of corticosteroids.
Data are periodically reviewed in order to swiftly identify & make all patients eligible for any effective treatments.
Randomized allocation of treatment for COVID-19
A web-based randomization was used to give treatments to eligible SARS-CoV-2 proven patients in addition to their routine care.
Eligible patients randomly assigned to =/> 1 treatment arms at once.
Randomization part E
Eligible patients (adult ≥18 years old without suspected or confirmed influenza coinfection) & requiring ventilatory support are randomized in a 1:1 ratio to 1 of the arms below:
No additional treatment
High-dose corticosteroids: dexamethasone 20 mg OD (PO, NGT, or IV) for 5 days, then 10 mg OD for 5 days.
Randomization part F:
Eligible patients (adult patients ≥18 years old) may be randomized in a 1:1 ratio to 1 of the below arms:
No additional treatment
Empagliflozin 10 mg OD PO for 28 days (or until discharge, if earlier).
Randomization part J (UK only):
Eligible patients (patients ≥12 years old) may be randomized in a 1:1 ratio to 1 of these arms:
No additional treatment
Sotrovimab 1000 mg in 100 mL 0.9% NaCl or D5% IV infusion.
Randomization part K:
Eligible patients (patients ≥18 years old) may be randomized in a 1:1 ratio to one of these arms:
No additional treatment
Molnupiravir 800 mg BID/5 d PO
Randomization part L (UK only):
Eligible patients (patients ≥18 years old) may be randomized in a 1:1 ratio to one of the arms listed below.
No additional treatment
Paxlovid (nirmatrelvir/ritonavir) 300/100 mg BID/5 d PO
========================= 2.Please summarize this article. Methodology
The RECOVERY trial was created to assess the effects of potential treatments in patients hospitalized with Covid-19 at 176 NHS organizations in the UK.
Patients are no longer being randomized to receive tocilizumab, lopinavir-ritonavir, hydroxychloroquine, azithromycin, or convalescent plasma.
The trial is still randomizing participants to other therapies, such as REGN-COV2 (monoclonal antibodies against the SARS-CoV-2 spike protein), aspirin, colchicine, or standard medical therapy alone.
Eligibility for the trial
Suspected or confirmed SARS-CoV-2 infection.
Any age (age limit removed from May 9, 2020
Pregnant or breast-feeding women were eligible.
Data (demographic data, level of respiratory support, major coexisting illnesses, suitability of the trial treatment) were collected using a Web-based case-report form.
Eligible & consenting patients were randomized (2:1) to either the usual standard of care alone or the usual standard of care plus oral or IV dexamethasone (6 mg OD for up to 10 days (or until hospital discharge if sooner) or to receive 1 of the other suitable & available treatments that were being evaluated in the trial.
Primary outcome:
All-cause mortality within 28 days after randomization
Secondary outcomes:
The time until discharge from the hospital
Receipt of invasive mechanical ventilation (for those not receiving it at the time of randomization) or death.
Other pre-specified clinical outcomes:
Cause-specific mortality
Receipt of renal dialysis or hemofiltration
Major cardiac arrhythmia
Receipt & duration of ventilation
Results
11,303 patients underwent randomization (March 19 to June 8, 2020)
9355 (83%) were eligible to dexamethasone (drug available & no contraindication)
6425 randomized to either dexamethasone (2104) or usual care alone (4321)
The remaining patients were randomized to 1 of the other treatments in the trial.
Mean age: 66.1 +/-15.7 years
Female: 36%
18% Black, Asian, or from a minor ethnicity.
H/O diabetes: 24%
Heart disease: 27%
Chronic lung disease: 21%
56% have at least 1 major coexisting illness recorded
Laboratory-confirmed SARSCoV-2: 89%
16%: invasive mechanical ventilation or extracorporeal membrane oxygenation
Oxygen only: 60%
Primary Outcome
Dexamethasone group’s 28-day mortality rate was considerably reduced compared to the standard care group.
A trend towards greatest benefit those receiving invasive mechanical ventilation
In mechanical ventilated patients, the rate of death was lower in the dexamethasone group than it was in the usual care group.
No obvious impact of dexamethasone in those not receiving any respiratory support at the randomization
Patients getting invasive mechanical ventilation at randomization were 10 years younger than those not receiving any respiratory support & had symptoms for around 7 days longer before randomization.
Secondary Outcomes
Shorter duration of hospitalization in the dexamethasone group
A higher likelihood of discharge alive within 28 days in the dexamethasone arm
Other pre-specified outcomes
Transition to mechanical ventilation was lower in the dexamethasone arm among patients who were not receiving mechanical ventilation at randomization.
Cessation of invasive mechanical ventilation was more likely in the dexamethasone group.
Need for RRT was lower in dexamethasone group
The majority of deaths were caused by Covid-19, less fatalities in the dexamethasone group.
Deaths from other causes similar in both arms
Discussion
Dexamethasone led to lower 28-day mortality in those receiving invasive mechanical ventilation at randomization.
No proof of benefit of dexamethasone in those not receiving respiratory support at randomization
A subsequent meta-analysis (7 trials of glucocorticoids for critically ill patients with Covid-19, including RECOVERY), has confirmed the findings of this trial.
Dexamethasone linked to a lower risk of invasive ventilation among those who were getting oxygen or, for those who were already receiving invasive mechanical ventilation, a higher likelihood of successful discontinuation.
Dexamethasone increased the chance of discharge from the hospital alive within 28 days.
========================= 3.What is the level of evidence provided by this article?
Level 1b (Evidence obtained from at least one Randomized Trial)
Covid-19 is associated with diffuse lung damage, respiratory faliure and increased mortality
RECOVERY is a randomized trial assessing different treatment options for covid 19 and its effect on mortality including Lopinavir-Ritonavir, Hydroxychloroquine, Corticosteroids, Azithromycin, Colchicine, IV Immunoglobulin (children only), Convalescent plasma, Casirivimab+Imdevimab, Tocilizumab, Aspirin, Baricitinib, Infliximab, Empagliflozin, Sotrovimab, Molnupiravir, Paxlovid or Anakinra (children only).
The current study is a randomized control study (Level of evidence I) is evaluating the rule of dexamethasone in hospitalized patients with Covid-19 regarding mortality after 28 days
2 groups are randomly assigned, first group (2104 patients) received 10 days’ course of 6 mg oral or intravenous dexamethasone and the second group (4321 patients) received standard of case with no steroids
Results
Overall mortality after 28 days was 22.9% in the dexamethasone group and 25.7% in the standard of care group
Mortality in patients receiving mechanical ventilation was 23.3% in dexamethasone group compared to . 41.4% in the standard of care group
Mortality in patients receiving O2 but not mechanical ventilation was 29.3% in dexamethasone group compared to 26.2% in the standard of care group
Mortality in patients not receiving respiratory support (either O2 or mechanical ventilation) was 17.8% in dexamethasone group compared to 14% in the standard of care group
Conclusion
Dexamethasone therapy is effective in reducing mortality only in patients on respiratory support either O2 or mechanically ventilated and should be considered in these settings and should not be used in patients with no respiratory support
RECOVARY trial is assessing other arms of therapy of covid 19
Baricitinib (4 mg orally once daily for up to 14 days)
Baricitinib is JAK inhibitor used for treatment of RA.
It was found that baricitinib improves 28-days mortality in patients with severe disease requiring respiratory support either O2 or mechanical ventilation (12 % in treatment group versus 14% in usual of care group), around 95% of cases received this therapy was on corticosteroids, 20% were on remdesivir, and 23 % were on tocilizumab
Tofacitinib (10mg twice daily)
It is another JAK inhibitor.
It was found that baricitinib improves 28-days mortality and respiratory failure in patients with hospitalized covid 19 (18 % in treatment group versus 29% in usual of care group), most of patients was on corticosteroids.
Toclizumab (8 mg/kg as a single intravenous dose)
It is IL-6 pathway inhibitors
It was found that adding 1 to 2 doses of toclizumab improves 28-days mortality in patients with severe disease requiring respiratory support either O2 or mechanical ventilation (31 % in treatment group versus 35% in usual of care group), around 82% of cases received this therapy was on corticosteroids.
Anakinra (100 mg subcutaneously daily for 10 days)
It is IL-1 inhibitors
Anakinra increase recovery at 28 days (50.4 versus 26.5 %)
It is indicated if 3 of the followings are present : age ≥75 years, severe pneumonia, current or previous smoking, SOFA score ≥3, neutrophil-to-lymphocyte ratio ≥7, hemoglobin ≤10.5 g/dL, history of ischemic stroke, blood urea ≥50 mg/dL and/or medical history of renal disease
Remdesivir (200 mg intravenously on day 1 followed by 100 mg daily for 5-10 days total)
Remdesivir is a novel nucleotide analog that has in vitro activity against SARS-CoV-2
Remdesiver reduce mortality and progression to mechanical ventilation in only non-ventilated patients, while it was not significant in patietns who are receiving ventilator support
Other therapies with no clear benefit
Including aspirin, monoclonal antibodies , convalescent plasma, hydroxychloroquine , colchicine, lopinavir-ritonavir, interferon beta , and azithromycin show no clear benefit in the treatment of covid 19
I like your well-structured summary in great details, and conclusions. I appreciate level of evidence that you have allocated to this open labelled trial usage of steroids in patients of COVID19 requiring respiratory support.
One of the most feared complications of COVID-19 infection that could result in mortality is diffuse lung damage, and glucocorticoid has been known to regulate the inflammation-mediated lung injury
Methodology
It is a controlled open-labeled trial
The study comprised two groups of population with COVID-19 infection but randomized into those that received oral or I.V glucocorticoid for treatment, and those that received usual care
The primary outcome is 28-day mortality, and the secondary outcome is the time until discharge from the hospital
Written and informed consent were obtained from all the patient or their legal representatives
Eligible and consenting patients were assigned in a 2:1 ratio to receive either the usual standard of care alone or the usual standard of care plus oral or intravenous dexamethasone
Results
6425 underwent randomization to receive either dexamethasone (2104 patients) or usual care alone (4321 patients)
95% of the patients received at least one dose of glucocorticoid in the dexamethasone with the median duration of treatment for 7 days
. In the usual care group, 8% of the patients received a glucocorticoid as part of their clinical care
Primary outcomes
Mortality at 28 days was significantly lower in the dexamethasone group than in the usual care group, with deaths reported in 482 of 2104 patients (22.9%) and in 1110 of 4321 patients (25.7%), respectively.
There was no clear effect of dexamethasone on those not receiving any form of respiratory support
Secondary outcomes
Patients in the dexamethasone group had a shorter duration of hospitalization than those in the usual care group (median, 12 days vs. 13 days) and a greater probability of discharge alive within 28 days
Among those who were receiving invasive mechanical ventilation at randomization, successful cessation of invasive mechanical ventilation was more likely in the dexamethasone group than in the usual care group
Discussion
The use of 6mg dexamethasone for 10 days reduced the 28-day mortality than the usual care patient and was also confirmed by the RECOVERY trial
There was no evidence that dexamethasone provide any support among those not receiving any respiratory support
It is likely that the beneficial effect of glucocorticoids in severe viral respiratory infections is dependent on the selection of the right dose, at the right time, in the right patient.
High doses may be more harmful than helpful, as may such treatment given at a time when control of viral replication is paramount and inflammation is minimal
I like your well-structured summary in great details, and conclusions. I appreciate level of evidence that you have allocated to this open labelled trial usage of steroids in patients of COVID19 requiring respiratory support.
Introduction
· Coronavirus 2 (SARS-CoV-2) is the virus responsible for coronavirus disease 2019 (COVID-19) which is mainly a respiratory tract disease. It was discovered in China towards the end of 2019 and it was beloved to be a zoonotic disease.
· At the beginning of 202o the case fatality rate was 26% in UK and > 36% of patients required mechanical ventilation
· Remdesivir reduced recovery time in hospitalized patient but no treatment has been shown to decreased mortality
· Covid-19 causes diffuse alveolar damage, inflammation and microvascular thrombosis
· Glucocorticoid may modulate the intensity of inflammatory process and hence the development of acute respiratory failure and death Methodology
· This was randomized, open labelled control trial at 176 National Health Service organization in the UK
· All hospitalized patients due to COVID-19 were included, and those who were no suitable for randomization to dexamethasone were excluded.
· Participants were randomized to dexamethasone 6 mg once daily oral/IV for 10 days or usual care (lopinavir-ritonavir, hydroxychloroquine, & azithromycin)
· The primary outcome was 28-day mortality Results
· In this trial, 2014 were randomized to dexamethasone arm, and 4321 to the usual care
· In general, at 28-days, 23% death in dexamethasone arm and 26 % death in the usual care
· Patients on invasive mechanical ventilation: in these cohorts, the death rate was lower in those who were given dexamethasone versus the usual care (29% vs 41%)
· Patients on oxygen support without invasive mechanical ventilation: Again, dexamethasone had lower death rate (23% vs 26%
· However, the death rate was higher in the dexamethasone group in with patients not on any respiratory support at the time of randomization in comparison to usual care group (18%, 14% respectively) Conclusion
· The use of dexamethasone was associated with lower incidence of 28 -day mortality compared to standard care in a hospitalized patients who were receiving respiratory supports due to COVID-19
Please go through this paper well. It is an opportunity for us to learn togather how guidelines should developed, defined and validated in a scientific manner using real RCTs.
Using this paper, I would address some key features of a good trial. It amounts to side-tracking but there are good reasons here. This paper will generate discussion about trials and many good lessons learnt the way trials were conducted during COVID19 pandemic.
While I am not trying trash any approach or recommendations, I wish to use this short story of a ‘dog who lived on a railway platform’ (yes, it happens in Indian subcontinent).
I watched the events in India during COVID pandemic. A lot good happened but, at the same time, many illogical approaches were in vogue:
Please allow me to quote a short story highlighting the role of coincidences (rather than causations) in medical sciences specifically and in life in general.
#HCQS #Ivermectin #Doxycycline #Azithromycin #Favipiravir #Zinc #Vitamin C #Vitamin D #Plasma #IVIG # mega doses of steroids 40-60 mg of prednisone (or similar drugs) for many weeks as a blanket treatment for everyone (mild moderate and severe disease)
A dog lived at a railway station and he didn’t like the trains pulling over because it blocked his views.
As soon as the train would come to halt, he would start barking and lo and behold the train would start moving. He presented his data in a dog conference and all the attendees endorsed his views and they all concluded barking moves the train.
There however a wise dog was also there, he said just stand there and don’t bark and see what happens? They did, and the train moved without the barking!
Let’s add a twist. Further studies showed that out of approximately every 100 trains that passed by, 4 trains were delayed and stayed in the station longer but on continued barking, the train moved on. Only 1 train didn’t move because of engine failure and to be removed from service. Results: 99% of trains moved on when the dog barked.
Please do your own search and summarise the outcome of the different arms of the recovery trial.Aspirin: Aspirin did not reduce the 28-day mortality rate in COVID-19 patients who were hospitalized, the risk of dying or moving to invasive mechanical ventilation, but it did slightly raise the percentage of patients who were discharged alive after 28 days.Azithromycin: Azithromycin did not increase survival or any other predetermined clinical outcomes in individuals who were hospitalized with COVID-19. Patients with a clear antimicrobial indication should only be given azithromycin when they have been admitted to the hospital with COVID-19.Baricitinib: Baricitinib considerably decreased the risk of death in COVID-19 patients who were hospitalized, but the benefit was not as great as earlier studies had predicted. According to all available randomised evidence, JAK medicines (mostly baricitinib) lower mortality in COVID-19 patients who are hospitalized by around one-fifth.Colchicine: In adults hospitalised with COVID-19, colchicine was not associated with reductions in 28-day mortality, duration of hospital stay, or risk of progressing to invasive mechanical ventilation or death.Hydroxychloroquine: hydroxychloroquine group were less likely to be discharged from the hospital alive within 28 days than those in the usual-care group, the hydroxychloroquine group had a higher frequency of invasive mechanical ventilation or death Dexamethasone small dose and Dexamethasone high dose: improves patient status of health, high dose reported with higher death. Dimethyl fumarate: It was not associated with an improvement in clinical outcomes.
Casirivimab and imdevimab: In patients admitted to hospital with COVID-19, the monoclonal antibody combination of casirivimab and imdevimab reduced 28-day mortality in patients who were seronegative (and therefore had not mounted their own humoral immune response) at baseline but not in those who were seropositive at baseline.
Regeneron’s monoclonal antibody combination: It reduced 28-day mortality in patients who were seronegative (and therefore had not mounted their own humoral immune response) at baseline but not in those who were seropositive at baseline.
Tocilizumab: Tocilizumab enhanced survival and other clinical outcomes in COVID-19 patients with hypoxia and signs of systemic inflammation (C-reactive protein 75 mg/L).
Please summarise this article. Introduction: SARS-CoV-2, the cause of severe acute respiratory syndrome (Covid-19), emerged in China in late 2019 from a zoonotic source. It is characterized by an acute pneumonic process with extensive radiologic opacity and diffuse alveolar damage, inflammatoryinfiltrates, and microvascular thrombosis. Inflammatory organ injury may occur in severe Covid-19, with a subgroup of patients having markedly elevated levels of inflammatory markers. Several therapeutic interventions have been proposed to mitigate inflammatory organ injury, but the value of glucocorticoids has been widely debated.
Design: The RECOVERY trial was designed to evaluate the effects of potential treatments in patients hospitalized with Covid-19 at 176 National Health Service organizations in the United Kingdom. Inclusion criteria: Patients had clinically suspected or laboratory confirmed SARS-CoV-2 infection and no medical history that might put them at substantial risk. Written informed consent was obtained from all patients. Open labeled randomized trial, in a 2:1 ratio to receive either the usual standard of care or dexamethasone for 10 days. Patients excluded are (dexamethasone was unavailable at the hospital at the time of enrollment or was considered by the managing physician to be either definitely indicated or definitely contraindicated). Procedure and outcomes: A single online follow-up form was completed to record adherence to treatment, duration of admission, respiratory support, renal dialysis, and vital status. Primary outcome was all-cause mortality within 28 days after randomization; secondary outcomes were time until discharge, subsequent receipt of invasive mechanical ventilation, cause-specific mortality, renal dialysis or hemofiltration, major cardiac arrhythmia, and receipt and duration of ventilation. Results: The 11,303 patients who underwent randomization from March 19 to June 8, 2020 were eligible to receive dexamethasone (83%) or usual care alone (4321 patients). The mean (±SD) age of the patients was 66.1±15.7 years, 36% were female, and 18% were Black, Asian, or from a minority ethnic group. 89% had laboratory-confirmed SARSCoV-2 infection, 16% were receiving invasive mechanical ventilation or extracorporeal membrane oxygenation, 60% were receiving oxygen only (with or without noninvasiveventilation), and 24% were receiving neither. 95% of the patients received at least one dose of a glucocorticoid, and the median duration of treatment was 7 days. After remdesivir became available in the UK on May 26, 2020, the drug was administered to 3 patients before randomization and 2 patients during the follow-up period. Outcomes: Mortality at 28 days was significantly lower in the dexamethasone group than in the usual care group, with deaths reported in 482 of 2104 patients (22.9%) and 1110 of 4321 patients (25.7%). In a prespecified analysis according to the level of respiratory support that the patients were receiving at randomization, there was the greatest absolute and proportional benefit among patients who were receiving invasive mechanical ventilation (P<0.001) and those receiving oxygen without invasive mechanical ventilation. The results were similar in a post hoc exploratory analysis restricted to the 5744 patients (89.4%) with a positive SARS-CoV-2 test result. Sensitivity analyses without adjustment for age resulted in similar findings. Patients with invasive mechanical ventilation at randomization were on average 10 years younger than those not receiving any respiratory support and had a history of symptoms before randomization for an average of 7 days longer. Patients in the dexamethasone group had a shorter duration of hospitalization and a greater probability of discharge alive within 28 days, with the greatest effect seen among those receiving invasive mechanical ventilation at randomization. The dexamethasone group had a lower risk of progression to invasive mechanical ventilation than the usual care group, and successful cessation of invasive mechanical ventilation was more likely. Most deaths were due to Covid-19, and the incidence of death from other causes was similar. There were four reports of serious adverse reactions, two of hyperglycemia, one of gastrointestinal hemorrhage, and one of psychosis. Discussion: he RECOVERY trial found that the use of dexamethasone for up to 10 days resulted in lower 28-day mortality than usual care in patients who were receiving invasive mechanical ventilation at randomization and those who were receiving oxygen without invasive mechanical ventilation. However, there was no evidence of any benefit among patients who were not receiving respiratory support at randomization, and the results were consistent with possible harm in this subgroup. The protocol combines the methods used in large, simple trials of treatments for acute myocardialinfarction in the 1980s with the opportunities provided by digital health care in the 2020s. Preliminary results for dexamethasone were announced on June 16, 2020, and were adopted into U.K. practice later the same day.
Glucocorticoids have been widely used in severe viral respiratory infections, but the evidence to support their use is weak due to lack of data from sufficiently powered randomized, controlled trials. The greater mortality benefit of patients with Covid-19 who are receiving respiratory support and after the first week of their illness suggests that at that stage the disease may be dominated by immunopathological elements, with active viral replication playing a secondary role.
Conclusion: The RECOVERY trial found that dexamethasone at a dose of 6 mg once daily for up to 10 days reduces 28-day mortality in patients with Covid-19 who are receiving respiratory support.
What is the level of evidence provided by this article?Level of evidence I – Randomized control trial.
II. Dexamethasone in Hospitalized Patients with Covid-19
=================================================================== Outcome of the different arms of the recovery trial.
The RECOVERY trial evaluated the effects of potential treatments in patients hospitalized with Covid-19 at 176 National Health Service organizations in the UK, supported by the National Institute for Health Research Clinical Research Network.
The trial continues randomization to other treatments, including REGN-COV2, aspirin, colchicine, or usual care.
Hospitalized patients were eligible for the trial if they had clinically suspected or laboratory confirmed SARS-CoV-2 infection and no medical history.
The trial was conducted in accordance with Good Clinical Practice guidelines and approved by the U.K. Medicines and Health-care Products Regulatory Agency.
Funders had no role in the analysis of data, preparation or approval of the manu-script, or decision to submit it for publication.
Randomization was performed using a Web-based system with concealment of the trial-group assignment.
Eligible and consenting patients were assigned either the usual standard of care alone or dexamethasone.
The randomly assigned treatment was prescribed by the treating clinician, and patients and local members of the trial staff were aware of it.
Procedures
A single online follow-up form was completed to record adherence to treatment, receipt of other treatments, duration of ad-mission, respiratory support, renal dialysis, and vital status.
The primary outcomewas all causemortality within 28 days after randomization, with secondary outcomes such as time until discharge, receipt of renal dialysis, major cardiac arrhythmia, and ventilation.
The trial steering committee determined that at least 2000 patients in the dexamethasone group and 4000 in the usual care group would provide a power of 90% at a two sided P value of 0.01 to detect a clinically relevant proportional reduction of 20%.
Cox regression was used to estimate 28-day mortality rate ratio, Kaplan-Meier survival curves were constructed to show cumulative mortality, and logbinomial regression models were used to estimate risk ratios for noninvasive or invasive mechanical ventilation and renal replacement therapy.
The mean age was 1.1 years older among patients in the dexamethasone group than those in the usual care group, so estimates of rate and risk ratios were adjusted for the baseline age in three categories (<70 years, 70 to 79 years, and ≥80 years).
Results without age adjustment (corresponding to the first version of the analysis plan) are provided in the Supplementary Appendix.
All analyses were performed according to the intention to treat principle.
Primary Outcome
Mortality at 28 days was significantly lower in the dexamethasone group than in the usual care group, with deaths reported in 482 of 2104 patients (22.9%) and 1110 of 4321 patients (25.7%).
In a prespecified analysis according to the level of respiratory support that the patients were receiving at randomization, there was a trend showing the greatest absolute and proportional benefit among patients who were receiving invasive mechanical ventilation (11.8% vs. 14.4%; rate ratio, 0.83; 95% confidence interval [CI], 0.75 to 0.93).
However, there was no clear effect of the drug on patients who were not receiving any respiratory support at randomization.
Post hoc exploratory analysis restricted to the 5744 patients with a positive SARS-CoV-2 test result resulted in similar findings.
Dexamethasone was associated with a reduction in 28-day mortality among those with symptoms for more than 7 days, but not among those with a more recent symptom onset.
Secondary Outcomes
Patients in the dexamethasone group had a shorter duration of hospitalization and a greater probability of discharge alive within 28 days, with the greatest effect seen among those receiving invasive mechanical ventilation at randomization.
Other Prespecified Clinical Outcomes
The dexamethasone group had a lower risk of progression to invasive mechanical ventilation than the usual care group, and renal-replacement therapy was more likely to be received within 28 days.
Most deaths were due to Covid-19, and the incidence of death from other causes was similar.
There were four reports of serious adverse reactions, two of hyperglycemia, one of gastrointestinal hemorrhage, and one of psychosis.
==================================================================== Please summarise this article.
Covid-19 is a zoonotic cause of severe acute respiratory syndrome (SARS-CoV-2) that can progress to critical illness with prolonged ventilatory support.
Remdesivir has been shown to shorten recovery, but no therapeutic agents have been shown to reduce mortality.
The pathophysiology of severe Covid-19 is dominated by an acute pneumonic process with extensive radiologic opacity and diffuse alveolar damage, inflammatory infiltrates, and microvascular thrombosis.
Inflammatory organ injury may occur in patients with markedly elevated levels of inflammatory markers, and glucocorticoids have been proposed to mitigate this. However, there is uncertainty about their effectiveness.
==================================================================== Methods Trial Design and Oversight
The RECOVERY trial was designed to evaluate the effects of potential treatments in patients hospitalized with Covid-19 at 176 National Health Service organizations in the United Kingdom.
Patients were eligible for the trial if they had clinically suspected or laboratory-confirmed SARS-CoV-2 infection and no medical history that might put them at substantial risk.
Written informed consent was obtained from all patients or from a legal representative if they were unable to provide consent.
The trial was conducted in accordance with the principles of the Good Clinical Practice guidelines of the International Conference on Harmonisation and approved by the U.K.
Medicines and Healthcare Products Regulatory Agency and the Cambridge East Research Ethics Committee.
The initial version of the manuscript was drafted by the first and last authors, developed by the writing committee, and approved by all members of the trial steering committee.
Results Patients
11,303 patients underwent randomization from March 19 to June 8, 2020 to receive dexamethasone or usual care alone.
The mean age of the patients was 66.1±15.7 years, 36% were female, and 18% were Black, Asian, or from a minority ethnic group.
89% had laboratory-confirmed SARS-CoV-2 infection, 16% were receiving invasive mechanical ventilation or extra-corporeal membrane oxygenation, 60% were re-ceiving oxygen only (with or without noninvasive ventilation), and 24% were receiving neither.
95% of the patients received at least one dose of a glucocorti-coid, and the median duration of treat-ment was 7 days.
Remdesivir was administered to 3 patients before and 2 during follow-up.
The use of dexamethasone for up to 10 days resulted in lower 28-day mortality than usual care in patients receiving invasive mechanical ventilation and oxygen without invasive mechanical ventilation.
It also increased the chance of being discharged from the hospital alive within 28 days.
The RECOVERY trial was designed to assess the effect of readily available potential treatments for Covid-19 on 28-day mortality, with 10% of all hospitalized patients enrolled and mortality consistent with the overall case fatality rate.
Glucocorticoids have been widely used in SARS, MERS, severe influenza, and community-acquired pneumonia, but the evidence to support or discourage their use has been weak.
The RECOVERY trial provides evidence that treatment with dexamethasone at a dose of 6 mg once daily for up to 10 days reduces 28-day mortality in patients with Covid-19 who are receiving respiratory support and among those recruited after the first week of their illness.
This suggests that at that stage the disease may be dominated by immuno-pathological elements, with active viral replication playing a secondary role.
28 days mortality significantly reduced in the dexamethasone group
Vital status
a) Age-adjusted mortality 21.6% vs 24.6%. b) When not adjusted for the age imbalance in the baseline the result was similar.
The rate ratio is closely related to the risk ratio and is computed as the ratio of the incidence rate in the dexamethasone group divided by the incidence rate in the usual care group.
2. Secondary outcome (dexamethasone vs usual care)
Pre-specified subgroups
a) Mechanically ventilated; 28 days mortality- significantly reduced in dexamethasone group; I) 29% vs 40.7%. II) Mechanically ventilated patients were on average 10 days younger than those not receiving respiratory support and were randomized on average 7 days later after symptom onset than those not receiving support. b) Patients receiving O2; 28 days mortality – significantly reduced in the dexamethasone group I) 21.5% vs 25%. c) Patients not receiving respiratory support; no significant difference I) 17% vs 13.2%. d) Time from symptoms onset to randomization influenced outcome, dexamethasone was associated with a reduction in 28 days mortality among those with symptoms for > 7 days but not among those with symptoms for < 7 days.
Length of the hospital stay- significantly reduced in the dexamethasone group
a) median 12 days vs 13 days.
The composite secondary outcome of invasive mechanical ventilation and death- was significantly reduced in the dexamethasone group.
a) rate ratio 0.91.
Use of ventilation- significantly reduced in the dexamethasone group
a) Rate ratio 0.76.
Use of renal dialysis or hemofiltration; not reported.
Documented new major cardiac arrhythmia (including atrial and ventricular arrhythmia).
Summary of the Article The primary outcome
11,303 patients were recruited
a) 1948 were excluded. b) 357 did not have dexamethasone available. c) 1707 were not considered suitable for randomization to dexamethasone.
9355 underwent randomization between dexamethasone and other treatments.
a) 2930 were assigned to receive other active treatment b) 1183 were assigned to receive lopinavir-ritonavir c) 1172 were assigned to receive hydroxychloroquine. d) 575 were assigned to receive azithromycin.
6425 underwent randomization between dexamethasone and usual care alone.
a) 2104 were assigned to receive dexamethasone, 1996/2095 receive dexamethasone I) 95 proceed to the second randomization II) 2104 were included in the 28-day intension-to-treat analysis. b) 4321 were assigned to receive usual care alone, 347/4306 receive dexamethasone I) 276 proceed to the second randomization. II) 4321 were included in the 28-day intention-to-treat analysis
Mortality at 28 days was significantly lower in the dexamethasone group than in the usual care group, with death reported in 482 of 2104 patients and 1110 of 4321 patients, respectively.
The secondary outcome
Discharged from the hospital within 28 days 1416/2104 in dexamethasone group, 2748/4321 in the usual care group.
Invasive MV or death; 462/1780 in the dexamethasone group. 1003/3638 in the usual care group.
Invasive MV 110/1780 in the DEXA group, 298/3638 in the usual care group.
Death 387/1780 in the DEXA group, 827/3638 in the usual care group.
Patients in the DEXA group had a shorter duration of hospitalization and a greater probability of being discharged alive within 28 days.
Invasive MV or death was lower in the DEXA group.
Level of evidence Level ((I)) References
Horby P Lim WS et al.The Recovery Collaborative Group
Dexamethasone in hospitalized patients with Covid-19—preliminary report.
N Engl J Med. 2020; (published online July 17.)
A living WHO guideline on drugs for covid-19.
BMJ. 2020; 370m337
3.Dequin PF Heming N Meziani F et al.
Effect of hydrocortisone on 21-day mortality or respiratory support among critically ill patients with COVID-19: a randomized clinical trial.
JAMA. 2020; 324: 1298
4.Tomazini BM Maia IS Cavalcanti AB et al.
Effect of dexamethasone on days alive and ventilator-free in patients with moderate or severe acute respiratory distress syndrome and COVID-19: the CoDEX randomized clinical trial.
This is an open-label randomized controlled trial comparing treatment possibilities for patients hospitalized for COVID-19.
Level of Evidence I
Introduction
SARS-CoV 2 has led to severe lung disease all over the planet with alveolar damage and compromised respiratory and systemic conditions.
Inflammatory disease is different from viral pathologies, including Influenza.
Methods
Randomized double-blind study using data from 176 national health services in the United Kingdom with the University of Oxford team comparing a range of medications and their effectiveness.
Primary Endpoint – 28-day mortality Secondary Objectives – duration of ECMO mechanical ventilation, specific mortality, dialysis, arrhythmias, and other manifestations.
All data were collected until December 2020 (all unvaccinated patients).
Results
11,303 patients with a mean age of 66.1 years. Of these, 6,425 were randomized to Dexamethasone (2,104) or standard treatments (4,321). 16% on mechanical ventilation, 60% on oxygen therapy, and 24% without the need for O2.
28-day mortality was lower in the dexamethasone group 22.9% vs. 25.7% (OR 0.83).
Mechanical ventilation 29.3 x 41.4% (OR 0.64), oxygen therapy 23.3 x 26.2% (OR 0.82).
There was no statistical difference or benefit for patients not requiring oxygen therapy.
In secondary outcomes, patients in the dexamethasone group had a shorter hospital stay and a greater chance of being discharged alive.
– Invasive mechanical ventilation OR 0.79
– Use of non-invasive ventilation OR 0.77
– Successful extubation OR 1.47
– Dialysis OR 0.61
Discussion
The RECOVERY Study shows the impact of dexamethasone on patients in need of oxygen therapy and its impact on minimizing the risks of severity established by the disease. The dose of 6mg for ten days proved to be effective in reducing mortality and complications.
1- Outcome of different arms of Recovery trial
RECOVERY trial recommended
· stopping colchicine arm due to it’s inefficiency in hospitalized cases with COVID-19.
· No clinical benefit from hydroxychloroquine adminstartion in hospitalised COVID-19 cases.
· dexamethasone as anti-inflammatory agents have positive impact on survival for severe COVID-19 cases if used early at the correct time ,while dexamethasone decreased mortality rate by 1/3.
· Lopinavir had no significant effect on mortality rate due to COVID-19
· Aspirin can prevent blood clots, those cases are at higher risk of thromboembolic manifestations . It is also cheap and available
· Convalescent plasma have not shown enough benefits in COVID-19 therapy
· Azithromycin did not show any clinical benefits
· Tocilizumab lowered mortality rate in hospitalised cases with severe COVID -19 infection.
· Baricitinib reduced mortality in hospitalised severe COVID-19 cases.
· Sotrovimab as a monoclonal antibody for treatment of early mild COVID cases to decrease the need of hospitalisation
· Molnupiravir as an antiviral drug doesn’t prevent COVID-19 hospitalizations or deaths in high-risk, nonhospitalized, vaccinated patients but can speed recovery.
· paxlovid an antiviral treatment was used to treat cases of early COVID with high risk of deterioration but it’s unknown if it can benefit hospitalised cases with COVID-19.
· Dimethyl fumarate did not enhance recovery for COVID 19 hospitalised cases.
· Regeneron’s monoclonal antibody combination decreased death rate in hospitalised COVID cases
· Empagliflozin The recent DARE-19 trial demonstrated but inconclusivly that SGLTSI can decraese the risk of lung, heart, and kidney injury or death in patients hospitalised with COVID-19. By including empagliflozin in a much larger comparison within the RECOVERY trial, can determine whether this promising or not.
2-Summary Introduction
Covid 19 that first appeared in China presented with acute pneumonic features that can lead to respiratory failure with high fatality rate.
The extensive radiologic opacity , diffuse alveolar damage, inflammatory
infiltrates, and microvascular thrombosis revealed the severe inflammatory response confirmed with elevated inflammatory markers.
Meanwhile steroids role was controversial.
Glucocorticoids use was not recommended except in severe cases Methods
This trial evaluate the IV dexamethasone with usual treatment or oral dexamethasone therapy with usual treatment or usual treatment only for 10 days in hospitalized patients with Covid-19.
The primary outcome was all-cause mortality within 28 days.Secondary
outcome was the discharge time from the hospital. Results
2104 patients received dexamethasone and 4321 received usual care. 22.9% in the dexamethasone group and 25.7% in the usual care group died within 28 days after randomization.
Mortality between groups varied according to the level of respiratory support needed. Incidence of death was less in the dexamethasone group than that in the usual care group among patients who had invasive mechanical ventilation and those receiving oxygen without invasive mechanical ventilation and not among those who did not need respiratory support. Discussion
Among hospitalized patients with Covid-19 ,dexamethasone use for 10 days decreased 28-day mortality rate compared to usual care in cases receiving invasive mechanical ventilation and those received oxygen supply particularly for cases receiving treatment for more than 7 days due to injurious inflammatory response in the lung but did not reveal any benefit for cases not on oxygen supply.
Also dexamethasone administration was associated with a lower risk of invasive mechanical ventilation or for cases whom received invasive mechanical ventilation, a better outcome of being weaned off the ventilator.
In concordance with Recovery trial which demonstrated that
Dexamethasone use at a dose of 6 mg once daily for 10 days reduces 28-day mortality in Covid-19 cases receiving respiratory support.
On the other hand glucocorticoid dos e, disease severity and medical conditions were heterogenous.
The mortality benefit of dexamethasone in Covid-19 cases receiving respiratory support and among those engaged after the first week of their illness suppose that at that stage the disease may be dominated by immunopathological effects can be dominant while active viral replication has a secondary role. Conclusion
Dexamethasone intake resulted in lower 28-day mortality in hospitalised cases among those who had either invasive mechanical ventilation or oxygen alone but not among those without respiratory support but dexamethasone did not show any benefit for cases who did not need respiratory support .
Please do your own search and summarise the outcome of the different arms of the recovery trial.
The clinical experiment resulted in the revelation, which was made within only a few short months, that the steroid dexamethasone reduced the risk of mortality in ventilated patients by a third.
Patients diagnosed with Covid-19 who are hospitalized in the UK and elsewhere are now being given the steroid as part of their treatment. In addition, the researchers discovered that four medicines (lopinavir-ritonavir, hydroxychloroquine, azithromycin, and convalescent plasma) did not give any therapeutic benefit.
This enables healthcare practitioners to direct their attention away from these treatments and toward others. Tocilizumab, an anti-inflammatory medication, the monoclonal antibody therapy developed by Regeneron, aspirin, and colchicine are all now being tested as part of the ongoing experiment. The trial is scheduled to conclude in January 2021. (an anti-inflammatory treatment used for gout).
Please summarise this article.Introduction:
In late 2019, zoonotic SARS-CoV-2, which causes COVID-19, developed in China.
Most COVID-19 instances are asymptomatic or mild. Nevertheless, a significant number of individuals develop a respiratory illness necessitating hospitalization,2 and such infections may progress to severe disease with hypoxemic respiratory failure needing extended ventilatory support. 3-6 In the first half of 2020,-26% of UK hospitalized Covid-19 patients died, and 37% of those receiving invasive mechanical ventilation died.
Method:
In this controlled, open-label study evaluating a variety of therapies for hospitalized COVID-19 patients, we randomly assigned patients to receive oral or intravenous dexamethasone (6 mg once daily) for up to 10 days or for normal care alone. 28-day mortality was key.
RESULTS
2104 patients received dexamethasone and 4321 received standard care. 482 dexamethasone patients (22.9%) and 1110 usual care patients (25.7%) died within 28 days after randomization.
Patients’ respiratory assistance at randomization affected death proportionally and absolutely. In the dexamethasone group, the incidence of death was lower than in the usual care group among patients receiving invasive mechanical ventilation and oxygen without invasive mechanical ventilation but not among those receiving no respiratory support at randomization.
CONCLUSIONS
In patients hospitalized with COVID-19, the use of dexamethasone resulted in lower 28-day mortality among those who were receiving either invasive mechanical ventilation or oxygen alone at the time of randomization. However, this was not the case for patients who were receiving no respiratory support at the time of randomization.
What is the level of evidence provided by this article?level 1
Tocilizumab reduce death in hospitalized severe COVID-19 patients
Baricitinib reduce death & reduce progression of invasive mechanical ventilator(IMV).
Aspirin didn’t improve survival.
Convalescent plasma didn’t improve survival or other clinical outcome
Regenerons monoclonal antibodies combination reduce death for hospitalized patients who have not mounted their own immune response.
Summary:
Introduction:
Majority of COVID-19 patients either asymptomatic or presented with mils symptoms.
Large percentage of patient need hospital admission mainly due to respiratory symptoms which can progressed to hypoxia & respiratory failure & need for IMV.
IN UK 2020, mortality was 26% and >37% of patients need IMV.
Remdesivir reduce hospital stay, but no drug reduce mortality.
CRP, ferritin , IL-1 & IL-6 were high in COVID-19 patients.
Method:
Controlled open-label randomized trial.
9355 patients underwent randomization between dexamethasone & other treatment.
6425 patients randomized between dexamethasone & usual care alone(2104 patients in dexamethasone group & 4321 in usual care group).
Included suspected or diagnosed COVID-19 hospitalized patient including pregnant & breast feeding females.
Patients assigned with 2:1 ratio to receive usual standard care alone or usual standard care with oral or IV dexamethasone(6 mg for 10 days) or receive one of other citable & available treatment evaluated in trial.
Patient didn’t receive dexamethasone (due to unavailability) excluded from randomization.
Primary outcome was all cause mortality within 28 days after randomization(other analysis specified at 6 months).
Secondary outcome: time until discharge from hospital & among patients not receive IMV at time of randomization, subsequent receipt of IMV or death.
Other pre-specified clinical outcome include cause specific mortality, receipt of renal dialysis or hemofiltration, major cardiac arrhythmia & recent & duration of ventilation.
Result & discussion:
28 days mortality reduced in patients used dexamethasone for 10 days (in patients on IMV or patients need oxygen with or without IMV).
No evidence of benefit from steroid among patients not receive respiratory support & it may cause harm.
Benefit was clear in patients who use steroid >7 days after symptoms onset(common lung damage).
Dexamethasone used to reduce risk of IMV in patients receive oxygen & in patients on IMV increase chance of cessation & discharge from hospital life within 28 days.
Mortality in usual care group was consistent with over all case fatality rate for hospitalized COVID-19 patients in UK at time of dexamethasone comparison was active.
Dexamethasone results released at June16,2020(<100 days after protocol first drafted) & adopted in UK practice at same day.
Corticosteroid widely used in SARS, MERS, severe influenza & community acquired pneumonia .
Beneficial effect of steroid depends on right dose, right time & right patients.
High dose steroids may be more harmful than helpful.
Viral replication of COVID-19 high in early stage of disease, so beneficial effect of steroid after 1 week may be due to immunopathological element.
Guidelines update to recommend use of steroids in hospital patients with COVID-19 need O2 with or without need of IMV.
Please do your own search and summarise the outcome of the different arms of the recovery trial. Aspirin (1)
Dose used 150 mg od
It not associated with reductions in 28 day mortality or in the risk of progressing to invasive mechanical ventilation or death. It was associated with a small increase in the rate of being discharged alive within 28 days. (median 8 days, IQR 5 to >28, vs 9 days, IQR 5 to >28) subtle difference
Azithromycin (2)
Dose: azithromycin 500 mg once per day by mouth or intravenously for 10 days or until discharge
It did not improve survival or other prespecified clinical outcomes
Baricitinib (3)
Baricitinib significantly reduced the risk of death but the size of benefit was somewhat smaller than that suggested by previous trials. The total randomised evidence to date suggests that JAK inhibitors (chiefly baricitinib) reduce mortality in patients hospitalised for COVID-19 by about one-fifth.
Colchicine (4)
Dose 1 mg after randomisation followed by 500 μg 12 h later and then 500 μg twice a day by mouth or nasogastric tube for 10 days in total or until discharge
It was not associated with reductions in 28-day mortality, duration of hospital stay, or risk of progressing to invasive mechanical ventilation or death.
Convalescent Plasma (5)
high-titre convalescent plasma did not improve survival or other prespecified clinical outcomes.
Dexamethasone small dose (6)
oral or intravenous dexamethasone (at a dose of 6 mg once daily) for up to 10 days
The use of dexamethasone resulted in lower 28-day mortality among those who were receiving either invasive mechanical ventilation or oxygen alone at randomization but not among those receiving no respiratory support.
Dexamethasone high dose (7)
(dexamethasone 20 mg once daily for 5 days followed by 10 mg once daily for 5 days or until discharge if sooner)
clinical hypoxia but requiring either no oxygen or simple oxygen only, higher dose corticosteroids significantly increased the risk of death compared to usual care, which included low dose corticosteroids.
Dimethyl fumarate (8)
DMF 120mg twice daily for 2 days followed by 240mg twice daily for 8 days, or until discharge if sooner
It was not associated with an improvement in clinical outcomes.
Hydroxychloroquine (9)
The results suggest that patients in the hydroxychloroquine group were less likely to be discharged from the hospital alive within 28 days than those in the usual-care group (59.6% vs. 62.9%; rate ratio, 0.90; 95% CI, 0.83 to 0.98). Among the patients who were not undergoing mechanical ventilation at baseline, those in the hydroxychloroquine group had a higher frequency of invasive mechanical ventilation or death
Lopinavir-Ritonavir results (10)
lopinavir–ritonavir (400 mg and 100 mg, respectively) by mouth for 10 days or until discharge
lopinavir–ritonavir was not associated with reductions in 28-day mortality, duration of hospital stay, or risk of progressing to invasive mechanical ventilation or death. These findings do not support the use of lopinavir–ritonavir for treatment of patients admitted to hospital with COVID-19.
It is non-competing monoclonal antibodies that bind to two different sites on the receptor binding domain of the SARS-CoV-2 spike glycoprotein, blocking viral entry into host cells.
Dose: casirivimab 4 g and imdevimab 4 g administered together in a single intravenous infusion.
It reduced 28-day mortality in patients who were seronegative (and therefore had not mounted their own humoral immune response) at baseline but not in those who were seropositive at baseline.
Tocilizumab (12)
Dose tocilizumab at a dose of 400 mg–800 mg (depending on weight) given intravenously. A second dose could be given 12–24 h later if the patient’s condition had not improved
COVID-19 patients with hypoxia and evidence of systemic inflammation (C-reactive protein ≥75 mg/L), tocilizumab improved survival and other clinical outcomes. These benefits were seen regardless of the amount of respiratory support and were additional to the benefits of systemic corticosteroids.
References:
Abani, Obbina, et al. “Aspirin in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial.” The Lancet 399.10320 (2022): 143-151.
Abaleke, Eugenia, et al. “Azithromycin in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial.” The Lancet 397.10274 (2021): 605-612.
Abani, Obbina, et al. “Baricitinib in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial and updated meta-analysis.” The Lancet 400.10349 (2022): 359-368.
RECOVERY Collaborative Group. “Colchicine in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial.” The Lancet Respiratory Medicine 9.12 (2021): 1419-1426.
Abani, Obbina, et al. “Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial.” The Lancet 397.10289 (2021): 2049-2059.
RECOVERY Collaborative Group. “Dexamethasone in hospitalized patients with Covid-19.” New England Journal of Medicine 384.8 (2021): 693-704.
RECOVERY Collaborative Group, et al. “Higher dose corticosteroids in hospitalised COVID-19 patients with hypoxia but not requiring ventilatory support (RECOVERY): a randomised, controlled, open-label, platform trial.” medRxiv (2022): 2022-12.
RECOVERY Collaborative Group, et al. “Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial.” medRxiv (2022): 2022-09.
RECOVERY Collaborative Group. “Effect of hydroxychloroquine in hospitalized patients with Covid-19.” New England Journal of Medicine 383.21 (2020): 2030-2040.
Horby, Peter W., et al. “Lopinavir–ritonavir in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial.” The Lancet 396.10259 (2020): 1345-1352.
RECOVERY Collaborative Group. “Casirivimab and imdevimab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial.” Lancet (London, England) 399.10325 (2022): 665.
RECOVERY Collaborative Group. “Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial.” Lancet (London, England) 397.10285 (2021): 1637.
Summary of the article RCT open label multicentral trial Population: Hospitalized patients with COVID-19 Intervention: Dexamethasone, a corticosteroid Comparison: Standard care without dexamethasone Outcome: Reduction in mortality rate among patients requiring respiratory support The study found that dexamethasone reduced mortality rates among patients who required mechanical ventilation by one-third and reduced mortality rates among patients who required oxygen therapy by one-fifth. However, there was no benefit of dexamethasone among patients who did not require respiratory support.
That was one of many treatments driven by ‘impression-based medicine’: high-titre convalescent plasma did not improve survival or other prespecified clinical outcomes.
The use of corticosteroid [both dexamethazon and methylprednisolon], was shown to improve survival rate and recovery for patients infected with Covid-19 causing severe pneumonia leading to respiratory failure treated with assisted ventilation particularly those in need for endotracheal intubation and ventilatory support.
in Recovery trial , adminstration of dexamethazon of 6 mg for 10 days was associated with improvement of 28 days mortality rate for patient on ventilatory support and endotracheal intubation.
However, it was reported to be linked to worse outcome with higher mortality for patients with covid pneumia without respiratory failure.
This conclusion might be reflecting the incidence and impotence of immunologic hyper-reactive syndrome with detrimental consequences in patients on ventilators. hence the maximum benefit gained from using steroid therapy.
On the contrary, in patients with Covid pneumonia without respiratory failure are featuring normal response of immune system, therefore, administration of steroid is of no use, or negatively impacting the immune system, rendering the patient at higher risk of propagation and worsening of the outcome.
The common recommendations stemmed from several studies were consistent on adminstering Corticosteroid for patients who are diagnosed with covid 19 pneumonia, and in need for
1] high O2 flow.
2] Non invasive ventilation.
3] mechanical ventilation.
4] ECMO.
In an article published in JAMA 2023, Ahmed Murad et al concluded the same finding discovered by Recovery study. with main conclusion of reducing the odds associated with COVID 19 pneumonia of mortality and discharge to hospice in those on need for O2 supply and ventilatory support.
level of evidence 1
1. Please do your own search and summarise the outcome of the different arms of the recovery trial.The RECOVERY trail was the world’s largest clinical trial into treatment for COVID, there are >40000 participants across 185 trails sites in the UK. It was demonstrated that dexa saved around 22000 COVID infected patients.The trail has identified four treatment for sever COVID patients, For COVID Sotrovimab, that is anti-spike protein monoclonal antibody and two other antiviral treatment (molnupiravir and paxlovid).For influenza, the Osltamivir and Baloxavir and low dose of steroids. It was demonstrated that web-based randomization to give treatment for COVID.Patient were allocated randomly to treat the eligible COVID proven patients. The collected data using a web- based case report and included demographic data.Eligible and consenting patient were assigned in a 2:1 ratio.One with standard dose of dexa for up-to 10 days, while other until admitted and discharged from hospital.The primary outcomes was all cause mortality within 28 days after randomization, and further analysis were extended at six months.Secondary outcomes, the dexa group had shorter duration of hospitalization, other clinical outcomes decrease need of mechanical ventilation.2. Please summarise this article.Background; coronavirus disease is associated with diffuse lung damage.Method; this is a controlled open label trail comparing a range of possible treatment in patient infected with COVID, patient were randomly assigned to receive oral or IV dexamethasone. Primary outcomes was 28-day mortality.Result ; total of 2104 patient were assigned to receive dexa and 4321 to receive usual care, in 482 in the dexa, and 1110 from usual group died with in the 28 days after randomization.Conclusion; those patient hospitalized with infected COVID, primary outcome was 28 days mortality, those who were receiving mechanical ventilation alone or oxygen alone. 3. What is the level of evidence provided by this article?Level I
1. Please do your own search and summarise the outcome of the different arms of the recovery trial.
The recovery trial(Randomized Evaluation of Covid-19 Therapy) examined various treatments outcomes in hospitalized COVID-patients. 22.9% of those received dexamethasone died within 28 days. 25.7% of those received the normal standard of care passed away within 28 days of the randomization.
2. Please summarise this article.
RCT , oper label trial, of patients with COVID19 who were randomly assigned to receive oral or intravenous dexamethasone or to receive usual care alone. 2104 patients in the dexamethasone group and 4321 in the usual care group . In the dexamethasone group, the incidence of death was lower than that in the usual care group among patients receiving invasive mechanical ventilation or oxygen without invasive mechanical ventilation
3. What is the level of evidence provided by this article?
RCT is level 1
Please do your own search and summarise the outcome of the different arms of the recovery trial
The RECOVERY Study has identified 4 treatments for severe COVID-19, & it is presently evaluating the following suggested treatments to see if they are more successful at promoting recovery than the standard therapy that all patients receive:
For COVID-19
For influenza
Randomized allocation of treatment for COVID-19
Randomization part E
Randomization part F:
Randomization part J (UK only):
Randomization part K:
Randomization part L (UK only):
References
Please summarize this article.
Methodology
Eligibility for the trial
Primary outcome:
Secondary outcomes:
Other pre-specified clinical outcomes:
Results
Primary Outcome
Secondary Outcomes
Other pre-specified outcomes
Discussion
What is the level of evidence provided by this article?
RECOVERY Trial (Randomised Evaluation of Covid-19 Therapy)
Background
SARS-CoV-2 infection cause diffuse alveolar injury, inflammatory infiltrates, and microvascular thrombosis. Glucocorticoids modulates inflammation-mediated lung injury, and may slow progression to respiratory failure and mortality.
Methods
The study examined various treatments outcomes in hospitalized COVID-patients in UK.
Clinically suspected SARS-CoV-2 infection or RTPCR-confirmed cases were enrolled, randomized to receive standard care alone or oral / intravenous dexamethasone 6mg OD for up to 10 days (or until discharge from hospital, whichever is earlier).
Primary outcome: death (from any cause) within 28 days of randomization.
Secondary outcomes include length of hospital stay; requirement of invasive mechanical ventilation (IMV), including ECMO; and mortality.
Additional predetermined clinical outcomes, included cause-specific mortality, receiving HD or hemofiltration, experiencing severe cardiac arrhythmias, and duration of ventilator dependence.
Results:
· 482 of 2104 patients (22.9%) in the dexamethasone arm died within 28 days.
· 1110 out of 4321 (25.7%) among the patients in the normal standard of care arm, passed away within 28 days of the randomization.
· 89% had laboratory-confirmed SARS-CoV-2 infection, mean (SD) age 66.1 15.7 years, 36% female, 18% black, 24% diabetes, 27% heart disease, 21% chronic lung illness, 16% on invasive mechanical ventilation or ECMO, 60% on oxygen alone (non-invasive ventilation), and 24% not on either.
· In the dexamethasone group, the median length of treatment was 7 days, and 95% of the patients got at least one dose of glucocorticoid.
8% of the patients in the group receiving conventional care also received glucocorticoids.
· Azithromycin use was comparable across the two groups.
· Level of respiratory support the patient was getting at the time of randomization affected mortality.
· Mortality at 28 days in Dexamethasone group was lower than standard of care group. (22.9% vs 25.7%).
· Patients receiving ventilation (IMV) and those receiving oxygen without IMV experienced lower incidence of death in the dexamethasone group compared to the usual care group, but not among patients who were not receiving any respiratory support at the time of randomization.
· Patients on IMV at randomization had symptoms for a longer period of time and were 10 years younger than those who weren’t on respiratory assistance.
· Those on IMV and those with longer-lasting symptoms benefited from dexamethasone.
· Among individuals who had symptoms for longer than 7 days, dexamethasone was linked to a lower 28-day mortality rate.
· Dexamethasone was linked to shorter hospital stay.
· Following randomization, patients receiving dexamethasone were less likely to need IMV and renal replacement therapy.
· Both groups’ incidence of new cardiac arrhythmias was comparable.
Discussion
Dexamethasone use (about 10 days) reduced 28-day mortality in hospitalized patients with Covid-19 by 12.3 age-adjusted percentage points (proportional reduction of about one third) in patients receiving invasive mechanical ventilation at randomization and by 4.2 age-adjusted percentage points (a proportional reduction of about one third) in patients receiving oxygen without invasive mechanical ventilation.
Level of evidence: 1
Trial Design and Oversight
The RECOVERY trial was designed to evaluate the effects of potential treatments in patients hospitalizedwithCovid-19at176NationalHealth Service organizations in the United Kingdom and was supported by the National Institute for Health Research Clinical Research Network.
Hospitalized patients were eligible for the trial if they had clinically suspected or laboratory- confirmed SARS-CoV-2 infection and no medical history that might, in the opinion of the attend- ing clinician, put patients at substantial risk if they were to participate in the trial. Initially, re- cruitment was limited to patients who were at least 18 years of age, but the age limit was re- moved starting on May 9, 2020. Pregnant or breast-feeding women were eligible.
The initial version of the manuscript was drafted by the first and last authors, developed by the writing committee, and approved by all members of the trial steering committee. The funders had no role in the analysis of the data, in the preparation or approval of the manu- script, or in the decision to submit the manu- script for publication. The first and last mem- bers of the writing committee vouch for the completeness and accuracy of the data and for the fidelity of the trial to the protocol and sta- tistical analysis plan.
Randomization
We collected baseline data using a Web-based case-report form that included demographic data, the level of respiratory support, major coexisting illnesses, suitability of the trial treatment for a particular patient, and treatment availability at the trial site. Randomization was performed with the use of a Web-based system with con- cealment of the trial-group assignment. Eligible and consenting patients were assigned in a 2:1 ratio to receive either the usual standard of care alone or the usual standard of care plus oral or intravenous dexamethasone (at a dose of 6 mg once daily) for up to 10 days (or until hospital discharge if sooner) or to receive one of the other suitable and available treatments that were being evaluated in the trial.
Procedures
A single online follow-up form was to be com- pleted by the local trial staff when each patient was discharged or had died or at 28 days after randomization, whichever occurred first. Infor- mation was recorded regarding the patients’ adherence to the assigned treatment, receipt of other treatments for Covid-19, duration of ad- mission, receipt of respiratory support (with duration and type), receipt of renal dialysis or hemofiltration, and vital status (including the cause of death). In addition, we obtained routine health care and registry data, including informa- tion on vital status (with date and cause of death), discharge from the hospital, and respira- tory and renal support therapy.
Outcome Measures
The primary outcome was all-cause mortality within 28 days after randomization; further analyses were specified at 6 months. Secondary outcomes were the time until discharge from the hospital and, among patients not receiving inva- sive mechanical ventilation at the time of ran- domization, subsequent receipt of invasive me- chanical ventilation (including extracorporeal membrane oxygenation) or death. Other prespeci- fied clinical outcomes included cause-specific mortality, receipt of renal dialysis or hemofiltra- tion, major cardiac arrhythmia (recorded in a subgroup), and receipt and duration of ventila- tion.
Patients
Of the 11,303 patients who underwent random- ization from March 19 to June 8, 2020, a total of 9355 (83%) were eligible to receive dexametha- sone (i.e., the drug was available in the hospital at the time and the patient had no known indica- tion for or contraindication to dexamethasone). Of these patients, 6425 underwent randomiza- tion to receive either dexamethasone (2104 pa- tients) or usual care alone (4321 patients) (Fig. 1). The remaining patients were randomly assigned to one of the other treatment groups being evalu- ated in the trial.
Secondary Outcomes
Patients in the dexamethasone group had a shorter duration of hospitalization than those in the usual care group (median, 12 days vs. 13 days) and a greater probability of discharge alive within 28 days (rate ratio, 1.10; 95% CI, 1.03 to 1.17)
The greatest effect regarding discharge within 28 days was seen among pa- tients who were receiving invasive mechanical ventilation at randomization
Other Prespecified Clinical Outcomes
Among patients who were not receiving invasive mechanical ventilation at randomization, the risk of progression to invasive mechanical ventilation was lower in the dexamethasone group than in the usual care group (risk ratio, 0.79; 95% CI, 0.64 to 0.97)
Among those who were receiving invasive mechanical ventilation at ran- domization, successful cessation of invasive me- chanical ventilation was more likely in the dexa- methasone group than in the usual care group (rate ratio, 1.47; 95% CI, 1.20 to 1.78)
Our results show that among hospitalized pa- tients with Covid-19, the use of dexamethasone for up to 10 days resulted in lower 28-day mor- tality than usual care in patients who were re- ceiving invasive mechanical ventilation at ran- domization (by 12.3 age-adjusted percentage points, a proportional reduction of approximate- ly one third) and those who were receiving oxy- gen without invasive mechanical ventilation (by 4.2 age-adjusted percentage points, a proportional reduction of approximately one fifth).
The RECOVERY trial was designed to pro- vide a rapid and robust assessment of the effect of readily available potential treatments for Covid-19 on 28-day mortality. Approximately 10% of all hospitalized patients with Covid-19 in the United Kingdom were enrolled in the trial, and mortality in the usual care group was con- sistent with the overall case fatality rate for hospitalized patients with Covid-19 in the United Kingdom at the time that the dexamethasone comparison was active.7 Only essential data were collected at hospital sites, with additional infor- mation (including longer-term mortality) ascer- tained through linkage with routine data sources. We did not collect information on physiologic, laboratory, or virologic measures.
Glucocorticoids have been widely used in syndromes closely related to Covid-19, including SARS,MiddleEastrespiratorysyndrome(MERS), severe influenza, and community-acquired pneu- monia. However, the evidence to support or discourage the use of glucocorticoids under these conditions has been weak owing to the lack of data from sufficiently powered random- ized, controlled trials. In addition, the evi- dence base has suffered from heterogeneity in glucocorticoid doses, medical conditions, and disease severity.
Level I
Summary of the outcome of the different arms of the recovery trial;
Regarding hydroxychloroquine no benefits were suggested clinically, whereas dexamethasone proved to reduce mortality especially in hospitalized patients requiring either invasive mechanical ventilation or oxygen support. As for antivirals as Lopinavir or ritonavir or colchicine no significant advantages were added. By mentioning azithromycin or convalescent plasma proved to have no value as well. Both Tocilizumab and Baricitinib had proved to improve mortality, respiratory support and hospital discharge.
Introduction
The emergence of COVID disease in 2019 resulted in worldwide mortality being higher in immunosuppressed population. The pathological explanation was detected in autopsies by the presence of diffuse alveolar damage, inflammatory infiltrates, and microvascular thrombosis.
As the host immune response is believed to be the key player in the pathophysiology of organ failure, the levels of some inflammatory markers like C-reactive protein, ferritin, interleukin-1, and interleukin-6 were increased confirming severe systemic inflammation. Therefore, the value of glucocorticoids has been widely debated.
The results of the controlled, open-label Randomized Evaluation of Covid-19 Therapy (RECOVERY) trial of dexamethasone in patients hospitalized with Covid-19 were important as it included a large scale population for study.
Methods
The aim was to evaluate the effects of potential treatments in patients hospitalized with Covid-19 at 176 National Health Service organizations in the United Kingdom. The randomization of patients was to receive dexamethasone, hydroxychloroquine, lopinavir–ritonavir, azithromycin, convalescent plasma, tocilizumab as well as other treatments as REGN-COV2 (a combination of two monoclonal antibodies directed against the SARS-CoV-2 spike protein), aspirin, colchicine, or usual care alone.
The study group involved all hospitalized patients who had clinically suspected or laboratory confirmed SARS-CoV-2 infection. There was no age limit to the study after May 2020, even pregnant and breast-feeding women were eligible.
Randomization
Eligible and consenting patients were assigned in a 2:1 ratio to receive either the usual standard of care alone or the usual standard of care plus oral or IV dexamethasone (at a dose of 6 mg once daily) for up to 10 days (or until hospital discharge if sooner) or to receive one of the other suitable and available treatments that were being evaluated in the trial.
Data included demographic data, the level of respiratory support, major coexisting illnesses, suitability of the trial treatment for a particular patient, and treatment availability at the trial site.
Cases were dexamethasone was unavailable at the hospital at the time of enrollment or was confirmed by the managing physician to be either definitely indicated or definitely contraindicated were excluded from the study.
Procedures
Follow-up form was single, online, done for each patient at either discharge or death or at 28 days after randomization, whichever occurred first.
Important information as the patients ‘adherence to the assigned treatment, receipt of other treatments for Covid-19, duration of admission, receipt of respiratory support (with duration and type), receipt of renal dialysis or hemofiltration, and vital status (including the cause of death) were all reported.
Outcome Measures
The primary outcome was all-cause mortality within 28 days after randomization.
Other outcomes involved the time until discharge from the hospital, patients not receiving invasive mechanical ventilation at the time of randomization, subsequent receipt of invasive mechanical ventilation (including extracorporeal membrane oxygenation), receipt of renal dialysis or hemofiltration, major cardiac arrhythmia and receipt and duration of ventilation or death.
Statistical Analysis
For the primary and secondary outcomes, the hazard ratio from Cox regression was used.
Kaplan–Meier survival curves were constructed to show cumulative mortality over the 28-day period.
The mean age was 1.1 years older among patients in the dexamethasone group than among those in the usual care group.
Characteristics at randomization: age, sex, race, level of respiratory support, days since symptom onset, and predicted 28-day mortality risk.
Chi-square tests for heterogeneity or linear trends were used. P values were significant when less than 0.005.
Results
11,303 patients who underwent randomization from March 19 to June 8, 2020, a total of 9355 (83%) were eligible to receive dexamethasone.
The mean SD age of the patients in this comparison was 66.1±15.7 years, 36% of the patients were female, and 18% were Black, Asian, or from a minority ethnic group.
Any reported history of diabetes was present in 24% of the patients, heart disease in 27%, and chronic lung disease in 21%, with 56% having at least one major coexisting illness was recorded. Laboratory-confirmed SARSCoV-2 infection in this analysis were 89% of the patients.
At randomization, 16% were receiving invasive mechanical ventilation or extracorporeal membrane oxygenation, 60% were receiving oxygen only (with or without noninvasive ventilation), and 24% were receiving neither.
In the dexamethasone group, 95% of the patients received at least one dose of glucocorticoid. The median duration of treatment was 7 days (interquartile range, 3 to 10). In the usual care group, 8% of the patients received a glucocorticoid as part of their clinical care.
The use of azithromycin or another macrolide antibiotic during the follow-up period was similar in the dexamethasone group and the usual care group (24% vs. 26%), and 0 to 3% of patients received hydroxychloroquine, lopinavir–ritonavir, or interleukin-6 antagonists during follow-up.
After May 26, 2020, the remdesivir drug was administered to 3 patients before randomization and 2 patients during the follow-up period.
Primary Outcome
Mortality at 28 days was significantly lower in the dexamethasone group than in the usual care group where deaths reported in 482 of 2104 patients (22.9%) and in 1110 of 4321 patients (25.7%), respectively (rate ratio, 0.83; 95% confidence interval [CI], 0.75 to 0.93; P<0.001).
In the dexamethasone group, the incidence of death was less than the usual care group among patients receiving invasive mechanical ventilation (29.3% vs. 41.4%; rate ratio, 0.64; 95% CI, 0.51 to 0.81).
Also the incidence of death was lower in the dexamethasone group than the usual care group receiving oxygen support without mechanical ventilation (23.3% vs. 26.2%; rate ratio, 0.82; 95% CI, 0.72 to 0.94).
Fortunately, there was no clear effect of dexamethasone among patients who were not receiving any respiratory support at randomization (17.8% vs. 14.0%; rate ratio, 1.19; 95% CI, 0.92 to 1.55).
Finally, the administration of dexamethasone was associated with a reduction in 28-day mortality among those with symptoms for more than 7 days.
Secondary Outcomes
Patients in the dexamethasone group had a shorter duration of hospitalization than those in the usual care group (median, 12 days vs. 13 days). Also, they had a higher probability of being discharged alive within 28 days (rate ratio, 1.10; 95% CI, 1.03 to 1.17).
Regarding those patients who were not receiving invasive mechanical ventilation, the number of patients who progressed to either invasive mechanical ventilation or death was lower in the dexamethasone group than in the usual care group (risk ratio, 0.93; 95% CI, 0.85 to 1.01).
Among those who were receiving invasive mechanical ventilation at randomization, successful cessation of invasive mechanical ventilation was more likely in the dexamethasone group than in the usual care group (rate ratio, 1.47; 95% CI, 1.20 to 1.78).
Among the patients who were not receiving renal-replacement therapy (renal dialysis or hemofiltration) at randomization, the number of patients who received this treatment within 28 days was lower in the dexamethasone group than in the usual care group (risk ratio, 0.61; 95% CI, 0.48 to 0.76).
Most deaths were due to Covid-19, and such deaths were less frequent in the dexamethasone group than in the usual care group.
The incidence of new cardiac arrhythmia was similar in the dexamethasone group and the usual care group.
Only four reports of serious adverse reaction related to dexamethasone were documented: two of hyperglycemia, one of gastrointestinal hemorrhage, and one of psychosis (all recognized adverse effects of glucocorticoids).
Discussion
The study results showed that among hospitalized patients with Covid-19, the use of dexamethasone proportional reduction of approximately one third of 28-day mortality than usual care patients group who were receiving invasive mechanical ventilation at randomization. While more reduction was noticed compared to those who received oxygen therapy in usual group by approximately one fifth.
Yet, no clear evidence that dexamethasone provided any benefit among patients who were not receiving respiratory support at randomization. Meanwhile there was advantage in patients who were being treated more than 7 days after symptom onset, when inflammatory lung damage is likely to be confirmed. This was also confirmed by RECOVERY trial.
Favourable data results included that among the patients who were receiving oxygen, the use of dexamethasone was associated with a lower risk of invasive mechanical ventilation as well as also for those already receiving invasive mechanical ventilation, they had a greater chance of successful cessation. In summary, both groups after the use of dexamethasone had better chance of being discharged from the hospital alive within 28 days.
As in epidemic conditions, trials are designed to get rapid results but facing many difficulties manipulating the evidence base due to heterogeneity in glucocorticoid doses, medical conditions, and disease severity. It is also necessary to mention that the beneficial effect of glucocorticoids in severe viral respiratory infections is mainly dependent on the selection of the right dose, at the right time, in the right patient.
The higher mortality benefit of dexamethasone in patients with Covid-19 who are receiving respiratory support and among those recruited after the first week of their illness suggests that at that stage the disease may be dominated by immunopathological elements prior to active viral replication playing a secondary role.
The RECOVERY trial demonstrated evidence of treatment with dexamethasone at a dose of 6 mg once daily for up to 10 days reduces 28-day mortality in patients with Covid-19 who are receiving respiratory support.
Level of evidence I
Severe COVID-19 induces a systemic inflammatory response that can lead to lung injury and multisystem organ dysfunction.
It has been proposed that the potent anti-inflammatory effects of corticosteroids might prevent or mitigate these harmful effects.
Hospitalized patients in the United Kingdom showed that patients who were randomized to receive dexamethasone had a reduced rate of mortality compared to those who received SOC.
This benefit was observed in patients with severe COVID-19,those who required supplemental oxygen and was best in those who required mechanical ventilation at enrollment. No benefit of dexamethasone was observed in patients who did not require supplemental oxygen.
In the RECOVERY trial, patients were not enrolled into the dexamethasone study arm (or included in the analysis) if their physicians decided that they were not suitable for corticosteroid therapy for any reason.
Before initiating dexamethasone, clinicians should review the patient’s medical history and assess the potential risks and benefits
Closely monitor patients with COVID-19 who are receiving dexamethasone for adverse effects (e.g., hyperglycemia, secondary infections).
Using systemic corticosteroids may increase the risk of reactivation of latent infections (e.g., hepatitis B virus, herpesviruses, strongyloidiasis, tuberculosis).
Dexamethasone is a moderate cytochrome P450 (CYP) 3A4 inducer, which may reduce the concentration and potential efficacy of concomitant medications that are CYP3A4 substrates.
It is not known whether other corticosteroids, such as prednisone, methylprednisolone, or hydrocortisone, will have a similar benefit to dexamethasone. Of note, the dose equivalencies for dexamethasone 6 mg daily are prednisone 40 mg, methylprednisolone 32 mg, and hydrocortisone 160 mg.
Hydroxychloroquine
Doxycycline
Azithromycin
Summaryof the article.
SARS-CoV-2 the cause of Covid-19, emerged in China in late 2019 from a zoonotic source.
The pathophysiological features of severe Covid-19 are dominated by an acute pneumonic process with extensive radiologic opacity and, on autopsy, diffuse alveolar damage, inflammatory infiltrates, and microvascular thrombosis.
Although one small trial has reported improved clinical outcomes in patients with Covid-19 who were given methylprednisolone,17 the absence of reliable evidence from large-scale randomized clinical trials means there is uncertainty about the effectiveness of glucocorticoids in patients with Covid-19.
Methods
open-label controlled, trial
Compared a range of possible treatments in patients who were hospitalized with Covid-19,
Patients randomized to receive oral or IV dexamethasone for up to 10 days or to receive the usual care.
Inclusion: hospitalized patients if clinically suspected or laboratory confirmed SARS-CoV-2 infection, No medical prevent them from participating, no restriction for, pregnant and breastfeeding women included.
The primary outcome was all-cause mortality within 28 days after randomization; further analyses were specified at 6 months.
Secondary outcomes were the time until discharge from the hospital and, among patients not receiving invasive mechanical ventilation at the time of randomization, subsequent receipt of invasive mechanical ventilation (including extracorporeal membrane oxygenation) or death.
Results
Discussion
What is the level of evidence provided by this article?
1 B
RECOVERY Trial (Randomised Evaluation of Covid-19 Therapy)
Background
Infection with SARS-CoV-2 is linked to diffuse alveolar injury, inflammatory infiltrates, and microvascular thrombosis. By modulating the inflammation-mediated lung injury, glucocorticoids may slow the progression to respiratory failure and mortality.
Methods
The study examined the outcomes of the various treatments given to patients with COVID-19 who were hospitalized in the UK.
Inpatient patients with a clinical suspicion of SARS-CoV-2 infection or a test confirmation were enrolled in the study.
Participants were randomized to receive standard care alone or oral or intravenous dexamethasone 6mg OD for up to 10 days (or until hospital release, whichever occurred first).
Death from any cause within 28 days of randomization was the primary outcome.
Secondary outcomes include the length of stay in the hospital, the number of patients who had invasive mechanical ventilation (IMV), including ECMO, after randomization and mortality.
Additional clinical outcomes that were predetermined in advance included cause-specific mortality, receiving HD or hemofiltration, experiencing severe cardiac arrhythmias, and the duration of ventilator dependance.
Results
· 482 individuals (22.9%) who were in the dexamethasone arm out of 2104 patients died within 28 days of the randomization.
· Among the 4321 patients in the normal standard of care arm, 1110 patients (or 25.7%) passed away within 28 days of the randomization.
· 89% had laboratory-confirmed SARS-CoV-2 infection, mean (SD) age 66.1 15.7 years, 36% female, 18% black, 24% diabetes, 27% heart disease, 21% chronic lung illness, 16% on invasive mechanical ventilation or ECMO, 60% on oxygen alone (noninvasive ventilation), and 24% not on either.
· In the dexamethasone group, the median length of treatment was 7 days, and 95% of the patients got at least one dose of glucocorticoid.
· 8% of the patients in the group receiving conventional care also received glucocorticoids.
· Azithromycin use was comparable across the two groups.
· The level of respiratory support a patient was getting at the time of randomization affected mortality.
· Dexamethasone group mortality at 28 days was lower than typical standard of care group mortality (22.9% vs 25.7%, respectively).
· Patients receiving invasive mechanical ventilation and patients receiving oxygen without invasive mechanical ventilation experienced a lower incidence of death in the dexamethasone group compared to the usual care group, but not among patients who were not receiving any respiratory support at the time of randomization.
· Patients on IMV at randomization had symptoms for a longer period of time and were 10 years younger than those who weren’t on respiratory assistance.
· Those on IMV and those with longer-lasting symptoms benefited from dexamethasone.
· Among individuals who had symptoms for longer than 7 days, dexamethasone was linked to a lower 28-day mortality rate.
· Dexamethasone was linked to a shorter hospital stay time.
· Following randomization, patients receiving dexamethasone were less likely to need IMV and renal replacement therapy.
· Both groups’ incidence of new cardiac arrhythmias was comparable.
Discussion
Dexamethasone use for up to 10 days reduced 28-day mortality in hospitalized patients with Covid-19 by 12.3 age-adjusted percentage points (a proportional reduction of about one third) in patients receiving invasive mechanical ventilation at randomization and by 4.2 age-adjusted percentage points (a proportional reduction of about one third) in patients receiving oxygen without invasive mechanical ventilation.
Level of evidence: 1
Open label RCT
Population: Patients who hospitalized for COVID-19
Intervention: Oral or IV dexamethasone 6 mg daily up to 10 days
Comparison: Oral or IV dexamethasone 6 mg daily up to 10 days (2104) vs usual care (4321)
Outcome: 28-day mortality (22.9% dexamethasone vs 25.7% usual care died) and the incidence of death lower among those receiving mechanical ventilation and receiving oxygen (no difference in patient who were not on any respiratory support)
Level 1B RCT
RECOVERY TRIAL
uk -nhs
LOW DOSE 6 MG DAILY DEXAMETHASONE upto 10 days LOWERS THE MORTALITY
covid patients with invasive ventilation and o2 therapy were included
all age group
28 day mortality was reported
following is found not to benefit study population
lopinavir–ritonavir
hydroxychloroquine
azithromycin
there was no clear effect of dexamethasone among patients who were not receiving any respiratory support at randomization
level 1 b evidence
Coronavirus disease 2019 (Covid-19) is associated with diffuse lung damage. Glucocorticoids may modulate inflammation-mediated lung injury and thereby reduce progression to respiratory failure and death.
In patients hospitalized with Covid-19, the use of dexamethasone resulted in lower 28-day mortality among those who were receiving either invasive mechanical ventilation or oxygen alone at randomization but not among those receiving no respiratory support.
Although remdesivir has been shown to shorten the time until recovery in hospitalized patients, no therapeutic agents have been shown to reduce mortality.
The pathophysiological features of severe Covid-19 are dominated by an acute pneumonic process with extensive radiologic opacity and, on autopsy, diffuse alveolar damage, inflammatory infiltrates, and microvascular thrombosis.
Inflammatory organ injury may occur in severe Covid-19, with a subgroup of patients having markedly elevated levels of inflammatory markers, including C-reactive protein, ferritin, interleukin-1, and interleukin-6.
Randomization was performed with the use of a Web-based system with concealment of the trial-group assignment. Eligible and consenting patients were assigned in a 2:1 ratio to receive either the usual standard of care alone or the usual standard of care plus oral or intravenous dexamethasone (at a dose of 6 mg once daily) for up to 10 days (or until hospital discharge if sooner) or to receive one of the other suitable and available treatments that were being evaluated in the trial.
Primary Outcome
Mortality at 28 days was significantly lower in the dexamethasone group than in the usual care group.
Patients with a longer duration of symptoms (who were more likely to have been receiving invasive mechanical ventilation at randomization) had a greater mortality benefit in response to treatment with dexamethasone. The receipt of dexamethasone was associated with a reduction in 28-day mortality among those with symptoms for more than 7 days but not among those with a more recent symptom onset.
There were four reports of a serious adverse reaction that was deemed by the investigators to be related to dexamethasone: two of hyperglycemia, one of gastrointestinal hemorrhage, and one of psychosis (all recognized adverse effects of glucocorticoids).
the evidence to support or discourage the use of glucocorticoids under these conditions has been weak owing to the lack of data from sufficiently powered randomized, controlled trials. 28-31 In addition, the evidence base has suffered from heterogeneity in glucocorticoid doses, medical conditions, and disease severity. It is likely that the beneficial effect of glucocorticoids in severe viral respiratory infections is dependent on the selection of the right dose, at the right time, in the right patient. High doses may be more harmful than helpful, as may such treatment given at a time when control of viral replication is paramount and inflammation is minimal. Slower clearance of viral RNA has been observed in patients with SARS, MERS, and influenza who were treated with systemic glucocorticoids, but the clinical significance of these findings is unknown.
The RECOVERY trial provides evidence that treatment with dexamethasone at a dose of 6 mg once daily for up to 10 days reduces 28-day mortality in patients with Covid-19 who are receiving respiratory support. We found no benefit (and the possibility of harm) among patients who did not require oxygen. Before the completion of the trial, many Covid-19 treatment guidelines stated that the use of glucocorticoids was either contraindicated or not recommended. Dexamethasone is on the list of essential medicines of the World Health Organization and is readily available worldwide at low cost. Guidelines issued by the U.K. chief medical officers, the European Medicines Agency, the World Health Organization, and the National Institutes of Health in the United States have been updated to recommend the use of glucocorticoids in patients hospitalized with Covid-19 requiring oxygen with or without ventilatory support.
Level of evidence: 1
Dexamethasone in Hospitalized Patients with Covid-19
Q1- Please do your own search and summarize the outcome of the different arms of the recovery trial.
v Aspirin: dose not improve survival for hospitalized patients with COVID-19 found by recovery trial.
v Azithromycin : no benefit from azithromycin in patients hospitalized with COVID-19 .
v Baricitinib : reduces deaths in patients hospitalized with COVID-19 .
v Colchicine : recovery trial closes recruitment to colchicine treatment for patients hospitalized with COVID-19.
v Convalescent Plasma: closes by recovery trial
v Dexamethasone : Low-cost dexamethasone reduces death by up to one third in hospitalized patients with severe respiratory complications of COVID-19.
v Dimethyl Fumarate: does not improve recovery for patients hospitalized with COVID-19
v Hydroxychloroquine: No clinical benefit from use of hydroxychloroquine in hospitalized patients with COVID-19.
v Lopinavir-Ritonavir : No clinical benefit from use of lopinavir-ritonavir in hospitalized COVID-19 patients studied in RECOVERY .
v Regeneron’s monoclonal antibody combination : recovery trial finds that reduces deaths for hospitalized COVID-19 patients who have not mounted their own immune response.
v Tocilizumab : reduces deaths in patients hospitalized with COVID-19
Q2- Please summarize this article
Introduction:
Coronavirus disease 2019 (Covid-19) is associated with diffuse lung damage. Glucocorticoids may modulate inflammation-mediated lung injury and thereby reduce progression to respiratory failure and death. patients may presented with mild or severe symptoms that appear in elevated inflammatory markers and opacity radiologically corticosteroid recommended in severe cases but it role is controversial.
Methods:
Patients randomly receive oral or intravenous dexamethasone at a dose of 6 mg once daily for up to 10 days.
The primary outcome was 28-day mortality.
Result:
A total of 2104 patients were assigned to receive dexamethasone and 4321 to receive usual care. Overall, 482 patients (22.9%) in the dexamethasone group and 1110 patients (25.7%) in the usual care group died within 28 days after randomization (age-adjusted rate ratio, 0.83; 95% confidence interval [CI], 0.75 to 0.93; P<0.001). In the dexamethasone group, the incidence of death was lower than that in the usual care group among patients receiving invasive mechanical ventilation (29.3% vs. 41.4%; rate ratio, 0.64; 95% CI, 0.51 to 0.81) and among those receiving oxygen without invasive mechanical ventilation (23.3% vs. 26.2%; rate ratio, 0.82; 95% CI, 0.72 to 0.94) but not among those who were receiving no respiratory support at randomization (17.8% vs. 14.0%; rate ratio, 1.19; 95% CI, 0.92 to 1.55).
Conclusion:
In patients hospitalized with Covid-19, the use of dexamethasone resulted in lower 28-day mortality among those who were receiving either invasive mechanical ventilation or oxygen alone at randomization but not among those receiving no respiratory support.
Q3- What is the level of evidence provided by this article?
Randomized control trial – LEVEL 1b
Severe COVID-19 induces a systemic inflammatory response that can lead to lung injury and multisystem organ dysfunction.
It has been proposed that the potent anti-inflammatory effects of corticosteroids might prevent or mitigate these harmful effects.
Hospitalized patients in the United Kingdom showed that patients who were randomized to receive dexamethasone had a reduced rate of mortality compared to those who received SOC.
This benefit was observed in patients with severe COVID-19,those who required supplemental oxygen and was best in those who required mechanical ventilation at enrollment. No benefit of dexamethasone was observed in patients who did not require supplemental oxygen.
In the RECOVERY trial, patients were not enrolled into the dexamethasone study arm (or included in the analysis) if their physicians decided that they were not suitable for corticosteroid therapy for any reason.
Before initiating dexamethasone, clinicians should review the patient’s medical history and assess the potential risks and benefits
Closely monitor patients with COVID-19 who are receiving dexamethasone for adverse effects (e.g., hyperglycemia, secondary infections).
Using systemic corticosteroids may increase the risk of reactivation of latent infections (e.g., hepatitis B virus, herpesviruses, strongyloidiasis, tuberculosis).
Dexamethasone is a moderate cytochrome P450 (CYP) 3A4 inducer, which may reduce the concentration and potential efficacy of concomitant medications that are CYP3A4 substrates.
It is not known whether other corticosteroids, such as prednisone, methylprednisolone, or hydrocortisone, will have a similar benefit to dexamethasone. Of note, the dose equivalencies for dexamethasone 6 mg daily are prednisone 40 mg, methylprednisolone 32 mg, and hydrocortisone 160 mg.
Hydroxychloroquine
Doxycycline
Azithromycin
Summaryof the article.
SARS-CoV-2 the cause of Covid-19, emerged in China in late 2019 from a zoonotic source.
The pathophysiological features of severe Covid-19 are dominated by an acute pneumonic process with extensive radiologic opacity and, on autopsy, diffuse alveolar damage, inflammatory infiltrates, and microvascular thrombosis.
Although one small trial has reported improved clinical outcomes in patients with Covid-19 who were given methylprednisolone,17 the absence of reliable evidence from large-scale randomized clinical trials means there is uncertainty about the effectiveness of glucocorticoids in patients with Covid-19.
Methods
open-label controlled, trial
Compared a range of possible treatments in patients who were hospitalized with Covid-19,
Patients randomized to receive oral or IV dexamethasone for up to 10 days or to receive the usual care.
Inclusion: hospitalized patients if clinically suspected or laboratory confirmed SARS-CoV-2 infection, No medical prevent them from participating, no restriction for, pregnant and breastfeeding women included.
The primary outcome was all-cause mortality within 28 days after randomization; further analyses were specified at 6 months.
Secondary outcomes were the time until discharge from the hospital and, among patients not receiving invasive mechanical ventilation at the time of randomization, subsequent receipt of invasive mechanical ventilation (including extracorporeal membrane oxygenation) or death.
Results
Discussion
What is the level of evidence provided by this article?
1 B
Please do your own search and summarise the outcome of the different arms of the recovery trial.
The Recovery trial was a randomised controlled open-label trial that evaluated various treatments for patients admitted with severe Covid 19 in the UK.
It was later expanded to Indonesia, Nepal and Vietnam.
It was a multi-arm adaptive clinical trial that allowed addition of other drugs into the trial and closure of some treatment arms.
The primary objective was to provide reliable estimates of the effect of study treatments on all-cause mortality at 28 days after first randomization.
Findings:
Please summarise this article.
Introduction:
Remdesvir has been shown to shorten the time to recovery, however no drug had shown a mortality benefit.
Small trials has reported benefit with methylprednisolone however, there were no large scale randomised clinical trial that evaluated the benefits of glucocorticoids.
Methodology: Randomised controlled open label trial
Study Population: Initially it was restricted to adults admitted with Covid 19 in the UK, however this was later expanded to include all patients.
Inclusion criteria: Patients with clinical suspected or laboratory confirmed Sars-cov2.
Primary outcome: All-cause mortality within 28 days after randomization.
Secondary outcome: Time until discharge from the hospital and, among patients not receiving invasive mechanical ventilation at the time of randomization, subsequent receipt of invasive mechanical ventilation or death.
Treatment: Patients were randomised 2:1 to receive either usual care alone or usual care plus IV or oral dexamethasone at a dose of 6mg OD for 10 days.
Results
2104 patients in the dexamethasone arm and 4321 patients in the usual care.
Overall patients characteristics:
24% had diabetes, 27% had heart disease, 21% had chronic lung disease and 56% had at least one major co- existing illness recorded.
16% were receiving invasive mechanical ventilation or extra- corporeal membrane oxygenation, 60% were receiving oxygen only (with or without noninvasive ventilation), and 24% were receiving neither.
Primary outcome: Low dose dexamethasone reduced mortality rate by nearly a third in hospitalised patients with severe Covid 19 needing invasive ventilation and by fifth in patients needing supportive oxygen therapy.
There was no benefit in patient who didn’t require oxygen.
Secondary outcome: Patients in the dexamethasone group had a shorter duration of hospitalization than those in the usual care group
Patients not receiving invasive mechanical ventilation the risk of progression was lower in the dexamethasone arm.
Discussion
Use of dexamethasone for 10 days was associated with lower 28day mortality in patients receiving invasive mechanical ventilation and in those receiving supplemental oxygen.
Patients not receiving any respiratory support use of dexamethasone was associated with possible harm than benefit.
Use of dexamethasone increased once chances of being discharged and reduced the risk of progression.
Thus the benefits of glucocorticoid in respiratory illness is dependent on the selection of the right dose, right time and the right patient.
What is the level of evidence provided by this article?
Level 1
Dexamethasone in Hospitalized Patients with Covid-19
Q1- Please do your own search and summarise the outcome of the different arms of the recovery trial.
1- Aspirin: RECOVERY trial finds aspirin does not improve survival for patients hospitalized with COVID-19 .
2- Azithromycin results : RECOVERY trial finds no benefit from azithromycin in patients hospitalised with COVID-19 .
3- Baricitinib results : New RECOVERY trial result: Baricitinib reduces deaths in patients hospitalised with COVID-19 .
4- Colchicine results: RECOVERY trial closes recruitment to colchicine treatment for patients hospitalized with COVID-19.
5- Convalescent Plasma results: RECOVERY trial closes recruitment to convalescent plasma treatment for patients hospitalised with COVID-19.
6- Dexamethasone results : Low-cost dexamethasone reduces death by up to one third in hospitalised patients with severe respiratory complications of COVID-19.
7- Dimethyl Fumarate results: RECOVERY trial finds that dimethyl fumarate does not improve recovery for patients hospitalised with COVID-19
8- Hydroxychloroquine results : No clinical benefit from use of hydroxychloroquine in hospitalised patients with COVID-19.
9- Lopinavir-Ritonavir results : No clinical benefit from use of lopinavir-ritonavir in hospitalised COVID-19 patients studied in RECOVERY .
10- Regeneron’s monoclonal antibody combination results : RECOVERY trial finds Regeneron’s monoclonal antibody combination reduces deaths for hospitalised COVID-19 patients who have not mounted their own immune response.
11- Tocilizumab results : Tocilizumab reduces deaths in patients hospitalised with COVID-19
Q2- Please summarise this article
Introduction:
Coronavirus disease 2019 (Covid-19) Covid 19 that first appeared in China is associated with diffuse lung damage. Glucocorticoids may modulate inflammation-mediated lung injury and thereby reduce progression to respiratory failure and death.
The extensive radiologic opacity with elevated inflammatory markers may reflect sever lung damage.
But steroids role in these patient was controversial. These drug ( corticosteroid ) is only recommended in sever cases. Most patient with COVID19 are asymptomatic or presented with mild symptoms.
Proportion of these patient may need hospital admission.
METHODS
This is a controlled, open-label trial
Are randomly assigned to receive oral or intravenous dexamethasone (at a dose of 6 mg once daily) for up to 10 days or to receive usual care alone.
The primary outcome was 28-day mortality.
RESULTS
A total of 2104 patients were assigned to receive dexamethasone and 4321 to receive usual care.
Overall, 482 patients (22.9%) in the dexamethasone group and 1110 patients (25.7%) in the usual care group died within 28 days after randomization (age-adjusted rate ratio, 0.83; 95% confidence interval [CI], 0.75 to 0.93; P<0.001).
The proportional and absolute between-group differences in mortality varied considerably according to the level of respiratory support that the patients were receiving at the time of randomization.
In the dexamethasone group, the incidence of death was lower than that in the usual care group among patients receiving invasive mechanical ventilation (29.3% vs. 41.4%)
and among those receiving oxygen without invasive mechanical ventilation (23.3% vs. 26.2%) but not among those who were receiving no respiratory support at randomization (17.8% vs. 14.0%)
CONCLUSIONS :
In patients hospitalized with Covid-19, the use of dexamethasone resulted in
lower 28-day mortality among those who were receiving either invasive mechanical
ventilation or oxygen alone at randomization but not among those receiving no
respiratory support.
Q3- What is the level of evidence provided by this article?
RCT – LEVEL 1b
W 9 j2
Dexamethasone in Hospitalized Patients with Covid-19
Q1- Please do your own search and summarise the outcome of the different arms of the recovery trial.
1- Aspirin: RECOVERY trial finds aspirin does not improve survival for patients hospitalized with COVID-19 .
2- Azithromycin results : RECOVERY trial finds no benefit from azithromycin in patients hospitalised with COVID-19 .
3- Baricitinib results : New RECOVERY trial result: Baricitinib reduces deaths in patients hospitalised with COVID-19 .
4- Colchicine results: RECOVERY trial closes recruitment to colchicine treatment for patients hospitalized with COVID-19.
5- Convalescent Plasma results: RECOVERY trial closes recruitment to convalescent plasma treatment for patients hospitalised with COVID-19.
6- Dexamethasone results : Low-cost dexamethasone reduces death by up to one third in hospitalised patients with severe respiratory complications of COVID-19.
7- Dimethyl Fumarate results: RECOVERY trial finds that dimethyl fumarate does not improve recovery for patients hospitalised with COVID-19
8- Hydroxychloroquine results : No clinical benefit from use of hydroxychloroquine in hospitalised patients with COVID-19.
9- Lopinavir-Ritonavir results : No clinical benefit from use of lopinavir-ritonavir in hospitalised COVID-19 patients studied in RECOVERY .
10- Regeneron’s monoclonal antibody combination results : RECOVERY trial finds Regeneron’s monoclonal antibody combination reduces deaths for hospitalised COVID-19 patients who have not mounted their own immune response.
11- Tocilizumab results : Tocilizumab reduces deaths in patients hospitalised with COVID-19
Q2- Please summarise this article
Introduction:
Coronavirus disease 2019 (Covid-19) Covid 19 that first appeared in China is associated with diffuse lung damage. Glucocorticoids may modulate inflammation-mediated lung injury and thereby reduce progression to respiratory failure and death.
The extensive radiologic opacity with elevated inflammatory markers may reflect sever lung damage.
But steroids role in these patient was controversial. These drug ( corticosteroid ) is only recommended in sever cases. Most patient with COVID19 are asymptomatic or presented with mild symptoms.
Proportion of these patient may need hospital admission.
METHODS
This is a controlled, open-label trial
Are randomly assigned to receive oral or intravenous dexamethasone (at a dose of 6 mg once daily) for up to 10 days or to receive usual care alone.
The primary outcome was 28-day mortality.
RESULTS
A total of 2104 patients were assigned to receive dexamethasone and 4321 to receive usual care.
Overall, 482 patients (22.9%) in the dexamethasone group and 1110 patients (25.7%) in the usual care group died within 28 days after randomization (age-adjusted rate ratio, 0.83; 95% confidence interval [CI], 0.75 to 0.93; P<0.001).
The proportional and absolute between-group differences in mortality varied considerably according to the level of respiratory support that the patients were receiving at the time of randomization.
In the dexamethasone group, the incidence of death was lower than that in the usual care group among patients receiving invasive mechanical ventilation (29.3% vs. 41.4%)
and among those receiving oxygen without invasive mechanical ventilation (23.3% vs. 26.2%) but not among those who were receiving no respiratory support at randomization (17.8% vs. 14.0%)
CONCLUSIONS :
In patients hospitalized with Covid-19, the use of dexamethasone resulted in
lower 28-day mortality among those who were receiving either invasive mechanical
ventilation or oxygen alone at randomization but not among those receiving no
respiratory support.
Q3- What is the level of evidence provided by this article?
RCT – LEVEL 1b
Please do your own search and summarise the outcome of the different arms of the recovery trial.
Only Dexamethasone shows benefit in patient with severe Covid ,those with oxygen nd mechanical ventilation .Other medication shows no effect like aspirin Colchicine.
Abstract:
Coronavirus disease is associated with diffuse lung damage. Glucocorticoids may modulate inflammation-mediated lung injury and thereby reduce progression to respiratory failure and death.
Methods:
Controlled, open-label trial comparing patient received CS OR NOT. The results of the controlled, open-label Randomized Evaluation of Covid-19 Therapy (RECOVERY) trial of dexamethasone in patients hospitalized with Covid-19
Primary outcome was 28-day mortality.
RESULTS:
the dexamethasone group, the incidence of death was lower than that in the usual care group among patients receiving invasive mechanical ventilation (29.3% vs. 41.4%; rate ratio, 0.64; 95% CI, 0.51 to 0.81) and among those receiving oxygen without invasive mechanical ventilation (23.3% vs. 26.2%; rate ratio, 0.82; 95% CI, 0.72 to 0.94) but not among those who were receiving no respiratory support at randomization (17.8% vs. 14.0%; rate ratio, 1.19; 95% CI, 0.92 to 1.55).
Other Prespecified Clinical Outcomes:
Among patients who were not receiving invasive mechanical ventilation at randomization,
The risk of progression to invasive mechanical ventilation was lower in the dexamethasone group than in the usual care group.
Among those who were receiving invasive mechanical ventilation at randomization, successful cessation of invasive mechanical ventilation was more likely in the dexamethasone group than in the usual care group.
Among the patients who were not receiving renal-replacement therapy at randomization, the number of patients who received this treatment within 28 days was lower in the dexamethasone group than in the usual care group.
Most deaths were due to Covid-19, and such deaths were less frequent in the dexamethasone group than in the usual care group.
CONCLUSIONS:
The use of dexamethasone resulted in lower 28-day mortality among those who were receiving either invasive mechanical ventilation or oxygen alone at randomization but not among those receiving no respiratory support.
Discussion:
Results show that among hospitalized patients with Covid-19, the use of dexamethasone for up to 10 days resulted in lower 28-day mortality than usual care in patients who were receiving invasive mechanical ventilation at randomization and those who were receiving oxygen without invasive mechanical ventilation.
No evidence that dexamethasone provided any benefit among patients who were not receiving respiratory support at randomization, and the results were consistent with possible harm in this subgroup.
Results also show that among the patients who were receiving oxygen, the use of dexamethasone was associated with a lower risk of invasive mechanical ventilation.
Or, for those already receiving invasive mechanical ventilation, a greater chance of successful cessation.
In both these groups, the use of dexamethasone increased the chance of being discharged from the hospital alive within 28 days.
The RECOVERY trial provides evidence that treatment with dexamethasone at a dose of 6 mg once daily for up to 10 days reduces 28-day mortality in patients with Covid-19 who are receiving respiratory support.
Level of evidence 1.
Please do your own search and summarise the outcome of the different arms of the recovery trial.RECOVERY Collaborative group trial was conducted to assess effect of dexamethasone, hydroxychloroquine, lopinavir-ritonavir, azithromycin, convalescent plasma, or Tocilizumab in hospitalized COVID-19 patients.The following conclusions were derived from different arms of the trial:
Hydroxychloroquine: No clinical benefit.Dexamethasone: Reduced mortality in patients requiring respiratory support.Lopinavir-ritonavir: No significant mortality benefit.Colchicine: No benefit.Azithromycin: No benefit.Tocilizumab: Reduced risk of death, length of hospital stay, and need for ventilator support.Baricitinib: Reduces death in hospitalized COVID-19 patients by 20%.Aspirin: No benefit.Convalescent plasma: No clinical benefit.
2. Please summarise this article.
The article deals with one arm of the RECOVERY Collaborative group trial, related to dexamethasone use in hospitalized patients with COVID-19.
Introduction: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19 presenting in most cases with either symptomatic or mild disease presentation. But the case fatality rate is high among hospitalized patients having diffuse lung damage, especially in those requiring mechanical ventilation. Inflammatory organ injury, characterized by elevated CRP, IL-1, IL-6 and ferritin, may occur in severe COVID-19. Glucocorticoids may modulate the lung injury associated with inflammation, decreasing progression to respiratory failure and death. The study was conducted to evaluate the effect of dexamethasone on such patients’ outcomes with respect to mortality.
Methods: Randomized Evaluation of Covid-19 Therapy (RECOVERY) trial was designed to evaluate effects of potential therapies in hospitalized patients with COVID-19, who were randomized to be given either usual care alone or dexamethasone (oral or intravenous, 6 mg per day for up to 10 days) in addition to the usual care in 2:1 ratio. All cause 28-day mortality was assessed in the 2 groups with time until discharge from the hospital as secondary outcome.
Results: Out of total 11303 patients undergoing randomization, 9355 were eligible to receive dexamethasone. Total 6425 underwent randomization in the dexamethasone arm of RECOVERY trial, out of which 2104 patients received dexamethasone while 4321 patients received the usual care alone. In the dexamethasone group 95% received at least 1 dose of dexamethasone, with median duration of treatment being 7 days. Mortality at 28 days was significantly reduced in the dexamethasone group (22.9%) as compared to the usual care alone group (25.7%), with trend of greatest benefit in patients receiving invasive mechanical ventilation (29% versus 41.4%) as well those requiring oxygen therapy without ventilator support (23.3% versus 26.2%). Effect of dexamethasone was not seen in those who did not require oxygen support. There was 12.3 and 4.2 percentage point age-adjusted absolute reduction in 28-day mortality with dexamethasone use in patients receiving mechanical ventilation and oxygen therapy respectively. Patients with longer duration of symptoms had greater mortality benefit with dexamethasone. Dexamethasone use was associated with reduced length of stay in hospital, and increased probability of discharged alive from the hospital within 28 days. Successful mechanical ventilation cessation was more in the dexamethasone group.
Discussion: Dexamethasone use upto 10 days in COVID-19 resulted in lower 4-week mortality in patients receiving oxygen therapy or mechanical ventilation. Dexamethasone use in COVID-19 patients requiring respiratory support led to reduced chances of renal replacement therapy use, reduced progression to ventilator support, increased chances of ventilator removal, and reduced COVID-19 associated mortality.
Conclusion: Dexamethasone use in hospitalized COVI-19 patients requiring respiratory support is associated with lower 28-day mortality.
3. What is the level of evidence provided by this article?
Level of evidence: level 1b: RCT
◇ Please do your own search and summarise the outcome of the different arms of the recovery trial
● The RECOVERY trial is a multi-center randomized control trial testing multiple treatments in patients hospitalized with Covid-19 at the same time
☆ Hydroxychloroquine has no clinical benefits
☆ Dexamethasone reduces deaths by up to one third
☆ No significant mortality impact for lopinavir
☆ Colchicine and aspirin add no benefits for patients
☆ Azithromycin has no clinical benefits
☆ Tocilizumab reduces deaths in patients hospitalised with COVID-19 and shortens the time taken for patients to discharged and reduces the need for a mechanical ventilator.
☆ Baricitinib reduces deaths in hospitalised patients also it reduced the chance of progressing to invasive mechanical ventilation.
◇ Please summarise this article
● Some patients with COVID19 have a respiratory illness requiring hospital care or critical illness with hypoxemic respiratory failure requiring prolonged ventilatory support.
● Mortality in Covid-19 hospitalized patients was 26% and 37% among patients with mechanical ventilation
● Inflammatory organ injury may occur in severe Covid-19, with elevated levels of
C-reactive protein, ferritin, IL-1, and IL-6 .
● Many guidelines have stated that glucocorticoids were either contraindicated or not recommended
● controlled, open-label Randomized Evaluation of Covid-19 Therapy (RECOVERY) trial of dexamethasone in patients hospitalized with Covid-19.
Methods
Trial Design and Oversight
● The RECOVERY trial was designed to evaluate the effects of potential treatments in patients hospitalized with Covid-19
● Randomiz patients to receive dexamethasone, hydroxychloroquine, lopinavir–ritonavir, azithromycin, convalescent plasma, or tocilizumab has now been stopped, the trial continues randomization to other treatments, as REGN-COV2 , aspirin, colchicine, or usual care alone.
Outcome Measures
● The primary outcome was all-cause mortality within 28 days and further analyses at 6 months.
● Secondary outcomes :
☆ Time until discharge from the hospital
☆ Receipt invasive mechanical ventilation
☆ Cause-specific mortality
☆ Receipt renal dialysis or hemofiltration
☆ Major cardiac arrhythmia
☆ Receipt and duration of ventilation.
☆ Outcome of successful cessation of invasive mechanical ventilation among who receiving it
Results
● 11,303 patients under randomization
● from March 19 to June 8, 2020
● 9355 (83%) were eligible to receive dexa
● 6425 under randomization to receive either dexamethasone or usual care alone
● The remaining patients were randomly assigned to one of the other treatment
● The mean age was 66.1±15.7 years
● 36% were female
● 18% were Black, Asian, or from a minority ethnic group
● Diabetes was present in 24%
● Heart disease in 27%
● Chronic lung disease in 21%
● 56% having major coexisting illness
● 89%had laboratory-confirmed SARS CoV-2 infection.
● 16% were receiving invasive mechanical ventilation or extracorporeal membrane oxygenation
● 60% were receiving oxygen only
● 24% were receiving neither.
☆ In the dexamethasone group 95% received at least one dose of a glucocorticoid with median duration 7 days
☆ In the usual care group, 8% of the patients received a glucocorticoid as part of their clinical care.
☆ Use of macrolide antibiotic during the follow-up period was similar in the dexamethasone group and the usual care group (24% vs. 26%), and 0 to 3% of patients received hydroxychloroquine, lopinavir–ritonavir, or interleukin-6 antagonists during follow-up
☆ remdesivir was administered to 3 patients before randomization and 2 patients during the follow-up period
Primary Outcome
● Mortality at 28 days was significantly lower in the dexamethasone group (22.9%) than in the usual care group (25.7%)
● There was no clear effect of dexamethasone among patients who were not receiving any respiratory support
● Patients who were receiving invasive mechanical ventilation were on average 10 years younger than those not receiving any respiratory support and had a history of symptoms for an average of 7 days longer
● Patients with a longer duration of symptoms (who were more likely to have been receiving invasive mechanical ventilation ) had a greater mortality benefit in response to treatment with dexa
● The receipt of dexamethasone was associated with a reduction in 28-day mortality among those with symptoms for more than 7 days but not among those with a more recent symptom onset
Secondary Outcomes
● Patients in the dexamethasone group had a shorter duration of hospitalization than those in the usual care group and a greater probability of discharge alive within 28 days especially among patients who were receiving invasive mechanical ventilation
● The risk of progression to invasive mechanical ventilation was lower in the dexamethasone group than in the usual care group among patients who were not receiving invasive mechanical ventilation
● Successful cessation of invasive mechanical ventilation was more in the dexamethasone group than in the usual care group among who were receiving invasive mechanical ventilation
● patients who received RRT within 28 days was lower in the dexamethasone group than in the usual care group
● Deaths due to Covid-19 were less frequent in the dexamethasone group than in the usual care group
● The incidence of death from other causes was similar in the dexamethasone group and the usual care group
● Incidence of cardiac arrhythmia was similar in the dexamethasone group and the usual care group
● Adverse effects of glucocorticoids were hyperglycemia, gastrointestinal hemorrhage, and psychosis
Discussion
● Use of dexamethasone for 10 days resulted in lower 28-day mortality than usual care and in patients with invasive mechanical ventilation
● There was no evidence that dexamethasone provided any benefit among patients who were not receiving respiratory support with possible harm
● A mong patients who were receiving oxygen, the use of dexamethasone was associated with a lower risk of invasive mechanical ventilation or, for those already receiving invasive mechanical ventilation, a greater chance of successful cessation.
● In both these groups, the use of dexamethasone increased the chance of being discharged from the hospital alive within 28 days.
● The RECOVERY trial was designed to provide a rapid and robust assessment of the effect of readily available potential treatments for Covid-19 on 28-day mortality
● Protocol combines methods used in treatments for acute myocardial infarction
● Glucocorticoids have been widely used in syndromes closely related to Covid-19, including SARS, MERS, severe influenza, and community-acquired pneumonia.
● Limitations :
☆ lack of randomized,controlled trials
☆ Heterogeneity in glucocorticoid doses, medical conditions, and disease severity.
● Beneficial effect of glucocorticoids in severe viral respiratory infections is dependent on the selection of the right dose, at the right time, in the right patient.
● Unlike with SARS, in which viral replication peaks in the second week of illness, viral shedding in SARS-CoV-2 appears to be higher early in the illness and declines thereafter.
● The greater mortality benefit of dexamethasone in patients with Covid-19 who are receiving respiratory support and among those recruited after the first week of their illness suggests that at that stage the disease may be dominated by immunopathological elements, with active viral replication playing a secondary role.
● This hypothesis would caution against extrapolation of the effect of dexamethasone in patients with Covid-19 to patients with other viral respiratory diseases with a different natural history.
● The RECOVERY trial provides that treatment with dexamethasone at a dose of 6 mg once daily for up to 10 days reduces 28-day mortality in patients with Covid-19 who are receiving respiratory support.
● We found no benefit (and possibility of harm) among patients who did not require oxygen.
● Before the completion of the trial, many Covid-19 treatment guidelines stated that the use of glucocorticoids was either contraindicated or not recommended.
● Dexamethasone is on the list of essential medicines of the World Health Organization and is readily available worldwide at low cost.
What is the level of evidence provided by this article?
1b
II. Dexamethasone in Hospitalized Patients with Covid-19
Summarise the outcome of the different arms of the recovery trial
Drugs/ biologics recommended in the treatment of Covid-19 infection include:
– Remdesivir
– Tocilizumab
– Nirmatrelvir/ ritonavir
– Baricitinib (JAK inhibitors)
– Systemic corticosteroids
– anticoagulants
Drugs not recommended because of proven lack of efficacy include:
– Hydroxychloroquine/ chloroquine
– Ivermectin
– Fluvoxamine
– Lopinavir/ ritonavir
– Colchicine
– Interferons
– Convalescent plasma
– Lactoferrin
Drugs with insufficient evidence to recommend for or against include:
– Nitazoxanide
– GMCSF inhibitors
– Anakinra
– Vitamin C and D
Summarise this article
Background
– SARS-CoV-2 infection is associated with diffuse alveolar damage, inflammatory infiltrates and microvascular thrombosis
– use of glucocorticoids may reduce progression to respiratory failure and death by modulating the inflammation-mediated lung injury
Methods
– open label RCT, RECOVERY Trial (Randomised Evaluation of Covid-19 Therapy)
– compared the effects of the various treatment options offered to patients admitted with Covid-19 in the UK
– recruited hospitalized patients who had clinically suspected or laboratory confirmed SARS-CoV-2 infection
– in a 2:1 ratio, patients were randomly assigned to receive oral or IV dexamethasone 6mg OD for up to 10 days (or until hospital discharge if sooner) or to receive usual standard of care alone
– primary outcome: all-cause mortality within 28 days after randomization
– secondary outcomes: time until discharge from the hospital, subsequent receipt of invasive mechanical ventilation (IMV) including ECMO in patients who were not on IMV at the time of randomization, death
– other prespecified clinical outcomes included: cause-specific mortality, receipt of HD or hemofiltration, major cardiac arrythmias, receipt and duration of ventilation
Results
– dexamethasone arm: 2104 patients, 482 patients (22.9%) died within 28 days after randomization
– usual standard of care alone arm: 4321 patients, 1110 patients (25.7%) died within 28 days after randomization
– mean (± SD) age 66.1 ± 15.7 years, 36% female, 18% black, 24% diabetes, 27% heart disease, 21% chronic lung disease, 89% had laboratory-confirmed SARS-CoV-2 infection, 16% were on invasive mechanical ventilation or ECMO, 60% were on oxygen only (± noninvasive ventilation), 24% were not on either
– in the dexamethasone group, 95% of the patients received at least one dose of glucocorticoid, median duration of treatment was 7 days
– in the usual standard of care group, 8% of the patients received a glucocorticoid as well
– use of azithromycin was similar in both groups (24% in the dexamethasone group, 26% usual standard of care group 26%), 0-3% of patients were on HCQ, LPV/r or IL-6 antagonists during follow up
– mortality varied according to the level of respiratory support the patient was receiving at the time of randomization
– mortality at 28 days was lower in the dexamethasone group than in the usual standard of care group (22.9% vs 25.7% respectively)
– incidence of death was lower in the dexamethasone group compared to the usual care group among patients on invasive mechanical ventilation and patients on oxygen without invasive mechanical ventilation but not among patients who were not on any respiratory support at randomization
– patients on IMV at randomization were 10 years younger than those not on respiratory support and had a longer duration of symptoms prior to randomization
– dexamethasone was beneficial to patients who had a longer duration of symptoms and patients on IMV
– dexamethasone was associated with a reduction in 28-day mortality among patients who had symptoms for more than 7 days
– dexamethasone was associated with a shorter duration of hospitalization
– patients on dexamethasone were less likely to require IMV after randomization and they were also less likely to require kidney replacement therapy
– the incidence of new cardiac arrythmias was similar in both groups
Discussion
– use of dexamethasone resulted in lower 28-day mortality in patients on IMV, patients on oxygen, patients with a long duration of symptoms but no benefit among patients not on respiratory support
– dexamethasone use was associated with lower risk for the need of IMV in patients on oxygen and improved mortality outcomes as well
– dexamethasone use among patients on IMV was associated with an increased the chance of successful cessation of IMV and hospital discharge alive within 28 days
– the beneficial effect of glucocorticoids therefore depends on selection of the right dose at the right time for the right patient
Conclusion
– use of dexamethasone 6mg OD for up to 10 days reduces 28-day mortality in patients with Covid-19 requiring oxygen with or without respiratory support
Level of evidence provided by this article
– Level 1b
II. Dexamethasone in Hospitalized Patients with Covid-19
Please do your own search and summarise the outcome of the different arms of the recovery trial.
Patients with severe COVID-19 develop a systemic inflammatory response that can lead to lung injury and multisystem organ dysfunction.
It has been proposed that the potent anti-inflammatory effects of corticosteroids might prevent or mitigate these harmful effects.
hospitalized patients in the United Kingdom showed that patients who were randomized to receive dexamethasone had a reduced rate of mortality compared to those who received standard of care.
This benefit was observed in patients with severe COVID-19 (defined as those who required supplemental oxygen) and was greatest in those who required mechanical ventilation at enrollment. No benefit of dexamethasone was observed in patients who did not require supplemental oxygen at enrollment.
The results of the RECOVERY trial have not yet been published.
In the RECOVERY trial, patients were not enrolled into the dexamethasone study arm (or included in the analysis) if their physicians decided that they were not suitable for corticosteroid therapy for any reason.
Before initiating dexamethasone, clinicians should review the patient’s medical history and assess the potential risks and benefits of administering corticosteroids to the patient.
Should closely monitor patients with COVID-19 who are receiving dexamethasone for adverse effects (e.g., hyperglycemia, secondary infections).
Using systemic corticosteroids may increase the risk of reactivation of latent infections (e.g., hepatitis B virus, herpesviruses, strongyloidiasis, tuberculosis).
Dexamethasone is a moderate cytochrome P450 (CYP) 3A4 inducer, which may reduce the concentration and potential efficacy of concomitant medications that are CYP3A4 substrates.
Should review a patient’s medication regimens to assess potential interactions.
At this time, it is not known whether other corticosteroids, such as prednisone, methylprednisolone, or hydrocortisone, will have a similar benefit to dexamethasone. Of note, the dose equivalencies for dexamethasone 6 mg daily are prednisone 40 mg, methylprednisolone 32 mg, and hydrocortisone 160 mg.
HCQ
Multiple studies provide data that hydroxychloroquine (brand name: Plaquenil) does not provide a medical benefit for hospitalized patients with COVID-19. Hydroxychloroquine, an FDA-approved prescription drug used for malaria, rheumatoid arthritis and lupus erythematosus, has been suggested as a possible treatment or preventive for COVID-19 based on demonstrated antiviral or immune system activity.
The use of hydroxychloroquine in randomized trials for the treatment of hospitalized patients with COVID-19 has not been shown to have a benefit in reducing death.
In addition, concerns exist over the benefit of the drug compared to its safety risk, especially with regard to abnormal heart rhythms.
Multiple worldwide public health organizations, including the FDA, NIH and WHO recommend against use of hydroxychloroquine as a treatment for hospitalized patients with COVID-19 based on studies showing a lack of effect and possible serious side effects. Studies are still ongoing looking at use in early COVID disease, but prospective, randomized, controlled studies are not yet available.
#Doxycycline
Doxycycline, as an easily available and low-cost medication, should be considered as a COVID-19 therapy in all patients in the first days of symptoms of SARS-CoV-2 infection.
Due to its immunomodulatory, anti-inflammatory, cardioprotective and antiviral effects, it seems to be an ideal drug for patients with mild, moderate and severe type of COVID-19.
A large multicentre study to evaluate the effects of this medication is needed.
#Azithromycin
azithromycin plus usual care did not substantially shorten the time to first self-reported recovery or decrease the risk of hospitalisation.
azithromycin should not be used routinely to treat COVID-19 in the community in older adults, in the absence of additional indications.
#Favipiravir
Favipiravir might be crucial for ensuring an efficient treatment, decrease mortality and allow early discharge in relation to Covid-19. However more clinical studies are urgently needed to evaluate the efficacy and safety of this antiviral nucleoside for COVID-19 treatment.
Please summarise this article.
Introduction
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (Covid-19), emerged in China in late 2019 from a zoonotic source.
However, in a substantial percentage of patients, a respiratory illness requiring hospital care develops, and such infections can progress to critical illness with hypoxemic respiratory failure requiring prolonged ventilatory support.
The pathophysiological features of severe Covid-19 are dominated by an acute pneumonic process with extensive radiologic opacity and, on autopsy, diffuse alveolar damage, inflammatory infiltrates, and microvascular thrombosis.
Although one small trial has reported improved clinical outcomes in patients with Covid-19 who were given methylprednisolone,17 the absence of reliable evidence from large-scale randomized clinical trials means there is uncertainty about the effectiveness of glucocorticoids in patients with Covid-19.
Methods
Controlled, open-label trial.
-Compared a range of possible treatments in patients who were hospitalized with Covid-19,
-Patients randomized to receive oral or IV dexamethasone for up to 10 days or to receive the usual care.
– Eligibility: hospitalized patients if clinically suspected or laboratory confirmed SARS-CoV-2 infection, No medical prevent them from participating, no restriction for, pregnant and breastfeeding women included.
The primary outcome was all-cause mortality within 28 days after randomization; further analyses were specified at 6 months.
Secondary outcomes were the time until discharge from the hospital and, among patients not receiving invasive mechanical ventilation at the time of randomization, subsequent receipt of invasive mechanical ventilation (including extracorporeal membrane oxygenation) or death.
Results
Total 11,303 patients who underwent randomization from March 19 to June 8, 2020, a total of 9355 (83%) were eligible to receive dexamethasone Of these patients, 6425 underwent randomization to receive either dexamethasone (2104 patients) or usual care alone (4321 patients).
In this analysis, 89% of the patients had laboratory-confirmed SARSCoV-2 infection.
At randomization, 16% were receiving invasive mechanical ventilation or extracorporeal membrane oxygenation, 60% were receiving oxygen only (with or without noninvasive ventilation), and 24% were receiving neither.
In the dexamethasone group, 95% of the patients received at least one dose of a glucocorticoid.
In the usual care group, 8% of the patients received a glucocorticoid as part of their clinical care.
The use of azithromycin or another macrolide antibiotic during the follow-up period was similar in the dexamethasone group and the usual care group (24% vs. 26%), and 0 to 3% of patients received hydroxychloroquine, lopinavir–ritonavir, or interleukin-6 antagonists during followup .
Discussion
Results show that among hospitalized patients with Covid-19, the use of dexamethasone for up to 10 days resulted in lower 28-day mortality than usual care in patients who were receiving invasive mechanical ventilation at randomization (by 12.3 age-adjusted percentage points, a proportional reduction of approximately one third) and those who were receiving oxygen without invasive mechanical ventilation (by 4.2 age-adjusted percentage points, a proportional reduction of approximately one fifth)
no evidence that dexamethasone provided any benefit among patients who were not receiving respiratory support at randomization, and the results were consistent with possible harm in this subgroup.
What is the level of evidence provided by this article?1 b.
Introduction.
· SARS-CoV-2, the cause of coronavirus disease 2019 (Covid-19), emerged in China in late 2019 from a zoonotic source.
· It is characterized by an acute pneumonic process with extensive radiologic opacity and diffuses alveolar damage, inflammatory infiltrates, and microvascular thrombosis.
· Inflammatory organ injury may occur in severe Covid-19, with a subgroup of patients having markedly elevated levels of inflammatory markers.
· Several therapeutic interventions have been proposed to mitigate inflammatory organ injury in viral pneumonia, but the value of glucocorticoids has been widely debated.
Trial Design and Oversight
· The RECOVERY trial evaluated the effects of potential treatments in patients hospitalized with Covid-19, with randomization to REGN-COV2, aspirin, colchicine, or usual care.
· Hospitalized patients eligible for SARS-CoV-2 trial if they had suspected or laboratory-confirmed infection and no medical history that could put them at risk.
· The trial was approved by the U.K. Medicines and Health- care Products Regulatory Agency and the Cambridge East Research Ethics Committee.
Randomization
· Randomization was conducted using a Web-based system with concealment of the trial-group assignment, with eligible and consenting patients assigned to either the usual standard of care or dexamethasone for up to 10 days.
· The randomly assigned treatment was prescribed by the treating clinician and patients and local members of the trial staff were aware of the assigned treatments.
Procedures
· A single online follow-up form was completed to record adherence to treatment, receipt of other treatments, duration of admission, respiratory support, and vital status.
Outcome Measures
· Primary outcome was all-cause mortality within 28 days after randomization; secondary outcomes were time until discharge, subsequent receipt of invasive mechanical ventilation, cause-specific mortality, renal dialysis or hemofiltration, major cardiac arrhythmia, and receipt and duration of ventilation.
· Information is complete for 99.9% of trial participants.
Patients
· Patients randomized to either dexamethasone or usual care alone were randomly assigned to one of the other treatment groups.
· The mean (±SD) age of the patients in this comparison was 66.1±15.7 years, 36% were female, and 18% were Black, Asian, or from a minority ethnic group. 89% had laboratory-confirmed SARS-CoV-2 infection, 16% were receiving invasive mechanical ventilation or extracorporeal membrane oxygenation, 60% were receiving oxygen only, and 24% were receiving neither. 95% of the patients received at least one dose of glucocorticoid, and the median duration of treatment was 7 days.
· The use of azithromycin or another macrolide antibiotic during the follow-up period was similar in the dexamethasone group and the usual care group and 0 to 3% of patients received hydroxychloroquine, lopinavir–ritonavir, or interleukin-6 antagonists.
Primary Outcome
· Mortality at 28 days was significantly lower in the dexamethasone group than in the usual care group, with deaths reported in 482 of 2104 patients (22.9%) and 1110 of 4321 patients (25.7%). In a prespecified analysis according to the level of respiratory support that the patients were receiving at randomization, there was a trend showing the greatest absolute and proportional benefit among patients who were receiving invasive mechanical ventilation (11.3% vs. 14.4%; rate ratio, 0.83; 95% confidence interval [CI], 0.75 to 0.93; P<0.001).
· Post hoc exploratory analysis restricted to 5744 patients with a positive SARS-CoV-2 test result showed similar findings.
· Exposure to dexamethasone reduced 28-day mortality by an average of 7 days.
· Dexamethasone was associated with a reduction in 28-day mortality among those with symptoms for more than 7 days, but not among those with more recent symptom onset.
Secondary Outcomes
· Patients in the dexamethasone group had a shorter duration of hospitalization and a greater probability of discharge alive within 28 days than those in the usual care group, with the greatest effect seen among those receiving invasive mechanical ventilation at randomization.
Other prespecified Clinical Outcomes
· The risk of progression to invasive mechanical ventilation was lower in the dexamethasone group than in the usual care group, with successful cessation of invasive mechanical ventilation more likely in the dexamethasone group.
· The incidence of death from other causes was similar, and the incidence of new cardiac arrhythmia was similar.
· There were four reports of serious adverse reactions, two of hyperglycemia, one of gastrointestinal hemorrhage, and one of psychosis, all recognized adverse effects of glucocorticoids.
Discussion
· The RECOVERY trial found that the use of dexamethasone for up to 10 days resulted in lower 28-day mortality than usual care in patients who were receiving invasive mechanical ventilation at randomization and those who were receiving oxygen without invasive mechanical ventilation.
· The benefit was also clear in patients being treated more than 7 days after symptom onset when inflammatory lung damage is likely to have been more common.
· A subsequent meta-analysis of seven trials of glucocorticoids for critically ill patients with Covid-19 confirmed the findings of the trial.
· The protocol combines the methods used in large, simple trials of treatments for acute myocardial infarction in the 1980s with the opportunities provided by digital health care in the 2020s. Preliminary results for dexamethasone were announced on June 16, 2020, and were adopted into the U.K.
· The views expressed in this article are those of the authors and do not necessarily reflect those of the National Health Service, the National Institute for Health Research, the Medical Research Council of United Kingdom Research and Innovation, or the Department of Health and Social Care.
· Guidelines issued by the U.K. chief medical officers, the European Medicines Agency, the World Health Organization, and the National Institutes of Health have been updated to recommend the use of glucocorticoids in patients hospitalized with Covid-19 requiring oxygen with or without ventilatory support.
· Tocilizumab was provided free of charge for this study by Roche, AbbVie contributed supplies of lopinavir–ritonavir, Regeneron contributed supplies of REGN-COV2, and the National Health Service supplied dexamethasone.
Conclusion
· In patients hospitalized with Covid-19, the use of dexamethasone resulted in lower 28-day mortality
among those who were receiving either invasive mechanical ventilation or oxygen
alone at randomization but not among those receiving no respiratory support.
==============================
Level of Evidence
Ib
Different arms of Recovery trial
The RECOVERY Trial has found four treatments that are effective for severe COVID-19 and is currently testing the following suggested treatments to find out whether they are more effective in helping people recover than the standard care that all patients receive:
For COVID-19
For influenza
Data from the trial are regularly reviewed so that any effective treatment can be identified quickly and made available to all patients.
SUMMARY
Recovery trial was a land mark trial which confirmed the utility of dexamethasone as treatment modality reducing mortality in deadly Covid 19
METHODS
In this controlled, open-label trial comparing a range of possible treatments in patients who were hospitalized with Covid-19, we randomly assigned patients to receive oral or intravenous dexamethasone (at a dose of 6 mg once daily) for up to 10 days or to receive usual care alone.
A total of 2104 patients were assigned to receive dexamethasone and 4321 to receive usual care. Overall, 482 patients (22.9%) in the dexamethasone group and 1110 patients (25.7%) in the usual care group died within 28 days after randomization (age-adjusted rate ratio, 0.83; 95% confidence interval [CI], 0.75 to 0.93; P<0.001).
In the dexamethasone group, the incidence of death was lower than that in the usual care group among patients receiving invasive mechanical ventilation (29.3% vs. 41.4%; rate ratio, 0.64; 95% CI, 0.51 to 0.81) and among those receiving oxygen without invasive mechanical ventilation (23.3% vs. 26.2%; rate ratio, 0.82; 95% CI, 0.72 to 0.94) but not among those who were receiving no respiratory support at randomization.
CONCLUSIONS
In patients hospitalized with Covid-19, the use of dexamethasone resulted in lower 28-day mortality among those who were receiving either invasive mechanical ventilation or oxygen alone at randomization but not among those receiving no respiratory support.
Secondary Outcomes
Patients in the dexamethasone group had a shorter duration of hospitalization than those in the usual care group (median, 12 days vs. 13 days) and a greater probability of discharge alive within 28 days.
Among the patients who were not receiving invasive mechanical ventilation at randomiza- tion, the number of patients who progressed to the prespecified composite secondary outcome of invasive mechanical ventilation or death was lower in the dexamethasone group than in the usual care group.
Among those who were receiving invasive mechanical ventilation at ran- domization, successful cessation of invasive me- chanical ventilation was more likely in the dexa- methasone group than in the usual care group
Among the patients who were not receiving renal-replacement therapy (renal dialy- sis or hemofiltration) at randomization, the num- ber of patients who received this treatment within 28 days was lower in the dexamethasone group than in the usual care group
LEVEL OF EVIDENCE
RCTs are given the highest levelbecause they are designed to be unbiased and have less risk of systematic errors.
Dexamethasone in Hospitalized Patients with Covid-19:
Introduction;
-Coronavirus disease 2019 (Covid-19) is associated with diffuse lung damage.
-Glucocorticoids may modulate inflammation-mediated lung injury and thereby reduce progression to respiratory failure and death.
-Glucocorticoids have been widely used in syndromes closely related to Covid-19, including SARS, Middle East respiratory syndrome (MERS), severe influenza, and community-acquired pneumonia .
Aim;
-This controlled, open-label Randomized trial for evaluation of Covid-19 Therapy (RECOVERY) trial of dexamethasone in patients hospitalized with Covid-19.
Methodology;
-In this controlled, open-label trial comparing a range of possible treatments in patients who were hospitalized with Covid-19, we randomly assigned patients to receive oral or intravenous dexamethasone (at a dose of 6 mg once daily) for up to 10 days or to receive usual care alone.
-The primary outcome was 28-day mortality.
Results;
-A total of 2104 patients were assigned to receive dexamethasone and 4321 to receive usual care. Overall, 482 patients (22.9%) in the dexamethasone group and 1110 patients (25.7%) in the usual care group died within 28 days after randomization .
Conclusion;
-In patients hospitalized with Covid-19, the use of dexamethasone resulted in lower 28-day mortality among those who were receiving either invasive mechanical ventilation or oxygen alone at randomization but not among those receiving no respiratory support.
-This open –label trial with Level of evidence: 1b
Dexamethasone in Hospitalized Patients with Covid-19
The RECOVERY Collaborative Group
published in the new England journal of medicine February 25, 2021
Methodology
It is a open-labeled randomized controlled trial (The level of evidence is 1B)
Results
Discussion
Summary of outcome of the different arms of the recovery trial:
This international clinical trial is identifying treatments that may be beneficial for people hospitalized with suspected or confirmed COVID-19. A total of 48465 Participants from 195 Active sites were included.
Azithromycin and standard care, no clinical benefit
Aspirin was not associated with improved 28 days mortality
Baricitinib for 10 days and standard care reduced the risk of death
Colchicine and standard care, no improvement in survival
Hydroxychloroquine did not improve survival
Lopinavir/Rotinavir did not improve survival as compared to standard care alone
Tocilizumab improve outcomes in patients with hypoxia and inflammation
Please summarise this article
Introduction:
SARS-CoV-2, the cause of severe acute respiratory syndrome (Covid-19), emerged in China in late 2019. The majority of Covid-19 cases either are asymptomatic or result in only mild disease. Covid-19 is associated with diffuse lung damage. Glucocorticoids may modulate inflammation-mediated lung injury and thereby reduce progression to respiratory failure and death.
Methods:
In this controlled, open-label trial comparing a range of possible treatments in patients who were hospitalized with Covid-19, we randomly assigned patients to receive oral or intravenous dexamethasone (at a dose of 6 mg once daily) for up to 10 days or to receive usual care alone. The primary outcome was 28-day mortality.
Result:
A total of 2104 patients received dexamethasone. 4321 patients received usual care. 482 patients (22.9%) in the dexamethasone group died and 1110 patients (25.7%) in the usual care group. In the dexamethasone group, the incidence of death was lower than that in the usual care group among patients receiving invasive mechanical ventilation and among those receiving oxygen without invasive mechanical ventilation but not among those who were receiving no respiratory support at randomization .
Conclusion:
In patients hospitalized with Covid-19, the use of dexamethasone resulted in lower 28-day mortality among those who were receiving either invasive mechanical ventilation or oxygen alone at randomization.
Level of evidence: 1b
Please do your own search and summarise the outcome of the different arms of the recovery trial.
Please summarise this article.
What is the level of evidence provided by this article?
1b
Use of low dose DEXA in severe cases of COVID 19
Summary
· The current RCT compared IV dexamethasone to usual care
· Primary outcome was mortality at 6 months from randomization, and secondary outcomes were need for mechanical ventilation or ECMO, duration of MV, occurrence of arrhythmia, the need to dialysis and duration of hospital stay.
· The current study concluded that low dose dexa (6 mg/day) for 3-10 days was beneficial in reducing the mortality in cases with severe disease (on oxygen or invasive mechanical ventilation).
· However, dexa had no added benefits in those not requiring respiratory support.
· Steroid use need meticulous decision (right dose, at the right time, in the right patient)…usually start at later stage of the disease (at least 7 days from the onset of symptoms, only in severe cases who are oxygen dependent or need MV)
· Remdisivir may fasten recovery but did not decrease mortality.
· Lung autopsy in severe cases shows extensive infiltration by inflammatory cells and microvascular thrombosis. In addition, high levels of inflammatory markers as g C-RP, ferritin, interleukin-1 and -6 which raise the possibility o steroid use in severe cases.
· Trial of dexamethasone, hydroxychloroquine, lopinavir–ritonavir, azithromycin, convalescent plasma, or tocilizumab has now been stopped.
Level of evidence: RCT (level II)
The outcome of the different arms of the recovery trial
The RECOVERY trial(1)was designed to evaluate the effects of potential treatments in patients hospitalized with Covid-19 at 176 National Health Service organizations in the United Kingdom and was supported by the National Institute for Health Research Clinical Research Network.
1. The randomization of patients to receive dexamethasone, hydroxychlo- roquine, lopinavir–ritonavir, azithromycin, convalescent plasma, or tocilizumab has now been stopped.
· Hydroxychloroquine has no clinical benefits.
· No significant mortality impact for lopinavir.
· Azithromycin has no clinical benefits.
· Aspirin was added to the trial because it is used to prevent blood clots, patients with COVID-19 are at higher risk of blood clots forming in their blood vessels. It is also cheap and widely available, which make it a good candidate.
· Tocilizumab reduces deaths in patients hospitalized with COVID-19. The study also showed that tocilizumab shortens the time taken for patients to be successfully discharged from hospital, and reduces the need for a mechanical ventilator.
· Baricitinib reduces deaths in hospitalized patients. The RECOVERY team found that treatment with baricitinib reduced deaths by 13%. It also reduced the chance of progressing to invasive mechanical ventilation.
· Dexamethasone reduces deaths by up to one third.
2. The trial continues randomization to other treatments, including REGN-COV2 (a combination of two monoclonal antibodies directed against the SARS-CoV-2 spike protein), aspirin, colchicine, or usual care alone.
· In March 2021, the trial closed the colchicine arm of the trial, as it had found no benefit to patients.
Summary of the article
Dexamethasone in Hospitalized Patients with Covid-19
This is a controlled, open-label trial comparing a range of possible treatments in patients who were hospitalized with Covid-19, randomly assigned to receive oral or intravenous dexamethasone (at a dose of 6 mg once daily) for up to 10 days or to receive usual care alone. The primary outcome was 28-day mortality.
The use of dexamethasone resulted in lower 28-day mortality among those who were receiving either invasive mechanical ventilation or oxygen alone at randomization but not among those receiving no respiratory support.
The level of evidence provided by this article:
This is a controlled, open-label trial. It is a prospective cohort study with level of evidence grade 2.
Reference
1. UK Search and Innovation ; The Recovery Trialk https://www.ukri.org/
The RECOVERY trial: Hydroxychloroquine : Has no clinical benefit Dexamethazone : : Dexamethasone is proven to improve survival in COVID-19. lopinavir : Had no significant mortality benefits
Cholchicine and aspirine :
Acholchicine: is a commonly used anti-inflammatory treatment. Inflammation is a key component of severe COVID-19 and can lead to lung damage, the need for mechanical ventilation and death.But unfortunately it had no benefit to patients .
Aspirin : Was added to the trial because it is used to prevent blood clots, but it did not reduce the 28-day mortality rate in COVID-19 patients who were hospitalized, the risk of dying or moving to invasive mechanical ventilation, but it did slightly raise the percentage of patients who were discharged alive after 28 days.
Azithromycin : Azithromycin is a widely-used antibiotic that also reduces inflammation, a key feature of severe COVID-19 but unfortunately has no clinical benefits.
Tocizumab:
It reduces the risk of death for hospitalized patients with severe COVID-19,
also shortens the time of stay in the hospital, and reduces the need for a mechanical ventilator.
Baricitinib: : Is an anti-inflammatory drug normally used to treat rheumatoid arthritis , it is found to improve survival for patients with severe COVID-19.
Introduction :
SARS-CoV-2, the cause of severe acute respiratory syndrome (Covid-19), emerged in China in late 2019 from a zoonotic source. The majority of Covid-19 cases either are asymptomatic or result in only mild disease
It is characterized by an acute pneumonic process with extensive radiologic opacity and diffuse alveolar damage, inflammatory infiltrates, and microvascular thrombosis.
Several therapeutic interventions have been proposed to mitigate inflammatory organ injury, but the value of glucocorticoids has been widely debated.
Methods and result :
11,303 patients underwent randomization from March 19 to June 8, 2020 to receive dexamethasone or usual care alone. The mean age of the patients was 66.1±15.7 years, 36% were female, and 18% were Black, Asian, or from a minority ethnic group. 89% had laboratory-confirmed SARSCoV-2 infection, 16% were receiving invasive mechanical ventilation or extracorporeal membrane oxygenation, 60% were receiving oxygen only, and 24% were receiving neither. 95% of the patients received at least one dose of a glucocorticoid, and the median duration of treatment was 7 days. The use of azithromycin or another macrolide antibiotic during the follow-up period was similar.
Outcome :
Primary outcome : The dexamethasone group had a significantly lower incidence of death at 28 days than the usual care group, with the greatest absolute and proportional benefit among those receiving invasive mechanical ventilation.
Secondary outcome : The dexamethasone group had a shorter duration of hospitalization and a greater probability of discharge alive within 28 days than the usual care group.
Conclusion :
The RECOVERY trial found that treatment with dexamethasone at a dose of 6 mg once daily for up to 10 days reduces 28-day mortality in patients with Covid-19 who are receiving respiratory support
level 1b
Please do your own search and summarise the outcome of the different arms of the recovery trial.
1- trial is supported by grants to the University of Oxford
The RECOVERY Trial has found four treatments that are effective for severe COVID-19 and is currently testing the following suggested treatments to find out whether they are more effective in helping people recover than the standard care that all patients receive:
For COVID-19
2-Sponsor:
University of Oxford
RECOVERY is a randomised trial investigating whether treatment with Lopinavir-Ritonavir, Hydroxychloroquine, Corticosteroids, Azithromycin, Colchicine, IV Immunoglobulin (children only), Convalescent plasma, Casirivimab+Imdevimab, Tocilizumab, Aspirin, Baricitinib, Infliximab, Empagliflozin, Sotrovimab, Molnupiravir, Paxlovid or Anakinra (children only) prevents death in patients with COVID-19.
Please summarise this article. randomly assigned patients to receive oral or intravenous dexamethasone (at a dose of 6 mg once daily) for up to 10 days or to receive usual care alone.
The primary outcome was 28-day mortality.
RESULTS
2104 patients were assigned to receive dexamethasone and 4321 to receive usual care. Overall, 482 patients (22.9%) in the dexamethasone group and 1110 patients (25.7%) in the usual care group died within 28 days after randomization
In patients hospitalized with Covid-19, the use of dexamethasone resulted in lower 28-day mortality among those who were receiving either invasive mechanical ventilation or oxygen alone at randomization but not among those receiving no respiratory support.
Covid-19 were admitted to hospitals in the United Kingdom in the first half of 2020, the case fatality rate was approximately 26% overall and more than 37% among patients who were undergoing invasive mechanical ventilation.
Although remdesivir has been shown to shorten the time until recovery in hospitalized patients,8 no therapeutic agents have been shown to reduce mortality.
Several therapeutic interventions have been proposed to mitigate inflammaory organ injury in viral pneumonia, but the value of glucocorticoids has been widely debated
Although one small trial has reported improved clinical outcomes in patients with Covid-19 who were given methylprednisolone,the absence of reliable evidence from large-scale randomized clinical trials means there is uncertainty about the effectiveness of glucocorticoids in patients with Covid-19.
Many guidelines for the treatment of such patients have stated that glucocorticoids were either contraindicated or not recommended,
although in China, glucocorticoids have been recommended for severe cases
However, in the first 6 months of the pandemic, practice varied widely across the world: in some series, as many as 50% of patients were treated with glucocorticoids.
Here, we report the results of the controlled, open-label Randomized Evaluation of Covid-19 Therapy (RECOVERY) trial of dexamethasone in patients hospitalized with Covid-19.
Methods
Trial Design and Oversight
The RECOVERY trial
was designed to evaluate the effects of potential treatments in patients hospitalized with Covid-19 at 176 National Health Service organizations in the United Kingdom and was supported by the National Institute for Health Research Clinical Research Network.
. Although the randomization of patients to receive dexamethasone, hydroxychloroquine, lopinavir–ritonavir, azithromycin, convalescent plasma, or tocilizumab has now been stopped,
the trial continues randomization to other treatments, including REGN-COV2 (a combination of two monoclonal antibodies directed against the SARS-CoV-2 spike protein), aspirin, colchicine, or usual care alone.
Procedures
A single online follow-up form was to be completed by the local trial staff when each patient was discharged or had died or at 28 days after randomization, whichever occurred first
Information was recorded regarding the patients’
adherence to the assigned treatment, receipt of other treatments for Covid-19, duration of admission, receipt of respiratory support (with duration and type), receipt of renal dialysis or hemofiltration, and vital status (including the cause of death). routine health care and registry data, including information on vital status (with date and cause of death), discharge from the hospital, and respiratory and renal support therapy
Outcome Measures
The primary outcome was all-cause mortality within 28 days after randomization; further analyses were specified at 6 months
. Secondary outcomes were the time until discharge from the hospital and, among patients not receiving invasive mechanical ventilation at the time of randomization, subsequent receipt of invasive mechanical ventilation (including extracorporeal membrane oxygenation) or death.
Consequently, on June 8, 2020, the steering committee closed recruitment to the dexamethasone group, since enrollment had exceeded 2000 patients. For the primary outcome of 28-day mortality, the hazard ratio from Cox regression was used to estimate the mortality rate ratio.
The RECOVERY trial provides evidence that treatment with dexamethasone at a dose of 6 mg once daily for up to 10 days reduces 28-day mortality in patients with Covid-19 who are receiving respiratory support.
We found no benefit (and the possibility of harm) among patients who did not require oxygen.
What is the level of evidence provided by this article?A1b Individual randomized controlled trials
Please do your own search and summarise the outcome of the different arms of the recovery trial.
Recovery Trial
Coronavirus disease 2019 (Covid-19) is associated with diffuse lung damage. Glucocorticoids may modulate inflammation-mediated lung injury and thereby reduce progression to respiratory failure and death.
Methodology
In this controlled, open-label trial comparing a range of possible treatments in patients who were hospitalized with Covid-19, we randomly assigned patients to receive oral or intravenous dexamethasone (at a dose of 6 mg once daily) for up to 10 days or to receive usual care alone. The primary outcome was 28-day mortality.
Azithromycin
Standard Care + Azithromycin 500 mg OD 10 days VS Standard care
Azithromycin did not improve outcomes
Aspirin
Aspirin 150 mg OD plus standard care VS Standard Care
Aspirin was not associated with improved 28 days mortality
Baricitinib
Baricitinib for 10 days and standard care VS Standard care
Baricitinib reduced the risk of death
Colchicine
Colchicine + Standard care VS Standard care
No improvement in survival
Hydroxychloroquine -HCQ
HCQ + standard care VS Standard care
HCQ did not improve survival
Lopinavir/Rotinavir
It did not improve survival as compared to standard care alone
Rengen COV
Rengen COV 8 mg and standrad care VS standard care
Rengen COV did improve 28 days mortality
Tocilizumab
It improved outcomes in patients with hypoxia and inflammation
Please summarise this article.
Introduction
Coronavirus disease is associated with diffuse lung damage. Glucocorticoids may modulate inflammation-mediated lung injury and thereby reduce progression to respiratory failure and death.
METHODOLOGY
In this trial comparing a range of possible treatments in patients who were hospitalized with Covid-19 patients received oral or intravenous dexamethasone (at a dose of 6 mg once daily) for up to 10 days or to receive usual care alone.
The primary outcome- 28-day mortality.
RESULTS
Total of 2104 patients received dexamethasone
4321 to received usual care
482 patients (22.9%) in the dexamethasone group died
1110 patients (25.7%) in the usual care group died
In the dexamethasone group, the incidence of death was lower than that in the usual care group among patients receiving invasive mechanical ventilation and among those receiving oxygen without invasive mechanical ventilation but not among those who were receiving no respiratory support at randomization .
CONCLUSIONS
In patients hospitalized with Covid-19, the use of dexamethasone resulted in lower 28-day mortality among those who were receiving either invasive mechanical ventilation or oxygen alone at randomization but not among those receiving no respiratory support.
1. What is the level of evidence provided by this article
Level is 1b
Summary
Introduction
This article is focussed around the usage of Dexamethasone in COVID 19 patients in the hospital setting. The reasoning behind using dexamethasone is that it is a glucocorticoid, and this group of drugs modulate inflammation mediated lung injury, and thereby reduce progression to respiratory failure and death.
Discussion
This article is based on a controlled open label trial where different treatments of COVID 19 patients in the hospital setting have been compared and contrasted by randomly assigning patients to receive either oral or intravenous dexamethasone 6 mg OD for a period of 10 days.
Inflammatory lung damage is more prominent a week after the onset of symptoms, and dexamethasone benefit can also be seen more clearly after this period. Patients requiring oxygen support have benefited greatly with this drug regimen, with a greater chance of cessation of the need for mechanical support for ventilation. Patients also have a decreased risk of the need for mechanical ventilation when on this regimen. The use of dexamethasone has greatly increased the chance of such patients being discharged from the hospital alive within a time frame of 28 days.
The exact treatment dosage and frequency used in this trial is beneficial, with higher doses leading to possible harm to the patient. In addition, different glucocorticoids can have different effects in patients with other viral replication diseases, and thus caution is to be observed.
Conclusion
Dexamethasone, administered either in the oral or IV form, can reduce 28-day mortality rates in patients infected with COVID-19. The drug is administered to in-patients and includes those who receive invasive mechanical ventilation, just oxygen alone, and those who do not need respiratory support of any kind. However, with those who do not need respiratory support of any kind, this drug may cause possible harm instead of benefit.
The findings of this trial have been confirmed by a meta-analysis of six other trials of using glucocorticoids for critically ill patients with COVID 19.
Level of evidence
Level of evidence is 1 since this article is based on a randomized controlled trial.
I like your well-structured summary, and conclusions. I appreciate level of evidence I. Any further sub-classification of level I?
This study is level 1A – randomized controlled trial.
Reference :
Kapoor MC. Types of studies and research design. Indian J Anaesth. 2016 Sep;60(9):626-630. doi: 10.4103/0019-5049.190616. PMID: 27729687; PMCID: PMC5037941.
I think it’s 1A because this study is part of a meta-analysis and it is a randomized controlled trial.
I have attached an image below. The reference is the same one as mentioned above in my comment.
The RECOVERY Trial:
The RECOVERY trial is a randomized, open-label, adaptive platform trial that is looking at several treatments compared with usual standard of care in patients admitted in hospitals in the UK with COVID 19. The primary outcome is 28 day mortality with other secondary prespecified outcomes of length of hospital stay and progression to mechanical ventilation. There were several treatments evaluated:
Azithromycin:
Azithromycin 500 mg once daily for 10 days plus usual standard of care versus usual standard of care
The results showed that azithromycin did not improve survival or other pre-specified clinical outcomes
Aspirin:
Aspirin 150 mg once daily until discharge plus usual standard of care versus usual standard of care
The results showed that aspirin was not associated with a reduction in 28 day mortality
Baricitinib:
Baricitinib 4 mg mg once daily for 10 days plus usual standard of care versus usual standard of care
The results showed that baricitinib significantly reduced the risk of death but the size of benefit was somewhat smaller than that suggested by previous trials
Colchicine:
Colchicine twice daily plus usual standard of care versus usual standard of care
The results showed that colchicine did not improve survival
Convalescent Plasma:
Convalescent plasma plus usual standard of care versus usual standard of care
The results showed that high-titer convalescent plasma did not improve survival or other pre-specified clinical outcomes
Dimethylfuroate (DMF):
DMF 120 mg twice daily for 2 days followed by 240 mg twice daily for eight days plus usual standard of care versus usual standard of care
The results showed that DMF did not improve survival or other pre-specified clinical outcomes
Hydroxychloroquine (HCQ):
Hydroxychloroquine daily for 10 days plus usual standard of care versus usual standard of care
The results showed that HCQ did not improve survival or other pre-specified clinical outcomes
Lopinavir/Ritonavir:
Lopinavir/Ritonavir (400mg/100mg) once daily plus usual standard of care versus usual standard of care
The results showed that Lopinavir/Ritonavir did not improve survival or other pre-specified clinical outcomes
RENGEN-COV:
RENGEN COV 8 gm intravenously as a single dose plus usual standard of care versus usual standard of care
The results showed that RENGEN-COV reduced 28 day mortality
Tocilizumab:
Tocilizumab 400-800 mg once given intravenously as a single dose or 2 doses depending on the response plus usual standard of care versus usual standard of care
The results showed that tocilizumab improved survival and other outcomes in patients with hypoxia and inflammation
Summary Of The Article:
Introduction
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in China in 2019, and caused coronavirus disease 2019 (COVID-19). Many patients had mild disease, unfortunately a substantial percentage of patients developed critical illness requiring hospital care. The pathophysiological features of severe COVID-19 included an acute pneumonic process with extensive radiologic opacity, diffuse alveolar damage, inflammatory infiltrates and microvascular thrombosis. It is thought that the host immune response may result in inflammatory organ injury. This study reports the results of the trial of dexamethasone in patients hospitalized with COVID-19.
Methods
The study, a controlled, open-label Randomized Evaluation of COVID-19 Therapy (RECOVERY) trial was designed to evaluate the effects of potential treatment in patients hospitalized with COVID-19 infection. It involved 176 National Health Service organizations in the United Kingdom. Patients were randomized to receive either the usual standard of care alone, or the usual standard of care plus oral or intravenous dexamethasone for up to 10 days. The primary outcome was all cause mortality within 28 days of randomization. Secondary outcomes included the time until discharge from the hospital, progression to invasive mechanical ventilation or death. Other pre-specified clinical outcomes included cause-specific mortality, requirement of renal dialysis or hemofiltration, major cardiac arrhythmias and duration of ventilation.
Results
11,303 patients underwent randomization from 19th March to 8th June 2020. A total of 9355 were eligible to receive dexamethasone, out of which 6425 underwent randomization to receive either dexamethasone, or usual care alone. 36% of the patients were female and 18% were black Asian or from a minority ethnic group. The mean age was 66.1+/-15.7 years. 24% of the patient had diabetes, 27% had heart disease, 21% had chronic lung disease and 56% had at least one major coexisting illness.
The mortality at 28 days was significantly lower in the patients receiving dexamethasone compared to that in the usual care group. In patients receiving dexamethasone, there was a great benefit seen among those on invasive ventilation.
A shorter duration of hospital stay was seen in those patients who receive dexamethasone. The risk of progressing to invasive mechanical ventilation was lower in the dexamethasone group. Among patients who were not receiving dialysis or hemofiltration, the number of patients who progressed to renal replacement therapy was lower in the dexamethasone group. The deaths due to COVID-19 infection was less frequent in the dexamethasone group. There was no difference in the incidence of new cardiac arrhythmias in both groups.
Discussion
The results showed that the use of dexamethasone for up to 10 days resulted in a lower 28 day mortality than usual care in patients hospitalized and on mechanical ventilation with COVID-19 infection. However, there was no evidence that dexamethasone was of any benefit among patients who were not receiving respiratory support. It was noted that high doses may be more harmful than helpful due to the possible risk of infections
Level Of Evidence: This was a randomized controlled trial – Level I
I like your well-structured summary, and conclusions. I appreciate level of evidence I. Any further sub-classification of level I?
Thank you Professor Sharma
Its Ib
Please do your own search and summarize the outcome of the different arms of the recovery trial.
RECOVERY trial:
Evaluate the effects of potential treatments in hospitalized patient with Covid-19 on 28-day mortality
Aspirin:
-Aspirin 150 mg once daily
-It was not associated with reductions in 28-day mortality or in the risk of progressing to invasive mechanical ventilation or death.
-Although there was a small increase in the likelihood of being discharged alive this does not seem to be sufficient to justify its widespread use for patients hospitalized with COVID-19.
Azithromycin:
-Azithromycin 500 mg OD for 10 days.
-There was also no evidence of beneficial effects on the risk of progression to mechanical ventilation or length of hospital stay.
Colchicine:
-There has been no convincing evidence of the effect of colchicine on clinical outcomes in patients admitted to hospital with COVID-19
Baricitinib (JAK inhibitors):
-The dose 4mg tablet once daily for 10 days (or until discharge from hospital if sooner).
– The result confirms and extends earlier findings in other trials.
– Treatment significantly reduced deaths: a reduction of 13%
– It is also reduced the chance of progressing to invasive mechanical ventilation or death
– The benefit of baricitinib was consistent regardless of which other COVID-19 treatments the patients were also receiving, including corticosteroids, tocilizumab, or remdesivir.
Hydroxychloroquine:
-Enrollment stooped.
-There was no significant difference in the primary endpoint of 28-day mortality
-There was also no evidence of beneficial effects on hospital stay duration or other outcomes
Convalescent plasma:
– Shows no significant difference in the primary endpoint of 28-day mortality
– Follow-up of patients is ongoing and final results will be published as soon as possible.
Dexamethasone:
-Low dose 6 mg once per day PO/ IV for 10 days
-It reduced deaths by one-third in ventilated patients (rate ratio 0.65) and by one fifth in other patients receiving oxygen only (0.800)
There was no benefit among those patients who did not require respiratory support
-High dose 20 mg once daily for 5 days followed by 10 mg once daily for 5 days or until discharge if sooner.
-Higher dose corticosteroids significantly increased the risk of death compared to usual care, which included low dose corticosteroids.
lopinavir–ritonavir:
– No significant difference in the primary endpoint of 28-day mortality
– No evidence of beneficial effects on the risk of progression to mechanical ventilation or length of hospital stay
Dimethyl fumarate DMF
– Dose:120 mg by mouth every 12 hours for the first four doses followed by 240mg every 12 hours for the total treatment duration of 10 days or until hospital discharge, whichever was sooner.
-Treatment with DMF was not associated with an improvement in this measure compared with usual care alone
Tocilizumab.
-Treatment with tocilizumab significantly reduced deaths, increased the probability of discharge alive within 28 days and significantly reduced the chance of progressing to invasive mechanical ventilation or death
-There was no evidence that tocilizumab had any effect on the chance of successful cessation of invasive mechanical ventilation.
– In hospitalized COVID-19 patients with hypoxia and systemic inflammation, tocilizumab improved survival and other clinical outcomes. These benefits were seen regardless of the amount of respiratory support and were additional to the benefits of systemic corticosteroids.
REGN-COV2
–a combination of two monoclonal antibodies directed against the SARS-CoV-2 spike protein.
-seronegative: had not mounted a natural antibody response of their own.
-seropositive : had already developed natural antibodies.
-Among seronegative patients at baseline treatment reduced the primary outcome of 28-day mortality by one-fifth but not in seropositive.
Please summarize this article.
Introduction:
– Covid-19 infection caused severe respiratory illness and diffuse lung injury with high fatality rate.
– Several therapeutic interventions have been proposed to mitigate inflammatory organ injury in viral pneumonia, but the value of glucocorticoids has been widely debated.
Method:
-Controlled, open-label trial
-Compared a range of possible treatments in patients who were hospitalized with Covid-19,
-Patients randomized to receive oral or IV dexamethasone (at a dose of 6 mg once daily) for up to 10 days or to receive the usual care.
– Eligibility: hospitalized patients if clinically suspected or laboratory confirmed SARS-CoV-2 infection, No medical prevent them from participating, no restriction for, pregnant and breastfeeding women included.
Primary outcome was 28-day all causes of mortality.
Secondary outcomes: Time until discharge from the hospital. Cessation from mechanical ventilation (MV). In nonventilated patient, subsequent receipt of invasive MV or death.
Results:
– Total of 6425 randomized to receive either dexamethasone (2104 patients) or usual care alone (4321 patients)
– At randomization: 16% were receiving invasive mechanical ventilation or ECMO, 60% were receiving oxygen only (with or without noninvasive ventilation), and 24% were receiving neither.
– Overall, 28 days mortality (22.9%) in the dexamethasone group and (25.7%) in the usual care group.
-The proportional and absolute differences in mortality varied according to the level of respiratory support
at the time of randomization.
– The greatest benefit among patients who were receiving invasive MV.
-In the dexamethasone group, the incidence of death was lower than that in the usual care group among patients receiving:
– Invasive mechanical ventilation (29.3% vs. 41.4)
– Oxygen without invasive mechanical ventilation (23.3% vs. 26.2%)
– Not among patients with no respiratory support at randomization (17.8% vs. 14.0%)
– Secondary Outcomes: dexamethasone group had a shorter duration, lower risk for progression to MV and less need for dialysis.
Level of evidence: 1b evidence obtained from single RCT.
I like your well-structured summary, and conclusions. I appreciate level of evidence Ib.
Summarise this article.
METHODS
Open-label trial comparing a range of possible treatments in patients who were hospitalized with Covid-19, we randomly assigned patients to receive oral or intravenous dexamethasone for up to 10 days or to receive usual care alone.
The primary outcome was 28-day mortality.Here, we report the final results of this assessment
RESULTS
A total of 2104 patients were assigned to receive dexamethasone and 4321 to receive usual care.
482 patients (22.9%) in the dexamethasine group and 1110 patients (25.7%) in the usual care group died within 28 days after randomization.
The proportional and absolute between-group differences in mortality varied considerably according to the level of respiratory support that the patients were receiving at the time of randomization.
The incidence of death was lower than that in the usual care group among patients receiving invasive mechanical ventilation CI, 0.51 to 0.81) and among those receiving oxygen without invasive mechanical ventilation (23.3% vs 26.2%; rate ratio, 0.82; 95% CI, 0.72 to 0.94) but not among those who were receiving no respiratory support at randomization (17.8% vs 14.0%; rate ratio, 1.19; 95% CI, 0.92 to 1.55)
CONCLUSIONS
In patients hospitalized with Covid-19, the use of dexamethasine resulted in lower 28-day mortality among those who were receiving either invasive mechanical ventilation or oxygen alone at randomization but not among those receiving no respiratory support.
We report the results of the controlled, open-label Randomized Evaluation of Covid-19 Therapy (RECOVERY) trial of dexamethasone in patients hospitalized with Covid-19.
The RECOVERY trial was designed to evaluate the effects of potential treatments in patients hospitalized with Covid-19 at 176 National Health Service organizations in the United Kingdom and was supported by the National Institute for Health Research Clinical Research Network.
Randomization We collected baseline data using a Web-based case-report form that included demographic data,the level of respiratory support, major coexisting illnesses, suitability of the trial treatment for a particular patient, and treatment availability at the trial site.
The randomly assigned treatment was prescribed by the treating clinician.Patients and local members of the trial staff were aware of the assigned treatments
Procedures
A single online follow-up form was to be completed by the local trial staff when each patient was discharged or had died or at 28 days after randomization, whichever occurred first.
Through the play of chance in the unstratified randomization, the mean age was 1.1 years older among patients in the dexamethasine group than among those in the usual care group (Table 1)
To account for this imbalance in an important prognostic factor, estimates of rate and risk ratios were adjusted for the baseline age in three categories (<70 years, 70 to 79 years, and ≥80 years).
Among the patients who were not receiving invasive mechanical ventilation at randomization, the number of patients who progressed to the prespecified composite secondary outcome of invasive mechanical ventilation or death was lower in the dexamethasine group than in the usual care group (Table 2).
There were four reports of a serious adverse reaction that was deemed by the investigators to be related to dexamethasone two of hyperglycemia, one of gastrointestinal hemorrhage, and one of psychosis
Discussion
Our results show that among hospitalized patients with Covid-19, the use of dexamethasine for up to 10 days resulted in lower 28-day mortality than usual care in patients who were receiving invasive mechanical ventilation at randomization and those who were receiving oxygen without invasive mechanical ventilation The greater mortality benefit of dexamethasone in patients with Covid-19 who are receiving respiratory support and among those recruited after the first week of their illness suggests that at that stage the disease may be dominated by immunopathological elements, with active viral replication playing a secondary role.
The RECOVERY trial provides evidence that treatment with dexamethasone at a dose of 6 mg once daily for up to 10 days reduces 28-day mortality in patients with Covid-19 who are receiving respiratory support.
summarise the outcome of the different arms of the recovery trial.
Tocilizmumab
Tocilizumab increased survival and other clinical outcomes in COVID-19 hospitalized patients with hypoxia and systemic inflammation.
These advantages were noted in addition to those of systemic corticosteroids and were independent of the level of respiratory support.
Azithromycine
Azithromycin did not enhance clinical outcomes such as survival or other predetermined clinical outcomes in patients admitted to hospitals with COVID-19.
Only patients with a clear antibacterial indication should receive azithromycin when they are hospitalized with COVID-19.
Hydroxycholowuinine
The rate of death at 28 days was not any lower among Covid-19 hospitalized patients who got hydroxychloroquine compared to those who received standard therapy.
Aspirin
Aspirin did not reduce the 28-day mortality rate in COVID-19 patients who were hospitalized, the risk of dying or progressing to invasive mechanical ventilation, but it did slightly raise the percentage of patients who were released alive after 28 days.
Colchicines
Colchicine was not linked to decreased 28-day mortality, length of hospital stay, likelihood of advancing to invasive mechanical ventilation, or risk of death in persons hospitalized with COVID-19.
level of evidence; 1
I like your well-structured summary, and conclusions. I appreciate level of evidence that you have allocated to this open labelled trial usage of steroids in patients of COVID19 requiring respiratory support.
Any further sub-classification of level I?
However, spellings of many drugs are incorrect.
i will take care next time
1. Please do your own search and summarise the outcome of the different arms of the recovery trial.
Aspirin dose 150 mg/d
It does not reduce 28-day mortality, invasive mechanical ventilation, or death. It was linked to a little increase in 28-day survival.
Azithromycin Dose 500 mg oral or IV daily for 10 days or till discharge.
no increase in survival or clinical outcomes.
JAK inhibitors—primarily baricitinib —reduce COVID-19 hospitalized mortality by roughly 20%.
Colchicine Dosage 1 mg once, 500 μg 12 h later, 500 μg twice a day by mouth or nasogastric tube for 10 days or until discharge.
It did not reduce 28-day mortality, hospital stay, invasive mechanical ventilation, or death.
Convalescent Plasma:
Survival and other clinical outcomes were unaffected by high-titer convalescent plasma.
Hydroxychloroquine:
The hydroxychloroquine group had a lower rate of hospital discharge within 28 days than the usual-care group. The hydroxychloroquine group had more invasive mechanical ventilation or death in non-mechanically ventilated patients.
lopinavir–ritonavir(400 mg and 100 mg) orally for 10 days or till discharge:
did not reduce 28-day mortality, hospital stay, risk of invasive mechanical ventilation, or death.
Intravenous tocilizumab 400–800 mg (weight-dependent). If the patient’s condition didn’t improve, a second dose could be administered 12–24 h later.
Tocilizumab enhanced survival and other outcomes in COVID-19 patients with hypoxia and systemic inflammation (C-reactive protein >75 mg/L)used in addition to steroids & , regardless of respiratory support.
2. Please summarise this article.
Randomized control open-label multicentre trial, comparing the effect of the use of dexamethasone in hospitalized covid-19 patients with the usual care without steroids
it indicated that dexamethasone ( oral or intravenous dose of 6 mg once daily for up to 10 days) lowered mortality rates by one-third among patients requiring mechanical ventilation and by one-fifth among patients requiring oxygen therapy.
however, it shows little advantage for those who did not require respiratory support.
Primary outcome Death at 28 days Secondary outcomes Discharged from the hospital within 28 days, Invasive mechanical ventilation, or death
Subsidiary clinical outcomes: Use of ventilation, Noninvasive ventilation, Invasive mechanical ventilation), Successful cessation of invasive mechanical &renal-replacement therapy
3. What is the level of evidence provided by this article?
Level 1 RCT
I like your well-structured summary, and conclusions. I appreciate level of evidence that you have allocated to this open labelled trial usage of steroids in patients of COVID19 requiring respiratory support.
Any further sub-classification of level I?
Dexamethasone in Hospitalized Patients with Covid-19
Please do your own search and summarise the outcome of the different arms of the recovery trial.
Aspirin 1
Dose used 150 mg daily.
It not associated with reductions in 28-day mortality or in the risk of progressing to invasive mechanical ventilation or death. It was associated with a small increase in the rate of being discharged alive within 28 days. (Median 8 days, IQR 5 to >28, vs 9 days, IQR 5 to >28) subtle difference
Aspirin didn’t improve survival.
Azithromycin 2
Dose: azithromycin 500 mg once per day by mouth or intravenously for 10 days or until discharge
It did not improve survival or other prespecified clinical outcomes.
Azithromycin has no clinical benefit.
Baricitinib 3
Baricitinib significantly reduced the risk of death, but the size of benefit was somewhat smaller than that suggested by previous trials. The total randomised evidence to date suggests that JAK inhibitors (chiefly baricitinib) reduce mortality in patients hospitalised for COVID-19 by about one-fifth.
Baricitinib reduce death and reduce progression of invasive mechanical ventilator (IMV).
Colchicine 4
Dose 1 mg after randomisation followed by 500 μg 12 h later and then 500 μg twice a day by mouth or nasogastric tube for 10 days in total or until discharge.
It was not associated with reductions in 28-day mortality, duration of hospital stays, or risk of progressing to invasive mechanical ventilation or death.
Colchicine has no benefit.
Convalescent Plasma 5
high-titre convalescent plasma did not improve survival or other prespecified clinical outcomes.
Convalescent plasma didn’t improve survival or another clinical outcome.
Dexamethasone small dose 6
PO or intravenous dexamethasone at a dose of 6 mg once daily for up to 10 days
Dexamethasone high dose 7
(Dexamethasone 20 mg once daily for 5 days followed by 10 mg once daily for 5 days or until discharge if sooner)
clinical hypoxia but requiring either no oxygen or simple oxygen only, higher dose corticosteroids significantly increased the risk of death compared to usual care, which included low dose corticosteroids.
Dimethyl fumarate 8
DMF 120mg twice daily for 2 days followed by 240mg twice daily for 8 days, or until discharge if sooner.
It was not associated with an improvement in clinical outcomes.
Hydroxychloroquine 9
The results suggest that patients in the hydroxychloroquine group were less likely to be discharged from the hospital alive within 28 days than those in the usual-care group (59.6% vs. 62.9%; rate ratio, 0.90; 95% CI, 0.83 to 0.98). Among the patients who were not undergoing mechanical ventilation at baseline, those in the hydroxychloroquine group had a higher frequency of invasive mechanical ventilation or death.
Hydroxychloroquine: has no clinical benefit
Lopinavir-Ritonavir results 10
lopinavir–ritonavir (400 mg and 100 mg, respectively) by mouth for 10 days or until discharge
lopinavir–ritonavir was not associated with reductions in 28-day mortality, duration of hospital stays, or risk of progressing to invasive mechanical ventilation or death. These findings do not support the use of lopinavir–ritonavir for treatment of patients admitted to hospital with COVID-19.
Lopinavir has no significant mortality benefit.
Regeneron’s monoclonal antibody combination results 11
It is non-competing monoclonal antibodies that bind to two different sites on the receptor binding domain of the SARS-CoV-2 spike glycoprotein, blocking viral entry into host cells.
Dose: casirivimab 4 g and imdevimab 4 g administered together in a single intravenous infusion.
It reduced 28-day mortality in patients who were seronegative (and therefore had not mounted their own humoral immune response) at baseline but not in those who were seropositive at baseline.
Regenerons monoclonal antibodies combination reduce death for hospitalized patients who have not mounted their own immune response.
Tocilizumab 12
Dose tocilizumab at a dose of 400 mg–800 mg (depending on weight) given intravenously. A second dose could be given 12–24 h later if the patient’s condition had not improved.
COVID-19 patients with hypoxia and evidence of systemic inflammation (C-reactive protein ≥75 mg/L), tocilizumab improved survival and other clinical outcomes. These benefits were seen regardless of the amount of respiratory support and were additional to the benefits of systemic corticosteroids.
Tocilizumab reduce death in hospitalized severe COVID-19 patients.
Summary this article
Introduction
Covid 19 that first appeared in China presented with acute pneumonic features that can lead to respiratory failure with high fatality rate.
The extensive radiologic opacity, diffuse alveolar damage, inflammatory
infiltrates, and microvascular thrombosis revealed the severe inflammatory response confirmed with elevated inflammatory markers.
Meanwhile steroids role was controversial.
Glucocorticoids use was not recommended except in severe cases.
Majority of COVID-19 patients either asymptomatic or presented with mild symptoms.
Large percentage of patient need hospital admission mainly due to respiratory symptoms which can progressed to hypoxia & respiratory failure & need for IMV.
IN UK 2020, mortality was 26% and >37% of patients need IMV.
Remdesivir reduce hospital stay, but no drug reduce mortality.
CRP, ferritin, IL-1 & IL-6 were high in COVID-19 patients.
Method
Controlled open-label randomized trial.
9355 patients underwent randomization between dexamethasone & other treatment.
6425 patients randomized between dexamethasone and usual care alone (2104 patients in dexamethasone group & 4321 in usual care group).
Included suspected or diagnosed COVID-19 hospitalized patient including pregnant and breast-feeding females.
Patients assigned with 2:1 ratio to receive usual standard care alone or usual standard care with oral or IV dexamethasone (6 mg for 10 days) or receive one of other citable and available treatment evaluated in trial.
Patient didn’t receive dexamethasone (due to unavailability) excluded from randomization.
Primary outcome was all cause mortality within 28 days after randomization (other analysis specified at 6 months).
Secondary outcome: time until discharge from hospital and among patients do not receive IMV at time of randomization, subsequent receipt of IMV or death.
Other pre-specified clinical outcome includes cause specific mortality, receipt of renal dialysis or hemofiltration, major cardiac arrhythmia and recent and duration of ventilation.
Result & discussion
28 days mortality reduced in patients used dexamethasone for 10 days (in patients on IMV or patients need oxygen with or without IMV).
No evidence of benefit from steroid among patients do not receive respiratory support & it may cause harm.
Benefit was clear in patients who use steroid >7 days after symptoms onset (common lung damage).
Dexamethasone used to reduce risk of IMV in patients receive oxygen & in patients on IMV increase chance of cessation & discharge from hospital life within 28 days.
Mortality in usual care group was consistent with over all case fatality rate for hospitalized COVID-19 patients in UK at time of dexamethasone comparison was active.
Dexamethasone results released at June16,2020(<100 days after protocol first drafted) & adopted in UK practice at same day.
Corticosteroid widely used in SARS, MERS, severe influenza & community acquired pneumonia.
Beneficial effect of steroid depends on right dose, right time & right patients.
High dose steroids may be more harmful than helpful.
Viral replication of COVID-19 high in early stage of disease, so beneficial effect of steroid after 1 week may be due to immunopathological element.
Guidelines update to recommend use of steroids in hospital patients with COVID-19 need O2 with or without need of IMV.
Conclusion
Dexamethasone intake resulted in lower 28-day mortality in hospitalized cases among those who had either invasive mechanical ventilation or oxygen alone but not among those without respiratory support but dexamethasone did not show any benefit for cases who did not need respiratory support .
What is the level of evidence provided by this article? Level of evidence is 1.
References:
1)Abani, Obbina, et al. “Aspirin in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial.” The Lancet 399.10320 (2022): 143-151.
2)Abaleke, Eugenia, et al. “Azithromycin in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial.” The Lancet 397.10274 (2021): 605-612.
3)Abani, Obbina, et al. “Baricitinib in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial and updated meta-analysis.” The Lancet 400.10349 (2022): 359-368.
4)RECOVERY Collaborative Group. “Colchicine in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial.” The Lancet Respiratory Medicine 9.12 (2021): 1419-1426.
5)Abani, Obbina, et al. “Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial.” The Lancet 397.10289 (2021): 2049-2059.
6)RECOVERY Collaborative Group. “Dexamethasone in hospitalized patients with Covid-19.” New England Journal of Medicine 384.8 (2021): 693-704.
7)RECOVERY Collaborative Group, et al. “Higher dose corticosteroids in hospitalised COVID-19 patients with hypoxia but not requiring ventilatory support (RECOVERY): a randomised, controlled, open-label, platform trial.” medRxiv (2022): 2022-12.
8)RECOVERY Collaborative Group, et al. “Dimethyl fumarate in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial.” medRxiv (2022): 2022-09.
9)RECOVERY Collaborative Group. “Effect of hydroxychloroquine in hospitalized patients with Covid-19.” New England Journal of Medicine 383.21 (2020): 2030-2040.
10)Horby, Peter W., et al. “Lopinavir–ritonavir in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial.” The Lancet 396.10259 (2020): 1345-1352.
11)RECOVERY Collaborative Group. “Casirivimab and imdevimab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial.” Lancet (London, England) 399.10325 (2022): 665.
12)RECOVERY Collaborative Group. “Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomised, controlled, open-label, platform trial.” Lancet (London, England) 397.10285 (2021): 1637.
I like your well-structured summary in great details and conclusions with a long list in relevant references. I appreciate level of evidence that you have allocated to this open labelled trial usage of steroids in patients of COVID19 requiring respiratory support.
Any further sub-classification of level I?
Please do your own search and summarise the outcome of the different arms of the recovery trial.
Hydroxychloroquine
1172 Were assigned to receive hydroxychloroquine
In June 2020, the RECOVERY trial concluded that hydroxychloroquine had no beneficial effect in patients hospitalised with COVID-19, and stopped enrolling participants to that arm of the trial immediately
Dexamethasone
Reduced deaths of hospitalised COVID-19 patients with severe respiratory complications by up to one third
Dexamethasone is the first drug to be shown to improve survival in COVID-19. It is inexpensive, on the shelf, and can be used immediately to save lives worldwide
Lopinavir–ritonavir
1183 Were assigned to receive lopinavir–ritonavir
No significant mortality benefit in hospitalised COVID-19 patients
Colchicines
In March 2021, the trial closed the colchicine arm of the trial, as it had found no benefit to patients
Aspirin
o 7351 patients were randomly allocated (1:1) to receive aspirin and 7541 patients to receive usual care alone
o Slightly shorter duration of hospitalisation and a higher proportion were discharged from hospital alive within 28 days
o Among patients not on invasive mechanical ventilation at baseline, there was no significant difference
Azithromycin
575 were assigned to receive azithromycin
In December 2020, the RECOVERY team released preliminary results showing it has no effect on clinical outcomes in COVID-19
Tocilizumab
Reduces the risk of death for hospitalised patients with severe COVID-19, shortens the time taken for patients to be successfully discharged from hospital, and reduces the need for a mechanical ventilator
Baricitinib
In March 2022, the RECOVERY trial reported that baricitinib reduces the risk of death when given to hospitalised patients with severe COVID-19 (reduced deaths by 13%)
It also reduced the chance of progressing to invasive mechanical ventilation
Remdesivir
Superior to placebo in shortening the time to recovery in adults who were hospitalized with Covid-19 and had evidence of lower respiratory tract infection
Convalescent plasma
No convincing evidence of the effect of convalescent plasma on clinical outcomes in patients admitted to hospital with COVID-19
Dimethyl fumarate
Does not improve recovery for patients hospitalised with COVID-19
Regeneron monoclonal antibody combination
Reduces the risk of death when given to patients hospitalised with severe COVID-19 who have not mounted a natural antibody response of their own
Promising treatments:
Please summarise this article.
Introduction
o Covid-19 can be associated with severe pneumonia with high mortality rate. Glucocorticoids may reduce progression to respiratory failure and death
o One small trial has reported improved clinical outcomes in patients recieving methylprednisolone (no large-scale randomized clinical trials)
Methods
o Clinically suspected or laboratory confirmed SARS-CoV-2 infection were eligible. Also pregnant or breast-feeding women were eligible
o This is an open-label controlled trial of patients hospitalized with Covid-19. They randomly receive oral or intravenous dexamethasone (at a dose of 6 mg once daily) for up to 10 days or to receive usual care alone
o The primary outcome: death at 28 days
o Secondary outcomes: discharged from hospital within 28 days/ Invasive mechanical ventilation or death
Results
o 6425 underwent randomization to receive either dexamethasone (2104 patients) or usual care alone (4321 patients)
o In the dexamethasone group, 95% of the patients received at least one dose of a glucocorticoid (The median duration of treatment was 7 days)
o Mortality at 28 days was significantly lower in the dexamethasone group than in the usual care group, with deaths reported in 482 of 2104 patients (22.9%) and in 1110 of 4321 patients (25.7%), respectively
o In the dexamethasone group, the incidence of death was lower than that in the usual care group among patients receiving invasive mechanical ventilation (29.3% vs. 41.4%) and among those receiving oxygen without invasive mechanical ventilation (23.3% vs. 26.2%) but not among those who were receiving no respiratory support at randomization (17.8% vs. 14.0%)
o Patients in the dexamethasone group had a shorter duration of hospitalization than those in the usual care group (median, 12 days vs. 13 days) and a greater probability of discharge alive within 28 days
Discussion
o The RECOVERY trial provides evidence that treatment with dexamethasone at a dose of 6 mg once daily for up to 10 days reduces 28-day mortality in patients with Covid-19 who are receiving respiratory support
o Guidelines issued by the U.K. chief medical officers, the European Medicines Agency, the WHO, and the National Institutes of Health in the United States have been updated to recommend the use of glucocorticoids in patients hospitalized with Covid-19 requiring oxygen with or without ventilatory support
Conclusions
The use of dexamethasone in patients hospitalized with Covid-19 resulted in lower 28-day mortality among those who were receiving respiratory supports (invasive mechanical ventilation or oxygen alone) but not among those receiving no respiratory support
What is the level of evidence provided by this article?Level I (open-label randomized control trial)
I like your well-structured summary in great details, and conclusions. I appreciate level of evidence that you have allocated to this open labelled trial usage of steroids in patients of COVID19 requiring respiratory support.
Any further sub-classification of level I?
Thank you prof.
Ib
Study design
This is a controlled open liable trial of two arms of the clinical intervention in hospitalized covid 19 patients on different o2 therapy support, the dexamethasone arm 6mg iv, oral for 10 days, and the usual care arm. A recovery trial was published in NEJM with an IF of 176.082 for 2023.
Primary outcome
Compare the 28 days mortality between the two intervention groups
Please summarize this article.
Introduction
Severe acute respiratory SRAS-2 COVID-19 viral pneumonia with pandemic effect happening in China and spread globally from zoonotic infection in late 2019. the disease has a very variable clinical presentation from asymptomatic or mild illness in the majority of cases to severe acute respiratory distress syndrome requiring hospitalization and in some percentage, invasive ventilation in intensive care complicated with Multiple organ dysfunction with death in UK case fatality reported up to 26% in those requiring invasive ventilation, antiviral like remidesvir shows benefit in term of hasten the recovery in severe cases but not affect the overall mortality risk based reports from many studies no therapeutic agents have been shown to reduce mortality with sever Sars 2 covid 19 pneumonia. the main finding includes a pneumonic process with extensive radiologic opacity and, on autopsy, diffuse alveolar damage, inflammatory infiltrates, and microvascular thrombosis.
Method
Setting
Open liable RCT with treatment intervention in hospitalized patients with Covid-19 at 176 National Health Service organizations in the United Kingdom were supported by the National Institute for Health Research Clinical Research Network consent formed was taken from the patients or their representatives including all cases with clinical suspicion or diagnosed with covid 19, earlier age limited 18 and above however after may 2020 they removed the age limit, web-based data collection including patients demographics and clinical characteristics, comorbid, level of o2 therapy and support, treatment in each arm eligible and consented patients were assigned into 2;1 ratio One arm for the standard of care and another group standard of care with oral or IV dexamethasone 6 mg for 10 days or till discharge. Both the patient and the staff member from the trial are aware of the assigned treatment, however, some patients did not receive the dexamethasone assigned treatment because of not available or contraindicated so those patients are excluded from the randomization. The data of a single FU chart was documented by the allocated trial staff upon discharge or the date of the death or at 28 days after randomization whichever occur first.
The primary outcome
Death at 28 days
Secondary outcome
1. hospital discharge within 28 days in patients not received ventilatory support at the time of randomization
2. Successful cessation from mechanical invasive ventilatory support including ECMO support or death within 28 days.
Subgroup analysis
Receipt of renal dialysis or hemofiltration.
major cardiac arrhythmia
receipt and duration of ventilation. Among those receiving invasive mechanical ventilation at the time of randomization use measured death
outcome of successful cessation of invasive mechanical ventilation was defined as cessation within (and survival till) 28 days
The data was completed for all patients 99.9%
Results
11,303 enrolled
3% (370) excluded not received Dexamethasone and an additional 15% are not fit for dexa therapy
83% underwent randomization > 9350 patients
2930 Were assigned to receive other active treatment
1183 Were assigned to receive lopinavir-ritonavir
1172 Were assigned to receive hydroxychloroquine
575 Were assigned to receive azithromycin
6425 (57%) underwent randomization between dexamethasone and usual care alone
2104 (100%) Were assigned to receive dexamethasone
1996/2095 (95%) Received dexamethasone, 2 dropped the consent.
4321 (100%) Were assigned to receive usual care alone,47/4306 (8%) Received dexamethasone
Primary outcome
Figure 2 shows Kaplan Meier the survival at 28 days for all patients according to the type of oxygen support ( primary outcome ) which is not adjusted to age while the rate ratio adjusted to age ( 3 groups < 70, 70-79, > 80 )
There is a better survival rate seen in the group with invasive ventilatory support and dexamethasone as shown in fig 3 (29.3% vs. 41.4%; rate ratio, 0.64; 95% CI,
0.51 to 0.81). However, there was no clear effect of dexamethasone among patients who were not receiving any respiratory support at randomization (17.8% vs. 14.0%; rate ratio, 1.19; 5% CI, 0.92 to 1.55), patients with longer duration of symptoms > 7 days they benefit from the addition of dexamethasone
Secondary outcome
All secondary outcomes result in favor of the dexamethasone treatment arm compared to the usual care arm as shown in Table 2
show that among the patients who were receiving oxygen, the use of dexamethasone was associated with a lower risk of invasive mechanical ventilation or, for those already receiving
invasive mechanical ventilation, a greater chance of successful cessation
Conclusion
The RECOVERY trial provides evidence that treatment with dexamethasone at a dose of 6 mg once daily for up to 10 days reduces 28-day mortality in patients with Covid-19 who are receiving respiratory support. We found no benefit (and the possibility of harm) among patients who did not require oxygen
What is the level of evidence provided by this article?
RCT with level 1A of evidence
please do your own search and summarise the outcome of the different arms of the recovery trial.
1. RECOVERY Collaborative Group. Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomized controlled, open-label, platform trial. Lancet. 2021 May 29;397(10289):2049-2059. doi: 10.1016/S0140-6736(21)00897-7. Epub 2021 May 14. PMID: 34000257; PMCID: PMC8121538.
Clarification: In patients hospitalized with COVID-19, high-titer convalescent plasma did not improve survival or other prespecified clinical outcomes
2. RECOVERY Collaborative Group. Tocilizumab in patients admitted to hospital with COVID-19 (RECOVERY): a randomized, controlled, open-label, platform trial. Lancet. 2021 May 1;397(10285):1637-1645. doi: 10.1016/S0140-6736(21)00676-0. PMID: 33933206; PMCID: PMC8084355.
Eligible criteria for inclusion are all patients with ever covid pneumonia with O2 saturation < 92% in RA and requiring o2 support with high inflammatory markers CRP> 75, randomization ratio 1:1 one arm standard of care therapy, and the daclizumab arm 400mg or 800mg plus standard of care
The primary outcome was 28-day mortality, assessed in the intention-to-treat population
this trial in favor of the tocilizumab arm with better survival at 28 days, patients allocated to tocilizumab were more likely to be discharged from hospital within 28 days (57% vs 50%; rate ratio 1·22; 1·12-1·33; p<0·0001).
The Conclusion of this trial, tocilizumab improved survival and another clinical outcome in patients with severe covid -19 pneumonia (hypoxic and high inflammatory response)
3. RECOVERY Collaborative Group. Colchicine in patients admitted to hospital with COVID-19 (RECOVERY): a randomized, controlled, open-label, platform trial. Lancet Respir Med. 2021 Dec;9(12):1419-1426. doi: 10.1016/S2213-2600(21)00435-5. Epub 2021 Oct 18. PMID: 34672950; PMCID: PMC8523117.
Interpretation: In adults hospitalized with COVID-19, colchicine was not associated with reductions in 28-day mortality, duration of hospital stay, or risk of progressing to invasive mechanical ventilation or death.
4. RECOVERY Collaborative Group. Aspirin in patients admitted to hospital with COVID-19 (RECOVERY): a randomized, controlled, open-label, platform trial. Lancet. 2022 Jan 8;399(10320):143-151. doi: 10.1016/S0140-6736(21)01825-0. Epub 2021 Nov 17. PMID: 34800427; PMCID: PMC8598213.
The aspirin arm did not show survival benefits over the standard-of-care group. Aspirin was not associated with reductions in 28-day mortality or in the risk of progressing to invasive mechanical ventilation or death but was associated with a small increase in the rate of being discharged alive within 28 days.
5. RECOVERY Collaborative Group. Azithromycin in patients admitted to hospital with COVID-19 (RECOVERY): a randomized, controlled, open-label, platform trial. Lancet. 2021 Feb 13;397(10274):605-612. doi: 10.1016/S0140-6736(21)00149-5. Epub 2021 Feb 2. PMID: 33545096; PMCID: PMC7884931.
Azithromycin did not improve survival or other prespecified clinical outcomes. Azithromycin use in patients admitted to hospitals with COVID-19 should be restricted to patients in whom there is a clear antimicrobial indication.
6. RECOVERY Collaborative Group. Lopinavir-ritonavir in patients admitted to hospital with COVID-19 (RECOVERY): a randomized, controlled, open-label, platform trial. Lancet. 2020 Oct 24;396(10259):1345-1352. doi: 10.1016/S0140-6736(20)32013-4. Epub 2020 Oct 5. PMID: 33031764; PMCID: PMC7535623.
lopinavir-ritonavir was not associated with reductions in 28-day mortality, duration of hospital stay, or risk of progressing to invasive mechanical ventilation or death. These findings do not support the use of lopinavir-ritonavir for the treatment of patients admitted to hospitals with COVID-19.
in summary, only dexamethasone and tocilizumab did show survival benefits among different arms of clinical interventions of recovery trial platfrom based RCT
That is a superb list of summaries and take-home message of a number of relevant trials in relation to COVID19.
Typing whole sentence in bold amounts to shouting.
Ia? Really!
Thank you, prof Ajay
I’m correcting the level of evidence 1B
Dexamethasone in Hospitalized Patients with Covid-19.
COVID 19 infection has been emerging on 2019 in China, mortality rate was approximately 26% overall and more than 37% among patients who were undergoing invasive mechanical ventilation. It cause severe acute pneumonic
process with extensive radiologic opacity and, on autopsy, diffuse alveolar damage, inflammatory infiltrates, and microvascular thrombosis, this sever inflammatory process may be propagate and cause multi-organ failure and the main role is to mitigate this inflammatory process to avoid further systems damage which is the role of glucocorticoids that still dose not have strong evident based but here, this controlled, open-label Randomized Evaluation of Covid-19 Therapy (RECOVERY) trial of dexamethasone in patients hospitalized with Covid-19 will discuss this issue.
Methods:
Controlled, open-label trial comparing a range of possible treatment in patients who were hospitalized with Covid-19 patients at 176 National Health service organizations in the United Kingdom, we randomly assigned patients to receive oral or intravenous dexamethasone (at a dose of 6 mg once daily) for up to 10 days or to receive usual care alone. The primary outcome was 28-day mortality.
Results:
A total of 2104 patients were assigned to receive dexamethasone and 4321 to receive usual care with total number 6425 underwent randomization.
Overall, 482 patients (22.9%) in the dexamethasone group and 1110 patients (25.7%) in the usual care group died within 28 days after randomization.
The proportional and absolute between-group differences in mortality varied considerably according to the level of respiratory support that the patient were receiving at the time of randomization. (at randomization, 16% were receiving invasive mechanical ventilation or extracorporeal membrane oxygenation, 60% were receiving oxygen only (with or without noninvasive ventilation), and 24% were receiving neither.
In the dexamethasone group (95% of the patients received at least one dose of a glucocorticoid with median duration of treatment was 7 days), the incidence of death was lower than that in the usual care group (with deaths reported in 482 of 2104 patients (22.9%) and in 1110 of 4321 patients (25.7%), respectively )among patient receiving invasive mechanical ventilation and among those receiving oxygen without invasive mechanical ventilation but not among those who were receiving no respiratory support at randomization.
Patients in the dexamethasone group had a shorter duration of hospitalization than those in the usual care group (median, 12 days vs. 13 days) and a greater probability of discharge alive within 28 days and decrease the incidence of shifting to invasive ventilation from non-invasive group on dexamethasone, also successful cessation of invasive mechanical ventilation was more likely in the dexamethasone group than in the usual care group.
Conclusion:
The study shown evidence that treatment with dexamethasone at a dose of 6 mg once daily for up to 10 days reduces 28-day mortality in patients with Covid-19 who are receiving respiratory support and found that no benefit among patients who did not require oxygen. Before the completion of the trial, many Covid-19 treatment guidelines stated that the use of glucocorticoids was either contraindicated or not recommended and this study give strong evident with large sample size.
Level of evidence: I b (individual RCT)
Yes, I b
1.Please do your own search and summarize the outcome of the different arms of the recovery trial.
The RECOVERY Study has identified 4 treatments for severe COVID-19, & it is presently evaluating the following suggested treatments to see if they are more successful at promoting recovery than the standard therapy that all patients receive:
For COVID-19
For influenza
Randomized allocation of treatment for COVID-19
Randomization part E
Randomization part F:
Randomization part J (UK only):
Randomization part K:
Randomization part L (UK only):
References
=========================
2.Please summarize this article.
Methodology
Eligibility for the trial
Primary outcome:
Secondary outcomes:
Other pre-specified clinical outcomes:
Results
Primary Outcome
Secondary Outcomes
Other pre-specified outcomes
Discussion
=========================
3.What is the level of evidence provided by this article?
Yes Ib.
Results
Conclusion
RECOVARY trial is assessing other arms of therapy of covid 19
Baricitinib (4 mg orally once daily for up to 14 days)
Tofacitinib (10mg twice daily)
Toclizumab (8 mg/kg as a single intravenous dose)
Anakinra (100 mg subcutaneously daily for 10 days)
Remdesivir (200 mg intravenously on day 1 followed by 100 mg daily for 5-10 days total)
Other therapies with no clear benefit
I like your well-structured summary in great details, and conclusions. I appreciate level of evidence that you have allocated to this open labelled trial usage of steroids in patients of COVID19 requiring respiratory support.
SUMMARY
Introduction
One of the most feared complications of COVID-19 infection that could result in mortality is diffuse lung damage, and glucocorticoid has been known to regulate the inflammation-mediated lung injury
Methodology
Results
Primary outcomes
Secondary outcomes
Discussion
The level of evidence is 1
I like your well-structured summary in great details, and conclusions. I appreciate level of evidence that you have allocated to this open labelled trial usage of steroids in patients of COVID19 requiring respiratory support.
Introduction
· Coronavirus 2 (SARS-CoV-2) is the virus responsible for coronavirus disease 2019 (COVID-19) which is mainly a respiratory tract disease. It was discovered in China towards the end of 2019 and it was beloved to be a zoonotic disease.
· At the beginning of 202o the case fatality rate was 26% in UK and > 36% of patients required mechanical ventilation
· Remdesivir reduced recovery time in hospitalized patient but no treatment has been shown to decreased mortality
· Covid-19 causes diffuse alveolar damage, inflammation and microvascular thrombosis
· Glucocorticoid may modulate the intensity of inflammatory process and hence the development of acute respiratory failure and death
Methodology
· This was randomized, open labelled control trial at 176 National Health Service organization in the UK
· All hospitalized patients due to COVID-19 were included, and those who were no suitable for randomization to dexamethasone were excluded.
· Participants were randomized to dexamethasone 6 mg once daily oral/IV for 10 days or usual care (lopinavir-ritonavir, hydroxychloroquine, & azithromycin)
· The primary outcome was 28-day mortality
Results
· In this trial, 2014 were randomized to dexamethasone arm, and 4321 to the usual care
· In general, at 28-days, 23% death in dexamethasone arm and 26 % death in the usual care
· Patients on invasive mechanical ventilation: in these cohorts, the death rate was lower in those who were given dexamethasone versus the usual care (29% vs 41%)
· Patients on oxygen support without invasive mechanical ventilation: Again, dexamethasone had lower death rate (23% vs 26%
· However, the death rate was higher in the dexamethasone group in with patients not on any respiratory support at the time of randomization in comparison to usual care group (18%, 14% respectively)
Conclusion
· The use of dexamethasone was associated with lower incidence of 28 -day mortality compared to standard care in a hospitalized patients who were receiving respiratory supports due to COVID-19
RCT, level 1
Hi Dr Ben,
Any further sub-classification of level 1?
Mortality in CVOID patients requiring mechanical ventilation was much higher than you have quoted.
Thank you prof, noted
Dear colleagues in WKA fellowship,
Please go through this paper well. It is an opportunity for us to learn togather how guidelines should developed, defined and validated in a scientific manner using real RCTs.
Using this paper, I would address some key features of a good trial. It amounts to side-tracking but there are good reasons here. This paper will generate discussion about trials and many good lessons learnt the way trials were conducted during COVID19 pandemic.
While I am not trying trash any approach or recommendations, I wish to use this short story of a ‘dog who lived on a railway platform’ (yes, it happens in Indian subcontinent).
I watched the events in India during COVID pandemic. A lot good happened but, at the same time, many illogical approaches were in vogue:
Please allow me to quote a short story highlighting the role of coincidences (rather than causations) in medical sciences specifically and in life in general.
#HCQS
#Ivermectin
#Doxycycline
#Azithromycin
#Favipiravir
#Zinc
#Vitamin C
#Vitamin D
#Plasma
#IVIG
# mega doses of steroids 40-60 mg of prednisone (or similar drugs) for many weeks as a blanket treatment for everyone (mild moderate and severe disease)
A dog lived at a railway station and he didn’t like the trains pulling over because it blocked his views.
As soon as the train would come to halt, he would start barking and lo and behold the train would start moving. He presented his data in a dog conference and all the attendees endorsed his views and they all concluded barking moves the train.
There however a wise dog was also there, he said just stand there and don’t bark and see what happens?
They did, and the train moved without the barking!
Let’s add a twist.
Further studies showed that out of approximately every 100 trains that passed by, 4 trains were delayed and stayed in the station longer but on continued barking, the train moved on.
Only 1 train didn’t move because of engine failure and to be removed from service.
Results: 99% of trains moved on when the dog barked.
Statistically significant findings!
Please do your own search and summarise the outcome of the different arms of the recovery trial.Aspirin: Aspirin did not reduce the 28-day mortality rate in COVID-19 patients who were hospitalized, the risk of dying or moving to invasive mechanical ventilation, but it did slightly raise the percentage of patients who were discharged alive after 28 days.Azithromycin: Azithromycin did not increase survival or any other predetermined clinical outcomes in individuals who were hospitalized with COVID-19. Patients with a clear antimicrobial indication should only be given azithromycin when they have been admitted to the hospital with COVID-19.Baricitinib: Baricitinib considerably decreased the risk of death in COVID-19 patients who were hospitalized, but the benefit was not as great as earlier studies had predicted. According to all available randomised evidence, JAK medicines (mostly baricitinib) lower mortality in COVID-19 patients who are hospitalized by around one-fifth.Colchicine: In adults hospitalised with COVID-19, colchicine was not associated with reductions in 28-day mortality, duration of hospital stay, or risk of progressing to invasive mechanical ventilation or death.Hydroxychloroquine: hydroxychloroquine group were less likely to be discharged from the hospital alive within 28 days than those in the usual-care group, the hydroxychloroquine group had a higher frequency of invasive mechanical ventilation or death
Dexamethasone small dose and Dexamethasone high dose: improves patient status of health, high dose reported with higher death.
Dimethyl fumarate: It was not associated with an improvement in clinical outcomes.
Casirivimab and imdevimab: In patients admitted to hospital with COVID-19, the monoclonal antibody combination of casirivimab and imdevimab reduced 28-day mortality in patients who were seronegative (and therefore had not mounted their own humoral immune response) at baseline but not in those who were seropositive at baseline.
Regeneron’s monoclonal antibody combination: It reduced 28-day mortality in patients who were seronegative (and therefore had not mounted their own humoral immune response) at baseline but not in those who were seropositive at baseline.
Tocilizumab: Tocilizumab enhanced survival and other clinical outcomes in COVID-19 patients with hypoxia and signs of systemic inflammation (C-reactive protein 75 mg/L).
Please summarise this article.
Introduction:
SARS-CoV-2, the cause of severe acute respiratory syndrome (Covid-19), emerged in China in late 2019 from a zoonotic source. It is characterized by an acute pneumonic process with extensive radiologic opacity and diffuse alveolar damage, inflammatoryinfiltrates, and microvascular thrombosis. Inflammatory organ injury may occur in severe Covid-19, with a subgroup of patients having markedly elevated levels of inflammatory markers. Several therapeutic interventions have been proposed to mitigate inflammatory organ injury, but the value of glucocorticoids has been widely debated.
Design:
The RECOVERY trial was designed to evaluate the effects of potential treatments in patients hospitalized with Covid-19 at 176 National Health Service organizations in the United Kingdom.
Inclusion criteria: Patients had clinically suspected or laboratory confirmed SARS-CoV-2 infection and no medical history that might put them at substantial risk. Written informed consent was obtained from all patients.
Open labeled randomized trial, in a 2:1 ratio to receive either the usual standard of care or dexamethasone for 10 days.
Patients excluded are (dexamethasone was unavailable at the hospital at the time of enrollment or was considered by the managing physician to be either definitely indicated or definitely contraindicated).
Procedure and outcomes:
A single online follow-up form was completed to record adherence to treatment, duration of admission, respiratory support, renal dialysis, and vital status.
Primary outcome was all-cause mortality within 28 days after randomization; secondary outcomes were time until discharge, subsequent receipt of invasive mechanical ventilation, cause-specific mortality, renal dialysis or hemofiltration, major cardiac arrhythmia, and receipt and duration of ventilation.
Results:
The 11,303 patients who underwent randomization from March 19 to June 8, 2020 were eligible to receive dexamethasone (83%) or usual care alone (4321 patients). The mean (±SD) age of the patients was 66.1±15.7 years, 36% were female, and 18% were Black, Asian, or from a minority ethnic group. 89% had laboratory-confirmed SARSCoV-2 infection, 16% were receiving invasive mechanical ventilation or extracorporeal membrane oxygenation, 60% were receiving oxygen only (with or without noninvasiveventilation), and 24% were receiving neither. 95% of the patients received at least one dose of a glucocorticoid, and the median duration of treatment was 7 days. After remdesivir became available in the UK on May 26, 2020, the drug was administered to 3 patients before randomization and 2 patients during the follow-up period.
Outcomes:
Mortality at 28 days was significantly lower in the dexamethasone group than in the usual care group, with deaths reported in 482 of 2104 patients (22.9%) and 1110 of 4321 patients (25.7%). In a prespecified analysis according to the level of respiratory support that the patients were receiving at randomization, there was the greatest absolute and proportional benefit among patients who were receiving invasive mechanical ventilation (P<0.001) and those receiving oxygen without invasive mechanical ventilation.
The results were similar in a post hoc exploratory analysis restricted to the 5744 patients (89.4%) with a positive SARS-CoV-2 test result. Sensitivity analyses without adjustment for age resulted in similar findings. Patients with invasive mechanical ventilation at randomization were on average 10 years younger than those not receiving any respiratory support and had a history of symptoms before randomization for an average of 7 days longer.
Patients in the dexamethasone group had a shorter duration of hospitalization and a greater probability of discharge alive within 28 days, with the greatest effect seen among those receiving invasive mechanical ventilation at randomization.
The dexamethasone group had a lower risk of progression to invasive mechanical ventilation than the usual care group, and successful cessation of invasive mechanical ventilation was more likely. Most deaths were due to Covid-19, and the incidence of death from other causes was similar. There were four reports of serious adverse reactions, two of hyperglycemia, one of gastrointestinal hemorrhage, and one of psychosis.
Discussion:
he RECOVERY trial found that the use of dexamethasone for up to 10 days resulted in lower 28-day mortality than usual care in patients who were receiving invasive mechanical ventilation at randomization and those who were receiving oxygen without invasive mechanical ventilation. However, there was no evidence of any benefit among patients who were not receiving respiratory support at randomization, and the results were consistent with possible harm in this subgroup. The protocol combines the methods used in large, simple trials of treatments for acute myocardialinfarction in the 1980s with the opportunities provided by digital health care in the 2020s. Preliminary results for dexamethasone were announced on June 16, 2020, and were adopted into U.K. practice later the same day.
Glucocorticoids have been widely used in severe viral respiratory infections, but the evidence to support their use is weak due to lack of data from sufficiently powered randomized, controlled trials. The greater mortality benefit of patients with Covid-19 who are receiving respiratory support and after the first week of their illness suggests that at that stage the disease may be dominated by immunopathological elements, with active viral replication playing a secondary role.
Conclusion:
The RECOVERY trial found that dexamethasone at a dose of 6 mg once daily for up to 10 days reduces 28-day mortality in patients with Covid-19 who are receiving respiratory support.
What is the level of evidence provided by this article?Level of evidence I – Randomized control trial.
Any further sub-classification of level 1?
yes Prof. it is Ib
II. Dexamethasone in Hospitalized Patients with Covid-19
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Outcome of the different arms of the recovery trial.
Procedures
The primary outcome was all cause mortality within 28 days after randomization, with secondary outcomes such as time until discharge, receipt of renal dialysis, major cardiac arrhythmia, and ventilation.
Primary Outcome
Secondary Outcomes
Other Prespecified Clinical Outcomes
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Please summarise this article.
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Methods
Trial Design and Oversight
Results
Patients
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Discussion
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CONCLUSIONS
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What is the level of evidence provided by this article?
The level of evidance is 1
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Any further sub-classification of level 1?
Typing whole sentence in bold or typing in capitals amounts to shouting.
I quote you, ‘The trial steering committee determined that at least 2000 patients in the dexamethasone group and 4000 in the usual care group.’
Would the sample size be more is the number would be 3000 in each of these groups?
The different arms of the recovery trial
a) Age-adjusted mortality 21.6% vs 24.6%.
b) When not adjusted for the age imbalance in the baseline the result was similar.
2. Secondary outcome (dexamethasone vs usual care)
a) Mechanically ventilated; 28 days mortality- significantly reduced in dexamethasone group;
I) 29% vs 40.7%.
II) Mechanically ventilated patients were on average 10 days younger than those not receiving respiratory support and were randomized on average 7 days later after symptom onset than those not receiving support.
b) Patients receiving O2; 28 days mortality – significantly reduced in the dexamethasone group
I) 21.5% vs 25%.
c) Patients not receiving respiratory support; no significant difference
I) 17% vs 13.2%.
d) Time from symptoms onset to randomization influenced outcome, dexamethasone was associated with a reduction in 28 days mortality among those with symptoms for > 7 days but not among those with symptoms for < 7 days.
a) median 12 days vs 13 days.
a) rate ratio 0.91.
a) Rate ratio 0.76.
Summary of the Article
The primary outcome
a) 1948 were excluded.
b) 357 did not have dexamethasone available.
c) 1707 were not considered suitable for randomization to dexamethasone.
a) 2930 were assigned to receive other active treatment
b) 1183 were assigned to receive lopinavir-ritonavir
c) 1172 were assigned to receive hydroxychloroquine.
d) 575 were assigned to receive azithromycin.
a) 2104 were assigned to receive dexamethasone, 1996/2095 receive dexamethasone
I) 95 proceed to the second randomization
II) 2104 were included in the 28-day intension-to-treat analysis.
b) 4321 were assigned to receive usual care alone, 347/4306 receive dexamethasone
I) 276 proceed to the second randomization.
II) 4321 were included in the 28-day intention-to-treat analysis
The secondary outcome
Level of evidence
Level ((I))
References
Any further sub-classification of level 1?Typing whole sentence in bold or typing in capitals amounts to shouting.
This is an open-label randomized controlled trial comparing treatment possibilities for patients hospitalized for COVID-19.
Level of Evidence I
Introduction
SARS-CoV 2 has led to severe lung disease all over the planet with alveolar damage and compromised respiratory and systemic conditions.
Inflammatory disease is different from viral pathologies, including Influenza.
Methods
Randomized double-blind study using data from 176 national health services in the United Kingdom with the University of Oxford team comparing a range of medications and their effectiveness.
Primary Endpoint – 28-day mortality
Secondary Objectives – duration of ECMO mechanical ventilation, specific mortality, dialysis, arrhythmias, and other manifestations.
All data were collected until December 2020 (all unvaccinated patients).
Results
11,303 patients with a mean age of 66.1 years. Of these, 6,425 were randomized to Dexamethasone (2,104) or standard treatments (4,321). 16% on mechanical ventilation, 60% on oxygen therapy, and 24% without the need for O2.
28-day mortality was lower in the dexamethasone group 22.9% vs. 25.7% (OR 0.83).
Mechanical ventilation 29.3 x 41.4% (OR 0.64), oxygen therapy 23.3 x 26.2% (OR 0.82).
There was no statistical difference or benefit for patients not requiring oxygen therapy.
In secondary outcomes, patients in the dexamethasone group had a shorter hospital stay and a greater chance of being discharged alive.
– Invasive mechanical ventilation OR 0.79
– Use of non-invasive ventilation OR 0.77
– Successful extubation OR 1.47
– Dialysis OR 0.61
Discussion
The RECOVERY Study shows the impact of dexamethasone on patients in need of oxygen therapy and its impact on minimizing the risks of severity established by the disease. The dose of 6mg for ten days proved to be effective in reducing mortality and complications.
Any example of over-usage of dexa in COVID 19 pandemic?
Yes. When patients became serious, there were protocols with doses of 20mg/day
1- Outcome of different arms of Recovery trial
RECOVERY trial recommended
· stopping colchicine arm due to it’s inefficiency in hospitalized cases with COVID-19.
· No clinical benefit from hydroxychloroquine adminstartion in hospitalised COVID-19 cases.
· dexamethasone as anti-inflammatory agents have positive impact on survival for severe COVID-19 cases if used early at the correct time ,while dexamethasone decreased mortality rate by 1/3.
· Lopinavir had no significant effect on mortality rate due to COVID-19
· Aspirin can prevent blood clots, those cases are at higher risk of thromboembolic manifestations . It is also cheap and available
· Convalescent plasma have not shown enough benefits in COVID-19 therapy
· Azithromycin did not show any clinical benefits
· Tocilizumab lowered mortality rate in hospitalised cases with severe COVID -19 infection.
· Baricitinib reduced mortality in hospitalised severe COVID-19 cases.
· Sotrovimab as a monoclonal antibody for treatment of early mild COVID cases to decrease the need of hospitalisation
· Molnupiravir as an antiviral drug doesn’t prevent COVID-19 hospitalizations or deaths in high-risk, nonhospitalized, vaccinated patients but can speed recovery.
· paxlovid an antiviral treatment was used to treat cases of early COVID with high risk of deterioration but it’s unknown if it can benefit hospitalised cases with COVID-19.
· Dimethyl fumarate did not enhance recovery for COVID 19 hospitalised cases.
· Regeneron’s monoclonal antibody combination decreased death rate in hospitalised COVID cases
· Empagliflozin The recent DARE-19 trial demonstrated but inconclusivly that SGLTSI can decraese the risk of lung, heart, and kidney injury or death in patients hospitalised with COVID-19. By including empagliflozin in a much larger comparison within the RECOVERY trial, can determine whether this promising or not.
2-Summary
Introduction
Covid 19 that first appeared in China presented with acute pneumonic features that can lead to respiratory failure with high fatality rate.
The extensive radiologic opacity , diffuse alveolar damage, inflammatory
infiltrates, and microvascular thrombosis revealed the severe inflammatory response confirmed with elevated inflammatory markers.
Meanwhile steroids role was controversial.
Glucocorticoids use was not recommended except in severe cases
Methods
This trial evaluate the IV dexamethasone with usual treatment or oral dexamethasone therapy with usual treatment or usual treatment only for 10 days in hospitalized patients with Covid-19.
The primary outcome was all-cause mortality within 28 days.Secondary
outcome was the discharge time from the hospital.
Results
2104 patients received dexamethasone and 4321 received usual care. 22.9% in the dexamethasone group and 25.7% in the usual care group died within 28 days after randomization.
Mortality between groups varied according to the level of respiratory support needed. Incidence of death was less in the dexamethasone group than that in the usual care group among patients who had invasive mechanical ventilation and those receiving oxygen without invasive mechanical ventilation and not among those who did not need respiratory support.
Discussion
Among hospitalized patients with Covid-19 ,dexamethasone use for 10 days decreased 28-day mortality rate compared to usual care in cases receiving invasive mechanical ventilation and those received oxygen supply particularly for cases receiving treatment for more than 7 days due to injurious inflammatory response in the lung but did not reveal any benefit for cases not on oxygen supply.
Also dexamethasone administration was associated with a lower risk of invasive mechanical ventilation or for cases whom received invasive mechanical ventilation, a better outcome of being weaned off the ventilator.
In concordance with Recovery trial which demonstrated that
Dexamethasone use at a dose of 6 mg once daily for 10 days reduces 28-day mortality in Covid-19 cases receiving respiratory support.
On the other hand glucocorticoid dos e, disease severity and medical conditions were heterogenous.
The mortality benefit of dexamethasone in Covid-19 cases receiving respiratory support and among those engaged after the first week of their illness suppose that at that stage the disease may be dominated by immunopathological effects can be dominant while active viral replication has a secondary role.
Conclusion
Dexamethasone intake resulted in lower 28-day mortality in hospitalised cases among those who had either invasive mechanical ventilation or oxygen alone but not among those without respiratory support but dexamethasone did not show any benefit for cases who did not need respiratory support .
3- level of evidence is 1
Any further sub-classification of level 1?
Please do your own search and summarise the outcome of the different arms of the recovery trial.
The clinical experiment resulted in the revelation, which was made within only a few short months, that the steroid dexamethasone reduced the risk of mortality in ventilated patients by a third.
Patients diagnosed with Covid-19 who are hospitalized in the UK and elsewhere are now being given the steroid as part of their treatment. In addition, the researchers discovered that four medicines (lopinavir-ritonavir, hydroxychloroquine, azithromycin, and convalescent plasma) did not give any therapeutic benefit.
This enables healthcare practitioners to direct their attention away from these treatments and toward others. Tocilizumab, an anti-inflammatory medication, the monoclonal antibody therapy developed by Regeneron, aspirin, and colchicine are all now being tested as part of the ongoing experiment. The trial is scheduled to conclude in January 2021. (an anti-inflammatory treatment used for gout).
Please summarise this article.Introduction:
In late 2019, zoonotic SARS-CoV-2, which causes COVID-19, developed in China.
Most COVID-19 instances are asymptomatic or mild. Nevertheless, a significant number of individuals develop a respiratory illness necessitating hospitalization,2 and such infections may progress to severe disease with hypoxemic respiratory failure needing extended ventilatory support. 3-6 In the first half of 2020,-26% of UK hospitalized Covid-19 patients died, and 37% of those receiving invasive mechanical ventilation died.
Method:
In this controlled, open-label study evaluating a variety of therapies for hospitalized COVID-19 patients, we randomly assigned patients to receive oral or intravenous dexamethasone (6 mg once daily) for up to 10 days or for normal care alone. 28-day mortality was key.
RESULTS
2104 patients received dexamethasone and 4321 received standard care. 482 dexamethasone patients (22.9%) and 1110 usual care patients (25.7%) died within 28 days after randomization.
Patients’ respiratory assistance at randomization affected death proportionally and absolutely. In the dexamethasone group, the incidence of death was lower than in the usual care group among patients receiving invasive mechanical ventilation and oxygen without invasive mechanical ventilation but not among those receiving no respiratory support at randomization.
CONCLUSIONS
In patients hospitalized with COVID-19, the use of dexamethasone resulted in lower 28-day mortality among those who were receiving either invasive mechanical ventilation or oxygen alone at the time of randomization. However, this was not the case for patients who were receiving no respiratory support at the time of randomization.
What is the level of evidence provided by this article?level 1
Thanks, Weam
Outcome of different RECOVERY trial arm:
Summary:
Introduction:
Method:
Result & discussion:
Level of evidence is 1
Thanks, Ban
Please do your own search and summarise the outcome of the different arms of the recovery trial.
Aspirin (1)
Azithromycin (2)
Baricitinib (3)
Colchicine (4)
Convalescent Plasma (5)
Dexamethasone small dose (6)
Dexamethasone high dose (7)
Dimethyl fumarate (8)
Hydroxychloroquine (9)
Lopinavir-Ritonavir results (10)
Regeneron’s monoclonal antibody combination results (11)
Tocilizumab (12)
References:
Summary of the article
RCT open label multicentral trial
Population: Hospitalized patients with COVID-19
Intervention: Dexamethasone, a corticosteroid
Comparison: Standard care without dexamethasone
Outcome: Reduction in mortality rate among patients requiring respiratory support
The study found that dexamethasone reduced mortality rates among patients who required mechanical ventilation by one-third and reduced mortality rates among patients
who required oxygen therapy by one-fifth. However, there was no benefit of
dexamethasone among patients who did not require respiratory support.
What is the level of evidence provided by this article?level 1
Thanks, Ahmed
Excellent Ahmed
That was one of many treatments driven by ‘impression-based medicine’: high-titre convalescent plasma did not improve survival or other prespecified clinical outcomes.