Current best evidence for clinical care (more info)
BACKGROUND: World Health Organization expert groups recommended mortality trials of four repurposed antiviral drugs - remdesivir, hydroxychloroquine, lopinavir, and interferon beta-1a - in patients hospitalized with coronavirus disease 2019 (Covid-19).
METHODS: We randomly assigned inpatients with Covid-19 equally between one of the trial drug regimens that was locally available and open control (up to five options, four active and the local standard of care). The intention-to-treat primary analyses examined in-hospital mortality in the four pairwise comparisons of each trial drug and its control (drug available but patient assigned to the same care without that drug). Rate ratios for death were calculated with stratification according to age and status regarding mechanical ventilation at trial entry.
RESULTS: At 405 hospitals in 30 countries, 11,330 adults underwent randomization; 2750 were assigned to receive remdesivir, 954 to hydroxychloroquine, 1411 to lopinavir (without interferon), 2063 to interferon (including 651 to interferon plus lopinavir), and 4088 to no trial drug. Adherence was 94 to 96% midway through treatment, with 2 to 6% crossover. In total, 1253 deaths were reported (median day of death, day 8; interquartile range, 4 to 14). The Kaplan-Meier 28-day mortality was 11.8% (39.0% if the patient was already receiving ventilation at randomization and 9.5% otherwise). Death occurred in 301 of 2743 patients receiving remdesivir and in 303 of 2708 receiving its control (rate ratio, 0.95; 95% confidence interval [CI], 0.81 to 1.11; P = 0.50), in 104 of 947 patients receiving hydroxychloroquine and in 84 of 906 receiving its control (rate ratio, 1.19; 95% CI, 0.89 to 1.59; P = 0.23), in 148 of 1399 patients receiving lopinavir and in 146 of 1372 receiving its control (rate ratio, 1.00; 95% CI, 0.79 to 1.25; P = 0.97), and in 243 of 2050 patients receiving interferon and in 216 of 2050 receiving its control (rate ratio, 1.16; 95% CI, 0.96 to 1.39; P = 0.11). No drug definitely reduced mortality, overall or in any subgroup, or reduced initiation of ventilation or hospitalization duration.
CONCLUSIONS: These remdesivir, hydroxychloroquine, lopinavir, and interferon regimens had little or no effect on hospitalized patients with Covid-19, as indicated by overall mortality, initiation of ventilation, and duration of hospital stay. (Funded by the World Health Organization; ISRCTN Registry number, ISRCTN83971151; ClinicalTrials.gov number, NCT04315948.).
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The Interim WHO Solidarity trial, published in the New England Journal of Medicine, included 11,330 hospitalized patients in over 30 countries with COVID-19 with intention to treat analysis using four pairwise comparisons of each medication and its control. Medications included remdesivir, hydroxychloroquine, lopinavir without interferon, and interferon (some with lopinavir). No drug was associated with reduced mortality, need for ventilation, or length of stay. Context is important when assessing these results, as patients may present with a variety of risk factors and different settings and stages of disease. This trial included patients form a wide range of settings and different disease timepoints. It contributes necessary information concerning the lack of efficacy of these medications in COVID-19 in reducing mortality.
This is a very controversial article, at least regarding remdesivir. There have been major articles in other journals rebutting their conclusions.
Of the drugs studied, remdesivir is the only one approved by the FDA for this indication. Remdesivir will likely continue to be used, even outside the FDA-approved indications, unless data result in rescinding FDA approval.
Official release of WHO multinational trial looking at anti-viral agents for treatment of Covid-19. The study clearly shows no role for hydroxychloroquine, lopinavir, or interferon beta 1a. Remdesivir was not found to affect mortality in this study. The authors discuss discrepancies between this study and other remdesivir trials.
This is the long-awaited publication of the WHO Solidarity trial of repurposed drugs for patients hospitalized with COVID-19. These results have been available by preprint for some time now. This is a landmark study in its scope, rapidity, and relevance. Despite some faults (e.g., open label), the study is quite persuasive in demonstrating that several agents (remdesivir, HCQ, lopinavir, interferon) have little to no effect on patient-important outcomes in COVID-19 and should not generally be used outside of the context of a clinical trial for this disease. As an intensive care physician, this trial re-emphasizes that high-quality supportive care, with the addition of steroids(!), should remain the standard treatment for COVID-19 until further evidence is available.
Really important work, especially in regard to remdesivir and HCQ, which continue to be used widely and, according to this well done international RCT, don't improve outcomes in hospitalized COVID patients.
The best COVID study to date.
As a hospitalist, I find therapeutic answers for COVID are incredibly important. This simple trial gave a wealth of information for 11,000 patients. I think it closes the door on interferon, HCQ and Lopinivir for me, none of which we currently use. Questions still remain for the place of remdesivir, which we still do use. Answers regarding whether there still could be a benefit is lost in the heterogeneity associated with hospital systems across many countries and timing of first symptoms.
The Solidarity trial shows no evidence of mortality benefit for hydroxychloroquine, lopinavir, interferon beta-1a or remdesivir in COVID-19. Because this was a large pragmatic trial limited to mortality as an endpoint, the interpretation of the results depends on other available data. For example, the other available data for hydroxychloroquine support no role in treating patients outside a clinical trial; whereas, other data regarding remdesivir demonstrate a benefit on illness severity and time to recovery, making it appropriate to use in certain groups of patients despite the lack of effect on mortality.