Abstract
BACKGROUND
The efficacy of simvastatin in critically ill patients with coronavirus disease 2019 (Covid-19) is unclear.
METHODS
In an ongoing international, multifactorial, adaptive platform, randomized, controlled trial, we evaluated simvastatin (80 mg daily) as compared with no statin (control) in critically ill patients with Covid-19 who were not receiving statins at baseline. The primary outcome was respiratory and cardiovascular organ support–free days, assessed on an ordinal scale combining in-hospital death (assigned a value of −1) and days free of organ support through day 21 in survivors; the analyis used a Bayesian hierarchical ordinal model. The adaptive design included prespecified statistical stopping criteria for superiority (>99% posterior probability that the odds ratio was >1) and futility (>95% posterior probability that the odds ratio was <1.2).
RESULTS
Enrollment began on October 28, 2020. On January 8, 2023, enrollment was closed on the basis of a low anticipated likelihood that prespecified stopping criteria would be met as Covid-19 cases decreased. The final analysis included 2684 critically ill patients. The median number of organ support–free days was 11 (interquartile range, −1 to 17) in the simvastatin group and 7 (interquartile range, −1 to 16) in the control group; the posterior median adjusted odds ratio was 1.15 (95% credible interval, 0.98 to 1.34) for simvastatin as compared with control, yielding a 95.9% posterior probability of superiority. At 90 days, the hazard ratio for survival was 1.12 (95% credible interval, 0.95 to 1.32), yielding a 91.9% posterior probability of superiority of simvastatin. The results of secondary analyses were consistent with those of the primary analysis. Serious adverse events, such as elevated levels of liver enzymes and creatine kinase, were reported more frequently with simvastatin than with control.
CONCLUSIONS
Although recruitment was stopped because cases had decreased, among critically ill patients with Covid-19, simvastatin did not meet the prespecified criteria for superiority to control. (REMAP-CAP ClinicalTrials.gov number, NCT02735707. opens in new tab.)
The efficacy of simvastatin in critically ill patients with coronavirus disease 2019 (Covid-19) is unclear.
METHODS
In an ongoing international, multifactorial, adaptive platform, randomized, controlled trial, we evaluated simvastatin (80 mg daily) as compared with no statin (control) in critically ill patients with Covid-19 who were not receiving statins at baseline. The primary outcome was respiratory and cardiovascular organ support–free days, assessed on an ordinal scale combining in-hospital death (assigned a value of −1) and days free of organ support through day 21 in survivors; the analyis used a Bayesian hierarchical ordinal model. The adaptive design included prespecified statistical stopping criteria for superiority (>99% posterior probability that the odds ratio was >1) and futility (>95% posterior probability that the odds ratio was <1.2).
RESULTS
Enrollment began on October 28, 2020. On January 8, 2023, enrollment was closed on the basis of a low anticipated likelihood that prespecified stopping criteria would be met as Covid-19 cases decreased. The final analysis included 2684 critically ill patients. The median number of organ support–free days was 11 (interquartile range, −1 to 17) in the simvastatin group and 7 (interquartile range, −1 to 16) in the control group; the posterior median adjusted odds ratio was 1.15 (95% credible interval, 0.98 to 1.34) for simvastatin as compared with control, yielding a 95.9% posterior probability of superiority. At 90 days, the hazard ratio for survival was 1.12 (95% credible interval, 0.95 to 1.32), yielding a 91.9% posterior probability of superiority of simvastatin. The results of secondary analyses were consistent with those of the primary analysis. Serious adverse events, such as elevated levels of liver enzymes and creatine kinase, were reported more frequently with simvastatin than with control.
CONCLUSIONS
Although recruitment was stopped because cases had decreased, among critically ill patients with Covid-19, simvastatin did not meet the prespecified criteria for superiority to control. (REMAP-CAP ClinicalTrials.gov number, NCT02735707. opens in new tab.)
| Original language | English |
|---|---|
| Pages (from-to) | 2341-2354 |
| Number of pages | 14 |
| Journal | New England Journal of Medicine |
| Volume | 389 |
| Issue number | 25 |
| Early online date | 25 Oct 2023 |
| DOIs | |
| Publication status | E-pub ahead of print - 25 Oct 2023 |
Bibliographical note
Funding Information:Supported by the Platform for European Preparedness Against (Re-)emerging Epidemics (PREPARE) consortium of the European Union FP7-HEALTH-2013-INNOVATION-1 framework program (grant 602525), the Rapid European COVID-19 Emergency Research Response (RECOVER) consortium of the European Union Horizon 2020 Research and Innovation Program (grant 101003589), the Australian National Health and Medical Research Council (grant APP1101719), Australian Medical Research Future Fund (MRFF) International Clinical Trial Collaborations (grant 2015788), Australian MRFF COVID-19 Treatment Access and Public Health Activities (grant 2016162), the Health Research Council of New Zealand (grant 16/631), the Canadian Institutes of Health Research Strategy for Patient-Oriented Research Innovative Clinical Trials Program (grant 158584), the U.K. National Institute for Health and Care Research ( NIHR ) and the NIHR Imperial Biomedical Research Centre , the Health Research Board of Ireland (grant CTN 2014-012), the University of Pittsburgh Medical Center Learning While Doing Program, the Translational Breast Cancer Research Consortium , the French Ministry of Health (grant PHRC-20-0147 ), Office of Health and Medical Research NSW Health , the Minderoo Foundation , the Wellcome Trust Innovations Project (grant 215522), the Japan Agency for Medical Research and Development (grants 20fk0108526h0001, 21fk0108591h0001, and 22fk0108528h0001), and the National University Health System research office , Singapore.
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