1. In this randomized controlled trial, high-dose simvastatin did not reduce the need for organ support among critically ill patients with coronavirus disease 2019 (COVID-19).
2. High-dose simvastatin was associated with increased rates of serious adverse events amongst critically ill patients with COVID-19.
Evidence Rating Level: 1 (Excellent)
Study Rundown: Among critically ill patients who are admitted to hospitals with COVID-19, access to affordable and effective medications continues to remain inequitably distributed around the world. Simvastatin is a lipid-lowering mediation with anti-inflammatory and cardioprotective properties, which has been thought to have mortality benefits amongst patients with specific sub-types of acute respiratory distress syndrome (ARDS). This was a randomized controlled study nested within a larger Randomized, Embedded, Multifactorial Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP) trial, which investigated the effect of high-dose simvastatin for critically ill adult patients with COVID-19 when compared to no simvastatin use. The analysis found that simvastatin was not superior to no simvastatin in reducing morbidity, such as hospitalization and organ-support requirements, nor mortality. However, high-dose simvastatin was demonstrated to have an increased rate of severe adverse reactions when compared to no simvastatin. A key limitation to consider is that the trial was stopped earlier than intended, and it employed an open-label design. Despite these limitations, this trial provided valuable insights into the effect of high-dose simvastatin in critically ill patients with COVID-19.
In-Depth [randomized controlled trial]: This was an open-label randomized trial nested within the REMAP-CAP trial evaluating the efficacy of high-dose enteral simvastatin against no statin use amongst critically ill adult patients admitted to hospital due to COVID-19 on morbidity and mortality. The primary outcome of interest was 21 days of survival without requiring organ support. Additional outcomes of interest included survival to hospital discharge, duration of time without requiring vasoactive or inotropic medication, duration of stay, and duration of time without requiring respiratory support. Adults meeting prior criteria for the REMAP-CAP trial admitted to the hospital with COVID-19 were included in the study and subsequently randomized to one of the study arms through response-adaptive randomization. Overall, 2,739 critically ill patients were randomized to receive simvastatin (n=1,884) or no simvastatin (n=855). Ultimately, the trial was stopped before prespecified stopping criteria due to low anticipated numbers of patients meeting the criteria for inclusion as the COVID-19 pandemic evolved. Results of the analysis showed that simvastatin was not superior to no simvastatin concerning the median number of organ support-free days (posterior mean adjusted odds ratio, 1.15; 95% Credible Interval [CI], 0.98 to 1.34), nor the likelihood of survival beyond 90-days (hazard ratio, 1.12; 95% CI 0.95 to 1.32). Further, high-dose enteral simvastatin was demonstrated to be associated with a greater rate of serious adverse events compared to the no-simvastatin group. In summary, this trial provided valuable insights into the effect of high-dose enteral simvastatin on critically ill patients with COVID-19.
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