Compared with no statin in the REMAP-CAP trial, simvastatin did not meet the prespecified criteria for superiority to control COVID-19. “We found a 95.9% probability that the initiation of simvastatin therapy was superior to standard care with respect to the primary outcome, a composite of organ support–free days and death, among critically ill patients with Covid-19,” the investigators conclude. “This probability did not meet the prespecified 99% threshold. The association of simvastatin with outcomes appeared consistent among secondary and sensitivity analyses.”
The ongoing international, multifactorial, adaptive platform, randomized, controlled trial looked at the effects of simvastatin 80 mg daily in critically ill patients with COVID-19 who were not receiving statins at baseline. Based on a primary outcome of respiratory and cardiovascular organ support–free days, the study showed: “The final analysis included 2,684 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.”
Editorial: “These results raise important questions for understanding and studying the heterogeneity of [acute respiratory distress syndrome (ARDS)],” editorialists write. “What standards for phenotyping in patients with ARDS and Covid-19 are useful for comparisons among studies and populations? What does ‘hyperinflammatory’ mean mechanistically, and how should ‘inflammation’ be measured? Are trajectories of subphenotypes altered with treatment? With increasing precision and personalization in trial enrollment, REMAP-CAP may be a cautionary tale against excluding certain subgroups of patients on the basis of post hoc analyses of previous studies. A broader approach that enrolls all patients and subsequently assesses heterogeneity of treatment effect according to selected biomarkers may protect against premature trial closure and allow for further refinement of relevant phenotypes.”