Simvastatin was superior to standard care in avoiding organ support among patients critically ill with COVID-19; however, its 95.9% probability of superiority fell short of meeting the 99% superiority threshold required by the REMAP-CAP clinical trial, according to study findings published in the New England Journal of Medicine.
Investigators reported results of the simvastatin domain of the REMAP-CAP clinical trial (Randomized, Embedded, Multifactorial Adaptive Platform Trial for Community-Acquired Pneumonia; ClinicalTrials.gov Identifier: NCT02735707).
The REMAP-CAP trial included adult patients (aged ≥18 years) with clinically suspected or microbiologically confirmed COVID-19 who were admitted to the hospital. They were assigned randomly to receive simvastatin 80 mg daily or no statin (control), starting with balanced assignment.
The study’s primary outcome was respiratory and cardiovascular organ support-free days up to day 21, and all deaths within the hospital were assigned the worst outcome (−1). The predefined statistical criteria for discontinuing enrollment and finding a treatment effect were superiority (>99% posterior probability that the odds ratio was >1) and futility (>95% posterior probability that the odds ratio was <1.2).
Enrollment was initiated on October 28, 2020, and was closed on January 8, 2023, owing to a low anticipated likelihood that 1 of the prespecified stopping criteria would be met because of low recruitment, as the number of COVID-19 cases had decreased.
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[W]e 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 final analysis included 2684 critically ill patients. The simvastatin group had 1843 participants (median age, 56 years; 33.4% female), and the control group had 841 participants (median age, 57 years; 34.4% female).
The simvastatin group had a median of 11 organ support-free days (interquartile range, −1 to 17) compared with 7 (interquartile range, −1 to 16) in the control group. The median adjusted odds ratio for the primary outcome was 1.15 (95% credible interval, 0.98-1.34) for simvastatin, with a 95.9% posterior probability of superiority of simvastatin vs control. The probability was less than the prespecified 99% threshold, and so the prespecified statistical criteria were not met.
Survival until hospital discharge was achieved in 1352 of 1843 patients (73.4%) in the simvastatin group and in 589 of 841 participants (70.0%) in the control group, for an adjusted odds ratio of 1.04 (95% credible interval, 0.85-1.27), with a 64.4% posterior probability of simvastatin’s superiority vs control.
In the simvastatin group, death within 90 days occurred in 504 of 1835 patients (27.5%) compared with 257 of 837 patients (30.7%) in the control group, excluding 8 and 4 patients, respectively, who had censored data. The 90-day survival analysis produced an adjusted hazard ratio (aHR) of 1.12 (95% credible interval, 0.95-1.32), with a 91.9% posterior probability of superiority of simvastatin vs control.
Serious adverse events occurred in 57 of 1846 patients (3.1%) in the simvastatin group and in 17 of 842 individuals (2.0%) in the control group.
Study limitations include its open-label design and the inclusion of more patients in the simvastin vs control group due to the response-adaptive randomization process. Additionally, the trial was stopped for operational futility before a prespecified stopping trigger was reached.
“In this domain of an adaptive platform trial, 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 stated. “This probability did not meet the prespecified 99% threshold.”
Disclosure: Some of the study authors declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.
