Efforts Continue to Prove Statin Benefits for Reducing COVID-19 Severity
Observational studies have shown that common cholesterol-lowering medications, including simvastatin, can reduce severe COVID-19 symptoms. The latest randomized clinical trial on that drug failed to meet prespecified criteria with a participant group smaller than planned, but the researchers advise that some benefits were demonstrated. Here are more details.
LONDON, UK – A clinical trial looking at the use of the common cholesterol-lowering drug simvastatin to reduce severe COVID-19 symptoms was ended early because of recruitment issues, but questions remain about the use of simvastatin and similar drugs in treating SARS-CoV-2 infection.
Enrollment for the clinical trial was closed in January 2023 because, with a decrease in COVID-19 cases, meeting prespecified criteria was deemed unlikely, write .
Randomized, Embedded, Multifactorial Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP) researchers. REMAP-CAP is an ongoing international platform trial designed to evaluate treatments for patients with severe pneumonia in both pandemic and non-pandemic contexts.
“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,” wrote the authors of the study published in the New England Journal of Medicine. “This probability did not meet the prespecified 99% threshold. The association of simvastatin with outcomes appeared consistent among secondary and sensitivity analyses.”
The researchers advise that their findings “align with observational data that antecedent statin use is associated with improved COVID-19 outcomes. A meta-analysis of published randomized, controlled trials of statins begun as treatment for COVID-19 showed a risk ratio for death from any cause (statins vs. controls) of 0.92 (95% confidence interval, 0.75 to 1.13), the point estimate of which is similar to the effect size seen in REMAP-CAP.”
They add their trial was larger than the 7 previous randomized, controlled trials of statin therapy in COVID-19 combined, which enrolled 1830 participants in total, explaining, “It is plausible that smaller trials were underpowered to detect a modest beneficial effect.”
As part of the ongoing international, multifactorial, adaptive platform, randomized, controlled trial, simvastatin at 80 mg daily was compared with no statin (control) in critically ill patients with COVID-19 who were not receiving statins at baseline.
Defined as 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 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).
The final analysis included 2,684 critically ill patients. Results indicate that 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 authors note that “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.”
They add that the results of secondary analyses were consistent with those of the primary analysis. In addition, serious adverse events, such as elevated levels of liver enzymes and creatine kinase, were reported more frequently with simvastatin than with control.
Background information in the article points out that simvastatin is an inexpensive and widely available medication that is on the World Health Organization (WHO) list of essential medicines. It is predominantly used for its lipid-lowering and cardioprotective properties but also has anti-inflammatory and immunomodulatory effects, according to the report, which explains, “Simvastatin therapy reduces pulmonary and systemic inflammation in murine and human models of lung injury.”
Meta-analyses of observational studies involving patients with COVID-19 have shown an association between previous statin use and improved clinical outcomes, including reduced mortality.
In this trial, the researchers write that a subgroup analysis suggested a larger association of simvastatin with organ support–free days in critically ill patients who were not receiving mechanical ventilation at randomization. “In this subgroup of patients, 37.0% of those in the simvastatin group and 42.5% of those in the control group had progression to invasive mechanical ventilation, extracorporeal membrane oxygenation, or death,” they note.
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