Simvastatin in Critically Ill Patients with Covid-19

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.).

Figure 1. Screening, Enrollment, Randomization, and Inclusion in Analysis.

A domain describes a specific set of competing interventions which, for the purposes of the platform, are mutually exclusive and exhaustive. Patients could meet more than one ineligibility criterion; full details are provided in the Supplementary Appendix. Contraindications to simvastatin are hypersensitivity, severe liver disease, a creatinine level of more than 2.26 mg per deciliter (200 μmol per liter) unless the patient was receiving renal-replacement therapy, current treatment with a medicine that cannot be coadministered with simvastatin, and current or planned treatment with any statin. Full details regarding noncritically ill patients are provided in the Supplementary Appendix. The primary analysis of interventions within the simvastatin domain is performed with a model that adjusts for patient factors and for assignment to interventions in other domains. To obtain the most reliable estimation of the effect of these patient factors and of other interventions on the primary outcome, all the patients who were enrolled in the critically ill coronavirus disease 2019 (Covid-19) cohort (for whom there is consent and follow-up) are included in the analytic model, but only concurrent controls in the simvastatin domain are used to estimate the effectiveness of simvastatin relative to control. REMAP-CAP denotes Randomized, Embedded, Multifactorial Adaptive Platform Trial for Community-Acquired Pneumonia.

Figure 2. Distribution of Organ Support–free Days.

Panel A shows the cumulative proportion of patients for each intervention group according to day, with death listed first. Curves that rise more gradually indicate a more favorable distribution of the number of days alive and free of organ support. The height of each curve at the point labeled “Death” indicates the in-hospital mortality for each intervention. The height of each curve at any point indicates the proportion of patients who had that number of organ support–free days or fewer (e.g., the height at day 10 indicates the proportion of patients with ≤10 organ support–free days). The difference in height of the two curves at any point represents the difference in the percentile in the distribution of organ support–free days associated with that number of days alive and free of organ support. Panel B shows organ support–free days as horizontally stacked proportions according to intervention group. Red represents worse outcomes, and blue represents better outcomes. The median adjusted odds ratio from the primary analysis, which used a Bayesian cumulative logistic model, 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.

Figure 3. Selected Secondary Clinical Outcomes.

Panel A shows the Kaplan–Meier curves for survival. The median follow-up time was 90 days in both treatment groups; 8 patients (0.4%) in the simvastatin group and 4 patients (0.5%) in the control group had data censored before day 90. Death occurred in 504 of 1835 patients (27.5%) in the simvastatin group and 257 of 837 patients (30.7%) in the control group; denominators exclude patients with censored data. The hazard ratio was 1.12 (95% credible interval, 0.95 to 1.32), yielding a 91.9% posterior probability of superiority of simvastatin to control. Data for patients known to be alive at 90 days are censored at 90 days. Data for patients with unknown 90-day mortality status are censored at the date of last follow-up (the date of discharge if discharged from the hospital or the date last known alive for those in the hospital). Panel B shows the distribution of scores on the modified World Health Organization 8-point scale, measured at day 14, for simvastatin and control. Scores of 0, 1, or 2 indicate no longer hospitalized, 3 hospitalized without oxygen therapy, 4 hospitalized with oxygen by mask or nasal cannula, 5 receiving noninvasive ventilation or high-flow nasal oxygen, 6 receiving intubation and mechanical ventilation, 7 receiving mechanical ventilation and additional organ support (vasopressor, renal-replacement therapy, or extracorporeal membrane oxygenation), and 8 deceased. Panel C shows the distributions of days free of respiratory support through 28 days as horizontally stacked proportions according to intervention group. Panel D shows the distributions of days free of vasopressors or inotropes through 28 days as horizontally stacked proportions according to intervention group.