INSPIRATION-S led by Behnood Bikdeli, MD, MS, and presented at the American College of Cardiology 2021 Meeting, failed to show the efficacy of atorvastatin in reducing thrombotic events and all-cause mortality. According to the presenter, the subgroup analysis demonstrated some hypothesis-generating signals that need to be further investigated in future research.
Coronavirus disease-2019 (COVID-19) is an acute viral illness that involves multi-systems of the body and has caused major morbidity and mortality worldwide. COVID-19 associated coagulopathy is particularly a major cause of this morbidity and mortality especially among critically ill patients with COVID-19. In addition, the risk of thrombotic events remains to be high despite the routine use of a standard dose of anticoagulant medications. Statins, a class of lipid-lowering medications, have been reported to possess anti-inflammatory and anti-platelet properties. Given that these medications are not associated with an increased risk of bleeding complications, their use may be beneficial in critically ill patients with COVID-19. The INSPIRATION-S (INtermediate versus Standard-dose Prophylactic anticoagulation In cRitically-ill pATIents with COVID-19: An opeN label randomized controlled trial–statin, NCT04486508) trial designed to investigate whether atorvastatin, compared with placebo, confer benefit in patients with COVID-19 hospitalized in intensive care unit (ICU).
Bikdeli and his colleagues conducted a multicenter, double-blind, randomized trial with a 2×2 factorial design in patients with a confirmed COVID-19 diagnosis admitted to ICU, with an estimated survival time of >24h. Patients were assigned to receive once-daily oral atorvastatin 20 mg or placebo for 30 days. Primary efficacy outcome included a composite of adjudicated venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation, or mortality within 30 days. The safety outcomes of interest included a rise in liver enzymes larger than three times of the upper normal limit and clinically diagnosed myopathy.
The trial included 587 patients who were randomized to receive atorvastatin 20 mg (290 individuals) or placebo (297 individuals). The primary efficacy outcome of interest occurred in 95 (32.8%) patients assigned to statin therapy and 108 (36.4%) patients assigned to placebo (odds ratio [OR]: 0.84, 95% confidence interval [CI]: 0.58-1.21; risk difference: -3.6%, 95% CI: -11.2-4.0, P=0.35). No significant differences were observed between the treatment and placebo group with regard to secondary efficacy outcomes such as all-cause mortality and ventilator-free days. Of note, the use of atorvastatin did not result in an increase in serious adverse events, compared with placebo. The results remained consistent within most subgroups and in the sensitivity analysis. There was a slight difference between the treatment and placebo group if treatment was initiated within seven days of symptom onset (OR: 0.60, 95% CI: 0.37-0.99, P=0.05).
When asked for potential economic implications of the study, Dr. Bikdeli stated: “Statins are relatively inexpensive medications, and many (including atorvastatin) are available in generic forms. If proven to be beneficial, there is the possibility of widespread use to improve outcomes. Prior to that, however, efficacy should be demonstrated.” Further research is required to determine whether a higher dose of statins or their use in patients who present earlier, would confer benefit.