INSPIRATION-S: Statin therapy fails to prevent thrombosis, death in severe COVID-19
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Atorvastatin therapy did not reduce risk for venous or arterial thrombosis or all-cause death among patients with COVID-19 admitted to the ICU compared with placebo, according to data from the INSPIRATION-S study.
A smaller treatment effect and findings within specific subgroups warrant additional investigation, Behnood Bikdeli, MD, MS, a clinical fellow in the cardiovascular medicine division at Brigham and Women’s Hospital and Harvard Medical School, said during a presentation at the American College of Cardiology Scientific Session.
“We observed some hypothesis-generating signals within subgroups that require further investigation,” Bikdeli told Healio. “Additionally, the acuity of illness in our study cohort and the rate of thrombotic events were both lower than what we had expected. Second, we were pleasantly surprised to note that a rise in liver enzymes was not observed with statin therapy. This notion of potential safety may give room for dose escalation in future potential trials.”
INSPIRATION-S was a double-blind, randomized controlled trial assessing the use of 20 mg atorvastatin once daily vs. placebo in 605 patients with confirmed COVID-19 who were admitted to the ICU across 11 hospitals in Iran (mean age, 57 years; 44% women; 16% with diabetes). Enrollment began in July 2020. Participants were naive to statin therapy prior to randomization; those with severe liver dysfunction were excluded. More than 90% of patients were receiving corticosteroids while hospitalized.
The primary outcome was a composite of adjudicated venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation (ECMO) or death within 30 days. Researchers also assessed liver enzyme levels and incidence of clinically diagnosed myopathy as the main safety outcomes.
Researchers found statin therapy was not associated with a significant reduction in the primary outcome (HR = 0.84 95% CI, 0.58-1.21; P = .35); however, numerically fewer events occurred in the statin group compared with the placebo group (95 vs. 108). Individual endpoint components of all-cause death (HR = 0.84; 95% CI, 0.58-1.22; P = .39) and adjudicated venous thromboembolism (HR = 0.71; 95% CI, 0.24-2.06; P = .53) failed to reach significance, though fewer events for each occurred in the statin group vs. placebo, according to the researchers.
There were no between-group differences in safety outcomes. A rise in liver enzymes was observed in five adults in the statin group and six adults in the placebo group.
In subgroup analyses, Bikdeli noted that among patients who presented within the first 7 days of COVID-19 symptom onset, “there was some hint for potential protective effects.”
“The interesting observation for people who presented earlier on ... is [benefit is] plausible because they may be in a different phase of the disease; however, it was not adjusted for multiplicity,” Bikdeli said during the presentation.
Bikdeli said there are several study limitations. A smaller treatment effect cannot be excluded, and the rate of thrombotic events was less than expected; however, many patients were tested according to clinicians’ suspicions.
“There are three other randomized statin trials that include ICU patients with COVID-19,” Bikdeli told Healio. “Results from these studies will be very important in broadening our knowledge about the role of statins in COVID-19. Our own group is also deliberating the design of a follow-up trial.”
Perspective
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Doreen DeFaria Yeh, MD
Surprisingly, there was no significant difference among the statin-treated group and placebo group. Atorvastatin did not result in a reduction in the primary endpoint, which included a composite of venous or arterial thrombosis, treatment with ECMO or death within 30 days.
Other studies have demonstrated the benefits of statin therapy for patients in acute settings and around the time of surgery. In this scenario of acute illness with COVID-19 infection, many were hopeful that there would be a similar positive benefit with statin use, given the known anti-inflammatory and pleuripotent effects of statins. That was not borne out in this study.
One interesting observation is noted in subgroup analyses: Patients who received statin therapy within 7 days of symptom onset seemed to have potential for benefit. Further investigation could help us understand why introduction of statins earlier in the disease course might present an opportunity for benefit.
There are many unknowns about the pathobiology of COVID-19 that we have yet to learn. Clearly, it is a complex disease. We see thrombosis, bleeding, uniquely heterogenous manifestations of pulmonary pathology as well as variability in the CV impacts. Every patient is unique, and it may be that we have not yet identified the patients where statin therapy could have a beneficial impact on the disease course.
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Bikdeli B. Featured Clinical Research II. Presented at: American College of Cardiology Scientific Session; May 15-17, 2021 (virtual meeting).
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