Atorvastatin: Is there evidence of benefit in COVID-19?

Treatment with the HMG-CoA reductase inhibitor atorvastatin in critically ill patients with COVID-19 did not significantly reduce the primary composite outcome of venous or arterial thrombosis risk, treatment with extracorporeal membrane oxygenation (ECMO), or mortality vs placebo in the INSPIRATION-S study presented at ACC.21.

Thrombotic events are commonly reported in critically ill patients with COVID-19. “Hence, it is interesting to think about statins as potential agents in COVID-19 because other than having lipid-lowering actions, they are also thought to have anti-inflammatory and antithrombotic effects,” said study investigator Dr Behnood Bikdeli from the  Brigham and Women’s Hospital in Boston, Massachusetts, US.

In the trial, the composite of adjudicated venous or arterial thrombosis, treatment with ECMO, or mortality within 30 days occurred in 32.7 percent of the atorvastatin group vs 36.3 percent with placebo (odds ratio [OR], 0.84; p=0.35). Atorvastatin was not associated with any significant differences in the individual components of the primary composite endpoint. There was also no difference between atorvastatin and placebo in terms of the safety endpoints including major bleeding and elevation in liver enzyme level.

Interestingly, benefits were hinted in the subgroup of patients treated within 7 days of COVID-19 symptom onset, although this warrants additional investigation.

Limited evidence exists

“If we were to look at observational studies on statins, many were associated with lower mortality in hospitalized COVID-19 patients,” said Bikdeli. “But there is a scarcity of data to guide clinical practice.”

To dig deeper into the association, Bikdeli and his team investigated different anticoagulation strategies and statins, including atorvastatin, in COVID-19 patients admitted to the intensive care units (ICUs) of 10 hospitals in Iran. In the prophylactic anticoagulation part of the study (first hypothesis), there was no evidence to support routine empirical use of intermediate-dose prophylactic anticoagulation in unselected patients with COVID-19 admitted to the ICU. [JAMA 2021;325(16):1620-1630. doi:10.1001/jama.2021.4152]

For the statin part of the study (second hypothesis, INSPIRATION-S), which was reported at ACC.21, 605 patients were randomly assigned to receive atorvastatin 20 mg daily or a placebo. About 25 percent of the patients were taking aspirin and over 90 percent were on steroids. Baseline characteristics were similar in both groups.

Potentially protective, but more studies needed

A potential protective effect was seen in the subgroup of patients (n=171) who presented within the first 7 days of COVID-19 symptom onset. The primary endpoint occurred in 30.9 percent of patients taking atorvastatin vs 40.3 percent in those taking placebo (OR, 0.60; p=0.055).

“This is an interesting observation … it is also plausible, as these patients may be in a different phase of COVID-19 disease. However, we need to be cognizant of the multiplicity of comparisons, and this needs to be further investigated in subsequent studies,” Bikdeli emphasized.

Early administration, higher doses: The better strategy?

Dr Binita Shah, an interventional cardiologist at NYU Langone Health, New York, US, who is unaffiliated with the study, commented that  ICU patients may not be the right population to test statins. “Maybe, it’s just too late for these very sick patients … Trying to rein in the inflammatory cytokine storm and the interaction with thrombosis at this point is quite difficult.”

She said it might have been better if statins were administered earlier in the disease course to prevent the inflammatory process. She even questioned the rationale behind the administration of low-dose atorvastatin. “In this inflammatory milieu, a high-intensity regimen might be more beneficial.”

To which Bikdeli responded: “We didn’t want to exacerbate the liver enzyme elevation associated with several antiviral agents, for example, ritonavir, which is given to COVID-19 patients early in the pandemic. Now, we’ve known atorvastatin to be  safe in these patients, and in retrospect, yes, a higher dose might be better.”