Atorvastatin: A Potential Treatment in COVID-19?

May 17, 2021

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For patients with COVID-19 admitted to intensive care, giving atorvastatin 20 mg/d did not result in a significant reduction in risk for venous or arterial thrombosis, for treatment with extracorporeal membrane oxygenation (ECMO), or for all-cause mortality compared with placebo in the INSPIRATION-S study.

However, there was a suggestion of benefit in the subgroup of patients who were treated within 7 days of COVID-19 symptom onset.

The study was presented by Behnood Bikdeli, MD, Brigham and Women's Hospital, Boston, Massachusetts, on May 16 at the virtual American College of Cardiology (ACC) 2021 Scientific Session.

He explained that COVID-19 is characterized by an exuberant immune response and that there is a potential for thrombotic events because of enhanced endothelial activation and a prothrombotic state.

"In this context, it is interesting to think about statins as potential agents to be studied in COVID-19, because as well as having lipid-lowering actions, they are also thought to have anti-inflammatory and antithrombotic effects," he said.

In the HARP-2 trial of simvastatin in acute respiratory distress syndrome (ARDS), published a few years ago, the main results were neutral, but in the subgroup of patients with hyperinflammatory ARDS, there was a reduction in mortality with simvastatin in comparison with placebo, Bikdeli noted.

Moreover, in a series of observational studies of patients with COVID-19, use of statins was associated with a reduction in mortality among hospitalized patients. However, there are limited high-quality data to guide clinical practice, he said.

The INSPIRATION study, conducted in 11 hospitals in Iran, had a two-by-two factorial design to investigate different anticoagulant strategies and the use of atorvastatin for COVID-19 patients in the intensive care unit (ICU).

In the anticoagulation part of the trial, which was published in JAMA last month, there was no difference in the primary endpoint of an intermediate dose and standard dose of enoxaparin.

For the statin part of the trial (INSPIRATION-S), 605 patients were randomly assigned to receive atorvastatin 20 mg daily or placebo. Patients who had been taking statins beforehand were excluded. Baseline characteristics were similar for the two groups, with around a quarter of patients taking aspirin and more than 90% taking steroids.

Results showed that atorvastatin was not associated with a significant reduction in the primary outcome ― a composite of adjudicated venous or arterial thrombosis, treatment with ECMO, or mortality within 30 days ― which occurred in 32.7% of the statin group vs 36.3% of the placebo group (odds ratio [OR], 0.84; P = .35).

Atorvastatin was not associated with any significant differences in any of the individual components of the primary composite endpoint. There was also no significant difference in any of the safety endpoints, which included major bleeding and elevations in liver enzyme levels.

Subgroup analyses were mostly consistent with the main findings, with one exception.

In the subgroup of patients who presented within the first 7 days of COVID-19 symptom onset, there was a hint of a potential protective effect with atorvastatin.

In this group of 171 patients, the primary endpoint occurred in 30.9% of those taking atorvastatin, vs 40.3% of those taking placebo (OR, 0.60; P = .055).

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

Higher Dose in Less Sick Patients a Better Strategy?

Discussing the study at the ACC presentation, Binita Shah, MD, said the importance of enrolling COVID-19 patients into clinical trials was paramount but that these patients in the ICU may not have been the right population in which to test a statin.

"Maybe for these very sick patients, it is just too late. Trying to rein in the inflammatory cytokine storm and the interaction with thrombosis at this point is very difficult," Shah commented.

She suggested that it might be appropriate to try statins in an earlier phase of the disease in order to prevent the inflammatory process, rather than trying to stop it after it had already started.

Shah also questioned the use of such a low dose of atorvastatin for these patients. "In the cardiovascular literature ― at least in ACS [acute coronary syndrome] ― high statin doses are used to see short-term benefits. In this very inflammatory milieu, I wonder whether a high-intensity regimen would be more beneficial," she speculated.

Bikdeli replied that a low dose of atorvastatin was chosen because early on, several antiviral agents, such as ritonavir, were being used for COVID-19 patients, and these drugs were associated with increases in liver enzyme levels.

"We didn't want to exacerbate that with high doses of statins," he said. "But we have now established the safety profile of atorvastatin in these patients, and in retrospect, yes, a higher dose might have been better."

The INSPIRATION study was funded by the Rajaie Cardiovascular Medical and Research Center, Tehran, Iran. Bikdeli has disclosed no relevant financial relationships.

American College of Cardiology (ACC) 2021 Scientific Session: Presented May 16, 2021.

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