Evidence suggests no COVID-19-related harm from RAAS antagonists

Issue: June 2020

ByErik Swain

Paul K. Whelton

Editor's Note: The study by Mehra and colleagues published in the New England Journal of Medicine and mentioned in this story has been retracted by the authors because the raw data were not made available to the authors or a third-party auditor. You can read the letter to the editor with the retraction here.

Because the virus that causes COVID-19 acts through the ACE2 receptor, there was concern that use of renin-angiotensin-aldosterone system antagonists such as ACE inhibitors and angiotensin receptor blockers, which are used to treat hypertension, HF and other CV conditions, might predispose people to COVID-19 or worsen its effects. But emerging data suggest that concern is unfounded.

“We now have at least 11 observational studies that have reported on this issue. They are of varying quality, but some are very good studies, albeit none are randomized controlled trials. Overall, they are quite consistent in failing to show a relationship between renin-angiotensin-aldosterone system (RAAS) inhibitors and COVID-19 infection or severe/fatal complications,” Paul K. Whelton, MB, MD, MSc, Show Chwan Professor of Global Public Health, department of epidemiology, Tulane University School of Public Health and Tropical Medicine and Tulane University of Medicine, told Healio.

Taken together, the findings confirm recommendations released in March by various cardiology societies, including the American College of Cardiology, the American Heart Association, the European Society of Cardiology and the Heart Failure Society of America, that patients on RAAS antagonists continue to take them.

Ankur Kalra

“The question came up because these medications upregulate the same receptor that the virus is using to enter the host cells,” Ankur Kalra, MD, FACP, FACC, FSCAI, assistant professor of medicine at Cleveland Clinic Lerner College of Medicine of Case Western Reserve University and staff interventional cardiologist in the department of cardiovascular medicine, Heart, Vascular and Thoracic Institute at Cleveland Clinic, told Healio. “Also, the earlier data that came out from China and Italy showed that patients with underlying disease conditions, particularly hypertension and heart disease, were at an increased risk. It even compounded the theory as to whether these medications are putting them at heightened risk for contracting the infection.”

Harmony R. Reynolds, MD, associate professor of medicine and associate director of the Cardiovascular Clinical Research Center at NYU Grossman School of Medicine.

Growing evidence base

The studies published so far all suggest that people taking RAAS inhibitors are not more likely to test positive for COVID-19 nor more likely to die of it if they contract it.

Mandeep R. Mehra

In one study published in The New England Journal of Medicine by Mandeep R. Mehra, MD, The William Harvey Distinguished Chair in Advanced Cardiovascular Disease at Brigham and Women’s Hospital and professor of medicine at Harvard Medical School, and colleagues, in a cohort of 8,910 patients with COVID-19 from three continents, there was no elevated risk for in-hospital death from use of ACE inhibitors (users, 2.1%; nonusers, 6.1%; OR = 0.33; 95% CI, 0.2-0.54) or angiotensin receptor blockers (users, 6.8%; nonusers, 5.7%; OR = 1.23; 95% CI, 0.87-1.74).

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In a cohort of 12,594 patients documented in the NYU Langone Health electronic health record to have been tested for COVID-19 between March 1 and April 15, there was no relationship between a positive test for COVID-19 and use of any class of BP medication, including ACE inhibitors and/or angiotensin receptor blockers, beta-blockers, calcium channel blockers and thiazide-type diuretics, Harmony R. Reynolds, MD, associate professor of medicine and associate director of the Cardiovascular Clinical Research Center at NYU Grossman School of Medicine, and colleagues reported in NEJM.

“The most important take-home message from our study is that it is safe to take heart and blood pressure medications, including ACE inhibitors/angiotensin receptor blockers,” Reynolds told Healio. “Even though the study did not address mechanisms of the interaction of the virus with the drugs, we see no harm in the large group of patients studied, and that should be reassuring for all patients taking ACE inhibitors and angiotensin receptor blockers, including during the pandemic.”

In a case-control study from Florence, Italy, published in NEJM, use of ACE inhibitors and angiotensin receptor blockers was more common in 6,272 patients with COVID-19 compared with 30,759 matched controls, but among the cases, there was no association with their use and COVID-19 or their use and a severe or fatal course.

A case-control study of 1,139 patients with COVID-19 and 11,390 matched controls from the Madrid region published in The Lancet found similar results.

Mina K. Chung

In JAMA Cardiology, a group including Kalra; Neil Mehta, MBBS, staff physician at Cleveland Clinic and associate dean for curricular affairs at the Cleveland Clinic Lerner College of Medicine of Case Western Reserve University; Mina K. Chung, MD, FAHA, FHRS, staff cardiologist in the section of pacing and electrophysiology in department of cardiovascular medicine, Cleveland Clinic; and Amy S. Nowacki, PhD, associate staff at Cleveland Clinic Lerner Research Institute, found no relationship between RAAS antagonist use and contracting COVID-19 in a cohort of 18,472 patients tested for the disease (overlap propensity score-weighted OR = 0.97; 95% CI, 0.81-1.15).

“Patients who are on ACE inhibitors and angiotensin receptor blockers can be rest assured that taking those medications is not specifically predisposing them to increased risk for contracting COVID-19,” Kalra told Healio. “That is a very important message. Our study is the largest to answer that question, and we have definitively answered that question for everyone.”

A living systematic review published in the Annals of Internal Medicine confirmed the results of the individual papers, finding that in 14 observational studies, there was no evidence of a link between RAAS inhibitor use and risk for contracting COVID-19 or getting a severe form of the disease.

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Next steps

Future research will examine the mechanistic interactions between the SARS-CoV-2 virus and RAAS antagonists and attempt to determine whether their use might be protective, Kalra said in an interview.

“In the secondary, hypothesis-generating analysis we published on ACE inhibitors and angiotensin receptor blockers, there may be a signal of patients on angiotensin receptor blockers doing slightly better than patients on ACE inhibitors,” he said. “That may be because at the level of the epithelium of the lung, if you can upregulate ACE2, the COVID-19 receptor, that enzyme is actually playing a very important role in breaking down angiotensin II, which is proinflammatory, profibrotic and vasoconstrictive, into angiotensin 1-7, which is anti-inflammatory, vasodilatory and antifibrotic. So, at the level of the epithelium, there may be a role for angiotensin receptor blockers to be protective because they can upregulate ACE2 at the level of the lung epithelial tissue. Whereas the virus, as soon as it enters the host cell through ACE2, actually downregulates it. Mechanistically, there may be a signal there, but it warrants more study and more data. That is something we are in the midst of doing right now.”

Whelton said although those findings are an outlier for now, “several clinical trials are underway to look at the possibility of RAAS inhibitor effect modification for COVID-19 clinical outcomes, albeit none are sufficiently powered to detect an effect on mortality.”

For the latest news on COVID-19 including case counts, information about the global public health response and emerging research, please visit the COVID-19 Resource Center on Healio. – by Erik Swain

References:

de Abajo FJ, et al. Lancet. 2020;doi:10.1016/S0140-6736(20)31030-8.

Mackey K, et al. Ann Intern Med. 2020;doi:10.7326/M20-1515.

Mancia G, et al. N Engl J Med. 2020;doi:10.1056/NEJMoa2006923.

Mehra MR, et al. N Engl J Med. 2020;doi:10.1056/NEJMoa2007621.

Mehta N, et al. JAMA Cardiol. 2020;doi:10.1001/jamacardio.2020.1855.

Reynolds HR, et al. N Engl J Med. 2020;doi:10.1056/NEJMoa2008975.

For more information:

Ankur Kalra, MD, FACP, FACC, FSCAI, can be reached at kalraa@ccf.org.

Harmony R. Reynolds, MD, can be reached at harmony.reynolds@nyulangone.org.

Paul K. Whelton, MB, MD, MSc, can be reached at pkwhelton@gmail.com.

Disclosures: Kalra, Reynolds and Whelton report no relevant financial disclosures.