Inhibitors of the renin-angiotensin-aldosterone system (RAAS) do not appear to increase the risk of COVID-19 or its severity, according to the findings of 3 studies published on May 1 in the New England Journal of Medicine.

Physicians have been concerned about a potential increased risk of COVID-19 related to medications that act on the RAAS because the viral receptor is angiotensin-converting enzyme 2 (ACE2).

One study, by Harmony R. Reynolds, MD, and collaborators at New York University Grossman School of Medicine, examined the relationship between previous treatment with ACE inhibitors, angiotensin-receptor blockers (ARBs), beta-blockers, calcium-channel blockers, or thiazide diuretics and the likelihood of a positive or negative COVID-19 test result. The study included 12,594 patients who were tested for COVID-19. Of these, 5894 (46.8%) tested positive, and 1002 (17%) of them had severe illness. A total of 4357 patients (34.6%) had a history of hypertension. Of these, 2573 (59.1%) had a positive test, and 634 (24.6%) of them had severe illness. Dr Reynolds’ team reporting finding no association between any single medication class and an increased likelihood of a positive test.

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In a population-based case-control study in the Lombardy region of Italy, Giuseppe Mancia, MD, at the University of Milano-Bicocca, and colleagues compared 6272 confirmed cases of severe acute respiratory syndrome due to SARS-CoV-2, the novel coronavirus that causes COVID-19, to 30,759 beneficiaries of the Regional Health Service matched by age, sex, and municipality of residence. Because of their greater prevalence of cardiovascular disease, the COVID-19 patients were more likely to use ACE inhibitors and ARBs. The investigators found no evidence, however, that use of these drugs influenced COVID-19 risk.

The third study evaluated the relationship of cardiovascular disease and drug therapy with in-hospital mortality among 8910 patients with COVID-19 at 169 hospitals in Asia, Europe, and North America. Of these, 515 (5.8%) died in the hospital and 8395 (94.2%) survived to discharge. The study, led by Mandeep R. Mehra, MD, of Brigham and Women’s Hospital in Boston, found no increased risk of in-hospital death associated with the use of ACE inhibitors or ARBs. Factors independently associated with an increased risk of in-hospital mortality were age greater than 65 years, coronary artery disease, heart failure, cardiac arrhythmia, and chronic obstructive pulmonary disease, the investigators reported.

“We were not able to confirm previous concerns regarding a potential harmful association of ACE inhibitors or ARBs with in-hospital mortality in this clinical context,” Dr Mehra’s team wrote.

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“Taken together, these three studies do not provide evidence to support the hypothesis that ACE inhibitor or ARB use is associated with the risk of SARS-CoV-2 infection, the risk of severe Covid-19 among those infected, or the risk of in-hospital death among those with a positive test,” John A. Jarcho, MD, a deputy editor for the New England Journal of Medicine, and coauthors wrote in an accompanying editorial. “Each of these studies has weaknesses inherent in observational data, but we find it reassuring that three studies in different populations and with different designs arrive at the consistent message that the continued use of ACE inhibitors and ARBs in unlikely to be harmful in patients with Covid-19.”


Reynolds HR, Adhikari S, Pulgarin C, et al. Renin-angiotensin-aldosterone system inhibitors and risk of Covid-19 [published online May 1, 2020]. N Engl J Med. doi: 10.1056/NEJMoa2008975

Mancia G, Rea F, Ludergnani M, et al. Renin-angiotensin-aldosterone system blockers and the risk of Covid-19 [published online May 1, 2020]. N Engl J Med. doi: 10.1056/NEJMoa2006923

Mehra MR, Desai SS, Kuy S, et al. Cardiovascular disease, drug therapy, and mortality in Covid-19. N Engl J Med.  doi: 10.1056/NEJMoa2007621

Jarcho JA, Ingelfinger JR, Hamel MB, et al. Inhibitors of the renin-angiotensin-aldosterone system and Covid-19. N Engl J Med. doi: 10.1056/NEJMe2012924