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Editor's note: The New England Journal of Medicine retracted the Mehra paper cited below on June 4 because the authors determined they could not vouch for the data's accuracy; however, the journal's editors had previously noted that other studies with other data sources had come to similar conclusions.

Antihypertensive drugs targeting the renin-angiotensin-aldosterone system (RAAS) were exonerated from worsening risk of COVID-19 infection or death from it in three large studies -- offering a strong counter to theoretical concerns that these agents could be dangerous.

RAAS drugs include angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) commonly used to treat high blood pressure. One of their effects is to increase expression of ACE2 receptors in human cells -- the same receptors that serve as a portal for the SARS-CoV-2 virus to enter cells. Thus, it had been hypothesized that patients on these agents might be more susceptible to COVID-19 infection and/or suffer more heavily from it.

But of more than 12,500 patients tested for the SARS-CoV-2 virus that causes COVID-19 at NYU Langone Health in New York City through April 15, the 46.8% who tested positive were . Nor were there associations with severe illness in the Bayesian analysis, Harmony Reynolds, MD, of NYU Grossman School of Medicine in New York City, and colleagues reported in the New England Journal of Medicine.

A similar study from Italy published alongside it came to similar conclusions. In a population-based look at all 6,272 cases that tested positive for SARS-CoV-2 in the Lombardy region from Feb. 21 through March 11, 2020, they were about than 30,759 controls matched by sex, age, and municipality.

However, this was because of their relative 28% higher prevalence of cardiovascular disease, wrote Giovanni Corrao, PhD, of the University of Milano-Bicocca in Milan, Italy. After adjustment for baseline and other factors in conditional logistic-regression multivariate analysis, the odds of testing positive was 0.95 for ARBs (95% CI 0.86-1.05) and 0.96 for ACE inhibitors (95% CI 0.87-1.07).

Likewise, a severe or fatal course of the disease was not significantly linked to either class of drugs in the Italian study.

A third study in NEJM affirmed no link between hospital mortality from COVID-19 and RAAS drugs in the observational Surgical Outcomes Collaborative (Surgisphere) database.

Among the 8,910 COVID-19 patients admitted to 169 hospitals in Asia, Europe, and North America who had either died in the hospital or survived to hospital discharge, for the 6.2% on angiotensin receptor blockers at admission (6.8% vs 5.7% among controls, OR 1.23, 95% CI 0.87-1.74).

The 8.6% on ACE inhibitors at admission were actually less likely to die than were other COVID-19 patients (2.1% vs 6.1%, OR 0.33, 95% CI 0.20-0.54), Mandeep Mehra, MD, of Brigham and Women's Hospital in Boston, and colleagues reported.

A secondary analysis of only patients with an indication for a RAAS drug due to having hypertension likewise showed no evidence of harm.

"All are observational studies with the looming possibility of confounding, but each has unique strengths, and their message is consistent -- none of the three studies showed evidence of harm with continued use of ACE inhibitors and ARBs," concluded an accompanying editorial by John Jarcho, MD, of Brigham and Women's, and colleagues.

The lower mortality risk seen with ACE inhibitor use in Mehra's paper might be due to unmeasured confounding, and "should not be regarded as evidence to prescribe these drugs in patients with Covid-19," they added. At the same time, though, the editorialists wrote that the overall message from NEJM papers "is consistent -- none of the three studies showed evidence of harm with continued use of ACE inhibitors and ARBs."

They also support the unified voice of professional societies urging against discontinuation of ACE inhibitor or ARB therapy over COVID-19 concerns, Jarcho's group noted.

Still, randomized trial data will be needed to answer definitively the question of whether RAAS drugs pose a harm to patients with COVID-19, they added.

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