New Angiotensin Studies in COVID-19 Give More Reassurance

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MAY 05, 2020 — Four more studies of the relationship of angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) with COVID-19 have been published in the past few days in top-tier peer-reviewed journals, and on the whole, the data are reassuring.

Three of the new studies were published in the New England Journal of Medicine on May 1, and one study was published in JAMA Cardiology on May 5.

Although all the studies are observational in design and have some confounding factors, overall, the results do not suggest that continued use of ACE inhibitors and ARBs causes harm. However, there are some contradictory findings in secondary analyses regarding possible differences in the effects of the two drug classes.

Commenting for Medscape Medical News, John McMurray, MD, professor of medical cardiology, University of Glasgow, United Kingdom, said: “The overall picture seems to suggest no increase in risk of adverse outcomes in patients taking renin-angiotensin system [RAS] blockers ― but with lots of caveats: these are all observational rather than randomized studies, and there may be residual or unmeasured confounding.”

“Much Ado About Nothing”?

Franz Messerli, MD, professor of medicine at the University of Bern, Switzerland, added: “Given this state of the art, I am inclined to consider RAS blockade and COVID-19 ― despite all the hype in the news media ― as much ado about nothing.”

But both McMurray and Messerli said they were intrigued about possible differences in the effects of ACE inhibitors and ARBs that some of the new results suggest.

In one study that was published in the NEJM, a team led by Mandeep Mehra, MD, Brigham and Women’s Hospital Heart and Vascular Center, Boston, analyzed data from 8910 patents admitted to 169 hospitals with COVID-19 in Asia, Europe, and North America who had either died in the hospital (5.8%) or survived to hospital discharge (94.2%).

In multivariate logistic-regression analysis, age greater than 65 years, coronary artery disease, congestive heart failure, history of cardiac arrhythmia, chronic obstructive pulmonary disease, and current smoking were associated with an increased risk for in-hospital death. Female sex was associated with a decreased risk. Neither ACE inhibitors nor ARBs were associated with an increased risk for in-hospital death.


In fact, ACE inhibitors were associated with a significant reduction in mortality (odds ratio [OR], 0.33), as were statins (OR, 0.35).

The authors, however, stress that these observations about reduced mortality with ACE inhibitors and statins “should be considered with extreme caution.”

“Because our study was not a randomized, controlled trial, we cannot exclude the possibility of confounding. In addition, we examined relationships between many variables and in-hospital death, and no primary hypothesis was prespecified; these factors increased the probability of chance associations being found. Therefore, a cause-and-effect relationship between drug therapy and survival should not be inferred,” they write.

A secondary analysis that was restricted to patients with hypertension (those for whom an ACE inhibitor or an ARB would be indicated) also did not show harm.

A second study published in the NEJM had a case-control design. The authors, led by Giuseppe Mancia, MD, University of Milano-Bicocca, Italy, compared 6272 patients with confirmed COVID-19 (case patients) with 30,759 control persons who were matched according to age, sex, and municipality of residence.

In a conditional logistic-regression multivariate analysis, neither ACE inhibitors nor ARBs were associated with the likelihood of SARS-CoV-2 infection.

“Thus, our results do not provide evidence of an independent relationship between renin angiotensin aldosterone blockers and the susceptibility to COVID-19 in humans,” the authors conclude.

In addition, a second analysis that compared patients who had severe or fatal infections with matched control persons did not show an association between ACE inhibitors or ARBs and severe disease.

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