From the Journals

New angiotensin studies in COVID-19 give more reassurance


Are there different effects between ACE inhibitors and ARBs?

A secondary exploratory analysis showed a higher likelihood of hospital admission among patients who tested positive and who were taking either ACE inhibitors (OR, 1.84) or ARBs (OR, 1.61), and there was a higher likelihood of ICU admission among patients who tested positive and who were taking an ACE inhibitor (OR 1.77), but no such difference was observed among those taking ARBs.

Coauthor Ankur Kalra, MD, of the Cleveland Clinic, said in an interview that results of the exploratory analysis fit with the hypothesis that the two drugs classes may have different effects in patients with COVID-19.

“Angiotensin II promotes vasoconstriction, inflammation, and fibrosis in the lungs, and ARBs block the effects of angiotensin II more effectively than ACE inhibitors. In addition, ACE inhibitors (but not ARBs) increase levels of bradykinin, which may be one factor leading to acute respiratory distress syndrome,” he noted.

“However, these results should only be considered exploratory, as there is inherent bias in observational data,” Dr. Kalra stressed.

In an accompanying editorial in JAMA Cardiology, a group led by Laine E. Thomas, PhD, of Duke Clinical Research Institute, Durham, North Carolina, said that the results of this secondary exploratory analysis are limited by a small number of patients and “are likely explained by confounding and should not be inferred as causal.”

The New England Journal of Medicine editorialists reached a similar conclusion regarding the lower mortality in COVID-19 patients who took ACE inhibitors in the study by Dr. Mehra and colleagues. They say this unexpected result “may be due to unmeasured confounding and, in the absence of a randomized trial, should not be regarded as evidence to prescribe these drugs in patients with COVID-19.”

Providing further comment, Dr. McMurray said: “Normally, I would not read too much into the different effects of ACE inhibitors and ARBs suggested in the Cleveland study because of the small numbers (about 28 ACE inhibitor–treated patients admitted to ICU) and the limited information about matching and/or adjustment for potential differences between groups.

“I could also argue that the comparison that would best answer the question about risk related to type of RAS blocker would be the direct comparison of people taking an ACE inhibitor with those taking an ARB (and that doesn’t look very different). The only thing that makes me a little cautious about completely dismissing the possibility of a difference between ACE inhibitor and ARB here is the suggestion of a similar trend in another large study from the VA [Veterans Affairs] system,” he added.

He also noted that speculation about there being mechanisms that involve different effects of the two drug classes on bradykinin and angiotensin II was “plausible but unproven.”

Dr. Messerli added: “Before turning the page, I would like to see an analysis comparing ACE inhibitors and ARBs, since experimentally, their effect on ACE2 (the receptor to which the virus binds) seems to differ. The study of Mehta et al in JAMA Cardiology may be the first clinical hint indicating that ARBs are more protective than ACEIs. However even here, the looming possibility of confounding cannot be excluded.”

Dr. Messerli also pointed to a hypothesis that suggests that direct viral infection of endothelial cells expressing ACE2 receptors may explain worse outcomes in patients with cardiovascular comorbidities, which provides a rationale for therapies to stabilize the endothelium, particularly with anti-inflammatory anticytokine drugs, ACE inhibitors, and statins.

A version of this article originally appeared on


Next Article:

   Comments ()