New Angiotensin Studies in COVID-19 Give More Reassurance

May 05, 2020

Editor's note: Find the latest COVID-19 news and guidance in Medscape's Coronavirus Resource Center.

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.

In the third study published in the NEJM, a group led by Harmony R. Reynolds, MD, NYU Grossman School of Medicine, New York City, analyzed data from the health records of 12,594 patients in the New York University (NYU) Langone Health system who had been tested for COVID-19. They found 5894 patients whose test results were positive test. Of these patients, 1002 had severe illness, which was defined as illness requiring admission to the intensive care unit, need for mechanical ventilation, or death.

Using Bayesian analysis and propensity-score matching, the researchers assessed the relation between previous treatment with five different classes of antihypertensive drugs (ACE inhibitors, ARBs, beta blockers, calcium blockers, and thiazide diuretics) and the likelihood of a positive or negative result on COVID-19 testing, as well as the likelihood of severe illness (defined as illness requiring intensive care, need for mechanical ventilation, or death) among patients who tested positive.

Results showed no positive association for any of the analyzed drug classes for either a positive test result or severe illness.

In an accompanying editorial, a group led by John A. Jarcho, MD, assistant professor, Harvard Medical School, and deputy editor of the NEJM, write: "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.

"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 is unlikely to be harmful in patients with Covid-19. Several other smaller studies from China and the United Kingdom have come to the same conclusion," they state.

In the study published in JAMA Cardiology, a group led by Neil Mehta, MBBS, Cleveland Clinic, Ohio, analyzed data on 18,472 patients who had been tested for COVID-19 between March 8 and April 12 in the Cleveland Clinic Health System in Ohio and Florida. Of these patients, 9.4% tested positive.

After overlap propensity-score weighting for both ACE inhibitors and ARBs to take into account relevant comorbidities, there was no difference in risk for testing positive among patients taking an ACE inhibitor or an ARB in comparison with those not taking such medication.

Different Effects of 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, Cleveland Clinic, commented to Medscape Medical News 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," Kalra stressed.

In an accompanying editorial in JAMA Cardiology, a group led by Laine E. Thomas, PhD, Duke Clinical Research Institute, Durham, North Carolina, say 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 NEJM editorialists reach a similar conclusion regarding the lower mortality in COVID-19 patients who took ACE inhibitors in the study by 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."

Commenting for Medscape Medical News, 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."

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."

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

N Engl J Med. Published online May 1, 2020. Mehra et al, Abstract; Mancia et al, Abstract; Reynolds et al, Abstract; Editorial

JAMA Cardiol. Published online May 5, 2020. Full text, Editorial

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