Three observational studies agree: no RAAS/SARS-CoV-2 link

For those who continue to harbor doubts about the safety of RAAS inhibitors, The New England Journal of Medicine published side-by-side-by-side three observational studies from three different populations, all of which reached the same conclusion: neither ACE-inhibitors nor angiotensin receptor blockers (ARBs) increase the risk of infection with SARS-CoV-2, nor does the use of these agents increase the risk of a worse outcome for those diagnosed with Covid-19.

A group of Boston-based researchers studied databases from 169 hospitals in Asia, Europe, and North America to evaluate “the relationship of cardiovascular disease and drug therapy with in-hospital deaths from Dec. 20, 2019 through March 15, 2020.”

Mandeep R. Mehra, MD, from Brigham and Women’s Hospital Heart and Vascular Center/Harvard Medical School, and colleagues identified 8,910 Covid-19 patients, of whom 8,395 survived to discharge.

Although they found no increased risk for in-hospital mortality associated with ACE inhibitor or ARB use, they did identify a number of factors independently associated with in-hospital mortality, including:

  • Age greater than 65 years OR, 1.93; 95% CI, 1.60-2.41).
  • Coronary artery disease OR, 2.70; 95% CI, 2.08-3.51).
  • Heart failure OR, 2.48; 95% CI, 1.62-3.79).
  • Cardiac arrhythmia OR 1.95; 95% CI, 1.33-2.86).
  • COPD OR, 2.96; 95% CI, 2.00-4.40).
  • Current smoker OR, 1.79; 95% CI, 1.29 to 2.47).

“Our study confirmed previous observations suggesting that underlying cardiovascular disease is associated with an increased risk of in-hospital death among patients hospitalized with Covid-19,” Mehra and colleagues wrote.

Researchers in Milan led by Giuseppe Mancia, MD, of the University of Milano-Bicocca, based their study on data from patients in the Lombardy region of Italy, a recognized Covid-19 hotspot. They identified 6,272 confirmed cases from Feb. 21 through March 11, 2020 and matched them to 30,759 sex, age, and municipality of residence controls drawn from a Regional Health Service registry.

The mean age of patients and controls was 68 and 37% were women.

“The use of ACE inhibitors and ARBs was more common among case patients than among controls, as was the use of other antihypertensive and non-antihypertensive drugs, and case patients had a worse clinical profile,” Mancia and colleagues wrote. But the use of ACE inhibitors or ARBs, “did not show any association with Covid-19 among case patients overall (adjusted odds ratio, 0.95 [95% confidence interval {CI}, 0.86-1.05] for ARBs and 0.96 [95% CI, 0.87-1.07] for ACE inhibitors) or among patients who had a severe or fatal course of the disease (adjusted odds ratio, 0.83 [95% CI, 0.63-1.10] for ARBs and 0.91 [95% CI, 0.69-1.21] for ACE inhibitors), and no association between these variables was found according to sex.”

So, although use of RAAS inhibitors was common, that use did not increase the risk of Covid-19. What did increase the risk was “the higher prevalence of cardiovascular disease.”

Finally, a team from the Cardiovascular Research Center at NYU Grossman School of Medicine, headed by Harmony Reynolds, MD, looked at the likelihood of Covid-19 among patients taking antihypertensives.

“Among 12,594 patients who were tested for Covid-19, a total of 5894 (46.8%) were positive; 1002 of these patients (17.0%) had severe illness. A history of hypertension was present in 4357 patients (34.6%), among whom 2573 (59.1%) had a positive test; 634 of these patients (24.6%) had severe illness,” they wrote. “There was no association between any single medication class and an increased likelihood of a positive test. None of the medications examined was associated with a substantial increase in the risk of severe illness among patients who tested positive.”

Reynolds and colleagues added a wishful note hoping the findings “may help to allay concerns on the part of patients and providers regarding the continued use of these agents in patients undergoing tests or receiving treatment for Covid-19.”

An editorial authored by five NEJM editors, led by Deputy Editor, John A. Jarcho, MD, pointed out that when taken together, the three studies, although observational, “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.”

  1. Be aware that findings from three observational studied failed to confirm an increased risk for infection with SARS-CoV-2 virus or with more serious illness among those who develop Covid-19.

  2. Note that cardiovascular disease is an independent risk factor for Covid-19.

Peggy Peck, Editor-in-Chief, BreakingMED™

Mancia reported personal fees from Bayer, personal fees from Boehringer Ingelheim, personal fees from CVRx, personal fees from Daiichi Sankyo, personal fees from Ferrer, personal fees from Medtronic, personal fees from Menarini Int., personal fees from Merck, personal fees from Novartis, personal fees from Recordati, personal fees from Servier, outside the submitted work.

Mehra reported personal fees from Abbott, personal fees from Medtronic, personal fees from Janssen, personal fees from Mesoblast , personal fees from Baim Institute for Clinical Research, personal fees from Portola, personal fees from Bayer, personal fees from Triple Gene, personal fees from Leviticus, personal fees from NupulseCV, personal fees from FineHeart, other from Riovant, outside the submitted work.

Reynolds reported non-financial support from Abbott Vascular, non-financial support from Biotel, non-financial support from Siemens, outside the submitted work.

Cat ID: 3

Topic ID: 74,3,791,932,3,308,6,838,914,190,926,192,927,151,928,925,934