COVID-19, ACE Inhibitors, and ARBs: Multiple Studies Show No Increased Risk

A series of papers published in recent days provide reassuring data that patients taking inhibitors of the renin-angiotensin-aldosterone system (RAAS), such as ACE inhibitors and angiotensin receptor blockers, are not more susceptible to developing COVID-19. Nor are they more likely to develop a more severe form of the disease if they are infected.

One large study of 8,910 patients with COVID-19 admitted to hospitals in Asia, Europe, and North America also showed that the presence of cardiovascular disease—not the use of RAAS inhibitors or other cardiovascular medications—is what’s linked to an increased risk of death in hospitalized COVID-19 patients,

Mandeep Mehra, MD (Brigham and Women’s Hospital, Boston, MA), who led that study, published May 1, 2020, in the New England Journal of Medicine, said these new papers fill an important gap in the literature, especially since some physicians and patients have been stopping their cardiac medications based on theoretical concerns the drugs might be harmful in the setting of COVID-19.

“Early on, during the infection phase of the pandemic, we learned that one of the unique vulnerabilities with this virus was in patients with underlying cardiovascular disease,” said Mehra. “At that point, there was a debate about whether it was the underlying disease that induces the risk of worse outcomes with COVID-19 or if the drugs we used for the underlying disease caused this risk. That’s why, in our observational analysis, we wanted to sort these two questions out from each other.”

The bottom line, said Mehra, is that older patients, particularly men with a history of cardiovascular disease, are particularly vulnerable and should do everything possible not to be exposed to the virus. “But the most important thing they need to do is make sure they mitigate their risk by staying in a compensated state with their cardiovascular disease,” Mehra told TCTMD. “And the best way to do that is to not interrupt their medication.”

Increased Expression of ACE2

In addition to concerns that the use of RAAS inhibitors might increase COVID-19 severity and even mortality in patients with hypertension, diabetes, and other cardiovascular diseases there was also speculation that these agents could increase the susceptibility to contracting COVID-19.  

SARS-CoV-2, which is the virus responsible for COVID-19, binds to the ACE2 receptor to gain entry into host cells. ACE2 is expressed in heart, intestine, kidney, and pulmonary alveolar cells, and at least in animal studies, chronic exposure to ACE inhibitors and ARBs has been shown to upregulate ACE2 expression. The hypothesis was that increased expression of ACE2 might lead to more-severe infection or adverse outcomes with COVID-19. Based on animal models, it had also been speculated that ACE2 could be protective in acute lung injury, which meant treatment with ACE inhibitors or ARBs could increase ACE2 and theoretically improve outcomes.

Harmony Reynolds, MD (NYU Langone Medical Center, New York, NY), who led one of the three studies on the topic published in NEJM, said the early reports led to numerous discussions amongst cardiologists about whether patients should continue with ACE inhibitors and ARBs in light of COVID-19.

“There were theoretical reasons why they might be harmful and, counterbalancing that, reasons why they might be protective,” Reynolds told TCTMD. “We didn’t really know what to think. It had bubbled up to the patients. I had a number of calls from patients asking if they should stop these medicines or telling me they had stopped the medicine because they had concerns.”

Ankur Kalra, MD (Cleveland Clinic, OH), who along with first author Neil Mehta, MBBS (Cleveland Clinic), led a study published in JAMA Cardiology, told TCTMD that patients are savvy consumers of medical news and that the theoretical concerns about RAAS inhibition had reached their ears. “The early data coming out of China and then Italy showed that a lot of patients with severe forms of COVID-19 were hypertensive or had underlying heart disease,” said Kalra. “A lot of our patients are on ACE inhibitors and ARBs, so it’s extremely relevant and important for our field to understand the mechanisms that exposure to these medications might play.” 

Mehra pointed to a recent study of the characteristics, comorbidities, and outcomes of patients with COVID-19 in New York City. Of those taking an ACE inhibitor or ARB prior to hospitalization, roughly 50% had the medication stopped during their hospital visit. “The practice until now has been based on conjecture and theoretical concerns and debates, none of which had answered the question clearly,” he said.

In March, the American Society of Cardiology, American Heart Association, and Heart Failure Society of America issued guidance stating that patients should not stop taking their RAAS inhibitors unless directed to do so by their physician. The societies asked for further studies, quickly, to address the issue. Researchers answered the call, with the three studies published last week in NEJM, plus the one by Mehta, Kalra, and colleagues at the Cleveland Clinic and Lerner Research Institute, published today in JAMA Cardiology.

Call for Research, Physicians Respond

In the NEJM paper by Mehra and colleagues, 5.8% died in hospital and 8,395 survived to discharge. In total, 30.5% of patients had hyperlipidemia, 26.3% had hypertension, 14.3% had diabetes mellitus, and 22.3% were current or former smokers. More than 11% of patients had preexisting CAD, while 2.1% and 3.4% had a history of heart failure and cardiac arrhythmias, respectively.

In multivariate logistic regression analysis, age > 65 years was associated with an increased risk of in-hospital death (OR 1.93; 95% CI 1.60-2.41). Similarly, preexisting CAD, a history of heart failure, cardiac arrhythmias, and chronic obstructive pulmonary disease, as well as current smoking, were associated with a significantly increased risk of death among COVID-19 patients.

None of the medications—antiplatelets, beta-blockers, ACE inhibitors, ARBs, statins, and insulin or other hypoglycemic drugs—were associated with an increased risk of dying in the hospital. In fact, statins and ACE inhibitors were associated with significant 65% and 67% lower risks of death, respectively. Mehra said the finding may be chance, but also pointed to the possibility that it reveals something about the pathophysiology of COVID-19.

“The interesting thing about ACE inhibitors and statins is that they both have salutary effects on endothelial cell stabilization,” he said. ACE2, said Mehra, is expressed in endothelial cells and one recent study showed that COVID-19 can infect endothelial cells directly. This might also explain some of the thromboembolic complications associated with COVID-19, he said. “This is a vascular disease, and the signal of a benefit from statins and ACE inhibitors in our study, whether it’s true or not, really makes us think.”   

Drugs Don’t Predispose Patients to a Positive Test

In their retrospective cohort study, Mehta, Kalra, and colleagues identified 18,472 patients (mean age 49 years; 40% male) tested for COVID-19 at the Cleveland Clinic Health System between March 8 and April 12, 2020. Of those tested, 2,285 were taking either an ACE inhibitor or ARB. A positive SARS-CoV-2 test result was documented in 1,735 patients (9.4%), and 214 of these patients were taking either an ACE inhibitor or ARB. For those who tested positive, 24.3% were admitted to the hospital, 9.3% were admitted to the ICU, and 6.4% required mechanical ventilation. 

After overlap propensity-score weighting for both ACE inhibitors and ARBs, 8.6% of patients taking an ACE inhibitor tested positive for SARS-CoV-2 compared with 9.5% of patients not taking an ACE inhibitor (OR 0.89; 95% CI 0.72-1.10). Similarly, 10.0% of patients taking an ARB tested positive for SARS-CoV-2 compared with 9.3% of those not taking an ARB (OR 1.09; 95% CI 0.87-1.37). Combined, 9.1% of patients taking an ACE inhibitor or ARB tested positive compared with 9.4% not taking either drug class (OR 0.97; 95% CI 0.81-1.15). 

“Chronic administration of this medication class does not predispose you to becoming infected with COVID-19,” said Kalra. “That is good news and the implications are relevant for a lot of the patients worldwide. . . . It’s extremely important for our cardiac patients, and our hypertensive patients, to stay on these medications for chronic disease management.”

The researchers did observe that, compared with patients not taking a RAAS inhibitor, patients infected with SARS-CoV-2 taking ACE inhibitors were more likely to be admitted to hospital and to the ICU, and positive patients taking ARBs were more likely to be admitted to hospital. However, Kalra said these secondary findings should be cautiously interpreted, noting that the numbers were small and require replication in a larger cohort of patients. 

In an editorial, JAMA Cardiology editors Laine Thomas, MD (Duke Clinical Research Institute, Durham, NC), Robert Bonow, MD (Northwestern University Feinberg School of Medicine, Chicago, IL), and Michael Pencina, PhD (Duke Clinical Research Institute), agree the secondary results need to be interpreted with care, but say the study by Mehta et al provides “important clinical data to support current treatment recommendations” for ACE inhibitors and ARBs in the current pandemic.

No Higher Risk of Positive COVID-19 Test With Any Meds

Finally, in their study, Reynolds and colleagues examined the characteristics and outcomes of 12,594 patients who had a COVID-19 test result between March 1 and April 15, 2020, in the NYU Langone Health system. Here, 46.8% of patients tested positive for COVID-19, of whom 17.0% were severely sick defined as admission to the ICU, mechanical ventilation, or death. Of the tested patients, 4,357 had a history of hypertension and 59.1% of these hypertensive patients tested positive for COVID-19. Among the hypertensive patients positive for COVID-19, 24.6% were severely sick.

In a propensity-matched analysis of patients with hypertension, no medication class (including ACE inhibitors, ARBs, beta-blockers, calcium-channel blockers, or thiazide diuretics) was associated with a positive test result for COVID-19, nor was use of any of the drug classes associated with increased severity of COVID-19. The same results also were observed in the propensity-matched analysis of the entire cohort regardless of hypertension status.  

“We looked at two different outcomes in our patients, the likelihood of a positive test among those who were tested and the likelihood of severe illness among those who had a positive test,” said Reynolds. “These reflect the two places where ACE inhibitors or ARBs were theoretically going to show a benefit or harm.”

Reynolds believes there is now robust data showing that ACE inhibitors and ARBs do not increase the susceptibility to contracting SARS-CoV-2 in the outpatient setting. They also don’t appear to increase the severity of disease among patients with a positive diagnosis. “What remains an unanswered question for me is inpatient treatment,” she said. “We didn’t analyze if these drugs were continued in the hospital and how that might have related to in-hospital outcomes. I think that’s an important remaining question.”

In another editorial, John Jarcho, MD, the deputy editor of the NEJM, and several coauthors also highlight an analysis by Giuseppe Mancia, MD (University of Milano–Bicocca, Italy), and colleagues that looked at 6,272 patients with confirmed SARS-CoV-2 infection in Lombardy, Italy. Like the other studies, this one too showed that neither ACE inhibitors nor ARBs were associated with an increased risk of infection.

“Taken together, these three [NEJM] 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.”