COVID-19, ACE inhibitors and BRA: multiple studies show no increased risk

A series of articles published in the past few days provide reassuring data that patients taking renin-angiotensin-aldosterone system inhibitors (RAAS), such as ACE inhibitors and angiotensin receptor blockers, are no longer susceptible to develop COVID-19. They are also not more likely to develop a more severe form of the disease if they are infected.

A large study of 8,910 COVID-19 patients 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 is related to an increased risk of death. in hospitalized patients with COVID-19,

Mandeep Mehra, MD (Brigham and Women’s Hospital, Boston, MA), who led that study, published May 1, 2020, in the New England Journal of MedicineHe said that these new documents fill a significant gap in the literature, especially as some doctors and patients have stopped taking their cardiac medications due to theoretical concerns that the drugs could be harmful in the context of COVID-19.

“At first, 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 the time, there was a debate about whether it was the underlying disease that induced the risk of worse outcomes with COVID-19 or whether the drugs we used for the underlying disease caused this risk. So in our observational analysis, we wanted to solve these two questions from each other. ”

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

Increased expression of ACE2

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

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

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

“There were theoretical reasons why they could be harmful and, counteracting that, reasons why they could be protective,” Reynolds told TCTMD. “We really didn’t know what to think. I had bubbled up to the patients. I received several calls from patients asking if they should stop these medications or telling me they had stopped taking the medication because they had concerns.”

Ankur Kalra, MD (Cleveland Clinic, OH), who led a study published in JAMA Cardiology, he told TCTMD that patients are smart consumers of medical news and that theoretical concerns about RAAS inhibition had reached their ears. “The first data that came out of China and then Italy showed that many patients with severe forms of COVID-19 were hypertensive or had underlying heart disease,” said Kalra. “Many of our patients are taking ACE and BRA inhibitors, so it is extremely relevant and important for our field to understand the mechanisms that exposure to these drugs might play.”

Mehra noted a recent study of the characteristics, comorbidities, and outcomes of COVID-19 patients in New York City. Of those who take an ACE inhibitor or an ARB before hospitalization, about 50% stopped taking the medication during their hospital visit. “The practice so far has been based on guesswork and theoretical debate and concern, none of which had answered the question clearly,” he said.

In March, the American Cardiology Society, the American Heart Association, and the American Heart Failure Society released a guideline indicating that patients you should not stop taking your RAAS inhibitors unless your doctor tells you to. Societies called for more studies, quickly, to address the problem. The researchers answered the call, with all three studies published last week in NEJM, plus another by Kalra and first author Neil Mehta, MBBS (Cleveland Clinic), published today in JAMA Cardiology.

Call for investigation, doctors respond

At NEJM In an article by Mehra and colleagues, 5.8% died in hospital and 8,395 survived to discharge. In total, 30.5% of the patients had hyperlipidemia, 26.3% had hypertension, 14.3% had diabetes mellitus and 22.3% were current or previous 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 the multivariate logistic regression analysis, age> 65 years was associated with an increased risk of death in hospital (OR 1.93, 95% CI 1.60-2.41). Similarly, pre-existing 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 medications) were associated with an increased risk of dying in hospital. In fact, statins and ACE inhibitors were associated with a significant risk of death of 65% and 67%, respectively. Mehra said the finding may be casual, but he also pointed to the possibility that it may reveal something about the pathophysiology of COVID-19.

“The interesting thing about ACE inhibitors and statins is that they both have healthy effects in stabilizing endothelial cells,” he said. ACE2, Mehra said, is expressed in endothelial cells and A recent study showed that COVID-19 can infect endothelial cells directly.. This could also explain some of the thromboembolic complications associated with COVID-19, he said. “This is a vascular disease, and the sign of a benefit of statins and ACE inhibitors in our study, whether true or not, really makes us think.”

Drugs do not predispose patients to a positive test

In their retrospective cohort study, Kalra, Mehta, and colleagues identified 18,472 patients (mean age 49 years; 40% male) evaluated for COVID-19 at the Cleveland Clinic Health System between March 8 and April 12, 2020. Of those evaluated, 2,285 were taking an ACE inhibitor or an ARB. A positive SARS-CoV-2 test result was documented in 1,735 patients (9.4%), and 214 of these patients were taking an ACE inhibitor or an 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 overlapping the propensity score weighting for both ACE inhibitors and ARBs, 8.6% of patients taking an ACE inhibitor tested positive for SARS-CoV-2 compared to 9.5% of patients who did not take an ACE inhibitor (OR 0.89, 95% CI 0.72-1.10) Similarly, 10.0% of patients who took an ARB tested positive for SARS-CoV-2 compared to 9.3% of those who did not take an ARB (OR 1.09, 95% CI 0.87-1.37). Overall, 9.1% of patients taking an ACE inhibitor or ARB tested positive compared to 9.4% who did not take any class of medication (OR 0.97, 95% CI 0.81-1.15).

“Chronic administration of this class of drugs does not predispose you to becoming infected with COVID-19,” said Kalra. That is good news and the implications are relevant to many patients around the world. . . . It is extremely important that our heart patients and our hypertensive patients continue to take these medications for the management of chronic diseases. “

The researchers noted that, compared to patients not taking a RAAS inhibitor, patients infected with SARS-CoV-2 taking ACE inhibitors were more likely to be admitted to the hospital and ICU, and positive patients taking ARB were more likely to be admitted to the hospital. However, Kalra said these secondary findings should be interpreted with caution, 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 that Secondary results need to be interpreted carefully, but says the Mehta et al study provides “important clinical data to support current treatment recommendations” for ACE inhibitors and ARBs in the current pandemic.

No increased risk of positive COVID-19 test with any medication

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, at NYU’s Langone Health System. . Here, 46.8% of patients tested positive for COVID-19, of whom 17.0% were seriously ill defined as ICU admission, mechanical ventilation, or death. Of the patients evaluated, 4,357 had a history of hypertension and 59.1% of these hypertensive patients tested positive for COVID-19. Among COVID-19 positive hypertensive patients, 24.6% were seriously ill.

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

“We observed two different results in our patients, the probability of a positive test among those who were evaluated and the probability of serious 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 benefit or harm.”

Reynolds believes that 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. Nor do they appear to increase the severity of the disease among patients with a positive diagnosis. “What remains an unanswered question for me is hospital treatment,” he said. “We did not analyze whether these medications were continued in the hospital and how that might have been related to the results in the hospital. I think that is an important pending question.”

In another editorial, John Jarcho, MD, the deputy editor of the NEJMand several co-authors also highlight an analysis by Giuseppe Mancia, MD (University of Milano-Bicocca, Italy), and colleagues who analyzed 6,272 patients with confirmed SARS-CoV-2 infection in Lombardy, Italy. Like the other studies, this one also 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 the use of ACE inhibitors or ARBs is associated with the risk of SARS-CoV-2 infection, the risk of severe COVID-19 among infected people, or the risk of death. in the hospital among people 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 reach the consistent message that continued use of ACE and ARB inhibitors is unlikely to be harmful in COVID patients. 19. ”