From Pages to Practice

By James S. Yeh, MD, MPH

Published May 20, 2020


Mrs. Bunbury is a 65-year-old woman with a history of hypertension (managed on lisinopril) and diabetes (HbA1c 8.1; managed on metformin). She was recently hospitalized for COVID-19 illness after developing acute hypoxemic respiratory failure that required intubation and mechanical ventilation with prone positioning. She was subsequently extubated, and her hospital course was complicated by ventilator-associated pneumonia, pulmonary embolism, and mild acute kidney injury. Fortunately, after a prolonged hospitalization and subsequent acute care and rehabilitation, she recovered well enough to be discharged home. When you see her in clinic for follow-up, she mentions that she read something online that made her wonder if the lisinopril that she takes for high blood pressure increased her risk of becoming infected by the SARS-COV2 virus and caused her to have severe COVID-19 illness.

The SARS-COV2 virus enters human cells by binding to the monocarboxypeptidase angiotensin-converting enzyme 2 (ACE2), which is found on the surface of a variety of cell types, including pulmonary alveolar (type II) cells. Patients with comorbidities such as hypertension, coronary artery disease, and diabetes are at higher risk for severe COVID-19 illness and complications than those without such comorbidities. Often, individuals with these chronic illnesses take medications such as the inhibitors of the renin-angiotensin-aldosterone system (RAAS) — either ACE inhibitors or angiotensin receptor blockers (ARBs). One hypothesis is that individuals who take RAAS inhibitors are at higher risk for SARS-COV2 infection, and if infected, at higher risk for a more severe form of illness due to up-regulation of the ACE2.

Three recent observational studies conducted in different settings and using different study methodologies address Mrs. Bunbury’s questions. A summary of the results of these studies are as follows:

Mehra et al. studied 8910 hospitalized patients with COVID-19 from the Surgical Outcomes Collaborative (Surgisphere), an international registry of data from 169 hospitals. Using multivariate logistic regressionthey found no association between the use of RAAS inhibitors and increased risk of in-hospital death:

  • ACE inhibitor use vs. nonuse: 2.1% vs. 6.1%; odds ratio (OR), 0.33; 95% CI, 0.20−0.54

  • ARB use vs. nonuse: 6.8% vs. 5.7%; OR, 1.23; 95% CI, 0.87−1.74

Mancia et al. performed a case–control study in 6272 individuals in Italy with SARS-CoV-2 and 30,759 controls matched by age, sex, and municipality of residence. They found no evidence that RAAS inhibitors affected the risk of COVID-19:

The use of RAAS inhibitors was not associated with Covid-19 infection:

  • ACE inhibitor use vs. nonuse: adjusted OR, 0.96; 95% CI, 0.87−1.07

  • ARB use vs. nonuse: adjusted OR, 0.95; 95% CI, 0.86−1.05

The use of RAAS inhibitors was not associated with severe or fatal course of the disease:

  • ACE inhibitor use vs. nonuse: adjusted OR, 0.91; 95% CI, 0.69−1.21

  • ARB use vs. nonuse: adjusted OR, 0.83; 95% CI, 0.63−1.10

Reynolds et al. performed a propensity-matched analysis to assess the association between several antihypertensive drug classes and the likelihood of a positive or negative Covid-19 test result in a cohort of 12,594 patients who underwent SARS-COV2 testing at New York University Langone Health. They found no differences between those who were and were not taking a RAAS inhibitor in the likelihood of having a positive test (median difference, 0.5; 95% CI -2.6−3.6) or the likelihood of severe COVID-19 illness (median difference, -0.1; 95% CI -3.7−3.5).

Based on the existing observational data, you tell Mrs. Bunbury that the ACE inhibitor she takes for hypertension did not appear to increase her risk for infection with SARS-COV2 or severe COVID-19 illness. She then asks if the use of the ACE inhibitor had actually reduced her risk of death. You share the conclusion of NEJM editors Jarcho et al. stated in an accompanying editorial: “The unexpected result [of a benefit of ACE inhibitors] in the study by Mehra et al. may be due to unmeasured confounding” and randomized trials are needed to answer definitively her question of whether ACE inhibitors (or ARBs) pose a harm or confer benefit to patients with Covid-19.

The following NEJM Journal Watch summary describes the studies in more detail.


Hypertension, Medications, and COVID-19 Risks

Harlan M. Krumholz, MD, SM reviewing Mehra MR et al. N Engl J Med 2020 May 1 Reynolds HR et al. N Engl J Med 2020 May 1 Mancia G et al. N Engl J Med 2020 May 1

The relationship between cardiovascular disease (CVD), CV treatment, and the risk for adverse outcomes in patients with COVID-19 has been receiving much attention. Three other research groups now provide more insights.

To investigate CVD as a risk factor for patients with COVID-19 and the association between CVD pharmacotherapy and COVID-19 outcomes, Mehra and colleagues used a large, deidentified, international database that included 8910 people hospitalized with COVID-19 who either died or were discharged. Angiotensin-converting–enzyme (ACE) inhibitors were more common among survivors than those who died. In a multivariable model, higher risks for death were associated with age >65, coronary artery disease, congestive heart failure, cardiac arrhythmia, chronic obstructive pulmonary disease, and current smoking. Being a woman, using ACE inhibitors, and using statins were associated with lower death risks. No associations were found for angiotensin-receptor blockers (ARBs).

Reynolds and colleagues examined diagnoses and medications via electronic health record codes in 12,594 people tested for COVID-19 in New York City; 5894 patients had positive results. Accuracy of coding was not reported. Of 2573 patients with hypertension and positive COVID-19 tests, 634 had severe COVID-19 disease (i.e., intensive care unit admission, mechanical ventilation, or death). In analyses requiring differences of 10 percentage points for statistical significance, no medication class was associated with lower risk for severe disease, although ACE inhibitors had an absolute difference of 3.3%; no other class showed benefits ≥1.5%. The investigators acknowledged that smaller effects could be meaningful.

Mancia and colleagues studied 6272 people (age, ≥40) with SARS-CoV-2 infection from the Lombardy region of Italy and 30,759 uninfected controls matched by age, sex, and residence. Infected patients more commonly used ACE inhibitors and ARBs than controls. However, after multivariable adjustment, these medications were not associated with infection or severe disease.

Comment: These early studies have shortcomings, especially the use of selected populations, but they clearly do not show a harm from inhibition of the renin-angiotensin-aldosterone system. The findings are consistent with results from three other recent studies (NEJM JW Gen Med Apr 28 2020; [e-pub]) and with professional societies' guidance to not discontinue these medications. As to the more intriguing, unanswered question of whether ACE inhibition might be beneficial, trials are still in process. These drugs do not directly interact with the ACE2 receptor used by the virus, but many scientists have speculated that ACE inhibitors could influence the course of infection. In the meantime, there is no reason to discontinue these medications in our patients with CVD.

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James Yeh, MD MPH, Physician at NEJM Group
James Yeh, MD MPH is an internist and assistant in medicine at the Massachusetts General Hospital and an instructor in medicine at Harvard Medical School. His clinical and academic interests are in evidence-based medicine, medical education, continuing medical education, cardiopulmonary diseases, cardiovascular risk reduction, critical illness, care transition, polypharmacy, and health communication. He was a NEJM editorial fellow in 2015-2016.
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