Two recent papers published in the New England Journal of Medicine sought to rigorously study the relationship between COVID-19 and antihypertensive medications that impact the renin-angiotensin-aldosterone system (RAAS), including Angiotensin Converting Enzyme (ACE) inhibitors and Angiotensin Receptor Blockers (ARBs). A link has been suggested on the basis that SARS-CoV-2 enters cells by binding to membrane-bound ACE2 [1]. Thus, drugs that inhibit RAAS function could lead to a compensatory increase in ACE2 expression, which could in turn augment the ability of the virus to infect cells. The concern was that this could have clinical implications such as leading to greater vulnerability to initial SARS-CoV-2 infection and greater severity of disease.

Mancia et al. report the results of a case-control study done in Lombary, Italy [2]. They studied 6,272 patients who tested positive for SARS-CoV-2 and 30,759 matched controls. Data about participants included drugs prescribed in 2019, reason for hospitalization in the past 5 years, and a calculated clinical status score. The rate of prescriptions for all medications studied was higher in the SARS-CoV-2-positive cases than the controls, including for ACE inhibitors (23.9% vs 21.4%) and ARBs (22.2% vs 19.2%). However, after adjusting for multiple clinical variables, patients prescribed one of these medications were not at elevated risk of having a positive SARS-CoV-2 test. The authors likewise found no significant effect of antihypertensive medications on severity of COVID-19.

Reynold et al. report the results of an observational study done in New York City [3]. They followed 12,594 patients being tested for SARS-CoV-2, and recorded diagnoses and prescriptions for these patients from the electronic medical record. Patients with hypertension had a higher rate of positive SARS-CoV-2 tests than those without (59.1% vs 46.8%), and a larger fraction of hypertensive COVID-19 patients had severe cases than non-hypertensive COVID-19 patients (24.6% vs 17.0%). After applying a propensity score matching approach to account for confounders, there was no increased risk of SARS-CoV-2 positivity or severe COVID-19 associated with ACE inhibitors, ARBs, or other antihypertensive medications studied.

Both studies suggest that there is no added risk of SARS-CoV-2 infection or severe illness from ACE inhibitors and ARBs beyond the risks associated with the conditions these medications are treating. The results of these studies would support the recommendations released by the American College of Cardiology in March that clinicians caring for COVID-19 patients “be advised not to add or remove any RAAS-related treatments, beyond actions based on standard clinical practice[4].”

These studies are limited in several ways. Neither study tracked patients past the last day of testing; this could lead to undercounting severe COVID-19 cases as a portion of patients who test positive near the end of the enrollment period may have gone on to experience complications after the end of the study. It is worth noting that a third paper considering only COVID-19 patients who had been discharged from hospital or died found no effect of ACE inhibitors or ARBs on in-hospital death [5]. In addition, neither study was equipped to study asymptomatic SARS-CoV-2 infection, and Mancia et al. may have included asymptomatic patients in their control group. Finally, neither study was able to account for adherence with medications as prescribed.

References:

1. Li W, Moore MJ, Vasilieva N, et al. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature 2003;426:450-454.
2. Mancia G, Rea F, Ludergnani M, Apolone G, Corrao G. Renin–angiotensin–aldosterone system blockers and the risk of Covid-19. N Engl J Med. DOI: 10.1056/NEJMoa2006923.
3. Reynolds HR, Adhikari S, Pulgarin C, et al. Renin–angiotensin–aldosterone system inhibitors and risk of Covid-19. N Engl J Med. DOI: 10.1056/NEJMoa2008975.
4. American College of Cardiology. HFSA/ACC/AHA statement addresses concerns re: using RAAS antagonists in COVID-19. March 17, 2020.
5. Mehra MR, Desai SS, Kuy S, Henry TD, Patel AN. Cardiovascular disease, drug therapy, and mortality in Covid-19. N Engl J Med. DOI: 10.1056/NEJMoa2007621.

The Department of Medicine COVID-19 Journal Club is dedicated to understanding and applying data on COVID-19 to inform prevention and management efforts for healthcare workers and patients.

This article by Richard Merkhofer, PhD, student in the Medical Scientist Training Program. Reviewed by Nasia Safdar, MD, PhD, professor, Infectious Disease, vice chair for research, Department of Medicine.

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