Assessment of ACE inhibitors/angiotensin receptor blockers in COVID-19 patients.

to the editor: As recently noted by Morty and Ziebuhr (4), numerous communications have been published, including in AJP-Lung, regarding the role of angiotensin-converting enzyme 2 (ACE2; the SAR-Cov-2 “receptor”) in viral infectivity and the COVID-19 pandemic. Mortality from this disease is greater among elderly patients: ~10% for those >80 years old; the majority of deaths occur in patients beyond age 60 [e.g., (1, 9)]. Several age-associated comorbidities (e.g., diabetes and hypertension) increase mortality in COVID-19 (6). Safe, effective therapies are urgently needed, especially for vulnerable patients. Scientists and clinicians should consider the advisability of assessing approved drugs that target COVID-19 pathophysiology and that have favorable efficacy and safety profiles.

As noted above, much discussion has focused on angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) in COVID-19 (2, 5–8). Concerns that such drugs are harmful, because they might increase the expression of ACE2, have largely been allayed by evaluation of preclinical studies (7) and epidemiological evidence (2, 5, 10). The latter evidence revealed not only a lack of association of ACEI/ARB use with harm (if one adjusts for confounders with appropriate statistical analysis) but also that ACEIs/ARBS may be beneficial (10). Recommendations from major medical associations and an emerging scientific consensus thus advocate that patients prescribed ACEIs/ARBs should continue their medication during this pandemic [summarized in (5)].

It has been hypothesized that a key mechanism for COVID-19 pathobiology involves ACE2 inhibition (resulting in ACE1/ACE2 imbalance) by SARS-CoV-2 and consequently, increased effects of angiotensin II, which drives pathology via interactions among multiple cell types in the lung, heart, and other organs (6). This mechanism can help explain age-related, comorbidity-associated tissue injury in COVID-19 and predicts mitigation of pathology by ACEIs/ARBs and other agents that target angiotensin signaling (6). Given their widespread use, low cost, and favorable safety profile, early administration of ACEIs/ARBs could be a valuable therapeutic strategy for COVID-19, in particular for elderly patients and those with comorbidities that increase the risk of severe disease.

The rationale for this approach to treat COVID-19 includes: its high mortality rate; the current dearth of effective therapies; epidemiological data indicating lack of harm and potential benefit of ACEIs/ARBs; and a mechanistic basis for their use in blunting COVID-19 pathobiology. A stronger evidence-based rationale for efficacy and safety appears to exist for repurposing ACEIs/ARBs in the treatment of COVID-19 than for certain other approved drugs tested thus far (e.g., hydroxychloroquine). Even so, much remains to be learned, including from preclinical studies that can help optimize the choice among the many ACEIs/ARBs, readouts (biochemical, immunological, and physiological) and mechanisms of efficacy. Clinicians may be tempted to administer ACEIs/ARBs on an off-label/compassionate use basis as a possible means to reduce COVID-19 morbidity and mortality. However, randomized control trials, perhaps adaptive trials that reject or accept the use of various drugs, will be the “gold standard” to define the benefit:risk calculus regarding ACEIs/ARBs for COVID-19 patients and perhaps for future SARS-CoV infections (3).

GRANTS

Support was provided by Academic Senate of the University of California, San Diego.

DISCLOSURES

K. Sriram has no conflicts of interest, financial or otherwise, to declare. P. A. Insel is not currently but within the past 3 years has served as a consultant or received research support from Merck, Pfizer, and Bristol Myers Squibb.

AUTHOR CONTRIBUTIONS

K.S. and P.A.I. drafted manuscript; edited and revised manuscript; and approved final version of manuscript.