We read with great interest the original investigation by Zhang et al
and the accompanying editorial by Shah et al.
The study question is urgent and important, given the potential relationships among
ACE (angiotensin-converting enzyme) inhibitor or ARB (angiotensin receptor blocker)
use, ACE2 expression/activity, and coronavirus disease 2019 (COVID-19) severity.
We appreciate that the authors appropriately tempered their interpretation of the
results based on several limitations noted in their publication and the accompanying
editorial. Nonetheless, we are concerned that many readers may still overinterpret
the impressive hazard ratios. Notably, exposure assignments were based only on antihypertensive
medications administered at any point during hospitalization. Patients had to survive
long enough, or be clinically stable enough, to achieve the exposure (ie, ACE inhibitors/ARB
use). This time-dependent bias (or immortal time bias) underestimates the hazard of
the exposure group,
which may result in a false or exaggerated apparent protective effect of ACE inhibitors/ARBs.
Also, fewer patients were on ACE inhibitors/ARBs than expected (17% versus 30%–40%
), suggesting substantial unmeasured confounding and nonsystematic exposure ascertainment:
sicker patients will almost invariably be less likely to receive ACE inhibitors/ARBs
during hospitalization. These limitations may explain contradictory results in observational
US veteran data which did not show an association between baseline ACE inhibitors/ARB
use and need for intensive care in patients with COVID-19 (unadjusted odds ratio,
1.94 [95% CI, 1.30–2.90] and adjusted odds ratio, 1.66 [95% CI, 0.94–2.93]).
Based on several clinical and mechanistic considerations, we believe that there is
equipoise regarding potential benefit or harm from ACE inhibitors/ARB use in patients
at risk for or who have COVID-19.
The current study reinforces the urgent need for randomized controlled trial evidence
to address this important issue.
We are currently conducting an international, multicenter, randomized controlled trial
(REPLACE COVID trial [The Randomized Elimination or Prolongation of Angiotensin Converting
Enzyme Inhibitors and Angiotensin Receptor Blockers in Coronavirus Disease 2019],
URL: https://www.clinicaltrials.gov. Unique identifier: NCT04338009) randomizing patients
on chronic ACE inhibitors/ARBs who are hospitalized with COVID-19 to continuation
versus withdrawal of their ACE inhibitors/ARB upon admission, evaluating a hierarchical
outcome including death, mechanical ventilation, pressor requirement, and other markers
of severity of critical illness. Another ongoing trial in Ireland (URL: https://www.clinicaltrials.gov.
Unique identifier: NCT04330300) is randomizing outpatients with hypertension to continuation
versus withdrawal of ACE inhibitors/ARBs, evaluating the risk of COVID-19-related
hospitalization and mortality.
Sources of Funding
This study was supported by National Institutes of Health: K23-HL133843 (J.B. Cohen),
T32-HL007891 (T.C. Hanff), R01-HL146818 (A.M. South), UC4DK108173 (A.M. South), R01-HL133468
(A.P. Bress), R01-HL 121510-01A1 (J.A. Chirinos), R61-HL-146390 (J.A. Chirinos), R01-AG058969
(J.A. Chirinos), 1R01-HL104106 (J.A. Chirinos), P01-HL094307 (J.A. Chirinos), R03-HL146874-01
(J.A. Chirinos), and R56-HL136730 (J.A. Chirinos), K23HL128909 (J.B. Byrd). FastGrants
(J.B. Byrd), University of Michigan Frankel Cardiovascular Center (J.B. Byrd), Department
of Medicine, University of Ottawa (S. Hiremath).
J.A. Chirinos has received honoraria from Sanifit, Microsoft, Fukuda-Denshi, Bristol
Myers Squibb, OPKO Healthcare, Ironwood Pharmaceuticals, Pfizer, Akros Pharma, Merck,
Edwards Lifesciences, Bayer and Johnson & Johnson and research grants from Microsoft,
Fukuda-Denshi and Bristol Myers Squibb. The other authors report no conflicts.