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      Response by Cohen et al to Letter Regarding Article, “Association of Inpatient Use of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers With Mortality Among Patients With Hypertension Hospitalized With COVID-19”

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          In Response: We read with great interest the original investigation by Zhang et al 1 and the accompanying editorial by Shah et al. 2 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. 3–5 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, 6 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% prevalent use 7,8 ), 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]). 9 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. 3,4 The current study reinforces the urgent need for randomized controlled trial evidence to address this important issue. 2 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: 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: 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). Disclosures 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.

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          Most cited references 4

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          Time-dependent study entries and exposures in cohort studies can easily be sources of different and avoidable types of bias.

          To display and discuss the reasons and consequences of length and time-dependent bias. They might occur in presence of a time-dependent study entry or a time-dependent exposure which might change from unexposed to exposed.
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            Covid-19 testing, hospital admission, and intensive care among 2,026,227 United States veterans aged 54-75 years.

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              Is there an association between COVID-19 mortality and the renin-angiotensin system-a call for epidemiologic investigations [published online March 26, 2020].


                Author and article information

                Circ Res
                Circ. Res
                Circulation Research
                Lippincott Williams & Wilkins
                05 June 2020
                17 April 2020
                : 126
                : 12
                : e140-e141
                [1 ]From the Renal-Electrolyte and Hypertension Division (J.B.C.), Perelman School of Medicine, University of Pennsylvania, Philadelphia
                [2 ]Department of Biostatistics, Epidemiology, and Informatics (J.B.C., T.C.H.), Perelman School of Medicine, University of Pennsylvania, Philadelphia
                [3 ]Division of Cardiovascular Medicine, Hospital of the University of Pennsylvania and Perelman School of Medicine, University of Pennsylvania (T.C.H., J.A.C.)
                [4 ]Section of Nephrology, Department of Pediatrics, Wake Forest School of Medicine and Brenner Children’s Hospital, Winston-Salem, NC (A.M.S.)
                [5 ]Division of Public Health Sciences, Department of Epidemiology and Prevention, and Department of Surgery-Hypertension and Vascular Research, Wake Forest School of Medicine, Winston-Salem, NC (A.M.S.)
                [6 ]Division of Nephrology, Department of Medicine, Duke School of Medicine, Durham, NC (M.A.S.)
                [7 ]Renal Section, Durham Veterans Affairs Medical Center, NC (M.A.S.)
                [8 ]Division of Nephrology, Department of Medicine, University of Ottawa, Canada (S.H.)
                [9 ]Division of Health System Innovation and Research, Department of Population Health Sciences, University of Utah, Salt Lake City (A.P.B.)
                [10 ]Division of Cardiovascular Medicine, University of Michigan Medical School, Ann Arbor (J.B.B.).
                © 2020 American Heart Association, Inc.

                This article is made available via the PMC Open Access Subset for unrestricted re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the COVID-19 pandemic or until permissions are revoked in writing. Upon expiration of these permissions, PMC is granted a perpetual license to make this article available via PMC and Europe PMC, consistent with existing copyright protections.

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