Renin-angiotensin system blockers and susceptibility to COVID-19: a multinational open science cohort study

Morales, Daniel R.; Conover, Mitchell M.; You, Seng Chan; Pratt, Nicole; Kostka, Kristin; Duarte-Salles, Talita; Fernández-Bertolín, Sergio; Aragón, Maria; DuVall, Scott L.; Lynch, Kristine; Falconer, Thomas; van Bochove, Kees; Sung, Cynthia; Matheny, Michael E.; Lambert, Christophe G.; Nyberg, Fredrik; Alshammari, Thamir M.; Williams, Andrew E.; Park, Rae Woong; Weaver, James; Sena, Anthony G.; Schuemie, Martijn J.; Rijnbeek, Peter R.; Williams, Ross D.; Lane, Jennifer C.E.; Prats-Uribe, Albert; Zhang, Lin; Areia, Carlos; Krumholz, Harlan M.; Prieto-Alhambra, Daniel; Ryan, Patrick B.; Hripcsak, George; Suchard, Marc A

INTRODUCTION: Angiotensin converting enzyme inhibitors (ACEs) and angiotensin receptor blockers (ARBs) could influence infection risk of coronavirus disease (COVID-19). Observational studies to date lack pre-specification, transparency, rigorous ascertainment adjustment and international generalizability, with contradictory results. METHODS: Using electronic health records from Spain (SIDIAP) and the United States (Columbia University Irving Medical Center and Department of Veterans Affairs), we conducted a systematic cohort study with prevalent ACE, ARB, calcium channel blocker (CCB) and thiazide diuretic (THZ) users to determine relative risk of COVID-19 diagnosis and related hospitalization outcomes. The study addressed confounding through large-scale propensity score adjustment and negative control experiments. RESULTS: Following over 1.1 million antihypertensive users identified between November 2019 and January 2020, we observed no significant difference in relative COVID-19 diagnosis risk comparing ACE/ARB vs CCB/THZ monotherapy (hazard ratio: 0.98; 95% CI 0.84 – 1.14), nor any difference for mono/combination use (1.01; 0.90 – 1.15). ACE alone and ARB alone similarly showed no relative risk difference when compared to CCB/THZ monotherapy or mono/combination use. Directly comparing ACE vs. ARB demonstrated a moderately lower risk with ACE, non-significant for monotherapy (0.85; 0.69 – 1.05) and marginally significant for mono/combination users (0.88; 0.79 – 0.99). We observed, however, no significant difference between drug-classes for COVID-19 hospitalization or pneumonia risk across all comparisons. CONCLUSION: There is no clinically significant increased risk of COVID-19 diagnosis or hospitalization with ACE or ARB use. Users should not discontinue or change their treatment to avoid COVID-19.