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

Abstract

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) use 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.

Outcomes of COVID-19 Hospitalized Patients Previously Treated with Renin-Angiotensin System Inhibitors

“…In our study, hypertension was associated with all-cause death in univariate analysis but not after adjustment for confounders, in line with Morales et al's results showing no increased risk of COVID-19 hospitalization for pneumonia in hypertensive patients treated with ACEIs or ARBs [29].…”

FDA approved drugs with pharmacotherapeutic potential for SARS-CoV-2 (COVID-19) therapy

“…In the early stages of the pandemic, a hypothesis was proposed where chronic use of ACE-I and AT1-A could lead to an increase in ACE2 in the pulmonary circulation, which in turn increases the number of receptors available for the virus ( Ferrario et al, 2005 ), thus the risk of severe COVID-19 increases ( Diaz, 2020 ; Xu et al, 2020a ). However, the results of the recent animal and human studies do not support this theory ( Cappuccio and Siani, 2020 ; Sriram and Insel, 2020 ; Morales et al, 2020 ; Fosbøl et al, 2020 ; Alexandre et al, 2020 ).…”

“…The knowledge gained thus far does not allow stating that long-term therapy with drugs inhibiting the cascade of reactions in the renin-angiotensin-aldosterone (RAA) system is associated with worse patient prognosis, while their immediate supply can save the patient. There is no reason to discontinue therapy with these groups of drugs after the infection is diagnosed ( Cappuccio and Siani, 2020 ; Sriram and Insel, 2020 ; Morales et al, 2020 ; Fosbøl et al, 2020 ; Alexandre et al, 2020 ; American Heart, 2020 ).…”

Agile analytics to support rapid knowledge pipelines

“…The resistance to adopting new technology, data sources, and analytical methods has begun to yield to the urgency of the moment. Access to information has transformed the literature, with numerous publications that leverage digital health data, such as that from the electronic health record, to generate the evidence needed to better understand SARS-CoV-2 infection, treatment, and outcomes 1,2 .…”