Renin–angiotensin system blockers and susceptibility to COVID-19: an international, open science, cohort analysis

Background Angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) have been
postulated to affect susceptibility to COVID-19. Observational studies so far have lacked rigorous ascertainment
adjustment and international generalisability. We aimed to determine whether use of ACEIs or ARBs is associated
with an increased susceptibility to COVID-19 in patients with hypertension.

Methods In this international, open science, cohort analysis, we used electronic health records from Spain (Information
Systems for Research in Primary Care [SIDIAP]) and the USA (Columbia University Irving Medical Center data
warehouse [CUIMC] and Department of Veterans Affairs Observational Medical Outcomes Partnership [VA-OMOP]) to
identify patients aged 18 years or older with at least one prescription for ACEIs and ARBs (target cohort) or calcium
channel blockers (CCBs) and thiazide or thiazide-like diuretics (THZs; comparator cohort) between Nov 1, 2019, and
Jan 31, 2020. Users were defined separately as receiving either monotherapy with these four drug classes, or monotherapy
or combination therapy (combination use) with other antihypertensive medications. We assessed four outcomes:
COVID-19 diagnosis; hospital admission with COVID-19; hospital admission with pneumonia; and hospital admission
with pneumonia, acute respiratory distress syndrome, acute kidney injury, or sepsis. We built large-scale propensity
score methods derived through a data-driven approach and negative control experiments across ten pairwise comparisons,
with results meta-analysed to generate 1280 study effects. For each study effect, we did negative control outcome
experiments using a possible 123 controls identified through a data-rich algorithm. This process used a set of predefined
baseline patient characteristics to provide the most accurate prediction of treatment and balance among patient cohorts
across characteristics. The study is registered with the EU Post-Authorisation Studies register, EUPAS35296.

Findings Among 1 355 349 antihypertensive users (363 785 ACEI or ARB monotherapy users, 248 915 CCB or THZ
monotherapy users, 711 799 ACEI or ARB combination users, and 473 076 CCB or THZ combination users) included
in analyses, no association was observed between COVID-19 diagnosis and exposure to ACEI or ARB monotherapy
versus CCB or THZ monotherapy (calibrated hazard ratio [HR] 0·98, 95% CI 0·84–1·14) or combination use
exposure (1·01, 0·90–1·15). ACEIs alone similarly showed no relative risk difference when compared with CCB or
THZ monotherapy (HR 0·91, 95% CI 0·68–1·21; with heterogeneity of >40%) or combination use (0·95, 0·83–1·07).
Directly comparing ACEIs with ARBs demonstrated a moderately lower risk with ACEIs, which was significant with
combination use (HR 0·88, 95% CI 0·79–0·99) and non-significant for monotherapy (0·85, 0·69–1·05). We observed
no significant difference between drug classes for risk of hospital admission with COVID-19, hospital admission with
pneumonia, or hospital admission with pneumonia, acute respiratory distress syndrome, acute kidney injury, or
sepsis across all comparisons.

Interpretation No clinically significant increased risk of COVID-19 diagnosis or hospital admission-related outcomes
associated with ACEI or ARB use was observed, suggesting users should not discontinue or change their treatment to
decrease their risk of COVID-19.