Renin-Angiotensin Aldosterone System Inhibitors and COVID-19: A Systematic Review and Meta-Analysis Revealing Critical Bias Across a Body of Observational Research

Abstract

BACKGROUND: Renin-angiotensin aldosterone system (RAAS) inhibitor—COVID-19 studies, observational in design, appear to use biased methods that can distort the interaction between RAAS inhibitor use and COVID-19 risk. This study assessed the extent of bias in that research and reevaluated RAAS inhibitor—COVID-19 associations in studies without critical risk of bias. METHODS AND RESULTS: Searches were performed in MEDLINE, EMBASE, and CINAHL databases (December 1, 2019 to October 21, 2021) identifying studies that compared the risk of infection and/or severe COVID-19 outcomes between those using or not using RAAS inhibitors (ie, angiotensin-converting enzyme inhibitors or angiotensin II type-I receptor blockers). Weighted hazard ratios (HR) and 95% CIs were extracted and pooled in fixed-effects meta-analyses, only from studies without critical risk of bias that assessed severe COVID-19 outcomes. Of 169 relevant studies, 164 had critical risks of bias and were excluded. Ultimately, only two studies presented data relevant to the meta-analysis. In 1 351 633 people with uncomplicated hypertension using a RAAS inhibitor, calcium channel blocker, or thiazide diuretic in monotherapy, the risk of hospitalization (angiotensin-converting enzyme inhibitor: HR, 0.76; 95% CI, 0.66–0.87; P<0.001; angiotensin II type-I receptor blockers: HR, 0.86; 95% CI, 0.77–0.97; P=0.015) and intubation or death (angiotensin-converting enzyme inhibitor: HR, 0.64; 95% CI, 0.48– 0.85; P=0.002; angiotensin II type-I receptor blockers: HR, 0.74; 95% CI, 0.58–0.95; P=0.019) with COVID-19 was lower in those using a RAAS inhibitor. However, these protective effects are probably not clinically relevant. CONCLUSIONS: This study reveals the critical risk of bias that exists across almost an entire body of COVID-19 research, rais-ing an important question: Were research methods and/or peer-review processes temporarily weakened during the surge of COVID-19 research or is this lack of rigor a systemic problem that also exists outside pandemic-based research? REGISTRATION: URL: www.crd.york.ac.uk/prosp​ero/; Unique identifier: CRD42021237859.