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

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