Comparative real-world effectiveness of antihypertensive agents on complications: a systematic review and meta-analysis of observational studies employing propensity score methods

To address the efficacy-effectiveness gap while explicitly acknowledging the limitations of real-world evidence, this systematic review and meta-analysis of observational studies using propensity score (PS) methods evaluated the comparative effectiveness of antihypertensive drug classes on mortality, cardiovascular outcomes, and blood pressure in adults with hypertension. Medline and Scopus were searched up to November 26, 2025. Eligible studies were observational studies applying PS methods to compare antihypertensive drug class, and reporting outcomes including all-cause and cardiovascular mortality, composite cardiovascular events, heart failure, myocardial infarction, stroke, and blood pressure in hypertensive adults. Data were pooled using random- or fixed-effects models. Risk of bias and certainty of evidence were assessed using ROBINS-I and GRADE frameworks. Forty-nine studies (approximately 13 million patients) were included. Compared with angiotensin-converting enzyme inhibitors (ACEIs), angiotensin receptor blockers (ARBs) were associated with lower risks of all-cause mortality [adjusted hazard ratio (aHR) 0.89; 95% confidence interval (CI) 0.84, 0.95], cardiovascular mortality [0.74 (0.58, 0.95)], heart failure [0.94 (0.90, 0.98)], composite cardiovascular events [0.87 (0.85, 0.88)], and myocardial infarction [0.89 (0.79, 0.99)]. Diuretics were associated with lower risks of all-cause mortality [0.72 (0.55, 0.96)], stroke [0.70 (0.50, 0.98)], and myocardial infarction [0.83 (0.69, 1.00)] versus ACEIs. Compared with calcium channel blockers (CCBs), ARBs were associated with lower risks of all-cause mortality [0.65 (0.52, 0.81)], stroke [0.82 (0.80, 0.84)], and myocardial infarction [0.89 (0.83, 0.96)]. Beta-blockers (BBs) were associated with increased risk of heart failure versus renin–angiotensin–aldosterone system inhibitors (RASIs) [1.91 (1.07, 3.39)]. The certainty of evidence was low to very low across most comparisons. In real-world observational settings, ARBs and diuretics were associated with more favorable cardiovascular outcomes compared with ACEIs; ARBs were associated with more favorable cardiovascular outcomes compared with CCBs, while BBs were associated with increased heart failure risk compared with RASIs. However, given that nearly half of the included studies were at serious risk of bias and that residual confounding, these findings should be interpreted cautiously as associative rather than causal. These results provide complementary real-world evidence to randomized trials but are not sufficient to support definitive changes in first-line treatment recommendations.