Impact of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on cardiovascular and non-cardiovascular outcomes in patients at high/very-high cardiovascular risk without heart failure: a systematic review and meta-analysis of randomized, double-blind, placebo-controlled trials

Aims: To assess the impact of angiotensin-converting enzyme inhibitors (ACE-Is) and angiotensin receptor blockers (ARBs) on all-cause and cardiovascular (CV) mortality, as well as CV, cerebrovascular, and renal outcomes in patients at high/very-high CV risk without heart failure by a systematic review and meta-analysis of placebo-controlled, double-blind, randomized trials. Methods and results: The CENTRAL, ClinicalTrials.gov, Ovid-MEDLINE, Ovid-Embase, Science Citation Index-Expanded, and WHO-ICTRP databases were searched between August and September 2023. Heart failure trials were excluded. The hypothesis of a homogeneous treatment effect between ACE-Is and ARBs was tested with a Cochran's Q statistic. The protocol for the systematic review was registered on PROSPERO (CRD42023452406) and the study reported as per PRISMA guidelines.17 trials (9 ACE-Is and 8 ARBs, total of 87 908 participants) were included. The event rates for all-cause mortality, CV mortality, and major CV events (MACEs) did not differ in the parallel placebo arms of ACE-I and ARB trials; however, compared to placebo, ACE-Is reduced the rate of CV mortality [hazard ratio (HR) 0.88; 95% confidence interval (CI) 0.78-0.99], all-cause mortality (HR 0.92; 95% CI 0.85-0.99) and myocardial infarction (HR 0.83; 95% CI 0.73-0.94), while ARBs did not. The rates of HF, stroke, and MACEs were significantly reduced by both drug classes. Angiotensin-converting enzyme inhibitors induced a greater reduction of CV mortality than ARBs ( Conclusion: In patients at high/very-high CV risk, ACE-Is were more protective against CV mortality than ARBs, supporting their preferential use for CV protection.