ACEIs vs. ARBs
Are angiotensin-converting-enzyme inhibitors (ACEIs) superior to angiotensin receptor blockers (ARBs) for reducing risk of major adverse cardiovascular outcomes in patients without a reduced ejection fraction?
Background: Over the past 20 years there has been conflicting evidence published regarding the efficacy of ARBs in comparison to ACEIs. Cardiovascular guidelines frequently recommend using ACEIs preferentially based on previous meta-analyses that have reported ACEIs to be superior to ARBs for reducing all-cause mortality, cardiovascular (CV) death, and myocardial infarction (MI).1 However, multiple studies have been published suggesting no difference in efficacy between the two classes and improved tolerability with ARBs.2
Critiquing the previous studies: Meta-analyses that concluded ACEIs are superior to ARBs obtained their results from indirect comparisons of ACEI and ARB placebo-controlled trials.1 In these trials ACEIs, but not ARBs, reduced death, CV death, and MI compared to placebo.1 However, most ACEI trials were completed a decade prior to ARB trials during which there were significant improvements in primary and secondary prevention strategies and an overall reduction in cardiovascular disease rates.1
What if we correct for the different placebo rate? A meta-analysis of ACEI/ARB placebo-controlled trials initially appeared to support the results that ACEIs were superior to ARBs.2 However, when the authors conducted a meta- regression analysis of the data they determined the difference in outcomes of death, CV death, and MI was due to a higher placebo event rate in the ACEI trials.2 Additionally, a sensitivity analysis restricting included studies to those published after the year 2000, demonstrated no difference between ACEI and ARBs for all tested outcomes.2 This meta-analysis included patients with a normal ejection fraction and either primary hypertension or high risk vascular conditions.2
Have there been any head-to-head trials? The ON-TARGET trial demonstrated no difference between ramipril and telmisartan for reducing the primary composite outcome of CV death, MI, stroke, or hospitalization due to heart failure.3 The trial included patients with vascular disease or high-risk diabetes with a normal ejection fraction.3 A meta-analysis of head-to-head ACEI/ARB trials demonstrated no difference in all efficacy outcomes including death, CV death, and MI.2 They also found that ARBs had a lower incidence of withdrawal due to adverse effects.2
Other evidence: A meta-analysis including almost 3 million patients from observational studies compared ACEIs and ARBs for treatment of hypertension.4 The study demonstrated no difference in cardiovascular outcomes including acute MI.4 Additionally, ACEIs were associated with increased risk of angioedema and cough compared to ARBs.4 A meta-analysis comparing ACEIs and ARBs in patients with MI found no difference in incidence of major adverse cardiovascular events (MACE), cardiovascular mortality, and all-cause mortality between the two classes.5
Boom-line: Current evidence suggests that, in patients without a reduced ejection fraction, ARBs are non-inferior to ACEIs for reducing risk of major adverse cardiovascular events and are better tolerated.
References:
1. Messerli H, Bangalore S. Angiotensin Receptor Blockers Reduce Cardiovascular Events, Including the Risk of Myocardial Infarction. Circulation. 2017;135:2085-2087. doi: 10.1161/CIRCULATIONAHA.117.026112.
2. Bangalore S, et al. Angiotensin-converting enzyme inhibitors or angiotensin receptor blockers in patients without heart failure? Insights from 254,301 patients from randomized trials. Mayo Clin Proc. 2016;91:51–60. doi: 10.1016/j.mayocp.2015.10.019.
3. Yusuf S, et al. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med. 2008;358(15): 1547-1559 doi: 10.1056/NEJMoa0801317
4. Chen R, et al.Comparative First-Line Effectiveness and Safety of ACE (Angiotensin-Converting Enzyme) Inhibitors and Angiotensin Receptor Blockers: A Multinational Cohort Study. Hypertension. 2021 Sep;78(3):591-603. doi: 10.1161/HYPERTENSIONAHA.120.16667.
5. Escobar J, et al. Comparison of Outcomes Between Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers in Patients With Myocardial Infarction: A Meta-Analysis. Cureus. 2023 Oct 30;15(10):e47954. doi: 10.7759/cureus.4795
Reprinted with permission from Shaelyn Gustafson, BSc PharmD Candidate 2025
