ACE inhibitor and ARB therapy: Practical recommendations

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Inhibition of the renin-angiotensin-aldosterone system with angiotensin-converting enzyme (ACE) inhibitors and angiotensin II receptor blockers (ARBs) is widely used in the treatment of heart failure, hypertension, chronic kidney disease, and coronary artery disease with left ventricular dysfunction.

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In this issue, Momoniat et al1 review the benefits of ACE inhibitors and ARBs and how to manage adverse effects. I would like to add some of my own observations.


ACE inhibitors have been the cornerstone of treatment for patients with heart failure with reduced ejection fraction (HFrEF), in whom their use is associated with reduced rates of morbidity and death.2,3 The use of ARBs in these patients is also associated with decreased rates of morbidity and death4,5; however, in early comparisons, ACE inhibitors were deemed more effective in decreasing the incidence of myocardial infarction, cardiovascular death, and all-cause mortality in patients with hypertension, diabetes, and increased cardiovascular risk,6 and all-cause mortality in patients with HFrEF.7

This presumed superiority of ACE inhibitors over ARBs was thought to be a result of a greater vasodilatory effect caused by inhibiting the degradation of bradykinin and leading to increased levels of nitric oxide and vasoactive prostaglandins.8 Another proposed explanation was that because ARBs block angiotensin II AT1 receptors but not AT2 receptors, the increased stimulation of markedly upregulated AT2 receptors in atheromatous plaques in response to elevated serum levels of angiotensin II was deleterious.6 Therefore, ACE inhibitors have been recommended as first-line therapy by most guidelines, whereas ARBs are recommended as second-line therapy, when patients are unable to tolerate ACE inhibitors.

Nevertheless, the much debated differences in outcomes between ACE inhibitors and ARBs do not seem to be real and may have originated from a generational gap in the trials.

The ACE inhibitor trials were performed a decade earlier than the ARB trials. Indirect comparisons of their respective placebo-controlled trials assumed that the placebo groups used for comparison in the 2 sets of trials were similar.9,10 Actually, the rate of cardiovascular disease decreased nearly 50% between the decades of 1990 to 2000 and 2000 to 2010, the likely result of aggressive primary and secondary prevention strategies in clinical practice, including revascularization and lipid-lowering therapy.10

In fact, a meta-regression analysis showed that the differences between ACE inhibitors and ARBs compared with placebo were due to higher event rates in the placebo groups in the ACE inhibitor trials than in the ARB trials for the outcomes of death, cardiovascular death, and myocardial infarction.11 Sensitivity analyses restricted to trials published after 2000 to control for this generational gap showed similar efficacy with ACE inhibitors vs placebo and with ARBs vs placebo for all clinical outcomes.11 Moreover, recent studies have shown that ARBs produce a greater decrease in cardiovascular events than ACE inhibitors, especially in patients with established cardiovascular disease.12,13

An advantage of ARBs over ACE inhibitors is fewer adverse effects: in general, ARBs are better tolerated than ACE inhibitors.14 There are also ethnic differences in the risks of adverse reactions to these medications. African Americans have a higher risk of developing angioedema with ACE inhibitors compared with the rest of the US population, and Chinese Americans have a higher risk than whites of developing cough with ACE inhibitors.9,15

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