Clinical Question

How does the effectiveness of angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) compare in head-to-head studies of patients with hypertension?

Evidence-Based Answer

ACE inhibitors and ARBs have similar effects on cardiovascular outcomes and total mortality in head-to-head trials. However, slightly more adverse effects were noted in patients assigned to ACE inhibitor therapy. (Strength of Recommendation: B, based on inconsistent, moderate-quality patient-oriented evidence.)

Practice Pointers

In 2014, the Eighth Joint National Committee (JNC 8) published evidence-based recommendations for the management of hypertension. The panel concluded that ACE inhibitors and ARBs are comparable and thus essentially interchangeable for the initial treatment of hypertension in patients who do not have heart failure.¹ However, only ACE inhibitors have shown reductions in morbidity and mortality in placebo-controlled trials.² Head-to-head comparison of these two drug classes is therefore highly relevant to family physicians. The authors of this Cochrane review compared the effectiveness of ACE inhibitors and ARBs for reducing total mortality and cardiovascular events, as well as rates of adverse effects.

This meta-analysis included nine randomized controlled trials with 11,007 participants that directly compared an ACE inhibitor with an ARB for the treatment of essential hypertension for at least one year. Eight of the trials provided data on rates of withdrawal from adverse effects. Patients who were enrolled in the trials had uncontrolled or controlled primary hypertension, defined as a systolic blood pressure greater than 140 mm Hg or a diastolic blood pressure greater than 90 mm Hg. Almost all participants had uncontrolled blood pressure before initiation of treatment and ranged from 55 to 72 years of age with approximately equal representation of both sexes. The ACE inhibitors used in the studies were enalapril (Vasotec), ramipril (Altace), lisinopril, fosinopril (Monopril), and quinapril (Accupril). The ARBs included telmisartan (Micardis), losartan (Cozaar), candesartan (Atacand), valsartan (Diovan), and irbesartan (Avapro).

The authors found no evidence of a difference between ACE inhibitors and ARBs when analyzing any of the primary outcomes: total mortality (relative risk [RR] = 0.98; 95% confidence interval [CI], 0.88 to 1.10), total cardiovascular events (RR = 1.07; 95% CI, 0.96 to 1.19), or cardiovascular mortality (RR = 0.98; 95% CI, 0.85 to 1.13). The evidence for comparison of total mortality and cardiovascular mortality was of moderate quality, whereas the data for total cardiovascular events relied on low-quality evidence (in part because of deviation from the prepublished protocol).

ARBs were slightly superior to ACE inhibitors for the secondary outcomes of withdrawal due to adverse effects, based on a high level of evidence (RR = 0.83; 95% CI, 0.74 to 0.93; number needed to treat for an additional beneficial outcome = 55 over 4.1 years), mainly because of a higher incidence of dry cough with ACE inhibitors. Dry cough accounted for 43% of the reported adverse effects in the ACE inhibitor arm vs. 4% in the ARB arm. Patients who stopped taking their ACE inhibitor also cited such adverse effects as atrial flutter, edema, rash, and rise in creatinine levels. For those taking ARBs, the reasons for discontinuation of therapy included dizziness, hypotension, palpitations, and dyspnea. The study that contributed the most weight to the meta-analysis (ONTARGET 2008) did not provide adequate information regarding adverse effects.

The primary outcomes of this review support U.S. and British hypertension guideline recommendations that ACE inhibitors and ARBs may be used interchangeably.^1,3 Each medication class, however, affects a unique step of the renin-angiotensin-aldosterone system, which may account for the differences in adverse effect profiles and tolerability. Although previous studies had already established the similar effectiveness of ACE inhibitors and ARBs in lowering blood pressure,⁴ this meta-analysis goes a step further by assessing the outcomes that really matter to patients—mortality and cardiovascular events. Given the limitations of some of the evidence, the Agency for Healthcare Research and Quality has identified future comparative studies of ACE inhibitors and ARBs as a priority,⁴ particularly because of how few head-to-head studies have been published.