The Impact of ACE Inhibition on All-Cause and Cardiovascular Mortality in Contemporary Hypertension Trials

A Review

Roberto Ferrari; Eric Boersma


Expert Rev Cardiovasc Ther. 2013;11(6):705-717. 

In This Article

Abstract and Introduction


The renin–angiotensin–aldosterone system is a key therapeutic target in hypertension. The latest meta-analysis of mortality reduction with angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) in hypertension features 158,998 patients from 20 contemporary hypertension trials. ACE inhibitors and ARBs significantly reduced relative risk for all-cause mortality by 5% (p = 0.032) and cardiovascular mortality by 7% (p = 0.018) in populations with a high prevalence of hypertension (≥66%). ACE inhibitors produced a 10% reduction in relative risk for all-cause mortality (p = 0.004) and a trend toward a 12% reduction in cardiovascular mortality (p = 0.051), whereas ARBs had no effect. On balance, mortality evidence suggests that in hypertension, ACE inhibitors should be considered ahead of ARBs, and ARBs restricted to patients intolerant of ACE inhibitors.


More than a quarter of the world's population and more than half of 60-year-olds have hypertension,[1] the leading cause of premature death worldwide.[101,102] European hypertension guidelines state that mortality reduction should be the ultimate goal of antihypertensive treatment,[2] a goal confirmed by the 2011 NICE guidelines.[101]

Management of hypertension is a challenge, particularly in patients with high cardiovascular risk. In 1509 American hypertensive patients aged ≥30 years from the 2005–2006 National Health and Nutrition Examination Survey, treatment rates ranged from 58% to 75%, depending on Framingham cardiovascular risk score.[3] Hypertension control rates ranged from good (>80%) in patients with low cardiovascular risk (assessed using the 10-year Framingham risk score) to unsatisfactory (<50%) in patients with high cardiovascular risk.[3] Thus, interestingly, patients in most need of treatment in the National Health and Nutrition Examination Survey were the worst protected.

The renin–angiotensin–aldosterone system (RAAS) is one of the key therapeutic targets in patients with hypertension, as an overactive RAAS is strongly associated with high blood pressure (BP). The RAAS is an important regulator of hemodynamic stability and controls circulating volume and electrolyte balance in the human body.[4] RAAS inhibitors, which have been used in the treatment of hypertension for the past 30 years, include angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs).[3] These drugs could positively influence cardiovascular and cerebrovascular outcomes in hypertensive patients, as hypertension is a known risk factor for both cardiovascular and cerebrovascular disease.[2,4]

Most individual ACE inhibitor and ARB trials in hypertension are statistically underpowered to detect any impact on mortality. Quantitative meta-analyses of multiple trials can overcome this statistical problem.[5] All of which makes the results of our recent meta-analysis of randomized controlled trial data in populations receiving contemporary antihypertensive medication particularly relevant for determining the long-term consequences of treatment with ACE inhibitors and ARBs on all-cause and cardiovascular mortality in hypertension.[6] The meta-analysis showed several discrepancies between the two classes of drugs as well as between individual compounds within one of these classes.

The aim of this article is to review the impact of RAAS inhibitors on mortality reduction in hypertensive patients and to explore the differences between ACE inhibitors and ARBs in terms of clinical and pathophysiological effects.