Angiotensin-Converting Enzyme Inhibitors Reduce Mortality in Hypertension: A Meta-Analysis of Randomized Clinical Trials of Renin–Angiotensin–Aldosterone System Inhibitors Involving 158,998 Patients

Study Questions:

What are the effects of renin–angiotensin–aldosterone system (RAAS) inhibitors as a class of drugs, as well as of angiotensin-converting enzyme (ACE) inhibitors and AT1 receptor blockers (ARBs) separately, on all-cause mortality in hypertensive patients?


The investigators performed a pooled analysis of 20 cardiovascular morbidity–mortality trials. In each trial at least two-thirds of the patients had to be diagnosed with hypertension, according to the trial-specific definition, and randomized to treatment with an RAAS inhibitor or control treatment. The cohort included 158,998 patients (71,401 RAAS inhibitor; 87,597 controls). The authors conducted linear regression analyses, based on trial-level data (so-called “meta-regression”).


The incidence of all-cause death was 20.9 and 23.3 per 1,000 patient-years in patients randomized to RAAS inhibition and controls, respectively. Overall, RAAS inhibition was associated with a 5% reduction in all-cause mortality (hazard ratio [HR], 0.95; 95% confidence interval [CI], 0.91-1.00; p = 0.032), and a 7% reduction in cardiovascular mortality (HR, 0.93; 95% CI, 0.88-0.99; p = 0.018). The observed treatment effect resulted entirely from the class of ACE inhibitors, which were associated with a significant 10% reduction in all-cause mortality (HR, 0.90; 95% CI, 0.84-0.97; p = 0.004), whereas no mortality reduction could be demonstrated with ARB treatment (HR, 0.99; 95% CI, 0.94-1.04; p = 0.683). This difference in treatment effect between ACE inhibitors and ARBs on all-cause mortality was statistically significant (p value for heterogeneity, 0.036).


The authors concluded that in patients with hypertension, treatment with an ACE inhibitor results in a significant further reduction in all-cause mortality.


This meta-analysis, which included almost 160,000 patients, reported a 5% reduction in all-cause mortality during a 4-year follow-up period associated with the class of RAAS inhibitors. A stratified analysis, according to the class of drug, showed that the observed overall all-cause mortality reduction was almost completely a result of the beneficial effect of the class of ACE inhibitors, whereas the ARBs showed a neutral treatment effect. In view of the high prevalence of hypertension in the general population, use of ACE inhibitors may result in a considerable gain in lives saved. The observed mortality reduction may be used as a convincing argument to stimulate patients to adhere to the prescribed treatment.

Clinical Topics: Heart Failure and Cardiomyopathies, Prevention, Hypertension

Keywords: Cause of Death, Incidence, Cardiovascular Agents, Follow-Up Studies, Angiotensin II Type 1 Receptor Blockers, Cardiovascular Diseases, Renin-Angiotensin System, Hypertension

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