Angiotensin converting enzyme (ACE) inhibitors versus angiotensin receptor blockers for primary hypertension

Background

Hypertension, or persistent high blood pressure above 140/90 mmHg, is a prevalent risk factor that is associated with strokes and heart disease. To prevent these events, angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) are used widely to treat hypertension, with ARBs often substituted for ACE inhibitors due to a reputation of having fewer side effects. However, while studies have shown a preventive benefit for ACE inhibitors, there are no such studies for ARBs. Therefore, we aimed to further test this substitution by reviewing studies that directly compared an ACE inhibitor and an ARB.

Study characteristics

We searched scientific databases for randomized controlled trials (clinical studies where people are randomly put into one of two or more treatment groups) of people with uncontrolled or controlled hypertension with or without other risk factors (an aspect of a person's condition, lifestyle or environment that affects the probability of occurrence of a disease). The evidence is current to July 2014.

Key results

We found no reliable difference between ACE inhibitors and ARBs for total deaths, deaths due to heart disease, or total heart disease and stroke. However, our conclusions alone cannot be taken to mean that ARBs would show similar benefit like ACE inhibitors if compared with placebo (a dummy treatment). ARBs do have a 1.8% lower chance of being stopped due to side effects over 4.1 years, meaning that for every 55 people treated with an ARB instead of an ACE inhibitor for 4.1 years, one person would be spared from a side effect leading to stopping the drug. This difference in side effects was mainly due to a higher rate of dry cough in people taking ACE inhibitors.

Quality of the evidence

In summary, while ARBs are slightly better tolerated than ACE inhibitors, there is a higher quality of data supporting the use of ACE inhibitors to prevent death, strokes, and heart disease that must be considered before choosing ARBs over ACE inhibitors.

Authors' conclusions: 

Our analyses found no evidence of a difference in total mortality or cardiovascular outcomes for ARBs as compared with ACE inhibitors, while ARBs caused slightly fewer WDAEs than ACE inhibitors. Although ACE inhibitors have shown efficacy in these outcomes over placebo, our results cannot be used to extrapolate the same conclusion for ARBs directly, which have not been studied in placebo-controlled trials for hypertension. Thus, the substitution of an ARB for an ACE inhibitor, while supported by evidence on grounds of tolerability, must be made in consideration of the weaker evidence for the efficacy of ARBs regarding mortality and morbidity outcomes compared with ACE inhibitors. Additionally, our data mostly derives from participants with existing clinical sequelae of hypertension, and it would be useful to have data from asymptomatic people to increase the generalizability of this review. Unpublished subgroup data of hypertensive participants in existing trials comparing ACE inhibitors and ARBs needs to be made available for this purpose.

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Background: 

Angiotensin converting enzyme inhibitors (ACE inhibitors) and angiotensin receptor blockers (ARBs) are widely prescribed for primary hypertension (systolic blood pressure > 140 mmHg or diastolic blood pressure > 90 mmHg). However, while ACE inhibitors have been shown to reduce mortality and morbidity in placebo-controlled trials, ARBs have not. Therefore, a comparison of the efficacies of these two drug classes in primary hypertension for preventing total mortality and cardiovascular events is important.

Objectives: 

To compare the effects of ACE inhibitors and ARBs on total mortality and cardiovascular events, and their rates of withdrawals due to adverse effects (WDAEs), in people with primary hypertension.

Search strategy: 

We searched the Cochrane Hypertension Group Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, the World Health Organization (WHO) International Clinical Trials Registry Platform, and the ISI Web of Science up to July 2014. We contacted study authors for missing and unpublished information, and also searched the reference lists of relevant reviews for eligible studies.

Selection criteria: 

We included randomized controlled trials enrolling people with uncontrolled or controlled primary hypertension with or without other risk factors. Included trials must have compared an ACE inhibitor and an ARB in a head-to-head manner, and lasted for a duration of at least one year. If background blood pressure lowering agents were continued or added during the study, the protocol to do so must have been the same in both study arms.

Data collection and analysis: 

We used standard methodological procedures expected by The Cochrane Collaboration.

Main results: 

Nine studies with 11,007 participants were included. Of the included studies, five reported data on total mortality, three reported data on total cardiovascular events, and four reported data on cardiovascular mortality. No study separately reported cardiovascular morbidity. In contrast, eight studies contributed data on WDAE. Included studies were of good to moderate quality. There was no evidence of a difference between ACE inhibitors and ARBs for total mortality (risk ratio (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). Conversely, a high level of evidence indicated a slightly lower incidence of WDAE for ARBs as compared with ACE inhibitors (RR 0.83; 95% CI 0.74 to 0.93; absolute risk reduction (ARR) 1.8%, number needed to treat for an additional beneficial outcome (NNTB) 55 over 4.1 years), mainly attributable to a higher incidence of dry cough with ACE inhibitors. The quality of the evidence for mortality and cardiovascular outcomes was limited by possible publication bias, in that several studies were initially eligible for inclusion in this review, but had no extractable data available for the hypertension subgroup. To this end, the evidence for total mortality was judged to be moderate, while the evidence for total cardiovascular events was judged to be low by the GRADE approach.

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