The authors concluded that angiotensin-converting enzyme inhibitors or angiotensin receptor blockers were effective in patients with atherosclerosis or at an increased risk of it, even when they had normal systolic blood pressure. The authors' conclusions reflect the evidence presented and, despite unavailable data from seven eligible trials, they are probably reliable.

To examine the effectiveness of angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs) for patients with atherosclerosis, or those at an increased risk of atherosclerosis, and with normal blood pressure.

MEDLINE, Cochrane Central Register of Controlled Trials (CENTRAL) and EMBASE were searched up to March 2011; search terms were not reported. References of identified studies and reviews were checked. Unpublished data were obtained from the Renin Angiotension System Modulator Meta-Analysis Investigators.

Eligible studies were placebo randomised controlled trials (RCTs) examining the effectiveness of ACE inhibitors or ARBs. These trials were required to have a sample of at least1,000 patients with atherosclerotic vascular disease or at an increased risk of developing this disorder. Patients had to receive the intervention for at least 12 months. Cardiovascular endpoints, including death, myocardial infarction, or stroke, had to be reported. Trials that used combination therapy, or were conducted exclusively in patients with hypertension were excluded.

In included trials, the mean age ranged from 55 to 67 years, the mean systolic blood pressure ranged from 126 to 152mmHg, and most patients received other antihypertensive medication as well as ACE inhibitors or ARBs. Three trials included only patients with systolic heart failure and two included only those with diabetes mellitus.

Two reviewers selected trials independently.

The authors did not report a formal quality assessment, but characteristics of the trials, such as blinding and intention-to-treat analysis, were reported. No checking of the individual patient data was reported.

Where possible, individual patient data were obtained from trial investigators, otherwise summary data grouped by baseline systolic blood pressure were used to calculate odds ratios and 95% confidence intervals. The data were extracted on an intention-to-treat basis.

Patients were grouped by their baseline systolic blood pressure (less than 130mmHg, 130 to 139mmHg, or 140mmHg or over) and individual patient data or summary data were pooled using the fixed-effect Peto model. Heterogeneity was assessed using Ι² and Χ². Meta-regression and subgroup analyses were conducted to examine the impact of: age (older or younger than 65 years), known coronary disease, prior cerebrovascular disease, prior systolic heart failure, and diabetes mellitus. Publication bias was assessed using the Egger and Begg tests.

Twenty eligible trials were found and 13 trials, with 80,594 patients (11,005 events), were analysed. No subgroup data were available for the seven trials, with 12,418 patients (1,618 events), which were not analysed. All trials included blinding of the outcome assessor. Individual patient data were available for 10 trials and three trials provided summary data by baseline systolic blood pressure.

There were statistically significant reductions in all outcomes, except death from any cause, which approached statistical significance. For example, the odds ratio for the composite outcome was 0.89 (95% CI 0.85 to 0.93; Ι²= 25%).

There were no statistically significant differences between subgroups on any outcome, except cardiovascular death. There was a greater risk of cardiovascular death in those with a systolic blood pressure less than 130mmHg (OR 0.83, 95% CI 0.75 to 0.91; Ι²=9%).

There was no statistically significant evidence of associations with the effectiveness of the intervention for age, baseline systolic blood pressure, degree of systolic blood pressure reduction during the trial, and duration of the trial. There was consistent benefit for those without diabetes and those without systolic heart failure.

Sensitivity analyses showed that the pooled results were similar for trials that were excluded due to a small sample size, or because no systolic blood pressure subgroup data were available. There was no evidence of publication bias.

ACE inhibitors or ARBs were effective in patients with atherosclerosis or at an increased risk of it, even if their systolic blood pressure was normal (below 130mmHg).

The review question and inclusion criteria were clear. The electronic search included an acceptable range of databases. Trial investigators were contracted for individual patient data. Data were not available for seven trials and the impact of this missing data on the analyses is unclear. The investigators in three of these trials indicated they found similar results to this meta-analysis.

Appropriate methods were used to minimise error and bias in trial selection. Trial details were provided, but there was limited information on their quality, which limits the ability to critically appraise the data. Whether or how the individual patient data were checked was not reported. Suitable methods were used to pool the data and to explore heterogeneity.

The authors' conclusions reflect the evidence presented and, despite data being unavailable for seven trials, the conclusions are probably reliable.

Practice: The authors stated that the prescribing of ACE inhibitors or ARBs should be based on the assessment of a patient's cardiovascular risk and not on their measured blood pressure alone.

Research: The authors did not state any implications for research.

Support received from the Canadian Institutes of Health, Alberta Innovates-Health Solutions, and the National Heart Foundation of Australia.