A Systematic Review of Angiotensin Receptor Blockers in Preventing Stroke
Background and Purpose— Angiotensin receptor blockers are widely used in patients at high risk of cardiocerebrovascular events. The aim of this meta-analysis was to investigate the effects of angiotensin receptor blockers on the risk of stroke.
Methods— Electronic searches of MEDLINE, EMBASE, and the Cochrane central register of controlled trials were performed. A total of 20 randomized clinical trials with 108 286 patients reporting stroke were available for this clinical outcome analysis.
Results— Angiotensin receptor blockers were associated with a significant reduction in the risk of stroke than placebo with an OR of 0.91 (0.84 to 0.98). Angiotensin receptor blockers were associated with no significant reduction in the risk of stroke compared with angiotensin-converting enzyme inhibitors (OR, 0.93; 0.84 to 1.03) and calcium antagonists (OR, 1.16; 0.91 to 1.48).
Conclusions— Evidence of the benefit of angiotensin receptor blockers on the risk of stroke is provided when compared with placebo. There was no evidence of the benefit when comparing angiotensin receptor blockers with angiotensin-converting enzyme inhibitors and with calcium antagonists.
Stroke is the second most frequent cause of death in the world and is responsible for approximately 5 million deaths each year.1 Evidence is very strong for the use of angiotensin-converting enzyme inhibitors (ACEIs) to reduce the risk of stroke.2,3 Angiotensin receptor blockers (ARBs) theoretically produce more complete inhibition of angiotensin II and are more effective than ACEIs.4 However, recent trials concluded that ARBs did not lower the rates of stroke.5 To determine the effect of ARBs in the prevention of stroke, we undertook a systematic review of all published randomized, controlled trials of ARBs in patients who are at high risk of cardiocerebrovascular events.
A systematic review was performed according to the Quality of Reporting of Meta-analyses (QUOROM) guidelines.6 Because of the benefits of ACEIs and calcium antagonists,2 we did separate overviews of trials comparing ARBs with placebo, with ACEIs, and with calcium antagonists. Published trials were identified through an electronic search of MEDLINE, EMBASE, and the Cochrane central register of controlled trials and through manual review of journals and crossreferences of dedicated articles. The randomized clinical trials involving patients at high risk for cardiocerebrovascular events who are treated with ARBs and reporting stroke were included. Data extraction was performed by 3 reviewers independently. Any disagreement was resolved by discussion. Methodological quality was assessed by using standard criteria (allocation concealment, blinding, intention-to-treat analysis, loss to follow-up) and scored out of a maximum of 5.
The statistical analysis was performed by RevMan software Version 4.2.6 (Cochrane Collaboration, Oxford, UK). We used the random effects model to calculate the OR and its 95% CI. We also performed subgroup analyses according to the impact of the baseline characteristics and the difference in blood pressure (BP). We constructed standard funnel plots to investigate the potential for publication bias influencing the analysis.
A total of 20 randomized, controlled trials with 108 286 patients were included in the final meta-analysis. The baseline characteristics of all the trials are shown in Table 1. Eleven trials had the maximum score of 5; 4 trials scored 4, 4 scored 3, and one scored 2. Funnel plots for the studies comparing ARBs with placebo and with ACEIs are qualitatively symmetrical, indicating the absence of publication bias.
In the overview of 11 trials involving 44 971 patients, ARBs was associated with a significant decrease of the rate of stroke than placebo with a pooled OR of 0.91 (95% CI, 0.84 to 0.98; Table 2). In subgroup analysis of 5 trials reporting lower BP in the ARB group, evidence of the benefit of ARBs is also provided. There was no evidence of the benefit of ARBs in the subgroup analyses by different diseases.
There was no significant reduction in the risk of stroke comparing ARBs with ACEIs with a pooled OR of 6 trials being 0.93 (0.84 to 1.03). In subgroup analysis of 2 trials reporting the lower BP of ARBs, there was a trend toward a decrease of strokes in patients receiving ARBs versus those receiving ACEIs (P=0.05).
ARBs were associated with no significant reduction in the risk of stroke compared with calcium antagonists (4 trials, 22 446 patients, pooled OR 1.16 [0.91 to 1.48]). Two trials reported the BP levels in the ARB group were higher than those in a calcium antagonist group, and patients receiving ARBs almost had a significantly higher rate of stroke (P=0.05).
The results of this meta-analysis of 20 randomized clinical trials reveal that ARBs provide benefit on preventing stroke when compared with placebo. However, there was no evidence of the benefit when comparing ARBs with ACEIs and with calcium antagonists.
Two previous meta-analyses have evaluated the effect of ARBs in preventing stroke.7,8 Turnbull et al undertook a systematic review involving 4 trials and found that the risk of stroke was reduced with ARB-based regimens compared with control regimens (placebo and atenolol).7 The other meta-analysis included 10 trials, including 6 trials comparing ARBs with ACEIs and 4 trials comparing ARBs + ACEIs with ACEIs and demonstrated that ARBs were slightly more protective than ACEIs on the risk of stroke.8 In contrast to the earlier meta-analyses, we examined 20 randomized clinical trials and undertook separately overviews comparing ARBs with placebo (11 trials), with ACEIs (6 trials), and with calcium antagonists (4 trials). To evaluate the effects of baseline diseases on the results of meta-analysis, we carried out subgroup analyses, and there was no influence of the baseline diseases. The potential influence of different BP levels on the risk of stroke was also evaluated, and strong evidence of the benefit of lower BP level was provided.
One limitation of this systematic review is that the data of stroke rates were extracted from trials of different durations. Some caution is therefore needed in their interpretation. These data are derived from a selected and limited data set available in the literature and therefore affected by publication bias. Another limitation is that several trials lacked adequate allocation concealment, blinding, and intention-to-treat analysis, which may leave them vulnerable to bias.
In conclusion, this meta-analysis shows that there is moderate evidence of the benefit of ARBs on the risk of stroke. However, there are some factors such as BP level that may potentially influence the risk of stroke. Therefore, pragmatic randomized, controlled trials are warranted to fully elucidate the benefit of ARBs in normotensive patients at high risk of cardiocerebrovascular events.
Source of Funding
Supported by China Basic Research Programme No 2009CB521900.
G.-C.L., J.-W.C., and K.-M.Z. contributed equally to this work.
- Received June 10, 2009.
- Accepted June 25, 2009.