The Effects of Calcium Channel Blockers in the Prevention of Stroke in Adults with Hypertension: A Meta-Analysis of Data from 273,543 Participants in 31 Randomized Controlled Trials

Abstract

Introduction

Hypertension (MIM #14500) is one of the most common chronic diseases, and the most frequent reason for people to consult their doctor and take medication. Hypertension can burst a blood vessel or/and accelerate narrowing of arteries in the brain to cause a stroke which, if not lethal, can result in many catastrophic complications such as paralysis, aphasia, coma and so forth. The damage to the brain cannot be repaired, so the only rational approach is prevention. Hypertension is a major risk factor for the development of stroke. In 1964, it was first demonstrated that antihypertensive agents could reduce the risk of strokes [1]. It is well known that lowering blood pressure decreases the risk of stroke in people with moderate to severe hypertension [2]. There are eight classifications of antihypertensive agents in use today: α-adrenergic blockers, angiotensin-converting enzyme inhibitors (ACEIs), angiotensin II receptor antagonists, antiadrenergic agents, β-adrenergic blockers or β blockers, calcium channel blockers (CCBs), diuretics, and vasodilators. Despite the widespread use of blood-pressure-lowering agents which one is better against the development of stroke is unclear [3]. Controlling blood pressure in the patients with hypertension or/and stroke has important clinical implications including improved prognosis, reduced mortality and so on [4]. Angiotensin-converting enzyme inhibitors, β-adrenergic blockers, calcium channel blockers and diuretics are used extensively and listed as the first-line agents in the 1989 WHO/International Society of Hypertension Guidelines [5]. Because each study may have insufficient power to detect the effect of calcium channel blockers against stroke in the patients with hypertension; a meta-study to accumulate data from different studies may address this issue, and the specific effects of CCBs against stroke in patients with hypertension as compared to no treatment and other antihypertensive drug classes are not known. Therefore, the major goal of this work was to perform a systematic review and a meta-analysis of the published data and to figure out whether calcium-channel blockers are better than other first-line antihypertensive agents in the prevention of stroke, as well as to quantify the potential heterogeneity between different studies.

Methods

Study Selection

A total of 177 published studies were identified using the screening procedure shown in Figure 1 (see Supplementary Information online). Among them, fifty-eight are systematic reviews and meta-analyses, one hundred and nineteen are randomized controlled trials. After searching, the following information was extracted: author, ethnicity of research subjects, year of publication, numbers of hypertension- and stroke-cases, medicine of treatment, age of patients, and years of followed-up. Studies were eligible for inclusion if they were randomized controlled trials and reported on stroke risk associated with the current use of the first-line antihypertensive agents in population settings.

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Figure 1

A schematic diagram for the search strategy of published reports.

Results

The derivation of the databases and published articles is described in Figure 1. A total of one hundred and seventy-seven studies concerning the stroke risk associated with the use of antihypertensive agents in the patients with hypertension were identified. Among them, one hundred and forty-six studies were excluded for (1) No numbers of hypertension- and stroke-cases; (2) Data duplication; (3) Not written in English or Chinese; (4) No randomized controlled trials; (5) Data missing or lacking; (6) No control group. Therefore, thirty-one studies [3]–[5], [12]–[39] and a total of 273,543 participants (including 130,466 experimental subjects and 143,077 controls) matched the inclusion criteria and were selected for the statistical test; and a total of 9,550 stroke events (4,145 in experimental group and 5,405 in control group) were reported (see Table 1). The quantity and quality of original investigations play an important role in determining the quality of the meta-analysis. To controlling the publication bias, the funnel test was performed (see Figure 2). No evidence of publication bias was found for the included thirty-one studies. Our analysis also indicated that the heterogeneity between studies was not statistical significance (p>0.05), therefore, the fixed effects model was used for the meta-analysis. The results of quality assessment for each included study indicated that among the included thirty-one studies, twenty-eight reports [3]–[5], [12]–[15], [17]–[25], [27]–[32], [34]–[39] were high quality and the remaining three studies [16], [26], [33] were moderate quality (see Table 1 and Supplementary Information online). The overall quality of the evidence was high in our statistical tests.

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Figure 2

Funnel plots of odds ratios for all studies in the meta-analyses.

(a) Calcium channel blockers vs Placebo, (b) Calcium channel blockers vs ACEIs, and (c) Calcium channel blockers vs Diuretics or/and β blockers. No evidence of publication bias was found in any of them.

The issue of lost to follow-up or withdrew was identified as follows: 1) six studies [4], [24], [29], [32], [34], [37] reported that no patient was lost to follow-up or withdrew; 2) eight studies [14], [17]–[18], [23], [25], [35]–[36], [38] did not report the information of the patient’s follow-up or withdrew; 3) the remaining seventeen studies [3], [5], [12]–[13], [15]–[16], [19]–[22], [26]–[28], [30]–[31], [33], [39] reported that some patients were lost to follow-up or withdrew but not gave out the reasons, and the rate of lost to follow-up was not significantly difference between the experimental and control groups (see Supplementary Information online). Therefore, we did not perform the comparisons of incidence of withdrawals due to adverse effects for CCBs versus other drugs, because it was easy to result in a bias.

The results from the risk of bias assessment for each included study indicated that among the included thirty-one studies, fifteen reports [3], [5], [14], [17], [20]–[22], [27], [29]–[33], [37], [39] were low risk of bias, thirteen reports [4], [12], [13], [15], [18], [19], [23], [25], [28], [34]–[36], [38] were unclear risk of bias, and the remaining three studies [16], [26], [33] were high risk of bias (see Table 1 and Supplementary Information online).

There are two types of stroke, ischemic stroke (80%) and hemorrhagic stroke (20%). A total of 60–80% of hypertension patients (blood pressure >140/90 mmHg) face the risk of stroke. Hypertension is associated with ischemic- and hemorrhagic-stroke [40]. The detailed information of ischemic- or hemorrhagic-stroke was not presented in most original studies. The authors of included thirty-one studies have contact. Six reports authors could not contacted, nine reports authors did not response to us, five reports authors responded to us with the information we need, and eleven reports authors responded to us but did not give back the information we need. Therefore, we can not perform sub-groups analysis.

Stroke Events of CCBs vs Placebo

Ten studies were included in this test [12], [14]–[16], [21], [23], [25]–[26], [37]–[38], which consisted of 21,844 experimental subjects and 21,690 controls, and 1,574 stroke events (622 in experimental group and 907 in control group). Statistic test revealed that the CCBs could significantly decline the stroke risk (OR = 0.68, 95% CI 0.61–0.75, p<1×10⁻⁵) compared with that of placebo (see Figure 3a). The incidence of stroke in CCBs group was decreased by 33.33% [(4.2%-2.8%) ÷ 4.2% × 100%] compared with that of placebo group (see Table 1).

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Figure 3

OR and 95% CI of individual studies and pooled data against stroke in the patients with hypertension.

(a) Calcium channel blockers vs Placebo, (b) Calcium channel blockers vs ACEIs, and (c) Calcium channel blockers vs Diuretics or/and β Blockers.

Discussion

This study demonstrates that the use of calcium channel blockers therapy, compared with placebo therapy (OR, 0.68), β-adrenergic blockers therapy (OR, 0.79), diuretics combined with β-adrenergic blockers therapy (OR, 0.89), angiotensin-converting enzyme inhibitors therapy (OR, 0.92), and diuretics therapy (OR, 0.95), was associated with a lower incidence of stroke events in the patients with hypertension. In this combined study of different hypertension populations, the risk of stroke events reduction for patients receiving calcium channel blockers therapy was similar. Due to different sample size in different treatment groups, it is essential to use and interpret the above results with cautions. These findings present new evidence to support the idea that the CCBs reduced stroke more than placebo and β-adrenergic blockers but were not different than ACEIs and diuretics. Hypertension is only one of the major risk factors in the development of stroke, the number of stroke events remains high even though the antihypertensive agents are used extensively [39]. Therefore, other risk factors or/and the biological processes underlying the pathophysiology of stroke warrant further studies in the near future.

The findings of our work indicated that CCBs reduced stroke more than placebo and β-adrenergic blockers, but the detail molecular mechanisms are not well known and remain to be excavated in the future. By now, it can be explained in part by that CCBs can generate stronger antihypertensive effect (by dilating the blood vessels) than that of beta-blockers (by reducing the blood flow of cardiac output) or that of placebo (by confounders). These results reported here provide strong evidence linking controlling hypertension to a reduced risk of stroke. Meanwhile, this study has some limitations and caveats. First, as not all clinical data were available from each original report, other subclasses-stratified analyses could not be performed; the risk of bias assessment in this work could rob the credibility of results. Second, only studies reported in English or Chinese were included, which might be vulnerable to the bias of language and ethnicity. Third, the whole sample size in this study is sufficient for statistic purposes, but the sample size of each subgroup is relatively small and susceptible to false positive or negative results. Fourth, after the treatment of antihypertensive agents, the years of followed-up between studies varied greatly (from 1 to 5.5 years), which also could result in a bias. Finally, only four kinds of antihypertensive agents were tested in this report; addition of other drugs and withdrawals of treatment may also lead to an underestimation of the real differences in stroke risk between the previous reports. Further studies are required to investigate the association between other antihypertensive agents and stroke-risk, and to provide a better estimate the benefits of antihypertensive agents against stroke in the hypertension populations.

In conclusions, the present analysis shows that CCBs, ACEIs, diuretics, and β-adrenergic blockers can decline the incidence of stroke in the hypertension populations. Among them, CCBs reduced stroke more than placebo and β-adrenergic blockers, but were not different than ACEIs and diuretics. More head to head RCTs are warranted. This systematic review and meta-analysis provides a thorough examination of the literature on the effect of first-line antihypertensive agents in the prevention of stroke, and provide a foundation of knowledge on which clinical and public health messaging deserves to be further discussed.

Supporting Information

Acknowledgments

Funding Statement

This work was supported by grants from Chongqing Medical University (XBZD200701) and The Program for Excellent Talents of University in Chongqing Municipality. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

References