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Open Access

Peer-reviewed

Research Article

Comparative efficacy of different antihypertensive drug classes for stroke prevention: A network meta-analysis of randomized controlled trials

  • Ding Yu ,

    Contributed equally to this work with: Ding Yu, Jun-xia Li

    Roles Project administration, Writing – original draft

    Affiliation Heart Center, The First Hospital of Hebei Medical University, Shijiazhuang, China

    ⨯
  • Jun-xia Li ,

    Contributed equally to this work with: Ding Yu, Jun-xia Li

    Roles Data curation, Investigation, Methodology, Writing – review & editing

    Affiliation Department of Pharmacology, Hebei Medical University, Shijiazhuang, China

    ⨯
  • Yuan Cheng,

    Roles Data curation, Formal analysis

    Affiliation Department of Pathology, Hebei University of Chinese Medicine, Luquan, Shijiazhuang, China

    ⨯
  • Han-dong Wang,

    Roles Investigation, Methodology

    Affiliation Department of General Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, China

    ⨯
  • Xin-di Ma,

    Roles Software, Visualization

    Affiliation Undergraduate of Clinical Medicine, Hebei Medical University, Shijiazhuang, China

    ⨯
  • Tao Ding ,

    Roles Formal analysis, Writing – review & editing

    zzn1970@hotmail.com (Z-NZ); domdt2019@126.com (TD)

    Affiliation Department of Pathology, Hebei University of Chinese Medicine, Luquan, Shijiazhuang, China

    ⨯
  • Zhong-ning Zhu

    Roles Project administration

    zzn1970@hotmail.com (Z-NZ); domdt2019@126.com (TD)

    Affiliation Department of Pharmacology, Hebei Medical University, Shijiazhuang, China

    ⨯

Abstract

Objective

The study aimed to compare the effectiveness of various antihypertensive drugs in preventing strokes in hypertensive patients.

Methods

We conducted a comprehensive search of PubMed, Embase, the Cochrane Library, and ClinicalTrials.gov to identify randomized controlled trials (RCTs) investigating the efficacy of antihypertensive drugs in stroke prevention from inception until April 2023. A network meta-analysis in a Bayesian framework was performed using the random-effects model.

Results

This study included 88 RCTs involving 487,076 patients to investigate the effects of antihypertensive drugs in preventing stroke. Among these trials, 58 RCTs specifically focused on comparing the impact of such drugs on hypertensive subjects. In overall population, Angiotensin-converting enzyme inhibitor (ACEIs), Angiotensin receptor blockers (ARBs), Calcium channel blockers (CCBs), and Diuretics (DIs) demonstrated superiority over placebo in in reducing stroke, all-cause mortality, and cardiovascular mortality. CCBs and DIs outperformed β adrenergic receptor blockers (BBs), ACEIs, and ARBs in stroke reduction. However, when focusing on hypertensive patients, ACEIs, CCBs, and DIs proved superior to placebo in reducing stroke, all-cause mortality, and cardiovascular mortality. ARBs reduced stroke and all-cause mortality but lacked efficacy in reducing cardiovascular mortality. Of the various CCB subclasses, only the Dihydropyridines displayed efficacy in preventing stroke, all-cause mortality, and cardiovascular mortality. Among diuretic subclasses, thiazide-type DIs exhibited no efficacy in preventing all-cause mortality. ACEIs+CCBs were more effective than ACEIs or ARBs monotherapy in reducing stroke, more effective than ACEIs, ARBs, CCBs, or DIs monotherapy in reducing all-cause mortality, and more effective than ARBs in reducing cardiovascular mortality.

Conclusion

These findings suggest that ACEIs, dihydropyridine CCBs, and thiazide-like diuretics may provide superior prevention against stroke, all-cause mortality, and cardiovascular mortality in hypertensive patients. Combinations of ACEIs and CCBs may provide enhanced protection of stroke than ACEIs or ARBs monotherapy.

Citation: Yu D, Li J-x, Cheng Y, Wang H-d, Ma X-d, Ding T, et al. (2025) Comparative efficacy of different antihypertensive drug classes for stroke prevention: A network meta-analysis of randomized controlled trials. PLoS ONE 20(2): e0313309. https://doi.org/10.1371/journal.pone.0313309

Editor: Amir Hossein Behnoush, Tehran University of Medical Sciences, ISLAMIC REPUBLIC OF IRAN

Received: March 8, 2024; Accepted: October 23, 2024; Published: February 21, 2025

Copyright: © 2025 Yu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Data Availability: All relevant data are within the manuscript and its Supporting Information files.

Funding: The author(s) received no specific funding for this work.

Competing interests: NO authors have competing interests.

Abbreviations: ARBs, angiotensin receptor blockers; DIs, Diuretics; CCBs, calcium channel blockers; ACEIs, angiotensin-converting enzyme inhibito; BBs, β adrenergic receptor blockers; RCT, randomized controlled trial

Introduction

Despite the considerable improvements in diagnosis and treatment, stroke remains the second leading cause of death for people aged above 60 years and the fifth cause for those between 15 and 59 years old [1]. Hypertension poses a high attributable risk for stroke (25%–50%) [2], and is considered as the primary cause of stroke. Previous clinical trials have confirmed that antihypertensive therapy is most effective in controlling hypertension and preventing subsequent stroke events [3].

The current hypertension guidelines recommend the use of angiotensin-converting enzyme inhibitors (ACEIs), angiotensin-II receptor blockers (ARBs), calcium-channel blockers (CCBs), diuretics (DIs), and β blockers (BBs) alone or in combination as first-line agents for hypertension and its complications, including stroke [4,5]. However, there is no consensus on the most appropriate treatment for stroke prevention. First, despite several published systematic reviews and pairwise meta-analyses, the lack of direct, head-to-head comparisons between antihypertensive medication classes limits the identification of the most effective and safe treatment strategy for stroke prevention. Second, a network meta-analysis of 93 studies by Zhong et al. revealed that DI, CCB, and ARB, either alone or in combination, could be considered as first-line treatments for stroke prevention in the general population [6]. Another network meta-analysis by Wang et al. showed that CCB and DI had the highest probability of reducing stroke incidence in cardiovascular disease patients [7]. However, it remains unclear which antihypertensive drugs are most effective for preventing stroke in hypertensive patients. Third, all major systematic reviews have not considered the differences among the sub-classes of DIs and CCBs. For example, diuretics can either be thiazide-type or thiazide-like subclass, while CCBs can be categorized as dihydropyridine and non-dihydropyridine subclass. Therefore, the primary aim of this study is to conduct a comprehensive network meta-analysis of all relevant RCTs to determine the efficacy of different antihypertensive drugs in hypertensive patients, hoping to provide a foundation for the selection of antihypertensive drugs in clinical practice for stroke prevention in hypertensive patients.

Methods

The study was conducted in accordance with the PRISMA guidance [8]. The PRISMA checklist was reported in “S1 PRISMA NMA checklist”.

Literature search strategy

We searched the databases including Pubmed, Embase, the Cochrane Library, and Clinical Trials.gov (Last search was updated on April, 2023). We used search terms (‘‘stroke” OR ‘‘ischemic stroke” OR ‘‘cerebrovascular accident” OR ‘‘CVA”) AND (“antihypertensive agents” OR “blood pressure-lowering” OR “blood pressure lowering” OR “blood-pressure lowering” OR “diuretics” OR “Angiotensin-converting enzyme inhibitors” OR “Angiotensin receptor antagonists” OR “calcium channel blockers” OR “beta blocker” OR “ACEI” OR “ARB” OR “CCB”). Additionally, we conducted a manual search of the bibliographies of all the included articles and related reviews to identify any other potentially eligible trials. The search strategy used for each database are present in S1 Table.

Study selection criteria

Studies were eligible if they fulfilled all the following: 1) they were randomized controlled trials; 2) they compared an antihypertensive agent (alone or in combination) against a second antihypertensive agent or combination therapy, placebo, or control; 3) they provided information on stroke, all-cause mortality, or cardiovascular mortality events. Trials with a follow-up <6 months were excluded. For duplicated trials, the longest follow-up trials were included.

Outcomes assessments

Our outcomes of interest were stroke (including fatal and non-fatal events), all-cause mortality, and cardiovascular mortality.

Data extraction

Two independent investigators reviewed the publications and extracted the data. Controversial data would be reviewed by a third investigator. We extracted the following data: first author, publication year, sample size, treatment class, duration interventions, and outcomes of interest.

Study quality assessment

We assessed the risk of bias of the included randomized trials using a revised version of the Cochrane’s ’Risk of bias’ tool (RoB 2.0). Each trial was judged to be at ’low risk of bias’, ’some concerns’ or ’high risk of bias’ [9].

Statistical analysis

We conducted a Bayesian network meta-analysis using Markov chain Monte Carlo methods in JAGS and the GeMTC package (version 0.8–2) in R(version 4.2.3) software [10] and the web application “MetaInsight V4.1.0” (https://crsu.shinyapps.io/MetaInsight/). We calculated treatment estimates as relative risks (RRs) with their 95% credible intervals (CrIs). Model fit was assessed according to the deviance information criteria (DIC). Three different models were run for each outcome: fixed-effect model, random-effects model, and random-effects inconsistency model. The model with the lowest DIC was considered the model providing the best fit to the data. We set 20,000 simulations for each chain as the “burn-in” period, yielding 50,000 iterations to obtain effect estimates, when 4 Markov chains run simultaneously. The assumption of inconsistency between direct and indirect evidence was assessed globally (by fitting both an inconsistency model and a consistency model) and locally (by carrying out the sidesplitting method). We plotted comparison-adjusted funnel plots for each outcome to make visual assessments of possible publication bias. The overall quality of the network meta-analysis was evaluated using the web application CINeMA (Confidence in Network Meta-Analysis). We rated the certainty of each outcome as ‘high’, ‘moderate’, ‘low’ or ‘very low’ [11].

We performed subgroup analyses to investigate whether the treatment effect varies across different subgroups. The diuretic class was categorized into thiazide-type diuretics and thiazide-like diuretics, while the CCB class was subdivided into dihydropyridine, Verapamil, and Diltiazem CCBs. We then reanalyzed the data to assess the effects.

Results

Search results and study characteristics

A total of 1347 records were identified from the initial database search. A total of 1223 records were excluded for various reasons based on the titles and abstracts screen (reviews, letters, animal studies, not RCTs, or irrelevant to the analysis). The full texts of the remaining 124 studies were reviewed in detail. Then, 29 articles were excluded for the following reasons: study protocol, non-reporting of the outcomes of interest, non-reporting of comparison of interests. Finally, 88 RCTs with 487,076 patients were included in the network meta-analysis. Of the 88 studies, 58 trials (305,171 patients) compared the effects of antihypertensive drugs for patients with hypertension.

The selection process is shown in Fig 1. The main characteristics of the included studies are shown in Table 1. The quality appraisals of the 88 RCTs are shown in S1 and S2 Figs. The network structure diagram is shown in Fig 2. Network structure diagrams are applied to display the direct association between different treatment regimens and the thicknesses of the lines provide a measure of the number of direct comparisons between two regimens.

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Fig 1. Flowchart of selecting process for meta-analysis.

https://doi.org/10.1371/journal.pone.0313309.g001

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Fig 2. Network structure diagrams.

(A) stroke in the overall population, (B) stroke in hypertensive patients, (C) subgroup analysis of stroke in hypertensive patients, (D) all-cause mortality in the overall population, (E) all-cause mortality in hypertensive patients, (F) subgroup analysis of all-cause mortality in hypertensive patients, (G) cardiovascular mortality in the overall population, (H) cardiovascular mortality in hypertensive patients, (I) subgroup analysis of cardiovascular mortality in hypertensive patients. Abbreviations: ARB, angiotensin receptor blockers; DI, Diuretics; DI(TL), thiazide-like diuretics; DI(TT), thiazide-type diuretics; CCB, calcium channel blockers; CCB(DH), dihydropyridine calcium channel blockers; CCB(D), calcium channel blockers (diltiazem); CCB(V), calcium channel blockers (verapamil); ACEI, angiotensin-converting enzyme inhibitors; BB, βadrenergic receptor blockers; nonRASI, non-renin-angiotensin system (RAS) inhibitors; RI, renin inhibitors.

https://doi.org/10.1371/journal.pone.0313309.g002

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Table 1. Characteristics of the trials included in the meta-analysis.

https://doi.org/10.1371/journal.pone.0313309.t001

Synthesis of results

The deviance information criteria (DIC) statistics showed that the random effects model provided a better fit to the data than the fixed-effect model. Additionally, for global inconsistency assessment, the consistency model was a better fit for the data than the inconsistency model (S2 Table). Node-splitting method and its relative Bayesian P value were utilized to report the local inconsistency assessment (S3–S11 Tables). All of the P values between direct and indirect comparisons were above 0.05, indicating that our results were reliable.

Network meta-analysis results

Fig 2 presents the network plot that represents eligible comparisons among the overall population and hypertensive patients. The network meta-analysis evaluated the effect of 21 interventions on stroke and all-cause mortality rates for the overall population: including ACEI, ARB, BB, CCB, conventional therapy, DI, non-BB, non-renin-angiotensin system inhibitors (non-RASI), renin inhibitors (RI), ACEI+BB, ACEI+CCB, ACEI+DI, ARB+ACEI, ARB+ACEI+BB, ARB+BB, ARB+CCB, ARB+DI, BB+DI, CCB+BB, CCB+DI, and placebo. The same interventions, except for RI, were evaluated among hypertensive patients. A total of 20 interventions were utilized to evaluate the cardiovascular mortality in the overall population (ACEI, ARB, BB, CCB, conventional therapy, DI, non-RASI, RI, ACEI+BB, ACEI+CCB, ACEI+DI, ARB+ACEI, ARB+ACEI+BB, ARB+BB, ARB+CCB, ARB+DI, BB+DI, CCB+BB, CCB+DI, and placebo). For hypertensive patients, 19 interventions (excluding RI) were utilized for cardiovascular mortality assessment.

For the overall population (Table 2-1, S19–S27 Tables)

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Table 2. 2–1 Network meta-analysis results for strokes in the overall population.

2–2 Network meta-analysis results for strokes in hypertensive patients.

https://doi.org/10.1371/journal.pone.0313309.t002

The study included a total of 88 trials (n = 487,076) to analyze stroke incidence, 85 trials (n = 471,815) to assess all-cause mortality rates, and 78 trials (n = 463,452) to examine cardiovascular mortality rates in the overall population.

ACEIs, ARBs, CCBs, and DIs exhibited superior efficacy in reducing stroke, all-cause mortality, and cardiovascular mortality compared to placebo. Conversely, BBs demonstrated no efficacy in preventing stroke, all-cause mortality, and cardiovascular mortality when compared to placebo. Furthermore, CCBs were significantly more effective than BBs, ACEIs, and ARBs in reducing stroke, and more effective than ARBs in reducing cardiovascular mortality. DIs were also significantly more effective than BBs, ACEIs, and ARBs in reducing stroke, and more effective than both ARBs and BBs in reducing cardiovascular mortality. Moreover, ACEIs were significantly more effective than BBs and ARBs in reducing all-cause mortality, and more effective than ARBs in reducing cardiovascular mortality. The combination of ACEIs and CCBs was more effective in reducing stroke than monotherapy with ACEIs or ARBs, more effective in reducing all-cause mortality than monotherapy with ACEIs, ARBs, CCBs, or DIs, and more effective in reducing cardiovascular mortality than monotherapy with ACEIs, ARBs, or CCBs.

For hypertensive patients (Table 2-2, S19–S27 Tables)

The analysis for hypertensive patients included 58 trials (n = 305,171) investigating stroke incidence, 54 trials (n = 289,358) assessing all-cause mortality rates, and 49 trials (n = 272,622) examining cardiovascular mortality rates.

ACEIs, CCBs, and DIs were significantly more effective than placebo in reducing stroke, all-cause mortality, and cardiovascular mortality. ARBs were significantly more effective than placebo in reducing stroke and all-cause mortality but were ineffective in reducing cardiovascular mortality. BBs showed no efficacy compared to placebo in preventing stroke, all-cause mortality, and cardiovascular mortality. Furthermore, CCBs were significantly more effective than BBs in reducing stroke, all-cause mortality, and cardiovascular mortality. DIs were significantly more effective than BBs in reducing stroke, and cardiovascular mortality. ACEIs were significantly more effective than BBs in reducing all-cause mortality. Additionally, the combination of ACEIs and CCBs was significantly more effective in reducing stroke than monotherapy with ACEIs or ARBs, more effective in reducing all-cause mortality than monotherapy with ACEIs, ARBs, CCBs, or DIs, and more effective than ARBs in reducing cardiovascular mortality.

In subgroup analyses within the diuretic class, the subclass of thiazide-type diuretics showed no efficacy compared to placebo in preventing all-cause mortality. Within the calcium channel blocker class, the effects of preventing stroke, all-cause mortality, and cardiovascular mortality were limited to the dihydropyridine subclass. Additionally, the dihydropyridine subclass was more effective than the verapamil subclass in preventing cardiovascular mortality.

Publication bias

Comparison-adjusted funnel plots are provided in S3–S11 Figs, and all of them were visually symmetrical, indicating no dominant publication bias.

Quality of the evidence

The results of Confidence in Network Meta-analysis (CINeMA) evaluations are presented in S12–S17 Tables. The overall quality of evidence for which we could assess ranged from very low to high. The main reasons for downgrading the certainty of evidence were within-study bias, imprecision, incoherence, and heterogeneity. The evidence of within-study bias was due to inadequate reporting of randomization and blinding. The evidence for imprecision, heterogeneity, and incoherence was identified because of the limited number of trials available for analysis (S18 Table).

Discussion

The present meta-analysis employed a refined classification of antihypertensive medications to assess the effectiveness of all available antihypertensive agents in preventing strokes. This study provided a thorough systematic review and network meta-analysis to enrich the current knowledge on the optimal selection of antihypertensive medications for hypertensive patients. In the overall population, we found that ACEIs, ARBs, CCBs, and diuretics demonstrated superiority over placebo in reducing stroke, all-cause mortality, and cardiovascular mortality. CCBs and diuretics outperformed BBs, ACEIs, and ARBs in reducing the risk of stroke. However, when focusing on hypertensive patients, ACEIs, CCBs, and diuretics were found to be superior to placebo in reducing stroke, all-cause mortality, and cardiovascular mortality. ARBs reduced stroke and all-cause mortality but lacked efficacy in reducing cardiovascular mortality. Among the various CCB subclasses, only the dihydropyridines showed efficacy in preventing stroke, all-cause mortality, and cardiovascular mortality. Among diuretic subclasses, thiazide-type diuretics exhibited no efficacy in preventing all-cause mortality. The combination of ACEIs with CCBs proved more effective than monotherapy with ACEIs or ARBs in reducing stroke, more effective than monotherapy with ACEIs, ARBs, CCBs, or diuretics in reducing all-cause mortality, and more effective than ARBs in reducing cardiovascular mortality.

The Renin-Angiotensin System (RAS) is a well-known mechanism in the development of hypertension. As a result, antihypertensive agents that inhibit the RAS have been widely utilized for managing hypertension [102]. In 2018, Chen et al. conducted a meta-analysis to explore the efficacy and safety of RAS inhibitors in comparison to other antihypertensive drug classes among hypertensive patients. The authors reported that first-line thiazides and CCBs led to a lower incidence of strokes compared to first-line RAS inhibitors. Moreover, first-line RAS inhibitors were superior to first-line BBs for reducing strokes, but the study did not distinguish between ACEIs and ARBs [103]. Dimou et al. conducted a network meta-analysis that examined the relative effectiveness of ACEIs and ARBs in essential hypertension. The study showed that ACEIs and ARBs had a similar effect on all-cause mortality, cardiovascular mortality, and stroke [104]. Another meta-analysis by Thomopoulos et al. examined 50 trials involving 247,006 participants with hypertension prevalence of over 40%. The study indicated that RAS inhibitors were more effective than placebos and BBs but less effective than diuretics and CCBs in preventing strokes. ACEIs were superior to placebo, but inferior to CCBs and other classes, whereas ARBs were superior to placebo and BBs [105]. Similarly, our study found that ARBs and ACEIs were superior to placebos but inferior to diuretics and CCBs in the prevention of strokes in the overall population. However, when specifically analyzing hypertensive patients, we discovered that ARBs and ACEIs exhibited a comparable effectiveness to diuretics and CCBs in reducing strokes and all-cause mortality. Nonetheless, ARBs did not show any impact on cardiovascular mortality.

Calcium ions contribute to tissue damage in the heart and other organs, leading to stroke and myocardial infarction. CCBs are widely used in the treatment of angina and hypertension. Several meta-analyses have evaluated the effects of CCBs on both cardiovascular and cerebrovascular outcomes. Costanzo et al. (2009) conducted a meta-analysis to investigate the impacts of CCBs on cardiovascular outcomes in comparison with other drugs. Their analysis confirmed that the use of CCBs reduced the risk of stroke compared to ACEIs, without increasing the risk of cardiovascular death, myocardial infarction, or major cardiovascular events [106]. Chen et al. (2010) revealed in a Cochrane systematic review that CCBs reduced the risk of stroke compared to ACEIs, the risk of stroke and myocardial infarction compared to ARBs, and the risk of stroke and cardiovascular mortality compared to BBs [107]. However, Chen et al.’s (2013) meta-analysis showed that although CCBs reduces stroke risk in hypertensive patients when compared to placebo and BBs, it shows no significant difference when compared to ACEIs and diuretics [108]. The meta-analysis conducted by Thomopoulos et al., involving 247,006 participants with hypertension prevalence over 40%, reported that CCBs were more effective than placebos, BBs, ACEIs, RAS blockers, and all other classes together in preventing stroke [105]. Wei et al. (2020) conducted a network meta-analysis and reported that ACEIs, dihydropyridine CCBs, and diuretics had similar effects on cardiovascular mortality and stroke [109]. A meta-analysis, synthesizing data from 13 clinical studies involving 103,793 participants, indicated a significant reduction in stroke risk for individuals treated with dihydropyridine CCBs compared to those receiving non-dihydropyridine CCBs or other antihypertensive drugs. The associated meta-regression analysis revealed that the decrease in stroke risk attributed to dihydropyridine CCBs is independent of the extent of systolic blood pressure reduction. This decrease might be partially due to the potential neuroprotective and preventive effects of CCBs on the progression of carotid atherosclerosis. In addition, dihydropyridine CCBs, such as benidipine, are also known to inhibit the production of reactive oxygen species derived from polymorphonuclear leukocytes in high-salt-loaded spontaneously hypertensive rats. This inhibition is facilitated by their antioxidant capacity and the ability to suppress the Ca2⁺/protein kinase C/nicotinamide adenine dinucleotide phosphate (NADPH) oxidase signaling pathway [110]. Our study also verified that CCBs were more effective than placebos, BBs, ACEIs, and ARBs in preventing strokes in the overall population. Conversely, when specifically examining hypertensive patients, CCBs demonstrated comparable effects to diuretics, ACEIs, and ARBs in terms of both all-cause mortality and strokes. Moreover, our findings indicate that, among the different subclasses of CCBs, only the dihydropyridine subclass showed effectiveness in preventing stroke, all-cause mortality, and cardiovascular mortality compared to both placebos and BBs. Additionally, the dihydropyridine subclass demonstrated superior efficacy in preventing cardiovascular mortality compared to the verapamil subclass.

Thiazide diuretics, including thiazide-type (chlorothiazide, hydrochlorothiazide, bendroflumethiazide, trichlormethiazide, and bendrofluazide) and thiazide-like diuretics (indapamide and chlorthalidone), have been used to treat hypertension for over five decades. Chen et al. conducted a 2015 meta-analysis to investigate the cardioprotective effects of thiazide diuretics, including thiazide-type and thiazide-like diuretics, in hypertensive patients. The authors reported that diuretics were associated with reduced risks of cardiovascular diseases and heart failure but showed no significant differences in stroke risk when compared to the control group [111]. However, Wright et al.’s (2018) meta-analysis showed that first-line low-dose thiazides were effective in reducing the risk of mortality, stroke, and heart attack compared to control group [112]. Thomopoulos et al.’s meta-analysis revealed that diuretics were more effective than placebos and RAS blockers in preventing strokes [105]. Our study also confirmed that diuretics exhibited superior efficacy compared to placebos, BBs, ACEIs, and ARBs in preventing strokes in the overall population. However, in the specific examination of hypertensive patients, diuretics demonstrated similar effects to CCBs, ACEIs, and ARBs in terms of both all-cause mortality and strokes. Moreover, in subgroup analyses conducted within the diuretic class, the subclass of thiazide-type diuretics exhibited no efficacy in preventing all-cause mortality.

For more than four decades, beta blockers (BBs) have served as the standard hypertension treatment. However, recent evidence suggests that their effectiveness as a first-line therapy is debatable, as they have not demonstrated sufficient cardiovascular protection in randomized placebo-controlled trials. According to Wiysonge et al.’s (2017) Cochrane systematic review, first-line BBs modestly reduce stroke in hypertensive individuals, but are not associated with significant effects on total mortality or coronary heart disease. Additionally, their efficacy at stroke prevention is less notable than CCBs and renin-angiotensin system inhibitors [113]. Furthermore, Thomopoulos et al. (2020) conducted a meta-analysis which demonstrated that BBs are less effective than other antihypertensive drugs in preventing stroke and all-cause mortality across all trials, as well as trials conducted exclusively among hypertensive patients [114]. Our study also presents evidence indicating that BBs were ineffective in preventing stroke, all-cause mortality, and cardiovascular mortality among both the overall population and hypertensive patients.

Drug combinations are recommended in hypertension guidelines for most patients due to their superior blood pressure lowering effect compared to monotherapy. Thomopoulos et al.’s meta-analysis revealed that antihypertensive treatments based on two or more drugs are associated with a reduction in the risk of all or most hypertension-related outcomes compared with simpler treatment regimens [115]. Zhong et al. concluded that diuretics, CCBs, and ARBs, either alone or in combination, can be considered as first-line treatments for stroke prevention [6]. Our study has confirmed that combining ACEI and CCB can provide additional benefits for stroke prevention, reducing the risk of all-cause mortality more effectively than other antihypertensive medications used alone.

Strengths and limitations

Our analysis was different in many aspects from other meta-analyses. First, we employed a refined classification of antihypertensive medications to assess the effectiveness of all available antihypertensive agents. For example, we clearly distinguished conventional therapy, nonRASI treatment, and nonBB treatment, instead of grouping these treatments together as a control. Second, we further analysed differences in the effectiveness between subgroups of calcium channel blockers and between subgroups of thiazide diuretics. Third, we not only compared the effects of monotherapy with different classes of antihypertensive drugs on preventing stroke events but also examined the effects of combination therapy with different classes of antihypertensive drugs on preventing stroke events.

There are several limitations in this network meta-analysis. First, the approach to antihypertensive treatment has evolved in response to changing perspectives on hypertension over the last three decades. Differences have been noted in the types of antihypertensive medications, their dosages, and the therapeutic goals for stroke prevention in older versus more recent trials. However, the scarcity of information on this particular aspect in clinical trials limits the comparative analysis of older and newer trials. Second, most of the comparison arms in our network had only one trial connecting them; more studies in the future would lead to more precise and accurate estimates. Third, due to the limited information, we did not perform further analysis to compared the effects of antihypertensive drugs according to gender, race. Forth, no comparison between patients with and without diabetes or with and without hyperlipidemia was possible for the different drug classes since insufficient data were available in each drug class for patients with diabetes or hyperlipidemia.

Conclusions

In conclusion, the current evidence demonstrated that ACEIs, dihydropyridine CCBs, and thiazide-like diuretics may provide superior prevention against stroke, all-cause mortality, and cardiovascular mortality in patients with hypertension. The combination of ACEIs and CCBs may provide enhanced protection of stroke than ACEIs or ARBs monotherapy. The results of this study may help physicians determine the best treatment options for their hypertensive patients for stroke prevention.

Supporting information

S1 PRISMA NMA checklist. Search strategy.

https://doi.org/10.1371/journal.pone.0313309.s001

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S1 Table. Search strategy.

https://doi.org/10.1371/journal.pone.0313309.s002

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S2 Table. Model fit statistics.

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S3 Table. Node-splitting results for stroke in the overall population.

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S4 Table. Node-splitting results for all-cause mortality in the overall population.

https://doi.org/10.1371/journal.pone.0313309.s005

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S5 Table. Node-splitting results for cardiovascular mortality in the overall population.

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S6 Table. Node-splitting results for stroke in hypertensive patients.

https://doi.org/10.1371/journal.pone.0313309.s007

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S7 Table. Node-splitting results for all-cause mortality in hypertensive patients.

https://doi.org/10.1371/journal.pone.0313309.s008

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S8 Table. Node-splitting results for cardiovascular mortality in hypertensive patients.

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S9 Table. Node-splitting results for subgroup analysis of stroke in hypertensive patients.

https://doi.org/10.1371/journal.pone.0313309.s010

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S10 Table. Node-splitting results for subgroup analysis of all-cause mortality in hypertensive patients.

https://doi.org/10.1371/journal.pone.0313309.s011

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S11 Table. Node-splitting results for subgroup analysis of cardiovascular mortality in hypertensive patients.

https://doi.org/10.1371/journal.pone.0313309.s012

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S12 Table. Outcomes of CINeMA evaluation regarding the outcome of stroke in the overall population.

https://doi.org/10.1371/journal.pone.0313309.s013

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S13 Table. Outcomes of CINeMA evaluation regarding the outcome of all-cause mortality in the overall population.

https://doi.org/10.1371/journal.pone.0313309.s014

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S14 Table. Outcomes of CINeMA evaluation regarding the outcome of cardiovascular mortality in the overall population.

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S15 Table. Outcomes of CINeMA evaluation regarding the outcome of stroke in hypertensive patients.

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S16 Table. Outcomes of CINeMA evaluation regarding the outcome of all-cause mortality in hypertensive patients.

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S17 Table. Outcomes of CINeMA evaluation regarding the outcome of cardiovascular mortality in hypertensive patients.

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S18 Table. Reasons for downgrading the confidence in the results.

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S19 Table. Relative risk [RR] with 95% CrI for stroke of the overall population.

https://doi.org/10.1371/journal.pone.0313309.s020

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S20 Table. Relative risk [RR] with 95% CrI for stroke of hypertensive patients.

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S21 Table. Relative risk [RR] with 95% CrI for subgroup analysis of stroke among hypertensive patients.

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S22 Table. Relative risk [RR] with 95% CrI for all-cause mortality of the overall population.

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S23 Table. Relative risk [RR] with 95% CrI for all-cause mortality of hypertensive patients.

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S24 Table. Relative risk [RR] with 95% CrI for subgroup analysis of all-cause mortality among hypertensive patients.

https://doi.org/10.1371/journal.pone.0313309.s025

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S25 Table. Relative risk [RR] with 95% CrI for cardiovascular mortality of the overall population.

https://doi.org/10.1371/journal.pone.0313309.s026

(DOCX)

S26 Table. Relative risk [RR] with 95% CrI for cardiovascular mortality of hypertensive patients.

https://doi.org/10.1371/journal.pone.0313309.s027

(DOCX)

S27 Table. Relative risk [RR] with 95% CrI for subgroup analysis of cardiovascular mortality among hypertensive patients.

https://doi.org/10.1371/journal.pone.0313309.s028

(DOCX)

S28 Table. Studies included and excluded.

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S29 Table. Risk of bias for each study.

https://doi.org/10.1371/journal.pone.0313309.s030

(XLS)

S30 Table. Raw data used in current meta-analysis.

https://doi.org/10.1371/journal.pone.0313309.s031

(XLS)

S1 Fig. Risk of bias summary for RCTs.

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(DOCX)

S2 Fig. Risk of bias graph for RCTs.

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S3 Fig. Comparison-adjusted funnel plots regarding the outcome of stroke in the overall population.

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S4 Fig. Comparison-adjusted funnel plots regarding the outcome of stroke in hypertensive patients.

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S5 Fig. Comparison-adjusted funnel plots regarding the outcome of subgroup analysis of stroke in hypertensive patients.

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(DOCX)

S6 Fig. Comparison-adjusted funnel plots regarding the outcome of all-cause mortality in the overall population.

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S7 Fig. Comparison-adjusted funnel plots regarding the outcome of all-cause mortality in hypertensive patients.

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S8 Fig. Comparison-adjusted funnel plots regarding the outcome of subgroup analysis of all-cause mortality in hypertensive patients.

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S9 Fig. Comparison-adjusted funnel plots regarding the outcome of cardiovascular mortality in the overall population.

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S10 Fig. Comparison-adjusted funnel plots regarding the outcome of cardiovascular mortality in hypertensive patients.

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(DOCX)

S11 Fig. Comparison-adjusted funnel plots regarding the outcome of subgroup analysis of cardiovascular mortality in hypertensive patients.

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(DOCX)

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