Research Article
Comparative efficacy of β-blockers on mortality and cardiovascular outcomes in patients with hypertension: a systematic review and network meta-analysis

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Highlights

  • Lipophilic β-blockers showed a significant reduction for the risk of cardiovascular mortality (odds ratio [OR] 0.72, 95% confidence interval [CI] [0.54–0.97]) compared with hydrophilic β-blocker.

  • Lipophilic β-blockers showed a significant reduction in the risk of stroke (OR 0.63, 95% CI [0.41–0.99]) compared with hydrophilic β-blocker in patients aged <65 years.

  • Lipophilic β-blockers showed decreased trend for the risk of all-cause mortality (OR 0.86, 95% CI [0.72-1.03]) and coronary heart disease (OR 0.88, 95% CI [0.64-1.23]).

  • Lipophilic β-blockers could reduce cardiovascular death and the risk of stroke. The differential effects of hydrophilic and lipophilic β-blockers may be related to their lipophilicity.

Abstract

The differential efficacy of lipophilic and hydrophilic β-blockers on clinical outcomes has not been investigated. We sought to compare the effects of lipophilic and hydrophilic β-blockers on mortality and cardiovascular outcomes by conducting a comprehensive systematic review and network meta-analysis. MEDLINE/PubMed, EMBASE, and the Cochrane Database were searched for all dates to January 5, 2015, for randomized trials with comparisons between all β-blockers or between β-blockers and other antihypertensive agents. Mortality and cardiovascular outcomes were also reported. Characteristics of each study and associated clinical outcomes were extracted, including all-cause mortality, coronary heart disease, stroke, and cardiovascular death. Thirteen trials with 90,935 participants were included, focusing on lipophilic β-blockers (metoprolol, propranolol, and oxprenolol) and a hydrophilic β-blocker (atenolol). In this review, lipophilic β-blockers showed a significant reduction for the risk of cardiovascular mortality (odds ratio [OR] 0.72, 95% confidence interval [CI; 0.54–0.97]) compared with hydrophilic β-blocker, and lipophilic β-blockers showed decreased trend for the risk of all-cause mortality (OR 0.86, 95% CI [0.72–1.03]) and coronary heart disease (OR 0.88, 95% CI [0.64–1.23]). When the risk of stroke was evaluated using age stratification, lipophilic β-blockers showed a significant reduction in the risk of stroke (OR 0.63, 95% CI [0.41–0.99]) compared with hydrophilic β-blocker in patients aged <65 years.

Introduction

β-Blockers have been used for hypertension treatment for decades because of their antihypertension and long-term beneficial effects on all-cause and cardiovascular mortalities.1, 2, 3 However, recent studies have found that β-blockers are less effective in reducing the incidence of stroke4 and the composite of major cardiovascular outcomes, including stroke, myocardial infarction, and death, compared with other antihypertensive drugs.5 A meta-analysis has shown that β-blockers are associated with modest reductions in cardiovascular disease, yet had no significant benefit on mortality. The study also demonstrated there was no difference between cardioselective and nonselective β-blockers in the treatment of hypertension and cardiovascular outcomes.6 Studies, however, have shown that β-blockers with moderate-to-high lipophilicity decrease mortality in coronary heart disease, all-cause mortality, and sudden cardiac death.7 The results of a recent meta-analysis demonstrated that atenolol (a hydrophilic β-blocker) was associated with an increased risk of stroke in the elderly, whereas lipophilic β-blockers, mainly metoprolol and propranolol (with moderate-to-high lipophilicity) did not increase the risk of stroke in this population.8 Furthermore, drugs with high lipophilicity may penetrate the brain and cell membrane more easily, which may help to prevent stroke and cardiac death, indicating that β-blockers with moderate-to-high lipophilicity could have a greater impact on clinical outcomes than hydrophilic β-blocker. However, there are no clinical studies or meta-analyses to directly compare the effects of lipophilic and hydrophilic β-blockers on clinical outcomes in hypertensive patients. A network meta-analysis could evaluate the comparative efficacy of different treatments that have or have not been compared directly with each other in head-to-head comparisons, provided all treatments under investigation are linked to a network of evidence. In this review, we sought to use a network meta-analysis to compare the efficacy of lipophilic β-blockers (metoprolol, propranolol, and oxprenolol) and hydrophilic β-blocker (atenolol) on clinical outcomes, including all-cause mortality, coronary heart disease, stroke, and cardiogenic mortality, in hypertensive patients.

Section snippets

Methods

This study was conducted according to the Cochrane Collaboration and Preferred Reporting Items for Systematic Reviews and Meta-Analyses statements.9

Network of Evidence

The literature search identified 8886 publications (2991 from MEDLINE/PubMed, 1599 from EMBASE, and 4296 from the Cochrane Database). After excluding duplicates and additional articles after review of the title or abstract, the meta-analysis included 13 hypertension studies and a total of 90,935 participants (Figure 1). The primary network of evidence is detailed in Figure 2. The characteristics of the eligible studies and the detailed results of each study are summarized in Table 1, Table 2.

Discussion

This was the first network meta-analysis to compare the lipophilic and hydrophilic β-blockers for the protective effects on all-cause mortality, stroke, cardiovascular death, and coronary heart disease. Lipophilic β-blockers were associated with less cardiovascular death than hydrophilic β-blocker. After an adjustment in baseline blood pressure, hydrophilic β-blocker was also associated with a trend to increase the risk of cardiovascular death compared with lipophilic β-blockers. Lipophilic

Conclusions

Beta-blockers play a crucial role in the management of essential hypertension. Our analysis demonstrated that compared with hydrophilic β-blocker, lipophilic β-blockers could reduce cardiovascular death and the risk of stroke. The differential effects of hydrophilic and lipophilic β-blockers may be related to their lipophilicity. Taken together, the results suggest that lipophilicity may be the important factor for the efficacy of β-blockers on clinical outcomes. Additional studies are needed

Acknowledgments

The authors thank all the staff who participated in this study.

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    Yuqing Zhang and Ningling Sun are co-first authors.

    Conflict of interest: This work was supported by AstraZeneca (China).

    Grant Support: This meta-analysis was supported by AstraZeneca.

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