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      Beta-blockers for hypertension

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          Abstract

          Background

          Beta-blockers refer to a mixed group of drugs with diverse pharmacodynamic and pharmacokinetic properties. They have shown long-term beneficial effects on mortality and cardiovascular disease (CVD) when used in people with heart failure or acute myocardial infarction. Beta-blockers were thought to have similar beneficial effects when used as first-line therapy for hypertension. However, the benefit of beta-blockers as first-line therapy for hypertension without compelling indications is controversial. This review is an update of a Cochrane Review initially published in 2007 and updated in 2012.

          Objectives

          To assess the effects of beta-blockers on morbidity and mortality endpoints in adults with hypertension.

          Search methods

          The Cochrane Hypertension Information Specialist searched the following databases for randomized controlled trials up to June 2016: the Cochrane Hypertension Specialised Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (2016, Issue 6), MEDLINE (from 1946), Embase (from 1974), and ClinicalTrials.gov. We checked reference lists of relevant reviews, and reference lists of studies potentially eligible for inclusion in this review, and also searched the the World Health Organization International Clinical Trials Registry Platform on 06 July 2015.

          Selection criteria

          Randomised controlled trials (RCTs) of at least one year of duration, which assessed the effects of beta-blockers compared to placebo or other drugs, as first-line therapy for hypertension, on mortality and morbidity in adults.

          Data collection and analysis

          We selected studies and extracted data in duplicate, resolving discrepancies by consensus. We expressed study results as risk ratios (RR) with 95% confidence intervals (CI) and conducted fixed-effect or random-effects meta-analyses, as appropriate. We also used GRADE to assess the certainty of the evidence. GRADE classifies the certainty of evidence as high (if we are confident that the true effect lies close to that of the estimate of effect), moderate (if the true effect is likely to be close to the estimate of effect), low (if the true effect may be substantially different from the estimate of effect), and very low (if we are very uncertain about the estimate of effect).

          Main results

          Thirteen RCTs met inclusion criteria. They compared beta-blockers to placebo (4 RCTs, 23,613 participants), diuretics (5 RCTs, 18,241 participants), calcium-channel blockers (CCBs: 4 RCTs, 44,825 participants), and renin-angiotensin system (RAS) inhibitors (3 RCTs, 10,828 participants). These RCTs were conducted between the 1970s and 2000s and most of them had a high risk of bias resulting from limitations in study design, conduct, and data analysis. There were 40,245 participants taking beta-blockers, three-quarters of them taking atenolol. We found no outcome trials involving the newer vasodilating beta-blockers (e.g. nebivolol).

          There was no difference in all-cause mortality between beta-blockers and placebo (RR 0.99, 95% CI 0.88 to 1.11), diuretics or RAS inhibitors, but it was higher for beta-blockers compared to CCBs (RR 1.07, 95% CI 1.00 to 1.14). The evidence on mortality was of moderate-certainty for all comparisons.

          Total CVD was lower for beta-blockers compared to placebo (RR 0.88, 95% CI 0.79 to 0.97; low-certainty evidence), a reflection of the decrease in stroke (RR 0.80, 95% CI 0.66 to 0.96; low-certainty evidence) since there was no difference in coronary heart disease (CHD: RR 0.93, 95% CI 0.81 to 1.07; moderate-certainty evidence). The effect of beta-blockers on CVD was worse than that of CCBs (RR 1.18, 95% CI 1.08 to 1.29; moderate-certainty evidence), but was not different from that of diuretics (moderate-certainty) or RAS inhibitors (low-certainty). In addition, there was an increase in stroke in beta-blockers compared to CCBs (RR 1.24, 95% CI 1.11 to 1.40; moderate-certainty evidence) and RAS inhibitors (RR 1.30, 95% CI 1.11 to 1.53; moderate-certainty evidence). However, there was little or no difference in CHD between beta-blockers and diuretics (low-certainty evidence), CCBs (moderate-certainty evidence) or RAS inhibitors (low-certainty evidence). In the single trial involving participants aged 65 years and older, atenolol was associated with an increased CHD incidence compared to diuretics (RR 1.63, 95% CI 1.15 to 2.32). Participants taking beta-blockers were more likely to discontinue treatment due to adverse events than participants taking RAS inhibitors (RR 1.41, 95% CI 1.29 to 1.54; moderate-certainty evidence), but there was little or no difference with placebo, diuretics or CCBs (low-certainty evidence).

          Authors' conclusions

          Most outcome RCTs on beta-blockers as initial therapy for hypertension have high risk of bias. Atenolol was the beta-blocker most used. Current evidence suggests that initiating treatment of hypertension with beta-blockers leads to modest CVD reductions and little or no effects on mortality. These beta-blocker effects are inferior to those of other antihypertensive drugs. Further research should be of high quality and should explore whether there are differences between different subtypes of beta-blockers or whether beta-blockers have differential effects on younger and older people.

          Beta-blockers for hypertension

          What is the aim of this review?

          The aim of this Cochrane Review was to assess whether beta-blockers decrease the number of deaths, strokes, and heart attacks associated with high blood pressure in adults. We collected and analysed all relevant studies to answer this question and found 13 relevant studies.

          Are beta-blockers as good as other medicines when used for treatment of adults with high blood pressure?

          Beta-blockers were not as good at preventing the number of deaths, strokes, and heart attacks as other classes of medicines such as diuretics, calcium-channel blockers, and renin-angiotensin system inhibitors. Most of these findings come from one type of beta-blocker called atenolol. However, beta-blockers are a diverse group of medicines with different properties, and we need more well-conducted research in this area.

          What was studied in the review?

          Millions of people with high blood pressure have strokes, heart attacks, and other diseases, and many of them die. This situation could be prevented with appropriate treatment. Researchers have tried different medicines for treating high blood pressure.

          What are the main results of the review?

          We found 13 studies from high-income countries, mainly Western Europe and North America. In the studies, the people receiving beta-blockers were compared to people who received no treatment or other medicines. The studies showed the following.

          Beta-blockers probably make little or no difference in the number of deaths among people on treatment for high blood pressure. This effect appears to be similar to that of diuretics and renin-angiotensin system inhibitors, but beta-blockers are probably not as good at preventing deaths from high blood pressure as calcium-channel blockers.

          Beta-blockers may reduce the number of strokes, an effect which appears to be similar to that of diuretics. However, beta-blockers may not be as good at preventing strokes as renin-angiotensin system inhibitors or calcium-channel blockers.

          Beta-blockers may make little or no difference to the number of heart attacks among people with high blood pressure. The evidence suggests that this effect may not be different from that of diuretics, renin-angiotensin system inhibitors, or calcium-channel blockers. However, among people aged 65 years and older, the evidence suggests that beta-blockers may not be as good at reducing heart attacks as diuretics.

          People given beta-blockers are more likely to have side effects and stop treatment than people taking renin-angiotensin system inhibitors, but there may be little or no difference in side effects between beta-blockers and diuretics or calcium-channel blockers.

          How up-to-date is this review?

          The review authors searched for studies that had been published up to June 2016.

          Related collections

          Most cited references159

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          The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial.

          In patients with heart failure, beta-blockade has improved morbidity and left-ventricular function, but the impact on survival is uncertain. We investigated the efficacy of bisoprolol, a beta1 selective adrenoceptor blocker in decreasing all-cause mortality in chronic heart failure. In a multicentre double-blind randomised placebo-controlled trial in Europe, we enrolled 2647 symptomatic patients in New York Heart Association class III or IV, with left-ventricular ejection fraction of 35% or less receiving standard therapy with diuretics and inhibitors of angiotensin-converting enzyme. We randomly assigned patients bisoprolol 1.25 mg (n=1327) or placebo (n=1320) daily, the drug being progressively increased to a maximum of 10 mg per day. Patients were followed up for a mean of 1.3 years. Analysis was by intention to treat. CIBIS-II was stopped early, after the second interim analysis, because bisoprolol showed a significant mortality benefit. All-cause mortality was significantly lower with bisoprolol than on placebo (156 [11.8%] vs 228 [17.3%] deaths with a hazard ratio of 0.66 (95% CI 0.54-0.81, p<0.0001). There were significantly fewer sudden deaths among patients on bisoprolol than in those on placebo (48 [3.6%] vs 83 [6.3%] deaths), with a hazard ratio of 0.56 (0.39-0.80, p=0.0011). Treatment effects were independent of the severity or cause of heart failure. Beta-blocker therapy had benefits for survival in stable heart-failure patients. Results should not, however, be extrapolated to patients with severe class IV symptoms and recent instability because safety and efficacy has not been established in these patients.
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            Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol Or Metoprolol European Trial (COMET): randomised controlled trial.

            Beta blockers reduce mortality in patients who have chronic heart failure, systolic dysfunction, and are on background treatment with diuretics and angiotensin-converting enzyme inhibitors. We aimed to compare the effects of carvedilol and metoprolol on clinical outcome. In a multicentre, double-blind, and randomised parallel group trial, we assigned 1511 patients with chronic heart failure to treatment with carvedilol (target dose 25 mg twice daily) and 1518 to metoprolol (metoprolol tartrate, target dose 50 mg twice daily). Patients were required to have chronic heart failure (NYHA II-IV), previous admission for a cardiovascular reason, an ejection fraction of less than 0.35, and to have been treated optimally with diuretics and angiotensin-converting enzyme inhibitors unless not tolerated. The primary endpoints were all-cause mortality and the composite endpoint of all-cause mortality or all-cause admission. Analysis was done by intention to treat. The mean study duration was 58 months (SD 6). The mean ejection fraction was 0.26 (0.07) and the mean age 62 years (11). The all-cause mortality was 34% (512 of 1511) for carvedilol and 40% (600 of 1518) for metoprolol (hazard ratio 0.83 [95% CI 0.74-0.93], p=0.0017). The reduction of all-cause mortality was consistent across predefined subgroups. The composite endpoint of mortality or all-cause admission occurred in 1116 (74%) of 1511 on carvedilol and in 1160 (76%) of 1518 on metoprolol (0.94 [0.86-1.02], p=0.122). Incidence of side-effects and drug withdrawals did not differ by much between the two study groups. Our results suggest that carvedilol extends survival compared with metoprolol.
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              Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: results from the AASK trial.

              Hypertension is a leading cause of end-stage renal disease (ESRD) in the United States, with no known treatment to prevent progressive declines leading to ESRD. To compare the effects of 2 levels of blood pressure (BP) control and 3 antihypertensive drug classes on glomerular filtration rate (GFR) decline in hypertension. Randomized 3 x 2 factorial trial with enrollment from February 1995 to September 1998. A total of 1094 African Americans aged 18 to 70 years with hypertensive renal disease (GFR, 20-65 mL/min per 1.73 m(2)) were recruited from 21 clinical centers throughout the United States and followed up for 3 to 6.4 years. Participants were randomly assigned to 1 of 2 mean arterial pressure goals, 102 to 107 mm Hg (usual; n = 554) or 92 mm Hg or less (lower; n = 540), and to initial treatment with either a beta-blocker (metoprolol 50-200 mg/d; n = 441), an angiotensin-converting enzyme inhibitor (ramipril 2.5-10 mg/d; n = 436) or a dihydropyridine calcium channel blocker, (amlodipine 5-10 mg/d; n = 217). Open-label agents were added to achieve the assigned BP goals. Rate of change in GFR (GFR slope); clinical composite outcome of reduction in GFR by 50% or more (or > or =25 mL/min per 1.73 m2) from baseline, ESRD, or death. Three primary treatment comparisons were specified: lower vs usual BP goal; ramipril vs metoprolol; and amlodipine vs metoprolol. Achieved BP averaged (SD) 128/78 (12/8) mm Hg in the lower BP group and 141/85 (12/7) mm Hg in the usual BP group. The mean (SE) GFR slope from baseline through 4 years did not differ significantly between the lower BP group (-2.21 [0.17] mL/min per 1.73 m2 per year) and the usual BP group (-1.95 [0.17] mL/min per 1.73 m2 per year; P =.24), and the lower BP goal did not significantly reduce the rate of the clinical composite outcome (risk reduction for lower BP group = 2%; 95% confidence interval [CI], -22% to 21%; P =.85). None of the drug group comparisons showed consistent significant differences in the GFR slope. However, compared with the metoprolol and amlodipine groups, the ramipril group manifested risk reductions in the clinical composite outcome of 22% (95% CI, 1%-38%; P =.04) and 38% (95% CI, 14%-56%; P =.004), respectively. There was no significant difference in the clinical composite outcome between the amlodipine and metoprolol groups. No additional benefit of slowing progression of hypertensive nephrosclerosis was observed with the lower BP goal. Angiotensin-converting enzyme inhibitors appear to be more effective than beta-blockers or dihydropyridine calcium channel blockers in slowing GFR decline.
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                Author and article information

                Journal
                Cochrane Database Syst Rev
                Cochrane Database Syst Rev
                cd
                The Cochrane Database of Systematic Reviews
                John Wiley & Sons, Ltd (Chichester, UK )
                1469-493X
                20 January 2017
                : 1
                : CD002003
                Affiliations
                [1 ]Cochrane South Africa, South African Medical Research Council Cape Town, South Africa
                [2 ]Centre for Evidence-based Health Care, Faculty of Medicine and Health Sciences, Stellenbosch University Cape Town, South Africa
                [3 ]School of Public Health, University of the Western Cape Cape Town, South Africa
                [4 ]Department of Medicine, J Floor, Old Groote Schuur Hospital Cape Town, South Africa
                [5 ]Hatter Cardiovascular Research Institute, Medical School Cape Town, South Africa
                Author notes
                Cochrane South Africa, South African Medical Research Council, Francie van Zijl Drive , Parow Valley, Cape Town, Western Cape, 7505, South Africa. charles.wiysonge@ 123456mrc.ac.za wiysonge@ 123456yahoo.com .
                Article
                10.1002/14651858.CD002003.pub5
                5369873
                28107561
                f706f0b2-926f-46d8-9981-d081717fd73b
                Copyright © 2016 The Authors. Cochrane Database of Systematic Reviews published by John Wiley & Sons, Ltd. on behalf of The Cochrane Collaboration.

                This is an open access article under the terms of the Creative Commons Attribution-Non-Commercial-No-Derivatives Licence, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

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