Metoprolol Associated with Lower Rates of Major CV Events in POISE Trial for High Risk Patients Undergoing Noncardiac Surgery

Metoprolol Associated with Lower Rates of Major CV Events in POISE Trial for High Risk Patients Undergoing Noncardiac Surgery


Originally presented at AHA Scientific Sessions 2007 by Dr. P.J. Deveraux.


November 7, 2007 By Scott P. Williams [1]


Orlando, FL: The results of the POISE trial indicate that, when compared to placebo, treatment of patients with the beta-blocker metoprolol prior to and following non-cardiac surgery is associated with a reduced occurrence rate of major cardiovascular events at 30 days. The results were released today for the American Heart Association’s Scientific Sessions.


The POISE study enrolled patients over the age of 45 (mean=69 years old), who were undergoing non-cardiac surgery which would require a hospital stay of 24 hours or longer. To be included in the study patients also had to be considered at high risk for a cardiovascular event, which was defined by the patient meeting at least one of the following criteria: 1.) Coronary artery disease (43% of patients) 2.) Peripheral vascular disease (41% of patients) 3.) History of stroke due to atherothrombotic disease (15% of patients) 4.) Hospitalization for congestive heart failure within 3 years of randomization 5.) Undergoing major vascular surgery 6.) 3 of 7 other high risk criteria


Prior to surgery patients were randomized in a double-blind, 1:1 manner to receive either metorpolol (n=4174) or placebo (n=4177). The metoprolol group of patients received two 100 mg controlled release doses of metoprolol (one dose 2-4 hours pre-surgery and the other 0-6 hours post-surgery), followed by daily 200 mg doses for the next 30 days. 42% of the study patients underwent a vascular procedure, 22% an intraperitoneal procedure, 21% an orthopedic procedure, and 15% underwent an additional form of surgery.


The occurrence of at least one of three major cardiovascular events (major cardiovascular death, nonfatal myocardial infarction, and nonfatal cardiac arrest) served as the POISE trial’s primary endpoint. 6.9% of the patients who received placebo suffered a major cardiovascular event, compared to only 5.8% of the patients who received metoprolol (p=0.04). Additionally, the group of patients who received metoprolol displayed lower occurrence for revascularization (0.3% vs. 0.6%, p=0.01) and atrial fibrillation (2.2% vs. 2.9%, p=0.04).


These positive benefits displayed by the metoprolol group were offset by increased rates of total mortality (3.1% vs. 2.3%, p=0.03), stroke (1.0% vs. 0.5%, p=0.005), hypotension (15.0% vs. 9.7%, p<0.0001), and significant bradycardia (6.6% vs. 2.4%, p<0.0001) among this same group of patients. The increase in the rates of hypotension and bradycardia due to the use of metoprolol displayed in the POISE trial are similar to the results of the MaVS and DIPOM trials. Unlike the POISE trial the patients treated with metoprolol in the MaVS and DIPOM trials displayed no benefit with regard to clinical events.


Overall, metoprolol treatment was associated with a reduction in the rate of major cardiovascular events among the patients, but the increase in the overall mortality, stroke, significant hypotension, and significant bradycardia rates suggest that routine of the drug may not be the best way to reduce cardiovascular events in high risk patients.


The trial was sponsored by AstraZeneca.

Are Beta Blockers Effective First-line Treatments for Hypertension?

Are Beta Blockers Effective First-line Treatments for Hypertension?


Cochrane for Clinicians


Putting Evidence into Practice



WILLIAM E. CAYLEY, JR., md, University of Wisconsin Eau Claire Family Medicine Residency, Eau Claire, Wisconsin


Cochrane Abstract


Background: Two recent systematic reviews found first-line beta blockers to be less effective in reducing the incidence of stroke and the combined end point of stroke, myocardial infarction, and death compared with all other antihypertensive drugs taken together. However, beta blockers might be better or worse than a specific class of drugs for a particular outcome measure; therefore, comparing beta blockers with all other classes taken together could be misleading. In addition, these systematic reviews did not assess the tolerability of beta blockers relative to other antihypertensive medications. Thus, we undertook this review to reassess the place of beta blockers as first-line therapy for hypertension compared with other major classes of antihypertensive drugs.


Objectives: To quantify the effectiveness and safety of beta blockers on morbidity and mortality end points in adults with hypertension.



Search Strategy: We searched eligible studies up to June 2006 in the Cochrane Controlled Trials Register, Medline, Embase, and reference lists of previous reviews, and by contacting hypertension experts.


Selection Criteria: We selected randomized controlled trials (RCTs) that assessed the effects of beta blockers compared with placebo, no therapy, or other drug classes (as monotherapy or first-line therapy for hypertension) on mortality and morbidity end points in men and nonpregnant women 18 years or older.


Data Collection and Analysis: At least two authors independently applied study selection criteria, assessed study quality, and extracted data; differences were resolved by consensus. We expressed study results as relative risks (RRs) with 95% confidence intervals (CIs), and conducted quantitative analyses with trial participants in groups to which they were randomly allocated, regardless of which or how much treatment they actually received. In the absence of significant heterogeneity among studies (P > .1), we performed a meta-analysis using a fixed-effects method. Otherwise, we used the random-effects method and investigated the cause of heterogeneity by stratified analysis. In addition, we used the Higgins statistic (I2) to quantify the amount of between-study variability in effect attributable to true heterogeneity rather than chance.


Main Results: Thirteen RCTs (n = 91,561) that met our inclusion criteria compared beta blockers with placebo or no treatment (four trials with 23,613 participants), diuretics (five trials with 18,241 participants), calcium channel blockers (four trials with 44,825 participants), and renin-angiotensin system (RAS) inhibitors (three trials with 10,828 participants). The risk of all-cause mortality was not different between first-line beta blockers and placebo (RR = 0.99; 95% CI, 0.88 to 1.11; I2 = 0 percent); diuretics; or RAS inhibitors, but the risk was higher for beta blockers compared with calcium channel blockers (RR = 1.07; 95% CI, 1.00 to 1.14; I2 = 2.2%; absolute risk increase [ARI] = 0.5 percent; number needed to harm [NNH] = 200).

The risk of total cardiovascular disease was lower for first-line beta blockers compared with placebo (RR = 0.88; 95% CI, 0.79 to 0.97;I2 = 21.4 percent; absolute risk reduction [ARR] = 0.7 percent; number needed to treat [NNT] = 140). This is primarily a reflection of the significant decrease in stroke (RR = 0.80; 95% CI, 0.66 to 0.96; I2 = 0 percent; ARR = 0.5 percent; NNT = 200). Coronary heart disease risk was not significantly different between beta blockers and placebo. The effect of beta blockers on cardiovascular disease was significantly worse than that of calcium channel blockers (RR = 1.18; 95% CI, 1.08 to 1.29; I2 = 0 percent; ARI = 1.3 percent; NNH = 80) but was not significantly different from that of diuretics or RAS inhibitors. Increased total cardiovascular disease was caused by an increase in stroke compared with calcium channel blockers (RR = 1.24; 95% CI, 1.11 to 1.40; I2 = 0 percent; ARI = 0.6 percent; NNH = 180). There was also an increase in stroke with beta blockers compared with RAS inhibitors (RR = 1.30; 95% CI, 1.11 to 1.53; I2 = 29.1 percent; ARI = 1.5 percent; NNH = 65).

Coronary heart disease risk was not significantly different between beta blockers and diuretics or calcium channel blockers or RAS inhibitors. In addition, patients taking beta blockers were more likely to discontinue treatment because of adverse effects than those taking diuretics (RR = 1.86; 95% CI, 1.39 to 2.50; I2 = 78.2 percent; ARI = 6.4 percent; NNH = 16) or RAS inhibitors (RR = 1.41; 95% CI, 1.29 to 1.54; I2 = 12.1 percent; ARI = 5.5 percent; NNH=18); there was no significant difference between beta blockers and calcium channel blockers.


Authors' conclusions: The available evidence does not support the use of beta blockers as first-line drugs in the treatment of hypertension. This conclusion is based on the relatively weak effect of beta blockers to reduce stroke and the absence of an effect on coronary heart disease when compared with placebo or no treatment. More importantly, it is based on the trend towards worse outcomes compared with calcium channel blockers, RAS inhibitors, and thiazide diuretics. Most of the evidence for these conclusions comes from trials in which atenolol (Tenormin) was the beta blocker used (75 percent of participants taking beta blockers in this review). However, it is not known whether beta blockers have differential effects on younger and older patients or whether there are differences among the subtypes of beta blockers.

A Meta-Analysis of 94,492 Patients With Hypertension Treated With Beta Blockers to Determine the Risk of New-Onset Diabetes Mellitus

A Meta-Analysis of 94,492 Patients With Hypertension Treated With Beta Blockers to Determine the Risk of New-Onset Diabetes Mellitus


The American Journal of Medicine


Volume 100, Issue 8, Pages 1254-1262 (15 October 2007)


Sripal Bangalore, MD, MHAa, Sanobar Parkar, MD, MPHa, Ehud Grossman, MDb, Franz H. Messerli, MDa


Beta blockers used for the treatment of hypertension may be associated with increased risk for new-onset diabetes mellitus (DM).

A search of Medline, PubMed, and EMBASE was conducted for randomized controlled trials of patients taking β blockers as first-line therapy for hypertension with data on new-onset DM and follow-up for ≥1 year. Twelve studies evaluating 94,492 patients fulfilled the inclusion criteria. Beta-blocker therapy resulted in a 22% increased risk for new-onset DM (relative risk 1.22, 95% confidence interval [CI] 1.12 to 1.33) compared with nondiuretic antihypertensive agents. A higher baseline fasting glucose level (odds ratio [OR] 1.01, 95% CI 1.00 to 1.02, p = 0.004) and greater systolic (OR 1.05, 95% CI 1.05 to 1.08, p = 0.001) and diastolic (OR 1.06, 95% CI 1.01 to 1.10, p = 0.011) blood pressure differences between the 2 treatment modalities were significant univariate predictors of new-onset DM.

Multivariate meta-regression analysis showed that a higher baseline body mass index (OR 1.17, 95% CI 1.01 to 1.33, p = 0.034) was a significant predictor of new-onset DM. The risk for DM was greater with atenolol, in the elderly, and in studies in which β blockers were less efficacious antihypertensive agents and increased exponentially with increased duration on β blockers. For the secondary end points, β blockers resulted in a 15% increased risk for stroke, with no benefit for the end point of death or myocardial infarction.

In conclusion, β blockers are associated with an increased risk for new-onset DM, with no benefit for the end point of death or myocardial infarction and with a 15% increased risk for stroke compared with other agents. This risk was greater in patients with higher baseline body mass indexes and higher baseline fasting glucose levels and in studies in which β blockers were less efficacious antihypertensive agents compared with other treatments.

Comparative effectiveness of Beta-adrenergic antagonists (atenolol, metoprolol tartrate, carvedilol) on the risk of rehospitalization in adults with h

Comparative effectiveness of Beta-adrenergic antagonists (atenolol, metoprolol tartrate, carvedilol) on the risk of rehospitalization in adults with heart failure

Am J Cardiol. 2007 Aug 15;100(4):690-6. Epub 2007 Jun 26.

Go AS, Yang J, Gurwitz JH, Hsu J, Lane K, Platt R.

Division of Research, Kaiser Permanente of Northern California, Oakland, California; Departments of Epidemiology, Biostatistics, and Medicine, University of California, San Francisco, San Francisco, California.

Placebo-controlled randomized trials have demonstrated the efficacy of selected beta blockers on outcomes in chronic heart failure (HF), but the relative effectiveness of different beta blockers in usual clinical care is poorly understood.

We compared 12-month risk of rehospitalization for HF associated with receipt of different beta blockers in 7,883 adults hospitalized for HF within 2 large health plans between January 1, 2001 and December 31, 2002.

Beta-blocker use was ascertained from electronic pharmacy databases and readmissions within 12 months were identified from hospital discharge databases.

Extended Cox regression was used to examine the association between receipt of different beta blockers and risk of readmission for HF after adjustment for potential confounders.

During follow-up, there were 3,234 person-years of exposure to beta blockers (39.3% atenolol, 42.0% metoprolol tartrate, 12.3% carvedilol, and 6.4% other).

Crude 12-month rates of readmissions for HF were high overall (42.6 per 100 person-years).

After adjustment for potential confounders, cumulative exposure to each beta blocker, and propensity to receive carvedilol compared with atenolol, adjusted risks of readmission were not significantly different for metoprolol tartrate (adjusted hazard ratio 0.95, 95% confidence interval 0.85 to 1.05) or for carvedilol (adjusted hazard ratio 0.92, 95% confidence interval 0.74 to 1.14).

In conclusion, in a contemporary cohort of high-risk patients hospitalized with HF, we found that adjusted risks of rehospitalization for HF within 12 months were not significantly different in patients receiving atenolol, shorter-acting metoprolol tartrate, or carvedilol.

Beta Blockers in Uncomplicated Hypertension

New review "beats the drum" for not using beta blockers in uncomplicated

August 8, 2007

New York, NY - A new review published in the August 14, 2007 issue of the Journal of the American College of Cardiology further explores the use of beta blockers in uncomplicated hypertension, with experts arguing that doctors should stop prescribing the drugs as monotherapy or first-line agents in uncomplicated hypertension, as there is a lack of evidence to support their use

http://www.theheart.org/article/805319

"Year after year, the use of beta blockers has been increasing in the United States," Dr Franz Messerli (St Luke's-Roosevelt Hospital, New York), one of the authors, told heartwire. "This is despite the fact that we showed many, many years ago, for hypertension, that there is basically no evidence for their use."

Messerli said that despite a number of meta-analyses showing no benefit of beta-blocker use in patients with hypertension the agents appear to have the "myth of cardioprotection attached to them." This myth, explained Messerli, originates from studies showing benefit in the post-MI patient. While beta blockers reduce reinfarction rates and even morbidity and mortality in these patients, the cardioprotection myth is erroneously extended to a number of different indications, most notably hypertension, all under the assumption that "what is good for the goose must be good for the gander," he said.

Beta blockers in hypertension

Speaking with heartwire, Messerli said that beta blockers, specifically atenolol, were the fourth-most-prescribed drug in the US and that, based on a report in the New York Times, there are more than 44 million prescriptions for the popular beta blocker yearly. Most of these prescriptions, said Messerli, are for hypertension, and many guidelines, including the US and European guidelines, still recommend the use of beta blockers as first-line therapy or as on an "equal footing" with thiazide diuretics, calcium antagonists, or renin angiotensin aldosterone system (RAAS) blockers. The most recent UK hypertension guidelines, however, have omitted beta blockers for routine use.

The purpose of the new review, explained Messerli, was to highlight the paucity of data supporting the use of beta blockers in uncomplicated hypertension and to "beat the drum among cardiologists to make them realize that what they are doing is no longer appropriate."

Since the Veterans Administration (VA) study in the 1970s, numerous studies have documented reductions in stroke, and to a lesser extent, MI and cardiovascular morbidity and mortality, in hypertensive patients treated with a diuretic-based antihypertensive therapy. However, after more than 30 years, no study of beta blockers has shown that their use as monotherapy reduces morbidity and mortality in hypertensive patients, said Messerli.

"What is the evidence for atenolol in hypertension?" asked Messerli. "Zero. Zilch. There has never been a study in hypertension with atenolol that has shown a reduction in heart attacks or strokes."

The most recent evidence, a meta-analysis previously reported by heartwire and cited by Messerli and lead author Dr Spiral Banagalore (St Luke's-Roosevelt Hospital, New York) in their review, recently showed beta blockers to be ineffective as first-line drugs in the treatment of hypertension.

The review, published in January, bases this conclusion on "the relatively weak effect of beta blockers to reduce stroke and the absence of an effect on coronary heart disease when compared with placebo or no treatment" and "the trend toward worse outcomes in comparison with calcium-channel blockers, renin-angiotensin-system inhibitors, and thiazide diuretics."

Different types of patients

Post-MI patients, in whom beta blockers are appropriately prescribed, differ from hypertensive patients in that they have severe manifest coronary artery disease, Messerli explained. In post-MI and congestive heart failure patients, beta blockers slow the heart rate and shield the heart from surges in catecholamines, physiological effects beneficial to patients with coronary disease.

Uncomplicated hypertensive patients, on the other hand, particularly the elderly, are characterized by low cardiac output, low heart rate, and very high peripheral resistance, and prescribing beta blockers in this setting "accelerates the biological clock, said Messerli. Heart rate slows further, cardiac output decreases, and peripheral resistance increases, and for this reason, beta blockers should not be prescribed in uncomplicated hypertension.

Messerli concludes that the risk/benefit ratio of beta blockers does not make them an option for the treatment of uncomplicated hypertension. "Hypertension," he said, "is an asymptomatic disease, and our treatment for it should also remain asymptomatic." Given the increased risk of stroke, the failure to lower central aortic pressure, and numerous adverse effects, including predisposing patients to diabetes mellitus, drowsiness, and lethargy, as well as peripheral vascular and pulmonary side effects, the risk/benefit ratio for beta blockers is "not acceptable for this indication.

Sources:
Bangalore S, Messerli FH, Kostis JB, Pepine CJ. Cardiovascular protection using beta blockers. J Am Coll Cardiol 2007; 50:563-72.

Wiysonge CS, Bradley H, Mayosi BM, et al. Beta blockers for hypertension. Cochrane Database Review 2007;1: CD002003

Related links:

Cochrane review: Beta blockers should not be first line for hypertension
HeartWire News; Feb 02, 2007

New UK hypertension guidelines omit beta blockers for routine use HeartWire News; Jul 06, 2006

Beta-Blockers and Coronary Artery Disease

Beta-Blockers Slow, Even Reverse Coronary Artery Disease

Cleveland Clinic Study Shows - 12 Jul 2007

A Cleveland Clinic study is reporting that beta-blockers, a class of drugs used to lower blood pressure and prevent symptoms in a variety of heart conditions, can slow progression and can even induce regression of coronary artery disease.

The study appears in the July 3, 2007, issue of the Annals of Internal Medicine and suggests that all patients with coronary disease can benefit from this class of agents.

Coronary artery disease or clogging of vessels supplying the heart is one of the most common causes of death in the United States and other developed countries. Currently, more than 15 million Americans have coronary artery disease.

Researchers aimed to identify whether beta-blockers have any effect on progression of coronary disease in a group of more than 1,500 patients with this disease.

They began by measuring the amount of fatty plaque found in the arteries of these patients, using high-resolution intravascular ultrasound.

This required the insertion of tiny ultrasonic transducers in the coronary arteries to provide a baseline examination. Subsequently, the ultrasound examination was repeated after 18 to 24 months and the progression rate of coronary disease was compared in patients who were treated with beta-blockers and those who were not treated with these agents.

The researchers found that patients treated with beta-blockers had a significant reduction in the amount of fatty plaque at the follow-up examination, whereas those not on a beta-blocker experienced no change in the amount of plaque. "Our results have important implications," said Ilke Sipahi, M.D., F.A.C.C., a Cardiologist at the Cleveland Clinic and the study's lead author. "Up to now, we thought that beta-blockers were beneficial only to preserve heart muscle function in patients with a previous injury to their heart due to a heart attack. Now we learn that these drugs also have favorable effects on the coronary arteries by reducing clogging of these vessels in a similar fashion to cholesterol-lowering statin drugs. Our results indicate that all patients with coronary disease, such as those with coronary stents, previous bypass surgery and even patients with earlier stages of coronary artery disease can benefit from treatment with beta-blockers."

ß-Blockers and Progression of Coronary Atherosclerosis

ß-Blockers and Progression of Coronary Atherosclerosis: Pooled Analysis of 4 Intravascular Ultrasonography Trials

Ilke Sipahi, MD; E. Murat Tuzcu, MD; Katherine E. Wolski, MPH; Stephen J. Nicholls, MBBS, PhD; Paul Schoenhagen, MD; Bo Hu, PhD; Craig Balog, BS; Mehdi Shishehbor, DO; William A. Magyar, BS; Timothy D. Crowe, BS; Samir Kapadia, MD; and Steven E. Nissen, MD

3 July 2007 Volume 147 Issue 1 Pages 10-18

Background: In patients with myocardial infarction, ß-adrenergic blockers reduce recurrent myocardial infarction and total mortality rates. However, whether a direct influence of ß-blockers on coronary atherosclerosis contributes to reduced recurrent myocardial infarction and total mortality rates is not known.

Objective: To assess whether ß-blocker therapy is associated with reduced atheroma progression in adults with known coronary artery disease.
Design: Post hoc, pooled analysis of individual patient data from 4 intravascular ultrasonography (IVUS) trials.

Setting: Four IVUS trials conducted in the United States, Europe, and Australia.

Patients: 1515 patients with coronary artery disease.

Intervention: The original trials used 3 different statins, a calcium-channel blocker, an angiotensin-converting enzyme inhibitor, or an acyl coenzyme A–cholesterol acyltransferase inhibitor.

Measurements: Changes in atheroma volume, as determined by IVUS after adjustment for possible confounders by using linear mixed-effects models, were compared in patients who did and did not receive concomitant ß-blocker treatment.

Results: Patients who received ß-blockers (n = 1154) were more likely to have histories of myocardial infarction, angina, and hypertension than were patients who did not receive ß-blockers (n = 361). The estimated annual change in atheroma volume was statistically significantly less in patients who received ß-blockers. This was true for univariate and multivariable analyses that controlled for history of myocardial infarction, angina, and hypertension (mean [±SE] atheroma volume, –2.4 ± 0.5 mm3/y in treated patients vs. –0.4 ± 0.8 mm3/y in untreated patients; P = 0.034). Accordingly, atheroma volume statistically significantly decreased at follow-up IVUS in patients who received ß-blockers (P < 0.001) and did not change in patients who did not receive ß-blockers (P = 0.86). Additional adjustments for low-density lipoprotein cholesterol level, concomitant medications, and clinical trial did not change the results.

Limitations: Patients were not randomly assigned to ß-blocker therapy, and interventions other than ß-blocker therapy could have influenced the changes in atheroma volume. Whether progression rate of atherosclerosis as detected by IVUS predicts cardiovascular outcomes is unknown.

Conclusions: The analysis demonstrates that ß-blockers can slow progression of coronary atherosclerosis. The findings provide additional support for the current clinical guidelines advocating long-term use of ß-blockers to treat most forms of coronary artery disease.


Editors' Notes

Context
The mechanisms by which ß-blockers prevent recurrent myocardial infarction are not clear.

Contribution
This pooled analysis of individual patient data examines changes in coronary atheroma volume as measured by serial intravascular ultrasonography in 4 randomized trials. The trials followed 1515 patients with coronary artery disease for 18 to 24 months. Atheroma volume decreased in patients who were receiving ß-blockers but stayed the same in those not receiving ß-blockers.

Cautions
The trials tested other interventions (such as statins) that could have affected atheromas. We do not know whether changes in atheroma volume predict cardiovascular outcomes.

Implication
ß-Blockers probably slow progression of coronary atherosclerosis.

Beta-blockers for hypertension. Cochrane Database of Systematic Reviews

Review

Beta-blockers for hypertension
CS Wiysonge, H Bradley, BM Mayosi, R Maroney, A Mbewu, LH Opie, J Volmink

Cochrane Database of Systematic Reviews 2007 Issue 2Copyright © 2007
The Cochrane Collaboration. Published by John Wiley & Sons, Ltd.DOI: 10.1002/14651858.CD002003.pub2
This version first published online: 24 January 2007 in Issue 1, 2007
Date of Most Recent Substantive Amendment: 25 October 2006
This record should be cited as: Wiysonge CS, Bradley H, Mayosi BM, Maroney R, Mbewu A, Opie LH, Volmink J. Beta-blockers for hypertension.
Cochrane Database of Systematic Reviews 2007, Issue 1. Art. No.: CD002003. DOI: 10.1002/14651858.CD002003.pub2.

Abstract

Background

Two recent systematic reviews found first-line beta-blockers to be less effective in reducing the incidence of stroke and the combined endpoint of stroke, myocardial infarction, and death compared to all other antihypertensive drugs taken together. However, beta-blockers might be better or worse than a specific class of drugs for a particular outcome measure so that comparing beta-blockers with all other classes taken together could be misleading. In addition, these systematic reviews did not assess the tolerability of beta-blockers relative to other antihypertensive medications. We thus undertook this review to re-assess the place of beta-blockade as first-line therapy for hypertension relative to each of the other major classes of antihypertensive drugs.

Objectives

To quantify the effectiveness and safety of beta-blockers on morbidity and mortality endpoints in adults with hypertension.

Search strategy

We searched eligible studies up to June 2006 in the Cochrane Controlled Trials Register, Medline, Embase, and reference lists of previous reviews, and by contacting hypertension experts.

Selection criteria

We selected randomised controlled trials which assessed the effectiveness of beta-blockers compared to placebo, no therapy or other drug classes, as monotherapy or first-line therapy for hypertension, on mortality and morbidity endpoints in men and non-pregnant women aged 18 years or older.

Data collection and analysis

At least two authors independently applied study selection criteria, assessed study quality, and extracted data; with differences resolved by consensus. We expressed study results as relative risks (RR) with 95% confidence intervals (CI) and conducted quantitative analyses with trial participants in groups to which they were randomly allocated, regardless of which or how much treatment they actually received. In the absence of significant heterogeneity between studies (p>0.1), we performed meta-analysis using a fixed effects method. Otherwise, we used the random effects method and investigated the cause of heterogeneity by stratified analysis. In addition, we used the Higgins statistic (I2) to quantify the amount of between-study variability in effect attributable to true heterogeneity rather than chance.

Main results

Thirteen randomised controlled trials (N=91,561 participants), which met our inclusion criteria, compared beta-blockers to placebo or no treatment (4 trials with 23,613 participants), diuretics (5 trials with 18,241 participants), calcium-channel blockers (CCBs: 4 trials with 44,825 participants), and renin-angiotensin system (RAS) inhibitors (3 trials with 10,828 participants). The risk of all-cause mortality was not different between first-line beta-blockers and placebo (RR 0.99, 95%CI 0.88 to 1.11, I2=0%), diuretics or RAS inhibitors, but was higher for beta-blockers compared to CCBs (RR 1.07, 95%CI 1.00 to 1.14, I2=2.2%; ARI=0.5%, NNH=200). The risk of total cardiovascular disease (CVD) was lower for first-line beta-blockers compared to placebo (RR 0.88, 95%CI 0.79 to 0.97, I2=21.4%, ARR=0.7%, NNT=140). This is primarily a reflection of the significant decrease in stroke (RR 0.80, 95%CI 0.66 to 0.96; I2=0%; ARR=0.5%, NNT=200); coronary heart disease (CHD) risk was not significantly different between beta-blockers and placebo. The effect of beta-blockers on CVD was significantly worse than that of CCBs (RR 1.18, 95%CI 1.08 to 1.29, I2=0%; ARI=1.3%, NNH=80), but was not significantly different from that of diuretics or RAS inhibitors. Increased total CVD was due to an increase in stroke compared to CCBs (RR 1.24, 95%CI 1.11 to 1.40, I2=0%; ARI=0.6%, NNH=180).There was also an increase in stroke with beta-blockers as compared to RAS inhibitors (RR 1.30, 95%CI 1.11 to 1.53, I2=29.1%; ARI=1.5%, NNH=65). CHD was not significantly different between beta-blockers and diuretics or CCBs or RAS inhibitors. In addition, patients on beta-blockers were more likely to discontinue treatment due to side effects than those on diuretics (RR 1.86, 95%CI 1.39 to 2.50, I2=78.2%, ARI=6.4% NNH=16) and RAS inhibitors (RR 1.41, 95%CI 1.29 to 1.54, I2=12.1%; ARI=5.5%, NNH=18), but there was no significant difference with CCBs.

Authors' conclusions

The available evidence does not support the use of beta-blockers as first-line drugs in the treatment of hypertension. This conclusion is based on the relatively weak effect of beta-blockers to reduce stroke and the absence of an effect on coronary heart disease when compared to placebo or no treatment. More importantly, it is based on the trend towards worse outcomes in comparison with calcium-channel blockers, renin-angiotensin system inhibitors, and thiazide diuretics. Most of the evidence for these conclusions comes from trials where atenolol was the beta-blocker used (75% of beta-blocker participants in this review). However, it is not known at present whether beta-blockers have differential effects on younger and elderly patients or whether there are differences between the different sub-types of beta-blockers.

Plain language summary

At the present time members of the class of drugs called beta-blockers are commonly used as first-line treatment for elevated blood pressure. We asked whether this class of drugs was as good as other classes in preventing death, stroke and heart attacks associated with elevated blood pressure. The available scientific literature was searched to find all the randomised controlled trial (RCT) evidence to assess this question. Thirteen RCTs were found and these trials suggested that first-line beta-blockers for elevated blood pressure were not as good at decreasing mortality and morbidity as other classes of drugs: thiazides, calcium channel blockers, and renin angiotensin system inhibitors.