Beta-blockers for hypertension: Are they going out of style?

BETA-BLOCKERS IN THE MANAGEMENT OF HYPERTENSION

Beta-blockers were initially used to treat arrhythmias, but by the early 1970s they were also widely accepted for managing hypertension. ¹⁴ Their initial acceptance as one of the first-line classes of drugs for hypertension was based on their better side-effect profile compared with other antihypertensive drugs available at that time.

In the 1980s and 1990s, beta-blockers were listed as preferred first-line antihypertensive drugs along with diuretics in national hypertension guidelines.¹⁵ Subsequent updates of the guidelines favored diuretics as initial therapy and relegated all other classes of antihypertensive medications to be alternatives to diuretics.¹⁶ Although beta-blockers remain alternative first-line drugs in the latest guidelines (published in 2003; see reference 66), they are the preferred antihypertensive agents for patients with cardiac disease.

The current recommendations reflect the findings from hypertension trials in which patients with myocardial infarction and congestive heart failure had better cardiovascular outcomes if they received these drugs,^17–19 including a lower risk of death.^20,21 It was widely assumed that beta-blockers would also prevent first episodes of cardiovascular events.

However, to date, there is no evidence that beta-blockers are effective as primary prevention. Several large randomized controlled trials showed no benefit with beta-blockers compared with other antihypertensive drugs—in fact, there were more cardiovascular events with beta-blockers (see below).

Beta-blockers are well tolerated in clinical practice, although they can have side effects that include fatigue, depression, impaired exercise tolerance, sexual dysfunction, and asthma attacks.

Wiysonge et al²² analyzed how many patients withdrew from randomized trials of antihypertensive treatment because of drug-related adverse events. There was no significant difference in the incidence of fatigue, depressive symptoms, or sexual dysfunction with beta-blockers compared with placebo, and trial participants on a beta-blocker were not statistically significantly more likely to discontinue treatment than those receiving a placebo in three trials with 22,729 participants (relative risk [RR] 2.34, 95% confidence interval [CI] 0.84–6.52).

THE CONTROVERSY: WHAT THE TRIALS SHOWED

Messerli et al²³ performed a meta-analysis published in 1998 that suggested that beta-blockers may not be as effective as diuretics in preventing cardiovascular events when used as first-line antihypertensive therapy in elderly patients. In 10 randomized controlled trials in 16,164 patients who were treated with either a diuretic or a beta-blocker (atenolol), blood pressure was normalized in two-thirds of diuretic-treated patients but only one-third of patients treated with atenolol as monotherapy. Diuretic therapy was superior with regard to all end points, and beta-blockers were found to be ineffective except in reducing cerebrovascular events.

The LIFE study (Losartan Intervention for Endpoint Reduction in Hypertension)²⁴ compared the angiotensin-receptor blocker losartan (Cozaar) and atenolol in 9,193 patients with hypertension and left ventricular hypertrophy. At 4 years of follow-up, the rate of primary cardiovascular events (death, myocardial infarction, or stroke) was lower in the losartan group than in the atenolol group. The difference was mainly due to a 25% lower incidence of stroke, which was statistically significant. The rates of myocardial infarction and death from cardiovascular causes were not significantly different between the two treatment groups. The systolic blood pressure was 1 mm Hg lower in the losartan group than in the atenolol group, which was statistically significant.

Carlberg et al²⁵ performed another important meta-analysis that questioned whether atenolol reduces rates of cardiovascular morbidity and death in hypertensive patients. The results were surprising: eight randomized controlled trials including more than 6,000 patients and comparing atenolol with placebo or no treatment showed no differences between the treatment groups with regard to the outcomes of all-cause mortality (RR 1.01, 95% CI 0.89–1.15), cardiovascular mortality (RR 0.99, 95% CI 0.83–1.18), or myocardial infarction (RR 0.99, 95% CI 0.83–1.19).

In addition, when atenolol was compared with other antihypertensives in five other randomized controlled trials that included more than 14,000 patients, those treated with atenolol had a higher risk of stroke (RR 1.30, 95% CI 1.12–1.50) and death (RR 1.13, 95% CI 1.02–1.25).

The ASCOT-BPLA trial (Anglo-Scandinavian Cardiac Outcomes Trial—Blood Pressure Lowering Arm)²⁶ had similar results. This trial compared the combination of atenolol plus the diuretic bendroflumethiazide against the combination of the calcium channel blocker amlodipine (Norvasc) plus the angiotensin-converting enzyme (ACE) inhibitor perindopril (Aceon). Although no significant difference was seen in the primary outcome of nonfatal myocardial infarction or fatal coronary heart disease (unadjusted hazard ratio [HR] with amlodipine-perindopril 0.90, 95% CI 0.79–1.02, P = .1052), the amlodipine-plus-perindopril group had significantly fewer strokes (327 vs 422, HR 0.77, 95% CI 0.66–0.89, P = .0003), fewer total cardiovascular events (1,362 vs 1,602, HR 0.84, 95% CI 0.78–0.90, P = .0001), and fewer deaths from any cause (738 vs 820; HR 0.89, 95% CI 0.81–0.99, P = .025).

Lindholm et al²⁷ performed a meta-analysis that included studies of selective beta-blockers (including atenolol) and nonselective beta-blockers, with a follow-up time of more than 2 years. Compared with placebo or no treatment, beta-blockers reduced the risk of stroke by 19% but had no effect on myocardial infarction or all-cause mortality. Compared with other antihypertensive drugs, beta-blockers were less than optimum, and the relative risk of stroke was 16% higher. Atenolol was the beta-blocker used in most of the randomized clinical trials included in this meta-analysis.

The Cochrane group²² found beta-blockers to be inferior to all other antihypertensive drugs with respect to the ability to lower the risk of stroke.