ELEVATED BLOOD PRESSURE IS ASSOCIATED WITH an increased risk of cardiovascular illness and death. Efforts to reduce that risk have led to recommendations for a wide array of nondrug and drug therapies. Choosing the optimal first-line drug for hypertensive patients should address a hierarchy of treatment goals: decrease in morbidity and mortality associated with hypertension, decrease in blood pressure, good tolerance, dosing convenience and low cost. This article examines the evidence for β-blockers as a class of first-line antihypertensive drugs in light of these treatment goals. The evidence indicates that β-blockers are probably not as effective in reducing morbidity and mortality as low-dose thiazide diuretics and that there may be significant differences in effectiveness among various β-blockers.
Published evidence for the use of thiazides in managing hypertension indicates that thiazides, given at a low dose, are the drugs of first choice.1 However, for a variety of reasons, we cannot rely on a single drug class to treat hypertensive patients. In this article I compare the evidence for β-blockers as first-line therapy for hypertension with that for thiazides. β-Blockers were initially introduced for the treatment of angina pectoris. They were subsequently discovered to lower blood pressure in hypertensive patients with angina pectoris. Despite the widespread use of β-blockers in the management of hypertension the precise mechanism for reduction of blood pressure remains unknown.
What is a β-blocker?
β-Blockers are drugs designed to competitively inhibit β-receptors and thus to modulate activity of the sympathetic nervous system. There are 2 main classes of β-receptors, β1 and β2. β1-receptor-blockers (which are cardioselective) have a greater specificity for β1 receptors than for β2 receptors. However, this specificity diminishes as the dose of the β-blocker increases. Some β-blockers have partial agonist (intrinsic sympathomimetic) activity. The main effect of a partial agonist is inhibition if the receptors are being stimulated and stimulation if the receptors are quiescent. An important question follows from knowledge of the mechanism of action: Do β-blockers with different mechanisms of action have different benefit-harm ratios in outcome trials? This question is examined here.
What is the evidence that β-blockers reduce cardiovascular morbidity and mortality?
Only 2 randomized trials comparing β-blockers with placebo in the first-line management of hypertension can be assessed.2,3 Two other trials — Coope and Warrender4 and the Swedish Trial in Old Patients with Hypertension (STOP-Hypertension) trial5 — are sometimes quoted as providing evidence of the effectiveness of β-blockers. However, these latter studies cannot be used as evidence of the effectiveness of β-blockers as distinct from thiazides. In Coope and Warrender's study4 67% of the active treatment group received bendrofluazide in addition to a β-blocker, and in the STOP-Hypertension trial5 more than 70% of the active treatment group received hydrochlorothiazide in addition to a β-blocker.
A recent systematic review6 compared the results of the 2 valid placebo-controlled β-blocker trials with data from 16 placebo-controlled trials in which a thiazide was used as the first-line drug. The thiazides had a statistically significant benefit in terms of all adverse outcomes, whereas the β-blockers had no significant benefit for any of the outcomes (Table 1). However, this finding cannot be taken as definitive evidence that thiazides are better, as it is based on an indirect comparison in different patient populations and the confidence intervals overlap.
Five head-to-head trials have compared first-line thiazides with first-line β-blockers.6 In these trials there was no statistically significant difference between the two drug classes (Table 2); the data favouring thiazides over β-blockers in terms of total adverse cardiovascular events just failed to reach statistical significance. These trials involved a total of 3 different β-blockers, and it was possible to combine the mortality data for each of these agents. On this basis, the mortality rate was statistically significantly lower with thiazides than with atenolol, but there was no difference between thiazides and propranolol or metoprolol (Table 2).
Two other trials deserve mention. The International Prospective Primary Prevention Study in Hypertension trial7 randomly assigned hypertensive patients to receive oxprenolol or placebo as first-line therapy and allowed the addition of thiazides, sympatholytic agents and vasodilator drugs as necessary. Seventy percent of the treatment group and 85% of the placebo group required additional therapy of some form. Despite lower mean blood pressure in the oxprenolol group (143.6/88.9 mm Hg) than in the placebo group (147.4/90.1 mm Hg), the addition of a β-blocker was not associated with a significant reduction in clinical events, including sudden death, myocardial infarction (MI) or stroke. The Metoprolol Atherosclerosis Prevention in Hypertensives trial,8,9 which purportedly showed a benefit of metoprolol over hydrochlorothiazide, cannot be included, as it represents a post hoc extension of the Heart Attack Primary Prevention in Hypertension (HAPPHY) trial, and to include it would constitute double counting.10,11
Messerli and colleagues12 performed a meta-analysis of β-blockers for hypertension in elderly patients and concluded that the lack of evidence of effectiveness was limited to this age group. It is true that most of the evidence of poor outcomes with β-blockers comes from the MRC trial in the elderly,3 in which atenolol was used. However, a trend toward worse outcomes with atenolol than with thiazides was also seen in the HAPPHY trial (age range 40-64 years),10 which suggests that the result may be specific to atenolol and unrelated to the age of the patients. However, the evidence does not consistently disfavour atenolol: a recent, relatively small trial compared atenolol with captopril, an angiotensin-converting enzyme (ACE) inhibitor, in patients with type 2 diabetes and hypertension.13 The risk of adverse outcome in the atenolol group relative to the captopril group (relative risk, RR) was as follows: for stroke, RR 0.90 (confidence interval [CI] 0.49-1.69); for coronary artery disease, RR 0.84 (CI 0.59-1.20); for all adverse cardiovascular events, RR 0.78 (CI 0.60-1.00); and for total deaths, RR 0.88 (0.65-1.20). Two recent trials with larger study populations, the Captopril Prevention Project14 and STOP-Hypertension 2,15 compared newer therapies with the combination of thiazides and β-blockers, which makes it impossible to distinguish between the benefit conferred by the thiazide or the β-blocker.
There are so few trials of β-blockers in hypertension that not much can be said about differences between drugs within this class. The best evidence of benefit for different β-blockers comes from trials of patients who have had MI. This evidence is probably relevant to hypertension for 2 reasons: a substantial proportion of post-MI patients also have elevated blood pressure, so some of the benefit in these trials could be due to a reduction in blood pressure; and a shared major outcome in antihypertensive trials and post-MI trials is coronary artery disease events, so benefit in preventing this type of event should be common to both types of trials. The data from a systematic review of the randomized placebo-controlled trials in which a β-blocker was administered for at least 3 months are relevant to this issue.16 In addition, 2 other trials have been published since that review.17,18 Because several β-blockers, with different actions on receptors, were used in the systematic review16 it is possible to compare their effectiveness in terms of reduction in mortality rate. Table 3 shows that most of the nonselective β-blockers were associated with a statistically significant reduction in mortality rate, whereas almost all of the cardioselective and partial agonist β-blockers were not.
The reasons for these apparent differences are unknown. They could be due to chance alone, given that the 95% CIs overlap, or there might be a real survival advantage associated with blocking the β2 receptor. However, other factors may be involved, such as the magnitude or duration of β-blockade and lipophilicity (a measure of the ability of the drug to enter the brain). These factors differ between the different drugs, and little or nothing is known about their effects on morbidity and mortality.
How efficacious are β-blockers in lowering blood pressure?
Data from the 5 comparative trials summarized in Table 2 have been used to compare β-blockers with thiazides as first-line therapy in terms of reduction in blood pressure.6 In these trials, which involved totals of about 9000 patients per group, the mean reduction from baseline was 26.6/15.5 mm Hg with thiazides and 24.3/15.2 mm Hg with β-blockers. The greater reduction in systolic blood pressure with thiazides (2.3 mm Hg) was statistically significant (p < 0.01). This difference could be expected to have clinical significance and could explain why there is a trend toward fewer adverse outcomes with thiazide therapy. However, even a greater reduction in blood pressure with β-blockers would not be sufficient reason to choose these drugs, because morbidity and mortality evidence outweighs any surrogate parameters such as reduction in blood pressure. There is no convincing evidence that any drug class or specific β-blocker is better at lowering blood pressure than thiazides, although this issue has not been systematically studied. Different effects on other surrogate markers, such as lipids, glucose and left ventricular hypertrophy, for which there are various relationships to cardiovascular outcomes, likewise do not justify ignoring the morbidity and mortality evidence.
Do β-blockers and other drugs differ in tolerability?
For the 5 comparative trials listed in the article on thiazides1 it was possible to quantify the rate of withdrawal from studies because of possible or probable adverse drug reactions. The mean withdrawal rate due to adverse drug reactions was 10.3% for β-blockers, significantly higher than for thiazides (7.0%) (p < 0.01). This difference was observed even though the trials excluded potential subjects if they had conditions for which a β-blocker might cause serious adverse effects (e.g., asthma, arteriovenous block, sick sinus syndrome or sinus bradycardia [less than 50 beats/min]).
Do β-blockers have advantages in terms of convenience or cost?
Some β-blockers do have a long enough half-life to be effective throughout a 24-h period if given only once daily. The drugs with longer half-life have an advantage in terms of convenience and are easier to titrate to the minimum dose required to achieve the desired blood pressure response. There is no evidence that supramaximal doses have any advantage, and higher doses are associated with a higher frequency of adverse effects. There are considerable differences in cost among the available β-blockers (Table 4). Even the least expensive β-blockers are many times more expensive than the least expensive thiazides.
In which patients with elevated blood pressure is a β-blocker the drug of first choice?
β-Blockers have proven effective in reducing the symptoms of angina pectoris and in reducing morbidity and mortality after MI. Therefore, in patients with elevated blood pressure and MI or angina, a β-blocker would be the drug of first choice. Although evidence is lacking, it may also be reasonable to use a β-blocker as the drug of first choice in patients in whom the drug can be used to treat more than elevated blood pressure (e.g., those with frequent recurrent migraine or hypertrophic obstructive cardiomyopathy).
On the basis of the available evidence of effectiveness, β-blockers are not a first-line choice for most patients with hypertension. When a β-blocker is required, the drug of choice is a nonselective agent. If drug choice is limited to those proven effective in randomized controlled trials, propranolol would be appropriate for treating elevated blood pressure and propranolol or timolol for patients with MI. Twice-daily generic propranolol is significantly less expensive than twice-daily timolol. If it is accepted that the benefits of nonselective β-blockers represent a class effect, the nonselective drug nadolol, given once daily, combines the attributes of convenience, ease of titration and reasonably low cost (Table 4).
This article has been peer reviewed.
Competing interests: None declared.
Reprint requests to: Dr. James M. Wright, Department of Medicine, University Hospital — UBC Site, 2211 Wesbrook Mall, Vancouver BC V6T 2B5; fax 604 822-0701; email@example.com