Efficacy of β Blockers in Lowering Blood Pressure

BBs are universally considered a cornerstone therapy in heart failure, chronic stable angina, myocardial infarction, and some forms of tachyarrhythmias. Their efficacy in these settings relies mainly on the antagonism of catecholamine-mediated cardiotoxic effects and of hyperactivity of the sympathetic system. These mechanisms, however, play an important role in a few patients with uncomplicated hypertension and, eventually, more often in young than in elderly patients. In fact, the efficacy of BBs in lowering BP involves other mechanisms, such as a decrease in cardiac output, the inhibition of renin release and angiotensin II production, the blockade of presynaptic α-adrenoceptors that increase the release of norepinephrine from sympathetic nerve terminals, and a decrease in central vasomotor activity. In contrast, β blockade is known to determine a vasoconstrictive effect in arteries and veins through β ₂ receptor antagonism, thus antagonizing the antihypertensive effect of BBs. Moreover, it should not be forgotten that BBs are a complex class of drugs involving several compounds that differ from one another in terms of pharmacologic characteristics, such as β ₁ /β ₂ -selectivity, intrinsic sympathomimetic activity, and vasodilatory capabilities. Thus, it is clear that the effect of β blockade in BP control is complex and not yet completely understood. Irrespectively of their exact mechanisms of action, it is a fact that a number clinical trials have proved the efficacy of BBs in lowering BP compared to no treatment or placebo ( Table 1 ). On the basis of these data, the perception of the efficacy of BBs as hypertensive agents has become stronger over the decades. Moreover, it must be acknowledged that they have been used as reference drugs in several randomized controlled trials of hypertension.

A Change of View After Losartan Intervention for End Point Reduction in Hypertension (LIFE) and the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT-BPLA)

The robustness of the evidence for use of BBs as first-line therapy for uncomplicated hypertension was first challenged by the results of 2 of the latest large hypertension trials: the Losartan Intervention for End Point Reduction in Hypertension (LIFE) study and the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT)–Blood Pressure Lowering Arm (BPLA), which demonstrated the superiority of a strategy based on newer antihypertensive drugs, losartan and amlodipine, respectively, compared to atenolol. After LIFE and ASCOT-BPLA, all the published research supporting the use of BBs in primary hypertension was critically reanalyzed.

Carlberg et al first systematically collected all published data regarding atenolol, the most frequently prescribed BB worldwide. In 2005, the same group extended these observations from atenolol to all BBs. The results of these meta-analysis first revealed that despite a BP reduction compared to placebo, BBs did not reduce the risk for myocardial infarction or CV mortality, although they did reduce the risk for stroke by about half (19% vs 38%) of that usually believed from previous hypertension trials and from the meta-analysis by Collins et al, which is frequently referenced in hypertension guidelines. Moreover, compared to other drugs, although no difference were observed for myocardial infarction, BB treatment resulted in a 16% higher relative risk for stroke. Even a recent Cochrane review, the most complete and comprehensive document analyzing the available research regarding BBs in primary hypertension, concluded that BBs (1) exert a relatively weak effect in reducing stroke compared to placebo or no treatment, (2) do not have any protective effect with regard to coronary artery disease, and (3) compared to other drugs, such as calcium channel blockers, renin-angiotensin-aldosterone system (RAAS) inhibitors, and thiazide diuretics, show evidence of worse outcomes, particularly with regard to stroke. The final message was categorical: “The available evidence does not support the use of BB as first-line drugs in the treatment of hypertension.”

Because these data were obtained mainly in an elderly population, one could argue that BB therapy might have a better prognostic impact in younger patients. However, Khan and McAlister, in their meta-analysis of a cohort of younger patients (mean age <60 years), found that compared to placebo, BB therapy showed no benefit with regard to all-cause mortality, myocardial infarction, or stroke. Similarly, compared to other antihypertensive agents, although there was no increased risk for stroke (as seen with the elderly cohort), there was also no benefit for the end points of all-cause mortality, myocardial infarction, and stroke.

A Change of View After Losartan Intervention for End Point Reduction in Hypertension (LIFE) and the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT-BPLA)

The robustness of the evidence for use of BBs as first-line therapy for uncomplicated hypertension was first challenged by the results of 2 of the latest large hypertension trials: the Losartan Intervention for End Point Reduction in Hypertension (LIFE) study and the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT)–Blood Pressure Lowering Arm (BPLA), which demonstrated the superiority of a strategy based on newer antihypertensive drugs, losartan and amlodipine, respectively, compared to atenolol. After LIFE and ASCOT-BPLA, all the published research supporting the use of BBs in primary hypertension was critically reanalyzed.

Carlberg et al first systematically collected all published data regarding atenolol, the most frequently prescribed BB worldwide. In 2005, the same group extended these observations from atenolol to all BBs. The results of these meta-analysis first revealed that despite a BP reduction compared to placebo, BBs did not reduce the risk for myocardial infarction or CV mortality, although they did reduce the risk for stroke by about half (19% vs 38%) of that usually believed from previous hypertension trials and from the meta-analysis by Collins et al, which is frequently referenced in hypertension guidelines. Moreover, compared to other drugs, although no difference were observed for myocardial infarction, BB treatment resulted in a 16% higher relative risk for stroke. Even a recent Cochrane review, the most complete and comprehensive document analyzing the available research regarding BBs in primary hypertension, concluded that BBs (1) exert a relatively weak effect in reducing stroke compared to placebo or no treatment, (2) do not have any protective effect with regard to coronary artery disease, and (3) compared to other drugs, such as calcium channel blockers, renin-angiotensin-aldosterone system (RAAS) inhibitors, and thiazide diuretics, show evidence of worse outcomes, particularly with regard to stroke. The final message was categorical: “The available evidence does not support the use of BB as first-line drugs in the treatment of hypertension.”

Because these data were obtained mainly in an elderly population, one could argue that BB therapy might have a better prognostic impact in younger patients. However, Khan and McAlister, in their meta-analysis of a cohort of younger patients (mean age <60 years), found that compared to placebo, BB therapy showed no benefit with regard to all-cause mortality, myocardial infarction, or stroke. Similarly, compared to other antihypertensive agents, although there was no increased risk for stroke (as seen with the elderly cohort), there was also no benefit for the end points of all-cause mortality, myocardial infarction, and stroke.

A Critical Reanalysis of Older Trials

Given this evidence, one may ask why this suboptimal effect of BBs has not been appropriately taken into account in hypertension guidelines over the years and why the efficacy of β blockade on “hard” end points, such as CV morbidity or mortality, has never been appropriately encountered.

The main reason resides in the fact that BBs have often been analyzed together with diuretics, assuming that for the same BP decrease, treatment with the 2 classes of drugs was associated with similar effects in terms of CV morbidity and mortality. This extrapolation led to the wrong attribution to BBs of the beneficial effect effectively conferred by diuretics. Messerli et al, for instance, first demonstrated that less than one-third over more than 2,000 patients were controlled on BB monotherapy, whereas the adjunction of diuretic therapy appropriately controlled BP in two-thirds of patients. Notwithstanding this evidence, no effort was made to analyze their efficacy separately. To simplify this concept, the example of gin and tonic has been previously used, whereby, on the basis of a study in which two-thirds of patients assume gin and tonic and one-third tonic water alone, one would paradoxically affirm that the tonic water causes hepatic cirrhosis without separately assessing their specific effects. Conversely, some evidence exists that adding BBs to diuretics to reach appropriate BP control distinctly reduces the benefits of the antihypertensive therapy. In fact, in the Medical Research Council (MRC) trial, patients who received the combination of BBs and diuretics fared consistently worse than those taking diuretics alone, but they did somewhat better than those receiving BBs alone. Another potential explanation for the reduced efficacy of β blockade is that most older trials used atenolol at low doses, such as 50 mg, which are perhaps not effective in allowing 24-hour BP control.

Second, economic issues may have played a role. In the 1980s and 1990s, in fact, most of the trials with BBs were sponsored by the pharmaceutical industry and often specifically designed to show a cardioprotective role of BBs over the less remunerative generic thiazide diuretics. Moreover, most of these studies were performed in an era when the importance of the strict and accurate control of BP was not perceived as it is today. In fact, the baseline BP values of the study population were very high and, more important, BB therapy resulted in a low and insufficient decrease in BP values, at least considering the BP targets recommended by most recent guidelines (see Table 1 ). For instance, in the Swedish Trial on Old Patients (STOP), less than half of the patients assigned to BB therapy had well-controlled BP while receiving monotherapy, whereas almost two-thirds of the patients assigned to diuretics reached the target BP. Hypertension guidelines then confirmed BBs as first-line therapy on the basis of a few studies in which, concomitantly with BBs, thiazide diuretics were used in two-thirds of patients.

Finally, the largest studies, consisting of large numbers of patients (>50% of all ever studied patients), have been published fairly recently (since 2002), and the interpretation of their results was focused more on the superiority of newer drugs rather than the less than optimal CV effect of BB themselves.