Why -Blockers Should Not Be Used as First Choice in Uncomplicated Hypertension Alberto Ranieri De Caterina, MD*, and Antonio Maria Leone, MD In the past 4 decades,  blockers (BBs) have been widely used in the treatment of uncomplicated hypertension and are still recommended as first-line agents in national and international guidelines. Their putative cardioprotective properties, however, derive from the extrapolation into primary prevention of data relative to the reduction of mortality observed in the 1970s in patients with previous myocardial infarctions. In the past 5 years, a critical reanalysis of older trials, together with several meta-analyses, has shown that in patients with uncomplicated hypertension BBs exert a relatively weak effect in reducing stroke compared to placebo or no treatment, do not have any protective effect with regard to coronary artery disease and, compared to other drugs, such as calcium channel blockers, renin-angiotensin-aldosterone system inhibitors or thiazide diuretics, show evidence of worse outcomes, particularly with regard to stroke. Several reasons can explain their reduced cardioprotection: their suboptimal effect in lowering blood pressure compared to other drugs; their “pseudoantihypertensive” efficacy (failure to lower central aortic pressure); their undesirable adverse effects, which reduce patients’ compliance; their unfavorable metabolic effects; their lack of an effect on regression of left ventricular hypertrophy and endothelial dysfunction. In conclusion, the available evidence does not support the use of BBs as first-line drugs in the treatment of hypertension. Whether newer BBs, such as nebivolol and carvedilol, which show vasodilatory properties and a more favorable hemodynamic and metabolic profile, will be more efficacious in reducing morbidity and mortality remains to be determined. © 2010 Elsevier Inc. All rights reserved. (Am J Cardiol 2010;105:1433–1438) Beta blockers (BBs) have been considered a cornerstone in therapy for hypertension in the past 4 decades, especially for their putative cardioprotective properties. The concept of cardiovascular (CV) protection mediated by BBs was born in the 1970s from several prospective randomized trials in patients with previous myocardial infarctions, in whom mortality of about 25% was observed.1 This observation was then uncritically translated from secondary to primary prevention of the broad spectrum of CV diseases, including uncomplicated hypertension. On the basis of this extrapolation, and the common idea that reducing blood pressure (BP) automatically reduces CV morbidity and mortality, even most recent international guidelines2,3 recommend BBs as first-line agents in uncomplicated hypertension. The concept of cardioprotection mediated by BBs penetrated so deeply into clinical practice that in 2005, the New York Times reported that BBs, in particular atenolol, were the fourth most prescribed drug in the United States, with 44 million prescriptions yearly.4 Nowadays, a large number of physicians perceive BBs as the most protective class of drugs for the heart and brain and consider them the most effective therapy in reducing CV mortality among all other drugs.5 However, the cardioprotective effect of BBs in primary prevention is based on assumptions that are still far Institute of Cardiology, Catholic University of the Sacred Heart, Rome, Italy. Manuscript received October 25, 2009; revised manuscript received and accepted December 20, 2009. *Corresponding author: Tel: 39-06-30154444; fax: 39-06-3055535. E-mail address: [email protected] (A.R. De Caterina). 0002-9149/10/$ – see front matter © 2010 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2009.12.068 from being scientifically proved. The recently updated National Institute for Health and Clinical Excellence guidelines in Great Britain reflected this concern, having changed the indication for BBs from use as first-line agents for hypertension treatment to fourth-line add-on therapy in patients requiring multiple drugs.6 In this review, we analyze the current evidence supporting the use of BBs in hypertension in primary prevention. Efficacy of  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 catecholaminemediated 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 ␣-adrenoceptors that increase the release of norepinephrine from sympathetic nerve terminals, and a decrease in central vasomotor activity.7,8 In contrast,  blockade is known to determine a vasoconstrictive effect in arteries and veins through 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 www.AJConline.org 1434 The American Journal of Cardiology (www.AJConline.org) Table 1 Main studies assessing the antihypertensive effect of  blockers (BBs) from 1985 to 2000 Study Year of No. of Follow-Up Publication Patients in (years) BB Group MRC9 Coope et al10 STOP11 1985 1986 1991 2,285 419 812 4.8 4.4 4 MRCOA12 Dutch TIA Trial13 TEST14 NORDIL15 1992 1993 1994 2000 1,099 732 720 5,471 5.8 2.6 2.6 5 Drug Comparison Arm Mean Age Baseline Final (years) Systolic/Diastolic Systolic/Diastolic BP (mm Hg) BP (mm Hg) Propranolol Atenolol Atenolol/metoprolol/ pindolol Atenolol Atenolol Atenolol Mixed BB and diuretic Benfluorazide Open control Placebo Placebo Placebo Placebo Diltiazem 51 68.8 75.7 158/98 197/99 195/102 137/85 188/87 166/85 70.3 54% ⬎65 70.4 60.5 183/91 158/91 161/89 173/105 169/84 152/88 157/86 149/87 MRCOA ⫽ Medical Research Council Trial in Older Adults; NORDIL ⫽ Nordic Diltiazem Study; TEST ⫽ aTEnolol in the Secondary prevention after Stroke; TIA ⫽ transient ischemic attack. characteristics, such as 1/2-selectivity, intrinsic sympathomimetic activity, and vasodilatory capabilities. Thus, it is clear that the effect of  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 placebo9 –15 (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 (ASCOTBPLA) The robustness of the evidence for use of BBs as firstline 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) study16 and the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT)–Blood Pressure Lowering Arm (BPLA),17 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 al18 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.19 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,20 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.19 Even a recent Cochrane review,21 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.”21 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,22 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  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,23 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,24 whereby, on the basis of a study in which two-thirds Review/Reasons for Suboptimal Cardioprotective Effect of -blockers 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.9 Another potential explanation for the reduced efficacy of  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.11–13,15 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.11 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. The Reasons for the Lack of Cardiovascular Protection Why BBs do not confer similar CV protection to other classes of agents despite their proved efficacy in lowering BP? Several mechanisms, which we summarize here, could be responsible for this reduced or lack of efficacy of BBs in uncomplicated hypertension. Reduced antihypertensive effect: Some evidence exists that compared to other antihypertensive treatment, the BPlowering efficacy of BBs is suboptimal. This was first observed in older trials, in which BB therapy resulted in small decreases in BP values, requiring the addition of second drugs in most patients.9 Even in more recent trials, such as LIFE, BP control was achieved in ⬍50% of patients assigned to the BB group, and only ⬍10% of patients continued receiving BB monotherapy.16 In ASCOT-BPLA, compared to the atenolol-based arm, an amlodipine-based regimen conferred a small but statistically significantly higher effect in BP lowering (1.7 mm Hg mean lower 1435 systolic BP and 2.0 mm Hg mean lower diastolic BP).17 Because it is widely accepted that even a small adjunctive decrease in BP confers prognostic relevance, the small difference between the 2 treatment arms in ASCOT-BPLA might have played a role in the lower risk for coronary events and stroke with amlodipine-based compared to atenolol-based treatment. Unfavorable hemodynamic effect and pseudoantihypertensive efficacy: In the elderly, the hemodynamic profile is typically characterized by low cardiac output and high peripheral resistance. Focusing on their pure pharmacodynamic effects, most BBs lower BP by further decreasing cardiac output and increasing systemic vascular resistance. The difference pattern of hypertension, such as mainly systolic or diastolic, also might affect BBs efficacy. Because of their negative chronotropic effect, BBs should not be prescribed to patients with predominantly systolic hypertension. In fact, the decrease in heart rate tends to be compensated by a parallel increase in stroke volume, which will elevate systolic BP and decrease diastolic BP, resulting in an unfavorable increase in pulse pressure. Moreover, even taking into account the favorable independent prognostic impact conferred by lowering heart rate,25 either by nonpharmacologic interventions or by heart rate–lowering drugs, a recent reanalysis from Bangalore et al26 of nearly 65,000 patients with uncomplicated hypertension showed that, in patients treated with BBs, lower heart rates were associated with a significantly higher risk for all-cause mortality, CV mortality, myocardial infarction, stroke, and heart failure. The same concept can be also be applied to hypertensive patients with higher heart rates at rest, a group of patients in whom it is a widely accepted belief that BB therapy would be indicated as the first choice. In contrast, a recent reanalysis of a subgroup of ASCOT concluded that the superiority of amlodipine-based over atenolol-based therapy for patients with uncomplicated hypertension was independent from heart rate and, more interestingly, was maintained in those patients with higher baseline heart rates.27 Finally, although they reduce peripheral BP, which is commonly measured and considered a reference in everyday clinical practice, BBs have been shown to be less efficacious in reducing central aortic BP compared with RAAS blockers, diuretics, and calcium channel blockers, a phenomenon commonly called the pseudoantihypertensive effect. Specifically, in the Conduit Artery Function Evaluation (CAFE) study,28 for the same peripheral BP, central aortic systolic BP and central aortic pulse pressure were significantly higher with atenolol-based compared to amlodipine-based treatment. The increase in central aortic systolic BP should be more predictive of CV events, such as stroke and myocardial infarction, than the traditional peripheral (brachial) BP measurements. The pseudoantihypertensive effect thus might explain the increased risk for stroke seen in clinical trials.19 Reduced compliance: BBs considered as a class have many undesirable adverse effects, including drowsiness, lethargy, sleep disturbance, visual hallucinations, depression, blurring of vision, dreams or nightmares, pulmonary side effects such as increased airway resistance in asthmatics, and peripheral vascular side effects such as cold extremities, Raynaud’s phenomenon, and erectile and orgas- 1436 The American Journal of Cardiology (www.AJConline.org) mic dysfunction. It is common experience that BBs are often less tolerated in elderly patients than other drugs. For instance, in MRC trial, twice as many patients withdrew from the BB arm because of major adverse effects than from the diuretic arm.9 Thus, BBs might expose elderly patients to adverse effects and costs while conferring little if any true benefit. Reduced effect on left ventricular hypertrophy (LVH) regression: It is now more clear that BP lowering represents a surrogate end point that does not automatically lead to a parallel decrease in CV morbidity and mortality. Conversely, intermediate end points, such as LVH, have been shown to be reliably linked to CV mortality and morbidity. Specifically, the regression of LVH has been shown to lower CV risk independently of other risk factors.29 In the LIFE study, antihypertensive treatment with losartan-based therapy resulted in greater LVH regression than conventional atenolol-based therapy.16 Moreover, a meta-analysis of 109 studies of more than 2,000 patients comparing the effects of various antihypertensive strategies on LVH regression, BB-based therapy induced a significantly lower LVH regression compared to other drugs, especially RAAS blockers.30 A potential mechanism of the reduced efficacy on LVH regression might reside in BBs inability, as opposed to RAAS blockers, to decrease collagen content in the myocardium.31 Unfavorable metabolic effects: Metabolic side effects induced by long-term BB treatment could have a particular negative influence in younger patients. Traditional BBs, in fact, have been shown to increase insulin resistance and predispose patients to diabetes. In a meta-analysis including almost 150,000 patients without diabetes, the risk for newonset diabetes was significantly increased with diuretics and BBs than with placebo or other classes of antihypertensive drugs.32 Possible mechanisms by which BBs may contribute to the development of diabetes include weight gain, attenuation of the -receptor-mediated release of insulin from pancreatic  cells and decreased blood flow through the microcirculation in skeletal-muscle tissue, leading to decreased glucose uptake and increased insulin-resistance.33 Second, BBs can worsen the blood lipid profile. In fact, the long-term administration of BBs has been shown to increase triglyceride levels by 20% to 50% and decrease high-density lipoprotein cholesterol by 10% to 20%.33 BB therapy also hampers exercise capacity. The mechanism of reduced exercise tolerance in patients taking BBs may be attributed to their hemodynamic effects, such as decrease in heart rate, cardiac output, and mean BP, together with some of their side effects, such as lethargy, sleep disturbance, or depression. As a consequence, BB use has been associated with small but systematic weight gain. In the few hypertension studies that reported weight status, in fact, BB use resulted in weight gains of as much as 1.2 kg.34 The weight gain secondary to BBs can be attributed to their effect in decreasing metabolic activity by as much as 10% and also to other effects on energy metabolism. Given the negative influence of obesity on global CV risk and new-onset diabetes, the effects of BBs in obese patients or patients with risk factors for diabetes cannot be ignored. Lack of vascular effects: Theoretically, the ideal antihypertensive agent should aim not only to control BP but also to improve endothelial function. Traditional BBs have no effect on endothelial function compared to other antihypertensive agents. In a small prospective study of 19 untreated hypertensive patients randomized to atenolol or amlodipine, after 1 year of treatment, whereas the amlodipine group had correction of altered resistance artery structure (on gluteal resistance vessels) and tended to have improved endothelial function, patients treated with atenolol did not show any vascular benefit given a similar BP control compared to amlodipine group.35 Similar results were obtained with the RAAS blocker olmesartan.36 Furthermore, in another study, switching from a BB to irbesartan resulted in the correction of previously persistently altered vascular structure and endothelial dysfunction, suggesting a structural and endothelial protective effect of angiotensin-1 receptor antagonists.37 This effect on endothelial function is thus independent of BP control and seems to be an intrinsic property of these antihypertensive agents (calcium channel blockers and RAAS blockers). Therefore, the lack of cardioprotective effects of BBs in patients with essential hypertension may be due partially to their failure in improving endothelial function. Newer -Blocking Agents: Are They Different? Most of data regarding the efficacy of BB therapy in primary hypertension derive from studies conducted with older agents, such as propranolol, atenolol, and metoprolol. Newer BBs showing vasodilatory properties, such as carvedilol and nebivolol, show a much better hemodynamic and metabolic profile than older compounds. Theoretically, these properties may confer to these agents a cardioprotective effect similar to other class of antihypertensive agents. Carvedilol is a third-generation vasodilating BB that lacks intrinsic sympathomimetic activity and blocks ␣1-, 1-, and 2-adrenergic receptors without exhibiting high levels of inverse agonist activity,38,39 thus being a much better tolerated compound than the older BBs. Carvedilol lowers BP by decreasing peripheral vascular resistance, without affecting cardiac output. Because of the ␣1-adrenergic blocking effect, which accounts for its vasodilatory effects, the hemodynamic effect of carvedilol is similar to those of RAAS inhibitors and calcium channel blockers, thus conferring to this agent a more beneficial effect on LVH regression compared to conventional BBs.40 Moreover, carvedilol shows a significantly better metabolic profile than older compounds. In the Glycemic Effects in Diabetes Mellitus: Carvedilol-Metoprolol Comparison in Hypertensives (GEMINI) trial,41 as opposed to metoprolol, patients taking carvedilol showed no significant weight gain. Interestingly, in the same study, patients with diabetes treated with metoprolol showed an increase in glycosylated hemoglobin, whereas those treated with carvedilol did not. This favorable metabolic profile was also confirmed in nondiabetic population. In the Carvedilol or Metoprolol European Trial (COMET),42 in fact, the risk for new-onset diabetes was 22% lower in patients receiving carvedilol than in those receiving metoprolol. Finally, as opposed to older BBs, carvedilol seems to have a neutral or beneficial effect Review/Reasons for Suboptimal Cardioprotective Effect of -blockers on lipoprotein lipase activity and levels of triglycerides and high-density lipoprotein.43 These findings suggest that in the class of BBs, carvedilol should be the compound of choice in subjects with metabolic syndrome, impaired glucose tolerance, or type 2 diabetes. Nebivolol is a third-generation selective -adrenergic receptor antagonist. Its vasodilatory properties may be attributable to its ability to increase nitric oxide bioavailability, as demonstrated in animals, human volunteers, and patients with hypertension.44,45 The mechanisms of nebivolol-mediated increases in nitric oxide bioavailability are still debated. Nebivolol may decrease oxidative stress in essential hypertension and increase nitric oxide by reducing its oxidative inactivation.46 In contrast, other investigators have suggested the direct involvement of the 3-adrenoceptor as a possible nebivolol-mediated stimulation of endothelial nitric oxide synthase.47 Alternatively, nebivolol might reduce circulating levels of asymmetric dimethylarginine, a potent inhibitor of endothelial nitric oxide synthase.48 The augmented nebivolol-mediated nitric oxide bioavailability may partially explain its favorable hemodynamic effects compared to older BBs. In fact, Mahmud and Feely49 showed, in a small group of patients with untreated hypertension, that given an equal reduction in brachial blood pressure, aortic pulse pressure was reduced to a greater extent by nebivolol compared to atenolol. Finally, similarly to carvedilol, nebivolol has been shown to have a neutral or even favorable effect on carbohydrate and lipid metabolism.50 Whether newer vasodilating agents such as carvedilol and nebivolol, which show a more favorable hemodynamic and metabolic profile, will be more efficacious in reducing CV morbidity and mortality remains to be determined. 1. Yusuf S, Peto R, Lewis J, Collins R, Sleight P. Beta blockade during and after myocardial infarction: an overview of the randomized trials. Prog Cardiovasc Dis 1985;27:335–371. 2. 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