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β-Blockers for Primary Prevention in Hypertension: Era Bygone?
b -Blockers for Primary Prevention in Hypertension: Era Bygone? Gurusher S. Panjrath and Franz H. Messerli
b-Blockers are used commonly worldwide in clinical practice for lowering blood pressure. Most of the agents in this class are efficacious in reducing blood pressure, although they vary widely in their pharmacokinetic and pharmacodynamic properties. This variability may confer significant differences in clinical benefits associated with use of specific agents. Although commonly used in managing hypertension, the role of b-blockers for primary prevention in uncomplicated hypertension has been controversial. Evidence from recent trials suggest relatively poor efficacy toward primary prevention and worse outcomes for certain end points, when compared with other blood pressure– lowering agents, Recently updated National Institute for Health and Clinical Excellence guidelines for England and Wales reflect this concern and have changed the indication for b-blockers for blood pressure control from primary agents to use as an add-on agent in patients requiring multiple therapy. In this review, considering the extended debate on this topic, we discuss the general properties of b-blockers and evidence from clinical trials supporting or refuting their use in various clinical scenarios. Newer b-blockers have additional properties which may be beneficial. Although, whether these additional benefits will help in primary prevention is not clear. n 2006 Elsevier Inc. All rights reserved.
B
y definition, all antihypertensives lower blood pressure. Such medications include b-blockers, diuretics, calcium antagonists, From the Department of Cardiology, St. Lukes-Roosevelt Hospital Center, Department of Medicine, Division of Cardiology, Columbia University, NY. Address reprint request to Franz H. Messerli, MD, Division of Cardiology, St. Luke’s Roosevelt Hospital, Suite 3B.30, 1000 10th Avenue, New York, NY 10019. E-mail: [email protected] 0033-0620/$ - see front matter n 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.pcad.2006.07.002
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angiotensin-converting enzyme (ACE) inhibitors, and angiotensin receptor inhibitors. However, the goal of treatment is not only so much as to lower blood pressure but, more importantly, the reduction of morbidity and mortality, that is, stroke, coronary artery disease, myocardial infarction (MI), congestive heart failure (CHF), and end-stage renal disease. Careful selection of antihypertensive agents based on efficacy and safety is essential.
Historical Perspective and Clinical Use b-Blockers were first described in 1964 and were developed for the treatment of angina pectoris and arrhythmias. Subsequently, indications widened to encompass a multitude of clinical scenarios including Food and Drug Administration approval as antihypertensive agent in 1967. Currently, b-blockers are commonly used in clinical practice for a variety of cardiac and noncardiac indications (Table 1). Importantly, b-blockers are recommended as first-line agents or in combination with other classes of antihypertensive drugs as per the JNC (Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure) VII guidelines1 and are routinely prescribed in clinical settings for control of hypertension. However, there is little evidence supporting the use of b-blockers as a first-line agent in uncomplicated hypertension, although use of b-blockers in specific patient populations is still beneficial and appropriate (Fig 1).
Antihypertensive Effect The exact mechanism of blood pressure–lowering effect of b-blockers is debatable but is probably multifactorial. Various proposed mechanisms
Progress in Cardiovascular Diseases, Vol. 49, No. 2 (September/October), 2006: pp 76-87
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Table 1. Clinical Indications for b -Blockers Cardiac
Noncardiac
Hypertension Angina pectoris Myocardial ischemia Supraventricular arrythmias Ventricular arrhythmias Dissection of aorta Hypertrophic cardiomyopathy Digitalis intoxication Mitral valve prolapse Mitral stenosis Congestive heart failure Tetralogy of Fallot QT-interval prologation Hyper b-adrenergic state
Glaucoma Portal hypertension Migraine prophlyaxis Situational anxiety Panic attacks Schizophrenia Alcohol withdrawal Essential tremor Thyrotoxicosis
include a decrease in cardiac output, inhibition of renin secretion, central nervous system effects, decreased noradrenaline release by competitive inhibition of action of adrenaline on prejunctional b 2 receptors, resetting of baroreceptor levels, and reduction in plasma volume and vasomotor tone. Mechanism of Action Competitive b-adrenergic receptor antagonism is the common feature responsible for blood pressure lowering. These agents are classified based on their selectivity for b 1 or b 2 receptors. Distribution of b-adrenoreceptors varies depending on species and organ system. b 1 Adrenoreceptors are predominantly found in cardiac and adipose tissues, whereas b 2 adrenoreceptors are present in tissues such as bronchi and vasculature.2. Effect of b-blockers on either receptor depends on receptor selectivity and drug concentration. Selectivity is lost with increasing doses of the drug. In addition, certain agents are nonselective, and effects are mediated by both receptor types. Finally, certain b-blockers possess both a- as well as b-blocking effects, resulting in vasodilator activity. Labetalol and carvedilol are 2 b-blockers with concomitant a blocking effect. Carvedilol, in addition to a- and b-blocking effects, has antioxidant and antiproliferative properties. Similarly, nebivolol, which is currently available in Europe, activates nitric oxide synthase in blood vessels in addition to b-adrenergic blocking effects.
Pharmacokinetics b-blockers vary widely in their structure and their pharmacokinetics (Table 2). Important attributes include partial b-agonist activity, otherwise known as intrinsic sympathomimetic activity (ISA), lipid solubility, membrane stabilizing activity, and combined a- and b-blocking activity. Absorption Most of the b-blockers are well absorbed in the small intestine. Exceptions such as nadolol and atenolol are less well absorbed from the gut.3 Rates of absorption ranges vary from 30% for nadolol to more than 90% for most of the other agents in this class. Absorption tends to be rapid for the short-acting lipid soluble drugs, whereas water-soluble drugs take longer. Lipid Solubility Lipid-soluble agents have a relatively low and variable oral bioavailability as they are metabolized in the wall of the gastrointestinal tract as well as the liver. Lipid-soluble drugs have unpredictable levels in patients receiving drugs that alter metabolism and hepatic blood flow, especially in the elderly or in patients with congestive heart failure and liver cirrhosis. In contrast, hydrophilic agents have relatively poorer absorption from the gut and are excreted from the kidneys relatively unchanged and have
Fig 1. Schematic representation of proposed b -blocker usage in management of hypertension. b -Blockers should not be used as first-line agents in patients with uncomplicated hypertension. In comparison, patients with specific morbidities such as CHF and post-MI, b -blocker use is suggested unless contraindicated.
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Table 2. Pharmacokinetic Differences Among b -Blockers
Acebutolol Atenolol Betaxolol Bisoprolol Bucindolol Carteolol Carvedilol Celiprolol Esmolol Labetalol Metoprolol Nadolol Nebivolol Oxprenolol Penbutolol Pindolol Propranolol Sotalol Timolol
Lipid Solubility
Bioavailability
Selectivity
ISA
Clearance
Low Low Low Low Moderate Low Moderate Low Low Moderate Moderate Low Low Moderate High Moderate High Low Low
~40 ~40 ~80 ~88 ~30 ~90 ~30 ~30 NA ~33 ~50 ~30 12-96 19-74 ~100 ~90 30-70 ~90 ~75
b1 b1 b1 b1 b1, b2 b1, b 2 b1, b2 and a1 b1 and a2 b1 b1, b2, and a1 b1 b1, b2 b1 b1, b2 b1, b2 b1, b2 b1, b2 b1, b2 b1, b2
+ + + + + + + +
Liver/biliary Kidney Liver Liver/kidney Liver Kidney Liver/biliary Kidney Erthryocytes Liver Liver Kidney Kidney Kidney Liver Liver/kidney Liver Kidney Liver
poor transport across the blood brain barrier. These drugs tend to have a longer half-life, which is further increased in renal insufficiency. Interaction of hydrophilic agents with other liver-metabolized drugs is minimal. Lipid solubility is associated with certain central nervous side effects such as confusion, lethargy, depression, vivid dreams, and nightmares. Similarly, this property provides clinical use in certain patients with tremors and anxiety. Intrinsic Sympathetic Activity Intrinsic sympathomimetic activity refers to partial agonist properties of certain b-blockers resulting in characteristic pharmacologic attributes including profound hemodynamic effects. The overall effect depends on the sympathetic state of the patient. b-Blockers with b 1 ISA results in decreased reduction in heart rate and cardiac output, which may blunt the antihypertensive effect. Drugs with b 2 ISA result in higher cardiac output due to stimulation of b 2 vasodilator receptors and resultant vasodilation. Membrane-Stabilizing Activity Certain b-blockers possess the ability to exert a quinidine-like effect or local anesthetic effect at doses much higher than those required to produce effective b-blockade. Importantly, membrane-stabilizing activity does not contribute to the antihypertensive effect.
Clinical Effects and Applications Wide variance in effects due to differences in selectivity and other attributes, as mentioned earlier, have allowed use of b-blockers in a wide spectrum of clinical conditions. Discussion in this review is limited to role of b-blockers in management of patients with uncomplicated hypertension as well as those with certain specific comorbidities. b-Blocker and Primary Prevention Despite the endorsement of b-blockers by JNC IV, V, VI, and VII as a first-line agent along with diuretics in uncomplicated hypertension, no study has clearly documented that monotherapy with b-blockers or b-blocker–based therapy reduces morbidity and mortality compared with placebo. Although b-blockers indeed do have efficacy in lowering blood pressure, traditional b-blockers are not known to be effective in preventing coronary artery disease, cardiovascular mortality, and all-cause mortality. Table 3 provides a chronological summary of important clinical trials4 - 24 involving use of b-blockers in management of hypertension. According to the Medical Research Council (MRC) studies, bb-blockers failed to significantly reduce cardiovascular morbidity and mortality. . .and in fact, the stroke rate was 2 to 4 times higher in patients receiving b-blockers.Q In the Losartan Intervention for Endpoint Reduction in
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Table 3. Summary of Important Clinical Trials Involving b -Blockers Trial
Year
Mean Age (y)
VA COOP MRC
1982 1985
49.7 52
Patients
IPPPSH HEP Berglund HAPPHY
1985 1986 1986 1988
52 68.8 50 52.2
348 8700 13057 6357 884 106 6569
STOP
1991
75.7
1627
Yurenev MRC-old
1992 1992
45.5 70.3
TEST UKPDS CAPPP STOP2
1995 1998 1999 1999
70.4 56.2 52.5 76
304 2183 3315 720 758 10985 6614
NORDIL ELSA AASK LIFE DUTCH TIA CONVINCE INVEST ASCOT-BPLA
2000 2002 2002 2002 2003 2003 2003 2005
60.4 56 54.6 66.9 65 65.6 66.1 63
10881 2334 1094 9193 1473 16476 22576 19257
b-Antagonist
Comparison drug
Propranolol Propranolol Propranolol Oxprenolol Atenolol Propranolol Atenolol Metoprololpropranolol Atenolol Metoprolol Pindolol Propranolol Atenolol Atenolol Atenolol Atenolol
Hydrochlorothiazide Bendroflumethiazide Placebo Placebo Open Control Bendroflumethiazide Hydrochlorothiazide Bendroflumethiazide Placebo
Atenolol Metoprolol Pindolol Any b-antagonist Atenolol Atenolol Atenolol Atenolol Atenolol Atenolol
Hypertension Study (LIFE) trial, where an atenolol-based was compared with a losartanbased strategy in patients with left ventricular hypertrophy (LVH), losartan was found to be superior to atenolol therapy alone or in combination in patients with hypertension and diabetes. Despite nearly identical blood pressure reduction, atenolol-treated patients experienced a 13% greater risk of death and a 25% greater risk of fatal or nonfatal stroke than losartantreated patients. In the Dutch Transient Ischemic Attack (DUTCH TIA) trial, use of atenolol significantly lowered blood pressure but resulted in no protection for fatal or nonfatal MI and recurrent stroke, as compared with placebo in patients with previous transient ischemic attack or nondisabling ischemic stroke. Two recent meta-analyses from Lindholm et al25,26 showed no benefit associated with use of b-blockers in primary prevention. The studies showed that although atenolol reduced blood pressure greater than placebo and, comparably, with other antihypertensive agents, there was no difference in mortality or MI compared with placebo and an
Diuertic Diuertic Placebo Placebo Captopril ACE Enalapril Lisinopril Felodipine Diltiazem Lacidipine Calcium/ACE Losartan Placebo Verapamil Verapamil Amlodipine
Follow-up (y) 1.5 5.5 4.0 4.4 10 3.8 2.1 4.0 5.8 2.6 9.0 5.0 4.5 3.75 4.8 2.6 3.0 2.7 5.7
increased risk of mortality and stroke, compared with other antihypertensives. Atenolol resulted in nonsignificant reduction in stroke compared with placebo, although there was a significant difference in blood pressure in both groups.25 In the second meta-analysis, authors included different b-blockers, thus extending their analysis beyond atenolol.26 In their meta-analysis including 13 trials comparing b-blockers with other antihypertensive patients, authors reported 16% higher relative risk of stroke with b-blockers (95% confidence interval [CI], 4-30%; P = .009) than with other drugs. A tendency for all-cause mortality was seen in the same direction, the relative risk being increased by 3% for b-blockers (95% CI, 1% to 8%; P = .14). There was, however, no difference for MI. Analysis of 7 trials comparing b-blockers with placebo or no antihypertensive treatment showed a relative risk reduction of stroke by 19% (95% CI, 7%-21%) associated with b-blockers use. Indeed, although b-blockers were more efficacious compared with placebo, this modest reduction was much lower than previous or expected estimates. In an
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associated editorial, Beevers27 aptly quipped about bthe end of b-blockers for uncomplicated hypertension.Q We previously found, in a metaanalysis of 10 placebo-controlled clinical trials of more than 16 000 elderly patients (=60 years old), that although traditional b-blockers significantly lowered blood pressure, they were ineffective in preventing coronary heart disease, defined as fatal or nonfatal MI and sudden cardiac death, cardiovascular mortality, and all-cause mortality.28 Subsequently, several authors raised the concern of differential effect of b-blockers based on age groups. It was postulated that although elderly patients may have decreased arterial compliance and b-blockers may further depress the cardiac output, younger patients seem to have a higher adrenergic state, as seen from a recent report from the Framingham group and, thus, may benefit from b-blockade. To address this issue, Khan and McAlister29 performed a meta-analysis of hypertension trials involving b-blockers wherein they separated trials based on the mean age of enrolled patients at baseline. Studies were reanalyzed based on 2 categories: mean age equal to or greater than 60 years or those younger than 60 years. Unlike meta-
analysis by Lindholm et al,26 where the study end points were MI, stroke, or death, separately, Khan and McAlister focused on composite end points. Results involving elderly patients were similar to the previous meta-analyses; b-blockers showed a similar lack of efficacy compared with other antihypertensive agents and reduced major cardiovascular outcomes, compared with placebo. In contrast, although younger patients, when compared with other antihypertensive agents, had similar outcomes on b-blockers, a reduction in cardiovascular outcomes was demonstrated on comparison with placebo. In addition to differences in studied end points, the analysis by Khan and McAlister incorporated 3 studies,4,15,19 which were excluded in previous meta-analysis due to paucity of data regarding b-blocker use, quality concerns, and comorbidity of included patients. Hypertension in the elderly is marked by reduced cardiac output and increased peripheral vascular resistance (Table 4).30 Traditional b-blockers lower blood pressure by reducing cardiac output through their negative inotropic effect and induce a compensatory increase in vascular tone mediated through a 1 vascular
Table 4. Possible Reasons for Poor Performance of b -Blockers in Elderly Pathophysiologic entity
Specific changes in the elderly4
Effect of by-Blockade
Further decrease in cardiac output and heart rate; further increase in vascular resistance29,30 Blood pressure pattern Lesser effect on systolic blood pressure Hypertensive heart disease Least efficient in reducing LVH31-36 Hypertensive renal disease Further decrease in renal blood flow and glomerular infiltration rate; no effect on microproteinuria40-44 Hypertensive No effect on arterial stiffness or vascular disease hypertrophy (in contrast to other drugs)46,47 Metabolic effects Insulin resistance, glucose intolerance, Increase the risk of developing and lipid abnormalities are common. diabetes by 4 to 648-52; increase in triglycerides and decrease in high-density lipoprotein cholesterol52-62 54,56-62 b-Adrenergic responsiveness Decreased Diminished efficacy60 Exercise tolerance Decreased Further decrease in exercise tolerance Comorbidity Chronic obstructive pulmonary disease, Affecting all of these comorbid peripheral vascular disease, diabetes mellitus, conditions adversely depression, dementia, and sexual dysfunction are common
Systemic hemodynamics
Decreased cardiac output, and heart rate; elevated systemic vascular resistance27,28 Predominantly systolic hypertension Left ventricular hypertrophy is common. Decreased renal blood flow, glomerular infiltration rate, and increased microproteinuria36-43 Increased arterial stiffness, vascular hypertrophy45
Adapted with permission from JAMA 1998;279:1903-1907. 4Compared with younger patients with similar blood pressure elevation. yWith the exception of the vasodilating blockers.
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receptors. In addition, nonselective b-blockers can also promote vasoconstriction by blocking vasodilatory b 2 vascular receptors.31 Cardioselective b-blockers with low lipid solubility may have a preferable side effect profile in older persons. b-Blockers that are lipophilic cross the blood-brain barrier, possibly causing more sedation, depression, and sexual dysfunction in older patients.22 Particularly in older patients, b-blockers as a class can cause bradycardia, conduction abnormalities, and acute heart failure if started too aggressively in patients with preexisting left ventricular dysfunction.6,22,23 However, b-blockers remain a cornerstone in management of CHF. Multiple experimental and clinical studies have demonstrated that b-blocker alters adrenergic activity and resultant gene expression, thereby reducing myocyte dysfunction, changes in Ca2+ handling, cell loss, and cell and ventricular remodeling. Early initiation of b-blocker and reaching target dose results in improvement of ventricular function, symptoms, and rate of hospitalization, leads to reversal of remodeling, and decreases mortality. Poor efficacy of b-blockers in the elderly may be attributed to unfavorable effects on the hemodynamics in the vasculature and end organs and metabolism. Thus, b-blockers are not suited as first-line agents for hypertension in the elderly unless there are other comorbid conditions such as CHF or MI.32 Whether newer b-blockers have a role to play in younger patients with uncomplicated patients is not clear. While exploring possible role of b-blockers in younger patients with uncomplicated hypertension, we should keep in mind the metabolic and hyperglycemic side effects associated with their use in this population, which may be exposed to them for long duration. Left Ventricular Hypertrophy Multiple studies have shown that b-blockers perform poorly, as compared with other antihypertensive agents in reducing LVH. A metaanalysis of 80 double-blind, randomized, controlled trials with 3767 hypertensive patients found that b-blockers were the least effective in reducing left ventricular mass compared with angiotensin receptor blockers, calcium-channel antagonists, and ACE inhibitors despite similar
blood pressure reduction among these antihypertensive drug classes ( P = .004).33 Similarly, in the LIFE study, which was one of the largest trials on antihypertensive treatment in patients with LVH, atenolol was less effective in reduction of left ventricular mass, compared with losartan. In a randomized study with 42 elderly patients with hypertension, atenolol failed to reduce left ventricular mass, compared with verapamil after 6 months of treatment despite comparable blood pressure lowering.34 Post-MI and Left Ventricular Dysfunction In acute setting, b-blockers are useful in patients with ventricular arrhythmias and, thus, prevention of sudden cardiac death. The routine use of b-blockers in post MI patients has been shown to reduce cardiovascular mortality. Noteworthy trials supporting the role of b-blockade in postMI are b-Blocker Heart Attack Trial,35 Norwegian Multicenter Study of Timolol after Myocardial Infarction,36 and the Carvedilol Post-Infarct Survival Control in LV Dysfunction trial.37 Some of these trials were meta-analyzed by Houghton et al38 showing a 22.6 % reduction in odds of death. The b-Blocker Heart Attack Trial compared the incidence of coronary events in 3837 patients receiving propanolol or placebo. Patients were followed up for an average of 25 months, and the trial was terminated early on evidence of clear differences in reduction of coronary incidents (23%) in the propranolol group.35,39 Similarly, timolol was compared with placebo in the Norwegian Timolol study in 1884 patients. It was concluded that chronic treatment with timolol in survivors of acute MI who can tolerate b-adrenergic blockade is effective in reducing both total mortality and reinfarction over 33 months.36 More recently, the Carvedilol Post-Infarct Survival Control in LV Dysfunction trial compared effect of carvedilol and placebo on cardiovascular end points in 1959 survivors of acute MI with reduced ejection fractions. Carvediloltreated patients experienced a significant 23% greater reduction in all-cause mortality, a 25% greater reduction in cardiovascular death, and a 41% greater reduction in nonfatal recurrent MI compared with placebo-treated patients. Of note,
82 these patients were concomitantly treated with aspirin, ACE inhibitors, and statins. Post-MI patients with conditions that are often considered contraindications to b-blockade (such as heart failure, pulmonary disease, and older age) and nontransmural infarction may still benefit from b-blocker therapy.40 Controlled trials in patients who are post-MI with normal or close to normal left ventricular function are needed to assess use of b-blockers in this subgroup.41 b-Blockers in Acute Coronary Syndromes Multiple studies have addressed the role of b blocker use in acute coronary syndrome. Results from ISIS-1 show nonsignificant reduction of early inhospital events described as nonfatal cardiac arrests and reinfarctions with use of atenolol, as compared with placebo. Subsequent necropsy of patients with complication in the International Studies of Infarct Survival-1 (ISIS-1) study failed to reveal any b-blocker effect on limitation of infarct size or prevention of reinfarction or cardiac arrest. The extent of thrombolytic use in these studies is also not clear. The recent Clopidogrel and Metoprolol in Myocardial Infarction Trial42 involving 45 852 patients associated the early use of intravenous b-blockers in both high- and low-risk patients with acute MI with a highly significant 30% relative increase in the risk of cardiogenic shock. Although use of b-blockers resulted in a relative reduction of ventricular fibrillation and reinfarction by 15% to 20%, these benefits clearly did not outweigh the risk of cardiogenic shock. In addition, the beneficial effects on arrhythmias and reinfarction were more gradual in onset. Thus, the Clopidogrel and Metoprolol in Myocardial Infarction Trial supports use of oral b-blockers only when patient becomes hemodynamically stable and suggests avoiding intravenous use of b-blockers and use of b-blockers in general within 12 hours of acute MI. Diabetes Mellitus Risk of new-onset diabetes is elevated in nondiabetic hypertensive patients on treatment with b-blockers.43,44 As a consequence, b-blockers were considered to be relatively contraindicated in diabetes. Recent evidence points to the contrary. Although nonselective b-blockers can
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prevent normalization of blood glucose after an episode of hypoglycemia in patients on insulin and worsen insulin sensitivity and promote glucose imbalance, b 1-selective agents along with agents having a-blockade45 or b 2 ISA46 are noted to be less detrimental. Unfortunately, traditional b-blockers are associated with the worsening of insulin resistance, deterioration of glycemic control, peripheral vasoconstriction, potentially worsening peripheral vascular disease, and more frequent and severe hypoglycemia. Some of the newer b-blockers have unique properties, such as a 1 blockade, which may improve glycemic control and vasodilate resistance arterioles. The Carvedilol Or Metoprolol European Trial showed that, compared with metoprolol, use of carvedilol resulted in a decrease in new onset of diabetes in patients with heart failure.47 The Glycemic Effects in Diabetes Mellitus: Carvedilol-Metoprolol Comparison in Hypertensives trial,48 which compared carvedilol and metoprolol in patients with hypertension and type 2 diabetes mellitus, showed again that compared with metoprolol, carvedilol use was associated with improvement in insulin sensitivity, prevention of worsening of hemoglobin A1c, and microalbuminuria. More participants withdrew due to worsening glycemic control and needed statin therapy in the metoprolol group. In the Glycemic Effects in Diabetes Mellitus: Carvedilol-Metoprolol Comparison in Hypertensives, metoprolol (and carvedilol) was given twice a day, and no conclusion can be drawn as to the effect of long-acting metoprolol (Toprol XL) on glycemic control.
Drug Interactions Bioavailability of lipophilic b-blockers is decreased by those agents that induce hepatic biotransformation enzymes (eg, alcohol, phenytoin, rifampin, phenobarbital, and smoking). In contrast, drugs inhibiting hepatic enzymes (eg, cimetidine, hydralazine, etc) can increase bioavailability. Concomitant use of antiarrythmic drugs and nondihydropyridine calcium antagonists may cause sinus node or conduction anomalies. Nonsteroidal anti-inflammatory drugs may have an antagonistic effect on the antihypertensive
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effect of b-blockers. Coadministration of clonidine and b-blockers can result in elevated blood pressure, and stopping clonidine in presence of propranolol, like in one instance, resulted in cerebral hemorrhage.49
Side Effects Not only do the above studies give reason to believe that b-blockers should be abandoned as first-line agents in uncomplicated hypertension, but the list of adverse effects (Table 5) is longer than any of the other antihypertensive medications. This leads to a greater likelihood of poor compliance; discontinuation; and as a consequence, less successful blood pressure control.50 The dropout rate in b-blocker–treated patients due to adverse side effects in clinical trial is significant. Traditional nonselective b-blockers may also further reduce already-compromised renal blood flow in individuals with hypertension and may even decrease the glomerular filtration rate.51 Cardiovascular b-Blockers, by virtue of their chronotropic effects, reduce heart rate, reduce the firing rate of ectopic pacemakers, decrease conduction, and increase the refractory time of the atrioventricular (AV) node, resulting in bradycardia and AV block. b-Blockers should be used with caution in
Table 5. Adverse Effects Related to b -blockers General—arthralgias, asthenia, fatigue, diaphoresis, edema, myalgia, pharyngitis, urinary retention Central nervous system—depression, dizziness, hallucinations, headache, insomnia, nightmares, paresthesias Eye—lacrimation, ocular irritation, xerosis Cardiovascular—orthostatic hypotension, peripheral vasoconstriction, peripheral edema, QT prolongation, sinus bradycardia, syncope, torsade de pointes, ventricular tachycardia, angina, AV block, cardiac arrest Respiratory—bronchospasm, wheezing, dyspnea Gastrointestinal—jaundice, diarrhea, dyspepsia, hepatic necrosis, nausea, vomiting, constipation, flatulence, hypoglycemia, elevated liver function tests Sexual—erectile and ejaculation dysfunction, impotence, libido decrease Skin—skin hyperpigmentation, alopecia, exfoliative dermatitis, pruritis Metabolic—weight gain, increases cholesterol and triglycerides, increases insulin resistance
combination with other negative chronotropes, such as diltiazem, verapamil, or digoxin. b-Blockers may worsen symptoms of peripheral vascular disease by producing cold extremities and Raynaud’s phenomenon. b-Blockers with vasodilatory effects and b 1-selective agents may produce lesser effects on peripheral vasculature. b-Adrenergic antagonism with a nonselective blocker results in up-regulation of b-receptors. Suddenly stopping the drug exposes the upregulated receptors to catecholamines, resulting in rebound symptoms such as hypertension, arrhythmias, anxiety, and increased risk of myocardial ischemia in susceptible patients.52,53 Hence, b-blockers should be tapered over a period of a few days before discontinuation to minimize the risk of sudden rebound. Metabolic Use of nonselective b-blockers in type 1 diabetes mellitus may mask warning symptoms of hypoglycemia, including tremor and tachycardia. It is advised to use selective b-blockers in patients with type 1 diabetes mellitus.54 b-Blockers have been shown to increase triglyceride levels and decrease high-density lipoprotein levels. 55 b-Blockers with ISA have a smaller effect on serum lipoproteins, as compared with those lacking it. Pulmonary Use of b-blockers in patients with asthma or significant reactive airway disease can lead to life-threatening bronchospasm or increase in airway resistance. Although threat of worsening of airway disease exists, certain patients with chronic obstructive pulmonary disease may benefit from b-blockade.56 Hence, chronic obstructive pulmonary disease itself, in absence of significant reactive component, is not a contraindication to use of b-blockers. Sexual Dysfunction Certain patients may experience worsening impotence or loss of libido and orgasmic dysfunction. Higher rate of withdrawals resulting from impotence was seen in propanolol group, as compared with placebo in the MRC mild hypertension study.57,58
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Table 6. Effect of Antihypertensive Drugs on Hemodynamic and Metabolic Profile
Mean arterial blood pressure Total peripheral resistance Cardiac output Heart rate Activation of sympathetic nervous system Renin-angiotensin-aldosterone system Lipid metabolism Glucose metabolism
Ideal drug
Traditional b-blockers
Carvedilol
Decrease Decrease None None/decrease Decrease Decrease None/positive None/positive
Decrease Increase Decrease Decrease Decrease Decrease Negative Negative
Decrease Decrease None None/decrease Decrease Decrease None None
Adapted with permission from Am J Cardiol 93:7B-12B, 2004.
Central Effects As mentioned earlier, central effects are more common with lipophilic agents, as compared with hydrophilic agents.59 Central effects include fatigue, headache, sleep disturbance, nightmares, insomnia, vivid dreams, confusion, and depression.
Newer Agents b-Blockers as a class are still undoubtedly used widely (and inappropriately) for the treatment of hypertension. Nevertheless, it should be kept in mind that traditional b-blockers have an unfavorable and undesirable hemodynamic and metabolic profile. Despite that all b-blockers reduce blood pressure, newer b-blockers with vasodilatory effect may provide a better alternative. Carvedilol and nebivolol, newer b-blockers, have been shown to differ and perhaps have more benefits on cardiovascular effects than traditional b-blockers (Table 6). These agents maintain cardiac output, have a lesser effect on heart rate, and decrease blood pressure by decreasing systemic vascular resistance.60 Carvedilol increases plasma flow to the kidneys, as opposed to decreased glomerular filtration rate seen with traditional b-blockers. These hemodynamic properties are an advantage especially in the elderly where the cardiac output is low and systemic vascular resistance elevated. The beneficial effect of carvedilol and nebivolol on systemic resistance is similar to ACE inhibitors and calcium-channel blockers. Both of these b-blockers seem to have less metabolic adverse effects, then the traditional agents. This may particularly be of importance in younger patients who will be exposed to these drugs for a longer
duration. In addition, newer agents may be more efficacious at lowering central aortic pressures. As seen in the recently published Conduit Artery Function Evaluation study, aortic pulse pressure may be an independent predictor of cardiovascular events in hypertensive patients. In the Conduit Artery Function Evaluation study, atenolol had significantly different effect on aortic and brachial pressures.61 In contrast, vasodilating b-blockers maybe more effective in lowering aortic pressures.62
Conclusion b-Blockers have been and still are popular antihypertensive agents in clinical practice worldwide. However, the efficacy of b-blockers on cardiovascular events in hypertension has been poorly documented, and we ought to redraft the guidelines for b-blocker usage. Indeed, the British Hypertension Society (BHS)/National Institute for Health and Clinical Excellence guidelines recently were appropriately revised excluding b-blockers for management of uncomplicated hypertension. If b-blockers are indeed indicated, we perhaps should consider newer b-blockers rather than the traditional agents such as atenolol and metoprolol. Further evidence on the role of newer b-blockers in primary prevention of cardiovascular events and mortality in uncomplicated hypertension is needed.
References 1. Chobanian AV, Bakris GL, Black HR, et al: The seventh report of the joint national committee on prevention, detection, evaluation, and treatment of high blood pressure: The JNC 7 report. JAMA 289:2560 - 2572, 2003
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BETA BLOCKERS 2. Cruickshank JM, PB JM: Beta-blockers in clinical practice (ed 2). Churchill-Livingstone, Edinburgh, 1994, pp 1-1204 3. McDevitt DG: Comparison of pharmacokinetic properties of beta-adrenoceptor blocking drugs. Eur Heart J 8:9 - 14, 1987 (Suppl M) 4. Comparison of propranolol and hydrochlorothiazide for the initial treatment of hypertension. II. Results of long-term therapy. Veterans Administration Cooperative Study Group on antihypertensive agents. JAMA 248:2004 - 2011, 1982 5. MRC trial of treatment of mild hypertension: principal results. Medical Research Council Working Party. Br Med J (Clin Res Ed) 291:97 - 104, 1985 6. Cardiovascular risk and risk factors in a randomized trial of treatment based on the beta-blocker oxprenolol: The International Prospective Primary Prevention Study in Hypertension (IPPPSH). The IPPPSH Collaborative Group. J Hypertens 3:379 - 392, 1985 7. Coope J, Warrender TS: Randomised trial of treatment of hypertension in elderly patients in primary care. Br Med J (Clin Res Ed) 293:1145 - 1151, 1986 8. Berglund G, Andersson O, Widgren B, et al: Lowdose antihypertensive treatment with a thiazide diuretic is not diabetogenic. A 10-year controlled trial with bendroflumethiazide. Acta Med Scand 220: 419 - 424, 1986 9. Wilhelmsen L, Berglund G, Elmfeldt D, et al: Betablockers versus diuretics in hypertensive men: Main results from the HAPPHY trial. J Hypertens 5: 561 - 572, 1987 10. Dahlof B, Lindholm LH, Hansson L, et al: Morbidity and mortality in the Swedish Trial in Old Patients with Hypertension (STOP-Hypertension). Lancet 338: 1281 - 1285, 1991 11. Yurenev AP, Dyakonova HG, Novikov ID, et al: Management of essential hypertension in patients with different degrees of left ventricular hypertrophy. Multicenter trial. Am J Hypertens 5:182S - 189S, 1992 (6 Pt 2) 12. Medical Research Council trial of treatment of hypertension in older adults: Principal results. MRC working party. BMJ 304:405 - 412, 1992 13. Eriksson SE, Olsson JE: Survival and recurrent strokes in patients with different subtypes of stroke: A fourteen-year follow-up study. Cerebrovasc Dis 12: 171 - 180, 2001 14. United Kingdom Prospective Diabetes Study (UKPDS): 13: Relative efficacy of randomly allocated diet, sulphonylurea, insulin, or metformin in patients with newly diagnosed non–insulin dependent diabetes followed for three years. Bmj 310:83 - 88, 1995 15. Hansson L, Lindholm LH, Niskanen L, et al: Effect of angiotensin-converting-enzyme inhibition compared with conventional therapy on cardiovascular morbidity and mortality in hypertension: The Captopril Prevention Project (CAPPP) randomised trial. Lancet 353:611 - 616, 1999 16. Hansson L, Lindholm LH, Ekbom T, et al: Randomised trial of old and new antihypertensive drugs in
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elderly patients: cardiovascular mortality and morbidity the Swedish Trial in Old Patients with Hypertension–2 study. Lancet 354:1751 - 1756, 1999 Hansson L, Hedner T, Lund-Johansen P, et al: Randomised trial of effects of calcium antagonists compared with diuretics and beta-blockers on cardiovascular morbidity and mortality in hypertension: The Nordic Diltiazem (NORDIL) study. Lancet 356: 359 - 365, 2000 Zanchetti A, Bond MG, Hennig M, et al: Calcium antagonist lacidipine slows down progression of asymptomatic carotid atherosclerosis: principal results of the European Lacidipine Study on Atherosclerosis (ELSA), a randomized, double-blind, longterm trial. Circulation 106:2422 - 2427, 2002 Wright Jr JT, Bakris G, Greene T, et al: Effect of blood pressure lowering and antihypertensive drug class on progression of hypertensive kidney disease: Results from the AASK trial. JAMA 288: 2421 - 2431, 2002 Dahlof B, Devereux RB, Kjeldsen SE, et al: Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): A randomised trial against atenolol. Lancet 359:995 - 1003, 2002 Trial of secondary prevention with atenolol after transient ischemic attack or nondisabling ischemic stroke. The Dutch TIA Trial Study Group. Stroke 24:543 - 548, 1993 Black HR, Elliott WJ, Grandits G, et al: Principal results of the Controlled Onset Verapamil Investigation of Cardiovascular End Points (CONVINCE) trial. JAMA 289:2073 - 2082, 2003 Pepine CJ, Handberg EM, Cooper-DeHoff RM, et al: A calcium antagonist vs a non-calcium antagonist hypertension treatment strategy for patients with coronary artery disease. The International Verapamil-Trandolapril Study (INVEST): A randomized controlled trial. JAMA 290:2805 - 2816, 2003 Dahlof B, Sever PS, Poulter NR, et al: Prevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial–Blood Pressure Lowering Arm (ASCOT-BPLA): A multicentre randomised controlled trial. Lancet 366:895 - 906, 2005 Carlberg B, Samuelsson O, Lindholm LH: Atenolol in hypertension: Is it a wise choice? Lancet 364: 1684 - 1689, 2004 Lindholm LH, Carlberg B, Samuelsson O: Should beta blockers remain first choice in the treatment of primary hypertension? A meta-analysis. Lancet 366:1545 - 1553, 2005 Beevers DG: The end of beta blockers for uncomplicated hypertension? Lancet 366:1510 - 1512, 2005 Messerli FH, Grossman E, Goldbourt U: Are betablockers efficacious as first-line therapy for hypertension in the elderly? A systematic review. JAMA 279:1903 - 1907, 1998
86 29. Khan N, McAlister FA: Re-examining the efficacy of beta-blockers for the treatment of hypertension: A meta-analysis. CMAJ 174:1737 - 1742, 2006 30. Messerli FH, Sundgaard-Riise K, Ventura HO, et al: Essential hypertension in the elderly: haemodynamics, intravascular volume, plasma renin activity, and circulating catecholamine levels. Lancet 2:983 - 986, 1983 31. Weber K, Bohmeke T, van der Does R, et al: Comparison of the hemodynamic effects of metoprolol and carvedilol in hypertensive patients. Cardiovasc Drugs Ther 10:113 - 117, 1996 32. Grossman E, Messerli FH: Why beta-blockers are not cardioprotective in elderly patients with hypertension. Curr Cardiol Rep 4:468 - 473, 2002 33. Klingbeil AU, Schneider M, Martus P, et al: A metaanalysis of the effects of treatment on left ventricular mass in essential hypertension. Am J Med 115:41 - 46, 2003 34. Schulman SP, Weiss JL, Becker LC, et al: The effects of antihypertensive therapy on left ventricular mass in elderly patients. N Engl J Med 322: 1350 - 1356, 1990 35. The beta-blocker heart attack trial. beta-Blocker Heart Attack Study Group. JAMA 246:2073 - 2074, 1981 36. Pedersen TR: The Norwegian multicenter study of timolol after myocardial infarction. Circulation 67:I49, 1983 (6 Pt 2) 37. Dargie HJ: Effect of carvedilol on outcome after myocardial infarction in patients with left-ventricular dysfunction: the CAPRICORN randomised trial. Lancet 357:1385 - 1390, 2001 38. Houghton T, Freemantle N, Cleland JGF, et al: Are beta-blockers effective in patients who develop heart failure soon after myocardial infarction? A metaregression analysis of randomised trials. Eur J Heart Fail 2:333 - 340, 2000 39. A randomized trial of propranolol in patients with acute myocardial infarction. II. Morbidity results. JAMA 250:2814 - 2819, 1983 40. Gottlieb SS, McCarter RJ, Vogel RA: Effect of betablockade on mortality among high-risk and low-risk patients after myocardial infarction. N Engl J Med 339:489 - 497, 1998 41. Mickley H, Eiskjaer H, Botker HE: Is an additional post-myocardial infarction beta-blocker trial required in the era of early revascularization? Eur Heart J 25:96 - 97, 2004 42. Chen ZM, Pan HC, Chen YP, et al: Commit (CLOPIDOGREL and METOPROLOL in Myocardial Infarction Trial) Collaboration Group. Lancet 366:1622 - 1632, 2005 43. Bengtsson C, Blohme G, Lapidus L, et al: Diabetes incidence in users and non-users of antihypertensive drugs in relation to serum insulin, glucose tolerance and degree of adiposity: A 12-year prospective population study of women in Gothenburg, Sweden. J Intern Med 231:583 - 588, 1992 44. Pollare T, Lithell H, Selinus I, et al: Sensitivity to insulin during treatment with atenolol and metoprolol: A randomised, double blind study of effects on
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carbohydrate and lipoprotein metabolism in hypertensive patients. BMJ 298:1152 - 1157, 1989 Ehmer B, van der Does R, Rudorf J: Influence of carvedilol on blood glucose and glycohaemoglobin A1 in non–insulin-dependent diabetics. Drugs 36: 136 - 140, 1988 (Suppl 6) Poirier L, Cleroux J, Nadeau A, et al: Effects of nebivolol and atenolol on insulin sensitivity and haemodynamics in hypertensive patients. J Hypertens 19:1429 - 1435, 2001 Poole-Wilson PA, Swedberg K, Cleland JG, et al: Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol Or Metoprolol European Trial (COMET): Randomised controlled trial. Lancet 362:7 - 13, 2003 Bakris GL, Fonseca V, Katholi RE, et al: Metabolic effects of carvedilol vs metoprolol in patients with type 2 diabetes mellitus and hypertension: A randomized controlled trial. JAMA 292:2227 - 2236, 2004 Vernon C, Sakula A: Fatal rebound hypertension after abrupt withdrawal of clonidine and propranolol. Br J Clin Pract 33:112 - 121, 1979 Messerli FH, Beevers DG, Franklin SS, et al: betaBlockers in hypertension—the emperor has no clothes: an open letter to present and prospective drafters of new guidelines for the treatment of hypertension. Am J Hypertens 16:870 - 873, 2003 Heitmann M, Davidsen U, Stokholm KH, et al: Renal and cardiac function during alpha1-beta–blockade in congestive heart failure. Scand J Clin Lab Invest 62:97 - 104, 2002 Houston MC, Hodge R: Beta-adrenergic blocker withdrawal syndromes in hypertension and other cardiovascular diseases. Am Heart J 116:515 - 523, 1988 (2 Pt 1) Psaty BM, Koepsell TD, Wagner EH, et al: The relative risk of incident coronary heart disease associated with recently stopping the use of beta-blockers. JAMA 263:1653 - 1657, 1990 Cruickshank JM: Beta-blockers continue to surprise us. Eur Heart J 21:354 - 364, 2000 Grimm RH Jr3: Antihypertensive therapy: taking lipids into consideration. Am Heart J 122:910 - 918, 1991 (3 Pt 2) Chen J, Radford MJ, Wang Y, et al: Effectiveness of beta-blocker therapy after acute myocardial infarction in elderly patients with chronic obstructive pulmonary disease or asthma. J Am Coll Cardiol 7:1950 - 1956, 2001 Adverse reactions to bendrofluazide and propranolol for the treatment of mild hypertension. Report of Medical Research Council Working Party on Mild to Moderate Hypertension. Lancet 2:539 - 543, 1981 Messerli FH, Grossman E: Beta-blocker therapy and depression. JAMA 16 288:1845 - 1846, 2002 [author reply 1846] Salem SA, McDevitt DG: Central effects of betaadrenoceptor antagonists. Clin Pharmacol Ther 33: 52 - 57, 1983
BETA BLOCKERS 60. Messerli FH, Grossman E: Beta-blockers in hypertension: Is carvedilol different? Am J Cardiol 93: 7B - 12B, 2004 61. Williams B, Lacy PS, Thom SM, et al: Differential impact of blood pressure-lowering drugs on central aortic pressure and clinical outcomes: Prin-
87 cipal results of the Conduit Artery Function Evaluation (CAFE) study. Circulation 113:1213 - 1225, 2006 62. Kelly R, Daley J, Avolio A, et al: Arterial dilation and reduced wave reflection. Benefit of dilevalol in hypertension. Hypertension 14:14 - 21, 1989
b-Blockers are used commonly worldwide in clinical practice for lowering blood pressure. Most of the agents in this class are efficacious in reducing blood pressure, although they vary widely in their pharmacokinetic and pharmacodynamic properties. This variability may confer significant differences in clinical benefits associated with use of specific agents. Although commonly used in managing hypertension, the role of b-blockers for primary prevention in uncomplicated hypertension has been controversial. Evidence from recent trials suggest relatively poor efficacy toward primary prevention and worse outcomes for certain end points, when compared with other blood pressure– lowering agents, Recently updated National Institute for Health and Clinical Excellence guidelines for England and Wales reflect this concern and have changed the indication for b-blockers for blood pressure control from primary agents to use as an add-on agent in patients requiring multiple therapy. In this review, considering the extended debate on this topic, we discuss the general properties of b-blockers and evidence from clinical trials supporting or refuting their use in various clinical scenarios. Newer b-blockers have additional properties which may be beneficial. Although, whether these additional benefits will help in primary prevention is not clear. n 2006 Elsevier Inc. All rights reserved.
B
y definition, all antihypertensives lower blood pressure. Such medications include b-blockers, diuretics, calcium antagonists, From the Department of Cardiology, St. Lukes-Roosevelt Hospital Center, Department of Medicine, Division of Cardiology, Columbia University, NY. Address reprint request to Franz H. Messerli, MD, Division of Cardiology, St. Luke’s Roosevelt Hospital, Suite 3B.30, 1000 10th Avenue, New York, NY 10019. E-mail: [email protected] 0033-0620/$ - see front matter n 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.pcad.2006.07.002
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angiotensin-converting enzyme (ACE) inhibitors, and angiotensin receptor inhibitors. However, the goal of treatment is not only so much as to lower blood pressure but, more importantly, the reduction of morbidity and mortality, that is, stroke, coronary artery disease, myocardial infarction (MI), congestive heart failure (CHF), and end-stage renal disease. Careful selection of antihypertensive agents based on efficacy and safety is essential.
Historical Perspective and Clinical Use b-Blockers were first described in 1964 and were developed for the treatment of angina pectoris and arrhythmias. Subsequently, indications widened to encompass a multitude of clinical scenarios including Food and Drug Administration approval as antihypertensive agent in 1967. Currently, b-blockers are commonly used in clinical practice for a variety of cardiac and noncardiac indications (Table 1). Importantly, b-blockers are recommended as first-line agents or in combination with other classes of antihypertensive drugs as per the JNC (Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure) VII guidelines1 and are routinely prescribed in clinical settings for control of hypertension. However, there is little evidence supporting the use of b-blockers as a first-line agent in uncomplicated hypertension, although use of b-blockers in specific patient populations is still beneficial and appropriate (Fig 1).
Antihypertensive Effect The exact mechanism of blood pressure–lowering effect of b-blockers is debatable but is probably multifactorial. Various proposed mechanisms
Progress in Cardiovascular Diseases, Vol. 49, No. 2 (September/October), 2006: pp 76-87
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BETA BLOCKERS
Table 1. Clinical Indications for b -Blockers Cardiac
Noncardiac
Hypertension Angina pectoris Myocardial ischemia Supraventricular arrythmias Ventricular arrhythmias Dissection of aorta Hypertrophic cardiomyopathy Digitalis intoxication Mitral valve prolapse Mitral stenosis Congestive heart failure Tetralogy of Fallot QT-interval prologation Hyper b-adrenergic state
Glaucoma Portal hypertension Migraine prophlyaxis Situational anxiety Panic attacks Schizophrenia Alcohol withdrawal Essential tremor Thyrotoxicosis
include a decrease in cardiac output, inhibition of renin secretion, central nervous system effects, decreased noradrenaline release by competitive inhibition of action of adrenaline on prejunctional b 2 receptors, resetting of baroreceptor levels, and reduction in plasma volume and vasomotor tone. Mechanism of Action Competitive b-adrenergic receptor antagonism is the common feature responsible for blood pressure lowering. These agents are classified based on their selectivity for b 1 or b 2 receptors. Distribution of b-adrenoreceptors varies depending on species and organ system. b 1 Adrenoreceptors are predominantly found in cardiac and adipose tissues, whereas b 2 adrenoreceptors are present in tissues such as bronchi and vasculature.2. Effect of b-blockers on either receptor depends on receptor selectivity and drug concentration. Selectivity is lost with increasing doses of the drug. In addition, certain agents are nonselective, and effects are mediated by both receptor types. Finally, certain b-blockers possess both a- as well as b-blocking effects, resulting in vasodilator activity. Labetalol and carvedilol are 2 b-blockers with concomitant a blocking effect. Carvedilol, in addition to a- and b-blocking effects, has antioxidant and antiproliferative properties. Similarly, nebivolol, which is currently available in Europe, activates nitric oxide synthase in blood vessels in addition to b-adrenergic blocking effects.
Pharmacokinetics b-blockers vary widely in their structure and their pharmacokinetics (Table 2). Important attributes include partial b-agonist activity, otherwise known as intrinsic sympathomimetic activity (ISA), lipid solubility, membrane stabilizing activity, and combined a- and b-blocking activity. Absorption Most of the b-blockers are well absorbed in the small intestine. Exceptions such as nadolol and atenolol are less well absorbed from the gut.3 Rates of absorption ranges vary from 30% for nadolol to more than 90% for most of the other agents in this class. Absorption tends to be rapid for the short-acting lipid soluble drugs, whereas water-soluble drugs take longer. Lipid Solubility Lipid-soluble agents have a relatively low and variable oral bioavailability as they are metabolized in the wall of the gastrointestinal tract as well as the liver. Lipid-soluble drugs have unpredictable levels in patients receiving drugs that alter metabolism and hepatic blood flow, especially in the elderly or in patients with congestive heart failure and liver cirrhosis. In contrast, hydrophilic agents have relatively poorer absorption from the gut and are excreted from the kidneys relatively unchanged and have
Fig 1. Schematic representation of proposed b -blocker usage in management of hypertension. b -Blockers should not be used as first-line agents in patients with uncomplicated hypertension. In comparison, patients with specific morbidities such as CHF and post-MI, b -blocker use is suggested unless contraindicated.
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Table 2. Pharmacokinetic Differences Among b -Blockers
Acebutolol Atenolol Betaxolol Bisoprolol Bucindolol Carteolol Carvedilol Celiprolol Esmolol Labetalol Metoprolol Nadolol Nebivolol Oxprenolol Penbutolol Pindolol Propranolol Sotalol Timolol
Lipid Solubility
Bioavailability
Selectivity
ISA
Clearance
Low Low Low Low Moderate Low Moderate Low Low Moderate Moderate Low Low Moderate High Moderate High Low Low
~40 ~40 ~80 ~88 ~30 ~90 ~30 ~30 NA ~33 ~50 ~30 12-96 19-74 ~100 ~90 30-70 ~90 ~75
b1 b1 b1 b1 b1, b2 b1, b 2 b1, b2 and a1 b1 and a2 b1 b1, b2, and a1 b1 b1, b2 b1 b1, b2 b1, b2 b1, b2 b1, b2 b1, b2 b1, b2
+ + + + + + + +
Liver/biliary Kidney Liver Liver/kidney Liver Kidney Liver/biliary Kidney Erthryocytes Liver Liver Kidney Kidney Kidney Liver Liver/kidney Liver Kidney Liver
poor transport across the blood brain barrier. These drugs tend to have a longer half-life, which is further increased in renal insufficiency. Interaction of hydrophilic agents with other liver-metabolized drugs is minimal. Lipid solubility is associated with certain central nervous side effects such as confusion, lethargy, depression, vivid dreams, and nightmares. Similarly, this property provides clinical use in certain patients with tremors and anxiety. Intrinsic Sympathetic Activity Intrinsic sympathomimetic activity refers to partial agonist properties of certain b-blockers resulting in characteristic pharmacologic attributes including profound hemodynamic effects. The overall effect depends on the sympathetic state of the patient. b-Blockers with b 1 ISA results in decreased reduction in heart rate and cardiac output, which may blunt the antihypertensive effect. Drugs with b 2 ISA result in higher cardiac output due to stimulation of b 2 vasodilator receptors and resultant vasodilation. Membrane-Stabilizing Activity Certain b-blockers possess the ability to exert a quinidine-like effect or local anesthetic effect at doses much higher than those required to produce effective b-blockade. Importantly, membrane-stabilizing activity does not contribute to the antihypertensive effect.
Clinical Effects and Applications Wide variance in effects due to differences in selectivity and other attributes, as mentioned earlier, have allowed use of b-blockers in a wide spectrum of clinical conditions. Discussion in this review is limited to role of b-blockers in management of patients with uncomplicated hypertension as well as those with certain specific comorbidities. b-Blocker and Primary Prevention Despite the endorsement of b-blockers by JNC IV, V, VI, and VII as a first-line agent along with diuretics in uncomplicated hypertension, no study has clearly documented that monotherapy with b-blockers or b-blocker–based therapy reduces morbidity and mortality compared with placebo. Although b-blockers indeed do have efficacy in lowering blood pressure, traditional b-blockers are not known to be effective in preventing coronary artery disease, cardiovascular mortality, and all-cause mortality. Table 3 provides a chronological summary of important clinical trials4 - 24 involving use of b-blockers in management of hypertension. According to the Medical Research Council (MRC) studies, bb-blockers failed to significantly reduce cardiovascular morbidity and mortality. . .and in fact, the stroke rate was 2 to 4 times higher in patients receiving b-blockers.Q In the Losartan Intervention for Endpoint Reduction in
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Table 3. Summary of Important Clinical Trials Involving b -Blockers Trial
Year
Mean Age (y)
VA COOP MRC
1982 1985
49.7 52
Patients
IPPPSH HEP Berglund HAPPHY
1985 1986 1986 1988
52 68.8 50 52.2
348 8700 13057 6357 884 106 6569
STOP
1991
75.7
1627
Yurenev MRC-old
1992 1992
45.5 70.3
TEST UKPDS CAPPP STOP2
1995 1998 1999 1999
70.4 56.2 52.5 76
304 2183 3315 720 758 10985 6614
NORDIL ELSA AASK LIFE DUTCH TIA CONVINCE INVEST ASCOT-BPLA
2000 2002 2002 2002 2003 2003 2003 2005
60.4 56 54.6 66.9 65 65.6 66.1 63
10881 2334 1094 9193 1473 16476 22576 19257
b-Antagonist
Comparison drug
Propranolol Propranolol Propranolol Oxprenolol Atenolol Propranolol Atenolol Metoprololpropranolol Atenolol Metoprolol Pindolol Propranolol Atenolol Atenolol Atenolol Atenolol
Hydrochlorothiazide Bendroflumethiazide Placebo Placebo Open Control Bendroflumethiazide Hydrochlorothiazide Bendroflumethiazide Placebo
Atenolol Metoprolol Pindolol Any b-antagonist Atenolol Atenolol Atenolol Atenolol Atenolol Atenolol
Hypertension Study (LIFE) trial, where an atenolol-based was compared with a losartanbased strategy in patients with left ventricular hypertrophy (LVH), losartan was found to be superior to atenolol therapy alone or in combination in patients with hypertension and diabetes. Despite nearly identical blood pressure reduction, atenolol-treated patients experienced a 13% greater risk of death and a 25% greater risk of fatal or nonfatal stroke than losartantreated patients. In the Dutch Transient Ischemic Attack (DUTCH TIA) trial, use of atenolol significantly lowered blood pressure but resulted in no protection for fatal or nonfatal MI and recurrent stroke, as compared with placebo in patients with previous transient ischemic attack or nondisabling ischemic stroke. Two recent meta-analyses from Lindholm et al25,26 showed no benefit associated with use of b-blockers in primary prevention. The studies showed that although atenolol reduced blood pressure greater than placebo and, comparably, with other antihypertensive agents, there was no difference in mortality or MI compared with placebo and an
Diuertic Diuertic Placebo Placebo Captopril ACE Enalapril Lisinopril Felodipine Diltiazem Lacidipine Calcium/ACE Losartan Placebo Verapamil Verapamil Amlodipine
Follow-up (y) 1.5 5.5 4.0 4.4 10 3.8 2.1 4.0 5.8 2.6 9.0 5.0 4.5 3.75 4.8 2.6 3.0 2.7 5.7
increased risk of mortality and stroke, compared with other antihypertensives. Atenolol resulted in nonsignificant reduction in stroke compared with placebo, although there was a significant difference in blood pressure in both groups.25 In the second meta-analysis, authors included different b-blockers, thus extending their analysis beyond atenolol.26 In their meta-analysis including 13 trials comparing b-blockers with other antihypertensive patients, authors reported 16% higher relative risk of stroke with b-blockers (95% confidence interval [CI], 4-30%; P = .009) than with other drugs. A tendency for all-cause mortality was seen in the same direction, the relative risk being increased by 3% for b-blockers (95% CI, 1% to 8%; P = .14). There was, however, no difference for MI. Analysis of 7 trials comparing b-blockers with placebo or no antihypertensive treatment showed a relative risk reduction of stroke by 19% (95% CI, 7%-21%) associated with b-blockers use. Indeed, although b-blockers were more efficacious compared with placebo, this modest reduction was much lower than previous or expected estimates. In an
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associated editorial, Beevers27 aptly quipped about bthe end of b-blockers for uncomplicated hypertension.Q We previously found, in a metaanalysis of 10 placebo-controlled clinical trials of more than 16 000 elderly patients (=60 years old), that although traditional b-blockers significantly lowered blood pressure, they were ineffective in preventing coronary heart disease, defined as fatal or nonfatal MI and sudden cardiac death, cardiovascular mortality, and all-cause mortality.28 Subsequently, several authors raised the concern of differential effect of b-blockers based on age groups. It was postulated that although elderly patients may have decreased arterial compliance and b-blockers may further depress the cardiac output, younger patients seem to have a higher adrenergic state, as seen from a recent report from the Framingham group and, thus, may benefit from b-blockade. To address this issue, Khan and McAlister29 performed a meta-analysis of hypertension trials involving b-blockers wherein they separated trials based on the mean age of enrolled patients at baseline. Studies were reanalyzed based on 2 categories: mean age equal to or greater than 60 years or those younger than 60 years. Unlike meta-
analysis by Lindholm et al,26 where the study end points were MI, stroke, or death, separately, Khan and McAlister focused on composite end points. Results involving elderly patients were similar to the previous meta-analyses; b-blockers showed a similar lack of efficacy compared with other antihypertensive agents and reduced major cardiovascular outcomes, compared with placebo. In contrast, although younger patients, when compared with other antihypertensive agents, had similar outcomes on b-blockers, a reduction in cardiovascular outcomes was demonstrated on comparison with placebo. In addition to differences in studied end points, the analysis by Khan and McAlister incorporated 3 studies,4,15,19 which were excluded in previous meta-analysis due to paucity of data regarding b-blocker use, quality concerns, and comorbidity of included patients. Hypertension in the elderly is marked by reduced cardiac output and increased peripheral vascular resistance (Table 4).30 Traditional b-blockers lower blood pressure by reducing cardiac output through their negative inotropic effect and induce a compensatory increase in vascular tone mediated through a 1 vascular
Table 4. Possible Reasons for Poor Performance of b -Blockers in Elderly Pathophysiologic entity
Specific changes in the elderly4
Effect of by-Blockade
Further decrease in cardiac output and heart rate; further increase in vascular resistance29,30 Blood pressure pattern Lesser effect on systolic blood pressure Hypertensive heart disease Least efficient in reducing LVH31-36 Hypertensive renal disease Further decrease in renal blood flow and glomerular infiltration rate; no effect on microproteinuria40-44 Hypertensive No effect on arterial stiffness or vascular disease hypertrophy (in contrast to other drugs)46,47 Metabolic effects Insulin resistance, glucose intolerance, Increase the risk of developing and lipid abnormalities are common. diabetes by 4 to 648-52; increase in triglycerides and decrease in high-density lipoprotein cholesterol52-62 54,56-62 b-Adrenergic responsiveness Decreased Diminished efficacy60 Exercise tolerance Decreased Further decrease in exercise tolerance Comorbidity Chronic obstructive pulmonary disease, Affecting all of these comorbid peripheral vascular disease, diabetes mellitus, conditions adversely depression, dementia, and sexual dysfunction are common
Systemic hemodynamics
Decreased cardiac output, and heart rate; elevated systemic vascular resistance27,28 Predominantly systolic hypertension Left ventricular hypertrophy is common. Decreased renal blood flow, glomerular infiltration rate, and increased microproteinuria36-43 Increased arterial stiffness, vascular hypertrophy45
Adapted with permission from JAMA 1998;279:1903-1907. 4Compared with younger patients with similar blood pressure elevation. yWith the exception of the vasodilating blockers.
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receptors. In addition, nonselective b-blockers can also promote vasoconstriction by blocking vasodilatory b 2 vascular receptors.31 Cardioselective b-blockers with low lipid solubility may have a preferable side effect profile in older persons. b-Blockers that are lipophilic cross the blood-brain barrier, possibly causing more sedation, depression, and sexual dysfunction in older patients.22 Particularly in older patients, b-blockers as a class can cause bradycardia, conduction abnormalities, and acute heart failure if started too aggressively in patients with preexisting left ventricular dysfunction.6,22,23 However, b-blockers remain a cornerstone in management of CHF. Multiple experimental and clinical studies have demonstrated that b-blocker alters adrenergic activity and resultant gene expression, thereby reducing myocyte dysfunction, changes in Ca2+ handling, cell loss, and cell and ventricular remodeling. Early initiation of b-blocker and reaching target dose results in improvement of ventricular function, symptoms, and rate of hospitalization, leads to reversal of remodeling, and decreases mortality. Poor efficacy of b-blockers in the elderly may be attributed to unfavorable effects on the hemodynamics in the vasculature and end organs and metabolism. Thus, b-blockers are not suited as first-line agents for hypertension in the elderly unless there are other comorbid conditions such as CHF or MI.32 Whether newer b-blockers have a role to play in younger patients with uncomplicated patients is not clear. While exploring possible role of b-blockers in younger patients with uncomplicated hypertension, we should keep in mind the metabolic and hyperglycemic side effects associated with their use in this population, which may be exposed to them for long duration. Left Ventricular Hypertrophy Multiple studies have shown that b-blockers perform poorly, as compared with other antihypertensive agents in reducing LVH. A metaanalysis of 80 double-blind, randomized, controlled trials with 3767 hypertensive patients found that b-blockers were the least effective in reducing left ventricular mass compared with angiotensin receptor blockers, calcium-channel antagonists, and ACE inhibitors despite similar
blood pressure reduction among these antihypertensive drug classes ( P = .004).33 Similarly, in the LIFE study, which was one of the largest trials on antihypertensive treatment in patients with LVH, atenolol was less effective in reduction of left ventricular mass, compared with losartan. In a randomized study with 42 elderly patients with hypertension, atenolol failed to reduce left ventricular mass, compared with verapamil after 6 months of treatment despite comparable blood pressure lowering.34 Post-MI and Left Ventricular Dysfunction In acute setting, b-blockers are useful in patients with ventricular arrhythmias and, thus, prevention of sudden cardiac death. The routine use of b-blockers in post MI patients has been shown to reduce cardiovascular mortality. Noteworthy trials supporting the role of b-blockade in postMI are b-Blocker Heart Attack Trial,35 Norwegian Multicenter Study of Timolol after Myocardial Infarction,36 and the Carvedilol Post-Infarct Survival Control in LV Dysfunction trial.37 Some of these trials were meta-analyzed by Houghton et al38 showing a 22.6 % reduction in odds of death. The b-Blocker Heart Attack Trial compared the incidence of coronary events in 3837 patients receiving propanolol or placebo. Patients were followed up for an average of 25 months, and the trial was terminated early on evidence of clear differences in reduction of coronary incidents (23%) in the propranolol group.35,39 Similarly, timolol was compared with placebo in the Norwegian Timolol study in 1884 patients. It was concluded that chronic treatment with timolol in survivors of acute MI who can tolerate b-adrenergic blockade is effective in reducing both total mortality and reinfarction over 33 months.36 More recently, the Carvedilol Post-Infarct Survival Control in LV Dysfunction trial compared effect of carvedilol and placebo on cardiovascular end points in 1959 survivors of acute MI with reduced ejection fractions. Carvediloltreated patients experienced a significant 23% greater reduction in all-cause mortality, a 25% greater reduction in cardiovascular death, and a 41% greater reduction in nonfatal recurrent MI compared with placebo-treated patients. Of note,
82 these patients were concomitantly treated with aspirin, ACE inhibitors, and statins. Post-MI patients with conditions that are often considered contraindications to b-blockade (such as heart failure, pulmonary disease, and older age) and nontransmural infarction may still benefit from b-blocker therapy.40 Controlled trials in patients who are post-MI with normal or close to normal left ventricular function are needed to assess use of b-blockers in this subgroup.41 b-Blockers in Acute Coronary Syndromes Multiple studies have addressed the role of b blocker use in acute coronary syndrome. Results from ISIS-1 show nonsignificant reduction of early inhospital events described as nonfatal cardiac arrests and reinfarctions with use of atenolol, as compared with placebo. Subsequent necropsy of patients with complication in the International Studies of Infarct Survival-1 (ISIS-1) study failed to reveal any b-blocker effect on limitation of infarct size or prevention of reinfarction or cardiac arrest. The extent of thrombolytic use in these studies is also not clear. The recent Clopidogrel and Metoprolol in Myocardial Infarction Trial42 involving 45 852 patients associated the early use of intravenous b-blockers in both high- and low-risk patients with acute MI with a highly significant 30% relative increase in the risk of cardiogenic shock. Although use of b-blockers resulted in a relative reduction of ventricular fibrillation and reinfarction by 15% to 20%, these benefits clearly did not outweigh the risk of cardiogenic shock. In addition, the beneficial effects on arrhythmias and reinfarction were more gradual in onset. Thus, the Clopidogrel and Metoprolol in Myocardial Infarction Trial supports use of oral b-blockers only when patient becomes hemodynamically stable and suggests avoiding intravenous use of b-blockers and use of b-blockers in general within 12 hours of acute MI. Diabetes Mellitus Risk of new-onset diabetes is elevated in nondiabetic hypertensive patients on treatment with b-blockers.43,44 As a consequence, b-blockers were considered to be relatively contraindicated in diabetes. Recent evidence points to the contrary. Although nonselective b-blockers can
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prevent normalization of blood glucose after an episode of hypoglycemia in patients on insulin and worsen insulin sensitivity and promote glucose imbalance, b 1-selective agents along with agents having a-blockade45 or b 2 ISA46 are noted to be less detrimental. Unfortunately, traditional b-blockers are associated with the worsening of insulin resistance, deterioration of glycemic control, peripheral vasoconstriction, potentially worsening peripheral vascular disease, and more frequent and severe hypoglycemia. Some of the newer b-blockers have unique properties, such as a 1 blockade, which may improve glycemic control and vasodilate resistance arterioles. The Carvedilol Or Metoprolol European Trial showed that, compared with metoprolol, use of carvedilol resulted in a decrease in new onset of diabetes in patients with heart failure.47 The Glycemic Effects in Diabetes Mellitus: Carvedilol-Metoprolol Comparison in Hypertensives trial,48 which compared carvedilol and metoprolol in patients with hypertension and type 2 diabetes mellitus, showed again that compared with metoprolol, carvedilol use was associated with improvement in insulin sensitivity, prevention of worsening of hemoglobin A1c, and microalbuminuria. More participants withdrew due to worsening glycemic control and needed statin therapy in the metoprolol group. In the Glycemic Effects in Diabetes Mellitus: Carvedilol-Metoprolol Comparison in Hypertensives, metoprolol (and carvedilol) was given twice a day, and no conclusion can be drawn as to the effect of long-acting metoprolol (Toprol XL) on glycemic control.
Drug Interactions Bioavailability of lipophilic b-blockers is decreased by those agents that induce hepatic biotransformation enzymes (eg, alcohol, phenytoin, rifampin, phenobarbital, and smoking). In contrast, drugs inhibiting hepatic enzymes (eg, cimetidine, hydralazine, etc) can increase bioavailability. Concomitant use of antiarrythmic drugs and nondihydropyridine calcium antagonists may cause sinus node or conduction anomalies. Nonsteroidal anti-inflammatory drugs may have an antagonistic effect on the antihypertensive
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effect of b-blockers. Coadministration of clonidine and b-blockers can result in elevated blood pressure, and stopping clonidine in presence of propranolol, like in one instance, resulted in cerebral hemorrhage.49
Side Effects Not only do the above studies give reason to believe that b-blockers should be abandoned as first-line agents in uncomplicated hypertension, but the list of adverse effects (Table 5) is longer than any of the other antihypertensive medications. This leads to a greater likelihood of poor compliance; discontinuation; and as a consequence, less successful blood pressure control.50 The dropout rate in b-blocker–treated patients due to adverse side effects in clinical trial is significant. Traditional nonselective b-blockers may also further reduce already-compromised renal blood flow in individuals with hypertension and may even decrease the glomerular filtration rate.51 Cardiovascular b-Blockers, by virtue of their chronotropic effects, reduce heart rate, reduce the firing rate of ectopic pacemakers, decrease conduction, and increase the refractory time of the atrioventricular (AV) node, resulting in bradycardia and AV block. b-Blockers should be used with caution in
Table 5. Adverse Effects Related to b -blockers General—arthralgias, asthenia, fatigue, diaphoresis, edema, myalgia, pharyngitis, urinary retention Central nervous system—depression, dizziness, hallucinations, headache, insomnia, nightmares, paresthesias Eye—lacrimation, ocular irritation, xerosis Cardiovascular—orthostatic hypotension, peripheral vasoconstriction, peripheral edema, QT prolongation, sinus bradycardia, syncope, torsade de pointes, ventricular tachycardia, angina, AV block, cardiac arrest Respiratory—bronchospasm, wheezing, dyspnea Gastrointestinal—jaundice, diarrhea, dyspepsia, hepatic necrosis, nausea, vomiting, constipation, flatulence, hypoglycemia, elevated liver function tests Sexual—erectile and ejaculation dysfunction, impotence, libido decrease Skin—skin hyperpigmentation, alopecia, exfoliative dermatitis, pruritis Metabolic—weight gain, increases cholesterol and triglycerides, increases insulin resistance
combination with other negative chronotropes, such as diltiazem, verapamil, or digoxin. b-Blockers may worsen symptoms of peripheral vascular disease by producing cold extremities and Raynaud’s phenomenon. b-Blockers with vasodilatory effects and b 1-selective agents may produce lesser effects on peripheral vasculature. b-Adrenergic antagonism with a nonselective blocker results in up-regulation of b-receptors. Suddenly stopping the drug exposes the upregulated receptors to catecholamines, resulting in rebound symptoms such as hypertension, arrhythmias, anxiety, and increased risk of myocardial ischemia in susceptible patients.52,53 Hence, b-blockers should be tapered over a period of a few days before discontinuation to minimize the risk of sudden rebound. Metabolic Use of nonselective b-blockers in type 1 diabetes mellitus may mask warning symptoms of hypoglycemia, including tremor and tachycardia. It is advised to use selective b-blockers in patients with type 1 diabetes mellitus.54 b-Blockers have been shown to increase triglyceride levels and decrease high-density lipoprotein levels. 55 b-Blockers with ISA have a smaller effect on serum lipoproteins, as compared with those lacking it. Pulmonary Use of b-blockers in patients with asthma or significant reactive airway disease can lead to life-threatening bronchospasm or increase in airway resistance. Although threat of worsening of airway disease exists, certain patients with chronic obstructive pulmonary disease may benefit from b-blockade.56 Hence, chronic obstructive pulmonary disease itself, in absence of significant reactive component, is not a contraindication to use of b-blockers. Sexual Dysfunction Certain patients may experience worsening impotence or loss of libido and orgasmic dysfunction. Higher rate of withdrawals resulting from impotence was seen in propanolol group, as compared with placebo in the MRC mild hypertension study.57,58
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Table 6. Effect of Antihypertensive Drugs on Hemodynamic and Metabolic Profile
Mean arterial blood pressure Total peripheral resistance Cardiac output Heart rate Activation of sympathetic nervous system Renin-angiotensin-aldosterone system Lipid metabolism Glucose metabolism
Ideal drug
Traditional b-blockers
Carvedilol
Decrease Decrease None None/decrease Decrease Decrease None/positive None/positive
Decrease Increase Decrease Decrease Decrease Decrease Negative Negative
Decrease Decrease None None/decrease Decrease Decrease None None
Adapted with permission from Am J Cardiol 93:7B-12B, 2004.
Central Effects As mentioned earlier, central effects are more common with lipophilic agents, as compared with hydrophilic agents.59 Central effects include fatigue, headache, sleep disturbance, nightmares, insomnia, vivid dreams, confusion, and depression.
Newer Agents b-Blockers as a class are still undoubtedly used widely (and inappropriately) for the treatment of hypertension. Nevertheless, it should be kept in mind that traditional b-blockers have an unfavorable and undesirable hemodynamic and metabolic profile. Despite that all b-blockers reduce blood pressure, newer b-blockers with vasodilatory effect may provide a better alternative. Carvedilol and nebivolol, newer b-blockers, have been shown to differ and perhaps have more benefits on cardiovascular effects than traditional b-blockers (Table 6). These agents maintain cardiac output, have a lesser effect on heart rate, and decrease blood pressure by decreasing systemic vascular resistance.60 Carvedilol increases plasma flow to the kidneys, as opposed to decreased glomerular filtration rate seen with traditional b-blockers. These hemodynamic properties are an advantage especially in the elderly where the cardiac output is low and systemic vascular resistance elevated. The beneficial effect of carvedilol and nebivolol on systemic resistance is similar to ACE inhibitors and calcium-channel blockers. Both of these b-blockers seem to have less metabolic adverse effects, then the traditional agents. This may particularly be of importance in younger patients who will be exposed to these drugs for a longer
duration. In addition, newer agents may be more efficacious at lowering central aortic pressures. As seen in the recently published Conduit Artery Function Evaluation study, aortic pulse pressure may be an independent predictor of cardiovascular events in hypertensive patients. In the Conduit Artery Function Evaluation study, atenolol had significantly different effect on aortic and brachial pressures.61 In contrast, vasodilating b-blockers maybe more effective in lowering aortic pressures.62
Conclusion b-Blockers have been and still are popular antihypertensive agents in clinical practice worldwide. However, the efficacy of b-blockers on cardiovascular events in hypertension has been poorly documented, and we ought to redraft the guidelines for b-blocker usage. Indeed, the British Hypertension Society (BHS)/National Institute for Health and Clinical Excellence guidelines recently were appropriately revised excluding b-blockers for management of uncomplicated hypertension. If b-blockers are indeed indicated, we perhaps should consider newer b-blockers rather than the traditional agents such as atenolol and metoprolol. Further evidence on the role of newer b-blockers in primary prevention of cardiovascular events and mortality in uncomplicated hypertension is needed.
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