Considerable progress has been made over the last few decades in the management of clinically stable coronary heart disease (SCHD), including improvements in interventions (e.g., percutaneous revascularization), pharmacological management, and risk factor control (e.g., smoking, diet, activity level, hypercholesterolemia, hypertension). Although β blockers have long been used for the treatment of SCHD, their efficacy was established in the era before widespread use of reperfusion interventions, modern medical therapy (e.g., angiotensin-converting enzyme inhibitors, angiotensin receptor blockers), or preventive treatments (e.g., aspirin, statins). On the basis of these older data, β blockers are assumed beneficial, and their use has been extrapolated beyond patients with heart failure and previous myocardial infarction, which provided the best evidence for efficacy. However, there are no randomized clinical trials demonstrating that β blockers decrease clinical events in patients with SCHD in the modern era. Furthermore, these agents are associated with weight gain, problems with glycemic control, fatigue, and bronchospasm, underscoring the fact that their use is not without risk. In conclusion, data are currently lacking to support the widespread use of β blockers for all SCHD patients, but contemporary data suggest that they be reserved for a well-defined high-risk group of patients with evidence of ongoing ischemia, left ventricular dysfunction, heart failure, and perhaps some arrhythmias.
Beta-adrenergic blockers have long been used for the treatment of coronary artery disease (CAD); however, evidence for their efficacy is derived mostly from post–myocardial infarction (MI) trials conducted before modern reperfusion or medical therapy. Nevertheless, based on this evidence, use of β blockers has been considered beneficial, and their use has been extrapolated to the broader group of patients with stable coronary heart disease (SCHD) without previous MI and those at high risk for CAD. Despite the common belief that β blockers are effective for prevention of chronic angina, the long-term efficacy of β blockers in the era of contemporary therapies remains unproven. As noted in the most recent European Society of Cardiology guidelines, there are no randomized, controlled trials demonstrating a reduction in clinical events in the treatment of patients with SCHD. In addition, because of the substantial limitations of β blockers and the identification of other therapies that are safe and effective for treating CHD, the role of β blockers in SCHD should be reconsidered. For example, in the 2012 American Heart Association/American College of Cardiology guidelines for the management of patients with SCHD, the use of β blockers as long-term therapy for patients with no history of MI or left ventricular dysfunction is a class IIb, level of evidence C recommendation.
Historical Perspective
In the United States, CHD accounts for approximately 1/3 of all deaths. CAD pathophysiology is related to the adrenergic nervous system, which consists of 2 major receptor types in the adrenergic system (α and β), and was first described in the mid-20th century. Alpha receptor activation is associated with contraction of vascular smooth muscle. Beta receptor activation is associated with stimulation of the heart (β1) and relaxation of vascular smooth muscle, bronchi, and uterus (β2). Sir James Black reasoned that the catecholamine isoproterenol had structural characteristics that allowed it to interact with β receptors in the heart. By mimicking the structure of isoproterenol, he developed the first β-adrenergic receptor blocking agent (propranolol) for treatment of angina and hypertension. Beta antagonists competitively inhibit endogenous catecholamines to B 1 receptors leading to reductions in heart rate, blood pressure, and myocardial contractility, lessening myocardial oxygen demand at rest and during exertion or stress. This reduces myocardial oxygen requirements, preventing ischemia and angina. Beta blockers may reduce ischemia by prolonging diastole and by increasing vascular resistance in nonischemic areas.
These drugs were widely adopted, and several large studies from the 1970s to 1990s documented that β blockers reduce angina episodes, improve exercise performance, and decrease the use of sublingual nitrates compared with baseline. However, most of these early studies were conducted in angina patients not receiving background therapies.
The β-Blocker Heart Attack Trial (BHAT), a landmark randomized, double-blind, multicenter study sponsored by the National Heart, Lung and Blood Institute compared propranolol with placebo in patients 5 to 21 days after acute MI to assess mortality. After 2 years of follow-up, the study was terminated as the propranolol group had a 26% lower all-cause mortality (9.8%, n = 188 deaths in the placebo group and 7.2%, n = 138 deaths in the propranolol group, p <0.005). CHD-related mortality was also significantly greater (8.5%, n = 164) with placebo versus propranolol (6.2%, n = 119, p <0.01). However, the trial was not designed to evaluate the optimal duration of β-blocker therapy after MI. More recently, a meta-analysis of 31 long-term randomized clinical trials evaluated >24,000 patients randomized to a β blocker or control in post-MI patients and demonstrated a 23% reduction in the risk of death among post-MI patients receiving long-term β-blocker therapy. In most of these trials, the benefit was concentrated to the early period (e.g., first year) and high-risk patients.
Changes in Stable CHD Management over Time
There has been a dramatic reduction in CHD since the 1960s in the industrialized countries. After peaking in 1964 to 1968, at a rate of >200 deaths per 100,000 people, the CHD death rate in the United States has steadily decreased to 135 deaths per 100,000 people in 2006 and an age-adjusted rate of 113 per 100,000 population in 2010 ( Figure 1 ). CHD mortality has reduced substantially in many European countries, decreasing by >50% between 1980 and 2009. A 2007 analysis of CHD suggested that improvements in medical treatments accounted for 47% of the decrease in CHD, whereas changes in risk factors accounted for 44% of the reduction in deaths. Since the introduction of β blockers, other treatments, such as thrombolysis, coronary artery bypass grafting, angioplasty and stents, angiotensin-converting enzyme inhibitors, and statins, have contributed to reductions in CHD mortality. In patients with chronic angina, coronary artery bypass grafting was associated with 80% of the mortality reduction, followed by angioplasty and aspirin and statin use.
Role of β blockers in the current era
Although β blockers are widely used for the treatment of patients with SCHD, there are no randomized, placebo-controlled trials directly evaluating the efficacy of these agents in patients with stable coronary disease, particularly among those receiving contemporary medical management. Beta blockers are commonly used for treatment of angina or asymptomatic cardiac ischemia and, while effective, do not demonstrate superiority in reducing angina symptoms compared with other medical therapies. The International Verapamil-SR Trandolopril Study (INVEST) compared an atenolol/hydrochlorothiazide strategy with a verapamil/trandolapril strategy and found no advantage to the β blocker strategy for control of blood pressure or for reducing death, stroke, or MI although a secondary analysis of risk predictors suggested the verapamil/trandolapril strategy may be beneficial. An analysis performed in diabetic patients from INVEST showed no advantage with the β-blocker strategy, although there was an increase in the development of new diabetes with the β-blocker strategy. Patients from INVEST were also classified by angina status (new-onset, resolved, never, and persistent angina), and no reduction in mortality was seen when accounting for the treatment assignment.
Similarly, a more recent, international, observational study of β blockers in >40,000 patients in 3 separate cohorts (i.e., known MI, known CAD without MI, CAD risk factors only) suggested that β-blocker use was not associated with a decreased risk of cardiovascular (CV) events in any of these cohorts. Aspirin and statins were used by approximately 75% of all patients. In the cohorts with documented previous MI, there were no significant differences in event rates among those receiving versus those not receiving β blockers for either the primary (composite of CV death, nonfatal MI, or nonfatal stroke, Figure 2 ) or secondary (primary outcome plus hospitalization for atherothrombotic events or revascularization, Figure 2 ) outcomes. For the cohort with CAD risk factors only, the event rates were actually higher in patients using β blockers compared with those not using β blockers.
Another observational study of 13,110 patients with acute ST elevation MI demonstrated a detrimental effect associated with early (within 24 hours of symptom onset) intravenous administration of β blockers. Early use of both intravenous and oral β blockers was associated with an increased risk of dying during hospitalization, whereas delaying β-blocker therapy was beneficial.
A meta-analysis of 48 prereperfusion era trials compared with 12 reperfusion era trials found that β blockers reduced mortality in the prereperfusion era but not in the postreperfusion era. In the reperfusion era, β blockers were associated with reductions in MI and angina but increases in heart failure (HF), cardiogenic shock, drug discontinuation and had no impact on CV mortality, sudden death, or stroke. The findings were largely similar in the acute MI and post-MI setting. Increases in drug discontinuations and HF continued to be noted after 30 days and up to a year of treatment. This is in contrast to the prereperfusion era, when significant benefits for all-cause mortality, CV mortality, and angina were present at 30 days and for all-cause mortality, CV mortality, sudden death, and MI were present up to and, for all-cause mortality and sudden death, beyond a year of treatment. These results support the short-term use of β blockers to reduce the incidence of MI and angina after acute MI. The risk of HF, cardiogenic shock, and adverse events has to be taken into consideration, particularly because the mortality benefits appear to be negligible.
Changes in Stable CHD Management over Time
There has been a dramatic reduction in CHD since the 1960s in the industrialized countries. After peaking in 1964 to 1968, at a rate of >200 deaths per 100,000 people, the CHD death rate in the United States has steadily decreased to 135 deaths per 100,000 people in 2006 and an age-adjusted rate of 113 per 100,000 population in 2010 ( Figure 1 ). CHD mortality has reduced substantially in many European countries, decreasing by >50% between 1980 and 2009. A 2007 analysis of CHD suggested that improvements in medical treatments accounted for 47% of the decrease in CHD, whereas changes in risk factors accounted for 44% of the reduction in deaths. Since the introduction of β blockers, other treatments, such as thrombolysis, coronary artery bypass grafting, angioplasty and stents, angiotensin-converting enzyme inhibitors, and statins, have contributed to reductions in CHD mortality. In patients with chronic angina, coronary artery bypass grafting was associated with 80% of the mortality reduction, followed by angioplasty and aspirin and statin use.
Role of β blockers in the current era
Although β blockers are widely used for the treatment of patients with SCHD, there are no randomized, placebo-controlled trials directly evaluating the efficacy of these agents in patients with stable coronary disease, particularly among those receiving contemporary medical management. Beta blockers are commonly used for treatment of angina or asymptomatic cardiac ischemia and, while effective, do not demonstrate superiority in reducing angina symptoms compared with other medical therapies. The International Verapamil-SR Trandolopril Study (INVEST) compared an atenolol/hydrochlorothiazide strategy with a verapamil/trandolapril strategy and found no advantage to the β blocker strategy for control of blood pressure or for reducing death, stroke, or MI although a secondary analysis of risk predictors suggested the verapamil/trandolapril strategy may be beneficial. An analysis performed in diabetic patients from INVEST showed no advantage with the β-blocker strategy, although there was an increase in the development of new diabetes with the β-blocker strategy. Patients from INVEST were also classified by angina status (new-onset, resolved, never, and persistent angina), and no reduction in mortality was seen when accounting for the treatment assignment.
Similarly, a more recent, international, observational study of β blockers in >40,000 patients in 3 separate cohorts (i.e., known MI, known CAD without MI, CAD risk factors only) suggested that β-blocker use was not associated with a decreased risk of cardiovascular (CV) events in any of these cohorts. Aspirin and statins were used by approximately 75% of all patients. In the cohorts with documented previous MI, there were no significant differences in event rates among those receiving versus those not receiving β blockers for either the primary (composite of CV death, nonfatal MI, or nonfatal stroke, Figure 2 ) or secondary (primary outcome plus hospitalization for atherothrombotic events or revascularization, Figure 2 ) outcomes. For the cohort with CAD risk factors only, the event rates were actually higher in patients using β blockers compared with those not using β blockers.
Another observational study of 13,110 patients with acute ST elevation MI demonstrated a detrimental effect associated with early (within 24 hours of symptom onset) intravenous administration of β blockers. Early use of both intravenous and oral β blockers was associated with an increased risk of dying during hospitalization, whereas delaying β-blocker therapy was beneficial.
A meta-analysis of 48 prereperfusion era trials compared with 12 reperfusion era trials found that β blockers reduced mortality in the prereperfusion era but not in the postreperfusion era. In the reperfusion era, β blockers were associated with reductions in MI and angina but increases in heart failure (HF), cardiogenic shock, drug discontinuation and had no impact on CV mortality, sudden death, or stroke. The findings were largely similar in the acute MI and post-MI setting. Increases in drug discontinuations and HF continued to be noted after 30 days and up to a year of treatment. This is in contrast to the prereperfusion era, when significant benefits for all-cause mortality, CV mortality, and angina were present at 30 days and for all-cause mortality, CV mortality, sudden death, and MI were present up to and, for all-cause mortality and sudden death, beyond a year of treatment. These results support the short-term use of β blockers to reduce the incidence of MI and angina after acute MI. The risk of HF, cardiogenic shock, and adverse events has to be taken into consideration, particularly because the mortality benefits appear to be negligible.
Limitations and side effects of β blockade
Beta blockers have a number of side effects that may limit their role in contemporary management. Discontinuation rates of β blockers may be as high as 25% within the first year and 50% over longer periods of time. High discontinuation rates for β blockers are at least partially attributable to these adverse effects that are disagreeable to patients.
Metabolic
Beta blockers should be used with caution in patients with or at risk for diabetes. Nonselective agents can mask the symptoms of hypoglycemia (e.g., tremor, tachycardia) exposing patients to risk. Beta blockers also have diverse effects on glucose metabolism including a reduction in insulin sensitivity, decreased glycemic control, and an increase in risk of new-onset diabetes. New-onset diabetes was more frequent in patients treated with β blockers in the INVEST trial than in patients treated with calcium channel antagonists (p <0.01). Similarly, in the Prevention of Events with Angiotensin Converting Enzyme Inhibition trial, patients with stable CAD were randomly assigned to trandolapril or placebo. Patients taking β blockers with placebo were at increased risk for new-onset diabetes (hazard ratio 1.63, 95% confidence interval [CI] 1.29 to 2.05, p <0.001); however, the risk was attenuated and nonsignificant for patients randomized to β blockers plus angiotensin-converting enzyme inhibitor therapy (hazard ratio 1.11, 95% CI 0.87 to 1.42, p = 0.39). Long-term β-blocker use is associated with weight gain. In a mechanistic study, diet-induced thermogenesis, fat oxidation rate, and weekly habitual activity were lowered by 50%, 32%, and 30%, respectively, among β-blocker users compared with matched controls. Some β blockers can also increase triglycerides and decrease high-density lipoprotein cholesterol.
Cardiovascular
Beta blockers are known to decrease sinus node firing and atrioventricular nodal conduction through blockade of cardiac β 1 -adrenoreceptors and resulting in bradycardia. Although these effects are sought therapeutically, patients with impaired sinus node function and atrioventricular node conduction can experience severe bradycardia or atrioventricular block with β blockers. If this does occur, the effect is usually reversible by withdrawing the drug. Some patients may require temporary pacing or antidotes such as calcium, glucagon, inotropic drugs, or β agonists.
Fatigue
Fatigue with β blockers could be related to physiological changes induced by β blockers, including reduction in heart rate and cardiac output, local alterations to blood flow, changes to muscle, and liver glycogenolysis, and alterations to adipose and intramuscular lipolysis have been identified that contribute to causing the exercise limitations associated with these drugs. A recent meta-analysis of randomized trials analyzed side effects of β blockers and observed that β blockers were associated with a significant increase in discontinuation because of fatigue (relative risk [RR] 2.63, 95% CI 1.16 to 5.94). In the context of therapeutic benefit, for every stroke or heart attack prevented, 8 patients had to withdraw from β-blocker therapy because of fatigue. Compared with later-generation β blockers, early-generation β-blocker use was associated with a greater risk of fatigue (RR 1.78, 95% CI 1.08 to 2.93).
Sexual dysfunction
Sexual dysfunction has been reported, for decades, to occur with β blockers. In a meta-analysis by Ko et al, an increased risk of impotence was observed (RR 1.22, 95% CI 1.05 to 1.41). The overall report of sexual dysfunction was not significant (RR 1.10, 95% CI 0.96 to 1.25); however, the withdrawal rate from β-blocker therapy was 5 times than that seen in patients receiving placebo; therefore, for every stroke or MI prevented by β-blocker therapy, 3 patients experienced impotency related to the therapy. Some have questioned the pathophysiology of this effect, with Silvestri et al elegantly demonstrating that a strong degree of anxiety and nocebo effect may be the cause.
Depression
Worsening of depressive symptoms is a persistent concern with β-blocker use. An analysis of patients from the INVEST trial demonstrated improvement in depressive symptoms with the calcium antagonist strategy, whereas assignment to the β-blocker strategy was associated with worsened depressive symptoms. In a study of healthy men, atenolol was not associated with changes in mood, but definitive evidence of a central effect as measured by tests of level of arousal or integration potential of the central nervous system and of sensorimotor performance was observed. Tests of perception and recognition were impaired at higher doses only. Nevertheless, electroencephalographic studies indicate the central nervous system effects of β blockers are clear and similar to those associated with the use of benzodiazepines or tricyclic antidepressants. The meta-analysis by Ko et al found that depressive symptoms were not associated with β-blocker therapy (RR 1.12, 95% CI 0.89 to 1.41); however, lipid-soluble β-blocker use was associated with a nonsignificant trend toward greater risk of depressive symptoms (RR 1.41, 95% CI 0.91 to 2.20).
Arterial vasomotor dysfunction
A double-blind placebo-controlled trial in patients with vasotonic angina showed a significant difference between the duration of peripheral arterial ischemic episodes on placebo, low-dose, and high-dose propranolol (1.3, 3.1, and 3.4 minutes, respectively). There was also a trend toward increased nitroglycerin consumption during propranolol treatment. Beta blockers have been associated with Raynaud’s phenomenon and aggravation of peripheral arterial disease. Randomized trial data and meta-analysis, however, have not substantiated these effects on the peripheral circulation.
Bronchospasm
Beta blockers can cause life-threatening increases in airway resistance and are to be used with caution in patients with asthma or bronchospastic chronic obstructive pulmonary disease. Despite these concerns, β blockers have even been shown to produce substantial reductions in mortality after MI among patients with chronic obstructive pulmonary disease. When needed, low doses of a short-acting, β 1 -selective agents should be used.
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