Beta blockers in the management of chronic coronary syndrome

INTRODUCTION — Beta blockers are first-line therapy in the control of symptoms in patients with chronic stable angina, particularly effort-induced angina.

The major issues regarding the use of beta blockers in the medical management of the patient with stable angina and the evidence that these drugs are effective will be reviewed here. Their role, compared with other drugs, in the overall management of angina is discussed separately. (See "Chronic coronary syndrome: Overview of care".)

In this topic, and others, the term "stable ischemic heart disease" has been changed to "chronic coronary syndrome."

MECHANISM OF ACTION — The physiologic effects of catecholamines (norepinephrine and epinephrine) are mediated by activation of specific alpha and beta adrenergic receptors. There are at least three distinct types of beta receptors [1-3]:

●Beta-1, which are found primarily in heart muscle. Activation of these receptors results in increases in heart rate, contractility, and atrioventricular (AV) conduction, and a decrease in AV node refractoriness.

●Beta-2, which are present in heart muscle but are more prominent in bronchial and peripheral vascular smooth muscle. Activation of these receptors results in vasodilatation and bronchodilatation.

●Beta-3, which are found in adipose tissue and the heart. Activation of these receptors may mediate catecholamine-induced thermogenesis and may reduce cardiac contractility [2,3].

Beta blockers act by competitively inhibiting catecholamines from binding to these receptors. Some are more selective for the beta-1 receptor. (See 'Cardioselectivity' below.)

Upregulation of beta receptors — Beta receptor density is a dynamic process that can change under varying physiologic conditions. In particular, chronic beta blocker therapy leads to an increase in receptor density [4]. This can be clinically important, since sudden withdrawal of the beta blocker results in transient supersensitivity to catecholamines, possibly precipitating angina, myocardial infarction, or death [5,6]. These complications can occur even in patients without previously apparent coronary disease [6]. (See "Major side effects of beta blockers", section on 'Beta blocker withdrawal'.)

Cardiovascular effects of beta blockers — The beneficial therapeutic effects of beta blockade in patients with stable angina pectoris are mediated by a reduction in myocardial oxygen demand. Myocardial oxygen demand varies directly with heart rate, contractility, and left ventricular wall stress, each of which is diminished by beta blockade. The decrease in wall stress is mediated in part by the antihypertensive action of these drugs.

The decline in heart rate is determined both by the degree to which the heart rate is sympathetically activated (as with exercise or stress) [7] and to the properties of the beta blocker. Those drugs with intrinsic sympathomimetic activity may actually increase the resting heart rate. They are, however, still effective in the treatment of angina because it is the reduction in the exercise heart rate that is of primary importance. (See 'Intrinsic sympathomimetic activity' below.)

The negative inotropic effects of beta blockers may, at least theoretically, have a favorable impact on myocardial oxygen consumption in the patient with angina. In the past, beta blockers were avoided in patients with left ventricular dysfunction, from concern that negative inotropic effects could precipitate or worsen heart failure. However, extensive clinical experience and the results of major clinical trials have demonstrated that these agents actually prolong survival in patients with heart failure. In such patients, beta blocker therapy should be initiated at low dose, and volume overload should be corrected prior to the initiation of therapy. (See "Primary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Beta blocker'.)

Beta blockers may also affect coronary blood flow, although there are competing effects. Beta blockers inhibit adrenergically mediated coronary vasodilation, thereby increasing coronary vascular resistance and decreasing coronary blood flow [8]. However, this potentially deleterious effect is overcome by the reductions in heart rate (which enhances coronary perfusion by prolonging diastole) and myocardial oxygen demand.

Nonselective beta blockers may exacerbate coronary vasospasm in patients with variant angina and should be avoided. (See "Vasospastic angina".)

PHARMACOLOGIC CHARACTERISTICS — A number of different beta blockers are available for clinical use. Properties such as pharmacokinetics, cardioselectivity, intrinsic sympathomimetic activity, and alpha adrenergic blocking activity are important characteristics that should be considered when choosing a particular agent.

Pharmacokinetics — Although the beta blockers have similar pharmacotherapeutic effects, their pharmacokinetic properties differ significantly in ways that may influence their clinical usefulness and side effects [9]. Among individual drugs, there are differences in completeness of gastrointestinal absorption, amount of first-pass hepatic metabolism, lipid solubility, protein binding, extent of distribution in the body, penetration into the brain, concentration in the heart, rate of hepatic biotransformation, pharmacologic activity of metabolites, and renal clearance of the drug and its metabolites [9-11].

On the basis of their pharmacokinetic properties, the beta blockers can be classified into two broad categories [10]:

●Those eliminated by hepatic metabolism

●Those excreted unchanged by the kidney

Drugs in the first group (such as propranolol and metoprolol) are lipid-soluble, almost completely absorbed by the small intestine, and largely metabolized by the liver. They enter the central nervous system (CNS) in high concentrations, possibly resulting in an increased incidence of CNS side effects. They tend to have highly variable bioavailability and relatively short plasma half-lives.

In contrast, drugs in the second category (such as atenolol and sotalol) are more water soluble, incompletely absorbed through the gut, eliminated unchanged by the kidney, and do not as readily enter the CNS [10,11]. They show less variance in bioavailability and have longer plasma half-lives.

Cardioselectivity — Cardioselectivity refers to the ability of a drug to preferentially block the beta-1 receptors. Nonselective beta blockers have equal affinity for the beta-1 and beta-2 receptors, while cardioselective agents will primarily inhibit the beta 1-receptors. Cardioselectivity is a relative property and substantial beta-2 receptor blockade can also occur at the higher doses that are often required to treat angina [12].

Intrinsic sympathomimetic activity — Some beta blockers (such as pindolol and acebutolol) have intrinsic sympathomimetic activity (ISA), also called partial agonist activity, providing low-grade beta stimulation at rest but acting as typical beta blockers when sympathetic activity is high [13].

Alpha-adrenergic blocking activity — Labetalol and carvedilol block both beta and alpha receptors. As a result, they reduce peripheral and coronary vascular resistance. They are both non-selective beta blockers without ISA.

ADVERSE EFFECTS OF BETA BLOCKERS — Beta blockers are generally well tolerated in patients with stable angina, but have a well-recognized set of potential side effects that can limit their use. The major side effects of beta blockers are discussed fully elsewhere. (See "Major side effects of beta blockers".)

The most frequent adverse effects include:

●Decreases in heart rate, contractility, and atrioventricular (AV) node conduction.

●Bronchoconstriction, due to beta-2 receptor blockade, can be induced by nonselective agents and high doses of cardioselective agents. As a result, many clinicians have assumed that chronic obstructive pulmonary disease (COPD) or asthma is a contraindication to beta blocker therapy. However, beta blockers are safe and effective in patients with mild COPD/asthma who are not taking a beta-2 adrenergic agonist. Furthermore, some patients carry a diagnosis of COPD that has not been confirmed. The data supporting these observations primarily come from studies of patients with an acute coronary syndrome and are discussed elsewhere. (See "Acute myocardial infarction: Role of beta blocker therapy", section on 'Contraindications'.)

●Worsening of symptoms of peripheral artery disease or Raynaud phenomenon. However, there appears to be no adverse effect on mild to moderate claudication symptoms when beta-1 selective blockers are used. (See "Clinical manifestations and diagnosis of Raynaud phenomenon" and "Overview of lower extremity peripheral artery disease", section on 'Claudication'.)

●Fatigue may be due to the reduction in cardiac output or to direct effects on the central nervous system.

●Central side effects that can occur include nightmares, insomnia, and hallucinations. Although depression is often mentioned as a side effect of beta blockers, this association was not seen in randomized trials. Central side effects may be more common in older adults.

●Erectile dysfunction is often a problem [14].

EFFICACY OF BETA BLOCKERS IN STABLE ANGINA — All of the beta blockers, regardless of pharmacologic properties, appear to be equally effective in the treatment of stable angina pectoris. They improve exercise capacity, reduce exercise-induced ST-segment depression on the electrocardiogram, decrease the frequency of anginal episodes, and diminish the requirement for sublingual nitroglycerin. No randomized trials have examined the effect of beta blockers on survival in patients with stable angina. (See 'Survival' below.)

For both nonselective and cardioselective agents, we use doses (up to the recommended maximum) that allow the patient to reach targeted resting and exercise heart rates. (See 'Therapeutic goals' below.)

Nonselective agents — Propranolol was the first beta blocker introduced clinically. It is a nonselective agent that has been used extensively for stable angina.

Evidence of long-term efficacy was provided in a study of 63 patients with severe stable angina who were treated with propranolol for five to eight years [15]. A 50 percent or greater reduction in anginal episodes occurred in 84 percent of patients. Those with a lesser or no response had a fourfold increase in mortality. There was no evidence of tachyphylaxis to beta blockade.

Cardioselective drugs — As noted above, cardioselective beta blockers (the most commonly used being atenolol and metoprolol) offer the potential advantage of not interfering with bronchodilatation or peripheral vasodilatation. The clinical applicability of this effect is uncertain since cardioselectivity may be lost at the high doses needed to treat angina [12]. Nevertheless, cardioselective drugs are used in most patients with stable angina.

Atenolol, metoprolol, and nadolol are as effective as propranolol (and more effective than placebo) in reducing anginal attacks, nitroglycerin use, and increasing exercise capacity [16-18]. In addition, once daily dosing of atenolol is as effective (and more convenient) as twice daily dosing [17]. Metoprolol is available in a short acting form (metoprolol tartrate) for twice daily dosing and in a long acting form (metoprolol succinate) for once daily dosing.

The efficacy of metoprolol was demonstrated in the International Multicenter Angina Exercise (IMAGE) study in which 280 patients with chronic stable angina were randomly assigned to six weeks of therapy with long-acting preparations of metoprolol (200 mg daily) or nifedipine (20 mg twice daily) [19]. Metoprolol reduced the frequency of angina and increased the mean exercise time to 1 mm ST segment depression. Furthermore, the increase in exercise time was significantly greater than that seen with nifedipine (70 versus 43 seconds).

Agents with intrinsic sympathomimetic activity — Pindolol and acebutolol are as effective in treating angina as other beta blockers but have the potential advantage of causing less depression of cardiac function. One report, for example, compared the efficacy of propranolol and pindolol in 52 patients with stable angina [20]. Both agents were equally effective in relieving angina, but pindolol caused less pronounced resting bradycardia or impairment in left ventricular function. In another study, pindolol (when compared to propranolol) was associated with a higher resting heart rate and, at low levels of exercise, a higher heart rate, cardiac output, oxygen consumption [13]. These differences disappeared at higher rates of exercise.

Despite some potential benefits, these drugs are rarely used in the treatment of stable angina except possibly in patients with underlying resting bradycardia. They may not decrease heart rate and blood pressure at rest and should not be given to patients with a prior myocardial infarction or heart failure in whom beta blockade improves survival.

Agents with alpha blocking activity — Carvedilol is a nonselective beta blocker that has vasodilating properties as a result of selective alpha-1 antagonism. One study of 122 patients with chronic stable angina found that carvedilol, at doses of 25 or 50 mg twice daily, was superior to placebo, significantly increasing the time to angina and to one mm ST segment depression during exercise testing [21]. There was no difference in the frequency of side effects when compared to placebo. In another randomized trial, carvedilol was at least as effective as verapamil [22].

Data are more limited with labetalol but demonstrate significant reductions in heart rate and angina frequency and an increase in exercise time [23].

SURVIVAL — In addition to control of angina symptoms, beta blockers improve survival in certain subgroups of patients with stable coronary disease:

●Patients who have had a myocardial infarction. (See "Acute myocardial infarction: Role of beta blocker therapy".)

●Patients with systolic heart failure. (See "Primary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Beta blocker'.)

In contrast, beta blockers have never been shown to improve survival or reduce the incidence of myocardial infarction in patients with chronic stable angina in the absence of myocardial infarction or heart failure.

Three observational studies have found no difference in mortality in this patient population:  

●In the international REACH registry of patients with established cardiovascular disease [24], patients were enrolled in 2003 and 2004 and followed prospectively for up to four years. The primary outcome was a composite of cardiovascular death, nonfatal myocardial infarction (MI), or nonfatal stroke. Propensity score matching identified 3599 pairs of patients (with known coronary artery disease but without prior MI) who were or were not taking beta blocker. Aspirin use was 70 percent and statin use 75 percent. After a median follow-up of 44 months, there was no difference in the primary outcome (12.9 versus 13.6 percent, respectively; hazard ratio [HR] 0.92, 95% CI 0.79-1.08).

●In a study involving 26,793 patients discharged after a first coronary heart disease event (acute coronary syndrome or coronary revascularization), 19,843 individuals started beta blockers within seven days of discharge [25]. During an average of 3.7 years of follow-up, beta blocker treatment was associated with a 10 percent lower risk of death (HR 0.90, 95% CI 0.84-0.96) in the entire cohort. However, among those without prior MI, there was no difference in the risk of death (HR 1.02, 95% CI 0.91-1.15).

●A 2016 study evaluated outcomes in 755,215 patients ≥65 years of age with chronic coronary syndrome who underwent percutaneous coronary intervention in the National Cardiovascular Data Registry (United States) [26]. These patients had no prior MI or heart failure and had a left ventricular ejection fraction ≥40 percent. There was no significant difference in adjusted all-cause mortality at three years between those discharged with beta blocker and those not (14 versus 13.3 percent; adjusted hazard ratio 1.00, 95% CI 0.96-1.03).

THERAPEUTIC GOALS — The primary therapeutic goal of beta blockers in chronic stable angina is to reduce the frequency and severity of angina and to improve exercise capacity without significant side effects. As noted above, the efficacy of beta blockers in relieving angina is dose-dependent. It is therefore important to be certain that adequate beta blockade has been attained.

With regard to the initiation of beta blocker therapy, we suggest starting at the lowest recommended dose for the chosen agent. Since the overall goal is a reduction in the frequency and severity of angina, it may not be necessary to titrate to high doses in some patients. Avoidance of high doses may decrease the likelihood of side effects.

Reasonable goals when titrating the dose include:

●Resting heart rate in the 60 to 70 beats/min range. Although we do not have a specific heart rate goal for exercise, relief of angina without causing dyspnea and fatigue from being overly beta blocked is a reasonable approach.

Patients with resting bradycardia prior to therapy can be treated with nitrates, or, if a beta blocker is necessary, a drug with intrinsic sympathomimetic activity. It is also reasonable to treat with a standard beta blocker in low doses and titrate according to resting and exercise heart rates.

Similar considerations apply to patients with atrioventricular conduction delay.

●Blunting of peak heart rate and blood pressure during exercise, which can be measured by the patient or during exercise testing, if performed.

●Absence of significant side effects.

CHOOSING AN AGENT — Given the general efficacy of most beta blockers in the management of stable angina, ancillary properties, such as dosing interval and cost, become important considerations when determining which beta blocker to use. We generally use a cardioselective agent (atenolol or metoprolol). There are no major advantages of a nonselective agent, and there are potential disadvantages in patients with certain underlying diseases such as obstructive lung disease, asthma, peripheral artery disease, diabetes, and depression. Clearance of atenolol is dependent upon kidney functioning and active drug can accumulate in patients with renal impairment (CRCL <35 mL/minute per 1.73 m²). In general, we use metoprolol in patients with chronic kidney disease or unstable renal function because it is cleared by hepatic metabolism and does not need to be dose adjusted in renal impairment.

Beta blockers with intrinsic sympathomimetic activity are rarely used in the treatment of stable angina except possibly in patients with underlying resting bradycardia. They may not decrease heart rate and blood pressure at rest and should not be given to patients with a prior myocardial infarction or heart failure in whom beta blockade improves survival.

We agree with the 2012 American College of Cardiology Foundation/American Heart Association/American College of Physicians/American Association for Thoracic Surgery/Preventive Cardiovascular Nurses Association/Society for Cardiovascular Angiography and Interventions/Society of Thoracic Surgeons guideline on the diagnosis and management of chronic coronary syndrome, which reached the following conclusions on the role of beta blockers [27,28]:

●Beta blockers are recommended as initial therapy for the relief of anginal symptoms in patients with chronic coronary syndrome. Calcium channel blockers and long-acting nitrates are recommended when beta blockers are contraindicated or poorly tolerated and in addition to beta blockers when angina persists with beta blocker monotherapy.

Patients with heart failure due to systolic dysfunction — The use of beta blockers in patients with heart failure due to systolic dysfunction is discussed elsewhere. (See "Primary pharmacologic therapy for heart failure with reduced ejection fraction", section on 'Beta blocker'.)

RECOMMENDATIONS OF OTHERS — Beta blockers are recommended for use in patients with stable ischemic heart disease in guidelines from the American College of Cardiology Foundation/American Heart Association/American College of Physicians/American Association for Thoracic Surgery/Preventive Cardiovascular Nurses Association/Society for Cardiovascular Angiography and Interventions/Society of Thoracic Surgeons and from the European Society of Cardiology [27-30].

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Chronic coronary syndrome".)

SUMMARY AND RECOMMENDATIONS

●Beta blockers are highly effective in the reduction of symptoms of angina and the development of myocardial ischemia in stable patients. However, they have never been shown to decrease mortality in these individuals in the absence of myocardial infarction or heart failure associated with a reduction in left ventricular systolic function. (See 'Efficacy of beta blockers in stable angina' above.)

●The physician should become familiar with one or two beta blockers in each class (eg, atenolol or metoprolol, propranolol, and pindolol) for cardioselective, nonselective, and intrinsic sympathomimetic activity, respectively. The choice of agent depends upon the clinical setting since all beta blockers are equally effective in treating angina. (See 'Choosing an agent' above.)

●Unless contraindicated, we treat most patients with stable angina pectoris with a beta blocker and generally as first-line antianginal therapy. (See "Chronic coronary syndrome: Overview of care", section on 'Antianginal therapy'.)

●For patients with ischemic heart disease, we suggest using a cardioselective agent, such as atenolol or metoprolol, rather than a nonselective agent (Grade 2C). (See 'Cardioselective drugs' above.)

ACKNOWLEDGMENT — The UpToDate editorial staff thank Dr. Julian M. Aroesty for his contributions as an author to prior versions of this topic review.