What is the current value of beta-adrenoreceptor antagonists for angina?

1. Introduction

Ischemic heart disease is one of the leading causes of mortality worldwide [1]. Management of patients with stable ischemic heart disease involves risk modification, anti-platelet therapy, anti-anginal pharmacotherapy, and selective coronary revascularization for refractory angina despite maximal medical therapy. Clinical trials comparing revascularization and medical therapy showed that revascularization does not provide a survival benefit or improve exercise tolerance in patients with stable angina. Guidelines recommend beta-blockers, calcium channel blockers, and nitrates as the first-line anti-anginal agents. Ranolazine is used as a second-line agent in patients unable to tolerate first-line anti-anginal agents due to side effects or as a combination therapy with first-line agents in patients with residual angina. Ivabradine, nicorandil, and trimetazidine are other newer drugs that are being studied for angina. Although current guidelines recommend a hierarchical approach to the treatment of angina, there is no evidence for the superiority of one anti-anginal agent over the others. Beta-adrenoreceptor blockers have been used for chronic coronary artery disease since the 1960s. Beta-blockers significantly reduce mortality in patients with recent myocardial infarction and left ventricular dysfunction, while there is limited evidence to support such a mortality benefit in stable ischemic heart disease with normal ejection fraction. This editorial inspects the evidence behind the current use and future of beta-blockers for the treatment of angina.

2. Beta-blocking agents – types, mechanism, and safety profile

Beta-blockers are competitive antagonists of catecholamines, epinephrine, and norepinephrine. β-1 receptors are predominantly located in the heart and are responsible for the increase in heart rate and myocardial contractility, hence associated with an inherent increase in myocardial oxygen requirements in response to sympathetic stimulation. Blocking this response is the primary mechanism of the anti-anginal effect of beta-blockers [2]. Beta-blockers decrease the resting heart rate and the degree of rise in heart rate with exercise. The resultant decrease in heart rate increases the diastolic filling time and the coronary perfusion time, improving myocardial oxygen supply while lowering myocardial oxygen demand by decreasing the rate-pressure product. As a whole, beta-blockers effectively reduce anginal symptoms, ischemic burden, and significantly improve exercise tolerance in patients with chronic coronary syndrome. The dose is adjusted weekly to achieve a resting heart rate of 55–60 beats per minute. (Bisoprolol initial dose 5 mg and maximum dose 20 mg; Metoprolol tartrate initial dose 50 mg twice daily, maximum dose 200 mg twice daily; Metoprolol succinate initial dose 100 mg daily, maximum dose 400 mg daily; Atenolol initial dose 50 mg daily, maximum dose 100 mg daily; Carvedilol initial dose 12.5 mg twice daily, maximum dose 50 mg twice daily; Propranolol initial dose 80 mg daily, maximum dose 320 mg daily) The number of surface β-1 receptors is increased after prolonged therapy with beta-blocking agents. This could lead to worsening ischemic symptoms after an abrupt discontinuation of treatment [2]. Nonselective beta-blockers also inhibit the β-2 adrenergic receptors, which are responsible for bronchial and peripheral vascular smooth muscle relaxation [2]. Other recognized adverse effects of beta-blockers include fatigue, worsening of peripheral vascular disease, sleep disturbances, and weight gain. A metanalysis of randomized controlled trials did not show a significant association of depression, sexual dysfunction, and fatigue with the use of beta-blockers. While these symptoms may be associated with the underlying comorbidities, these side effects are commonly attributed to beta-blocker use and are likely to cause poor adherence [3]. A population-based study showed that only 62% of US patients diagnosed with angina were treated with beta-blockers [4].

Various beta-blocking agents have shown a comparable decrease in anginal symptoms [5,6]. Thus, the selection of a particular beta-blocker primarily depends on patients’ comorbidities [2]. For example, β-1 selective agents like metoprolol, bisoprolol, and acebutolol may be preferred in patients with obstructive pulmonary disease, in patients with diabetes mellitus prone to hypoglycemia, and those with significant peripheral arterial disease to improve tolerance. Beta-blockers may mask symptoms of hypoglycemia and may increase the risk of adverse cardiovascular events in diabetic patients treated with hypoglycemic agents. Beta-blockers with intrinsic sympathomimetic activity (pindolol, acebutolol, and nebivolol) are generally not preferred for the treatment of angina but may be considered in patients with baseline bradycardia. Beta-blockers are not recommended as first-line antihypertensives due to poorer tolerance and efficacy; however, if needed, agents with concomitant alpha-adrenergic blocking properties like carvedilol or labetalol can be used for patients with angina and uncontrolled hypertension. Lipophilic beta-blockers such as metoprolol and propranolol are metabolized by the liver, hence safely used in patients with renal dysfunction. Beta-blockers should not be combined with non-dihydropyridine calcium channel blockers (verapamil, diltiazem) for the treatment of angina because of the additive risk of atrioventricular blocks. Beta-blockers can be safely combined with dihydropyridine calcium channel blockers, nitrates, nicorandil, ivabradine, and ranolazine. When used with nitrates or nicorandil, they can prevent reflex tachycardia. Nitrates and non-dihydropyridine calcium channel blockers can be utilized in addition to beta-blockers for additional symptom control and improvement in quality of life in patients with angina, especially in those with vasospastic angina. However, it should be noted that there are no large prospective studies in assessing the efficacy therapy of beta-blockers with that of nitrates or calcium channel blockers. Severe bradycardia, hypotension, acute decompensated heart failure with a low cardiac output state, cardiogenic shock, acute asthma, high-grade atrioventricular conduction abnormalities, and vasospastic angina are the major contraindications for beta-blocker therapy [2].

3. Efficacy of beta-adrenoreceptor blocking agents in patients with angina

In 1994, the ASIST trial evaluating the efficacy of beta-blockers in asymptomatic or mildly symptomatic patients with chronic coronary syndrome with documented ischemia showed a significant improvement in time to anginal symptoms, exercise duration, and ischemic burden with atenolol compared to placebo [7]. The TIBET trial found comparable improvements in exercise capacity and angina symptoms between atenolol, nifedipine extended-release, and the combination of the two therapies, with no additional improvement in the combination group [8]. Similarly, another small randomized study including males with stable angina pectoris found atenolol to be effective in improving the time to exercise-induced ischemia with better tolerability than nifedipine [9]. A small but randomized blinded study comparing bisoprolol versus nitrates in patients with stable angina found that the bisoprolol was more effective in improving the total workload and reducing the time to onset of symptoms of angina than isosorbide dinitrate with fewer reported side effects [10]. Another trial comparing the combination therapy in patients who were previously on metoprolol controlled-release or nifedipine therapy found that the addition of a second drug may recruit the non-responders to individual initial therapy. The addition of metoprolol to nifedipine led to a symptomatic improvement in an additional 24% of patients. In addition, metoprolol led to a significantly greater increase in time to ST depression with activity [11]. These anti-anginal effects of beta-blockers are consistently demonstrated in real-world cohort studies as well over many years of drug therapy [12].

Despite the proven symptomatic benefits of beta-blockers in treating angina, the evidence behind the role of beta-blockers in reducing cardiovascular mortality and recurrent acute coronary syndromes is limited [2,13]. In a posthoc analysis of the CHARISMA trial, the beta-blockers were found not to reduce major cardiovascular events in patients without prior myocardial infarction, and the ACTION trial sub-analysis showed that beta-blockers did not reduce the risk of mortality from myocardial ischemia [14,15]. The meta-analyses of previous studies comparing beta-blockers versus placebo or other anti-anginal therapies did not find a mortality benefit with beta-blockers in patients with stable angina even though cardioselective beta-blockers showed a trend toward benefit [16]. The low event rate among patients with chronic coronary syndrome is one of the major reasons it is harder to show a statistically significant mortality benefit with these proven medical therapies for stable angina. However, few studies have shown lower recurrent ischemic cardiac events, including myocardial infarction with the use of beta-blockers [7,17], and lower infarct size and possible reduction in short-term mortality due to ischemic preconditioning among patients on chronic beta-blocker therapy [18]. The role of beta-blocker therapy in myocardial salvage through ischemic preconditioning, ischemic postconditioning, and remote ischemic conditioning needs to be elucidated with future pre-clinical and clinical studies [19].

Apart from stable ischemic heart disease, beta-blockers are useful in symptomatic relief in patients with angina secondary to coronary microvascular dysfunction (CMD) (previously known as cardiac syndrome X). The CMD is characterized by abnormalities in coronary microcirculation such as arteriolar vasoconstriction, with non-obstructive epicardial coronary arteries. While propranolol and acebutolol have not been effective in these patients, atenolol and bisoprolol have been shown to reduce ischemic symptoms and improve exercise capacity [20]. CMD could be one of the major reasons for recurrent angina after successful coronary angioplasty. Beta-blockers are recommended as one of the first-line medical therapy in such patients to reduce symptom burden [21].

Although beta-blockers are conventionally regarded as the first-line therapy for angina in patients with chronic therapy syndrome, this is not supported by strong clinical evidence. Interestingly, a recent network meta-analysis failed to demonstrate the superiority of beta-blockers over other anti-anginal agents. They found no one anti-anginal drug to be superior to another, and all three classes of anti-anginal drugs studied – beta-blockers (atenolol), calcium antagonists (amlodipine, nifedipine), and If channel inhibitors (ivabradine) showed therapeutic equivalence [22]. Nevertheless, the beta-blockers are used in at least three-fourths of patients with stable angina. It is noteworthy that the heart rate control achieved with beta-blockers in real-world clinical practice is less than ideal due to sub-maximal dosing [23]. It is important that anti-anginal therapy with beta-blockers should be titrated to achieve a low target heart rate with prompt up-titration of the doses. Combining beta-blockers with other anti-anginal medications, such as perhexiline maleate, has been shown to improve efficacy in patients with refractory angina [24,25]. The combination therapy with newer anti-anginal agents (ivabradine and trimetazidine) along with maximally tolerated beta-blockers seems to be a promising approach to achieve maximal clinical benefits of medical therapy for the chronic coronary syndrome [26,27].

4. Expert opinion

Beta-blockers are effective in reducing symptom burden and improving exercise capacity in patients with angina pectoris. The beta-blockers should be up titrated to a goal of low target heart rate to achieve the maximal clinical benefit. Most studies on beta-blockers for angina have demonstrated good clinical efficacy for symptom control. However, there is no substantial evidence to suggest a definitive mortality benefit unless used in the setting of recent myocardial infarction or heart failure with reduced ejection fraction. While angina, due to significant coronary artery disease or coronary microvascular dysfunction, is more common in women, they are under-represented in clinical trials. Similarly, the data on the safety and efficacy of beta-blockers in elderly adults with angina is limited. Observational studies have shown significant functional decline in elderly adults started on beta-blocker therapy despite the mortality benefit [28]. However, in elderly adults who have had a recent myocardial infarction or have concomitant systolic heart failure, the beta-blockers confer a true mortality benefit and should be considered as first-line agents. Clinicians should exercise caution and be mindful of the risk versus benefits in high-risk patient groups.

Future studies should focus on the effect of chronic beta-blocker therapy on ischemic conditioning for myocardial protection, combination therapy of beta-blockers with other conventional or newer anti-anginal agents to achieve better target heart rate control and improved clinical outcomes. The available data on the efficacy of a selected beta-blockers in CMD is promising but needs further validation, with future studies addressing the variability in the effectiveness of various beta-blockers and their impact on long-term clinical outcomes, including mortality. Lastly, high-quality and contemporary evidence on the comparative efficacy of various anti-anginal agents continues to increase. With increasing evidence and experience with second-line agents, clinicians should strive to customize angina therapy according to patients’ comorbidities and underlying mechanism of angina. The ‘diamond’ approach for choosing a specific therapy over another based on the patient’s comorbidities and clinical characteristics for treatment of angina may be more effective, and this hybrid approach should be evaluated in future clinical investigations [29].

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Reviewer disclosures

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