Introduction

Cardiovascular (CV) disease is the leading cause of mortality and morbidity in the Western world,¹ and various medical therapies have proven useful in terms of improving outcomes as secondary prevention measures.^2-4 In patients with stable ischemic heart disease (SIHD) and normal left ventricular (LV) function, beta-blockers have shown significant effects with regard to reducing symptoms and improving exercise capacity.^2-4 Their impact on survival, however, remains to be clarified. Here we briefly review the most recent findings regarding the role of beta-blockade therapy in patients with SIHD and normal LV function, with a particular emphasis on data provided by the CLARIFY registry (Prospective Observational Longitudinal Registry of Patients with Stable Coronary Artery Disease), a prospective observational study that offers a unique opportunity to analyze the contemporary management of patients with SIHD.

The CLARIFY Registry

The CLARIFY registry is a large international registry providing detailed information on 32,703 patients with SIHD enrolled between 2009 and 2010, followed up for a median of 5 years, and treated according to contemporary guidelines.⁵ Patients were enrolled in 45 countries in Africa, Asia, Australia, Europe, the Middle East, and North, Central, and South America. Baseline demographics, ongoing therapies, and clinical outcomes were prospectively collected.⁵ Patients were eligible if they presented with one of the following (which were not mutually exclusive):

• Prior myocardial infarction (MI) (>3 months)
• Documented coronary artery disease on coronary angiogram (stenosis >50%)
• History of chest pain with evidence of myocardial ischemia
• History of myocardial revascularization (either percutaneous coronary intervention or coronary artery bypass grafting)⁵

Baseline Characteristics of Patients in the CLARIFY Registry

Patients enrolled in the CLARIFY registry were predominantly Caucasian (64.6%), male (77.6%), overweight (median body mass index of 27.3) patients with a mean age of 64.2 ± 10.5 years. The majority of patients had CV risk factors (diabetes in 29.1%, hypertension in 71%, dyslipidemia in 74.9%, and current or former smoking in 58.7%); 68.0% were treated with beta-blockers, and 57.7% had a medical history of prior MI. The mean LV ejection fraction was 56.1% ± 11.1% (measured in n = 22,519 patients). Importantly, at the time of enrollment, most patients were asymptomatic; 77.9% had no angina, and 84.9% had no heart failure.⁵

The Evidence-Based Use of Beta-Blockers in Patients With SIHD

Beta-blockers are recommended as first-line treatment for symptomatic management of patients with SIHD and normal LV function in order to reduce effort-induced angina and improve exercise capacity.^2,3 However, their real impact on mortality remains controversial because most evidence suggesting their benefit on survival are based on large observational studies conducted in the pre-reperfusion era when the benefit from therapy was primarily driven by their role in preventing sudden cardiac death in the acute phase of MI.⁶ Data accounting for more contemporary management have indeed failed to demonstrate any positive effect on survival.^7-9 Moreover, in a meta-analysis of 60 randomized controlled trials, Bangalore et al. found increased rates of symptomatic heart failure, cardiogenic shock, and drug discontinuation in patients treated with beta-blockers.⁸ Therefore, one might hypothesize that changes in the management of patients, including the widespread use of reperfusion therapy and the more aggressive medical approach for secondary prevention, have modified the expected benefit from beta-blockade therapy.

Data from the CLARIFY registry have recently provided novel insights regarding the use of beta-blockers in patients with SIHD.¹⁰ Indeed, although not associated with a significant benefit in the overall population, in the recently published analysis of 22,006 patients from the CLARIFY registry,¹⁰ beta-blockers were associated with lower 5-year all-cause death (hazard ratio [HR] 0.68; 95% confidence interval [CI], 0.50-0.91; p = 0.01) in the subgroup of patients with prior MI within the last year before inclusion. This improvement was mainly driven by a reduction in CV death (HR 0.52; 95% CI, 0.37-0.73; p = 0.0001) and recurrent MI (HR 0.69; 95% CI, 0.52-0.93; p = 0.01).¹⁰ These results are consistent with those from other groups. In a retrospective study from Andersson et al. (n = 26,793 patients with recent acute coronary syndrome or coronary revascularization), the use of beta-blockers was associated with a reduction in death or death/MI limited to the subgroup of patients presenting with a recent MI.¹¹ Finally, in a post-hoc analysis of the CHARISMA trial (Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance), beta-blockers were associated with a lower rate of the composite endpoint of nonfatal MI, nonfatal stroke, and CV death (HR 0.69; 95% CI, 0.50-0.94; p = 0.021) at 28 months, which was primarily driven by a significant reduction of recurrent MI.¹² Taken together, these data support an association of beta-blocker use with better clinical outcomes in patients with SIHD managed according to contemporary guidelines. However, it is important to note that these data were obtained from registries of non-randomized patients or post-hoc analyses, which greatly limit the strength of the conclusions.

Optimal Duration of Beta-Blockade Therapy in Patients With SIHD

Data are lacking regarding the optimal duration of beta-blockade therapy in the post-MI setting, with no strong recommendation being currently available.^2,4 Data provided by the CLARIFY registry have recently shown no difference in outcomes in patients who were treated with beta-blockers compared with those who were not¹⁰ among those enrolled beyond the first year post-MI, suggesting a short- or mid-term rather than long-term benefit from beta-blockers in patients post-MI. This has also been demonstrated by Bangalore et al. in 6,758 patients with SIHD included in the REACH registry (Reduction of Atherothrombosis for Continued Health), where beta-blockers had a beneficial effect on the secondary end-points of CV death, nonfatal MI, and nonfatal stroke and of hospitalization for atherothrombotic events and myocardial revascularization, but only in patients with MI within the last year.⁷ Of note, the 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS Guideline for the diagnosis and management of patients with stable ischemic heart disease recommended that beta-blockers be started early and continued for 3 years in all patients with normal LV function in the post-MI or acute coronary syndrome context (Class 1 recommendation, Level of Evidence B) and that beta-blockers may be considered as chronic therapy for stable patients with coronary or other vascular disease (Class IIb recommendation, Level of Evidence C).⁴

Therapeutic Options for Heart Rate Reduction in SIHD and Normal LV Function

The beneficial effect of beta-blockers on symptoms in SIHD has been shown to be mainly mediated by a reduction in myocardial oxygen demand, therefore preventing or delaying ischemia during stress or exercise.⁷ Heart rate reduction has shown favorable effects on myocardial oxygen demand and coronary blood flow and, consequently, on exercise-induced angina.¹³ As such, effective lowering of heart rate is of key importance in stable angina, and beta-blockers are considered to be first-line therapy in this setting.^2,4 However, and as previously detailed, observational data from the CLARIFY registry suggest that outside of the post-MI setting, beta-blockade therapy has no effect on CV events.¹⁰ Furthermore, it has also been demonstrated that calcium channel blockers offer no improvement of CV outcomes in SIHD,¹⁰ nor did the specific If-channel blocker ivabradine in the randomized controlled SIGNIFY study (Study Assessing the Morbidity–Mortality Benefits of the If Inhibitor Ivabradine in Patients with Coronary Artery Disease).^14,15 A randomized controlled trial would be necessary to appropriately and definitively assess the role of long-term use of beta-blockers as a secondary prevention measure in patients with SIHD and normal LV ejection fraction.

Conclusion

Beta-blockers are highly effective in the symptomatic treatment of SIHD in terms of reducing exercise-induced angina. However, their beneficial impact on mortality and non-fatal CV events outside the setting of recent MI or poor LV systolic function has never been demonstrated. The appropriate duration of beta-blockade therapy post-MI in the contemporary era of prompt revascularization and aggressive medical therapy has also not been evaluated. A randomized controlled trial is needed to determine the value of beta-blockade therapy and potentially its optimal duration in patients with SIHD and normal LV ejection fraction.

References

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2. Task Force Members, Montalescot G, Sechtem U, et al. 2013 ESC guidelines on the management of stable coronary artery disease: the Task Force on the management of stable coronary artery disease of the European Society of Cardiology. Eur Heart J 2013;34:2949-3003.
3. Fihn SD, Blankenship JC, Alexander KP, et al. 2014 ACC/AHA/AATS/PCNA/SCAI/STS focused update of the guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines, and the American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol 2014;64:1929-49.
4. Fihn SD, Gardin JM, Abrams J, et al. 2012 ACCF/AHA/ACP/AATS/PCNA/SCAI/STS Guideline for the diagnosis and management of patients with stable ischemic heart disease: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines, and the American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons. J Am Coll Cardiol 2012;60:e44-e164.
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6. Freemantle N, Cleland J, Young P, Mason J, Harrison J. beta Blockade after myocardial infarction: systematic review and meta regression analysis. BMJ 1999;318:1730-7.
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8. Bangalore S, Makani H, Radford M, et al. Clinical outcomes with β-blockers for myocardial infarction: a meta-analysis of randomized trials. Am J Med 2014;127:939-53.
9. Huang HL, Fox KA. The impact of beta-blockers on mortality in stable angina: a meta-analysis. Scott Med J 2012;57:69-75.
10. Sorbets E, Steg PG, Young R, et al. β-blockers, calcium antagonists, and mortality in stable coronary artery disease: an international cohort study. Eur Heart J 2018; Dec 27:[Epub ahead of print].
11. Andersson C, Shilane D, Go AS, et al. β-blocker therapy and cardiac events among patients with newly diagnosed coronary heart disease. J Am Coll Cardiol 2014;64:247-52.
12. Bangalore S, Bhatt DL, Steg PG, et al. β-blockers and cardiovascular events in patients with and without myocardial infarction: post hoc analysis from the CHARISMA trial. Circ Cardiovasc Qual Outcomes 2014;7:872-81.
13. Steg PG, Ferrari R, Ford I, et al. Heart rate and use of beta-blockers in stable outpatients with coronary artery disease. PLoS One 2012;7:e36284.
14. Fox K, Ford I, Steg PG, Tardif JC, Tendera M, Ferrari R. Rationale, design, and baseline characteristics of the Study assessInG the morbidity-mortality beNefits of the If inhibitor ivabradine in patients with coronarY artery disease (SIGNIFY trial): a randomized, double-blind, placebo-controlled trial of ivabradine in patients with stable coronary artery disease without clinical heart failure. Am Heart J 2013;166:654-61.
15. Fox K, Ford I, Steg PG, et al. Ivabradine in stable coronary artery disease without clinical heart failure. N Engl J Med 2014;371:1091-9.

Keywords: Angina, Stable, Secondary Prevention, Coronary Artery Disease, Myocardial Infarction, Prospective Studies, Stroke Volume, Myocardial Ischemia, Angina Pectoris, Systole, Registries, Ventricular Function, Left

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