Editor's Note: Commentary based on Andersson C, Shilane D, Go AS, et al. Beta-blocker therapy and cardiac events among patients with newly diagnosed coronary heart disease. J Am Coll Cardiol 2014;64:247-52.

Background

The role of beta-blockers in stable coronary heart disease (CHD) has principally been an extrapolation of the benefits observed in patients with acute myocardial infarction (AMI) and left ventricular systolic dysfunction (LVSD). This study assessed the association of beta-blocker use with future adverse cardiac events among patients with newly-diagnosed CHD, and sought to determine whether there was a differential benefit in patients with and without incident AMI.

Methods

This retrospective analysis used electronic health records from Kaiser Permanente Northern California, and included all patients ≥30 years of age with a new diagnosis of CHD between January 1, 2000 and December 31, 2008. Patients with AMI, unstable angina, and those who underwent PCI or CABG were included. Patients with a history of AMI, unstable angina, coronary revascularization, or prescription for a beta-blocker within the year before study entry were excluded. Two endpoints were analyzed: 1) all-cause mortality, and 2) the composite of death from any cause or hospitalization for an AMI. Time-dependent multivariable Cox proportional hazard regression models were used to adjust for confounders. The a priori hypothesis was that the presence of a recent AMI would modify the association of beta-blocker use with outcomes.

Results

Of 26,793 total patients, 19,843 (74%) were initiated on beta-blocker treatment on discharge, 3,819 (14%) started beta-blockers during the first year of follow-up, and 3,131 (12%) did not use beta-blockers during the average 3.7 years follow-up. 4,240 patients (16%) died and 6,968 (26%) had a cardiac event (death or AMI). The unadjusted mortality rate and rate of death or AMI were lower in patients taking beta-blockers than among those not taking beta-blockers. After adjustment for baseline factors and time-varying exposure to other cardiac medications, beta-blocker treatment was associated with a significantly lower risk of death (Hazard ratio (HR) 0.90, 95% confidence limit [CL]: 0.84 to 0.96) and AMI (HR 0.92, CL: 0.87 to 0.97). However, this benefit was seen only in patients with an index AMI; no benefit of beta blockade was seen in patients without AMI with respect to either death (p for interaction: 0.007) or death or AMI (p for interaction: 0.005).

Conclusion

Among patients with newly diagnosed CHD, beta-blockers were associated with a reduced rate of cardiac events only among patients with AMI.

Commentary/Perspective

In the setting of AMI, beta-blockers reduce mortality by approximately 20% in randomized trials and 40% in observational studies. The maximum duration of follow-up data available is six years. Evidence suggests that this benefit accrues primarily early on and in those patients at the highest risk.¹ However, the majority of these studies were performed in the early era of medical management of AMI, before the advent of reperfusion therapy, renin-angiotensin-aldosterone system (RAAS) inhibitors, statins, and antiplatelet therapies. Bangalore et al.² showed that in the reperfusion-era, beta-blockers had no mortality benefit but did reduce recurrent MI and angina at the expense of an increase in heart failure, cardiogenic shock, and drug discontinuation. Recently, other long-term retrospective studies in AMI have shown conflicting results.^3-5

There have been very few studies of beta-blocker use in stable CAD without MI, angina, or abnormal left ventricular systolic function. Bunch et al. in 2005⁶ evaluated 4,304 patients over a mean of three years with angiographically confirmed CAD without AMI or heart failure. The results suggested that these patients may have the same beta-blocker-related protective benefit against death but no effect on AMI or the combination of death/nonfatal MI. More recently, the REduction of Atherothrombosis for Continued Health (REACH) Registry investigators in 2012⁷ found that, after a median 44 months of follow-up, beta-blockers were not associated with a reduced rate of composite cardiovascular events in 21,860 stable CAD patients, even in the subset of patients with known prior MI (n = 14,043). In 2013, another large multi-center registry of 5,288 patients found that beta-blocker use was associated with a higher risk of cardiac death/MI in CAD patients who underwent PCI but had no history of MI or heart failure.⁸

In the present retrospective study of patients with newly diagnoses CHD, Andersson et al.⁹ found that the benefit of beta-blockers was confined to patients presenting with AMI. However, it should be noted that the study population consisted primarily of those with an acute coronary syndrome undergoing revascularization. Therefore, the results of the study may not be generalizable to the broader population of stable CHD patients who may be managed without revascularization. In addition, information regarding the presence of angina and left ventricular systolic dysfunction, conditions in which the benefits of beta-blockers are well established, was not available.

In summary, multiple trials have shown the mortality benefit of beta-blockers following AMI, although the optimal duration of treatment is unknown. Recent observational studies have utilized varying definitions of "stable CHD," and have shown conflicting results with respect to the benefits of beta blockade in these populations. This suggests a need for randomized control trials to: 1) evaluate the appropriate duration of beta-blocker treatment post-AMI; and 2) test whether beta-blockers confer any benefit in reducing important clinical outcomes in stable CHD patients without AMI, angina, and/or left ventricular systolic dysfunction. Until such trials are conducted, current guidelines recommend that beta-blocker therapy be started and continued for three years in all patients with AMI or ACS (Class 1; Level of Evidence: B).¹⁰ Beta-blocker use for more than three years post-MI (Class IIA, Level of Evidence: B), and as therapy for all stable CHD patients (Class IIb, Level of Evidence: C) have weaker recommendations and require further evidence to inform clinical decision-making.

References

1. Kezerashvili A, Marzo K, De Leon J. Beta blocker use after acute myocardial infarction in the patient with normal systolic function: when is it "ok" to discontinue? Curr Cardiol Rev 2012;8:77-84.
2. Bangalore S, Makani H, Radford M, et al. Clinical outcomes with beta-blockers for myocardial infarction: a meta-analysis of randomized trials. Am J Med 2014;127:939-53.
3. Choo EH, Chang K, Ahn Y, et al. Benefit of beta-blocker treatment for patients with acute myocardial infarction and preserved systolic function after percutaneous coronary intervention. Heart 2014;100:492-9.
4. Nakatani D, Sakata Y, Suna S, et al. Impact of beta blockade therapy on long-term mortality after ST-segment elevation acute myocardial infarction in the percutaneous coronary intervention era. Am J Cardiol 2013;111:457-64.
5. Ozasa N, Kimura T, Morimoto T, et al. Lack of effect of oral beta-blocker therapy at discharge on long-term clinical outcomes of ST-segment elevation acute myocardial infarction after primary percutaneous coronary intervention. Am J Cardiol 2010;106:1225-33.
6. Bunch TJ, Muhlestein JB, Bair TL, et al. Effect of beta-blocker therapy on mortality rates and future myocardial infarction rates in patients with coronary artery disease but no history of myocardial infarction or congestive heart failure. Am J Cardiol 2005;95:827-31.
7. Bangalore S, Steg G, Deedwania P, et al. beta-Blocker use and clinical outcomes in stable outpatients with and without coronary artery disease. JAMA 2012;308:1340-9.
8. Ozasa N, Morimoto T, Bao B, et al. beta-blocker use in patients after percutaneous coronary interventions: one size fits all? Worse outcomes in patients without myocardial infarction or heart failure. Int J Cardiol 2013;168:774-9.
9. Andersson C, Shilane D, Go AS, et al. beta-blocker therapy and cardiac events among patients with newly diagnosed coronary heart disease. J Am Coll Cardiol 2014;64:247-52.
10. Smith SC, Jr., Benjamin EJ, Bonow RO, et al. AHA/ACCF secondary prevention and risk reduction therapy for patients with coronary and other atherosclerotic vascular disease: 2011 update: a guideline from the American Heart Association and American College of Cardiology Foundation. J Am Coll Cardiol 2011;58:2432-46.

Keywords: Acute Coronary Syndrome, Adrenergic beta-Antagonists, Angina Pectoris, Angina, Stable, Angina, Unstable, Blood Platelets, Coronary Disease, Electronic Health Records, Follow-Up Studies, Heart Failure, Hospitalization, Humans, India, Longitudinal Studies, Myocardial Infarction, Registries, Research Personnel, Retrospective Studies, Shock, Cardiogenic

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