Beta-Blockers, Calcium Channel Blockers, Mortality in Stable CAD

Study Questions:

What are the effects of beta-blockers and calcium antagonists on clinical outcomes in stable coronary artery disease (CAD)?


The authors performed a post hoc analysis of the CLARIFY (prospeCtive observational LongtudinAl RegIstry oF patients with stable coronary arterY disease) registry to evaluate the association between beta-blocker or calcium antagonist use and clinical outcomes. Patients with stable CAD (n = 32,703) in 45 countries were enrolled between November 2009 and June 2010, and followed annually for up to 5 years. Patients with ≥1 of the following criteria were eligible for enrollment: documented myocardial infarction (MI) >3 months prior; coronary artery bypass grafting (CABG) or percutaneous coronary intervention (PCI) >3 months prior; chest pain with proven myocardial ischemia; and prior coronary angiography with ≥1 coronary stenosis >50%. Exclusion criteria were hospitalization for cardiovascular disease within 3 months of planned enrollment, planned revascularization, and conditions that would interfere with life expectancy (e.g., severe heart failure). The primary outcome was all-cause mortality. Secondary outcomes were cardiovascular mortality and a composite of cardiovascular mortality and nonfatal MI. Beta-blocker and calcium antagonist use was assessed at baseline and yearly. Patients with prior MI were subdivided into groups based on the time from MI to enrollment in CLARIFY. Hazard ratios (HRs) associated with beta-blocker use versus nonuse and calcium antagonist use versus nonuse were calculated from Cox proportional hazards models. HRs were adjusted for cardiovascular risk factors, medical history of cardiovascular disease, treatments, geographical area, pulmonary comorbidities, blood pressure, left ventricular ejection fraction, history of revascularization, chronic obstructive pulmonary disease, and the REACH cardiovascular event risk score (adjusting for sex, age, smoking, diabetes, body mass index, extent of vascular disease, history of MI, heart failure, atrial fibrillation, statin or aspirin therapies, and geographical zone).


Beta-blockers were used in 17,135 (77.9%) patients. Among patients without use, approximately 40% had a prior history of intolerance or a contraindication to beta-blockers. Of the patients receiving beta-blockers, 45.1% received less than half of target dose, 41.5% half to less than full dose, and 13.3% the full target dose. The rate of death was 1.80 per 100 patient-years. For the primary and secondary outcomes, multivariable adjusted HRs showed no association between beta-blocker use at baseline and outcomes. HR for all-cause mortality was 0.94 (95% confidence interval [CI], 0.84-1.06). HR for cardiovascular mortality/nonfatal MI were 0.91 (95% CI, 0.79-1.05) and 1.3 (95% CI, 0.91-1.16), respectively. Among patients with MI ≤1 year prior to enrollment, beta-blocker use compared to nonuse was associated with a lower risk of all-cause mortality (HR, 0.68; 95% CI, 0.50-0.91; p = 0.01), lower cardiovascular mortality (HR, 0.52; 95% CI, 0.37-0.73; p = 0.0001), and lower cardiovascular mortality/nonfatal MI (HR, 0.69; 95% CI, 0.52-0.93; p = 0.01). In patients with prior MI >1 year, there was no difference in outcomes between groups. Calcium antagonists were used in 5,885 (26.7%) patients. Among users, ~80% received long-acting dihydropyridines, ~15% received diltiazem, and ~5% received verapamil. The overall death rate was 1.80 per 100 patient-years. Multivariable adjusted HR for the primary and secondary outcomes showed no association between calcium antagonist use at baseline and any outcome, regardless of time from MI to enrollment.


In this large, contemporary cohort of stable CAD patients, after multivariable adjustment, beta-blockers were not associated with lower all-cause mortality or improved outcomes except in those patients enrolled in the first year following MI. The use of calcium antagonists was not associated with improved outcomes, regardless of prior history of MI.


This large contemporary cohort analysis describes that beta-blockers are not associated with an all-cause mortality benefit in stable CAD patients except for patients enrolled within 1 year post-MI. In patients with stable CAD (and prior MI after 1 year), beta-blockers and calcium antagonists may be used for symptom treatment; however, a mortality benefit may not be present. While an observational study, Sorbets and colleagues present an important analysis, which highlights the question: What is the optimal duration of beta-blocker therapy for contemporary CAD patients with stable disease without heart failure? A large, adequately powered randomized clinical trial assessing the effect of beta-blocker therapy in patients with CAD in the absence of left ventricular systolic dysfunction would be needed to answer this question.

Clinical Topics: Acute Coronary Syndromes, Cardiac Surgery, Invasive Cardiovascular Angiography and Intervention, Noninvasive Imaging, Prevention, Atherosclerotic Disease (CAD/PAD), Cardiac Surgery and Arrhythmias, Interventions and ACS, Interventions and Coronary Artery Disease, Interventions and Imaging, Angiography, Nuclear Imaging

Keywords: Acute Coronary Syndrome, Adrenergic beta-Antagonists, Calcium Channel Blockers, Chest Pain, Coronary Angiography, Coronary Artery Bypass, Coronary Artery Disease, Coronary Stenosis, Myocardial Infarction, Myocardial Ischemia, Outcome Assessment (Health Care), Primary Prevention

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