By Michael H. Crawford, MD, Editor

SYNOPSIS: A multivariate analysis of a large registry of patients with stable ischemic heart disease revealed that beta-blocker use was associated with lower mortality only when prescribed in the first year after acute myocardial infarction.

SOURCES: Sorbets E, Steg PG, Young R, et al. Beta-blockers, calcium antagonists, and mortality in stable coronary artery disease: An international cohort study. Eur Heart J 2019;40:1399-1407.

Nissen SE, Reed GW. Can we trust observational data for clinical decision-making? Eur Heart J 2019;40:1408-1410.

The European Society of Cardiology recommends both beta-blockers and calcium channel blockers as first-line treatment for symptomatic patients with stable ischemic heart disease (SIHD). However, there are little data on whether such therapy improves outcomes. In the absence of randomized, controlled trials (RCTs), Sorbet et al examined the association between beta-blockers or calcium channel blockers and clinical outcomes.

Patients were enrolled between November 2009 and June 2010 in 45 countries and followed for five years. The primary outcome was all-cause mortality. Other outcomes included cardiovascular mortality, myocardial infarction, and stroke. Beta-blocker and calcium channel blocker therapy and their doses were ascertained annually. The total study population was 32,378, of which a complete data set was available for 68%. At baseline, 78% of patients were on beta-blockers. Multivariate adjusted hazard ratios (HR) showed no relationship between beta-blockers and any primary or secondary outcome.

In patients ≤ 1 year post-myocardial infarction (MI), beta-blocker use was associated with a lower risk of all-cause mortality (HR, 0.68; 95% confidence interval [CI], 0.50-0.91; P = 0.01) and cardiovascular mortality (HR, 0.52; 95% CI, 0.37-0.73; P = 0.0001). In patients > 1 year post-MI, there were no differences in outcomes for those on beta-blockers, and there was no difference in outcomes with beta-blockers after categorization by presence of angina. At baseline, 27% of patients were on calcium channel blockers, most of which were long-acting dihydropyridines (80%). There was no association with calcium channel blockers and outcomes. The authors concluded that in a contemporary population of SIHD patients, beta-blocker use was associated only with lower mortality if patients were ≤ 1 year following an acute MI. Calcium channel blocker use was not associated with lower mortality or MI.

COMMENTARY

The recommendation to use beta-blockers in almost all SIHD patients is an abstraction from RCTs conducted decades ago in acute MI patients. These trials were performed before the extensive use of reperfusion and revascularization and prior to the widespread use of secondary prevention therapies such as statins. The potential benefits of calcium channel blockers were extrapolated from their demonstrated efficacy for relieving angina and small, randomized, post-MI trials.1 Considering the absence of RCTs showing a benefit of beta-blockers and calcium channel blockers in SIHD patients, Sorbets et al conceived the prospective, observational CLARIFY study (prospeCtive observational LongitudinAl RegIstry oF patients with stable coronary arterY disease). Its strengths included its large, international design and the fact that the authors recruited SIHD patients with a spectrum of characteristics from whom data were collected prospectively. Also, this was a contemporary study, with high rates of revascularization and proven secondary prevention therapies. In addition, the authors chose relatively hard endpoints: all-cause and cardiovascular mortality, MI, and stroke. They showed that beta-blockers significantly reduced mortality only in patients who were within one year of an acute MI. Further, their findings suggest calcium channel blockers do not reduce mortality. These results are consistent with those of smaller studies and post hoc analyses of larger trials. Further, a subgroup analysis showed that the results were robust across all subgroups analyzed. Since no harm was discovered, Sorbets et al stated that it was acceptable to use beta-blockers and calcium channel blockers for symptom relief and other indications (e.g., hypertension in SIHD patients), but not as secondary prevention agents).

Sorbets et al, along with Nissen and Reed in an accompanying editorial, noted the study’s weaknesses. Like any observational study, there may be residual confounders that were not accounted for in Cox models. The authors did not employ the more rigorous propensity score adjustments. Although patients were enrolled prospectively, the data analysis was not prespecified, so this was essentially a post hoc analysis, which is inherently biased. Also, the study was not blinded, and the outcomes were not adjudicated.

Further, patients were not enrolled at the time of drug initiation, which biases the study toward those who can tolerate the therapy. Finally, patients with clear indications for beta-blockers, such as severe heart failure and life-threatening ventricular arrhythmias, were excluded.

Considering these weaknesses, Nissen and Reed opined that size alone does not guarantee accuracy. They pointed out that the HRs in the study did not meet the more rigorous criteria beyond statistical significance (> 2.0 or < 0.5). Thus, they consider this study only hypothesis-generating. However, since no RCT is likely to be conducted on this issue and considering the consistency of this study with others, I do not plan on recommending beta-blockers purely for secondary prevention in SIHD patients.

REFERENCE

  1. Gibson RS, Boden WE, Theroux P, et al. Diltiazem and reinfarction in patients with non-Q-wave myocardial infarction. N Engl J Med 1986;315:423-429.