Editorials
Qualifying the Use of Common Cardiovascular Drugs in Cardiology
– Time to Think Again About Beta-Blockers? –
2015 Volume 79 Issue 3 Pages 517-518
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2015 Volume 79 Issue 3 Pages 517-518
Recent years have seen a number of publications question the widespread use of common cardiovascular drugs. In particular, the utility of β-blockers have come under scrutiny in patients with hypertension, myocardial infarction (MI) and those with heart failure and concomitant atrial fibrillation (AF), as well as for perioperative reduction of cardiac events. Beta-blockers have been used for many decades for these indications, but with changing patient demographics as well as the routine use of interventional therapies in current practice, we should continue to re-examine presumed benefits.
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In hypertension trials, β-blockers do not reduce the risk of death or MI and have less beneficial effects on incident stroke than other antihypertensive therapies in the elderly.1,2 These data are mainly based on older trials using atenolol, and the effect of newer agents on cardiovascular outcomes in hypertension is less clear (particular those with vasodilating properties).3,4 On the contrary, in patients with heart failure and reduced ejection fraction (HFrEF), β-blockers are associated with substantial reductions in adverse outcomes. In an individual patient data meta-analysis of 10 major randomized trials comparing β-blockers with placebo (n=18,254), the hazard ratio for all-cause mortality was 0.73 (95% confidence interval (CI) 0.67 to 0.80; P<0.001) and 0.78 for cardiovascular hospitalization (95% CI 0.73 to 0.83; P<0.001).5 However β-blockers were only effective for those in sinus rhythm at baseline; for patients in AF, a remarkable lack of benefit was noted for all of the evaluated outcomes, despite a large sample size of over 3,000 patients with concomitant HFrEF and AF.5 The widespread and liberal prescription practice of β-blockers is further challenged by trials assessing perioperative use of β-blockers for non-cardiac surgery. After excluding trials discredited for abnormalities in data collection and analysis,6 a recent meta-analysis demonstrated a 27% increase in 30-day mortality for patients randomized to β-blockers.7 The results include the large Perioperative Ischemic Evaluation Study (POISE), which identified a small reduction in incident MI (4.2% in the metoprolol arm vs. 5.7% with placebo), but also a doubling of stroke with active therapy (1.0% vs. 0.5%).8
So how do the available data guide our use of β-blockers following MI, a classical indication that has endured for over 40 years? Superseding a prior meta-analysis which informed practice guidelines,9 Bangalore and colleagues have recently published a comprehensive review of 60 randomized trials including over 100,000 patients during a mean follow-up of 10 months.10 Their analysis illustrates the temporal changes in β-blocker efficacy because of improving background medical and interventional therapies. In the pre-reperfusion era, β-blockers were associated with a significant reduction in cardiovascular death and recurrent MI. However, in the current era of thrombolysis, revascularization and advanced antiplatelet therapy, β-blockers had no effect on overall mortality (incident rate ratio 0.98; 95% CI 0.92 to 1.05). There were benefits for reducing recurrent MI in the short-term up to 30 days (number needed to treat: 209), but these marginal effects were offset by significantly higher rates of heart failure and cardiogenic shock (number needed to harm: 79 and 90, respectively),10 consistent with data from the Clopidogrel and Metoprolol in Myocardial Infarction Trial (COMMIT).11
In this issue of the Journal, Grall et al12 examine the association of β-blockers and angiotensin-converting-enzyme inhibitors (ACEI) with outcomes following ST-elevation MI from a prospective observational cohort in France, recruited between 2003 and 2009 (the Registre des infarctus du Maine-Anjou [RIMA registry]). A history of prior MI, low systolic blood pressure and the absence of β-blocker therapy within the first 24 h were associated with in-hospital mortality. By 1 year, the use of β-blockers was no longer independently associated with a reduction in cardiovascular mortality, unlike that of ACEI; however, the authors raise the possibility of a dose-dependent effect.12 As expected from an observation cohort, there were marked differences in the baseline demographics of those patients receiving β-blockers or ACEI, and unpicking these effects with regard to dosage is virtually impossible in a non-randomized cohort. Although the authors performed a standard multivariate analysis, adjusting for a propensity score was not performed and in addition a number of different types of β-blockers were prescribed.
Current European Society of Cardiology practice guidelines recommend initial prescription of β-blockers in all ST-elevation MI patients.13 The American Heart Association/American College of Cardiology Foundation suggest continuation for 3 years in those with normal left ventricular function.14 The Japanese Circulation Society guidelines give a Class IA recommendation for β-blockers in patients not at low risk (where low-risk patients are those with successful reperfusion therapy and near-normal left ventricular function) and IIaA for patients at low risk.15 In light of the recent developments just discussed, supported by reviews,16 observational studies17 and the data from Grall et al,12 any benefit from β-blockers appears to dwindle within 1 year of MI and there is little robust evidence for continued treatment, except in patients who develop chronic HFrEF and remain in sinus rhythm (Figure). The current article reaffirms the need for clinicians to approach their patients on an individual basis, as well as the ongoing requirement for randomized assessment and re-evaluation of therapies that previously had secure indications.
A remaining strong indication for β-blockers? Heart failure with reduced ejection fraction (but only in sinus rhythm). Reproduced from Kotecha D, et al (Figure 1).5 Kaplan-Meier survival curve for patients in sinus rhythm (A) and atrial fibrillation (B) in the β-blocker and placebo groups. Data are unadjusted survival curves for all reported deaths. CI, confidence interval; HR, hazard ratio.
D.K. is supported by the National Institute of Health Research (NIHR) Clinical Lecturer scheme. The opinions expressed are those of the author and do not represent the NIHR or the UK Department of Health.
D.K. has previously received research funding and honoraria from Menarini Pharmaceuticals and is the Lead for the Beta-blockers in Heart Failure Collaborative Group (BB-meta-HF). T.G.v.L. has received consultancy fees from Novartis and Vifor.
