NATURE REVIEWS | CARDIOLOGY VOLUME 11 | DECEMBER 2014

NEWS & VIEWSATRIAL FIBRILLATION

Challenging the status quo: β‑blockers for HF plus AFPaul Khairy and Denis Roy

A new meta-analysis challenges the notion that β-blockers improve survival in patients with heart failure (HF) and concomintant atrial fibrillation (AF). These results should be interpreted with caution. Although the mortality reduction conferred by β-blockers was likely overestimated in the past, benefits should be expected in a sizeable proportion of patients with HF and AF.Khairy, P. & Roy, D. Nat. Rev. Cardiol. 11, 690–692 (2014); published online 14 October 2014; doi:10.1038/nrcardio.2014.166

Over the past 25 years, the survival of patients with heart failure (HF) and reduced ejection fraction (HFrEF) has been pro­longed, owing to advances in both pharma­cological and device therapy, including angiotensin­converting­enzyme inhibitors, angiotensin­receptor blockers, β­blockers, mineralocorticoid­receptor antagonists, implantable cardioverter–defibrillators, cardiac resynchronization therapy, and left ventricular assist devices. The randomized controlled trials in which the efficacy of these therapies was first demonstrated have shaped current guidelines on HF management.1 In some instances, however, data from subse­quent observational studies have contested the purported benefits of the treatment in particular patient subgroups and raised con­cerns over safety in the real­world setting.2,3 β­Blockers were developed in the 1960s by the Nobel Prize recipient, James Black, and have since become a staple in the manage­ment of HF.4 The benefits of β­blockers have largely gone unchallenged, but a new meta­analysis published in The Lancet calls into question their efficacy in reducing mortality in the subgroup of patients with HFrEF and coexisting atrial fibrillation (AF).5

The Beta­Blockers in Heart Failure Collaborative Group analysed individual patient­level data from 10 major randomized clinical trials that compared β­blockers to placebo for the treatment of HF.5 This multinational consortium was created to determine the efficacy of β­blockers in understudied subgroups, including patients with concomitant AF.5,6 As expected, β­blocker administration was associated with

a significant reduction in both all­cause mor­tality (HR 0.73, 95% CI 0.67–0.80, P <0.001) and cardiovascular mortality (HR 0.72, 95% CI 0.65–0.80, P <0.001) in the 13,942 patients with HF who were in normal sinus rhythm (as determined on baseline electro­cardiogram [ECG]).5 By contrast, in the 3,063 patients with HF and concomitant AF (or atrial flutter in 6%) on their baseline ECG, β­blockers did not reduce all­cause mortal­ity (HR 0.97, 95% CI 0.83–1.14, P = 0.73) or cardio vascular mortality (HR 0.92, 95% CI 0.77–1.10, P = 0.35).5 The investigators concluded that β­blockers “should not be used preferentially over other rate­control medications and not regarded as standard therapy to improve prognosis in patients with c oncomitant heart failure and AF”.5

As a type of observational study, meta­analyses are subject to limitations including search, selection, and publication bias, hetero­geneity of results, incomplete data, and con­straints related to analyses of pooled statistics. Nevertheless, the meta­analysis conducted by Kotecha and colleagues5 is exemplary in its methodological rigour, including careful study selection backed by a validated bias­assessment tool and sensitivity analyses with alternate censoring points, additional base­line adjustments, and random­effects mod­elling that support the main fixed­effects

analyses. The data from this meta­analysis was extracted from individual patient­level data from large randomized controlled trials.5 Considerable advantages exist to using indi­vidual patient­level data over pooled analyses derived from summary statistics, because it permits greater control over potential con­founders and is conducive to time­to­event analyses, which enhances clinical relevance and increases statistical power.

Current management guidelines state, in no uncertain terms, that β­blockers (specifi­cally bisoprolol, carvedilol, or metoprolol) should be prescribed to all patients with stable HFrEF, barring a contraindication or intolerance.1 This class I recommenda­tion is supported by consistent evidence from numerous randomized clinical trials.1 More over, the ACC/AHA guidelines convey a strong sense of urgency in initiating β­blockers, by reiterating that “even when symptoms are mild or improve with other therapies, β­blocker therapy should not be delayed until symptoms return or disease progression is documented”.1 Should these forceful recommendations now be consid­ered null and void in patients with HFrEF and concomitant AF on the basis of this meta­analysis?

In our opinion, a more nuanced perspec­tive is warranted. A generic counterargument is that subgroup effects from randomized clinical trials might be unreliable, particu­larly if based on post hoc analyses with a less­than­definitive biological rationale (Box 1). Despite the meticulous meta­analysis meth­odology, subgroups based on AF were not prespecified in the 11 randomized trials ana­lysed. As such, ECG tracings were not subject to adjudication, and scant information is available regarding the type, pattern (par­oxysmal, persistent, or permanent), and time course of AF, thereby obscuring inferences to a target population. Moreover, a single ECG recording is an insensitive screening tool for AF detection. Investigators in the AF­CHF trial7 randomly allocated 1,376 patients with HFrEF and a history of AF to receive rhythm­control or rate­control therapy. All patients had at least one AF episode lasting ≥6 h or required cardioversion within the previous 6 months, or an AF episode lasting ≥10 min within the previous 6 months with a previous electrical cardioversion. Although

‘‘…beneficial effects of β‑blockers ... are difficult to discount on the basis of underlying rhythm alone…’’

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DECEMBER 2014 | VOLUME 11 www.nature.com/nrcardio

NEWS & VIEWS

AF was electrocardiographically diagnosed in all patients, 44% exhibited normal sinus rhythm on their baseline ECG. A substan­tial proportion of patients with nonperma­nent AF in Kotecha and colleagues’ study, therefore, likely escaped detection and were included in the sinus­rhythm subgroup, which experienced an undisputed survival advantage from β­blockers.

In a multivariate efficacy analysis of the AF­CHF trial, β­blockers were associated with a 30% reduction in all­cause mortality (HR 0.70, 95% CI 0.55–0.90, P = 0.006) and a 34% reduction in cardiovascular mortal­ity (HR 0.66, 95% CI 0.49–0.87, P = 0.003).8 Furthermore, in a combined analysis of individual patient­level data from both the AF­CHF and AFFIRM trials, β­blockers were associated with a 35% reduction in cardiovascular mortality (HR 0.65, 95% CI 0.46–0.92, P = 0.016) in patients with AF and a left ventricular ejection fraction <30%.9 These seemingly disparate findings might be reconciled if the study population in Kotecha and colleagues’ meta­analysis was indeed comprised predominantly of patients with permanent AF (captured by a single ECG), whereas investigators in the AF­CHF and

AFFIRM trials enrolled patients with non­permanent forms of AF. On the basis of these differences in study populations, the effect of β­blockers on survival in patients with AF and HFrEF might be hypothesized to be inversely proportional to time spent in sinus rhythm. This hypothesis is consistent with the observation that slower heart rates are associated with longer survival when m easured in sinus rhythm, but not in AF.10

Nevertheless, the well­characterized bene­ficial effects of β­blockers on ventricular myo­cardial metabolism and function are difficult to discount on the basis of underlying rhythm alone. A plausible mechanism to support the findings of Kotecha and colleagues remains elusive and to exclude a bene ficial effect of β­blockers in patients with HFrEF and per­manent AF would be pre mature. Indeed, Kotecha et al. reported a tendency for β­blockers to reduce the combined outcome measure of all­cause mortality and cardio­vascular hospitalization (HR 0.89, 95% CI 0.89–1.01, P = 0.06).5 In a population with HFrEF in whom antiarrhythmic agents that confer a neutral impact on mortality are cele­brated, this reassuring trend suggests that, in the absence of trials comparing β­blockers to other rate­controlling agents, β­blockers should remain the preferred p harmacological therapy for rate control.

In conclusion, data presented by the Beta­Blockers in Heart Failure Collaborative Group challenges the status quo and sets an inspiring precedent for the conduct of co­operative multinational patient­level meta­analyses. In our opinion, the current evidence base suggests that a survival advan­tage conferred by β­blockers in patients with HFrEF and nonpermanent AF should continue to be expected. By contrast, the convincing analyses performed by Kotecha et al. indicate that the reduction in mortality previously attributed to β­blockers was prob­ably overestimated in patients with HFrEF and permanent AF. Although the results of this meta­analysis are unlikely to drastically alter clinical practice, the expected efficacy of β­blockers in patients with HFrEF and p ermanent AF requires recalibration.

Electrophysiology Service and Research Center, Montreal Heart Institute, Université de Montréal, 5000 Bélanger Street, Montréal H1T 1C8, Canada (P.K., D.R.). Correspondence to: P.K. paul.khairy@umontreal.ca

Competing interestsThe authors declare no competing interests.

AcknowledgementsP.K. is supported by a Canada Research Chair in Electrophysiology and Adult Congenital Heart Disease.

1. Yancy, C. W. et al. 2013 ACCF/AHA guideline for the management of heart failure: a report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. J. Am. Coll. Cardiol. 62, e147–e239 (2013).

2. O’Meara, E. et al. Mineralocorticoid receptor antagonists and cardiovascular mortality in patients with atrial fibrillation and left ventricular dysfunction: insights from the Atrial Fibrillation and Congestive Heart Failure Trial. Circ. Heart Fail. 5, 586–593 (2012).

3. Al-Khatib, S. M. et al. Do patients with a left ventricular ejection fraction between 30% and 35% benefit from a primary prevention implantable cardioverter defibrillator? Int. J. Cardiol. 172, 253–254 (2014).

4. Black, J. W. & Stephenson, J. S. Pharmacology of a new adrenergic beta-receptor-blocking compound (Nethalide). Lancet 2, 311–314 (1962).

5. Kotecha, D. et al. Efficacy of beta blockers in patients with heart failure plus atrial fibrillation: an individual-patient data meta-analysis. Lancet http://dx.doi.org/10.1016/S0140-6736(14)61373-8.

6. Kotecha, D. et al. Individual patient data meta-analysis of beta-blockers in heart failure: rationale and design. Syst. Rev. 2, 7 (2013).

7. Roy, D. et al. Rhythm control versus rate control for atrial fibrillation and heart failure. N. Engl. J. Med. 358, 2667–2677 (2008).

8. Talajic, M. et al. Maintenance of sinus rhythm and survival in patients with heart failure and atrial fibrillation. J. Am. Coll. Cardiol. 55, 1796–1802 (2010).

9. Cadrin-Tourigny, J. et al. Efficacy of amiodarone in patients with atrial fibrillation with and without left ventricular dysfunction: a pooled analysis of AFFIRM and AF-CHF trials. J. Cardiovasc. Electrophysiol. http://dx.doi.org/ 10.1111/jce.12535.

10. Andrade, J. et al. Baseline heart rate and adverse outcomes in patients with atrial fibrillation: a combined AFFIRM and AF-CHF substudy. Can. J. Cardiol. 28, S271–S272 (2012).

Box 1 | Main practice points

■ Subgroup effects from randomized clinical trials can be unreliable, especially if analyses are not defined a priori and pre-existing biological support is not strong

■ A single baseline electrocardiogram (ECG) lacks sensitivity as a screening test to detect atrial fibrillation (AF)

■ A well-defined study population (for example, type, pattern, and history of AF) is required to generalize results to a target population (that is, external validity)

■ Prior studies in patients with heart failure with reduced ejection fraction (HFrEF) and non-permanent AF suggest that β-blockers significantly reduce mortality

■ In the absence of trials comparing β-blockers to other rate-control agents, β-blockers should remain the preferred pharmacological therapy for rate control in patients with HFrEF and AF

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