AF-CHF

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Roy D, et al. "Rhythm Control versus Rate Control for Atrial Fibrillation and Heart Failure". The New England Journal of Medicine. 2008. 358(25):2667-2677.
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Clinical Question

Among patients with atrial fibrillation and heart failure, does rhythm-control reduce cardiovascular mortality, as compared to rate control?

Bottom Line

Among patients with atrial fibrillation and heart failure, rhythm-control does not reduce cardiovascular mortality, as compared to rate control.

Major Points

The AFFIRM trial showed that among patients with non-valvular atrial fibrillation (AF), there was no significant mortality difference between rate-control and rhythm-control strategies.[1] There are specific issues related to patients with AF and heart failure (HF). Heart failure patients have a higher risk of developing AF. They are also at a higher risk for adverse effect from certain anti-arrhythmic drugs. Hence, the investigators aimed to determine if rhythm-control would reduce cardiovascular mortality, as compared to rate control.

The Atrial Fibrillation and Congestive Heart Failure (AF-CHF) trial was a multicenter, prospective, randomized trial which randomized 1,376 patients with AF and HF to receive rhythm-control or rate-control treatment. Rhythm-control did not reduce cardiovascular mortality significantly as compared to rate-control (27% vs. 25% in rate-control; hazard ratio in the rhythm-control group, 1.06; 95% CI 0.86-1.30; P=0.59).

The 2014 AHA/ACC/HRS guidelines recommends that rhythm-control strategy can be attempted in patients with HF who remain symptomatic from AF despite a rate-control strategy.[2] The 2012 focused update of European Society of Cardiology guidelines recommends that rhythm-control be reserved for patients who experience symptoms from AF or worsening HF despite adequate rate control.[3]

Guidelines

AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation (2014, adapted)[4]

Rate-control

  • Rate control with a beta blocker or non-dihydropyridine (DHP) calcium-channel blocker (CCB) for patients with paroxysmal, persistent, or permanent AF and HF with preserved EF (class I level B)
  • IV beta blocker or non-DHP CCB is recommended in the acute setting in patients without pre-excitation. In hemodynamically unstable patients, electrical cardioversion is preferred (class I level B)
  • HR <80 beats/min is reasonable for symptomatic AF management (class IIa level B)
  • HR <110 is reasonable if asymptomatic and LV systolic function is preserved (class IIb level B)
  • Oral amiodarone may be useful for rate control when other interventions are unsuccessful or contraindicated (class IIb level C)
  • Non-DHP CCBs is not recommended in patients with decompensated HF (class III level C)
  • AV nodal ablation with permanent ventricular pacing should not be performed without prior pharmacological rate-control attempts (class III level C)
  • Digoxin, non-DHP CCBs, or IV amiodarone is not recommended in the presence of AF with pre-excitation, as it may result in VF (class III level B)

Rhythm Control

  • Flecainide, dofetilide, propafenone, and intravenous ibutilide are useful for pharmacological cardioversion of AF or atrial flutter in the absence of drug-specific contraindications. (class I level A)
  • Depending on underlying heart disease and comorbidities, these drugs are recommended in patients with AF to maintain sinus rhythm: amiodarone, dofetilide, dronedarone, flecainide, propafenone and sotalol. (class I level A)
  • Once determined to be safe, propafenone or flecainide (“pill-in-the-pocket”) in addition to a beta blocker or non-DHP CCB is reasonable to terminate AF outside the hospital (class IIa level B)
  • For patients with chronic HF who remain symptomatic from AF despite rate-control treatment, it is reasonable to use a rhythm-control strategy. (class IIa level C)

Design

  • Multicenter, prospective, randomized, controlled trial
  • N=1,376 patients with nonvalvular atrial fibrillation
    • Rhythm-control strategy (n=682)
    • Rate-control strategy (n=694)
  • Enrollment: 2001-2005
  • Setting: 123 centers in Canada, United States, Brazil, Argentina, Europe, and Israel
  • Mean follow-up: 37±19 months
  • Analysis: Intention-to-treat
  • Primary outcome: cardiovascular mortality

Population

Inclusion Criteria

  • age ≥18 years
  • AF (with ECG documentation) which fulfills 1 of the following:
    • 1 episode lasting for ≥6 hours or requiring cardioversion within the previous 6 months
    • 1 episode lasting for ≥10 minutes within the previous 6 months and previous electrical cardioversion for atrial fibrillation
  • HF, defined as
    • left ventricular ejection fraction (LVEF) ≤35%, measured by nuclear imaging, echocardiography, or cardiac angiography within 6 months prior to enrollment
    • NYHA class II or IV heart failure within the previous 6 months
    • asymptomatic condition for which the patient had been hospitalized for HF during the previous 6 months
    • LVEF ≤25%

Exclusion Criteria

  • persistent AF >12 months
  • reversible cause of AF or HF
  • decompensated HF within 48 hours prior to randomization
  • use of antiarrhythmic drugs for other arrhythmias
  • second-degree or third-degree atrioventricular block (bradycardia of <50/minute)
  • long-QT syndrome
  • previous ablation of an atrioventricular node
  • anticipated cardiac transplantation within 6 months
  • chronic kidney disease requiring dialysis
  • lack of contraception in women of child-bearing potential
  • estimated life expectancy of <1 year

Baseline Characteristics

From the rhythm-control group

  • Demographics: age 66±11 years, male 78%, non-Caucasian 16%
  • Predominant cardiac diagnosis: coronary artery disease 48%, nonischemic cardiomyopathy 36%, hypertensive heart disease 10%, valvular disease 5%, congenital heart disease 1%
  • Comorbidities: hypertension 49%, diabetes 22%, previous stroke or TIA 11%
  • AF:
    • paroxysmal 33%, persistent 67%; ≥6 month since first diagnosis: 41%; captured on ECG 54%
    • previous electrical cardioversion 34%; previous hospitalization for AF 51%; previous antiarrhythmic agent 43%
  • HF:
    • LVEF 27±6%; hospitalization during past 6 months 54%
  • Other cardiac parameters: left atrial dimension 49±7 mm, QRS 112±30 msec
  • Concomitant drug therapy: digoxin 64%, beta-blocker 80%, nitrate (long-acting) 17%, ACE-I 86%, ARB 11%, aldosterone antagonist 43%, oral anticoagulant 86%, aspirin 40%, lipid-lowering drug 44%
  • implantable cardioverter-defibrillator 7%

Interventions

Rhythm-control Strategy

  • aggressive therapy to prevent AF was recommended
  • electrical cardioversion was recommended within 6 weeks post-randomisation if patients did not convert to sinus rhythm after antiarrhythmic drug therapy
  • second cardioversion was recommended within 3 months after enrollment if necessary
  • amiodarone was the first-line drug for the maintenance of sinus rhythm, and sotalol or dofetilide was used as second-line therapy
  • permanent pacemaker was recommended if bradycardia prevented the use of antiarrhythmic drugs

Rate-Control Strategy

  • beta-blockers and digitalis were used
  • targeted heart rate was defined as a resting ventricular rate of <80 beats/min and <110 beats/min during a 6-minute walk test. Both tests were performed at 4, 12 months and yearly thereafter
  • AV nodal ablation and pacemaker therapy were recommended if drug therapy was unsuccessful

Heart failure management

  • ACEI or ARB and beta-blockers was recommended for all patients
  • anticoagulation was recommended for all patients
  • ICD and CRT were recommended if indicated

Outcomes

Comparisons are rhythm vs. rate-control strategies.

Primary Outcomes

Cardiovascular mortality
27% vs. 25% (unadjusted HR 1.06; 95% CI 0.86-1.3; P=0.59)
The adjusted HR was 1.05 (95% CI 0.85-1.29; P=0.67)

Secondary Outcomes

Composite of all-cause mortality, stroke, worsening heart failure
43% vs. 46% (HR 0.9; 95% CI 0.77-1.06, P=0.2)
All-cause mortality
32% vs. 33% (HR 0.97; 95% CI 0.8-1.17, P=0.73)
Ischemic or hemorrhagic strokes
3% vs. 4% (HR 0.74; 95% CI 0.4-1.35,P=0.32)
Worsening heart failure
28% vs 31% (HR 0.87; 95% CI 0.72-1.06, P=0.17)
Hospitalization
64% vs. 59% (P=0.06)
during the first year, the rate was 46% vs. 39% (P=0.001)
In the rhythm control group, there were higher incidences of hospitalization for AF (14% vs. 9%, P=0.001) and for bradyarrhythmia (6% vs. 3%, P=0.02)

Other outcomes

Requirement for electrical cardioversion
59% vs. 9% (P<0.001)
Requirement for permanent pacemaker
9% vs. 10% (P=0.66)
Requirement for ICD
8% vs. 10% (P=0.11)
Requirement for catheter ablation
3.2% vs. 3.5% (P=0.81)
Therapy-related outcomes
1. 21% in the rhythm-control group crossed over to the rate-control group during the study, most commonly due to inability to maintain sinus rhythm
2. 10% in the rate-control group crossed over to the rhythm-control group, most commonly due to worsening heart failure
3. The prevalence of AF in the rhythm-control group was 54% at baseline, 33% at 3 weeks, 17% at 4 months, under 20% until the 24-month visit and 27% at 4-years. In the rate-control group, the prevalence was 59%-70% during follow-up.
4. 58% of patients in the rhythm-control group had at least 1 recurrence of AF
5. In the rate-control group, the ventricular rate was within the target range during 6-min walk test in 72% of patients at baseline, and 82-88% during first 3-years of follow-up

Subgroup Analysis

No significant interactions with pre-specified subgroups including comorbidities (hypertension, coronary artery disease), LVEF, NYHA status, paroxysmal or persistent AF, 6-min walk test results, creatinine, use of beta-blocker, ICD therapy

Adverse Events

Ventricular tachycardia
5.3% vs. 5.3% (P=0.97)
Bradyarrhythmia
8.5% vs. 4.9% (P=0.007)
Major non-CNS hemorrhage
4.4% vs. 3.6% (P=0.45)

Criticisms

  • The rhythm-control strategies did not achieve 100% maintenance of sinus rhythm.[5]
  • 21% of patients had to crossover to rate control as sinus rhythm could not be maintained.[5]
  • The toxicity of antiarrhythmic drugs may have contributed to the lack of benefit seen in the rhythm-control group.[5]
  • Patients in the rhythm-control group may not have required antiarrythmic drug treatment due to the low risk of AF recurrence.[5]

Funding

Funding provided by the NHLBI and Wyeth-Ayerst Laboratories. Authors with significant disclosures.

Further Reading

  1. Wyse DG et al. A comparison of rate control and rhythm control in patients with atrial fibrillation. N. Engl. J. Med. 2002. 347:1825-33.
  2. January CT et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation 2014. 130:2071-104.
  3. Camm AJ et al. 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association. Eur. Heart J. 2012. 33:2719-47.
  4. January CT et al. 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: executive summary: a report of the American College of Cardiology/American Heart Association Task Force on practice guidelines and the Heart Rhythm Society. Circulation 2014. 130:2071-104.
  5. 5.0 5.1 5.2 5.3 Cain ME & Curtis AB Rhythm control in atrial fibrillation--one setback after another. N. Engl. J. Med. 2008. 358:2725-7.