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 AF and HFrEF, does rhythm-control reduce cardiovascular mortality, as compared to rate control?

Bottom Line

Among patients with AF and HFrEF, rhythm-control does not reduce cardiovascular mortality, as compared to rate control.

Major Points

The AFFIRM trial showed that among patients with non-valvular AF, there was no significant mortality difference between rate-control and rhythm-control strategies. 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 HFrEF 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.[1] 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.[2]

Guidelines

AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation (2014, adapted)[3]

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
  • HFrEF, defined as one of the following:
    • 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 congestive heart failure within the previous 6 months
      • Note that the definition of HF has changed and "congestive heart failure" could presumably include patients with either HFrEF or HFpEF. The WJC editors have interpreted this trial to assess adults with what is currently defined as HFrEF based upon the baseline characteristics and broader interpretation of the study.
    • 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.[4]
  • 21% of patients had to crossover to rate control as sinus rhythm could not be maintained.[4]
  • The toxicity of antiarrhythmic drugs may have contributed to the lack of benefit seen in the rhythm-control group.[4]
  • Patients in the rhythm-control group may not have required antiarrythmic drug treatment due to the low risk of AF recurrence.[4]

Funding

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

Further Reading

  1. 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.
  2. 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.
  3. 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.
  4. 4.0 4.1 4.2 4.3 Cain ME & Curtis AB Rhythm control in atrial fibrillation--one setback after another. N. Engl. J. Med. 2008. 358:2725-7.