AATAC

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Di Biase et al. "Ablation vs. amiodarone for treatment of persistent atrial fibrillation in patients with congestive heart failure and an implanted device". Circulation. 2016. 133(17):1637-1634.
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Clinical Question

In patients with symptomatic (NYHA II-III) heart failure with reduced ejection fraction (LVEF ≤40%) and persistent atrial fibrillation (AF) chosen for a rhythm control strategy, is AF ablation superior to amiodarone with regard to AF-free survival?

Bottom Line

In patients with symptomatic (NYHA II-III) heart failure with reduced ejection fraction (HFrEF, LVEF ≤40%) and persistent atrial fibrillation (AF) chosen for a rhythm control strategy, AF ablation was associated with a 36% absolute increase in AF-free survival at 24 months. There was also a 26% absolute reduction in unplanned hospitalizations and a 10% absolute reduction in overall mortality with AF ablation.

Major Points

Multiple RCTs including the landmark AFFIRM trial (2002) have demonstrated similar outcomes with a rate control strategy (i.e., use of AV nodal blockade to attain a safe heart rate with no intent to restore sinus rhythm) versus a rhythm control strategy (i.e., use of antiarrhythmic drugs [AAD] or procedures to restore and maintain sinus rhythm) in patients with AF. Nevertheless, these initial trials included primarily older patients without structural heart disease and in particular patients with significant LV dysfunction were underrepresented. The later AF-CHF trial (2008), however, specifically studied patients with concomitant AF and systolic HF and again found no significant difference in outcomes with rate versus rhythm control.

Despite these large randomized trials, patients with significant LV dysfunction often fail to tolerate the degree of AV nodal blockade required to maintain adequate rate control due to negative inotropic effects or appear to be dependent on atrial contraction to maintain adequate forward flow. Furthermore, AF has been shown to be an independent predictor of mortality in the HFrEF population.[1] As a result, patients with significant HFrEF are often chosen for a rhythm control strategy despite clear evidence for its benefit.

One explanation for the failure of rhythm control to improve outcomes is the significant side-effect profile of AADs, particularly amiodarone which is one of the few AADs thought to be safe in HFrEF. Recently, however, catheter-based ablation techniques utilizing selective ablation of AF foci have demonstrated good efficacy in maintaining sinus rhythm and do not pose the same risk of long-term side effects as AADs (see FIRE and ICE, 2016). As a result, it is possible that in the era of AF ablation rhythm control may prove superior to AAD therapy (and perhaps even rate control) in patients with AF and HFrEF.

The 2016 Ablation versus Amiodarone for Treatment of persistent Atrial fibrillation in patients with Congestive heart failure and an implanted device (AATAC) trial investigated the efficacy of AF ablation versus amiodarone in patients with symptomatic HFrEF (LVEF ≤40%, NYHA II-III) and persistent AF chosen for a rhythm control strategy with regard to AF-free survival. At 2 years, there was a 36% absolute increase in AF-free survival with ablation compared to amiodarone. Furthermore, randomization to amiodarone emerged as an independent predictor of AF recurrence in multivariable modeling. There was also a 26% absolute reduction in unplanned hospitalizations and a 10% absolute reduction in overall mortality with AF ablation. Procedural complications with AF ablation occurred at rates <2%.

The AATAC trial suggests that in patients with HFrEF and AF chosen for a rhythm control strategy, AF ablation is potentially superior to AAD as a method for achieving and maintaining sinus rhythm not only with regard to AF-free survival but also in regards to cardiovascular outcomes and mortality. Given the novelty of this finding and the relative youth of AF ablation, reproduction of these findings is likely required before AF ablation becomes a first-line option for rhythm control in this population. Nevertheless, on the basis of AATAC the threshold for deciding to embark upon AF ablation should likely be lower in patients with HFrEF chosen for rhythm control. It is critical to remember, however, that the superiority of rhythm control (over rate control) in patients with AF has never been established in any population, including those with HFrEF, and that AATAC does not address this fundamental question, although it does suggest that a direct comparison of rate control with AF ablation may be indicated. In the interim, the choice of rhythm control in the first place should likely only be made when rate control has failed or in the presence of other compelling indications.

Guidelines

As of September 2016, no guidelines have been published that reflect the results of this trial.

Design

Design details not reported in the manuscript were extracted from the AATAC ClinicalTrials.gov listing.[2]

  • Multicenter, parallel-group, open-label, randomized controlled trial
  • N=203
    • Catheter ablation (n=102)
    • Amiodarone (n=101)
  • Setting: 9 centers in the US, Canada, and Italy
  • Duration follow-up: 24 months
  • Analysis: Intention-to-treat
  • Primary outcome: AF-free survival at 24 months

Population

Inclusion Criteria

  • Age ≥18
  • Persistent AF
  • Dual chamber ICD or CRT-D in place
  • NYHA II-III
  • LVEF ≤40 within last 6 months

Exclusion Criteria

  • AF caused by reversible etiology (including post-operative AF)
  • Valvular or coronary heart disease requiring surgical intervention
  • Life expectancy ≤2 years
  • Prolonged QT interval
  • Hypothyroidism
  • Severe pulmonary disease
  • Liver failure
  • On amiodarone (≥200mg/day) at baseline

Baseline Characteristics

From the ablation group.

  • Demographics: Age 62yr, male 75%
  • AF/CHF Characteristics: Duration 8.6 months, LA 4.7cm, LVEF 29%
  • Co-morbidities: BMI 30, HTN 45%, DM 22%, CAD 62%, OSA 45%
  • Functional Measures: 6MWD 348m, MLHFQ score 52
  • Medications: ACEi/ARB 92%, aldosterone antagonist 45%, beta blocker 76%

Interventions

  • Patients randomized 1:1 to AF ablation or amiodarone
    • AF ablation: In all patients a double transseptal was performed. IV heparin was given with goal ACT 300-400 seconds. A circular mapping catheter was used to guide the ablation. Intracardiac echocardiography (ICE) could be used to guide transseptal catheterization and for anatomical orientation. The main goal of ablation was pulmonary vein isolation. In addition, the SVC was empirically isolated when PV-like potentials were found. Additional linear lesions for ablation of complex fractionated electrograms and elimination of non-PV triggers were advised but performed according to the preference of the center or the operator. AADs could be restarted at the discretion of the treating physician during the blanking period. A second ablation procedure could be performed during the blanking period (three months)
    • Amiodarone: Amiodarone was initiated with a loading dose approximately 10g in the first 2 weeks after randomization followed by maintenance 200mg daily
  • Treatment period included a 3 month "blanking period" during which repeat ablation could be performed (ablation group) or amiodarone dose changes could be considered (AAD group)
  • 27 patients (12 in ablation group and 15 in amiodarone group) were on low-dose amiodarone (<200mg/day) at baseline and included in the study.
  • Digoxin was discontinued if possible, or the dose reduced by at least 50%
  • Dofetilide was discontinued 4-5 days before ablation
  • Patients on low-dose amiodarone (up to 200mg daily) were allowed to discontinue the drug after the blanking period
  • Screening PFTs and CXR performed at baseline, and PFTs yearly thereafter. LFTs and TFTs assessed at baseline and every 6 months thereafter
  • All patients were on the optimal tolerated medical therapy for CHF (ACEi/ARB, BB, diuretics, hydral/isordil, spironolactone, digoxin as appropriate)
  • Baseline LVEF quantified by 2D and Doppler echocardiography
  • Minnesota Living with Heart Failure Quality of Life score and 6-Minute Walk Distance measured at baseline and at 24 months
  • Arrhythmia recurrence evaluated using remote monitoring capabilities on implanted devices or with device interrogation at 3,6,12, and 24 months follow-up.

Outcomes

Comparisons are ablation vs. amiodarone.

Primary Outcome

Atrial arrhythmia-free survival (at 24-27 months)
71 (70.0%, 95% CI 60%-78%) vs. 34 (34.0%, 95% CI 25%-44%) [p<0.001]

Secondary Outcomes

Unplanned hospitalization
32 (31.0%, 95% CI 20%-41%) vs. 58 (57.0%, 95% CI 51%-69%) [RR 0.55, 95% CI 0.39 to 0.76, NNT 3.8, p<0.001]
Death
8 (8.0%) vs. 18 (18.0%) [RR 0.44, 95% CI -0.20 to 0.96, NNT 10, p=0.037]
LVEF (change from baseline to follow-up)
8.1 (±4) vs. 4.0 (±5) [p=0.02]
6-Minute Walk Distance (change from baseline to follow-up)
22 (±22) vs. 10 (±37) [p=0.02]
MLHFQ Score (change from baseline to follow-up)
11 (±19) vs. 6 (±17) [p=0.04]

Predictors of Arrhythmia Recurrence (Multivariable)

Randomization to Amiodarone
HR 2.5 [95% CI 1.5-4.3, p<0.001]
Diabetes
HR 1.1 [95% CI 1.07-1.26, p=0.01]

Subgroup Analysis

When stratifying the population by recurrence status, recurrence free patients experienced significantly better improvement in all secondary outcome parameters (LVEF, 6-Minute Walk Distance, MLHFQ Score) compared to those who experienced recurrence (all interactions p<0.001).

Adverse Events

Procedural complications (Group 1 only)
2 (1.96%) groin hematoma, 1 (0.98%) pericardial effusion
Amiodarone toxicity (Group 2 only)
7 withdrawals (4 thyroid toxicity, 2 pulmonary toxicity, 1 liver toxicity)

Criticisms

  • Trial was not designed to assess clinical outcomes (hospitalization for heart failure, mortality). Results suggesting improved outcomes with AF ablation thus require reproduction
  • Lack of a rate-control arm prevents comparison of AF ablation (or AAD use) to what is considered standard of care in this population
  • Multiple ablation procedures were allowed in the ablation arm (average of 1.4 procedures per patient) and there was no clear protocol for determining when a repeat procedure was indicated. Further study will be required to determine the optimal number and frequency of ablations required
  • Variability in procedural technique among centers (PVI alone in 22, PVI and posterior wall ablation in 80) makes results more difficult to generalize
  • The relative cost-efficacy of AF ablation (versus AADs) in rhythm control remains to be defined

Funding

  • Texas Cardiac Arrhythmia Research Foundation
  • Authors with multiple ties to industry

Further Reading