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Andrade J, et al. "Cryoablation or Drug Therapy for Initial Treatment of Atrial Fibrillation". The New England Journal of Medicine. 2021. 384(4):305-315.
PubMedFull textPDFClinicalTrials.gov

Clinical Question

In patients with symptomatic paroxysmal atrial fibrillation with onset in the prior 24 months, does catheter ablation reduce the recurrence of symptomatic or asymptomatic atrial tachyarrhythmias compared to antiarrhythmics?

Bottom Line

Among patients with symptomatic paroxysmal atrial fibrillation with onset in the prior 24 months, cryoablation was associated with lower recurrence of symptomatic or asymptomatic atrial tachyarrhythmia from month 3-12 when compared to an initial management strategy using antiarrhythmic medications.

Major Points

Symptomatic paroxysmal AF can be managed by antiarrhythmic medications or catheter ablation. There was not clear evidence for the use of ablation as first-line treatment prior to 2021. Published in 2021, the Early Aggressive Invasive Intervention for Atrial Fibrillation (EARLY-AF) trial randomized 303 patients with symptomatic paroxysmal AF not on Class I or III antiarrhythmics to cryoablation with a cryothermy balloon or antiarrhythmic therapy. All participants had an implantable loop recorder placed. The analysis did not consider any recurrent atrial tachyarrhythmias occurring in the first 90 days. At 1 year, there was a lower incidence of recurrent atrial tachyarrhythmia in the cryoablation group than the antiarrhythmic group (68% vs. 43%; HR 0.48; 95% CI 0.35-0.66; NNT=4). There were few adverse events in either group.

The 2020 EAST-AFNET 4 trial found a decreased risk of the composite of CV mortality, stroke, HF or ACS hospitalization with a rhythm control strategy vs a rate control strategy in patients with recently diagnosed AF. Approximately 20% of patients in the rhythm-control group underwent ablation in that trial. Potentially the lower rate of atrial AF to less negative remodeling. Therefore, the lower rate of atrial fibrillation burden found with catheter ablation compared to drug therapy in the EARLY-AF trial may lead to improvement in cardiovascular outcomes over the long-term, but notably this trial was not powered to answer this question.

EARLY-AF was published concurrently with the STOP AF First Trial,[1] which was a similar trial performed in the US with similar findings.


As of October 2021, no guidelines have been published that reflect the results of this trial.


  • Multicenter, open-label, end-point blinded, randomized, open label trial
  • N=303
    • Cryoablation (n=154)
    • Anti-arrhythmics (n=149)
  • Setting: 18 centers in Canada
  • Enrollment: 2017-2018
  • Follow-up: 1 year
  • Analysis: Intention-to-treat
  • Primary outcome: Atrial tachyarrhythmia recurrence


Inclusion Criteria

  • Age ≥18 years
  • Symptomatic AF and at ≥1 episode of AF detected by rhythm monitoring in prior 24 months

Exclusion Criteria

  • Current use of class I or III antiarrhythmic drug
  • Prior LAA or related procedure
  • AF due to reversible causes
  • Current intracardiac thrombus
  • Pulmonary vein stenosis/stent
  • Hemi-diaphragmatic paralysis
  • Anticoagulation or radiocontrast materials contraindication
  • At least moderately-severe mitral valve disease
  • MI or stent in prior 3 months
  • NYHA class ≥III symptoms
  • LVEF <35%
  • Hypertrophic cardiomyopathy
  • CKD stage ≥IV
  • Life expectancy <1 year

Baseline Characteristics

From ablation group

  • Demographics: Age 57.7 years, sex 72.7% male,
  • Mean BMI: 30.9
  • AF details:
    • Median year since diagnosis: 1
    • Symptomatic AF episodes/month: 3
    • CHA2DS2-VASc score: 1.9
  • Medications:
    • Beta-blockers: 55.2%
    • Non-DHP CCB: 7.1%
    • Prior use of class I or class III antiarrhythmic drug: 26.0%
    • Oral anticoagulation: Warfarin 3.2%, NOAC 63.6%


  • Randomized to catheter cryoablation with pulmonary-vein isolation vs antiarrhythmic therapy.
  • All received implantable cardiac monitor.
  • The analysis censored atrial tachyarrhythmia recurrence occurring in the first 90 days.
  • Antiarrhythmic titration protocols are listed in detail for flecainide, propafenone, sotalol, amiodarone, and dronedarone beginning on page 3 of the supplemental appendix.[2]


Comparisons are ablation vs antiarrhythmic.

Primary Outcomes

Recurrent atrial tachyarrhythmia (symptomatic or asymptomatic) after 90-day blanking period
42.9% vs 67.8% (HR 0.48; 95% CI 0.35-0.66)

Secondary Outcomes

Not adjusted for multiplicity.

Recurrence of symptomatic atrial tachyarrhythmia
11.0% vs 26.2% (HR 0.39; 95% CI 0.22-0.68)
Median percent time in Atrial Fibrillation
0 (IQR 0-0.08) vs 0.13 (IQR 0-1.60)
AFEQT symptom survey change in baseline at 12 months
26.9 +/- 1.9 vs 22.9 +/- 2.0 (Treatment effect 8.0+/-2.2)

Subgroup Analysis

Treatment effect did not vary significantly when comparing predefined subgroups by ablation experience, left atrial enlargement presence, or duration of AF. Details are shown on page 20 of the supplemental appendix.[2]

Adverse Events

Selected adverse event rates are shown below; see the article for a full listing

Any adverse serious adverse event related to the trial regimen
3.2% vs. 4.0%


  • Open label.
  • The use of a single ablation technology in the trial reduces the generalizability toward other ablation energy sources.
  • Long-term effect of early ablation on AF progression, healthcare utilization, and cost-effectiveness could not be evaluated due to the limited follow-up length of 1 year.
  • The change in atrial fibrillation burden from baseline was not evaluated in the trial.
  • Low use of amiodarone.[3]
  • Limited generalizability to other populations, including those with persistent AF, structural heart disease, or multicomorbidities.[4]


  • The study was funded by the Cardiac Arrhythmia Network of Canada, Medtronic, Baylis Medical, and the University of British Columbia.

Further Reading

  1. Wazni OM et al. Cryoballoon Ablation as Initial Therapy for Atrial Fibrillation. N Engl J Med 2021. 384:316-324.
  2. 2.0 2.1 Supplemental Appendix
  3. DiMarco A & Lavesa-Cesana J Cryoablation as Initial Therapy for Atrial Fibrillation. N Engl J Med 2021. 384:e82.
  4. Marine JE & Early Ablation for Paroxysmal Atrial Fibrillation - Safety First. N Engl J Med 2021. 384:374-375.