#CardsJC: Atrial Fibrillation Trials: EARLY-AF & STOP AF First

CardioNerds Journal Club is a monthly forum for Cardionerds to discuss and breakdown recent publications on twitter and are produced with a corresponding infographic and detailed blog post. For more information, check out the CardioNerds Journal Club Page. This Journal Club focuses on the EARLY-AF and STOP AF First Trials.

Table of contents for the EARLY-AF & STOP AF First Trials summary:

January 28, 2021

Cryoablation or Drug Therapy for Initial Treatment of Atrial Fibrillation

The EARLY-AF Trial

Jason G. Andrade, M.D., George A. Wells, Ph.D., Marc W. Deyell, M.D., Matthew Bennett, M.D., Vidal Essebag, M.D., Ph.D., Jean Champagne, M.D., Jean-Francois Roux, M.D., Derek Yung, M.D., Allan Skanes, M.D., Yaariv Khaykin, M.D., Carlos Morillo, M.D., Umjeet Jolly, M.D., Paul Novak, M.D., Evan Lockwood, M.D., Guy Amit, M.D., Paul Angaran, M.D., John Sapp, M.D., Stephan Wardell, M.D., Sandra Lauck, Ph.D., Laurent Macle, M.D., and Atul Verma, M.D. for the EARLY-AF Investigators

Link to The EARLY-AF Trial article

January 28, 2021

Cryoballoon Ablation as Initial Therapy for Atrial Fibrillation

STOP-AF First Trial

Oussama M. Wazni, M.D., Gopi Dandamudi, M.D., Nitesh Sood, M.D., Robert Hoyt, M.D., Jaret Tyler, M.D., Sarfraz Durrani, M.D., Mark Niebauer, M.D., Kevin Makati, M.D., Blair Halperin, M.D., Andre Gauri, M.D., Gustavo Morales, M.D., Mingyuan Shao, Ph.D., Jeffrey Cerkvenik, M.S., Rachelle E. Kaplon, Ph.D., and Steven E. Nissen, M.D. for the STOP-AF First Trial Investigators

Link to SOP-AF First Trial article

  • Recent trials suggest early rhythm control strategy improved cardiovascular mortality in patients with atrial fibrillation.1
  • Pulmonary vein isolation (PVI) via catheter ablation is emerging as superior to drug therapy for the prevention of recurrent atrial arrhythmias.2
  • Cryoballoon ablation is an FDA-approved, safe, effective, and efficient therapy for drug-refractory, recurrent, symptomatic paroxysmal and persistent atrial fibrillation;3 however, few studies compared cryoballoon ablation to antiarrhythmic drugs.

Relevant Guidelines

  • AF catheter ablation:
    • Is currently recommended for rhythm control after one failed or intolerant class I or III antiarrhythmics, to improve symptoms of AF recurrences in patients with paroxysmal AF, or persistent AF with or without major risk factors for recurrence (Class I).
    • May be considered in selected patients with symptomatic persistent AF refractory or intolerant to at least 1 class I or III antiarrhythmic medication (Class IIa).
    • May be considered in patients with recurrent symptomatic paroxysmal Afib before antiarrhythmic drug trial after weighing the risks and outcomes of drug and ablation therapy (Class IIa).
    • May be considered for persistent AF >12 months refractory or intolerant to at least 1 class I or III antiarrhythmic medication (Class IIb).
    • May be considered before antiarrhythmic drugs for symptomatic persistent AF (Class IIb).
    • May be considered in selected patients with symptomatic heart failure with reduced left ventricular ejection fraction to potentially lower mortality and reduce heart failure hospitalization (Class IIb).
    • Should be avoided in patients who cannot be treated with anticoagulant therapy during and after the procedure (Class III).

Studies Rationale

  • Previous clinical trials have focused on ablation in patients who have already failed antiarrhythmic therapy.
  • Few studies have compared ablation to antiarrhythmic drugs as initial therapy, and those studies have been limited by high incidence of recurrent arrhythmia, complications, and crossover between study arms and therefore the magnitude of benefit of early ablation is still unknown.
  • These randomized clinical trials investigated the difference between PVI and antiarrhythmic drugs as the first treatment for patients with recurrent symptomatic paroxysmal or early persistent AF.
  • They differed from previous studies in 3 ways:
    1. Cryoballoon ablation was utilized rather than radiofrequency ablation.
    2. EARLY-AF utilized implantable cardiac monitors rather than non-invasive rhythm monitoring.
    3. Looked beyond endpoint of arrhythmia recurrence through analysis of patient-reported outcomes.


The Early Aggressive Invasive Intervention for Atrial Fibrillation (EARLY-AF) trial was designed to compare the use of catheter cryoballoon ablation with antiarrhythmic drugs to prevent the recurrence of atrial tachyarrhythmia, as assessed by an implantable continuous rhythm monitor.

The Cryoballoon Catheter Ablation in Antiarrhythmic Drug Naïve Paroxysmal Atrial Fibrillation (STOP AF First) trial was designed to evaluate cryoballoon ablation as compared with drug therapy as an initial treatment for patients with symptomatic paroxysmal atrial fibrillation.


In both EARLY-AF and STOP AF First, patients were randomly assigned to undergo PVI with cryoballoon ablation or receive antiarrhythmic drug therapy (chosen based on local practice & up-titrated to maximum dose) for initial rhythm control.

In EARLY-AF, all patients underwent insertion of implantable cardiac monitor.

In STOP AF First, patients were monitored with 12-lead EKG at each follow-up visit (1, 3, 6, and 12 months) and with 24-hour ambulatory EKG monitoring at 6 and 12 months.

Enrollment criteria 


Statistical Analysis
Both trials used intention-to treat analysis.

Notable Baseline Characteristics

Primary Outcome (Ablation vs. antiarrhythmic drugs)

  • EARLY-AF: At 1 year, recurrence of atrial tachyarrhythmia (symptomatic or asymptomatic): 42.9% vs. 67.8% (hazard ratio, 0.48; 95% CI 0.35-0.66, p<0.001).
  • STOP AF First: At 1 year, treatment success: 74.6% vs 45.0% (p<0.001).

Secondary Outcomes (Ablation vs. antiarrhythmic drugs)

    • Recurrence of symptomatic atrial tachyarrhythmia: 11.0% vs. 26.2% (hazard ratio, 0.39; 95% CI 0.22- 0.68)
    • Median percentage of time in AF: 0% (interquartile range, 0 to 0.08) vs. 0.13% (interquartile range, 0 to 1.60)
    • At 1 year, change in AFEQT survey score: 26.9±1.9 vs. 22.9±2.0 (treatment effect 8.0± 2.2)
    • Emergency department visits: 18.2% vs. 20.1% (HR 0.90; 95% CI 0.57-1.44)
    • Hospitalization >24 hour: 3.2% vs. 8.7% of patients (HR 0.37, 95%CI 0.14-1.02)
  • STOP AF First:
    • At 1 year, change in AFEQT survey score in ablation arm: 92.2±12.2, treatment effect 35.2 (31.2-39.3, p<0.001).
    • At least one cardiovascular-related healthcare utilization event: 29.8% (ablation) vs. 43.43% (drug therapy).
    • Cardioversions: 3% (ablation) vs. 7% (drug therapy).
    • No significant differences between the 2 groups at 12 months in percentages of patients free from a cardiovascular healthcare utilization event (69.9% vs 53.5%) or free from cardioversion (97.1% vs 92.4%).

Adverse events

    • Serious adverse events occurred in 5 patients (3.2%) who underwent ablation and in 6 patients (4.0%) who received antiarrhythmic drugs.
    • 3 cases of phrenic-nerve palsy and 2 cases of symptomatic bradycardia for which pacemaker implantation was warranted in ablation group.
    • Number needed to treat was 4 to prevent atrial tachyarrhythmia recurrence.
  • STOP AF First:
    • Serious adverse events occurred in 15 patients (14%) who underwent ablation and in 14 (14%) patients who received antiarrhythmic drugs.
    • 1 case of pericardial effusion, 1 case of muscle hemorrhage, 1 case of ventricular tachyarrhythmia, and 2 cases of acute myocardial infarction in the ablation group.  There were no cases of pulmonary vein stenosis.

Among patients receiving initial treatment for symptomatic, paroxysmal AF, cryoballoon ablation was superior to antiarrhythmic drug therapy for the prevention of atrial arrhythmia recurrence in patients who had not previously received antiarrhythmic drug therapies.

Limitations & Considerations

  • Trend towards reduction for hospitalization, although overall outcome of health care utilization was not significantly different between groups based on current practices.
  • Quality-of-life results demonstrate improvement with the ablation strategy (STOP AF First) or superiority of the ablation strategy over AADs (EARLY AF).  Lack of blinding limits interpretation of these results.
  • Trials did not have enough power to examine cardiovascular outcomes.
  • Length of follow-up was limited to 1 year.
  • May not be generalizable to other ablation technologies.
  • In STOP AF First, there was intermittent cardiac rhythm monitoring, so AF episodes may have been missed on the scheduled EKG and Holter monitoring.
  • In EARLY-AF, cardiac monitor was implanted when treatment initiated so did not evaluate change in AF burden from baseline. Additionally, continuous monitoring captured higher AF recurrence.
  • Data suggesting the benefit of early cryoballoon ablation continues to emerge. Cryo-FIRST, a European-based multi-center randomized trial which compared cryoballoon ablation to antiarrhythmic drugs as first-line therapy for the treatment of symptomatic paroxysmal AF, revealed similar conclusions to EARLY-AF and STOP AF First.
  1. Kirchhof P, Camm AJ, Goette A, et al. Early Rhythm-Control Therapy in Patients with Atrial Fibrillation. N Engl J Med. 2020;383(14):1305-1316.
  1. Packer DL, Mark DB, Robb RA, et al. Effect of Catheter Ablation vs Antiarrhythmic Drug Therapy on Mortality, Stroke, Bleeding, and Cardiac Arrest Among Patients With Atrial Fibrillation: The CABANA Randomized Clinical Trial. Jama. 2019;321(13):1261-1274.
  1. Tondo C, Iacopino S, Pieragnoli P, et al. Pulmonary vein isolation cryoablation for patients with persistent and long-standing persistent atrial fibrillation: Clinical outcomes from the real-world multicenter observational project. Heart Rhythm. 2018;15(3):363-368.
  1. Morillo CA, Verma A, Connolly SJ, et al. Radiofrequency ablation vs antiarrhythmic drugs as first-line treatment of paroxysmal atrial fibrillation (RAAFT-2): a randomized trial. Jama. 2014;311(7):692-700.
  1. Cosedis Nielsen J, Johannessen A, Raatikainen P, et al. Radiofrequency ablation as initial therapy in paroxysmal atrial fibrillation. N Engl J Med. 2012;367(17):1587-1595.
  1. Wazni OM, Marrouche NF, Martin DO, et al. Radiofrequency ablation vs antiarrhythmic drugs as first-line treatment of symptomatic atrial fibrillation: a randomized trial. Jama. 2005;293(21):2634-2640.


Dr. Dinu Balanescu, @dinubalanescu, Internal Medicine Resident at Beaumont Health, Royal Oak, MI. 
Dr. Gurleen Kaur, Gurleen_Kaur96, Medical Student at Albany Medical College, Albany, NY


Dr. Omid Amidi, @OAmidiMD, Cardiology Fellow at UCLA, Los Angeles, CA. 


Dr. Najah Khan, @najahakhan, Internal Medicine Resident at Houston Methodist Hospital, Houston, TX. 



Dr. Evelyn Song, @EvelynSongMD, Internal Medicine Resident at the Johns Hopkins Hospital, Baltimore, MD. 


Dr. Rachita Navara, @DrRachitaEP, Cardiology Fellow at Washington University, St. Louis, MO

Dr. Ajay Pillai, @AjayPMD, Cardiology Fellow at VCU, Richmond, VA


Dr. Carine Hamo, @CarineHamo, cardiology fellow at the Johns Hopkins Hospital, Baltimore, MD

The published archive features curated twitter highlights from the journal club event.

Management of New-onset AF

Initial therapy depends on symptom control and attempt to return to SR

After the patient’s AF is rate/rhythm controlled


Cryoballoon ablation as an ablation technology

Dosing anti-arrhythmics between the two trials

Inclusion vs Exclusion criteria between the two trials

Advice to clinicians

Early AF used an implantable LR while Stop AF used an Intermittent 24-hour ECG monitor

Directions for Future Studies                             

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