Cryoballoon Ablation as Initial Therapy for AF: STOP-AF First

Pulmonary vein isolation is currently recommended when antiarrhythmic drug (AAD) therapy fails to control symptoms in patients with paroxysmal atrial fibrillation (AF). Although catheter ablation is a Class Ia recommendation after failed treatment with AADs in the current guidelines, it is a Class IIa recommendation for fist-line therapy. However, more recent studies have shown that early rhythm control is associated with better cardiovascular outcomes1 and that earlier diagnosis to ablation times is associated with decreased AF burden. Some studies suggest that early ablation decreases the risk of progression to more persistent AF, which is more difficult to manage.2-5

STOP-AF FIRST (Cryoballoon Catheter Ablation in Antiarrhythmic Drug Naive Paroxysmal Atrial Fibrillation)6 was designed to compare initial ablation to initial therapy with AADs in patient with symptomatic paroxysmal AF s with a relatively recent diagnosis.

Study Design
STOP-AF FIRST was a multicenter randomized study with a 1:1 randomization to cryoballoon ablation versus AADs in drug naïve patients.

Inclusion Criteria
Patients who were 18-80 years of age with recurrent symptomatic paroxysmal AF were enrolled at 24 centers in the United States. Key exclusion criteria were

  • previous treatment with an AAD (Class I or III) for 7 or more days,
  • an enlarged left atrial diameter (>5 cm), and
  • a previous left atrial ablation or left atrial surgical procedure.

The primary efficacy endpoint was treatment success at 12 months, which was defined as freedom from the following:

  • Initial failure of the procedure
  • Any subsequent AF surgery ablation in the left atrium (including those performed during the blanking period)
  • Any atrial arrhythmia recurrence (documented AF, atrial tachycardia, or atrial flutter for ≥30 seconds during ambulatory monitoring or for ≥10 seconds on a 12-lead electrocardiogram) outside the 90-day blanking period
  • Cardioversion outside the 90-day blanking period
  • Use of Class I or III AADs (ablation group only) outside the 90-day blanking period

The primary safety endpoint was analyzed only in the ablation group and was a composite of the following pre-specified procedure-related serious adverse events:

  • Development of a clinically significant pericardial effusion within 30 days
  • Symptomatic pulmonary vein stenosis
  • Atrial-esophageal fistula within 12 months
  • Unresolved phrenic nerve injury at 12 months
  • Transient ischemic attack, stroke
  • Myocardial infarction
  • Major vascular complication or major bleeding within the first 7 days

There were 104 patients in the ablation group and 99 in the AAD group with a relatively early diagnosis of AF (within 1.3 years) and with normal left atrial size and left ventricular function.

Efficacy Endpoint
Freedom from failure was 74.6 % in the ablation group versus 45% in the AAD group (Figure 1). There were only 2 safety events in the ablation group: 1 pericardial effusion and 1 myocardial infarction 7 days after the procedure. There were no significant major pro-arrhythmic complications in the AAD group; however, 15 patients in the AAD group crossed over to ablation due to documented AAD side effects in 10 patients, ongoing symptoms in 4 patients, and atrial arrhythmia detected on cardiac monitoring conducted outside of the trial protocol in 3 patients.

Figure 1

Figure 1

Another 19 patients in the drug-therapy group underwent ablation after having a primary efficacy endpoint event. Quality of life improved significantly in the ablation group. In the ablation group, there were 13 hospitalizations,10 emergency department visits, and 44 unscheduled office visits. In the drug-therapy group, there were 32 hospitalizations, 17 emergency department visits, and 39 unscheduled office visits.

In STOP-AF FIRST, initial therapy with cryoballoon ablation was superior to initial therapy with AADs. In the ablation group, 75% were free from primary events versus only 45% in the AAD group. There were only 2 safety events (1.9%) in the ablation group. In the drug arm, 13% discontinued treatment within 12 months and 34% underwent ablation within a year after randomization. These findings highlight the challenges associated with drug therapy for long-term rhythm control. Moreover, there were more than double the number of hospitalizations and emergency department visits in the AAD group versus the ablation group.

Initial therapy with cryoablation is superior to initial therapy with AADs for maintenance of sinus rhythm and is associated with improved quality of life and less health care utilization.


  1. Kirchhof P, Camm AJ, Goette A, et al. Early Rhythm-Control Therapy in Patients with Atrial Fibrillation. N Engl J Med 2020;383:1305-16.
  2. Bisbal F, Alarcón F, Ferrero-De-Loma-Osorio A, et al. Diagnosis-to-ablation time in atrial fibrillation: A modifiable factor relevant to clinical outcome. J Cardiovasc Electrophysiol 2019;30:1483-90.
  3. Bunch TJ, May HT, Bair TL, et al. Increasing time between first diagnosis of atrial fibrillation and catheter ablation adversely affects long-term outcomes. Heart Rhythm 2013;10:1257-62.
  4. Kawaji T, Shizuta S, Yamagami S, et al. Early choice for catheter ablation reduced readmission in management of atrial fibrillation: Impact of diagnosis-to-ablation time. Int J Cardiol 2019;291:69-76.
  5. Hussein AA, Saliba WI, Barakat A, et al. Radiofrequency Ablation of Persistent Atrial Fibrillation: Diagnosis-to-Ablation Time, Markers of Pathways of Atrial Remodeling, and Outcomes. Circ Arrhythm Electrophysiol 2016;9:e003669.
  6. Wazni OM, Dandamudi G, Sood N, et al.  Cryoballoon Ablation as Initial Therapy for Atrial Fibrillation. N Engl J Med 2020;Nov 16:[Epub ahead of print].

Clinical Topics: Arrhythmias and Clinical EP, Cardiac Surgery, Pericardial Disease, Implantable Devices, EP Basic Science, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular Arrhythmias, Cardiac Surgery and Arrhythmias

Keywords: Arrhythmias, Cardiac, Ischemic Attack, Transient, Pulmonary Veins, Atrial Fibrillation, Atrial Flutter, Cryosurgery, Electric Countershock, Ventricular Function, Left, Pericardial Effusion, Quality of Life, Phrenic Nerve, Random Allocation, Anti-Arrhythmia Agents, Catheter Ablation

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