Catheter Ablation as First Line Therapy for Atrial Fibrillation: Are we there yet?

For the last two decades, the management of patients with atrial fibrillation (AF) had stayed in an “equipoise” between rate and rhythm control as shown by AFFIRM and RACE trials 1,2. However, rate control strategy remained the predominant mantra in AF management for the majority of patients in clinical practice.

The most recent American College of Cardiology/American Heart Association/Heart Rhythm Society AF guidelines were written in 2014 followed by a guideline update in 2019 3,4. At that time, most randomized controlled trials comparing CA with medical therapy included patients after they had failed at least 1 anti-arrhythmic drug (AAD), and very few trials utilized AF ablation as first-line therapy. These guidelines recommend CA for paroxysmal AF in symptomatic patients if they are intolerant to at least 1 AAD as a Class I-A recommendation. Guidelines also suggest that CA is reasonable as an initial rhythm control strategy for some patients with recurrent symptomatic AF even before the therapeutic trial of AAD (Class II-B).

Over the last 3 years, the pendulum has swung dramatically in the favor of rhythm control with much credit to CA. The “big bang” started with CASTLE-AF showing the benefit of catheter ablation in reducing all-cause mortality or heart failure hospitalizations in AF patients with heart failure 5. While the CABANA trial did not deliver the paradigm shifting results everyone in the electrophysiology community had hoped for, it still demonstrated the safety of CA and its superior role in preventing recurrent AF 6.

The last 6 months have been incredible in AF management with mounting evidence in favor of early rhythm control. EAST-AFNET 4 trial showed that early rhythm control with Flecainide (35.9%), Amiodarone (19.6%), and Dronaderone (16.7%) results in an improvement in the composite outcome of death, stroke or major adverse effects as compared with rate control (HR 0.79; 96% CI 0.66-0.66; p=0.005) 7. Important to note that only 8% of patients in this trial underwent CA.

Following this momentum 3 landmark trials in the last 4 months have demonstrated the benefits of CA with cryoballoon as the initial therapy in AF. The STOP AF First Trial randomized 203 paroxysmal AF patients to cryoablation or drug therapy and showed that CA was superior to AAD in preventing recurrent AF (P<0.001) 8. Similarly, the EARLY AF investigators randomized 303 patients to cryoablation or AAD and showed a significantly lower rate of recurrent AF with cryoablation using continuous cardiac rhythm monitoring post-ablation 9.  The CRYO FIRST trial continued the same theme and showed that CA was superior to AAD as initial therapy for the management of symptomatic paroxysmal AF 10.  Importantly, all 3 trials also demonstrated the safety profile of cryoablation. Now there are several reasons why CA is superior to AAD.

  1. AAD has limited efficacy and they have rare but life-threatening side effects. A significant proportion of patients discontinue AAD due to these side effects. The most feared side effects include prolonged QTc related arrhythmias like Torsade de Pointes or multiorgan side effects from Amiodarone.
  2. The safety profile of CA is excellent and it continues to improve.
  3. The advances in ablation techniques have resulted in improved efficacy of CA in maintaining long-term sinus rhythm.

3 older randomized trials have also compared CA to drug therapy and when the pooled evidence is considered for CA as first-line therapy in AF, similar results are observed 11. Overall, CA results in a 38% reduction in recurrent atrial arrhythmia (P<0.001), and the number needed to treat (NNT) to prevent 1 arrhythmia was 5 with effects consistent across radiofrequency or cryoablation 11. The hospitalization rates in CA were also significantly lower (68% reduction, P<0.001). These results were achieved without any significant increase in major adverse events.  The possible rationale for these results is that early effective rhythm control may modify the electrical and structural substrate that sustains AF and thus prevents atrial myopathy as it is well known that recurrent paroxysmal AF episodes can potentially progress to persistent AF (AF begets AF).

Based on this data, I believe there is sufficient evidence to consider CA as first line therapy in symptomatic patients with paroxysmal AF after a careful discussion of risks and benefits. Of course, such decision making should be patient centered. It is possible that future guideline updates may upgrade CA as a Class 1-A recommendation in this patient population.


  1. Van Gelder IC, Hagens VE, Bosker HA, Kingma JH, Kamp O, Kingma T, et al. A Comparison of Rate Control and Rhythm Control in Patients with Recurrent Persistent Atrial Fibrillation. New England Journal of Medicine 2002;347:1834–1840. doi:10.1056/NEJMoa021375.
  2. A Comparison of Rate Control and Rhythm Control in Patients with Atrial Fibrillation. New England Journal of Medicine 2002;347:1825–1833. doi:10.1056/NEJMoa021328.
  3. January Craig T., Wann L. Samuel, Calkins Hugh, Chen Lin Y., Cigarroa Joaquin E., Cleveland Joseph C., et al. 2019 AHA/ACC/HRS Focused Update of the 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society in Collaboration With the Society of Thoracic Surgeons. Circulation 2019;140:e125–e151. doi:10.1161/CIR.0000000000000665.
  4. January Craig T., Wann L. Samuel, Alpert Joseph S., Calkins Hugh, Cigarroa Joaquin E., Cleveland Joseph C., et al. 2014 AHA/ACC/HRS Guideline for the Management of Patients With Atrial Fibrillation. Journal of the American College of Cardiology 2014;64:e1–e76. doi:10.1016/j.jacc.2014.03.022.
  5. Marrouche NF, Brachmann J, Andresen D, Siebels J, Boersma L, Jordaens L, et al. Catheter Ablation for Atrial Fibrillation with Heart Failure. New England Journal of Medicine 2018;378:417–427. doi:10.1056/NEJMoa1707855.
  6. Packer DL, Mark DB, Robb RA, Monahan KH, Bahnson TD, Poole JE, 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;321:1261. doi:10.1001/jama.2019.0693.
  7. Kirchhof P, Camm AJ, Goette A, Brandes A, Eckardt L, Elvan A, et al. Early Rhythm-Control Therapy in Patients with Atrial Fibrillation. New England Journal of Medicine 2020;383:1305–1316. doi:10.1056/NEJMoa2019422.
  8. Wazni OM, Dandamudi G, Sood N, Hoyt R, Tyler J, Durrani S, et al. Cryoballoon Ablation as Initial Therapy for Atrial Fibrillation. New England Journal of Medicine 2021;384:316–324. doi:10.1056/NEJMoa2029554.
  9. Andrade JG, Wells GA, Deyell MW, Bennett M, Essebag V, Champagne J, et al. Cryoablation or Drug Therapy for Initial Treatment of Atrial Fibrillation. New England Journal of Medicine 2021;384:305–315. doi:10.1056/NEJMoa2029980.
  10. Kuniss M, Pavlovic N, Velagic V, Hermida JS, Healey S, Arena G, et al. Cryoballoon ablation vs. antiarrhythmic drugs: first-line therapy for patients with paroxysmal atrial fibrillation. EP Europace 2021. doi:10.1093/europace/euab029.
  11. Turagam MK, Musikantow D, Whang W, Koruth JS, Miller MA, Langan M-N, et al. Assessment of Catheter Ablation or Antiarrhythmic Drugs for First-line Therapy of Atrial Fibrillation: A Meta-analysis of Randomized Clinical Trials. JAMA Cardiology 2021. doi:10.1001/jamacardio.2021.0852.

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