First-line Cryoablation for Early Treatment of Persistent Atrial Fibrillation

Summary

The goal of this multicentre, prospective, randomized, open, blinded for evaluation of end point (PROBE) controlled parallel-group superiority trial, is to compare the efficacy of antiarrhythmic drug (AAD) therapy and cryoballoon pulmonary vein isolation (PVI) regarding freedom from atrial fibrillation (%) assessed by an implantable cardiac monitor (ICM), ECG tracing or Holter at 12 months in patients with persistent AF. The main question\[s\] it aims to answer are: * Will first-line cryoballoon ablation for PVI compared to AAD, result in 25 % higher freedom from atrial tachyarrhythmias lasting \> 6 minutes at 12 months (primary outcome) excluding three months initial blanking period, in patients with symptomatic and recurrent persistent AF? * Will first-line cryoablation for PVI, compared to AAD result in a superior improvement in health related Quality of Life (HRQoL), AF/AT burden, AF/AT progression and reversion, more reverse atrial remodeling, cognitive function, healthcare utilization with associated costs, better safety, at 12-24-36 months as compared with drug use? Participants will be randomized 1:1 to first-line PVI using the cryoballoon or to first-line antiarrhythmic drug therapy and during 3 years follow-up undergo regular; * Continuous ECG monitoring for assessment of first AF recurrence and AF burden using an implantable cardiac monitor, * Regular echocardiographic exams for reverse atrial remodelling assessment, * HRQoL questionnaires * Assessment of cognitive function * Atrial fibrillation evaluation regarding structured characterisation and AF progression/regression * Assessment of Health care use and costs * Safety

Timeline

Start

2023-08-21

Primary completion

2027-12

Completion

2028-12

Publications

• Background Wazni OM, Dandamudi G, Sood N, Hoyt R, Tyler J, Durrani S, Niebauer M, Makati K, Halperin B, Gauri A, Morales G, Shao M, Cerkvenik J, Kaplon RE, Nissen SE; STOP AF First Trial Investigators. Cryoballoon Ablation as Initial Therapy for Atrial Fibrillation. N Engl J Med. 2021 Jan 28;384(4):316-324. doi: 10.1056/NEJMoa2029554. Epub 2020 Nov 16.
• Background Kuniss M, Pavlovic N, Velagic V, Hermida JS, Healey S, Arena G, Badenco N, Meyer C, Chen J, Iacopino S, Anselme F, Packer DL, Pitschner HF, Asmundis C, Willems S, Di Piazza F, Becker D, Chierchia GB; Cryo-FIRST Investigators. Cryoballoon ablation vs. antiarrhythmic drugs: first-line therapy for patients with paroxysmal atrial fibrillation. Europace. 2021 Jul 18;23(7):1033-1041. doi: 10.1093/europace/euab029.
• Background Wazni OM, Marrouche NF, Martin DO, Verma A, Bhargava M, Saliba W, Bash D, Schweikert R, Brachmann J, Gunther J, Gutleben K, Pisano E, Potenza D, Fanelli R, Raviele A, Themistoclakis S, Rossillo A, Bonso A, Natale A. Radiofrequency ablation vs antiarrhythmic drugs as first-line treatment of symptomatic atrial fibrillation: a randomized trial. JAMA. 2005 Jun 1;293(21):2634-40. doi: 10.1001/jama.293.21.2634.
• Background Morillo CA, Verma A, Connolly SJ, Kuck KH, Nair GM, Champagne J, Sterns LD, Beresh H, Healey JS, Natale A; RAAFT-2 Investigators. Radiofrequency ablation vs antiarrhythmic drugs as first-line treatment of paroxysmal atrial fibrillation (RAAFT-2): a randomized trial. JAMA. 2014 Feb 19;311(7):692-700. doi: 10.1001/jama.2014.467.
• Background Cosedis Nielsen J, Johannessen A, Raatikainen P, Hindricks G, Walfridsson H, Kongstad O, Pehrson S, Englund A, Hartikainen J, Mortensen LS, Hansen PS. Radiofrequency ablation as initial therapy in paroxysmal atrial fibrillation. N Engl J Med. 2012 Oct 25;367(17):1587-95. doi: 10.1056/NEJMoa1113566.
• Background De Greef Y, Schwagten B, Chierchia GB, de Asmundis C, Stockman D, Buysschaert I. Diagnosis-to-ablation time as a predictor of success: early choice for pulmonary vein isolation and long-term outcome in atrial fibrillation: results from the Middelheim-PVI Registry. Europace. 2018 Apr 1;20(4):589-595. doi: 10.1093/europace/euw426.
• Background Kawaji T, Shizuta S, Yamagami S, Aizawa T, Komasa A, Yoshizawa T, Kato M, Yokomatsu T, Miki S, Ono K, Kimura T. Early choice for catheter ablation reduced readmission in management of atrial fibrillation: Impact of diagnosis-to-ablation time. Int J Cardiol. 2019 Sep 15;291:69-76. doi: 10.1016/j.ijcard.2019.03.036. Epub 2019 Mar 20.
• Background Hussein AA, Saliba WI, Barakat A, Bassiouny M, Chamsi-Pasha M, Al-Bawardy R, Hakim A, Tarakji K, Baranowski B, Cantillon D, Dresing T, Tchou P, Martin DO, Varma N, Bhargava M, Callahan T, Niebauer M, Kanj M, Chung M, Natale A, Lindsay BD, Wazni OM. Radiofrequency Ablation of Persistent Atrial Fibrillation: Diagnosis-to-Ablation Time, Markers of Pathways of Atrial Remodeling, and Outcomes. Circ Arrhythm Electrophysiol. 2016 Jan;9(1):e003669. doi: 10.1161/CIRCEP.115.003669.
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• Background Hindricks G, Potpara T, Dagres N, Arbelo E, Bax JJ, Blomstrom-Lundqvist C, Boriani G, Castella M, Dan GA, Dilaveris PE, Fauchier L, Filippatos G, Kalman JM, La Meir M, Lane DA, Lebeau JP, Lettino M, Lip GYH, Pinto FJ, Thomas GN, Valgimigli M, Van Gelder IC, Van Putte BP, Watkins CL; ESC Scientific Document Group. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Eur Heart J. 2021 Feb 1;42(5):373-498. doi: 10.1093/eurheartj/ehaa612. No abstract available.
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• Background Chun KJ, Byeon K, Im SI, Park KM, Park SJ, Kim JS, On YK. Efficacy of dronedarone versus propafenone in the maintenance of sinus rhythm in patients with atrial fibrillation after electrical cardioversion. Clin Ther. 2014 Sep 1;36(9):1169-75. doi: 10.1016/j.clinthera.2014.07.013. Epub 2014 Aug 16.
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• Background Gwag HB, Chun KJ, Hwang JK, Park SJ, Kim JS, Park KM, On YK. Which antiarrhythmic drug to choose after electrical cardioversion: A study on non-valvular atrial fibrillation patients. PLoS One. 2018 May 22;13(5):e0197352. doi: 10.1371/journal.pone.0197352. eCollection 2018.
• Background Haissaguerre M, Jais P, Shah DC, Takahashi A, Hocini M, Quiniou G, Garrigue S, Le Mouroux A, Le Metayer P, Clementy J. Spontaneous initiation of atrial fibrillation by ectopic beats originating in the pulmonary veins. N Engl J Med. 1998 Sep 3;339(10):659-66. doi: 10.1056/NEJM199809033391003.
• Background Malmborg H, Lonnerholm S, Blomstrom P, Blomstrom-Lundqvist C. Ablation of atrial fibrillation with cryoballoon or duty-cycled radiofrequency pulmonary vein ablation catheter: a randomized controlled study comparing the clinical outcome and safety; the AF-COR study. Europace. 2013 Nov;15(11):1567-73. doi: 10.1093/europace/eut104. Epub 2013 May 22.
• Background Blomstrom-Lundqvist C, Gizurarson S, Schwieler J, Jensen SM, Bergfeldt L, Kenneback G, Rubulis A, Malmborg H, Raatikainen P, Lonnerholm S, Hoglund N, Mortsell D. Effect of Catheter Ablation vs Antiarrhythmic Medication on Quality of Life in Patients With Atrial Fibrillation: The CAPTAF Randomized Clinical Trial. JAMA. 2019 Mar 19;321(11):1059-1068. doi: 10.1001/jama.2019.0335.
• Background Packer DL, Mark DB, Robb RA, Monahan KH, Bahnson TD, Poole JE, Noseworthy PA, Rosenberg YD, Jeffries N, Mitchell LB, Flaker GC, Pokushalov E, Romanov A, Bunch TJ, Noelker G, Ardashev A, Revishvili A, Wilber DJ, Cappato R, Kuck KH, Hindricks G, Davies DW, Kowey PR, Naccarelli GV, Reiffel JA, Piccini JP, Silverstein AP, Al-Khalidi HR, Lee KL; CABANA Investigators. 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 Apr 2;321(13):1261-1274. doi: 10.1001/jama.2019.0693.
• Background Mortsell D, Jansson V, Malmborg H, Lonnerholm S, Blomstrom-Lundqvist C. Clinical outcome of the 2nd generation cryoballoon for pulmonary vein isolation in patients with persistent atrial fibrillation - A sub-study of the randomized trial evaluating single versus dual cryoballoon applications. Int J Cardiol. 2019 Mar 1;278:120-125. doi: 10.1016/j.ijcard.2018.10.097. Epub 2018 Oct 29.
• Background Tilz RR, Rillig A, Thum AM, Arya A, Wohlmuth P, Metzner A, Mathew S, Yoshiga Y, Wissner E, Kuck KH, Ouyang F. Catheter ablation of long-standing persistent atrial fibrillation: 5-year outcomes of the Hamburg Sequential Ablation Strategy. J Am Coll Cardiol. 2012 Nov 6;60(19):1921-9. doi: 10.1016/j.jacc.2012.04.060. Epub 2012 Oct 10.
• Background B Schnabel R, Pecen L, Engler D, Lucerna M, Sellal JM, Ojeda FM, De Caterina R, Kirchhof P. Atrial fibrillation patterns are associated with arrhythmia progression and clinical outcomes. Heart. 2018 Oct;104(19):1608-1614. doi: 10.1136/heartjnl-2017-312569. Epub 2018 Mar 17.
• Background de Vos CB, Pisters R, Nieuwlaat R, Prins MH, Tieleman RG, Coelen RJ, van den Heijkant AC, Allessie MA, Crijns HJ. Progression from paroxysmal to persistent atrial fibrillation clinical correlates and prognosis. J Am Coll Cardiol. 2010 Feb 23;55(8):725-31. doi: 10.1016/j.jacc.2009.11.040.
• Background Ogawa H, An Y, Ikeda S, Aono Y, Doi K, Ishii M, Iguchi M, Masunaga N, Esato M, Tsuji H, Wada H, Hasegawa K, Abe M, Lip GYH, Akao M; Fushimi AF Registry Investigators. Progression From Paroxysmal to Sustained Atrial Fibrillation Is Associated With Increased Adverse Events. Stroke. 2018 Oct;49(10):2301-2308. doi: 10.1161/STROKEAHA.118.021396.
• Background J Albano A, Bush J, L Parker J, Corner K, W Lim H, P Brunner M, I Dahu M, Dandamudi S, Elmouchi D, Gauri A, Woelfel A, Chalfoun NT. Left Atrial Volume Index Predicts Arrhythmia-Free Survival in Patients with Persistent Atrial Fibrillation Undergoing Cryoballoon Ablation. J Atr Fibrillation. 2019 Aug 31;12(2):2192. doi: 10.4022/jafib.2192. eCollection 2019 Aug-Sep.
• Background Csecs I, Yamaguchi T, Kheirkhahan M, Czimbalmos C, Fochler F, Kholmovski EG, Morris AK, Kaur G, Vago H, Merkely B, Chelu MG, Marrouche NF, Wilson BD. Left atrial functional and structural changes associated with ablation of atrial fibrillation - Cardiac magnetic resonance study. Int J Cardiol. 2020 Apr 15;305:154-160. doi: 10.1016/j.ijcard.2019.12.010. Epub 2019 Dec 6.
• Background Costa FM, Ferreira AM, Oliveira S, Santos PG, Durazzo A, Carmo P, Santos KR, Cavaco D, Parreira L, Morgado F, Adragao P. Left atrial volume is more important than the type of atrial fibrillation in predicting the long-term success of catheter ablation. Int J Cardiol. 2015 Apr 1;184:56-61. doi: 10.1016/j.ijcard.2015.01.060. Epub 2015 Jan 27.
• Background Walters TE, Nisbet A, Morris GM, Tan G, Mearns M, Teo E, Lewis N, Ng A, Gould P, Lee G, Joseph S, Morton JB, Zentner D, Sanders P, Kistler PM, Kalman JM. Progression of atrial remodeling in patients with high-burden atrial fibrillation: Implications for early ablative intervention. Heart Rhythm. 2016 Feb;13(2):331-9. doi: 10.1016/j.hrthm.2015.10.028. Epub 2015 Oct 17.
• Background Scherschel K, Hedenus K, Jungen C, Lemoine MD, Rubsamen N, Veldkamp MW, Klatt N, Lindner D, Westermann D, Casini S, Kuklik P, Eickholt C, Klocker N, Shivkumar K, Christ T, Zeller T, Willems S, Meyer C. Cardiac glial cells release neurotrophic S100B upon catheter-based treatment of atrial fibrillation. Sci Transl Med. 2019 May 22;11(493):eaav7770. doi: 10.1126/scitranslmed.aav7770.
• Background Antman EM, Tanasijevic MJ, Thompson B, Schactman M, McCabe CH, Cannon CP, Fischer GA, Fung AY, Thompson C, Wybenga D, Braunwald E. Cardiac-specific troponin I levels to predict the risk of mortality in patients with acute coronary syndromes. N Engl J Med. 1996 Oct 31;335(18):1342-9. doi: 10.1056/NEJM199610313351802.
• Background Sawhney V, Schilling RJ, Providencia R, Cadd M, Perera D, Chatha S, Mercer B, Finlay M, Halimi F, Pavin D, Anselme F, Cebron JP, Chun J, Schmidt B, Defaye P, Dhillon G, Boveda S, Albenque JP, Tayebjee M, de Asmundis C, Chierchia G, Hunter RJ. Cryoablation for persistent and longstanding persistent atrial fibrillation: results from a multicentre European registry. Europace. 2020 Mar 1;22(3):375-381. doi: 10.1093/europace/euz313.
• Background Chun KR, Stich M, Furnkranz A, Bordignon S, Perrotta L, Dugo D, Bologna F, Schmidt B. Individualized cryoballoon energy pulmonary vein isolation guided by real-time pulmonary vein recordings, the randomized ICE-T trial. Heart Rhythm. 2017 Apr;14(4):495-500. doi: 10.1016/j.hrthm.2016.12.014. Epub 2016 Dec 9.
• Background Bollmann A, Ueberham L, Schuler E, Wiedemann M, Reithmann C, Sause A, Tebbenjohanns J, Schade A, Shin DI, Staudt A, Zacharzowsky U, Ulbrich M, Wetzel U, Neuser H, Bode K, Kuhlen R, Hindricks G. Cardiac tamponade in catheter ablation of atrial fibrillation: German-wide analysis of 21 141 procedures in the Helios atrial fibrillation ablation registry (SAFER). Europace. 2018 Dec 1;20(12):1944-1951. doi: 10.1093/europace/euy131.
• Background Oikawa J, Fukaya H, Wada T, Horiguchi A, Kishihara J, Satoh A, Saito D, Sato T, Matsuura G, Arakawa Y, Kobayashi S, Shirakawa Y, Nishinarita R, Ishizue N, Katada C, Tanabe S, Niwano S, Ako J. Additional posterior wall isolation is associated with gastric hypomotility in catheter ablation of atrial fibrillation. Int J Cardiol. 2021 Mar 1;326:103-108. doi: 10.1016/j.ijcard.2020.10.069. Epub 2020 Oct 31.
• Background Sulke N, Dulai R, Freemantle N, Sugihara C, Podd S, Eysenck W, Lewis M, Hyde J, Veasey RA, Furniss SS. Long Term outcomes of percutaneous atrial fibrillation ablation in patients with continuous monitoring. Pacing Clin Electrophysiol. 2021 Jul;44(7):1176-1184. doi: 10.1111/pace.14282. Epub 2021 Jun 11.
• Background Wechselberger S, Kronborg M, Huo Y, Piorkowski J, Neudeck S, Passler E, El-Armouche A, Richter U, Mayer J, Ulbrich S, Pu L, Kirstein B, Gaspar T, Piorkowski C. Continuous monitoring after atrial fibrillation ablation: the LINQ AF study. Europace. 2018 Nov 1;20(FI_3):f312-f320. doi: 10.1093/europace/euy038.
• Results Calkins H, Hindricks G, Cappato R, Kim YH, Saad EB, Aguinaga L, Akar JG, Badhwar V, Brugada J, Camm J, Chen PS, Chen SA, Chung MK, Nielsen JC, Curtis AB, Davies DW, Day JD, d'Avila A, de Groot NMSN, Di Biase L, Duytschaever M, Edgerton JR, Ellenbogen KA, Ellinor PT, Ernst S, Fenelon G, Gerstenfeld EP, Haines DE, Haissaguerre M, Helm RH, Hylek E, Jackman WM, Jalife J, Kalman JM, Kautzner J, Kottkamp H, Kuck KH, Kumagai K, Lee R, Lewalter T, Lindsay BD, Macle L, Mansour M, Marchlinski FE, Michaud GF, Nakagawa H, Natale A, Nattel S, Okumura K, Packer D, Pokushalov E, Reynolds MR, Sanders P, Scanavacca M, Schilling R, Tondo C, Tsao HM, Verma A, Wilber DJ, Yamane T. 2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation. Heart Rhythm. 2017 Oct;14(10):e275-e444. doi: 10.1016/j.hrthm.2017.05.012. Epub 2017 May 12. No abstract available.
• Results Andrade JG, Wells GA, Deyell MW, Bennett M, Essebag V, Champagne J, Roux JF, Yung D, Skanes A, Khaykin Y, Morillo C, Jolly U, Novak P, Lockwood E, Amit G, Angaran P, Sapp J, Wardell S, Lauck S, Macle L, Verma A; EARLY-AF Investigators. Cryoablation or Drug Therapy for Initial Treatment of Atrial Fibrillation. N Engl J Med. 2021 Jan 28;384(4):305-315. doi: 10.1056/NEJMoa2029980. Epub 2020 Nov 16.

Drugs

Indications