First Line Radiofrequency Ablation Versus Antiarrhythmic Drugs for Persistent Atrial Fibrillation Treatment (RAAFT-3)

Atrial Fibrillation Clinical Trial

— RAAFT-3  

Official title:

First Line Radiofrequency Ablation Versus Antiarrhythmic Drugs for Persistent Atrial Fibrillation Treatment

Clinical Trial Details — Status: Active, not recruiting

Administrative data

• NCT number: NCT04037397
• Other study ID #: 829475
• Status: Active, not recruiting
• Phase: Phase 3
• Start date: September 24, 2019
• Est. completion date: March 1, 2025

Study information

• Verified date: October 2023
• Source: University of Pennsylvania
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The purpose of this study is to determine if catheter-based atrial fibrillation (AF) ablation is superior to treatment with antiarrhythmic drugs as a first-line therapy for symptomatic persistent AF.

Description:

The burden of atrial fibrillation (AF) on Western countries healthcare systems is steadily increasing, with over 2 million Americans and 4 million Europeans affected by this condition. It is by far the most common sustained arrhythmia encountered in clinical practice, with a striking impact on morbidity and mortality. Achieving a definite cure is highly desirable, as this would have profound social and economic implication. In patients with drug-refractory paroxysmal AF, multiple clinical trials have established the superiority of catheter ablation over further antiarrhythmic drug (AAD) therapy for the long-term maintenance of sinus rhythm, to improve quality of life, and reduce hospitalizations. Recent randomized controlled trials have also demonstrated a beneficial role of catheter ablation as a first-line therapy in patients with paroxysmal AF, with significantly better arrhythmia control and improved quality of life compared to AAD therapy. Patients with symptomatic persistent AF represent a more challenging group to treat, given the overall lower success rate of catheter ablation procedures in this group of patients. Pharmacologic rhythm-control strategies are also less effective in persistent AF, with a substantially increased economic burden given the repeat admissions for electrical cardioversions and AAD initiation/titration. In patients with symptomatic persistent AF who have already failed AADs, catheter ablation has been shown superior to further AAD therapy for sinus rhythm restoration in a recent randomized controlled trial. However, the value of an upstream adoption of catheter ablation for the treatment of symptomatic persistent AF (i.e., before a trial with AADs) is unknown. The purpose of the third Radiofrequency Ablation vs Antiarrhythmic Drugs for Atrial Fibrillation Treatment (RAAFT-3) trial is to determine whether catheter ablation is superior to AAD as a first-line therapy in patients with persistent AF who had not been exposed to antiarrhythmic treatment.

Recruitment information / eligibility

• Status: Active, not recruiting
• Enrollment: 120
• Est. completion date: March 1, 2025
• Est. primary completion date: October 1, 2024
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

Eligible patients have a history of persistent AF with at least 2 episodes in the 9 months prior to enrollment. Persistent AF is defined according to 2014 AHA/ACC/HRS guidelines as continuous AF that is sustained for more than 7 days.Patients are enrolled if they are:

1. Older than 18.

2. Symptomatic with persistent AF.

3. Experienced at least one AF episode that was documented by surface ECG, 6 months before randomization.

Exclusion Criteria:

1. Documented LVEF <40%.

2. Documented left atrial diameter >/=6cm.

3. Moderate to severe LVH (LV wall thickness >1.5cm).

4. Documented severe valvular disease (aortic stenosis, mitral regurgitation, tricuspid regurgitation or presence of mechanical cardiac valves), active coronary artery disease (defined as the presence of >70% stenosis of coronary arteries or documentation of active myocardial ischemia), recent (within 6 months) CABG.

5. Untreated hypothyroidism or hyperthyroidism. Patients who are euthyroid on thyroid hormone replacement therapy are acceptable.

6. Contraindication for the use of all antiarrhythmic drugs including sotalol, dofetilide, amiodarone and 1C antiarrhythmic drugs (liver enzymes and serum creatinine that are outside the upper normal lab values, e.g. > 3 times ULN with 2 abnormal lab values). [Note: Participants will not be excluded if they are able to take any single or combination of drugs without contraindications]

7. Previous left heart ablation procedure, either by surgery or by percutaneous catheter, for atrial fibrillation.

8. Current enrollment in another investigational drug or device study.

9. Presence of any other condition that the investigator feels would be problematic or would restrict or limit the participation of the Patient for the entire study period.

10. Absolute contra-indication to the use of heparin and or oral anticoagulation.

11. Increase risk of bleeding, current peptic ulceration, proliferative diabetic retinopathy, history of severe systemic bleeding, or other history of bleeding diathesis or coagulopathy.

12. Severe pulmonary disease e.g. restrictive pulmonary disease, chronic obstructive disease (COPD).

13. Documented intra-atrial thrombus, tumor, or another abnormality, which precludes left atrial catheter ablation.

14. Previous use of an antiarrhythmic drug, including amiodarone, propafenone, flecainide, sotalol, quinidine, dofetilide, dronedarone (see below for specifications: Antiarrhythmic Drug Group).

15. Women with a positive pregnancy test.

16. Evidence of active cardiac or systemic infection.

17. Medical condition limiting expected survival to less than one year.

Related Conditions & MeSH terms

• Atrial Fibrillation

Intervention

Drug:
• Anti Arrhythmics
Propafenone or Flecanide or Sotalol or Dofetilide or Dronedarone or Amiodarone. The subject must first fail a Class 1C or III drug prior to starting Amiodarone

Procedure:
• Pulmonary Vein Isolation performed by Radio Frequency Catheter Ablation
Approved Biosense Webster Inc. catheter devices should be used to perform RFCA. Ablation will be done to achieve entrance block into all pulmonary veins

Locations

Country	Name	City	State
United States	Montefiore Medical Center	Bronx	New York
United States	MetroHealth	Cleveland	Ohio
United States	Penn Presbyterian Medical Center	Philadelphia	Pennsylvania
United States	University of Pennsylvania	Philadelphia	Pennsylvania
United States	University of Arizona	Tucson	Arizona

Sponsors (3)

Lead Sponsor	Collaborator
University of Pennsylvania	Biosense Webster, Inc., Texas Cardiac Arrhythmia Research Foundation

Country where clinical trial is conducted

United States, 

References & Publications (17)

Bialy D, Lehmann H, Schumacher DN, Steinman RT, Meissner MD. Hospitalization for arrhythmias in the United States: importance of atrial fibrillation. J Am Coll Cardiol. 1992;19:41A

Calkins H, Kuck KH, Cappato R, Brugada J, Camm AJ, Chen SA, Crijns HJ, Damiano RJ Jr, Davies DW, DiMarco J, Edgerton J, Ellenbogen K, Ezekowitz MD, Haines DE, Haissaguerre M, Hindricks G, Iesaka Y, Jackman W, Jalife J, Jais P, Kalman J, Keane D, Kim YH, Kirchhof P, Klein G, Kottkamp H, Kumagai K, Lindsay BD, Mansour M, Marchlinski FE, McCarthy PM, Mont JL, Morady F, Nademanee K, Nakagawa H, Natale A, Nattel S, Packer DL, Pappone C, Prystowsky E, Raviele A, Reddy V, Ruskin JN, Shemin RJ, Tsao HM, Wilber D; Heart Rhythm Society Task Force on Catheter and Surgical Ablation of Atrial Fibrillation. 2012 HRS/EHRA/ECAS expert consensus statement on catheter and surgical ablation of atrial fibrillation: recommendations for patient selection, procedural techniques, patient management and follow-up, definitions, endpoints, and research trial design: a report of the Heart Rhythm Society (HRS) Task Force on Catheter and Surgical Ablation of Atrial Fibrillation. Developed in partnership with the European Heart Rhythm Association (EHRA), a registered branch of the European Society of Cardiology (ESC) and the European Cardiac Arrhythmia Society (ECAS); and in collaboration with the American College of Cardiology (ACC), American Heart Association (AHA), the Asia Pacific Heart Rhythm Society (APHRS), and the Society of Thoracic Surgeons (STS). Endorsed by the governing bodies of the American College of Cardiology Foundation, the American Heart Association, the European Cardiac Arrhythmia Society, the European Heart Rhythm Association, the Society of Thoracic Surgeons, the Asia Pacific Heart Rhythm Society, and the Heart Rhythm Society. Heart Rhythm. 2012 Apr;9(4):632-696.e21. doi: 10.1016/j.hrthm.2011.12.016. Epub 2012 Mar 1. No abstract available. — View Citation

Calkins H, Reynolds MR, Spector P, Sondhi M, Xu Y, Martin A, Williams CJ, Sledge I. Treatment of atrial fibrillation with antiarrhythmic drugs or radiofrequency ablation: two systematic literature reviews and meta-analyses. Circ Arrhythm Electrophysiol. 2009 Aug;2(4):349-61. doi: 10.1161/CIRCEP.108.824789. Epub 2009 Jun 2. — View Citation

Catherwood E, Fitzpatrick WD, Greenberg ML, Holzberger PT, Malenka DJ, Gerling BR, Birkmeyer JD. Cost-effectiveness of cardioversion and antiarrhythmic therapy in nonvalvular atrial fibrillation. Ann Intern Med. 1999 Apr 20;130(8):625-36. doi: 10.7326/0003-4819-130-8-199904200-00002. — View Citation

Di Biase L, Santangeli P, Natale A. How to ablate long-standing persistent atrial fibrillation? Curr Opin Cardiol. 2013 Jan;28(1):26-35. doi: 10.1097/HCO.0b013e32835b59bb. — View Citation

Friberg J, Buch P, Scharling H, Gadsbphioll N, Jensen GB. Rising rates of hospital admissions for atrial fibrillation. Epidemiology. 2003 Nov;14(6):666-72. doi: 10.1097/01.ede.0000091649.26364.c0. — View Citation

Go AS, Hylek EM, Phillips KA, Chang Y, Henault LE, Selby JV, Singer DE. Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. JAMA. 2001 May 9;285(18):2370-5. doi: 10.1001/jama.285.18.2370. — View Citation

Jais P, Cauchemez B, Macle L, Daoud E, Khairy P, Subbiah R, Hocini M, Extramiana F, Sacher F, Bordachar P, Klein G, Weerasooriya R, Clementy J, Haissaguerre M. Catheter ablation versus antiarrhythmic drugs for atrial fibrillation: the A4 study. Circulation. 2008 Dec 9;118(24):2498-505. doi: 10.1161/CIRCULATIONAHA.108.772582. Epub 2008 Nov 24. Erratum In: Circulation. 2009 Sep 8;120(10):e83. — View Citation

January CT, Wann LS, Alpert JS, Calkins H, Cigarroa JE, Cleveland JC Jr, Conti JB, Ellinor PT, Ezekowitz MD, Field ME, Murray KT, Sacco RL, Stevenson WG, Tchou PJ, Tracy CM, Yancy CW; American College of Cardiology/American Heart Association Task Force on Practice Guidelines. 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 Practice Guidelines and the Heart Rhythm Society. J Am Coll Cardiol. 2014 Dec 2;64(21):e1-76. doi: 10.1016/j.jacc.2014.03.022. Epub 2014 Mar 28. No abstract available. Erratum In: J Am Coll Cardiol. 2014 Dec 2;64(21):2305-7. — View Citation

Macle L, Khairy P, Weerasooriya R, Novak P, Verma A, Willems S, Arentz T, Deisenhofer I, Veenhuyzen G, Scavee C, Jais P, Puererfellner H, Levesque S, Andrade JG, Rivard L, Guerra PG, Dubuc M, Thibault B, Talajic M, Roy D, Nattel S; ADVICE trial investigators. Adenosine-guided pulmonary vein isolation for the treatment of paroxysmal atrial fibrillation: an international, multicentre, randomised superiority trial. Lancet. 2015 Aug 15;386(9994):672-9. doi: 10.1016/S0140-6736(15)60026-5. Epub 2015 Jul 23. — View Citation

Miyasaka Y, Barnes ME, Gersh BJ, Cha SS, Bailey KR, Abhayaratna WP, Seward JB, Tsang TS. Secular trends in incidence of atrial fibrillation in Olmsted County, Minnesota, 1980 to 2000, and implications on the projections for future prevalence. Circulation. 2006 Jul 11;114(2):119-25. doi: 10.1161/CIRCULATIONAHA.105.595140. Epub 2006 Jul 3. Erratum In: Circulation. 2006 Sep 12;114(11):e498. — View Citation

Mont L, Bisbal F, Hernandez-Madrid A, Perez-Castellano N, Vinolas X, Arenal A, Arribas F, Fernandez-Lozano I, Bodegas A, Cobos A, Matia R, Perez-Villacastin J, Guerra JM, Avila P, Lopez-Gil M, Castro V, Arana JI, Brugada J; SARA investigators. Catheter ablation vs. antiarrhythmic drug treatment of persistent atrial fibrillation: a multicentre, randomized, controlled trial (SARA study). Eur Heart J. 2014 Feb;35(8):501-7. doi: 10.1093/eurheartj/eht457. Epub 2013 Oct 17. — View Citation

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. Erratum In: JAMA. 2014 Jun 11;311(22):2337. JAMA. 2021 Jul 27;326(4):360. — View Citation

Santangeli P, Di Biase L, Natale A. Ablation versus drugs: what is the best first-line therapy for paroxysmal atrial fibrillation? Antiarrhythmic drugs are outmoded and catheter ablation should be the first-line option for all patients with paroxysmal atrial fibrillation: pro. Circ Arrhythm Electrophysiol. 2014 Aug;7(4):739-46. doi: 10.1161/CIRCEP.113.000629. No abstract available. — View Citation

Verma A, Jiang CY, Betts TR, Chen J, Deisenhofer I, Mantovan R, Macle L, Morillo CA, Haverkamp W, Weerasooriya R, Albenque JP, Nardi S, Menardi E, Novak P, Sanders P; STAR AF II Investigators. Approaches to catheter ablation for persistent atrial fibrillation. N Engl J Med. 2015 May 7;372(19):1812-22. doi: 10.1056/NEJMoa1408288. — View Citation

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. — View Citation

Wilber DJ, Pappone C, Neuzil P, De Paola A, Marchlinski F, Natale A, Macle L, Daoud EG, Calkins H, Hall B, Reddy V, Augello G, Reynolds MR, Vinekar C, Liu CY, Berry SM, Berry DA; ThermoCool AF Trial Investigators. Comparison of antiarrhythmic drug therapy and radiofrequency catheter ablation in patients with paroxysmal atrial fibrillation: a randomized controlled trial. JAMA. 2010 Jan 27;303(4):333-40. doi: 10.1001/jama.2009.2029. — View Citation

* Note: There are 17 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Recurrence of symptomatic Atrial Fibrillation	Recurrence (post 90- day blanking period) of symptomatic or asymptomatic AF, atrial flutter, or atrial tachycardia lasting more than 30 seconds documented by the pre-defined ECG monitoring is the primary efficacy outcome. Any episodes occurring during the 90-day blanking period are not considered as recurrences	18 Months
Secondary	Time to AF recurrence	Time to first documented recurrence of AF, atrial flutter, and atrial tachycardia episodes	18 Months
Secondary	Repeat Episodes of AF	Repeated episodes (=2) of symptomatic or asymptomatic AF, atrial flutter, and atrial tachycardia episodes	18 Months
Secondary	AF/AT Burden	Cumulative AF/AT burden (defined as percentage of time in AF/AT during follow-up)	18 Months
Secondary	CV Hospitalizations	Hospitalization for cardiovascular and non-cardiovascular causes during follow-up	18 Months
Secondary	Quality of Life Questionnaire	Quality of life at the 1-year follow-up by SF-36	18 Months