1. A Randomized Multicenter Comparison of Radiofrequency Ablation and Antiarrhythmic Drug Therapy as First Line Treatment in 294 Patients with Paroxysmal Atrial Fibrillation Jens Cosedis Nielsen, Professor, MD, DMSc, Aarhus, Denmark on behalf of the MANTRA-PAF investigators

2. MANTRA-PAF Investigators Arne Johannessen Gentofte University Hospital, CPH, Denmark Pekka Raatikainen Oulu University Hospital, Finland Gerhard HindricksLeipzig University Hospital, Germany Håkan Walfridsson University Hospital Linköping, Sweden Ole KongstadLund University Hospital, Sweden Steen PehrsonRigshospitalet, Copenhagen, Denmark Anders Englund University Hospital, Örebro, Sweden Juha HartikainenKuipio University Hospital, Finland Leif Spange MortensenUNI-C, Denmark (Datamanagement and statistics) Peter Steen Hansen Aarhus University Hospital, Skejby, Denmark (Chair, investigator committee) Jens Cosedis Nielsen Aarhus University Hospital, Skejby, Denmark (Coordinating investigator) Funding: The trial was supported by unrestricted grants from the Danish Heart Foundation and from Biosense Webster and Johnson&Johnson

3. Aim To compare radiofrequency ablation (RFA) with antiarrhythmic drug therapy (AAD) as first-line treatment in patients with paroxysmal atrial fibrillation (AF).

4. Methods Randomized controlled multicenter trial Antiarrhythmic drug therapy (Class IC or III) (AAD) versus pulmonary vein isolation (RFA) Power calculation: Assumed freedom from AF after 24 months in 75% (RFA) versus 60% (AAD) of the patients, α=0.05, 1-β=0.80, N=150 patients in each group Follow-up with 7-day Holter recordings after 3, 6, 12, 18 and 24 months Intention-to-treat analysis

5. Endpoints Primary endpoints: –Cumulative burden of AF –AF-burden at each 7-day Holter recording Secondary endpoints: –Freedom from any AF after 24 months –Freedom from symptomatic AF after 24 months –Burden of symptomatic AF after 3, 6, 12, 18, and 24 months –Atrial flutter –Quality of Life after 12 and 24 months –Serious adverse events

6. 294 Patients Randomized 146 Assigned to RFA 140 Underwent RFA (96%) 148 Assigned to AAD 146 Started AAD (99%) After 24 months N=140; 223 RFA procedures (1.6±0.7) On AAD: N=13/138 (9%) (IC: 10, III: 3) Withdrawn N=5 Died N=3 666 7D Holter recordings After 24 months N=54; 87 RFA procedures (1.6±0.7) On AAD: N=100 /137 (73%) (IC: 86, III:14) Withdrawn N=7 Died N=4 665 7D Holter recordings 69 underwent repeated RFA Treatment with 1.24±0.48 AAD’s

7. Baseline Characteristics IRFAAAD N146148 Age (years)56±954±10 Male gender100 (68%)106 (72%) Body Mass Index27±4 Hypertension43 (29%)53 (36%) Coronary artery disease6 (4%)2 (1%) Valvular disease7 (5%)15 (10%) Previous stroke or TIA6 (4%)5 (3%) Diabetes6 (4%)10 (7%) Chronic lung disease8 (5%)6 (4%) Pacemaker5 (3%)6 (4%) Thyroid disease10 (7%) Previous Cardioversions 0103100 1817 2116 374 426 >415

8. Baseline Characteristics IIRFAAAD Duration of usual AF episodes ≤1 hour2729 >1 hour, ≤7 hours57 >7 hours, ≤24 hours4345 >24 hours, ≤2 days148 >2 days, ≤7 days37 Average interval between AF episodes 0-7 days8287 >7 days, ≤1 month4841 >1 month, ≤6 months1418 >6 months10 Left atrial size (echo), mm40±640±5 Left ventricular ejection fraction >60%116121 40-60%2926 Medication last week before randomization Warfarin69 (47%)65 (44%) Betablocker106 (73%)107 (72%) Calcium channel blocker28 (19%)16 (11%) * Digoxin17 (12%)13 (9%) * p<0.05

9. Mann-Whitney Test Mean rank 149 146 145 150 144 151 141 154 141 154 138 157 140 155 P-value 0.72 0.49 0.34 0.08 0.07 0.007 0.10 AF Burden A: RFA D: AAD

10. AF after 24 Months Number of patients P=0.012 P=0.004

11. Quality of Life (SF-36) Physical Component Summary (PCS)Mental Component Summary (MCS) Mean values of PCS and MCS p=0.01p=0.02 ns

12. Atrial Flutter P=0.25 Number of patients

13. Serious Adverse EventsRFAAAD Death34 Stroke10 Transient ischemic attack11 Pulmonary vein stenosis10 Tamponade30 Pericardial effusion, no puncture01 Suspected perforation at transseptal puncture10 Atrial flutter, 1:1 AV conduction02 Atrial flutter or atrial tachycardia33 Cardiac incompensation02 Perimyocarditis10 Bradycardia with need of pacemaker01 Ventricular tachycardia and need for ICD10 Hematoma related to anticoagulation10 Retroperitoneal bleeding, coiling of small artery10 Chest discomfort10 Discomfort probably due to medication02 Cancer64 Other (Rotator cuff rupture, Arthroscopy, Gallbladder surgery)12 Total2522

14. Conclusions At 24 months AF-burden and occurrence of any and symptomatic AF were significantly lower in the RFA group than in the AAD group. No significant difference was observed in the cumulative burden of AF between AAD and RFA. QOL (PCS) better in the RFA group after 12 and 24 months. These data support RFA as a first-line treatment in patients with paroxysmal AF.

15. Discussion Selected patient population. Not an argument for offering all patients with paroxysmal AF radiofrequency ablation! Both strategies should be discussed with the patients and considered by patients and physicians when rhythm control for symptomatic paroxysmal AF is indicated. The results of the MANTRA-PAF trial support the idea of early ablation for AF to avoid progression of AF on the long term.