Jens Cosedis Nielsen, Professor, MD, DMSc, Aarhus, Denmark on behalf of the MANTRA-PAF investigators

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 • PekkaRaatikainen Oulu University Hospital, Finland • Gerhard Hindricks Leipzig University Hospital, Germany • HåkanWalfridsson University Hospital Linköping, Sweden • Ole Kongstad Lund University Hospital, Sweden • Steen Pehrson Rigshospitalet, Copenhagen, Denmark • Anders Englund University Hospital, Örebro, Sweden • JuhaHartikainenKuipioUniversity Hospital, Finland • Leif SpangeMortensen UNI-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 trialwassupported by unrestrictedgrants 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%) 665 7D Holter recordings 666 7D Holter recordings 69 underwent repeated RFA Treatment with 1.24±0.48 AAD’s After 24 months N=54; 87 RFA procedures (1.6±0.7) On AAD: N=100 /137 (73%) (IC: 86, III:14) Withdrawn N=7 Died N=4 After 24 months N=140; 223 RFA procedures (1.6±0.7) On AAD: N=13/138 (9%) (IC: 10, III: 3) Withdrawn N=5 Died N=3

8. * p<0.05

9. AF Burden A: RFA D: AAD 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

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

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

12. Atrial Flutter P=0.25 Number of patients

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.