Optimal Method and Outcomes of Catheter Ablation of Persistent AF: The STAR AF 2 Trial Atul Verma, Jiang Chen-yang, Tim Betts, John Radcliffe, Jian Chen, Isabel Deisenhofer, Roberto Mantovan, Laurent Macle, Carlos Morillo, Prashanthan Sanders on behalf of the STAR AF 2 Investigators ClinicalTrials.gov NCT The STAR AF 2 trial was funded by St Jude Medical Inc.

Disclosures Dr Verma reports having served on advisory boards for and receiving grant support from Bayer, Boehringer Ingelheim, Medtronic, Biosense Webster, and St Jude Medical. Dr Betts reports lecture fees and grant support from St Jude Medical. Dr Macle reports receiving consulting fees from St Jude Medical, Biosense Webster, Bristol Meyers Squibb, and Pfizer and grant support from St Jude Medical and Biosense Webster. Dr Morillo reports receiving consulting fees from Boston Scientific, Medtronic, St Jude Medical, and Boehringer Ingelheim and grant support from Boston Scientific, Biosense Webster, Pfizer, and Merck. Dr Sanders reports having served on advisory boards for and receiving grant support and lecture fees from Biosense-Webster, Medtronic, St Jude Medical, Sanofi-Aventis, and Merck; receiving lecture fees and grant support from Biotronik; and receiving grant support from Sorin. Drs. Jiang, Chen, Deisenhofer, and Mantovan do not have any disclosures.

Background Catheter ablation is an effective treatment for symptomatic paroxysmal atrial fibrillation (AF) Pulmonary vein isolation (PVI) is considered the cornerstone for catheter ablation of AF Ablation of persistent AF is challenging and typically has less favorable outcomes compared to paroxysmal AF

Background To improve outcomes for persistent AF, guidelines suggest that “operators should consider more extensive ablation based on linear lesions or complex fractionated electrograms” in addition to PV isolation Whether more extensive ablation improves outcomes is unclear

Purpose To compare the efficacy of three different AF ablation strategies in patients with persistent AF: (1) Pulmonary vein isolation (PVI) alone (2) PVI plus complex fractionated electrograms (PVI+CFE) (3) PVI plus linear ablation (PVI+Lines).

Methods - Patients 589 patients were recruited from 48 experienced ablation centers in 12 countries Inclusion: symptomatic persistent AF (a sustained episode > 7 days and < 3 years) refractory to at least one antiarrhythmic drug undergoing first-time ablation Exclusion: paroxysmal AF, sustained AF episode > 3 years, left atrial diameter > 60 mm

Methods – Trial Design Patients were randomized 1:4:4 to the three strategies: – PVI, PVI+CFE, PVI+Lines Patients were blinded to the strategy (single blind) Repeat ablation procedures allowed between 3-6 months using the same randomized strategy as the first ablation

Methods – Ablation Strategy PVI = PV antral isolation with endpoint of entrance and exit block by a circular mapping catheter PVI+CFE = PVI followed by mapping and ablation of complex fractionated electrograms during AF identified by validated software in the 3D mapping system (Ensite Velocity) PVI+Lines = PVI followed by a left atrial roof line and a line along the mitral valve isthmus with endpoint of bidirectional block confirmed by pre-specified pacing maneuvers

Methods – Ablation Strategy Linear strategy CFE strategy

Methods – Follow-up Patients were followed for 18 months Visit, ECG and 24 hour Holter at 3, 6, 9, 12 and 18 months Weekly TTM transmissions for 18 months TTM transmissions every time symptoms felt – Tele-ECG-Card, Vitaphone, Germany

Outcomes Primary Outcome – Freedom from documented AF episode > 30 seconds after one ablation procedure with or without antiarrhythmic medications* Episodes during initial 3 month “blanking period” excluded from analysis Secondary Outcomes – Freedom from documented AF > 30 seconds after 2 procedures with or without antiarrhythmic medications – Freedom from any atrial arrhythmia (AF/AFL/AT) after one or two procedures – Procedural time – Incidence of repeat procedures – Procedural complications** – Use of antiarrhythmic medications * TTMs and recurrences blindly adjudicated, ** blinded events committee adjudication

Results - Baseline Characteristics CharacteristicPVIPVI+CFEPVI+Lines Age - year58 ± 1060 ± 961 ± 9 Male sex – n (%)52 (78)213 (82)196 (76) Ejection fraction (%)55 ± 1157 ± 10 Left atrial diameter (mm)44 ± 6 46 ± 6 Time from first AF diagnosis (yrs)4.3 ± ± ± 4.2 AF burden at Baseline* (hr/month)83 ± 3685 ± 3380 ± 37 Constantly in AF >6 months – n (%)52 (78)207 (80)186 (72) Medical history – n (%) Hypertension32 (48)143 (55)158 (62) Diabetes6 (9)31 (12)26 (10) Coronary disease2 (3)21 (8)29 (11) Stroke/TIA6 (9)14 (5)19 (7) Heart failure3 (4)10 (4)15 (6) CHADS 2 score - n (%) 031 (46)93 (36)81 (32) 125 (37)126 (48)127 (50) 26 (9)31 (12)29 (11) >25 (7)10 (4)19 (7)

Results - Ablation characteristics 79% of patients presented to EP lab in spontaneous AF Successful PV isolation obtained in 97% of all patients (all groups) CFE were eliminated in 80% of patients – 11% not ablated because AF non-inducible after PVI – 9% all CFE could not be eliminated Both lines with block achieved in 74% of patients – Roof line only 93% – Mitral line only 75%

PVIPVI+CFEPVI+LINESp value Procedure time (min) ± ± ± 89.37< Mapping time (min) ± ± ± 7.68< Fluoroscopy time (min) ± ± ± Results - Procedural Characteristics

Results - Primary Outcome p=0.15 Documented AF > 30 seconds after one procedure with or without AAD 59% 48% 44%

PVIPVI+CFEPVI+LINESp value Freedom from AF/AFL/AT after 1 procedure 49 %41 %37 %0.15 Freedom from AF after 2 procedures 72 %60 %58 %0.18 Freedom from AF/AFL/AT after 2 procedures 60 %50 %48 %0.24 Percentage of patients still on AAD at 18 mo 11 %12 % 0.35 Results - Secondary Outcomes * AAD = antiarrhythmic drug

Results - Subgroups

Results - Complications Category PVI (n=64) PVI+CFE (n=254) PVI+Lines (n=250) Total (n=568) Access site hematoma2035 Access site arteriovenous fistula or pseudoaneurysm 0336 Pericarditis0123 Fluid overload0134 Sedation related complication 0358 Skin burn1001 Cardiac tamponade1023 Transient ischemic attack or Stroke 0213 Atrial esophageal fistula - procedural death 0101

Conclusions Largest randomized trial to examine outcomes of catheter ablation in persistent AF Additional CFE or Lines ablation increased procedural time (may increase risk) No benefit in AF reduction when additional substrate ablation (CFE or Lines) was performed in addition to PVI PVI alone achieved freedom from recurrence in about 50% of patients – comparable to published success rates from randomized, multicenter trials in paroxysmal AF