Table 3. Seminal clinical trials of novel techniques for atrial fibrillation ablation.

Study	Design	Patient population	N	Intervention	Comparator	Endpoints	Follow-up (mean ± SD)	Outcomes
Contact force
TOCCASTAR Reddy et al60	RCT Multicenter Noninferiority	Symptomatic drug-refractory PAF Pooled mean age 60 ± 10 years 65% male	295	Ablation with CF-sensing catheter	Ablation with non-CF catheter	Primary: Efficacy (acute PVI, freedom from symptomatic AF off AAD); safety Secondary: Optimal vs nonoptimal CF, quality of life	12 months	Efficacy: 67.8% CF vs 69.4% control (noninferiority endpoint met) Efficacy within stratified CF arm: 75.9% optimal CF vs 58.1% nonoptimal CF Serious adverse events in 2.0% CF vs 1.4% control (safety noninferior endpoint met)
Cryoablation
FIRE and ICE Kuck et al61	RCT Multicenter Noninferiority	Symptomatic drug-refractory PAF Pooled mean age 60 ± 10 years 61% male	750	Cryoablation	Standard ablation	Primary: Efficacy (time to first recurrence of arrhythmia, AAD use, or repeat ablation), safety Secondary: Quality of life	18 months	Noninferiority efficacy and safety endpoints met No significant difference among the 4 types of ablation catheters
CFAE
STAR AF Verma et al62	RCT Multicenter Superiority	Symptomatic drug-refractory PAF (65%) or persistent AF Pooled mean age 57 ± 10 years 74% male	100	CFE alone CFE + PVI	PVI alone	Primary: Freedom from AF Secondary: Freedom from any arrhythmia, complications, procedural characteristics	12 months	PVI + CFE had the highest freedom from AF vs PVI alone or CFE alone CFE alone had lowest success rate after 1 or 2 procedures, and higher incidence of repeat procedures required
STAR AF II Verma et al63	RCT Multicenter	Symptomatic drug-refractory persistent AF Pooled mean age 60 ± 9 years 78% male	589	PVI + CFAE PVI + linear ablation	PVI alone	Primary: Freedom from atrial arrhythmia after index ablation off AAD or repeat ablation Secondary: Freedom from any AF after 2 procedures, freedom from any atrial arrhythmia, AAD use, complications, procedural characteristics	18 months	No significant difference in outcomes between groups after a first or repeat procedure PVI alone tended to be associated with shorter procedure and radiation times
Rotor modulation
CONFIRM Narayan et al64	RCT Single-center	Symptomatic PAF (28%) or persistent AF Pooled mean age 62 ± 8 years 95% male	92	FIRM-guided ablation + conventional ablation	Conventional ablation: WACA (+LA roof line for persistent AF cases)	Primary: Acute procedural termination of AF, long-term freedom from AF, safety Secondary: Freedom from AF after first ablation, freedom from all atrial arrhythmias	Median 22 months	Acute procedural endpoint achieved in 86% FIRM-guided vs 20% conventional ablation cases Total ablation time same for both groups Greater freedom from AF for FIRM-guided (82%) vs conventional (45%) after single procedure Safety: No significant difference in complication rates between groups
Dominant frequency ablation
RADAR AF Atienza et al65	RCT Multicenter Single-blind Noninferiority	Symptomatic PAF (50%) and persistent AF Pooled mean age 54 ± 10 years 80% male	232	PAF: HFSA Persistent AF: PVI	PAF: PVI Persistent AF: PVI 1 HFSA	Primary:Freedom from AF at 6 months after index ablation Secondary: Freedom from AF/AT at 6 and 12 months, periprocedural complications, adverse events, quality of life.	12 months	PAF: HFSA noninferior to PVI at 12 months (failed to achieve noninferiority at 6 months) Fewer serious adverse events in HFSA group Persistent AF: No significant difference between HFSA and PVI for primary or secondary endpoints, but a trend toward more serious adverse events with PVI + HFSA
Adenosine
ADVICE Macle et al66	RCT Multicenter Superiority	Symptomatic AF undergoing ablation Pooled mean age 60 ±10 years 71% male	534	PVI + adenosine-guided dormant conduction ablation	PVI alone	Primary: Time to first recurrence of atrial tachyarrhythmia after index ablation or repeat ablation <1 year Secondary: Time to first recurrence of atrial tachyarrhythmia, AAD use, periprocedural complications	12.2 ± 1.4 months	Adenosine unmasked dormant PV conduction in 53% of patients Adenosine-guided ablation associated with greater freedom from AF (69% vs 42%) Similar occurrence of serious adverse events in each group
UNDER-ATP Kobori et al67	RCT Multicenter Superiority	Symptomatic PAF or persistent AF undergoing first-time ablation Pooled mean age 63.3 ± 10 years 74% male	2113	PVI + adenosine-guided dormant conduction ablation	PVI alone	Primary: Recurrent atrial tachyarrhythmia <1 year Secondary: Repeat ablation for any atrial tachyarrhythmia, periprocedural complications	Median 384 days (interquartile range 366–450 days)	No significant difference in incidence of recurrent atrial tachyarrhythmias at 1 year between the 2 groups
GP ablation
Katritsis et al68	RCT 2-center	Symptomatic PAF Pooled mean age 56 ± 8 years 66% male	242	PVI + GP ablation GP alone	PVI alone	Primary: Freedom from AF/AT after index ablation Secondary: Radiofrequency delivery time, fluoroscopy time, adverse events	2 years	Addition of GP ablation to PVI conferred significantly higher success rate compared with either PVI or GP alone in patients with PAF

AT = atrial tachycardia; CF = contact force; CFAE = contact force atrial electrogram; CFE = contact force electrograms; FIRM = focal impulse and rotor modulation; GP = ganglion plexi; HFSA = high-frequency source ablation; PV = pulmonary vein; WACA = wide area circumferential ablation. Other abbreviations as in Tables 1 and 2.