Optimizing Sedation for Pulsed-Field Ablation in Atrial Fibrillation: Results of the COOPERATIVE-PFA Trial

Atrial fibrillation (AF), the most common sustained cardiac arrhythmia, presents significant morbidity and increases risks of stroke and heart failure. Catheter ablation targeting pulmonary vein isolation has become an established rhythm control strategy, particularly with emerging techniques like pulsed-field ablation (PFA). PFA offers tissue-selective myocardial ablation with reduced collateral damage compared with thermal methods, but requires deep analgosedation (DAS) or general anesthesia for optimal procedure conditions. Conventional sedation regimens vary, with notable concerns about sedation-related adverse events such as hypoxemia and hemodynamic instability. This creates an unmet clinical need to identify the safest and most effective sedation approach that balances procedural comfort, airway safety, and cardiovascular stability in patients undergoing PFA for AF.

Study Design

The COOPERATIVE-PFA trial was a prospective, randomized controlled trial designed to evaluate the safety and efficacy of three different sedation regimens during PFA for atrial fibrillation. A total of 127 patients (mean age 62.9 years, 35.1% women, 47.2% paroxysmal AF) were randomized in a 1:1:1 ratio into three parallel arms:

1. Arm P: Deep analgosedation via intermittent boluses of propofol combined with opioid analgesics.
2. Arm R: Continuous deep analgosedation using the combination of remimazolam, a novel benzodiazepine, and ketamine.
3. Arm TIVA: Total intravenous anesthesia with continuous propofol-opioid infusion and secured airway management.

The FARAPULSE system (Boston Scientific) was utilized for catheter ablation. Patients with obstructive sleep apnea syndrome were excluded to minimize confounding respiratory risks. The primary endpoint was a composite of sedation-related adverse events, including hypoxemia (low oxygen saturation), hypotension (low blood pressure), or hypertension (high blood pressure) events that required clinical intervention or led to procedure discontinuation. Secondary endpoints addressed hemodynamic instability events regardless of intervention, procedure duration, serious adverse event rates, and patient-reported satisfaction measured by the PROcedural Sedation Assessment Survey.

Key Findings

Analysis by intention-to-treat revealed dramatic differences in sedation safety profiles:

– The primary endpoint incidence was markedly lower in the remimazolam-ketamine arm R (27.9%) compared to both the propofol-opioid bolus arm P (85.7%) and the propofol-opioid TIVA arm (66.7%) (P < 0.001).
– Hypoxemic events predominated in arm P, occurring in over 85% of patients, but were significantly fewer in arms R (14.0%) and TIVA (7.1%).
– Hypotension was significantly more frequent in the TIVA arm (66.7%) than in arms P (23.8%) and R (18.6%).
– Hypertensive events were rare and did not differ significantly among groups.

Additional observations included increased airway management interventions (e.g., jaw thrust maneuvers, increased inspired oxygen) in the P arm due to frequent hypoxemia, whereas vasoactive drug use for blood pressure support was higher in the TIVA group. Procedure duration was statistically similar among treatment arms, although a slight trend toward longer duration was noted in TIVA patients. Bispectral index (BIS) monitoring showed deeper sedation levels in the TIVA arm than P, consistent with anesthesiologist observations that patients in arm P were hardest to sedate. Interestingly, patient satisfaction scores did not differ significantly across sedation strategies.

Safety outcomes demonstrated no significant differences in serious adverse event rates among arms. The per-protocol analysis confirmed these findings with statistically significant differences in all pairwise comparisons.

Expert Commentary

These results provide compelling evidence supporting the remimazolam-ketamine combination as a superior DAS regimen in the context of pulsed-field ablation for AF. The novel use of remimazolam, with its rapid onset and recovery profile, combined with ketamine’s unique analgesic and sympathomimetic properties, likely explains the improved respiratory and hemodynamic stability observed. This contrasts with propofol-opioid regimens commonly associated with respiratory depression and hypotension, especially when administered as boluses without secured airway.

While TIVA with airway protection reduced hypoxemia compared with intermittent boluses, its higher incidence of hypotension and the requirement for airway management underline the challenges of general anesthesia in this population. The lack of difference in patient satisfaction despite these variations suggests that patient experience may be similarly acceptable among sedation modalities if appropriately managed.

Limitations of the study include exclusion of patients with obstructive sleep apnea, which limits generalizability to higher-risk respiratory populations. Additionally, single-center or operator-dependent variables were not detailed and could impact procedural or sedation outcomes. Further multicenter studies may expand upon these findings.

Conclusion

The COOPERATIVE-PFA trial establishes remimazolam-ketamine deep analgosedation as a safer and more effective sedation choice for pulsed-field ablation in atrial fibrillation, associated with the lowest rates of hypoxemia and hypotension. Given that over 80% of patients receiving conventional propofol-opioid bolus sedation experienced hypoxemia, clinical practice should consider adopting remimazolam-ketamine DAS to enhance patient safety and procedural outcomes. These findings pave the way for refining anesthetic protocols in electrophysiology, aligning novel pharmacologic agents with advancing catheter ablation technologies.

References

1. Sochorová V, Kunštátová V, Osmančík P, Duška F, Heřman D, Waldauf P, et al. COOPERATIVE-PFA: A Three-Arm Randomized Controlled Trial. Circulation. 2025 Jul 22;152(3):150-159. doi:10.1161/CIRCULATIONAHA.125.074427 IF: 38.6 Q1

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