Study Endpoints
Endpoint definitions: Procedural outcomes were defined based on the 2017 HRS consensus statement. Full endpoint definitions are included in the Supplement.
Primary Efficacy Endpoint: Failure free rate at 12 months post procedure, with failure defined as occurrence of any of the following events; acute procedural failure, surgical treatment for AF/AFL/AT, use of non-study catheter for AF targets, more than 1 repeat during blanking, repeat or surgical treatment after blanking, documented recurrence of AF, AFL, or AT after blanking; electrical or pharmacological cardioversion after blanking, use of Class I/III AADs or any other AADs for control of AF/AFL/AT, any use of amiodarone (pre or post blanking).
Primary Safety Endpoint: Primary safety event free rate at 12 months post procedure. Event free rate was defined as a composite of the following acute and chronic procedure-related and device-related adverse events: Acute primary safety endpoint events, events occurring up to 7 days post index or hospital discharge, whichever is later, include: Death; myocardial infarction (MI); transient ischemic attack (TIA); stroke/ cerebrovascular accident (CVA); vascular access complications; mitral or tricuspid valvular damage; thromboembolism/ air embolism (leading to a life-threatening event such as a ventricular arrhythmia, stroke, pulmonary embolism, or myocardial infarction and, thromboembolic events that result in permanent injury, require intervention for treatment, or prolongs/requires hospitalization for more than 48 hours); gastroparesis/injury to vagal nerve; pneumothorax; pulmonary edema/heart failure; atrioventricular block; cardiac tamponade/perforation (occurring up to 30 days post index procedure). chronic primary safety endpoint events, events occurring through 12 months post procedure, include: atrial esophageal fistula; severe PV stenosis (≥ 70% reduction in the diameter of the PV or PV branch from baseline); persistent phrenic nerve palsy. Safety events, including but not limited to the predefined safety endpoint, were reviewed by an independent Clinical Events Committee.
Stenosis Sub-study: Fifty treatment patients were assessed for stenosis associated with cryoablation. Patients PVs were imaged by CT/MRI at baselines and 3 to 6 months post procedure. The degree of narrowing (mild <50%, moderate 50-70%, severe ≥70%) from the 3 to 6 months follow-up scan compared to baseline was assessed by a central lab.
FIT Extension: In addition to the primary study arm, an extension arm to FROZEN AF treated 50 pts to assess safety of novel variable size balloon that allows inflation and ablation at both 28mm and 31mm. Patients received at least one PV cryoablation with the 31mm sized cryoballoon, otherwise pts treatment and design were similar to the larger cohort.
Statistical Analysis: The primary arm of this study was designed around an expected event-free rates of 94% (Safety) 60% (Effectiveness), targeting 90% power to compare to performance goals of 89% (Safety) and 50% (Effectiveness) with a 95% one-sides confidence limit. The FIT extension arm was designed with a primary safety endpoint based on 3-month follow-up and acute success, with the same performance goal as the parent study (89% freedom from safety events), while the effectiveness endpoint did not have a designated acceptance criteria. For ease of comparison, the pre-defined primary effectiveness endpoint of the initial study was also calculated for the 50 patient FIT extension arm. Secondary analysis reported here include survival analysis to efficacy component events. Analyses were performed with SAS version 9.4 (SAS Institute Software Company). Data are reported as mean ± standard deviation, median (IQR, or N (%) as appropriate.