Surgical Ablation of AF Efficacy Trial (SAFE)

SAFE is an international multicentre RCT of concomitant surgical atrial fibrillation (AF) ablation in patients with paroxysmal or persistent AF undergoing cardiac surgery.

Study Overview

• Status: Recruiting
• Conditions: Heart Failure; Atrial Fibrillation
• Intervention / Treatment: Procedure: Surgical Atrial Fibrillation Ablation

Detailed Description

Atrial fibrillation (AF) affects more than 1% of the general population and is an important risk factor for stroke. AF prevalence increases with age, occurring in 10 to 15% of patients older than 80 years of age, which is important with the aging population. Of patients undergoing cardiac surgery, 10.8% have a history of AF. AF is believed to cause the left atrium to dilate and lose its transport function. AF significantly increases the risk of ischemic stroke of cardioembolic origin, but is also associated with heart failure and impairs quality of life. Although the causal relationship between the 2 clinical entities has not been fully elucidated, AF is believed to cause heart failure via several mechanisms.

Ablation of AF is the application of scars to the atrial tissue to disrupt faulty electrical signals that cause the arrhythmia. If surgical ablation of AF yields a benefit similar to catheter-based AF ablation, thousands of people undergoing cardiac surgery could benefit from this procedure each year. SAFE will be a landmark trial in cardiac surgery, definitely establishing surgical AF ablation's impact on cardiovascular outcomes. Cardiac surgery is the optimal setting to establish whether maintenance of sinus rhythm through AF ablation yields clinical benefit, and is a setting where sham-control is possible. This will not only provide evidence for the cardiac surgical patients but will bolster the evidence for ablation (catheter or stand-alone surgical) in other AF patients.

The intervention under investigation is concomitant surgical AF ablation which is compared to no surgical AF ablation. The primary outcome is hospital readmissions with heart failure during 4 years of follow-up. This study will enroll 2000 patients from 50 centres, globally. Patients will be followed at hospital discharge, 4 to 6 weeks after surgery, 6 months after surgery, and then at 6-month intervals until the final follow-up visit, for a median follow-up for 4 years.

• Study Type: Interventional
• Enrollment (Estimated): 2000
• Phase: Not Applicable

Contacts and Locations

• Study Contact: Name: Richard Whitlock; Phone Number: 905-521-2100; Email: Richard.Whitlock@phri.ca
• Study Contact Backup: Name: SAFE Coordinators; Email: SAFE@phri.ca

Study Locations

• Canada
  • Ontario
    • Hamilton, Ontario, Canada, L8L 2X2
      • Recruiting
      • Hamilton General Hospital
      • Contact: Richard Whitlock, MD PhD FRCSC; Phone Number: 40306 905-527-4322; Email: richard.whitlock@phri.ca
      • Principal Investigator: Richard Whitlock, MD MSc FRCSC

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age ≥ 18 years;
• Undergoing a clinically indicated cardiac surgical procedure: CABG, AVR, ascending aorta replacement, or combinations thereof;
• Documented history of paroxysmal or persistent AF
• Provide informed consent

Exclusion Criteria:

• Dominant atrial arrhythmia is atrial flutter;
• Documented left atrial diameter ≥ 6 cm;
• Previous cardiac surgery requiring opening of the pericardium;

• Patients undergoing any of the following procedures:

  1. Heart transplant
  2. Complex congenital heart surgery
  3. Sole indication for surgery is ventricular assist device insertion
  4. Mitral valve repair or replacement
  5. Tricuspid valve repair or replacement
• Patient resides in a long-term care facility

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Surgical Atrial Fibrillation Ablation Group; Surgeon will perform left atrial ablation during patient's cardiac surgery procedure.	Procedure: Surgical Atrial Fibrillation Ablation; Surgeon will preform surgical atrial fibrillation ablation using either cryoablation or bipolar radiofrequency clamps including 2 layers of atrium or vein, a minimum of 2 burns per clamping with at least 3 lines in the ablation group. Cavo-tricuspid isthmus and mitral lines will be allowed.
No Intervention: No Surgical Atrial Fibrillation Ablation Group; Surgeon will not perform left atrial ablation during the patient's cardiac surgery procedure.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of hospital readmissions for heart failure over duration of follow-up	Total number of hospital readmissions for heart failure.	Common termination point for trial (median follow-up of 4 years)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Ischemic stroke or systemic arterial embolism events over duration of follow up	Number of Ischemic stroke or systemic arterial embolism events over duration of follow up	Common termination point for trial (median follow-up of 4 years)
Length of ICU stay	Length of ICU stay, including readmissions, from study intervention surgery to hospital discharge, including readmissions	From the date of study intervention surgery completion to the date of index hospital discharge, assessed up to the common termination point for trial (median follow-up of 4 years)
Length of hospital stay	Length of hospital stay	From the date of study intervention surgery completion to the date of index hospital discharge, assessed up to the common termination point for trial (median follow-up of 4 years)
Freedom from recurrence of atrial tachyarrhythmia	Freedom from recurrence of atrial tachyarrhythmia	1 year post-operatively
Number of days free from admission to healthcare facility or presentation to the emergency department for heart failure	Number of days free admission to healthcare facility or presentation to the emergency department for heart failure	Common termination point for trial (median follow-up of 4 years)
All-cause mortality	All-cause mortality	Common termination point for trial (median follow-up of 4 years)
Cardiovascular mortality	Cardiovascular mortality	Common termination point for trial (median follow-up of 4 years)
Antiarrhythmic drug use	Antiarrhythmic drug use	Beyond 6 weeks until common termination point for trial (median follow-up of 4 years)
Number of patients undergoing atrial fibrillation ablation	Number of patients undergoing atrial fibrillation ablation	90 days post- study surgery until common termination point for trial (median follow-up of 4 years)
Quality of Life - atrial fibrillation specific	Atrial fibrillation specific quality of life as assessed by the Atrial Fibrillation Effect on QualiTy of Life questionnaire (AFEQT) which is 20 questions using a 7 point Likert scale where a higher score means a worse outcome.	At 1 year, and at common termination point for trial (median follow-up of 4 years)
Quality of Life - heart failure specific	Heart failure specific quality of life assessed by the Kansas City Cardiomyopathy Questionnaire (KCCQ-12) which is a 12 questions using Likert scales where a higher score is a better outcome.	At 1 year, and at common termination point for trial (median follow-up of 4 years)
Quality of Life - General	Quality of life- general as assessed by the European quality of life index version 5D (EQ-5D-5L) which consists of a descriptive system and the EQ visual analogue scale (EQ VAS). The descriptive system comprises five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. Each dimension has 5 levels: no problems, slight problems, moderate problems, severe problems and extreme problems. The EQ VAS records the patient's self-rated health on a vertical visual analogue scale, where the endpoints are labelled 'The best health you can imagine' and 'The worst health you can imagine'. The VAS can be used as a quantitative measure of health outcome that reflect the patient's own judgement.	At 1 year, and at common termination point for trial (median follow-up of 4 years)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of Ischemic stroke and systemic arterial embolism	Safety outcome	Up to 30 days post-operatively
Number of patients requiring permanent pacemaker implantation	Safety outcome	Up to 1 year post-operatively
Volume of chest tube output	Safety outcome - chest tube output measured in mL.	Up to 24 hours post-operatively
Re-operation for bleeding	Safety outcome	From date of study intervention surgery completion to date of index hospital discharge, assessed up to the common termination point for trial (median follow-up of 4 years)
All-cause mortality	Safety outcome	Prior to discharge or within 30 days post-operatively (whichever occurs first)
Post-operative major bleeding	Safety outcome	<48 hours after surgery
Number of patients with pulmonary vein stenosis	Safety outcome	At 1 year, and at common termination point for trial (median follow-up of 4 years)
Number of patients with stiff left atrium syndrome	Safety outcome	At 1 year, and at common termination point for trial (median follow-up of 4 years)
Number of patients with esophageal to atrial fistula	Safety outcome	At 1 year, and at common termination point for trial (median follow-up of 4 years)
Health economic analysis of surgical atrial fibrillation	Economic analysis will be assessed via health care utilization by patients	At 1 year, and at common termination point (median follow-up of 4 years)
Health economic analysis of surgical atrial fibrillation	Economic analysis will be assessed via a questionnaire of health care visits and costs incurred by patients.	At 1 year, and at common termination point (median follow-up of 4 years)

Collaborators and Investigators

• Sponsor: Population Health Research Institute
• Collaborators: Hamilton Health Sciences Corporation
• Investigators: Principal Investigator: Richard Whitlock, Population Health Research Institute; Principal Investigator: Emilie Belley-Côté, Population Health Research Institute

Study record dates

Study Major Dates

• Study Start (Actual): June 1, 2023
• Primary Completion (Estimated): September 30, 2026
• Study Completion (Estimated): December 31, 2026

Study Registration Dates

• First Submitted: May 4, 2022
• First Submitted That Met QC Criteria: June 22, 2022
• First Posted (Actual): June 28, 2022

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: February 27, 2025
• Last Verified: February 1, 2025

More Information

Terms related to this study

• Keywords: Cardiac Surgery; Surgical Ablation
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Pathologic Processes; Heart Diseases; Arrhythmias, Cardiac; Atrial Fibrillation
• Other Study ID Numbers: SAFEV1.0

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No