STOP AF First: Cryoballoon Catheter Ablation in an Antiarrhythmic Drug Naive Paroxysmal Atrial Fibrillation

• Sponsor: Medtronic Cardiac Rhythm and Heart Failure (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03118518
• Collaborator: (none)
• Enrollment: 225
• Locations: 24
• Arms: 2
• Actual Duration (Months): 36.1
• Patients Per Site: 9.4
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

To provide data demonstrating the safety and effectiveness of the Arctic Front Advance™ Cardiac CryoAblation Catheter for the treatment of recurrent symptomatic paroxysmal atrial fibrillation, without the requirement that the subjects be drug refractory.

Condition or Disease	Intervention/Treatment	Phase
Atrial Fibrillation; Atrial Fibrillation New Onset	Device: Cryoablation; Drug: Antiarrhythmic drug	N/A

Detailed Description

Subjects with paroxysmal atrial fibrillation with no history of treatment with anti-arrhythmic drugs are randomized 1:1 to either an anti-arrhythmic drug or pulmonary vein isolation using the cryoballoon catheter.

Study Design

• Study Type: Interventional
• Actual Enrollment: 225 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: STOP AF First: Cryoballoon Catheter Ablation in an Antiarrhythmic Drug Naive Paroxysmal Atrial Fibrillation
• Actual Study Start Date: Jun 23, 2017
• Actual Primary Completion Date: Jun 25, 2020
• Actual Study Completion Date: Jun 25, 2020

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Anti-arrhythmic drug	Drug: Antiarrhythmic drug; Antiarrhythmic drug initiation
Experimental: Cryoablation	Device: Cryoablation; Pulmonary vein isolation via ablation with cryoballoon catheter; Other Names: ArcticFront Advance Cardiac CryoAblation Catheter

Outcome Measures

Primary Outcome Measures

1. Percentage of Participants With Treatment Success at 12 Months After Antiarrhythmic Drug (AAD) Initiation or Ablation Utilizing the Arctic Front Advance™ Cardiac CryoAblation Catheter. [Randomization to 12 months]

   Treatment success after AAD initiation (control arm) or pulmonary vein isolation ablation procedure utilizing the Arctic Front Advance™ Cardiac CryoAblation Catheter (treatment arm). Treatment success is the opposite of treatment failure. Treatment failure was defined as any of the following: Acute procedural failure (treatment arm only). Documented AF/AT/AFL on ambulatory monitoring/12-lead ECG after the 90-day post-ablation blanking period (treatment)/AAD optimization period (control arm). Minimum of 30 seconds on ambulatory monitoring or 10 seconds on 12-lead ECG. Any subsequent AF surgery or ablation in the left atrium. Any subsequent cardioversion after the 90-day post-ablation blanking period (treatment)/AAD optimization period (control arm). Class I or III antiarrhythmic drug (or sotalol) use after the 90-day blanking period (treatment arm only).

2. Primary Safety Endpoint - Rate of Composite List of Serious Adverse Events. [Randomization to 12 months]

   Measured by rate of composite list of serious adverse events in cryoablation-treated as randomized arm. Includes: TIA within 7 days Cerebrovascular accident within 7 days Major bleed that requires transfusion or results in a 20% or greater fall in hematocrit (HCT) within 7 days Development of a significant pericardial effusion within 30 days. (One that results in hemodynamic compromise, requires elective or urgent pericardiocentesis, or results in a 1-cm or more pericardial effusion as documented by echocardiography). Symptomatic PV stenosis within 12 months; accompanied by one of the following: 50%-75% reduction in diameter of the pulmonary vein, with symptoms not explained by other conditions; OR >75% reduction in diameter of the pulmonary vein MI within 7 days PNI unresolved at 12 months AE fistula within 12 months Major vascular complication that requires intervention, prolongs hospital stay, or requires hospital admission (within 7 days).

Secondary Outcome Measures

1. Quality of Life Scores at Baseline Compared to 12 Months [Baseline and 12 Months]

   There are two hypotheses tested in the objective, with separate hypothesis tests for (1) the difference in composite scores from the AFEQT questionnaire taken at baseline and 12 month visits, and (2) for the difference in composite scores for the EQ-5D questionnaire taken at baseline and 12-month visits. Composite AFEQT score is on a scale of zero to one hundred. Higher scores are better. Composite EQ-5D score is on a scale of zero to one. Higher scores are better.

2. Healthcare Utilization [Initial treatment through 12 months.]

   Compare health care utilization between the treatment and control arms. There are two hypotheses tested in the objective, with separate hypothesis tests for: (1) the rate of total health care utilization events (cardiovascular-related hospitalizations, emergency room visits, or unscheduled office visits) over 12 months shown as freedom from cardiovascular health care utilization by treatment arm, and (2) freedom from cardioversions (electrical or pharmacological) over 12 months by treatment arm.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 80 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• A diagnosis of symptomatic paroxysmal AF with the following documentation: (1) physician's note indicating recurrent self- terminating AF or paroxysmal AF; and (2) any ECG documented AF within 6 months prior to enrollment.

• Age 18-80

Exclusion Criteria:

• History of AF treatment with class I or III antiarrhythmic drug, including sotalol, with the intention to prevent an AF recurrence. However, patients pretreated with above AAD for less than 7 days with the intention to convert an AF episode are allowed.

• Prior persistent AF (cardioversion after 48 hours or continuous AF that is sustained

7 days)

• Left atrial diameter greater than 5.0 cm

• Prior left atrial ablation or left atrial surgical procedure

• Presence or likely implant of a permanent pacemaker, biventricular pacemaker, loop recorder, or any type of implantable cardiac defibrillator (with or without biventricular pacing function)

• Body mass index (BMI) >35 kg/m2

• Presence of any pulmonary vein stents

• Known presence of any pre-existing pulmonary vein stenosis

• Pre-existing hemidiaphragmatic paralysis

• Presence of any cardiac valve prosthesis

• Moderate or severe mitral valve regurgitation or stenosis

• Any cardiac surgery, myocardial infarction, percutaneous coronary intervention/ percutaneous transluminal coronary angioplasty or coronary artery stenting which occurred during the 90 day interval preceding the date the subject signed the Informed Consent Form

• Unstable angina

• New York Heart Association (NYHA) class III or IV congestive heart failure and/or known left ventricular ejection fraction (LVEF) less than 45%

• Diagnosis of primary pulmonary hypertension

• Rheumatic heart disease

• Thrombocytosis, thrombocytopenia

• Contraindication to anticoagulation therapy

• Active systemic infection

• Hypertrophic cardiomyopathy

• Cryoglobulinemia

• Known reversible causes of AF, including but not limited to uncontrolled hyperthyroidism, obstructive sleep apnea, and acute alcohol toxicity.

• Any cerebral ischemic event (strokes or transient ischemic attacks) which occurred during the 180 day interval preceding the date the subject signed the Informed Consent Form, or any known unresolved complications from previous stroke/transient ischemic attack

• Existing thrombus

• Pregnancy

• Patient with life expectancy that makes it unlikely 12 months of follow-up will be completed.

• Current or anticipated participation in any other clinical trial of a drug, device or biologic during the duration of this study not pre-approved by Medtronic

• Patients with contraindications to a Holter monitor

• Unwilling or unable to comply fully with study procedures and follow-up

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Grandview Medical Center	Birmingham	Alabama	United States	35243
2	Alaska Heart Institute	Anchorage	Alaska	United States	50266-8209
3	Hoag Hospital Newport Beach	Newport Beach	California	United States	92663
4	MedStar Washington Hospital Center	Washington	District of Columbia	United States	20010-3017
5	Tallahassee Research Institute Inc	Tallahassee	Florida	United States	32308-4646
6	BayCare Medical Group Cardiology	Tampa	Florida	United States	33607
7	Wellstar Research Institute	Marietta	Georgia	United States	30060
8	Krannert Institute of Cardiology	Indianapolis	Indiana	United States	46202
9	Iowa Heart Center	West Des Moines	Iowa	United States	50266-8209
10	Our Lady of the Lake Office of Research	Baton Rouge	Louisiana	United States	50266-8209
11	Southcoast Health System	New Bedford	Massachusetts	United States	02740
12	University of Michigan Health System - University Hospital	Ann Arbor	Michigan	United States	50266-8209
13	Spectrum Health Hospitals	Grand Rapids	Michigan	United States	49503
14	HealthEast Saint Josephs Hospital	Saint Paul	Minnesota	United States	55102-1062
15	Bryan Heart	Lincoln	Nebraska	United States	07450-2726
16	Hackensack University Medical Center	Hackensack	New Jersey	United States	07601
17	The Valley Hospital	Ridgewood	New Jersey	United States	07450-2726
18	Cleveland Clinic	Cleveland	Ohio	United States	44195-0001
19	Ohio State University	Columbus	Ohio	United States	43210
20	Integris Baptist Medical Center, Inc.	Oklahoma City	Oklahoma	United States	73112-4418
21	Providence Saint Vincent Medical Center	Portland	Oregon	United States	97225
22	Lehigh Valley Health	Allentown	Pennsylvania	United States	18105
23	Geisinger Medical Center	Danville	Pennsylvania	United States	17821
24	Aurora Cardiovascular Services	Milwaukee	Wisconsin	United States	50266-8209

Sponsors and Collaborators

• Medtronic Cardiac Rhythm and Heart Failure

Investigators

• Principal Investigator: Oussama Wazni, MD, The Cleveland Clinic
• Principal Investigator: Gopi Dandamudi, MD, Franciscan Heart & Vascular Associates at St. Joseph
• Principal Investigator: Steve Nissen, MD, The Cleveland Clinic

Study Documents (Full-Text)

• Study Protocol: Version 4 - Apr 10, 2017
• Study Protocol: Version 5 - Dec 5, 2017
• Study Protocol: Version 6 - Jan 16, 2018
• Statistical Analysis Plan - May 9, 2018

More Information

Publications

None provided.

• Responsible Party: Medtronic Cardiac Rhythm and Heart Failure
• ClinicalTrials.gov Identifier: NCT03118518
• Other Study ID Numbers: MDT16012AFS001
• First Posted: Apr 18, 2017
• Last Update Posted: Aug 11, 2021
• Last Verified: Jul 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: Yes
• Additional relevant MeSH terms: Atrial Fibrillation; Anti-Arrhythmia Agents

Study Results

Participant Flow

Recruitment Details	The first enrollment in the STOP AF First study occurred in the United States on 23-JUN-2017. The final enrollment occurred on 13-MAY-2019.
Pre-assignment Detail	Of 225 enrolled participants, 210 met inclusion criteria and were randomized to treatment. Of the 15 who exited prior to randomization: 11 did not meet inclusion/exclusion criteria, 2 withdrew, 1 was lost to follow-up and 1 had study enrollment close prior to randomization.

Arm/Group Title	Subjects Randomized to Cryoballoon Catheter Ablation	Subjects Randomized to Antiarrhythmic Drug Therapy
Arm/Group Description	Subjects Randomized to Cryoballoon Catheter Ablation.	Subjects Randomized to Antiarrhythmic Drug Therapy.
Period Title: Overall Study
STARTED	108	102
Subject Treated According to Randomization Assignment	104	99
COMPLETED	102	91
NOT COMPLETED	6	11

Baseline Characteristics

Arm/Group Title	Subjects Treated With Cryoballoon Catheter Ablation as Randomized	Subjects Treated With Antiarrhythmic Drug Initiation	Total
Arm/Group Description	Subjects Treated with Cryoballoon Catheter Ablation as Randomized.	Subjects Treated with Antiarrhythmic Drug Initiation.	Total of all reporting groups
Overall Participants	104	99	203
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	59 56.7%	49 49.5%	108 53.2%
>=65 years	45 43.3%	50 50.5%	95 46.8%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	60.4 (11.2)	61.6 (11.2)	61.0 (11.2)
Sex: Female, Male (Count of Participants)
Female	41 39.4%	42 42.4%	83 40.9%
Male	63 60.6%	57 57.6%	120 59.1%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	2 1.9%	3 3%	5 2.5%
Not Hispanic or Latino	97 93.3%	91 91.9%	188 92.6%
Unknown or Not Reported	5 4.8%	5 5.1%	10 4.9%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	1 1%	2 2%	3 1.5%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	5 4.8%	5 5.1%	10 4.9%
White	94 90.4%	91 91.9%	185 91.1%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	4 3.8%	1 1%	5 2.5%
Region of Enrollment (participants) [Number]
United States	104 100%	99 100%	203 100%

Outcome Measures

1. Primary Outcome

Title	Percentage of Participants With Treatment Success at 12 Months After Antiarrhythmic Drug (AAD) Initiation or Ablation Utilizing the Arctic Front Advance™ Cardiac CryoAblation Catheter.
Description	Treatment success after AAD initiation (control arm) or pulmonary vein isolation ablation procedure utilizing the Arctic Front Advance™ Cardiac CryoAblation Catheter (treatment arm). Treatment success is the opposite of treatment failure. Treatment failure was defined as any of the following: Acute procedural failure (treatment arm only). Documented AF/AT/AFL on ambulatory monitoring/12-lead ECG after the 90-day post-ablation blanking period (treatment)/AAD optimization period (control arm). Minimum of 30 seconds on ambulatory monitoring or 10 seconds on 12-lead ECG. Any subsequent AF surgery or ablation in the left atrium. Any subsequent cardioversion after the 90-day post-ablation blanking period (treatment)/AAD optimization period (control arm). Class I or III antiarrhythmic drug (or sotalol) use after the 90-day blanking period (treatment arm only).
Time Frame	Randomization to 12 months

Outcome Measure Data

Analysis Population Description

Subjects who were received the treatment they were randomized to (modified intent to treat).

Arm/Group Title	Subjects Treated With Cryoballoon Catheter Ablation as Randomized	Subjects Treated With Antiarrhythmic Drug Initiation
Arm/Group Description	Subjects Treated with Cryoballoon Catheter Ablation as Randomized.	Subjects Treated with Antiarrhythmic Drug Initiation.
Measure Participants	104	99
Number (95% Confidence Interval) [percentage of participants]	73.7 70.9%	45.0 45.5%

2. Primary Outcome

Title	Primary Safety Endpoint - Rate of Composite List of Serious Adverse Events.
Description	Measured by rate of composite list of serious adverse events in cryoablation-treated as randomized arm. Includes: TIA within 7 days Cerebrovascular accident within 7 days Major bleed that requires transfusion or results in a 20% or greater fall in hematocrit (HCT) within 7 days Development of a significant pericardial effusion within 30 days. (One that results in hemodynamic compromise, requires elective or urgent pericardiocentesis, or results in a 1-cm or more pericardial effusion as documented by echocardiography). Symptomatic PV stenosis within 12 months; accompanied by one of the following: 50%-75% reduction in diameter of the pulmonary vein, with symptoms not explained by other conditions; OR >75% reduction in diameter of the pulmonary vein MI within 7 days PNI unresolved at 12 months AE fistula within 12 months Major vascular complication that requires intervention, prolongs hospital stay, or requires hospital admission (within 7 days).
Time Frame	Randomization to 12 months

Outcome Measure Data

Analysis Population Description

Subjects who were cryoablation-treated as randomized (as was pre-specified in both the protocol and Statistical Analysis Plan)

Arm/Group Title	Subjects Treated With Cryoballoon Catheter Ablation as Randomized
Arm/Group Description	Subjects Treated with Cryoballoon Catheter Ablation as Randomized.
Measure Participants	104
Number (95% Confidence Interval) [percentage of participants]	1.92 1.8%

3. Secondary Outcome

Title	Quality of Life Scores at Baseline Compared to 12 Months
Description	There are two hypotheses tested in the objective, with separate hypothesis tests for (1) the difference in composite scores from the AFEQT questionnaire taken at baseline and 12 month visits, and (2) for the difference in composite scores for the EQ-5D questionnaire taken at baseline and 12-month visits. Composite AFEQT score is on a scale of zero to one hundred. Higher scores are better. Composite EQ-5D score is on a scale of zero to one. Higher scores are better.
Time Frame	Baseline and 12 Months

Outcome Measure Data

Analysis Population Description

Subjects treated with cryoballoon catheter ablation as randomized (as was pre-specified in both the protocol and Statistical Analysis Plan) and who had QOL score available at both baseline and 12 month time points.

Arm/Group Title	Subjects Treated With Cryoballoon Catheter Ablation as Randomized
Arm/Group Description	Subjects Treated with Cryoballoon Catheter Ablation as Randomized.
Measure Participants	99
AFEQT composite score (change from baseline to 12 months)	33.3
Composite EQ-5D score (change from baseline to 12 months)	0.04

4. Secondary Outcome

Title	Healthcare Utilization
Description	Compare health care utilization between the treatment and control arms. There are two hypotheses tested in the objective, with separate hypothesis tests for: (1) the rate of total health care utilization events (cardiovascular-related hospitalizations, emergency room visits, or unscheduled office visits) over 12 months shown as freedom from cardiovascular health care utilization by treatment arm, and (2) freedom from cardioversions (electrical or pharmacological) over 12 months by treatment arm.
Time Frame	Initial treatment through 12 months.

Outcome Measure Data

Analysis Population Description

All subjects treated as randomized (mITT).

Arm/Group Title	Subjects Treated With Cryoballoon Catheter Ablation as Randomized	Subjects Treated With Antiarrhythmic Drug Initiation
Arm/Group Description	Subjects Treated with Cryoballoon Catheter Ablation as Randomized.	Subjects Treated with Antiarrhythmic Drug Initiation.
Measure Participants	104	99
Freedom from Cardiovascular health care utilization.	69.9 67.2%	53.5 54%
Freedom from Cardioversion	97.1 93.4%	92.4 93.3%

Adverse Events

Time Frame	During or after treatment initiation through study completion (12 months visit).
Adverse Event Reporting Description	Adverse events occurring during the study were continuously monitored and collected. The following adverse events were collected starting at the time subjects signed the Informed Consent Form through the duration of the subject's participation in the study: All procedure related AEs All cryoablation system related AEs All AAD related AEs All cardiovascular related AEs All Serious Adverse Events (SAEs), regardless of relatedness
Arm/Group Title	Randomized and Treated With Cryoablation		Randomized and Treated With Antiarrhythmic Drugs
Arm/Group Description	Subjects Treated with Cryoballoon Catheter Ablation as Randomized.		Subjects Treated with Antiarrhythmic Drug Initiation as Randomized
All Cause Mortality
	Randomized and Treated With Cryoablation		Randomized and Treated With Antiarrhythmic Drugs
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/104 (0%)		0/99 (0%)
Serious Adverse Events
	Randomized and Treated With Cryoablation		Randomized and Treated With Antiarrhythmic Drugs
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	16/104 (15.4%)		14/99 (14.1%)
Cardiac disorders
Acute myocardial infarction	1/104 (1%)	2	0/99 (0%)	0
Angina unstable	0/104 (0%)	0	1/99 (1%)	1
Atrial fibrillation	2/104 (1.9%)	3	1/99 (1%)	1
Bradycardia	0/104 (0%)	0	1/99 (1%)	1
Cardiac sarcoidosis	1/104 (1%)	1	0/99 (0%)	0
Palpitations	0/104 (0%)	0	1/99 (1%)	1
Pericardial effusion	1/104 (1%)	1	0/99 (0%)	0
Pericarditis	0/104 (0%)	0	1/99 (1%)	1
Ventricular tachyarrhythmia	1/104 (1%)	1	0/99 (0%)	0
General disorders
Chest pain	1/104 (1%)	1	1/99 (1%)	1
Stenosis	0/104 (0%)	0	1/99 (1%)	1
Infections and infestations
Appendicitis	1/104 (1%)	1	0/99 (0%)	0
Influenza	0/104 (0%)	0	1/99 (1%)	1
Investigations
Heart rate increased	1/104 (1%)	1	0/99 (0%)	0
Metabolism and nutrition disorders
Fluid overload	0/104 (0%)	0	1/99 (1%)	1
Obesity	1/104 (1%)	1	0/99 (0%)	0
Musculoskeletal and connective tissue disorders
Muscle haemorrhage	1/104 (1%)	1	0/99 (0%)	0
Osteoarthritis	2/104 (1.9%)	2	1/99 (1%)	1
Rotator cuff syndrome	0/104 (0%)	0	1/99 (1%)	1
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Hepatic cyst	1/104 (1%)	1	0/99 (0%)	0
Breast cancer	1/104 (1%)	1	0/99 (0%)	0
Nervous system disorders
Encephalopathy	1/104 (1%)	1	0/99 (0%)	0
Migraine	1/104 (1%)	1	0/99 (0%)	0
Syncope	0/104 (0%)	0	2/99 (2%)	2
Renal and urinary disorders
Nephrolithiasis	1/104 (1%)	1	0/99 (0%)	0
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease	0/104 (0%)	0	1/99 (1%)	1
Non-cardiac chest pain	1/104 (1%)	1	0/99 (0%)	0
Pulmonary embolism	0/104 (0%)	0	1/99 (1%)	1
Vascular disorders
Hypertension	1/104 (1%)	1	0/99 (0%)	0
Hypotension	1/104 (1%)	1	0/99 (0%)	0
Presyncope	0/104 (0%)	0	1/99 (1%)	1
Other (Not Including Serious) Adverse Events
	Randomized and Treated With Cryoablation		Randomized and Treated With Antiarrhythmic Drugs
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/104 (7.7%)		16/99 (16.2%)
Cardiac disorders
Atrial fibrillation	8/104 (7.7%)	12	16/99 (16.2%)	20

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.