Cryoballoon Ablation Versus Medical Therapy in Patients With Atrial Fibrillation and Heart Failure With Different Ejection Fraction Categories
Conditions: Cardiovascular Diseases
Sponsor: Affiliated Hospital of Nantong University

                                  Version: 2.0                   Date: March 8, 2022 
Study Protocol and Statistical Analysis Plan 
 
Cryoballoon Ablation Versus Medical Therapy in Patients 
with Atrial Fibrillation and Heart Failure with Different 
Ejection Fraction Categories 
 
1. Study objective 
This study is to assess the effectiveness and safety of cryoballoon ablation comparing 
with medical therapy in patients with atrial fibrillation and heart failure with different 
ejection fraction categories 
 
2. Study Design 
Study Type 
Interventional (Clinical Trial) 
Estimated Enrollment: 
200 participants 
Allocation: 
No-Randomized 
Intervention Model: 
Parallel Assignment 
Primary Purpose: 
Treatment 
Estimated Study Start Date: 
May 1,2022 
Estimated Primary Completion Date: 
December 31, 2023 
Estimated Study Completion Date: 
June 1, 2024 
 
3. Study subjects 
Subjects with atrial fibrillation and heart failure with different ejection fraction 
categories are divided to either an anti-arrhythmic drug or cryoballoon catheter 
pulmonary vein isolation. 
(1) Medical treatment group：receive class I or class III AAD to restore or maintain 
sinus rhythm; Antiarrhythmic drug including Propafenone, Sotalol, Dronedarone and 

                                  Version: 2.0                   Date: March 8, 2022 
Amiodarone;  
(2) Experimental: cryoballoon ablation group receive cryoballoon ablation to restore 
sinus rhythm; Pulmonary vein isolation by cryoballoon ablation using Medtronic Arctic 
Front Advance™ Cardiac CryoAblation Catheters (23mm and 28mm); 
 
4.  Eligibility Criteria 
➢ Inclusion Criteria: 
(1) Diagnosed with symptomatic paroxysmal or persistent atrial fibrillation：defined 
as at least two symptomatic episodes in the last six months prior to enrollment. 
(2) At least 18 years old and not older than 80 years old. 
(3) Able and willing to give informed consent. 
➢ Exclusion Criteria: 
(1) History of AF treatment with class I or III AAD, 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; 
(2) Previous left atrial ablation; 
(3) Previous cardiac surgery including prosthetic valves; 
(4) Permanent pacemaker or defibrillator implant; 
(5) Second degree type II or third-degree AV-block or a pattern of left/right bundle 
branch block; 
(6) History of previous myocardial infarction or percutaneous intervention during the 
last 3 months; 
(7) Any history of previous transient ischemic attack, prolonged reversible ischemic 
neurological deficit, and/or stroke; 
(8) Known intracardiac thrombus formation; 
(9) Pulmonary vein stent; 
(10) Known cryoglobulinaemia; 
(11) Active systemic infection; 
(12) Hypertrophic cardiomyopathy; 
(13) Life expectancy is ≤1 year; 
(14) Reversible cause of atrial fibrillation (eg, hyperthyroidism or alcoholism); 
(15) Abnormal long or short QT intervals, signs of Brugada syndrome, known family 
history of inherited ion channel disease, and/or arrhythmogenic right ventricular 
dysplasia; 

                                  Version: 2.0                   Date: March 8, 2022 
(16) Chronic obstructive pulmonary disease with detected pulmonary hypertension 
and/or any other evidence of significant lung disease; 
(17) Contraindication for oral anticoagulation; 
(18) Pregnant women or woman of childbearing potential with inadequate birth 
control; 
(19) Women who are breastfeeding; 
(20) Any significant congenital heart defect corrected or not corrected; however, 
patent foramen ovale is allowed; 
(21) Thrombocytosis (platelet count＞600,000 /μL) or thrombocytopenia (platelet 
count＜100,000 /μL); 
(22) Untreated or uncontrolled hyperthyroidism or hypothyroidism; 
(23) Renal dysfunction with glomerular filtration rate ＜60 mL/min; 
(24) Unstable angina pectoris; 
(25) Symptomatic carotid stenosis; 
(26) Myxoma based on laboratory abnormalities; 
(27) Sarcoidosis; 
(28) Unwilling to unable to comply with the study procedure and follow-up schedule 
due to any disease condition; 
(29) Legal incapacity or evidence that the patient cannot understand the purpose and 
risks of the study, including inability to comply fully with study procedures and 
follow-up; 
(30) Employed by Medtronic, or the department of an investigator, or close-familial 
relative of an investigator; 
(31) Enrolled or planning to participate in a potentially confounding drug or device 
trial during this study. 
 
5. Study Process 
5.1 Medical treatment group 
Patients admitted to the medical treatment group after screening could receive 
electrocardiography and receive class I or class III AAD to restore or maintain sinus 
rhythm. The survey included variables that concern the baseline characteristics of 
patients, including risk factors, clinical history, cardiac diagnosis, electrocardiogram, 
echocardiography, laboratory blood tests, and treatments. All patients were 
symptomatic (functional NYHA class II–IV) and were treated according to 
contemporary clinical guidelines.  

                                  Version: 2.0                   Date: March 8, 2022 
 
5.2 Cryoballoon ablation group 
➢ Pre-procedure  
In addition to survey contents for medical treatment group, the Transesophageal 
echocardiography (TEE) was performed in all patients prior to the procedure. The 
echocardiographic parameters include left ventricular ejection fraction (LVEF), peak 
early trans-mitral inflow velocity/peak late mitral inflow velocity ratio (E/A), left atrial 
diameter (LAD), LV end-diastolic diameter (LVEDD), and LV mass. All recordings 
were performed and analyzed by the same investigator. In patients on vitamin K 
antagonists, anticoagulation was continued throughout the procedure, aiming at an 
international normalized ratio (INR) of 2-3. In patients treated with novel oral 
anticoagulants (NOACs), the drug was discontinued 12-24 hour prior to the procedure 
and re-initiated 6-hour post-ablation at half the regular dose, and then at full dose on 
the following day. 
 
➢ Procedure  
All procedures were performed under deep sedation using midazolam, fentanyl, 
and propofol. A single trans-septal puncture was performed via the right femoral vein 
under fluoroscopic guidance. Heparin was administered after trans-septal puncture to 
maintain an activated clotting time ranging from 250 - 350s. In order to identify all PV 
ostia, selective PV angiography was performed. The second-generation 28-mm CB was 
advanced into the LA via the 12Fr steerable sheath and a spiral mapping catheter (20-
mm diameter; Achieve, Medtronic, Inc.) was advanced into the target PV to record 
electrical activity. In patients demonstrating AF at the time of the procedure, electrical 
cardioversion was performed after the final freeze-cycle and PVI was reconfirmed in 
SR. Phrenic nerve capture was monitored by intermittent fluoroscopy and by tactile 
feedback of diaphragmatic contraction by the operator’s hand positioned on the 
patient’s abdomen. The procedure-related complications such as bleeding, phrenic 
nerve palsy (PNP), cerebral embolism, pericardial effusion/ tamponade or 
atrioesophageal fistula were evaluated. 

                                  Version: 2.0                   Date: March 8, 2022 
  
➢ Post-procedure  
Following ablation, low-molecular-weight heparin was administered to patients on 
vitamin K antagonists and an INR <2.0 until a therapeutic INR of 2–3 was achieved. 
NOACs were re-initiated 6 h post-ablation. Anticoagulation was recommended for at 
least 3 months and thereafter according to the individual CHA2DS2-VASc scores. 
Previously ineffective antiarrhythmic drugs were continued for 3 months post-ablation. 
All patients were treated with proton-pump inhibitors for 6 weeks. All patients were 
treated with optimal medical treatment according to the latest guidelines. 
Post-ablation, all patients had in-office Follow-up visit at discharge. A subset of 
patients reconsented for 1, 3, 6, and 12-month follow-up visits. On follow-up visits 
physical examination was performed, a 12-lead electrocardio gram (ECG) and 24-h 
Holter monitor were recorded, and medication changes were documented. In addition, 
regular telephone interviews were performed. Additional outpatient clinic visits were 
immediately initiated in cases of symptoms suggestive of recurrent arrhythmia. Repeat 
ablation was offered to the patient in cases of symptomatic AF/AT recurrence after the 
blanking period or symptomatic drug-refractory recurrent AF/AT within the blanking 
period that could not be managed without intervention. Furthermore, LVEF and the 
NYHA score were systematically evaluated at follow-up on TTE.  
 
6. Outcome Measures 
➢ Primary Outcome Measures: 
(1) Treatment success at one year 
Treatment success at 12 months after antiarrhythmic drug (AAD) initiation or 
ablation utilizing cryoballoon catheter measured by freedom from AF recurrence 
following a 3-month period after the index ablation or AAD initiation. 
The primary outcome was time to first documented recurrence of symptomatic or 
asymptomatic atrial tachyarrhythmia (AF, atrial flutter, or atrial tachycardia) 
(2) Rate of serious adverse events 

                                  Version: 2.0                   Date: March 8, 2022 
Rate of complications and adverse events occurred during cryoballoon ablation 
and postoperative follow-up, including procedure-related complications such as 
bleeding, phrenic nerve palsy (PNP), cerebral embolism, pericardial effusion/ 
tamponade, atrioesophageal fistula, and all-cause mortality, re- hospitalization for HF, 
and the composite event of all-cause mortality or HF hospitalization. 
 
➢ Secondary Outcome Measures 
(1) Quality of life changes at 12 months measured by AF Quality of Life Survey 
(AFEQT)  
The improvement in quality of life between baseline and 12 months after the index 
ablation procedure or AAD measured by AFEQT is evaluated. 
(2) Quality of life changes at 12 months measured by 12-Item Short Form Survey (SF-
12)  
The improvement in quality of life between baseline and 12 months after the index 
ablation procedure or AAD measured by SF-12 is evaluated. 
(3) Arrhythmia recurrence during blanking period (Time Frame: 3 months) 
Atrial tachycardia recurrence rate during the blanking period is evaluated. 
 
7. Statistical analysis 
(1) All statistical analyses were performed using SPSS version 22.0 software (SPSS, 
Chicago, IL, USA).  
(2) All continuous variables were recorded as mean ± standard deviation (SD). 
Categorical variables were presented as numbers or percentages. Between-group 
comparisons were performed using t-test, Mann–Whitney test, or Chi-square test. 
Fisher’s exact test was used when the observed value in any of the 2×2 contingency 
table cells was <5. Continuous variables were compared among groups using one-way 
analysis of variance or Kruskal–Wallis test.  
(3) The effect of variables on the EF value was analyzed by univariate and multivariate 
logistic regression analyses. Baseline clinical features, medical history, and clinical and 

                                  Version: 2.0                   Date: March 8, 2022 
laboratory parameters on admission were considered as candidate variables in the 
multivariate analysis.  
(4) The association between the EF group and the outcomes was assessed using 
univariable and multivariable Cox analyses. Variables of relevant clinical interest 
considered as covariates were included in the multivariable model to identify the 
predictors for adverse outcomes according to EF category.  
(5)A 2-sided p value less than 0.05 was considered as statistically significant.