A New Operation (Left Atrial Geometric Volume Reduction, Pulmonary Vein Island Isolation and Left Appendage Base Closure) for the Treatment of Long Standing Persistent Atrial Fibrillation (AF) During Mitral Valve Surgery
Phase: NA
Conditions: Cardiovascular Disease
Sponsor: Fujian Medical University

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A New Operation (Left Atrial Geometric Volume Reduction, 
Pulmonary Vein Island Isolation and Left Appendage Base 
Closure) for the Treatment of Long Standing Persistent Atrial 
Fibrillation (AF) During Mitral Valve Surgery 
 
 
NCT number: NCT03347695 
 
 
 
 
 
 
 
Ethical committee approval: 
The study was approved by research ethical committee in Fujian Medical 
University Union Hospital (Protocol NO. CLW2017AF). 
Document date: August 2018 
 
 
 

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Table of contents 
1. Abbreviations 
2. Study summary 
3. Background 
4. Objectives 
5. Study design  
6. Study population 
7. Interventions 
8. Endpoints 
9. Data collection 
10. Data management 
11. Quality control and quality assurance 
12. Analytical plan 
13. Specific adverse event definitions 
 
 
 

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1. ABBREVIATIONS 
 
Atrial Fibrillation      AF 
Mitral Valvular Surgery      MVS 
Radiofrequency ablation      RFA 
Transthoracic Doppler Echocardiography      TDE 
Electrocardiogram      ECG 
 

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2. STUDY SUMMARY 
Title  
A New Operation (Left Atrial Geometric Volume Reduction, 
Pulmonary Vein Island Isolation and Left Appendage Base Closure) 
for the Treatment of Long Standing Persistent Atrial Fibrillation 
(AF) During Mitral Valve Surgery 
Objectives 
Phase I: To examine the feasibility of our new operation (left atrial 
geometric volume reduction, pulmonary vein island isolation and 
left appendage base closure) based on a new concept for AF 
elimination 
 
Phase II: To assess the safety and efficacy of the new operation for 
the treatment of long-standing persistent AF during mitral valve 
surgery 
Protocol 
Number  
NCT 03347695 
Study 
Design  
Phase I: Prospective, single-arm pilot study 
Phase II: Prospective, single-arm clinical trial 
Study 
Duration  
3 years, (Phase I:  from 2017 to 2018; Phase II:  from 2018 to 2020) 
Study 
Center  
Fujian Medical University Union Hospital 
Study 
Population  
Adult patients with long-standing persistent AF had clinical 
indications for mitral valvular surgery (MVS) 
Sample Size 
The study will enroll a maximum of 140 patients.  
Phase I:  20 patients with longstanding persistent AF.  
Phase II: 120 patients with longstanding persistent AF. 
Intervention 
Evaluation: Transthoracic 2-dimensional echocardiography and 
Holter 
 
Operation: new operation (left atrial geometric volume reduction, 
pulmonary vein island isolation and left appendage base closure) 
 
Routine 
postoperative 
management: 
receiving 
amiodarone 
beginning within 24 hours post-operation until the 3-month point.  
 
Primary 
endpoints 
Efficacy: freedom from AF at both 6 months and 12 months after 
surgery, assessed by 7-days continuous Holter monitoring. 
 
Safety: cardiopulmonary bypass time; and a composite of death, 
stroke, serious cardiac events (heart failure, myocardial infarction), 
cardiac re-hospitalizations, transient ischemic attack, pulmonary 
embolism, peripheral embolism, coronary artery injury, anatomical 
excessive bleeding, deep sternal wound infection/mediastinitis, 
damage to specialized conduction system requiring permanent 
pacemaker, and superior vena cava stenosis, within 30 days after the 
procedure or hospital discharge (whichever was later) 
Secondary 
endpoints 
Efficacy: The left atrial linear dimensions and A wave reappearance 
measured by transthoracic echocardiography at 3 time points 
(before surgery, 6 and 12 months after surgery).  

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Safety: Major adverse cardiac events, which were defined as a non-
weighted composite score of: death, stroke, worsening heart failure 
(+1 NYHA Class), hospitalization for heart failure, and mitral valve 
re-intervention within 12 months after surgery; and incidence of 
protocol-defined 
serious 
adverse 
events 
(especially 
thromboembolic and hemorrhagic events) within 12 months after 
surgery. 
Follow-up 
Schedule 
Pre-discharge, and at 30 days, 3, 6, and 12 months after surgery. 
 

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3. BACKGROUND 
Atrial fibrillation (AF) often occurs in patients with valvular disease, especially in those 
with mitral valve disease, leading to an elevated mortality.1 Though valvular 
replacement and plasty are the effective methods to treat valve disease, valvular 
procedure alone is not enough to cure AF.2,3 AF can cause thromboembolism and stroke 
in approximately 5 -10% of high-risk patients, the risk of which increases with age and 
the coexistence of structural heart disease.3-5  
  The cut-and-sew Cox-Maze III operation, developed in 1989, has been regarded as the 
golden standard surgery for AF elimination.6 In this surgical procedure, the atrial wall 
is divided into small areas to electrically isolate from each other, which is then not large 
enough to sustain the macro-reentry circuits. While it has not been widely used because 
it is complex and time-consuming, and the incisions are risky in both atria. Another 
procedure, known as Cox-Maze IV, was then developed and broadly accepted as the 
preferred technique for AF elimination, in which the classic cut and sew lesions are 
replaced with ablative lines using various energy sources. However, completion of so 
many ablative lines is still time-consuming.5  
  AF is always accompanied with an enlarged left atrium. Volume reduction of the 
enlarged atrium can decrease operative morbidity and incidence of AF recurrence after 
simultaneous mitral and AF surgery.7 Unfortunately, the additional left atrial volume 
reduction was rarely performed because it will further prolong the aortic cross-clamp 
time. In both analogous Cox-Maze III and IV, the division of the entire intact atria into 
small areas has been proven to negatively affect the restoration of atrial transport 
function after appearance of sinus rhythm.8-10 Therefore, it is desirable to develop a 
simple AF elimination technique which will benefit both atrial appropriate volume 
restoration and transport function reappearance.  
  In a cross-sectional study, we found the left atrial spatial enlargement and the fibrosis 
regional distribution were not uniform. We thus proposed a new concept that 
reconstructing a new left atrium with appropriate size and shape and a uniform fibrosis 
distribution for conduction is effective for AF elimination. Based on this concept, a new 
procedure (left atrial geometric volume reduction, pulmonary veins island isolation and 
left appendage base closure), was developed to render left atrium appropriate geometry 
and achieve uniform fibrosis distribution. Therefore, we conduct this proof-of-concept 
study to determine the feasibility, efficacy and safety of the new procedure. 

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4. OBJECTIVES 
Primary objective 
The primary objective is to assess the efficacy and safety of the new procedure (left 
atrial geometric volume reduction, pulmonary veins island isolation and left appendage 
base closure) for treating long standing persistent AF elimination. Efficacy will be 
evaluated by freedom from AF within 6 months and 12 months after surgery. Safety 
will be assessed by a composite of early adverse outcomes (within 30 days post-
procedure or hospital discharge, whichever is later), including death, stroke, serious 
cardiac events (heart failure, myocardial infarction), cardiac re-hospitalizations, 
transient ischemic attack, pulmonary embolism, peripheral embolism, coronary artery 
injury, anatomical excessive bleeding, deep sternal wound infection/mediastinitis, 
damage to specialized conduction system requiring permanent pacemaker, and superior 
vena cava stenosis. We hypothesize that the new procedure will reduce the risk of AF 
post-MVS reoccurrence and lower the incidence of adverse outcomes, as compared to 
that was historically reported in patients undergoing MVS concomitantly with COX 
MAZE IV.  
 
Secondary objectives 
(a) To assess the incidence of major adverse cardiac events and protocol-defined and 
serious adverse events (especially thromboembolic and hemorrhagic events) within 12 
months after surgery, which is hypothesized to be lower than MVS concomitantly with 
COX MAZE IV. 
(b) To assess the intra-operation cardiopulmonary bypass time(CPB), which if 
prolonged could increase risk of poor prognosis within 30 days post-procedure or 
hospital discharge. CPB time is hypothesized to be shorter than that historically 
reported in COX MAZE IV procedure. 
(c) To assess the changes of size and shape of left atrium. The post-surgical shape and 
size of left atrium is hypothesized to be closer to normal status. 
(d) To assess the function of left atrium. The incidence of peak late trans-mitral flow 
velocity (A) at 12 months post-surgery is supposed to be high. 

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5. STUDY DESIGN 
This is a prospective, single-arm objective performance criteria study, consisting of two 
phases.  
Phase I: A single-arm pilot study, 20 patients will be enrolled to test the feasibility of 
the procedure. 
Phase II: A single-arm clinical trial, 120 patients will be enrolled to determine the safety 
and efficacy of the procedure. 
Total study period is expected to take 40 months, and all patients will be followed for 
12 months after surgery.  
 

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6. STUDY POPULATION 
Recruitment  
Patients admitted to our center will be enrolled in this study. Based on the average 
hospitalization admissions in our center, it is estimated that approximately 50 patients 
could be enrolled annually.  
 
Characterization of Patient Population 
The patient population for the pilot study is adult patients with both longstanding 
persistent AF and mitral valve disease requiring surgical intervention. Longstanding 
persistent AF is defined as continuous AF of greater than one year duration. This 
definition applies only to AF episodes that are of at least 30 seconds’ duration and do 
not have a reversible cause such as acute pulmonary disease or hyperthyroidism. All 
patients who meet the eligibility criteria will be included in the study regardless of 
gender, race or ethnicity. 
 
Phase I 
Inclusion Criteria 
1. Able to sign Informed Consent and Release of Medical Information forms 
2. Age ≥ 18 years and ≤ 60 years old 
3. Clinical indications for only mitral valve surgery for the following: 
  Organic mitral valve disease without other cardiac disorders (functional or structural).  
4. Longstanding persistent AF is defined as continuous AF of greater than one year 
duration. 
  Duration of AF must be documented by medical history and 
  Presence of AF must be documented by a direct electrocardiographic assessment upon 
arrival in the clinic. 
5. Able to use heart rhythm monitor 
6. Anteroposterior diameter of left atrial between 45mm and 60mm  
7. Without history of stroke. 
Exclusion Criteria 
1. AF without indication for mitral valve surgery; or 
2. Ischemic mitral regurgitation with evidence of concomitant structural mitral valve 
disease; or 

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3. Functional tricuspid regurgitation; or 
4. AF is only or paroxysmal persistent; or 
5. Evidence of active infection; or 
6. Mental impairment or other conditions that may not allow patient to understand 
the nature, significance, and scope of study; or 
7. Surgical management of hypertrophic obstructive cardiomyopathy; or 
8. Previous catheter ablation for AF; or 
9. Life expectancy of less than one year; or 
10. Absolute contraindications for anticoagulation therapy; or 
11. Enrollment in concomitant drug or device trials; or 
12. Uncontrolled hypo- or hyperthyroidism; or 
13. FEV1 < 30% of predicted value; or 
14. Women who are pregnant as evidenced by positive pregnancy test; or 
15. Women of childbearing age who do not agree to be on adequate birth control 
throughout the period of the trial; or 
16. Diagnosed with infective endocarditis; or 
17. Need emergency surgery. 
Phase II 
Inclusion Criteria 
1. Able to sign Informed Consent and Release of Medical Information forms 
2. Age ≥ 18 years 
3. Clinical indications for mitral valve surgery for the following: 
  Organic mitral valve disease; or 
  Functional non-ischemic mitral regurgitation; or 
  Ischemic mitral regurgitation with evidence of concomitant structural mitral valve 
disease. 
Note: May include need for surgical management of functional tricuspid regurgitation 
or patent foramen ovale. May also include concomitant CABG, aortic arch or aortic 
valve procedure. Surgical intervention may be performed via sternotomy or minimally 
invasive procedure. 
4. Longstanding persistent AF is defined as continuous AF of greater than one year 
duration. 
  Duration of AF must be documented by medical history and 

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  Presence of AF must be documented by a direct electrocardiographic assessment upon 
arrival in the clinic. 
5. Able to use heart rhythm monitor 
 
Exclusion Criteria 
1. AF without indication for mitral valve surgery; or 
2. AF is only or paroxysmal persistent; or 
3. Evidence of active infection; or 
4. Mental impairment or other conditions that may not allow patient to understand 
the nature, significance, and scope of study; or 
5. Surgical management of hypertrophic obstructive cardiomyopathy; or 
6. Previous catheter ablation for AF; or 
7. Life expectancy of less than one year; or 
8. Absolute contraindications for anticoagulation therapy; or 
9. Enrollment in concomitant drug or device trials; or 
10. Uncontrolled hypo- or hyperthyroidism; or 
11. Women who are pregnant as evidenced by positive pregnancy test; or 
12. Women of childbearing age who do not agree to be on adequate birth control 
throughout the period of the trial; or 
13. Diagnosed with infective endocarditis; or 
14. Need emergency surgery. 
 

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7. INTERVENTIONS 
The new procedure 
All patients will have their left atrial geometric volume reduced, pulmonary vein island 
isolated and left appendage ligated or suture closed. After the superior vena cava was 
transected, two circular incisions were usually made in the left atrial wall between the 
pulmonary veins and the mitral annulus for circumferential atrial strip resection and 
pulmonary vein island isolation. The first circular incision was performed around the 
pulmonary veins. With this incision, pulmonary vein island was isolated and the left 
atrium was opened. The second one was performed in the interatrial groove and 
extended around the mitral annulus, leaving a 2 cm inferior wall margin from the 
annulus and the appendage in situ. With those two incisions, a circumferential strip of 
the left atrium was excised. Then the base of the left atrial appendage was ligated or 
excised and sutured. After the mitral manipulations, the center of the pulmonary vein 
island was longitudinally reef-imbricated with a 3-0 polypropylene continuous running 
suture to exclude toward the outside of the left atrial cavity. This plicated pulmonary 
vein island was directly anastomosed to the resected margin around the mitral annulus 
and the intraatrial septum instead of the interatrial groove. Finally, caval continuity was 
restored after aortic cross-clamp removal using a running 4-0 polypropylene suture.  
Mitral Valve Surgery 
For mitral regurgitation, the procedures will be a valve repair in the majority of cases. 
For valves that are not amenable to repair, and for most cases of mitral stenosis, a valve 
replacement will be performed. And the cardiopulmonary bypass time will be recorded. 
Transthoracic Doppler Echocardiography 
Transthoracic Doppler Echocardiography(TDE) will be used to measure left atrial size 
and volumes, quantify mitral valve function, detect intracardiac thrombi, and to assess 
left atrial and left ventricular function. TDE will be used to measure LA size as well as 
diameters in LA. 
Electrocardiogram (ECG) 
An ECG will be done upon arrival in the operating room. This tracing will be used to 
assess heart rhythm on all patients and provide part of the documentation needed to 
establish the diagnosis of longstanding persistent AF. 
Postoperative management 
Standardization of Anti-arrhythmic Drug Use during Follow-up 

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Unless contraindicated (hypotension or bradycardia defined as heart rate less than 60 
beats per minute), all patients will receive prophylactic amiodarone beginning within 
24 hours post-operation. Patients will be discharged on the anti-arrhythmic agent. At 
the 3-month point, antiarrhythmic agents will be terminated in all patients and this 
recommendation communicated by study personnel to the managing physician. Direct 
current cardioversion will be performed as clinically indicated by managing physicians 
and recorded by study personnel for the duration of follow-up.  
 
Anticoagulation 
Unless specifically contraindicated, warfarin will be prescribed for all patients at 
hospital discharge, with a target INR of 2.0-2.5. It is recommended that warfarin be 
continued in patients for the entire duration of the study if in mechanical valve 
replacement status or AF was detected at follow-up time points. 

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8. ENDPOINTS 
Primary Endpoints 
Efficacy 
Freedom from AF in patients with longstanding persistent AF undergoing MVS at 6 
months and 12 months. AF will be measured by 7 days continuous Holter monitoring 
at 6 months and 12 months post-surgery; and freedom of AF will be defined by absence 
of AF lasting > 30 seconds at 12 months.  
Patients will be considered as treatment failures (not free of AF) if: 1) they die prior to 
the 12-month assessment; 2) or they are determined by an independent adjudicator to 
be too ill to undergo AF assessment; 3) or they require additional ablation therapy for 
AF (including surgical ablation or percutaneous catheter ablation) subsequent to the 
index procedure. 
Safety 
(a)Cardiopulmonary bypass time, which if prolonged could increase risk of poor 
prognosis within 30 days post-procedure or hospital discharge; 
(b)The adverse events within 30 days after surgery, including: death, stroke, serious 
cardiac events (heart failure, myocardial infarction), cardiac re-hospitalizations, 
transient ischemic attack, pulmonary embolism, peripheral embolism, coronary artery 
injury, anatomical excessive bleeding, deep sternal wound infection/mediastinitis, 
damage to specialized conduction system requiring permanent pacemaker, and superior 
vena cava stenosis. 
 
Secondary Endpoints 
Efficacy 
(a)The changes of size and shape of left atrium, which will be measured by comparing 
the anteroposterior, transversal, and superoinferior diameters of left atrium between 3 
time points (i.e., before surgery, 6 months and 12 months post-surgery) by using 
transthoracic echocardiography. 
(b)The peak late trans-mitral flow velocity (A) at 6 months and 12 months post-surgery, 
which will be measured by transthoracic echocardiography. 
Safety 
(a)MACEs within 12 months after surgery: defined as a non-weighted composite score 

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of: death, stroke, worsening heart failure (+1 NYHA Class), CHF hospitalization, and 
mitral valve [MV] re-intervention. 
(b)Protocol-defined and serious cerebrovascular adverse events (especially 
thromboembolic and hemorrhagic events) within 12 months after surgery. 
(c)All-cause mortality at 12 months after surgery. 
 
 

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9. DATA COLLECTION 
Data collected at hospital admission 
Demographics  
A screened patient is defined as an individual (a consented patient) who was referred 
to, or identified at a clinical site for consideration of entry into the study, and for whom 
some preliminary (i.e. medical record) data have been collected and/or reviewed. For 
all patients screened, the first, middle, and last initial, date of birth, ethnic origin, and 
sex will be captured on the screening log and registration form. The EDC will generate 
a unique 8-digit identification code that will identify the patient throughout the course 
of the study. 
Medical History 
Within 30 days prior to surgery 
This form captures the information pertaining to the medical history, including but not 
limited to previous myocardial infarction, myocardial revascularization, arrhythmias, 
automatic implantable cardioverter-defibrillator, permanent right ventricular or 
biventricular pacemaker, stroke and other comorbidities such as diabetes and peripheral 
vascular disease. Information regarding the current medical condition is also captured, 
including but not limited to disposition at time of screening (outpatient, inpatient, ICU 
monitoring, etc) and intra-aortic balloon pump use. 
Medications 
Within 30 days prior to surgery 
This form captures all protocol-defined medications taken within 7 days prior to surgery. 
Physical Examination 
Within 30 days prior to surgery 
This form captures the comprehensive physical examination including vital signs 
cardiopulmonary examination, abdominal examination, and anthropometrics (height, 
weight and BSA). 
Laboratory Assessment 
Within 30 days prior to randomization 
• White blood cell (103/μL) 
• Hemoglobin (g/dL) 
• Hematocrit (%) 
• Platelet count (10 3/μL) 

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• Prothrombin time (PT/sec), partial thromboplastin time (PTT/sec) 
• International Normalized Ratio (INR) 
• Blood chemistries, including sodium (mM/L), potassium (mM/L), blood urea 
nitrogen (mg/dL), creatinine (mg/dL). 
• Liver function tests, including total bilirubin (mg/dL), alanine aminotransferase 
(ALT U/L), aspartate aminotransferase AST (U/L), albumin (g/dL), lactate 
dehydrogenase (LDH). 
• Urine or serum beta HCG (IU/L) is required for women who have the potential 
to 
• become pregnant 
Cardiovascular Rhythm Assessment 
Prior to surgery 
Physicians must document in the Medical History Form the timing and duration of AF. 
An ECG or other direct assessment of heart rhythm will be obtained within 1 year prior 
to document the presence of long-standing persistent AF. All long-standing persistent 
AF patients will undergo an ECG upon arrival in the operating room (OR).Furthermore, 
there will be a baseline transthoracic Doppler echocardiogram performed within 3 
months prior to surgery.  
 
Data collected during hospitalization 
Informed consent  
A detailed explanation of the risks and benefits of the study will be outlined by the 
investigator to each patient or their legally authorized representative before any 
preoperative assessments that are not part of the routine preparation and they will be 
asked to sign a consent form. 
Surgical Procedures 
Initial surgical intervention and event driven  
Includes information regarding specific primary procedure, operative variables, lesion 
sets created, additional procedures performed at time of initial operation, intra-
operative 
pharmacological 
agents, 
intra-operative 
blood 
transfusions, 
the 
cardiopulmonary bypass time.  
Medications 

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All cardiovascular medications are recorded, including amiodarone given 
prophylactically since surgery. 
Physical Examination (including vital signs and cardiopulmonary examination) 
Electrocardiogram (12-lead ECG) 
Adverse Events 
Detailed information regarding adverse events is recorded at the time an event occurs 
during hospitalization. Investigators are asked to make a judgment as to the seriousness 
and relationship of the event to the surgical intervention.  
Patient Discharge 
Patients clinically stable for discharge may be discharged to an affiliated rehabilitation 
center, intermediate care center, long-term care facility, step-down facility or home.  
 
Data collected at follow-up  
Follow-up visits will be conducted at 30 days, 3 months, 6 months and 12 months after 
surgery (±30 days) after surgery provided that the patient is still alive. The following 
assessments are scheduled at each visit: 
Transthoracic Doppler Echocardiogram 
All patients will undergo follow-up transthoracic Doppler echocardiography at the 
investigative center*. Transthoracic Doppler echocardiography will be used to measure 
LA function (a) atrial filling, (b) LA ejection fraction, (c) atrial systolic mitral annular 
velocity (TDI). MV function, mitral regurgitation and LV function will be measured. 
24-hour Holter Monitoring 
The 24-hour holter monitoring provided to patients will be used for this assessment. 
Medications 
All cardiovascular, inotropic, antiplatelet agents, and anticoagulants will be recorded. 
Medications (including AADs) will be recorded at the study visit, and also as indicated 
at the time of associated adverse events. Response to DC cardioversions (success or 
failure) will also be recorded. 
Functional Status 
NYHA classification will be determined by a coordinator or physician not otherwise 
involved in this trial and blinded to the treatment assignment. The NYHA class will be 
documented on the “New York Heart Association Classification” form. 
Adverse Events, Anti-arrhythmic Interventions, and Hospitalizations 

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Patients will be asked to recall any adverse events (including stroke and bleeding) and 
the number of hospitalizations that occurred out of network since the last contact. 
Patients will also be asked if they had a permanent pacemaker insertion, cardioversion 
or subsequent ablation since the last contact. 
 

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10. DATA MANAGEMENT 
Source data 
All source data for this study will be maintained in the Electronic Medical Record 
system, in accordance with hospital regulatory and requirements for the protection of 
confidentiality of patients. The investigator will be responsible to ensure the accuracy 
and completeness of the data reported timely. Incoming data will be double checked to 
detect inconsistent or missing data. All related hard copies will be secured to ensure 
confidentiality. Access to the clinical information will be based on individuals' roles 
and responsibilities. 
Investigator Records 
Investigators will maintain complete and accurate records of this study, which will be 
maintained until two years after the date of the study completeness/termination. The 
following materials will be included in investigator records: 
(a) Correspondence: Documentation of all verbal and written correspondence with 
investigator, the Clinical Monitor, the Clinical Events Committee (CEC), and patients 
enrolled in this study. 
(b) Patient records: Signed informed consent forms and copies of all documents 
(medical records, laboratory reports, reports of diagnostic tests, etc.).  
(c) Clinical Study Protocol: A copy of the Clinical Study Protocol. 
(d) Ethics Committee (EC) Information: All information related to EC review and 
approval of this clinical study. 
(e) Other: Any other records that may be required. 
 

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11. QUALITY CONTROL AND QUALITY ASSURANCE 
Protocol deviations 
A protocol deviation is a failure to comply with the requirements of this clinical study 
protocol. Each investigator shall conduct this clinical study in compliance with this 
clinical study protocol, hospital regulations, ISO guidelines, Good Clinical Practices 
(GCP), and other study requirements. 
The protocol deviations include, but not limited to the following: 
• Failure to obtain patient’s informed consent  
• Failure to meet all of the inclusion/exclusion criteria  
• Failure to conduct follow-ups required by this protocol 
All deviations shall be assessed for the impact by investigators. Continued protocol 
deviations may result in termination of the study. The investigators reserve the right to 
terminate the study at any time.  
Investigator and monitor training 
The investigators and monitors will be trained appropriately to monitor study 
progress.  
Clinical Events Committee (CEC)  
An independent group of physicians that are not involved in the clinical investigations 
will act as the Clinical Events Committee (CEC), which will be responsible for the 
review and validation of reported potential adverse events. The CEC will be. The CEC 
will be developed before the study start and blinded to the study details during the study 
period. This CEC shall include consistent definitions for each type of event and outline 
the review process.   
Data and Safety Monitoring Board 
To meet the study's ethical responsibility to its subjects, an independent data safety 
monitoring board (DSMB) will monitor the progress of the study. The board consists 
of physicians, biostatisticians, ethicists and bioengineers, who have no formal 
involvement or conflict of interest with the participants or the investigators. The DSMB 
will act in a senior advisory capacity regarding data and safety matters and review 
interim summary results of the accumulating data every 6 months. These data include 
adverse events (e.g., infection, bleeding, right heart failure) and mortality.  
 

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12. ANALYTICAL PLAN 
Statistical overview 
The aim of this study is to assess the safety and efficacy of our new operation (left atrial 
geometric volume reduction, pulmonary vein island isolation and left appendage base 
closure) in patients with MV disease and longstanding persistent AF. This study 
included a pilot study and a clinical trial, both of which are prospective, single-arm 
studies with similar statistical analysis plan. 
Sample size 
Sample size is based on previously published data, and on ensuring the ability to detect, 
with high probability, a clinically meaningful presumed benefit for our new operation. 
To date there have been some studies examining effect of COX MAZE IV in treating 
AF in MVS patients. The reported absence of AF one year post MVS with COX MAZE 
IV is about 60%-80%. For computing sample size, according to our pilot study, a 
reasonable proportion of patients free from AF at 1 year, will be assumed.  
As observed in the pilot study that 20/20 (100%) patients free from AF at 6-month 
follow-up, we assume that 90% of patients treated with our new operation will be free 
of AF at 1-year post-surgery. A total of 120 patients enrolled in the clinical trial provides 
80% power to detect an absolute increase of 10% (80% versus 90%) in the proportion 
of patients free of AF, based on a single-tailed 0.025 level continuity corrected chi-
squared test and 10% drop-out rate. (ADDED at August 2018) 
Primary analysis 
The primary outcome of efficacy is freedom from AF over one year post surgery. The 
rate of free of AF will be calculated after finishing 1-year follow-up for 120 patients. 
Patients who die within 12 months will be considered treatment failures (not free of 
AF).  Patients who die prior to the 12-month assessment, or who are determined by an 
independent adjudicator to be too ill to undergo AF measurement, will be considered as 
treatment failures (not free of AF). In the primary analysis, patients who undergo 
ablation therapy for AF (including surgical ablation or percutaneous catheter ablation) 
subsequent to the index procedure will be considered treatment failures (not free of AF).  
The primary safety endpoint of this trial include: 
(a) CPB time will be recorded. 
(b)a composite of death, stroke, serious cardiac events (heart failure, myocardial 
infarction), cardiac re-hospitalizations, transient ischemic attack, pulmonary embolism, 

23 
 
peripheral embolism, coronary artery injury, anatomical excessive bleeding, deep 
sternal wound infection/mediastinitis, damage to specialized conduction system 
requiring permanent pacemaker, and superior vena cava stenosis, within 30 days post-
procedure or hospital discharge (whichever is later). The rate of these safety endpoints 
will be calculated within 30 days after surgery. 
Secondary Analyses 
Efficacy 
(a)The size and shape of left atrium. The anteroposterior, transversal, and superoinferior 
diameters, as well as their ratios, of left atrium between two time points (i.e., before 
surgery and 12 months post-surgery), will be measured by transthoracic 
echocardiography. The absolute change and reduction rate of each diameter will be 
analyzed, and the post-surgery size and shape will be compared with Chinese standards. 
(b)Left ventricular ejection fraction and peak late transmitral flow velocity (A) at 12 
months post-surgery will be measured by transthoracic echocardiography. These 
measurements evaluate the function of heart pump. 
Safety 
(a)Major adverse cardiac events (MACE) defined as a non-weighted composite score 
of: death, stroke, worsening heart failure (+1 NYHA Class), CHF hospitalization, and 
mitral valve [MV] re-intervention within 12 months of surgery. The rate of MACE will 
be calculated and compared with MACE rate historically reported in COX MAZE IV 
procedure. 
(b)Incidence 
of 
protocol-defined 
and 
serious 
adverse 
events 
(especially 
thromboembolic and hemorrhagic events) within 12 months of surgery. The rate of SAE 
will be calculated and compared with MACE rate historically reported in COX MAZE 
IV procedure. 
(c)All-cause mortality at 12 months post-surgery. The Kaplan-Meier curve will be 
plotted to show the probability of death at a respective time interval and compared with 
1-year deaths historically reported in COX MAZE IV procedure. 
 
 

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13. SPECIFIC ADVERSE EVENT DEFINITIONS 
Bleeding 
A bleeding event is defined by any one of the following: 
• Transfusion of > 2 units RBC within the first 24 hours following surgery 
• Death due to hemorrhage 
• Re-operation for hemorrhage or tamponade 
NOTE: Hemorrhagic stroke is considered a neurological event and not as a separate 
bleeding event. 
Cardiac Arrhythmias 
Any documented arrhythmia that results in clinical compromise (e.g., hemodynamic 
compromise, oliguria, pre-syncope or syncope) that requires hospitalization or requires 
a physician visit or occurs during a hospital stay. 
Cardiac arrhythmias are classified as: 
1. Sustained ventricular arrhythmia requiring defibrillation or cardioversion 
2. Sustained supraventricular arrhythmia requiring drug treatment or cardioversion 
3. Cardiac conduction abnormalities requiring permanent pacemaker 
Pericardial Fluid Collection 
Accumulation of fluid or clot in the pericardial space that requires surgical intervention 
or percutaneous catheter drainage. This event will be subdivided into those with clinical 
signs of tamponade (e.g. increased central venous pressure and decreased cardiac output) 
and those without signs of tamponade. 
Pleural Effusion 
Accumulation of fluid or clot in the pleural space documented by chest radiogram or 
chest CT that requires evacuation with surgical intervention or chest tube placement. 
Atrial Rupture 
Disruption in the integrity of the left or right atrial wall, documented by direct 
inspection or diagnostic testing, that necessitates surgical repair. 
Valvular Injury 
Injury to a cardiac valve (excluding the mitral valve), as evidenced by new regurgitation 
or stenosis following the treatment intervention. This definition excludes changes to the 
mitral valve because it will be surgically repaired at the time of the treatment 
intervention. 
Non-infectious Pericarditis 

25 
 
Signs and symptoms of pericardial inflammation, with or without electrocardiographic 
evidence, requiring pharmacologic anti-inflammatory therapy. This definition excludes 
infectious pericarditis (see Major Infection infectious pericarditis definition below). 
Superior vena cava Stenosis 
A ≥ 50% decrease in the diameter of the superior vena cava as documented by 
echocardiography. 
Diaphragmatic Paralysis 
Phrenic nerve injury as evidenced by new elevation of a hemi-diaphragm on chest 
radiogram. 
Pneumothorax 
Presence of gas in the pleural space, documented by chest radiogram or chest CT, that 
requires evacuation or prolongs the duration of chest tube drainage. 
Hepatic Dysfunction 
An increase in any two of the following hepatic laboratory values (total bilirubin, 
aspartate aminotransferase/AST and alanine aminotranferease/ALT) to a level greater 
than three times the upper limit of normal for the hospital, (or if hepatic dysfunction is 
the primary cause of death). 
Major Infection 
A new clinical infection accompanied by pain, fever, drainage and/or leukocytosis that 
is treated by anti-microbial agents (non-prophylactic). A positive culture from the 
infected site or organ should be present unless strong clinical evidence indicates the 
need for treatment despite negative cultures. The general categories of infection are 
listed below: 
Endocarditis 
Signs, symptoms and laboratory findings consistent with endocarditis, including but 
not limited to fever ≥ 38.0o C, positive blood cultures, new regurgitant murmurs or 
heart failure, evidence of embolic events (e.g., focal neurologic impairment, 
glomerulonephritis, renal and splenic infarcts, and septic pulmonary infarcts), and 
peripheral cutaneous or mucocutaneous lesions (e.g., petechiae, conjunctival or splinter 
hemorrhages, Janeway lesions, Osler's nodes, and Roth spots). Echocardiographic 
evidence of a new intra-cardiac vegetation with or without other signs and symptoms 
should be considered adequate evidence to support the diagnosis of endocarditis. TEE 
should be the modality of choice for diagnosis of prosthetic valve endocarditis. 

26 
 
Mediastinitis/Deep Sternal Wound Infection 
Signs and symptoms consistent with mediastinitis, include but are not limited to fever, 
chills, leukocytosis and chest or back pain, and mediastinal inflammation documented 
by diagnostic testing (e.g., chest CT). Information regarding deep sternal wound 
infections will be collected. 
Infectious Pericarditis 
Signs and symptoms, including but not limited to fever, leukocytosis and pericardial 
inflammation, necessitating surgical exploration, drainage and treatment with 
intravenous antibiotics. 
Sepsis 
Evidence of systemic involvement by infection, manifested by positive blood cultures 
and/or hypotension. In addition, we will record systemic antibiotic use for presumptive 
sepsis. 
Localized Infection 
Infection localized to any organ system or region other than the mediastinum, 
pericardium, or endocardium without evidence of systemic involvement (see sepsis 
definition), ascertained by standard clinical methods and either associated with 
evidence of bacterial, viral, fungal or protozoal infection, and/or requiring empirical 
treatment. 
Heart Failure 
New onset of signs or symptoms of congestive heart failure or worsening of preexisting 
heart failure by ≥ 1 NYHA class. 
Myocardial Infarction 
Myocardial infarction (MI) should be classified when there is evidence of myocardial 
necrosis in a clinical setting consistent with myocardial ischemia. 
Under these conditions, any one of the following criteria meets the diagnosis for 
myocardial infarction4: 
Myocardial Infarction 
Detection of rise and/or fall of cardiac biomarkers (preferably troponin) with at least 
one value above the 99th percentile of the upper reference limit (URL) together with 
evidence of myocardial ischemia with at least one of the following:  
• Symptoms of ischemia; 

27 
 
• ECG changes indicative of new ischemia (new ST-T changes or new left bundle 
branch block [LBBB]); 
• Development of pathological Q waves in the ECG; 
• Imaging evidence of new loss of viable myocardium or new regional wall 
motion abnormality. 
Peri-CABG Myocardial Infarction 
For CABG in patients with normal baseline troponin values, elevations of cardiac 
biomarkers above the 99th percentile URL are indicative of peri-procedural myocardial 
necrosis. By convention, increases in biomarkers > 5 x 99th percentile URL plus either 
new pathological Q waves or new LBBB, or angiographically documented new graft 
of native coronary artery occlusion, or imaging evidence of new loss of viable 
myocardium have been designated as defining CABG-related MI. 
Peri-Percutaneous Intervention (PCI) Myocardial Infarction 
For PCI in patients with normal baseline troponin values, elevations of cardiac 
biomarkers above the 99th percentile URL are indiciative of peri-procedural myocardial 
necrosis. By convention, increases in biomarkers > 3 x 99th percentile URL have been 
designated as defining PCI-related MI. A subtype related to a documented stent 
thrombosis is recognized. 
Sudden unexpected cardiac death, involving cardiac arrest, often with symptoms 
suggestive of myocardial ischemia, and accompanied by presumed new ST elevation 
or new LBBB, and/or evidence of fresh thrombus by coronary angiography and/or 
autopsy, with death occurring before blood samples obtained, or at a time before the 
expected appearance of cardiac biomarkers in blood will be classified as a mortality 
due to MI. 
Neurologic Dysfunction 
Any new, temporary or permanent, focal or global neurological deficit ascertained by a 
standard neurological examination (administered by a neurologist or other qualified 
physician and documented with appropriate diagnostic tests and consultation note). The 
examining physician will distinguish between a transient ischemic attack (TIA), which 
is fully reversible within 24 hours (and without evidence of infarction), and a stroke, 
which lasts longer than 24 hours (or less than 24 hours if there is evidence of infarction). 
The Modified Rankin Scale and the NIH Stroke Scale (NIHSS) must be administered 
at time of event (within 72 hours following the event) and 90 days following the event 

28 
 
to document the presence and severity of neurological deficits. The Modified Rankin 
Scale and NIHSS can be found in Appendix III. 
Each neurological event must be subcategorized as: Transient Ischemic Attack 
Defined as an acute event that resolves completely within 24 hours with no imaging 
evidence of infarction. 
Ischemic or Hemorrhagic Stroke (Cerebrovascular Accident) 
Defined as an event that persists beyond 24 hours or less than 24 hours associated with 
infarction on an imaging study. Hemorrhagic conversion of an ischemic stroke should 
be classified as ischemic. 
Toxic Metabolic Encephalopathy 
Defined as a disorder of the brain function that arises from abnormal systemic 
metabolism or exogenous substances, altering awareness and/or consciousness, in 
which there is a non-focal neurological examination and a negative brain image. 
Other Neurologic Dysfunction 
Renal Events 
Two categories of renal events will be identified: 
• Renal Dysfunction: Abnormal kidney function defined by > 100% rise in serum 
creatinine (Cr) from baseline, and Cr > 2.0 
• Renal Failure: New requirement for hemodialysis related to renal dysfunction. 
This definition excludes aquapheresis for volume removal alone. 
Respiratory Failure 
Impairment of respiratory function requiring re-intubation, tracheostomy or the 
inability to discontinue ventilatory support within 48 hours post-surgical intervention. 
This excludes intubation for re-operation or temporary intubation for diagnostic or 
therapeutic procedures. 
Right Heart Failure 
Symptoms and signs of persistent right ventricular dysfunction [central venous pressure 
(CVP) > 18 mmHg with a cardiac index <2.0 L/min/m2 in the absence of elevated left 
atrial/pulmonary capillary wedge pressure (> 18 mmHg), tamponade, ventricular 
arrhythmias or pneumothorax] requiring RVAD implantation, inhaled nitric oxide or 
inotropic therapy, for a duration of > 7 days. 
Arterial Non-CNS Thromboembolism 

29 
 
An acute systemic arterial perfusion deficit in any non-cerebrovascular organ system 
due to thromboembolism confirmed by one or more of the following: 
• Standard clinical and laboratory testing 
• 
Operative findings  
• Autopsy findings 
This definition excludes neurological events. 
Venous Thromboembolic Event 
Evidence of venous thromboembolic event (e.g. deep vein thrombosis, pulmonary 
embolism) by standard clinical and laboratory testing. 
Wound Dehiscence 
Disruption of the apposed surfaces of a surgical incision, excluding infectious etiology, 
and requiring surgical repair. 
Other 
An event that causes clinically relevant changes in the patient’s health, or any event that 
is life-threatening, results in a fatality, results in permanent disability, requires 
hospitalization, or prolongs an existing hospital stay. 
 
 

30 
 
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