Conditions: Coronary Artery Bypass Grafting Postoperative Atrial Fibrilation Stroke Systemic Embolism Deep Venous Thrombosis
Keywords: apixaban anticoagulant CABG thrombosis fibrillation
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 56
Healthy volunteers: no

Brief summary:
In this open-label, prospective, randomized pilot study, patients who develop atrial fibrillation after isolated coronary artery bypass grafting surgery will be identified. Patients with persistent atrial fibrillation (\>12 hours) or recurrent sustained atrial fibrillation (\>2 episodes of atrial fibrillation lasting longer than 30 minutes) will be candidates for inclusion. Upon meeting study inclusion and exclusion criteria, and after informed consent, patients will be randomized to either the standard of care (warfarin per protocol) or apixaban arms of the trial. Routine postoperative care after CABG will occur in both groups. Upon discharge, anticoagulation in both groups will be managed by the anticoagulation clinic. Patients will be followed for 30 days after surgery.

Detailed description:

Arms:
arm 1: Apixaban is to be dosed at 5 mg by mouth twice daily, except in the case of the criteria listed below in "dose modifications". The duration of therapy will be at least 30 days. The patient's physician may determine that anticoagulation therapy should be continued after the study period, based on their examination of the patient at the 30-day post-operative examination. arm 2: While patients are hospitalized, warfarin will be dosed daily, with daily INR monitoring per hospital protocol. Daily doses may vary from 0.5mg to 15mg by mouth, as determined by patient specific factors such as patient size, hepatic function, INR, concomitant medications, diet, or other factors. Based on these factors or others not listed, there may also be days in which the patient is prescribed to not get does not receive a dose of warfarin.

After discharge from the hospital, warfarin dosing will be subsequently managed by an anticoagulation clinic, per established protocols. All patients will have a goal INR of 2-3 during the duration of the study. The duration of therapy will be at least 30 days. The patient's physician may determine that anticoagulation therapy should be continued after the study period, based on their examination of the patient at the 30-day post-operative examination.

Interventions: intervention 1: Apixaban intervention 2: Warfarin
Intervention descriptions: intervention 1: Study arm that patient can be randomized to. Apixaban is a novel, orally active, potent, direct selective inhibitor of coagulation FXa that directly and reversibly binds to the active site of FXa and exerts anticoagulant and antithrombotic effects by diminishing the conversion of prothrombin to thrombin. intervention 2: Study arm that patient can be randomized to. Warfarin therapy has been the mainstay of therapy for patients with POAF. While the duration of therapy is usually short (3-4 weeks), complications of anticoagulation do occur. Additionally, warfarin therapy for POAF is associated with increased length of stay, need for monitoring, and bleeding complications.

Protocol document:
Prot_SAP_000.pdf: 
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Apixaban ISR Protocol Shell 
 
14 June  2014 
 
 
 
 
 
 
 
 
 
 
 
Apixaban versus warfarin for the management of post-operative atrial 
fibrillation: a prospective, controlled, randomized pilot study 
 
NCT02889562 
 
IRB Approved: 05JUN2018 
 
 
 
 
 
 
 
 
 
 
 
 


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Apixaban ISR Protocol Shell 
 
14 June  2014 
 
 
 
 
 
 
 
Apixaban versus warfarin for the management of post-operative atrial 
fibrillation: a prospective, controlled, randomized pilot study 
 
BMS PROTOCOL NUMBER: CV185-505 
 
 
Principal Investigator: 
 
 Cornelius Dyke, MD. 
Department of Cardiothoracic Surgery 
Sanford Medical Center- Fargo 
5225 23rd Ave S 
Fargo, ND 58104 
Phone: 701-417-2799 
cornelius.dyke@sanfordhealth.org 
 
 
Protocol Version/Date:  Version 11.0 04/10/2018 
 
 
 
 


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Apixaban ISR Protocol Shell 
 
14 June  2014 
TABLE OF CONTENTS 
TABLE OF CONTENTS .................................................................... 3 
PROTOCOL SYNOPSIS ................................................................... 5 
1 
INTRODUCTION ............................................................... 11 
1.1 
Scientific or Scholarly Background ............................... 10 
1.2 
Overall Risk/Benefit Assessment .................................. 10 
1.3 
Research Hypothesis ...................................................... 13 
1.4 
Study Rationale ............................................................... 13 
2 
STUDY OBJECTIVES ...................................................... 14 
2.1 
Primary Objective ............................................................ 14 
3 
ETHICAL CONSIDERATIONS ......................................... 14 
3.1 
Good Clinical Practice .................................................... 14 
3.2 
Institutional Review Board/Independent Ethics 
Committee ....................................................................... 15 
3.3 
Informed Consent ........................................................... 15 
4 
INVESTIGATIONAL PLAN ............................................... 16 
4.1 
Study Design and Duration ............................................ 16 
4.2 
Study Population ............................................................. 18 
4.2.1 
Inclusion Criteria ............................................................................. 18 
4.2.2 
Exclusion Criteria ............................................................................ 19 
4.2.3 
Women of Childbearing Potential .................................................. 21 
4.2.4 
Discontinuation of Subjects from Treatment ................................ 21 
5 
TREATMENTS .................................................................. 20 
5.1 
Study Treatment: Apixaban ............................................ 20 
5.1.1 
Identification .................................................................................... 20 
5.1.2 
Handling and Dispensing ............................................................... 21 
5.1.3 
Drug Destruction ............................................................................. 24 


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5.2 
Drug Ordering and Accountability ................................. 24 
5.2.1 
Initial Orders .................................................................................... 24 
5.2.2 
Re-Supply ......................................................................................... 24 
5.2.3 
Accountability .................................................................................. 24 
5.3 
Method of Assigning Subjects to a Treatment .............. 24 
5.4 
Selection and Timing of Dose for Each Subject ........... 24 
5.4.1 
Dose Modifications ......................................................................... 26 
5.4.2 
Temporary Discontinuation of Apixabanor Warfarin ................... 26 
5.5 
Blinding/Unblinding ........................................................ 26 
5.6 
Concomitant Treatments ................................................ 26 
5.6.1 
Prohibited and/or Restricted Treatments ...................................... 26 
5.6.2 
Other Restrictions and Precautions .............................................. 26 
5.7 
Treatment Compliance .................................................... 27 
6 
STUDY ASSESSMENTS AND PROCEDURES ............... 27 
6.1 
Time and Events Schedule ............................................. 27 
6.2 
Study Materials ................................................................ 30 
6.3 
Safety Assessments ....................................................... 30 
6.4 
Study Assessments ........... 29Error! Bookmark not defined. 
6.4.1 
Primary Assessment ....................................................................... 31 
6.4.2 
Secondary Assessments ................................................................ 31 
7 
ADVERSE EVENTS ......................................................... 32 
7.1 
Serious Adverse Events ................................................. 32 
7.1.1 
Serious Adverse Event Collecting and Reporting ........................ 34 
7.1.2 
SAE Reconciliation ......................................................................... 35 
7.1.3 
Health Authority Reporting (US FDA IND) ..................................... 35 
7.2 
Non-Serious Events ........................................................ 36 
7.2.1 
Non-Serious Adverse Events (NSAEs) Collecting and 
Reporting ......................................................................................... 36 
7.3 
Laboratory Test Abnormalities ...................................... 36 


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7.4 
Pregnancy ........................................................................ 37 
7.5 
Overdose ......................................................................... 37 
7.6 
Other Safety Considerations .......................................... 38 
8 
DATA MONITORING COMMITTEE .................................. 38 
9 
STATISTICAL CONSIDERATIONS .................................. 38 
9.1 
Sample Size DeterminationError! Bookmark not defined.36 
9.2 
Populations for Analyses ............................................... 38 
9.3 
Analyses .......................................................................... 36 
10 
STUDY MANAGEMENT ................................................... 39 
10.1 
Compliance with the Protocol ........................................ 39 
10.2 
Records Retention .......................................................... 40 
10.2.1 
Records Retention .......................................................................... 40 
10.2.2 
Study Drug Records ........................................................................ 40 
10.3 
Destruction of Investigational Product .......................... 41 
11 
GLOSSARY OF TERMS ................................................... 42 
12 
LIST OF ABBREVIATIONS .............................................. 43 
13 
REFERENCES .................................................................. 44 
 
 
 
 
 
 
 


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PROTOCOL SYNOPSIS 
Protocol Title: 
Apixaban versus warfarin for the management of post-
operative atrial fibrillation: a prospective, controlled, 
randomized pilot study 
Site Numbers & Names: Sanford Medical Center, Fargo, ND 
Research Hypothesis: 
We hypothesize that there will be no significant differences 
between apixaban and warfarin anticoagulation strategies 
for the outcomes of venous thromboembolism/stroke or 
bleeding events when utilized for new-onset postoperative 
atrial fibrillation after isolated coronary artery bypass 
grafting (CABG).  
Study Schema: 
Drugs / Doses / 
Length of Treatment) 
Patients who develop persistent atrial fibrillation after 
isolated coronary artery bypass grafting will be identified 
and randomized to anticoagulation with either warfarin 
(standard of care) or apixaban. 
Warfarin will be dosed daily, with International 
Normalized Ratio (INR) monitoring per hospital protocol.  
After discharge, warfarin dosing will be managed by the 
anticoagulation clinic per protocol with a target INR of 2-3. 
Apixaban will be dosed at 5 mg twice daily, or 2.5 mg 
twice daily in patients with at least two of the following 
characteristics: age ≥ 80 years, weight ≤ 60 kg, or serum 
creatinine ≥ 1.5 mg/dL. 
Patients will remain on anticoagulation until no longer 
needed (typically within 30 days of surgery).  Study 
follow-up will be through the patient’s 30-day follow-up 
appointment. 


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14 June  2014 
Study Objectives: 
 
1) Primary endpoint: freedom from stroke or 
thromboembolic event will be captured.  
 
2) Secondary endpoints:  
-units of blood given after initiation of anticoagulation 
medication 
-total post-operative length of stay 
-duration from diagnosis of post-operative atrial fibrillation 
(POAF) to discharge from hospital 
-time in therapeutic range of INR if on warfarin 
-patient compliance percentage to apixaban if on apixaban 
 
3) Safety assessments: major and minor bleeding events, as 
defined by the International Society on Thrombosis and 
Haemostasis, will be captured.  Clinical events and blood 
product utilization will be identified and captured. 
 
Study Design: 
In this open-label, prospective, randomized pilot study, 
patients who develop atrial fibrillation after isolated 
coronary artery bypass grafting surgery will be identified. 
Patients with persistent atrial fibrillation (>12 hours) or 
recurrent sustained atrial fibrillation (>2 episodes of atrial 
fibrillation lasting longer than 30 minutes) will be 
candidates for inclusion.  Upon meeting study inclusion 
and exclusion criteria, and after informed consent, patients 
will be randomized to either the standard of care (warfarin 
per protocol) or apixaban arms of the trial. Routine 
postoperative care after CABG will occur in both groups. 
Upon discharge, anticoagulation in both groups will be 
managed by the anticoagulation clinic. Patients will be 
followed for 30 days after surgery.  
Accrual Goal: 
(Total number of subjects) 
56 patients 
Accrual Rate: 
(Number of subjects 
expected per month) 
We anticipate enrolling 2-3 patients per month based on 
current projections. 
FPFV: 
LPFV: 
Follow Up: 
(mm/dd/yy) 
FPFV:  9/1/16 
LPFV: 12/31/18Follow up: 30 days per patient 
Final Report:  3/31/19 


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Correlative Studies: 
(PK/PD, etc.) 
Retrospective analysis conducted at our facility:  
Anderson E, Johnke K, Leedahl D, Dyke,C. Novel oral 
anticoagulants vs warfarin for the management of 
postoperative atrial fibrillation: clinical outcomes and cost 
analysis. American Journal of Surgery. Volume 210, Issue 
6,1095-11032  
 
Inclusion Criteria: 
Patients diagnosed with new-onset persistent or recurrent 
atrial fibrillation after isolated CABG surgery.  Persistent 
atrial fibrillation is defined as an episode of >12hours. 
Recurrent atrial fibrillation is defined as 2 or more episodes 
of atrial fibrillation lasting longer than 30 minutes.  


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Exclusion Criteria: 
1. Patients undergoing valve replacement or with an 
artificial heart valve, or with moderate or severe 
mitral stenosis 
2. Stroke within the previous 7 days. 
3. Patients currently experiencing active bleeding 
precluding initialization of anticoagulation therapy 
in the opinion of their managing physician, or with 
increased bleeding risk (as determined by the 
attending surgeon) believed to be a contraindication 
to anticoagulation at the time of randomization.   
4. Atrial fibrillation due to a reversible cause other 
than recent surgery 
5. Planned major surgery requiring stoppage of 
anticoagulation therapy during the trial period.  
6. Patients taking warfarin, apixaban, rivaroxaban, 
dabigatran, edoxaban, or enoxaparin at home for 
any indication in the 15 days prior to surgery.  
Patients taking clopidogrel or ticagrelor within 5 
days prior to surgery, patients taking prasugrel 
within 7 days prior to surgery, and patients taking 
ticlopidine within 10 days prior to surgery.   
7. Patients receiving clopidogrel, ticagrelor, prasugrel, 
or ticlopidine during the study period.  
8. Patients diagnosed with persistent atrial fibrillation 
chronically before undergoing surgery.   
9. Patients with paroxysmal atrial fibrillation requiring 
oral anticoagulation prior to surgery.   
10. Severe renal insufficiency (serum creatinine level 
of >2.5 mg/dL or CrCL<25 ml/min) for consecutive 
measurements. 
11. Patients who are pregnant or of child-bearing age. 
12. Patients <18 years of age. 
13. Patients unable to give informed consent 


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Criteria for Evaluation: 
(Efficacy, safety, 
stopping rules, etc.) 
Efficacy will be measured by the freedom from systemic 
thromboembolism or stroke during the study period. Events 
relating to thromboembolism or stroke will be adjudicated 
using pre-determined definitions by independent 
committee members that remain blinded to the patient’s 
treatment arm.   
Safety, including major and minor bleeding will be 
quantified and defined by the Society on Thrombosis and 
Haemostasis, as described in section 6.4.2, subsection (2). 
Clinical events that occur during the study period will be 
quantified and measured, including adverse events, serious 
adverse events, blood product utilization, length of stay, 
duration of atrial fibrillation, and time to adequate 
anticoagulation.  
Data Analysis Plan 
Efficacy and safety data will retrospectively assessed and 
analyzed after the patient has completed the 30-day course 
of therapy.  Events relating to thromboembolism or stroke 
will be adjudicated using pre-defined endpoint definitions 
by independent committee members that remain blinded to 
treatment arm. Safety events, including major bleeding will 
be as defined by the International Society on Thrombosis 
and Haemostasis.3  In the hospital, bleeding will be 
assessed daily by monitoring hemoglobin and the need for 
transfusions, and defined by a drop in hemoglobin of > 2 
gm/dL in the previous 24 hours, or transfusion of at least 
two units of blood products.  After discharge, we will 
monitor for readmissions related to bleeding, indicated by 
the need of transfusion of at least two units of blood 
products.  
Statistics: 
Continuous variables will be expressed as mean ± standard 
deviation or median with interquartile range (IQR) as 
appropriate. Continuous variables will be compared using 
t-tests for parametric data or Wilcoxon analysis for 
nonparametric data.  We will complete the analysis in an 
intent-to-treat manner.  We will include analysis for 
confidence intervals and other appropriate statistical tests 
to assess binary outcomes.  We realize that statistical 
comparison between groups will be of limited utility in this 
pilot study as this study is not powered for comparison of 
events between groups. Data will be analyzed using JMP 
software, version 12.0.0 (Cary, NC). 


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1 
INTRODUCTION 
Apixaban is a novel, orally active, potent, direct selective inhibitor of coagulation FXa 
that directly and reversibly binds to the active site of FXa and exerts anticoagulant and 
antithrombotic effects by diminishing the conversion of prothrombin to thrombin. 
Apixaban is currently indicated to reduce stroke and systemic embolism in patients with 
nonvalvular atrial fibrillation, for the treatment of deep venous thrombosis (DVT), and 
for the prophylaxis of DVT in patients who have undergone hip or knee replacement 
surgery. Apixaban is not indicated for the treatment of atrial fibrillation caused by 
valvular heart disease or for patients with mechanical prosthetic valves requiring chronic 
oral anticoagulation. 
Patients undergoing coronary artery bypass grafting (CABG) are at risk for the 
development of postoperative atrial fibrillation (POAF).  POAF adversely impacts patient 
outcomes, and patients who develop POAF are at increased risk for stroke or 
thromboembolic complications, with an increased duration of hospitalization.  Usually 
occurring in the early postoperative period and usually short-lived, POAF requires 
anticoagulation when persistent or recurrent.  Duration of therapy for POAF is typically 
short-term, as POAF is usually short-term and self-limiting over 3-4 weeks.  
Warfarin therapy has been the mainstay of therapy for patients with POAF. While the 
duration of therapy is usually short (3-4 weeks), complications of anticoagulation do 
occur.  Additionally, warfarin therapy for POAF is associated with increased length of 
stay, need for monitoring, and bleeding complications.  
Apixaban has been demonstrated to be superior to warfarin for the reduction of stroke or 
systemic embolism in patients with non-valvular atrial fibrillation.  Additionally, major 
bleeding was significantly reduced in patients receiving apixaban compared to warfarin.  
The use of apixaban in patients with POAF has not been well studied, however, and 
whether these benefits will be seen in patients with POAF is unclear. In this small 
prospective pilot study, we aim to compare apixaban and warfarin anticoagulation 
strategies for the outcomes of venous thromboembolism/stroke and bleeding events when 
utilized in patients with new-onset postoperative atrial fibrillation after isolated coronary 
artery bypass grafting (CABG).   
 
 


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1.1 
Scientific or Scholarly Background 
Post-operative atrial fibrillation is defined as atrial fibrillation of new onset in the 
immediate post-operative period.  Published rates of POAF after cardiac surgery is 
traditionally 20-30%, which is similar to rates observed at our facility.1-4  Patients at the 
highest risk for POAF are those of advanced age; for each 10-year increase in age, the 
odds of developing atrial fibrillation after surgery increase by 75%.5 Other patients at 
increased risk for developing POAF are those with a history of smoking, hypertension, or 
congestive heart failure, as well as patients undergoing urgent or emergent coronary 
artery bypass graft surgery.  While atrial fibrillation occurs at any time after cardiac 
bypass surgery, it is most common within four days of surgery, and the peak incidence is 
on post-operative day two.5  For persistent POAF, the American College of Cardiology, 
American Heart Association, and European Society of Cardiology recommend 
anticoagulation if rate-control measures and cardioversion therapy fail to return the 
patient to normal sinus rhythm.6 In addition to warfarin, there are four novel 
anticoagulants approved for the management of non-valvular atrial fibrillation: apixaban, 
rivaroxaban, edoxaban, and dabigatran etexilate mesylate. Apixaban, rivaroxaban, and 
edoxaban are FDA approved for prophylaxis of cerebrovascular accidents and systemic 
thromboembolisms in the maintenance of atrial fibrillation.7,8 Dabigatran is FDA 
approved for prophylaxis of thromboembolic disorders in patients with atrial fibrillation9.  
These novel agents have well-established safety and efficacy profiles, but have not been 
well studied for atrial fibrillation due to reversible causes such as POAF, or immediately 
after a major surgery such as a CABG.  The ARISTOTLE study excluded patients with 
atrial fibrillation due to reversible causes such as surgery, and the RE-LY and ROCKET 
AF trials excluded patients with an increased risk of bleeding, including those that 
underwent major surgery in the previous 30 days, as well as patients with atrial 
fibrillation due to reversible causes, specifically cardiac surgery.10-12  
1.2 
Overall Risk/Benefit Assessment 
Patients experiencing POAF after undergoing isolated CABG that require anticoagulation 
are currently placed on warfarin with a goal INR of 2-3. Compared to the current 
standard of care, apixaban may offer similar or improved safety and efficacy profiles, and 
this pilot study may provide a valuable signal of benefit and safety for apixaban use in the 
setting of POAF.  
 


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1.3 
Research Hypothesis 
In this pilot study, we hypothesize that there will be no significant differences between 
apixaban and warfarin anticoagulation strategies for the outcomes of venous 
thromboembolism/stroke or bleeding events, when utilized for new-onset postoperative 
atrial fibrillation after isolated coronary artery bypass grafting (CABG). This small 
prospective pilot study will not likely be adequately powered to show statistically 
significant differences in safety or efficacy between patients treated with apixaban or 
warfarin.  
1.4 
Study Rationale 
Post-operative atrial fibrillation is defined as atrial fibrillation of new onset in the 
immediate post-operative period.  Published rates of POAF after cardiac surgery is 
traditionally 20-30%, which is similar to rates observed at our facility.2,4-6 Patients at the 
highest risk for POAF are those of advanced age; for each 10-year increase in age, the 
odds of developing atrial fibrillation after surgery increase by 75%.7 Other patients at 
increased risk for developing POAF are those with a history of smoking, hypertension, or 
congestive heart failure, as well as patients undergoing urgent or emergent coronary 
artery bypass graft surgery.  While atrial fibrillation occurs at any time after cardiac 
bypass surgery, it is most common within four days of surgery, and the peak incidence is 
on post-operative day two.7  For persistent POAF, the American College of Cardiology, 
American Heart Association, and European Society of Cardiology recommend 
anticoagulation if rate-control measures and cardioversion therapy fail to return the 
patient to normal sinus rhythm.8 In addition to warfarin, there are four novel 
anticoagulants approved for the management of non-valvular atrial fibrillation: apixaban, 
rivaroxaban, edoxaban, and dabigatran etexilate mesylate, although none of these have 
been studied in patients with POAF.  Apixaban is indicated as follows: 
INDICATIONS AND USAGE---------------------------- 
ELIQUIS is a factor Xa inhibitor indicated: 
• to reduce the risk of stroke and systemic embolism in patients with nonvalvular 
atrial fibrillation. (1.1) 
• for the prophylaxis of deep vein thrombosis (DVT), which may lead topulmonary 
embolism (PE), in patients who have undergone hip or knee 
replacement surgery. (1.2) 
• for the treatment of DVT and PE, and for the reduction in the risk of recurrent 
DVT and PE following initial therapy. (1.3, 1.4, 1.5).1  
Rivaroxaban, and edoxaban are FDA approved for prophylaxis of DVT and prevention of 
pulmonary embolism and for the reduction of stroke and systemic thromboembolism in 
patients with nonvalvular atrial fibrillation.9,10 Dabigatran is FDA approved for 
prophylaxis of thromboembolic disorders in patients with atrial fibrillation11.  These 
novel agents have well-established safety and efficacy profiles, but have not been well 
studied for atrial fibrillation due to reversible causes such as POAF, or after major 


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14 June  2014 
surgery such as a CABG.  The ARISTOTLE study excluded patients with atrial 
fibrillation due to reversible causes such as surgery, and the RE-LY and ROCKET AF 
trials excluded patients with an increased risk of bleeding, including those that underwent 
major surgery in the previous 30 days, as well as patients with atrial fibrillation due to 
reversible causes, specifically cardiac surgery.12-14  
 
2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
1) Efficacy: Venous thromboembolism or stroke, followed until postoperative day 30.  
 
2) Safety: major and minor bleeding events, followed until postoperative day 30, as 
defined by the International Society on Thrombosis and Haemostasis3 
3) Clinical relevant non-major bleed. 
4) Transfusions: units of blood or blood products given after the first dose of 
anticoagulation. 
5) Total post-operative length of stay  in days, defined as the time the patient leaves the 
operating room (day 0) until hospital discharge. Length of say will increase by 1 day with 
each midnight that is passed.  
6) Time in therapeutic range of INR, if on warfarin, (eg. 2-3), measured as a percentage 
and defined for each patient using the Rosendaal equation. 
 
7) Patient compliance percentage to apixaban dosing, calculated as a percentage using the 
following equation 
 
a. (# doses prescribed - # of doses not taken and returned to investigator at follow 
up appointment) / # doses prescribed; the follow up visit will occur after anticoagulation 
prescription has ended.  
 
 
3 
ETHICAL CONSIDERATIONS 
3.1 
Good Clinical Practice 
This study will be conducted in accordance with Good Clinical Practice (GCP), as 
defined by the International Conference on Harmonisation (ICH) and in accordance with 
the ethical principles underlying European Union Directive 2001/20/EC and the United 
States Code of Federal Regulations, Title 21, Part 50 (21CFR50). 


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The study will be conducted in compliance with the protocol. The protocol, any 
amendments, and the subject informed consent will receive Institutional Review 
Board/Independent Ethics Committee (IRB/IEC) approval/favorable opinion before 
initiation of the study. 
All potential serious breaches must be reported to Bristol-Myers Squibb (BMS) 
immediately. A serious breach is a breach of the conditions and principles of GCP in 
connection with the study or the protocol, which is likely to affect, to a significant degree, 
the safety or physical or mental integrity of the subjects of the study or the scientific 
value of the study. 
Study personnel involved in conducting this study will be qualified by education, 
training, and experience to perform their respective tasks.  
This study will not use the services of study personnel where sanctions have been 
invoked or where there has been scientific misconduct or fraud (eg, loss of medical 
licensure; debarment).  
3.2 
Institutional Review Board/Independent Ethics 
Committee 
Before study initiation, the investigator must have written and dated approval/favorable 
opinion from the IRB/IEC for the protocol, consent form, subject recruitment 
materials/process (eg, advertisements), and any other written information to be provided 
to subjects. The investigator or sponsor should also provide the IRB/IEC with a copy of 
the Investigator  Brochure or product labeling information to be provided to subjects, and 
any updates.  
The investigator should provide the IRB/IEC with reports, updates, and other information 
(eg, expedited safety reports, amendments, and administrative letters) according to 
regulatory requirements or institution procedures. 
3.3 
Informed Consent 
Investigators must ensure that subjects are clearly and fully informed about the purpose, 
potential risks, and other critical issues regarding clinical studies in which they volunteer 
to participate. 


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14 June  2014 
Investigators must: 
1) Provide a copy of the consent form and written information about the study in the 
language in which the subject is most proficient prior to clinical study participation. 
The language must be non-technical and easily understood. 
2) Allow time necessary for subject to inquire about the details of the study. 
3) Obtain an informed consent signed and personally dated by the subject and by the 
person who conducted the informed consent discussion.  
4) Obtain the IRB/IEC’s written approval/favorable opinion of the written informed 
consent form and any other information to be provided to the subjects, prior to the 
beginning of the study, and after any revisions are completed for new information. 
5) Revise the informed consent whenever important new information becomes available 
that is relevant to the subject's consent. The investigator, or a person designated by 
the investigator, should fully inform the subject of all pertinent aspects of the study 
and of any new information relevant to the subject's willingness to continue 
participation in the study. This communication should be documented.  
6) Reconsenting of patients can be done in person or, if the patient is unable to reconsent 
in person, over the phone. If the reconsent is required to be performed over the phone, 
the coordinator will send an updated consent form to the patient via mail or 
electronically. When the patient has received the consent, the coordinator will review 
the consent with the patient over the phone. Any questions can be answered by the 
coordinator during the consenting process. The patient will then send the original 
signed consent back to the coordinator. The coordinator who conducted the phone 
consent will sign and date the applicable line and upload to the patient’s chart. The 
coordinator must also document the consent discussion and receipt of the consent in 
the patient’s EMR. 
The rights, safety, and well-being of the study subjects are the most important 
considerations and should prevail over interests of science and society. 
4 
INVESTIGATIONAL PLAN 
4.1 
Study Design and Duration 
Planned study design: prospective, controlled, randomized pilot study 
Screening procedures/study population:  Patients will be eligible for screening if they 
develop atrial fibrillation in the postoperative period that: 
1. Persists 12 hours or more. 
2. Develop recurrent atrial fibrillation with two or more episodes 
of persistent AFib of at least 30 minutes duration during the 
same hospital stay. 


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Number of subjects per arm: 28 
Randomization ratio/method: 1:1, determined in permuted block fashion 
Duration of treatment: 30 days of oral anticoagulation therapy.  This period will start with 
the first dose of anticoagulation (either apixaban or warfarin) given in the hospital, and 
continue until the patient’s 30-day post-operative appointment. 
Criteria for evaluation:  
• Efficacy: systemic thromboembolism or stroke will be assessed retrospectively 
after the patient has completed the 30-day course of therapy.   
o Events relating to thromboembolism or stroke will be adjudicated using 
pre-determined definitions by independent committee members that 
remain blinded to the patient’s treatment arm.    
• Safety: major bleeding will be as defined by the Society on Thrombosis and 
Haemostasis, as follows:  
o 1. Fatal bleeding, and/or  
o 2. Symptomatic bleeding that occurs in a critical area or organ, such as 
intracranial, intraspinal, intraocular, retroperitoneal, pericardial, in a non-
operated joint, or intramuscular with compartment syndrome, assessed in 
consultation with the surgeon, and/or  
o 3. Extrasurgical site bleeding causing a fall in hemoglobin level of 20 g/L 
(2g/dL) or more, or leading to transfusion of two or more units of whole 
blood or red cells within 24-48 hours of the bleeding and/or  
o 4. Surgical site bleeding that requires a second intervention – open, 
arthroscopic, endovascular- or a hemarthrosis of sufficient size as to 
interfere with rehabilitation by delaying mobilization or delayed wound 
healing, resulting in prolonged hospitalization or a deep wound infection, 
and/or  
o 5. Unexpected surgical site bleeding, prolonged and/or sufficiently large to 
cause hemodynamic instability, as assessed by the surgeon, with a fall in 
hemoglobin of at least 20 g/L (2g/dL) or transfusion of two or more units 
of whole blood or red cells within 24 hours of the bleeding. 3  


18 
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14 June  2014 
In the hospital, bleeding will be assessed daily by monitoring hemoglobin and the need 
for transfusions.  After discharge and until the patient’s 30-day post-operative evaluation, 
we will monitor for readmissions related to bleeding, indicated by the need for 
transfusion of at least two units of blood products.  Any patient phone calls that already 
occur as part of routine post-operative care will continue; however, there are no 
additional post-discharge phone calls to the patient related to this study.  
 
4.2 
Study Population 
4.2.1 
Inclusion Criteria 
1) Signed Written Informed Consent 
• Before any study procedures are performed, subjects will have the details of the 
study described to them, and they will be given a written informed consent 
document to read. Then, if subjects consent to participate in the study, they will 
indicate that consent by signing and dating the informed consent document in the 
presence of study personnel. This informed consent will be scanned into the 
patient’s EMR, as well as retained for a period not less than three years after the 
completion of the study. 
2) Target Population 
• Patients diagnosed with new-onset persistent or recurrent atrial fibrillation after 
isolated CABG surgery.  Persistent atrial fibrillation is defined as an episode of 
>12 hours. Recurrent atrial fibrillation is defined as two or more episodes of atrial 
fibrillation lasting longer than 30 minutes. 
3) Age and Reproductive Status 
• Males and Females, at least 18 years of age 
• Women of childbearing potential (WOCBP) must have a negative serum or urine 
pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 
24 hours prior to the start of study drug.  Patients undergoing isolated CABG 
must have this tested and documented prior to the procedure, and this will be 
verified prior to randomization. 
• Women must not be breastfeeding. 
• WOCBP must agree to follow instructions for method(s) of contraception for the 
duration of treatment with study drug(s):  30 days of treatment plus 5 half-lives of 
study drug Apixaban (3 days) or warfarin (8 days) plus 30 days (duration of 
ovulatory cycle) for a total of 38 days post-treatment completion. 
• Males who are sexually active with WOCBP must agree to follow instructions for 
method(s) of contraception for the duration of treatment with study drug(s): 30 


19 
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14 June  2014 
days of treatment plus 5 half-lives of study drug Apixaban (3 days) or warfarin (8 
days) plus 90 days (duration of sperm turnover) for a total of 98 days post-
treatment completion. 
• Azoospermic males and WOCBP who are continuously not heterosexually active 
are exempt from contraceptive requirements.  However they must still undergo 
pregnancy testing as described in this section. 
 
Investigators shall counsel WOCBP and male subjects who are sexually active with 
WOCBP on the importance of pregnancy prevention and the implications of an 
unexpected pregnancy. Investigators shall advise WOCBP and male subjects who are 
sexually active with WOCBP on the use of highly effective methods of contraception. 
Highly effective methods of contraception have a failure rate of < 1% when used 
consistently and correctly. 
At a minimum, subjects must agree to the use of one method of highly effective 
contraception as listed below: 
• Male condoms with spermicide 
• Hormonal methods of contraception including combined oral contraceptive pills, 
vaginal ring, injectables, implants and intrauterine devices (IUDs) such as Mirena 
by WOCBP subject or male subject’s WOCBP partnerFemale partners of male 
subjects participating in the study may use hormone based contraceptives as one of 
the acceptable methods of contraception since they will not be receiving study drug  
• IUDs, such as ParaGard 
• Tubal ligation 
• Vasectomy. 
• Complete Abstinence* 
 
*Complete abstinence is defined as complete avoidance of heterosexual intercourse 
and is an acceptable form of contraception for all study drugs. Female subjects must 
continue to have pregnancy tests. Acceptable alternate methods of highly effective 
contraception must be discussed in the event that the subject chooses to forego 
complete abstinence 
4.2.2 
Exclusion Criteria 
Target Disease Exceptions  
• Atrial fibrillation due to a reversible cause other than recent surgery 
• Patients diagnosed with persistent or paroxysmal atrial fibrillation chronically 
before undergoing surgery 


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14 June  2014 
• Patients with mechanical heart valves 
Medical History and Concurrent Diseases 
• Patients currently experiencing active bleeding precluding initialization of 
anticoagulation therapy in the opinion of their managing physician, or with 
increased bleeding risk (as determined by the attending surgeon) believed to be a 
contraindication to anticoagulation at the time of randomization Planned major 
surgery requiring stoppage of anticoagulation therapy during trial period 
• Stroke within the previous 7 days 
• Moderate or severe mitral stenosis 
• Conditions other than atrial fibrillation that required anticoagulation (prosthetic 
mechanical heart valve) 
Concomitant Medications  
•  
•  Patients taking warfarin, apixaban, rivaroxaban, dabigatran, edoxaban, or 
enoxaparin at home for any indication in the 15 days prior to surgery.  Patients 
taking clopidogrel or ticagrelor within 5 days prior to surgery, patients taking 
prasugrel within 7 days prior to surgery, and patients taking ticlopidine within 10 
days prior to surgery 
• Patients receiving clopidogrel, ticagrelor, prasugrel, or ticlopidine during the 
study period 
Physical and Laboratory Test Findings 
• Severe renal insufficiency (serum creatinine level of >2.5 mg/dL or CrCL<25 
ml/min) for consecutive measurements 
Allergies and Adverse Drug Reactions 
• Allergies to warfarin or apixaban, or components of warfarin or apixaban 
Sex and Reproductive Status 
• See Section on WOCBP above (Section 4.2.1, item # 3.) 
Other Exclusion Criteria 
• Prisoners or subjects who are involuntarily incarcerated. 
• Subjects who are compulsorily detained for treatment of either a psychiatric or 
physical (eg, infectious disease) illness. 
• Patients <18 years of age. 
• Patients unable to give informed consent.  
 
Eligibility criteria for this study have been carefully considered to ensure the safety of the 
study subjects and to ensure that the results of the study can be used. It is imperative that 
subjects fully meet all eligibility criteria. 


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14 June  2014 
4.2.3 
Women of Childbearing Potential 
A Women of childbearing potential (WOCBP) is defined as any female who has 
experienced menarche and who has not undergone surgical sterilization (hysterectomy or 
bilateral oophorectomy) and is not postmenopausal. Menopause is defined as 12 months 
of amenorrhea in a woman over age 45 years in the absence of other biological or 
physiological causes. In addition, females under the age of 55 years must have a serum 
follicle stimulating hormone, (FSH) level > 40mIU/mL to confirm menopause. 
*Females treated with hormone replacement therapy, (HRT) are likely to have artificially 
suppressed FSH levels and may require a washout period in order to obtain a physiologic 
FSH level. The duration of the washout period is a function of the type of HRT used. The 
duration of the washout period below are suggested guidelines and the investigators 
should use their judgement in checking serum FSH levels. If the serum FSH level is >40 
mIU/ml at any time during the washout period, the woman can be considered 
postmenopausal : 
• 1 week minimum for vaginal hormonal products (rings, creams, gels) 
• 4 week minimum for transdermal products 
• 8 week minimum for oral products 
Other parenteral products may require washout periods as long as 6 months. 
 
4.2.4 
Discontinuation of Subjects from Treatment 
Subjects MUST discontinue investigational product (and non-investigational product at 
the discretion of the investigator) for any of the following reasons: 
• Withdrawal of informed consent (subject’s decision to withdraw for any reason). 
• Any clinical adverse event, laboratory abnormality, or intercurrent illness which, 
in the opinion of the investigator, indicates that continued participation in the 
study is not in the best interest of the subject. 
• Pregnancy 
− Instruct WOCBP to contact the investigator or study staff immediately if they 
suspect they might be pregnant (eg, missed or late menstrual period) at any 
time during study participation. Institutional policy and local regulations 
should determine the frequency of on-study pregnancy tests for WOCBP 
enrolled in the study. 
− The investigator must immediately notify BMS if a study subject becomes 
pregnant. 


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14 June  2014 
• Loss of ability to freely provide consent through imprisonment or involuntary 
incarceration for treatment of either a psychiatric or physical (eg, infectious 
disease) illness. 
• While patients may request withdrawal from the study at any time, they will be 
advised to check with their medical provider before discontinuing any 
anticoagulant medication, for their safety. 
•  Subjects can voluntarily withdraw from the study at any time, but the 
investigators will continue to follow the patient so that an intent-to-treat analysis 
can be performed. Failure to take study medication as prescribed, or failure to 
follow up as directed with the anticoagulation clinic, will be noted in our analysis 
to the best extent we are able. 
• Any data collected before withdrawal will be used for study outcomes, although it 
will be noted that the participant did not complete the 30-day course of therapy.  
Attempts will be made to determine and note the reason for withdrawal. 
• All subjects who discontinue should comply with protocol-specified follow-up 
procedures outlined in Section 6. The only exception to this requirement is when a 
subject withdraws consent for all study procedures or loses the ability to consent 
freely (ie, is imprisoned or involuntarily incarcerated for the treatment of either a 
psychiatric or physical illness). If a subject withdraws before completing the 
study, the reason for withdrawal must be documented appropriately.  
 
5 
TREATMENTS 
5.1 
Study Treatment: Apixaban 
Definition of Investigational Product: A pharmaceutical form of an active substance or 
placebo being tested or used as a reference in a clinical study, including products already 
with a marketing authorization but used or assembled (formulated or packaged) in a way 
different from the authorized form, or used for an unauthorized indication, or when used 
to gain further information about the authorized form. In this protocol, the investigational 
product is apixaban.  The control (current standard of care) is warfarin. 
Definition of Non-Investigational Product: Other medications used in the study as 
support or escape medication for preventative, diagnostic, or therapeutic reasons as 
components of a given standard of care. In this protocol, the non-investigational products 
are: none. 
 


23 
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14 June  2014 
5.1.1 
Identification 
Product 
Description / 
Class and Dosage 
Form 
Potency 
Blinded or 
Open Label 
Packaging/ Appearance 
Apixaban 
5mg 
Open 
Pink, oval, biconvex 
Debossed with “894” on one side and “5” 
on the other side 
Apixaban 
2.5mg 
Open 
Yellow, round, biconvex 
Debossed with “893” on one side and 
“2½” on the other side 
Warfarin 
 
 
 
 
1mg 2mg, 
2.5mg, 3mg,  
4mg, 5mg,  
6mg, 7.5mg, 
10mg 
Open 
 
 
 
 
All strengths are tablets. 
1mg: pink,  2mg: lavender,  
2.5mg: light green,  3mg: tan,  
4mg: blue,  5mg: peach,  
6mg: teal,  7.5mg: yellow,  
10mg: white 
Medication storage:  
Apixaban: Store at 20°C to 25°C (68°F-77°F); excursions permitted between 15°C and 
30°C (59°F-86°F).  Protect from light and moisture. 
Warfarin: Store at controlled room temperature, (59°-86°F, 15°-30°C). Protect from light 
and moisture. 
5.1.2 
Handling and Dispensing 
The investigational product should be stored in a secure area according to local 
regulations. The investigator is responsible for ensuring that it is dispensed only to study 
subjects and only from official study sites by authorized personnel, as dictated by local 
regulations. 
If concerns regarding the quality or appearance of the investigational product arise, do 
not dispense the investigational product, and contact BMS immediately. 


24 
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14 June  2014 
5.1.3 
Drug Destruction 
Ensure that arrangements have been made for investigational drug disposal, and that 
procedures for proper disposal have been established according to applicable regulations, 
guidelines, and institutional procedures. 
5.2 
Drug Ordering and Accountability 
5.2.1 
Initial Orders 
 Following submission and approval of the required regulatory documents, a supply of 
STUDY DRUG (apixaban) may be ordered through the BMS protocol manager by 
completing a Drug Request Form. The first request will take place upon site opening.   
5.2.2 
      Re-Supply 
Drug re-supply request form should be submitted electronically or by fax to the BMS 
protocol manager at least ten business days before the expected delivery date. 
5.2.3 
Accountability 
Investigational product documentation must be maintained that includes all processes 
required to ensure drug is accurately administered. This includes documentation of drug 
storage, administration and, as applicable, storage temperatures, reconstitution, and use of 
required processes (eg, required diluents, administration sets). 
5.3 
Method of Assigning Subjects to a Treatment 
Patients will be randomized to a treatment arm (apixaban or warfarin) in a 1:1 ratio by 
utilizing a random permuted block method, using blocks of four to eight, which was 
randomly generated.  This ensures that with every four, six, or eight patients randomized, 
an equal number of subjects will be in each treatment arm, without the possibility of 
study personnel knowing or predicting the next randomization event.   
5.4 
Selection and Timing of Dose for Each Subject 
Apixaban: Apixaban is to be dosed at 5 mg by mouth twice daily, except in the case of 
the criteria listed below in “dose modifications”.  The duration of therapy will be at least 
30 days.  The patient’s physician may determine that anticoagulation therapy should be 
continued after the study period, based on their examination of the patient at the 30-day 
post-operative examination. 
Apixaban should not be used if a patient has active pathological bleeding. 


25 
Apixaban ISR Protocol Shell 
 
14 June  2014 
If a dose of apixaban is not taken at the scheduled time, the dose should be taken as soon 
as possible on the same day and then continue with twice daily administration as before.   
The dose should not be doubled to make up for a missed dose. 
Apixaban can be taken with or without food. 
Apixaban is not recommended in patients with severe hepatic impairment.  No dose 
adjustment is recommended for patients with renal impairment alone, including those 
with end-stage renal disease (ESRD) maintained on hemodialysis, except nonvalvular 
atrial fibrillation patients who meet the criteria for dosage adjustment.  Patients with 
ESRD (CrCl <15 mL/min) receiving or not receiving hemodialysis were not studied in 
clinical efficacy and safety studies with ELIQUIS; therefore, the dosing 
recommendations are based on pharmacokinetic and pharmacodynamic (anti-Factor Xa 
activity) data in subjects with ESRD maintained on dialysis. 
Warfarin: While patients are hospitalized, warfarin will be dosed daily, with daily INR 
monitoring per hospital protocol.  Daily doses may vary from 0.5mg to 15mg by mouth, 
as determined by patient specific factors such as patient size, hepatic function, INR, 
concomitant medications, diet, or other factors. Based on these factors or others not 
listed, there may also be days in which the patient is prescribed to not get does not 
receive a dose of warfarin. 
After discharge from the hospital, warfarin dosing will be subsequently managed by an 
anticoagulation clinic, per established protocols.  All patients will have a goal INR of 2-3 
during the duration of the study.  The duration of therapy will be at least 30 days.  The 
patient’s physician may determine that anticoagulation therapy should be continued after 
the study period, based on their examination of the patient at the 30-day post-operative 
examination. 
Warfarin should not be used if a patient has active pathological bleeding. 
If a dose of warfarin is not taken at the scheduled time, the dose should be taken as soon 
as possible on the same day and then continue with daily administration as before, or as 
recommended by the anticoagulation clinic.  The dose should not be doubled to make up 
for a missed dose.   
Warfarin can be taken with or without food, but it is recommended to maintain a 
consistent intake of vitamin K containing foods. 


26 
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14 June  2014 
5.4.1 
Dose Modifications 
Apixaban: in patients with at least 2 of the following characteristics, age ≥80 years, body 
weight ≤60 kg, or serum creatinine ≥1.5 mg/dL (133 µmol/L), the recommended dose of 
apixaban is 2.5 mg twice daily. 
Warfarin: doses of warfarin will be determined on a daily basis while the patient is in the 
hospital.  After discharge from the hospital, after each INR check, a pharmacist or nurse 
will contact the patient to communicate the appropriate dosing. 
5.4.2 
Temporary Discontinuation of Apixaban or Warfarin  
Discontinuing anticoagulants, including apixaban or warfarin, for active bleeding, 
elective surgery, or invasive procedures places patients at an increased risk of thrombosis. 
Lapses in therapy should be avoided, and if anticoagulation with apixaban and warfarin 
must be temporarily discontinued for any reason, therapy should be restarted as soon as 
possible. 
5.5 
Blinding/Unblinding 
Not applicable; study is unblinded. 
5.6 
Concomitant Treatments 
5.6.1 
Prohibited and/or Restricted Treatments 
Concomitant use of drugs affecting hemostasis increases the risk of bleeding. These 
include 
aspirin and other antiplatelet agents, other anticoagulants, heparin, thrombolytic agents, 
selective serotonin reuptake inhibitors, serotonin norepinephrine reuptake inhibitors, and 
nonsteroidal anti-inflammatory drugs (NSAIDs). 
5.6.2 
Other Restrictions and Precautions 
Apixaban should be discontinued at least 48 hours prior to elective surgery or invasive 
procedures with a moderate or high risk of unacceptable or clinically significant bleeding.  
Apixaban  should be discontinued at least 24 hours prior to elective surgery or invasive 
procedures with a low risk of bleeding or where the bleeding would be non-critical in 
location and easily controlled. Bridging anticoagulation during the 24 to 48 hours after 
stopping apixaban and prior to the intervention is not generally required. Apixaban 
should be restarted after the surgical or other procedures as soon as adequate hemostasis 


27 
Apixaban ISR Protocol Shell 
 
14 June  2014 
has been established.  If surgery or invasive procedures cannot be delayed, exercise 
appropriate caution taking into consideration an increased risk of bleeding. This risk of 
bleeding should be weighed against the urgency of intervention. 
The concomitant use of apixaban or warfarin with antiplatelet agents increases the risk of 
bleeding. In patients with atrial fibrillation and a condition that warrants mono or dual 
antiplatelet therapy, a careful assessment of the potential benefits against the potential 
risks should be made before combining this therapy with apixaban.  Patients taking 
clopidogrel or ticagrelor within 5 days prior to surgery, patients taking prasugrel within 7 
days prior to surgery, and patients taking ticlopidine within 10 days prior to surgery, and 
patients taking clopidogrel, ticagrelor, prasugrel, or ticlopidine during the study period 
will be excluded from participation in this study. 
Use apixaban and warfarin with caution when co-administered with non-steroidal anti-
inflammatory drugs (NSAIDs), including aspirin. 
5.7 
Treatment Compliance 
Patient compliance will be monitored during the study.  While the patient is hospitalized, 
we will monitor whether apixaban or warfarin is given as directed by the study 
coordinator.  After the patient has been discharged from the hospital, apixaban 
compliance will be measured by asking the patient to bring any unused medication to 
their 30-day post-operative appointment, where remaining tablets will be counted.  As 60 
tablets will be dispensed to each patient (30-day supply), we use the following formula: 
[(60-(# of remaining tablets)) * 100)] / [2 * (days since filled)] = percent compliance. 
 
After hospital discharge, warfarin compliance will be monitored by measuring the time in 
therapeutic INR range (2-3).  
 
6 
STUDY ASSESSMENTS AND PROCEDURES 
6.1 
Time and Events Schedule 
If a subject chooses to be removed from the study, withdraws informed consent, or if 
therapy must be stopped in the interest of the patient’s safety, data collected to that point 
of the study will be collected for intent-to treat analysis.  We will document the reason 
for a patient’s early withdrawal from the study, or the discontinuation of treatment for a 
patient by the patient’s physician or study coordinator. 


28 
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14 June  2014 
After the 30-day post-operative physician examination, there will no further patient 
assessments.  Analysis of all outcomes will be done by EMR analysis, except for 
treatment compliance as noted above. 


29 
Apixaban ISR Protocol Shell 
 
14 June  2014 
Time and Events Schedule for Protocol: CV185-505 
Procedure 
Prior to 
Surgery (day of 
surgery, or <30 
days prior) 
After 
Diagnosis of 
AFib 
Upon 
Hospital 
Discharge 
At Each 
Anticoagulation 
Clinic Visit 
(warfarin) 
At 30-Day 
Post-
Operative 
Examination 
After 30-Day Post-
Operative 
Examination 
Eligibility Assessments 
 
 
 
 
 
 
Informed Consent 
 
X 
 
 
 
 
Medical History  
 
X 
 
 
 
 
Inclusion/Exclusion Criteria 
 
X 
 
 
 
 
Clinical Drug Supplies 
 
 
 
 
 
 
Randomize 
 
X 
 
 
 
 
Dispense Study Treatment 
 
 
X 
 
 
 
Patient Medication Consultation 
 
 
X 
 
 
 
Safety Assessments 
 
 
 
 
 
 
Pregnancy Test for WOCBP 
X 
 
 
 
 
 
Renal Function Test 
X 
X 
 
 
 
 
Hepatic Function Test 
 
X 
 
 
 
 
INR measurement 
X 
X 
 
X 
 
 
Monitoring for Bleeding Events 
 
 
X 
X 
X 
 
Monitoring for Thrombotic Events 
 
 
X 
X 
X 
 
Efficacy Assessments 
 
 
 
 
 
 
Measure Apixaban Adherence 
 
 
 
 
X 
 
EMR Analysis of All Other Outcomes 
 
 
 
 
 
X 
Outcomes Statistical Analysis 
 
 
 
 
 
X 


30 
Apixaban ISR Protocol Shell 
 
14 June  2014 
6.2 
Study Materials 
Bristol-Myers Squibb (BMS) will provide apixaban at no cost for this study. 
6.3 
Safety Assessments 
1) Major bleeding, as defined by the International Society on Thrombosis and 
Haemostasis based on the following criterion:  
a. Fatal bleeding, and/or  
b. Symptomatic bleeding that occurs in a critical area or organ, such as 
intracranial, intraspinal, intraocular, retroperitoneal, pericardial, in a non-operated 
joint, or intramuscular with compartment syndrome, assessed in consultation with 
the surgeon, and/or  
c. Extrasurgical site bleeding causing a fall in hemoglobin level of 20 g/L (2g/dL) 
or more, or leading to transfusion of two or more units of whole blood or red cells 
within 24-48 hours of the bleeding and/or  
d. Surgical site bleeding that requires a second intervention – open, arthroscopic, 
endovascular- or a hemarthrosis of sufficient size as to interfere with 
rehabilitation by delaying mobilization or delayed wound healing, resulting in 
prolonged hospitalization or a deep wound infection, and/or  
e. Unexpected surgical site bleeding, prolonged and/or sufficiently large to cause 
hemodynamic instability, as assessed by the surgeon, with a fall in hemoglobin of 
at least 20 g/L (2g/dL) or transfusion of two or more units of whole blood or red 
cells within 24 hours of the bleeding. 3 
2) Clinical relevant non-major bleed, defined as any notable bleeding not classified as 
major. 
3) Pregnancy tests will be performed pre-operatively on the day of surgery for all 
WOCBP, via urine hCG screening.   
4) A baseline renal function panel will be obtained either pre-operatively or within 30 
days of surgery.  The renal function panel includes: glucose, BUN, creatinine, 
BUN/creatinine ratio, sodium, potassium, bicarbonate, chloride, calcium, phosphorus, 
albumin, and anion gap.  


31 
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14 June  2014 
5) The hepatic function test panel will be ordered before initiating warfarin (if a recent 
baseline is not available).  This panel includes: total protein, albumin, alk phos, AST, 
ALT, total bilirubin, direct bilirubin, and indirect bilirubin.   
6) INR will be checked before surgery to ensure the patient’s INR is within normal limits 
in preparation for their surgery, regardless of whether they were previously on warfarin, 
and again upon initiation of warfarin therapy.  INR will be checked daily in the hospital, 
and at each visit to the anticoagulation clinic.  These visits are usually scheduled within 
three days of discharge from the hospital, then twice weekly until the INR is therapeutic, 
then weekly for the duration of the study. 
6.4 
Study Assessments  
6.4.1 
Primary Assessment 
The primary assessment is freedom from systemic thromboembolism or stroke: this will 
be as diagnosed by a physician, to include pulmonary embolism, deep vein thrombosis, 
and both hemorrhagic and ischemic stroke.  Events relating to thromboembolism or 
stroke will be adjudicated using pre-determined definitions by independent committee 
members that remain blinded to the patient’s treatment arm.  
6.4.2 
 Secondary  Assessments 
1) Units of blood or blood products given after the first dose of anticoagulation. 
2) Total post-operative length of stay: This will be measured from the date/time of the 
end of the subject’s surgery until the date/time of the patient’s discharge from the 
hospital.  This will be measured in hours, to the nearest tenth of an hour. 
3) Duration from diagnosis of post-operative atrial fibrillation (POAF) to discharge from 
the hospital: This will be measured from the time of the EKG that is obtained after AFib 
is noted on telemetry (confirming the diagnosis of AFib), until hospital discharge.  This 
will be measured in hours, to the nearest tenth of an hour. 
4) Time in therapeutic range of INR, if on warfarin, (eg. 2-3), measured as a percentage 
and defined for each patient using the Rosendaal equation 
5) Patient compliance percentage to apixaban: measured by asking the patient to bring 
any unused medication to their 30-day post-operative appointment, where remaining 
tablets will be counted.  This will be calculated as a percentage using the following 


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14 June  2014 
equation: (# doses prescribed - # of doses not taken and returned to investigator at follow 
up appointment) / # days prescribed. 
7 
ADVERSE EVENTS 
An Adverse Event [AE] is defined as any new untoward medical occurrence 
or worsening of a pre-existing medical condition in a patient or clinical 
investigation subject administered an investigational (medicinal) product and 
that does not necessarily have a causal relationship with this treatment. An 
AE can therefore be any unfavorable and unintended sign (including an 
abnormal laboratory finding, for example), symptom, or disease temporally 
associated with the use of investigational product, whether or not considered 
related to the investigational product. 
 
The causal relationship to study drug is determined by a physician and should 
be used to assess all adverse events (AEs). The causal relationship can be 
one of the following: 
Related: There is a reasonable causal relationship between study drug 
administration and the AE. 
Not related: There is not a reasonable causal relationship between study 
drug administration and the AE. 
 
The term “reasonable causal relationship” means there is evidence to suggest 
a causal relationship.  
 
Adverse events can be spontaneously reported or elicited during open-ended 
questioning, examination, or evaluation of a subject. (In order to prevent 
reporting bias, subjects should not be questioned regarding the specific 
occurrence of one or more adverse events).  
 
7.1 
Serious Adverse Events 
A Serious Adverse Event (SAE) is any untoward medical occurrence at any 
dose that:  
• results in death 
• is life-threatening (defined as an event in which the subject was at risk of 
death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe) 
• requires inpatient hospitalization or causes prolongation of existing 
hospitalization (see NOTE*: below for exceptions) 


33 
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14 June  2014 
• results in persistent or significant disability/incapacity 
• is a congenital anomaly/birth defect 
• is an important medical event, defined as a medical event that may not be 
immediately life-threatening or result in death or hospitalization but, based 
on appropriate medical and scientific judgment, may jeopardize the 
subject or may require intervention (e.g., medical, surgical) to prevent one 
of the other serious outcomes listed above. Examples of such events 
include but are not limited to intensive treatment in an emergency 
department or at home for allergic bronchospasm; blood dyscrasias or 
convulsions that do not result in hospitalization.  
Suspected transmission of an infectious agent (eg, pathogenic or non-
pathogenic) via the study drug is an SAE.  
Although pregnancy, overdose, and cancer are not always serious by regulatory 
definition, these events must be handled as SAEs. 
*NOTE: The following hospitalizations are not considered SAEs:  
− 
A visit to the emergency room or other hospital department lasting less 
than 24 hours that does not result in admission (unless considered an 
“important medical event” or a life-threatening event) 
− 
Elective surgery planned before signing consent 
− 
Admissions as per protocol for a planned medical/surgical procedure 
− 
Routine health assessment requiring admission for baseline/trending of 
health status (eg, routine colonoscopy) 
− 
Medical/surgical admission other than remedying ill health state that 
was planned before study entry. Appropriate documentation is required in 
these cases 
− 
Admission encountered for another life circumstance that carries no 
bearing on health status and requires no medical/surgical intervention (eg, 
lack 
of 
housing, 
economic 
inadequacy, 
caregiver 
respite, 
family 
circumstances, administrative reason) 
− 
 
Adverse Events of Special Interest 
 
In this study, the following adverse events are to be reported to BMS, regardless 
of whether these reports are classified as serious or unexpected. 
 
- 
Potential or suspected cases of liver injury including but not limited to liver 
test abnormalities, jaundice, hepatitis or cholestasis. 
 


34 
Apixaban ISR Protocol Shell 
 
14 June  2014 
 
7.1.1 
Serious Adverse Event Collecting and Reporting  
Following the subject’s written consent to participate in the study, all SAEs, 
whether related or not related to study drug, must be collected, including those 
thought to be associated with protocol-specified procedures. All SAEs must be 
collected that occur during the screening period and within 30 days of 
discontinuing dosing. If applicable, SAEs must be collected that relate to any 
later protocol-specific procedure (such as follow-up skin biopsy). 
The investigator should report any SAE occurring after these time periods that is 
believed to be related to study drug or protocol-specified procedure.  
An SAE report should be completed for any event where doubt exists regarding 
its status of seriousness.  
If the investigator believes that an SAE is not related to study drug, but is 
potentially related to the conditions of the study (such as withdrawal of previous 
therapy, or a complication of a study procedure), the relationship should be 
specified in the narrative section of the SAE Report Form. 
SAEs, whether related or unrelated to the study drug, and pregnancies must be 
reported to BMS within 24 hours. SAEs must be recorded on the FDA MedWatch 
Form 3500A ; Pregnancies on a Pregnancy Surveillance Form. 
SAE Email Address: Worldwide.Safety@BMS.com 
SAE Fax Number: 609-818-3804 
If only limited information is initially available, follow-up reports are required. 
(Note: Follow-up SAE reports should include the same investigator term(s) 
initially reported.)  
If an ongoing SAE changes in its intensity or relationship to study drug or if new 
information becomes available, a follow-up SAE report should be sent within 24 
hours to the BMS (or designee) using the same procedure used for transmitting 
the initial SAE report.  
All SAEs should be followed to resolution or stabilization. 
 


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7.1.2 
SAE Reconciliation 
The investigator will reconcile the clinical database SAE cases transmitted to 
BMS Global Pharmacovigilance (GPV&E). Reconciliation will occur every three 
months and once just prior to database lock/Final Study Report (FSR).  The 
investigator will request a safety data reconciliation report to 
aepbusinessprocess@bms.com.  BMS GPV&E will e-mail upon request from the 
investigator, the GPV&E reconciliation report. The data elements listed on the 
GPV&E safety data reconciliation report will be used for case identification 
purposes. If the investigator determines a case was not transmitted to BMS 
GPV&E, the case will be sent immediately. 
 
7.1.3 
Health Authority Reporting (US FDA IND) 
Investigators must adhere to local Health Authority Reporting Requirements. For 
studies conducted under an investigator sponsored US FDA IND, provide details 
of the following: 
 
- 
Any event that is both serious and unexpected must be reported to the 
Food and Drug Administration (FDA) as soon as possible and no later 
than 7 days (for a death or life-threatening event) or 15 days (for all other 
SAEs) after the investigator’s or institution’s initial receipt of the 
information.  
- 
BMS will be provided with a simultaneous copy of all adverse events filed 
with the FDA. SAEs should be reported on MedWatch Form 3500A, which 
can be accessed at: http://www.accessdata.fda.gov/scripts/medwatch/. 
 
MedWatch SAE forms should be sent to the FDA at: 
MEDWATCH 
5600 Fishers Lane 
Rockville, MD 20852-9787 
Fax: 1-800-FDA-0178 (1-800-332-0178) 
http://www.accessdata.fda.gov/scripts/medwatch/ 
 
All SAEs should simultaneously be faxed or e-mailed to BMS at: 
Global Pharmacovigilance & Epidemiology 


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14 June  2014 
Bristol-Myers Squibb Company 
Fax Number: 609-818-3804 
Email: Worldwide.safety@bms.com 
 
7.2 
Non-Serious Events 
A non-serious adverse event is an AE not classified as serious. 
7.2.1 
Non-Serious Adverse Events (NSAEs) Collecting and 
Reporting 
The collection of non-serious adverse event (NSAE) information should begin at 
initiation of study drug. Non-serious adverse event information should also be 
collected from the start of a placebo lead-in period or other observational period 
intended to establish a baseline status for the subjects.  
Non-serious AEs should be followed to resolution or stabilization, or reported as 
SAEs if they become serious. Follow-up is also required for non-serious AEs that 
cause interruption or discontinuation of study drug, or those that are present at 
the end of study treatment as appropriate.  
Non-serious Adverse Events are provided to BMS via annual safety reports (if 
applicable), and interim or final study reports. 
 
7.3 
Laboratory Test Abnormalities 
The following laboratory abnormalities should be captured and reported as 
appropriate: 
- 
Any laboratory test result that is clinically significant or meets the definition 
of an SAE 
- 
Any laboratory test result abnormality that required the subject to have 
study drug discontinued or interrupted 
- 
Any laboratory test result abnormality that required the subject to receive 
specific corrective therapy.  


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It is expected that wherever possible, the clinical rather than the laboratory term 
will be used by the reporting investigator (eg, use the term anemia rather than 
low hemoglobin value).  
Laboratory test abnormalities are provided to BMS via annual safety reports (if 
applicable), and interim or final study reports. 
 
7.4 
Pregnancy 
If, following initiation of the investigational product, it is subsequently discovered 
that a study subject is pregnant or may have been pregnant at the time of 
investigational product exposure, including during at least 5 half-lives after 
product administration, the investigational product will be permanently 
discontinued in an appropriate manner (eg, dose tapering if necessary for subject 
safety).  
The investigator must immediately notify WorldwideSafety@BMS.com of this 
event via the Pregnancy Surveillance Form within 24 hours and in accordance 
with SAE reporting procedures. 
Follow-up information regarding the course of the pregnancy, including perinatal 
and neonatal outcome and, where applicable, offspring information must be 
reported on a Pregnancy Surveillance Form. 
Any pregnancy that occurs in a female partner of a male study participant should 
be reported to BMS. Information on this pregnancy may also be collected on the 
Pregnancy Surveillance Form. 
Protocol-required procedures for study discontinuation and follow-up must be 
performed on the subject unless contraindicated by pregnancy (eg, x-ray 
studies). Other appropriate pregnancy follow-up procedures should be 
considered if indicated. 
 
7.5 
Overdose 
An overdose is defined as the accidental or intentional administration of any dose 
of a product that is considered both excessive and medically important. All 
occurrences of overdose must be reported as SAEs. 


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7.6 
Other Safety Considerations 
Any significant worsening noted during interim or final physical examinations, 
electrocardiograms, x-rays, and any other potential safety assessments, whether 
or not these procedures are required by the protocol, should also be recorded as 
a non-serious or serious adverse event, as appropriate, and reported 
accordingly. 
 
8 
DATA MONITORING COMMITTEE 
Not Applicable. 
 
9 
STATISTICAL CONSIDERATIONS 
9.1 
Sample Size Determination 
For this pilot study, we anticipate 300 patients will be eligible for inclusion over the 28-
month study period (estimate two patient enrollments per month).  With an expected 
POAF rate of 25%, and a 5% exclusion rate, we expect 70 patients will be eligible for 
study participation within the study period.  We will enroll the first 56 patients meeting 
the required criteria, to be included in the final analysis of endpoints.  This pilot study 
should therefore be used as a reference for future studies of novel anticoagulants use in 
patients that have had a recent surgery, or have atrial fibrillation due to other reversible 
causes.  
9.2 
Populations for Analyses 
Patients diagnosed with post-operative atrial fibrillation after undergoing isolated CABG 
that require anticoagulation and meet inclusion/exclusion criteria will be asked to 
participate in this study.   
 
9.3 
Analyses 
Continuous variables will be expressed as mean ± standard deviation or median with 
interquartile range (IQR) as appropriate. Continuous variables will be compared using t-


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14 June  2014 
tests for parametric data or Wilcoxon analysis for nonparametric data.  We will complete 
the analysis in an intent-to-treat manner.  We will include analysis for confidence 
intervals and other appropriate statistical tests to assess binary outcomes.  We realize that 
statistical tests alone will be of limited value as this is a pilot study.  Data will be 
analyzed using JMP software, version 12.0.0 (Cary, NC). All statistics collected will be 
analyzed after completion of the 30-day trial period for all subjects. 
10 
STUDY MANAGEMENT 
10.1 
Compliance with the Protocol 
The study shall be conducted as described in this approved protocol. All revisions to the 
protocol must be discussed with, BMS. The investigator should not implement any 
deviation or change to the protocol without prior review and documented 
approval/favorable opinion from the IRB/IEC of an amendment, except where necessary 
to eliminate an immediate hazard(s) to study subjects. 
If a deviation or change to a protocol is implemented to eliminate an immediate hazard(s) 
prior to obtaining IRB/IEC approval/favorable opinion, as soon as possible the deviation 
or change will be submitted to: 
• IRB/IEC for review and approval/favorable opinion 
• Bristol-Myers Squibb 
• Regulatory Authority(ies), if required by local regulations 
Documentation of approval signed by the chairperson or designee of the IRB(s)/IEC(s) 
must be sent to BMS. 
If an amendment substantially alters the study design or increases the potential risk to the 
subject: (1) the consent form must be revised and submitted to the IRB(s)/IEC(s) for 
review and approval/favorable opinion; (2) the revised form must be used to obtain 
consent from subjects currently enrolled in the study if they are affected by the 
amendment; and (3) the new form must be used to obtain consent from new subjects prior 
to enrollment. 
Patients who need to be reconsented can be reconsented over the phone if they are unable 
to do so at the clinic. The coordinator will send an updated consent form to the patient via 
mail or electronically. When the patient has the consent, the coordinator will review the 
consent with the patient over the phone. Any questions can be answered by the 
coordinator during the consenting process. The patient will then send the original signed 


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14 June  2014 
consent back to the coordinator. The coordinator who conducted the phone consent will 
sign and date the applicable line and upload to the patient’s chart. The coordinator must 
also document the consent discussion and receipt of the consent in the patient’s EMR. 
If the revision is an administrative letter, investigators must inform their IRB(s)/IEC(s). 
For complete information on the requirements for protocols, protocol amendments, 
and informed consents, refer to 21CFR50. 
10.2 
Records Retention  
10.2.1 
Records Retention 
The investigator must retain all study records and source documents for the maximum 
period required by applicable regulations and guidelines, or institution procedures, or for 
the period specified by BMS, whichever is longer.  
If the investigator withdraws from the study (eg, relocation, retirement), the records shall 
be transferred to a mutually agreed upon designee (eg, another investigator, IRB). Notice 
of such transfer will be given in writing to BMS.  
10.2.2 
Study Drug Records  
It is the responsibility of the investigator to ensure that a current disposition record of 
investigational product (those supplied by the BMS) is maintained at each study site 
where study drug and noninvestigational product(s) is/are inventoried and dispensed. 
Records or logs must comply with applicable regulations and guidelines and should 
include: 
• amount received and placed in storage area 
• amount currently in storage area 
• label ID number or batch number  
• amount dispensed to and returned by each subject, including unique subject 
identifiers 
• amount transferred to another area/site for dispensing or storage 
• non-study disposition (eg, lost, wasted)  
• amount destroyed at study site, if applicable 
• amount returned to the BMS 
• retain samples for bioavailability/bioequivalence, if applicable  
• dates and initials of person responsible for Investigational Product (IP) 
dispensing/accountability, as per the Delegation of Authority Form. 


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10.3 
Destruction of Investigational Product  
If the study drugs are to be destroyed on site, it is the investigator’s responsibility to 
ensure that arrangements have been made for disposal, and that procedures for proper 
disposal have been established according to applicable regulations, guidelines, and 
institutional procedures. Appropriate records of the disposal must be maintained.  


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11 
GLOSSARY OF TERMS 
Term 
Definition 
Adverse Reaction 
An adverse event that is considered by either the 
investigator or the sponsor to be related to the 
investigational product 
Expedited Safety Report 
Rapid notification to investigators of all SAEs that are 
suspected (related to the investigational product) and 
unexpected (ie, not previously described in the 
Investigator Brochure), or that could be associated with 
the study procedures.  
SUSAR 
Suspected, Unexpected, Serious Adverse Reaction as 
termed by the European Clinical Trial Directive 
(2001/20/EC).  
Unexpected Adverse 
Reaction 
An adverse reaction, the nature or severity of which is 
not consistent with the applicable product information 
(eg, Investigator Brochure for an unapproved 
investigational product) 
 


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12 
LIST OF ABBREVIATIONS 
AE 
Adverse Event 
AFib 
Atrial Fibrillation 
BMS 
Bristol-Myers Squibb 
CTCAE 
Common Terminology Criteria for Adverse Events 
DVT 
Deep Vein Thrombosis 
EMR 
Electronic Medical Record 
ESR 
Expedited Safety Report 
ESRD 
End Stage Renal Disease 
FDA 
Food and Drug Administration 
FSH 
Follicle-Stimulating Hormone 
GCP 
Good Clinical Practice 
HCG 
Human Chorionic Gonadotropin 
HRT 
Hormone Replacement Therapy 
IB 
Investigator Brochure 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug (Application) 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
ISR 
Investigator-Sponsored Research 
NCI 
National Cancer Institute 
NSAE 
Non-Serious Adverse Event 
PE 
Pulmonary Embolism 
SAE 
Serious Adverse Event 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
WOCBP 
Women of Child-Bearing Potential 
 


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13 
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8. Fuster V, Ryden LE, Asinger RW, et al.  ACC/AHA/ESC guidelines for the management of 
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13. Connolly SJ, Ezekowitz MD, Yusuf S, et al, RE-LY Steering Committee and Investigators. 
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