Clinical trial NCT04142658
Conditions: Aortic Valve Disease Aortic Valve Stenosis Aortic Valve Failure
Sponsor: Artivion Inc.
Start date: 2020-05-01; Completion date: 2022-12-12
Enrollment: 863 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Currently, warfarin is the only approved anticoagulation for patients with mechanical valves. The purpose of this study is to determine if participants with an On-X Prosthetic Heart Valve / On-X aortic valve can be maintained safely and effectively on apixaban. Both the On-X aortic valve and apixaban have been approved for use by the US Food and Drug Administration (FDA) but they have not been approved to be used together.

Detailed description:
There is an unmet clinical need for an alternative to warfarin, such as a direct oral anticoagulant (DOAC), as anticoagulation in participants with an aortic mechanical prosthetic valve. Some participants may be genetically hyper- or hypo-responsive to warfarin, which makes management difficult. Another small group of participants is allergic to warfarin. A much larger group of participants has difficulty maintaining warfarin control due to dietary and drug interactions. Finally, the requirement for routine blood testing makes people reluctant to take warfarin. All of these factors drive younger participants in need of aortic valve replacement (AVR) toward selection of a tissue valve instead of a mechanical valve. Despite multiple studies (randomized, matched and risk adjusted) that show that tissue valves are associated with worse outcomes, younger participants choose this type of valve to avoid warfarin. In addition, multiple clinical studies have shown valve reoperation rates are higher for tissue valves used in these younger participants. Providing an alternative to warfarin anticoagulation may lead younger participants to choose a mechanical valve with greater durability and better clinical outcomes.

Arms: arm 1: Apixaban 5 mg twice daily(BID) or 2.5 mg BID arm 2: Patients randomized to the warfarin arm will continue warfarin in the INR range of (2.0-3.0)
Interventions: intervention 1: Apixaban 5 MG intervention 2: Apixaban 2.5 MG intervention 3: Warfarin intervention 4: On-X Aortic Mechanical Valve
Intervention descriptions: intervention 1: For patients that do NOT meet the following criteria

* age ≥ 80 years
* weight ≤ 60 kilograms
* creatinine ≥ 1.5 mg/dL (133 micromol/L) intervention 2: For patients that meet at least 2 of the following criteria

* age ≥ 80 years
* weight ≤ 60 kilograms
* creatinine ≥ 1.5 mg/dL (133 micromol/L) intervention 3: Active Control Intervention intervention 4: Inclusion Criterion: Implantation of an On-X mechanical valve in the aortic position at least 3 months (90 days) ago.

Protocol documents:
Prot_SAP_000.pdf: 
PROACT Xa - A Trial to Determine if Participants With an 
On-X Aortic Valve Can be Maintained Safely on Apixaban 
(NCT04142658) 
 
Protocol Version 1.0; 15 Jan 2020 
Statistical Analysis Plan, V1.0; January 15, 2020 
Statistical Analysis Plan, v1.4; January 11, 2023 


This supplement contains the following items: 
1.
Protocol (first and final version).
2.
Original and final versions of the statistical analysis plan with a summary of changes.




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CryoLife PROACT Xa Protocol Version 1.0; 15 Jan 2020  
 
 
2 
 
 
 
 
 
 
 
 
 
 
 
 
Coordinating Investigators and Contact Information: 
 
John H. Alexander, MD, MHS 
Lars Svensson, MD 
Duke Clinical Research Institute 
Cleveland Clinic 
919-668-8955 
216-444-6962 
  john.h.alexander@duke.edu 
 
 
  svenssl@ccf.org 
 
  
 
 
 


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CryoLife PROACT Xa Protocol Version 1.0; 15 Jan 2020  
 
 
3 
 
Table of Contents 
1 
Protocol Summary .............................................................................................................. 6 
1.1 
Schedule of Activities (SoA)....................................................................................... 9 
2 
Introduction ....................................................................................................................... 11 
2.1 
Study Rationale ......................................................................................................... 11 
2.2 
Background ............................................................................................................... 11 
2.3 
Benefit/Risk Assessment ........................................................................................... 13 
2.3.1 
Benefits ............................................................................................................. 13 
2.3.2 
Risks ................................................................................................................. 13 
3 
Objectives and Outcomes ................................................................................................. 15 
4 
Study Design ...................................................................................................................... 16 
4.1 
Overall Design .......................................................................................................... 16 
4.2 
Scientific Rationale for Study Design ....................................................................... 16 
4.3 
Justification for Dose ................................................................................................ 17 
4.4 
End of Study Definition ............................................................................................ 17 
4.5 
Study Population ....................................................................................................... 17 
4.5.1 
Inclusion Criteria .............................................................................................. 17 
4.5.2 
Exclusion Criteria ............................................................................................. 18 
4.6 
Lifestyle Considerations ............................................................................................ 18 
4.7 
Screen Failures .......................................................................................................... 18 
5 
Study Intervention(s)/Test Article(s) Administered ...................................................... 19 
5.1 
Study Drugs ............................................................................................................... 19 
5.2 
Medical Devices ........................................................................................................ 19 
5.3 
Preparation/Handling/Storage/Accountability .......................................................... 20 
5.4 
Measures to Minimize Bias: Randomization and Blinding ...................................... 20 
5.5 
Study Intervention Compliance ................................................................................. 20 
5.6 
Concomitant Therapy ................................................................................................ 21 
5.7 
Dose Modification ..................................................................................................... 21 
5.8 
Intervention after the End of the Study ..................................................................... 21 
5.9 
Discontinuation of Study Intervention and Participant Discontinuation/Withdrawal
 ................................................................................................................................... 22 
5.9.1 
Discontinuation of Study Intervention .............................................................. 22 
5.9.2 
Participant Discontinuation/Withdrawal from the Study .................................. 22 
5.9.3 
Lost to Follow up .............................................................................................. 22 
6 
Study Assessments and Procedures ................................................................................. 23 
6.1 
Efficacy Assessments ................................................................................................ 23 
6.2 
Safety Assessments ................................................................................................... 24 
6.3 
Other Assessments .................................................................................................... 24 
7 
Adverse Events (AEs) and Serious Adverse Events (SAEs) ......................................... 25 
7.1 
Time Period and Frequency for Collecting AE Information ..................................... 25 
7.2 
Regulatory Reporting Requirements for SAEs ......................................................... 25 
7.3 
Medical Device Incidents (Including Malfunctions, ADEs, UADEs) ...................... 25 
7.4 
Treatment of Overdose .............................................................................................. 26 


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8 
Statistical Considerations ................................................................................................. 27 
8.1 
Statistical Hypotheses ............................................................................................... 27 
8.2 
Sample Size Determination ....................................................................................... 27 
8.3 
Populations for Analyses ........................................................................................... 30 
8.4 
Statistical Analyses ................................................................................................... 30 
8.4.1 
Efficacy Analyses ............................................................................................. 31 
8.4.2 
Safety Analyses ................................................................................................. 31 
8.4.3 
Other Analyses .................................................................................................. 32 
9 
Supporting Documentation and Operational Considerations ...................................... 33 
9.1 
Regulatory, Ethical, and Study Oversight Considerations ........................................ 33 
9.1.1 
Regulatory and Ethical Considerations ............................................................. 33 
9.1.2 
Financial Disclosure ......................................................................................... 33 
9.1.3 
Informed Consent Process ................................................................................ 33 
9.2 
Data Protection .......................................................................................................... 34 
9.3 
Data Quality Control and Assurance ......................................................................... 34 
9.4 
Source Documents .................................................................................................... 35 
9.5 
Study and Site Closure .............................................................................................. 35 
9.6 
Publication Policy ..................................................................................................... 36 
9.7 
Clinical Laboratory Tests .......................................................................................... 36 
9.8 
Contraceptive Guidance and Collection of Pregnancy Information.......................... 36 
9.8.1 
Definitions: ....................................................................................................... 36 
9.8.2 
Female Participants who become pregnant ...................................................... 37 
10 
Medical Device Incidents: Definition and Procedures for Recording, Evaluating, 
Follow-up, and Reporting ................................................................................................ 37 
10.1 
Definitions of a Medical Device Incident ................................................................. 37 
10.2 
Documentation of Medical Device Incidents/Effects ............................................... 38 
11 
References for sample size calculation ............................................................................ 39 
12 
Abbreviations .................................................................................................................... 41 
13 
References .......................................................................................................................... 43 
 
 


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5 
List of Tables 
Table 1 
Study Drugs ................................................................................................................19 
Table 2. 
Event rates and confidence intervals for warfarin, DAPT, and apixaban in all-
comer AVR population. .............................................................................................29 
Table 3. 
References used to estimate the primary outcome rate of warfarin (%/pt-yr). ...........39 
Table 4. 
Estimated event rates of standard warfarin and DAPT for low risk patients in the 
PROACT trial. ............................................................................................................40 
  
List of Figures 
Figure 1. 
Comparison of valve thrombus weight. .....................................................................13 
 
 
 
 


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CryoLife PROACT Xa Protocol Version 1.0; 15 Jan 2020  
 
 
6 
1 Protocol Summary 
 
Protocol Title: A prospective, randomized, active (warfarin) controlled, parallel-arm clinical 
trial to determine if patients with an On-X aortic valve can be maintained safely 
and effectively on the factor Xa inhibitor apixaban 
 
Short Title: PROACT Xa 
 
Rationale: 
There is an unmet clinical need for an alternative to warfarin, such as a direct oral anticoagulant 
(DOAC), as anticoagulation in patients with an aortic mechanical prosthetic valve. Some 
patients may be genetically hyper- or hypo-responsive to warfarin, which makes management 
difficult. Another small group of patients is allergic to warfarin. A much larger group of patients 
has difficulty maintaining warfarin control due to dietary and drug interactions. Finally, the 
requirement for routine blood testing makes people reluctant to take warfarin. All of these 
factors drive younger patients in need of aortic valve replacement (AVR) toward selection of a 
tissue valve instead of a mechanical valve. Despite multiple studies (randomized, matched and 
risk adjusted) that show that tissue valves are associated with worse outcomes, younger patients 
choose this type of valve to avoid warfarin (Goldstone et al., 2017; Head et al., 2017; Glaser et 
al., 2016). In addition, multiple clinical studies have shown valve reoperation rates are higher 
for tissue valves used in these younger patients (McClure et al., 2010 and Bourguignon et al., 
2016). Providing an alternative to warfarin anticoagulation may lead younger patients to choose 
a mechanical valve with greater durability and better clinical outcomes.  
Objectives and Outcomes: 
Co-Primary Efficacy Objectives 
 To determine if apixaban is non-inferior to warfarin (INR target range 2.0 - 3.0) for 
patients with an On-X mechanical heart valve implanted in the aortic position for the 
primary composite outcome of valve thrombosis and valve-related thromboembolism  
 To determine if apixaban provides acceptable anticoagulation for patients with an On-X 
mechanical heart valve implanted in the aortic position for the primary composite 
outcome of valve thrombosis and valve-related thromboembolism compared with an 
objective performance criterion (OPC)1 
Primary Safety Objective 
 To determine if apixaban is superior to warfarin (INR target range 2.0 - 3.0) for the safety 
outcome of major bleeding in patients with an On-X mechanical heart valve implanted in the 
aortic position 
Secondary Efficacy Objectives 
                                                     
1 On-X mechanical heart valve implanted in the aortic position refers to either an On-X Aortic Prosthetic Heart Valve or 
an On-X Ascending Aortic Prosthesis 


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CryoLife PROACT Xa Protocol Version 1.0; 15 Jan 2020  
 
 
7 
 To determine if apixaban is superior to warfarin (INR target range 2.0 - 3.0) for the primary 
composite outcome of valve thrombosis and valve-related thromboembolism in patients with 
an On-X mechanical heart valve implanted in the aortic position 
 To compare apixaban with warfarin (INR target range 2.0 – 3.0) for the individual 
components of the primary outcome (valve thrombosis and valve-related 
thromboembolism) in patients with an On-X mechanical heart valve implanted in the 
aortic position 
 To compare apixaban with warfarin (INR target range 2.0 - 3.0) for the primary composite 
outcome of valve thrombosis and valve-related thromboembolism in pre-specified 
subgroups of patients with an On-X mechanical heart valve implanted in the aortic position 
 
 
Overall Design: 
This is a prospective, multicenter, open-label, randomized active controlled clinical trial to 
determine if apixaban is non-inferior to warfarin (INR target range 2.0 - 3.0) for the primary 
composite outcome of valve thrombosis and valve-related thromboembolism in patients with an 
On-X mechanical heart valve implanted in the aortic position. A co-primary efficacy objective 
will determine if apixaban provides acceptable anticoagulation for patients with an On-X 
mechanical heart valve implanted in the aortic position for the primary composite outcome of 
valve thrombosis and valve-related thromboembolism compared with an OPC (Wu et al., 2014). 
Each participant will be followed for at least 2 years and each randomized arm will achieve at 
least 800 patient-years. 
The study will consist of approximately 1000 participants (randomized 1:1 with approximately 
500 participants in each of the apixaban and warfarin arms) at a minimum of 3 sites and up to 
60 sites in North America, and potentially in Europe and/or Japan, who are 18 years of age or 
older, at least 3 months out from an On-X aortic valve implantation, and currently 
anticoagulated with warfarin. 
Participants will be randomized to either continue warfarin with a target INR of 2.0 to 3.0 or 
switch to apixaban 5 mg twice daily (BID), or 2.5 mg BID in participants with 2 or 3 of the 
following characteristics: 
 age ≥ 80 years 
 weight ≤ 60 kilograms 
 creatinine ≥ 1.5 mg/dL (133 micromol/L) 
 
For participants randomized to apixaban, INR testing will be performed on the current 
warfarin dose with the following algorithm to initiate apixaban: 
1. 
INR < 2; stop warfarin and start apixaban 
2. 
INR 2.0 to 3.0; hold warfarin for 2 days, start apixaban on day 3 
3. 
INR > 3.0 to 4.0; hold warfarin for 4 days, start apixaban on day 5 
4. 
INR > 4.0; hold warfarin for 2 days, recheck INR, refer to steps 1, 2, or 3 
 


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CryoLife PROACT Xa Protocol Version 1.0; 15 Jan 2020  
 
 
8 
Number of Participants: 
Approximately 1000 participants will be randomly assigned to study intervention with 
an estimated total of 500 participants in the apixaban arm and 500 participants in the 
warfarin arm (see Section 8.2). 
 
Intervention Groups and Duration: 
All participants are expected to participate in this study for at least 2 years which includes the 
following study periods: screening/randomization, intervention, and follow-up. Participants will 
either continue warfarin with a target INR between 2.0 and 3.0, or switch to apixaban after 
randomization. A participant randomized to apixaban will start on apixaban 5 mg twice daily. If 
2 of the following 3 characteristics are met at any time during the study, participants 
randomized to apixaban will be started on a reduced dose of 2.5 mg twice daily: 
 age ≥ 80 years 
 weight ≤ 60 kilograms 
 creatinine ≥ 1.5 mg/dL (133 micromol/L) 
 
Data Safety and Monitoring Board: 
An independent Data Safety Monitoring Board (DSMB) will be responsible for the ongoing, 
independent evaluation of participants’ safety.  Clinical events, as outlined in Section 7, will be 
collected and reported overall and unblinded to study group to the DSMB. DSMB membership 
will be independent from the study investigators, and will consist of at least 3 members with at 
least 1 statistician and 1 cardiothoracic surgeon.  The DSMB will review clinical outcomes and 
other safety concerns, and may recommend modification or termination of the trial if safety 
concerns warrant such a recommendation. The DSMB will establish criteria for recommending 
study termination, to the extent possible that the DSMB can predict adverse outcomes, before 
the proposed study begins. The DSMB will meet at least two times during the study in order to 
assure close and timely monitoring of clinical outcomes and safety. DSMB recommendations 
will be considered and acted upon by the academic leadership of the trial (Steering Committee) 
and the trial sponsor (CryoLife).  
 
 
 


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CryoLife PROACT Xa Protocol Version 1.0; 15 Jan 2020  
 
 
9 
1.1 
Schedule of Activities (SoA) 
 
 
Procedure 
Screening (up 
to 30 days 
before Day 1)1 
Day 1 
Randomization2 
Every 
month  
(±14 
days) 
Intervention Period (Months)1 
 
Notes 
 
1 
 
2 
 
3 
 
6 
 
12 
 
18 
 
243 
Every 6 
months 
(±45 days)  
if 
applicable 
Final 
Study 
Visit 
 
(±14 days) 
(±45 days) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test 
X 
 
 
 
 
 
 
 
 
 
 
 
Serum or urine pregnancy test, 
women of childbearing potential 
Demographics 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Prior warfarin history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medication 
review 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Valve characteristics 
 
X 
 
 
 
 
 
 
 
 
 
 
Including date and size of valve 
implant, conduit, etc. 
 
Vital Signs 
 
X 
 
 
 
 
 
X 
 
X 
X4 
 
Including pulse rate, blood 
pressure, and weight within 45 
days before visit 
Hemoglobin 
 
X 
 
 
 
 
 
X 
 
X 
X4 
 
Obtained by study physician if no 
clinical results available within 45 
days before visit 
Serum creatinine 
 
X 
 
 
 
 
 
X 
 
X 
X4 
 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
Randomization initiates first 30-day 
supply of study drug  


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CryoLife PROACT Xa Protocol Version 1.0; 15 Jan 2020  
 
 
10 
Procedure 
Screening (up 
to 30 days 
before Day 1)1 
Day 1 
Randomization2 
Every 
month  
(±14 
days) 
Intervention Period (Months)1 
 
Notes 
 
1 
 
2 
 
3 
 
6 
 
12 
 
18 
 
243 
Every 6 
months 
(±45 days)  
if 
applicable 
Final 
Study 
Visit 
 
(±14 days) 
(±45 days) 
 
Call for supply of 
study medication 
 
 
 
 
 X 
 
 
 
 
 
 
 
 
 
After the first study drug fill, a 
telephone call will occur to assess 
gaps and dosing changes prior to 
filling the next supply of study 
medication 
 
 
 
INR levels 
 
X 
      X 
 
 
 
 
 
 
 
 
 
At least monthly INR testing 
required for participants 
randomized to warfarin. Assess for 
gaps in INR testing. INR obtained 
by study physician if no INR test 
results available within 37 days 
Assess for thrombosis and 
thromboembolic events 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Assess for bleeding 
events 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Assess for changes in 
antithrombotic 
therapy (aspirin, 
anticoagulant) 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Assess quality of 
life and satisfaction 
with anticoagulation 
 
X 
 
X 
 
 
X 
X 
 
X 
 
X 
 
EQ5D and Duke Anticoagulation 
Satisfaction Scale 
Discontinue study 
drug and return to 
warfarin 
 
 
 
 
 
 
 
 
 
 
 
X 
 
1. Month = 30 days.  
2. Screening and Day 1 activities may be performed at the same visit. 
3. Month 24 assessments will be performed if a participant withdraws early from the study (not just stops study drug but withdraws consent to participate). These assessments should be 
performed within 3 months after withdrawal. 
4. Vital Signs, Hemoglobin, and Serum creatinine to be performed annually (at 12, 24, 36, and 48 months) 


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2 Introduction 
PROACT Xa is designed to determine if patients with an On-X aortic valve, alone or as an On-X 
Ascending Aortic Prosthesis, can be maintained safely and effectively on the factor Xa inhibitor apixaban 
(Eliquis). The primary outcome is a composite rate of valve thrombosis and valve-related 
thromboembolism, which will be used for co-primary analyses. The first co-primary analysis will 
determine whether apixaban is non-inferior to warfarin (INR target range 2.0 - 3.0) in patients with an 
On-X mechanical heart valve implanted in the aortic position. The second co-primary analysis will 
compare the composite rate for apixaban-treated participants to updated OPC for FDA-approved 
mechanical heart valves in the aortic position. This is an open-label study in which patients who are at 
least 3 months out from implantation of an On-X valve in the aortic position will be randomized in a 1:1 
fashion to either apixaban 5 mg twice daily or 2.5 mg twice daily in selected participants meeting 
reduced dose criteria or warfarin adjusted to an INR of 2.0-3.0. Participants will be followed for at least 2 
years after randomization with at least 800 patient-years of follow-up in each randomized group.  If the 
primary efficacy hypothesis is proven, the data will be used to support a change in the On-X valve device 
label to state that apixaban is an acceptable alternative to warfarin for anticoagulation in patients 3 or 
more months after implantation of an On-X valve in the aortic position. 
2.1 
Study Rationale 
There is an unmet clinical need for an alternative to warfarin, such as a direct oral anticoagulant 
(DOAC), as anticoagulation in patients with an aortic mechanical prosthetic valve. Some 
patients may be genetically hyper- or hypo-responsive to warfarin, which makes management 
difficult. Another small group of patients is allergic to warfarin. A much larger group of 
patients has difficulty maintaining warfarin control due to dietary and drug interactions. Finally, 
the requirement for routine blood testing makes people reluctant to take warfarin. All of these 
factors drive younger patients in need of aortic valve replacement toward selection of a tissue 
valve instead of a mechanical valve. Despite multiple studies (randomized, matched and risk 
adjusted) that show that tissue valves are associated with worse outcomes, younger patients 
choose this type of valve to avoid warfarin (Goldstone et al., 2017; Head et al., 2017; Glaser et 
al., 2016). In addition, multiple clinical studies have shown valve reoperation rates are higher 
for tissue valves used in these younger patients (McClure et al., 2010 and Bourguignon et al., 
2016). Providing an alternative to warfarin anticoagulation may lead younger patients to choose 
a mechanical valve with greater durability and better clinical outcomes. 
 
2.2 
Background 
The On-X Prosthetic Heart Valve is a bileaflet mechanical heart valve, which consists of an 
orifice housing and 2 leaflets. The prosthesis was originally approved by the Food and Drug 
Administration in 2001 with more than 200,000 implants worldwide. There have been multiple 
studies and publications evaluating the valve’s safety and efficacy in the aortic position 
(Palatianos et al., 2007, McNicholas et al., 2006, and Chambers et al., 2013). Multicenter 
premarket clinical studies conducted in Europe (Palatianos et al., 2007) and North America 
(McNicholas et al., 2006) exhibited low thromboembolic (TE) rates at 0.88 and 0.9 %/patient-
year (pt-yr). Longer-term data of up to 12 years was reported on 214 patients (Chambers et al., 
2013) for On-X valves in the aortic position demonstrating a low rate of adverse clinical events 
and TE rate of 0.6%/pt-yr. An interesting finding that stood out in these reported studies was 
the low rate of thrombosis with the On-X valve in the aortic valve position. The preclinical and 


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clinical history of the On-X valve includes studies looking at thrombotic potential and studies 
in poorly anticoagulated populations. Flameng et al., 2002 conducted a study of the valve in a 
non-anticoagulated sheep model designed to predict resistance to thrombosis and found that 
the On-X valve statistically outperformed both the St. Jude Medical (SJM) and Carbomedics 
(CMI) valves. The first thrombosis of an On-X valve occurred at 6 weeks compared to 2 weeks 
for the other 2 valves. Additionally, 2 of 6 test valves survived the test without thrombosis 
compared to 0 of 7 valves for the others. A South African clinical trial conducted by Wu  et al., 
2006 assessed 104 On-X valves in the aortic position with no or inadequate anticoagulation in 
up to 40% of the study population. Despite these limitations in anticoagulation management, 
there was no valve thrombosis and a TE rate of 1.1%/pt-yr. Given these favorable clinical 
outcomes, the On-X valve was believed to be an ideal candidate to assess using an alternate 
anticoagulation strategy. These data formed the basis for the Prospective Randomized On-X 
Valve Anticoagulation Clinical Trial (PROACT trial) investigating the safety and efficacy of 
lower anticoagulation goals with the On-X valve (ClinicalTrials.gov number, NCT00291525). 
On-X Life Technologies conducted a study looking at the use of reduced anticoagulation 
therapy, (ie, warfarin with a lower target INR of 1.5 to 2.0) (Puskas et al., 2014 and Puskas et 
al., 2018) 3 months after valve implantation. The PROACT trial was conducted in 375 patients 
at high risk of thromboembolism (eg, atrial fibrillation, low ejection fraction, or enlarged left 
atrium). With a mean follow-up of 3.8 years, the mean INR was 2.50 ± 0.63 for the control and 
1.89 ± 0.49 for the test groups (P < .0001). The participants anticoagulated with a lower target 
INR had significantly lower incidence of major (1.59% vs 3.94%/pt-yr; P = 0.002) and minor 
(1.27% vs 3.49%/pt-yr; P = 0.002) bleeding. The incidence of stroke, transient ischemic attack, 
total neurologic events, and all-cause mortality were not significantly different between the 2 
groups. 
An alternative to warfarin is the use of one of the DOACs. These drugs fall generally into 
2 categories: direct thrombin inhibitors and factor Xa inhibitors. DOACs, including the thrombin 
inhibitor (dabigatran) and factor Xa inhibitors (apixaban, rivaroxaban, and edoxaban), have been 
approved for use in patients with nonvalvular atrial fibrillation; apixaban and rivaroxaban have 
also been approved for the prevention and treatment of venous thromboembolism. 
A trial of dabigatran in patients with mechanical valves (RE-ALIGN) was conducted and 
ultimately halted due to increases in both bleeding and thrombotic events with dabigatran 
compared to warfarin (Eikelboom et al., 2013). The reason for these poor results is ultimately 
unclear. Study design may be a contributor as the study examined multiple dabigatran doses, 
multiple drug ‘conversion’ strategies, valves in all positions and all brands of mechanical valves. 
Additionally, RE-ALIGN included patients with newly implanted valves, and clinical outcomes 
were worse in these patients. Our hypothesis is that the favorable mechanical features of the 
On--X valve, will permit a higher likelihood of success with use of a DOAC than observed in the 
RE-ALIGN study. This trial differs from the RE-ALIGN trial design by including a single 
implant position (aortic), a single valve type (On-X aortic valve or On-X AAP), and excluding 
patients who are within 3 months from valve implantation surgery. 
In addition to modifications in trial design and valve type versus the RE-ALIGN trial, PROACT 
Xa will be conducted using the factor Xa inhibitor, apixaban. Apixaban has a favorable bleeding 
profile and similar thromboembolism prevention compared with warfarin (Granger et al., 2011). 
For mechanical valves, a preclinical study was performed using a heterotopic aortic valve porcine 
model with bileaflet mechanical aortic valve implants (Lester et al., 2017). In the 4 randomized 


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groups, postmortem valve thrombus weight was lowest in the apixaban infusion group, see Figure 
1. The apixaban infusion group dose was modeled after human pharmacokinetic data based on 
the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation 
study (ARISTOTLE) (Granger et al., 2011). The apixaban infusion was designed to mimic the 
human 5 mg oral twice daily area under the curve values. These results suggest that apixaban may 
be a viable alternative to warfarin for thromboprophylaxis of the On-X valve. 
 
Figure 1. 
Comparison of valve thrombus weight. 
 
2.3 
Benefit/Risk Assessment 
2.3.1 Benefits 
In addition to its potent and predictable anticoagulant activity, apixaban does not require 
therapeutic monitoring to be administered safely. It is available for oral administration without a 
food effect on absorption and is simple to dose. It has a well-behaved pharmacokinetic profile 
and low toxicity. It does not have the same potential for drug and botanical interactions as 
warfarin, and has a wider therapeutic index. These features may make it superior to currently 
available alternatives, thus addressing an unmet clinical need. 
In the ARISTOTLE trial comparing apixaban to warfarin for the prevention of stroke and 
systemic embolism in NVAF patients, apixaban was found to be superior to warfarin for the 
prevention of stroke or systemic embolism (1.27% per year on apixaban versus 1.60% on 
warfarin, HR 0.79, 95% CI 0.66 to 0.95, p < 0.001 for non-inferiority, p = 0.01 for superiority). 
In addition, apixaban was found to cause significantly less bleeding than warfarin (major bleed 
on apixaban 2.13% versus 3.09% on warfarin, HR 0.69, 95% CI 0.60 to 0.80, p < 0.001) and 
resulted in a significant reduction in all-cause mortality (3.52% on apixaban versus 3.94% on 
warfarin, HR 0.89, 95% CI 0.80 to 0.99, p = 0.047).  
 
2.3.2 Risks 
As with other anticoagulants, patients administered apixaban are to be carefully observed for 
signs of bleeding. Apixaban is recommended to be used with caution in patients with increased 
risk of hemorrhage, such as congenital or acquired bleeding disorders; active ulcerative GI 
disease; bacterial endocarditis; thrombocytopenia; platelet disorders; history of hemorrhagic 


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stroke; severe uncontrolled hypertension; and recent brain, spinal, or ophthalmological surgery. 
Apixaban is not recommended in patients with hepatic disease associated with coagulopathy and 
clinically relevant bleeding risk. Limited clinical data in patients with severe renal impairment 
indicate that apixaban plasma concentrations are increased in this patient population; therefore, 
apixaban should be used with caution in these patients because of a potentially higher bleeding 
risk. The trial will exclude patients who have severe renal impairment or who are on 
concomitant combined strong P-gp and CYP3A4 inducers or inhibitors given their drug-drug 
interactions with apixaban. Detailed information about the known and expected benefits and 
risks and reasonably expected adverse events of apixaban may be found in the Package Insert. 
 
 


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3 Objectives and Outcomes 
 
Co-Primary Efficacy Objective 
 To determine if apixaban is non-inferior to warfarin (INR target range 2.0 - 3.0) for 
patients with an On-X mechanical heart valve implanted in the aortic position for the 
primary composite outcome of valve thrombosis and valve-related thromboembolism  
 To determine if apixaban provides acceptable anticoagulation for patients with an On-X 
mechanical heart valve implanted in the aortic position for the primary composite 
outcome of valve thrombosis and valve-related thromboembolism compared with an 
objective performance criterion 
Primary Safety Objective 
 To determine if apixaban is superior to warfarin (INR target range 2.0 - 3.0) for the 
safety outcome of major bleeding in patients with an On-X mechanical heart valve 
implanted in the aortic position 
Secondary Efficacy Objectives 
 To determine if apixaban is superior to warfarin (INR target range 2.0 - 3.0) for the 
primary composite outcome of valve thrombosis and valve-related thromboembolism in 
patients with an On-X mechanical heart valve implanted in the aortic position 
 To compare apixaban with warfarin (INR target range 2.0 – 3.0) for the individual 
components of the primary outcome (valve thrombosis and valve-related 
thromboembolism) in patients with an On-X mechanical heart valve implanted in the 
aortic position 
 To compare apixaban with warfarin (INR target range 2.0 - 3.0) for the primary 
composite outcome of valve thrombosis and valve-related thromboembolism in pre-
specified subgroups of patients with an On-X mechanical heart valve implanted in the 
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4 Study Design 
4.1 
Overall Design 
This is a prospective, multicenter, open-label, randomized, active controlled clinical trial to 
determine if patients with an On-X aortic valve, alone or as an On-X Ascending Aortic 
Prosthesis, can be maintained safely and effectively on apixaban. The primary outcome is a 
composite rate of valve thrombosis and valve-related thromboembolism, which will be used for 
co-primary analyses. The first co-primary analysis will determine whether apixaban is non-
inferior to warfarin (INR target range 2.0 - 3.0) in patients with an On-X mechanical heart valve 
implanted in the aortic position. The second co-primary analysis will compare the composite 
rate for apixaban-treated participants to updated OPC for FDA-approved mechanical heart 
valves in the aortic position. Each participant will be followed for at least 2 years and each 
randomized arm will achieve at least 800 patient years. 
The study will consist of approximately 1000 participants (randomized 1:1 with approximately 
500 participants in the apixaban arm and 500 participants in the warfarin arm) at a minimum of 
3 sites and up to 60 sites in North America, and potentially in Europe and/or Japan, who are 18 
years of age or older, at least 3 months out from an On-X aortic valve implantation, and 
currently managing their anticoagulation with warfarin. 
Participants will be randomized to either continue warfarin or switch to apixaban. 
Participants randomized to apixaban will receive 5 mg twice daily (BID), or apixaban 2.5 
mg BID in participants with 2 or 3 of the following characteristics: 
 age ≥ 80 years 
 weight ≤ 60 kilograms 
 creatinine ≥ 1.5 mg/dL (133 micromol/L) 
 
For participants randomized to apixaban, INR testing will be performed on the current 
warfarin dose with the following algorithm to initiate apixaban: 
1. INR < 2; stop warfarin and start apixaban 
2. INR 2.0 to 3.0; hold warfarin for 2 days, start apixaban on day 3 
3. INR > 3.0 to 4.0; hold warfarin for 4 days, start apixaban on day 5 
4. INR > 4.0; hold warfarin for 2 days, recheck INR, refer to steps 1, 2, or 3 
 
4.2 
Scientific Rationale for Study Design 
Warfarin has long been the main-stay of thromboembolism prophylaxis for participants with 
mechanical heart valves. In patients with non-valvular atrial fibrillation, a number of non- 
warfarin anticoagulation (DOAC) alternatives have been developed and received FDA approval. 
Among these, apixaban is one of two DOACs shown to be superior to warfarin in both efficacy 
and safety (Granger et al., 2011) and provides similar levels of in vitro anticoagulation. 
Additionally, the On-X valve implanted in the aortic position has been shown to be safe with 
lower levels of anticoagulation – outcomes of a target INR 1.5-2.0 non-inferior to those of a 
target INR 2.0-3.0 (Puskas et al., 2018). Note, while composite mechanical valves assembled 
during surgery were included in the PROACT trial, the On-X AAP device was not commercially 
available at the time of the trial and has, thus, not been assessed with low INR. For these 


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reasons, the PROACT-Xa trial has selected apixaban to study as an alternative to warfarin in 
participants with On-X mechanical valves implanted in the aortic position, hypothesizing that 
apixaban will be non-inferior to warfarin in preventing mechanical valve-related 
thromboembolism. The primary events of interest include thrombosis of the mechanical valve 
itself, as well as thromboembolic events, such as stroke, transient ischemic attacks, or 
myocardial infarction, related to thrombus formed on the valvular apparatus. For patients who 
require aortic valve replacement, clinicians engage in shared decision-making that prioritizes 
selection of a valve that is durable and safe. Mechanical heart valves are a much more durable 
option than bioprosthetic valves, and are preferred for patients of younger ages to reduce the 
need for reoperation. However, safe warfarin anticoagulation requires frequent INR testing and 
dietary restrictions to reduce INR lability that may be cumbersome. The ability to safely 
anticoagulate a patient with a mechanical heart valve with a DOAC would directly benefit 
participants, not only in convenience of treatment and treatment monitoring, but also expanding 
the ability to receive a mechanical heart valve if these considerations were what led to selection 
of a bioprosthetic valve previously. The demonstrated relative bleeding advantage of apixaban 
over warfarin in the atrial fibrillation population would be expected to be maintained among 
patients with an On-X mechanical valve implanted in the aortic position. Should that prove to be 
the case, then apixaban may provide a safe, effective, and convenient alternative to warfarin for 
patients with On-X aortic valves. 
4.3 
Justification for Dose 
This study will use a previously-established apixaban dose of 5 mg twice daily that was shown to 
be superior to warfarin in preventing stroke or other thromboembolic events in participants with 
atrial fibrillation. For participants who meet 2 or more of the following characteristics: age 80 
years or older, body weight 60 kg or less, or serum creatinine 1.5 mg/dL or more, a commercially 
available lower dose of apixaban (2.5 mg twice daily) will be used, consistent with prior trials. 
Patients receiving combined strong P-gp and CYP3A4 inhibitors/inducers will be excluded from 
the trial. For additional information regarding the apixaban 2.5 mg dose, refer to Section 5.7. 
4.4 
End of Study Definition 
End of Study occurs when the last enrolled participant has completed the 2-year follow-up visit and at 
least 800 patient-years of cumulative follow-up has been reached in each randomized arm. 
4.5 
Study Population 
Approximately 1000 patients who are at least 3 months out from an On-X mechanical valve 
implanted in the aortic position and receiving warfarin anticoagulation will be considered for 
enrollment in the study if they meet all of the inclusion criteria and none of the exclusion criteria. 
 
4.5.1 Inclusion Criteria 
Participants are eligible to be included in the study if all of the following criteria apply: 
1. Male or female at least 18 years of age at the time of giving informed consent. 
2. Able to receive warfarin with a target INR 2.0 to 3.0. 
3. Able to take low-dose aspirin at a dose of 75 -100 mg daily or have a documented 
contraindication to aspirin use. 
4. Implantation of an On-X mechanical valve in the aortic position at least 3 months 
(90 days) prior to enrollment 


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5. If female participant of childbearing potential, including those who are less than 2 years 
post-menopausal, she must agree to and be able to use a highly effective method of birth 
control (eg, barrier contraceptives [condom or diaphragm with a spermicidal gel], 
hormonal contraceptives [implants, injectables, combination oral contraceptives, 
transdermal patches, or contraceptive rings], intrauterine devices or sexual abstinence) 
continuously through the study until the last study visit. 
6. Able to provide written informed consent. 
4.5.2 Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
1. Mechanical valve in any position other than aortic valve. 
2. Any cardiac surgery in the 3 months (90 days) prior to enrollment 
3. Need to be on aspirin >100 mg daily or a P2Y12 inhibitor (clopidogrel, ticagrelor, 
prasugrel, or ticlopidine). 
4. Known hypersensitivity or other contraindication to apixaban. 
5. On dialysis or a creatinine clearance < 25 mL/min. 
6. Experienced an ischemic stroke or intracranial hemorrhage within 3 months of screening for 
enrollment. 
7. Active pathological bleeding at the time of screening for enrollment 
8. Active endocarditis at the time of screening for enrollment. 
9. Pregnant at the time of screening for enrollment, plan to become pregnant at any point during 
the study, or are breast feeding at the time of screening for enrollment. 
10. On concomitant combined strong P-glycoprotein (P-gp) and cytochrome P450 3A4 (CYP3A4) 
inducers or inhibitors 
11. History of non-compliance with recommended monthly INR testing 
. 
4.6 
Lifestyle Considerations 
Participants receiving warfarin during this study will need to eat a normal, balanced diet 
maintaining a consistent amount of vitamin K and should avoid drastic changes in dietary habits, 
such as eating large amounts of green leafy vegetables.  
4.7 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomized in the study. Individuals who do not meet the criteria for 
participation in this study (screen failure) may be rescreened. 
 
 


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5 Study Intervention(s)/Test Article(s) Administered 
5.1 
Study Drugs 
   Table 1 
Study Drugs 
ARM Name 
Apixaban 
Warfarin 
Intervention 
Name 
apixaban 
warfarin 
Type 
Factor Xa inhibitor 
(anticoagulant) 
vitamin K antagonist 
(anticoagulant) 
Dose Formulation tablet 
tablet 
Dosage Level(s) 
5 mg twice daily, or 
2.5 mg twice daily if 2 or 
more of the following 3 
criteria are met: 
- age ≥80 years 
- body weight ≤60 kg 
- serum creatinine ≥1.5 mg/dL 
As directed by primary anticoagulation- 
managing clinician targeting INR levels 
of 2-3 
Route of 
Administration 
oral 
oral 
Sourcing 
Study drug supplied by designated 
drug distribution center 
Study drug supplied by designated drug 
distribution center 
Packaging and 
Labeling 
Study drug will be provided in a 
container that will be labeled as 
required per country requirement. 
Study drug will be provided in a 
container that will be labeled as 
required per country requirement. 
 
5.2 
Medical Devices 
Inclusion criteria for this study require that participants have an On-X aortic valve replacement, 
including the On-X Ascending Aortic Prosthesis, and are at least 3 months from implantation. 
The On-X Prosthetic Heart Valve is a bileaflet mechanical heart valve, which consists of an 
orifice housing and 2 leaflets. The orifice inflow area has a flared inlet designed to reduce flow 
turbulence, and the outflow rim consists of leaflet guards designed to protect the leaflets while 
in the closed position. The leaflets rotate around tabs located in the inner circumference of the 
orifice ring. In the closed position, each leaflet forms a nominal angle of 40° relative to the 
plane of the orifice. In the open position, the plane of each leaflet forms a nominal angle of 90° 
relative to the plane of the orifice. The leaflets have a travel arc of 50° to the closed position. 
The orifice is composed of graphite substrate coated with On-X Carbon, a pure unalloyed form 


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of pyrolytic carbon. The leaflets consist of On-X Carbon deposited on a graphite substrate, 
which is impregnated with 10 weight% tungsten to provide radiopacity. The sewing ring is 
constructed of polytetrafluoroethylene (PTFE) fabric mounted on the orifice using titanium 
retaining rings and 5-0 suture material. This form of sewing ring attachment to the orifice 
allows for rotation of the sewing ring in situ during implantation. Orientation reference marks 
are provided on the sewing ring for valve orientation. 
The On-X Prosthetic Heart Valve is available in 3 aortic sewing ring configurations. All aortic 
configurations are available in sizes 19, 21, 23, 25 and 27/29 mm. Aortic valves, size 19 mm 
through 25 mm, are designed for intrasupra-annular sewing ring position, while the valve size 
27/29 mm is designed for intra-annular sewing ring position. 
The On-X Prosthetic Heart Valve was originally approved by the Food and Drug Administration 
in 2001 with more than 260,000 implanted worldwide to date. 
The On-X Ascending Aortic Prosthesis combines the On-X Prosthetic Heart Valve and the 
Gelweave Valsalva™ Vascular Prosthesis. The Gelweave Valsalva is incorporated into the cuff 
structure of the On-X valve to create the Ascending Aortic Prosthesis (AAP). The AAP is 
available in sizes 19, 21, 23, 25 and 27/29 mm. The On-X AAP has been commercialized since 
2011 with more than 7,000 shipments. The On-X Ascending Aortic Prosthesis was approved by 
the Food and Drug Administration in 2011. 
5.3 
Preparation/Handling/Storage/Accountability 
Both apixaban and warfarin are commercially available. After informed consent, participants 
will be randomized in a 1:1 ratio to receive apixaban or warfarin in an open-label fashion. 
Participants randomized to warfarin will undergo INR testing with warfarin dosing conducted 
based on recommended monthly INR levels, targeting an INR of 2.0-3.0. INR monitoring can be 
done by the site investigator or designee (including the participant’s prior INR manager) or by 
home monitoring, with the site investigator providing oversight and guiding dose adjustments. 
Participants randomized to either apixaban or warfarin will obtain their study medication from a 
designated drug distribution center, with monthly telephone contact to coordinate medication 
resupply. 
 
5.4 
Measures to Minimize Bias: Randomization and Blinding 
Participants will be randomized in a 1:1 ratio to receive apixaban or warfarin. An unmasked 
study statistician will generate the randomization schedule and this schedule and stratification 
scheme will be pre-programmed into the randomization module of the EDC database. All 
randomizations will be performed using the EDC-embedded randomization module.  
This is an open- label study; potential bias will be reduced by having outcome events adjudicated 
by reviewers blinded to study drug assignment using standardized criteria. Randomization will 
be stratified by whether the On-X valve was implanted within or greater than 1 year of study 
enrollment; this stratification is designed to reduce potential bias introduced by inter-site 
differences in participant recruitment strategies. 
 
5.5 
Study Intervention Compliance 
For participants randomized to apixaban, participant compliance with the study intervention will 
be assessed by filling of the drug with a gap in filled supply >14 days defined as non- 


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compliance. For participants randomized to warfarin, participant compliance with the study 
intervention will be assessed by INR levels. Site investigators will advise and reinforce with the 
participant the importance of regular INR monitoring.  Participants will undergo at least monthly 
INR monitoring; monitoring can be done by the site investigator or designee (including the 
participant’s prior INR manager) or by home monitoring. Study investigators will closely 
monitor all participants randomized to warfarin with collection of at least monthly INR data to 
maximize time in therapeutic range (INR levels between 2.0 and 3.0).  If INR results measured 
by the designee or home monitoring repeatedly trend outside of acceptable therapeutic range, the 
site investigator will conduct INR testing as needed and/or guide warfarin dose adjustments to 
achieve target INR levels between 2.0 and 3.0. If a >37-day gap in INR measurement occurs, the 
site investigator will contact the participant to perform INR testing.  All INR values will be 
recorded on the eCRF and the time in therapeutic range for the warfarin arm will be calculated 
and results will be provided to the DSMB.  Satisfaction with anticoagulation will be assessed 
using the Duke Anticoagulation Satisfaction Scale (Samsa et al., 2004). 
5.6 
Concomitant Therapy 
All concomitant medications will be self-reported by the participant or abstracted from the 
medical records. Participants will report concomitant medications throughout the study as 
specified in the Schedule of Activities. 
Details on the use of aspirin and other antithrombotic medications will be collected at baseline 
and during study follow-up as specified in the Schedule of Activities.  Participants should take 
low-dose aspirin at a dose of 75 - 100 mg daily as recommended by current practice guidelines, 
unless there is a documented contraindication to the use of aspirin. 
 
5.7 
Dose Modification 
Participants randomized to apixaban will be dosed at 5 mg twice daily, unless they meet at least 2 of the 
following criteria for dose reduction to 2.5 mg twice daily as per the apixaban package label: 
 Age ≥ 80 years 
 Weight ≤ 60 kg 
 Serum creatinine ≥ 1.5 mg/dL (133 micromol/L) 
Participants randomized to apixaban 5 mg twice daily will have their dose decreased if he/she 
meets at least 2 of the 3 criteria at any time during the study. 
Participants randomized to warfarin should be titrated to an INR target goal of 2.0 to 3.0. 
Dosages of warfarin to achieve that range will be directed by the site investigator or designee 
(including the participant’s prior INR manager) or by home monitoring. If a > 37-day gap in 
INR measurement occurs or if INR results measured by the designee or home monitoring 
repeatedly trend outside of acceptable therapeutic range, the site investigator will conduct INR 
testing as needed and/or guide warfarin dose adjustments to achieve target INR levels between 
2.0 and 3.0. All INR values will be recorded on the eCRF. 
 
5.8 
Intervention after the End of the Study 
After the completion of the last follow-up visit for the study, all participants randomized to 
apixaban will be returned to warfarin therapy at a dose judged appropriate by the treating 
physician; e.g. based on the clinical profile of the subject including age, dry body weight or 


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hemodialysis target body weight, creatinine clearance, concomitant therapies or other clinical 
conditions. A resource that can be used to choose initial dose is www.warfarindosing.org. On 
the day following the final study-mandated apixaban dose, warfarin will be initiated so that 
the participant will take both apixaban and warfarin until an INR of at least 2.0 has been 
obtained. As soon as the INR level is ≥2.0, apixaban will be discontinued.  
5.9 
Discontinuation of Study Intervention and Participant Discontinuation/Withdrawal 
For participants randomized to apixaban who develop a thrombotic or major bleeding event, the 
study investigator or designee will decide whether the participant should continue with 
apixaban, temporarily pause apixaban, or return to standard warfarin therapy. Such decisions are 
at the discretion of the participant’s treating clinician. Participants who are returned to warfarin 
(section 5.8) or stop anticoagulation, regardless of whether or not they have either a thrombotic 
or major bleeding event, will continue to be followed in the study. 
5.9.1 Discontinuation of Study Intervention 
In rare instances, it may be necessary for a participant to permanently discontinue study drug 
(apixaban or warfarin). If study drug is permanently discontinued, the participant will remain in 
the study for all follow-up visits. See the SoA for data to be collected at the time of 
discontinuation of study drug. 
 
5.9.2 Participant Discontinuation/Withdrawal from the Study 
A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral, compliance, or 
administrative reasons. This is expected to be uncommon. 
At the time of discontinuing from the study, if possible, an early discontinuation visit should be 
conducted, as shown in the SoA. See SoA for data to be collected at the time of study 
discontinuation and follow-up and for any further evaluations that need to be completed. 
If the participant withdraws consent for disclosure of future information, the sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. 
 
5.9.3 Lost to Follow up 
A participant will be considered lost to follow-up if he or she is unable to be contacted by the 
study site and no information can be obtained about the participant’s primary outcome and 
vital status. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
 
The site staff must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to and/or 
should continue in the study. 
 
Before the participant is deemed lost to follow up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant’s last known mailing address 


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or local equivalent methods). These contact attempts should be documented in the 
participant’s medical record. Where possible, the participant’s medical record should 
be searched for evidence of vital status and thromboembolic and bleeding clinical 
outcome events (eg, clinic, telemedicine, or hospitalization encounters).  
6 Study Assessments and Procedures 
Study procedures and their timing are summarized in the SoA. Protocol waivers or exemptions 
will not be allowed. Immediate safety concerns should be discussed with the sponsor 
immediately upon occurrence or awareness to determine if the participant should continue or 
discontinue study intervention. 
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct. All screening evaluations must be completed and reviewed to 
confirm that potential participants meet all eligibility criteria. The investigator will maintain a 
screening log to record details of all participants screened and to confirm eligibility. 
Procedures conducted as part of the participant’s routine clinical management and obtained 
before signing of the ICF may be used for screening or baseline purposes provided the 
procedures met the protocol-specified criteria and were performed within the time frame defined 
in the SoA. 
The protocol includes screening participants for symptoms suggestive of valve thrombosis, 
such as new onset heart failure (dyspnea, edema, etc) or thromboembolic phenomena (e.g., 
hospitalization for stroke or urgent revascularization). This will be implemented via a 
standardized questionnaire at monthly intervals. Additional imaging (echocardiography, CT, 
MRI, angiography, and/or non-cardiac ultrasound), selected based on clinical indication, will 
be pursued for participants that report symptoms or signs potentially suggestive of valve 
thrombosis or valve-related thromboembolism.  Imaging results will be collected to 
independently adjudicate whether or not valve thrombosis or valve-related thromboembolism 
occurred. 
The maximum amount of blood collected from each participant over the duration of the study, 
including any extra assessments that may be required, will not exceed 500 mL. Repeat or 
unscheduled samples may be taken for safety reasons or for technical issues with the samples. 
6.1 
Efficacy Assessments 
Efficacy will be assessed by the evaluation of the hazard rates of the primary efficacy outcome, 
the composite of valve thrombosis and valve-related thromboembolism. An independent 
Clinical Events Classification (CEC) Committee will adjudicate whether any valve thrombosis 
and/or valve-related thromboembolism event has occurred. 
Valve thrombosis: defined as any thrombus not caused by infection attached to or near an 
implanted On-X valve that occludes part of the blood flow path, interferes with valve function, or 
is sufficiently large to warrant treatment other than continued oral anticoagulation. Furthermore, 
valve thrombus found at autopsy in a participant whose cause of death was not valve related or 
found at operation for an unrelated indication will also be reported as valve thrombosis. (Akins et 
al., 2008).  
Valve-related thromboembolism: defined as any thromboembolic stroke, thromboembolic 
transient ischemic attack (TIA), thromboembolic myocardial infarction, or arterial 


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thromboembolism to another organ or limb, occurring after the immediate perioperative period 
and not associated with infection or intracardiac tumor.  The independent CEC committee will 
determine whether a thromboembolism was related to the On-X valve based on clinical 
evaluation, surgery, and autopsy data.  If the thromboembolism is determined to be of unknown 
origin after clinical evaluation, surgery, and/or autopsy, the thromboembolism will be 
conservatively considered to be related to the On-X valve.    
6.2 
Safety Assessments 
Safety will be assessed by the evaluation of the hazard rates of the primary safety outcome,  
major bleeding, defined as any episode of internal or external bleeding that causes death, 
hospitalization, or permanent injury (e.g., vision loss) or necessitates transfusion, 
pericardiocentesis or reoperation.  Bleeding will be adjudicated by the CEC Committee. 
Secondary definitions of bleeding, including Bleeding Academic Research Consortium 
(BARC) and International Society of Thrombosis and Hemostasis (ISTH) definitions of 
bleeding, will also be adjudicated. 
Planned time points for all safety assessments are provided in the SoA. 
 
6.3 
Other Assessments 
Vital Signs  
At day 1 (randomization) and yearly thereafter, data on pulse rate, blood pressure, and weight will be 
collected.  If no clinical results are available within 45 days before the visit, an in-person visit will be 
required to collect these data. 
 
Clinical Safety Laboratory Assessments 
At day 1 (randomization) and yearly thereafter, study investigators will obtain hemoglobin and serum 
creatinine levels. If no clinical results are available within 45 days before the visit, an in-person visit will 
be required to collect these data. 
 
 
 


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7 Adverse Events (AEs) and Serious Adverse Events (SAEs) 
Because apixaban and warfarin have both been extensively studied and used clinically and have 
well established safety profiles in populations similar to and at higher-risk of adverse outcomes 
than those with an On-X mechanical aortic valve prosthesis, only the specific serious and non-
serious AEs listed in this section will be collected and reported. 
The following suspected events will be collected on the eCRF and adjudicated by the CEC: 
 valve thrombosis or dysfunction (see Section 7.3) 
 stroke or TIA 
 myocardial infarction 
 arterial thromboembolism 
 bleeding 
 hospitalization and the reason for hospitalization 
 death and the cause of death 
7.1 
Time Period and Frequency for Collecting AE Information 
All clinical events will be collected from the signing of the informed consent form (ICF) until the 
final visit at the time points specified in the SoA (Section 1.1). 
Events that begin before randomization but after obtaining informed consent will be recorded 
on the Medical History/Current Medical Conditions section of the eCRF. 
7.2 
Regulatory Reporting Requirements for SAEs 
Clinical events, as outlined in Section 7, will be collected and reported in aggregate and 
unblinded to study group to the Data Safety Monitoring Board (DSMB). Other serious adverse 
events will not be collected. The study DSMB will be responsible for the ongoing evaluation 
of participants’ safety (eg, event trends). Site investigators may report individual SAEs to their 
IRBs according to their local IRB requirements. 
 
7.3 
Medical Device Incidents (Including Malfunctions, ADEs, UADEs) 
Inclusion criteria for this study require that participants have an On-X aortic valve replacement 
and are at least 3 months following implantation. In order to fulfill regulatory reporting 
obligations worldwide, investigators are responsible for the detection and documentation of 
events meeting the definitions of device incident or malfunction that occur during the study. 
The definition of a Medical Device Incident can be found in Section 10.1.  
All valve-related Adverse Device Effects (ADEs) and Unanticipated Adverse Device Effects 
(UADEs) occurring from informed consent through the final study visit will be collected. ADEs 
and UADEs will be reported in aggregate unblinded to study group to the DSMB. 
Investigators are responsible for reporting UADEs to their IRB within 10 working days of first 
learning of the event as per local requirements. 
It is understood that complete information about an event may not be known at the time the 
initial report is recorded. The investigator must assess the causal relationship of the event to the 
study drug and the investigational device (including rationale for assessment) and should make 
every attempt to obtain as much information as possible concerning the event. Additional 


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information pertaining to an event should be reported as it becomes available. All UADEs will 
be followed to resolution or stabilization. Stabilization means the investigator does not expect 
any further improvement or worsening of the AE. 
 
7.4 
Treatment of Overdose 
For this study, the following will be considered an overdose: 
 any dose of apixaban greater than 15 mg within a 24-hour time period 
 any dose of warfarin resulting in an INR above 7 
No specific treatment is recommended for an overdose of apixaban or warfarin. If major 
bleeding occurs in the setting of an overdose of apixaban, prothrombin complex concentrate 
(PCC) or andexanet alfa may be used to reverse the anticoagulant effect of apixaban. If major 
bleeding occurs in the setting of an overdose of warfarin, fresh frozen plasma, PCC, or vitamin 
K may be used to reverse the anticoagulant effect of warfarin. 
In the event of an overdose of apixaban or warfarin, the investigator should closely monitor the 
participant for bleeding. 
 
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the sponsor’s Coordinating Investigator based on the clinical evaluation 
of the participant. 
 
 


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8 Statistical Considerations 
8.1 
Statistical Hypotheses 
The primary efficacy outcome is the composite of valve thrombosis and valve-related 
thromboembolism. Assuming that time-to-event for the primary efficacy outcome is 
approximately exponentially distributed (ie, a constant hazard), the first co-primary analysis 
is to determine whether the hazard rate of the device using apixaban (test) is non-inferior to 
the hazard rate of the device using warfarin (control) by the margin of 1.75%/ pt-yr. The 
hypothesis statement is as follows: 
H0: 𝜆apixaban  𝜆warfarin  1.75%/pt-yr  
HA: 𝜆apixaban  𝜆warfarin < 1.75%/pt-yr, 
where λ is the hazard rate of the primary efficacy outcome. The second co-primary analysis is to compare 
the hazard rate for the apixaban arm to two times the OPC for thromboembolism and valve thrombosis or 
3.4%/pt-yr (= 2×1.7%/pt-yr). (Error! Not a valid bookmark self-reference. et al., 2014)  
Once non-inferiority has been met, we will test the hypothesis that the hazard rate of the device 
using apixaban (test) is superior to the hazard rate of the device using warfarin (control) for the 
primary efficacy outcome. 
 
For major bleeding (primary safety outcome), the hypothesis test is to determine whether the 
hazard rate of the device using apixaban (test) is superior to the hazard rate of the device using 
warfarin (control). The hypothesis statement is as follows: 
H0: 𝜆apixaban  𝜆warfarin  0 
HA: 𝜆apixaban  𝜆warfarin < 0, 
where λ is the hazard rate of the primary safety outcome. 
 
8.2 
Sample Size Determination 
Approximately 1000 participants will be randomly assigned to study intervention for an 
estimated total of 500 participants per intervention group with one-sided alpha of 2.5% and an 
approximate power of 90%. Since the OPC test does not require a statistical significance 
level, this study is powered for the NI test. 
The assumed primary outcome rate is 1.75%/pt-yr with warfarin based on a review of literature 
available with the On-X aortic devices (Puskas et al., 2018; Tossios et al., 2007; On-X Original 
PMA #P000037, 2001; McNicholas et al., 2006; Chambers et al., 2013; and Wu  et al., 2006). It 
was assumed that all historical trials enrolled a mixture of high and low risk population (HRP 
and LRP), but only the PROACT clinical trial (Puskas et al., 2014; Puskas et al., 2018) reported 
the proportion of high and low risk populations (65% and 35% respectively), which was taken 
into account to estimate the primary outcome rate for the trial. 
The thromboembolism (TE), thrombosis and valve-related mortality (VRM) rates are coincident 
to the remaining events in the composite. Thus, the sample size will be based on a composite of 
TE, thrombosis and VRM rates. Except for the PROACT clinical trial data, the publications 
report the non-hierarchical event rate for VRM and TE. If a participant died due to a TE, it 
would be counted in both the VRM and the TE rate. The trial by Tossios et al., 2007 report the 
number of deaths related to TE (n=5) and all valve-related deaths (n=19). The percent of deaths 
due TE is 26%. It was assumed that for any publication that did not report the number of deaths 
related to TE that 26% of the deaths were due to TE. Thus, the VRM rates are reduced by 26%.  


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Table 3 (see section 11) summarizes the available literature, the event rates and their variances. 
Since the number of historical trials to estimate the event rate in warfarin arm is not large, the 
Hartung-Knapp-Sidik-Jonkman (HKSJ) method was used to produce more robust estimates of 
variance of the event rate (IntHout et al., 2014). The pooled event rate of warfarin was estimated 
as 1.75%/pt-yr with a 95% confidence interval of 1.09%/pt-yr and 2.81%/pt-yr by a random 
effects HKSJ meta-analysis model with the R metafor package. We project that there will be a 
similar event rate with apixaban and set the non-inferiority margin for this study at 1.75%/pt-yr, 
equivalent to a doubling of the estimated event rate in warfarin arm. 
To confirm that the non-inferiority margin preserves the treatment effect, we would need to 
estimate the treatment effect for the use of warfarin post-implantation as compared to placebo. 
There are no placebo-controlled trials of warfarin for patients with AVR. In the PROACT trial 
that randomized low risk AVR patients to warfarin (INR 2.0-3.0) or dual antiplatelet therapy 
(DAPT), the warfarin arm had a hazard rate of 1.15%/pt-yr and the DAPT arm had a hazard rate 
of 7.02%/pt-yr (detailed in Section 11, Table 4). Given the substantially higher event rate in the 
DAPT versus warfarin arm, we have conservatively assumed that DAPT was a placebo 
equivalent. Though not ideal, the treatment effect calculated from this data will be conservative 
(i.e., smaller) than the treatment effect estimated from a true placebo arm. However, the trial 
involving DAPT enrolled only low risk AVR patients (i.e., no chronic atrial fibrillation, left 
ventricular ejection fraction > 30 %, left atrium < 50mm diameter, no spontaneous echo contrasts 
in the left atrium, no neurological events, no hypercoagulability, and no left or right ventricular 
aneurysm). 
To extrapolate these results to an all-comer AVR population, we employed a conversion factor. 
The event rate for warfarin in the low risk population is 1.15%/pt-yr, the meta-analysis above 
demonstrated a pooled event rate of 1.75%/pt-yr for warfarin-treated patients (INR 2.0-3.0), 
therefore the conversion factor was calculated to be 1.52 (= 1.75/1.15). The number of observed 
events (95% CI) with 26% reduction to VRM for TE overlap of DAPT in the low risk population 
is 20.2 (13.00, 30.89) using the Poisson distribution, which translated to an event rate (95% CI) 
of DAPT arm of 7.02% (4.51%/pt-yr, 10.72%/pt-yr). Multiplying by the conversion factor of 
1.52, the DAPT event rate (95% CI) in an all-comer AVR population is 10.65%/pt-yr (6.85%/pt- 
yr, 16.28%/pt-yr).  
 
 
 
Table 2 presents the estimated event rates and confidence intervals for warfarin, DAPT and 
apixaban in all-comer AVR population. Even if an event rate in apixaban arm is 5%/pt-yr, which 
is unlikely, the estimated upper 95% CI of the apixaban arm will still remain below the lower 
95% CI of the event rate of DAPT.   
 
 
 


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Table 2. 
Event rates and confidence intervals for warfarin, DAPT, and apixaban in all-
comer AVR population. 
Treatment in all-comer AVR population 
Event rate 
(%/pt-yr) 
Lower 95% CI 
(%/pt-yr) 
Upper 95% CI 
(%/pt-yr) 
Warfarin* 
1.75% 
1.09% 
2.81% 
DAPT† 
10.65% 
6.85% 
16.28% 
 
 
 
 
 
 
 
Apixaban† 
1.00% 
0.52% 
1.66% 
1.25% 
0.71% 
1.98% 
1.50% 
0.90% 
2.30% 
1.75% 
1.10% 
2.60% 
2.00% 
1.30% 
2.91% 
2.25% 
1.50% 
3.21% 
2.50% 
1.71% 
3.51% 
3.00% 
2.13% 
4.10% 
4.00% 
2.98% 
5.27% 
5.00% 
3.86% 
6.42% 
* The confidence interval was estimated using the random effects HKSJ meta-analysis model; † The confidence intervals were 
estimated using Poisson distribution. 
Assuming that the event rates for warfarin and apixaban would be similar, a conservative 
estimate of the treatment effect is 4.04%/pt-yr, which reflects the difference between the upper 
bound of the 95% CI of the pooled event rate of warfarin (2.81%/pt-yr) and the lower bound 
of the 95% CI of the event rate in DAPT (6.85%/pt-yr). The non-inferiority margin of 
1.75%/pt-yr is approximately 43% (1.75/4.04) of the treatment effect and below ½ of the 
treatment effect as cited in the 2016 FDA guidance “Non-Inferiority Clinical Trials to 
Establish Effectiveness Guidance for Industry” (CDER/FDA, 2016). 
With an accrual time of 1 year, an assumption that 50% of the expected number of participants 
will be enrolled in about 5 months (40% of the total accrual time), and a minimum follow-up 
period of 2 years, the assumed loss to follow-up rate for the period of 2 years is 5%, which is 
equivalent to a loss hazard rate of 0.026 for both the test and control groups. Assuming a one- 
sided alpha of 2.5%, an approximate power of 90%, an equal event rate of 1.75%/pt-yr in both 
warfarin and apixaban arms, and an absolute NI margin of 1.75%/pt-yr, the estimated sample 
size is 990, therefore this study will recruit approximately 1000 participants. 
The major bleeding hazard rate for the control group is assumed to equal 3.63%/pt-yr (Puskas et 
al., 2018). The reference value was calculated by summing up numbers of events and follow-up 
years from both high and low risk controls. Using the proposed sample size of 1000, a 
superiority test for major bleeding has 90% power to detect a difference of 2.13%/pt-yr (i.e., 
3.63%/pt-yr for warfarin arm and 1.5%/pt-yr for apixaban arm). 
All sample size calculations were done via PASS 16.0.5 (released May, 2019) using Non- 
Inferiority and Inequality Tests for the Difference of Two Hazard Rates Assuming an 
Exponential Model for the primary efficacy outcome and Tests for the Difference of Two 
Hazard Rates Assuming an Exponential Model for the primary safety outcome.  


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8.3 
Populations for Analyses 
For purposes of analysis, the following populations are defined: 
Population 
Description 
Intent-to-treat (ITT) 
All participants who are randomly assigned to study intervention, 
regardless of treatment discontinuation or switching, will be 
included in the ITT population. 
On treatment 
Participants will be censored 1 week after anticoagulant 
switching or discontinuation of the assigned treatment; ie, all 
events occurring within 7 days after anticoagulant change (day 1 
is first changed dose or time due for next dose) will be attributed 
to the randomized group and all events occurring > 7 days will be 
censored. Participants who took the assigned treatment will be 
included in the corresponding treatment group until they switch 
or discontinue as above. 
As treated (AT) 
All participants randomly assigned to study intervention and who 
take at least 1 dose of study intervention. Participants will be 
analyzed according to the intervention they initially received. 
 
8.4 
Statistical Analyses 
The statistical analysis plan will be developed and approved before the first participant is 
enrolled and will describe the participant populations to be included in the analyses, and 
procedures for accounting for missing, unused, and spurious data. This section is a summary of 
the planned statistical analyses of the primary and secondary outcomes. 
 
 
 
 


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8.4.1 Efficacy Analyses 
Outcome 
Statistical Analysis Methods 
Primary 
A linearized event rate for each treatment group will be calculated as 
percentage per patient-year using the ITT population and used for the co-
primary analyses. For the first co-primary analysis, if the upper bound of 
95% confidence interval of the difference of event rates is less than the non-
inferiority margin of 1.75%/pt-yr, it will be concluded that apixaban is 
non-inferior to warfarin (INR target range 2.0 - 3.0) for the primary efficacy 
outcome in participants with an On-X mechanical heart valve implanted in the 
aortic position. For the second co-primary analysis, if the apixaban arm 
achieves at least 800 patient-years and the linearized event rate for the apixaban 
arm is less than two times the OPC (3.4%/pt-yr), the OPC test is passed. (Wu 
et al., 2014) 
 
Once both co-primary analyses are met using the ITT population, we declare 
success and that apixaban is a reasonable alternative to warfarin for 
thromboembolic event prevention in this population.  
 
If a non-inferiority for the primary efficacy outcome is established, a superior 
test for the primary efficacy outcome will be performed as follows; if the 
upper bound of the 95% CI is less than zero, it will be concluded that 
apixaban is superior to warfarin (INR target range 2.0 - 3.0) for the primary 
efficacy outcome in participants with an On-X mechanical heart valve 
implanted in the aortic position. 
Secondary 
For the individual components of the primary efficacy outcome as secondary 
outcomes, a linearized event rate for each treatment group and the 95% CI for 
the difference of linearized event rates will be calculated. The ITT population 
will be used. Statistical testing will be considered exploratory. 
 
8.4.2 Safety Analyses 
All safety analyses will be performed on the AT Population. 
 
Outcome 
Statistical Analysis Methods 
Primary 
Major bleeding as a primary safety outcome will be tested for a 
superiority using a log-rank test with a one-sided significance 
level of 0.025. A linearized event rate of major bleeding for both 
warfarin and apixaban arms will be compared with two times the 
major hemorrhage OPC, or 0.032/pt-yr (=3.2%/pt-yr). (Wu et al., 
2014) 
Secondary 
All secondary bleeding definitions and clinical events cases defined in 
Section 7 will be summarized with frequencies and percentages per 
treatment group. 
 


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8.4.3 Other Analyses 
As sensitivity analyses, the non-inferiority hypothesis for the primary efficacy outcome will be 
tested using the NI margin of 1.75%/pt-yr and the On treatment and AT populations and using a 
Cox proportional hazard regression model with a hazard ratio of 2 for the NI margin and the ITT 
population.  
There are no guideline or consensus definitions of aortic valve replacement patients who are at 
high risk of valve thrombosis or valve-related thromboembolism. Subgroup analyses for the 
primary efficacy outcome will stratify by age, race, sex, conduit type, time from surgery, valve 
size, baseline apixaban dose, and post-randomization time in therapeutic range. We will perform 
an additional subgroup analysis stratified by risk, with high-risk patients defined as having  any 
of the following: atrial fibrillation, left ventricular ejection fraction < 30%, left atrial dimension 
>50mm, significant vascular disease, and history of neurological events within 1 year, as utilized 
in the PROACT trial (Puskas et al., 2018). 
No interim analysis for efficacy or futility is planned. The trial will be completed as planned, 
unless there is a safety issue that warrants modifying or stopping the trial.   
 
 
 
 


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9 Supporting Documentation and Operational Considerations 
9.1 
Regulatory, Ethical, and Study Oversight Considerations 
9.1.1 Regulatory and Ethical Considerations 
 
This study will be conducted in accordance with the protocol and with the following:
o Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) International Ethical Guidelines 
o Applicable ICH Good Clinical Practice (GCP) Guidelines 
o Applicable laws and regulations 
 
The protocol, protocol amendments, ICF, and other relevant documents (eg, 
advertisements) must be submitted to an IRB/IEC by the investigator and reviewed and 
approved by the IRB/IEC before the study is initiated.
 
Any amendments to the protocol will require IRB/IEC approval before implementation 
of changes made to the study design, except for changes necessary to eliminate an 
immediate hazard to study participants.
 
The investigator will be responsible for the following:
o Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC 
o Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
o Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 
for clinical studies (if applicable), and all other applicable local regulations 
 
9.1.2 Financial Disclosure 
 
Investigators and sub-investigators will provide the sponsor with sufficient, 
accurate financial information as requested to allow the sponsor to submit 
complete and accurate financial certification or disclosure statements to the 
appropriate regulatory authorities. Investigators are responsible for providing 
information on financial interests during the course of the study and for 1 year 
after completion of the study. 
9.1.3 Informed Consent Process 
 
The investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions 
regarding the study.
 
Participants must be informed that their participation is voluntary. Participants or 
their legally authorized representative will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50, local regulations, 
ICH guidelines, Health Insurance Portability and Accountability Act (HIPAA) 
requirements, where applicable, and the IRB/IEC or study center. 


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 
HIPAA: Data collected during the study enables investigators to answer the scientific 
questions for which the study was designed, to ensure that the study has been done 
properly, and use the information to prepare reports or publications of the study 
results. The investigators and study sponsor may use the information to report adverse 
events to regulatory agencies, such as the FDA. Investigators and study sponsor may 
also transfer the information to contracted partners to provide study-related services; 
or re-analyze the data from this study in the future or combine it with data from other 
studies for analysis. Other than as described above, protected health information will 
not be shared beyond the study investigators and sponsor. 
 
A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative.
 
9.2 
Data Protection 
 
This protocol is a confidential communication of CryoLife. Acceptance of this 
document constitutes the agreement by the recipient that no unpublished information 
contained within will be published or disclosed without prior written approval, except 
that this document may be disclosed to the IRB under the condition that it is requested 
that they keep it confidential.
 
The privacy of participants who participate in this study will be protected by all 
reasonable means. The Principal Investigator is responsible for study records at study 
sites. Access to study records, and especially participant information, will be limited to 
the Investigator, the Sponsor and its representatives, and Regulating Bodies.
 
All participant data will remain confidential. Participant names, social security number, 
address, or any other identifying information will not be reported. Participants and their 
data will be collected with a unique Participant Number.
 
The site staff will be provided with a participant log that they will use to record the 
unique participant numbers and participant information at the time of each screening. 
The site staff are responsible for maintaining the log. The unique 6-digit Participant 
identification number will be assigned according to the following scheme: the first 
three digits are the site-assigned abbreviation, followed by the sequential number in 
which the participant was consented (starting with 001).  
9.3 
Data Quality Control and Assurance 
 
All participant data relating to the study will be recorded on printed or electronic CRF 
unless transmitted to the sponsor or designee electronically (eg, laboratory data). The 
investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the eCRF.
 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF.
 
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.


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 
Monitoring details describing strategy (eg, risk-based initiatives in operations and 
quality such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site 
monitoring) are provided in the Monitoring Plan.
 
The sponsor or designee is responsible for the data management of this study including 
quality checking of the data.
 
The sponsor assumes accountability for actions delegated to other individuals (eg, 
Contract Research Organizations).
 
Study monitors will perform ongoing data surveillance to discern trends and outliers 
in the data. On-site visits will be performed to ensure that the safety and rights of 
participants are being protected; and that the study is being conducted in accordance 
with the currently approved protocol and any other study agreements, ICH GCP, 
and all applicable regulatory requirements.
 
Records and documents, including signed ICFs, pertaining to the conduct of this study 
must be retained for a period of 2 years following the date the marketing application is 
approved for the indication for which it is being investigated; or, if no application is to 
be filed or if the application is not approved for such indication, until 2 years after the 
investigation is discontinued and FDA is notified (§312.62(c)). No records may be 
destroyed during the retention period without the written approval of the sponsor. No 
records may be transferred to another location or party without written notification to 
the sponsor.
9.4 
Source Documents 
 
Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the investigator’s site.
 
Data reported on the eCRF or entered in the eCRF that are transcribed from source 
documents must be consistent with the source documents or the discrepancies must be 
explained. The investigator may need to request previous medical records or transfer 
records, depending on the study. Also, current medical records must be available.
 
Correspondence regarding a study participant memorandum sent to IRB(s).  
9.5 
Study and Site Closure 
 The sponsor reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study 
supplies have been collected and a study-site closure visit has been performed.
 
Reasons for the early closure of a study site by the sponsor may include, but are not limited to: 
o Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines 
o Inadequate recruitment of participants by the investigator 
o Discontinuation of further study intervention development 


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9.6 
Publication Policy 
 
The results of the study will be presented and published in a timely fashion after the 
results are available. The publications process for the primary and for all secondary 
analyses will be overseen by the Steering Committee as outlined in the Steering 
Committee Charter. Interested participating investigators will have access to the clinical 
trial data through this publications process. CryoLife reserves the right to future 
discussions with the Steering Committee including, but not limited to, continuance of 
current study and/or combining the study data with other data with the intent of 
publishing a multi-center evaluation.
 
The study will be registered on https://www.clinicaltrials.gov. 
 
9.7 
Clinical Laboratory Tests 
Hemoglobin and serum creatinine tests will be performed by the local laboratory, and all results 
must be entered into the eCRF. Additional tests may be performed at any time during the study 
as determined necessary by the investigator or required by local regulations.  
 
9.8 
Contraceptive Guidance and Collection of Pregnancy Information 
9.8.1 Definitions: 
 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below). 
If fertility is unclear (eg, amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first dose of study intervention, additional evaluation should be considered. 
Women in the following categories are not considered WOCBP 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
 Documented hysterectomy 
 Documented bilateral salpingectomy 
 Documented bilateral oophorectomy 
3. Postmenopausal female 
 A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
 A high follicle stimulating hormone (FSH) level in the postmenopausal range 
may be used to confirm a postmenopausal state in women not using hormonal 
contraception or hormonal replacement therapy (HRT). 
 Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-estrogen hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment. 
 


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For individuals with permanent infertility due to an alternate medical cause other than the above, 
(eg, mullerian agenesis, androgen insensitivity), investigator discretion should be applied to 
determining study entry. 
 
9.8.2 Female Participants who become pregnant 
 The investigator will collect pregnancy information on any female participant who becomes 
pregnant while participating in this study. 
 Participants randomized to apixaban will return to warfarin anticoagulation for the duration 
of the pregnancy, with management, including warfarin dosing and/or discontinuation, at the 
discretion of study investigator or designee. 
 The participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on the participant and the neonate. Generally, 
follow-up will not be required for longer than 6 to 8 weeks beyond the estimated delivery 
date. Any termination of pregnancy will be collected, regardless of fetal status (presence or 
absence of anomalies) or indication for the procedure.  
 
10 Medical Device Incidents: Definition and Procedures for Recording, Evaluating, 
Follow-up, and Reporting 
10.1 Definitions of a Medical Device Incident 
The detection and documentation procedures described in this protocol apply to the sponsor 
medical devices in use in this study 
 
Medical Device Incident/Effect Definitions 
Adverse Device Effect (ADE) 
 
Adverse event related to the use of the On-X medical device. This includes any adverse 
event resulting from insufficiencies or inadequacies in the instructions for use, the 
deployment, the implantation, the installation, the operation, or any malfunction of the 
investigational medical device. This also includes any event that is a result of a use error 
or intentional misuse. 
Unanticipated Adverse Device Effect (UADE) 
 An Unanticipated Adverse Device Effect is any serious adverse effect on health or safety 
or any life-threatening problem or death caused by, or associated with, a device, if that 
effect, problem, or death was not previously identified in nature, severity, or degree of 
incidence in the investigational plan or application (including a supplementary plan or 
application), or any other unanticipated serious problem associated with a device that 
relates to the rights, safety, or welfare of participants. 


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10.2 Documentation of Medical Device Incidents/Effects 
 
Medical Device Incident/Effect Documenting and Reporting 
 Any medical device incident/effect occurring during the study will be documented in the 
participant’s medical records, in accordance with the investigator’s normal clinical 
practice, and on the appropriate valve function form of the eCRF. 
 For incidents fulfilling the definition of an ADE or UADE, the valve function eCRF page 
will be completed. 
 The eCRF will be completed as thoroughly as possible 
 It is very important that the investigator provides his/her assessment of causality 
(relationship to the medical device provided by the sponsor) at the time of the initial ADE 
or UADE report and describes any corrective or remedial actions taken to prevent 
recurrence of the incident. 
 A remedial action is any action other than routine maintenance or servicing of a medical 
device where such action is necessary to prevent recurrence of an incident. This includes 
any amendment to the device design to prevent recurrence. 
 Investigators are responsible for reporting UADEs to their IRB per local requirements. 


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11 References for sample size calculation 
 
Table 3. 
References used to estimate the primary outcome rate of warfarin (%/pt-yr). 
 
 
Author 
Chambers 
McNicholas 
On-X 
Original 
PMA# 
P000037 
PROACT 
Tossios 
Wu  
High 
Risk 
Control 
Low 
Risk 
Control 
 
 
Year 
2013 
2006 
2001 
2018 
2007 
2006 
 
Country 
UK, 
Spain, 
Greece 
 
USA 
Germany, 
Spain, 
Greece 
US, 
Canada 
 
Germany 
South 
Africa 
Sample size 
214 
142 
184 
190 
102 
264 
104 
% of total 
18% 
12% 
15% 
16% 
9% 
22% 
9% 
Mean patient age 
(yrs) 
59.7 
58.6 
60.2 
55.8 
52.5 
62 
39.7 
Median Follow-up 
(yrs) 
5.5 
4.5* 
2.2* 
5.7 
3.4 
3.9 
1.8* 
Total Follow-up 
(pt-yr) 
1360 
659 
411.8 
1090 
343.5 
1069.4 
172.5 
Target INR 
2.0-3.0 
2.5-3.5 
SoC 
2.0-3.0 
2.0-3.0 
2.5-3.5 
1.5-2.5 
Mean INR 
NR 
NR 
NR 
2.5 
NR 
NR 
43% out of 
range 
NR = Not Reported in the manuscript; * Mean follow-up (yrs) was reported; 
Number of events  
 
 
 
 
 
 
- TE† 
8 
6 
7 
19 
1 
16 
2 
- Thrombosis 
0 
0 
0 
2 
0 
0 
0 
- VRM 
7 
5 
1 
7 
4 
19 
7 
- % TEs in VRM 
NR 
NR 
NR 
NR 
NR 
26%§ 
NR 
Total number of 
events with 26% 
reduction to VRM 
for TE overlap 
(r)§ 
 
 
13.2 
 
 
9.7 
 
 
7.7 
 
 
30.1# 
 
 
30.1 
 
 
7.2 
Linearized event 
rate with 26% 
Reduction to 
VRM for TE 
overlap (λ)§ 
 
 
0.97% 
 
 
1.47% 
 
 
1.88% 
 
 
2.10%# 
 
 
2.81% 
 
 
4.16% 
Standard error of 
linearized event 
rate‡ 
 
0.0027 
 
0.0047 
 
0.0068 
 
0.0038 
 
0.0051 
 
0.0155 
† Peripheral TE was included if provided; § A 26% VRM was assumed to be related to TE event; # calculated by summing up 
numbers of events and follow-up years from both high and low risk controls; ‡ calculated as 𝜆/√𝑟 


40 
CONFIDENTIAL 
CryoLife PROACT Xa Protocol Version 1.0; 15 Jan 2020  
 
 
Table 4. 
Estimated event rates of standard warfarin and DAPT for low risk patients in 
the PROACT trial. 
 
 
Standard 
Warfarin 
(INR 2.0-3.0) 
 
DAPT 
Total Follow-up (pt-yr) 
343.5 pt-yr 
288.1 pt-yr 
Sample size 
102 
99 
Number of all TE 
1 
14 
Number of thrombosis 
0 
4 
Number of VRM 
4 
3 
Total number of events with 26% reduction to VRM for TE overlap 
4.0 
20.2 
Linearized event rate with 26% Reduction to VRM for TE overlap 
1.15% 
7.02% 


41 
CONFIDENTIAL 
CryoLife PROACT Xa Protocol Version 1.0; 15 Jan 2020  
 
 
12 Abbreviations 
 
 
Abbreviation 
Definition 
AAP 
ascending aortic prosthesis 
AVR 
Aortic valve replacement 
ADE 
adverse device effect 
AE 
adverse event 
AT 
as treated 
BID 
twice daily 
CDER 
Center for Drug Evaluation and Research 
CIOMS 
Council for International Organizations of Medical Sciences 
CMI 
Carbomedics 
DAPT 
dual antiplatelet therapy 
DOAC 
direct oral anticoagulant 
DSMB 
data safety monitoring board 
eCRF 
electronic case report form 
FDA 
Food and Drug Administration 
GCP 
good clinical practice 
HIPAA 
Health Insurance Portability and Accountability Act 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
institutional ethics committee 
INR 
international normalized ratio (for anticoagulant monitoring) 
IRB 
Institutional Review Board 
ITT 
intent to treat 


42 
CONFIDENTIAL 
CryoLife PROACT Xa Protocol Version 1.0; 15 Jan 2020  
 
 
Abbreviation 
Definition 
HRP 
high-risk population 
LRP 
low-risk population 
OPC 
objective performance criteria 
PCC 
prothrombin complex concentrate 
PROACT 
prospective randomized on-x valve anticoagulation clinical trial 
PTFE 
polytetrafluoroethylene 
pt-yr 
patient-year 
SAE 
serious adverse event 
SJM 
Saint Jude Medical 
SoA 
schedule of activities 
TE 
thromboembolic 
UADE 
unanticipated adverse device effect 
VRM 
valve-related mortality 
WOCBP 
woman of childbearing potential 


43 
CONFIDENTIAL 
CryoLife PROACT Xa Protocol Version 1.0; 15 Jan 2020  
 
 
13 References 
Akins CW, Miller DC, Turina MI, Kouchoukos NT, Blackstone EH, Grunkemeier 
GL, Takkenberg JJ, David TE, Butchart EG, Adams DH, Shahian DM, Hagl S, Mayer JE, Lytle 
BW. Joint STS/AATS/EACTS report: Guidelines for Reporting Mortality and Morbidity After 
Cardiac Valve Interventions. Ann Thorac Surg 2008 85(4):1490-5. 
Bourguignon T, Lhommet P, El Khoury, R, et al. Very long-term outcomes of the Carpentier- 
Edwards Perimount aortic valve in participants aged 50-65 years. Euro Journal of Cardio- 
Thoracic Surgery 49(2016) 1462-1468. 
CDER/FDA Non-Inferiority Clinical Trials to Establish Effectiveness Guidance for Industry, 
November, 2016. 
Chambers J, Pomar J, Mestres C, et al. Clinical event rates with the On-X bileaflet mechanical 
heart valve: A multicenter experience with follow-up to 12 years. J Thorac Cardiovasc Surg 
2013;145:420-4. 
Eikelboom JW, Connally SJ, Brueckmann M, et al. Dabigatran versus warfarin in participants 
with mechanical heart valves. N Engl J Med 2013; 369:1206-14. 
Flameng W and Meuris B. Performance of bileaflet heart valve prosthesis in an animal model 
of heart valve thrombosis. 6th Annual Hilton Head Workshop on Prosthetic Heart Valves 
March 2002 (abstract). 
Glaser N, Jackson V, Holzmann M, et al. Aortic valve replacement with mechanical vs. 
biological prostheses in participants aged 50–69 years. European Heart Journal (2016) 37, 
2658–2667. 
Goldstone A, Chiu P, Baiocchi M, et al. Mechanical or biologic prostheses for aortic-valve and 
mitral-valve replacement. N Engl J Med (2017); 377:1847-57. 
Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in participants with 
atrial fibrillation. N Engl J Med. 2011 Sep 15;365(11):981-92. 
Head SJ, Mylotte D, Mack MJ, et al. Considerations and recommendations for the introduction 
of objective performance criteria for transcatheter aortic heart valve device approval. 
Circulation. 2016 May 24;133(21):2086-93. 
Head S, Celik M, Kappetein P. Mechanical versus bioprosthetic aortic valve replacement. 
European Heart Journal (2017) 0, 1–13. 
IntHout, J, Ioannidis JPA, and Borm GF. "The Hartung-Knapp-Sidik-Jonkman method for 
random effects meta-analysis is straightforward and considerably outperforms the standard 
DerSimonian-Laird method." BMC Medical Research Methodology 14.1 (2014): 25. 
Samsa G, Matchar DB, Dolor RJ, et al. A new instrument for measuring anticoagulation-related 
quality of life: development and preliminary validation. Health and quality of life 
outcomes.2004 Dec;2(1):22. 
Lester P, Coleman D, Diaz J, et al. Apixaban versus warfarin for mechanical heart valve 
thromboprophylaxis in a swine aortic heterotopic valve model. Arterioscler Thromb Vasc Biol. 
2017;37:942-948. 
McClure S, Narayanasamy N, Wiegerink E, et al. Late outcomes for aortic valve replacement 


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CryoLife PROACT Xa Protocol Version 1.0; 15 Jan 2020  
 
 
with the Carpentier-Edwards Pericardial Bioprosthesis: up to 17-Year follow-up in 1,000 
participants. Ann Thorac Surg 2010;89:1410–6. 
McNicholas K, Ivey T, Metras J, et al. North American multicenter experience with the On-X 
prosthetic heart valve. J Heart Valve Dis 2006;15:73-79. 
Palatianos G, Laczkovics A, Simon P, et al. Multicentered European study on the safety and 
effectiveness of the On-X Prosthetic Heart Valve: Intermediate follow-up. Ann Thorac Surg 
2007;83:40-46. 
Puskas J, Gerdisch M, Nichols D, et al. Reduced anticoagulation after mechanical aortic valve 
replacement: interim results from the prospective randomized on-X valve anticoagulation 
clinical trial randomized Food and Drug Administration investigational device exemption trial. 
J Thorac Cardiovasc Surg. 2014 Apr;147(4):1202-1210. 
Puskas JD, Gerdisch M, Nichols D, et al. Anticoagulation and Antiplatelet Strategies After On-
X Mechanical Aortic Valve Replacement. Journal of the American College of Cardiology. 2018 
Jun 11;71(24):2717-26. 
Tossios P, Reber D, Oustria M, et al. Single-center experience with the On-X prosthetic heart 
valve between 1996 and 2005. The Journal of Heart Valve Disease 2007;16:551-557. 
Williams MA and van Riet S. The On-X heart valve – Mid-term results in a poorly 
anticoagulated population. J Heart Valve Dis 2006;15:80-86. 
Wu Y, Butchart E, Borer J, et al. Clinical Evaluation of New Heart Valve Prostheses: Update of 
Objective Performance Criteria. Ann Thorac Surg 2014:98:1865-74. 


PROACT Xa Statistical Analysis Plan, V1.0; January 15, 2020 
Page 1 of 22 
 
 
 
 
A prospective, randomized, active (warfarin) controlled, parallel‐arm clinical trial to 
determine if patients with an On‐X aortic valve can be maintained safely and effectively on 
the factor Xa inhibitor apixaban  
(PROACT Xa) 
 
Statistical Analysis Plan 
 
 
 
Protocol Version:  
1.0 
 
 
Protocol Date: 
January 15, 2020 
 
 
Analysis Plan Version:  
1.0  
 
 
Analysis Plan Date:  
January 15, 2020 
 
 
 
 
 


PROACT Xa Statistical Analysis Plan, V1.0; January 15, 2020 
Page 2 of 22 
 
Revision History 
Version Date 
File Name 
Summary of Changes 
 
 
 
 
 






PROACT Xa Statistical Analysis Plan, V1.0; January 15, 2020 
Page 3 of 22 
 
Signature page 
 
Prepared by: 
 
………………………………………….. 
Hwasoon Kim, PhD 
Biostatistician III 
Duke Clinical Research Institute 
 
 
 
 
Reviewed by: 
 
………………………………………….. 
Kevin J. Anstrom, PhD 
Reviewing Biostatistician 
Professor of Biostatistics and Bioinformatics 
Duke Clinical Research Institute 
 
 
 
 
Approved by: 
 
………………………………………….. 
Tracy Y. Wang, MD, MHS, MSc 
Principal Investigator 
Associate Professor of Medicine, Cardiology 
Duke Clinical Research Institute 
 
 
 
 
………………………………………….. 
Scott B. Capps, MS 
Vice President of Clinical Research 
CryoLife, Inc. 
 
 


PROACT Xa Statistical Analysis Plan, V1.0; January 15, 2020 
Page 4 of 22 
 
 
TABLE OF CONTENTS 
1 
Introduction .......................................................................................................................................... 7 
1.1 
Study Objectives ........................................................................................................................... 7 
1.1.1 
Co‐Primary Efficacy Objectives ............................................................................................. 7 
1.1.2 
Primary Safety Objective ....................................................................................................... 7 
1.1.3 
Secondary Efficacy Objectives .............................................................................................. 7 
1.2 
Study Design .................................................................................................................................. 8 
2 
Study Populations ................................................................................................................................. 9 
3 
Definitions and Derived Variables....................................................................................................... 10 
3.1 
Valve thrombosis ........................................................................................................................ 10 
3.2 
Valve‐related thromboembolism ................................................................................................ 10 
3.3 
Major bleeding ............................................................................................................................ 10 
4 
Efficacy Parameters ............................................................................................................................ 11 
4.1 
Primary Efficacy Outcome ........................................................................................................... 11 
4.2 
Secondary Efficacy Outcome ...................................................................................................... 11 
5 
Safety Parameters ............................................................................................................................... 12 
5.1 
Primary Safety Outcome ............................................................................................................. 12 
5.2 
Secondary Safety Outcome ......................................................................................................... 12 
6 
Statistical Methodology ...................................................................................................................... 13 
6.1 
Statistical and Analytical Issues................................................................................................... 13 
6.1.1 
Statistical Methods ............................................................................................................. 13 
6.1.2 
End of study ........................................................................................................................ 14 
6.1.3 
Handling of Dropouts and Missing Data ............................................................................. 14 
6.1.4 
Determination of Sample Size ............................................................................................. 14 
6.2 
Participant Characteristics .......................................................................................................... 16 
6.2.1 
Participant Disposition ........................................................................................................ 16 
6.2.2 
Baseline Characteristics ...................................................................................................... 16 
6.2.3 
Treatment Exposure and Compliance ................................................................................. 16 
6.2.4 
Concomitant Medications ................................................................................................... 17 
6.2.5 
Medical Histories ................................................................................................................ 17 
6.3 
Efficacy Analysis .......................................................................................................................... 17 
6.3.1 
Primary Efficacy Variable .................................................................................................... 17 


PROACT Xa Statistical Analysis Plan, V1.0; January 15, 2020 
Page 5 of 22 
 
6.3.2 
Secondary Efficacy Variables............................................................................................... 18 
6.4 
Safety Analysis ............................................................................................................................ 18 
6.4.1 
Primary Safety Variable ....................................................................................................... 18 
6.4.2 
Secondary Safety Variables ................................................................................................. 18 
6.5 
Interim Analysis ........................................................................................................................... 18 
6.6 
Subgroup Analysis ....................................................................................................................... 18 
6.7 
Sensitivity Analysis ...................................................................................................................... 19 
7 
Tables, Figures, and Listings ................................................................................................................ 20 
7.1 
List of Tables ............................................................................................................................... 20 
7.1.1  
Demographic and Background Data ................................................................................... 20 
7.1.2  
Efficacy Data ........................................................................................................................ 20 
7.1.3  
Safety Data .......................................................................................................................... 20 
7.2 
List of Figures .............................................................................................................................. 20 
7.3  
List of Data Listings ..................................................................................................................... 21 
7.3.1  
Participant Data Listings ...................................................................................................... 21 
7.3.2  
Efficacy Data ........................................................................................................................ 21 
7.3.3  
Adverse Events .................................................................................................................... 21 
8 
References .......................................................................................................................................... 22 
 
 
 


PROACT Xa Statistical Analysis Plan, V1.0; January 15, 2020 
Page 6 of 22 
 
Abbreviations 
 
Abbreviation 
Definition 
AE 
Adverse Event  
AM 
Arithmetic Mean  
AT 
As Treated 
BID 
Twice Daily  
CI 
Confidence Interval  
CRF 
Case Report Form  
CSR 
Clinical Study Report  
ICF 
Informed Consent Form  
ICH 
International Conference On Harmonization  
INR 
International Normalized Ratio  
ITT 
Intent‐To‐Treat 
NI 
Non‐Inferior 
NYHA 
New York Heat Association  
OT 
On Treatment 
OPC 
Objective Performance Criteria 
Pt‐yrs 
Patient‐Years 
SAE 
Serious Adverse Event 
SD 
Standard Deviation  
SE 
Standard Error  
TTR 
Time in Therapeutic Range 
 
 
 
 
 


PROACT Xa Statistical Analysis Plan, V1.0; January 15, 2020 
Page 7 of 22 
 
1 
Introduction 
PROACT Xa is designed to determine if patients with an On‐X aortic valve, alone or as an On‐X Ascending 
Aortic Prosthesis, can be maintained safely and effectively on the factor Xa inhibitor apixaban (Eliquis). 
The primary outcome is a composite rate of valve thrombosis and valve‐related thromboembolism, 
which will be used for co‐primary analyses. The first co‐primary analysis will determine whether 
apixaban is non‐inferior to warfarin (INR target range 2.0 ‐ 3.0) in patients with an On‐X mechanical 
heart valve implanted in the aortic position. The second co‐primary analysis will compare the composite 
rate for apixaban‐treated participants to updated objective performance criteria (OPC) (Wu et al., 2014) 
for FDA‐approved mechanical heart valves in the aortic position. This is an open‐label study in which 
patients who are at least 3 months out from  implantation of an On‐X valve in the aortic position will be 
randomized in a 1:1 fashion to either apixaban 5 mg twice daily (2.5 mg twice daily in selected 
participants meeting reduced dose criteria) or warfarin adjusted to an INR of 2.0‐3.0. Participants will be 
followed for at least 2 years after randomization with at least 800 patient‐years (pt‐yrs) of follow‐up in 
each randomized group.  If the primary efficacy hypothesis is proven, the data will be used to support a 
change in the On‐X valve device label to state that apixaban is an acceptable alternative to warfarin for 
anticoagulation in patients 3 or more months after implantation of an On‐X valve in the aortic position.  
1.1 
Study Objectives 
1.1.1  Co‐Primary Efficacy Objectives 
 
 
To determine if apixaban is non‐inferior to warfarin (INR target range 2.0 ‐ 3.0) for patients with 
an On‐X mechanical heart valve implanted in the aortic position for the primary composite 
outcome of valve thrombosis and valve‐related thromboembolism  
 
To determine if apixaban provides acceptable anticoagulation for patients with an On‐X 
mechanical heart valve implanted in the aortic position for the primary composite outcome of 
valve thrombosis and valve‐related thromboembolism compared with an OPC  
1.1.2 Primary Safety Objective 
 
To determine if apixaban is superior to warfarin (INR target range 2.0 ‐ 3.0) for the safety 
outcome of major bleeding in patients with an On‐X mechanical heart valve implanted in the 
aortic position 
 
1.1.3 Secondary Efficacy Objectives 
 
 
To determine if apixaban is superior to warfarin (INR target range 2.0 ‐ 3.0) for the primary 
composite outcome of valve thrombosis and valve‐related thromboembolism in patients with an 
On‐X mechanical heart valve implanted in the aortic position 
 
To compare apixaban with warfarin (INR target range 2.0 – 3.0) for the individual components of 
the primary outcome (valve thrombosis and valve‐related thromboembolism) in patients with 
an On‐X mechanical heart valve implanted in the aortic position 


PROACT Xa Statistical Analysis Plan, V1.0; January 15, 2020 
Page 8 of 22 
 
 
To compare apixaban with warfarin (INR target range 2.0 ‐ 3.0) for the primary composite 
outcome of valve thrombosis and valve‐related thromboembolism in pre‐specified subgroups of 
patients with an On‐X mechanical heart valve implanted in the aortic position 
1.2 
Study Design 
This is a prospective, multicenter, open‐label, randomized, active controlled clinical trial to determine if 
patients with an On‐X aortic valve, alone or as an On‐X Ascending Aortic Prosthesis, can be maintained 
safely and effectively on apixaban. The primary outcome is a composite rate of valve thrombosis and 
valve‐related thromboembolism, which will be used for co‐primary analyses. The first co‐primary 
analysis will determine whether apixaban is non‐inferior to warfarin (INR target range 2.0 ‐ 3.0) in 
patients with an On‐X mechanical heart valve implanted in the aortic position. The second co‐primary 
analysis will compare the composite rate for apixaban‐treated participants to updated OPC for FDA‐
approved mechanical heart valves in the aortic position. Each participant will be followed for at least 2 
years and each randomized arm will achieve at least 800 pt‐yrs. 
The study will consist of approximately 1000 participants (randomized 1:1 with approximately 500 
participants in the apixaban arm and 500 participants in the warfarin arm) at a minimum of 3 sites and 
up to 60 sites in North America, and potentially in Europe and/or Japan, who are 18 years of age or 
older, at least 3 months out from an On‐X aortic valve implantation, and currently managing their 
anticoagulation with warfarin. 
Participants will be randomized to either continue warfarin or switch to apixaban. Participants 
randomized to apixaban will receive 5 mg twice daily (BID), or apixaban 2.5 mg BID in participants with 2 
or 3 of the following characteristics: 
• 
age ≥ 80 years 
• 
weight ≤ 60 kilograms 
• 
creatinine ≥ 1.5 mg/dL (133 micromol/L)  
For participants randomized to apixaban, INR testing will be performed on the current warfarin dose 
with the following algorithm to initiate apixaban: 
1. 
INR < 2; stop warfarin and start apixaban 
2. 
INR 2.0 to 3.0; hold warfarin for 2 days, start apixaban on day 3 
3. 
INR > 3.0 to 4.0; hold warfarin for 4 days, start apixaban on day 5 
4. 
INR > 4.0; hold warfarin for 2 days, recheck INR, refer to steps 1, 2, or 3 
The procedures to be performed throughout the study are outlined in the Schedule of Activities in the 
study protocol (see Section 1.1 of the study protocol). 
 
 


PROACT Xa Statistical Analysis Plan, V1.0; January 15, 2020 
Page 9 of 22 
 
2 
Study Populations 
For purposes of analysis, the following populations are defined. 
Intent‐to‐treat (ITT) 
 
All participants who are randomly assigned to study intervention, regardless of treatment 
discontinuation or switching, will be included in the intent‐to‐treat (ITT) population. 
On treatment (OT) 
Participants will be censored 1 week after anticoagulant switching or discontinuation of the assigned 
treatment; i.e., all events occurring within 7 days after anticoagulant change (day 1 is first changed dose 
or time due for next dose) will be attributed to the randomized group and all events occurring >7 days 
will be censored. Participants who took the assigned treatment will be included in the corresponding 
treatment group until they switch or discontinue as above.   
As treated (AT)  
All participants randomly assigned to study intervention and who take at least 1 dose of study 
intervention. Participants will be analyzed according to the intervention they initially received. For 
example, if a participant was randomized to apixaban, took 1 dose of apixaban and then switched to 
non‐study warfarin, this participant will be included in the apixaban arm for the as treated (AT) 
population.  
 


PROACT Xa Statistical Analysis Plan, V1.0; January 15, 2020 
Page 10 of 22 
 
3 
Definitions and Derived Variables 
3.1 
Valve thrombosis 
Value thrombosis is defined as any thrombus not caused by infection attached to or near an implanted 
On‐X valve that occludes part of the blood flow path, interferes with valve function, or is sufficiently 
large to warrant treatment other than continued oral anticoagulation. Furthermore, valve thrombus 
found at autopsy in a participant whose cause of death was not valve related or found at operation for 
an unrelated indication will also be reported as valve thrombosis (Akins et al., 2008).  
3.2 
Valve‐related thromboembolism 
Valve‐related thromboembolism is defined as any thromboembolic stroke, thromboembolic transient 
ischemic attack (TIA), thromboembolic myocardial infarction, or arterial thromboembolism to another 
organ or limb, occurring after the immediate perioperative period and not associated with infection or 
intracardiac tumor. The independent CEC committee will determine whether a thromboembolism was 
related to the On‐X valve based on clinical evaluation, surgery, and autopsy data. If the 
thromboembolism is determined to be of unknown origin after clinical evaluation, surgery, and/or 
autopsy, the thromboembolism will be conservatively considered to be related to the On‐X valve.  
3.3 
Major bleeding 
Major bleeding is defined as any episode of internal or external bleeding that causes death, 
hospitalization, or permanent injury (e.g., vision loss) or necessitates transfusion, pericardiocentesis or 
reoperation. Bleeding will be adjudicated by the CEC Committee. Secondary definitions of bleeding, 
including Bleeding Academic Research Consortium (BARC) and International Society of Thrombosis and 
Hemostasis (ISTH) definitions of bleeding, will also be adjudicated. 
 


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4 
Efficacy Parameters 
4.1 
Primary Efficacy Outcome 
The primary efficacy outcome is the composite of valve thrombosis and valve‐related 
thromboembolism. The primary efficacy outcome will be analyzed using a linearized adverse event rate, 
measured as percentage per patient‐year (%/pt‐yr). 
4.2 
Secondary Efficacy Outcome 
The secondary efficacy outcome is the individual components of the primary efficacy outcome of valve 
thrombosis and valve‐related thromboembolism. The secondary efficacy outcome will be analyzed using 
a linearized adverse event rate, measured as %/pt‐yr. 
 
 
 
 


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5 
Safety Parameters 
5.1 
Primary Safety Outcome 
The primary safety outcome is major bleeding and Kaplan‐Meier freedom from bleeding at 2 years will 
be compared using a log‐rank test. Major bleeding will be also analyzed using a linearized adverse event 
rate, measured as percentage per patient‐year (%/pt‐yr).  
5.2 
Secondary Safety Outcome 
All secondary bleeding definitions and clinical outcomes defined in Section 7 of the study protocol, 
including valve thrombosis or dysfunction, stroke or TIA, myocardial infarction, arterial 
thromboembolism, bleeding, hospitalization and the reason for hospitalization, death and the cause of 
death, will be collected and be summarized with frequencies and percentages per treatment group.  
 
 


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6 
Statistical Methodology 
6.1 
Statistical and Analytical Issues 
6.1.1  Statistical Methods 
Statistical methods will be based on the International Conference on Harmonization (ICH) E9 document 
“Statistical Principles for Clinical Trials”. 
For screening, demographic and efficacy outputs, data will be summarized by randomized treatment. 
Safety outputs will be summarized by actual treatment received. 
In summary tables of continuous variables, the minimum and maximum statistics will be presented to 
the same number of decimal places as the original data. The arithmetic mean (AM), median, 95% 
confidence interval (CI), standard deviation (SD) and standard error (SE) will be presented to one more 
decimal place than the original data. 
In summary tables of categorical variables, counts and percentages will be used. The denominator for 
each percentage will be the number of participants within the population treatment group unless 
otherwise specified. 
For efficacy parameters, treatment groups will be compared by the difference in linearized event rates. 
The estimate of difference in linearized event rates and its 95% CI be presented in statistical analysis 
outputs. 
All hypothesis testing will be carried out at the 2.5% (1‐sided) significance level unless otherwise 
specified. 
P‐values will be rounded to three decimal places. P‐values less than 0.001 will be reported as <0.001 in 
tables. P‐values greater than 0.999 will be reported as >0.999. 
Case report form (CRF) data collected will be presented within data listings. The data listings will be 
sorted by treatment group, site number, participant number and visit. 
The treatment label for all Tables, Listings and Figures will be: 
Treatment 
Treatment Label for TFLs 
Apixaban (5 mg BID or 2.5 mg BID) 
Apixaban 
Warfarin (INR target range 2.0 ‐ 3.0)  Warfarin 
All Treatments 
Total 
Should any of the statistical methods proposed prove unsuitable during the final analysis, more 
appropriate methods will be used, and any changes will be documented in the clinical study report 
(CSR), including the rationale for use. These include the transformation of the data (for example to a 
logarithmic scale) in order to satisfy the model assumptions such as normally distributed residuals with 
constant variance; or the application of non‐parametric techniques. 


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Additional ad‐hoc analyses may be conducted as deemed appropriate. 
All statistical analysis will be performed using SAS® v9.4 (Cary, NC USA) or higher. 
6.1.2  End of study 
The end of study is defined as that time when the last participant has been followed for 2 years (that 
participant’s 24 month visit). At that time, the study will end and all participants in the apixaban arm will 
be transitioned to medically prescribed warfarin, as described in Section 5.8 of the study protocol. 
Because each participant will have a protocol‐mandated final study visit that will be scheduled based on 
the last participant’s 24‐month visit, there will not be a definitive study end date because those visits 
may occur after the last participants 24‐month visit. Data analysis will include information collected 
through each participant’s final study visit.  
6.1.3  Handling of Dropouts and Missing Data 
During the course of the trial, missing data will be monitored by the operations team via system queries 
in the database and aggregate reports. Participants who are event‐free will be censored at their last 
known alive date (which is typically based on the last non‐missing follow‐up visit date). If the participant 
withdraws consent for disclosure of future information, the participant will be censored at the date of a 
withdrawal of consent. 
6.1.4  Determination of Sample Size 
With an expected accrual time of 1 year, an assumption that 50% of the expected number of 
participants will be enrolled in about 5 months (40% of the total accrual time), and a minimum follow‐up 
period of 2 years, the assumed loss to follow‐up rate for the period of 2 years is 5%, which is equivalent 
to a loss hazard rate of 0.026 for both the test and control groups. Assuming one‐sided alpha of 2.5%, an 
approximate power of 90%, an equal event rate of 1.75%/pt‐yr in both warfarin and apixaban arms, and 
an absolute NI margin of 1.75%/pt‐yr, the estimated sample size is 990, therefore this study will recruit 
approximately 1000 participants. Refer to Section 8.2 of the study protocol for the full sample size 
calculation and the NI margin justification. 
As noted in Table 1 showing the expected statistical power based on observed event rates with 1000 
participants, the power to rule out an absolute difference of 1.75%/pt‐yr or a hazard ratio of 2 is greater 
than 70% for all scenarios where the event rates for the warfarin and apixaban arms are less than 
2.8%/pt‐yr. Based on historical trials with warfarin anticoagulation and the On‐X valve, the hazard rate in 
warfarin arm is expected to be ≤2.8%/pt‐yr. However, recognizing the uncertainty regarding the 
background event rate in warfarin arm, the study is designed to have the co‐primary analysis with the NI 
and OPC tests as described in Section 1.2 of this document. Also, as a sensitivity analysis, a proportional 
hazard regression model with a hazard ratio of 2 for the NI margin will be performed.  
 
 


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Table 1. Expected statistical power by event rate and statistical method with 1000 participants 
Event rate in 
warfarin arm 
(%/pt‐yr) 
Event rate in 
apixaban arm 
(%/pt‐yr) 
Hazard rate approach  
with a NI margin of 1.75%/pt‐yr 
Hazard ratio approach  
with a NI margin of 2.0 
1.00 
1.00 
99.1% 
33.8% 
1.25 
1.25 
97.2% 
40.6% 
1.50 
1.50 
94.1% 
47.0% 
1.75 
1.75 
90.3% 
52.9% 
2.00 
2.00 
86.1% 
58.3% 
2.25 
2.25 
81.8% 
63.3% 
2.50 
2.50 
77.5% 
67.8% 
2.80 
2.80 
72.6% 
72.5% 
3.00 
3.00 
69.5% 
75.3% 
3.50 
3.50 
62.5% 
86.0% 
4.00 
4.00 
56.6% 
100.0% 
4.50 
4.50 
51.5% 
100.0% 
5.00 
5.00 
47.2% 
100.0% 
The empirical type I error rate and power were evaluated using Markov chain Monte Carlo  simulations 
with 10,000 iterations per scenario as presented in Table 2. The hypothesis statements are as follows: 
H0: 𝜆apixaban  𝜆warfarin  1.75%/pt‐yr  
HA: 𝜆apixaban  𝜆warfarin < 1.75%/pt‐yr, 
where λ is the hazard rate of the primary efficacy outcome. The type I error rate was calculated as a 
proportion of rejecting the null hypothesis, i.e., how many times the upper bound of the 95% CI of 
hazard rate difference is less than the NI margin of 1.75%/pt‐yr, when simulated 10,000 iterations under 
the null hypothesis (𝜆apixaban=1.75%/pt‐yr and 𝜆warfarin=3.50%/pt‐yr). The empirical power was calculated 
in the same way when simulated 10,000 iterations under the alternative hypothesis (𝜆apixaban=1.75%/pt‐
yr and 𝜆warfarin=1.75%/pt‐yr).  
 
 


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Table 2. Simulation results with 1000 participants (90% power) 
 
Simulation scenario 
Hazard rate  
in warfarin (%/pt‐yr) 
Hazard rate  
in apixaban (%/pt‐yr)  Rate of passing NI test*  
Under the alternative hypothesis 
(Power) 
1.75 
1.75 
89.4% 
Under the null hypothesis  
(Type I error) 
1.75 
3.50 
2.7% 
* The data were simulated 10,000 iterations.  
6.2 
Participant Characteristics 
6.2.1  Participant Disposition 
The participant disposition table will summarize the following and will be presented for all participants 
by treatment group and overall. 
 
The number (%) of participants randomized at the screening visit 
 
The number (%) of participants withdrawn before the end of study 
 
The number (%) of participants who completed the study 
 
The number (%) of participants who crossed over to other treatment than their assigned 
treatment 
 
The number (%) of participants who were lost to follow‐up 
 
The number (%) of participants in the ITT population 
 
The number (%) of participants in the OT population 
 
The number (%) of participants in the AT population 
6.2.2  Baseline Characteristics 
Demographic data presented will be age, race and gender. Etiology, lesion, time from surgery and New 
York Heat Association (NYHA) functional class at screening will be presented as background data. 
Demographic and background data will be summarized using summary statistics for continuous variables 
(number of participants, mean, standard deviation, median, minimum and maximum) or by way of 
group frequencies and percentages for categorical variables, as appropriate. These data will be 
presented for all three populations (ITT, OT, and AT). 
6.2.3  Treatment Exposure and Compliance 
For participants randomized to apixaban, participant compliance with the study intervention will be 
assessed by filling of the drug with a gap in filled supply >14 days defined as non‐compliance. For 
participants randomized to warfarin, participant compliance with the study intervention will be assessed 
by INR levels. The number (%) of compliant and noncompliant participants will be summarized using the 
ITT population.  


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6.2.4  Concomitant Medications 
The number (%) of participants reporting the use of any concomitant medications, and the number of 
reported concomitant medications will be summarized using the ITT population.  
6.2.5 Medical Histories 
The number of participants reporting one or more conditions for past medical history will be 
summarized using counts and percentages. Both prior and concomitant medical conditions summaries 
will use the ITT population. 
6.3 
Efficacy Analysis 
6.3.1  Primary Efficacy Variable 
The co‐primary analysis will be conducted for the primary efficacy outcome using the ITT population.  
A linearized event rate per arm is defined as the total number of adjudicated efficacy outcomes divided 
by the total patient time (years). The approximate 95% CI for the difference of linearized event rates will 
be calculated as  
൬𝑟஺
𝑇஺
െ𝑟ௐ
𝑇ௐ
൰േ1.96ඨ
𝑟஺
𝑇஺
ଶ൅𝑟ௐ
𝑇ௐ
ଶ, 
where subscript A and W denote the apixaban and warfarin arms, respectively, and r is the total number 
of adjudicated efficacy outcomes, and T is the total patient time (years). (Liu et al. 2006) 
As the first co‐primary analysis, if the upper bound of the 95% CI for the difference of linearized event 
rates is less than the non‐inferiority margin of 0.0175/pt‐yr (=1.75%/pt‐yr), it will be concluded that 
apixaban is non‐inferior to warfarin for the primary efficacy outcome in participants with an On‐X 
mechanical heart valve implanted in the aortic position. 
As the second co‐primary analysis, if the apixaban arm achieves at least 800 pt‐yrs and the linearized 
event rate is less than two times the OPC or 0.034/pt‐yr (=3.4%/pt‐yr), the OPC test is passed. (Wu et al., 
2014) 
Once both co‐primary analyses are met using the ITT population, we declare success and that apixaban 
is a reasonable alternative to warfarin for thromboembolic event prevention in this population. 
If a non‐inferiority for the primary efficacy outcome is established, a superiority test for the primary 
efficacy outcome will be performed using the ITT population. If the upper bound of the 95% CI for the 
difference of linearized event rates is less than zero, it will be concluded that apixaban is superior to 
warfarin for the primary efficacy outcome in participants with an On‐X mechanical heart valve implanted 
in the aortic position. 


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6.3.2  Secondary Efficacy Variables 
For the individual components of the primary efficacy outcome as secondary outcomes, a linearized 
event rate for each treatment group will be calculated as percentage per patient year, and the 95% CI 
for the difference of linearized event rates will be estimated as Section 6.3.1 above. The ITT population 
will be used, and statistical testing will be considered exploratory. 
6.4 
Safety Analysis 
6.4.1  Primary Safety Variable 
Major bleeding as a primary safety outcome will be tested for a superiority by a log‐rank test with a one‐
sided significance level of 0.025 using the AT population.  
A linearized event rate per arm is calculated as the total number of adjudicated major bleeding divided 
by the total patient time (years) using the AT population. The major bleeding rate for both warfarin and 
apixaban arms will be compared with two times the major hemorrhage OPC, or 0.032/pt‐yr (=3.2%/pt‐
yr). (Wu et al., 2014) 
6.4.2  Secondary Safety Variables 
All secondary bleeding definitions and clinical events cases defined in Section 7 of the study protocol will 
be summarized with frequencies and percentages per treatment group using the AT population. 
6.5 
Interim Analysis 
No interim analysis for efficacy or futility is planned. The trial will be completed as planned, unless there 
is a safety issue that warrants modifying or stopping the trial.   
6.6 
Subgroup Analysis 
Subgroup analyses for the primary efficacy outcome will be performed by the following factors at 
baseline (Day 1 Randomization).  
 
Age: <= 65 years vs. > 65 years 
 
Race: white vs. non‐white 
 
Sex: female vs. male 
 
Conduit type: valve alone vs. valve in a conduit 
 
Baseline apixaban dose: 5 mg BID vs. 2.5 mg BID 
 
Time from surgery: <= 1 year vs. > 1 year 
 
Valve size (mm): <= 21 mm vs. > 21 mm 
An additional analysis will be done comparing outcomes by post‐randomization time in therapeutic 
range (TTR) in the warfarin arm as <50%, 50‐69%, and ≥ 70%. Details of this analysis will be described in 
a supplementary analysis plan. 


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There are no guideline or consensus definitions of aortic valve replacement patients who are at high risk 
of valve thrombosis or valve‐related thromboembolism. An additional subgroup analysis will stratify 
based on the high‐risk criteria utilized in the original PROACT trial (Puskas et al., 2018) with high‐risk 
patients defined as having any of the following: atrial fibrillation, left ventricular ejection fraction < 30%, 
left atrial dimension >50mm, significant vascular disease, and history of neurological events within 1 
year. 
For each subgroup factor, the linearized event rates of the primary efficacy outcome for both treatment 
groups and the 95% CI for the difference of linearized event rates will be estimated as Section 6.3.1 
above. The ITT population will be used, and statistical testing will be considered exploratory. 
6.7 
Sensitivity Analysis 
Three sensitivity analyses are planned for the non‐inferiority hypothesis of the primary efficacy outcome 
– using the NI margin of 1.75%/pt‐yr and the OT population, using the NI margin of 1.75%/pt‐yr and the 
AT population, and using a Cox proportional hazard regression model with a hazard ratio of 2 for the NI 
margin and the ITT population.   
The superiority hypothesis for the primary safety outcome will be tested using the ITT and OT 
populations as sensitivity analyses.  
 
 


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7 
Tables, Figures, and Listings 
7.1 
List of Tables 
7.1.1   Demographic and Background Data 
Table 14.1.1  
Summary of Participant Disposition, by Treatment (All Participants) 
Table 14.1.2  
Summary of Final Status and Reason for Withdrawal, by Treatment (All 
Participants) 
Table 14.1.3.1  
Summary of Participant Demographics and Baseline Characteristics, by 
Treatment (ITT Population) 
Table 14.1.3.2  
Summary of Participant Demographics and Baseline Characteristics, by 
Treatment (OT Population) 
Table 14.1.3.3  
Summary of Participant Demographics and Baseline Characteristics, by 
Treatment (AT Population) 
7.1.2   Efficacy Data  
Table 14.2.1.1  
Outcomes by Treatment (ITT Population) 
Table 14.2.1.2  
Outcomes by Treatment (OT Population) 
Table 14.2.1.3  
Outcomes by Treatment (AT Population) 
7.1.3   Safety Data  
Table 14.3.1.1  
Summary of Adverse Events by Treatment (AT Population) 
Table 14.3.1.2  
Summary of Adverse Device Effects (ADEs) and Unanticipated Adverse 
Device Effects (UADEs) by Treatment (AT Population) 
7.2 
List of Figures 
Figure 1 
Participant Flow (All participants) 
Figure 2  
Kaplan‐Meier Curves for Primary End Point and Major Bleeding 
 


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7.3  
List of Data Listings  
7.3.1   Participant Data Listings  
Listing 16.2.1  
Discontinued Participants  
Listing 16.2.2  
Protocol Deviations  
Listing 16.2.4.1  
Demographic Data  
Listing 16.2.4.2  
Baseline Characteristic Data  
Listing 16.2.5.1  
Compliance  
Listing 16.2.5.2  
Participants Who Received Study Treatment Different to Randomized 
Treatment  
7.3.2   Efficacy Data  
Listing 16.2.6.1  
Individual Efficacy data 
7.3.3   Adverse Events  
Listing 16.2.7  
All Related Adverse Events 
 
 
 


PROACT Xa Statistical Analysis Plan, V1.0; January 15, 2020 
Page 22 of 22 
 
8 
References 
Akins CW, Miller DC, Turina MI, Kouchoukos NT, Blackstone EH, Grunkemeier GL, Takkenberg JJ, David 
TE, Butchart EG, Adams DH, Shahian DM, Hagl S, Mayer JE, Lytle BW. Joint STS/AATS/EACTS report: 
Guidelines for Reporting Mortality and Morbidity After Cardiac Valve Interventions. Ann Thorac Surg 
2008 85(4):1490‐5. 
Liu, G. Frank, et al. "Confidence intervals for an exposure adjusted incidence rate difference with 
applications to clinical trials." Statistics in medicine 25.8 (2006): 1275‐1286. 
Puskas JD, Gerdisch M, Nichols D, et al. Anticoagulation and Antiplatelet Strategies After On‐X 
Mechanical Aortic Valve Replacement. Journal of the American College of Cardiology. 2018 Jun 
11;71(24):2717‐26. 
Wu, YingXing, et al. "Clinical evaluation of new heart valve prostheses: update of objective performance 
criteria." The Annals of thoracic surgery 98.5 (2014): 1865‐1874. 
 


PROACT Xa Statistical Analysis Plan, v1.4; January 11, 2023 
Page 1 of 28 
 
 
 
 
A prospective, randomized, active (warfarin) controlled, parallel‐arm clinical trial to 
determine if patients with an On‐X aortic valve can be maintained safely and effectively on 
the factor Xa inhibitor apixaban  
(PROACT Xa) 
 
Statistical Analysis Plan 
 
 
 
Protocol Version:  
1.0 
 
 
Protocol Date: 
January 15, 2020 
 
 
Analysis Plan Version:  
1.4  
 
 
Analysis Plan Date:  
January 11, 2023 
 
 
 
 
 


PROACT Xa Statistical Analysis Plan, v1.4; January 11, 2023 
Page 2 of 28 
 
Revision History 
Version Date 
File Name 
Summary of Changes 
1.0 
PROACTXa_SAP_2020 01 15_final_clean 
Original 
1.1 
PROACTXa_SAP_2020 04 16_v1.1 
Modified the definition of the On 
treatment population; added the 
following: calculation of time in 
therapeutic range, details of time 
to event analysis, censoring rules, 
and assessment of model 
assumptions; updated the lists of 
tables, figures and listings 
1.2 
Final‐SAP_2020‐12‐16_v1.2 
Modified censoring dates, 
calculation of time to event for 
outcomes, and imputation of 
partially missing event dates; 
added the following: a sensitivity 
analysis for different censoring 
dates, the calculation of time in 
therapeutic range of INR before 
the study 
1.3 
PROACTXa_SAP_20221027_V1.3 
Add analysis for questionnaire; 
modify end of study. 
 
1.4 
PROACTXa_SAP_20230111_V1.4 
Modified censoring date for AT 
population 
Modified start date for primary 
safety outcome 
Modified definitions and derived 
variables for Quality of Life (EQ‐
5D‐5L) Questionnaire and Duke 
Anticoagulation Satisfaction Scale 
(DASS) 
Modified rules to handle missing 
value for exploratory analysis 
 
 


PROACT Xa Statistical Analysis Plan, v1.4; January 11, 2023 
Page 3 of 28 
 
Signature page 
 
 
 
 
Reviewed by: 
 
………………………………………….. 
Hussein Al‐Khalidi, PhD 
Reviewing Biostatistician 
Professor of Biostatistics and Bioinformatics 
Duke Clinical Research Institute 
 
 
 
 
Approved by: 
 
………………………………………….. 
John Alexander, MD 
Principal Investigator 
Associate Professor of Medicine, Cardiology 
Duke Clinical Research Institute 
 
 
 
 
………………………………………….. 
Marshall Stanton, MD 
Senior Vice President of Clinical Research, 
Artivion 
 
 


PROACT Xa Statistical Analysis Plan, v1.4; January 11, 2023 
Page 4 of 28 
 
TABLE OF CONTENTS 
1 
Introduction .......................................................................................................................................... 7 
1.1 
Study Objectives ........................................................................................................................... 7 
1.1.1 
Co‐Primary Efficacy Objectives ............................................................................................. 7 
1.1.2 
Primary Safety Objective ....................................................................................................... 7 
1.1.3 
Secondary Efficacy Objectives .............................................................................................. 7 
1.1.4 
Exploratory Objectives .......................................................................................................... 8 
1.2 
Study Design .................................................................................................................................. 8 
2 
Study Populations ............................................................................................................................... 10 
3 
Definitions and Derived Variables....................................................................................................... 11 
3.1 
Valve thrombosis ........................................................................................................................ 11 
3.2 
Valve‐related thromboembolism ................................................................................................ 11 
3.3 
Major bleeding ............................................................................................................................ 11 
3.4 
Quality of Life (EQ‐5D‐5L) Questionnaire ................................................................................... 11 
3.5    Duke Anticoagulation Satisfaction Scale (DASS) ............................................................................ 12 
4 
Efficacy Parameters ............................................................................................................................ 13 
4.1 
Primary Efficacy Outcome ........................................................................................................... 13 
4.2 
Secondary Efficacy Outcome ...................................................................................................... 13 
5 
Safety Parameters ............................................................................................................................... 14 
5.1 
Primary Safety Outcome ............................................................................................................. 14 
5.2 
Secondary Safety Outcome ......................................................................................................... 14 
6 
Statistical Methodology ...................................................................................................................... 15 
6.1 
Statistical and Analytical Issues................................................................................................... 15 
6.1.1 
General principles ............................................................................................................... 15 
6.1.2 
Analysis visits ...................................................................................................................... 16 
6.1.3 
End of study ........................................................................................................................ 16 
6.1.4 
Handling of Dropouts and Missing Data ............................................................................. 17 
6.1.5 
Time to event analysis ........................................................................................................ 17 
6.1.6  
Censoring ............................................................................................................................ 18 
6.1.7  
Assessment of Model Assumptions .................................................................................... 18 
6.1.8 
Determination of Sample Size ............................................................................................. 18 
6.2 
Patient Characteristics ................................................................................................................ 20 
6.2.1 
Patient Disposition .............................................................................................................. 20 


PROACT Xa Statistical Analysis Plan, v1.4; January 11, 2023 
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6.2.2 
Baseline Characteristics ...................................................................................................... 20 
6.2.3 
Treatment Exposure and Compliance ................................................................................. 20 
6.2.4 
Concomitant Medications ................................................................................................... 21 
6.2.5 
Medical Histories ................................................................................................................ 21 
6.3 
Efficacy Analysis .......................................................................................................................... 22 
6.3.1 
Primary Efficacy Variable .................................................................................................... 22 
6.3.2 
Secondary Efficacy Variables............................................................................................... 22 
6.4 
Safety Analysis ............................................................................................................................ 23 
6.4.1 
Primary Safety Variable ....................................................................................................... 23 
6.4.2 
Secondary Safety Variables ................................................................................................. 23 
6.5   Exploratory Analysis ........................................................................................................................ 23 
6.6 
Interim Analysis ........................................................................................................................... 24 
6.7 
Subgroup Analysis ....................................................................................................................... 24 
6.8 
Sensitivity Analysis ...................................................................................................................... 24 
7 
Tables and Figures............................................................................................................................... 26 
7.1 
List of Tables ............................................................................................................................... 26 
7.1.1  
Baseline Characteristics ...................................................................................................... 26 
7.1.2  
Patient Disposition .............................................................................................................. 26 
7.1.3  
Study Drug ........................................................................................................................... 26 
7.1.4  
Outcome ............................................................................................................................. 26 
7.1.5  
Quality of Life and Satisfaction with Anticoagulation ......................................................... 27 
7.2 
List of Figures .............................................................................................................................. 27 
8 
References .......................................................................................................................................... 28 
 
 
 


PROACT Xa Statistical Analysis Plan, v1.4; January 11, 2023 
Page 6 of 28 
 
Abbreviations 
 
Abbreviation 
Definition 
AE 
Adverse Event  
AM 
Arithmetic Mean  
AT 
As Treated 
BID 
Twice Daily  
CI 
Confidence Interval  
CRF 
Case Report Form  
CSR 
Clinical Study Report  
ICF 
Informed Consent Form  
ICH 
International Conference On Harmonization  
INR 
International Normalized Ratio  
ITT 
Intent‐To‐Treat 
NI 
Non‐Inferior 
NYHA 
New York Heat Association  
OT 
On Treatment 
OPC 
Objective Performance Criteria 
Pt‐yrs 
Patient‐Years 
SAE 
Serious Adverse Event 
SD 
Standard Deviation  
SE 
Standard Error  
TTR 
Time in Therapeutic Range 
 
 
 
 
 


PROACT Xa Statistical Analysis Plan, v1.4; January 11, 2023 
Page 7 of 28 
 
1 
Introduction 
PROACT Xa is designed to determine if patients with an On‐X aortic valve, alone or as an On‐X Ascending 
Aortic Prosthesis, can be maintained as safely and effectively on the factor Xa inhibitor apixaban (Eliquis) 
as on warfarin (target INR 2‐3). The primary outcome is a composite rate of valve thrombosis and valve‐
related thromboembolism, which will be used for co‐primary analyses. The first co‐primary analysis will 
determine whether apixaban is non‐inferior to warfarin (INR target range 2.0 ‐ 3.0) in patients with an 
On‐X mechanical heart valve implanted in the aortic position. The second co‐primary analysis will 
compare the composite rate for apixaban‐treated patients to updated objective performance criteria 
(OPC)1 (Wu et al., 2014) for FDA‐approved mechanical heart valves in the aortic position. This is an open‐
label study in which patients who are at least 3 months out from implantation of an On‐X valve in the 
aortic position will be randomized in a 1:1 fashion to either apixaban 5 mg twice daily (2.5 mg twice daily 
in selected patients meeting reduced dose criteria) or warfarin adjusted to an INR of 2.0‐3.0. Patients 
will be followed for at least 2 years after randomization with at least 800 patient‐years (pt‐yrs) of follow‐
up in each randomized group.  If the primary efficacy hypothesis is proven, the data will be used to 
support a change in the On‐X valve device label to state that apixaban is an acceptable alternative to 
warfarin for anticoagulation in patients 3 or more months after implantation of an On‐X valve in the 
aortic position.  
1.1 
Study Objectives 
1.1.1  Co‐Primary Efficacy Objectives 
 
 
To determine if apixaban is non‐inferior to warfarin (INR target range 2.0 ‐ 3.0) for patients with 
an On‐X mechanical heart valve implanted in the aortic position for the primary composite 
outcome of valve thrombosis and valve‐related thromboembolism  
 
To determine if apixaban provides acceptable anticoagulation for patients with an On‐X 
mechanical heart valve implanted in the aortic position for the primary composite outcome of 
valve thrombosis and valve‐related thromboembolism compared with an OPC  
1.1.2 Primary Safety Objective 
 
To determine if apixaban is superior to warfarin (INR target range 2.0 ‐ 3.0) for the safety 
outcome of major bleeding in patients with an On‐X mechanical heart valve implanted in the 
aortic position 
 
1.1.3 Secondary Efficacy Objectives 
 
To determine if apixaban is superior to warfarin (INR target range 2.0 ‐ 3.0) for the primary 
composite outcome of valve thrombosis and valve‐related thromboembolism in patients with an 
On‐X mechanical heart valve implanted in the aortic position 


PROACT Xa Statistical Analysis Plan, v1.4; January 11, 2023 
Page 8 of 28 
 
 
To compare apixaban with warfarin (INR target range 2.0 – 3.0) for the individual components of 
the primary outcome (valve thrombosis and valve‐related thromboembolism) in patients with 
an On‐X mechanical heart valve implanted in the aortic position 
 
To compare apixaban with warfarin (INR target range 2.0 ‐ 3.0) for the primary composite 
outcome of valve thrombosis and valve‐related thromboembolism in pre‐specified subgroups of 
patients with an On‐X mechanical heart valve implanted in the aortic position  
1.1.4 Exploratory Objectives 
 
 
To compare apixaban with warfarin (INR target range 2.0 – 3.0) for health‐related quality of life 
(EQ-5D-5L) in patients with an On‐X mechanical heart valve implanted in the aortic position 
 
To compare apixaban with warfarin (INR target range 2.0 – 3.0) for the anticoagulation 
satisfaction (DASS) in patients with an On‐X mechanical heart valve implanted in the aortic 
position 
1.2 
Study Design 
This is a prospective, multicenter, open‐label, randomized, active controlled clinical trial to determine if 
patients with an On‐X aortic valve, alone or as an On‐X Ascending Aortic Prosthesis, can be maintained 
safely and effectively on apixaban. The primary outcome is a composite rate of valve thrombosis and 
valve‐related thromboembolism, which will be used for co‐primary analyses. The first co‐primary 
analysis will determine whether apixaban is non‐inferior to warfarin (INR target range 2.0 ‐ 3.0) in 
patients with an On‐X mechanical heart valve implanted in the aortic position. The second co‐primary 
analysis will compare the composite rate for apixaban‐treated patients to updated OPC for FDA‐
approved mechanical heart valves in the aortic position. Each patient will be followed for at least 2 years 
and each randomized arm will achieve at least 800 pt‐yrs. 
The study will consist of approximately 1000 patients (randomized 1:1 with approximately 500 patients 
in the apixaban arm and 500 patients in the warfarin arm) at a minimum of 3 sites and up to 60 sites in 
North America, and potentially in Europe and/or Japan, who are 18 years of age or older, at least 3 
months out from an On‐X aortic valve implantation, and currently managing their anticoagulation with 
warfarin. 
Patients will be randomized to either continue warfarin or switch to apixaban. Patients randomized to 
apixaban will receive 5 mg twice daily (BID), or apixaban 2.5 mg BID in patients with 2 or 3 of the 
following characteristics: 
• 
age ≥ 80 years 
• 
weight ≤ 60 kilograms 
• 
creatinine ≥ 1.5 mg/dL (133 micromol/L)  
For patients randomized to apixaban, INR testing will be performed on the current warfarin dose with 
the following algorithm to initiate apixaban: 
1. 
INR < 2; stop warfarin and start apixaban 


PROACT Xa Statistical Analysis Plan, v1.4; January 11, 2023 
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2. 
INR 2.0 to 3.0; hold warfarin for 2 days, start apixaban on day 3 
3. 
INR > 3.0 to 4.0; hold warfarin for 4 days, start apixaban on day 5 
4. 
INR > 4.0; hold warfarin for 2 days, recheck INR, refer to steps 1, 2, or 3 
The procedures to be performed throughout the study are outlined in the Schedule of Activities in the 
study protocol (see Section 1.1 of the study protocol). 
 
 


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2 
Study Populations 
For purposes of analysis, the following populations are defined. 
Intent‐to‐treat (ITT) 
 
All patients who are randomly assigned to study intervention, regardless of treatment discontinuation or 
switching, will be included in the intent‐to‐treat (ITT) population. 
On treatment (OT) 
Patients will be censored 1 week after permanent discontinuation of the assigned treatment. All events 
occurring while on study drug up until 7 days of permanent discontinuation of the assigned treatment 
will be attributed to the randomized treatment assignment. Any event occurring when not on study 
drug will not be counted. All events occurring >7 days after permanent discontinuation of study drug will 
be censored. Patients who took the assigned treatment will be included in the corresponding treatment 
group until they permanently discontinue assigned treatment. 
As treated (AT)  
All patients randomly assigned to study intervention and who take at least 1 dose of study intervention. 
Patients will be analyzed according to the intervention they initially received. For example, if a patient 
was randomized to apixaban, took 1 dose of apixaban and then switched to non‐study warfarin, this 
patient will be included in the apixaban arm for the as treated (AT) population.  
 


PROACT Xa Statistical Analysis Plan, v1.4; January 11, 2023 
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3 
Definitions and Derived Variables 
3.1 
Valve thrombosis 
Value thrombosis is defined as any thrombus not caused by infection attached to or near an implanted 
On‐X valve that occludes part of the blood flow path, interferes with valve function, or is sufficiently 
large to warrant treatment other than continued oral anticoagulation. Furthermore, valve thrombus 
found at autopsy in a patient whose cause of death was not valve related or found at operation for an 
unrelated indication will also be reported as valve thrombosis2 .(Akins et al., 2008) 
3.2 
Valve‐related thromboembolism 
Valve‐related thromboembolism is defined as any thromboembolic stroke, thromboembolic transient 
ischemic attack (TIA), thromboembolic myocardial infarction, or arterial thromboembolism to another 
organ or limb, occurring after the immediate perioperative period and not associated with infection or 
intracardiac tumor. The independent CEC committee will determine whether a thromboembolism was 
related to the On‐X valve based on clinical evaluation, surgery, and autopsy data. If the 
thromboembolism is determined to be of unknown origin after clinical evaluation, surgery, and/or 
autopsy, the thromboembolism will be conservatively considered to be related to the On‐X valve.  
3.3 
Major bleeding 
Major bleeding is defined as any episode of internal or external bleeding that causes death, 
hospitalization, or permanent injury (e.g., vision loss) or necessitates transfusion, pericardiocentesis or 
reoperation. Bleeding will be adjudicated by the CEC Committee. Secondary definitions of bleeding, 
including Bleeding Academic Research Consortium (BARC) and International Society of Thrombosis and 
Hemostasis (ISTH) definitions of bleeding, will also be adjudicated. 
3.4 
Quality of Life (EQ‐5D‐5L) Questionnaire 
The survey is collected at Baseline, Month 1, Month 6, Month 12, and Month 24.  
EQ‐5D‐5L questionnaire asks questions that are used to derive 5 subscales: mobility, self‐care, usual 
activities, pain/discomfort, and anxiety/depression. Each question has 5 choices for health state ranging 
from best (“no problems”) to worst. A Each subscale is created by summing up the answers to the 
questions affiliated with the subscale, ensuring that 1 is assigned to the answer indicating no problems 
and 5 is assigned to the answer indicating worst problem.  
An index‐based summary score is created as follows: 
a) Each subscale is multiplied by a constant obtained from table 2 of the US Valuation of EQ‐5D‐%L 
Health States Using an International Protocol3 (Simon et al., 2019)   
b) After subscales have been multiplied by the constant, the index is derived as follows:  1 – 
absolute value (sum of subscales multiplied by the constant in step a. Lower summary score 
represents better quality of life. If any items of those 5 items is missing, the summary score is 
missing.  


PROACT Xa Statistical Analysis Plan, v1.4; January 11, 2023 
Page 12 of 28 
 
The EQ VAS score is a separate question on the EQ‐5D‐5L that represents health status at the time the 
questionnaire was filled out (0 indicating worst health one could imagine through 100 indicating best 
health one can imagine. 
Section 6.5 of this document describes the analysis for these measures. 
 
3.5    Duke Anticoagulation Satisfaction Scale (DASS) 
The survey is collected at Baseline, Month 1, Month 6, Month 12, and Month 24.  
Duke Anticoagulation Satisfaction Scale (DASS)4 (Samsa et al., 2004)  is a 25‐items questionnaires to 
measure the positive and negative impact of anticoagulation, and each item has 7 choices ranging from 
“not at all” to “very much”.  The 25‐items are unitilized to create 3subscales: hassle, limitation, and 
positive impact.  
Subscales are created by summing answers to the questions below: 
Hassle: Answers 1 =not at all through 7 = very much 
 
How much of a hassle (inconvenience) are the daily tasks of anti‐clot treatment 
 
How much of a hassle (inconvenience) are the occasional tasks of anti‐clot treatment? ( 
 
How complicated do you find your anti‐clot treatment to be?  
 
How time‐consuming do you find your anti‐clot treatment to be?  
 
How frustrating do you find your anti‐clot treatment to be? 
 
How painful do you find your anti‐clot treatment to be?  
 
Overall, how much of a burden do you find your anti‐clot treatment to be?  
 
Overall, how much has anti‐clot treatment had a negative impact on your life? 
 
Compared with other treatments you have had, how difficult is your anti‐clot treatment to 
manage?  
Limitations: Answers 1 =not at all through 7 = very much 
 
How much does the possibility of bleeding or bruising limit you from taking part in physical 
activities (for example, housework, gardening, dancing, sports, or anything else you would 
usually do)?  
 
How much does the possibility of bleeding or bruising limit you from traveling?  
 
How much does the possibility of bleeding or bruising limit you from getting the medical care 
you need (for example, visiting a dentist, chiropractor, or doctor of your choice)?  
 
How much does the possibility of bleeding or bruising limit your ability to work for pay?  
 
Overall, how much does the possibility of bleeding or bruising affect your daily life?  
 
Being on anti‐clot treatment may mean changing some of your other habits as well.  
 
How much does anti‐clot treatment limit your choice of food (diet)? ( 
 
How much does anti‐clot treatment limit the alcoholic beverages you might wish to drink 
 
How much does anti‐clot treatment limit the over‐the‐counter medications (for example, 
aspirin, ibuprofen, vitamins) you might wish to take?  
 
How much do you worry about bleeding and bruising? QSTESTCD = “DASS0120”) 


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Positive Impact: Answers 7 =not at all through 1 = very much 
 
Overall, how confident are you about handling your anti‐clot treatment  
 
How well do you feel that you understand the medical reason for your anti‐clot treatment?  
 
How much do you feel reassured because of your anti‐clot treatment?  
 
Overall, how much has anti‐clot treatment had a positive impact on your life?  
 
Overall, how satisfied are you with your anti‐clot treatment?  
 
How likely would you be to recommend this form of anti‐clot treatment to someone else with 
your disease or medical condition?  
Total score of DASS is the sum of the subscale scores. The score range is 175 (worst) and 25 (best), and if 
any item of those 25 items is missing, the total score is missing. Higher DASS total score represents 
higher negative impact (less satisfaction) of anticoagulation. The DASS was validated with 3 subscales: 
(1) limitations to daily activities, (2) hassles of anticlot treatment, and (3) positive psychological impact 
of anticoagulation. 
Section 6.5 of this document describes the analysis for these measures. 
4 
Efficacy Parameters 
4.1 
Primary Efficacy Outcome 
The primary efficacy outcome is the composite of valve thrombosis and valve‐related 
thromboembolism. The primary efficacy outcome will be analyzed using a linearized adverse event rate, 
measured as percentage per patient‐year (%/pt‐yr). 
4.2 
Secondary Efficacy Outcome 
The secondary efficacy outcome is the individual components of the primary efficacy outcome of valve 
thrombosis and valve‐related thromboembolism. The secondary efficacy outcome will be analyzed using 
a linearized adverse event rate, measured as %/pt‐yr. 
 
 
 
 


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5 
Safety Parameters 
5.1 
Primary Safety Outcome 
The primary safety outcome is major bleeding and Kaplan‐Meier freedom from bleeding at 2 years will 
be compared using a log‐rank test. Major bleeding will be also analyzed using a linearized adverse event 
rate, measured as percentage per patient‐year (%/pt‐yr).  
5.2 
Secondary Safety Outcome 
All secondary bleeding definitions and clinical outcomes defined in Section 7 of the study protocol, 
including valve thrombosis or dysfunction, stroke or TIA, myocardial infarction, arterial 
thromboembolism, bleeding, hospitalization and the reason for hospitalization, death and the cause of 
death, will be collected and be summarized with frequencies and percentages per treatment group.  
 
 


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6 
Statistical Methodology 
6.1 
Statistical and Analytical Issues 
6.1.1  General principles 
Statistical methods will be based on the International Conference on Harmonization (ICH) E9 document 
“Statistical Principles for Clinical Trials”. All hypothesis testing will be carried out at the 2.5% (1‐sided) 
significance level unless otherwise specified. P‐values will be rounded to three decimal places. P‐values 
less than 0.001 will be reported as <0.001 in tables. P‐values greater than 0.999 will be reported as 
>0.999. All statistical analysis will be performed using SAS® v9.4 or higher (Cary, NC USA). 
In summary tables of continuous variables, the minimum and maximum statistics will be presented to 
the same number of decimal places as the original data. The arithmetic mean (AM), median (Q1, Q3), 
95% confidence interval (CI), standard deviation (SD) and standard error (SE) will be presented to one 
more decimal place than the original data. In the event no meaningful information is available through 
the aforementioned decimal place, the statistician in consultation with the PI or designee will determine 
the most relevant number of decimals to display. Summaries of continuous characteristics will be based 
on non‐missing observations. 
In summary tables of categorical variables, counts and percentages will be used. The denominator for 
each percentage will be the number of patients with non‐missing values for the variable within the 
population treatment group unless otherwise specified. In the event that the summary displayed is for a 
subcategory (“child”) of a main category (“parent”), the denominator for the “child” will be based on the 
non‐missing observations for the “parent” (e.g., Heart Failure (Y/N) is a “parent” question and Heart 
Failure Functional Class (e.g. Class I) is a “child” question. The denominator for Class I will be number of 
patients who answered yes/no to the Heart Failure question). 
Unless otherwise specified in this document, relative study day is defined as the (assessment date of a 
measurement – randomization date) if assessment date is prior to randomization date and will be 
defined as (assessment date of measurement – randomization date) + 1 if assessment date is on/after 
date of randomization. Using this derivation, the day of randomization will be considered study day 1.   
Data displayed by visit will utilize an “analysis visit” which will be derived based on windowing outlined 
in section 6.1.2. 
A baseline value is defined as the most recent assessment taken prior to/on day of randomization.  
When there is a missing assessment, it will not be imputed, thus, patients are excluded from any 
changes from baseline analysis for which they have a missing baseline value. 
Due to the anticipated small number of events, stratification by site would produce sparse data and 
therefore, the baseline hazard within each stratum would be poorly estimated with such models.  For 
this reason, sites will be pooled together and all Cox proportional hazards models will be adjusted for 
age of valve only.   


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Unless otherwise specified, all Kaplan‐Meier rates and Kaplan‐Meier curves will be performed only with 
the treatment group. 
Case report form (CRF) data collected will be presented within data listings. The data listings will be 
sorted by treatment group, site number, patient number and visit. 
The treatment label for all Tables, Listings and Figures will be: 
Treatment 
Treatment Label for TFLs 
Apixaban (5 mg BID or 2.5 mg BID) 
Apixaban 
Warfarin (INR target range 2.0 ‐ 3.0)  Warfarin 
All Treatments 
All Patients 
Should any of the statistical methods proposed prove unsuitable during the final analysis, more 
appropriate methods will be used, and any changes will be documented in the clinical study report 
(CSR), including the rationale for use. These include the transformation of the data (for example to a 
logarithmic scale) in order to satisfy the model assumptions such as normally distributed residuals with 
constant variance; or the application of non‐parametric techniques. 
Additional ad‐hoc analyses may be conducted as deemed appropriate. 
6.1.2  Analysis visits 
Information displayed “by visit” will utilize analysis visits based on windows as opposed to the visits at 
which the information was collected, except baseline information. Baseline can be referred to the date 
of screening or Day 1 Randomization when a patient is randomized (see Section 1.1 of the study 
protocol). Analysis day for purposes of the visit windows are derived as follows (the reference date is 
the randomization date and is considered to be day 1): 
 
If date of information is missing, analysis day cannot be calculated 
 
If date of information < reference date, analysis day = analysis date – reference date 
 
If date of information ≥ reference date, analysis day = (analysis date – reference date) + 1 
The visit windows will be as follows for EQ5D and Duke Anticoagulation Satisfaction Scale obtained at 
month 1, 6, 12, and 24. 
Analysis Visit 
Analysis Visit Window 
Analysis Visit Target Day 
Month 1 
1 < analysis day ≤ 45 
30 
Month 6 
45 < analysis day ≤ 270 
180 
Month 12 
270 < analysis day ≤ 540 
360 
Month 24 
540 < analysis day ≤ 900 
720 
 
6.1.3  End of study 
As described in the study protocol (Section 5.8), the original plan for the end of study was defined as 
that time when the last patient has been followed for 2 years (that patient’s 24 month visit). However, 


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the study has been stopped by the DSMB due to safety concerns, thus the end of study has been 
modified as 30 days after the last dose of study drug or the end of study date.  
6.1.4  Handling of Dropouts and Missing Data 
For the assessment of primary hypothesis, missing data relating to the indicator for the valve thrombosis 
or valve thromboembolic events will not be imputed. 
Any partially missing date for an adjudicated or site reported event and for termination dates at the 
time of database lock will be imputed as follows: 
 
If the day is missing, then the 1st of the month will be used. 
 
If missing day and month, then June 1st of provided year will be used.   
 
If year is missing, no imputation will be performed. 
If imputation leads to a date being prior to the randomization date, it will be set to the randomization 
date. If imputation leads to a date being after end of study date, it will be set to the end of study date. 
If study drug initiation dates are partially missed, the randomization date will be used.  
If a patient is determined as lost to follow‐up at the end of study, most recent date of contact where 
elements of the outcome of interest were assessed will be used for the last date of study. 
6.1.5  Time to event analysis 
Unless otherwise specified in this document, time to event for the ITT population will be defined as 
[event date – randomization date] +1 where event occurs and as [appropriate censoring date based on 
analytic population – randomization date] +1 where event does not occur.  
Time to event for the OT population will be defined as [event date – study drug initiation date] +1 where 
event occurs prior to/at 7 days after permanent study drug discontinuation and as [appropriate 
censoring date based on analytic population – study drug initiation date] +1 where event does not occur 
or occurs greater than 7 days after permanent study drug discontinuation. 
Unless otherwise specified in this document, time to event for the AT population will be defined as 
[event date – study drug initiation date] +1 where event occurs and as [appropriate censoring date 
based on analytic population – study drug initiation date] +1 where event does not occur. 
Treatment differences will be evaluated using a Cox proportional hazards model that includes treatment 
as an indicator variable and adjusted for age of valve, unless specified otherwise.  The Breslow method 
will be used for handling ties. P‐value and CI for the HR will be based on the Wald statistic. In addition, 
the summary tables of these analyses will include the number (%) of patients with event, Kaplan‐Meier 
rates as well as the 95% CI by treatment monthly from randomization through the maximum follow‐up. 
Competing risks are not taken into account for any of the Cox proportional hazards models.  Competing 
risks may be taken into account as a sensitivity analysis if a considerable number of deaths are observed. 
Kaplan‐Meier curves will be produced through maximum follow up available in the study, with number 
of patients at risk indicated below the plot at specific times. 


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6.1.6   Censoring 
In this study we expect missing outcome data to be infrequent and every effort will be made to collect 
all information regarding the primary outcomes through the end of the study, even in those who have 
discontinued the study treatment.   
The censoring date for ITT analyses will be the earliest of the following: 1) most recent date of contact 
where the hospitalization question was assessed for the primary composite outcome or where all 
elements of bleeding were assessed for the primary safety outcome, including the date of a withdrawal 
of consent, and 2) death date (when death is not part of the outcome). Patients without any assessment 
of the outcome of interest will be censored at randomization.   
The censoring date for AT analyses will be the earliest of the following: 1) most recent date of contact 
where the hospitalization question was assessed for the primary composite outcome or where all 
elements of bleeding were assessed for the primary safety outcome, including the date of a withdrawal 
of consent, and 2) death date (when death is not part of the outcome). Patients without any assessment 
of the outcome of interest will be censored at study drug initiation.   
The censoring date for OT analysis will be the earliest of 1) most recent date of contact where the 
hospitalization question was assessed for the primary composite outcome or where all elements of 
bleeding were assessed for the primary safety outcome, including the date of a withdrawal of consent, 
2) death date (when death is not part of the outcome), and 3) 7 days after the permanent 
discontinuation of assigned study drug. Patients without any assessment of the outcome of interest will 
be censored at study drug initiation. 
A sensitivity analysis with the more conservative censoring date where all elements of the primary 
composite outcome were assessed will be performed for all three analysis populations. 
6.1.7   Assessment of Model Assumptions 
The validity of the proportional hazards assumption made in the sensitivity analysis for the non‐
inferiority hypothesis of the primary efficacy outcome will be examined using a standard graphical 
methods such as Schoenfeld residual plots; if the assumption holds, the survival curves should be 
approximately parallel to each other. 
An additional analytical method that includes the supremum test as implemented by using the ASSESS 
statement in PROC PHREG in SAS version 9.4 or higher may be utilized. A p‐value of < 0.05 indicates 
violation of the proportional hazards assumption. 
If there is evidence of non‐proportionality, a time dependent covariate will be included in the model to 
account for this.   
6.1.8  Determination of Sample Size 
With an expected accrual time of 1 year, an assumption that 50% of the expected number of patients 
will be enrolled in about 5 months (40% of the total accrual time), and a minimum follow‐up period of 2 
years, the assumed loss to follow‐up rate for the period of 2 years is 5%, which is equivalent to a loss 
hazard rate of 0.026 for both the test and control groups. Assuming one‐sided alpha of 2.5%, an 


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approximate power of 90%, an equal event rate of 1.75%/pt‐yr in both warfarin and apixaban arms, and 
an absolute NI margin of 1.75%/pt‐yr, the estimated sample size is 990, therefore this study will recruit 
approximately 1000 patients. Refer to Section 8.2 of the study protocol for the full sample size 
calculation and the NI margin justification. 
As noted in Table 1 showing the expected statistical power based on observed event rates with 1000 
patients, the power to rule out an absolute difference of 1.75%/pt‐yr or a hazard ratio of 2 is greater 
than 70% for all scenarios where the event rates for the warfarin and apixaban arms are less than 
2.8%/pt‐yr. Based on historical trials with warfarin anticoagulation and the On‐X valve, the hazard rate in 
warfarin arm is expected to be ≤2.8%/pt‐yr. However, recognizing the uncertainty regarding the 
background event rate in warfarin arm, the study is designed to have the co‐primary analysis with the NI 
and OPC tests as described in Section 1.1.1 of this document. Also, as a sensitivity analysis, a 
proportional hazard regression model with a hazard ratio of 2 for the NI margin will be performed.  
Table 1. Expected statistical power by event rate and statistical method with 1000 patients 
Event rate in 
warfarin arm 
(%/pt‐yr) 
Event rate in 
apixaban arm 
(%/pt‐yr) 
Hazard rate approach  
with a NI margin of 1.75%/pt‐yr 
Hazard ratio approach  
with a NI margin of 2.0 
1.00 
1.00 
99.1% 
33.8% 
1.25 
1.25 
97.2% 
40.6% 
1.50 
1.50 
94.1% 
47.0% 
1.75 
1.75 
90.3% 
52.9% 
2.00 
2.00 
86.1% 
58.3% 
2.25 
2.25 
81.8% 
63.3% 
2.50 
2.50 
77.5% 
67.8% 
2.80 
2.80 
72.6% 
72.5% 
3.00 
3.00 
69.5% 
75.3% 
3.50 
3.50 
62.5% 
86.0% 
4.00 
4.00 
56.6% 
100.0% 
4.50 
4.50 
51.5% 
100.0% 
5.00 
5.00 
47.2% 
100.0% 
The empirical type I error rate and power were evaluated using Markov chain Monte Carlo simulations 
with 10,000 iterations per scenario as presented in Table 2. The hypothesis statements are as follows: 
H0: 𝜆apixaban  𝜆warfarin  1.75%/pt‐yr  
HA: 𝜆apixaban  𝜆warfarin < 1.75%/pt‐yr, 
where λ is the hazard rate of the primary efficacy outcome. The type I error rate was calculated as a 
proportion of rejecting the null hypothesis, i.e., how many times the upper bound of the 95% CI of 
hazard rate difference is less than the NI margin of 1.75%/pt‐yr, when simulated 10,000 iterations under 
the null hypothesis (𝜆apixaban=1.75%/pt‐yr and 𝜆warfarin=3.50%/pt‐yr). The empirical power was calculated 
in the same way when simulated 10,000 iterations under the alternative hypothesis (𝜆apixaban=1.75%/pt‐
yr and 𝜆warfarin=1.75%/pt‐yr).  


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Table 2. Simulation results with 1000 patients (90% power) 
 
Simulation scenario 
Hazard rate  
in warfarin (%/pt‐yr) 
Hazard rate  
in apixaban (%/pt‐yr)  Rate of passing NI test*  
Under the alternative hypothesis 
(Power) 
1.75 
1.75 
89.4% 
Under the null hypothesis  
(Type I error) 
1.75 
3.50 
2.7% 
* The data were simulated 10,000 iterations.  
6.2 
Patient Characteristics 
6.2.1  Patient Disposition 
The patient disposition table will summarize the following and will be presented for all patients by 
treatment group and overall. 
 
The number (%) of patients withdrawn before the protocol‐mandated end of study 
 
The number (%) of patients who completed the study at the end of study 
 
The number (%) of patients who followed for a minimum of 2 years 
 
The number (%) of patients who died during the study follow‐up period 
 
The number (%) of patients who were lost to follow‐up 
 
The number (%) of patients who experienced early discontinuation of their assigned treatment 
 
The number (%) of patients who were lost to follow‐up 
 
Length of follow‐up 
 
The number (%) of patients in the ITT population 
 
The number (%) of patients in the OT population 
 
The number (%) of patients in the AT population 
6.2.2  Baseline Characteristics 
Demographic data presented will be age, race and gender. Etiology, lesion, time from surgery and New 
York Heat Association (NYHA) functional class at screening will be presented as background data. 
Demographic and background data will be summarized using summary statistics for continuous variables 
(number of patients, mean, standard deviation, median (Q1, Q3), minimum and maximum) or by way of 
group frequencies and percentages for categorical variables, as appropriate. These data will be 
presented for the ITT population. 
6.2.3  Treatment Exposure and Compliance 
For patients randomized to apixaban, patient compliance with the study intervention will be assessed by 
filling of the drug with a gap in filled supply >14 days defined as non‐compliance.  
For patients randomized to warfarin, patient compliance with the study intervention will be assessed by 
time in therapeutic range (TTR) using INR levels. TTR will be determined by Rosendaal’s method that 


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assumes that the INR value between two measurements varies linearly from the first value to the 
second value5 . (Rosendaal et al. 1993) 
 
Let INRi and INRi+1 be the two consecutive INR values 
 
Let Di and Di+1 be the dates associated with these two consecutive INR values, [(Di+1 ‐ Di) = k, k>1] 
 
Assuming the linear increase or decrease between the two consecutive INR measurements, the 
unit change per day in INR is m = (INRi+1 ‐ INRi)/(Di+1 ‐ Di) 
 
The estimated INR value for the date after Di (Di+1) will be INRi + (m × 1) 
 
Similarly, the estimated INR value for the date (Di+2) will be INRi + (m × 2), etc.; the estimated 
INR value on the date immediately prior to Di+1 will be INRi + (m × (k ‐ 1)). 
Each patient randomized to warfarin will have an INR measurement every day, either actual or by 
estimation through linear interpolation. Percent time in INR target 2.0‐3.0 (i.e. TTR) will be calculated in 
three ways:  
1) 100 × (total number of unique days where estimated or actual INR matches the specified INR 
regimen) / (total number of unique days from the date of the first INR value prior to/at 
randomization to the date of the last INR value prior to/at randomization) 
2) 100 × (total number of unique days where 2.0 ≤ estimated or actual INR value ≤ 3.0) / (total 
number of unique days from the date of the first INR value after randomization to the date of 
the last INR value while on study drug warfarin) 
3) 100 × (total number of unique days where 2.0 ≤ estimated or actual INR value ≤ 3.0) / (total 
number of unique days from the date of the first INR value after randomization to the date of 
the last INR value while in the study) 
The number (%) of compliant and noncompliant patients who took warfarin will be summarized using 
the ITT population. 
6.2.4  Concomitant Medications 
All medications will be coded using the most recent version of the WHO Drug dictionary. The number 
(%) of patients reporting the use of any concomitant medications including non‐study warfarin, expect 
aspirin, and the number of reported concomitant medications will be summarized at randomization and 
after that by treatment group using the ITT population.  
6.2.5 Medical Histories 
The number of patients reporting one or more conditions for past medical history will be summarized 
using counts and percentages. Both prior and concomitant medical conditions summaries will use the 
ITT population. 


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6.3 
Efficacy Analysis 
6.3.1  Primary Efficacy Variable 
The co‐primary analysis will be conducted for the primary efficacy outcome using the ITT population.  
A linearized event rate per arm is defined as the total number of patients with adjudicated efficacy 
outcomes divided by the total patient time (years). The approximate 95% CI for the difference of 
linearized event rates will be calculated as  
൬𝑟஺
𝑇஺
െ𝑟ௐ
𝑇ௐ
൰േ1.96ඨ
𝑟஺
𝑇஺
ଶ൅𝑟ௐ
𝑇ௐ
ଶ, 
where subscript A and W denote the apixaban and warfarin arms, respectively, and r is the total number 
patients with adjudicated efficacy outcomes, and T is the total patient time (years)6. (Liu et al. 2006) 
As the first co‐primary analysis, if the upper bound of the 95% CI for the difference of linearized event 
rates is less than the non‐inferiority margin of 0.0175/pt‐yr (=1.75%/pt‐yr), it will be concluded that 
apixaban is non‐inferior to warfarin for the primary efficacy outcome in patients with an On‐X 
mechanical heart valve implanted in the aortic position. 
As the second co‐primary analysis, if the apixaban arm achieves at least 800 pt‐yrs and the linearized 
event rate is less than two times the OPC or 0.034/pt‐yr (=3.4%/pt‐yr), the OPC test is passed. (Wu et al., 
2014) 
Once both co‐primary analyses are met using the ITT population, we declare success and that apixaban 
is a reasonable alternative to warfarin for thromboembolic event prevention in this population. 
If a non‐inferiority for the primary efficacy outcome is established, a superiority test for the primary 
efficacy outcome will be performed using the ITT population. If the upper bound of the 95% CI for the 
difference of linearized event rates is less than zero, it will be concluded that apixaban is superior to 
warfarin for the primary efficacy outcome in patients with an On‐X mechanical heart valve implanted in 
the aortic position. 
6.3.2  Secondary Efficacy Variables 
For the individual components of the primary efficacy outcome as secondary outcomes, a linearized 
event rate for each treatment group will be calculated as percentage per patient year, and the 95% CI 
for the difference of linearized event rates will be estimated as Section 6.3.1 above. The ITT population 
will be used, and statistical testing will be considered exploratory. 


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6.4 
Safety Analysis 
6.4.1  Primary Safety Variable 
Major bleeding as a primary safety outcome will be tested for a superiority by a log‐rank test with a one‐
sided significance level of 0.025 using the AT population. Time from the study drug initiation date to the 
date of first adjudicated major bleeding or censoring will be determined as specified in Section 6.1.6. 
A linearized event rate per arm is calculated as the total number of patients with adjudicated major 
bleeding divided by the total patient time (years) using the AT population. The major bleeding rate for 
both warfarin and apixaban arms will be compared with two times the major hemorrhage OPC, or 
0.032/pt‐yr (=3.2%/pt‐yr)1. (Wu et al., 2014) 
6.4.2  Secondary Safety Variables 
All secondary bleeding definitions and clinical events cases defined in Section 7 of the study protocol will 
be summarized with frequencies and percentages per treatment group using the AT population. 
6.5   Exploratory Analysis   
The total DASS score as well as the 3 subscales (hassle, limitations, and positive impact will be analyzed 
as described below. 
The EQ‐5D‐5L index, the subscales (mobility, self‐care, usual activities, pain/discomfort, and 
anxiety/depression) as well as the EQ VAS score will be analyzed as described below. A repeated‐
measures mixed‐effects model with Baseline score as a covariate will be run for each measure described 
above. The follow‐up time‐points responses (Month1, Month6, Month 12, and Month 24) will be 
included as outcome variables, and time as a fixed‐effect variable.  
Restricted maximum likelihood estimation will be used to model all available data from each subject 
without imputing missing values. An unstructured covariance matrix will be used, if the model doesn’t 
converge, then a compound symmetry will be used. 
Point estimates for each treatment group and treatment group mean differences (Apixaban ‐ warfarin 
treatment) with 95% confidence intervals (CIs) will be generated for each time point. Additionally, the 
treatment effect will be averaged across all follow‐up time points. The estimated treatment difference 
and 95% CIs will be obtained using the ESTIMATE Statement in SAS PROC MIXED. However, if the total 
missing value is greater than 10%, then descriptive statistics will be presented for the non‐missing values 
by visits and overall.  
“Total Missing” is derived as follows: 
 
Numerator:  Number of participants missing measure of interest across visits 
 
Denominator:  Number of participants expected to have the measure of interest across visits (# 
patients in population * 5 visits).  Denominator will not take into account when patients died, 
were lost to follow‐up, or withdrew consent. 


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6.6 
Interim Analysis 
No interim analysis for efficacy or futility is planned. The trial will be completed as planned, unless there 
is a safety issue that warrants modifying or stopping the trial.   
6.7 
Subgroup Analysis 
Subgroup analyses for the primary efficacy outcome will be performed by the following factors at 
baseline (Day 1 Randomization).  
 
Age: ≤ 65 years vs. > 65 years 
 
Race: white vs. non‐white 
 
Sex: female vs. male 
 
Conduit type: valve alone vs. valve in a conduit 
 
Baseline apixaban dose: 5 mg BID vs. 2.5 mg BID 
 
Time from surgery: ≤ 1 year vs. > 1 year 
 
Valve size (mm): ≤ 21 mm vs. > 21 mm 
An additional analysis will be done comparing outcomes by post‐randomization TTR in the warfarin arm 
as <50%, 50‐69%, and ≥ 70%. Details of this analysis will be described in a supplementary analysis plan. 
There are no guideline or consensus definitions of aortic valve replacement patients who are at high risk 
of valve thrombosis or valve‐related thromboembolism. An additional subgroup analysis will stratify 
based on the high‐risk criteria utilized in the original PROACT trial7 (Puskas et al., 2018) with high‐risk 
patients defined as having any of the following: atrial fibrillation, left ventricular ejection fraction < 30%, 
left atrial dimension >50mm, significant vascular disease, and history of neurological events within 1 
year. 
For each subgroup factor, the linearized event rates of the primary efficacy outcome for both treatment 
groups and the 95% CI for the difference of linearized event rates will be estimated as Section 6.3.1 
above. The ITT population will be used, and statistical testing will be considered exploratory. 
6.8 
Sensitivity Analysis 
Three sensitivity analyses are planned for the non‐inferiority hypothesis of the primary efficacy outcome 
– using the NI margin of 1.75%/pt‐yr and the OT population, using the NI margin of 1.75%/pt‐yr and the 
AT population, and using a Cox proportional hazard regression model with a hazard ratio of 2 for the NI 
margin and the ITT population.  
For the sensitivity analysis using a Cox proportional hazard regression model, the proportional hazards 
assumption will be assessed and time from the randomization date to the date of first adjudicated 
primary composite outcome or censoring will be determined as specified in Section 6.1.6. As mentioned 
in Section 6.1.6, a sensitivity analysis will be done for all three analysis populations with the more 
conservative censoring date where all elements of the primary composite outcome were assessed.  


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The superiority hypothesis for the primary safety outcome will be tested using the ITT and OT 
populations as sensitivity analyses. Time to the date of first adjudicated major bleeding or censoring will 
be determined as specified in Section 6.1.6. 
 


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7 
Tables and Figures 
7.1 
List of Tables 
7.1.1   Baseline Characteristics 
Table 1.1  
Demographics 
Table 1.2  
Cardiac Surgery History 
Table 1.3 
Warfarin History at Baseline 
Table 1.4 
Medical History at Baseline 
Table 1.4a 
Table 1.5  
Medical History Post Baseline 
Concomitant Medication at Baseline 
Table 1.6 
Vital Signs and Labs at Baseline 
7.1.2   Patient Disposition  
Table 2.1  
Patient Disposition and Population 
7.1.3   Study Drug  
Table 3.1  
Warfarin Adherence and INR 
Table 3.2 
Apixaban Adherence and Dose 
Table 3.3 
Aspirin Compliance 
7.1.4   Outcome  
Table 4.1  
Table 4.1a 
Event Rate of Primary Efficacy Outcome 
Event Rate of Primary Efficacy Outcome by Adjudicated Status 
Table 4.2 
Hazard Ratio of Primary Efficacy Outcome 
Table 4.3 
Event Rate of Primary Safety Outcome 
Table 4.4 
KM Rate of Primary Safety Outcome by Analysis Population 
Table 4.5 
Death 
Table 4.6 
Valve Dysfunction 
Table 4.7 
Non‐Thromboembolic Events 


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Table 4.8 
Bleed by Bleeding Classification 
Table 4.9 
Site of Bleeding 
Table 4.10 
Hospitalization 
Table 4.11 
Subgroup Analysis of Primary Outcomes 
7.1.5   Quality of Life and Satisfaction with Anticoagulation 
Table 5.1  
EQ‐5D‐5L Index Score Change Over Time by Treatment 
Table 5.2 
Duke Anticoagulation Satisfaction Scale Total Score Change Over Time by 
Treatment 
7.2 
List of Figures 
Figure 1 
Patient Flow 
Figure 2  
Kaplan‐Meier Curves for Primary Efficacy Outcome 
Figure 3 
Kaplan‐Meier Curves for Primary Safety Outcome 
Figure 4  
Forest Plot for Subgroup Analyses 
Figure 5 
 EQ‐5D‐5L Summary Scores over‐time by treatment using side‐by‐side Box‐
Plots 
Figure 6  
 
 
 DASS Summary Scores over‐time by treatment using side‐by‐side Box‐
Plots 
 
 
 
 
 


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8 
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