Clinical trial NCT04865978
Conditions: Heart Failure
Keywords: ventricular assist device LVAD anticoagulation apixaban warfarin
Sponsor: Palak Shah
Start date: 2021-12-14; Completion date: 2023-11-07
Enrollment: 30 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Prospective, randomized, controlled, open label, trial of LVAD patients with 1:1 randomization to either apixaban or warfarin.

Detailed description:
This pilot study will be a prospective, randomized, controlled, open label, trial of HeartMate 3 (HM3) LVAD patients with 1:1 randomization to either apixaban or warfarin. All patients will be treated with aspirin 81 mg daily as per the LVAD manufacturer instructions for use (IFU).

Arms: arm 1: LVAD patients randomized to the experimental arm will be prescribed apixaban 5 mg twice daily. arm 2: LVAD patients randomized to the control arm will be prescribed warfarin which will be dosed to achieve an INR goal of 2-2.5
Interventions: intervention 1: Apixaban intervention 2: Warfarin intervention 3: LVAD implant
Intervention descriptions: intervention 1: Patients randomized to apixaban will be started on a dose of 5 mg BID. intervention 2: Patients randomized to warfarin will be started on a dose per institutional protocol and titrated to an INR goal of 2.0 - 2.5. intervention 3: Subjects will undergo HeartMate 3 LVAD implant prior to randomization

Protocol documents:
Prot_SAP_000.pdf: 
 
 
 
 
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Evaluation of the hemocompatibility of the Direct Oral Anti-Coagulant apixaban in Left 
Ventricular Assist Devices (DOAC LVAD) 
 
 
Compiled by: 
Inova Heart and Vascular Institute 
Date of the Document: 11/8/2021 
 
 
 
 
 
Sponsor/ 
 
 
 
 
 
 
Coordinating Center:  
 
 
Inova Heart and Vascular Institute 
Falls Church, VA 
 
Study Funding:  
 
 
 
Abbott Vascular, Abbott Park IL 
 
Protocol Principal Investigator:  Palak Shah, MD, MS 
 
 
 
 
 
 
 
 
 
Protocol Development Team:  
Mary Looby, PharmD 
                                                       Ramesh Singh, MD 
 
 
 
 
 
 
 
 
Daniel Tang, MD 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Clinicaltrials.gov Registration  
NCT# 04865978 
 
Food and Drug Administration  
IND# 156522 
  
 
  
 
 
 


 
 
 
 
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1 
List of Abbreviations  
Abbreviation
Definition
ACC
American College of Cardiology
AHA
American Heart Association
AE
Adverse Event
AF
Atrial Fibrillation
CC 
CNS
Coordinating Center 
Central Nervous System
CRF 
DSMB
Case Report Form 
Data Safety Monitoring Board
DOAC
Direct Oral Anticoagulant
EE
Expedited Event
ER 
GIB
Emergency Room 
Gastrointestinal Bleeding
HF 
INR
Heart Failure 
International Normalized Ratio
INTERMACS
Interagency Registry for Mechanically Assisted Circulatory Support
ITT
Intention to Treat
IRB
Institutional Review Board
IV 
LDH
Intravenous 
Lactate Dehydrogenase
LV
Left Ventricular
LVAD
Left Ventricular Assist Device
NVAF
Non-valvular Atrial Fibrillation
NYHA
New York Heart Association
RCT
Randomized Clinical Trial
SAE
Serious Adverse Event
VKA
Vitamin K Antagonist
VTE
Venous Thromboembolism
 
 
 


 
 
 
 
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2 
Table of Contents 
1 
List of Abbreviations ................................................................................................. 2 
2 
Table of Contents ..................................................................................................... 3 
3 
EXECUTIVE SUMMARY .......................................................................................... 6 
4 
OBJECTIVES AND ENDPOINTS ............................................................................. 8 
4.1 Primary Objectives ................................................................................................. 8 
4.2 Secondary Objectives ............................................................................................ 8 
4.3 Tertiary Objectives ................................................................................................. 8 
5 
BACKGROUND ........................................................................................................ 8 
6 
PRELIMINARY STUDIES (STUDY RATIONALE) .................................................. 10 
7 
STUDY DESIGN ..................................................................................................... 10 
7.1 Screening / Baseline ............................................................................................ 10 
7.2 Randomization Phase .......................................................................................... 11 
7.3 Study Intervention Phase ..................................................................................... 11 
7.4 Biobank Study ...................................................................................................... 11 
8 
PATIENT POPULATION ........................................................................................ 12 
8.1 Study Population .................................................................................................. 12 
8.2 Inclusion Criteria .................................................................................................. 12 
8.3 Exclusion Criteria ................................................................................................. 12 
9 
TREATMENT .......................................................................................................... 13 
9.1 Intervention .......................................................................................................... 13 
9.2 Drug Dispensing .................................................................................................. 13 
9.3 Drug Administration ............................................................................................. 13 
9.4 Drug Storage Requirements ................................................................................ 13 
9.5 Drug accountability .............................................................................................. 14 
9.6 Destruction ........................................................................................................... 14 
9.7 Randomization, Stratification and Blinding ........................................................... 14 
9.8 Concomitant Medication....................................................................................... 14 
10 RECRUITMENT AND SCREENING PROCEDURES ............................................. 14 
10.1 Common Recruitment Procedures ..................................................................... 14 
10.2 Estimated Enrollment Period .............................................................................. 15 
10.3 Informed Consent Procedures ........................................................................... 15 


 
 
 
 
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10.1.1 
Informed Consent ................................................................................................ 15 
10.1.2 
Confidentiality and HIPAA Requirements ............................................................. 15 
10.1.3 
Protections of Human Subjects ............................................................................ 15 
10.1.4 
Summary of the Risks and Benefits ..................................................................... 15 
11 VISIT SCHEDULE AND ASSESSMENTS .............................................................. 16 
11.1 Baseline Evaluation and Randomization Visit .................................................... 16 
11.2 Follow-up Evaluations ........................................................................................ 17 
11.3 Phone and Other Media Follow-up .................................................................... 18 
12 OUTCOME DETERMINATIONS ............................................................................ 18 
12.1 Primary Endpoint ............................................................................................... 18 
12.2 Secondary Endpoints ......................................................................................... 19 
12.3 Tertiary Endpoints .............................................................................................. 19 
13 METHODS TO PROMOTE ADHERENCE ............................................................. 19 
13.1 Protocol Training ................................................................................................ 19 
13.2 Data Quality Reports .......................................................................................... 19 
14 SAFETY MONITORING AND REPORTING ........................................................... 19 
14.1 Institutional Review Board .................................................................................. 19 
14.2 Definitions .......................................................................................................... 20 
14.1.1 
Adverse Events .................................................................................................... 20 
14.1.2 
Suspected Adverse Reaction ............................................................................... 20 
14.1.3 
Serious Adverse Events (SAE) ............................................................................ 20 
14.1.4 
Laboratory Test Abnormalities ............................................................................. 20 
14.1.5 
Assessment of Causal Relationship ..................................................................... 21 
14.1.6 
Assessment of Adverse Event Severity ................................................................ 21 
Anticipated Disease Related Events and Events of Interest ...................................... 21 
14.1.7 
Recording and Reporting of Adverse Events........................................................ 21 
14.1.8 
Subject Stopping Criteria and Drug Modification .................................................. 22 
14.1.9 
Suspected Unexpected Serious Adverse Reaction .............................................. 23 
14.1.10 Pregnancy ........................................................................................................... 23 
15 STATISTICAL METHODS AND DATA ANALYSIS ................................................. 23 
15.1 General Design Issues ....................................................................................... 23 
15.2 Sample Size Justification and Randomization ................................................... 24 
15.3 Analysis of the Primary Endpoint ....................................................................... 24 
15.4 Analysis of Secondary and Tertiary Endpoints ................................................... 24 
16 DATA MANAGEMENT PROCEDURES ................................................................. 25 


 
 
 
 
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16.1 Overview of Data Management .......................................................................... 25 
16.2 Data Security ..................................................................................................... 25 
16.3 Publication Policy ............................................................................................... 25 
17 STUDY ADMINISTRATION .................................................................................... 25 
17.1 Data and Safety Monitoring Board ..................................................................... 25 
18 REGULATORY ISSUES ......................................................................................... 26 
18.1 Ethics and Good Clinical Practice ...................................................................... 26 
18.2 Institutional Review Board/Independent Ethics Committee ................................ 26 
18.3 Informed Consent .............................................................................................. 26 
19 APPENDICES......................................................................................................... 28 
19.1 Appendix A – Warfarin Dosing Protocol ............................................................. 28 
Inova Fairfax Medical Center Warfarin New Start Guideline (Days 3 – 7) ................. 29 
19.2 Appendix B – Adverse Event Definitions ............................................................ 30 
19.3 
Appendix C – Schedule of Assessment ........................................................... 32 
20 REFERENCES ....................................................................................................... 33 
 


 
 
 
 
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3 
EXECUTIVE SUMMARY 
 
Title 
Evaluation of the hemocompatibility of the Direct Oral Anti-
Coagulant apixaban in Left Ventricular Assist Devices (DOAC 
LVAD) 
Indication 
Heart failure with reduced ejection fraction patients supported with 
a continuous flow left ventricular assist device (LVAD).  
Location 
Inova Heart and Vascular Institute at Inova Fairfax Medical 
Campus 
Brief Rationale 
 
Adverse effects such as stroke and gastrointestinal bleeding (GIB) 
continue limit widescale adoption of LVAD therapy. Despite a 
reduction of stroke or neurologic dysfunction with the newer 
generation LVADs, stroke remains the leading cause of mortality 
accounting for 19% of deaths. Gastrointestinal bleeding is one of 
the most common adverse event for patients with LVADs, 
occurring most often in the first 3 months and affecting up to 25% 
of patients within the first year.3  
 
The HeartMate 3 (HM3) LVAD is a fully magnetically levitated 
centrifugal flow device which was designed to improve 
hemocompatibility by decreasing surface contact activation, 
widened gaps between the rotor and pump housing, and through 
the addition of artificial intermittent pulsatility by fluctuating the 
rotor speed every 2 seconds. In the Multicenter Study of MagLev 
Technology in Patients Undergoing Mechanical Circulatory 
Support Therapy with HeartMate 3 (MOMENTUM 3), HM3 
decreased the composite endpoint of survival at 2 years free of 
disabling stroke or reoperation to replace or remove a 
malfunctioning device compared to the HeartMate II axial flow 
device.4 Patients with a HM3 LVAD require chronic antithrombotic 
therapy with a vitamin K antagonist (VKA) and antiplatelet therapy 
with aspirin 81-100 mg as outlined in the instructions for use 
(IFU).5 Even in patients with excellent INR control, bleeding and 
thrombotic events are common and difficult to predict.7 
 
Direct oral anticoagulants (DOACs) have become first-line 
anticoagulant therapy for patients with atrial fibrillation (AF) and 
venous thromboembolism (VTE).8,9 DOACs FDA approved for 
stroke prevention in AF or treatment of VTE include the direct 
thrombin inhibitor, dabigatran, and factor Xa inhibitors, apixaban, 


 
 
 
 
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edoxaban, and rivaroxaban. When compared to warfarin for stroke 
prevention in AF, apixaban is the only DOAC to demonstrate 
superior efficacy and lower bleeding rates.10–12  
 
Hypothesis: In patients with a HM3 LVAD, treatment with 
apixaban for 24 weeks will be non-inferior with respect to freedom 
from death or hemocompatibility related adverse events (stroke, 
device thrombosis, bleeding, and arterial non-CNS 
thromboembolism), compared to treatment with warfarin. 
Study Design 
This pilot study will be a prospective, randomized, controlled, open 
label, trial of LVAD patients with 1:1 randomization to either 
apixaban or warfarin. Approximately 40 patients will be randomized 
into the study. 
Treatment 
Apixaban (Eliquis) or warfarin  
Primary Objective 
and Endpoint 
Freedom from death or hemocompatibility related adverse events 
(stroke, device thrombosis, bleeding, aortic root thrombus, and 
arterial non-CNS thromboembolism) at 24-weeks. 
Secondary 
Objectives and 
Endpoints 
1. Survival free of any stroke 
2. Survival free of ischemic stroke 
3. Survival free of hemorrhagic stroke 
4. Survival free of device thrombosis 
5. Survival free of gastrointestinal bleeding 
6. Survival free of major non-gastrointestinal bleeding 
7. All-cause mortality 
8. Cardiovascular mortality 


 
 
 
 
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4 
 OBJECTIVES AND ENDPOINTS 
4.1 Primary Objectives 
The primary objective is to evaluate the safety of apixaban as compared to warfarin in 
LVAD patients. 
 
Hypothesis: In patients with a HM3 LVAD, treatment with apixaban for 24 weeks will be 
non-inferior with respect to freedom from death or hemocompatibility related adverse 
events (stroke, device thrombosis, bleeding, aortic root thrombus, and arterial non-CNS 
thromboembolism), compared to treatment with warfarin. 
4.2 Secondary Objectives 
1. Survival free of any stroke 
2. Survival free of ischemic stroke 
3. Survival free of hemorrhagic stroke 
4. Survival free of device thrombosis 
5. Survival free of aortic root thrombus 
6. Survival free of gastrointestinal bleeding 
7. Survival free of major non-gastrointestinal bleeding 
8. All-cause mortality 
9. Cardiovascular mortality 
4.3 Tertiary Objectives 
1. Time in the therapeutic range for patients on warfarin 
2. Anti-Xa trough concentration at 4 weeks, 12 weeks, and 24 weeks for patients on 
apixaban 
3. A subgroup analysis of above endpoints will be completed for patients enrolled 
immediately after LVAD implantation versus those enrolled ≥ 3 months from LVAD 
implantation 
5 
BACKGROUND  
Compared with optimal medical management, LVADs reduce heart failure symptoms, 
improve quality of life and decrease mortality in patients with New York Heart 
Association class IIIb/IV heart failure (HF) symptoms.1,2 Unfortunately, adverse effects 
such as stroke and gastrointestinal bleeding (GIB) continue limit wide scale adoption of 
the therapy. Despite a reduction of stroke or neurologic dysfunction with the newer 
generation LVADs, stroke remains the leading cause of mortality accounting for 19% of 
deaths. Gastrointestinal bleeding is one of the most common adverse event for patients 
with LVADs, occurring most often in the first 3 months and affecting up to 25% of 
patients within the first year.3  
 


 
 
 
 
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The HeartMate 3 (HM3) LVAD is a fully magnetically levitated centrifugal flow device 
which was designed to improve hemocompatibility by decreasing surface contact 
activation, widened gaps between the rotor and pump housing, and through the addition 
of artificial intermittent pulsatility by fluctuating the rotor speed every 2 seconds. In the 
Multicenter Study of MagLev Technology in Patients Undergoing Mechanical Circulatory 
Support Therapy with HeartMate 3 (MOMENTUM 3), HM3 decreased the composite 
endpoint of survival at 2 years free of disabling stroke or reoperation to replace or 
remove a malfunctioning device compared to the HeartMate II axial flow device.4 While 
hemocompatibility has improved with this device, in order to prevent device thrombosis 
and stroke, patients with a HM3 LVAD require chronic antithrombotic therapy with a 
vitamin K antagonist (VKA) and antiplatelet therapy with aspirin 81-100 mg as outlined 
in the instructions for use (IFU).5 Vitamin K antagonists require careful titration to INR 
goal, as elevations in INR are associated with hemorrhagic events and subtherapeutic 
INR values associated with thrombotic events including device thrombosis and ischemic 
strokes.6 Even in patients with excellent INR control, bleeding and thrombotic events 
are common and difficult to predict.7 
 
Direct oral anticoagulants (DOACs) have become first-line anticoagulant therapy for 
patients with atrial fibrillation (AF) and venous thromboembolism (VTE).8,9 DOACs are 
FDA approved for stroke prevention in AF or treatment of VTE include the direct 
thrombin inhibitor, dabigatran, and factor Xa inhibitors, apixaban, edoxaban, and 
rivaroxaban. When compared to warfarin for stroke prevention in AF, apixaban is the 
only DOAC to demonstrate superior efficacy and lower bleeding rates.10–12 Unlike 
apixaban, all other DOACs are associated with increased rates of GIB when compared 
with warfarin, a complication already plaguing LVAD patients.3  
 
DOACs have been slow to be adopted in patients with LVADs for multiple reasons. A 
publication in 2013 raised alarm for the efficacy and safety of DOACs in patients with a 
mechanical prosthesis. The Randomized, Phase II Study to Evaluate the Safety and 
Pharmacokinetics of Oral Dabigatran Etexilate in Patients after Heart Valve 
Replacement (RE-ALIGN) trial compared high doses of dabigatran with warfarin for 
patients with a mechanical heart valve.13 This trial was terminated early due to safety 
events in the dabigatran group. Compared with warfarin, patients on dabigatran 
experienced a higher rate of stroke, myocardial infarction, valve thrombosis, and major 
and non-major bleeding. Simultaneously, a pilot study examined the safety of 
dabigatran in patients with LVADs. This trial was also terminated early due to excess 
thromboembolic and bleeding complications in the dabigatran group.14 Mechanical heart 
valves trigger a prothrombotic state via thrombin production through the intrinsic clotting 
cascade (i.e. contact activation pathway). Standard dosing of dabigatran is insufficient 
to suppress this thrombin burst and higher doses which may sufficiently inhibit thrombin 
are prohibitive due to bleeding risk.15 It is believed that vitamin K antagonists are more 
effective at preventing thrombin production through their upstream inhibition of the 
intrinsic and common coagulation pathways. Apixaban, which acts at the start of the 
common pathway inhibiting factor Xa and preventing thrombin production, may result in 
outcomes more similar to the standard of care, vitamin k antagonists.  


 
 
 
 
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A second reason DOACs have been slow to be adopted in patients with mechanical 
devices is due to lack of reversal agents in the event of a life-threatening bleed or need 
for urgent surgery such as transplantation. Andexanet alfa, the first direct reversal agent 
for apixaban and rivaroxaban, was FDA approved in 2018. Prior to 2018, non-specific 
hemostatic agents such as 4-factor prothrombin complex concentrate (4F-PCC) were 
used commonly for patients on oral factor Xa requiring urgent reversal due to bleeding 
complications or need for urgent surgery. In a multicenter retrospective analysis of 
patients on apixaban or rivaroxaban presenting with an intracranial hemorrhage treated 
with 4F-PCC, hemostatic efficacy was reported in 82% of patients.16 This rate of 
hemostasis was the same as that found in the Andexanet Alfa, A Novel Antidote to the 
Anticoagulation Effects of Factor Xa Inhibitors (ANNEXA-4) study, where excellent or 
good hemostasis was reported in 82% of patients presenting primarily with intracranial 
or gastrointestinal bleeding.17 Because of significant cost, lack of data in patients 
requiring surgery, and the short duration of activity of andexanet alfa, many hospitals 
have maintained 4F-PCC as the agent of choice for oral factor Xa inhibitor reversal until 
additional data are available.  
6 
PRELIMINARY STUDIES (STUDY RATIONALE) 
While no randomized control trials have evaluated the safety and efficacy of factor Xa 
inhibitors in patients with LVADs. Apixaban is currently being studied in a randomized 
trial of patients with On-X mechanical heart valves (NCT# 04142658). For patients with 
LVADs, the potential safety and efficacy of using apixaban as an anti-coagulant is 
supported by a mock loop study performed with the HeartWare HVAD which utilized a 
control (no antithrombotic therapy), blood from patients on warfarin, in vitro addition of 
apixaban approximating a dose of 2.5 mg twice daily, and in vitro addition of apixaban 
approximating a dose of 5 mg twice daily. In this study, time to clot formation was lowest 
in the control group (71 minutes) and similar for circuits with warfarin and in vitro 
apixaban 2.5 mg twice daily (80 minutes). No clot formation was identified for the mock 
loop containing in vitro apixaban 5 mg twice daily after 90 minutes.18 In recent years 
there have been 4 case reports and case series totaling 53 patients with LVADs which 
found satisfactory outcomes using apixaban in patients non-compliant or failing warfarin 
therapy.19–21 The retrospective nature of these reports, as well as the different types of 
LVADs and patient characteristics makes it difficult to draw reliable conclusions on the 
efficacy and safety of apixaban in preventing thromboembolic and bleeding 
complications.  
7 
STUDY DESIGN 
7.1 Screening / Baseline    
Patients will have an initial screening evaluation, at which time patient eligibility will be 
determined. Those who willing participants, who meet all entry criteria and are 
interested in study participation will be consented and enrolled.   


 
 
 
 
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7.2 Randomization Phase  
This will be a 2-arm prospective, randomized, controlled, open label trial with an active 
treatment arm (apixaban).  
 
Patients will be randomized 1:1 to apixaban or warfarin. Patients will be randomized 
using procedures determined by the Coordinating Center (CC) to one of the two 
treatment groups. 
7.3 Study Intervention Phase  
Study treatment will be using the target dose of apixaban 5mg po BID or warfarin po 
daily for a goal INR of 2.0 to 2.5. All patients will be treated with aspirin 81mg daily as 
per the IFU. Randomized participants will receive the first dose of study drug as follows: 
 LVAD patients randomized to warfarin will begin treatment once all anticipated 
surgical procedures are complete and the patient is deemed stable for transfer 
out of the ICU. Warfarin will be overlapped with low intensity heparin until the INR 
is at least 2.0. Warfarin will be dosed to maintain an INR goal of 2.0-2.5. For 
ambulatory LVAD patients, warfarin therapy will be continued. 
 LVAD patients randomized to apixaban will transition from heparin to apixaban 
once all anticipated surgical procedures are complete and the patient is deemed 
stable for transfer out of the ICU. Heparin will be discontinued at the same time 
apixaban is initiated. For ambulatory LVAD patients on warfarin, warfarin will be 
transitioned to apixaban when the INR < 2.0. 
 
Dose adjustments of apixaban will not occur. Dose adjustments of warfarin will be made 
no less than every 4 weeks to achieve the goal INR of 2.0 to 2.5. Participants will return 
to clinic according to the schedule shown in Appendix C. 
 
For patients upgraded on the transplant list from a status 4 or below to a status 1-3, 
apixaban will be transitioned to warfarin, to allow for drug reversal at time of transplant. 
Patients randomized to the apixaban arm will be replaced to ensure 20 LVAD patients 
are exposed to apixaban over the duration of the study. Warfarin patients will not be 
replaced, as warfarin is standard of care therapy for LVAD patients.  
7.4 Biobank Study  
Biobank samples will be collected for future biomedical research to examine the impact 
of apixaban on markers of inflammation and the coagulation system. Candidate 
biomarkers may predict drug response to the treatment. Biomarker blood samples will 
be collected at the time points indicated in the schedule of events.  
 
Samples will be collected at the study site into a lithium heparin, EDTA, serum and 
citrate tube. ~25 to 30cc of blood will be collected, processed, and stored for up to 7-
years after study completion. No DNA analyses will be performed. 
 


 
 
 
 
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Investigators will not receive the results of analyses during the study, and no alerts will 
be sent.  
8 
PATIENT POPULATION  
8.1 Study Population  
It is anticipated that approximately 40 patients meeting eligibility criteria listed below will 
be randomized into the study. Participants suitable for this protocol are individuals 
already implanted with a HM3 LVAD. Patients may be currently hospitalized or 
ambulatory. Enrollment of existing HM3 LVAD patients, implanted ≥ 3 months will 
be capped at 20 patients to ensure adequate representation of newer LVAD implants 
who have a higher risk of thromboembolic adverse events.  
8.2 Inclusion Criteria 
1. Patients implanted with a HM3 LVAD 
2. Age ≥ 18 years and able to provide written informed consent 
3. Females of childbearing age must agree to use adequate contraception 
8.3 Exclusion Criteria 
1. History of post-LVAD device thrombosis, stroke, or gastrointestinal bleeding 
2. Patients who are bridge to transplant and a current UNOS status 1-3 
3. Ongoing inotrope therapy after LVAD (e.g., milrinone, dobutamine, epinephrine) 
4. Permanent right ventricular assist device at the time of LVAD implant 
5. Patients with a mechanical heart valve 
6. Patients with end-stage renal disease on dialysis 
7. Pregnant patients 
8. Known history of ischemic stroke, intracranial bleed, or neurosurgery within 3 
months 
9. Known history of intracerebral arteriovenous malformation, cerebral aneurysm or 
mass lesions of the central nervous system. 
10. Recent (<48 hours) or planned spinal or epidural anesthesia or puncture 
11. Prior history of known thrombophilia (e.g., factor V Leiden, prothrombin gene 
mutation, protein C or S deficiency, antithrombin 3 deficiency, 
hyperhomocysteinemia, antiphospholipid antibody syndrome) or indication for 
higher INR goal (>2.5) with warfarin. 
12. Thrombolysis within the previous 7 days  
13. Patients with an allergy or contraindication to aspirin, warfarin, or apixaban 
14. Patients on antiplatelet therapy other than aspirin (e.g., clopidogrel, prasugrel, 
ticagrelor, dipyridamole, or pentoxifylline)  
15. Patients on combined P-glycoprotein and strong CPY3A4 inhibitors or inducers 
(e.g., fluconazole, posaconazole, rifampin)  
16. Known bleeding within the last 30 days requiring emergency room 
presentation or hospitalization 


 
 
 
 
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17. Known history of an inherited bleeding disorder (e.g., hemophilia, von 
Willebrand disease) 
18. Patients with active bleeding or a hemoglobin < 8.0 g/dl 
19. Total bilirubin > 2.0 mg/dl, shock liver, hepatic encephalopathy, or biopsy proven 
liver cirrhosis 
20. INR > 2.0 not due to anticoagulation therapy 
21. Platelet count <100,000 cells/mm3  
9 
TREATMENT  
9.1 Intervention  
This will be a 2-arm prospective, randomized, controlled, open label trial with an active 
treatment arm (apixaban). The therapeutic intervention will be treatment with either 
apixaban or warfarin. 
 
Study drug will be given for 24 weeks for primary endpoint data.  
 
Warfarin dose will be determined based on hospital protocol (Appendix A). The INR will 
be checked daily while inpatient. For outpatients INR will be checked at least weekly 
until two consecutive values are in range at which point INRs will be checked every 2-4 
weeks. 
9.2 Drug Dispensing 
Apixaban will be manufactured by Bristol Myers Squibb Co. and provided by the Inova 
Health System Research Pharmacy. Apixaban will be supplied in bottles containing 5-
mg (normal dose) tablets. Warfarin will be prescribed per normal prescribing practices 
and available through the patient’s normal pharmacy. Participants will receive a 
sufficient supply of study drug at each study visit to last until the next study visit. Drug 
storage, inventory, accountability, and dispensing will be managed by and unblinded 
pharmacist at the CC. Patients will be instructed to take the medication as required by 
the protocol and compliance will be assessed at each visit (as described in the 
protocol). 
9.3 Drug Administration 
Participants will take apixaban twice daily by mouth or warfarin daily, according to the 
Dosing Guidelines below. The total number of anticoagulation pills taken will be 1-2 pills 
per day. 
9.4 Drug Storage Requirements 
Store at 25°C (77°F) with excursions between 15°C and 30°C (59°F and 86°F) 
permitted [see USP Controlled Room Temperature]. Protect from moisture. 


 
 
 
 
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9.5 Drug accountability 
Participants are instructed to return all used, partly used, and unused trial product 
(apixaban) at each study visit. Returned trial product(s) (used, partly used or unused 
including empty packaging material) must be stored separately from the non-allocated 
trial product(s) until drug accountability has been reconciled. The investigators will keep 
track of all received, used, partly used and unused trial products. 
9.6 Destruction 
Used and unused study drug may be destroyed at the site according to accepted 
pharmacy practice, local and national guidelines, using the site’s destruction procedure 
after the CRA has reviewed drug accountability and approved and accounted for the 
study drug to be destroyed. A copy of the site drug destruction SOP should be 
maintained in the Pharmacy section of the Regulatory Binder. Study drug destruction 
should be documented in the comments section of the Participant Specific Drug 
Accountability Log.  
9.7 Randomization, Stratification and Blinding 
Patients will be consented, enrolled, and randomized at the first study visit. Participants 
will be randomized using procedures determined by the CC to one of 2 treatment 
groups. Participants will be randomized in a 1:1 allocation ratio using a permuted block 
design with stratification based on time from LVAD implant (<3 months v. ≥ 3 months). 
Enrollment of existing HM3 LVAD patients, implanted ≥ 3 months will be capped at 20 to 
ensure adequate representation of newer LVAD implants who have a higher risk of 
thromboembolic adverse events. 
9.8 Concomitant Medication 
Participants should be treated per clinical center practice with standard HF medical 
therapy (diuretics for congestion, beta-blockers, mineralocorticoid receptor antagonists 
and sacubitril/valsartan or if intolerant or unable to afford this medication and 
angiotensin II receptor blocker (ARB) or angiotensin-converting enzyme inhibitor (ACE-
I).  
10 RECRUITMENT AND SCREENING PROCEDURES 
10.1 Common Recruitment Procedures 
All LVAD patients followed at Inova Health System will be screened by a study 
coordinator. Patients meeting eligibility criteria will be approached regarding 
participation in this study.  


 
 
 
 
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10.2 Estimated Enrollment Period 
This study will randomize approximately 40 at one-center in the U.S. The anticipated 
enrollment period is approximately 12-24 months. 
10.3 Informed Consent Procedures 
10.1.1 Informed Consent 
Center clinicians will explain to eligible patients the purpose of the study, study 
interventions and evaluations, and the potential risks and benefits of participation, and 
will answer any questions. If a patient agrees to participate in the study, they will review 
and sign the site-specific IRB approved informed consent form (ICF).  
10.1.2   Confidentiality and HIPAA Requirements 
All information collected on study participants will be stored in a confidential manner. 
Only approved study personnel will have access to data collected as part of the study. 
Consented study participants will be identified by a participant ID number on all study 
documents. Data will be stored securely using standard operating procedures. 
10.1.3 Protections of Human Subjects 
Protections for human subjects of research are required under Department of Health 
and Human Services (HHS) regulations at 21 CFR parts 50, 56, and 312. 
10.1.4 Summary of the Risks and Benefits 
Blood draws: The risks of drawing blood include bleeding at the puncture site, bruising 
and pain. These occur in a very small portion of the population.  
 
Eliquis (apixaban): Direct oral anticoagulants, the class to which apixaban belongs to, 
have been shown to reduce the risk of stroke and systemic embolism in patients with 
non-valvular atrial fibrillation (NVAF). These agents are recommended over warfarin in 
eligible patients with NVAF and a CHA2DS2-VASc score ≥ 2 in men or ≥ 3 in women to 
reduce the risk of stroke and systemic embolism (1, LOE A).  The risks for apixaban use 
in LVAD patients in this study are not known, particularly the risks associated with 
device thrombosis or stroke, but the risks are expected to be similar as use of apixaban 
for the prevention of stroke and systemic embolism in patients with NVAF. The most 
common (>1%) adverse reactions are related to bleeding as apixaban may cause 
serious, potentially fatal, bleeding. Compared with warfarin, DOACs reduce the risk of 
intracranial hemorrhage. Apixaban is not known to be teratogenic however it should not 
be used in pregnancy due to the increased risk of bleeding.  
 
Coumadin (warfarin): Warfarin was the comparator to all DOACs in studies evaluating 
DOAC use for patients with NVAF. Warfarin is standard anticoagulation for LVAD 
patients. Warfarin is recommended in patients with atrial fibrillation and a CHA2DS2-
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embolism who are not considered eligible for a DOAC (moderate-to-severe mitral 
stenosis or a mechanical heart valve) (1, LOE A). The most common (>1%) adverse 
reactions are related to bleeding as warfarin may cause serious, potentially fatal, 
bleeding. Warfarin is associated with a higher risk of intracranial and gastrointestinal 
bleeding when compared with apixaban in NVAF and VTE. Warfarin is known to be 
teratogenic and should be avoided in the first trimester of pregnancy. 
11 VISIT SCHEDULE AND ASSESSMENTS 
11.1 Baseline Evaluation and Randomization Visit  
A complete schedule of assessments throughout the study is given in Appendix B. 
 
Study Visit 0 (Enrollment & Randomization after LVAD implant) 
This visit will include the screening and informed consent process followed by a 
baseline assessment including:  
 Demographic information 
 Medical history including review of history of thromboembolism and atrial fibrillation  
 Physical examination including height and weight  
 Review of medications  
 Local laboratory testing, including white blood cells, hemoglobin, platelet count, 
sodium, potassium, BUN, creatinine, magnesium, AST/ALT, total and direct 
bilirubin, albumin, total protein, alkaline phosphatase, activated partial 
thromboplastin time, prothrombin time/INR, LDH, fibrinogen, and d-dimer. Labs 
obtained within 1 week prior to randomization can be used to assess patient 
eligibility and apixaban dosing. 
 Serum or urine pregnancy test on all women of childbearing potential 
 Biobank blood collection 
 Verification of listing status for transplant 
 
At this visit, participants will be randomized to either apixaban or warfarin. Doses will be 
assigned in the following fashion: 
 
In ambulatory patients assigned to warfarin, they will remain on their current warfarin 
dose adjusted to achieve an INR of 2.0-2.5.  
 
For inpatients assigned to warfarin, warfarin dose will be determined based on the 
hospital protocol (Appendix A). Warfarin dose will be titrated and overlapped with 
heparin until an INR of 2.0-2.5 is reached. 
 
In ambulatory patients randomized to apixaban a baseline INR will be obtained. 
Warfarin will be held until INR < 2.0 and the apixaban will be initiated at a dose of 5 mg 
BID. 
 


 
 
 
 
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For inpatients randomized to apixaban, apixaban will be initiated as first-line oral 
anticoagulation at a dose of 5 mg BID. Heparin will be discontinued at the time of 
apixaban initiation. No overlap should occur. 
11.2 Follow-up Evaluations 
Study Visit 1 (2 weeks post-randomization +/- 7 days) – Virtual Visit 
 
At this visit, two weeks after randomization, interim history, review of medications, 
adherence and tolerance assessment, and adverse event monitoring.  
 
Study Visit 2 (4 weeks post-randomization +/- 7 days) 
 
At this visit, four weeks after randomization, interim history, review of medications, 
physical examination, laboratory testing (white blood cells, hemoglobin, platelet count, 
sodium, potassium, BUN, creatinine, magnesium, AST/ALT, total and direct bilirubin, 
albumin, total protein, alkaline phosphatase, activated partial thromboplastin time, 
prothrombin time/INR, LDH, fibrinogen, d-dimer  and Anti-Xa level), adherence and 
tolerance assessment, and adverse event monitoring. A biobank blood collection will be 
performed. Verification of listing status for transplant to ensure ongoing eligibility for 
study participation. 
 
Study Visit 3 (6 weeks post-randomization +/- 7 days) – Virtual Visit 
 
At this visit, six weeks after randomization, interim history, review of medications, 
adherence and tolerance assessment, and adverse event monitoring.  
 
Study Visit 4 (8 weeks post-randomization +/- 7 days) – Virtual Visit with Labs 
 
At this visit, eight weeks after randomization, interim history, review of medications, 
adherence and tolerance assessment, and adverse event monitoring. Remote lab 
testing will include white blood cells, hemoglobin, platelet count, sodium, potassium, 
BUN, creatinine, magnesium, AST/ALT, total and direct bilirubin, albumin, total protein, 
alkaline phosphatase, prothrombin time/INR, LDH. 
 
Study Visit 5 (12 weeks post-randomization +/- 14 days) 
 
At this visit, 12 weeks after randomization, interim history, review of medications, 
physical examination, laboratory testing (white blood cells, hemoglobin, platelet count, 
sodium, potassium, BUN, creatinine, magnesium, AST/ALT, total and direct bilirubin, 
albumin, total protein, alkaline phosphatase, activated partial thromboplastin time, 
prothrombin time/INR, LDH, fibrinogen, d-dimer  and Anti-Xa level), adherence and 
tolerance assessment, and adverse event monitoring. A biobank blood collection will be 
performed. Verification of listing status for transplant to ensure ongoing eligibility for 
study participation. 


 
 
 
 
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Study Visit 6 (18 weeks post-randomization +/- 14 days) – Virtual Visit 
 
At this visit, eighteen weeks after randomization, interim history, review of medications, 
adherence and tolerance assessment, and adverse event monitoring.  
 
Study Visit 7 (24 weeks after randomization +/- 14 days) 
 
At this visit, 24 weeks after randomization, interim history, review of medications, 
physical examination, laboratory testing (white blood cells, hemoglobin, platelet count, 
sodium, potassium, BUN, creatinine, magnesium, AST/ALT, total and direct bilirubin, 
albumin, total protein, alkaline phosphatase, activated partial thromboplastin time, 
prothrombin time/INR, LDH, fibrinogen, d-dimer  and Anti-Xa level), adherence and 
tolerance assessment, and adverse event monitoring. A biobank blood collection will be 
performed. Verification of listing status for transplant to ensure ongoing eligibility for 
study participation. After this visit, the study phase is complete. 
 
At this visit patients will be provided the opportunity to continue open label apixaban 
therapy if randomized to apixaban arm of the study. Patients randomized to warfarin will 
continue warfarin therapy.  
 
End of Study Visit or Visit 8 (28 weeks after randomization +/- 7 days) – Virtual Visit 
 
At this visit, 28 weeks after randomization and 4 weeks after study drug completion, 
interim history, review of medications, and adverse event monitoring. 
11.3 Phone and Other Media Follow-up  
General procedures: At Study Visit 1, participants and study staff will define optimal 
times and phone numbers for the protocol-specified phone contacts to encourage 
compliance with study procedures. In addition video visit structure for follow-up study 
visits will be reviewed. 
 
During the follow-up visits, the participant will receive:  
 Reminder of appropriate study drug dose for the stage of the protocol. 
 Confirm plans for future study visits 
 Confirm need to bring study drug to future study visits.  
12 OUTCOME DETERMINATIONS 
12.1 Primary Endpoint 
Freedom from death or hemocompatibility related adverse events (stroke, device 
thrombosis, bleeding, aortic root thrombus and arterial non-CNS thromboembolism) at 
24-weeks. 


 
 
 
 
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12.2 Secondary Endpoints 
1. Survival free of any stroke 
2. Survival free of ischemic stroke 
3. Survival free of hemorrhagic stroke 
4. Survival free of device thrombosis 
5. Survival free of aortic root thrombus 
6. Survival free of gastrointestinal bleeding 
7. Survival free of major non-gastrointestinal bleeding 
8. All-cause mortality 
9. Cardiovascular mortality 
12.3 Tertiary Endpoints 
1. Time in the therapeutic range for patients on warfarin 
2. Anti-Xa trough concentration at 1 month, 3 months, and 6 months for patients on 
apixaban 
3. A subgroup analysis of above endpoints will be completed for patients enrolled 
immediately after LVAD implantation versus those enrolled ≥ 3 months from LVAD 
implantation 
13 METHODS TO PROMOTE ADHERENCE 
13.1 Protocol Training 
Protocol training and adherence will be a major focus of the investigator training. Based 
on our experience in prior studies, identifying and correcting non-adherence is best 
accomplished in a stepped approach. The site will be responsible for managing 
participant compliance with study drug administration and visit compliance.   
13.2 Data Quality Reports 
The CC will provide data quality reports for review and will follow-up to reemphasize the 
importance of adherence as needed. Significant non-adherence issues will be 
discussed with the principal investigator. 
14 SAFETY MONITORING AND REPORTING 
14.1 Institutional Review Board 
The study protocol, consent form, and other study documents will be subject to IRB 
approval. Any amendments to the protocol, other than minor administrative changes, 
must be approved by the IRB before they are implemented. 


 
 
 
 
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14.2 Definitions 
14.1.1 Adverse Events 
An adverse event (AE) is any untoward medical occurrence associated with the use of a 
drug in a participant, whether or not it is considered directly related to the drug or 
biologic related. An AE can therefore be any undesirable sign, symptom or medical 
condition occurring after starting study drug, even if the event is not considered to be 
related to the pharmaceutical product. Study drug includes the drug under evaluation, 
and any reference drug given during any phase of the trial. Safety monitoring for 
adverse events will begin upon randomization.  
14.1.2 Suspected Adverse Reaction  
A suspected adverse reaction (SAR) is any adverse event for which there is a 
reasonable possibility that the drug caused the event. “Reasonable possibility” suggests 
there is a causal relationship between the drug and the adverse event. “Suspected 
adverse reaction” implies a lesser degree of certainty about causality than adverse 
reaction, which means any adverse event caused by a drug.  
14.1.3 Serious Adverse Events (SAE) 
An adverse event or suspected adverse reaction is considered serious if the investigator 
or sponsor believes any of the following outcomes occurred: 
 Death 
 Life-threatening AE:  Places the participant at immediate risk of death at the time 
of the event as it occurred. It does not include an AE that, had it occurred in a 
more severe form, might have caused death. 
 Persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions. 
 Important medical events that may not result in death, be life threatening, or 
require hospitalization may be considered a serious adverse event when, based 
upon appropriate medical judgment, they may jeopardize the participant and may 
require medical or surgical intervention to prevent one of the outcomes listed in 
this definition above. 
 
This determination is based on the opinion of either the investigator or sponsor (e.g., if 
either believes it is serious, it must be considered serious). 
14.1.4 Laboratory Test Abnormalities 
For laboratory test abnormalities that meet the definition of an SAE, that required the 
participant to have the investigational product discontinued or interrupted or required the 
participant to receive specific corrective therapy, the clinical diagnosis rather than the 
laboratory term will be used by the reporting investigator (e.g., anemia versus low 
hemoglobin value). 
 


 
 
 
 
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14.1.5 Assessment of Causal Relationship 
A medically qualified investigator must assess the relationship of any AE to the use of 
study drug, based on available information, using the following guidelines:  
 Not related: There is not a reasonable causal relationship to the investigational 
product and the adverse event.  
 Unlikely related: No temporal association or the cause of the event has been 
identified, or the drug or biologic cannot be implicated. 
 Possibly related: There is reasonable evidence to suggest a causal relationship 
between the drug and adverse event. 
 Related: There is evidence to suggest a causal relationship, and the influence of 
other factors is unlikely. 
14.1.6 Assessment of Adverse Event Severity 
The determination of adverse event severity rests on medical judgment of a medically 
qualified Investigator. The severity of AEs will be graded using the following definitions:  
 Mild: Awareness of sign, symptom, or event, but easily tolerated.  
 Moderate: Discomfort enough to cause interference with usual activity and may 
warrant intervention.  
 Severe: Incapacitating with inability to do usual activities or significantly affects 
clinical status, and warrants intervention.  
Anticipated Disease Related Events and Events of Interest 
The following are anticipated, disease-related events in patients with LVAD or 
anticipated events of interest in patients with apixaban or warfarin: 
 Arrhythmias 
 Cardiac Transplantation  
 Device Explant 
 Infection 
 Transient Ischemic Attack 
 Unplanned hospitalization, ER visit or clinic visit 
 
Anticipated events will not be captured as AEs/SAEs during the study but will be 
entered on the appropriate electronic case report form (eCRF) module (“Anticipated 
Disease Related Events” page). 
14.1.7    Recording and Reporting of Adverse Events 
The site Investigator is responsible for monitoring the safety of participants enrolled into 
the study at the study sites. For this study, non-serious AEs will not be collected on the 
safety reporting page of the eCRF but should be documented in the source documents 
and followed according to local standard of care. Events significant enough to 
necessitate modification of antithrombotic therapy dosing will be captured on the 
appropriate eCRF module (“Adverse Events” page).  


 
 
 
 
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14.1.8    Subject Stopping Criteria and Drug Modification 
 
For patients in the apixaban arm with a thromboembolic event (stroke, device 
thrombosis or arterial non-CNS thromboembolism), will be considered a study drug 
failure and converted to warfarin (withdrawn from active treatment). For patients 
experiencing a bleeding event, the aspirin will be discontinued. Only in patients with 
recurrent bleeding will the apixaban be discontinued (withdrawn from active treatment) 
and warfarin initiated at an INR goal of 1.5 to 2.0. Patients will continue to be followed 
per the study schedule through study completion. 
 
For apixaban patients listed for transplant, who are upgraded to a status 1-3, the 
apixaban will be discontinued and the patient converted to warfarin. These patients will 
be followed until transplant or study completion. Each apixaban patient who does not 
complete the 6-month study duration will be replaced to ensure 20 patients are in the 
apixaban arm with complete follow-up. 
 
For patients in the warfarin arm with a thromboembolic event, will be managed with a 
higher INR goal of 2.5 to 3.0. For patients experiencing a bleeding event, the aspirin will 
be discontinued. Only in patients with recurrent bleeding will the INR goal range be 
reduced to 1.5 to 2.0. For patients with a 3rd bleeding event, warfarin will be stopped, 
and the patient will be withdrawn from treatment and the patient followed according to 
the study protocol. 
 
Any AE events occurring up to 72 hours after the study drug is discontinued will be 
considered a treatment-emergent adverse event. 
  
All SAEs, except for those anticipated events listed above, occurring from signed 
informed consent through study completion will be captured on the AE eCRF.  Unless 
exempted as described above, all SAEs, whether or not deemed drug-related or 
expected, must be reported to the IRB by the investigator or qualified designee within 
24 hours of first becoming aware of the event.  For this study, all-cause deaths will be 
reported on the AE eCRF. The investigator or qualified designee will enter the required 
information regarding the SAE into the appropriate module of the eCRF. If the eCRF 
system is temporarily unavailable, the event, including the investigator-determined 
causality to study drug should be reported via the back-up paper AE form. Upon return 
of the availability of the electronic data capture (EDC) system, the SAE information must 
be entered into the eCRF. 
 
Follow-up 
When additional relevant information becomes available, the Investigator will record 
follow-up information according to the same process used for reporting the initial event 
as described above. The Investigator will follow all reportable events until resolution, 
stabilization or the event is otherwise explained.  
 


 
 
 
 
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The investigator will follow all SAEs until resolution, stabilization, until otherwise 
explained or until the participant completes the final follow-up, whichever occurs first.  
Investigators are also responsible for promptly reporting AEs to their reviewing IRB/EC 
in accordance with local requirements.   
14.1.9 Suspected Unexpected Serious Adverse Reaction 
 AEs that meet the criteria of serious, related to study drug, and unexpected per 
investigator brochure, qualify for expedited reporting to the regulatory authorities. The 
site Investigator will assess all SAE’s occurring at his/her site and evaluate for 
“unexpectedness” and relationship to study drug. The site Investigator is required to 
complete and submit a voluntary MedWatch Report for events deemed, as serious, 
study drug related and unexpected at: 
https://www.accessdata.fda.gov/scripts/medwatch/. 
 
A copy of this report should be kept at the site. 
14.1.10 Pregnancy 
Pregnancy occurring during a clinical investigation, although not considered a serious 
adverse event, must be reported within the same timelines as a serious adverse event. 
The pregnancy will be recorded on the appropriate paper pregnancy tracking form. The 
pregnancy will be followed until final outcome. Any associated AEs or SAEs that occur 
to the mother or fetus will be recorded in the AE eCRF, within the EDC system.  
15 STATISTICAL METHODS AND DATA ANALYSIS 
15.1 General Design Issues 
All planned analyses will be prospectively defined for this study and approved by the 
CC. The statistical analysis plan (SAP) will contain detailed information regarding the 
data analysis. The SAP will be finalized prior to trial completion and will be approved by 
the coordinating center statistical team. 
 
Analysis of the DOAC LVAD Study will be based on intention to treat (ITT). That is, 
participants will be analyzed (and endpoints attributed) according to the treatment 
strategy to which participants are randomized, regardless of subsequent additional post-
randomization treatment and medical care. The ITT population will correspond to all 
randomized participants. The primary and secondary analyses will follow the ITT 
principle.  
 
Baseline demographic and clinical variables will be summarized for each randomized 
arm of the study. Descriptive summaries of the distribution of continuous variables will 
be presented in terms of percentiles (e.g., median, 25th and 75th percentiles) along with 
means and standard deviations.  Categorical variables will be summarized in terms of 
frequencies and percentages. 


 
 
 
 
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In addition, exploratory analyses will be performed to help explain and understand 
findings observed from the planned analyses. Statistical tests with a p-value <0.05 will 
be considered statistically significant, unless otherwise stated. Analyses will be 
performed using SAS software (SAS Institute, Inc, Cary, NC).  
15.2 Sample Size Justification and Randomization 
Participants will be randomized in a 1:1 allocation ratio using a permuted block design 
with stratification based on the time from LVAD implant (<3 months or ≥3 months). The 
number of patients ≥3 months from LVAD implant will be capped at 20 participants. As 
this is an initial pilot study to assess safety and feasibility, we plan to enroll 40 patients. 
  
For the primary purposes of this pilot study, each patient’s data will be reviewed 
individually. Patients newly implanted vs previously implanted with a HM3 LVAD may be 
analyzed as distinct subgroups. The sample size of up to forty (40) implanted patients is 
based upon industry standards for early-stage studies of medical devices; the sample 
size was not statistically derived. This study is not designed to provide statistical 
significance of the outcomes. The study will provide data to be used for subsequent 
design and development of the phase III clinical trials. An interim report may be 
generated prior to completion of enrollment for regulatory or publication purposes.  
15.3 Analysis of the Primary Endpoint 
For the primary endpoint, a time-to-event analysis will be conducted. The Cox 
regression model for survival data will be used to test the statistical significance of 
differences in the composite endpoint (survival free of major hemocompatibility related 
adverse event) between the two treatment groups. Certain clinical covariates may be 
used in the regression model (age, sex, race, atrial fibrillation, history of stroke or 
bleeding prior to LVAD, early (<3 months) or late (≥3 months) after implant, laboratory 
parameters, hemodynamics, coagulation marker measures). 
15.4 Analysis of Secondary and Tertiary Endpoints 
The key secondary endpoint will be analyzed for time-to-event endpoints, using the Cox 
regression model for survival data will be used to test the statistical significance of 
differences in mortality between the treatments. Kaplan-Meier curves will be generated 
to graphically display the mortality rates as a function of time from randomization in 
each treatment. Patients will be censored when upgraded to a status 1-3, at the time of 
transplant, transfer of care to another LVAD center, device decommissioning or explant 
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16 DATA MANAGEMENT PROCEDURES 
16.1 Overview of Data Management  
The CC will have primary responsibility for data management, including the 
development of data collection systems, data monitoring processes, and data storage 
and back-up. State-of-the-art technology will be used for the management of the 
network’s data.  
16.2 Data Security  
Access to databases will be controlled centrally by the CC through user passwords 
linked to appropriate privileges. This protects the data from unauthorized changes and 
inadvertent loss or damage. Database and web servers will be secured by a firewall and 
through controlled physical access. Database back-up will be performed daily using 
standard procedures in place at the CC. All disk drives that provide network services, 
and all user computers, will be protected using virus-scanning software. 
16.3 Publication Policy 
Dissemination of preliminary information can adversely affect the objectivity of study 
data. For this reason, investigators will not be allowed to perform subset analyses at 
any point before the conclusion of the study, and any data, other than safety data, 
cannot be used for publication or reporting outside of this study until the study is 
completed or discontinued by the principal investigator.  
17 STUDY ADMINISTRATION 
17.1 Data and Safety Monitoring Board 
An independent Data and Safety Monitoring Board (DSMB) has been convened to 
assess the progress of the clinical study, the safety data, and critical efficacy endpoints 
(if appropriate) and provide recommendations to the sponsor. The members of the 
DSMB serve in an individual capacity and provide their expertise, including 
recommendations regarding the continuation, modification, or termination of any or all 
arms of the study.  The DSMB will review cumulative study data to evaluate safety, 
study conduct, scientific validity, and data integrity of the study. A separate DSMB 
charter outlines their roles and responsibilities.   
17.2 Study Termination 
The study may be terminated by the Sponsor at any time with suitable written notice to 
the reviewing IRB and applicable regulatory agencies. The study may be terminated by 
the DSMB based on concerns for significant harm to study participants based on criteria 
outlined in the DSMB charter. The following clinical events in the apixaban arm will 
result in an immediate pause of study enrollment for an evaluation by the independent 
DSMB: 


 
 
 
 
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 ≥ 2 thromboembolic events (ischemic stroke, arterial non-CNS embolism, device 
thrombosis, aortic root thrombus) 
 ≥ 4 major bleeding events (Types 3-5) 
 ≥ 2 deaths due to either thromboembolic events or major bleeding events 
 
Patients who are already enrolled in the study will continue study-related activities 
during the enrollment pause. 
18 REGULATORY ISSUES 
18.1 Ethics and Good Clinical Practice 
This study must be carried out in compliance with the protocol. These procedures are 
designed to ensure adherence to Good Clinical Practice, as described in the following 
documents: 
1. ICH Harmonized Tripartite Guidelines for Good Clinical Practice 1996. 
2. US 21 Code of Federal Regulations dealing with clinical studies (including parts 50 
and 56 concerning informed consent and IRB regulations). 
3. US 21 Code of Federal Regulations Part 312, Food and Drug Administration 
Investigational New Drug Application 
 
The investigator agrees to adhere to the instructions and procedures described in the 
protocol and thereby to adhere to the principles of Good Clinical Practice that it 
conforms to. 
18.2 Institutional Review Board/Independent Ethics Committee 
Before implementing this study, the protocol, the proposed informed consent form, and 
other information to participants must be reviewed by a properly constituted Institutional 
Review Board/Independent Ethics Committee (IRB/IEC). Documentation that the 
protocol and informed consent have been approved by the IRB/IEC must be provided 
before study initiation.  Any amendments to the protocol, other than administrative ones, 
must be approved by this committee. 
18.3 Informed Consent 
The investigator or designee must explain to each participant (or legally authorized 
representative) the nature of the study, its purpose, the procedures involved, the 
expected duration, the potential risks and benefits involved and any discomfort it may 
entail. Each participant must be informed that participation in the study is voluntary and 
that he/she may withdraw from the study at any time and that withdrawal of consent will 
not affect his/her subsequent medical treatment or relationship with the treating 
physician. 
 
The informed consent form(s) must be submitted by the investigator for IRB/IEC 
approval. 


 
 
 
 
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18.4 Subject Withdrawal  
 
Subjects may withdraw consent at any time for any reason or be dropped from the trial 
at the discretion of the investigator should any untoward effect occur. In addition, a 
subject may be withdrawn by the investigator or the Sponsor if enrollment into the trial is 
inappropriate, the trial plan is violated, or for administrative and/or other safety reasons. 
Should the subject be withdrawn from the study, the reason for withdrawal must be 
documented in the CRF.  
 
Subjects who discontinue/withdraw from treatment prior to completion of the treatment 
regimen should be encouraged to continue to be followed for all remaining study visits. 
 
18.5 Investigational New Drug (IND) Application 
 
The investigator or designee will file for an investigational new drug (IND) with the Food 
and Drug Administration (FDA) prior to initiation of the clinical trial.  This will permit the 
FDA to determine that apixaban is reasonably safe for initial use in LVAD patients. This 
is an investigator IND for an approved product (apixaban), that will be used in a new 
patient population (LVAD patients).  This IND will not be used to change the labeling of 
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19 APPENDICES 
19.1 Appendix A – Warfarin Dosing Protocol  
Inova Fairfax Medical Center Inpatient Warfarin New Start Guideline (Days 1 – 2) 
If warfarin was intentionally held on admission for reason other than supratherapeutic INR (e.g., need for 
surgery), resume home dose on days 1-2 and then and then utilize Guideline for Days 3-7 thereafter 
 
Step 1: Assess for patient characteristics that may impact warfarin sensitivity 
Factors that increase warfarin sensitivity: 
 
Baseline INR > 1.5 
 
 > 70 years of age 
 
Decompensated HF 
 
Significant liver disease 
 
Weight < 60 Kg 
 
 Malabsorption syndrome 
 
 Chronic diarrhea 
 
 Malnourished  
 
 Hypoalbuminemia (esp < 2 g/dl) 
Factors that decrease warfarin sensitivity: 
 
< 60 years of age 
 
BMI > 30 
Step 2: Evaluate for severe and major drug-drug interactions 
Severe drug-drug interactions: 
 
 SMX/TMP 
 
 Metronidazole 
 
Major drug-drug interactions: 
 
 Azole antifungals 
 
Macrolide antibiotics 
 
Fluoroquinolones 
 
Propafenone 
 
Amiodarone or dronedarone 
 
Disulfiram 
 
Tamoxifen 
Step 3: Determine warfarin initiation dose 
Warfarin 2.5 mg
Warfarin 4 mg 
Warfarin 5 mg
Warfarin 7.5 mg
Any factor that 
increases warfarin 
sensitivity 
 
OR 
 
Any severe drug-
drug interaction 
 
OR 
 
≥ 2 Major drug-drug 
interactions 
No factor that 
increases warfarin 
sensitivity 
 
AND 
 
No severe drug-
drug interactions 
 
AND 
 
1 major drug-drug 
interaction 
No factor that 
increases warfarin 
sensitivity 
 
AND 
 
No severe or major 
drug-drug 
interactions 
 
No factor that 
increases warfarin 
sensitivity 
 
AND 
 
No severe or major 
drug-drug 
interactions 
 
AND 
 
BOTH factors that 
decrease warfarin 
sensitivity 
Recommended starting dose is intended for days 1 and 2 of warfarin therapy. 
Subsequently see “IFMC Inpatient Warfarin New Start Guideline (D3-D7)”
 
 
 


 
 
 
 
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Inova Fairfax Medical Center Warfarin New Start Guideline (Days 3 – 7) 
 
Day 
INR Goal 
2.0 – 2.5 
Instruction 
In additional to instructions below, consideration should be given to the rate 
of INR increase/decrease, perceived warfarin 
responsiveness/sensitivity, initiation/discontinuation of 
interacting medications, and clinical status of the patient. The 
INR should increase 0.1 – 0.3 per day until steady state is 
achieved at approximately one week. 
If INR increases ≥ 0.4 per day, decrease dose by 25 – 
50% 
If INR increases ≥ 1 per day, HOLD a dose 
1 – 2 
-- 
See ”IFMC Inpatient Warfarin New Start Guideline (Days 1 – 
2)” 
3 
< 1.5 
1 – 2x initial dose 
1.5 – 1.9 
Continue initial dose 
2.0 – 2.5 
0.25 – 0.5x initial dose 
≥ 2.6 
HOLD 
4 
< 1.5 
1.5 – 2x initial dose 
1.5 – 1.9 
1 – 1.5x initial dose 
2.0 – 2.5 
Continue last dose 
2.6 – 2.9 
0.75x last dose 
≥ 3.0 
0.25x last dose or HOLD 
5 
< 1.5 
2x initial dose 
1.5 – 1.9 
1 – 2x initial dose 
2.0 – 2.5 
Continue last dose 
2.6 – 2.9 
0.5x last dose 
≥ 3.0 
0.25x last dose or HOLD 
6 
< 1.5 
2 – 3x initial dose 
1.5 – 1.9 
1.5 – 2x initial dose 
2.0 – 2.5 
Continue last dose 
2.6 – 2.9 
0.75x last dose 
≥ 3.0 
0.25x last dose or HOLD 
7 
< 2.0 
2 – 3x initial dose 
2.0 – 2.5 
Continue last dose 
2.6 – 2.9 
0.8 – 0.9x last dose 
≥ 3.0 
0.75x last dose or HOLD 
See “IFMC Inpatient Warfarin Maintenance Protocol” for dosing after 7 days 
 
 
 
 


 
 
 
 
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19.2 Appendix B – Adverse Event Definitions 
 Arrhythmias: Any documented arrhythmia that results in clinical compromise, or 
requires hospitalization or treatment. Arrhythmias will be further classified as 
sustained ventricular arrhythmia or sustained supraventricular arrhythmia  
 Arterial non-CNS thromboembolism: Acute systemic arterial perfusion deficit in any 
non-cerebrovascular organ system due to thromboembolism confirmed by 1 or more 
of the following: 1) standard clinical and laboratory testing, 2) operative findings, 3) 
autopsy findings  
 Bleeding: the location/source of the bleed will be recorded and subsequently 
categorized as follows; CNS bleeding will be captured under cerebrovascular 
event/stroke 
o Type 2: Any overt, actionable sign of hemorrhage that does not fit the 
criteria for Type 3, 4, or 5 but does meet at least one of the following 
criteria: 
 1) requiring non-surgical, medical intervention by a healthcare 
professional 
 2) leading to hospitalization or increased level of care; or  
 3) prompting evaluation 
o Type 3a 
 Overt bleeding accompanied by hemoglobin drop of 3 to < 5 g/dL 
 Any transfusion with overt bleeding 
o Type 3b 
 Overt bleeding plus hemoglobin drop 5 g/dL or greater 
 Cardiac tamponade 
 Bleeding requiring surgical intervention for control (excluding 
dental/nasal/skin/hemorrhoid) 
 Bleeding requiring intravenous vasoactive agents 
o Type 4: VAD implantation-related bleeding (includes concomitant cardiac or 
non-cardiac surgical procedure) 
 Reoperation after the closure of incision or incisions used to implant 
the VAD to control bleeding 
 ≥ 50 kg: ≥ 4U pRBC within any 48 hours during the first 7 days post-
implant 
 < 50 kg: ≥ 20 cm3/kg pRBC within any 24 hours during the first 7 
days post-implant 
 Chest tube output > 2 liters within 24 hours 
o Type 5a: Probably fatal bleeding; no autopsy or imaging confirmation but 
clinically suspicious 
o Type 5b: Definite fatal bleeding; overt bleeding or autopsy or imaging 
confirmation 
o For all types of bleeding, the event will be classified as: 
 Patient-related (e.g., coagulopathy unrelated to surgical technique 
such as non-adherence with anticoagulation medication resulting in 
inappropriately high level of anticoagulation, hepatic failure) 
 Management-related (e.g., related to surgical technique, 
hypertension, bleeding in the setting of inappropriate levels of 
anticoagulation) 
 Pump-related (e.g., bleeding from the outflow graft, apical connector, 
or other internal components 
 Major bleeding: Bleeding Types 3-5  
 Cerebrovascular event: This refers to cerebrovascular accidents (stroke) of any 
cause (ischemic or hemorrhagic). 
 Device Explant: This refers to LVAD explantation or LVAD decommissioning for 
myocardial recovery. 
 Device Thrombosis:  This refers to suspected or confirmed device thrombosis. 
o Suspected device thrombosis is a major device-related malfunction which 
clinical or device parameters suggest thrombus on the blood-contacting 
components of the pump, cannula, or grafts. Suspected device thrombosis 
will be defined as signs and symptoms to include at least 1 of the 3 
following criteria: 


 
 
 
 
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 1) Presence of major hemolysis by LDH or clinical evidence of 
hemolysis by hemoglobinuria 
 2) Presence of heart failure not explained by structural heart disease 
 Abnormal pump parameters consistent with diminished pump 
output/pump efficiency/pump performance 
And 
o Suspected device thrombus will be accompanied by 1 or more of the 
following events or interventions: 
 1) Death 
 2) Stroke or TIA 
 3) Arterial non-CNS embolism 
 4) De-novo need for inotrope therapy 
 5) Treatment with IV anticoagulation, IV thrombolytics, or IV 
antiplatelet therapy 
 6) Pump replacement 
 7) Pump explanation with or without exchange  
 8) Pump deactivation without pump removal 
 9) Operation to repair or replace any internal components of the 
circulatory support system 
 10) Urgent transplant listing (immediate urgent listing for transplant) 
o Confirmed device thrombosis is major device-related malfunction in which 
thrombus is confirmed within the blood-contacting surfaces of device inflow 
cannula or outflow conduit or grafts. This can be reported through direct 
visualization inspection or by incontrovertible contrast radiographic 
evidence or by the absence of an appropriate Doppler flow signal that 
results in or could potentially induce circulatory failure or result in 
thromboembolism 
 Gastrointestinal Bleeding:  This refers to bleeding from the gastrointestinal tract that 
is or is not identified.  
 Infection: This refers to any infection requiring antibiotic or antifungal therapy. 
 Transient Ischemic Attack: a transient neurologic deficit that may persist for up to 24 
hours. 
 Unplanned hospitalization, ER visit or clinic visit: This refers to any medical 
evaluation for an LVAD patient that is unplanned.  
 Aortic root thrombus: thrombus located on the aortic valve or in the aortic cusp or 
aortic root which is visualized on echocardiography or CT imaging. 
 
 
 
 


 
 
 
 
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19.3 Appendix C – Schedule of Assessment 
Visit number 
0 
1 
2 
3 
4 
5 
6 
7 
Final Visit 
Time of Visit 
Enrollment & 
Randomization
2 weeks 
(±7D) 
4 weeks 
(±7D) 
6 weeks 
(±7D) 
8 weeks 
(±7D) 
12 weeks 
(±14D) 
18 weeks 
(±14D) 
24 weeks 
(±14D) 
28 weeks 
(±7D) 
Virtual Visit 
 
x 
 
x 
x 
 
x 
 
x 
Inclusion/Exclusion criteria 
x 
 
 
 
 
 
 
 
 
Information & Informed consent 
x 
 
 
 
 
 
 
 
 
Medical History & 
 
 
 
 
 
 
 
 
 
Concomitant Meds 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Physical examination & Vitals 
x 
 
x 
 
 
x 
 
x 
 
Laboratory tests*– CBC, CMP, Mg, aPTT, 
PT/INR**, LDH, Fibrinogen and D-dimer 
x 
 
x 
 
x† 
x 
 
x 
 
Anti-Xa Level (apixaban arm only) 
 
 
x 
 
 
x 
 
x 
 
Biobank sample collection 
x 
 
x 
 
 
x 
 
x 
 
Pregnancy Test*** 
x 
 
 
 
 
 
 
 
 
Dispense study medication**** 
x 
 
x 
 
 
x 
 
 
 
Adverse events 
 
x 
x 
x 
x 
x 
x 
x 
x 
*Labs obtained within 1 week prior to randomization can be used to assess patient eligibility and apixaban dosing.  
**Additional INR monitoring may be required in the warfarin patients to achieve the protocol INR goal.  
***Pregnancy test only required in females of childbearing potential (age < 50 years). 
****Randomization will occur at enrollment. Study drug treatment will be initiated as described in protocol above.  
†Week 8 visit is conducted virtually, remote labs to be collected include:  CBC (white blood cells, hemoglobin, platelet count), CMP (sodium, potassium, BUN, creatinine, magnesium, AST/ALT, 
total and direct bilirubin, albumin, total protein, alkaline phosphatase), prothrombin time/INR, LDH. 


 
 
 
 
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