Conditions: LVAD (Left Ventricular Assist Device) Thrombosis
Keywords: HeartMate 3 LVAD (Left Ventricular Assist Device) NOAC
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 45
Healthy volunteers: no

Brief summary:
A prospective, single-center, randomized controlled trial of the feasibility and safety of apixaban in HeartMate 3 patients.

Detailed description:
HeartMate 3 (HM3) Left Ventricular Assist System (LVAS) is a centrifugal, fully magnetically levitated, continuous-flow pump designed to facilitate hemocompatibility by reducing shear stress on blood elements and to optimize pump washout by intrinsic pulsatility.

The Multicenter Study of MagLev Technology in Patients Undergoing Mechanical Circulatory Support Therapy with HeartMate 3 (MOMENTUM 3) trial 2-year data demonstrated an absence of confirmed pump thrombosis requiring pump exchange and marked reduction in stroke rates. On the backdrop of conventional anticoagulation protocols used in the study, observed bleeding complication rates in HM 3 were reduced, yet there is a need for further improvement as the overall intensity of conventional anti-thrombotic therapy represents a major contributor to non-surgical bleeding-related outcomes.

The HM3 LVAS Instructions for Use (IFU) recommend maintaining patients on Warfarin and Aspirin for long-term anticoagulation therapy. Recent results of The Minimal AnticoaGulation EvaluatioN To aUgment heMocompatibility (MAGENTUM 1) pilot study has demonstrated substantially lower-intensity anticoagulation (INR range 1.5 - 1.9) is achievable and supports the safety of lower targets with select patients implanted with the HeartMate 3 beyond 1 year with no thromboembolic complications or pump thrombosis. The observed outcomes were similar to those with the higher intensity anticoagulation targets and further support a signal of enhanced intrinsic thromboresistance of the HM3.

Direct oral anticoagulants (DOACs) are a class of drugs which directly exert therapeutic effect on specific coagulation factors. Broadly, they can be categorized as direct thrombin inhibitors (dabigatran) and factor Xa inhibitors (apixaban, rivaroxaban, and edoxaban) or FXai. Warfarin, which inhibits vitamin K dependent synthesis of coagulation factors in a manner that prevents activation of these factors, has wide inter-individual variation in metabolism and a narrow therapeutic window, as well as both food-drug and drug-drug interactions; the result is that patients taking warfarin require frequent monitoring of the anticoagulant effect to maintain safety and efficacy. The DOAC directly enter the blood to bind to the activated coagulation factor target; they have predictable pharmacokinetics, little interindividual variation in metabolism, few drug-drug interactions, and no interactions with foods. The large phase 3 RCT in both AF and VTE established both efficacy and safety-without the need for monitoring. The FXai may provide better anticoagulation than the oral direct thrombin inhibitor due to their action earlier in the coagulation cascade prior to the generation of thrombin which may ameliorate the likelihood of initiation of the feedback loop resulting in \>1000-fold increase in thrombin production. Of the studied FXai , apixaban has the lowest major bleeding complication rate and has not been shown to increase GI-bleeding. It also has the least dependence on renal clearance.

Consequently, with the documented enhanced hemocompatibility of the HeartMate 3 and the potential for reduced major bleeding with apixaban in indicated patient populations, the investigators provide the rationale that patients with the HM3 are in clinical equipoise to be randomized in a feasibility study of a new antithrombotic strategy testing apixaban with or without aspirin compared to the current standard of care warfarin and aspirin in a rigorously structured study to evaluate safety in stable patients with the HM3 device.

Apixaban Safety and Efficacy Data Apixaban is a DOAC that directly inhibits Factor Xa (FXai) in the coagulation cascade. Its therapeutic effect is more consistent and predictable due to its mechanism of action, and it is not subject to the disadvantages inherent to Vitamin K antagonist (VKA) anticoagulants.

The rationale for Apixaban use with the HeartMate 3 There have been no studies to date that have systematically evaluated the feasibility of using apixaban alone or combined with low dose aspirin in HM3 patients. All the primary phase 3 clinical trials assessing DOACs have focused on patients with non-valvular atrial fibrillation or venous thromboembolism with or without cancer. Within the literature, there are sparse reports of apixaban use with LVAD patients due to recurrent bleeding or non-compliance with warfarin. These small sample size studies reported encouraging low rates of thromboembolic events. In all but one instance, aspirin was withheld due to the history of bleeding events. Patients in these studies either had the HeartMate II or HeartWare HVAD.

Reduction in bleeding and thromboembolic events with HeartMate 3 compared to the HeartMate II was demonstrated by the MOMENTUM 3 IDE Trial. Yet, bleeding complications remain a burdensome limitation while on support and represent a significant cause of rehospitalizations and morbidity. Independently, both a reduction in major bleeding events and stable anticoagulation intensity constitute a compelling potential benefit of a modified antithrombotic strategy with a direct oral anticoagulant. However, these apixaban associated benefits remain to be validated in advanced heart failure population supported with the HeartMate 3 LVAS. Therefore, the objective of this study is to assess safety and feasibility of apixaban use in HM3 supported patients.

DATA COLLECTION \& FOLLOW-UP ASSESSMENTS The patient will be assessed at baseline. Lactate dehydrogenase (LDH) will be assessed once a week for 4 weeks, then once every 2 weeks for the next month and monthly thereafter; TTE ECHO follow-up will be performed at baseline, at 1 month and at 3 months, followed until study completion per site standard of care.

Study duration Patients enrolled will be followed-up for 90 days post-transition to a designated antithrombotic regimen based on randomization. Provided the individual patients clinical course is uneventful regarding the primary endpoint, the patient's follow-up within the antithrombotic study protocol will be extended to the next pre-specified time point for analysis at 180 days. After the 180 days timepoint is reached, the patients will be given a chance to prolong the study until 1 year ( study extension, approved by Institutional Ethics Commitee on 10-12-2022, approval number: 27261/22; A-21-23). All apixaban subsets will be treated according to their original study arm, the patients from the Vitamin K antagonist and aspirin group will be randomized in a 1:1 manner to apixaban with or without aspirin.

If the individual uneventful primary safety endpoint is established, the patient follow-up will be prolonged with next pre-specified time point for analysis at 1 year. If the second safety endpoint is reached, the patients could be followed for the duration of support with the HeartMate 3. (second study extension, approved by Institutional Ethics Commitee on 05-10-2023, approval number:16047/21; A-21-23).

Advanced Pump Thrombosis Monitoring Protocol

* Monitor LDH at baseline and after initiation of determined antithrombotic therapy based on randomization algorithm once a week during first 4 weeks, then once every 2 weeks for the next month and monthly after that
* If LDH rises more than 1.2x baseline:

  * repeat LDH within the next 1-3 business days
  * monitor plasma free hemoglobin (pf-Hb) and haptoglobin if available; and total bilirubin
  * complete evaluation with the team to rule out other reasons for LDH rise
  * echocardiogram to evaluate for aortic insufficiency
  * prompt study team to review within 48 hours
  * retrospective data log files analysis (particularly rotor noise and rotor displacement trends) followed by prospective analysis 2 weeks post event

Arms:
arm 1: This study group will contain 30 patients that will be stratified further by 1:1 randomization to 2 groups of 15 patients - one group will be given only apixaban 5mg twice a day, the second group will be given apixaban 5mg twice a day and aspirin 100mg per day. arm 2: This study group will contain 15 patients that will by treated following standard anticoagulation protocol (Warfarin INR 2-3 + aspirin 100mg/day).

Interventions: intervention 1: HeartMate 3 intervention 2: Apixaban
Intervention descriptions: intervention 1: Patients implanted with HeartMate 3 will be randomized in 2:1 ratio in interventional and control group. Patients in interventional group will be switched to therapy with apixaban instead of warfarin. intervention 2: Patients implanted with HeartMate 3 will be randomized in 2:1 ratio in interventional and control group. Patients in interventional group will be switched to therapy with apixaban instead of warfarin.

Protocol document:
SAP_004.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
Direct Oral Anticoagulant Therapy with the HeartMate 3 LVAD: A Pilot Study 
DOT-HM3 Study 
Statistical Analysis Plan 
 
 
 
 
 
 
 
Investigator initiated study 
The study site:  
Institute for Clinical and Experimental Medicine, Prague, Czech Republic  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
05/15/2021 
 


 
DOT HM3 Study – Statistical analysis plan 
 
Stable HM3 patients who have not suffered a Major hemocompatibility-related 
adverse after index hospitalization discharge and are at least 3 months post-implant 
will be screened for participation in the study. Upon meeting the study criteria and 
patient informed consent, the individuals will be randomized to either continued 
therapy with a Vitamin K antagonist and aspirin or conversion to apixaban 5 mg twice 
a day in a 1:2 manner; the apixaban group will be stratified further by 1:1 
randomization to continued use of 100 mg aspirin once daily or cessation. Thus, 45 
patients are planned to be enrolled and randomized in 3 subgroups of 15 patients in 
each arm. The sample size of 45 patients was calculated to be sufficient to elucidate 
any safety signal. After 180 days follow-up is reached, the Vitamin K antagonist and 
aspirin arm will be transitioned to apixaban and randomized in a 1:1 manner to 
groups with or without aspirin. 
 
Survival free of a hemocompatibility-related adverse events event (Stroke 
ischemic/hemorrhagic, Pump thrombosis, Severe bleeding, Peripheral arterial 
thromboembolic events) at the endpoint of 90 days will be evaluated as primary 
endpoint as proportion of success calculated between the apixaban and the warfarin 
arms. The prevalence (percent of patients with events) and incidence (event rates in 
events per pt-year) of adverse events and rehospitalizations will be determined. The 
secondary endpoints include an evaluation of the following adverse events per 
INTERMACS definitions (version 5.0) throughout the study period: 
 
• 
Stroke (ischemic/hemorrhagic) 
• 
Pump thrombosis 
• 
Major bleeding 
• 
GI Bleeding 
• 
Peripheral arterial thromboembolic events 
• 
Transient ischemic attack 
• 
Hemolysis  
• 
Venous thromboembolism  
• 
Myocardial infarction 
• 
Right heart failure  
• 
Cardiac arrhythmias  
• 
Liver and kidney dysfunction  
• 
Death due to any cause 
 
 
Time to event analyses will be done by Kaplan-Meier analysis.  The overall outcomes 
being evaluated for clinical safety as assessed by the study’s oversight committee.  

Prot_002.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Direct Oral Anticoagulant Therapy with the HeartMate 3 LVAD: A Pilot Study 
DOT-HM3 Study 
 
 
 
 
 
 
 
 
 
Investigator initiated study 
The study site:  
Institute for Clinical and Experimental Medicine, Prague, Czech Republic  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Version 3.0 
                                                                                                      4/25/2023 


2 
 
TABLE of CONTENTS 
TABLE of APPENDICES .......................................................................................................... 3 
1 
Introduction ................................................................................................................ 4 
2 
Study Objectives ......................................................................................................... 6 
2.1 
Primary Endpoint .......................................................................................... 6 
2.2 
Secondary Endpoints .................................................................................... 7 
3 
Study Design ............................................................................................................... 7 
3.1 
Study Center and Patients ............................................................................ 7 
3.2 
Study Duration ............................................................................................. 7 
3.3 
Study Design ................................................................................................. 8 
3.3.1 Study design ..................................................................................... 8 
3.3.2 Adverse events adjudication and outcomes assessment ................ 8 
4 
Patient Population ...................................................................................................... 8 
4.1 
Inclusion Criteria .......................................................................................... 8 
4.2 
Exclusion Criteria .......................................................................................... 8 
5 
Study Course ............................................................................................................... 9 
5.1 
Enrollment Procedures ................................................................................. 9 
5.2 
Data Collection & Follow-up Assessments ................................................... 9 
5.2.1 Demographics ................................................................................. 11 
5.2.2 Medical History ............................................................................... 11 
5.2.3 Enrollment form ............................................................................. 12 
5.2.4 Laboratory Assessments and Diagnostics ...................................... 11 
 
 
 
5.2.4.1. Apixaban plasma concentration…………………………………….11 
5.2.5 Adverse Events ............................................................................... 11 
5.2.6 Changes to antithrombotic regimen .............................................. 11 
5.2.7 Rehospitalizations/Reoperations ................................................... 11 
5.2.8 Outcome ......................................................................................... 11 
 
 
5.2.9  Completion of study follow up……………………………………………………12 
5.3 
Data Analysis and Statistical Issues ............................................................ 13 
6 
Ethical and Regulatory Considerations..................................................................... 12 
6.1 
Informed Consent/Patient Authorization .................................................. 12 
6.2 
Ethics Review Board (ERB) ......................................................................... 12 
7 
Data Reporting and Record-Keeping ........................................................................ 12 
7.1 
Data Reporting ........................................................................................... 12 
7.2 
Confidentiality ............................................................................................ 12 
7.3 
Maintenance of Study Documentation ...................................................... 13 
8 
References ................................................................................................................ 13 
 
 
 


3 
 
TABLE of APPENDICES 
 
Appendix 
Contents 
I 
Study design flow chart 
II 
Severe Bleeding Definition  
III 
Data Collection spreadsheet  
IV 
Therapeutic efficacy adjustments and safety monitoring 
V 
Apixaban effect reversal protocol 
 


4 
 
Study organization 
Expert Advisory Committee: Chair – Mandeep R. Mehra, MD, member - Jean M. Connors, 
MD (both BWH and Harvard Medical School, Massachusetts, U.S.A.) 
Study Principal Investigator: Ivan Netuka, MD 
Executive Committee (s): Expert Advisory Committee + CEC + DSMB – (TBD) 
Study Site:  Institute for Clinical and Experimental Medicine, Prague, Czech Republic 
 
 
1 
INTRODUCTION 
HeartMate 3 (HM3) Left Ventricular Assist System (LVAS) is a centrifugal, fully 
magnetically 
levitated, 
continuous-flow 
pump 
designed 
to 
facilitate 
hemocompatibility by reducing shear stress on blood elements and to optimize 
pump washout by intrinsic pulsatility.  
The Multicenter Study of MagLev Technology in Patients Undergoing Mechanical 
Circulatory Support Therapy with HeartMate 3 (MOMENTUM 3) trial 2-year data1 
demonstrated an absence of confirmed pump thrombosis requiring pump 
exchange and marked reduction in stroke rates. On the backdrop of conventional 
anticoagulation protocols used in the study, observed bleeding complication rates 
in HM 3 were reduced, yet there is a need for further improvement as the overall 
intensity of conventional anti-thrombotic therapy represents a major contributor 
to non-surgical bleeding-related outcomes. 
The HM3 LVAS Instructions for Use (IFU) recommend maintaining patients on 
Warfarin and Aspirin for long-term anticoagulation therapy. Recent results of The 
Minimal 
AnticoaGulation 
EvaluatioN 
To 
aUgment 
heMocompatibility 
(MAGENTUM 1) pilot study2 has demonstrated substantially lower-intensity 
anticoagulation (INR range 1.5 – 1.9) is achievable and supports the safety of lower 
targets with select patients implanted with the HeartMate 3 beyond 1 year with 
no thromboembolic complications or pump thrombosis. The observed outcomes 
were similar to those with the higher intensity anticoagulation targets and further 
support a signal of enhanced intrinsic thromboresistance of the HM3.  
Direct oral anticoagulants (DOACs) are a class of drugs which directly exert 
therapeutic effect on specific coagulation factors. Broadly, they can be categorized 
as direct thrombin inhibitors (dabigatran) and  factor Xa  inhibitors (apixaban, 
rivaroxaban, and edoxaban) or FXai.  Warfarin, which inhibits vitamin K dependent 
synthesis of coagulation factors in a manner that prevents activation of these 
factors, has wide inter-individual variation in metabolism and a narrow 
therapeutic window, as well as both food-drug and drug-drug interactions; the 
result is that patients taking warfarin require frequent monitoring of the 
anticoagulant effect to maintain safety and efficacy.  The DOAC  directly enter the 
blood to bind to the activated coagulation factor target; they have predictable 
pharmacokinetics, little interindividual variation in metabolism, few drug-drug 
interactions, and no interactions with foods. The large phase 3 RCT in both AF and 
VTE established both efficacy and safety—without the need for monitoring. The 
FXai may provide better anticoagulation than the oral direct thrombin inhibitor 
due to their action earlier in  the coagulation cascade prior to the generation of 


5 
 
thrombin which may ameliorate the likelihood of initiation of the feedback loop 
resulting in >1000-fold increase in thrombin production. Of the studied FXai , 
apixaban has the lowest major bleeding complication rate and has not been shown 
to increase GI-bleeding3, 4, 5. It also has the least dependence on renal clearance. 
Consequently, with the documented enhanced hemocompatibility of the 
HeartMate 3 and the potential for reduced major bleeding with apixaban in 
indicated patient populations, we provide the rationale  that patients with the 
HM3 are in clinical equipoise to be randomized in a feasibility study of a new 
antithrombotic  strategy testing apixaban with or without aspirin compared to the 
current standard of care warfarin and aspirin in a rigorously structured study to 
evaluate  safety in stable patients with the HM3 device. 
 
Apixaban Safety and Efficacy Data 
 
Apixaban is a DOAC that directly inhibits Factor Xa (FXai) in the coagulation 
cascade. Its therapeutic effect is more consistent and predictable due to its 
mechanism of action, and it is not subject to the disadvantages inherent to Vitamin 
K antagonist (VKA) anticoagulants. In phase 3 clinical trial that resulted in FDA 
approval, involving 18,201 patients with non-valvular AF, Apixaban was shown to 
be non-inferior in antithrombotic effect and superior in terms of major bleeding 
relative to VKA anticoagulants (ARISTOTLE study; NCT00412984).3 Major bleeding, 
per the International Society on Thrombosis and Haemostasis (ISTH) definition, 
was reduced with Apixaban relative to VKA, primarily due to a 58% reduction in 
intracranial hemorrhage (ICH) and 21% drop in locations other than the 
gastrointestinal (GI) tract.3 Clinically relevant non-major bleeds were also 
significantly reduced in this study.4 GI bleeding was not significantly different 
between Apixaban and warfarin.  
 
In the AMPLIFY study (NCT00643201), the safety and efficacy of apixaban for the 
prevention of recurrent venous thromboembolic (VTE) events and death due to 
VTE were compared with warfarin in 5,395 patients with acute VTE. Apixaban was 
found to be non-inferior to warfarin preventing recurrent VTE events (RR: 0.84; 
95% CI: 0.6 – 1.18 ), and major bleeding was reduced by 69% in the apixaban 
group.6 In a meta-analysis of DOAC studies in the VTE population, FXa inhibitors 
were found to have 60 % lower rate of ICH and fatal bleeds compared to VKA.7 In 
a retrospective study of Medicare beneficiaries, 36% fewer patients were 
hospitalized for upper-GI bleeding with apixaban than with warfarin.8 In another 
post-market study, apixaban was compared with rivaroxaban and dabigatran using 
propensity-matched cohorts of Medicare beneficiaries, with non-valvular AF, in 
terms of safety and efficacy. Apixaban was found to have a lower risk of causing 
GI and major bleeds than the other DOACs.5 No differences were seen between 
the three DOACs in strokes or systemic embolism.8 Even in cancer patients in 
whom the risk of bleeding is higher than in other popualtions, treatment of VTE 
with apixaban showed no increase in major bleeding compared to dalteparin, 
unlike edoxaban and rivaroxaban, both of which had increased major bleeding 
compared to dalteparin.  
 


6 
 
The rationale for Apixaban use with the HeartMate 3 
There have been no studies to date that have systematically evaluated the 
feasibility of using apixaban alone or combined with low dose aspirin in HM3 
patients. All the primary phase 3 clinical trials assessing DOACs have focused on 
patients with non-valvular atrial fibrillation or venous thromboembolism with or 
without cancer. 7, 10  Within the literature, there are sparse reports of apixaban use 
with LVAD patients due to recurrent bleeding or non-compliance with warfarin.32-
35 These small sample size studies reported encouraging low rates of 
thromboembolic events. In all but one instance, aspirin was withheld due to the 
history of bleeding events. Patients in these studies either had the HeartMate II or 
HeartWare HVAD.  
 
Reduction in bleeding and thromboembolic events with HeartMate 3 compared to 
the HeartMate II was demonstrated by the MOMENTUM 3 IDE Trial. Yet, bleeding 
complications remain a burdensome limitation while on support and represent a 
significant cause of rehospitalizations and morbidity. Independently, both a 
reduction in major bleeding events and stable anticoagulation intensity constitute 
a compelling potential benefit of a modified antithrombotic strategy with a direct 
oral anticoagulant. However, these apixaban associated benefits remain to be 
validated in advanced heart failure population supported with the HeartMate 3 
LVAS. Therefore, the objective of this study is to assess safety and feasibility of 
apixaban use in HM3 supported patients.  
 
 
 
2 
STUDY OBJECTIVES 
2.1 
PRIMARY ENDPOINT 
The primary endpoint to evaluate the safety and feasibility of apixaban with the 
HeartMate 3 LVAS is survival free of major HRAEs (hemocompatibility related 
adverse events) at 90 days post-enrollment. The primary analysis will compare the 
apixaban groups (n=30) to control (n=15). A separate analysis will compare the 
primary endpoint in patients randomized to receive aspirin (n=15) and no-aspirin 
(n=15) within the apixaban group.  
 
Major HRAEs include:  
• 
Stroke (ischemic/hemorrhagic) 
• 
Pump thrombosis 
• 
Severe bleeding (see Appendix II) 
• 
Peripheral arterial thromboembolic events 
 
HRAEs are influenced by several patient-specific risk factors, including 
anticoagulation, poor general health, altered circulation, the pump's 
hemocompatibility, and the presence of other comorbidities (e.g., AF, infections, 
etc.). In standard use, clinicians balance the risk of stroke and other 
thromboembolic (TE) events with the increased risk of bleeding when prescribing 


7 
 
anticoagulation or antiplatelet medications. Therefore, a composite endpoint 
comprising TE, bleeding, and pump-related events were chosen for the analysis.  
 
 
2.2 
SECONDARY ENDPOINTS 
The secondary endpoints include an evaluation of the following adverse events 
per INTERMACS definitions (version 5.0) throughout the study period: 
 
• 
Stroke (ischemic/hemorrhagic) 
• 
Pump thrombosis 
• 
Major bleeding 
• 
GI Bleeding 
• 
Peripheral arterial thromboembolic events 
• 
Transient ischemic attack 
• 
Hemolysis  
• 
Venous thromboembolism  
• 
Myocardial infarction 
• 
Right heart failure  
• 
Cardiac arrhythmias  
• 
Liver and kidney dysfunction  
• 
Death due to any cause 
 
 
3 
STUDY DESIGN  
A prospective, single-center, randomized controlled trial of the feasibility and 
safety of apixaban in HeartMate 3 patients.   
3.1 
STUDY CENTER AND PATIENTS  
 
Eligible patients implanted with HeartMate 3 LVAS and meeting predefined criteria 
will be included in this study. The study will be conducted at the Institute for 
Clinical and Experimental Medicine in Prague and will be made open to other 
selected centers. The study design anticipates 45 patients to be enrolled. 
 
3.2 
STUDY DURATION 
Patients enrolled will be followed-up for 90 days post-transition to a designated 
antithrombotic regimen based on randomization. Provided the individual patients 
clinical course is uneventful regarding the primary endpoint, the patient’s follow-
up within the antithrombotic study protocol will be extended to the next pre-
specified time point for analysis at 180 days. After the 180 days timepoint is 
reached, the patients will be given a chance to prolong the study until 1 year. All 
apixaban subsets will be treated according to their original study arm, the patients 
from the Vitamin K antagonist and aspirin group will be randomized in a 1:1 
manner to apixaban with or without aspirin. 
 


8 
 
If the individual uneventful primary safety endpoint is established, the patient 
follow-up will be prolonged with next pre-specified time point for analysis at 1 
year. If the second safety endpoint is reached, the patients could be followed for 
the duration of support with the HeartMate 3.  
 
 
3.3 
STUDY DESIGN 
3.3.1 Study design 
Stable HM3 patients who have not suffered a Major hemocompatibility-related 
adverse event after index hospitalization discharge and are at least 3 months post-
implant will be screened for participation in the study. Upon meeting the study 
criteria and patient informed consent, the individuals will be randomized to either 
continued therapy with a Vitamin K antagonist and aspirin or conversion to 
apixaban 5 mg twice a day in a 2:1 manner (dose targeted to renal function); the 
apixaban group will be stratified further by 1:1 randomization to continued use of 
100 mg aspirin once daily or cessation. Thus, 45 patients are planned to be enrolled 
and randomized in 3 subgroups of 15 patients in each arm (see Appendix I). After 
180 days follow-up is reached, the Vitamin K antagonist and aspirin arm will be 
transitioned to apixaban and randomized in a 1:1 manner to groups with or 
without aspirin. 
 
3.3.2 Adverse events adjudication and outcomes assessment  
All suspected or confirmed HRAEs (safety surveillance see Appendix IV) will be 
promptly reported to and adjudicated by the Expert Advisory Committee to 
determine individual patient safety to continue with the assigned treatment arm 
and the overall study safety and eligibility for continuation. All adverse events will 
be periodically reported to the Institutional Ethics Committee.  
 
4 
PATIENT POPULATION 
 
4.1 
INCLUSION CRITERIA:  
- 
The patient has been implanted with HeartMate 3 LVAS  
- 
The patient is, at a minimum, 3 months post HeartMate 3 implant 
- 
The patient is stable, ambulatory, and has been discharged home 
- 
The patient provides written informed consent before any clinical investigation 
related procedure 
 
4.2 
EXCLUSION CRITERIA:  
- 
Non-compliance with anticoagulation and antiplatelet medication, in the opinion 
of the investigator 
- 
Weight ≤ 60 kgs. or age ≥ 80 years 


9 
 
- 
Poor kidney function with serum creatinine ≥ 221umol/L or creatinine clearance < 
0.042  mL/s, or the need for chronic renal replacement therapy 
- 
Total bilirubin > 43 umol/L, shock liver, or biopsy-proven liver cirrhosis 
- 
Absence of an informed consent 
- 
Presence of any mechanical prosthetic valve or any ancillary circulatory assist 
device system (other than the HM3) 
- 
Recent  history of cardioembolic stroke  
- 
Hemodynamically significant carotid arteries stenosis (documented by imaging 
investigation not older than 12 months) 
- 
Need for antiplatelet therapy for reasons other than LVAD therapy 
- 
Major HRAE event after HeartMate 3 index hospitalization discharge 
- 
Known history of hyper- or hypo- coagulable disorder 
- 
Anti-phospholipid syndrome positive patients with documented history of 
thrombotic/thromboembolic events 
- 
Known hypersensitivity or allergy to apixaban or aspirin 
- 
The patient is involved in another interventional  study or any study that could 
potentially affect the functioning of the HM3 LVAD or the therapeutic effect of 
any of the study anticoagulants (warfarin, apixaban or aspirin), or could 
potentially confound the study results 
- 
The patient is currently pregnant, breastfeeding, or intending to get pregnant 
during the study 
- 
Presence of other anatomic or comorbid conditions, or other medical, social, 
non-compliance or psychological conditions that, in the investigator’s opinion, 
could limit the subject’s ability to participate in the clinical investigation or to 
comply with follow-up requirements or impact the scientific soundness of the 
clinical investigation results. 
 
5 
 STUDY COURSE 
 
5.1 
ENROLLMENT PROCEDURES 
Patients will sign an informed consent form at the time of the study enrollment. 
The consent form states that the data collected for this study will be used by 
authorized personnel only. The patient’s privacy will be maintained according to 
local legislation and, patients will be identified by study specific code. The 
aggregate and/or de-identified patient specific data may be published or 
presented.     
 
5.2 
DATA COLLECTION & FOLLOW-UP ASSESSMENTS 
The patient will be assessed at baseline. Lactate dehydrogenase (LDH) will be 
assessed once a week for 4 weeks, then once every 2 weeks for the next month 
and monthly thereafter; TTE ECHO follow–up will be performed at baseline, at 1 
month and at 3 months, followed until study completion per site standard of care.  
A complete list of data fields to be collected is provided in Appendix II.  A summary 


10 
 
of the data collection is provided in Table 1 below, and follow-up assessments are 
further described in the following sections.   
 
 
 
 
 
 
 


11 
 
Table 1 – Summary of Patient Assessments and Data Collection 
 
Baseline1 
Once a 
week2 
 
Once a 
month2 
 
During regular 
ambulatory 
visits 
At time 
of event 
Consent Form 
X 
 
 
 
 
Demographics & 
Medical History 
X 
 
 
 
 
Enrollment form 
X 
 
 
 
 
Laboratory 
Assessment (study 
site standard of care) 
X 
 
X 
X 
X 
LDH Assessment 
X 
X3 
X3 
X 
X 
ECHO assessment 
X 
 
X4 
X 
X 
Anti-coagulation / 
anti-platelet regimen 
X 
X 
 
X 
X 
Adverse Events: 
thrombosis, other 
adverse events 
 
 
 
 
X 
Rehospitalizations / 
Reoperations 
 
 
 
 
X 
Outcome 
 
 
 
 
X 
1 Baseline is defined as the time point of the patient enrollment to the study.  
2 The follow-up assessments commence after the study enrollment.  
3 LDH assessment once a week for 4 weeks, then once every 2 weeks for the next month 
and monthly thereafter 
4 ECHO follow–up will be performed at baseline, at 1 month and at 3 months, followed by 
periodical 6-monthly examinations 
 
5.2.1 Demographics 
Patient demographics will be collected at baseline, including age, gender,  
height, weight, BMI, blood type, vital signs, etiology of heart failure, 
duration of mechanical circulatory support prior to study enrollment, 
Modified Rankin Score, INTERMACS Profile prior to HM3 implant, and 
therapeutic intent of HM3 support. 
5.2.2 Medical History  
The patient’s medical history will be collected at baseline, including a 
history of cardiac arrhythmias, diabetes, smoking, hypertension, and 
cancer.  
 
 


12 
 
5.2.3 Enrollment form  
Information will be captured on whether the patient met the study 
inclusion/exclusion criteria.    
 
5.2.4 Laboratory Assessments and Diagnostics 
LDH assessment will be performed once a week for 4 weeks after the 
randomization, then once every 2 weeks for the next month and monthly 
thereafter; other regular laboratory assessments will include standard of 
care work-up, including measurements of kidney and liver function and 
hemostasis. Desirably, the same local authorized laboratory facility should 
be used by the patients to ensure consistency of a laboratory follow-up.   
 
5.2.4.1 Apixaban plasma concentration 
Apixaban peak and trough levels will be performed using a commercially 
available anti-Xa assay with apixaban calibrators at 4 weeks visit per study 
protocol. Levels will also be drawn at the time of presentation with any 
HRAE. 
5.2.5 Adverse Events 
All INTERMACS adverse event definitions (version 5.0) will be used in this 
study for the evaluation of primary and secondary objectives. Laboratory 
values will be determined at the time of an adverse event. 
 
5.2.6 Changes to the antithrombotic regimen 
Any changes to the designated antithrombotic regimen based on 
randomization algorithm will be documented during the follow-up visits or 
with the occurrence of an adverse event.   
 
5.2.7 Rehospitalizations/Reoperations 
Once a patient is admitted to the hospital, details will be collected on the 
admission date and the reason for the rehospitalization and date of 
discharge and antithrombotic therapy status.   
 
Reoperations will also be captured, including the date and reason for the 
reoperation.   
 
5.2.8 Outcome 
The patient’s outcome (transplanted, expired, explanted or withdrew) and 
date of outcome will be captured.    
 
 
 


13 
 
5.2.9 Completion of study follow up 
Upon completion of study follow up, patients will be transitioned back to 
their pre-study anticoagulation regimen (e.g. warfarin with aspirin).  
 
5.3 
DATA ANALYSIS AND STATISTICAL ISSUES 
Survival free of a hemocompatibility-related endpoint 90 days will be evaluated. 
The prevalence (percent of patients with events) and incidence (event rates in 
events per pt-year) of adverse events and rehospitalizations will be determined.  
 
 
6 
ETHICAL AND REGULATORY CONSIDERATIONS 
 
6.1 
INFORMED CONSENT/PATIENT AUTHORIZATION 
The patient, before study enrollment, must provide informed consent.  The 
informed consent form, where patient informed consent is captured, must have 
prior approval from the Ethics Review Board (ERB).  
 
6.2 
ETHICS REVIEW BOARD (ERB)  
ERB approval will be obtained prior to enrolling any patients in this study.  ERB will 
maintain oversight of the study in accordance with local policies and procedures.   
 
 
7 
DATA REPORTING AND RECORD-KEEPING 
7.1 
DATA REPORTING 
The data to be collected are identified in Appendix I.  These will be captured by 
investigators and entered into a Microsoft Office Excel sheet in anonymized form 
according to local regulatory standards. The investigator must ensure that the 
study required observations and findings are recorded correctly and completely 
and in a timely manner.  Source data will be maintained by the study site (e.g. in 
the form of patient medical records) for verification of data listed in the study data 
tables.     
 
7.2 
CONFIDENTIALITY 
Patient Confidentiality will be enforced as per General Data Protection Regulation 
(GDPR) of the EU Directive no. 2016/679 (effective since 25th May 2018).     
 
The patient will be made aware (via the patient authorization) that certain 
personally identifiable information will be collected as part of this study and will 
be disclosed outside the hospital.  This information will include date of birth, date 
of death, admission and discharge dates, and dates of treatment.  Except when 
required by law or except by the patient’s authorization, the patient will not be 


14 
 
identified by name, address or telephone number in the study records disclosed 
outside of the hospital.  In the study records disclosed outside of the hospital the 
patient will be assigned a unique study code. 
7.3 
MAINTENANCE OF STUDY DOCUMENTATION 
The following study documents will be maintained by the study site and be 
available for periodic review by Abbott or the expert advisory committee per 
explicit request: 
 
• Copy of the Study Protocol 
• Ethics Committee Approvals and Correspondence: a copy of all Ethics Committee 
approvals and any significant correspondence will also be provided Abbott.   
• Ethics Committee approved Patient Authorization/Informed Consent Forms: a 
copy will also be provided to Abbott. 
• Signature Verification Form: all study site individuals approved by the investigator 
to participate in this study and/or complete data entry must sign the Signature 
Verification Form. This form will be maintained on site. 
• Study Agreement: the Investigator and the Institution will complete a Study 
Agreement prior to patient enrollment.  The agreement will identify the 
investigator’s legal and ethical commitments with respect to the conduct of this 
study.   
• Patient Authorization/Informed Consents for each patient enrolled in the study 
• Source documentation (such as patient clinic charts, medical records, lab records) 
 
 
8 
REFERENCES 
1. Mehra, M. R. et al. A Fully Magnetically Levitated Left Ventricular Assist Device - 
Final Report. The New England journal of medicine 380, 1618-1627, 
doi:10.1056/NEJMoa1900486 (2019). 
2. Netuka I., Ivák P., Tučanová Z., et al: Evaluation of low-intensity anticoagulation 
with a fully magnetically levitated centrifugal-flow circulatory pump – the 
MAGENTUM 1 study. J Heart Lung Transplant. 2018;37(5):579-586.  
3. Granger, C. B. et al. Apixaban versus warfarin in patients with atrial fibrillation. 
The New England journal of medicine 365, 981-992, 
doi:10.1056/NEJMoa1107039 (2011). 
4. Bahit, M. C. et al. Non-major bleeding with Apixaban versus warfarin in patients 
with atrial fibrillation. Heart 103, 623-628, doi:10.1136/heartjnl-2016-309901 
(2017). 
5. Abraham, N. S., Noseworthy, P. A., Yao, X., Sangaralingham, L. R. & Shah, N. D. 
Gastrointestinal Safety of Direct Oral Anticoagulants: A Large Population-Based 
Study. Gastroenterology 152, 1014-1022 e1011, 
doi:10.1053/j.gastro.2016.12.018 (2017). 
6. Agnelli, G. et al. Oral Apixaban for the treatment of acute venous 
thromboembolism. The New England journal of medicine 369, 799-808, 
doi:10.1056/NEJMoa1302507 (2013). 


15 
 
7. van Es, N., Coppens, M., Schulman, S., Middeldorp, S. & Buller, H. R. Direct oral 
anticoagulants compared with vitamin K antagonists for acute venous 
thromboembolism: evidence from phase 3 trials. Blood 124, 1968-1975, 
doi:10.1182/blood-2014-04-571232 (2014). 
8. Noseworthy, P. A. et al. Direct Comparison of Dabigatran, Rivaroxaban, and 
Apixaban for Effectiveness and Safety in Nonvalvular Atrial Fibrillation. Chest 150, 
1302-1312, doi:10.1016/j.chest.2016.07.013 (2016). 
9. Ray, W. A. et al. Association of Oral Anticoagulants and Proton Pump Inhibitor 
Cotherapy With Hospitalization for Upper Gastrointestinal Tract Bleeding. Jama 
320, 2221-2230, doi:10.1001/jama.2018.17242 (2018). 
10. Ruff, C. T. et al. Comparison of the efficacy and safety of new oral anticoagulants 
with warfarin in patients with atrial fibrillation: a meta-analysis of 
randomrandomizeds. Lancet 383, 955-962, doi:10.1016/S0140-6736(13)62343-0 
(2014). 
11. Curran, L. in 20th Annual Scientific Meeting of HFSA Vol. 22   (Journal of Cardiac 
Failure, 2016). 
12. Parikh, V. et al. in ISHLT 2019.   (Elsevier). 
13. Pollari, F., Fischlein, T., Fittkau, M. & Santarpino, G. Anticoagulation with 
Apixaban in a patient with a left ventricular assist device and gastrointestinal 
bleeding: A viable alternative to warfarin? Journal of Thoracic and Cardiovascular 
Surgery 152, 79-81 (2016). 
14. Schulte-Estrup, S., Mayer-Wingert, N., Reiss, N., Sindermann, J. & Warnecke, H. in 
ISHLT 2019    (Elsevier, Orlando, FL, 2019). 
 
 


16 
 
Appendix I:  Study design flow chart 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


17 
 
Appendix II:  Severe Bleeding Definition 
 
 
SEVERE BLEEDING: 
 
Type A: (Meets any of the below) 
• Overt bleeding plus hemoglobin drop of 3 to < 5 g/dL(30-50g/L) (provided 
hemoglobin drop is related to bleed) 
• Any transfusion with overt bleeding 
 
Type B: (Meets any of the below) 
• Overt bleeding plus hemoglobin drop 5 g/dL (50g/L) or greater (provided 
hemoglobin drop is related to bleed) 
• Cardiac tamponade 
• Bleeding requiring surgical intervention for control (excluding dental, nasal, skin, 
or hemorrhoid) 
• Hypotension attributable to bleeding and requiring intravenous vasoactive 
agents for hemodynamic support 
• Intracranial Hemorrhage that does not meet the definition of hemorrhagic stroke 
 
Type C1: Probable fatal bleeding; no autopsy or imaging confirmation but clinically 
suspicious 
Type C2: Definite fatal bleeding; overt bleeding or autopsy or imaging confirmation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


18 
 
Appendix III:  Data Collection spreadsheet 
 
 
  
Baseline 
At regular 
ambulatory 
visits 
Once 
a 
week 
Once 
a 
month 
At the 
time of 
the 
event 
Baseline info: 
  
  
  
  
  
Patient identifier 
x 
  
  
  
  
Date of birth 
x 
  
  
  
  
Gender 
x 
  
  
  
  
Ethnicity 
x 
  
  
  
  
Race 
x 
  
  
  
  
Etiology 
x 
  
  
  
  
Current device strategy 
x 
 
 
 
 
Blood type 
x 
  
  
  
  
Assessment of routine tests done 
to evaluate the prothrombotic 
state   
x 
 
 
 
 
  
  
  
  
  
  
Medical History 
  
  
  
  
  
INTERMACS Profile at time of 
implant 
x 
  
  
  
  
Coronary artery disease 
x 
  
  
  
  
Arrhythmia: atrial/ventricular; 
Afib (yes/no) 
x 
  
  
  
  
Ventricular pacing 
x 
  
  
  
  
Cancer 
x 
  
  
  
  
ICD 
x 
  
  
  
  
Stents, location 
x 
  
  
  
  
Myocardial infarction 
x 
  
  
  
  
Diabetes 
x 
  
  
  
  
Smoking history 
x 
  
  
  
  
Diverticular disease or diagnosed 
AVMs 
x 
  
  
  
  
GI Ulcer 
x 
  
  
  
  
Significant carotid stenosis (or if 
last examination > 12 months 
old) 
x 
 
 
 
 
AEs since pump implant: 
x 
  
  
  
  
 
 
 
 
 
 
Enrollment Form 
x 
  
  
  
  
Date enrolled 
x 
  
  
  
  
Incl/excl criteria (yes/no) 
x 
  
  
  
  
Date of study therapy initiation  
x 
  
 
  
 
 
  
  
  
  
 


19 
 
 
Baseline 
At regular 
ambulatory 
visits 
Once 
a 
week 
Once 
a 
month 
At the 
time of 
the 
event 
 
 
 
 
 
 
Physical Exam 
  
  
  
  
 
Heart rate 
x 
  
  
  
x 
Height in cm 
x 
  
  
  
x 
Weight in kg 
x 
  
  
  
x 
BP_MEAN – Doppler 
x 
  
  
  
x 
Pump parameters (speed, flow, 
PI, power) 
x 
x 
 
 
x 
 
 
 
 
 
 
Laboratory tests 
  
  
  
  
 
Creatinine 
x 
x 
  
  
x 
Urea 
x 
x 
  
  
x 
Total Bilirubin 
x 
x 
  
  
x 
Hgb 
x 
x 
  
 
x 
Hct 
x 
x 
  
 
x 
WBC (leucocytes) 
x 
x 
  
 
x 
PLT 
x 
x 
  
 
x 
Verify-now test 
x 
x 
 
 
x 
INR 
x 
x 
 
 
x 
Fibrinogen 
x 
x 
  
 
x 
aPTT 
x 
x 
  
 
x 
LDH 
x 
x 
x1 
x 
x 
Plasma free hemoglobin 
x 
x 
  
 
x 
BNP (or NT Pro BNP) 
x 
x 
 
 
x 
Anti Xa apixaban  
 
x3 
 
 
x 
 
 
 
 
 
 
Baseline diagnostics 
  
  
  
  
  
ECG (date, rhythm) 
x 
 x 
  
  
x 
Echocardiography 
x 
  
  
x2  
x 
Carotid ultrasound (if more than 
12 months since last 
examination ) 
x 
 
 
 
 
  
  
  
  
  
 
Implant information 
  
  
  
  
 
Date implanted 
x 
  
  
  
 
  
  
  
  
  
 
Follow-up  
  
  
  
  
 
Reoperation for 
bleeding/thrombosis? Date, 
reason 
 x 
  
 
 
x 
Date of initial discharge post 
LVAD implant  
x 
  
  
  
 


20 
 
  
Baseline 
At regular 
ambulatory 
visits 
Once 
a 
week 
Once 
a 
month 
At time 
of event 
 
 
 
 
 
 
Current anticoagulation regimen 
(date, medication, dosages) 
 x 
x 
 
 
x 
Re-hospitalization for 
thrombosis/other AE? Admission 
date, reason, treatment, 
discharge 
  
 
 
 
x 
 
 
 
 
 
 
HRAE  
  
  
 
 
x 
Onset date 
  
  
 
 
x 
Is event stroke, TIA, or device 
thrombosis 
  
  
 
 
x 
If stroke, is it ischemic or 
hemorrhagic? 
  
  
 
 
x 
If stroke, head CT examination 
  
  
 
 
x 
If device thrombosis: Hemolysis 
seen? Thrombolytics given? 
Increase in pump power? Pump 
replaced? Other clinical 
symptoms?  
  
  
 
 
x 
Collect laboratory tests listed 
above 
  
  
 
 
x 
Current anticoag/antiplt 
medications 
  
  
 
 
x 
Any change to anticoag/antiplt 
meds? If yes, what 
  
  
 
 
x 
Infection requiring antibx or + BC    
  
 
 
x 
Describe event and treatment 
  
  
 
 
x 
Resolution date 
  
  
 
 
x 
 
 
 
 
 
 
Other AE 
 
 
 
 
 
Onset date 
 
 
 
 
x 
Type of event 
 
 
 
 
x 
Examination incl. imaging 
methods 
 
 
 
 
x 
Laboratory tests 
 
 
 
 
x 
Rehospitalisation/reoperation 
 
 
 
 
x 
Treatment 
 
 
 
 
x 
 
 
 
 
 
 
Outcome  
  
  
 
  
  
Date 
  
  
 
 
x 


21 
 
  
Baseline 
At regular 
ambulatory 
visits 
Once 
a 
week 
Once 
a 
month 
At time 
of event 
Type of outcome (expired, 
explanted, transplanted) 
  
  
 
 
x 
If expired, cause of death 
  
  
 
 
x 
1 LDH assessment once a week for 4 weeks, then once every 2 weeks for the next month 
and monthly thereafter 
2 ECHO follow–up will be performed at baseline, at 1 month and at 3 months, followed by 
periodical 6-monthly examinations 
3 Performed at 4 weeks visit after the anticoagulation transition in patient on apixaban 
only 
 
 


22 
 
 Appendix IV: Therapeutic efficacy adjustments and safety monitoring 
 
 Advanced Pump Thrombosis Monitoring Protocol 
• Monitor LDH at baseline and after initiation of determined antithrombotic 
therapy based on randomization algorithm once a week during first 4 weeks, 
then once every 2 weeks for the next month and monthly after that 
• If LDH rises more than 1.2x baseline: 
o repeat LDH within the next 1-3 business days 
o monitor plasma free hemoglobin (pf-Hb) and haptoglobin if available; and 
total bilirubin  
o complete evaluation with the team to rule out other reasons for LDH rise 
o echocardiogram to evaluate for aortic insufficiency  
o prompt study team to review within 48 hours 
o retrospective data log files analysis (particularly rotor noise and rotor 
displacement trends) followed by prospective analysis 2 weeks post event 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


23 
 
Appendix V: Apixaban effect reversal protocol 
In case of need of reversal of the effect of apixaban, following protocol will be executed.   
 
 
 
 
 
 

Prot_001.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Direct Oral Anticoagulant Therapy with the HeartMate 3 LVAD: A Pilot Study 
DOT-HM3 Study 
 
 
 
 
 
 
 
 
 
Investigator initiated study 
The study site:  
Institute for Clinical and Experimental Medicine, Prague, Czech Republic  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Version 2.0 
                                                                                                      9/25/2022 


2 
 
TABLE of CONTENTS 
TABLE of APPENDICES .......................................................................................................... 3 
1 
Introduction ................................................................................................................ 4 
2 
Study Objectives ......................................................................................................... 6 
2.1 
Primary Endpoint .......................................................................................... 6 
2.2 
Secondary Endpoints .................................................................................... 7 
3 
Study Design ............................................................................................................... 7 
3.1 
Study Center and Patients ............................................................................ 7 
3.2 
Study Duration ............................................................................................. 7 
3.3 
Study Design ................................................................................................. 8 
3.3.1 Study design ..................................................................................... 8 
3.3.2 Adverse events adjudication and outcomes assessment ................ 8 
4 
Patient Population ...................................................................................................... 8 
4.1 
Inclusion Criteria .......................................................................................... 8 
4.2 
Exclusion Criteria .......................................................................................... 8 
5 
Study Course ............................................................................................................... 9 
5.1 
Enrollment Procedures ................................................................................. 9 
5.2 
Data Collection & Follow-up Assessments ................................................... 9 
5.2.1 Demographics ................................................................................. 11 
5.2.2 Medical History ............................................................................... 11 
5.2.3 Enrollment form ............................................................................. 12 
5.2.4 Laboratory Assessments and Diagnostics ...................................... 11 
 
 
 
5.2.4.1. Apixaban plasma concentration…………………………………….11 
5.2.5 Adverse Events ............................................................................... 11 
5.2.6 Changes to antithrombotic regimen .............................................. 11 
5.2.7 Rehospitalizations/Reoperations ................................................... 11 
5.2.8 Outcome ......................................................................................... 11 
 
 
5.2.9  Completion of study follow up……………………………………………………12 
5.3 
Data Analysis and Statistical Issues ............................................................ 13 
6 
Ethical and Regulatory Considerations..................................................................... 12 
6.1 
Informed Consent/Patient Authorization .................................................. 12 
6.2 
Ethics Review Board (ERB) ......................................................................... 12 
7 
Data Reporting and Record-Keeping ........................................................................ 12 
7.1 
Data Reporting ........................................................................................... 12 
7.2 
Confidentiality ............................................................................................ 12 
7.3 
Maintenance of Study Documentation ...................................................... 13 
8 
References ................................................................................................................ 13 
 
 
 


3 
 
TABLE of APPENDICES 
 
Appendix 
Contents 
I 
Study design flow chart 
II 
Severe Bleeding Definition  
III 
Data Collection spreadsheet  
IV 
Therapeutic efficacy adjustments and safety monitoring 
V 
Apixaban effect reversal protocol 
 


4 
 
Study organization 
Expert Advisory Committee: Chair – Mandeep R. Mehra, MD, member - Jean M. Connors, 
MD (both BWH and Harvard Medical School, Massachusetts, U.S.A.) 
Study Principal Investigator: Ivan Netuka, MD 
Executive Committee (s): Expert Advisory Committee + CEC + DSMB – (TBD) 
Study Site:  Institute for Clinical and Experimental Medicine, Prague, Czech Republic 
 
 
1 
INTRODUCTION 
HeartMate 3 (HM3) Left Ventricular Assist System (LVAS) is a centrifugal, fully 
magnetically 
levitated, 
continuous-flow 
pump 
designed 
to 
facilitate 
hemocompatibility by reducing shear stress on blood elements and to optimize 
pump washout by intrinsic pulsatility.  
The Multicenter Study of MagLev Technology in Patients Undergoing Mechanical 
Circulatory Support Therapy with HeartMate 3 (MOMENTUM 3) trial 2-year data1 
demonstrated an absence of confirmed pump thrombosis requiring pump 
exchange and marked reduction in stroke rates. On the backdrop of conventional 
anticoagulation protocols used in the study, observed bleeding complication rates 
in HM 3 were reduced, yet there is a need for further improvement as the overall 
intensity of conventional anti-thrombotic therapy represents a major contributor 
to non-surgical bleeding-related outcomes. 
The HM3 LVAS Instructions for Use (IFU) recommend maintaining patients on 
Warfarin and Aspirin for long-term anticoagulation therapy. Recent results of The 
Minimal 
AnticoaGulation 
EvaluatioN 
To 
aUgment 
heMocompatibility 
(MAGENTUM 1) pilot study2 has demonstrated substantially lower-intensity 
anticoagulation (INR range 1.5 – 1.9) is achievable and supports the safety of lower 
targets with select patients implanted with the HeartMate 3 beyond 1 year with 
no thromboembolic complications or pump thrombosis. The observed outcomes 
were similar to those with the higher intensity anticoagulation targets and further 
support a signal of enhanced intrinsic thromboresistance of the HM3.  
Direct oral anticoagulants (DOACs) are a class of drugs which directly exert 
therapeutic effect on specific coagulation factors. Broadly, they can be categorized 
as direct thrombin inhibitors (dabigatran) and  factor Xa  inhibitors (apixaban, 
rivaroxaban, and edoxaban) or FXai.  Warfarin, which inhibits vitamin K dependent 
synthesis of coagulation factors in a manner that prevents activation of these 
factors, has wide inter-individual variation in metabolism and a narrow 
therapeutic window, as well as both food-drug and drug-drug interactions; the 
result is that patients taking warfarin require frequent monitoring of the 
anticoagulant effect to maintain safety and efficacy.  The DOAC  directly enter the 
blood to bind to the activated coagulation factor target; they have predictable 
pharmacokinetics, little interindividual variation in metabolism, few drug-drug 
interactions, and no interactions with foods. The large phase 3 RCT in both AF and 
VTE established both efficacy and safety—without the need for monitoring. The 
FXai may provide better anticoagulation than the oral direct thrombin inhibitor 
due to their action earlier in  the coagulation cascade prior to the generation of 


5 
 
thrombin which may ameliorate the likelihood of initiation of the feedback loop 
resulting in >1000-fold increase in thrombin production. Of the studied FXai , 
apixaban has the lowest major bleeding complication rate and has not been shown 
to increase GI-bleeding3, 4, 5. It also has the least dependence on renal clearance. 
Consequently, with the documented enhanced hemocompatibility of the 
HeartMate 3 and the potential for reduced major bleeding with apixaban in 
indicated patient populations, we provide the rationale  that patients with the 
HM3 are in clinical equipoise to be randomized in a feasibility study of a new 
antithrombotic  strategy testing apixaban with or without aspirin compared to the 
current standard of care warfarin and aspirin in a rigorously structured study to 
evaluate  safety in stable patients with the HM3 device. 
 
Apixaban Safety and Efficacy Data 
 
Apixaban is a DOAC that directly inhibits Factor Xa (FXai) in the coagulation 
cascade. Its therapeutic effect is more consistent and predictable due to its 
mechanism of action, and it is not subject to the disadvantages inherent to Vitamin 
K antagonist (VKA) anticoagulants. In phase 3 clinical trial that resulted in FDA 
approval, involving 18,201 patients with non-valvular AF, Apixaban was shown to 
be non-inferior in antithrombotic effect and superior in terms of major bleeding 
relative to VKA anticoagulants (ARISTOTLE study; NCT00412984).3 Major bleeding, 
per the International Society on Thrombosis and Haemostasis (ISTH) definition, 
was reduced with Apixaban relative to VKA, primarily due to a 58% reduction in 
intracranial hemorrhage (ICH) and 21% drop in locations other than the 
gastrointestinal (GI) tract.3 Clinically relevant non-major bleeds were also 
significantly reduced in this study.4 GI bleeding was not significantly different 
between Apixaban and warfarin.  
 
In the AMPLIFY study (NCT00643201), the safety and efficacy of apixaban for the 
prevention of recurrent venous thromboembolic (VTE) events and death due to 
VTE were compared with warfarin in 5,395 patients with acute VTE. Apixaban was 
found to be non-inferior to warfarin preventing recurrent VTE events (RR: 0.84; 
95% CI: 0.6 – 1.18 ), and major bleeding was reduced by 69% in the apixaban 
group.6 In a meta-analysis of DOAC studies in the VTE population, FXa inhibitors 
were found to have 60 % lower rate of ICH and fatal bleeds compared to VKA.7 In 
a retrospective study of Medicare beneficiaries, 36% fewer patients were 
hospitalized for upper-GI bleeding with apixaban than with warfarin.8 In another 
post-market study, apixaban was compared with rivaroxaban and dabigatran using 
propensity-matched cohorts of Medicare beneficiaries, with non-valvular AF, in 
terms of safety and efficacy. Apixaban was found to have a lower risk of causing 
GI and major bleeds than the other DOACs.5 No differences were seen between 
the three DOACs in strokes or systemic embolism.8 Even in cancer patients in 
whom the risk of bleeding is higher than in other popualtions, treatment of VTE 
with apixaban showed no increase in major bleeding compared to dalteparin, 
unlike edoxaban and rivaroxaban, both of which had increased major bleeding 
compared to dalteparin.  
 


6 
 
The rationale for Apixaban use with the HeartMate 3 
There have been no studies to date that have systematically evaluated the 
feasibility of using apixaban alone or combined with low dose aspirin in HM3 
patients. All the primary phase 3 clinical trials assessing DOACs have focused on 
patients with non-valvular atrial fibrillation or venous thromboembolism with or 
without cancer. 7, 10  Within the literature, there are sparse reports of apixaban use 
with LVAD patients due to recurrent bleeding or non-compliance with warfarin.32-
35 These small sample size studies reported encouraging low rates of 
thromboembolic events. In all but one instance, aspirin was withheld due to the 
history of bleeding events. Patients in these studies either had the HeartMate II or 
HeartWare HVAD.  
 
Reduction in bleeding and thromboembolic events with HeartMate 3 compared to 
the HeartMate II was demonstrated by the MOMENTUM 3 IDE Trial. Yet, bleeding 
complications remain a burdensome limitation while on support and represent a 
significant cause of rehospitalizations and morbidity. Independently, both a 
reduction in major bleeding events and stable anticoagulation intensity constitute 
a compelling potential benefit of a modified antithrombotic strategy with a direct 
oral anticoagulant. However, these apixaban associated benefits remain to be 
validated in advanced heart failure population supported with the HeartMate 3 
LVAS. Therefore, the objective of this study is to assess safety and feasibility of 
apixaban use in HM3 supported patients.  
 
 
 
2 
STUDY OBJECTIVES 
2.1 
PRIMARY ENDPOINT 
The primary endpoint to evaluate the safety and feasibility of apixaban with the 
HeartMate 3 LVAS is survival free of major HRAEs (hemocompatibility related 
adverse events) at 90 days post-enrollment. The primary analysis will compare the 
apixaban groups (n=30) to control (n=15). A separate analysis will compare the 
primary endpoint in patients randomized to receive aspirin (n=15) and no-aspirin 
(n=15) within the apixaban group.  
 
Major HRAEs include:  
• 
Stroke (ischemic/hemorrhagic) 
• 
Pump thrombosis 
• 
Severe bleeding (see Appendix II) 
• 
Peripheral arterial thromboembolic events 
 
HRAEs are influenced by several patient-specific risk factors, including 
anticoagulation, poor general health, altered circulation, the pump's 
hemocompatibility, and the presence of other comorbidities (e.g., AF, infections, 
etc.). In standard use, clinicians balance the risk of stroke and other 
thromboembolic (TE) events with the increased risk of bleeding when prescribing 


7 
 
anticoagulation or antiplatelet medications. Therefore, a composite endpoint 
comprising TE, bleeding, and pump-related events were chosen for the analysis.  
 
 
2.2 
SECONDARY ENDPOINTS 
The secondary endpoints include an evaluation of the following adverse events 
per INTERMACS definitions (version 5.0) throughout the study period: 
 
• 
Stroke (ischemic/hemorrhagic) 
• 
Pump thrombosis 
• 
Major bleeding 
• 
GI Bleeding 
• 
Peripheral arterial thromboembolic events 
• 
Transient ischemic attack 
• 
Hemolysis  
• 
Venous thromboembolism  
• 
Myocardial infarction 
• 
Right heart failure  
• 
Cardiac arrhythmias  
• 
Liver and kidney dysfunction  
• 
Death due to any cause 
 
 
3 
STUDY DESIGN  
A prospective, single-center, randomized controlled trial of the feasibility and 
safety of apixaban in HeartMate 3 patients.   
3.1 
STUDY CENTER AND PATIENTS  
 
Eligible patients implanted with HeartMate 3 LVAS and meeting predefined criteria 
will be included in this study. The study will be conducted at the Institute for 
Clinical and Experimental Medicine in Prague and will be made open to other 
selected centers. The study design anticipates 45 patients to be enrolled. 
 
3.2 
STUDY DURATION 
Patients enrolled will be followed-up for 90 days post-transition to a designated 
antithrombotic regimen based on randomization. Provided the individual patients 
clinical course is uneventful regarding the primary endpoint, the patient’s follow-
up within the antithrombotic study protocol will be extended to the next pre-
specified time point for analysis at 180 days. 
After the 180 days timepoint is reached, the patients will be given a chance to 
prolong the study until 1 year. All apixaban subsets will be treated according to 
their original study arm, the patients from the Vitamin K antagonist and aspirin 
group will be randomized in a 1:1 manner to apixaban with or without aspirin 
 


8 
 
 
3.3 
STUDY DESIGN 
3.3.1 Study design 
Stable HM3 patients who have not suffered a Major hemocompatibility-related 
adverse event after index hospitalization discharge and are at least 3 months post-
implant will be screened for participation in the study. Upon meeting the study 
criteria and patient informed consent, the individuals will be randomized to either 
continued therapy with a Vitamin K antagonist and aspirin or conversion to 
apixaban 5 mg twice a day in a 2:1 manner (dose targeted to renal function); the 
apixaban group will be stratified further by 1:1 randomization to continued use of 
100 mg aspirin once daily or cessation. Thus, 45 patients are planned to be enrolled 
and randomized in 3 subgroups of 15 patients in each arm (see Appendix I). After 
180 days follow-up is reached, the Vitamin K antagonist and aspirin arm will be 
transitioned to apixaban and randomized in a 1:1 manner to groups with or 
without aspirin. 
 
3.3.2 Adverse events adjudication and outcomes assessment  
All suspected or confirmed HRAEs (safety surveillance see Appendix IV) will be 
promptly reported to and adjudicated by the Expert Advisory Committee to 
determine individual patient safety to continue with the assigned treatment arm 
and the overall study safety and eligibility for continuation. All adverse events will 
be periodically reported to the Institutional Ethics Committee.  
 
4 
PATIENT POPULATION 
 
4.1 
INCLUSION CRITERIA:  
- 
The patient has been implanted with HeartMate 3 LVAS  
- 
The patient is, at a minimum, 3 months post HeartMate 3 implant 
- 
The patient is stable, ambulatory, and has been discharged home 
- 
The patient provides written informed consent before any clinical investigation 
related procedure 
 
4.2 
EXCLUSION CRITERIA:  
- 
Non-compliance with anticoagulation and antiplatelet medication, in the opinion 
of the investigator 
- 
Weight ≤ 60 kgs. or age ≥ 80 years 
- 
Poor kidney function with serum creatinine ≥ 221umol/L or creatinine clearance < 
0.042  mL/s, or the need for chronic renal replacement therapy 
- 
Total bilirubin > 43 umol/L, shock liver, or biopsy-proven liver cirrhosis 
- 
Absence of an informed consent 
- 
Presence of any mechanical prosthetic valve or any ancillary circulatory assist 
device system (other than the HM3) 


9 
 
- 
Recent  history of cardioembolic stroke  
- 
Hemodynamically significant carotid arteries stenosis (documented by imaging 
investigation not older than 12 months) 
- 
Need for antiplatelet therapy for reasons other than LVAD therapy 
- 
Major HRAE event after HeartMate 3 index hospitalization discharge 
- 
Known history of hyper- or hypo- coagulable disorder 
- 
Anti-phospholipid syndrome positive patients with documented history of 
thrombotic/thromboembolic events 
- 
Known hypersensitivity or allergy to apixaban or aspirin 
- 
The patient is involved in another interventional  study or any study that could 
potentially affect the functioning of the HM3 LVAD or the therapeutic effect of 
any of the study anticoagulants (warfarin, apixaban or aspirin), or could 
potentially confound the study results 
- 
The patient is currently pregnant, breastfeeding, or intending to get pregnant 
during the study 
- 
Presence of other anatomic or comorbid conditions, or other medical, social, 
non-compliance or psychological conditions that, in the investigator’s opinion, 
could limit the subject’s ability to participate in the clinical investigation or to 
comply with follow-up requirements or impact the scientific soundness of the 
clinical investigation results. 
 
5 
 STUDY COURSE 
 
5.1 
ENROLLMENT PROCEDURES 
Patients will sign an informed consent form at the time of the study enrollment. 
The consent form states that the data collected for this study will be used by 
authorized personnel only. The patient’s privacy will be maintained according to 
local legislation and, patients will be identified by study specific code. The 
aggregate and/or de-identified patient specific data may be published or 
presented.     
 
5.2 
DATA COLLECTION & FOLLOW-UP ASSESSMENTS 
The patient will be assessed at baseline. Lactate dehydrogenase (LDH) will be 
assessed once a week for 4 weeks, then once every 2 weeks for the next month 
and monthly thereafter; TTE ECHO follow–up will be performed at baseline, at 1 
month and at 3 months, followed until study completion per site standard of care.  
A complete list of data fields to be collected is provided in Appendix II.  A summary 
of the data collection is provided in Table 1 below, and follow-up assessments are 
further described in the following sections.   
 
 
 
 


10 
 
 
 
 


11 
 
Table 1 – Summary of Patient Assessments and Data Collection 
 
Baseline1 
Once a 
week2 
 
Once a 
month2 
 
During regular 
ambulatory 
visits 
At time 
of event 
Consent Form 
X 
 
 
 
 
Demographics & 
Medical History 
X 
 
 
 
 
Enrollment form 
X 
 
 
 
 
Laboratory 
Assessment (study 
site standard of care) 
X 
 
X 
X 
X 
LDH Assessment 
X 
X3 
X3 
X 
X 
ECHO assessment 
X 
 
X4 
X 
X 
Anti-coagulation / 
anti-platelet regimen 
X 
X 
 
X 
X 
Adverse Events: 
thrombosis, other 
adverse events 
 
 
 
 
X 
Rehospitalizations / 
Reoperations 
 
 
 
 
X 
Outcome 
 
 
 
 
X 
1 Baseline is defined as the time point of the patient enrollment to the study.  
2 The follow-up assessments commence after the study enrollment.  
3 LDH assessment once a week for 4 weeks, then once every 2 weeks for the next month 
and monthly thereafter 
4 ECHO follow–up will be performed at baseline, at 1 month and at 3 months, followed by 
periodical 6-monthly examinations 
 
5.2.1 Demographics 
Patient demographics will be collected at baseline, including age, gender,  
height, weight, BMI, blood type, vital signs, etiology of heart failure, 
duration of mechanical circulatory support prior to study enrollment, 
Modified Rankin Score, INTERMACS Profile prior to HM3 implant, and 
therapeutic intent of HM3 support. 
5.2.2 Medical History  
The patient’s medical history will be collected at baseline, including a 
history of cardiac arrhythmias, diabetes, smoking, hypertension, and 
cancer.  
 
 


12 
 
5.2.3 Enrollment form  
Information will be captured on whether the patient met the study 
inclusion/exclusion criteria.    
 
5.2.4 Laboratory Assessments and Diagnostics 
LDH assessment will be performed once a week for 4 weeks after the 
randomization, then once every 2 weeks for the next month and monthly 
thereafter; other regular laboratory assessments will include standard of 
care work-up, including measurements of kidney and liver function and 
hemostasis. Desirably, the same local authorized laboratory facility should 
be used by the patients to ensure consistency of a laboratory follow-up.   
 
5.2.4.1 Apixaban plasma concentration 
Apixaban peak and trough levels will be performed using a commercially 
available anti-Xa assay with apixaban calibrators at 4 weeks visit per study 
protocol. Levels will also be drawn at the time of presentation with any 
HRAE. 
5.2.5 Adverse Events 
All INTERMACS adverse event definitions (version 5.0) will be used in this 
study for the evaluation of primary and secondary objectives. Laboratory 
values will be determined at the time of an adverse event. 
 
5.2.6 Changes to the antithrombotic regimen 
Any changes to the designated antithrombotic regimen based on 
randomization algorithm will be documented during the follow-up visits or 
with the occurrence of an adverse event.   
 
5.2.7 Rehospitalizations/Reoperations 
Once a patient is admitted to the hospital, details will be collected on the 
admission date and the reason for the rehospitalization and date of 
discharge and antithrombotic therapy status.   
 
Reoperations will also be captured, including the date and reason for the 
reoperation.   
 
5.2.8 Outcome 
The patient’s outcome (transplanted, expired, explanted or withdrew) and 
date of outcome will be captured.    
 
 
 


13 
 
5.2.9 Completion of study follow up 
Upon completion of study follow up, patients will be transitioned back to 
their pre-study anticoagulation regimen (e.g. warfarin with aspirin).  
 
5.3 
DATA ANALYSIS AND STATISTICAL ISSUES 
Survival free of a hemocompatibility-related endpoint 90 days will be evaluated. 
The prevalence (percent of patients with events) and incidence (event rates in 
events per pt-year) of adverse events and rehospitalizations will be determined.  
 
 
6 
ETHICAL AND REGULATORY CONSIDERATIONS 
 
6.1 
INFORMED CONSENT/PATIENT AUTHORIZATION 
The patient, before study enrollment, must provide informed consent.  The 
informed consent form, where patient informed consent is captured, must have 
prior approval from the Ethics Review Board (ERB).  
 
6.2 
ETHICS REVIEW BOARD (ERB)  
ERB approval will be obtained prior to enrolling any patients in this study.  ERB will 
maintain oversight of the study in accordance with local policies and procedures.   
 
 
7 
DATA REPORTING AND RECORD-KEEPING 
7.1 
DATA REPORTING 
The data to be collected are identified in Appendix I.  These will be captured by 
investigators and entered into a Microsoft Office Excel sheet in anonymized form 
according to local regulatory standards. The investigator must ensure that the 
study required observations and findings are recorded correctly and completely 
and in a timely manner.  Source data will be maintained by the study site (e.g. in 
the form of patient medical records) for verification of data listed in the study data 
tables.     
 
7.2 
CONFIDENTIALITY 
Patient Confidentiality will be enforced as per General Data Protection Regulation 
(GDPR) of the EU Directive no. 2016/679 (effective since 25th May 2018).     
 
The patient will be made aware (via the patient authorization) that certain 
personally identifiable information will be collected as part of this study and will 
be disclosed outside the hospital.  This information will include date of birth, date 
of death, admission and discharge dates, and dates of treatment.  Except when 
required by law or except by the patient’s authorization, the patient will not be 


14 
 
identified by name, address or telephone number in the study records disclosed 
outside of the hospital.  In the study records disclosed outside of the hospital the 
patient will be assigned a unique study code. 
7.3 
MAINTENANCE OF STUDY DOCUMENTATION 
The following study documents will be maintained by the study site and be 
available for periodic review by Abbott or the expert advisory committee per 
explicit request: 
 
• Copy of the Study Protocol 
• Ethics Committee Approvals and Correspondence: a copy of all Ethics Committee 
approvals and any significant correspondence will also be provided Abbott.   
• Ethics Committee approved Patient Authorization/Informed Consent Forms: a 
copy will also be provided to Abbott. 
• Signature Verification Form: all study site individuals approved by the investigator 
to participate in this study and/or complete data entry must sign the Signature 
Verification Form. This form will be maintained on site. 
• Study Agreement: the Investigator and the Institution will complete a Study 
Agreement prior to patient enrollment.  The agreement will identify the 
investigator’s legal and ethical commitments with respect to the conduct of this 
study.   
• Patient Authorization/Informed Consents for each patient enrolled in the study 
• Source documentation (such as patient clinic charts, medical records, lab records) 
 
 
8 
REFERENCES 
1. Mehra, M. R. et al. A Fully Magnetically Levitated Left Ventricular Assist Device - 
Final Report. The New England journal of medicine 380, 1618-1627, 
doi:10.1056/NEJMoa1900486 (2019). 
2. Netuka I., Ivák P., Tučanová Z., et al: Evaluation of low-intensity anticoagulation 
with a fully magnetically levitated centrifugal-flow circulatory pump – the 
MAGENTUM 1 study. J Heart Lung Transplant. 2018;37(5):579-586.  
3. Granger, C. B. et al. Apixaban versus warfarin in patients with atrial fibrillation. 
The New England journal of medicine 365, 981-992, 
doi:10.1056/NEJMoa1107039 (2011). 
4. Bahit, M. C. et al. Non-major bleeding with Apixaban versus warfarin in patients 
with atrial fibrillation. Heart 103, 623-628, doi:10.1136/heartjnl-2016-309901 
(2017). 
5. Abraham, N. S., Noseworthy, P. A., Yao, X., Sangaralingham, L. R. & Shah, N. D. 
Gastrointestinal Safety of Direct Oral Anticoagulants: A Large Population-Based 
Study. Gastroenterology 152, 1014-1022 e1011, 
doi:10.1053/j.gastro.2016.12.018 (2017). 
6. Agnelli, G. et al. Oral Apixaban for the treatment of acute venous 
thromboembolism. The New England journal of medicine 369, 799-808, 
doi:10.1056/NEJMoa1302507 (2013). 


15 
 
7. van Es, N., Coppens, M., Schulman, S., Middeldorp, S. & Buller, H. R. Direct oral 
anticoagulants compared with vitamin K antagonists for acute venous 
thromboembolism: evidence from phase 3 trials. Blood 124, 1968-1975, 
doi:10.1182/blood-2014-04-571232 (2014). 
8. Noseworthy, P. A. et al. Direct Comparison of Dabigatran, Rivaroxaban, and 
Apixaban for Effectiveness and Safety in Nonvalvular Atrial Fibrillation. Chest 150, 
1302-1312, doi:10.1016/j.chest.2016.07.013 (2016). 
9. Ray, W. A. et al. Association of Oral Anticoagulants and Proton Pump Inhibitor 
Cotherapy With Hospitalization for Upper Gastrointestinal Tract Bleeding. Jama 
320, 2221-2230, doi:10.1001/jama.2018.17242 (2018). 
10. Ruff, C. T. et al. Comparison of the efficacy and safety of new oral anticoagulants 
with warfarin in patients with atrial fibrillation: a meta-analysis of 
randomrandomizeds. Lancet 383, 955-962, doi:10.1016/S0140-6736(13)62343-0 
(2014). 
11. Curran, L. in 20th Annual Scientific Meeting of HFSA Vol. 22   (Journal of Cardiac 
Failure, 2016). 
12. Parikh, V. et al. in ISHLT 2019.   (Elsevier). 
13. Pollari, F., Fischlein, T., Fittkau, M. & Santarpino, G. Anticoagulation with 
Apixaban in a patient with a left ventricular assist device and gastrointestinal 
bleeding: A viable alternative to warfarin? Journal of Thoracic and Cardiovascular 
Surgery 152, 79-81 (2016). 
14. Schulte-Estrup, S., Mayer-Wingert, N., Reiss, N., Sindermann, J. & Warnecke, H. in 
ISHLT 2019    (Elsevier, Orlando, FL, 2019). 
 
 


16 
 
Appendix I:  Study design flow chart 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


17 
 
Appendix II:  Severe Bleeding Definition 
 
 
SEVERE BLEEDING: 
 
Type A: (Meets any of the below) 
• Overt bleeding plus hemoglobin drop of 3 to < 5 g/dL(30-50g/L) (provided 
hemoglobin drop is related to bleed) 
• Any transfusion with overt bleeding 
 
Type B: (Meets any of the below) 
• Overt bleeding plus hemoglobin drop 5 g/dL (50g/L) or greater (provided 
hemoglobin drop is related to bleed) 
• Cardiac tamponade 
• Bleeding requiring surgical intervention for control (excluding dental, nasal, skin, 
or hemorrhoid) 
• Hypotension attributable to bleeding and requiring intravenous vasoactive 
agents for hemodynamic support 
• Intracranial Hemorrhage that does not meet the definition of hemorrhagic stroke 
 
Type C1: Probable fatal bleeding; no autopsy or imaging confirmation but clinically 
suspicious 
Type C2: Definite fatal bleeding; overt bleeding or autopsy or imaging confirmation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


18 
 
Appendix III:  Data Collection spreadsheet 
 
 
  
Baseline 
At regular 
ambulatory 
visits 
Once 
a 
week 
Once 
a 
month 
At the 
time of 
the 
event 
Baseline info: 
  
  
  
  
  
Patient identifier 
x 
  
  
  
  
Date of birth 
x 
  
  
  
  
Gender 
x 
  
  
  
  
Ethnicity 
x 
  
  
  
  
Race 
x 
  
  
  
  
Etiology 
x 
  
  
  
  
Current device strategy 
x 
 
 
 
 
Blood type 
x 
  
  
  
  
Assessment of routine tests done 
to evaluate the prothrombotic 
state   
x 
 
 
 
 
  
  
  
  
  
  
Medical History 
  
  
  
  
  
INTERMACS Profile at time of 
implant 
x 
  
  
  
  
Coronary artery disease 
x 
  
  
  
  
Arrhythmia: atrial/ventricular; 
Afib (yes/no) 
x 
  
  
  
  
Ventricular pacing 
x 
  
  
  
  
Cancer 
x 
  
  
  
  
ICD 
x 
  
  
  
  
Stents, location 
x 
  
  
  
  
Myocardial infarction 
x 
  
  
  
  
Diabetes 
x 
  
  
  
  
Smoking history 
x 
  
  
  
  
Diverticular disease or diagnosed 
AVMs 
x 
  
  
  
  
GI Ulcer 
x 
  
  
  
  
Significant carotid stenosis (or if 
last examination > 12 months 
old) 
x 
 
 
 
 
AEs since pump implant: 
x 
  
  
  
  
 
 
 
 
 
 
Enrollment Form 
x 
  
  
  
  
Date enrolled 
x 
  
  
  
  
Incl/excl criteria (yes/no) 
x 
  
  
  
  
Date of study therapy initiation  
x 
  
 
  
 
 
  
  
  
  
 


19 
 
 
Baseline 
At regular 
ambulatory 
visits 
Once 
a 
week 
Once 
a 
month 
At the 
time of 
the 
event 
 
 
 
 
 
 
Physical Exam 
  
  
  
  
 
Heart rate 
x 
  
  
  
x 
Height in cm 
x 
  
  
  
x 
Weight in kg 
x 
  
  
  
x 
BP_MEAN – Doppler 
x 
  
  
  
x 
Pump parameters (speed, flow, 
PI, power) 
x 
x 
 
 
x 
 
 
 
 
 
 
Laboratory tests 
  
  
  
  
 
Creatinine 
x 
x 
  
  
x 
Urea 
x 
x 
  
  
x 
Total Bilirubin 
x 
x 
  
  
x 
Hgb 
x 
x 
  
 
x 
Hct 
x 
x 
  
 
x 
WBC (leucocytes) 
x 
x 
  
 
x 
PLT 
x 
x 
  
 
x 
Verify-now test 
x 
x 
 
 
x 
INR 
x 
x 
 
 
x 
Fibrinogen 
x 
x 
  
 
x 
aPTT 
x 
x 
  
 
x 
LDH 
x 
x 
x1 
x 
x 
Plasma free hemoglobin 
x 
x 
  
 
x 
BNP (or NT Pro BNP) 
x 
x 
 
 
x 
Anti Xa apixaban  
 
x3 
 
 
x 
 
 
 
 
 
 
Baseline diagnostics 
  
  
  
  
  
ECG (date, rhythm) 
x 
 x 
  
  
x 
Echocardiography 
x 
  
  
x2  
x 
Carotid ultrasound (if more than 
12 months since last 
examination ) 
x 
 
 
 
 
  
  
  
  
  
 
Implant information 
  
  
  
  
 
Date implanted 
x 
  
  
  
 
  
  
  
  
  
 
Follow-up  
  
  
  
  
 
Reoperation for 
bleeding/thrombosis? Date, 
reason 
 x 
  
 
 
x 
Date of initial discharge post 
LVAD implant  
x 
  
  
  
 


20 
 
  
Baseline 
At regular 
ambulatory 
visits 
Once 
a 
week 
Once 
a 
month 
At time 
of event 
 
 
 
 
 
 
Current anticoagulation regimen 
(date, medication, dosages) 
 x 
x 
 
 
x 
Re-hospitalization for 
thrombosis/other AE? Admission 
date, reason, treatment, 
discharge 
  
 
 
 
x 
 
 
 
 
 
 
HRAE  
  
  
 
 
x 
Onset date 
  
  
 
 
x 
Is event stroke, TIA, or device 
thrombosis 
  
  
 
 
x 
If stroke, is it ischemic or 
hemorrhagic? 
  
  
 
 
x 
If stroke, head CT examination 
  
  
 
 
x 
If device thrombosis: Hemolysis 
seen? Thrombolytics given? 
Increase in pump power? Pump 
replaced? Other clinical 
symptoms?  
  
  
 
 
x 
Collect laboratory tests listed 
above 
  
  
 
 
x 
Current anticoag/antiplt 
medications 
  
  
 
 
x 
Any change to anticoag/antiplt 
meds? If yes, what 
  
  
 
 
x 
Infection requiring antibx or + BC    
  
 
 
x 
Describe event and treatment 
  
  
 
 
x 
Resolution date 
  
  
 
 
x 
 
 
 
 
 
 
Other AE 
 
 
 
 
 
Onset date 
 
 
 
 
x 
Type of event 
 
 
 
 
x 
Examination incl. imaging 
methods 
 
 
 
 
x 
Laboratory tests 
 
 
 
 
x 
Rehospitalisation/reoperation 
 
 
 
 
x 
Treatment 
 
 
 
 
x 
 
 
 
 
 
 
Outcome  
  
  
 
  
  
Date 
  
  
 
 
x 


21 
 
  
Baseline 
At regular 
ambulatory 
visits 
Once 
a 
week 
Once 
a 
month 
At time 
of event 
Type of outcome (expired, 
explanted, transplanted) 
  
  
 
 
x 
If expired, cause of death 
  
  
 
 
x 
1 LDH assessment once a week for 4 weeks, then once every 2 weeks for the next month 
and monthly thereafter 
2 ECHO follow–up will be performed at baseline, at 1 month and at 3 months, followed by 
periodical 6-monthly examinations 
3 Performed at 4 weeks visit after the anticoagulation transition in patient on apixaban 
only 
 
 


22 
 
 Appendix IV: Therapeutic efficacy adjustments and safety monitoring 
 
 Advanced Pump Thrombosis Monitoring Protocol 
• Monitor LDH at baseline and after initiation of determined antithrombotic 
therapy based on randomization algorithm once a week during first 4 weeks, 
then once every 2 weeks for the next month and monthly after that 
• If LDH rises more than 1.2x baseline: 
o repeat LDH within the next 1-3 business days 
o monitor plasma free hemoglobin (pf-Hb) and haptoglobin if available; and 
total bilirubin  
o complete evaluation with the team to rule out other reasons for LDH rise 
o echocardiogram to evaluate for aortic insufficiency  
o prompt study team to review within 48 hours 
o retrospective data log files analysis (particularly rotor noise and rotor 
displacement trends) followed by prospective analysis 2 weeks post event 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


23 
 
Appendix V: Apixaban effect reversal protocol 
In case of need of reversal of the effect of apixaban, following protocol will be executed.   
 
 
 
 
 
 

Prot_000.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Direct Oral Anticoagulant Therapy with the HeartMate 3 LVAD: A Pilot Study 
DOT-HM3 Study 
 
 
 
 
 
 
 
 
 
Investigator initiated study 
The study site:  
Institute for Clinical and Experimental Medicine, Prague, Czech Republic  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Version 1.0 
                                                                                                      5/25/2021 


2 
 
TABLE of CONTENTS 
TABLE of APPENDICES .......................................................................................................... 3 
1 
Introduction ................................................................................................................ 4 
2 
Study Objectives ......................................................................................................... 6 
2.1 
Primary Endpoint .......................................................................................... 6 
2.2 
Secondary Endpoints .................................................................................... 7 
3 
Study Design ............................................................................................................... 7 
3.1 
Study Center and Patients ............................................................................ 7 
3.2 
Study Duration ............................................................................................. 7 
3.3 
Study Design ................................................................................................. 8 
3.3.1 Study design ..................................................................................... 8 
3.3.2 Adverse events adjudication and outcomes assessment ................ 8 
4 
Patient Population ...................................................................................................... 8 
4.1 
Inclusion Criteria .......................................................................................... 8 
4.2 
Exclusion Criteria .......................................................................................... 8 
5 
Study Course ............................................................................................................... 9 
5.1 
Enrollment Procedures ................................................................................. 9 
5.2 
Data Collection & Follow-up Assessments ................................................... 9 
5.2.1 Demographics ................................................................................. 10 
5.2.2 Medical History ............................................................................... 10 
5.2.3 Enrollment form ............................................................................. 11 
5.2.4 Laboratory Assessments and Diagnostics ...................................... 11 
 
 
 
5.2.4.1. Apixaban plasma concentration…………………………………….11 
5.2.5 Adverse Events ............................................................................... 11 
5.2.6 Changes to antithrombotic regimen .............................................. 11 
5.2.7 Rehospitalizations/Reoperations ................................................... 11 
5.2.8 Outcome ......................................................................................... 11 
 
 
5.2.9  Completion of study follow up……………………………………………………12 
5.3 
Data Analysis and Statistical Issues ............................................................ 12 
6 
Ethical and Regulatory Considerations..................................................................... 12 
6.1 
Informed Consent/Patient Authorization .................................................. 12 
6.2 
Ethics Review Board (ERB) ......................................................................... 12 
7 
Data Reporting and Record-Keeping ........................................................................ 12 
7.1 
Data Reporting ........................................................................................... 12 
7.2 
Confidentiality ............................................................................................ 12 
7.3 
Maintenance of Study Documentation ...................................................... 13 
8 
References ................................................................................................................ 13 
 
 
 


3 
 
TABLE of APPENDICES 
 
Appendix 
Contents 
I 
Study design flow chart 
II 
Severe Bleeding Definition  
III 
Data Collection spreadsheet  
IV 
Therapeutic efficacy adjustments and safety monitoring 
V 
Apixaban effect reversal protocol 
 


4 
 
Study organization 
Expert Advisory Committee: Chair – Mandeep R. Mehra, MD, member - Jean M. Connors, 
MD (both BWH and Harvard Medical School, Massachusetts, U.S.A.) 
Study Principal Investigator: Ivan Netuka, MD 
Executive Committee (s): Expert Advisory Committee + CEC + DSMB – (TBD) 
Study Site:  Institute for Clinical and Experimental Medicine, Prague, Czech Republic 
 
 
1 
INTRODUCTION 
HeartMate 3 (HM3) Left Ventricular Assist System (LVAS) is a centrifugal, fully 
magnetically 
levitated, 
continuous-flow 
pump 
designed 
to 
facilitate 
hemocompatibility by reducing shear stress on blood elements and to optimize 
pump washout by intrinsic pulsatility.  
The Multicenter Study of MagLev Technology in Patients Undergoing Mechanical 
Circulatory Support Therapy with HeartMate 3 (MOMENTUM 3) trial 2-year data1 
demonstrated an absence of confirmed pump thrombosis requiring pump 
exchange and marked reduction in stroke rates. On the backdrop of conventional 
anticoagulation protocols used in the study, observed bleeding complication rates 
in HM 3 were reduced, yet there is a need for further improvement as the overall 
intensity of conventional anti-thrombotic therapy represents a major contributor 
to non-surgical bleeding-related outcomes. 
The HM3 LVAS Instructions for Use (IFU) recommend maintaining patients on 
Warfarin and Aspirin for long-term anticoagulation therapy. Recent results of The 
Minimal 
AnticoaGulation 
EvaluatioN 
To 
aUgment 
heMocompatibility 
(MAGENTUM 1) pilot study2 has demonstrated substantially lower-intensity 
anticoagulation (INR range 1.5 – 1.9) is achievable and supports the safety of lower 
targets with select patients implanted with the HeartMate 3 beyond 1 year with 
no thromboembolic complications or pump thrombosis. The observed outcomes 
were similar to those with the higher intensity anticoagulation targets and further 
support a signal of enhanced intrinsic thromboresistance of the HM3.  
Direct oral anticoagulants (DOACs) are a class of drugs which directly exert 
therapeutic effect on specific coagulation factors. Broadly, they can be categorized 
as direct thrombin inhibitors (dabigatran) and  factor Xa  inhibitors (apixaban, 
rivaroxaban, and edoxaban) or FXai.  Warfarin, which inhibits vitamin K dependent 
synthesis of coagulation factors in a manner that prevents activation of these 
factors, has wide inter-individual variation in metabolism and a narrow 
therapeutic window, as well as both food-drug and drug-drug interactions; the 
result is that patients taking warfarin require frequent monitoring of the 
anticoagulant effect to maintain safety and efficacy.  The DOAC  directly enter the 
blood to bind to the activated coagulation factor target; they have predictable 
pharmacokinetics, little interindividual variation in metabolism, few drug-drug 
interactions, and no interactions with foods. The large phase 3 RCT in both AF and 
VTE established both efficacy and safety—without the need for monitoring. The 
FXai may provide better anticoagulation than the oral direct thrombin inhibitor 
due to their action earlier in  the coagulation cascade prior to the generation of 


5 
 
thrombin which may ameliorate the likelihood of initiation of the feedback loop 
resulting in >1000-fold increase in thrombin production. Of the studied FXai , 
apixaban has the lowest major bleeding complication rate and has not been shown 
to increase GI-bleeding3, 4, 5. It also has the least dependence on renal clearance. 
Consequently, with the documented enhanced hemocompatibility of the 
HeartMate 3 and the potential for reduced major bleeding with apixaban in 
indicated patient populations, we provide the rationale  that patients with the 
HM3 are in clinical equipoise to be randomized in a feasibility study of a new 
antithrombotic  strategy testing apixaban with or without aspirin compared to the 
current standard of care warfarin and aspirin in a rigorously structured study to 
evaluate  safety in stable patients with the HM3 device. 
 
Apixaban Safety and Efficacy Data 
 
Apixaban is a DOAC that directly inhibits Factor Xa (FXai) in the coagulation 
cascade. Its therapeutic effect is more consistent and predictable due to its 
mechanism of action, and it is not subject to the disadvantages inherent to Vitamin 
K antagonist (VKA) anticoagulants. In phase 3 clinical trial that resulted in FDA 
approval, involving 18,201 patients with non-valvular AF, Apixaban was shown to 
be non-inferior in antithrombotic effect and superior in terms of major bleeding 
relative to VKA anticoagulants (ARISTOTLE study; NCT00412984).3 Major bleeding, 
per the International Society on Thrombosis and Haemostasis (ISTH) definition, 
was reduced with Apixaban relative to VKA, primarily due to a 58% reduction in 
intracranial hemorrhage (ICH) and 21% drop in locations other than the 
gastrointestinal (GI) tract.3 Clinically relevant non-major bleeds were also 
significantly reduced in this study.4 GI bleeding was not significantly different 
between Apixaban and warfarin.  
 
In the AMPLIFY study (NCT00643201), the safety and efficacy of apixaban for the 
prevention of recurrent venous thromboembolic (VTE) events and death due to 
VTE were compared with warfarin in 5,395 patients with acute VTE. Apixaban was 
found to be non-inferior to warfarin preventing recurrent VTE events (RR: 0.84; 
95% CI: 0.6 – 1.18 ), and major bleeding was reduced by 69% in the apixaban 
group.6 In a meta-analysis of DOAC studies in the VTE population, FXa inhibitors 
were found to have 60 % lower rate of ICH and fatal bleeds compared to VKA.7 In 
a retrospective study of Medicare beneficiaries, 36% fewer patients were 
hospitalized for upper-GI bleeding with apixaban than with warfarin.8 In another 
post-market study, apixaban was compared with rivaroxaban and dabigatran using 
propensity-matched cohorts of Medicare beneficiaries, with non-valvular AF, in 
terms of safety and efficacy. Apixaban was found to have a lower risk of causing 
GI and major bleeds than the other DOACs.5 No differences were seen between 
the three DOACs in strokes or systemic embolism.8 Even in cancer patients in 
whom the risk of bleeding is higher than in other popualtions, treatment of VTE 
with apixaban showed no increase in major bleeding compared to dalteparin, 
unlike edoxaban and rivaroxaban, both of which had increased major bleeding 
compared to dalteparin.  
 


6 
 
The rationale for Apixaban use with the HeartMate 3 
There have been no studies to date that have systematically evaluated the 
feasibility of using apixaban alone or combined with low dose aspirin in HM3 
patients. All the primary phase 3 clinical trials assessing DOACs have focused on 
patients with non-valvular atrial fibrillation or venous thromboembolism with or 
without cancer. 7, 10  Within the literature, there are sparse reports of apixaban use 
with LVAD patients due to recurrent bleeding or non-compliance with warfarin.32-
35 These small sample size studies reported encouraging low rates of 
thromboembolic events. In all but one instance, aspirin was withheld due to the 
history of bleeding events. Patients in these studies either had the HeartMate II or 
HeartWare HVAD.  
 
Reduction in bleeding and thromboembolic events with HeartMate 3 compared to 
the HeartMate II was demonstrated by the MOMENTUM 3 IDE Trial. Yet, bleeding 
complications remain a burdensome limitation while on support and represent a 
significant cause of rehospitalizations and morbidity. Independently, both a 
reduction in major bleeding events and stable anticoagulation intensity constitute 
a compelling potential benefit of a modified antithrombotic strategy with a direct 
oral anticoagulant. However, these apixaban associated benefits remain to be 
validated in advanced heart failure population supported with the HeartMate 3 
LVAS. Therefore, the objective of this study is to assess safety and feasibility of 
apixaban use in HM3 supported patients.  
 
 
 
2 
STUDY OBJECTIVES 
2.1 
PRIMARY ENDPOINT 
The primary endpoint to evaluate the safety and feasibility of apixaban with the 
HeartMate 3 LVAS is survival free of major HRAEs (hemocompatibility related 
adverse events) at 90 days post-enrollment. The primary analysis will compare the 
apixaban groups (n=30) to control (n=15). A separate analysis will compare the 
primary endpoint in patients randomized to receive aspirin (n=15) and no-aspirin 
(n=15) within the apixaban group.  
 
Major HRAEs include:  
• 
Stroke (ischemic/hemorrhagic) 
• 
Pump thrombosis 
• 
Severe bleeding (see Appendix II) 
• 
Peripheral arterial thromboembolic events 
 
HRAEs are influenced by several patient-specific risk factors, including 
anticoagulation, poor general health, altered circulation, the pump's 
hemocompatibility, and the presence of other comorbidities (e.g., AF, infections, 
etc.). In standard use, clinicians balance the risk of stroke and other 
thromboembolic (TE) events with the increased risk of bleeding when prescribing 


7 
 
anticoagulation or antiplatelet medications. Therefore, a composite endpoint 
comprising TE, bleeding, and pump-related events were chosen for the analysis.  
 
 
2.2 
SECONDARY ENDPOINTS 
The secondary endpoints include an evaluation of the following adverse events 
per INTERMACS definitions (version 5.0) throughout the study period: 
 
• 
Stroke (ischemic/hemorrhagic) 
• 
Pump thrombosis 
• 
Major bleeding 
• 
GI Bleeding 
• 
Peripheral arterial thromboembolic events 
• 
Transient ischemic attack 
• 
Hemolysis  
• 
Venous thromboembolism  
• 
Myocardial infarction 
• 
Right heart failure  
• 
Cardiac arrhythmias  
• 
Liver and kidney dysfunction  
• 
Death due to any cause 
 
 
3 
STUDY DESIGN  
A prospective, single-center, randomized controlled trial of the feasibility and 
safety of apixaban in HeartMate 3 patients.   
3.1 
STUDY CENTER AND PATIENTS  
 
Eligible patients implanted with HeartMate 3 LVAS and meeting predefined criteria 
will be included in this study. The study will be conducted at the Institute for 
Clinical and Experimental Medicine in Prague and will be made open to other 
selected centers. The study design anticipates 45 patients to be enrolled with a 
follow-up duration of 90 days.  
 
3.2 
STUDY DURATION 
Patients enrolled will be followed-up for 90 days post-transition to a designated 
antithrombotic regimen based on randomization. Provided the individual patients 
clinical course is uneventful regarding the primary endpoint , the patient’s follow-
up within the antithrombotic study protocol will be extended to the next pre-
specified time point for analysis at 180 days while all apixaban subsets will be 
treated as a single therapy without aspirin between 90-180 days.  
 


8 
 
 
3.3 
STUDY DESIGN 
3.3.1 Study design 
Stable HM3 patients who have not suffered a Major hemocompatibility-related 
adverse event after index hospitalization discharge and are at least 3 months post-
implant will be screened for participation in the study. Upon meeting the study 
criteria and patient informed consent, the individuals will be randomized to either 
continued therapy with a Vitamin K antagonist and aspirin or conversion to 
apixaban 5 mg twice a day in a 2:1 manner (dose targeted to renal function); the 
apixaban group will be stratified further by 1:1 randomization to continued use of 
100 mg aspirin once daily or cessation. Thus, 45 patients are planned to be enrolled 
and randomized in 3 subgroups of 15 patients in each arm (see Appendix I). 
 
3.3.2 Adverse events adjudication and outcomes assessment  
All suspected or confirmed HRAEs (safety surveillance see Appendix IV) will be 
promptly reported to and adjudicated by the Expert Advisory Committee to 
determine individual patient safety to continue with the assigned treatment arm 
and the overall study safety and eligibility for continuation. All adverse events will 
be periodically reported to the Institutional Ethics Committee.  
 
4 
PATIENT POPULATION 
 
4.1 
INCLUSION CRITERIA:  
- 
The patient has been implanted with HeartMate 3 LVAS  
- 
The patient is, at a minimum, 3 months post HeartMate 3 implant 
- 
The patient is stable, ambulatory, and has been discharged home 
- 
The patient provides written informed consent before any clinical investigation 
related procedure 
 
4.2 
EXCLUSION CRITERIA:  
- 
Non-compliance with anticoagulation and antiplatelet medication, in the opinion 
of the investigator 
- 
Weight ≤ 60 kgs. or age ≥ 80 years 
- 
Poor kidney function with serum creatinine ≥ 221umol/L or creatinine clearance < 
0.042  mL/s, or the need for chronic renal replacement therapy 
- 
Total bilirubin > 43 umol/L, shock liver, or biopsy-proven liver cirrhosis 
- 
Absence of an informed consent 
- 
Presence of any mechanical prosthetic valve or any ancillary circulatory assist 
device system (other than the HM3) 
- 
Recent  history of cardioembolic stroke  
- 
Hemodynamically significant carotid arteries stenosis (documented by imaging 
investigation not older than 12 months) 


9 
 
- 
Need for antiplatelet therapy for reasons other than LVAD therapy 
- 
Major HRAE event after HeartMate 3 index hospitalization discharge 
- 
Known history of hyper- or hypo- coagulable disorder 
- 
Anti-phospholipid syndrome positive patients with documented history of 
thrombotic/thromboembolic events 
- 
Known hypersensitivity or allergy to apixaban or aspirin 
- 
The patient is involved in another interventional  study or any study that could 
potentially affect the functioning of the HM3 LVAD or the therapeutic effect of 
any of the study anticoagulants (warfarin, apixaban or aspirin), or could 
potentially confound the study results 
- 
The patient is currently pregnant, breastfeeding, or intending to get pregnant 
during the study 
- 
Presence of other anatomic or comorbid conditions, or other medical, social, 
non-compliance or psychological conditions that, in the investigator’s opinion, 
could limit the subject’s ability to participate in the clinical investigation or to 
comply with follow-up requirements or impact the scientific soundness of the 
clinical investigation results. 
 
5 
 STUDY COURSE 
 
5.1 
ENROLLMENT PROCEDURES 
Patients will sign an informed consent form at the time of the study enrollment. 
The consent form states that the data collected for this study will be used by 
authorized personnel only. The patient’s privacy will be maintained according to 
local legislation and, patients will be identified by study specific code. The 
aggregate and/or de-identified patient specific data may be published or 
presented.     
 
5.2 
DATA COLLECTION & FOLLOW-UP ASSESSMENTS 
The patient will be assessed at baseline. Lactate dehydrogenase (LDH) will be 
assessed once a week for 4 weeks, then once every 2 weeks for the next month 
and monthly thereafter; TTE ECHO follow–up will be performed at baseline, at 1 
month and at 3 months, followed until study completion per site standard of care.  
A complete list of data fields to be collected is provided in Appendix II.  A summary 
of the data collection is provided in Table 1 below, and follow-up assessments are 
further described in the following sections.   
 
 
 
 
 
 
 


10 
 
Table 1 – Summary of Patient Assessments and Data Collection 
 
Baseline1 
Once a 
week2 
 
Once a 
month2 
 
During regular 
ambulatory 
visits 
At time 
of event 
Consent Form 
X 
 
 
 
 
Demographics & 
Medical History 
X 
 
 
 
 
Enrollment form 
X 
 
 
 
 
Laboratory 
Assessment (study 
site standard of care) 
X 
 
X 
X 
X 
LDH Assessment 
X 
X3 
X3 
X 
X 
ECHO assessment 
X 
 
X4 
X 
X 
Anti-coagulation / 
anti-platelet regimen 
X 
X 
 
X 
X 
Adverse Events: 
thrombosis, other 
adverse events 
 
 
 
 
X 
Rehospitalizations / 
Reoperations 
 
 
 
 
X 
Outcome 
 
 
 
 
X 
1 Baseline is defined as the time point of the patient enrollment to the study.  
2 The follow-up assessments commence after the study enrollment.  
3 LDH assessment once a week for 4 weeks, then once every 2 weeks for the next month 
and monthly thereafter 
4 ECHO follow–up will be performed at baseline, at 1 month and at 3 months, followed by 
periodical 6-monthly examinations 
 
5.2.1 Demographics 
Patient demographics will be collected at baseline, including age, gender,  
height, weight, BMI, blood type, vital signs, etiology of heart failure, 
duration of mechanical circulatory support prior to study enrollment, 
Modified Rankin Score, INTERMACS Profile prior to HM3 implant, and 
therapeutic intent of HM3 support. 
5.2.2 Medical History  
The patient’s medical history will be coplallected at baseline, including a 
history of cardiac arrhythmias, diabetes, smoking, hypertension, and 
cancer.  
 
 


11 
 
5.2.3 Enrollment form  
Information will be captured on whether the patient met the study 
inclusion/exclusion criteria.    
 
5.2.4 Laboratory Assessments and Diagnostics 
LDH assessment will be performed once a week for 4 weeks, then once 
every 2 weeks for the next month and monthly thereafter; other regular 
laboratory assessments will include standard of care work-up, including 
measurements of kidney and liver function and hemostasis. Desirably, the 
same local authorized laboratory facility should be used by the patients to 
ensure consistency of a laboratory follow-up.   
 
5.2.4.1 Apixaban plasma concentration 
Apixaban peak and trough levels will be performed using a commercially 
available anti-Xa assay with apixaban calibrators at 4 weeks visit per study 
protocol. Levels will also be drawn at the time of presentation with any 
HRAE. 
5.2.5 Adverse Events 
All INTERMACS adverse event definitions (version 5.0) will be used in this 
study for the evaluation of primary and secondary objectives. Laboratory 
values will be determined at the time of an adverse event. 
 
5.2.6 Changes to the antithrombotic regimen 
Any changes to the designated antithrombotic regimen based on 
randomization algorithm will be documented during the follow-up visits or 
with the occurrence of an adverse event.   
 
5.2.7 Rehospitalizations/Reoperations 
Once a patient is admitted to the hospital, details will be collected on the 
admission date and the reason for the rehospitalization and date of 
discharge and antithrombotic therapy status.   
 
Reoperations will also be captured, including the date and reason for the 
reoperation.   
 
5.2.8 Outcome 
The patient’s outcome (transplanted, expired, explanted or withdrew) and 
date of outcome will be captured.    
 
 
 


12 
 
5.2.9 Completion of study follow up 
Upon completion of study follow up, patients will be transitioned back to 
their pre-study anticoagulation regimen (e.g. warfarin with aspirin).  
 
5.3 
DATA ANALYSIS AND STATISTICAL ISSUES 
Survival free of a hemocompatibility-related endpoint 90 days will be evaluated. 
The prevalence (percent of patients with events) and incidence (event rates in 
events per pt-year) of adverse events and rehospitalizations will be determined.  
 
 
6 
ETHICAL AND REGULATORY CONSIDERATIONS 
 
6.1 
INFORMED CONSENT/PATIENT AUTHORIZATION 
The patient, before study enrollment, must provide informed consent.  The 
informed consent form, where patient informed consent is captured, must have 
prior approval from the Ethics Review Board (ERB).  
 
6.2 
ETHICS REVIEW BOARD (ERB)  
ERB approval will be obtained prior to enrolling any patients in this study.  ERB will 
maintain oversight of the study in accordance with local policies and procedures.   
 
 
7 
DATA REPORTING AND RECORD-KEEPING 
7.1 
DATA REPORTING 
The data to be collected are identified in Appendix I.  These will be captured by 
investigators and entered into a Microsoft Office Excel sheet in anonymized form 
according to local regulatory standards. The investigator must ensure that the 
study required observations and findings are recorded correctly and completely 
and in a timely manner.  Source data will be maintained by the study site (e.g. in 
the form of patient medical records) for verification of data listed in the study data 
tables.     
 
7.2 
CONFIDENTIALITY 
Patient Confidentiality will be enforced as per General Data Protection Regulation 
(GDPR) of the EU Directive no. 2016/679 (effective since 25th May 2018).     
 
The patient will be made aware (via the patient authorization) that certain 
personally identifiable information will be collected as part of this study and will 
be disclosed outside the hospital.  This information will include date of birth, date 
of death, admission and discharge dates, and dates of treatment.  Except when 
required by law or except by the patient’s authorization, the patient will not be 


13 
 
identified by name, address or telephone number in the study records disclosed 
outside of the hospital.  In the study records disclosed outside of the hospital the 
patient will be assigned a unique study code. 
7.3 
MAINTENANCE OF STUDY DOCUMENTATION 
The following study documents will be maintained by the study site and be 
available for periodic review by Abbott or the expert advisory committee per 
explicit request: 
 
• Copy of the Study Protocol 
• Ethics Committee Approvals and Correspondence: a copy of all Ethics Committee 
approvals and any significant correspondence will also be provided Abbott.   
• Ethics Committee approved Patient Authorization/Informed Consent Forms: a 
copy will also be provided to Abbott. 
• Signature Verification Form: all study site individuals approved by the investigator 
to participate in this study and/or complete data entry must sign the Signature 
Verification Form. This form will be maintained on site. 
• Study Agreement: the Investigator and the Institution will complete a Study 
Agreement prior to patient enrollment.  The agreement will identify the 
investigator’s legal and ethical commitments with respect to the conduct of this 
study.   
• Patient Authorization/Informed Consents for each patient enrolled in the study 
• Source documentation (such as patient clinic charts, medical records, lab records) 
 
 
8 
REFERENCES 
1. Mehra, M. R. et al. A Fully Magnetically Levitated Left Ventricular Assist Device - 
Final Report. The New England journal of medicine 380, 1618-1627, 
doi:10.1056/NEJMoa1900486 (2019). 
2. Netuka I., Ivák P., Tučanová Z., et al: Evaluation of low-intensity anticoagulation 
with a fully magnetically levitated centrifugal-flow circulatory pump – the 
MAGENTUM 1 study. J Heart Lung Transplant. 2018;37(5):579-586.  
3. Granger, C. B. et al. Apixaban versus warfarin in patients with atrial fibrillation. 
The New England journal of medicine 365, 981-992, 
doi:10.1056/NEJMoa1107039 (2011). 
4. Bahit, M. C. et al. Non-major bleeding with Apixaban versus warfarin in patients 
with atrial fibrillation. Heart 103, 623-628, doi:10.1136/heartjnl-2016-309901 
(2017). 
5. Abraham, N. S., Noseworthy, P. A., Yao, X., Sangaralingham, L. R. & Shah, N. D. 
Gastrointestinal Safety of Direct Oral Anticoagulants: A Large Population-Based 
Study. Gastroenterology 152, 1014-1022 e1011, 
doi:10.1053/j.gastro.2016.12.018 (2017). 
6. Agnelli, G. et al. Oral Apixaban for the treatment of acute venous 
thromboembolism. The New England journal of medicine 369, 799-808, 
doi:10.1056/NEJMoa1302507 (2013). 


14 
 
7. van Es, N., Coppens, M., Schulman, S., Middeldorp, S. & Buller, H. R. Direct oral 
anticoagulants compared with vitamin K antagonists for acute venous 
thromboembolism: evidence from phase 3 trials. Blood 124, 1968-1975, 
doi:10.1182/blood-2014-04-571232 (2014). 
8. Noseworthy, P. A. et al. Direct Comparison of Dabigatran, Rivaroxaban, and 
Apixaban for Effectiveness and Safety in Nonvalvular Atrial Fibrillation. Chest 150, 
1302-1312, doi:10.1016/j.chest.2016.07.013 (2016). 
9. Ray, W. A. et al. Association of Oral Anticoagulants and Proton Pump Inhibitor 
Cotherapy With Hospitalization for Upper Gastrointestinal Tract Bleeding. Jama 
320, 2221-2230, doi:10.1001/jama.2018.17242 (2018). 
10. Ruff, C. T. et al. Comparison of the efficacy and safety of new oral anticoagulants 
with warfarin in patients with atrial fibrillation: a meta-analysis of 
randomrandomizeds. Lancet 383, 955-962, doi:10.1016/S0140-6736(13)62343-0 
(2014). 
11. Curran, L. in 20th Annual Scientific Meeting of HFSA Vol. 22   (Journal of Cardiac 
Failure, 2016). 
12. Parikh, V. et al. in ISHLT 2019.   (Elsevier). 
13. Pollari, F., Fischlein, T., Fittkau, M. & Santarpino, G. Anticoagulation with 
Apixaban in a patient with a left ventricular assist device and gastrointestinal 
bleeding: A viable alternative to warfarin? Journal of Thoracic and Cardiovascular 
Surgery 152, 79-81 (2016). 
14. Schulte-Estrup, S., Mayer-Wingert, N., Reiss, N., Sindermann, J. & Warnecke, H. in 
ISHLT 2019    (Elsevier, Orlando, FL, 2019). 
 
 


15 
 
Appendix I:  Study design flow chart 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


16 
 
Appendix II:  Severe Bleeding Definition 
 
 
SEVERE BLEEDING: 
 
Type A: (Meets any of the below) 
• Overt bleeding plus hemoglobin drop of 3 to < 5 g/dL(30-50g/L) (provided 
hemoglobin drop is related to bleed) 
• Any transfusion with overt bleeding 
 
Type B: (Meets any of the below) 
• Overt bleeding plus hemoglobin drop 5 g/dL (50g/L) or greater (provided 
hemoglobin drop is related to bleed) 
• Cardiac tamponade 
• Bleeding requiring surgical intervention for control (excluding dental, nasal, skin, 
or hemorrhoid) 
• Hypotension attributable to bleeding and requiring intravenous vasoactive 
agents for hemodynamic support 
• Intracranial Hemorrhage that does not meet the definition of hemorrhagic stroke 
 
Type C1: Probable fatal bleeding; no autopsy or imaging confirmation but clinically 
suspicious 
Type C2: Definite fatal bleeding; overt bleeding or autopsy or imaging confirmation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


17 
 
Appendix III:  Data Collection spreadsheet 
 
 
  
Baseline 
At regular 
ambulatory 
visits 
Once 
a 
week 
Once 
a 
month 
At the 
time of 
the 
event 
Baseline info: 
  
  
  
  
  
Patient identifier 
x 
  
  
  
  
Date of birth 
x 
  
  
  
  
Gender 
x 
  
  
  
  
Ethnicity 
x 
  
  
  
  
Race 
x 
  
  
  
  
Etiology 
x 
  
  
  
  
Current device strategy 
x 
 
 
 
 
Blood type 
x 
  
  
  
  
Assessment of routine tests done 
to evaluate the prothrombotic 
state   
x 
 
 
 
 
  
  
  
  
  
  
Medical History 
  
  
  
  
  
INTERMACS Profile at time of 
implant 
x 
  
  
  
  
Coronary artery disease 
x 
  
  
  
  
Arrhythmia: atrial/ventricular; 
Afib (yes/no) 
x 
  
  
  
  
Ventricular pacing 
x 
  
  
  
  
Cancer 
x 
  
  
  
  
ICD 
x 
  
  
  
  
Stents, location 
x 
  
  
  
  
Myocardial infarction 
x 
  
  
  
  
Diabetes 
x 
  
  
  
  
Smoking history 
x 
  
  
  
  
Diverticular disease or diagnosed 
AVMs 
x 
  
  
  
  
GI Ulcer 
x 
  
  
  
  
Significant carotid stenosis (or if 
last examination > 12 months 
old) 
x 
 
 
 
 
AEs since pump implant: 
x 
  
  
  
  
 
 
 
 
 
 
Enrollment Form 
x 
  
  
  
  
Date enrolled 
x 
  
  
  
  
Incl/excl criteria (yes/no) 
x 
  
  
  
  
Date of study therapy initiation  
x 
  
 
  
 
 
  
  
  
  
 


18 
 
 
Baseline 
At regular 
ambulatory 
visits 
Once 
a 
week 
Once 
a 
month 
At the 
time of 
the 
event 
 
 
 
 
 
 
Physical Exam 
  
  
  
  
 
Heart rate 
x 
  
  
  
x 
Height in cm 
x 
  
  
  
x 
Weight in kg 
x 
  
  
  
x 
BP_MEAN – Doppler 
x 
  
  
  
x 
Pump parameters (speed, flow, 
PI, power) 
x 
x 
 
 
x 
 
 
 
 
 
 
Laboratory tests 
  
  
  
  
 
Creatinine 
x 
x 
  
  
x 
Urea 
x 
x 
  
  
x 
Total Bilirubin 
x 
x 
  
  
x 
Hgb 
x 
x 
  
 
x 
Hct 
x 
x 
  
 
x 
WBC (leucocytes) 
x 
x 
  
 
x 
PLT 
x 
x 
  
 
x 
Verify-now test 
x 
x 
 
 
x 
INR 
x 
x 
 
 
x 
Fibrinogen 
x 
x 
  
 
x 
aPTT 
x 
x 
  
 
x 
LDH 
x 
x 
x1 
x 
x 
Plasma free hemoglobin 
x 
x 
  
 
x 
BNP (or NT Pro BNP) 
x 
x 
 
x 
x 
Anti Xa apixaban  
 
x3 
 
 
x 
 
 
 
 
 
 
Baseline diagnostics 
  
  
  
  
  
ECG (date, rhythm) 
x 
 x 
  
  
x 
Echocardiography 
x 
  
  
x2  
x 
Carotid ultrasound (if more than 
12 months since last 
examination ) 
x 
 
 
 
 
  
  
  
  
  
 
Implant information 
  
  
  
  
 
Date implanted 
x 
  
  
  
 
  
  
  
  
  
 
Follow-up  
  
  
  
  
 
Reoperation for 
bleeding/thrombosis? Date, 
reason 
 x 
  
 
 
x 
Date of initial discharge post 
LVAD implant  
x 
  
  
  
 


19 
 
  
Baseline 
At regular 
ambulatory 
visits 
Once 
a 
week 
Once 
a 
month 
At time 
of event 
 
 
 
 
 
 
Current anticoagulation regimen 
(date, medication, dosages) 
 x 
x 
 
 
x 
Re-hospitalization for 
thrombosis/other AE? Admission 
date, reason, treatment, 
discharge 
  
 
 
 
x 
 
 
 
 
 
 
HRAE  
  
  
 
 
x 
Onset date 
  
  
 
 
x 
Is event stroke, TIA, or device 
thrombosis 
  
  
 
 
x 
If stroke, is it ischemic or 
hemorrhagic? 
  
  
 
 
x 
If stroke, head CT examination 
  
  
 
 
x 
If device thrombosis: Hemolysis 
seen? Thrombolytics given? 
Increase in pump power? Pump 
replaced? Other clinical 
symptoms?  
  
  
 
 
x 
Collect laboratory tests listed 
above 
  
  
 
 
x 
Current anticoag/antiplt 
medications 
  
  
 
 
x 
Any change to anticoag/antiplt 
meds? If yes, what 
  
  
 
 
x 
Infection requiring antibx or + BC    
  
 
 
x 
Describe event and treatment 
  
  
 
 
x 
Resolution date 
  
  
 
 
x 
 
 
 
 
 
 
Other AE 
 
 
 
 
 
Onset date 
 
 
 
 
x 
Type of event 
 
 
 
 
x 
Examination incl. imaging 
methods 
 
 
 
 
x 
Laboratory tests 
 
 
 
 
x 
Rehospitalisation/reoperation 
 
 
 
 
x 
Treatment 
 
 
 
 
x 
 
 
 
 
 
 
Outcome  
  
  
 
  
  
Date 
  
  
 
 
x 


20 
 
  
Baseline 
At regular 
ambulatory 
visits 
Once 
a 
week 
Once 
a 
month 
At time 
of event 
Type of outcome (expired, 
explanted, transplanted) 
  
  
 
 
x 
If expired, cause of death 
  
  
 
 
x 
1 LDH assessment once a week for 4 weeks, then once every 2 weeks for the next month 
and monthly thereafter 
2 ECHO follow–up will be performed at baseline, at 1 month and at 3 months, followed by 
periodical 6-monthly examinations 
3 Performed at 4 weeks visit after the anticoagulation transition in patient on apixaban 
only 
 
 


21 
 
 Appendix IV: Therapeutic efficacy adjustments and safety monitoring 
 
 Advanced Pump Thrombosis Monitoring Protocol 
• Monitor LDH at baseline and after initiation of determined antithrombotic 
therapy based on randomization algorithm once a week during first 4 weeks, 
then once every 2 weeks for the next month and monthly after that 
• If LDH rises more than 1.2x baseline: 
o repeat LDH within the next 1-3 business days 
o monitor plasma free hemoglobin (pf-Hb) and haptoglobin if available; and 
total bilirubin  
o complete evaluation with the team to rule out other reasons for LDH rise 
o echocardiogram to evaluate for aortic insufficiency  
o prompt study team to review within 48 hours 
o retrospective data log files analysis (particularly rotor noise and rotor 
displacement trends) followed by prospective analysis 2 weeks post event 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


22 
 
Appendix V: Apixaban effect reversal protocol 
In case of need of reversal of the effect of apixaban, following protocol will be executed.