Randomized Controlled Trial of Extended-Duration Low-Intensity Apixaban to Prevent Recurrence in High-Risk Patients With Provoked Venous Thromboembolism
Phase: PHASE4
Conditions: Deep Vein Thrombosis, Pulmonary Embolism, Venous Thromboembolism
Sponsor: Brigham and Women's Hospital

 
 
 
 
 
 
 
 
 
 
*Please note: there is only one version of the SAP. No amendments or changes were 
made. 
 

 
 
 
 
Randomized Controlled Trial of Extended-Duration Low-
Dose Apixaban to Prevent Recurrence in High-Risk 
Patients with Provoked Venous Thromboembolism  
(HI-PRO Trial) 
 
Original protocol 
BMS Protocol #: CV185-745 
Protocol Version Date: 8/3/20 
 
 
 
 
 
 
 
 
 
Sponsor:  
Gregory Piazza, MD, MS 
 
Cardiovascular Division 
75 Francis Street 
Boston, MA 02115 
(617) 732-6984 (Phone) 
(617) 738-7652 (Fax) 
gpiazza@partners.org 
 
 
 

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Table of Contents
 
Protocol Summary ...................................................................................................................... 3 
Study Flow Diagram ................................................................................................................... 4 
Study Subject Contact Calendar: ................................................................................................ 5 
Abbreviations and Definitions .................................................................................................... 6 
Study Contacts ............................................................................................................................ 8 
Specific Aims ............................................................................................................................ 11 
Introduction and Background ................................................................................................... 13 
Rationale for the Proposed Study and Trial Design .................................................................. 15 
Study Objectives ....................................................................................................................... 19 
Study Design ............................................................................................................................. 19 
Study Duration .......................................................................................................................... 19 
Study Population ....................................................................................................................... 19 
Study Inclusion Criteria ............................................................................................................ 20 
Study Exclusion Criteria ........................................................................................................... 21 
Screening Procedures ................................................................................................................ 24 
Treatment Description .............................................................................................................. 25 
Safety Outcomes ....................................................................................................................... 26 
Efficacy Outcomes .................................................................................................................... 26 
Drug Accountability.................................................................................................................. 28 
Follow-Up ................................................................................................................................. 29 
Safety Monitor .......................................................................................................................... 30 
Assessment and Reporting of Adverse Events ......................................................................... 30 
Data Reporting, Processing, and Quality Control ..................................................................... 40 
Monitoring Plan ........................................................................................................................ 41 
Statistical Methods .................................................................................................................... 49 
Interim Analysis ........................................................................................................................ 55 
Investigator Responsibilities ..................................................................................................... 56 
Feasibility .................................................................................................................................. 57 
Potential Risks and Benefits ..................................................................................................... 60 
Ethical Considerations .............................................................................................................. 63 
References ................................................................................................................................. 64 
Case Report Form ..................................................................................................................... 70 
Appendix ................................................................................................................................... 85 

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Protocol Summary 
 
Title: Randomized Controlled Trial of Extended-Duration Low-Dose Apixaban to 
Prevent Recurrence in High-Risk Patients with Provoked Venous Thromboembolism 
(HI-PRO Trial) 
 
 
Design: U.S.-based, single-center, randomized placebo-controlled trial. 
 
Brief Treatment Description: Low-dose apixaban (2.5mg twice daily) for extended-
duration secondary prevention of VTE after initial treatment for provoked VTE. 
 
 
Purpose: To establish the safety and efficacy of low-dose apixaban versus placebo 
for extended prevention of recurrence after provoked VTE in patients with at least 
one persistent provoking factor.  
 
 
Population: Outpatients with provoked VTE with at least one persistent provoking 
factor. 
 
 
Enrollment: 600 subjects  
 
Randomization: 1:1 
 
 
Clinical Site Locations: 1 center (
   
 
 
Study Duration: 36 months; enrollment period of up to 20 months with 12-month 
follow-up. 
 
 
Primary Safety and Efficacy Outcomes: 
 
 
Primary Safety Outcome: International Society on Thrombosis and Haemostasis 
(ISTH) major bleeding at 12 months. 
 
Primary Efficacy Outcome: Symptomatic, recurrent VTE, defined as the composite 
of deep vein thrombosis and/or pulmonary embolism at 12 months.  
 
Secondary Safety Outcome:  ISTH clinically relevant non-major bleeding at 12 
months. 
 
Secondary Efficacy Outcome: The composite of death due to cardiovascular 
cause, nonfatal myocardial infarction, stroke or systemic embolism, critical limb 
ischemia, or coronary or peripheral ischemia requiring revascularization (major 
adverse cardiovascular events, including major adverse limb events) at 12 months. 
 

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Follow-Up: Follow-up will consist of Electronic Health Record (EHR) review at 12-
months from study enrollment. 
 
Interim Analysis: An interim analysis for the primary safety and efficacy outcomes 
will be performed when 300 subjects have completed 12-month follow-up. 
 
Study Flow Diagram 
 
 
 
DVT, deep vein thrombosis; PE, pulmonary embolism; VTE, venous 
thromboembolism 
 
Figure 1.  Study flow-diagram for a single-center, randomized placebo-controlled trial 
of extended low-intensity apixaban for high-risk provoked VTE. 
 
 
 
 
 
 
 

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Study Subject Contact Calendar:
 
Date  
Event  
Study Drug  
Enrollment (Month 0) 
Subject will be consented 
by study physician and 
randomized through the 
Investigational Drug 
Service computer 
randomization program.  
3 months of study drug 
(apixaban or placebo) will 
be given during this visit 
or sent to subject within 2 
business days of the 
enrollment visit via mail or 
courier.  
Month 3  
Study nurse check-in  
First 3 months drug 
containers and unused 
drug collected via mail 
and returned to pharmacy 
for proper disposal, 3 
of medication will be given 
or sent to subject.   
Month 6  
Study nurse check-in 
Drug containers and 
unused drug collected via 
mail and returned to 
pharmacy for proper 
disposal, 3 additional 
medication will be given 
or sent to subject.   
Month 9  
Study nurse check-in 
Drug containers and 
unused drug collected via 
mail returned to pharmacy 
for proper disposal, 3 
of medication will be given 
or sent to subject.   
Month 12  
End-of-treatment visit 
All remaining medications, 
drug containers, and 12-
month drug diary will be 
collected. 
 
 
 
 
 
 
 

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Abbreviations and Definitions
 
Listed in alphabetical order 
 
ACCP, American College of Chest Physicians 
 
ALI, acute limb ischemia 
 
ALT, alanine transaminase 
 
AST, aspartate aminotransferase 
 
BMI, body mass index 
 
BMS, Bristol-Myers Squibb 
 
BWH, Brigham and 
 
 
CEC, clinical endpoints committee 
 
CI, confidence interval 
 
CLI, critical limb ischemia 
 
COPD, chronic obstructive pulmonary disease 
 
CrCl, creatinine clearance 
 
CT, computed tomography 
 
cTn, cardiac troponin 
 
DOAC, direct oral anticoagulant  
 
 
 
DSMB, Data Safety Monitoring Board 
 
DVT, deep vein thrombosis 
 
eCRF, electronic case report form 
 
FDA, food and drug administration 
 
FSH, follicle stimulating hormone 
 

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GPV&E, Global Pharmacovigilance & Epidemiology
 
HCG, human chorionic gonadotropin 
 
HRT, hormone replacement therapy 
 
IND, investigational new drug 
 
INR, international normalized ratio 
 
IRB, institutional review board 
 
ISTH, International Society on Thrombosis and Haemostasis 
 
IUD, intrauterine device 
 
LMWH, low-molecular weight heparin 
 
MI, myocardial infarction 
 
MR, magnetic resonance 
 
NOACs, non-vitamin K oral anticoagulants 
 
NSAID, nonsteroidal anti-inflammatory drug 
 
PCC, prothrombin complex concentrate 
 
PE, pulmonary embolism 
 
PI, Proteasome inhibitors 
 
REDCap, Research electronic data capture 
 
SAE, significant adverse event 
 
TRG, thrombosis research group 
 
UADE, unanticipated adverse drug effect  
 
UFH, unfractionated heparin 
 
U.S., United States 
 
VTE, venous thromboembolism 
 

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Study Contacts
 
Study Principal 
Investigator: 
 
Gregory Piazza, MD, MS 
 
75 Francis Street  
Boston MA  02115 
Phone: (617) 732-6984 
Fax: (617) 738-7652 
Email: gpiazza@bwh.harvard.edu 
 
Study Co-Principal 
Investigator: 
 
Samuel Z. Goldhaber, MD 
 
75 Francis Street  
Boston MA  02115 
Phone: 857-307-1932 
Fax: (857) 307-1955 
Email: sgoldhaber@bwh.harvard.edu   
 
Study Co-
Investigator 
Umberto Campia, MD 
 
75 Francis Street  
Boston MA  02115 
Phone: (617) 732-6984 
Fax: (617) 738-7652 
Email: ucampia@bwh.harvard.edu 
 
Jean M. Connors, MD 
 
75 Francis Street  
Boston MA  02115 
Phone: (617) 525-9337 
Fax: 617-264-6388 
Email: jconnors@bwh.harvard.edu 
  
Research Nurse 
Ruth Morrison, RN 
Hospital 
75 Francis Street  
Boston MA  02115 
Phone: (617) 732-6984 
Fax: (617) 738-7652 
Email: rmorrison@bwh.harvard.edu  
 
Research Assistant 
Julia E. Snyder, BS 
 
75 Francis Street  
Boston MA  02115 

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Phone: (617) 732-6984
Fax: (617) 738-7652 
Email: jesnyder@bwh.harvard.edu  
 
Research 
Pharmacist 
John Fanikos, RPh, MBA 
 
75 Francis St. 
 
Boston, MA 02115 
Phone: (617) 605-3237 
 
Email: jfanikos@bwh.harvard.edu 
 
Data Safety and 
Monitoring Board 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Safety 
Monitor 
Brett Carroll, MD (Chair) 
Beth Israel Deaconess Medical Center 
185 Pilgrim Rd. 
Boston, MA 02215 
Phone: (978) 944-2142 
Email: bcarrol2@bidmc.harvard.edu 
 
Alexander J. Blood, MD 
 
75 Francis St. 
 
Boston, MA 02115 
Phone: (617)-732-7144 
Email: ablood@bwh.harvard.edu 
 
Shelley Hurwitz, PhD (Biostatistician) 
 
75 Francis St. 
 
Boston, MA 02115 
Phone: (617) 584-2943 
Email: Hurwitz@hms.harvard.edu 
 
 
Arvind Pandey, MD 
 
75 Francis St. 
 
Boston, MA 02115 
Phone: (504)-875-5740 
Pager: 34304 
Email: apandey5@bwh.harvard.edu 
 
 
Clinical Endpoints 
Committee 
Laurel Lee, MD 
 
75 Francis St. 
 
Boston, MA 02115 
Phone: (617)-732-5500 

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Pager: 32682
Email: lylee@bwh.harvard.edu 
 
Zaid Almarzooq, MD 
 
75 Francis St. 
 
Boston, MA 02115 
Phone: (617)-732-5500 
Pager: 34290 
Email: zalmarzooq@bwh.harvard.edu 
 
Behnood Bikdeli, MD 
 
75 Francis Street  
Boston MA  02115 
Phone: (617) 732-6984 
Fax: (617) 738-7652 
Email: bbikdeli@bwh.harvard.edu 
 
 
 
 
 
 
 
 
 
 
 
 

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Specific Aims
 
Provoked VTE is traditionally considered a transient acute disorder requiring a limited 
duration of anticoagulant therapy.  Patients who suffer deep vein thrombosis (DVT) or 
pulmonary embolism (PE) following major surgery, major trauma, or periods of 
immobility are generally treated with time-limited anticoagulation for 3 months.  
However, provoked VTE patients have recently been recognized as a heterogeneous 
population comprised of those with transient provoking and persistent provoking risk 
factors (1).  Common risk factors in provoked VTE such as obesity, immobility, 
atherosclerotic cardiovascular disease, heart failure, chronic lung disease, chronic 
kidney disease, and inflammatory disorders frequently contribute to an enduring 
rather than transient risk.   
 
Data from 4,553 patients in the EINSTEIN CHOICE trial and the EINSTEIN VTE 
Continued Treatment Study demonstrate that provoked VTE patients with persistent 
provoking factors have a reduction in recurrence with extended duration 
anticoagulation compared with low-dose aspirin or placebo (1.5% vs. 4.9%) (2,3).  
Common persistent provoking factors included immobility, obesity, heart failure, and 
prevalent, persistent provoking factors are rarely considered when stopping 
anticoagulation in patients with provoked VTE who have completed the typical 3- to 
6-month duration of therapy.  The 2016 American College of Chest Physicians 
(ACCP) Guidelines on Antithrombotic Therapy for VTE do not distinguish between 
transient and persistent provoking risk factors and recommend limited-duration 
anticoagulation for provoked events (4). 
 
However, an emerging opinion is that optimal duration of anticoagulation in provoked 
VTE patients should be determined based on data from the extended duration 
rivaroxaban trials (5).  Such a strategy breaks from the tradition of dichotomizing VTE 
as provoked or unprovoked.  Rather, persisting risk factors such as heart failure, 
obesity, family history of VTE, acquired or hereditary thrombophilia, and 
immobilization are incorporated into the decision-making process for pathways 
focused on secondary prevention.  A suitable long-term strategy for secondary 
prevention has been recommended in evidence-based clinical practice guidelines for 
patients with unprovoked VTE (4).  Extended-duration anticoagulation with warfarin or 
the direct oral anticoagulants (DOACs) is validated and recommended for prevention 
of recurrent unprovoked VTE in patients with a low-risk of bleeding (6).  In a landmark 
extension trial of patients with unprovoked VTE, the AMPLIFY-EXT trial compared 
two doses of apixaban (2.5 mg and 5 mg, twice daily) with placebo in 2486 patients 
with VTE who had completed 6 to 12 months of anticoagulation therapy and for 
whom there was clinical equipoise regarding the need for extended-duration 
anticoagulant therapy for secondary prevention (7).  Symptomatic recurrent VTE or 
death from VTE occurred in 73 of the 829 patients (8.8%) who were receiving 
placebo versus 14 of the 840 patients (1.7%) who were receiving 2.5 mg of apixaban 
and 14 of the 813 patients (1.7%) who were receiving 5 mg of apixaban (p<0.001 for 
both comparisons). In Kaplan-Meier analysis, the apixaban 2.5 mg twice daily 

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regimen demonstrated a major and clinically-relevant nonmajor bleeding rate similar
to that of placebo.   
 
Based on the emerging evidence that provoked VTE patients may require extended-
duration anticoagulation for secondary prevention, the apixaban 2.5 mg twice daily 
dose could be a critical addition to our armamentarium in those at high risk for 
recurrence at the transition of care from the acute to the chronic treatment phase.  
However, this hypothesis needs to be tested in a randomized clinical trial.  We 
propose a single-center, randomized placebo-controlled trial conducted at Brigham 
BWH) to evaluate the impact of low-dose apixaban (2.5 mg 
twice daily) in a study population exclusively comprised of provoked VTE patients 
with at least one persistent provoking factor.  We have the following study aims: 
 
Specific Aim #1: To compare the 12-month rate of recurrent symptomatic VTE in 
patients with provoked VTE and at least one persistent provoking factor who are 
randomized to either apixaban (2.5 mg orally twice daily) as monotherapy or placebo 
after completing at least 3 months of therapeutic anticoagulation and who have a low 
risk of bleeding. 
 
Hypothesis #1: Compared with placebo, oral apixaban (2.5 mg twice daily) will 
reduce the 12-month rate of symptomatic VTE in patients with provoked VTE and at 
least one persistent provoking factor who have completed at least 3 months of 
therapeutic anticoagulation and who have a low risk of bleeding. 
 
Specific Aim #2: To compare the 12-month rate of ISTH major bleeding in patients 
with provoked VTE and at least one persistent provoking factor who are randomized 
to either apixaban (2.5 mg orally twice daily) as monotherapy or placebo after 
completing at least 3 months of therapeutic anticoagulation and who have a low risk 
of bleeding. 
 
Hypothesis #2: Compared with placebo, oral apixaban (2.5 mg twice daily) will be 
associated with a similar rate of ISTH major bleeding at 12 months in patients with 
provoked VTE and at least one persistent provoking factor who are randomized to 
either apixaban (2.5 mg orally twice daily) as monotherapy or placebo after 
completing at least 3 months of therapeutic anticoagulation and who have a low risk 
of bleeding. 
 
 
 
 
 
 
 
 

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Introduction and Background
 
Provoked venous thromboembolism (VTE) is traditionally considered a transient 
acute disorder requiring a limited duration of anticoagulant therapy.  Patients who 
suffer deep vein thrombosis (DVT) or pulmonary embolism (PE) following major 
surgery, major trauma, or periods of immobility are generally treated with time-limited 
anticoagulation for 3 months.  However, provoked VTE patients have recently been 
recognized as a heterogeneous population comprised of those with transient 
provoking and persistent provoking risk factors (1).  Common risk factors in provoked 
VTE such as obesity, immobility, atherosclerotic cardiovascular disease, heart failure, 
chronic lung disease, chronic kidney disease, and inflammatory disorders frequently 
contribute to an enduring rather than transient risk.  Furthermore, epidemiological 
studies (8,9) and the randomized clinical trial EINSTEIN CHOICE (3) suggest that 
VTE is best characterized as a chronic disorder with periodic relapses.  A landmark 
Danish National Registry analysis demonstrated that patients who suffer provoked or 
unprovoked VTE have an increased risk of recurrence over the ensuing 30 years and 
that recurrent PE causes increased mortality (10).  While the rate of VTE recurrence 
ranges 30-50% over 10 years for unprovoked VTE (also termed idiopathic; 
unprovoked implies that an immediate trigger for the VTE cannot be identified), 
recurrent events occur in about 20% of patients over 10 years after a provoked event 
(provoked VTE is defined as post-operative, post-major trauma, post-hospitalization, 
or related to pregnancy, hormonal contraception/replacement therapy, or immobility) 
(11 13).  Based on these data, provoked VTE patients represent a population 
vulnerable to VTE recurrence, especially at the transition of care from the initial 
(acute) treatment phase to the chronic treatment phase, at which point 
anticoagulation is discontinued in most of these patients.   
 
The EINSTEIN CHOICE trial recently evaluated the safety and efficacy of regimens 
of full- or lower-intensity anticoagulant therapy versus low-dose aspirin for secondary 
prevention of VTE after an initial provoked or unprovoked event (2).  The EINSTEIN 
CHOICE Investigators randomly assigned 3396 patients with VTE to receive either 
once-daily rivaroxaban (at doses of 20 mg or 10 mg) or 100 mg of aspirin.  Prior to 
enrollment in EINSTEIN CHOICE, all study patients completed 6 to 12 months of 
anticoagulation therapy, and their providers were in equipoise regarding the need for 
extended anticoagulation.  Approximately 60% of patients in EINSTEIN CHOICE had 
suffered provoked VTE.  Symptomatic recurrent VTE occurred in 17 of 1107 patients 
(1.5%) receiving 20 mg of rivaroxaban and in 13 of 1127 patients (1.2%) receiving 10 
mg of rivaroxaban, and in 50 of 1131 patients (4.4%) receiving low-dose aspirin 
(hazard ratio for 20 mg of rivaroxaban vs. aspirin, 0.34; 95% confidence interval [CI], 
0.20 to 0.59; hazard ratio for 10 mg of rivaroxaban vs. aspirin, 0.26; 95% CI, 0.14 to 
0.47; P<0.001 for both comparisons).  Rates of major bleeding were similar (0.5% in 
the group receiving 20 mg of rivaroxaban, 0.4% in the group receiving 10 mg of 
rivaroxaban, and 0.3% in the low-dose aspirin group) (2).   
 
Data from 4,553 patients in EINSTEIN CHOICE and the EINSTEIN VTE Continued 
Treatment Study demonstrate that provoked VTE patients with persistent provoking 

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factors have a reduction in recurrence with extended duration anticoagulation 
compared with low-dose aspirin or placebo (1.5% vs. 4.9%) (2,3).  Common 
persistent provoking factors included immobility, obesity, heart failure, and chronic 
 and rheumatoid arthritis.  Despite 
being highly prevalent, persistent provoking factors are rarely considered when 
stopping anticoagulation in patients with provoked VTE who have completed the 
typical 3- to 6-month duration of therapy.  The 2016 American College of Chest 
Physicians (ACCP) Guidelines on Antithrombotic Therapy for VTE do not distinguish 
between transient and persistent provoking risk factors and recommend limited-
duration anticoagulation for provoked events (4). 
 
However, an emerging opinion is that optimal duration of anticoagulation in provoked 
VTE patients should be determined based on data from the extended duration 
rivaroxaban trials (5).  Such a strategy breaks from the tradition of dichotomizing VTE 
as provoked or unprovoked.  Rather, persisting risk factors such as heart failure, 
obesity, family history of VTE, acquired or hereditary thrombophilia, and 
immobilization are incorporated into the decision-making process for pathways 
focused on secondary prevention. 
 
A suitable long-term strategy for secondary prevention has been recommended in 
evidence-based clinical practice guidelines for patients with unprovoked VTE (4).  
Extended-duration anticoagulation with warfarin or the direct oral anticoagulants 
(DOACs) is validated and recommended for prevention of recurrent unprovoked VTE 
in patients with a low-risk of bleeding (6).  However, current evidence-based clinical 
practice guidelines are inadequate for secondary prevention in patients with provoked 
VTE based on several extended-duration anticoagulation trials that included patients 
with provoked and unprovoked VTE.  In a randomized controlled trial of rivaroxaban 
for extended-duration secondary prevention in patients with either provoked (26%) or 
unprovoked (74%) DVT, recurrent VTE occurred in 8 patients (1.3%) in the 
rivaroxaban group compared with 42 patients (7.1%) in the placebo group (hazard 
ratio, 0.18; 95% CI, 0.09 to 0.39; P<0.001, relative risk reduction, 82%) (3).   
 
In a landmark extension trial of patients with unprovoked VTE, the AMPLIFY-EXT trial 
compared two doses of apixaban (2.5 mg and 5 mg, twice daily) with placebo in 2486 
patients with VTE who had completed 6 to 12 months of anticoagulation therapy and 
for whom there was clinical equipoise regarding the need for extended-duration 
anticoagulant therapy for secondary prevention (7).  Symptomatic recurrent VTE or 
death from VTE occurred in 73 of the 829 patients (8.8%) who were receiving 
placebo versus 14 of the 840 patients (1.7%) who were receiving 2.5 mg of apixaban 
and 14 of the 813 patients (1.7%) who were receiving 5 mg of apixaban (p<0.001 for 
both comparisons). In Kaplan-Meier analysis, the apixaban 2.5 mg twice daily 
regimen demonstrated a major and clinically-relevant nonmajor bleeding rate similar 
to that of placebo.  While approximately 9% of the patients in the AMPLIFY-EXT trial 
had transient or reversible risk factors for VTE, the provoked VTE population only 
accounted for approximately 200 patients and precluded a well-powered analysis.  
Furthermore, the intent of the AMPLIFY-EXT trial was to study unprovoked VTE (7).  

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Finally, the HI-PRO trial is evaluating a more complex aspect of VTE secondary 
prevention.  Rather than using the simple dichotomized view of VTE as provoked or 
unprovoked, HI-PRO is focusing on how the risk of recurrence in patients with 
persisting provoking factors may be modulated by low-dose apixaban.  The 
foundation of this question is based on the current direction in which the field of VTE 
is moving (5) and supported by the more pathophysiologically-sound ISTH 
classification of risk factors (1). 
 
Apixaban 2.5 mg twice daily may have additional advantages for extended-duration 
secondary prevention of VTE compared with rivaroxaban 10 mg daily (which has U.S. 
FDA approval for extended-duration therapy).  Apixaban is a more 
pharmacokinetically rational regimen, given the half-life of these two DOACs.  In trials 
of stroke prevention of atrial fibrillation, apixaban demonstrated a relatively lower 
frequency of gastrointestinal bleeding compared with warfarin (14 17).  Apixaban has 
fewer off-target side effects than rivaroxaban, which can cause severe headache 
(necessitating urgent head CT) and severe rash.   
 
Based on the emerging evidence that provoked VTE patients may require extended-
duration anticoagulation for secondary prevention, the apixaban 2.5 mg twice daily 
dose could be a critical addition to our armamentarium in those at high risk for 
recurrence at the transition of care from the acute to the chronic treatment phase.  
However, this hypothesis needs to be tested in a clinical trial.  We propose a single-
(BWH) to evaluate the feasibility of low-dose apixaban (2.5 mg twice daily) in a study 
population exclusively comprised of provoked VTE patients with persistently 
provoking risk factors for VTE. 
 
 
Rationale for the Proposed Study and Trial Design 
 
The rationale for the study design is focused on the lack of data on the safety and 
efficacy of extended-duration low-dose apixaban for secondary prevention in patients 
with provoked VTE.  A single-center, randomized placebo-controlled trial of extended 
low-intensity apixaban with a study population enriched for recurrent VTE event rates 
will be able to provide such data.   
 
The rationale for a single-center study is that Watkins Cardiovascular Clinic at BWH 
is a Center of Excellence for thrombosis care not only in the New England region but 
also along the East coast.  The BWH Thrombosis Center evaluates an average of 
1200 new and follow-up outpatients with VTE per year.  In addition, the Vascular 
Medicine Section at BWH includes 4 additional full-time faculty and 4 full-time 
Vascular Medicine fellows who also see a high volume of VTE patients.  Accordingly, 
enrollment of 600 patients meeting the entry criteria and none of the exclusion criteria 
will be accomplished efficiently at our single center. 
 

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The rationale behind using a low-dose of apixaban is three-fold.  First, low-dose 
rivaroxaban 10 mg orally daily was effective and safe in the EINSTEIN CHOICE trial 
(2) for extended-duration anticoagulation in secondary prevention after unprovoked 
VTE.  Second, AMPLIFY-EXT demonstrated efficacy and enhanced safety to a low-
dose apixaban regimen (2.5 mg orally twice daily) for extended-duration 
anticoagulation in secondary prevention after predominantly unprovoked VTE (7).  
Finally, because the relative risk of recurrence is less (although still unacceptably 
high) for provoked VTE than unprovoked VTE, a lower dose of apixaban may 
maintain efficacy while offering a reduction in the risk of major and clinically-relevant 
non-major bleeding. 
 
The rationale for using low-dose apixaban in a study population that will include 
obese patients is that an analysis of the AMPLIFY-EXT data by weight demonstrated 
results for the primary efficacy outcome and the composite outcome of major and 
clinically relevant nonmajor bleeding were consistent with overall study results (7). 
 
The rationale for using a placebo-control is that current evidence-based guidelines do 
not recommend any extended thromboprophylactic measures after provoked VTE.  
Trials of low-dose aspirin for secondary prevention of VTE have largely focused on 
unprovoked VTE or a mixed population of unprovoked and provoked VTE.  In the 
EINSTEIN CHOICE trial, low-dose aspirin was associated with a bleeding risk similar 
to anticoagulation with rivaroxaban and a recurrent VTE rate 70% higher than 
anticoagulation with rivaroxaban (2). 
 
aspirin is based on several factors.  First, the HI-PRO trial will include atherosclerotic 
cardiovascular disease, which will enrich the study population in VTE events because 
of the strong pathophysiological link between the two (18 21).  Many of these 
patients will be receiving low-
eligible patients will be receiving low-
cardiovascular events.  Excluding these patients would significantly hinder 
enrollment.  Finally, none of the major landmark trials of low-intensity apixaban (2.5 
mg twice daily) excluded patients taking low-
-EXT 
and ADOPT allowed up to 165 mg of aspirin daily (7,22).   
 
Atherosclerosis is associated with an increased risk of VTE.  A link between 
atherosclerotic cardiovascular disease and VTE was first suggested by Prandoni and 
colleagues, who observed that the presence of carotid plaque was associated with a 
doubling in VTE risk (23).  Many risk factors for VTE, such as obesity, hypertension, 
dyslipidemia, diabetes, and smoking, overlap with those for atherosclerosis (21,24).  
The link between VTE and atherosclerotic cardiovascular disease also appears to be 
reciprocal.  A recent analysis of TRA2P-TIMI 50 (Thrombin Receptor Antagonist in 
Secondary Prevention of Atherothrombotic Ischemic Events-Thrombolysis in 
Myocardial Infarction) and PEGASUS-TIMI 54 (Prevention of Cardiovascular Events 
in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a 
Background of Aspirin-Thrombolysis in Myocardial Infarction 54) demonstrated the 

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risk of VTE increased with the number of symptomatic vascular territories affected by 
atherosclerosis (18).  A recent editorial in Circulation called for medicine to abandon 
the dichotomized view of VTE as provoked or unprovoked and called for the basis of 
the optimal duration of anticoagulation to be determined by persisting risk factors, 
including cardiovascular disease (5).  Because of the potential for a majority of 
patients in the study to have atherosclerotic cardiovascular disease limiting the 
generalizability of the results, up to 35% in each study group may have 
atherosclerotic cardiovascular disease as a qualifying persistent risk factor. 
 
The rationale for enrollment at 3-months is derived from the 2016 American College 
of Chest Physicians (ACCP) evidence-based clinical practice document entitled 
with proximal DVT or pulmonary embolism (PE), we recommend 
long-
(Kearon C, Akl EA, Ornelas J, et al. Antithrombotic Therapy for VTE Disease: CHEST 
Guideline and Expert Panel Report. Chest 2016;149:315-52).  This statement 
supports the 3-month timepoint as an appropriate juncture to determine whether 
extended duration anticoagulation or discontinuation of antithrombotic therapy is 
appropriate. 
 
The 2016 ACCP evidence-based clinical practice guidelines rely upon a more 
traditional classification for determining the risk of VTE recurrence after 3 months, a 
that has subsequently fallen out of favor.  The 2016 ACCP guidance document states 
the following regarding extended-duration antithrombotic therapy for prevention of 
recurrent VTE: 
 
recommend treatment with anticoagulation for 3 months over (i) treatment of a 
shorter period (Grade 1B), (ii) treatment of a longer time-limited period (eg, 6, 12, or 
24 months) (Grade 1B), or (iii) extended therapy (no scheduled stop date) (Grade 
1B). 
 
In patients with a proximal DVT of the leg or PE provoked by a nonsurgical transient 
risk factor, we recommend treatment with anticoagulation for 3 months over (i) 
treatment of a shorter period (Grade 1B) and (ii) treatment of a longer time-limited 
period (eg, 6, 12, or 24 months) (Grade 1B). We suggest treatment with 
anticoagulation for 3 months over extended therapy if there is a low or moderate 
bleeding risk (Grade 2B), and recommend treatment for 3 months over extended 
therapy if there is a high risk of 
 
 
These guidelines fail to address the large population of patients with VTE who may 
have had a provoking factor but also have enduring risk factors for recurrence, such 
as those with persistent immobility, obesity, heart failure, chronic lung disease, 
chronic kidney disease, chronic inflammatory/autoimmune disorder, and 
atherosclerotic cardiovascular disease (Albertsen IE, Piazza G, Goldhaber SZ. Let's 

HI-PRO Trial    
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18 
 
Stop Dichotomizing Venous Thromboembolism as Provoked or Unprovoked. 
Circulation. 2018 Dec 4;138(23):2591-2593 and Albertsen IE, Piazza G, Søgaard M, 
Nielsen PB, Larsen TB. Extended oral anticoagulation after incident venous 
thromboembolism - a paradigm shift? Expert Rev Cardiovasc Ther. 2020 
Apr;18(4):201-208).   
 
More recently, the 2019 European Society of Cardiology Guidelines for the Diagnosis 
and Management of Acute Pulmonary Embolism, developed in collaboration with the 
European Respiratory Society (ERS), have recognized the importance of identifying 
persistent, or enduring, risk factors for VTE recurrence (Konstantinides SV, Meyer G, 
Becattini C, et al. 2019 ESC Guidelines for the diagnosis and management of acute 
pulmonary embolism developed in collaboration with the European Respiratory 
Society (ERS). Eur Heart J 2019).  This paradigm shift away from the previous 
endorsed by the International Society on Thrombosis and Haemostasis (ISTH), which 
recommends that clinicians consider persistent predisposing factors when 
determining whether to extend anticoagulation beyond 3 months (Kearon, C, Ageno, 
W, Cannegieter, SC, Cosmi, B, Geersing, G J and Kyrle, PA, for the Subcommittees 
on Control of Anticoagulation, and Predictive and Diagnostic Variables in Thrombotic 
Disease. Categorization of patients as having provoked or unprovoked venous 
thromboembolism: guidance from the SSC of ISTH. J Thromb Haemost 2016; 14: 
1480-3). 
 
Accordingly, the 2019 European Society of Cardiology Guidelines state that the 
decision to pursue extended-duration anticoagulation should rest upon recognition of 
both transient risk factors for VTE but also the presence of persistent, or enduring, 
conditions that result in a prolonged risk of VTE recurrence after an initial event.  
These include chronic medical disorders like inflammatory bowel disease, connective 
tissue disease, and other hypercoagulable states.  Rather than dichotomizing VTE 
patients in
Guidelines recommend assessment of persistent predisposing factors and an 
estimated long-term recurrence risk (if anticoagulation is discontinued after 3 
months).  The Guidelines suggest that only patients with an estimated recurrence risk 
of less than 3% per year should receive time-limited treatment (see figure below).  
Patients with greater than 8% risk of recurrence per year (for example, those with 
cancer-related VTE) are mandated to receive indefinite duration anticoagulation.  
There is clinical and research equipoise for the patient population that has an 
intermediate risk for recurrence (3-8% risk of recurrence per year). 
 
The inclusion and exclusion criteria for the current study follows the evidence-based 
clinical practice guideline recommendations from the ESC and ISTH and identify a 
population of patients with VTE who have a 3-8% of VTE recurrence per year.  We 
have estimated a 12-month VTE recurrence rate of 6% in our proposed study 
population, exactly within this range of clinical and research equipoise. 
 

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Study Objectives
 
Primary Safety Objective: To quantitatively assess the International Society on 
Thrombosis and Haemostasis (ISTH) major bleeding at 12 months. 
 
Primary Efficacy Objective: To quantitatively assess the 12-month rate of 
symptomatic, recurrent VTE, defined as the composite of deep vein thrombosis 
and/or pulmonary embolism.  
 
 
Secondary Safety Objective: To quantitatively assess the 12-month rate of ISTH 
clinically relevant non-major bleeding. 
 
Secondary Efficacy Objective: To quantitatively assess the composite of death due 
to cardiovascular cause, nonfatal myocardial infarction, stroke or systemic embolism, 
critical limb ischemia, or coronary or peripheral ischemia requiring revascularization 
(major adverse cardiovascular events, including major adverse limb events) at 12 
months. 
 
Study Design 
 
600-patient U.S.-based, single-center, randomized, double-blinded, placebo-
controlled study of apixaban 2.5 mg orally twice daily for extended prevention of 
recurrence after provoked VTE in patients with at least one persistent provoking 
factor who have completed at least 3 months of standard therapeutic anticoagulation 
and who have a low risk of bleeding. 
 
Study Duration 
 
The study will be completed in 36 months: 2 months for start-up (including Human 
Research Committee/Institutional Review Board [IRB] approval and finalizing the 
Case Report Form), 32 months for patient enrollment, follow-up, and data collection, 
and 2 months for data analysis and writing up the results (Table 1). 
 
Table 1.  Study timeline. 
Milestone 
Duration (months) 
Start-up 
2 
Patient enrollment 
20 
Completion of data collection 
12 
Data analysis and completion of study report 
2 
TOTAL 
36 
 
Study Population 
 

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Patients who are 18 years of age or older with provoked deep vein thrombosis and/or 
pulmonary embolism, have completed at least 3 months of therapeutic 
anticoagulation, have a low risk of bleeding, and have at least one persistent 
provoking risk factor. 
 
Low risk of bleeding is defined by several of the exclusion criteria: 
 have contraindications to antithrombotic or antiplatelet therapy  
 have a requirement for ongoing anticoagulant therapy, dual antiplatelet 
therapy, or aspirin at a dose of > 81 mg daily 
 have a hemoglobin level < 9 mg/dL, a platelet count < 100,000/mm3, a serum 
creatinine level > 2.5 mg/dL, an ALT or AST level > 2 times the upper limit of 
the normal range, or a total bilirubin level > 1.5 times the upper limit of the 
normal range 
 have history of bleeding diathesis or have had recent active bleeding 
 have active hepatobiliary disease 
 
In a recent propensity score-
-
diagnosed VTE patients in the Truven Health MarketScan commercial and Medicare 
Supplement claims databases in the U.S., apixaban compared with rivaroxaban was 
associated with an optimal balance of decreased risk of recurrent VTE (HR 0.37 [95% 
CI 0.24 0.55]; p<0·0001) and major bleeding events (0·54 [0·37 0·82]; p=0.0031) 
(25).  Based on these data, we believe that apixaban will provide superb efficacy and 
safety compared with placebo in the prespecified high-risk for VTE recurrence and 
low-risk for bleeding patient population of HI-PRO. 
 
Study Inclusion Criteria 
 
 Man or woman 
 Age  18 years 
 Objectively-confirmed DVT and/or PE 
 Treated for at least 3 months with standard therapeutic anticoagulant therapy  
 Has not suffered symptomatic recurrence during prior anticoagulant therapy 
 Outpatient follow-up at BWH 
 AND have at least one of the following persistent provoking VTE risk factors: 
o Persistent immobility (defined as paralysis, other inability to ambulate 
freely, bed-bound, wheelchair-bound) 
o 
 
o Heart failure (systolic, diastolic, or combined) 
o Chronic lung disease (COPD, asthma, interstitial lung disease) 
o Chronic kidney disease (eGFR <60 mL/min/1.73m2)  
o Chronic inflammatory/autoimmune disorder (inflammatory arthritis, 
vasculitis, inflammatory bowel disease, chronic infection) 
o Atherosclerotic cardiovascular disease (coronary, cerebrovascular, or 
peripheral artery disease) (up to 35% in each study group may have 

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atherosclerotic cardiovascular disease as a qualifying persistent risk 
factor) 
o NOTE:  Eligible patients will be allowed to have multiple risk factors, 
and there will not be a limit as to how many of the above risk factors a 
subject may have.  In addition, we will place no limit on the number of 
patients included with multiple risk factors.  A study population with 
multiple risk factors is highly representative of the provoked VTE 
population and will provide the greatest generalizability of the study 
results to real-world clinical practice.  Including patients with single and 
multiple persistent provoking risk factors will also facilitate enrollment.  
As noted, there is clinical and research equipoise regarding whether 
patients with a single or multiple persistent provoking VTE risk factors 
should receive extended duration thromboprophylaxis for secondary 
prevention.   
 Willing to provide written informed consent 
 
Study Exclusion Criteria 
 
 Women who are pregnant or breastfeeding 
 Women of child-bearing potential who are unwilling or unable to use an 
acceptable method of birth control (such as oral contraceptives, other 
hormonal contraceptives [vaginal products, skin patches, or implanted or 
injectable products], or mechanical products such as an intrauterine device or 
barrier methods [diaphragm, condoms, spermicides]) to avoid pregnancy for 
the entire study 
 Active cancer within the past 5 years 
 Contraindication to antithrombotic or antiplatelet therapy 
 Requirement for ongoing anticoagulant therapy, dual antiplatelet therapy, 
P2Y12 inhibition, or aspirin at a dose of > 81 mg daily 
 Hemoglobin level < 9 mg/dL, a platelet count < 100,000/mm3, a serum 
creatinine level > 2.5 mg/dL or CrCl <25 mL/minute (as determined by 
Cockcroft-Gault equation), an ALT or AST level > 2 times the upper limit of the 
normal range, or a total bilirubin level > 1.5 times the upper limit of the normal 
range 
 History of a platelet disorder such as Von Willebrand Disease  
 History of bleeding diathesis or have had recent active bleeding 
 Active severe hepatobiliary disease 
 More than 6 months that have elapsed without taking an anticoagulant or low-
dose aspirin 
o NOTE: The risk of recurrent VTE following cessation of anticoagulation 
rises slowly over the first 3-6 months (26).  After this initial period, the 
cumulative risk of recurrent VTE steepens.  Using a limit of no greater 
than 6 months of interruption in anticoagulation before potential re-
initiation of anticoagulation as part of this trial will safely facilitate 

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enrollment as opposed to restricting the population to no greater than 3 
months of interruption. 
 Known severe thrombophilia (any increased titer antiphospholipid antibody or 
positive lupus anticoagulant/DRVVT or deficiency of antithrombin, protein C, or 
protein S) which would indicate long-term full therapeutic anticoagulation with 
a vitamin K antagonist 
 Life expectancy < 12 months or hospice care 
 Prisoners or subjects who are involuntarily incarcerated 
 Subjects who are compulsorily detained for treatment of either a psychiatric or 
physical (e.g., infectious disease) illness 
 Receiving concurrent non-FDA-approved or investigational agents or has received an 
investigational agent within the past 30 days prior to the first dose of study treatment (with 
the exception of approved medications being used for an approved indication, e.g., 
investigating a new dosing regimen for an approved indication)  
 Any condition, which in the opinion of the investigator, would put the subject at 
an unacceptable risk from participating in the study 
 Any other medical, social, logistical, or psychological reason, which in the 
opinion of the investigator, would preclude compliance with, or successful 
completion of, the study protocol 
 History of a severe hypersensitivity reaction to apixaban 
 Required prescription of a medication that is contraindicated to be co-
administered with apixaban 
 
Enrollment of Women of Childbearing Potential and Partners 
 
 All of the following criteria must be met for women of childbearing potential and 
their partners:  Women of childbearing potential must have a negative serum 
or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of 
HCG) within 24 hours prior to the start of study drug. 
 Women must not be breastfeeding. 
 Women of childbearing potential must agree to follow instructions for 
method(s) of contraception for the duration of treatment with study drug 6 
months plus 5 half-lives of study drug (2.5 days) plus 30 days (duration of 
ovulatory cycle) for a total of 212.5 days post-treatment completion. 
 Males who are sexually active with women of childbearing potential must 
agree to follow instructions for method(s) of contraception for the duration of 
treatment with study drug 6 months plus 5 half-lives of the study drug (2.5 
days) plus 90 days (duration of sperm turnover) for a total of 272.5 days post-
treatment completion. 
 Azoospermic males and women of childbearing potential who are continuously 
not heterosexually active are exempt from contraceptive requirements.  
However, women of childbearing potential who are continuously not 
heterosexually active must still undergo pregnancy testing. 
 
Investigators will counsel women of childbearing potential and male subjects who are 
sexually active with women of childbearing potential on the importance of pregnancy 

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prevention and the implications of an unexpected pregnancy Investigators will advise 
women of childbearing potential and male subjects who are sexually active with 
women of childbearing potential on the use of highly effective methods of 
contraception. Highly effective methods of contraception have a failure rate of < 1% 
when used consistently and correctly. 
 
At a minimum, subjects must agree to the use of one method of highly effective 
contraception as listed below: 
 Male condoms with spermicide 
 Hormonal methods of contraception including combined oral contraceptive 
pills, vaginal ring, injectables, implants and hormone-impregnated intrauterine 
devices (IUDs) by women of childbearing potential subject.  Female partners 
of male subjects participating in the study may use hormone based 
contraceptives as one of the acceptable methods of contraception since they 
will not be receiving study drug.  
 IUDs 
 Tubal ligation 
 Vasectomy 
 Complete Abstinence* 
 
*Complete abstinence is defined as complete avoidance of heterosexual intercourse 
and is an acceptable form of contraception for all study drugs. Female subjects must 
continue to have pregnancy tests. Acceptable alternative methods of highly effective 
contraception must be discussed in the event that the subject chooses to forego 
complete abstinence. 
 
A woman of childbearing potential is defined as any female who has experienced 
menarche and who has not undergone surgical sterilization (hysterectomy or bilateral 
oophorectomy) and is not postmenopausal. Menopause is defined as 12 months of 
amenorrhea in a woman over age 45 years, in the absence of other biological or 
physiological causes. In addition, females under the age of 55 years must have a serum 
follicle stimulating hormone (FSH) level > 40mIU/mL to confirm menopause. 
 
*Females treated with hormone replacement therapy (HRT) are likely to have 
artificially suppressed FSH levels and may require a washout period in order to obtain 
a physiologic FSH level. The duration of the washout period is a function of the type 
of HRT used. The duration of the washout period below are suggested guidelines and 
the investigators should use their judgement in checking serum FSH levels. If the 
serum FSH level is > 40 mIU/ml at any time during the washout period, the woman 
can be considered postmenopausal: 
 
1 week minimum for vaginal hormonal products (rings, creams, gels) 
 
4 week minimum for transdermal products 
 
8 week minimum for oral products 
 
Other parenteral products may require washout periods as long as 6 months. 
 

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Screening Procedures
 
When a potentially eligible study subject is identified, the following screening 
procedures will be followed: 
1. The Principal Investigator or designee will be contacted by the responsible 
provider to initiate screening. 
 
2. The Principal Investigator or designee will confirm that patient is  18 years of 
age or older. 
 
3. The Principal Investigator or designee will confirm fulfillment of the study 
inclusion criteria and the absence of all exclusion criteria. 
 
4. The Principal Investigator or designee will provide the potential study subject 
with the study Informed Consent Form to review, sign, and date.  Informed 
consent must be obtained from a subject with the capacity for medical 
decision-making.  The process for obtaining informed consent must be in 
compliance with the Partners IRB guidelines and policies.  Informed consent 
may be obtained by the Principal Investigator or Co-Investigators.  Potential 
study subjects will not be enrolled if Informed Consent cannot be obtained.  A 
copy of the signed Informed Consent Form must be provided to the subject.  
must always be available for verification.   
 
5. A research staff member will enter the patient demographic data into the 
screening portion of the electronic case report form (eCRF). 
 
6. Subjects who agree to participate in the study and sign the Informed Consent 
Form will be considered for enrollment in the study and should have baseline 
data which includes:  
a. History and physical examination within the past 6 months 
b. Review of relevant laboratory data from within the past three months.  If  
laboratory data for a complete blood count, basic chemistry panel, and 
coagulation (prothrombin time and activated partial thromboplastin time) 
are not available from the past three months, these will be drawn at the 
initial study visit and paid for by the study.  
c. 
-HCG) or urine pregnancy test (u-HCG) for women of child-
bearing potential 
 
7. If the potential study subject does not meet all the inclusion criteria or meets 
any of the exclusion criteria, the rationale for exclusion from the study will be 
recorded in the screening section of the electronic case report form (eCRF). 
 
 
Assessment of Enrollment 
 

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After 10 months of study recruitment, an assessment of enrollment will be conducted.  
If 300 study subjects have not been recruited by 10 months, activation of second 
study site, 
Faulkner Hospital, will be considered by the Study 
Investigators.  Activation of the 
Faulkner Hospital as a study 
site will require submission to and approval by the Partners Human Research 
Committee/IRB.   
 
Treatment Description   
 
Subjects will begin anticoagulation within 3 weeks of passing the screening 
procedure.  Subjects who are 18 years of age or older with provoked DVT and/or PE, 
have completed at least 3 months of therapeutic anticoagulation, have a low risk of 
bleeding, and have at least one persistent provoking risk factor will be randomly 
assigned to receive apixaban 2.5 mg orally twice daily or oral placebo for extended 
secondary prevention of VTE for a duration of 12 months.   
 
If during the study period the patient requires an invasive procedure or surgery that 
necessitates the discontinuation of anticoagulation (study drug), apixaban should be 
held as per the prescribing guidelines (Appendix, 
http://packageinserts.bms.com/pi/pi_eliquis.pdf).  If appropriate based on the 
judgment of the responsible clinician, apixaban should be restarted when safe to do 
so postoperatively. 
 
Patients and providers will be blinded as to the study group assignment. 
 
Both study drug and placebo will be dispensed by the BWH Investigation Drug 
Service in 3-month allotments either in person at the screening visit, other non-study 
related office visit at BWH, or directly to the patient within 2 business days of the 
enrollment visit via mail or courier in accordance with BWH Investigation Drug 
Service policy.  Subsequent allotments will be dispensed via mail or courier in 
accordance with BWH Investigation Drug Service policy.  Our Research Nurse will 
communicate with study subjects by telephone at 3 months intervals in advance of 
releasing a 3-month allotment of study drug or placebo to ensure that treatment is not 
 
 
 
Randomization 
 
Subjects who are 18 years of age or older with provoked DVT and/or PE, have 
completed at least 3 months of therapeutic anticoagulation, have a low risk of 
bleeding, and have at least one persistent provoking risk factor will be randomly 
assigned by computer in a 1:1 ratio to receive apixaban 2.5 mg orally twice daily or 
oral placebo for extended secondary prevention of VTE for a duration of 12 months. 
 

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Safety Outcomes
 
Primary Safety Outcome 
 
The primary safety outcome will be major bleeding at 12 months.  Major bleeding is 
 
site, or contributes to death (27).  The primary safety outcome will be independently 
adjudicated by a blinded Clinical Endpoints Committee (CEC) review. 
 
Secondary Safety Outcome 
 
Clinically relevant non-major bleeding at 12 months will be evaluated (please see 
below) and is defined as overt bleeding that does not meet the criteria for major 
bleeding but that is associated with the need for medical intervention, unscheduled 
contact with a physician, interruption or discontinuation of the study drug, or 
discomfort or impairment of activities of daily living (28).   
 
 
Efficacy Outcomes 
 
Primary Efficacy Outcome 
 
The primary efficacy outcome will be symptomatic, recurrent VTE, defined as the 
composite of deep vein thrombosis and/or pulmonary embolism at 12 months. The 
primary efficacy outcome will be independently adjudicated by a blinded CEC review. 
 
DVT is diagnosed as a newly non-compressible venous segment or segments on 
ultrasonography or a filling defect on computed tomographic (CT) venography, 
magnetic resonance (MR) venography, or contrast venography.   
 
PE is diagnosed based on new mismatched perfusion defect(s) on ventilation 
perfusion scan, the presence of a new pulmonary artery filling defect on contrast-
enhanced chest CT, a new finding of intraluminal filling defect on invasive pulmonary 
angiography, or evidence of PE at autopsy. 
 
Secondary Efficacy Outcome 
 
A secondary efficacy outcome will be the composite of death due to cardiovascular 
cause, nonfatal myocardial infarction (MI), stroke or systemic embolism, critical limb 
ischemia (CLI), or coronary or peripheral ischemia requiring revascularization (major 
adverse cardiovascular events, including major adverse limb events) at 12 months.  
The secondary efficacy outcome will be independently adjudicated by a blinded CEC 
review. 
 

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An acute MI is defined as the presence of at least 2 of the 3 following conditions (29):
 The detection of a rise and/or fall of cardiac biomarkers, with at least one of 
the values being elevated (preferably cardiac troponin [cTn] with at least one 
value above the 99th percentile upper reference limit) and with at least one of 
the following:   
 symptoms of myocardial ischemia  
 new (or presumably new) significant ST-segment/T-wave changes 
or left bundle branch block  
 development of pathological Q waves on ECG  
 new loss of viable myocardium or regional wall motion abnormality 
by imaging 
 identification of intracoronary thrombus by angiography or autopsy 
 
An acute stroke is defined as a new, focal neurologic deficit of sudden onset, lasting 
at least 24 hours, not due to a readily identifiable nonvascular cause (i.e. brain tumor, 
trauma), as confirmed by a neurologist and neuroimaging (7). All strokes during the 
study will be assessed by imaging or autopsy, and classified as primary hemorrhagic, 
non-hemorrhagic, infarction with hemorrhagic conversion, or unknown, as defined by 
the American College of Cardiology. 
 
 Primary hemorrhagic: a stroke with documentation on imaging (e.g., 
CT scan or magnetic resonance imaging) of hemorrhage in the cerebral 
parenchyma, or subarachnoid hemorrhage. Evidence of hemorrhagic 
stroke obtained from lumbar puncture, neurosurgery, or autopsy can 
also confirm the diagnosis.  
 Non-hemorrhagic: an ischemic focal neurological deficit (and not due 
to hemorrhage) that appears and is still partially evident at 24 hours. 
 Infarction with hemorrhagic conversion: no evidence of hemorrhage 
on an initial scan, but found on a subsequent scan and is clinically 
relevant to the event, as determined by a neurologist. 
 Unknown type/no imaging performed: the type of stroke could not be 
determined by imaging or other means (lumbar puncture, 
neurosurgery). 
 
Cardiovascular death is defined as a death for which a definite non-cardiovascular 
cause (e.g. cancer) has not been identified. Uncertain causes of deaths are 
presumed to be cardiovascular unless proven otherwise. 
 
Major adverse limb events include acute limb ischemia (ALI) and critical limb 
ischemia (CLI) (30).  Acute limb ischemia is defined as limb-threatening ischemia 
which is confirmed by limb hemodynamics or imaging and leads to an acute vascular 
intervention (i.e. pharmacologic [heparin, thrombolysis], peripheral arterial 
surgery/reconstruction, peripheral angioplasty/stent, or amputation) within 30 days of 
onset of symptoms. In the absence of confirmation by limb hemodynamics or 
imaging, absent pedal pulses is acceptable as hemodynamic criterion for acute limb 
ischemia. If the event does not meet the definition for ALI it may be classified as 

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chronic limb ischemia, peripheral vascular intervention or other peripheral vascular
hospitalization. 
 
CLI is defined as continuing ischemic limb, foot or digit pain leading to hospitalization 
and intervention and not meeting the definition of ALI, or Fontaine 3 or 4 at baseline 
with peripheral intervention during the trial. 
 
Peripheral vascular intervention is defined as peripheral vascular intervention not 
meeting the definition for ALI or CLI. 
 
Additional Study Outcomes:  Admission for heart failure will also be assessed at 12 
months.  Adherence to the twice-daily regimen of apixaban (and placebo) will be 
recorded as the total number of doses taken divided by the total number of doses 
prescribed.  Adherence data will be recorded on patient-maintained drug diaries. 
 
Clinical Endpoints Committee Adjudication of Study Outcomes 
 
Primary and secondary safety and efficacy outcome will be independently 
adjudicated by a Clinical Endpoints Committee (CEC) that is blinded with regards to 
allocation (randomization).  The CEC will include a 
chairperson and independent reviewers who are physicians with experience in 
vascular medicine and thrombosis. The CEC will adjudicate all index events (proximal 
DVT and/or PE). During the study period and the post-treatment observation period, 
the CEC will adjudicate all suspected occurrences/recurrences of venous or arterial 
thromboembolic events, deaths, and the following events of special interest: acute 
myocardial infarction, acute stroke, and thrombocytopenia. The CEC will also review 
all suspected episodes of bleeding, and categorize adjudicated bleeding as major, 
clinically relevant non-major, or minor bleeding. The Committee will be provided with 
all relevant documentation related to the events 
treatment allocation. The criteria and definitions of the study outcomes as well as the 
procedures followed by the Committee are described in this protocol. 
 
Drug Accountability 
 
Study drug and placebo will be physically stored at BWH in our Investigational Drug 
Pharmacy.  Drug handling and dispensing will be accomplished through our BWH 
Investigational Drug Service.  The Director of Pharmacy at BWH will oversee the 
Investigational Drug Service in this regard for the purposes of the clinical trial.  
Documentation of administration will by accomplished by our Electronic Health 
Record (EHR; EPIC) in addition to a patient drug diary, which is being kept to assess 
medication adherence.  The Investigational Drug Service will collect empty study drug 
containers and unused drug via mail using prepaid labels that will be provided to the 
patient or courier as per Investigational Drug Service policy.  We will perform drug 
accountability assessment when the drug containers are collected at each 3-month 
interval.   

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Follow-Up 
 
Follow-Up Evaluation 
 
Routine laboratory testing is neither recommended nor required in patients receiving 
extended duration apixaban, including the 2.5 mg twice daily dosing regimen.  
Patients enrolled in the study will either have been identified from one of the practices 
of our Vascular Medicine faculty or will be assigned to one of our faculty for long-term 
management of VTE.  Accordingly, every patient enrolled in the study will have 
ongoing medical care with a dedicated Vascular Medicine provider.  Study patients 
will be encouraged to follow-up with their primary care, , and other appropriate 
clinicians. Specifically, at the end of the treatment visit, every patient will be reminded 
to follow-up with a PCP as dictated by routine care and best clinical practice. 
Demographic, clinical characteristics, medication records, and outcomes will be 
abstracted from the BWH Electronic Health Record (EPIC).   
 
When our Research Nurse conducts the every 3-month telephone call in advance of 
releasing a 3-month allotment of study drug or placebo the subject will be queried for 
any issues with the study or adverse events.  
 
We will conduct an end-of-treatment visit to obtain data relevant to the study end 
points. 
 
We will assess medication adherence via pill count.  Medication adherence will be 
calculated in three month intervals as the total number of doses taken divided by the 
total number of doses prescribed for that time period ([ x / 180] x 100 = medication 
adherence [%]) and also for the total 360-day study period ([x / 720] x 100 = 
medication adherence [%]).  Subjects will be given a study drug diary to fill out at 
home each day.  Subjects will write down the time they take their study drug and any 
side effects.  The study drug diary will be collected at a regularly scheduled office visit 
or the end-of-treatment visit at conclusion of the study period.  
 
Subject Retention, Withdrawal, and Termination 
 
Continued participation of study subjects will be encouraged at the time of outpatient 
evaluation through the 12-month follow-up interval.  However, study subjects will be 
informed that they retain the right to withdraw from the study at any time without 
compromise to their current or subsequent medical care.  Subjects will be terminated 
from the study if they expire or elect to withdraw.   
 
If study subjects elect to withdraw, they will be asked for permission to do the 
following: 
1. Be contacted by telephone AND 
2. Have their physicians contacted 

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Withdrawal criteria will include: 
1. Patient requests to withdraw 
2. Reasons related to SAE: 
a. Initiating or continuing study drug places the subject at undue hazard as 
determined by the Investigator;   
b. SAE or other safety concern that is related to study drug treatment;   
c. Major or life-threatening bleeding (as defined in the protocol)  
d. 
 
e. Calculated CrCL decreased to < 30 mL/min confirmed by repeat testing 
at least one week later, or need for dialysis 
3. Pregnancy 
4. Patient develops severe hepatic impairment (Child-Pugh class C) during the trial 
5. Death 
6. Lost to follow-up (every attempt will be made by the Investigator not to have 
-
 
7. Study terminated by sponsor (termination of all or part of the study by the 
sponsor, in concert with the study leadership) 
 
Safety Monitor 
 
An independent Safety Monitor has been selected for this study.  The Safety Monitor 
is an expert in VTE and is distinct from the DMSB and Study Staff and will be 
available throughout the study to assess patient safety issues that may arise, 
objectively.  The Safety Monitor will have the ability to break the blind of a study 
patient as the need arises (immediately, in real-time).  If the Safety Monitor is 
unavailable because of travel, one of the Physician Study Investigators will serve as 
back-up.  The Safety Monitor will attend DSMB meetings, although will be non-voting.  
The Safety Monitor will have the ability to request an ad hoc DSMB meeting should a 
safety issue arise that warrants further review. 
Assessment and Reporting of Adverse Events 
 
Definitions 
 
Adverse events 
 
An adverse event (AE) is defined as any new untoward medical occurrence or 
worsening of a pre-existing medical condition in a patient or clinical investigation subject 
administered an investigational (medicinal) product and that does not necessarily have 
a causal relationship with this treatment.  An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding, for example), symptom, or 
disease temporally associated with the use of investigational product, whether or not 
considered related to the investigational product.  The causal relationship to study drug 
is determined by a physician and should be used to assess all AEs.  

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Adverse events can be spontaneously reported or elicited during open-ended 
questioning, examination, or evaluation of a subject. (In order to prevent reporting 
bias, subjects should not be questioned regarding the specific occurrence of one or 
more adverse events). 
 
through 30 days of discontinuation of dosing will be reported to BMS Worldwide Safety. 
 
Serious Adverse Events 
 
A serious adverse event (SAE) is any untoward medical occurrence at any dose that: 
  
 results in death 
 is life-threatening (defined as an event in which the subject was at risk of 
death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe) 
 requires inpatient hospitalization or causes prolongation of existing hospitalization  
 results in persistent or significant disability/incapacity 
 is a congenital anomaly/birth defect 
 is an important medical event, defined as a medical event that may not be 
immediately life-threatening or result in death or hospitalization but, based 
on appropriate medical and scientific judgment, may jeopardize the subject 
or may require intervention (e.g., medical, surgical) to prevent one of the 
other serious outcomes listed above. Examples of such events include but 
are not limited to intensive treatment in an emergency department or at 
home for allergic bronchospasm; blood dyscrasias or convulsions that do 
not result in hospitalization. 
 
Suspected transmission of an infectious agent (e.g., pathogenic or non-pathogenic) via the 
study drug is an SAE.  Although pregnancy, overdose, and cancer are not always serious 
by regulatory definition, these events must be handled as SAEs. 
 
 The following hospitalizations are not considered SAEs:  
 A visit to the emergency room or other hospital department lasting less 
than 24 hours that does not result in admission (unless considered an 
-threatening event) 
 Elective surgery planned before signing consent 
 Admissions as per protocol for a planned medical/surgical procedure 
 Routine health assessment requiring admission for baseline/trending of 
health status (e.g., routine colonoscopy) 
 Medical/surgical admission other than remedying ill health state that was 
planned before study entry. Appropriate documentation is required in these 
cases 
 Admission encountered for another life circumstance that carries no 
bearing on health status and requires no medical/surgical intervention (e.g., 

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lack of housing, economic inadequacy, caregiver respite, family 
circumstances, administrative reason) 
 
Adverse Events of Special Interest 
 
In this study, the following adverse events will to be reported to BMS, regardless of 
whether these reports are classified as serious or unexpected. 
 
 Potential or suspected cases of liver injury including but not limited to liver test 
abnormalities, jaundice, hepatitis or cholestasis. 
 
Pre-Existing Medical Conditions 
 
A pre-existing medical condition is one that is present at the start of the study.  Pre-
existing medical conditions should be recorded in the baseline and demographic data 
section of the electronic case report form (eCRF).  Pre-existing medical conditions 
should be reassessed during the trial and reported as an adverse event or severe 
adverse event only if the frequency, severity, or character of the conditions worsens 
significantly or unexpectedly during the study.  When reporting such adverse events, 
the description should convey that the pre-existing condition has changed by 
including applicable descriptors (e.g.
scheduled hospitalizations and hospitalizations required for diagnostic or elective 
surgical procedures for the management of unchanged pre-existing medical condition 
should not be considered adverse events. 
 
Serious Adverse Event Collecting and Reporting 
 
related or not related to study drug, must be collected, including those thought to be 
associated with protocol-specified procedures. All SAEs must be collected that occur 
during the screening period and within 30 days of discontinuing dosing. If applicable, 
SAEs must be collected that relate to any later protocol-specific procedure.  
 
When our Research Nurse conducts the every 3 month telephone call in advance of 
releasing a 3-month allotment of study drug or placebo the subject will be queried for 
any issues with the study or adverse events.  The Electronic Health Record, Epic, will 
notify study staff when a study subject is admitted to the hospital or presents to the 
Emergency Department.  This notification will be an additional avenue for detection of 
SAEs.  Providers will also be able to see that the patient is enrolled in the study and 
how to contact study staff through the EHR. 
 
SAEs 
a study physician or staff member, or identification from the EHR during data 
collection.  Patients that report AEs to the study staff will be contacted by a study 
physician and triaged to the appropriate setting for care depending on the nature and 
severity of the AE and in accordance with best clinical practices. 

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The investigator should report any SAE occurring after these time periods that is 
believed to be related to study drug or protocol-specified procedure.  An SAE report 
should be completed for any event where doubt exists regarding its status of 
seriousness.  If the investigator believes that an SAE is not related to study drug, but 
is potentially related to the conditions of the study (such as withdrawal of previous 
therapy, or a complication of a study procedure), the relationship should be specified 
in the narrative section of the SAE Report Form. 
 
SAEs, whether related or unrelated to the study drug, and pregnancies must be 
reported to BMS within 1 business day of becoming aware of the event:  
 
SAE Email Address: Worldwide.Safety@BMS.com 
SAE Fax Number: 609-818-3804 
 
SAEs must be recorded on the FDA MedWatch Form 3500A. Pregnancies must be 
reported on a Pregnancy Surveillance Form. 
 
If only limited information is initially available, follow-up reports are required. (Note: 
Follow-up SAE reports should include the same investigator term(s) initially reported.)  
 
If an ongoing SAE changes in its intensity or relationship to study drug or if new 
information becomes available, a follow-up SAE report should be sent within 24 hours 
to the BMS (or designee) using the same procedure used for transmitting the initial 
SAE report. All SAEs should be followed to resolution or stabilization. 
 
SAE Reconciliation 
 
 
The Sponsor will reconcile the clinical database AE cases (case level only) 
transmitted to BMS Global Pharmacovigilance (GPV&E) 
(Worldwide.Safety@bms.com).  
 The Investigator will request from BMS GPV&E, 
aepbusinessprocess@bms.com the SAE reconciliation report and include the 
BMS protocol number every 3 months and prior to data base lock or final data 
summary 
 GPV&E will send the investigator the report to verify and confirm all SAEs 
have been transmitted to BMS GPV&E. 
 The data elements listed on the GPV&E reconciliation report will be used for 
case identification purposes. If the Investigator determines a case was not 
transmitted to BMS GPV&E, the case should be sent immediately to BMS 
(Worldwide.Safety@bms.com). 
 
Health Authority Reporting (U.S. FDA IND) 
 

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Investigators must adhere to local Health Authority Reporting Requirements. For 
studies conducted under an investigator sponsored U.S. FDA IND, provide details of 
the following: 
 
 Any event that is both serious and unexpected must be reported to the 
Food and Drug Administration (FDA) as soon as possible and no later than 
7 days (for a death or life-threatening event) or 15 days (for all other SAEs) 
 
 BMS will be provided with a simultaneous copy of all adverse events filed 
with the FDA. SAEs should be reported on MedWatch Form 3500A, which 
can be accessed at: http://www.accessdata.fda.gov/scripts/medwatch/. 
 
MedWatch SAE forms should be sent to the FDA at: 
 
MEDWATCH 
5600 Fishers Lane 
Rockville, MD 20852-9787 
Fax: 1-800-FDA-0178 (1-800-332-0178) 
http://www.accessdata.fda.gov/scripts/medwatch/ 
 
All SAEs should simultaneously be faxed or e-mailed to BMS at: 
 
Global Pharmacovigilance & Epidemiology 
Bristol-Myers Squibb Company 
Fax: 609-818-3804 
Email: Worldwide.safety@bms.com 
 
Health Authority (HA), suspected serious adverse reactions (whether expected or 
unexpected) shall be reported by BMS to the relevant competent health authorities in 
all concerned countries according to local regulations (either as expedited and/or in 
aggregate reports). 
 In accordance with local regulations, BMS will notify sponsor investigators of all 
reported SAEs that are suspected (related to the investigational product) and 
unexpected (ie, not previously described in the 
IB)). An 
event meeting these criteria is termed a Suspected, Unexpected Serious 
Adverse Reaction (SUSAR). Sponsor investigator notification of these events 
will be in the form of either a SUSAR Report or a Semi-Annual SUSAR Report.  
 Other important findings which may be reported by BMS as an Expedited 
Safety Report (ESR) include: increased frequency of a clinically significant 
expected SAE, an SAE considered associated with study procedures that 
could modify the conduct of the study, lack of efficacy that poses significant 
hazard to study subjects, clinically significant safety finding from a 
nonclinical (eg, animal) study, important safety recommendations from a 

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study data monitoring committee, or sponsor or BMS decision to end or 
temporarily halt a clinical study for safety reasons. 
 Upon receiving an ESR from BMS, the investigator must review and retain 
the ESR with the IB. Where required by local regulations or when there is a 
central IRB/Independent Ethics Committee (IEC) for the study, the sponsor 
will submit the ESR to the appropriate IRB/IEC. The investigator and 
IRB/IEC will determine if the informed consent requires revision. The 
investigator should also comply with the IRB/IEC procedures for reporting 
any other safety information.  
 
 
Non-Serious Adverse Events  
 
A non-serious adverse event (NSAE) is an AE not classified as serious. 
 
Non-Serious Event Collecting and Reporting 
 
 
The collection of non-
written consent to participate in the study. All non-serious adverse events (not only 
those deemed to be treatment-related) should be collected continuously during the 
treatment period and for a minimum of 30 days following the last dose of study 
treatment.  
Non-serious AEs should be followed to resolution or stabilization, or reported as 
SAEs if they become serious. Follow-up is also required for non-serious AEs that 
cause interruption or discontinuation of study drug and for those present at the end of 
study treatment as appropriate.  
Non-serious Adverse Events (AE) are to be provided to BMS in aggregate via interim 
or final study reports as specified in the agreement or, if a regulatory requirement [eg, 
IND US trial] as part of an annual reporting requirement.  
 
Laboratory Test Abnormalities 
 
All laboratory test results captured as part of the study should be recorded following 
institutional procedures. Test results that constitute SAEs should be documented and 
reported to BMS as such. 
 
The following laboratory abnormalities should be captured and reported as 
appropriate: 
 
 Any laboratory test result that is clinically significant or meets the definition of an SAE 
 Any laboratory test result abnormality that required the subject to have study 
drug discontinued or interrupted 

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 Any laboratory test result abnormality that required the subject to receive 
specific corrective therapy.  
 
It is expected that wherever possible, the clinical rather than the laboratory term will 
be used by the reporting investigator (e.g., use the term anemia rather than low 
hemoglobin value).  Laboratory test abnormalities are provided to BMS via annual 
safety reports (if applicable), and interim or final study reports. 
 
Pregnancy 
 
If, following initiation of apixaban, it is subsequently discovered that a study subject is 
pregnant or may have been pregnant at the time of apixaban exposure, including 
during at least 5 half-lives after product administration, the investigational product will 
be permanently discontinued in an appropriate manner.  The investigator must 
immediately notify WorldwideSafety@BMS.com of this event via the Pregnancy 
Surveillance Form within 24 hours and in accordance with SAE reporting procedures. 
 
 
Follow-up information regarding the course of the pregnancy, including perinatal and 
neonatal outcome and, where applicable, offspring information must be reported on a 
Pregnancy Surveillance Form. 
 
Any pregnancy that occurs in a female partner of a male study participant should be 
reported to BMS. Information on this pregnancy may also be collected on the 
Pregnancy Surveillance Form. In order for Sponsor or designee to collect any 
pregnancy surveillance information from the female partner, the female partner must 
sign an informed consent form for disclosure of this information. 
 
Protocol-required procedures for study discontinuation and follow-up must be 
performed on the subject unless contraindicated by pregnancy.  Other appropriate 
pregnancy follow-up procedures should be considered if indicated. 
 
 
Other Safety Considerations 
 
Any significant worsening noted during interim or final physical examinations, 
electrocardiograms, X-rays, and any other potential safety assessments, whether or 
not these procedures are required by the protocol, should also be recorded as a non-
serious or serious adverse event, as appropriate, and reported accordingly. 
 
Documentation of Adverse Events 
 
Information about potential adverse events should be reviewed during the 6-month 
follow-up period.  Subjects should be encouraged to report adverse events 
spontaneously or in response to non-directed questioning by their usual healthcare 
providers.  If it is determined that an adverse event has occurred, the study staff 

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member entering data into the eCRF should obtain all of the information necessary to 
complete the Adverse Event section.  All observed or reported adverse events, 
regardless of the suspected causal relationship to study treatment must be recorded 
in the Adverse Event section of the eCRF. The Sponsor will be notified when an 
event has been entered into the database. 
 
 
Duration of Adverse Event Reporting Period 
 
Bleeding adverse events and other serious adverse events must be reported throughout 
the 6-month follow-up period. All observed or reported serious adverse events occurring 
through the 6-month follow-up period, regardless of the suspected causal relationship 
with treatment, must be recorded in the appropriate section of the eCRF. Procedures to 
expedite reporting serious adverse events are described later in this section.   
 
 
Specific Adverse Event Reporting Guidelines 
 
Study investigators should follow the following guidelines to ensure the quality and 
precision of adverse event reporting: 
1. Use recognized medical terms 
2. Avoid the use of colloquialisms and non-standard abbreviations 
3. If known at the time of adverse event reporting, a diagnosis should be reported 
instead of individual symptoms and signs (e.g.
 
4. If the reported symptoms and signs cannot be medically characterized as a 
single diagnosis or syndrome at the time of adverse event reporting, the 
information that is available should be reported.  If a diagnosis is subsequently 
established, it should be reported as follow-up information as described earlier. 
5. A cascade of clinical events (such as sequelae of an adverse event) should be 
identified as the primary, causative event.  The cascade of events can be 
further described in the adverse event narrative.  For example, when recording 
a death, the event or condition that caused or contributed to the fatal outcome 
should be reported as the serious adverse event.  If the cause of death is 
 
6. Any adverse event that results in inpatient hospitalization or prolongs a 
hospitalization should be reported as a serious adverse event.  If a subject is 
hospitalized to undergo a medical or surgical procedure as a result of an 
adverse event, the event responsible for the procedure (not the procedure 
itself) should be reported as the serious adverse event.  For example, if a 
subject is hospitalized to undergo exploratory surgery as a result of a major 
bleeding event, record the major bleeding event that necessitated surgery as 
the serious adverse event. 
 

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to participate in the study through 30 days of discontinuation of dosing must be 
reported to BMS Worldwide Safety. 
 
Categorization of Adverse Events 
 
All adverse events must be classified according to intensity or severity, 
expectedness, relatedness, outcome, and treatment or action taken. 
 
Intensity or Severity 
 
The following categories for intensity or severity of an adverse event should be used 
in reporting: 
 
Mild  
Awareness of a symptom or sign that does not interfere with the 
treatment and without sequelae 
Moderate 
still able to function 
Severe 
medication, surgery, or other intervention for treatment 
 
Expectedness 
 
Each adverse event should be evaluated as to whether it was expected or 
unexpected as follows: 
 
Expected 
The specificity and severity of the event is consistent with 
applicable information on apixaban. 
Unexpected 
The specificity or severity of the event is not consistent with 
applicable information on apixaban.               
Unanticipated 
Adverse 
Device Effect 
(UADE) 
Any serious adverse effect on health or safety or any life-
threatening problem or death caused by, or associated with, 
apixaban, if that effect, problem, or death was not previously 
identified in nature, severity, or degree of incidence in the 
investigational plan or application or any other unanticipated 
serious problem associated with apixaban that relates to the 
rights, safety, or welfare of subjects.  
 
 
Relatedness 
 
Each adverse event should be evaluated as to whether it was related to the study 
procedures or apixaban as follows: 
 
Definite 
An adverse event is clearly related to apixaban 

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Probable
An adverse event has a reasonable causal relationship to the 
use of apixaban; another etiology is significantly less likely 
Possible 
An adverse event has a reasonable causal relationship to the 
use of apixaban; an alternative etiology is equally or less likely  
Unlikely 
An adverse event has little or no causal relationship to the use 
of apixaban; an alternative etiology is more likely 
Not related 
An adverse event is not related to the use of apixaban; there is 
no temporal relationship or a much more likely alternative 
etiology exists 
 
causal relationship.  
 
Outcome 
 
The clinical course of all adverse events should be followed until a medical outcome 
is determined (resolution, stabilization, or determination that it was unrelated to study 
participation).  If a subject is pregnant or becomes pregnant within 30 days of 
receiving apixaban, follow-up should be obtained from the medical record to 
determine the outcome of the pregnancy (successful live-birth, etc.).  The clinical 
outcome of all adverse events should be recorded as follows: 
 
Death 
Patient expired 
Recovered 
Patient returned to baseline health and functional 
status 
Not yet recovered 
Patient did not recover and symptoms or 
sequelae persist 
Recovered with sequelae 
Patient did recover but continues to experience 
clinical sequelae from the adverse event 
 
Treatment or Action Taken 
 
Adverse events and serious adverse events will be categorized by the actions taken 
in response to the event: 
 
Intervention 
Surgery or other invasive procedure 
Non-surgical treatment 
Drug initiation, interruption, dose reduction, dose 
increase, or discontinuation 
None 
No action was taken 
 
Expedited Reporting of Serious Adverse Events (SAE) 
 
The study investigators must use the following procedure for reporting serious 
adverse events: 
1. Report any serious adverse event that occurs to the Sponsor within 24 hours 
of knowledge of the event (Monday through Friday).  If the investigator does 

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not have all information regarding the SAE, he/she will not wait to receive 
additional information before notifying the Sponsor of the event and 
completing the eCRF.  The investigator shall provide an event update when 
additional information is received. 
 
NOTE:  The Sponsor will automatically be notified when an adverse event or 
serious adverse event has been entered into the database when the 
investigator fills in an eCRF.  
 
2. In the reporting of serious adverse events, the study investigator shall provide 
any potentially relevant information including: 
a. Subject demographics 
b. Pre-existing conditions 
c. The complete description of the adverse event. 
d. Date and time of adverse event onset 
e. Severity 
f. Treatment 
g. Results of diagnostic testing 
h. Duration of sequelae 
i. Outcome (if known) 
j. Date and time of adverse event resolution. 
k. Information on suspected medications including dose, route of 
administration, frequency, dates, lot number, expiration date, and 
concomitant medications 
 
3. When reporting a death, the primary event or condition that caused or contributed 
to the fatal outcome shall be reported as the serious adverse event.  Death will be 
reported as the outcomes of the serious adverse event.  If the cause of death is 
unknown a
 
 
4. The investigator shall report unanticipated adverse device effects (UADEs) to 
the sponsor and Institutional Review Board within 10 working days after the 
investigator first learns of the event.   
 
Sponsor Unanticipated Adverse Drug Effects (UADEs) Reporting Responsibilities 
 
Any serious adverse event determined to be caused by apixaban will be reviewed for 
possible reporting to the U.S. Food and Drug Administration and IRBs.  Upon notice 
of an unanticipated adverse drug effect (UADE), the sponsor shall immediately 
conduct an evaluation of the UADE and report the results of the evaluation to the 
FDA, all reviewing IRBs, and participating investigators within 10 days of first 
receiving the report.   
 
Data Reporting, Processing, and Quality Control 
 

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Data Acquisition, Monitoring, and Quality Control
 
Subject data will be collected using a web-based electronic case report form (eCRF) 
called REDCap.  Database monitoring and quality control will be performed by the 
Data Safety Monitoring Board (DSMB). 
Monitoring Plan 
 
Monitoring procedures will consist of the following: 
 
During the study, the study staff shall perform monthly random reviews of data with 
checks for accuracy and completeness, and document that corrective actions have 
been taken in response to protocol deviations or other forms of non-compliance.  
These reports will be provided to the Data Safety Monitoring Board. 
 
Data Safety Monitoring Board 
 
Three independent individuals with relevant expertise in VTE and anticoagulation will 
be appointed to a data safety monitoring board (DSMB) whose primary responsibility 
is to protect the safety of study subjects and to provide ongoing, critical, and 
unbiased evaluation of the progress of the study. The DSMB will be comprised of two 
independent physicians and an independent statistician.  To further ensure 
idependence of the DSMB, the DSMB Chair has been selected and is an expert in 
VTE AND comes from outside the Mass General Brigham Network. 
 
The DSMB will: 
 Provide independent safety evaluation of events and adjudicate all actual and 
potential serious adverse events experienced by study subjects during this 
study 
 Review aggregate efficacy and safety data including the frequency of adverse 
safety outcomes, particularly death, symptomatic VTE and major bleeding; and 
can recommend premature stopping of the study to the Sponsor and Principal 
Investigator at any time. 
 
The DSMB will meet virtually via Zoom under the restrictions imposed by the COVID-
19 pandemic.  The DSMB will meet once before the initiation of the trial and then at 
least once every three months for the duration of the trial in addition to prespecified 
meetings at 10 months and 50% of enrollment (Table).  In addition, the DSMB may 
be convened on an ad hoc basis at the request of the study investigators if the need 
(for example, due to a study-related concern) arises in between regularly scheduled 
meetings.  The DSMB chair may call an emergency meeting at any time should 
questions of patient safety arise or at the request of the Study Safety Monitor.  The 
exact dates and times of the DSMB meetings will be determined based on the 
availability of all three members to meet and will take place within the first two weeks 
of the given month. 

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1. Prior to the first meeting, the DSMB will be provided with FDA- and IRB-
approved protocol, DSMB Charter, and DSMB Adjudication Report Form to 
allow for review and charter revisions prior to the first meeting called the DSMB 
Kick-off meeting. 
2. The DSMB Kick-Off meeting will provide formal training on the protocol provided 
by the Thrombosis Research Group staff. During the first meeting, the DSMB 
will review and approve the final Charter. The DSMB will determine reports 
needed for safety review and establish stopping rules. 
3. Planned DSMB meetings will take place every three months. The DSMB will 
review all safety data collected to date on the initial subjects enrolled. The DSMB 
will also assess whether the study is on-track to meet its enrollment goal.  Once 
the review is complete and no safety or enrollment concerns are raised, the trial 
will continue. 
4. A DSMB meeting will be held at the halfway point through the enrollment period 
(10 months).  At this point the DSMB will assess whether the study is on-track 
to meet its enrollment goal.  The DSMB will also assess any safety concerns at 
that time.  Once the review is complete and no safety or enrollment concerns 
are raised, the trial will continue. 
5. A DSMB meeting will also occur when 50% of the planned enrollment population 
has completed 12-month follow-up as part of the prespecified interim analysis.  
This planned interim analysis will inform the DSMB on whether the study should 
be stopped early due to efficacy, safety concerns, or futility or continue to enroll 
the full 600-patient cohort. 
6. A final DSMB meeting will take place after follow-up completion of the last 
subject. The DSMB will review all remaining safety data collected on the 
subjects enrolled. 
7. The DSMB chair may call an emergency meeting at any time should questions 
of patient safety arise or at the request of the independent Study Safety Monitor.  
All materials, discussions, and proceedings of the DSMB are completely 
confidential. The Chair and other participants present at DSMB meetings are 
expected to maintain confidentiality. 
 
Table.  Schedule of Planned DSMB Assessments. 
Milestone-Based Meetings 
Timing 
Kick-Off 
1 month before enrollment of first patient 
Halfway Point of Enrollment Period 
10 months after first patient enrolled 
300th Patient Interim Analysis 
After follow-up completion in the 300th 
patient 
Final Meeting 
After follow-up completion in last patient 
 
 

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Recurring Meetings
#2 
3 months after first patient enrolled 
#3 
6 months after first patient enrolled 
#4 
9 months after first patient enrolled 
#5 
12 months after first patient enrolled 
#6 
15 months from first patient enrolled 
#7 
18 months from first patient enrolled 
#8 
21 months from first patient enrolled 
 
 
Interim Safety and Efficacy Analysis 
 
The DSMB will meet to review the safety and efficacy outcomes for the first 300 
patients enrolled in the study when they have completed 12-month follow up. 
Whether to continue, amend, suspend, or terminate the study will be made based in 
this interim analysis.  The DSMB will review the safety and efficacy outcomes again 
at the completion of follow up completion of the last patient enrolled in the study. 
 
The DSMB will be responsible for: 
1. Assessing study enrollment and likelihood of completion of 600 patients 
randomized 
2. Assessing the study event rate in the placebo group and likelihood of obtaining 
enough events to satisfy the requirements for the primary efficacy analysis 
3. Assessing the event rates in the treatment and placebo groups 
4. Assessing the accumulated SAEs to determine whether the safety stopping 
criteria have been meet 
 
Actions taken by the DSMB will include the following recommendations: 
1. Study termination if stopping criteria for safety or futility have been met 
2. Study modification if the DSMB deems that remediation measures have a 
reasonable probability of successful completion of the study 
3. Continuation of the study as is 
 
 
Blinding/Unblinding 
 
This study will be conducted in a blinded fashion. To maintain blinding of study 
treatment, study medications will be prepared using placebo matching the active 
treatments.  Subjects, Investigators, members of any of the administrative and 
adjudicating 
access to individual subject treatment assignments.  
 
Blinding is critical to the integrity of this clinical study. However, in the event of a 
medical emergency or pregnancy in an individual subject, in which knowledge of the 
investigational product is critical to the subject's management, the blind for that 

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subject may be broken by the Safety Monitor (or if unavailable, the treating 
investigator). Before breaking the blind of an individual subject's treatment, the Safety 
Monitor should have determined that the information is necessary, i.e., that it will alter 
the subject's immediate management. In many cases, particularly when the 
emergency is clearly not investigational product-related, the problem may be properly 
managed by assuming that the subject is receiving active product without the need 
for unblinding. 
 
The Safety Monitor should ensure that health care professionals who may provide 
any elective, urgent or emergent medical or surgical care for a subject after 
randomization are informed that: 
1. The subject is enrolled in a clinical study and is receiving blinded oral study 
treatment, consisting of: 
a.  Factor Xa inhibitor, OR 
b.  Placebo 
2. The factor Xa inhibitor is an anticoagulant, with a half-life of approximately 12 
hours, which cannot be monitored using standard laboratory tests, such as PT, 
PTT, ACT, and INR 
3. In the event of an emergency, this person should be treated symptomatically 
as would any other person being treated with anticoagulants. Treatment in an 
emergency may include discontinuation of all study treatment, and the use of 
standard resuscitative management and hemostatic agents such as 
prothrombin complex concentrate or andexanet alfa, if appropriate. 
 
 
meaningful impact on individual management, for example in many cases of clinically 
treatment assignment should be unblinded. This information should be provided to 
those who are caring for the subject and as few other people as possible. In these 
cases, we will minimize bias by assuring that the clinical events committee remains 
blinded to treatment assignment, even if the investigator has been unblinded. Every 
subject will be provided with an alert card.  
 
The alert card: 
 Will indicate that the subject is participating in a double-blind clinical trial. 
 
 
 Will note that the subject may be receiving either placebo or an 
investigational anticoagulant drug (a factor Xa inhibitor). 
 
information to provide information to emergency medical personnel 
 
The need to break the blind must first be discussed with the responsible Safety 
Monitor who will be available to page at all times by the responsible care provider. 
can thereby break the blind.  
 

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Invasive Procedures and Surgery
 
Several factors govern the management of anticoagulation in this study with respect 
to surgery and invasive procedures, as well as the management of bleeding that may 
occur in subjects on study drugs. These are: 
 The risk of thromboembolism in an individual subject (low, intermediate or 
high). 
  The risk of bleeding associated with the procedure or surgery. 
 Whether the surgery or invasive procedure is elective or emergent in 
nature. 
 The desirability of maintaining blinding, if at all possible, without creating 
risk for the subject. 
 The times of onset and offset of anticoagulant effect for apixaban 
 
Elective Procedures 
 
In general, local standards of care for discontinuation of anticoagulation prior to 
elective procedures/surgery should be employed; these may be informed by current 
guidelines. 
 
These are summarized below: 
 Stop apixaban/apixaban-placebo 2-4 days before the planned procedure. 
 If the procedure is associated with an increased risk of thrombosis, brief 
postoperative protection with UFH or LMWH may be considered. 
 Restart apixaban/apixaban-placebo postoperatively (usually the day after 
surgery) when it is deemed safe to do so. If UFH/LMWH is used in the 
postoperative period, it is recommended that apixaban/apixaban-placebo 
begin: 
 
 2 hours after the last dose of UFH; 
 
 6 hours after the last dose of LMWH indicated for twice daily 
administration; or 
 
 12 hours after the last dose of LMWH indicated for once daily 
administration (or fondaparinux). 
 
Emergency Procedures 
 
For urgent or emergent invasive procedures, when waiting 4 - 5 days is not an option, 
management will in part depend on the randomized treatment assignment (placebo 
or apixaban) and unblinding may be necessary (see Section on Blinding/Unblinding). 
Regardless of treatment, study drugs should be discontinued and standard laboratory 
coagulation tests (PT/INR, aPTT, platelet count, etc.) performed. The procedure 
should be carried out and in such a way to minimize the risk of bleeding. For subjects 
receiving apixaban, the risk of bleeding with invasive procedures is unknown. At 
therapeutic doses, the anticoagulant effects of apixaban will not be reflected in 
standard coagulation tests. Given its half-life (12 hours), however, the anticoagulant 
effect of apixaban abates in 24 - 

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46 
 
bleeding with the procedure, subjects receiving apixaban who require an invasive or 
surgical procedure within 24 hours of their last dose may be treated with prothrombin 
complex concentrate or andexanet alfa.  If treatment with an alternative open label 
anticoagulant/antithrombotic is indicated for the procedure, it should be used at the 
lowest therapeutic dose (if at all) in the 12 hours following last dose of apixaban.  
 
Treatment Guidelines for Bleeding/Suspected Bleeding 
 
Subjects with bleeding or suspected bleeding will undergo confirmatory laboratory or 
other testing (e.g., US, CT, MRI) and a (S)AE CRF must be completed. The date and 
time of the onset of the bleeding event will be recorded on the CRF. 
 
For subjects with minor bleeding, study drug may or may not be held at the discretion 
of the local physician and investigator. A risk/benefit determination should be made 
 
thromboembolism and benefit from continued anticoagulation. Minor bleeding should 
otherwise be managed according to local standard of care. 
 
For subjects with clinically significant bleeding, the study drugs should generally be 
held. Bleeding should be managed according to local standard of care and may 
include measures such as: 
 
 Local measures to stop the bleeding 
 Volume resuscitation, and transfusion of blood products as appropriate 
 Standard laboratory tests (e.g., hemoglobin, hematocrit, platelet count, 
etc.) 
 
Note: Neither apixaban nor the comparator affects standard coagulation tests. 
 
The management of clinically significant bleeding will in part depend on the 
randomized treatment assignment (placebo or apixaban) so unblinding may be 
necessary (see Section on Blinding/Unblinding). Should unblinding occur, subjects 
receiving placebo should be managed according to the local standard of care. 
Given its half-life (12 - 15 hours), however, the anticoagulant effect of apixaban 
abates in 24 - 48 hours. Subjects receiving apixaban with clinically significant 
bleeding that does not respond to local measures may be treated with prothrombin 
complex concentrate (PCC) or andexanet alfa as per Good Clinical Practice and local 
anticoagulant reversal protocols. 
 
Management of Recurrent Venous Thromboembolic Events 
 
If a subject has a confirmed recurrent symptomatic VTE (DVT or PE), as deemed by 
the primary investigator, then the patient must discontinue study treatment and 
transition to the appropriate standard of care. The subject should remain in the study 
and should be followed in the same manner as a subject who has discontinued study 
treatment as described in the protocol. 

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Prohibited and/or Restricted Treatments 
 
Prohibited Treatments: 
 
The following medications or therapies are prohibited during the study treatment 
period: 
 Potent inhibitors of CYP3A4 (e.g., azole antifungals [itraconazole and 
ketoconazole], macrolide antibiotics [clarithromycin and telithromycin], 
protease inhibitors [ritonavir, indinavir, nelfinavir, atazanavir, and saquinavir], 
and nefazadone) 
 Aspirin > 81 mg/day 
 Dual antiplatelet therapy such as concomitant (simultaneous) use of both 
aspirin and a thienopyridine (e.g., clopidogrel, ticlopidine) 
 Other antithrombotic agents (e.g., UFH, LMWH, direct thrombin inhibitors, 
fondaparinux)  
 GP IIb/IIIa inhibitors (e.g., abciximab, eptifibatide, tirofiban) 
 
If treatment with a prohibited agent becomes necessary, study drug should be 
temporarily interrupted, and restarted as soon as possible following discontinuation of 
the prohibited medication or therapy. 
 
Restricted Treatments: 
 
The administration of the following agents in subjects on study drug should be done 
cautiously given the increased risk of bleeding. In such cases, consideration of 
interruption of the study drug may be warranted; this decision should be made after a 
careful assessment of the risks and potential benefits. 
 
Examples: 
 Chronic (> 3 months) daily NSAIDs. NSAIDs should not be administered in 
doses that exceed those in the approved label 
 Cytotoxic/myelosuppressive therapy 
 
In addition, if a subject is currently receiving an agent that is a potent inducer of 
CYP3A4 (e.g.
of thromboembolism, as the plasma concentration of apixaban may be lower than 
that in subjects not receiving a potent inducer of CYP3A4 
 
Stopping Criteria 
 
The DSMB will consider efficacy events, in addition to safety events, before making 
any study stopping recommendations to the principal investigator.   
 
1. General Stopping Rules 

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A. The DSMB, IRBs, regulatory authorities, or the Investigator may make 
recommendations to terminate the study if the safety and well-being of the 
subjects is in jeopardy.  
B. If the study is terminated or suspended, prompt notification will be provided 
to all parties of the study. 
C. Patient enrollment may be paused or terminated early if the DSMB 
determines that the potential benefits of continuing the trial are unlikely to 
outweigh the risks.  For example, if the probability of achieving the target 
primary endpoints falls below a certain threshold, the trial will be stopped or 
paused for re-evaluation. 
2. Safety Stopping Rules 
The study will be terminated by the DSMB and principal investigator at any point 
if the following stopping criterion is met: 
a. An excess of morbidity or mortality is observed in patients receiving 
apixaban. 
b. When 3 of the subjects receiving apixaban experience an unprovoked 
intracranial hemorrhage, confirmed by independent adjudication and did 
not have a protocol violation such that he/she cannot be considered as 
representative of the intended patient population. 
c. When 3 of the subjects receiving apixaban experience an unprovoked 
major bleed (including fatal hemorrhagic events) and did not have a 
protocol violation such that he/she cannot be considered as 
representative of the intended patient population. 
 
3. Stopping Rules for Futility 
The study will be terminated by the DSMB and principal investigator if any of the 
following stopping criteria is met: 
a. Fewer than 36 events are observed in the placebo group at the time of 
the 300th patient interim statistical analysis 
b. Enrollment progress has been limited such that the study does not have 
a reasonable chance of randomizing 600 patients even after efforts to 
remediate recruitment 
 
 
Protocol Violations 
 
The study staff will rapidly and firmly address any protocol violations with the 
DSMB. If a protocol violation is detected or suspected, the investigator(s) will first 
be asked to provide a written explanation.  After reviewing the available information, 
the study staff will categorize protocol violations as either major (eligibility or 

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primary/secondary endpoint determination compromised or indefinite) or minor (data 
still able to be used for endpoint determination), and will record and track them.  
Protocol violations with be reviewed by the DSMB.  Major protocol deviations will be 
reported to the Partners Human Research Committee within five working days of the 
date the investigator becomes aware of the unapproved deviation.  Minor deviations 
will be recorded in a Minor Deviation Log and this will be submitted to the Partners 
IRB with the continuing review. 
 
 
Data Confidentiality 
 
Hardcopy and electronic subject data will be maintained in a locked office at the site 
and will only be available to the study personnel and sponsor personnel during 
monitoring visits.  Patient identifiers including names and other personal information 
will be kept separate from the study data. 
 
Compliance with Laws and Regulations 
 
The study will be conducted in accordance with this protocol, Title 21 Code of Federal 
Regulations, Parts 10, 50, 54,56 and 812, International Harmonized Standards- E6 
Good Clinical Practices Guidance, and local ethical and legal requirements. 
 
Statistical Methods 
 
Sample Size Calculation 
 
This study is a 600-patient single-center, randomized controlled trial utilizing an 
enriched population.  Based on the contemporary (within the last 10 years) large 
pivotal trials of extended duration anticoagulation (2,3,7) and a large meta-analysis of 
low-dose aspirin (31) for prevention of recurrent events in patients with initial 
unprovoked VTE or clinically suspected to have a high risk of recurrence, we 
conservatively estimate an average 12-month VTE recurrence rate in patients not 
treated with extended-duration anticoagulation (placebo group) of 6% (Table 2).   
 
VTE Recurrence Rates in the Control Arm in Major Extended Duration Secondary 
Prevention Trials including Provoked Events 
Trial 
% Provoked 
Control 
Rate 
Follow-Up 
Period 
EINSTEIN 
CHOICE 
60% 
Aspirin 81 mg 
QD 
3.6% 
<12 months 
(follow-up 
shorter than 
planned in 

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subset of 
patients) 
EINSTEIN 
VTE 
Continued 
Treatment 
25% 
Placebo 
7.1% 
12 months 
AMPLIFY EXT 
9% 
Placebo 
8.8% 
12 months 
 
 
In EINSTEIN CHOICE which randomized 60% of patients with provoked VTE, the 
control group received low-dose aspirin (which based on a meta-analysis in 
unprovoked VTE patients confers about a 33% relative risk reduction) had a 
recurrence rate of 3.6% (2,31).  Accordingly, we would expect the 12-month VTE 
recurrence rate to be at least 33% higher in patients assigned to placebo in the 
proposed study and therefore approximately 5-6%.  The recurrent VTE rate among 
placebo patients in the AMPLIFY-EXT trial of apixaban was quite a bit higher at 8.8% 
(7).  By requiring that at least one additional persistent provoking VTE risk factor be 
present (persistent immobility, obesity, heart failure, chronic lung disease, chronic 
kidney disease, inflammatory disorder, or atherosclerotic cardiovascular disease), we 
2-fold (all of these persistent provoking risk factors increase the risk of VTE by 2-4-
fold; Table 3) (32).  Many patients enrolled in the study will have multiple persistent 
provoking VTE risk factors (for example, heart failure, obesity, and atherosclerotic 
cardiovascular disease) and thereby have an even higher risk for recurrence.   In an 
effort to be ultra-conservative, we kept the multiplier for this enriched study population 
to 2-fold (while in reality for many study patients it could be 4-fold or even higher).  
Accordingly, our estimate of a 12-month VTE recurrence rate of 6% is very 
conservative and still below the VTE recurrence rates reported in EINSTEIN VTE 
Continued Treatment and AMPLIFY EXT (neither of which included an enriched 
population). 
 
Table 3.  Relative risk of VTE by persistent provoking risk factor. 
 
Persistent Provoking Risk Factor 
Relative Risk 
Persistent immobility 
4-fold 
 
2-3-fold 
Heart failure 
2-fold 
Chronic lung disease 
2-fold 
Chronic kidney disease 
2-fold 
Inflammatory/autoimmune disorder 
3-fold 
Atherosclerotic cardiovascular disease 
4-fold 
 
Based on the data from EINSTEIN CHOICE, we conservatively estimate that low-
intensity apixaban (2.5 mg twice daily) compared with placebo will provide a similar 

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reduction (75%) in recurrent VTE as low-intensity rivaroxaban (10 mg daily) 
compared with low-dose aspirin (2).  The 75% relative risk reduction was reported 
specifically for recurrent VTE and in the provoked VTE patient population, comparing 
rivaroxaban 10 mg daily versus low-dose aspirin.  This relative risk reduction 
specifically pertains to our primary study outcome and our exact patient population 
and comes from a robust randomized controlled trial analysis.  If anything, the 
reduction in the proposed study should be even greater since we propose a placebo-
control instead of active (aspirin) control and we will be following our patients for 12 
months, instead of allowing shorter follow-up as was reported in EINSTEIN CHOICE.  
Accordingly, assuming an estimated incidence in the placebo group of 6% at 12 
months and a decrease in the primary outcome of 75% with apixaban 2.5 mg twice 
daily as compared with placebo, we calculated that we would need to enroll 279 
patients in each group for the study to have 80% power to show the superiority of 
low-intensity apixaban over placebo, at a two-sided alpha level of 0.05.  To account 
for patients who may be lost to follow-up or withdraw from the study, we will recruit 
300 in each arm and 600 total.   
 
EINSTEIN-CHOICE enrolled patients after a required 6 to 12 months of anticoagulant 
therapy.  Our study requires that patients complete at least 3 months of anticoagulant 
therapy in accordance with current and widely-accepted evidence-based clinical 
practice guidelines (Eur Heart J. 2020; 41: 543 603, Chest. 2016;149:315-352, and 
Circulation. 2011;123:1788 1830).  Data from the PADIS-PE study showed that the 
rate of VTE recurrence is higher closer in temporal proximity to the initial event, such 
that the recurrence rate is higher at 3-6 months after diagnosis than it is at 6-12 
months (Couturaud F, et al. Six Months vs Extended Oral Anticoagulation After a 
First Episode of Pulmonary Embolism. JAMA. 2015;314(1):31-40).  Accordingly, the 
anticipated event rate should be higher in our study than EINSTEIN-CHOICE and the 
resultant observed relative risk reduction is likely to be higher. 
 
Sensitivity analyses performed for the comparison between apixaban 2.5 mg twice 
daily and placebo (Tables 4 - 6) show that our sample size is most sensitive to 
change in the impact of the extended duration anticoagulation.  However, we have 
been very conservative in our effect size calculation and baseline recurrent VTE rate 
(for example, we have not taken into account the increase in event rates of an 
enriched population with persistent immobility, obesity, heart failure, chronic lung 
disease, chronic kidney disease, inflammatory disorder, or atherosclerotic 
cardiovascular disease), as above. 
 
Table 4. Sensitivity of sample size to changes in power. 
Power 
Total Sample Size 
60% 
350 
70% 
440 
80% 
558 
90% 
746 
99% 
1300 
(assuming event rate of 6%; 75% risk reduction attributed to low-dose apixaban) 

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Table 5. Sensitivity of sample size to changes in VTE event rate. 
VTE Event Rate 
Total Sample Size 
3% 
1140 
4% 
848 
6% 
558 
8% 
412 
10% 
326 
(assuming 80% power; 75% risk reduction attributed to low-dose apixaban) 
 
Table 6. Sensitivity of sample size to changes in impact of extended duration 
anticoagulation with low-intensity apixaban (effect size). 
Relative Risk Reduction 
Total Sample Size 
45% 
1908 
55% 
1198 
65% 
800 
75% 
558 
80% 
472 
(assuming 80% power; event rate of 6%) 
 
The sample size calculation for the trial was calculated based upon 12-month rates of 
recurrent VTE from pivotal randomized controlled trials (2,3,7,33) and a large meta-
analysis of low-dose aspirin vs. placebo (31).  Accordingly, assuming an estimated 
incidence in the placebo group of 6% at 12 months and a decrease in the primary 
outcome of 75% with apixaban 2.5 mg twice daily as compared with placebo, we 
calculate that we will need to enroll 279 patients in each group for the study to have 
80% power to show the superiority of low-intensity apixaban over placebo, at a two-
sided alpha level of 0.05.  If the trial utilized 6-month follow-up instead of 12-month, 
we would observe fewer recurrent VTE events and would require an increase in the 
sample size, which would require a longer enrollment period and would incur greater 
cost.  As such, we have determined 12-month follow-up to facilitate the most efficient 
and cost-effective trial. 
 
We have conducted a retrospective analysis using an ongoing BWH registry of 405 
patients with pulmonary embolism/deep vein thrombosis.  We identified 83 patients 
without active cancer and with at least one provoking risk factor.  Among those who 
received 3-6 months of anticoagulation, 11.1% developed symptomatic recurrent 
venous thromboembolism in the ensuing year after stopping anticoagulation.  If we 
utilize this baseline rate of recurrent VTE in our sample size calculation, we will 
require 212 patients in each study group, assuming a 75% relative risk reduction with 
apixaban 2.5 mg twice daily compared with placebo and 90% power to show the 
superiority of low-intensity apixaban over placebo, at a two-sided alpha level of 0.05.   
 
We have also consulted with an independent biostatistician from the Harvard Catalyst 
Biostatistics Program (Shelley Hurwitz, PhD) to review our sample size requirement.  
She confirmed our sample size calculation using a recurrent VTE rate in the placebo 

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53 
 
group of 6% from the best available literature and also using the rate of 11.1% from 
our observational cohort of patients that would be eligible for this study (see Table 7. 
below). 
 
Table 7.  Harvard Catalyst Biostatistics Program Consultant Sample Size 
Calculations (performed by Dr. Hurwitz using STATA). 
Anticipated Event Rate = 6% 
Anticipated Event Rate = 11.1% 
. power twoproportions .06 .015, 
test(chi2) n(558) 
Estimated power for a two-sample 
proportions test 
Pearson's chi-squared test 
Ho: p2 = p1  versus  Ha: p2 != p1 
Study parameters: 
        alpha =    0.0500 
  N per group =       279 
           p1 =    0.0600 
           p2 =    0.0150 
Estimated power:         power =    0.8005
. power twoproportions .111 .0278, 
test(chi2) n(424) 
Estimated power for a two-sample 
proportions test 
Pearson's chi-squared test 
Ho: p2 = p1  versus  Ha: p2 != p1 
Study parameters: 
        alpha =    0.050 
  N per group =       212 
           p1 =    0.1110 
           p2 =    0.0278 
Estimated power:        power =    0.9236 
Required N = 279 per group 
Required N = 212 per group 
 
It was also suggested that we consider using the lower limit of the 95% confidence 
interval around our estimate of 11.1%, which would be 8.2%.  The statistician 
suggested that this would also provide a conservative estimate of the frequency of 
recurrent VTE for the sample size calculation (see Table 8 below). 
 
Table. 8 Harvard Catalyst Biostatistics Program Consultant Sample Size Calculation 
Using Lower Limit of 95% Confidence Interval of Our Observational Cohort Estimate 
(performed by Dr. Hurwitz using STATA). 
Anticipated Event Rate = 8.2% 
. power twoproportions .082 .0205, 
test(chi2) n(558) 
Estimated power for a two-sample 
proportions test 
Pearson's chi-squared test 
Ho: p2 = p1  versus  Ha: p2 != p1 
Study parameters: 
        alpha =    0.0500 
            N =       558 
  N per group =       279 
           p1 =    0.0820 
           p2 =    0.0205 
Estimated power:       power =    0.9111 
Required N = 279 per group 
 

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Using this more conservative sample size calculation, we would aim to enroll 300 
patients in each arm for a total trial population of 600. 
 
 
Statistical Analysis Plan 
 
For this study, we will calculate: 
1) the 12-month frequency of major and clinically relevant non-major bleeding 
2) the 12-month frequency of symptomatic recurrent VTE 
 
The primary efficacy objective of this trial is to determine whether apixaban 2.5 mg 
twice daily is superior to placebo for the primary endpoint of symptomatic, 
recurrent VTE after 12 months of extended therapy.  The analysis will include 
descriptive statistics of event rates and 95% CI, and risk difference and 95% CI. The 
Mantel-Haenszel statistic will be used to test this hypothesis formally.  Superiority 
over placebo will be claimed for a dose if the Hochberg adjusted p-
and the RR is < 1.  The analysis will be supported by Kaplan-Meier curves.  The 
primary efficacy outcome analysis will be intention-to-treat.  We will also perform an 
on-treatment analysis. 
 
The primary safety objective will be to determine whether apixaban 2.5 mg twice daily 
results in a statistically significant difference in major bleeding at 12 months (during 
the treatment period) compared with placebo. Analysis of incidence of these 
endpoints will be based on the safety analysis set. The analysis will include 
descriptive statistics of event rates and 95% CI, and risk difference and 95% CI. 
Hypotheses will be tested using Mantel-Haenszel statistic.  The analysis will be 
supported by Kaplan-Meier curves of the time to first adjudicated major bleeding 
event.  All bleeding analyses will be conducted on the safety dataset. 
 
Baseline characteristics will be summarized by group. Any imbalances between the 
treatment groups for any demographic or baseline characteristic will be assessed based 
on clinical relevance in reviewing the summaries. For any differences deemed clinically 
relevant to the efficacy comparisons, exploratory analyses that include the imbalanced 
factor as a categorized covariate will be performed. 
 
To account for the effect of baseline low-dose aspirin use in the study population on the 
rate of recurrent VTE after an initial provoked event, we will perform a pre-specified 
stratified efficacy analysis of patients receiving low-dose apixaban or placebo with low-
dose aspirin compared with patients just receiving low-dose apixaban or placebo.  We 
will calculate stratum-
unadjusted) and stratum-specific risk ratios will enable us to determine whether aspirin 
modifies the effect of low-dose apixaban and to what extent.  If the stratum-specific risk 
ratio is similar to the crude risk ratio, then there is minimal impact of low-dose aspirin. 
However, if the stratum-specific risk ratio differs from the unadjusted estimate by 10% or 
more, then low-dose aspirin modifies the effect of low-dose apixaban.  We will conduct a 
similar analysis for the safety outcome of major bleeding. 

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We will also pre-specify subgroup analyses focused on the safety and efficacy of major 
 65 years), women, and those 
with persistent provoking factors of immobility, obesity, heart failure, chronic lung 
disease, chronic kidney disease, hemodialysis, chronic inflammatory/autoimmune 
disorder, and atherosclerotic cardiovascular disease. 
 
Means, medians, and frequency distributions will be calculated for continuous 
variables.  Number and percentages will be reported for binary and categorical 
variables.  Differences between subgroups of interest will be examined using the chi-
square or Fish
-test or 
Wilcoxon Rank Sum for continuous variables (if the subgroups are of sufficient size 
for statistical comparison).   
 
Safety outcome analyses will be performed among patients who received one or 
more doses of a study drug (Safety Population).  All p-values reported will be two-
sided. A p-value < 0.05 will be considered significant.  All analyses will be performed 
using SAS software.   
 
Interim Analysis  
 
We will conduct a pre-specified interim analysis to assess the primary safety and 
efficacy outcomes after 50% of the planned enrollment population has completed 12-
month follow-up.  This planned interim analysis will inform the Data Safety Monitoring 
Board on whether the study should be stopped early due to efficacy, safety concerns, 
or futility or continue to enroll the full 600-patient cohort. 
 
The DSMB will be responsible for: 
 
5. Assessing study enrollment and likelihood of completion of 600 patients 
randomized 
6. Assessing the study event rate in the placebo group and likelihood of obtaining 
enough events to satisfy the requirements for the primary efficacy analysis 
7. Assessing the event rates in the treatment and placebo groups 
8. Assessing the accumulated SAEs to determine whether the safety stopping 
criteria have been meet 
 
Actions taken by the DSMB will include the following recommendations: 
4. Study termination if stopping criteria for safety or futility have been met 
5. Study modification if the DSMB deems that remediation measures have a 
reasonable probability of successful completion of the study 
6. Continuation of the study as is 
 

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Investigator Responsibilities
 
Study Initiation 
 
Before enrollment of the first subject at the study site, the following documents must 
be on file with the funding provider (BMS/Pfizer): 
1. Current curriculum vitae of the principal investigator and all co-investigators 
2. Current, dated Institutional Review Board (IRB) membership list 
3. Written documentation of IRB protocol approval (protocol number/title and approval 
date) and Informed Consent Form (protocol number/title and approval date) 
4. A copy of the IRB-approved Informed Consent Form (The Informed Consent 
Form must be reviewed by the study Principal Investigator prior to IRB 
submission.) 
 
Study Completion 
 
The following data and materials must be on file at the study site before the study can 
be considered complete or terminated: 
1. Completed electronic case report forms (eCRFs) for all study subjects. 
2. All regulatory documents including: 
a. Curriculum vitae for each investigator and study staff member 
b. Signed confidentiality agreement 
c. Study protocol and protocol amendments 
d. Institutional Review Board approval letter(s) for initial protocol and any 
protocol amendments; as well as continuing review approval letters 
e. All Institutional Review Board correspondence  
f. Study termination letter 
g. Institutional Review Board membership list 
h. Site personnel signature list 
i. Financial Disclosure and Conflict of Interest forms for all site investigators 
j. Patient screening and enrollment logs 
k. Signed study Informed Consent Forms for each subject 
l. Supporting source documentation for values and responses in case report forms 
m. Supporting source documentation for adverse events 
 
Informed Consent 
 
The Informed Consent Form must be signed by the subject before enrollment into the 
study.  A hardcopy of the Informed Consent Form must be provided to the subject.  If 
applicable, informed consent should be obtained using Interpreter Services.  If an 
interpreter is required to explain the study, the informed consent form will be 
document will presented to the patient for signature in the language in which the 
patient is literate. 
 

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Signed Informed Consent Forms must remain in
for verification by the Study Sponsor at all times.  Documentation of the date informed 
consent was obtained and a notation that a signed copy of the Informed Consent Form 
was provided to the study subject should be recorded.  The informed consent process 
must always be conducted in a non-coercive manner. 
 
 
Disclosure of Data 
 
Subject data obtained for this study will be maintained as confidential, and disclosure 
permission, medical information may be given to his or her physician or other medical 
personnel for his or her welfare. 
 
Retention of Records 
 
Records and documents pertaining to the conduct of this study including case report 
forms, signed informed consent forms, protocol and amendments, supporting source 
documentation for values and responses in the case report forms, and supporting 
documentation for adverse events must be retained by the investigators for at least 
two years after conclusion of the study.   
 
Feasibility 
 
 
793-bed acute tertiary care facility 
providing medical and surgical care for patients with general medical, cardiothoracic, 
orthopedic, oncologic, neurologic, obstetric, gynecologic, and gastrointestinal 
conditions.  With the opening of the Heart and Vascular Center in 2014, BWH has 
solidified its position as a world leader in cardiovascular care and research, 
supporting an integrated care model in a single location.  The Watkins Cardiovascular 
Clinic provides care to a large a growing outpatient population from the metropolitan 
cardiovascular medicine outpatient practice in the Watkin Cardiovascular Clinic, 
which is based in the Heart and Vascular Center, includes a large number of referrals 
for VTE and determination of the optimal duration of anticoagulation.  The Watkin 
Cardiovascular Clinic also houses the outpatient practices of an additional seven 
Vascular Medicine faculty members and four Vascular Medicine fellows.  These 
providers will serve as an important additional source of eligible study patients.  The 
Vascular Medicine Section at BWH also staffs the Cardiovascular Medicine 
Consultation Service which evaluates and treats several hundred patients with VTE 
each year.  The vast majority of these patients follow up in our outpatient clinics. 
 
The BWH Thrombosis Research Group 
 

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The Thrombosis Research Group (TRG), directed by Dr. Goldhaber, Professor of 
Medicine, Harvard Medical School and Interim Chief of the Division of Cardiovascular 
Medicine and Section Head of Vascular Medicine, is based at BWH and Harvard 
Medical School.  The Thrombosis Research Group has a decades-long commitment 
to VTE prevention and a dedication to improving the outcomes of all patients at risk 
for VTE.  Dr. Piazza, Associate Professor of Medicine, Harvard Medical School, is the 
Associate Director of the Thrombosis Research Group and Assistant Section Head of 
Vascular Medicine at BWH as well as the Director of the Vascular Medicine Training 
Program.  Dr. Piazza is the Chair of the ACC PVD Section Leadership Council and 
serves on the Scientific Session Planning Committees for the AHA and SVM.  Dr. 
Piazza appreciates the national and global burden of recurrent VTE from his roles 
leading the Vascular Medicine educational initiatives for the ACC and AHA and from 
his perspective as a Co-Investigator on a number of VTE-related clinical trials (34
36) and observational studies (37).  Dr. Piazza is currently leading a clinical trial 
evaluating the safety and efficacy of apixaban for primary prevention of VTE in 
multiple myeloma patients on immunomodulatory regimens known to increase the 
risk of thrombosis (38)
subject recruitment is clearly highlighted in their participation in the 7000-patient, 
multi-center, National Heart Lung and Blood Institute-sponsored Cardiovascular 
Inflammation Reduction Trial (CIRT) (39)
made BWH the top enrolling site for CIRT.  Dr. Goldhaber was the Principal 
Investigator of the ADOPT Trial of apixaban 2.5 mg twice daily for prevention of VTE 
in acutely ill medical patients during hospitalization and in the extended period after 
their discharge from the hospital (22). 
 
The Thrombosis Research Group has an infrastructure of experienced leadership, 
with trained personnel in a multidisciplinary academic team (research pharmacists, 
cardiology fellows, research nurses, research coordinators, biostatisticians, 
administrators, and medical informatics specialists).  Data storage and computing 
resources, as well as a network of regional, national, and international collaborating 
investigators, facilitate our execution of ongoing research projects and our planning of 
future research projects.  The Thrombosis Research Group has studied all aspects of 
VTE, including epidemiology, diagnosis, treatment, and prevention.  According to 
www.pubmed.gov, the group has authored more than 100 Original Reports since 
2010.   
 
Drs. Piazza and Goldhaber have extensive experience leading randomized controlled 
trials focused on prevention and treatment of thromboembolic disease.  Examples of 
major Thrombosis Research Group-lead trials in this area include the 2500-patient 
multicenter Electronic Alert Trial (40), the 2500-patient multicenter Physician Alert 
Trial (41), the 2500-patient Discharge Alert Trial (42), and the 85-patient multicenter 
eTRIS trial (35).   
 
Vascular Medicine at BWH is a regional Center of Excellence for VTE care.  An EPIC 
Electronic Health Record query of the outpatient clinic volume of the five Vascular 
Medicine faculty providers and the 4 full-time Vascular Medicine fellows 

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demonstrated a provoked VTE volume of approximately 1500 new and follow-up 
patients. 
 
 
Table 7. EPIC query estimate of new and follow-up provoked VTE patient volume in 
2018. 
Provider 
Provoked VTE Volume 
(patients/year) 
Piazza 
300 
Goldhaber 
400 
Campia 
400 
Gerhard-Herman 
100 
Sobieszczyk 
100 
4 Full-Time Vascular Medicine Fellows 
200 
TOTAL 
1500 
 
 
Since running this EPIC analysis, we have also added two additional full-time 
Vascular Medicine faculty, Dr. Arvind Pandey and Dr. Laurel Lee.  Both specialize in 
the care of patients with VTE and see frequent referrals for determination of optimal 
duration of anticoagulation and long-term secondary prevention of recurrent events.  
Furthermore, we will recruit from our inpatient cardiovascular medicine consult 
service and cardiovascular medicine ward service which receive a high volume of 
provoked VTE referrals.  Accordingly, we anticipate having the ability to draw on 
these additional sources of provoked VTE patients for at least another 100 provoked 
VTE patients per year. 
 
Even without the added VTE patient volumes of Dr. Pandey and Dr. Lee, we 
calculate 1600 new and follow-up provoked VTE patients who present for outpatient 
visits at BWH per year and we conservatively estimate that 25% will fail to meet all 
the inclusion criteria or will meet at least one exclusion criterion.  Therefore, an 
estimated 1200 patients will be eligible for enrollment in the trial in the first year.   
 
We will also have our research nurse run reports from EPIC to identify other patients 
in our non-Vascular Medicine cardiology practices that will be eligible but may not be 
scheduled to see us.  We will also aggressively communicate the launch of the study 
to our non-Vascular Medicine cardiology colleagues.  Furthermore, we will recruit 
from our inpatient cardiovascular medicine consult service and cardiovascular 
medicine ward service which receive a high volume of provoked VTE.  Accordingly, 
we anticipate having the ability to draw on these additional sources of provoked VTE 
patients for at least another 100 provoked VTE patients per year. 
 
As the trial will enroll over 20 months, we estimate that we will be able to draw from 
1200 patients in the first year and 800 patients in the 8 months that comprise the 
second year of enrollment.  This will yield 2000 patients from which to enroll 600 
subjects for the trial. 

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Based on our prior clinical trial experience at the BWH Thrombosis Research Group, 
we conservatively estimate that 50% of the patients who are screened and found to 
be eligible for the trial will consent to participate.  Therefore, an estimated 1000 
eligible patients would be willing to provide informed consent to participate in the HI-
PRO trial.  Accordingly, enrollment of the planned 600-patient study population 
should be feasible and efficiently accomplished at BWH.   
 
Additionally, the BWH Thrombosis Research Group has the infrastructure to 
operationalize this enrollment plan.  The Thrombosis Research Group has two full-
time dedicated research assistants, a research intern, a research nurse, three faculty 
physicians, a full-time advanced Vascular Medicine fellow, and a number of general 
Cardiovascular Medicine fellows who participate in our research studies.  We have 
coordinated our ongoing research projects to accommodate the percent efforts 
required by our research staff and physician team members to maximize our success 
at enrollment for this trial.  Accordingly, we have adequate staffing and physician 
support to add to the research personnel for this trial, identify eligible patients, and 
maintain our enrollment on track.  We also have an adequate reserve in staffing and 
flexibility to augment our effort should enrollment require it. 
 
 
TRG led the patient recruitment effort for the Cardiovascular Inflammation Reduction 
Trial (CIRT), a randomized, double-blind trial of low-dose methotrexate in 4786 
patients with previous myocardial infarction or multivessel coronary disease who 
additionally had either type 2 diabetes or the metabolic syndrome (39).  CIRT was a 
landmark study which involved a novel application of a challenging anti-inflammatory 
drug, serial laboratory evaluations, and a high number of follow-up phone calls and 
in-person office visits, which required patients to travel from as far as California to 
Boston.  Despite these challenges, TRG made BWH the overall top enrolling site in 
the CIRT trial. 
 
We anticipate rapid enrollment in the HI-PRO trial.  First, all the patients in the study 
will be familiar with anticoagulation and many will have received apixaban.  Second, 
there are no study-mandated laboratory tests or office visits.  Third, many patients 
with provoked VTE are reluctant to discontinue anticoagulation after the acute 
treatment phase because of the fear of recurrent events.  We anticipate that many 
patients with provoked VTE will be highly interested in participating in a clinical trial of 
extended secondary prevention thromboprophylaxis, especially with the favorable 
safety and efficacy profile of low-intensity apixaban.  It is quite possible that greater 
than 50% of eligible patients will want to participate and provide informed consent.  In 
such a scenario, we would expect to enroll more quickly. 
 
Potential Risks and Benefits 
 
Potential benefits to the subject 

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The potential benefit of treatment with low-dose apixaban in patients with provoked 
VTE is secondary prevention of VTE, including fatal PE. 
 
Potential Benefits to Society 
 
The major potential benefit to society of the proposed trial of apixaban for secondary 
prevention of VTE in patients with provoked VTE is that if successful, the study will 
provide the foundation for a new indication for extended-duration anticoagulation for 
VTE prevention. The data acquired from this randomized, placebo-controlled trial will 
establish the safety and efficacy of low-dose apixaban versus placebo for extended 
prevention of recurrence after provoked VTE in patients with at least one persistent 
provoking factor. The study will draw widespread interest for apixaban in the 
extended prevention of recurrence after provoked VTE and will most certainly be of 
interest to high-impact peer-reviewed journals and to a broad spectrum of clinicians 
who will be better able to care for their VTE patients using these data. 
 
Potential Risks to the Subject 
 
The foreseeable risk of apixaban for secondary prevention of VTE in patients with 
provoked VTE is major bleeding. 
 
Risks of Research Procedures Performed on Subjects 
 
The risk of research procedures includes psychological discomfort from participating in a 
clinical trial (less likely) and loss of confidentiality of medical records or economic data (rare).   
 
Women of childbearing potential (able to get pregnant) must have a negative pregnancy 
test before being considered for the study.  It is not known how apixaban could affect an 
unborn child. Women of childbearing potential must use an effective method of birth 
control while participating in this research, as directed by their physician.   
 
Anticipated Risks of Drug 
 
 
Adverse reactions occurring in 1% of patients treated for DVT and PE in the 
AMPLIFY study (source table 6 USPI) 
 Epistaxis 
 Contusion 
 Hematuria  
 Menorrhagia 
 Hematoma 
 Hemoptysis 
 Rectal hemorrhage 
 Gingival bleeding 
 

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Less common adverse reactions occurring in Eliquis-treated patients in AMPLIFY or 
AMPLIFY-EXT studies occurring with a frequency of 0.1% to <1%: 
 
 Blood and lymphatic system disorders: hemorrhagic anemia 
 Gastrointestinal disorders: hematochezia, hemorrhoidal hemorrhage, 
gastrointestinal hemorrhage, hematemesis, melena, anal hemorrhage 
 Injury, poisoning, and procedural complications: wound hemorrhage, 
postprocedural hemorrhage, traumatic hematoma, periorbital hematoma 
 Musculoskeletal and connective tissue disorders: muscle hemorrhage 
 Reproductive system and breast disorders: vaginal hemorrhage, metrorrhagia, 
menometrorrhagia, genital hemorrhage 
 Vascular disorders: hemorrhage 
 Skin and subcutaneous tissue disorders: ecchymosis, skin hemorrhage, 
petechiae 
 Eye disorders: conjunctival hemorrhage, retinal hemorrhage, eye hemorrhage 
 Investigations: blood urine present, occult blood positive, occult blood, red 
blood cells urine positive 
 General disorders and administration-site conditions: injection-site hematoma, 
vessel puncture-site hematoma 
 
Additional information about the risks of apixaban can be found in the Apixaban Med 
Guide (see Appendix). 
 
Protection of Subjects against the Risks of Research Procedures 
 
Before Study Enrollment 
 
A rigorous screening process will be utilized to ensure that subjects with an increased 
risk of harm due to enrollment in the study are excluded from the study.  This will 
include performing a detailed history and physical examination (to ensure that enrolled 
subjects truly fulfill all eligibility criteria) and carefully reviewing the results of laboratory 
testing (in particular, hematocrit, platelet count, INR, and serum creatinine).   
 
During Follow-Up 
 
Changes in health status during the 12-month follow-up period will be evaluated by 
, and other routine providers.  All subjects enrolled will 
also have ongoing medical care with a dedicated Vascular Medicine provider.  As 
apixaban is an FDA-approved drug commonly used for thromboprophylaxis and does 
not require routine follow-up clinical or laboratory monitoring for toxicity, the study will 
not mandate any follow-up visits or procedures other than those required for the 
 
 
 
Protection against Loss of Confidentiality 

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Subject confidentiality will be protected by maintaining all paper records in locked file 
cabinets in locked offices and all electronic records in password-protected computer 
files.  All study data will be de-identified for storage in the electronic data repository.  In 
addition, any identifying information will be removed from images or other data used in 
publication or presentations.  All database information will be stored on computer 
systems that are located behind an electronic firewall, which will only permit access to 
certified study personnel.  Access to study data files will be password-protected.   
 
Use of Information and Publication 
 
All information concerning and relating to the study is considered confidential 
information.  This information includes the clinical investigational plan, case report 
forms (CRFs), training materials, and scientific data.   
 
Ethical Considerations 
 
In this prospective, single-center randomized placebo-controlled study, we will be 
evaluating the impact of apixaban for secondary prevention of VTE in patients with 
provoked VTE with at least one persistent provoking factor.  The benefits of apixaban 
for secondary prevention of VTE in patients with provoked VTE have not been 
assessed.  The risk of bleeding in provoked VTE patients receiving apixaban has not 
been determined.   
 
Because the proposed clinical trial involves a novel application of a U.S. FDA-
approved anticoagulant, we will obtain written consent from all study subjects and 
Institutional Review Board approval at the study site. 
 

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Kearon C, Ageno W, Cannegieter SC, et al. Categorization of patients as 
having provoked or unprovoked venous thromboembolism: guidance from the 
SSC of ISTH. J Thromb Haemost. 2016;14(7):1480 3.  
2.  
Weitz, Jeffrey I. Lensing A, Weitz JI, Lensing AWA, et al. Rivaroxaban or 
aspirin for extended treatment of venous thromboembolism. N Engl J Med. 
2017;376(13):1211 22.  
3.  
Investigators TE. Oral Rivaroxaban for Symptomatic Venous 
Thromboembolism. N Engl J Med. 2010 Dec 23;363:2499 510.  
4.  
Kearon C, Akl EA, Ornelas J, et al. Antithrombotic Therapy for VTE Disease: 
CHEST Guideline and Expert Panel Report. Chest. 2016;149(2):315 52.  
5.  
Thromboembolism as Provoked or Unprovoked. Circulation. 
2018;138(23):2591 3.  
6.  
Goldhaber SZ, Piazza G. Optimal Duration of Anticoagulation After Venous 
Thromboembolism. Circulation. 2011;123(6):664 7.  
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Agnelli G, Buller HR, Cohen A, et al. Apixaban for Extended Treatment of 
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Piazza G, Ridker PM. Is venous thromboembolism a chronic inflammatory 
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9.  
the recurrent nature of venous thromboembolism? Vasc Med. 2015;20(2):102
4.  

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10. 
Søgaard KK, Schmidt M, Pedersen L, et al. 30-Year Mortality After Venous 
Thromboembolism. Circulation. 2014;130(10):829 36.  
11.  Martinez C, Cohen AT, Bamber L, et al. Epidemiology of first and recurrent 
venous thromboembolism: A population-based cohort study in patients without 
active cancer. Thromb Haemost. 2014;112(08):255 63.  
12.  Huang W, Goldberg RJ, Anderson FA, et al. Occurrence and predictors of 
recurrence after a first episode of acute venous thromboembolism: population-
based Worcester Venous Thromboembolism Study. J Thromb Thrombolysis. 
2016;41(3):525 38.  
13.  Prandoni P, Noventa F, Ghirarduzzi A, et al. The risk of recurrent venous 
thromboembolism after discontinuing anticoagulation in patients with acute 
proximal deep vein thrombosis or pulmonary embolism. A prospective cohort 
study in 1,626 patients. Haematologica. 2007;92(2):199 205.  
14.  Granger CB, Alexander JH, McMurray JJ V, et al. Apixaban versus Warfarin in 
Patients with Atrial Fibrillation. N Engl J Med. 2011;365(11):981 92.  
15.  Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus Warfarin in 
Patients with Atrial Fibrillation. N Engl J Med. 2009;361(12):1139 51.  
16.  Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus Warfarin in 
Nonvalvular Atrial Fibrillation. N Engl J Med. 2011;365(10):883 91.  
17.  Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus Warfarin in 
Patients with Atrial Fibrillation. N Engl J Med. 2013 Nov 19;369(22):2093 104.  
18.  Cavallari I, Morrow DA, Creager MA, et al. Frequency, Predictors, and Impact 
of Combined Antiplatelet Therapy on Venous Thromboembolism in Patients 

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With Symptomatic Atherosclerosis. Circulation. 2018;137(7):684 92. 
19.  Vardi M, Piazza G, Pencina MJ, et al. Risk assessment to predict arterial and 
venous events in patients undergoing percutaneous coronary intervention. Clin 
Appl Thromb. 2014;20(5):478 83.  
20.  Piazza G, Goldhaber SZ, Lessard DM, et al. Venous thromboembolism in 
patients with symptomatic atherosclerosis. Thromb Haemost. 
2011;106(6):1095 102.  
21.  Piazza G, Goldhaber SZ. Venous Thromboembolism and Atherothrombosis. 
Circulation. 2010;121(19):2146 50.  
22.  Goldhaber SZ, Leizorovicz A, Kakkar AK, et al. Apixaban versus Enoxaparin for 
Thromboprophylaxis in Medically Ill Patients. N Engl J Med. 2011;365:2167 77.  
23.  Prandoni P, Prins MH, Lensing AWA, et al. An Association between 
Atherosclerosis and Venous Thrombosis. N Engl J Med. 2003;348(15):1435
41.  
24.  Ageno W, Becattini C, Brighton T, et al. Cardiovascular risk factors and venous 
thromboembolism: a meta-analysis. Circulation. 2008;117(1):93 102.  
25.  Dawwas GK, Brown J, Dietrich E, et al. Effectiveness and safety of apixaban 
versus rivaroxaban for prevention of recurrent venous thromboembolism and 
adverse bleeding events in patients with venous thromboembolism: a 
retrospective population-based cohort analysis. Lancet Haematol. 
2019;6(1):e20 8.  
26.  Couturaud F, Sanchez O, Pernod G, et al. Six Months vs Extended Oral 
Anticoagulation After a First Episode of Pulmonary Embolism. JAMA. 

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2015;314(1):31. 
27.  Schulman S, Kearon C, Subcommittee on Control of Anticoagulation of the 
Scientific and Standardization Committee of the International Society on 
Thrombosis and Haemostasis. Definition of major bleeding in clinical 
investigations of antihemostatic medicinal products in non-surgical patients. J 
Thromb Haemost. 2005;3(4):692 4.  
28.  Investigators T van G. Idraparinux versus Standard Therapy for Venous 
Thromboembolic Disease. N Engl J Med. 2007;357(11):1094 104.  
29.  Thygesen K, Alpert JS, Jaffe AS, et al. Third Universal Definition of Myocardial 
Infarction. Circulation. 2012;126(16):2020 35.  
30.  Eikelboom JW, Connolly SJ, Bosch J, et al. Rivaroxaban with or without Aspirin 
in Stable Cardiovascular Disease. N Engl J Med. 2017 Aug 27;377:1319 30.  
31.  Simes J, Becattini C, Agnelli G, et al. Aspirin for the prevention of recurrent 
venous thromboembolism the INSPIRE collaboration. Circulation. 
2014;130(13):1062 71.  
32.  Goldhaber SZ. Risk factors for venous thromboembolism. J Am Coll Cardiol. 
2010;56(1):1 7.  
33.  Schulman S, Kearon C, Kakkar AK, et al. Extended Use of Dabigatran, 
Warfarin, or Placebo in Venous Thromboembolism. N Engl J Med. 2013;  
34.  Everett BM, Pradhan AD, Solomon DH, et al. Rationale and design of the 
Cardiovascular Inflammation Reduction Trial: A test of the inflammatory 
hypothesis of atherothrombosis. Am Heart J. 2013;166(2):199 207.e15.  
35.  Piazza G, Mani V, Goldhaber SZ, et al. Magnetic resonance venography to 

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assess thrombus resolution with edoxaban monotherapy versus parenteral 
anticoagulation/warfarin for symptomatic deep vein thrombosis: A multicenter 
feasibility study. Vasc Med. 2016;21(4):361 8.  
36.  Piazza G, Hohlfelder B, Jaff MR, et al. A Prospective, Single-Arm, Multicenter 
Trial of Ultrasound-Facilitated, Catheter-Directed, Low-Dose Fibrinolysis for 
Acute Massive and Submassive Pulmonary Embolism: The SEATTLE II Study. 
JACC Cardiovasc Interv. 2015;8(10):1382 92.  
37.  Weitz JI, Haas S, Ageno W, et al. Global Anticoagulant Registry in the Field - 
Venous Thromboembolism (GARFIELD-VTE). Rationale and design. Thromb 
Haemost. 2016;116(6):1172 9.  
38.  Cornell RF, Goldhaber SZ, Engelhardt BG, et al. Prospective Study of 
Apixaban for Primary Prevention of Venous Thromboembolism in Patients with 
Multiple Myeloma Receiving Immunomodulatory Therapy. Blood. 
2018;132(Suppl 1):1233.  
39.  Ridker PM, Everett BM, Pradhan A, et al. Low-Dose Methotrexate for the 
Prevention of Atherosclerotic Events. N Engl J Med. 2019;380:752 62.  
40.  Kucher N, Koo S, Quiroz R, et al. Electronic Alerts to Prevent Venous 
Thromboembolism among Hospitalized Patients. N Engl J Med. 2005 Mar 
10;352:969 77.  
41.  Piazza G, Rosenbaum EJ, Pendergast W, et al. Physician Alerts to Prevent 
Symptomatic Venous Thromboembolism in Hospitalized Patients. Circulation. 
2009;119(16):2196 201.  
42.  Piazza G, Anderson FA, Ortel TL, et al. Randomized Trial of Physician Alerts 

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for Thromboprophylaxis after Discharge. Am J Med. 2013;126(5):435 42. 
 
 
 
Table 8. Study Calendar 
Procedure 
Screening 
12-Month 
Follow-Up 
Informed Consent 
X 
Inclusion/Exclusion 
X 
Demographics 
X 
Medical History  
X 
 
Prior/Concomitant Medications  
X 
 
Urine Pregnancy (if clinically indicated) 
X 
Cardio-vascular History 
X 
 
Thrombosis Evaluation 
X 
Bleeding Evaluation 
X 
Pill Diary Collection 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Case Report Form
 
Screening 
Inclusion criteria (all 
must be checked) 
[ ] Age  18 years 
[ ] Objectively-confirmed DVT and/or PE 
[ ] Treated for at least 3 months with standard therapeutic 
anticoagulant therapy 
[ ] Has not suffered symptomatic recurrence during prior 
anticoagulant therapy 
[ ] Outpatient follow-up at BWH 
[ ] Willing to provide written informed consent 
 
AND have at least one of the following persistent provoking 
VTE risk factors: 
[ ] Persistent immobility (defined as paralysis, other 
inability to ambulate freely, bed-bound, wheelchair-
bound) 
[ ] 
 
[ ] Heart failure (systolic, diastolic, or combined) 
[ ] Chronic lung disease (COPD, asthma, interstitial 
lung disease) 
[ ] Chronic kidney disease (eGFR <60 
mL/min/1.72m2)  
[ ] Chronic inflammatory/autoimmune disorder 
(inflammatory arthritis, vasculitis, inflammatory bowel 
disease, chronic infection) 
[ ] Atherosclerotic cardiovascular disease (coronary, 
cerebrovascular, or peripheral artery disease) (up to 
35% in each study group may have atherosclerotic 
cardiovascular disease as a qualifying persistent risk 
factor) 
 
Exclusion criteria 
(NONE must be 
checked) 
[ ] Women who are pregnant or breastfeeding 
[ ] Women of child-bearing potential who are unwilling or 
unable to use an acceptable method of birth control (such as 
oral contraceptives, other hormonal contraceptives [vaginal 
products, skin patches, or implanted or injectable products], 
or mechanical products such as an intrauterine device or 
barrier methods [diaphragm, condoms, spermicides]) to 
avoid pregnancy for the entire study 
[ ] Active cancer within the past 5 years 
[ ] Contraindication to antithrombotic or antiplatelet therapy 
[ ] Requirement for ongoing anticoagulant therapy (including 
atrial fibrillation with a CHADSVASC >1, diagnosed 
antiphospholipid antibody syndrome/deficiency of protein C, 

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S, or antithrombin), dual antiplatelet therapy, P2Y12 
inhibition, or aspirin at a dose of >81 mg daily 
[ ] Hemoglobin level < 9 mg/dL, a platelet count < 
100,000/mm3, a serum creatinine level > 2.5 mg/dL, an ALT 
or AST level > 2 times the upper limit of the normal range, or 
a total bilirubin level > 1.5 times the upper limit of the normal 
range 
[ ] History of a platelet disorder such as Von Willebrand 
Disease 
[ ] History of bleeding diathesis or have had recent active 
bleeding 
[ ] Active hepatobiliary disease 
[ ] More than 6 months that have elapsed without taking an 
anticoagulant or low-dose aspirin 
[ ] Known severe thrombophilia (any increased titer 
antiphospholipid antibody or positive lupus 
anticoagulant/DRVVT or deficiency of antithrombin, protein 
C, or protein S) 
[ ] Life expectancy < 12 months or hospice care 
[ ] Prisoners or subjects who are involuntarily incarcerated 
[ ] Subjects who are compulsorily detained for treatment of 
either a psychiatric or physical (e.g., infectious disease) 
illness 
[ ] Receiving concurrent non-FDA-approved or 
investigational agents or has received an investigational 
agent within the past 30 days prior to the first dose of study 
treatment (with the exception of approved medications being 
used for an approved indication, e.g., investigating a new 
dosing regimen for an approved indication).  
[ ] Any condition, which in the opinion of the investigator, 
would put the subject at an unacceptable risk from 
participating in the study 
[ ] Any other medical, social, logistical, or psychological 
reason, which in the opinion of the investigator, would 
preclude compliance with, or successful completion of, the 
study protocol 
 
STOP HERE AND DO NOT ENROLL PATIENT IF ANY OF THE INCLUSION 
CRITERIA ARE ABSENT OR ANY EXCLUSION CRITERIA ARE PRESENT 
Eligible 
 
[ ] Yes 
[ ] No 
 
Written informed 
consent signed 
[ ] Yes 
[ ] No 
 
 

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Patient Demographics 
Study ID number 
_ _ _ _ _ _ 
Date of enrollment 
           ______/______/________ 
              MM      DD        YYYY 
 
Date of birth 
           ______/______/________ 
              MM      DD       YYYY 
 
Gender 
 
[ ] Male                                         
[ ] Female 
 
Ethnicity 
[ ] Hispanic/Latino 
[ ] Non-Hispanic/Non-Latino 
 
Race 
[ ] American Indian or Alaskan Native 
[ ] Asian 
[ ] White 
[ ] Hispanic or Latino 
[ ] Native Hawaiian or Pacific Islander 
[ ] Black or African-American 
[ ] Mixed race 
[ ] Other, specify:___________ 
 
BMI calculated 
             ___________________(kg/m²) 
 
 
Venous Thromboembolism Characteristics*** 
 
***Patient may have both PE and DVT; if so complete both fields 
Deep Vein 
Thrombosis 
DVT confirmed by imaging (ultrasound, CT, MRI, or 
venogram) 
              [ ] Yes                                        [ ] No 
 
 
Date of imaging diagnosis   ____/____/_____        
                                              MM     DD    YYYY  
             
Site of DVT 
           [ ] Upper extremity                                
           [ ] Pelvic vein 
           [ ] Leg      
[ ] Proximal with calf 
[ ] Proximal without calf 
[ ] Calf only 

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[ ] Other (describe):___________ 
 
Pulmonary 
Embolism 
 PE confirmed by:           
             [ ] Ventilation perfusion scan                                      
             [ ] Chest CT 
             [ ] Contrast pulmonary angiogram   
Hypotension, shock, cardiac arrest or respiratory failure as 
presenting sign of PE: 
              [ ] Yes                                        [ ] No 
RV dysfunction 
              [ ] Yes                                        [ ] No 
Diagnosed by: 
              [ ] CT                                         [ ] Echocardiogram 
Positive cardiac biomarker (troponin or BNP) 
[ ] yes                                            [ ] no 
 
 
Date of imaging confirmed diagnosis ____/____/_____        
                                                           MM     DD     YYYY        
       
Both PE and DVT 
present  
[ ] Yes                                            [ ] No 
Symptomatic DVT 
or PE  
 
[ ] Yes                                            [ ] No 
Advanced therapy 
for VTE 
             [ ] Inferior vena cava filter 
             [ ] Thrombolytic therapy for PE 
             [ ] Catheter thrombectomy for DVT 
             [ ] Catheter direct therapy for PE 
             [ ] Surgical thrombectomy for DVT 
             [ ] Surgical embolectomy for PE 
 
Outpatient VTE 
treatment history 
             [ ] LMWH monotherapy 
             [ ] Fondaparinux  
             [ ] Direct oral anticoagulant 
             [ ] Warfarin 
              
Duration of anticoagulation: 
___ months (enter number out to the tenth place and round-
up; for example 3.48 months would be 3.5 months) 
 

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Persistent Provoking VTE Risk Factors 
Persistent provoking 
VTE risk factors 
(patient must have at 
least one but can have 
multiple; record all 
that apply) 
 
 [ ] Persistent immobility (defined as paralysis, other 
inability to ambulate freely, bed-bound, wheelchair-
bound) 
[ ] 
 
[ ] Heart failure (systolic, diastolic, or combined) 
[ ] Chronic lung disease (COPD, asthma, interstitial 
lung disease) 
[ ] Chronic kidney disease (eGRF <60 
mL/min/1.72m2) 
[ ] Chronic inflammatory/autoimmune disorder 
(inflammatory arthritis, vasculitis, inflammatory bowel 
disease, chronic infection) 
[ ] Atherosclerotic cardiovascular disease (coronary, 
cerebrovascular, or peripheral artery disease) (up to 
35% in each study group may have atherosclerotic 
cardiovascular disease as a qualifying persistent risk 
factor) 
 
 
 
VTE Risk Factors and Comorbid Conditions 
Cardiovascular disease 
[ ] Cardiomyopathy/diminished left ventricular 
systolic function 
If yes, EF (%) ____ 
[ ] Heart failure with reduced EF 
[ ] Heart failure with preserved EF (EF >50%) 
[ ] Coronary artery disease 
If yes,  
Prior CABG [ ] 
Prior coronary stent(s) [ ] 
Prior MI [ ] 
History of unstable angina [ ] 
Stable angina [ ] 
[ ] Valvular heart disease 
[ ] Atrial fibrillation or atrial flutter 
[ ] Pulmonary hypertension 
 
Hypertension 
[ ] Yes                                             
[ ] No 
 
Peripheral artery 
disease 
[ ] Yes                                             
[ ] No 

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Carotid occlusive 
disease 
[ ] Yes                                             
[ ] No 
 
Prior cerebrovascular 
accident (strokes or 
TIAs) 
[ ] Yes                                             
[ ] No 
Family history of VTE 
[ ] Yes 
[ ] No 
 
Prior personal history of 
VTE (other than the 
event that made the 
patient eligible for this 
trial) 
 
[ ] Yes 
[ ] No 
 
Hypercholesterolemia 
[ ] Yes                                             
[ ] No 
 
Chronic liver disease 
(as noted in chart) 
[ ] Yes                                             
[ ] No  
 
If yes, cirrhosis 
[ ] yes 
[ ] no 
 
Cigarette smoking 
(check only 1) 
[ ] Current smoker           
[ ] Former smoker     
[ ] Never smoker       
       
Major surgery within 3 
months of VTE 
diagnosis 
[ ] Yes                                             
[ ] No 
 
If yes, date            ______/______/________ 
                   MM          DD      YYYY 
 
Prior hospitalization 
within 30 days of VTE 
diagnosis 
 
[ ] Yes                                             
[ ] No  
Chronic lung disease 
(COPD, asthma, 
pulmonary fibrosis, 
interstitial lung disease) 
 
[ ] Yes                                             
[ ] No 
 
Diabetes mellitus  
[ ] Yes 

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(Type I or II)
 
[ ] No
 
Inflammatory arthritis 
(rheumatoid arthritis, 
psoriatic arthritis) 
 
[ ] Yes 
[ ] No 
 
Inflammatory bowel 
Disease, Ulcerative 
Colitis) 
 
[ ] Yes 
[ ] No 
 
Inherited thrombophilia 
             [ ] Yes                                        [ ] No 
                              If yes, indicate:     
[ ] Factor V Leiden (heterozygous 
or homozygous)  
[ ] Prothrombin gene mutation 
(heterozygous or homozygous) 
 
Active use of oral 
contraceptive or 
hormone replacement 
at time of VTE 
diagnosis 
 
             [ ] Yes                                        [ ] No 
 
Infectious illness 
requiring antibiotics or 
antiviral therapy within 
3 months of VTE 
diagnosis 
[ ] Yes                                        [ ] No 
Serum creatinine >2.5 
mg/dL  
[ ] Yes                                             
[ ] No                        
 If yes, is patient on dialysis?  
[ ] Yes                                             
[ ] No 
 
If yes, patient should not be enrolled. 
 
Concomitant 
medications 
[ ] aspirin 
If yes, dose = _ _ _ mg/daily 
 
If >81 mg/daily, patient should not be enrolled. 
 
[ ] daily NSAID use 
 
 
 

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Study Treatment Characteristics 
Randomization 
[ ] Oral Apixaban 2.5 mg twice daily 
[ ] Oral placebo twice daily 
 
Date study drug 
started 
____/____/_____        
MM     DD     YYYY              
 
Date study drug 
stopped  
____/____/_____        
MM     DD     YYYY    
 
Completed full 12 months of study drug? 
[ ] Yes 
[ ] No 
 
If did not stay on drug for 12 months, reason why not? 
[ ] Fulfilled criteria for a primary study outcome (recurrent VTE or 
major/clinically relevant non-major bleed) 
[ ] Patient expired 
[ ] Adverse drug event or side-effect 
[ ] Change in clinical status (such as change in goals of care, 
comfort measures, hospice care) 
[ ] Patient preference/withdrawal of consent           
 
Medication 
adherence (via pill 
count) 
Total doses taken/total doses prescribed = ( __ / 720) x 100  
= _ _ _ % 
 
 
12-Month Study Outcomes 
Deep vein thrombosis 
[ ] Yes 
[ ] No 
 
If yes, date ____/____/_____        
                 MM     DD     YYYY              
 
Confirmed by diagnostic imaging: 
[ ] Yes 
[ ] No 
 
If yes, by? 
[ ] Ultrasound 
[ ] CT 
[ ] MRI 
[ ] Venography 
 

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Location:
[ ] Upper extremity 
If checked: 
[ ] Bilateral or SVC 
 
[ ] Lower extremity 
If checked: 
[ ] Bilateral or IVC 
[ ] Proximal (popliteal or higher) 
[ ] Calf 
 
Hospitalized? 
[ ] Yes 
[ ] No 
 
Treatment: 
[ ] Anticoagulation 
[ ] Pharmacomechanical (catheter-based) therapy 
[ ] Surgery 
[ ] IVC filter 
 
Superficial vein thrombosis 
[ ] Yes 
[ ] No 
 
If yes, date ____/____/_____        
                 MM     DD     YYYY              
 
Other venous thrombosis 
(mesenteric, cerebral sinus, 
gonadal, etc.) 
[ ] Yes 
[ ] No 
 
If yes, date ____/____/_____        
                 MM     DD     YYYY              
 
Pulmonary embolism 
[ ] Yes 
[ ] No 
 
If yes, date ____/____/_____        
                 MM     DD     YYYY              
 
Confirmed by diagnostic imaging: 
[ ] Yes 
[ ] No 
 
If yes, by? 
[ ] CT 
[ ] MRI 

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[ ] Pulmonary angiography
[ ] V/Q scan 
 
Location: 
[ ] Unilateral 
[ ] Bilateral 
 
RV dysfunction on echocardiogram or CT? 
[ ] Yes 
[ ] No 
 
Positive cardiac biomarker? 
[ ] Yes 
[ ] No 
 
Associated with hemodynamic or respiratory instability 
(respiratory failure, shock, hypotension, cardiac 
arrest)? 
[ ] Yes 
[ ] No 
 
Fatal? 
[ ] Yes 
[ ] No 
 
Hospitalized? 
[ ] Yes 
[ ] No 
 
Treatment: 
[ ] Anticoagulation 
[ ] Systemic fibrinolysis 
[ ] Pharmacomechanical (catheter-based) therapy 
[ ] Surgical embolectomy 
[ ] IVC filter 
 
Death 
[ ] Yes 
[ ] No 
 
If yes, date ____/____/_____        
                 MM     DD     YYYY              
 
Cause of death: 
[ ] PE 
[ ] Myocardial infarction 
[ ] Stroke  

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[ ] Other cardiovascular 
[ ] Cancer-related 
[ ] Non-cardiovascular, non-cancer 
[ ] Unknown 
 
[ ] CV Death: includes death due to PE, MI, stroke, 
other cardiovascular cause, or unknown 
 
Major or clinically relevant 
non-major bleed 
[ ] Yes 
[ ] No 
 
If yes, date ____/____/_____        
                 MM     DD     YYYY              
 
Major bleed 
[ ] Yes 
[ ] No 
 
If yes, date ____/____/_____        
                 MM     DD     YYYY              
 
Location: 
[ ] Intracranial 
[ ] Surgical/operative site 
[ ] Gastrointestinal 
[ ] Genitourinary 
[ ] Retroperitoneal 
[ ] Pericardial 
[ ] Pulmonary 
[ ] Other thoracic 
[ ] Musculoskeletal 
[ ] Nasopharyngeal 
[ ] Hematocrit or hemoglobin decrease without clear 
source 
[ ] Other 
 
Fatal? 
[ ] Yes 
[ ] No 
 
Hospitalized? 
[ ] Yes 
[ ] No 
 
Associated with hemodynamically instability? 
[ ] Yes 
[ ] No 

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Treatment: 
[ ] Blood products 
[ ] Surgery 
[ ] Invasive procedure 
[ ] Medical therapy (PCC, andexanet, etc.) 
 
Clinically relevant non-major 
bleed 
[ ] Yes 
[ ] No 
 
If yes, date ____/____/_____        
                 MM     DD     YYYY              
 
Location: 
[ ] Intracranial 
[ ] Surgical/operative site 
[ ] Gastrointestinal 
[ ] Genitourinary 
[ ] Retroperitoneal 
[ ] Pericardial 
[ ] Pulmonary 
[ ] Other thoracic 
[ ] Musculoskeletal 
[ ] Nasopharyngeal 
[ ] Hematocrit or hemoglobin decrease without clear 
source 
[ ] Other: _______________ 
 
Hospitalized? 
[ ] Yes 
[ ] No 
 
Treatment: 
[ ] Blood products 
[ ] Surgery 
[ ] Invasive procedure 
[ ] Medical therapy (PCC, andexanet, etc.) 
 
Non-bleed adverse drug 
reaction 
[ ] Yes 
[ ] No 
 
If yes, date ____/____/_____        
                 MM     DD     YYYY              
 
Type of reaction: 
[ ] Anaphylaxis 

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[ ] Cutaneous (rash, etc.)
[ ] Liver function abnormalities 
[ ] Other: _______________ 
 
Hospitalized? 
[ ] Yes 
[ ] No 
 
Study drug discontinuation? 
[ ] Permanent stop 
[ ] Temporary stop 
[ ] Not discontinued 
 
Myocardial infarction 
(defined as the presence of at 
least 2 of the 3 following 
conditions: 
 The detection of a rise 
and/or fall of cardiac 
biomarkers, with at 
least one of the values 
being elevated 
[preferably cardiac 
troponin (cTn) with at 
least one value above 
the 99th percentile 
upper reference limit] 
and with at least one of 
the following:   
(1) symptoms of 
myocardial 
ischemia;  
(2) new (or 
presumably 
new) 
significant 
ST-
segment/T-
wave 
changes or 
left bundle 
branch 
block;  
(3) development 
of 
pathological 
[ ] Yes 
[ ] No 
 
If yes, date ____/____/_____        
                 MM     DD     YYYY              
 
Type: 
[ ] ST elevation 
[ ] Non-ST elevation 
 
Fatal? 
[ ] Yes 
[ ] No 
 
Treatment: 
[ ] Systemic fibrinolysis 
[ ] Percutaneous coronary intervention (angioplasty, 
stenting, etc.) 
[ ] CABG 
[ ] Medical management 
 

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Q waves on 
ECG;  
(4) new loss of 
viable 
myocardium 
or regional 
wall motion 
abnormality 
by imaging; 
(5) identification 
of 
intracoronary 
thrombus by 
angiography 
or autopsy) 
Non-MI coronary 
revascularization  
 
[ ] Yes 
[ ] No 
 
If yes, date ____/____/_____        
                 MM     DD     YYYY              
 
Recascularization: 
[ ] Percutaneous coronary intervention (angioplasty, 
stenting, etc.) 
[ ] CABG 
 
Stroke/TIA 
(defined as a new, focal 
neurologic deficit of sudden 
onset, lasting at least 24 
hours, not due to a readily 
identifiable nonvascular 
cause (i.e. brain tumor, 
trauma), as confirmed by a 
neurologist and 
neuroimaging.) 
 
[ ] Yes 
[ ] No 
 
If yes, date ____/____/_____        
                 MM     DD     YYYY              
 
Confirmation (both must be present): 
[ ] By neurologist 
[ ] By neuroimaging 
 
TIA? 
[ ] Yes 
[ ] No 
 
Stroke? 
[ ] Yes 
[ ] No 
 
If yes, type of stroke: 
[ ] Ischemic 

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[ ] Hemorrhagic
[ ] Other 
 
Fatal stroke? 
[ ] Yes 
[ ] No 
 
 
Treatment: 
[ ] Systemic fibrinolysis 
[ ] Percutaneous thrombectomy 
[ ] Surgery 
[ ] Other 
 
Major adverse limb event  
 
[ ] Yes                                  [ ] No 
 
Acute limb ischemia 
[ ] Yes                                    [ ] No 
 
(Acute limb ischemia defined as limb-threatening 
ischemia which is confirmed by limb hemodynamics or 
imaging and leads to an acute vascular intervention 
within 30 days of onset of symptoms or absent pedal 
pulses) 
 
Critical limb ischemia (CLI) 
[ ] Yes                                   [ ] No 
 
(CLI is defined as continuing ischemic limb, foot or 
digit pain leading to hospitalization and intervention 
and not meeting the definition of ALI, or Fontaine 3 or 
4 at baseline with peripheral intervention during the 
trial) 
 
Peripheral intervention 
[ ] Yes                                   [ ] No 
 
(Peripheral vascular intervention is defined as 
peripheral vascular intervention not meeting the 
definition for ALI or CLI) 
 
Amputation 
[ ] Yes                                   [ ] No 
 
Admission for heart failure 
(HFPEF or HFREF) 
[ ] Yes                                  [ ] No 
 

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Appendix 
 
1. Apixaban Package Insert (Version June 2018) 
https://packageinserts.bms.com/pi/pi_eliquis.pdf 
 
 
2. Eliquis Medication Guide  
https://packageinserts.bms.com/medguide/medguide_eliquis.pdf 
 
3. Informed Consent Form 
 
 
 
 

 
 
 
 
Randomized Controlled Trial of Extended-Duration Low-
Dose Apixaban to Prevent Recurrence in High-Risk 
Patients with Provoked Venous Thromboembolism  
(HI-PRO Trial) 
 
Final version  
BMS Protocol #: CV185-745 
Protocol Version Date: 11/19/2021 
 
 
 
 
 
 
Sponsor:  
Gregory Piazza, MD, MS 
 
Cardiovascular Division 
75 Francis Street 
Boston, MA 02115 
(617) 732-6984 (Phone) 
(617) 738-7652 (Fax) 
gpiazza@partners.org 
 
 
 
 
 
 

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Table of Contents
 
Protocol Summary ...................................................................................................................... 3 
Study Flow Diagram ................................................................................................................... 4 
Study Subject Contact Calendar: ................................................................................................ 5 
Abbreviations and Definitions .................................................................................................... 6 
Study Contacts ............................................................................................................................ 8 
Specific Aims ............................................................................................................................ 11 
Introduction and Background ................................................................................................... 13 
Rationale for the Proposed Study and Trial Design .................................................................. 15 
Study Objectives ....................................................................................................................... 19 
Study Design ............................................................................................................................. 19 
Study Duration .......................................................................................................................... 19 
Study Population ....................................................................................................................... 19 
Study Inclusion Criteria ............................................................................................................ 20 
Study Exclusion Criteria ........................................................................................................... 21 
Screening Procedures ................................................................................................................ 24 
Treatment Description .............................................................................................................. 25 
Safety Outcomes ....................................................................................................................... 26 
Efficacy Outcomes .................................................................................................................... 26 
Drug Accountability.................................................................................................................. 28 
Follow-Up ................................................................................................................................. 29 
Safety Monitor .......................................................................................................................... 30 
Assessment and Reporting of Adverse Events ......................................................................... 30 
Data Reporting, Processing, and Quality Control ..................................................................... 40 
Monitoring Plan ........................................................................................................................ 41 
Statistical Methods .................................................................................................................... 49 
Interim Analysis ........................................................................................................................ 55 
Investigator Responsibilities ..................................................................................................... 56 
Feasibility .................................................................................................................................. 57 
Potential Risks and Benefits ..................................................................................................... 60 
Ethical Considerations .............................................................................................................. 63 
References ................................................................................................................................. 64 
Case Report Form ..................................................................................................................... 70 
Appendix ................................................................................................................................... 85 

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Protocol Summary 
 
Title: Randomized Controlled Trial of Extended-Duration Low-Dose Apixaban to 
Prevent Recurrence in High-Risk Patients with Provoked Venous Thromboembolism 
(HI-PRO Trial) 
 
 
Design: U.S.-based, single-center, randomized placebo-controlled trial. 
 
Brief Treatment Description: Low-dose apixaban (2.5mg twice daily) for extended-
duration secondary prevention of VTE after initial treatment for provoked VTE. 
 
 
Purpose: To establish the safety and efficacy of low-dose apixaban versus placebo 
for extended prevention of recurrence after provoked VTE in patients with at least 
one persistent provoking factor.  
 
 
Population: Outpatients with provoked VTE with at least one persistent provoking 
factor. 
 
 
Enrollment: 600 subjects  
 
Randomization: 1:1 
 
 
Clinical Site Locations: 1 center (
   
 
 
Study Duration: 36 months; enrollment period of up to 20 months with 12-month 
follow-up. 
 
 
Primary Safety and Efficacy Outcomes: 
 
 
Primary Safety Outcome: International Society on Thrombosis and Haemostasis 
(ISTH) major bleeding at 12 months. 
 
Primary Efficacy Outcome: Symptomatic, recurrent VTE, defined as the composite 
of deep vein thrombosis and/or pulmonary embolism at 12 months.  
 
Secondary Safety Outcome:  ISTH clinically relevant non-major bleeding at 12 
months. 
 
Secondary Efficacy Outcome: The composite of death due to cardiovascular 
cause, nonfatal myocardial infarction, stroke or systemic embolism, critical limb 
ischemia, or coronary or peripheral ischemia requiring revascularization (major 
adverse cardiovascular events, including major adverse limb events) at 12 months. 
 

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Follow-Up: Follow-up will consist of Electronic Health Record (EHR) review at 12-
months from study enrollment. 
 
Interim Analysis: An interim analysis for the primary safety and efficacy outcomes 
will be performed when 300 subjects have completed 12-month follow-up. 
 
Study Flow Diagram 
 
 
 
DVT, deep vein thrombosis; PE, pulmonary embolism; VTE, venous 
thromboembolism 
 
Figure 1.  Study flow-diagram for a single-center, randomized placebo-controlled trial 
of extended low-intensity apixaban for high-risk provoked VTE. 
 
 
 
 
 
 
 

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Study Subject Contact Calendar:
 
Date  
Event  
Study Drug  
Enrollment (Month 0) 
Subject will be consented 
by study physician and 
randomized through the 
Investigational Drug 
Service computer 
randomization program.  
3 months of study drug 
(apixaban or placebo) will 
be given during this visit 
or sent to subject within 2 
business days of the 
enrollment visit via mail or 
courier.  
Month 3  
Study nurse check-in  
First 3 months drug 
containers and unused 
drug collected via mail 
and returned to pharmacy 
for proper disposal, 3 
of medication will be given 
or sent to subject.   
Month 6  
Study nurse check-in 
Drug containers and 
unused drug collected via 
mail and returned to 
pharmacy for proper 
disposal, 3 additional 
medication will be given 
or sent to subject.   
Month 9  
Study nurse check-in 
Drug containers and 
unused drug collected via 
mail returned to pharmacy 
for proper disposal, 3 
of medication will be given 
or sent to subject.   
Month 12  
End-of-treatment visit 
All remaining medications, 
drug containers, and 12-
month drug diary will be 
collected. 
 
 
 
 
 
 
 

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Abbreviations and Definitions
 
Listed in alphabetical order 
 
ACCP, American College of Chest Physicians 
 
ALI, acute limb ischemia 
 
ALT, alanine transaminase 
 
AST, aspartate aminotransferase 
 
BMI, body mass index 
 
BMS, Bristol-Myers Squibb 
 
BWH, Brigham and 
 
 
CEC, clinical endpoints committee 
 
CI, confidence interval 
 
CLI, critical limb ischemia 
 
COPD, chronic obstructive pulmonary disease 
 
CrCl, creatinine clearance 
 
CT, computed tomography 
 
cTn, cardiac troponin 
 
DOAC, direct oral anticoagulant  
 
 
 
DSMB, Data Safety Monitoring Board 
 
DVT, deep vein thrombosis 
 
eCRF, electronic case report form 
 
FDA, food and drug administration 
 
FSH, follicle stimulating hormone 
 

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GPV&E, Global Pharmacovigilance & Epidemiology
 
HCG, human chorionic gonadotropin 
 
HRT, hormone replacement therapy 
 
IND, investigational new drug 
 
INR, international normalized ratio 
 
IRB, institutional review board 
 
ISTH, International Society on Thrombosis and Haemostasis 
 
IUD, intrauterine device 
 
LMWH, low-molecular weight heparin 
 
MI, myocardial infarction 
 
MR, magnetic resonance 
 
NOACs, non-vitamin K oral anticoagulants 
 
NSAID, nonsteroidal anti-inflammatory drug 
 
PCC, prothrombin complex concentrate 
 
PE, pulmonary embolism 
 
PI, Proteasome inhibitors 
 
REDCap, Research electronic data capture 
 
SAE, significant adverse event 
 
TRG, thrombosis research group 
 
UADE, unanticipated adverse drug effect  
 
UFH, unfractionated heparin 
 
U.S., United States 
 
VTE, venous thromboembolism 
 

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Study Contacts
 
Study Principal 
Investigator: 
 
Gregory Piazza, MD, MS 
 
75 Francis Street  
Boston MA  02115 
Phone: (617) 732-6984 
Fax: (617) 738-7652 
Email: gpiazza@bwh.harvard.edu 
 
Study Co-Principal 
Investigator: 
 
Samuel Z. Goldhaber, MD 
 
75 Francis Street  
Boston MA  02115 
Phone: 857-307-1932 
Fax: (857) 307-1955 
Email: sgoldhaber@bwh.harvard.edu   
 
Study Co-
Investigator 
Umberto Campia, MD 
 
75 Francis Street  
Boston MA  02115 
Phone: (617) 732-6984 
Fax: (617) 738-7652 
Email: ucampia@bwh.harvard.edu 
 
Jean M. Connors, MD 
 
75 Francis Street  
Boston MA  02115 
Phone: (617) 525-9337 
Fax: 617-264-6388 
Email: jconnors@bwh.harvard.edu 
  
Research Nurse 
Ruth Morrison, RN 
Hospital 
75 Francis Street  
Boston MA  02115 
Phone: (617) 732-6984 
Fax: (617) 738-7652 
Email: rmorrison@bwh.harvard.edu  
 
Research Assistant 
Candrika Dini Khairani, MD, MMSc 
 
75 Francis Street  
Boston MA  02115 

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Phone: (617) 732-6984
Fax: (617) 738-7652 
Email: jesnyder@bwh.harvard.edu  
 
Research 
Pharmacist 
John Fanikos, RPh, MBA 
 
75 Francis St. 
 
Boston, MA 02115 
Phone: (617) 605-3237 
 
Email: jfanikos@bwh.harvard.edu 
 
Data Safety and 
Monitoring Board 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Safety 
Monitor 
Brett Carroll, MD (Chair) 
Beth Israel Deaconess Medical Center 
185 Pilgrim Rd. 
Boston, MA 02215 
Phone: (978) 944-2142 
Email: bcarrol2@bidmc.harvard.edu 
 
Alexander J. Blood, MD 
 
75 Francis St. 
 
Boston, MA 02115 
Phone: (617)-732-7144 
Email: ablood@bwh.harvard.edu 
 
Shelley Hurwitz, PhD (Biostatistician) 
 
75 Francis St. 
 
Boston, MA 02115 
Phone: (617) 584-2943 
Email: Hurwitz@hms.harvard.edu 
 
 
Arvind Pandey, MD 
 
75 Francis St. 
 
Boston, MA 02115 
Phone: (504)-875-5740 
Pager: 34304 
Email: apandey5@bwh.harvard.edu 
 
 
Clinical Endpoints 
Committee 
Laurel Lee, MD 
 
75 Francis St. 
 
Boston, MA 02115 
Phone: (617)-732-5500 

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Pager: 32682
Email: lylee@bwh.harvard.edu 
 
Zaid Almarzooq, MD 
 
75 Francis St. 
 
Boston, MA 02115 
Phone: (617)-732-5500 
Pager: 34290 
Email: zalmarzooq@bwh.harvard.edu 
 
Behnood Bikdeli, MD 
 
75 Francis Street  
Boston MA  02115 
Phone: (617) 732-6984 
Fax: (617) 738-7652 
Email: bbikdeli@bwh.harvard.edu 
 
 
 
 
 
 
 
 
 
 
 
 

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Specific Aims
 
Provoked VTE is traditionally considered a transient acute disorder requiring a limited 
duration of anticoagulant therapy.  Patients who suffer deep vein thrombosis (DVT) or 
pulmonary embolism (PE) following major surgery, major trauma, or periods of 
immobility are generally treated with time-limited anticoagulation for 3 months.  
However, provoked VTE patients have recently been recognized as a heterogeneous 
population comprised of those with transient provoking and persistent provoking risk 
factors (1).  Common risk factors in provoked VTE such as obesity, immobility, 
atherosclerotic cardiovascular disease, heart failure, chronic lung disease, chronic 
kidney disease, and inflammatory disorders frequently contribute to an enduring 
rather than transient risk.   
 
Data from 4,553 patients in the EINSTEIN CHOICE trial and the EINSTEIN VTE 
Continued Treatment Study demonstrate that provoked VTE patients with persistent 
provoking factors have a reduction in recurrence with extended duration 
anticoagulation compared with low-dose aspirin or placebo (1.5% vs. 4.9%) (2,3).  
Common persistent provoking factors included immobility, obesity, heart failure, and 
prevalent, persistent provoking factors are rarely considered when stopping 
anticoagulation in patients with provoked VTE who have completed the typical 3- to 
6-month duration of therapy.  The 2016 American College of Chest Physicians 
(ACCP) Guidelines on Antithrombotic Therapy for VTE do not distinguish between 
transient and persistent provoking risk factors and recommend limited-duration 
anticoagulation for provoked events (4). 
 
However, an emerging opinion is that optimal duration of anticoagulation in provoked 
VTE patients should be determined based on data from the extended duration 
rivaroxaban trials (5).  Such a strategy breaks from the tradition of dichotomizing VTE 
as provoked or unprovoked.  Rather, persisting risk factors such as heart failure, 
obesity, family history of VTE, acquired or hereditary thrombophilia, and 
immobilization are incorporated into the decision-making process for pathways 
focused on secondary prevention.  A suitable long-term strategy for secondary 
prevention has been recommended in evidence-based clinical practice guidelines for 
patients with unprovoked VTE (4).  Extended-duration anticoagulation with warfarin or 
the direct oral anticoagulants (DOACs) is validated and recommended for prevention 
of recurrent unprovoked VTE in patients with a low-risk of bleeding (6).  In a landmark 
extension trial of patients with unprovoked VTE, the AMPLIFY-EXT trial compared 
two doses of apixaban (2.5 mg and 5 mg, twice daily) with placebo in 2486 patients 
with VTE who had completed 6 to 12 months of anticoagulation therapy and for 
whom there was clinical equipoise regarding the need for extended-duration 
anticoagulant therapy for secondary prevention (7).  Symptomatic recurrent VTE or 
death from VTE occurred in 73 of the 829 patients (8.8%) who were receiving 
placebo versus 14 of the 840 patients (1.7%) who were receiving 2.5 mg of apixaban 
and 14 of the 813 patients (1.7%) who were receiving 5 mg of apixaban (p<0.001 for 
both comparisons). In Kaplan-Meier analysis, the apixaban 2.5 mg twice daily 

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regimen demonstrated a major and clinically-relevant nonmajor bleeding rate similar
to that of placebo.   
 
Based on the emerging evidence that provoked VTE patients may require extended-
duration anticoagulation for secondary prevention, the apixaban 2.5 mg twice daily 
dose could be a critical addition to our armamentarium in those at high risk for 
recurrence at the transition of care from the acute to the chronic treatment phase.  
However, this hypothesis needs to be tested in a randomized clinical trial.  We 
propose a single-center, randomized placebo-controlled trial conducted at Brigham 
BWH) to evaluate the impact of low-dose apixaban (2.5 mg 
twice daily) in a study population exclusively comprised of provoked VTE patients 
with at least one persistent provoking factor.  We have the following study aims: 
 
Specific Aim #1: To compare the 12-month rate of recurrent symptomatic VTE in 
patients with provoked VTE and at least one persistent provoking factor who are 
randomized to either apixaban (2.5 mg orally twice daily) as monotherapy or placebo 
after completing at least 3 months of therapeutic anticoagulation and who have a low 
risk of bleeding. 
 
Hypothesis #1: Compared with placebo, oral apixaban (2.5 mg twice daily) will 
reduce the 12-month rate of symptomatic VTE in patients with provoked VTE and at 
least one persistent provoking factor who have completed at least 3 months of 
therapeutic anticoagulation and who have a low risk of bleeding. 
 
Specific Aim #2: To compare the 12-month rate of ISTH major bleeding in patients 
with provoked VTE and at least one persistent provoking factor who are randomized 
to either apixaban (2.5 mg orally twice daily) as monotherapy or placebo after 
completing at least 3 months of therapeutic anticoagulation and who have a low risk 
of bleeding. 
 
Hypothesis #2: Compared with placebo, oral apixaban (2.5 mg twice daily) will be 
associated with a similar rate of ISTH major bleeding at 12 months in patients with 
provoked VTE and at least one persistent provoking factor who are randomized to 
either apixaban (2.5 mg orally twice daily) as monotherapy or placebo after 
completing at least 3 months of therapeutic anticoagulation and who have a low risk 
of bleeding. 
 
 
 
 
 
 
 
 

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Introduction and Background
 
Provoked venous thromboembolism (VTE) is traditionally considered a transient 
acute disorder requiring a limited duration of anticoagulant therapy.  Patients who 
suffer deep vein thrombosis (DVT) or pulmonary embolism (PE) following major 
surgery, major trauma, or periods of immobility are generally treated with time-limited 
anticoagulation for 3 months.  However, provoked VTE patients have recently been 
recognized as a heterogeneous population comprised of those with transient 
provoking and persistent provoking risk factors (1).  Common risk factors in provoked 
VTE such as obesity, immobility, atherosclerotic cardiovascular disease, heart failure, 
chronic lung disease, chronic kidney disease, and inflammatory disorders frequently 
contribute to an enduring rather than transient risk.  Furthermore, epidemiological 
studies (8,9) and the randomized clinical trial EINSTEIN CHOICE (3) suggest that 
VTE is best characterized as a chronic disorder with periodic relapses.  A landmark 
Danish National Registry analysis demonstrated that patients who suffer provoked or 
unprovoked VTE have an increased risk of recurrence over the ensuing 30 years and 
that recurrent PE causes increased mortality (10).  While the rate of VTE recurrence 
ranges 30-50% over 10 years for unprovoked VTE (also termed idiopathic; 
unprovoked implies that an immediate trigger for the VTE cannot be identified), 
recurrent events occur in about 20% of patients over 10 years after a provoked event 
(provoked VTE is defined as post-operative, post-major trauma, post-hospitalization, 
or related to pregnancy, hormonal contraception/replacement therapy, or immobility) 
(11 13).  Based on these data, provoked VTE patients represent a population 
vulnerable to VTE recurrence, especially at the transition of care from the initial 
(acute) treatment phase to the chronic treatment phase, at which point 
anticoagulation is discontinued in most of these patients.   
 
The EINSTEIN CHOICE trial recently evaluated the safety and efficacy of regimens 
of full- or lower-intensity anticoagulant therapy versus low-dose aspirin for secondary 
prevention of VTE after an initial provoked or unprovoked event (2).  The EINSTEIN 
CHOICE Investigators randomly assigned 3396 patients with VTE to receive either 
once-daily rivaroxaban (at doses of 20 mg or 10 mg) or 100 mg of aspirin.  Prior to 
enrollment in EINSTEIN CHOICE, all study patients completed 6 to 12 months of 
anticoagulation therapy, and their providers were in equipoise regarding the need for 
extended anticoagulation.  Approximately 60% of patients in EINSTEIN CHOICE had 
suffered provoked VTE.  Symptomatic recurrent VTE occurred in 17 of 1107 patients 
(1.5%) receiving 20 mg of rivaroxaban and in 13 of 1127 patients (1.2%) receiving 10 
mg of rivaroxaban, and in 50 of 1131 patients (4.4%) receiving low-dose aspirin 
(hazard ratio for 20 mg of rivaroxaban vs. aspirin, 0.34; 95% confidence interval [CI], 
0.20 to 0.59; hazard ratio for 10 mg of rivaroxaban vs. aspirin, 0.26; 95% CI, 0.14 to 
0.47; P<0.001 for both comparisons).  Rates of major bleeding were similar (0.5% in 
the group receiving 20 mg of rivaroxaban, 0.4% in the group receiving 10 mg of 
rivaroxaban, and 0.3% in the low-dose aspirin group) (2).   
 
Data from 4,553 patients in EINSTEIN CHOICE and the EINSTEIN VTE Continued 
Treatment Study demonstrate that provoked VTE patients with persistent provoking 

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14 
 
factors have a reduction in recurrence with extended duration anticoagulation 
compared with low-dose aspirin or placebo (1.5% vs. 4.9%) (2,3).  Common 
persistent provoking factors included immobility, obesity, heart failure, and chronic 
 and rheumatoid arthritis.  Despite 
being highly prevalent, persistent provoking factors are rarely considered when 
stopping anticoagulation in patients with provoked VTE who have completed the 
typical 3- to 6-month duration of therapy.  The 2016 American College of Chest 
Physicians (ACCP) Guidelines on Antithrombotic Therapy for VTE do not distinguish 
between transient and persistent provoking risk factors and recommend limited-
duration anticoagulation for provoked events (4). 
 
However, an emerging opinion is that optimal duration of anticoagulation in provoked 
VTE patients should be determined based on data from the extended duration 
rivaroxaban trials (5).  Such a strategy breaks from the tradition of dichotomizing VTE 
as provoked or unprovoked.  Rather, persisting risk factors such as heart failure, 
obesity, family history of VTE, acquired or hereditary thrombophilia, and 
immobilization are incorporated into the decision-making process for pathways 
focused on secondary prevention. 
 
A suitable long-term strategy for secondary prevention has been recommended in 
evidence-based clinical practice guidelines for patients with unprovoked VTE (4).  
Extended-duration anticoagulation with warfarin or the direct oral anticoagulants 
(DOACs) is validated and recommended for prevention of recurrent unprovoked VTE 
in patients with a low-risk of bleeding (6).  However, current evidence-based clinical 
practice guidelines are inadequate for secondary prevention in patients with provoked 
VTE based on several extended-duration anticoagulation trials that included patients 
with provoked and unprovoked VTE.  In a randomized controlled trial of rivaroxaban 
for extended-duration secondary prevention in patients with either provoked (26%) or 
unprovoked (74%) DVT, recurrent VTE occurred in 8 patients (1.3%) in the 
rivaroxaban group compared with 42 patients (7.1%) in the placebo group (hazard 
ratio, 0.18; 95% CI, 0.09 to 0.39; P<0.001, relative risk reduction, 82%) (3).   
 
In a landmark extension trial of patients with unprovoked VTE, the AMPLIFY-EXT trial 
compared two doses of apixaban (2.5 mg and 5 mg, twice daily) with placebo in 2486 
patients with VTE who had completed 6 to 12 months of anticoagulation therapy and 
for whom there was clinical equipoise regarding the need for extended-duration 
anticoagulant therapy for secondary prevention (7).  Symptomatic recurrent VTE or 
death from VTE occurred in 73 of the 829 patients (8.8%) who were receiving 
placebo versus 14 of the 840 patients (1.7%) who were receiving 2.5 mg of apixaban 
and 14 of the 813 patients (1.7%) who were receiving 5 mg of apixaban (p<0.001 for 
both comparisons). In Kaplan-Meier analysis, the apixaban 2.5 mg twice daily 
regimen demonstrated a major and clinically-relevant nonmajor bleeding rate similar 
to that of placebo.  While approximately 9% of the patients in the AMPLIFY-EXT trial 
had transient or reversible risk factors for VTE, the provoked VTE population only 
accounted for approximately 200 patients and precluded a well-powered analysis.  
Furthermore, the intent of the AMPLIFY-EXT trial was to study unprovoked VTE (7).  

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Finally, the HI-PRO trial is evaluating a more complex aspect of VTE secondary 
prevention.  Rather than using the simple dichotomized view of VTE as provoked or 
unprovoked, HI-PRO is focusing on how the risk of recurrence in patients with 
persisting provoking factors may be modulated by low-dose apixaban.  The 
foundation of this question is based on the current direction in which the field of VTE 
is moving (5) and supported by the more pathophysiologically-sound ISTH 
classification of risk factors (1). 
 
Apixaban 2.5 mg twice daily may have additional advantages for extended-duration 
secondary prevention of VTE compared with rivaroxaban 10 mg daily (which has U.S. 
FDA approval for extended-duration therapy).  Apixaban is a more 
pharmacokinetically rational regimen, given the half-life of these two DOACs.  In trials 
of stroke prevention of atrial fibrillation, apixaban demonstrated a relatively lower 
frequency of gastrointestinal bleeding compared with warfarin (14 17).  Apixaban has 
fewer off-target side effects than rivaroxaban, which can cause severe headache 
(necessitating urgent head CT) and severe rash.   
 
Based on the emerging evidence that provoked VTE patients may require extended-
duration anticoagulation for secondary prevention, the apixaban 2.5 mg twice daily 
dose could be a critical addition to our armamentarium in those at high risk for 
recurrence at the transition of care from the acute to the chronic treatment phase.  
However, this hypothesis needs to be tested in a clinical trial.  We propose a single-
(BWH) to evaluate the feasibility of low-dose apixaban (2.5 mg twice daily) in a study 
population exclusively comprised of provoked VTE patients with persistently 
provoking risk factors for VTE. 
 
 
Rationale for the Proposed Study and Trial Design 
 
The rationale for the study design is focused on the lack of data on the safety and 
efficacy of extended-duration low-dose apixaban for secondary prevention in patients 
with provoked VTE.  A single-center, randomized placebo-controlled trial of extended 
low-intensity apixaban with a study population enriched for recurrent VTE event rates 
will be able to provide such data.   
 
The rationale for a single-center study is that Watkins Cardiovascular Clinic at BWH 
is a Center of Excellence for thrombosis care not only in the New England region but 
also along the East coast.  The BWH Thrombosis Center evaluates an average of 
1200 new and follow-up outpatients with VTE per year.  In addition, the Vascular 
Medicine Section at BWH includes 4 additional full-time faculty and 4 full-time 
Vascular Medicine fellows who also see a high volume of VTE patients.  Accordingly, 
enrollment of 600 patients meeting the entry criteria and none of the exclusion criteria 
will be accomplished efficiently at our single center. 
 

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The rationale behind using a low-dose of apixaban is three-fold.  First, low-dose 
rivaroxaban 10 mg orally daily was effective and safe in the EINSTEIN CHOICE trial 
(2) for extended-duration anticoagulation in secondary prevention after unprovoked 
VTE.  Second, AMPLIFY-EXT demonstrated efficacy and enhanced safety to a low-
dose apixaban regimen (2.5 mg orally twice daily) for extended-duration 
anticoagulation in secondary prevention after predominantly unprovoked VTE (7).  
Finally, because the relative risk of recurrence is less (although still unacceptably 
high) for provoked VTE than unprovoked VTE, a lower dose of apixaban may 
maintain efficacy while offering a reduction in the risk of major and clinically-relevant 
non-major bleeding. 
 
The rationale for using low-dose apixaban in a study population that will include 
obese patients is that an analysis of the AMPLIFY-EXT data by weight demonstrated 
results for the primary efficacy outcome and the composite outcome of major and 
clinically relevant nonmajor bleeding were consistent with overall study results (7). 
 
The rationale for using a placebo-control is that current evidence-based guidelines do 
not recommend any extended thromboprophylactic measures after provoked VTE.  
Trials of low-dose aspirin for secondary prevention of VTE have largely focused on 
unprovoked VTE or a mixed population of unprovoked and provoked VTE.  In the 
EINSTEIN CHOICE trial, low-dose aspirin was associated with a bleeding risk similar 
to anticoagulation with rivaroxaban and a recurrent VTE rate 70% higher than 
anticoagulation with rivaroxaban (2). 
 
aspirin is based on several factors.  First, the HI-PRO trial will include atherosclerotic 
cardiovascular disease, which will enrich the study population in VTE events because 
of the strong pathophysiological link between the two (18 21).  Many of these 
patients will be receiving low-
eligible patients will be receiving low-
cardiovascular events.  Excluding these patients would significantly hinder 
enrollment.  Finally, none of the major landmark trials of low-intensity apixaban (2.5 
mg twice daily) excluded patients taking low-
-EXT 
and ADOPT allowed up to 165 mg of aspirin daily (7,22).   
 
Atherosclerosis is associated with an increased risk of VTE.  A link between 
atherosclerotic cardiovascular disease and VTE was first suggested by Prandoni and 
colleagues, who observed that the presence of carotid plaque was associated with a 
doubling in VTE risk (23).  Many risk factors for VTE, such as obesity, hypertension, 
dyslipidemia, diabetes, and smoking, overlap with those for atherosclerosis (21,24).  
The link between VTE and atherosclerotic cardiovascular disease also appears to be 
reciprocal.  A recent analysis of TRA2P-TIMI 50 (Thrombin Receptor Antagonist in 
Secondary Prevention of Atherothrombotic Ischemic Events-Thrombolysis in 
Myocardial Infarction) and PEGASUS-TIMI 54 (Prevention of Cardiovascular Events 
in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a 
Background of Aspirin-Thrombolysis in Myocardial Infarction 54) demonstrated the 

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risk of VTE increased with the number of symptomatic vascular territories affected by 
atherosclerosis (18).  A recent editorial in Circulation called for medicine to abandon 
the dichotomized view of VTE as provoked or unprovoked and called for the basis of 
the optimal duration of anticoagulation to be determined by persisting risk factors, 
including cardiovascular disease (5).  Because of the potential for a majority of 
patients in the study to have atherosclerotic cardiovascular disease limiting the 
generalizability of the results, up to 35% in each study group may have 
atherosclerotic cardiovascular disease as a qualifying persistent risk factor. 
 
The rationale for enrollment at 3-months is derived from the 2016 American College 
of Chest Physicians (ACCP) evidence-based clinical practice document entitled 
with proximal DVT or pulmonary embolism (PE), we recommend 
long-
(Kearon C, Akl EA, Ornelas J, et al. Antithrombotic Therapy for VTE Disease: CHEST 
Guideline and Expert Panel Report. Chest 2016;149:315-52).  This statement 
supports the 3-month timepoint as an appropriate juncture to determine whether 
extended duration anticoagulation or discontinuation of antithrombotic therapy is 
appropriate. 
 
The 2016 ACCP evidence-based clinical practice guidelines rely upon a more 
traditional classification for determining the risk of VTE recurrence after 3 months, a 
that has subsequently fallen out of favor.  The 2016 ACCP guidance document states 
the following regarding extended-duration antithrombotic therapy for prevention of 
recurrent VTE: 
 
recommend treatment with anticoagulation for 3 months over (i) treatment of a 
shorter period (Grade 1B), (ii) treatment of a longer time-limited period (eg, 6, 12, or 
24 months) (Grade 1B), or (iii) extended therapy (no scheduled stop date) (Grade 
1B). 
 
In patients with a proximal DVT of the leg or PE provoked by a nonsurgical transient 
risk factor, we recommend treatment with anticoagulation for 3 months over (i) 
treatment of a shorter period (Grade 1B) and (ii) treatment of a longer time-limited 
period (eg, 6, 12, or 24 months) (Grade 1B). We suggest treatment with 
anticoagulation for 3 months over extended therapy if there is a low or moderate 
bleeding risk (Grade 2B), and recommend treatment for 3 months over extended 
therapy if there is a high risk of 
 
 
These guidelines fail to address the large population of patients with VTE who may 
have had a provoking factor but also have enduring risk factors for recurrence, such 
as those with persistent immobility, obesity, heart failure, chronic lung disease, 
chronic kidney disease, chronic inflammatory/autoimmune disorder, and 
atherosclerotic cardiovascular disease (Albertsen IE, Piazza G, Goldhaber SZ. Let's 

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18 
 
Stop Dichotomizing Venous Thromboembolism as Provoked or Unprovoked. 
Circulation. 2018 Dec 4;138(23):2591-2593 and Albertsen IE, Piazza G, Søgaard M, 
Nielsen PB, Larsen TB. Extended oral anticoagulation after incident venous 
thromboembolism - a paradigm shift? Expert Rev Cardiovasc Ther. 2020 
Apr;18(4):201-208).   
 
More recently, the 2019 European Society of Cardiology Guidelines for the Diagnosis 
and Management of Acute Pulmonary Embolism, developed in collaboration with the 
European Respiratory Society (ERS), have recognized the importance of identifying 
persistent, or enduring, risk factors for VTE recurrence (Konstantinides SV, Meyer G, 
Becattini C, et al. 2019 ESC Guidelines for the diagnosis and management of acute 
pulmonary embolism developed in collaboration with the European Respiratory 
Society (ERS). Eur Heart J 2019).  This paradigm shift away from the previous 
endorsed by the International Society on Thrombosis and Haemostasis (ISTH), which 
recommends that clinicians consider persistent predisposing factors when 
determining whether to extend anticoagulation beyond 3 months (Kearon, C, Ageno, 
W, Cannegieter, SC, Cosmi, B, Geersing, G J and Kyrle, PA, for the Subcommittees 
on Control of Anticoagulation, and Predictive and Diagnostic Variables in Thrombotic 
Disease. Categorization of patients as having provoked or unprovoked venous 
thromboembolism: guidance from the SSC of ISTH. J Thromb Haemost 2016; 14: 
1480-3). 
 
Accordingly, the 2019 European Society of Cardiology Guidelines state that the 
decision to pursue extended-duration anticoagulation should rest upon recognition of 
both transient risk factors for VTE but also the presence of persistent, or enduring, 
conditions that result in a prolonged risk of VTE recurrence after an initial event.  
These include chronic medical disorders like inflammatory bowel disease, connective 
tissue disease, and other hypercoagulable states.  Rather than dichotomizing VTE 
patients in
Guidelines recommend assessment of persistent predisposing factors and an 
estimated long-term recurrence risk (if anticoagulation is discontinued after 3 
months).  The Guidelines suggest that only patients with an estimated recurrence risk 
of less than 3% per year should receive time-limited treatment (see figure below).  
Patients with greater than 8% risk of recurrence per year (for example, those with 
cancer-related VTE) are mandated to receive indefinite duration anticoagulation.  
There is clinical and research equipoise for the patient population that has an 
intermediate risk for recurrence (3-8% risk of recurrence per year). 
 
The inclusion and exclusion criteria for the current study follows the evidence-based 
clinical practice guideline recommendations from the ESC and ISTH and identify a 
population of patients with VTE who have a 3-8% of VTE recurrence per year.  We 
have estimated a 12-month VTE recurrence rate of 6% in our proposed study 
population, exactly within this range of clinical and research equipoise. 
 

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Study Objectives
 
Primary Safety Objective: To quantitatively assess the International Society on 
Thrombosis and Haemostasis (ISTH) major bleeding at 12 months. 
 
Primary Efficacy Objective: To quantitatively assess the 12-month rate of 
symptomatic, recurrent VTE, defined as the composite of deep vein thrombosis 
and/or pulmonary embolism.  
 
 
Secondary Safety Objective: To quantitatively assess the 12-month rate of ISTH 
clinically relevant non-major bleeding. 
 
Secondary Efficacy Objective: To quantitatively assess the composite of death due 
to cardiovascular cause, nonfatal myocardial infarction, stroke or systemic embolism, 
critical limb ischemia, or coronary or peripheral ischemia requiring revascularization 
(major adverse cardiovascular events, including major adverse limb events) at 12 
months. 
 
Study Design 
 
600-patient U.S.-based, single-center, randomized, double-blinded, placebo-
controlled study of apixaban 2.5 mg orally twice daily for extended prevention of 
recurrence after provoked VTE in patients with at least one persistent provoking 
factor who have completed at least 3 months of standard therapeutic anticoagulation 
and who have a low risk of bleeding. 
 
Study Duration 
 
The study will be completed in 36 months: 2 months for start-up (including Human 
Research Committee/Institutional Review Board [IRB] approval and finalizing the 
Case Report Form), 32 months for patient enrollment, follow-up, and data collection, 
and 2 months for data analysis and writing up the results (Table 1). 
 
Table 1.  Study timeline. 
Milestone 
Duration (months) 
Start-up 
2 
Patient enrollment 
20 
Completion of data collection 
12 
Data analysis and completion of study report 
2 
TOTAL 
36 
 
Study Population 
 

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Patients who are 18 years of age or older with provoked deep vein thrombosis and/or 
pulmonary embolism, have completed at least 3 months of therapeutic 
anticoagulation, have a low risk of bleeding, and have at least one persistent 
provoking risk factor. 
 
Low risk of bleeding is defined by several of the exclusion criteria: 
 have contraindications to antithrombotic or antiplatelet therapy  
 have a requirement for ongoing anticoagulant therapy, dual antiplatelet 
therapy, or aspirin at a dose of > 81 mg daily 
 have a hemoglobin level < 9 mg/dL, a platelet count < 100,000/mm3, a serum 
creatinine level > 2.5 mg/dL, an ALT or AST level > 2 times the upper limit of 
the normal range, or a total bilirubin level > 1.5 times the upper limit of the 
normal range 
 have history of bleeding diathesis or have had recent active bleeding 
 have active hepatobiliary disease 
 
In a recent propensity score-
-
diagnosed VTE patients in the Truven Health MarketScan commercial and Medicare 
Supplement claims databases in the U.S., apixaban compared with rivaroxaban was 
associated with an optimal balance of decreased risk of recurrent VTE (HR 0.37 [95% 
CI 0.24 0.55]; p<0·0001) and major bleeding events (0·54 [0·37 0·82]; p=0.0031) 
(25).  Based on these data, we believe that apixaban will provide superb efficacy and 
safety compared with placebo in the prespecified high-risk for VTE recurrence and 
low-risk for bleeding patient population of HI-PRO. 
 
Study Inclusion Criteria 
 
 Man or woman 
 Age  18 years 
 Objectively-confirmed provoked DVT and/or PE 
(Note: including post COVID-19 infection and post COVID-19 vaccination) 
 Treated for at least 3 months with standard therapeutic anticoagulant therapy  
 Has not suffered symptomatic recurrence during prior anticoagulant therapy 
 Outpatient follow-up at BWH 
 AND have at least one of the following persistent provoking VTE risk factors: 
o Persistent immobility (defined as paralysis, other inability to ambulate 
freely, bed-bound, wheelchair-bound) 
o 
 
o Heart failure (systolic, diastolic, or combined) 
o Chronic lung disease (COPD, asthma, interstitial lung disease) 
o Chronic kidney disease (eGFR <60 mL/min/1.73m2)  
o Chronic inflammatory/autoimmune disorder (inflammatory arthritis, 
vasculitis, inflammatory bowel disease, chronic infection) 
o Atherosclerotic cardiovascular disease (coronary, cerebrovascular, or 
peripheral artery disease) (up to 35% in each study group may have 

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21 
 
atherosclerotic cardiovascular disease as a qualifying persistent risk 
factor) 
o NOTE:  Eligible patients will be allowed to have multiple risk factors, 
and there will not be a limit as to how many of the above risk factors a 
subject may have.  In addition, we will place no limit on the number of 
patients included with multiple risk factors.  A study population with 
multiple risk factors is highly representative of the provoked VTE 
population and will provide the greatest generalizability of the study 
results to real-world clinical practice.  Including patients with single and 
multiple persistent provoking risk factors will also facilitate enrollment.  
As noted, there is clinical and research equipoise regarding whether 
patients with a single or multiple persistent provoking VTE risk factors 
should receive extended duration thromboprophylaxis for secondary 
prevention.   
 Willing to provide written informed consent 
 
Study Exclusion Criteria 
 
 Women who are pregnant or breastfeeding 
 Women of child-bearing potential who are unwilling or unable to use an 
acceptable method of birth control (such as oral contraceptives, other 
hormonal contraceptives [vaginal products, skin patches, or implanted or 
injectable products], or mechanical products such as an intrauterine device or 
barrier methods [diaphragm, condoms, spermicides]) to avoid pregnancy for 
the entire study 
 Active cancer within the past 5 years 
 Contraindication to antithrombotic or antiplatelet therapy 
 Requirement for ongoing anticoagulant therapy, dual antiplatelet therapy, 
P2Y12 inhibition, or aspirin at a dose of > 81 mg daily 
 Hemoglobin level < 9 mg/dL, a platelet count < 100,000/mm3, a serum 
creatinine level > 2.5 mg/dL or CrCl <25 mL/minute (as determined by 
Cockcroft-Gault equation), an ALT or AST level > 2 times the upper limit of the 
normal range, or a total bilirubin level > 1.5 times the upper limit of the normal 
range 
 History of a platelet disorder such as Von Willebrand Disease  
 History of bleeding diathesis or have had recent active bleeding 
 Active severe hepatobiliary disease 
 More than 6 months that have elapsed without taking an anticoagulant or low-
dose aspirin 
o NOTE: The risk of recurrent VTE following cessation of anticoagulation 
rises slowly over the first 3-6 months (26).  After this initial period, the 
cumulative risk of recurrent VTE steepens.  Using a limit of no greater 
than 6 months of interruption in anticoagulation before potential re-
initiation of anticoagulation as part of this trial will safely facilitate 

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enrollment as opposed to restricting the population to no greater than 3 
months of interruption. 
 Known severe thrombophilia (any increased titer antiphospholipid antibody or 
positive lupus anticoagulant/DRVVT or deficiency of antithrombin, protein C, or 
protein S) which would indicate long-term full therapeutic anticoagulation with 
a vitamin K antagonist 
 Life expectancy < 12 months or hospice care 
 Prisoners or subjects who are involuntarily incarcerated 
 Subjects who are compulsorily detained for treatment of either a psychiatric or 
physical (e.g., infectious disease) illness 
 Receiving concurrent non-FDA-approved or investigational agents or has received an 
investigational agent within the past 30 days prior to the first dose of study treatment (with 
the exception of approved medications being used for an approved indication, e.g., 
investigating a new dosing regimen for an approved indication)  
 Any condition, which in the opinion of the investigator, would put the subject at 
an unacceptable risk from participating in the study 
 Any other medical, social, logistical, or psychological reason, which in the 
opinion of the investigator, would preclude compliance with, or successful 
completion of, the study protocol 
 History of a severe hypersensitivity reaction to apixaban 
 Required prescription of a medication that is contraindicated to be co-
administered with apixaban 
 
Enrollment of Women of Childbearing Potential and Partners 
 
 All of the following criteria must be met for women of childbearing potential and 
their partners:  Women of childbearing potential must have a negative serum 
or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of 
HCG) within 24 hours prior to the start of study drug. 
 Women must not be breastfeeding. 
 Women of childbearing potential must agree to follow instructions for 
method(s) of contraception for the duration of treatment with study drug 6 
months plus 5 half-lives of study drug (2.5 days) plus 30 days (duration of 
ovulatory cycle) for a total of 212.5 days post-treatment completion. 
 Males who are sexually active with women of childbearing potential must 
agree to follow instructions for method(s) of contraception for the duration of 
treatment with study drug 6 months plus 5 half-lives of the study drug (2.5 
days) plus 90 days (duration of sperm turnover) for a total of 272.5 days post-
treatment completion. 
 Azoospermic males and women of childbearing potential who are continuously 
not heterosexually active are exempt from contraceptive requirements.  
However, women of childbearing potential who are continuously not 
heterosexually active must still undergo pregnancy testing. 
 
Investigators will counsel women of childbearing potential and male subjects who are 
sexually active with women of childbearing potential on the importance of pregnancy 

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prevention and the implications of an unexpected pregnancy Investigators will advise 
women of childbearing potential and male subjects who are sexually active with 
women of childbearing potential on the use of highly effective methods of 
contraception. Highly effective methods of contraception have a failure rate of < 1% 
when used consistently and correctly. 
 
At a minimum, subjects must agree to the use of one method of highly effective 
contraception as listed below: 
 Male condoms with spermicide 
 Hormonal methods of contraception including combined oral contraceptive 
pills, vaginal ring, injectables, implants and hormone-impregnated intrauterine 
devices (IUDs) by women of childbearing potential subject.  Female partners 
of male subjects participating in the study may use hormone based 
contraceptives as one of the acceptable methods of contraception since they 
will not be receiving study drug.  
 IUDs 
 Tubal ligation 
 Vasectomy 
 Complete Abstinence* 
 
*Complete abstinence is defined as complete avoidance of heterosexual intercourse 
and is an acceptable form of contraception for all study drugs. Female subjects must 
continue to have pregnancy tests. Acceptable alternative methods of highly effective 
contraception must be discussed in the event that the subject chooses to forego 
complete abstinence. 
 
A woman of childbearing potential is defined as any female who has experienced 
menarche and who has not undergone surgical sterilization (hysterectomy or bilateral 
oophorectomy) and is not postmenopausal. Menopause is defined as 12 months of 
amenorrhea in a woman over age 45 years, in the absence of other biological or 
physiological causes. In addition, females under the age of 55 years must have a serum 
follicle stimulating hormone (FSH) level > 40mIU/mL to confirm menopause. 
 
*Females treated with hormone replacement therapy (HRT) are likely to have 
artificially suppressed FSH levels and may require a washout period in order to obtain 
a physiologic FSH level. The duration of the washout period is a function of the type 
of HRT used. The duration of the washout period below are suggested guidelines and 
the investigators should use their judgement in checking serum FSH levels. If the 
serum FSH level is > 40 mIU/ml at any time during the washout period, the woman 
can be considered postmenopausal: 
 
1 week minimum for vaginal hormonal products (rings, creams, gels) 
 
4 week minimum for transdermal products 
 
8 week minimum for oral products 
 
Other parenteral products may require washout periods as long as 6 months. 
 

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Screening Procedures
 
When a potentially eligible study subject is identified, the following screening 
procedures will be followed: 
1. The Principal Investigator or designee will be contacted by the responsible 
provider to initiate screening. 
 
2. The Principal Investigator or designee will confirm that patient is  18 years of 
age or older. 
 
3. The Principal Investigator or designee will confirm fulfillment of the study 
inclusion criteria and the absence of all exclusion criteria. 
 
4. The Principal Investigator or designee will provide the potential study subject 
with the study Informed Consent Form to review, sign, and date.  Informed 
consent must be obtained from a subject with the capacity for medical 
decision-making.  The process for obtaining informed consent must be in 
compliance with the Partners IRB guidelines and policies.  Informed consent 
may be obtained by the Principal Investigator or Co-Investigators.  Potential 
study subjects will not be enrolled if Informed Consent cannot be obtained.  A 
copy of the signed Informed Consent Form must be provided to the subject.  
must always be available for verification.   
 
5. A research staff member will enter the patient demographic data into the 
screening portion of the electronic case report form (eCRF). 
 
6. Subjects who agree to participate in the study and sign the Informed Consent 
Form will be considered for enrollment in the study and should have baseline 
data which includes:  
a. History and physical examination within the past 6 months 
b. Review of relevant laboratory data from within the past three months.  If  
laboratory data for a complete blood count, basic chemistry panel, and 
coagulation (prothrombin time and activated partial thromboplastin time) 
are not available from the past three months, these will be drawn at the 
initial study visit and paid for by the study.  
c. 
-HCG) or urine pregnancy test (u-HCG) for women of child-
bearing potential 
 
7. If the potential study subject does not meet all the inclusion criteria or meets 
any of the exclusion criteria, the rationale for exclusion from the study will be 
recorded in the screening section of the electronic case report form (eCRF). 
 
 
Assessment of Enrollment 
 

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After 10 months of study recruitment, an assessment of enrollment will be conducted.  
If 300 study subjects have not been recruited by 10 months, activation of second 
study site, 
Faulkner Hospital, will be considered by the Study 
Investigators.  Activation of the 
Faulkner Hospital as a study 
site will require submission to and approval by the Partners Human Research 
Committee/IRB.   
 
Treatment Description   
 
Subjects will begin anticoagulation within 3 weeks of passing the screening 
procedure.  Subjects who are 18 years of age or older with provoked DVT and/or PE, 
have completed at least 3 months of therapeutic anticoagulation, have a low risk of 
bleeding, and have at least one persistent provoking risk factor will be randomly 
assigned to receive apixaban 2.5 mg orally twice daily or oral placebo for extended 
secondary prevention of VTE for a duration of 12 months.   
 
If during the study period the patient requires an invasive procedure or surgery that 
necessitates the discontinuation of anticoagulation (study drug), apixaban should be 
held as per the prescribing guidelines (Appendix, 
http://packageinserts.bms.com/pi/pi_eliquis.pdf).  If appropriate based on the 
judgment of the responsible clinician, apixaban should be restarted when safe to do 
so postoperatively. 
 
Patients and providers will be blinded as to the study group assignment. 
 
Both study drug and placebo will be dispensed by the BWH Investigation Drug 
Service in 3-month allotments either in person at the screening visit, other non-study 
related office visit at BWH, or directly to the patient within 2 business days of the 
enrollment visit via mail or courier in accordance with BWH Investigation Drug 
Service policy.  Subsequent allotments will be dispensed via mail or courier in 
accordance with BWH Investigation Drug Service policy.  Our Research Nurse will 
communicate with study subjects by telephone at 3 months intervals in advance of 
releasing a 3-month allotment of study drug or placebo to ensure that treatment is not 
 
 
 
Randomization 
 
Subjects who are 18 years of age or older with provoked DVT and/or PE, have 
completed at least 3 months of therapeutic anticoagulation, have a low risk of 
bleeding, and have at least one persistent provoking risk factor will be randomly 
assigned by computer in a 1:1 ratio to receive apixaban 2.5 mg orally twice daily or 
oral placebo for extended secondary prevention of VTE for a duration of 12 months. 
 

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Safety Outcomes
 
Primary Safety Outcome 
 
The primary safety outcome will be major bleeding at 12 months.  Major bleeding is 
 
site, or contributes to death (27).  The primary safety outcome will be independently 
adjudicated by a blinded Clinical Endpoints Committee (CEC) review. 
 
Secondary Safety Outcome 
 
Clinically relevant non-major bleeding at 12 months will be evaluated (please see 
below) and is defined as overt bleeding that does not meet the criteria for major 
bleeding but that is associated with the need for medical intervention, unscheduled 
contact with a physician, interruption or discontinuation of the study drug, or 
discomfort or impairment of activities of daily living (28).   
 
 
Efficacy Outcomes 
 
Primary Efficacy Outcome 
 
The primary efficacy outcome will be symptomatic, recurrent VTE, defined as the 
composite of deep vein thrombosis and/or pulmonary embolism at 12 months. The 
primary efficacy outcome will be independently adjudicated by a blinded CEC review. 
 
DVT is diagnosed as a newly non-compressible venous segment or segments on 
ultrasonography or a filling defect on computed tomographic (CT) venography, 
magnetic resonance (MR) venography, or contrast venography.   
 
PE is diagnosed based on new mismatched perfusion defect(s) on ventilation 
perfusion scan, the presence of a new pulmonary artery filling defect on contrast-
enhanced chest CT, a new finding of intraluminal filling defect on invasive pulmonary 
angiography, or evidence of PE at autopsy. 
 
Secondary Efficacy Outcome 
 
A secondary efficacy outcome will be the composite of death due to cardiovascular 
cause, nonfatal myocardial infarction (MI), stroke or systemic embolism, critical limb 
ischemia (CLI), or coronary or peripheral ischemia requiring revascularization (major 
adverse cardiovascular events, including major adverse limb events) at 12 months.  
The secondary efficacy outcome will be independently adjudicated by a blinded CEC 
review. 
 

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An acute MI is defined as the presence of at least 2 of the 3 following conditions (29):
 The detection of a rise and/or fall of cardiac biomarkers, with at least one of 
the values being elevated (preferably cardiac troponin [cTn] with at least one 
value above the 99th percentile upper reference limit) and with at least one of 
the following:   
 symptoms of myocardial ischemia  
 new (or presumably new) significant ST-segment/T-wave changes 
or left bundle branch block  
 development of pathological Q waves on ECG  
 new loss of viable myocardium or regional wall motion abnormality 
by imaging 
 identification of intracoronary thrombus by angiography or autopsy 
 
An acute stroke is defined as a new, focal neurologic deficit of sudden onset, lasting 
at least 24 hours, not due to a readily identifiable nonvascular cause (i.e. brain tumor, 
trauma), as confirmed by a neurologist and neuroimaging (7). All strokes during the 
study will be assessed by imaging or autopsy, and classified as primary hemorrhagic, 
non-hemorrhagic, infarction with hemorrhagic conversion, or unknown, as defined by 
the American College of Cardiology. 
 
 Primary hemorrhagic: a stroke with documentation on imaging (e.g., 
CT scan or magnetic resonance imaging) of hemorrhage in the cerebral 
parenchyma, or subarachnoid hemorrhage. Evidence of hemorrhagic 
stroke obtained from lumbar puncture, neurosurgery, or autopsy can 
also confirm the diagnosis.  
 Non-hemorrhagic: an ischemic focal neurological deficit (and not due 
to hemorrhage) that appears and is still partially evident at 24 hours. 
 Infarction with hemorrhagic conversion: no evidence of hemorrhage 
on an initial scan, but found on a subsequent scan and is clinically 
relevant to the event, as determined by a neurologist. 
 Unknown type/no imaging performed: the type of stroke could not be 
determined by imaging or other means (lumbar puncture, 
neurosurgery). 
 
Cardiovascular death is defined as a death for which a definite non-cardiovascular 
cause (e.g. cancer) has not been identified. Uncertain causes of deaths are 
presumed to be cardiovascular unless proven otherwise. 
 
Major adverse limb events include acute limb ischemia (ALI) and critical limb 
ischemia (CLI) (30).  Acute limb ischemia is defined as limb-threatening ischemia 
which is confirmed by limb hemodynamics or imaging and leads to an acute vascular 
intervention (i.e. pharmacologic [heparin, thrombolysis], peripheral arterial 
surgery/reconstruction, peripheral angioplasty/stent, or amputation) within 30 days of 
onset of symptoms. In the absence of confirmation by limb hemodynamics or 
imaging, absent pedal pulses is acceptable as hemodynamic criterion for acute limb 
ischemia. If the event does not meet the definition for ALI it may be classified as 

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chronic limb ischemia, peripheral vascular intervention or other peripheral vascular
hospitalization. 
 
CLI is defined as continuing ischemic limb, foot or digit pain leading to hospitalization 
and intervention and not meeting the definition of ALI, or Fontaine 3 or 4 at baseline 
with peripheral intervention during the trial. 
 
Peripheral vascular intervention is defined as peripheral vascular intervention not 
meeting the definition for ALI or CLI. 
 
Additional Study Outcomes:  Admission for heart failure will also be assessed at 12 
months.  Adherence to the twice-daily regimen of apixaban (and placebo) will be 
recorded as the total number of doses taken divided by the total number of doses 
prescribed.  Adherence data will be recorded on patient-maintained drug diaries. 
 
Clinical Endpoints Committee Adjudication of Study Outcomes 
 
Primary and secondary safety and efficacy outcome will be independently 
adjudicated by a Clinical Endpoints Committee (CEC) that is blinded with regards to 
allocation (randomization).  The CEC will include a 
chairperson and independent reviewers who are physicians with experience in 
vascular medicine and thrombosis. The CEC will adjudicate all index events (proximal 
DVT and/or PE). During the study period and the post-treatment observation period, 
the CEC will adjudicate all suspected occurrences/recurrences of venous or arterial 
thromboembolic events, deaths, and the following events of special interest: acute 
myocardial infarction, acute stroke, and thrombocytopenia. The CEC will also review 
all suspected episodes of bleeding, and categorize adjudicated bleeding as major, 
clinically relevant non-major, or minor bleeding. The Committee will be provided with 
all relevant documentation related to the events 
treatment allocation. The criteria and definitions of the study outcomes as well as the 
procedures followed by the Committee are described in this protocol. 
 
Drug Accountability 
 
Study drug and placebo will be physically stored at BWH in our Investigational Drug 
Pharmacy.  Drug handling and dispensing will be accomplished through our BWH 
Investigational Drug Service.  The Director of Pharmacy at BWH will oversee the 
Investigational Drug Service in this regard for the purposes of the clinical trial.  
Documentation of administration will by accomplished by our Electronic Health 
Record (EHR; EPIC) in addition to a patient drug diary, which is being kept to assess 
medication adherence.  The Investigational Drug Service will collect empty study drug 
containers and unused drug via mail using prepaid labels that will be provided to the 
patient or courier as per Investigational Drug Service policy.  We will perform drug 
accountability assessment when the drug containers are collected at each 3-month 
interval.   

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Follow-Up 
 
Follow-Up Evaluation 
 
Routine laboratory testing is neither recommended nor required in patients receiving 
extended duration apixaban, including the 2.5 mg twice daily dosing regimen.  
Patients enrolled in the study will either have been identified from one of the practices 
of our Vascular Medicine faculty or will be assigned to one of our faculty for long-term 
management of VTE.  Accordingly, every patient enrolled in the study will have 
ongoing medical care with a dedicated Vascular Medicine provider.  Study patients 
will be encouraged to follow-up with their primary care, , and other appropriate 
clinicians. Specifically, at the end of the treatment visit, every patient will be reminded 
to follow-up with a PCP as dictated by routine care and best clinical practice. 
Demographic, clinical characteristics, medication records, and outcomes will be 
abstracted from the BWH Electronic Health Record (EPIC).   
 
When our Research Nurse conducts the every 3-month telephone call in advance of 
releasing a 3-month allotment of study drug or placebo the subject will be queried for 
any issues with the study or adverse events.  
 
We will conduct an end-of-treatment visit to obtain data relevant to the study end 
points. 
 
We will assess medication adherence via pill count.  Medication adherence will be 
calculated in three month intervals as the total number of doses taken divided by the 
total number of doses prescribed for that time period ([ x / 180] x 100 = medication 
adherence [%]) and also for the total 360-day study period ([x / 720] x 100 = 
medication adherence [%]).  Subjects will be given a study drug diary to fill out at 
home each day.  Subjects will write down the time they take their study drug and any 
side effects.  The study drug diary will be collected at a regularly scheduled office visit 
or the end-of-treatment visit at conclusion of the study period.  
 
Subject Retention, Withdrawal, and Termination 
 
Continued participation of study subjects will be encouraged at the time of outpatient 
evaluation through the 12-month follow-up interval.  However, study subjects will be 
informed that they retain the right to withdraw from the study at any time without 
compromise to their current or subsequent medical care.  Subjects will be terminated 
from the study if they expire or elect to withdraw.   
 
If study subjects elect to withdraw, they will be asked for permission to do the 
following: 
1. Be contacted by telephone AND 
2. Have their physicians contacted 

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Withdrawal criteria will include: 
1. Patient requests to withdraw 
2. Reasons related to SAE: 
a. Initiating or continuing study drug places the subject at undue hazard as 
determined by the Investigator;   
b. SAE or other safety concern that is related to study drug treatment;   
c. Major or life-threatening bleeding (as defined in the protocol)  
d. 
 
e. Calculated CrCL decreased to < 30 mL/min confirmed by repeat testing 
at least one week later, or need for dialysis 
3. Pregnancy 
4. Patient develops severe hepatic impairment (Child-Pugh class C) during the trial 
5. Death 
6. Lost to follow-up (every attempt will be made by the Investigator not to have 
-
 
7. Study terminated by sponsor (termination of all or part of the study by the 
sponsor, in concert with the study leadership) 
 
Safety Monitor 
 
An independent Safety Monitor has been selected for this study.  The Safety Monitor 
is an expert in VTE and is distinct from the DMSB and Study Staff and will be 
available throughout the study to assess patient safety issues that may arise, 
objectively.  The Safety Monitor will have the ability to break the blind of a study 
patient as the need arises (immediately, in real-time).  If the Safety Monitor is 
unavailable because of travel, one of the Physician Study Investigators will serve as 
back-up.  The Safety Monitor will attend DSMB meetings, although will be non-voting.  
The Safety Monitor will have the ability to request an ad hoc DSMB meeting should a 
safety issue arise that warrants further review. 
Assessment and Reporting of Adverse Events 
 
Definitions 
 
Adverse events 
 
An adverse event (AE) is defined as any new untoward medical occurrence or 
worsening of a pre-existing medical condition in a patient or clinical investigation subject 
administered an investigational (medicinal) product and that does not necessarily have 
a causal relationship with this treatment.  An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding, for example), symptom, or 
disease temporally associated with the use of investigational product, whether or not 
considered related to the investigational product.  The causal relationship to study drug 
is determined by a physician and should be used to assess all AEs.  

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Adverse events can be spontaneously reported or elicited during open-ended 
questioning, examination, or evaluation of a subject. (In order to prevent reporting 
bias, subjects should not be questioned regarding the specific occurrence of one or 
more adverse events). 
 
through 30 days of discontinuation of dosing will be reported to BMS Worldwide Safety. 
 
Serious Adverse Events 
 
A serious adverse event (SAE) is any untoward medical occurrence at any dose that: 
  
 results in death 
 is life-threatening (defined as an event in which the subject was at risk of 
death at the time of the event; it does not refer to an event which 
hypothetically might have caused death if it were more severe) 
 requires inpatient hospitalization or causes prolongation of existing hospitalization  
 results in persistent or significant disability/incapacity 
 is a congenital anomaly/birth defect 
 is an important medical event, defined as a medical event that may not be 
immediately life-threatening or result in death or hospitalization but, based 
on appropriate medical and scientific judgment, may jeopardize the subject 
or may require intervention (e.g., medical, surgical) to prevent one of the 
other serious outcomes listed above. Examples of such events include but 
are not limited to intensive treatment in an emergency department or at 
home for allergic bronchospasm; blood dyscrasias or convulsions that do 
not result in hospitalization. 
 
Suspected transmission of an infectious agent (e.g., pathogenic or non-pathogenic) via the 
study drug is an SAE.  Although pregnancy, overdose, and cancer are not always serious 
by regulatory definition, these events must be handled as SAEs. 
 
 The following hospitalizations are not considered SAEs:  
 A visit to the emergency room or other hospital department lasting less 
than 24 hours that does not result in admission (unless considered an 
-threatening event) 
 Elective surgery planned before signing consent 
 Admissions as per protocol for a planned medical/surgical procedure 
 Routine health assessment requiring admission for baseline/trending of 
health status (e.g., routine colonoscopy) 
 Medical/surgical admission other than remedying ill health state that was 
planned before study entry. Appropriate documentation is required in these 
cases 
 Admission encountered for another life circumstance that carries no 
bearing on health status and requires no medical/surgical intervention (e.g., 

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lack of housing, economic inadequacy, caregiver respite, family 
circumstances, administrative reason) 
 
Adverse Events of Special Interest 
 
In this study, the following adverse events will to be reported to BMS, regardless of 
whether these reports are classified as serious or unexpected. 
 
 Potential or suspected cases of liver injury including but not limited to liver test 
abnormalities, jaundice, hepatitis or cholestasis. 
 
Pre-Existing Medical Conditions 
 
A pre-existing medical condition is one that is present at the start of the study.  Pre-
existing medical conditions should be recorded in the baseline and demographic data 
section of the electronic case report form (eCRF).  Pre-existing medical conditions 
should be reassessed during the trial and reported as an adverse event or severe 
adverse event only if the frequency, severity, or character of the conditions worsens 
significantly or unexpectedly during the study.  When reporting such adverse events, 
the description should convey that the pre-existing condition has changed by 
including applicable descriptors (e.g.
scheduled hospitalizations and hospitalizations required for diagnostic or elective 
surgical procedures for the management of unchanged pre-existing medical condition 
should not be considered adverse events. 
 
Serious Adverse Event Collecting and Reporting 
 
consent to participate in the study, all SAEs, whether 
related or not related to study drug, must be collected, including those thought to be 
associated with protocol-specified procedures. All SAEs must be collected that occur 
during the screening period and within 30 days of discontinuing dosing. If applicable, 
SAEs must be collected that relate to any later protocol-specific procedure.  
 
When our Research Nurse conducts the every 3 month telephone call in advance of 
releasing a 3-month allotment of study drug or placebo the subject will be queried for 
any issues with the study or adverse events.  The Electronic Health Record, Epic, will 
notify study staff when a study subject is admitted to the hospital or presents to the 
Emergency Department.  This notification will be an additional avenue for detection of 
SAEs.  Providers will also be able to see that the patient is enrolled in the study and 
how to contact study staff through the EHR. 
 
SAEs 
a study physician or staff member, or identification from the EHR during data 
collection.  Patients that report AEs to the study staff will be contacted by a study 
physician and triaged to the appropriate setting for care depending on the nature and 
severity of the AE and in accordance with best clinical practices. 

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The investigator should report any SAE occurring after these time periods that is 
believed to be related to study drug or protocol-specified procedure.  An SAE report 
should be completed for any event where doubt exists regarding its status of 
seriousness.  If the investigator believes that an SAE is not related to study drug, but 
is potentially related to the conditions of the study (such as withdrawal of previous 
therapy, or a complication of a study procedure), the relationship should be specified 
in the narrative section of the SAE Report Form. 
 
SAEs, whether related or unrelated to the study drug, and pregnancies must be 
reported to BMS within 1 business day of becoming aware of the event:  
 
SAE Email Address: Worldwide.Safety@BMS.com 
SAE Fax Number: 609-818-3804 
 
SAEs must be recorded on the FDA MedWatch Form 3500A. Pregnancies must be 
reported on a Pregnancy Surveillance Form. 
 
If only limited information is initially available, follow-up reports are required. (Note: 
Follow-up SAE reports should include the same investigator term(s) initially reported.)  
 
If an ongoing SAE changes in its intensity or relationship to study drug or if new 
information becomes available, a follow-up SAE report should be sent within 24 hours 
to the BMS (or designee) using the same procedure used for transmitting the initial 
SAE report. All SAEs should be followed to resolution or stabilization. 
 
SAE Reconciliation 
 
 
The Sponsor will reconcile the clinical database AE cases (case level only) 
transmitted to BMS Global Pharmacovigilance (GPV&E) 
(Worldwide.Safety@bms.com).  
 The Investigator will request from BMS GPV&E, 
aepbusinessprocess@bms.com the SAE reconciliation report and include the 
BMS protocol number every 3 months and prior to data base lock or final data 
summary 
 GPV&E will send the investigator the report to verify and confirm all SAEs 
have been transmitted to BMS GPV&E. 
 The data elements listed on the GPV&E reconciliation report will be used for 
case identification purposes. If the Investigator determines a case was not 
transmitted to BMS GPV&E, the case should be sent immediately to BMS 
(Worldwide.Safety@bms.com). 
 
Health Authority Reporting (U.S. FDA IND) 
 

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Investigators must adhere to local Health Authority Reporting Requirements. For 
studies conducted under an investigator sponsored U.S. FDA IND, provide details of 
the following: 
 
 Any event that is both serious and unexpected must be reported to the 
Food and Drug Administration (FDA) as soon as possible and no later than 
7 days (for a death or life-threatening event) or 15 days (for all other SAEs) 
 
 BMS will be provided with a simultaneous copy of all adverse events filed 
with the FDA. SAEs should be reported on MedWatch Form 3500A, which 
can be accessed at: http://www.accessdata.fda.gov/scripts/medwatch/. 
 
MedWatch SAE forms should be sent to the FDA at: 
 
MEDWATCH 
5600 Fishers Lane 
Rockville, MD 20852-9787 
Fax: 1-800-FDA-0178 (1-800-332-0178) 
http://www.accessdata.fda.gov/scripts/medwatch/ 
 
All SAEs should simultaneously be faxed or e-mailed to BMS at: 
 
Global Pharmacovigilance & Epidemiology 
Bristol-Myers Squibb Company 
Fax: 609-818-3804 
Email: Worldwide.safety@bms.com 
 
Health Authority (HA), suspected serious adverse reactions (whether expected or 
unexpected) shall be reported by BMS to the relevant competent health authorities in 
all concerned countries according to local regulations (either as expedited and/or in 
aggregate reports). 
 In accordance with local regulations, BMS will notify sponsor investigators of all 
reported SAEs that are suspected (related to the investigational product) and 
unexpected (ie, not previously described in the 
IB)). An 
event meeting these criteria is termed a Suspected, Unexpected Serious 
Adverse Reaction (SUSAR). Sponsor investigator notification of these events 
will be in the form of either a SUSAR Report or a Semi-Annual SUSAR Report.  
 Other important findings which may be reported by BMS as an Expedited 
Safety Report (ESR) include: increased frequency of a clinically significant 
expected SAE, an SAE considered associated with study procedures that 
could modify the conduct of the study, lack of efficacy that poses significant 
hazard to study subjects, clinically significant safety finding from a 
nonclinical (eg, animal) study, important safety recommendations from a 

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study data monitoring committee, or sponsor or BMS decision to end or 
temporarily halt a clinical study for safety reasons. 
 Upon receiving an ESR from BMS, the investigator must review and retain 
the ESR with the IB. Where required by local regulations or when there is a 
central IRB/Independent Ethics Committee (IEC) for the study, the sponsor 
will submit the ESR to the appropriate IRB/IEC. The investigator and 
IRB/IEC will determine if the informed consent requires revision. The 
investigator should also comply with the IRB/IEC procedures for reporting 
any other safety information.  
 
 
Non-Serious Adverse Events  
 
A non-serious adverse event (NSAE) is an AE not classified as serious. 
 
Non-Serious Event Collecting and Reporting 
 
 
The collection of non-
written consent to participate in the study. All non-serious adverse events (not only 
those deemed to be treatment-related) should be collected continuously during the 
treatment period and for a minimum of 30 days following the last dose of study 
treatment.  
Non-serious AEs should be followed to resolution or stabilization, or reported as 
SAEs if they become serious. Follow-up is also required for non-serious AEs that 
cause interruption or discontinuation of study drug and for those present at the end of 
study treatment as appropriate.  
Non-serious Adverse Events (AE) are to be provided to BMS in aggregate via interim 
or final study reports as specified in the agreement or, if a regulatory requirement [eg, 
IND US trial] as part of an annual reporting requirement.  
 
Laboratory Test Abnormalities 
 
All laboratory test results captured as part of the study should be recorded following 
institutional procedures. Test results that constitute SAEs should be documented and 
reported to BMS as such. 
 
The following laboratory abnormalities should be captured and reported as 
appropriate: 
 
 Any laboratory test result that is clinically significant or meets the definition of an SAE 
 Any laboratory test result abnormality that required the subject to have study 
drug discontinued or interrupted 

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 Any laboratory test result abnormality that required the subject to receive 
specific corrective therapy.  
 
It is expected that wherever possible, the clinical rather than the laboratory term will 
be used by the reporting investigator (e.g., use the term anemia rather than low 
hemoglobin value).  Laboratory test abnormalities are provided to BMS via annual 
safety reports (if applicable), and interim or final study reports. 
 
Pregnancy 
 
If, following initiation of apixaban, it is subsequently discovered that a study subject is 
pregnant or may have been pregnant at the time of apixaban exposure, including 
during at least 5 half-lives after product administration, the investigational product will 
be permanently discontinued in an appropriate manner.  The investigator must 
immediately notify WorldwideSafety@BMS.com of this event via the Pregnancy 
Surveillance Form within 24 hours and in accordance with SAE reporting procedures. 
 
 
Follow-up information regarding the course of the pregnancy, including perinatal and 
neonatal outcome and, where applicable, offspring information must be reported on a 
Pregnancy Surveillance Form. 
 
Any pregnancy that occurs in a female partner of a male study participant should be 
reported to BMS. Information on this pregnancy may also be collected on the 
Pregnancy Surveillance Form. In order for Sponsor or designee to collect any 
pregnancy surveillance information from the female partner, the female partner must 
sign an informed consent form for disclosure of this information. 
 
Protocol-required procedures for study discontinuation and follow-up must be 
performed on the subject unless contraindicated by pregnancy.  Other appropriate 
pregnancy follow-up procedures should be considered if indicated. 
 
 
Other Safety Considerations 
 
Any significant worsening noted during interim or final physical examinations, 
electrocardiograms, X-rays, and any other potential safety assessments, whether or 
not these procedures are required by the protocol, should also be recorded as a non-
serious or serious adverse event, as appropriate, and reported accordingly. 
 
Documentation of Adverse Events 
 
Information about potential adverse events should be reviewed during the 6-month 
follow-up period.  Subjects should be encouraged to report adverse events 
spontaneously or in response to non-directed questioning by their usual healthcare 
providers.  If it is determined that an adverse event has occurred, the study staff 

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member entering data into the eCRF should obtain all of the information necessary to 
complete the Adverse Event section.  All observed or reported adverse events, 
regardless of the suspected causal relationship to study treatment must be recorded 
in the Adverse Event section of the eCRF. The Sponsor will be notified when an 
event has been entered into the database. 
 
 
Duration of Adverse Event Reporting Period 
 
Bleeding adverse events and other serious adverse events must be reported throughout 
the 6-month follow-up period. All observed or reported serious adverse events occurring 
through the 6-month follow-up period, regardless of the suspected causal relationship 
with treatment, must be recorded in the appropriate section of the eCRF. Procedures to 
expedite reporting serious adverse events are described later in this section.   
 
 
Specific Adverse Event Reporting Guidelines 
 
Study investigators should follow the following guidelines to ensure the quality and 
precision of adverse event reporting: 
1. Use recognized medical terms 
2. Avoid the use of colloquialisms and non-standard abbreviations 
3. If known at the time of adverse event reporting, a diagnosis should be reported 
instead of individual symptoms and signs (e.g.
 
4. If the reported symptoms and signs cannot be medically characterized as a 
single diagnosis or syndrome at the time of adverse event reporting, the 
information that is available should be reported.  If a diagnosis is subsequently 
established, it should be reported as follow-up information as described earlier. 
5. A cascade of clinical events (such as sequelae of an adverse event) should be 
identified as the primary, causative event.  The cascade of events can be 
further described in the adverse event narrative.  For example, when recording 
a death, the event or condition that caused or contributed to the fatal outcome 
should be reported as the serious adverse event.  If the cause of death is 
 
6. Any adverse event that results in inpatient hospitalization or prolongs a 
hospitalization should be reported as a serious adverse event.  If a subject is 
hospitalized to undergo a medical or surgical procedure as a result of an 
adverse event, the event responsible for the procedure (not the procedure 
itself) should be reported as the serious adverse event.  For example, if a 
subject is hospitalized to undergo exploratory surgery as a result of a major 
bleeding event, record the major bleeding event that necessitated surgery as 
the serious adverse event. 
 

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to participate in the study through 30 days of discontinuation of dosing must be 
reported to BMS Worldwide Safety. 
 
Categorization of Adverse Events 
 
All adverse events must be classified according to intensity or severity, 
expectedness, relatedness, outcome, and treatment or action taken. 
 
Intensity or Severity 
 
The following categories for intensity or severity of an adverse event should be used 
in reporting: 
 
Mild  
Awareness of a symptom or sign that does not interfere with the 
treatment and without sequelae 
Moderate 
still able to function 
Severe 
daily activities and generally requires 
medication, surgery, or other intervention for treatment 
 
Expectedness 
 
Each adverse event should be evaluated as to whether it was expected or 
unexpected as follows: 
 
Expected 
The specificity and severity of the event is consistent with 
applicable information on apixaban. 
Unexpected 
The specificity or severity of the event is not consistent with 
applicable information on apixaban.               
Unanticipated 
Adverse 
Device Effect 
(UADE) 
Any serious adverse effect on health or safety or any life-
threatening problem or death caused by, or associated with, 
apixaban, if that effect, problem, or death was not previously 
identified in nature, severity, or degree of incidence in the 
investigational plan or application or any other unanticipated 
serious problem associated with apixaban that relates to the 
rights, safety, or welfare of subjects.  
 
 
Relatedness 
 
Each adverse event should be evaluated as to whether it was related to the study 
procedures or apixaban as follows: 
 
Definite 
An adverse event is clearly related to apixaban 

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Probable
An adverse event has a reasonable causal relationship to the 
use of apixaban; another etiology is significantly less likely 
Possible 
An adverse event has a reasonable causal relationship to the 
use of apixaban; an alternative etiology is equally or less likely  
Unlikely 
An adverse event has little or no causal relationship to the use 
of apixaban; an alternative etiology is more likely 
Not related 
An adverse event is not related to the use of apixaban; there is 
no temporal relationship or a much more likely alternative 
etiology exists 
 
causal relationship.  
 
Outcome 
 
The clinical course of all adverse events should be followed until a medical outcome 
is determined (resolution, stabilization, or determination that it was unrelated to study 
participation).  If a subject is pregnant or becomes pregnant within 30 days of 
receiving apixaban, follow-up should be obtained from the medical record to 
determine the outcome of the pregnancy (successful live-birth, etc.).  The clinical 
outcome of all adverse events should be recorded as follows: 
 
Death 
Patient expired 
Recovered 
Patient returned to baseline health and functional 
status 
Not yet recovered 
Patient did not recover and symptoms or 
sequelae persist 
Recovered with sequelae 
Patient did recover but continues to experience 
clinical sequelae from the adverse event 
 
Treatment or Action Taken 
 
Adverse events and serious adverse events will be categorized by the actions taken 
in response to the event: 
 
Intervention 
Surgery or other invasive procedure 
Non-surgical treatment 
Drug initiation, interruption, dose reduction, dose 
increase, or discontinuation 
None 
No action was taken 
 
Expedited Reporting of Serious Adverse Events (SAE) 
 
The study investigators must use the following procedure for reporting serious 
adverse events: 
1. Report any serious adverse event that occurs to the Sponsor within 24 hours 
of knowledge of the event (Monday through Friday).  If the investigator does 

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not have all information regarding the SAE, he/she will not wait to receive 
additional information before notifying the Sponsor of the event and 
completing the eCRF.  The investigator shall provide an event update when 
additional information is received. 
 
NOTE:  The Sponsor will automatically be notified when an adverse event or 
serious adverse event has been entered into the database when the 
investigator fills in an eCRF.  
 
2. In the reporting of serious adverse events, the study investigator shall provide 
any potentially relevant information including: 
a. Subject demographics 
b. Pre-existing conditions 
c. The complete description of the adverse event. 
d. Date and time of adverse event onset 
e. Severity 
f. Treatment 
g. Results of diagnostic testing 
h. Duration of sequelae 
i. Outcome (if known) 
j. Date and time of adverse event resolution. 
k. Information on suspected medications including dose, route of 
administration, frequency, dates, lot number, expiration date, and 
concomitant medications 
 
3. When reporting a death, the primary event or condition that caused or contributed 
to the fatal outcome shall be reported as the serious adverse event.  Death will be 
reported as the outcomes of the serious adverse event.  If the cause of death is 
unknown a
 
 
4. The investigator shall report unanticipated adverse device effects (UADEs) to 
the sponsor and Institutional Review Board within 10 working days after the 
investigator first learns of the event.   
 
Sponsor Unanticipated Adverse Drug Effects (UADEs) Reporting Responsibilities 
 
Any serious adverse event determined to be caused by apixaban will be reviewed for 
possible reporting to the U.S. Food and Drug Administration and IRBs.  Upon notice 
of an unanticipated adverse drug effect (UADE), the sponsor shall immediately 
conduct an evaluation of the UADE and report the results of the evaluation to the 
FDA, all reviewing IRBs, and participating investigators within 10 days of first 
receiving the report.   
 
Data Reporting, Processing, and Quality Control 
 

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Data Acquisition, Monitoring, and Quality Control
 
Subject data will be collected using a web-based electronic case report form (eCRF) 
called REDCap.  Database monitoring and quality control will be performed by the 
Data Safety Monitoring Board (DSMB). 
Monitoring Plan 
 
Monitoring procedures will consist of the following: 
 
During the study, the study staff shall perform monthly random reviews of data with 
checks for accuracy and completeness, and document that corrective actions have 
been taken in response to protocol deviations or other forms of non-compliance.  
These reports will be provided to the Data Safety Monitoring Board. 
 
Data Safety Monitoring Board 
 
Three independent individuals with relevant expertise in VTE and anticoagulation will 
be appointed to a data safety monitoring board (DSMB) whose primary responsibility 
is to protect the safety of study subjects and to provide ongoing, critical, and 
unbiased evaluation of the progress of the study. The DSMB will be comprised of two 
independent physicians and an independent statistician.  To further ensure 
idependence of the DSMB, the DSMB Chair has been selected and is an expert in 
VTE AND comes from outside the Mass General Brigham Network. 
 
The DSMB will: 
 Provide independent safety evaluation of events and adjudicate all actual and 
potential serious adverse events experienced by study subjects during this 
study 
 Review aggregate efficacy and safety data including the frequency of adverse 
safety outcomes, particularly death, symptomatic VTE and major bleeding; and 
can recommend premature stopping of the study to the Sponsor and Principal 
Investigator at any time. 
 
The DSMB will meet virtually via Zoom under the restrictions imposed by the COVID-
19 pandemic.  The DSMB will meet once before the initiation of the trial and then at 
least once every three months for the duration of the trial in addition to prespecified 
meetings at 10 months and 50% of enrollment (Table).  In addition, the DSMB may 
be convened on an ad hoc basis at the request of the study investigators if the need 
(for example, due to a study-related concern) arises in between regularly scheduled 
meetings.  The DSMB chair may call an emergency meeting at any time should 
questions of patient safety arise or at the request of the Study Safety Monitor.  The 
exact dates and times of the DSMB meetings will be determined based on the 
availability of all three members to meet and will take place within the first two weeks 
of the given month. 

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1. Prior to the first meeting, the DSMB will be provided with FDA- and IRB-
approved protocol, DSMB Charter, and DSMB Adjudication Report Form to 
allow for review and charter revisions prior to the first meeting called the DSMB 
Kick-off meeting. 
2. The DSMB Kick-Off meeting will provide formal training on the protocol provided 
by the Thrombosis Research Group staff. During the first meeting, the DSMB 
will review and approve the final Charter. The DSMB will determine reports 
needed for safety review and establish stopping rules. 
3. Planned DSMB meetings will take place every three months. The DSMB will 
review all safety data collected to date on the initial subjects enrolled. The DSMB 
will also assess whether the study is on-track to meet its enrollment goal.  Once 
the review is complete and no safety or enrollment concerns are raised, the trial 
will continue. 
4. A DSMB meeting will be held at the halfway point through the enrollment period 
(10 months).  At this point the DSMB will assess whether the study is on-track 
to meet its enrollment goal.  The DSMB will also assess any safety concerns at 
that time.  Once the review is complete and no safety or enrollment concerns 
are raised, the trial will continue. 
5. A DSMB meeting will also occur when 50% of the planned enrollment population 
has completed 12-month follow-up as part of the prespecified interim analysis.  
This planned interim analysis will inform the DSMB on whether the study should 
be stopped early due to efficacy, safety concerns, or futility or continue to enroll 
the full 600-patient cohort. 
6. A final DSMB meeting will take place after follow-up completion of the last 
subject. The DSMB will review all remaining safety data collected on the 
subjects enrolled. 
7. The DSMB chair may call an emergency meeting at any time should questions 
of patient safety arise or at the request of the independent Study Safety Monitor.  
All materials, discussions, and proceedings of the DSMB are completely 
confidential. The Chair and other participants present at DSMB meetings are 
expected to maintain confidentiality. 
 
Table.  Schedule of Planned DSMB Assessments. 
Milestone-Based Meetings 
Timing 
Kick-Off 
1 month before enrollment of first patient 
Halfway Point of Enrollment Period 
10 months after first patient enrolled 
300th Patient Interim Analysis 
After follow-up completion in the 300th 
patient 
Final Meeting 
After follow-up completion in last patient 
 
 

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Recurring Meetings
#2 
3 months after first patient enrolled 
#3 
6 months after first patient enrolled 
#4 
9 months after first patient enrolled 
#5 
12 months after first patient enrolled 
#6 
15 months from first patient enrolled 
#7 
18 months from first patient enrolled 
#8 
21 months from first patient enrolled 
 
 
Interim Safety and Efficacy Analysis 
 
The DSMB will meet to review the safety and efficacy outcomes for the first 300 
patients enrolled in the study when they have completed 12-month follow up. 
Whether to continue, amend, suspend, or terminate the study will be made based in 
this interim analysis.  The DSMB will review the safety and efficacy outcomes again 
at the completion of follow up completion of the last patient enrolled in the study. 
 
The DSMB will be responsible for: 
1. Assessing study enrollment and likelihood of completion of 600 patients 
randomized 
2. Assessing the study event rate in the placebo group and likelihood of obtaining 
enough events to satisfy the requirements for the primary efficacy analysis 
3. Assessing the event rates in the treatment and placebo groups 
4. Assessing the accumulated SAEs to determine whether the safety stopping 
criteria have been meet 
 
Actions taken by the DSMB will include the following recommendations: 
1. Study termination if stopping criteria for safety or futility have been met 
2. Study modification if the DSMB deems that remediation measures have a 
reasonable probability of successful completion of the study 
3. Continuation of the study as is 
 
 
Blinding/Unblinding 
 
This study will be conducted in a blinded fashion. To maintain blinding of study 
treatment, study medications will be prepared using placebo matching the active 
treatments.  Subjects, Investigators, members of any of the administrative and 
adjudicating 
access to individual subject treatment assignments.  
 
Blinding is critical to the integrity of this clinical study. However, in the event of a 
medical emergency or pregnancy in an individual subject, in which knowledge of the 
investigational product is critical to the subject's management, the blind for that 

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subject may be broken by the Safety Monitor (or if unavailable, the treating 
investigator). Before breaking the blind of an individual subject's treatment, the Safety 
Monitor should have determined that the information is necessary, i.e., that it will alter 
the subject's immediate management. In many cases, particularly when the 
emergency is clearly not investigational product-related, the problem may be properly 
managed by assuming that the subject is receiving active product without the need 
for unblinding. 
 
The Safety Monitor should ensure that health care professionals who may provide 
any elective, urgent or emergent medical or surgical care for a subject after 
randomization are informed that: 
1. The subject is enrolled in a clinical study and is receiving blinded oral study 
treatment, consisting of: 
a.  Factor Xa inhibitor, OR 
b.  Placebo 
2. The factor Xa inhibitor is an anticoagulant, with a half-life of approximately 12 
hours, which cannot be monitored using standard laboratory tests, such as PT, 
PTT, ACT, and INR 
3. In the event of an emergency, this person should be treated symptomatically 
as would any other person being treated with anticoagulants. Treatment in an 
emergency may include discontinuation of all study treatment, and the use of 
standard resuscitative management and hemostatic agents such as 
prothrombin complex concentrate or andexanet alfa, if appropriate. 
 
 
meaningful impact on individual management, for example in many cases of clinically 
treatment assignment should be unblinded. This information should be provided to 
those who are caring for the subject and as few other people as possible. In these 
cases, we will minimize bias by assuring that the clinical events committee remains 
blinded to treatment assignment, even if the investigator has been unblinded. Every 
subject will be provided with an alert card.  
 
The alert card: 
 Will indicate that the subject is participating in a double-blind clinical trial. 
 
 
 Will note that the subject may be receiving either placebo or an 
investigational anticoagulant drug (a factor Xa inhibitor). 
 
information to provide information to emergency medical personnel 
 
The need to break the blind must first be discussed with the responsible Safety 
Monitor who will be available to page at all times by the responsible care provider. 
can thereby break the blind.  
 

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Invasive Procedures and Surgery
 
Several factors govern the management of anticoagulation in this study with respect 
to surgery and invasive procedures, as well as the management of bleeding that may 
occur in subjects on study drugs. These are: 
 The risk of thromboembolism in an individual subject (low, intermediate or 
high). 
  The risk of bleeding associated with the procedure or surgery. 
 Whether the surgery or invasive procedure is elective or emergent in 
nature. 
 The desirability of maintaining blinding, if at all possible, without creating 
risk for the subject. 
 The times of onset and offset of anticoagulant effect for apixaban 
 
Elective Procedures 
 
In general, local standards of care for discontinuation of anticoagulation prior to 
elective procedures/surgery should be employed; these may be informed by current 
guidelines. 
 
These are summarized below: 
 Stop apixaban/apixaban-placebo 2-4 days before the planned procedure. 
 If the procedure is associated with an increased risk of thrombosis, brief 
postoperative protection with UFH or LMWH may be considered. 
 Restart apixaban/apixaban-placebo postoperatively (usually the day after 
surgery) when it is deemed safe to do so. If UFH/LMWH is used in the 
postoperative period, it is recommended that apixaban/apixaban-placebo 
begin: 
 
 2 hours after the last dose of UFH; 
 
 6 hours after the last dose of LMWH indicated for twice daily 
administration; or 
 
 12 hours after the last dose of LMWH indicated for once daily 
administration (or fondaparinux). 
 
Emergency Procedures 
 
For urgent or emergent invasive procedures, when waiting 4 - 5 days is not an option, 
management will in part depend on the randomized treatment assignment (placebo 
or apixaban) and unblinding may be necessary (see Section on Blinding/Unblinding). 
Regardless of treatment, study drugs should be discontinued and standard laboratory 
coagulation tests (PT/INR, aPTT, platelet count, etc.) performed. The procedure 
should be carried out and in such a way to minimize the risk of bleeding. For subjects 
receiving apixaban, the risk of bleeding with invasive procedures is unknown. At 
therapeutic doses, the anticoagulant effects of apixaban will not be reflected in 
standard coagulation tests. Given its half-life (12 hours), however, the anticoagulant 
effect of apixaban abates in 24 - 

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bleeding with the procedure, subjects receiving apixaban who require an invasive or 
surgical procedure within 24 hours of their last dose may be treated with prothrombin 
complex concentrate or andexanet alfa.  If treatment with an alternative open label 
anticoagulant/antithrombotic is indicated for the procedure, it should be used at the 
lowest therapeutic dose (if at all) in the 12 hours following last dose of apixaban.  
 
Treatment Guidelines for Bleeding/Suspected Bleeding 
 
Subjects with bleeding or suspected bleeding will undergo confirmatory laboratory or 
other testing (e.g., US, CT, MRI) and a (S)AE CRF must be completed. The date and 
time of the onset of the bleeding event will be recorded on the CRF. 
 
For subjects with minor bleeding, study drug may or may not be held at the discretion 
of the local physician and investigator. A risk/benefit determination should be made 
 
thromboembolism and benefit from continued anticoagulation. Minor bleeding should 
otherwise be managed according to local standard of care. 
 
For subjects with clinically significant bleeding, the study drugs should generally be 
held. Bleeding should be managed according to local standard of care and may 
include measures such as: 
 
 Local measures to stop the bleeding 
 Volume resuscitation, and transfusion of blood products as appropriate 
 Standard laboratory tests (e.g., hemoglobin, hematocrit, platelet count, 
etc.) 
 
Note: Neither apixaban nor the comparator affects standard coagulation tests. 
 
The management of clinically significant bleeding will in part depend on the 
randomized treatment assignment (placebo or apixaban) so unblinding may be 
necessary (see Section on Blinding/Unblinding). Should unblinding occur, subjects 
receiving placebo should be managed according to the local standard of care. 
Given its half-life (12 - 15 hours), however, the anticoagulant effect of apixaban 
abates in 24 - 48 hours. Subjects receiving apixaban with clinically significant 
bleeding that does not respond to local measures may be treated with prothrombin 
complex concentrate (PCC) or andexanet alfa as per Good Clinical Practice and local 
anticoagulant reversal protocols. 
 
Management of Recurrent Venous Thromboembolic Events 
 
If a subject has a confirmed recurrent symptomatic VTE (DVT or PE), as deemed by 
the primary investigator, then the patient must discontinue study treatment and 
transition to the appropriate standard of care. The subject should remain in the study 
and should be followed in the same manner as a subject who has discontinued study 
treatment as described in the protocol. 

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Prohibited and/or Restricted Treatments 
 
Prohibited Treatments: 
 
The following medications or therapies are prohibited during the study treatment 
period: 
 Potent inhibitors of CYP3A4 (e.g., azole antifungals [itraconazole and 
ketoconazole], macrolide antibiotics [clarithromycin and telithromycin], 
protease inhibitors [ritonavir, indinavir, nelfinavir, atazanavir, and saquinavir], 
and nefazadone) 
 Aspirin > 81 mg/day 
 Dual antiplatelet therapy such as concomitant (simultaneous) use of both 
aspirin and a thienopyridine (e.g., clopidogrel, ticlopidine) 
 Other antithrombotic agents (e.g., UFH, LMWH, direct thrombin inhibitors, 
fondaparinux)  
 GP IIb/IIIa inhibitors (e.g., abciximab, eptifibatide, tirofiban) 
 
If treatment with a prohibited agent becomes necessary, study drug should be 
temporarily interrupted, and restarted as soon as possible following discontinuation of 
the prohibited medication or therapy. 
 
Restricted Treatments: 
 
The administration of the following agents in subjects on study drug should be done 
cautiously given the increased risk of bleeding. In such cases, consideration of 
interruption of the study drug may be warranted; this decision should be made after a 
careful assessment of the risks and potential benefits. 
 
Examples: 
 Chronic (> 3 months) daily NSAIDs. NSAIDs should not be administered in 
doses that exceed those in the approved label 
 Cytotoxic/myelosuppressive therapy 
 
In addition, if a subject is currently receiving an agent that is a potent inducer of 
CYP3A4 (e.g.
of thromboembolism, as the plasma concentration of apixaban may be lower than 
that in subjects not receiving a potent inducer of CYP3A4 
 
Stopping Criteria 
 
The DSMB will consider efficacy events, in addition to safety events, before making 
any study stopping recommendations to the principal investigator.   
 
1. General Stopping Rules 

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A. The DSMB, IRBs, regulatory authorities, or the Investigator may make 
recommendations to terminate the study if the safety and well-being of the 
subjects is in jeopardy.  
B. If the study is terminated or suspended, prompt notification will be provided 
to all parties of the study. 
C. Patient enrollment may be paused or terminated early if the DSMB 
determines that the potential benefits of continuing the trial are unlikely to 
outweigh the risks.  For example, if the probability of achieving the target 
primary endpoints falls below a certain threshold, the trial will be stopped or 
paused for re-evaluation. 
2. Safety Stopping Rules 
The study will be terminated by the DSMB and principal investigator at any point 
if the following stopping criterion is met: 
a. An excess of morbidity or mortality is observed in patients receiving 
apixaban. 
b. When 3 of the subjects receiving apixaban experience an unprovoked 
intracranial hemorrhage, confirmed by independent adjudication and did 
not have a protocol violation such that he/she cannot be considered as 
representative of the intended patient population. 
c. When 3 of the subjects receiving apixaban experience an unprovoked 
major bleed (including fatal hemorrhagic events) and did not have a 
protocol violation such that he/she cannot be considered as 
representative of the intended patient population. 
 
3. Stopping Rules for Futility 
The study will be terminated by the DSMB and principal investigator if any of the 
following stopping criteria is met: 
a. Fewer than 36 events are observed in the placebo group at the time of 
the 300th patient interim statistical analysis 
b. Enrollment progress has been limited such that the study does not have 
a reasonable chance of randomizing 600 patients even after efforts to 
remediate recruitment 
 
 
Protocol Violations 
 
The study staff will rapidly and firmly address any protocol violations with the 
DSMB. If a protocol violation is detected or suspected, the investigator(s) will first 
be asked to provide a written explanation.  After reviewing the available information, 
the study staff will categorize protocol violations as either major (eligibility or 

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primary/secondary endpoint determination compromised or indefinite) or minor (data 
still able to be used for endpoint determination), and will record and track them.  
Protocol violations with be reviewed by the DSMB.  Major protocol deviations will be 
reported to the Partners Human Research Committee within five working days of the 
date the investigator becomes aware of the unapproved deviation.  Minor deviations 
will be recorded in a Minor Deviation Log and this will be submitted to the Partners 
IRB with the continuing review. 
 
 
Data Confidentiality 
 
Hardcopy and electronic subject data will be maintained in a locked office at the site 
and will only be available to the study personnel and sponsor personnel during 
monitoring visits.  Patient identifiers including names and other personal information 
will be kept separate from the study data. 
 
Compliance with Laws and Regulations 
 
The study will be conducted in accordance with this protocol, Title 21 Code of Federal 
Regulations, Parts 10, 50, 54,56 and 812, International Harmonized Standards- E6 
Good Clinical Practices Guidance, and local ethical and legal requirements. 
 
Statistical Methods 
 
Sample Size Calculation 
 
This study is a 600-patient single-center, randomized controlled trial utilizing an 
enriched population.  Based on the contemporary (within the last 10 years) large 
pivotal trials of extended duration anticoagulation (2,3,7) and a large meta-analysis of 
low-dose aspirin (31) for prevention of recurrent events in patients with initial 
unprovoked VTE or clinically suspected to have a high risk of recurrence, we 
conservatively estimate an average 12-month VTE recurrence rate in patients not 
treated with extended-duration anticoagulation (placebo group) of 6% (Table 2).   
 
VTE Recurrence Rates in the Control Arm in Major Extended Duration Secondary 
Prevention Trials including Provoked Events 
Trial 
% Provoked 
Control 
Rate 
Follow-Up 
Period 
EINSTEIN 
CHOICE 
60% 
Aspirin 81 mg 
QD 
3.6% 
<12 months 
(follow-up 
shorter than 
planned in 

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subset of 
patients) 
EINSTEIN 
VTE 
Continued 
Treatment 
25% 
Placebo 
7.1% 
12 months 
AMPLIFY EXT 
9% 
Placebo 
8.8% 
12 months 
 
 
In EINSTEIN CHOICE which randomized 60% of patients with provoked VTE, the 
control group received low-dose aspirin (which based on a meta-analysis in 
unprovoked VTE patients confers about a 33% relative risk reduction) had a 
recurrence rate of 3.6% (2,31).  Accordingly, we would expect the 12-month VTE 
recurrence rate to be at least 33% higher in patients assigned to placebo in the 
proposed study and therefore approximately 5-6%.  The recurrent VTE rate among 
placebo patients in the AMPLIFY-EXT trial of apixaban was quite a bit higher at 8.8% 
(7).  By requiring that at least one additional persistent provoking VTE risk factor be 
present (persistent immobility, obesity, heart failure, chronic lung disease, chronic 
kidney disease, inflammatory disorder, or atherosclerotic cardiovascular disease), we 
2-fold (all of these persistent provoking risk factors increase the risk of VTE by 2-4-
fold; Table 3) (32).  Many patients enrolled in the study will have multiple persistent 
provoking VTE risk factors (for example, heart failure, obesity, and atherosclerotic 
cardiovascular disease) and thereby have an even higher risk for recurrence.   In an 
effort to be ultra-conservative, we kept the multiplier for this enriched study population 
to 2-fold (while in reality for many study patients it could be 4-fold or even higher).  
Accordingly, our estimate of a 12-month VTE recurrence rate of 6% is very 
conservative and still below the VTE recurrence rates reported in EINSTEIN VTE 
Continued Treatment and AMPLIFY EXT (neither of which included an enriched 
population). 
 
Table 3.  Relative risk of VTE by persistent provoking risk factor. 
 
Persistent Provoking Risk Factor 
Relative Risk 
Persistent immobility 
4-fold 
 
2-3-fold 
Heart failure 
2-fold 
Chronic lung disease 
2-fold 
Chronic kidney disease 
2-fold 
Inflammatory/autoimmune disorder 
3-fold 
Atherosclerotic cardiovascular disease 
4-fold 
 
Based on the data from EINSTEIN CHOICE, we conservatively estimate that low-
intensity apixaban (2.5 mg twice daily) compared with placebo will provide a similar 

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reduction (75%) in recurrent VTE as low-intensity rivaroxaban (10 mg daily) 
compared with low-dose aspirin (2).  The 75% relative risk reduction was reported 
specifically for recurrent VTE and in the provoked VTE patient population, comparing 
rivaroxaban 10 mg daily versus low-dose aspirin.  This relative risk reduction 
specifically pertains to our primary study outcome and our exact patient population 
and comes from a robust randomized controlled trial analysis.  If anything, the 
reduction in the proposed study should be even greater since we propose a placebo-
control instead of active (aspirin) control and we will be following our patients for 12 
months, instead of allowing shorter follow-up as was reported in EINSTEIN CHOICE.  
Accordingly, assuming an estimated incidence in the placebo group of 6% at 12 
months and a decrease in the primary outcome of 75% with apixaban 2.5 mg twice 
daily as compared with placebo, we calculated that we would need to enroll 279 
patients in each group for the study to have 80% power to show the superiority of 
low-intensity apixaban over placebo, at a two-sided alpha level of 0.05.  To account 
for patients who may be lost to follow-up or withdraw from the study, we will recruit 
300 in each arm and 600 total.   
 
EINSTEIN-CHOICE enrolled patients after a required 6 to 12 months of anticoagulant 
therapy.  Our study requires that patients complete at least 3 months of anticoagulant 
therapy in accordance with current and widely-accepted evidence-based clinical 
practice guidelines (Eur Heart J. 2020; 41: 543 603, Chest. 2016;149:315-352, and 
Circulation. 2011;123:1788 1830).  Data from the PADIS-PE study showed that the 
rate of VTE recurrence is higher closer in temporal proximity to the initial event, such 
that the recurrence rate is higher at 3-6 months after diagnosis than it is at 6-12 
months (Couturaud F, et al. Six Months vs Extended Oral Anticoagulation After a 
First Episode of Pulmonary Embolism. JAMA. 2015;314(1):31-40).  Accordingly, the 
anticipated event rate should be higher in our study than EINSTEIN-CHOICE and the 
resultant observed relative risk reduction is likely to be higher. 
 
Sensitivity analyses performed for the comparison between apixaban 2.5 mg twice 
daily and placebo (Tables 4 - 6) show that our sample size is most sensitive to 
change in the impact of the extended duration anticoagulation.  However, we have 
been very conservative in our effect size calculation and baseline recurrent VTE rate 
(for example, we have not taken into account the increase in event rates of an 
enriched population with persistent immobility, obesity, heart failure, chronic lung 
disease, chronic kidney disease, inflammatory disorder, or atherosclerotic 
cardiovascular disease), as above. 
 
Table 4. Sensitivity of sample size to changes in power. 
Power 
Total Sample Size 
60% 
350 
70% 
440 
80% 
558 
90% 
746 
99% 
1300 
(assuming event rate of 6%; 75% risk reduction attributed to low-dose apixaban) 

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Table 5. Sensitivity of sample size to changes in VTE event rate. 
VTE Event Rate 
Total Sample Size 
3% 
1140 
4% 
848 
6% 
558 
8% 
412 
10% 
326 
(assuming 80% power; 75% risk reduction attributed to low-dose apixaban) 
 
Table 6. Sensitivity of sample size to changes in impact of extended duration 
anticoagulation with low-intensity apixaban (effect size). 
Relative Risk Reduction 
Total Sample Size 
45% 
1908 
55% 
1198 
65% 
800 
75% 
558 
80% 
472 
(assuming 80% power; event rate of 6%) 
 
The sample size calculation for the trial was calculated based upon 12-month rates of 
recurrent VTE from pivotal randomized controlled trials (2,3,7,33) and a large meta-
analysis of low-dose aspirin vs. placebo (31).  Accordingly, assuming an estimated 
incidence in the placebo group of 6% at 12 months and a decrease in the primary 
outcome of 75% with apixaban 2.5 mg twice daily as compared with placebo, we 
calculate that we will need to enroll 279 patients in each group for the study to have 
80% power to show the superiority of low-intensity apixaban over placebo, at a two-
sided alpha level of 0.05.  If the trial utilized 6-month follow-up instead of 12-month, 
we would observe fewer recurrent VTE events and would require an increase in the 
sample size, which would require a longer enrollment period and would incur greater 
cost.  As such, we have determined 12-month follow-up to facilitate the most efficient 
and cost-effective trial. 
 
We have conducted a retrospective analysis using an ongoing BWH registry of 405 
patients with pulmonary embolism/deep vein thrombosis.  We identified 83 patients 
without active cancer and with at least one provoking risk factor.  Among those who 
received 3-6 months of anticoagulation, 11.1% developed symptomatic recurrent 
venous thromboembolism in the ensuing year after stopping anticoagulation.  If we 
utilize this baseline rate of recurrent VTE in our sample size calculation, we will 
require 212 patients in each study group, assuming a 75% relative risk reduction with 
apixaban 2.5 mg twice daily compared with placebo and 90% power to show the 
superiority of low-intensity apixaban over placebo, at a two-sided alpha level of 0.05.   
 
We have also consulted with an independent biostatistician from the Harvard Catalyst 
Biostatistics Program (Shelley Hurwitz, PhD) to review our sample size requirement.  
She confirmed our sample size calculation using a recurrent VTE rate in the placebo 

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group of 6% from the best available literature and also using the rate of 11.1% from 
our observational cohort of patients that would be eligible for this study (see Table 7. 
below). 
 
Table 7.  Harvard Catalyst Biostatistics Program Consultant Sample Size 
Calculations (performed by Dr. Hurwitz using STATA). 
Anticipated Event Rate = 6% 
Anticipated Event Rate = 11.1% 
. power twoproportions .06 .015, 
test(chi2) n(558) 
Estimated power for a two-sample 
proportions test 
Pearson's chi-squared test 
Ho: p2 = p1  versus  Ha: p2 != p1 
Study parameters: 
        alpha =    0.0500 
  N per group =       279 
           p1 =    0.0600 
           p2 =    0.0150 
Estimated power:         power =    0.8005
. power twoproportions .111 .0278, 
test(chi2) n(424) 
Estimated power for a two-sample 
proportions test 
Pearson's chi-squared test 
Ho: p2 = p1  versus  Ha: p2 != p1 
Study parameters: 
        alpha =    0.050 
  N per group =       212 
           p1 =    0.1110 
           p2 =    0.0278 
Estimated power:        power =    0.9236 
Required N = 279 per group 
Required N = 212 per group 
 
It was also suggested that we consider using the lower limit of the 95% confidence 
interval around our estimate of 11.1%, which would be 8.2%.  The statistician 
suggested that this would also provide a conservative estimate of the frequency of 
recurrent VTE for the sample size calculation (see Table 8 below). 
 
Table. 8 Harvard Catalyst Biostatistics Program Consultant Sample Size Calculation 
Using Lower Limit of 95% Confidence Interval of Our Observational Cohort Estimate 
(performed by Dr. Hurwitz using STATA). 
Anticipated Event Rate = 8.2% 
. power twoproportions .082 .0205, 
test(chi2) n(558) 
Estimated power for a two-sample 
proportions test 
Pearson's chi-squared test 
Ho: p2 = p1  versus  Ha: p2 != p1 
Study parameters: 
        alpha =    0.0500 
            N =       558 
  N per group =       279 
           p1 =    0.0820 
           p2 =    0.0205 
Estimated power:       power =    0.9111 
Required N = 279 per group 
 

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Using this more conservative sample size calculation, we would aim to enroll 300 
patients in each arm for a total trial population of 600. 
 
 
Statistical Analysis Plan 
 
For this study, we will calculate: 
1) the 12-month frequency of major and clinically relevant non-major bleeding 
2) the 12-month frequency of symptomatic recurrent VTE 
 
The primary efficacy objective of this trial is to determine whether apixaban 2.5 mg 
twice daily is superior to placebo for the primary endpoint of symptomatic, 
recurrent VTE after 12 months of extended therapy.  The analysis will include 
descriptive statistics of event rates and 95% CI, and risk difference and 95% CI. The 
Mantel-Haenszel statistic will be used to test this hypothesis formally.  Superiority 
over placebo will be claimed for a dose if the Hochberg adjusted p-
and the RR is < 1.  The analysis will be supported by Kaplan-Meier curves.  The 
primary efficacy outcome analysis will be intention-to-treat.  We will also perform an 
on-treatment analysis. 
 
The primary safety objective will be to determine whether apixaban 2.5 mg twice daily 
results in a statistically significant difference in major bleeding at 12 months (during 
the treatment period) compared with placebo. Analysis of incidence of these 
endpoints will be based on the safety analysis set. The analysis will include 
descriptive statistics of event rates and 95% CI, and risk difference and 95% CI. 
Hypotheses will be tested using Mantel-Haenszel statistic.  The analysis will be 
supported by Kaplan-Meier curves of the time to first adjudicated major bleeding 
event.  All bleeding analyses will be conducted on the safety dataset. 
 
Baseline characteristics will be summarized by group. Any imbalances between the 
treatment groups for any demographic or baseline characteristic will be assessed based 
on clinical relevance in reviewing the summaries. For any differences deemed clinically 
relevant to the efficacy comparisons, exploratory analyses that include the imbalanced 
factor as a categorized covariate will be performed. 
 
To account for the effect of baseline low-dose aspirin use in the study population on the 
rate of recurrent VTE after an initial provoked event, we will perform a pre-specified 
stratified efficacy analysis of patients receiving low-dose apixaban or placebo with low-
dose aspirin compared with patients just receiving low-dose apixaban or placebo.  We 
will calculate stratum-
unadjusted) and stratum-specific risk ratios will enable us to determine whether aspirin 
modifies the effect of low-dose apixaban and to what extent.  If the stratum-specific risk 
ratio is similar to the crude risk ratio, then there is minimal impact of low-dose aspirin. 
However, if the stratum-specific risk ratio differs from the unadjusted estimate by 10% or 
more, then low-dose aspirin modifies the effect of low-dose apixaban.  We will conduct a 
similar analysis for the safety outcome of major bleeding. 

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We will also pre-specify subgroup analyses focused on the safety and efficacy of major 
 65 years), women, and those 
with persistent provoking factors of immobility, obesity, heart failure, chronic lung 
disease, chronic kidney disease, hemodialysis, chronic inflammatory/autoimmune 
disorder, and atherosclerotic cardiovascular disease. 
 
Means, medians, and frequency distributions will be calculated for continuous 
variables.  Number and percentages will be reported for binary and categorical 
variables.  Differences between subgroups of interest will be examined using the chi-
square or Fish
-test or 
Wilcoxon Rank Sum for continuous variables (if the subgroups are of sufficient size 
for statistical comparison).   
 
Safety outcome analyses will be performed among patients who received one or 
more doses of a study drug (Safety Population).  All p-values reported will be two-
sided. A p-value < 0.05 will be considered significant.  All analyses will be performed 
using SAS software.   
 
Interim Analysis  
 
We will conduct a pre-specified interim analysis to assess the primary safety and 
efficacy outcomes after 50% of the planned enrollment population has completed 12-
month follow-up.  This planned interim analysis will inform the Data Safety Monitoring 
Board on whether the study should be stopped early due to efficacy, safety concerns, 
or futility or continue to enroll the full 600-patient cohort. 
 
The DSMB will be responsible for: 
 
5. Assessing study enrollment and likelihood of completion of 600 patients 
randomized 
6. Assessing the study event rate in the placebo group and likelihood of obtaining 
enough events to satisfy the requirements for the primary efficacy analysis 
7. Assessing the event rates in the treatment and placebo groups 
8. Assessing the accumulated SAEs to determine whether the safety stopping 
criteria have been meet 
 
Actions taken by the DSMB will include the following recommendations: 
4. Study termination if stopping criteria for safety or futility have been met 
5. Study modification if the DSMB deems that remediation measures have a 
reasonable probability of successful completion of the study 
6. Continuation of the study as is 
 

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Investigator Responsibilities
 
Study Initiation 
 
Before enrollment of the first subject at the study site, the following documents must 
be on file with the funding provider (BMS/Pfizer): 
1. Current curriculum vitae of the principal investigator and all co-investigators 
2. Current, dated Institutional Review Board (IRB) membership list 
3. Written documentation of IRB protocol approval (protocol number/title and approval 
date) and Informed Consent Form (protocol number/title and approval date) 
4. A copy of the IRB-approved Informed Consent Form (The Informed Consent 
Form must be reviewed by the study Principal Investigator prior to IRB 
submission.) 
 
Study Completion 
 
The following data and materials must be on file at the study site before the study can 
be considered complete or terminated: 
1. Completed electronic case report forms (eCRFs) for all study subjects. 
2. All regulatory documents including: 
a. Curriculum vitae for each investigator and study staff member 
b. Signed confidentiality agreement 
c. Study protocol and protocol amendments 
d. Institutional Review Board approval letter(s) for initial protocol and any 
protocol amendments; as well as continuing review approval letters 
e. All Institutional Review Board correspondence  
f. Study termination letter 
g. Institutional Review Board membership list 
h. Site personnel signature list 
i. Financial Disclosure and Conflict of Interest forms for all site investigators 
j. Patient screening and enrollment logs 
k. Signed study Informed Consent Forms for each subject 
l. Supporting source documentation for values and responses in case report forms 
m. Supporting source documentation for adverse events 
 
Informed Consent 
 
The Informed Consent Form must be signed by the subject before enrollment into the 
study.  A hardcopy of the Informed Consent Form must be provided to the subject.  If 
applicable, informed consent should be obtained using Interpreter Services.  If an 
interpreter is required to explain the study, the informed consent form will be 
document will presented to the patient for signature in the language in which the 
patient is literate. 
 

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Signed Informed Consent Forms must remain in
for verification by the Study Sponsor at all times.  Documentation of the date informed 
consent was obtained and a notation that a signed copy of the Informed Consent Form 
was provided to the study subject should be recorded.  The informed consent process 
must always be conducted in a non-coercive manner. 
 
 
Disclosure of Data 
 
Subject data obtained for this study will be maintained as confidential, and disclosure 
permission, medical information may be given to his or her physician or other medical 
personnel for his or her welfare. 
 
Retention of Records 
 
Records and documents pertaining to the conduct of this study including case report 
forms, signed informed consent forms, protocol and amendments, supporting source 
documentation for values and responses in the case report forms, and supporting 
documentation for adverse events must be retained by the investigators for at least 
two years after conclusion of the study.   
 
Feasibility 
 
 
793-bed acute tertiary care facility 
providing medical and surgical care for patients with general medical, cardiothoracic, 
orthopedic, oncologic, neurologic, obstetric, gynecologic, and gastrointestinal 
conditions.  With the opening of the Heart and Vascular Center in 2014, BWH has 
solidified its position as a world leader in cardiovascular care and research, 
supporting an integrated care model in a single location.  The Watkins Cardiovascular 
Clinic provides care to a large a growing outpatient population from the metropolitan 
cardiovascular medicine outpatient practice in the Watkin Cardiovascular Clinic, 
which is based in the Heart and Vascular Center, includes a large number of referrals 
for VTE and determination of the optimal duration of anticoagulation.  The Watkin 
Cardiovascular Clinic also houses the outpatient practices of an additional seven 
Vascular Medicine faculty members and four Vascular Medicine fellows.  These 
providers will serve as an important additional source of eligible study patients.  The 
Vascular Medicine Section at BWH also staffs the Cardiovascular Medicine 
Consultation Service which evaluates and treats several hundred patients with VTE 
each year.  The vast majority of these patients follow up in our outpatient clinics. 
 
The BWH Thrombosis Research Group 
 

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The Thrombosis Research Group (TRG), directed by Dr. Goldhaber, Professor of 
Medicine, Harvard Medical School and Interim Chief of the Division of Cardiovascular 
Medicine and Section Head of Vascular Medicine, is based at BWH and Harvard 
Medical School.  The Thrombosis Research Group has a decades-long commitment 
to VTE prevention and a dedication to improving the outcomes of all patients at risk 
for VTE.  Dr. Piazza, Associate Professor of Medicine, Harvard Medical School, is the 
Associate Director of the Thrombosis Research Group and Assistant Section Head of 
Vascular Medicine at BWH as well as the Director of the Vascular Medicine Training 
Program.  Dr. Piazza is the Chair of the ACC PVD Section Leadership Council and 
serves on the Scientific Session Planning Committees for the AHA and SVM.  Dr. 
Piazza appreciates the national and global burden of recurrent VTE from his roles 
leading the Vascular Medicine educational initiatives for the ACC and AHA and from 
his perspective as a Co-Investigator on a number of VTE-related clinical trials (34
36) and observational studies (37).  Dr. Piazza is currently leading a clinical trial 
evaluating the safety and efficacy of apixaban for primary prevention of VTE in 
multiple myeloma patients on immunomodulatory regimens known to increase the 
risk of thrombosis (38)
subject recruitment is clearly highlighted in their participation in the 7000-patient, 
multi-center, National Heart Lung and Blood Institute-sponsored Cardiovascular 
Inflammation Reduction Trial (CIRT) (39)
made BWH the top enrolling site for CIRT.  Dr. Goldhaber was the Principal 
Investigator of the ADOPT Trial of apixaban 2.5 mg twice daily for prevention of VTE 
in acutely ill medical patients during hospitalization and in the extended period after 
their discharge from the hospital (22). 
 
The Thrombosis Research Group has an infrastructure of experienced leadership, 
with trained personnel in a multidisciplinary academic team (research pharmacists, 
cardiology fellows, research nurses, research coordinators, biostatisticians, 
administrators, and medical informatics specialists).  Data storage and computing 
resources, as well as a network of regional, national, and international collaborating 
investigators, facilitate our execution of ongoing research projects and our planning of 
future research projects.  The Thrombosis Research Group has studied all aspects of 
VTE, including epidemiology, diagnosis, treatment, and prevention.  According to 
www.pubmed.gov, the group has authored more than 100 Original Reports since 
2010.   
 
Drs. Piazza and Goldhaber have extensive experience leading randomized controlled 
trials focused on prevention and treatment of thromboembolic disease.  Examples of 
major Thrombosis Research Group-lead trials in this area include the 2500-patient 
multicenter Electronic Alert Trial (40), the 2500-patient multicenter Physician Alert 
Trial (41), the 2500-patient Discharge Alert Trial (42), and the 85-patient multicenter 
eTRIS trial (35).   
 
Vascular Medicine at BWH is a regional Center of Excellence for VTE care.  An EPIC 
Electronic Health Record query of the outpatient clinic volume of the five Vascular 
Medicine faculty providers and the 4 full-time Vascular Medicine fellows 

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demonstrated a provoked VTE volume of approximately 1500 new and follow-up 
patients. 
 
 
Table 7. EPIC query estimate of new and follow-up provoked VTE patient volume in 
2018. 
Provider 
Provoked VTE Volume 
(patients/year) 
Piazza 
300 
Goldhaber 
400 
Campia 
400 
Gerhard-Herman 
100 
Sobieszczyk 
100 
4 Full-Time Vascular Medicine Fellows 
200 
TOTAL 
1500 
 
 
Since running this EPIC analysis, we have also added two additional full-time 
Vascular Medicine faculty, Dr. Arvind Pandey and Dr. Laurel Lee.  Both specialize in 
the care of patients with VTE and see frequent referrals for determination of optimal 
duration of anticoagulation and long-term secondary prevention of recurrent events.  
Furthermore, we will recruit from our inpatient cardiovascular medicine consult 
service and cardiovascular medicine ward service which receive a high volume of 
provoked VTE referrals.  Accordingly, we anticipate having the ability to draw on 
these additional sources of provoked VTE patients for at least another 100 provoked 
VTE patients per year. 
 
Even without the added VTE patient volumes of Dr. Pandey and Dr. Lee, we 
calculate 1600 new and follow-up provoked VTE patients who present for outpatient 
visits at BWH per year and we conservatively estimate that 25% will fail to meet all 
the inclusion criteria or will meet at least one exclusion criterion.  Therefore, an 
estimated 1200 patients will be eligible for enrollment in the trial in the first year.   
 
We will also have our research nurse run reports from EPIC to identify other patients 
in our non-Vascular Medicine cardiology practices that will be eligible but may not be 
scheduled to see us.  We will also aggressively communicate the launch of the study 
to our non-Vascular Medicine cardiology colleagues.  Furthermore, we will recruit 
from our inpatient cardiovascular medicine consult service and cardiovascular 
medicine ward service which receive a high volume of provoked VTE.  Accordingly, 
we anticipate having the ability to draw on these additional sources of provoked VTE 
patients for at least another 100 provoked VTE patients per year. 
 
As the trial will enroll over 20 months, we estimate that we will be able to draw from 
1200 patients in the first year and 800 patients in the 8 months that comprise the 
second year of enrollment.  This will yield 2000 patients from which to enroll 600 
subjects for the trial. 

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Based on our prior clinical trial experience at the BWH Thrombosis Research Group, 
we conservatively estimate that 50% of the patients who are screened and found to 
be eligible for the trial will consent to participate.  Therefore, an estimated 1000 
eligible patients would be willing to provide informed consent to participate in the HI-
PRO trial.  Accordingly, enrollment of the planned 600-patient study population 
should be feasible and efficiently accomplished at BWH.   
 
Additionally, the BWH Thrombosis Research Group has the infrastructure to 
operationalize this enrollment plan.  The Thrombosis Research Group has two full-
time dedicated research assistants, a research intern, a research nurse, three faculty 
physicians, a full-time advanced Vascular Medicine fellow, and a number of general 
Cardiovascular Medicine fellows who participate in our research studies.  We have 
coordinated our ongoing research projects to accommodate the percent efforts 
required by our research staff and physician team members to maximize our success 
at enrollment for this trial.  Accordingly, we have adequate staffing and physician 
support to add to the research personnel for this trial, identify eligible patients, and 
maintain our enrollment on track.  We also have an adequate reserve in staffing and 
flexibility to augment our effort should enrollment require it. 
 
 
TRG led the patient recruitment effort for the Cardiovascular Inflammation Reduction 
Trial (CIRT), a randomized, double-blind trial of low-dose methotrexate in 4786 
patients with previous myocardial infarction or multivessel coronary disease who 
additionally had either type 2 diabetes or the metabolic syndrome (39).  CIRT was a 
landmark study which involved a novel application of a challenging anti-inflammatory 
drug, serial laboratory evaluations, and a high number of follow-up phone calls and 
in-person office visits, which required patients to travel from as far as California to 
Boston.  Despite these challenges, TRG made BWH the overall top enrolling site in 
the CIRT trial. 
 
We anticipate rapid enrollment in the HI-PRO trial.  First, all the patients in the study 
will be familiar with anticoagulation and many will have received apixaban.  Second, 
there are no study-mandated laboratory tests or office visits.  Third, many patients 
with provoked VTE are reluctant to discontinue anticoagulation after the acute 
treatment phase because of the fear of recurrent events.  We anticipate that many 
patients with provoked VTE will be highly interested in participating in a clinical trial of 
extended secondary prevention thromboprophylaxis, especially with the favorable 
safety and efficacy profile of low-intensity apixaban.  It is quite possible that greater 
than 50% of eligible patients will want to participate and provide informed consent.  In 
such a scenario, we would expect to enroll more quickly. 
 
Potential Risks and Benefits 
 
Potential benefits to the subject 

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The potential benefit of treatment with low-dose apixaban in patients with provoked 
VTE is secondary prevention of VTE, including fatal PE. 
 
Potential Benefits to Society 
 
The major potential benefit to society of the proposed trial of apixaban for secondary 
prevention of VTE in patients with provoked VTE is that if successful, the study will 
provide the foundation for a new indication for extended-duration anticoagulation for 
VTE prevention. The data acquired from this randomized, placebo-controlled trial will 
establish the safety and efficacy of low-dose apixaban versus placebo for extended 
prevention of recurrence after provoked VTE in patients with at least one persistent 
provoking factor. The study will draw widespread interest for apixaban in the 
extended prevention of recurrence after provoked VTE and will most certainly be of 
interest to high-impact peer-reviewed journals and to a broad spectrum of clinicians 
who will be better able to care for their VTE patients using these data. 
 
Potential Risks to the Subject 
 
The foreseeable risk of apixaban for secondary prevention of VTE in patients with 
provoked VTE is major bleeding. 
 
Risks of Research Procedures Performed on Subjects 
 
The risk of research procedures includes psychological discomfort from participating in a 
clinical trial (less likely) and loss of confidentiality of medical records or economic data (rare).   
 
Women of childbearing potential (able to get pregnant) must have a negative pregnancy 
test before being considered for the study.  It is not known how apixaban could affect an 
unborn child. Women of childbearing potential must use an effective method of birth 
control while participating in this research, as directed by their physician.   
 
Anticipated Risks of Drug 
 
 
Adverse reactions occurring in 1% of patients treated for DVT and PE in the 
AMPLIFY study (source table 6 USPI) 
 Epistaxis 
 Contusion 
 Hematuria  
 Menorrhagia 
 Hematoma 
 Hemoptysis 
 Rectal hemorrhage 
 Gingival bleeding 
 

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Less common adverse reactions occurring in Eliquis-treated patients in AMPLIFY or 
AMPLIFY-EXT studies occurring with a frequency of 0.1% to <1%: 
 
 Blood and lymphatic system disorders: hemorrhagic anemia 
 Gastrointestinal disorders: hematochezia, hemorrhoidal hemorrhage, 
gastrointestinal hemorrhage, hematemesis, melena, anal hemorrhage 
 Injury, poisoning, and procedural complications: wound hemorrhage, 
postprocedural hemorrhage, traumatic hematoma, periorbital hematoma 
 Musculoskeletal and connective tissue disorders: muscle hemorrhage 
 Reproductive system and breast disorders: vaginal hemorrhage, metrorrhagia, 
menometrorrhagia, genital hemorrhage 
 Vascular disorders: hemorrhage 
 Skin and subcutaneous tissue disorders: ecchymosis, skin hemorrhage, 
petechiae 
 Eye disorders: conjunctival hemorrhage, retinal hemorrhage, eye hemorrhage 
 Investigations: blood urine present, occult blood positive, occult blood, red 
blood cells urine positive 
 General disorders and administration-site conditions: injection-site hematoma, 
vessel puncture-site hematoma 
 
Additional information about the risks of apixaban can be found in the Apixaban Med 
Guide (see Appendix). 
 
Protection of Subjects against the Risks of Research Procedures 
 
Before Study Enrollment 
 
A rigorous screening process will be utilized to ensure that subjects with an increased 
risk of harm due to enrollment in the study are excluded from the study.  This will 
include performing a detailed history and physical examination (to ensure that enrolled 
subjects truly fulfill all eligibility criteria) and carefully reviewing the results of laboratory 
testing (in particular, hematocrit, platelet count, INR, and serum creatinine).   
 
During Follow-Up 
 
Changes in health status during the 12-month follow-up period will be evaluated by 
, and other routine providers.  All subjects enrolled will 
also have ongoing medical care with a dedicated Vascular Medicine provider.  As 
apixaban is an FDA-approved drug commonly used for thromboprophylaxis and does 
not require routine follow-up clinical or laboratory monitoring for toxicity, the study will 
not mandate any follow-up visits or procedures other than those required for the 
 
 
 
Protection against Loss of Confidentiality 

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Subject confidentiality will be protected by maintaining all paper records in locked file 
cabinets in locked offices and all electronic records in password-protected computer 
files.  All study data will be de-identified for storage in the electronic data repository.  In 
addition, any identifying information will be removed from images or other data used in 
publication or presentations.  All database information will be stored on computer 
systems that are located behind an electronic firewall, which will only permit access to 
certified study personnel.  Access to study data files will be password-protected.   
 
Use of Information and Publication 
 
All information concerning and relating to the study is considered confidential 
information.  This information includes the clinical investigational plan, case report 
forms (CRFs), training materials, and scientific data.   
 
Ethical Considerations 
 
In this prospective, single-center randomized placebo-controlled study, we will be 
evaluating the impact of apixaban for secondary prevention of VTE in patients with 
provoked VTE with at least one persistent provoking factor.  The benefits of apixaban 
for secondary prevention of VTE in patients with provoked VTE have not been 
assessed.  The risk of bleeding in provoked VTE patients receiving apixaban has not 
been determined.   
 
Because the proposed clinical trial involves a novel application of a U.S. FDA-
approved anticoagulant, we will obtain written consent from all study subjects and 
Institutional Review Board approval at the study site. 
 

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2015;314(1):31. 
27.  Schulman S, Kearon C, Subcommittee on Control of Anticoagulation of the 
Scientific and Standardization Committee of the International Society on 
Thrombosis and Haemostasis. Definition of major bleeding in clinical 
investigations of antihemostatic medicinal products in non-surgical patients. J 
Thromb Haemost. 2005;3(4):692 4.  
28.  Investigators T van G. Idraparinux versus Standard Therapy for Venous 
Thromboembolic Disease. N Engl J Med. 2007;357(11):1094 104.  
29.  Thygesen K, Alpert JS, Jaffe AS, et al. Third Universal Definition of Myocardial 
Infarction. Circulation. 2012;126(16):2020 35.  
30.  Eikelboom JW, Connolly SJ, Bosch J, et al. Rivaroxaban with or without Aspirin 
in Stable Cardiovascular Disease. N Engl J Med. 2017 Aug 27;377:1319 30.  
31.  Simes J, Becattini C, Agnelli G, et al. Aspirin for the prevention of recurrent 
venous thromboembolism the INSPIRE collaboration. Circulation. 
2014;130(13):1062 71.  
32.  Goldhaber SZ. Risk factors for venous thromboembolism. J Am Coll Cardiol. 
2010;56(1):1 7.  
33.  Schulman S, Kearon C, Kakkar AK, et al. Extended Use of Dabigatran, 
Warfarin, or Placebo in Venous Thromboembolism. N Engl J Med. 2013;  
34.  Everett BM, Pradhan AD, Solomon DH, et al. Rationale and design of the 
Cardiovascular Inflammation Reduction Trial: A test of the inflammatory 
hypothesis of atherothrombosis. Am Heart J. 2013;166(2):199 207.e15.  
35.  Piazza G, Mani V, Goldhaber SZ, et al. Magnetic resonance venography to 

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68 
 
assess thrombus resolution with edoxaban monotherapy versus parenteral 
anticoagulation/warfarin for symptomatic deep vein thrombosis: A multicenter 
feasibility study. Vasc Med. 2016;21(4):361 8.  
36.  Piazza G, Hohlfelder B, Jaff MR, et al. A Prospective, Single-Arm, Multicenter 
Trial of Ultrasound-Facilitated, Catheter-Directed, Low-Dose Fibrinolysis for 
Acute Massive and Submassive Pulmonary Embolism: The SEATTLE II Study. 
JACC Cardiovasc Interv. 2015;8(10):1382 92.  
37.  Weitz JI, Haas S, Ageno W, et al. Global Anticoagulant Registry in the Field - 
Venous Thromboembolism (GARFIELD-VTE). Rationale and design. Thromb 
Haemost. 2016;116(6):1172 9.  
38.  Cornell RF, Goldhaber SZ, Engelhardt BG, et al. Prospective Study of 
Apixaban for Primary Prevention of Venous Thromboembolism in Patients with 
Multiple Myeloma Receiving Immunomodulatory Therapy. Blood. 
2018;132(Suppl 1):1233.  
39.  Ridker PM, Everett BM, Pradhan A, et al. Low-Dose Methotrexate for the 
Prevention of Atherosclerotic Events. N Engl J Med. 2019;380:752 62.  
40.  Kucher N, Koo S, Quiroz R, et al. Electronic Alerts to Prevent Venous 
Thromboembolism among Hospitalized Patients. N Engl J Med. 2005 Mar 
10;352:969 77.  
41.  Piazza G, Rosenbaum EJ, Pendergast W, et al. Physician Alerts to Prevent 
Symptomatic Venous Thromboembolism in Hospitalized Patients. Circulation. 
2009;119(16):2196 201.  
42.  Piazza G, Anderson FA, Ortel TL, et al. Randomized Trial of Physician Alerts 

HI-PRO Trial    
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for Thromboprophylaxis after Discharge. Am J Med. 2013;126(5):435 42. 
 
 
 
Table 8. Study Calendar 
Procedure 
Screening 
12-Month 
Follow-Up 
Informed Consent 
X 
Inclusion/Exclusion 
X 
Demographics 
X 
Medical History  
X 
 
Prior/Concomitant Medications  
X 
 
Urine Pregnancy (if clinically indicated) 
X 
Cardio-vascular History 
X 
 
Thrombosis Evaluation 
X 
Bleeding Evaluation 
X 
Pill Diary Collection 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Case Report Form
 
Screening 
Inclusion criteria (all 
must be checked) 
[ ] Age  18 years 
[ ] Objectively-confirmed DVT and/or PE 
[ ] Treated for at least 3 months with standard therapeutic 
anticoagulant therapy 
[ ] Has not suffered symptomatic recurrence during prior 
anticoagulant therapy 
[ ] Outpatient follow-up at BWH 
[ ] Willing to provide written informed consent 
 
AND have at least one of the following persistent provoking 
VTE risk factors: 
[ ] Persistent immobility (defined as paralysis, other 
inability to ambulate freely, bed-bound, wheelchair-
bound) 
[ ] 
 
[ ] Heart failure (systolic, diastolic, or combined) 
[ ] Chronic lung disease (COPD, asthma, interstitial 
lung disease) 
[ ] Chronic kidney disease (eGFR <60 
mL/min/1.72m2)  
[ ] Chronic inflammatory/autoimmune disorder 
(inflammatory arthritis, vasculitis, inflammatory bowel 
disease, chronic infection) 
[ ] Atherosclerotic cardiovascular disease (coronary, 
cerebrovascular, or peripheral artery disease) (up to 
35% in each study group may have atherosclerotic 
cardiovascular disease as a qualifying persistent risk 
factor) 
 
Exclusion criteria 
(NONE must be 
checked) 
[ ] Women who are pregnant or breastfeeding 
[ ] Women of child-bearing potential who are unwilling or 
unable to use an acceptable method of birth control (such as 
oral contraceptives, other hormonal contraceptives [vaginal 
products, skin patches, or implanted or injectable products], 
or mechanical products such as an intrauterine device or 
barrier methods [diaphragm, condoms, spermicides]) to 
avoid pregnancy for the entire study 
[ ] Active cancer within the past 5 years 
[ ] Contraindication to antithrombotic or antiplatelet therapy 
[ ] Requirement for ongoing anticoagulant therapy (including 
atrial fibrillation with a CHADSVASC >1, diagnosed 
antiphospholipid antibody syndrome/deficiency of protein C, 

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S, or antithrombin), dual antiplatelet therapy, P2Y12 
inhibition, or aspirin at a dose of >81 mg daily 
[ ] Hemoglobin level < 9 mg/dL, a platelet count < 
100,000/mm3, a serum creatinine level > 2.5 mg/dL, an ALT 
or AST level > 2 times the upper limit of the normal range, or 
a total bilirubin level > 1.5 times the upper limit of the normal 
range 
[ ] History of a platelet disorder such as Von Willebrand 
Disease 
[ ] History of bleeding diathesis or have had recent active 
bleeding 
[ ] Active hepatobiliary disease 
[ ] More than 6 months that have elapsed without taking an 
anticoagulant or low-dose aspirin 
[ ] Known severe thrombophilia (any increased titer 
antiphospholipid antibody or positive lupus 
anticoagulant/DRVVT or deficiency of antithrombin, protein 
C, or protein S) 
[ ] Life expectancy < 12 months or hospice care 
[ ] Prisoners or subjects who are involuntarily incarcerated 
[ ] Subjects who are compulsorily detained for treatment of 
either a psychiatric or physical (e.g., infectious disease) 
illness 
[ ] Receiving concurrent non-FDA-approved or 
investigational agents or has received an investigational 
agent within the past 30 days prior to the first dose of study 
treatment (with the exception of approved medications being 
used for an approved indication, e.g., investigating a new 
dosing regimen for an approved indication).  
[ ] Any condition, which in the opinion of the investigator, 
would put the subject at an unacceptable risk from 
participating in the study 
[ ] Any other medical, social, logistical, or psychological 
reason, which in the opinion of the investigator, would 
preclude compliance with, or successful completion of, the 
study protocol 
 
STOP HERE AND DO NOT ENROLL PATIENT IF ANY OF THE INCLUSION 
CRITERIA ARE ABSENT OR ANY EXCLUSION CRITERIA ARE PRESENT 
Eligible 
 
[ ] Yes 
[ ] No 
 
Written informed 
consent signed 
[ ] Yes 
[ ] No 
 
 

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Patient Demographics 
Study ID number 
_ _ _ _ _ _ 
Date of enrollment 
           ______/______/________ 
              MM      DD        YYYY 
 
Date of birth 
           ______/______/________ 
              MM      DD       YYYY 
 
Gender 
 
[ ] Male                                         
[ ] Female 
 
Ethnicity 
[ ] Hispanic/Latino 
[ ] Non-Hispanic/Non-Latino 
 
Race 
[ ] American Indian or Alaskan Native 
[ ] Asian 
[ ] White 
[ ] Hispanic or Latino 
[ ] Native Hawaiian or Pacific Islander 
[ ] Black or African-American 
[ ] Mixed race 
[ ] Other, specify:___________ 
 
BMI calculated 
             ___________________(kg/m²) 
 
 
Venous Thromboembolism Characteristics*** 
 
***Patient may have both PE and DVT; if so complete both fields 
Deep Vein 
Thrombosis 
DVT confirmed by imaging (ultrasound, CT, MRI, or 
venogram) 
              [ ] Yes                                        [ ] No 
 
 
Date of imaging diagnosis   ____/____/_____        
                                              MM     DD    YYYY  
             
Site of DVT 
           [ ] Upper extremity                                
           [ ] Pelvic vein 
           [ ] Leg      
[ ] Proximal with calf 
[ ] Proximal without calf 
[ ] Calf only 

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[ ] Other (describe):___________ 
 
Pulmonary 
Embolism 
 PE confirmed by:           
             [ ] Ventilation perfusion scan                                      
             [ ] Chest CT 
             [ ] Contrast pulmonary angiogram   
Hypotension, shock, cardiac arrest or respiratory failure as 
presenting sign of PE: 
              [ ] Yes                                        [ ] No 
RV dysfunction 
              [ ] Yes                                        [ ] No 
Diagnosed by: 
              [ ] CT                                         [ ] Echocardiogram 
Positive cardiac biomarker (troponin or BNP) 
[ ] yes                                            [ ] no 
 
 
Date of imaging confirmed diagnosis ____/____/_____        
                                                           MM     DD     YYYY        
       
Both PE and DVT 
present  
[ ] Yes                                            [ ] No 
Symptomatic DVT 
or PE  
 
[ ] Yes                                            [ ] No 
Advanced therapy 
for VTE 
             [ ] Inferior vena cava filter 
             [ ] Thrombolytic therapy for PE 
             [ ] Catheter thrombectomy for DVT 
             [ ] Catheter direct therapy for PE 
             [ ] Surgical thrombectomy for DVT 
             [ ] Surgical embolectomy for PE 
 
Outpatient VTE 
treatment history 
             [ ] LMWH monotherapy 
             [ ] Fondaparinux  
             [ ] Direct oral anticoagulant 
             [ ] Warfarin 
              
Duration of anticoagulation: 
___ months (enter number out to the tenth place and round-
up; for example 3.48 months would be 3.5 months) 
 

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Persistent Provoking VTE Risk Factors 
Persistent provoking 
VTE risk factors 
(patient must have at 
least one but can have 
multiple; record all 
that apply) 
 
 [ ] Persistent immobility (defined as paralysis, other 
inability to ambulate freely, bed-bound, wheelchair-
bound) 
[ ] 
 
[ ] Heart failure (systolic, diastolic, or combined) 
[ ] Chronic lung disease (COPD, asthma, interstitial 
lung disease) 
[ ] Chronic kidney disease (eGRF <60 
mL/min/1.72m2) 
[ ] Chronic inflammatory/autoimmune disorder 
(inflammatory arthritis, vasculitis, inflammatory bowel 
disease, chronic infection) 
[ ] Atherosclerotic cardiovascular disease (coronary, 
cerebrovascular, or peripheral artery disease) (up to 
35% in each study group may have atherosclerotic 
cardiovascular disease as a qualifying persistent risk 
factor) 
 
 
 
VTE Risk Factors and Comorbid Conditions 
Cardiovascular disease 
[ ] Cardiomyopathy/diminished left ventricular 
systolic function 
If yes, EF (%) ____ 
[ ] Heart failure with reduced EF 
[ ] Heart failure with preserved EF (EF >50%) 
[ ] Coronary artery disease 
If yes,  
Prior CABG [ ] 
Prior coronary stent(s) [ ] 
Prior MI [ ] 
History of unstable angina [ ] 
Stable angina [ ] 
[ ] Valvular heart disease 
[ ] Atrial fibrillation or atrial flutter 
[ ] Pulmonary hypertension 
 
Hypertension 
[ ] Yes                                             
[ ] No 
 
Peripheral artery 
disease 
[ ] Yes                                             
[ ] No 

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Carotid occlusive 
disease 
[ ] Yes                                             
[ ] No 
 
Prior cerebrovascular 
accident (strokes or 
TIAs) 
[ ] Yes                                             
[ ] No 
Family history of VTE 
[ ] Yes 
[ ] No 
 
Prior personal history of 
VTE (other than the 
event that made the 
patient eligible for this 
trial) 
 
[ ] Yes 
[ ] No 
 
Hypercholesterolemia 
[ ] Yes                                             
[ ] No 
 
Chronic liver disease 
(as noted in chart) 
[ ] Yes                                             
[ ] No  
 
If yes, cirrhosis 
[ ] yes 
[ ] no 
 
Cigarette smoking 
(check only 1) 
[ ] Current smoker           
[ ] Former smoker     
[ ] Never smoker       
       
Major surgery within 3 
months of VTE 
diagnosis 
[ ] Yes                                             
[ ] No 
 
If yes, date            ______/______/________ 
                   MM          DD      YYYY 
 
Prior hospitalization 
within 30 days of VTE 
diagnosis 
 
[ ] Yes                                             
[ ] No  
Chronic lung disease 
(COPD, asthma, 
pulmonary fibrosis, 
interstitial lung disease) 
 
[ ] Yes                                             
[ ] No 
 
Diabetes mellitus  
[ ] Yes 

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(Type I or II)
 
[ ] No
 
Inflammatory arthritis 
(rheumatoid arthritis, 
psoriatic arthritis) 
 
[ ] Yes 
[ ] No 
 
Inflammatory bowel 
Disease, Ulcerative 
Colitis) 
 
[ ] Yes 
[ ] No 
 
Inherited thrombophilia 
             [ ] Yes                                        [ ] No 
                              If yes, indicate:     
[ ] Factor V Leiden (heterozygous 
or homozygous)  
[ ] Prothrombin gene mutation 
(heterozygous or homozygous) 
 
Active use of oral 
contraceptive or 
hormone replacement 
at time of VTE 
diagnosis 
 
             [ ] Yes                                        [ ] No 
 
Infectious illness 
requiring antibiotics or 
antiviral therapy within 
3 months of VTE 
diagnosis 
[ ] Yes                                        [ ] No 
Serum creatinine >2.5 
mg/dL  
[ ] Yes                                             
[ ] No                        
 If yes, is patient on dialysis?  
[ ] Yes                                             
[ ] No 
 
If yes, patient should not be enrolled. 
 
Concomitant 
medications 
[ ] aspirin 
If yes, dose = _ _ _ mg/daily 
 
If >81 mg/daily, patient should not be enrolled. 
 
[ ] daily NSAID use 
 
 
 

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Study Treatment Characteristics 
Randomization 
[ ] Oral Apixaban 2.5 mg twice daily 
[ ] Oral placebo twice daily 
 
Date study drug 
started 
____/____/_____        
MM     DD     YYYY              
 
Date study drug 
stopped  
____/____/_____        
MM     DD     YYYY    
 
Completed full 12 months of study drug? 
[ ] Yes 
[ ] No 
 
If did not stay on drug for 12 months, reason why not? 
[ ] Fulfilled criteria for a primary study outcome (recurrent VTE or 
major/clinically relevant non-major bleed) 
[ ] Patient expired 
[ ] Adverse drug event or side-effect 
[ ] Change in clinical status (such as change in goals of care, 
comfort measures, hospice care) 
[ ] Patient preference/withdrawal of consent           
 
Medication 
adherence (via pill 
count) 
Total doses taken/total doses prescribed = ( __ / 720) x 100  
= _ _ _ % 
 
 
12-Month Study Outcomes 
Deep vein thrombosis 
[ ] Yes 
[ ] No 
 
If yes, date ____/____/_____        
                 MM     DD     YYYY              
 
Confirmed by diagnostic imaging: 
[ ] Yes 
[ ] No 
 
If yes, by? 
[ ] Ultrasound 
[ ] CT 
[ ] MRI 
[ ] Venography 
 

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Location:
[ ] Upper extremity 
If checked: 
[ ] Bilateral or SVC 
 
[ ] Lower extremity 
If checked: 
[ ] Bilateral or IVC 
[ ] Proximal (popliteal or higher) 
[ ] Calf 
 
Hospitalized? 
[ ] Yes 
[ ] No 
 
Treatment: 
[ ] Anticoagulation 
[ ] Pharmacomechanical (catheter-based) therapy 
[ ] Surgery 
[ ] IVC filter 
 
Superficial vein thrombosis 
[ ] Yes 
[ ] No 
 
If yes, date ____/____/_____        
                 MM     DD     YYYY              
 
Other venous thrombosis 
(mesenteric, cerebral sinus, 
gonadal, etc.) 
[ ] Yes 
[ ] No 
 
If yes, date ____/____/_____        
                 MM     DD     YYYY              
 
Pulmonary embolism 
[ ] Yes 
[ ] No 
 
If yes, date ____/____/_____        
                 MM     DD     YYYY              
 
Confirmed by diagnostic imaging: 
[ ] Yes 
[ ] No 
 
If yes, by? 
[ ] CT 
[ ] MRI 

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[ ] Pulmonary angiography
[ ] V/Q scan 
 
Location: 
[ ] Unilateral 
[ ] Bilateral 
 
RV dysfunction on echocardiogram or CT? 
[ ] Yes 
[ ] No 
 
Positive cardiac biomarker? 
[ ] Yes 
[ ] No 
 
Associated with hemodynamic or respiratory instability 
(respiratory failure, shock, hypotension, cardiac 
arrest)? 
[ ] Yes 
[ ] No 
 
Fatal? 
[ ] Yes 
[ ] No 
 
Hospitalized? 
[ ] Yes 
[ ] No 
 
Treatment: 
[ ] Anticoagulation 
[ ] Systemic fibrinolysis 
[ ] Pharmacomechanical (catheter-based) therapy 
[ ] Surgical embolectomy 
[ ] IVC filter 
 
Death 
[ ] Yes 
[ ] No 
 
If yes, date ____/____/_____        
                 MM     DD     YYYY              
 
Cause of death: 
[ ] PE 
[ ] Myocardial infarction 
[ ] Stroke  

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[ ] Other cardiovascular 
[ ] Cancer-related 
[ ] Non-cardiovascular, non-cancer 
[ ] Unknown 
 
[ ] CV Death: includes death due to PE, MI, stroke, 
other cardiovascular cause, or unknown 
 
Major or clinically relevant 
non-major bleed 
[ ] Yes 
[ ] No 
 
If yes, date ____/____/_____        
                 MM     DD     YYYY              
 
Major bleed 
[ ] Yes 
[ ] No 
 
If yes, date ____/____/_____        
                 MM     DD     YYYY              
 
Location: 
[ ] Intracranial 
[ ] Surgical/operative site 
[ ] Gastrointestinal 
[ ] Genitourinary 
[ ] Retroperitoneal 
[ ] Pericardial 
[ ] Pulmonary 
[ ] Other thoracic 
[ ] Musculoskeletal 
[ ] Nasopharyngeal 
[ ] Hematocrit or hemoglobin decrease without clear 
source 
[ ] Other 
 
Fatal? 
[ ] Yes 
[ ] No 
 
Hospitalized? 
[ ] Yes 
[ ] No 
 
Associated with hemodynamically instability? 
[ ] Yes 
[ ] No 

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Treatment: 
[ ] Blood products 
[ ] Surgery 
[ ] Invasive procedure 
[ ] Medical therapy (PCC, andexanet, etc.) 
 
Clinically relevant non-major 
bleed 
[ ] Yes 
[ ] No 
 
If yes, date ____/____/_____        
                 MM     DD     YYYY              
 
Location: 
[ ] Intracranial 
[ ] Surgical/operative site 
[ ] Gastrointestinal 
[ ] Genitourinary 
[ ] Retroperitoneal 
[ ] Pericardial 
[ ] Pulmonary 
[ ] Other thoracic 
[ ] Musculoskeletal 
[ ] Nasopharyngeal 
[ ] Hematocrit or hemoglobin decrease without clear 
source 
[ ] Other: _______________ 
 
Hospitalized? 
[ ] Yes 
[ ] No 
 
Treatment: 
[ ] Blood products 
[ ] Surgery 
[ ] Invasive procedure 
[ ] Medical therapy (PCC, andexanet, etc.) 
 
Non-bleed adverse drug 
reaction 
[ ] Yes 
[ ] No 
 
If yes, date ____/____/_____        
                 MM     DD     YYYY              
 
Type of reaction: 
[ ] Anaphylaxis 

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[ ] Cutaneous (rash, etc.)
[ ] Liver function abnormalities 
[ ] Other: _______________ 
 
Hospitalized? 
[ ] Yes 
[ ] No 
 
Study drug discontinuation? 
[ ] Permanent stop 
[ ] Temporary stop 
[ ] Not discontinued 
 
Myocardial infarction 
(defined as the presence of at 
least 2 of the 3 following 
conditions: 
 The detection of a rise 
and/or fall of cardiac 
biomarkers, with at 
least one of the values 
being elevated 
[preferably cardiac 
troponin (cTn) with at 
least one value above 
the 99th percentile 
upper reference limit] 
and with at least one of 
the following:   
(1) symptoms of 
myocardial 
ischemia;  
(2) new (or 
presumably 
new) 
significant 
ST-
segment/T-
wave 
changes or 
left bundle 
branch 
block;  
(3) development 
of 
pathological 
[ ] Yes 
[ ] No 
 
If yes, date ____/____/_____        
                 MM     DD     YYYY              
 
Type: 
[ ] ST elevation 
[ ] Non-ST elevation 
 
Fatal? 
[ ] Yes 
[ ] No 
 
Treatment: 
[ ] Systemic fibrinolysis 
[ ] Percutaneous coronary intervention (angioplasty, 
stenting, etc.) 
[ ] CABG 
[ ] Medical management 
 

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Q waves on 
ECG;  
(4) new loss of 
viable 
myocardium 
or regional 
wall motion 
abnormality 
by imaging; 
(5) identification 
of 
intracoronary 
thrombus by 
angiography 
or autopsy) 
Non-MI coronary 
revascularization  
 
[ ] Yes 
[ ] No 
 
If yes, date ____/____/_____        
                 MM     DD     YYYY              
 
Recascularization: 
[ ] Percutaneous coronary intervention (angioplasty, 
stenting, etc.) 
[ ] CABG 
 
Stroke/TIA 
(defined as a new, focal 
neurologic deficit of sudden 
onset, lasting at least 24 
hours, not due to a readily 
identifiable nonvascular 
cause (i.e. brain tumor, 
trauma), as confirmed by a 
neurologist and 
neuroimaging.) 
 
[ ] Yes 
[ ] No 
 
If yes, date ____/____/_____        
                 MM     DD     YYYY              
 
Confirmation (both must be present): 
[ ] By neurologist 
[ ] By neuroimaging 
 
TIA? 
[ ] Yes 
[ ] No 
 
Stroke? 
[ ] Yes 
[ ] No 
 
If yes, type of stroke: 
[ ] Ischemic 

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[ ] Hemorrhagic
[ ] Other 
 
Fatal stroke? 
[ ] Yes 
[ ] No 
 
 
Treatment: 
[ ] Systemic fibrinolysis 
[ ] Percutaneous thrombectomy 
[ ] Surgery 
[ ] Other 
 
Major adverse limb event  
 
[ ] Yes                                  [ ] No 
 
Acute limb ischemia 
[ ] Yes                                    [ ] No 
 
(Acute limb ischemia defined as limb-threatening 
ischemia which is confirmed by limb hemodynamics or 
imaging and leads to an acute vascular intervention 
within 30 days of onset of symptoms or absent pedal 
pulses) 
 
Critical limb ischemia (CLI) 
[ ] Yes                                   [ ] No 
 
(CLI is defined as continuing ischemic limb, foot or 
digit pain leading to hospitalization and intervention 
and not meeting the definition of ALI, or Fontaine 3 or 
4 at baseline with peripheral intervention during the 
trial) 
 
Peripheral intervention 
[ ] Yes                                   [ ] No 
 
(Peripheral vascular intervention is defined as 
peripheral vascular intervention not meeting the 
definition for ALI or CLI) 
 
Amputation 
[ ] Yes                                   [ ] No 
 
Admission for heart failure 
(HFPEF or HFREF) 
[ ] Yes                                  [ ] No 
 

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Appendix 
 
1. Apixaban Package Insert (Version June 2018) 
https://packageinserts.bms.com/pi/pi_eliquis.pdf 
 
 
2. Eliquis Medication Guide  
https://packageinserts.bms.com/medguide/medguide_eliquis.pdf 
 
3. Informed Consent Form 
 
 
 
 

 
 
 
 
 
 
 
 
 
 

HI-PRO Trial
Protocol CV185-745
1 
 
 
 
 
 
 
 
 
 
 
 
 
Date: 03/24/2025 
(First and final version) 
 
Study PI: Gregory Piazza, MD, MS  
 
 
 
 
 
 
 
 

HI-PRO Trial
Protocol CV185-745
2 
 
Table of Contents 
1. 
Study Overview ................................................................................................................... 3 
2. 
Specific Aims ...................................................................................................................... 3 
3. 
Definitions ........................................................................................................................... 3 
3.1 
Target Population ....................................................................................................... 3 
3.2 
Study Inclusion Criteria ............................................................................................... 4 
3.3 
Study Exclusion Criteria .............................................................................................. 4 
4. 
Outcomes ........................................................................................................................... 4 
4.1 
Efficacy Outcomes ...................................................................................................... 4 
4.1.1 
Primary Efficacy Outcomes ..................................................................................... 5 
4.1.2 
Secondary Efficacy Outcomes ................................................................................ 5 
4.2 
Safety Outcomes ........................................................................................................ 5 
4.2.1 
Principal Safety Outcome ....................................................................................... 5 
4.2.2 
Secondary Safety Outcome .................................................................................... 5 
5. 
Details of Randomization and Blinding ................................................................................ 6 
6. 
Statistical Plan .................................................................................................................... 6 
6.1 
Power Calculation ....................................................................................................... 6 
6.2 
Cohort Definition ......................................................................................................... 7 
6.2.1 
Table. Analysis cohorts. .......................................................................................... 8 
6.3 
Baseline Demographics and Clinical Comorbidities Description ................................. 9 
6.4 
Survival Analysis ........................................................................................................ 9 
6.4.1 
Principal Analysis .................................................................................................... 9 
6.4.2 
Subgroup Analysis .................................................................................................10 
6.5 
Back-Up Methods if Proportional Hazard Assumption is Violated ..............................10 
6.6 
Interim Analysis .........................................................................................................10 
6.7 
Stopping for safety: ....................................................................................................10 
6.8 
Stopping for futility: ....................................................................................................11 
6.9 
Stopping for efficacy (superiority): ..............................................................................11 
 
 
 
 
 
 

HI-PRO Trial
Protocol CV185-745
3 
 
1.
Study Overview
Patients who have experienced at least one persistent provoking factor following an initial 
provoked venous thromboembolism (VTE) are suspected to be at an increased risk of recurrence. 
However, it is still unclear whether extended-duration anticoagulation is beneficial for such 
patients. The HI-
(BWH) has been designed to investigate the safety and efficacy of extended-duration low-dose 
apixaban 2.5 mg twice daily for preventing recurrence in high-risk patients after initial provoked 
VTE. 
2. Specific Aims 
In this section, we provide an overview 
evidence that provoked VTE patients may require extended-duration anticoagulation for 
secondary prevention, the apixaban 2.5 mg twice daily dose could be a critical addition to our 
armamentarium in those at high risk for recurrence at the transition of care from the acute to the 
chronic treatment phase.  However, this hypothesis needs to be tested in a randomized clinical 
trial.  We propose a single-center (BWH), randomized placebo-controlled trial conducted at to 
evaluate the impact of low-dose apixaban (2.5 mg twice daily) in a study population exclusively 
comprised of provoked VTE patients with at least one persistent provoking factor.  We have the 
following study aims: 
Specific Aim #1: To compare the 12-month recurrent symptomatic VTE in patients with provoked 
VTE and at least one enduring factor who are randomized to either apixaban (2.5 mg orally twice 
daily) as monotherapy or placebo after completing at least 3 months of therapeutic anticoagulation 
and who have a low risk of bleeding. 
Specific Aim #2: To compare the 12-month ISTH major bleeding in patients with provoked VTE 
and at least one enduring factor who are randomized to either apixaban (2.5 mg orally twice daily) 
as monotherapy or placebo after completing at least 3 months of therapeutic anticoagulation and 
who have a low risk of bleeding. 
3. Definitions 
3.1 Target Population 
The study design is a single center randomized controlled trial that will take place at BWH. The 
allocation ratio for the study is 1:1, meaning that half of the participants will be assigned to 
apixaban 2.5 mg twice daily, and the other half will be assigned to placebo for a duration of one 
year. 
To ensure that the study enrolls the most appropriate participants, a set of detailed inclusion and 
exclusion criteria have been developed. These criteria are intended to identify individuals who are 
at high risk of recurrent VTE and are likely to benefit from extended-duration anticoagulation 
therapy without incurring a prohibitive risk of bleeding. 
The allocation of treatments will be conducted by randomization procedures, ensuring that each 
participant has an equal chance of being assigned to the apixaban or placebo group. The study 
will be closely monitored for safety, and participants will be closely followed up throughout the 
study period to assess the efficacy and safety of the treatment. Below, we provide the detailed 
inclusion and exclusion criteria, which has been described. 

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3.2 Study Inclusion Criteria
The study is looking for men and women aged 18 years or older who have been objectively 
confirmed with provoked DVT and/or PE, and have been treated with standard therapeutic 
anticoagulant therapy for at least three months without symptomatic recurrence. Participants must 
have at least one enduring VTE risk factor, such as obesity, heart failure, chronic lung disease, 
chronic kidney disease, pregnancy, or use of hormonal therapies such as oral contraceptives, or 
chronic inflammatory/autoimmune disorder. They must be willing to provide written informed 
consent and have outpatient follow-up at BWH. Participants who have atherosclerotic 
cardiovascular disease may also be eligible for the study, with up to 35% in each study group 
having this condition as a qualifying persistent risk factor. The study also includes individuals who 
have experienced VTE post-COVID-19 infection and post-COVID-19 vaccination. 
Eligible patients will be allowed to have multiple risk factors, and there will not be a limit as to how 
many of the above risk factors a subject may have.  In addition, we will place no limit on the 
number of patients included with multiple risk factors.  A study population with multiple risk factors 
is highly representative of the provoked VTE population and will provide the greatest 
generalizability of the study results to real-world clinical practice.  Including patients with single 
and multiple persistent provoking risk factors will also facilitate enrollment.  As noted, there is 
clinical and research equipoise regarding whether patients with a single or multiple persistent 
provoking VTE risk factors should receive extended duration thromboprophylaxis for secondary 
prevention. 
3.3 Study Exclusion Criteria 
The study excludes pregnant or breastfeeding women, women who are of child-bearing potential 
and unwilling or unable to use an acceptable method of birth control, and individuals with active 
cancer within the past 5 years or a contraindication to antithrombotic or antiplatelet therapy. The 
study also excludes those who require ongoing anticoagulant therapy, dual antiplatelet therapy, 
P2Y12 inhibition, or aspirin at a dose of > 81 mg daily. Other exclusion criteria include various 
medical conditions, such as severe thrombophilia, hemoglobin level < 9 mg/dL, platelet count < 
100,000/mm3, serum creatinine level > 2.5 mg/dL, ALT or AST level > 2 times the upper limit of 
the normal range, or a total bilirubin level > 1.5 times the upper limit of the normal range. 
Additionally, individuals with a history of a platelet disorder, bleeding diathesis, or recent active 
bleeding, active severe hepatobiliary disease, or more than 6 months that have elapsed without 
taking an anticoagulant or low-dose aspirin are excluded. The study also excludes individuals with 
a known severe thrombophilia, life expectancy < 12 months or hospice care, prisoners, and 
individuals who are compulsorily detained for treatment of either a psychiatric or physical illness. 
Finally, individuals who are receiving concurrent non-FDA-approved or investigational agents or 
have received an investigational agent within the past 30 days prior to the first dose of study 
treatment are also excluded, as well as those who have a history of a severe hypersensitivity 
reaction to apixaban or require a medication that is contraindicated to be co-administered with 
apixaban. 
 
4.  Outcomes 
Both safety and efficacy will be assessed in this trial. Outcome definitions are as follows: 
4.1 Efficacy Outcomes 

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4.1.1 Primary Efficacy Outcomes
The primary efficacy outcome will be the time to first symptomatic, recurrent VTE, defined as the 
composite of fatal or nonfatal deep vein thrombosis and/or pulmonary embolism within 12 months 
from randomization. The primary efficacy outcome will be independently adjudicated by a Clinical 
Events Committee (CEC) blinded to assigned treatments. DVT is diagnosed as a newly non-
compressible venous segment or segments on ultrasonography or a filling defect on computed 
tomographic (CT) venography, magnetic resonance (MR) venography, or contrast venography. 
PE is diagnosed based on new mismatched perfusion defect(s) on ventilation-perfusion scan, the 
presence of a new pulmonary artery filling defect on contrast-enhanced chest CT, a new finding 
of intraluminal filling defect on invasive pulmonary angiography, or evidence of PE at autopsy.  
Death due to causes other than DVT or PE will be considered a competing risk for this outcome. 
4.1.2 Secondary Efficacy Outcomes 
Secondary efficacy outcomes include the time to first occurrence of a composite of death due to 
cardiovascular causes, nonfatal myocardial infarction (MI), stroke or systemic embolism, chronic 
limb-threatening ischemia (CLTI), or coronary or peripheral ischemia requiring revascularization 
(major adverse cardiovascular events, including major adverse limb events) within 12 months, 
and the individual components of this outcome. An additional composite outcome will include all 
the components of the above composite of major adverse cardiovascular events as well as 
symptomatic VTE.  A composite thrombotic outcome will be analyzed and will include 
symptomatic VTE, fatal or nonfatal myocardial infarction (MI), stroke/TIA or systemic embolism. 
The secondary efficacy outcomes will be independently adjudicated by a CEC blinded to assigned 
treatments. Non-cardiovascular death will be considered a competing risk. 
 
4.2 Safety Outcomes 
4.2.1 Principal Safety Outcome 
The principal safety outcome will be the time to first major bleeding within 12 months from 
randomization.  Major bleeding is defined according to the International Society on Thrombosis 
and Haemostasis (ISTH) as overt bleeding that is associated with a decrease in the hemoglobin 
contributes to death 1.  The principal safety outcome will be independently adjudicated by a 
blinded CEC review. Non-hemorrhagic death will be considered a competing risk for this outcome. 
4.2.2 Secondary Safety Outcome 
The time to first clinically relevant non-major bleeding within 12 months will be evaluated and is 
defined per the ISTH as overt bleeding that does not meet the criteria for major bleeding but that 
is associated with the need for medical intervention, unscheduled contact with a physician, 
interruption or discontinuation of the study drug, or discomfort or impairment of activities of daily 
living 2. Like the primary safety outcome, this outcome will be assessed by the CEC, blinded to 
assigned treatments. All-cause death will be considered a competing risk for this outcome.  We 
will also assess a composite outcome of major bleeding and clinically-relevant nonmajor bleeding.  
Non-hemorrhagic death will be considered a competing risk for these outcomes. 
For all the outcomes, the last time contact date will be used for determining censoring.  

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5.
Details of Randomization and Blinding
Subjects who are 18 years of age or older with provoked DVT and/or PE, have completed at least 
3 months of therapeutic anticoagulation, have a low risk of bleeding, and have at least one 
enduring risk factor will be randomly assigned by computer in a 1:1 ratio to receive apixaban 2.5 
mg orally twice daily or oral placebo for extended secondary prevention of VTE for a duration of 
12 months. 
This study will be conducted in a blinded fashion. To maintain blinding of study treatment, the 
active study drug and placebo will be matched for color, size and box.  Subjects, investigators, 
members of any of the administrative and adjudicating committee
conducting the study, will not have access to individual subject treatment assignments. 
An independent Safety Monitor has been selected for this study.  The Safety Monitor is an expert 
in VTE and is distinct from the DMSB and Study Staff and will be available throughout the study 
to assess patient safety issues that may arise, objectively.  The Safety Monitor will have the ability 
to break the blind of a study patient as the need arises (immediately, in real-time).  If the Safety 
Monitor is unavailable because of travel, one of the Physician Study Investigators will serve as 
back-up.   
6. Statistical Plan 
6.1 Power Calculation 
Our power calculation accommodates efficacy outcomes. This is an implementation of the power 
calculation method described in Section 14.12 (page 807) of Rosner (2006). The equitation of 
power calculation based on 1:1 randomization is expressed as below: 
 
where   is the expected total number of events over both groups,  is the total sample size, 
 
and 
 are the probabilities of event in treatment group and placebo group over the maximum 
time of the study,  is postulated hazard ratios for the treatment over placebo.  
We postulated the following anticipated parameters for the power calculation: a) by the end of 
follow up, the event rate of the placebo arm is 6% and there is 75% reduction rate with active 
treatment (low-intensity apixaban), i.e., the event rate of the placebo arm is 1.5%; b) the 
postulated hazard ratios for the treatment over placebo by 1-year follow-up ranges from 0.2-0.24. 
These anticipated parameters are based on previous studies 3,4. In Figure 1, we provide the power 
analysis given certain sample size. The power under the significance of 0.05 is given for the total 
sample with 1:1 randomization ranging from 500-700. To achieve sufficient sample sizes needed 
for reach the power of 80%, we conservatively choose 600 patients to ensure the enough power. 
 
 

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Figure 1. The power calculation given the postulated hazard ratios and with 1:1 randomization. 
The red curve indicates the power of 80%. 
6.2 Cohort Definition 
In this section, we define a main cohort and four confirmatory cohorts for the analysis of efficacy 
and safety (Table). 
Main Cohort (ITT): we will use the intention-to-treat (ITT) cohort since it maintains the original 
randomization scheme 
 5.  
Confirmatory Cohort (MITT): the modified intention-to-treat (MITT) cohort consisting of all 
randomized patients who took at least one dose of the assigned treatment and did not undergo 
post-randomization exclusion. 
Confirmatory Cohort (PP-1): Additional analyses will include a per-protocol (PP) population for 
subjects who took 80% of the study drug (or placebo). 

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Confirmatory Cohort (PP-2): Additional analyses will include a per-protocol (PP) population for 
subjects who took 80% of the study drug (or placebo) with censoring for either ISTH major 
bleeding or clinically relevant nonmajor bleeding event. 
Confirmatory Cohort (Safety Cohort): In this cohort, we will only consider bleeding events (major 
bleed or clinically relevant non-major bleed) that occurred within 96 hours of taking a dose of the 
study drug (or placebo). The follow-up duration will be considered until the occurrence of a 
bleeding event or 96 hours after taking the last dose of the study drug (or placebo), whichever 
comes first. 
6.2.1 Table. Analysis cohorts. 
Analysis Set 
Definition 
Primary Efficacy-  
12-month recurrent 
symptomatic VTE 
Primary Safety-  
12-month ISTH ma-
jor bleeding 
ITT 
All randomized 
Number of events 
Proportion 
Cumulative incidence 
Hazard ratio 
95% confidence inter-
val 
P-value 
Number of events 
Proportion 
Cumulative incidence 
Hazard ratio 
95% confidence inter-
val 
 
mITT 
All randomized 
who took at least 
one dose of as-
signed treatment 
(apixaban or pla-
cebo) and did not 
undergo post-ran-
domization exclu-
sion  
Number of events 
Proportion 
Cumulative incidence 
Hazard ratio 
95% confidence inter-
val 
Number of events 
Proportion 
Cumulative incidence 
Hazard ratio 
95% confidence inter-
val 
Per protocol without 
censoring for bleed-
ing events 
Subjects who took 
80% of assigned 
treatment doses 
(apixaban or pla-
cebo) 
Number of events 
Proportion 
Cumulative incidence 
Hazard ratio 
95% confidence inter-
val 
Number of events 
Proportion 
Cumulative incidence 
Hazard ratio 
95% confidence inter-
val 
Per protocol with 
censoring for bleed-
ing events 
Subjects who took 
80% of assigned 
treatment doses 
(apixaban or pla-
cebo) with censor-
ing for either ISTH 
major bleeding or 
clinically relevant 
nonmajor bleeding 
event 
Number of events 
Proportion 
Cumulative incidence 
Hazard ratio 
95% confidence inter-
val 
Number of events 
Proportion 
Cumulative incidence 
Hazard ratio 
95% confidence inter-
val 
Safety set 
Subjects who took 
at least one dose 
of the study drug 
(or placebo) until 
Number of events 
Proportion 
Cumulative incidence 
Hazard ratio 
Number of events 
Proportion 
Cumulative incidence 
Hazard ratio 

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96 hours after the 
administration of 
the last dose of the 
study drug. 
95% confidence inter-
val 
95% confidence inter-
val 
P-value 
 
6.3 Baseline Demographics and Clinical Comorbidities Description 
Understanding the baseline demographics and clinical comorbidities of a cohort is crucial for 
interpreting study results and drawing conclusions about the generalizability of findings. In the HI-
PRO trial, a table of descriptive statistics will be provided to summarize the baseline 
demographics of the intention-to-treat cohort. The table will include information on logical and 
categorical variables, such as age, sex, race, and comorbidities. The numbers and percentages 
will be provided for these variables, allowing for an assessment of the distribution and prevalence 
of different characteristics among the study population. In addition to logical and categorical 
variables, the table will also provide information on continuous variables, such as body mass 
index, hemoglobin level, and serum creatinine level. For these variables, the mean and standard 
deviation (SD) will be provided to summarize the central tendency and variability of the data. 
According to the recent statistical reporting guideline from some experts 6, we will not provide p-
values for testing the differences in baseline characteristics of the two assigned groups. However, 
the balances should be checked to see the quality of randomization by inspecting the 
standardized difference. We will consider the ones with a standardized difference >0.1 as clinically 
different. For a certain category whose observations are smaller than five counts, we may 
consider regrouping the categories. 
6.4 Survival Analysis 
6.4.1 Principal Analysis 
 
We first provide analysis without adjustment of baseline demographics. For both the primary and 
secondary efficacy outcomes and principal and secondary safety outcomes, we use the Kaplan-
Meier curve to estimate the survival functions of each group. If there is a presence of competing 
risks, cumulative incidence functions (CIFs) will be used to estimate the survival function7. The 
two-side log-rank test is used to measure if the apixaban 2.5 mg twice a day has a better survival 
chance than placebo (i.e., better chance of meeting the primary outcome). If there is a presence 
of competing risk, the log-rank based on cause-specific hazards 8 will be used. The corresponding 
hazard ratio of treatment effect and its confidence interval will be reported. 
 
While our analysis is based on randomization, we also provide confirmatory analyses with the 
adjustment of baseline demographics and clinical comorbidities since it may capture any potential 
variations to make the statistical analysis more powerful. We use Cox regression to assess both 
the primary and secondary efficacy outcomes, while with adjustment of baseline demographics 
and clinical comorbidities. No interaction effects will be added. If there are competing risks, a 
cause-specific hazard model 7 will be used. The hazard ratio for be being treatment with the 
apixaban 2.5 mg twice a day will be used to test the treatment effect. The hazard ratio of other 
baseline demographics will be reported as supplementary information. 
If the trial has a good randomization, we expect that the hazard ratio of treatment in analysis with 
the adjustment of baseline demographics and its p-value implies the same conclusion as in 
analysis without adjustment of baseline demographics. However, if they are not consistent in 

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clinical interpretation, i.e., a) the interpretation directions are different; b) p-values indicate 
different conclusion of significance, we will use the hazard ratio of treatment in analysis with the 
adjustment of baseline demographics as the main results to report, and the results of unadjusted 
one is treated as supplementary materials. 
 
6.4.2 Subgroup Analysis 
 
The study will conduct subgroup analyses based on certain predetermined factors such as 
whether the patient has PE versus non-PE, age (65 years or older versus younger), sex (male 
versus female), chronic kidney disease (defined as presence or absence of eGFR<60 
mL/min/1.72m2), atherosclerotic cardiovascular disease (present versus absent), baseline low-
dose aspirin use (present versus absent), the number of provoking risk factors (2 or more versus 
less than 2), provoking factor of travel, and baseline aspirin use. The survival analysis within each 
subgroup will be repeated using the main cohort and tested in confirmatory cohorts, as needed. 
The p-value of the additive interaction effect between treatment and subgroup will be reported. 
  
In case the subgroup analysis of baseline aspirin use indicates a relevant modification effect (the 
p-value for the additive interaction effect <0.05), the study will repeat the primary analysis by 
reporting the treatment effect of apixaban vs placebo with the adjustments for a) the use of aspirin 
and b) the interaction term. 
 
6.5 Back-Up Methods if Proportional Hazard Assumption is Violated 
The Cox regression relies on the assumption of proportional hazards over time. The hazard 
proportionality test9 is used to check the assumption. If the assumption of proportional hazard is 
violated. We will use the following backup methods. The log-rank test will be replaced by Kaplan
Meier curve-based tests (including weighted Kaplan Meier and restricted mean survival time) 10. 
Survival analysis based on restricted mean survival time will be implemented and restricted mean 
time lost (RMTL) ratios will replace the hazard ratio for reporting. 
6.6 Interim Analysis 
We will conduct a pre-specified interim analysis to assess the primary safety and efficacy 
outcomes after 50% of the planned enrollment population has completed 12-month follow-up. 
This planned interim analysis will inform the Data Safety Monitoring Board on whether the study 
should be stopped early due to efficacy, safety concerns, or futility or continue to enroll the full 
600-patient cohort. The following three elements are used in considering the interim analysis: 
6.7 Stopping for safety: 
In the event that three distinct occurrences of unprovoked intracranial hemorrhages or major 
bleeding episodes are observed within the group of patients receiving apixaban, a thorough 
investigation will be conducted. This investigation will involve a review by an adjudication 
committee to confirm the authenticity of these incidents, ensuring that there have been no 
breaches of the study protocol that could have contributed to the adverse events. If the committee 
determines that these incidents are indeed linked to the apixaban treatment, specific measures 
will be implemented in response to these findings. 
The decision to take action upon the confirmation of three such events is rooted in the clinical 
expertise of the researchers involved in the study. This threshold was established after extensive 
deliberation and consultation with the Mass General-Brigham Institutional Review Board (IRB). 

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The IRB is an independent body responsible for protecting the rights and welfare of human 
subjects involved in research, and their guidance plays a crucial role in maintaining the ethical 
standards of the study. 
6.8 Stopping for futility: 
The futility stopping rule is in place to prevent the unnecessary continuation of a clinical trial if 
there is a high likelihood that the primary efficacy outcome rate in the placebo arm falls below 6%. 
This threshold is considered clinically safe and is set to ensure that resources are not wasted on 
a trial that is unlikely to produce meaningful results. The problem is framed as a hypothesis testing 
scenario, where the null hypothesis states that the primary efficacy rate is greater than or equal 
to 0.06, and the alternative hypothesis suggests that it is less than 0.06. 
If the null hypothesis is rejected, it indicates that the actual event rates in the placebo arm are 
less than 6%. To reject the null hypothesis, fewer than 4 events must be observed. In this context, 
the trial's progress will be assessed during an interim statistical analysis when the 12-month 
follow-up is completed for the 300th patient. At this point, if there are fewer than 4 events observed 
in the placebo group, the decision to terminate the trial will be considered. 
6.9 Stopping for efficacy (superiority): 
The efficacy stopping rule is a guideline used to determine whether a clinical trial should be 
terminated early based on the observed results. This rule is applied in situations where the data 
collected from the trial's participants, in this case, 300 patients, clearly demonstrates that the 
treatment being studied has a significantly higher efficacy than the placebo. The objective is to 
avoid exposing more patients to an inferior treatment (placebo) and to expedite the process of 
bringing a highly effective treatment to the market. 
In this specific scenario, the efficacy stopping rule is based on the unadjusted hazard ratio, which 
is a measure of the relative risk of an event occurring in the treatment group compared to the 
placebo group. A hazard ratio of less than 0.1 is considered as "overwhelmingly superior efficacy," 
indicating that the treatment group has a much lower risk of the event than the placebo group. 
To determine whether the trial should be stopped, a hypothesis test is conducted. The null 
hypothesis (H0) states that the hazard ratio is larger than or equal to 0.1, while the alternative 
hypothesis (H1) states that the hazard ratio is smaller than 0.1. If the null hypothesis is rejected 
based on the data collected from the enrolled patients, it would be concluded that the treatment 
has overwhelmingly superior efficacy compared to the placebo. As a result, the trial would be 
terminated early, allowing for a more rapid progression towards making the effective treatment 
available to patients who could benefit from it. 
 
 
 

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