Cost Comparison Between Apixaban and Low Molecular Weight Heparin (LMWH) Among Venous Thromboembolism (VTE) Cancer Patients
Conditions: Thromboembolism
Sponsor: Pfizer

Apixaban
B0661183 NON-INTERVENTIONAL STUDY PROTOCOL
Protocol Version: 2.0 29 July 2022
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NON-INTERVENTIONAL STUDY PROTOCOL
Study information
Title
Cost comparison between apixaban and low 
molecular
weight heparin (LMWH) among 
venous thromboembolism (VTE) cancer patients
Protocol number
B0661183
Protocol version identifier
2.0
Date
29 July 2022
Research question and objectives
To evaluate the costs and healthcare resource 
utilization (HCRU) associated with treating VTE 
cancer patients with apixaban
compared to 
LMWH
To compare costs and HCRU associated with 
recurrent VTE, major bleeding, and clinically 
relevant non-major (CRNM) bleeding among 
VTE cancer patients treated with apixaban vs 
LMWH
Authors
IQVIA 
3110 Fairview Park Drive 
Suite 400
Falls Church, VA 22042 USA
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PPD
PPD

Apixaban 
B0661183 NON-INTERVENTIONAL STUDY PROTOCOL 
Protocol Version: 2.0 29 July 2022 
 
 
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1. TABLE OF CONTENTS 
1. TABLE OF CONTENTS .......................................................................................................2 
2. LIST OF ABBREVIATIONS ................................................................................................4 
3. RESPONSIBLE PARTIES ....................................................................................................7 
4. ABSTRACT ...........................................................................................................................8 
5. AMENDMENTS AND UPDATES .....................................................................................10 
6. MILESTONES .....................................................................................................................13 
7. RATIONALE AND BACKGROUND ................................................................................14 
8. RESEARCH QUESTION AND OBJECTIVES .................................................................15 
9. RESEARCH METHODS ....................................................................................................16 
9.1. Study period and study design ................................................................................16 
9.1.1. Inclusion criteria .........................................................................................16 
9.1.2. Exclusion criteria ........................................................................................18 
9.2. Cohorts ....................................................................................................................19 
9.3. Variables ..................................................................................................................19 
9.3.1. Baseline Measures ......................................................................................19 
9.3.2. All-cause HCRU and Costs Over the Post-Index Period (Post-IPTW) ......23 
9.3.3. Recurrent VTE, major bleeding, and CRNM bleeding related HCRU 
and costs in the post-index period ....................................................................26 
9.4. Data sources ............................................................................................................27 
9.5. Study size ................................................................................................................28 
9.6. Data management ....................................................................................................28 
9.6.1. Case report forms (CRFs)/Data collection tools (DCTs)/Electronic 
data record ........................................................................................................28 
9.6.2. Record retention ..........................................................................................28 
9.7. Data analysis ...........................................................................................................29 
9.8. Quality control .........................................................................................................30 
9.9. Limitations of the research methods .......................................................................30 
9.10. Other aspects .........................................................................................................30 
10. PROTECTION OF HUMAN SUBJECTS ........................................................................31 
10.1. Patient information ................................................................................................31 
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Apixaban 
B0661183 NON-INTERVENTIONAL STUDY PROTOCOL 
Protocol Version: 2.0 29 July 2022 
 
 
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10.2. Patient consent .......................................................................................................31 
10.3. Institutional review board (IRB)/Independent ethics committee (IEC) ................31 
11. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS ......................................................................................................................31 
12. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS........31 
13. REFERENCES ..................................................................................................................32 
14. LIST OF TABLES .............................................................................................................34 
15. LIST OF FIGURES ...........................................................................................................34 
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS .........................................................34 
ANNEX 2. ADDITIONAL INFORMATION .........................................................................35 
 
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Apixaban 
B0661183 NON-INTERVENTIONAL STUDY PROTOCOL 
Protocol Version: 2.0 29 July 2022 
 
 
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2. LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
AE 
adverse event 
ACE 
Angiotensin-converting enzyme 
AIDS 
acquired immune deficiency syndrome 
APS 
antiphospholipid syndrome 
ARB 
Angiotensin receptor blockers 
ASH 
American Society of Hematology 
BMS 
Bristol Myers Squibb 
CCI 
Charlson comorbidity index   
COPD 
chronic obstructive pulmonary disease 
CRNM 
clinically relevant non-major bleeding 
DCTs 
data collection tools 
DVT 
deep vein thrombosis 
ER 
emergency room 
ESA 
Erythropoiesis stimulating agents 
GI 
gastrointestinal 
GLM 
generalized linear models 
HCPCS 
healthcare common procedure coding system 
HCRU 
healthcare resource utilization 
HIPAA 
health insurance portability and accountability act 
HMO 
health maintenance organization 
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Apixaban 
B0661183 NON-INTERVENTIONAL STUDY PROTOCOL 
Protocol Version: 2.0 29 July 2022 
 
 
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ICD-10-CM 
international classification of diseases, tenth 
revision, clinical modification 
ICH 
intracranial hemorrhage 
ID 
identifier 
IEC 
independent ethics committee 
IPTW 
inverse probability of treatment weighting 
IQR 
Interquartile range 
IRB 
institutional review board 
LMWH 
low molecular weight heparin 
LOS 
Length of stay 
NDC 
National Drug Codes 
NSAID 
Nonsteroidal anti-inflammatory drugs 
OAC  
oral anticoagulant 
PAC 
parenteral anticoagulant 
PCP 
primary care provider 
PE 
pulmonary embolism 
PPO 
preferred provider organization 
SAS 
statistical analysis system 
SCHIP 
State Children’s Health Insurance Program 
SD 
standard deviation 
SERM 
Selective estrogen receptor modulators 
SMD 
standardized mean difference 
US 
United States 
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Apixaban 
B0661183 NON-INTERVENTIONAL STUDY PROTOCOL 
Protocol Version: 2.0 29 July 2022 
 
 
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USD 
United States dollars 
VTE 
venous thromboembolism 
 
 
 
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Apixaban 
B0661183 NON-INTERVENTIONAL STUDY PROTOCOL 
Protocol Version: 2.0 29 July 2022 
 
 
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3. RESPONSIBLE PARTIES 
Principal Investigators of the Protocol 
Name, degree(s) 
Job Title 
Affiliation 
Address 
Mitch DeKoven, 
MHSA 
Senior Principal 
IQVIA 
3110 Fairview Park 
Drive, Suite 400, 
Falls Church, VA 
22042 USA 
Dionne Hines, 
MPH, PhD 
Director, HEOR 
Pfizer 
235 East 42nd Street, 
New York, NY 10017 
 
 
 
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Apixaban 
B0661183 NON-INTERVENTIONAL STUDY PROTOCOL 
Protocol Version: 2.0 29 July 2022 
 
 
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4. ABSTRACT 
Title 
Cost comparison between apixaban and low molecular weight heparin (LMWH) among 
venous thromboembolism (VTE) cancer patients  
 
Version: 2.0 
Date: 29 July 2022 
 
Primary author:  
Pfizer, Inc.  
 
Rationale and background 
Venous thromboembolism (VTE), comprising deep vein thrombosis (DVT) and pulmonary 
embolism (PE), is a common complication in patients with cancer. The risk of developing VTE 
in these patients is four to seven times higher compared to patients without cancer, with a 
reported incidence of up to 15% per year.1,2 American Society of Hematology (ASH) 
guidelines recommend direct-acting oral anticoagulants (OAC) or low molecular weight 
heparin (LMWH) in ambulatory patients with cancer at high risk for VTE or for initial 
treatment of VTE.4  
 
The risk of recurrent VTE, despite anticoagulant therapy, and bleeding complications is higher 
among patients with cancer compared to those without cancer.5 Apixaban, an oral factor Xa 
inhibitor has been previously shown to be efficacious in treating cancer-associated VTE 
without increased risk of major bleeding.7 There is a lack of evidence comparing the direct 
medical cost of using LMWH with direct-acting OAC’s such as apixaban which has been 
previously demonstrated to decrease the risk of recurrent VTE and major bleeding in cancer 
patients with VTE.8,9 Therefore, this study will evaluate the costs and healthcare resource 
utilization (HCRU) associated with treating VTE cancer patients with apixaban compared to 
LMWH. 
 
Research question and objectives 
The purpose of this study is to evaluate the costs and HCRU associated with treating VTE 
cancer patients with apixaban compared to LMWH (dalteparin or enoxaparin). 
 
The objectives of the study are as follows: 
Primary objectives: 
• 
To compare all-cause healthcare costs among VTE patients with cancer treated with 
apixaban vs LMWH 
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Apixaban 
B0661183 NON-INTERVENTIONAL STUDY PROTOCOL 
Protocol Version: 2.0 29 July 2022 
 
 
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• 
To compare costs associated with recurrent VTE, major bleeding, and clinically 
relevant non-major (CRNM) bleeding among VTE patients with cancer treated with 
apixaban vs LMWH 
Secondary objectives: 
• 
To compare all-cause HCRU among VTE patients with cancer treated with apixaban 
vs LMWH 
• 
To compare HCRU associated with recurrent VTE, major bleeding, and CRNM 
bleeding among VTE patients with cancer treated with apixaban vs LMWH 
 
Study design 
A retrospective database analysis will be conducted using IQVIA’s PharMetrics® Plus 
database among newly diagnosed VTE patients with active cancer who received apixaban or a 
LMWH on or within 30 days following the VTE diagnosis. The analysis will be conducted 
using data from 01 January 2016 through 31 December 2021 (i.e., the study period), including 
a 12-month pre-index period and 1-month post-index period and patients will be followed 
through the earliest of the following: health plan disenrollment, index therapy discontinuation, 
switch to another anticoagulant or end of study period. 
 
Population 
Adult patients with evidence of cancer and newly diagnosed VTE, followed by a claim of 
apixaban or LMWH will be identified. The date of the first apixaban or LMWH prescription 
will be termed as the index date and two cohorts will be identified based on this index 
prescription. Patient will be continuously enrolled during the 12-month pre-index period and 
with a variable post-index period. Other exclusion criteria will also be applied such as patients 
with evidence of atrial fibrillation, mechanical heart valve, inferior vena cava filter, 
antiphospholipid syndrome, pregnancy and with any data quality issues. 
 
Variables  
Exposures and explanatory variables in the pre-index period or on index date: 
x Demographic characteristics  
x Clinical characteristics  
x Baseline HCRU and costs 
Outcomes 
x All-cause HCRU and costs 
x Recurrent VTE related HCRU and costs 
x Major bleeding related HCRU and costs 
x CRNM bleeding related HCRU and costs 
 
Data sources 
IQVIA’s PharMetrics® Plus database comprises adjudicated claims for more than 190 million 
unique enrollees across the United States (US). Enrollees with both medical and pharmacy 
coverage in 2020 represented 40 million lives. PharMetrics Plus has diverse representation of 
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B0661183 NON-INTERVENTIONAL STUDY PROTOCOL 
Protocol Version: 2.0 29 July 2022 
 
 
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geography, employers, payers, providers and therapy areas. Patients in each zip code and every 
Metropolitan Statistical Area of the US are included, with coverage of data from 90% of US 
hospitals, 80% of all US doctors, and representation from 85% of the Fortune 100 companies. 
In addition to standard fields such as inpatient and outpatient diagnosis and procedures, retail 
and mail-order prescription records, PharMetrics Plus has detailed information on the 
pharmacy and medical benefit (copayment, deductible), the inpatient stay (admission type and 
source, discharge status) and provider details (specialty, provider identifier [ID]). Payment 
amounts include the negotiated rate between the plan and providers (allowed) and the actual 
amount paid by health plans to the provider for all services rendered. Charge amount is also 
available for a subset of claims. Other data elements include dates of service, demographic 
variables (age, gender, and geographic region), product type (e.g., health maintenance 
organization [HMO], preferred provider organization [PPO]), payer type (e.g., commercial, self-
insured), and start and stop dates of health-plan enrollment.  
 
Study size 
An earlier feasibility study estimated that there were 4,972 VTE patients with cancer with 
evidence of apixaban in PharMetrics® Plus.  
A minimum sample of 1,867 patients in each cohort is required to achieve 80% power at a 5% 
level of significane (two-sided) using recurrent VTE event rates from Agneli at al.7 of 5.6% in 
apixaban cohort and 7.9% in dalteparin cohort. Using recurrent VTE rates 4.362% in apixaban 
cohort and 6.483% in LMWH cohort from Cohen et al.,8 we require a minimum sample of 
1,788 patients in each cohort to achieve 80% power. Based on the sample size calculations, for 
the current study we need a minimum sample in the range of 1,788-1,867 patients in each 
cohort. 
 
Data analysis 
Descriptive statistics will be produced for all relevant study measures, for the 2 therapy 
cohorts. Stabilized inverse probability treatment weighting (IPTW) will be used to balance 
patient characteristics between apixaban and LMWH cohorts. Post-IPTW, comparisons will 
be conducted using weighted chi-square tests for categorical variables and weighted t-tests 
(mean) for continuous variables. Comparisons between independent samples (e.g., among 
patients with ≥1 hospitalization) and pre-IPTW samples will be conducted using the parametric 
t-test (mean) and non-parametric Wilcoxon rank-sum test (median) for continuous variables. 
A p value of ≤ 0.05 will be considered significant. 
Up to 4 regression models will be developed and these may include weighted generalized linear 
models (GLM) with log transformation and gamma distribution to estimate adjusted (all-cause) 
cost ratio between the two cohorts or a negative binomial distribution may be developed to 
estimate adjusted visits such as physician office visits, emergency room visits or other HCRU. 
 
Milestones 
Protocol and table shells: 12 August 2022 
Start of data analysis: 15 August 2022 
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Final results: 21 October 2022 
Final study reports and presentation: 18 November 2022 
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B0661183 NON-INTERVENTIONAL STUDY PROTOCOL 
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5. AMENDMENTS AND UPDATES 
Amendment 
number 
Date 
Protocol section(s) 
changed 
Summary of 
amendment(s) 
Reason 
None 
 
 
 
 
 
 
 
 
 
 
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6. MILESTONES 
 
Milestone 
Planned date 
Protocol approval 
12 August 2022 (estimated) 
Start of analysis 
15 August 2022 (estimated) 
Analysis completion 
21 October 2022 (estimated) 
Final study report 
18 November 2022 (estimated) 
 
 
 
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B0661183 NON-INTERVENTIONAL STUDY PROTOCOL 
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7. RATIONALE AND BACKGROUND 
Venous thromboembolism (VTE), comprising deep vein thrombosis (DVT) and pulmonary 
embolism (PE), is a common complication in patients with cancer. The risk of developing VTE 
in these patients is four to seven times higher compared to patients without cancer, with a 
reported incidence of up to 15% per year.1,2 Several cancer-associated risk factors for VTE 
have been identified, including patient-, treatment-, and tumor-related factors. Currently, 
patients with cancer often undergo imaging for tumor staging and evaluation of treatment 
response, which further increases the underlying possibility of VTE detection.3 When VTE is 
diagnosed, anticoagulant therapy is indicated in most cases. 2021 American Society of 
Hematology (ASH) guidelines recommend direct-acting oral anticoagulants (OAC) or low 
molecular weight heparin (LMWH) in ambulatory patients with cancer at high risk for VTE or 
for initial treatment of VTE.4 However, the management of VTE remains challenging in this 
patient population. The risk of recurrent VTE, despite anticoagulant therapy, and bleeding 
complications is higher among patients with cancer compared to those without cancer.5 
Recurrent VTE among patients with cancer is associated with significant healthcare resource 
use and, notably, hospitalizations.6 
Apixaban, an oral factor Xa inhibitor has been previously shown to be efficacious in treating 
cancer-associated VTE without increased risk of major bleeding.7 A study Cohen A. et al.8 
compared LMWH to apixaban for the treatment of VTE associated with cancer, however this 
study primarily focused on the effectiveness and safety profile of these treatments. Another 
study by Hlavaceck et al.9 compared healthcare costs of major bleeding and CRNM bleeding 
but this study was conducted only among VTE patients. Apixaban has been demonstrated to 
decrease the risk of recurrent VTE and major bleeding in cancer patients with VTE, however, 
there is a lack of evidence comparing the direct medical cost of using LMWH with direct-
acting OAC’s among such patients. Therefore, this study will evaluate the costs and 
healthcare resource utilization (HCRU) associated with treating VTE cancer patients with 
apixaban compared to LMWH. 
 
 
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8. RESEARCH QUESTION AND OBJECTIVES 
The purpose of this study is to evaluate the costs and HCRU associated with treating VTE 
cancer patients with apixaban compared to LMWH (dalteparin, enoxaparin, or tinzaparin). 
The objectives of the study are as follows: 
Primary objectives: 
• 
To compare all-cause healthcare costs among VTE patients with cancer treated with 
apixaban vs LMWH 
• 
To compare costs associated with recurrent VTE, major bleeding, and clinically 
relevant non-major (CRNM) bleeding among VTE patients with cancer treated with 
apixaban vs LMWH 
Secondary objectives: 
• 
To compare all-cause HCRU among VTE patients with cancer treated with apixaban 
vs LMWH 
• 
To compare HCRU associated with recurrent VTE, major bleeding, and CRNM 
bleeding among VTE patients with cancer treated with apixaban vs LMWH 
 
 
 
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9. RESEARCH METHODS       
A retrospective database analysis will be conducted among newly diagnosed VTE patients with 
active cancer who received apixaban or a LMWH on or within 30 days following the VTE 
diagnosis. IQVIA’s PharMetrics® Plus will be used for this analysis. See Annex 2. 
9.1. Study period and study design  
The analysis will be conducted using data from 01 January 2016 through 31 December 2021 
or the latest available data at the time of extraction (i.e., the study period).  Patients will be 
identified during a selection window of 01 January 2017 to 31 October 2021. The date of the 
first apixaban or LMWH prescription on or within the 30 days following a VTE diagnosis will 
be termed as the index date. Patients will be required to have continuous enrollment with 
medical and pharmacy benefits for 12-months prior to the index date to assess study eligibility 
criteria and to measure baseline characteristics (the baseline or pre-index period). Patients will 
also be required to have continuous enrollment with medical and pharmacy benefits for at least 
one month (30 days) starting on and following the index date (the follow-up or post-index 
period) and will be followed through the earliest of the following: health plan disenrollment, 
index therapy discontinuation, switch to another anticoagulant (includes switch to the other 
study medication or unfractionated heparin, fondaparinux, warfarin, rivaroxaban, dabigatran, 
or edoxaban), or end of study period (31 December 2021).  
Note: Patients in the LMWH cohort will NOT be considered to have discontinued or switched 
if they change to an LMWH other than the index LMWH (dalteparin, enoxaparin, or 
tinzaparin). 
Figure 1. Study Period 
 
 
9.1.1. Inclusion criteria 
Patients must meet all of the following inclusion criteria to be eligible for inclusion in the 
study: 
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1. Patients with ≥1 diagnosis code for VTE (inpatient [primary or secondary  discharge 
diagnosis] or any position on an outpatient  non-ancillary medical claim) between 
January 1, 2017 and October 31, 2021 (selection window). 
x Note: Qualifying outpatient encounters followed by qualifying inpatient 
encounters within 7 days will be considered an inpatient VTE event, unless 
LMWH or apixaban was initiated between encounters, in which case it will be 
classified as an outpatient VTE event   
x First date of claim with a VTE diagnosis code will be termed the ‘index VTE 
encounter’ 
2. Evidence of having active cancer, defined as ≥2 medical claims with a cancer diagnosis 
(excluding nonmelanoma skin cancer) on different days during the 6 months before or 
within 30-days after the index VTE event 
OR  
≥1 medical claim for a cancer diagnosis AND ≥1 claim for cancer treatment (eg: 
chemotherapy, radiation, immunotherapy, hormone therapy or cancer related surgery 
using national drug codes (NDC), international classification of diseases, tenth 
revision, clinical modification [ICD-10-CM] procedure codes or healthcare common 
procedure coding system [HCPCS] codes) during 6 months before or within 30 days 
after the index VTE encounter 
3. ≥1 claim of apixaban or LMWH (dalteparin orenoxaparin) on or within 30 days 
following the index VTE encounter.  
a. The date of the first apixaban or LMWH prescription fill will be designated as 
the index date 
4. ≥12 months of continuous enrollment prior to the index date (pre-index) 
5. ≥1 months of continuous enrollment including and following the index date (post-
index) 
a. Note: Each patient will have a variable follow-up period with a minimum of 1-
month follow-up. Patients will be followed from the day after the index date 
through the earliest of the following: health plan disenrollment, index therapy 
discontinuation, switch to another anticoagulant, or study end (December 31, 
2021).  
b. Discontinuation will be defined as occurrence of a ≥30 day gap from the run-
out of days’ supply of the index LMWH or apixaban prescription. The date of 
the discontinuation will be defined as the last day of the days’ supply of the last 
filled prescription. 
c. Switching will be defined as a prescription for an anticoagulant other than the 
index apixaban/LMWH prescription (unfractionated heparin, fondaparinux, 
other OAC, or LMWH for patients indexed on apixaban; unfractionated 
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heparin, fondaparinux, or OAC (including apixaban) for patients indexed on 
LMWH) within 30 days following discontinuation of the index medication.   
Note: Patients indexed on LMWH cohort will NOT be considered to have 
discontinued or switched if they change to an LMWH other than the index 
LMWH (dalteparin, enoxaparin, or tinzaparin) 
6. ≥18 years of age at index 
9.1.2. Exclusion criteria 
Patients meeting any of the following criteria will be excluded from the study: 
1. ≥1 claim with a ICD-10 diagnosis code of atrial fibrillation/flutter during the 12-month 
pre-index 
2. ≥1 claim with a ICD-10 procedure code of mechanical heart valve during the 12-month 
pre-index 
3. ≥1 claim with a ICD-10 diagnosis code of VTE diagnosis during the 12-month prior to 
index VTE encounter 
4. ≥1 prescription claim of OAC or parenteral anticoagulant (PAC) (unless prophylactic)  
before the index VTE encounter  
a. The OAC or PAC prescription claim will be considered prophylactic  
if duration of the prescription is ≤42 days AND the start date of OAC or PAC 
occurs within 2 days before or 7 days after knee/hip replacement surgery 
OR 
Start date of OAC or PAC occurred within 7 days after the admission of an 
hospitalization associated with ‘medically ill’ (primary discharge diagnosis; 
codes provided separately) AND with a ≥3-day length of stay of the 
hospitalization 
5. ≥1 claim with a ICD-10 procedure code or Common Procedural Terminology (CPT) code 
of inferior vena cava filter during the study period 
6. ≥1 claim with a ICD-10 diagnosis code of antiphospholipid syndrome (APS) during 
the study period 
7. ≥1 claim with a ICD-10 diagnosis code or procedure code (ICD-10 or HCPCS codes) 
of pregnancy during the study period 
8. ≥1 prescription claim of an anticoagulant other than index apixaban or LMWH 
treatment between the index VTE encounter and index date. Other anticoagulants 
include heparin, fodaparinux, warfarin, dabigatran, rivaroxaban, and edoxaban 
9. Data quality issues (with Medicare Cost coverage or State Children’s Health Insurance 
Program (SCHIP), invalid year of birth or health plan enrollment dates) (‘missing’ will 
be reported for gender and region) 
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A preliminary attrition table will be provided to Pfizer/Bristol Myers Squibb (BMS) for review, 
at which time modifications to the inclusion and exclusion criteria may be implemented. 
9.2. Cohorts 
From the overall cohort of VTE patients with cancer, two cohorts of interest will be created 
based on the type of anticoagulation treatment received within 30 days following the index 
VTE encounter date.  
x Cohort #1 – Apixaban: Evidence of apixaban use (and no other anticoagulant [LMWH, 
other OAC, heparin or fodaparinux] between the index VTE encounter date and index 
date). 
x Cohort #2 – LMWH: Evidence of LMWH use (and no apixaban or other anticoagulant 
between the VTE index date and LMWH initiation date).  
LMWH should be used for at least 14 days to ensure that LMWH was not intended for 
short-term bridge therapy.  
Analyses will be stratified by these two cohorts, as defined in section 8.3.1-8.3.3. 
9.3. Variables 
Unadjusted subject demographic and clinical characteristics and select HCRU and cost 
characteristics will be described for subjects in the apixaban and LMWH cohorts. Stabilized 
inverse probability of treatment weighting (IPTW) will be used to adjust for imbalances in 
measured confounders between the two therapy cohorts. Subject characteristics will then be 
reported for the therapy cohorts post-IPTW. Post-index economic outcomes of interest (i.e., 
HCRU  and costs) will be evaluated following both IPTW and GLM adjustment.   
9.3.1. Baseline Measures  
Baseline demographic/clinical characteristics will be descriptively reported for the Apixaban 
and LMWH cohorts, both pre- and post-IPTW. Demographic characteristics will be measured 
as of the patient’s index date while clinical characteristics will be measured over the 1-year 
pre-index baseline period. 
Demographic Characteristics 
x Age (mean, standard deviation [SD], median, interquartile range [IQR]) 
x Age group (18-24, 25-34, 35-44, 45-54, 55-64, 65-74, ≥75 years; n, %) 
x Gender (male, female, unknown/missing; n, %) 
x Geographic region (Northeast, Midwest, South, West, unknown/missing; n, %) 
x Payer type (commercial, Medicaid, Medicare Risk, self-insured, other/unknown; n, %) 
x Health plan type (consumer directed health care, health maintenance organization 
[HMO], indemnity, point-of-service [POS], preferred provider organization [PPO], 
other/unknown; n, %)  
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x Index date year (2017, 2018, 2019, 2020, 2021; n, %)  
x Follow up duration in months (mean, SD, median, IQR) 
o Patients censored due to switching (n, %) 
o Patients censored due to discontinuation (n, %) 
Clinical Characteristics  
x Prescriber physician specialty (associated with the visit on or closest to the index date, 
as available) (n, %) 
o Primary care physician (PCP - general practice/family practice/internal 
medicine) 
o Cardiologist 
o Oncologist 
o Others 
o Unknown/missing 
x Index VTE event setting (n, %) 
o Inpatient 
o Total inpatient cost of index VTE hospitalization (mean, SD, median) 
o Length of stay (LOS) of index hospitalization (mean, SD, median) 
o Outpatient 
o Note: Qualifying outpatient encounters followed by qualifying inpatient 
encounters within 7 days will be considered an inpatient VTE event, unless 
LMWH or apixaban was initiated between encounters, in which case it will be 
classified as an outpatient VTE event   
x Index VTE type (n, %) 
o DVT 
o PE 
o DVT and PE 
x Charlson Comorbidity Index (CCI, Dartmouth-Manitoba adaptation excluding cancer; 
continuous and categorical [0-1, 2, 3, 4+]) (n, %) 
x NCI comorbidity index (continuous and categorical [0-1, 2, 3, 4+] (n, %)) 
x Comorbidities of interest (ICD-10 diagnosis codes; n, %) 
o Acquired immune deficiency syndrome (AIDS) 
o Alcohol/drug abuse  
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o Anemia  
o Central Venous Catheter 
o Cerebrovascular disease 
o Coronary heart disease/ischemic heart disease  
o Congestive heart failure  
o Chronic obstructive pulmonary disease (COPD)  
o COVID-19 
o Dementia/Alzheimer's disease  
o Dyspepsia or stomach discomfort 
o Diabetes Mellitis  
o Hemiplegia/Paraplegia 
o Hematologic disorders associated with bleeding (thrombocytopenia)  
o Hyperlipidemia 
o Hypertension  
o Inflammatory bowel disease 
o Liver/Gall bladder/Pancreatic disease 
o Obesity 
o Peptic ulcer  
o Peripheral vascular disease  
o Pneumonia 
o Renal disease  
o Rheumatologic disease 
o Sleep apnea 
o Spinal cord injury 
o Thrombocytopenia 
o Thrombophilia 
o Varicose veins 
x Baseline bleeds (ICD-10 diagnosis or procedure codes, CPT codes, HCPCS codes) (n, 
%) 
o Gastrointestinal 
o Intracranial 
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o Others 
x History of falls (ICD-10 diagnosis codes) (n, %) 
x Fracture/trauma involving lower extremities (ICD-10 diagnosis codes) (n, %) 
x Orthopedic/pelvic surgeries (n, %) 
x Time (in days) from index VTE encounter date to index date (mean, SD, median, IQR) 
x Medications of interest ( n, %) 
o Angiotensin-converting enzyme (ACE) inhibitors/Angiotensin receptor 
blockers (ARB) 
o Antiarrhythmic agents 
o Antiplatelet agents  
o Aromatase inhibitors 
o Beta blockers 
o Erythropoiesis stimulating agents (ESA) 
o Gastroprotective agents 
o Nonsteroidal anti-inflammatory drugs (NSAID) 
o Selective estrogen receptor modulators (SERM) 
o Statins 
x Cancer-related variables (measured 6 months prior to the index VTE encounter date 
until 30 days after the index VTE encounter date) 
o Cancer site (n, %) 
o Bladder 
o Blood (leukemia, lymphoma, multiple myeloma) 
o Brain 
o Breast 
o Gastrointestinal (GI) 
 Upper GI 
 Lower GI 
o Gynecologic 
o Lung 
o Prostate 
o Testicular 
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o Cancer type (n, %) 
 Hematologic cancers  
o Leukemia 
o Lymphoma 
o Multiple myeloma 
 Non-hematologic cancers 
o Cancer related treatments (n, %) 
 Chemotherapy 
 Hormone therapy 
 Immunotherapy 
 Radiation 
 Cancer related surgery 
o Modified VTE Khorana Risk Scale10 (n, %) 
 Very high risk (brain, stomach, and pancreas)  
 High risk (lung, lymphoma, gynecologic, bladder, testicular and renal 
cell carcinoma)  
 Other cancers  
Baseline HCRU and costs 
x Patients with a pre-index hospitalization (n, %) 
x Patients with a pre-index emergency room (ER) visit (n, %) 
x Patients with a pre-index outpatient physician office visit (n, %) 
o Number of pre-index outpatient physician office visits (mean, SD, median, 
IQR) 
x Total all-cause healthcare costs (mean, SD median, IQR) 
o Inpatient 
o Outpatient medical 
o ER 
o Pharmacy 
 
9.3.2. All-cause HCRU and Costs Over the Post-Index Period (Post-IPTW) 
All-cause HCRU and costs will be reported for the Apixaban and LMWH cohorts over the 
variable post-index period (minimum 1 month enrollment), post-IPTW. Costs will be reported 
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as per patient per month (PPPM). Over the post-index period, a 30 day period will be used (to 
represent a month) to ‘standardize’ the period of time for which costs and HCRU will be 
reported. For each patient, costs will be divided by the variable post-index period in total-
person days and then multiplied by 30 to calculate PPPM costs. For example, if a patient has 
total costs of $10,000 with 60 days of follow-up, the PPPM will be calculated as ($10,000/60) 
* 30 = $5,000.  
HCRU will be expressed as both the proportion of patients with such utilization (e.g., the 
percentage of patients with at least one pharmacy claim, the percentage of patients with at least 
one physician office visits, etc.) as well as per-patient mean, SD, median and IQR number of 
visits/services. Costs will be expressed as per-patient mean, SD, median and IQR. Utilization 
and costs will be calculated on a per patient basis, averaged across the cohort. The denominator 
will include all patients in the cohort. Costs will be converted to 2021 US dollars (USD) using 
the medical component of the Consumer Price Index.  
HCRU and costs will be reported for mutually exclusive categories: outpatient pharmacy, 
inpatient hospitalizations, and outpatient care. Outpatient care will comprise the following 
categories: ER visits, outpatient physician office visits, outpatient surgical visits, laboratory 
and pathology, radiology and all other services. 
All-cause HCRU and costs will be reported for each of the following services: 
x Pharmacy  
o Patients with ≥1 prescription fill (n, %) 
o Number of prescription fills per patient (mean, SD, median, IQR) 
o Total pharmacy cost per patient (mean, SD, median, IQR) 
x Outpatient Services 
o Total outpatient medical care cost per patient (mean, SD, median, IQR) 
o Physician office visits 
 Patients with ≥1 physician office visit (n, %) 
 Number of physician office visits per patient (mean, SD, median, IQR) 
 Total physician office cost per patient (mean, SD, median, IQR) 
o ER only visits (ER visit without admission to hospital) 
 Patients with ≥1 ER visit (n, %) 
 Number of ER visits per patient (mean, SD, median, IQR) 
 Total ER cost per patient (mean, SD, median, IQR) 
o Laboratory/pathology tests  
 Patients with ≥1 laboratory test (n, %) 
 Number of laboratory tests per patient (mean, SD, median, IQR) 
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 Total laboratory cost per patient (mean, SD, median, IQR) 
o Radiology  
 Patients with ≥1 outpatient radiology exam (n, %) 
 Number of outpatient radiology exams per patient (mean, SD, median, 
IQR) 
 Total radiology cost per patient (mean, SD, median, IQR) 
o Surgical services  
 Patients with ≥1 outpatient surgical visit (n, %) 
 Number of outpatient surgical visits per patient (mean, SD, median, 
IQR) 
 Total outpatient surgical visit cost per patient (mean, SD, median, IQR) 
o Ancillary/other services  
 Patients with ≥1 outpatient ancillary/other service (n, %) 
 Number of outpatient ancillary/other services per patient (mean, SD, 
median, IQR) 
 Total outpatient ancillary/other cost per patient (mean, SD, median, 
IQR) 
x Total HCPCS drug cost per patient (mean, SD, median, IQR) 
x Inpatient hospitalizations  
o Patients with ≥1 hospitalization (n, %)  
 Average length of stay per patient for all hospitalizations (mean,  
 SD, median, IQR) 
 Number of hospitalizations per patient (mean, SD, median, IQR) 
 Total hospitalization days per patient (mean, SD, median, IQR) 
 Top 10 primary discharge diagnosis associated with the first  
hospitalization, overall (ICD 10-CM 3-digit level; n, %) 
 Total inpatient cost per patient (mean, SD, median, IQR) 
o Number of hospitalizations per patient (mean, SD, median, IQR) 
o Total inpatient cost per patient (mean, SD, median, IQR) 
x Total all-cause cost per patient (total pharmacy + total outpatient + total inpatient; 
mean, SD, median, IQR) 
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9.3.3. Recurrent VTE, major bleeding, and CRNM bleeding related HCRU and costs in 
the post-index period 
Recurrent VTE will be identified based on inpatient claims with VTE as the primary discharge 
diagnosis (ICD-10 diagnosis codes). If the admissions for recurrent VTE occur within 7 days 
of the index VTE event, irrespective of care setting, the events will not be considered as 
recurrent VTE events due to the proximity to the index VTE event and the index date.  
Major bleeding will be defined by primary discharge diagnosis in the inpatient setting, 
including GI bleeding, intracranial hemorrhage (ICH), and other major bleeding.  
CRNM bleeding will be defined as an inpatient encounter with a secondary diagnosis code for 
bleeding (without a major bleeding code in the primary position) or an outpatient encounter 
with a diagnosis code in any position for CRNM GI bleeding or other non-critical types of 
bleeding.Error! Bookmark not defined.,Error! Bookmark not defined. Specifically, it is 
defined as: 
(1)  An inpatient admission with a secondary diagnosis for “noncritical site” bleeding such as 
GI bleeding or other selected noncritical types/sites of bleeding (excluded if major bleeding 
occurred during the same hospitalization), OR 
(2) An outpatient encounter with a diagnosis code for GI bleeding and other selected 
noncritical types/sites of bleeding. 
Any CRNM bleeding events (as described above) that follow a major bleeding event (described 
above) will not be included in the analysis of CRNM bleeding.  
For the two therapy cohorts, the following outcomes related to recurrent VTE, major bleeding 
and CRNM will be reported post-IPTW. 
x Recurrent VTE across the cohort  
o Patients with ≥1 such event (n, %) 
 Number of hospitalizations for VTE events (denoted by inpatient 
hospitalizations that meet the definition above)  (mean, median, SD, IQR)  
 Time (in days) from index date to first recurrent VTE event (mean, median, 
SD, IQR) 
x Major bleeding across the cohort  
o Patients with ≥1 such event (n, %) 
 Number of hospitalizations for major bleeding events (denoted by inpatient 
hospitalizations that meet the definition above) (mean, median, SD, IQR)  
 Time (in days) from index date to first major bleeding event (mean, median, 
SD, IQR) 
x CRNM bleeding across the cohort  
o Patients with ≥1 such event (n, %) 
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 Number of CRNM bleeding events (denoted by inpatient or outpatient 
events that meet the definition above) (mean, median, SD, IQR)  
 Time (in days) from index date to first CRNM bleeding event (mean, 
median, SD, IQR) 
The Cost, and HCRU, for each event will be defined as the cost associated with the 
hospitalization for the respective event (i.e., recurrent VTE, MB, or CRNM bleeding) as well 
as all subsequent event-related medical costs (pharmacy costs will not be included). These can 
be determined via an appropriate diagnosis code that relates to the event of interest. Major 
bleeding-related medical costs will be defined as  costs associated with the first major bleeding 
hospitalization plus all subsequent bleeding costs occurring in the inpatient (primary or 
secondary diagnosis) or outpatient setting (any position). Recurrent VTE-related medical costs 
will be defined as the costs associated with the first recurrent VTE hospitalization plus all 
subsequent VTE costs in the inpatient (primary or secondary diagnosis) or outpatient (any 
position) setting. Similarly, CRNM bleeding-related medical costs will be defined as 
hospitalization costs or outpatient costs associated with the first CRNM bleeding as defined 
above and all the subsequent CRNM bleeding costs in the inpatient (primary or secondary 
diagnosis) or outpatient (any position) setting.  
The outpatient services and inpatient hospitalization HCRU and cost variables presented in 
section 8.3.2 will also be reported for recurrent VTE-related, major bleeding-related and 
CRNM bleedingrelated utilization and costs. 
9.4. Data sources  
This study will utilize data from IQVIA’s PharMetrics® Plus. IQVIA’s collaboration with 
Health Intelligence Company, which operates as Blue Health Intelligence, allows IQVIA’s 
bio-pharmaceutical clients sole access to one of the largest United States (US) health plan 
claims databases and adds IQVIA’s market leading health plan claims database. The 
aggregated database comprises adjudicated claims for more than 190 million unique enrollees 
across the US. Enrollees with both medical and pharmacy coverage in 2020 represented 40 
million lives. Data are available from 2010 onwards, with a typical 4- to 6-month lag due to 
claims adjudication.  
PharMetrics Plus has diverse representation of geography, employers, payers, providers and 
therapy areas. Patients in each zip code and every Metropolitan Statistical Area of the US are 
included, with coverage of data from 90% of US hospitals, 80% of all US doctors, and 
representation from 85% of the Fortune 100 companies. In addition to standard fields such as 
inpatient and outpatient diagnosis and procedures, retail and mail-order prescription records, 
PharMetrics Plus has detailed information on the pharmacy and medical benefit (copayment, 
deductible), the inpatient stay (admission type and source, discharge status) and provider 
details (specialty, provider identifier [ID]). All zip codes in the US are covered and reported 
allowing more granular patient segmentation and comparisons by geography. Payment 
amounts include the negotiated rate between the plan and providers (allowed) and the actual 
amount paid by health plans to the provider for all services rendered. Charge amount is also 
available for a subset of claims. Other data elements include dates of service, demographic 
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variables (age, gender, and geographic region), product type (e.g., HMO, PPO), payer type 
(e.g., commercial, self-insured), and start and stop dates of health-plan enrollment.  
Due to the broad reach of the data, records in PharMetrics Plus are representative of the 
national, commercially insured population in terms of age and gender for individuals aged 65 
and under. The data are also longitudinal, with more than 20 million patients who have both 
medical and pharmacy coverage with 3 or more years of continuous enrollment. Data 
contributions are subjected to a series of quality checks to ensure a standardized format and to 
minimize error rates. All data are Health Insurance Portability and Accountability Act 
(HIPAA)-compliant to protect patient privacy. 
PharMetrics Plus will be largely commercially- or self-insured and may not be representative 
of un-insured or Medicare or Medicaid populations. Further research will be warranted to 
understand the costs of patient archetypes among these other populations, particularly those 
aged 65+ and covered by traditional fee-for-service Medicare. Additionally, there is a lack of 
visibility into HCRU or prescriptions obtained outside of the plan benefit. 
9.5. Study size 
An earlier feasibility study estimated that there were 4,972 VTE patients with cancer with 
evidence of apixaban in PharMetrics® Plus. These counts were for informational purposes only 
and will not represent the actual number of patients to be utilized in the study. Application of 
other inclusion and exclusion criteria or other factors will reduce the sample size. 
Sample size calculation was conducted to identify minimum number of patients in each cohort 
required for the analysis using the recurrent VTE event rates from Cohen et al.Error! Bookmark not 
defined. and Agneli et al.Error! Bookmark not defined. to achieve a power of 80% at a 5% 
level of significance (two-sided). Using recurrent VTE rates 4.362% (148 recurrent VTE cases 
in 3,393 patients) in apixaban cohort and 6.483% (396 recurrent VTE cases in 6,108 patients) 
in LMWH cohort from Cohen et al., we require a minimum sample of 1,788 patients in each 
cohort to achieve 80% power. A minimum sample of 1,867 patients in each cohort is required 
to achieve 80% power at a 5% level of significane (two-sided) using recurrent VTE event rates 
from Agneli at al. of 5.6% in apixaban cohort and 7.9% in dalteparin cohort. Based on the 
sample size calculations, for the current study we need a minimum sample in the range of 
1,788-1,867 patients in each cohort. 
9.6. Data management  
See sections 8.4 and 8.7. 
9.6.1. Case report forms (CRFs)/Data collection tools (DCTs)/Electronic data record 
Not applicable. 
9.6.2. Record retention 
To enable evaluations and/or inspections/audits from regulatory authorities or Pfizer, IQVIA 
agrees to keep all study-related records, including study documentation, archived analytic 
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datasets, and adequate documentation of relevant correspondence.  The records should be 
retained by IQVIA according to local regulations or as specified in the study protocol, 
whichever is longer.  IQVIA must ensure that the records continue to be stored securely for so 
long as they are retained. 
If IQVIA becomes unable for any reason to continue to retain study records for the required 
period, Pfizer should be prospectively notified. The study records must be transferred to a 
designee acceptable to Pfizer. 
Study records must be kept for a minimum of 15 years after completion or discontinuation of 
the study, unless IQVIA and Pfizer have expressly agreed to a different period of retention via 
a separate written agreement.  Record must be retained for longer than 15 years or as required 
by applicable local regulations.   
IQVIA must obtain Pfizer's written permission before disposing of any records, even if 
retention requirements have been met. 
9.7. Data analysis  
Descriptive statistics will be produced for all relevant study measures previously described, 
for the 2 therapy cohorts of interest. Categorical measures will be presented using frequency 
(number of patients [n]) and percentage (%) of total study patients observed in each category. 
Continuous and count variables will be presented as the mean, SD, median and IQR. As 
relevant, continuous variables will also be categorized into intervals.  
Stabilized IPTW will be used to balance patient characteristics between apixaban and LMWH 
cohorts.11,12 Weights will be constructed by estimating each subject’s probability of receiving 
treatment based on covariates. For comparisons of baseline characteristics between the 
apixaban and LMWH cohorts, both pre- and post-IPTW, standardized mean difference (SMD) 
will be calculated to evaluate the difference in baseline covariates between cohorts. SMD is 
calculated as the difference in means or proportions of a variable divided by the pooled 
standard deviation. SMD of ≥0.10 between groups is considered meaningful.13 For 
comparisons of events and HCRU/cost over the variable post-index period post-IPTW,  
comparisons will be conducted using weighted chi-square tests for categorical variables and 
weighted t-tests (mean) for continuous variables (note there is no corresponding weighted test 
for the median). Comparisons between independent samples (e.g., among patients with ≥1 
hospitalization) and pre-IPTW samples will be conducted using the parametric t-test (mean) 
and non-parametric Wilcoxon rank-sum test (median) for continuous variables; data will be 
reported for the unweighted sample. A p-value <0.05 will be considered statistically 
significant. However, to account for multiple comparisons, a Bonferroni correction may be 
implemented such that the critical p-value (p<.05) may be divided by the number of 
comparisons (i.e., 3 comparisons, in order to yield a new critical p-value, .05/3 = 0.0167). 
Analyses will be conducted using SAS® (statistical analysis software) Release 9.4 (SAS 
Institute Inc., Cary, NC). 
IQVIA will develop up to 4 multivariable analysis models, to be mutually agreed upon Pfizer/ 
BMS and IQVIA. For example these may include weighted generalized linear models (GLM) 
with log transformation and gamma distribution to estimate adjusted (all-cause) cost ratio 
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between the two cohorts. A negative binomial distribution may be developed to estimate 
adjusted visits such as physician office visits, emergency room visits or other HCRU.Two-part 
regression analyses will be used to evaluate the impact of the LMWH treatments relative to 
apixaban on recurrent VTE-related, major bleeding-related, CRNM-related medical HCRU or 
costs. The 2-part regression analyses14 will be used to avoid the analytical issues associated 
with the large number of data with  0 values for HCRU andcosts for VTE-related, major 
bleeding-related, CRNM related HCRU and costs. In the two-part model, first the probability 
of observing a positive versus zero outcome will be determined using a binary choice model. 
In the second part of the model, conditional on a positive outcome, an appropriate regression 
model such as a GLM model for costs or a negative binomial model for HCRU will be fit for 
the positive outcome. Covariates to be considered for inclusion into the models will include 
demographic and clinical characteristics of interest guided by the univariate findings. These 
candidate variables will be considered and retained in the model if significant (SMD ≥0.10) 
using a stepwise approach. Collinearity among the variables of interest will be evaluated during 
model development. 
Any major modifications of primary endpoint definitions or their analyses would be reflected 
in a protocol amendment. 
9.8. Quality control 
Not applicable.  
9.9. Limitations of the research methods 
While claims data are valuable for the efficient and effective examination of healthcare 
outcomes, treatment patterns, HCRU, and costs, all claims databases have certain inherent 
limitations affecting generalizability because the claims are collected for the purpose of 
payment within the commercially-insured population and not research. Results and 
conclusions are limited to the patient population, which consisted of patients enrolled in 
managed care plans, and may not be generalizable to other or non-commercially-insured 
populations in the US. These limitations do not significantly reduce the strength of this study 
and its results, but they must be considered during interpretation.  
Presence of a diagnosis code on a medical encounter or outside claim may have not been 
conclusive of positive presence of disease, as the diagnosis code may have been incorrectly 
coded or included as rule-out criteria rather than actual disease. This risk may be minimal in 
this study. Presence of a claim for a dispensed medication does not indicate that the medication 
was consumed or that it was taken as prescribed. Medications provided as samples by the 
physician are not observable in the pharmacy data. 
Only patients with a continuous eligibility were included, and thus patients who did not 
maintain membership for at least 13 months (i.e., 12 months prior to and 1-month following 
the index date) were not included in the sample.   
9.10. Other aspects 
Not applicable. 
 
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10. PROTECTION OF HUMAN SUBJECTS 
10.1. Patient information  
This study involves structured data that exist as structured data by the time of study start. 
In these data sources, individual patient data are not retrieved or validated, and it is not 
possible to link (i.e., identify a potential association between) a particular product and medical 
event for any individual.  Thus, the minimum criteria for reporting an adverse event (AE) (i.e., 
identifiable patient, identifiable reporter, a suspect product, and event) cannot be met. 
10.2. Patient consent 
As this study involves anonymized structured data, which according to applicable legal 
requirements do not contain data subject to privacy laws, obtaining informed consent from 
patients by Pfizer is not required. 
10.3. Institutional review board (IRB)/Independent ethics committee (IEC) 
Not applicable. 
11. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS  
Not applicable.  
12. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS 
Tables of study results will be shared with Pfizer throughout the analytic phase of the study.  
The draft and final study report will be provided to Pfizer upon completion of the analytic 
phase. 
In the event of any prohibition or restriction imposed (e.g., clinical hold) by an applicable 
competent authority in any area of the world, or if IQVIA is aware of any new information 
which might influence the evaluation of the benefits and risks of a Pfizer product, Pfizer should 
be informed immediately.   
 
 
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13. REFERENCES 
1. Timp JF, Braekkan SK, Versteeg HH, Cannegieter SC. Epidemiology of cancer-
associated venous thrombosis. Blood. 2013;122(10):1712-1723. doi:10.1182/blood-
2013-04-460121 
2. Cohen AT, Katholing A, Rietbrock S, Bamber L, Martinez C. Epidemiology of first 
and recurrent venous thromboembolism in patients with active cancer. A population-
based cohort study. Thromb Haemost. 2017;117(1):57-65. doi:10.1160/TH15-08-0686 
3. Di Nisio M, Carrier M. Incidental venous thromboembolism: is anticoagulation 
indicated? Hematology Am Soc Hematol Educ Program. 2017;2017(1):121-127. 
doi:10.1182/asheducation-2017.1.121 
4. Lyman GH, Carrier M, Ay C, et al. American Society of Hematology 2021 guidelines 
for management of venous thromboembolism: prevention and treatment in patients 
with cancer. Blood Adv. 2021;5(4):927-974. doi:10.1182/bloodadvances.2020003442 
5. Prandoni P, Lensing AWA, Piccioli A, et al. Recurrent venous thromboembolism and 
bleeding complications during anticoagulant treatment in patients with cancer and 
venous thrombosis. Blood. 2002;100(10):3484-3488. doi:10.1182/blood-2002-01-
0108 
6. Khorana AA, McCrae KR, Milentijevic D, et al. Healthcare resource utilization and 
costs associated with venous thromboembolism recurrence in patients with cancer. J 
Med Econ. 2020;23(4):323-329. doi:10.1080/13696998.2019.1703190 
7. Agnelli G, Becattini C, Meyer G, Muñoz A, Huisman MV, Connors JM, Cohen A, 
Bauersachs R, Brenner B, Torbicki A, Sueiro MR, Lambert C, Gussoni G, Campanini 
M, Fontanella A, Vescovo G, Verso M; Caravaggio Investigators. Apixaban for the 
Treatment of Venous Thromboembolism Associated with Cancer. N Engl J Med. 2020 
Apr 23;382(17):1599-1607. doi: 10.1056/NEJMoa1915103. Epub 2020 Mar 29. 
PMID: 32223112. 
8. Cohen A, Keshishian A, Lee T, et al. Effectiveness and Safety of Apixaban, Low-
Molecular-Weight Heparin, and Warfarin among Venous Thromboembolism Patients 
with Active Cancer: A U.S. Claims Data Analysis. Thromb Haemost. 2021;121(3):383-
395. doi:10.1055/s-0040-1718728 
9. Hlavacek P, Guo JD, Rosenblatt L, et al. Safety, effectiveness, and health care cost 
comparisons among elderly patients with venous thromboembolism prescribed 
warfarin or apixaban in the United States Medicare population. Curr Med Res Opin. 
2019;35(12):2043-2051. doi:10.1080/03007995.2019.1653067 
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10. Khorana AA, McCrae KR. Risk stratification strategies for cancer-associated 
thrombosis: an update. Thrombosis Research. 2014;133:S35-S38. doi:10.1016/S0049-
3848(14)50006-0 
11. Austin PC, Stuart EA. Moving towards best practice when using inverse probability of 
treatment weighting (IPTW) using the propensity score to estimate causal treatment 
effects 
in 
observational 
studies. 
Stat 
Med. 
2015;34(28):3661-3679. 
doi:10.1002/sim.6607 
12. Xu S, Ross C, Raebel MA, Shetterly S, Blanchette C, Smith D. Use of stabilized inverse 
propensity scores as weights to directly estimate relative risk and its confidence 
intervals. 
Value 
Health. 
2010 
Mar-Apr;13(2):273-7. 
doi: 
10.1111/j.1524-
4733.2009.00671.x. Epub 2009 Nov 12. 
13. Austin PC. Balance diagnostics for comparing the distribution of baseline covariates 
between treatment groups in propensity-score matched samples. Stat Med. 
2009;28(25):3083-3107. doi:10.1002/sim.3697 
14. Belotti F, Deb P, Manning WG, Norton EC. Twopm: Two-Part Models. The Stata 
Journal. 2015;15(1):3-20. doi:10.1177/1536867X1501500102 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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14. LIST OF TABLES 
See table shells 
15. LIST OF FIGURES 
Figure 1. Study Period 
ANNEX 1. LIST OF STAND-ALONE DOCUMENTS 
Table shells will be provided in a separate file. 
Codes used in this study are provided in separate files.  Categories include: 
 
VTE and cancer diagnosis 
Diagnosis codes of interest 
Comorbidities of interest 
Medications of interest 
Procedures of interest 
Major bleeding and CRNM bleeding diagnosis 
 
Number 
Document reference 
number 
Date 
Title 
1 
 
16 June 2022 
IQVIA Pfizer Apixaban LMWH_Final Table 
Shells_20220616 
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2 
 
16 June 2022 
VTE Cancer study Codes 
 
ANNEX 2. Additional Information 
Not applicable 
 
 
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