Post-Discharge Treatment Patterns and Outcomes in Patients With Venous Thromboembolism
Conditions: Venous Thromboembolism
Sponsor: Pfizer

Apixaban  
B0661190 NON-INTERVENTIONAL STUDY PROTOCOL 
Protocol Version:1.0, 14 February 2023 
 
 
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NON-INTERVENTIONAL STUDY PROTOCOL 
Study information 
Title 
Post-Discharge Treatment Patterns and Outcomes 
in Patients with Venous Thromboembolism 
 
Protocol number 
B0661190 
Protocol version identifier 
Version 1.0 
Date 
14 Feb 2023 
Active substance 
B01AF02; Apixaban 
Medicinal product 
Eliquis  
Research question and objectives 
The purpose of this study is to evaluate the post-
discharge 
treatment 
patterns 
including 
persistence, recurrent  venous thromboembolism 
(VTE) and bleeding among hospitalized adult 
VTE patients treated with apixaban or warfarin. 
The study objectives are as to: 
1. Describe the proportion of patients with 
VTE treated with apixaban or warfarin in 
the hospital 
2. Understand the post-discharge treatment 
patterns (including persistence, switch, 
and discontinuation) among patients who 
started on apixaban or warfarin in the 
hospital 
The secondary objective is to: 
3. Assess recurrent VTE, major bleeding, 
and 
clinically 
relevant 
non-major 
(CRNM) bleeding among patients who 
continue on apixaban or warfarin in the 
outpatient setting, while persistent on 
index therapy 
 
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Authors 
, MPH, PhD  
 
Pfizer, Inc. 
     
 
 
, MS  
 
 
IQVIA, Inc. 
  
 
, MHSA 
 
 
IQVIA, Inc. 
 
 
 
, PhD, MBBS 
 
 
IQVIA, Inc. 
  
 
This document contains confidential information belonging to Pfizer.  Except as otherwise agreed to in writing, 
by accepting or reviewing this document, you agree to hold this information in confidence and not copy or 
disclose it to others (except where required by applicable law) or use it for unauthorized purposes.  In the event 
of any actual or suspected breach of this obligation, Pfizer must be promptly notified. 
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1. TABLE OF CONTENTS 
1. TABLE OF CONTENTS .......................................................................................................3 
2. LIST OF ABBREVIATIONS ................................................................................................5 
3. RESPONSIBLE PARTIES ....................................................................................................7 
4. ABSTRACT ...........................................................................................................................8 
5. AMENDMENTS AND UPDATES .....................................................................................11 
6. MILESTONES .....................................................................................................................12 
7. RATIONALE AND BACKGROUND ................................................................................13 
8. RESEARCH QUESTION AND OBJECTIVES .................................................................14 
9. RESEARCH METHODS ....................................................................................................15 
9.1. Study period and study design ................................................................................15 
9.1.1. Inclusion criteria .........................................................................................16 
9.1.2. Exclusion criteria ........................................................................................16 
9.2. Variables ..................................................................................................................17 
9.2.1. Baseline Measures ......................................................................................19 
9.2.2. Outcome measures ......................................................................................22 
9.3. Data sources ............................................................................................................24 
9.4. Study size ................................................................................................................26 
9.5. Data management ....................................................................................................26 
9.5.1. Case report forms (CRFs)/Data collection tools (DCTs)/Electronic 
data record ........................................................................................................26 
9.5.2. Record retention ..........................................................................................26 
9.6. Data analysis ...........................................................................................................27 
9.7. Quality control .........................................................................................................27 
9.8. Limitations of the research methods .......................................................................28 
9.9. Other aspects ...........................................................................................................28 
10. PROTECTION OF HUMAN SUBJECTS ........................................................................29 
10.1. Patient information ................................................................................................29 
10.2. Patient consent .......................................................................................................29 
10.3. Institutional review board (IRB)/Independent ethics committee (IEC) ................29 
11. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS ......................................................................................................................29 
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12. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS........29 
13. REFERENCES ..................................................................................................................30 
14. LIST OF TABLES .............................................................................................................31 
15. LIST OF FIGURES ...........................................................................................................31 
 
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2. LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
ACE 
Angiotensin-converting enzyme 
AIDS 
Acquired Immune Deficiency Syndrome 
ARB 
Angiotensin Receptor Blockers 
CCI 
Charlson Comorbidity Index   
CDM 
Hospital Charge Data Master 
COPD 
Chronic Obstructive Pulmonary Disease 
COVID-19 
Coronavirus Disease 2019 
CPT-4 
Current Procedural Terminology version 4 
CRF 
Case Report Form 
CRNM 
Clinically-relevant non-major 
DOAC 
Direct Oral Anticoagulant 
DCT 
Data Collection Tools 
DVT 
Deep Vein Thrombosis 
Dx 
Professional Fee/ Medical Claims 
ER 
Emergency Room 
HCPCS 
Healthcare Common Procedure Coding System 
HIPAA 
Health Insurance Portability and Accountability Act 
ICD-9-CM 
International Classification of Diseases, ninth revision, 
clinical modification 
ICD-10-CM 
International Classification of Diseases, tenth revision, 
clinical modification 
ID 
Identifier 
IEC 
Independent Ethics Committee 
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IQR 
Interquartile Range 
IRB 
Institutional Review Board 
LMWH 
Low molecular weight heparin 
LRx 
Longitudinal prescription claims database 
NSAID 
Nonsteroidal anti-inflammatory drugs 
OAC 
 
Oral Anticoagulant 
PAC 
Parenteral Anticoagulant 
PCP 
Primary Care Provider 
PE 
Pulmonary Embolism 
SAS 
Statistical Analysis System 
SD 
Standard Deviation 
SERM 
Selective Estrogen Receptor Modulators 
US 
United States 
VTE 
Venous Thromboembolism 
 
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3. RESPONSIBLE PARTIES 
Principal Investigators of the Protocol 
Name, degree(s) 
Job Title 
Affiliation 
Address 
Mitch DeKoven, 
MHSA 
Senior Principal, HEOR 
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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4. ABSTRACT 
Title 
Post-Discharge Treatment Patterns and Outcomes in Patients with Venous Thromboembolism 
Version: 1.0 
Date: 14 Feb 2023 
Primary author:  
  
 
Pfizer, Inc.  
 
Rationale and background 
Venous thromboembolism (VTE), comprising deep vein thrombosis (DVT) and pulmonary 
embolism (PE), is a major health concern associated with significant mortality and morbidity. 
There are >330,000 hospital admissions for VTE every year in the United States (US).3 
Historical data suggests that the rate of hospitalization for VTE increased from 7.0 to 8.4 per 
1,000 discharges in the US.4  
 
Management of VTE during an acute hospital encounter involves rapid anticoagulation. 
Current guidelines recommend continuing anticoagulation therapy post-discharge with 
warfarin, a vitamin K antagonist, or one of the newer direct oral anticoagulants (DOACs) 
which do not require Parental Anticoagulant (PAC) bridging therapy.5 Over the past decade, 
the use of DOACs, particularly apixaban, to treat VTE has increased dramatically.6  
 
There are some gaps in real world evidence (RWE) regarding oral anticoagulant (OAC) use 
among patients hospitalized with VTE. First, there is a need for RWE regarding the proportion 
of patients treated with particular OACs during the VTE hospitalization. Second, there needs 
to be a better understanding of the OAC-related treatment patterns post-discharge following 
the VTE hospitalizations.  There is evidence that a large proportion of patients treated in both 
inpatient and observational hospital settings do not fill an anticoagulant prescription post-
discharge.7 Research shows that the choice of treatment regimen and/or setting could influence 
the likelihood of post-discharge continuation of OAC medication.7 This study will investigate 
the initial treatment patterns during VTE hospitalization and further investigate the treatment 
patterns post-discharge and factors associated with poor outcomes among these patients. 
 
Research question and objectives 
The purpose of this study is to evaluate the post-discharge treatment patterns including 
persistence and outcomes such as recurrent VTE and bleeding among hospitalized adults with 
VTE treated with apixaban or warfarin. 
 
The study objectives are to: 
1. Describe the proportion of patients with VTE treated with apixaban or warfarin in the 
hospital 
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2. Understand the post-discharge treatment patterns (including persistence, switch, and 
discontinuation) among patients who started on apixaban or warfarin in the hospital 
The secondary objective is to: 
3. Assess recurrent VTE, major bleeding, and clinically relevant non-major (CRNM) 
bleeding among patients who continue on apixaban or warfarin in the outpatient setting 
while persistent on index therapy 
 
Study design 
A retrospective database analysis will be conducted among patients hospitalized with a primary 
diagnosis of VTE. This study will utilize linked data from IQVIA’s hospital charge master data 
(CDM), professional fee claims (Dx) and prescription claims (LRx) from 01 July 2017 through 
31 December 2022 or the latest available data at the time of extraction (i.e., the study period), 
including 6-month pre-hospitalization period (starting the day before the admit date of 
hospitalization and a minimum 1-month post-hospitalization (starting a day after discharge 
date of hospitalization) period. The first apixaban or warfarin treatment during the index 
hospitalization will be flagged. Following discharge, patients who continue apixaban or 
warfarin, respectively, in the outpatient setting (with outpatient treatment claim occurng on or 
within 30-days following the discharge date) will be identified. The date of the first apixaban 
or warfarin claim will serve as the treatment index date. The baseline period will be 6 months 
prior to the treatment index. 
 
Population 
The study cohorts will be identified during the selection window from 01 January 2018 to 30 
November 2022. Based on the treatment (apixaban or warfarin) received during the VTE 
hospitalization, patients will be classified into apixaban and warfarin cohorts. Patients will be 
required to have medical and pharmacy activity during the 6 month pre-hospitalization period 
and 1-month post-hospitalization period i.e. post-discharge. Following discharge, patients will 
be indexed to either apixaban or warfarin based on the first observed outpatient pharmacy 
claim for the respective therapy, and will have a 6-month baseline period prior to the treatment 
index date and a variable follow-up period after the treatment index date. Treatment patterns 
and clinical outcomes will be evaluated during the variable follow-up period. 
 
Variables  
Exposures and explanatory variables on the treatment index date and 6-months prior to the 
treatment index period (which includes the hospitalization)  
• Demographic characteristics  
• Clinical characteristics  
 
Characteristics of hospitalization 
• Hospital characteristics 
 
Outcomes  
• Apixaban and warfarin treatment rates during hospitalization  
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• Post-discharge continuity (i.e. persistence of hospitalization treatment/treatment 
discontinuation or switch) 
• Post-discharge treatment patterns among those who continue the same treatment 
provided during hospitalization (persistent days, discontinuation, switching) 
• Post treatment-index recurrent VTE and bleeding hospitalizations 
 
Data sources 
IQVIA’s CDM database linked with Dx and LRx will be utilized for this analysis. IQVIA’s 
CDM is comprised of hospital-based data which are sourced from hospital CDM files. CDM 
covers more than 450 hospitals per month and approximately 8 million inpatient visits and 105 
million outpatient visits per year. Dx database includes outpatient medical claims which will 
be necessary for describing baseline clinical characteristics. Dx database captures over one 
billion pre-adjudicated claims and three billion records obtained annually from approximately 
800,000 office-based physicians and specialists. LRx database captures information on 
dispensed prescriptions sourced from retail, mail, long-term care, and specialty pharmacies. 
IQVIA has industry-leading coverage in the following channels: 92% coverage of the retail 
channel, 72% coverage of standard mail service, and 76% of long-term care facilities. LRx will 
be necessary for describing baseline treatment history and reporting post-index treatment 
patterns. 
 
Study size 
All eligible patients will be included in the study.  
 
Data analysis 
Descriptive analysis will be conducted for all relevant study measures for the two cohorts of 
interest. No comparisons will be conducted in this analysis. Four multivariable regression 
models or Cox proportional hazards model will be conducted to evaluate factors associated 
with outcomes of interest. All analyses will be based on observed, not projected data. Analyses 
will be conducted using Statistical Analysis System® (SAS) Release 9.4 (SAS Institute Inc., 
Cary, NC), and the results will be reported in Excel tables. 
 
Milestones (tentative) 
Protocol approval:  
 
 
17 February, 2023 
Start of data analysis:   
 
27 February , 2023 
Final results:   
 
 
05 May, 2023 
Final study report:  
 
 
09 June, 2023 
 
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5. AMENDMENTS AND UPDATES 
None 
Amendment 
number 
Date 
Protocol section(s) 
changed 
Summary of 
amendment(s) 
Reason 
1 
 
 
 
 
2 
 
 
 
 
 
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6. MILESTONES 
 
Milestone 
Planned date 
Protocol approval 
17 February, 2023 
Start of analysis 
27 February, 2023 
Analysis completion 
05 May, 2023 
Final study report 
09 June, 2023 
 
 
 
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7. RATIONALE AND BACKGROUND 
Venous thromboembolism (VTE), comprising deep vein thrombosis (DVT) and pulmonary 
embolism (PE), is a major health concern associated with significant mortality and morbidity. 
It is the third most common cause of vascular disease-related death and poses a substantial 
economic burden to the healthcare system. In the United States (US), approximately 1 million 
people develop symptomatic VTE each year.1,2 There are >330,000 hospital admissions for 
VTE every year in the United States (US).3 Historical data suggests that the rate of 
hospitalizations for VTE increased from 7.0 to 8.4 per 1,000 discharges in the US.4  
 
Management of VTE during an acute hospital encounter involves rapid anticoagulation. 
Current guidelines recommend continuing anticoagulation therapy post-discharge with vitamin 
K antagonists such as warfarin, or one of the newer direct oral anticoagulants (DOAC) which 
do not require PAC bridging therapy.5 Over the past decade, the use of DOACs, particularly 
apixaban  to treat VTE has increased dramatically.6 
 
There are some gaps in RWE regarding OAC use among patients hospitalized with VTE. First, 
there is need for RWE regarding the proportion of patients treated with particular OAC during 
the VTE hospitalization. Second, there needs to be a better understanding of the OAC-related 
treatment patterns post-discharge following VTE hospitalizations.  There is evidence that a 
large proportion of patients treated in inpatient and observational hospital settings do not fill 
an anticoagulant prescription post-discharge7.  Research shows that the choice of treatment 
regimen and/or setting could influence the likelihood of post-discharge continuation of OAC 
medication.7 This study will investigate the initial treatment patterns during VTE 
hospitalization and further investigate the treatment patterns and factors associated with poor 
outcomes among these patients. 
 
The study team, comprised of members from Pfizer and Bristol Myers Squibb (hereon referred 
to as the ‘Alliance’), is collaborating with IQVIA in conducting a study to assess treatment 
patterns and health outcomes post hospital discharge for VTE. 
 
 
 
 
 
 
 
 
 
 
 
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8. RESEARCH QUESTION AND OBJECTIVES 
The purpose of this study is to evaluate the post-discharge treatment patterns including 
persistence and outcomes such as recurrent VTE and bleeding among hospitalized adults with 
VTE treated with apixaban or warfarin. 
The study objectives are to: 
1. Describe the proportion of patients with VTE treated with apixaban or warfarin in the 
hospital 
2. Understand the post-discharge treatment patterns (including persistence, switch, and 
discontinuation) among patients who started on apixaban or warfarin in the hospital 
The secondary objective is to: 
3. Assess recurrent VTE, major bleeding, and clinically relevant non-major (CRNM) 
bleeding among patients who continue on apixaban or warfarin in the outpatient setting 
while persistent on index therapy 
 
 
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9. RESEARCH METHODS       
A retrospective database analysis will be conducted among patients hospitalized with a primary 
diagnosis of VTE. This study will utilize linked data from IQVIA’s hospital charge  data master 
(CDM), professional fee claims (Dx) and longitudinal prescription claims (LRx) using data 
from 01 July 2017 through 31 December 2022 or the latest available data at the time of 
extraction (i.e., the study period), including a 6-month pre-hospitalization period (to confirm 
study eligibility) and minimum 1-month post-hospitalization period (to identify post-discharge 
treatment). Following discharge, patients will be indexed to the apixaban or warfarin cohort, 
based on the first observed outpatient pharmacy claim for the respective therapy. A 6-month 
pre-treatment index period (baseline) will be applied to capture demographic and clinical 
characteristics, and  a variable follow-up period will be used to capture post- treatment index 
patterns and clinical  outcomes. 
9.1. Study period and study design  
The analysis will be conducted using data from 01 July 2017 through 31 December 2022 or 
the latest available data at the time of extraction (i.e., the study period). Figure 1 illustrates the 
study schematic for this project. The study cohorts will be identified during a selection window 
from 01 January 2018 to 30 November 2022. The date of the first treatment with apixaban or 
warfarin during the hospitalization will be flagged. Based on this treatment during the VTE 
hospitalization, patients will be classified into the apixaban and warfarin cohorts. Patients will 
be required to have medical and pharmacy activity during the 6 months prior to the admit date 
of the hospitalization (pre hospitalization period) and 1-month (minimum) from the discharge 
date of the hospitalization (post hospitalization period).  The date of the first outpatient 
prescription for apixaban or warfarin on or within 30 days after discharge date from the 
hospitalization will be termed as ‘treatment index date’. 
  
Figure 1. Study Period 
  
*Latest available data at the time of extraction will be utilized for this study 
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9.1.1. Inclusion criteria 
Patients must meet all of the following inclusion criteria to be eligible for inclusion in the 
study: 
1. Patients with an inpatient hospitalization with admit date and discharge date between 
01 January 2018 and 30 November 2022 (selection window) in CDM with a primary 
diagnosis of VTE 
Note: The admit date of the first hospitalization with primary diagnosis of VTE during 
the selection window will be flagged. Only patients with overnight stays with discharge 
date after the admit date (to confirm inpatient stay with overnight admission) will be 
included in the study.  
Note: Number of patients who died during hospitalization (identified from discharge 
disposition measure) will be reported and these patients will be excluded from the 
study.  
2. With evidence of receiving apixaban or warfarin during the hospitalization  
Note: The date of the record with first apixaban or warfarin administration during the 
hospitalization will be flagged as the start of apixaban or warfarin treatment. Patients 
will be assigned to the apixaban or warfarin cohort based on this treatment received 
during hospitalization. 
3. With linkage to LRx between 01 July 2017 and 31 December 2022 (i.e. study period) 
4. With linkage to Dx during the study period 
5. With activity in the 6 months prior to the admit date of hospitalization, defined as ≥1 
claim in Dx and ≥1 prescription claim in LRx (pre hospitalization period) 
6. With activity in the 1-month after the discharge date of hospitalization, defined as ≥1 
claim in Dx and ≥1 prescription claim in LRx (variable post hospitalization period) 
Note: Patients will have a minimum 1-month post discharge period (to capture 
outpatient treatment)   
7. With age ≥18 years on apixaban or warfarin administration date during index 
hospitalization 
9.1.2. Exclusion criteria 
Patients meeting any of the following criteria will be excluded from the study: 
1. Patients with hospitalization with a primary diagnosis of VTE in the 6-month pre 
hospitalization period 
2. Patients with any OAC administration other than apixban for apixaban cohort (except 
warfarin use before apixaban) or warfarin for warfarin cohort during hospitalization  
Note: Apixaban cohort patients will be allowed to have warfarin prior to apixaban 
administration. At this step, we will also report the number of patients that have both 
apixaban and warfarin use during the hospitalization. 
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3. Patients with unfractioned heparin or low molecular weight heparin (LMWH) 
administration after apixaban (for apixaban cohort) or warfarin (for warfarin cohort) 
administration during hospitalization.  
Note: that unfractionated heparin or LMWH prior to apixaban or warfarin will be 
allowed.  
4. With ≥1 claim/record with a diagnosis code for atrial fibrillation/flutter in Dx or CDM 
during the hospitalization and in the 6-month pre hospitalization period 
5. With ≥1 claim with a procedure code for mechanical heart valve in Dx or CDM during 
the hospitalization and in the 6-month pre hospitalization period 
6. With ≥1 claim with a procedure code for inferior vena cava filter in Dx or CDM during 
the study period 
7. With ≥1 claim with a diagnosis code or procedure code of pregnancy in Dx or CDM 
during the study period 
8. With use of OAC or PAC (in LRx or Dx) (unless prophylactic) during the 6-month pre- 
hospitalization period 
Note: 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 a 
hospitalization associated with ‘medically ill’ (primary discharge diagnosis; codes 
provided separately) AND with a ≥ 3-day length of stay of the hospitalization. 
9. With data quality issues (invalid/missing enrollment dates, gender and payer type) 
 
A preliminary attrition table will be provided to the Alliance for review, at which time 
modifications to the inclusion and exclusion criteria may be considered. 
 
 
9.2. Variables 
From the final sample, the following measures will be reported (Figure 2): 
1. Patients with a claim for the respective treatment (apixaban for apixaban cohort or 
warfarin for warfarin cohort; using NDC from LRx) as their first post-discharge 
outpatient treatment (on or within 30 days following discharge i.e. discharge date or 
≤30 days after discharge date) (n, %). These patients will comprise the analytic cohort 
for outcomes assessment. 
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a. The date of the first post-discharge outpatient prescription claim in LRx 
(apixaban or warfarin) will be defined as the ‘treatment index date’ for patients 
in both cohorts respectively. 
b. Patients will be required to have pharmacy stability during the 6-month period 
preceding the treatment index date, defined as consistent reporting of data in 
each month from the pharmacy associated with the treatment index date in LRx 
to ensure continuous visibility within LRx. The number of patients excluded 
due to lack of stability will be reported (n, %)  
c. Patients with recurrent VTE, major bleeding, or CRNM bleeding between the 
discharge date and the treatment index date will be excluded. The number of 
patients excluded due to these reasons will be reported (n, %).  
d. Patients will be followed from the treatment index date until the earliest of last 
prescription, last patient medical claim, end of pharmacy stability, or end of 
study period using the Dx/Rx databases. 
2. Patients with OAC (warfarin, apixaban, rivaroxabn, dabigatran, or edoxaban) other 
than the respective inpatient treatment as their first outpatient prescription claim (on 
discharge date or within 30 days of discharge) (NDC codes from LRx; n, %). These 
patients will be captured as having switched from inpatient therapy and will not be 
further evaluated for outcomes.  
3. Patients with no post-discharge outpatient prescription claim for any OAC (on or within 
30 days of discharge) (NDC from LRx; n, %) 
 
All study outcomes will be evaluated for the apixaban and warfarin cohorts. 
 
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Figure 2. Study Flow 
 
 
9.2.1. Baseline Measures  
Baseline demographic, hospitalization and clinical characteristics will be assessed for the 
apixaban and warfarin cohorts, specifically among patients with their first outpatient index 
prescription (i.e. treatment index date) and with pharmacy stability. Demographic features will 
be measured on the patient’s treatment index date. Clinical characteristics will be assessed 
during the 6-months prior to the treatment-index date. Index hospitalization characteristics will 
also be assessed and reported for the apixaban and warfarin cohorts.  
Baseline demographic characteristics (using LRx data) 
• Age (years; mean, standard deviation [SD], median, interquartile range (IQR), min, 
max) 
• Age group (18-34, 35-44, 45-54, 55-64, ≥65 years; n, %) 
• Gender (male, female; n, %) 
• Payer type (Third party, Medicaid, Medicare, Medicare part D, cash, other; n, %) 
• Index date year (2018, 2019, 2020, 2021, 2022; n, %) 
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• Follow-up duration (mean, SD, median, IQR, min, max) 
Hospitalization characteristics (using CDM data) 
• Hospital geographic region (Northeast, Midwest, South, West) 
• Number of hospital beds (1-99 beds, 100-199 beds, 200-299 beds, 300-499 beds, 500+ 
beds) 
• Hospital location (Rural, Urban) 
• Teaching status (Teaching, Non-teaching) 
• Admitting source (ER, referral and transfer, routine admission, other, unspecified) 
• Discharge disposition (Alive – Home, Left Against Medical Advice or Discontinued 
Care [LAMA], Transferred – Long Term Care, Transferred – Other Institution, 
Transferred – Short-Term Hospital, Unknown/Other) 
• Index VTE type (DVT only, PE only, DVT and PE; n, %). 
• VTE etiology: (Provoked: VTE preceded by hormone therapy, fracture/trauma 
involving lower extremities, pelvic/orthopedic surgery, or hospitalization for any 
reason for ≥3 days during 3 months prior to index VTE event. Unprovoked: VTE events 
not classified as provoked) 
Baseline clinical characteristics  
• Prescribing provider specialty associated with the treatment index prescription in LRx 
(primary 
care 
[general 
practice/family 
practice/internal 
medicine/physician 
assistant/nurse practitioner], cardiologist, other, unknown; n, %) (Frequency table will 
be provided with details on provider specialty counts within ‘other’ category) 
• Charlson Comorbidity Index (CCI, Dartmouth-Manitoba adaptation; mean, SD, 
median, IQR, min, max) 
• CCI (categorical [0-1, 2, 3, 4+]); n, %) 
• Comorbidities of interest (ICD-10 diagnosis codes in Dx or CDM; n, %) 
o Acquired immune deficiency syndrome (AIDS) 
o Alcohol/drug abuse  
o Anemia  
o Cerebrovascular disease 
o Coronary heart disease/ischemic heart disease  
o Congestive heart failure  
o Chronic obstructive pulmonary disease (COPD)  
o Coronavirus disease 2019 (COVID-19) 
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o Dementia/Alzheimer's disease  
o Dyspepsia or stomach discomfort 
o Diabetes mellitus  
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 
• Procedures of interest (ICD-10 diagnosis or procedure codes, CPT Codes, HCPCS 
codes in Dx or CDM; n, %) 
o Orthopedic surgery 
o Central Venous Catheter 
• Baseline bleeds (ICD-10 diagnosis or procedure codes, CPT Codes, HCPCS codes in 
Dx or CDM; n, %)  
o Gastrointestinal 
o Intracranial 
o Others 
• History of falls (ICD-10 diagnosis codes in Dx or CDM; n, %) 
• Fracture/trauma involving lower extremities (ICD-10 diagnosis codes in Dx or CDM; 
n, %) 
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• Medications of interest (NDC or HCPCS codes in LRx or Dx; 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 
9.2.2. Outcome measures 
The following outcome measures are assessed post-discharge, and will be measured during the 
variable post-index period starting on the treatment index date for the apixaban and warfarin 
cohorts. 
Treatment patterns 
•  Persistent days (mean, SD, median, IQR, min, max) will be reported for patients until 
they discontinue, switch or end of follow-up based on definitions below 
• Patients discontinuing outpatient treatment of apixaban or warfarin, respectively (NDC 
codes from LRx; n, %) 
Note: Discontinuation will be defined as the occurrence of a ≥ 30 day gap from the run-out of 
days’ supply of the treatment (post-discharge) index prescription (i.e. apixaban or warfarin) 
to the date of the next claim for the respective therapy or with no other claims for the respective 
therapy. The date of the discontinuation will be defined as the last day of the days’ supply of 
the last filled prescription. 
o Time (in days) from treatment index date to discontinuation date (mean, SD, 
median, IQR, min, max) 
Note: Kaplan-Meier (KM) curves will be generated to measure median time (and 95 % CI) to 
discontinuation.   
• Patients switching to an OAC other than apixaban or warfarin, respectively (switched) 
(NDC codes from LRx; n, %) 
Note: Patients will be considered to have switched if they filled a prescription for OAC other 
than  apixaban or warfarin, respectively (identified through NDC codes in LRx) or for PAC 
within 30 days before or after the run out date of index treatment. The date of the switch will 
be defined as date of the prescription of such a therapy (OAC or PAC). 
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o Time (in days) from treatment index date to switch date, defined as the date of 
the first claim for the new OAC or PAC (mean, SD, median, IQR, min, max) 
Note: KM curves will be generated to measure median time (and 95 % CI) to switching 
 
Clinical Outcomes 
The following clinical outcomes will be assessed during the time patients are persistent with 
their respective index apixaban or warfarin treatment (treatment index): 
• Patients with ≥1 hospitalization for  recurrent VTE (ICD-10 codes in CDM; n, %) 
• Incidence rate (IR) of recurrent VTE (per 100 patient years) 
o The date of the first observed event will be flagged. The numerator for IR will 
be the number of patients with the event of interest and denominator will be the 
‘at risk’ period i.e. the time to first event. The 95% confidence intervals (CI) 
will also be reported. 
Note: Recurrent VTE will be defined as inpatient hospitalization with a primary diagnosis of 
VTE occurring 7 or more days after the first hospitalization discharge date.  
o Time (days) from first hospitalization discharge date to first recurrent VTE 
hospitalization (mean, SD, median, IQR, min, max) 
o Time (days) from treatment index date to first recurrent VTE hospitalization 
(mean, SD, median, IQR, min, max) 
• Patients with ≥1 hospitalization for major bleeding (ICD-10 codes in CDM; n, %) 
• IR of major bleeding (per 100 patient years) 
Note: Major bleeding will be defined as inpatient hospitalization with primary diagnosis 
of gastro-intestinal bleeding, intracranial hemorrhage (ICH) or other major bleeding  
o Time (days) from first hospitalization discharge date to first major bleeding 
episode (mean, SD, median, IQR, min, max) 
o Time (days) from treatment index date to first major bleeding episode (mean, 
SD, median, IQR, min, max) 
• Patients with ≥1 CRNM bleeding event (n, %) 
• IR of CRNM bleeding (per 100 patient years) 
Note: CRNM bleeding will be defined as inpatient hospitalization 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. 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 
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(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 
o Time (days) from first hospitalization discharge date to first CRNM bleeding 
episode (mean, SD, median, IQR, min, max) 
o Time (days) from treatment index date to first CRNM bleeding episode (mean, 
SD, median, IQR, min, max) 
9.3. Data sources  
IQVIA’s CDM database will be linked to Dx and LRx for this analysis. 
 
Hospital Charge Data Master (CDM) 
IQVIA’s Hospital CDM is comprised of hospital-based data which are sourced from hospital 
CDM files that roll up to the UB-04 files which are submitted for payment. Data covers non-
federal, acute-care short-stay hospitals, covering inpatient and outpatient services, including 
emergency room (ER) utilization with information on diagnoses, procedures, treatment and 
daily un-adjudicated charge details. Limited patient and hospital characteristics are also 
available. Data is available from 2001, with a data lag of approximately 6 weeks. The data 
cover more than 450 hospitals per month and approximately 8 million inpatient visits and 105 
million outpatient visits per year. Charge details during a stay are provided on a daily basis 
(and lack a time stamp). Diagnoses lack a time or day stamp. 
 
It is important to note some limitations of this dataset. Firstly, because this is an open-source 
database, there is a loss of visibility to healthcare activity and consumption outside of hospitals 
that participate in/contribute to the database. Secondly, unlike administrative health plan 
claims data, it is not possible to apply continuous enrollment (CE) requirements. Proxies for 
CE must be implemented based on hospital reporting to provide greater assurance that patient 
healthcare activity within this database is captured during the study period. Socioeconomic 
details, such as race/ethnicity or income, are unavailable in the data. Clinical detail is also 
limited. Due to patient privacy reasons, a subject who is 85 years or older will only have the 
recorded age of “85”. And finally, only charges are available in CDM, thus a national cost to 
charge ratio must be applied to charges. 
 
Medical claims (Dx) database 
IQVIA’s Dx database captures over one billion pre-adjudicated claims and three billion records 
obtained annually from approximately 800,000 office-based physicians and specialists. Dx 
database is updated on a weekly basis with approximately a 30-60 day lag for data 
completeness. Key information includes International Classification of Diseases, ninth revision, 
clinical modification (ICD-9-CM) and International Classification of Diseases, tenth revision, clinical 
modification (ICD-10-CM) diagnoses, CPT/procedure/Healthcare Common Procedure Coding 
System (HCPCS) for medical conditions and procedures, date of service, location of care, (pre-
adjudicated) charged amount for service, payer types (commercial, Medicaid, Medicare, cash 
payment), patient age and sex. Note that inpatient data is limited. 
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Longitudinal Prescription Claims (LRx) 
IQVIA LRx database captures information on dispensed prescriptions sourced from retail, 
mail, long-term care, and specialty pharmacies. These suppliers have direct, long-standing 
relationships with IQVIA, with many providing data on a daily basis, and all suppliers sup-
port weekly data feeds with an ability to provide insight within ten days of the end of each 
week. This enables IQVIA to ensure that the LRx database has good longitudinal, repre-
sentative, and current data from consistent and stable suppliers. IQVIA has industry-leading 
coverage in the following channels: 92% coverage of the retail channel, 72% coverage of 
standard mail service, and 76% of long-term care facilities. IQVIA receives specialty data 
directly from the pharmacy resulting in near census data coverage, contributing to greater 
precision for longitudinal analysis. Additionally, diagnosis is included directly on the majority 
of specialty pharmacy transactions from the specialty pharmacy providers. An important 
strength of the LRx database for this analysis is the longitudinal capture of adjudicated and 
cash prescriptions for all age categories, regardless of insurance type. 
 
Linkage Methodology   
A proposed dataset will be constructed utilizing patient data from LRx, Dx and CDM, with the 
appropriate dataset being selected based upon proportion of linked patients. This process which 
is compliant with The Health Insurance Portability and Accountability Act of 1996 (HIPAA) 
is described below:  
● IQVIA has developed a patented and proprietary encryption algorithm that utilizes 
actual patient-level information to create a unique Patient identifier (ID)8 
o First Name 
o Last Name 
o Date of Birth 
o Gender 
o Street Address 
o ZIP Code (5-digit) 
● IQVIA deploys this encryption tool across its data suppliers to de-identify patient data 
at the source 
● Once IQVIA brings the encrypted and de-identified data in house, the data undergoes 
a deterministic matching process to be assigned a unique and persistent IQVIA patient 
ID; we are then able to match the Patient ID across our portfolio of databases 
 
It is important to note that IQVIA uses a deterministic matching algorithm to link patients 
across databases.9  This type of algorithm uses actual patient information, rather than statistical 
probability based on patient age, number of visits, etc. to ensure continuity of patient records 
across datasets. Source data is passed through an encryption engine and a one-way hash 
algorithm results in “tokens” that cannot be decrypted. The resulting output is de-identified 
patient records that can be linked to other assets in the IQVIA patient data warehouse. Patient 
Tokens as well as other attributes (e.g., gender) are used for matching to the IQVIA Patient 
Master to assign an existing or new IQVIA Patient ID which can be used as available across 
data sources. The IQVIA matching algorithm achieves a balance between false positives 
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(~2%) and false negative (~3%) rates, optimizing the size of the linked sample that can be 
obtained. 
 
9.4. Study size 
An earlier feasibility assessment estimated that there were 139,061 hospitalized patients with 
a primary diagnosis of VTE in CDM between 01 January 2017 and 30 August 2022. Among 
these, 53,918 patients received apixaban and 18,035 received warfarin during the 
hospitalization. Among the patients receiving apixaban during first VTE hospitalization, 
47,029 patients had linked data in Dx and LRx between 01 January 2017 and 30 August 2022. 
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. All eligible participants will be included in the study.  
 
9.5. Data management  
Data contributions are subjected to a series of quality checks to ensure a standardized format 
and to minimize error rates. IQVIA standardizes a limited number of fields, such as gender, 
place of service and state, for which the standard is easy to define and widely agreed upon. For 
every active health plan, IQVIA compares the current submission to the previous submission. 
The frequency distributions of key fields are compared. In addition, basic statistical analyses 
are generated for key fields to check for trend breaks and data gaps. Data management, 
calculations and analyses will be performed using SAS, version 9.4 or later (SAS Institute Inc., 
Cary, NC, USA). Please refer to section 8.7 for details regarding quality control. 
 
9.5.1. Case report forms (CRFs)/Data collection tools (DCTs)/Electronic data record 
Not applicable. 
 
9.5.2. 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 
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 
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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. 
 
9.6. Data analysis  
Descriptive statistics will be produced for all relevant study measures previously described, 
for the overall cohort and for each treatment (apixaban and warfarin). 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, minimum, maximum and IQR. As relevant, continuous variables will also 
be categorized into intervals.  Univariate statistics will be calculated for each measure of 
interest. No comparisons will be made between the two cohorts..  
Four multivariable regression models will be developed for this study. Cox proportional 
hazards models will be conducted to evaluate both the risk (expressed as hazard ratios with 
corresponding 95% confidence intervals) of discontinung or switching from the index 
treatment as well as the risk of experiencing a clinical event  (i.e., recurrent VTE, major 
bleeding, or CRNM bleeding)..   The main effect variable will be the treatment cohort 
(apixaban vs. warfarin, with warfarin as the reference group). Covariates to be considered for 
inclusion into the models will include demographic and clinical characteristics of interest. A 
backward elimination of independent variables least associated with the dependent variable 
may be used. Clinically relevant covariates that are not retained during backward elimination 
may also be forced into the model. Collinearity among the variables of interest will be 
evaluated during model development.  
Kaplan-Meier analyses will also be utilized to report the time to an event of interest (e.g., 
switch, discontinuation). Kaplan-Meier is a method for estimating the probability of the 
proportion of individuals remaining in the sample at a particular time from an initiation point. 
It takes into account patients lost or censored before the study endpoint. All analyses will be 
based on observed, not projected, data. Analyses will be conducted using SAS® Release 9.4 
(SAS Institute Inc., Cary, NC), and the results will be reported in Excel tables. 
Any major modifications of primary endpoint definitions (treatment patterns) or their analyses 
would be reflected in a protocol amendment. 
 
9.7. Quality control 
Data management for this study will be conducted using standard IQVIA processes. The 
process will take into consideration any data governance imposed on the data source. All 
patient-level data is de-identified and fully HIPAA-compliant. After study specific data 
extraction from the databases, anonymized patient-level linked data extract will be securely 
transferred to IQVIA’s secure server compliant with US data protection laws. Only aggregated, 
anonymous, cohort-level data are provided to the study sponsor. 
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The IQVIA Advanced Analytics team employs a two-programmer approach to ensure accuracy 
and reproducibility of coding, including a multi-point quality control checklist for retrospective 
database studies. All data are stored on secure servers and are auto-archived and password-
protected for any future access requirements. Study documents are retained in a minimum of 
two secure locations and are only removed or deleted upon written request from the sponsor. 
 
9.8. Limitations of the research methods 
This study will have limitations inherent to observational studies involving claims and hospital 
charge data, as well as limitations related to the study design. Results from retrospective studies 
must be interpreted with caution and can only establish associations and not cause-and-effect 
relationships.  
Claims data do not provide as much clinical detail as medical records as they are primarily 
collected for the purposes of payment. Therefore, there is a potential for miscoding or 
misclassification (e.g., identification of newly treated VTE patients). There is also the potential 
for under-coding if they are not captured for billing purposes.  
Because these are open-source databases, there is a loss of visibility to healthcare 
activity/consumption at pharmacies, offices and hospitals that do not participate/contribute to 
the databases. Pharmacy stability requirements will be applied to the index prescription 
pharmacy at the patient level. Nevertheless, LRx has high prescription coverage (e.g., 63% of 
retail pharmacies in the US). Over-the-counter products will not be captured.   
Unlike administrative health plan claims data, it is not possible to define periods of continuous 
enrollment (CE). Only proxies can be implemented based on patient activity and pharmacy 
stability to provide greater assurance that patient healthcare activity within these databases is 
captured during the study period. The data also lack information on mortality.  
Only patients with a hospitalization or outpatient visit to a hospital in the CDM database are 
present in the CDM database, therefore potentially representing a more severe population. 
9.9. Other aspects 
Not applicable. 
 
 
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10. PROTECTION OF HUMAN SUBJECTS 
 
10.1. Patient information  
This study involves data that exist in anonymized structured format and contain no patient 
personal information.   
All parties will comply with all applicable laws, including laws regarding the implementation 
of organizational and technical measures to ensure protection of patient personal data.  Such 
measures will include omitting patient names or other directly identifiable data in any reports, 
publications, or other disclosures, except where required by applicable laws. 
 
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 the Alliance is not required. 
 
10.3. Institutional review board (IRB)/Independent ethics committee (IEC) 
Not applicable. 
 
11. MANAGEMENT AND REPORTING OF ADVERSE EVENTS/ADVERSE 
REACTIONS  
This study involves 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. 
 
12. PLANS FOR DISSEMINATING AND COMMUNICATING STUDY RESULTS 
Tables of study results will be shared with the Alliance throughout the analytic phase of the 
study.  The draft and final study report will be provided to the Alliance 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 an Alliance product, Alliance 
should be informed immediately.   
 
 
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13. REFERENCES 
1. Heit JA, Cohen AT, Anderson FA. Estimated annual number of incident and recurrent, 
non-fatal and fatal venous thromboembolism (VTE) events in the US. Blood. 
2005;106(11):267A. 
2. Wakefield TW, McLafferty RB, Lohr JM, Caprini JA, Gillespie DL, Passman MA., 
Executive Committee of the American Venous Forum. Call to action to prevent venous 
thromboembolism. J Vasc Surg. 2009 Jun;49(6):1620-3. 
3. Healthcare Cost and Utilization Project (HCUP) HCUP Databases. Agency for Healthcare 
Research and Quality; Rockville, MD: www.hcup-us.ahrq.gov/nisoverview.jsp 
4. Rogers MA, Levine DA, Blumberg N, Flanders SA, Chopra V, Langa KM. Triggers of 
hospitalization for venous thromboembolism. Circulation. 2012 May 1;125(17):2092- 
5. Kearon C, Akl EA, Ornelas J, et al. Antithrombotic therapy for VTE disease: CHEST 
guideline and expert panel report. Chest. 2016;149 (2):315–352. 
6. Lutsey PL, Walker RF, MacLehose RF, Alonso A, Adam TJ, Zakai NA. Direct oral 
anticoagulants and warfarin for venous thromboembolism treatment: Trends from 2012 to 
2017. Res Pract Thromb Haemost. 2019 Jun 9;3(4):668-673. 
7. Burton T, Hlavacek P, Guo JD, Rosenblatt L, Mardekian J, Ferri M, Russ C, Kline JA. 
Clinical characteristics and treatment patterns of patients with venous thromboembolism 
(VTE) transitioning from hospital to post-discharge settings. Hosp Pract (1995). 2020 
Oct;48(4):196-205.  
8. Issued and pending patents: System and Method for Generating De-Identified Health Care 
Data (US Patents 6,732,113/7,376,677), Anonymously Linking a Plurality of Data 
Records, (US Patent 6,397,224). 
9. Huse DM, Russo PA, Vasey J. Expanding the evidence base in outcomes research: linking 
electronic medical records and claims data. ISPOR Connections Vol 19 No 3. May-June 
2013. 
 
 
 
 
 
 
 
 
 
 
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14. LIST OF TABLES 
Not applicable 
 
15. LIST OF FIGURES 
Figure 1: Study Period 
Figure 2: Study Flow 
 
 
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