Comparison of Apixaban Versus Enoxaparin as Venous Thromboembolism Prophylaxis After Radical Cystectomy
Phase: NA
Conditions: Bladder Cancer
Sponsor: Abramson Cancer Center at Penn Medicine

 
 
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CLINICAL RESEARCH PROTOCOL 
PROTOCOL(S) TITLE: 
Comparison of Apixaban versus Enoxaparin for VTE 
Prevention after Radical Cystectomy (CARE) 
VERSION NUMBER: 
V3 
Date Submitted: 
 
Principal Investigator: 
 
Sub-Investigators: 
Statistician: 
1/16/2024 
 
Katharine F. Michel, MD MSHP 
 
Trinity J. Bivalacqua, MD PhD 
Luke J. Keele, PhD 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
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Abbreviations 
AE 
Adverse Event 
BMI 
Body Mass Index 
COST 
Comprehensive Score for Financial Toxicity 
CrCl 
Creatinine Clearance 
CRF 
Case Report Form 
CTCAE 
Common Terminology Criteria for Adverse Events 
DOAC 
Direct oral anticoagulant 
EP 
Extended Prophylaxis 
HIPAA 
Health Insurance Portability and Accountability Act  
IRB 
Institutional Review Board 
ITT 
Intention-To-Treat 
NIH 
National Institute of Health 
NSQIP 
National Surgical Quality Improvement Program 
PDC 
Proportion of Days Covered 
PE 
Pulmonary Embolism 
PI 
Principal Investigator 
PMAS 
PROMIS Medication Adherence Scale 
POD  
Post operative day 
PROMIS 
Patient-Reported Outcomes Measurement Information System 
PMAS 
PROMIS Medication Adherence Scale 
RC 
Radical Cystectomy 
SQH 
Subcutaneous heparin 
SUO 
Society of Urologic Oncology 
US 
United States 
VTE 
Venous thromboembolism 

 
 
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STUDY SUMMARY 
1.1 
Synopsis 
Title:  
Comparison of Apixaban versus Enoxaparin for VTE Prevention after 
Radical Cystectomy (the CARE trial) 
Short Title: 
Comparison of Apixaban versus Enoxaparin (CARE) 
Study 
Description:  
Patients who have undergone radical cystectomy for bladder cancer will be 
randomized to receive a prescription for either enoxaparin or apixaban to 
self-administer at home until post operative day 30. Their adherence to the 
assigned medication will be the primary outcome. Comparisons of patient 
satisfaction, barriers to adherence, and cost will also be collected. The 
hypothesis is that adherence, satisfaction, and cost will be greater in the 
apixaban arm. 
Objectives:  
1. To compare rates of adherence to discharge on enoxaparin vs 
apixaban  
a. Hypothesis: The apixaban group will exhibit non-inferior 
adherence, as measured by the proportion of prescribed 
medication accurately administered. 
2. To compare costs of discharge on enoxaparin vs apixaban 
a. Hypothesis: The median patient out-of-pocket cost, 
obtained from the institution’s outpatient pharmacy data, is 
expected to be higher in the apixaban group compared to 
enoxaparin group. 
3. To explore factors contributing to EP adherence 
a. Hypothesis: it is anticipated that barriers to adherence to 
enoxaparin will primarily manifest as operational 
challenges and patient dissatisfaction, while for apixaban, 
they will predominantly arise from lack of insurance 
coverage and cost considerations. To evaluate these 
barriers, a combination of validated questionnaires and 
novel measures will be employed. 
4. To collect safety and efficacy data on enoxaparin and apixaban 
a. Considering that our study size will limit statistical power 
to detect risk reduction in venous thromboembolism (VTE) 
and/or bleeding events in either enoxaparin or apixaban, we 
will instead closely monitor and assess VTE and bleeding 
events in both treatment arms to contribute to existing 
studies for possible meta-analysis. This will be achieved 

 
 
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through the implementation of screening questions at each 
visit.  
 
Primary 
Endpoint:  
To address our primary objective, adherence, the primary endpoint 
will be measured as the proportion of days covered (PDC), ie the 
proportion of days between discharge and post operative day 30 during 
which the participant took their anticoagulant as prescribed. 
Secondary 
Endpoints: 
To address our secondary objective of comparing risk factors for 
adherence/non-adherence, secondary endpoints include: 
1. National Institute of Health (NIH) Patient-Reported Outcomes 
Measurement Information System (PROMIS) Medication 
Adherence Scale (PMAS) – a validated, nine-item, patient-reported 
measure of medication adherence1 
2. Patient Satisfaction – a series of independent questions that 
investigate barriers to adherence specific to apixaban or enoxaparin 
To address our secondary objective of comparing cost, secondary 
endpoints also include: 
3. Patient out of pocket cost for anticoagulant prescription (in dollars) 
4. COST-FACIT, a 12-item survey developed and validated in the 
cancer population for assessing patient-reported financial distress 
due to healthcare costs2 
Study 
Population: 
Inclusion Criteria: All patients undergoing RC with urinary diversion and 
pelvic lymph node dissection for urothelial bladder cancer (any T stage, 
N0-1, M0) at the participating institutions.  
Exclusion Criteria: 
1. Preoperative use of a therapeutic dose of anticoagulant (this notably 
does not exclude patients taking antiplatelet agents) 
2. Failure to undergo radical cystectomy with concurrent urinary 
diversion and pelvic lymph node dissection 
3. Failure to be discharged by POD14 
4. Failure to be discharged on prophylactic enoxaparin or apixaban. 
5. Any medical condition which precludes treatment with either 
enoxaparin or apixaban (including dialysis,hemophilia, or any other 
bleeding diathesis) 
6. Inability to communicate over the phone in English 
 

 
 
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Due to the natural history of bladder cancer, the expected population will 
be mixed in age, race, gender, and general health status, though likely to be 
majority white males between the ages of 50-80 in generally good health 
status (enough that they are safe to undergo RC, which is a major surgery).  
Target sample size is 108 participants 
Enrolling Sites: 
Hospital of the University of Pennsylvania (HUP), Philadelphia, PA 
Vanderbilt University Medical Center, Nashville, TN 
 
Description of 
Study 
Intervention: 
Enoxaparin and apixaban are both established treatments in clinical 
practice and considered acceptable standards of care. However, 
enoxaparin has historically been utilized for extended prophylaxis prior to 
the availability of apixaban and is slightly more commonly prescribed. 
Hence, in this study, randomization to apixaban will be considered the 
intervention for convention. 
Enoxaparin is taken by subcutaneous injection 40 mg once daily for VTE 
prophylaxis. Apixaban is taken orally as a tablet at a 2.5 mg twice daily for 
VTE prophylaxis. 
Study Duration: 
30 months 
Participant 
Duration: 
From preoperative clinic visit to 90 days postop, approximately 4 months 
 
 
 
 
 
 
 
 
 

 
 
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1.2 Schema 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
Screening participants by inclusion and exclusion criteria 
Obtaining informed consent, Enrolling participants  
Demographics Questionnaire 
Phone Call #1: 
• Medication counting 
• PROMIS, Patient Satisfaction Questionnaire 
• Chart review for perioperative variables & pharmacy 
cost data 
• Screening for VTE & bleeding 
Randomization 
Enoxaparin 
Apixaban 
Phone Call #2: 
• COST Questionnaire 
• Screening for VTE & bleeding 
Pre-operative 
Clinic Visit 
Surgery, 
Inpatient 
Recovery 
POD 30 
(end of 
prophylactic 
anticoagulation) 
POD 90 
Discharge 
At home, self-administration of anticoagulant 

 
 
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2 INTRODUCTION AND BACKGROUND 
2.1 
Study Rationale 
Venous thromboembolism (VTE), including both deep venous thrombosis (DVT) and 
pulmonary embolism (PE), after radical cystectomy (RC) constitutes a significant burden on 
bladder cancer patients in terms of morbidity, mortality, and cost. PE is one of the most common 
causes of perioperative mortality after RC, reported to be 16% in one study.3 Patients diagnosed 
with DVT or PE require at least six months of anticoagulation and treatment, resulting in 
burdensome medication use and followup appointments. The annual per-patient cost of DVT or 
PE has been reported as high as $3,000 or $6,000, respectively.4 Prior analyses of large datasets 
suggest the incidence of symptomatic VTE ranges from 2-12% in the first 30 days after 
surgery,5–12 and data confirm the risk is sustained after hospital discharge.5,9,10,12  
 
Growing recognition of this burden led to the practice of extending the period of 
pharmacologic prophylaxis against VTE beyond just the patient’s inpatient stay so that the 
patient continues prophylaxis until the 30th postoperative day (POD).  This practice is well 
established and codified into many surgical oncologic guidelines, both urologic and others. The 
data supporting the practice in oncologic surgery populations are quite robust; a recent Cochrane 
Review of seven randomized, controlled trials of patients postop from abdominal and pelvic 
oncologic operations shows the rate of VTE was reduced from 13% in the non-prophylaxis group 
to 5.3% in the group receiving the blood thinner enoxaparin for 28 days after surgery.13   
 
Regarding the bladder cancer population and RC specifically, a single institution study of 
over 400 patients showed a decrease in VTE rate from 12% to 5% after instituting the practice of 
28 days of enoxaparin after discharge,14 and a more recent study showed an even bigger decrease 
from 17.6% to 5.06% in the 90 days after discharge.15 The European Association of Urology 
(EAU) has thus adopted a recommendation stating, “the optimal duration of pharmacological 
prophylaxis is approximately four weeks post-surgery.”16  
 
In the face of the mounting evidence and these emerging guidelines, the practice of 
extended VTE prophylaxis has rapidly expanded in the past several years and become standard 
of care. An analysis of the Optum database of prescription data suggests the practice of 
prescribing enoxaparin after discharge after RC increased from only 9% of cases in 2012 to 26% 
in 2017.17 Even more recently, a 2020 survey of 121 physician members of the Society of 
Urologic Oncology (SUO) reported 80% endorsed the use of extended prophylaxis (EP) for this 
duration.18 
 
There are still several barriers that exist to the full adoption of discharge on enoxaparin 
injections. In addition to the eligibility restrictions based on renal function, patients continue to 
face significant operational and quality of life barriers, including issues related to insurance 
coverage, cost, as well as the pain and discomfort experienced during self-injections. In the 
described SUO survey, half of providers that prescribe EP report experiencing issues with lack of 

 
 
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insurance coverage for enoxaparin injections (38%), inability of patients to afford the medication 
(51%), and need to perform cumbersome additional insurance authorization processes (44%). 
Approximately 20% report issues with patient adherence and refusal to perform the enoxaparin 
injections. The providers who elected not to prescribe EP correspondingly cited these as reasons 
they elected not to use it.19 Similar reports exist in non-urologic cancer surgery; among those 
surgeons who were noncompliant with EP guidelines for pancreatic and hepatobiliary surgeries, 
the most significant barriers reported were “drug cost,” “subcutaneous injections, and “logistical 
challenges of prescribing.”20 
 
 
Direct Oral Anticoagulants (DOACs), specifically apixaban, have recently emerged as a 
viable option for providing pharmacologic VTE prophylaxis to patients after discharge while 
avoiding some of the persistent issues encountered with discharge on enoxaparin. Gynecologic 
oncologists have been early adopters of this practice and their pelvic cancer surgeries offer a 
reasonable comparator to RC. In a recent trial, 400 women undergoing gynecologic cancer 
surgery were randomized to 28 days of either prophylactic enoxaparin or apixaban with results 
showing there were no differences between groups for rates of major bleeding or venous 
thromboembolic events but patients in the apixaban group reported increased ease and decreased 
pain associated with taking the medication.21  There is even stronger data supporting the efficacy 
of apixaban as compared to enoxaparin in the orthopedic field, with a randomized trial of over 
3,000 patients showing a 15% VTE rate using apixaban as EP compared to 24% using 
enoxaparin.22  
 
2.2 
Previous Literature 
 
In the urologic field, there have been only a handful of exceedingly small, retrospective 
studies investigating the feasibility of using apixaban after discharge.23–25  Urologists from the 
University of Missouri and St. Louis University initiated a quality improvement pathway for 
recovery after RC which included prescribing apixaban at discharge until POD 28. Their 
retrospective review of 72 patients who completed the apixaban protocol showed no increase in 
rates of DVT, major bleeding, or other complications compared to their historical rates.25  The 
Mayo clinic in Arizona similarly made an institutional change to using a DOAC rather than 
enoxaparin as EP in 2019 and performed a retrospective comparison of 46 patients who received 
a DOAC, 55 patients who received enoxaparin and 556 patients who received no EP (from either 
before or after 2019). Their results show VTE rates of 0%, 3.6% and 7.2% in the cohorts who 
received a DOAC, enoxaparin, and no VTE prophylaxis, respectively (p=0.11). They also 
indicate no significant difference in GI bleeding among the three groups.23 Looking specifically 
at patients who underwent robot-assisted radical cystectomy at another academic center, Ortiz et 
al. perform a retrospective comparison enoxaparin vs DOACs following an institutional change 
to using DOACs. Of 66 patients included in their review, their data show DVT rates of 3/37 
patients in the enoxaparin arm vs 1/29 in the DOAC arm; a difference which was not statistically 

 
 
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significant. They also show no statistical difference in postoperative complication rates including 
ED returns, readmissions, bleeding events, or wound complications.24,25  
 
The largest of these types of retrospective cohort studies was performed by Westerman et 
al. at MD Anderson in 2021. Similarly, it is a retrospective comparison of the outcomes 
following an institutional change from the use of enoxaparin to the use of apixaban; Westerman 
et al. capture 145 patients in each phase. Their results suggest a possibly improved DVT rate on 
apixaban (0% vs 3.1%) following the switch, as well as fewer compliance “events” (0% with 
apixaban vs 33.5% with enoxaparin).26 Notably, this was not a randomized study, not all patients 
who were discharged on prophylaxis had undergone RC, and not all patients who underwent RC 
were discharged on prophylaxis; apixaban was simply used in urologic cancer cases where 
surgeon discretion would have led to discharge on enoxaparin prophylaxis. 
 
In summary, the clinical benefit of extended prophylaxis in reducing venous 
thromboembolism (VTE) immediately after major abdominal oncologic surgery is evident. 
The use of DOACs as a substitute for enoxaparin has been extensively studied in non-
urologic cancer patients, but its adoption by urologic cancer surgeons is still in the early 
stages. While several small retrospective reports have been published, demonstrating the 
safety outcomes of switching to DOACs as EP, the potential advantages of using DOACs to 
mitigate the issues associated with enoxaparin self-injection and enhance patient adherence 
and accessibility to these medications remain unexplored. 
 
2.3 
Preliminary Institutional Results 
Given the earlier data suggesting barriers to adoption include cost, we sought to assess 
the state of prescription costs at our institution and determine how likely this is to pose a barrier 
to patient adherence. We reviewed our institution’s outpatient pharmacy data from July to 
December of 2022, including the copays that patients being discharged on prophylactic dose 
apixaban and enoxaparin face at our institution as well as difficulties encountered with prior 
authorizations. Data suggest that copays may vary from as low as $0 to >$100, and that copays 
are much more likely to be increased with apixaban (Table 1). Review of prior authorizations 
show that a substantial number of prior authorizations were submitted, and in particular that 
denial of these prior authorizations and insurance coverage may pose a problem for both 
medications, in particular apixaban (Table 2). 
 

 
 
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Table 1. Patient copays for Enoxaparin and Apixaban
 
 
Table 2. Outcomes of prior authorizations submitted for Enoxaparin and Apixaban   
  

 
 
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3 STUDY OBJECTIVES AND ENDPOINTS 
 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Primary 
 
 
To compare rates of 
adherence to discharge on 
enoxaparin vs apixaban 
Proportion of days covered (PDC). 
This will be calculated based on the 
size of prescription the patient was 
provided, day of surgery, day of 
discharge, and how many 
pills/syringes are remaining at 
POD30.   
 
This is an objective and 
quantitative way to measure 
adherence.  
Secondary 
 
 
To explore possible reasons 
for adherence vs non 
adherence  
 
PROMIS Medication Adherence 
Scale: a nine-item questionnaire26,27 
This is a validated measure of 
medication adherence that 
focuses on the possible reasons 
for non-adherence  
Participant satisfaction 
Participants will answer 
questions specific to the use of 
enoxaparin and apixaban at home 
after RC. These questions were 
selected based on the clinical 
experience of the PIs as well as 
other studies that have examined 
adherence to enoxaparin and 
apixaban21,27,28 
COST-FACIT: a 12-item 
questionnaire2 
This is a questionnaire that was 
developed and validated in the 
cancer population for assessing 
patient-reported financial distress 
due to healthcare costs. This 
questionnaire adds a patient 
reported component, as simple 
cost data does not capture how 
burdensome that cost is to each 
specific patient 
To compare the cost of 
enoxaparin vs apixaban 
Out of pocket cost of prescription for 
anticoagulant, in dollars 
This provides objective measure 
of the cost comparison between 
enoxaparin and apixaban. This 
data combined with adherence 
data may allow providers to 
determine the most cost effective 
option.  

 
 
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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Tertiary 
 
 
To collect mefficacy and safety 
data regarding both forms of 
prophylaxis 
Rate of VTE, either PE or DVT 
 
Rate of bleeding events, classified as 
major, clinically relevant nonmajor, 
or nonmajor. 
While data suggest VTE rates are 
comparable between enoxaparin 
and apixaban in both non-
urologic and urologic studies, the 
urologic studies are in small 
populations. We therefore plan to 
track VTE and bleeding as 
outcomes to continue 
contributing to the pool of data. 
These outcomes would likely 
have been measured even if they 
were not outcomes as part of 
safety monitoring. 
  

 
 
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4 STUDY DESIGN 
This is a pragmatic, multi-site, randomized, controlled trial comparing two anticoagulant 
medications, enoxaparin and apixaban, when given to bladder cancer patients as VTE 
prophylaxis after RC.  
The primary objective of the study is to assess participant adherence to the at-home 
anticoagulation regimen. Other objectives include participant satisfaction and cost burden. 
At 30 days postop study team members will call participants to assess the primary endpoint of 
adherence as well as secondary endpoints of cost and patient satisfaction. At 90 days the 
participants will receive another phone call to complete one additional questionnaire assessing 
financial burden since surgery. While both drugs are considered standard of care for EP after RC, 
apixaban is considered the intervention arm due to its more recent introduction and use at this 
institution. The study is powered to detect if adherence to apixaban is noninferior to enoxaparin. 
If this criterion is met the study will also test for the superiority of apixaban. 
4.1 
Minimizing Bias 
Patients will be randomized to a prescription for one of the two anticoagulants at the time 
of postoperative discharge, and instructed to continue the medication until POD30. 
Randomization will be performed in a simple 1:1 fashion.  
The randomization will be non-blinded. Given that this trial aims to explore the real 
experience of patients on these medications, blinding and placebo would actually detract from 
the important clinical context and understanding that participants have. Furthermore, enoxaparin 
and apixaban have different routes of administration (enoxaparin is injectable and apixaban is 
oral) which makes blinding and placebo infeasible. Blinding of the investigators is not necessary 
given the outcomes are patient reported surveys and pill/vial counts. Bias will be sufficiently 
reduced by randomization.  
The University of Pennsylvania will serve as the primary site, and Vanderbilt University 
Medical Center as a second site. The addition of a second site will also introduce variety into the 
study population and strengthen its applicability.  
4.2 
Risk/Benefit Assessment 
Enoxaparin and apixaban are both FDA approved in the context of VTE prophylaxis and 
prescribed after cystectomy as standard of care (SOC). The benefits of postoperative 
anticoagulation for reducing rates of VTE have been repeatedly demonstrated in the literature 
and are included in society guidelines (see Section 2.1). The most relevant clinical risk with 
either medication is bleeding, which is a low risk at the prophylactic dose utilized in this study.  
The most important point in assessing risk/benefit in this study is that the standard of care 
includes extended prophylaxis (EP) postoperatively. Thus, participants will neither gain 
clinical benefit nor avoid clinical risk by participating because they would have been given 
EP regardless. The selection of one of these two anticoagulants is currently determined by 

 
 
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prescriber preference in clinical practice. Enoxaparin is currently the more commonly prescribed 
at this institution so is considered the “control” group for notation purposes in this trial. 
5 STUDY POPULATION 
5.1 
Inclusion Criteria 
In order to be eligible to participate in this study, an individual must meet all of the following 
criteria: 
1. Provision of signed and dated informed consent form  
2. Stated willingness to comply with all study procedures and availability for the duration of the 
study 
3. Able to communicate in English over the phone 
4. Male or female, age >18 years 
5. Diagnosed with biopsy-proven, urothelial cell carcinoma (any T stage, N0-1, M0) with plan 
for radical cystectomy with urinary diversion and concurrent pelvic lymph node dissection as 
treatment 
5.2 
Exclusion Criteria 
An individual who meets any of the following criteria will be excluded from participation in this 
study: 
1. Preoperative use of a therapeutic dose of anticoagulant (this notably does not exclude 
patients taking antiplatelet agents) 
2. Failure to undergo radical cystectomy with concurrent urinary diversion and pelvic lymph 
node dissection 
3. Failure to be discharged by POD14 
4. Failure to receive a script for enoxaparin or apixaban. 
5. Any medical condition which precludes treatment with either enoxaparin or apixaban 
(including dialysis, hemophilia or any other bleeding diathesis) 
 
5.3 
Recruitment 
The University of Pennsylvania historically performs ~70 cystectomies per year. 
Vanderbilt University Medical Center performs ~90 per year. To achieve the target analysis 
group of 90 patients we plan to enroll 108  (see section 9.3.1). Thus the planned 
recruitment/enrollment period is approximately 12 months. 
Recruitment will take place in outpatient offices. We will review the medical charts of 
patients seeing our Urologic oncology surgeons a week ahead of time and flag charts that suggest 
a radical cystectomy may be an indicated therapy for a patient. Staff will plan to be available on 
these days to screen and enroll as able.  

 
 
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The treating physician will discuss post-operative extended prophylaxis (EP) with 
anticoagulants with the patient during their visit because it is standard of care. Within this 
context the treating physician will introduce the option to participate in the trial and undergo 
randomization between forms of EP, however it will be made clear to the potential participant 
that they will receive standard of care EP regardless of their choice to participate or not.  
After the visit, further discussion of the trial and screening will be performed by trial staff 
other than the treating physician, and participants will be allowed to think about their decision 
after the initial discussion and enroll at a later date (as long as they enroll prior to undergoing 
surgery). Both of these features will help further mitigate any undue pressure patients may feel. 
If a patient cannot be approached in person or decides they would like to think longer about their 
decision to participate, a member of the research team will contact them by phone and complete 
the remaining enrollment process over the phone and electronically.  
6 STUDY INTERVENTION 
Both enoxaparin and apixaban are FDA approved in the setting of VTE prophylaxis 
and considered standard of care for EP after radical cystectomy.  Study personnel will not 
be directly providing or administering either drug. Rather, the study intervention is the 
randomization to receive a prescription (with standard clinical counseling) for either of the 
two forms of prophylaxis. The participant will then be responsible for filling the 
prescription at their own cost and self-administering the anticoagulant, as would be 
standard of care after a radical cystectomy. The anticoagulants will be prescribed according to 
the clinical standard of care: 40 mg injected subcutaneously once daily for enoxaparin and 2.5 
mg tablet taken orally twice daily for apixaban. Doses may be reduced in increased based on the 
patient’s medical comorbidity profile (for example weight and CrCl) according to standard 
prescribing practices. Regardless of the time of day of discharge, participants will be instructed 
to start self-administering the medication the day after discharge, and continue through post-op 
day 30.  
Participants who fail to receive a prescription for either anticoagulant will be considered 
not to have received the study intervention. Participants who receive the prescription but report 
poor compliance with the prescription have still received the study intervention; their poor 
compliance is tracked as the primary outcome of the study. 
 
7 STUDY ASSESSMENTS 
 
At the time of enrollment, participants will be offered to complete the Demographics 
questionnaire either in person (if applicable), via phone (if applicable), or via a secure REDCap 
link emailed to them. 
 
Participants will be contacted via phone on POD30 and POD90. During the phone call, 
participants will be given the option to receive an email with a secure link to REDCap to 
complete the majority of the study visit electronically (PMAS, Patient Satisfaction, and COST 

 
 
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questionnaires). Medication counting and screening for adverse events including VTE and 
bleeding must be done over the phone rather than via emailed link. 
 
Study assessments will be conducted by staff other than the treating physician, and staff 
members will clearly state the contact is part of the research study, not part of routine clinical 
care. 
7.1 
Adherence & Satisfaction Assessments 
The following assessments will be made to assess the adherence and satisfaction with 
anticoagulants after cystectomy (corresponding to primary and secondary objectives in section 
3): 
1. Medication counting– study personnel will assist with medication counting over the 
phone. This involves the participant counting the pills/vials of medication they have 
remaining and then the study personnel will use the date of surgery, date of discharge, 
and size of prescription found in the medical record to calculate the proportion of days 
covered (PDC). PDC is the primary endpoint of the study and is the most objective 
measure of adherence.  
2. National Institute of Health (NIH) Patient-Reported Outcomes Measurement Information 
System (PROMIS) Medication Adherence Scale (PMAS)29,30 – this questionnaire is a 
validated, nine-item, patient-reported measure of medication adherence that can be either 
administered by study personnel over the phone or filled out directly in RedCap by study 
participants who elect to have a secure weblink emailed to them. 
3. Patient Satisfaction – study personnel will ask a series of independent questions over the 
phone or participants will answer them directly in RedCap if they elect to have a secure 
weblink emailed to them. These questions elucidate possible reasons for 
compliance/noncompliance that are hypothesized specifically to apply to enoxaparin and 
apixaban.  
7.2 
Cost Assessments 
The following assessments will be made to assess the cost of anticoagulants when used as EP 
(corresponding to secondary objectives in section 3). 
1. COST-FACIT – this is a 12-item questionnaire developed and validated in the cancer 
population for assessing patient-reported financial distress due to healthcare costs that 
can be either administered by study personnel over the phone or filled out directly in 
RedCap by study participants who elect to have a secure weblink emailed to them. 
2. The total cost, amount paid by insurance, and patient out of pocket cost for each 
anticoagulant (in dollars) will be tracked by the inpatient pharmacy. This is collected via 
electronic review of pharmacy records.  

 
 
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7.3 
Assessing Covariates 
1. Demographics Questionnaire – this questionnaire is administered by study personnel 
either in person, over the phone, or filled out directly in RedCap by study participants 
who elect to have a secure weblink emailed to them. Some chart review may be 
performed to assist in completion. It will collect variables to help evaluate what 
sociodemographic covariates may be influencing study endpoints.  
a. The Demographics Questionnaire we include the modified, 5-item Frailty 
Index.29 Initially developed a an 11-item index, the Frailty Index was developed 
using NSQIP comorbidities and then shortened to a 5-item index that has been 
shown to predict complications, discharge destination, and healthcare utilization 
after radical cystectomy.30,31  
2. In addition to these discrete questionnaires, chart review will be performed ascertain 
what perioperative variables may be influencing study endpoints: 
a. Length of surgery 
b. Surgical approach (robotic vs open) 
c. Type of diversion (ileal conduit, catheterizable channel, or neobladder) 
d. Number of blood transfusions both intraop and periop (in units) 
e. Length of stay (in days) 
 
7.4 
Drug Efficacy & Safety Assessments 
In order to achieve the tertiary objective of collecting data regarding the efficacy and 
safety of both enoxaparin and apixaban when used as EP in the setting of radical cystectomy, we 
will directly enquire about instances of VTE and instances of bleeding. Screening questions for 
VTE and bleeding will be performed by study personnel and any positive screen will trigger 
review by one of the investigators, including review of the participant’s medical record for 
results of imaging, labwork, notes from ED visits or inpatient admissions, or any other 
information deemed necessary by the investigator to confirm presence of VTE or bleeding and 
describe the outcome. This review will be conducted in accordance with HIPPA regulation. 
Review of the VTE or bleeding event will be performed for study documentation purposes; 
participants will be referred to their treating clinician for management of the VTE or bleeding, or 
if deemed necessary by the PI, to the emergency department for expedited care and their treating 
clinician notified of this for continued management. 
7.4.1 
Assessing VTE 
VTE will be categorized as DVT, PE, or both. To asses for VTE, all participants will be 
directly asked if they have been diagnosed with a blood clot. A positive screen will be reported 
to the investigators who will review the event as described above,  

 
 
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Development of VTE may result in the patient being discontinued from the study 
intervention (because they will likely no longer be on prophylactic dose of anticoagulant, but 
rather therapeutic dose) but not discontinuation from the study. 
7.4.2 
Assessing Bleeding 
Bleeding events will be categorized as Major, Clinically-Relevant Non-Major (CRNM), 
and Minor. Major events and CRNM  are defined according to the International Society on 
Thrombosis and Haemostasis (ISTH) Subcommittee of Scientific and Standardization 
Committee.32,33 Minor bleeding is defined as clinically overt bleeding that does not meet criteria 
for Major or CRNM bleeding. 
To assess for Major and CRNM bleeding, participants will be directly asked if they have 
had bleeding that resulted in presentation to ED, inpatient admission, transfusion, or procedural 
intervention. To assess for Minor bleeding (or bleeding that is Major/CRNM but not yet 
diagnosed) participants will be asked about bruising or any other bothersome bleeding. All 
positive screens for bleeding events will be reviewed by a trial investigator to ensure appropriate 
clinical classification as Major, CRNM, or Minor. A positive screen will be reported to the 
investigators who will review the event as described above 
 
8 SCREEN FAILURE, DISCONTINUATION, AND CROSSOVER 
8.1 
Screen Failures 
Screen failures are defined as participants who agree to participate in the clinical trial but 
do not ultimately enroll. In order to comply with the Consolidated Standards of Reporting Trials 
(CONSORT) publishing requirements, all potential participants who are screen failures will 
complete a demographics form and the reason for their screen failure will be documented.  
Participants who are screen failures due to a medical contraindication to enoxaparin or 
apixaban which then improves to meet the trial standard may be rescreened and will be assigned 
the same participant number as for the initial screening.  
8.2 
Discontinuation of Study Intervention, Discontinuation from Study 
Prophylactic anticoagulation is standard of care after RC and therefore the decision to 
stop prophylaxis should be situated within a discussion with the treating clinician.  The following 
are anticipated reasons participants may be told to discontinue study intervention (ie stop their 
anticoagulant) by their treating clinician:  
- 
Development of blood clot. This would require discontinuation of prophylactic dose in 
favor of therapeutic dose and may involve switching anticoagulant type 
- 
Development of bleeding event 
- 
Development of an adverse event possibly related to the anticoagulant 

 
 
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- 
Development of a serious adverse event that would make prophylactic anticoagulation 
contraindicated 
 
If study personnel discover any of these occurrences during study visits and they are not 
known already to the treating clinician, study personnel will refer the participant to their treating 
clinician for management, which may include consideration of discontinuation of the 
anticoagulant.  
Study personnel will screen for discontinuation of the study intervention (ie 
discontinuation of the assigned anticoagulant) that has already occurred at the beginning of the 
POD30 and POD90 telephone calls. Any instances of study discontinuation will be brought to 
the attention of the PI and at the discretion of the PI participants who must discontinue the study 
intervention may remain in the study and complete portions of study visits depending on their 
reason for anticoagulant discontinuation and length of time they were following study protocol. 
 
Participants may alternatively be discontinued completely from the study for the following 
reasons: 
- 
Failure to undergo radical cystectomy and pelvic lymph node dissection 
- 
Failure to be discharged on prophylactic anticoagulant 
- 
Failure to be discharged by POD14 
- 
Lost to Follow Up, defined as failing to complete the study visit despite three attempts to 
contact the participant via phone and/or email  
- 
Participant request; participants are free to withdraw at any time 
Any study discontinuation or discontinuation of the study intervention will be 
documented, including the date and reason for discontinuation. All instances will be reviewed by 
PI..  Participants who are discontinued will not be replaced.  
8.3 
Crossover Between Study Arms  
If a participant has or develops a contraindication to the specific drug they have been 
randomized to receive prior to discharge on EP (ie prior to initiation of the study intervention), 
they will be considered for crossover to the other arm and, if there is no contraindication to the 
other drug, can be switched to that arm. These instances and reasons for crossover will be 
documented.  Crossover in this way will be allowed so that patients are not deprived of the 
standard of care anticoagulation after RC for their participation in the study and to better mimic 
the current prescribing patterns in which the drugs are frequently substituted for each other. 
Potential bias from allowing crossover is expected to be minimal as there is not a strongly 
plausible link between the contraindications to enoxaparin or apixaban and adherence to 
enoxaparin or apixaban. Furthermore, the contraindications to enoxaparin and apixaban are 
mostly quite rare; the only anticipated contraindication will be creatinine clearance (CrCl) <30 
for enoxaparin. Any other possible indication for crossover will be reviewed by PI. Patients who 
crossover should still complete the study visits and both an intention to treat (ITT) and per-
protocol (PP) analyses will be completed.  

 
 
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9 STATISTICAL CONSIDERATIONS 
9.1 
General Approach 
Continuous variables will be presented as means with standard deviation or median with 
interquartile range. All statistical tests of significance will be two-sided with alpha level 0.05. 
Stata will be used for all statistical analysis.  
9.2 
Baseline Descriptive Statistics 
Participants in the two study arms will be compared on their baseline demographics 
characteristics, collected from the Demographics Questionnaire, and on their operative 
characteristics, collected by chart review. Inferential statistics will be used to test for significant 
differences across study arms at baseline. To conduct these statistical tests, we will apply either 
standard t-tests for continuous measures or difference in proportion tests for binary measures.  
9.3 
Analysis of the Primary Endpoint 
The primary objective of this study is to compare drug adherence between the two study 
arms, and the corresponding primary endpoint of the study is the proportion of days at home 
during which the participant took the prescribed anticoagulant. This is defined as the proportion 
of days covered (PDC).  
PDC = number of days of anticoagulant actually taken / 
number of days of anticoagulant supposed to take 
Number of days of anticoagulant actually taken is determined during the POD 30 phone 
call by asking the participant how many pills/vials they have remaining and then subtracting that 
from the size of the prescription they were given. Number of days of anticoagulant supposed to 
take is calculated by subtracting the number of days postop the patient was discharged from 30.  
PDC will be compared between the two groups using a non-inferiority trial design with 
difference in proportions test with the following hypothesis: 
H0: Apixaban is inferior to Enoxaparin in terms of the average PDC response.  
HA: Apixaban is non-inferior to Enoxaparin in terms of the average PDC response. 
9.3.1 
Sample Size Calculation 
Prior studies suggest the at-home adherence to daily lovenox regimen is around 
85%.21,28,34,35 Assuming a baseline PDC in the control group of 85% and non-inferiority margin 
of 15%, a sample size of 45 subjects per arm, 90 subjects total, will provide 80% power to detect 
non-inferiority at a one-sided significance level of 0.05..36  

 
 
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9.4 
Analysis of Secondary Endpoints 
The following secondary endpoints will be assessed to further characterize adherence and 
also related elements of satisfaction and cost, though analyses of these related elements are not 
dependent on findings of the primary endpoint.  
1. A binary measure of adherence: adherent vs non-adherent. Adherent is defined as taking 
all intended anticoagulant. Adherence in this definition will be compared using a test of 
proportions (proportion of patients in one study arm that were “adherent” vs proportion 
of patients in the other arm that were “adherent”) within the ITT and population.  
2. Cost of the medication. There are several measures of cost that will be studied as 
endpoints, including overall medication cost, cost paid by insurance, and most 
importantly participant out of pocket cost. Cost will be measured in dollars and reported 
as median and as mean depending on the presence of outliers. This will be collected from 
pharmacy review of prescriptions. Cost will be compared using a rank sum test. 
3. Scores on the two validated questionnaires given: PROMIS and COST. These validated 
questionnaires both have scoring systems and a t test of the average score of participants 
in each arm will be compared (ie average score on COST for participants in apixaban arm 
vs average score on COST for participants in enoxaparin arm). A rank sum test will be 
used if distributions have outliers.  
9.5 
Exploratory Analysis 
Analysis of other factors influencing adherence to at home anticoagulation in this 
population are considered exploratory. To explore what factors other than type of anticoagulant 
may be impacting adherence, we plan to perform a logistic regression with the outcome variable 
of PDC. Covariates will include the following: age, gender, ethnicity, marital status, living 
situation, occupational status, education level, annual household income, insurance status, 
history of prior blood clot, number of daily medications, discharge destination, study arm, and 
items from the Satisfaction Questionnaire. Univariate regression will be performed first followed 
by multivariate regression including all variables that were significantly associated on univariate 
regression.  
A second exploratory analysis will be comparing elements of the novel satisfaction 
questionnaire trial between the apixaban and enoxaparin arms.  Items from this questionnaire 
may be compared by presenting descriptive statistics without formal tests for statistical 
significance in order to explore how patient satisfaction varies between the study arms and allow 
future physicians to give anticipatory guidance. 
9.6 
Analysis of Safety Endpoints 
Given the well-established safety profile of both drugs and their use as SOC after 
cystectomy there is no formal safety endpoint for this study. However, both bleeding and VTE 
events will be solicited and tracked (see section 7) for safety analysis. DVT, PE, and a composite 

 
 
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outcome of the two will be compared between the two study arms using a test of proportions. For 
bleeding events, medical review of the chart by an investigator will determine if the event is 
Major, Clinically Relevant Non-Major (CRNM), or Minor (see section 7) and these three 
outcomes will be compared between the two groups as well as a composite outcome of Non-
Minor Bleeding (Major and CRNM) using test of proportions.  
These as well as any other adverse events will be graded (see section 7) and presented in 
a descriptive way with any further detail deemed clinically relevant by the PI (including but not 
limited to the treatment and outcome of the AE) included. 
9.7 
Populations for Analyses 
The analysis of primary endpoint, PDC, as well as analyses comparing the results of the 
questionnaires will be conducted using an Intention-to-Treat (ITT) Dataset consisting of all 
randomized participants. We expect minimal crossover after randomization however if there is 
significant crossover we would also perform the analysis in an “As Treated” (AT) dataset 
consisting of participants categorized to the drug they ultimately received after crossover. Cost 
analyses will be performed using a dataset of all prescriptions (there may be more than one 
prescription per participant if there is crossover between study arms, though again this is 
expected to be minimal). Safety analyses will be performed in the ITT dataset as well as in 
participants who meet criteria for “adherent” to their anticoagulant (as defined above in section 
9.4). Missing data will be assumed random and discarded from all analyses; missing data is 
expected to be low as there are only two study visits.  
 
10 OPERATIONAL CONSIDERATIONS 
10.1 
Study Personnel 
The study personnel will consist of the PIs, sub-investigators, research coordinators, 
pharmacists, statisticians, research nurses, and medical students from both sites.  
10.2 
Informed Consent Process 
Informed consent will be administered by members of the study team. To ensure privacy, 
the screening, enrollment, and informed consent process will take place in a patient exam room, 
study investigator/team member’s private office, other private clinical space, or over the phone if 
the patient cannot be met in person immediately following their preoperative visit. This will 
ensure privacy during open discussion.  
A verbal explanation will be provided in terms suited to the participant’s comprehension 
of the purposes, procedures, and potential risks of the study and of their rights as research 
participants. Questions will be solicited and answered.  
Since we believe that this study represents no more than minimal risk to the subjects, 
there will be no required waiting period between informed consent, enrollment, and participation 

 
 
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in the study. Since the intervention of the study involves only randomization between two 
standard of care drugs and completion of questionnaires, we believe that there is minimal risk of 
coercion or undue influence. Participants will however have the opportunity to carefully review 
the written consent form and ask questions prior to signing. The participants will also be allowed 
to delay signing consent form to discuss the study with their family or surrogates or think about 
it prior to agreeing to participate. The rights and welfare of the participants will be protected by 
emphasizing to them that the quality of their medical care will not be adversely affected if they 
decline to participate in this study. The informed consent process will be conducted, 
documented, and the form signed, before the participant undergoes any study-specific 
procedures.   
Consent will be given electronically using the secure platform REDCap for participants 
who enroll in person after their pre-op visit. Participants will have time to review the electronic 
consent form on the computer prior to signing electronically. They will receive a copy of their 
signed consent form. Some participants may be contacted via phone for screening and enrollment 
after their visit and will be emailed a link to REDCap to provide electronic consent and receive a 
signed copy of their consent form. For participants who are not able to give electronic consent a 
paper copy will be used. 
10.3 
Confidentiality and Privacy 
Participant confidentiality and privacy is strictly held in trust by all study personnel. The 
study protocol, documentation, data, and all other information generated will be held in strict 
confidence. No information concerning the study or the data will be released to any unauthorized 
third party without prior written approval of the PI and IRB. 
10.3.1 
Data Collection, Handling, and Management 
Data collection is the responsibility of the clinical trial staff at the site under the 
supervision of the site PI. The site PI is responsible for ensuring the accuracy, completeness, 
legibility, and timeliness of the data reported.  
Source data include data from the questionnaires (which includes demographic 
information as well as participant reported outcomes) as well as data abstracted from the medical 
record and hospital pharmacy. Data will be stored, managed, and analyzed on a secure, encrypted 
server behind the University of Pennsylvania Health System (UPHS) firewall. Data from the 
questionnaires will be captured directly through the HIPAA complaint REDCap service housed 
at the University of Pennsylvania (http://www.med.upenn.edu/scrcm/redcap.html), either by the 
participant directly entering their responses into REDCap or by study personnel completing a 
phone interview and recording participant responses directly into REDCap. Additional data 
captured by review of epic medical chart and pharmacy records will also be entered directly into 
REDCap by study personnel. All research activities including chart review and phone interviews 
will be conducted in as private a setting as possible.  
All study personnel that will use this data are listed on the IRB application and have 
completed training in HIPAA standards and the CITI human subjects research. Data access will 

 
 
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be password protectedand only study team members will have access to the REDCap database. 
Participants are given a unique number in REDCap for linkage. If data is shared with outside 
researchers, data will be de-identified by standard REDCap procedure for removing personal 
identifiers. 
If plans to add additional sites arise, a Data Use Agreement will be executed between the 
University of Pennsylvania and any participating sites. All outside sites will be given access to 
the site-specific REDCap data access group. Participating sites will be asked to share data with 
the central site investigator for data collection and analysis.  
10.3.2 
Protected Health Information 
We plan to collect he following PHI from subjects: 
1. Name 
2. Birth date 
3. Address 
4. Telephone number 
5. Electronic mail addresses 
6. Medical record numbers 
7. Medical comorbidities 
8. Sex assigned at birth, gender 
10.3.3 
Study Records Retention and Future Use of Data 
All study records will be retained in REDCap for future use in research projects 
conducted within the division of Urology. This may include sub-analyses to inform possible 
future projects, or use of this trial as a pilot to be expanded into a larger study with greater power 
to analyze some of the secondary, tertiary, and safety/efficacy outcomes. Any future use will be 
limited to within the Penn division of Urology. Subjects will have the option to elect out of the 
storage of the PHI elements for future use. 
10.4 
Adverse Events 
The medical complication rate after radical cystectomy is relatively high; it has been 
reported around 60% for all complications and 30% for Common Terminology Criteria for 
Adverse Events (CTCAE) Grade 3 complications in the first 90 days postoperatively.37 
Therefore the vast majority of adverse events in this study are expected and have no plausible 
relation to VTE prophylaxis with either enoxaparin or apixaban. The known risks of enoxaparin 
and lovenox are defined on the drug labels 
The study goal is to evaluate VTE and bleeding events.These will be specifically and 
directly solicited from participants at the study visits as a well as screened for in patients who do 
not directly report events. Patients will be referred to their treating provider for management. See 
section 7.4 for further detail on the screening for and management of VTE and bleeding events.  
Additional adverse events will be screened for during telephone calls at POD 30 and POD 
90. The AE assessment period will start when participants are discharged as this coincides with 

 
 
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the start of the study intervention. Adverse events are classified as serious or non-serious. A 
serious adverse event is any AE that, in the view of the investigator, is: 
• fatal 
• life-threatening 
• requires or prolongs hospital stay 
• results in persistent or significant disability or incapacity 
SAEs discovered in telephone calls will be immediately referred to a study investigator, who will 
review the event, possibly contact the participant to ensure they are referred to an appropriate 
level of immediate management, and notify the participant’s treating clinician for any further 
management. The SAE form will be completed, including start and stop date, description, and 
grade according to the CTCAE version 5 (full guideline: 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5_Quick_R
eference_8.5x11.pdf): 
Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; 
intervention not indicated.  
Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age appropriate 
instrumental ADL.  
Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self care ADL.  
Grade 4 Life-threatening consequences; urgent intervention indicated.  
Grade 5 Death related to AE. 
AEs will also be categorized by their possible relatedness to the VTE prophylaxis as follows: 
1. 
Definitely Related – There is clear evidence to suggest a causal relationship, and other 
possible contributing factors can be ruled out. The clinical event, including an abnormal 
laboratory test result, occurs in a plausible time relationship to prophylactic anticoagulant 
administration and cannot be explained by concurrent disease or other drugs or 
chemicals. The response to withdrawal of the prophylactic anticoagulant should be 
clinically plausible.  
2. 
Probably Related – There is evidence to suggest a causal relationship, and the influence 
of other factors is unlikely. The clinical event, including an abnormal laboratory test 
result, occurs within a reasonable time after administration of the prophylactic 
anticoagulant is unlikely to be attributed to concurrent disease or other drugs or 
chemicals, and follows a clinically reasonable response on withdrawal (dechallenge).  
3. 
Possibly Related – There is some evidence to suggest a causal relationship (e.g., the event 
occurred within a reasonable time after administration of the prophylactic anticoagulant). 

 
 
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However, other factors may have contributed to the event (e.g., the participant’s clinical 
condition, other concomitant events).  
4. 
Unlikely to be related – A clinical event, including an abnormal laboratory test result, 
whose temporal relationship to prophylactic anticoagulant administration makes a causal 
relationship improbable (e.g., the event did not occur within a reasonable time after 
administration of the prophylactic anticoagulant) and in which other drugs or chemicals 
or underlying disease provides plausible explanations (e.g., the participant’s clinical 
condition, other concomitant treatments). 
5. 
Unrelated – The AE is completely independent of prophylactic anticoagulant 
administration, and/or evidence exists that the event is definitely related to another 
etiology. There must be an alternative, definitive etiology documented by the clinician. 
AEs will be categorized as at least “Possibly Related” (or “Probably” or “Definitely”) if the AE 
is listed as a possible event on the applicable drug label. Any SAEs or events that are bothrelated 
to participation in the trial (“Possibly” or higher) and also unexpected in terms of their nature or 
severity such that it suggests that the research places subjects or others at a greater risk of harm 
than was previously known will be reported to the IRB for further review. 
10.5 
Medical Monitor 
The study will assign a Medical Monitor (MM) for approval by the Clinical Trials 
Scientific Review and Monitoring Committee. The Medical Monitor will be tasked with 
monitoring the adverse events captured in this study (see previous section 10.4). They will have 
access to all study data for their review including access to adverse event forms, PHI and patient 
medical charts, drug labels, study questionnaires, and study protocol. 
 
The Medical Monitor will be either an internal or external expert however they will not 
be a collaborator with the PI. They will not be compensated. The MM may resign from this role 
at his/her discretion. A thirty-day notification should be provided to the PI to allow for a 
replacement MM to be appointed.  
 
The MM will have the authority to request a study hold or discontinuation. The MM may 
also at his/her discretion report information to and/or consult with other institutional oversight 
committees such as the University of Pennsylvania IRB when there are significant concerns 
about research safety and/or integrity. The MM is responsible for contacting the appropriate 
committee with any concerns related to his/her role as MM.  
10.6 
Unanticipated Problems 
Beyond medical complications, any event or incident during the trial that is unexpected in 
nature and severity, possibly related to the trial, and suggests that the research places participants 
or others at a greater risk of harm (including physical, psychological, economic, or social harm) 
than was previously recognized will be considered an “Unanticipated Problem” and will be 
reported to the IRB as soon as it is recognized. Complete cooperation with the IRB and any other 
regulatory bodies thereafter will be supplied.  

 
 
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10.7 
Compensation 
Participants at the University of Pennsylvania will be given a $20 Greenphire ClinCard, 
either electronic or physically mailed based on patient preference, at the completion of the 
study as a gesture of thanks for their time in participating. Receipt is contingent only on 
completing both study visits. This effort is supported by the American Urologic Association 
Resident Research Award. 
 
 
11 REFERENCES 
 
1. 
Peipert JD, Badawy SM, Baik SH, et al. Development of the NIH Patient-Reported 
Outcomes Measurement Information System (PROMIS) Medication Adherence Scale 
(PMAS). Patient Prefer Adherence. 2020;14:971-983. 
2. 
de Souza JA, Yap BJ, Wroblewski K, et al. Measuring financial toxicity as a clinically 
relevant patient-reported outcome: The validation of the COmprehensive Score for financial 
Toxicity (COST). Cancer. 2017;123(3):476-484. 
3. 
Quek ML, Stein JP, Daneshmand S, et al. A critical analysis of perioperative mortality from 
radical cystectomy. J Urol. 2006;175(3 Pt 1):886-889; discussion 889-90. 
4. 
Caprini JA, Botteman MF, Stephens JM, et al. Economic burden of long-term complications 
of deep vein thrombosis after total hip replacement surgery in the United States. Value 
Health. 2003;6(1):59-74. 
5. 
Alberts BD, Woldu SL, Weinberg AC, Danzig MR, Korets R, Badani KK. Venous 
thromboembolism after major urologic oncology surgery: a focus on the incidence and 
timing of thromboembolic events after 27,455 operations. Urology. 2014;84(4):799-806. 
6. 
De Martino RR, Goodney PP, Spangler EL, et al. Variation in thromboembolic 
complications among patients undergoing commonly performed cancer operations. J Vasc 
Surg. 2012;55(4):1035-1040.e4. 
7. 
Tikkinen KAO, Craigie S, Agarwal A, et al. Procedure-specific Risks of Thrombosis and 
Bleeding in Urological Non-cancer Surgery: Systematic Review and Meta-analysis. Eur 
Urol. 2018;73(2):236-241. 
8. 
Abdullah O, Parashar D, Mustafa IJ, Young AM. Venous Thromboembolism Rate in 
Patients With Bladder Cancer According to the Type of Treatment: A Systematic Review. 
Cureus. 2022;14(3):e22945. 

 
 
Protocol 854199 – CARE 
 
Page 28 of 30 
 
 
 
9. 
Sun AJ, Djaladat H, Schuckman A, Miranda G, Cai J, Daneshmand S. Venous 
thromboembolism following radical cystectomy: significant predictors, comparison of 
different anticoagulants and timing of events. J Urol. 2015;193(2):565-569. 
10. VanDlac AA, Cowan NG, Chen Y, et al. Timing, incidence and risk factors for venous 
thromboembolism in patients undergoing radical cystectomy for malignancy: a case for 
extended duration pharmacological prophylaxis. J Urol. 2014;191(4):943-947. 
11. James AC, Holt SK, Wright JL, Porter MP, Gore JL. Burden and timing of venothrombolic 
events in patients younger than 65 years undergoing radical cystectomy for bladder cancer. 
Urol Oncol. 2014;32(6):815-819. 
12. Doiron RC, Booth CM, Wei X, Siemens DR. Risk factors and timing of venous 
thromboembolism after radical cystectomy in routine clinical practice: a population-based 
study. BJU Int. 2016;118(5):714-722. 
13. Felder S, Rasmussen MS, King R, et al. Prolonged thromboprophylaxis with low molecular 
weight heparin for abdominal or pelvic surgery. Cochrane Database Syst Rev. 
2018;11:CD004318. 
14. Pariser JJ, Pearce SM, Anderson BB, et al. Extended Duration Enoxaparin Decreases the 
Rate of Venous Thromboembolic Events after Radical Cystectomy Compared to Inpatient 
Only Subcutaneous Heparin. J Urol. 2017;197(2):302-307. 
15. Schomburg J, Krishna S, Soubra A, et al. Extended outpatient chemoprophylaxis reduces 
venous thromboembolism after radical cystectomy. Urol Oncol. 2018;36(2):77.e9-77.e13. 
16. K.A.O. Tikkinen, R. Cartwright, M.K. Gould, R. Naspro, G. Novara, P.M. Sandset, P.D. 
Violette, G.H. Guyatt. Thromboprophylaxis. Uroweb - European Association of Urology. 
Accessed December 12, 2022. 
https://uroweb.org/guidelines/thromboprophylaxis/chapter/introduction 
17. Lyon TD, Shah ND, Tollefson MK, et al. Trends in Extended-Duration Venous 
Thromboembolism Prophylaxis Following Radical Cystectomy. Urology. 2020;136:105-
111. 
18. Dall CP, Shaw N, Egan J, et al. Practice patterns for extended venous thromboembolism 
chemoprophylaxis among urologic oncologists after radical cystectomy. Urol Oncol. 
2020;38(11):849.e19-849.e23. 
19. Dall* C, Shaw N, Egan J, Carvalho F, Krasnow R, Stamatakis L. PD60-06 PRACTICE 
PATTERNS FOR EXTENDED VTE CHEMOPROPHYLAXIS AMONG UROLOGIC 
ONCOLOGISTS. J Urol. Published online 2020. doi:10.1097/JU.0000000000000977.06 

 
 
Protocol 854199 – CARE 
 
Page 29 of 30 
 
 
 
20. Griffiths CD, Simunovic M, Gafni A, Parpia S, Linkins LA, Serrano PE. Posthospital 
discharge venous thromboembolism prophylaxis among colorectal and hepatobiliary 
surgeons: A practice survey. Surgery. 2021;170(1):173-179. 
21. Guntupalli SR, Brennecke A, Behbakht K, et al. Safety and Efficacy of Apixaban vs 
Enoxaparin for Preventing Postoperative Venous Thromboembolism in Women Undergoing 
Surgery for Gynecologic Malignant Neoplasm: A Randomized Clinical Trial. JAMA Netw 
Open. 2020;3(6):e207410. 
22. Lassen MR, Raskob GE, Gallus A, et al. Apixaban versus enoxaparin for 
thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind 
trial. Lancet. 2010;375(9717):807-815. 
23. Faraj KS, Durant A, Mauler D, et al. Extended anticoagulation after radical cystectomy 
using direct acting oral anticoagulants: A single-institutional experience. Urol Pract. 
2022;9(5):451-458. 
24. Ortiz RM, Golijanin B, O’Rourke TK, et al. Direct Oral Anticoagulants for Venous 
Thromboembolism Prophylaxis Following Robot-assisted Radical Cystectomy: A 
Retrospective Feasibility Study at a Single Academic Medical Center. Urology. 
2021;156:154-162. 
25. Rosen G, Anwar T, Syed J, et al. Initial Experience with Apixaban for Extended Venous 
Thromboembolism Prophylaxis After Radical Cystectomy. Eur Urol Focus. 2022;8(2):480-
482. 
26. Apixaban vs Enoxaparin for Post-Surgical Extended-Duration Venous Thromboembolic 
Event Prophylaxis: A Prospective Quality Improvement Study. 
doi:10.1097/JU.0000000000002788 
27. Schulman S, Carlson V, Serrano PE, et al. Adherence to apixaban for extended 
thromboprophylaxis after major abdominal or pelvic surgery for cancer: A prospective 
cohort study. J Surg Oncol. 2022;126(2):386-393. 
28. Wiznia DH, Swami N, Nguyen J, et al. Patient compliance with deep vein thrombosis 
prophylaxis after total hip and total knee arthroplasty. Hematol Rep. 2019;11(2):7914. 
29. Subramaniam S, Aalberg JJ, Soriano RP, Divino CM. New 5-Factor Modified Frailty Index 
Using American College of Surgeons NSQIP Data. J Am Coll Surg. 2018;226(2):173-
181.e8. 
30. Sathianathen NJ, Jarosek S, Lawrentschuk N, Bolton D, Konety BR. A Simplified Frailty 
Index to Predict Outcomes After Radical Cystectomy. Eur Urol Focus. 2019;5(4):658-663. 

 
 
Protocol 854199 – CARE 
 
Page 30 of 30 
 
 
 
31. Taylor BL, Xia L, Guzzo TJ, Scherr DS, Hu JC. Frailty and Greater Health Care Resource 
Utilization Following Major Urologic Oncology Surgery. Eur Urol Oncol. 2019;2(1):21-27. 
32. Schulman S, Angerås U, Bergqvist D, et al. Definition of major bleeding in clinical 
investigations of antihemostatic medicinal products in surgical patients. J Thromb Haemost. 
2010;8(1):202-204. 
33. Kaatz S, Ahmad D, Spyropoulos AC, Schulman S, Subcommittee on Control of 
Anticoagulation. Definition of clinically relevant non-major bleeding in studies of 
anticoagulants in atrial fibrillation and venous thromboembolic disease in non-surgical 
patients: communication from the SSC of the ISTH. J Thromb Haemost. 2015;13(11):2119-
2126. 
34. Lemke M, Beyfuss K, Hallet J, Coburn NG, Law CHL, Karanicolas PJ. Patient Adherence 
and Experience with Extended Use of Prophylactic Low-Molecular-Weight Heparin 
Following Pancreas and Liver Resection. J Gastrointest Surg. 2016;20(12):1986-1996. 
35. Marchocki Z, Norris L, O’Toole S, Gleeson N, Saadeh FA. Patients’ experience and 
compliance with extended low molecular weight heparin prophylaxis post-surgery for 
gynecological cancer: a prospective observational study. Int J Gynecol Cancer. Published 
online April 16, 2019. doi:10.1136/ijgc-2019-000284 
36. Chow SC, Shao J, Wang H, Lokhnygina Y. Sample Size Calculations in Clinical Research 
3rd Edition. Chapman and Hall; 2017. 
37. Hautmann RE, de Petriconi RC, Volkmer BG. Lessons learned from 1,000 neobladders: the 
90-day complication rate. J Urol. 2010;184(3):990-994; quiz 1235. 
 
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