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Venous thromboembolism rates following radical cystectomy stratified by method of prophylaxis

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Venous thromboembolism rates following radical cystectomy stratified by method of prophylaxis

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Content 1
Title Page

Title: Venous Thromboembolism Rates Following Radical Cystectomy Stratified by Method of
Prophylaxis

Authors: Cory M Hugen, Alexander Stern, Jie Cai, Gus Miranda, Anne Schuckman, Hooman
Djaladat, Siamak Daneshmand

Conferring Major/Program: Master of Science (CLINICAL AND BIOMEDICAL INVESTIGATIONS)

Degree Conferral Date: December 2017

Academic Affiliation for Authors:

University of Southern California
Norris Comprehensive Cancer Center
Institute of Urology
1441 Eastlake Ave Suite 7416
Los Angeles, CA 90033

2
Table of Contents

I. Abstract – Page 3

II. Introduction – Page 4

III. Patients and Methods – Page 4

IV. Results – Page 5

V. Discussion – Page 6

VI. Conclusion – Page 8

VII. References – Page 8

VIII. Table 1 – Page 10

IX. Table 2 – Page 11

X. Table 3 – Page 12

XI. Table 4 – Page 13

3
Abstract

Objectives
To evaluate whether extended duration venous thromboembolism (VTE) prophylaxis decreased
rates of symptomatic VTE compared to warfarin or perioperative subcutaneous heparin in
patients who underwent radical cystectomy in a real world non-trial setting.

Patients and Methods
Patients who underwent radical cystectomy at our institution between 1985-2015 were
identified. VTE events and complications were tabulated and rates were compared by era of
VTE prophyalxis. Multivariable logistic regression was used to identify predictors of VTE.

Results
2694 patients underwent radical cystectomy and VTEs occurred in 112 (4.16%) at a median of
19 days post-operatively. There were no differences in VTE rates by era of prophylaxis (p=0.87).
Multivariable logistic regression identified age (OR=1.027), BMI (OR=1.073), hospital length of
stay (OR=1.036), and non-orthotopic urinary diversion (OR=0.456) as predictors for VTE.

90-day complication rates varied significantly between warfarin (37.1%), heparin (67.6%), and
extended duration (75.4%) groups (p=<0.0001). Bleeding rates were higher in the extended
duration era (14.8% vs 6.7%, p=0.0001) which was almost entirely accounted for by increased
post-operative transfusions given prior to the administration of enoxaparin. Lymphocele rates
were higher in the extended duration era (3.89% vs 1.05%, p=0.001). There were no
differences in VTE rates when stratified by open vs robotic approach (p=0.25).

Conclusion
VTE rates following radical cystectomy did not significantly differ in patients using warfarin, in-
house SQ heparin, or extended duration prophylaxis.

4
Introduction
Venous thromboembolism (VTE), consisting of deep venous thrombosis (DVT) and pulmonary
embolus (PE), is a serious complication following radical cystectomy. VTE remains a common
cause of morbidity and mortality and is routinely cited as the most common cause of death
following radical cystectomy(1, 2). Evidence demonstrates that using perioperative heparin
prophylaxis can decrease VTE rates by approximately 50%(3). However, despite the widespread
implementation of both mechanical and pharmacologic preventive measures, nearly 32% of
urologists in the United States who responded to a survey reported no use of pharmacologic
prophylaxis in high risk patients undergoing radical cystectomy(4).

While prior strategies focused on preventing VTE during the post-operative hospitalization
period, multiple studies have demonstrated most VTE events occur after the patient has been
discharged from the hospital(5-8). Additionally, VTE rates have increased while VTE lethality
has decreased possibly secondary to increased education and recognition of VTE following
surgery(9).

One prevention strategy that has been studied using randomized controlled trials is providing
patients with prophylactic dosed enoxaparin following discharge from the hospital. This
strategy, commonly referred to as extended duration dosing, has been shown in two systematic
reviews to decrease overall rates of VTE without increased risk of post-operative bleeding(10-
12) in patients treated with abdominal or pelvic surgery for cancer. However, there was also no
difference in PE rates(11, 12) or all cause mortality(11).

We have previously reviewed our institutional practice by era utilizing warfarin (1971-2007) vs
subcutaneous heparin (2009-2012) and reported no difference in VTE rates(8). Starting in 2013,
our institutional practice changed again and we began treating patients with extended duration
prophylaxis for a total of 30 days post-operatively. The purpose of this study is to evaluate
whether extended duration VTE prophylaxis decreased rates of symptomatic VTE compared to
warfarin or perioperative subcutaneous heparin in patients who underwent radical cystectomy
in a real world non-trial setting. Additionally, we evaluated whether the use of extended
duration prophylaxis was associated with increased complication rates and identified predictors
of VTE.

Patients and Methods

We queried our IRB approved bladder cancer database to identify all patients who underwent
radical cystectomy from 1985-2015. We divided patients into three eras based on the type of
VTE pharmacologic prophylaxis administered. During the first era, our institutional database
was retrospectively maintained, while during the latter two eras data were prospectively
collected by a single dedicated database manager. VTE events were defined as any DVT, PE, or
both within 90 days of surgery that presented symptomatically and confirmed with imaging.
Routine screening for VTE was not performed. Missing data were managed using complete
case analysis.

5
VTE pharmacologic prophylaxis consisted of three different regimens as determined by
institutional practice. From 1985-2007 warfarin was utilized whereby a 10mg dose was
administered in the recovery room and continued daily until discharge. The dose was titrated
to an international normalized ratio (INR) goal of 2.0-3.0. Starting in 2008, unfractionated
subcutaneous (SQ) heparin was utilized and 5000u were administered 2-3x daily starting on
post-operative day 1 and continued while the patient was hospitalized. In 2012, our
institutional practice changed again to include a preoperative dose of 5000u SQ heparin,
continued every 8-hours post-operatively, and added extended duration prophylaxis consisting
of daily 40mg SQ enoxaparin starting at hospital discharge (median 4 days post-operatively) and
continued at home until the 30
th
post-operative day. To account for changing institutional
practices, we excluded patients during periods of transition from warfarin to heparin (in 2008)
and from heparin to extended duration prophylaxis (in 2012) from our analysis to account for
potential overlap.

We calculated rates of DVT and PE and compared these rates for patients treated with warfarin,
SQ heparin, and extended duration dosing. Overall 90-day complication rates and individual
complications including bleeding, lymphocele, wound infection, post-operative transfusion
were compared between eras. A bleeding event was defined as any active bleed, hematoma,
or receipt of any post-operative transfusion. Lymphoceles were diagnosed by CT scan and
wound infections were diagnosed clinically. We then performed a multivariable regression
analysis to identify predictors of VTE. Pearson chi-square or Fisher exact test were used to
identify risk factors for VTE and the Kruskal-Wallis test was used for non-parametric or ordinal
variables. A multivariable logistic regression was performed to identify significant predictors of
VTE and compare prophylaxis eras. All reported p-values are two sided. SASâ 9.2 (Cary, NC)
was used for analyses.

Results

A total of 2694 patients underwent radical cystectomy with urinary diversion between 1985-
2015. Symptomatic VTE occurred in 112 (4.16%) patients at 90 days post-operatively with 62
(2.3%) PE and 57 (2.12%) DVT events recorded. VTE events occurred at a median of 19 days
following surgery demonstrating the majority of VTE events occurred after the patient was
discharged from the hospital.

The overall VTE rate, as shown in Table 2, was not significantly different when stratified by
prophylactic era (p=0.87). Similarly, no significant difference was detected in rate of PE
(p=0.69) or DVT (p=0.85) by era.

Multivariable logistic regression identified age, BMI, non-orthotopic urinary diversion and HLOS
as significant predictors for developing a VTE (Table 3). Notably, neither the SQ Heparin nor the
extended duration era were found to be independent predictors of VTE. The median operative
time was 6 hours (IQR 5-7) both for patients who did and did not develop a VTE.

6
Complication rates varied significantly by era. 30-day complication rates were 30.5%, 57.7%
and 58.6% for the warfarin, heparin, and heparin + enoxaparin groups (p=<0.0001). The 90-day
complication rates were also significantly different for the warfarin, heparin, and heparin +
enoxaparin groups of 37.1%, 67.6%, and 75.4%, respectively (p=<0.0001).

A comparison of the heparin and extended duration prophylaxis eras is shown in Table 4. The
overall 90-day complication rates varied significantly between the heparin and extended
duration groups (p=0.01). Additionally, there were significant differences between eras in
bleeding rates, rates of transfusion, and lymphoceles.

There were no significant differences in VTE, PE, or DVT at 90 days when stratified by open vs
robotic surgery in these two eras (p=0.25, 0.18, and 1.0 respectively). Patients who underwent
open surgery experienced a significantly decreased overall complication rate at 90 days (68.6%
vs 78.8%) compared with robotic surgery (p=0.004). There were no significant differences in
the rates of lymphocele, wound infection, bleeding, or transfusion requirements between these
groups.

Discussion

VTE following radical cystectomy is an infrequent yet potentially devastating complication. Our
data demonstrate no significant differences in the rates of overall VTE, PE, or DVT in patients
undergoing radical cystectomy who received VTE prophylaxis with either warfarin, in hospital
SQ heparin, or in hospital SQ heparin along with extended duration prophylaxis with
enoxaparin. Additionally, there were no differences in VTE rates between patients who
underwent open vs robotic cystectomy.

These results differ from a recently published retrospective study from Pariser, et al(13) who
showed decreased VTE rates in radical cystectomy patients treated with extended duration VTE
prophylaxis compared with patients treated with standard duration prophylaxis. One
explanation for the discrepancy between these studies could be related to the relatively high
VTE rate reported by Pariser prior to implementing extended duration prophylaxis as the
authors acknowledge in their publication. Our VTE rate is similar to multiple other reports(5,
14, 15) and has remained remarkably stable over the past 30 years regardless of VTE
prophylaxis method.

Our results also differ from two meta-analyses of studies of patients undergoing abdominal or
pelvic surgery for cancer(10, 11). This difference could be due to the heterogeneity of patients
included in the randomized trials, ie colorectal cancer where lymphadenectomy is not
performed. Alternatively, the retrospective nature of our study may not accurately reflect the
true VTE rate in our patient population. Interestingly, a separate systematic review and meta-
analysis from Guo, et al(12) did not show any difference in the rates of PE or bleeding between
patients administered standard vs extended duration VTE prophylaxis, however, there was a
7
decrease in the rate of DVT highlighting the importance patient inclusion criteria and surgery
type.

There was a significant increase in the overall 90-day complication rate between patients
receiving heparin vs extended-duration for VTE prophylaxis. This increase rate is largely due to
the increased rate of post-operative transfusion in the patients receiving extended duration
prophylaxis and to a lesser degree to the increased rate of lymphocele. While the post-
operative transfusion rate is certainly higher in the extended duration cohort, it is almost
certainly not related to use of extended duration enoxaparin as this is not administered until
the patient is discharged and its use would not be reflected in the in-hospital post-operative
transfusion rate. A more plausible explanation for the increased post-operative transfusion
rate detected in the extended duration cohort could be due to a more restrictive intraoperative
transfusion protocol that was implemented during this time period(16) which likely resulted in
increased post-operative transfusions. It should be noted there were no increases in GI bleeds,
active hemorrhage, or pelvic hematomas in the extended duration prophylaxis era compared
with the other two eras.

We also identified clinical predictors for the development of VTE, namely age, BMI, HLOS, and
non-orthotopic urinary diversion. While the first three factors could be expected based on
prior studies and associations with known risk factors for VTE, the effect of a non-orthtopic
urinary diversion was an unexpected finding. We are unaware of an obvious explanation for
this finding and may warrant further investigation.

Several limitations exist in our study inherent to all single-institution retrospective studies.
These limitations are clearly demonstrated in the overall 90-day complication rate which more
than doubled from the earliest to most recent cohorts likely reflecting better and more
stringent reporting in the more recent cohorts. However, the rate of VTE remained stable
during the 30 years reported in the study demonstrating that at least this parameter was likely
accurately reported, particularly since symptomatic VTE’s are generally well documented and
captured in databases given the physical examination and radiological findings, as well as
therapeutic medicinal administration. Another limitation in our study is the lack of formal
documented compliance with extended duration prophylaxis. While patients who experienced
a VTE event invariably stated they were compliant with prophylaxis, this was not routinely
documented in this cohort. Conversely, our cohort likely reflects the compliance and results
one would achieve in a non-trial setting and is likely high given the limited duration required
using an injectable medication in a group of motivated immediate post-operative patients.
Finally, while we recognize individual surgeons can have varying rates of VTE, there are too
many inter-related factors to include as a separate variable in our multivariable regression
model and therefore was excluded.

The strengths of our study include large patient cohorts treated with a consistent VTE
prophylaxis protocol as well as our detailed prospectively maintained cystectomy database
using a short-term outcome. Additionally, as opposed to the randomized trial data referenced
8
in this paper which includes a heterogeneous surgical population, our data may better reflect
the real-world outcomes expected following radical cystectomy.

Our data do not demonstrate superiority of extended duration VTE prophylaxis compared with
prior prophylactic regimens at our institution. A randomized trial in cystectomy patients might
demonstrate extended duration prophylaxis is beneficial, however, whether equipoise exists
considering the results from previous trials remains unknown.

Conclusion:
VTE rates following radical cystectomy did not significantly differ in patients using warfarin, in-
house SQ heparin, or extended duration prophylaxis.

References

1. Agnelli G, Bolis G, Capussotti L, Scarpa RM, Tonelli F, Bonizzoni E, et al. A clinical
outcome-based prospective study on venous thromboembolism after cancer surgery: the
@RISTOS project. Annals of surgery. 2006;243(1):89-95.
2. Schiavina R, Borghesi M, Guidi M, Vagnoni V, Zukerman Z, Pultrone C, et al.
Perioperative complications and mortality after radical cystectomy when using a standardized
reporting methodology. Clinical genitourinary cancer. 2013;11(2):189-97.
3. Gould MK, Garcia DA, Wren SM, Karanicolas PJ, Arcelus JI, Heit JA, et al. Prevention of
VTE in nonorthopedic surgical patients: Antithrombotic Therapy and Prevention of Thrombosis,
9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest.
2012;141(2 Suppl):e227S-77S.
4. Sterious S, Simhan J, Uzzo RG, Gershman B, Li T, Devarajan K, et al. Familiarity and self-
reported compliance with American Urological Association best practice recommendations for
use of thromboembolic prophylaxis among American Urological Association members. The
Journal of urology. 2013;190(3):992-8.
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. 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):714-22.
7. VanDlac AA, Cowan NG, Chen Y, Anderson RE, Conlin MJ, La Rochelle JC, et al. Timing,
incidence and risk factors for venous thromboembolism in patients undergoing radical
cystectomy for malignancy: a case for extended duration pharmacological prophylaxis. The
Journal of urology. 2014;191(4):943-7.
8. 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. The Journal of urology. 2015;193(2):565-9.
9
9. Trinh VQ, Karakiewicz PI, Sammon J, Sun M, Sukumar S, Gervais MK, et al. Venous
thromboembolism after major cancer surgery: temporal trends and patterns of care. JAMA
surgery. 2014;149(1):43-9.
10. Rasmussen MS, Jorgensen LN, Wille-Jorgensen P. Prolonged thromboprophylaxis with
low molecular weight heparin for abdominal or pelvic surgery. The Cochrane database of
systematic reviews. 2009(1):Cd004318.
11. Fagarasanu A, Alotaibi GS, Hrimiuc R, Lee AY, Wu C. Role of Extended
Thromboprophylaxis After Abdominal and Pelvic Surgery in Cancer Patients: A Systematic
Review and Meta-Analysis. Annals of surgical oncology. 2016;23(5):1422-30.
12. Guo Q, Huang B, Zhao J, Ma Y, Yuan D, Yang Y, et al. Perioperative Pharmacological
Thromboprophylaxis in Patients With Cancer: A Systematic Review and Meta-analysis. Annals of
surgery. 2016.
13. Pariser JJ, Pearce SM, Anderson BB, Packiam VT, Prachand VN, Smith ND, et al. Extended
Duration Enoxaparin Decreases the Rate of Venous Thromboembolic Events after Radical
Cystectomy Compared to Inpatient Only Subcutaneous Heparin. The Journal of urology.
2017;197(2):302-7.
14. Tyson MD, Castle EP, Humphreys MR, Andrews PE. Venous thromboembolism after
urological surgery. The Journal of urology. 2014;192(3):793-7.
15. Zareba P, Patterson L, Pandya R, Margel D, Hotte SJ, Mukherjee SD, et al.
Thromboembolic events in patients with urothelial carcinoma undergoing neoadjuvant
chemotherapy and radical cystectomy. Urologic oncology. 2014;32(7):975-80.
16. Syan-Bhanvadia S, Drangsholt S, Shah S, Cai J, Miranda G, Djaladat H, et al. Restrictive
transfusion in radical cystectomy is safe. Urologic oncology. 2017.

10

Table 1: Demographics
Median Age (IQR) 68 (61-75)
Gender (%)
Female 552 (20.5)
Male 2142 (79.5)
Median HLOS (IQR) 10 (7-11)
Median EBL mL (IQR) 858 (450-1050)
Median BMI (IQR) 27 (24-30)
No. Smoking (%)
Yes 2020 (75.0)
No 720 (25.0)
Neoadjuvant
chemotherapy (%)
431 (16.0)
No. Diversion (%)
Orthotopic 1694 (62.9)
Non-orthotopic 1000 (37.1)
No. Lymph node + (%) 660 (24.5)
No. Surgical Margin + (%) 131 (4.9)
No. Anticoagulant (%)
Warfarin 1805 (67%)
Heparin 478 (17.7)
Heparin + Enoxaparin 411 (15.3)

11
Table 2. Comparison of VTE by Prophylactic Era
No. VTE (%) No. PE (%) No. DVT (%)
Warfarin 76 (4.21) 43 (2.38) 38 (2.11)
Heparin 21 (4.39) 12 (2.51) 9 (1.88)
Heparin + Enoxaparin 15 (3.64) 7 (1.7) 10 (2.43)

p-value 0.87 0.69 0.84

12
Table 3: Multivariable Logistic Regression
Odds Ratio 95% CI
Age 1.027 1.003-1.051
BMI 1.073 1.034-1.113
Heparin 1.058 0.618-1.809
Heparin + Enoxaparin 1.067 0.571-1.993
HLOS 1.036 1.011-1.064
Non-orthotopic urinary
diversion
0.456 0.261-0.794

13
Table 4. 90-Day Complication Rates Comparing Heparin vs Heparin +Enoxaparin Cohorts
90-day
Complication (%)
Bleeding % Lymphocele
%
Wound
Infection
Post-op
Transfusion
(%)

Heparin 67.6 6.7 1.05 4.18 6.38
Heparin +
Enoxaparin
75.4 14.8 3.89 2.68 14.8

p-value 0.0115 0.0001 0.0068 0.27 <0.0001

Abstract (if available)

Abstract Objectives: To evaluate whether extended duration venous thromboembolism (VTE) prophylaxis decreased rates of symptomatic VTE compared to warfarin or perioperative subcutaneous heparin in patients who underwent radical cystectomy in a real world non-trial setting. ❧ Patients and Methods: Patients who underwent radical cystectomy at our institution between 1985-2015 were identified. VTE events and complications were tabulated and rates were compared by era of VTE prophyalxis. Multivariable logistic regression was used to identify predictors of VTE. ❧ Results: 2694 patients underwent radical cystectomy and VTEs occurred in 112 (4.16%) at a median of 19 days post-operatively. There were no differences in VTE rates by era of prophylaxis (p=0.87). Multivariable logistic regression identified age (OR=1.027), BMI (OR=1.073), hospital length of stay (OR=1.036), and non-orthotopic urinary diversion (OR=0.456) as predictors for VTE. ❧ 90-day complication rates varied significantly between warfarin (37.1%), heparin (67.6%), and extended duration (75.4%) groups (p=<0.0001). Bleeding rates were higher in the extended duration era (14.8% vs 6.7%, p=0.0001) which was almost entirely accounted for by increased post-operative transfusions given prior to the administration of enoxaparin. Lymphocele rates were higher in the extended duration era (3.89% vs 1.05%, p=0.001). There were no differences in VTE rates when stratified by open vs robotic approach (p=0.25). ❧ Conclusion: VTE rates following radical cystectomy did not significantly differ in patients using warfarin, in-house SQ heparin, or extended duration prophylaxis.

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Asset Metadata

Creator Hugen, Cory Michael (author)

Core Title Venous thromboembolism rates following radical cystectomy stratified by method of prophylaxis

Contributor Electronically uploaded by the author (provenance)

School Keck School of Medicine

Degree Master of Science

Degree Program Clinical and Biomedical Investigations

Publication Date 11/10/2017

Defense Date 11/10/2017

Publisher University of Southern California (original), University of Southern California. Libraries (digital)

Tag bladder cancer,OAI-PMH Harvest,prophylaxis,venous thromboembolism

Language English

Advisor Daneshmand, Siamak (committee chair), Djaladat, Hooman (committee member), Schuckman, Anne (committee member)

Creator Email chugen@usc.edu,coryhugen@gmail.com

Permanent Link (DOI) https://doi.org/10.25549/usctheses-c40-454993

Unique identifier UC11264444

Identifier etd-HugenCoryM-5896.pdf (filename),usctheses-c40-454993 (legacy record id)

Legacy Identifier etd-HugenCoryM-5896-0.pdf

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Rights Hugen, Cory Michael

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Source University of Southern California (contributing entity), University of Southern California Dissertations and Theses (collection)

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