Cost-Effectiveness of Extended Duration Venous Thromboembolism Prophylaxis in High Risk Urological Oncology Surgical Patients

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Cost-Effectiveness of Extended Duration Venous Thromboembolism Prophylaxis in High Risk Urological Oncology Surgical Patients Janet E. Baack Kukreja,* Helen R. Levey, Ahmed Ghazi, Hani Rashid, Guan Wu, Edward M. Messing and James G. Dolan From the Departments of Urology (HRL, AG, HR, GW, EMM) and Public Health Sciences (JGD), University of Rochester School of Medicine and Dentistry (JEBK), Rochester, New York

Abstract

Abbreviations and Acronyms

Introduction: Major urological oncology surgery carries a significant risk of postoperative venous thromboembolism events, resulting in major morbidity, possible mortality and substantial costs. We determined the incremental cost-effectiveness for in-hospital and low molecular weight heparin extended duration prophylaxis for venous thromboembolism prevention in patients at high risk following major urological oncology surgery. Methods: A decision analytical model was developed to compare inpatient hospital costs, venous thromboembolism incidence within 365 days and outcomes associated with extended duration prophylaxis for 4 prophylaxis strategies. The 4 strategies grouped by protocol adherence were 1) per protocol in-hospital prophylaxis with extended duration prophylaxis in 88 cases, 2) per protocol inhospital prophylaxis without extended duration prophylaxis in 42, 3) not per protocol in-hospital prophylaxis with extended duration prophylaxis in 80 and 4) not per protocol in-hospital prophylaxis without extended duration prophylaxis in 99. Between June 2011 and March 2014, 707 patients underwent major urological oncology surgery. Using the Caprini risk score 309 patients were at high risk.

ACCP = American College of Chest Physicians ASCO = American Society of Clinical Oncology DVT = deep vein thrombosis EDP = extended duration prophylaxis ICER = incremental costeffectiveness ratio LMWH = low molecular weight heparin

Results: The group 1 strategy was the dominant (most effective) strategy when the probability of preventing venous thromboembolism with extended duration prophylaxis was greater than 80%. Effectiveness for preventing venous thromboembolism was most influenced by the group 2 venous thromboembolism incidence rate. Costs in group 1 vs group 2 were calculated at $1,531 vs $1,563. Using the incremental cost-effectiveness ratio to compare groups 1 and 2, which were the 2 groups with the closest costs and effectiveness, an overall cost savings of $1,390 per patient was seen.

NCCN = National Comprehensive Cancer NetworkÒ

Conclusions: Compared with competing strategies in-hospital and extended duration prophylaxis for venous thromboembolism prevention in patients at high risk undergoing major urological oncology surgery is effective to prevent venous thromboembolism and it is cost saving.

VTE = venous thromboembolism

PE = pulmonary embolus QALY = quality adjusted life-years

Key Words: urology, venous thrombosis, pulmonary embolism, cost-benefit analysis, prevention & control

Submitted for publication May 23, 2015. No direct or indirect commercial incentive associated with publishing this article. The corresponding author certifies that, when applicable, a statement(s) has been included in the manuscript documenting institutional review board, ethics committee or ethical review board study approval; principles of Helsinki Declaration were followed in lieu of formal ethics committee approval; 2352-0779/16/34-1/0 UROLOGY PRACTICE Ó 2016 by AMERICAN UROLOGICAL ASSOCIATION EDUCATION

AND

institutional animal care and use committee approval; all human subjects provided written informed consent with guarantees of confidentiality; IRB approved protocol number; animal approved project number. * Correspondence: Department of Urology, University of Rochester Medical Center, 601 Elmwood Ave., Box 656, Rochester, New York 14642 (telephone: 585-275-3343; FAX: 585-273-1068; e-mail address: Janet_kukreja@urmc. rochester.edu).

RESEARCH, INC.

http://dx.doi.org/10.1016/j.urpr.2015.08.004 Vol. 3, 1-8, July 2016 Published by Elsevier

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Cost-Effectiveness of Extended Duration Venous Thromboembolism Prophylaxis

Major urological oncology surgery is associated with an increased risk of VTE,1 a generic term encompassing DVT and PE. It is estimated that before the initiation of heparin prophylaxis to prevent VTEs after pelvic surgery the DVT incidence is between 10% and 30%, and the PE incidence is between 1% and 10%.1,2 Several authoritative bodies have published guidelines recommending VTE prophylaxis with LMWH for 4 weeks after major abdominal and pelvic surgery in patients at high risk. LMWH, which is used for VTE prophylaxis, has more predictable absorption than unfractionated heparin and provides once daily dosing for most patients. VTEs are often counted as preventable events. These guidelines come from ACCP, a group of pulmonary physicians who publish evidence based guidelines about preventing VTE in all surgical and nonsurgical patients; NCCN, another organization of oncologists that makes evidence based recommendations for cancer care, including the prevention of VTE in oncology patients; and ASCO, an organization of oncologists who make evidence based recommendations for preventing VTE in oncology patients.3e5 Following the ACCP, NCCN and ASCO guidelines of prescribing extended duration VTE prophylaxis in high risk cancer surgery cases decreases the incidence of VTE between 7% and 14%.6e8 EDP consists of 28 days of low molecular weight heparin given once daily in prophylactic doses, for example enoxaparin 40 mg or dalteparin 5,000 mg, with the dose adjusted for renal function and patient weight. Despite this the current clinical prescriptive patterns for 28 days of LMWH in postoperative patients at high risk is not well recognized as standard practice. VTEs are often counted as preventable events. VTE reduction could help achieve health care cost containment as it is estimated that the estimated economic burden of total hospital acquired preventable VTEs in the United States is between $11.9 and $39.3 billion annually.9,10 A recent clinical study demonstrated the effectiveness of EDP in urological oncology patients but a cost comparison was not included.7 The purpose of the current study was to extend effectiveness findings and compare the costs of the 4 alternative VTE prevention options using EDP for VTE prophylaxis in urological oncology patients at high risk undergoing major surgery.

Methods

After receiving approval from the research studies review board VTE quality improvement measures were implemented in July 2012. For standardized administration of prophylaxis a protocol was developed to provide

pharmacological prevention in accordance with the guide- 148 lines recommended by ACCP, NCCN and ASCO.3e5 149 Further details of the protocol can be found in previously 150 published data from the clinical outcomes study of EDP for 151 152 major urological oncology surgery.7 7 Figure 1 shows groupings based on protocol adherence. ½F1153 Briefly, the records of patients who underwent major uro- 154 logical surgery for malignancy were consecutively reviewed 155 retrospectively from June 2011 to July 2012 and prospectively 156 from July 2012 to March 2014. Of the 707 patients under- 157 going major urological oncology surgery 309 qualified as 158 being at high risk as determined by the Caprini risk assessment 159 score.7,11,12 Patients were followed for 365 days. The VTE 160 incidence was obtained by telephone or office interviews at 161 162 30, 90 and 365 days to ascertain the development of VTE. Clinical data were modeled based on study data on the 163 prevention of VTEs in patients at high risk after major 164 urological oncology surgery.7 Patients were divided into 4 165 groups according to protocol adherence and violation in the 166 clinical study (fig. 1),8 including group 1dper protocol 167 prophylaxis in the hospital with EDP, group 2dper protocol 168 prophylaxis in the hospital with no EDP, group 3dnot per 169 protocol prophylaxis in the hospital with EDP and group 170 4dnot per protocol prophylaxis in the hospital without 171 EDP.7 During hospitalization patients in all 4 groups wore 172 173 174 VTE Prophylaxis 175 176 309 High Risk PaƟents 177 178 179 180 130 PaƟents 179 PaƟents VTE Prophylaxis administered VTE Prophylaxis not administered 181 exactly per protocol per hospital protocol -Heparin 5000 units preoperaƟvely -Any violaƟon of protocol 182 -VTE prophylaxis postoperaƟvely -No period of >24 hours of 183 prophylaxis held during the hospital stay 184 185 186 88 PaƟents 42 paƟents 99 PaƟents 80 PaƟents EDP No EDP No EDP EDP 187 188 Group 1 Group 2 Group 3 Group 4 189 Hospital protocol Hospital protocol Hospital protocol Hospital protocol followed exactly followed exactly not followed, but not followed and 190 and EDP given without EDP no EDP given EDP given 191 192 Figure 1. VTE prophylaxis prevention protocol of how clinical groups 193 were divided by prophylaxis adherence. All patients had intermittent 194 pneumatic compression devices. Asterisk indicates enoxaparin, dal195 teparin or heparin adjusted to FDA (Food and Drug Administration) approved dose for weight and renal function. Yen sign indicates 196 within 8 hours of wound closure according to manufacturer 197 recommendations. 198

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Cost-Effectiveness of Extended Duration Venous Thromboembolism Prophylaxis

199 intermittent pneumatic compression stockings starting 200 before the induction of anesthesia. Importantly, all groups 201 included an equal ratio of each surgical procedure.7 202 All patients treated with surgery prior to July 2012 were 203 assigned to group 2 or 4. In July 2012 the VTE prevention 204 protocol was initiated and these patients were assigned to 205 group 1 or 3. If VTE prophylaxis was withheld for concerns 206 of postoperative bleeding, patients were assigned to group 3 207 or 4 based on EDP discharge status. However, because pa208 tients were left in the intent to treat groups, if they experi209 enced a VTE event before prophylaxis was initiated prior to 210 discharge home, the patient data remained in group 3. 211 212 213 Project Organization 214 Although the clinical study was nonrandomized, the data and 215 subsequent analysis were organized and presented according 216 to recommendations from the ISPOR RCT-CEA (Interna217 tional Society of Pharmacoeconomics and Outcomes 218 Research Randomized Controlled Trial Cost-Effectiveness 219 Analysis) task force for ease of interpretation.13 220 221 222 Data Elements 223 Range estimations for base case assumptions were derived 224 from a literature review, incorporating estimates from avail225 able literature. The point estimations used were those from 226 the described clinical study data.7 All study data values were 227 in the range of acceptable values in the existing literature for 228 effectiveness, health utility values and costs. To account for 229 uncertainty 1-way ANOVA was performed. The probability 230 of a VTE event was based on clinically significant VTE 231 events. VTE risks were considered across 365 days. 232 The probability of no VTE occurrence, VTE occurrence 233 (defined a priori as the clinical or symptomatic presentation 234 of DVT or PE) and death likely attributable to PE were ob235 tained from clinical study data.7 The highest frequency was 236 ½T1 in group 4 and the lowest frequency was in group 1 (table 1). 237 238 239 Preference Weights 240 241 Preference weights were obtained from the literature based 242 on reports of health utility values for the type of surgery that 243 the patient underwent. If no data were available on a specific 244 urological procedure, a value based on general abdominal 245 surgery was used. There were adjustments for stage specific 246 cancer based on pathology reports. This used life expectancy 247 during the 365 days, which allowed for quality of life in 248 surgical patients with low quality of life and poor life ex249 pectancy to be comparable to those in patients with better

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250 251 252 Group 253 1 2 3 4 254 No. pts 88 42 80 99 255 DVT 3 6 7 14 256 No. PE/No. fatal 2/0 1/1 5/1 5/1 Effectiveness 0.984 0.961 0.960 0.959 257 QALY 0.78 0.76 0.73 0.77 258 Cost ($) 1,532 1,563 2,511 2,164 259 quality of life and more favorable life expectancy. Periop- 260 erative health state was assigned for 3 months. VTE health 261 utility values were assigned for 6 months and then returned 262 to the usual state of health (table 2).14e25 QALYs, which are ½T2263 used to compare health care interventions across in- 264 terventions in terms of patient quality of life after in- 265 terventions, were calculated based on available utility data 266 267 and life expectancy greater than 365 days. 268 269 270 Cost Data 271 Actual hospital costs were obtained directly from the billing 272 department at our institution. Based on previous literature 273 hospital costs are adequate to describe cost estimates for 274 surgical complications.26 The actual hospital costs included 275 fixed and variable costs. Costs were determined by adjusting 276 specifically to each surgery if the patient experienced an 277 event during the primary hospitalization. VTE event cost 278 was determined as the difference between the mean costs of 279 the VTE patient hospitalization specific to the surgical 280 procedure and the mean of a patient without a VTE event 281 specific to the surgical procedure. This adjusted for the 282 varying costs of procedures and lengths of stay after pro- 283 cedures. If a patient was rehospitalized and a new VTE was 284 diagnosed, only the readmission cost was included in the 285 calculation and not the original surgical admission. Also, 286 some patients were not admitted or were admitted elsewhere 287 to treat VTE and these costs were unobtainable. 288 LMWH costs were based on generic enoxaparin for once 289 daily dosing during 22 days. The average hospital stay was 6 290 days, leaving 22 days remaining for home administration. 291 LMWH cost was obtained directly from the outpatient 292 pharmacy at our institution and it should be viewed as a 293 retail price without discounts. 294 All actual costs in this cohort were comparable to those in 295 published literature.14e25 Thus, the adjusted real hospital 296 cost values calculated for actual patient events were used in 297 analysis (table 2).14e25 The study was done during 33 298 months. Using the CPI (Consumer Price Index) for medical 299 care the costs were inflated to United States dollars when the 300 Table 1. VTE events in clinical study obtained from cost-effectiveness analysis decision tree

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Cost-Effectiveness of Extended Duration Venous Thromboembolism Prophylaxis

301 Table 2. 302 Effectiveness, cost and health utility according to base case inputs based on decision tree calculation and literature Literature 303 Baseline Assumption Sensitivity Range* Value Range References 304 305 Group 1 probability: Preventing VTE 0.94 0.96e0.99 0.90e0.98 Kakkar et al14 306 DVT 0.03 e e e 307 PE 0.02 e e e Fatal PE 0 e 0.01 Kakkar et al14 308 Group 2 probability: 309 Preventing VTE 0.86 0.720e1.0 0.86e0.98 Kakkar et al14 310 DVT 0.14 e 0.10 Kakkar et al14 PE 0.05 e 0.015 Kakkar et al14 311 Fatal PE 0.02 e 0.004e0.25 Kakkar et al14 312 Group 3 probability: 313 Preventing VTE 0.86 0.743e0.995 e e 15 DVT 0.583 e 0.081e0.162 Cohen et al 314 PE 0.417 e 0.054e0.126 Cohen et al15 315 Fatal PE 0.2 e e 316 Group 4 probability: Preventing VTE 0.81 0.782e1 e e 317 DVT 0.14 e 0.1e0.3 Kibel and Loughlin2 þ Cohen et al15 318 PE 0.06 e 0.103e0.241 Kibel and Loughlin2 þ Cohen et al15 Fatal PE 0.01 e 0.01e0.05 Kibel and Loughlin2 þ Cohen et al15 319 320 Cost ($): 22-Day generic LMWH 740 740e1,412.83 e e 321 DVT 11,392 1,116e11,160 8,780e25,977 Lefebre et al16 PE 17,777 e 17,719.50e20,883 Lefebre et al16 322 Fatal PE 9,770 e e e 323 Utility: 324 LMWH 0.995 e e Pishko et al17 DVT 0.84 0.839e0.990 e Spangler18 325 PE 0.76 e e Spangler18 326 Prostatectomy 0.86 e e Ku et al19 327 Open nephrectomy 0.74 e e Novara et al20 Laparoscopic nephrectomy 0.80 e e Chang et al21 328 Laparoscopic partial nephrectomy 0.88 e e Chang et al21 329 Open partial nephrectomy 0.86 e e Klinghoffer et al22 330 Cystectomy 0.80 e e Kulkarni et al23 Abdominal surgery 0.8 e e Karuna et al24 331 Death 0 0 0 Assumed 332 No symptomatic VTE 1 e e Assumed 333 Ca specific testis, renal cell, prostate þ bladder Ca 0.17e1 e e National Institutes of Health25 1-yr survival rates by pathological stage 334 *All values within literature ranges. 335 336 VTE events. If a patient experienced both PE and DVT, this 337 last patient was included in study at the end of March 2014. was assigned to the more morbid condition of PE when 338 Because the study was not modeled longer than 1 year, there was no need for discounting on future costs. input into the model. VTE counts in the model were done so 339 that VTE that occurred during the primary hospital admis340 sion and after discharge were assigned the same utilities and 341 Analysis costs. Table 2 lists base case assumptions.14e25 The 342 outcome of VTE was obtained by clinical diagnosis. The 343 Decision Model. A decision analytical model was used to assumptions were made that testing was accurate in all pa344 compare 4 competing strategies for pharmacological pretients diagnosed with VTE had and a VTE diagnosis was not 345 vention of VTEs in patients at high risk after major uromissed by diagnostic testing. Additionally, patient compli346 logical oncology surgery. PrecisionTree, version 6.2.0 ance was assumed to be 100%. 347 (Palisade, Ithaca, New York) was used for decision tree There was no difference in bleeding complications in the 348 development. Each strategy was based on the clinical data 4 groups. Because this was consistent with previous ran349½F2 groupings. Figure 2 shows the decision tree. domized, controlled trials,13,27,28 these complications were 350 The development of VTEs within 365 days was included not incorporated into the model. 351 in a 1-year time horizon model. Table 1 shows a summary of FLA 5.4.0 DTD  URPR144_proof  8 April 2016  6:13 pm  EO: UP-15-51

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454 455 456 Group 1 Group 4 Group 2 Group 3 457 458 81% 19% 6% 14% 14% 86% 86% 94% 459 VTE No VTE 460 VTE No VTE VTE VTE No VTE No VTE 461 $739.44 $739.44 14.3% 85.7% 41.7% 58.3% 40% 60% $0 $0 462 41.7% 58.3% DVT PE 463 DVT DVT PE PE DVT PE 464 $11,392 $11,392 $11,392 $11,392 465 100% 80% 20% 100% 0% 0% 20% 80% 466 Die Live Live Die Live Die Die Live 467 $9770 $17,777 $9770 $17,777 $17,777 $9770 $17,777 $9770 468 469 Figure 2. Cost-effectiveness analysis decision tree incorporates all 4 clinical groups to help determine whether adherence to 1 or all parts of 470 clinical protocol is needed to cost-effectively decrease VTE incidence. 471 472 Cost-Effectiveness Analysis. Cost-effectiveness was calcueach group strategy as detailed. LMWH for 4 weeks and lated as probabilities and utilities over cost differences. This perioperatively per protocol remained the dominant strategy 473 was also converted to QALYs. Table 1 shows the costs, for effective prevention of VTEs postoperatively based on 474 475 effectiveness and utilities in each clinical group. QALYs. The strategies were then compared and the most cost- 476 effective strategy was also group 1. ICER was calculated 477 Results after ordering the groups by effectiveness (table 3). This ½T3478 was done to determine whether an intervention was cost- 479 The dominant strategy was group 1, in which inpatient effective. It represents the difference between the costs 480 prophylaxis was given per protocol and EDP. Effectiveness over the differences between the effectiveness. This value 481 was also evaluated with the calculated baseline QALY for 482 483 Table 3. 484 Effectiveness and QALY ICER calculations 485 Group Cost ($) Effectiveness QALY Incremental Cost ($) Incremental Effect ICER 486 ICERs: e 487 4 2,164 0.959 2,164 0.959 2,257 488 3 2,511 0.960 347 0.001 347,000 2 1,563 0.961 948 0.001 948,000 489 1 1,532 0.984 31 0.023 1,347 490 Excluding more costly þ less effective e 491 alternatives: 2 1,563 0.961 1,563 0.961 1,626 492 1 1,532 0.984 31 0.023 1,347 493 QALY ICERS: e 494 3 2,511 0.73 2,511 0.73 3,440 2 1,563 0.76 948 0.03 31,600 495 4 2,164 0.77 601 0.01 60,100 496 1 1,532 0.78 632 0.01 63,200 497 Excluding more costly þ less effective e alternatives: 498 2 1,563 0.76 1,563 0.76 2,057 499 1 1,532 0.78 31 0.02 1,550 500 Incremental cost effectiveness ratios (ICERs) are calculated in this table. A is the initial calculation for effectiveness as the endpoint. B is the ICER calculated with 501 exclusion of the more costly and less effective prophylaxis strategies. C is the ICER with QALYs as the units. D is the ICERs calculated with the more expensive and less effective alternatives removed. In parts A and C this was initially done for all groups, the least effective is listed first. After calculations the more expensive and 502 least effective alternatives were excluded. The least effective intervention ICER was calculated by comparing it to the alternative of doing nothing in parts B and D of 503 the table. Here are the calculations for B and D: ($1,532-$1,563) / (0.984-0.961) ¼ -$1,3471] QALYs were also calculated and $1550 was saved per QALY. [Calculated as: (($1,532-$1,563) / (0.78-0.76) ¼ -$1,550]. So $1,347 was saved per patient in Group 1 and $1,550 was saved per QALY gained. 504 High Risk VTE

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556 557 Sensitivity analyses were performed to assess the uncer- 558 tainty for effectiveness and costs. Tornado diagrams were 559 constructed that showed that effectiveness was most influ- 560 enced by the development of VTE with hospital only 561 (group 2) treatment strategy and development of VTE with 562 the group 4 treatment strategy. Costs were most influenced 563 by development of VTE with hospital per protocol and EDP 564 (group 1). An additional factor strongly influencing costs 565 was the cost of LMWH prophylaxis for EDP. On 1-way 566 sensitivity analysis for effectiveness as long as the chance of 567 developing VTE on the group 1 strategy was less than 20%, 568 that was the preferred strategy (fig. 3). ½F3 569 570 571 Discussion 572 The results presented are in accordance with NCCN, ASCO, 573 ACCP and new AUA (American Urological Association) 574 recommendations that patients at risk for VTE who undergo 575 abdominal and pelvic operations for cancer should be 576 considered for 4 weeks of LMWH postoperatively.3e5,29 577 Our findings prove that it is a cost saving measure of VTE 578 prevention. If patients are found to be at high risk, there 579 580 581 1 582 583 584 0.98 585 586 587 0.96 588 589 590 0.94 591 592 593 0.92 594 595 596 0.9 597 598 599 0.88 600 601 602 Hospital + EDP (Group 1) 603 Figure 3. One-way sensitivity analysis of effectiveness. Blue curve represents group 1 chance of VTE prevention by in-hospital and extended 604 LMWH VTE prophylaxis. Curve crosses other strategies at 0.2, meaning that group 1 is preferred strategy as long as there is 80% chance of 605 preventing VTE using group 1 strategy. Purple line indicates group 2dper protocol no EDP. Green line indicates group 3dno protocol EDP. 606 Yellow line indicates group 4dno protocol no EDP.

is used to help decision makers decide whether the willingness to pay value for the outcome is at such a level that they want to adopt the intervention. ICER helps provide more evidence of possible benefits from the interventions. ICERs are plotted on a cost-effectiveness plane. The y-axis is the costs and the x-axis is the effectiveness. This results in the left upper quadrant being less effective and increasing costs. The left lower quadrant is less effective but cost saving. The right upper quadrant is more effective and cost increasing. The right lower quadrant is where the benefits are more effective and cost is less or it is a cost saving measure. Depending on where the willingness to pay line is, the intervention will be considered acceptable. ICERs can also be done using QALYs to determine the quality gained. Since group 1 was determined to be the most effective and least costly, no further evaluation of competing interventions or willingness to pay was necessary. Although the cost of EDP was $740 per patient in group 1, there was an overall cost saving of about $1,347 per patient in group 1 compared to group 2. Additionally, there was a cost saving of $1,550 for each life year gained in group 1 compared to group 2.

Uncertainty

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1.200

1.000

0.800

0.600

0.400

0.200

0.000

-0.200

Expected Value

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Cost-Effectiveness of Extended Duration Venous Thromboembolism Prophylaxis

Cost-Effectiveness of Extended Duration Venous Thromboembolism Prophylaxis

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should be a risk-benefit consideration of VTE prophylaxis.3e5,28 Because numerous studies have demonstrated the safety of EDP,7,8,14 unless there is active bleeding prophylaxis should be considered safe in this patient population. Our study supports the notion that VTE prophylaxis perioperatively in these urological oncology patients at high risk is not only effective for VTE prevention but also one of the few interventions that is cost saving. Like previous studies, our study of cost-effectiveness illustrates the cost-effective reduction of VTE events with the appropriate use of perioperative VTE prophylaxis and EDP.18,19 It is important that as health care costs are increasing, interventions that are cost saving are considered for wider implementation. Quality improvements are also essential in the cost containment of health care. VTE reduction is now a quality improvement goal of Medicare for many specialties and EDP is effective at improving the quality of the surgical care provided.30 This should be kept in mind particularly since compliance with VTE prophylaxis will be part of surgical quality improvement overall.30 For urologists who perform major urological oncology surgeries in patients at high risk hospital perioperative VTE prophylaxis along with EDP provides an opportunity for quality improvement in care and cost savings. Limitations of this study include the fact that it was based on a nonrandomized cohort study. Also, the number of patients with cost data available is small due to the small number of events in each surgery specific category. Because the costs obtained were hospital costs, they can only be extrapolated to hospital costs of VTE and not to outpatient treatment of VTE. Costs of training patients to selfadminister LMWH prior to discharge were assumed in the hospital costs. Home prophylaxis costs were based on once daily dosing of enoxaparin 40 mg but some patients required doses adjusted for weight and renal function. Additionally, costs of needle disposal and LMWH administration by a visiting nurse were not included. Progression from DVT to PE was also not included. After VTE events occurred these patients were not followed due to the sometimes long followup required to ascertain costs of disabilities caused by VTE, such as post-thrombotic syndrome. Thus, there is no cost information on complications of VTE. There was no evaluation of the societal impact by incorporating the costs of lost wages and other social factors. Societal costs such as time missed from work were not available in all patients. Thus, the true cost benefits of EDP may be underestimated. Given the limitations of this study, it is likely that the current analysis may underestimate the real cost savings of

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VTE prevention using a hospital protocol and EDP in accordance with ACCP, NCCN, ASCO and AUA recommendations.3e5,29 For example, adding values of economics to factor in such items as societal costs would increase the gap between groups 1 and 2 but since the intervention is already cost saving, this was not necessary. Additional strengths of this study include high patient compliance, long followup, no missing data points, high fidelity followup and the use of actual hospital costs. Not using insurance or billed costs allows for an understanding of the true economics of the disease process and the prevention of VTE, which can be carried across health systems. Although this was a nonrandomized study, the protocol of VTE prophylaxis in hospital and EDP was well adhered to in this cohort study, providing evidence that VTE prophylaxis with EDP is effective and cost saving. Future studies should focus on the cost-effectiveness of different LMWHs and potentially could include the new oral anti-Xa VTE prophylaxis. Conclusions

In-hospital and EDP for VTE prevention in patients at high risk undergoing major urological oncology surgeries are effective for decreasing VTEs compared to competing strategies. Perioperative prophylaxis and EDP for VTE prevention in urological oncology surgery patients at high risk is a cost saving strategy to reduce VTE events. References 1. Clément C, Rossi P, Aissi K et al: Incidence, risk profile and morphological pattern of lower extremity venous thromboembolism after urological cancer surgery. J Urol 2011; 186: 2293. 2. Kibel AS and Loughlin KR: Pathogenesis and prophylaxis of postoperative thromboembolic disease in urological pelvic surgery. J Urol 1995; 153: 1763. 3. Gould MK, Garcia DA, Wren SM 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. American College of Chest Physicians. Chest, suppl., 2012; 141: e227S. 4. Streiff MB: The NCCN guidelines on the management of venous thromboembolism in cancer patients. National Comprehensive Cancer Network. Thromb Res, suppl., 2010; 125: S128. 5. Lyman GH, Khorana AA, Kuderer NM et al: Venous thromboembolism prophylaxis and treatment in patients with cancer: American Society of Clinical Oncology clinical practice guideline update. American Society of Clinical Oncology Clinical Practice. J Clin Oncol 2013 jun10; 31: 2189. 6. Bergqvist D, Agnelli G, Cohen AT et al: Duration of prophylaxis against venous thromboembolism with enoxaparin after surgery for cancer. N Engl J Med 2002; 346: 975.

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8 709 710 711 712 713 714 715 716 717 718 719 720 721 722 723 724 725 726 727 728 729 730 731 732 733 734 735 736 737 738 739 740 741 742 743 744 745 746 747 748 749 750 751 752 753 754 755 756 757 758 759 760 761

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7. Kukreja JE, Levey HR, Scosyrev E et al: Effectiveness and safety of extended-duration prophylaxis for venous thromboembolism in major urologic oncology surgery. Urol Oncol 2015; 33: 387.

19. Ku J, Krahn M, Trachtenberg J et al: Changes in health utilities and health-related quality of life over 12 months following radical prostatectomy. Can Urol Assoc J 2009; 6: 445.

8. Bottaro FJ, Elizondo MC, Doti C et al: Efficacy of extended thrombo-prophylaxis in major abdominal surgery: what does the evidence show? A meta-analysis. Thromb Haemost 2008; 99: 1104.

20. Novara G, Secco S, Botteri M et al: Predicting health-related quality of life recovery in patients undergoing surgical treatment for renal tumors: prospective evaluation using the RAND SF-36 health survey. Eur Urol 2009; 57: 112.

9. Mahan CE, Holdsworth MT, Welch SM et al: Deep-vein thrombosis: a United States cost model for a preventable and costly adverse event. Thromb Haemost Sep; 106: 405.

21. Chang SL, Cipriano LE, Harchman LC et al: Cost-effectiveness analysis of nephron sparing options for the management of small renal masses. J Urol 2011; 185: 1591.

10. Mahan CE, Borrego ME, Woersching AL et al: Venous thromboembolism: annualised United States models for total, hospitalacquired and preventable costs utilising long-term attack rates. Thromb Haemost 2012; 108: 291.

22. Klinghoffer Z, Tarride JE, Barga LH et al: Cost-utility analysis of radical nephrectomy versus partial nephrectomy in the management of small renal masses: adjusting for the burden of ensuing chronic kidney disease. Can Urol Assoc J 2013; 7: 108.

11. Caprini JA: Risk assessment as a guide to thrombosis prophylaxis. Curr Opin Pulm Med 2010; 16: 448.

23. Kulkarni GS, Alibhai SM, Finelli A et al: Cost-effectiveness analysis of immediate radical cystectomy versus bacillus Calmette-Guerin therapy for high-risk, high-grade bladder cancer. Cancer 2009; 115: 5450.

12. Bahl V, Hu HM, Henke PK et al: A validation study of a retrospective venous thromboembolism risk scoring method. Ann Surg 2010; 251: 344. 13. Ramsey SD, Wilke RJ, Briggs AH et al: Good research practices for cost-effectiveness analysis alongside clinical trials: the ISPOR RCT-CEA Task Force report. Value Health 2005; 8: 521. 14. Kakkar VV, Balibrea JL, Martínez-González J et al: Extended prophylaxis with bemiparin for the prevention of venous thromboembolism after abdominal or pelvic surgery for cancer: the CANBESURE randomized study. CANBESURE Study Group. J Thromb Haemost 2010; 8: 12231229. 15. Cohen AT, Agnelli G, Anderson FA et al: Venous thromboembolism in Europe: the number of VTE events and associated morbidity and mortality. VTE Impact Assessment Group in Europe (VITAE). Thromb Haemost 2007; 98: 756. 16. Lefebvre P, Laliberté F, Nutescu EA et al: All-cause and potentially disease-related health care costs associated with venous thromboembolism in commercial, Medicare, and Medicaid beneficiaries. J Manag Care Pharm 2012; 18: 363. 17. Pishko AM, Ragni MV and Smith KJ: Anticoagulation in ambulatory cancer patients with no indication for prophylactic or therapeutic anticoagulation. A cost-effectiveness analysis from a U.S. perspective. Thromb Haemost 2012; 108: 303. 18. Spangler EL: Cost-effectiveness of guidelines for insertion of inferior vena cava filters in high-risk trauma patients. J Vasc Surg 2010; 52: 1537.

24. Karuna S, Tanner B, Thomas T et al: Cost-effectiveness of laparoscopy versus laparotomy for initial surgical evaluation and treatment of potentially resectable hepatic colorectal metastases: a decision analysis. J Surg Oncol 2008; 97: 396. 25. National Institutes of Health: Cancer Query Systems. Available at http://seer.cancer.gov/canques. Accessed May 3, 2014. 26. Dimick JB, Chen SL, Taheri PA et al: Hospital costs associated with surgical complications: a report from the private-sector National Surgical Quality Improvement Program. J Am Coll Surg 2004; 199: 531. 27. Akl EA, Terrenato I, Barba M et al: Extended perioperative thromboprophylaxis in patients with cancer A systematic review. Thromb Haemost 2008; 100: 1176. 28. Caprini JA: Identification of patient venous thromboembolism risk across the continuum of care. Clin Appl Thromb Hemost 2011; 17: 590. 29. Weigelt JA, Lal A and Riska R: Venous thromboembolism prophylaxis in surgical patients: identifying a patient group to maximize performance improvement. Jt Comm J Qual Patient Saf 2011; 37: 178. 30. Culkin DJ, Exaire EJ, Green D et al: Anticoagulation and Antiplatelet Therapy in Urologic Practice: ICUD and AUA Review Paper, 2014. Available at http://www.auanet.org/education/otheraua-clinical-guidance-documents.cfm. Accessed July 21, 2015.

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