The Journal of Arthroplasty 30 (2015) 159–164
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Cost-Effective Prophylaxis Against Venous Thromboembolism After Total Joint Arthroplasty: Warfarin Versus Aspirin Reza Mostafavi Tabatabaee, MD, Mohammad R. Rasouli, MD, Mitchell G. Maltenfort, PhD, Javad Parvizi, MD FRCS The Rothman Institute of Orthopaedics, Thomas Jefferson University, Philadelphia, Pennsylvania
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Article history: Received 11 July 2014 Accepted 27 August 2014 Keywords: aspirin warafarin venous thromboembolism total joint arthroplasty cost-effectiveness analysis
a b s t r a c t Although recent guidelines suggest aspirin for venous thromboembolism (VTE) prophylaxis in low risk patients following total hip arthroplasty (THA) and total knee arthroplasty (TKA), there are no cost-effectiveness studies comparing aspirin and warfarin. In a Markov cohort cost-effectiveness analysis, we found that aspirin cost less and saved more quality-adjusted life-years (QALYs) than warfarin in all age groups. Cost per QALY gained by aspirin was $24,506.20 at age of 55 and $47,148.10 at the age of 85 following THA and $15,117.20 and $24,458.10 after TKA, which were greater than warfarin. In patients undergoing THA/TKA without prior VTE, aspirin is more cost-effective prophylactic agent than warfarin. Warfarin might be a better prophylaxis in TKA patients with high probability of VTE and very low probability of bleeding. © 2014 Elsevier Inc. All rights reserved.
Although total hip arthroplasty (THA) and total knee arthroplasty (TKA) are very safe procedures [1], patients undergoing these procedures are considered to be at risk of venous thromboembolism (VTE), including deep venous thrombosis (DVT) and pulmonary embolism (PE) [2]. Without prophylaxis, VTE may occur in more than 35% of patients after total joint arthroplasty (TJA), although most VTEs are asymptomatic [2–5]. It remains unclear which agent for prophylaxis against VTE after TJA is the most effective and safest. The recent guideline issued by the American College of Chest Physicians (ACCP), endorses the use of aspirin as an effective chemoprophylaxis for prevention of VTE following TJA [2]. The guideline proposed by the American Academy of Orthopaedic Surgeons (AAOS), though it does not endorse one agent over another, lists aspirin as a potential chemoprophylactic agents against VTE following TJA anticoagulation agent [6]. Over the last few years there has been a trend towards the use of aspirin as prophylactic agent in patients undergoing TJA. At our institution aspirin replaced warfarin as the preferred method of VTE prophylaxis a few years ago. Warfarin is a commonly-used anticoagulant that is associated with a higher risk of bleeding compared to aspirin [7]. Because of unpredictable pharmacokinetics, obtaining the optimal level of anticoagulation with warfarin is increasingly difficult, requiring continuous blood monitoring [5,8]. Recently, a Markov cohort cost-effectiveness analysis was performed by Schousboe and Brown to compare the costs, health benefits, and costs per quality-adjusted life-year (QALY) of Low Molecular Weight Heparin (LMWH) versus 160 mg of aspirin per day for 14 days after TJA in
The Conflict of Interest statement associated with this article can be found at http://dx. doi.org/10.1016/j.arth.2014.08.018. Reprint requests: Javad Parvizi, MD, FRCS, The Rothman Institute at Thomas Jefferson University, 125 S 9th St. Suite 1000, Philadelphia, PA 19107. http://dx.doi.org/10.1016/j.arth.2014.08.018 0883-5403/© 2014 Elsevier Inc. All rights reserved.
patients with no history of VTE. The authors concluded that for these patients, aspirin is a cost-effective option for VTE prophylaxis following THA. The study, however, stated that the preferred chemoprophylactic agent after TKA depends on age and is uncertain for patients younger than 80 years old [9]. Although the aforementioned study showed the superiority of aspirin over LMWH in the majority of cases, there are no data comparing cost, health benefits, and QALY of warfarin, which is commonly used for VTE prophylaxis following TJA, versus aspirin. Therefore, the present study was designed and conducted to compare cost and health benefits of anticoagulation using warfarin with aspirin following TJA using a comparable Markov cohort cost-effectiveness model. Materials and Methods Markov modeling is applicable when a treatment decision involves consideration of continuous risk, the timing of events is necessary, and important events may occur more than once [10]. We adapted the Schousboe and Brown model, excluding the thrombocyteopenia state (a consequence of LMWH) and including periprosthetic joint infection (PJI) and chronic pulmonary hypertension, which had been included in Schousboe and Brown’s extended model [9]. After TJA, patients were allocated into the following groups: healthy state, postoperative bleeding at operation site, non-operation-site bleeding, symptomatic DVT, and symptomatic PE. Individuals then transitioned to one of four health states: healthy, no postphlebitic syndrome (PPS) after VTE, PPS after VTE, survival after intracranial hemorrhage, or chronic pulmonary hypertension (Fig. 1). Patients with intracranial hemorrhage following VTE prophylaxis who survived were transitioned to the post-intracranial hemorrhage state to capture the costs and disutility. As calculated by Schousboe and Brown [9], the post-intracranial hemorrhage state persists for the
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R. Mostafavi Tabatabaee et al. / The Journal of Arthroplasty 30 (2015) 159–164 Table 1 The Incidence Rates of Adverse Events Following Total Joint Arthroplasty in Patients Treated With Warfarin Versus Aspirin. The Incidence Rates
Symptomatic DVT Symptomatic PE Asymptomatic DVT Bleeding at operative site Bleeding at non-operative site
Warfarin
Aspirin
THA
TKA
THA
TKA
0.82% 0.92% 32% 3.2% 2.15%
1.25% 0.63% 30.48% 3.5% 2.7%
0.79% 0.40% 16% 0.83% 1.41%
2.18% 0.26% 51% 1.06% 0.48%
DVT: deep vein thrombosis, PE: pulmonary embolism, THA: total hip arthroplasty, TKA: total knee arthroplasty.
Fig. 1. Health states and model transitions following total joint arthroplasty (TJA). DVT: deep venous thrombosis, PE: pulmonary embolism, PPS: postphlebitic syndrome, CPHTN: Chronic pulmonary hypertension, TJA: total joint arthroplasty, PJI/SSI: periprosthetic joint infection/surgical site infection, VTE: venous thromboembolism.
following four years. After uneventful TJA or full recovery from one-time postoperative events (non-intracranial hemorrhage), patients transited to the healthy state. Because patients are at increased risk of developing PPS during the first five years following a postoperative asymptomatic VTE event [11], patients may transit from the healthy state to the PPS status during this period. Otherwise, asymptomatic DVT is assumed to not result in any cost or lost QALY. Hypothetical Markov cohorts were run for THA and TKA separately, and patients were divided into the following age groups: 55–60, 61–65, 66–70, 71–74, 75–80, 81–85, and N85 years. We considered a lifetime horizon and followed individuals until death or the age of 100 years. We found the estimation of the probabilities of postoperative adverse health events and their associated costs and disutility based on the available literature, particularly systematic reviews and meta-analyses. Transition Probabilities In the meta-analysis by Brown, the incidence rates of postoperative symptomatic VTE and PE events were estimated to be 2.01% and 0.40%, respectively, for patients undergoing TJA who received warfarin [5]. In a retrospective study comparing the prophylactic effects of aspirin and warfarin following TJA, the risk of symptomatic DVT and PE events was estimated to be 0.82% and 0.47% respectively after THA and 1.18% and 1.74% after TKA [8]. Using pooled data from these studies and other reports [12–14], we estimated the risk of symptomatic DVT and PE to be 0.82% and 0.92% respectively after THA and 1.25% and 0.63% after TKA for warfarin prophylaxis. We also assigned rates of asymptomatic DVT and major bleeding at the operative and nonoperative sites to be 32%, 3.2%, and 2.15% for THA and 30.5%, 3.5%, and 2.7% for TKA on the basis of the available literature [5,8,12–14] (Table 1). Transition probabilities for aspirin were mainly obtained from Schousboe and Brown’s study. For patients treated with aspirin, they estimated the rates of symptomatic DVT and PE, asymptomatic DVT,
and major bleeding at the operative and non-operative sites as 1.10%, 0.51%, 16%, 2.13%, and 0.97% for THA and 1.09%, 51%, 2.13%, and 0.97% for TKA correspondingly [9]. In the retrospective study by Raphael et al, the risks of symptomatic DVT and PE events were estimated to be 0.57% and 0.38% in TKA patients. In that study, 0.23% of patients who underwent THA were affected with symptomatic DVT during treatment with aspirin and there was no report of PE [8]. Table 1 demonstrates the estimated risks of adverse events in the aspirin and warfarin groups following THA and TKA. Because we limited our analysis to patients without previous history of VTE, all above VTE rates were adjusted using the relative risk of VTE after TJA in patients with history of VTE versus those without history of VTE, which is 8.1% [15]; and the following equation, which is the same that Schousboe et al used in their study [9]. RiskNo
prior h VTE ¼ RiskAll = 1 þ RiskPrior
VTE vs No prior VTE –1
PrevalencePrior
VTE
The age-specific incidence of prior VTE was estimated based on a population-based study in Norway[16] and ranged from 0.72% at the age of 55 years to 4.73% at the age of 85 years. The incidence rate of intracranial hemorrhage (ICH) was considered to be 0.02% for patients treated with aspirin [17] and 0.45% for patients treated with warfarin [18]. In the study by Saleh et al [19] hematoma developed in 19 cases out of 33 of SSI episodes (58%) while the corresponding number was 4 out of 64 (6%) in patients without SSI after TJA. Based on this study and rate of operative site bleeding after THA (0.032) and TKA (0.035), the incidence rates of surgical site infection (SSI)/PJI after operative site bleeding following THA and TKA were estimated as 1.86% and 2.03% for warfarin and 0.48% and 0.61% for aspirin respectively. Over a 2-year period, 3.8% of patients with PE may experience chronic pulmonary hypertension because of persistent obstruction of the pulmonary artery. The risk of chronic pulmonary hypertension is higher in patients with idiopathic PE than those PE cases with known etiology (odds ratio, 5.7). Pengo et al found that the proportion of all patients with a first time idiopathic PE was 37.2% [20]. Using these facts and the same adjustment for no prior VTE, we calculated the rate of chronic pulmonary hypertension following PE after TJA to be 0.014%. The risk of PPS was considered to rise for 20 years after a VTE event, with a cumulative incidence of 16% in all patients with a symptomatic VTE event [21]. According to the study conducted by Mohr et al, we considered that 7%, 14%, 20%, and 27% of survivors would develop PPS at 1, 5, 10, and 20 years after the VTE event respectively [21]. We considered that the risk of PPS after an asymptomatic VTE would be one fifth of the risk after a symptomatic VTE event [11]. Mortality Intracranial hemorrhage and other non-operative site bleeding have a 25.5% [22] and 6% [23] risk of death, respectively. Major operative site
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bleeding was assumed not to cause mortality, but 42% of these patients would have reoperations [5,24]. The fatality rate after PE was estimated to be 15% [25]. We used age-specific background mortality due to other causes in United States for 2008 [26].
Table 3 Lifetime Cost, QALYs Gained, and Costs per QALY for Warfarin and Aspirin for Different Ages Using the Markov Cohort Model. Total Hip Arthroplasty
The Costs and Health State Utilities and Disutilities of One-Time Adverse Health Events
55 years old Costs QALYs Cost per QALY 60 years old Costs QALYs Cost per QALY 65 years old Costs QALYs Cost per QALY 70 years old Costs QALYs Cost per QALY 75 years old Costs QALYs Cost per QALY 80 years old Costs QALYs Cost per ALY 85 years old Costs QALYs Cost per QALY
In addition to the costs of medication (warfarin and aspirin), Table 2 shows costs related to laboratory tests required for monitoring of warfarin [9,27]. It also contains the costs and QALYs for one-time episodes of DVT, PE, and bleeding according to previous studies [9,24,28–30]. Yearly costs for chronic health states, loss of QALY for a single event, and QALY value gained for chronic health states during one year are shown in table 2 [9,24,28–36]. Using the Consumer Price Index for medical care, all costs were updated to 2013 US dollars (available at http://www.bls.gov/cpi/). The quality-adjusted life-year (QALY) is a measure for assessing disease burden both quantitatively and qualitatively. The value of QALY ranges from 0 (death) to 1 (perfect health). Calculating QALY using some specific methods such as the EuroQol 5D (EQ-5D), a negative number can be calculated. Because of senile chronic conditions and loss of mobility, QALY values decrease with age even for healthy individuals [36]. Model Runs and Sensitivity Analyses We used decision analysis software (TreeAge Pro, ©2013; TreeAge Software, Williamstown, MA) for Markov cohort analysis. The starting age was incrementally increased from 55 to 85. For each starting age and joint, total cost and QALY were assessed. A cycle length of one month was used. Two-way sensitivity analysis was performed to see if changing the relative rates of symptomatic VTE and bleeding events affected the results.
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Total Knee Arthroplasty
Warfarin
Aspirin
Warfarin
Aspirin
$3287.14 13.21979 $24,506.2
$1959.5 13.27396
$3816.3 13.19451 $15,117.2
$1516.3 13.34666
$2980.3 11.78769 $25,553.0
$1769.5 11.83508
$3460.3 11.76519 $15,690.2
$1350.2 11.89967
$2654.8 10.26823 $27,020.2
$1567.5 10.30847
$3082.6 10.24866 $16,467.7
$1176.0 10.36445
$2325.0 8.69975 $29,156.7
$1362.2 8.73277
$2698.8 8.68325 $17,524.0
$1006.8 8.77981
$2004.1 7.10954 $32,460.9
$1161.3 7.1355
$2323.0 7.0962 $18,995.9
$856.1 7.17342
$1708.3 5.56106 $37,837.0
$974.9 5.58044
$1973.5 5.55084 $21,133.1
$733.8 5.6095
$1448.1 4.12862 $47,148.1
$810.0 4.14215
$1663.6 4.12128 $24,458.1
$640.4 4.16311
QALY: Quality-adjusted life-year.
Table 2 Costs and Quality-Adjusted Life-Year (QALYs). Parameter
Adjusted Value for 2013
Reference
Aspirin (160 mg per day) The monthly cost of warfarin monitoring per patient: (Medications, Laboratory, and Pharmacist monitoring) Costs for one-time events Symptomatic DVT During surgical hospital stay After surgical hospital stay Pulmonary embolism During surgical hospital stay After surgical hospital stay Operative site hemorrhage Non-operative site hemorrhage Yearly costs for chronic health states Postphlebitic syndrome First year Subsequent years Post-intracranial hemorrhage Periprosthetic Joint Infection (The sum of the inpatient and outpatient costs) Loss of QALY for a single event Symptomatic DVT During surgical hospital stay After surgical hospital stay Pulmonary embolism During surgical hospital stay After surgical hospital stay Nonoperative site hemorrhage Operative site hemorrhage Estimated QALY value for chronic health states during a year Healthy state Postphlebitic syndrome Survival after intracranial hemorrhage
$0.80 for 1 mon $80.78
Schousboe & Brown (2013)9 Biskupiak et al (2013)27
DVT: deep venous thrombosis, QALY: quality-adjusted life-year.
$24,079 $8243 $15,836 $34,788 $14,674 $20,114 $7355 $4993
Bullano et al (2005),28 Dobesh (2009)30 Bullano et al (2005)28 Ollendorf et al (2002)29 Bullano et al (2005)28 Vera-Llonch et al (2006)24 Vera-Llonch et al (2006)24
$4147 $1822 $13,714 $168,398
Caprini et al (2003)31 and Dobesh (2009)30 Caprini et al (2003)31 and Dobesh (2009)30 Lee et al (2007)22 Schousboe & Brown (2013)9
−0.007 −0.0123
Ollendorf et al (2002)29 Bullano et al (2005)28
−0.013 −0.0148 −0.0029 −0.0038
Ollendorf et al (2002)29 Bullano et al (2005)28 Vera-Llonch et al (2006)24 Vera-Llonch et al (2006)24
0.76 Ostendorf et al (2004)33 0.735 Lenert and Soetikno (1997)34 and Caprini et al (2003)31 0.29 × 3 mos, then 0.45 × 3.75 yrs, then 0.76 Lee et al (2010)32 and O’Meara et al (1994)35
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Fig. 2. Two-way sensitivity analysis in patients aged 65 years demonstrating rates of venous thromboembolism events versus the rate of major bleeding compared to the base case. Part A comparing aspirin versus warfarin in total hip arthroplasty and Part B comparing aspirin versus warfarin in total knee arthroplasty.
Results In all age groups and in both THA and TKA, aspirin was consistently associated with higher QALY and lower cost than warfarin (Table 3). However, the reduced QALY for patients using warfarin was very small compared to those using aspirin and the extra cost of using warfarin was no more than $4000 per patient. By increasing age in both THA and TKA groups, cost per QALYs gained by using aspirin increased. At age 55–60, cost per QALY gained by aspirin was $24,506.20 following THA, which increased to $47,148.10 by age 85. The corresponding costs in TKA were $15,117.20 and $24,458.10 respectively. In THA patients, cost per QALYs gained by aspirin was greater than the corresponding ages in the TKA group. Two-way sensitivity analysis was performed for the 65–70 age group for THA and TKA separately to determine chosen VTE prophylaxis agent for a given rate of VTE versus the rate of major bleeding compared
to the base case. Sensitivity analysis indicated that in all rates of VTE events, aspirin is the preferred VTE prophylaxis agent in patients aged 65–70 years undergoing THA. However, in the sensitivity analysis for TKA, warfarin was dominant for all risks of VTE when risk of major bleeding was assumed to be extremely low (Fig. 2). Discussion The most effective agents for prevention of venous thromboembolism following TJA continues to be debated with no one agent proving to be superior to another when all risks and benefits are taken into account [37]. Some studies have shown better efficacy for new agents such as oral direct factor Xa inhibitor over other modalities in prevention of DVT [38–41]. Although safety profile of the newer anticoagulants has improved, the use of these aggressive anticoagulants such as LMWH is associated with higher incidence of wound drainage, bleeding, reoperation,
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infection, and even mortality and predisposes patients who are at low risk of VTE to a great risk of these adverse events [42,43]. Thus, the choice of most appropriate VTE prophylaxis following TJA remains largely at the discretion of the orthopedic surgeon and the caring medical team. Because of its proven efficacy and low rate of postoperative complications, aspirin has been endorsed as an acceptable VTE prophylaxis by the recent guidelines [2,6]. At our institution we have been utilizing aspirin as the preferred method of VTE prophylaxis over the last few years. Prior to the use of aspirin majority of our patients were placed on warfarin for VTE prophylaxis. One of the main issues related to administration of anticoagulation relates to cost. With the limited resources and the scrutiny on “quality” of care, cost for each episode of care and the ensuing complications that may arise, have taken a center stage. This study was designed to examine the cost of VTE prophylaxis following TJA comparing warfarin or aspirin using the Markov modeling. The Markov modeling is used with increasing frequency to determine “cost-effectiveness” of various modalities when a treatment decision involves consideration of continuous risk, the timing of events is necessary, and important events may occur more than once. It is often difficult to evaluate such clinical settings using conventional decision options and may lead to unrealistic simplifying assumptions [10]. In this study, the cost burden, QALY, and cost per QALY for aspirin and warfarin in THA and TKA were calculated separately. Our findings indicated that in all THA and the majority of TKA patients without history of VTE who have low risk of developing VTE, aspirin is associated with lower cost and saves more QALYs compared to warfarin. Sensitivity analysis for patients aged 65–70 years demonstrated that when rate of major bleedings is very low versus all rates of VTE, aspirin might be more cost-effective in patients undergoing TKA. This is similar to the findings of a recently published study by Schousboe and Brown, when the costs and QALYs gained by aspirin versus LMWH were compared [9]. It was shown that aspirin is superior to LMWH in THA cases, while the benefit of aspirin in TKA cases depends on patient’s age. Based on these two studies, it seems that aspirin is a cost-effective VTE prophylaxis agent and can be used safely in patients without history of VTE who are at low risk for development of VTE following TJA. There are several reasons explaining why aspirin is more costeffective compared to warfarin. There is growing evidence associating warfarin with increased risk of postoperative-site bleeding which in turn increases risk of SSI/PJI following TJA [5,7]. Moreover, warfarin is associated with a higher risk of major nonoperative site bleeding compared to aspirin. On the other hand, based on a large retrospective study, it does not seem that warfarin has an advantage over aspirin in reducing the rate of DVT and PE following TJA [8]. The main strengths of our study are our consideration of almost all long-term adverse consequences associated with VTE and major bleeding events, and performing sensitivity analyses to ensure that the findings hold up against changes in parameters to the model for tested scenarios. However, our model shares the limitations of the study by Schousboe and Brown, such as not considering additional benefits of mechanical prophylaxis and the weakness of evidence comparing aspirin versus warfarin for VTE prophylaxis [9]. However, we attempted to update the transition probabilities and use the rates from the Schousboe and Brown model whenever new evidence was available. To the best of our knowledge there is no clinical trial comparing aspirin versus warfarin for VTE prophylaxis after TJA and we mainly obtained rate of events using available meta-analyses and recently published studies. One of these recent studies was the study published by Raphael et al, which is a single-institution retrospective study comparing 2800 cases receiving aspirin with 26,123 cases receiving warfarin for VTE prophylaxis [8]. The authors indicated that patients who received aspirin had a lower rate of VTE and wound-related problems compared to patients in the warfarin group. Moreover, we only considered VTE prophylaxis during the first two weeks following TJA; therefore, further studies may be needed to study VTE prophylaxis beyond this period.
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In conclusion, the present study demonstrated that aspirin is the preferred VTE prophylaxis agent in patients undergoing THA without a history of VTE compared to warfarin. In patients undergoing TKA, aspirin is also more cost-effective, although in rare occasions (particularly when probability of VTE is high and probability of bleeding is very low), warfarin outperforms aspirin in terms of cost. References 1. Zhan C, Kaczmarek R, Loyo-Berrios N, et al. Incidence and short-term outcomes of primary and revision hip replacement in the United States. J Bone Joint Surg Am 2007;89(3):526. 2. Falck-Ytter Y, Francis CW, Johanson NA, et al. Prevention of VTE in orthopedic surgery patients: antithrombotic therapy and prevention of thrombosis. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines, 141(2 Suppl). Chest, 9th ed.; 2012. p. e278S. 3. Handoll HH, Farrar MJ, McBirnie J, et al. Heparin, low molecular weight heparin and physical methods for preventing deep vein thrombosis and pulmonary embolism following surgery for hip fractures. Cochrane Database Syst Rev 2002;4:CD000305. 4. National Collaborating Centre for Acute Care. Venous thromboembolism: reducing the risk of venous thromboembolism in inpatients undergoing surgery. London: Royal College of Surgeons; 2007. 5. Brown GA. Venous thromboembolism prophylaxis after major orthopaedic surgery: a pooled analysis of randomized controlled trials. J Arthroplasty 2009;24(6 Suppl):77. 6. American Academy of Orthopedic Surgeons. Preventing venous thromboembolic disease in patients undergoing elective hip and knee arthroplasty. Evidence based guidelines and evidence report. Available at http://www.aaos.org/research/guidelines/VTE/ VTE_full_guideline.pdf; 2011. [Accessed February 25, 2014]. 7. Haas SB, Barrack RL, Westrich G, et al. Venous thromboembolic disease after total hip and knee arthroplasty. J Bone Joint Surg Am 2008;90(12):2764. 8. Raphael IJ, Tischler EH, Huang R, et al. Aspirin: an alternative for pulmonary embolism prophylaxis after arthroplasty? Clin Orthop Relat Res 2014;472(2):482. 9. Schousboe JT, Brown GA. Cost-effectiveness of low-molecular-weight heparin compared with aspirin for prophylaxis against venous thromboembolism after total joint arthroplasty. J Bone Joint Surg Am 2013;95:1256. 10. Sonnenberg FA, Beck JR. Markov models in medical decision making: a practical guide. Med Decis Making 1993;13:322. 11. Ginsberg JS, Turkstra F, Buller HR, et al. Postthrombotic syndrome after hip or knee arthroplasty: a cross-sectional study. Arch Intern Med 2000;160(5):669. 12. Kapoor A, Chuang W, Radhakrishnan N, et al. Cost effectiveness of venous thromboembolism pharmacological prophylaxis in total hip and knee replacement: a systematic review. Pharmacoeconomics 2010;28(7):521. 13. Colwell Jr CW, Berkowitz SD, Lieberman JR, et al. Oral direct thrombin inhibitor ximelagatran compared with warfarin for the prevention of venous thromboembolism after total knee arthroplasty. J Bone Joint Surg Am 2005;87(10):2169. 14. Francis CW, Berkowitz SD, Comp PC, et al. Comparison of ximelagatran with warfarin for the prevention of venous thromboembolism after total knee replacement. N Engl J Med 2003;349(18):1703. 15. Pedersen AB, Sorensen HT, Mehnert F, et al. Risk factors for venous thromboembolism in patients undergoing total hip replacement and receiving routine thromboprophylaxis. J Bone Joint Surg Am 2010;92(12):2156. 16. Næss IA, Christiansen SC, Romundstad P, et al. Incidence and mortality of venous thrombosis: a population-based study. J Thromb Haemost 2007;5:692. 17. Gorelick PB, Weisman Steven M. Risk of hemorrhagic stroke with aspirin use an update. Stroke 2005;36(8):1801. 18. Hart RG, Tonarelli SB, Pearce LA. Avoiding central nervous system bleeding during antithrombotic therapy recent data and ideas. Stroke 2005;36(7):1588. 19. Saleh K, Olson M, Resig S, et al. Predictors of wound infection in hip and knee joint replacement: results from a 20 year surveillance program. J Orthop Res 2002;20 (3):506. 20. Pengo V, Lensing AW, Prins MH, et al. Incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism. N Engl J Med 2004;350(22):2257. 21. Mohr DN, Silverstein MD, Heit JA, et al. The venous stasis syndrome after deep venous thrombosis or pulmonary embolism: a population-based study. Mayo Clin Proc 2000; 75(12):1249. 22. Lee WC, Christensen MC, Joshi AV, et al. Long-term cost of stroke subtypes among Medicare beneficiaries. Cerebrovasc Dis 2007;23(1):57. 23. Linkins LA, Choi PT, Douketis JD. Clinical impact of bleeding in patients taking oral anticoagulant therapy for venous thromboembolism: a meta-analysis. Ann Intern Med 2003;139(11):893. 24. Vera-Llonch M, Hagiwara M, Oster G. Clinical and economic consequences of bleeding following major orthopedic surgery. Thromb Res 2006;117(5):569. 25. Kearon C. Natural history of venous thromboembolism. Circulation 2003;107 (23 Suppl 1):I22. 26. Arias E. Centers for Disease Control. United States life tables, 2008. Natl Vital Stat Rep 2012;61(3):1. 27. Biskupiak J, Ghate SR, Jiao T, et al. Cost implications of formulary decisions on oral anticoagulants in nonvalvular atrial fibrillation. J Manag Care Pharm 2013;19(9):789. 28. Bullano MF, Willey V, Hauch O, et al. Longitudinal evaluation of health plan cost per venous thromboembolismor bleed event in patients with a prior venous thromboembolism event during hospitalization. J Manag Care Pharm 2005;11(8):663. 29. Ollendorf DA, Vera-Llonch M, Oster G. Cost of venous thromboembolism following major orthopedic surgery in hospitalized patients. Am J Health Syst Pharm 2002;59 (18):1750.
164
R. Mostafavi Tabatabaee et al. / The Journal of Arthroplasty 30 (2015) 159–164
30. Dobesh PP. Economic burden of venous thromboembolism in hospitalized patients. Pharmacotherapy 2009;29(8):943. 31. 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. 32. Lee HY, Hwang JS, Jeng JS, et al. Quality-adjusted life expectancy (QALE) and loss of QALE for patients with ischemic stroke and intracerebral hemorrhage: a 13-year follow-up. Stroke 2010;41(4):739. 33. Ostendorf M, van Stel HF, Buskens E, et al. Patient-reported outcome in total hip replacement. A comparison of five instruments of health status. J Bone Joint Surg (Br) 2004;86(6):801. 34. Lenert LA, Soetikno RM. Automated computer interviews to elicit utilities: potential applications in the treatment of deep venous thrombosis. J Am Med Inform Assoc 1997;4(1):49. 35. O’Meara III JJ, McNutt RA, Evans AT, et al. A decision analysis of streptokinase plus heparin as compared with heparin alone for deep-vein thrombosis. N Engl J Med 1994;330(26):1864. 36. Sassi F. Calculating QALYs, comparing QALY and DALY calculations. Health Policy Plan 2006;21(5):402.
37. Stewart DW, Freshour JE. Aspirin for the prophylaxis of venous thromboembolic events in orthopedic surgery patients: a comparison of the AAOS and ACCP guidelines with review of the evidence. Ann Pharmacother 2013;47(1):63. 38. Eriksson BI, Borris LC, Friedman RJ, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med 2008;358(26): 2765. 39. Lassen MR, Ageno W, Borris LC, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med 2008;358(26): 2776. 40. Lassen MR, Gallus A, Raskob GE, et al. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. N Engl J Med 2010;363(26):2487. 41. Mahmoudi M, Sobieraj DM. The cost-effectiveness of oral direct factor Xa inhibitors compared with low-molecular-weight heparin for the prevention of venous thromboembolism prophylaxis in total hip or knee replacement surgery. Pharmacotherapy 2013;33(12):1333. 42. Parvizi J, Ghanem E, Joshi A, et al. Does "excessive" anticoagulation predispose to periprosthetic infection? J Arthroplasty 2007;22(6 Suppl 2):24. 43. McDougall CJ, Gray HS, Simpson PM, et al. Complications related to therapeutic anticoagulation in total hip arthroplasty. J Arthroplasty 2013;28(1):187.
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Cost-Effective Prophylaxis Against Venous Thromboembolism After Total Joint Arthroplasty: Warfarin Versus Aspirin Reza Mostafavi Tabatabaee, MD, Mohammad R. Rasouli, MD, Mitchell G. Maltenfort, PhD, Javad Parvizi, MD FRCS The Rothman Institute of Orthopaedics, Thomas Jefferson University, Philadelphia, Pennsylvania
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Article history: Received 11 July 2014 Accepted 27 August 2014 Keywords: aspirin warafarin venous thromboembolism total joint arthroplasty cost-effectiveness analysis
a b s t r a c t Although recent guidelines suggest aspirin for venous thromboembolism (VTE) prophylaxis in low risk patients following total hip arthroplasty (THA) and total knee arthroplasty (TKA), there are no cost-effectiveness studies comparing aspirin and warfarin. In a Markov cohort cost-effectiveness analysis, we found that aspirin cost less and saved more quality-adjusted life-years (QALYs) than warfarin in all age groups. Cost per QALY gained by aspirin was $24,506.20 at age of 55 and $47,148.10 at the age of 85 following THA and $15,117.20 and $24,458.10 after TKA, which were greater than warfarin. In patients undergoing THA/TKA without prior VTE, aspirin is more cost-effective prophylactic agent than warfarin. Warfarin might be a better prophylaxis in TKA patients with high probability of VTE and very low probability of bleeding. © 2014 Elsevier Inc. All rights reserved.
Although total hip arthroplasty (THA) and total knee arthroplasty (TKA) are very safe procedures [1], patients undergoing these procedures are considered to be at risk of venous thromboembolism (VTE), including deep venous thrombosis (DVT) and pulmonary embolism (PE) [2]. Without prophylaxis, VTE may occur in more than 35% of patients after total joint arthroplasty (TJA), although most VTEs are asymptomatic [2–5]. It remains unclear which agent for prophylaxis against VTE after TJA is the most effective and safest. The recent guideline issued by the American College of Chest Physicians (ACCP), endorses the use of aspirin as an effective chemoprophylaxis for prevention of VTE following TJA [2]. The guideline proposed by the American Academy of Orthopaedic Surgeons (AAOS), though it does not endorse one agent over another, lists aspirin as a potential chemoprophylactic agents against VTE following TJA anticoagulation agent [6]. Over the last few years there has been a trend towards the use of aspirin as prophylactic agent in patients undergoing TJA. At our institution aspirin replaced warfarin as the preferred method of VTE prophylaxis a few years ago. Warfarin is a commonly-used anticoagulant that is associated with a higher risk of bleeding compared to aspirin [7]. Because of unpredictable pharmacokinetics, obtaining the optimal level of anticoagulation with warfarin is increasingly difficult, requiring continuous blood monitoring [5,8]. Recently, a Markov cohort cost-effectiveness analysis was performed by Schousboe and Brown to compare the costs, health benefits, and costs per quality-adjusted life-year (QALY) of Low Molecular Weight Heparin (LMWH) versus 160 mg of aspirin per day for 14 days after TJA in
The Conflict of Interest statement associated with this article can be found at http://dx. doi.org/10.1016/j.arth.2014.08.018. Reprint requests: Javad Parvizi, MD, FRCS, The Rothman Institute at Thomas Jefferson University, 125 S 9th St. Suite 1000, Philadelphia, PA 19107. http://dx.doi.org/10.1016/j.arth.2014.08.018 0883-5403/© 2014 Elsevier Inc. All rights reserved.
patients with no history of VTE. The authors concluded that for these patients, aspirin is a cost-effective option for VTE prophylaxis following THA. The study, however, stated that the preferred chemoprophylactic agent after TKA depends on age and is uncertain for patients younger than 80 years old [9]. Although the aforementioned study showed the superiority of aspirin over LMWH in the majority of cases, there are no data comparing cost, health benefits, and QALY of warfarin, which is commonly used for VTE prophylaxis following TJA, versus aspirin. Therefore, the present study was designed and conducted to compare cost and health benefits of anticoagulation using warfarin with aspirin following TJA using a comparable Markov cohort cost-effectiveness model. Materials and Methods Markov modeling is applicable when a treatment decision involves consideration of continuous risk, the timing of events is necessary, and important events may occur more than once [10]. We adapted the Schousboe and Brown model, excluding the thrombocyteopenia state (a consequence of LMWH) and including periprosthetic joint infection (PJI) and chronic pulmonary hypertension, which had been included in Schousboe and Brown’s extended model [9]. After TJA, patients were allocated into the following groups: healthy state, postoperative bleeding at operation site, non-operation-site bleeding, symptomatic DVT, and symptomatic PE. Individuals then transitioned to one of four health states: healthy, no postphlebitic syndrome (PPS) after VTE, PPS after VTE, survival after intracranial hemorrhage, or chronic pulmonary hypertension (Fig. 1). Patients with intracranial hemorrhage following VTE prophylaxis who survived were transitioned to the post-intracranial hemorrhage state to capture the costs and disutility. As calculated by Schousboe and Brown [9], the post-intracranial hemorrhage state persists for the
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R. Mostafavi Tabatabaee et al. / The Journal of Arthroplasty 30 (2015) 159–164 Table 1 The Incidence Rates of Adverse Events Following Total Joint Arthroplasty in Patients Treated With Warfarin Versus Aspirin. The Incidence Rates
Symptomatic DVT Symptomatic PE Asymptomatic DVT Bleeding at operative site Bleeding at non-operative site
Warfarin
Aspirin
THA
TKA
THA
TKA
0.82% 0.92% 32% 3.2% 2.15%
1.25% 0.63% 30.48% 3.5% 2.7%
0.79% 0.40% 16% 0.83% 1.41%
2.18% 0.26% 51% 1.06% 0.48%
DVT: deep vein thrombosis, PE: pulmonary embolism, THA: total hip arthroplasty, TKA: total knee arthroplasty.
Fig. 1. Health states and model transitions following total joint arthroplasty (TJA). DVT: deep venous thrombosis, PE: pulmonary embolism, PPS: postphlebitic syndrome, CPHTN: Chronic pulmonary hypertension, TJA: total joint arthroplasty, PJI/SSI: periprosthetic joint infection/surgical site infection, VTE: venous thromboembolism.
following four years. After uneventful TJA or full recovery from one-time postoperative events (non-intracranial hemorrhage), patients transited to the healthy state. Because patients are at increased risk of developing PPS during the first five years following a postoperative asymptomatic VTE event [11], patients may transit from the healthy state to the PPS status during this period. Otherwise, asymptomatic DVT is assumed to not result in any cost or lost QALY. Hypothetical Markov cohorts were run for THA and TKA separately, and patients were divided into the following age groups: 55–60, 61–65, 66–70, 71–74, 75–80, 81–85, and N85 years. We considered a lifetime horizon and followed individuals until death or the age of 100 years. We found the estimation of the probabilities of postoperative adverse health events and their associated costs and disutility based on the available literature, particularly systematic reviews and meta-analyses. Transition Probabilities In the meta-analysis by Brown, the incidence rates of postoperative symptomatic VTE and PE events were estimated to be 2.01% and 0.40%, respectively, for patients undergoing TJA who received warfarin [5]. In a retrospective study comparing the prophylactic effects of aspirin and warfarin following TJA, the risk of symptomatic DVT and PE events was estimated to be 0.82% and 0.47% respectively after THA and 1.18% and 1.74% after TKA [8]. Using pooled data from these studies and other reports [12–14], we estimated the risk of symptomatic DVT and PE to be 0.82% and 0.92% respectively after THA and 1.25% and 0.63% after TKA for warfarin prophylaxis. We also assigned rates of asymptomatic DVT and major bleeding at the operative and nonoperative sites to be 32%, 3.2%, and 2.15% for THA and 30.5%, 3.5%, and 2.7% for TKA on the basis of the available literature [5,8,12–14] (Table 1). Transition probabilities for aspirin were mainly obtained from Schousboe and Brown’s study. For patients treated with aspirin, they estimated the rates of symptomatic DVT and PE, asymptomatic DVT,
and major bleeding at the operative and non-operative sites as 1.10%, 0.51%, 16%, 2.13%, and 0.97% for THA and 1.09%, 51%, 2.13%, and 0.97% for TKA correspondingly [9]. In the retrospective study by Raphael et al, the risks of symptomatic DVT and PE events were estimated to be 0.57% and 0.38% in TKA patients. In that study, 0.23% of patients who underwent THA were affected with symptomatic DVT during treatment with aspirin and there was no report of PE [8]. Table 1 demonstrates the estimated risks of adverse events in the aspirin and warfarin groups following THA and TKA. Because we limited our analysis to patients without previous history of VTE, all above VTE rates were adjusted using the relative risk of VTE after TJA in patients with history of VTE versus those without history of VTE, which is 8.1% [15]; and the following equation, which is the same that Schousboe et al used in their study [9]. RiskNo
prior h VTE ¼ RiskAll = 1 þ RiskPrior
VTE vs No prior VTE –1
PrevalencePrior
VTE
The age-specific incidence of prior VTE was estimated based on a population-based study in Norway[16] and ranged from 0.72% at the age of 55 years to 4.73% at the age of 85 years. The incidence rate of intracranial hemorrhage (ICH) was considered to be 0.02% for patients treated with aspirin [17] and 0.45% for patients treated with warfarin [18]. In the study by Saleh et al [19] hematoma developed in 19 cases out of 33 of SSI episodes (58%) while the corresponding number was 4 out of 64 (6%) in patients without SSI after TJA. Based on this study and rate of operative site bleeding after THA (0.032) and TKA (0.035), the incidence rates of surgical site infection (SSI)/PJI after operative site bleeding following THA and TKA were estimated as 1.86% and 2.03% for warfarin and 0.48% and 0.61% for aspirin respectively. Over a 2-year period, 3.8% of patients with PE may experience chronic pulmonary hypertension because of persistent obstruction of the pulmonary artery. The risk of chronic pulmonary hypertension is higher in patients with idiopathic PE than those PE cases with known etiology (odds ratio, 5.7). Pengo et al found that the proportion of all patients with a first time idiopathic PE was 37.2% [20]. Using these facts and the same adjustment for no prior VTE, we calculated the rate of chronic pulmonary hypertension following PE after TJA to be 0.014%. The risk of PPS was considered to rise for 20 years after a VTE event, with a cumulative incidence of 16% in all patients with a symptomatic VTE event [21]. According to the study conducted by Mohr et al, we considered that 7%, 14%, 20%, and 27% of survivors would develop PPS at 1, 5, 10, and 20 years after the VTE event respectively [21]. We considered that the risk of PPS after an asymptomatic VTE would be one fifth of the risk after a symptomatic VTE event [11]. Mortality Intracranial hemorrhage and other non-operative site bleeding have a 25.5% [22] and 6% [23] risk of death, respectively. Major operative site
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bleeding was assumed not to cause mortality, but 42% of these patients would have reoperations [5,24]. The fatality rate after PE was estimated to be 15% [25]. We used age-specific background mortality due to other causes in United States for 2008 [26].
Table 3 Lifetime Cost, QALYs Gained, and Costs per QALY for Warfarin and Aspirin for Different Ages Using the Markov Cohort Model. Total Hip Arthroplasty
The Costs and Health State Utilities and Disutilities of One-Time Adverse Health Events
55 years old Costs QALYs Cost per QALY 60 years old Costs QALYs Cost per QALY 65 years old Costs QALYs Cost per QALY 70 years old Costs QALYs Cost per QALY 75 years old Costs QALYs Cost per QALY 80 years old Costs QALYs Cost per ALY 85 years old Costs QALYs Cost per QALY
In addition to the costs of medication (warfarin and aspirin), Table 2 shows costs related to laboratory tests required for monitoring of warfarin [9,27]. It also contains the costs and QALYs for one-time episodes of DVT, PE, and bleeding according to previous studies [9,24,28–30]. Yearly costs for chronic health states, loss of QALY for a single event, and QALY value gained for chronic health states during one year are shown in table 2 [9,24,28–36]. Using the Consumer Price Index for medical care, all costs were updated to 2013 US dollars (available at http://www.bls.gov/cpi/). The quality-adjusted life-year (QALY) is a measure for assessing disease burden both quantitatively and qualitatively. The value of QALY ranges from 0 (death) to 1 (perfect health). Calculating QALY using some specific methods such as the EuroQol 5D (EQ-5D), a negative number can be calculated. Because of senile chronic conditions and loss of mobility, QALY values decrease with age even for healthy individuals [36]. Model Runs and Sensitivity Analyses We used decision analysis software (TreeAge Pro, ©2013; TreeAge Software, Williamstown, MA) for Markov cohort analysis. The starting age was incrementally increased from 55 to 85. For each starting age and joint, total cost and QALY were assessed. A cycle length of one month was used. Two-way sensitivity analysis was performed to see if changing the relative rates of symptomatic VTE and bleeding events affected the results.
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Total Knee Arthroplasty
Warfarin
Aspirin
Warfarin
Aspirin
$3287.14 13.21979 $24,506.2
$1959.5 13.27396
$3816.3 13.19451 $15,117.2
$1516.3 13.34666
$2980.3 11.78769 $25,553.0
$1769.5 11.83508
$3460.3 11.76519 $15,690.2
$1350.2 11.89967
$2654.8 10.26823 $27,020.2
$1567.5 10.30847
$3082.6 10.24866 $16,467.7
$1176.0 10.36445
$2325.0 8.69975 $29,156.7
$1362.2 8.73277
$2698.8 8.68325 $17,524.0
$1006.8 8.77981
$2004.1 7.10954 $32,460.9
$1161.3 7.1355
$2323.0 7.0962 $18,995.9
$856.1 7.17342
$1708.3 5.56106 $37,837.0
$974.9 5.58044
$1973.5 5.55084 $21,133.1
$733.8 5.6095
$1448.1 4.12862 $47,148.1
$810.0 4.14215
$1663.6 4.12128 $24,458.1
$640.4 4.16311
QALY: Quality-adjusted life-year.
Table 2 Costs and Quality-Adjusted Life-Year (QALYs). Parameter
Adjusted Value for 2013
Reference
Aspirin (160 mg per day) The monthly cost of warfarin monitoring per patient: (Medications, Laboratory, and Pharmacist monitoring) Costs for one-time events Symptomatic DVT During surgical hospital stay After surgical hospital stay Pulmonary embolism During surgical hospital stay After surgical hospital stay Operative site hemorrhage Non-operative site hemorrhage Yearly costs for chronic health states Postphlebitic syndrome First year Subsequent years Post-intracranial hemorrhage Periprosthetic Joint Infection (The sum of the inpatient and outpatient costs) Loss of QALY for a single event Symptomatic DVT During surgical hospital stay After surgical hospital stay Pulmonary embolism During surgical hospital stay After surgical hospital stay Nonoperative site hemorrhage Operative site hemorrhage Estimated QALY value for chronic health states during a year Healthy state Postphlebitic syndrome Survival after intracranial hemorrhage
$0.80 for 1 mon $80.78
Schousboe & Brown (2013)9 Biskupiak et al (2013)27
DVT: deep venous thrombosis, QALY: quality-adjusted life-year.
$24,079 $8243 $15,836 $34,788 $14,674 $20,114 $7355 $4993
Bullano et al (2005),28 Dobesh (2009)30 Bullano et al (2005)28 Ollendorf et al (2002)29 Bullano et al (2005)28 Vera-Llonch et al (2006)24 Vera-Llonch et al (2006)24
$4147 $1822 $13,714 $168,398
Caprini et al (2003)31 and Dobesh (2009)30 Caprini et al (2003)31 and Dobesh (2009)30 Lee et al (2007)22 Schousboe & Brown (2013)9
−0.007 −0.0123
Ollendorf et al (2002)29 Bullano et al (2005)28
−0.013 −0.0148 −0.0029 −0.0038
Ollendorf et al (2002)29 Bullano et al (2005)28 Vera-Llonch et al (2006)24 Vera-Llonch et al (2006)24
0.76 Ostendorf et al (2004)33 0.735 Lenert and Soetikno (1997)34 and Caprini et al (2003)31 0.29 × 3 mos, then 0.45 × 3.75 yrs, then 0.76 Lee et al (2010)32 and O’Meara et al (1994)35
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Fig. 2. Two-way sensitivity analysis in patients aged 65 years demonstrating rates of venous thromboembolism events versus the rate of major bleeding compared to the base case. Part A comparing aspirin versus warfarin in total hip arthroplasty and Part B comparing aspirin versus warfarin in total knee arthroplasty.
Results In all age groups and in both THA and TKA, aspirin was consistently associated with higher QALY and lower cost than warfarin (Table 3). However, the reduced QALY for patients using warfarin was very small compared to those using aspirin and the extra cost of using warfarin was no more than $4000 per patient. By increasing age in both THA and TKA groups, cost per QALYs gained by using aspirin increased. At age 55–60, cost per QALY gained by aspirin was $24,506.20 following THA, which increased to $47,148.10 by age 85. The corresponding costs in TKA were $15,117.20 and $24,458.10 respectively. In THA patients, cost per QALYs gained by aspirin was greater than the corresponding ages in the TKA group. Two-way sensitivity analysis was performed for the 65–70 age group for THA and TKA separately to determine chosen VTE prophylaxis agent for a given rate of VTE versus the rate of major bleeding compared
to the base case. Sensitivity analysis indicated that in all rates of VTE events, aspirin is the preferred VTE prophylaxis agent in patients aged 65–70 years undergoing THA. However, in the sensitivity analysis for TKA, warfarin was dominant for all risks of VTE when risk of major bleeding was assumed to be extremely low (Fig. 2). Discussion The most effective agents for prevention of venous thromboembolism following TJA continues to be debated with no one agent proving to be superior to another when all risks and benefits are taken into account [37]. Some studies have shown better efficacy for new agents such as oral direct factor Xa inhibitor over other modalities in prevention of DVT [38–41]. Although safety profile of the newer anticoagulants has improved, the use of these aggressive anticoagulants such as LMWH is associated with higher incidence of wound drainage, bleeding, reoperation,
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infection, and even mortality and predisposes patients who are at low risk of VTE to a great risk of these adverse events [42,43]. Thus, the choice of most appropriate VTE prophylaxis following TJA remains largely at the discretion of the orthopedic surgeon and the caring medical team. Because of its proven efficacy and low rate of postoperative complications, aspirin has been endorsed as an acceptable VTE prophylaxis by the recent guidelines [2,6]. At our institution we have been utilizing aspirin as the preferred method of VTE prophylaxis over the last few years. Prior to the use of aspirin majority of our patients were placed on warfarin for VTE prophylaxis. One of the main issues related to administration of anticoagulation relates to cost. With the limited resources and the scrutiny on “quality” of care, cost for each episode of care and the ensuing complications that may arise, have taken a center stage. This study was designed to examine the cost of VTE prophylaxis following TJA comparing warfarin or aspirin using the Markov modeling. The Markov modeling is used with increasing frequency to determine “cost-effectiveness” of various modalities when a treatment decision involves consideration of continuous risk, the timing of events is necessary, and important events may occur more than once. It is often difficult to evaluate such clinical settings using conventional decision options and may lead to unrealistic simplifying assumptions [10]. In this study, the cost burden, QALY, and cost per QALY for aspirin and warfarin in THA and TKA were calculated separately. Our findings indicated that in all THA and the majority of TKA patients without history of VTE who have low risk of developing VTE, aspirin is associated with lower cost and saves more QALYs compared to warfarin. Sensitivity analysis for patients aged 65–70 years demonstrated that when rate of major bleedings is very low versus all rates of VTE, aspirin might be more cost-effective in patients undergoing TKA. This is similar to the findings of a recently published study by Schousboe and Brown, when the costs and QALYs gained by aspirin versus LMWH were compared [9]. It was shown that aspirin is superior to LMWH in THA cases, while the benefit of aspirin in TKA cases depends on patient’s age. Based on these two studies, it seems that aspirin is a cost-effective VTE prophylaxis agent and can be used safely in patients without history of VTE who are at low risk for development of VTE following TJA. There are several reasons explaining why aspirin is more costeffective compared to warfarin. There is growing evidence associating warfarin with increased risk of postoperative-site bleeding which in turn increases risk of SSI/PJI following TJA [5,7]. Moreover, warfarin is associated with a higher risk of major nonoperative site bleeding compared to aspirin. On the other hand, based on a large retrospective study, it does not seem that warfarin has an advantage over aspirin in reducing the rate of DVT and PE following TJA [8]. The main strengths of our study are our consideration of almost all long-term adverse consequences associated with VTE and major bleeding events, and performing sensitivity analyses to ensure that the findings hold up against changes in parameters to the model for tested scenarios. However, our model shares the limitations of the study by Schousboe and Brown, such as not considering additional benefits of mechanical prophylaxis and the weakness of evidence comparing aspirin versus warfarin for VTE prophylaxis [9]. However, we attempted to update the transition probabilities and use the rates from the Schousboe and Brown model whenever new evidence was available. To the best of our knowledge there is no clinical trial comparing aspirin versus warfarin for VTE prophylaxis after TJA and we mainly obtained rate of events using available meta-analyses and recently published studies. One of these recent studies was the study published by Raphael et al, which is a single-institution retrospective study comparing 2800 cases receiving aspirin with 26,123 cases receiving warfarin for VTE prophylaxis [8]. The authors indicated that patients who received aspirin had a lower rate of VTE and wound-related problems compared to patients in the warfarin group. Moreover, we only considered VTE prophylaxis during the first two weeks following TJA; therefore, further studies may be needed to study VTE prophylaxis beyond this period.
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In conclusion, the present study demonstrated that aspirin is the preferred VTE prophylaxis agent in patients undergoing THA without a history of VTE compared to warfarin. In patients undergoing TKA, aspirin is also more cost-effective, although in rare occasions (particularly when probability of VTE is high and probability of bleeding is very low), warfarin outperforms aspirin in terms of cost. References 1. Zhan C, Kaczmarek R, Loyo-Berrios N, et al. Incidence and short-term outcomes of primary and revision hip replacement in the United States. J Bone Joint Surg Am 2007;89(3):526. 2. Falck-Ytter Y, Francis CW, Johanson NA, et al. Prevention of VTE in orthopedic surgery patients: antithrombotic therapy and prevention of thrombosis. American College of Chest Physicians Evidence-Based Clinical Practice Guidelines, 141(2 Suppl). Chest, 9th ed.; 2012. p. e278S. 3. Handoll HH, Farrar MJ, McBirnie J, et al. Heparin, low molecular weight heparin and physical methods for preventing deep vein thrombosis and pulmonary embolism following surgery for hip fractures. Cochrane Database Syst Rev 2002;4:CD000305. 4. National Collaborating Centre for Acute Care. Venous thromboembolism: reducing the risk of venous thromboembolism in inpatients undergoing surgery. London: Royal College of Surgeons; 2007. 5. Brown GA. Venous thromboembolism prophylaxis after major orthopaedic surgery: a pooled analysis of randomized controlled trials. J Arthroplasty 2009;24(6 Suppl):77. 6. American Academy of Orthopedic Surgeons. Preventing venous thromboembolic disease in patients undergoing elective hip and knee arthroplasty. Evidence based guidelines and evidence report. Available at http://www.aaos.org/research/guidelines/VTE/ VTE_full_guideline.pdf; 2011. [Accessed February 25, 2014]. 7. Haas SB, Barrack RL, Westrich G, et al. Venous thromboembolic disease after total hip and knee arthroplasty. J Bone Joint Surg Am 2008;90(12):2764. 8. Raphael IJ, Tischler EH, Huang R, et al. Aspirin: an alternative for pulmonary embolism prophylaxis after arthroplasty? Clin Orthop Relat Res 2014;472(2):482. 9. Schousboe JT, Brown GA. Cost-effectiveness of low-molecular-weight heparin compared with aspirin for prophylaxis against venous thromboembolism after total joint arthroplasty. J Bone Joint Surg Am 2013;95:1256. 10. Sonnenberg FA, Beck JR. Markov models in medical decision making: a practical guide. Med Decis Making 1993;13:322. 11. Ginsberg JS, Turkstra F, Buller HR, et al. Postthrombotic syndrome after hip or knee arthroplasty: a cross-sectional study. Arch Intern Med 2000;160(5):669. 12. Kapoor A, Chuang W, Radhakrishnan N, et al. Cost effectiveness of venous thromboembolism pharmacological prophylaxis in total hip and knee replacement: a systematic review. Pharmacoeconomics 2010;28(7):521. 13. Colwell Jr CW, Berkowitz SD, Lieberman JR, et al. Oral direct thrombin inhibitor ximelagatran compared with warfarin for the prevention of venous thromboembolism after total knee arthroplasty. J Bone Joint Surg Am 2005;87(10):2169. 14. Francis CW, Berkowitz SD, Comp PC, et al. Comparison of ximelagatran with warfarin for the prevention of venous thromboembolism after total knee replacement. N Engl J Med 2003;349(18):1703. 15. Pedersen AB, Sorensen HT, Mehnert F, et al. Risk factors for venous thromboembolism in patients undergoing total hip replacement and receiving routine thromboprophylaxis. J Bone Joint Surg Am 2010;92(12):2156. 16. Næss IA, Christiansen SC, Romundstad P, et al. Incidence and mortality of venous thrombosis: a population-based study. J Thromb Haemost 2007;5:692. 17. Gorelick PB, Weisman Steven M. Risk of hemorrhagic stroke with aspirin use an update. Stroke 2005;36(8):1801. 18. Hart RG, Tonarelli SB, Pearce LA. Avoiding central nervous system bleeding during antithrombotic therapy recent data and ideas. Stroke 2005;36(7):1588. 19. Saleh K, Olson M, Resig S, et al. Predictors of wound infection in hip and knee joint replacement: results from a 20 year surveillance program. J Orthop Res 2002;20 (3):506. 20. Pengo V, Lensing AW, Prins MH, et al. Incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism. N Engl J Med 2004;350(22):2257. 21. Mohr DN, Silverstein MD, Heit JA, et al. The venous stasis syndrome after deep venous thrombosis or pulmonary embolism: a population-based study. Mayo Clin Proc 2000; 75(12):1249. 22. Lee WC, Christensen MC, Joshi AV, et al. Long-term cost of stroke subtypes among Medicare beneficiaries. Cerebrovasc Dis 2007;23(1):57. 23. Linkins LA, Choi PT, Douketis JD. Clinical impact of bleeding in patients taking oral anticoagulant therapy for venous thromboembolism: a meta-analysis. Ann Intern Med 2003;139(11):893. 24. Vera-Llonch M, Hagiwara M, Oster G. Clinical and economic consequences of bleeding following major orthopedic surgery. Thromb Res 2006;117(5):569. 25. Kearon C. Natural history of venous thromboembolism. Circulation 2003;107 (23 Suppl 1):I22. 26. Arias E. Centers for Disease Control. United States life tables, 2008. Natl Vital Stat Rep 2012;61(3):1. 27. Biskupiak J, Ghate SR, Jiao T, et al. Cost implications of formulary decisions on oral anticoagulants in nonvalvular atrial fibrillation. J Manag Care Pharm 2013;19(9):789. 28. Bullano MF, Willey V, Hauch O, et al. Longitudinal evaluation of health plan cost per venous thromboembolismor bleed event in patients with a prior venous thromboembolism event during hospitalization. J Manag Care Pharm 2005;11(8):663. 29. Ollendorf DA, Vera-Llonch M, Oster G. Cost of venous thromboembolism following major orthopedic surgery in hospitalized patients. Am J Health Syst Pharm 2002;59 (18):1750.
164
R. Mostafavi Tabatabaee et al. / The Journal of Arthroplasty 30 (2015) 159–164
30. Dobesh PP. Economic burden of venous thromboembolism in hospitalized patients. Pharmacotherapy 2009;29(8):943. 31. 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. 32. Lee HY, Hwang JS, Jeng JS, et al. Quality-adjusted life expectancy (QALE) and loss of QALE for patients with ischemic stroke and intracerebral hemorrhage: a 13-year follow-up. Stroke 2010;41(4):739. 33. Ostendorf M, van Stel HF, Buskens E, et al. Patient-reported outcome in total hip replacement. A comparison of five instruments of health status. J Bone Joint Surg (Br) 2004;86(6):801. 34. Lenert LA, Soetikno RM. Automated computer interviews to elicit utilities: potential applications in the treatment of deep venous thrombosis. J Am Med Inform Assoc 1997;4(1):49. 35. O’Meara III JJ, McNutt RA, Evans AT, et al. A decision analysis of streptokinase plus heparin as compared with heparin alone for deep-vein thrombosis. N Engl J Med 1994;330(26):1864. 36. Sassi F. Calculating QALYs, comparing QALY and DALY calculations. Health Policy Plan 2006;21(5):402.
37. Stewart DW, Freshour JE. Aspirin for the prophylaxis of venous thromboembolic events in orthopedic surgery patients: a comparison of the AAOS and ACCP guidelines with review of the evidence. Ann Pharmacother 2013;47(1):63. 38. Eriksson BI, Borris LC, Friedman RJ, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med 2008;358(26): 2765. 39. Lassen MR, Ageno W, Borris LC, et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med 2008;358(26): 2776. 40. Lassen MR, Gallus A, Raskob GE, et al. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. N Engl J Med 2010;363(26):2487. 41. Mahmoudi M, Sobieraj DM. The cost-effectiveness of oral direct factor Xa inhibitors compared with low-molecular-weight heparin for the prevention of venous thromboembolism prophylaxis in total hip or knee replacement surgery. Pharmacotherapy 2013;33(12):1333. 42. Parvizi J, Ghanem E, Joshi A, et al. Does "excessive" anticoagulation predispose to periprosthetic infection? J Arthroplasty 2007;22(6 Suppl 2):24. 43. McDougall CJ, Gray HS, Simpson PM, et al. Complications related to therapeutic anticoagulation in total hip arthroplasty. J Arthroplasty 2013;28(1):187.
