Farzad Vosooghi, Mohammad S Abdelaal, SM Javad Mortazavi.
Response/Recommendation: Aspirin (ASA) is the most cost-effective venous thromboembolism (VTE) prophylaxis as the cost of drug is nominal, the rate of complications such as bleeding associated with administration of ASA is low, and there is no need for blood tests or other methods to monitor the agent. The cost-effectiveness of different methods of VTE prophylaxis depends mostly on the initial cost of the chemical or mechanical modality, the need for monitoring, rate of complications associated with administration of the modality, and the need for reversal agents. We recognize that the cost of various prophylactic agents varies widely across the globe.
Strength of Recommendation: Intermediate.
Rationale: Major orthopaedic surgeries are reported to be associated with considerable risk of developing VTE. If no perioperative VTE prophylaxis is provided, these procedures can be associated with up to 44% risk of postoperative deep venous thrombosis (DVT), 3% of pulmonary embolism (PE), and 0.7% of all-cause mortality1. VTE is the third most common cause of death and is considered the most common preventable cause of death in hospitalized patients2. These presumed drastic consequences have resulted in thromboprophylaxis to become standard of care after major orthopaedic surgeries. Main VTE preventable measures include mechanical prophylaxis and chemo-prophylactic agents such as ASA, warfarin, low-molecular-weight heparin (LMWH), low dose unfractionated heparin (UFH), fondaparinux, and direct oral anticoagulants (DOAC), (e.g., rivaroxaban, apixaban and dabigatran).
With substantial increase in the volume of major orthopaedic procedures, the increasing cost of thromboprophylaxis, and limitations in health care resources, there is an indispensable need to create a balance between the effectiveness of different prophylactic measures and their cost2. Most cost-effectiveness analyses in the literature evaluated the cost utility of VTE prophylactic measures following total hip arthroplasty (THA), total knee arthroplasty (TKA) and hip fracture surgeries with scarce evidence regarding other orthopaedic procedures.
In an audience response poll during the 2018 Annual meeting of the American Association of Hip and Knee Surgeons (AAHKS), ASA was the most popular agent used for VTE prophylaxis after THA and TKA (86% of respondents)3. It is effective, inexpensive, well-tolerated by patients, and is an oral agent that requires no blood tests or other methods of monitoring4. When studied against warfarin, the use of ASA was associated with a higher quality-adjusted life-year (QALY) measure and lower cost than warfarin for both TKA and THA in all ages5. When compared to LMWH, 160 mg ASA had higher cost-effectiveness for VTE prophylaxis following THA for patients with no history of VTE6. Following TKA, the evidence was less certain, but ASA was still superior to warfarin in TKA cases with no additional risk factor of thrombosis6. Also, compared with LMWH, ASA was associated with a cost-effectiveness benefit in TKA patients more than 80-years of age6. It was demonstrated that in older patients with less life expectancy, less QALYs are lost secondary to mortality from PE and postphlebitic syndrome5. The cost per QALY gained is thus much higher following potent anticoagulants administration (e.g., LMWH) compared to ASA. Therefore, the older a patient is, the more cost-effective ASA might be7.
In 2018, Dawoud et. al.8, performed a systematic review and cost-effectiveness study of different VTE prophylactic strategies comparing no prophylaxis, LMWH (short term use [7 – 10 days]), LMWH (long term duration [28 – 30 days]), LMWH (short term use) followed by extended ASA use (28 days), LMWH + antiembolic stocking (AES), AES, intermittent pneumatic compression (IPC) devices, foot pump, foot pump + AES, fondaparinux + AES, ASA (short term use), apixaban and rivaroxaban. They considered a lifetime horizon and tried to include different drug complications including major bleeding, clinically related non-major bleeding, and heparin-induced thrombocytopenia. They concluded that after THA, 14 days LMWH followed by 28 days ASA administration has the best cost-effectiveness. Regarding TKA, foot pump and ASA were the most cost-effective measures against VTE.
Previous studies demonstrated superior cost-efficacy of LMWH after major orthopaedic surgeries compared to low dose UFH, warfarin, and no prophylaxis2,9,10. Lazo-Langner et. al., compared the cost effectiveness of warfarin, UFH, LMWH, fondaparinux and ximelgatran11. They found that compared to placebo, Ximelgatran has the best cost-effectiveness profile among other agents, especially with TKA. Their findings showed that the highest rate of VTE occurred with prophylaxis with UFH, while the lowest VTE rate was seen with fondaparinux. Warfarin has the least bleeding complication, while fondaparinux has the highest rate of bleeding. They estimated 2.55 fatality ratio of major bleeding compared to VTE episode emphasizing the threatening potential of bleeding complications.
The cost-effectiveness of rivaroxaban 10 mg/day compared to LMWH (enoxaparin 40 mg/day) following TKA and THA was demonstrated by several studies from the United Kingdom (UK)12 , the United States (US)13, Canada14, Sweden15, the Republic of Ireland16, France, Italy, and Spain17. These papers either compared extended rivaroxaban use (35 days) to extended LMWH administration (31 – 39 days) (RECORD 1)18, extended rivaroxaban use (31 – 39 days) to short term LMWH administration (10 – 14 days) (RECORD 2)19, or short term rivaroxaban to short term LMWH administration (RECORD 3 trial)20. Most of them considered the benefit of VTE reduction against the cost of drug acquisition, as well as the major bleeding and its consequences. However, these studies did not take into account the cost of “non-major but clinically related” bleeding episodes. A few studies evaluating both major and non-major bleeding complications demonstrated a better profile of LMWH compared to rivaroxaban8.
Further, studies performed in Canada21 and the UK19 concluded the cost-effectiveness of apixaban over LMWH after THA and TKA and reports from Russia22, Ireland16 and UK12,23 favoring dabigatran (compared to LMWH) following TKA and THA. Two studies found apixaban more cost-effective than dabigatran23. Four studies demonstrated the superiority of rivaroxaban over dabigatran performed in the UK12, France, Italy, Spain17, Ireland16, and Norway24. One study concluded the superiority of rivaroxaban compared to apixaban12.
Rafael et. al., compared the cost-effectiveness of apixaban, dabigatran, rivaroxaban, LMWH, IPC, IPC + LMWH and simultaneous IPC and apixaban administration. They demonstrated IPC with/without apixaban to be appropriate according to their cost effectiveness profile. They recommended to use prophylactic measures in accordance with the bleeding/thrombosis risk of each patient25.
Interestingly, the cost-effectiveness of different methods depended mostly on the cost of acquisition of the drug or mechanical prophylactic device and their complications25. For instance, studies comparing rivaroxaban versus LMWH in countries with more expensive rivaroxaban acquisition including Germany (from hospital perspective) and China, favored LMWH following either THA or TKA despite the higher efficacy of rivaroxaban in preventing VTE1. In addition, complications other than bleeding such as hematoma formation and infection which may lead to subsequent readmission or reoperation have not been considered in most of these studies1,5. Further, most of these studies on antithrombotic agents have compared LMWH and DOAC, or various DOAC. However, the most commonly used orally administered antithrombotic agents (ASA, rivaroxaban, and apixaban) have not been compared. Large-scale studies are required to explore the difference in cost-utility of these oral agents.
1. Zindel S, Stock S, Müller D, Stollenwerk B. A multi-perspective cost-effectiveness analysis comparing rivaroxaban with enoxaparin sodium for thromboprophylaxis after total hip and knee replacement in the German healthcare setting. BMC Health Serv Res. 2012;12:192. doi:10.1186/1472-6963-12-192
2. Avorn J, Winkelmayer WC. Comparing the Costs, Risks, and Benefits of Competing Strategies for the Primary Prevention of Venous Thromboembolism. Circulation. 2004;110(24_suppl_1):IV-25. doi:10.1161/01.CIR.0000150642.10916.ea
3. Abdel MP, Berry DJ. Current Practice Trends in Primary Hip and Knee Arthroplasties Among Members of the American Association of Hip and Knee Surgeons: A Long-Term Update. The Journal of Arthroplasty. 2019;34(7):S24-S27. doi:10.1016/j.arth.2019.02.006
4. Lieberman JR, Heckmann N. Venous Thromboembolism Prophylaxis in Total Hip Arthroplasty and Total Knee Arthroplasty Patients: From Guidelines to Practice. JAAOS – Journal of the American Academy of Orthopaedic Surgeons. 2017;25(12):789-798. doi:10.5435/JAAOS-D-15-00760
5. Mostafavi Tabatabaee R, Rasouli MR, Maltenfort MG, Parvizi J. Cost-effective prophylaxis against venous thromboembolism after total joint arthroplasty: warfarin versus aspirin. J Arthroplasty. 2015;30(2):159-164. doi:10.1016/j.arth.2014.08.018
6. 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(14):1256-1264. doi:10.2106/JBJS.L.00400
7. Landy DC, Bradley AT, King CA, Puri L. Stratifying Venous Thromboembolism Risk in Arthroplasty: Do High-Risk Patients Exist? J Arthroplasty. 2020;35(5):1390-1396. doi:10.1016/j.arth.2020.01.013
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9. Menzin J, Colditz GA, Regan MM, Richner RE, Oster G. Cost-effectiveness of enoxaparin vs low-dose warfarin in the prevention of deep-vein thrombosis after total hip replacement surgery. Arch Intern Med. 1995;155(7):757-764.
10. O’Brien BJ, Anderson DR, Goeree R. Cost-effectiveness of enoxaparin versus warfarin prophylaxis against deep-vein thrombosis after total hip replacement. CMAJ. 1994;150(7):1083-1090.
11. Lazo-Langner A, Rodger MA, Barrowman NJ, Ramsay T, Wells PS, Coyle DA. Comparing multiple competing interventions in the absence of randomized trials using clinical risk-benefit analysis. BMC Medical Research Methodology. 2012;12(1):3. doi:10.1186/1471-2288-12-3
12. Migliaccio-Walle K, Rublee D, Simon TA. Anticoagulation prophylaxis in orthopedic surgery: an efficiency frontier approach. Postgrad Med. 2012;124(1):41-49. doi:10.3810/pgm.2012.01.2516
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14. Diamantopoulos A, Lees M, Wells PS, Forster F, Ananthapavan J, McDonald H. Cost-effectiveness of rivaroxaban versus enoxaparin for the prevention of postsurgical venous thromboembolism in Canada. Thromb Haemost. 2010;104(4):760-770. doi:10.1160/TH10-01-0071
15. Ryttberg L, Diamantopoulos A, Forster F, Lees M, Fraschke A, Björholt I. Cost-effectiveness of rivaroxaban versus heparins for prevention of venous thromboembolism after total hip or knee surgery in Sweden. Expert Rev Pharmacoecon Outcomes Res. 2011;11(5):601-615. doi:10.1586/erp.11.65
16. McCullagh L, Tilson L, Walsh C, Barry M. A cost-effectiveness model comparing rivaroxaban and dabigatran etexilate with enoxaparin sodium as thromboprophylaxis after total hip and total knee replacement in the irish healthcare setting. Pharmacoeconomics. 2009;27(10):829-846. doi:10.2165/11313800-000000000-00000
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19. Kakkar AK, Brenner B, Dahl OE, et al. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial. The Lancet. 2008;372(9632):31-39. doi:10.1016/S0140-6736(08)60880-6
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24. Thromboprophylactic treatment with rivaroxaban or dabigatran compared with enoxaparin or dalteparin in patients undergoing elective hip- or knee replacement surgery. Norwegian Institute of Public Health. Accessed September 24, 2021. https://www.fhi.no/en/publ/2011/tromboseprofylakse-ved-hofte-og-kneprotesekirurgi/
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