This Clinical Resource gives subscribers additional insight related to the Recommendations published in May 2018 ~ Resource #340506 VTE Prevention After Hip or Knee Replacement The American College of Chest Physicians (ACCP) 2012 guidelines recommend over other anticoagulants for VTE prophylaxis in hip or knee arthroplasty. 12 The American Academy of Orthopaedic Surgeons and Thrombosis Canada do not cite a preference. 14,18 The chart below compares alternatives in regard to efficacy and bleeding risk, and provides dosing guidance. Choice should be individualized, taking into account patient VTE risk factors and bleeding risk. 15 ACCP suggests prophylaxis for up to 35 days (minimum 10 to 14 days), while Thrombosis Canada recommends 14 to 35 days, depending on patient risk. 12,14 However, product labeling is more specific, and is based on durations used in the clinical trials. --Information in table may differ from product labeling.-- Abbreviations: HIT = heparin-induced thrombocytopenia; = low-molecular-weight heparin; SC = subcutaneous Alternatives to Drug Dose/Duration Efficacy vs Bleeding Risk vs When to Consider Apixaban (Eliquis) (See footnote a ) 2.5 mg twice daily x 35 days (hip [Canada: 32 to 38 days]) or 12 days (knee [Canada: 10 to 14 days]) starting 12 to 24 hrs post-op (Canada: if hemostasis achieved). 1,2 Some experts recommend starting 18 to 24 hrs post-op due to bleeding risk. 15 Similar for VTE prevention [Evidence level A-1]. 3,4 Similar major or clinically relevant nonmajor bleeding (combined endpoint) [Evidence level A-1]. 3,4 When an oral option is desired, or patient has history of HIT. Aspirin Dabigatran (Pradaxa) 162 mg once daily for at least 10 to 14 days, up to 35,16 (See information below regarding aspirin use after 5 days of rivaroxaban.) 220 mg once daily x 28 to 35 days (hip) or 10 days (knee [Canada]). If started on day of surgery (1 to 4 hrs post-op, assuming hemostasis achieved), initial dose is 110 mg. 5,6 Some experts recommend starting 18 to 24 hrs post-op due to bleeding risk. 15 14 fewer VTEs compared to per 1,000 patients treated for up to Similar for combined endpoint of VTE and mortality [Evidence level A-1]. 7-9 No proof bleeding risk is lower. 12 Similar major bleeding [Evidence level A-1]. 7-9 If patient would not otherwise get VTE prophylaxis. 17 Not an option per Thrombosis Canada. 14 One ACCP member felt aspirin monotherapy should not be an option. 12 When an oral option is desired.
(Clinical Resource #340506: Page 2 of 5) Drug Fondaparinux (Arixtra, generics) Heparin, unfractionated Rivaroxaban (Xarelto) Rivaroxaban, followed by aspirin Dose/Duration (See footnote a ) 2.5 mg SC once daily starting 6 to 8 hours postop, for up to 11 days (Canada: up to one month). 20,21 Caution in severe renal impairment or weight <50 kg. 21 Contraindicated per U.S. labeling. 20 5,000 units SC q 8 to q 12 hrs, starting 1 to 2 hours pre-op. 12,19,22 Follow general guideline recommendations (see above) for duration of therapy. 10 mg once daily for 35 days (hip) or 12 days (knee [Canada: 14 days]) starting 6 to 10 hrs post-op, assuming hemostasis achieved. 10,11 Some experts recommend starting 18 to 24 hrs post-op due to bleeding risk. 15 Rivaroxaban 10 mg once daily for 5 days, then aspirin 81 mg once daily for 9 days (knee) or 30 days (hip). 13 Warfarin Dose to achieve target INR of 2 to 3. 12 Pneumatic compression Follow general guideline recommendations (see above) for duration of therapy. 18 hours per day for at least 10 to 14 days. Use of a device capable of recording wear-time is recommended. 12 Consider use with pharmacologic prophylaxis during hospital stay. 12 Efficacy vs 3 fewer VTEs per 3 fewer VTEs per Higher. Prevents 4 more VTEs per N/A. Similar to rivaroxaban for symptomatic VTE [Evidence level A-1]. 13 3 fewer VTEs per 14 10 fewer VTEs per 14 Bleeding Risk vs Higher. Nine more major, nonfatal bleeds, or bleeds requiring reoperation per 1,000 patients Similar. 12 Higher. Nine more serious bleeds per 1,000 patients N/A. Similar to rivaroxaban for major and clinically important bleeding [Evidence level A-1]. 13 Lower. Four fewer major bleeding events per 1,000 patients But risk may be higher than with extended prophylaxis. 12 Lower. Ten fewer major bleeds per 14 When to Consider An injectable alternative when formulary issues or a history of HIT preclude use of. 12 An injectable alternative when cost is an issue. Not an option per Thrombosis Canada. 14 When an oral option is desired. When an oral option is desired and patient is not at high VTE risk 14 (e.g., metastatic cancer, history of VTE). 13,18 When an oral option with ability to monitor anticoagulant effect is desired. Patient at high risk of bleeding 14,18 (e.g., bleeding disorder, liver disease). 18 Patent who places high value on avoiding bleeding and low value on inconvenience. 12
(Clinical Resource #340506: Page 3 of 5) Drug Enoxaparin (Lovenox, generics) Dalteparin (Fragmin) Usual Dose/Duration (See footnote b ) 30 mg SC q 12 h starting 12 to 24 hrs post-op, assuming hemostasis achieved (hip or knee) for 7 to 14 days, 23,24 or 40 mg SC once daily (hip) starting 9 to 15 hrs pre-op, for 7 to14 days. 14,23,c Renal dosing: CrCl <30 ml/min: 30 mg SC once daily. 23,24 Post-op start: 2,500 units SC 4 to 8 hours post-op (assuming hemostasis achieved), then 5,000 units SC once daily (starting at least 6 hrs after the previous dose). 25,26,c Pre-op start, day of surgery: 2,500 units SC within 2 hrs pre-op followed by 2,500 units SC 4 to 8 hrs post-op (assuming hemostasis achieved), then 5,000 IU SC once daily (starting at least 6 hrs after the previous dose). 25,26,c Pre-op start, evening before surgery: 5,000 units SC 10 to 14 hrs pre-op, then 5,000 units SC once daily starting 4 to 8 hrs post-op (and about 24 hrs after the first dose), assuming hemostasis achieved. 25,26,c Duration: 5 days minimum 25,26 Not FDA- or Health Canada-approved for VTE prophylaxis after knee replacement. 25,26,c Renal dosing: Consider dose reduction (Canadian labeling) or monitor factor Xa levels (U.S. labeling) in patients with severe renal impairment (CrCl <30 ml/min). 25,26 Nadroparin (Fraxiparine) (Canada) 38 U/kg SC once daily on post-op days 1 to 3 (1,900 units if <50 kg, 2,850 units if 50 to 69 kg, 3,800 units if 70 kg), followed by 57 U/kg SC once daily (2,850 units if <50 kg, 3,800 units if 50 to 69 kg, 5,700 units if 70 kg) on day 4 onward. May start 12 hrs preop, with second dose 12 hrs post-op. 27,c Minimum duration 10 days. 27 Tinzaparin (Innohep, Canada) Renal dosing: Contraindicated if CrCl <30 ml/min. Consider reduced dose for CrCl 30 to 50 ml/min. 27 4,500 U 14 or 75 U/kg SC once daily post-op for 7 to 10 days. 28,c For hip surgery, may give 50 units/kg once daily starting 2 hrs preop. 28,c Renal dosing: Use caution and consider dose reduction if CrCl <30 ml/min. 28 a. See our chart, Comparison of Oral Anticoagulants, for dosing in special populations (e.g., renal or hepatic impairment, elderly, low body weight). Consult product labeling regarding initiation in patients with perioperative epidural/spinal anesthesia. b. See our chart, Dosing in Special Populations, for more dosing and monitoring considerations in obesity, pregnancy, renal impairment, and underweight/frail patients. c. ACCP guidelines recommend starting 12 hrs pre-op or 12 hrs post-op. 12 Users of this resource are cautioned to use their own professional judgment and consult any other necessary or appropriate sources prior to making clinical judgments based on the content of this document. Our editors have researched the information with input from experts, government agencies, and national organizations. Information and internet links in this article were current as of the date of publication.
(Clinical Resource #340506: Page 4 of 5) Levels of Evidence In accordance with our goal of providing Evidence- Based information, we are citing the LEVEL OF EVIDENCE for the clinical recommendations we publish. Level Definition Study Quality A B C Good-quality patient-oriented evidence.* Inconsistent or limited-quality patient-oriented evidence.* 1. High-quality RCT 2. SR/Meta-analysis of RCTs with consistent findings 3. All-or-none study 1. Lower-quality RCT 2. SR/Meta-analysis with low-quality clinical trials or of studies with inconsistent findings 3. Cohort study 4. Case control study Consensus; usual practice; expert opinion; disease-oriented evidence (e.g., physiologic or surrogate endpoints); case series for studies of diagnosis, treatment, prevention, or screening. *Outcomes that matter to patients (e.g., morbidity, mortality, symptom improvement, quality of life). RCT = randomized controlled trial; SR = systematic review [Adapted from Ebell MH, Siwek J, Weiss BD, et al. Strength of Recommendation Taxonomy (SORT): a patient-centered approach to grading evidence in the medical literature. Am Fam Physician 2004;69:548-56. http://www.aafp.org/afp/2004/0201/p548.pdf.] Project Leader in preparation of this clinical resource (340506): Melanie Cupp, Pharm.D., BCPS References 1. Product information for Eliquis. Pfizer. New York, NY 10017. February 2018. 2. Product monograph for Eliquis. Pfizer Canada. Kirkland, QC H9J 2M5. April 2018. 3. Lassen MR, Gallus A, Raskob GE, et al. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. N Engl J Med 2010;363:2487-98. 4. Lassen MR, Raskob GE, Gallus A, et al. Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised doubleblind trial. Lancet 2010;375:807-15. 5. Product information for Pradaxa. Boehringer Ingelheim Pharmaceuticals. March 2018. 6. Product monograph for Pradaxa. Boehringer Ingelheim Canada. Burlington, ON L7L 5H4. August 2016. 7. The RE-MOBILIZE Writing Committee. Oral thrombin inhibitor dabigatran etexilate vs North American enoxaparin regimen for prevention of venous thromboembolism after knee arthroplasty surgery. J Arthroplasty 2009;24(1):1-9. 8. Eriksson BI, Dahl OE, Rosencher N, et al. Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, noninferiority trial. Lancet 2007;370:949-56. 9. Eriksson BI, Dahl OE, Rosencher N, et al. Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE-MODEL randomized trial. J Thromb Haemost 2007;5:2178-85. 10. Product information for Xarelto. Janssen Pharmaceuticals. Titusville, NJ 08560. October 2017. 11. Product monograph for Xarelto. Bayer. Mississauga, ON L4W 5R6. February 2018. 12. Falck-Ytter Y, Francis CW, Johanson NA, et al. Prevention of VTE in orthopedic surgery patients: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2012;141(Suppl 2):e278S-e325S. 13. Anderson DR, Dunbar M, Murnaghan J, et al. Aspirin or rivaroxaban for VTE prophylaxis after hip or knee arthroplasty. N Engl J Med 2018;378:699-707. 14. Thrombosis Canada. Thromboprophylaxis: orthopedic surgery. 2018. http://thrombosiscanada.ca/wp- content/uploads/2018/03/thromboprophylaxis- Orthopedic-2018Feb21-Final.pdf. (Accessed April 3, 2018). 15. Lieberman JR, Heckman N. Venous thromboembolism prophylaxis in total hip arthroplasty and total knee arthroplasty patients: from guidelines to practice. J Am Acad Orthop Surg 2017;25:789-98. 16. No authors listed. Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin: Pulmonary Embolism Prevention (PEP) trial. Lancet 2000;355:1295-302. 17. PL Voices, Aspirin for Prevention of Thrombosis. Pharmacist s Letter/Prescriber s Letter. March 2012. 18. Jacobs JJ, Mont MA, Bozic KJ, et al. American Academy of Orthopaedic Surgeons clinical practice guideline on: preventing venous thromboembolic disease in patients undergoing elective hip and knee arthroplasty. J Bone Joint Surg Am 2012;94:746-7. 19. American Academy of Orthopaedic Surgeons. Preventing venous thromboembolic disease in patients undergoing elective hip and knee arthroplasty. Evidence-based guideline and evidence report. 2011. https://www.aaos.org/research/guidelines/vte/vte_f ull_guideline.pdf. (Accessed April 4, 2018). 20. Product information for Arixtra. Mylan Institutional. Rockford, IL 61103. August 2017. 21. Product monograph for Arixtra. Aspen Pharmacare Canada. Toronto, ON M5C 1S2. April 2017.
(Clinical Resource #340506: Page 5 of 5) 22. Clinical Pharmacology powered by Clinical Key. Tampa (FL): Elsevier. 2018. http://www.clinicalkey.com. (Accessed April 4, 2018). 23. Product information for Lovenox. Sanofi-Aventis U.S. Bridgewater, NJ 08807. October 2017. 24. Product monograph for Lovenox. Sanofi-Aventis Canada. Laval, QC H7V 0A3. June 2017. 25. Product information for Fragmin. Pfizer Labs. New York, NY 10017. June 2017. 26. Product monograph for Fragmin. Pfizer Canada. Kirkland, QC H9J 2M5. September 2017. 27. Product monograph for Fraxiparine. Aspen Pharmacare Canada. Toronto, ON M5C 1S2. December 2017. 28. Product monograph for Innohep. Leo Pharma. Thornhill, ON L3T 7W8. May 2017. Cite this document as follows: Clinical Resource, VTE Prevention After Hip or Knee Replacement. Pharmacist s Letter/Prescriber s Letter. May 2018. Evidence and Recommendations You Can Trust 3120 West March Lane, Stockton, CA 95219 ~ TEL (209) 472-2240 ~ FAX (209) 472-2249 Copyright 2018 by Therapeutic Research Center Subscribers to the Letter can get clinical resources, like this one, on any topic covered in any issue by going to PharmacistsLetter.com, PrescribersLetter.com, PharmacyTechniciansLetter.com, or NursesLetter.com