Asia-Pacific Thrombosis Advisory Board consensus paper on prevention of venous thromboembolism after major orthopaedic surgery

Summary

The incidence of postoperative venous thromboembolism (VTE) in Asian populations is generally thought to be lower than in Western populations, and the use of thromboprophylaxis after surgery is not routine. This paper is authored by the Asia-Pacific Thrombosis Advisory Board. To provide guidance on the most effective postoperative thrombo prophylaxis management, this paper reviews the available data on the incidence of VTE in Asian populations, considers current clinical guidelines for the prevention of VTE to determine whether these guidelines are applicable to Asian populations, and evaluates the potential of new thromboprophylactic agents. Based on the available evidence, it was agreed that VTE represents a genuine problem in Asian patients, although the exact incidence in local populations requires confirmation in large, well-designed clinical trials. Furthermore, there was consensus that current guideline recommendations for the routine use of postoperative thromboprophylaxis should be implemented in Asia, and that new oral agents now available represent an effective and potentially more convenient therapeutic option. In conclusion, we call for recognition that VTE is an issue in Asian patients, and that effective thromboprophylaxis is the most important strategy.

Keywords

Anticoagulation - postoperative venous thromboembolism - thromboprophylaxis

^* See Appendix.

• References

• 1 Geerts WH. et al. Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition).. Chest 2008; 133: 381S-453S.
• 2 Friedman RJ. Optimal duration of prophylaxis for venous thromboembolism following total hip arthroplasty and total knee arthroplasty.. J Am Acad Orthop Surg 2007; 15: 148-155.
• 3 Kahn SR. The post-thrombotic syndrome: the forgotten morbidity of deep venous thrombosis.. J Thromb Thrombolysis 2006; 21: 41-48.
• 4 Pengo V. et al. Incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism.. N Engl J Med 2004; 350: 2257-2264.
• 5 U.S. Department of Health and Human Services.. The Surgeon General’s Call to Action to Prevent Deep Vein Thrombosis and Pulmonary Embolism.. Available at: http://www.surgeongeneral.gov/topics/deepvein/calltoaction/call-to-action-ondvt-2008.pdf Last accessed September 24, 2010.
• 6 Centers for Medicare & Medicaid Services.. Medicare and Medicaid move aggressively to encourage greater patient safety in hospitals and reduce never events.. Available at: http://www.cms.hhs.gov/apps/media/press/release.asp?Counter=3219&intNumPerPage=10&checkDate=&checkKey=&srchType=1&numDays=3500&srchOpt=0&srchData=&keywordType=All&chkNewsType=1%2C+2%2C+3%2C+4%2C+5&intPage=&showAll=&pYear=&year=&desc=false&cboOrder=date Accessed November 13, 2009.
• 7 Cohen AT. et al. Venous thromboembolism (VTE) in Europe. The number of VTE events and associated morbidity and mortality.. Thromb Haemost 2007; 98: 756-764.
• 8 White RH, Keenan CR. Effects of race and ethnicity on the incidence of venous thromboembolism.. Thromb Res 2009; 123 (04) S11-S17.
• 9 Leizorovicz A. et al. Epidemiology of venous thromboembolism in Asian patients undergoing major orthopedic surgery without thromboprophylaxis. The SMART study.. J Thromb Haemost 2005; 03: 28-34.
• 10 Leizorovicz A. Epidemiology of post-operative venous thromboembolism in Asian patients. Results of the SMART venography study.. Haematologica 2007; 92: 1194-1200.
• 11 Piovella F. et al. Deep-vein thrombosis rates after major orthopedic surgery in Asia. An epidemiological study based on postoperative screening with centrally adjudicated bilateral venography.. J Thromb Haemost 2005; 03: 2664-2670.
• 12 Leizorovicz A. et al. Epidemiology of post-operative venous thromboembolism in Asian countries.. Int J Angiol 2004; 13: 101-108.
• 13 Liew NC. et al. Postoperative venous thromboembolism in Asia: a critical appraisal of its incidence.. Asian J Surg 2003; 26: 154-158.
• 14 Turpie AG. et al. A randomized controlled trial of a low-molecular-weight heparin (enoxaparin) to prevent deep-vein thrombosis in patients undergoing elective hip surgery.. N Engl J Med 1986; 315: 925-929.
• 15 Segers AE. et al. Is contrast venography a valid surrogate outcome measure in venous thromboembolism prevention studies?. J Thromb Haemost 2005; 03: 1099-1102.
• 16 Callaghan JJ. et al. Prophylaxis for thromboembolic disease: recommendations from the American College of Chest Physicians ﺹ are they appropriate for orthopaedic surgery?. J Arthroplasty 2005; 20: 273-274.
• 17 Schindler OS, Dalziel R. Post-thrombotic syndrome after total hip or knee arthroplasty: incidence in patients with asymptomatic deep venous thrombosis.. J Orthop Surg (Hong Kong) 2005; 13: 113-119.
• 18 Eriksson BI. et al. Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, non-inferiority trial.. Lancet 2007; 370: 949-956.
• 19 Eriksson BI. et al. Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the REMODEL randomized trial.. J Thromb Haemost 2007; 05: 2178-2185.
• 20 Eriksson BI. et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty.. N Engl J Med 2008; 358: 2765-2775.
• 21 Kakkar AK. 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.. Lancet 2008; 372: 31-39.
• 22 Lassen MR. et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty.. N Engl J Med 2008; 358: 2776-2786.
• 23 Lassen MR. et al. The ADVANCE-2 study: a randomized double-blind trial comparing apixaban with enoxaparin for thromboprophylaxis after total knee replacement.. J Thromb Haemost. 2009 7 (Suppl. 2): Abstract LB-MO-005.
• 24 Turpie AGG. et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial.. Lancet 2009; 373: 1673-1680.
• 25 Friedman RJ. et al. Physician compliance with guidelines for deep-vein thrombosis prevention in total hip and knee arthroplasty.. Curr Med Res Opin 2008; 24: 87-97.
• 26 Bergqvist D. et al. Evaluation of duration of thromboembolic prophylaxis after major orthopedic surgery: the ETHOS regsitry.. J Thromb Haemost. 2009 7 (Suppl. 2): Abstract OC-TU-019.
• 27 Monreal M. et al. The outcome after treatment of venous thromboembolism is different in surgical and acutely ill medical patients. Findings from the RIETE registry.. J Thromb Haemost 2004; 02: 1892-1898.
• 28 Arcelus JI. et al. Clinical presentation and time-course of postoperative venous thromboembolism: results from the RIETE Registry.. Thromb Haemost 2008; 99: 546-551.
• 29 Kalka C. et al. Lack of extended venous thromboembolism prophylaxis in high-risk patients undergoing major orthopaedic or major cancer surgery. Electronic Assessment of VTE Prophylaxis in High-Risk Surgical Patients at Discharge from Swiss Hospitals (ESSENTIAL).. Thromb Haemost 2009; 102: 56-61.
• 30 Nicolaides AN. et al. Prevention and treatment of venous thromboembolism. International Consensus Statement (guidelines according to scientific evidence).. Int Angiol 2006; 25: 101-161.
• 31 Bagaria V. et al. Incidence and risk factors for development of venous thromboembolism in Indian patients undergoing major orthopaedic surgery: results of a prospective study.. Postgrad Med J 2006; 82: 136-139.
• 32 Kim YH, Suh JS. Low incidence of deep-vein thrombosis after cementless total hip replacement.. J Bone Joint Surg Am 1988; 70: 878-882.
• 33 Xu GG. et al. A review of clinical pathway data of 1,663 total knee arthroplasties in a tertiary institution in Singapore.. Ann Acad Med Singapore 2008; 37: 924-928.
• 34 Kim HA. et al. The epidemiology of total knee replacement in South Korea: national registry data.. Rheumatology 2008; 47: 88-91.
• 35 Mehrotra C. et al. Trends in total knee replacement surgeries and implications for public health, 1990–2000.. Public Health Rep 2005; 120: 278-282.
• 36 Merx H. et al. International variation in hip replacement rates.. Ann Rheum Dis 2003; 62: 222-226.
• 37 Liu YE. et al. The epidemiology and surgical outcomes of patients undergoing primary total hip replacement: an Asian perspective.. Singapore Med J 2009; 50: 15-19.
• 38 Lai YS. et al. Incidence of hip replacement among national health insurance enrol-lees in Taiwan.. J Orthop Surg 2008; 03: 42.
• 39 Cohen AT. et al. Venous thromboembolism risk and prophylaxis in the acute hospital care setting (ENDORSE study): a multinational cross-sectional study.. Lancet 2008; 371: 387-394.
• 40 Jain V. et al. Deep vein thrombosis after total hip and knee arthroplasty in Indian patients.. Postgrad Med J 2004; 80: 729-731.
• 41 Shukla PJ. et al. Postoperative deep vein thrombosis in patients with colorectal cancer.. Indian J Gastroenterol 2008; 27: 71-73.
• 42 Lee AD. et al. Venous thrombo-embolism in India.. Eur J Vasc Endovasc Surg 2009; 37: 482-485.
• 43 Shead GV, Narayanan R. Incidence of postoperative venous thromboembolism in South India.. Br J Surg 1980; 67: 813-814.
• 44 Kim YH. The incidence of deep vein thrombosis after cementless and cemented knee replacement.. J Bone Joint Surg Br 1990; 72: 779-783.
• 45 Kim YH, Kim JS. Incidence and natural history of deep-vein thrombosis after total knee arthroplasty. A prospective, randomised study.. J Bone Joint Surg Br 2002; 84: 566-570.
• 46 Kim YH. et al. Factors leading to decreased rates of deep vein thrombosis and pulmonary embolism after total knee arthroplasty.. J Arthroplasty 2007; 22: 974-980.
• 47 Kim YH. et al. Incidence and natural history of deep-vein thrombosis after total hip arthroplasty. A prospective and randomised clinical study.. J Bone Joint Surg Br 2003; 85: 661-665.
• 48 Moon KH. et al. Deep vein thrombosis after cementless total hip replacement arthroplasty using doppler ultrasound.. J Korean Orthop Assoc 1998; 33: 1553-1559.
• 49 Seah VW. et al. Thirty-day mortality and morbidity after total knee arthroplasty.. Ann Acad Med Singapore 2007; 36: 1010-1012.
• 50 Nathan S. et al. The incidence of proximal deep vein thrombosis following total knee arthroplasty in an Asian population: a Doppler ultrasound study.. J Orthop Surg (Hong Kong) 2003; 11: 184-189.
• 51 Ruban P. et al. Deep vein thrombosis after total knee replacement.. Ann Acad Med Singapore 2000; 29: 428-433.
• 52 Lim YW. et al. Deep vein thrombosis following hip fracture and prevalence of hyperhomocysteinaemia in the elderly.. Ann Acad Med Singapore 2004; 33: 235-238.
• 53 Ng HJ, Lee LH. Trends in prevalence of deep venous thrombosis among hospitalised patients in an Asian institution.. Thromb Haemost 2009; 101: 1095-1099.
• 54 Cheuk BL. et al. Epidemiology of venous thromboembolism in a Chinese population.. Br J Surg 2004; 91: 424-428.
• 55 Nandi P. et al. Incidence of postoperative deep vein thrombosis in Hong Kong Chinese.. Br J Surg 1980; 67: 251-253.
• 56 Chan YK. et al. The incidence of deep vein thrombosis in elderly Chinese suffering hip fracture is low without prophylaxis: a prospective study using serial duplex ultrasound.. J Orthop Surg (Hong Kong) 2004; 12: 178-183.
• 57 Ko PS. et al. Deep venous thrombosis after total hip or knee arthroplasty in a ″low-risk″ Chinese population.. J Arthroplasty 2003; 18: 174-179.
• 58 Kew J. et al. Deep vein thrombosis in elderly Hong Kong Chinese with hip fractures detected with compression ultrasound and Doppler imaging: incidence and effect of low molecular weight heparin.. Arch Orthop Trauma Surg 1999; 119: 156-158.
• 59 Mok CK. et al. The incidence of deep vein thrombosis in Hong Kong Chinese after hip surgery for fracture of the proximal femur.. Br J Surg 1979; 66: 640-642.
• 60 Atichartakarn V. et al. Deep vein thrombosis after hip surgery among Thai.. Arch Intern Med 1988; 148: 1349-1353.
• 61 Chotanaphuti T. et al. Incidence of deep vein thrombosis in postoperative hip fracture patients in Phramongkutklao Hospital.. J Med Assoc Thai 2005; 88 (03) S159-S163.
• 62 Pookarnjanamorakot C. et al. The incidence of deep vein thrombosis and pulmonary embolism after total knee arthroplasty: the screening study by radio-nuclide venography.. J Med Assoc Thai 2004; 87: 869-876.
• 63 Koike S. Study on postoperative deep venous thrombosis with reference to prevention.. Nippon Geka Gakkai Zasshi 1988; 89: 270-281.
• 64 Miyagi J. et al. Predictive indicators of deep venous thrombosis and pulmonary arterial thromboembolism in 54 subjects after total knee arthroplasty using multislice computed tomography in logistic regression models.. Int J Cardiol 2007; 119: 90-94.
• 65 Terao M. et al. Diagnosis of deep vein thrombosis after operation for fracture of the proximal femur: comparative study of ultrasonography and venography.. J Orthop Sci 2006; 11: 146-153.
• 66 Fukuda A. et al. Effect of tourniquet application on deep vein thrombosis after total knee arthroplasty.. Arch Orthop Trauma Surg 2007; 127: 671-675.
• 67 Fujita S. et al. Deep venous thrombosis after total hip or total knee arthroplasty in patients in Japan.. Clin Orthop Relat Res 2000; 168-174.
• 68 Dhillon KS. et al. Postoperative deep-vein thrombosis in Asian patients is not a rarity: a prospective study of 88 patients with no prophylaxis.. J Bone Joint Surg Br 1996; 78: 427-430.
• 69 Tambunan KL. et al. Venous thromboembolism in 13 Indonesian patients undergoing orthopaedic surgery.. Med J Indones 2009; 18: 249-256.
• 70 Chau KY. et al. Clinicopathological pattern of pulmonary thromboembolism in Chinese autopsy patients: comparison with Caucasian series.. Pathology 1997; 29: 263-266.
• 71 Dickens P. et al. Fatal pulmonary embolism: a comparative study of autopsy incidence in Hong Kong and Cardiff, Wales.. Forensic Sci Int 1997; 90: 171-174.
• 72 Tapson VF. et al. The diagnostic approach to acute venous thromboembolism. Clinical practice guideline. American Thoracic Society.. Am J Respir Crit Care Med 1999; 160: 1043-1066.
• 73 O’Donnell M. et al. Reduction of out-of-hospital symptomatic venous thromboembolism by extended thromboprophylaxis with low-molecular-weight heparin following elective hip arthroplasty: a systematic review.. Arch Intern Med 2003; 163: 1362-1366.
• 74 Collins R. et al. Reduction in fatal pulmonary embolism and venous thrombosis by perioperative administration of subcutaneous heparin. Overview of results of randomized trials in general, orthopedic, and urologic surgery.. N Engl J Med 1988; 318: 1162-1173.
• 75 Koch A. et al. Low molecular weight heparin and unfractionated heparin in thrombosis prophylaxis: meta-analysis based on original patient data.. Thromb Res 2001; 102: 295-309.
• 76 Nurmohamed MT. et al. Low-molecular-weight heparin versus standard heparin in general and orthopaedic surgery: a meta-analysis.. Lancet 1992; 340: 152-156.
• 77 Turpie AG. et al. Fondaparinux vs enoxaparin for the prevention of venous thromboembolism in major orthopedic surgery: a meta-analysis of 4 randomized double-blind studies.. Arch Intern Med 2002; 162: 1833-1840.
• 78 Hirsh J. et al. Heparin and low-molecular-weight heparin: mechanisms of action, pharmacokinetics, dosing, monitoring, efficacy, and safety.. Chest 2001; 119: 64S-94S.
• 79 Warkentin TE. et al. Heparin-induced thrombocytopenia in patients treated with low-molecular-weight heparin or unfractionated heparin.. N Engl J Med 1995; 332: 1330-1335.
• 80 Sanofi-Aventis.. Idraparinux shows encouraging results in the prevention of thromboembolic events in patients with atrial fibrillation.. Available at: http://en.sanofi-aventis.com/binaries/070711_Idraparinux_pdf_tcm28–15295.pdf Accessed November 27, 2008.
• 81 Walenga JM. et al. Fondaparinux: a synthetic heparin pentasaccharide as a new antithrombotic agent.. Expert Opin Investig Drugs 2002; 11: 397-407.
• 82 Arixtra (fondaprinux sodium 2.5 mg/0.5ml injection, pre-filled syringe) summary of product characteristics.. Available at: http://emc.medicines.org.uk/medicine/15123 Accessed February 2, 2010.
• 83 Mismetti P. et al. Prevention of venous thromboembolism in orthopedic surgery with vitamin K antagonists: a meta-analysis.. J Thromb Haemost 2004; 02: 1058-1070.
• 84 Ansell J. et al. The pharmacology and management of the vitamin K antagonists: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy.. Chest 2004; 126: 204S-233S.
• 85 Prevention of pulmonary embolism and deep vein thrombosis with low dose aspirin: Pulmonary Embolism Prevention (PEP) trial.. Lancet 2000; 355: 1295-1302.
• 86 Pradaxa^→ (dabigatran etexilate) Summary of Product Characteristics.. Available at: http://www.pradaxa.com/Include/media/pdf/Pradaxa_SPC_EMEA.pdf Accessed May 18, 2009.
• 87 Xarelto^→ Summary of Product Characteristics.. Available at: http://www.xarelto.com/html/downloads/Xarelto_Summary_of_Product_Characteristics_May2009.pdf Accessed February 15, 2010.
• 88 Wolowacz SE. et al. Efficacy and safety of dabigatran etexilate for the prevention of venous thromboembolism following total hip or knee arthroplasty. A meta-analysis.. Thromb Haemost 2009; 101: 77-85.
• 89 Turpie AGG. et al. A pooled analysis of four pivotal studies of rivaroxaban for the prevention of venous thromboembolism after orthopaedic surgery: effect on symptomatic venous thromboembolism and death, and bleeding.. Haematologica 2009; 94 (02) 212.
• 90 Yoo MC. et al. A prospective randomized study on the use of nadroparin calcium in the prophylaxis of thromboembolism in Korean patients undergoing elective total hip replacement.. Int Orthop 1997; 21: 399-402.
• 91 Fong YK. et al. Use of low molecular weight heparin for prevention of deep vein thrombosis in total knee arthroplasty--a study of its efficacy in an Asian population.. Ann Acad Med Singapore 2000; 29: 439-441.
• 92 Li XL. et al. Prophylaxis for deep vein thrombosis with low molecular weight heparin following hip and knee surgery.. Zhongguo Xiu Fu Chong Jian Wai Ke Za Zhi 2001; 15: 39-41.
• 93 Chin PL. et al. Thromboembolic prophylaxis for total knee arthroplasty in Asian patients: a randomised controlled trial.. J Orthop Surg (Hong Kong) 2009; 17: 1-5.
• 94 Nakase J. et al. Heparin versus danaproid for prevention of venous thromboembolism after hip surgery.. J Orthop Surg (Hong Kong) 2009; 17: 6-9.
• 95 Kim YH. et al. Prophylaxis for deep vein thrombosis with aspirin or low molecular weight dextran in Korean patients undergoing total hip replacement. A randomized controlled trial.. Int Orthop 1998; 22: 6-10.
• 96 Tian H. et al. Efficacy and safety of aspirin in prevention of venous thromboembolism after total joint arthroplasty.. Zhonghua Yi Xue Za Zhi 2007; 87: 3349-3352.
• 97 Fuji T. et al. Fondaparinux prevents venous thromboembolism after joint replacement surgery in Japanese patients.. Int Orthop 2008; 32: 443-451.
• 98 Fuji T. et al. Randomized, double-blind, multi-dose efficacy, safety and biomarker study of the oral Factor Xa inhibitor DU-176b compared with placebo for prevention of venous thromboembolism in patients after total knee arthroplasty.. Blood (ASH Annual Meeting Abstracts). 2008 112: Abstract 34.
• 99 Houshan L, Wang Y. Rivaroxaban for thromboprophylaxis of venous thromboembolism after total hip or knee replacement in Chinese subjects included in the RECORD program. (presented at the Asia-Pacific Arthroplasty Society Meeting 2008; Malaysia, October 23-25, 2008).
• 100 American Academy of Orthopaedic Surgeons.. American Academy of Orthopaedic Surgeons clinical guideline on prevention of symptomatic pulmonary embolism in patients undergoing total hip or knee arthroplasty.. Available at: www.aaos.org/Research/guidelines/PE_guideline.pdf Accessed June 13, 2009.
• 101 Eikelboom JW. et al. American Association of Orthopedic Surgeons and American College of Chest Physicians guidelines for venous thromboembolism prevention in hip and knee arthroplasty differ: what are the implications for clinicians and patients?. Chest 2009; 135: 513-520.
• 102 Mashio N. Japanese Guidelines for Prevention of Venous Thromboembolism.. J Japan Soc Clin Anesth 2004; 24: 480-487.
• 103 Korean Society on Thrombosis and Haemostasis.. Japanese guideline for prevention of venous thromboembolism. – 2nd edition Korea. 2009
• 104 Guidelines for prevention of venous thromboembolism after major orthopaedic surgery (draft).. Chin J Orthop 2007; 27: 790-792.
• 105 Warwick D. et al. Insufficient duration of venous thromboembolism prophylaxis after total hip or knee replacement when compared with the time course of thromboembolic events: findings from the Global Orthopaedic Registry.. J Bone Joint Surg Br 2007; 89: 799-807.
• 106 Zairul-Nizam ZF, Gul YA. Malaysian orthopaedic surgeons’ approach to venous thromboembolic disease prophylaxis: attitudes and practice.. J Orthop Surg (Hong Kong) 2003; 11: 178-183.
• 107 Tan LH, Tan SC. Venous thromboembolism prophylaxis for surgical patients in an Asian hospital.. ANZ J Surg 2004; 74: 455-459.
• 108 Weitz JI. New oral anticoagulants in development.. Thromb Haemost 2010; 103: 62-70.
• 109 Stangier J. et al. The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects.. Br J Clin Pharmacol 2007; 64: 292-303.
• 110 Stangier J. et al. Pharmacokinetics and pharmacodynamics of the direct oral thrombin inhibitor dabigatran in healthy elderly subjects.. Clin Pharmacokinet 2008; 47: 47-59.
• 111 Stangier J. Clinical pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor dabigatran etexilate.. Clin Pharmacokinet 2008; 47: 285-295.
• 112 Stangier J. et al. Pharmacokinetics and pharmacodynamics of dabigatran etexilate, an oral direct thrombin inhibitor, are not affected by moderate hepatic impairment.. J Clin Pharmacol 2008; 48: 1411-1419.
• 113 Kubitza D. et al. Safety, pharmacodynamics, and pharmacokinetics of single doses of BAY 59–7939, an oral, direct factor Xa inhibitor.. Clin Pharmacol Ther 2005; 78: 412-421.
• 114 Kubitza D. et al. Safety, pharmacodynamics, and pharmacokinetics of BAY 59–7939 ﺹ an oral, direct Factor Xa inhibitor ﺹ after multiple dosing in healthy male subjects.. Eur J Clin Pharmacol 2005; 61: 873-880.
• 115 Kubitza D. et al. The effect of extreme age, and gender, on the pharmacology and tolerability of rivaroxaban ﺹ an oral, direct Factor Xa inhibitor.. Blood. 2006 108: Abstract 905.
• 116 Kubitza D. et al. Body weight has limited influence on the safety, tolerability, pharmacokinetics, or pharmacodynamics of rivaroxaban (BAY 59–7939) in healthy subjects.. J Clin Pharmacol 2007; 47: 218-226.
• 117 Kubitza D. et al. Dose-escalation study of the pharmacokinetics and pharmacodynamics of rivaroxaban in healthy elderly subjects.. Curr Med Res Opin 2008; 24: 2757-2765.
• 118 Zhao X. et al. Safety, pharmacokinetics and pharmacodynamics of single/ multiple doses of the oral, direct Factor Xa inhibitor rivaroxaban in healthy Chinese subjects.. Br J Clin Pharmacol 2009; 68: 77-88.
• 119 Samama MM. et al. Assessment of laboratory assays to measure rivaroxaban – an oral, direct Factor Xa inhibitor.. Thromb Haemost 2010; 103: 815-825.
• 120 Kubitza D. et al. Rivaroxaban (BAY 59–7939) ﺹ an oral, direct Factor Xa inhibitor ﺹ has no clinically relevant interaction with naproxen.. Br J Clin Pharmacol 2007; 63: 469-476.
• 121 Kubitza D. et al. Safety, tolerability, pharmacodynamics, and pharmacokinetics of rivaroxaban – an oral, direct Factor Xa inhibitor – are not affected by aspirin.. J Clin Pharmacol 2006; 46: 981-990.
• 122 Eriksson B. et al. A Pooled Analysis of Four Pivotal Studies of Rivaroxaban for the Prevention of Venous Thromboembolism after Orthopaedic Surgery: Effects of Specified Co-Medications.. Blood (ASH Annual Meeting Abstracts). 2008 112: Abstract 1986.
• 123 Eriksson BI. et al. Risk of bleeding with dabigatran etexilate in patients undergoing major orthopaedic surgery is not increased by concomitant use of non-steroidal anti-inflammatory drugs or acetylsalicylic acid.. J Thromb Haemost. 2009 Abstract PP-MO-167.
• 124 Lee LH. et al. Deep vein thrombosis is not rare in Asia – the Singapore General Hospital experience.. Ann Acad Med Singapore 2002; 31: 761-764.
• 125 The RE-MOBILIZE Writing Committee.. The oral thrombin inhibitor dabigatran etexilate vs the North American enoxaparin regimen for the prevention of venous thromboembolism after knee arthroplasty surgery.. J Arthroplasty 2009; 24: 1-9.
• 126 Lassen MR. et al. Apixaban or enoxaparin for thromboprophylaxis after knee replacement.. N Engl J Med 2009; 361: 594-604.