Download PDF
Thromb Haemost 2015; 113(02): 231-246
DOI: 10.1160/TH14-06-0484
Review Article
Schattauer GmbH

Benefit–risk profile of non-vitamin K antagonist oral anticoagulants in the management of venous thromboembolism

Jan Beyer-Westendorf
1   Center for Vascular Diseases and Medical Clinic III, Dresden University Hospital “Carl Gustav Carus”, Dresden, Germany
,
Walter Ageno
2   Department of Clinical and Experimental Medicine, University of Insubria, Varese, Italy
› Author Affiliations Financial support: Editorial support was funded by Bayer HealthCare Pharmaceuticals and Janssen Scientific Affairs, LLC.
Further Information

Publication History

Received: 02 June 2014

Accepted after major revision: 03 September 2014

Publication Date:
27 November 2017 (online)

    Permissions and Reprints

Summary

The prevention and treatment of venous thromboembolism (VTE) remains a clinical challenge, primarily owing to drawbacks associated with the use of heparins and vitamin K antagonists (VKAs). These and other factors, including a growing elderly population, mean that VTE presents a continuing burden to patients and physicians. Anticoagulant therapy is a fundamental approach for VTE management. Non- VKA oral anticoagulants, including the factor Xa inhibitors apixaban, edoxaban and rivaroxaban, and the thrombin inhibitor dabigatran, have been studied in phase III trials across a spectrum of thromboembolic disorders. These agents offer simplified care, with similar or improved efficacy and safety outcomes compared with heparins and vitamin K antagonists. There are several factors a physician must consider when prescribing an anticoagulant. An important consideration with all anticoagulant use is bleeding risk, especially in high-risk groups such as the elderly or those with renal impairment or cancer. In orthopaedic patients, other risks include a need for surgical revision or blood transfusion, or wound complications. Therefore, the clinical benefits of an anticoagulant should ideally be balanced with any risks associated with the therapy. Quantitative benefit–risk assessments are lacking, and owing to differences in trial design the non-VKA oral anticoagulants cannot be compared directly. Based on trial and “reallife” data, this review will summarise the clinical data for the non-VKA oral anticoagulants in the prevention and treatment of VTE, focusing on the balance between the benefits and risks of anticoagulation with these drugs, and their potential impact on VTE management.

Keywords

Benefit–risk assessment - non-VKA oral anticoagulants - real-life - thromboprophylaxis - venous thromboembolism
 

  • References

  • 1 Goldhaber SZ, Bounameaux H. Pulmonary embolism and deep vein thrombosis. Lancet 2012; 379: 1835-1846.
    CrossrefPubMedGoogle Scholar
  • 2 Liu X. et al. Epidemiology and mortality of venous thromboembolism across patient populations: a systematic literature review. Value Health 2013; 16:: A272: Abstract PCV5.
    PubMedGoogle Scholar
  • 3 van Korlaar IM. et al. The impact of venous thrombosis on quality of life. Thromb Res 2004; 114: 11-18.
    CrossrefPubMedGoogle Scholar
  • 4 Pengo V. et al. Incidence of chronic thromboembolic pulmonary hypertension after pulmonary embolism. N Engl J Med 2004; 350: 2257-2264.
    CrossrefPubMedGoogle Scholar
  • 5 Falck-Ytter Y. et al. Prevention of VTE in orthopedic surgery patients: anti-thrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2012; 141: e278S-e325S.
    CrossrefPubMedGoogle Scholar
  • 6 Kearon C. et al. Antithrombotic therapy for VTE disease: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physiciansevidence-basedclinicalpracticeguidelines. Chest 2012; 141: e419S-e494S..
    CrossrefPubMedGoogle Scholar
  • 7 Buller HR. et al. Treatment of venous thromboembolism. J Thromb Haemost 2005; 03: 1554-1560.
    CrossrefPubMedGoogle Scholar
  • 8 Harder S, Graff J. Novel oral anticoagulants: clinical pharmacology, indications and practical considerations. Eur J Clin Pharmacol 2013; 69: 1617-1633.
    CrossrefPubMedGoogle Scholar
  • 9 Bayer Pharma AG. Xarelto® (rivaroxaban) Summary of Product Characteristics. 2014 Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000944/WC500057108.pdf. Accessed July 15, 2014.
    PubMedGoogle Scholar
  • 10 Bristol-Myers Squibb, Pfizer EEIG. Eliquis® (apixaban) Summary of Product Characteristics. 2013 Available at: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/002148WC500107728.pdf. Accessed July 15, 2014.
    PubMedGoogle Scholar
  • 11 Boehringer Ingelheim International GmbH.. Pradaxa® (dabigatran etexilate) Summary of Product Characteristics. 2014 Available at: http://www.ema.euro/pa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000829/WC500041059.pdf. Accessed July 14, 2014.
    PubMedGoogle Scholar
  • 12 Bathala MS. et al. Pharmacokinetics, biotransformation, and mass balance of edoxaban, a selective, direct Factor Xa inhibitor, in humans. Drug Metab Dispos 2012; 40: 2250-2255.
    CrossrefPubMedGoogle Scholar
  • 13 Anderson Jr. FA, Spencer FA. Risk factors for venous thromboembolism. Circulation 2003; 107: I9-I16.
    CrossrefPubMedGoogle Scholar
  • 14 Eriksson BI. et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med 2008; 358: 2765-2775.
    CrossrefPubMedGoogle Scholar
  • 15 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.
    CrossrefPubMedGoogle Scholar
  • 16 Lassen MR. et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med 2008; 358: 2776-2786.
    CrossrefPubMedGoogle Scholar
  • 17 Turpie AGG. et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial. Lancet 2009; 373: 1673-1680.
    CrossrefPubMedGoogle Scholar
  • 18 The RE-MOBILIZE Writing Committee.. Oral thrombin inhibitor dabigatran et-exilate vs North American enoxaparin regimen for prevention of venous throm-boembolism after knee arthroplasty surgery. J Arthroplasty 2009; 24: 1-9.
    CrossrefPubMedGoogle Scholar
  • 19 Lassen MR. et al. Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial. Lancet 2010; 375: 807-815.
    CrossrefPubMedGoogle Scholar
  • 20 Lassen MR. et al. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. N Engl J Med 2010; 363: 2487-2498.
    CrossrefPubMedGoogle Scholar
  • 21 Lassen MR. et al. Apixaban or enoxaparin for thromboprophylaxis after knee replacement. N Engl J Med 2009; 361: 594-604.
    CrossrefPubMedGoogle Scholar
  • 22 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.
    CrossrefPubMedGoogle Scholar
  • 23 Eriksson BI. et al. Oral dabigatran versus enoxaparin for thromboprophylaxis after primary total hip arthroplasty (RE-NOVATE II). A randomised, doubleblind, non-inferiority trial. Thromb Haemost 2011; 105: 721-729.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 24 Eriksson BI. et al. Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, doubleblind, non-inferiority trial. Lancet 2007; 370: 949-956.
    CrossrefPubMedGoogle Scholar
  • 25 Fuji T. et al. Efficacy and safety of edoxaban versus enoxaparin for the prevention of venous thromboembolism following total hip arthroplasty: STARS J-V trial. Blood (ASH Annual Meeting Abstracts). 2010 116. Abstract 3320.
    PubMedGoogle Scholar
  • 26 Fuji T. et al. Edoxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty: the STARS E-3 trial. 21st International Congress on Thrombosis. Milan, Italy,: 6-9 July 2010; Abstract OC297.
    PubMedGoogle Scholar
  • 27 Harenberg J. et al. Interpretation of endpoints in a network meta-analysis of new oral anticoagulants following total hip or total knee replacement surgery. Thromb Haemost 2012; 108: 903-912.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 28 Cohen A. et al. The efficacy and safety of pharmacological prophylaxis of venous thromboembolism following elective knee or hip replacement: systematic review and network meta-analysis. Clin Appl Thromb Hemost 2012; 18: 611-627.
    CrossrefPubMedGoogle Scholar
  • 29 Gómez-Outes A. et al. Dabigatran, rivaroxaban, or apixaban versus enoxaparin for thromboprophylaxis after total hip or knee replacement: systematic review, meta-analysis, and indirect treatment comparisons. Br Med J 2012; 344: e3675.
    CrossrefPubMedGoogle Scholar
  • 30 Levitan B. et al. Benefit-risk assessment of rivaroxaban versus enoxaparin for the prevention of venous thromboembolism after total hip or knee arthroplasty. Vasc Health Risk Manag 2014; 10: 157-167.
    PubMedGoogle Scholar
  • 31 Schulman S, Majeed A. A benefit-risk assessment of dabigatran in the prevention of venous thromboembolism in orthopaedic surgery. Drug Saf 2011; 34: 449-463.
    CrossrefPubMedGoogle Scholar
  • 32 Turpie AGG. et al. Rivaroxaban for the prevention of venous thromboembolism after hip or knee arthroplasty. Pooled analysis of four studies. Thromb Haemost 2011; 105: 444-453.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 33 Fuji T. et al. Safety and efficacy of edoxaban in patients undergoing hip fracture surgery. Thromb Res 2014; 133: 1016-1022.
    CrossrefPubMedGoogle Scholar
  • 34 European Medicines Agency.. Guideline on clinical investigation of medicinal products for prevention of venous thromboembolism (VTE) in patients undergoing high VTE-risk surgery. Available at: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2012/05/WC500127902.pdf. Accessed August 6, 2014.
    PubMedGoogle Scholar
  • 35 Ahrens I, Bode C. Oral anticoagulation with edoxaban. Focus on current phase III clinical development. Hamostaseologie 2012; 32: 212-215.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 36 Rosencher N. et al. Real-world study of dabigatran etexilate for thromboprophy-laxis in over 5000 hip or knee replacement patients: favourable safety profile in subgroups with different BMI, renal function and age. Blood (ASH Annual Meeting Abstracts). 2012 120. Abstract 1160.
    PubMedGoogle Scholar
  • 37 Kendoff D. et al. Oral thromboprophylaxis following total hip or knee replacement: review and multicentre experience with dabigatran etexilate. Open Orthop J 2011; 05: 395-399.
    CrossrefPubMedGoogle Scholar
  • 38 Subramanian P. et al. A 12 month review of a modified protocol using low dose dabigatran etexilate in postoperative thromboembolic prophylaxis in joint replacement surgery. Thromb J 2012; 10: 14.
    CrossrefPubMedGoogle Scholar
  • 39 Turpie AGG. et al. A non-interventional comparison of rivaroxaban with standard of care for thromboprophylaxis after major orthopaedic surgery in 17,701 patients with propensity score adjustment. Thromb Haemost 2014; 111: 94-102.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 40 Beyer-Westendorf J. et al. Efficacy and safety of rivaroxaban or fondaparinux thromboprophylaxis in major orthopedic surgery: findings from the ORTHO-TEP registry. J Thromb Haemost 2012; 10: 2045-2052.
    CrossrefPubMedGoogle Scholar
  • 41 Beyer-Westendorf J. et al. Efficacy and safety of thromboprophylaxis with low-molecular-weight heparin or rivaroxaban in hip and knee replacement surgery. Findings from the ORTHO-TEP registry. Thromb Haemost 2013; 109: 154-163.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 42 Alikhan R. et al. Risk factors for venous thromboembolism in hospitalized patients with acute medical illness: analysis of the MEDENOX Study. Arch Intern Med 2004; 164: 963-968.
    CrossrefPubMedGoogle Scholar
  • 43 Kahn SR. et al. Prevention of VTE in nonsurgical patients: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physiciansevidence-basedclinicalpracticeguidelines. Chest 2012; 141: e195S-e226S.
    CrossrefPubMedGoogle Scholar
  • 44 Samama MM. et al. A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients. Prophylaxis in Medical Patients with Enoxaparin Study Group. N Engl J Med 1999; 341: 793-800.
    CrossrefPubMedGoogle Scholar
  • 45 Cohen AT. et al. Efficacy and safety of fondaparinux for the prevention of venous thromboembolism in older acute medical patients: randomised placebo controlled trial. Br Med J 2006; 332: 325-329.
    CrossrefPubMedGoogle Scholar
  • 46 Kahn SR. et al. Multicenter evaluation of the use of venous thromboembolism prophylaxis in acutely ill medical patients in Canada. Thromb Res 2007; 119: 145-155.
    CrossrefPubMedGoogle Scholar
  • 47 Tapson VF. et al. Venous thromboembolism prophylaxis in acutely ill hospitalized medical patients: Findings from the International Medical Prevention Registry on Venous Thromboembolism. Chest 2007; 132: 936-945.
    CrossrefPubMedGoogle Scholar
  • 48 Cohen AT. et al. Rivaroxaban for thromboprophylaxis in acutely ill medical patients. N Engl J Med 2013; 368: 513-523.
    CrossrefPubMedGoogle Scholar
  • 49 Goldhaber SZ. et al. Apixaban versus enoxaparin for thromboprophylaxis in medically ill patients. N Engl J Med 2011; 365: 2167-2177.
    CrossrefPubMedGoogle Scholar
  • 50 Franchini M, Mannucci PM. New anticoagulants for treatment of venous thromboembolism. Eur J Intern Med 2012; 23: 692-695.
    CrossrefPubMedGoogle Scholar
  • 51 Linkins LA. et al. Clinical impact of bleeding in patients taking oral anticoagulant therapy for venous thromboembolism: a meta-analysis. Ann Intern Med 2003; 139: 893-900.
    CrossrefPubMedGoogle Scholar
  • 52 Halbritter K. et al. Hospitalization for vitamin-K-antagonist-related bleeding: treatment patterns and outcome. J Thromb Haemost 2013; 11: 651-659.
    CrossrefPubMedGoogle Scholar
  • 53 Schulman S. et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009; 361: 2342-2352.
    CrossrefPubMedGoogle Scholar
  • 54 Schulman S. et al. Treatment of acute venous thromboembolism with dabi-gatran or warfarin and pooled analysis. Circulation 2014; 129: 764-772.
    CrossrefPubMedGoogle Scholar
  • 55 Agnelli G. et al. Oral apixaban for the treatment of acute venous thromboem-bolism. N Engl J Med 2013; 369: 799-808.
    CrossrefPubMedGoogle Scholar
  • 56 The Hokusai-VTE Investigators.. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med 2013; 369: 1406-1415.
    CrossrefPubMedGoogle Scholar
  • 57 The EINSTEIN Investigators.. Oral rivaroxaban for symptomatic venous throm-boembolism. N Engl J Med 2010; 363: 2499-2510.
    CrossrefPubMedGoogle Scholar
  • 58 The EINSTEIN-PE Investigators.. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012; 366: 1287-1297.
    CrossrefPubMedGoogle Scholar
  • 59 Prins MH. et al. Oral rivaroxaban versus standard therapy for the treatment of symptomatic venous thromboembolism: a pooled analysis of the EINSTEIN-DVT and PE randomized studies. Thromb J 2013; 11: 21.
    CrossrefPubMedGoogle Scholar
  • 60 Fox BD. et al. Efficacy and safety of novel oral anticoagulants for treatment of acute venous thromboembolism: direct and adjusted indirect meta-analysis of randomised controlled trials. Br Med J 2012; 345: e7498.
    CrossrefPubMedGoogle Scholar
  • 61 van der Hulle T. et al. Effectiveness and safety of novel oral anticoagulants as compared with vitamin K antagonists in the treatment of acute symptomatic venous thromboembolism: a systematic review and meta-analysis. J Thromb Haemost 2014; 12: 320-328.
    CrossrefPubMedGoogle Scholar
  • 62 Kang N, Sobieraj DM. Indirect treatment comparison of new oral anticoagulants for the treatment of acute venous thromboembolism. Thromb Res 2014; 133: 1145-1151.
    CrossrefPubMedGoogle Scholar
  • 63 Lega JC. et al. Consistency of safety profile of new oral anticoagulants in patients with renal failure. J Thromb Haemost 2014; 12: 337-343.
    CrossrefPubMedGoogle Scholar
  • 64 Heit JA. et al. Predictors of recurrence after deep vein thrombosis and pulmonary embolism: a population-based cohort study. Arch Intern Med 2000; 160: 761-768.
    CrossrefPubMedGoogle Scholar
  • 65 Boutitie F. et al. Influence of preceding length of anticoagulant treatment and initial presentation of venous thromboembolism on risk of recurrence after stopping treatment: analysis of individual participants’ data from seven trials. Br Med J 2011; 342: d3036.
    CrossrefPubMedGoogle Scholar
  • 66 Schulman S. et al. The duration of oral anticoagulant therapy after a second episode of venous thromboembolism. The Duration of Anticoagulation Trial Study Group. N Engl J Med 1997; 336: 393-398.
    CrossrefPubMedGoogle Scholar
  • 67 Schulman S. et al. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med 2013; 368: 709-718.
    CrossrefPubMedGoogle Scholar
  • 68 Agnelli G. et al. Apixaban for extended treatment of venous thromboembolism. N Engl J Med 2013; 368: 699-708.
    CrossrefPubMedGoogle Scholar
  • 69 Beyer-Westendorf J. et al. Treatment of acute VTE with rivaroxaban. Updated results of the prospective Dresden NOAC registry (NCT01588119). J Thromb Haemost 2013; 11: 314-315 Abstract PA 1.10-5.
    PubMedGoogle Scholar
  • 70 Beyer-Westendorf J. et al. Pattern and management of bleeding complications with new oral anticoagulants. Results of the prospective Dresden NOAC Registry (NCT01588119). J Thromb Haemost 2013; 11: 774: Abstract PB 3.26-6.
    PubMedGoogle Scholar
  • 71 Beyer-Westendorf J, Büller H. External and internal validity of open label or double-blind trials in oral anticoagulation: better, worse or just different?. J Thromb Haemost 2011; 09: 2153-2158.
    CrossrefPubMedGoogle Scholar
  • 72 Fiessinger JN. et al. Ximelagatran vs low-molecular-weight heparin and warfarin for the treatment of deep vein thrombosis: a randomized trial. J Am Med Assoc 2005; 293: 681-689.
    CrossrefPubMedGoogle Scholar
  • 73 van Gogh Investigators,. et al. Idraparinux versus standard therapy for venous thromboembolic disease. N Engl J Med 2007; 357: 1094-1104.
    CrossrefPubMedGoogle Scholar
  • 74 Lee AY. et al. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med 2003; 349: 146-153.
    CrossrefPubMedGoogle Scholar
  • 75 Gould MK. et al. Prevention of VTE in nonorthopedic surgical patients: anti-thrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2012; 141: e227S-e277S.
    CrossrefPubMedGoogle Scholar
  • 76 Stein PD, Matta F. Thrombolytic therapy in unstable patients with acute pulmonary embolism: saves lives but underused. Am J Med 2012; 125: 465-470.
    CrossrefPubMedGoogle Scholar
  • 77 Sanchez O. et al. Prognostic value of right ventricular dysfunction in patients with haemodynamically stable pulmonary embolism: a systematic review. Eur Heart J 2008; 29: 1569-1577.
    CrossrefPubMedGoogle Scholar
  • 78 Beyer-Westendorf J. et al. Chronic VTE treatment VTE with rivaroxaban. Updated results of the prospective Dresden NOAC registry (NCT01588119). J Thromb Haemost 2013; 11: 439 Abstract PA 3.19-2.
    PubMedGoogle Scholar
  • 79 Laporte S. et al. Clinical predictors for fatal pulmonary embolism in 15,520 patients with venous thromboembolism: findings from the Registro Informatizado de la Enfermedad TromboEmbolica venosa (RIETE) Registry. Circulation 2008; 117: 1711-1716.
    CrossrefPubMedGoogle Scholar
  • 80 Kittelson JM. et al. Balancing risk and benefit in venous thromboembolism trials: concept for a bivariate endpoint trial design and analytic approach. J Thromb Haemost 2013; 11: 1443-1448.
    CrossrefPubMedGoogle Scholar
  • 81 Cook RJ, Sackett DL. The number needed to treat: a clinically useful measure of treatment effect. Br Med J 1995; 310: 452-454.
    CrossrefPubMedGoogle Scholar
  • 82 Prins M. et al. Patient-reported treatment satisfaction with oral rivaroxaban versus standard therapy in the treatment of acute symptomatic pulmonary embolism. Blood (ASH Annual Meeting Abstracts). 2012 120. Abstract 1163.
    PubMedGoogle Scholar
  • 83 Bamber L. et al. Patient-reported treatment satisfaction with oral rivaroxaban versus standard therapy in the treatment of acute symptomatic deep-vein thrombosis. Thromb Haemost 2013; 110: 732-741.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 84 Osterberg L, Blaschke T. Adherence to medication. N Engl J Med 2005; 353: 487-497.
    CrossrefPubMedGoogle Scholar
  • 85 Barbosa CD. et al. A literature review to explore the link between treatment satisfaction and adherence, compliance, and persistence. Patient Prefer Adherence 2012; 06: 39-48.
    PubMedGoogle Scholar
  • 86 van Bellen B. et al. Reduction in the length of stay with rivaroxaban as a single-drug regimen for the treatment of deep vein thrombosis and pulmonary embolism. Curr Med Res Opin 2014; 30: 829-837.
    CrossrefPubMedGoogle Scholar
  • 87 Wolowacz SE. et al. Economic evaluation of dabigatran etexilate for the prevention of venous thromboembolism after total knee and hip replacement surgery. Clin Ther 2009; 31: 194-212.
    CrossrefPubMedGoogle Scholar
  • 88 Wolowacz SE. et al. Economic evaluation of dabigatran etexilate for the preven-tionof venous thromboembolism in patients aged over 75 years or with moderate renal impairment undergoing total knee or hip replacement. Thromb Hae-most 2010; 103: 360-371.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 89 Holmes M. et al. Dabigatran etexilate for the prevention of venous thromboem-bolism in patients undergoing elective hip or knee surgery: a NICE single technology appraisal. Pharmacoeconomics 2012; 30: 137-146.
    CrossrefPubMedGoogle Scholar
  • 90 Revankar N. et al. A Canadian study of the cost-effectiveness of apixaban compared with enoxaparin for post-surgical venous thromboembolism prevention. Postgrad Med 2013; 125: 141-153.
    CrossrefPubMedGoogle Scholar
  • 91 Kwong LM. Cost-effectiveness of rivaroxaban after total hip or total knee arth-roplasty. Am J Manag Care 2011; 17: S22-S26.
    PubMedGoogle Scholar
  • 92 Diamantopoulos A. et al. Cost-effectiveness of rivaroxaban versus enoxaparin for the prevention of postsurgical venous thromboembolism in Canada. Thromb Haemost 2010; 104: 760-770.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 93 Monreal M. et al. Cost-effectiveness impact of rivaroxaban versus new and existing prophylaxis for the prevention of venous thromboembolism after total hip or knee replacement surgery in France, Italy and Spain. Thromb Haemost 2013; 110: 987-994.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 94 Lefebvre P. et al. Cost-effectiveness of rivaroxaban compared with enoxaparin plus a vitamin K antagonist for the treatment of venous thromboembolism. J Med Econ 2014; 17: 52-64.
    CrossrefPubMedGoogle Scholar
  • 95 Seaman CD. et al. Cost-effectiveness of rivaroxaban versus warfarin anticoagu-lation for the prevention of recurrent venous thromboembolism: A U. S. perspective. Thromb Res 2013; 132: 647-651.
    CrossrefPubMedGoogle Scholar
  • 96 Coleman CI. et al. Cost-effectiveness analysis of extended duration anticoagu-lation with rivaroxaban to prevent recurrent venous thromboembolism. Thromb Res 2014; 133: 743-749.
    CrossrefPubMedGoogle Scholar
  • 97 Guyatt GH. et al. Executive summary: antithrombotic therapy and prevention, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2012; 141: 7S-47S.
    CrossrefPubMedGoogle Scholar
  • 98 National Institute for Health and Clinical Excellence.. Rivaroxaban for the treatment of deep vein thrombosis and prevention of recurrent deep vein thrombosis and pulmonary embolism. Technology appraisal 261. Available at: http://www.nice.org.uk/ta261. Accessed August 6, 2014.
    PubMedGoogle Scholar
  • 99 National Institute for Health and Care Excellence.. Rivaroxaban for treating pulmonary embolism and preventing recurrent venous thromboembolism; NICE technology appraisal guidance 287. Available at: http://www.nice.org.uk/guid/ance/TA287. Accessed August 6, 2014.
    PubMedGoogle Scholar
  • 100 National Institute for Health and Clinical Excellence.. Rivaroxaban for the prevention of venous thromboembolism after total hip or total knee replacement in adults. Technology appraisal guidance 170. Available at: http://www.nice.org.uk/guidance/TA170. Accessed August 6, 2014.
    PubMedGoogle Scholar
  • 101 National Institute for Health and Clinical Excellence.. Apixaban for the prevention of venous thromboembolism after total hip or knee replacement in adults. Technology appraisal 245. Available at: http://www.nice.org.uk/guidance/TA245. Accessed August 6, 2014.
    PubMedGoogle Scholar
  • 102 National Institute for Health and Clinical Excellence.. Dabigatran etexilate for the prevention of venous thromboembolism after hip or knee replacement surgery in adults. Technology appraisal 157. Available at: http://www.nice.org.uk/guidance/TA157. Accessed August 6, 2014.
    PubMedGoogle Scholar
  • 103 Monreal M. et al. Cost-effectiveness impact of rivaroxaban versus new and existing prophylaxis for the prevention of venous thromboembolism after total hip or knee replacement surgery in France, Italy and Spain. Thromb Haemost 2013; 110: 987-994.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 104 http://bidocs.boehringer-ingelheim.com/BIWebAccess/ViewServlet.ser?doc-Base=renetnt&folderPath=/Prescribing%20Information/PIs/Pradaxa/Prada-xa.pdf
    PubMed