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Semin Thromb Hemost 2015; 41(02): 237-243
DOI: 10.1055/s-0035-1544160
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Novel or Non–Vitamin K Antagonist Oral Anticoagulants and the Treatment of Cancer-Associated Thrombosis

Cynthia Wu
1   Division of Hematology, Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
,
Agnes Y. Y. Lee
2   Division of Hematology, Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
3   Thrombosis Program, Vancouver Coastal Health Authority, Vancouver, British Columbia, Canada
› Author Affiliations
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Publication History

Publication Date:
15 February 2015 (online)

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Abstract

Cancer-associated thrombosis remains a common and challenging clinical presentation. Despite advances in therapy using low-molecular-weight heparins, both venous thromboembolic recurrence and clinically relevant bleeding while on therapeutic anticoagulation occur at high rates. Multiple novel (or non–vitamin K antagonist) oral anticoagulants have recently been developed for the treatment and prevention of venous thromboembolism. There are many attractive features of these agents including convenience and simplicity of administration. Unfortunately, there are also several limitations such as dependency on gastrointestinal absorption, renal clearance, and some significant drug–drug interactions. The use of these newer oral agents in cancer patients is not recommended, as their safety and efficacy are not yet established and the complexity of these patients warrants further cancer-specific clinical trials.

Keywords

cancer - venous thromboembolism - novel oral anticoagulants
 

  • References

  • 1 Silverstein MD, Heit JA, Mohr DN, Petterson TM, O'Fallon WM, Melton III LJ. Trends in the incidence of deep vein thrombosis and pulmonary embolism: a 25-year population-based study. Arch Intern Med 1998; 158 (6) 585-593
    CrossrefPubMedGoogle Scholar
  • 2 Geerts WH, Bergqvist D, Pineo GF , et al; American College of Chest Physicians. Prevention of venous thromboembolism: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest 2008; 133 (6, Suppl): 381S-453S
    CrossrefPubMedGoogle Scholar
  • 3 Prandoni P, Noventa F, Ghirarduzzi A , et al. The risk of recurrent venous thromboembolism after discontinuing anticoagulation in patients with acute proximal deep vein thrombosis or pulmonary embolism. A prospective cohort study in 1,626 patients. Haematologica 2007; 92 (2) 199-205
    CrossrefPubMedGoogle Scholar
  • 4 Virchow RLK. Thrombose und Embolie. Gefässentzündung und septische infection. Gesammelte abhandlungen zur wissenschaftlichen medcin. Frankfurt am Main: Von Meidinger & Sohn. Thrombosis and Embolie (1846–1856). In: Matzdorff AC, Bell WR, , eds. Science History Publications. Canton, MA: 1998: 219-732
    Google Scholar
  • 5 Heit JA, Silverstein MD, Mohr DN, Petterson TM, O'Fallon WM, Melton III LJ. Risk factors for deep vein thrombosis and pulmonary embolism: a population-based case-control study. Arch Intern Med 2000; 160 (6) 809-815
    CrossrefPubMedGoogle Scholar
  • 6 Hutten BA, Prins MH, Gent M, Ginsberg J, Tijssen JG, Büller HR. Incidence of recurrent thromboembolic and bleeding complications among patients with venous thromboembolism in relation to both malignancy and achieved international normalized ratio: a retrospective analysis. J Clin Oncol 2000; 18 (17) 3078-3083
    CrossrefPubMedGoogle Scholar
  • 7 Levitan N, Dowlati A, Remick SC , et al. Rates of initial and recurrent thromboembolic disease among patients with malignancy versus those without malignancy. Risk analysis using Medicare claims data. Medicine (Baltimore) 1999; 78 (5) 285-291
    CrossrefPubMedGoogle Scholar
  • 8 Palareti G, Legnani C, Lee A , et al. A comparison of the safety and efficacy of oral anticoagulation for the treatment of venous thromboembolic disease in patients with or without malignancy. Thromb Haemost 2000; 84 (5) 805-810
    Article in Thieme ConnectPubMedGoogle Scholar
  • 9 Prandoni P, Lensing AW, Piccioli A , et al. Recurrent venous thromboembolism and bleeding complications during anticoagulant treatment in patients with cancer and venous thrombosis. Blood 2002; 100 (10) 3484-3488
    CrossrefPubMedGoogle Scholar
  • 10 Sørensen HT, Mellemkjaer L, Olsen JH, Baron JA. Prognosis of cancers associated with venous thromboembolism. N Engl J Med 2000; 343 (25) 1846-1850
    CrossrefPubMedGoogle Scholar
  • 11 Khorana AA, Francis CW, Culakova E, Kuderer NM, Lyman GH. Thromboembolism is a leading cause of death in cancer patients receiving outpatient chemotherapy. J Thromb Haemost 2007; 5 (3) 632-634
    CrossrefPubMedGoogle Scholar
  • 12 Lee AY, Levine MN, Baker RI , et al; Randomized Comparison of Low-Molecular-Weight Heparin versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer (CLOT) Investigators. Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med 2003; 349 (2) 146-153
    CrossrefPubMedGoogle Scholar
  • 13 Hull RD, Pineo GF, Brant RF , et al; LITE Trial Investigators. Long-term low-molecular-weight heparin versus usual care in proximal-vein thrombosis patients with cancer. Am J Med 2006; 119 (12) 1062-1072
    CrossrefPubMedGoogle Scholar
  • 14 Hull RD, Pineo GF, Brant RF , et al; LITE Trial Investigators. Self-managed long-term low-molecular-weight heparin therapy: the balance of benefits and harms. Am J Med 2007; 120 (1) 72-82
    CrossrefPubMedGoogle Scholar
  • 15 Meyer G, Marjanovic Z, Valcke J , et al. Comparison of low-molecular-weight heparin and warfarin for the secondary prevention of venous thromboembolism in patients with cancer: a randomized controlled study. Arch Intern Med 2002; 162 (15) 1729-1735
    CrossrefPubMedGoogle Scholar
  • 16 Deitcher SR, Kessler CM, Merli G, Rigas JR, Lyons RM, Fareed J ; ONCENOX Investigators. Secondary prevention of venous thromboembolic events in patients with active cancer: enoxaparin alone versus initial enoxaparin followed by warfarin for a 180-day period. Clin Appl Thromb Hemost 2006; 12 (4) 389-396
    CrossrefPubMedGoogle Scholar
  • 17 Kearon C, Akl EA. Duration of anticoagulant therapy for deep vein thrombosis and pulmonary embolism. Blood 2014; 123 (12) 1794-1801
    CrossrefPubMedGoogle Scholar
  • 18 Agnelli G, Buller HR, Cohen A , et al; AMPLIFY Investigators. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med 2013; 369 (9) 799-808
    CrossrefPubMedGoogle Scholar
  • 19 Büller HR, Décousus H, Grosso MA , et al; Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med 2013; 369 (15) 1406-1415
    CrossrefPubMedGoogle Scholar
  • 20 Bauersachs R, Berkowitz SD, Brenner B , et al; EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010; 363 (26) 2499-2510
    CrossrefPubMedGoogle Scholar
  • 21 Büller HR, Prins MH, Lensin AW , et al; EINSTEIN–PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012; 366 (14) 1287-1297
    CrossrefPubMedGoogle Scholar
  • 22 Schulman S, Kearon C, Kakkar AK , et al; RE-COVER Study Group. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009; 361 (24) 2342-2352
    CrossrefPubMedGoogle Scholar
  • 23 Garcia DA, Baglin TP, Weitz JI, Samama MM ; American College of Chest Physicians. Parenteral anticoagulants: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141 (2, Suppl): e24S-e43S
    CrossrefPubMedGoogle Scholar
  • 24 Ageno W, Gallus AS, Wittkowsky A, Crowther M, Hylek EM, Palareti G ; American College of Chest Physicians. Oral anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141 (2, Suppl): e44S-e88S
    CrossrefPubMedGoogle Scholar
  • 25 Nutescu EA, Spinler SA, Wittkowsky A, Dager WE. Low-molecular-weight heparins in renal impairment and obesity: available evidence and clinical practice recommendations across medical and surgical settings. Ann Pharmacother 2009; 43 (6) 1064-1083
    CrossrefPubMedGoogle Scholar
  • 26 Carrier M, Le Gal G, Cho R, Tierney S, Rodger M, Lee AY. Dose escalation of low molecular weight heparin to manage recurrent venous thromboembolic events despite systemic anticoagulation in cancer patients. J Thromb Haemost 2009; 7 (5) 760-765
    CrossrefPubMedGoogle Scholar
  • 27 Lee AY, Peterson EA. Treatment of cancer-associated thrombosis. Blood 2013; 122 (14) 2310-2317
    CrossrefPubMedGoogle Scholar
  • 28 Carrier M, Khorana AA, Zwicker J, Noble S, Lee AY ; Subcommittee on Haemostasis and Malignancy for the SSC of the ISTH. Management of challenging cases of patients with cancer-associated thrombosis including recurrent thrombosis and bleeding: guidance from the SSC of the ISTH. J Thromb Haemost 2013; 11 (9) 1760-1765
    CrossrefPubMedGoogle Scholar
  • 29 Kahn SR, Lim W, Dunn AS , et al; American College of Chest Physicians. Prevention of VTE in nonsurgical patients: Antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2012; 141 (2, Suppl): e195S-e226S
    CrossrefPubMedGoogle Scholar
  • 30 Mandalà M, Falanga A, Roila F ; ESMO Guidelines Working Group. Management of venous thromboembolism (VTE) in cancer patients: ESMO Clinical Practice Guidelines. Ann Oncol 2011; 22 (6) (Suppl. 06) vi85-vi92
    CrossrefPubMedGoogle Scholar
  • 31 Lyman GH, Khorana AA, Kuderer NM , et al; American Society of Clinical Oncology Clinical Practice. Venous thromboembolism prophylaxis and treatment in patients with cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol 2013; 31 (17) 2189-2204
    CrossrefPubMedGoogle Scholar
  • 32 Francis CW. Prevention of venous thromboembolism in hospitalized patients with cancer. J Clin Oncol 2009; 27 (29) 4874-4880
    CrossrefPubMedGoogle Scholar
  • 33 Carrier M, Moretto P, Le Gal G, Karp R, Zwicker JI. Lack of data to support thromboprophylaxis in hospitalized medical patients with cancer. Am J Med 2014; 127 (1) 82-86
    CrossrefPubMedGoogle Scholar
  • 34 Alikhan R, Cohen AT. Heparin for the prevention of venous thromboembolism in general medical patients (excluding stroke and myocardial infarction). Cochrane Database Syst Rev 2009; (3) CD003747
    PubMedGoogle Scholar
  • 35 Dentali F, Douketis JD, Gianni M, Lim W, Crowther MA. Meta-analysis: anticoagulant prophylaxis to prevent symptomatic venous thromboembolism in hospitalized medical patients. Ann Intern Med 2007; 146 (4) 278-288
    CrossrefPubMedGoogle Scholar
  • 36 Goldhaber SZ, Leizorovicz A, Kakkar AK , et al; ADOPT Trial Investigators. Apixaban versus enoxaparin for thromboprophylaxis in medically ill patients. N Engl J Med 2011; 365 (23) 2167-2177
    CrossrefPubMedGoogle Scholar
  • 37 Cohen AT, Spiro TE, Spyropoulos AC ; MAGELLAN Steering Committee. Rivaroxaban for thromboprophylaxis in acutely ill medical patients. N Engl J Med 2013; 368 (20) 1945-1946
    PubMedGoogle Scholar
  • 38 Gerotziafas GT, Mahé I, Elalamy I. New orally active anticoagulant agents for the prevention and treatment of venous thromboembolism in cancer patients. Ther Clin Risk Manag 2014; 10: 423-436
    PubMedGoogle Scholar
  • 39 Khorana AA, Kuderer NM, Culakova E, Lyman GH, Francis CW. Development and validation of a predictive model for chemotherapy-associated thrombosis. Blood 2008; 111 (10) 4902-4907
    CrossrefPubMedGoogle Scholar
  • 40 Agnelli G, Gussoni G, Bianchini C , et al; PROTECHT Investigators. Nadroparin for the prevention of thromboembolic events in ambulatory patients with metastatic or locally advanced solid cancer receiving chemotherapy: a randomised, placebo-controlled, double-blind study. Lancet Oncol 2009; 10 (10) 943-949
    CrossrefPubMedGoogle Scholar
  • 41 Agnelli G, George DJ, Kakkar AK , et al; SAVE-ONCO Investigators. Semuloparin for thromboprophylaxis in patients receiving chemotherapy for cancer. N Engl J Med 2012; 366 (7) 601-609
    CrossrefPubMedGoogle Scholar
  • 42 Levine MN, Gu C, Liebman HA , et al. A randomized phase II trial of apixaban for the prevention of thromboembolism in patients with metastatic cancer. J Thromb Haemost 2012; 10 (5) 807-814
    CrossrefPubMedGoogle Scholar
  • 43 Kakkar VV, Balibrea JL, Martínez-González J, Prandoni P ; CANBESURE Study Group. Extended prophylaxis with bemiparin for the prevention of venous thromboembolism after abdominal or pelvic surgery for cancer: the CANBESURE randomized study. J Thromb Haemost 2010; 8 (6) 1223-1229
    CrossrefPubMedGoogle Scholar
  • 44 Rasmussen MS, Jørgensen LN, Wille-Jørgensen P. Prolonged thromboprophylaxis with low molecular weight heparin for abdominal or pelvic surgery. Cochrane Database Syst Rev 2009; (1) CD004318
    PubMedGoogle Scholar
  • 45 Gould MK, Garcia DA, Wren SM , et al; American College of Chest Physicians. Prevention of VTE in nonorthopedic surgical patients: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141 (2, Suppl): e227S-e277S
    CrossrefPubMedGoogle Scholar
  • 46 Falck-Ytter Y, Francis CW, Johanson NA , et al; American College of Chest Physicians. 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 (2, Suppl): e278S-e325S
    CrossrefPubMedGoogle Scholar
  • 47 van der Hulle T, den Exter PL, Kooiman J, van der Hoeven JJ, Huisman MV, Klok FA. Meta-analysis of the efficacy and safety of new oral anticoagulants in patients with cancer-associated acute venous thromboembolism. J Thromb Haemost 2014; 12 (7) 1116-1120
    CrossrefPubMedGoogle Scholar
  • 48 Carrier M, Cameron C, Delluc A , et al. Efficacy and safety of anticoagulant therapy for the treatment of acute cancer-associated thrombosis: a systematic review and meta-analysis. Thromb Res 2014; 134 (6) 1214-1219
    CrossrefPubMedGoogle Scholar
  • 49 Vedovati MC, Germini F, Agnelli G, Becattini C. Direct oral anticoagulants in patients with venous thromboembolism and cancer: a systematic review and meta-analysis. Chest 2014; (e-pub ahead of print). doi: 10.1378/chest.14-0402
    PubMedGoogle Scholar
  • 50 Agnelli G, Buller HR, Cohen A , et al. Apixaban for the treatment of venous thromboembolism in cancer patients: data from the AMPLIFY trial. European Cardiology Society meeting 2014: Abstract P5527
    PubMedGoogle Scholar
  • 51 Raskob GE, Buller H, Angchaisuksiri P , et al. Edoxaban for long-term treatment of venous thromboembolism in cancer patients. Blood 2013; 122: abstract 211 . ASH Annual Meeting
    PubMedGoogle Scholar
  • 52 Prins MH, Lensing AWA, Brighton TA , et al. Oral rivaroxaban versus enoxaparin with vitamin K antagonist for the treatment of symptomatic venous thromboembolism in patients with cancer (EINSTEIN-DVT and EINSTEIN-PE): a pooled subgroup analysis of two randomised controlled trials. Lancet Haematology 2014; 1 (1) e37-e46
    PubMedGoogle Scholar
  • 53 Akl EA, Kahale L, Barba M , et al. Anticoagulation for the long-term treatment of venous thromboembolism in patients with cancer. Cochrane Database Syst Rev 2014; 7 (7) CD006650
    PubMedGoogle Scholar