Are New Oral Anticoagulants Ready for Use in Patients With Cancer?

Authors: Paul C. Hendrie MD, PhDa and David A. Garcia MDa
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  • a From Seattle Cancer Care Alliance and Division of Hematology, University of Washington, Seattle, Washington.

Patients with cancer have long been an important and enigmatic part of basic science and clinical research in thromboembolic disease. The reciprocal deleterious effects on outcomes of a cancer diagnosis on patients with thrombosis and a thrombotic event on patients with cancer have been observed and documented for more than a century. Patients with cancer continue to be one of the more difficult populations to manage using the available unfractionated and low-molecular-weight heparins and the oral vitamin K antagonists. High rates of failure and bleeding complications have made researchers and practitioners alike seek newer more effective anticoagulation agents. The novel oral direct thrombin and activated factor Xa inhibitors have been shown in large clinical trials to be safe and efficacious in many prophylaxis and treatment settings. However, practitioners who treat patients with cancer should be cautious using these agents until more studies are specifically performed in this thrombophilic patient population.

Cancer and venous thromboembolism (VTE) have strong associations. According to the Computerized Registry of Patients with Venous Thromboembolism (RIETE), cancer was present in 20% of patients with venous thrombosis.1 Furthermore, patients with cancer seem to have a more aggressive form of VTE and tend to experience a higher rate of anticoagulant-associated bleeding.2,3 Patients with cancer who develop VTE also have a higher risk of death, only partly explained by recurrent thrombosis.4,5 Better strategies to treat and prevent VTE in patients with cancer are needed.

Until recently, anticoagulation for the prevention and treatment of VTE has been limited to oral vitamin K antagonists (eg, warfarin) and parenteral agents derived from heparin with anti-factor Xa and antithrombin activity. Unfractionated heparin (UFH) and low-molecular-weight heparins (LMWHs) have been the mainstay for in-hospital-based prophylaxis, both postsurgically and on medicine floors, and for the acute management of deep vein thrombosis and pulmonary embolisms.6 The agents are given intravenously or subcutaneously and offer the advantages of quick pharmacologic effects. UFH is inexpensive and can be reversed with protamine sulfate, but, compared with LMWH,7,8 UFH has less predictable bioavailability. Whether UFH confers a greater risk of heparin-induced thrombocytopenia in patients with cancer is uncertain.7,8 LMWHs offer the advantage of more convenient dosing, administration, and more predictable anticoagulant effects; however, the anticoagulant effect of LMWH is incompletely reversed with protamine sulfate.9 Other parenteral factor Xa inhibitors and direct thrombin inhibitors have been used less frequently.10

For most patients with VTE, warfarin is a highly effective therapy and has several advantages, including oral administration and reversibility with vitamin K and fresh frozen plasma or prothrombin complex concentrates.11,12 The disadvantages of warfarin are a slow onset of anticoagulation, a long pharmacodynamic half-life, and interactions with diet and concomitant medications that require regular monitoring and dose adjustment. Although warfarin can virtually eliminate the risk of VTE progression/recurrence for most patients, individuals with cancer-associated VTE have a disturbingly high risk of recurrent thrombosis when treated with warfarin.13 Citing several studies14-16 that show a reduction in VTE recurrence, NCCN and other organizations recommend LMWH over warfarin in patients with cancer for at least the first 6 months of VTE treatment.6,17

Although LMWHs have become the preferred VTE treatment for patients with cancer, problems with its use have prompted clinicians to seek newer antithrombotic agents. The biggest disadvantage of LMWH is that it cannot be given orally. Repeated needle injections can be cumbersome and occasionally painful for patients already dealing with the emotional and physical effects of malignancy. In addition to the storage and disposal of the needles, other disadvantages include the cost of LMWH and its inefficient reversibility. Finally, the efficacy of the LMWHs in this setting, although better than that of the vitamin K antagonists, leaves significant room for improvement; the landmark trial that forms the basis of current recommendations reported that almost 9% of patients assigned to LMWH were diagnosed with recurrent VTE during 6 months of follow-up versus 17% in the oral anticoagulation group.15 The ideal anticoagulant agent would be oral and have predictable pharmacologic effects, rare or insignificant interactions with other medications, low need for monitoring, and a favorable safety profile. A rapid onset of action, reversibility, and affordability would be welcome.

The available new oral direct thrombin inhibitors and factor Xa inhibitors fulfill some of these expectations. The new agents are dabigatran, a direct thrombin inhibitor, and rivaroxaban and apixaban, activated factor X inhibitors.18 First, they offer an oral alternative to the parenteral heparins. This is desirable for most patients with cancer, but may not be useful in patients whose gastrointestinal tract is unavailable because of disease involvement, surgery, radiation, or nausea. These agents also have easy dosing schedules without monitoring requirements in most patients, and all 3 have a rapid onset of pharmacologic effect.19 Their relatively low potential for drug-drug interactions would be useful for patients with cancer who are often receiving numerous other treatments. In large studies of surgical and medical patients, these agents have been shown to be as effective as more traditional strategies for VTE prophylaxis and treatment.20-24 Safety end points were equivalent for the VTE treatment studies; however, for VTE prophylaxis in the acutely ill medical patients, more bleeding events occurred in the rivaroxaban group than in the enoxaparin group (2.8% vs 1.2%).20-24

Although subgroup analyses of patients with cancer in the large VTE treatment trials have been performed, they are of limited value because the number of patients with cancer and VTE events are very small, and the comparator in these studies has been warfarin, not LMWH. At least one preliminary study compared a novel oral agent, apixaban, with placebo for primary VTE prophylaxis in patients with cancer. This phase II feasibility study suggested that apixaban could be used safely in patients with cancer, but the number of thrombosis and bleeding events was too small for definitive conclusions.25

Although the new oral anticoagulants have the potential to eliminate the inconvenience and discomfort of subcutaneous injections, clinicians who treat patients with cancer should be cautious before adopting the novel agents for widespread use. First, limited experience has been published with these target-specific agents in patients with cancer.26 Second, they have not been compared with LMWH, the current gold standard for the long-term treatment of cancer-associated VTE. Thrombosis associated with cancer has been recognized as unique since Armand Trousseau’s description in 1865.27 Recent studies have identified involvement of tissue factor and vascular endothelial growth factor in the pathophysiology of cancer-associated hypercoagulability.28-30 Mucin-producing cancers, those with the highest rates of thrombosis, have been shown to activate neutrophils and platelets through the adhesion molecules P- and L-selectin.31 It has been postulated that heparins, which are glycosaminoglycans of varying molecular weight, may directly interfere with one or more of these mucin-mediated interactions. If this explains all or part of the clinical effectiveness observed with heparin therapy, small molecules such as the new oral anticoagulants may be less able to antagonize thrombosis.

A recent meta-analysis of primary prevention trials using LMWH suggests a possible survival benefit of LMWH in patients with malignancies.32 Whether the novel oral inhibitors would have a similar impact on cancer mortality is not known. Other factors, such as venous stasis from vessel compression, immobility, central venous catheters (CVC), and thrombogenic anticancer therapies, such as tamoxifen and thalidomide, play a role in some patients. The new agents have not been evaluated with specific chemotherapy regimens and have not been shown to reduce CVC-associated thrombosis. Given the incomplete understanding (and complexity) of the mechanisms and factors underlying the cancer-thrombosis association, extrapolating the conclusions from trials involving unselected patients with VTE to patients with active malignancy would be unwise.

The lack of an antidote or evidence-based reversal strategy for the new anticoagulants is especially problematic for patients with cancer, because they commonly develop significant thrombocytopenia. Although the short half-life of the new oral agents seems attractive for patients who require elective procedures, little is known about the safety of interrupting and restarting these drugs around the time of surgery. Finally, for patients with advanced renal insufficiency, the newer oral anticoagulants are contra-indicated. Among individuals with cancer, this subgroup is particularly challenging, because LMWHs also depend heavily on renal clearance mechanisms.

The biology of venous thrombosis in the setting of an active malignancy seems to be different from VTE in other settings. Insufficient evidence exists to recommend the new oral anticoagulants for patients with (or at risk for) cancer-associated VTE. Although several pharmacologic characteristics of the new anticoagulant agents make them attractive, dedicated clinical trials will be necessary to define the safety and efficacy of these drugs in patients with cancer.

Dr. Hendrie has disclosed that he has no financial interests, arrangements, affiliations, or commercial interests with the manufacturers of any products discussed in this article or their competitors. Dr. Garcia has disclosed that he has chaired or served on advisory boards for Janssen Pharmaceuticals, Inc.; Bristol-Myers Squibb Company; and Pfizer Inc. He is also a member of the steering committee for the ARISTOTLE trial, sponsored by Bristol-Myers Squibb Company and Pfizer Inc.

References

  • 1.

    Laporte S, Mismetti P, Décousus H 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;117:17111716.

    • Search Google Scholar
    • Export Citation
  • 2.

    Chew HK, Wun T, Harvey D et al. . Incidence of venous thromboembolism and its effect on survival among patients with common cancers. Arch Intern Med 2006;166:458464.

    • Search Google Scholar
    • Export Citation
  • 3.

    Trujillo-Santos J, Nieto JA, Tiberio G et al. . Predicting recurrences or major bleeding in cancer patients with venous thromboembolism. Findings from the RIETE Registry. Thromb Haemost 2008;100:435439.

    • Search Google Scholar
    • Export Citation
  • 4.

    Khorana AA, Francis CW, Culakova E et al. . Thromboembolism is a leading cause of death in cancer patients receiving outpatient chemotherapy. J Thromb Haemost 2007;5:632634.

    • Search Google Scholar
    • Export Citation
  • 5.

    Khorana AA. Venous thromboembolism and prognosis in cancer. Thromb Res 2010;125:490493.

  • 6.

    Streiff MB. The National Comprehensive Cancer Center Network (NCCN) guidelines on the management of venous thromboembolism in cancer patients. Thromb Res 2010;125(Suppl 2):S128133.

    • Search Google Scholar
    • Export Citation
  • 7.

    Junqueira DR, Perini E, Penholati RR, Carvalho MG. Unfractionated heparin versus low molecular weight heparin for avoiding heparin-induced thrombocytopenia in postoperative patients. Cochrane Database Syst Rev 2012;9:CD007557.

    • Search Google Scholar
    • Export Citation
  • 8.

    Akl EA, Terrenato I, Barba M et al. . Low-molecular-weight heparin vs unfractionated heparin for perioperative thromboprophylaxis in patients with cancer: a systematic review and meta-analysis. Arch Intern Med 2008;168:12611269.

    • Search Google Scholar
    • Export Citation
  • 9.

    Verstraete M. Pharmacotherapeutic aspects of unfractionated and low molecular weight heparins. Drugs 1990;40:498530.

  • 10.

    Prandoni P, Falanga A, Piccioli A. Cancer, thrombosis and heparin-induced thrombocytopenia. Thromb Res 2007;120(Suppl 2):S137140 [erratum in Thromb Res 2008;123:187-190].

    • Search Google Scholar
    • Export Citation
  • 11.

    Ansell J, Hirsh J, Hylek E et al. . Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest 2008;133(6 Suppl):160S198S.

    • Search Google Scholar
    • Export Citation
  • 12.

    Leissinger CA, Blatt PM, Hoots WK, Ewenstein B. Role of prothrombin complex concentrates in reversing warfarin anticoagulation: a review of the literature. Am J Hematol 2008;83:137143.

    • Search Google Scholar
    • Export Citation
  • 13.

    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;100:34843488.

    • Search Google Scholar
    • Export Citation
  • 14.

    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;162:17291735.

    • Search Google Scholar
    • Export Citation
  • 15.

    Lee AY, Levine MN, Baker RI 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;349:146153.

    • Search Google Scholar
    • Export Citation
  • 16.

    Hull RD, Pineo GF, Brant RF et al. . Long-term low-molecular-weight heparin versus usual care in proximal-vein thrombosis patients with cancer. Am J Med 2006;119:10621072.

    • Search Google Scholar
    • Export Citation
  • 17.

    Kearon C, Akl EA, Comerota AJ et al. . Antithrombotic therapy for VTE disease: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2012;141(2 Suppl):e419S494S.

    • Search Google Scholar
    • Export Citation
  • 18.

    King CS, Holley AB, Moores LK. Moving toward a more ideal anticoagulant: the oral direct thrombin and factor xa inhibitors. Chest 2013;143:11061116.

    • Search Google Scholar
    • Export Citation
  • 19.

    Rojas-Hernandez CM, Garcia DA. The novel oral anticoagulants. Semin Thromb Hemost 2013;39:117126.

  • 20.

    Schulman S, Kearon C, Kakkar AK et al. . Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009;361:23422352.

    • Search Google Scholar
    • Export Citation
  • 21.

    EINSTEIN-PE Investigators, Bauersachs R, Berkowitz SD et al. . Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010;363:24992510.

    • Search Google Scholar
    • Export Citation
  • 22.

    EINSTEIN-PE Investigators, Buller HR, Prins MH et al. . Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012;366:12871297.

    • Search Google Scholar
    • Export Citation
  • 23.

    Agnelli G, Buller HR, Cohen A et al. . Apixaban for extended treatment of venous thromboembolism. N Engl J Med 2013;368:699708.

  • 24.

    Cohen AT, Spiro TE, Spyropoulos AC et al. . Rivaroxaban for thromboprophylaxis in acutely ill medical patients. N Engl J Med 2013;368:513523.

  • 25.

    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;10:807814.

    • Search Google Scholar
    • Export Citation
  • 26.

    Siegal DM, Garcia D. Anticoagulants in cancer. J Thromb Haemost 2012;11:22302241.

  • 27.

    Trousseau A. Phlegmasia alba dolens. In: Clinique Medicale de l’Hotel-Dieu de Paris, Vol. 3 Paris, France: The Sydenham Society: 1865:654712.

    • Search Google Scholar
    • Export Citation
  • 28.

    Eroglu A, Gulec S, Akar N. Vascular endothelial growth factor C936T polymorphism in cancer patients with thrombosis. Am J Hematol 2007;82:174.

  • 29.

    Ruf W, Disse J, Carneiro-Lobo TC et al. . Tissue factor and cell signalling in cancer progression and thrombosis. J Thromb Haemost 2011;9(Suppl 1):306315.

    • Search Google Scholar
    • Export Citation
  • 30.

    Anand M, Brat DJ. Oncogenic regulation of tissue factor and thrombosis in cancer. Thromb Res 2012;129(Suppl 1):S464931.

  • 31.

    Shao B, Wahrenbrock MG, Yao L et al. . Carcinoma mucins trigger reciprocal activation of platelets and neutrophils in a murine model of Trousseau syndrome. Blood 2011;118:40154023.

    • Search Google Scholar
    • Export Citation
  • 32.

    Akl EA, Schunemann HJ. Routine heparin for patients with cancer? One answer, more questions. N Engl J Med 2012;366:661662.

Correspondence: Paul C. Hendrie, MD, PhD, Seattle Cancer Care Alliance, 825 Eastlake Avenue E, Seattle, WA 98109. E-mail: phendrie@uw.edu
  • 1.

    Laporte S, Mismetti P, Décousus H 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;117:17111716.

    • Search Google Scholar
    • Export Citation
  • 2.

    Chew HK, Wun T, Harvey D et al. . Incidence of venous thromboembolism and its effect on survival among patients with common cancers. Arch Intern Med 2006;166:458464.

    • Search Google Scholar
    • Export Citation
  • 3.

    Trujillo-Santos J, Nieto JA, Tiberio G et al. . Predicting recurrences or major bleeding in cancer patients with venous thromboembolism. Findings from the RIETE Registry. Thromb Haemost 2008;100:435439.

    • Search Google Scholar
    • Export Citation
  • 4.

    Khorana AA, Francis CW, Culakova E et al. . Thromboembolism is a leading cause of death in cancer patients receiving outpatient chemotherapy. J Thromb Haemost 2007;5:632634.

    • Search Google Scholar
    • Export Citation
  • 5.

    Khorana AA. Venous thromboembolism and prognosis in cancer. Thromb Res 2010;125:490493.

  • 6.

    Streiff MB. The National Comprehensive Cancer Center Network (NCCN) guidelines on the management of venous thromboembolism in cancer patients. Thromb Res 2010;125(Suppl 2):S128133.

    • Search Google Scholar
    • Export Citation
  • 7.

    Junqueira DR, Perini E, Penholati RR, Carvalho MG. Unfractionated heparin versus low molecular weight heparin for avoiding heparin-induced thrombocytopenia in postoperative patients. Cochrane Database Syst Rev 2012;9:CD007557.

    • Search Google Scholar
    • Export Citation
  • 8.

    Akl EA, Terrenato I, Barba M et al. . Low-molecular-weight heparin vs unfractionated heparin for perioperative thromboprophylaxis in patients with cancer: a systematic review and meta-analysis. Arch Intern Med 2008;168:12611269.

    • Search Google Scholar
    • Export Citation
  • 9.

    Verstraete M. Pharmacotherapeutic aspects of unfractionated and low molecular weight heparins. Drugs 1990;40:498530.

  • 10.

    Prandoni P, Falanga A, Piccioli A. Cancer, thrombosis and heparin-induced thrombocytopenia. Thromb Res 2007;120(Suppl 2):S137140 [erratum in Thromb Res 2008;123:187-190].

    • Search Google Scholar
    • Export Citation
  • 11.

    Ansell J, Hirsh J, Hylek E et al. . Pharmacology and management of the vitamin K antagonists: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th edition). Chest 2008;133(6 Suppl):160S198S.

    • Search Google Scholar
    • Export Citation
  • 12.

    Leissinger CA, Blatt PM, Hoots WK, Ewenstein B. Role of prothrombin complex concentrates in reversing warfarin anticoagulation: a review of the literature. Am J Hematol 2008;83:137143.

    • Search Google Scholar
    • Export Citation
  • 13.

    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;100:34843488.

    • Search Google Scholar
    • Export Citation
  • 14.

    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;162:17291735.

    • Search Google Scholar
    • Export Citation
  • 15.

    Lee AY, Levine MN, Baker RI 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;349:146153.

    • Search Google Scholar
    • Export Citation
  • 16.

    Hull RD, Pineo GF, Brant RF et al. . Long-term low-molecular-weight heparin versus usual care in proximal-vein thrombosis patients with cancer. Am J Med 2006;119:10621072.

    • Search Google Scholar
    • Export Citation
  • 17.

    Kearon C, Akl EA, Comerota AJ et al. . Antithrombotic therapy for VTE disease: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2012;141(2 Suppl):e419S494S.

    • Search Google Scholar
    • Export Citation
  • 18.

    King CS, Holley AB, Moores LK. Moving toward a more ideal anticoagulant: the oral direct thrombin and factor xa inhibitors. Chest 2013;143:11061116.

    • Search Google Scholar
    • Export Citation
  • 19.

    Rojas-Hernandez CM, Garcia DA. The novel oral anticoagulants. Semin Thromb Hemost 2013;39:117126.

  • 20.

    Schulman S, Kearon C, Kakkar AK et al. . Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009;361:23422352.

    • Search Google Scholar
    • Export Citation
  • 21.

    EINSTEIN-PE Investigators, Bauersachs R, Berkowitz SD et al. . Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010;363:24992510.

    • Search Google Scholar
    • Export Citation
  • 22.

    EINSTEIN-PE Investigators, Buller HR, Prins MH et al. . Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012;366:12871297.

    • Search Google Scholar
    • Export Citation
  • 23.

    Agnelli G, Buller HR, Cohen A et al. . Apixaban for extended treatment of venous thromboembolism. N Engl J Med 2013;368:699708.

  • 24.

    Cohen AT, Spiro TE, Spyropoulos AC et al. . Rivaroxaban for thromboprophylaxis in acutely ill medical patients. N Engl J Med 2013;368:513523.

  • 25.

    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;10:807814.

    • Search Google Scholar
    • Export Citation
  • 26.

    Siegal DM, Garcia D. Anticoagulants in cancer. J Thromb Haemost 2012;11:22302241.

  • 27.

    Trousseau A. Phlegmasia alba dolens. In: Clinique Medicale de l’Hotel-Dieu de Paris, Vol. 3 Paris, France: The Sydenham Society: 1865:654712.

    • Search Google Scholar
    • Export Citation
  • 28.

    Eroglu A, Gulec S, Akar N. Vascular endothelial growth factor C936T polymorphism in cancer patients with thrombosis. Am J Hematol 2007;82:174.

  • 29.

    Ruf W, Disse J, Carneiro-Lobo TC et al. . Tissue factor and cell signalling in cancer progression and thrombosis. J Thromb Haemost 2011;9(Suppl 1):306315.

    • Search Google Scholar
    • Export Citation
  • 30.

    Anand M, Brat DJ. Oncogenic regulation of tissue factor and thrombosis in cancer. Thromb Res 2012;129(Suppl 1):S464931.

  • 31.

    Shao B, Wahrenbrock MG, Yao L et al. . Carcinoma mucins trigger reciprocal activation of platelets and neutrophils in a murine model of Trousseau syndrome. Blood 2011;118:40154023.

    • Search Google Scholar
    • Export Citation
  • 32.

    Akl EA, Schunemann HJ. Routine heparin for patients with cancer? One answer, more questions. N Engl J Med 2012;366:661662.

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