How to Choose An Appropriate Anticoagulant for Cancer-Associated Thrombosis

Authors: Jordan K. Schaefer MD1, Amro Elshoury MBBCh2, Victoria R. Nachar PharmD, BCOP3, Michael B. Streiff MD4, and Ming Y. Lim MBBChir5
View More View Less
  • 1 Division of Hematology/Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan;
  • | 2 Roswell Park Comprehensive Cancer Center, Buffalo, New York;
  • | 3 University of Michigan Rogel Cancer Center, Ann Arbor, Michigan;
  • | 4 Division of Hematology, Department of Medicine, The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; and
  • | 5 Division of Hematology and Hematologic Malignancies, Department of Internal Medicine, University of Utah, Salt Lake City, Utah.

Venous thromboembolic disease can be a fatal complication of cancer. Despite advances in prevention, thousands of patients require treatment of cancer-associated thrombosis (CAT) each year. Guidelines have advocated low-molecular-weight heparin (LMWH) as the preferred anticoagulant for CAT for years, based on clinical trial data showing LMWH to be associated with a lower risk of recurrent thrombosis when compared with vitamin K antagonists. However, the potentially painful, subcutaneously administered LMWH injections can be expensive, and clinical practice has not been consistent with guideline recommendations. Recently, studies have compared LMWH to the direct oral anticoagulants (DOACs) for the management of CAT. Based on promising trial results outlined in this review, DOACs are now preferred anticoagulants for CAT occurring in patients without gastric or gastroesophageal lesions. For patients with gastrointestinal cancers, who may be at higher risk of hemorrhage with the DOACs, LMWH remains the anticoagulant of choice. Applying the latest data from this rapidly evolving field to care for diverse patient groups can be challenging. This article provides an evidence-based review of outpatient anticoagulant selection for lower-extremity deep vein thrombosis or pulmonary embolism in the setting of cancer, and takes into account special populations with cancer.

Submitted May 18, 2021; final revision received August 6, 2021; accepted for publication August 9, 2021.

Disclosures: Dr. Streiff has disclosed consulting for Bayer, Bristol-Myers Squibb, DisperSol, Janssen, and Pfizer; and receiving research support from Novo Nordisk, Sanofi, and Tremeau. Dr. Lim has disclosed receiving honorarium from Sanofi, Argenx, Dova Pharmaceuticals, and Hema Biologics; and receiving honorarium and travel expenses for educational participation in the Hemostasis and Thrombosis Research Society Trainee Workshop which was supported by Novo Nordisk. The remaining authors have disclosed that they have no financial interests, arrangements, or affiliations with the manufacturers of any products discussed in this article or their competitors.

Correspondence: Jordan K. Schaefer, MD, Division of Hematology/Oncology, Department of Internal Medicine, University of Michigan, C366 Med Inn Building, 1500 East Medical Center Drive, Ann Arbor, MI 48109. Email: jschaef@med.umich.edu

Supplementary Materials

    • Supplemental Materials (PDF 435 KB)
  • 1.

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

  • 2.

    Abdol Razak NB, Jones G, Bhandari M, et al. Cancer-associated thrombosis: an overview of mechanisms, risk factors, and treatment. Cancers (Basel) 2018;10:E380.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3.

    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.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 4.

    Streiff MB, Holmstrom B, Angelini D, et al. NCCN Clinical Practice Guidelines in Oncology: Cancer-Associated Venous Thromboembolic Disease. Version 1.2021. Accessed April 1, 2021. To view the most recent version, visit NCCN.org

    • Search Google Scholar
    • Export Citation
  • 5.

    Key NS, Khorana AA, Kuderer NM, et al. Venous thromboembolism prophylaxis and treatment in patients with cancer: ASCO clinical practice guideline update. J Clin Oncol 2020;38:496520.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 6.

    Lee AY, Peterson EA, Wu C. Clinical practice guidelines on cancer-associated thrombosis: a review on scope and methodology. Thromb Res 2016;140(Suppl 1):S119127.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 7.

    Farge D, Frere C, Connors JM, et al. 2019 international clinical practice guidelines for the treatment and prophylaxis of venous thromboembolism in patients with cancer. Lancet Oncol 2019;20:e566581.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 8.

    Schaefer JK, Li M, Wu Z, et al. Clinical and sociodemographic factors associated with anticoagulant use for cancer associated venous thromboembolism. J Thromb Thrombolysis 2021;52:214223.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 9.

    Mahé I, Chidiac J, Helfer H, et al. Factors influencing adherence to clinical guidelines in the management of cancer-associated thrombosis. J Thromb Haemost 2016;14:21072113.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 10.

    Lee AY, Peterson EA. Treatment of cancer-associated thrombosis. Blood 2013;122:23102317.

  • 11.

    Ageno W, Beyer-Westendorf J, Garcia DA, et al. Guidance for the management of venous thrombosis in unusual sites. J Thromb Thrombolysis 2016;41:129143.

  • 12.

    Kraaijpoel N, Carrier M. How I treat cancer-associated venous thromboembolism. Blood 2019;133:291298.

  • 13.

    Dalteparin sodium [package insert]. New York, NY: Pfizer Inc; 2019.

  • 14.

    Nachar VR, Schepers AJ. Clinical controversies in the treatment of cancer-associated venous thromboembolism. J Oncol Pharm Pract 2021;27:939953.

  • 15.

    Witt DM, Nieuwlaat R, Clark NP, et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: optimal management of anticoagulation therapy. Blood Adv 2018;2:32573291.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 16.

    Curry MA, LaFollette JA, Alexander BR, et al. Evaluation of treatment-dose enoxaparin in acutely ill morbidly obese patients at an academic medical center: a randomized clinical trial. Ann Pharmacother 2019;53:567573.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 17.

    Kreuziger LB, Streiff M. Anti-Xa monitoring of low-molecular-weight heparin in adult patients with cancer. Hematology (Am Soc Hematol Educ Program) 2016;2016:206207.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 18.

    Streiff MB, Abutalib SA, Farge D, et al. Update on guidelines for the management of cancer-associated thrombosis. Oncologist 2021;26:e2440.

  • 19.

    Garcia DA, Baglin TP, Weitz JI, et al. 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):e24S43S.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 20.

    Bates SM, Rajasekhar A, Middeldorp S, et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: venous thromboembolism in the context of pregnancy. Blood Adv 2018;2:33173359.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 21.

    Ageno W, Gallus AS, Wittkowsky A, et al. 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):e44S88S.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 22.

    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.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 23.

    Lee AYY, Kamphuisen PW, Meyer G, et al. Tinzaparin vs warfarin for treatment of acute venous thromboembolism in patients with active cancer: a randomized clinical trial. JAMA 2015;314:677686.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 24.

    Warkentin TE, Greinacher A. Management of heparin-induced thrombocytopenia. Curr Opin Hematol 2016;23:462470.

  • 25.

    Robinson DM, Wellington K. Fondaparinux sodium: a review of its use in the treatment of acute venous thromboembolism. Am J Cardiovasc Drugs 2005;5:335346.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 26.

    Amin A. Therapeutic interchange of parenteral anticoagulants: challenges for pharmacy and therapeutics committees. Pharmaceuticals (Basel) 2011;4:14751487.

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 27.

    van Doormaal FF, Raskob GE, Davidson BL, et al. Treatment of venous thromboembolism in patients with cancer: subgroup analysis of the Matisse clinical trials. Thromb Haemost 2009;101:762769.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 28.

    Gosselin RC, Adcock DM, Bates SM, et al. International Council for Standardization in Haematology (ICSH) recommendations for laboratory measurement of direct oral anticoagulants. Thromb Haemost 2018;118:437450.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 29.

    Douxfils J, Ageno W, Samama CM, et al. Laboratory testing in patients treated with direct oral anticoagulants: a practical guide for clinicians. J Thromb Haemost 2018;16:209219.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 30.

    Young AM, Marshall A, Thirlwall J, et al. Comparison of an oral factor Xa inhibitor with low molecular weight heparin in patients with cancer with venous thromboembolism: results of a randomized trial (SELECT-D). J Clin Oncol 2018;36:20172023.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 31.

    Raskob GE, van Es N, Verhamme P, et al. Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med 2018;378:615624.

  • 32.

    McBane RD II, Wysokinski WE, Le-Rademacher JG, et al. Apixaban and dalteparin in active malignancy-associated venous thromboembolism: the ADAM VTE trial. J Thromb Haemost 2020;18:411421.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 33.

    Agnelli G, Becattini C, Meyer G, et al. Apixaban for the treatment of venous thromboembolism associated with cancer. N Engl J Med 2020;382:15991607.

  • 34.

    Chapelle C, Ollier E, Girard P, et al. An epidemic of redundant meta-analyses. J Thromb Haemost 2021;19:12991306.

  • 35.

    Moik F, Posch F, Zielinski C, et al. Direct oral anticoagulants compared to low-molecular-weight heparin for the treatment of cancer-associated thrombosis: updated systematic review and meta-analysis of randomized controlled trials. Res Pract Thromb Haemost 2020;4:550561.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 36.

    Cimminiello C, Anderson FA Jr. Physician and patient perceptions of the route of administration of venous thromboembolism prophylaxis: results from an international survey. Thromb Res 2012;129:139145.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 37.

    Noble S, Matzdorff A, Maraveyas A, et al. Assessing patients’ anticoagulation preferences for the treatment of cancer-associated thrombosis using conjoint methodology. Haematologica 2015;100:14861492.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 38.

    Schaefer JK, Li M, Wu Z, et al. Anticoagulant medication adherence for cancer-associated thrombosis: a comparison of LMWH to DOACs. J Thromb Haemost 2021;19:212220.

  • 39.

    Khorana AA, Yannicelli D, McCrae KR, et al. Evaluation of US prescription patterns: are treatment guidelines for cancer-associated venous thromboembolism being followed? Thromb Res 2016;145:5153.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 40.

    Bussell JK, Cha E, Grant YE, et al. Ways health care providers can promote better medication adherence. Clin Diabetes 2017;35:171177.

  • 41.

    Lee AY, Bauersachs R, Janas MS, et al. CATCH: a randomised clinical trial comparing long-term tinzaparin versus warfarin for treatment of acute venous thromboembolism in cancer patients. BMC Cancer 2013;13:284.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 42.

    Khorana AA, Noble S, Lee AYY, et al. Role of direct oral anticoagulants in the treatment of cancer-associated venous thromboembolism: guidance from the SSC of the ISTH. J Thromb Haemost 2018;16: 18911894.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 43.

    Chai-Adisaksopha C, Hillis C, Isayama T, et al. Mortality outcomes in patients receiving direct oral anticoagulants: a systematic review and meta-analysis of randomized controlled trials. J Thromb Haemost 2015;13:20122020.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 44.

    Ray WA, Chung CP, Murray KT, et al. Association of oral anticoagulants and proton pump inhibitor cotherapy with hospitalization for upper gastrointestinal tract bleeding. JAMA 2018;320:22212230.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 45.

    Abraham NS, Singh S, Alexander GC, et al. Comparative risk of gastrointestinal bleeding with dabigatran, rivaroxaban, and warfarin: population based cohort study. BMJ 2015;350:h1857.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 46.

    Holster IL, Valkhoff VE, Kuipers EJ, et al. New oral anticoagulants increase risk for gastrointestinal bleeding: a systematic review and meta-analysis. Gastroenterology 2013;145:105112.e15.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 47.

    Ruff CT, Giugliano RP, Braunwald E, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet 2014;383:955962.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 48.

    Fanikos J, Burnett AE, Mahan CE, et al. Renal function considerations for stroke prevention in atrial fibrillation. Am J Med 2017;130:10151023.

  • 49.

    Menichelli D, Ronca V, Di Rocco A, et al. Direct oral anticoagulants and advanced liver disease: a systematic review and meta-analysis. Eur J Clin Invest 2021;51:e13397.

  • 50.

    Martin K, Beyer-Westendorf J, Davidson BL, et al. Use of the direct oral anticoagulants in obese patients: guidance from the SSC of the ISTH. J Thromb Haemost 2016;14:13081313.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 51.

    Wang TF, Carrier M. How I treat obese patients with oral anticoagulants. Blood 2020;135:904911.

  • 52.

    Covert K, Branam DL. Direct-acting oral anticoagulant use at extremes of body weight: literature review and recommendations. Am J Health Syst Pharm 2020;77:865876.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 53.

    Hakeam HA, Al-Sanea N. Effect of major gastrointestinal tract surgery on the absorption and efficacy of direct acting oral anticoagulants (DOACs). J Thromb Thrombolysis 2017;43:343351.

    • Crossref
    • PubMed
    • Search Google Scholar
    • Export Citation
  • 54.

    Martin KA, Lee CR, Farrell TM, et al. Oral anticoagulant use after bariatric surgery: a literature review and clinical guidance. Am J Med 2017;130:517524.

  • 55.

    Rottenstreich A, Barkai A, Arad A, et al. The effect of bariatric surgery on direct-acting oral anticoagulant drug levels. Thromb Res 2018;163:190195.

  • 56.

    Peterson JJ, Hoehns JD. Administration of direct oral anticoagulants through enteral feeding tubes. J Pharm Technol 2016;32:196200.

All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 4288 4288 148
PDF Downloads 3403 3403 138
EPUB Downloads 0 0 0