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Phlebologie 2017; 46(06): 340-351
DOI: 10.1055/s-0038-1625439
Review
Schattauer GmbH

Direct oral anticoagulants for the treatment of cancer-associated venous thromboembolism

What do we know so far?Behandlung der tumorassoziierten venösen Thromboembolie mit direkten oralen AntikoagulanzienWas wissen wir bisher?
M. Voigtlaender
1   II. Medizinische Klinik und Poliklinik, Hubertus Wald Tumorzentrum – Universitäres Cancer Center Hamburg (UCCH), Universitätsklinikum Hamburg-Eppendorf, Germany
,
F. Langer
1   II. Medizinische Klinik und Poliklinik, Hubertus Wald Tumorzentrum – Universitäres Cancer Center Hamburg (UCCH), Universitätsklinikum Hamburg-Eppendorf, Germany
› Author Affiliations
Further Information

Publication History

Publication Date:
11 January 2018 (online)

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Summary

Cancer patients with venous thromboembolism (VTE) are at increased risk for both bleeding and VTE recurrence. Anticoagulation with low-molecular-weight heparin (LMWH) is the standard of care during the initial and longterm treatment phase (i.e. during the first 3–6 months of therapy) based on its overall beneficial safety and efficacy profile compared to vitamin K antagonists (VKAs). The direct oral anticoagulants (DOACs) rivaroxaban, apixaban, edoxaban, and dabigatran are approved for the treatment of acute VTE, and the combined six phase-3 trials have included > 1 500 patients with active cancer, as defined by variable selection criteria. Subgroup analyses of these patients, either pooled or separately reported, suggest that DOACs could be a safe and efficacious alternative to VKA therapy for the treatment of cancer-associated VTE. However, the populations of cancer patients included in the DOAC and LMWH trials are not comparable with regard to mortality and VTE risk, and no specific data from direct head-to-head comparisons of DOACs with LMWHs are currently available. The use of DOACs for the management of VTE in cancer is thus not recommended by clinical practice guidelines.

Zusammenfassung

Tumorpatienten mit venöser Thromboembolie (VTE) haben ein erhöhtes Blutungs- und VTE-Rezidivrisiko. In der ersten Behandlungsphase (d. h. in den ersten 3–6 Monaten) ist die Antikoagulation mit niedermolekularem Heparin (NMH) aufgrund des gegenüber Vitamin- K-Antagonisten (VKAs) vorteilhaften Sicherheits- und Wirksamkeitsprofils der Therapiestandard. Die direkten oralen Antikoagulanzien (DOAKs) Rivaroxaban, Apixaban, Edoxaban und Dabigatran sind zur VTE-Therapie zugelassen. In die sechs Phase-3-Studien waren zusammen > 1 500 Patienten mit aktiver Krebserkrankung, definiert durch variable Selektionskriterien, eingeschlossen. Kombinierte und separate Subgruppenanalysen dieser Patienten legen nahe, dass DOAKs eine sichere und wirksame Alternative zu den VKAs in der Therapie der tumorassoziierten VTE darstellen. Allerdings sind die Kohorten an Krebspatienten zwischen den DOAK- und NMH-Studien bezüglich des Mortalitäts- und VTE-Risikos nicht vergleichbar. Zudem sind aktuell keine spezifischen Studiendaten zum direkten Vergleich von DOAKs mit NMHs verfügbar. Der routinemäßige Einsatz von DOAKs zur Therapie der tumorassoziierten VTE wird deshalb in den aktuellen Leitlinien nicht empfohlen.

Keywords

Malignancy - venous thrombosis - pulmonary embolism - heparins

Schlüsselwörter

Malignom - venöse Thrombose - Lungenembolie - Heparine
 

  • References

  • 1 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; 05 (03) 632-634.
    CrossrefPubMedGoogle Scholar
  • 2 Horsted F, West J, Grainge MJ. Risk of venous thromboembolism in patients with cancer: a systematic review and meta-analysis. PLoS Med 2012; 09 (07) e1001275.
    CrossrefPubMedGoogle Scholar
  • 3 Lubberts B, Paulino NRPereira, Kabrhel C. et al. What is the effect of venous thromboembolism and related complications on patient reported health-related quality of life?. A meta-analysis. Thromb Haemost 2016; 116 (03) 417-431.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 4 Cavo M, Zamagni E, Cellini C. et al. Deep-vein thrombosis in patients with multiple myeloma receiving first-line thalidomide-dexamethasone therapy. Blood 2002; 100 (06) 2272-2273.
    CrossrefPubMedGoogle Scholar
  • 5 Sorensen 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
  • 6 Kabbinavar F, Hurwitz HI, Fehrenbacher L. et al. Phase II, randomized trial comparing bevacizumab plus fluorouracil (FU)/leucovorin (LV) with FU/LV alone in patients with metastatic colorectal cancer. J Clin Oncol 2003; 21 (01) 60-65.
    CrossrefPubMedGoogle Scholar
  • 7 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
  • 8 Hutten BA, Prins MH, Gent M. et al. 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
  • 9 Vrijens B, Heidbuchel H. Non-vitamin K antagonist oral anticoagulants: considerations on oncevs. twice-daily regimens and their potential impact on medication adherence. Europace 2015; 17 (04) 514-523.
    CrossrefPubMedGoogle Scholar
  • 10 Stampfuss J, Kubitza D, Becka M, Mueck W. The effect of food on the absorption and pharmacokinetics of rivaroxaban. Int J Clin Pharmacol Ther 2013; 51 (07) 549-561.
    CrossrefPubMedGoogle Scholar
  • 11 Beyer-Westendorf J, Siegert G. Of men and meals. J Thromb Haemost 2015; 13 (06) 943-945.
    CrossrefPubMedGoogle Scholar
  • 12 Zhang N, Liu XS, Li G, Liu T. Dabigatran-induced esophagitis: A frequently overlooked adverse effect. Int J Cardiol 2016; 212: 358-359.
    CrossrefPubMedGoogle Scholar
  • 13 Ollier E, Hodin S, Basset T. et al. In vitro and in vivo evaluation of drug-drug interaction between dabigatran and proton pump inhibitors. Fundam Clin Pharmacol 2015; 29 (06) 604-614.
    CrossrefPubMedGoogle Scholar
  • 14 Humphreys BD, Soiffer RJ, Magee CC. Renal failure associated with cancer and its treatment: an update. J Am Soc Nephrol 2005; 16 (01) 151-161.
    PubMedGoogle Scholar
  • 15 Lapi F, Azoulay L, Niazi MT. et al. Androgen deprivation therapy and risk of acute kidney injury in patients with prostate cancer. JAMA 2013; 310 (03) 289-296.
    CrossrefPubMedGoogle Scholar
  • 16 Launay-Vacher V, Aapro M, De Castro Jr G. et al. Renal effects of molecular targeted therapies in oncology: a review by the Cancer and the Kidney International Network (C-KIN). Ann Oncol 2015; 26 (08) 1677-1684.
    CrossrefPubMedGoogle Scholar
  • 17 Marcolino MS, Boersma E, Clementino NC. et al. Imatinib treatment duration is related to decreased estimated glomerular filtration rate in chronic myeloid leukemia patients. Ann Oncol 2011; 22 (09) 2073-2079.
    CrossrefPubMedGoogle Scholar
  • 18 Oh GS, Kim HJ, Shen A. et al. Cisplatin-induced Kidney Dysfunction and Perspectives on Improving Treatment Strategies. Electrolyte Blood Press 2014; 12 (02) 55-65.
    CrossrefPubMedGoogle Scholar
  • 19 Lameire N. Nephrotoxicity of recent anti-cancer agents. Clin Kidney J 2013; 07 (01) 11-22.
    Google Scholar
  • 20 Stangier J, Rathgen K, Stahle H, Mazur D. Influence of renal impairment on the pharmacokinetics and pharmacodynamics of oral dabigatran etexilate: an open-label, parallel-group, singlecentre study. Clin Pharmacokinet 2010; 49 (04) 259-268.
    CrossrefPubMedGoogle Scholar
  • 21 Samama MM, Gerotziafas GT. Evaluation of the pharmacological properties and clinical results of the synthetic pentasaccharide (fondaparinux). Thromb Res 2003; 109 (01) 1-11.
    CrossrefPubMedGoogle Scholar
  • 22 Buller HR, Prins MH, Lensin AW. et al. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012; 366 (14) 1287-1297.
    CrossrefPubMedGoogle Scholar
  • 23 Agnelli G, Buller HR, Cohen A. et al. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med 2013; 369 (09) 799-808.
    CrossrefPubMedGoogle Scholar
  • 24 Bauersachs R, Berkowitz SD, Brenner B. et al. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010; 363 (26) 2499-2510.
    CrossrefPubMedGoogle Scholar
  • 25 Buller HR, Decousus H, Grosso MA. et al. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med 2013; 369 (15) 1406-1415.
    CrossrefPubMedGoogle Scholar
  • 26 Schulman S, Kearon C, Kakkar AK. et al. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009; 361 (24) 2342-2352.
    CrossrefPubMedGoogle Scholar
  • 27 Schulman S, Kakkar AK, Goldhaber SZ. et al. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation 2014; 129 (07) 764-772.
    CrossrefPubMedGoogle Scholar
  • 28 Carrier M, Khorana AA, Zwicker J. et al. Management of challenging cases of patients with cancerassociated thrombosis including recurrent thrombosis and bleeding: guidance from the SSC of the ISTH. J Thromb Haemost 2013; 11 (09) 1760-1765.
    CrossrefPubMedGoogle Scholar
  • 29 Lee AY, Peterson EA. Treatment of cancer-associated thrombosis. Blood 2013; 122 (14) 2310-2317.
    CrossrefPubMedGoogle Scholar
  • 30 Hellwig T, Gulseth M. Pharmacokinetic and pharmacodynamic drug interactions with new oral anticoagulants: what do they mean for patients with atrial fibrillation?. Ann Pharmacother 2013; 47 (11) 1478-1487.
    CrossrefPubMedGoogle Scholar
  • 31 Parasrampuria DA, Mendell J, Shi M. et al. Edoxaban drug-drug interactions with ketoconazole, erythromycin, and cyclosporine. Br J Clin Pharmacol 2016; 82 (06) 1591-1600.
    CrossrefPubMedGoogle Scholar
  • 32 Dincq AS, Lessire S, Douxfils J. et al. Management of non-vitamin K antagonist oral anticoagulants in the perioperative setting. Biomed Res Int 2014; 2014: 385014.
    PubMedGoogle Scholar
  • 33 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 (Suppl. 06) 160S-198S.
    CrossrefPubMedGoogle Scholar
  • 34 Wutschert R, Piletta P, Bounameaux H. Adverse skin reactions to low molecular weight heparins: frequency, management and prevention. Drug Saf 1999; 20 (06) 515-525.
    CrossrefPubMedGoogle Scholar
  • 35 Prandoni P, Siragusa S, Girolami B, Fabris F. The incidence of heparin-induced thrombocytopenia in medical patients treated with low-molecularweight heparin: a prospective cohort study. Blood 2005; 106 (09) 3049-3054.
    CrossrefPubMedGoogle Scholar
  • 36 Cimminiello C, Anderson Jr FA. Physician and patient perceptions of the route of administration of venous thromboembolism prophylaxis: results from an international survey. Thromb Res 2012; 129 (02) 139-145.
    CrossrefPubMedGoogle Scholar
  • 37 Pesavento R, Amitrano M, Trujillo-Santos J. et al. Fondaparinux in the initial and long-term treatment of venous thromboembolism. Thromb Res 2015; 135 (02) 311-317.
    CrossrefPubMedGoogle Scholar
  • 38 Douketis JD, Foster GA, Crowther MA. et al. Clinical risk factors and timing of recurrent venous thromboembolism during the initial 3 months of anticoagulant therapy. Arch Intern Med 2000; 160 (22) 3431-3436.
    CrossrefPubMedGoogle Scholar
  • 39 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 (02) 146-153.
    CrossrefPubMedGoogle Scholar
  • 40 Lee AY, 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 (07) 677-686.
    CrossrefPubMedGoogle Scholar
  • 41 Mandala M, Falanga A, Roila F. Management of venous thromboembolism (VTE) in cancer patients: ESMO Clinical Practice Guidelines. Ann Oncol 2011; 22 (Suppl. 06) vi85-vi92.
    PubMedGoogle Scholar
  • 42 Lyman GH, Khorana AA, Kuderer NM. et al. 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
  • 43 Farge D, Debourdeau P, Beckers M. et al. International clinical practice guidelines for the treatment and prophylaxis of venous thromboembolism in patients with cancer. J Thromb Haemost 2013; 11 (01) 56-70.
    CrossrefPubMedGoogle Scholar
  • 44 Streiff MB. The National Comprehensive Cancer Center Network (NCCN) guidelines on the management of venous thromboembolism in cancer patients. Thromb Res 2010; 125 (Suppl. 02) S128-S133.
    CrossrefPubMedGoogle Scholar
  • 45 Kearon C, Akl EA, Ornelas J. et al. Antithrombotic Therapy for VTE Disease: CHEST Guideline and Expert Panel Report. Chest 2016; 149 (02) 315-352.
    CrossrefPubMedGoogle Scholar
  • 46 Hull RD, Pineo GF, Brant RF. et al. Long-term lowmolecular-weight heparin versus usual care in proximal-vein thrombosis patients with cancer. Am J Med 2006; 119 (12) 1062-1072.
    CrossrefPubMedGoogle Scholar
  • 47 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
  • 48 Deitcher SR, Kessler CM, Merli G. et al. 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 (04) 389-396.
    CrossrefPubMedGoogle Scholar
  • 49 Prins MH, Lensing AW, 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 Haematol 2014; 01 (01) e37-e46.
    Google Scholar
  • 50 Agnelli G, Buller HR, Cohen A. et al. Oral apixaban for the treatment of venous thromboembolism in cancer patients: results from the AMPLIFY trial. J Thromb Haemost 2015; 13 (12) 2187-2191.
    CrossrefPubMedGoogle Scholar
  • 51 Raskob G, van Es N, Segers A. et al. Edoxaban for venous thromboembolism in patients with cancer: results from a non-inferiority subgroup analysis of the Hokusai-VTE randomised, double-blind, double-dummy trial. Lancet Haematol 2016; 03 (08) e379-e387.
    Google Scholar
  • 52 Schulman S, Goldhaber SZ, Kearon C. et al. Treatment with dabigatran or warfarin in patients with venous thromboembolism and cancer. Thromb Haemost 2015; 114 (01) 150-157.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 53 van Es N, Coppens M, Schulman S. et al. Direct oral anticoagulants compared with vitamin K antagonists for acute venous thromboembolism: evidence from phase 3 trials. Blood 2014; 124 (12) 1968-1975.
    CrossrefPubMedGoogle Scholar
  • 54 van der Hulle T, den Exter PL, Kooiman J. et al. Meta-analysis of the efficacy and safety of new oral anticoagulants in patients with cancer-associated acute venous thromboembolism. J Thromb Haemost 2014; 12 (07) 1116-1120.
    CrossrefPubMedGoogle Scholar
  • 55 Vedovati MC, Germini F, Agnelli G, Becattini C. Direct oral anticoagulants in patients with VTE and cancer: a systematic review and meta-analysis. Chest 2015; 147 (02) 475-483.
    CrossrefPubMedGoogle Scholar
  • 56 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 (06) 1214-1219.
    CrossrefPubMedGoogle Scholar
  • 57 Larsen TB, Nielsen PB, Skjoth F. et al. Non-vitamin K antagonist oral anticoagulants and the treatment of venous thromboembolism in cancer patients: a semi systematic review and meta-analysis of safety and efficacy outcomes. PLoS One 2014; 09 (12) e114445.
    CrossrefPubMedGoogle Scholar
  • 58 Posch F, Konigsbrugge O, Zielinski C. et al. Treatment of venous thromboembolism in patients with cancer: A network meta-analysis comparing efficacy and safety of anticoagulants. Thromb Res 2015; 136 (03) 582-589.
    CrossrefPubMedGoogle Scholar
  • 59 van Es N, Di Nisio M, Bleker SM. et al. Edoxaban for treatment of venous thromboembolism in patients with cancer. Rationale and design of the Hokusai VTE-cancer study. Thromb Haemost 2015; 114 (06) 1268-1276.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 60 Liebman HA, O’Connell C. Incidental venous thromboembolic events in cancer patients: what we know in 2016. Thromb Res 2016; 140 (Suppl. 01) S18-S20.
    CrossrefPubMedGoogle Scholar
  • 61 Francis CW, Kessler CM, Goldhaber SZ. et al. Treatment of venous thromboembolism in cancer patients with dalteparin for up to 12 months: the DALTECAN Study. J Thromb Haemost 2015; 13 (06) 1028-1035.
    CrossrefPubMedGoogle Scholar