Moderne Antikoagulation mit FXa-Inhibitoren in der Onkologie: Ist die gastrointestinale Blutungsrate (mit)-entscheidend?

Zusammenfassung

Das erhöhte Thrombose- und Blutungsrisiko bei aktiver Tumorerkrankung wird als sog. „thrombo-hämorrhagisches Syndrom“ bezeichnet, welches hohe Anforderungen an die Antikoagulation stellt. Aktuell liegen 4 randomisierte, prospektive Studien zum Einsatz von neuen, nicht Vitamin K-abhängigen oralen Antikoagulantien (NOAK) zur Behandlung von in der Onkologie aufgetretenen venösen Thromboembolien (VTE) vor. Dabei wurden die FXa-Inhibitoren Rivaroxaban, Edoxaban und zweimal Apixaban jeweils in einzelnen Studien gegenüber dem Standardtherapeutikum Dalteparin eingesetzt. Da es keinen direkten Head-to-Head-Vergleich der genannten FXa-Inhibitoren innerhalb einer Studie gibt, wurde zu jedem NOAK die jeweils größte Studie – stets verglichen gegenüber Dalteparin – ausgewertet. Die Studien wurden bzgl. ihrer Wirksamkeit, Sicherheit, fataler Blutungsraten, dem Risiko für gastrointestinale Blutungen (GIB) und sonstiger Unterschiede anhand deskriptiver Statistik analysiert. Unter Dalteparin ergab sich eine mittlere VTE-Rezidivrate von ca. 9% bei einem 6-monatigen Behandlungszeitraum. Alle 3 FXa-Inhibitoren waren gegenüber Dalteparin bezüglich der Wirksamkeit nicht unterlegen. Die VTE-Rezidivrate war bei mit Edoxaban und Apixaban behandelten Patienten um – 2,3% und bei Rivaroxaban um – 5,0% niedriger.

Bei der Sicherheit fanden sich – jeweils gegenüber Dalteparin – für Rivaroxaban und Edoxaban eine erhöhte Rate an schweren Blutungen (jeweils +2,4%); insbesondere war hierbei die Zahl GIB deutlich erhöht. Dagegen war für Apixaban die Zahl schwerer Blutungen, wie auch für verschiedene Blutungstypen inkl. GIB, nicht erhöht. In der Apixabanstudie war insgesamt die Rate von schweren GIB, die ca. 50% aller schweren Blutungen ausmachten, und die der klinisch-relevanten nicht schweren Blutungen, am niedrigsten. Die FXa-Inhibitoren sind der Standardtherapie mit Dalteparin in der VTE-Rezidivrate bei onkologischen Patienten nicht unterlegen. Die GIB-Rate scheint ein wichtiger prädiktiver Faktor für die Sicherheit dieser Substanzgruppe zu sein, sodass Tumorlokalisation, gastrointestinale Risikofaktoren und andere individuelle Kriterien in Zukunft stärker bei der Therapieentscheidung für oder gegen einen FXa-Inhibitor berücksichtigt werden sollten.

Abstract

The increased risk of thrombosis and bleeding with an active tumor disease is known as the so-called “thrombo-hemorrhagic syndrome”, which places high demands on anticoagulation. There are currently 4 randomized, prospective studies on the use of new, non-vitamin K dependent oral anticoagulants (NOAC) for the treatment of venous thromboembolism (VTE) that have occurred in oncology. The FXa inhibitors rivaroxaban, edoxaban and twice apixaban were each used in individual studies versus the standard therapeutic agent dalteparin. Since there is no direct head-to-head comparison of the FXa inhibitors mentioned within a study, the largest study – always compared to dalteparin – was evaluated for each NOAC. The studies were analyzed with regard to their effectiveness, safety, fatal bleeding rates, the risk of gastrointestinal bleeding (GIB) and other differences using descriptive statistics. With dalteparin, the mean VTE recurrence rate was approximately 9% over a 6-month treatment period. All three FXa inhibitors were not inferior to dalteparin in terms of potency. The VTE recurrence rate was – 2.3% lower in edoxaban and apixaban-treated patients and – 5.0% in rivaroxaban-treated patients. In terms of safety, there was an increased rate of severe bleeding (both + 2.4%) for rivaroxaban and edoxaban compared to dalteparin; in particular, the number of GIBs was significantly increased. In contrast, the number of severe bleeding was not increased for apixaban, as was the case for various bleeding types including GIB. In the Apixaban study, the overall rate of severe GIB, which accounted for about 50% of all severe bleeding, and that of clinically relevant non-severe bleeding, were the lowest. The FXa inhibitors are not inferior to the standard therapy with dalteparin in the VTE recurrence rate in oncological patients. The GIB rate appears to be an important predictive factor for the safety of this group of substances, so that tumor location, gastrointestinal risk factors and other individual criteria should be given greater consideration in future therapy decisions for or against an FXa inhibitor.

Schlüsselwörter

Maligne Tumorerkrankungen - venöse Thromboembolien - Niedermolekulare Heparine - Vitamin K Antagonisten - nicht Vitamin K-abhängige orale Antikoagulantien

Keywords

malignant tumor diseases - venous thromboembolism - low molecular weight heparins - vitamin K antagonists - non-vitamin K dependent oral antocoagulants

Publication History

Received: 28 November 2021

Accepted: 21 June 2022

Article published online:
25 July 2022

• Literatur

• 1 Khorana AA. Venous thromboembolism and prognosis in cancer. Thromb Res 2010; 125: 490-493
• 2 Grilz E, Königsbrügge O, Posch F. et al. Frequency, risk factors, and impact on mortality of arterial thromboembolism in patients with cancer. Haematologica 2018; 103: 1549-1555
• 3 Cohen AT, Katholing A, Rietbrock S. et al. Epidemiology of first and recurrent venous thromboembolism in patients with active cancer. A population-based cohort study. Thromb Haemost 2017; 117: 57-65
• 4 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: CD006650
• 5 Kamphuisen PW, Lee AYY, Meyer G. et al. Clinically relevant bleeding in cancer patients treated for venous thromboembolism from the CATCH study. J Thromb Haemost 2018; 16: 1069-1077
• 6 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: 146-153
• 7 Loffredo L, Perri L, Violi F. Impact of new oral anticoagulants on gastrointestinal bleeding in atrial fibrillation: A meta-analysis of interventional trials. Dig Liver Dis 2015; 47: 429-431
• 8 Sherwood MW, Nessel CC, Hellkamp AS. et al. Gastrointestinal Bleeding in Patients With Atrial Fibrillation Treated With Rivaroxaban or Warfarin: ROCKET AF Trial. J Am Coll Cardiol 2015; 66: 2271-2281
• 9 Hohnloser SH, Basic E, Nabauer M. Comparative risk of major bleeding with new oral anticoagulants (NOACs) and phenprocoumon in patients with atrial fibrillation: a post-marketing surveillance study. Clin Res Cardiol 2017; 106: 618-628
• 10 Delluc A, Wang TF, Yap ES. et al. Anticoagulation of cancer patients with non-valvular atrial fibrillation receiving chemotherapy: Guidance from the SSC of the ISTH. J Thromb Haemost 2019; 17: 1247-1252
• 11 Albrecht H, Maass LS, Hagel AF. et al. Anticoagulant-related gastrointestinal bleeding: a real-life data analysis on bleeding profiles, frequency and etiology of patients receiving direct oral anticoagulants versus vitamin K antagonists. J Physiol Pharmacol 2019; 70 (06)
• 12 Abraham NS, Noseworthy PA, Yao X. et al. Gastrointestinal Safety of Direct Oral Anticoagulants: A Large Population-Based Study. Gastroenterology 2017; 152: 1014-1022
• 13 Yao X, Abraham NS, Sangaralingham LR. et al. Effectiveness and Safety of Dabigatran, Rivaroxaban, and Apixaban Versus Warfarin in Nonvalvular Atrial Fibrillation. J Am Heart Assoc 2016; 5: e003725
• 14 Li A, Garcia DA, Lyman GH. et al. DOAC vs LMWH for treatment of cancer associated thrombosis (CAT): A systematic review and meta-analysis. Thromb Res 2019; 173: 158-163
• 15 Majeed A, Schulman S. Bleeding and antidotes in new oral anticoagulants. Best Pract Res Clin Haematol 2013; 26: 191-202
• 16 Young AM, Marshall A, Thirlwall J. et al. Comparison of an oral factor Xa inhibitor with low molecular weight heparin in patients with cancer venous thromboembolism: results of a randomized trial (Select-D Rivaroxaban). J Clin Oncol 2018; 36: 2017-2023
• 17 Raskob GE, van Es N, Verhamme P. et al. Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med 2018; 378: 615-24
• 18 Mc Bane RD, 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: 411-421
• 19 Agnelli G, Becattini C, Meyer G. et al. Apixaban for the treatment of venous thromboembolism associated with cancer. N Engl J Med 2020; 382: 1599-1607
• 20 Vedovati MC, Germini F, Agnelli G. et al. Direct oral anticoagulants in patients with VTE and cancer: a systematic review and meta-analysis. Chest 2015; 147: 475-483
• 21 Desai J, Granger CB, Weitz JI. et al. Novel oral anticoagulants in gastroenterology practice. Gastrointest Endosc 2013; 78: 227-239
• 22 Götz M, Anders M, Biecker E. et al. S2k-Leitlinie Gastrointestinale Blutung. Z Gastroenterol 2017; 55: 883-936
• 23 Kichenadasse G, Minors JO, Mangoni AA. et al. Proton pump inhibitors and survival in patients with colorectal cancer receiving fluoropyrimidine-based chemotherapy. J Natl Compr Canc Netw 2021; 19: 1037-1044
• 24 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: 517-524
• 25 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: 1891-1894
• 26 Kraaijpoel N, Di Nisio M, Mulder FI. et al. Clinical Impact of Bleeding in Cancer-Associated Venous Thromboembolism: Results from the Hokusai VTE Cancer Study. Thromb Haemost 2018; 118: 1439-1449
• 27 Steffel J, Verhamme P, Potpara TS. et al. The 2018 European Heart Rhythm Association Practical Guide on the use of NOAKs in patients with atrial fibrillation. European Heart Journal 2018; 39: 1330-1393