Risk Factors for Bleeding in Cancer Patients Treated with Conventional Dose Followed by Low-Dose Apixaban for Venous Thromboembolism

Abstract

Background Incidence of and risk factors for bleeding in cancer patients with venous thromboembolism (VTE) treated with apixaban are poorly described.

Methods We analyzed data from the prospective CAP study where 298 cancer patients with any type of VTE received 5 mg apixaban twice daily for 6 months, and then 2.5 mg apixaban twice daily for 30 months. For most analyses, major bleedings and clinically relevant nonmajor bleedings were merged to “clinically relevant bleedings.” Risk factors were estimated by odds ratios (OR) and 95% confidence intervals (CIs).

Results The incidence of clinically relevant bleedings was 38% per person-year during the first 6 months of treatment, 21% per person-year from 7 to 12 months, and between 4 and 8% per person-year from 13 to 36 months. Clinically relevant bleedings were associated with age above 74 years (OR: 2.0, 95% CI: 1.0–4.1), body mass index (BMI) below 21.7 (OR: 2.3, 95% CI: 1.1–4.8), and hemoglobin at baseline below 10.5 for females (OR: 2.8, 95% CI: 1.1–7.3) and 11.1 for males (OR: 3.3, 95% CI: 1.3–8.4) during the first 6 months. Gastrointestinal (GI) or urogenital cancer was not associated with clinically relevant bleedings compared with other cancers. Among patients with luminal GI cancer, nonresected cancer had increased risk of bleeding (OR: 3.4, 95% CI: 1.0–11.6) compared with resected GI cancer.

Conclusion There were very few bleedings while patients were on low-dose apixaban. Factors associated with bleeding in patients treated with full-dose apixaban were high age, low BMI, and low hemoglobin, and probably nonresected luminal GI cancer.

Keywords

anticoagulant - apixaban - cancer - venous thromboembolism - risk factors for bleeding

Publikationsverlauf

Eingereicht: 11. Juni 2023

Angenommen: 09. Oktober 2023

Accepted Manuscript online:
10. Oktober 2023

Artikel online veröffentlicht:
15. November 2023

• References

• 1 Naess IA, Christiansen SC, Romundstad P, Cannegieter SC, Rosendaal FR, Hammerstrøm J. Incidence and mortality of venous thrombosis: a population-based study. J Thromb Haemost 2007; 5 (04) 692-699
• 2 Flinterman LE, van Hylckama Vlieg A, Cannegieter SC, Rosendaal FR. Long-term survival in a large cohort of patients with venous thrombosis: incidence and predictors. PLoS Med 2012; 9 (01) e1001155-e1001155
• 3 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 (06) 809-815
• 4 Blom JW, Doggen CJM, Osanto S, Rosendaal FR. Malignancies, prothrombotic mutations, and the risk of venous thrombosis. JAMA 2005; 293 (06) 715-722
• 5 Buller HR, van Doormaal FF, van Sluis GL, Kamphuisen PW. Cancer and thrombosis: from molecular mechanisms to clinical presentations. J Thromb Haemost 2007; 5 (Suppl. 01) 246-254
• 6 Prandoni P, Lensing AWA, 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
• 7 David Green HCK. Coagulation in Cancer. New York, NY: Springer US; 2009
• 8 Peterson DE, Cariello A. Mucosal damage: a major risk factor for severe complications after cytotoxic therapy. Semin Oncol 2004; 31 (3, Suppl 8): 35-44
• 9 McBane II 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 (02) 411-421
• 10 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 (20) 2017-2023
• 11 Agnelli G, Becattini C, Meyer G. et al; Caravaggio Investigators. Apixaban for the treatment of venous thromboembolism associated with cancer. N Engl J Med 2020; 382 (17) 1599-1607
• 12 Raskob GE, van Es N, Verhamme P. et al; Hokusai VTE Cancer Investigators. Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med 2018; 378 (07) 615-624
• 13 Riaz IB, Fuentes HE, Naqvi SAA. et al. Direct oral anticoagulants compared with dalteparin for treatment of cancer-associated thrombosis: a living, interactive systematic review and network meta-analysis. Mayo Clin Proc 2022; 97 (02) 308-324
• 14 Giustozzi M, Agnelli G, Del Toro-Cervera J. et al. Direct oral anticoagulants for the treatment of acute venous thromboembolism associated with cancer: a systematic review and meta-analysis. Thromb Haemost 2020; 120 (07) 1128-1136
• 15 Ageno W, Vedovati MC, Cohen A. et al. Bleeding with apixaban and dalteparin in patients with cancer-associated venous thromboembolism: results from the Caravaggio study. Thromb Haemost 2021; 121 (05) 616-624
• 16 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 (08) 1439-1449
• 17 Mulder FI, Bosch FTM, Young AM. et al. Direct oral anticoagulants for cancer-associated venous thromboembolism: a systematic review and meta-analysis. Blood 2020; 136 (12) 1433-1441
• 18 Agnelli G, Muñoz A, Franco L. et al. Apixaban and dalteparin for the treatment of venous thromboembolism in patients with different sites of cancer. Thromb Haemost 2022; 122 (05) 796-807
• 19 Hannevik T-L, Brekke J, Enden T. et al. Thrombosis and bleedings in a cohort of cancer patients treated with apixaban for venous thromboembolism. Thromb Res 2020; 196: 238-244
• 20 Larsen TL, Garresori H, Brekke J. et al. Low dose apixaban as secondary prophylaxis of venous thromboembolism in cancer patients - 30 months follow-up. J Thromb Haemost 2022; 20 (05) 1166-1181
• 21 Schulman S, Kearon C. Subcommittee on Control of Anticoagulation of the Scientific and Standardization Committee of the International Society on Thrombosis and Haemostasis. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost 2005; 3 (04) 692-694
• 22 Kaatz S, Ahmad D, Spyropoulos AC, Schulman S. Subcommittee on Control of Anticoagulation. Definition of clinically relevant non-major bleeding in studies of anticoagulants in atrial fibrillation and venous thromboembolic disease in non-surgical patients: communication from the SSC of the ISTH. J Thromb Haemost 2015; 13 (11) 2119-2126
• 23 Ruíz-Giménez N, Suárez C, González R. et al; RIETE Investigators, Findings from the RIETE Registry. Predictive variables for major bleeding events in patients presenting with documented acute venous thromboembolism. Thromb Haemost 2008; 100 (01) 26-31
• 24 Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns HJ, Lip GY. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest 2010; 138 (05) 1093-1100
• 25 Klok FA, Barco S, Turpie AGG. et al. Predictive value of venous thromboembolism (VTE)-BLEED to predict major bleeding and other adverse events in a practice-based cohort of patients with VTE: results of the XALIA study. Br J Haematol 2018; 183 (03) 457-465
• 26 Weitz JI, Farjat AE, Ageno W. et al; GARFIELD-VTE Investigators. Influence of body mass index on clinical outcomes in venous thromboembolism: insights from GARFIELD-VTE. J Thromb Haemost 2021; 19 (12) 3031-3043
• 27 Vicente-Ibarra N, Marín F, Pernías-Escrig V. et al. Impact of anemia as risk factor for major bleeding and mortality in patients with acute coronary syndrome. Eur J Intern Med 2019; 61: 48-53
• 28 van der Meer FJM, Rosendaal FR, Vandenbroucke JP, Briët E. Bleeding complications in oral anticoagulant therapy. An analysis of risk factors. Arch Intern Med 1993; 153 (13) 1557-1562
• 29 Fihn SD, Callahan CM, Martin DC, McDonell MB, Henikoff JG, White RH. The National Consortium of Anticoagulation Clinics. The risk for and severity of bleeding complications in elderly patients treated with warfarin. Ann Intern Med 1996; 124 (11) 970-979
• 30 Fang MC, Chang Y, Hylek EM. et al. Advanced age, anticoagulation intensity, and risk for intracranial hemorrhage among patients taking warfarin for atrial fibrillation. Ann Intern Med 2004; 141 (10) 745-752
• 31 Bosch FTM, Mulder FI, Huisman MV. et al. Risk factors for gastrointestinal bleeding in patients with gastrointestinal cancer using edoxaban. J Thromb Haemost 2021; 19 (12) 3008-3017
• 32 Vedovati MC, Giustozzi M, Munoz A. et al. Risk factors for recurrence and major bleeding in patients with cancer-associated venous thromboembolism. Eur J Intern Med 2023; 112: 29-36
• 33 de Winter MA, Dorresteijn JAN, Ageno W. et al. Estimating bleeding risk in patients with cancer-associated thrombosis: evaluation of existing risk scores and development of a new risk score. Thromb Haemost 2022; 122 (05) 818-829
• 34 Houghton DE, Vlazny DT, Casanegra AI. et al. Bleeding in patients with gastrointestinal cancer compared with nongastrointestinal cancer treated with apixaban, rivaroxaban, or enoxaparin for acute venous thromboembolism. Mayo Clin Proc 2021; 96 (11) 2793-2805