Major Bleeding Risk Assessment in Patients with Cancer-Associated Venous Thromboembolism Treated with DOACs: Data from a Multicenter Cohort

Maria Cristina Vedovati; Rosa Talerico; Clara Sacco; Matteo Mazzetti; Elena Campello; Simone Birocchi; Sofia Beccatini; Angelo Porfidia; Rachele Caprari; Corrado Lodigiani; Paolo Simioni; Gian Marco Podda; Isabella Mastandrea; Cecilia Becattini; Roberto Pola

doi:10.1055/a-2605-9015

Thrombosis and Haemostasis, Table of Contents

Thromb Haemost
DOI: 10.1055/a-2605-9015

Stroke, Systemic or Venous Thromboembolism

Major Bleeding Risk Assessment in Patients with Cancer-Associated Venous Thromboembolism Treated with DOACs: Data from a Multicenter Cohort

Maria Cristina Vedovati

¹Internal, Vascular and Emergency Medicine – Stroke Unit, University of Perugia, Perugia, Italy

,

Rosa Talerico

²Department of Geriatric, Orthopedic, and Rheumatologic Sciences, University Polyclinic Foundation A. Gemelli IRCCS, Rome, Italy

,

Clara Sacco

³Thrombosis and Hemorragic Diseases Unit, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy

,

Matteo Mazzetti

⁴Interdisciplinary Internal Medicine, Careggi University Hospital, Florence, Italy

,

Elena Campello

⁵First Chair of Internal Medicine and Thrombotic and Hemorrhagic Diseases Unit, Department of Medicine, University of Padova, Italy

,

Simone Birocchi

⁶Medicine II Unit, ASST Santi Paolo e Carlo, Department of Health Sciences, University of Milan, Milan, Italy

,

Sofia Beccatini

¹Internal, Vascular and Emergency Medicine – Stroke Unit, University of Perugia, Perugia, Italy

,

Angelo Porfidia

²Department of Geriatric, Orthopedic, and Rheumatologic Sciences, University Polyclinic Foundation A. Gemelli IRCCS, Rome, Italy

,

Rachele Caprari

²Department of Geriatric, Orthopedic, and Rheumatologic Sciences, University Polyclinic Foundation A. Gemelli IRCCS, Rome, Italy

,

Corrado Lodigiani

³Thrombosis and Hemorragic Diseases Unit, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy

,

Paolo Simioni

⁵First Chair of Internal Medicine and Thrombotic and Hemorrhagic Diseases Unit, Department of Medicine, University of Padova, Italy

,

Gian Marco Podda

⁶Medicine II Unit, ASST Santi Paolo e Carlo, Department of Health Sciences, University of Milan, Milan, Italy

,

Isabella Mastandrea

³Thrombosis and Hemorragic Diseases Unit, IRCCS Humanitas Research Hospital, Rozzano, Milan, Italy

,

Cecilia Becattini

¹Internal, Vascular and Emergency Medicine – Stroke Unit, University of Perugia, Perugia, Italy

,

Roberto Pola

²Department of Geriatric, Orthopedic, and Rheumatologic Sciences, University Polyclinic Foundation A. Gemelli IRCCS, Rome, Italy

› Author Affiliations

Abstract

Background

In cancer-associated venous thromboembolism (CAT), extended anticoagulation should be considered when the risk–benefit profile is favorable. However, optimal predictors of major bleeding (MB) remain unclear.

Methods

This multicenter observational study included CAT patients treated with direct oral anticoagulants (DOACs). Study objectives were: (i) assess the performance of nine bleeding risk scores (ATRIA, CAT-BLEED, CHAP, DOAC, HAS-BLED, Kuijer, ORBIT, RIETE, VTE-BLEED), (ii) identify predictors of MB (ISTH definition), and (iii) propose an improved bleeding risk model (Perform score).

Results

Overall, 823 patients were followed (mean 1.6 years). MB occurred in 44 cases (3.4% per patient-year). The predictive performance of bleeding risk scores was modest (c-statistics range 0.513–0.606). Risk factors included increasing age (HR 1.04, 95% CI 1.00–1.07), use of steroids (HR 2.69, 95% CI 1.34–5.40), antimetabolites (HR 2.51, 95% CI 1.28–4.93), and unresected gastrointestinal cancer (HR 7.30, 95% CI 1.70–31.30). Conversely, prior cancer surgery (HR 0.41, 95% CI 0.20–0.82) and anticancer hormones (HR 0.22, 95% CI 0.05–0.92) showed a possible protective effect toward MB risk. The Perform score provided a slight enhancement in risk prediction (c-statistics 0.678), but remained suboptimal.

Conclusion

In this real-world cohort of CAT patients treated with DOACs, unresected gastrointestinal cancer and use of steroids or antimetabolites were associated with increased MB risk, while prior cancer surgery and anticancer hormones were linked to a lower risk. These factors, not considered in current bleeding risk scores, may refine bleeding prediction. Further studies should clarify their role in guiding anticoagulation decisions and improving personalized risk assessment.

Keywords

cancer - major bleeding - venous thromboembolism - prediction rule

Full Text

References

References
1 Donnellan E, Khorana AA. Cancer and venous thromboembolic disease: a review. Oncologist 2017; 22 (02) 199-207
2 Mulder FI, Horváth-Puhó E, van Es N. et al. Venous thromboembolism in cancer patients: a population-based cohort study. Blood 2021; 137 (14) 1959-1969
3 Frere C, Font C, Esposito F, Crichi B, Girard P, Janus N. Incidence, risk factors, and management of bleeding in patients receiving anticoagulants for the treatment of cancer-associated thrombosis. Support Care Cancer 2022; 30 (04) 2919-2931
4 Weitz JI, Haas S, Ageno W. et al; GARFIELD-VTE investigators. Cancer associated thrombosis in everyday practice: perspectives from GARFIELD-VTE. J Thromb Thrombolysis 2020; 50 (02) 267-277
5 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
6 Hutten BA, Prins MH, Gent M, Ginsberg J, Tijssen JGP, Büller HR. 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
7 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
8 Becattini C, Di Nisio M, Franco L, Lee A, Agnelli G, Mandalà M. Treatment of venous thromboembolism in cancer patients: the dark side of the moon. Cancer Treat Rev 2021; 96: 102190
9 Angelini DE, Radivoyevitch T, McCrae KR, Khorana AA. Bleeding incidence and risk factors among cancer patients treated with anticoagulation. Am J Hematol 2019; 94 (07) 780-785
10 Kamphuisen PW, Beyer-Westendorf J. Bleeding complications during anticoagulant treatment in patients with cancer. Thromb Res 2014; 133 (Suppl. 02) S49-S55
11 Trujillo-Santos J, Nieto JA, Tiberio G. et al; RIETE Registry, Findings from the RIETE Registry. Predicting recurrences or major bleeding in cancer patients with venous thromboembolism. Thromb Haemost 2008; 100 (03) 435-439
12 Moik F, Colling M, Mahé I, Jara-Palomares L, Pabinger I, Ay C. Extended anticoagulation treatment for cancer-associated thrombosis—rates of recurrence and bleeding beyond 6 months: a systematic review. J Thromb Haemost 2022; 20 (03) 619-634
13 Yamashita Y, Morimoto T, Muraoka N. et al. Rivaroxaban for 18 months versus 6 months in patients with cancer and acute low-risk pulmonary embolism: an open-label, multicenter, randomized clinical trial (ONCO PE Trial). Circulation 2024
14 Mahé I, Agnelli G, Ay C. et al. Extended anticoagulant treatment with full- or reduced-dose apixaban in patients with cancer-associated venous thromboembolism: rationale and design of the API-CAT study. Thromb Haemost 2022; 122 (04) 646-656
15 Falanga A, Ay C, Di Nisio M. et al; ESMO Guidelines Committee. Electronic address: clinicalguidelines@esmo.org. Venous thromboembolism in cancer patients: ESMO Clinical Practice Guideline. Ann Oncol 2023; 34 (05) 452-467
16 Key NS, Khorana AA, Kuderer NM. et al. Venous thromboembolism prophylaxis and treatment in patients with cancer: ASCO guideline update. J Clin Oncol 2023; 41 (16) 3063-3071
17 Kuijer PMM, Hutten BA, Prins MH, Büller HR. Prediction of the risk of bleeding during anticoagulant treatment for venous thromboembolism. Arch Intern Med 1999; 159 (05) 457-460
18 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
19 Klok FA, Hösel V, Clemens A. et al. Prediction of bleeding events in patients with venous thromboembolism on stable anticoagulation treatment. Eur Respir J 2016; 48 (05) 1369-1376
20 Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns HJGM, Lip GYH. 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
21 Fang MC, Go AS, Chang Y. et al. A new risk scheme to predict warfarin-associated hemorrhage: the ATRIA (Anticoagulation and Risk Factors in Atrial Fibrillation) Study. J Am Coll Cardiol 2011; 58 (04) 395-401
22 O'Brien EC, Simon DN, Thomas LE. et al. The ORBIT bleeding score: a simple bedside score to assess bleeding risk in atrial fibrillation. Eur Heart J 2015; 36 (46) 3258-3264
23 de Winter MA, Büller HR, Carrier M. et al; VTE-PREDICT study group. Recurrent venous thromboembolism and bleeding with extended anticoagulation: the VTE-PREDICT risk score. Eur Heart J 2023; 44 (14) 1231-1244
24 Wells PS, Tritschler T, Khan F. et al. Predicting major bleeding during extended anticoagulation for unprovoked or weakly provoked venous thromboembolism. Blood Adv 2022; 6 (15) 4605-4616
25 Aggarwal R, Ruff CT, Virdone S. et al. Development and validation of the DOAC score: a novel bleeding risk prediction tool for patients with atrial fibrillation on direct-acting oral anticoagulants. Circulation 2023; 148 (12) 936-946
26 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
27 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
28 Frere C, Farge D, Schrag D, Prata PH, Connors JM. Direct oral anticoagulant versus low molecular weight heparin for the treatment of cancer-associated venous thromboembolism: 2022 updated systematic review and meta-analysis of randomized controlled trials. J Hematol Oncol 2022; 15 (01) 69
29 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
30 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
31 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
32 Collins GS, Reitsma JB, Altman DG, Moons KGM. Transparent reporting of a multivariable prediction model for individual prognosis or diagnosis (TRIPOD): the TRIPOD statement. BMJ 2015; 350 (04) g7594
33 Prandoni P, Bilora F, Pesavento R. et al; RIETE Investigators. DOAC score for prediction of major bleeding in patients with venous thromboembolism: findings from the RIETE registry. Thromb Res 2025; 245: 109226
34 Riaz IB, Fuentes H, Deng Y. et al. Comparative effectiveness of anticoagulants in patients with cancer-associated thrombosis. JAMA Netw Open 2023; 6 (07) e2325283
35 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
36 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
37 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
38 Zheng Y, Zhang N, Tse G, Li G, Lip GYH, Liu T. Co-administered oral anticoagulants with nonsteroidal anti-inflammatory drugs and the risk of bleeding: a systematic review and meta-analysis. Thromb Res 2023; 232: 15-26
39 Wang TF, Clarke AE, Awan AA, Tanuseputro P, Carrier M, Sood MM. Hemorrhage risk among patients with breast cancer receiving concurrent direct oral anticoagulants with tamoxifen vs aromatase inhibitors. JAMA Netw Open 2022; 5 (06) e2219128
40 Tufano A, Coppola A. How to manage anticoagulation for cancer-associated thrombosis and atrial fibrillation in cancer. Thromb Update 2024; 15: 100169
41 Vedovati MC, Mancuso A, Pierpaoli L. et al. Prediction of major bleeding in patients receiving DOACs for venous thromboembolism: a prospective cohort study. Int J Cardiol 2020; 301: 167-172
42 Xi S, Liu C, Yu S, Qiu J, He S, Yi Z. Comparison of performances among four bleeding-prediction scores in elderly cancer patients with venous thromboembolism. Hamostaseologie 2023; 43 (04) 281-288
43 Mahé I, Carrier M, Mayeur D. et al; API-CAT Investigators. Extended reduced-dose apixaban for cancer-associated venous thromboembolism. N Engl J Med 2025; 392 (14) 1363-1373

Supplementary Material

Supplementary Material