Subscribe to RSS
DOI: 10.1055/s-0041-1735251
Estimating Bleeding Risk in Patients with Cancer-Associated Thrombosis: Evaluation of Existing Risk Scores and Development of a New Risk Score
Funding All authors except M.A.d.W. and J.A.N.D. are member of TEAM (Thrombosis ExchAnge Program). TEAM has received network sponsoring from Daiichi Sankyo, Inc. No other funding has been received for this project.![](https://www.thieme-connect.de/media/10.1055-s-00035024/202205/lookinside/thumbnails/10-1055-s-0041-1735251_210205-1.jpg)
Abstract
Background Bleeding risk is highly relevant for treatment decisions in cancer-associated thrombosis (CAT). Several risk scores exist, but have never been validated in patients with CAT and are not recommended for practice.
Objectives To compare methods of estimating clinically relevant (major and clinically relevant nonmajor) bleeding risk in patients with CAT: (1) existing risk scores for bleeding in venous thromboembolism, (2) pragmatic classification based on cancer type, and (3) new prediction model.
Methods In a posthoc analysis of the Hokusai VTE Cancer study, a randomized trial comparing edoxaban with dalteparin for treatment of CAT, seven bleeding risk scores were externally validated (ACCP-VTE, HAS-BLED, Hokusai, Kuijer, Martinez, RIETE, and VTE-BLEED). The predictive performance of these scores was compared with a pragmatic classification based on cancer type (gastrointestinal; genitourinary; other) and a newly derived competing risk-adjusted prediction model based on clinical predictors for clinically relevant bleeding within 6 months after CAT diagnosis with nonbleeding-related mortality as the competing event (“CAT-BLEED”).
Results Data of 1,046 patients (149 events) were analyzed. Predictive performance of existing risk scores was poor to moderate (C-statistics: 0.50–0.57; poor calibration). Internal validation of the pragmatic classification and “CAT-BLEED” showed moderate performance (respective C-statistics: 0.61; 95% confidence interval [CI]: 0.56–0.66, and 0.63; 95% CI 0.58–0.68; good calibration).
Conclusion Existing risk scores for bleeding perform poorly after CAT. Pragmatic classification based on cancer type provides marginally better estimates of clinically relevant bleeding risk. Further improvement may be achieved with “CAT-BLEED,” but this requires external validation in practice-based settings and with other DOACs and its clinical usefulness is yet to be demonstrated.
Author Contributions
All authors contributed to study conception and design. M.A. de Winter analyzed the data and drafted the manuscript in close collaboration with J.A.N. Dorresteijn and M. Nijkeuter. All authors critically revised the manuscript, were responsible for and approved its final version.
Publication History
Received: 08 April 2021
Accepted: 23 July 2021
Article published online:
20 September 2021
© 2021. Thieme. All rights reserved.
Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany
-
References
- 1 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
- 2 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
- 3 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
- 4 Delluc A, Miranda S, Exter PD. et al. Accuracy of the Ottawa score in risk stratification of recurrent venous thromboembolism in patients with cancer-associated venous thromboembolism: a systematic review and meta-analysis. Haematologica 2020; 105 (05) 1436-1442
- 5 Konstantinides SV, Meyer G, Becattini C. et al; ESC Scientific Document Group. 2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS). Eur Heart J 2020; 41 (04) 543-603
- 6 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
- 7 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 (05) 496-520
- 8 Mandalà M, Falanga A, Roila F. ESMO Guidelines Working Group. Management of venous thromboembolism (VTE) in cancer patients: ESMO clinical practice guidelines. Ann Oncol 2011; 22 (Suppl. 06) vi85-vi92
- 9 Streiff MB, Holmstrom B, Angelini D. et al. NCCN guidelines insights: cancer-associated venous thromboembolic disease, version 2.2018. J Natl Compr Canc Netw 2018; 16 (11) 1289-1303
- 10 Farge D, Frere C, Connors JM. et al; International Initiative on Thrombosis and Cancer (ITAC) advisory panel. 2019 international clinical practice guidelines for the treatment and prophylaxis of venous thromboembolism in patients with cancer. Lancet Oncol 2019; 20 (10) e566-e581
- 11 Lyman GH, Khorana AA, Kuderer NM. et al; American Society of Clinical Oncology Clinical Practice. 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
- 12 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 (09) 1891-1894
- 13 Klok FA, Kooiman J, Huisman MV, Konstantinides S, Lankeit M. Predicting anticoagulant-related bleeding in patients with venous thromboembolism: a clinically oriented review. Eur Respir J 2015; 45 (01) 201-210
- 14 Di Nisio M, Ageno W, Rutjes AWS, Pap AF, Büller HR. Risk of major bleeding in patients with venous thromboembolism treated with rivaroxaban or with heparin and vitamin K antagonists. Thromb Haemost 2016; 115 (02) 424-432
- 15 Di Nisio M, Raskob G, Büller HR. et al. Prediction of major and clinically relevant bleeding in patients with VTE treated with edoxaban or vitamin K antagonists. Thromb Haemost 2017; 117 (04) 784-793
- 16 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
- 17 Ruíz-Giménez N, Suárez C, González R. et al; RIETE Investigators. Predictive variables for major bleeding events in patients presenting with documented acute venous thromboembolism. Findings from the RIETE Registry. Thromb Haemost 2008; 100 (01) 26-31
- 18 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
- 19 Trujillo-Santos J, Nieto JA, Tiberio G. et al; RIETE Registry. Predicting recurrences or major bleeding in cancer patients with venous thromboembolism. Findings from the RIETE Registry. Thromb Haemost 2008; 100 (03) 435-439
- 20 Mahé I, Chidiac J, Helfer H, Noble S. Factors influencing adherence to clinical guidelines in the management of cancer-associated thrombosis. J Thromb Haemost 2016; 14 (11) 2107-2113
- 21 Lee AYY. When can we stop anticoagulation in patients with cancer-associated thrombosis?. Blood 2017; 130 (23) 2484-2490
- 22 Elalamy I, Mahé I, Ageno W, Meyer G. Long-term treatment of cancer-associated thrombosis: the choice of the optimal anticoagulant. J Thromb Haemost 2017; 15 (05) 848-857
- 23 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
- 24 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
- 25 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
- 26 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
- 27 de Winter MA, van Es N, Büller HR, Visseren FLJ, Nijkeuter M. Prediction models for recurrence and bleeding in patients with venous thromboembolism: a systematic review and critical appraisal. Thromb Res 2021; 199 (199) 85-96
- 28 Kooiman J, van Hagen N, Iglesias Del Sol A. et al. The HAS-BLED score identifies patients with acute venous thromboembolism at high risk of major bleeding complications during the first six months of anticoagulant treatment. PLoS One 2015; 10 (04) e0122520
- 29 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
- 30 Martinez C, Katholing A, Wallenhorst C, Cohen AT. Prediction of significant bleeding during vitamin K antagonist treatment for venous thromboembolism in outpatients. Br J Haematol 2020; 189 (03) 524-533
- 31 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
- 32 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
- 33 Carrier M, Blais N, Crowther M. et al. Treatment algorithm in cancer-associated thrombosis: Canadian expert consensus. Curr Oncol 2018; 25 (05) 329-337
- 34 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
- 35 Collins GS, Reitsma JB, Altman DG, Moons KGM. Transparent Reporting of a multivariable prediction model for Individual Prognosis or Diagnosis (TRIPOD): the TRIPOD statement. Ann Intern Med 2015; 162 (01) 55-63
- 36 Moons KGM, Wolff RF, Riley RD. et al. PROBAST: a tool to assess risk of bias and applicability of prediction model studies: explanation and elaboration. Ann Intern Med 2019; 170 (01) W1-W33
- 37 Brown JD, Goodin AJ, Lip GYH, Adams VR. Risk stratification for bleeding complications in patients with venous thromboembolism: application of the HAS-BLED bleeding score during the first 6 months of anticoagulant treatment. J Am Heart Assoc 2018; 7 (06) 1-9
- 38 Damen JAAG, Debray TPA, Pajouheshnia R. et al. Empirical evidence of the impact of study characteristics on the performance of prediction models: a meta-epidemiological study. BMJ Open 2019; 9 (04) e026160
- 39 Riva N, Bellesini M, Di Minno MND. et al. Poor predictive value of contemporary bleeding risk scores during long-term treatment of venous thromboembolism. A multicentre retrospective cohort study. Thromb Haemost 2014; 112 (03) 511-521
- 40 Poli D, Antonucci E, Testa S, Cosmi B, Palareti G, Ageno W. FCSA Italian Federation of Anticoagulation Clinics. The predictive ability of bleeding risk stratification models in very old patients on vitamin K antagonist treatment for venous thromboembolism: results of the prospective collaborative EPICA study. J Thromb Haemost 2013; 11 (06) 1053-1058
- 41 Rief P, Raggam RB, Hafner F. et al. Calculation of HAS-BLED score is useful for early identification of venous thromboembolism patients at high risk for major bleeding events: a prospective outpatients cohort study. Semin Thromb Hemost 2018; 44 (04) 348-352
- 42 Palareti G, Antonucci E, Mastroiacovo D. et al. The American College of Chest Physician score to assess the risk of bleeding during anticoagulation in patients with venous thromboembolism. J Thromb Haemost 2018; 16 (10) 1994-2002
- 43 Klok FA, Presles E, Tromeur C. et al; PADIS, ‐PE Investigators. Evaluation of the predictive value of the bleeding prediction score VTE-BLEED for recurrent venous thromboembolism. Res Pract Thromb Haemost 2019; 3 (03) 364-371
- 44 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
- 45 Moik F, Posch F, Zielinski C, Pabinger I, Ay C. 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 (04) 550-561
- 46 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
- 47 Short NJ, Connors JM. New oral anticoagulants and the cancer patient. Oncologist 2014; 19 (01) 82-93
- 48 Thapa N, Shatzel J, Deloughery TG, Olson SR. Direct oral anticoagulants in gastrointestinal malignancies: is the convenience worth the risk?. J Gastrointest Oncol 2019; 10 (04) 807-809
- 49 Lancaster TR, Singer DE, Sheehan MA. et al; Boston Area Anticoagulation Trial for Atrial Fibrillation Investigators. The impact of long-term warfarin therapy on quality of life. Evidence from a randomized trial. Arch Intern Med 1991; 151 (10) 1944-1949