Download PDF
CC BY 4.0 · TH Open 2024; 08(01): e61-e71
DOI: 10.1055/a-2214-8101
Original Article

Treatment Patterns of Cancer-associated Thrombosis in the Netherlands: The Four Cities Study

Fleur H.J. Kaptein   *
1   Department of Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, the Netherlands
,
Noori A.M. Guman    *
2   Department of Vascular Medicine, Amsterdam University Medical Center Location University of Amsterdam, Amsterdam, the Netherlands
3   Department of Pulmonary Hypertension and Thrombosis, Amsterdam Cardiovascular Sciences, Amsterdam, the Netherlands
4   Department of Internal Medicine, Tergooi Medical Center, Hilversum, the Netherlands
,
Susan B. Lohle
2   Department of Vascular Medicine, Amsterdam University Medical Center Location University of Amsterdam, Amsterdam, the Netherlands
3   Department of Pulmonary Hypertension and Thrombosis, Amsterdam Cardiovascular Sciences, Amsterdam, the Netherlands
,
Frederikus A. Klok 
1   Department of Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, the Netherlands
,
Albert T.A. Mairuhu
5   Department of Internal Medicine, Haga Hospital, The Hague, the Netherlands
,
Pieter W. Kamphuisen
2   Department of Vascular Medicine, Amsterdam University Medical Center Location University of Amsterdam, Amsterdam, the Netherlands
3   Department of Pulmonary Hypertension and Thrombosis, Amsterdam Cardiovascular Sciences, Amsterdam, the Netherlands
4   Department of Internal Medicine, Tergooi Medical Center, Hilversum, the Netherlands
,
Nick Van Es
2   Department of Vascular Medicine, Amsterdam University Medical Center Location University of Amsterdam, Amsterdam, the Netherlands
3   Department of Pulmonary Hypertension and Thrombosis, Amsterdam Cardiovascular Sciences, Amsterdam, the Netherlands
,
Menno V. Huisman
1   Department of Thrombosis and Hemostasis, Leiden University Medical Center, Leiden, the Netherlands
› Author Affiliations Funding The LUMC received independent financial support for part of salary costs of F.H.J.K. from Pfizer, Bayer Health Care, and LEO Pharma. F.A.K. has received research support from Bayer, Bristol-Myers Squibb, Boehringer-Ingelheim, MSD, VarmX, Daiichi Sankyo, Actelion, The Netherlands Organisation for Health Research and Development, The Dutch Thrombosis Association, The Dutch Heart Foundation, and the Horizon Europe Program, all unrelated to this work and paid to his institution. M.V.H. has received research grants from Dutch Healthcare Fund, Dutch Heart Foundation, Bayer Health Care, Pfizer, BMS, Boehringer-Ingelheim, and LEO Pharma. P.W.K. has received research grants from Daiichi Sankyo and Roche Diagnostics and the Tergooi Academy, all transferred to his institute. N.v.E. reports advisory board honoraria from Daiichi Sankyo, Bayer, and LEO Pharma, which were transferred to his institute.
› Further Information
   Permissions and Reprints

Abstract

Background Current guidelines recommend either low-molecular weight heparin (LMWH) or direct oral anticoagulants (DOACs) as first-line treatment in cancer-associated venous thromboembolism (VTE).

Aim This study aimed to investigate treatment regimens for cancer-associated VTE over the past 5 years, explore predictors for initial treatment (LMWH vs. DOAC), and to assess the risks of recurrent VTE and bleeding.

Methods This was a Dutch, multicenter, retrospective cohort study including consecutive patients with cancer-associated VTE between 2017 and 2021. Treatment predictors were assessed with multivariable logistic regression models. Six-month cumulative incidences for recurrent VTE and major bleeding (MB) were estimated with death as competing risk.

Results In total, 1,215 patients were included. The majority (1,134/1,192; 95%) started VTE treatment with anticoagulation: 561 LMWH (47%), 510 DOACs (43%), 27 vitamin K antagonist (2.3%), and 36 other/unknown type (3.0%). The proportion of patients primarily treated with DOACs increased from 18% (95% confidence interval [CI] 12–25) in 2017 to 70% (95% CI 62–78) in 2021. Poor performance status (adjusted odds ratio [aOR] 0.72, 95% CI 0.53–0.99) and distant metastases (aOR 0.61, 95% CI 0.45–0.82) were associated with primary treatment with LMWH. Total 6-month cumulative incidences were 6.0% (95% CI 4.8–7.5) for recurrent VTE and 7.0% (95% CI 5.7–8.6) for MB. During follow-up, 182 patients (15%) switched from LMWH to a DOAC, and 54 patients (4.4%) vice versa, for various reasons, including patient preference, recurrent thrombosis, and/or bleeding.

Conclusion DOAC use in cancer-associated VTE has increased rapidly over the past years. Changes in anticoagulation regimen were frequent over time, and were often related to recurrent thrombotic and bleeding complications, illustrating the complexity and challenges of managing cancer-associated VTE.

Keywords

venous thromboembolism - anticoagulants - neoplasms - hemorrhage - cohort studies

Authors' Contributions

F.H.J.K. and M.V.H. were responsible for conception of this study and drafted the manuscript. F.H.J.K. and S.B.L. collected data in two hospitals. F.H.J.K. analyzed the data. All authors revised the manuscript for intellectual content, approved the final manuscript, and agreed to submission.


* These authors contributed equally to this work.


Supplementary Material



Publication History

Received: 03 August 2023

Accepted: 17 November 2023

Accepted Manuscript online:
21 November 2023

Article published online:
30 January 2024

© 2024. The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. (https://creativecommons.org/licenses/by/4.0/)

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 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
    CrossrefPubMedGoogle Scholar
  • 2 Cohen AT, Katholing A, Rietbrock S, Bamber L, Martinez C. Epidemiology of first and recurrent venous thromboembolism in patients with active cancer. A population-based cohort study. Thromb Haemost 2017; 117 (01) 57-65
    Article in Thieme ConnectPubMedGoogle Scholar
  • 3 Lee AYY, Levine MN, Baker RI. et al; Randomized Comparison of Low-Molecular-Weight Heparin versus Oral Anticoagulant Therapy for the Prevention of Recurrent Venous Thromboembolism in Patients with Cancer (CLOT) Investigators. 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
  • 4 Khorana AA, Mackman N, Falanga A. et al. Cancer-associated venous thromboembolism. Nat Rev Dis Primers 2022; 8 (01) 11
    CrossrefPubMedGoogle Scholar
  • 5 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
    CrossrefPubMedGoogle Scholar
  • 6 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
    CrossrefPubMedGoogle Scholar
  • 7 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
    CrossrefPubMedGoogle Scholar
  • 8 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
    CrossrefPubMedGoogle Scholar
  • 9 Lyman GH, Carrier M, Ay C. et al. American Society of Hematology 2021 guidelines for management of venous thromboembolism: prevention and treatment in patients with cancer. Blood Adv 2021; 5 (04) 927-974
    CrossrefPubMedGoogle Scholar
  • 10 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
    CrossrefPubMedGoogle Scholar
  • 11 Federatie Medisch Specialisten-NIV. Richtlijn Antitrombotisch beleid. Last updated on September 1, 2022 . Accessed June 2, 2023 at: https://richtlijnendatabase.nl/richtlijn/antitrombotisch_beleid
    PubMedGoogle Scholar
  • 12 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
    CrossrefPubMedGoogle Scholar
  • 13 Stevens SM, Woller SC, Kreuziger LB. et al. Antithrombotic therapy for VTE disease: second update of the CHEST Guideline and expert panel report. Chest 2021; 160 (06) e545-e608
    CrossrefPubMedGoogle Scholar
  • 14 Khorana AA, Connolly GC. Assessing risk of venous thromboembolism in the patient with cancer. J Clin Oncol 2009; 27 (29) 4839-4847
    CrossrefPubMedGoogle Scholar
  • 15 Hanna-Sawires RG, Groen JV, Hamming A. et al. Incidence, timing and risk factors of venous thromboembolic events in patients with pancreatic cancer. Thromb Res 2021; 207: 134-139
    CrossrefPubMedGoogle Scholar
  • 16 Dronkers CEA, Klok FA, Huisman MV. Current and future perspectives in imaging of venous thromboembolism. J Thromb Haemost 2016; 14 (09) 1696-1710
    CrossrefPubMedGoogle Scholar
  • 17 Huisman MV, Klok FA. Diagnostic management of acute deep vein thrombosis and pulmonary embolism. J Thromb Haemost 2013; 11 (03) 412-422
    CrossrefPubMedGoogle Scholar
  • 18 Huisman MV, Barco S, Cannegieter SC. et al. Pulmonary embolism. Nat Rev Dis Primers 2018; 4 (01) 18028
    CrossrefPubMedGoogle Scholar
  • 19 van Dijk WB, Fiolet ATL, Schuit E. et al. Text-mining in electronic healthcare records can be used as efficient tool for screening and data collection in cardiovascular trials: a multicenter validation study. J Clin Epidemiol 2021; 132: 97-105
    CrossrefPubMedGoogle Scholar
  • 20 Scrucca L, Santucci A, Aversa F. Competing risk analysis using R: an easy guide for clinicians. Bone Marrow Transplant 2007; 40 (04) 381-387
    CrossrefPubMedGoogle Scholar
  • 21 Kaliel H, Mior M, Quan S, Ghosh S, Wu C, Bungard TJ. Retrospective review of prescribing patterns in cancer-associated thrombosis: a single center experience in Edmonton, Alberta, Canada. Clin Appl Thromb Hemost 2021; 27: 1076029620975489
    CrossrefPubMedGoogle Scholar
  • 22 Wysokinski WE, Houghton DE, Casanegra AI. et al. Comparison of apixaban to rivaroxaban and enoxaparin in acute cancer-associated venous thromboembolism. Am J Hematol 2019; 94 (11) 1185-1192
    CrossrefPubMedGoogle Scholar
  • 23 Brenner B, Bikdeli B, Tzoran I. et al; RIETE Investigators. Arterial ischemic events are a major complication in cancer patients with venous thromboembolism. Am J Med 2018; 131 (09) 1095-1103
    CrossrefPubMedGoogle Scholar
  • 24 Navi BB, Reiner AS, Kamel H. et al. Risk of arterial thromboembolism in patients with cancer. J Am Coll Cardiol 2017; 70 (08) 926-938
    CrossrefPubMedGoogle Scholar
  • 25 Chee CE, Ashrani AA, Marks RS. et al. Predictors of venous thromboembolism recurrence and bleeding among active cancer patients: a population-based cohort study. Blood 2014; 123 (25) 3972-3978
    CrossrefPubMedGoogle Scholar
  • 26 Lapébie F-X, Bura-Rivière A, Espitia O. et al. Predictors of recurrence of cancer-associated venous thromboembolism after discontinuation of anticoagulant therapy: a multicenter cohort study. J Thromb Haemost 2023; 21 (08) 2189-2201
    CrossrefPubMedGoogle Scholar
  • 27 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 (09) 1549-1556
    CrossrefPubMedGoogle Scholar
  • 28 Gervaso L, Dave H, Khorana AA. Venous and arterial thromboembolism in patients with cancer: JACC: CardioOncology State-of-the-Art Review. JACC Cardiooncol 2021; 3 (02) 173-190
    CrossrefPubMedGoogle Scholar
  • 29 Zhu VW, Zhao JJ, Gao Y. et al. Thromboembolism in ALK+ and ROS1+ NSCLC patients: a systematic review and meta-analysis. Lung Cancer 2021; 157: 147-155
    CrossrefPubMedGoogle Scholar
  • 30 Khorana AA, Yannicelli D, McCrae KR. et al. Evaluation of US prescription patterns: are treatment guidelines for cancer-associated venous thromboembolism being followed?. Thromb Res 2016; 145: 51-53
    CrossrefPubMedGoogle Scholar
  • 31 Ogino Y, Ishigami T, Minamimoto Y. et al. Direct oral anticoagulant therapy for cancer-associated venous thromboembolism in routine clinical practice. Circ J 2020; 84 (08) 1330-1338
    CrossrefPubMedGoogle Scholar
  • 32 Khorana AA, McCrae KR, Milentijevic D. et al. Current practice patterns and patient persistence with anticoagulant treatments for cancer-associated thrombosis. Res Pract Thromb Haemost 2017; 1 (01) 14-22
    CrossrefPubMedGoogle Scholar
  • 33 Meyre PB, Blum S, Hennings E. et al. Bleeding and ischaemic events after first bleed in anticoagulated atrial fibrillation patients: risk and timing. Eur Heart J 2022; 43 (47) 4899-4908
    CrossrefPubMedGoogle Scholar
  • 34 de Jong CMM, Rosovsky RP, Klok FA. Outcomes of venous thromboembolism care: future directions. J Thromb Haemost 2023; 21 (05) 1082-1089
    CrossrefPubMedGoogle Scholar
  • 35 Larsen T-L, 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
    CrossrefPubMedGoogle Scholar
  • 36 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
    Article in Thieme ConnectPubMedGoogle Scholar
  • 37 McBane II RD, Loprinzi CL, Ashrani A. et al. Extending venous thromboembolism secondary prevention with apixaban in cancer patients: The EVE trial. Eur J Haematol 2020; 104 (02) 88-96
    CrossrefPubMedGoogle Scholar