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Thromb Haemost 2020; 120(04): 702-713
DOI: 10.1055/s-0040-1708481
Stroke, Systemic or Venous Thromboembolism
Georg Thieme Verlag KG Stuttgart · New York

A Meta-Analysis of Case Fatality Rates of Recurrent Venous Thromboembolism and Major Bleeding in Patients with Cancer

Alym Abdulla 
1   Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
,
Wendy M. Davis
1   Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
,
Namali Ratnaweera
2   Faculty of Social Sciences, University of Victoria, Victoria, British Columbia, Canada
,
Elena Szefer
3   Emmes Canada, Burnaby, British Columbia, Canada
,
Brooke Ballantyne Scott
4   Department of Evaluation and Research Services, Royal Columbian Hospital, New Westminster, British Columbia, Canada
,
Agnes Y. Y. Lee
1   Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
5   British Columbia Cancer Agency, Vancouver, British Columbia, Canada
› Author Affiliations Funding None.
Further Information

Publication History

05 November 2019

01 February 2020

Publication Date:
14 April 2020 (online)

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Abstract

Background Knowing the case fatality rates of recurrent venous thromboembolism (VTE) and major bleeding is important for weighing the relative risks and benefits of anticoagulation and deciding on the duration of anticoagulant therapy, but these rates are uncertain in patients with cancer-associated thrombosis.

Methods We performed a systematic review and a meta-analysis to determine the incidence of recurrent VTE and major bleeding and their respective case fatality rates in patients with cancer-associated VTE.

Results Our analysis included 29 studies (15 prospective cohort studies and 14 randomized controlled trials) from 1980 to January 2019. Data from 8,000 cancer patients with 4,786 patient-years of follow-up were summarized. Rates of recurrent VTE and fatal recurrent VTE were 23.7 (95% confidence interval [CI]: 20.1–27.8) and 1.9 (95% CI: 0.8–4.0) per 100 patient-years of follow-up, respectively, with a case fatality rate of 14.8% (95% CI: 6.6–30.1%). The rates of major bleeding and fatal major bleeding events were 13.1 (95% CI: 10.3–16.7) and 0.8 (95% CI: 0.3–2.1) per 100 patient-years of follow-up, respectively, with a case fatality rate of 8.9% (95% CI: 3.5–21.1%). While the estimates of case fatality vary by anticoagulation regimen and study design, the differences between them were not statistically significant.

Conclusion In cancer patients receiving anticoagulation, the case fatality rate of recurrent VTE is higher than the case fatality rate of major bleeding. These findings may help to inform decisions regarding the management of anticoagulation in patients with active cancer and VTE.

Keywords

thrombosis - malignancy - clinical trials: heparins/low-molecular-weight heparin - clinical trials: oral anticoagulants

Authors' Contributions

A.A. and B.B.S. conducted the initial literature search. A.A. and W.M.D. reviewed abstracts for inclusion in the study. A.A., W.M.D., and N.R. extracted data from included studies. E.S. conducted the analysis and synthesized results. A.A., W.M.D., and A.Y.Y.L designed the research, analyzed and interpreted the results, and wrote the manuscript. All authors have read and approved the manuscript for submission for final publication.


Note

N.R. was funded by a summer studentship from the Centre for Blood Research, University of British Columbia.


Supplementary Material

 

  • References

  • 1 Khorana AA, Francis CW, Culakova E, Kuderer NM, Lyman GH. Thromboembolism is a leading cause of death in cancer patients receiving outpatient chemotherapy. J Thromb Haemost 2007; 5 (03) 632-634
    CrossrefPubMedGoogle Scholar
  • 2 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
  • 3 Lee AYY, Kamphuisen PW, Meyer G. , et al; CATCH Investigators. Tinzaparin vs warfarin for treatment of acute venous thromboembolism in patients with active cancer: a randomized clinical trial. JAMA 2015; 314 (07) 677-686
    CrossrefPubMedGoogle Scholar
  • 4 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
  • 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 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
  • 7 Blom JW, Doggen CJM, Osanto S, Rosendaal FR. Malignancies, prothrombotic mutations, and the risk of venous thrombosis. JAMA 2005; 293 (06) 715-722
    CrossrefPubMedGoogle Scholar
  • 8 Trujillo-Santos J, Martos FM, Font C. , et al. Analysis of clinical factors affecting the rates of fatal pulmonary embolism and bleeding in cancer patients with venous thromboembolism. Heliyon 2017; 3 (01) e00229
    CrossrefPubMedGoogle Scholar
  • 9 Carrier M, Le Gal G, Wells PS, Rodger MA. Systematic review: case-fatality rates of recurrent venous thromboembolism and major bleeding events among patients treated for venous thromboembolism. Ann Intern Med 2010; 152 (09) 578-589
    CrossrefPubMedGoogle Scholar
  • 10 Douketis JD, Kearon C, Bates S, Duku EK, Ginsberg JS. Risk of fatal pulmonary embolism in patients with treated venous thromboembolism. JAMA 1998; 279 (06) 458-462
    CrossrefPubMedGoogle Scholar
  • 11 Linkins L-A, Choi PT, Douketis JD. Clinical impact of bleeding in patients taking oral anticoagulant therapy for venous thromboembolism: a meta-analysis. Ann Intern Med 2003; 139 (11) 893-900
    CrossrefPubMedGoogle Scholar
  • 12 Wu C, Alotaibi GS, Alsaleh K, Sean McMurtry M. Case fatality of bleeding and recurrent venous thromboembolism during, initial therapy with direct oral anticoagulants: a systematic review. Thromb Res 2014; 134 (03) 627-632
    CrossrefPubMedGoogle Scholar
  • 13 Lecumberri R, Alfonso A, Jiménez D. , et al; RIETE investigators. Dynamics of case-fatalilty rates of recurrent thromboembolism and major bleeding in patients treated for venous thromboembolism. Thromb Haemost 2013; 110 (04) 834-843
    Article in Thieme ConnectPubMedGoogle Scholar
  • 14 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
    CrossrefPubMedGoogle Scholar
  • 15 Higgins JPT, Green S. Cochrane Handbook for Systematic Reviews of Interventions. Hoboken, NJ: John Wiley & Sons; 2011
    Google Scholar
  • 16 Wells GA, Shea B, OConnell D, Peterson J, Welch V, Losos M. The Newcastle-Ottawa Scale (NOS) for Assessing the Quality of Nonrandomised Studies in Metaanalyses. Ottawa, Canada: Ottawa Health Research Institute; 1999
    Google Scholar
  • 17 Firth D. Bias reduction of maximum likelihood estimates. Biometrika 1993; 80 (01) 27-38
    CrossrefPubMedGoogle Scholar
  • 18 Higgins JPT, Thompson SG. Quantifying heterogeneity in a meta-analysis. Stat Med 2002; 21 (11) 1539-1558
    CrossrefPubMedGoogle Scholar
  • 19 Monreal M, Roncales FJ, Ruiz J. , et al. Secondary prevention of venous thromboembolism: A role for low-molecular-weight heparin. Haemostasis 1998; 28 (05) 236-243
    PubMedGoogle Scholar
  • 20 Monreal M, Zacharski L, Jiménez JA, Roncales J, Vilaseca B. Fixed-dose low-molecular-weight heparin for secondary prevention of venous thromboembolism in patients with disseminated cancer: a prospective cohort study. J Thromb Haemost 2004; 2 (08) 1311-1315
    CrossrefPubMedGoogle Scholar
  • 21 Siragusa S, Arcara C, Malato A. , et al. Home therapy for deep vein thrombosis and pulmonary embolism in cancer patients. Ann Oncol 2005; 16 (4, Suppl 4): iv136-iv139
    CrossrefPubMedGoogle Scholar
  • 22 Nijkeuter M, Söhne M, Tick LW. , et al; Christopher Study Investigators. The natural course of hemodynamically stable pulmonary embolism: clinical outcome and risk factors in a large prospective cohort study. Chest 2007; 131 (02) 517-523
    CrossrefPubMedGoogle Scholar
  • 23 Font C, Carmona-Bayonas A, Fernández-Martinez A. , et al. Outpatient management of pulmonary embolism in cancer: data on a prospective cohort of 138 consecutive patients. J Natl Compr Canc Netw 2014; 12 (03) 365-373
    CrossrefPubMedGoogle Scholar
  • 24 Amato B, Compagna R, Rocca A. , et al. Fondaparinux vs warfarin for the treatment of unsuspected pulmonary embolism in cancer patients. Drug Des Devel Ther 2016; 10: 2041-2046
    PubMedGoogle Scholar
  • 25 Bott-Kitslaar DM, Saadiq RA, McBane RD. , et al. Efficacy and Safety of rivaroxaban in patients with venous thromboembolism and active malignancy: a Single-Center Registry. Am J Med 2016; 129 (06) 615-619
    CrossrefPubMedGoogle Scholar
  • 26 Francis CW, Kessler CM, Goldhaber SZ. , et al. Treatment of venous thromboembolism in cancer patients with dalteparin for up to 12 months: the DALTECAN Study. J Thromb Haemost 2015; 13 (06) 1028-1035
    CrossrefPubMedGoogle Scholar
  • 27 Zhang S, Zhai Z, Yang Y. , et al. Long-term treatment with low-molecular-weight heparin prolonged the survival time for acute pulmonary embolism patients concurrent with malignancy: an observational analysis from a long-term follow-up study. Thromb Res 2015; 135 (04) 582-587
    CrossrefPubMedGoogle Scholar
  • 28 Jara-Palomares L, Solier-Lopez A, Elias-Hernandez T. , et al. Tinzaparin in cancer associated thrombosis beyond 6months: TiCAT study. Thromb Res 2017; 157: 90-96
    CrossrefPubMedGoogle Scholar
  • 29 Mantha S, Laube E, Miao Y. , et al. Safe and effective use of rivaroxaban for treatment of cancer-associated venous thromboembolic disease: a prospective cohort study. J Thromb Thrombolysis 2017; 43 (02) 166-171
    CrossrefPubMedGoogle Scholar
  • 30 van der Wall SJ, Klok FA, den Exter PL. , et al. Continuation of low-molecular-weight heparin treatment for cancer-related venous thromboembolism: a prospective cohort study in daily clinical practice. J Thromb Haemost 2017; 15 (01) 74-79
    CrossrefPubMedGoogle Scholar
  • 31 van Es N, Louzada M, Carrier M. , et al. Predicting the risk of recurrent venous thromboembolism in patients with cancer: A prospective cohort study. Thromb Res 2018; 163: 41-46
    CrossrefPubMedGoogle Scholar
  • 32 Schulman S, Zondag M, Linkins L. , et al. Recurrent venous thromboembolism in anticoagulated patients with cancer: management and short-term prognosis. J Thromb Haemost 2015; 13 (06) 1010-1018
    CrossrefPubMedGoogle Scholar
  • 33 Deitcher SR, Kessler CM, Merli G, Rigas JR, Lyons RM, Fareed J. ; ONCENOX Investigators. Secondary prevention of venous thromboembolic events in patients with active cancer: enoxaparin alone versus initial enoxaparin followed by warfarin for a 180-day period. Clin Appl Thromb Hemost 2006; 12 (04) 389-396
    CrossrefPubMedGoogle Scholar
  • 34 Meyer G, Marjanovic Z, Valcke J. , et al. Comparison of low-molecular-weight heparin and warfarin for the secondary prevention of venous thromboembolism in patients with cancer: a randomized controlled study. Arch Intern Med 2002; 162 (15) 1729-1735
    CrossrefPubMedGoogle Scholar
  • 35 Hull RD, Pineo GF, Brant RF. , et al; LITE Trial Investigators. Long-term low-molecular-weight heparin versus usual care in proximal-vein thrombosis patients with cancer. Am J Med 2006; 119 (12) 1062-1072
    CrossrefPubMedGoogle Scholar
  • 36 Romera A, Cairols MA, Vila-Coll R. , et al. A randomised open-label trial comparing long-term sub-cutaneous low-molecular-weight heparin compared with oral-anticoagulant therapy in the treatment of deep venous thrombosis. Eur J Vasc Endovasc Surg 2009; 37 (03) 349-356
    CrossrefPubMedGoogle Scholar
  • 37 Prins MH, Lensing AWA, Brighton TA. , et al. Oral rivaroxaban versus enoxaparin with vitamin K antagonist for the treatment of symptomatic venous thromboembolism in patients with cancer (EINSTEIN-DVT and EINSTEIN-PE): a pooled subgroup analysis of two randomised controlled trials. Lancet Haematol 2014; 1 (01) e37-e46
    PubMedGoogle Scholar
  • 38 Napolitano M, Saccullo G, Malato A. , et al. Optimal duration of low molecular weight heparin for the treatment of cancer-related deep vein thrombosis: the Cancer-DACUS Study. J Clin Oncol 2014; 32 (32) 3607-3612
    CrossrefPubMedGoogle Scholar
  • 39 Raskob GE, van Es N, Segers A. , et al; Hokusai-VTE investigators. Edoxaban for venous thromboembolism in patients with cancer: results from a non-inferiority subgroup analysis of the Hokusai-VTE randomised, double-blind, double-dummy trial. Lancet Haematol 2016; 3 (08) e379-e387
    PubMedGoogle Scholar
  • 40 Agnelli G, Buller HR, Cohen A. , et al. Oral apixaban for the treatment of venous thromboembolism in cancer patients: results from the AMPLIFY trial. J Thromb Haemost 2015; 13 (12) 2187-2191
    CrossrefPubMedGoogle Scholar
  • 41 Schulman S, Goldhaber SZ, Kearon C. , et al. Treatment with dabigatran or warfarin in patients with venous thromboembolism and cancer. Thromb Haemost 2015; 114 (01) 150-157
    Article in Thieme ConnectPubMedGoogle Scholar
  • 42 van Doormaal FF, Raskob GE, Davidson BL. , et al. Treatment of venous thromboembolism in patients with cancer: subgroup analysis of the Matisse clinical trials. Thromb Haemost 2009; 101 (04) 762-769
    Article in Thieme ConnectPubMedGoogle Scholar
  • 43 Cushman M, Tsai AW, White RH. , et al. Deep vein thrombosis and pulmonary embolism in two cohorts: the longitudinal investigation of thromboembolism etiology. Am J Med 2004; 117 (01) 19-25
    CrossrefPubMedGoogle Scholar
  • 44 Tagalakis V, Patenaude V, Kahn SR, Suissa S. Incidence of and mortality from venous thromboembolism in a real-world population: the Q-VTE Study Cohort. Am J Med 2013; 126 (09) 832.e13-832.e21
    CrossrefPubMedGoogle Scholar
  • 45 Wu C, Alotaibi GS, Alsaleh K, Linkins L-A, McMurtry MS. Case-fatality of recurrent venous thromboembolism and major bleeding associated with aspirin, warfarin, and direct oral anticoagulants for secondary prevention. Thromb Res 2015; 135 (02) 243-248
    CrossrefPubMedGoogle Scholar
  • 46 van der Wall SJ, van der Pol LM, Ende-Verhaar YM. , et al. Fatal recurrent VTE after anticoagulant treatment for unprovoked VTE: a systematic review. Eur Respir Rev 2018; 27 (150) 180094
    CrossrefPubMedGoogle Scholar
  • 47 Fishman MJ, Wu L-T, Woody GE. Buprenorphine for prescription opioid addiction in a patient with depression and alcohol dependence. Am J Psychiatry 2011; 168 (07) 675-679
    CrossrefPubMedGoogle Scholar
  • 48 Kraaijpoel N, Tritschler T, Guillo E, Girard P, Le Gal G. Definitions, adjudication, and reporting of pulmonary embolism-related death in clinical studies: A systematic review. J Thromb Haemost 2019; 17 (10) 1590-1607
    CrossrefPubMedGoogle Scholar