Download PDF
Semin Thromb Hemost 2018; 44(04): 377-387
DOI: 10.1055/s-0038-1642644
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Causes of Death in Patients with Venous Thromboembolism Anticoagulated with Direct Oral Anticoagulants: A Systematic Review and Meta-Analysis

Antonio Gómez-Outes
1   Division of Pharmacology and Clinical Drug Evaluation, Spanish Agency for Medicines and Medical Devices (AEMPS), Madrid, Spain
,
Ana Isabel Terleira-Fernández
2   Department of Clinical Pharmacology, Hospital Clínico San Carlos, Madrid, Spain
3   Department of Pharmacology, Universidad Complutense, Madrid, Spain
,
Ramón Lecumberri
4   Hematology Service, University Clinic of Navarra, Pamplona, Spain
5   Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III, Madrid, Spain
,
Mª Luisa Suárez-Gea
1   Division of Pharmacology and Clinical Drug Evaluation, Spanish Agency for Medicines and Medical Devices (AEMPS), Madrid, Spain
,
Gonzalo Calvo-Rojas
6   Department of Clinical Pharmacology, Hospital Clinic, Barcelona, Spain
,
Emilio Vargas-Castrillón
2   Department of Clinical Pharmacology, Hospital Clínico San Carlos, Madrid, Spain
3   Department of Pharmacology, Universidad Complutense, Madrid, Spain
› Author Affiliations Funding No funding/grant support was received for conducting this systematic review.
Further Information

Publication History

Publication Date:
03 May 2018 (online)

    Permissions and Reprints

Abstract

Death is more frequent than nonfatal recurrent venous thromboembolism (VTE) and major bleeding after acute VTE. The analysis of the causes of death is fundamental to explore new strategies to reduce mortality rates in these patients. The authors performed a meta-analysis to analyze mortality and independently adjudicated causes of death in anticoagulated patients due to VTE, and to evaluate potential differences between different anticoagulant schemes. They searched MEDLINE and CENTRAL, from January 1, 2000, to January 31, 2017, and performed additional searches in Web sites of regulatory agencies, clinical trial registers, and conference proceedings. Two investigators independently selected studies and extracted the data. Study quality was assessed with the Cochrane Collaboration's tool for assessing the risk of bias in randomized studies. Seven prospective randomized trials in 29,844 patients (22,025 patient-year follow-up) were included, comparing dabigatran, rivaroxaban, apixaban, and edoxaban with the standard anticoagulant treatment of VTE. A total of 718 patients died during the follow-up (3.4% per year; 95% confidence interval [CI]: 2.3–4.8). The most frequent causes of death were cancer (42%), followed by VTE (20%), infections (13%), hemorrhage (6%), heart disease (4%), and stroke (2%). There were no differences in the overall survival and causes of death according to the anticoagulant type. Concomitant active cancer during the study was significantly associated with death (odds ratio: 15.2; 95% CI: 9.2–25.1). Cancer is the leading cause of death in contemporary VTE trials. Interventions beyond anticoagulation, particularly in patients with active cancer, are needed.

Keywords

venous thromboembolism - anticoagulation - mortality - death - cancer

Supplementary Material

 

  • References

  • 1 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
    CrossrefPubMedGoogle Scholar
  • 2 Lyman GH, Bohlke K, Khorana AA. , et al; American Society of Clinical Oncology. Venous thromboembolism prophylaxis and treatment in patients with cancer: American Society of Clinical Oncology clinical practice guideline update 2014. J Clin Oncol 2015; 33 (06) 654-656
    CrossrefPubMedGoogle Scholar
  • 3 Farge D, Debourdeau P, Beckers M. , et al. International clinical practice guidelines for the treatment and prophylaxis of venous thromboembolism in patients with cancer. J Thromb Haemost 2013; 11 (01) 56-70
    CrossrefPubMedGoogle Scholar
  • 4 Gómez-Outes A, Suárez-Gea ML, Lecumberri R, Terleira-Fernández AI, Vargas-Castrillón E. Direct-acting oral anticoagulants: pharmacology, indications, management, and future perspectives. Eur J Haematol 2015; 95 (05) 389-404
    CrossrefPubMedGoogle Scholar
  • 5 van der Hulle T, Kooiman J, den Exter PL, Dekkers OM, Klok FA, Huisman MV. Effectiveness and safety of novel oral anticoagulants as compared with vitamin K antagonists in the treatment of acute symptomatic venous thromboembolism: a systematic review and meta-analysis. J Thromb Haemost 2014; 12 (03) 320-328
    CrossrefPubMedGoogle Scholar
  • 6 Higgins JP, Altman DG, Gøtzsche PC. , et al; Cochrane Bias Methods Group; Cochrane Statistical Methods Group. The Cochrane Collaboration's tool for assessing risk of bias in randomised trials. BMJ 2011; 343: d5928
    CrossrefPubMedGoogle Scholar
  • 7 Liberati A, Altman DG, Tetzlaff J. , et al. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ 2009; 339: b2700
    CrossrefPubMedGoogle Scholar
  • 8 DerSimonian R, Laird N. Meta-analysis in clinical trials revisited. Contemp Clin Trials 2015; 45 (A): 139-145
    CrossrefPubMedGoogle Scholar
  • 9 Schulman S, Kearon C, Kakkar AK. , et al; RE-COVER Study Group. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 2009; 361 (24) 2342-2352
    CrossrefPubMedGoogle Scholar
  • 10 Schulman S, Kakkar AK, Goldhaber SZ. , et al; RE-COVER II Trial Investigators. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation 2014; 129 (07) 764-772
    CrossrefPubMedGoogle Scholar
  • 11 Schulman S, Kearon C, Kakkar AK. , et al; RE-MEDY Trial Investigators; RE-SONATE Trial Investigators. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med 2013; 368 (08) 709-718
    CrossrefPubMedGoogle Scholar
  • 12 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
  • 13 Therapeutic Goods Administration (TGA). Australian public assessment report (AusPAR) on dabigatran etexilate. Published on February 11, 2016. https://www.tga.gov.au/auspar/auspar-dabigatran-etexilate . Accessed February 17, 2017
    PubMedGoogle Scholar
  • 14 Bauersachs R, Berkowitz SD, Brenner B. , et al; EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 2010; 363 (26) 2499-2510
    CrossrefPubMedGoogle Scholar
  • 15 Büller HR, Prins MH, Lensin AW. , et al; EINSTEIN–PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 2012; 366 (14) 1287-1297
    CrossrefPubMedGoogle Scholar
  • 16 Prins MH, Lensing AW, 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 randomized controlled trials. Lancet Haematol 2014; 1 (01) e37-e46
    PubMedGoogle Scholar
  • 17 Committee for Medicinal Products for Human Use (CHMP). Xarelto (rivaroxaban). Assessment report no. EMEA/H/C/000944/X/0010. Published on September 22, 2011. http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Assessment_Report_-_Variation/human/000944/WC500120736.pdf . Accessed February 10, 2017
    PubMedGoogle Scholar
  • 18 Canadian Agency for Drugs and Technologies in Health (CADTH). Rivaroxaban (Xarelto). Treatment of Venous Thromboembolic Events (Deep Vein Thrombosis [DVT], Pulmonary Embolism [PE]) and Prevention of Recurrent DVT and PE. Common Drug Review. 2015. https://www.ncbi.nlm.nih.gov/books/NBK344331/ . Accessed February 17, 2017
    PubMedGoogle Scholar
  • 19 Agnelli G, Buller HR, Cohen A. , et al; AMPLIFY Investigators. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med 2013; 369 (09) 799-808
    CrossrefPubMedGoogle Scholar
  • 20 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
  • 21 Committee for Medicinal Products for Human Use (CHMP). Eliquis (apixaban). Assessment report no. EMEA/H/C/002148/II/0014/G. Published on June 26, 2014 http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Assessment_Report_-_Variation/human/002148/WC500173870.pdf . Accessed February 10, 2017
    PubMedGoogle Scholar
  • 22 Büller HR, Décousus H, Grosso MA. , et al; Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med 2013; 369 (15) 1406-1415
    CrossrefPubMedGoogle Scholar
  • 23 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
  • 24 Committee for Medicinal Products for Human Use (CHMP). Lixiana (edoxaban). Assessment report no. EMEA/H/C/002629/0000. Published on July 3, 2015 http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Public_assessment_report/human/002629/WC500189047.pdf . Accessed February 10, 2017
    PubMed
  • 25 Chai-Adisaksopha C, Hillis C, Isayama T, Lim W, Iorio A, Crowther M. Mortality outcomes in patients receiving direct oral anticoagulants: a systematic review and meta-analysis of randomized controlled trials. J Thromb Haemost 2015; 13 (11) 2012-2020
    CrossrefPubMedGoogle Scholar
  • 26 Spirk D, Husmann M, Hayoz D. , et al. Predictors of in-hospital mortality in elderly patients with acute venous thrombo-embolism: the SWIss Venous ThromboEmbolism Registry (SWIVTER). Eur Heart J 2012; 33 (07) 921-926
    CrossrefPubMedGoogle Scholar
  • 27 Khan F, Vaillancourt C, Carrier M. Should we screen extensively for cancer after unprovoked venous thrombosis?. BMJ 2017; 356: j1081
    PubMedGoogle Scholar
  • 28 Jiménez D, de Miguel-Díez J, Guijarro R. , et al; RIETE Investigators. Trends in the management and outcomes of acute pulmonary embolism: analysis from the RIETE Registry. J Am Coll Cardiol 2016; 67 (02) 162-170
    CrossrefPubMedGoogle Scholar
  • 29 Fermann GJ, Erkens PM, Prins MH, Wells PS, Pap ÁF, Lensing AW. Treatment of pulmonary embolism with rivaroxaban: outcomes by simplified Pulmonary Embolism Severity Index score from a post hoc analysis of the EINSTEIN PE study. Acad Emerg Med 2015; 22 (03) 299-307
    CrossrefPubMedGoogle Scholar
  • 30 Faller N, Limacher A, Méan M. , et al. Predictors and causes of long-term mortality in elderly patients with acute venous thromboembolism: a prospective cohort study. Am J Med 2017; 130 (02) 198-206
    CrossrefPubMedGoogle Scholar
  • 31 Piepoli MF, Hoes AW, Agewall S. , et al; Authors/Task Force Members. 2016 European Guidelines on cardiovascular disease prevention in clinical practice: The Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts) Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Eur Heart J 2016; 37 (29) 2315-2381
    CrossrefPubMedGoogle Scholar
  • 32 Fox CS, Golden SH, Anderson C. , et al; American Heart Association Diabetes Committee of the Council on Lifestyle and Cardiometabolic Health, Council on Clinical Cardiology, Council on Cardiovascular and Stroke Nursing, Council on Cardiovascular Surgery and Anesthesia, Council on Quality of Care and Outcomes Research, and the American Diabetes Association. Update on prevention of cardiovascular disease in adults with type 2 diabetes mellitus in light of recent evidence: a scientific statement from the American Heart Association and the American Diabetes Association. Circulation 2015; 132 (08) 691-718
    CrossrefPubMedGoogle Scholar
  • 33 Gómez-Outes A, Lagunar-Ruíz J, Terleira-Fernández AI, Calvo-Rojas G, Suárez-Gea ML, Vargas-Castrillón E. Causes of death in anticoagulated patients with atrial fibrillation. J Am Coll Cardiol 2016; 68 (23) 2508-2521
    CrossrefPubMedGoogle Scholar
  • 34 Girard P, Penaloza A, Parent F. , et al. Reproducibility of clinical events adjudications in a trial of venous thromboembolism prevention. J Thromb Haemost 2017; 15 (04) 662-669
    CrossrefPubMedGoogle Scholar
  • 35 Mahé I, Chidiac J, Bertoletti L. , et al; RIETE investigators. The clinical course of venous thromboembolism may differ according to cancer site. Am J Med 2017; 130 (03) 337-347
    CrossrefPubMedGoogle Scholar
  • 36 Cohen AT, Imfeld S, Rider T. Phase III trials of new oral anticoagulants in the acute treatment and secondary prevention of VTE: comparison and critique of study methodology and results. Adv Ther 2014; 31 (05) 473-493
    CrossrefPubMedGoogle Scholar