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Direct oral anticoagulants for the treatment of venous thromboembolism in patients with active malignancy: a systematic review and meta-analysis

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A Correction to this article was published on 26 November 2018

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Abstract

Low molecular weight heparins (LMWHs) are considered the standard of care for the treatment of venous thromboembolism (VTE) associated with cancer. We conducted a meta-analysis to evaluate the safety and efficacy of direct oral anticoagulants (DOACs) in patients with cancer. We systematically searched Medline for potential randomized-control clinical trials (RCTs) and post-hoc analyses. For each study, data on recurrent VTE, major or clinically relevant non-major bleeding (CRNMB), and major bleeding (MB) were extracted. Initially, a total of 1395 citations were identified. Eight studies met our eligibility criteria. The utilization of DOACs in patients with cancer showed a statistically significant reduction in the risk of VTE recurrence compared to LMWH or warfarin (RR = 0.64; 95% CI 0.46–0.88). Similar rates of major or CRNMB were observed between DOACs and LMWH or warfarin (RR = 1.00; 95% CI 0.75–1.33). There was no significant difference in the rate of MB between DOACs and LMWH or warfarin (RR = 1.31; 95% CI 0.71–2.44). Our results suggest that DOACs might reduce the incidence of VTE recurrence in patients with cancer without putting them at high risk for MB/CRNMB or MB. Our findings were mainly driven by the results of the Hokusai VTE Cancer trial. Given the level of investigated evidence, our findings should be interpreted with caution since the majority of the data were originated from sub-group analyses of large (RCTs). Future studies that are adequately powered are warranted to assess efficacy and safety data of DOACs for the treatment of VTE in patients with different types of cancer.

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Change history

  • 26 November 2018

    Unfortunately the author list in the original article is incomplete. The correct list of contributing authors is given in this Correction.

  • 26 November 2018

    Unfortunately the author list in the original article is incomplete. The correct list of contributing authors is given in this Correction.

  • 26 November 2018

    Unfortunately the author list in the original article is incomplete. The correct list of contributing authors is given in this Correction.

References

  1. Beckman MG, Hooper WC, Critchley SE, Ortel TL (2010) Venous thromboembolism: a public health concern. Am J Prev Med 38(4):S495–S501

    Article  Google Scholar 

  2. Huang W, Goldberg RJ, Anderson FA, Kiefe CI, Spencer FA (2014) Secular trends in occurrence of acute venous thromboembolism: the Worcester VTE study (1985–2009). Am J Med 127(9):829–839. e825

    Article  Google Scholar 

  3. Heit JA, Silverstein MD, Mohr DN, Petterson TM, O’fallon WM, Melton LJ (2000) Risk factors for deep vein thrombosis and pulmonary embolism: a population-based case-control study. Arch Intern Med 160(6):809–815

    Article  CAS  Google Scholar 

  4. Chee CE, Ashrani AA, Marks RS, Petterson TM, Bailey KR, Melton LJ, Heit JA (2014) Predictors of venous thromboembolism recurrence and bleeding among active cancer patients: a population-based cohort study. Blood 123(25):3972–3978

    Article  CAS  Google Scholar 

  5. Lee AY, Levine MN, Baker RI, Bowden C, Kakkar AK, Prins M, Rickles FR, Julian JA, Haley S, Kovacs MJ (2003) Low-molecular-weight heparin versus a coumarin for the prevention of recurrent venous thromboembolism in patients with cancer. N Engl J Med 349(2):146–153

    Article  CAS  Google Scholar 

  6. Kearon C, Akl EA, Ornelas J, Blaivas A, Jimenez D, Bounameaux H, Huisman M, King CS, Morris TA, Sood N (2016) Antithrombotic therapy for VTE disease: CHEST guideline and expert panel report. Chest 149(2):315–352

    Article  Google Scholar 

  7. Schulman S, Kearon C, Kakkar AK, Mismetti P, Schellong S, Eriksson H, Baanstra D, Schnee J, Goldhaber SZ (2009) Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med 361(24):2342–2352

    Article  CAS  Google Scholar 

  8. Investigators E (2010) Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med 363(26):2499–2510

    Article  Google Scholar 

  9. Investigators EP (2012) Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med 366(14):1287–1297

    Article  Google Scholar 

  10. Investigators H-V (2013) Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med 369(15):1406–1415

    Article  Google Scholar 

  11. Schulman S, Kearon C, Kakkar AK, Schellong S, Eriksson H, Baanstra D, Kvamme AM, Friedman J, Mismetti P, Goldhaber SZ (2013) Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med 368(8):709–718

    Article  CAS  Google Scholar 

  12. Agnelli G, Buller H, Cohen A, Gallus A, Lee T, Pak R, Raskob G, Weitz J, Yamabe T (2015) Oral apixaban for the treatment of venous thromboembolism in cancer patients: results from the AMPLIFY trial. J Thromb Haemost 13(12):2187–2191

    Article  CAS  Google Scholar 

  13. Raskob GE, van Es N, Segers A, Angchaisuksiri P, Oh D, Boda Z, Lyons RM, Meijer K, Gudz I, Weitz JI (2016) 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 3(8):e379–e387

    Article  Google Scholar 

  14. Raskob GE, van Es N, Verhamme P, Carrier M, Di Nisio M, Garcia D, Grosso MA, Kakkar AK, Kovacs MJ, Mercuri MF, Meyer G, Segers A, Shi M, Wang TF, Yeo E, Zhang G, Zwicker JI, Weitz JI, Büller HR, Hokusai VTE Cancer Investigators (2018) Edoxaban for the treatment of cancer-associated venous thromboembolism. N Engl J Med 378:615–624. https://doi.org/10.1056/NEJMoa1711948

    Article  CAS  PubMed  Google Scholar 

  15. Schulman S, Kakkar AK, Goldhaber SZ, Schellong S, Eriksson H, Mismetti P, Christiansen AV, Friedman J, Le Maulf F, Peter N (2014) Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation 129:764–772. https://doi.org/10.1161/CIRCULATIONAHA.113.004450

    Article  CAS  PubMed  Google Scholar 

  16. Eriksson H, Goldhaber SZ, Kakkar A, Kearon C, Schellong SM, Feuring M, Peter N, Friedman J (2013) Influence of active cancer on the efficacy and safety of dabigatran versus warfarin for the treatment of acute venous thromboembolism: a pooled analysis from RE-Cover and RE-Cover II. Blood 122(21):582

    Google Scholar 

  17. Streiff MB, Milentijevic D, McCrae K, Yannicelli D, Fortier J, Nelson WW, Laliberté F, Crivera C, Lefebvre P, Schein J (2018) Effectiveness and safety of anticoagulants for the treatment of venous thromboembolism in patients with cancer. Am J Hematol 93(5):664–671

    Article  CAS  Google Scholar 

  18. Brunetti ND, Gesuete E, De Gennaro L, Correale M, Caldarola P, Gaglione A, Di Biase M (2017) Direct oral anti-coagulants compared with vitamin-K inhibitors and low-molecular-weight-heparin for the prevention of venous thromboembolism in patients with cancer: a meta-analysis study. Int J Cardiol 230:214–221

    Article  Google Scholar 

  19. Hulle T, Exter P, Kooiman J, Hoeven J, Huisman M, Klok F (2014) Meta-analysis of the efficacy and safety of new oral anticoagulants in patients with cancer-associated acute venous thromboembolism. J Thromb Haemost 12(7):1116–1120

    Article  Google Scholar 

  20. Jun M, Lix LM, Durand M, Dahl M, Paterson JM, Dormuth CR, Ernst P, Yao S, Renoux C, Tamim H (2017) Comparative safety of direct oral anticoagulants and warfarin in venous thromboembolism: multicentre, population based, observational study. bmj 359:j4323

    Article  Google Scholar 

  21. Young A, Marshall A, Thirlwall J, Hill C, Hale D, Dunn J, Lokare A, Kakkar AK, Levine MN, Chapman O (2017) Anticoagulation therapy in selected cancer patients at risk of recurrence of venous thromboembolism: results of the Select-D™ pilot trial. Blood 130:625

    Article  Google Scholar 

  22. Khorana AA, McCrae KR, Milentijevic D, Fortier J, Nelson WW, Laliberté F, Crivera C, Lefebvre P, Yannicelli D, Schein J (2017) Current practice patterns and patient persistence with anticoagulant treatments for cancer-associated thrombosis. Res Pract Thromb Haemost 1(1):14–22

    Article  CAS  Google Scholar 

  23. Prins MH, Lensing AW, Brighton TA, Lyons RM, Rehm J, Trajanovic M, Davidson BL, Beyer-Westendorf J, Pap ÁF, Berkowitz SD (2014) 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 1(1):e37–e46

    Article  Google Scholar 

  24. Guntupalli S, Brennecke A, Sheeder J, Babayan L, Cheng G, Behbakht K, Corr B, Lefkowits C, Matsuo K, Flink D (2017) A multiinstitutional, prospective randomized open-blinded end-point trial for safety of oral apixaban versus subcutaneous enoxaparin for thromboprophylaxis in women with suspected gynecologic malignancy. Gynecol Oncol 145:221

    Article  Google Scholar 

  25. AIO-Studien-gGmbH Rivaroxaban in the treatment of venous thromboembolism (VTE) in cancer patients. https://clinicaltrials.gov/ct2/show/NCT02583191?id=NCT02583191&rank=1&load=cart. Accessed 4 June 2018

  26. Brekelmans M, Kappelhof M, Nieuwkerk P, Nierman M, Buller H, Coppens M (2017) Preference for direct oral anticoagulants in patients treated with vitamin K antagonists for venous thromboembolism. Neth J Med 75(02):50–55

    CAS  PubMed  Google Scholar 

  27. Keita I, Aubin-Auger I, Lalanne C, Aubert J-P, Chassany O, Duracinsky M, Mahé I (2017) Assessment of quality of life, satisfaction with anticoagulation therapy, and adherence to treatment in patients receiving long-course vitamin K antagonists or direct oral anticoagulants for venous thromboembolism. Patient Prefer Adher 11:1625

    Article  Google Scholar 

  28. McBane IIR, Loprinzi CL, Ashrani A, Botero JP, Ferre RAL, Henkin S, Lenz CJ, Le-Rademacher JG, Wysokinski WE (2017) Apixaban and dalteparin in active malignancy associated venous thromboembolism. Thromb Haemost 117(10):1952–1961

    Article  Google Scholar 

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Authors and Affiliations

  1. Department of Pharmacy Practice, College of Pharmacy, King Saud bin Abdulaziz University for Health Sciences, P.O Box 3660, Riyadh, 11426, Saudi Arabia

    Majed S. Al Yami, Hisham A. Badreldin, Abdelhameed H. Mohammed, Ahmed M. Elmubark, Mohammed Y. Alzahrani & Abdulmajeed M. Alshehri

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  1. Majed S. Al Yami
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  2. Hisham A. Badreldin
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  3. Abdelhameed H. Mohammed
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  4. Ahmed M. Elmubark
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  5. Mohammed Y. Alzahrani
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  6. Abdulmajeed M. Alshehri
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Correspondence to Majed S. Al Yami.

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Al Yami, M.S., Badreldin, H.A., Mohammed, A.H. et al. Direct oral anticoagulants for the treatment of venous thromboembolism in patients with active malignancy: a systematic review and meta-analysis. J Thromb Thrombolysis 46, 145–153 (2018). https://doi.org/10.1007/s11239-018-1696-0

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