Advertisement

International Journal of Hematology

, Volume 106, Issue 6, pp 777–786 | Cite as

Efficacy and safety of a 4-factor prothrombin complex concentrate for rapid vitamin K antagonist reversal in Japanese patients presenting with major bleeding or requiring urgent surgical or invasive procedures: a prospective, open-label, single-arm phase 3b study

  • Shigeki Kushimoto
  • Toshio Fukuoka
  • Akio Kimura
  • Kazunori Toyoda
  • Andres Brainsky
  • Amy Harman
  • Thomas Chung
  • Masahiro Yasaka
Original Article
  • 635 Downloads

Abstract

Rapid vitamin K antagonist (VKA) reversal is required in patients experiencing major bleeding or requiring urgent surgery. Four-factor prothrombin complex concentrate (4F-PCC; Beriplex®/Kcentra®) was shown in two large randomized controlled, international phase 3b trials to be an effective alternative to plasma for urgent VKA reversal. In the present prospective, open-label, single-arm phase 3b trial, we evaluate the efficacy and safety of 4F-PCC in Japanese patients. Eleven patients [international normalized ratio (INR) ≥2] requiring rapid VKA reversal owing to major bleeding (n = 6) or before urgent surgical/invasive procedures (n = 5) were administered 4F-PCC dosed based on INR and weight. INR reduction (≤1.3 0.5 h postinfusion; primary endpoint) was achieved in 81.8% of patients (major bleeding, 83.3%; surgical/invasive procedures, 80.0%). Effective hemostasis (main secondary endpoint) was met in 60.0% (major bleeding) and 100% (surgical/invasive procedure) of evaluable patients. Adverse events (AEs) and serious AEs were reported in 90.9 and 45.5% of patients, respectively. Two AEs were considered treatment-related; thromboembolic events rated mild and not clinically relevant by investigators. There were no deaths, fluid overload events, or viral transmission cases. Consistent with the previous results, 4F-PCC may be an effective and well-tolerated treatment for rapid VKA reversal in Japanese patients experiencing major bleeding or requiring urgent surgical/invasive procedures.

Keywords

Anticoagulant Hemorrhage Prothrombin complex concentrate Surgery Vitamin K antagonist 

Notes

Acknowledgements

This study was sponsored by CSL Behring. Medical writing assistance was provided by Leanne Regan of Fishawack Communications Ltd., funded by the sponsor.

Compliance with ethical standards

Conflict of interest

AB, AH, and TC are employees of CSL Behring. SK is on an advisory board for CSL Behring. TF, AK, KT, and MY declare that they have no conflicts of interest.

Ethical approval

The study was approved by the Independent Ethics Committees of the participating centers and performed in accordance with local ethical and legal requirements. Written informed consent was obtained from all patients or their legally authorized representatives.

Supplementary material

12185_2017_2311_MOESM1_ESM.doc (40 kb)
Supplementary material 1 (DOC 40 kb)
12185_2017_2311_MOESM2_ESM.doc (30 kb)
Supplementary material 2 (DOC 30 kb)

References

  1. 1.
    Toyoda K, Arihiro S, Todo K, Yamagami H, Kimura K, Furui E, et al. Trends in oral anticoagulant choice for acute stroke patients with nonvalvular atrial fibrillation in Japan: the SAMURAI-NVAF study. Int J Stroke. 2015;10:836–42.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    IMS data Global Prescription Audit; MAT (moving annual total) 2014/15 to 2015/16.Google Scholar
  3. 3.
    Inoue H, Fujiki A, Origasa H, Ogawa S, Okumura K, Kubota I, et al. Prevalence of atrial fibrillation in the general population of Japan: an analysis based on periodic health examination. Int J Cardiol. 2009;137:102–7.CrossRefPubMedGoogle Scholar
  4. 4.
    Go AS, Hylek EM, Phillips KA, Chang Y, Henault LE, Selby JV, et al. Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. JAMA. 2001;285:2370–5.CrossRefPubMedGoogle Scholar
  5. 5.
    Miyasaka Y, Barnes ME, Gersh BJ, Cha SS, Bailey KR, Abhayaratna WP, et al. Secular trends in incidence of atrial fibrillation in Olmsted County, Minnesota, 1980 to 2000, and implications on the projections for future prevalence. Circulation. 2006;114:119–25.CrossRefPubMedGoogle Scholar
  6. 6.
    Schulman S, Beyth RJ, Kearon C, Levine MN. Hemorrhagic complications of anticoagulant and thrombolytic treatment: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines (8th Edition). Chest. 2008;133:257S–98S.CrossRefPubMedGoogle Scholar
  7. 7.
    Palareti G, Leali N, Coccheri S, Poggi M, Manotti C, D’Angelo A, et al. Bleeding complications of oral anticoagulant treatment: an inception-cohort, prospective collaborative study (ISCOAT). Italian Study on Complications of Oral Anticoagulant Therapy. Lancet. 1996;348:423–8.CrossRefPubMedGoogle Scholar
  8. 8.
    Yamaguchi T. Optimal intensity of warfarin therapy for secondary prevention of stroke in patients with nonvalvular atrial fibrillation: a multicenter, prospective, randomized trial. Japanese Nonvalvular Atrial Fibrillation-Embolism Secondary Prevention Cooperative Study Group. Stroke. 2000;31:817–21.CrossRefPubMedGoogle Scholar
  9. 9.
    Moriyasu H, Yasaka M, Oita J, Yamaguchi T. Warfarin therapy for secondary prevention of cardioembolic stroke with nonvalvular atrial fibrillation–a retrospective study. Rinsho Shinkeigaku. 1993;33:850–5.PubMedGoogle Scholar
  10. 10.
    Shen AY, Yao JF, Brar SS, Jorgensen MB, Chen W. Racial/ethnic differences in the risk of intracranial hemorrhage among patients with atrial fibrillation. J Am Coll Cardiol. 2007;50:309–15.CrossRefPubMedGoogle Scholar
  11. 11.
    Toyoda K. Pharmacotherapy for the secondary prevention of stroke. Drugs. 2009;69:633–47.CrossRefPubMedGoogle Scholar
  12. 12.
    van Asch CJ, Luitse MJ, Rinkel GJ, van der Tweel I, Algra A, Klijn CJ. Incidence, case fatality, and functional outcome of intracerebral haemorrhage over time, according to age, sex, and ethnic origin: a systematic review and meta-analysis. Lancet Neurol. 2010;9:167–76.CrossRefPubMedGoogle Scholar
  13. 13.
    Watson HG, Baglin T, Laidlaw SL, Makris M, Preston FE. A comparison of the efficacy and rate of response to oral and intravenous vitamin K in reversal of over-anticoagulation with warfarin. Br J Haematol. 2001;115:145–9.CrossRefPubMedGoogle Scholar
  14. 14.
    Ageno W, Gallus AS, Wittkowsky A, Crowther M, Hylek EM, Palareti G. Oral anticoagulant therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141:e44S–88S.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Holbrook A, Schulman S, Witt DM, Vandvik PO, Fish J, Kovacs MJ, et al. Evidence-based management of anticoagulant therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141:e152S–84S.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Rossaint R, Bouillon B, Cerny V, Coats TJ, Duranteau J, Fernandez-Mondejar E, et al. The European guideline on management of major bleeding and coagulopathy following trauma: fourth edition. Crit Care. 2016;20:100.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    JCS Joint Working Group. Guidelines for pharmacotherapy of atrial fibrillation (JCS 2013). Circ J. 2014;78:1997–2021.CrossRefGoogle Scholar
  18. 18.
    Shinohara Y, Yanagihara T, Abe K, Yoshimine T, Fujinaka T, Chuma T, et al. III. Intracerebral hemorrhage. J Stroke Cerebrovasc Dis. 2011;20:S74–99.CrossRefPubMedGoogle Scholar
  19. 19.
    Kuwashiro T, Yasaka M, Itabashi R, Nakagaki H, Miyashita F, Naritomi H, et al. Effect of prothrombin complex concentrate on hematoma enlargement and clinical outcome in patients with anticoagulant-associated intracerebral hemorrhage. Cerebrovasc Dis. 2011;31:170–6.CrossRefPubMedGoogle Scholar
  20. 20.
    Yasaka M, Oomura M, Ikeno K, Naritomi H, Minematsu K. Effect of prothrombin complex concentrate on INR and blood coagulation system in emergency patients treated with warfarin overdose. Ann Hematol. 2003;82:121–3.PubMedGoogle Scholar
  21. 21.
    Yasaka M, Sakata T, Naritomi H, Minematsu K. Optimal dose of prothrombin complex concentrate for acute reversal of oral anticoagulation. Thromb Res. 2005;115:455–9.CrossRefPubMedGoogle Scholar
  22. 22.
    Goldstein AH, Refaai MA, Milling TJ, Lewis B, Goldberg-Alberts R, Hug BA, et al. Four-factor prothrombin complex concentrate versus plasma for rapid vitamin K antagonist reversal in patients needing urgent surgical or invasive interventions: a phase 3b, open-label, non-inferiority, randomised trial. Lancet. 2015;385:2077–87.CrossRefPubMedGoogle Scholar
  23. 23.
    Sarode R, Milling TJ, Refaai MA, Mangione A, Schneider A, Durn BL, et al. Efficacy and safety of a 4-factor prothrombin complex concentrate in patients on vitamin k antagonists presenting with major bleeding: a randomized, plasma-controlled phase IIIb study. Circulation. 2013;128:1234–43.PubMedGoogle Scholar
  24. 24.
    CSL Behring. Kcentra® Highlights of Prescribing Information. http://labeling.cslbehring.com/PI/US/Kcentra/EN/Kcentra-Prescribing-Information.pdf. Accessed 2 June 2014.
  25. 25.
    Schulman S, Kearon C. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost. 2005;3:692–4.CrossRefPubMedGoogle Scholar
  26. 26.
    Keeling D, Baglin T, Tait C, Watson H, Perry D, Baglin C, et al. Guidelines on oral anticoagulation with warfarin—fourth edition. Br J Haematol. 2011;154:311–24.CrossRefPubMedGoogle Scholar
  27. 27.
    Maeda K, Koga M, Okada Y, Kimura K, Yamagami H, Okuda S, et al. Nationwide survey of neuro-specialists’ opinions on anticoagulant therapy after intracerebral hemorrhage in patients with atrial fibrillation. J Neurol Sci. 2012;312:82–5.CrossRefPubMedGoogle Scholar
  28. 28.
    Kohler M. Thrombogenicity of prothrombin complex concentrates. Thromb Res. 1999;95:S13–7.CrossRefPubMedGoogle Scholar
  29. 29.
    Dentali F, Marchesi C, Giorgi Pierfranceschi M, Crowther M, Garcia D, Hylek E, et al. Safety of prothrombin complex concentrates for rapid anticoagulation reversal of vitamin K antagonists. A meta-analysis. Thromb Haemost. 2011;106:429–38.CrossRefPubMedGoogle Scholar
  30. 30.
    Witt DM, Delate T, Garcia DA, Clark NP, Hylek EM, Ageno W, et al. Risk of thromboembolism, recurrent hemorrhage, and death after warfarin therapy interruption for gastrointestinal tract bleeding. Arch Intern Med. 2012;172:1484–91.CrossRefPubMedGoogle Scholar
  31. 31.
    Milling TJ Jr, Refaai MA, Goldstein JN, Schneider A, Omert L, Harman A, et al. Thromboembolic events after vitamin K antagonist reversal with 4-factor prothrombin complex concentrate: exploratory analyses of two randomized, plasma-controlled studies. Ann Emerg Med. 2016;67(96–105):e5.Google Scholar
  32. 32.
    Milling TJ Jr, Refaai MA, Sarode R, Lewis B, Mangione A, Durn BL, et al. Safety of a four-factor prothrombin complex concentrate versus plasma for vitamin K antagonist reversal: an integrated analysis of two phase IIIb clinical trials. Acad Emerg Med. 2016;23:466–75.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Hanke AA, Joch C, Gorlinger K. Long-term safety and efficacy of a pasteurized nanofiltrated prothrombin complex concentrate (Beriplex P/N): a pharmacovigilance study. Br J Anaesth. 2013;110:764–72.CrossRefPubMedGoogle Scholar

Copyright information

© The Japanese Society of Hematology 2017

Authors and Affiliations

  • Shigeki Kushimoto
    • 1
  • Toshio Fukuoka
    • 2
  • Akio Kimura
    • 3
  • Kazunori Toyoda
    • 4
  • Andres Brainsky
    • 5
  • Amy Harman
    • 5
  • Thomas Chung
    • 5
  • Masahiro Yasaka
    • 6
  1. 1.Division of Emergency and Critical Care MedicineTohoku University Graduate School of MedicineSendaiJapan
  2. 2.Kurashiki Central HospitalKurashikiJapan
  3. 3.Center Hospital, National Center for Global Health and MedicineTokyoJapan
  4. 4.Department of Cerebrovascular MedicineNational Cerebral and Cardiovascular CenterSuitaJapan
  5. 5.CSL BehringKing of PrussiaUSA
  6. 6.National Hospital Organization, Kyushu Medical CenterFukuokaJapan

Personalised recommendations