Download PDF
Thromb Haemost 2018; 118(05): 842-851
DOI: 10.1055/s-0038-1636541
Coagulation and Fibrinolysis
Schattauer GmbH Stuttgart

Prothrombin Complex Concentrate for Major Bleeding on Factor Xa Inhibitors: A Prospective Cohort Study

Sam Schulman
1   Department of Medicine, McMaster University and Thrombosis and Atherosclerosis Research Institute, Hamilton, Ontario, Canada
2   Department of Hematology, Karolinska Institutet, Stockholm, Sweden
,
Peter L. Gross
1   Department of Medicine, McMaster University and Thrombosis and Atherosclerosis Research Institute, Hamilton, Ontario, Canada
,
Bruce Ritchie
3   Department of Medicine, University of Alberta, Edmonton, Alberta, Canada
,
Susan Nahirniak
4   Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada
,
Yulia Lin
5   Department of Clinical Pathology, Sunnybrook Health Sciences Centre, University of Toronto, Ontario, Canada
,
Lani Lieberman
6   Department of Laboratory Medicine and Pathobiology, University of Toronto, Ontario, Canada
,
Marc Carrier
7   Department of Clinical Pathology, University Health Network, University of Toronto, Toronto, Ontario, Canada
,
Mark A. Crowther
1   Department of Medicine, McMaster University and Thrombosis and Atherosclerosis Research Institute, Hamilton, Ontario, Canada
,
Indy Ghosh
8   Department of Medicine, The Ottawa Hospital Research Institute at the University of Ottawa, Ottawa, Ontario, Canada
,
Alejandro Lazo-Langner
9   Department of Emergency Medicine, Trillium Hospital, Mississauga, Ontario, Canada
,
Michelle Zondag
10   Department of Medicine, Western University, London, Ontario, Canada
,
On Behalf of the Study Investigators › Author Affiliations
Further Information

Publication History

16 October 2017

11 January 2018

Publication Date:
21 March 2018 (online)

   Permissions and Reprints

Corrected by:

Erratum to: Prothrombin Complex Concentrate for Major Bleeding on Factor Xa Inhibitors: A Prospective Cohort StudyThromb Haemost 2018; 118(12): 2188-2188
DOI: 10.1055/s-0038-1675417

Abstract

Oral factor Xa inhibitors are increasingly used for anticoagulation, but there is no approved reversal agent. Prothrombin complex concentrate (PCC) for the management of Xa-inhibitor–associated bleeding has been described in small case series and one cohort study. Patients on apixaban or rivaroxaban, suffering a major bleed, were treated at nine Canadian hospitals as per existing hospital protocol with a fixed dose of PCC 2,000 units and subsequently recruited for a 30-day follow-up. The treating physician evaluated the haemostatic effectiveness as observed during the first day as good, moderate or poor/none, using an assessment guide. Safety outcomes were thromboembolism or death. We recruited 66 patients with major bleeding who were treated with PCC and who were receiving rivaroxaban (56%) or apixaban (44%). The effectiveness was assessed as good in 65% (95% confidence interval [CI], 53–77), moderate in 20% (95% CI, 10–30) and poor/none in 15% (95% CI, 6–24). For the 36 patients with intracranial haemorrhage, the corresponding ratings were 67, 17 and 17%, and for 16 patients with gastrointestinal bleeding they were 69, 12 and 19%, respectively. There were nine deaths (14%) by 30 days, and five (8%) major thromboembolic events. In a post hoc analysis, according to International Society on Thrombosis and Haemostasis criteria, reversal was effective in 68% and ineffective in 32%. For major bleeding associated with oral Xa inhibitors, PCC may have a beneficial effect. The risk of thromboembolism after reversal of anticoagulation in patients with a prothrombotic background has to be taken into account.

Keywords

antagonists and inhibitors - haemorrhage - atrial fibrillation - rivaroxaban - apixaban

Authors' Contribution

S. Schulman, B. Ritchie and M. Carrier conceived and designed the study; S. Schulman analysed and interpreted the data; all authors provided study patients, collected data, wrote and gave final approval of the manuscript.


* The investigators are listed in Appendix A.


 

  • References

  • 1 Connolly SJ, Eikelboom J, Joyner C. , et al; AVERROES Steering Committee and Investigators. Apixaban in patients with atrial fibrillation. N Engl J Med 2011; 364 (09) 806-817
    CrossrefPubMedGoogle Scholar
  • 2 Giugliano RP, Ruff CT, Braunwald E. , et al; ENGAGE AF-TIMI 48 Investigators. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2013; 369 (22) 2093-2104
    CrossrefPubMedGoogle Scholar
  • 3 Patel MR, Mahaffey KW, Garg J. , et al; ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365 (10) 883-891
    CrossrefPubMedGoogle Scholar
  • 4 Piccini JP, Garg J, Patel MR. , et al; ROCKET AF Investigators. Management of major bleeding events in patients treated with rivaroxaban vs. warfarin: results from the ROCKET AF trial. Eur Heart J 2014; 35 (28) 1873-1880
    CrossrefPubMedGoogle Scholar
  • 5 Chai-Adisaksopha C, Crowther M, Isayama T, Lim W. The impact of bleeding complications in patients receiving target-specific oral anticoagulants: a systematic review and meta-analysis. Blood 2014; 124 (15) 2450-2458
    CrossrefPubMedGoogle Scholar
  • 6 Hylek EM, Held C, Alexander JH. , et al. Major bleeding in patients with atrial fibrillation receiving apixaban or warfarin: The ARISTOTLE Trial (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation): Predictors, Characteristics, and Clinical Outcomes. J Am Coll Cardiol 2014; 63 (20) 2141-2147
    CrossrefPubMedGoogle Scholar
  • 7 Eerenberg ES, Middeldorp S, Levi M, Lensing AW, Büller HR. Clinical impact and course of major bleeding with rivaroxaban and vitamin K antagonists. J Thromb Haemost 2015; 13 (09) 1590-1596
    CrossrefPubMedGoogle Scholar
  • 8 Connolly SJ, Milling Jr TJ, Eikelboom JW. , et al; ANNEXA-4 Investigators. Andexanet alfa for acute major bleeding associated with factor Xa inhibitors. N Engl J Med 2016; 375 (12) 1131-1141
    CrossrefPubMedGoogle Scholar
  • 9 Goldstein JN, Refaai MA, Milling Jr TJ. , 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 (9982): 2077-2087
    CrossrefPubMedGoogle Scholar
  • 10 Cheung YW, Barco S, Hutten BA, Meijers JC, Middeldorp S, Coppens M. In vivo increase in thrombin generation by four-factor prothrombin complex concentrate in apixaban-treated healthy volunteers. J Thromb Haemost 2015; 13 (10) 1799-1805
    CrossrefPubMedGoogle Scholar
  • 11 Eerenberg ES, Kamphuisen PW, Sijpkens MK, Meijers JC, Buller HR, Levi M. Reversal of rivaroxaban and dabigatran by prothrombin complex concentrate: a randomized, placebo-controlled, crossover study in healthy subjects. Circulation 2011; 124 (14) 1573-1579
    CrossrefPubMedGoogle Scholar
  • 12 Zahir H, Brown KS, Vandell AG. , et al. Edoxaban effects on bleeding following punch biopsy and reversal by a 4-factor prothrombin complex concentrate. Circulation 2015; 131 (01) 82-90
    CrossrefPubMedGoogle Scholar
  • 13 Grandhi R, Newman WC, Zhang X. , et al. Administration of 4-factor prothrombin complex concentrate as an antidote for intracranial bleeding in patients taking direct factor Xa inhibitors. World Neurosurg 2015; 84 (06) 1956-1961
    CrossrefPubMedGoogle Scholar
  • 14 Majeed A, Ågren A, Holmström M. , et al. Management of rivaroxaban- or apixaban-associated major bleeding with prothrombin complex concentrates: a cohort study. Blood 2017; 130 (15) 1706-1712
    CrossrefPubMedGoogle Scholar
  • 15 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
  • 16 Sarode R, Milling Jr TJ, Refaai MA. , 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 (11) 1234-1243
    CrossrefPubMedGoogle Scholar
  • 17 Broderick JP, Brott TG, Duldner JE, Tomsick T, Huster G. Volume of intracerebral hemorrhage. A powerful and easy-to-use predictor of 30-day mortality. Stroke 1993; 24 (07) 987-993
    CrossrefPubMedGoogle Scholar
  • 18 Khorsand N, Majeed A, Sarode R, Beyer-Westendorf J, Schulman S, Meijer K. ; Subcommittee on Control of Anticoagulation. Assessment of effectiveness of major bleeding management: proposed definitions for effective hemostasis: communication from the SSC of the ISTH. J Thromb Haemost 2016; 14 (01) 211-214
    CrossrefPubMedGoogle Scholar
  • 19 Marlu R, Hodaj E, Paris A, Albaladejo P, Cracowski JL, Pernod G. Effect of non-specific reversal agents on anticoagulant activity of dabigatran and rivaroxaban: a randomised crossover ex vivo study in healthy volunteers. Thromb Haemost 2012; 108 (02) 217-224
    Article in Thieme ConnectPubMedGoogle Scholar
  • 20 Kubitza D, Becka M, Zuehlsdorf M, Mueck W. Body weight has limited influence on the safety, tolerability, pharmacokinetics, or pharmacodynamics of rivaroxaban (BAY 59-7939) in healthy subjects. J Clin Pharmacol 2007; 47 (02) 218-226
    CrossrefPubMedGoogle Scholar
  • 21 Mueck W, Lensing AW, Agnelli G, Decousus H, Prandoni P, Misselwitz F. Rivaroxaban: population pharmacokinetic analyses in patients treated for acute deep-vein thrombosis and exposure simulations in patients with atrial fibrillation treated for stroke prevention. Clin Pharmacokinet 2011; 50 (10) 675-686
    CrossrefPubMedGoogle Scholar
  • 22 Upreti VV, Wang J, Barrett YC. , et al. Effect of extremes of body weight on the pharmacokinetics, pharmacodynamics, safety and tolerability of apixaban in healthy subjects. Br J Clin Pharmacol 2013; 76 (06) 908-916
    CrossrefPubMedGoogle Scholar
  • 23 Yin OQ, Tetsuya K, Miller R. Edoxaban population pharmacokinetics and exposure-response analysis in patients with non-valvular atrial fibrillation. Eur J Clin Pharmacol 2014; 70 (11) 1339-1351
    CrossrefPubMedGoogle Scholar
  • 24 Barco S, Whitney Cheung Y, Coppens M, Hutten BA, Meijers JC, Middeldorp S. In vivo reversal of the anticoagulant effect of rivaroxaban with four-factor prothrombin complex concentrate. Br J Haematol 2016; 172 (02) 255-261
    CrossrefPubMedGoogle Scholar
  • 25 Liotta EM, Garg RK, Temes RE. , et al. Warfarin-associated intracerebral hemorrhage is inadequately treated at community emergency departments. Stroke 2012; 43 (09) 2503-2505
    CrossrefPubMedGoogle Scholar
  • 26 Pollack Jr CV, Reilly PA, Eikelboom J. , et al. Idarucizumab for dabigatran reversal. N Engl J Med 2015; 373 (06) 511-520
    CrossrefPubMedGoogle Scholar