Download PDF
Thromb Haemost 2016; 116(02): 241-250
DOI: 10.1160/TH15-11-0910
Coagulation and Fibrinolysis
Schattauer GmbH

A randomised, double blind comparison of tecarfarin, a novel vitamin K antagonist, with warfarin

The EmbraceAC Trial
Richard P. Whitlock
1   Population Health Research Institute, McMaster University, Hamilton, Ontario, Canada
,
Christopher B. Fordyce
2   Duke Clinical Research Institute, Durham, North Carolina, USA
,
Mark G. Midei
3   Armetheon Incorporated, Milpitas, California, USA
,
Dave Ellis
4   Durect Corporation, Cupertino, California, USA
,
David Garcia
5   Division of Hematology, Department of Medicine, University of Washington, Seattle, Washington, USA
,
Jeffrey I. Weitz
6   Thrombosis and Atherosclerosis Research Institute and McMaster University, Hamilton, Ontario, Canada
,
Daniel M. Canafax
7   Theravance Biopharma, South San Francisco, California, USA
,
Detlef Albrecht
3   Armetheon Incorporated, Milpitas, California, USA
,
Peter G. Milner
3   Armetheon Incorporated, Milpitas, California, USA
› Author Affiliations Financial support: Funding for this study was provided entirely by ARYx Therapeutics, Inc, Fremont, CA, USA.
Further Information

Publication History

Received: 30 November 2015

Accepted after major revision: 05 April 2016

Publication Date:
09 November 2017 (online)

    Permissions and Reprints

Summary

Tecarfarin is a novel vitamin K antagonist that is metabolised by carboxyl estererase, thereby eliminating the variability associated with cytochrome-mediated metabolism. EmbraceAC was designed to compare the quality of anticoagulation with tecarfarin and warfarin as determined by time in therapeutic range (TTR). In this phase 2/3 randomised and blinded trial, 607 patients with indications for chronic anticoagulation were assigned to warfarin (n=304) or tecarfarin (n=303). Dosing of study drugs was managed by a centralised dose control centre, which had access to genotyping. The primary analysis tested superiority of tecarfarin over warfarin for TTR. Patients were recruited between May 12, 2008 and May 12, 2009. TTR with tecarfarin and warfarin were similar (72.3% and 71.5%, respectively; p=0.51). In those taking CYP2C9 interacting drugs, the TTR on tecarfarin (n=92) was similar to that on warfarin (n=87, 72.2% and 69.9%, respectively; p=0.15). In patients with mechanical heart valves, the TTR of tecarfarin (n=42) was similar to that of warfarin (n=42, 68.4% and 66.3%, respectively; p=0.51). The same was true for the TTR in patients with any CYP2C9 variant allele and on CYP2C9-interacting drugs (tecarfarin, n=24, 76.5% vs warfarin, n=31, 69.5%; p=0.09). There was no difference in thromboembolic or bleeding events. In conclusion, superiority of tecarfarin over warfarin for TTR was not demonstrated. The TTR with tecarfarin was similar to that with well-controlled warfarin and tecarfarin appeared to be safe and well tolerated with few major bleeding and no thrombotic events. Favourable trends in certain subpopulations make tecarfarin a promising oral anticoagulant that deserves further study.

Supplementary Material to this article is available online at www.thrombosis-online.com.

Keywords

Anticoagulation - warfarin - tecarfarin - CYP2C9

 

  • References

  • 1 Pirmohamed M. et al. A randomised trial of genotype-guided dosing of warfarin. N Engl J Med 2013; 369: 2294-2303.
    CrossrefPubMedGoogle Scholar
  • 2 Budnitz DS. et al. Emergency hospitalisations for adverse drug events in older Americans. N Engl J Med 2011; 365: 2002-2012.
    CrossrefPubMedGoogle Scholar
  • 3 Ageno W. et al. Oral anticoagulant therapy: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest 2012; 141 (Suppl. 02) e44S-88S.
    CrossrefPubMedGoogle Scholar
  • 4 Cannegieter SC. et al. Optimal oral anticoagulant therapy in patients with mechanical heart valves. N Engl J Med 1995; 333: 11-17.
    CrossrefPubMedGoogle Scholar
  • 5 Currie CJ. et al. Evaluation of survival and ischaemic and thromboembolic event rates in patients with non-valvar atrial fibrillation in the general population when treated and untreated with warfarin. Heart 2006; 92: 196-200.
    CrossrefPubMedGoogle Scholar
  • 6 Rose AJ. et al. Risk-adjusted percent time in therapeutic range as a quality indicator for outpatient oral anticoagulation: results of the Veterans Affairs Study to Improve Anticoagulation (VARIA). Circ Cardiovasc Qual Outcomes 2011; 4: 22-29.
    CrossrefPubMedGoogle Scholar
  • 7 White HD. et al. Comparison of outcomes among patients randomised to warfarin therapy according to anticoagulant control: results from SPORTIF III and V. Arch Intern Med 2007; 167: 239-245.
    CrossrefPubMedGoogle Scholar
  • 8 Sanderson S. et al. CYP2C9 gene variants, drug dose, and bleeding risk in warfarin-treated patients: a HuGEnet systematic review and meta-analysis. Genet Med 2005; 7: 97-104.
    CrossrefPubMedGoogle Scholar
  • 9 Apostolakis S. et al. Factors affecting quality of anticoagulation control among patients with atrial fibrillation on warfarin: the SAMe-TT(2)R(2) score. Chest 2013; 144: 1555-1563.
    CrossrefPubMedGoogle Scholar
  • 10 Flaker G. et al. Amiodarone, anticoagulation, and clinical events in patients with atrial fibrillation: insights from the ARISTOTLE trial. J Am Coll Cardiol 2014; 64: 1541-1550.
    CrossrefPubMedGoogle Scholar
  • 11 Dentali F. et al. Efficacy and safety of the novel oral anticoagulants in atrial fibrillation: a systematic review and meta-analysis of the literature. Circulation 2012; 126: 2381-2391.
    CrossrefPubMedGoogle Scholar
  • 12 Makaryus JN. et al. Oral anticoagulants in the management of venous thromboembolism. Nature Rev Cardiol 2013; 10: 397-409.
    CrossrefPubMedGoogle Scholar
  • 13 Desai NR. et al. Patterns of initiation of oral anticoagulants in patients with atrial fibrillation- quality and cost implications. Am J Med 2014; 127: 1075-1082 e1.
    CrossrefPubMedGoogle Scholar
  • 14 Eikelboom JW. et al. Dabigatran versus warfarin in patients with mechanical heart valves. N Engl J Med 2013; 369: 1206-1214.
    CrossrefPubMedGoogle Scholar
  • 15 Bavisotto LM. et al. Tecarfarin, a novel vitamin K reductase antagonist, is not affected by CYP2C9 and CYP3A4 inhibition following concomitant administration of fluconazole in healthy participants. J Clin Pharmacol 2011; 51: 561-574.
    CrossrefPubMedGoogle Scholar
  • 16 Ellis DJ. et al. The first evaluation of a novel vitamin K antagonist, tecarfarin (ATI-5923), in patients with atrial fibrillation. Circulation 2009; 120: 1029-1035.
    CrossrefPubMedGoogle Scholar
  • 17 Gage BF. et al. Use of pharmacogenetics and clinical factors to predict the maintenance dose of warfarin. Thromb Haemost 2004; 91: 87-94.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 18 Sconce EA. et al. The impact of CYP2C9 and VKORC1 genetic polymorphism and patient characteristics upon warfarin dose requirements: proposal for a new dosing regimen. Blood 2005; 106: 2329-2333.
    CrossrefPubMedGoogle Scholar
  • 19 Voora D. et al. Prospective dosing of warfarin based on cytochrome P-450 2C9 genotype. Thromb Haemost 2005; 93: 700-705.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 20 American College of C, American Heart Association Task Force on Practice G, Society of Cardiovascular A. Bonow RO, Carabello BA, Chatterjee K. et al. ACC/AHA 2006 guidelines for the management of patients with valvular heart disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (writing Committee to Revise the 1998 guidelines for the management of patients with valvular heart disease) developed in collaboration with the Society of Cardiovascular Anesthesiologists endorsed by the Society for Cardiovascular Angiography and Interventions and the Society of Thoracic Surgeons. J Am Coll Cardiol 2006; 48: e1-148.
    CrossrefPubMedGoogle Scholar
  • 21 Rosendaal FR. et al. A method to determine the optimal intensity of oral anticoagulant therapy. Thromb Haemost 1993; 69: 236-239.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 22 Connolly SJ. et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med 2009; 361: 1139-1151.
    CrossrefPubMedGoogle Scholar
  • 23 Granger CB. et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med 2011; 365: 981-992.
    CrossrefPubMedGoogle Scholar
  • 24 Patel MR. et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med 2011; 365: 883-891.
    CrossrefPubMedGoogle Scholar
  • 25 Pokorney SD. et al. Patients' time in therapeutic range on warfarin among US patients with atrial fibrillation: Results from ORBIT-AF registry. Am Heart J 2015; 170: 141-148 8e1.
    CrossrefPubMedGoogle Scholar
  • 26 Yang J. et al. Influence of CYP2C9 and VKORC1 genotypes on the risk of haemorrhagic complications in warfarin-treated patients: a systematic review and meta-analysis. Int J Cardiol 2013; 168: 4234-4243.
    CrossrefPubMedGoogle Scholar
  • 27 Olesen JB. et al. Non-vitamin K antagonist oral anticoagulation agents in anticoagulant naive atrial fibrillation patients: Danish nationwide descriptive data 2011–2013. Europace 2015; 17: 187-193.
    CrossrefPubMedGoogle Scholar
  • 28 Eikelboom JW. et al. Risk of bleeding with 2 doses of dabigatran compared with warfarin in older and younger patients with atrial fibrillation: an analysis of the randomised evaluation of long-term anticoagulant therapy (RE-LY) trial. Circulation 2011; 123: 2363-2372.
    CrossrefPubMedGoogle Scholar
  • 29 Hohnloser SH. et al. Myocardial ischaemic events in patients with atrial fibrillation treated with dabigatran or warfarin in the RE-LY (Randomised Evaluation of Long-Term Anticoagulation Therapy) trial. Circulation 2012; 125: 669-676.
    CrossrefPubMedGoogle Scholar
  • 30 Uchino K, Hernandez AV.. Dabigatran association with higher risk of acute coronary events: meta-analysis of noninferiority randomised controlled trials. Arch Intern Med 2012; 172: 397-402.
    CrossrefPubMedGoogle Scholar
  • 31 Jaffer IH. et al. Dabigatran is Less Effective Than Warfarin at Attenuating Mechanical Heart Valve-Induced Thrombin Generation. J Am Heart Assoc. 2015 Epub ahead of print.
    PubMedGoogle Scholar