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Journal of Thrombosis and Thrombolysis

, Volume 34, Issue 1, pp 44–55 | Cite as

Pharmacodynamic effects of cangrelor and clopidogrel: the platelet function substudy from the cangrelor versus standard therapy to achieve optimal management of platelet inhibition (CHAMPION) trials

  • Dominick J. Angiolillo
  • David J. Schneider
  • Deepak L. Bhatt
  • William J. French
  • Matthew J. Price
  • Jorge F. Saucedo
  • Tamaz Shaburishvili
  • Kurt Huber
  • Jayne Prats
  • Tiepu Liu
  • Robert A. Harrington
  • Richard C. Becker
Article

Abstract

Cangrelor is an intravenous antagonist of the P2Y12 receptor characterized by rapid, potent, predictable, and reversible platelet inhibition. However, cangrelor was not superior to clopidogrel in reducing the incidence of ischemic events in the cangrelor versus standard therapy to achieve optimal management of platelet inhibition (CHAMPION) trials. A prospectively designed platelet function substudy was performed in a selected cohort of patients to provide insight into the pharmacodynamic effects of cangrelor, particularly in regard to whether cangrelor therapy may interfere with the inhibitory effects of clopidogrel. This pre-defined substudy was conducted in a subset of patients from the CHAMPION-PCI trial (n = 230) comparing cangrelor with 600 mg of clopidogrel administered before percutaneous coronary intervention (PCI) and from the CHAMPION-PLATFORM trial (n = 4) comparing cangrelor at the time of PCI and 600 mg clopidogrel given after the PCI. Pharmacodynamic measures included P2Y12 reaction units (PRU) assessed by VerifyNow P2Y12 testing (primary endpoint marker), platelet aggregation by light transmittance aggregometry following 5 and 20 μmol/L adenosine diphosphate stimuli, and markers of platelet activation determined by flow cytometry. The primary endpoint was the percentage of patients who achieved <20 % change in PRU between baseline and >10 h after PCI. The main trial was stopped early limiting enrollment in the platelet substudy. A total of 167 patients had valid pharmacodynamic assessments for the primary endpoint. The percent of individuals achieving <20 % change in PRU between baseline and >10 h after PCI was higher with cangrelor + clopidogrel (32/84, 38.1 %) compared with placebo + clopidogrel (21/83, 25.3 %), but this was not statistically significant (difference:12.79 %, 95 % CI: −1.18 %, 26.77 %;p = 0.076). All pharmacodynamic markers as well as the prevalence of patients with high on-treatment platelet reactivity were significantly lower in patients treated with cangrelor. A rapid platelet inhibitory effect was achieved during cangrelor infusion and a rapid offset of action after treatment discontinuation. This CHAMPION platelet function substudy represents the largest pharmacodynamic experience with cangrelor, demonstrating its potent P2Y12 receptor inhibitory effects, and rapid onset/offset of action. Although there was no significant pharmacodynamic interaction when transitioning to clopidogrel therapy, further studies are warranted given that enrollment in this study was limited due to premature interruption of the main trial.

Keywords

Platelet function PCI Clopidogrel Cangrelor 

Notes

Acknowledgments

Funding: This work was supported by The Medicines Company.

Disclosures

Dominick J. Angiolillo reports receiving: honoraria for lectures from Bristol Myers Squibb; Sanofi-Aventis; Eli Lilly Co; Daiichi Sankyo, Inc; Astra Zeneca; Abbott Vascular; consulting fees from Bristol Myers Squibb; Sanofi-Aventis; Eli Lilly Co; Daiichi Sankyo, Inc.; The Medicines Company; Portola; Novartis; Medicure; Accumetrics; Arena Pharmaceuticals; Astra Zeneca; Merck; research grants from Bristol Myers Squibb; Sanofi-Aventis; GlaxoSmithKline; Otsuka; Eli Lilly Co; Daiichi Sankyo, Inc., The Medicines Company; Portola; Accumetrics; Schering-Plough; Astra-Zeneca; Eisai. David J. Schneider reports receiving honoraria and research grants from Bristol Myers Squibb; Sanofi-Aventis; The Medicines Company; Johnson & Johnson; Bayer Pharmaceuticals. Deepak L. Bhatt reports receiving: research grants (all significant) from Astra Zeneca, Bristol-Myers Squibb, Eisai, Sanofi Aventis, The Medicines Company. William J. French reports receiving: honoraria for lectures from Sanofi-Aventis and Eli Lilly Co; consulting fees from The Medicines Company and Portola; and research grants from Eli Lilly Co; Daiichi Sankyo, Inc., The Medicines Company, Portola and Schering-Plough. Matthew J. Price reports receiving received consulting fees and honoraria from The Medicines Company, AstraZeneca, Daiichi-Sankyo/Eli Lily & Co, Accumetrics, Bristol-Myers Squibb/sanofi aventis, and Medicure; honoraria for lectures from the Medicines Company and Daiichi-Sankyo/Eli Lily & Co.; and research grants from Accumetrics and Bristol-Myers Squibb/sanofi aventis. Jorge Saucedo reports receiving: honoraria for lectures from Eli Lilly Co; Daiichi Sankyo, Inc; and Merck; consulting fees; Eli Lilly Co; Daiichi Sankyo, Inc.; Medicure; Merck; research grants from Eli Lilly Co; Daiichi Sankyo, Inc., The Medicines Company; Accumetrics; Schering-Plough. Tamaz Shaburishvili reports receiving: consulting fees from New England Research Institute, The Medicines Company. Kurt Huber reports receiving: honoraria for lectures from AstraZenecaM; Bayer Austira; Boehringer-Ingelheim; Eli Lilly Co; Daiichi Sankyo, Inc; Sanofi-Aventis; The Medicines Company. Jayne Prats is an employee of The Medicines Company. Tiepu Liu is an employee of The Medicines Company. Robert A. Harrington reports receiving: research funding to the DCRI from The Medicines Company, Eli Lilly, Daiichi Sankyo, Sanofi-Aventis, Bristol-Myers-Squibb, Portola, Novartis, Merck, and AstraZeneca. Consulting fees from AstraZeneca, Sanofi-aventis, BMS, Novartis, and Merck. Full disclosure of all relationships with industry are available at http://www.dcri.duke.edu/research/coi.jsp. Richard C. Becker reports receiving: research grants from The Medicines Company, AstraZeneca, Johnson and Johnson,Bayer, and Regado Biosciences.Scientific advisory boards and honoraria from Daiich-Sankyo, Regado Biosciences, Boehringer Ingelheim, Merck, and Bristol-Myers-Squibb.

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Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  • Dominick J. Angiolillo
    • 1
  • David J. Schneider
    • 2
  • Deepak L. Bhatt
    • 3
  • William J. French
    • 4
  • Matthew J. Price
    • 5
  • Jorge F. Saucedo
    • 6
  • Tamaz Shaburishvili
    • 7
  • Kurt Huber
    • 8
  • Jayne Prats
    • 9
  • Tiepu Liu
    • 9
  • Robert A. Harrington
    • 10
  • Richard C. Becker
    • 10
  1. 1.University of Florida College of Medicine-JacksonvilleJacksonvilleUSA
  2. 2.University of VermontBurlingtonUSA
  3. 3.VA Boston Healthcare System, Brigham and Women’s Hospital, and Harvard Medical SchoolBostonUSA
  4. 4.Harbor–UCLA Medical CenterTorranceUSA
  5. 5.Division of Cardiovascular Diseases, Scripps ClinicLa JollaUSA
  6. 6.University of Oklahoma Health Sciences CenterOklahoma CityUSA
  7. 7.Diagnostic Services ClinicTbilisiUSA
  8. 8.3rd Department of Medicine, Cardiology and Emergency Medicine, Wilhelminen HospitalViennaAustria
  9. 9.The Medicines CompanyParsippanyUSA
  10. 10.Duke Clinical Research InstituteDuke University Medical CenterDurhamUSA

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