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Thromb Haemost 2016; 116(01): 69-77
DOI: 10.1160/TH15-12-0981
Cellular Haemostasis and Platelets
Schattauer GmbH

Diabetes mellitus, CYP2C19 genotype, and response to escalating doses of clopidogrel

Insights from the ELEVATE-TIMI 56 Trial

Authors

  • Edward T. Carreras

    1   Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital, Boston, Massachusetts, USA

  • Willibald Hochholzer

    2   University Heart Center Freiburg, Bad Krozingen, Department of Cardiology and Angiology II, Bad Krozingen, Germany

  • Andrew L. Frelinger III

    3   Center for Platelet Research Studies, Division of Hematology/Oncology, Boston Children’s Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA

  • Francesco Nordio

    4   TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA

  • Michelle L. O’Donoghue

    4   TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA

  • Stephen D. Wiviott

    4   TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA

  • Dominick J. Angiolillo

    5   University of Florida College of Medicine-Jacksonville, Jacksonville, Florida, USA

  • Alan D. Michelson

    3   Center for Platelet Research Studies, Division of Hematology/Oncology, Boston Children’s Hospital, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA

  • Marc S. Sabatine

    4   TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA

  • Jessica L. Mega   #

    4   TIMI Study Group, Cardiovascular Division, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts, USA
    6   Verily Life Sciences, Mountain View, California, USA

Financial support: The ELEVATE-TIMI 56 trial was funded by an investigator-initiated grant from Bristol-Myers Squibb/sanofi-aventis. Research supplies were provided by Accumetrics and Nanosphere. Dr. Mega was supported in part by grant K99/R00 HL098461 from the National Institutes of Health. Dr. Hochholzer is supported in part by the German Heart Foundation.
Further Information

Publication History

Received: 23 December 2015

Accepted after minor revision: 10 March 2016

Publication Date:
27 November 2017 (online)

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Summary

Both diabetes mellitus (DM) and carriage of the CYP2C19*2 allele are associated with a reduced response to clopidogrel. The relative contributions of these factors and whether higher clopidogrel doses can overcome both factors remain unknown. The objective of this study was to test the ability of clopidogrel doses up to 300 mg daily to decrease platelet reactivity in patients with DM and/or CYP2C19*2. ELEVATE-TIMI 56 randomised 333 patients with coronary artery disease to different maintenance doses of clopidogrel in four treatment periods, each lasting approximately 14 days. On-treatment platelet reactivity was compared between patients stratified by DM, CYP2C19*2 status and clopidogrel dose. Both DM and CYP2C19*2 were independently associated with elevated on-treatment platelet reactivity with clopidogrel 75 mg daily (p<0.0001 for each). With 75 mg, mean on-treatment PRU was progressively higher (p trend <0.001) when evaluating patients: with neither DM nor CYP2C19*2 (150.7; 95 % CI 140.5–162.6), with only DM (187.2; 95 % CI, 171.3–206.9), with only CYP2C19*2 (227.9; 95 % CI, 205.1–250.8), and with both DM and CYP2C19*2 (239.9; 95 % CI, 209.7–270.1). Notably, with 75 mg, patients with only CYP2C19*2 had higher ontreatment platelet reactivity than those with only DM (p=0.0068). To achieve on-treatment platelet reactivity similar to that seen with clopidogrel 75 mg in patients with neither DM nor CYP2C19*2, the following doses were required: 150 mg with only DM, 225 mg with only CYP2C19*2, and 300 mg with both DM and CYP2C19*2. Patients with both DM and CYP2C19*2 required a four-fold increase in clopidogrel maintenance dose as compared to patients without these factors to achieve a similar antiplatelet response.

Keywords

Diabetes mellitus - ischaemic heart disease - platelet pharmacology - polymorphisms

# On leave.