Author + information
- Received May 30, 2008
- Revision received September 16, 2008
- Accepted September 29, 2008
- Published online December 1, 2008.
- Patrick Gladding, FRACP⁎,⁎ (, )
- Mark Webster, FRACP⁎,
- Irene Zeng, MSc⁎,
- Helen Farrell, BHSc⁎,
- Jim Stewart, FRACP⁎,
- Peter Ruygrok, FRACP⁎,
- John Ormiston, FRACP⁎,
- Seif El-Jack, FRACP⁎,
- Guy Armstrong, FRACP⁎,
- Patrick Kay, FRACP⁎,
- Douglas Scott, FRACP⁎,
- Arzu Gunes, MD, PhD† and
- Marja-Liisa Dahl, MD, PhD†
- ↵⁎Reprint requests and correspondence:
Dr. Patrick Gladding, Green Lane Cardiovascular Service, Auckland City Hospital, Private Bag 92 024, Auckland 1030, New Zealand
Objectives This study assessed the effect of pharmacogenetics on the antiplatelet effect of clopidogrel.
Background Variability in clopidogrel response might be influenced by polymorphisms in genes coding for drug metabolism enzymes (cytochrome P450 [CYP] family), transport proteins (P-glycoprotein) and/or target proteins for the drug (adenosine diphosphate–receptor P2Y12).
Methods Sixty patients undergoing elective percutaneous coronary intervention in the randomized PRINC (Plavix Response in Coronary Intervention) trial had platelet function measured using the VerifyNow P2Y12 analyzer after a 600-mg or split 1,200-mg loading dose and after a 75- or 150-mg daily maintenance dosage. Polymerase chain reaction–based genotyping evaluated polymorphisms in the CYP2C19, CYP2C9, CYP3A4, CYP3A5, ABCB1, P2Y12, and CES genes.
Results CYP2C19*1*1 carriers had greater platelet inhibition 2 h after a 600-mg dose (median: 23%, range: 0% to 66%), compared with platelet inhibition in CYP2C19*2 or *4 carriers (10%, 0% to 56%, p = 0.029) and CYP2C19*17 carriers (9%, 0% to 98%, p = 0.026). CYP2C19*2 or *4 carriers had greater platelet inhibition with the higher loading dose than with the lower dose at 4 h (37%, 8% to 87% vs. 14%, 0% to 22%, p = 0.002) and responded better with the higher maintenance dose regimen (51%, 15% to 86% vs. 14%, 0% to 67%, p = 0.042).
Conclusions Carriers of the CYP2C19*2 and *4 alleles showed reduced platelet inhibition after a clopidogrel 600-mg loading dose but responded to higher loading and maintenance dose regimens. Genotyping for the relevant gene polymorphisms may help to individualize and optimize clopidogrel treatment. (Australia New Zealand Clinical Trials Registry; ACTRN12606000129583)
Funded in part by the Green Lane Research and Educational Fund and National Heart Foundation of New Zealand and the Swedish Research Council. The VerifyNow platelet function analyzer was provided by Sanofi Aventis, New Zealand. Medication packs and placebo matching were supplied by the Auckland City Hospital Pharmacy, Clinical Trials Unit.
- Received May 30, 2008.
- Revision received September 16, 2008.
- Accepted September 29, 2008.
- American College of Cardiology Foundation