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The Antiplatelet Effect of Higher Loading and Maintenance Dose Regimens of Clopidogrel

The PRINC (Plavix Response in Coronary Intervention) Trial

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, Marja-Liisa Dahl, MD, PhD

^_* Green Lane Cardiovascular Service, Auckland City Hospital, Auckland, New Zealand
Department of Medical Sciences, Clinical Pharmacology, Uppsala University, Uppsala, Sweden

^_* Reprint requests and correspondence: Dr. Patrick Gladding, Green Lane Cardiovascular Service, Auckland City Hospital, Private Bag 92 024, Auckland 1030, New Zealand (Email: patrickg{at}adhb.govt.nz).

Objectives: This study evaluated the antiplatelet effect of a higher loading and maintenance dose regimen of clopidogrel and a possible drug interaction with verapamil.

Background: Clopidogrel loading doses above 600 mg have not resulted in more rapid or complete platelet inhibition. Higher maintenance dosages may be more effective than 75 mg/day.

Methods: A double-blind, randomized, placebo-controlled trial was undertaken in 60 patients undergoing percutaneous coronary intervention. All patients received clopidogrel 600 mg at the start of the procedure. Using a 2 x 2 design, patients were allocated to clopidogrel 600 mg given 2 h later or matching placebo, and to verapamil 5 mg intra-arterial or placebo. Platelet function was measured using the VerifyNow P2Y12 analyzer (Accumetrics Ltd., San Diego, California) at 2, 4, and 7 h. Patients were further randomized to receive a clopidogrel 75 or 150 mg once daily, with platelet function assessed after 1 week.

Results: Two hours after the second dose of clopidogrel or placebo, platelet inhibition was 42 ± 27% with clopidogrel, compared with 24 ± 22% with placebo (p = 0.0006). By 5 h after the second dose, platelet inhibition was 49 ± 30% with clopidogrel, compared with 29 ± 22% with placebo (p = 0.01). No drug interaction was seen with verapamil. A clopidogrel maintenance dosage of 150 mg daily for 1 week resulted in greater platelet inhibition than 75 mg daily (50 ± 28% vs. 29 ± 19%, p = 0.01).

Conclusions: In an unselected population undergoing percutaneous coronary intervention a clopidogrel 1,200-mg loading dose, given as two 600-mg doses 2 h apart, results in more rapid and complete platelet inhibition than a single 600-mg dose. A maintenance dosage of 150 mg daily produces greater platelet inhibition than 75 mg daily. (The PRINC trial; ACTRN12606000129583)

Key Words: angioplasty • catheterization pharmacology • platelets • stents

Abbreviations and Acronyms   PCI = percutaneous coronary intervention   PRU = platelet response unit   RPFA = rapid platelet function analyzer

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