European Heart Journal Advance Access originally published online on December 16, 2007
European Heart Journal 2008 29(3):423-424; doi:10.1093/eurheartj/ehm551
A double blind, randomized study on platelet aggregation in patients treated with a daily dose of 150 or 75 mg of clopidogrel for 30 days
Department of Internal Medicine
Lincoln Medical and Mental Health Center
Weill Medical College of Cornell University
234 E 149th Street, Bronx
NY 10451
USA
Tel: +1 718 579 3456
Email: lizhli{at}hotmail.com
Department of Internal Medicine
Lincoln Medical and Mental Health Center
Weill Medical College of Cornell University
234 E 149th Street, Bronx
NY 10451
USA
In reference to the interesting study by von Beckerath et al.,1 we would like to offer the following comments.
The predicted induced platelet aggregation (IPA) of 50% in the 75 mg clopidogrel group is lower than the actual observations of 65% noted in the study controls. Underestimation of the control IPA impacts effect size and study power, and could limit the validity.2
Further, the 5 and 20 µM ADP IPA observed in the study control groups receiving 75 mg clopidogrel were 65.3 and 80%, values that are much higher than other reports. One study3 showed both 5 and 20 µM ADP IPA of 
30% in patients receiving 75 mg maintenance clopidogrel. Another report4 showed that 20 µM ADP IPA was 42% after a 600 mg clopidogrel loading dose. The higher IPA noted in the study will certainly limit the generalizability of the study findings to other populations with lower IPA. The effect of high dose clopidogrel in subjects with lower IPA remains to be clarified.
Very few female subjects were enrolled, thus limiting the generalizability of the findings to women. It would be interesting to know regarding the gender distribution of all subjects screened and excluded from the study before randomization. Further, by employing a block randomization selection strategy, gender distribution could have been improved.5
As diabetes affects platelet function,6 analysis of the confounding effect of diabetes on platelet activity may be informative. Further, it would be interesting to analyse the data from patients with atherosclerosis in other vascular beds such as those with peripheral artery disease who are known to have abnormal platelet functions7 and are at higher risk for coronary artery disease (CAD).
Clopidogrel pharmacokinetics and pharmacodynamics depends on cytochrome P450 3A inhibition.8 Therefore, the use of medications that influence P450 3A activity on clopidogrel should be evaluated.
Up to 30% of CAD patients may not have inhibition of platelet aggregation with the standard clopidogrel dose and many studies have recommended increasing the clopidogrel dose.1,3 Lack of data on measurements of ADP IPA in this study prevents the comparability of the two groups at baseline, and precludes the assessment of individual platelet responsiveness to clopidogrel treatment.
References
- von Beckerath N, Kastrati A, Wieczorek A, Pogatsa-Murray G, Sibbing D, Graf I, Schömig A. A double blind, randomized study on platelet aggregation in patients treated with a daily dose of 150 or 75 mg of clopidogrel for 30 days. Eur Heart J (2007) 28:1814–1819.
[Abstract/Free Full Text] - Ederer F, Church TR, Mandel JS. Sample sizes for prevention trials have been too small. Am J Epidemiol (1993) 137:787–796.
[Abstract/Free Full Text] - Jernberg T, Payne CD, Winters KJ, Darstein C, Brandt JT, Jakubowski JA, Naganuma H, Siegbahn A, Wallentin L. Prasugrel achieves greater inhibition of platelet aggregation and a lower rate of non-responders compared with clopidogrel in aspirin-treated patients with stable coronary artery disease. Eur Heart J (2006) 27:1166–1173.
[Abstract/Free Full Text] - Hochholzer W, Trenk D, Frundi D, Neumann FJ. Whole blood aggregometry for evaluation of the antiplatelet effects of clopidogrel. Thromb Res (2007) 119:285–291.[CrossRef][Web of Science][Medline]
- Schulz KF, Grimes DA. Generation of allocation sequences in randomized trials: chance, not choice. Lancet (2002) 359:515–519.[CrossRef][Web of Science][Medline]
- Carr ME. Diabetes mellitus: a hyper coagulable state. J Diabetes Complications (2001) 15:44–54.[CrossRef][Web of Science][Medline]
- Reininger CB, Graf J, Reininger AJ, Spannagl M, Steckmeier B, Schweiberer L. Increased platelet and coagulatory activity indicate ongoing thrombogenesis in peripheral arterial disease. Thromb Res (1996) 82:523–532.[CrossRef][Web of Science][Medline]
- Farid NA, Payne CD, Small DS, Winters KJ, Ernest CS II, Brandt JT, Darstein C, Jakubowski JA, Salazar DE. Cytochrome P450 3A inhibition by ketoconazole affects prasugrel and clopidogrel pharmacokinetics and pharmacodynamics differently. Clin Pharmacol Ther (2007) 81:735–741.[CrossRef][Web of Science][Medline]
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