IJCM  Vol.3 No.6 , November 2012
Clinical Analysis of the Pharmacological Interactions of Clopidogrel and Gender Differences: A Case-Control Study
ABSTRACT
Background: Clopidogrel is a prodrug metabolized by cytochrome P450-2C19. Drugs inhibiting this enzyme might reduce its antiplatelet activity. In order to reduce gastrointestinal bleedings, proton-pump inhibitors are usually prescribed in association with clopidogrel. The study aims at assessing the clinical importance of interactions between clopidogrel and inhibitors of CYP2C19. It also aims to evaluate any possible factors that may reduce the therapeutic efficacy of the drug. Particular attention was devoted to possible gender differences in responsiveness to treatment with clopidogrel or clopidogrel plus proton-pump inhibitors. This analysis is a retrospective case-control observational study carried out by the University Hospital of Ferrara. Methods: Subjects were patients who had received clopidogrel from 01-01-2008 to 31-12-2008. For them, we analysed hospital admissions and data of drug prescriptions relative to dispensing of drugs cytochrome P-450-2C19 inhibitors. Patients were subdivided into case and control groups based on the occurrence or not of cardiovascular or cerebrovascular secondary events during therapy with clopidogrel. Results: The study focused on 781 patients, 20.1% of which (n.157) experienced secondary effects. The mean age is 70 years old. Men (67% of the analyzed population) experienced secondary events more than women (OR 1.54; CI 95% 1.04 - 2.28; p < 0.03). 70% of patients took PPIs and we noticed that the risk of secondary events increased by 2.2% with respect to the remaining patients (20.77% vs 18.57%; OR 1.15; CI 0.78 - 1.70; p = NS). Among PPIs, lansoprazole is the most used. For this subgroup the risk is 5.2% higher (risk in those exposed of 23.75% vs 18.57% in those not exposed; or 1.37, 95% CI 0.92 - 2.03; p = NS). The interaction with PPIs is particularly interesting only among women, with a risk 6.3% higher (17.46% exposed, 11.11% non exposed). The risk remains the same among men. Conclusions: Analyzed data show an increase in cardiovascular or cerebral secondary events for patients exposed to PPIs. It also demonstrated the existence of differrent gender in therapeutic response to clopidogrel.

Cite this paper
B. Stefano, C. Casellato, B. Erica and S. Paola, "Clinical Analysis of the Pharmacological Interactions of Clopidogrel and Gender Differences: A Case-Control Study," International Journal of Clinical Medicine, Vol. 3 No. 6, 2012, pp. 518-523. doi: 10.4236/ijcm.2012.36093.
References
[1]   J. L. Mega, S. L. Close, S. D. Wiviott, et al., “Cytochrome P-450 Polymorphisms and Response to Clopidogrel,” New England Journal of Medicine, Vol. 360, 2009, pp. 354-362. doi:10.1056/NEJMoa0809171

[2]   FDA Drug Safety Communication, “Reduced Effectiveness of Plavix (Clopidogrel) in Patients Who Are Poor Metabloizers of the Drug,” 2010. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm203888.htm

[3]   FDA, “Early Communication about an Ongoing Safety Review of Clopidogrel Bisulfate,” 2009. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformation forHeathcareProfessionals/ucm079520.htm

[4]   Clopidogrel RCP, 2010. http://www.ema.europa.eu/humandocs/Humans/EPAR/clopidogreltevapharma/clopidogreltevapharma.htm

[5]   P450 Drug Interaction Table. Division of Clinical Pharmacology, Indiana University Department of Medicine, 2010. http://medicine.iupui.edu/clinpharm/DDIs/table.asp

[6]   M. Gilard, B. Arnaud, G. Le Gal, J. F. Abgrall and J. Boschat, “Influence of Omeprazole on the Antiplatelet Action of Clopidogrel Associated with Aspirin,” Journal of Thrombosis and Haemostasis, Vol. 4, No. 11, 2006, pp. 2508-2509. doi:10.1111/j.1538-7836.2006.02162.x

[7]   M. Gilard, B. Arnaud, J. C. Cornily, G. Le Gal, K. Lucut, G. Le Calvez, J. Mansourati, D. Mottier, J. F. Abgrall and J. Boschat, “Influence of Omeprazole on the Antiplatelet Action of Clopidogrel Associated with Aspirin: The Randomized, Double-Blind OCLA Study,” Journal of the American College of Cardiology, Vol. 51, No. 3, 2008, pp. 256-260. doi:10.1016/j.jacc.2007.06.064

[8]   S. D. Wiviott, D. Trenk, A. L. Frelinger, et al., “Prasugrel Compared with High Loading and Maintenance Dose Clopidogrel in Patients with Planned Percutaneous Coronary Intervention: The Prasugrel in Comparison to Clopidogrel for Inhibition of Platelet Activation and Ag-gregation-Thrombolysis in Myocardial Infarction 44 Trials,” Circulation, Vol. 116, 2007, pp. 2923-2932. doi:10.1161/CIRCULATIONAHA.107.740324

[9]   M. L. O’Donoghue, et al., “Pharmacodynamic Effect and Clinical Efficacy of Clopidogrel and Prasugrel with or without a Proton-Pump Inhibitor: An Analysis of Two Randomised Trials,” Lancet, Vol. 374, No. 9694, 2009, pp. 989-997. doi:10.1016/S0140-6736(09)61525-7

[10]   P. M. Ho, et al., “Risk of Adverse Outcomes Associated with Concomitant Use of Clopidogrel and Proton Pump Inhibitors Following Acute Coronary Syndrome,” Journal of the American Medical Association, Vol. 301, No. 9, 2009, pp. 937-944. doi:10.1001/jama.2009.261

[11]   D. N. Juurlink, T. Gomes, D. T. Ko, et al., “A Population-Based Study of the Drug Interaction between Proton Pump Inhibitors and Clopidogre,” CMAJ, Vol. 180, No. 7, 2009, pp. 1228-1229. doi:10.1503/cmaj.082001

[12]   D. Sibbing, T. Morath, J. Stegherr, S. Braun, W. Vogt, M. Hadamitzky, A. Schvmig, A. Kastrati, N. von Beckerath, “Impact of Proton Pump Inhibitors on the Antiplatelet Effects of Clopidogrel,” Journal of Thrombosis and Haemostasis, Vol. 101, No. 4, 2009, pp. 714-719.

[13]   J. A. Rassen, N. K. Choudhry, J. Avorn and S. Schneeweiss, “Cardiovascular Outcomes and Mortality in Patients Using Clopidogrel with Proton Pump Inhibitors after Percutaneous Coronary Intervention or Acute Coronary Syndrome,” Circulation, Vol. 120, 2009, pp. 2322- 2329. doi:10.1161/CIRCULATIONAHA.109.873497

[14]   S. D. Wiviott, et al., “Evaluation of Prasugrel Compared with Clopidogrel in Patients with Acute Coronary Syndromes: Design and Rational for the Trial Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel Thrombolysis in Myocardial Infarction 38 (TRITON-TIMI 38),” American Heart Journal, Vol. 152, No. 4, 2006, pp. 627-635. doi:10.1016/j.ahj.2006.04.012

[15]   S. D. Wiviott, et al., “Prasugrel versus Clopidogrel in Patients with Acute Coronary Syndromes,” New England Journal of Medicine, Vol. 357, 2007, pp. 2001-2015. doi:10.1056/NEJMoa0706482

[16]   D. Sibbing and A. Kastrati, “Risk of Combining PPIs with Thienopyridines: Fact or Fiction? Lancet, Vol. 374, No. 9694, 2009, pp. 952-954. doi:10.1016/S0140-6736(09)61562-2

[17]   X.-Q. Li, T. B. Andersson, M. Ahlstrom and L. Weidolf, “Comparison of Inhibitory Effects of the Proton Pump-Inhibiting Drugs Omeprazole, Esomeprazole, Lansoprazole, Pantoprazole, and Rabeprazole on Human Cytochrome P450 Activities,” Drug Metabolism and Disposition, Vol. 32, No. 8, 2004, pp. 821-827.

[18]   EMA, “Public Statement. Interaction between Clopidogrel and Proton Pump Inhibitors,” 2010. www.ema.europa.eu/humandocs/PDFs/EPAR/Plavix/17494810en.pdf

[19]   ICD-9 CM, “International Classification of Diseases, 9th Revision, Clinical Modification,” Italian Version, 2002.

[20]   Y. B. Pride, S. D. Wiviott, J. L. Buros, C. Zorkun, M. U. Tariq, E. M. Antman, E. Braunwald and C. M. Gibson, “Effect of Prasugrel versus Clopidogrel on Outcomes among Patients with Acute Coronary Syndrome Undergoing Percutaneous Coronary Intervention without Stent Implantation: A Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel (TRITON)-Thrombolysis in Myocardial Infarction (TIMI) 38 Substudy,” American Heart Journal, Vol. 158, No. 3, 2009, pp. e21-e26.

 
 
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