Drug Interaction Between Clopidogrel and Ranitidine or Omeprazole in Stable Coronary Artery Disease: A Double-Blind, Double Dummy, Randomized Study
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Proton-pump inhibitors (PPIs) are often prescribed to patients receiving dual antiplatelet therapy (DAPT). However, this class of medication, especially omeprazole, has been associated with a reduction in clopidogrel efficacy, leading many clinicians to substitute omeprazole with ranitidine.
Our objective was to compare the antiplatelet effect of clopidogrel before and after the addition of omeprazole or ranitidine.
We measured platelet aggregability at baseline and after 1 week of clopidogrel 75 mg daily. Subjects were then randomized in a double-blinded, double-dummy fashion to omeprazole 20 mg twice daily (bid) or ranitidine 150 mg bid. We repeated aggregability tests after 1 additional week, using VerifyNow P2Y12™ (Accumetrics; San Diego, CA, USA), depicting aggregability as percent inhibition of platelet aggregation (IPA).
We enrolled 41 patients in the omeprazole group and 44 in the ranitidine group. IPA was significantly decreased after the addition of omeprazole to clopidogrel (from 26.3 ± 32.9 to 17.4 ± 33.1 %; p = 0.025), with no statistical significant changes observed in the ranitidine group (from 32.6 ± 28.9 to 30.1 ± 31.3 %; p = 0.310). The comparison of IPA in both groups at the end of the follow-up showed a trend toward significance (p = 0.07, 95 % confidence interval [CI] −1.19 to 26.59); after excluding homozygous patients for 2C19*2 genotype, the comparison of IPA between the groups reached statistical significance (32.7 ± 30.8 vs. 17.7 ± 33.4 %, respectively, for ranitidine and omeprazole groups; p = 0.04).
Unlike omeprazole, ranitidine did not influence platelet aggregability response to clopidogrel.
Clinical Trial Registration
KeywordsPercutaneous Coronary Intervention Acute Coronary Syndrome Clopidogrel Omeprazole Atorvastatin
The authors thank Paul A Gurbel (Sinai Center for Thrombosis Research, Baltimore, MD, USA) and Marco Cattaneo (University of Milan, Milan, Italy) for their contribution to the study protocol.
JC Nicolau and RHM Furtado: conception, analysis and interpretation of data, drafting the manuscript; RP Giugliano: analysis and interpretation of data, drafting the manuscript; CMC Strunz, C Cavalheiro Filho, AC Pereira, EA D´Amico, JAF Ramires, R Kalil Filho, PA.Lemos Neto, TR Rocha, BT Freire: critically revised the manuscript and made important contributions to its final format.
Compliance with Ethical Standards
Our protocol is in accordance with the recommendations of the Helsinki Declaration and Good Clinical Practice norms on medical research in humans. The Heart Institute Ethics Committee approved the protocol before study inclusion began. All patients signed an ICF before participating in the protocol. All authors fulfilled conflict of interest disclosure forms.
This study was financially supported by the São Paulo Research Foundation (FAPESP), process #2010/16324-1. The funder did not participate in protocol design, study conduct, or statistical analysis.
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