An association of aspirin with clopidogrel is the reference treatment for prevention of thrombosis secondary to coronary angioplasty [1Mehta S.R. Yusuf S. Peters R.J. Bertrand M.E. Lewis B.S. Natarajan M.K. Malmberg K. Rupprecht H. Zhao F. Chrolavicius S. Copland I. Fox K.A. Effects of pretreatment with clopidogrel and aspirin followed by long‐term therapy in patients undergoing percutaneous coronary intervention: the PCI‐CURE study.Lancet. 2001; 358: 527-33Abstract Full Text Full Text PDF PubMed Scopus (0) Google Scholar]. Clopidogrel inhibits platelet activation by blocking the P2Y12 platelet receptor, activation of which is associated with dephosphorylation of intraplatelet vasodilator‐stimulated phosphoprotein (VASP). VASP phosphorylation provides an index of platelet reactivity to clopidogrel, which varies between individuals: the greater it is the more frequently thrombosis occurs [2Barragan P. Bouvier J.L. Roquebert P.O. Macaluso G. Commeau P. Comet B. Lafont A. Camoin L. Walter U. Eigenthaler M. Resistance to thienopyridines: clinical detection of coronary stent thrombosis by monitoring of vasodilator‐stimulated phosphoprotein phosphorylation.Catheter Cardiovasc Interv. 2003; 59: 295-302Crossref PubMed Scopus (0) Google Scholar]. Clopidogrel is a prodrug, activated by cytochrome 2C19. We investigated whether interactions with other substances could account for the observed variation in biological response to clopidogrel. The VASP test was performed on 105 consecutive patients (mean age: 63.7 years, 61% male) receiving aspirin + clopidogrel bitherapy in a context of high‐risk coronary angioplasty. The mean VASP test result, performed at least 48 h after initiation of treatment, was 52.2 ± 18.7, with a range of 6–89. Platelet response was analyzed by Mann–Whitney U‐test according to the different standard accompanying treatments: no significant differences were found for statins, angiotensin‐converting enzyme inhibitors, angiotensin II receptor antagonist and beta blockers. Conversely, proton pump inhibitors (PPI) users had significantly higher VASP values than non‐users [61.4 ± 23.2 (n = 24), vs. 49.5 ± 16.3 (n = 81) respectively, P = 0.007]. These results are the first to show an association between PPI treatment and diminished biological action of clopidogrel. CYP 2C19, which the 681G>A polymorphism has recently been shown to determine the response to clopidogrel [3Hulot J.S. Bura A. Villard E. Azizi M. Remones V. Goyenvalle C. Aiach M. Lechat P. Gaussem P. Cytochrome P450 2C19 loss‐of‐function polymorphism is a major determinant of clopidogrel responsiveness in healthy subjects.Blood. 2006; 13Google Scholar], is involved in both clopidogrel activation and PPI metabolism [4Furata T. Shirai N. Xiao F. Ohashi K. Ishizaki T. Effect of high‐dose lansoprazole on intragastric pH in subjects who are homozygous extensive metabolizers of cytochrome P4502C19.Clin Pharmacol Ther. 2001; 70: 484-92Crossref PubMed Scopus (0) Google Scholar]. A competitive effect of PPIs on CYP 2C19 might thus underlie clopidogrel's reduced effectiveness in patients receiving PPIs. Demonstrating an interaction between these two drugs, which are so routinely associated in cardiology, would have major implications for the management of the risk of thrombosis following angioplasty, but will require the results of a randomized study that is currently under way.