Effects Of Omeprazole And Pantoprazole On The Antiplatele Efficacy Of Clopidogrel

Research background and ObjectiveThe clopidogrel plus aspirin has become a cornerstone of medical treatment for patients with coronary artery disease who present acute coronary syndrome or have had a percutaneous coronary intervention. Proton-pump inhibitors (PPIs) are often administered in combination with dual antiplatelet treatment to help reducing the risk of gastrointestinal bleeding. However, the antiplatelet effects of clopidogrel could be diminished by the concurrent use of PPIs. Clopidogrel, a derivant of thienopyridines, inhibits platelet activation induced by adenosine diphosphate (ADP). Clopidogrel is a prodrug, and must be metabolized in the liver to acquire its anti-aggregation properties. Clopidogrel is biotransformed into an active metabolite mainly through 2C19 pathway, one of hepatic cytochrome P-450 isoenzymes, partially throguh the other pathways of CYP3A4,2B6,1A2, or1A1. Its antiplatelet effect is produced by forming an inactivating disulfide bond with the platelet P2Y12 ADP receptor. Since several PPIs are metabolized through 2C19 pathway of cytochrome P450 isoenzymes too. Competition on the same metabolic pathway between PPIs and clopidogrel may inhibit the metabolism of clopidogrel into the active form and diminish its antiplatelet effect. Several observational studies had raised concerns that many PPIs, especially omeprazole, but not pantoprazol, might diminish the antiplatelet effects and the clinical outcomes of clopidogrel. However, the other studies especially the recent subgroup analysis of randomized clinical trials didn't support the above presumption and conclusion. With these conflicting results, the clinical implications of co-administration of PPI and clopidogrel remain unclear, especially in Chinese population.The antiplatelet effect of clopidogrel is present by inhibiting the bouding of ADP to the P2Y12 receptor which is associated with dephosphorylation of intraplatelet vasodilator-stimulated phosphoprotein (VASP). Therefore, phosphorylation of VASP could provide an index of platelet reactivity (PRI) to assess the effects of clopidogrel. In this study, we tested the influence of omeprazole and pantoprazole on the antiplatelet efficacy of clopidogrel in Chinese population, by using a standardized flow cytometry to assess the phosphorylation degree of VASP and obtain the PRI. And meanwhile, the adenosine diphosphate-induced platelet aggregation rates (ADP-Ag) were measured to assess platelet function.Methods1.Patients selection:All consecutive patients undergoing selective coronary stent implantation and patients suffering acute coronary syndromes without accepting percutaneous coronary intervention from September,2009 to June,2010 in General Hospital of Guangzhou Military Command of PLA were considered for inclusion. Among all of the patients, the inclusive criteria are as below:A:clopidogrel and/or PPIs are not used in previous treatment; B:patients with compelling indications for dual antiplatelet therapy; C:willing to sign an informed consent. The exclusive criteria were as followings:A:clopidogrel and/or PPIs were used in previous 2 weeks; B:with history of thrombocytopenia (<150×109/L) or bleeding, liver disease, gastrointestinal ulcer, or pregnant women.2.All selected patients received aspirin (300mg loading dose and followed by 100 mg/day) and clopidogrel (300mg loading dose and followed by 75 mg/day). Then all patients were randomized into 2 groups:clopidogrel concomitant with omeprazole 20 mg/day (Omeprazole group) or pantoprazol 40 mg/day (Pantoprazole group) for 7 days. Blood samples for testing platelet reactivity were drawn before and after the treatment of 7 days. And then, after hospital discharge, treatment with above drugs was continued, and major adverse cardiovascular events (including myocardial infarction, stroke, death and revascularization), the incidence of gastrointestinal bleeding (including hematemesis, melena, positive occult blood in stools) and gastrointestinal adverse events (abdominal pain and abdominal distension), were obversed in the 30 days3. Venous blood from patients were obtained with a 9G needle (without tourniquet, the former 2 ml is abandoned), before antiplatelet therapy and at the 7th day after treatment respectively.1.8 ml of each was injected into a BD anticoagulation tube containing 0.2 ml 3.8% sodium citrate. After antigrading of the blood samples, the degree of VASP phosphorylation and PRI were measured within 2 hours with a standardized flow cytometry. And meanwhile, the adenosine diphosphate-induced platelet aggregation rates (ADP-Ag) were measured to assess platelet function.4. All statistical calculations were performed using commercially available statistical software (SPSS Version 13.0). Statistical comparisons were performed with the Kruskal-Wallis analysis of variance, theχ2 test, and the Mann-Whitney U test. A 2-tailed P value of <0.05 was considered statistically significant.Results1. Totally 60 patients were included and divided into omeprazole group (n=30) and pantoprazole group (n=30).Baseline characteristics (male, age and BMI), atherosclerosis risk factors (smoking, dyslipidemia, diabetes and hypertension), old myocardial infarction, and concomitant cardiovascular medications (statins, beta-blockers, or angiotensin-converting enzyme inhibitors) were not significantly different in the two groups.2. There were no differences between two groups in both of PRI and ADP-Ag before as well as after the comconmitant therapy (all P> 0.05).3. After 7 days, we observed a significant difference in PRI and ADP-Ag in the omeprazole groups:(74.06±16.28)% versus (57.78±18.69)%(P=0.001), (41.84±32.66)% versus (27.19±24.67)%(P=0.023), respectively.However, in Pantoprazole group, we only observed a significant reduction in ADP-Ag, (35.71±27.57)% versus (19.85±19.79)%(P=0.008), but not in PRI, (70.38±18.52)% versus (65.15±19.52)%(P=0.27).4. The decline of PRI and ADP-Ag was not significantly different between Pantoprazole group and Omeprazole group (all P> 0.05).5. MACE in 30 days:Both groups have not MACE in 30 days.6. The incidence of gastrointestinal bleeding and gastrointestinal adverse events in the two groups:Both groups have not gastrointestinal bleeding and gastrointestinal adverse events.ConclusionThis study indicated that omeprazole does not impact the efficacy of dual antiplatelet theraphy with aspirin and clopidogrel while pantoprazole may inhibit the laboratory antiplatelet efficacy of clopidogrel. However, it doesn't transfer into clinical outcomes.