Comparison of Omeprazole and Pantoprazole Influence on a High 150-mg Clopidogrel Maintenance Dose The PACA (Proton Pump Inhibitors And Clopidogrel Association) Prospective Randomized Study

Département de Cardiologie, CHU Timone, Marseille, France.
Journal of the American College of Cardiology (Impact Factor: 16.5). 09/2009; 54(13):1149-53. DOI: 10.1016/j.jacc.2009.05.050
Source: PubMed


This study sought to compare the effect of 2 proton pump inhibitors (PPIs) on platelet response to clopidogrel after coronary stenting for non-ST-segment elevation acute coronary syndrome (NSTE ACS).
Use of omeprazole has been reported to significantly decrease the clopidogrel antiplatelet effect because of cytochrome P450 interaction. Because all PPIs are metabolized by CYP2C19, but to a varying degree, we hypothesized that the reported negative omeprazole-clopidogrel drug interaction may not be caused by a class effect.
A total of 104 patients undergoing coronary stenting for NSTE ACS were prospectively included and randomized to omeprazole or pantoprazole 20 mg. They received at discharge 75-mg aspirin and 150-mg clopidogrel. Platelet reactivity index (PRI) vasoactive stimulated phosphoprotein (VASP) was used to assess clopidogrel response and adenosine diphosphate (ADP)-induced aggregation for platelet reactivity (ADP-Ag).
After 1 month, patients receiving pantoprazole had a significantly better platelet response to clopidogrel as assessed with the PRI VASP: 36 +/- 20% versus 48 +/- 17% (p = 0.007). We identified more clopidogrel nonresponders in the omeprazole group than in the pantoprazole group: 44% versus 23% (p = 0.04), odds ratio: 2.6 (95% confidence interval: 1.2 to 6.2). Conversely, we did not observe any significant difference in platelet reactivity with ADP-Ag between the omeprazole and pantoprazole groups: 52 +/- 15% and 50 +/- 18%, respectively (p = 0.29).
The present findings suggest the preferential use of pantoprazole compared with omeprazole in patients receiving clopidogrel to avoid any potential negative interaction with CYP2C19.

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Available from: Pierre Emmanuel Morange, Sep 18, 2014
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    • "Oméprazole Pantoprazole Ésoméprazole Multiplate ® Oméprazole (p = 0,001) Pantoprazole (p = 0,69) Ésoméprazole (p = 0,88) Cuisset, 2009 [28] "
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    ABSTRACT: Proton pump inhibitors (PPI) and antiplatelet agents, especially aspirin and clopidogrel, are among the most prescribed medications worldwide. Their co-administration is justified by the increased risk of gastrointestinal bleeding related to the antiplatelet therapy. The issue of the interaction between PPI and clopidogrel has been raised with the emergence of the concept of "high on-clopidogrel platelet reactivity" (or "clopidogrel resistance") together with the discovery of the role of CYP2C19 isoform in the pharmacokinetics of those two medications. Indeed, CYP2C19 is involved in the conversion of the clopidogrel pro-drug into its active metabolite and is involved in the metabolisation of PPI into inactive metabolites, acting as substrates/inhibitors of CYP2C19. Despite their heterogeneity, most pharmacodynamic studies have shown a decreased clopidogrel antiplatelet effect when associated to PPI, especially those with the highest CYP2C19 inhibiting activity (omeprazole, lansoprazole, rabeprazole). On the other hand, clinical studies are inconclusive. Retrospective studies have shown an increased risk of major cardiovascular events or mortality when clopidogrel and PPI are associated in comparison with clopidogrel alone, particularly in the patients with the higher cardiovascular risk. However, the two prospective randomized studies published so far did not find any interaction and confirmed the benefit of PPI on the gastrointestinal bleeding. As a conclusion, as the clinical studies are not conclusive, the French health authorities have recently removed the alert about this interaction. PPI and clopidogrel can thus be co-prescribed.
    La Revue de Médecine Interne 11/2012; 34(2). DOI:10.1016/j.revmed.2012.11.001 · 1.07 Impact Factor
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    • "A study of 104 patients undergoing coronary stenting for non-ST wave elevation acute coronary syndrome (ACS) were randomized to either omeprazole or pantoprazole and received aspirin and clopidogrel at hospital discharge. After 1 month, patients who received pantoprazole had a significantly better platelet response to clopidogrel , suggesting preferential use compared with omeprazole [Cuisset et al. 2009]. There are no current guidelines to provide an evidence-based recommendation on PPI therapy in patients "
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    ABSTRACT: Proton-pump inhibitors (PPIs) remain the leading evidence-based therapy for upper gastrointestinal disorders, including gastroesophageal reflux disease, dyspepsia, and peptic ulcer disease. The effectiveness of PPIs has led to overutilization in multiple treatment arenas, exposing patients to an increasing number of potential risks. The overutilization of PPIs in ambulatory care settings is often a result of failure to re-evaluate the need for continuation of therapy, or insufficient use of on-demand and step-down therapy. PPI overutilization in the inpatient setting is often a result of inappropriate stress ulcer prophylaxis (SUP) in nonintensive care unit patients, and failure to discontinue SUP prior to hospital discharge. Potential consequences of prolonged PPI therapy include hypergastrinemia, enterochromaffin-like cell hyperplasia, and parietal cell hypertrophy, leading to rebound acid hypersecretion. PPIs have been linked via retrospective studies to increased risk of enteric infections including Clostridium difficile-associated diarrhea, community-acquired pneumonia, bone fracture, nutritional deficiencies, and interference with metabolism of antiplatelet agents. Reducing inappropriate prescribing of PPIs in the inpatient and outpatient settings can minimize potential for adverse events, and foster controllable cost expenditure.
    Therapeutic Advances in Gastroenterology 07/2012; 5(4):219-32. DOI:10.1177/1756283X12437358 · 3.93 Impact Factor
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    • "Recent studies have suggested that proton pump inhibitors (PPIs) might reduce the antiplatelet effects of clopidogrel through inhibition of CYP2C19 [1] [2] [3] [4]. In addition, several reports have shown that concomitant use of clopidogrel and PPIs is associated with an increased risk of adverse outcomes compared to use of clopidogrel without PPIs [3] [5]. "
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    ABSTRACT: Recent studies have reported that concomitant use of clopidogrel with proton-pump inhibitors (PPIs) might decrease antiplatelet effects and increase the risk of adverse outcomes after coronary stenting. However, little is known about the difference between clopidogrel and ticlopidine in concomitant use with PPIs, especially within the Asian population. We retrospectively analyzed 302 consecutive patients (248 males, mean age 66 ± 12 years) undergoing primary stenting for acute myocardial infarction from July 2006 to June 2010. PPIs were administered to 92% (278/302) of the patients. The patients were divided into two groups on the basis of clopidogrel (clopidogrel group, n=187) or ticlopidine (ticlopidine group, n=91) with PPI. Their characteristics, medications, and 30-day clinical outcomes were examined. There were no significant differences in 30-day major adverse cardiac events (cardiac death, non-fatal myocardial infarction, and definite stent thrombosis), bleeding events, and stroke between the two groups. The discontinuation of clopidogrel due to side effects was significantly less frequent than that of ticlopidine (1.1% vs 7.7%, p=0.003, respectively). Our findings suggest that concomitant use of clopidogrel with PPIs might be safer than ticlopidine with PPIs in patients undergoing primary stenting for acute myocardial infarction.
    Journal of Cardiology 03/2012; 60(1):7-11. DOI:10.1016/j.jjcc.2012.02.003 · 2.78 Impact Factor
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