Clinical Events as a Function of Proton Pump Inhibitor Use, Clopidogrel Use, and Cytochrome P450 2C19 Genotype in a Large Nationwide Cohort of Acute Myocardial Infarction Results From the French Registry of Acute ST-Elevation and Non-ST-Elevation Myocardial Infarction (FAST-MI) Registry

Department of Pharmacology, Clinical Research Unit, APHP, St. Antoine Hospital, UMPC-Paris 06 University, 27 Rue Chaligny, Paris, France.
Circulation (Impact Factor: 14.43). 02/2011; 123(5):474-82. DOI: 10.1161/CIRCULATIONAHA.110.965640
Source: PubMed


Clopidogrel requires metabolic activation by cytochrome P450 2C19 (CYP2C19). Proton pump inhibitors (PPIs) that inhibit CYP2C19 are commonly coadministered with clopidogrel to reduce the risk of gastrointestinal bleeding. This analysis compares treatment outcomes for patients in the French Registry of Acute ST-Elevation and Non-ST-Elevation Myocardial Infarction (FAST-MI) who did or did not receive clopidogrel and/or PPIs.
The FAST-MI registry included 3670 patients (2744 clopidogrel- and PPI-naïve patients) presenting with definite MI. Patients were categorized according to use of clopidogrel and/or PPI within 48 hours after hospital admission. PPI use was not associated with an increased risk for any of the main in-hospital events (in-hospital survival, reinfarction, stroke, bleeding, and transfusion). Likewise, PPI treatment was not an independent predictor of 1-year survival (hazard ratio, 0.97; 95% confidence interval [CI], 0.87 to 1.08; P=0.57) or 1-year MI, stroke, or death (hazard ratio, 0.98; 95% CI, 0.90 to 1.08; P=0.72). No differences were seen when the type of PPI or CYP2C19 genotype was taken into account. In the propensity-matched cohorts, the odds ratios for major in-hospital events in PPI versus no PPI were 0.29 (95% CI, 0.06 to 1.44) and 1.70 (95% CI, 0.10 to 30.3) for patients with 1 and 2 variant alleles, respectively. Similarly, the hazard ratio for 1-year events in hospital survivors was 0.68 (95% CI, 0.26 to 1.79) and 0.55 (95% CI, 0.06 to 5.30), respectively.
PPI use was not associated with an increased risk of cardiovascular events or mortality in patients administered clopidogrel for recent MI, whatever the CYP2C19 genotype, although harm could not be formally excluded in patients with 2 loss-of-function alleles.

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Available from: Thierry Lefevre, Aug 03, 2015
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    • "In addition, concomitant use of clopidogrel and PPIs is associated with an increased risk of adverse outcomes compared with use of clopidogrel without PPIs [3] [5]. In contrast, several studies have reported PPI use is not associated with an increased risk of cardiovascular events or mortality in patients with administration of clopidogrel [4] [20] [21]. To date, the clinical outcomes of various studies have shown conflicting results. "
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    • "patients on sulfonylureas before the AMI, comparing those treated with glibenclamide, a medication known to block the mechanisms of ischaemic preconditioning, with those receiving the pancreatic-specific sulfonylureases gliclazide or glimepiride; in-hospital mortality and complications were more frequent in the patients on glibenclamide, a finding which suggested a true protective role of ischaemic preconditioning in patients developing AMI [8]. Recently, we investigated the influence of the co-prescription of proton pump inhibitors on clinical outcomes in patients treated with clopidogrel, and found no deleterious effect on the occurrence of ischaemic events [9]. Finally, the collection of serum and DNA in a large proportion of the patients gave us the opportunity to test new biological markers and to assess the interactions of gene variants with the efficacy of medications , opening a door into the field of pharmaco-genetics; for instance, in the FAST-MI population, patients with two variant alleles of the cytochrome CYP2C19, an enzymatic system needed for the transformation of clopidogrel into its active metabolite, were at higher risk of developing ischaemic events, both at the acute stage and during follow-up, suggesting a reduced efficacy of clopidogrel in this subgroup of patients [10]. "

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