Effect of comedication with proton pump inhibitors (PPIs) on post-interventional residual platelet aggregation in patients undergoing coronary stenting treated by dual antiplatelet therapy. Thromb Res 125(2):e51-e54
Currently, there is an intense debate about whether comedication with proton pump inhibitors (PPIs) weakens the antiplatelet effect of clopidogrel in patients undergoing coronary stent implantation. Competing mechanisms on the hepatic cytochrome 2C19 level are proposed. The aim of this study was to assess the impact of PPI treatment on clopidogrel response by measuring the ex vivo platelet aggregation in patients with coronary intervention.
1425 consecutive patients with symptomatic coronary artery disease undergoing percutaneous coronary intervention were enrolled in this single centre study. PPI comedication was defined as PPI intake > or =1 week prior to a 600 mg clopidogrel loading dose. PPI treatment was based on physician preference. Residual platelet aggregation (RPA) was measured by optical aggregometry. To correct for potential selection bias, propensity score matching was applied.
RPA was significantly higher in PPI-treated patients compared with non-PPI-users (final aggregation 34.0% vs. 29.8%, p<0.001). Low responder defined as RPA in the upper tertile were more often found in PPI-users. After adjustment for relevant confounders, PPI treatment was independently associated with higher RPA-levels.
We demonstrated that peri-procedural co-administration of PPIs significantly decreases the effect of clopidogrel on RPA. To assess if clopidogrel-PPI interaction results in a higher susceptibility for cardiovascular events remains subject to further investigations.
"Evidence has documented that CYP2C19 plays an important role in clopidogrel bioactivation in the liver –, , and that some (if not all) PPIs can inhibit CYP2C19 activity  and affect clopidogrel platelet response –, -. To further exclude the potential impact of known covariates (such as coexisting diseases, drug interactions, and marked heterogeneity of recruited patients) on the platelet response to clopidogrel, healthy subjects should be chosen to determine such a drug interaction. "
[Show abstract][Hide abstract] ABSTRACT: Some clinical studies have demonstrated that the proton pump inhibitor (PPI) could decrease clopidogrel platelet response and increase major adverse cardiovascular events (MACE) in white or black subjects. However, that remains to be determined in Chinese patients. In this study, we sought to determine whether there could be an increased risk for developing MACE after concomitant use of dual antiplatelet therapy (DAT) and a PPI in Chinese patients treated with percutaneous coronary intervention (PCI) and stenting.
This study was a 5-year, single-center, retrospective cohort analysis of eligible patients (n = 6188) who received DAT and a PPI concomitantly (defined as PPI users) before discharge and/or 12-month follow-up after discharge as compared with those who received DAT alone (also defined as non-PPI users, n = 1465). The incidence of recurrent MACE, such as myocardial infarction (MI), definite stent thromboses (ST), or cardiovascular death, was compared between the PPI users and non-users.
PPI users had a significantly higher incidence of the MACE than non-users (13.9% vs. 10.6%; adjusted HR: 1.33; 95% CI: 1.12 - 1.57, P = 0.007). Stratified analysis revealed that concurrent use of DAT and a PPI was associated with a significantly increased risk for developing ST compared with DAT alone (1% vs. 0.4%; adjusted HR: 2.66, 95% CI: 1.16 - 5.87, P = 0.012). However, there were no significant differences in the risk of MI, cardiovascular death and other adverse events, regardless of combination of clopidogrel and a PPI.
The study further suggests that concomitant use of DAT and a PPI may be associated with an increased risk for developing MACE, in particular definite ST, in Chinese PCI patients after discharge as compared with use of DAT alone.
PLoS ONE 01/2014; 9(1):e84985. DOI:10.1371/journal.pone.0084985 · 3.23 Impact Factor
"In addition, the prevalence of low responders to clopidogrel (>456 AU*min, upper quintile) was significantly higher following omeprazole treatment (33% versus 19%, P = 0.008).37 However, in another study of patients (n = 1425) undergoing PCI, on-treatment platelet aggregation (∼20 h after a 600-mg clopidogrel oral loading dose) was significantly higher in patients receiving concomitant PPI (similar for omeprazole, esomeprazole, and pantoprazole) compared to patients not treated with PPI (P < 0.001).38 In additional, nonrandomized analysis of 300 patients undergoing PCI following a 600-mg oral clopidogrel loading dose, no apparent interaction between pantoprazole or esomeprazole with clopidogrel with regard to platelet inhibition was observed.39 "
[Show abstract][Hide abstract] ABSTRACT: Dual antiplatelet therapy (DAPT) with clopidogrel and aspirin has been successful in reducing ischemic events in a wide range of patients with cardiovascular diseases. However, the anti-ischemic effects of DAPT may also be associated with gastrointestinal (GI) complications including ulceration and bleeding particularly in 'high risk' and elderly patients. Current guidelines recommend the use of proton-pump inhibitors (PPIs) to reduce the risk of GI bleeding in patients treated with DAPT. However, pharmacodynamic studies suggest an effect of PPIs on clopidogrel metabolism with a resultant reduction in platelet inhibitory effects. Similarly, several observational studies have demonstrated reduced clopidogrel benefit in patients who coadministered PPIs. Although recent US Food and Drug Administration and European Medicines Agency statements discourage PPI (particularly omeprazole) and clopidogrel coadministration, the 2009 AHA/ACC/SCAI PCI guidelines do not support a change in current practice in the absence of adequately powered prospective randomized clinical trial data. The data regarding pharmacologic and clinical interactions between PPI and clopidogrel therapies are herein examined and treatment strategies are provided.
Drug, Healthcare and Patient Safety 11/2010; 2:233-40. DOI:10.2147/DHPS.S7297
"Both concomitant treatment with strong CYP3A4 inhibitors (Suh et al., 2006; Farid et al., 2007; Siller-Matula et al., 2008) as well as a reduced activity of CYP2C19 in patients with CYP2C19 single nucleotide polymorphisms were associated with an impaired pharmacological activity of clopidogrel (Kim et al., 2008; Mega et al., 2009; Simon et al., 2009). Several clinical studies with ex vivo determination of residual platelet aggregation demonstrated that CYP2C19 inhibitors such as proton pump inhibitors (PPIs) decrease the pharmacological effect of clopidogrel (Gilard et al., 2008; O'Donoghue et al., 2009; Price et al., 2009; Zuern et al., 2010). These findings are supported by two retrospective studies with clinical endpoints (death, re-hospitalization and/or re-infarction) (Ho et al., 2009; Juurlink et al., 2009), whereas a third clinical study failed to show an increased cardiovascular risk for patients with concomitant ingestion of clopidogrel and a PPI (O'Donoghue et al., 2009). "
[Show abstract][Hide abstract] ABSTRACT: The conversion of clopidogrel to its active metabolite, R-130964, is a two-step cytochrome P450 (CYP)-dependent process. The current investigations were performed to characterize in vitro the effects of different CYP inhibitors on the biotransformation and on the antiplatelet effect of clopidogrel.
Clopidogrel biotransformation was studied using human liver microsomes (HLM) or specific CYPs and platelet aggregation using human platelets activated with ADP.
Experiments using HLM or specific CYPs (3A4, 2C19) revealed that at clopidogrel concentrations >10 microM, CYP3A4 was primarily responsible for clopidogrel biotransformation. At a clopidogrel concentration of 40 microM, ketoconazole showed the strongest inhibitory effect on clopidogrel biotransformation and clopidogrel-associated inhibition of platelet aggregation with IC(50) values of 0.03 +/- 0.07 microM and 0.55 +/- 0.06 microM respectively. Clarithromycin, another CYP3A4 inhibitor, impaired clopidogrel biotransformation and antiplatelet activity almost as effectively as ketoconazole. The CYP3A4 substrates atorvastatin and simvastatin both inhibited clopidogrel biotransformation and antiplatelet activity, less potently than ketoconazole. In contrast, pravastatin showed no inhibitory effect. As clopidogrel itself inhibited CYP2C19 at concentrations >10 microM, the CYP2C19 inhibitor lansozprazole affected clopidogrel biotransformation only at clopidogrel concentrations < or =10 microM. The carboxylate metabolite of clopidogrel was not a CYP substrate and did not affect platelet aggregation.
At clopidogrel concentrations >10 microM, CYP3A4 is mainly responsible for clopidogrel biotransformation, whereas CYP2C19 contributes only at clopidogrel concentrations < or =10 microM. CYP2C19 inhibition by clopidogrel at concentrations >10 microM may explain the conflicting results between in vitro and in vivo investigations regarding drug interactions with clopidogrel.
British Journal of Pharmacology 09/2010; 161(2):393-404. DOI:10.1111/j.1476-5381.2010.00881.x · 4.84 Impact Factor
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