Variability in aggregometry response before and after initiation of clopidogrel therapy

Meen, Øystein; Brosstad, Frank; Bjørnsen, Stine; Pedersen, Turid M.; Erikssen, Gunnar

doi:10.3109/00365510902971875

Cited by 5 publications

(1 citation statement)

References 41 publications

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“…The appropriate sample size for studies 1-3 was determined on the basis of historical pharmacodynamic data indicating that intraindividual variation in platelet response is ≥10%. 35 A >10% difference in platelet aggregation values has been suggested to be indicative of a clinically relevant effect. 36 Allowing for a 10% true difference between treatment with clopidogrel + omeprazole and treatment with clopidogrel alone in the mean values of MPA induced by ADP 5 μmol/l, the number of subjects required to demonstrate equipotency with 90% power was 58 (assuming a true within-subject standard deviation (SD within ) of 9%, obtained from four internal repeated dose studies of clopidogrel 75 mg/ day) and ensuring that the CI of the absolute difference between treatments in MPA induced by ADP 5 μmol/l was not greater than the prespecified threshold of ±15%.…”

Section: Articlesmentioning

confidence: 99%

Differential Effects of Omeprazole and Pantoprazole on the Pharmacodynamics and Pharmacokinetics of Clopidogrel in Healthy Subjects: Randomized, Placebo-Controlled, Crossover Comparison Studies

Angiolillo

Gibson

Cheng

et al. 2010

Clin Pharmacol Ther

253

218

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Four randomized, placebo-controlled, crossover studies were conducted among 282 healthy subjects to investigate whether an interaction exists between clopidogrel (300-mg loading dose/75-mg/day maintenance dose) and the proton-pump inhibitor (PPI) omeprazole (80 mg) when they are administered simultaneously (study 1); whether the interaction, if any, can be mitigated by administering clopidogrel and omeprazole 12 h apart (study 2) or by increasing clopidogrel to 600-mg loading/150-mg/day maintenance dosing (study 3); and whether the interaction applies equally to the PPI pantoprazole (80 mg) (study 4). Relative to levels after administration of clopidogrel alone in studies 1,2,3, and 4, coadministration of PPI decreased the AUC(0-24) of the clopidogrel active metabolite H4 by 40, 47, 41, and 14% (P ≤ 0.002), respectively; increased maximal platelet aggregation (MPA) induced by 5 micromol/l adenosine diphosphate (ADP) by 8.0, 5.6, 8.1, and 4.3% (P ≤ 0.014), respectively; and increased the vasodilator-stimulated phosphoprotein phosphorylation-platelet reactivity index (VASP-PRI) by 20.7, 27.1, 19.0 (P < 0.0001), and 3.9% (P = 0.3319), respectively. The results suggest that a metabolic drug-drug interaction exists between clopidogrel and omeprazole but not between clopidogrel and pantoprazole.

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Section: Articlesmentioning

confidence: 99%

Differential Effects of Omeprazole and Pantoprazole on the Pharmacodynamics and Pharmacokinetics of Clopidogrel in Healthy Subjects: Randomized, Placebo-Controlled, Crossover Comparison Studies

Angiolillo

Gibson

Cheng

et al. 2010

Clin Pharmacol Ther

253

218

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Clopidogrel: A multifaceted affair

Martínez‐Quintana

Tugores

2014

The Journal of Clinical Pharma

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Clopidogrel has been the therapy of choice, combined with aspirin, against platelet aggregation in patients at risk of suffering a vascular thrombotic event. Not all patients respond equally to clopidogrel, an observation that has led to searching for a test that, in the clinical setting, could predict patients' "resistance" to therapy. The evidence reveals a complex pharmacokinetic profile for clopidogrel, with multiple players involved, including cytochromes, characteristics of the target tissue, and accompanying clinical conditions. Despite FDA black box warnings recommending CYP2C19 genotyping before clopidogrel use, no robust evidence indicates that CYP2C19 function determines clinical response to the drug, either based on the presence of loss of function alleles or drug interactions with CYP2C19 inhibitors, like omeprazole. A tailored anti-aggregation treatment based on ex vivo platelet reactivity also seems unlikely due to the lack of robustness of most assays. The identification of clinical conditions that are at higher risk of new cardiovascular events, such as diabetes, obesity, coronary artery disease, or specific stenting procedures, seems to be a prudent approach to tailor anti-platelet therapy with more powerful drugs, accompanied by careful counseling to promote patient compliance. Keywords clopidogrel, response, pharmacogenetics, clinicalPlatelet anti-aggregation is the main therapeutic approach to prevent new cardiovascular complications in patients who have suffered a major acute cardiovascular event (MACE) and may have undergone a percutaneous coronary intervention (PCI). 1 A well-established treatment regime has been the combination of aspirin, that blocks thromboxane synthesis, and clopidogrel, a prodrug that, upon biotransformation, irreversibly blocks the binding of adenosine diphosphate (ADP) to its platelet P2Y 12 receptor (previously P2T), thus preventing the inactivation of adenylate cyclase (AC) and the subsequent activation of the glycoprotein GPIIb/IIIa complex, required for platelet aggregation. 2 The clinical benefit of adding clopidogrel to aspirin therapy has been demonstrated by several large, multicenter, randomized, controlled trials. The CAPRIE trial (clopidogrel vs. aspirin in patients at risk of ischemic events) was the first to prove the benefit of clopidogrel over aspirin, showing a relative risk reduction of 8.7% for the secondary prevention of cardiovascular events in 19,185 patients with clinical manifestations of atherosclerosis. 3 The CURE (clopidogrel in unstable angina to prevent recurrent events) study, performed in 12,562 patients with acute coronary syndrome (unstable angina or non-ST elevation myocardial infarction), demonstrated that a loading dose of 300 mg clopidogrel followed by a once daily treatment with 75 mg, in addition to aspirin (75-325 mg/day) significantly reduced the risk of the combined endpoint of cardiovascular death, myocardial infarction, and stroke (9.3% of the patients in the clopidogrel group vs. 11.4% of the patients in the p...

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Effect of rifampicin on the pharmacokinetics and pharmacodynamics of ticagrelor in healthy subjects

Teng

Mitchell

Butler

2012

Eur J Clin Pharmacol

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Variability in aggregometry response before and after initiation of clopidogrel therapy

Cited by 5 publications

References 41 publications

Differential Effects of Omeprazole and Pantoprazole on the Pharmacodynamics and Pharmacokinetics of Clopidogrel in Healthy Subjects: Randomized, Placebo-Controlled, Crossover Comparison Studies

Differential Effects of Omeprazole and Pantoprazole on the Pharmacodynamics and Pharmacokinetics of Clopidogrel in Healthy Subjects: Randomized, Placebo-Controlled, Crossover Comparison Studies

Clopidogrel: A multifaceted affair

Effect of rifampicin on the pharmacokinetics and pharmacodynamics of ticagrelor in healthy subjects

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