Matching the Evaluation of the Clinical Efficacy of Clopidogrel to Platelet Function Tests Relevant to the Biological Properties of the Drug

Labarthe, Benoit; Théroux, Pierre; Angioı̈, Michaël; Ghiţescu, M

doi:10.1016/j.jacc.2005.02.092

Cited by 115 publications

(79 citation statements)

References 28 publications

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“…A 2-step design allowed a double evaluation of the effect of 900 mg compared with lower doses. Using RPA, a more sensitive biological measure to identify suboptimal response to clopidogrel compared with MPA, 15 we found a significantly greater platelet inhibition at 4 hours with 900 mg compared with 600 or 300 mg clopidogrel. This highly significant difference 4 hours after the first load totally disappeared when the 2 lower-dose groups were loaded a second time to complete a full dose of 900 mg. At 24 hours, all patients displayed a similar level of platelet inhibition regardless of the 3 reloading strategies, suggesting also that no absorption-or metabolism-limiting factor was present when 900 mg was taken at one time.…”

Section: Discussionmentioning

confidence: 86%

“…Residual platelet aggregation (RPA) was selected because it is thought to be more specific than and to better reflect P2Y 12 function than other measurements like maximal platelet aggregation (MPA) or inhibition of platelet aggregation (IPA). 14,15 RPA corresponded to the level of aggregation curve (percentage) measured 6 minutes after induction of aggregation by ADP. Inhibition of RPA (IRPA in percentage) at time x was defined as follows: (intensity of RPA at baseline)Ϫ(intensity of RPA at time x)/(intensity of RPA at baseline).…”

Section: Laboratory Proceduresmentioning

confidence: 99%

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Dose Effect of Clopidogrel Reloading in Patients Already on 75-mg Maintenance Dose

et al. 2008

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Background-Clopidogrel loading has mostly been studied in clopidogrel-naïve patients. Whether clopidogrel-treated patients readmitted for an acute coronary syndrome or percutaneous coronary intervention can benefit from a new load of clopidogrel and at what dose remain unknown. Our aim was to evaluate the impact of 3 different strategies of administration of a loading dose of 900 mg clopidogrel in patients already treated with a maintenance dose of 75 mg clopidogrel for at least 7 days on residual platelet aggregation. Methods and Results-Patients treated long term by clopidogrel 75 mg/d were assigned to receive a first loading dose of 300, 600, or 900 mg clopidogrel and 4 hours later a second loading dose of 600, 300, or 0 mg, respectively, to achieve a total loading dose of 900 mg in all patients. Platelet aggregation was evaluated at baseline, at 4 hours after the initial load (and before second load), and at 24 hours using light transmission aggregometry with 20 mol ADP and the point-of-care assay VerifyNow P2Y 12 . The primary objective of the study was to evaluate the inhibition (relative change) of residual platelet aggregation (percentage of IRPA) between 600-and 900-mg first loading at 4 hours. IRPA at 24 hours also was evaluated as a secondary objective, as well as the rate of suboptimal response at 4 hours defined as IRPA Ͻ10%. We included 166 consecutive patients with acute coronary syndromes (nϭ80, 48%) or stable coronary artery disease (nϭ86, 52%). Baseline characteristics were similar in the 3 dose groups. A significant stepwise increase was found in percentage IRPA assessed at 4 hours in patients initially assigned to 300 versus 600 versus 900 mg (30.7% versus 40.3% versus 64.0%, respectively; Pϭ0.0024). The difference in percentage IRPA at 4 hours was not significant between 300 and 600 mg but was significant between 600 and 900 mg and between 300 and 900 mg. Percentage IRPA assessed at 24 hours when all patients had received 900 mg did not differ between the 3 loading regimens. The rates of suboptimal response (IRPA Ͻ10% at 4 hours) were 23.6%, 20.4%, and 5.3% with 300, 600, and 900 mg, respectively (Pϭ0.02 for all). Conclusions-In patients treated long term with 75 mg clopidogrel, a new loading dose of 900 mg improves IRPA and reduces poor and/or slow response to clopidogrel significantly more than that obtained with 300 or 600 mg.

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Section: Discussionmentioning

confidence: 86%

Section: Laboratory Proceduresmentioning

confidence: 99%

Dose Effect of Clopidogrel Reloading in Patients Already on 75-mg Maintenance Dose

et al. 2008

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“…Clopidogrel is a prodrug that is metabolized by CYP450 into an active metabolite, which irreversibly inhibits binding of ADP to the P2Y12 receptor on the platelet [56,57] . Increased body mass index, hemoglobin A1c, C-peptide levels, and von Willebrand factor were significant factors of clopidogrel resistance [58] .…”

Section: Clopidogrel Resistancementioning

confidence: 99%

Clinical importance of aspirin and clopidogrel resistance

Fehér

Fehér²,

Pusch³

et al. 2010

WJC

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“…5,6 This pathway provides an antiplatelet effect that is additive to the inhibition of the cyclooxygenase pathway by ASA. Clinical trial evidence supports the use of clopidogrel at a maintenance dose of 75 mg/d in adults for treatment and prevention of major cardiac events across a wide range of high-risk patients.…”

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confidence: 99%

Dosing of Clopidogrel for Platelet Inhibition in Infants and Young Children

et al. 2008

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for the PICOLO InvestigatorsBackground-Infants and young children with certain types of heart disease are at increased risk for thromboses. Clopidogrel 75 mg/d is used in adults to prevent thrombotic events. The dose to achieve similar platelet inhibition in children is unknown. The objectives of the present study were (1) to determine the dose of clopidogrel needed in infants and young children to achieve a mean 30% to 50% inhibition of 5-mol/L ADP-induced platelet aggregation (ie, inhibition similar to that observed with 75 mg in adults) and (2) to assess the safety and tolerability of clopidogrel in infants and young children. Methods and Results-We performed a prospective, multicenter, randomized, placebo-controlled trial evaluating the pharmacodynamics of clopidogrel in children (0 to 24 months) with a cardiac condition at risk for arterial thrombosis.Patients were randomized to clopidogrel versus placebo in a 3:1 ratio in 4 sequential groups (0.01, 0.10, 0.20, and 0.15 mg/kg) for Ն7 and Յ28 days. Platelet aggregation was assessed at baseline and steady state by light-transmission aggregometry. Of 116 patients enrolled, 92 (50% neonates, 50% infants/toddlers) were randomized, and 73 completed the study. A total of 79% of the randomized and treated patients were taking aspirin. Compared with placebo, clopidogrel 0.20 mg · kg Ϫ1 · d Ϫ1 resulted in a mean 49.3% (95% confidence interval 25.7% to 72.8%) inhibition of the maximum extent of platelet aggregation and a mean 43.9% (95% confidence interval 18.6% to 69.2%) inhibition of the rate of platelet aggregation. There was marked interpatient variability in the degree of platelet aggregation inhibition within each treatment-dose group and age group. No serious bleeding events occurred.

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Matching the Evaluation of the Clinical Efficacy of Clopidogrel to Platelet Function Tests Relevant to the Biological Properties of the Drug

Cited by 115 publications

References 28 publications

Dose Effect of Clopidogrel Reloading in Patients Already on 75-mg Maintenance Dose

Dose Effect of Clopidogrel Reloading in Patients Already on 75-mg Maintenance Dose

Clinical importance of aspirin and clopidogrel resistance

Dosing of Clopidogrel for Platelet Inhibition in Infants and Young Children

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