Individual variations of platelet inhibition after loading doses of clopidogrel

Järemo, Petter; Lindahl, Tomas; Fransson, Sven-Göran; Richter, Arina

doi:10.1046/j.1365-2796.2002.01027.x

Cited by 309 publications

(197 citation statements)

References 11 publications

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“…Clopidogrel response variability was first described using flow cytometry to detect ADP-induced fibrinogen binding in treated patients, 15 with subsequent confirmation in a study of percutaneous coronary intervention (PCI) patients using both turbidimetric aggregometry and flow cytometry. 16 Clopidogrel hyporesponsiveness appears to increase the risk for thrombotic events, particularly in patients undergoing PCI.…”

Section: Clopidogrelmentioning

confidence: 99%

Investigating the Mechanisms of Hyporesponse to Antiplatelet Approaches

et al. 2008

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Hyporesponsiveness, or resistance, to antiplatelet therapy may be a major contributor to poorer outcomes among cardiac patients and may be attributed to an array of mechanisms—both modifiable and unmodifiable. Recent evidence has uncovered clinical, cellular, and genetic factors associated with hyporesponsiveness. Patients with severe acute coronary syndromes (ACS), type 2 diabetes, and increased body mass index appear to be the most at risk for hyporesponsiveness. Addressing modifiable mechanisms may offset hyporesponsiveness, while recognizing unmodifiable mechanisms, such as genetic polymorphisms and diseases that affect response to antiplatelet therapy, may help identify patients who are more likely to be hyporesponsive. Hyporesponsive patients might benefit from different dosing strategies or additional antiplatelet therapies. Trials correlating platelet function test results to clinical outcomes are required. Results from these studies could cause a paradigm shift toward individualized antiplatelet therapy, improving predictability of platelet inhibition, and diminishing the likelihood for hyporesponsiveness. Copyright © 2008 Wiley Periodicals, Inc.

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Section: Clopidogrelmentioning

confidence: 99%

Investigating the Mechanisms of Hyporesponse to Antiplatelet Approaches

et al. 2008

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“…Clopidogrel is currently the thienopyridine of choice due to its more favourable safety profile compared with the first approved thienopyridine, ticlopidine. However, there are reported limitations of clopidogrel therapy, namely variability in antiplatelet effects and a relatively slow onset of action [15][16][17][18].…”

Section: Introductionmentioning

confidence: 99%

A multiple dose study of prasugrel (CS‐747), a novel thienopyridine P2Y₁₂ inhibitor, compared with clopidogrel in healthy humans

Jakubowski

Matsushima²,

Asai³

et al. 2006

Brit J Clinical Pharma

129

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AimsThis double-blind, placebo-controlled trial was designed to evaluate the pharmacodynamics, pharmacokinetics, safety, and tolerability of prasugrel (CS-747, LY640315), a novel thienopyridine P2Y12 ADP receptor antagonist compared with clopidogrel, during multiple oral dosing in healthy subjects. MethodsThirty subjects received placebo, prasugrel 5 mg, 10 mg, or 20 mg, or clopidogrel 75 mg orally, daily for 10 days. Platelet aggregation, bleeding time, and prasugrel metabolites were measured and adverse events were recorded. ResultsInhibition of ADP-induced platelet aggregation reached steady state by day 3 following prasugrel 10 and 20 mg compared with 5 days for clopidogrel 75 mg or prasugrel 5 mg. Compared with placebo, at 24 h after the last dose of study drug, inhibition of platelet aggregation using (20 mm) ADP was significantly higher in the prasugrel 10 mg group (58.2 Ϯ 4.9% vs. 9.2 Ϯ 4.0%, P < 0.001) with no difference in the clopidogrel group (15.7 Ϯ 6.8% vs. 9.2 Ϯ 4.0%, P = 0.78). With 5 mm ADP, inhibition of platelet aggregation with prasugrel 10 mg and clopidogrel 75 mg was significantly higher than with placebo (prasugrel 10 mg, 70.5 Ϯ 4.7%; clopidogrel 75 mg, 36.5 Ϯ 9.0%; vs. placebo, 11.3 Ϯ 5.1%; P < 0.0001 and P = 0.02). On day 10 at 4 h postdose, bleeding time was prolonged with prasugrel 10 mg (prasugrel 10 mg, 706 Ϯ 252 s vs. placebo, 221 Ϯ 38 s, P = 0.05) but not with clopidogrel (283 Ϯ 56 s, P = 0.98). There were no clinically significant bleeding events, serious adverse events, or discontinuations of the study drug. ConclusionsCompared with clopidogrel 75 mg, prasugrel 10 mg and 20 mg daily for 10 days resulted in more rapid, more consistent, and higher levels of platelet inhibition.

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“…Details of the assays for determining platelet reactivity have been explained before [4,5]. In short, platelets were stimulated in whole blood with ADP (1.7 and 8.5 mol/L) and a thrombin receptor activating peptide (TRAP-6) (54 and 74 mol/L).…”

Section: Laboratorymentioning

confidence: 99%

Atrial fibrillation and platelet reactivity

Milovanovic¹,

Fransson²,

Hallert³

et al. 2010

International Journal of Cardiology

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Objectve: Relationships between platelet reactivity and atrial fibrillation (AF) have not been investigated before. Thus, platelet reactions after stimulation were compared with the presence of sinus rhythm (SR) after a surveillance period exceeding two years after elective electrical cardioversion.Merthods: 33 individuals with non-valvular AF subject to elective electrical cardioversion were consented. Immediately before cardioversion determination of markers (see below) reflecting platelet reactivity was carried out. After an average of 26±8(SD) months an ECG was analyzed and platelet laboratory analysis were repeated.A flow cytometry technique was used to determine platelet reactivity i.e. surface bound fibrinogen after stimulation. ADP (1.7 and 8.5 mol/L) and a thrombin receptor activating peptide (TRAP-6) (54 and 74 mol/L) were used as platelet agonists. Results:As the study was brought to an end subjects with AF (n=18) had a trend towards lower platelet reactivity. Compared with day 1 it reached statistical significance (p=0,016) when using 1.7 mol/L ADP to activate platelets. Responses towards the other agonists did not change significantly over time. In contrast, after 26±8(SD) months subjects with SR (n=15) had significant lower platelet reactivity when stimulating with both agonists pairs. The p-values for the two ADP dilutions (1.7 and 8.5 mol/L) were p=0.002 and p=0.031, respectively. The corresponding figures for TRAP-6 (54 and 74 mol/L) proved to be p=0.042 and p=0.006. Conclusion:After 26±8(SD) months patients returning to AF had higher platelet reactivity than those who remained in SR. The finding provides a link between arrhythmia and clot formation.3

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Individual variations of platelet inhibition after loading doses of clopidogrel

Cited by 309 publications

References 11 publications

Investigating the Mechanisms of Hyporesponse to Antiplatelet Approaches

Investigating the Mechanisms of Hyporesponse to Antiplatelet Approaches

A multiple dose study of prasugrel (CS‐747), a novel thienopyridine P2Y₁₂ inhibitor, compared with clopidogrel in healthy humans

Atrial fibrillation and platelet reactivity

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Individual variations of platelet inhibition after loading doses of clopidogrel

Cited by 309 publications

References 11 publications

Investigating the Mechanisms of Hyporesponse to Antiplatelet Approaches

Investigating the Mechanisms of Hyporesponse to Antiplatelet Approaches

A multiple dose study of prasugrel (CS‐747), a novel thienopyridine P2Y12 inhibitor, compared with clopidogrel in healthy humans

Atrial fibrillation and platelet reactivity

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A multiple dose study of prasugrel (CS‐747), a novel thienopyridine P2Y₁₂ inhibitor, compared with clopidogrel in healthy humans