Intrinsic platelet reactivity before P2Y12 blockade contributes to residual platelet reactivity despite high-level P2Y12 blockade by prasugrel or high-dose clopidogrel. Results from PRINCIPLE-TIMI 44.
ABSTRACT It was the objective of this study to determine whether the intrinsic platelet response to adenosine diphosphate (ADP) before thienopyridine exposure contributes to residual platelet reactivity to ADP despite high level P2Y12 blockade by prasugrel (60 mg loading dose [LD]), 10 mg daily maintenance dose [MD]) or high-dose clopidogrel (600 mg LD, 150 mg daily MD). High residual platelet function during clopidogrel therapy is associated with poor clinical outcomes. It remains unknown whether the relationship between platelet reactivity prior to treatment with clopidogrel (300 mg LD, 75 mg daily MD) and residual on-treatment platelet reactivity is maintained after more potent P2Y12 inhibition. PRINCIPLE-TIMI 44 was a randomised, double-blind, two-phase crossover study of prasugrel compared with high-dose clopidogrel in 201 patients undergoing cardiac catheterisation for planned percutaneous coronary intervention. ADP-stimulated platelet-monocyte aggregates, platelet surface P-selectin and platelet aggregation were measured pre-treatment, during LD (6 h and 18-24 h) and MD (15 d). Correlations of pre-treatment to on-treatment values were determined by Spearman rank order. Prasugrel resulted in greater platelet inhibition than high-dose clopidogrel for each measure. However, for both drugs, pre-treatment reactivity to ADP predicted 6 h, 18-24 h and 15 day reactivity to ADP (correlations 0.24-0.62 for platelet-monocyte aggregates and P-selectin). In conclusion, a patient's intrinsic platelet response to ADP before exposure to thienopyridines contributes to residual platelet reactivity to ADP despite high level P2Y12 blockade with high-dose clopidogrel or even higher level P2Y12 blockade with prasugrel. Patients who are hyper-responsive to ADP pre-treatment are more likely to be hyper-responsive to ADP on-treatment, which may be relevant to therapeutic strategies.
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ABSTRACT: The serine protease thrombin is the most potent platelet activator, and acts mainly via protease-activated receptors (PAR)-1 and -4. Data linking in vitro thrombin generation potential with PAR-1-mediated platelet activation and adverse events after angioplasty and stenting are missing, so far. In this prospective cohort study, thrombin generation potential was measured with a commercially available assay in 108 patients undergoing infrainguinal angioplasty and stenting for lower extremity artery disease classified as Rutherford stages of peripheral arterial disease (PAD) 2-3. Thrombin receptor activating peptide (TRAP)-6-inducible P-selectin expression was determined by flow cytometry. One hundred and four patients entered statistical analysis. Peak thrombin generation potential correlated inversely with TRAP-6-inducible P-selectin (r= -0.2, p<0.05). Target vessel restenosis or reocclusion (TVR) occurred in 37 patients (35.6%), and the composite atherothrombotic endpoint of myocardial infarction, ischemic stroke or transient ischemic attack, and cardiovascular death occurred in 7 patients (6.7%) within 2-year follow-up. Peak thrombin generation was similar between patients without and with TVR (465nM [354 - 566 nM] vs. 440 nM [355 - 523 nM], p=0.6), but significantly lower in patients with the atherothrombotic endpoint than in patients without atherothrombotic events (357 nM [219 - 389 nM] vs. 463 nM (362 - 55 nM, p=0.03). Further, low thrombin generation potential was associated with an 11.7-fold (95% CI 1.4 - 97.6; p=0.02) increased risk of future atherothrombotic events. Residual thrombin generation potential is inversely correlated with PAR-1-mediated platelet activation and linked to the occurrence of atherothrombotic events in patients with PAD. This article is protected by copyright. All rights reserved.European Journal of Clinical Investigation 01/2014; · 3.37 Impact Factor
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ABSTRACT: Only limited data exist about the role of point of care CYP2C19 testing in the acute setting in the early phase of acute coronary syndromes (ACS). Therefore, the present study was designed to investigate the impact of CYP2C19 loss-of-function point-of-care (POC) genotyping in patients presenting with acute coronary syndromes (ACS) and treated with dual antiplatelet therapy in the emergency setting.Thrombosis Research 05/2014; · 3.13 Impact Factor
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