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: Platelet activation has been implicated in the pathogenesis of sickle cell disease (SCD) suggesting antiplatelet agents may be therapeutic. To evaluate the safety of prasugrel, a thienopyridine antiplatelet agent, in adult patients with SCD, we conducted a double-blind, randomized, placebo-controlled study. The primary endpoint, safety, was measured by hemorrhagic events requiring medical intervention. Patients were randomized to prasugrel 5 mg daily (n = 41) or placebo (n = 21) for 30 days. Platelet function by VerifyNow® P2Y12 and vasodilator-stimulated phosphoprotein assays at days 10 and 30 were significantly inhibited in prasugrel- compared with placebo-treated SCD patients. There were no hemorrhagic events requiring medical intervention in either study arm. Mean pain rate (percentage of days with pain) and intensity in the prasugrel arm were decreased compared with placebo. However, these decreases did not reach statistical significance. Platelet surface P-selectin and plasma soluble P-selectin, biomarkers of in vivo platelet activation, were significantly reduced in SCD patients receiving prasugrel compared with placebo. In sum, prasugrel was well tolerated and not associated with serious hemorrhagic events. Despite the small size and short duration of this study, there was a decrease in platelet activation biomarkers and a trend toward decreased pain.Journal of Hematology & Oncology 01/2013; 6(1):17. · 4.46 Impact Factor
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ABSTRACT: BACKGROUND: Chronic kidney disease (CKD) is a common co-morbidity of patients with atherosclerotic vascular disease, and may influence the response to antiplatelet therapy. We, therefore, sought to investigate its effect on platelet activation and on-treatment residual platelet reactivity. METHODS: We assessed platelet activation and the response to clopidogrel and aspirin in 316 patients after percutaneous intervention with stent implantation. CKD was defined as a glomerular filtration rate <60 mL/min/1.73 m(2) according to the Modification of Diet in Renal Disease formula. Surface expression of activated glycoprotein IIb/IIIa without the addition of agonists was determined to assess baseline platelet activation. GPIIb/IIIa in response to adenosine diphosphate (ADP) and arachidonic acid (AA), as well as the VerifyNow assays and light transmission aggregometry (LTA) were used to measure residual platelet reactivity. RESULTS: Baseline platelet activation was significantly increased in CKD patients compared with patients without renal insufficiency [3.1 versus 2.7 mean fluorescence intensity (MFI), P = 0.001]. Moreover, patients with CKD exhibited a more pronounced expression of GPIIb/IIIa in response to ADP (13 versus 9.6 MFI) and AA (6 versus 5.1 MFI; both P≤ 0.02) than patients without CKD. In the VerifyNow assays, CKD patients showed significantly higher platelet reactivity than patients without CKD (P2Y12 assay: 239 versus 182 P2Y12 Reaction Units; aspirin assay: 415 versus 399 Aspirin Reaction Units; both P≤ 0.03). Further, patients with CKD had significantly higher platelet reactivity by LTA in response to ADP (49.9 versus 43.2%, P = 0.01). Finally, high on-treatment residual ADP-inducible platelet reactivity by the VerifyNow P2Y12 assay and by LTA occurred significantly more frequent in patients with CKD (VerifyNow: 52.2 versus 26.2%, P < 0.001; LTA: 23.3 versus 12.1%, P = 0.01). CONCLUSIONS: Patients with CKD exhibit increased platelet activation, and an attenuated response to dual antiplatelet therapy compared with patients without renal insufficiency.Nephrology Dialysis Transplantation 05/2013; · 3.37 Impact Factor
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ABSTRACT: BACKGROUND: Thrombin is the most potent platelet activator, and achieves rapid platelet activation even in the presence of antiplatelet therapy. Since activated platelets respond stronger to additional stimuli, the extent of endogenous thrombin generation may in part be responsible for the reported response variability to aspirin and clopidogrel therapy. PATIENTS AND METHODS: Thrombin generation potential was measured with a commercially available assay, and platelet reactivity was assessed with the vasodilator-stimulated phosphoprotein (VASP) phosphorylation assay, light transmission aggregometry (LTA), the VerifyNow aspirin and P2Y12 assays, and multiple electrode aggregometry (MEA) in 316 patients on dual antiplatelet therapy undergoing angioplasty and stenting. RESULTS: Peak thrombin, the lag phase and the area under the curve of thrombin generation correlated poorly with on-treatment platelet reactivity by all test systems. High on-treatment residual platelet reactivity (HRPR) in response to arachidonic acid was seen in 33 (10.5%), 41 (13%), and 79 (25.7%) patients by LTA, the VerifyNow aspirin assay, and MEA, respectively. HRPR in response to adenosine diphosphate was seen in 150 (48.1%), 48 (15.3%), 106 (33.7%), and 118 (38.3%) patients by the VASP assay, LTA, the VerifyNow P2Y12 assay, and MEA, respectively. Peak thrombin generation did not differ between patients without and with HRPR by the VASP assay, LTA, the VerifyNow P2Y12 assay and MEA. In the VerifyNow aspirin assay, patients without HRPR had higher peak thrombin generation than patients with HRPR (p=0.01). Finally, patients without and with high peak thrombin generation exhibited similar on-treatment platelet reactivity by all test systems, and high peak thrombin generation occurred to a similar extent in patients without and with HRPR. CONCLUSION: Response to antiplatelet therapy with aspirin and clopidogrel is not associated with thrombin generation potential.Thrombosis Research 04/2013; · 3.13 Impact Factor