Intrinsic platelet reactivity before P2Y(12) blockade contributes to residual platelet reactivity despite high-level P2Y(12) blockade by prasugrel or high-dose clopidogrel Results from PRINCIPLE-TIMI 44
Center for Platelet Research Studies, Division of Hematology/Oncology, Children's Hospital Boston, Dana-Farber Cancer Institute, Harvard Medical School, Boston, Massachusetts, USA. Thrombosis and Haemostasis
(Impact Factor: 4.98).
06/2011; 106(2):219-26. DOI: 10.1160/TH11-03-0185
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.
Available from: John Strouse
- "Platelet activation was assessed by immunoassay determination of plasma, serum, and cellular biomarkers of platelet activation. Multi-color fluorescent activated cell sorting (FACS) and monoclonal antibodies were used to determine platelet P-selectin expression using previously published protocols [22,23]. Soluble P-selectin (sP-selectin), soluble CD40 ligand (sCD40L), thromboxane B2 (serum TXB2), and prothrombin fragment F1.2 (F1.2) were determined using standard enzyme-linked immunoassays according to manufacturer’s directions. "
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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 02/2013; 6(1):17. DOI:10.1186/1756-8722-6-17 · 4.81 Impact Factor
Thrombosis and Haemostasis 08/2011; 106(2):189-90. DOI:10.1160/TH11-07-0467 · 4.98 Impact Factor
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ABSTRACT: Combined inhibition of platelet aggregation is essential to prevent recurrent ischemic episodes in patients with acute coronary syndromes and after percutaneous coronary interventions (PCIs). In combination with aspirin, the ADP receptor antagonist clopidogrel is used widespread for this purpose; however, platelet reactivity after clopidogrel differs substantially between patients and high on-treatment platelet reactivity (HTPR) persists in a substantial proportion of cases. Since more than 20 prior observational studies linked HTPR to higher risk of ischemic events, including cardiovascular death, myocardial infarction, and stent thrombosis, monitoring post-clopidogrel platelet reactivity after PCI might be beneficial for risk assessment and to tailor the antiplatelet therapy to the patients' needs. However, there is no consensus on the role of routine platelet function monitoring in clinical guidelines. This article aims to review the available evidence regarding the clinical relevance of platelet function monitoring, highlighting possible reasons for the controversy between guidelines and observational studies.
Platelets 09/2011; 23(3):167-76. DOI:10.3109/09537104.2011.610475 · 2.98 Impact Factor
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