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Prasugrel• Category: Antiplatelet Agent, thienopyridine class of ADP receptor inhibitors• Target patients: acute coronary syndromes planned for percutaneous coronary intervention (PCI)
• Mechanism of Action: – a pro-drug that is metabolized to both active (R-138727) and inactive metabolites. – The active metabolite irreversibly blocks the P2Y12 component of ADP receptors on the platelet, which prevents activation of the GPIIb/IIIa receptor complex, thereby reducing platelet activation and aggregation. – Platelet aggregation returns to baseline within 5-9 days of discontinuation.• Metabolism: – Rapid intestinal and serum metabolism via esterase-mediated hydrolysis (Cholinesterase) to a thiolactone (inactive), – which is then converted, via CYP450-mediated (primarily CYP3A4 and CYP2B6) oxidation, to an active metabolite
Aim of study• Evaluation of bleeding rates and adherence to treatment in patients treated with Prasugrel
• Patients diagnosed with ACS where enrolled in this study• Indications to treatment with Prasugrel were: – STEMI – drug-eluting stent implantation in diabetics – Stent thrombosis – Left main CA drug-eluting stent implantation – PCI in pts with high residual platelet reactivity on Colpidogrel therapy
• Contraindications to prasugrel therapy were: – Recent bleeding event or major surgery – Previous TIA or stroke• LD was: 60mg• MD was: – Elders 5mg/day – Others10mg/day• Dual antiplatelet therapy was recommended for 12 months.
• platelet reactivity assessment by light transmittance aggregometry (APACT4, Helena Laboratories, Milan, Italy) 7 to 30 days after the index stenting procedure using adenosine diphosphate (ADP) 10 mol as an agonist• Blood samples anticoagulated with sodium citrate 0.109 mmol (ratio 9:1) were obtained 7 days after loading with prasugrel 60mg• Platelet-rich plasma, obtained by centrifuging whole blood for 10 minutes at 200g stimulated with ADP 10 mol.
• Platelet aggregation (according to the Born method) was evaluated considering maximal percent platelet aggregation in response to the stimulus• COV of ADP platelet aggregation was 6.8%• High residual platelet reacativity by ADP was as platelet aggregation ≥70%
• Primary end point study of any bleeding event (major, minor, or minimal) according to TIMI criteria •TIMI major bleeding involves a hemoglobin drop >5 g/dL (with or without an identified site) or intracranial hemorrhage or cardiac tamponade. •TIMI minor bleeding involves a hemoglobin drop >3 g/dL but ≤5 g/dL, with bleeding from a known site or spontaneous gross hematuria, hemoptysis, or hematemesis. •TIMI minimal bleeding involves a hemoglobin drop >4 g/dL but ≤5 g/dL without an identified bleeding site.• Secondary end point study of all-cause death, MI, stent thrombosis and stroke• Questionnaires were done to assess the clinical status of the patients
STATS• Data were expressed as mean ± SD• Chi-square test was used for comparison of variables• 2-tailed students test was used to test the differences among continuous variables.• Multivariable analyses to assess the contribution of different factors to bleeding events• Analyses were performed using SPSS 19
Findings of this study1. In clinical practice major and minor bleeding event rates associated with prasugrel therapy were comparable to those reported in controlled randomized trials.2. The minimal bleeding event rate was higher than reported but did not seem to affect adherence to treatment.3. Low residual platelet reactivity is the strongest predictor of bleeding events in patients treated with prasugrel.4. High residual platelet reactivity is an uncommon (but possible) occurrence during prasugrel therapy.5. inter-individual variability may be an issue in prasugrel in bleeding events in high responders (as in clopedogrel)
Limitations of this study1. Limited population in this study makes it difficult to evaluate prasugrel associated multicancer events reported in other studies2. Patient follow up was 6 months but other studies recommended more than 6 months follow up for patients treated by dual therapy
Summary• the main aim of this study was to report the incidence of bleeding events and its impact on adherence to treatment in real-world patients with coronary artery disease treated with prasugrel.• Other keys of interest about prasugrel in this study includes: – Inter-individual variability and prasugrel – Prasugrel’s association with cancer and metastasis