prasugrel

Antiplatelet drug

1. DRUG PRESENTATION Moderator Dr. Tariq Ahmed Chowdhury Assistant professor Cardiology,NICVD Presenter Dr. Swapan Kumar Ray MD(Neurology), Phase-A National institute of Neurosciences & Hospital

2. PRASUGREL NEWER ANTIPLATELET

3. Process of thrombus formation: 1 . Subendothelial tissue factor exposed to circulating blood following atherosclerotic plaque rupture. 2. Activation of coagulation cascade. 3 . Platelet adhesion, activation and aggregation. 4. Formation of thrombus. INTRODUCTION

4. Injury to the endothelium, exposes the subendothelial matrix Platelets adhere to exposed collagen & von Willebrand factor Platelet activation occur under the influence of thrombin Role of platelets in thrombus formation

5. Platelet activation changes its shape & liberate more thrombin, thromboxane A2 & ADP These substances bind to their respective platelets receptors & promote further activation Activated platelets bind each other & to vessel wall forming platelet plug. These aggregated platelet combine with fibrin polymer form thrombus. Role of platelets in thrombus formation

6. Role of platelets in thrombus formation

7. 1. COX1 Inhibitor: Aspirin 2 . P2Y12Inhibitors : a. Thienopyridine : Ticlopidine, Clopidogrel, Prasugrel b. Nonthienopyridine : Ticagrelor , Cangrelor 3. GP IIb / IIIa antagonists: Abciximab , Tirofiban , Eftifibatid 4. Dipyridamol Antiplatelet drugs

8. It is a newer generation thienopyridin . It is a prodrug . Irreversibly and noncompetitively inhibit the P2Y12 receptor. Prasugrel mediated inhibition of platelet aggregation is approximately 5 to 9 times more potent than that of clopidogrel . PRASUGREL

9. It blocks the binding of adenosine diphosphate (ADP) to the receptor P2Y12 on platelet thus inhibiting- -platelet activation and aggregation Mechanism of action

10. Absorption: Absorption: >79% Peak plasma concentration: 30 min Metabolism: Rapidly hydrolyzes in intestine to a thiolactone which is then converted in the liver to active metabolite via CYP3A4 and CYP2B6. Pharmacokinetics

11. Distribution: Volume of distribution: 44-48 L Elimination: Half life: 7hrs (2-15 hr) Excretion: Urine(68%), feces(27%) Pharmacokinetics

12. Reduction of thrombotic cardiovascular events (including stent thrombosis) in patients with ACS who are to be managed with PCI for – a. Unstable angina or non-ST-elevation MI b. ST-elevation-MI (STEMI) when managed with primary or delayed PCI. Indication

13. Recommendations for Specific P2Y12 Inhibitors COR LOE Recommendations IIa B-R In patients with ACS (NSTE-ACS or STEMI) treated with DAPT after coronary stent implantation who are not at high risk for bleeding complications and who do not have a history of stroke or TIA, it is reasonable to choose prasugrel over clopidogrel for maintenance of P2Y12 inhibitor therapy. III: Harm B-R Prasugrel should not be administered to patients with a prior history of stroke or TIA. 2016 ACC/AHA Guideline

14. 60mg PO once as loading dose, then 10mg orally once daily. If patient<60kg , consider 5mg orally once daily due to potentially increased bleeding risk(efficacy and safety not established). Dosage

15. 1. Active bleeding such as peptic ulcer or intracranial hemorrhage. 2. Prior transient ischemic attack or stroke. 3. Hypersensitivity. Contraindications

16. Common: Bleeding Thrombotic thrombocytopenic purpura Others: Abnormal hepatic function Allergic reaction Angioedema Hyperlipidemia Headache Back pain Adverse effects

17. 1. With warfarin : increases the risk of bleeding. 2. With NSAIDs(used chronically): may increase the risk of bleeding. 3. Other concomitant medications: It can be administered with cytochrome P450 enzymes inducers or inhibitors. Drug Interactions

18. It can also be administered with- Aspirin Statin Digoxin and Drugs that elevate gastric PH, including PPI and H2 blockers. Drug Interactions

19. 1.Renal impairment: a. mild to moderate renal impairment ( CrCL=30-50ml/min ): -No dosage adjustment require. b. End stage renal disease : -Limited experience. Use in specific populations

20. 2.Hepatic impairment: a. Mild to moderate(Child-Pugh Class A and B): -No dosages adjustment. b. Severe hepatic disease: - No study done but chance of higher risk of bleeding. Use in specific populations

21. 3.Pregnancy: -Category B 4.Geriatric use: -Patients >75 years of age increase risk of fatal bleeding 5.Low body weight: -Individual with body weight <60kg increase risk of bleeding Use in specific populations

22. 1. TRITON–TIMI 38 study: To compare prasugrel with clopidogrel in ACS with scheduled PCI. 2. TRILOGY-ACS: To compare clopidogrel and prasugrel in high risk NSTEMI and UA patients without revascularisation . 3. PRAGUE-18 Study: To compare the efficacy and safety of prasugrel and ticagrelor in ST elevation MI treated with primary PCI. CLINICAL STUDIES

23. TRITON-TIMI 38: Trial to Asses Improvement in Therapeutic Outcomes by Optimizing platelet inhibition with prasugrel Thrombolysis In MI). To compare prasugrel with clopidogrel in ACS with scheduled PCI. Randomized, double blind, parallel group study. 13,608 patients with moderate-to-high-risk acute coronary syndromes with scheduled PCI TRITON–TIMI 38 study

24. Prasugrel (60mg loading dose and 10mg daily maintenance dose) or clopidogrel (300mg loading dose and 75mg daily maintenance dose) for 6 to 15 months. Primary end point was death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The key safety end point was major bleeding. TRITON–TIMI 38 study

25. Prasugrel significantly reduced the primary efficacy end point ( Prasugrel 9.9% vs clopidogrel 12.1%). There were significant reductions in the prasugrel group in the rates of myocardial infarction ( prasugrel 7.4% vs. clopidogrel 9.7%). It also reduce the risk of urgent target vessel revascularization ( Prasugrel 2.5% vs clopidogrel 3.7%%) & stent thrombosis(1.1% vs 2.4%) RESULTS

26. Non CABG related major bleeding was observed in 2.4% of patients receiving prasugrel and in 1.8% of patients receiving clopidogrel . CABG-related major bleeding rates were 13.4% with prasugrel vs. 3.2% with clopidogrel . RESULTS

27. The TRILOGY trial - The Targeted platelet Inhibition to cLarify the Optimal strateGY to medically manage acute coronary syndromes trial Studied clopidogrel and prasugrel in high-risk NSTEMI and unstable angina (UA) patients selected for medical management without revascularisation . TRILOGY-ACS

28.  It was a randomised , double-blind trial with a sample size (n=9326) Primary analysis involving 7243 patients age< 75 years receiving aspirin, treatment with prasugrel (10 mg/day) vs clopidogrel (75 mg/day) up to 30 months . In a secondary analysis involving 2083 patients age 75 years or older, with 5 mg of prasugrel vs 75 mg of clopidogrel . TRILOGY-ACS

29. At a median follow-up of 17 months, the primary end point of death from cardiovascular causes, myocardial infarction, or stroke among patients <75 years occurred in 13.9% of the prasugrel group and 16.0% of the clopidogrel group. Similar results were observed in the overall population RESULTS

30. Rates of severe and intracranial bleeding were similar in the two groups in all age groups. Among patients with unstable angina or myocardial infarction without ST-segment elevation, prasugrel did not significantly reduce the frequency of the primary end point, as compared with clopidogrel , and similar risks of bleeding were observed. RESULTS

31. It was designed to compare the efficacy and safety of prasugrel and ticagrelor in ST elevation MI treated with primary PCI.  A total of 1230 patients were randomly assigned, across 14 sites.  Primary end-point was defined as death, re-infarction, urgent target vessel revascularization, stroke, serious bleeding requiring transfusion or prolonging hospitalization at 7 days.  PRAGUE-18 Study

32.  The occurrence of the primary endpoint did not differ between groups receiving prasugrel and ticagrelor (4.0% and 4.1%, respectively).    The occurrence of key secondary end-point within 30 days, composed of cardiovascular death, non-fatal MI, or stroke did not show any significant difference between prasugrel and ticagrelor (2.7% and 2.5%, respectively). RESULTS

33. Among patients with STEMI undergoing primary PCI, similar efficacy and bleeding was observed for either prasugrel or ticagrelor . Among such patients, the use of either agent is acceptable. RESULTS

34. Prasugrel inhibits ADP induced platelet aggregation more rapidly, more consistently, and to a greater extent than standard doses of clopidogrel . In ACS (NSTE-ACS or STEMI) patient,after coronary stent implantation who are not at high risk for bleeding complications, prasugrel is preferable to clopidogrel . Take home messages

35. Prasugrel should not use in patient with previous TIA/stroke. Patients with STEMI undergoing primary PCI, similar efficacy and bleeding was observed for either prasugrel or ticagrelor In UA or NSTEMI without revuscularisation , prasugrel did not show any superiority over clopidogrel . Take home masseges