Role of Prasugrel In Acute Coronary syndrome.pptx

Role of Prasugrel antiplatelet in Acute coronary syndrome.

1. Role of Prasugrel in Acute Coronary Syndrome Dr Anshul Kumar Gupta Consultant Interventional Cardiologist Manipal Hospital, Jaipur

2. Introduction Pivotal role of antiplatelet therapy in ACS Limitations of currently available antiplatelet agents Need of the hour Road Map Prasugrel Overview Indications Dosage & Administration Contraindications & Precautions Comparison with other P2Y12 inhibitors Clinical Evidences Guideline recommendations Acute Coronary Syndrome 1. Role of Prasugrel in ACS Management 2. Summary 3.

3. Acute Coronary Syndrome

4. Acute Coronary Syndrome (ACS) ACS is one of the leading causes of death worldwide and studies have shown higher mortality rates and premature death in South Asian countries ACS is an umbrella term for the clinical disorders like: https:// www.heart.org/en/health-topics/consumer-healthcare/what-is-cardiovascular-disease/coronary-artery-disease SUPPLEMENT TO JAPI • december 2011 • VOL. 59 BMC Cardiovasc Disord 19, 229 (2019) doi:10.1186/s12872-019-1217-x The dynamic nature of the Coronary Artery Disease (CAD) process results in various clinical presentations, which can be conveniently categorized as either Acute Coronary Syndromes ( ACS) or Chronic Coronary Syndromes (CCS)

5. Anti-platelet Therapy – Pivotal role in ACS Platelet activation and aggregation after plaque rupture plays the key role in formation of arterial thrombosis leading to ACS Reduces the risk of subsequent MI, stroke and vascular death by approx. 20-36%. Mitigates the risk of stent thrombosis GpIIb/ IIIa receptor antagonists are only employed intravenously in high risk ACS patients Aspirin and P2Y12 Inhibitors are widely used for the management of ACS J CARDIOVASC PHARMACOL THER 2013 18: 514 J Am Coll Cardiol.  2014 Dec 23;64(24): e139-e228

6. Limitations of Currently Available Antiplatelet Agents Agent Limitation Ticlopidine Currently discouraged due to life-threatening side effects including neutropenia , aplastic anemia Aspirin 5-60% treatment resistance Clopidogrel Delayed antiplatelet activity (Many steps of hepatic metabolism) Reduced potency: Only 15% drug is converted to active metabolite Increased inter-patient response variability 25% of patients only partially responsive Ticagrelor Higher incidence of hemorrhagic side effects than clopidogrel in non-CABG patients Interaction with CYP-targeted drugs Twice daily dosing

7. Need of The Hour

8. Role of Prasugrel in ACS Management

9. Prasugrel- Overview

10. Indications Acute Coronary Syndrome

11. Dosage & Administration

12. Adverse reactions, Contraindications & Precautions

13. Use in special population

14. Pharmacological properties of P2Y12-receptor inhibitors *The binding site of cangrelor at the P2Y12-receptor level is not clearly defined; nevertheless, cangrelor is associated with high levels of receptor occupancy preventing ADP signalling. Abbreviations: ACS, acute coronary syndromes; CAD, coronary artery disease; CYP, cytochrome P450; PCI, percutaneous coronary intervention.

15. Comparison of Clopidogrel, Prasugrel and Ticagrelor Clopidogrel Prasugrel Ticagrelor Contraindications Any active pathological bleeding Any active pathological bleeding; any history of TIA/stroke Any active pathological bleeding; ICH or severe hepatic disease Surgery hold time 5 days for elective surgery; 24 hours for urgent 7 days 5 days for elective surgery; 24 hours for urgent NSTE-ACS indication May be used regardless of treatment strategy; additional non-ACS indications Reasonable over clopidogrel in patients treated with PCI who are not at high risk for bleeding Preferable to clopidogrel for NSTEACS patients treated with early or invasive or ischemia-guided Approach STEMI indication Preferred when fibrinolytics used Superior to clopidogrel in STEMI or in other high risk patients like DM; not studied in patients receiving fibrinolytic therapy Superior to clopidogrel; not studied in patients receiving fibrinolytic Therapy

16. Antithrombotic treatments in non-ST-segment elevation acute coronary syndrome patients European Heart Journal (2020) 00, 179

17. Clinical Evidence

18. TR ial to Assess I mprovement in T herapeutic Outcomes by O ptimizing Platelet Inhibitio N with Prasugrel – TRITON TIMI 38 Method: N Engl J Med 2007; 357:2001-2015 Primary End Point: Death from CV causes, nonfatal MI, or nonfatal stroke Safety End Point: Major Bleeding 13,608 Pts (moderate to high risk ACS) going for schedule PCI) N= 6813 N=6708 Prasugrel (60-mg LD and a 10-mg OD MD) Clopidogrel (300-mg LD and 75-mg OD MD) 6-15 month LD= Loading dose; MD= Maintenance dose; OD= Once daily

19. TR ial to Assess I mprovement in T herapeutic Outcomes by O ptimizing Platelet Inhibitio N with Prasugrel – TRITON TIMI 38 The primary efficacy end point occurred in 12.1% of patients receiving clopidogrel and 9.9% of patients receiving prasugrel N Engl J Med 2007; 357:2001-2015 Results

20. TR ial to Assess I mprovement in T herapeutic Outcomes by O ptimizing Platelet Inhibitio N with Prasugrel – TRITON TIMI 38 Significant reductions in the prasugrel group in the rates of Stent thrombosis ( 2.4% for clopidogrel vs. 1.1% for prasugrel; P<0.001). N Engl J Med 2007; 357:2001-2015

21. TR ial to Assess I mprovement in T herapeutic Outcomes by O ptimizing Platelet Inhibitio N with Prasugrel – TRITON TIMI 38 Major bleeding was observed in 2.4% of patients receiving prasugrel and in 1.8% of patients receiving clopidogrel N Engl J Med 2007; 357:2001-2015

22. TR ial to Assess I mprovement in T herapeutic Outcomes by O ptimizing Platelet Inhibitio N with Prasugrel – TRITON TIMI 38 Prasugrel reduced the rate of the primary endpoint in diabetic patients Primary end point occurred in 17 % patients of clopidogrel group and 12.2% patients of prasugrel group. N Engl J Med 2007; 357:2001-2015

23. TR ial to Assess I mprovement in T herapeutic Outcomes by O ptimizing Platelet Inhibitio N with Prasugrel – TRITON TIMI 38 N Engl J Med 2007; 357:2001-2015 Prasugrel therapy In patients with ACS with scheduled PCI shows:

24. Intracoronary Stenting and Antithrombotic Regimen- Rapid Early for Coronary Treatment 5 - ISAR-REACT 5 Method : N Engl J Med 2019; 381:1524-1534 Primary End Point: Composite of death, MI, stroke Safety End Point: Bleeding 4018 Pts (Presented with ACS) going invasive evaluation) N= 2006 N=2012 Prasugrel Strategy (60-mg LD and a 10-mg OD MD) Ticagrelor Strategy (180-mg LD and 90-mg BID MD) 1 year follow up LD= Loading dose; MD= Maintenance dose; OD= Once daily; BID= Twice daily

25. Intracoronary Stenting and Antithrombotic Regimen- Rapid Early for Coronary Treatment 5 - ISAR-REACT 5 Fig .: Cumulative Incidence of the Primary End Point at 1 Year.   A primary-end point event occurred in 184 of 2012 patients (9.3%) in the ticagrelor group and in 137 of 2006 patients (6.9 %) in the prasugrel group 9.3% 6.9% N Engl J Med 2019; 381:1524-1534

26. Intracoronary Stenting and Antithrombotic Regimen- Rapid Early for Coronary Treatment 5 - ISAR-REACT 5 Fig .: Cumulative Incidence of the Safety End Point at 1 Year.   Major bleeding was observed in 5.4 % of patients in the ticagrelor group and in 4.8 % of patients in the prasugrel group 5.4% 4.8% N Engl J Med 2019; 381:1524-1534

27. Intracoronary Stenting and Antithrombotic Regimen- Rapid Early for Coronary Treatment 5 - ISAR-REACT 5 Results End points Ticagrelor (n=2012) Prasugrel (n=2006) Hazard ratio ( 95% CI) Primary end point 9.3 % (n=184) 6.9 % (n=137) 1.36 (CI=1.09-1.70) P value= 0.006 Death 4.5 % (n=90) 3.7 % (n=73) 1.23 (CI= 0.91-1.68) MI 4.8 % (n=96) 3.0 % (n=60) 1.63 (CI= 1.18-2.25) Stroke 1.1 % (n=22) 1.0 % (n=19) 1.17 (CI= 0.63-2.15) Definite or Probable stent thrombosis 1.3 % (n=26) 1.0 % (n=19) 1.30 (CI= 0.72-2.33) Define stent thrombosis 1.1 % (n=22) 0.6 % (n=12) - Major Bleeding 5.4% (n=95/1989) 4.8% (n=80/1773) 1.12 (0.83–1.51) N Engl J Med 2019; 381:1524-1534

28. Intracoronary Stenting and Antithrombotic Regimen- Rapid Early for Coronary Treatment 5 - ISAR-REACT 5 N Engl J Med 2019; 381:1524-1534 Conclusion:

29. TaRgeted Platelet Inhibition to CLarify the Optimal StrateGY to Medically Manage Acute Coronary Syndromes ( TRILOGY ACS ) Method: N Engl J Med 2012; 367:1297-130 Clopidogrel (LD 300 mg, MD 75 mg OD) Prasugrel (LD 30 mg, MD 5 mg OD) Clopidogrel (LD 300 mg, MD 75 mg OD) Prasugrel (LD 30 mg, MD 10 mg OD) Primary End Point: Composite of death from CV causes, nonfatal MI, or nonfatal stroke among pts <75 years age Secondary End Point: Death from CV causes, all MI & strokes Patients with UA or MI without STEMI who do not undergo invasive therapy Primary Analysis [N=7243 (age <75 years)] 30 month (Median follow up of 17 months Secondary Analysis [N=2083 (age >75 years)]

30. TaRgeted Platelet Inhibition to CLarify the Optimal StrateGY to Medically Manage Acute Coronary Syndromes ( TRILOGY ACS ) Results: N Engl J Med 2012; 367:1297-130 Fig .: Primary efficacy endpoint and TIMI Major bleeding through 30 months .   A primary efficacy end point event occurred in 20.3% patients in the Clopidogrel group and in 18.7% patients in the prasugrel group Rates of severe and intracranial bleeding were similar in the two groups in all age groups

31. TaRgeted Platelet Inhibition to CLarify the Optimal StrateGY to Medically Manage Acute Coronary Syndromes ( TRILOGY ACS ) N Engl J Med 2012; 367:1297-130 Conclusion

32. Effects of clopidogrel vs. prasugrel vs. ticagrelor on endothelial function, inflammatory parameters, and platelet function in patients with acute coronary syndrome undergoing coronary artery stenting: a randomized, blinded, parallel study

33. Aim: In a randomized, parallel, blinded study, authors investigated the impact of clopidogrel, prasugrel, or ticagrelor on peripheral endothelial function in patients undergoing stenting for an acute coronary syndrome. Single loading dose of 600mg (clopidogrel), 60mg (prasugrel), or 180mg (ticagrelor) followed by chronic treatment: clopidogrel 75mg o.d., 10mg o.d. prasugrel, or 90mg b.i.d. ticagrelor Primary End Point: Change in endothelium-dependent flow mediated dilation (FMD) following stenting Secondary End Point: To test the impact of the three study medications on parameters of endothelial function after an acute loading dose of the three study drugs Patients with unstable angina or NSTEMI undergoing coronary intervention with a drug-eluting stent. NSTEMI In 49 patients 2 h after the loading dose (only for patients recruited before amendment 1), and 1 day, 1 week, 1month after stenting. Unstable Angina in 41 patients Endothelium, stenting, and antiplatelet therapy (EST)—clopidogrel, prasugrel, ticagrelor study European Heart Journal (2020) 0, 1–10

34. RESULTS

35. Endothelium, stenting, and antiplatelet therapy (EST) clopidogrel, prasugrel, ticagrelor study Endothelial function data—FMD European Heart Journal (2020) 0, 1–10

36. Endothelium, stenting, and antiplatelet therapy (EST) clopidogrel, prasugrel, ticagrelor study Endothelial function data—L-FMC European Heart Journal (2020) 0, 1–10

37. Endothelium, stenting, and antiplatelet therapy (EST) clopidogrel, prasugrel, ticagrelor study The impact of the three study medications on flow-mediated dilation. Percutaneous coronary intervention impaired flow-mediated dilation in the clopidogrel and ticagrelor group, and flow-mediated dilation remained higher during follow-up in the prasugrel group. European Heart Journal (2020) 0, 1–10

38. Endothelium, stenting, and antiplatelet therapy (EST) clopidogrel, prasugrel, ticagrelor study The impact of the three study medications on interleukin-6 plasma levels post-percutaneous coronary intervention. Levels where lowest in the prasugrel group European Heart Journal (2020) 0, 1–10

39. CONCLUSION European Heart Journal (2020) 0, 1–10

40. Prasugrel + Aspirin

41. The TAXUS Liberté Post Approval Study ( TL-PAS) Method: Coprimary End Point: Composite of death, MI or stroke Safety End Point: Major Bleeding 2191 Pts (eligible for DAPT) N=1093 N=1098 Prasugrel + ASA (12 month) Prasugrel + ASA (30 month) 33 month clinical follow up

42. The TAXUS Liberté Post Approval Study ( TL-PAS) Results:

43. The TAXUS Liberté Post Approval Study ( TL-PAS)

44. Figure: Major adverse cardiac and cerebrovascular events (MACCEs ) The rates of MACCE (A) and its components (all-cause death [B], stroke [C], and Academic Research Consortium [ARC]-defined myocardial infarction [MI; D]) through 630 days after randomization (33 months of follow-up after index procedure) are shown for patients in the 12-month (red) and 30-month (black) prasugrel treatment groups. The TAXUS Liberté Post Approval Study ( TL-PAS)

45. The TAXUS Liberté Post Approval Study ( TL-PAS) Conclusion:

46. Guideline Recommendations

47. ESC 2020 guideline for NSTEMI ACS

48. What is new? European Heart Journal (2020) 00, 179

49. What is new? European Heart Journal (2020) 00, 179

50. What is new? European Heart Journal (2020) 00, 179

51. What is new? European Heart Journal (2020) 00, 179

52. European Heart Journal (2020) 00, 179

53. European Heart Journal (2020) 00, 179

54. Guideline Recommendations According to the 2016 ACC/AHA and 2017 ESC Guidelines, Prasugrel is preferred over clopidogrel in ACS

55. Guideline Recommendations 2017 ESC Guideline recommended Prasugrel on top of Aspirin for ACS patients undergoing for PCI

56. Summary

57. Thank you