1. NSTEMI: GPIIB/IIIA Inhibitors & Emerging Antiplatelets: Where Do We Stand? Rabih R. Azar, MD, MSc, FACC Director of Cardiovascular Research Hotel Dieu de France Hospital Associate Professor of Medicine Saint Joseph University School of Medicine Beirut, Lebanon

2. Role of the Platelets in Thrombosis ST  MI:occlusive thrombus (platelets, red blood cells, and fibrin) UA/NQMI:Partially-occlusive thrombus (primarily platelets) Intra-plaque thrombus (platelet dominated) Plaque core Intra-plaque thrombus (platelet dominated) Plaque core SUDDEN DEATH Adapted from Davies MJ. Circulation. 1990; 82 (supl II): 30-46.

3. GP IIb/IIIa Receptor Activation Pathway ADP Thrombin TXA2 PAF PLATELET ASPIRIN Vasopressin Epi ASPIRIN ASPIRIN HEPARINS ASPIRIN CLOPIDOGREL ASPIRIN ASPIRIN 5HT ASPIRIN Collagen GP IIb/IIIa Thickness of lineindicates strengthof activator Fibrinogen GP IIb/IIIa PLATELET

4. Blood vessel wall Platelet Platelet IIb/IIIa receptor blockers IIb/IIIa Fibrinogen Platelet aggregation Ib receptor Ib Ib Ib Ib Platelet adhesion Site of injury Platelet-fibrinogen interaction

5. PRISM-PLUS: Study Design • UA or NSTEMI patients • Chest pain within 12 h and ECG abnormalities or elevated CK-MB Randomization Heparin 5000 U loading, then 1000 U maintenance (n=797) AGGRASTAT 0.4 g/kg/min for 30 min, then 0.10 g/kg/min maintenance + heparin (n=773) 48 h • Endpoints • Primary: Composite death, MI, refractory ischemia, rehospitalization at 7 days • Secondary: Death, MI, refractory ischemia, rehospitalization at 48 h, 30 days, and 6 months • Safety: Major bleeding (>4.0 g/dLdecrease in Hb, blood transfusion >2 U, need for corrective surgery, or intracranial or retroperitoneal hemorrhage, or any combo) 8 PRISM-PLUS Study Investigators. N Engl J Med. 1998;338(21):1488-1497.

6. PRISM PLUS: Results NEJM 1998;338:1488

8. RAPPORT: Abciximab in primary PTCA reduces death/MI/urgent TVR at 30 days Brenner et al. Circulation 1998;98:734

9. Synergy between abciximab and stenting in primary angioplasty for acute MI. Event free suvival (death, acute coronary syndromes, TVR) Azar et al. J Am Coll Cardiol 1998;32:1996

10. GP IIb/IIIa Receptor Activation Pathway ADP Thrombin TXA2 PAF PLATELET ASPIRIN Vasopressin Epi ASPIRIN ASPIRIN HEPARINS ASPIRIN CLOPIDOGREL ASPIRIN ASPIRIN 5HT ASPIRIN Collagen GP IIb/IIIa Thickness of lineindicates strengthof activator Fibrinogen GP IIb/IIIa PLATELET

13. Does Clopidogrel Eliminate the Need for GPIIb/IIIaAntogonists?

14. Treatment with AGGRASTAT™ provides greater flexibility for early surgical procedures, transfer, or discharge Fast-On Approximate % platelet aggregation blocked Fast-Off Return to baselineof platelet function 100 100 80 80 60 60 % inhibition % inhibition 40 40 20 20 0 0 0.5 12 24 48 End infusion 2 3 4 5 6 7 8 Hours of infusion Hours postinfusion Adapted from Kereiakes DJ et al. Am Coll Cardiol 1996;27(3):536-542 Slide 14

16. EPISTENT: Effect of Thienopyridine Pretreatment 33% (P=0.033) 42% (P=0.028) PlaceboNo Pretreat PlaceboPretreat AbcixNo Pretreat AbcixPretreat Steinhubl S et al. Circulation 2001;103:1403-9

20. Enough Data to Support the Use of GPIIb/IIIa Antagonists during High-Risk PCI • GPIIb/IIIa antagonists: • Should be given for patients with high risk ACS undergoing PCI irrespective of the use of clopidogrel • Question is timing: upstream (as early as possible on admission) or downstream (in the cath lab at the time of PCI)

21. UpStream vs. Downstream GPIIb/IIIa InhibitorsACUITY Timing trial • 9207 patients with ACS • Upstream vs. downstream use of GPIIb/IIIa • Upstream: 98% received GPIIb/IIIa; mean duration 18.3 h • Downstream: 56% received GPIIb/IIIa; mean duration 13.1 h • Use of thienopyridines: 64% before angiography or PCI

22. UpStream vs. Downstream GPIIb/IIIa InhibitorsACUITY Timing trial P = NS P = 0.009 Stone et al. JAMA 2007;297:591-602

26. All-Cause Mortality 30 Days open label & double-blind, n = 1398

27. 1 Year Survival: Patients with Primary PCI open label & double-blind, n = 1.155 P = 0.007

28. But We Have New Oral Anti-platelet Agents that are MORE POTENT than Clopidogrel

30. Patients included in TRITON were “clopidogrel and prasugrel naives”. There was no PRE-TREATMENT with either of the 2 drug. Clopidogrel or prasugrel were given on the cath table, immediately prior or during PCI

39. STEMI Ticagrelor compared with clopidogrel in patients with acute coronary syndromesthe PLATelet Inhibition and patient Outcomes trial Outcomes in patients with STEMI and planned PCI Ph.Gabriel Steg*, Stefan James, Robert A Harrington, Diego Ardissino, Richard C. Becker, Christopher P. Cannon, Håkan Emanuelsson, Ariel Finkelstein, Steen Husted, Hugo Katus, Jan Kilhamn, Sylvia Olofsson, Robert F. Storey, Douglas Weaver, Lars Wallentin, for the PLATO study group *Unité INSERM U-698 Hôpital Bichat – Claude Bernard Université Paris VII – Denis Diderot The PLATO trial was funded by AstraZeneca

40. Primary endpoint: CV death, MI or stroke 12 11 10 9 8 7 6 5 4 3 2 1 0 Clopidogrel 11.0 9.3 Ticagrelor K-M estimated rate (% per year) HR: 0.85 (95% CI = 0.74–0.97), p=0.02 0 1 2 3 4 5 6 7 8 9 10 11 12 Months No. at risk Ticagrelor 4,201 3,887 3,834 3,732 3,011 2,297 1,891 Clopidogrel 4,229 3,892 3,823 3,730 3,022 2,333 1,868

41. Proposed Algorithm for Initial Management of NSTEMI Aspirin + Hep or Enoxaparin ST depression or + troponin ? NO YES Conservative therapy: No indication for GPIIb/IIIa antagonists • - clopidogrel (class I) or ticagrelor(class I) and early cath lab. If PCI: Tirofiban in cath lab (class I). If CABG: WAIT 5 DAYS • OR • Tirofiban (class I ACC/ Iia ESC) and early cath lab. If PCI prasugrel (class I) (or clopidogrel) on the table. If CABG, do it same or next day

42. Proposed Algorithm for Initial Management of STEMI Possibility of Primary PCI? NO Yes Aspirin + clopidogrel or prasugrel or ticagrelor* (class I) Fibrinolysis IIb/IIa antagonist - pre cath: IIb - During PCI: IIa

43. ESC Guidelines for GPIIb/IIIa Inhibitors in NSTEMI

44. ACC/AHA Guidelines for GPIIb/IIIa Inhibitors in NSTEMI

49. Treatment with AGGRASTAT™ provides greater flexibility for early surgical procedures, transfer, or discharge Fast-On Approximate % platelet aggregation blocked Fast-Off Return to baselineof platelet function 100 100 80 80 60 60 % inhibition % inhibition 40 40 20 20 0 0 0.5 12 24 48 End infusion 2 3 4 5 6 7 8 Hours of infusion Hours postinfusion Adapted from Kereiakes DJ et al. Am Coll Cardiol 1996;27(3):536-542 Slide 14

50. Keys Points in Anti-Platelet Therapy in NSTEMI During PCI: GPIIb/IIIaantogonists are class I indication in both ESC and ACC/AHA guidelines on top of aspirin and thienopyridines Dual anti-platelet therapy as early as possible in high-risk patients (asa + clopidogrel or ticagrelor; class I) or (asa + GPIIb/IIIa class I in ACC and class IIa in ESC) I favor GPIIb/IIIa antagonists rather than thienopyridines because safer if surgery (allows surgery sooner) Routine triple anti-platelet therapy in high-risk patients prior to PCI is class IIb indication in the ACC/AHA guidelines and class III indication in ESC guidelines (but it becomes class IIb if recurrent ischemia) GPIIb/IIIa antagonists are not recommended for low risk patients