1. EBM Chengyu (Cheryl) Xu March, 2012 ACS trials

2. Outline – over 70 ACS trials Mangement strategy Cardiogenic shock Lytics/Referfusion Stable CAD/Elective PCI ACEI/ARBs Aldosterone antagonists Anticoagulation Antiplatelets Beta blockers Calcium channel blockers Glycoprotein IIb/IIIa inhibitors Statins Nitrates

3. Q: A 65 y/o woman is evaluated in the hospital 36 hours after presenting in the ED with mid-sternal chest pain. She has a history of HTN and HLD and is a prior smoker. Home medications include ToprolXL 100mg daily, atorvastatin 80mg daily and asprin 325mg daily. Her troponin level rose to a peak of 4.2ng/ml at 24 hrs following the event. EKG on presentation demonstrated no ST-segment shifts, but T-wave inversion in leads V3 and V4. PCI was performed next day which demonstrates diffuse small coronary vessel disease not amenable to stent placement. What anti-platelet regimen will you choose, prior to PCI after PCI A. ASA 325mg X1 + Plavix 75mg X1ASA 325mg qd + plavix 75mg qd indefenitely B. ASA 325mg X1 + Plavix 600mg X1ASA 81mg qd + plavix 75mg qd indefinitely C. ASA 325mg X1 + Plavix 600mg X1ASA 81mg qd indefinitely + plavix 75mg qd X 1 month D. ASA 325mg X1 + Plavix 600mg X1ASA 81mg qd indefinitely + plavix 75mg qd X 1 year E.ASA 325mgX1 + Plavix 300mg X1ASA 325mg qd indefinitely + plavix 75mg qd X 1 month F.ASA 325mgX1 + Plavix 300mg X1ASA 81mg qd indefinitely + plavix 75mg qd X 1 year

4. Antiplatelets 1996: CAPRIEClopidogrel, ASA 2000: OPUS-TIMI 16BOrbofiban 2001: 2 nd SYMPHONYSibrafiban, ASA 2001: CUREClopidogrel 2005: CLARITY-TIMI 28Clopidogrel 2007: TRITON-TIMI 38Prasugrel, clopidogrel 2009: PLATOTicagrelor, clopidogrel 2010: CURRENT-OASIS 7ASA, Clopidogrel 2010: COGENTClopidogrel, omeprazole

5. CURE trial: Clopidogrel in UA/NSTEMI

6. CURE trial -- Summary 1 st trial to show that long-term clopidogrel, when added to asa, decreased the rate of recurrent ischemic events after UA/NSTEMI; 12,562 patients in 28 countries presenting with NSTEMI/UA and receiving asa were randomized to clopidogrel (300mgX1, then 75mg daily) or placebo. At a mean f/u of 9 mons, patients given clopidogrel had a reduction in the composite risk of death from CVS causes+non-fatal MI+stroke (9.3% vs 11.4%, p=0.001). There was a higher rate of major bleeding with clopidogrel (3.7% vs 2.7%, p=0.001), but no difference in life- threatening bleeding; The benefits of clopidogrel – which appeared within the 1 st day of administration and lasted throughout the study – was driven primarily by a decreased rate of re-infarction. Results were consistent across all analyzed subgroups, including in patients at high, medium, or low cardiac risk, and whether or not they had revascularization procedures;

7. For patients presenting with UA/NSTEMI managed with a conservative approach, adding a daily clopidogrel within 24 hours reduced long-term ischemic complications. Sponsored by Sanofi-Synthelabo and Bristol-Myers Squibb, marketers of clopidogrel under the name plavix. Take home Msg from CURE

8. CLARITY-TIMI 28: Clopidogrel with thrombolysis in STEMI

9. CLARITY – TIMI 28: Summary Designed to prove whether administration of clopidogrel would improve outcomes in STEMI patients who are receiving thrombolysis Rx; Randomized 3,491 patients in 23 countries presenting with STEMI and treated with thrombolysis to clopidogrel (300mgX1, then 75mg daily) or placebo. All patients received ASA, and anticoagulation was administered if a fibrin-specific lytic was chosen ( alteplase, reteplase, or tenecteplase). Clopidogrel significantly reduced the composite endpoint of persistent infarct-vessel occlusion+death+recurrent MI at 8 days (15% vs 21.7%, p=0.001). This was driven primarily by higher rates of infarct-vessel patency; Clopidogrel was not a/w increased rates of major bleeding or intracranial hemorrhage, though the study did exclude some at-risk populations (i.e, patients >75 y/o); Results from CLARITY helped form the basis of current ACC/AHA STEMI guidelines for patients receiving thrombolysis, which carry a ClassI recommendation for added administration of clopidogrel.

10. In STEMI patients treated with lytics and ASA, adding clopidogrel improved ischemic outcomes without increasing major bleeding. Sponsored by Sanofi-Synthelabo and Bristol-Myers Squibb, marketers of clopidogrel under the name plavix. Take home Msg from CLARITY-TIMI 28

11. CURRENT-OASIS 7: low vs high dose clopidogrel, ASA in ACS

12. CURRENT-OASIS 7: Summary Prior to CURRENT, dosing regimens for ASA and clopidogrel in ACS were based on tradition or platelet-activity studies rather than on trials examining clinical outcomes for patients. Thus, it is designed to establish evidence for the basis of future guidelines; Randomized 25,086 patients presenting with UA, NSTEMI or STEMI in a 2X2 factorial to double-dose clopidogrel (600mg load, 150qd X7Ds, then 75 qd), low dose clopidogrel (300mg load, then 75 qd), high dose asa (300 to 325mg qd) and low dose asa (75 to 100mg qd); There were no difference between groups with respect to the primary outcome, a composite of CVS death+MI+stroke at 30 days. Secondary analysis, showed that double-dose clopidogrel did reduce the incidence of stent thrombosis among patients who underwent PCI (1.6% vs 2.3%, p=0.001); Major bleeding occurred in significantly more pts in the high-dose clopidogrel group when compared with the low dose clopidogrel group (2.5% vs 2.0%, p=0.01). ASA dose did not affect major bleeding, but there was a small increase in the incidence of GIB in high dose group (0.4% vs 0.2%, p=0.04)

13. Clopidogrel: doubling the maintenance dose of clopidogrel to 150mg for the 1 st week after PCI increased bleeding events without influencing ischemic endpoints; Asprin: high dose daily ASA (300-325mg) had no benefit over low dose (75-100mg), but had a suggestion of more bleeding; A large meta-analysis has shown 600mg loading dose of clopidogrel is effective and safe followed by the 75mg maintenance daily dose, which is reflected in ACC/AHA guidelines. Sponsored by Sanofi-Synthelabo and Bristol-Myers Squibb, marketers of clopidogrel under the name plavix. Take home Msg from CURRENT-OASIS 7

14. 2011 UA/NSTEMI guidelines Patients with definite UA/NSTEMI at medium or high risk and in whom an initial invasive strategy is selected should receive dual-antiplt Rx. ASA should be initiated upon presentaion. The choice of a second antiplt Rx to be added to ASA on presentation includes 1 of the following: -- Before PCI: Clopidogrel; An IV GP IIb/IIIa inhibitor, iv eptifibatide or tirofiban are preferred -- At the time of PCI: Clopidogrel if not started before PCI; Prasugrel: An IV GP IIb/IIIa inhibitor A loading dose of thienopyridine is recommended for UA/NSTEMI pts for whom PCI is planned. Regimen should be 1 of the following: -- Clopidogrel 300 to 600mg should be given as early as possible before or at the time of PCI -- Prasugrel 60mg should be given promptly and no later than 1 hour after PCI once coronary anatomy is defined and a decision is made to proceed with PCI. ACS/AHA Guidelines

15. 2009 STEMI guidelines A loading dose of thienopyridine is recommended for STEMI patients for whom PCI is planned. Regimen should be 1 of the following: -- At least 300 to 600mg of clopidogrel should be given as early as possible before or at the time of primary or nonprimary PCI -- Prasugrel 60mg should be given asap for primary PCI ACS/AHA Guidelines