Antiplatelet Therapy: Where Are We Going

1. Antiplatelet Therapy: Where Are We Going? Shamir R Mehta MD MSc Associate Professor of Medicine McMaster University Director, Interventional Cardiology Hamilton Health Sciences Hamilton, ON

2. CURE: Benefit of Clopidogrel Irrespective of Revascularization Status

3. Benefit of Clopidogrel Pretreatment:PCI CURE and PCI CLARITY The beneficial effects of pretreatment with a thienopyridine before PCI have been reported in several studies, although none were randomized comparisons. In the PCI-CURE analysis, all patients in the aspirin + clopidogrel arm had been pretreated with clopidogrel for a median of 10 days, whereas the majority of patients in the aspirin + placebo arm received no pretreatment, although 25% did receive an open-label thienopyridine before PCI. The frequency of death or MI in the 30 days after PCI was significantly less among patients who had been pretreated than in those who had not (4.4% vs.2.8%, a relative risk reduction of 34%;p =0.04). Of note, unlike all recent PCI trials of GP IIb/IIIa antagonists, systematic monitoring of post-PCI myocardial enzymes was not performed in the CURE study, which likely led to an underestimation of the actual number of MIs and potentially the magnitude of pretreatment benefit. Reference: Mehta SR, Yusuf S, Peters RJ, et al. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet 2001; 358(9281):527-33. The beneficial effects of pretreatment with a thienopyridine before PCI have been reported in several studies, although none were randomized comparisons. In the PCI-CURE analysis, all patients in the aspirin + clopidogrel arm had been pretreated with clopidogrel for a median of 10 days, whereas the majority of patients in the aspirin + placebo arm received no pretreatment, although 25% did receive an open-label thienopyridine before PCI. The frequency of death or MI in the 30 days after PCI was significantly less among patients who had been pretreated than in those who had not (4.4% vs.2.8%, a relative risk reduction of 34%;p =0.04). Of note, unlike all recent PCI trials of GP IIb/IIIa antagonists, systematic monitoring of post-PCI myocardial enzymes was not performed in the CURE study, which likely led to an underestimation of the actual number of MIs and potentially the magnitude of pretreatment benefit. Reference: Mehta SR, Yusuf S, Peters RJ, et al. Effects of pretreatment with clopidogrel and aspirin followed by long-term therapy in patients undergoing percutaneous coronary intervention: the PCI-CURE study. Lancet 2001; 358(9281):527-33.

4. Initial Invasive Strategy: Antiplatelet Therapy For UA/NSTEMI patients in whom an initial invasive strategy is selected, antiplatelet therapy in addition to ASA should be initiated before diagnostic angiography (upstream) with either clopidogrel (loading dose followed by daily maintenance dose)* or an IV GP IIb/IIIa inhibitor.

5. TRITON TIMI-38: Study Design

7. TRITON TIMI-38: Stent Thrombosis(ARC Definite + Probable)

8. TRITON TIMI-38: Bleeding Events Safety Cohort

9. TRITON TIMI-38: Net Clinical BenefitBleeding Risk Subgroups Post-hoc Analysis

10. ALBION Study: Primary Endpoint: Faster Onset of Action and Higher Level of Platelet Inhibition The authors of the ALBION study sought to compare the antiplatelet effects of three clopidogrel loading doses (LDs). Patients (n = 103) with NSTE ACS were randomized to receive a 300-mg, 600-mg, or 900-mg clopidogrel LD, given on top of other standard therapy (including ASA). The main outcome measure was inhibition of adenosine diphosphate-induced inhibition of platelet aggregation (IPA); inhibition of platelet activation, inflammatory markers, troponin I release, and major adverse cardiac events also were evaluated; all measures were blindly evaluated. Compared with the 300-mg LD, greater doses were associated with significantly greater platelet inhibition, with dose-effect relationships observed for onset of action, maximal plateau, 24-h areas under the curves of IPA, and rates of low IPA (<10% at 6 h), using 20 micromol/l major adverse cardiac events. A significant dose-response was also observed for the vasodilator-stimulated phosphoprotein index, a measure of P2Y(12) receptor inhibition. Similar but nonsignificant trends were observed for troponin release and major adverse cardiac events. Bleeding rates were similar in each group. Reference: Montalescot G, Sideris G, Meuleman C, et al. A randomized comparison of high clopidogrel loading doses in patients with non-ST-segment elevation acute coronary syndromes: the ALBION (Assessment of the Best Loading Dose of Clopidogrel to Blunt Platelet Activation, Inflammation and Ongoing Necrosis) trial. J Am Coll Cardiol 2006; 48(5):931-8.The authors of the ALBION study sought to compare the antiplatelet effects of three clopidogrel loading doses (LDs). Patients (n = 103) with NSTE ACS were randomized to receive a 300-mg, 600-mg, or 900-mg clopidogrel LD, given on top of other standard therapy (including ASA). The main outcome measure was inhibition of adenosine diphosphate-induced inhibition of platelet aggregation (IPA); inhibition of platelet activation, inflammatory markers, troponin I release, and major adverse cardiac events also were evaluated; all measures were blindly evaluated. Compared with the 300-mg LD, greater doses were associated with significantly greater platelet inhibition, with dose-effect relationships observed for onset of action, maximal plateau, 24-h areas under the curves of IPA, and rates of low IPA (<10% at 6 h), using 20 micromol/l major adverse cardiac events. A significant dose-response was also observed for the vasodilator-stimulated phosphoprotein index, a measure of P2Y(12) receptor inhibition. Similar but nonsignificant trends were observed for troponin release and major adverse cardiac events. Bleeding rates were similar in each group. Reference: Montalescot G, Sideris G, Meuleman C, et al. A randomized comparison of high clopidogrel loading doses in patients with non-ST-segment elevation acute coronary syndromes: the ALBION (Assessment of the Best Loading Dose of Clopidogrel to Blunt Platelet Activation, Inflammation and Ongoing Necrosis) trial. J Am Coll Cardiol 2006; 48(5):931-8.

11. CURRENT-OASIS 7 Trial In the ISAR-REACT study, patients (N=2,159, mean age 66 years) received 600 mg clopidogrel at least 2 hours before a PCI procedure with aspirin and a heparin bolus of 70 U/kg. They were then randomized to either abciximab (bolus 0.25 mg/kg, infusion 0.125 mg/kg/min for 12 hours) or a placebo infusion. Thereafter, all patients received clopidogrel 75 mg twice daily until discharge and then 75 mg clopidogrel daily for at least 4 weeks along with aspirin (?100 mg/d). All patients had symptomatic coronary artery disease, but patients with acute coronary syndromes and other patients considered to be at high risk were excluded.* *High-risk exclusion criteria: acute coronary syndromes; acute myocardial infarction within 14 days, ST-segment depression, positive biomarkers, insulin-dependent diabetes, chronic total occlusions, ejection fraction ? 30%, thrombus and lesions in bypass grafts. Schömig A, Mehilli J, Dotzer F, et al. ISAR-REACT: glycoprotein IIb/IIIa inhibition with abciximab in patients undergoing coronary stenting after pretreatment with a high loading dose of clopidogrel: a multicenter, randomized, double blind, placebo-controlled trial. Presented at: 52nd Annual Scientific Session of the American College of Cardiology; March 30-April 2, 2003; Chicago, Ill.In the ISAR-REACT study, patients (N=2,159, mean age 66 years) received 600 mg clopidogrel at least 2 hours before a PCI procedure with aspirin and a heparin bolus of 70 U/kg. They were then randomized to either abciximab (bolus 0.25 mg/kg, infusion 0.125 mg/kg/min for 12 hours) or a placebo infusion. Thereafter, all patients received clopidogrel 75 mg twice daily until discharge and then 75 mg clopidogrel daily for at least 4 weeks along with aspirin (?100 mg/d). All patients had symptomatic coronary artery disease, but patients with acute coronary syndromes and other patients considered to be at high risk were excluded.* *High-risk exclusion criteria: acute coronary syndromes; acute myocardial infarction within 14 days, ST-segment depression, positive biomarkers, insulin-dependent diabetes, chronic total occlusions, ejection fraction ? 30%, thrombus and lesions in bypass grafts. Schömig A, Mehilli J, Dotzer F, et al. ISAR-REACT: glycoprotein IIb/IIIa inhibition with abciximab in patients undergoing coronary stenting after pretreatment with a high loading dose of clopidogrel: a multicenter, randomized, double blind, placebo-controlled trial. Presented at: 52nd Annual Scientific Session of the American College of Cardiology; March 30-April 2, 2003; Chicago, Ill.

13. AZD6140 (Ticagrelor) A non-thienopyridine, in the chemical class CPTP (CycloPentylTriazoloPyrimidine) First oral reversible ADP P2Y12 receptor antagonist Direct acting via the P2Y12 receptor - metabolism not required for activity More potent platelet inhibitor than clopidogrel

15. Cangrelor: Key Phase II Result Rapid reversal of dose-dependent effect

16. CHAMPION To answer this question, we are currently recruiting up to 850 sites for participation in a global phase 3 trial of prasugrel vs. clopidogrel in patients with acute coronary syndromes with planned PCI, called TRITON-TIMI 38. This trial will enroll 13,000 patients across the ACS spectrum. Patients will be randomized to either prasugrel or standard doses of clopidogrel. Patients will be followed on maintenance therapy for a median of 12 months. The primary endpoint will be the composite of cardiovascular death, MI and stroke. Important secondary endpoints include bleeding, recurrent ischemia and urgent target vessel revascularization. Thank you for your attention. To answer this question, we are currently recruiting up to 850 sites for participation in a global phase 3 trial of prasugrel vs. clopidogrel in patients with acute coronary syndromes with planned PCI, called TRITON-TIMI 38. This trial will enroll 13,000 patients across the ACS spectrum. Patients will be randomized to either prasugrel or standard doses of clopidogrel. Patients will be followed on maintenance therapy for a median of 12 months. The primary endpoint will be the composite of cardiovascular death, MI and stroke. Important secondary endpoints include bleeding, recurrent ischemia and urgent target vessel revascularization. Thank you for your attention.

17. Protease-Activated-Receptor (PAR-1) Inhibition

18. TRA-PCI: TRA (SCH 530348) MI & Bleeding

20. Summary: New Trials of Antiplatelet Agents