New P2Y12 Blockers are NOT Superior to Clopidogrel for some groups of cardiovascular patients Peter M Pollak MD ©2011 MFMER | 3138928-1 Disclosure Relevant Financial Relationship(s) • None Off Label Usage • None ©2012 MFMER | 3208595-2 New P2Y12 Drugs • Which drugs are they? • Ticagrelor • Prasugrel • Cangrelor • Which patients are they not superior for? • Patients excluded from the trials • Patients at risk of harm or side effects • Conditions not studied • Stable coronary disease ©2011 MFMER | 3138928-3 Ticagrelor • Oral P2Y12 antagonist • Not a Pro-drug • Does not require hepatic conversion • Rapidly absorbed from gut • Reversible Allosteric inhibitor • Binds at separate site from ADP ©2011 MFMER | 3138928-4 Ticagrelor: PLATO NNT = 52 Wallentin L et al N Engl J Med 2009;361:1045-1057 Ticagrelor and PLATO trials Important Exclusions • Thrombolytics within 24 hours • Not for pharmacoinvasive strategy • Any Oral Anticoagulation not for Afib/WOEST • Risk of Bradycardia (trend toward Syncope) • Use of strong P450 3A inhibitor Diltiazem, Verapamil, Antiviral & Antifungal Harm • More non CABG major bleeding (NNH=166) • But safer if CABG • Dyspnea – 14% (1% stopped drug) Wallentin L: NEJM 2009; Cannon CP: Lancet 2010 ©2012 MFMER | 3208595-6 No benefit with high dose Aspirin Mahaffey K W et al Circulation 2011;124:544-554 Prasugrel - TRITON – TIMI 38 Prasugrel vs Clopidogrel in High-risk ACS Prasugrel • Thienopyridine prodrug • Faster onset & stronger Key Exclusions % • Prior stroke • Risk of Bleeding/anemia Harm Signal • Weight 75y • CABG major bleeding 14 12.1 Prasugrel 12 10 9.9 Clopidogrel 9.5 7.3 2.4 1.1 2.4 1.8 Primary EP Wiviott SD: NEJM 2007 MI Stent TH Major bleed ©2012 MFMER | 3208595-8 Prasugrel - ACCOAST • Prasugrel given at ACS diagnosis vs at PCI • Increase in major and life-threatening bleeding • Including the non CABG patients 15 CV Death, MI, Stroke, UR, GPIIb/IIIa Bailout Pre-treatment 10.8 Endpoint (%) Pre-treatment 10.0 10 No Pre-treatment 10.8 No Pre-treatment 9.8 Hazard Ratio, 1.02 (95% 0.84, 1.25) P=0.81 Hazard Ratio, 0.997 (95% 0.83, 1.20) P=0.98 0 10 15 20 Days From First Dose 25 30 Prasugrel - TRILOGY ACS trial • ACS patients with no revascularization performed • Prolonged DAPT for 30 months • No difference in efficacy • Borderline fewer ischemic events in [...]... Country, Prior Clopidogrel Treatment (Primary analysis cohort — Age < 75 years) Medical Management Decision ≤72 hrs (No prior clopidogrel given) — 4% of total Clopidogrel1 300 mg LD + 75 mg MD Prasugrel1 30 mg LD + 5 or 10 mg MD Median Time to Enrollment = 4.5 Days Medical Management Decision ≤ 10 days (Clopidogrel started ≤ 72 hrs in-hospital OR on chronic clopidogrel) — 96% of total Clopidogrel1 Prasugrel1... On-Treatment PRU Through 30 Months < 75 years and ≥ 60 kg Clopidogrel 75 mg/day vs Prasugrel 10 mg/day Clopidogrel Prasugrel Median On-Treatment PRU Through 30 Months < 75 years and < 60 kg Clopidogrel 75 mg/day vs Prasugrel 5 mg/day Clopidogrel Prasugrel Median On-Treatment PRU Through 30 Months ≥ 75 years Clopidogrel 75 mg/day vs Prasugrel 5 mg/day Clopidogrel Prasugrel Landmark at 30 Days HPR Cut-Point... 3138928-12 Cangrelor – CHAMPION Trials • • • • Direct platelet P2Y12 receptor antagonist Parenteral administration T1/2 = 3 to 6 minutes Offset = 60 minutes • 8716 patients undergoing PCI • Pre-treated with 600mg Clopidogrel Conclusions - Themes • New P2Y12 platelet inhibitors provide more consistent and stronger antiplatelet effect when compared with Clopidogrel • Only studied in acute coronary syndromes... Bleeding Scale Cangrelor Clopidogrel (N=12,565) (N=12,5425) OR (95% CI) P Value GUSTO Severe 28 (0.2%) 23 (0.2%) 1.22 (0.70, 2.11) 0.4875 GUSTO Moderate 76 (0.6%) 56 (0.4%) 1.36 (0.96, 1.92) 0.0828 GUSTO Severe + Moderate 103 (0.8%) 79 (0.6%) 1.30 (0.97, 1.75) 0.0762 TIMI Major 32 (0.3%) 28 (0.2%) 1.14 (0.69, 1.90) 0.6101 TIMI Minor 77 (0.6%) 51 (0.4%) 1.51 (1.06, 2.15) 0.0218 TIMI Major + Minor 109... | 3138928-15 ROC Curve Analysis Relation of 30-day PRU With Primary Efficacy Endpoint HPR: Sensitivity: Specificity: > 178 47% 59% ACCOAST design NSTEMI + Troponin ≥ 1.5 times ULN local lab value Clopidogrel naive or on long term clopidogrel 75 mg Randomize 1:1 n~4100 (event driven) Double-blind CABG or Medical Management (no more prasugrel) Prasugrel 30 mg Placebo Coronary Angiography Coronary Angiography... bailout, at 7 days Montalescot G et al Am Heart J 2011;161:650-656 ACCOAST- Pharmacodynamic Sub-Study 350 Placebo LD1 Pre-treatment (30/30) No Pre-treatment (0/60) 60 mg LD2 *P