Interventional Pharmacology: Antiplatelet Therapy for ACS and PCI
Interventional Pharmacology: Antiplatelet Therapy for ACS and PCI Aspirin and ADP Antagonists Michael J. Cowley, MD, MSCAI First thing we do, kill all the platelets Platelet Receptors Platelet PAR-1 PAR-4 P2Y1 P2Y12 TBXA2 EPI-R 5HT2-A GP VI
GP Ia Platelet Receptors and Agonists Platelet Thrombin PAR-1 PAR-4 ADP TBX A2 Epinephrine Serotonin Collagen Platelet Fibrinogen GP IIb/IIIa P2Y1
P2Y12 TBXA2 GP IIb/IIIa EPI-R 5HT2-A GP VI GP Ia Anionic phospholipid surfaces Antiplatelet Therapy for ACS and PCI Aspirin GP 2b3a Inhibitors P2Y12 inhibitors PAR-1 Inhibitors
Aspirin ASA in UA/NSTEMI Death or MI p=0.008 p=0.0005 12 10.1 % 8 ASA 178 Lewis HD Jr: NEJM 1983 15
Post hoc analysis of 192,036 pts in 31 RCT 8% Major Bleeding 6 5.1 p=0.05 4 2 0 1.39 <100mg 1.6
100-200mg >200mg Serebrauny V: AJC 2005; 95: 1218-1222 Antiplatelet Therapy for ACS Balance between Efficacy and Safety i Ischemic Events vs h Bleeding Events Antiplatelet Therapy for ACS and PCI P2Y12 Inhibitors Clopidogrel CURE: DAPT for ACS Primary EP: CV Death, MI, Stroke Cumulative Hazard Rate N=12,562
p < 0.001 Months of Follow-up * In combination with standard therapy Yusuf S: N Engl J Med 2001;345:494-502 CURE PCI Substudy (n=2,658: 21%) CV Death or MI Cumulative Hazard Rates 0.10 12.6% Placebo 0.08 31% RRR
+37% -1% +3% Antiplatelet Therapy for PCI Ticagrelor Ticagrelor An Oral Reversible P2Y12 Antagonist Direct acting CPTP Not a prodrug Rapid onset of P2Y inhibition 12 12 Greater inhibition than clopidogrel
Reversibly bound Faster offset than clopidogrel Functional recovery of all circulating platelets PLATO Trial Ticagrelor vs Clopidogrel for ACS Primary Efficacy Endpoint CV death, MI or stroke % 12 Clopidogrel N=18,624 11.7% 10
p<0.001 0.7 0 Primary EP* * Death, MI, IDR, ST 4.4 p<0.008 3.5 1.3 ST 0.2
MI 0IDR FDA Advisory Panel presentation Champion Phoenix Efficacy Outcomes at 48 hrs (mITT) 10 % Cangrelor n=(5470) Clopidogrel (n=5469) p=0.005 p=0.02 5.9 5
4.7 p<0.01 0.8 0 Primary EP* * Death, MI, IDR, ST 4.7 3.8 1.4 ST p<0.22
0.5 0.7 MI IDR Bhatt DL: NEJM 2013; 368: 1303-13 Potential Uses for Cangrelor ACC/AHA/SCAI Guidelines for PCI Dual Anti-platelet Therapy (DAPT) ACS or STEMI DES: at least 12 mo BMS: 12 mo (unless h bleed risk) Elective PCI DES: at least 12 mo (unless h bleed risk) BMS: minimum of 1 mo 12 mo is preferable 2 wks if h bleeding risk
Choice of Antiplatelet Therapy Summary ASA effective and low dose is best Clopidogrel is effective but has significant issues Clopidogrel preferred for stable and low risk pts Prasugrel and ticagrelor are superior to clopidogrel for ACS (and STEMI) pts Cangrelor improves outcomes in pts not pretreated with a P2Y12 inhibitor 12 h platelet inhibition consistently i ischemic events at the expense of h bleeding Individualize DAPT duration to balance risks & benefits
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