Interventional Pharmacology: Antiplatelet Therapy for ACS and PCI

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

10 6.2 5 5 Placebo 158 0 17.1 10 5.0 0 11.9

10 4 20 15 15 12.9 p<0.0001 p=0.012 Placebo 279 ASA 276

Cairns JA: NEJM 1985 0 3.3 Placebo 118 ASA 121 Theroux P: NEJM 1988 6.5 5 0 Placebo 397

ASA 399 RISC Group: Lancet 1990 Aspirin Effectiveness in ACS Cardiac Death or MI Mean F/U 18 mo 20 N=555 pts No Aspirin % 10 Aspirin

17.0% 8.6% p=0.008 0 0 6 12 18 24 Months Cairns JA: NEJM 1985; 331: 1369-76 Aspirin Dose and Major Bleeding

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

8.8% 0.06 Clopidogrel 0.04 p = 0.002 0.02 0.00 0 100 200 300 400

Days of Follow-Up The CURE Investigators: Lancet August 2001 PCI-CURE Aspirin Dose and Outcomes with PCI 15 Bleeding % Death/MI/Stroke p=0.009 for Bleeding p=NS for MACE 10 7.8 5.5

4.5 5 1.5 0 <100mg 7.6 1.7 100-200mg >200mg Jolly S: Eur Heart J 2009; 30:900-907 CURE: Major Bleeding by Aspirin Dose Through Follow-Up

Yusef S: NEJM 2001; 345:494-502 DAPT and Long-term Bleeding Risk 15% p=0.07 10% p=0.001 8.8% 6.7% 5% 0% 3.7% ASA + Clopidogrel ASA + Placebo

p<0.001 3.8% 2.7% 2.6% CURE CREDO CHARISMA N = 12,563 12 mo CURE Major N = 2,116 12 mo TIMI Major

N = 15,603 28 mo GUSTO mod-severe Yusuf S: NEJM 2001 Steinhubl SR: JAMA 2002 Bhatt E: NEJM 2006 Clopidogrel Issues with Therapy Limitations of Clopidogrel Slow onset of action Variable degree of platelet inhibition Variable clinical response Hypo-reactive: 30% Hyper-reactive: 8-10%

Drug Interactions (i.e. PPI) Antiplatelet Therapy for ACS and PCI New P2Y12 inhibitors New P2Y12 ADP Receptor Antagonists Clinical Pharmacology Drug Type Route Action Onset T 1/2 Offset

Prasugrel Thieno Oral Irreversible 0.5-2 h 7h 7-10 days Ticagrelor CPTP Direct

Oral Comp binding 0.5-4 h 3-5 h 3-5 days Cangrelor ATP analogue Direct IV Comp binding

2-3 min 3-6 min 60 min Antiplatelet Therapy for PCI Prasugrel TRITON: ACS (incl STEMI) Primary EP: CV Death, MI, Stroke 15 N = 13,608 %

Clopidogrel 12.1 9.9 10 Prasugrel 5 HR 0.81 p=0.0004 HR 0.80 p=0.0003 HR 0.77 p=0.0001 NNT= 46 LTFU = 14 (0.1%)

0 0 30 60 90 180 Days 270 360 450 TRITON: Stent Thrombosis (Def/Prob) 3 Any Stent at Index PCI (n= 12,844) %

Clopidogrel 2.4% Prasugrel 1.1% 2 1 HR 0.48 p <0.0001 NNT= 77 0 0 30 60 90 180

Days 270 360 450 Wiviott SD et al: NEJM 2007 TRITON Stent Thrombosis* DES Only (N=5743) % 2.3% 2.5 Clopidogrel 2

i64% 0.8% 1 Prasugrel 0.5 50 100 150 200 250 300

350 400 Days * Definite or probable ST i48% 1.5 450 1.2% Prasugrel 1

HR 0.52 p=0.0009 0.5 HR 0.36 p<0.0001 0 2.4% Clopidogrel 2.5 2 1.5 0

BMS Only (N=6461) 0 0 50 100 150 200 250 300 350 400

450 Days Wiviott SD et al: NEJM 2007 TRITON Major / Minor Bleeding by Weight and Age 20 % Clopidogrel Weight 15 10 Prasugrel Age

10.1 9 p = 0.02 6.9 6.5 5 0 3.4 4.5 All ACS 3.3

<60 kg 4.2 >60 kg 2.9 3.8 <75yrs >75 yrs Net Clinical Benefit Bleeding Risk Subgroups HR Prior Stroke / TIA Pint = 0.006

Age > 75 Pint = 0.18 Wgt < 60 kg 0.5 Prasugrel Better Rel Risk Pint = 0.36 1 2 Clopidogrel Better

+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

9.8% 8 Ticagrelor 6 4 p=0.0003 2 HR 0.84 (95% CI 0.770.92) 0 0 60

120 240 300 360 Days No. at risk Ticagrelor Clopidogrel 180 9,333 9,291 8,628 8,521

8,460 8,362 8,219 8,124 6,743 6,743 5,161 5,096 4,147 4,047 Wallentin L: NEJM 2009; 361:1045-57 PLATO Primary and Secondary Endpoints

Wallentin L: NEJM 2009; 361: 1045-57 PLATO Non-CABG and CABG-related Major Bleeding Wallentin L: NEJM 2009; 361: 1045-57 Antiplatelet Therapy for PCI Cangrelor Cangrelor Direct P2Y12 receptor antagonist (non-thienopyridine) ATP analogue (MW = 800 Daltons) Parenteral administration Plasma t1/2 = 3 to 6 min Immediate onset of effect Offset (platelet recovery) ~ 1 hour Angiolillo DJ: J Thromb Thrombolysis 2012; 34: 44-45

Cangrelor Pharmacology PK/PD: onset of Effect <2 min; T 3-6 min; offset < 60 min Adapted from Akers WS: Clin Parmacol 2010; 50: 27-35 Cangrelor Pharmacokinetics and Platelet Inhibition Akers WS: J Clin Pharm 2010; 50: 27-35 Phoenix: Death, MI, IDR, Stent Thrombosis within 48 hrs N=10,942 % Hours from Randomization Bhatt DL: NEJM 2013; 368: 1303-13 Death, MI, IDR, or ST Landmark Analysis from Phoenix

N=10,942 % Hours from Randomization FDA Advisory Board Panel presentation Acute Stent Thrombosis (<2 hrs) OR [95%CI] = 0.53 (0.35-0.79) p=0.002 FDA Advisory Panel presentation Stent Thrombosis within 48 hrs OR [95%CI] = 0.62 (0.43-0.90) p=0.01

Bhatt DL: NEJM 2013; 368: 1303-13 Champion Phoenix Efficacy Outcomes within 2 hrs 10 Cangrelor n=(5470) Clopidogrel (n=5469) % p=0.002 p=0.01 5.4 5 4.1

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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