Antiplatelet Therapy for STEMI The Case for Ticagrelor

Antiplatelet Therapy for STEMI: The Case for Ticagrelor David J. Cohen, MD, MSc Director of Cardiovascular Research Saint-Luke’s Mid America Heart Institute Missouri Endowed Professor of Medicine University of Missouri-Kansas City School of Medicine DJC-CRT 2016

Disclosures Grant Support/Drugs − Daiichi-Sankyo - Eli Lilly − Astra-Zeneca - Merck Grant Support/Devices − Edwards Lifesciences - Abbott Vascular − Medtronic - Boston Scientific − Biomet Consulting/Advisory Boards − Medtronic - Astra-Zeneca − Edwards Lifesciences DJC: 2/16

Characteristics of an Optimal Antiplatelet Agent for STEMI • Pharmacologic profile • Effectiveness • Safety • Economics/Cost-Effectiveness • Ease of Use

Characteristics of an Optimal Antiplatelet Agent Ideal Characteristics Pharmacologic profile • Onset of antiplatelet effect within 60 -90 minutes • Reversibility less critical since very few STEMI patients require emergency CABG

Ticagrelor: Pharmacodynamic Profile IPA (%) Induced by 20 M ADP 100 Ticagrelor + aspirin (n=54) 88% 90 80 180 -mg loading dose 79% 70 60 Clopidogrel + aspirin (n=50) 600 -mg loading dose 50 40 41% 30 20 Placebo + aspirin (n=12) 10 0 0 0. 5 1 2 3 4 5 Time (Hours) 6 7 8 Gurbel P et al. Circulation. 2009; 120: 2577 -2585

Characteristics of an Optimal Antiplatelet Agent Ideal Characteristics Effectiveness • Reduced stent thrombosis • Reduced short and longterm mortality compared with standard of care

PLATO STEMI: Patient Disposition 18, 758 patients enrolled in PLATO 134 patients not randomized 18, 624 patients randomized NSTEMI/UA/other: 10, 194 patients STEMI as Final Dx: 8, 430 patients Randomized to ticagrelor: efficacy population N= 4, 201 No intake of study medication: 36 patients Safety population N=4, 165 Randomized to clopidogrel: efficacy population N= 4, 229 No intake of study medication: 48 patients Safety population N=4, 181

Primary Endpoint: CV Death, MI or Stroke 12 Clopidogrel K-M estimated rate (% per year) 11 10 9. 3 9 Ticagrelor 8 7 6 5 HR: 0. 85 (95% CI = 0. 74– 0. 97) P=0. 02 4 3 2 1 0 11. 0 0 1 2 3 4 5 6 7 8 9 10 11 12

PLATO STEMI: Endpoint Components Endpoint Ticag Clop HR (95% CI) P-Value CV death/MI/stroke 9. 3% 11. 0% 0. 85 (0. 74 -0. 97) 0. 02 CV death 4. 5% 5. 4% 0. 84 (0. 69 -1. 03) 0. 09 MI 4. 7% 6. 1% 0. 77 (0. 63 -0. 93) 0. 01 Stroke 1. 6% 1. 0% 1. 45 (0. 98 -2. 17) 0. 07 All death 4. 9% 6. 0% 0. 82 (0. 68 -0. 99) 0. 04

PLATO STEMI: Alternative Populations Population (N) HR for Primary Endpoint Hazard Ratio (95% CI) Overall (18, 624) 0. 84 (0. 77 – 0. 92) STEMI Final Dx (8402) 0. 85 (0. 74 -0. 97)) STE-ACS (7544) 0. 87 (0. 75 -1. 01) Primary PCI (4549) 0. 91 (0. 75 -1. 12) P-value for interactions = NS Ticagrelor Better Clopidogrel Better Steg PG. TCT 2014

PLATO STEMI: Stent Thrombosis Endpoint Ticag Clop HR (95% CI) P-Value Definite 1. 6% 2. 5% 0. 61 (0. 42 -0. 87) 0. 01 Definite or Probable 2. 5% 3. 6% 0. 69 (0. 52 -0. 92) 0. 01 Any 3. 2% 4. 4% 0. 73 (0. 56 -0. 94) 0. 02

Characteristics of an Optimal Antiplatelet Agent Ideal Characteristics Safety • No major increase in bleeding in either short or long-term

PLATO STEMI: Major Bleeding Cumulative Incidence (%) 10 Clopidogrel 8 Ticagrelor 6 4 2 HR 0. 96 (95% CI = 0. 83– 1. 12) P=0. 63 0 0 1 2 3 4 5 6 7 8 Months 9 10 11 12 9. 3 9. 0

PLATO STEMI: Alternative Bleeding Endpoints Endpoint Ticag Clop HR (95% CI) P-Value PLATO Major + Minor 13. 1% 12. 3% 1. 05 (0. 92 -1. 21) NS TIMI Major + Minor 4. 0% 3. 5% 0. 97 (0. 83 -1. 14) NS Non-CABG related TIMI Major + Minor 4. 0% 3. 5% 1. 08 (0. 85 -1. 38) NS Fatal Bleeding 0. 2% 0. 1% N/A NS

Characteristics of an Optimal Antiplatelet Agent Ideal Characteristics Cost. Effectiveness • Cost saving in short and long-term • If not cost-saving, then ICER favorable compared with other accepted therapies (<$50, 000/QALY gained)

Cost-Effectiveness of Ticagrelor US Perspective Primary Results D Cost = $4058 D QALYs = 0. 14 ICER = $ 29, 665/QALY Ticagrelor Cost = $7. 88/day Cowper PA, et al. J Am Coll Cardiol 2015; 65: 465 -76

PLATO: Subgroup Analyses ∆ Cost* D QALYs ICER ($/QALY) STEMI $3539 0. 09 $40, 800 NSTEMI $4385 0. 17 $26, 245 Invasive Strategy $4314 0. 16 $27, 331 Medical Strategy $3201 0. 07 $47. 068 Diabetes $3420 0. 11 $32, 145 No diabetes $4127 0. 14 $30, 189 * Base Case: No in-trial cost offset Cowper PA, et al. J Am Coll Cardiol 2015; 65: 465 -76

Characteristics of an Optimal Antiplatelet Agent Ideal Characteristics Ease of Use • Oral drug IV infusions cumbersome and prone to errors in dosing in emergency setting • Few contraindications that may predispose to medical errors

Ticagrelor: Practical Considerations • Simple loading dose for all patients – 180 mg = 2 pills • Minimal contraindications – Don’t need to figure out pt weight – Don’t need to worry about prior stroke or TIA • First aspirin dose doesn’t matter – Low dose ASA only important for maintenance phase • Easiest P 2 Y 12 inhibitor to use with cangrelor – All other drugs can only be initiated after cangrelor d/c’ed due to steric hindrance at ADP binding site

Summary In patients with STEMI being considered for primary PCI, treatment with ticagrelor provides… • Rapid and consistent inhibition of platelet function • Significant reductions in most ischemic endpoints compared with clopidogrel (all-cause mortality, MI, stent thrombosis) • No major increase in short- or long-term bleeding compared with clopidogrel • Simplified treatment algorithm in the ER setting that can apply to virtually all STEMI patients