What’s New in Acute Coronary Syndromes? Claudia Bucci BScPhm, PharmD Clinical Coordinator, Cardiovascular Diseases Sunnybrook Health Sciences Centre 13 th Annual Contemporary Therapeutic Issues in Cardiovascular Disease May 7, 2010

ObjectivesObjectives To review recent evidence of antiplatelet therapies in the management of ACS To review recent evidence of antiplatelet therapies in the management of ACS à Clopidogrel (CURRENT/OASIS-7) à Prasugrel (TRITON-TIMI 38) à Ticagrelor (PLATO) To provide an update on pharmacotherapeutic issues in the management of ACS. To provide an update on pharmacotherapeutic issues in the management of ACS.

Platelet Cascade Platelet 5HT PAF EPI ADP Thrombin Collagen TXA 2 Gp 2b/3a receptor Platelet Aggregation Clot Clopidogrel Prasugrel Ticagrelor ASA Platelet Abciximab Eptifibatide Tirofiban

Medication In Hospital Long-Term Aspirin 160mg to chew, followed by ECASA 81mg daily ECASA 81mg daily indefinitely Clopidogrel 300mg or 600mg X 1, followed by 75mg daily 75mg daily ≥ 1 year Minimum: 4 weeks (BMS) 3-6 months (DES) Use of Antiplatelets in ACS and PCI

Limitations of Current Antiplatelet Therapy Slow Onset Slow Onset Level of Platelet Inhibition Level of Platelet Inhibition Variability of Response Variability of Response à High on-treatment platelet reactivity leads to increased risk of ischemic events. increased risk of ischemic events. à Medication adherence à Patient factors à P2Y12 receptor affinity à Under-dosing

CURRENT/OASIS-7CURRENT/OASIS-7 R UA/NSTEMI or STEMI Clopidogrel Day 1 = 600 mg LD Day 2 – 7 = 150 mg daily Day 8-30 = 75 mg Clopidogrel Day 1 = 300 mg LD + placebo Day 2 – 7 = 75 mg daily + placebo Day mg daily HIGH DOSE STANDARD DOSE All patients: ASA low dose (75-100mg) OR high dose ( mg) Up to 30 days

25,087 ACS Patients (UA/NSTEMI 70.8%, STEMI 29.2%) Planned Early (<24 h) Invasive Management with intended PCI Ischemic ECG Δ (80.8%) or ↑cardiac biomarker (42%) 25,087 ACS Patients (UA/NSTEMI 70.8%, STEMI 29.2%) Planned Early (<24 h) Invasive Management with intended PCI Ischemic ECG Δ (80.8%) or ↑cardiac biomarker (42%) PCI 17,232 (70%) Angio 24,769 (99%) Angio 24,769 (99%) No PCI 7,855 (30%) No Sig. CAD 3,616CABG 1,809CAD 2,430 Efficacy Outcomes:CV Death, MI or stroke at day 30 Stent Thrombosis at day 30 Safety Outcomes:BleedingCURRENT/OASIS-7CURRENT/OASIS-7

Clopidogrel: Double vs Standard Dose StandardDoubleHR 95% CI PIntn CV Death/MI/Stroke PCI (2N=17,232) No PCI (2N=7855) Overall (2N=25,087) MI PCI (2N=17,232) No PCI (2N=7855) Overall (2N=25,087) CV Death PCI (2N=17,232) No PCI (2N=7855) Overall (2N=25,087) Stroke PCI (2N=17,232) No PCI (2N=7855) Overall (2N=25,087)

Days Cumulative Hazard Clopidogrel: Double vs Standard Dose Primary Outcome: PCI Patients Clopidogrel Standard Clopidogrel Double HR % CI P= % RRR CV Death, MI or Stroke

Stent Thrombosis Days Cumulative Hazard C Standard, A Low C Standard, A High C Double, A Low C Double, A High

CURRENT-OASIS 7 Conclusions High Dose Clopidogrel High Dose Clopidogrel à stent thrombosis and major CV events in PCI patients. à ↑ CURRENT-defined major bleeds but not TIMI major, ICH or fatal. High Dose ASA High Dose ASA à No significant difference in efficacy or bleeding (with trends towards greater efficacy).

Limitations of Current Antiplatelet Therapy Slow Onset Slow Onset Level of Platelet Inhibition Level of Platelet Inhibition Variability of Response Variability of Response à High on-treatment platelet reactivity leads to increased risk of ischemic events. à Medication adherence à Patient factors à P2Y12 receptor affinity à Under-dosing

Clopidogrel (Plavix®) Prasugrel (Effient®) Ticagrelor (Brilinta®) EvidenceCUREPCI-CURE TRITON-TIMI 38 PLATO Dose mg X 1 75 mg od (150mg X 7d) 60mg X 1, 10mg od 180mg X 1 90mg bid Approved Indications * MI, stroke, PAD (secondary prev’n) MI, stroke, PAD (secondary prev’n) ACS +/- PCI ACS +/- PCI NSTEMI/STEMI with PCI - Availability * Yes June Cost$2.58/day?? Update: Antiplatelet Agents in ACS and PCI *as of May 2010

Clopidogrel (Plavix®) Prasugrel (Effient®) Ticagrelor (Brilinta®) MechanismIrreversibleIrreversibleReversible Inhibitory effect Onset 2 h < 30 min 1-2 h Peak response 2-5 h 2-4 h 1-3 h MetabolismProdrug (CYP 2C19, 3A, 2B6, 1A2) Prodrug (3A4, 2B6, 2C9, 2C19) Not a prodrug Duration 5-7 days 24 – 48 h Comparison of Antiplatelet Agents in ACS

N Engl J Med 2009; 361:1108

Inhibition of Platelet Aggregation (IPA) at 24 Hours (Healthy Volunteers) Inhibition of Platelet Aggregation (%) Response to Prasugrel Response to Clopidogrel Clopidogrel Responder Clopidogrel Non-responder *Responder =  25% IPA at 4 and 24 h Interpatient Variability Brandt, Payne, Wiviott et al AHJ 2007

TRITON-TIMI 38 Double-blind ACS (STEMI or UA/NSTEMI) & Planned PCI ASA PRASUGREL 60 mg LD/ 10 mg MD CLOPIDOGREL 300 mg LD/ 75 mg MD 1 o endpoint: CV death, MI, Stroke 2 o endpoints:CV death, MI, Stroke, Rehosp-Rec Isch CV death, MI, UTVR Stent Thrombosis (ARC definite/prob.) Safety endpoints: TIMI major bleeds, Life-threatening bleeds Key Substudies: Pharmacokinetic, Genomic Median duration of therapy - 12 months N= 13,600 Wiviott SD et al. New Engl J Med 2007;357:

10 15 Days Prasugrel Clopidogrel Intent To Treat: n=13,608; Lost to Follow-Up: n=14 (0.1%) HR 0.81 ( ) P<0.001 ARR=2.2% NNT= (n=781) 9.9 (n=643) HR 0.77 ( ) P<0.001 HR 0.80 ( ) P<0.001 CV Death/MI/Stroke (%) TRITON-TIMI 38: CV Death, MI, Stroke Wiviott SD et al. New Engl J Med 2007;357:

Prasugrel Clopidogrel TRITON-TIMI Days After Randomization End Point (%) (n=111) 2.4 (n=146) Non-CABG TIMI Major Bleeds CV Death, MI, Stroke P=0.03 P<0.001 ↓138 events ↑ 35 events 12.1 (n=781) 9.9 (n=643) Prasugrel Clopidogrel Wiviott SD et al. New Engl J Med 2007;357:

TRITON-TIMI 38: Non-CABG TIMI Major Bleeds Patients (%) Non-CABG TIMI Major Through day 3 At study end After day 3 to study end (n=6,716) (n=6,741) Life Threatening Bleeds 1.8% 0.4% 0.3% 1.0% 0.6% n= % n= % n=56 1.4% n=85 P=0.03 P=0.26 P=0.03 P=0.01 Wiviott SD et al. New Engl J Med 2007;357:

P=0.002 Odds Ratio 4.73 P<0.001 TIMI Major or Minor CABG-related TIMI Major Bleeding Requiring Transfusion P<0.001 At risk 6/189 At risk 24/179 (n=6,716) (n=6,741) Patients (%) 3.2% 13.4% n=244 n=182 n=231 n= % 5.0% 3.0% 4.0% TRITON-TIMI 38: Other TIMI Bleeds Wiviott SD et al. New Engl J Med 2007;357:

Prasugrel BetterClopidogrel Better HR P* value P** interaction TRITON-TIMI 38: Non-CABG TIMI Major Bleed History of stroke or TIA Yes No Any of the following: Age >75 y, Body wt. <60 kg, History stroke/TIA Yes No *Tests HR=1.0 within subgroups; **Tests equality HR between subgroups Wiviott SD et al. New Engl J Med 2007;357:

Ticagrelor versus Clopidogrel in ACS (PLATO) Primary endpoint: CV death + MI + Stroke Key secondary: CV death + MI + Stroke in patients intended for invasive management Total mortality + MI + Stroke CV death + MI + Stroke + recurrent ischaemia + TIA + arterial thrombotic events MI alone / CV death alone / Stroke alone / Total mortality Primary safety: Total major bleeding 6–12 month exposure Clopidogrel If pre-treated, no additional loading dose; if naive, standard 300 mg loading dose, then 75 mg qd maintenance; (additional 300 mg allowed pre PCI) Ticagrelor 180 mg loading dose, then 90 mg bid maintenance; (additional 90 mg pre-PCI) UA/NSTEMI (moderate-to-high risk) STEMI (if primary PCI) All receiving ASA; clopidogrel-treated or naive; randomised within 24 hours of index event (N=18,624) NEJM 2009;361:

PLATO: CV Death, MI or Stroke Days after randomisation Cumulative incidence (%) P<0.001 HR 0.84 (95% CI 0.77–0.92 ) RRR = 16%, ARR = 1.87%, NNT = 54 Clopidogrel Ticagrelor NEJM 2009;361:

PLATO: Major Bleeding Days from first IP dose Clopidogrel Ticagrelor HR 1.04 (95% CI 0.95–1.13), p=0.43 K-M estimated rate (% per year) NEJM 2009;361:

PLATO Total Major Bleeding NS 0 K-M estimated rate (% per year) PLATO major bleeding TIMI major bleeding Red cell transfusion * PLATO life- threatening/ fatal bleeding Fatal bleeding Ticagrelor Clopidogrel NEJM 2009;361:

PLATO Non-CABG and CABG-related Major Bleeding p=0.03 NS K-M estimated rate (% per year) Non-CABG PLATO major bleeding Non-CABG TIMI major bleeding CABG PLATO major bleeding CABG TIMI major bleeding Ticagrelor Clopidogrel NEJM 2009;361:

PLATO: Safety TicagrelorN=9333 Clopidogrel n=9291 p Dyspnea Dyspnea requiring discontinuation 13.8%0.9%7.8%0.1%<0.001<0.001 Ventricular Pauses ≥ 3 sec ≥ 5 sec 5.8%2.0%3.6%1.2% Increase in SrCr (%) 1month 12 month End of Tx 10±22 11±22 8±21 9±22 10±22 <0.001< NEJM 2009;361:

These slides have been provided, on request, by the AstraZeneca Medical Affairs  Last Maintenance Dose Loading Dose Onset Maintenance Offset IPA % Ticagrelor (n=54) Clopidogrel (n=50) Placebo (n=12) weeks * * * * * * * * * ‡ † †  20 µM ADP- Final Extent Gurbel PA, et al Circulation ;120:

Intensive Statin Therapy in PCI JACC 2009;54: