Antiplatelet Options for ACS: The Changing Landscape Dr Harald Vangerow Medical Advisor Cardiovascular Eli Lilly UKEFF00329 Prescribing Information can be found at the end of this presentation EFIENT : Review of current guidance of NICE and SMC

Disclosure: I am a full-time employee of Eli Lilly UK, presenting on behalf of the alliance between Lilly and Daiichi-Sankyo UKEFF00329

GP = glycoprotein; PAR = protease-activated receptor; TP = thromboxane A 2 / prostaglandin H 2. Adapted from Storey RF. Curr Pharm Des. 2006;12: Antithrombotic therapy for PCI Thromboxane A 2 5HT P2Y 12 ADP 5HT PLATELET ACTIVATION P2Y 1 5HT 2A PAR-1 PAR-4 Dense granule Thrombin generation Shape change  IIb  3   3 Fibrinogen  IIb  3 Aggregation Amplification Alpha granule Coagulation factors Inflammatory mediators TP  Coagulation GPVI Collagen ATP P2X 1 ASPIRIN x CLOPIDOGREL PRASUGREL ACTIVE METABOLITE x GP IIb/IIIa ANTAGONISTS xx HEPARINS BIVALIRUDIN x Thrombin Background UKEFF00329

1. Matetzky S, et al. Circulation 2004;109: Wiviott SD, Antman EM. Circulation : Serebruany VL, J. Am Coll Cardiol 2005; 45: O’Donoghue M et al. Circulation 2006; 114(22): e600-e606 Clopidogrel response variability and increased risk of ischaemic events (1,2) Primary PCI for STEMI (N=60) The range of variability to clopidogrel ranges from 4% to 56% of subjects showing some degree of non-responsiveness (3,4). There are many different definitions of poor-/nonresponse and various techniques to measure inhibition of platelet aggregation. Is this clinically relevant? N=15 UKEFF00329

TRITON-TIMI 38 Study Design Wiviott SD et al. Am Heart J 2006;152: 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, UTVR, Stent thrombosis (ARC definite/prob.) Safety endpoints: TIMI major bleeds, life-threatening bleeds Key sub-studies:Pharmacokinetic, genomic Planned median duration of therapy - 12 months N = 13,608 TRITON UKEFF00329

TRITON-TIMI 38: Rates of Key Study End Points (All ACS) prasugrel + aspirin clopidogrel + aspirin Days After Randomisation End Point (%) (111) 2.4 (146) Non-CABG TIMI Major Bleeds CV Death, MI, Stroke P=0.03 P<0.001 ↓138 events ↑ 35 events 12.1 (781) 9.9 (643) prasugrel + aspirin clopidogrel + aspirin Wiviott SD et al. New Engl J Med 2007;357: CABG = Coronary Artery Bypass Graft surgery CV = Cardiovascular MI = Myocardial Infarction TIMI = Thrombolysis In Myocardial Infarction TRITON UKEFF00329

Events (%) ARD 0.6% HR 1.32 P = 0.03 NNH = 167 ClopidogrelPrasugrel ARD 0.5% HR 1.52 P = 0.01 ARD 0% P = 0.74 ARD 0.3% P = ICH in patients with prior stroke/TIA (n = 518) Clopidogrel 0 (0%) Prasugrel 6 (2.3%) (P = 0.02) ARD 0.2% P = 0.23 n = 13, Life- threatening Non-fatalFatalICH Bleeding Events: Safety Cohort TIMI Major Non-CABG Bleeding TRITON Antman EM et al. AHA Scientific Sessions; 2007, Nov 4-7; Orlando, FL UKEFF00329

Net Clinical Benefit: Bleeding Risk Subgroups Post-hoc analysis OVERALL >60 kg < 60 kg < 75 >75 No Yes Prior Stroke / TIA Age Wgt Risk (%) prasugrel betterclopidogrel better HR P int = P int = 0.18 P int = 0.36 Antman EM et al. AHA Scientific Sessions; 2007, Nov 4-7; Orlando, FL TRITON UKEFF00329

Therapeutic Considerations Significant Net Clinical Benefit with Prasugrel 80% MD 10 mg Recommend Reduced MD Guided PK Wt 75 y 16% Avoid Prasugrel Prior CVA/TIA 4% TRITON Antman EM et al. AHA Scientific Sessions; 2007, Nov 4-7; Orlando, FL UKEFF00329

After Careful Risk-Benefit Evaluation Appropriate Use of EFIENT ≥ 60kg and < 75 years < 60kg ≥ 75 years Generally not recommended 60mg Loading Dose Maintenance Dose 10mg 60mg5mg* 60mg5mg* ANY prior TIA/Stroke Contraindicated European SmPC * The evidence for a 5mg dose is based only on PK/PD analyses and no clinical data currently exist on the safety of this dose in the at risk sub groups. Appropriate Use UKEFF00329

Prasugrel (Efient) co-administered with aspirin is accepted for restricted use within NHS Scotland for the prevention of athero-thrombotic events in patients with acute coronary syndrome under-going primary or delayed percutaneous coronary intervention. Use is restricted to patients who are eligible to receive the 10mg dose of prasugrel. (...) Alternative treatments are available at a lower drug acquisition cost. Scottish Medicines Consortium %20August%202009%20Revised%20Sept% doc%20website.pdf 7 th August 2009 SMC UKEFF00329

Balance of Efficacy and Safety in Patients <75 Yrs, ≥60 kg, and Without TIA/Stroke Endpoint (%) Hazard Ratio, (95% CI, ) P=0.17 Hazard Ratio, 0.75 (95% CI, ) P<0.001 Clopidogrel Prasugrel Clopidogrel Prasugrel 1.95% 1.50% 11% 8.4% CV Death / NF MI / NF Stroke Non-CABG TIMI Major Bleeding Days NNT 37 NNH 222 FDA Briefing Document, terials/Drugs/CardiovascularandRenalDrugsAdvisoryCommittee/ucm pdf n= TRITON UKEFF00329

NICE TA 182 Guidance 1.1 Prasugrel in combination with aspirin is recommended as an option for preventing atherothrombotic events in people with acute coronary syndromes having percutaneous coronary intervention, only when: immediate primary percutaneous coronary intervention for ST-segment-elevation myocardial infarction is necessary Issued October 2009 Review September 2010 NICE UKEFF00329

Endpoint (%) Days 9.5% 6.5% HR 0.68 ( ) P = % 10.0% HR 0.79 ( ) P = 0.02 Clopidogrel Prasugrel NNT = 42 CV death / MI / stroke TIMI major non-CABG bleeds Clopidogrel Prasugrel 2.4% 2.1% Montalescot G et al Lancet 2009, in press N = 3534 STEMI Cohort (N= 3534) TRITON-STEMI UKEFF00329

[% Patients] TRITON-TIMI 38: STEMI cohort Mortality at 30 Days Montalescot G et al. Lancet 2009;373:723_731 p=0.0445p= TRITON – STEMI UKEFF00329

NICE TA 182 Guidance 1.1 Prasugrel in combination with aspirin is recommended as an option for preventing atherothrombotic events in people with acute coronary syndromes having percutaneous coronary intervention, only when: stent thrombosis has occurred during clopidogrel treatment Issued October 2009 Review September 2010 NICE UKEFF00329

TRITON-TIMI 38: Stent thrombosis rates at end of study All Stents Bare-metal Stents Stent Thrombosis* (%) Drug-eluting Stents N=6,422n=2,878n=3, N=6,422 n=2,865n=3,237 clopidogrel prasugrel 52% RRR (1.2% ARR) 64% RRR (1.5% ARR) 48% RRR (1.1% ARR) P=0.0009P< *Stent thrombosis defined as Academic Research Consortium definite plus probable ARC = Academic Research Consortium ARR = Absolute Risk Reduction HR = Hazard Ratio NNT = Number Needed to Treat PCI = Percutaneous Coronary Intervention RRR = Relative Risk Reduction Wiviott SD et al. Lancet 2008;371: TRITON – Stent Thrombosis UKEFF00329

TRITON-TIMI 38: Intensive antiplatelet therapy with prasugrel resulted in fewer ischaemic outcomes including stent thrombosis than with clopidogrel % of Subjects Days Early Stent Thrombosis Pras n=6,422; clop n=6,422 Late Stent Thrombosis pras n=6,271; clop n=6, % 0.64% 0.82% 0.49% clopidogrel + aspirin prasugrel + aspirin HR 0.41 ( ) P< RRR 59% HR 0.60 ( ) P=0.03 RRR 40% clopidogrel + aspirin prasugrel + aspirin ARC = Academic Research Consortium HR = Hazard ratio RRR = Relative risk reduction Wiviott SD et al. Lancet 2008;371: TRITON – Stent Thrombosis UKEFF00329

NICE TA 182 Guidance 1.1 Prasugrel in combination with aspirin is recommended as an option for preventing atherothrombotic events in people with acute coronary syndromes having percutaneous coronary intervention, only when: the patient has diabetes mellitus. Issued October 2009 Review September 2010 NICE UKEFF00329

TRITON-TIMI 38: Diabetic Subgroup Analysis (n=3,146) CABG = Coronary Artery Bypass Graft surgery CV = Cardiovascular HR = Hazard Ratio MI = Myocardial Infarction NNT = Number Needed to Treat TIMI = Thrombolysis In Myocardial Infarction HR 0.70 P<0.001 Days End Point (%) CV Death, MI, Stroke NNT= Non-CABG TIMI Major Bleeds prasugrel + aspirin clopidogrel + aspirin Adapted from Antman EM et al. AHA Scientific Sessions; 2007, Nov 4-7; Orlando, FL TRITON – Diabetes UKEFF00329

NICE TA 182 Guidance 1.1 Prasugrel in combination with aspirin is recommended as an option for preventing atherothrombotic events in people with acute coronary syndromes having percutaneous coronary intervention, only when: immediate primary percutaneous coronary intervention for ST- segment-elevation myocardial infarction is necessary or stent thrombosis has occurred during clopidogrel treatment or the patient has diabetes mellitus. 1.2 People currently receiving prasugrel for treatment of acute coronary syndromes whose circumstances do not meet the criteria in 1.1 should have the option to continue therapy until they and their clinicians consider it appropriate to stop. Issued October 2009 Review September 2010 NICE UKEFF00329

Conclusions Prasugrel is a more potent antiplatelet than clopidogrel This translates into fewer ischemic events in ACS patients undergoing PCI in TRITON A significant increase in bleeding events in Prasugrel treated patients was observed in this trial A post-hoc analysis was performed to define the population deriving net clinical benefit with prasugrel SMC and NICE have found EFIENT to be cost- effective in a subset of ACS patients undergoing PCI Conclusions UKEFF00329

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Adverse Event Reporting Adverse events should be reported. Reporting forms and information can be found at Adverse events should also be reported to Eli Lilly and Company Limited (Tel No ) UKEFF00288 UKEFF00329

Prescribing Information (1/5) EFIENT*▼ (PRASUGREL) ABBREVIATED PRESCRIBING INFORMATION Presentation Film-coated tablet; 5mg or 10mg prasugrel hydrochloride. Uses Efient, co-administered with acetylsalicylic acid (ASA), is indicated for the prevention of atherothrombotic events in patients with acute coronary syndrome (ie, unstable angina, non-ST segment elevation myocardial infarction [UA/NSTEMI], or ST segment elevation myocardial infarction [STEMI]) undergoing primary or delayed percutaneous coronary intervention (PCI). Dosage and Administration Adults: Initiate with a single 60mg loading dose and then continue at 10mg daily. Patients should also take ASA daily (75mg to 325mg). In patients with ACS who are managed with PCI, premature discontinuation of any antiplatelet agent, including Efient, could result in an increased risk of thrombosis, myocardial infarction, or death due to the patient’s underlying disease. Treatment of up to 12 months is recommended unless the discontinuation is clinically indicated. Patients ≥75 years old: Use in patients ≥75 years of age is generally not recommended. If, after a careful individual benefit/risk evaluation by the prescribing physician, treatment is deemed necessary, then following a 60mg loading dose a reduced maintenance dose of 5mg should be prescribed. Patients ≥75 years of age have greater sensitivity to bleeding and higher exposure to the active metabolite of prasugrel. The evidence for the 5mg dose is based only on pharmacodynamic/pharmacokinetic analyses and no clinical data currently exist on the safety of this dose in the age group ≥75 years. Patients weighing <60kg: Give as a single 60mg loading dose and then continue at 5mg once daily. The 10mg maintenance dose is not recommended. Renal impairment: No dose adjustment is necessary for patients with renal impairment, including patients with end stage renal disease. Hepatic impairment: No dose adjustment is necessary in subjects with mild to moderate hepatic impairment (Child-Pugh class A and B). Children and adolescents: Not recommended. Method of administration: For oral use. May be administered with or without food. Administration of the 60mg loading dose in the fasted state may provide most rapid onset of action. Do not crush or break the tablet. UKEFF00288 UKEFF00329

Prescribing Information (2/5) Contra-indications Hypersensitivity to the active substance or to any of the excipients. Active pathological bleeding. History of stroke or transient ischaemic attack (TIA). Severe hepatic impairment (Child-Pugh class C). Warnings and Special Precautions Bleeding risk: Increased risk of bleeding; anaemia; thrombocytopaenia; a history of pathological intracranial findings. Use in patients at increased risk of bleeding should only be considered when the benefits in terms of prevention of ischaemic events are deemed to outweigh the risk of serious bleedings. This concern applies especially to patients: ≥75 years of age. with a propensity to bleed. with body weight <60kg. In these patients the 10mg maintenance dose is not recommended. A 5mg maintenance dose should be used. with concomitant administration of medicinal products that may increase the risk of bleeding, including oral anticoagulants, clopidogrel, non-steroidal anti-inflammatory drugs (NSAIDs), and fibrinolytics. For patients with active bleeding for whom reversal of the pharmacological effects of Efient is required, platelet transfusion may be appropriate. Use in patients ≥75 years of age is generally not recommended and should only be undertaken with caution after a careful individual benefit/risk evaluation. Therapeutic experience with prasugrel is limited in patients with renal impairment (including ESRD) and in patients with moderate hepatic impairment. These patients may have an increased bleeding risk. Therefore, prasugrel should be used with caution in these patients. Use with caution in Asian patients as therapeutic experience is limited. Patients should be told that it might take longer than usual to stop bleeding and that they should report any unusual bleeding (site or duration) to their physician. Surgery: If a patient is to undergo elective surgery, and an antiplatelet effect is not desired, Efient should be discontinued at least 7 days prior to surgery. Increased frequency (3-fold) and severity of bleeding may occur in patients undergoing CABG surgery within 7 days of discontinuation of prasugrel. Lactose: Patients with rare hereditary problems of galactose intolerance, the Lapp lactase deficiency, or glucosegalactose malabsorption should not take Efient. UKEFF00288 UKEFF00329

Prescribing Information (3/5) Interactions Warfarin: Warfarin (or other coumarin derivatives) and prasugrel should be co-administered with caution. Non-steroidal anti-inflammatory drugs (NSAIDs): Chronic NSAIDs (including COX-2 inhibitors) and Efient should be co-administered with caution. Effects of Other Medicinal Products on Efient Acetylsalicylic acid: To be administered concomitantly with ASA. Although a pharmacodynamic interaction with ASA leading to an increased risk of bleeding is possible, the demonstration of the efficacy and safety of prasugrel comes from patients concomitantly treated with ASA. Effects of Efient on Other Medicinal Products Medicinal products metabolised by CYP2B6: Prasugrel is a weak inhibitor of CYP2B6. In healthy subjects, prasugrel decreased exposure to hydroxybupropion, a CYP2B6-mediated metabolite of bupropion, by 23%. This effect is likely to be of clinical concern only when prasugrel is co-administered with medicinal products for which CYP2B6 is the only metabolic pathway and have a narrow therapeutic window (eg, cyclophosphamide, efavirenz). Pregnancy and Lactation Should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the foetus. Driving, etc Prasugrel is expected to have no or negligible influence on the ability to drive and use machines. Undesirable Effects Safety in patients with acute coronary syndrome undergoing PCI was evaluated in one clopidogrel-controlled study (TRITON). Drug discontinuation due to adverse events was 7.2% for prasugrel and 6.3% for clopidogrel. Of these, bleeding was the most common adverse reaction for both drugs leading to study drug discontinuation (2.5% for prasugrel and 1.4% for clopidogrel). Bleeding Non-Coronary Artery Bypass Graft (CABG) related bleeding: In TRITON the incidence of non-CABG-related TIMI major bleeding, including life-threatening and fatal, as well as TIMI minor bleeding, was statistically significantly higher in subjects treated with prasugrel compared to clopidogrel in the UA/NSTEMI and all ACS populations. No significant difference was seen in the STEMI population. The most common site of spontaneous bleeding was the gastro-intestinal tract; the most frequent site of provoked bleeding was the arterial puncture site. UKEFF00288 UKEFF00329

Prescribing Information (4/5) CABG-related bleeding: In the Phase 3 clinical trial, 437 patients underwent CABG during the course of the study. Of those patients, the rate of CABG-related TIMI major or minor bleeding was 14.1% for the prasugrel group and 4.5% in the clopidogrel group. The higher risk for bleeding events in subjects treated with prasugrel persisted up to 7 days from the most recent dose of study drug. For patients who received their thienopyridine within 3 days prior to CABG, the frequencies of TIMI major or minor bleeding were 26.7% (12 of 45 patients) in the prasugrel group, compared with 5.0% (3 of 60 patients) in the clopidogrel group. For patients who received their last dose of thienopyridine within 4 to 7 days prior to CABG, the frequencies decreased to 11.3% (9 of 80 patients) in the prasugrel group and 3.3% (3 of 90 patients) in the clopidogrel group. Beyond 7 days after drug discontinuation, the observed rates of CABG-related bleeding were similar between treatment groups. Adverse Reactions The following is based on data from clinical trials: Common (≥1-<10%): Anaemia, haematoma, epistaxis, gastro-intestinal haemorrhage, rash, ecchymosis, haematuria, vessel puncture site haematoma, puncture site haemorrhage, contusion. Uncommon (≥1/1000-<1/100): Eye haemorrhage, retroperitoneal haemorrhage. For full details of these and other side-effects, please see the Summary of Product Characteristics, which is available at Legal Category POM Marketing Authorisation Numbers EU/1/08/503/001, EU/1/08/503/002, EU/1/08/503/003, EU/1/08/503/004, EU/1/08/503/005, EU/1/08/503/006, EU/1/08/503/007, EU/1/08/503/008, EU/1/08/503/009, EU/1/08/503/010, EU/1/08/503/011, EU/1/08/503/012, EU/1/08/503/013, EU/1/08/503/014 Basic NHS Cost £ per pack of 28 tablets Date of Preparation or Last Review June 2009 Full Prescribing Information is Available From Eli Lilly and Company Limited, Lilly House, Priestley Road, Basingstoke, Hampshire, RG24 9NL, Telephone: Basingstoke (01256) *EFIENT (prasugrel) is a trademark of Eli Lilly and Company. UKEFF00288 UKEFF00329

Prescribing Information (5/5) Adverse events should be reported. Reporting forms and information can be found at Adverse events should also be reported to Eli Lilly and Company Limited (Tel No ) UKEFF00288 UKEFF00329