RE 910 January 2007

Triple Anti-Platelet Therapy for PCI: An Evidence-Based Approach

Dr Paul MartinEuropean Brand Manager: New Indications

Lilly Critical Care Europe

RE 910 January 2007

Disclosure

Employee ELI LILLY & Co

RE 910 January 2007

Content

Elective PCIDiabetes & late TVRACS-PCID/MI/uTVRSafetyMortalityMortality vs. Safety

RE 910 January 2007

1. A. Kastrati et al, NEJM 2004; 350 (3): 232-238

ISAR-REACT

Excluded pts with:

• ACS

• MI <14 d

• IDDM

• SVG

• CTO >3 months

• Visible thrombus

• EF <30%

p= NS

RE 910 January 2007 2. J. Mehilli et al. Circulation 2004; 110: (24); 3627-35

ISAR-SWEET

Excluded pts with:

• ACS

• MI <14 d

• SVG

• CTO >3 months

• Visible thrombus

• EF <30%

• 29% IDDM

• 50% Oral Rx

• 20% No Rx

RE 910 January 2007

ISAR-SWEETISAR-SWEET

Secondary Endpoint at 12 Months

Incidence of Restenosis

37.8

30.428.9

23.2

0.0

10.0

20.0

30.0

40.0

50.0Placebo (n=350) Abciximab (n=351)

% o

f P

atie

nts

P=0.01 P=0.03

Angiographic Restenosis Target Lesion Revascularization

3. J. Mehilli et al. Circulation 2004; 110: (24); 3627-35

RE 910 January 2007

ISAR-SWEETISAR-SWEET

Stent Type and Restenosis

1y Incidence of Restenosis

40.2

4.9

31.9

7.3

0.0

10.0

20.0

30.0

40.0

50.0Placebo (n=350) Abciximab (n=351)

% o

f P

atie

nts

P=0.04P=NS

BMS DES

3. J. Mehilli et al. Circulation 2004; 110: (24); 3627-35

RE 910 January 2007

30 Day Composite Endpoint Summary in PCI30 Day Composite Endpoint Summary in PCI

12.8

15.9

11.710.8

11.9

7.6

9.38.9

5.35.2

11.3

8.3

6.36.0

0

5

10

15

20

EPIC CAPTURE EPILOG EPISTENT ISAR-REACT-II TARGET TARGET ACS pts

% I

nc

ide

nc

e

Placebo

AbciximabTirofiban

Abciximab

Abciximab - PCI Trials (excl. prim. PCI)

4. NEJM 1994;330:956-61 7. Lancet 1997;352:87-92 10. Circulation. 2002;105:2347-2354

5. Lancet 1997;349:1429-35 8. JAMA. 2006;295:April

6. NEJM 1997;336:1689-96A 9. N Engl J Med 2001;344:1888 –1894..

4 5 7

p = 0.008p <0.001

p =0.012

p <0.001

6

n=2099 n=1265 n=2792 n=2399 n=2022 n=4809 n=3025

p =0.03

8

Death, MI or Urgent TVR

p = 0.038

9 10

p = 0.002

RE 910 January 2007

11.2 10.5

14.6

7

10.5

5.8 56

4.6 4.5

0

5

10

15

20

25

RAPPORT ISAR-2 ADMIRAL CADILLAC ACE

% o

f p

ati

en

ts

Placebo

Abciximab

Abciximab – prim. PCI Trials

p = 0.03

p = 0.01

p = 0.038

p = 0.01

n=483 n=401 n=300 n=2082 n=400

p = 0.023

Death, MI or Urgent TVR

30 Day Composite Endpoint Summary30 Day Composite Endpoint Summary *CADILLAC includes ischemic stroke** ACE includes disabling stroke

NNT ~20

12. JACC 2000;35:915-21.

13. NEJM 2001;344:1895-1903.

11. Circ 1998;98:734-41.

15. JACC 2003;42:1879-85.

14. Circ 2003108: 1316-1323

11 12 13 14 15

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What about Bleeding ?

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Abciximab safety data summary

RE 910 January 2007

1.1 1.0 1.0 0.91.41.1 0.8 1.0

1.41.1

01

23

45

67

89

10

EPILOG EPISTENT ISAR REACT ISAR SWEET ISAR REACT 2

% B

leed

ing

Placebo ReoPro

Abciximab - SafetyAbciximab - Safety

ReoPro SafetyReoPro Safety

Non CABG TIMINon CABG TIMI MajorMajor Bleeding Bleeding

16. EPILOG: NEJM 1997;336:1689-96A , 17. EPISTENT: Lancet 1997;352:87-92. 18. ISAR REACT NEJM 2004; 350 (3): 232-238. 19. ISAR SWEET: Circulation.2004; 110:3627-3635, 20. ISAR REACT 2: JAMA. 2006;295 1531-1538:April

P=NS for all

RE 910 January 2007

3.7

1.7 2.01.4

3.34.0

2.92.0

4.23.4

01

23

45

67

89

10

EPILOG EPISTENT ISAR REACT ISAR SWEET ISAR REACT 2

% B

leed

ing

Placebo ReoPro

Abciximab - SafetyAbciximab - Safety

ReoPro SafetyReoPro Safety

TIMITIMI MinorMinor Bleedings Bleedings

P=NS for all

1616. . EPILOG: NEJM 1997;336:1689-96A , 17. EPISTENT: Lancet 1997;352:87-92. 18. ISAR REACT NEJM 2004; 350 (3): 232-238. 19. ISAR SWEET: Circulation.2004; 110:3627-3635, 20. ISAR REACT 2: JAMA. 2006;295:April

RE 910 January 2007

Abciximab Mortality data summary

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Intention to Treat22. Am J Med. 2002;113:1-6.

Consistent Survival BenefitConsistent Survival Benefit

Mortality: EPIC, EPILOG, and EPISTENT - Meta-Analysis

3.3

1.1 1.0

10.3

1.10.8

0

2

4

6

8

10

12

EPIC EPILOG EPISTENT

% N

on

CA

BG

maj

or

Ble

edin

g

Placebo

Abciximab

p=0.03

P<0.001

P=NSP=NS

21. EPIC: NEJM 1994;330:956-61 16. EPILOG: NEJM 1997;336:1689-96A 17. EPISTENT: Lancet 1997;352:87-92.

Major Bleeding

EPIC, EPILOG, EPISTENT: Mortality vs Bleeding

RE 910 January 2007

23. G. De Luca, et.al. JAMA 2005; 293 (14): 1759-65.

Meta-analysis primary angioplasty trials

Short and Long Term Mortality

3.4

6.2

2.4

4.4

0

1

2

3

4

5

6

7

30 Days 6-12 months

Control Abciximab

PCI Trials (N=3949)

RAPPORT ISAR-2 ADMIRAL CADILLAC Petronio (2002)Zorman ACEPetronio (2003)

Mo

rtal

ity

(%)

P=0.047

P=0.01

RE 910 January 2007

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SCAAR (2000-2004)

N= 7436 (Primary PCI pts)

52% Abciximab

Median follow-up 14.2 months

Mortality: 14% vs 8%

HR 0.82 (95% CI: 0.71-0.94)Abciximab

yes

Abciximab no

”Real World” Registry Mortality Data”Real World” Registry Mortality Data

24. P. Tornvall et al. J Intern Med 2006;260:363-368

RE 910 January 2007

”Real World” Survival Data”Real World” Survival Data

ACOS Registry (2000-2002)

• N= 2184 (Primary PCI pts) ; 43% Abciximab

• Median follow-up 375 days; Survival 91% vs. 79% p<0.05

• HR 0.68 (95% CI: 0.49-0.95)

25. T Heer et al., Heart 2006; 92:1484-1489

RE 910 January 2007

SUMMARY

Abciximab (ReoPro) has clinical trials evidence and “real world” data demonstrating robust efficacy in reducing the ischaemic complications of high-risk NSTEMI- and STEMI-PCI

Experience of more than 2 million patients treated 26

with Abciximab confirms proven safety profile Long-term mortality benefit shown

26. Data on File

RE 910 January 2007

Prescribing InformationREOPRO* ABBREVIATED PRESCRIBING INFORMATION(ABCIXIMAB)PresentationRubber-stoppered 5ml vials each containing 10mg abciximab as a 2mg/ml solution for injection or infusion.Uses: As an adjunct to heparin and aspirin for:1. Percutaneous coronary interventionThe prevention of ischaemic cardiac complications in patients undergoing percutaneous coronary intervention (balloon angioplasty, atherectomy, and stent).2. Unstable anginaThe short-term (1 month) reduction of the risk of myocardial infarction, in patients with unstable angina, not responding to full conventional therapy, who have been scheduled for percutaneous coronary intervention.Dosage and AdministrationAdults: ReoPro is for intravenous (IV) administration in adults.The recommended dose of ReoPro is a 0.25mg/kg intravenous bolus immediately followed by a 0.125 micrograms/kg/min (to a maximum of 10 micrograms/min) continuous intravenous infusion.For the stabilisation of unstable angina patients, the bolus dose followed by the infusion should be started up to 24 hours prior to the possible intervention and concluded 12 hours after the intervention.For the prevention of ischaemic cardiac complications in patients undergoing percutaneous coronary intervention, and who are not currently receiving a ReoPro infusion, the bolus should be administered 10 to 60 minutes prior to the intervention followed by the infusion for 12 hours.The elderly: Use in patients older than 80 years has not been studied.Children: Use in children has not been studied.Administration instructions: Please see Doctor’s Package Insert or Summary of Product Characteristics (SPC).Contra-indicationsKnown sensitivity to abciximab, to any component of the product, or to murine monoclonal antibodies.Because inhibition of platelet aggregation increases the risk of bleeding, ReoPro is contra-indicated in the following clinical situations: active internal bleeding; history of cerebrovascular accident within two years; recent (within two months) intracranial or intraspinal surgery or trauma; recent (within two months) major surgery; intracranial neoplasm, arteriovenous malformation or aneurysm; known bleeding diathesis or severe uncontrolled hypertension; pre-existing thrombocytopenia; vasculitis; hypertensive or diabetic retinopathy; severe hepatic or severe renal failure.

RE 910 January 2007

Prescribing Information cont….Warnings and PrecautionsCareful assessment of risk:benefit should be made in individual patients before commencing therapy with ReoPro. A favourable risk:benefit has not been established in low risk patients >65 years of age.Requirement for specialist facilities: ReoPro should only be administered in conjunction with extensive specialist medical and nursing care. In addition, there must be availability of laboratory tests of haematology function and facilities for administration of blood products.Concomitant aspirin and heparin therapy: ReoPro should be used as an adjunct to aspirin and heparin therapy. For aspirin and heparin dosages, please see Doctor’s Package Insert or SPC.Bleeding precautions, general nursing care, patient monitoring: Please see Doctor’s Package Insert or SPC.Use of thrombolytics, anticoagulants, and other antiplatelet agents: Because ReoPro inhibits platelet aggregation, caution should be employed when used with other drugs affecting haemostasis, such as heparin, oral anticoagulants, such as warfarin, thrombolytics, and antiplatelet agents other than aspirin, such as dipyridamole, ticlopidine, or low molecular weight dextrans (see ‘Drug interactions’ below).Thrombocytopenia: To reduce the possibility of thrombocytopenia, platelet counts should be monitored prior to treatment, 2 to 4 hours following the bolus dose of ReoPro, and at 24 hours. If a patient experiences an acute platelet decrease, additional platelet counts should be determined. If true thrombocytopenia is verified, ReoPro should be immediately discontinued and the condition appropriately monitored and treated. A daily platelet count should be obtained until it returns to normal. If a patient’s platelet count drops to 60,000 cells/µl, heparin and aspirin should be discontinued. If a patient’s platelet count drops below 50,000 cells/µl, platelets should be transfused.Readministration: There are limited data concerning readministration of ReoPro (please see ‘Undesirable Effects’ and the Doctor’s Package Insert or SPC).Renal disease: Benefits may be reduced in patients with renal disease.Drug interactions: In the presence of ReoPro, heparin is associated with an increase in the incidence of bleeding. Limited experience also suggests an increase in the risk of bleeding in ReoPro patients who have received thrombolytics.Pregnancy: Animal reproduction studies have not been conducted with ReoPro. It is also not known whether ReoPro can cause foetal harm when administered to a pregnant woman or can affect reproduction capacity. ReoPro should be given to a pregnant woman only if clearly needed.Lactation: Breast-feeding of infants should be discontinued in nursing mothers, since the secretion of abciximab in animal or human breast milk has not been studied.Undesirable EffectsThe most frequently reported side-effects reported in controlled clinical studies are back pain, hypotension, nausea, chest pain, vomiting, headache pain, bradycardia, fever, puncture site pain, and thrombocytopenia.Patients treated with ReoPro are more likely to experience thrombocytopenia. In a readministration study of patients receiving a secondor subsequent exposure to ReoPro, the incidence of thrombocytopenia was 5%, with incidence of profound thrombocytopenia of 2%.

RE 910 January 2007

Prescribing Information cont…Bleeding is a recognised complication during ReoPro therapy. In the EPIC trial, in which a non-weight-adjusted, standard heparin dose regimen was used, the most common complication during ReoPro therapy was bleeding during the first 36 hours.In the subsequent EPILOG trial, using the low-dose, weight-adjusted heparin regimen, sheath removal and femoral access care guidelines outlined in section 4.4 of the Doctor’s Package Insert or SPC, the incidence of major bleeding not associated with CABG surgery in patients treated with ReoPro (1.1%) was not different from patients receiving placebo (1.1%) and there was no significant increase in the incidence of intracranial haemorrhage. Likewise, in the EPISTENT trial, the incidence of major bleeding not associated with CABG surgery in patients receiving ReoPro plus balloon angioplasty (0.6%) or ReoPro with stent placement (0.8%) was not significantly different from patients receiving placebo with stent placement (1.0%).In the CAPTURE trial, which did not use the low-dose heparin regimen, the incidence of major bleeding not associated with CABG surgery was higher in patients receiving ReoPro (3.8%) than in patients receiving placebo (1.9%)There have been reports of intracranial haemorrhage, many of which are fatal. The total incidence of intracranial haemorrhage and non-haemorrhagic stroke in all 4 pivotal trials was similar, 9/3023 (0.30%) for placebo patients and 15/4680 (0.32%) for ReoPro-treated patients. The incidence of intracranial haemorrhage was 0.10% in placebo patients and 0.15% in ReoPro patients.Cardiac tamponade, pulmonary (mostly alveolar) haemorrhage, and adult respiratory distress syndrome have been reported rarely. Human antichimeric antibody (HACA) appears, generally as a low titre, in approximately 5% to 6% of patients after 2 to 4 weeks. Hypersensitivity or allergic reactions have been observed rarely following treatment with ReoPro. Nevertheless, anaphylaxis may potentially occur at any time during administration. For full details of side-effects please consult the SPC, which is available at http://emc.medicines.org.uk/.OverdoseTo evaluate the possibility of thrombocytopenia, platelet counts should be monitored prior to treatment, 2 to 4 hours following the bolus dose, and at 24 hours. If a patient experiences an acute platelet decrease, additional platelet counts should be determined.Legal Category POMPackage Quantities Vials 10mg/5ml: Single vials.Product Licence Number PL 08563/0015Basic NHS Cost £260.40Date of Preparation or Last Review February 2006Product Licence Holder: Centocor BV, Einsteinweg 101, 2333 CB Leiden, The NetherlandsFull Prescribing Information is Available FromEli Lilly and Company Limited, Lilly House, Priestley Road, Basingstoke, Hampshire, RG24 9NL Tel: Basingstoke (01256) 315 999

Information about adverse event reporting can be found at www.yellowcard.gov.uk.Adverse events should also be reported to Eli Lilly and Company Limited (Tel no: 0870 2401125).