Dr Jonathan Day Senior Director Global Medical The Medicines Company

1. Bivalirudin For patients with STEMI undergoing primary PCI Dr Jonathan Day Senior Director Global Medical The Medicines Company

2. MY CONFLICTS OF INTEREST ARE The Medicines Company (Employee)

3. New Indication for STEMI • Approved in the European Union in 2004 As an anticoagulant in patients undergoing percutaneous coronary intervention (PCI) • Type II variation approved in 2008 For the treatment of patients with ACS undergoing early or urgent intervention • Type II variation approved in 2009 As an anticoagulant in patients undergoing percutaneous coronary intervention (PCI) including primary PCI “The only anticoagulant approved for patients undergoing PPCI”

4. Broad spectrum of experience with bivalirudin in clinical trials 27,735 patients undergoing invasive management of CAD Increasing risk of ischaemic complications REPLACE-2 (N=6,002) CAD Planned PCI BAT (N=4,312) UA, NQWMI Planned PTCA ACUITY (N=13,819) NSTE-ACS PCI <72h HORIZONS (N=3,602) STEMI Emergency PCI Lincoff et al JAMA, 2003 Bittl et al AHJ, 2001 Stone et al NEJM, 2006 Stone et al NEJM, 2007

5. Consistent trial results • Meta-analysis of REPLACE-2, ACUITY and HORIZONS • 14,258 patients given aspirin, clopidogrel prior to angio/intervention Bivalirudin better Heparin+GPI better Data on file The Medicines Company Mehran ESC 2009

6. PREMIER Dataset • The data source for the analysis is the Premier Perspective Database • A total of 127,185 PCI procedures were identified from the database between June 2003 through December 2006 • Patients received either bivalirudin plus provisional GPI or the comparator, heparin plus GPIIb/IIIa Rassen JA et al Eur Heart J 2009

7. ANGIOX is Effective in Routine Care • Angiox reduced the risk of in-hospital death and blood transfusions Bivalirudin Better Heparin + GP IIb/IIIa Inhibitor Better 7 Rassen JA et al Eur Heart J 2009

8. HORIZONS AMI Trial Design • Open-label, randomised, prospective, multicenter trial FU=follow-up; pts=patients; R=randomised; UFH=unfractionated heparin. Stone GW. NEJM 2008;358:2218-30. 3,602 pts with STEMI with symptom onset ≤12 hours Aspirin, thienopyridine R 1:1 UFH + GP IIb/IIIa inhibitor (abciximab or eptifibatide) Bivalirudin monotherapy (± provisional GP IIb/IIIa) 3,000 pts eligible for stent randomisation Primary PCI Strategy R 1:3 Bare metal stent paclitaxel-eluting stent Clinical FU at 30 days, 1 yr, 2 years

9. 30-day Clinical Outcomes Diff = -2.9% [-4.9, -0.8] RR = 0.76 [0.63, 0.92] PNI ≤ 0.0001 Psup = 0.005 Diff = -3.3% [-5.0, -1.6] RR = 0.60 [0.46, 0.77] PNI ≤ 0.0001 Psup ≤ 0.0001 Diff = 0.0% [-1.6, 1.5] RR = 0.99 [0.76, 1.30] Psup = 0.95 30-day event rates (%) NACE Major Bleeding† MACE‡ *In HORIZONS AMI, 93% of bivalirudin patients received monotherapy, without provisional GP IIb/IIIa. †Not related to CABG. ‡MACE=all-cause death, reinfarction, ischaemic TVR, or stroke. Stone GW. NEJM 2008;358:2218-30:

10. *In HORisONS AMI, 93% of bivalirudin patients received monotherapy, without provisional GP IIb/IIIa. †Adjudicated. TLR=target lesion revascularisation. Stone GW. NEJM 2008;358:2218-30 30-day MACE Components

11. 2-Year Reinfarction Bivalirudin alone (n=1800) Heparin + GPIIb/IIIa (n=1802) 10 9 8 6.9% 7 6 5.1% Reinfarction (%) 5 4 HR [95%CI]= 3 0.75 [0.56, 0.98] 2 p= 0.038 1 0 0 3 6 9 12 15 18 21 24 Months Number at risk 1800 1644 1603 1554 1298 Bivalirudin alone 1802 1621 1576 1500 1244 Heparin+GPIIb/IIIa Stone GW TCT 2009

12. HORIZONS 2 year follow-up • Cardiac mortality in ITT population 5 Bivalirudin UFH+GPI 4.2% 4 ↓41%* 3.7 % 2.9% 3 ↓43%* 2.5% ↓38%* Cardiac mortality (%) 2 2.1% 1.8% All p≤0.03 1 *Relative risk reduction 0 0 3 6 9 12 15 18 21 24 Stone et al TCT 2009 Months

13. HORIZONS Stent thrombosis

14. 30 Day Stent Thrombosis (N=3,124) *Protocol definition of stent thrombosis, CEC adjudicated

15. Bivalirudin UFH+GPI HORIZONS ST to 30 days • Increase in acute ST offset by decrease in sub-acute ST 5 4 3 Estimated event rate (%) 30 sub-acute ST 2 24 acute ST 1 4 acute ST 20 sub-acute ST 0 0 0.5 1 5 10 15 20 25 30 Days from randomisation Stone et al NEJM, 2008

16. 1.0 0.8 P = .002 0.6 Cumulative Frequency of ST 0.4 No GP IIb/IIIa Pretreatment 0.2 GP IIb/IIIa Pretreatment 0 0 5 10 15 20 25 30 Days GPIIb/IIIa and stent thrombosis • Cumulative distribution for time to development of ST according to GPIIb-IIIa inhibitor exposure. Among patients who received GPIIb-IIIa blockade, the median time to development of ST was increased from 2 to 5 days (P = .002). Rinaldi Am Heart J 2008;155:654-60

17. Timing of Stent Thrombosis in Patients Treated with Tirofiban. Retrospective analysis of a single-center intervention database between January1997 and October 1999 . 13 patients identified with acute or subacute stent thrombosis The median time from stent deployment to ST was 7 hours (IQR, 2.5-33 hours) in patients not receiving a GPIIb/IIIa antagonist compared to 84.5 hours (IQR, 56-124.5 hours) in patients receiving one. Assali AR J Invasive Cardiol. 2000 Sep;12(9):460-3

18. 30 Day Stent Thrombosis – Risk of Subsequent Death

19. Deaths at 1 year subsequent to major events

20. HORIZONS Review Did the dose of clopidogrel impact outcomes?

21. Clopidogrel 300mg versus 600mg • The impact of bivalirudin was independent of the clopidogrel loading dose. Interaction P values = 0.48 (NACE) 0.41 (Major bleeding), and 0.75 (MACE). • Significant decrease in MACE in patients treated with 600mg versus 300mg clopidogrel Dangas et al, JACC 2009

22. Clopidogrel and Stent Thrombosis

23. Optimising outcomes with bivalirudin • Early adjunctive therapy Early adjunctive therapy with guideline recommended therapies (which should include aspirin and clopidogrel and may include UFH) was associated with a reduced rate of AST in both arms of HORIZONS • Adequate PY12 inhibition Treatment with Clopidogrel 600 mg vs. 300mg resulted in improved MACE in both arms Prasugrel 60 mg may be better than clopidogrel • Prolonged bivalirudin infusion A post PCI infusion of bivalirudin at 0.25/mg/kg infusion for up to 4 hours does not increase bleeding (BAT) and does not affect sheath pull times (AFRICA) Prolonged antithrombin therapy until such time that P2Y12 inhibition is effective may further reduce AST

24. Trends in 30d mortality after AMI • All-Cause risk-standardised mortality 1995-2006 Krumholz,. et al. JAMA 2009;302:767-773.

25. Conclusion • In HORIZONS-AMI the significant reductions in cardiac-related death at 30-days, 1-year and 2-years are important. • For every 59 patients with STEMI undergoing primary PCI with bivalirudin compared to conventional therapies one cardiac related death might be avoided (NNT= 59 at 1 yr). • The important implications of the HORIZONS study are now reflected in the recently updated ACC/AHA guidelines for the management of patients with STEMI undergoing primary PCI where bivalirudin received a (Class IB) recommendation [Kushner et al., 2009]. • In conclusion, the favourable risk–benefit profile of bivalirudin, make it clinically important alternative to current treatments for the contemporary management of STEMI patients undergoing primary PCI.