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

MY CONFLICTS OF INTEREST ARE The Medicines Company (Employee)

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”

Broad spectrum of experience with bivalirudin in clinical trials 27,735 patients undergoing invasive management of CAD 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 Increasing risk of ischaemic complications Lincoff et al JAMA, 2003 Bittl et al AHJ, 2001 Stone et al NEJM, 2006 Stone et al NEJM, 2007

Consistent trial results ● Meta-analysis of REPLACE-2, ACUITY and HORIZONS ● 14,258 patients given aspirin, clopidogrel prior to angio/intervention Risk ratio ±95% CIP-value Death, MI or revasc 30d1.0 ( )0.941 All cause death 30d0.73 ( )0.043 All cause death 1y0.80 ( )0.015 Major bleeding 30d0.54 ( )< Bivalirudin betterHeparin+GPI better Data on file The Medicines Company Mehran ESC 2009

● 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 PREMIER Dataset

Hazard Ratio ± 95% CI OR (95% CI) Fully adjusted HR for transfusion0.67 (0.61–0.73) Fully adjusted HR for repeat PCI0.96 (0.90–1.03) Fully adjusted HR for death0.51 (0.44–0.60) Bivalirudin Better Heparin + GP IIb/IIIa Inhibitor Better 7 ANGIOX is Effective in Routine Care ● Angiox reduced the risk of in-hospital death and blood transfusions Rassen JA et al Eur Heart J 2009

Primary PCI Strategy Aspirin, thienopyridine 3,000 pts eligible for stent randomisation Bare metal stentpaclitaxel-eluting stent Clinical FU at 30 days, 1 yr, 2 years 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: UFH + GP IIb/IIIa inhibitor (abciximab or eptifibatide) Bivalirudin monotherapy (± provisional GP IIb/IIIa) 3,602 pts with STEMI with symptom onset ≤12 hours R 1:3 R 1:1 8

30-day Clinical Outcomes 30-day event rates (%) NACEMajor 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: : 9 Diff = 0.0% [-1.6, 1.5] RR = 0.99 [0.76, 1.30] P sup = 0.95 Diff = -3.3% [-5.0, -1.6] RR = 0.60 [0.46, 0.77] P NI ≤ P sup ≤ Diff = -2.9% [-4.9, -0.8] RR = 0.76 [0.63, 0.92] P NI ≤ P sup = 0.005

30-day MACE Components 10 Bivalirudin (n=1,800)* UFH + GP IIb/IIIa (n=1,802)P value Mortality † 2.1%3.1% Cardiac1.8%2.9% Noncardiac0.3%0.2%0.75 Reinfarction1.8% Q-wave1.4%1.2% Non–Q-wave0.4%0.7%0.37 Ischaemic TVR2.6%1.9%0.18 Stroke0.7%0.6%0.68 *In HORisONS AMI, 93% of bivalirudin patients received monotherapy, without provisional GP IIb/IIIa. †Adjudicated. TLR=target lesion revascularisation. Stone GW. NEJM 2008;358:

2-Year Reinfarction p= HR [95%CI]= 0.75 [0.56, 0.98] 5.1% 6.9% Reinfarction (%) Number at risk Bivalirudin alone Heparin+GPIIb/IIIa Bivalirudin alone (n=1800) Heparin + GPIIb/IIIa (n=1802) Months Stone GW TCT 2009

HORIZONS 2 year follow-up ● Cardiac mortality in ITT population ↓41%* 2.5% 4.2% Months Cardiac mortality (%) 2.1% 3.7 % ↓43%* 1.8% 2.9% ↓38%* All p≤0.03 *Relative risk reduction BivalirudinUFH+GPI Stone et al TCT 2009

HORIZONS Stent thrombosis

30 Day Stent Thrombosis (N=3,124) UFH + GP IIb/IIIa (N=1553) Bivalirudin (N=1571) P Value ARC definite or probable* 1.9%2.5% definite 1.4%2.2% probable 0.5%0.3% acute (≤24 hrs) 0.3%1.3% subacute (>24 hrs – 30d) 1.7%1.2%0.30 *Protocol definition of stent thrombosis, CEC adjudicated

HORIZONS ST to 30 days ● Increase in acute ST offset by decrease in sub-acute ST BivalirudinUFH+GPI Estimated event rate (%) Days from randomisation acute ST 4 acute ST 30 sub-acute ST 20 sub-acute ST Stone et al NEJM, 2008

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) Cumulative Frequency of ST Days No GP IIb/IIIa Pretreatment GP IIb/IIIa Pretreatment P =.002 Rinaldi Am Heart J 2008;155:654-60

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

18 ST TypeBivalirudin (N=1800) UFH + GPI (N=1802) Risk of death (n/N [%]) STDeathSTDeath Acute231412/27 (7.4) Subacute /49 (34.7) 30 Day Stent Thrombosis – Risk of Subsequent Death

Deaths at 1 year subsequent to major events Number of deaths Major eventBivalirudin UFH + GP IIb/IIIa TotalDelta Acute ST1120 Subacute ST Late ST3693 Major Bleeding Re-Infarction Stroke5491

HORIZONS Review Did the dose of clopidogrel impact outcomes?

Clopidogrel 300mg versus 600mg 21 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 MACE at 30 days Clopidogrel 300mgClopidogrel 600mg P-value Bivalirudin 43/595 (7.2) 46/1125 (4.1) UFH + GP IIb/IIIa43/618 (7.0)48/1091 (4.4) Dangas et al, JACC 2009

Clopidogrel and Stent Thrombosis 22

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 23

Krumholz,. et al. JAMA 2009;302: Trends in 30d mortality after AMI ● All-Cause risk-standardised mortality

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.