Dr Jonathan Day Senior Director Global Medical The Medicines Company Bivalirudin Advancing Anticoagulation in ACS

MY CONFLICTS OF INTEREST ARE The Medicines Company (Employee)

ANGIOX ® (bivalirudin) indication ● Bivalirudin is indicated as an anticoagulant in patients undergoing percutaneous coronary intervention (PCI) ● Bivalirudin is indicated for the treatment of adult patients with acute coronary syndromes (unstable angina/non- ST segment elevation myocardial infarction (UA/NSTEMI)) planned for urgent or early intervention. ● Bivalirudin should be administered with aspirin and clopidogrel Please see full Prescribing Information.

Indirect inhibition by heparin requires the presence of antithrombin, the actual inhibitor. 1 Indirect versus direct thrombin inhibition ANGIOX inhibits thrombin directly with high affinity and specificity. 2 ANGIOX provides effective thrombin inhibition to prevent thrombosis and thrombin- mediated platelet effects Weitz JI et al. Thromb Res. 2002;106:V275-V284. Please see full Prescribing Information.

ANGIOX, with a high affinity for thrombin, displaces thrombin from fibrin. 2 ANGIOX effectively inhibits clot- bound and circulating thrombin. 2 The heparin-antithrombin complex is not effective against clot-bound thrombin. 1 This reservoir of active thrombin continues to activate platelets and trigger further clotting. 1 ANGIOX ® (bivalirudin) effectively inhibits clot-bound thrombin 1. Hirsh J et al. Chest. 2001;119(1 suppl):64S-94S. 2. Weitz JI et al. Thromb Res. 2002;106:V275-V284. Please see full Prescribing Information.

Return to haemostasis—safety advantage ANGIOX is cleaved by thrombin, allowing thrombin to quickly recover hemostatic activity upon discontinuation of ANGIOX. 2 The natural reversibility and the short, 25-minute half-life may explain the significantly lower bleeding rates seen in clinical trials. 3 When heparin dissociates from cells/proteins, there can be an anticoagulant effect even when it is not needed. This may explain the prolonged bleeding risk after discontinuation of heparin Hirsh J et al. Chest. 2001;119(suppl 1):64S-94S. 2. ANGIOX Prescribing Information. The Medicines Company; UK Ltd Please see full Prescribing Information.

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 ischemic complications Lincoff et al JAMA, 2003 Bittl et al AHJ, 2001 Stone et al NEJM, 2006 Stone et al NEJM, 2007

Ischemic protection, less major bleeding and reduced mortality in acute management of CAD 14,407 patients in REPLACE-2, ACUITY and HORIZONS † Bivalirudin alone betterHeparin + GP IIb/IIIa better † All patients administered ASA and clopidogrel *includes stroke for HORIZONS patients 30 day Odds ratio ±95% CI p-value Death, MI or revasc*1.01 ( )0.876 All cause death0.74 ( )0.044 Myocardial infarction1.07 ( )0.387 Major bleeding0.53 ( )<0.001 Data on file: The Medicines Company

30 day mortality Odds ratio ±95% CI p-value REPLACE ( )0.332 ACUITY0.90 ( )0.650 HORIZONS0.65 ( )0.046 All trials0.74 ( )0.044 Significant reduction in all-cause mortality Bivalirudin alone betterHeparin + GP IIb/IIIa better † All patients administered ASA and clopidogrel 14,407 patients in REPLACE-2, ACUITY and HORIZONS† Data on file: The Medicines Company

HORIZONS 30 Day Mortality: Cardiac and Non Cardiac Death (%) Time in Days 2.9% 1.8% Heparin + GPIIb/IIIa inhibitor (n=1802) Bivalirudin monotherapy (n=1800) 0.3% 0.2% Cardiac Non cardiac HR [95%CI] = 0.62 [0.40, 0.96] P=0.029

11 30 Day MACE – GPI Choice GPI Inhibitor Bivalirudin (N=1800) UFH + GPI (N=1802) Relative Risk (95% CI) Abciximab54/955 (5.7%) 51/960 (5.3%) 1.06 (0.73, 1.54) Eptifibatide44/845 (5.2%) 48/842 (5.7%) 0.91 (0.61, 1.36) In the control arm (53%) received abciximab and (47%) received eptifibatide. In the control arm MACE was independent of GP IIb/IIIa (interaction p-value for MACE = ).

12 30 Day MACE – 300 vs 600mg Clopidogrel GPI Inhibitor Bivalirudin (N=1800) UFH + GPI (N=1802) Relative Risk (95% CI) 300 mg 43/595 (7.2) 43/618 (7.0) 1.04 (0.69, 1.56) 600 mg 46/1125 (4.1) 47/1091 (4.3) 0.95 (0.64, 1.41) 34.6% of patients received 300 mg and 65.2% of patients received 600 mg. Outcomes were independent of the clopidogrel loading dose (interaction p-value = ).

HORIZONS 1-Year Mortality: Cardiac and Non Cardiac Number at risk Bivalirudin alone Heparin+GPIIb/IIIa Cardiac Non Cardiac Mortality (%) Time in Months 3.8% 2.1% 1.3% 1.1% HR [95%CI] = 0.57 [0.38, 0.84] P= % Δ = 1.1% P=0.03 Δ = 1.7% Bivalirudin alone (n=1800) Heparin + GPIIb/IIIa (n=1802) Mehran R, TCT 2008

HORIZONS 30 Day Mortality: Low Risk Trial? TRIAL Bivalirudin (30-day mortality) UFH + GPI (30-day mortality) ADMIRAL_ 3.4% HORIZONS2.1%3.1% CADILLAC_2.7% ACE_3.5%

Major Adverse Cardiovascular Events at 30 Days [ITT Population] HORIZONS Subgroup Analysis Data on file: The Medicines Company

Major Bleeding (non-CABG) at 30 Days [ITT Population] HORIZONS Subgroup Analysis Data on file: The Medicines Company

Death at 30 Days [ITT Population] HORIZONS Subgroup Analysis Data on file: The Medicines Company

HORIZONS 30 Day Bleeding Endpoints UFH + GP IIb/IIIa (N=1802)Bivalirudin(N=1800) P Value Protocol Major, non CABG* 8.3%4.9%< Protocol Major, All 10.8%6.8%< Protocol Minor 15.4%8.6%< Blood transfusion 3.5%2.1%0.01 TIMI Major 5.0%3.1%0.003 TIMI Minor 4.6%2.8%0.008 TIMI Major or Minor 9.6%5.9%< GUSTO LT** or Severe 0.6%0.4%0.65 GUSTO Moderate 5.0%3.1%0.003 GUSTO LT or Sev or Mod 5.6%3.5%0.003 Non-Access Site ## 2.6%1.1% GI Bleeding 0.5%0.1%0.10 *Primary endpoint; **Life threatening ## ## Intracranial bleeding, Intraocular, GI, GU, Pleural, Pulmonary, Head and Neck, Epistaxis, Haemoptysis, Haematemesis, Gingival, Malaena Data on file: The Medicines Company

30 Day Stent Thrombosis (N=3,124) UFH + GP IIb/IIIa (N=1553)Bivalirudin(N=1571)PValue ARC definite or probable*1.9%2.5% definite1.4%2.2% probable0.5%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

30 Day Stent Thrombosis (N=3,124) Bivalirudin: UFH + GP IIb/IIIa: Patients at Risk BivalirudinUFH + GP IIb/IIIa Estimated Event Rate (%) Days from Randomisation

21 30 Day Stent Thrombosis – IIb/IIIa vs P2Y12

22 ST TypeBivalirudin (N=1800) UFH + GPI (N=1802) Risk of death (n/N [%]) STDeathSTDeath Acute /27 (7.4) Subacute /49 (34.7) Overall /75 (25.0) 30 Day Stent Thrombosis – Risk of Subsequent Death Data on file: The Medicines Company Analysis of safety population in all patients receiving stents

Conclusions ● In HORIZONS-AMI the significant reductions in cardiac- related death at 30-days and 1-year are important. ● For every 96 patients with STEMI undergoing primary PCI with bivalirudin compared to conventional therapies one cardiac related death might be avoided (1 yr: NNT=58). ● The important implications of the HORIZONS study are now reflected in the recently updated ESC guidelines for the management of patients with STEMI undergoing primary PCI where bivalirudin received a (Class IIa-B) recommendation [Van De Werf et al., 2008]. ● In conclusion, the favourable risk–benefit profile of bivalirudin, make it clinically important alternative to current treatments for the contemporary management of ACS patients undergoing PCI.