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Dr Jonathan Day Senior Director Global Medical The Medicines Company Bivalirudin Advancing Anticoagulation in ACS
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MY CONFLICTS OF INTEREST ARE The Medicines Company (Employee)
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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.
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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. 2 2. Weitz JI et al. Thromb Res. 2002;106:V275-V284. Please see full Prescribing Information.
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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.
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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. 1 1. Hirsh J et al. Chest. 2001;119(suppl 1):64S-94S. 2. ANGIOX Prescribing Information. The Medicines Company; UK Ltd. 2008. Please see full Prescribing Information.
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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
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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 (0.89-1.15)0.876 All cause death0.74 (0.55-0.99)0.044 Myocardial infarction1.07 (0.92-1.25)0.387 Major bleeding0.53 (0.45-0.62)<0.001 Data on file: The Medicines Company
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30 day mortality Odds ratio ±95% CI p-value REPLACE-20.63 (0.24-1.62)0.332 ACUITY0.90 (0.57-1.42)0.650 HORIZONS0.65 (0.43-0.99)0.046 All trials0.74 (0.55-0.99)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
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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
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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 = 0.5820).
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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 = 0.7571).
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HORIZONS 1-Year Mortality: Cardiac and Non Cardiac Number at risk Bivalirudin alone Heparin+GPIIb/IIIa 18001705168416691520 18021678166316461486 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=0.005 2.9% Δ = 1.1% P=0.03 Δ = 1.7% Bivalirudin alone (n=1800) Heparin + GPIIb/IIIa (n=1802) Mehran R, TCT 2008
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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%
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Major Adverse Cardiovascular Events at 30 Days [ITT Population] HORIZONS Subgroup Analysis Data on file: The Medicines Company
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Major Bleeding (non-CABG) at 30 Days [ITT Population] HORIZONS Subgroup Analysis Data on file: The Medicines Company
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Death at 30 Days [ITT Population] HORIZONS Subgroup Analysis Data on file: The Medicines Company
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HORIZONS 30 Day Bleeding Endpoints UFH + GP IIb/IIIa (N=1802)Bivalirudin(N=1800) P Value Protocol Major, non CABG* 8.3%4.9%<0.0001 Protocol Major, All 10.8%6.8%<0.0001 Protocol Minor 15.4%8.6%<0.0001 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%<0.0001 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%0.0009 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
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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%0.33 - definite1.4%2.2%0.11 - probable0.5%0.3%0.26 - acute (≤24 hrs)0.3%1.3%0.0009 - subacute (>24 hrs – 30d)1.7%1.2%0.30 *Protocol definition of stent thrombosis, CEC adjudicated
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30 Day Stent Thrombosis (N=3,124) Bivalirudin: 174917141711167316631591 UFH + GP IIb/IIIa: 181818051804174617241625 Patients at Risk BivalirudinUFH + GP IIb/IIIa Estimated Event Rate (%) Days from Randomisation 0 1 2 3 4 5 5101520253000.51 23 4 30 19
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21 30 Day Stent Thrombosis – IIb/IIIa vs P2Y12
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22 ST TypeBivalirudin (N=1800) UFH + GPI (N=1802) Risk of death (n/N [%]) STDeathSTDeath Acute 231412/27 (7.4) Subacute 193301417/49 (34.7) Overall 414341519/75 (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
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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.
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