7 th Joint Bosnia Herzegovina and Turkish Cardiology Meeting May 25-27,2012

1. Antithrombotic and Antiplatelat Strategy in ACSEmir Fazlibegović,FESC SKB Mostar , Bosnia and Herzegovina 7 th Joint Bosnia Herzegovina and Turkish Cardiology Meeting May 25-27,2012 Sarajevo,Bosnia and Herzegovina

2. “These data, together with a major and statistically significant decrease in systolic blood pressure, measured in all streptokinase patients, are compatible with the hypothesis that streptokinase improves cardiac function after acute myocardial infarction by decreasing total peripheral resistance” NEJM 1979;301:797-802

3. Various and VeryDifferentThrombotic Situations • Venousthrombosis: fibrinrich thrombus • Important thrombus burden • VTE • Afib • Mechanicalheart valves • Arterialthrombosis: plateletrich thrombus • Modest thrombus burden • Acute coronary syndromes (STEMI,NSTEMI,NAP) • PCI / Stent implantation • CVD • PAD

4. ACS with persistent ST-segment elevation ACS without persistent ST-segment elevation Adapted from Michael Davies Adapted from Michael Davies Troponin elevated or not CK- MB or Troponin

7. AntiplateletTherapy in ACS ASA ASA + Clopidogrel ASA + Prasugrel Reduction inIschemicEvents - 22% - 20% - 19% Increase in Major Bleeds + 32% + 38% + 60% Single Antiplatelet Rx Dual Antiplatelet Rx Higher IPA

8. Predictors of Bleeding • Baseline characteristics • Age • Sex • Body weight • Chronickidneydisease • Diabetes • Anemia • History of bleeding • … • Invasive approach • Excessive dosing of antithromboticdrugs • Combination of antithrombotic agents

9. A novel score (HAS-BLED) to assess one-year risk of major bleeding in AF : The Euro Heart Survey R Pisters Chest 2010 DOI 10.1378/chest.10-0134

10. Balancing Safety and Efficacy High risk of ischemic events High risk of bleeding events “Sweet spot” Risk of any event Risk of any event Inhibition of platelet aggregation Ischemic risk Bleeding risk Ferreiro & Angiolillo. Thromb Haemost 2010

11. Targets for Antithrombotic Agents

12. Parenteral anticoagulants AT, antithrombin; DVT, deep vein thrombosis; FXa, Factor Xa; HIT, heparin-induced thrombocytopenia; PCI, percutaneous coronary interventions; PE, pulmonary embolism; VTE, venous thromboembolism

13. Recent and emerging anticoagulants Thrombin inhibitors Direct, oral Ximelagatran Dabigatran Factor Xa inhibitors Indirect, parenteral Fondaparinux Idraparinux/biotinylated Direct, oral Rivaroxaban Apixaban Others

14. OASIS-5Fewer Bleedings = Fewer Deaths Bleeding Reduced by 50% Deaths Reduced by 17% Yusuf S, Mehta S, et al. OASIS-5 Investigators NEJM 2006

15. Current Standard of care * with bolus of UFH in case of PCI

16. New strategieswithnew AC drugs Heparin(s) Fondaparinux Initialoverlapbetweentwo standard Tx AVK Switchfrom standard Tx to neworal agent Heparin(s) Fondaparinux Dabigatran One agent withdosemodification for LT prevention Apixaban, Rivaroxaban

17. PRIMARY EFFICACY ENDPOINTS: 2.5 mg PO BID In Patients Treated with ASA + Thienopyridine ATLAS ACS 2 TIMI 51 All Cause Death CV Death / MI / Stroke* Cardiovascular Death 5% 5% HR 0.85 mITT p=0.039 ITT p=0.011 Placebo Placebo HR 0.62 mITT p<0.001 ITT p<0.001 HR 0.64 mITT p<0.001 ITT p<0.001 Placebo 12% 4.5% 10.4% 4.2% 9.0% 2.7% Estimated Cumulative incidence (%) 2.5% Rivaroxaban 2.5 mg BID Rivaroxaban 2.5 mg BID Rivaroxaban 2.5 mg BID NNT = 71 NNT = 59 NNT = 56 12 12 12 0 24 24 0 0 24 Months Months Months *: First occurrence of cardiovascular death, MI, stroke (ischemic, hemorrhagic, and uncertain) as adjudicated by the CEC Two year Kaplan-Meier estimates, HR and 95% confidence interval estimates from Cox model stratified by thienopyridine use are provided per mITT approach; Stratified log-rank p-values are provided for both mITT and ITT approaches; NNT=Number needed to treat.

18. STENT THROMBOSIS* ARC Definite, Probable, Possible ATLAS ACS 2 2 Yr KM Estimate TIMI 51 2.9% Placebo 2.3% Estimated Cumulative incidence (%) HR 0.69 (0.51- 0.93) mITTp = 0.016 ITT p = 0.008 Rivaroxaban (both doses) ARC Definite/probable: HR=0.65, mITT p=0.017, ITT p=0.012 Months After Randomization * End point events are as adjudicated by the CEC across thienopyridine use strata Two year Kaplan-Meier estimates, HR and 95% confidence interval estimates from Cox model stratified by thienopyridine use are provided per mITT approach; Stratified log-rank p-values are provided for both mITT and ITT approaches; Rivaroxaban=Pooled Rivaroxaban 2.5 mg BID and 5 mg BID.

19. ATLAS ACS 2 TREATMENT-EMERGENT FATAL BLEEDS AND ICH TIMI 51 p=0.009 Riva Vs Placebo p=NS for Rivavs Placebo p=0.044 for 2.5 mg vs 5.0 mg p=NS for Riva vs Placebo * n=18 n=8 n=4 n=5 n=15 n=14 n=5 n=6 n=9 *Among patients treated with aspirin + thienopyridine, there was an increase in fatal bleeding among patients treated with 5.0 mg of Rivaroxaban (15/5110) vs 2.5 mg of Rivaroxaban (5/5115) (p=0.02)

20. Study Design Recent (7 days) Acute Coronary Syndrome plus at least one additional risk factor Phase A = 547 Phase A 1:1:1 • Randomized, double-blind. • Study drug for 6 months. • Aspirin 165 mg/d. • Clopidogrel per MD discretion (stratified randomization) Apixaban 10 mg QD n=184 Apixaban 2.5 mg BID n=179 Placebo n=184 Discontinued early due to excess bleeding in patients receiving apixaban and dual antiplatelet therapy Interim analysis (DSMB review) Phase B = 1168 Phase B 3:1:1:2:2 Placebo n=427 Apixaban 2.5 mg BID n=138 Apixaban 10 mg QD n=134 Apixaban 10 mg BID n=248 Apixaban 20 mg QD n=221 Apixaban 10 mg BID n=248 Apixaban 20 mg QD n=221 Total = 1715 Primary safety outcome: ISTH major or clinically relevant non-major bleeding (ISTH) Secondary efficacy outcome: cardiovascular death, MI, severe recurrent ischemia or ischemic stroke

21. ATLAS STUDY DESIGN TIMI 46 Recent ACS Patients Stabilized 1-7 Days Post-Index Event Aspirin 75-100 mg MD Decision to Treat with Clopidogrel NO YES N = 3,491 STRATUM 1 ASA Alone N=761 STRATUM 2 ASA + Clop. N=2,730 RIVA BID N=911 2.5 mg (76) 5 mg (430) 7.5 mg (178) 10 mg (227) PLACEBO N=253 5 mg (77) 10 mg (98) 20 mg (78) RIVA BID N=254 2.5 mg (77) 5 mg (97) 10 mg (80) RIVA QD N=254 5 mg (77) 10 mg (99) 20 mg (78) RIVA QD N=912 5 mg (78) 10 mg (430) 15 mg (178) 20 mg (226) PLACEBO N=907 5 mg (74) 10 mg (428) 15 mg (178) 20 mg (227) Treat for 6 Months Gibson CM, AHA 2008

22. Once daily Predictable pharmacokinetics and pharmacodynamics High oral bioavailability Rapid onset of action Fixed dose No requirement for coagulation monitoring Rivaroxaban: a novel oral, direct Factor Xa inhibitor Rivaroxaban Rivaroxaban binds directly to the active site of Factor Xa (Ki 0.4 nM) Roehrig et al. 2005; Perzborn et al. 2005; Kubitza et al. 2005; 2006; 2007

23. Recent acute coronary syndrome patients Stabilized 1–7 days post-index event Aspirin 75–100 mg N ~3,500 MD decision to treat with clopidogrel NO YES STRATUM 1 STRATUM 2 *Dose levels 5, 10 and 20 mg Placebo Placebo Rivaroxabantwice daily 3 dose levels* Rivaroxabantwice daily 3 dose levels* Rivaroxabanonce daily 3 dose levels* Rivaroxabanonce daily 3 dose levels* Treat for 6 months Primary endpoint:TIMI significant bleeding

27. New Antiplatelet Agents • Clopidogrel new regimen • Prasugrel • Ticagrelor

28. Risk of Infarction and Dabigatran Uchino Arch Intern Medicine 2012

30. Comparison of Efficacy and SafetyEndpointsatStudy End in Recent Major Antiplatelet Trials

31. Primary Endpoint: CV Death, MI, Stent Thrombosis JAMA. 2011;305(11):1097-1105

39. Risk of bleeding in patients with acute myocardial infarction treated with different combinations of aspirin, clopidogrel and vitamin K antagonists

40. New Parenteral Anticoagulants under Investigation • Idrabiotaparinux, • ultra-low-molecular-weight heparins, re-engineered UFH [M118]), • Direct FIIa inhibitors , flovagatran sodium, pegmusirudin, NU172, HD1-22), • Direct FXIa inhibitors (BMS-262084, antisense oligonucleotides targeting FXIa, clavatadine), • FIXa inhibitors (RB-006), • FVIIIa inhibitors (TB-402), • FVIIa/tissue factor inhibitors (tifacogin, NAPc2, PCI-27483, BMS-593214), • FVa inhibitors (drotrecogin alpha activated, ART-123) • Dual thrombin/FXa inhibitors (EP217609, tanogitran).

41. M118: Rationally engineered heparin • Xa and IIa binding sites on each chain • First LMWH with significant IIa activity • Constant Xa/IIa ratio over time • Presence of IIa activity allow for point-of-care anticoagulant monitoring • Reduced polydispersity • More predictable PK • Contributes to protamine neutralization • Unnecessary sequences eliminated/more accessible Xa/IIa sites • Reduced PF4 binding sites (potentially reduced HIT) • Contributes to TFPI release • IV and SC administration Thrombin Binding Sequence Pentasaccharide AT-III Binding Sequence

42. Semuloparin for Thromboprophylaxisin Patients Receiving Chemotherapy for CancerSAVE-ONCO Trial In total 8 ongoing trials with Semuloparin Agnelli N Engl J Med 2012;366:601-9.

43. Take-home messages • Cardiology is a complex discipline. Try to keepit simple • Standard of care isgoing to change dramatically • New antiplatelet agents have alreadychanged the standard of care. Ticagrelor has the potential to replace clopidogrel in all forms of ACS • New oral anticoagulants have the potential to revolutionize the treatment of VTE, AF and ACS. Rivaroxaban has the potential to cover all indications

44. Take-home messages-STEMI •  All patients with ST-elevation myocardial infarction (STEMI) should receive anticoagulation,irrespective of the reperfusion strategy, anticoagulant therapy should be given as soon as possible after diagnosis. • All patients with STEMI should receive dual antiplatelet therapy.

45. Take-home messages • The choice of anticoagulant agent depends upon the treatment strategy for each patient (unfractionated heparin [UFH], low molecular weight heparin, bivalirudin, or fondaparinux) • For all patients treated with primary PCI, we recommend anticoagulant therapy (Grade 1B).

46. Take-home messages • We recommend either bivalirudin (with provisional glycoprotein [GP] IIb/IIIa inhibitor in cases of ischemic complications or large thrombus burden) or UFH (and planned GP IIb/IIIa inhibitor) in preference to fondaparinux (Grade 1B). • We suggest bivalirudin (with provisional GP IIb/IIIa inhibitor) in preference to UFH (with planned GP IIb/IIIa inhibitor) (Grade 2B).

47. Take-home messages • For patientstreated with fibrinolytic therapy, we suggest anticoagulant therapy (Grade 2B). • For patients not at high risk of bleeding, we suggest using enoxaparin as opposed to UFH, fondaparinux, orbivalirudin • For those patients in whom PCI is possible or likely after fibrinolytic therapy, UFH a reasonable choice.

48. Take-home messages • For patients at high risk of a bleeding complication and who are not likely to require PCI, we suggest fondaparinux as opposed to enoxaparin or UFH (Gr. 2C). • For patients not treated with reperfusion therapy, we suggest anticoagulant therapy with enoxaparin, UFH, or fondaparinux, as opposed to no anticoagulant therapy, as soon as possible after presentation (Gr.2B).

49. Take-home messages-NSTEMI • Anticoagulant therapy with either bivalirudin, fondaparinux, unfractionated heparin (UFH), or enoxaparin prevents thrombus related ischemic events in patients with NSTE ACS(UAP+NSTEMI). • We recommend anticoagulant therapy for all patients (Grade 1A).

50. Take-home messages • For patients managed with an early invasive strategy (angiography within 4 to 48 h), we recommend bivalirudin, fondaparinux, or UFH as opposed to enoxaparin (Grade 1A).  • The choice between bivalirudin, fondaparinux, or UFH should be made based on issues of cost and local practice