1. Dr Adeel Shahzad Dr Rod Stables (PI) Liverpool Heart and Chest Hospital Liverpool, UK H ow E ffective are A ntithrombotic T herapies in PPCI

2. Anti-thrombotic therapy in PPCI Selective (‘bailout’) use of GP IIb/IIIa antagonists (GPI) Increasingly the norm in routine practice Recommended by international guidelines ESC ACCF / AHA

3. Anti-thrombotic therapy in PPCI Selective (‘bailout’) use of GP IIb/IIIa antagonists (GPI) Increasingly the norm in routine practice Recommended by key guidelines (ESC, ACCF / AHA) Bivalirudin + selective (7% - 15%) use of GPI Established anti-thrombotic treatment option

4. Bleeding is associated with less favourable outcomes Increased GPI use - results in increased bleeding Observed for both bivalirudin and heparin Relative performance of bivalirudin and heparin - Cannot be reliably assessed with differential GPI use HEAT PPCI Bivalirudin + selective GPI v Heparin + selective GPI

5. Bleeding is associated with less favourable outcomes Increased GPI use - results in increased bleeding Observed for both bivalirudin and heparin Relative performance of bivalirudin and heparin - Cannot be assessed reliably with differential GPI use HEAT PPCI Bivalirudin + ‘bailout’ GPI v Heparin + ‘bailout’ GPI

6. Single centre RCT Trial recruitment: Feb 2012 - Nov 2013 22 months Bivalirudin v Unfractionated Heparin STEMI patients Randomised at presentation Acute phase management with Primary PCI

7. Single centre RCT Trial recruitment: Feb 2012 - Nov 2013 22 months Bivalirudin v Unfractionated Heparin STEMI patients Randomised at presentation Acute phase management with Primary PCI Philosophy for clinical teams: Assess ‘Every Patient - Every Time’

8. Inclusion Criterion All STEMI patients activating PPCI pathway Exclusion Criteria Active bleeding at presentation Factors precluding administration of oral A-P therapy Known intolerance / contraindication to trial medication Previous enrolment in this trial

9. Dual oral anti-platelet therapy pre-procedure Heparin: 70 units/kg body weight pre-procedure Bivalirudin: Bolus 0.75 mg/kg Infusion 1.75 mg/kg/hr - procedure duration

10. Dual oral anti-platelet therapy pre-procedure Heparin: 70 units/kg body weight pre-procedure Bivalirudin: Bolus 0.75 mg/kg Infusion 1.75 mg/kg/hr - procedure duration GPI - Abciximab Selective (‘bailout’) use in both groups ESC guideline indications

11. At 28 days Primary Efficacy Outcome Measure Major Adverse Cardiac Events (MACE) - All-cause mortality Cerebrovascular accident (CVA) Re-infarction Unplanned target lesion revascularisation (TLR)

12. At 28 days Primary Efficacy Outcome Measure Major Adverse Cardiac Events (MACE) Primary Safety Outcome Measure Major bleeding - Type 3-5 bleeding as per BARC definitions

13. Data Monitoring and Safety Committee (DMSC) All key clinical events adjudicated Clinical Events Committee Blinded to the treatment allocation Use of a delayed consent strategy

14. Full UK ethical approval Patients randomised and treated without discussion Subsequent informed consent in recovery phase Additional national approval - Use of data from patients who died before consent

15. 1917 patients scheduled for emergency angiography

16. Representative ‘Real-World’ Population

17. Received allocated Rx 900 Received no study drug 14 Treatment cross-over 0 LMWH pre-procedure 3 907 Received allocated Rx 7 Received no study drug 1 Treatment cross-over 4 LMWH pre-procedure

18. 710 Received allocated Rx 900 Received no study drug 14 Treatment cross-over 0 LMWH pre-procedure 3 907 Received allocated Rx 7 Received no study drug 1 Treatment cross-over 4 LMWH pre-procedure

19. CharacteristicBivalirudinHeparin Median age (years)62.963.6 Female sex (%)28.526.9 Caucasian race (%)95.895.9 Diabetes mellitus (%)12.615.1 Previous MI (%)13.510.3 eGFR (ml/min/1.73m 2 ) 80.0 Haemoglobin (g/dl)13.613.7

20. CharacteristicBivalirudin (%) Heparin (%) P2Y12 use - Any99.699.5 - Clopidogrel11.810.0 - Prasugrel27.327.6 - Ticagrelor61.262.7 GPI use13.515.5 Radial arterial access80.382.0 PCI performed83.081.6

21. CharacteristicBivalirudin (%) Heparin (%) Thrombectomy59.157.6 Single vessel Tx93.290.3 Any stent implant92.892.2 DES implantation79.879.9 TIMI III flow - post PCI 93.392.7

23. BivalirudinHeparin n%n MACE798.7 % v 5.7 %52 Absolute risk increase = 3.0% (95% CI 0.6, 5.4) Relative risk = 1.52 (95% CI 1.1 – 2.1) P=0.01

24. Event curve shows first event experienced

25. BivalirudinHeparin n%n Death465.1 % v 4.3 %39 CVA151.6% v 1.2%11 Reinfarction242.7% v 0.9%8 TLR242.7% v 0.7%6 Any MACE798.7 % v 5.7 %52

26. BivalirudinHeparin n%n Death465.1 % v 4.3 %39 CVA151.6% v 1.2%11 Reinfarction242.7% v 0.9%8 TLR242.7% v 0.7%6 Any MACE798.7 % v 5.7 %52

27. BivalirudinHeparin n%n Death465.1 % v 4.3 %39 CVA111.2% v 0.6%6 Reinfarction212.3% v 0.8%7 TLR10.1% v 0%0 Any MACE798.7 % v 5.7 %52 Censored by the most significant event - in order displayed

28. BivalirudinHeparin n%n Death465.1 % v 4.3 %39 CVA111.2% v 0.6%6 Reinfarction212.3% v 0.8%7 TLR10.1% v 0%0 Any MACE798.7 % v 5.7 %52 Censored by the most significant event - in order displayed

29. BivalirudinHeparin n%n All Events243.4 % v 0.9 %6 Relative risk = 3.91 (95% CI 1.6 - 9.5) P=0.001 ARC definite or probable stent thrombosis events

30. BivalirudinHeparin n%n Definite233.3 % v 0.7 %5 Probable10.1 % v 1 Acute202.9 % v 0.9 %6 Subacute40.6% v 0%0 ARC definite or probable stent thrombosis events

31. BivalirudinHeparin n%n Major Bleed323.5 % v 3.1 %28 Relative risk = 1.15 (95% CI 0.7 - 1.9) P=0.59 Major Bleed BARC grade 3-5

32. BivalirudinHeparin n%n Minor Bleed839.2 % v 10.8 %98 Major or Minor11312.5 % v 13.5 %122 Minor Bleed P=0.25 Major or Minor P=0.54 Major Bleed BARC grade 3-5 Minor Bleed BARC grade 2

33. Single centre Potential impact minimised by: Meticulous trial conduct Unselected representative population Study treatments are iv drugs (no ‘skill’ component) Multiple operators Outcomes as expected by national norms

34. Single centre Open label Potential impact minimised by: Complete follow-up - No ‘lost’ cases Outcome measures were overt clinical events Most MI events involved angiographic imaging Independent blinded adjudication Open label used in HORIZONS and EUROMAX

35. A unique study with 100% recruitment of eligible patients

36. Use of heparin rather than bivalirudin Reduced rate of major adverse events (NNT = 33) Fewer stent thromboses and reinfarction events

37. A unique study with 100% recruitment of eligible patients Use of heparin rather than bivalirudin Reduced rate of major adverse events (NNT = 33) Fewer stent thromboses and reinfarction events Consistent effect across pre-specified subgroups

38. A unique study with 100% recruitment of eligible patients Use of heparin rather than bivalirudin Reduced rate of major adverse events (NNT = 33) Fewer stent thromboses and reinfarction events Consistent effect across pre-specified subgroups No increase in bleeding complications

39. A unique study with 100% recruitment of eligible patients Use of heparin rather than bivalirudin Reduced rate of major adverse events (NNT = 33) Fewer stent thromboses and reinfarction events Consistent effect across pre-specified subgroups No increase in bleeding complications Potential for substantial saving in drug costs

40. 0

41. 1

42. 2

43. Event curve shows first major bleed experienced 3

44. BivalirudinHeparinP value Thrombocytopenia (%) new onset <150 8.37.30.49 CKMB post procedure Median (ng/dl) 971060.55 Door-first device time Median (mins) 29 0.33 4

45. BivalirudinHeparinP value Normal (EF >54%)45.4%43.9%0.53 Mild (EF 45-54%)25.2%26.2%0.65 Moderate (EF 36-44%)20.1%19.8%0.88 Severe (EF <36%)9.3%10.1%0.60 5

46. Common assumptions - based on historic connotations Smaller studies - often underpowered Potential subversion of randomisation Less robust trial procedures and documentation No adjudication of adverse events 6

47. Common assumptions - based on historic connotations Smaller studies - often underpowered Potential subversion of randomisation Less robust trial procedures and documentation No adjudication of adverse events No active problems for HEAT PPCI 7

48. Issues related to the patient population Unselected: External referral to trial centre Near universal inclusion in trial Patients typical for UK population Predominantly Caucasian race 8

49. Issues related to the patient population Unselected: External referral to trial centre Near universal inclusion in trial Patients typical for UK population Predominantly Caucasian race May affect generalisation to other populations 8

50. Issues related to clinical performance and outcomes In HEAT PPCI - Randomised treatments are routine iv medications Established and standardised approach to Purchase and storage Administration and dosing Outcomes are not affected by practice pattern or ‘skill’ 9

51. Issues related to clinical performance and outcomes In HEAT PPCI - Randomised treatments are routine iv medications Established and standardised approach to Purchase and storage Administration and dosing Outcomes are not affected by practice pattern or ‘skill’ Minimal threat in HEAT PPCI 10

52. Issues related to clinical performance and outcomes Treatments administered in setting of a PPCI procedure Procedures performed by 14 different cardiologists Operator and institution outcomes as expected Match national and international norms for PPCI 11

53. Issues related to clinical performance and outcomes Treatments administered in setting of a PPCI procedure Procedures performed by 14 different cardiologists Operator and institution outcomes as expected Match national and international norms for PPCI Minimal threat in HEAT PPCI 12

54. Registry and Trial PPCI Outcomes Mortality (%) HORIZONS (30d)2.6 % EUROMAX (30d)3.0 % US CathPCI 2011 (In-Hosp)5.7 % UK BCIS 2012 (30d)6.4 % HEAT PPCI (28d)4.7 % 13

55. Comprehensive follow-up No ‘lost’ cases 14

56. Comprehensive follow-up All primary efficacy and safety outcome measures - Overt clinical events with robust documentation MI events substantiated by imaging in almost all cases 15

57. Comprehensive follow-up All primary efficacy and safety outcome measures Overt clinical events with robust documentation MI events substantiated by imaging in almost all cases Independent adjudication of events Blinded to patient identity and treatment allocation 16

58. Comprehensive follow-up All primary efficacy and safety outcome measures Overt clinical events with robust documentation MI events substantiated by imaging in almost all cases Independent adjudication of events Open label norm - used in HORIZONS EUROMAX 17

59. Estimated MACE rate = 7.5% Sample size 1800 patients Two-sided testing Allows superiority testing in favour of either agent Pre-specified boundaries for Non-Inferiority Equivalence Calculations based on absolute event rate difference 18

60. Assuming no observed treatment difference ‘Treatment A’ 7.5% = 7.5% ‘Treatment B’ Event rate difference = 0% Calculate 95% CI for the rate difference 0% +2.4%-2.4% 19

61. Assuming an observed treatment difference ‘Treatment A’ 5.5% = 8.0% ‘Treatment B’ Event rate difference = 2.5% Calculate 95% CI for the rate difference 2.5% +2.3%-2.3% 20

62. 0%1%2%3% 4% 3%2%1% Event Rate Difference Favours Treatment AFavours Treatment B 2.5% +2.3%-2.3% 21

63. 0%1%2%3% 4% 3%2%1% Event Rate Difference Favours Treatment AFavours Treatment B 2.5% +2.3%-2.3% 22

64. 0%1%2%3% 4% 3%2%1% Event Rate Difference Favours Treatment AFavours Treatment B Point estimate lies in zone ± 0.5% from zero difference 25

65. 0%1%2%3% 4% 3%2%1% Event Rate Difference Favours Treatment AFavours Treatment B 0.4% +2.4%-2.4% 0.4% +2.4%-2.4% 26

66. 0%1%2%3% 4% 3%2%1% Event Rate Difference Favours Treatment AFavours Treatment B Point estimate better than (-0.5%) 23

67. 0%1%2%3% 4% 3%2%1% Event Rate Difference Favours Treatment AFavours Treatment B Point estimate better than (-0.5%) 1% +2.4%-2.4% 24

68. Anti-thrombotic therapy in PPCI for STEMI Selective (‘bailout’) use of GP IIb/IIIa antagonists (GPI) Increasingly the norm in routine practice Recommended by key guidelines (ESC, ACCF / AHA) Bivalirudin + selective (7% - 15%) use of GPI Established anti-thrombotic treatment option

69. Bivalirudin and heparin - Appear to have similar anti-ischaemic efficacy Similar impact on MACE events

70. HASREPLACEREPLACE 2 ISAR REACT 4ACUITYISAR REACT 3 HORIZONSISAR REACT 3AEUROMAX No difference in ischaemic outcomes

71. Bivalirudin and heparin - similar impact on MACE events Use of GPI agents causes increased bleeding When used with heparin

72. Heparin EPICPlaceboGPI Universal RESTOREPlaceboGPI Universal PRISM PlusPlaceboGPI Universal CAPTUREPlaceboGPI Universal ↑ bleeding with ↑ GPI use

73. Bivalirudin and heparin - similar impact on MACE events Use of GPI agents causes increased bleeding When used with heparin When used with bivalirudin

74. Bivalirudin GPI BailoutGPI Universal ACUITY9 %97 % ↑ bleeding with ↑ GPI use

75. Bivalirudin and heparin - similar impact on MACE events Use of GPI agents causes increased bleeding With similar GPI use - Bivalirudin and heparin have similar bleeding rates

76. BivalirudinHeparin GPI Universal ACUITY97 % REPLACE72 %71 % No differences in bleeding

77. Bivalirudin and heparin - similar impact on MACE events Use of GPI agents causes increased bleeding With similar GPI use - Bivalirudin and heparin have similar bleeding rates With differential GPI use - Bivalirudin and heparin have different bleeding rates

78. BivalirudinHeparin GPI BailoutGPI Universal ACUITY9 %97 % ISAR REACT 40 %100 % HORIZONS7 %98 % EUROMAX9 %70 % ↑ bleeding with ↑ GPI use

79. Bleeding is associated with less favourable outcomes Increased GPI use - results in increased bleeding Observed for both bivalirudin and heparin Relative performance of bivalirudin and heparin - Cannot be assessed reliably with differential GPI use HEAT PPCI Bivalirudin + selective GPI v Heparin + selective GPI