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

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

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

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

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

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

Single centre RCT Trial recruitment: Feb Nov 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’

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

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

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

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)

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

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

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

1917 patients scheduled for emergency angiography

Representative ‘Real-World’ Population

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

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

CharacteristicBivalirudinHeparin Median age (years) Female sex (%) Caucasian race (%) Diabetes mellitus (%) Previous MI (%) eGFR (ml/min/1.73m 2 ) 80.0 Haemoglobin (g/dl)

CharacteristicBivalirudin (%) Heparin (%) P2Y12 use - Any Clopidogrel Prasugrel Ticagrelor GPI use Radial arterial access PCI performed

CharacteristicBivalirudin (%) Heparin (%) Thrombectomy Single vessel Tx Any stent implant DES implantation TIMI III flow - post PCI

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

Event curve shows first event experienced

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

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

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

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

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

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

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

BivalirudinHeparin n%n Minor Bleed839.2 % v 10.8 %98 Major or Minor % 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

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

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

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

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

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

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

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Event curve shows first major bleed experienced 3

BivalirudinHeparinP value Thrombocytopenia (%) new onset < CKMB post procedure Median (ng/dl) Door-first device time Median (mins)

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

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

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

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

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

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

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

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

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

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

Comprehensive follow-up No ‘lost’ cases 14

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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