Impact of clopidogrel loading dose on the safety and effectiveness of bivalirudin in patients undergoing primary angioplasty for acute myocardial infarction: The HORIZONS AMI trial George Dangas, Giulio Guagliumi, Bernhard Witzenbichler, Deepak Bhatt, Frederick Feit, Magnus Ohman, S. Chiu Wong, Helen Parise, Roxana Mehran, Gregg W. Stone Dangas et al, SCAI-ACCi2 2008

Background In the HORIZONS AMI trial, in pts undergoing primary PCI. bivalirudin monotherapy (Biv) compared to UFH plus GP IIb/IIIa inhibitors resulted in: – Reduced 30 day rates of major bleeding, – Comparable composite major adverse cardiovascular events (MACE) – Enhanced freedom from net adverse clinical events (NACE). All pts were to receive a clopidogrel loading dose in the ER, either 300 mg or 600 mg, and randomization was stratified by this decision. Whether the beneficial effects of bivalirudin are independent of the clopidogrel loading dose has not been reported. Dangas et al, SCAI-ACCi2 2008

Baseline Characteristics   300mg LD 600mg LD P value Age 60.5 [52.9, 70.5] 60.1 [52.2, 69.3] 0.14 Male 75.5% 76.9% 0.39 Diabetes 17.6% 15.6% 0.13 Insulin 3.7% 4.5% 0.27 Hypertension 51.9% 52.7% 0.63 Hyperlipidemia 41.5% 42.4% 0.62 Current smoking 43.4% 47.4% 0.03 Anemia 9.4% 10.7% 0.25 Platelet ct (x103 cells/mm3) 250.5 [210, 299] 245.0 [207, 287] 0.02 Renal insufficiency 2.9% 3.1% 0.86 Prior MI 9.6% 9.8% 0.89 Prior PCI 8.5% Prior CABG 2.3% 0.26 History of PVD 3.9% 0.46 History of CHF US stratification 30.6% 16.8% <.0001 Dangas et al, SCAI-ACCi2 2008

Baseline Characteristics   300mg LD 600mg LD P value Weight (kg) 80.0 [71.0, 90.0] [71.0, 90.7] 0.17 BMI (kg/m2) 27.1 [24.6, 30.1] 27.0 [24.5, 30.3] 0.50 Chest pain to ER (hours) 2.2 [1.3, 4.0] [1.3, 3.8] 0.45 KILLIP Class 2-4 11.5% 6.9% <.0001 LVEF <40% 15.1% 13.7% 0.28 Femoral a. access 87.3% 96.7% Radial a. access 12.4% 2.9% Venous access 10.1% 8.0% 0.03 Closure Device 20.3% 33.2% Peak ACT (sec) 299 [244, 379] 316 [254, 392] IABP 6.5% 4.8% 0.0353 Dangas et al, SCAI-ACCi2 2008

Drug Administration 300mg LD 600mg LD P- value HEPARIN   Pre-Randomization Heparin 60.7% 68.7% <.0001 Pre-Procedure Heparin 67.9% 72.9% 0.002 Heparin in cath lab, as anticoagulant 51.4% 50.0% 0.43 BIVALIRUDIN Bivalirudin in cath lab, as anticoagulant 48.4% 0.38 GP IIb/IIIa In the ER 3.2% 7.5% In the cath lab, before sheath insertion 11.5% 12.3% 0.50 In the cath lab, Any 52.0% 50.5% 0.42 ANY 55.2% 54.1% 0.54 Dangas et al, SCAI-ACCi2 2008

Procedural characteristics (PCI) 300mg LD 600mg LD P- value Treated vessels   LAD 41.9% 40.3% 0.38 LCX 15.5% 15.8% 0.80 RCA 40.6% 42.6% 0.28 LM 0.7% 0.5% 0.41 SVG 1.2% 0.8% 0.24 LIMA/ RIMA 0.1% 0.0% 0.35 Door to Balloon (hours) 1.8 [1.3, 2.3] 1.6 [1.2, 2.2] <.0001 One or more stents implanted 95.6% 96.3% 0.31 Multiple vessels treated 4.5% 4.1% 0.68 Multiple lesions treated 9.9% 11.3% 0.26 Dangas et al, SCAI-ACCi2 2008

Procedural characteristics (PCI) 300mg LD 600mg LD P- value TIMI flow pre PCI   TIMI 0/1 65.6% 65.2% 0.83 TIMI 2 15.5% 16.2% 0.58 TIMI 3 19.0% 18.6% 0.80 Final TIMI flow after PCI 2.5% 1.8% 0.16 5.0% 6.8% 0.048 92.5% 91.5% 0.31 Dangas et al, SCAI-ACCi2 2008

Overall: Primary Outcomes (ITT) *NACE = MACE or major bleeding **Not related to CABG ***MACE = All cause death, reinfarction, ischemic TVR or stroke Dangas et al, SCAI-ACCi2 2008

Primary Outcomes (ITT) The impact of Biv was independent of the dose of clopidogrel loading. Interaction P values for the above 3 endpoints = 0.48 (NACE) 0.41 (Major bleeding), and 0.75 (MACE). 300 mg LD 600 mg LD P=0.15 P=0.01 P=0.56 P=0.01 P=0.002 P=0.71 Dangas et al, SCAI-ACCi2 2008

Overall: 30 Day MACE Components* 300 mg LD 600 mg LD P-value Death 3.1% 1.9% 0.03 - Cardiac 2.7% 0.11 - Non cardiac 0.4% 0.1% 0.054 Reinfarction 2.4% 1.3% 0.02 - Q-wave 1.5% 1.1% 0.37 - Non Q-wave 1.0% 0.3% Ischemic TVR 2.8% 2.0% 0.15 - Ischemic TLR 2.6% 1.8% 0.13 - Ischemic remote TVR 0.76 Stroke 0.058 *CEC adjudicated Dangas et al, SCAI-ACCi2 2008

Bivalirudin group: 30 Day MACE Components* 300 mg LD 600 mg LD P-value Death 2.6% 1.4% 0.06 - Cardiac 2.1% 1.3% 0.19 - Non cardiac 0.5% 0.1% 0.11 Reinfarction 2.8% 0.02 - Q-wave 1.8% 1.1% 0.26 - Non Q-wave 0.2% Ischemic TVR 3.3% 2.3% 0.20 - Ischemic TLR 0.13 - Ischemic remote TVR 0.0% 1.00 Stroke 0.9% 0.6% 0.56 *CEC adjudicated Dangas et al, SCAI-ACCi2 2008

Overall: 30 Day Stent Thrombosis 300 mg LD 600 mg LD P-value ARC definite or probable* 2.8% 1.7% 0.04 - definite 2.1% 1.3% 0.11 - probable 0.7% 0.4% 0.20 - acute (≤24 hrs) 1.00 - subacute (>24 hrs – 30d) 2.2% 1.0% 0.008 *Protocol definition of stent thrombosis, CEC adjudicated Dangas et al, SCAI-ACCi2 2008

BIV group: 30 Day Stent Thrombosis 300 mg LD 600 mg LD P-value ARC definite or probable* 3.5% 1.7% 0.03 - definite 3.1% 1.5% 0.04 - probable 0.4% 0.2% 0.61 - acute (≤24 hrs) 1.6% 0.9% 0.26 - subacute (>24 hrs – 30d) 2.1% 0.8% *Protocol definition of stent thrombosis, CEC adjudicated Dangas et al, SCAI-ACCi2 2008

Overall: 30 Day Bleeding Endpoints 300 mg LD 600 mg LD P-Value Protocol Major, non CABG 8.7% 5.8% 0.002 Protocol Major, All 11.0% 7.2% 0.0002 Protocol Minor 13.9% 11.2% 0.02 Blood transfusion 3.6% 2.4% 0.057 TIMI Major 4.3% 3.4% 0.19 TIMI Minor 5.6% 2.5% <0.0001 TIMI Major or Minor 10.0% 6.2% GUSTO LT* or Severe 0.6% 0.4% 0.33 GUSTO Moderate 4.9% 3.2% GUSTO LT or Sev or Mod 5.4% *Life threatening Dangas et al, SCAI-ACCi2 2008

Prediction of 30-day Outcomes Multivariate predictors using logistic regression model Hazard Ratio 95% CI p Death (78 events) KILLIP class 1 0.3 0.18-0.49 <0.001 Ccr 0.97 0.96-0.98 History of PVD 2.01 1.05-3.83 0.035 Clopidogrel 600mg LD 0.76 0.48-1.19 0.232 Age - Death/Reinfarction (127 events) 0.33 0.22-0.49 Platelet count 1.002 1-1.004 0.029 1.02 1-1.05 0.042 0.7 0.49-1.01 0.056 Diabetes History of CHF US stratification Dangas et al, SCAI-ACCi2 2008

Prediction of 30-day Outcomes Multivariate Predictors Using Cox proportional hazards model Hazard Ratio 95% CI p MACE (172 events) KILLIP class 1 0.41 0.28-0.6 <0.001 Clopidogrel 600mg LD 0.72 0.53-0.98 0.036 Platelet count 1.002 1-1.004 0.026 Age 1.03 1.02-1.05 US stratification 1.49 1.07-2.08 0.019 History of PVD 1.87 1.12-3.12 0.016 History of CHF - Major bleeding (226 events) Bivalirudin 0.57 0.43-0.75 0.63 0.44-0.91 0.01 Creatinine clearance 0.99 0.98-0.99 0.002 Female 1.45 1.08-1.93 Anemia 1.62 1.13-2.32 0.008 2.44 1.84-3.23 IABP 3.53 2.49-5.01 Closure device 0.80 0.57-1.11 0.17 0.89 0.68-1.16 0.39 Dangas et al, SCAI-ACCi2 2008

Conclusions In patients with STEMI undergoing primary PCI: 600 mg loading dose of clopidogrel was associated with significantly lower 30- day mortality, reinfarction and stent thrombosis rates compared with 300 mg loading dose. 600 mg loading dose of clopidogrel did not increase the risk of bleeding compared with 300 mg loading dose. Biv monotherapy significantly reduces major bleeding and NACE, independently of the clopidogrel loading dose. By multivariate analysis, 600 mg loading dose of clopidogrel was an independent predictor of lower 30-day MACE (compared with 300 mg LD, Odds Ratio=0.72), but was not independently associated with death, reinfarction or major bleeding. Dangas et al, SCAI-ACCi2 2008