Bivalirudin SCAI-ACC/i2 2008 presentations HORIZONS AMI subgroups: Impact of clopidogrel Dangas et al Diabetes Witzenbichler et al Renal impairment Mehran et al Gender Grinfeld et al Age Dudek et al Abciximab, eptifibatide strata Gualiumi et al US, non-US Brodie et al

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

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 Biv are independent of the clopidogrel loading dose has not been reported.

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 count (x103 cells/mm3) 250.5 [210.0, 299.0] 245.0 [207.0, 287.0] 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) 299.0 [244.0, 379.0] 316.0 [254.0, 392.0] 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

BIV 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 Adverse 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 Adverse 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

Impact Of Diabetes Mellitus On The Safety And Effectiveness Of Bivalirudin In Patients With Acute Myocardial Infarction Undergoing Primary Angioplasty: The HORIZONS AMI Trial Bernhard Witzenbichler, Giulio Guagliumi, Martin Desaga, Janusz Kochman, Dennis W. Nilsen, Ariel Finkelstein, Morris Mosseri, Helen Parise, Roxana Mehran, Gregg W. Stone

Witzenbichler et al ACC 2008 Background Outcomes in the HORIZONS AMI trial were analyzed according to the presence of medically treated diabetes mellitus (DM) at the time of admission. This subgroup analysis was pre-specified in the protocol / statistical analysis plan. Since subgroups are generally underpowered, these analyses will be considered exploratory and hypothesis generating. Witzenbichler et al ACC 2008

Baseline characteristics 593 of 3.599 study patients (16.5%) in HORIZONS had medically treated diabetes. Baseline characteristics demonstrate that diabetics represent a significantly higher risk group compared to non-diabetics.   Diabetics (N=593; 16.5%) Non-Diabetics (N=3006; 83.5%) P value Age 64.4 [56.0, 71.8] 59.5 [51.8, 69.2] <0.0001 Male 73.5% 77.2% 0.0504 Weight (kg) 85.0 [75.0, 96.0] 80 [70.0, 90.0] BMI 28.9 [25.8, 31.9] 26.8 [24.4, 29.7] Waist circumference (cm) 102.5 [95.0, 112.0] 96.5 [89.0, 105.0] Hypertension 72.2% 49.8% Hyperlipidemia 60.0% 39.7% Current smoker 36.4% 48.0% Peripheral vasc. Disease 9.1% 3.5% Renal insufficiency 7.6% 2.0% Witzenbichler et al ACC 2008

Baseline characteristics (ii)   Diabetics (N=593; 16.5%) Non-Diabetics (N=3006; 83.5%) P value Prior MI 16.7% 9.7% <0.0001 Prior PCI 16.6% 9.6% Prior CABG 5.4% 2.4% KILLIP Class 2-4 12.4% 7.7% 0.0002 LVEF<40% 21.4% 13.4% Symptom onset to hospital arrial, hours 2.3 [1.4, 4.3] 2.1 [1.3, 3.8] 0.0137 Symptom onset to first balloon inflation 4.3 [2.9, 6.4] 3.6 [2.6, 5.5] Anemia 15.2% Thrombocytopenia 5.6% 3.9% 0.0629 Witzenbichler et al ACC 2008

Endpoints in non-diabetics, by study drug Non-Diabetics (n=3006) RR=0.60 [0.61, 0.94] P=0.006 RR=0.55 [0.41, 0.74] P=0.001 RR=1.14 [0.83, 1.56] P= n.s. *MACE = All cause death, reinfarction, ischemic TVR or stroke Witzenbichler et al ACC 2008

Endpoints in diabetics, by study drug Diabetics (n=593) RR=0.60 [0.61, 0.94] P=0.006 RR=0.55 [0.41, 0.74] P=0.001 RR=1.14 [0.83, 1.56] P= n.s. *MACE = All cause death, reinfarction, ischemic TVR or stroke Witzenbichler et al ACC 2008

30-day MACE components among diabetics UFH + GP IIb/IIIa (N=312) Bivalirudin (N=281) P Value Death 5.4% 3.6% 0.27 Cardiac 2.1% 0.037 Non cardiac 0% 1.4% 0.0499 Reinfarction 2.9% 0.56 Q-wave 2.2% 0.40% 0.63 Non Q-wave 1.0% 0.4% Ischemic TVR 2.6% 2.8% 0.83 Ischemic TLR 1.9% 0.46 Ischemic remote TVR 0.6% 1.00 Stroke 0.032 Ischemic Hemorrhagic N/A Witzenbichler et al ACC 2008

30 day bleeding endpoints among diabetics UFH + GP IIb/IIIa (N=312) Bivalirudin (N=281) P Value Protocol Major, non CABG* 9.6% 7.8% 0.44 Protocol Major, ALL 12.2% 11.4% 0.77 Blood transfusion 4.5% 4.3% 0.90 TIMI Major 4.8% 6.4% 0.40 TIMI Minor 5.1% 3.6% 0.35 TIMI Major or Minor 9.9% 10.0% 0.99 GUSTO LT or Severe 1.0% 0.4% 0.63 GUSTO Moderate 5.7% 0.72 GUSTO LT or Sev or Mod 7.1% 6.0% 0.62 Witzenbichler et al ACC 2008

Witzenbichler et al ACC 2008 Conclusions Compared to patients without diabetes mellitus, those with diabetes had greater rates of major bleeding (8.8% vs. 6.2%, P=0.02), MACE (8.1% vs. 5.0%, P=0.002) and NACE (14.2% vs. 10.0%, P=0.003). Among the diabetic subgroup: Bivalirudin significantly reduced cardiac death at 30 days (p=0.037). Total and hemorrhagic stroke rate occurred more often in the UFH + GPI group, whereas non-cardiac death rate was slightly increased in the Bivalirudin group, although based on small patient numbers. All other 30 day endpoints including stent thrombosis rate were not significantly different among diabetics between the two treatment arms In patients with AMI undergoing primary PCI, Bivalirudin monotherapy significantly reduces major bleeding and net adverse clinical events, effects which are independent of diabetic status (interaction P value for major bleeding = 0.22, for MACE = 0.10, and NACE = 0.90). Witzenbichler et al ACC 2008

For the HORIZONS AMI Investigators Impact of Baseline Renal Function on the Safety and Effectiveness of Bivalirudin in Patients with Acute MI Undergoing Primary Angioplasty: The HORIZONS AMI trial Roxana Mehran, Bernhard Witzenbichler, Giulio Guagliumi, Victor Guetta, Harry Suryapranata, Kurt Huber, Jochen Wöehrle, Chris Metzger, George Dangas, Helen Parise, Gregg W. Stone For the HORIZONS AMI Investigators

Background and Objectives In HORIZONS, bivalirudin monotherapy compared to heparin + GPI resulted in reduced rates of major bleeding and NACE, with comparable composite MACE in pts undergoing primary PCI. Whether the beneficial effects of Biv are independent of renal function, an important prognostic determinate after primary PCI, has not been reported. We evaluated 30-day outcomes overall and by randomized antithrombin treatment according to baseline renal function. Mehran et al ACC 2008

Baseline Characteristics CrCl ≥60 mL/min (N=2783) CrCl <60 mL/min (N=554) P-value Age (years) 57.9 [50.8, 65.5] 75.4 [70.4, 80.3] <0.0001 Male 81.1% 55.2% Diabetes 16.0% 19.3% 0.05 Hypertension 49.9% 69.1% Hyperlipidemia 42.2% 46.2% 0.08 Current smoking 50.4% 24.4% Prior MI 9.7% 15.3% Prior PCI 9.8% 13.9% 0.004 Prior CABG 2.3% 5.6% Mehran et al ACC 2008

30-Day Outcomes by Renal Function P<0.0001 for all *Not related to CABG **MACE = All cause death, reinfarction, ischemic TVR or stroke Mehran et al ACC 2008

30-Day Outcomes among Renally Impaired Patients (CrCl <60 mL/min) by Treatment *Not related to CABG **MACE = All cause death, reinfarction, ischemic TVR or stroke Mehran et al ACC 2008

30-Day Outcomes among Pts with Normal Renal Function (CrCl ≥60 mL/min) by Treatment *Not related to CABG **MACE = All cause death, reinfarction, ischemic TVR or stroke Mehran et al ACC 2008

Conclusions Patients with AMI and impaired renal function (CrCl <60 mL/min) undergoing primary PCI have significantly worse 30- day ischemic and bleeding outcomes compared to patients with normal renal function. There was no significant difference in 30-day outcomes among patients with impaired renal function treated with bivalirudin monotherapy or heparin + GPI in HORIZONS-AMI study. Among patients with normal renal function, bivalirudin monotherapy significantly reduces major bleeding and net adverse clinical events. Mehran et al ACC 2008

Impact of gender on the safety and effectiveness of bivalirudin in patients with acute myocardial infarction undergoing primary angioplasty L Grinfeld, J Belardi, AJ Lansky, B Witzenbichler, G Guagliumi, K Zmudka, M Moeckel, A Ochala, W Ruzyllo, H Parise, R Mehran, GW Stone

Objectives To evaluate the impact of gender on the safety and effectiveness of bivaliridun monotherapy compared to UFH + the routine use of GP IIb/IIIa inhibitors in patients with AMI undergoing primary angioplasty: Similar or reduced rates of NACE at 30 days Similar or reduced rates of major bleeding Grinfeld et al ACC 2008

Demographics Male (N=2760) Female (N=842) p value Age (years) 58.8 [51.4, 67.8] 66.0 [57.1, 75.3] < 0.0001 BMI 27.1 [24.7, 30.0] 26.7 [24.0, 30.8] 0.2 Diabetes 15.8% 18.7% 0.05 Hypertension 50.8% 62.3% < 0 0001 Hyperlipidemia 42.1% 46.1% 0.04 Current smoking 47.8% 40.8% 0.0004 Prior MI 12.0% 7.4% 0.0002 Prior PCI 11.6% 7.9% 0.002 Prior CABG 3.3% 1.8% 0.03 Grinfeld et al ACC 2008

Events by gender Male (N=2760) Female (N=842) p value 1° Endpoint (MACE or major bleeding) 9.2% 15.6% < 0.0001 MACE (death, MI, ischemic TVR or stroke) 4.9% 7.4% 0.006 Death 2.2% 3.8% 0.01 Reinfarction 1.8% 2.1% 0.6 Stroke 0.6% 0.8% 0.5 Ischemic TVR 2.0% 3.4% 0.02 Major bleeding (Non-CABG related) 5.7% 10.1% < 0.001 Minor bleeding 7.8% 14.3% Grinfeld et al ACC 2008

Events by gender (male) RR=0.77 [0.59, 0.97] P=0.03 RR=0.59 [0.43, 0.82] P=0.001 P= ns Grinfeld et al ACC 2008

Events by gender (female) RR=0.76 [0.54, 1.08] P=0.01 RR=0.59 [0.38, 0.92] P=0.02 P= ns Grinfeld et al ACC 2008

Conclusions Women and men with AMI undergoing PCI have different risk profiles. Women have a higher incidence of death, ischemic TVR, major and minor bleeding. Despite these differences, bivalirudin monotherapy significantly reduces major bleeding and net adverse clinical events compared to UFH plus the routine use of GP IIb/IIIa inhibitors both in women and men. Grinfeld et al ACC 2008

Impact of advanced age on the safety and effectiveness of bivalirudin in patients with acute myocardial infarction undergoing primary angioplasty: The HORIZONS AMI trial Dariusz Dudek, Krzyszto Zmudka, Bernhard Witzenbichler, Giulio Guagliumi, Jan Z. Peruga, Bruce R. Brodie, Ran Kornowski, Franz Hartmann, Martin Mockel, Andrzej Ochala, Helen Parise, Roxana Mehran, Gregg W. Stone

Methods A total of 3602 patients at 123 centers in 11 countries with AMI undergoing primary PCI were randomized to bivalirudin monotherapy or unfractionated heparin plus glycoprotein IIb/IIIa inhibitors. Outcomes were analyzed according to age above or below the median of 60.2 years: Bivalirudin (n=1800) age ≤60.2 years (n=923) age >60.2 years (n=877) UFH+GPI (n=1802) age ≤60.2 years (n=885) age >60.2 years (n=917) Dudek et al ACC 2008

Outcomes, Age ≤ 60.2 years *P<0.05 P=0.168 P=0.0012* P=0.354 Dudek et al ACC 2008

Outcomes, Age > 60.2 years P=0.156 P=0.013* P=0.512 P=0.033* *P<0.05 Dudek et al ACC 2008

Conclusions In patients with AMI undergoing primary PCI, bivalirudin monotherapy significantly reduces major bleeding and net adverse clinical events, effects which are independent of age. Dudek et al ACC 2008

Safety and effectiveness of bivalirudin compared to either abciximab or eptifibatide in patients with acute myocardial infarction undergoing primary angioplasty: The HORIZONS AMI trial Giulio Guagliumi, Bernhard Witzenbichler, Jan Z. Peruga, Bruce R. Brodie, Dariusz Dudek, Ran Kornowski, Janusz Kochman, Yaron Almagor, Dennis Nilsen, Ajay Kirtane, Helen Parise, Roxana Mehran, Gregg W. Stone

Methods A total of 1,915 pts (53%) were randomized in the abciximab strata, and 1,687 pts (47%) were randomized in the eptifibatide strata. Subgroup analyses pre-specified in the protocol. Gualiumi et al ACC 2008

Outcomes, abciximab strata (n=1915) RR=0.57 [0.39, 0.85] RR=0.91 [0.61, 1.36] RR=0.73 [0.55, 0.97] *MACE = death, reinfarction, ischemic TVR or stroke **NACE = (Net Adverse Clinical Events) = MACE or major bleeding Gualiumi et al ACC 2008

Outcomes, eptifibatide strata (n=1687) RR=0.57 [0.39, 0.85] RR=0.91 [0.61, 1.36] RR=0.73 [0.55, 0.97] *MACE = death, reinfarction, ischemic TVR or stroke **NACE = (Net Adverse Clinical Events) = MACE or major bleeding Gualiumi et al ACC 2008

Conclusions In patients with AMI undergoing primary PCI, bivalirudin monotherapy significantly reduces major bleeding and net adverse clinical events compared to UFH with either abciximab or double-bolus eptifibatide. Gualiumi et al ACC 2008

Major Adverse Events in STEMI Patients Treated with Primary Angioplasty Occur More Frequently at U.S. Compared with Non U.S. Sites: Analysis from the HORIZONS AMI Trial Bruce R. Brodie, Thomas Stuckey, Bernhard Witzenbichler, Giulio Guagliumi, Jan Z. Peruga, Dariusz Dudek, Ran Kornowski, Franz Hartmann, George Dangas, S.Chiu Wong, Helen Parise, Roxana Mehran, Gregg W. Stone

Background The HORIZONS trial trial provided an opportunity to compare outcomes with primary PCI for STEMI at sites in the United States versus at sites outside the United States. This has not been previously evaluated. Patients enrolled outside of the United States in Europe, Israel and Argentina (OUS) (n = 2,788) were compared with patients enrolled in the United States (US) (n = 814). Brodie et al ACC 2008

Baseline Demographics US (N=814) OUS (N=2788) p value Age (years) 59.8 60.2 NS Gender (Male) 74.8% 77.2% NS Race White 84.4% 96.5% <0.0001 Black 8.1% 0.2% <0.0001 Hispanic 6.2% 2.4% <0.0001 Asian 0.5% 0.7% NS Brodie et al ACC 2008

Baseline Clinical Variables US (N=814) OUS (N=2788) p value Diabetes 20.8% 15.2% 0.0002 Hypertension 59.1% 51.8% 0.0003 Hyperlipidemia 46.8% 42.0% 0.014 Current Smoker 43.0% 47.1% 0.041 Prior MI 13.8% 10.1% 0.003 Prior CABG 5.5% 2.2% <0.0001 Killip Class 3-4 2.1% 1.5% NS BMI 28.0 26.8 <0.0001 Renal Insufficiency 4.7% 2.4% 0.001 Brodie et al ACC 2008

Angiographic Variables US (N=814) OUS (N=2788) p value Infarct Artery LAD 35.3% 42.1% 0.0006 CFX 15.1% 16.0% NS RCA 47.1% 40.6% 0.001 SVG 2.1% 0.6% 0.0003 LVEF < 40% 20.8% 12.7% <0.0001 TIMI 2-3 Flow Initial 31.1% 35.6% 0.02 Symtom –Door (hrs) 1.8 2.3 <0.0001 Door-Angio (min) 67 61 0.0007 Brodie et al ACC 2008

Primary Management Strategy US OUS Primary PCI Deferred PCI CABG Medical Rx 89.6% 93.7% Brodie et al ACC 2008

Adjunctive Pharmacology US (N=814) OUS (N=2788) p value Pre-rand Heparin 70.8% 64.0% 0.0003 Clopidogrel Load 300 mg 49.6% 30.8% <0.0001 600 mg 49.7% 67.7% <0.0001 Any IIb/IIIa Inhibitor 55.7% 54.0% NS Abciximab 43.4% 55.4% 0.002 Eptifibatide 56.6% 43.9% <0.0001 Tirofiban 0% 0.9% 0.049 Bail-out IIb/IIIa Inhib 10.1% 6.8% 0.029 Brodie et al ACC 2008

30 Day Outcomes: US vs OUS Adjusted Hazard Ratios (95% CI) US Better DEATH DEATH/MI MACE MAJOR BLEEDING NACE US Better OUS Better Brodie et al ACC 2008

Conclusions STEMI patients enrolled in the HORIZONS-AMI Trial in the US had a much higher risk profile than patients enrolled outside the US. HORIZONS patients treated with primary PCI in the US had higher rates of death, death/MI, MACE, major bleeding and NACE compared with OUS patients. After adjusting for differences in baseline variables, US patients had significantly higher rates of MACE, Major Bleeding and NACE compared with OUS patients. Both US and OUS patients had lower event rates with bivalirudin compared with IIb/IIIa platelet inhibitors. There were no significant interactions between US vs OUS sites and randomization treatment. Brodie et al ACC 2008