1. 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

2. 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

3. 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. Witzenbichler et al ACC 2008 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]<0.0001 BMI28.9 [25.8, 31.9]26.8 [24.4, 29.7]<0.0001 Waist circumference (cm)102.5 [95.0, 112.0]96.5 [89.0, 105.0]<0.0001 Hypertension 72.2%49.8% <0.0001 Hyperlipidemia 60.0%39.7% <0.0001 Current smoker 36.4%48.0% <0.0001 Peripheral vasc. Disease 9.1%3.5% <0.0001 Renal insufficiency 7.6%2.0% <0.0001

4. Baseline characteristics (ii) Witzenbichler et al ACC 2008 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%<0.0001 Prior CABG 5.4%2.4%<0.0001 KILLIP Class 2-412.4%7.7%0.0002 LVEF<40%21.4%13.4%<0.0001 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] <0.0001 Anemia 15.2%9.6% <0.0001 Thrombocytopenia 5.6%3.9% 0.0629

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

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

7. 30-day MACE components among diabetics Witzenbichler et al ACC 2008 UFH + GP IIb/IIIa (N=312) Bivalirudin (N=281) P Value Death5.4%3.6%0.27 Cardiac5.4%2.1%0.037 Non cardiac0%1.4%0.0499 Reinfarction2.9%2.1%0.56 Q-wave2.2%0.40%0.63 Non Q-wave1.0%0.4%0.63 Ischemic TVR2.6%2.8%0.83 Ischemic TLR1.9%2.8%0.46 Ischemic remote TVR0.6%0.4%1.00 Stroke1.9%0%0.032 Ischemic1.9%0%0.032 Hemorrhagic0% N/A

8. 30 day bleeding endpoints among diabetics Witzenbichler et al ACC 2008 UFH + GP IIb/IIIa (N=312) Bivalirudin (N=281) P Value Protocol Major, non CABG*9.6%7.8%0.44 Protocol Major, ALL12.2%11.4%0.77 Blood transfusion4.5%4.3%0.90 TIMI Major4.8%6.4%0.40 TIMI Minor5.1%3.6%0.35 TIMI Major or Minor9.9%10.0%0.99 GUSTO LT or Severe1.0%0.4%0.63 GUSTO Moderate6.4%5.7%0.72 GUSTO LT or Sev or Mod7.1%6.0%0.62

9. 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