1. Clinical Trial Results. org Randomized Comparison of a High Clopidogrel Maintenance Dose in Patients with Diabetes Mellitus and Coronary Artery Disease: Results of the Optimizing Antiplatelet Therapy in Diabetes Mellitus (OPTIMUS) Study Dominick J. Angiolillo, MD, PhD; Steven B. Shoemaker, MD; Bhaloo Desai, PhD; Hang Yuan, PhD; Ronald K. Charlton, PhD; Esther Bernardo, BSc; Martin M. Zenni, MD; Luis A. Guzman, MD; Theodore A. Bass, MD; Marco A. Costa, MD, PhD Published online in Circulation January 29, 2007 OPTIMUS

2. Clinical Trial Results. org OPTIMUS: Background After treatment with clopidogrel, patients with type 2 diabetes mellitus have reduced platelet inhibition compared with patients who are not diabetic.After treatment with clopidogrel, patients with type 2 diabetes mellitus have reduced platelet inhibition compared with patients who are not diabetic. Recent studies have shown that type 2 diabetes mellitus patients have reduced response to P2Y 12 receptor antagonists, including clopidogrel, compared with nondiabetic subjects.Recent studies have shown that type 2 diabetes mellitus patients have reduced response to P2Y 12 receptor antagonists, including clopidogrel, compared with nondiabetic subjects. After treatment with clopidogrel, patients with type 2 diabetes mellitus have reduced platelet inhibition compared with patients who are not diabetic.After treatment with clopidogrel, patients with type 2 diabetes mellitus have reduced platelet inhibition compared with patients who are not diabetic. Recent studies have shown that type 2 diabetes mellitus patients have reduced response to P2Y 12 receptor antagonists, including clopidogrel, compared with nondiabetic subjects.Recent studies have shown that type 2 diabetes mellitus patients have reduced response to P2Y 12 receptor antagonists, including clopidogrel, compared with nondiabetic subjects. Angiolillo, et al. Circulation. 2007 Jan; 115: 708-716.

3. Clinical Trial Results. org OPTIMUS: Background (cont.) The aim of this pilot study was to evaluate the impact of a high maintenance dose of clopidogrel on platelet function profiles in type 2 diabetes mellitus patients with coronary artery disease (CAD) on long-term dual antiplatelet therapy who demonstrate suboptimal platelet inhibition.The aim of this pilot study was to evaluate the impact of a high maintenance dose of clopidogrel on platelet function profiles in type 2 diabetes mellitus patients with coronary artery disease (CAD) on long-term dual antiplatelet therapy who demonstrate suboptimal platelet inhibition. Angiolillo, et al. Circulation. 2007 Jan; 115: 708-716.

4. Clinical Trial Results. org OPTIMUS: Study Design  Primary Endpoint: Maximal ADP-induced platelet aggregation Group A 75 mg of Clopidogrel 30 days, n=20 Group A 75 mg of Clopidogrel 30 days, n=20 Group B 150 mg of Clopidogrel 30 days, n=20 Group B 150 mg of Clopidogrel 30 days, n=20 40 patients > 18 years with type 2 diabetes mellitus and coronary artery disease All patients also received aspirin (81 mg daily). Prospective. Randomized. Parallel-Group. 40 patients > 18 years with type 2 diabetes mellitus and coronary artery disease All patients also received aspirin (81 mg daily). Prospective. Randomized. Parallel-Group. R Platelet Function Testing Angiolillo, et al. Circulation. 2007 Jan; 115: 708-716. 75 mg of Clopidogrel 30 days n=20 75 mg of Clopidogrel 30 days n=20 75 mg of Clopidogrel 30 days n=20 75 mg of Clopidogrel 30 days n=20 Platelet Function Testing At 60 days Platelet Function Testing At 60 days

5. Clinical Trial Results. org OPTIMUS: Demographics Characteristic75mg(n=20)150mg(n=20)P-value Age, y 59+10 64+8 0.05 Male, n (%) 14 (70) 12 (60) 0.75 Race, n (%) White White Black Black Hispanic Hispanic 11 (55) 8 (40) 1 (5) 13 (65) 6 (30) 1 (5) 0.750.741.00 Risk Factors, n (%) IDDM* IDDM* NIDDM† NIDDM† HbA1-C± HbA1-C± Smoking Smoking Hyperlipidemia Hyperlipidemia Hypertension Hypertension 6 (30) 14 (70) 7.0+1.1 4 (20) 19 (95) 8 (40) 12 (60) 7.1+1.5 3 (15) 18 (90) 0.740.740.931.001.001.00 Angiolillo, et al. Circulation. 2007 Jan; 115: 708-716. *IDDM = Insulin-dependent diabetes mellitus; †NIDDM = Non-insulin-dependent diabetes mellitus; ±HbA1-C = hemoglobin A1C

6. Clinical Trial Results. org OPTIMUS: Demographics (Cont.) Characteristic75mg(n=20)150mg(n=20)P-value Risk Factors, n (%) Body Mass Index, kg/m 2 Body Mass Index, kg/m 2 Prior Myocardial Infarction Prior Myocardial Infarction Prior CABG Prior CABG Multivessel CAD Multivessel CAD 32.4+7 8 (40) 4 (20) 15 (75) 33.5+6 7 (35) 5 (25) 14 (70) 0.611.001.001.00 Treatment, n (%) β-Blockers β-Blockers Nitrates Nitrates ACE inhibitors/ARB ACE inhibitors/ARB Lipid-lowering agents Lipid-lowering agents CYP3A4 metabolizing statin CYP3A4 metabolizing statin Non-CYP3A4 metabolizing statin Non-CYP3A4 metabolizing statin 17 (85) 6 (30) 13 (65) 17 (85) 1 (5) 16 (80) 8 (40) 14 (70) 15 (75) 4 (20) 0.741.001.000.690.34 Angiolillo, et al. Circulation. 2007 Jan; 115: 708-716.

7. Clinical Trial Results. org Platelet aggregation was significantly reduced in the 150mg group compared with the 75mg group (63.1% vs. 52.3%, p=0.002)Platelet aggregation was significantly reduced in the 150mg group compared with the 75mg group (63.1% vs. 52.3%, p=0.002) (%) OPTIMUS Trial: Primary Endpoint n = 20 p = 0.002 Study Time Point 2: Maximal ADP-Induced (20 µmol/L) Platelet Aggregation Angiolillo, et al. Circulation. 2007 Jan; 115: 708-716.

8. Clinical Trial Results. org At one month, patients assigned to the 150mg clopidogrel maintenance dose had an approximate 15% reduction in late (5 minutes) platelet aggregation after stimulus with 20 µmol/L ADPAt one month, patients assigned to the 150mg clopidogrel maintenance dose had an approximate 15% reduction in late (5 minutes) platelet aggregation after stimulus with 20 µmol/L ADP (%) (%) OPTIMUS Trial: Results n = 20 p <0.0001 Late Adenosine Diphosphate Induced (20 µmol/L) Platelet Aggregation Angiolillo, et al. Circulation. 2007 Jan; 115: 708-716.

9. Clinical Trial Results. org OPTIMUS Trial: Results Patients assigned to 150mg dose returned to values comparable to those at baseline after a switch back to standard dosing (75mg)Patients assigned to 150mg dose returned to values comparable to those at baseline after a switch back to standard dosing (75mg) Study Time Point 3: Maximal ADP-Induced Platelet Aggregation (20µmol/L) n = 20 p=0.55 p=0.97 (%) n = 20 Angiolillo, et al. Circulation. 2007 Jan; 115: 708-716.

10. Clinical Trial Results. org OPTIMUS: Limitations The study did not account for performance of multiple significance tests or for potential correlation among various measures of platelet function.The study did not account for performance of multiple significance tests or for potential correlation among various measures of platelet function. This study was also not powered to evaluate the risk of bleeding with the use of high-dose clopidogrel in association with aspirin.This study was also not powered to evaluate the risk of bleeding with the use of high-dose clopidogrel in association with aspirin. The study was not designed to measure clinical outcomes and therefore the results are exploratory and should not be applied to clinical practice.The study was not designed to measure clinical outcomes and therefore the results are exploratory and should not be applied to clinical practice. The study did not account for performance of multiple significance tests or for potential correlation among various measures of platelet function.The study did not account for performance of multiple significance tests or for potential correlation among various measures of platelet function. This study was also not powered to evaluate the risk of bleeding with the use of high-dose clopidogrel in association with aspirin.This study was also not powered to evaluate the risk of bleeding with the use of high-dose clopidogrel in association with aspirin. The study was not designed to measure clinical outcomes and therefore the results are exploratory and should not be applied to clinical practice.The study was not designed to measure clinical outcomes and therefore the results are exploratory and should not be applied to clinical practice. Angiolillo, et al. Circulation. 2007 Jan; 115: 708-716.

11. Clinical Trial Results. org OPTIMUS: Summary This study demonstrates that the current recommended maintenance dose of clopidogrel is associated with a high incidence of suboptimal response for patients with type 2 diabetes mellitus and coronary artery disease.This study demonstrates that the current recommended maintenance dose of clopidogrel is associated with a high incidence of suboptimal response for patients with type 2 diabetes mellitus and coronary artery disease. Though some patients continued to show high platelet aggregation levels despite increased doses of clopidogrel, the study showed the overall biological effectiveness of a 150mg maintenance dose regimen compared with standard doses of 75mg in high risk patientsThough some patients continued to show high platelet aggregation levels despite increased doses of clopidogrel, the study showed the overall biological effectiveness of a 150mg maintenance dose regimen compared with standard doses of 75mg in high risk patients This study demonstrates that the current recommended maintenance dose of clopidogrel is associated with a high incidence of suboptimal response for patients with type 2 diabetes mellitus and coronary artery disease.This study demonstrates that the current recommended maintenance dose of clopidogrel is associated with a high incidence of suboptimal response for patients with type 2 diabetes mellitus and coronary artery disease. Though some patients continued to show high platelet aggregation levels despite increased doses of clopidogrel, the study showed the overall biological effectiveness of a 150mg maintenance dose regimen compared with standard doses of 75mg in high risk patientsThough some patients continued to show high platelet aggregation levels despite increased doses of clopidogrel, the study showed the overall biological effectiveness of a 150mg maintenance dose regimen compared with standard doses of 75mg in high risk patients Angiolillo, et al. Circulation. 2007 Jan; 115: 708-716.