1. Redefining Treatment Strategies for Optimal Medical Care in CAD COURAGE and MERLIN-TIMI 36

2. COURAGE Clinical Outcomes Utilizing Revascularization and Aggressive Drug Evaluation

3. COURAGE: Background and objective Elective PCI procedures are common in the US (~85% of all PCI) PCI decreases angina frequency but long-term prognostic effects on CV events are not known Antianginal agents also provide symptom relief whereas ACEIs, ASA, β-blockers, and statins have been shown to prevent MI and death Boden WE et al. N Engl J Med. 2007;356:1503-16. Boden WE et al. Am Heart J. 2006;151:1173-9. In patients with stable CAD COURAGE was designed to evaluate whether PCI plus optimal medical therapy, as initial management strategy, reduces risk of major CV events compared with optimal medical therapy alone in stable CAD patients

4. COURAGE: Study design Boden WE et al. Am Heart J. 2006;151:1173-9. Boden WE et al. N Engl J Med. 2007;356:1503-16. Optimal medical therapy* + PCI (n = 1149) Optimal medical therapy (n = 1138) AHA/ACC Class I/II indications for PCI, suitable coronary artery anatomy + ≥70% stenosis in ≥1 proximal epicardial vessel + objective evidence of ischemia (or ≥80% stenosis + CCS class III angina without provocation testing) Primary outcomes: All-cause mortality, nonfatal MI Follow-up: Median 4.6 years Randomized *Intensive pharmacologic therapy + lifestyle intervention CCS = Canadian Cardiovascular Society Secondary outcomes: Death, MI, stroke; ACS hospitalization

5. Lifestyle intervention and risk factor goals Smoking cessation Exercise program –≥30 min moderately intensive exercise 5x/week Nutrition counseling –Total dietary fat <30% of calories –Saturated fat<7% of calories –Dietary cholesterol <200 mg/day Weight control –BMI <25 kg/m 2 (if baseline BMI 25.0-27.5) –10% relative weight loss (if baseline BMI >27.5) LDL-C (mg/dL) 60-85 HDL-C (mg/dL) ≥40 Triglycerides (mg/dL) <150 BP (mm Hg) <130/85 <130/80 if diabetes or renal disease present A1C (%) <7.0 Boden WE et al. Am Heart J. 2006;151:1173-9.

6. Pharmacologic therapy Antiplatelet –Aspirin –Clopidogrel in accordance with established practice standards Dyslipidemia –Simvastatin ± ezetimibe or ER niacin ACEI or ARB –Lisinopril or losartan  -blocker –ER metoprolol succinate Calcium channel blocker –Amlodipine Nitrate –Isosorbide 5-mononitrate Boden WE et al. Am Heart J. 2006;151:1173-9. Boden WE et al. N Engl J Med. 2007;356:1503-16.

7. COURAGE: Baseline demographics PCI + medical therapy (n = 1149) Medical therapy (n = 1138) Age (years)61.561.8 Male (%)85 Race (%) White Black Hispanic Other 86 5 6 3 86 5 5 4 Boden WE et al. N Engl J Med. 2007;356:1503-16.

8. COURAGE: Baseline angiographic data PCI + medical therapy (n = 1149) Medical therapy (n = 1138) Vessels with disease (%) 1 2 3 31 39 30 30 39 31 Disease in graft vessel* (%)6269 Proximal LAD disease (%)3137 † Ejection fraction (%)60.860.9 Boden WE et al. N Engl J Med. 2007;356:1503-16. *Patients who underwent previous CABG † P = 0.01

9. COURAGE: Baseline angina PCI + medical therapy (n = 1149) Medical therapy (n = 1138) CCS class (%) 0 I II III 12 30 36 23 13 30 37 19 Median duration (mo) Interquartile range 5 1-15 Median episodes/week Interquartile range 3 1-6 Boden WE et al. N Engl J Med. 2007;356:1503-16.

10. COURAGE: Inducible ischemia at baseline PCI + medical therapy (n = 1149) Medical therapy (n = 1138) Nuclear imaging, % (n)70 (685)72 (708) Single reversible defect, % (n)22 (154)23 (161) Multiple reversible defect, % (n)65 (444)68 (483) Boden WE et al. N Engl J Med. 2007;356:1503-16.

11. COURAGE: Change in lifestyle factors Boden WE et al. N Engl J Med. 2007;356:1503-16. PCI + medical therapy (n = 1149) Medical therapy (n = 1138)

12. Treatment targets Baseline1 year PCI + medical therapy Medical therapy PCI + medical therapy Medical therapy SBP (mm Hg)131130126124 DBP (mm Hg)74 7270 Total cholesterol (mg/dL)172177156150 LDL-C (mg/dL)1001028481 HDL-C (mg/dL)39 4241 TG (mg/dL)143149129133 BMI (kg/m²)28.728.928.529.0 Moderate activity, 5x/week (%)25 4643 Boden WE et al. N Engl J Med. 2007;356:1503-16. COURAGE: Improvement in CV risk factors

13. Angiographic outcomes PCI attempted on 1688 lesions in 1077 patients –590 patients (59%) received 1 stent –416 (41%) received ≥2 stents –Reduction in stenosis diameter 83% (± 14%) to 31% (± 34%) in 244 non-stented lesions 82% (± 12%) to 1.9% (± 8%) in 1444 stented lesions Angiographic success rate* of 93% Boden WE et al. N Engl J Med. 2007;356:1503-16. *<50% residual stenosis after balloon angioplasty; <20% residual stenosis in stented artery

14. COURAGE: Treatment effect on primary outcome HR 1.05 (0.87-1.27) P = 0.62* Boden WE et al. N Engl J Med. 2007;356:1503-16. All-cause death, MI (time to first event) *Unadjusted No. at risk Medical therapy1138101795983463840819230 PCI1149101395283363741720035 Medical therapy PCI + medical therapy Survival free of primary outcome 0247 0 0.5 0.6 0.7 0.8 1.0 0.9 Years 6531

15. No. at risk Medical therapy PCI 38 44 302 312 468 488 717 733 917 929 1029 1051 1073 1094 1138 1149 120 134 192 200 409 418 638 637 834 833 962 954 1019 1015 1138 1149 COURAGE: Treatment effects Boden WE et al. N Engl J Med. 2007;356:1503-16. *Unadjusted All-cause deathMyocardial infarction Overall survival Survival free of MI PCI + medical therapy 1.0 0.9 0.7 0.8 Medical therapy 1.0 0.9 0.7 0.8 01234567 0 Years 01234567 0 HR 0.87 (0.65-1.16) P = 0.38* HR 1.13 (0.89-1.43) P = 0.33*

16. COURAGE: Treatment effect on hospitalization for ACS Boden WE et al. N Engl J Med. 2007;356:1503-16. *Unadjusted HR 1.07 (0.84-1.37) P = 0.56* No. at risk Medical therapy PCI 127 134 236 246 418 431 662 667 833 835 956 957 1025 1027 1138 1149 Survival free of ACS Years 0 01234567 1.0 0.9 0.7 0.8 PCI + medical therapyMedical therapy

17. COURAGE: Treatment effect on angina Boden WE et al. N Engl J Med. 2007;356:1503-16. P < 0.001 P = 0.02 NS Angina-free (%) NS

18. Boden WE et al. N Engl J Med. 2007;356:1503-16. Treatment effect in CV and diabetes subgroups 0.250.501.002.001.751.50 Medical therapy betterPCI better Myocardial infarction Yes No Extent of CAD Multivessel disease Single-vessel disease Diabetes Yes No Angina CCS 0-I CCS II-III Ejection fraction >50% Previous CABG No Yes ≤50% Baseline characteristics Hazard ratio (95% CI)

19. COURAGE: Summary and implications PCI added to optimal medical therapy did not reduce risk of death, MI, or other major CV events compared with optimal medical therapy alone Findings reinforce existing clinical practice guidelines –Optimal medical therapy and aggressive management of multiple treatment targets without initial PCI can be implemented safely in the majority of patients with chronic stable angina, even those with objective evidence of ischemia and significant multivessel CAD Boden WE et al. N Engl J Med. 2007;356:1503-16.

20. MERLIN-TIMI 36 Metabolic Efficiency With Ranolazine for Less Ischemia in Non-ST-Elevation Acute Coronary Syndromes- Thrombolysis In Myocardial Infarction 36

21. MERLIN-TIMI 36: Background Current management is designed to ↑myocardial O 2 supply (antithrombotic therapy, revascularization) and ↓myocardial O 2 demand (↓HR) Ion current modulation is under evaluation in ACS management Prolongation of the late Na + current during myocardial ischemia may contribute to deleterious cellular effects Ranolazine, an inhibitor of the late Na + current, exerts an anti- ischemic action without any clinically significant effect on HR or BP in stable CAD patients, but has not been studied in ACS patients Morrow DA et al. JAMA. 2007;297:1775-83. In non-ST-elevation ACS

22. MERLIN-TIMI 36: Objective MERLIN-TIMI 36 was designed to evaluate the efficacy and safety of ranolazine in reducing CV death, MI, and recurrent ischemia in ACS patients receiving standard therapy Morrow DA et al. JAMA. 2007;297:1775-83. Non-ST-elevation ACS

23. MERLIN-TIMI 36: Study design IV/oral ranolazinePlacebo Patients with non-ST-elevation ACS treated with standard medical/interventional therapies N = 6560 Primary efficacy endpoint: CV death, MI, recurrent ischemia Safety endpoints: All-cause death, CV hospitalization, symptomatic documented arrhythmia, clinically significant arrhythmia on Holter during first 7 days Randomized Double-blind Morrow DA et al. JAMA. 2007;297:1775-83.

24. MERLIN-TIMI 36: Effect on primary endpoint Morrow DA et al. JAMA. 2007;297:1775-83. N = 6560 with non-STE ACS; Ranolazine vs placebo ≤48hrs of ischemic symptom onset No. at risk Placebo Ranolazine 3281 3279 2454 2450 1223 268 269 HR 0.92 (95% CI 0.83-1.02) Log-rank P = 0.11 30 20 10 0 0180360540 Days PlaceboRanolazine CV death, MI, or recurrent ischemia (%)

25. MERLIN-TIMI 36: Effect on efficacy outcomes Morrow DA et al. JAMA. 2007;297:1775-83. P Primary endpoint Major secondary endpoint Cardiovascular death MI Recurrent ischemia Failure of therapy Hospitalization for heart failure 0.11 0.50 0.98 0.76 0.03 0.16 0.68 0.511.5 Hazard ratio (95% CI) Ranolazine better Placebo better

26. MERLIN-TIMI 36: Major safety outcomes Event rate (%) Ranolazine (n = 3268) Placebo (n = 3273)P All-cause death5.35.40.91 All-cause death or CV hospitalization33.233.40.53 Symptomatic documented arrhythmia3.03.10.84 Clinically significant arrhythmia on Holter73.783.1<0.001 Morrow DA et al. JAMA. 2007;297:1775-83.

27. MERLIN-TIMI 36: Summary and implications In patients with ACS, ranolazine added to standard therapy was associated with –No difference in composite efficacy endpoint of CV death, MI, or recurrent ischemia –No difference in safety endpoints of all-cause death, all-cause death or CV hospitalization, or symptomatic documented arrhythmia –Significant reduction in arrhythmias detected by Holter monitoring during first 7 days Findings do not support use of ranolazine in ACS but add to previous safety data and provide additional support for ranolazine as antianginal therapy in stable CAD Morrow DA et al. JAMA. 2007;297:1775-83.

28. COURAGE, MERLIN-TIMI 36: Optimal medical therapy for patients with CAD Establish aggressive treatment goals Utilize intensive, multifaceted therapy to achieve and maintain treatment goals –Lifestyle modification –Risk factor reduction –Antianginal therapy