The COURAGE trial found that adding PCI to optimal medical therapy did not reduce the risk of death or heart attack compared to medical therapy alone in stable coronary artery disease patients over a median 4.6 years. PCI did provide better relief of angina. The MERLIN TIMI-36 trial found that adding ranolazine to standard therapy reduced recurrent ischemia in NSTE-ACS patients compared to placebo with no increase in safety issues. A Danish registry study reported higher rates of late stent thrombosis over 1 year with drug-eluting stents compared to bare-metal stents based on ARC definitions.

1. ACS Critical Pathways 2007 Teleconferences This activity is supported by an educational grant from the Bristol-Myers Squibb/Sanofi Pharmaceuticals Partnership. This activity is co-provided by the Network for Continuing Medical Education and EduPro Resources LLC. APRIL 11, 2007

2. Faculty Christopher P. Cannon, MD Associate Professor of Medicine Harvard Medical School Senior Investigator, TIMI Study Group Associate Physician, Cardiovascular Division Brigham and Women’s Hospital Boston, Massachusetts

3. The Network for Continuing Medical Education and EduPro Resources LLC require that CME/CNE faculty disclose, during the planning of an activity, the existence of any personal financial or other relationships they or their spouses/partners have with the commercial supporter of the activity or with the manufacturer of any commercial product or service discussed in the activity. Disclosure Statement

4. Christopher P. Cannon, MD , has served as a consultant to Abbott Laboratories, Alnylam Pharmaceuticals, Arena Pharmaceuticals, AstraZeneca Pharmaceuticals LP, Biosite, Bristol-Myers Squibb Company, Eisai Inc., GlaxoSmithKline, Johnson & Johnson, Merck & Co., Inc., Pfizer Inc, sanofi-aventis, Schering-Plough Corporation, Tethys Bioscience, and Vertex Pharmaceuticals. He has received honoraria from Accumetrics, AstraZeneca Pharmaceuticals LP, BGB New York, Bristol-Myers Squibb Company, DIME, Genentech, Inc., Merck & Co. Inc., Pfizer Inc, sanofi-aventis, and Schering-Plough Corporation, and has received research support from Accumetrics, AstraZeneca Pharmaceuticals LP, Merck & Co., Inc., and Schering-Plough Corporation. The team from Aurora St. Luke's Medical Center reports no such relationships. Faculty Disclosure Statement

5. Highlights From the American College of Cardiology 2007 Annual Scientific Session Christopher P. Cannon, MD

6. Highlights From ACC 2007 COURAGE: C linical O utcomes U tilizing R evascularization and A ggressive G uideline-Driven Drug E valuation MERLIN TIMI-36: M etabolic E fficiency with R anolazine for L ess I schemia in N on-ST Elevation Acute Coronary Syndromes Danish Registry: More data on late stent thrombosis in DES-treated patients An International Risk Prediction Model for Recurrent CV Events in REACH: Re duction of A therothrombosis for C ontinued H ealth ACUITY: A cute C atheterization and U rgent I ntervention T riage Strateg Y (1 year results)

7. COURAGE C linical O utcomes U tilizing R evascularization and A ggressive G uideline-Driven Drug E valuation

8. COURAGE: Background Every year, more than 1 million PCI procedures are performed in the US The majority are undertaken electively in patients with stable CAD Successful PCI of flow-limiting stenoses might be expected to reduce the rate of death, MI or hospitalization for ACS, however: Prior studies have shown only that PCI decreases the frequency of angina and improves short-term exercise performance Boden WE, et al. N Engl J Med. 2007;356. Published online March 27, 2007.

9. COURAGE: Study Design 35,539 patients underwent assessment 1149 to PCI + OMT group 32,468 excluded for not meeting inclusion criteria, logistics, or for > 1 exclusions Randomize 1138 to OMT alone group Primary Outcome: Death or nonfatal MI Secondary Outcomes: Death, MI, or stroke Hospitalization for biomarker (-) ACS Cost, resource utilization Quality of life, including angina Cost-effectiveness Intensive, guideline-driven medical therapy and lifestyle intervention in both groups N = 2287 Boden WE, et al. N Engl J Med. 2007;356. Published online March 27, 2007. 3071 met eligibility criteria 2287 consented to participate 2.5 to 7 year (mean 4.6 year) follow-up

10. COURAGE: Inclusion and Exclusion Criteria Men and women 1, 2, or 3 vessel disease (>70% visual stenosis of proximal coronary segment) Anatomy suitable for PCI CCS class I-III angina Objective evidence of ischemia at baseline ACC/AHA class I or II indication for PCI Uncontrolled unstable angina Complicated post-MI course Revascularization within 6 months Ejection fraction <30% Cardiogenic shock/severe heart failure History of sustained or symptomatic VT/VF Severe non-CV comorbidity limiting survival Boden WE, et al. N Engl J Med. 2007;356. Published online March 27, 2007. Inclusion Criteria Exclusion Criteria CCS = Canadian Cardiovascular Society

11. COURAGE: Other Criteria Objective Evidence of Ischemia Spontaneous ST-T changes on ECG > 1 mm ST deviation on treadmill test Ischemic imaging defect Coronary Intervention Best practice May use all FDA or Health Canada approved devices Completeness of revascularization as clinically appropriate Boden WE, et al. N Engl J Med. 2007; 356. Published online March 27, 2007.

12. COURAGE: Risk Factor Goals Boden WE, et al. N Engl J Med. 2007;356. Published online March 27, 2007. 30-45 min. moderate intensity 5x/week Physical Activity Initial BMI Weight Loss Goal 25-27.5 BMI <25 >27.5 10% relative weight loss Body Weight by BMI <130/85 mm Hg Blood Pressure HbA lc <7.0% Diabetes <200 mg/day Dietary Cholesterol 60-85 mg/dL LDL-C (primary goal) >40 mg/dL HDL-C (secondary goal) <150 mg/dL Triglyceride (secondary goal) <30% calories / <7% calories Total Dietary Fat / Saturated Fat Cessation Smoking Goal Variable

13. COURAGE: Optimal Medical Therapy* Boden WE, et al. N Engl J Med. 2007;356. Published online March 27, 2007. *Applied to both arms by protocol and case-managed. Lisinopril or losartan ACE Inhibitor or ARB Long-acting metoprolol Beta blocker Amlodipine Calcium channel blocker Isosorbide 5-mononitrate Nitrate Simvastatin ± ezetimibe or extended-release niacin Statin Aspirin Clopidogrel in accordance with established practice standards Antiplatelet Agents Category

14. COURAGE: Baseline Demographic Characteristics Boden WE, et al. N Engl J Med. 2007;356. Published online March 27, 2007. .54 .95 .64 61.8±9.7 968 (85) 169 (15) 975 (86) 57 (5) 58 (5) 47 (4) 61.5±10.1 979 (85) 169 (15) 988 (86) 57 (5) 68 (6) 35 (3) Age (y) Sex (n, %) Male Female Race or ethnic (n, %) White Black Hispanic Other P value OMT (N = 1138) PCI + OMT (N = 1149) Characteristic

15. COURAGE: Baseline Characteristics – Angina Boden WE, et al. N Engl J Med. 2007;356. Published online March 27, 2007. .24 .53 .83 148 (13) 341 (30) 425 (37) 221 (19) 2 (<1) 5 1-15 3 1-6 135 (12) 340 (30) 409 (36) 261 (23) 3 (<1) 5 1-15 3 1-6 Angina CCS class (no, %) 0 I II III Missing data Duration of angina (months) Median Interquartile range Episodes/week with exertion or at rest within last month Median Interquartile range P value OMT (N = 1138) PCI + OMT (N = 1149) Characteristic

16. COURAGE: Survival Free of Death From Any Cause and MI No. at Risk OMT 1138 1017 959 834 638 408 192 30 PCI+OMT 1149 1013 952 833 637 417 200 35 Years 0 1 2 3 4 5 6 0.0 0.5 0.6 0.7 0.8 0.9 1.0 PCI + OMT: 19%* OMT: 18.5%* Hazard ratio: 1.05 95% CI (0.87-1.27) P = .62 7 Boden WE, et al. N Engl J Med. 2007;356. Published online March 27, 2007. Survival Free of Death From Any Cause and MI *Cumulative event rates at a median of 4.6 years.

17. COURAGE: Cumulative Event Rates at a Median of 4.6 Years <.001 0.51–0.71 0.60 32.6 21.1 Revasc. (PCI or CABG) .56 0.84–1.37 1.07 11.8 12.4 Hospitalization for ACS .19 0.80–3.04 1.56 1.8 2.1 Stroke .33 0.89–1.43 1.13 12.3 13.2 Nonfatal MI .38 0.65–1.16 0.87 8.3 7.6 Death .62 0.87–1.27 1.05 19.5 20 Death, MI, stroke .62 0.87–1.27 1.05 18.5 19 Death, MI P value 95% CI Hazard ratio OMT (%) PCI + OMT (%) Outcome Boden WE, et al. N Engl J Med. 2007;356. Published online March 27, 2007.

18. COURAGE: Overall Survival No. at Risk OMT 1138 1073 1029 917 717 468 302 38 PCI+OMT 1149 1094 1051 929 733 488 312 44 Years 0 1 2 3 4 5 6 0.0 0.5 0.6 0.7 0.8 0.9 1.0 PCI + OMT: 7.6%* OMT: 8.3%* 7 Hazard ratio: 0.87 95% CI (0.65-1.16) P = .38 Boden WE, et al. N Engl J Med. 2007;356. Published online March 27, 2007. Overall Survival *Cumulative event rates at a median of 4.6 years.

19. COURAGE: Freedom From Angina During Long-term Follow-up Boden WE, et al. N Engl J Med. 2007;356. Published online March 27, 2007. NS .02 <.001 NS P value OMT PCI + OMT Time Point (y) 72% 74% 5 y 67% 72% 3 y 58% 66% 1 y 13% 12% Baseline

20. COURAGE: Conclusions As an initial management strategy in patients with stable coronary artery disease, PCI did not reduce the risk of death, MI, or other major cardiovascular events when added to optimal medical therapy PCI resulted in better angina relief during most of the follow-up period, but medical therapy was also effective, with no between–group difference in angina-free status at 5 years Boden WE, et al. N Engl J Med. 2007;356. Published online March 27, 2007.

21. MERLIN TIMI-36 M etabolic E fficiency with R anolazine for L ess I schemia in N on-ST Elevation Acute Coronary Syndromes

22. MERLIN TIMI-36: Background Despite advances in antithrombotic therapies and invasive technology, risk of recurrent ischemic complications in patients with NSTE-ACS remains substantial Ranolazine is a novel agent that inhibits the late sodium current thereby reducing cellular sodium and calcium overload; has been shown to reduce ischemia in patients with chronic stable angina MERLIN TIMI-36 was designed to evaluate the safety and efficacy of long-term treatment with ranolazine compared with placebo in NSTE-ACS Morrow DA, et al. Am Heart J. 2006;151:1186.

23. MERLIN TIMI-36: Study Design Follow-up visits: Day 14, Month 4, Q4 Months Placebo (n = 3,281) Matched IV/PO Ranolazine (n = 3,279) IV -> PO Standard Therapy for ACS Morrow DA, et al. Am Heart J. 2006;151:1186. UA/NSTEMI (N = 6560) 1) Rest symptoms within 48 h 2) High-risk features Holter monitoring at enrollment x 7d Final Visit Additional end points : Exercise performance, new/worsening heart failure, quality of life, extent of myocardial injury, clinically significant arrhythmia . Duration Event-driven Mean Follow-up: Median, 348 Days Primary end point: Composite of CV death, MI, or recurrent ischemia Secondary end point: Composites of CV death, MI, severe recurrent ischemia; and positive Holter at 30 days

24. MERLIN: Efficacy Results Morrow D, et al. Presented at: American College of Cardiology 2007 Scientific Sessions; March 27, 2007; New Orleans, Louisiana. .030 0.87 13.9 16.1 Recurrent ischemia .87 0.99 10.4 10.5 CV death/MI .11 0.92 21.8 23.5 CV death/recurrent ischemia (primary end point) P value Hazard Ratio Ranolazine (n = 3279) Placebo (n = 3281) End point

25. MERLIN: Safety Results Morrow D, et al. Presented at: American College of Cardiology 2007 Scientific Sessions; March 27, 2007; New Orleans, Louisiana. <.001 0.89 73.1% 83.1% Clinically significant arrhythmia on Holter (% of patients) .84 0.97 99 102 Symptomatic documented arrhythmia (number of patients) .43 0.87 56 65 Sudden cardiac death (number of patients) .91 0.99 172 175 Death, any cause (number of patients) P value Hazard ratio Ranolazine (n = 3268) Placebo (n = 3273) End point

26. MERLIN: Conclusions In NSTE-ACS, no difference between ranolazine and placebo in death or MI, but improvements in recurrent ischemia with ranolazine Reduced need for anginal therapy intensification with ranolazine No adverse trend in death or arrhythmia with ranolazine; suggestion of possible antiarrhythmic effect with ranolazine Study supports use of ranolazine in stable disease

27. Danish Registry

28. Danish Registry: Background Use of drug-eluting stents (DES) recently associated with increased risk of stent thrombosis Based on Academic Research Consortium (ARC) definition, Maeng, et al reported on the incident of stent thrombosis in patients treated with DES (sirolimus- and paclitaxel-eluting) and bare-metal stents (BMS) in Western Denmark Maeng M, et al. Presented at: American College of Cardiology 2007 Scientific Sessions; March 24, 2007; New Orleans, Louisiana.

29. Academic Research Consortium: Proposed Definitions for Stent Thrombosis *Acute/Subacute can also be replaced by early stent thrombosis. Early stent thrombosis = 0-30 days. Cutlip D. Presented at TCT; October 2006; Washington, DC. Expanded Stent Thrombosis Definition Timing Acute Thrombosis*: 0 – 24 hrs. post Subacute Thrombosis*: >24 hrs – 30 days post Late Thrombosis: 30 days – 1 year post Very Late Thrombosis: >1 year post Definite/Confirmed Probable Possible

30. Academic Research Consortium: Proposed Definitions for Stent Thrombosis The incidental angiographic documentation of stent occlusion in the absence of clinical syndromes is not considered a confirmed stent thrombosis (silent thrombosis). Cutlip D. Presented at TCT; October 2006; Washington, DC. 1. Definite/Confirmed Autopsy evidence or angiographic confirmed stent thrombosis (definite) is considered to have occurred if: TIMI flow is: Grade 0 with occlusion originating in the stent or segment 5 mm proximal or distal to the stent region in the presence of thrombus Grade 1, 2, 3 originating in the stent or in the segment 5 mm proximal or distal to the stent region in the presence of thrombus AND at least one of the following criteria within 48 hrs: New onset of ischemic symptoms at rest (typical chest pain with duration >20 minutes) New ischemic ECG changes suggestive of acute ischemia Typical rise and fall in cardiac biomarkers (>2x ULN of CK)

31. Academic Research Consortium: Proposed Definitions for Stent Thrombosis Cutlip D. Presented at TCT; October 2006; Washington, DC. Probable stent thrombosis is considered to have occurred in the following cases: Any unexplained death within the first 30 days. Irrespective of the time after the index procedure, any MI in the absence of any obvious cause which is related to documented acute ischemia in the territory of the implanted stent without angiographic confirmation of stent thrombosis. Possible stent thrombosis is considered to have occurred with any unexplained death beyond 30 days. 3. Possible 2. Probable

32. Danish Registry: Results Maeng M, et al. Presented at: American College of Cardiology 2007 Scientific Sessions; March 24, 2007; New Orleans, Louisiana. <.0001 4.0 Data not Presented Data not Presented MI, 12-15 months .31 1.14 3.2 3.0 Overall MI .29 0.90 4.4 6.2 Overall death .029 10.9 0.09 0.009 Definite stent thrombosis, 12-15 months NS 0.92 1.8 2.15 Overall probable, possible, or definite stent thrombosis (ARC definition) <.0001 0.57 4.6 7.1 Target lesion revascularization P value Adj. RR DES (%) (n = 3268) BMS (%) (n = 8847) End point

33. Danish Registry: Conclusions After 15 months, the investigators noted no overall differences in rates of stent thrombosis or death and MI between DES and BMS After clopidogrel was discontinued at 12 months, rates of stent thrombosis and MI were significantly higher in DES-treated patients These findings are consistent with other recent studies Maeng M, et al. Presented at: American College of Cardiology 2007 Scientific Sessions; March 24, 2007; New Orleans, Louisiana.

34. REACH Update: An International Risk Prediction Model for Recurrent CV Events Re duction of A therothrombosis for C ontinued H ealth (International Risk Reduction Model for Recurrent CV Events)

35. REACH CV Events Prediction Model: Background The capability of CV risk factors to predict recurrent CV events in a “real world” setting not well characterized REACH is an international, prospective cohort of 68,236 patients with either established atherosclerotic arterial disease (CAD, PAD, CVD) or at least 3 risk factors for atherothrombosis REACH provides a global, well-defined, outpatient population with known CV disease Wilson PW. Presented at: American College of Cardiology 2007 Scientific Sessions; March 27, 2007; New Orleans, Louisiana.

36. REACH CV Events Prediction Model: Methods A prediction model was developed based on 18,802 men and 9,430 women with known CV disease (CAD, CVD, and/or PAD) at entry from North America/Western Europe Full baseline and 10-year data were available At 1 year, 709 CV events (CV death, MI, stroke) in men and 417 in women were reported A single sex-adjusted model was developed since results were similar in separate sex models Wilson PW. Presented at: American College of Cardiology 2007 Scientific Sessions; March 27, 2007; New Orleans, Louisiana.

37. REACH: Multivariable-adjusted HR and P Value for Variables Considered Morrow D, et al. Presented at: American College of Cardiology 2007 Scientific Sessions; March 27, 2007; New Orleans, Louisiana. Number at risk: 27,632; Number of events: 1,126. .2187 1.18 Hypertension therapy (yes/no) .0352 .87 Acetyl salicylic acid (yes/no) <.0001 .72 Statins (yes/no) <.0001 1.78 Cardiac failure (yes/no) <.0001 1.47 CV event in past year (yes/no) .0013 1.00, 1.20, 1.44 1, 2 or 3 vasc. beds (CAD, CVD, PAD) <.0001 1.60 Diabetes (yes/no) <.0001 1.42 Smoking (current vs other) <.0001 1.03 Age (year) .7087 1.02 Gender (male) P value HR per unit Variable (unit)

38. REACH CV Events Prediction Model: Results/Conclusions Statin therapy, number of vascular beds affected, diabetes, smoking, cardiac failure and history of CV event(s) <1 year were significantly associated with next CV event This prediction model is the first to estimate risk for recurrent CV events in outpatients Risk factors, burden of disease, and treatment are all related to increased risk for a subsequent CV event Wilson PW. Presented at: American College of Cardiology 2007 Scientific Sessions; March 27, 2007; New Orleans, Louisiana.

39. ACUITY: One Year Results A cute C atheterization and U rgent I ntervention T riage Strateg Y

40. ACUITY: Patient Follow-up at 1 Year* All patients N = 13,819 25 Withdrawn 62 Lost to Follow-up Heparin + IIb/IIIa 4,516 (98.1%) 1-year FU Bivalirudin + IIb/IIIa 4,502 (97.8%) 1-year FU Bivalirudin alone 4,521 (98.0%) 1-year FU 33 Withdrawn 69 Lost to Follow-up 25 Withdrawn 66 Lost to Follow-up *End points adjudicated: Composite ischemia (death, MI, unplanned revasc) and stent thrombosis Stone GW. Presented at: American College of Cardiology 2007 Scientific Sessions; March 26, 2007; New Orleans, Louisiana. Heparin + GP IIb/IIIa 4,603 Bivalirudin + GP IIb/IIIa 4,604 Bivalirudin alone 4,612 R

41. ACUITY: Ischemic Composite End Point (Death, MI, unplanned revascularization for ischemia) 0 30 60 90 120 150 180 210 240 270 300 330 360 390 0 5 15 25 Ischemic Composite (%) Days From Randomization 10 20 UFH/Enoxaparin + IIb/IIIa Bivalirudin + IIb/IIIa Bivalirudin alone Bivalirudin alone vs Hep + GPI HR [95% CI] = 1.05 (0.95-1.17) Bivalirudin + GPI vs Hep + GPI HR [95% CI] = 1.05 (0.94-1.16) UFH/Enoxaparin + GPI vs Bivalirudin + GPI vs Bivalirudin Alone Stone GW. Presented at: American College of Cardiology 2007 Scientific Sessions; March 26, 2007; New Orleans, Louisiana. Estimate P (log rank) 30-day 7.4% .36 7.8% .34 7.9% — Estimate P (log rank) 16.3% .38 16.5% .31 16.4% 1-year — P = .55

42. ACUITY: Stent Thrombosis (Protocol Defn.) 0 30 60 90 120 150 180 210 240 270 300 330 360 390 0 3 4 5 Stent Thrombosis (%) Days From Randomization 2 1 Drug-eluting Stents (DES) vs Bare-Metal Stents (BMS) Estimate P (log rank) ≥ 1 DES (N = 4630) .38 2.2% 1-year Stone GW. Presented at: American College of Cardiology 2007 Scientific Sessions; March 26, 2007; New Orleans, Louisiana. All BMS (N = 2528) 2.3% All (N = 7158) 2.2%

43. Mortality (%) Days From Randomization 0 30 60 90 120 150 180 210 240 270 300 330 360 390 0 5 15 30 10 25 20 1-year Estimate ACUITY: Impact of MI and Major Bleeding (non-CABG) in the First 30 Days on Risk of Death Over 1 Year 28.9% 12.5% 8.6% 3.4% Stone GW. Presented at: American College of Cardiology 2007 Scientific Sessions; March 26, 2007; New Orleans, Louisiana. Major Bleed only (without MI) (N = 551) 12.5% 28.9% Both MI and Major Bleed (N = 94) 3.4% No MI or Major Bleed (N = 2,557) MI only (without Major Bleed) (N = 611) 8.6%

44. ACUITY: Conclusions In patients with moderate and high risk ACS undergoing an early invasive strategy with the use of GP IIb/IIIa inhibitors Bivalirudin is an acceptable substitute for either unfractionated heparin or enoxaparin Compared to either UFH/enoxaparin with GP IIb/IIIa inhibitors or bivalirudin with GP IIb/IIIa inhibitors A bivalirudin alone strategy results in marked reduction of bleeding at 30 days, and similar rates of mortality and composite ischemia at 1 year The results of this study further establish the important relationship between iatrogenic bleeding complications and subsequent mortality in patients with ACS Stone GW. Presented at: American College of Cardiology 2007 Scientific Sessions; March 26, 2007; New Orleans, Louisiana.

45. Featured Institution Aurora St. Luke’s Medical Center Milwaukee, Wisconsin

46. Polling Question #2 1) We are currently on the same item 2) We have since moved to the next checkbox on the checklist 3) We have progressed by more than one item on the checklist 4) ACS pathways are up-to-date and regularly followed If you participated in a previous teleconference, how much progress have you made since then? (Please refer to the checklists on the next 3 slides.)

47. Progress Checklist: Immediate Goals Circulate discharge plan and other tools to all cardiology, ED, and CV nursing staff for comments  Circulate pathways to all cardiology, ED, and CV nursing staff for comments  Develop draft pathways  Assemble team and set up meeting of working group 

48. Progress Checklist: Short-term Goals/Activities Grand rounds/conference: Cardiology/IM  Grand rounds/conference: Emergency Dept.  Grand rounds/conference: Nursing  Circulate memo  Launch critical pathways  Finalize critical pathways 

49. Progress Checklist: Long-term Goals/Activities  NRMI  AHA Get With The Guidelines  ACC National Cardiovascular Data Registry  CRUSADE  GRACE  REACH  Other Monitor data: which registry? 

50. Question-and-Answer Session

51. Concluding Remarks Christopher P. Cannon, MD Next Program Christopher P. Cannon, MD Wednesday, May 16, 2007 12:00 Noon Eastern Time (9:00 AM Pacific Time) The AHA/ACC/SCAI/ACS/ADA Science Advisory on Prevention of Premature Discontinuation of Dual Antiplatelet Therapy in Patients With Coronary Artery Stents