1. E. Magnus Ohman, MB, FRCPI, FESC, FACC Professor of Cardiovascular Medicine Director, Program for Advanced Coronary Disease Duke University Medical Center Duke Clinical Research Institute Durham, North Carolina Evidence-Based Medicine Therapies in ACS: From Principles to Practice

2. Conflict of interest: Research grants - Berlex, Sanofi-Aventis, Schering-Plough, The Medicine Company, Bristol Meyer Squibb, CVT Therapeutics, and Eli Lilly Stock ownership - Medtronic, Savacor Consultant - Northpointe Domain, Liposcience, Abiomed, Datascope, and Inovise Medical Evidence-Based Medicine Therapies in ACS; From Principles to Practice

3. Changes in Health Care Systems: Moving From the 20 th to the 21 st Century l Provider-centered l Price-driven l Care decisions widely varying l Fragmented care l Little quality measurement l Persistent escalating costs l Provider-centered l Price-driven l Care decisions widely varying l Fragmented care l Little quality measurement l Persistent escalating costs l Patient-centered l Value-driven l Evidence-based care l Coordinated care l Ubiquitous quality measurement l Overall cost decline 20 th Century 21 st Century National Committee for Quality Health Care 2003

4. Quality of Care Incorporated in the “Drugs for the Elderly” Medicare Bill Passed by Congress in 2003 ProgramDescription Pay for performanceIOM to develop a strategy for aligning quality and payment Hospital to report onHospitals that report will get performance0.4% larger payments Changing MD’s practiceMD that participate will get higher pay Improving access forDevelop demonstration chronic illness (CHF)programs IT provisionGrants for electronic prescribing ProgramDescription Pay for performanceIOM to develop a strategy for aligning quality and payment Hospital to report onHospitals that report will get performance0.4% larger payments Changing MD’s practiceMD that participate will get higher pay Improving access forDevelop demonstration chronic illness (CHF)programs IT provisionGrants for electronic prescribing

5. Improvement in Performance Scores Pilot trial of Medicare Population: 270 Hospitals – 400,000 Patients Source: Centers for Medicare and Medicaid Services

6. Hospitalizations in the U.S. Due to Acute Coronary Syndromes (ACS) Acute Coronary Syndromes* 1.57 Million Hospital Admissions - ACS UA/NSTEMI † STEMI 1.24 million Admissions per year 0.33 million Admissions per year Heart Disease and Stroke Statistics – 2007 Update. Circulation 2007; 115:69-171. *Primary and secondary diagnoses. †About 0.57 million NSTEMI and 0.67 million UA.

7. 1990199219941996199820002002 1990 ACC/AHA AMI R. Gunnar 1994 AHCPR/NHLBI UA E. Braunwald 1996 1999 Rev Upd ACC/AHA AMI T. Ryan 2004 2007 Rev Upd ACC/AHA STEMI E. Antman 2000 2002 2007 Rev Upd Rev ACC/AHA UA/NSTEMI E. Braunwald J. Anderson 20042007 Figure 1. Evolution of Guidelines for Management of Patients with AMI The first guideline published by the ACC/AHA described the management of patients with acute myocardial infarction (AMI). The subsequent three documents were the Agency for Healthcare and Quality/National Heart, Lung and Blood Institute sponsored guideline on management of unstable angina (UA), the revised/updated ACC/AHA guideline on AMI, and the revised/updated ACC/AHA guideline on unstable angina/non- ST segment myocardial infarction (UA/NSTEMI). The present guideline is a revision and deals strictly with the management of patients presenting with ST segment elevation myocardial infarction (STEMI). The names of the chairs of the writing committees for each of the guidelines are shown at the bottom of each box. Rev, Revised; Upd, Update Evolution of Guidelines for ACS

8. CRUSADE National Quality Improvement Initiative n Academic collaboration between cardiology and emergency medicine specialties started in 2001 n Multiple industry sponsors l Millennium-Schering Plough l Bristol-Myers-Squibb l Sanofi-Aventis l Merck-Schering l PDL Pharma n Goal: Improve adherence to ACC/AHA ACS guidelines l UA and NSTEMI  STEMI added in 2004

9. CRUSADE Objectives n Determine the current state of awareness of and adherence to the ACC/AHA Acute Coronary Syndromes (ACS) Guidelines. n Implement quality improvement initiatives to promote ACC/AHA ACS Guidelines recommendations. n Improve clinical outcomes for ACS patients via early risk stratification and implementation of evidence-based care, both in-hospital and post-discharge.

10. Goals for CRUSADE: Improve Adherence to ACC/AHA Guidelines for Patients with Unstable Angina/Non-STEMI l Aspirin l Clopidogrel l Beta Blocker l Heparin (UFH or LMWH) l GP IIb-IIIa Inhibitor l All receiving cath/PCI l Aspirin l Clopidogrel l Beta Blocker l Heparin (UFH or LMWH) l GP IIb-IIIa Inhibitor l All receiving cath/PCI l Aspirin l Clopidogrel l Beta Blocker l ACE Inhibitor l Statin/Lipid Lowering l Smoking Cessation l Cardiac Rehabilitation Acute Therapies Discharge Therapies Circulation, JACC 2002 - ACC/AHA Guidelines update Evaluating the Process of Care An adherence score is applied to each patient. incorporating the components of process of care. The score from each patient then combined for all patients at each hospital. Typical scores ranged from 50 to 95%. All 400 hospital adherence scores then ranked in quartiles - best to worst. Evaluating the Process of Care An adherence score is applied to each patient. incorporating the components of process of care. The score from each patient then combined for all patients at each hospital. Typical scores ranged from 50 to 95%. All 400 hospital adherence scores then ranked in quartiles - best to worst.

11. Data Submission in CRUSADE n Data collection: Nov, 2001- Dec, 2006 n Total # of DCF’s submitted = 205,528 l ~ 195,00 UA/NSTEMI l ~ 9,000 STEMI n Total # of sites which submitted data = 568 n Maximum # of DCF’s per site = 2,439 n Average # of DCF’s per site = 359

12. Total sites = 568 (Active sites = 409) 205,528 patients included as of January 2007 AK (0) WA (7) OR (5) CA (35) ID (0) NV (1) MT (0) WY (0) CO (8) NM (2) ND (1) SD (2) NE (4) KS (3) OK (9) TX (17) MN (4) IA (5) MO (12) AR (3) LA (8) WI (5) MI (22) MI UT (1) AZ (9) HI (1) IL (14) IN (7) KY (8) TN (11) MS (6) AL (11) GA (15) FL (33) SC (6) NC (15) VA (16) OH (30) WV (3) PA (37) NY (37) MD (13) ME (0) VT (1) NH (2) NJ (10) MA (11) CT (8) DE (3) RI (1) DC (1) CRUSADE Site Distribution

13. A cute C oronary T reatment and I ntervention O utcomes N etwork n National ACS Surveillance System l Assess characteristics, treatments, and outcomes of ACS patients l Focuses on NSTEMI and STEMI n Optimize ACS management and outcomes l Implement evidence-based guideline recommendations in clinical practice n Improve quality and safety of ACS care n Investigate novel QI methods Follow Guidelines Adherence, Medication Dosing, and Outcomes with the ACC-ACTION  Registry

14. CRUSADE Site Feedback Reports – Stimulating Change with Continuous QI Feedback n 39,715 reports (7943 single) have been distributed to CRUSADE sites since July, 2002 l 1,032,590 pages l 2065 reams l 41,300 lbs. equivalent to: 5 ¼ adult female elephants

15. CRUSADE Lessons Learned n Complex patient population n Variations in use of medications n Disparities in use of invasive procedures n Rapid changes in revascularization procedures n Transfusions and bleeding are common n Importance of proper medication dosing n Comprehensive guidelines adherence saves lives n Academic output critical to success

16. CRUSADE Lessons Learned n Complex patient population n Variations in use of medications n Disparities in use of invasive procedures n Rapid changes in revascularization procedures n Transfusions and bleeding are common n Importance of proper medication dosing n Comprehensive guidelines adherence saves lives n Academic output critical to success

17. Baseline Characteristics: CRUSADE vs. ACS Clinical Trials VariablePURSUITCURESYNERGYCRUSADE (n = 9461)(n = 12,562)(n = 9975)(n = 195,240) Mean age ± SD (yrs)63 ± 1163 ± 1267 ± 1167 ± 14 Female sex (%)36393440 Diabetes mellitus (%)23232933 Prior MI (%)32252829 Prior CHF (%)118917 Prior PCI (%)1318*2021 Prior CABG (%)1218*1719 ST depression (%)50425534 NEJM 1998;339:436-43 NEJM 2001;345:494-502 JAMA 2004:292:45-54 CRUSADE cumulative through December 31, 2006 NEJM 1998;339:436-43 NEJM 2001;345:494-502 JAMA 2004:292:45-54 CRUSADE cumulative through December 31, 2006

18. CRUSADE vs. ACS Clinical Trials: Early Mortality Rates PURSUIT 1 (n = 9,461) PRISM-PLUS 2 (n = 1,915) SYNERGY 3 (n = 9,975) CRUSADE (n = 195,240) 1.8% 1.9% 1.5% 4.4% 7-day mortality rate In-hospital mortality rate 1.The PURSUIT Trial Investigators. N Engl J Med 1998 2.The PRISM-PLUS Study Investigators. N Engl J Med 1998 3. The Synergy Study JAMA 2004 CRUSADE cumulative data through 12/31/2006 1.The PURSUIT Trial Investigators. N Engl J Med 1998 2.The PRISM-PLUS Study Investigators. N Engl J Med 1998 3. The Synergy Study JAMA 2004 CRUSADE cumulative data through 12/31/2006

19. CRUSADE Lessons Learned n Complex patient population n Variations in use of medications n Disparities in use of invasive procedures n Rapid changes in revascularization procedures n Transfusions and bleeding are common n Importance of proper medication dosing n Comprehensive guidelines adherence saves lives n Academic output critical to success

20. Acute Medications by Risk of Mortality - UA/NSTEMI Patients from CRUSADE Medication Use (%) CRUSADE DATA: Q1 2006 – Q4 2006 (n=29,825)

21. Variations in Hospital Medication Utilization - UA/NSTEMI - 430 CRUSADE hospitals Acute Discharge Peterson et al, JAMA 2006;295:1863-1912

22. CRUSADE Lessons Learned n Complex patient population n Variations in use of medications n Disparities in use of invasive procedures n Rapid changes in revascularization procedures n Transfusions and bleeding are common n Importance of proper medication dosing n Comprehensive guidelines adherence saves lives n Academic output critical to success

23. ACTION/CRUSADE: April, 2006 – May, 2007 CRUSADE  ACTION – NSTEMI Patients Invasive Procedures in Cath-Eligible Population* * Excludes ~25% of patients with cath contraindications

24. Reason for No Cath Contraindication Among 9,884 High-Risk ACS Patients Reason % of Pts AgeMedian Renal Failure Mortality In- Hospital Pts refusal 18%8226%4.2% DNR16%8529%24.6% Advanced Age 11%9022%5.1% Active Bleeding 4%7730%10.4% Not Revasc Pt 17%7835%6.2% Co-morbidities20%7742%15.5% Other14%7021%5.7%

25. Early Cath (<48h) Use by Risk Status 26.6 32.2 53.5 63.2 64.1 75.5  18%  21% - Tricoci et al AHA 2005

26. Procedure Use as a Function of Age - Alexander, JACC 2005

27. Rates of Cardiac Catheterization According to Predictive Risk of Severe CAD (L-Main or 3 Vessel) in ACS Patients n = 97,004 - Cohen, et al AHA 2005

28. Risk – Treatment Paradox Cath, p=0.0002; PCI, p=0.03; CABG, p=0.01 24.6 53.6 38.0 5.4 16.0 5.8 GRACE Risk Score (Deciles)

29. Discharge Medication Use by Invasive Care – UA/NSTEMI Patients from CRUSADE Percentage Use Bhatt DL, JAMA 2004;292:2096-104.

30. CRUSADE Lessons Learned n Complex patient population n Variations in use of medications n Disparities in use of invasive procedures n Rapid changes in revascularization procedures n Transfusions and bleeding are common n Importance of proper medication dosing n Comprehensive guidelines adherence saves lives n Academic output critical to success

31. Independent Predictors of Early Cath Adjusted Odds Ratio 1 1 0.5 1.5 2 2 Cardiology Care Age (per 10 yrs) Prior CHF Renal Insufficiency Signs of CHF Caucasian Race Female Sex Bhatt et al, JAMA 2004

32. A Reduction in the Use of Medical Strategy Alone in ACS Patients After Introduction of DES - Gogo et al, ACC 2006

33. More PCI for 3-Vessel CAD After Introduction of DES - Gogo et al, ACC 2006

34. Trends for DES Use for UA/NSTEMI – CRUSADE to ACTION: July 2006 - March 2007

35. The Use of Medical Therapy Alone in Patients With 3-Vessel CAD Has Been Constant Over Time - Gogo et al, ACC 2006

36. CRUSADE Lessons Learned n Complex patient population n Variations in use of medications n Disparities in use of invasive procedures n Rapid changes in revascularization procedures n Transfusions and bleeding are common n Importance of proper medication dosing n Comprehensive guidelines adherence saves lives n Academic output critical to success

37. Use of Blood Transfusions in CRUSADE Use of Blood Transfusions in CRUSADE Yang X, JACC 2005;46:1490-5.

38. Major Bleeding Events: CRUSADE to ACTION Major Bleeding (%) CRUSADE Q2 2006 – ACTION Q1 2007

39. CRUSADE Lessons Learned n Complex patient population n Variations in use of medications n Disparities in use of invasive procedures n Rapid changes in revascularization procedures n Transfusions and bleeding are common n Importance of proper medication dosing n Comprehensive guidelines adherence saves lives n Academic output critical to success

40. Excessive Dosing of Anticoagulants by Age -- Alexander JAMA 2005;294:3108-3116 42% of patients got excess

41. Dosing Combinations and Transfusions: Heparin + GP IIb-IIIa Inhibitors* * Among patients receiving both Heparin (UFH or LMWH) and GP IIb-IIIa Inhibitors -- Alexander JAMA 2005;294:3108-3116

42. CRUSADE RBC Transfusions by Excess Dosing RBC Transfusion (%) Alexander KA, JAMA 2005;294:3108-16.

43. Impact of Overdosing Reporting in CRUSADE Overdosing (%)

44. CRUSADE Lessons Learned n Complex patient population n Variations in use of medications n Disparities in use of invasive procedures n Rapid changes in revascularization procedures n Transfusions and bleeding are common n Importance of proper medication dosing n Comprehensive guidelines adherence saves lives n Academic output critical to success

45. CRUSADE Composite Adherence Trends Quarter 1, 2002 – Quarter 4, 2006 Acute 82% Discharge 86% Acute 73% Discharge 73%

46. Link Between Overall ACC/AHA Guidelines Adherence and Mortality Peterson et al, ACC 2004 Every 10%  in guidelines adherence  11%  in mortality

47. Change in Mortality by Hospital Performance Improvement Peterson et al, AHA 2004

48. Hospital Mortality According to How Consistently Hospitals Follow Trial Evidence Quartiles of Hospital Composite of Medication Core Measures Granger Am J Med. 2005;118:858-65

49. In-Hospital Mortality by Age and Guidelines Adherence: Observations from CRUSADE - Boden et al, AHA 2005 Adj. OR: 0.71 (0.67-0.75)0.79 (0.75-0.83) Age Group

50. The Oldest Old (>90 years) with ACS: Observations From CRUSADE CQI CRUSADE Population N: 142,335 CRUSADE Population N: 142,335 The Elderly (age >75) N: 46,270 – 33% The Elderly (age >75) N: 46,270 – 33% Oldest Old (age >90) N: 5,557 – 4% Oldest Old (age >90) N: 5,557 – 4% Death MI Bleeding 7.8% 3.5% 13.1% 12.0% 3.0% 9.9% Death MI Bleeding 7.8% 3.5% 13.1% 12.0% 3.0% 9.9% - Skolnick et al, ACC 2006

51. Therapeutics in ACS Among Patients >90 Years Old Mortality Major Bleeding Even among oldest old – better outcomes with better adherence to ACC/AHA Guidelines Optimal - Skolnick et al, ACC 2006

52. Proportion of Patients Receiving 100% of All Guidelines- Recommended Therapies * *In patients without contraindications Mehta et al, AHA 2005

53. CRUSADE Lessons Learned: Conclusions n Disparities in use of invasive procedures l The highest risk patients frequently do not undergo an invasive management in ACS n Rapid changes in revascularization procedures l Substantial changes in DES and CABG use during the last year highlights physician uncertainty on safety n Transfusions and bleeding are common n Importance of proper medication dosing l Appropriate dosing of therapies need to be emphasized before and after interventions

54. “Humanity’s greatest advances are not in its discoveries – but in how those discoveries are applied...” Bill Gates, June 7, 2007 Harvard Commencement Address Bill Gates – only Harvard College drop-out who has received an honorary degree at Harvard !

55. STEMI NSTEMI Variable (n = 8,524) (n = 26,902) STEMI NSTEMI Variable (n = 8,524) (n = 26,902) Mean age ± SD (yrs) 62 ± 12 69 ± 14 Female sex 31% 40% Diabetes mellitus 22% 33% Prior MI 18% 29% Prior CHF 5% 16% Prior PCI 17% 23% Prior CABG 7% 19% ACTION/CRUSADE DATA: April 1, 2006 – May 31, 2007 CRUSADE  ACTION – STEMI vs. NSTEMI Baseline Characteristics

56. ST , LBBB  12h Sx non ST  ACS, mod–high risk pain-free, low–mod risk, neg or nonspecific ECG neg. CK-MB, TnT/I Chest Pain Unit Symptoms of Acute Ischemia ASA 325mg initial dose; 160mg qD  12h Sx Reperfusion Rx NSSTT  s, neg. cardiac markers Dynamic ST  s, pos. cardiac markers Antithrombotic Rx Fonda or Enoxaparin UFH cath in 12h no cath in 12h Anticoagulant Rx Eptifibatide or tirofiban Clopidogrel (Reasonable certainty patient will not have early CABG) ACS Algorithm Clopidogrel (if withheld, give at time of cath or after CABG) Cath <24 hrs Cath >24 hrs No or delayed cath Or bivalirudin* Fondaparinux or enoxaparin UFH Clopidogrel + + *cath <12 h or renal insuff. Enroll in Trials

57. Other Factors in Choosing Which Anticoagulant ConditionUFHLMWHFondaBival Severe renal insuff.cautionavoidavoid? best  bleeding riskneutralavoidyesyes Thrombocytopeniaworstbetterbetterbest Early cath strategyyesavoidavoidyes ConditionUFHLMWHFondaBival Severe renal insuff.cautionavoidavoid? best  bleeding riskneutralavoidyesyes Thrombocytopeniaworstbetterbetterbest Early cath strategyyesavoidavoidyes Continue anticoagulant until (effective) revascularization or day 7/hospital discharge, whichever comes first

58. n Overdosing heparins and GP IIb/IIIa 1 42% n Off clopidogrel at 30d s/p MI w/ DES 2 14% n Hold clopidogrel for 5d pre CABG 3 13% n Consistent use of ASA, BB, statin w CHD 4 21% n Overdosing heparins and GP IIb/IIIa 1 42% n Off clopidogrel at 30d s/p MI w/ DES 2 14% n Hold clopidogrel for 5d pre CABG 3 13% n Consistent use of ASA, BB, statin w CHD 4 21% The Gap Between Evidence (trials) and Practice (application): 1. CRUSADE, Alexander KA, JAMA 2005 2. PREMIER, Spertus JA, Circ 2006 3. CRUSADE, Mehta RH, JACC 2006 4. Duke Databank, Newby LK, Circ 2006 1. CRUSADE, Alexander KA, JAMA 2005 2. PREMIER, Spertus JA, Circ 2006 3. CRUSADE, Mehta RH, JACC 2006 4. Duke Databank, Newby LK, Circ 2006

59. Hospital Outcomes According to Degree or Renal Dysfunction *p < 0.05 across all categories of renal function within NSTEMI/UA subgroup **p < 0.0001 across all categories of renal function within NSTEMI/UA subgroup *p < 0.05 across all categories of renal function within NSTEMI/UA subgroup **p < 0.0001 across all categories of renal function within NSTEMI/UA subgroup