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

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

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

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

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

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: *Primary and secondary diagnoses. †About 0.57 million NSTEMI and 0.67 million UA.

ACC/AHA AMI R. Gunnar 1994 AHCPR/NHLBI UA E. Braunwald Rev Upd ACC/AHA AMI T. Ryan Rev Upd ACC/AHA STEMI E. Antman Rev Upd Rev ACC/AHA UA/NSTEMI E. Braunwald J. Anderson 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

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

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.

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 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.

Data Submission in CRUSADE n Data collection: Nov, 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

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

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

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

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

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

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 (%) Diabetes mellitus (%) Prior MI (%) Prior CHF (%) Prior PCI (%)1318*2021 Prior CABG (%)1218*1719 ST depression (%) NEJM 1998;339: NEJM 2001;345: JAMA 2004:292:45-54 CRUSADE cumulative through December 31, 2006 NEJM 1998;339: NEJM 2001;345: JAMA 2004:292:45-54 CRUSADE cumulative through December 31, 2006

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 The PRISM-PLUS Study Investigators. N Engl J Med The Synergy Study JAMA 2004 CRUSADE cumulative data through 12/31/ The PURSUIT Trial Investigators. N Engl J Med The PRISM-PLUS Study Investigators. N Engl J Med The Synergy Study JAMA 2004 CRUSADE cumulative data through 12/31/2006

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

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

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

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

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

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%

Early Cath (<48h) Use by Risk Status  18%  21% - Tricoci et al AHA 2005

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

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

Risk – Treatment Paradox Cath, p=0.0002; PCI, p=0.03; CABG, p= GRACE Risk Score (Deciles)

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

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

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

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

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

Trends for DES Use for UA/NSTEMI – CRUSADE to ACTION: July March 2007

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

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

Use of Blood Transfusions in CRUSADE Use of Blood Transfusions in CRUSADE Yang X, JACC 2005;46:

Major Bleeding Events: CRUSADE to ACTION Major Bleeding (%) CRUSADE Q – ACTION Q1 2007

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

Excessive Dosing of Anticoagulants by Age -- Alexander JAMA 2005;294: % of patients got excess

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:

CRUSADE RBC Transfusions by Excess Dosing RBC Transfusion (%) Alexander KA, JAMA 2005;294:

Impact of Overdosing Reporting in CRUSADE Overdosing (%)

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

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

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

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

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

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

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

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

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

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

“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 !

STEMI NSTEMI Variable (n = 8,524) (n = 26,902) STEMI NSTEMI Variable (n = 8,524) (n = 26,902) Mean age ± SD (yrs) 62 ± ± 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

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

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

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 PREMIER, Spertus JA, Circ CRUSADE, Mehta RH, JACC Duke Databank, Newby LK, Circ CRUSADE, Alexander KA, JAMA PREMIER, Spertus JA, Circ CRUSADE, Mehta RH, JACC Duke Databank, Newby LK, Circ 2006

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