After taking part in this activity, participants should be able to:

After taking part in this activity, participants should be able to:
Learning Objectives After taking part in this activity, participants should be able to: Apply the current ACC/AHA guidelines for management of STEMI and UA/NSTEMI patients to the development of critical pathways for ACS Develop or modify tools for effectively implementing critical pathways for ACS in the hospital Interpret the findings of recent clinical trials in ACS and assess their applicability to the development of up-to-date critical pathways for ACS

Learning Objectives (cont.)
After taking part in this activity, participants should be able to: Outline the results from national quality improvement initiatives showing that critical pathways work to enhance patient outcomes Work with hospital critical pathways teams to overcome barriers to developing, improving, and implementing critical pathways for ACS

Pathophysiology and Epidemiology of Acute Coronary Syndromes

Atherothrombosis: A Progressive Phenomenon
C S Unstable angina Atherosclerosis Thrombosis MI Ischemic stroke/TIA Acute limb ischemia Cardiovascular death Adapted from Libby P. Circulation. 2001;104: Libby P. Sci Am. 2002;286:46-55.

ACUTE CORONARY SYNDROMES
Spectrum of CAD/ACS No ST elevation ST elevation Stable angina Unstable angina NSTEMI STEMI ACUTE CORONARY SYNDROMES CAD = coronary artery disease; NSTEMI = non-ST-segment elevation myocardial infarction; STEMI = ST-segment elevation myocardial infarction. Source (Photos): Davies MJ. Heart. 2000;83: Cannon CP. Optimizing the treatment of unstable angina. J Thromb Thrombolysis. 1995;2: Photos courtesy of Davies MJ. The pathophysiology of acute coronary syndromes. Heart. 2000;83:

Epidemiology of CAD/ACS
1.56 Million Hospital Discharges for ACS UA/NSTEMI ~1.23 Million Discharges Per Year ~0.33 Million Discharges Per Year STEMI CAD = coronary artery disease; ACS = acute coronary syndrome; UA = unstable angina; MI = myocardial infarction; NSTEMI = non–ST-segment elevation MI; STEMI = ST-segment elevation MI. American Heart Association. Heart Disease and Stroke Statistics—2006 Update. Circulation. 2006; e85-e151. Estimates for STEMI and NSTEMI proportions of MI extrapolated from statistics in Wiviott S, et al. J Am Coll Cardiol. 2006;47; American Heart Association. Heart Disease and Stroke Statistics—2006 Update. Circulation. 2006; e85-e151. Wiviott SD, Morrow DA, Frederick PD, et al. Application of the thrombolysis in myocardial infarction risk index in non-ST-segment elevation myocardial infarction. J Am Coll Cardiol. 2006;47:

Evidence of Multiple “Vulnerable” Plaques in ACS
Angiographic and angioscopic images of a 58-year-old man with anterior myocardial infarction Multiple “vulnerable” plaques detected in nonculprit segments 1-7 Culprit lesion with thrombus (red) detected in #8 Multiple “vulnerable” plaques detected in nonculprit segments 9-12 Reprinted with permission from Asakura M, et al. J Am Coll Cardiol. 2001;37: Asakura M, Ueda Y, Yamaguchi O, et al. Extensive development of vulnerable plaques as a pan-coronary process in patients with myocardial infarction: an angioscopic study. J Am Coll Cardiol. 2001;37:

Overlap of Atherosclerotic Disease
Coronary Artery Disease Cerebrovascular Disease Peripheral Arterial Disease 38% overlap in 2 vascular beds Patients with 1 manifestation often have coexistent disease in other vascular beds Ness J, Aronow WS. J Am Geriatr Soc. 1999;47: Ness J, Aronow WS. Prevalence of coexistence of coronary artery disease, ischemic stroke, and peripheral arterial disease in older persons, mean age 80 years, in an academic hospital-based geriatrics practice. J Am Geriatr Soc. 1999;47:

The REACH Registry The REACH (REduction of Atherothrombosis for Continued Health) Registry has recruited outpatients who have had, or are at high risk of having, symptoms of atherothrombosis The Registry aims to study a contemporary stable patient population from various regions of the world in order to: Describe the characteristics and management of these patients and of each subgroup Assess the long-term risk of atherothrombotic events in the global population and in each subgroup Assess the amount of “cross-risk” across subgroups Compare outcomes within different subject profiles Define predictors of risk for subsequent atherothrombotic events Follow-up planned at 12 and 21 months, extended to 3 and 4 years Steg PG. Presented at: 55th Annual Scientific Session of the American College of Cardiology; March 12, 2006; Atlanta, Ga. Steg PG. Presented at: 55th Annual Scientific Session of the American College of Cardiology; March 12, 2006; Atlanta, GA.

Baseline Prevalence of Polyvascular Disease in the REACH Registry
Single Arterial Bed % Overall 65.9 CAD Alone 44.6 CVD Alone 16.6 PAD Alone 4.7 Polyvascular Disease Overall 15.9 CAD + CVD 8.4 CAD + PAD 4.7 CVD + PAD 1.2 CAD + CVD + PAD 1.6 Multiple Risk Factors 18.3 Bhatt DL, et al; for the REACH Registry Investigators. JAMA. 2006;295: Bhatt DL, Steg PG, Ohman EM, et al; for the REACH Registry Investigators. International Prevalence, Recognition, and Treatment of Cardiovascular Risk Factors in Outpatients With Atherothrombosis. JAMA. 2006;295:

REACH 1-Year Results: Single vs Multiple and Overlapping Atherothrombotic Locations: The Example of CAD % 1.5 1.4 0.9 3.1 13.3 2 1.6 3.7 6.4 20 2.9 1.3 4.8 23.3 3.6 1.8 4 7.4 26.9 5 10 15 25 30 CV Death Nonfatal MI Nonfatal Stroke Death/MI/ Stroke Death/MI/ Stroke/Hosp* CAD alone CAD+CVD CAD+PAD CAD+CVD+PAD Rates adjusted for age and risk factors. *TIA, unstable angina, other ischemic arterial event including worsening of PAD. Steg PG. Presented at: 55th Annual Scientific Session of the American College of Cardiology; March 12, 2006; Atlanta, Ga. Steg PG. Presented at: 55th Annual Scientific Session of the American College of Cardiology; March 12, 2006; Atlanta, GA.

ACS Treatment Strategies
Reperfusion/Revascularization Therapy Medical therapy Thrombolysis CABG PCI (with/ without stenting) Antithrombotic Cotherapy ASA UFH LMWH Penta DTI GP IIb/ IIIa ADP antagonist Acute and Long-term Medical Therapy Nitrates BBs ACEIs ARBs CCBs Statins APT PCI = percutaneous coronary intervention; CABG = coronary artery bypass grafting; ASA = aspirin; UFH = unfractionated heparin; LMWH = low-molecular-weight heparin; Penta = pentasaccharide; DTI = direct thrombin inhibitors; GP IIb/IIIa = glycoprotein IIb/IIIa inhibitors; ADP antagonist = adenosine diphosphate antagonist; BBs = beta blockers; ACEI = angiotensin converting enzyme inhibitors; ARBs = angiotensin receptor blockers; CCBs = calcium channel blockers; APT = antiplatelet therapy.

ST-Segment Elevation Myocardial Infarction (STEMI) in the Emergency Department

STEMI: Prehospital Issues
EMS Early defibrillation Use of automated external defibrillators (AEDs) 9-1-1 dispatcher training National protocols Chest pain evaluation and treatment Chewable ASA unless contraindicated Prehospital ECG Reperfusion checklist Prehospital fibrinolysis Upgraded to Class IIa (Level B) recommendation Antman EM, et al. J Am Coll Cardiol. 2004;44: Antman EM, Anbe DT, Armstrong PW, et al, American College of Cardiology, American Heart Association, Canadian Cardiovascular Society. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction—executive summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to revise the 1999 guidelines for the management of patients with acute myocardial infarction). J Am Coll Cardiol. 2004;44:

Options for Transport of Patients With STEMI and Initial Reperfusion Treatment
Hospital fibrinolysis: door-to-needle within 30 min Not PCI capable Call 9-1-1 Call fast EMS on-scene Encourage 12-lead ECGs Consider prehospital fibrinolytic if capable and EMS-to-needle within 30 min Onset of symptoms of STEMI 9-1-1 EMS dispatch EMS triage plan Inter-hospital transfer PCI capable GOALS 5 min 8 min EMS Transport Patient EMS Prehospital fibrinolysis EMS-to-needle within 30 min EMS transport EMS-to-balloon within 90 min Patient self-transport Hospital door-to-balloon within 90 min Dispatch 1 min Golden hr = 1st 60 min Total ischemic time: within 120 min Adapted with permission from Antman EM, et al. Available at: Accessed September 1, 2006 Antman EM, Anbe DT, Armstrong PW, et al, American College of Cardiology, American Heart Association, Canadian Cardiovascular Society. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction—executive summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to revise the 1999 guidelines for the management of patients with acute myocardial infarction). J Am Coll Cardiol. 2004;44:

Data=Median Times (Q1-Q3)
ER-TIMI 19: Time Saved to First r-PA Bolus with Prehospital Administration Data=Median Times (Q1-Q3) Ambulance arrival ED arrival Inhospital lytic 63 min (48–89) Control P<.0001* 31 min (24–37) 32 min saved Prehosp First r-PA bolus *Adjusted for any effect of site and interaction. Adapted with permission from Morrow DA, et al. J Am Coll Cardiol. 2002;40:71-77. Morrow DA, Antman EM, Sayah A, et al. Evaluation of the time saved by prehospital initiation of reteplase for ST-elevation myocardial infarction. Results of the Early Retevase-Thrombolysis In Myocardial Infarction (ER-TIMI) 19 trial. J Am Coll Cardiol. 2002;40:71-77.

STEMI: Brief Physical Exam in ED
Airway, breathing, circulation (ABC) Vital signs, general observation Presence or absence of Jugular venous distention Stroke Pulses Systemic hypoperfusion (cool, clammy, pale/ashen) Pulmonary auscultation for rales Cardiac auscultation for murmurs or gallops Antman EM, et al. Available at: Accessed September 1, 2006. Antman EM, Anbe DT, Armstrong PW, et al, American College of Cardiology, American Heart Association, Canadian Cardiovascular Society. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction—executive summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to revise the 1999 guidelines for the management of patients with acute myocardial infarction). J Am Coll Cardiol. 2004;44:

ACC/AHA 2004 STEMI Guidelines: Acute Medical Therapy
General treatment measures Analgesics Nitrates Oxygen β-blockers (Note: not for acute use in patients with evidence of heart failure) Primary PCI or coronary thrombolysis (primary PCI preferred after 3 hr) ASA (162–325 mg, acute dose) Heparin If PCI – Clopidogrel – GP IIb/IIIa inhibitors Infarct size limitation Reperfusion Antithrombotic and antiplatelet therapy Antman EM, et al. Available at: Accessed September 1, 2006. Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1999 Guidelines on the Management of Patients With Acute Myocardial Infarction). J Am Coll Cardiol Available at: Accessed May 15, 2006. .

Primary PCI vs Thrombolysis in STEMI: Quantitative Analysis (23 RCTs, N=7739)
25 Short-term outcomes (4-6 wk) P<.0001 20 P<.0001 15 P=.0002 P<.0001 Frequency (%) PCI P=.032 10 Thrombolytic therapy 5 P<.0001 Death Nonfatal MI Recurrent Ischemia Hemor- rhagic Stroke Major Bleed Death, Nonfatal Reinfarction, or Stroke Adapted with permission from Keeley EC, et al. Lancet. 2003;361:13-20. Keeley EC, Boura JA, Grines CL. Primary angioplasty versus intravenous thrombolytic therapy for acute myocardial infarction: a quantitative review of 23 randomised trials. Lancet. 2003;361:13-20.

Mortality With 1° PCI vs Time Delay
15 Circle sizes = sample size of individual study Solid line = weighted meta-regression 10 P=.006 Absolute Risk Difference in Death (%) 5 62 min Favors PCI Favors lysis -5 20 40 60 80 100 PCI-related Time Delay (Door-to-Balloon minus Door-to-Needle) For every 10-min delay to PCI: 1% reduction in mortality difference vs lytics. Nallamothu BK, Bates ER. Am J Cardiol. 2003;92: Antman EM, Anbe DT, Armstrong PW, et al, American College of Cardiology, American Heart Association, Canadian Cardiovascular Society. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction—executive summary. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to revise the 1999 guidelines for the management of patients with acute myocardial infarction). J Am Coll Cardiol. 2004;44: Nallamothu BK, Bates ER. Percutaneous coronary intervention versus fibrinolytic therapy in acute myocardial infarction: is timing (almost) everything? Am J Cardiol. 2003;92:

Clinical Trials of Interhospital Transfer for PCI vs Fibrinolysis
20 On-site fibrinolysis Transfer for PCI 15 14 12.1 10 Mortality (%) 10 8.4 8.5 7 6.7 6.7 6.8 6.5 5 LIMI1 PRAGUE-12 AIR-PAMI3 PRAGUE-24 DANAMI5 (N=150) (N=200) (N=137) (N=850) (N=1129) 1. Vermeer F, et al. Heart ;82: 2. Widimsky P, et al. Eur Heart J. 2000;21: 3. Grines CL, et al. J Am Coll Cardiol. 2002;39: 4. Widimsky P, et al. Eur Heart J. 2003;24: 5. Andersen HR, et al. N Engl J Med. 2003;349: Vermeer F, Oude Ophuis AJM, vd Berg EJ, et al. Prospective randomised comparison between thrombolysis, rescue PTCA, and primary PTCA in patients with extensive myocardial infarction admitted to a hospital without PTCA facilities: a safety and feasibility study. Heart.1999;82: Widimsky P, Groch L, Zelizko M, et al. Multicentre randomized trial comparing transport to primary angioplasty vs immediate thrombolysis vs combined strategy for patients with acute myocardial infarction presenting to a community hospital without a catheterization laboratory. The PRAGUE Study. Eur Heart J. 2000;21: Grines CL. Westerhausen DR Jr, Grines LL, et al. A randomized trial of transfer for primary angioplasty versus on-site thrombolysis in patients with high-risk myocardial infarction. The Air Primary Angioplasty in Myocardial Infarction Study. J Am Coll Cardiol. 2002;39: Widimsky P, Budesinsky T, Vorac D, et al. Long distance transport for primary angioplasty vs immediate thrombolysis in acute myocardial infarction. Final results of the randomized national multicentre trial – PRAGUE-2. Eur Heart J. 2003;24: Andersen HR, Nielsen TT, Rasmussen K, et al. A comparison of coronary angioplasty with fibrinolytic therapy in acute myocardial infarction. N Engl J Med. 2003;349:

STEMI: Transfer for PCI NRMI (1999-2002) 4278 Patients
Door-to-Balloon Time % of Patients <90 min 4.2 <2 h 16.2 2–4 h 55.4 >4 h 28.4 Nallamothu BK, et al. Circulation. 2005;111: Nallamothu BK, Bates ER, Herrin J, et al. Times to treatment in transfer patients undergoing primary percutaneous coronary intervention in the United States. National Registry of Myocardial Infarction (NRMI)-3/4 Analysis. Circulation. 2005;111:

Facilitated PCI, Rescue PCI, and Adjunctive Therapy for STEMI

Facilitated PCI and Rescue PCI: Definition of Terms
Fibrinolytics or other pharmacologic agents to “facilitate” immediate percutaneous coronary intervention Rescue PCI Percutaneous coronary intervention for failed fibrinolysis Dauerman HL, Sobel BE. J Am Coll Cardiol. 2003;42: Antman EM, et al. Available at: Dauerman HL, Sobel BE. Synergistic treatment of ST-segment elevation myocardial infarction with pharmacoinvasive recanalization. J Am Coll Cardiol. 2003;42: Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction: a report of the ACC/AHA Task Force on Practice Guidelines (Committee to Revise the 1999 Guidelines on the Management of Patients With Acute Myocardial Infarction). J Am Coll Cardiol Available at: Accessed November 1, 2005.

Meta-analysis of 17 Facilitated PCI Trials*
Event Facilitated PCI (%) PCI (%) P Death 5.0 3.0 .04 Reinfarction 2.0 .006 Urgent TVR 4.0 1.0 .010 Major bleeding 7.0 Stroke 1.1 0.3 .0008 *Includes 9 GP IIb/IIIa inhibitor trials (N=1148); 6 thrombolytic therapy trials (N=2957); 2 combination therapy trials (N=399). Keeley EC. Lancet. 2006;367: Keeley EC, Boura JA, Grines CL. Comparison of primary and facilitated percutaneous coronary interventions for ST-elevation myocardial infarction: quantitative review of randomised trials. Lancet ;367:

427 STEMI patients with failed thrombolysis Conservative Treatment
Rescue Angioplasty Versus Conservative Treatment or Repeat Thrombolysis (REACT) Trial 427 STEMI patients with failed thrombolysis ASA and thrombolytic therapy (60% rec’d streptokinase) within 6 h of chest pain onset, <50% ST-segment resolution within 90 minutes Repeated thrombolysis with alteplase or reteplase (n=142) Rescue PCI Angiography with or without revascularization (n=144) Conservative Treatment Including IV UFH for 24 h (n=141) Primary End Point Composite of death, reinfarction, stroke, or severe heart failure within 6 months Gershlick AH, et al. N Engl J Med. 2005;353: Gershlick AH, Stephens-Lloyd A, Hughes S, et al. Rescue angioplasty after failed thrombolytic therapy for acute myocardial infarction. N Engl J Med. 2005;353:

RESCUE PCI: REACT Trial — Primary End Point
Primary End Point = death, recurrent MI, severe heart failure, or cerebrovascular event within 6 months 1.00 0.90 0.80 0.70 0.60 0.00 Rescue PCI 84.6% 95% Cl, Conservative therapy 70.1% 95% Cl, Probability of Event-free Survival Repeated thrombolysis 68.7 95% Cl, P=.004 20 40 60 80 100 120 140 160 180 200 Days After Randomization REACT = Rescue Angioplasty versus Conservative Treatment or Repeat Thrombolysis. Adapted with permission from Gershlick AH, et al. N Engl J Med. 2005; 353: Gershlick AH, Stephens-Lloyd A, Hughes S, et al. Rescue angioplasty after failed thrombolytic therapy for acute myocardial infarction. N Engl J Med. 2005;353:

ExTRACT-TIMI 25: Protocol Design
STEMI < 6 h Lytic eligible Lytic choice by MD (TNK, tPA, rPA, SK) ASA Double-blind, double-dummy ENOXAPARIN (N=10,256) < 75 y: 30 mg IV bolus SC 1.0 mg / kg q 12 h (Hosp DC) ≥ 75 y: No bolus SC 0.75 mg / kg q 12 h (Hosp DC) CrCl < 30: 1.0 mg / kg q 24 h UFH (N = 10,223) 60 U / kg bolus (4000 U) Inf 12 U / kg / h (1000 U / h) Duration: at least 48 h Cont’d at MD discretion Day 30 1° Efficacy End Point: Death or Nonfatal MI 1° Safety End Point: TIMI Major Hemorrhage ExTRACT = Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Antman EM et al. N Engl J Med. 2006;354: Adapted with permission from Antman EM, Morrow DA, McCabe CH, Murphy SA, Ruda M, Sadowski Z, Budaj A, Lopez-Sendon JL, Guneri S, Jiang F, White HD, Fox KA, Braunwald E, for the ExTRACT-TIMI 25 Investigators. Enoxaparin versus unfractionated heparin with fibrinolysis for ST-elevation myocardial infarction. N Engl J Med. 2006;354:

Main Results From ExTRACT-TIMI 25
Primary End point: Death or nonfatal re-MI by 30 days Main Secondary Endpoint: Death, non-fatal re-MI, urgent revascularization by 30 days UFH 15 UFH 12.0 14.5 5 10 15 20 25 30 12 9 6 3 9.9 12 11.7 ENOX ENOX 9 RR = 0.83 p = % RR = 0.81 p = 6 % 3 5 10 15 20 25 30 Days Days Major bleeding: 1.4% with UFH vs 2.1% with enoxaparin (P<.001) ICH: .7% for UFH vs .8% for enoxaparin (P=.14) Adapted with permission from Adapted with permission from Antman EM, et al. N Engl J Med. 2006;354:

ExTRACT-TIMI 25: Net Clinical Benefit at 30 Days
Prespecified Definitions UFH (%) Enox (%) RRR (%) Death or Nonfatal MI or Nonfatal Disabling Stroke 12.3 10.1 18 P<.001 Death or Nonfatal MI or Nonfatal Major Bleed 12.8 11.0 14 P<.001 Death or Nonfatal MI or Nonfatal ICH 12.2 10.1 17 P<.001 0.8 0.9 1 1.25 Enoxaparin Better RR UFH Better Adapted with permission from Antman EM, et al. N Engl J Med. 2006;354: Antman EM, Morrow DA, McCabe CH, Murphy SA, Ruda M, Sadowski Z, Budaj A, Lopez-Sendon JL, Guneri S, Jiang F, White HD, Fox KA, Braunwald E, for the ExTRACT-TIMI 25 Investigators. Enoxaparin versus unfractionated heparin with fibrinolysis for ST-elevation myocardial infarction. N Engl J Med. 2006;354:

ExTRACT-TIMI 25 PCI Cohort: Primary End point Death or Nonfatal MI by 30 days
15 UFH 13.8% ENOX 10.7% 10 RR 0.77 P=0.001 Death or MI (%) 5 5 10 15 20 25 30 Days Gibson M. Presented at World Congress of Cardiology; September 4, 2006; Barcelona, Spain. Adapted with permission from

ExTRACT-TIMI 25 PCI Cohort: Safety
Event ENOX UFH RR P-Value n=2, n=2,377 TIMI Major Bleed 1.4% 1.6% 0.87 ( ) .56 TIMI Minor Bleed 3.3% 2.4% 1.34 ( ) .09 TIMI Major or 4.6% 4.0% 1.15 ( ) .31 Minor Bleed ICH 0.2% 0.4% 0.42 ( ) .18 Stroke 0.3% 0.9% 0.30 ( ) .006 Gibson M. Presented at World Congress of Cardiology; September 4, 2006; Barcelona, Spain. Adapted with permission from

OASIS-6 Trial: Study Design
12,092 patients presenting with STEMI within 24 hours of symptom onset (shortened to 12 hours of symptom onset midway through trial) Randomized, Blinded, Factorial 28% female; mean age, 62 years; mean follow-up, 3-6 months Stratum 1 (No UFH) n=5,658 Stratum 2 (UFH) n=6,434 Fondaparinux n=2,823 2.5 mg/day for up to 8 days or hospital discharge Placebo n=2,835 Fondaparinux n=3,213 2.5 mg/day for up to 8 days or hospital discharge UFH n=3,221 Primary end point: Composite of death or reinfarction at 30 days Secondary end point: Composite of death or reinfarction at 9 days and at final follow-up Yusuf S, et al. JAMA. 2006;295: Adapted with permission from Yusuf S, Mehta SR, Chrolavicius S, et al. for the OASIS-6 Trial Group. Effects of fondaparinux on mortality and reinfarction in patients with acute ST-segment elevation myocardial infarction: the OASIS-6 randomized trial. JAMA. 2006;295:

OASIS-6 Trial: Results Reduction in Death/MI at 30 days: Stratum 1 (No UFH indicated) P<.05 14 14% Primary End Point: Death/Reinfarction (%) 12% 11.2 10% 14.8 15% 8% 13.4 6% 12% 11.2 9.7 4% 8.9 9% 2% 7.4 Frequency 0% 6% Fondaparinux Placebo Reduction in Death/MI: Stratum 2 (UFH Indicated) P=NS 3% 14% P=.008 P=.003 P=.008 12% 0% 10% 8.3 8.7 30 days 9 days 3-6 months 8% p=0.97 Fondaparinux (n=6036) Control (n=6056) 6% 4% 2% Yusuf S, et al. JAMA. 2006;295: Adapted with permission from 0% Fondaparinux UFH Yusuf S, Mehta SR, Chrolavicius S, et al. for the OASIS-6 Trial Group. Effects of fondaparinux on mortality and reinfarction in patients with acute ST-segment elevation myocardial infarction: the OASIS-6 randomized trial. JAMA. 2006;295:

CLARITY–TIMI 28: Study Design
Double-blind, randomized, placebo-controlled trial in 3491 patients, aged yrs, with STEMI <12 hours Fibrinolytic, ASA, Heparin Randomized Clopidogrel 300 mg + 75 mg qd Placebo Study Drug Primary end point: Occluded artery (TIMI flow grade 0/1) or death/MI by time of angio Coronary Angiogram (2-8 days) Open-label clopidogrel per MD in both groups 30-day clinical follow-up CLARITY-TIMI 28 = CLopidogrel as Adjunctive ReperfusIon TherapY – Thrombolysis In Myocardial Infarction. Sabatine MS, et al. N Engl J Med. 2005;352: Sabatine M. Presented at: 54th Annual Scientific Session of the American College of Cardiology; March 9, 2005; Orlando, Fla. Sabatine MS, Cannon CP, Gibson CM, Lopez-Sendon JL, Montalescot G, Theroux P, Claeys MJ, Cools F, Hill KA, Skene AM, McCabe CH, Braunwald E; CLARITY-TIMI 28 Investigators. Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation. N Engl J Med. 2005;352:

CLARITY–TIMI 28: End Points
Primary End Point Occluded Artery (or Death/MI Through Angio/HD) CV Death, MI, RI  Urg Revasc 5 10 15 20 25 36% Odds Reduction 21.7 15 Placebo 20% 15.0 10 Clopidogrel Occluded Artery or Death/MI (%) Endpoint (%) Odds Ratio: 0.80 (95% CI, ) P=.03 5 n=1752 n=1739 5 10 15 20 25 30 Clopidogrel Placebo Days Sabatine MS, et al. N Engl J Med. 2005;352: Sabatine MS, Cannon CP, Gibson CM, Lopez-Sendon JL, Montalescot G, Theroux P, Claeys MJ, Cools F, Hill KA, Skene AM, McCabe CH, Braunwald E; CLARITY-TIMI 28 Investigators. Addition of clopidogrel to aspirin and fibrinolytic therapy for myocardial infarction with ST-segment elevation. N Engl J Med. 2005;352:

COMMIT/CCS-2: Study Design Mean treatment and follow-up: 16 days
Treatment: Clopidogrel 75 mg daily vs placebo (aspirin 162 mg daily in both groups) Inclusion: Suspected acute MI (ST change or LBBB) within 24 h of symptom onset Exclusion: Primary PCI or high risk of bleeding 1 Outcomes: Death and death, re-MI, or stroke up to weeks in hospital (or prior discharge) Mean treatment and follow-up: 16 days COMMIT = ClOpidogrel & Metoprolol in Myocardial Infarction Trial. COMMIT Collaborative Group. Lancet. 2005;366: Chen ZM, Jiang LX, Chen YP, Xie JX, Pan HC, Peto R, Collins R, Liu LS; COMMIT (ClOpidogrel and Metoprolol in Myocardial Infarction Trial) collaborative group. Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet :

COMMIT: Effect of Clopidogrel on Death, Re-MI, or Stroke
Placebo + ASA: events (10.1%) Placebo + ASA: deaths (8.1%) 9 8 7 6 5 4 3 2 1 7 6 5 4 3 2 1 Clopidogrel + ASA: 2125 events (9.3%) Clopidogrel + ASA: 1728 deaths (7.5%) 9% (SE3) relative risk reduction (2P=.002) 7% (SE3) relative risk reduction (2P=.03) Event (%) Mortality (%) 7 14 21 28 7 14 21 28 Days Since Randomization (up to 28 days) Days Since Randomization (up to 28 days) COMMIT = ClOpidogrel & Metoprolol in Myocardial Infarction Trial. COMMIT Collaborative Group. Lancet. 2005;366: Chen ZM, Jiang LX, Chen YP, Xie JX, Pan HC, Peto R, Collins R, Liu LS; COMMIT (ClOpidogrel and Metoprolol in Myocardial Infarction Trial) collaborative group. Addition of clopidogrel to aspirin in 45,852 patients with acute myocardial infarction: randomised placebo-controlled trial. Lancet :

2004 ACC/AHA STEMI Guidelines Secondary Prevention Goals
Preventive Measure Goal Smoking → Complete cessation BP control → <140/90 mm Hg or <130/80 mm Hg if chronic kidney disease or diabetes Physical activity → Minimum: 30 min 3-4 days per week; optimal: daily Lipid management (TG <200 mg/dL) → Primary goal: LDL-C <<100 mg/dL Lipid management (TG >200 mg/dL) → Primary goal: Non–HDL-C <<130 mg/dL Weight management → Goal: BMI 18.5 to 24.9 kg/m2 Diabetes management → Goal: HbA1c <7% Antman EM, et al. J Am Coll Cardiol. 2004;44:E1-E211. Available at: Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction: a report of the ACC/AHA Task Force on Practice Guidelines (Committee to Revise the 1999 Guidelines on the Management of Patients With Acute Myocardial Infarction). J Am Coll Cardiol Available at: Accessed September 1, 2005.

Managing STEMI in 2006: Summary
Acute therapy focuses on reperfusion and antithrombotic therapy PCI generally preferred over fibrinolysis when a skilled PCI lab is available with surgical backup and door-to-balloon time is <90 min Fibrinolysis generally preferred when invasive strategy is not an option or when delay to PCI is anticipated (>90 min door-to-balloon) Current ACC/AHA STEMI guidelines recommend IV UFH as ancillary therapy to reperfusion therapy (Class I) ExTRACT-TIMI 25 showed enoxaparin superior to current standard of UFH as the antithrombin to support fibrinolysis Fondaparinux effective in STEMI without increasing risk of bleeding or stroke (OASIS-6), but some subsets did not benefit (patients heading for PCI; patients in whom UFH, not placebo, was the control) Clopidogrel on top of aspirin results in significant further improvements in the reperfusion of patients with STEMI (CLARITY/COMMIT)

Risk Stratification and Medical Management
Unstable Angina/ Non–ST-Segment Elevation Myocardial Infarction (UA/NSTEMI) Risk Stratification and Medical Management

ACC/AHA Class I Recommendations For Evaluation of Chest Pain
Patients with suspected ACS with chest discomfort at rest for >20 min, hemodynamic instability, or recent syncope or presyncope should be strongly considered for immediate referral to an ED or to a specialized chest pain unit Assess likelihood of CAD Assess risk of adverse events Adapted from Braunwald E, et al. Available at: Braunwald E, Antman E, Beasley JW, et al. ACC/AHA guideline update for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Unstable Angina) Available at: Accessed April 29, 2006.

Likelihood of ACS Secondary to CAD “CONFIDENCE OF DIAGNOSIS”
High Intermediate Low History Chest or left arm pain Chest or left arm Sx w/o intermediate Sx as in prior angina pain; age >70 yr likelihood character- Known history of CAD Male sex; DM istics; recent cocaine Exam Transient MR, Extracardiac Chest pain hypotension, vascular reproduced diaphoresis, disease by palpation pulmonary edema, or rales ECG New transient Fixed Q waves T-wave flattening or ST-segment deviation Abnormal ST-seg inversion in leads or T-wave inversion or T-waves not w/dominant R waves with symptoms documented as new Normal ECG Cardiac Elevated Normal Normal Markers Adapted from Braunwald E, et al. Available at: Braunwald E, Antman E, Beasley JW, et al. ACC/AHA guideline update for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Unstable Angina) Available at: Accessed April 29, 2006.

TIMI Risk Score for UA/NSTEMI: 7 Independent Predictors
Age ≥65 y ≥3 CAD risk factors (high cholesterol, family history, hypertension, diabetes, smoking) Prior coronary stenosis ≥50% Aspirin in last 7 days ≥2 anginal events ≤24 h ST-segment deviation Elevated cardiac markers (CK-MB or troponin) Number of Predictors 5 10 15 20 25 30 35 40 45 0/1 2 3 4 6/7 % Death / MI / Revasc Antman EM, et al. JAMA. 2000;284: Antman EM, Cohen M, Bernink PJ, et al. The TIMI risk score for unstable angina/non–ST elevation MI: a method for prognostication and therapeutic decision making. JAMA. 2000;284: Antman EM, McCabe CH, Gurfinkel EP, et al. Enoxaparin prevents death and cardiac ischemic events in unstable angina/non–Q-wave myocardial infarction: results of the thrombolysis in myocardial infarction (TIMI) 11B trial. Circulation. 1999;100: Cohen M, Demers C, Gurfinkel EP, et al. A comparison of low-molecular-weight heparin with unfractionated heparin for unstable coronary artery disease. N Engl J Med. 1997;337:

Troponin I, C-Reactive Protein, and B-type Natriuretic Peptide as Determinants of 30-Day Mortality in Acute Coronary Ischemia: A Multimarker Approach OPUS-TIMI 16 TACTICS-TIMI 18 6 13 6 14 P=.014 P<.0001 5 12 10 4 3.5 8 30-Day Mortality Relative Risk 3 5.7 6 1.8 2 4 1 2.1 1 1 2 n=67 n=150 n=155 n=78 n=324 n=90 67 150 155 78 n=504 504 n=717 717 324 90 1 2 3 1 2 3 Elevated Cardiac Biomarkers (N) Elevated Cardiac Biomarkers (N) Adapted with permission from Sabatine MS, et al. Circulation. 2002;105: Sabatine MS, Morrow DA, de Lemos JA, et al. Multimarker approach to risk stratification in non-ST elevation acute coronary syndromes: simultaneous assessment of troponin I, C-reactive protein, and B-type natriuretic peptide. Circulation. 2002;105:

Future of Biomarkers in ACS: Toward a Multimarker Strategy
Myocyte Necrosis Troponin Hemodynamic Stress Inflammation hs-CRP, CD40L BNP, NT-proBNP HbA1c Blood glucose Accelerated Atherosclerosis Vascular Damage CrCl Microalbuminuria Biomarker Profile in ACS hs-CRP = high-sensitivity C-reactive protein; CD40L = CD 40 ligand; BNP = brain natriuretic peptide; NT = N-terminal; HbA1c = hemoglobin A1c; CrCl = creatinine clearance. Adapted with permission from Morrow DA, Braunwald E. Circulation. 2003;108: Morrow DA, Braunwald E. Future of biomarkers in acute coronary syndromes: moving toward a multimarker strategy. Circulation. 2003;108:

Evidence-Based Risk Stratification to Target Therapies in UA/NSTEMI
Aspirin, Clopidogrel, Heparin/LMWH (IIa Enox) β-blocker, Nitrates Higher Risk +Troponin, STs, TRS 3, Recurrent Ischemia, CHF, Prior Revascularization Lower Risk – ECG, – Markers, TRS 0-2 Invasive Strategy With GP IIb/IIIa Inhibitor Conservative Strategy Long-term Medical Therapy (Aspirin, Clopidogrel, Statin, β-blocker, ACEI) TRS = TIMI Risk Score. Adapted with permission from Cannon CP. Circulation. 2002;106: Cannon CP. Evidence-based risk stratification to target therapies in acute coronary syndromes. Circulation. 2002;106:

ACC/AHA Guidelines for UA/NSTEMI
Anti-ischemic Therapy Bed rest with continuous ECG monitoring Nitroglycerin started sublingual, then IV Supplemental O2 for cyanosis or respiratory distress; confirm SaO2 >90% Morphine sulfate IV for pain, anxiety, CHF β-blocker started IV, then PO; calcium antagonist if β-blocker and/or nitrates contraindicated or insufficient Add ACE inhibitor if hypertension persists Adapted from Braunwald E, et al. Available at: Braunwald E, Antman E, Beasley JW, et al. ACC/AHA guideline update for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Unstable Angina) Available at: Accessed April 29, 2006.

ACC/AHA Guidelines for UA/NSTEMI
Antithrombotic Therapy Class I Recommendations* Definite ACS With Cath and PCI or Higher Risk (IIa) Lower-Risk ACS Possible ACS Aspirin + IV heparin/LMWH* IV platelet GP IIb/IIIa inhibitor Aspirin + SQ LMWH* or IV heparin Aspirin clopidogrel clopidogrel *Class IIa: enoxaparin preferred over IV heparin. Adapted from Braunwald E, et al. Available at: Braunwald E, Antman E, Beasley JW, et al. ACC/AHA guideline update for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on the Management of Patients With Unstable Angina) Available at: Accessed April 29, 2005.

ASA in UA/NSTEMI Death or MI 12.9 10.1 11.9 5.0* 6.2* 3.3* 17.1 6.5*
*P=.0005 *P=.012 *P=.008 *P<.0001 20 12 15 15 12.9 17.1 10.1 11.9 15 8 10 10 Patients (%) 5.0* 6.2* 10 6.5* 4 5 5 3.3* 5 Placebo 158 ASA 178 Placebo 279 ASA 276 Placebo 118 ASA 121 Placebo 397 ASA 399 Lewis HD Jr, et al. N Engl J Med. 1983;309: Cairns JA, et al. N Engl J Med. 1985;313: Theroux P, et al. N Engl J Med. 1988;319: The RISC Group. Lancet. 1990;336: Lewis HD, Davis JW, et al. Protective effects of aspirin against acute myocardial infarction and death in men with unstable angina. Results of a Veterans Administration Cooperative Study. N Engl J Med. 1983;309: Cairns JA, Gent M, Singer J. Aspirin, sulfinpyrazone, or both in unstable angina. Results of a Canadian multicenter trial. N Engl J Med. 1985;313: Theroux P, Ouimet H, McCans J, et al. Aspirin, heparin, or both to treat acute unstable angina. N Engl J Med : The RISC Group. Risk of myocardial infarction and death during treatment with low dose aspirin and intravenous heparin in men with unstable coronary artery disease. Lancet. 1990;309: . . .

CURE Study: Event-Free Survival
CV Death, MI, or Stroke First 30 Days CV Death, MI, or Stroke >30 Days–1 Year 1.00 1.00 Clopidogrel Clopidogrel .98 .98 .96 .96 Placebo Proportion Event-Free Placebo Proportion Event-Free .94 .94 RRR: 21% 95% CI, 0.67–0.92 P=.003 RRR: 18% 95% CI, 0.70–0.95 P=.009 .92 .92 .90 .90 Week 1 2 3 4 Month 1 4 6 8 10 12 No. at Risk Clopidogrel Placebo RRR = relative risk reduction. Adapted with permission from Yusuf S, et al. Circulation. 2003;107: Yusuf S, Mehta SR, Zhao F, et al, for the Clopidogrel in Unstable angina to prevent Recurrent Events Trial Investigators. Early and late effects of clopidogrel in patients with acute coronary syndromes. Circulation. 2003;107:

CURE: Efficacy of Very Early Clopidogrel Therapy in ACS Patients
CV Death, MI, Stroke, Severe Ischemia Within First 24 Hours 0.025 34% Relative Risk Reduction 0.020 Placebo + Aspirin (n=6303) 0.015 Cumulative Hazard Rate 0.010 P=.003 Clopidogrel + Aspirin (n=6259) 0.005 0.0 2 4 6 8 10 12 14 16 18 20 22 24 Hours After Randomization Adapted with permission from Yusuf S, et al. Circulation. 2003;107: Yusuf S, Mehta SR, Zhao F, et al, for the Clopidogrel in Unstable angina to prevent Recurrent Events Trial Investigators. Early and late effects of clopidogrel in patients with acute coronary syndromes. Circulation. 2003;107:

CURE: Major Bleeding by Aspirin Dose Through Follow-up
Placebo + Aspirin* Clopidogrel + Aspirin* mg % 3.0% mg 2.8% 3.4% mg 3.7% 4.9% *Other standard therapies were used as appropriate. Peters RJ, et al. Circulation. 2003;108: Peters RJ, Mehta SR, Fox KA, et al, for the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) Trial Investigators. Effects of aspirin dose when used alone or in combination with clopidogrel in patients with acute coronary syndromes: observations from the Clopidogrel in Unstable angina to prevent Recurrent Events (CURE) study. Circulation. 2003;108:

Early Invasive Strategy, PCI/Drug-eluting Stents, Secondary Prevention
Unstable Angina/ Non–ST-Segment Elevation Myocardial Infarction (UA/NSTEMI) Early Invasive Strategy, PCI/Drug-eluting Stents, Secondary Prevention

ACC/AHA Guidelines for UA/NSTEMI: Early Invasive Strategy
Class I An early invasive strategy in patients with UA/NSTEMI and any of the following high-risk indicators (Level of Evidence: A) Recurrent angina/ischemia Ejection fraction <.40 Elevated TnT or Tnl Hemodynamic instability ST-segment depression Sustained VT Recurrent angina/ischemia with CHF, S3, PE, rales, etc. PCI within 6 months High-risk findings on noninvasive stress testing Prior CABG Braunwald E, et al. J Am Coll Cardiol. 2002;40: Braunwald E, Antman EM, Beasley JW, et al. ACC/AHA 2002 guideline update for the management of patients with unstable angina and non–ST-segment elevation myocardial infarction—summary article: a report of the American College of Cardiology/American Heart Association task force on practice guidelines (Committee on the Management of Patients With Unstable Angina). J Am Coll Cardiol. 2002;40:

Invasive Management of UA/NSTEMI Meta-analysis:  Death/MI at End of Follow-up (mean 17.3 months)
Odds Ratio Death or MI Trial (N) Inv (%) Cons (%) TIMI IIIB (1473) 11.6 13.8 VANQWISH (920) 32.9 30.3 MATE (201) 14.4 12.2 FRISC II (2457) 10.4 14.1 TACTICS (2220) 7.3 9.5 VINO (131) 6.3 22.4 RITA 3 (1810) 10.6 12.9 Total (N=9212) 12.2 14.4 OR 0.82, P<.001 0.1 0.5 1 2 5 Favors Invasive Favors Conservative Adapted with permission from Mehta S, et al. JAMA. 2005;293: Mehta SR, Cannon CP, Fox KAA, et al. Routine vs selective invasive strategies in patients with acute coronary syndromes: a collaborative meta-analysis of randomized trials. JAMA. 2005;293:

Optimal Strategy for UA/NSTEMI
ISAR-COOL RITA-3 ICTUS VINO VANQWISH TRUCS MATE TIMI IIIB TACTICS- TIMI 18 FRISC II Conservative Invasive Patients (N): Boden WE, O’Rourke RA, Crawford MH, et al. Outcomes in patients with acute non-Q-wave myocardial infarction randomly assigned to an invasive as compared with a conservative management strategy. N Engl J Med. 1998;338: Cannon CP, Weintraub WS, Demopoulos LA, et al. Comparison of early invasive and conservative strategies in patients with unstable coronary syndromes treated with the glycoprotein IIb/IIIa inhibitor tirofiban. N Engl J Med. 2001;344: McCullough PA, O’Neill WW, Graham M, et al. A time-to-treatment analysis in the medicine versus angiography in thrombolytic exclusion (MATE) trial. J Interv Cardiol. 2001;14: Williams DO, Braunwald E, Thompson B, Sharaf BL, Buller CE, Knatterud GL. Results of percutaneous transluminal coronary angioplasty in unstable angina and non-Q-wave myocardial infarction. Observations from the TIMI IIIB Trial. Circulation. 1996;94: FRISC Investigators. Invasive compared with non-invasive treatment in unstable coronary-artery disease: FRISC II prospective randomised multicentre study. Lancet. 1999;354: Morrow DA, Cannon CP, Rifai N, et al. Ability of minor elevations of troponins I and T to predict benefit from an early invasive strategy in patients with unstable angina and non-ST elevation myocardial infarction: results from a randomized trial. JAMA. 2001;286: Cannon CP, Turpie AG. Unstable angina and non-ST-elevation myocardial infarction: initial antithrombotic therapy and early invasive strategy. Circulation. 2003;107: de Winter RJ, Windhausen F, Cornel JH, Dunselman PH, Janus CL, Bendermacher PE, Michels HR, Sanders GT, Tijssen JG, Verheugt FW; Invasive versus Conservative Treatment in Unstable Coronary Syndromes (ICTUS) Investigators. Early invasive versus selectively invasive management for acute coronary syndromes. N Engl J Med. 2005;353: Adapted with permission from Cannon CP, Turpie AG. Circulation. 2003;107: .

Benefit of Clopidogrel in PCI-CURE According to Timing of PCI
PCI ≥ 48 hrs from rand and during initial hosp PCI after hospital discharge <48 hrs after rand 0.20 0.20 0.20 Denotes median Time to PCI 0.15 0.15 0.15 Placebo Cumulative Hazard Rates Cumulative Hazard Rates Cumulative Hazard Rates 0.10 0.10 0.10 Clopidogrel 0.05 0.05 0.05 RR:.53 ( ) RR:.72 ( ) RR:.70 ( ) 0.0 0.0 0.0 100 200 300 100 200 300 100 200 300 Days of Follow-up Days of Follow-up Days of Follow-up Lewis BS, et al. Am Heart J. 2005;150: Lewis BS, Mehta SR, Keith AA, et al. Benefit of clopidogrel according to timing of percutaneous coronary intervention in patients with acute coronary syndromes: further results from the Clopidogrel in Unstable angina to prevent Recurrent Events study. Am Heart J. 2005;150:

Meta-analysis of Clopidogrel Pretreatment
MI before PCI (%) Clopidogrel No Trial Pretreatment Pretreatment PCI-CURE CREDO n/a n/a PCI-CLARITY Overall Favors Pretreatment Favors No Pretreatment OR: 0.67 P=.005 0.25 0.5 1.0 2.0 OR (95% CI) CV Death or MI after PCI (%) Clopidogrel No Trial Pretreatment Pretreatment PCI-CURE CREDO PCI-CLARITY Overall OR: 0.71 P=.004 0.25 0.5 1.0 2.0 OR (95% CI) Adapted with permission from Sabatine MS, et al. JAMA. 2005;294:

ACC/AHA/SCAI 2005 Guideline Update for PCI Oral Antiplatelet Adjunctive Therapies
IIa IIb III A loading dose of clopidogrel should be administered before PCI is performed A An oral loading dose of 300 mg, administered at least 6 hours before the procedure, has the best established evidence of efficacy B Adapted from Smith SC Jr, et al. Available at: Adapted from Smith SC Jr, et al. Available at:

ARMYDA-2 Trial: Design and Primary End Point
Primary composite of death, MI, or target vessel revasc at 30 days P=.041 255 patients with stable CAD or NSTEMI prior to PCI 13% received GP IIb/IIIa inhibitors 20% received drug-eluting stents 14% 12 12% Randomized 4-8 Hours Pre-PCI 10% 8% 6% High Loading Dose of Clopidogrel 600 mg Pre-PCI Standard Loading Dose of Clopidogrel 300 mg Pre-PCI 4 4% 2% 0% High Dose Standard Dose ARMYDA-2 = Antiplatelet Therapy for Reduction of Myocardial Damage During Angioplasty. Patti G, et al. Circulation. 2005;111: Patti G, Colonna G, Pasceri V, et al. Randomized trial of high loading dose of clopidogrel for reduction of periprocedural myocardial infarction in patients undergoing coronary intervention: results from the ARMYDA-2 (Antiplatelet therapy for Reduction of MYocardial Damage during Angioplasty) study. Circulation. 2005;111:

GP IIb/IIIa Inhibition for Non–ST-Elevation ACS
30-Day Death or Nonfatal MI GP IIb/IIIa Inhibitor Trial n Risk Ratio and 95% CI Placebo PRISM 3,232 7.1% 5.8% PRISM-PLUS 1,915 11.9% 10.2% PARAGON A 2,282 11.7% 11.3% PURSUIT 9,461 15.7% 14.2% PARAGON B 5,165 11.4% 10.5% GUSTO-IV ACS 7,800 8.0% 8.7% 0.92 (0.86, 0.995) P=.037 11.5% 10.7% Pooled 29,855 0.5 GP IIb/IIIa Inhibitor Better 1.0 Placebo Better 1.5 CI = confidence interval. Boersma E, et al. Lancet. 2002;359: Boersma E, Harrington RA, Moliterno DJ, et al. Platelet glycoprotein IIb/IIIa inhibitors in acute coronary syndromes: a meta-analysis of all major randomised clinical trials. Lancet. 2002;359:

56 GP IIb/IIIa Inhibitor During Medical Rx and After PCI: CAPTURE, PURSUIT, PRISM-PLUS Medical Rx/Pre-PCI Post-PCI 10% N=12,296 P=.001 N=2754 P=.001 Control GP IIb/IIIa inhibitor 8.0% 8% 6% Death or MI 4.9% 4.3% 4% 2.9% 2% 0% +24 h +48 h +72 h +24 h +48 h PCI Adapted with permission from Boersma E, et al. Circulation. 1999;100: Boersma E, Akkerhuis KM, Theroux P, et al. Platelet glycoprotein IIb/IIIa receptor inhibition in non-ST-elevation acute coronary syndromes: early benefit during medical treatment only, with additional protection during percutaneous coronary intervention. Circulation. 1999; 100:

Benefits of GP IIb/IIIa by Troponin Status in Clinical Trials
TnT-Positive TnT-Negative PARAGON-B PRISM CAPTURE Combined 0.125 0.5 1 2 0.125 0.5 1 2 GP IIb/IIIa Better GP IIb/IIIa Worse GP IIb/IIIa Better GP IIb/IIIa Worse Newby KL, et al. Circulation. 2001;103: Newby LK, Ohman EM, Christenson RH, et al; for the PARAGON-B Investigators. The PARAGON-B Troponin T Substudy. Circulation. 2001;030:

Days After Randomization
ISAR-REACT 2: Cumulative Incidence of Death, MI, or Urgent TVR in Subsets With and Without Elevated Troponin levels (>0.03 µg/L) Placebo Group (n=1010) Abciximab Group (n=1012) 20 15 10 5 Troponin >0.03 µg/L Log-Rank P=.02 Cumulative Rate of Primary End Point, % Troponin <0.03 µg/L Log-Rank P=.98 5 10 15 20 25 30 Days After Randomization ISAR-REACT 2 = Intracoronary Stenting and Antithrombotic Regimen: Rapid Early Action for Coronary Treatment 2. Adapted with permission from Kastrati A, et al. JAMA. 2006;295: Kastrati A, Mehilli J, Neumann F-J, et al. Abciximab in patients with acute coronary syndromes undergoing percutaneous coronary intervention after clopidogrel pretreatment: The ISAR-REACT 2 randomized trial. JAMA. 2006;295:

ACC/AHA UA/NSTEMI 2002 Guideline Update: Platelet GP IIb/IIIa Inhibitors
Any GP IIb/IIIa inhibitor + ASA/heparin for all patients, if cath/PCI planned A Eptifibatide or tirofiban + ASA/heparin for high-risk* patients in whom early cath/PCI is not planned A B Any GP IIb/IIIa inhibitor for patients already on ASA + heparin + clopidogrel, if cath/PCI is planned *High-risk: age >75 y; prolonged, ongoing CP; hemodynamic instability; rest CP w/ ST ; VT; positive cardiac markers. Adapted from Braunwald E, et al. Available at: Braunwald E, Antman EM, Beasley JW, et al. ACC/AHA 2002 guideline update for the management of patients with unstable angina and non–ST-segment elevation myocardial infarction—summary article: a report of the American College of Cardiology/American Heart Association task force on practice guidelines (Committee on the Management of Patients With Unstable Angina). J Am Coll Cardiol. 2002;40:

Anticoagulation in UA/NSTEMI
4 classes of anticoagulants are available Unfractionated heparin (UFH) Low-molecular-weight heparins (LMWH) Direct thrombin inhibitors Factor Xa inhibitors Current guidelines support use of UFH and LMWH, with enoxaparin preferred over UFH (Class IIa) Recent studies suggest direct thrombin inhibitors (bivalirudin) and factor Xa inhibitors (fondaparinux) may be appropriate new options for anticoagulation Effective, lower risk of bleeding

Meta-analysis: Enoxaparin vs UFH in UA/NSTEMI Death or MI at 30 Days*
Trial Enox (%) UFH (%) Odds ratio [95% CI] Odds ratio (95% CI) ESSENCE [0.58, 1.01] TIMI 11B [0.60, 1.10] INTERACT [0.28, 1.08] A to Z [0.68, 1.67] SYNERGY [0.68, 1.05] Overall [0.70, 0.94] Test for heterogeneity: χ2 = 2.86, df = 4, P = .58 0.2 1.0 2.0 Enoxaparin better UFH better *No prerandomization therapy population. Petersen JL, et al. JAMA. 2004;292:89-96. Peterson JL, Mahaffey KW, Hasselblad V, et al. Efficacy and bleeding complications among patients randomized to enoxaparin or unfractionated heparin for antithrombin therapy in non–ST-segment elevation acute coronary syndromes: a systematic overview. JAMA. 2004;292:89-96.

SYNERGY: Study Design High-Risk ACS Patients Early invasive strategy
At least 2 of 3 required: Age  60 ST  (transient) or  (+) CK-MB or Troponin Randomize (N=10,027) Enoxaparin n=4993 IV Heparin n=4985 60 U/kg  12 U/kg/h (aPTT sec) 1 mg/kg SC q12hr Early invasive strategy Other therapy per ACC/AHA Guidelines (ASA, -blocker, ACEI, clopidogrel, GP IIb/IIIa) No prerandomization therapy population Primary end point: death or MI at 30 days Mahaffey KW, et al, for the SYNERGY Investigators. JAMA. 2004;292:45-54. The SYNERGY Trial Investigators. Enoxaparin vs unfractionated heparin in high-risk patients with non-ST-segment elevation acute coronary syndromes managed with an intended early invasive strategy: primary results of the SYNERGY randomized trial. JAMA. 2004;292:45-54.

SYNERGY: Primary End Point
1.0 Hazard Ratio (95% CI) 0.95 30-Day Death/MI n n Freedom From Death / MI 0.9 HR 0.96 ( ) 0.85 0.8 0.8 Enoxaparin 1 1 UFH 1.2 1.2 Enoxaparin UFH Better Better 0.8 5 10 15 20 25 30 Days From Randomization Mahaffey KW, et al, for the SYNERGY Investigators. JAMA. 2004;292:45-54. Adapted with permission from The SYNERGY Trial Investigators. Enoxaparin vs unfractionated heparin in high-risk patients with non-ST-segment elevation acute coronary syndromes managed with an intended early invasive strategy: primary results of the SYNERGY randomized trial. JAMA. 2004;292:45-54.

SYNERGY: Bleeding Events at 30 Days
Enoxaparin UFH P value (n=4993) (n=4983) GUSTO severe bleeding Any RBC transfusion TIMI major bleeding: Clinical CABG-related Non–CABG-related Hb drop <.001 12% of patients randomized to enoxaparin were switched to UFH 4% of patients randomized to UFH were switched to enoxaparin Mahaffey KW, et al, for the SYNERGY Investigators. JAMA. 2004;292:45-54. The SYNERGY Trial Investigators. Enoxaparin vs unfractionated heparin in high-risk patients with non-ST-segment elevation acute coronary syndromes managed with an intended early invasive strategy: primary results of the SYNERGY randomized trial. JAMA. 2004;292:45-54.

ACUITY Study Design: First Randomization
Moderate- to high-risk patients with UA or NSTEMI undergoing an invasive strategy (N=13,819) UFH or enox + GP IIb/IIIa n=4603 Bivalirudin + GP IIb/IIIa n=4604 alone n=4,612 R* Angiography within 72 h Medical management PCI CABG Moderate- to high- risk ACS Aspirin in all, Clopidogrel dosing and timing per local practice *Stratified by preangiography thienopyridine use or administration. Stone GW, et al. Am Heart J. 2004;148: Stone GW, Bertrand M, Colombo A, et al. Acute Catheterization and Urgent Intervention Triage strategY (ACUITY) trial: study design and rationale. Am Heart J. 2004;148:

ACUITY: Primary End Point Measures*
UFH/Enoxaparin + GP IIb/IIIa vs Bivalirudin + GP IIb/IIIa P value (noninferior) (superior) UFH/Enox + IIb/IIIa Primary end point Risk ratio ±95% CI Bival + IIb/IIIa RR (95% CI) Net clinical outcome <.001 .93 11.8% 11.7% 1.01 ( ) Ischemic composite .015 .39 Upper boundary noninferiority 7.7% 7.3% 1.07 ( ) Major bleeding <.001 .38 5.3% 5.7% 0.93 ( ) Bivalirudin + GP IIb/IIIa better UFH/Enox + GP IIb/IIIa better *ITT population Stone GW, et al. Presented at: 55th Annual Scientific Session of the American College of Cardiology; March 11-14, 2006; Atlanta, Georgia. Adapted with permission from Stone GW, et al. Presented at the 55th Annual Scientific Session of the American College of Cardiology; March 11-14, 2006; Atlanta, Georgia.

ACUITY: Primary End Point Measures*
UFH/Enoxaparin + GP IIb/IIIa vs Bivalirudin alone P value (noninferior) (superior) UFH/Enox + IIb/IIIa Primary end point Risk ratio ±95% CI Bival alone RR (95% CI) Net clinical outcome <.001 .015 10.1% 11.7% 0.86 ( ) Ischemic composite .02 .32 Upper boundary noninferiority 7.8% 7.3% 1.08 ( ) Major bleeding <.001 3.0% 5.7% 0.53 ( ) *ITT population. UFH = unfractionated heparin Bivalirudin alone better UFH/Enox + IIb/IIIa better Stone GW, et al. Presented at: 55th Annual Scientific Session of the American College of Cardiology; March 11-14, 2006; Atlanta, Georgia. Adapted with permission from Stone GW, et al. Presented at the 55th Annual Scientific Session of the American College of Cardiology; March 11-14, 2006; Atlanta, Georgia.

OASIS-5: Study Design Randomize N=20,078 Enoxaparin (n=10,021)
Patients with NSTE ACS, chest discomfort < 24 hours 2 of 3: age >60 y, ST-segment Δ,  cardiac markers ASA, Clop, GP IIb/IIIa, planned Cath/PCI as per local practice Randomize N=20,078 Fondaparinux (n=10,057) 2.5 mg SC once daily Enoxaparin (n=10,021) 1 mg/kg SC twice daily PCI <6 h: No additional UFH PCI >6 h: IV UFH With IIb/IIIa, 65 U/kg Without IIb/IIIa, 100 U/kg PCI <6 h: IV Fonda 2.5 mg without IIb/IIIa, 0 with IIb/IIIa PCI >6 h: IV Fonda 2.5 mg with and 5.0 mg without IIb/IIIa Outcomes Primary: Efficacy: Death, MI, refractory ischemia at 9 days Safety: Major bleeding at 9 days Risk benefit: Death, MI, refractory ischemia, major bleeds 9 days Hypothesis: First test noninferiority, then test superiority Yusuf S, et al. N Engl J Med. 2006;354: Adapted with permission from . Yusuf S, Mehta SR, Chrolavicius S, et al. Fifth Organization to Assess Strategies in Acute Ischemic Syndromes Investigators. Comparison of fondaparinux and enoxaparin in acute coronary syndromes. N Engl J Med. 2006;354:

Major Bleeding Through Day 9
OASIS-5: Results Death, MI, or Refractory Ischemia Through Day 9 Major Bleeding Through Day 9 0.06 Hazard ratio, 1.01 (95% CI, ) 0.04 Hazard ratio, 0.52 (95% CI, ) P<.001 0.05 Fondaparinux 0.04 0.03 Enoxaparin Cumulative Hazard 0.03 Cumulative Hazard 0.02 0.02 Enoxaparin Fondaparinux 0.01 0.01 0.00 0.00 1 Days 9 1 Days 9 30 Day and 6 Month Results Event Fondaparinux Enoxaparin P Mortality Day 30 2.9% 3.5% .02 Mortality 6 Months 5.8% 6.5% .05 1.5% thrombus on catheter (in fonda group) if no UFH given Adapted with permission from Yusuf S, et al. N Engl J Med. 2006:354: Yusuf S, Mehta SR, Chrolavicius S, et al. Fifth Organization to Assess Strategies in Acute Ischemic Syndromes Investigators. Comparison of fondaparinux and enoxaparin in acute coronary syndromes. N Engl J Med. 2006;354:

X X Drug-eluting Stents: Cell-Cycle Sites of
Action for Sirolimus and Paclitaxel Cell Division G1 M G2 G0 CELL CYCLE Resting S Sirolimus X Paclitaxel X Marx SO, Marks AR. Bench to bedside. The development of rapamycin and its application to stent restenosis. Circulation. 2001;104: Shah MA, Schwartz GK. Cell cycle-mediated drug resistance: an emerging concept in cancer therapy. Clin Cancer Res. 2001;7:

Drug-eluting Stents: Freedom From TLR
RAVEL, SIRIUS, E-SIRIUS, and C-SIRIUS (n=1,748) TAXUS II, IV, V, VI (n=3,445) 100 100 93.6% 90.6% 90 90 80.1% 76.8% 80 80 P<0.0001 P<0.0001 70 70 Bare-Metal Stent Bare-Metal Stent TAXUS CYPHER 60 60 6 12 18 24 30 36 6 12 18 24 30 36 Time After Initial Procedure (months) Time After Initial Procedure (months) Schampaert et al. Circulation 2005;112;II-650. Stone et al. Circulation 2005;112;II-651. Schampaert E, Moses JW, Schofer J, et al. Sustained efficacy and safety of sirolimus-eluting stents at 2 years: a pooled analysis of SIRIUS, E-SIRIUS, and C-SIRIUS with emphasis on stent thrombosis. Circulation. 2005;112:II-650. Stone GW, Ellis SG, Cox DA, et al. Three-year safety and efficacy of the polymer-based paclitaxel-eluting TAXUS stent: the TAXUS-IV trial.. Circulation. 2005;112:II-651.

Drug-eluting Stents: Freedom From Cardiac Death
RAVEL, SIRIUS, E-SIRIUS, and C-SIRIUS (n=1,748) TAXUS II, IV, V, VI (n=3,445) 6 7 8 9 1 CYPHER Bare-Metal Stent 98.2% 97.8% 12 18 24 30 36 TAXUS 98.0% 97.9% P=0.61 P=0.81 Time after Initial Procedure (months) Time after Initial Procedure (months) Schampaert et al. Circulation 2005;112;II-650. Stone et al. Circulation 2005;112;II-651. Schampaert E, Moses JW, Schofer J, et al. Sustained efficacy and safety of sirolimus-eluting stents at 2 years: a pooled analysis of SIRIUS, E-SIRIUS, and C-SIRIUS with emphasis on stent thrombosis. Circulation. 2005;112:II-650. Stone GW, Ellis SG, Cox DA, et al. Three-year safety and efficacy of the polymer-based paclitaxel-eluting TAXUS stent: the TAXUS-IV trial.. Circulation. 2005;112:II-651.

Drug-eluting Stents: Freedom From MI
RAVEL, SIRIUS, E-SIRIUS, and C-SIRIUS (n=1,748) TAXUS II, IV, V, VI (n=3,445) 100 95.3% 100 93.6% 95.2% 93.4% 90 90 P=0.93 P=0.96 80 80 70 70 Bare-Metal Stent Bare-Metal Stent CYPHER® TAXUS® 60 60 6 12 18 24 30 36 6 12 18 24 30 36 Time after Initial Procedure (months) Time after Initial Procedure (months) Schampaert et al. Circulation 2005;112;II-650. Stone et al. Circulation 2005;112;II-651. Schampaert E. Circulation. 2005;112:II-650. Stone GW. Circulation. 2005;112:II-651.

Predictors of Stent Thrombosis in DES Era
Premature discontinuation of antiplatelet therapy DES Platform Polymer (inflammatory, thrombogenic) Drug (cytotoxic) Mechanical/lesion-specific factors Incomplete stent apposition Lesion complexity (bifurcation, AMI, ISR) Stent length Hypercoaguable conditions Antiplatelet therapy ‘resistance’ High platelet reactivity and clot strength Wenaweser P, et al. J Am Coll Cardiol. 2005;45: Gurbel PA, et al. J Am Coll Cardiol. 2005;46: Gurbel PA, et al. J Am Coll Cardiol. 2005;46: Wenaweser P, Hess O. Stent thrombosis is associated with an impaired response to antiplatelet therapy. J Am Coll Cardiol. 2005;46:CS5-CS6. Gurbel PA, Bliden KP, Guyer K, et al. Platelet reactivity in patients and recurring events post-stenting: the PREPARE POST-STENTING study. J Am Coll Cardiol. 2005;46: Gurbel PA, Bliden KP, Samara W, et al. Clopidogrel effect on platelet reactivity in patients with stent thrombosis: results of the CREST study. J Am Coll Cardiol. 2005;46:

Milan/Siegburg Experience
2229 patients after successful DES implantation SES 1062 pts 2272 stents PES 1167 pts 2223 stents SAT 4 (0.4%) SAT 10 (0.9%) P=0.5 LST 5 (0.5%) LST 10 (0.9%) P=0.3 10.2  4.4 m 9.3  5.6 months Total DES 29/2229 (1.3%) 7.9  3.6 m Total SES 9 (0.9%) Total PES 20 (1.7%) P=0.09 Iakovou I, et al. JAMA. 2005;293: Iakovou I Schmidt T, Bonizzoni E, et al. JAMA. 2005;293;

Milan/Siegburg Experience
Stent thrombosis after DES (SES or PES) occurred in 29/2229 pts (1.3%) at 9.3 ± 5.6 mos Several patient and lesion subgroups have a higher stent thrombosis rate than identified in RCTs 2 9 . % 8 . 7 % 5 . 5 % 3 . 2 % 3 . 5 % 1 . 3 % 2 . % 2 . 6 % Unstable angina Thrombus Diabetes Unprot. left main Bifurcation Renal failure Prior brachyRx Premature antiplatelet d/c Iakovou I, et al. JAMA. 2005;293: Iakovou I Schmidt T, Bonizzoni E, et al. JAMA. 2005;293;

BASKET-LATE Trial: Study Design
743 PCI patients from BASKET Trial None had target vessel diameter ≥4mm, restenotic lesions, or MACE during the on-clopidogrel phase. Concomitant medications: aspirin indefinitely DES Group n=499 BMS Group n=244 Primary End Point: Composite cardiac death or nonfatal MI between months 7 and 18 Other End Points: - Thrombosis-related events: - angiographically documented stent thrombosis - cardiac death/target vessel MI - TVR Pfisterer ME, et al. Presented at ACC, Atlanta, Ga. March 14, 2006; Presentation Adapted with permission from Pfisterer ME, et al. Presented at: 55th Annual Scientific Session of the American College of Cardiology; March 12, 2006; Atlanta, GA. Presentation

BASKET-LATE: Primary Composite End Point
Composite of cardiac death or nonfatal MI (%) P=.01 Components of primary composite end point: nonfatal MI/cardiac death (%) 6 4.9 4.1 1.2 1.3 0.0 1.0 2.0 3.0 4.0 5.0 MI Cardiac Death DES BMS P=.04 P=.09 % Patients 5 4 % Patients 3 2 1.3 1 DES BMS Additional end point of thrombosis-related events (%) P=.23 3 2.6 2 % Patients 1.3 1 DES BMS Pfisterer ME, et al. ACC, Atlanta, Ga. March 14, 2006; Presentation Adapted with permission from Pfisterer ME, et al. Presented at: 55th Annual Scientific Session of the American College of Cardiology; March 12, 2006; Atlanta, GA. Presentation

Long-Term Medical Therapy for UA/NSTEMI: Class I Recommendations
Aspirin 75 to 325 mg/d Clopidogrel 75 mg/d when aspirin is not tolerated Combination of aspirin and clopidogrel for 9 months post-UA/NSTEMI β-blocker Lipid-lowering agent and diet in patients with LDL-C >130 mg/dL Lipid-lowering agent if LDL-C after diet >100 mg/dL* ACE inhibitor for patients with CHF, LV dysfunction (EF <.40), hypertension, or diabetes *NCEP ATP III update indicates optional goal of LDL-C < 70 mg/dL. Braunwald E, et al. J Am Coll Cardiol. 2002;40: Braunwald E, Antman EM, Beasley JW, et al. ACC/AHA 2002 guideline update for the management of patients with unstable angina and non–ST-segment elevation myocardial infarction—summary article: a report of the American College of Cardiology/American Heart Association task force on practice guidelines (Committee on the Management of Patients With Unstable Angina). J Am Coll Cardiol. 2002;40:

CTT Collaboration: Relation Between Proportional Reduction in Incidence of Major Vascular Events and Absolute LDL-C Reduction at 1 Year Major vascular events 50% 40% 30% Proportional Reduction in Event Rate (SE) 20% 10% 0% 0.5 1.0 1.5 2.0 -10% Reduction in LDL cholesterol (mmol/L) Cholesterol Treatment Trialists’ Collaborators. Lancet. 2005;366: Cholesterol Treatment Trialists’ Collaboration. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from participants in 14 randomised trials of statins. Lancet. 2005;366:

Meta-Analysis of CV Outcomes Trials Comparing Intensive vs Moderate Statin Therapy Trial Design and Baseline Characteristics Trial Population Duration, y Treatment Arms Primary End Point PROVE IT- TIMI 22 Post-ACS (N=4162) 2 40 mg pravastatin vs 80 mg atorvastatin Death, MI, UA requiring hospitalization (>30 d), stroke A to Z Post-ACS (N=4497) Placebo (4 mos) then 20 mg simvastatin vs 40 mg simvastatin (1 month) then 80 mg simvastatin CV death, MI, readmission for ACS, stroke TNT Stable CAD (N=10,001) 5 10 mg atorvastatin vs 80 mg atorvastatin CHD death, non-procedure-related MI, resuscitation after cardiac arrest, stroke IDEAL Stable CAD (N=8888) 20 mg simvastatin vs 80 mg atorvastatin CHD death, MI, cardiac arrest with resuscitation Cannon CP, et al. J Am Coll Cardiol. 2006;48: Cannon CP. The IDEAL cholesterol: lower is better. JAMA. 2005;294:2492.

Meta-Analysis of CV Outcomes Trials Comparing Intensive vs Moderate Statin Therapy Changes in LDL-C Levels Patients ACS Stable CAD Pooled n 4162 4497 10001 8888 27548 25.2% 0% 75.5% 28.2% Prior Statin Use 160 140 Baseline Standard Intensive 120 LDL-C(mg/dL) 100 80 60 40 PROVE IT- TIMI 22 A-to-Z TNT IDEAL Pooled* Baseline 108 113 152 122 130 Standard 97 101 104 Intensive 65 69 77 81 75 Adapted with permission from Cannon CP, et al. J Am Coll Cardiol. 2006;48:

Meta-Analysis of CV Outcomes Trials Comparing Intensive vs Moderate Statin Therapy Reduction in Risk of Coronary Death or MI Odds Reduction Event Rates No./Total (%) High Dose Std Dose -17% 147/2099 (7.0) 172/2063 (8.3) -15% 205/2265 (9.1) 235/2232 (10.5) -21% 334/4995 (6.7) 418/5006 -12% 411/4439 (9.3) 463/4449 (10.4) -16% 1097/13798 (8.0) 1288/13750 (9.4) Odds Ratio (95% CI) PROVE IT- TIMI 22 A-to-Z TNT IDEAL OR, 0.84 95% CI, P= Total .66 1 1.5 High-dose better High-dose worse Adapted with permission from Cannon CP, et al. J Am Coll Cardiol. 2006;48:

Safety of Achieving Ultra-Low LDL
LDL Level Event* 80-100 60-80 40-60 <40 P value Myositis or Myalgia (AE) 1.6 3.1 3.2 2.8 NS CK > 3x ULN 2.3 0.7 1.9 1.0 CK > 10x ULN 0.3 Rhabdomyolysis ALT > 3X ULN 3.0 3.6 Wiviott et al. J Am Coll Cardiol. 2005;46: Wiviott SD, Cannon CP, Morrow D, et al. Can low-density lipoprotein be too low? The safety and efficacy of achieving very low low-density lipoprotein with statin therapy: a PROVE-IT TIMI 22 stubstudy. J Am Coll Cardiol. 2005;46:

ACE Inhibitor Trials: Primary End Points
14 12 10 8 6 4 2 HOPE EUROPA 20 Placebo annual event rate: 2.4% Placebo Placebo 15 Ramipril Patients Reaching Composite End Point 10 CV Death, MI, or Cardiac Arrest (%) Perindopril [MI, Stroke, CV Death] (%) RRR = 22% P=.0003 RRR: 20% 5 P<.001 500 1000 1500 1 2 3 4 5 Follow-up (days) Years N = 12,218 PEACE 30 25 20 15 10 5 Placebo HOPE: Adapted with permission from the Heart Outcomes Prevention Evaluation (HOPE) study investigators. N Engl J Med. 2000;342: Trandolapril Incidence of Primary End Point (%) EUROPA: Adapted with permission from Fox KM; EUROPA Investigators. Lancet. 2003;362: PEACE: Adapted with permission from Braunwald E, et al; PEACE Trial Investigators. N Engl J Med. 2004;351: Years After Randomization No. at Risk Trandolapril Placebo The Heart Outcomes Prevention Study Investigators. Effects of an angiotensin-converting enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med. 2000;342: Fox KM; EURopean trial On Reduction of cardiac events with Perindopril in stable coronary Artery disease Investigators. Efficacy of perindopril in reduction of cardiovascular events among patients with stable coronary artery disease: randomised, double-blind, placebo-controlled, multicentre trial (the EUROPA study). Lancet. 2003;362: Braunwald E, Domanski MJ, Fowler SE, et al; PEACE Trial Investigators. Angiotensin-converting-enzyme inhibition in stable coronary artery disease. N Engl J Med. 2004;351:

Cumulative event rate (%) Months since randomization
CHARISMA Study: Overall Population: Primary Efficacy Outcome (MI, Stroke, or CV Death)† Placebo + ASA* 7.3% 8 Clopidogrel + ASA* 6.8% 6 Cumulative event rate (%) 4 RRR: 7.1% [95% CI: -4.5%, 17.5%] P = 0.22 2 6 12 18 24 30 Months since randomization † First occurrence of MI (fatal or non-fatal), stroke (fatal or non-fatal), or cardiovascular death. *All patients received ASA mg/day. §The number of patients followed beyond 30 months decreases rapidly to zero and there are only 21 primary efficacy events that occurred beyond this time (13 clopidogrel and 8 placebo). Adapted with permission from Bhatt DL, et al. N Eng J Med. 2006:354: Bhatt DL, Fox KAA, Hacke W, et al. Clopidogrel and Aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med. 2006;354:

Cumulative event rate (%) Months since randomization§
CHARISMA Study: Overall Population: Principal Secondary Efficacy Outcome (MI/Stroke/CV Death/Hospitalization)† Placebo + ASA* 17.9% Cumulative event rate (%) 5 10 15 20 Months since randomization§ 6 12 18 24 30 Clopidogrel + ASA* 16.7% RRR: 7.7% [95% CI: 0.5%, 14.4%] P = 0.04 †First occurrence of MI, stroke, CV death, or hospitalization for UA, TIA, or revascularization. *All patients received ASA mg/day. §The number of patients followed beyond 30 months decreases rapidly to zero and there are only 38 secondary efficacy events that occurred beyond this time (23 clopidogrel and 15 placebo). Adapted with permission from Bhatt DL, et al. N Eng J Med. 2006:354: Bhatt DL, Fox KAA, Hacke W, et al. Clopidogrel and Aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med. 2006;354:

CHARISMA Study Overall Population: Safety Results
Safety Outcome* – N (%) Clopidogrel + ASA (n=7802) Placebo + ASA (n=7801) RR (95% CI) P value GUSTO Severe Bleeding 130 (1.7) 104 (1.3) 1.25 (0.97, 1.61) 0.09 Fatal Bleeding 26 (0.3) 17 (0.2) 1.53 (0.83, 2.82) 0.17 Primary ICH 27 (0.3) 0.96 (0.56, 1.65) 0.89 GUSTO Moderate Bleeding 164 (2.1) 101 (1.3) 1.62 (1.27, 2.10) <0.001 *Adjudicated outcomes by intention to treat analysis. ICH = intracranial hemorrhage. Bhatt DL, et al. N Engl J Med. 2006;354: Bhatt DL, Fox KAA, Hacke W, et al. Clopidogrel and Aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med. 2006;354:

CHARISMA Study: Primary Efficacy Results (MI/Stroke/CV Death) by Pre-Specified Entry Category
Population RR (95% CI) P value Qualifying CAD, CVD or PAD* (0.77, 0.998) (n=12,153) Multiple Risk Factors * (0.91, 1.59) (n=3,284) Overall Population† (0.83, 1.05) (n=15,603) 0.6 0.8 1.4 1.2 Clopidogrel + ASA Better Placebo + ASA 1.6 0.4 *A statistical test for interaction showed marginally significant heterogeneity (P=0.045) in treatment response for these pre-specified subgroups of patients. †166 patients did not meet any of the main inclusion criteria but were followed (intent-to-treat analysis). Adapted with permission from Bhatt DL, et al. N Eng J Med. 2006:354: Bhatt DL, Fox KAA, Hacke W, et al. Clopidogrel and Aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med. 2006;354:

CHARISMA: Clinical Implications
In the acute setting, prior studies have shown the benefit of dual antiplatelet therapy for 1 year post ACS or PCI For stable patients, CHARISMA failed to demonstrate a reduction in CV death/MI/stroke with dual antiplatelet therapy CHARISMA may suggest differential long-term effects of dual antiplatelet therapy by patient type: NOT Recommended for Primary Prevention Potential benefit in Secondary Prevention (CAD, CVD, or PAD) CV death/MI/stroke - 9 events prevented per 1000 patients treated Balanced by 2 severe GUSTO bleeds per 1000 patients treated These data and future trials will help physicians decide which non-acute/stable patients should receive long-term dual antiplatelet therapy Bhatt DL, et al. N Engl J Med. 2006;354: Bhatt DL, Fox KAA, Hacke W, et al. Clopidogrel and Aspirin versus aspirin alone for the prevention of atherothrombotic events. N Engl J Med. 2006;354:

Quality Improvement Programs and Critical Pathways

Why Develop Critical Pathways?
“A treatment gap between therapy that is dictated by evidence-based medicine and therapy that occurs in practice is not a deficit of knowledge; rather, it is a deficit of implementation.” Sidney Smith, MD Director, Center for Cardiovascular Science and Medicine, UNC School of Medicine

Critical Pathways Standardized treatment protocols for the management of specific disorders Developed to optimize and streamline patient care Prevent underutilization of medications, time in ICU/hospital, costs Ensure quality-of-care measures (eg, door-to-drug times) Optimize patient triage Facilitate communication with specialists and PCP post-discharge Enhance patient compliance and outcomes Minimize potential for medical errors Improve compliance with national standards (JCAHO) Adapted from: Cannon CP, O’Gara PT. Critical Pathways in Cardiology. Lippincott Williams & Wilkins; 2001.

Joint Commission on Accreditation of Healthcare Organizations (JCAHO)
1997: Launched ORYX™ to integrate use of outcomes and other performance measures into accreditation process 2001: Announced 4 initial core measurement areas for hospitals (2 of 4 required): Acute MI Heart failure Community-acquired pneumonia Pregnancy 2004: New accreditation process (“Shared Visions–New Pathways”) introduced. Hospitals previously collecting 2 of 4 measure sets are now required to collect 3 of 4 measure sets

JCAHO Quality Measures in MI
Hospitals graded on: Antiplatelet therapy in AMI at arrival and discharge b-blocker therapy at arrival and discharge ACE inhibitor therapy for LVSD Time to thrombolysis Time to PCI Adult smoking cessation counseling Inpatient mortality

Why a Hospital-Based System?
Patients Patient capture point Have patients/family attention: “teachable moment” Predictor of care in community Hospital structure Standardized processes/protocols/orders/teams JCAHO (ORYX and “Shared Visions – New Pathways”) Source:

Practical Steps to Improve the Use of Evidence-Based Therapies for ACS
Develop critical pathways Establish a multidisciplinary team approach (cardiology, ED, primary care, nursing, laboratory) Identify local cardiology and ED “champions” Track adherence to ACC/AHA guidelines Develop educational materials to improve physicians’ knowledge of the guidelines Secure institution’s commitment to improved patient care Identify areas for continuous QI; provide QI tools Elicit ongoing quarterly feedback Cannon CP, et al. Am Heart J. 2002;143: Cannon CP, Hand MH, Bahr R, et al; National Heart Attack Alert Program (NHAAP) Coordinating Committee Critical Pathways Writing Group. Critical pathways for management of patients with acute coronary syndromes: an assessment by the National Heart Attack Alert Program. Am Heart J. 2002;143:

Critical Pathways Begin in Ambulance and Extend to Long-term, Office-based Care
EMS ED Community Inpatient Discharge Adapted from Cannon CP, O’Gara PT. Critical Pathways in Cardiology. Lippincott Williams & Wilkins; Corbelli J, et al. Critical Pathways in Cardiology. 2003;2:71-87. Cannon CP, O’Gara PT, eds. Critical Pathways in Cardiology. Philadelphia, Pa: Lippincott Williams & Wilkins; 2001. Corbelli JC, Janicke DM, Corbelli JA, Chow S, Pruski M. Acute Coronary Syndrome Emergency Treatment Strategies: a rationale and road map for critical pathway implementation. Critical Pathways in Cardiology. 2003;2:71-87.

EMS Reperfusion Checklist: Evaluation of the STEMI Patient
Step 1: Has patient experienced chest discomfort for > 15 min and < 12 h? STOP YES NO Are there contraindications to fibrinolysis? If ANY of the following are CHECKED, fibrinolysis MAY be contraindicated. Step 2: Systolic BP greater than 180 mm Hg □ Yes □ No □ Yes □ No Diastolic BP greater than 110 mm Hg □ Yes □ No Right vs left arm systolic BP difference greater than 15 mm Hg □ Yes □ No History of structural central nervous system disease □ Yes □ No Significant closed head/facial trauma within the previous 3 months □ Yes □ No Recent (< 6 wk) major trauma, surgery (including laser eye surgery), GI/GU bleed □ Yes □ No Bleeding or clotting problem or on blood thinners □ Yes □ No CPR greater than 10 min □ Yes □ No Pregnant female □ Yes □ No Serious systemic disease (eg, advanced/terminal cancer, severe liver or kidney disease) □ Yes □ No Step 3: Is patient at high risk such that PCI is preferable? □ Yes □ No Adapted from Antman EM, et al. Available at: Heart rate greater than or equal to 100 bpm □ Yes □ No Pulmonary edema (rales greater than halfway up) □ Yes □ No Systolic BP less than 100 mm Hg □ Yes □ No Systemic hypoperfusion (cool, clammy) Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee to Revise the 1999 Guidelines on the Management of Patients With Acute Myocardial Infarction). J Am Coll Cardiol Available at: Accessed May 1, 2006.

STEMI Critical Pathways
ST-ELEVATION MI (STEMI): EMERGENCY DEPARTMENT ORDERS Actual WEIGHT____________  kg  Estimated  lbs  Actual HEIGHT ____________  cm  Estimated  ft ALLERGIES DO NOT USE THESE UNSAFE ABBREVIATIONS “U” and “IU” should be unit, “Ug” should be mcg. “QD” should be daily. “QOD” should be every other day. “BIW” should be two times a week. “TIW” should be three times a week, “AU”, “AS”, “OS”, and “OD” should be written out in full. Correct Use of Leading and Trailing Zeros – Always Leading Never Trailing. .1 should be 0.1 and 1.0 should be 1 Initial Orders Check all that apply DIAGNOSTICS  Stat EKG, obtain old EKG record  Repeat stat EKG 60 minutes after initial bolus of Retavase Start Acute Coronary Syndrome Lab Panel: CMP, CBC/diff, PT/INR/aPTT, CK + CK-MB (site specific), Troponin-I, Magnesium, hs-CRP, lipid profile (routine) Stat portable CXR  Cardiac monitor and SaO2 monitors  Other ______________________________________ ANTI-ISCHEMIC THERAPY  Oxygen 2L/minute Nasal Cannula (titrate to keep pulse oximetry saturations > 94%)  IV – 0.9 NS:  Intermittent Infusion Device  KVO ____ ml/hour  Opiate: __________________________________ mg IV (suggest Morphine Sulfate) Nitroglycerin Therapy (Hold if patient has taken Sildenafil (Viagra) within 24 hours)  NTG 0.4mg SL every 5 minutes X 3 doses or until pain relief or systolic BP < 100 mm Hg  NTG paste _______________________inch(es) topically X 1  IV- start NTG infusion at 10 mcg/minute, then titrate as per pharmacy protocol (use 100mg in 250 ml D5W) ANTI-THROMBOTIC THERAPY  Aspirin 162 mg po (2 chewable 81 mg tablets) Corbelli J, et al. Critical Pathways in Cardiology. 2003;2:71-87.

STEMI Critical Pathways
Reperfusion Therapy Indications: Chest pain <12 hours, EKG ST-elevations or new left bundle branch block Fibrinolysis Indications 3-hr symptom onset Delay in PCI (door-to-balloon >90 min) Contraindications to PCI: poor arterial access, renal failure, dye allergy Assess for contraindications for fibrinolytic therapy: History of hemorrhagic stroke at any time; other stroke or cerebrovascular event within 1 year Known intracranial neoplasm Active internal bleeding Suspected aortic dissection (consider CT of chest)  Reteplase (Retavase) 10 units IV bolus, repeat 10 units IV bolus at 30 minutes HEPARIN THERAPY: (administer simultaneously with Retavase):  Unfractionated heparin: ___units IV bolus (1000 units/ml), then ___units/hour IV infusion Note: When using a fibrinolytic (eg, reteplase): Use Cardiac Unfractionated Heparin Nomogram on back of form Primary PCI Indications >3-hr symptom onset Presence of cardiogenic shock, CHF, contraindications to fibrinolysis  Stat cardiology consult/catheterization lab page  Eptifibatide (Integrilin) _____ml IV bolus, then ____ml/hr IV infusion (dosing nomogram on back of form) (Dose adjustment based on serum creatinine may be required.)  Unfractionated heparin _____ units IV bolus (1000 units/ml), then ______units/hour IV infusion

Sample Critical Pathways Grid: UA/NSTEMI
STRIVE Scientific Committee

Sample Pocket Card (front)

Sample Pocket Card (back)

Smooth Transition From Acute to Long-Term Management
Cardiology Acute Care Guidelines Primary Care Secondary Prevention Follow guidelines Improve communications Ensure compliance Improve quality of care and outcomes Adapted from the American Heart Association. Get With The Guidelines American Heart Association. Get With The Guidelines. Available at Accessed May 2, Cannon CP, O’Gara PT. Critical Pathways in Cardiology. Lippincott Williams & Wilkins; 2001.

Discharge Protocols Enhance communication with patient and between specialist(s) and primary care physicians1 Medications: aspirin, clopidogrel, ACE inhibitor, β-blocker, statin1 Diet, exercise, smoking cessation recommendations1 Patient symptom awareness, “Act in Time” protocol2 Wallet-/purse-sized copy of ECG3 Follow-up appointments1 American Heart Association Web site. Get With The Guidelines. Available at: Act in Time to Heart Attack Signs Campaign. Available at: Greenberg DI, et al. J Cardiovasc Manag. 2004;15:16-18. American Heart Association Web site. Get With The Guidelines. Available at: Accessed September 1, 2005. Act in Time to Heart Attack Signs Campaign. Available at Accessed September 1, 2005. Greenberg DI, Blonder RD, Eastburn TE, et al. Building a cardiology practice. J Cardiovasc Manag. 2004;15:16-18.

Sample Cardiac Discharge Checklist UA/NSTEMI
STRIVE Scientific Committee

Sample Letter to Patient’s PCP at Discharge for UA/NSTEMI
Dear Dr. ________________: Your patient, (name), has been discharged on (date) following treatment for ____ days with a diagnosis of acute coronary syndromes (unstable angina ___ or non-ST-segment elevation myocardial infarction ___). Risk stratification at discharge was _______________________. The patient underwent the following procedures: PCI _____ CABG _____ The following medications have been prescribed post-discharge: Aspirin + clopidogrel: Aspirin at a dose of _____ mg/d Clopidogrel at a dose of 75 mg/d Nitrates (________________) at a dose of ______ mg/d Beta-blocker (________________) at a dose of ______ mg/d ACE inhibitor (________________) at a dose of ______ mg/d Calcium channel blocker (________________) at a dose of ______ mg/d Lipid-lowering agent(s)(__________________) at a dose of ______ mg/d Other: ________________________________________________________________ The following counseling concerning risk modification was provided:______________________ Follow-up is strongly recommended in these areas: ___________________________________ If you have questions, please contact me at: telephone_______________ voice mail ____________ _______________________________ Sincerely, (Hospital discharge report attached)

What Is the Evidence That Critical Pathways Work?
UCLA Cardiac Hospitalization Atherosclerosis Management Program (CHAMP) ACC Guidelines Applied in Practice (GAP) initiative AHA “Get With The Guidelines” program CRUSADE (Can Rapid Risk Stratification of Unstable Angina Patients Suppress ADverse Outcomes with Early Implementation of the ACC/AHA Guidelines)

Cardiac Hospitalization Atherosclerosis Management Program
CHAMP Study: UCLA Cardiac Hospitalization Atherosclerosis Management Program Designed to determine whether physician/patient compliance with preventive therapies can be improved through a hospital- initiated program Tracked initiation of aspirin, β-blocker, ACE inhibitor, statins Used preprinted orders, guidelines, lectures, discharge forms Population: patients with symptomatic atherosclerosis treated at university-associated teaching hospital Methods: no specific algorithms used before CHAMP ( ) National guidelines (ACC/AHA, NCEP ATP I and ATP II) used in CHAMP ( ) Evaluation: treatment rates and clinical outcomes pre-CHAMP and CHAMP in patients hospitalized for acute MI Fonarow GC, Gawlinski A. Am J Cardiol. 2000;85(3A):10A-17A. Fonarow GC, Gawlinski A. Rationale and design of the Cardiac Hospitalization Atherosclerosis Management Program at the University of California Los Angeles. Am J Cardiol. 2000;85(3A):10A-17A.

Discharge Medications at UCLA Compared With 1437 NRMI Hospitals
CHAMP Over an 8-Year Period: Rapid and Sustained Improvement, Superior to National Benchmarks 92/93 Pre-CHAMP (UCLA) 98/99 Post-CHAMP (UCLA) 00/01 Post-CHAMP (UCLA) 94/95 Post-CHAMP (UCLA) 96/97 Post-CHAMP (UCLA) Nat’l Benchmark [NRMI Hospitals 00/01 (n=154,602)] 96 100 94 92 91 91 85 88 89 90 77 78 75 80 72 68 70 68 65 64 60 52 Utilization Rate (%) 42 37 40 20 12 Aspirin β-blockers ACEI Statins Discharge Medications at UCLA Compared With 1437 NRMI Hospitals Fonarow GC, et al. Am J Cardiol. 2001;87: Fonarow GC, Gawlinski A. Houghrabi S, Tillisch JH. Improved treatment of coronary heart disease by implementation of a Cardiac Hospitalization Atherosclerosis Management Program (CHAMP). Am J Cardiol. 2001;87:

ACC’s Guidelines Applied in Practice (GAP) Initiative: Impact on Aspirin Usage at Admission and Discharge P=.002 100 P=.02 Pre-GAP 92 80 87 Post-GAP 84 81 60 Aspirin Usage (%) 40 20 At Admission At Discharge Adapted from Mehta RH, et al. JAMA. 2002;287: Mehta RH, Montoye CK, Gallogly M, et al. Improving quality of care for acute myocardial infarction: the Guidelines Applied in Practice (GAP) initiative. JAMA. 2002;287:

GAP Initiative: Adherence Improves With Tool Use
Early Quality Indicators and Standard Admission Orders P=.001 P=.004 81 86 93 65 73 77 64 82 100 Preintervention Postintervention 80 No Tool Use Tool Use 60 Quality Adherence (%) 40 20 343 308 96 213 174 71 131 165 87 No. of Ideal Patients Aspirin β-Blocker LDL-C Adapted with permission from Mehta RH, et al. JAMA. 2002;287: Mehta RH, Montoye CK, Gallogly M, et al. Improving quality of care for acute myocardial infarction: the Guidelines Applied in Practice (GAP) initiative. JAMA. 2002;287:

GAP Initiative: Changes in Mortality Before and After GAP Project
45 P=.004 40 35 30 25 P=.001 % Baseline 20 P=.017 Post-GAP 15 10 5 In-hospital 30-d 1-yr Mortality Mortality Mortality Eagle KA, et al. J Am Coll Cardiol. 2005;46: Eagle KA, Montoye CK, Riba AL, et al. Guideline-based standardized care is associated with substantially lower mortality in medicare patients with acute myocardial infarction: the American College of Cardiology's Guidelines Applied in Practice (GAP) Projects in Michigan. J Am Coll Cardiol. 2005;46:

AHA “Get With The Guidelines” Program
Components Training materials for hospital staff Patient education materials Assistance in creating multidisciplinary team Secondary prevention guidelines CME workshops Sample materials (care maps, discharge protocols, discharge forms) American Heart Association Web site. Get With The Guidelines. Available at: American Heart Association Web site. Get With The Guidelines. Available at: Accessed April 29, 2005.

AHA Tool: Simple One-Page, Online Form
Demographics: 6 clicks Clinical/Lab: 8 clicks Interactively checks patient’s data with the AHA Guidelines Discharge meds and interventions: 7 clicks American Heart Association Web site. Get With The Guidelines. Available at: American Heart Association Web site. Get With The Guidelines. Available at: Accessed April 29, 2005.

Proportion of Patients
Get With The Guidelines 12-Month Pilot Results: 85 New England Hospitals Baseline 4-6 Months 9-12 Months Benchmark* 100 80 60 Proportion of Patients 40 N=1709 20 Smoking Counsel LDL-C BP Rehab/ Exercise Control Intervention *Benchmarks established by CMS AND NRMI. Reprinted with permission from the American Heart Association Web site. Get With The Guidelines. Available at: American Heart Association Web site. Get With The Guidelines. Available at: Accessed April 29, 2005.

CRUSADE Can Rapid Risk Stratification of Unstable Angina Patients Suppress ADverse Outcomes with Early Implementation of the ACC/AHA Guidelines Nationwide quality improvement (QI) initiative Up to 600 participating hospitals Collaborative effort between emergency medicine, cardiology, hospital QI, academia, and industry Focused on improving the care of NSTEMI ACS patients Adapted from CRUSADE Overview Available at: © 2005 Duke Clinical Research Institute. Used with permission. Can Rapid Risk Stratification of Unstable Angina Patients Suppress ADverse Outcomes with Early Implementation of the ACC/AHA Guidelines (CRUSADE) Available at:

CRUSADE: Inclusion Criteria
Ischemic symptoms lasting >10 minutes within previous 24 hours and at least one of the following: Positive cardiac markers CK-MB or Tnl/TnT above ULN Positive bedside troponin assay ST-segment ECG changes ST-segment depression >0.5 mm Transient ST-segment elevation 0.6–1 mm (lasting <10 mins) Transfer patients (with any of the above) must arrive at CRUSADE hospital within 24 hours of symptoms © 2005 Duke Clinical Research Institute. Used with permission. Available at Can Rapid Risk Stratification of Unstable Angina Patients Suppress ADverse Outcomes with Early Implementation of the ACC/AHA Guidelines (CRUSADE) Available at:

Improve Adherence to ACC/AHA Guidelines Improve Patient Outcomes
Goals for CRUSADE Improve Adherence to ACC/AHA Guidelines Improve Patient Outcomes Acute Therapy Discharge Therapy Aspirin Clopidogrel -Blocker Heparin (UFH or LMWH) GP IIb/IIIa Inhibitor Cath/PCI Aspirin Clopidogrel -Blocker ACE Inhibitor Statin/Lipid Lowering Smoking Cessation Cardiac Rehabilitation 2002 ACC/AHA Guidelines Update. Adapted from 2005 CRUSADE 2nd Quarter Results. Available at: © 2005 Duke Clinical Research Institute. Used with permission. Can Rapid Risk Stratification of Unstable Angina Patients Suppress ADverse Outcomes with Early Implementation of the ACC/AHA Guidelines (CRUSADE) Available at:

Hospital Presentation Characteristics in CRUSADE: July 1, 2005–June 30, 2006 (n=31,665)
Qualifying criteria ST-segment depression 28% Transient ST-segment elevation % Positive cardiac markers 93% Baseline cardiac markers Drawn Positive CK-MB 82% 75% TnT/TnI 99% 91% Presenting characteristics Tachycardia 23% Hypotension 4% Signs of CHF 23% Adapted from 2006 CRUSADE Results. Available at: © 2006 Duke Clinical Research Institute. Used with permission. Can Rapid Risk Stratification of Unstable Angina Patients Suppress ADverse Outcomes with Early Implementation of the ACC/AHA Guidelines (CRUSADE). Available at:

Baseline Characteristics: CRUSADE vs ACS Clinical Trials
Variable PURSUIT CURE SYNERGY CRUSADE (n = 9461) (n = 12,562) (n = 9975) (n = 180,842) Mean age ± SD (yrs) 63 ± ± ± ± 14 Female sex (%) Diabetes mellitus (%) Prior MI (%) Prior CHF (%) Prior PCI (%) 13 18* 20 21 Prior CABG (%) 12 18* 17 19 ST depression (%) N Engl J Med. 1998;339: N Engl J Med. 2001;345: JAMA. 2004:292:45-54. CRUSADE cumulative through June 30, 2006.

CRUSADE: Trends in Acute Therapy Adherence
100% 96% 97% 90% 93% 84% 88% 75% 50% 46% 50% 25% 0% Antiplatelet β-Blocker Heparin GP IIb/IIIa Inhibitor Quarter 3-05 Quarter 4-05 Quarter 1-06 Quarter 2-06 Quarter 3, 2005, through Quarter 2, 2006. Adapted from 2006 CRUSADE Results. Available at: © 2006 Duke Clinical Research Institute. Used with permission. Can Rapid Risk Stratification of Unstable Angina Patients Suppress ADverse Outcomes with Early Implementation of the ACC/AHA Guidelines (CRUSADE). Available at:

CRUSADE: Invasive Cardiac Procedures July 1, 2005 – June 30, 2006 (n=31,665) (Among Patients Without Contraindications to Cath) 100% 83% 80% 67% 60% 53% 40% 38% 20% 12% 0% Cath Cath PCI PCI <48 hr CABG <48 hr CRUSADE Data: July 1, 2005-June 30, 2006 (n=31,665) Adapted from 2006 CRUSADE Results. Available at: © 2006 Duke Clinical Research Institute. Used with permission. Can Rapid Risk Stratification of Unstable Angina Patients Suppress ADverse Outcomes with Early Implementation of the ACC/AHA Guidelines (CRUSADE). Available at:

CRUSADE: Trends in Discharge Therapy Adherence
100% 94% 95% 91% 94% 89% 88% 75% 72% 74% 66% 64% 50% 25% 0% Aspirin Clopidogrel β-Blocker ACE Inhibitor Lipid- Lowering Agent Quarter 3-05 Quarter 4-05 Quarter 1-06 Quarter 3, 2005, through Quarter 2, 2006 Adapted from 2006 CRUSADE Results. Available at: © 2006 Duke Clinical Research Institute. Used with permission. Can Rapid Risk Stratification of Unstable Angina Patients Suppress ADverse Outcomes with Early Implementation of the ACC/AHA Guidelines (CRUSADE). Available at:

CRUSADE: Trends in Discharge Recommendations Adherence
100% 92% 84% 84% 81% 75% 62% 62% 50% 25% 0% Smoking Cessation Dietary Modification Cardiac Rehabilitation Counseling Referral Quarter 3-06 Quarter 4-06 Quarter 1-06 Quarter 2-06 Quarter 3, 2005, through Quarter 2, Adapted from 2006 CRUSADE Results. Available at: © 2006 Duke Clinical Research Institute. Used with permission. Can Rapid Risk Stratification of Unstable Angina Patients Suppress ADverse Outcomes with Early Implementation of the ACC/AHA Guidelines (CRUSADE). Available at:

CRUSADE: Overall Guideline Adherence Trends Over Time
100% 83.2% 80.8% 78.0% 75% 73.0% 68.1% 50% 25% 0% Quarter Quarter Quarter Quarter Quarter Available at © 2006 Duke Clinical Research Institute. Used with permission. Can Rapid Risk Stratification of Unstable Angina Patients Suppress ADverse Outcomes with Early Implementation of the ACC/AHA Guidelines (CRUSADE) Available at:

Performance Matters! Association Between Hospital Guideline Adherence and In-hospital Mortality in CRUSADE NSTE ACS NSTEMI 8 8 7 7 6 6 5 5 In-Hospital Mortality, % 4 In-Hospital Mortality, % 4 3 3 2 2 1 1 1 2 3 4 1 2 3 4 Hospital Composite Guideline Adherence Quartiles Hospital Composite Guideline Adherence Quartiles NSTE ACS = non-ST-segment elevation ACS; NSTEMI = non-ST-segment elevation MI. CRUSADE = Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes With Early Implementation of the ACC/AHA Guidelines. Adapted with permission from Peterson ED, et al. JAMA.2006;295: Peterson ED, Roe MT, Mulgund J, et al. Association between hospital process performance and outcomes among patients with acute coronary syndromes. JAMA. 2006;295:

Importance of Data-Collection Registries
Track adherence to guidelines Support local quality-improvement programs Compare practice patterns/outcomes with national benchmarks Comply with regulatory requirements Provide research data Major data-collection registries NRMI AHA “Get With The Guidelines” Patient Management Tool ACC National Cardiovascular Data Registry GRACE CRUSADE REACH NRMI. Available at: Get With The Guidelines. Available at: ACC National Cardiovascular Data Registry. Available at: GRACE. Available at: CRUSADE. Available at: REACH. Available at: National Registry of Myocardial Infarction (NRMI). Available at: AHA Get With The Guidelines Patient Management Tool. Available at: ACC National Cardiovascular Data Registry. Available at: Global Registry of Acute Coronary Events (GRACE). Available at: Can Rapid Risk Stratification of Unstable Angina Patients Suppress Adverse Outcomes with Early Implementation of the ACC/AHA Guidelines (CRUSADE). Available at: Reducing Atherothrombosis for Continued Health (REACH). Available at

CRUSADE: Latest Results in NSTEMI ACS in US: Conclusions
Care for NSTEMI ACS is improving: Continued progress in adherence to ACC/AHA Guidelines for both acute and discharge treatments More early cath, leading to earlier discharge Yet opportunities for improvement persist Largest gaps: acute GP IIb/IIIa, D/C ACE, clopidogrel “Right dosing” to reduce adverse events And can lead to even better patient outcomes! Available at © 2005 Duke Clinical Research Institute. Used with permission. Can Rapid Risk Stratification of Unstable Angina Patients Suppress ADverse Outcomes with Early Implementation of the ACC/AHA Guidelines (CRUSADE) Available at:

Conclusions Gap between knowledge of guidelines and practice
Several studies show: Critical pathways interventions improve care and improve patient outcomes Need local champions, implementation plan, and action!

Your Hospital Needs You As Champions! Introduction to Breakout Session

Breakout Session Identify a spokesperson/“team leader” for your group Identify a “Champion” who will lead critical pathways implementation at hospital (spokesperson at workshop may or may not be the “Champion”) Review sample pathways in your binder and copies of your own pathways if you have them with you Faculty will circulate and respond to questions during the breakout sessions

Breakout Session The session will be divided into 3 time periods
Review pathways (15 min.) Identify barriers to implementation (15 min.) Develop a plan of action (15 min.) At the end of each period, spokesperson will report progress to the main group

Breakout Objective #1 (15 minutes) Review the sample critical pathways and tools (last tab in your binder and on the flash drive) If you already have ACS critical pathways for STEMI and UA/NSTEMI: Identify and discuss updates that can be made to your existing pathways If you do not have ACS critical pathways for STEMI and/or UA/NSTEMI: Review the samples and begin planning customized critical pathways for your institution

Breakout Objective #2 Identify barriers to implementing critical pathways at your hospital and list potential solutions to overcoming them (15 minutes)

Breakout Objective #3 Develop a short-term and long-term plan to implement your new or updated ACS critical pathways (15 minutes)

Concluding Remarks

Conclusions Guidelines for both UA/NSTEMI and STEMI have had updates in antithrombotic therapies and interventions Major gap exists between physicians’ knowledge of guidelines and therapies received by patients Studies show that critical pathways interventions (eg, GAP, CHAMP, GTWG, CRUSADE) Improve care Are associated with improved outcomes Participation in national data registries enables multidisciplinary hospital teams to monitor and refine critical pathways and improve outcomes

Revised ACC/AHA Guidelines Coming Soon…

Success is Up to You Important to identify/recruit a “Champion” (should be first order of business when you return to the hospital if not established this evening) Begin to assemble multidisciplinary team for pathways development/implementation Establish specific goals with time frames (eg, modify template or existing pathways to include new ACC/AHA Guidelines) Schedule regular meetings to discuss progress Begin to implement the new or revised ACS Critical Pathways -- set a time goal)

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