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  1. 1. <ul><ul><ul><ul><ul><li>Charles V. Pollack Jr, MA, MD, FACEP, FAAEM </li></ul></ul></ul></ul></ul><ul><ul><li>Program Chairman </li></ul></ul><ul><ul><li>Chairman, Department of Emergency Medicine </li></ul></ul><ul><ul><li>Pennsylvania Hospital </li></ul></ul><ul><ul><li>Professor of Emergency Medicine </li></ul></ul><ul><ul><li>University of Pennsylvania </li></ul></ul><ul><ul><li>School of Medicine </li></ul></ul><ul><ul><li>Philadelphia, Pennsylvania </li></ul></ul>Cardiovascular Emergencies— New Dimensions and Critical Practice Advances Evidence-Based Management of Acute Coronary Syndromes: Optimizing Patient Outcomes in the Complex and Challenging Sphere of Cardiovascular Emergency Care Getting in the Stream of Things
  2. 2. CME-accredited symposium jointly sponsored by the University of Massachusetts Medical School and CMEducation Resources, LLC Commercial Support: Sponsored by an independent educational grant from The Medicines Company Mission statement: Improve patient care through evidence-based education, expert analysis, and case study-based management Processes: Strives for fair balance and clinical relevance; stresses on-label indications for agents discussed, and emerging evidence and information from recent studies COI: Full faculty disclosures provided in syllabus and at the beginning of the program Welcome and Program Overview
  3. 3. Program Educational Objectives <ul><li>As a result of this session, emergency physicians will: </li></ul><ul><li>Learn to identify signs, symptoms, and prognostic features of acute coronary syndromes and related cardiovascular emergencies. </li></ul><ul><li>Learn to assess and implement optimal pharmacologic interventions, especially antithrombotic therapy in the upstream setting, for patients presenting with manifestations of ACS and related cardiovascular disease emergencies. </li></ul><ul><li>Learn to characterize, identify, and evaluate the safety, efficacy, and side effects of myriad therapeutic options used for acute ischemic coronary syndromes including, aspirin, antiplatelet agents, direct thrombin inhibitors, UFH, LMWHs, and factor Xa inhibitors — with a focus on new 2007 ACC/AHA UA/NSTEMI Guidelines </li></ul>
  4. 4. Program Faculty Program Chairman   Charles V. Pollack Jr, MA, MD, FACEP, FAAEM Chairman, Department of Emergency Medicine Pennsylvania Hospital Professor of Emergency Medicine University of Pennsylvania School of Medicine Philadelphia, Pennsylvania   Distinguished Presenters Judd E. Hollander, MD Professor and Clinical Research Director Department of Emergency Medicine University of Pennsylvania Philadelphia, Pennsylvania   Sunil Rao, MD, FACC Director of Interventional Cardiology Veterans Administration Medical Center Assistant Professor Division of Cardiovascular Medicine Duke University Medical Center Durham, North Carolina 
  5. 5. COI Faculty Disclosures   Charles V. Pollack Jr, MA, MD, FACEP, FAAEM Grant/Research Support: GlaxoSmithKline Consultant: The Medicines Co., Schering-Plough, Sanofi-Aventis, BMS, Genentech Speaker’s Bureau: Schering-Plough, Sanofi-Aventis, BMS, Genentech Judd E. Hollander, MD Grant/Research Support: Sanofi-Aventis, Biosite, Scios, The Medicines Company Consultant: Sanofi-Aventis, Biosite, Scios, The Medicines Company Speaker’s Bureau: Sanofi-Aventis, Biosite, Scios, The Medicines Company Sunil Rao, MD, FACC Grant/Research Support: Cordis Consultant: Sanofi-Aventis, The Medicines Company Speaker’s Bureau: Sanofi-Aventis, The Medicines Company, Cordis  
  6. 6. Acute Coronary Syndrome The 2007 ACC/AHA UA/NSTEMI Guidelines From the ED to CCU and Cath Lab — Adherence Yields Better Outcomes <ul><ul><ul><ul><ul><li>Charles V. Pollack Jr, MA, MD, FACEP, FAAEM </li></ul></ul></ul></ul></ul><ul><ul><li>Program Chairman </li></ul></ul><ul><ul><li>Chairman, Department of Emergency Medicine </li></ul></ul><ul><ul><li>Pennsylvania Hospital </li></ul></ul><ul><ul><li>Professor of Emergency Medicine </li></ul></ul><ul><ul><li>University of Pennsylvania </li></ul></ul><ul><ul><li>School of Medicine </li></ul></ul><ul><ul><li>Philadelphia, Pennsylvania </li></ul></ul>Getting in the (Up)Stream of Things
  7. 7. Changing the Calculation Assessing Adherence to Guidelines <ul><li>“ We need to invert the current equation to calculate an opportunity score for ACS patients rather than a risk score. Patients with higher baseline risks, such as the elderly, would have higher opportunity scores for benefit, even allowing for some of the greater risks from the treatment.” </li></ul>Anderson HV, Bach RG, J Am Coll Cardiol 2005;46:1488-9.
  8. 8. Acute Coronary Syndromes Clinical Spectrum and Presentation + + Ischemic Discomfort at Rest No ST-segment Elevation Non-Q-wave MI Unstable Angina Q-wave MI ST-segment Elevation + + (  : positive cardiac biomarker) Emergency Department In-hospital 6-24hrs Presentation NSTEMI
  9. 9. SYNERGY 1994 1995 1996 1997 1998 1999 2000 2002 2003 2004 2005 2006 2001 Bleeding risk Ischemic risk ACUITY ISAR-REACT 2 Milestones in ACS Management ICTUS Adapted from and with the courtesy of Steven Manoukian, MD LMWH ESSENCE CURE Clopidogrel GP IIb/IIIa blockers PRISM-PLUS PURSUIT TACTICS TIMI-18 Early invasive PCI ~ 5% stents ~85% stents Drug-eluting stents OASIS-5 [ Fondaparinux ] Anti-Thrombin Rx Anti-Platelet Rx Treatment Strategy Heparin Aspirin Conservative Bivalirudin REPLACE 2
  10. 10. We Must Risk Stratify Patients with Chest Pain <ul><li>Three levels of risk stratification are pertinent to Emergency Department Management </li></ul><ul><ul><li>Low , intermediate, or high risk that ischemic symptoms are a result of CAD </li></ul></ul><ul><ul><li>Low, intermediate , or high risk of short-term death or nonfatal MI from ACS </li></ul></ul><ul><ul><li>Dynamic, ongoing risk-oriented evaluation of low- or intermediate-risk patients for “conversion” to high-risk status that is linked to intensity of treatment </li></ul></ul>
  11. 11. “ Dynamic Risk Stratification” Tools <ul><li>History and Physical </li></ul><ul><li>Standard EKG and non-standard EKG leads </li></ul><ul><ul><li>15-lead ECGs should, perhaps, be “standard” in all but very-low-risk patients </li></ul></ul><ul><li>Biomarkers </li></ul><ul><ul><li>CPK-MB, Troponins I and T, Myoglobin </li></ul></ul><ul><ul><li>Ischemia-Modified Albumin </li></ul></ul><ul><li>Non-Invasive Imaging </li></ul><ul><ul><li>Echocardiogram </li></ul></ul><ul><ul><li>Stress testing </li></ul></ul><ul><ul><li>Technetium-99m-sestamibi </li></ul></ul><ul><li>Predictive Indices/Schemes </li></ul><ul><ul><li>Better as research tools than for real-time clinical decision-making </li></ul></ul>
  12. 12. <ul><li>Braunwald E, Antman EM, Beasley JW, et al: ACC/AHA guidelines 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). J Am Coll Cardiol 2000;36:970-1062 (2002 update at www.acc.org ; summary in Circulation 2002;106:1893-1900) </li></ul><ul><li>Pollack CV, Roe MT, Peterson ED: 2002 Update to the ACC/AHA guidelines for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction: Implications for emergency department practice. Ann Emerg Med 2003;41:355-69 </li></ul>NSTE ACS — Optimal Therapy: 2002
  13. 13. <ul><li>Anderson JL, Adams CD, Antman EM, et al. 2007 guidelines for the management of patients with unstable angina/non-ST-segment-elevation myocardial infarction: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines. J Am Coll Cardiol 2007;50:e1-e157, and Circulation 2007;116:e148-e304, and at www.acc.org and at www.americanheart.org . </li></ul><ul><li>Pollack CV, Braunwald E: 2007 Update to the ACC/AHA guidelines for the management of patients with unstable angina and non-ST-segment elevation myocardial infarction: Implications for emergency department practice. Ann Emerg Med 2007, in press. </li></ul>NSTE ACS — Optimal Therapy, 2007
  14. 14. “ The Guidelines” Classes of Recommendations <ul><li>Intervention is useful and effective </li></ul><ul><li>Evidence supportive; awaiting confirming data </li></ul><ul><li>Evidence conflicts/opinions differ; neutral statement </li></ul><ul><li>Intervention is not useful/effective and may be harmful </li></ul>I IIa IIb III
  15. 15. Evidence-Based Approach to ACS Weighing the Evidence <ul><li>Class I: Benefit > > Risk </li></ul><ul><li>Class IIa: Benefit > Risk </li></ul><ul><li>Class IIb: Benefit > Risk </li></ul><ul><li>Class III: Risk > Benefit </li></ul>
  16. 16. “ The Guidelines” Weighing the Evidence <ul><li>Weight of Evidence Grades </li></ul><ul><li>= Data from many large, randomized trials </li></ul><ul><ul><li>= Data from fewer, smaller randomized trials, careful analyses of nonrandomized studies, observational registries </li></ul></ul><ul><ul><li>= Expert consensus </li></ul></ul>
  17. 17. What Do The Guidelines Mean for Emergency Medicine Practice? <ul><li>Objective approach to risk stratification and treatment </li></ul><ul><li>Driven by risk, not patient geography </li></ul><ul><li>Multidisciplinary </li></ul><ul><li>Provides a foundation for communication, collaboration, and continuum of care from ED to cardiology service </li></ul><ul><li>2007 Guidelines push for that continuum to be compressed in duration </li></ul>
  18. 18. <ul><li>Acute </li></ul><ul><li>Coronary </li></ul><ul><li>Syndrome </li></ul>What Do The Guidelines Mean for Emergency Medicine Practice?
  19. 19. <ul><li>Acute </li></ul><ul><li>Controversy </li></ul><ul><li>Syndrome </li></ul>What Do The Guidelines Mean for Emergency Medicine Practice?
  20. 20. <ul><li>Acute </li></ul><ul><li>Confusional </li></ul><ul><li>Syndrome </li></ul>What Do The Guidelines Mean for Emergency Medicine Practice?
  21. 21. Acute Confounded Syndrome “ The Writing Committee believes that inadequate unconfounded, comparative information is available to recommend a preferred [anticoagulation] regimen when an early, invasive strategy is used for UA/NSTEMI, and physician and health care system preference, together with individualized patient application, is advised.” UA/NSTEMI Strategy Overview ACC/AHA 2007 Guidelines for the Management of UA/NSTEMI. August 6, 2007, Circulation.
  22. 22. <ul><li>Acute </li></ul><ul><li>Contentiousness </li></ul><ul><li>Syndrome </li></ul>What Do The Guidelines Mean for Emergency Medicine Practice?
  23. 23. <ul><li>Acute </li></ul><ul><li>Collaboration </li></ul><ul><li>Syndrome </li></ul>What Do The Guidelines Mean for Emergency Medicine Practice?
  24. 24. Big Picture: Early Invasive Vs. Initial Conservative Therapy “ An early invasive strategy (i.e., diagnostic angiography with intent to perform revascularization) is indicated in initially stabilized UA/NSTEMI patients (without serious comorbidities or contraindications to such procedures) who have an elevated risk for clinical events .” “ In initially stabilized patients, an initially conservative (i.e., a selectively invasive) strategy may be considered as a treatment strategy for UA/NSTEMI patients (without serious comorbidities or contraindications to such procedures) who have an elevated risk for clinical events, including those who are troponin positive .” “ The decision to implement an initial conservative (vs. initial invasive) strategy in these patients may be made by considering physician and patient preference .” UA/NSTEMI Strategy Overview ACC/AHA 2007 Guidelines for the Management of UA/NSTEMI. August 6, 2007, Circulation.
  25. 25. Algorithm for Evaluation and Management of Patients Suspected of Having ACS ACC/AHA 2007 Guidelines for the Management of UA/NSTEMI. August 6, 2007, Circulation. A Symptoms Suggestive of ACS Noncardiac Diagnosis Unstable Angina Treatment as indicated by alternative diagnosis See ACC/AHA Guidelines for Chronic Stable Angina BI B2 Possible ACS Definite ACS B3 B4
  26. 26. Algorithm for Evaluation and Management of Patients Suspected of Having ACS ACC/AHA 2007 Guidelines for the Management of UA/NSTEMI. August 6, 2007, Circulation. Possible ACS Nondiagnostic ECG Normal initial serum cardiac biomarkers OBSERVE 12 hours or more from symptom onset No recurrent pain, negative follow-up studies Recurrent pain, positive follow-up studies Diagnosis OF ACS confirmed Admit to hospital Manage via acute ischemia pathway Stress study to provoke ischemia Consider evaluation of LV function if ischemia is present (tests may be performed either prior to discharge or as outpatient D1 E1 F2 F1 G1 H3
  27. 27. Algorithm for Evaluation and Management of Patients Suspected of Having ACS ACC/AHA 2007 Guidelines for the Management of UA/NSTEMI. August 6, 2007, Circulation. Positive Diagnosis of ACS confirmed or highly likely Admin to hospital Manage via acute ischemia pathway H2 H3 Stress study to provoke ischemia Consider evaluation of LV function if ischemia is present (tests may be performed either prior to discharge or as outpatient G1 Negative Potential diagnoses: Nonischemic discomfort; low-risk ACS Arrangements for outpatient follow-up H1 I1
  28. 28. Specific Recommendations, Class Designation, and Levels Of Evidence Initial Invasive Strategy: What’s New? UA/NSTEMI Strategy Overview
  29. 29. New Strategies: Anticoagulants “ Two new anticoagulants, fondaparinux and bivalirudin , have undergone favorable testing in clinical trials and are recommended as alternatives to unfractionated heparin (UFH) and low-molecular-weight heparins (LMWHs) for specific or more general applications.” UA/NSTEMI Strategy Overview ACC/AHA 2007 Guidelines for the Management of UA/NSTEMI. August 6, 2007, Circulation.
  30. 30. Algorithm for Patients With UA/NSTEMI Managed by an Initial Invasive Strategy ACC/AHA 2007 Guidelines for the Management of UA/NSTEMI. August 6, 2007, Circulation. Diagnosis of UA/NSTEMI is Likely or Definite ASA (Class I, LOE:A)* Clopidogrel if ASA intolerant (Class I, LOE: A) Select Management Strategy † Invasive Strategy Initiate anticoagulant therapy (Class I, LOE: A): Acceptable options*: enoxaparin or UFH (Class I, LOE: A), bivalirudin or fondaparinux are preferable (Class I, LOE: B) Initial Conservative Strategy A B1
  31. 31. Algorithm for Patients With UA/NSTEMI Managed by an Initial Invasive Strategy ACC/AHA 2007 Guidelines for the Management of UA/NSTEMI. August 6, 2007, Circulation. Prior to Angiography Initiate at least one (Class I, LOE: A) or Both (Class IIa, LOE: B) of the following: Clopidogrel* ‡ IV GP IIb/IIIa inhibitor* ‡ Factors favoring administration of both clopidogrel and GP IIb/IIIa inhibitor include: Delay to angiography High risk features Early recurrent ischemic discomfort Diagnostic Angiography B2
  32. 32. Welcome To This Program! <ul><li>Move from confusion, controversy, and contentiousness to collaboration and more evidence-based care </li></ul><ul><li>Give emergency physicians familiarity they need with ACC/AHA 2007 UA/NSTEMI Guidelines in order to: </li></ul><ul><ul><li>(1) Treat patients optimally and; </li></ul></ul><ul><ul><li>(2) Work effectively and collegially with their cardiology consultants </li></ul></ul>
  33. 33. Recent Clinical Trials in STEMI and NSTEMI What New Evidence Tells Us and Implications for ED Cardiovascular Management Judd E. Hollander, MD Professor and Clinical Research Director Department of Emergency Medicine University of Pennsylvania Getting in the Stream of Things
  34. 34. ACS: Recent Clinical Trials in STEMI and NSTEMI Getting in the (Up)Stream of Things
  35. 35. PCI versus Fibrinolysis Systematic Overview Short term (4-6 weeks) Keeley EC, Boura JA, Grines CL. Lancet. 2003. P=0.0002 P=0.0003 P<0.0001 P<0.0001 P=0.0004 (23 RCTs, n=7,739)
  36. 36. Early Presenting Patients — Primary PCI versus Fibrinolytics p=0.058 p=0.47 CAPTIM p<0.02 PRAGUE-2 Widimsky P, et al. Eur Heart J . 2003;24(1):94-104. Steg PG, et al. Circulation . 2003;108(23):2851-2856.
  37. 37. Mortality Rates with Primary PCI as a Function of PCI Time Delay P =.006 Circle sizes = sample size of the study Solid line = weighted metaregression Nallamothu BK, Bates ER. Am J Cardiol . 2003;92:824-826. 62 min Benefit Favors PCI Harm Favors Lysis For every 10 min delay to PCI: 1% reduction in mortality difference towards lytics 5 10 15 0 Absolute risk difference in death (%) – 5 0 20 40 60 80 100 PCI-related time delay (door to balloon - door to needle)
  38. 38. Can We Improve STEMI Care With Fibrinolysis? Optimizing STEMI Outcomes
  39. 39. Adjunctive Medications — No Effect in STEMI <ul><li>Double-bolus t-PA </li></ul><ul><li>TNK </li></ul><ul><li>rPA </li></ul><ul><li>nPA </li></ul><ul><li>GP IIb/IIIa inhibition +lytic </li></ul><ul><li>Oral GP IIb/IIIa </li></ul><ul><li>Hirudin </li></ul><ul><li>Pexulizamab </li></ul><ul><li>Magnesium </li></ul><ul><li>Adenosine </li></ul><ul><li>PSGL </li></ul><ul><li>GIK </li></ul>USEFUL ADJUNCTS Aspirin Enoxaparin Clopidogrel
  40. 40. CLARITY–TIMI 28 Double-blind, randomized, placebo-controlled trial in 3491 Patients, aged 18 – 75 yr, with STEMI <12 hr Fibrinolytic, ASA, heparin Clopidogrel 300 + 75 mg qd Coronary angiogram (2 – 8 days) Primary endpoint Occluded artery (TIMI flow grade 0/1) or death/MI by time of angio Randomized Placebo Study drug 30-d clinical follow-up Open-label clopidogrel per MD in both groups Sabatine MS, et al. N Engl J Med . 2005;352:1179-1189.
  41. 41. Placebo Clopidogrel P =.001 Odds Ratio: 0.64 (95% CI, 0.53-0.76) 1.0 0.4 0.6 0.8 1.2 1.6 Clopidogrel Better Placebo Better n=1752 n=1739 36% Odds Reduction 15.0 21.7 Occluded Artery or Death/MI (%) Sabatine MS, et al. N Engl J Med . 2005;352:1179-1189. CLARITY–TIMI 28 0 5 10 15 20 25
  42. 42. CV Death, MI, and Urgent Revascularization Days Endpoint (%) 0 5 10 15 0 5 10 15 20 25 30 Placebo Clopidogrel Odds Ratio: 0.80 (95% CI, 0.65 – 0.97) P =.03 20% Sabatine MS, et al. N Engl J Med . 2005;352:1179-1189.
  43. 43. CLARITY–TIMI 28: Bleeding NS 7.2 7.5 In those undergoing CABG NS 7.9 9.1 CABG w/in 5 d of study med 0.9 1.7 0.7 0.5 1.1 Placebo (%) NS NS NS NS NS P 1.9 TIMI major 1.6 0.5 1.0 1.3 Clopidogrel (%) TIMI minor ICH Through 30 days TIMI minor TIMI major Through angiography Outcome Sabatine MS, et al. N Engl J Med . 2005;352:1179-1189.
  44. 44. EXTRACT: TIMI 25 STEMI < 6 hours Lytic eligible Lytic choice by MD (TNK, tPA, rPA, SK) ENOXAPARIN < 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 Double-blind, double-dummy ASA Day 30 1 ° Efficacy Endpoint: Death or Nonfatal MI 1° Safety Endpoint: TIMI Major Hemorrhage UFH 60 U / kg bolus (4000 U) Inf 12 U / kg / h (1000 U / h) Duration: at least 48 h Cont’d at MD discretion
  45. 45. Primary End Point (ITT) — Death or Nonfatal MI Primary End Point (%) ENOX UFH Relative Risk 0.83 (0.77 to 0.90) P<0.0001 Days 9.9% 12.0% Lost to follow up = 3 17% RRR Antman EM, et al. NEJM 354:1477-1488
  46. 46. Death or Nonfatal MI — Day 30 Medical Therapy vs Any PCI 0.0004 0.001 % Events N = 15,223 (75%) N = 4,676 (23%) P Value 9.7 RRR 16% 11.4 13.8 10.7 RRR 23% Enoxaparin UFH Antman EM, et al. NEJM 354:1477-1488
  47. 47. Death or Nonfatal MI — Day 30 Clopidogrel Use 0.0005 0.0006 % Events N = 14,752 (78%) N = 5,727 (28%) P Value 10.4 RRR15% 12.2 11.4 8.7 RRR24% * 2546 clopidogrel treated patients did not undergo PCI Enoxaparin UFH Antman EM, et al. NEJM 354:1477-1488
  48. 48. Net Clinical Benefit at 30 Days  1 1.25 0.9 0.8 Death or Nonfatal MI or Nonfatal ICH Death or Nonfatal MI or Nonfatal Major Bleed Death or Nonfatal MI or Nonfatal Disabl. Stroke ENOX Better UFH Better RR UFH (%) ENOX (%) RRR (%) 12.3 10.1 18 12.8 11.0 14 12.2 10.1 17 Prespecified Definitions P <0.0001 P <0.0001 P <0.0001 Antman EM, et al. NEJM 354:1477-1488
  49. 49. Trial Results In Perspective — PCI vs Lysis for STEMI % Events (30-42 Days) Reinfarction Lytic Arms (UFH) PCI Arms ENOX Overview of 23 RCTs The advance in adjunctive therapy with enoxaparin has narrowed the gap between PCI and Lysis as reperfusion for STEMI Keeley EC, Boura JA, Grines CL. Lancet. 2003.
  50. 50. 12,000 Patients with STEMI < 12 h of symptom onset Inclusion: ST  2 mm prec leads or  1 mm limb leads Exclusion: Contraindicated. For anticoagulant, INR > 1.8, pregnancy, ICH<12 mo <ul><li>UFH </li></ul><ul><li>not </li></ul><ul><li>indicated </li></ul>UFH not indicated Study Design: Randomized, Double Blind, Double Dummy Lytics (SK, TPA, TNK, RPA), Primary PCI or no reperfusion ( eg . late) Stratification <ul><li>UFH indicated </li></ul>UFH indicated Randomization Randomization Fondaparinux 2.5 mg Placebo Fondaparinux 2.5 mg UFH Keeley EC, Boura JA, Grines CL. Lancet. 2003.
  51. 51. Primary Efficacy Outcome Death/MI at 30 Days Days Cumulative Hazard 0.0 0.02 0.04 0.06 0.08 0.10 0.12 0 3 6 9 12 15 18 21 24 27 30 UFH/Placebo Fondaparinux HR 0.86 95% CI 0.77- 0.96 P=0.008 Keeley EC, Boura JA, Grines CL. Lancet. 2003.
  52. 52. Efficacy of Fondaparinux by Strata on Death/MI Interaction P=0.88 Keeley EC, Boura JA, Grines CL. Lancet. 2003. 0.76 - 1.02 0.88 11.2 12.7 Stratum II (n = 6434) (Fonda vs. UFH) 0.76 - 0.99 0.87 15.9 17.3 Stratum I (n = 5658) (Fonda vs. Placebo) 95% CI HR Fonda Control No. of Events (%)
  53. 53. STEMI — Conclusions <ul><li>There is still a role for fibrinolytic therapy in STEMI </li></ul><ul><li>Adjuvant clopidogrel and/or enoxaparin improve outcomes in combination with fibrinolytics </li></ul><ul><li>Fondaparinux improves outcomes relative to placebo </li></ul>
  54. 54. ACS: Recent Clinical Trials in STEMI and NSTEMI Getting in the (Up) Stream of Things
  55. 55. 5.95 6.33 5.16 5.07 4.97 4.16 0 1 2 3 4 5 6 7 Hospital Composite Quality Quartiles % In-hospital Mortality Every 10%  in guidelines adherence = 11%  in mortality (OR=0.89, 95% CI, 0.81-0.98) Peterson ED et al. J Am Coll Cardiol . 2004;43(suppl A):406A. Abstract 1077-71. The Link Between Guideline Implementation and Mortality Is Clear  25% 25% – 50% 50% – 75%  75% Adjusted Unadjusted 4.63 4.17
  56. 56. Antithrombotic and Antiplatelet Therapy in ACS ACC/AHA Guideline Update for UA and NSTEMI. 2002.
  57. 57. CURE: C lopidogrel in U nstable Angina to Prevent R ecurrent E vents
  58. 58. CURE: Primary End Point: MI/Stroke/CV Death (N=12,562*)
  59. 59. CURE Safety
  60. 60. SYNERGY Design Primary endpoint: Death or MI at 30 days High-risk ACS Patients Early invasive strategy Other therapy per ACC/AHA guidelines (ASA,  -blocker, ACE, clopidogrel, GP IIb/IIIa) SYNERGY Trial Investigators. JAMA 2004;292:45-54 <ul><li>At least 2 of 3 required: </li></ul><ul><li>Age  60 </li></ul><ul><li>ST  (transient) or  </li></ul><ul><li>(+) CK-MB or troponin </li></ul>Enoxaparin IV UFH Randomize (n = 10,000) 60 U/kg  12 U/kg/h (aPTT 50 – 70 sec) 1 mg/kg SC Q12 h
  61. 61. Death and MI at 30 Days HR 0.96 (0.86 – 1.06) 1.1 SYNERGY Trial Investigators. JAMA 2004;292:45-54  1 Hazard Ratio (95% CI) Enoxaparin UFH Better Better 30-day Death/MI 0.8 1.0 1.2 0 5 10 15 20 25 30 0.8 0.9 0.95 1.0 Freedom from Death / MI Days from Randomization 0.85 Enoxaparin UFH
  62. 62. 6-Month Survival — Death/MI (Intention-to-Treat) HR (95% CI) = 0.978 (0.891, 1.075) 0 30 60 90 120 150 180 0.7 0.75 0.8 0.85 0.9 0.95 1 Freedom from Death / MI at 6 Months Days from Randomization UFH Enoxaparin SYNERGY Trial Investigators. JAMA 2004;292:45-54
  63. 63. Bleeding Events <ul><li> </li></ul><ul><li>GUSTO severe 2.7 2.2 0.08 </li></ul><ul><li>TIMI major (clinical): 9.1 7.6 0.008 CABG-related 6.8 5.9 0.08 Non-CABG-related 2.4 1.8 0.03 </li></ul><ul><li>Hb/HCT drop (algorithm) 15.2 12.5 < 0.001 </li></ul><ul><li>Any RBC transfusion 17.0 16.0 0.16 </li></ul><ul><li>ICH < 0.1 < 0.1 NS </li></ul>Enoxaparin UFH P value (n = 4,993) (n = 4,985) — %— SYNERGY Trial Investigators. JAMA 2004;292:45-54
  64. 64. <ul><li>Enoxaparin was not superior to unfractionated heparin but was noninferior for non–ST-segment elevation ACS </li></ul><ul><li>More bleeding was observed with enoxaparin </li></ul><ul><li>Enoxaparin was an alternative to unfractionated heparin for non–ST-segment elevation ACS in high-risk patients being managed with a rapid transition to intervention </li></ul><ul><li>Do not change from </li></ul><ul><ul><li>UFH to Enoxaparin, or </li></ul></ul><ul><ul><li>Enoxaparin to UFH </li></ul></ul><ul><li>Stay with the agent initiated in the ED </li></ul><ul><ul><li>Collaboration </li></ul></ul><ul><ul><li>Pathways </li></ul></ul><ul><ul><li>Bivalirudin may be exception </li></ul></ul>SYNERGY: Conclusions/Caveats
  65. 65. OASIS-5 Study Design Yusuf S, et al. N Engl J Med . 2006;354(14):1464-76 Patients w/ NSTE ACS Chest pain < 24 hours 2/3: Age > 60 ST-segment ∆ ↑ cardiac markers ASA, clopidogrel, IIb/IIIa, planned cath per local practice Exclude Age < 21 Contraindication to enox Hemorrhagic stroke < 12 mo Creat > 3 mg/dL (265 umol/L) Randomize n = 20,000 Fondaparinux 2.5 mg sc qd Enoxaparin 1 mg/kg sc bid PCI < 6 h: IV fondaparinux 2.5 mg w/o IIb/IIIa, 0 w/ IIb/IIIa PCI > 6h: IV fondaparinux 5 mg w/o IIb/IIIa, 2.5 mg w/ IIb/IIIa Primary Efficacy: Death, MI, refractory ischemia at 9 days Safety: Major bleeding at 9 days Risk/Benefit: Death, MI, refractory ischemia and major bleeding at 9 days Secondary Above and each component separately at day 30 and 6 months PCI < 6 h: no UFH PCI > 6h: IV UFH 100 U/kg w/o IIb/IIIa 60 U/kg w/ IIb/IIIa Outcomes
  66. 66. OASIS–5: Efficacy at Day 9 0.8 1 1.2 Non-inferiority Margin = 1.185 Hazard Ratio Fonda Better Enox Better Yusuf S, et al. N Engl J Med . 2006;354(14):1464-76 —— %—— 5.9 5.8 Death/MI/RI 2.05 1.9 Refract Isch 2.7 2.7 MI 1.8 1.9 Death 4.1 4.1 Death/MI Fonda Enox
  67. 67. OASIS–5: Bleeding Rates at Day 9 Yusuf S, et al. N Engl J Med . 2006;354(14):1464-76 < 0.0001 < 0.0001 < 0.0001 < 0.0001 P 0.35 (0.28 – 0.43) 0.54 (0.41 – 0.73) 0.53 (0.45 – 0.62) 0.44 (0.39 – 0.51) HR (95% CI) 3.2 7.0 Total Bleed (%) 1.1 3.1 Minor Bleed (%) 10,057 10,021 No. Randomized 0.7 1.3 TIMI Major Bleed (%) 2.1 4.0 Major Bleed (%) Fonda Enox Outcome
  68. 68. Efficacy End Points at 6 Months Yusuf S, et al. N Engl J Med . 2006;354(14):1464-76 0.04 1.3% 1.7% Stroke 0.007 11.3% 12.5% Death/MI/stroke* NS 6.3% 6.6% MI 0.05 5.8% 6.5% Death 0.05 10.5% 11.4% Death/MI 0.06 12.3% 13.2% Death/MI/ refractory ischemia P value Fondaparinux Enoxaparin End point
  69. 69. PCI — Procedural Complications Yusuf S, et al. N Engl J Med . 2006;354(14):1464-76 <0.0001 1.6% 4.4% Large hematoma 0.39 1.0% 1.6% Pseudo-aneurysm <0.0001 3.3% 8.1% Vascular access 0.001 1.3% 0.5% Catheter thrombus 0.20 1.5% 1.1% Abrupt closure 0.18 9.6% 8.6% Any procedural complication 18.8% 53.8% Any UFH during PCI P value Fondaparinux n=3118 Enoxaparin n=3089 Events (30 Days)
  70. 70. ACUITY Study Design – First Randomization <ul><li>Moderate-high risk unstable angina or NSTEMI undergoing an invasive strategy (N = 13,819) </li></ul>Moderate- high risk ACS Aspirin in all Clopidogrel dosing and timing per local practice ACUITY Design. Stone GW et al. AHJ 2004;148:764–75 Primary endpoint: “Net Clinical Composite” Death, MI, TVR, Bleeding Angiography within 72h UFH or Enoxaparin + GP IIb/IIIa Bivalirudin + GP IIb/IIIa Bivalirudin Alone R* Medical management PCI CABG
  71. 71. ACUITY Study Design – Second Randomization <ul><li>Moderate-high risk unstable angina or NSTEMI undergoing an invasive strategy (N = 13,819) </li></ul>Moderate- high risk ACS Angiography within 72h ACUITY Design. Stone GW et al. AHJ 2004;148:764–75 Aspirin in all Clopidogrel dosing and timing per local practice Medical management PCI CABG Bivalirudin Alone UFH or Enoxaparin Routine upstream GPI in all pts GPI started in CCL for PCI only R Bivalirudin R Routine upstream GPI in all pts GPI started in CCL for PCI only
  72. 72. 3 Primary Endpoints (at 30 Days) 1. Composite net clinical benefit = 2. Ischemic composite or 3. Major bleeding <ul><li>Death from any cause </li></ul><ul><li>Myocardial infarction </li></ul><ul><li>- During medical Rx: Any biomarker elevation >ULN </li></ul><ul><ul><li>- Post PCI: CKMB >ULN with new Q waves or >3x ULN w/o Q waves </li></ul></ul><ul><ul><li>- Post CABG: CKMB >5x ULN with new Q waves, >10x ULN w/o Q waves </li></ul></ul><ul><li>Unplanned revascularization for ischemia </li></ul>Stone GW, McLaurin BT. NEJM . 2006 Nov 23;355(21):2203-16.
  73. 73. 3 Primary Endpoints (at 30 Days) 1. Composite net clinical benefit = 2. Ischemic composite or 3. Major bleeding <ul><li>Non CABG related bleeding </li></ul><ul><ul><li>– Intracranial bleeding or intraocular bleeding </li></ul></ul><ul><ul><ul><li>– Retroperitoneal bleeding </li></ul></ul></ul><ul><ul><li>– Access site bleed requiring intervention/surgery </li></ul></ul><ul><ul><li>– Hematoma ≥5 cm </li></ul></ul><ul><ul><li>– Hgb  ≥3g/dL with an overt source or  ≥4g/dL w/o overt source </li></ul></ul><ul><ul><li>– Blood product transfusion </li></ul></ul><ul><ul><li>-– Reoperation for bleeding </li></ul></ul>Stone GW, McLaurin BT. NEJM . 2006 Nov 23;355(21):2203-16.
  74. 74. Ischemic Composite Endpoint 0 5 10 15 0 5 10 15 20 25 30 35 Cumulative Events (%) Days from Randomization Estimate P (log rank) 7.3% UFH/Enoxaparin + IIb/IIIa (N=4603) Bivalirudin + IIb/IIIa (N=4604) 0.37 7.7% Bivalirudin alone (N=4612) 0.30 7.8% Stone GW, McLaurin BT. NEJM . 2006 Nov 23;355(21):2203-16.
  75. 75. Major Bleeding Endpoint Cumulative Events (%) Days from Randomization Estimate P (log rank) Bivalirudin + IIb/IIIa (N=4604) 0.41 5.3% Bivalirudin alone (N=4612) <0.0001 3.0% Stone GW, McLaurin BT. NEJM . 2006 Nov 23;355(21):2203-16. 0 5 10 15 0 5 10 15 20 25 30 35 5.7% UFH/Enoxaparin + IIb/IIIa (N=4603)
  76. 76. Net Clinical Outcome 0 5 10 15 0 5 10 15 20 25 30 35 Cumulative Events (%) Days from Randomization Stone GW, McLaurin BT. NEJM . 2006 Nov 23;355(21):2203-16. Estimate P (log rank) 11.7% UFH/Enoxaparin + IIb/IIIa (N=4603) Bivalirudin + IIb/IIIa (N=4604) 0.89 11.8% Bivalirudin alone (N=4612) 0.014 10.1%
  77. 77. ACUITY Mortality at 1-year 0 30 60 90 120 150 180 210 240 270 300 330 360 390 0 4 5 Mortality (%) Days from Randomization 2 1 Bivalirudin+GPI vs. Hep+GPI HR [95% CI] = 0.99 (0.80-1.22) 30 day 3 Bivalirudin alone vs. Hep+GPI HR [95% CI] = 0.95 (0.77-1.18) Stone GW, McLaurin BT. NEJM . 2006 Nov 23;355(21):2203-16. UFH/Enoxaparin + IIb/IIIa Bivalirudin + IIb/IIIa Bivalirudin alone Estimate P (log rank) 1.4% 0.53 1.6% 0.39 1.6% — Estimate P (log rank) 4.4% 0.93 4.2% 0.66 3.8% 1 year — p=0.90
  78. 78. <ul><li>Bivalirudin plus IIb/IIIa had similar ischemic outcomes, similar bleeding, and similar net clinical benefit to heparin plus IIb/IIIa </li></ul><ul><li>Bivalirudin alone (with provisional IIb/IIIa use) had similar ischemic outcomes, less bleeding, and superior net clinical benefit to heparin plus IIb/IIIa </li></ul><ul><li>Whether or not reductions in bleeding will translate into longer-term reductions in mortality is yet to be determined </li></ul>ACUITY — Conclusions
  79. 79. NSTEMI Conclusions <ul><li>Old and new options for ACS </li></ul><ul><ul><li>UFH or Enoxaparin </li></ul></ul><ul><ul><li>Bivalirudin </li></ul></ul><ul><ul><li>Fondaparinux (not tested adequately in cath lab) </li></ul></ul><ul><li>Balance ischemic efficacy and safety </li></ul><ul><ul><li>Customize approach for patient and institution </li></ul></ul><ul><li>Many choices </li></ul><ul><ul><li>Collaborate with IC and CARD on clinical pathways </li></ul></ul><ul><li>Adapt ACC/AHA 2007 Guidelines to Clinical Practice in ED (Endorsed by SAEM) </li></ul>
  80. 80. Acute Coronary Syndrome The 2007 ACC/AHA UA/NSTEMI Guidelines — From the ED to the CCU and Cath Lab Adherence as the Road to Better Outcomes Getting in the (Up)Stream of Things <ul><ul><ul><ul><ul><li>Charles V. Pollack Jr, MA, MD, FACEP, FAAEM </li></ul></ul></ul></ul></ul><ul><ul><li>Chairman, Department of Emergency Medicine </li></ul></ul><ul><ul><li>Pennsylvania Hospital </li></ul></ul><ul><ul><li>Professor of Emergency Medicine </li></ul></ul><ul><ul><li>University of Pennsylvania </li></ul></ul><ul><ul><li>School of Medicine </li></ul></ul><ul><ul><li>Philadelphia, Pennsylvania </li></ul></ul>
  81. 81. 1990 1992 1994 1996 1998 2000 2002 1990 ACC/AHA AMI R. Gunnar 1994 AHCPR/NHLBI UA E. Braunwald 1996 1999 Revised Updated ACC/AHA AMI T. Ryan 2004 2007 Revised Updated ACC/AHA STEMI E. Antman 2000 2002 2007 Revised Updated Revised ACC/AHA UA/NSTEMI E. Braunwald J. Anderson 2004 2007 Evolution of Guidelines for ACS
  82. 82. Sea and Stream Changes in ACS <ul><li>The 2007 Guidelines have created a “Sea Change” in the ED and IC T herapeutic approach to care of patients with UA/NSTEMI </li></ul><ul><ul><li>New “Streams” of care, with new anticoagulants, are in play </li></ul></ul><ul><ul><li>Clopidogrel use has been liberalized </li></ul></ul><ul><ul><li>Bleeding end points play a more important role in drug selection </li></ul></ul><ul><ul><li>Dogmatism is out, customization is in </li></ul></ul><ul><ul><li>Collaboration is emphasized </li></ul></ul>
  83. 83. Applying Classification of Recommendations Class III Risk ≥ Benefit No additional studies needed Procedure/Treatment should NOT be performed/administered SINCE IT IS NOT HELPFUL AND MAY BE HARMFUL Class IIb Benefit ≥ Risk Additional studies with broad objectives needed; Additional registry data would be helpful Procedure/Treatment MAY BE CONSIDERED Class IIa Benefit >> Risk Additional studies with focused objectives needed IT IS REASONABLE to perform procedure/administer treatment Class I Benefit >>> Risk Procedure/ Treatment SHOULD be performed/ administered Is not recommended Is not indicated Should not Is not useful/effective/ beneficial May be harmful May/might be considered May/might be reasonable Usefulness/ effectiveness is unknown/unclear/ uncertain or not well established Is reasonable Can be useful/effective/ beneficial Is probably recommended or indicated Should Is recommended Is indicated Is useful/effective/ beneficial
  84. 84. CRUSADE: A National Quality Improvement Initiative C an R apid Risk Stratification of U nstable Angina Patients S uppress AD verse Outcomes with E arly Implementation of the ACC/AHA Guidelines 2002-2007
  85. 85. Management Strategies: 2002 Guidelines Conservative versus Invasive Strategies <ul><li>Early (within 48h) invasive strategy in high-risk patients with any of the following: </li></ul><ul><li>Recurrent ischemia, despite meds </li></ul><ul><li>Elevated Troponin I or T </li></ul><ul><li>New ST-segment depression </li></ul><ul><li>New CHF symptoms </li></ul><ul><li>High-risk stress test findings </li></ul><ul><li>LV dysfunction (EF < 40%) </li></ul><ul><li>Hemodynamic instability, sustained VT </li></ul><ul><li>PCI within 6 months, prior CABG </li></ul>I IIa IIb III
  86. 86. <ul><li>Either strategy in low- to moderate-risk patients without contraindications to revascularization </li></ul><ul><li>Early invasive strategy for patients with repeated ACS presentations, without high-risk features or ongoing ischemia </li></ul>Management Strategies — 2002 Guidelines Conservative versus Invasive Strategies I IIa IIb III
  87. 87. Invasive Procedures in 2006 (Among Patients Without Contraindications To Cath) <ul><li>Median Times </li></ul><ul><li>Cath - 22 hrs </li></ul><ul><li>PCI - 21 hrs </li></ul><ul><li>CABG - 69 hrs </li></ul>
  88. 88. Management Strategies — 2007 Early Invasive versus Initial Conservative <ul><li>Early invasive: Diagnostic angiography with intent to perform revascularization </li></ul><ul><ul><li>Cath anticipated within 4-24 hours </li></ul></ul><ul><ul><li>Follows a foundation of risk-directed medical therapy </li></ul></ul><ul><li>Early Conservative (or selectively invasive ): Invasive evaluation only if optimal medical management fails </li></ul><ul><li>Note: from ED perspective, both strategies involve risk-directed, evidence-based medical therapy </li></ul>
  89. 89. <ul><li>EIS is indicated in initially stabilized UA/NSTEMI patients (without contraindications) who have an elevated risk for clinical events </li></ul><ul><li>EIS is indicated in UA/NSTEMI patients (without contraindications) who have refractory angina or hemodynamic or electrical instability </li></ul><ul><li>ICS may be considered in initially stabilized patients who have an elevated risk for clinical events (including ↑Tn) </li></ul>Management Strategies — 2007 Early Invasive versus Initial Conservative I IIa IIb III
  90. 90. <ul><li>EIS is indicated in initially stabilized UA/NSTEMI patients (without contraindications) who have an elevated risk for clinical events </li></ul><ul><li>EIS is indicated in UA/NSTEMI patients (without contraindications) who have refractory angina or hemodynamic or electrical instability </li></ul><ul><li>ICS may be considered in initially stabilized patients who have an elevated risk for clinical events (including ↑Tn) </li></ul>Management Strategies — 2007 Early Invasive vs Initial Invasive I IIa IIb III
  91. 91. <ul><li>The decision to employ an EIS vs ICS may be made by considering physician and patient preference </li></ul><ul><li>Invasive strategy may be preferable in patients with CKD </li></ul><ul><li>EIS if patient: </li></ul><ul><li>Will not consent to revascularization </li></ul><ul><li>Has too many comorbidities </li></ul><ul><li>Is low risk </li></ul>Management Strategies — 2007 Early Invasive versus Initial Conservative I IIa IIb III
  92. 92. Benefits of Early Catheterization by Risk Group Bhatt AHA 2002. % Inhospital Mortality
  93. 93. Invasive Procedure Use by Age Alexander KA, J Am Coll Cardiol 2005;46:1479-87.
  94. 94. Medical Management — 2002 Guidelines Antithrombotic Therapy <ul><li>Immediate aspirin </li></ul><ul><li>Clopidogrel, if aspirin contraindicated </li></ul><ul><li>Heparin (IV unfractionated, LMW) with antiplatelet agents listed above </li></ul><ul><li>Enoxaparin preferred over UFH unless CABG is planned within 24 hours </li></ul>I IIa IIb III
  95. 95. Acute (first 24 hours) Antithrombotic Therapies
  96. 96. Medical Management — 2007 Guidelines AntiThrombotic Therapy <ul><li>In EIS: </li></ul><ul><li>Enoxaparin or UFH </li></ul><ul><li>Bivalirudin* or fondaparinux  </li></ul><ul><li>In ICS: </li></ul><ul><li>Enoxaparin or UFH </li></ul><ul><li>Fondaparinux  </li></ul><ul><li>In ICS with ↑ risk of bleeding: Fondaparinux  </li></ul>I IIa IIb III
  97. 97. <ul><li>If ICS selected, either enoxaparin or fondaparinux  is preferred over UFH unless CABG is anticipated within 24 hours </li></ul>Medical Management — 2007 Guidelines Antithrombotic Therapy Relevant new studies for antithrombotic therapy: SYNERGY, JAMA 2004 OASIS-5, NEJM 2006 ACUITY, NEJM 2006 I IIa IIb III
  98. 98. SYNERGY: Primary Efficacy Outcome Enoxaparin is as effective as UFH in the treatment of high-risk patients with ACS undergoing a rapid invasive strategy SYNERGY Trial Investigators, JAMA 2004;292:45. HR 0.96 (0.86 – 1.06) 1.1  1 Hazard Ratio (95% CI) Enoxaparin UFH Better Better 30-day Death/MI 0.8 1.0 1.2 0 5 10 15 20 25 30 0.8 0.9 0.95 1.0 Freedom from Death / MI Days from Randomization 0.85 Enoxaparin UFH
  99. 99. OASIS-5 OASIS-5: Death/MI/RI at Day 9 Days Cumulative Hazard 0.0 0.01 0.02 0.03 0.04 0.05 0.06 0 1 2 3 4 5 6 7 8 9 Enoxaparin Fondaparinux HR 1.01 95% CI 0.90 - 1.13
  100. 100. OASIS-5 Major Bleeding at 9 Days Days Cumulative Hazard 0.0 0.01 0.02 0.03 0.04 0 1 2 3 4 5 6 7 8 9 HR 0.52 95% CI 0.44 - 0.61 P<0.001 Enoxaparin Fondaparinux OASIS-5
  101. 101. OASIS-5: 30-Day Mortality Days Cumulative Hazard 0.0 0.01 0.02 0.03 0 3 6 9 12 15 18 21 24 27 30 HR 0.83 HR 0.83 95% CI 0.71 95% CI 0.71 - - 0.97 0.97 P=0.02 Enoxaparin Fondaparinux OASIS-5
  102. 102. Patients Undergoing PCI within the first 8 Days of Randomization 0.001 3.59 (1.64 - 7.84) 29 (0.9%) 8 (0.4%) All catheter - related thrombi 0.08 2.99 (0.81 - 11.04) 9 (0.3%) 3 (0.1%) Catheter - related thrombus not resulting in clinical complications 1.16 (0.94 - 1.42) 188 (6.0%) 161 (5.2%) Abrupt closure, new thrombus with reduced flow, dissection, or no reflow 0.21 1.11 (0.94 - 1.29) 299 (9.5%) 268 (8.6%) Any complication PCI - related coronary complication 0.36 (0.26 - 0.49) 50 (1.6%) 138 (4.4%) Large hematoma 0.63 (0.40 - 0.98) 31 (1.0%) 49 (1.6%) Pseudoaneurysm <0.001 0.41 (0.33 - 0.51) 103 (3.3%) 251 (8.1%) Any complication No. of events (% of patients) Complications involving the vascular access site P Value Relative Risk (95% CI) Fondaparinux (n=3135) Enoxaparin (n=3104)
  103. 103. “ The ACUITY study, which tested bivalirudin for UA/NSTEMI, has led to a guidelines change to allow bivalirudin as an anticoagulant option .” UA/NSTEMI Strategy Overview ACC/AHA 2007 Guidelines for the Management of UA/NSTEMI. August 6, 2007, Circulation.
  104. 104. ACUITY: Primary Results – 30 days <ul><li>UFH/Enox + GP IIb/IIIa vs. Bivalirudin + GP IIb/IIIa vs. Bivalirudin Alone </li></ul>Stone GW et al. NEJM 2006;355:2203-16 P NI <0.001 P Sup = 0.015 P NI = 0.011 P Sup = 0.32 P NI <0.001 P Sup <0.001
  105. 105. Ischemic Composite Endpoint (Death, MI, unplanned revascularization for ischemia) 0 30 60 90 120 150 180 210 240 270 300 330 360 390 0 5 15 25 Ischemic Composite (%) Days from Randomization 10 20 Bivalirudin alone vs. Hep+GPI HR [95% CI] = 1.05 (0.95-1.17) Bivalirudin+GPI vs. Hep+GPI HR [95% CI] = 1.05 (0.94-1.16) UFH/Enoxaparin + GPI vs. Bivalirudin + GPI vs. Bivalirudin Alone Stone GW. ACC 2007 presentation UFH/Enoxaparin + IIb/IIIa Bivalirudin + IIb/IIIa Bivalirudin alone Estimate P (log rank) 30 day 7.4% 0.36 7.8% 0.34 7.9% — Estimate P (log rank) 16.3% 0.38 16.5% 0.31 16.4% 1 year — p=0.55
  106. 106. ACUITY Trial — Troponin Positive PCI Subgroup (N= 2949) UFH/Enoxaparin + IIb/IIIa vs. Bivalirudin Alone Stone GW et al, www.thelancet.com Vol 369 March 17, 2007. RR [95%CI] 0.93 [0.77-1.12] RR [95%CI] 1.12 [0.88-1.42] RR [95%CI] 0.59 [0.44-0.80]
  107. 107. No Thienopyridine Exposure – PCI pts* 30 Day Primary Endpoint Adverse Events *Thienopyridine at any time, any dose, up to time of PCI (Including 87 patients not receiving thienopyridine at any time) RR [95%CI] 0.61 (0.39-0.97) RR [95%CI] 1.37 (1.00-1.88) RR [95%CI] 1.07 (0.83-1.39) ACUITY PCI as presented at TCT 2006.
  108. 108. Composite Ischemia at 1 Year Hazard ratio ±95% CI Bival alone UFH/Enox + IIb/IIIa HR (95% CI) P int 0.67 Bivalirudin alone better UFH/Enox + IIb/IIIa better Actual Treatment PCI (n=5179) CABG (n=1040) Medical (n=2994) 0.11 Biomarkers (CK/Trop) Elevated (n=5072) Normal (n=3402) 0.07 Pre Thienopyridine Yes (n=5751) No (n=3305) UFH/Enoxaparin + GPIIb/IIIa vs. Bivalirudin alone 1 yr KM estimate ACUITY 1-Year Data as presented at ACC 2007. P value interaction only between subgroups 19.8% 19.2% 1.09 (0.96-1.23) 21.1% 20.7% 1.04 (0.79-1.36) 9.0% 9.6% 0.97 (0.76-1.24) 17.7% 14.6% 16.4% 16.1% 1.14 (0.99-1.30) 0.95 (0.80-1.14) 16.2% 16.4% 17.2% 14.3% 0.97 (0.86-1.11) 1.20 (1.01-1.44)
  109. 109. <ul><li>Unfractionated Heparin (UFH) </li></ul><ul><ul><li>Pro: Familiarity, reversibility </li></ul></ul><ul><ul><li>Con: Adverse PK </li></ul></ul><ul><li>Enoxaparin </li></ul><ul><ul><li>Pro: Ease of use, predictability, familiarity </li></ul></ul><ul><ul><li>Con: Bleeding concerns, transition to cath lab, needs dose adjustment for CKD, increased bleeding risk noted especially in patients with renal dysfunction (OASIS-5) </li></ul></ul>Upstream Antithrombotic Therapy: IA
  110. 110. <ul><li>Fondaparinux </li></ul><ul><ul><li>Pro: Ease of use, once daily </li></ul></ul><ul><ul><li>Con: Need additional anticoagulant (UFH? bivalirudin?) in cath lab (“clot on the wire”), lack of familiarity in ED, label, not studied in CrCl < 30, not accepted by IC community for PCI despite Guidelines </li></ul></ul><ul><li>Bivalirudin </li></ul><ul><ul><li>Pro: Comfort level in cath lab, short half-life, can omit GP IIb/IIIa’s (more to follow) in most patients, reduced bleeding risk, can switch to bivalirudin from other anticoaglants and antithrombotics </li></ul></ul><ul><ul><li>Con: Lack of familiarity in ED, limited data on prolonged infusion, cost of prolonged infusion, label, not studied in CrCl < 30 </li></ul></ul>Upstream Antithrombotic Therapy: IB
  111. 111. Oral Antiplatelet Therapy — 2002 Clopidogrel Guidance <ul><li>Aspirin + clopidogrel, for up to 1 month* </li></ul><ul><li>Aspirin + clopidogrel, for up to 9 months* </li></ul><ul><li>Withhold clopidogrel for 5-7 days for CABG </li></ul>* For patients managed with an early conservative strategy, and those who are planned to undergo early PCI Guidelines do not specify initial timing of using clopidogrel when coronary anatomy is unknown I IIa IIb III
  112. 112. Acute (< 24 hrs) Antiplatelet Therapies for High-Risk NSTE ACS 43% 10% 20% 30% 40% 50% 60% 52% 34% GP IIb/IIIa Clopidogrel GP IIb/IIIa + Neither Clopidogrel CRUSADE Q4 2003 data. 29%
  113. 113. Antiplatelet Therapy Year 2007 Clopidogrel Guidance <ul><li>Clopidogrel with full loading dose in ASA-allergic patients </li></ul><ul><li>EIS: Clopidogrel or IIb/IIIa administered upstream </li></ul><ul><li>ICS: Clopidogrel initiated “as soon as possible” and continued for at least one month . . .and preferably for one year </li></ul>I IIa IIb III
  114. 114. Antiplatelet Therapy: 2007 Platelet GP IIb/IIIa Inhibitors <ul><li>ICS with recurrent ischemia on ASA, clopidogrel, and anticoag: Add IIb/IIIa upstream </li></ul><ul><li>EIS: It is reasonable to give both clopidogrel and IIb/IIIa upstream </li></ul><ul><li>EIS: Can omit IIb/IIIa if bivalirudin is anticoagulant and at least 300mg clopidogrel given > 6h prior to cath </li></ul>I IIa IIb III
  115. 115. Antiplatelet Drug Targets Platelet Thrombin ADP Thromboxane A 2 Epinephrine Serotonin Collagen PAR-1 PAR-4 P2Y 1 P2Y 12 TXA2-R 5HT 2 A Anionic phospholipid surfaces GP IIb GP IIIa GP VI Platelet GP IIIa GP IIb Fibrinogen GP Ia TRA Clopidogrel Prasugrel Aspirin Gp IIb/IIIa inhibitors PAR - 1 P2Y 12
  116. 116. Clear Platelets Gurbel PA, et al. Circulation . 2005;111:1153-1159. * Platelet Inhibition * ‡ Platelet Inhibition * 0 20% 40% 60% 80% 100% 0 20% 40% 60% 80% 100% Group A: Clopidogrel 300 mg (n = 30) Group B: Clopidogrel 600 mg (n = 30) Group C: Clopidogrel 300 mg + eptifibatide (n = 30) Group D: Clopidogrel 600 mg + eptifibatide (n = 30) † 5 µmol/L ADP 20 µmol/L ADP † † *( P ≤ 0.001), Group A vs B; † ( P ≤ 0.001), Group C or D vs Group A or B. *( P = 0.09), Group A vs B; † ( P = 0.01), Group A vs B; ‡( P < 0.001), Groups C and D vs Group A and B; §( P -0.05), Groups C vs D. † ‡ ‡ §
  117. 117. <ul><li>Choices between dual (ASA+clopidogrel), dual (ASA+IIb/IIIa) and triple (ASA+clopidogrel+IIb/IIIa) antiplatelet therapy are driven by risk and upon consideration of a bivalirudin only EIS: </li></ul><ul><ul><li>Ischemic risk </li></ul></ul><ul><ul><ul><li>Conventional consideration in ED </li></ul></ul></ul><ul><ul><ul><li>Prefer triple therapy unless . . . </li></ul></ul></ul><ul><ul><li>Bleeding risk </li></ul></ul><ul><ul><ul><li>In ED: Female, elderly, CKD, anemic, proper dosing, use of bivalirudin only EIS </li></ul></ul></ul><ul><ul><li>CABG risk </li></ul></ul><ul><ul><ul><li>In ED, can’t accurately quantify </li></ul></ul></ul><ul><ul><ul><li>Small-molecule IIb/IIIa is reversible; clopidogrel is not </li></ul></ul></ul>Antiplatelet Therapy Driven By Risk
  118. 118. Parenteral Antiplatelet Therapy: 2002 Platelet GP IIb/IIIa Inhibitors <ul><li>Any GP IIb/IIIa inhibitor + ASA/Heparin for all patients, if cath/PCI planned </li></ul><ul><li>Eptifibatide or tirofiban + ASA/Heparin for high-risk* patients in whom early cath/PCI is not planned </li></ul><ul><li>Any GP IIb/IIIa inhibitor for patients already on ASA + Heparin + clopidogrel, if cath/PCI is planned </li></ul>* High-risk: Age > 75; prolonged, ongoing CP; hemodynamic instability; rest CP w/ ST  ; VT; positive cardiac markers I IIa IIb III
  119. 119. <ul><li>Eptifibatide or tirofiban + ASA/Heparin for patients without continuing ischemia in whom PCI is not planned </li></ul><ul><li>Abciximab for patients in whom PCI is not planned </li></ul>Parenteral Antiplatelet Therapy: 2002 Platelet GP IIb/IIIa Inhibitors I IIa IIb III
  120. 120. Antiplatelet Therapy: 2007 Platelet GP IIb/IIIa Inhibitors <ul><li>All patients receive ASA </li></ul><ul><li>EIS: Upstream clopidogrel or IIb/IIIa </li></ul><ul><li>EIS: Upstream IIb/IIIa should be small-molecule </li></ul><ul><li>ICS: If medical management fails, add IIb/IIIa or clopidogrel . . . upstream </li></ul>I IIa IIb III
  121. 121. <ul><li>ICS with recurrent ischemia on ASA, clopidogrel, and anticoagulant: Add IIb/IIIa upstream </li></ul><ul><li>EIS: It is reasonable to give both clopidogrel and IIb/IIIa upstream </li></ul><ul><li>EIS: Can omit IIb/IIIa if bivalirudin is anticoagulant and at least 300mg clopidogrel given > 6h prior to cath </li></ul>Antiplatelet Therapy: 2007 Platelet GP IIb/IIIa Inhibitors I IIa IIb III
  122. 122. ISAR-REACT-2, JAMA 2006 (ACUITY, NEJM 2006) Both of these studies have risk considerations that are important to upstream therapy Relevant New Studies Focusing on Antiplatelet Therapy
  123. 123. ISAR-REACT 2: Troponin Status Troponin negative ( <0.03µg/L, n=973) Primary Events p=0.98 Kastrati A, Mehilli J , et al. JAMA . 2006 Apr 5;295(13):1531-8. Troponin positive (>0.03 µg/L, n=1049) p=0.02
  124. 124. In-hospital Major and Minor Bleeding (%) p=NS ISAR-REACT 2 : Bleeding Kastrati A, Mehilli J , et al. JAMA . 2006 Apr 5;295(13):1531-8.
  125. 125. ACUITY Composite Ischemia at 1-Year UFH/Enoxaparin + GPIIb/IIIa vs. Bivalirudin Alone Hazard ratio ±95% CI Bival alone UFH/Enox + IIb/IIIa HR (95% CI) P int 0.67 Bivalirudin alone better UFH/Enox + IIb/IIIa better Actual Treatment PCI (n=5179) CABG (n=1040) Medical (n=2994) 0.11 Biomarkers (CK/Trop) Elevated (n=5072) Normal (n=3402) 0.07 Pre Thienopyridine Yes (n=5751) No (n=3305) 1 yr KM estimate ACUITY 1-Year Data as presented at ACC 2007. P value interaction only between subgroups 19.8% 19.2% 1.09 (0.96-1.23) 21.1% 20.7% 1.04 (0.79-1.36) 9.0% 9.6% 0.97 (0.76-1.24) 17.7% 14.6% 16.4% 16.1% 1.14 (0.99-1.30) 0.95 (0.80-1.14) 16.2% 16.4% 17.2% 14.3% 0.97 (0.86-1.11) 1.20 (1.01-1.44)
  126. 126. Death at One Year — Interaction Analysis UFH/Enoxaparin + GPIIb/IIIa vs. Bivalirudin alone Hazard ratio ±95% CI Bival alone UFH/Enox + IIb/IIIa HR (95% CI) P int 0.96 Bivalirudin alone better UFH/Enox + IIb/IIIa better Actual Treatment PCI (n=5179) CABG (n=1040) Medical (n=2994) 0.40 Biomarkers (CK/Trop) Elevated (n=5072) Normal (n=3402) 0.52 Pre Thienopyridine Yes (n=5751) No (n=3305) 1 yr KM estimate 3.2% 4.0% 0.95 (0.70-1.29) 6.8% 6.7% 1.03 (0.64-1.66) 4.0% 4.3% 0.95 (0.66-1.37) 4.8% 2.4% 5.0% 3.6% 1.04 (0.80-1.34) 0.84 (0.55-1.28) 3.5% 4.0% 4.2% 4.4% 0.90 (0.68-1.18) 1.05 (0.74-1.48)
  127. 127. Antiplatelet Therapy: 2007 Platelet GP IIb/IIIa Inhibitors <ul><li>ICS with recurrent ischemia on ASA, clopidogrel, and anticoag: add IIb/IIIa upstream </li></ul><ul><li>EIS: it is reasonable to give both clopidogrel and IIb/IIIa upstream </li></ul><ul><li>EIS: Can omit IIb/IIIa if bivalirudin is anticoagulant and at least 300mg clopidogrel given > 6h prior to cath </li></ul>I IIa IIb III
  128. 128. CREDO: 15 hrs (not 6 hrs) Until Clinical Benefit Seen with 300 mg Load Steinhubl S et al, J Am Coll Cardiol 2006;47:939-943. Death, MI, UTVR (%) Placebo Pretreatment (N_915) Clopidogrel Pretreatment < 15 hours (N=645) Clopidogrel Pretreatment > 15 hours (N=202) 8.3% 7.8% 3.5% 0 5 10 15 20 25 Days 10 8 6 4 2 0
  129. 129. ACUITY Timing Analysis (N=9,207) Quadruple Composite Ischemic Composite ACUITY Major Bleeding 1.00 (0.89-1.11) 1.12 (0.97-1.29) 0.80 (0.67-0.95) 0 1 2 Deferred GP IIb-IIIa better (n=4,602) Upstream GP IIb-IIIa better (n=4,605) RR (95% CI) Risk ratio ±95% CI ACUITY as presented at ACC 2006.
  130. 130. Excessive Dosing of Acute Medications by Age Alexander KA, JAMA 2005;294:3108-16.
  131. 131. RBC Transfusions by Excess Dosing RBC Transfusion (%) Alexander KA, JAMA 2005;294:3108-16.
  132. 132. Death Death or Re-MI 1 2.0 Adjusted Risk of In-Hospital Outcomes By Transfusion Status* * Non-CABG patients only Yang X, J Am Coll Cardiol 2005;46:1490-5.
  133. 133. Cumulative Effects of Dosing Errors Combined Use of Heparin and GP IIb-IIIa Alexander KA, JAMA 2005;294:3108-16.
  134. 134. Hospital Link Between Overall Guidelines Adherence and Mortality Peterson et al, JAMA 2006;295:1863-1912. Every 10%  in guidelines adherence  10%  in mortality (OR=0.90, 95% CI: 0.84-0.97)
  135. 135. <ul><li>We should be using optimal medical therapy for NSTE ACS in the ED, just as in the CCU or the cath lab. </li></ul><ul><li>There are new agents that will change the ED and the cath lab approach to ACS management, both in terms of pharmacologic stabilization (antithrombotic and antiplatelet therapy) and invasive management (namely, the speed with which the patient goes to the cath lab). </li></ul>Conclusions: NSTE ACS - 2007
  136. 136. <ul><li>We must work with our colleagues in cardiology to develop pathways for optimal use of antithrombotic and antiplatelet therapy at all levels, to facilitate early invasive management whenever feasible, and to address issues related to bleeding risk as well as ischemic risk. </li></ul><ul><li>New “(up)streams” of care have been introduced and require consideration in ED </li></ul><ul><li>In ACS management, one size clearly does NOT fit all! </li></ul>Conclusions: NSTE ACS
  137. 137. <ul><li>ECG and ASA within 10 min </li></ul><ul><ul><li>STEMI patients directed to their pathway </li></ul></ul><ul><li>Risk stratification </li></ul><ul><ul><li>Focused history and physical, biomarkers, serial ECGs, risk score, and bleeding risk </li></ul></ul><ul><li>Patients with high ischemic risk should go for EIS (Class I) or, in a minority of cases, for ICS (Class IIa), but only after medical stabilization </li></ul>Summary 2007 Guidelines: Upstream Management of Suspected ACS
  138. 138. <ul><li>Anticoagulation </li></ul><ul><ul><li>EIS: Enoxaparin (I-A), UFH (I-A), or bivalirudin (I-B) </li></ul></ul><ul><ul><ul><li>Strong support for bivalirudin when time to lab is quick and/or when bleeding risk is higher (screen for patients at hgher risk for bleeding) </li></ul></ul></ul><ul><ul><li>ECS: Enoxaparin (I-A), UFH (I-A), or fondaparinux </li></ul></ul><ul><ul><li>(I-B) </li></ul></ul><ul><ul><ul><li>Strong support for fondaparinux when bleeding risk is higher, but more problematic if catheterization later required </li></ul></ul></ul><ul><ul><li>Individual patient characteristics (ischemic risk, bleeding risk, time to cath) should drive choices, which should be made collaboratively by EM and cardiology </li></ul></ul>Summary 2007 Guidelines: Upstream Medical Stabilization
  139. 139. <ul><li>Anticoagulation </li></ul><ul><ul><li>“ The Writing Committee believes that inadequate unconfounded, comparative information is available to recommend a preferred [anticoagulation] regimen when an early, invasive strategy is used for UA/NSTEMI, and physician and health care system preference, together with individualized patient application, is advised.” </li></ul></ul>Summary 2007 Guidelines Upstream Medical Stabilization
  140. 140. <ul><li>Antiplatelet therapy </li></ul><ul><ul><li>Everybody gets ASA </li></ul></ul><ul><ul><li>Clopidogrel use much more strongly supported in 2007 Guidelines than in 2002, but CABG caveat still operative! </li></ul></ul><ul><ul><li>Clopidogrel OR a GPI upstream (I-A) for high risk patients, and consider BOTH (IIa-B) </li></ul></ul><ul><ul><li>Collaboration again critical, as choice of anticoagulant may impact choice of antiplatelet therapy, and institutional posture re: pretreatment with clopidogrel may override other concerns </li></ul></ul>Summary 2007 Guidelines Upstream Medical Stabilization
  141. 141. <ul><li>Earlier use of clopidogrel </li></ul><ul><li>New antithrombotics—bivalirudin (for invasive) and fondaparinux for conservative—and new antithrombotic/antiplatelet combinations </li></ul><ul><li>Faster time to cath for NSTE ACS patients </li></ul><ul><li>More emphasis by cardiologists on bleeding risk . . . sometimes prompting different considerations in the ED </li></ul>Summary 2007 Guidelines Changes Likely to Impact the ED
  142. 142. Why Bleeding Matters: A Cautionary Note For The Emergency Medicine Specialist Importance of Multi-specialty ED and IC Therapeutic (EDICT) Alignment of Upstream Care for ACS Sunil Rao, MD, FACC Director of Interventional Cardiology Veterans Administration Medical Center Assistant Professor Division of Cardiovascular Medicine Duke University Medical Center Getting in the (Up)Stream of Things
  143. 143. ACS Case Presentation <ul><li>77 year old female presents to ED with 2 weeks of progressive angina, one episode lasting 90 minutes </li></ul><ul><ul><li>History of Type 2 DM, HTN, cigarette smoking </li></ul></ul><ul><ul><li>Weight 65 kg </li></ul></ul><ul><li>ECG non-specific, POS TnI 0.79 (ULN 0.5), nl CKMB, CrCL 40 ml/min, Hgb 9.7 g/dl </li></ul><ul><li>Given ASA, 300 mg clopidogrel, 5 mg IV metoprolol, IV NTG </li></ul><ul><li>Continued chest pain </li></ul><ul><ul><li>Anticoagulation options in the ED? </li></ul></ul><ul><ul><li>Risk stratification strategy? </li></ul></ul><ul><ul><li>Which upstream strategy makes most sense? </li></ul></ul><ul><ul><li>Collaboration with cardiology colleagues? </li></ul></ul>
  144. 144. Medical Rx (cath) Time PCI Surgery Medical Rx (no cath) Medical Rx No disease (82 % of total) (18 % of total) (52% of total, 63% of those undergoing cath) (12% of total, 15% of those undergoing cath) CRUSADE Registry 10/04-9/05 n=35,897 Patient X ACS Management Pathways Cath Medical Rx Admission Cath Discharge No Cath Cath 40 % < 48 hrs 12 % > 48 hrs 63 % < 48 hrs 19 % > 48 hrs
  145. 145. Evolving ED Paradigm for Evaluating ACS Management Strategies Ischemic Complications Hemorrhage HIT <ul><li>Death </li></ul><ul><li>MI </li></ul><ul><li>Urgent TVR </li></ul><ul><li>Major Bleeding </li></ul><ul><li>Minor Bleeding </li></ul><ul><li>Thrombocytopenia </li></ul>Composite Adverse Event Endpoints Although these complications usually are not seen in the ED, choices made in the ED influence the likelihood of these adverse events!
  146. 146. Options for NSTE-ACS Therapy in 2007 <ul><li>Antiplatelet therapies </li></ul><ul><ul><li>ASA, Clopidogrel </li></ul></ul><ul><ul><li>Glycoprotein IIb/IIIa inhibitors </li></ul></ul><ul><li>Antithrombin therapy </li></ul><ul><ul><li>UFH </li></ul></ul><ul><ul><li>Enoxaparin </li></ul></ul><ul><ul><li>Fondaparinux </li></ul></ul><ul><ul><li>Bivalirudin </li></ul></ul><ul><li>Risk stratification </li></ul><ul><ul><li>Conservative </li></ul></ul><ul><ul><li>Invasive </li></ul></ul>
  147. 147. Balancing Ischemic Events and Bleeding Risk Risk of events Risk of bleeding Thrombosis Hemostasis Two sides of the same coin Degree of Anticoagulation Risk
  148. 148. CRUSADE In-Hospital Outcomes: 2006 <ul><li>Death 3.6% </li></ul><ul><li>(Re)-Infarction 1.8% </li></ul><ul><li>CHF 6.6% </li></ul><ul><li>Cardiogenic Shock 2.2% </li></ul><ul><li>Stroke 0.7% </li></ul><ul><li>RBC Transfusion* 9.1% </li></ul>* Excluding CABG-related transfusions CRUSADE DATA: January 1, 2006 – December 31, 2006 (n= 29,825)
  149. 149. ACS-related Bleeding —Relevant Questions for the Emergency Medicine Specialist <ul><li>Who bleeds? Can we risk stratify? </li></ul><ul><li>Should bleeding risk affect upstream antithrombotic care? If so, how? </li></ul><ul><li>Is bleeding bad or a necessary evil? </li></ul><ul><li>Can blood transfusion “correct” risks associated with bleeding? </li></ul><ul><li>Does bleeding affect resource use? </li></ul><ul><li>What options do we have to balance efficacy (reduced risk for ischemic outcomes) and safety (reduced bleeding)? </li></ul>
  150. 150. Bleeding in ACS — Identification Questions to be answered — 1] Who bleeds? 2] What risk factors are predictive of bleeding? 3] How should initial choices for upstream care be influenced by bleeding risk?
  151. 151. Predictors of Major Bleeding in ACS <ul><li>Older Age </li></ul><ul><li>Female Gender </li></ul><ul><li>Renal Failure </li></ul><ul><li>History of Bleeding </li></ul><ul><li>Right Heart Catheterization </li></ul><ul><li>GPIIb-IIIa Antagonists </li></ul>Independent predictors of major bleeding in marker- positive acute coronary syndromes Moscucci, GRACE Registry, Eur Heart J . 2003 Oct;24(20):1815-23.
  152. 152. Predictors of Major Bleeding P-value RR (95% CI) Risk ratio ± 95% CI Manoukian SV, Voeltz MD, Feit F et al. TCT 2006. Results: The ACUITY Trial — PCI Population Heparin(s) + GPI (vs. Bivalirudin) Prior antithrombotic therapy No prior PCI Hypertension High-risk (ST / biomarkers) Female gender Diabetes CrCl <60mL/min Anemia Age > 75 (vs. 55-75) <0.0001 0.0768 0.0019 0.0287 0.0178 <0.0001 0.0248 <0.0001 <0.0001 0.0009 2.08 (1.56-2.76) 1.23 (0.98-1.55) 1.47 (1.15-1.88) 1.33 (1.03-1.70) 1.42 (1.06-1.90) 2.08 (1.68-2.57) 1.30 (1.03-1.63) 1.68 (1.29-2.18) 1.89 (1.48-2.41) 1.56 (1.19-2.04)
  153. 153. P-value RR (95% CI) Predictors of Transfusion Risk ratio ± 95% CI Results: The ACUITY Trial Manoukian SV, Voeltz MD, Feit F et al. TCT 2006. Heparin(s) + GPI (vs. Bivalirudin ) Hypertension High-risk (ST / biomarkers) Female gender Diabetes CrCl <60mL/min Anemia Age > 75 (vs. 55-75) 0.0007 0.0241 0.0003 <0.0001 0.0060 <0.0001 <0.0001 0.0060 1.728 (1.256-2.379) 1.457 (1.051-2.020) 1.754 (1.297-2.372) 2.233 (1.739-2.867) 1.560 (1.209-2.014) 2.097 (1.568-2.803) 3.764 (2.919-4.855) 1.420 (1.055-1.910)
  154. 154. <ul><li>Older age, chronic kidney disease, female gender are consistently associated with bleeding and blood transfusion </li></ul><ul><li>Analysis of large randomized trials have also identified novel risk factors for bleeding such as diabetes and anemia </li></ul><ul><li>These risk factors can readily be identified during the ED evaluation of a patient with ACS </li></ul>Bleeding Predictors — Conclusions
  155. 155. Questions to be answered — 1] Is bleeding bad or a necessary evil? 2] What is the relationship between bleeding and patient outcomes in ACS? 3] What initial choices can the ED physician make that are compatible with guidelines and that will reduce bleeding? Bleeding in ACS — Consequences
  156. 156. Moscucci M et al. Eur Heart J 2003;24:1815-23. P<0.001 Overall Unstable NSTEMI STEMI ACS Angina Patients (%) Major Bleeding Predicts Mortality in ACS 24,045 ACS patients in the GRACE registry, in-hospital death
  157. 157. Bleeding and Outcomes in ACS log rank p-value for all four categories <0.0001 log-rank p-value for no bleeding vs. mild bleeding = 0.02 log-rank p-value for mild vs. moderate bleeding <0.0001 log-rank p-value for moderate vs. severe <0.001 Rao SV, et al. Am J Cardiol . 2005 Nov 1;96(9):1200-6. Epub 2005 Sep 12. Kaplan Meier Curves for 30-Day Death, Stratified by Bleed Severity N=26,452 ACS patients from GUSTO IIb, PARAGON A, PARAGON B, & PURSUIT
  158. 158. Bleeding and Outcomes in NSTE-ACS 26,452 patients from PURSUIT, PARAGON A, PARAGON B, GUSTO IIb NST Bleeding severity and adjusted hazard of death *p<0.0001 Bleeding Severity 30d Death 30d Death/MI 6 mo. Death Mild* 1.6 1.3 1.4 Moderate* 2.7 3.3 2.1 Severe* 10.6 5.6 7.5 *Bleeding as a time-dependent covariate Rao SV, et al. Am J Cardiol . 2005 Nov 1;96(9):1200-6. Epub 2005 Sep 12.
  159. 159. <ul><li>Bleeding is associated with adverse short- and long-term outcomes among patients with ACS and those undergoing PCI </li></ul><ul><ul><li>Mortality rates are higher among those who bleed </li></ul></ul><ul><ul><li>MI rates are higher among those who bleed </li></ul></ul><ul><li>The risk is “dose-dependent” with worse bleeding associated with worse outcomes </li></ul><ul><li>This relationship is persistent after robust statistical adjustment for confounders </li></ul><ul><li>Decisions made in the ED may affect subsequent bleeding risk, and in turn, clinical outcomes </li></ul>Bleeding and Outcomes — Conclusions
  160. 160. Bleeding in ACS <ul><li>Question To Be Answered </li></ul><ul><li>Can blood transfusion “correct” adverse outcomes associate with bleeding? </li></ul>
  161. 161. Transfusion in ACS 30-Day Survival By Transfusion Group Rao SV, et. al., JAMA 2004;292:1555–1562. N=24,111
  162. 162. Cox Model for 30-day Death *Transfusion as a time-dependent covariate N=24,111 Rao SV, et. al., JAMA 2004;292:1555–1562. PRBC Transfusion Among NSTE ACS Patients
  163. 163. Adjusted Risk of In-Hospital Outcomes By Transfusion Status* *Non-CABG patients only Yang X, J Am Coll Cardiol 2005;46:1490–5. N=74,271 ACS patients from CRUSADE
  164. 164. Transfusion, Ischemic Endpoints, and Mortality in ACUITY Trial P<0.0001 for all Manoukian SV, Voeltz MD, Feit F et al. TCT 2006. Results: The ACUITY Trial (N=13,819)
  165. 165. Transfusion Post PCI — REPLACE 2 One Year Mortality Increased 1-year mortality in transfused patients Adjusted Odds Ratio 4.26 (2.25–8.08) P<0.0001 Manoukian SV, Voeltz MD, Attubato MJ, Bittl JA, Feit F, Lincoff AM. CRT 2005. Abstract.
  166. 166. <ul><li>Blood transfusion is independently associated with death and re-MI </li></ul><ul><li>Transfusion does not correct the adverse impact bleeding and is not an “insurance policy” for choices made in the ED </li></ul><ul><li>Blood transfusion is best avoided in ACS patients whenever possible </li></ul><ul><li>Decisions regarding bleeding risk should be part of ED decision-making process </li></ul>Blood Transfusion — Conclusions
  167. 167. Bleeding in ACS <ul><li>Question To Be Answered </li></ul><ul><li>Does bleeding impact resource use? </li></ul>
  168. 168. Bleeding and Resource Use: Predictors of Total Costs Mod/sev bleed Per patient cost - $530 Transfusion - $2080, P < 0.01 Per patient cost - $287 Model C-index=0.87 Adjusted for patient characteristics Rao SV, et. al. ACC 2007. N=1235 pts from GUSTO IIb
  169. 169. <ul><li>The available costs data clearly show that a balance must be struck between ischemia reduction and bleeding </li></ul><ul><ul><li>Both ischemic complications and bleeding are associated with increased costs such that any cost savings realized by reducing one is offset by cost increases associated with the other </li></ul></ul><ul><li>Although these costs are not realized in the ED, the choices made there impact costs downstream </li></ul>Bleeding and Costs — Conclusions
  170. 170. <ul><li>What therapeutic options do ED physicans and cardiologists have to balance efficacy (reduced risk for ischemic outcomes) and safety (bleeding)? </li></ul>Bleeding in ACS Question To Be Answered
  171. 171. Targets for Intervention Va X Xa II IIa (Thrombin) (Prothrombin) TF VIIa IX IXa <ul><li>Xa Inhibitors - Fondaparinux </li></ul><ul><li>Direct Thrombin Inhibitors - Bivalirudin </li></ul>
  172. 172. New Strategies: Anticoagulants “ Two new anticoagulants, fondaparinux and bivalirudin , have undergone favorable testing in clinical trials and are recommended as alternatives to unfractionated heparin (UFH) and low-molecular-weight heparins (LMWHs) for specific or more general applications.” UA/NSTEMI Strategy Overview ACC/AHA 2007 Guidelines for the Management of UA/NSTEMI. August 6, 2007, Circulation.
  173. 173. OASIS 5 — Study Design *ICH, RP, IO, Transfusion,  Hgb 3 gm/dl NSTE ACS patients 2 of 3: Age > 60, ECG ∆,  Markers N=20,000 Fondaparinux 2.5 mg SC QD Enoxaparin 1 mg/kg SC BID Death-MI-ischemia at 9d Major bleeding* at 9d
  174. 174. OASIS 5
  175. 175. Patients Undergoing PCI OASIS 5 and 6 OASIS 5 Investigators NEJM 2006 OASIS 6 Investigators JAMA 2006 Rx None (n=2867) Lysis (n=5436) 1° PCI (n=3789) 1.0 2.0 0.5 Favors Fondaparinux Favors UFH or Placebo Catheter Thrombus
  176. 176. ACUITY Study Design – First Randomization <ul><li>Moderate-high risk unstable angina or NSTEMI undergoing an invasive strategy (N = 13,819) </li></ul>Moderate- high risk ACS Aspirin in all Clopidogrel dosing and timing per local practice ACUITY Design. Stone GW et al. AHJ 2004;148:764–75 Primary endpoint: “Net Clinical Composite” Death, MI, TVR, Bleeding Angiography within 72h UFH or Enoxaparin + GP IIb/IIIa Bivalirudin + GP IIb/IIIa Bivalirudin Alone R* Medical management PCI CABG
  177. 177. ACUITY: Primary results – 30 days <ul><li>UFH/Enox + GP IIb/IIIa vs. Bivalirudin + GP IIb/IIIa vs. Bivalirudin Alone </li></ul>Stone GW et al. NEJM 2006;355:2203-16 P NI <0.001 P Sup = 0.015 P NI = 0.011 P Sup = 0.32 P NI <0.001 P Sup <0.001
  178. 178. Mortality: 524 Total Deaths at 1-year 0 30 60 90 120 150 180 210 240 270 300 330 360 390 0 4 5 Mortality (%) Days from Randomization 2 1 UFH/Enoxaparin + GPI vs. Bivalirudin + GPI vs. Bivalirudin Alone Bivalirudin+GPI vs. Hep+GPI HR [95% CI] = 0.99 (0.80-1.22) 30 day 3 Bivalirudin alone vs. Hep+GPI HR [95% CI] = 0.95 (0.77-1.18) Stone GW, McLaurin BT. NEJM . 2006 Nov 23;355(21):2203-16. UFH/Enoxaparin + IIb/IIIa Bivalirudin + IIb/IIIa Bivalirudin alone Estimate P (log rank) 1.4% 0.53 1.6% 0.39 1.6% — Estimate P (log rank) 4.4% 0.93 4.2% 0.66 3.8% 1 year — p=0.90
  179. 179. ACUITY PCI: High Risk* Patients Risk Ratio ±95% CI RR (95% CI) Hazard Ratio ±95% CI HR (95% CI) UFH/Enox+ IIb/IIIa better * High risk = ↑Tn, CKMB or ECG Δ ’s Bivalirudin better Bivalirudin better 30 day Results 1 year Results UFH/Enox+ IIb/IIIa better 0.55 (0.42-0.72) Major bleeding 1.08 (0.88-1.32) Composite ischemia 0.94 (0.67-1.31) Mortality
  180. 180. Mortality (%) Days from Randomization 0 30 60 90 120 150 180 210 240 270 300 330 360 390 0 5 15 30 10 25 20 1 year Estimate Impact of MI and Major Bleeding (non-CABG) in the First 30 Days on Risk of Death Over 1 Year 28.9% 12.5% 8.6% 3.4% Major Bleed only (without MI) (N=551) 12.5% 28.9% Both MI and Major Bleed (N=94) 3.4% No MI or Major Bleed (N=12,557) MI only (without Major Bleed) (N=611) 8.6%
  181. 181. P-value Deaths (n/%) HR ± 95% CI 0.5 1 2 4 8 16 HR (CI) Impact of MI and Major Bleeding (non-CABG) in the First 30 Days on Risk of Death Over 1 Year Day 0 – 2 after MI 12.6 (7.8-20.4) 29 (37.6) <0.0001 Day 3 – 7 after MI 5.3 (2.7-10.4) 11 (14.3) <0.0001 Day 8 – 35 after MI 1.6 (0.8-3.1) 12 (15.6) 0.18 Day > 35 after MI 1.2 (0.8-1.9) 25 (32.5) 0.34 Day 0 – 2 after Major Bleed 3.0 (1.6-5.6) 12 (12.9) 0.0009 Day 3 – 7 after Major Bleed 4.0 (2.1-7.5) 15 (16.1) <0.0001 Day 8 – 35 after Major Bleed 4.5 (2.8-7.4) 25 (26.9) <0.0001 Day > 35 after Major Bleed 2.2 (1.5-3.2) 41 (44.1) <0.0001
  182. 182. ACS Case Presentation <ul><li>77 year-old female presented to ED with 2 weeks of progressive angina, one episode lasting 90 minutes </li></ul><ul><ul><li>History of Type 2 DM, HTN, cigarette smoking </li></ul></ul><ul><ul><li>Weight 65 kg </li></ul></ul><ul><li>ECG non-specific, POC TnI 0.79 (ULN 0.5), nl CKMB, CrCL 40 ml/min, Hgb 9.7 g/dl </li></ul><ul><li>Given ASA, 300 mg clopidogrel, 5 mg IV metoprolol, IV NTG </li></ul><ul><li>Continued chest pain </li></ul><ul><ul><li>Anticoagulant choices in ED? </li></ul></ul><ul><ul><li>Risk stratification strategy? </li></ul></ul>
  183. 183. <ul><li>Decision made to pursue rapid invasive risk stratification </li></ul><ul><ul><li>High-risk features </li></ul></ul><ul><ul><ul><li>Elevated troponin </li></ul></ul></ul><ul><ul><ul><li>Ongoing chest pain despite medical therapy </li></ul></ul></ul><ul><li>Antithrombin therapy choices </li></ul><ul><ul><li>Risk for bleeding </li></ul></ul><ul><ul><ul><li>Age, Female sex, renal insufficiency, anemia </li></ul></ul></ul><ul><ul><li>Bivalirudin bolus and gtt initiated </li></ul></ul><ul><li>Angiography </li></ul>Case Presentation
  184. 184. Addressing the Challenge of Selecting an Anticoagulation Strategy Bleeding Risk Ischemic Risk Renal function Age Time to cath Cost Ease of use PCI vs CABG vs Med Rx
  185. 185. Bleeding Among Patients with ACS Conclusions <ul><li>There are several therapeutic pathways for NSTE ACS care </li></ul><ul><li>The “(up)stream” of care begins in the emergency department </li></ul><ul><li>Choices made in the ED impact downstream events </li></ul><ul><ul><li>Ischemic complications </li></ul></ul><ul><ul><li>Bleeding complications </li></ul></ul>
  186. 186. Conclusions—Bleeding in ACS <ul><li>Certain patient and PCI procedure characteristics predict bleeding </li></ul><ul><ul><li>Age, female gender, CKD </li></ul></ul><ul><ul><li>Diabetes and anemia are newly identified risk factors for bleeding among ACS patients </li></ul></ul><ul><li>Bleeding is associated with worse short and long-term outcomes including death and MI </li></ul><ul><li>Blood transfusion is associated with increased mortality in ACS patients </li></ul><ul><li>In addition to clinical outcomes, bleeding is associated with increased cost of care </li></ul>
  187. 187. Conclusions — Bleeding in ACS <ul><li>Coordination of care through cooperation between ED and IC Treatment (EDICT for ACS) is essential to navigate the new landscape </li></ul><ul><li>ACC/AHA guidelines now recognize the value of bleeding reduction in ACS care </li></ul><ul><ul><li>Bivalirudin is a Class I ( Level of evidence: B) recommended antithrombin agent for NSTE ACS patients undergoing an invasive strategy </li></ul></ul><ul><ul><li>ACUITY demonstrates that bivalirudin provides protection from ischemic events while reducing bleeding risk </li></ul></ul>
  188. 188. The Mandate to Cooperate and Collaborate UPSTREAM ACS CARE Collaborations, Models, and Protocols ED Emergency Department IC Interventional Cardiology + T Therapeutic Teams + ACS for
  189. 189. ASA PCI Year 2007 ACC-AHA NSTEMI Guidelines Seven Streams of Success Early Invasive Therapy + Clopidogrel PCI 7 Fondaparinux 6 Bivalirudin 5 Enoxaparin + GPI 4 UFH + GPI 3 Clopidogrel 2 ASA 1 Bleeding risk factors CABG likely or planned <ul><li>Bleeding risk factors </li></ul><ul><li>Renal dysfunction </li></ul>PCI No clopidogrel pretreatment Aspirin allergy
  190. 190. PCI Clopidogrel+ ASA+ UFH/Enoxaparin Switching Bivalirudin PCI Bivalirudin + Clopidogrel/ASA
  191. 191. <ul><ul><ul><ul><ul><li>ACS (Acute Controversy Syndrome): Cardiovascular Emergency Case Studies — Emergency Medicine and Cardiovascular Specialists Engage in the “Acute Collaboration Syndrome” </li></ul></ul></ul></ul></ul><ul><ul><ul><ul><ul><li>From ACS Risk Profiles to Patient Care: Case Studies in ACS—Doing the Right Thing in the Right Patient </li></ul></ul></ul></ul></ul>Getting in the Stream of Things
  192. 192. Case Studies in Acute Coronary Syndromes Acknowledgement is made to Dr. Steven Manoukian, MD and CMEducation Resources, LLC for patient cases studies, cineangiograms, and/or assistance in preparation of case studies for this segment of the program
  193. 193. Case #1: History and Findings <ul><li>A 76 year-old white male with h/o stent to LAD 1 year ago </li></ul><ul><li>Presents with multiple episodes of recurrent chest pain including rest pain over 2 days </li></ul><ul><li>Pain similar to time of PCI in past </li></ul><ul><li>Symptoms relieved in ED with sl NTG </li></ul><ul><li>PMH: IDDM, HTN, CHOL elevation </li></ul><ul><li>PE: benign (weight 84 kg). </li></ul><ul><li>Labs: Hgb 10.7 , Cr 1.9, CK 173/2, Tr <0.03. </li></ul><ul><li>ECG (next slide) </li></ul>
  194. 194. Case #1: ECG New anterior and lateral ST / T changes.
  195. 195. Based on your clinical assessment, this patient’s risk of short-term (30-Day) ischemic events is: <ul><li>Low </li></ul><ul><li>Moderate </li></ul><ul><li>High </li></ul><ul><li>Very high </li></ul>Case #1
  196. 196. Which of this patient’s baseline factors do you consider most important for determining this patient’s ischemic risk? <ul><li>A. Advanced age </li></ul><ul><li>B. Anginal pattern </li></ul><ul><li>C. ECG findings </li></ul><ul><li>D. Biomarkers </li></ul>* Case #1
  197. 197. Based on your clinical assessment, this patient’s risk of incurring a short-term (30-Day) hemorrhagic event related to PCI is: <ul><li>Low </li></ul><ul><li>Moderate </li></ul><ul><li>High </li></ul><ul><li>Very high </li></ul>Case #1
  198. 198. Which of this patient’s baseline factors do you consider most important for determining hemorrhagic risk? <ul><li>A. Advanced age </li></ul><ul><li>B. Hypertension </li></ul><ul><li>C. Impaired creatinine clearance </li></ul><ul><li>D. Anemia </li></ul>* Case #1
  199. 199. In ACS patients, do you alter your choice of anticoagulant/ antithrombotic therapy based upon an assessment of the individual patient’s risk of hemorrhagic complications? <ul><li>A. Yes </li></ul><ul><li>B. No </li></ul>* Case #1
  200. 200. Among those of you who would alter or customize antithrombotic therapy based on an ACS patient’s risk for hemorrhage in the setting of PCI, which of the following baseline characteristics would you consider most important in supporting the use of a “hemorrhage-minimizing” anithrombotic regimen: <ul><li>Elderly and female </li></ul><ul><li>Renal insufficiency and positive biomarkers </li></ul><ul><li>Anemia and high risk ischemic features </li></ul>* Case #1
  201. 201. What would you likely use for anticoagulation in this patient, prior to catheterization, if you anticipated catheterization would occur in 4 hours or less? <ul><li>A. Unfractionated heparin alone </li></ul><ul><li>B. Enoxaparin alone </li></ul><ul><li>C. Bivalirudin alone </li></ul><ul><li>D. A heparin with a GP IIb/IIIa inhibitor </li></ul><ul><li>E. Fondaparinux </li></ul>* Case #1
  202. 202. What would your choice of upstream anticoagulation therapy be, if you anticipated cardiac catheterization the same day (within 12 hours)? <ul><li>A. Unfractionated heparin alone </li></ul><ul><li>B. Enoxaparin alone </li></ul><ul><li>C. Bivalirudin alone </li></ul><ul><li>D. A heparin with a GP IIb/IIIa inhibitor </li></ul><ul><li>E. Fondaparinux </li></ul>* Case #1
  203. 203. What would your choice of upstream anticoagulation therapy be, if you anticipated cardiac catheterization the next day (within 24 hours)? <ul><li>A. Unfractionated heparin alone </li></ul><ul><li>B. Enoxaparin alone </li></ul><ul><li>C. Bivalirudin alone </li></ul><ul><li>D. A heparin with a GP IIb/IIIa inhibitor </li></ul><ul><li>E. Fondaparinux </li></ul>* Case #1
  204. 204. At this point, your anticoagulation regimen for PCI in this patient would be? <ul><li>A. Additional heparin </li></ul><ul><li>B. Switch to enoxaparin </li></ul><ul><li>C. Switch to bivalirudin </li></ul><ul><li>D. Additional heparin plus GP IIb/IIIa inhibitor </li></ul>* Case #1
  205. 205. Case #2: History <ul><li>77 year-old white female without prior cardiac history </li></ul><ul><li>Multiple short episodes of chest pain today </li></ul><ul><li>Unrelieved with NTG sl and IV; metoprolol IV </li></ul><ul><li>PMH: DM, HTN, CHOL </li></ul><ul><li>PE: benign (weight 65 kg). </li></ul><ul><li>Labs: Hgb 11.7, Cr 1.1, CK 285/9, Tr 2.7 </li></ul><ul><li>ECG </li></ul>
  206. 206. Case #2: ECG New inferior changes New lateral changes
  207. 207. Based upon this patient’s overall profile, when selecting an antithrombotic regimen, you are more likely be concerned about: <ul><li>A. Ischemic risk </li></ul><ul><li>B. Hemorrhagic risk </li></ul>* Case #2
  208. 208. Which of the following factors would you consider most important when evaluating the need for immediate catheterization in this patient? <ul><li>A. Advanced age </li></ul><ul><li>B. Positive biomarkers </li></ul><ul><li>C. ECG findings </li></ul><ul><li>D. Refractory discomfort </li></ul>* Case #2
  209. 209. Would a plan of immediate versus delayed catheterization influence your choice of anticoagulation therapy? <ul><li>Yes </li></ul><ul><li>No </li></ul>* Case #2
  210. 210. If this patient was going for immediate catheterization (now), which of the following regimens would you start? <ul><li>A. Unfractionated heparin alone </li></ul><ul><li>B. Enoxaparin alone </li></ul><ul><li>C. Bivalirudin alone </li></ul><ul><li>D. A heparin with a GP IIb/IIIa inhibitor </li></ul><ul><li>E. Fondaparinux </li></ul>* Case #2
  211. 211. If catheterization had to be delayed 2-4 hours (availability of lab, transfer, etc.), which of the following regimens would you start? <ul><li>A. Unfractionated heparin alone </li></ul><ul><li>B. Enoxaparin alone </li></ul><ul><li>C. Bivalirudin alone </li></ul><ul><li>D. A heparin with a GP IIb/IIIa inhibitor </li></ul><ul><li>E. Fondaparinux </li></ul>* Case #2
  212. 212. Case #3: History <ul><li>82 year old white-female with history of MI, PTCA/LAD in 1997 </li></ul><ul><li>Presents with exertional chest pain as well as chest pressure at rest x 72 hours, but is now pain-free in ED </li></ul><ul><li>PMH: IRDM, HTN, CHOL </li></ul><ul><li>PE: 2/6 murmur at apex (weight 58 kg) </li></ul><ul><li>Labs: Hgb 11.1, Cr 1.6 , CK 37/1, Tr <0.03 </li></ul><ul><li>ECG. </li></ul>
  213. 213. Case #3: ECG No notable findings compared to old ECG.
  214. 214. What would you use for upstream anticoagulation in this patient whose catheterization is planned for the next day: i.e., within 24 hours? <ul><li>A. Unfractionated heparin alone </li></ul><ul><li>B. Enoxaparin alone </li></ul><ul><li>C. Bivalirudin alone </li></ul><ul><li>D. A heparin with a GP IIb/IIIa inhibitor </li></ul><ul><li>E. Fondaparinux </li></ul>* Case #3
  215. 215. In general, in an ACS patient with moderate or high risk ischemic features, at what point in the patient’s course would you administer clopidogrel? <ul><li>A. In the ED, immediately. </li></ul><ul><li>B. In the catheterization lab, prior to catheterization. </li></ul><ul><li>C. In the catheterization lab, after catheterization and decision to proceed with PCI, but prior to PCI. </li></ul><ul><li>D. In the catheterization lab, post-PCI. </li></ul>* Concluding Questions
  216. 216. In general, based on my interpretation of the current evidence for selecting anticoagulation therapy in ACS patients, therapy is best guided by: <ul><li>A. Ischemic risk (reduction of ischemic endpoints) </li></ul><ul><li>B. Bleeding risk (reduction of bleeding endpoints) </li></ul><ul><li>C. Balance of ischemic and bleeding risk, and selection of a strategy that optimizes “net clinical benefit” (optimizes aggregate reduction of both ischemic and bleeding endpoints) </li></ul>* Concluding Questions
  217. 217. 1) How do ED specialists incorporate new streams of care for NSTEMI introduced by Year 2007 ACC/AHA Guidelines for NSTEMI - Bivaliridion for initial invasive strategy? Fondaprinux for initial conservative therapy? 2) How do new guidelines affect clopidogrel treatment at front lines of ED care? 3) How do ED specialists and cardiologists synchronize on new GLs and newly introduced options? 4) Questions * Discussion Points

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