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WELCOME! Please take a moment to complete the short pre -program survey in your packet.

Acute Coronary Syndromes From the Emergency Department to the Coronary Care Unit to the Office. WELCOME! Please take a moment to complete the short pre -program survey in your packet. Your participation will help us assess the effectiveness of this program

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  1. Acute Coronary Syndromes From the Emergency Department to the Coronary Care Unit to the Office WELCOME! Please take a moment to complete the short pre-program survey in your packet. Your participation will help us assess the effectiveness of this program and shape future CME activities. Thank you.

  2. Faculty Disclosures The faculty reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: TO BE FILLED IN BY PRESENTING PHYSICIAN • Presenting Physician, MD • Category – Disclosures

  3. Steering Committee Disclosures The Steering Committee reported the following relevant financial relationships that they or their spouse/partner havewith commercial interests: • Deepak L. Bhatt, MD, MPH, FACC, FAHA, FSCAI: Principal Investigator: Amarin, AstraZeneca, Bristol-Myers Squibb, Eisai, Ethicon, Medtronic, Sanofi Aventis, The Medicines Company • Charles V. Pollack Jr., MA, MD, FACEP, FAAEM, FAHA: Honorarium: Merck, Forest

  4. Non-faculty Disclosures Non-faculty content contributors and/or reviewers reported the following relevant financial relationships that they or their spouse/partner have with commercial interests: • Barry Watkins, PhD; Bradley Pine; Blair St. Amand; Jay Katz; Dana Simpler, MD: Nothing to Disclose

  5. Educational Objectives This program is designed to address the following IOM competencies: provide patient-centered care and employ evidence-based practice. At the conclusion of this activity, participants should be able to: • Adopt ischemic risk assessment stratification strategies to choose the best course of action to manage patients with acute chest pain syndrome • Assess and stratify bleeding risk after antiplatelet treatment is initiated • Make treatment choices based on an understanding of the different mechanisms of action among antithrombotic agents and on pertinent clinical trial results • Analyze pharmacologic and clinical trial results of newer antithrombotic agents to determine how best to match treatment options with patients to achieve optimal clinical outcome

  6. Key Considerations for Clinical Management of ACS • Need for differential diagnosis of the spectrum of ACS • Fundamental aspects of management of acute chest pain • Elements for optimal early hospital care • The importance of risk stratification to guide practice decisions • Options: initial conservative or invasive strategy • If invasive strategy, rationale for early catheterization • The expanded field of existing antiplatelet treatment options • Clopidogrel, prasugrel, ticagrelor • Emerging antiplatelet/anticoagulant therapies for ACS • Strong contender: very low dose rivaroxaban • Standards of treatment for STEMI • The need to balance anti-ischemic effects versus bleeding risk • The growing importance of quality outcomes in ACS

  7. Chest Pain Case

  8. Chest Pain CaseInitial Presentation • 68-year-old female presents to the Emergency Department at 8:45 am • Epigastric pain radiating to left shoulder for two hours; onset was with exertion but continued at rest • Initial ECG shows widespread STT wave anomalies with T wave inversions (V2-V6) • ECG shows marked ST-segment depression in the lateral precordial leads (V5, V6) • CVD History: Suspected CAD with abnormal stress test, but declined catheterization one year ago; treated with beta-blockers and long-acting nitrates • Additional Medical History: Significant only for hypertension

  9. Chest Pain CaseInitial ECG

  10. Chest Pain CaseTreatment Stratification Issues • Choice of therapy depends at least in part on selection of management strategy for next 24h: • Invasive or conservative? • Patient’s creatinine clearance is 45 cc/min, her first troponin is negative, and she is not anemic • Once decided, medical therapy that supports that approach should be initiated: • Anticoagulant? • Which one? What dose? • Oral antiplatelet (beyond aspirin)? • Which one? What dose? • GP IIb/IIIa antagonist? • Small or large molecule? What dose? • Beta blocker? • IV or PO?

  11. Chest Pain CaseInitial Evaluation • Two hours later, repeat troponin assay is positive, and patient’s diagnosis is changed from UA to NSTEMI • Plan is to take her to cath lab as first case tomorrow morning if she remains stable and pain free • What are your choices of anticoagulation, antiplatelet, and beta-blocker therapy? • What therapy might you add (or change) in the cath lab?

  12. Clinical Spectrum and Presentation Acute Coronary Syndromes

  13. Acute Coronary SyndromesScope of the Problem • CHD is the leading cause of death in the US; 814,000 deaths in 2007 • 1,350,000 annual new or recurring ACS events annually • 34% of those with a coronary event die within a year • 14% of STEMI patients are rehospitalized within 30 days • Direct and indirect cost of CHD is $287,000,000,000 • Hospital adherence to ACC/AHA ACS treatment guidelines is only 74% Roger VT et al. Circulation. 2011;123:e18-e209 Lloyd-Jones D et al. Circulation. 2010;121:e46-e215.

  14. Acute Coronary Syndromes • Common Features of ACS • Similar pathophysiology • Similar presentation and early management rules • Differentiating Features • Unstable Angina • Non-occlusive thrombus • No diagnostic ECG changes, but ischemic ST-T changes confer higher risk • Normal cardiac enzymes • NSTEMI • Occluding thrombus sufficient to cause myocardial damage • No diagnostic ECG changes, but ischemic ST-T changes: higher risk • Elevated cardiac enzymes • STEMI • Complete thrombus occlusion • ST elevation or new LBBB • Elevated cardiac enzymes • More severe symptoms

  15. 16 12 8 4 0 % Mortality 0 30 60 90 120 150 180 Days Mortality in Acute Coronary SyndromesDeath from Hospital Admission to 6 Months STEMI NSTEMI UA GRACE n=43,810 Fox KA et al. BMJ. 2006;333:1091.

  16. Risk Stratification and Early Hospital Care

  17. Management of Acute Chest Pain SyndromeRole of the Emergency Physician • Stabilization • When required • Differential Diagnosis of ACS • “Atypical is the new typical” • Prompt STEMI Management • ~15% of our ACS population • Risk Stratification of UA and NSTEMI • >50% of acute chest pain patients don’t have ACS • Of those who have ACS, fewer than 30% are at high ischemic risk

  18. Risk Stratification Acute Coronary Syndromes

  19. Chest Pain Syndrome Suggestive of Ischemia • 12 lead ECG • Obtain initial cardiac enzymes • Electrolytes, CBC lipids, BUN/ creatinine, glucose, coags • Chest x-ray Immediate Assessment within 10 Minutes Initial Labs and Tests Emergent Care History & Physical • IV access • Cardiac monitoring • Oxygen • Aspirin • Nitrates • Establish diagnosis • Read ECG • Identify complications • Assess for reperfusion

  20. “Dynamic Risk Stratification” Tools • History and physical • Standard ECG and non-standard ECG leads • 15-lead ECGs should perhaps become “standard” in all but very-low-risk patients • Biomarkers • CK-MB, troponins I and T, myoglobin • High-sensitivity troponin • Non-invasive imaging • Echocardiogram • Stress testing • Technetium-99m-sestamibi • Invasive imaging • Cardiac computed tomography angiography (CCTA) • Predictive indices/schemes • Better as research tools than for real-time clinical decision-making

  21. TIMI RISK SCORE for UA/NSTEMIRisk Algorithms: TIMI, GRACE, PURSUIT;The Preponderance of Evidence Favors the TIMI Score HISTORICAL RISK OF CARDIAC EVENTS (%) BY 14 DAYS IN TIMI 11B Age ≥ 65 ≥ 3 CAD risk factors (FHx, HTN, ↑ chol, DM, active smoker) Known CAD (stenosis ≥ 50%) ASA use in past 7 days Recent (≤ 24H) severe angina ↑ cardiac markers ST deviation ≥ 0.5 mm DEATH, MI, OR URGENT REVASC RISK SCORE DEATH OR MI 0/1 3 5 2 3 8 3 5 13 4 7 20 5 12 26 6/7 19 41 PRESENTATION *Entry criteria: UA or NSTEMII defined as ischemic pain at rest within past 24H, with evidence of CAD (ST segment deviation or elevated cardiac marker) RISK SCORE = Total Points (0-7) Antman EM et al. JAMA. 2000;284:835-842.

  22. Anterior ST Segment DepressionClassifications Anterior ST-segment depression TIMI flow grade 2/3 in culprit artery TIMI flow grade 0/1 in culprit artery + Troponin - Troponin + Troponin Unstable angina NSTEMI STEMI Gibson CM et al. 2008 AHA Scientific Sessions

  23. Troponin Levels Predict Risk of Mortality in UA/NSTEMI % 7 . 5 8 7 % 6 . 0 6 5 % Mortality at 42 days; % of patients 3 . 7 % 3 . 4 4 3 % 1 . 7 2 % 1 . 0 1 831 174 148 134 50 67 0 0 t o < 0 . 4 0 . 4 t o < 1 . 0 1 . 0 t o < 2 . 0 2 . 0 t o < 5 . 0 5 . 0 t o < 9 . 0 ≥ 9 . 0 C a r d i a c t r o p o n i n I ( n g / mL ) Antman EM et al. N Engl J Med. 1996;335:1342-1949.

  24. Early Hospital Care Acute CoronarySyndromes

  25. Optimal Upstream Management ofIschemic Risk Assessment • Basis for assessment • “Pain story” • Background CVD risk • ECG • Troponin elevation in pertinent time frame • Predictive risk score • Options • Antiplatelet therapy increasingly important as ischemic risk increases • UFH and enoxaparin established • Bivalirudin and fondaparinux: New options that are non-inferior

  26. Treatment of Acute Coronary Syndrome Early Invasive Initial Conservative • * Also known as Q-wave MI • † Also known as non-Q-wave MI • Braunwald E et al. Available at: www.acc.org. • Bowen WE, McKay RG. N Engl J Med. 2001;344:1939-1942.

  27. Current Medical Management ofUnstable Angina and NSTEMI Acute Therapy Maintenance Therapy • Oxygen, Bed Rest • ECG Monitoring • Nitroglycerin • Beta Blockers • ACE Inhibitors • Antiplatelet Therapy • Anticoagulant Therapy • Antiplatelet Therapy • Beta Blockers • Calcium Channel Blockers • Lipid-lowering Agents • ACE Inhibitors • Oral Anticoagulant Therapy • Braunwald E et al. Available at: www.acc.org.

  28. Procedural Considerations: Initial Conservative or Invasive Strategy – Based on Risk Assessment Acute Coronary Syndrome

  29. Conservative Therapy Option for UA/NSTEMIEarly Revascularization or PCI Not Planned • Antiplatelet therapy • Aspirin • Clopidogrel • MONA + BAH (LMW or UFH) • Morphine, Oxygen, Nitroglycerin, Aspirin + Beta Blocker, ACEI, Heparin (Morphine has only Class IIa recommendation due to increased mortality risk – CRUSADE) • Glycoprotein IIb/IIIa inhibitors • Only in certain circumstances • Planning PCI, elevated troponin • Surveillance in hospital • Serial ECGs • Serial cardiac markers Anderson JL ete al. Circulation. 2007;116:e148-e304

  30. Invasive Therapy Option for UA/NSTEMI • Coronary angiography and revascularization within 12 to 48 hours after presentation to ED • For high-risk ACS • MONA + BAH (LMW or UFH) • Morphine, Oxygen, Nitroglycerin, Aspirin + Beta Blocker, ACEI, Heparin (Morphine has only Class IIa recommendation due to increased mortality risk–CRUSADE) • Antiplatelet therapy • Aspirin; thienopyridine (clopidogrel or prasugrel) • 20% reduction in death/MI/Stroke • PCI + BMS: at least 1 month, ideally 1 year • PCI + DES: at least 1 year • Glycoprotein IIb/IIIainhibitor • Anderson JL et al. Circulation. 2007;116:e148-e304

  31. I IIa IIb III ACCF/AHA Guidelines 2011 Focused UpdateEarly Invasive Strategies High-risk patients with: • Refractory ischemia • Recurrent angina/ischemia • Elevated cardiac biomarkers (T) • New ST-segment depression • New CHF or worsening MR • High-risk on non-invasive testing • LV dysfunction (EF <40%) • Hemodynamic instability • Sustained VT • Diabetics with single vessel disease • Mild to moderate kidney disease • PCI within 6 months, prior CABG high-risk score • Not in low-risk women Wright RS et al. Circulation. 2011;123:2022-2060

  32. TACTICS: Primary Endpoint Death, MI, Rehospitalized for ACS at 6 Months 19.4% 15.9% 20 16 12 O.R 0.78 95% CI (0.62, 0.97) P=0.025 % Patients 8 4 Conservative: Invasive: 0 0 1 2 3 4 5 6 Time (months) Cannon CP et al. N Engl J Med. 2001;344:1879-1887.

  33. Updated Meta-analysis: Mortality Deaths, n Follow-up Invasive Conservative Months 45 67 24 3 9 12 37 39 6 2 9 6 102 132 60 0 3 1 15 15 12 Study FRISC-II TRUCS TIMI-18 VINO RITA-3 ISAR-COOL ICTUS Overall RR (95% CI) 0.75 (0.63-0.90) 0.1 1 10 Favors Early Invasive Therapy Favors Conservative Therapy Bavry, AA et al. J Am Coll Cardiol. 2006;48:1319-1325.

  34. Rationale for Early Catheterization Invasive Strategy

  35. TIMACS Rates of death, MI, or stroke within 6 months according to GRACE risk level and HR (95% CI), early versus delayed invasive strategy *Low/intermediate risk=GRACE score <140 High risk=GRACE score ≥140 Mehta SR et al. N Engl J Med. 2009;310:2165-2175

  36. CRUSADE Registry Mortality Rates by Early Catheterization 10 Early Catheterization No Early Catheterization 8.6 8 6 % In-hospital Mortality 3.9 4 2.5 2.3 2 1.1 0.7 0 Low (n=4326) Moderate (n=4492) High (n=9108) Modified PURSUIT Risk Category Bhatt DL et al. JAMA. 2004;292:2096-2104..

  37. Evolving Antiplatelet Therapies Antithrombotic Therapy in ACS

  38. 0 3 6 9 12 CURE Study Primary End Point: MI/Stroke/CV Death 20% Relative RiskReduction 0.14 Placebo + Aspirin (n=6303) 0.12 0.10 0.08 Clopidogrel + Aspirin (n=6259) Cumulative Hazard Rate P<0.001 n=12,562 0.06 0.04 0.02 0.00 Months of Follow-up Yusuf S et al. N Engl J Med. 2001;345:494-502.

  39. CREDOLong-Term (1 Year) Benefits of Clopidogrel in PCI Patients MI, stroke, or death – ITT population 15 Placebo* Clopidogrel* 11.5% 27% RRR P=0.02 10 8.5% Combined endpoint occurrence (%) 5 0 0 3 6 9 12 Months from randomization * Plus ASA and other standard therapies Steinhubl S et al. JAMA. 2002;288:2411-2420.

  40. Primary Endpoint (MI/Stroke/CV Death) in Patients with Previous MI, IS, or PAD*CHARISMA: “CAPRIE-like Cohort” n=9,478 10 8.8% Placebo + ASA 7.3% Clopidogrel + ASA 8 6 Primary Outcome Event Rate (%) 4 RRR: 17.1 % (95% CI: 4.4%, 28.1%) P=0.01 2 0 0 6 12 18 24 30 Months Since Randomization * Post hoc analysis Bhatt DL et al.J Am Coll Cardiol. 2007;49:1982-1988.

  41. TRITON – TIMI 38 CV Death, MI, Stroke 15 Clopidogrel 12.1(781) 9.9 (643) 10 Primary Endpoint (%) Prasugrel HR 0.81(0.73-0.90)P=0.0004 HR 0.80P=0.0003 5 HR 0.77P=0.0001 NNT= 46 LTFU = 14 (0.1%) ITT= 13,608 0 0 30 60 90 180 270 360 450 Days Wiviott SD et al. N Engl J Med. 2007;357:2001-2005.

  42. PLATO: Kaplan-Meier Estimate of Time to First Primary Efficacy Event (Composite of CV Death, MI or Stroke) 13 12 11.7 Clopidogrel 11 10 9.8 9 Ticagrelor 8 7 Cumulative incidence (%) 6 5 4 HR = hazard ratio CI = confidence interval 3 2 HR 0.84 (95% CI 0.77–0.92), p=0.0003 1 0 0 60 120 180 240 300 360 Days after randomisation No. at risk Ticagrelor 9,333 8,628 8,460 8,219 6,743 5,161 4,147 Clopidogrel 9,291 8,521 8,362 8,124 6,743 5,096 4,047 Wallentin L et al. N Engl J Med. 2009;361:1045-1057

  43. Glycoprotein IIb/IIIa Inhibitors • Only indicated in highest risk UA/NSTEMI patients (dynamic changes on ECG, elevated biomarkers, electrical instability) and/or in whom early PCI is planned • Abciximab is a choice if early angiography and PCI are planned • Eptifibatide or tirofiban might be indicated when no PCI planned • Initiate in conjunction with your cardiologist • Discontinue anticoagulant therapy after PCI • Use of glycoprotein IIb/IIIa inhibitors is on the decline Anderson JL et al. J Am CollCardiol. 2007;50:e1-e157. Wright RS et al. Circulation. 2011;123:2022-2060

  44. Emerging Therapies Antithrombotic Therapy in ACS

  45. Key Investigational Antithrombotic Drugs • Factor Xa inhibitors • Rivaroxaban • Apixaban • PAR-1 thrombin inhibitors • Vorapaxar • Atopaxar

  46. RIVAROXABAN: ATLAS ACS 2 TIMI 51Primary Efficacy Endpoint: CV Death / MI / Stroke 2 Yr KM Estimate 12 Placebo 10.7% 10 8.9% 8 HR 0.84 (0.74-0.96) mITTp = 0.008 ITT p = 0.002 ARR 1.8% NNT = 56 6 Rivaroxaban (both doses 2.5 mg bid and 5 mg bid) 4 2 0 0 4 8 12 16 20 24 Months After Randomization No. at Risk 4307 3470 5113 1079 2664 1831 421 Placebo 8502 6753 Rivaroxaban 10229 5137 2084 3554 831 Mega JL et al. N Engl J Med. 2012;366:9-19.

  47. RIVAROXABAN: ATLAS ACS 2 TIMI 51Efficacy Endpoints: Very Low Dose 2.5 mg BIDPatients Treated with Aspirin + Thienopyridine CV Death / MI / Stroke Cardiovascular Death 5% Placebo Placebo HR 0.84 mITT p=0.04 ITT p=0.01 HR 0.66 mITT p<0.001 ITT p<0.001 12% 4.2% 10.4% 9.0% 2.5% Estimated Cumulative incidence (%) Rivaroxaban 2.5 mg BID Rivaroxaban 2.5 mg BID NNT = 59 NNT = 71 12 12 24 0 0 24 Months Months Mega JL et al. N Engl J Med. 2012;366:9-19.

  48. RIVAROXABAN: ATLAS ACS 2 TIMI 51 Treatment Emergent Fatal Bleeds and ICH 1.2 P = NS for Riva vs Placebo P = NS for Riva 5 vs Placebo P = NS for Riva 2.5 vs Placebo P = 0.044 for Riva 2.5 vs 5 P = 0.009 for Riva vs Placebo P = 0.005 Riva 5 vs Placebo P = 0.037 for Riva 2.5 vs Placebo P = 0.44 for Riva 2.5 vs 5 Placebo 2.5 mg Rivaroxaban 1 5.0 mg Rivaroxaban 0.8 0.7 P = NS for all comparisons 0.6 0.4 0.4 0.4 0.2 0.2 0.2 0.2 0.1 0.1 0.1 n=8 n=18 n=4 n=5 n=15 n=14 n=5 n=6 n=9 0 Fatal ICH Fatal ICH ICH: intracranial hemorrhage Adapted from Mega JL et al. N Engl J Med. 2012:336:9-19.

  49. Apixaban: APPRAISE-2 TrialPrimary Outcome: CV Death, MI, Ischemic Stroke Apixaban 279 (7.5%) Placebo 293 (7.9%) HR 0.95; 95% CI 0.80-1.11; p=0.509 Alexander JH et al. N Engl J Med. 2011;365:699-708.

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