1. Acute Coronary Syndrome Steven R. Bruhl MD, MS 3 rd Year Cardiology Fellow Internal Medicine Didactics July 14, 2010

2. Goals and Objectives Discuss the definition & pathophysiology of ACS Discuss the definition & pathophysiology of ACS Recognize the clinical features of low, intermediate and high risk ACS Recognize the clinical features of low, intermediate and high risk ACS Be able to identify and treat patients appropriate for a conservative or invasive strategy Be able to identify and treat patients appropriate for a conservative or invasive strategy Discuss new and controversial pharmacological treatments Discuss new and controversial pharmacological treatments

3. Gold Standard for Treatment of ACS ACC/AHA 2007 Guidelines for the Management of Patients With Unstable Angina/Non–ST-Elevation Myocardial Infarction http://circ.ahajournals.org/cgi/content/full/102/10/1193

5. Algorithm for evaluation and management of patients suspected of having ACS. Anderson JL, et al. J Am Coll Cardiol 2007;50:e1–e157, Figure 2.

6. ACS Overview Overview of ACS Overview of ACS Assessment of “Likelihood of ACS” Assessment of “Likelihood of ACS” Early Risk Stratification Early Risk Stratification Invasive vs Conservative Strategy Invasive vs Conservative Strategy Pharmacotherapy Pharmacotherapy Long-term Therapy/Secondary Prevention Long-term Therapy/Secondary Prevention

7. Scope of the Problem 5 million ER visits nationwide for CP 5 million ER visits nationwide for CP 800,000 experience an MI each year 800,000 experience an MI each year 213,000 die from their event 213,000 die from their event ½ of those die before reaching the ER ½ of those die before reaching the ER Pre-CCU, mortality for MI was >30% Pre-CCU, mortality for MI was >30% Fell to 15% with CCU Fell to 15% with CCU With current interventions, in hospital mortality of STEMI is 6-7% With current interventions, in hospital mortality of STEMI is 6-7%

8. Overview of ACS Acute Coronary Syndromes* 1.57 Million Hospital Admissions - ACS UA/NSTEMI † STEMI 1.24 million Admissions per year 0.33 million Admissions per year *Primary and secondary diagnoses. †About 0.57 million NSTEMI and 0.67 million UA. Heart Disease and Stroke Statistics – 2007 Update. Circulation 2007; 115:69–171.

9. Acute Coronary Syndrome (ACS) Definition: The spectrum of acute ischemia related syndromes ranging from UA to MI with or without ST elevation that are secondary to acute plaque rupture or plaque erosion. Definition: The spectrum of acute ischemia related syndromes ranging from UA to MI with or without ST elevation that are secondary to acute plaque rupture or plaque erosion. [----UA---------NSTEMI----------STEMI----] [----UA---------NSTEMI----------STEMI----]

10. Decreased O 2 Supply Flow- limiting stenosis Anemia Plaque rupture/clot Increased O 2 Demand O 2 supply/demand mismatch→Ischemia Myocardial ischemia→necrosis Pathophysiology ACS Asymptomatic Angina Myocardial Infarction Pathophysiology of Stable Angina and ACS

11. Pathophysiology of ACS Evolution of Coronary Thrombosis

12. Unstable Angina Unstable Angina STEMI NSTEMI NSTEMI Non occlusive thrombus Non specific ECG Normal cardiac enzymes Non-occlusive thrombus sufficient to cause tissue damage & mild myocardial necrosis ST depression +/- T wave inversion on ECG Elevated cardiac enzymes Complete thrombus occlusion ST elevations on ECG or new LBBB Elevated cardiac enzymes More severe symptoms

13. STEMI Name 3 situations in which you cannot diagnose STEMI Name 3 situations in which you cannot diagnose STEMI

14. STEMI Left Ventricular Hypertrophy Left Ventricular Hypertrophy Chronic or Rate Dependent LBBB Chronic or Rate Dependent LBBB Paced Rhythm Paced Rhythm

15. Cardiac Catheterization Name the only 3 situations that demand emergent cardiac catheterization. Name the only 3 situations that demand emergent cardiac catheterization.

16. Cardiac Catheterization Name the only 3 situations that demand emergent cardiac catheterization. Name the only 3 situations that demand emergent cardiac catheterization. STEMI or new LBBB STEMI or new LBBB ACS with hemodynamic or electrical instability despite optimal medical management ACS with hemodynamic or electrical instability despite optimal medical management Uncontrolled CP despite optimal medical management Uncontrolled CP despite optimal medical management

17. Diagnosis of ACS At least 2 of the following At least 2 of the following History ( angina or angina equivalent) History ( angina or angina equivalent) Acute ischemic ECG changes Acute ischemic ECG changes Typical rise and fall of cardiac markers Typical rise and fall of cardiac markers Absence of another identifiable etiology Absence of another identifiable etiology

18. Initial Evaluation and management of Non ST-elevation ACS

19. Likelihood of ACS by Hx/PE History/Examination History/Examination Pain in Chest or Left Arm Pain in Chest or Left Arm CP Radiation CP Radiation Right Shoulder Right Shoulder Left Arm Left Arm Both Left & Right Arm Both Left & Right Arm Diaphoresis Diaphoresis 3 rd Heart Sound 3 rd Heart Sound SBP < 80 mm Hg SBP < 80 mm Hg Pulmonary Crackles Pulmonary Crackles Panju AA. JAMA. 1998;280:1256. Panju AA. JAMA. 1998;280:1256. Suggesting AMI LR 2.7 LR 2.9 (1.4-6.0) LR 2.3 (1.7-3.1) LR 7.1 (3.6-14.2) LR 2.0 (1.9-2.2) LR 3.2 (1.6-6.5) LR 3.1 (1.8-5.2) LR 2.1 (1.4-3.1)

20. Likelihood of ACS by Hx/PE Clinical Examination – Clinical Examination – Pleuritic Chest Pain Pleuritic Chest Pain Sharp or Stabbing Pain Sharp or Stabbing Pain Positional Chest Pain Positional Chest Pain Reproducible Chest Pain Reproducible Chest Pain Panju AA. JAMA. 1998;280:1256. Panju AA. JAMA. 1998;280:1256. Against AMI LR 0.2 (0.2-0.3) LR 0.3 (0.2-0.5) LR 0.3 (0.2-0.4) LR 0.2-0.4

21. Risk Stratification by ECG Simple, quick, noninvasive tool Simple, quick, noninvasive tool Universally available, cheap Universally available, cheap Correlates with risk and prognosis Correlates with risk and prognosis Guides treatment decisions Guides treatment decisions Can identify alternative causes Can identify alternative causes

22. Risk Stratification by ECG ECG Findings and Associated LR for AMI ECG Findings and Associated LR for AMI New ST-E > 1mmLR 5.7-53.9 New ST-E > 1mmLR 5.7-53.9 New Q wavesLR 5.3-24.8 New Q wavesLR 5.3-24.8 Any ST-ELR 11.2 (7.1-17.8) Any ST-ELR 11.2 (7.1-17.8) New Conduction DefectLR 6.3 ( 2.5-15.7) New Conduction DefectLR 6.3 ( 2.5-15.7) New ST-DLR 3.0-5.2 New ST-DLR 3.0-5.2 NORMAL ECGLR 0.1-0.4 NORMAL ECGLR 0.1-0.4 Panju AA. JAMA. 1998;280:1256.

23. Risk Stratification by ECG CAVEATS 1-8% AMI have a normal ECG 1-8% AMI have a normal ECG Only Approx 50% of AMI patients have diagnostic changes on their initial ECG Only Approx 50% of AMI patients have diagnostic changes on their initial ECG Peter J. Zimetbaum, M.D., N Engl J Med 2003;348:933-40.

24. Risk Stratification by ECG CAVEATS cont. 1 ECG cannot exclude AMI 1 ECG cannot exclude AMI Brief sample of a dynamic process Brief sample of a dynamic process Small regions of ischemia or infarction may be missed Small regions of ischemia or infarction may be missed Peter J. Zimetbaum, M.D., N Engl J Med 2003;348:933-40.

26. How Sensitive is the ECG Alone?

27. How Predictive is NTG response?

28. Timing of Release of Various Biomarkers After Acute Myocardial Infarction Shapiro BP, Jaffe AS. Cardiac biomarkers. In: Murphy JG, Lloyd MA, editors. Mayo Clinic Cardiology: Concise Textbook. 3 rd ed. Rochester, MN: Mayo Clinic Scientific Press and New York: Informa Healthcare USA, 2007:773–80. Anderson JL, et al. J Am Coll Cardiol 2007;50:e1–e157, Figure 5.

29. Mortality at 42 Days 8311741481345067  % % % % % % Risk Stratification by Troponin

30. Non ACS causes of Troponin Elevation 1. Trauma (including contusion; ablation; pacing; ICD firings,, endomyocardial biopsy, cardiac surgery, after-interventional closure of ASDs) 2. Congestive heart failure (acute and chronic) 3. Aortic valve disease and HOCM with significant LVH 4. Hypertension 5. Hypotension, often with arrhythmias 6. Noncardiac surgery 7. Renal failure 8. Critically ill patients, especially with diabetes, respiratory failure 9. Drug toxicity (eg, adriamycin, 5 FU, herceptin, snake venoms) 10. Hypothyroidism 11. Coronary vasospasm, including apical ballooning syndrome 12. Inflammatory diseases (eg, myocarditis, Kawasaki disease, smallpox vaccination, 13. Post-PCI 14. Pulmonary embolism, severe pulmonary hypertension 15. Sepsis 16. Burns, especially if TBSA greater than 30% 17. Infiltrative diseases: amyloidosis, hemachromatosis, sarcoidosis, and scleroderma 18. Acute neurologic disease, including CVA, subarchnoid bleeds 19. Rhabdomyolysis with cardiac injury 20. Transplant vasculopathy 21. Vital exhaustion Modified from Apple FS, et al Heart J. 2002;144:981-986.

31. Combined Sensitivities for ACS

32. Early Invasive Conservative

33. Unstable angina/NSTEMI cardiac care Evaluate for conservative vs. invasive strategy based upon: Evaluate for conservative vs. invasive strategy based upon: Likelihood of actual ACS Likelihood of actual ACS Risk stratification by TIMI risk score Risk stratification by TIMI risk score ACS risk categories per AHA guidelines ACS risk categories per AHA guidelines Low Intermediate High

34. TIMI Risk Score Predicts risk of death, new/recurrent MI, need for urgent revascularization within 14 days

35. TIMI Risk Score T: Troponin elevation (or CK-MB elevation) H: History or CAD (>50% Stenosis) R: Risk Factors: > 3 (HTN, Hyperlipidemia, Family Hx, DM II, Active Smoker) E: EKG changes: ST elevation or depression 0.5 mm concordant leads A 2 : Aspirin use within the past 7 days; Age over 65 T: Two or more episodes of CP within 2 hours

36. Deciding between Early Invasive vs a Conservative Strategies Hemodynamic instabilityHemodynamic instability Elecrical instabilityElecrical instability Refractory anginaRefractory angina PCI in past 6 monthsPCI in past 6 months CABGCABG EF <40%EF <40%

38. Specifics of Early Hospital Care Anti-Ischemic Therapy Anti-Ischemic Therapy Anti-Platelet Therapy Anti-Platelet Therapy Anticoagulant Therapy Anticoagulant Therapy

39. Early Hospital Care Anti-Ischemic Therapy Class I Class I Bed/Chair rest and Telemetry Bed/Chair rest and Telemetry Oxygen (maintain saturation >90%) Oxygen (maintain saturation >90%) Nitrates (SLx3 Oral/topical. IV for ongoing iscemia, heart failure, hypertension) Nitrates (SLx3 Oral/topical. IV for ongoing iscemia, heart failure, hypertension) Oral B-blockers in First 24-hours if no contraindications. (IV B-blockers class IIa indication) Oral B-blockers in First 24-hours if no contraindications. (IV B-blockers class IIa indication) Non-dihydropyridine Ca-channel blockers for those with contraindication fo B-blockers Non-dihydropyridine Ca-channel blockers for those with contraindication fo B-blockers ACE inhibitors in first 24-hours for heart failure or EF<40% (Class IIa for all other pts) (ARBs for those intolerant) ACE inhibitors in first 24-hours for heart failure or EF<40% (Class IIa for all other pts) (ARBs for those intolerant) Statins Statins

40. Early Hospital Care Anti-Ischemic Therapy Class III Class III Nitrates if BP<90 mmHg or RV infarction Nitrates if BP<90 mmHg or RV infarction Nitrates within 24-hrs of Sildenafil or 48 hrs of Tadalafil Nitrates within 24-hrs of Sildenafil or 48 hrs of Tadalafil Immediate release dihydropyradine Ca-blockers in the absence of B-Blocker therapy Immediate release dihydropyradine Ca-blockers in the absence of B-Blocker therapy IV ACE-inhibitors IV ACE-inhibitors IV B-blockers in patients with acute HF, Low output state or cardiogenic shock, PR interval >0.24 sec, 2 nd or 3 rd degree heart block, active asthma, or reactive airway disease IV B-blockers in patients with acute HF, Low output state or cardiogenic shock, PR interval >0.24 sec, 2 nd or 3 rd degree heart block, active asthma, or reactive airway disease NSAIDS and Cox-2 inhibitors NSAIDS and Cox-2 inhibitors

41. Early Hospital Care Anti-Platelet Therapy Class I Class I Aspirin (162-325 mg), non enteric coated Aspirin (162-325 mg), non enteric coated Clopidogrel for those with Aspirin allergy/intolerance (300-600 mg load and 75 mg/d) Clopidogrel for those with Aspirin allergy/intolerance (300-600 mg load and 75 mg/d) GI prophylaxis if a Hx of GI bleed GI prophylaxis if a Hx of GI bleed GP IIb/IIIa inhibitors should be evaluated based on whether an invasive or conservative strategy is used GP IIb/IIIa inhibitors should be evaluated based on whether an invasive or conservative strategy is used GP IIb/IIIa inhibitors recommended for all diabetics and all patient in early invasive arm GP IIb/IIIa inhibitors recommended for all diabetics and all patient in early invasive arm

42. Early Hospital Care Anticoagulant Therapy Class I Class I Unfractionated Heparin Unfractionated Heparin Enoxaparin Enoxaparin Bivalarudin Bivalarudin Fondaparinux Fondaparinux Relative choice depends on invasive vs conservative strategy and bleeding risk Relative choice depends on invasive vs conservative strategy and bleeding risk

43. Early Hospital Care Statin Therapy MIRACL Trial Inclusion Criteria MIRACL Trial Inclusion Criteria 3086 patients with Non ST ACS 3086 patients with Non ST ACS Total cholesterol <270 mg/dl Total cholesterol <270 mg/dl No planned PCI No planned PCI Randomized to Atorvastatin vs Placebo Randomized to Atorvastatin vs Placebo Drug started at 24-96 hours Drug started at 24-96 hours

44. Statin Evidence: MIRACL Study Relative risk = 0.84 P =.048 95% CI 0.701-0.999 Atorvastatin Placebo 0 5 10 15 0481216 Time Since Randomization (weeks) Cumulative Incidence (%) Time to first occurrence of: Death (any cause) Nonfatal MI Resuscitated cardiac arrest Worsening angina with new objective evidence and urgent rehospitalization 17.4% 14.8% Primary Efficacy Measure Schwartz GG, et al. JAMA. 2001;285:1711-1718.

45. Statin Evidence: MIRACL Study 0 0.5 1 1.5 2 0481216 Time Since Randomization (weeks) Cumulative Incidence (%) Relative risk = 0.49 P =.04 95% CI 0.24-0.98 Atorvastatin Placebo Fatal and Nonfatal Stroke Waters DD, et al. Circulation. 2002;106:1690-1695. S24

46. All-Cause Death or Major CV Events in All Randomized Subjects031821242730691215 % with Event Months of Follow-up Pravastatin 40mg (26.3%) Atorvastatin 80mg (22.4%) 16% RR (P = 0.005) 30 25 20 15 10 5 0 PROVE-IT Trial

47. Summary of PROVE-IT Results In patients recently hospitalized within 10 days for an acute coronary syndrome: In patients recently hospitalized within 10 days for an acute coronary syndrome:  “Intensive” high-dose LDL-C lowering (median LDL-C 62 mg/dL) compared to “moderate” standard-dose lipid-lowering therapy (median LDL-C 95 mg/dL) reduced the risk of all cause mortality or major cardiac events by 16% (p=0.005)  Benefits emerged within 30 days post ACS with continued benefit observed throughout the 2.5 years of follow-up  Benefits were consistent across all cardiovascular endpoints, except stroke, and most clinical subgroups

48. Invasive vs Conservative Strategies

49. Invasive vs Conservative Strategy Clinical Trials TIMI IIIB (94) Conservative Strategy Favored N=920 Invasive Strategy Favored N=7,018 VANQWISH (98) MATE FRISC II (99) TACTICS- TIMI 18 (01) VINO RITA-3 (02) TRUCS ISAR- COOL ICTUS (05) No difference N=2,874 Weight of the evidence

50. How Early is Early?

51. Secondary Prevention Class I Indications Aspirin Aspirin Beta-blockers: (all pts, slow titration with moderate to severe failure Beta-blockers: (all pts, slow titration with moderate to severe failure ACE-Inhibitors: CHF, EF<40%, HTN, DM ACE-Inhibitors: CHF, EF<40%, HTN, DM (All pts-Class IIa) ARB when intolerant to ACE. (Class IIa as alternative to ACEI) (All pts-Class IIa) ARB when intolerant to ACE. (Class IIa as alternative to ACEI) Aldosterone blockade: An ACEI, CHF with either EF 30 ml/min and K 30 ml/min and K<5.0 mEq/L Statins Statins Standard Risk Factor Management Standard Risk Factor Management

52. Long-Term Antithrombotic Therapy at Hospital Discharge after UA/NSTEMI Medical Therapy without Stent Bare Metal Stent Group Drug Eluting Stent Group ASA 162 to 325 mg/d for at least 1 month, then 75 to 162 mg/d indefinitely (Class I, LOE: A) & Clopidogrel 75 mg/d for at least 1 month and up to 1 year (Class I, LOE:B) Add: Warfarin (INR 2.0 to 2.5) (Class IIb, LOE: B) Continue with dual antiplatelet therapy as above YesNo Indication for Anticoagulation? ASA 75 to 162 mg/d indefinitely (Class I, LOE: A) & Clopidogrel 75 mg/d at least 1 month (Class I, LOE: A) and up to 1 year (Class I, LOE: B) ASA 162 to 325 mg/d for at least 3 to 6 months, then 75 to 162 mg/d indefinitely (Class I, LOE: A) & Clopidogrel 75 mg/d for at least 1 year (Class I, LOE: B) Anderson JL, et al. J Am Coll Cardiol 2007;50:e1–e157, Figure 11. INR = international normalized ratio; LOE = level of evidence. UA/NSTEMI Patient Groups at Discharge New

53. Secondary Prevention Class III Hormone Replacement Therapy Hormone Replacement Therapy Antioxidants (Vit C, Vit E) Antioxidants (Vit C, Vit E) Folic Acid Folic Acid

54. New and Controversial Drug Therapies

55. Early Treatment with Clopidogrel

56. Shortcomings of the CURE Trial Conducted primarily at centers without routine use of early invasive strategy Conducted primarily at centers without routine use of early invasive strategy Only 462 (3.7%) patients enrolled from the U.S. Only 462 (3.7%) patients enrolled from the U.S. 44% had catheterization during index hospitalization 44% had catheterization during index hospitalization Adverse event reduced only in nonfatal MI set Adverse event reduced only in nonfatal MI set Major Bleeding rate of 9.6% among patients who were administered clopidogrel within 5 days of CABG Major Bleeding rate of 9.6% among patients who were administered clopidogrel within 5 days of CABG

57. Clopidogrel Bleeding Risk and CABG “In hospitals in which patients with UA/NSTEMI undergo rapid diagnostic catheterization within 24 hours of admission, clopidogrel is not started until it is clear that CABG will not be scheduled within the next several days. However, unstable patients should receive clopidogrel or be take for immediate angiography.” “In hospitals in which patients with UA/NSTEMI undergo rapid diagnostic catheterization within 24 hours of admission, clopidogrel is not started until it is clear that CABG will not be scheduled within the next several days. However, unstable patients should receive clopidogrel or be take for immediate angiography.”

58. Clopidogrel vs. Prasugrel

64. Prasugrel-Key Facts Contraindicated in pts with prior TIA/Stroke Contraindicated in pts with prior TIA/Stroke Not recommended for patients >75 years Not recommended for patients >75 years 5 mg maintenance dose suggested in patients <60 Kg, though this dose has not been studied 5 mg maintenance dose suggested in patients <60 Kg, though this dose has not been studied

65. Summary ACS includes UA, NSTEMI, and STEMI ACS includes UA, NSTEMI, and STEMI Management guideline focus Management guideline focus Immediate assessment/intervention (MONA+BAH) Immediate assessment/intervention (MONA+BAH) Risk stratification (UA/NSTEMI vs. STEMI) Risk stratification (UA/NSTEMI vs. STEMI) RAPID reperfusion for STEMI (PCI vs. Thrombolytics) RAPID reperfusion for STEMI (PCI vs. Thrombolytics) Conservative vs Invasive therapy for UA/NSTEMI Conservative vs Invasive therapy for UA/NSTEMI Aggressive attention to secondary prevention initiatives for ACS patients Aggressive attention to secondary prevention initiatives for ACS patients Beta blocker, ASA, ACE-I, Statin Beta blocker, ASA, ACE-I, Statin

66. Questions?