UNSTABLE ANGINA & NON–ST-SEGMENT ELEVATION MYOCARDIAL INFARCTION COMMITTEE MEMBERS

1. ACC/AHA GUIDELINES UNSTABLE ANGINA & NON–ST-SEGMENT ELEVATION MYOCARDIAL INFARCTION COMMITTEE MEMBERS Eugene Braunwald, MD, Chair Joel Kupersmith, MD Thomas N. Levin, MD Carl J. Pepine, MD John W. Schaeffer, MD Earl E. Smith, III, MD David E. Steward, MD Pierre Theroux, MD Elliott M. Antman, MD John W. Beasley, MD Robert M. Califf, MD Melvin D. Cheitlin, MD Judith S. Hochman, MD Robert H. Jones, MD Dean Kereiakes, MD

2. ACUTE CORONARY SYNDROME No ST Elevation ST Elevation NSTEMI NQMI QwMI Myocardial Infarction Unstable Angina

3. CAUSES OF UA/NSTEMI Mechanical Obstruction Thrombosis . Dynamic Obstruction  MVO2 Inflammation/ Infection Mechanical Obstruction Thrombosis . Dynamic Obstruction  MVO2 Braunwald, Circulation 98:2219, 1998 Inflammation/ Infection

4. UA/NSTEMI THREE PRINCIPAL PRESENTATIONS Rest Angina*Angina occurring at rest and prolonged, usually > 20 minutes New-onset AnginaNew-onset angina of at least CCS Class III severity Increasing AnginaPreviously diagnosed angina that has become distinctly more frequent, longer in duration, or lower in threshold (i.e., increased by > 1 CCS) class to at least CCS Class III severity. * Pts with NSTEMI usually present with angina at rest. Braunwald Circulation 80:410; 1989

5. UA/NSTEMI 9/00 TROPONIN I LEVELS PREDICT THE RISK OF MORTALITY IN UA/NSTEMI Changes in Focus on Heart Failure 7.5 8 6.0 6 3.7 Mortality at 42 Days (% of patients) 3.4 4 1.7 2 1.0 831 174 148 134 50 67 0 0 to <0.4 0.4 to <1.0 1.0 to <2.0 2.0 to <5.0 5.0 to <9.0 >9.0 Cardiac Troponin I (ng/ml) Risk Ratio 1.0 1.8 3.5 3.9 6.2 7.8 Antman N Engl J Med. 335:1342, 1996

6. PURSUIT TRIAL: DEATH OR MI 1 0.98 0.96 0.94 0.92 0.9 Prob of Event-Free Survival 0.88 0.86 0.84 0.82 0.8 0 30 60 90 120 150 180 Days N Engl J Med. 339:436-43, 1998

7. TROPONINS T AND IAS PREDICTORS OF MORTALITY Cardiac Mortality Total Mortality 6.9 6.4 7 6 5.0 5 4 3.3 3 2.0 1.7 2 1 0 PTS 1993 1057 RR 1641 792 RR Trop. Neg Pos Neg Pos No. Trials 6 7

8. RECOMMENDATION Class I 1. Patients with suspected ACS with chest discomfort at rest for >20 min, hemodynamic instability, or recent syncope or presyncope should be referred immediately to an ED or a specialized chest pain unit. Other patients with a suspected ACS may be seen initially in an ED, a chest pain unit, or an outpatient facility.

9. Class I 1. Noninvasive stress testing in low-risk pts free of ischemia at rest or with low-level activity and of CHF for a minimum of 12 to 24 h. 2. Noninvasive stress testing in pts at intermediate risk who have been free of ischemia at rest or with low-level activity and of CHF for a minimum of 2 or 3 days. RISK STRATIFICATION

10. Class I 3. Choice of stress test is based on the resting ECG, local expertise, and technologies. Treadmill exercise in pts able to exercise in whom the ECG is free of baseline ST-segment abnormalities, BBB, LVH, intraventricular conduction defect, paced rhythm, pre-excitation, and digoxin effect. 4. An imaging modality in pts with resting ST-segment depression (>0.1 mV), LVH, BBB, IVCD, pre-excitation, or digoxin who are able to exercise. RISK STRATIFICATION (cont’d)

11. RISK STRATIFICATION (cont’d) Class I 5. Pharmacological stress testing with imaging when physical limitations (e.g., arthritis, amputation, severe peripheral vascular disease, severe COPD, general debility) preclude adequate exercise stress. 6. Prompt angiography without noninvasive risk stratification for failure of stabilization with medical treatment.

12. 1. Severe LV dysfunction (LVEF < 0.35), rest or exercise 2. High-risk treadmill score (score < -11) 3. Stress-induced large perfusion defect 4. Stress-induced multiple perfusion defects NONINVASIVE RISK STRATIFICATION High risk (>3% annual mortality rate) Gibbons et al JACC 33:2092, 1999

13. 5. Large, fixed perfusion defect with LV dilation or increased lung uptake 6. Stress-induced moderate perfusion defect with LV dilation or increased lung uptake 7. Echocardiographic wall motion abnormality (>2 segments) at a low dose of dobutamine (< 10 mg•kg-1 •min-1) or at a low heart rate (<120 bpm) NONINVASIVE RISK STRATIFICATION High risk (>3% annual mortality rate) Gibbons et al JACC 33:2092, 1999

14. 1. Mild/moderate resting LV dysfunction (LVEF 0.35-0.49) 2. Intermediate-risk treadmill score (-11< score <5) 3. Stress-induced moderate perfusion defect without LV dilation or increased lung intake 4. Echocardiographic ischemia with wall motion abnormality involving < 2 segments only at higher doses of dobutamine NONINVASIVE RISK STRATIFICATION Intermediate Risk (1-3% annual mortality rate) Gibbons et al JACC 33:2092, 1999

15. NONINVASIVE RISK STRATIFICATION Low Risk (<1% annual mortality rate) 1. Low-risk treadmill score (score > 5) 2. Normal perfusion or small myocardial perfusion defect at rest or with stress 3. Normal echocardiographic wall motion or no change of limited resting wall motion abnormalities during stress Gibbons et al JACC 33:2092, 1999

16. DEATH OR MI AT 30 DAYS 16.7 18 Placebo GP IIb-IIIa Inhibitor 14.1 14 11.6 10.9 10.2 10.1 Percent of Patients 9 10 5.9 4.8 6 3.9 3.6 1.8 2 0 EPIC CAPTURE EPILOG EPISTENT PRISM-PLUS PURSUIT

17. DEATH, MI OR URGENT REVASC. @ 30 DAYS Placebo GP IIb-IIIa Inhibitor 15.9 16 14.8 12.8 12.2 11.5 11.3 12 10.5 10.3 Percent of Patients 8 8 4.9 4.8 4.5 4 0 EPIC CAPTURE EPILOG EPISTENT IMPACT II RESTORE

18. 1. Aspirin 75 to 325 mg/d 2. Clopidogrel 75 mg/qd for patients with contraindication to ASA 3. -Blocker 4. Lipid-lowering agent and diet in patients with LDL cholesterol >130 mg/dL 5. Lipid-lowering agent if LDL cholesterol level after diet is > 100 mg/dL 6. ACEI for patients with CHF, LV dysfunction (EF<0.40) hypertension, or diabetes MEDICATIONS AT HOSPITAL DISCHARGE Class I

19. 1. Smoking cessation and achievement or maintenance of optimal weight, daily exercise, and diet. 2. HMG-CoA reductase inhibitor for LDL cholesterol > 130 mg/dL. 3. Lipid-lowering agent if LDL cholesterol after diet is > 100 mg/dL. 4. Hypertension control to a BP < 130/85 mm Hg. 5. Tight control of hyperglycemia in diabetics. 6. Consider referral of smokers to a smoking cessation program. 1. Gemfibrozil or niacin for patients with HDL cholesterol < 40 mg/dL and triglycerides > 200 mg/dL. INSTRUCTIONS AT HOSPITAL DISCHARGE RISK FACTOR MODIFICATION Class I

20. EARLY INVASIVE STRATEGY Class I 1. Any of the following high-risk indicators: a. Recurrent angina/ischemia at rest or with low- level activities despite intensive anti-ischemic therapy b. Recurrent angina/ischemia with CHF symptoms, S3, pulmonary edema, increasing rales, or new or worsening MR c. High-risk findings on noninvasive stress testing d. Depressed LV systolic function (e.g., EF<0.40 on noninvasive study) e. Hemodynamic instability

21. EARLY INVASIVE STRATEGY (cont’d) Class I f. Sustained ventricular tachycardia g. PCI within 6 months h. Prior CABG 2. In the absence of these findings, either an early conservative or an early invasive strategy in hospitalized patients without contraindication for revascularization. Class IIa 1. An early invasive strategy in pts with repeated presentation for ACS despite therapy and without evidence for ongoing ischemia or high risk.

22. EARLY INVASIVE STRATEGY (cont’d) Class IIa 2. An early invasive strategy in pts >65 years or pts with ST-segment depression or elevated cardiac markers and no contraindication to revascularization. Class III 1. Coronary angiography in pts with extensive comorbidities, in whom risks of revascularization are not likely to outweigh benefits, in pts with a low likelihood of ACS and in pts who will not consent to revascularization.

23. All N = 12,296 OR = 0.66 P = 0.001 N = 2,754 OR = 0.59 P = 0.001 10% 8% 6% 4% 2% 0% 8.0% Death or MI 4.9% 4.3% 2.9% +24h +48h +72h +24h +48h Percutaneous Coronary Intervention Start GP IIb/IIIa inhibitor / placebo GP IIb/IIIa Inhibition in UA/NSTEMICAPTURE, PURSUIT, PRISM-PLUS Boersma et al. Circulation 100:2045, 2000

24. LMWH IN UNSTABLE ANGINAEFFECT ON TRIPLE ENDPOINT* Day FRISC 6 (dalteparin; n = 1,482 FRAXIS 14 (nadroparin; n = 2,357 ESSENCE 14 (enoxaparin; n = 3,171) TIMI 11B 14 (enoxaparin; n = 3,910) (P = 0.032) (P = 0.029) 0.75 1 1.5 LMWH better UFH better * Triple endpoint: death, MI, recurrent ischemia + urgent revascularization

25. ANTI - ISCHEMIC Rx Class IIa 1. Oral long-acting Ca2+ blocker for recurrent ischemia when -blocker and nitrate fully used. 2. ACEI for all post-ACS patients. 3. Intra-aortic balloon pump counterpulsation for severe ischemia that is continuing or recurs frequently despite intensive medical therapy or for hemodynamic instability in pts before or after coronary angiography. Class IIb 1. Extended-release form of nondihydropyridine Ca2+blocker instead of a -blocker. 2. Immediate-release dihydropyridine Ca2+ blocker in the presence of a -blocker.

26. ANTI - ISCHEMIC Rx Class I 1. Bed rest with continuous ECG monitoring in pts with ongoing rest pain. 2. NTG, sublingual tablet or spray, followed by IV administration for ongoing chest pain. 3. Supplemental O2 for pts with hypoxemia, cyanosis or respiratory distress; finger pulse oximetry or arterial blood gas determination to confirm SaO2>90%. 4. Morphine sulfate IV when symptoms are not immediately relieved with NTG or when acute pulmonary congestion and/or severe agitation is present.

27. ANTI - ISCHEMIC Rx (cont’d) Class I 5. A -blocker with the first dose administered IV if there is ongoing chest pain, followed by oral administration. 6. A nondihydropyridine Ca2+ blocker (e.g. verapamil or diltiazem) as initial therapy in pts with continuing or frequently recurring ischemia when -blocker is contraindicated. 7. An ACEI when hypertension persists despite treatment with NTG and a -blocker in pts with LV systolic dysfunction or congestive heart failure and in ACS patients with diabetes.

28. UA/NSTEMI HOSPITAL MANAGEMENT Monitoring (rhythm and ischemia)  blocker Nitrate Heparin GP IIb/IIIa inhibitor (?) Early invasive strategy Early conservative strategy Recurrent symptoms/ischemia Heart failure Serious arrhythmia Immediate angiography 12-48 hour angiography Patient stabilizes Evaluate LV function EF<.40 EF>.40 Stress Test Not low risk Low risk Medical Rx

29. UA/NSTEMI PATHOGENESIS (NON-EXCLUSIVE) Nonocclusive thrombus on pre-existing plaque Dynamic obstruction (coronary spasm or vasoconstriction) Progressive mechanical obstruction Inflammation and/or infection Secondary UA Braunwald Circulation 98:2219, 1998

30. RISK STRATIFICATION INEMERGENCY DEPARTMENT History Clinical findings ECG Cardiac markers HIGH RISK-FEATURES (RISK RISES WITH NUMBER) Prolonged ischemic discomfort (>20 min), ongoingrest pain, accelerating tempo of ischemia Pulmonary edema; S3 or new rales New MR murmur Hypotension, bradycardia, tachycardia Age >75 years Rest pain with transient ST-segment changes > 0.05 mV; new bundle-branch block, new sustained VT Elevated (e.g. TnT or TnI>0.1 ng/mL)

31. ED MANAGEMENT OF UA/NSTEMI  ST ? NO YES Nondiagnostic ECG Normal serum cardiac markers ST and/or T wave changes Ongoing pain + cardiac markers Hemodynamic abnormalities Observe Follow-up at 4-8 hours: ECG, cardiac markers Evaluate for Reperfusion No recurrent pain; Neg follow-up studies Recurrent ischemic pain or + UA/NSTEMI follow-up studies Diagnosis of UA/NSTEMI confirmed Stress study to provoke ischemia prior to discharge or as outpatient Neg: nonischemic discomfort;low-risk UA/NSTEMI + UA/NSTEMI confirmed ADMIT Outpatient follow-up

32. ANTIPLATELET AND ANTICOAGULATION Rx Patients with event (%) Risk ratio (95% CI) P-value Trials Active Placebo N % Death or MI ASA vs placebo 2448 6.4 12.5 0.0005 UFH + ASA vs ASA 999 2.6 5.5 0.018 LMWH + ASA vs ASA 2629 2.0 5.3 0.0005 All GP IIb/IIIa + UFH + ASA vs UFH + ASA 17044 5.1 6.2 0.0022 Active Treatment Superior Active Treatment Inferior

33. ANTIPLATELET Rx Class I Definite ACS with continuing Possible ACS Likely/Definite ACS Ischemia or Other High-Risk Features or planned PCI Aspirin Aspirin Aspirin + + Subcutaneous LMWH IV heparin + or IV heparin IV platelet GP IIb/IIIa antagonist

34. ANTIPLATELET Rx Class I 1. Administer ASA as soon as possible after presentation and continue indefinitely. 2. A thienopyridine (clopidogrel or ticlopidine) in pts unable to take ASA. 3. Add IV UFH or subcutaneous LMWH to antiplatelet therapy with ASA, clopidogrel, or ticlopidine. 4. Add platelet GP IIb/IIIa receptor antagonist in pts with continuing ischemia or with other high-risk features and in pts in whom early PCI is planned.

35. EVALUATION OF ACS PTS IN ED 10,689 Pts with suspected ACS Pain in chest, left arm, jaw, epigastrium, dyspnea, dizziness, palpitations Evaluation for acute ischemia Pos. Neg. 7,996 pts (75%) 2,672 pts (25%) Selker Ann Intern Med. 129:845, 1998

36. TELEPHONE TRIAGE Class I 1. Patients with symptoms that suggest possible ACS should not be evaluated only over the phone but should be referred to a facility that allows evaluation by a physician and the recording of a 12-lead ECG.

37. BIOCHEMICAL CARDIAC MARKERS IN PTS WITH SUSPECTED ACS WITHOUT STE Disadvantages CK-MB 1. Lack of specificity with skeletal muscle disease/injury 2. Low sensitivity during early MI (<6 h) or late (>36 h) after symptom onset and for minor myocardial damage Myoglobin 1. Very low specificity with skeletal muscle injury or disease 2. Rapid return to normal Troponins 1. Low sensitivity in early phase of MI (<6 h after symptom onset) 2. Limited ability to detect late minor reinfarction

38. BIOCHEMICAL CARDIAC MARKERS IN PTS WITH SUSPECTED ACS WITHOUT STE Advantages CK-MB 1. Rapid, cost-efficient, accurate assays 2. Ability to detect early reinfarction Myoglobin 1. High sensitivity 2. Useful in early detection of MI 3. Detection of reperfusion 4. Most useful in ruling out MI Troponins 1. Powerful for stratification 2. Greater sensitivity and specificity than CK-MB 3. Detection of recent MI up to 2 weeks after onset 4. Useful for selection of therapy 5. Detection of reperfusion

39. RISK STRATIFICATION INEMERGENCY DEPARTMENT History Clinical findings ECG Cardiac markers HIGH RISK-FEATURES (RISK RISES WITH NUMBER) Prolonged ischemic discomfort (>20 min), ongoingrest pain, accelerating tempo of ischemia Pulmonary edema; S3 or new rales New MR murmur Hypotension, bradycardia, tachycardia Age >75 years Rest pain with transient ST-segment changes > 0.05 mV; new bundle-branch block, new sustained VT Elevated (e.g. TnT or TnI>0.1 ng/mL)

40. UA/NSTEMI: A MAJOR MEDICAL PROBLEM • 5.32m ED visits for chest pain • 1.43m hospitalizations/year (1o diagnosis) • 60% > 65 years, 46% women National Center for Health Statistics

41. ANTI - ISCHEMIC Rx Class I 1. Bed rest with continuous ECG monitoring in pts with ongoing rest pain. 2. NTG, sublingual tablet or spray, followed by IV administration for ongoing chest pain. 3. Suplemental O2 for pts with hypoxemia, cyanosis or respiratory distress; finger pulse oximetry or arterial blood gas determination to confirm SaO2>90%. 4. Morphine sulfate IV when symptoms are not immediately relieved with NTG or when acute pulmonary congestion and/or severe agitation is present.

42. ANTI - ISCHEMIC Rx (cont’d) Class I 5. A -blocker with the first dose administered IV if there is ongoing chest pain, followed by oral administration. 6. A nondihydropyridine Ca2+ blocker (e.g. verapamil or diltiazem) as initial therapy in pts with continuing or frequently recurring ischemia when -blocker is contraindicated. 7. An ACEI when hypertension persists despite treatment with NTG and a -blocker in pts with LV systolic dysfunction or congestive heart failure and in ACS patients with diabetes.

43. ANTI - ISCHEMIC Rx Class Ila 1. Oral long-acting Ca2+ blocker for recurrent ischemia when -blocker and nitrate fully used. 2. ACEI for all post-ACS patients. 3. Intra-aortic balloon pump counterpulsation for severe ischemia that is continuing or recurs frequently despite intensive medical therapy or for hemodynamic instability in pts before or after coronary angiography.

44. INTERMEDIATE LIKELIHOOD THAT UA/NSTEMI IS CAUSED BY OBSTRUCTIVE CAD Chest or left arm pain reproducing prior reproducing prior documented angina. Known history of CAD, including MI Transient MR, hypotension, diaphoresis, pulmonary edema, or rales New, or presumably new, transient ST-segment deviation (0.05 mV) or T-wave inversion (0.2 mV) with symptoms Elevated cardiac Tnl, TnT, or CK-MB History Examination ECG Cardiac markers

45. INTERMEDIATE LIKELIHOOD THAT UA/NSTEMI IS CAUSED BY OBSTRUCTIVE CAD Absence of high-likelihood features and presence of any of the following: Chest or left arm pain or discomfort Age > 70 Male sex Diabetes mellitus Extracardiac vascular diseaseFixed Q waves Abnormal ST segments or Twaves not documented to be new Normal History Examination ECG Cardiac markers

46. UA/NSTEMIEMERGENCY ROOM TRIAGE • Chest pain or severe epigastric pain, typical of myocardial ischemia or MI: • Substernal compression or crushing chest pain • Pressure, tightness, heaviness, cramping, aching sensation • Unexplained indigestion, belching, epigastric pain • Radiating pain to neck, jaw, shoulders, back or to one or both arms • Associated dyspnea, nausea and/or vomiting, diaphoresis IF THESE SYMPTOMS ARE PRESENT, OBTAIN STAT ECG

47. HIGH OR INTERMEDIATE LIKELIHOOD THAT UA/NSTEMI IS CAUSED BY OBSTRUCTIVE CAD FEATURE HIGH LIKELIHOOD INTERMEDIATE LIKELIHOOD Absence of high-likelihood features and presence of any of the following: Chest or left arm pain or discomfort Age > 70 Male sex Diabetes mellitus Extracardiac vascular disease History Examination Chest or left arm pain reproducing prior documented angina. Known history of CAD, including MI Transient MR, hypotension, diaphoresis, pulmonary edema, or rales

48. HIGH OR INTERMEDIATE LIKELIHOOD THAT UA/NSTEMI IS CAUSED BY OBSTRUCTIVE CAD FEATURE HIGH LIKELIHOOD INTERMEDIATE LIKELIHOOD Absence of high-likelihood features Fixed Q waves Abnormal ST segments or T waves not documented to be new Normal and presence of any of the following: ECG Cardiac markers New transient ST-segment deviation or T-wave inversion (0.2 mV) with symptoms Elevated cardiac Tnl, TnT, or CK-MB

49. REVASCULARIZATIONSTRATEGY IN UA/NSTEMI Cardiac Catheterization Discharge from Protocol Coronary Artery Disease No Yes Left Main Disease CABG Yes No 1 or 2 VD 3 VD or 2 VD with proximal LAD LV Dysfunction or Diabetes No CABG No Medical Therapy PCI or CABG PCI or CABG

50. UA/NSTEMI MODE OF REVASCULARIZATION Extent of Disease Treatment Class/Level of Evidence Left main disease, candidate for CABG CABG I/A PCI IIb/C Left main disease not candidate for CABG CABG I/A Three-vessel disease with EF <0.50 Multivessel disease including proximal CABG I/A LAD with EF <0.50 or treated diabetes PCI IIb/B Multivessel disease with EF >0.50 and PCI I/A without diabetes