1. Antiplatelet Interventions in Acute Coronary Syndromes

2. VBWG Contents I.Acute Coronary Syndromes: Tailoring Treatment to Level of Risk II.Thrombus Susceptibility and the Vulnerable Plaque: Relationship Between Inflammation and Thrombosis III.ACC/AHA UA/NSTEMI Guidelines: Role of GP IIb/IIIa Inhibitors IV.Clinical Trials of GP IIb/IIIa Inhibition V.Clinical Insights, Risk Stratification, and Enhancing Outcomes VI.GP IIb/IIIa Inhibition in STEMI: Growing Clinical Trial Evidence

3. Acute Coronary Syndromes: Tailoring Treatment to Level of Risk

4. VBWG US hospital discharges: Unstable angina/NSTEMI and STEMI AHA. Heart Disease and Stroke Statistics– 2005 Update. STEMI = ST-elevation myocardial infarction (MI), or Q-wave MI NSTEMI = non–ST-elevation MI, or non–Q-wave MI 1.67 million hospital discharges STEMI 1.17 million discharges per year 500,000 discharges per year Acute coronary syndromes UA/NSTEMI

5. VBWG Braunwald E et al. J Am Coll Cardiol. 2002;40:1366-74. ACC/AHA 2002 UA/NSTEMI guidelines: High-risk indicators for early invasive strategy Recurrent angina/ischemia on treatment Elevated troponin levels New ST-segment depression Recurrent angina/ischemia with CHF symptoms, S3 gallop, pulmonary edema, worsening rales, new or worsening mitral regurgitation High-risk noninvasive test results Depressed LV function (EF <40%) Sustained ventricular tachycardia PCI within 6 months Prior CABG Class I (Level of evidence: A)

6. VBWG Odds ratio (95% CI) 0.10.20.512510 Favors routine invasive Favors selective invasive OR 1.60, P = 0.007 OR 0.76, P = 0.01 Mortality during hospitalization Mortality after discharge TIMI 3B3.32.8 VANQWISH 11.713.4 MATE 6.910.0 FRISC II 3.01.2 TACTICS 2.81.9 VINO 9.41.6 RITA 3 7.35.2 Subtotal 1.11.8 TIMI 3B1.92.2 VANQWISH 1.34.5 MATE 3.30.9 FRISC II 0.91.1 TACTICS 0.71.4 VINO 4.51.6 RITA 3 0.7 1.6 Subtotal 3.84.9 Cons (%)Inv (%) Invasive Rx in ACS: Early and late mortality Mehta SR et al. JAMA. 2005;293:2908-17. 7 trials, N = 9212

7. VBWG Mehta SR et al. JAMA. 2005;293:2908-17. 7 trials, N = 9212 *TIMI 3B, VANQWISH, MATE † FRISC II, TACTICS, VINO, RITA 3 ‡ Data by troponin status available only in FRISC II, TACTICS, RITA 3 Invasive management of UA/NSTEMI meta-analysis: Subgroups Trial Routine (%) Selective (%)Odds ratio Favors routine invasive Favors selective invasive P <0.001 0.001 0.42 0.01 0.40 0.92 After 1999 † 12.4 9.4 0.73 Positive troponin ‡ 10.0 14.0 0.69 Negative troponin 6.7 7.4 0.89 Marker positive 14.7 17.4 0.82 Marker negative 7.78.5 0.90 Before 1999*19.319.6 0.99 0.001 Overall12.214.4 0.82 Odds ratio (95% Cl) 0.5 1.02.0 Death or MI at follow-up

8. VBWG RITA 3: Benefit of routine invasive strategy mainly in high-risk patients Death or MI at 5 yrs Risk score quartile*Event rate (%)OR (95% CI) Invasive (n = 895) Conservative (n = 915) 1 st Q (  1.71) 6.66.10.96 (0.44–2.10) 2 nd Q (>1.71–2.20)12.812.21.10 (0.62–1.95) 3 rd Q (>2.20–2.83)16.019.00.80 (0.49–1.30) 4 th Q, lower (>2.83–3.28)31.335.40.76 (0.44–1.35) 4 th Q, upper (>3.28)29.248.50.44 (0.25–0.76) Fox KAA et al. Lancet. 2005;366:914-20. Randomized Intervention Trial of unstable Angina *Based on age, diabetes, prior MI, smoking, ST , pulse, grade 3/4 angina, sex, left bundle branch block, transient ST 

9. VBWG Clayton TC et al. Eur Heart J. 2004;25:1641-50. HR 0.61 (95% CI 0.44–0.85) HR 1.09 (95% CI 0.70–1.71) 20 0 12 16 8 4 0132 Time (years) Invasive Men Conservative Invasive 545491354189350316228125 Conservative583507356194332305230119 20 0 12 16 8 4 0132 Time (years) Women Invasive Conservative Death or MI (%) No. patients RITA 3: Greater benefit of early invasive strategy in men vs women with ACS n = 682 women, 1128 men with UA/NSTEMI

10. VBWG Death or MI (%) Lagerqvist B et al. J Am Coll Cardiol. 2001;38:41-8. Time (days) 20 16 12 8 4 0 0 4 8 20 060120180240300360 n = 749 women, 1708 men with UA/NSTEMI Time (days) Fragmin and fast Revascularization during InStability in Coronary artery disease 16 060120180240300360 MenWomen Invasive (n = 348) Noninvasive (n = 401) Invasive (n = 874) Noninvasive (n = 834) P < 0.001 ns 15.8% 9.6% 12.4% 10.5% FRISC II: Men with ACS show greater benefit from early invasive strategy than women

11. VBWG Multiples of the upper reference limit Days after onset of acute MI 50 20 10 5 2 1 012345678 Antman EM. N Engl J Med. 2002;346:2079-82. Upper reference limit Cardiac troponin after “classic” acute MI CK-MB after acute MI Cardiac troponin after “microinfarction” Release of cardiac troponins and CK-MB in acute MI 0

12. VBWG Roe MT et al. Arch Intern Med. 2005;165:1870-6. Reference limit: maximum troponin ratio 0–1x upper limit of normal Maximum troponin ratio 7 6 5 4 3 2 1 0 012345678910 In-hospital mortality (%) CRUSADE: N = 23,298 In-hospital mortality higher with any degree of troponin elevation in NSTEMI patients

13. VBWG *Family history of CAD, hypertension, elevated cholesterol, diabetes, current smoker † Creatine-kinase MB and/or cardiac troponins Antman EM et al. JAMA. 2000;284:835-42. TIMI risk score for UA/NSTEMI Age ≥65 years ≥3 CAD risk factors* Significant coronary stenosis ST-segment deviation Severe angina (≥2 anginal events in last 24 hours) Daily use of aspirin in prior 7 days Elevated serum cardiac markers †

14. VBWG Antman EM et al. JAMA. 2000;284:835-42.n = 1957 ACS patients Risk factors (n) 0 45 35 25 15 5 0/123456/7 Death/MI/ severe ischemia at 14 days (%) 4.7 8.3 13.2 19.9 26.2 40.9 TIMI risk score in UA/NSTEMI

15. VBWG OPUS-TIMI 16 Sabatine MS et al. Circulation. 2002;105:1760-3. TACTICS-TIMI 18 1 1.8 3.5 6 1 2.1 5.7 13 12301230 14 10 6 2 BNP = B-type natriuretic peptide CRP = C-reactive protein 6 4 2 0 30-day mortality relative risk Elevated cardiac biomarkers (n) P = 0.014P < 0.001 671501557850471732490 0 Multimarker strategy: Identifying high-risk patients by troponin I, CRP, and BNP n =

16. VBWG Hemodynamic stress Giugliano RP et al. J Am Coll Cardiol. 2005;46:906-19. Troponin++++++++ BNP+++++0 Renal dysfunction++++ Glucose metabolism+0+ CRP++ Blood glucose Myocyte necrosis Accelerated atherosclerosis Vascular damage Inflammation hs-CRP, CD40L Troponin BNP, NT-proBNP CrCl Microalbuminuria A1C Biomarker Independent predictor of risk Useful in multimarker strategy Therapeutic implication Multimarker approach in ACS