Antiplatelet Interventions in Acute Coronary Syndromes

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

Acute Coronary Syndromes: Tailoring Treatment to Level of Risk

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

VBWG Braunwald E et al. J Am Coll Cardiol. 2002;40: 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)

VBWG Odds ratio (95% CI) Favors routine invasive Favors selective invasive OR 1.60, P = OR 0.76, P = 0.01 Mortality during hospitalization Mortality after discharge TIMI 3B VANQWISH MATE FRISC II TACTICS VINO RITA Subtotal TIMI 3B VANQWISH MATE FRISC II TACTICS VINO RITA Subtotal Cons (%)Inv (%) Invasive Rx in ACS: Early and late mortality Mehta SR et al. JAMA. 2005;293: trials, N = 9212

VBWG Mehta SR et al. JAMA. 2005;293: 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 < After 1999 † Positive troponin ‡ Negative troponin Marker positive Marker negative Before 1999* Overall Odds ratio (95% Cl) Death or MI at follow-up

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) (0.44–2.10) 2 nd Q (>1.71–2.20) (0.62–1.95) 3 rd Q (>2.20–2.83) (0.49–1.30) 4 th Q, lower (>2.83–3.28) (0.44–1.35) 4 th Q, upper (>3.28) (0.25–0.76) Fox KAA et al. Lancet. 2005;366: 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 

VBWG Clayton TC et al. Eur Heart J. 2004;25: HR 0.61 (95% CI 0.44–0.85) HR 1.09 (95% CI 0.70–1.71) Time (years) Invasive Men Conservative Invasive Conservative 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

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

VBWG Multiples of the upper reference limit Days after onset of acute MI Antman EM. N Engl J Med. 2002;346: 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

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

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: 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 †

VBWG Antman EM et al. JAMA. 2000;284: n = 1957 ACS patients Risk factors (n) /123456/7 Death/MI/ severe ischemia at 14 days (%) TIMI risk score in UA/NSTEMI

VBWG OPUS-TIMI 16 Sabatine MS et al. Circulation. 2002;105: TACTICS-TIMI BNP = B-type natriuretic peptide CRP = C-reactive protein day mortality relative risk Elevated cardiac biomarkers (n) P = 0.014P < Multimarker strategy: Identifying high-risk patients by troponin I, CRP, and BNP n =

VBWG Hemodynamic stress Giugliano RP et al. J Am Coll Cardiol. 2005;46: Troponin BNP 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