1. TACTICS- TIMI 18 Treat Angina with Aggrastat TM and Determine Cost of Therapy with an Invasive or Conservative Strategy

2. Unstable Angina and Non-Q Wave MI Unstable Angina and Non-Q Wave MI è Center of spectrum of acute coronary syndromes è 2-2.5 million hospital admissions /year worldwide è ASA, heparin, beta-blockers beneficial è Tirofiban (Aggrastat TM ) dramatic benefit è Invasive vs. Consvative strategy ???? Background

3. Unstable angina and non-Q wave MI è Center of spectrum of acute coronary syndromes è 890,000 hospital admissions per year in U.S. è ASA, heparin, beta-blockers beneficial è Tirofiban (Aggrastat TM ) dramatic benefit è Invasive vs. Consvative strategy ???? Background

4. l Initial Medical Management: l ASA 160-325 mg daily for all patients with UA (except if ongoing major or life-threatening hemorrhage, recent GI bleed, or ASA hypersensitivity) l IV Heparin for intermediate or high-risk UA (i.e., prior CAD, rest pain, ECG changes, or age >65) l Beta-blockers for all patients in the absence of contraindications (e.g., bradycardia, hypotension, AV block, asthma, severe LV dysfunction with CHF or shock, signif. COPD) Recommendations AHCPR Unstable Angina Guideline Braunwald, E., et al. Circulation 1994;90:613-22.

5. l Initial Medical Management (con’t): l Nitrates: Use for patients with ongoing ischemia and use IV for high-risk patients. Switch to oral when stable l Calcium antagonists: May be used to control angina if already on beta-blocker and nitrates, or if unable to tolerate beta-blockers (e.g. severe COPD). Use heart-rate lowering Ca + blocker. Avoid in CHF or low EF. l No thrombolysis: Shown to increase subsequent MI in TIMI IIIB trial in patients with unstable angina Recommendations AHCPR Unstable Angina Guideline Braunwald, E., et al. Circulation 1994;90:613-22.

6. Cholesterol Lowering Post MI 4S CARE

7. l Cholesterol lowering: Check lipids 125 mg/dl. l Low Molecular Weight Heparin: At least as effective as IV heparin. ESSENCE trial: 16% better than IV heparin (Death, MI, recurrent angina) l IIb/IIIa inhibition: Tirofiban lead to a 34% reduction in death, MI, refarctory angina at 7 days in PRISM- PLUS. At 30 days, tirofiban (Aggrastat TM ) lead to a 31% redution in death or MI. In PRISM, there was a 36% reduction in composite endpoint at 48 hours. Eptifibatide (Integrilin TM ) lead to an 11% reduction in death or MI at 30 days in PURSUIT. Updating - 1997 AHCPR Unstable Angina Guideline

8. l Early invasive strategy - Cath in all patients between 18-48 hours. Revascularization when feasible based on anatomy: PTCA for 1 or 2 VD, CABG for 3VD l Early conservative strategy - catheterization if patient had recurrent ischemia at rest or on testing: l Recurrent ischemia at rest with ECG changes l Recurrent MI l Positive ETT / Thallium at HD or 6 weeks l Positive ST segment Holter (>20 mins) Invasive vs. Conservative TIMI IIIB Circulation 1994;89:1545-56

9. TIMI IIIB - One Year Results Death or MI PTCA or CABG P=<0.001 P=NS Anderson HV et al., JACC 1995;26:1643-1650. 12.2%10.8% 64%58% Early Conservative Early Invasive Early Conservative

10. TIMI IIIB - Primary Results to 42 days Invasive Conserv.P value Invasive Conserv.P value No. Pts 740 733 Death (%) 2.4 2.5NS MI (%) 5.1 5.7NS D/MI/+ETT (%) 16.2 18.1NS Rehosp Angina (%) 7.8 14.1<0.001 D/MI/Rehosp (%) 15 220.007 LOS (days) 10.2 10.9<0.001 # Days rehosp 365 930<0.001 Circulation 1994;89:1545-56

11. No. Pts Death or MI (%) Death (%) MI (%) Death < HD (%) Death > HD (%) 46229.917.312.64.512.8 Invasive Invasive45826.912.914.01.311.6 Conserv. Conserv.0.350.04NS0.007NS P value P value VANQWISH Trial VA Hosptials Study: Management post Non-Q wave MI

12. l Medical and interventional magagement of unstable angina markedly improved in last 5 yrs ( ASA, heparin, stents, operator exper.) l Tirofiban improves: è Medical management of unstable angina (PRISM, PRISM-PLUS) è Outcome following PTCA (RESTORE) l With current optimal management Which is better and more cost-effective -> Invasive vs. Consvative strategy ? Study Rationale

13. TIMI IIIB: Troponin I vs. 42 Day Mortality 0-<0.4 0.4-<1.0 1.0-<2.0 2.0-<5.0 5.0-<9.0 > 9.0 0 0 1 1 2 2 3 3 4 4 5 5 6 6 7 7 8 8 Death by 42 Days (%) cTnI at Baseline (ng/ml) 1.0 1.7 3.4 3.7 6.0 7.5 Risk Ratio 6.2 7.8 3. 5 3.9 1.0 1.8 831 174 148 134 50 67    p<0.001 Antman et al. NEJM 1996;335: 1342-9.

14. l Troponin T and I: associated with risk of death è TACTICS-TIMI 18 tests “Troponin Hypothesis” The troponins will be useful in determining the best treatment strategy (invasive vs. conservative) l Which is better - T or I? è TACTICS-TIMI 18 will be first large comparison Additional Objectives Troponin Hypothesis