The European Society of Cardiology Presented by RJ De Winter ICTUS Trial Invasive versus conservative treatment in unstable coronary syndromes (ICTUS) Trial Presented at The European Society of Cardiology Scientific Congress 2006 Presented by RJ De Winter

ICTUS Trial: Background The goal of the ICTUS trial was to evaluate the use of an early invasive strategy compared with a more conservative, selective invasive strategy in troponin positive patients with non-ST elevation myocardial infarction (MI) acute coronary syndromes (ACSs). Presented at ESC 2006

ICTUS Trial: Study Design 1200 patients with anginal symptoms at rest within 24 hours, troponin T ≥ 0.03 mcg/l, and a history of coronary artery disease or ischemic changes on ECG excluding those with Q-wave elevation MI or ST elevation MI within 48 hours or acute ST elevation MI Randomized. 26% female, median age 62 years, mean follow-up 3 years, concomitant medications: aspirin, enoxaparin, beta-blockers, nitrates, clopidogrel, high-dose statin therapy, and abcixamab at PCI Early Invasive Strategy Including: angiography within 24-48 hours and PCI within 48 hours or CABG ASAP n=604 Selective Invasive Strategy Including: medical stabilization with angiography and revascularization only in case of refractory angina or ischemia on predischarge exercise testing n=596 Primary Endpoint: Death, MI, or rehospitalization for ACS at 1 year Presented at ESC 2006

ICTUS Trial: Primary Endpoint Primary Composite Endpoint of Death, MI, or rehospitalization for ACS at one year (% patients) There was no difference by treatment group in the primary composite endpoint of death, MI, or rehospitalization for ACS at one year (22.7% in early invasive vs. 21.2% in selective invasive, [RR] 1.07, p=0.33). Median troponin T was 0.3 mcg/l and 62% of patients had ischemic EKG changes. p=0.33 % patients Presented at ESC 2006

ICTUS Trial: Primary Composite Endpoint Primary Component Endpoints of Death, MI, or rehospitalization for ACS (% of patients) The lack of difference in the primary endpoint is driven by divergent results for the endpoint of MI (15.0% vs. 10.0%, RR 1.50, p=0.005) and rehospitalization for ACS (7.4% vs. 10.9%, RR 0.68, p=0.04) in the early invasive and selective invasive treatment groups, respectively. There was no difference in mortality at one year (2.5% each, p=0.97). p=0.005 p=0.04 % patients p=0.97 Presented at ESC 2006

ICTUS Trial: MI Criteria Compared to TACTICS-TIMI 18 and FRISC-2 Rate of MI applying the TACTICS-TIMI 18 definition (% patients) p=0.07 Rate of MI applying the FRISC-2 definition (% patients) p=0.008 % patients % patients The criteria for MI was >1x the upper limit of normal, a less stringent definition than early trials such as TACTICS-TIMI 18 and FRISC-2. When applying the TACTICS-TIMI 18 definition for MI to the ICTUS trial, the rate of MI was 8.5% in the early invasive group and 5.9% in the selective invasive group (p=0.07). Similarly, when applying the FRISC-2 definition of MI, the rate of MI was 12.1% and 7.8%, respectively (p=0.008). Presented at ESC 2006

ICTUS Trial: 3 Year Follow-Up Primary Composite Endpoint, All-Cause Mortality, and Cardiac Death at 3 Year Follow-Up (% patients) At 3 year follow-up, the composite of death, MI, or rehospitalization for ACS did not significantly differ for the invasive group compared with the conservative group (30.0% vs. 26.0%, HR 1.20, p=0.10). There was also no difference in all-cause mortality (7.9% vs. 7.7%, RR 1.11, p=0.63) or cardiac death (5.0% vs. 4.5%, p=0.92). p=0.10 % patients p=0.63 p=0.92 Presented at ESC 2006

ICTUS Trial: Summary Among troponin positive patients with a non-ST elevation ACS, treatment with an early invasive strategy was not associated with a difference in the primary endpoint compared with a selective invasive strategy. However, the two major components of the primary endpoint, MI and rehospitalization for an ACS, show treatment differences in the opposite direction. The rate of MI in the present trial was notably higher than other similar trials, likely a reflection of peri-procedural MI given the less stringent definition of MI of creatine kinase-MB >1 times the upper limit of normal. Presented at ESC 2006

ICTUS Trial: Summary (cont.) The primary endpoint and MI data in the present trial are not consistent with the recent TACTICS-TIMI 18 trial and the FRISC-2 trial, which showed the benefit of an early invasive strategy over a conservative strategy in a similar patient population. In addition to the differences noted in the MI definition between the trials, a larger percentage of patients in the more conservative strategy in the present trial underwent early revascularization (40%) than in the TACTICS-TIMI 18 (36%) or FRISC-2 (9%). Unlike the RITA-3 and FRISC-2 trials, a late benefit with the invasive strategy was not observed at 3 year follow-up in ICTUS. This may reflect in part a difference in the risk of the populations enrolled. Presented at ESC 2006