Total Occlusion Study of Canada (TOSCA-2) Trial

1. TOSCA-2 Trial Total Occlusion Study of Canada (TOSCA-2) Trial Presented at The American Heart Association Scientific Sessions 2006 Presented by Dr. Vladimir Dzavik

2. TOSCA-2 Trial: Background • The goal of the trial was to evaluate late left ventricular (LV) function and artery patency associated with percutaneous coronary intervention (PCI) compared with medical therapy among stable, high-risk patients with persistent total occlusion of the infarct-related artery post-myocardial infarction (MI). • The TOSCA-2 study was a subgroup of patients in the larger Occluded Artery Trial (OAT). In TOSCA-2, patients with persistent total occlusion of the infarct-related artery 3-28 days post-MI were randomized to PCI with stenting (n=195) or medical therapy (n=185). • Follow-up angiography was performed 1 year after MI in 87% (n=332) of the 381 patients. Presented at AHA 2006

3. TOSCA-2 Trial: Study Design 381 patients with angiography 3-28 days post-MI with evidence of total occlusion of the infarct-related artery with poor or absent antegrade flow (TIMI flow grade 0 or 1); and met a criterion for increased risk, defined as ejection fraction <50%, proximal occlusion of a major epicardial vessel with a large risk region, or both Exclusions: NYHA class III or IV heart failure, shock , serum creatinine concentration >2.5 mg/dl, angiographically significant left main or three vessel coronary artery disease, angina at rest, or severe ischemia on stress testing. Randomized. 17% female, mean age 58 years, mean follow-up 1 year Concomitant medications: Aspirin, anticoagulation if indicated, ACE inhibitors, beta-blockers, and lipid lowering therapy, unless contraindicated Medical Therapy n=186 PCI with stenting n=195 • Primary Endpoints: 1) Change in LVEF and 2) infarct-related artery patency • Secondary Endpoints: Change in LVEDVI, LVESVI, and regional wall motion score Presented at AHA 2006

4. TOSCA-2 Trial: Primary Endpoint Change in LV Ejection Fraction at One Year (% increase) p=0.47 • Change in LV ejection fraction (LVEF) at one year did not differ between the PCI and medical therapy group (4.2% increase with PCI vs. 3.5% increase with medical therapy, p=0.47). Presented at AHA 2006

5. TOSCA-2 Trial: Primary Endpoint (cont.) Infarct-related Artery Patency at One Year (%) p<0.001 • The co-primary endpoint of patency at one year was higher in the PCI group compared with the medical therapy group (83% vs. 25%, p<0.001). • Percent diameter stenosis at one year averaged 52.5% in the PCI group and 90.2% in the medical therapy group (p<0.001). Presented at AHA 2006

6. TOSCA-2 Trial: Secondary Endpoint Change in LV End Diastolic Volume Index (ml/m2) P=0.07 • Change in the LV end-diastolic volume index (LVEDVI) trended lower in the PCI group compared to the medical therapy group (3.2 ml/m2 vs 5.3 ml/m2, p=0.07) • LV end systolic volume index (LVESVI) decreased by a median of 0.5 ml/m2 in the PCI group and increased by 1.0 ml/m2 (p=0.10). Presented at AHA 2006

7. TOSCA-2 Trial: Limitations • In the overall OAT trial, the rate of nonfatal reinfarction trended higher in PCI treated patients. • It is unclear whether the tendency for PCI to reduce expansion of the left ventricle (i.e. the ability of PCI to favorably impact LV remodeling) is of greater or lesser importance than the trend to toward a higher risk of recurrent MI with PCI. • It should be borne in mind that a totally occluded artery is obviously at low risk of re-occlusion. • The one-year follow-up in the TOSCA-2 study may not be long enough to fully evaluate long term risks and benefits. • Although the secondary endpoint of change in LVEDVI did trend toward statistical significance, this was drawn from a subset of a subset since only 42% of the TOSCA-2 cohort underwent volume determination studies. This subset of patients is enriched by patients who survived for one year and may reflect a lower risk population. Presented at AHA 2006

8. TOSCA-2 Trial: Summary • Among stable, high-risk patients with persistent total occlusion of the infarct-related artery post-MI, performance of PCI 3-28 days post-MI was not associated with a difference in LV function; however, higher rates of patency at one year were observed as compared with medical therapy. • This angiographic difference in artery patency did not translate into a clinical difference in the overall OAT trial, which showed no difference in the composite of death, reinfarction, or severe heart failure with PCI compared with medical therapy through a mean follow-up of three years. Presented at AHA 2006

9. TOSCA-2 Trial: Summary (cont.) • The TOSCA-2 trial was based on the assumption that increased patency with PCI would improve LV function and remodeling. • However, the higher patency rate at one year with PCI compared with medical therapy did not translate into improvements in LVEF. LVEF actually improved from baseline to one year in both treatment groups. • Early reperfusion therapy in ST elevation MI has been associated with reductions in clinical events which has led to the development of the early open artery hypothesis. However, data from the OAT and TOSCA-2 studies do not support a late open artery hypothesis for patients with stable but persistent total occlusion. Presented at AHA 2006