1. An International Randomized Trial of Early Versus Delayed Invasive Strategies in Patients with Non-ST Segment Elevation Acute Coronary Syndromes TIMACS Timing of Intervention in patients with AcuteCoronarySyndromes Funded by Canadian Institutes of Health Research Additional support from GSK and Sanofi-Aventis Preliminary Results

2. TIMACSTIMACS Preliminary Results as of Nov 7, 2008 Background Randomized trials and meta-analyses have demonstrated that an invasive strategy is superior to a conservative strategy in higher risk patients The timing of intervention varied greatly among the individual RCT’s Few data exist on the optimal timing of intervention in patients with ACS

3. TIMACSTIMACS Preliminary Results as of Nov 7, 2008 Early Invasive Large Variations in Timing of Intervention in Current RCT’s Delayed Invasive FRISCII RITA 3 ICTUSTACTICS Sample Size 2457181012012220 Cath Timing 96 h 48 h 19 h 22 h PCI Timing 96 h 72 h 23 h 24 h CABG Timing 7 d 22 d 9 d 4 d

4. TIMACSTIMACS Preliminary Results as of Nov 7, 2008 Study Objective To determine whether early intervention is superior to delayed intervention in patients with high risk non-ST segment elevation acute coronary syndrome

5. TIMACSTIMACS Preliminary Results as of Nov 7, 2008 Design, Eligibility Criteria and Protocol UA or NSTEMI 2 of 3 Criteria: Age > 60, ischemic ECG or biomarker AND suitable for revascularization RANDOMIZE* Early Invasive Coronary angio as soon as possible (<24 hours) Delayed Invasive Coronary angio >36 hrs *Randomization ratio 1:1, 1:2 or 2:1 Follow-up up to 180 days

6. TIMACSTIMACS Preliminary Results as of Nov 7, 2008 Outcomes Primary Composite of Death, new MI or Stroke at 180 days Secondary Composite of: 1. Death, new MI or refractory ischemia 2. Death, new MI, stroke, refractory ischemia or repeat revascularization 3. Stroke

7. TIMACSTIMACS Preliminary Results as of Nov 7, 2008 Study Flow Chart TIMACS Stand Alone N=1,398 TIMACS Total N=3,031 TIMACS OASIS 5 N=1,633 + Follow-up >99.9%

8. TIMACSTIMACS Preliminary Results as of Nov 7, 2008 Recommended Medical Treatment 1. 1.ASA, clopidogrel 2. 2.GP IIb/IIIa inhibitor at discretion of attending physician (especially if pt is not on a thienopyridine) 3. 3.Antithrombin: OASIS 5: Either fondaparinux or enoxaparin TIMACS stand alone: UFH or LMWH or fondaparinux or bivalirudin (investigator discretion) 4. 4.Beta blocker 5. 5.Statin

9. TIMACSTIMACS Preliminary Results as of Nov 7, 2008 Participating Countries North America 650 South America 442 Europe 1065 Asia 846 Australia 28

10. TIMACSTIMACS TIMACS Steering Committee A. Avezum – Brazil C. Morillo -- Columbia J-P. Bassand – France L. Piegas – Brazil W. Boden – USA J. Probstfield – USA J. Col – Belgium S. Qiao -- China R. Diaz – Argentina H-J Rupprecht – Germany D. Faxon – USA P. G. Steg – France C. Granger – USA P. Widimsky – Czech Rep C. Joyner -- Canada J. Varigos – Australia M. Kenda – Slovenia S. Yusuf -- Canada S. Mehta -- Canada J. Zhu – China T. Moccetti – Switzerland

11. TIMACSTIMACS Preliminary Results as of Nov 7, 2008 Study Organization Coordinating Center: PHRI, McMaster University S. Mehta, S. Yusuf, S. Jolly, C. Horsman, S. Chrolavicius, B. Meeks DSMB: P. Sleight (chair), J. Anderson, D. DeMets, D. Johnstone, D. Holmes Adjudication Committee: C. Joyner (chair), M. Rokoss (co-chair), M. Lawrence (coordinator)

12. TIMACSTIMACS Preliminary Results as of Nov 7, 2008 Analysis Study Power: 3000 patients 80% power to detect a RRR of 28% Randomization: Central 24 hour computer randomization Analysis: Intention to treat; Log rank statistic Follow-up: > 99% vital Status

13. TIMACSTIMACS Preliminary Results as of Nov 7, 2008 Criteria for Crossover from Delayed Group to Early Group 1.Refractory ischemia 2.New MI 3.Hemodynamic instability Crossover from Early to Delayed: 11.9% Crossover from Delayed to Early: 25%

14. TIMACSTIMACS Preliminary Results as of Nov 7, 2008 Interventions and Timing EarlyN=1,593DelayedN=1,438 Coronary Angiography (%) 97.695.5 Median time (h ± iqr) 14 (3-21) 50 (41-81) PCI (%) 59.655.0 Median time (h ± iqr) 16 (3-23) 52 (41-101) CABG (%) 14.713.6 Median time (d ± iqr) 7.7 (4.7-17.4) 10.8 (6.7-19.8) iqr=interquartile range

15. TIMACSTIMACS Preliminary Results as of Nov 7, 2008 Baseline Characteristics EarlyN=1,593DelayedN=1,438 Age65.165.8 % Female 34.834.7 Diabetes26.527.3 Prior MI 19.720.9 Prior PCI 13.814.1 Prior CABG 7.0 7.0 7.3 7.3 Prior Stroke 7.2 7.2 7.5 7.5 Ischemic ECG 80.579.9 Elevated Biomarker 77.276.9

16. TIMACSTIMACS Preliminary Results as of Nov 7, 2008 In-Hospital Medications EarlyN=1,593DelayedN=1,438 ASA98.098.1 Thienopyridine87.286.7 Thienopyridine or GP IIb/IIIa inhibitor 88.288.4 GP IIb/IIIa Inhibitor 23.222.5 Anticoagulant97%97% UFH24.624.6 LMWH64.064.6 Fondaparinux41.941.3 Bivalirudin0.50.4 Beta Blocker 86.886.9 Statin85.084.3

17. TIMACSTIMACS Primary and Secondary Outcomes EarlyN=1,593DelayedN=1,438HR 95% CI P Death, MI, Stroke9.711.40.850.68-1.060.15 Death, MI, refractory ischemia9.613.10.720.58-0.890.002 Death, MI, Stroke, refractory ischemia + repeat intervention16.719.70.840.71-0.990.039 Death4.96.00.810.60-1.110.19 MI4.85.80.830.61-1.140.25 Stroke1.31.40.900.48-1.680.74 Ref. Ischemia1.03.30.300.17-0.53<0.00001 Rep. Intervention*8.88.61.040.82-1.340.73 *At 30 days: 5.9% vs 4.2%, HR 1.39, 95% CI 1.00-1.95, P=0.047

18. TIMACSTIMACS Preliminary Results as of Nov 7, 2008 Primary Outcome Death, MI, or Stroke Days Cumulative Hazard 0.0 0.02 0.06 0.10 0306090120150180 Death/MI/Stroke at 180 days Early No. at Risk Delayed Early 1438132812691254123412291211 1593148414131398139113821363 Delayed HR 0.85 95% CI 0.68-1.06 P= 0.15

19. TIMACSTIMACS Preliminary Results as of Nov 7, 2008 Secondary Outcome Death, MI, or Refractory Ischemia Days Cumulative Hazard 0.0 0.04 0.08 0.12 0306090120150180 Death/MI/RI at 180 days Delayed Early No. at Risk Delayed Early 1438130312431230120912051187 1593148514171402139413861366 HR 0.72 95% CI 0.58-0.79 P=0.002

20. TIMACSTIMACS Preliminary Results as of Nov 7, 2008 Secondary Outcome Death, MI, Stroke, RFI or Rep Intervention Death/MI/RI/Stroke/Rep Intervention at 180 days Days Cumulative Hazard 0.0 0.05 0.10 0.15 0.20 0306090120150180 Delayed Early No. at Risk Delayed Early 1438125011661150112811181097 1593140013211304128712761256 HR 0.84 95% CI 0.71-0.99 P=0.039

21. TIMACSTIMACS Preliminary Results as of Nov 7, 2008 Safety Outcomes EarlyN=1,593DelayedN=1,438HRCIP Major Bleed during initial hospitalization 3.13.50.880.60-1.310.53 ICH00.1 Surg Intervention0.40.8 Retroperitoneal0.10.2 ↓ Hb >= 3 g/dL2.32.6 Transfusion ≥ 2 U2.22.9

22. TIMACSTIMACS Pre-specified Subgroups

23. TIMACSTIMACS Preliminary Results as of Nov 7, 2008 Conclusions 1. 1.Overall, we found no significant difference between an early and a delayed invasive strategy for prevention of death, MI or stroke (primary outcome). 2. 2.In the subgroup at highest risk (GRACE score > 140), an early invasive strategy appears to be superior to a delayed invasive strategy for prevention of death, MI or stroke. 3. 3.The early invasive strategy had a large impact on reducing the rate of refractory ischemia by 70%. 4. 4.There were no significant differences in major bleeding or other safety concerns between the two strategies.

24. TIMACSTIMACS Preliminary Results as of Nov 7, 2008 Implications 1. 1.Most patients with ACS can be managed safely with either an early or a delayed invasive strategy 2. 2.In a subset of patients at highest risk (GRACE score>140), early intervention appears to be superior and these patients should be considered for early cath 3. 3.In all other patients, the decision regarding timing of intervention can depend on other factors, such as cath lab availability and economic considerations.