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TIMACS

TIMACS. Tim. ing of Intervention. in patients with. A. cute. C. oronary. S. yndromes. An International Randomized Trial of Early Versus Delayed Invasive Strategies in Patients with Non-ST Segment Elevation Acute Coronary Syndromes. Preliminary Results.

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TIMACS

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

  2. 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. Delayed Invasive Early Invasive Large Variations in Timing of Intervention in Current RCT’s

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

  6. Outcomes • Primary • Composite of Death, new MI or Stroke at 180 days • Secondary Composite of: • Death, new MI or refractory ischemia • Death, new MI, stroke, refractory ischemia or repeat revascularization • Stroke

  7. Study Flow Chart TIMACS OASIS 5 N=1,633 TIMACS Stand Alone N=1,398 + TIMACS Total N=3,031 Follow-up >99.9%

  8. Recommended Medical Treatment • ASA, clopidogrel • GP IIb/IIIa inhibitor at discretion of attending physician (especially if pt is not on a thienopyridine) • Antithrombin: • OASIS 5: Either fondaparinux or enoxaparin • TIMACS stand alone: UFH or LMWH or fondaparinux or bivalirudin (investigator discretion) • Beta blocker • Statin

  9. Participating Countries Europe 1065 North America 650 Asia 846 South America 442 Australia 28

  10. TIMACS Steering Committee

  11. 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. 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. Criteria for Crossover from Delayed Group to Early Group • Refractory ischemia • New MI • Hemodynamic instability • Crossover from Early to Delayed: 11.9% • Crossover from Delayed to Early: 25%

  14. Interventions and Timing iqr=interquartile range

  15. Baseline Characteristics

  16. In-Hospital Medications

  17. Primary and Secondary Outcomes *At 30 days: 5.9% vs 4.2%, HR 1.39, 95% CI 1.00-1.95, P=0.047

  18. Primary OutcomeDeath, MI, or Stroke Death/MI/Stroke at 180 days Delayed Early 0.10 Cumulative Hazard 0.06 HR 0.85 95% CI 0.68-1.06 P= 0.15 0.02 0.0 0 30 60 90 120 150 180 Days No. at Risk Delayed 1438 1328 1269 1254 1234 1229 1211 Early 1593 1484 1413 1398 1391 1382 1363

  19. Death/MI/RI at 180 days Delayed 0.12 Early 0.08 Cumulative Hazard 0.04 0.0 0 30 60 90 120 150 180 Days No. at Risk Delayed 1438 1303 1243 1230 1209 1205 1187 Early 1593 1485 1417 1402 1394 1386 1366 Secondary OutcomeDeath, MI, or Refractory Ischemia HR 0.72 95% CI 0.58-0.79 P=0.002

  20. Death/MI/RI/Stroke/Rep Intervention at 180 days Delayed 0.20 Early 0.15 Cumulative Hazard 0.10 HR 0.84 95% CI 0.71-0.99 P=0.039 0.05 0.0 0 30 60 90 120 150 180 Days No. at Risk Delayed 1438 1250 1166 1150 1128 1118 1097 Early 1593 1400 1321 1304 1287 1276 1256 Secondary OutcomeDeath, MI, Stroke, RFI or Rep Intervention

  21. Safety Outcomes

  22. Characteristic N Early % Delayed % HR (95% CI) Interaction p-Value Overall 3031 9.7 11.4 0.85 ( 0.68 - 1.06 ) Age < 65 1293 6.5 6.5 0.98 ( 0.64 - 1.52 ) >=65 1736 12.3 14.8 0.83 ( 0.64 - 1.07 ) 0.463 Female 1052 9.7 12.3 0.77 ( 0.54 - 1.12 ) Male 1976 9.8 10.9 0.89 ( 0.68 - 1.18 ) 0.540 No ST deviation 1523 7.6 8.7 0.88 ( 0.62 - 1.26 ) ST deviation 1508 11.7 14.3 0.81 ( 0.61 - 1.07 ) 0.722 No elevated marker 668 10.5 10.5 1.00 ( 0.62 - 1.60 ) Elevated marker 2363 9.5 11.7 0.81 ( 0.63 - 1.04 ) 0.423 GRACE 0-140 2070 7.7 6.7 1.14 ( 0.82 - 1.58 ) GRACE >=141 961 14.1 21.6 0.65 ( 0.48 - 0.88 ) 0.0097 0.33 0.5 0.7 1.00 1.5 2.0 3.0 Early better Delayed better Hazard Ratio (95% CI) Pre-specified Subgroups

  23. Conclusions • Overall, we found no significant difference between an early and a delayed invasive strategy for prevention of death, MI or stroke (primary outcome). • 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. • The early invasive strategy had a large impact on reducing the rate of refractory ischemia by 70%. • There were no significant differences in major bleeding or other safety concerns between the two strategies.

  24. Implications • Most patients with ACS can be managed safely with either an early or a delayed invasive strategy • 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 • In all other patients, the decision regarding timing of intervention can depend on other factors, such as cath lab availability and economic considerations.

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