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Principal Investigator: Michel Le May, MD

ClinicalTrials.gov Identifier: NCT00251823. A. s. s. I. s. T. A S afety and Efficacy S tudy of I ntegrilin Facilitated PCI versus Primary PCI in ST Elevation Myocardial Infarction. Principal Investigator: Michel Le May, MD. Disclosure Statement of Financial Interest.

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Principal Investigator: Michel Le May, MD

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  1. ClinicalTrials.gov Identifier: NCT00251823 A s s I s T ASafetyand EfficacyStudyofIntegrilinFacilitated PCI versus Primary PCI inSTElevation Myocardial Infarction Principal Investigator: Michel Le May, MD

  2. Disclosure Statementof Financial Interest Within the past 12 months, I or my spouse/partner have had a financial interest/arrangement or affiliation with the organization(s) listed below. Affiliation/Financial RelationshipCompany Grant/Research Support Investigator initiated trial with financial support from Schering- Plough of Canada Inc., & Medtronic of Canada Ltd. Consulting Fees/Honoraria Major Stock Shareholder/Equity Royalty Income Ownership/Founder Intellectual Property Rights Other Financial Benefit

  3. Investigators Michel R. Le May MD, George A. Wells, PhD, Chris A. Glover, Derek Y. So, MD, MD, Michael P. Froeschl, MD, Jean-François Marquis, MD, Edward R. O'Brien, MD, Michele Turek, MD, Marino Labinaz, MD Research Nurses/Staff Allyson Thomas, Tanya. Abarbanel, Julie Finnigan Adjudication Committee Cathy McLellan (chair), Waytak. Kong , Paul Malik Data Safety Monitoring Jean-Claude Tardif (chair), Philippe L'Allier Participating Hospitals University of Ottawa Heart Institute (on-site cath lab) Ottawa Hospital (Alta Vista campus) Ottawa Hospital (Civic campus)

  4. Background • Randomized trials have shown that abciximab is a useful adjunct in pts referred for primary PCI. • Observational studies have shown that eptifibatide yields similar results to abciximab. • No study has examined clinical outcomes by directly comparing eptifibatide to a control group in primary PCI. • Studies with high clopidogrel loading dose are limited in primary PCI.

  5. Trial Design Primary endpoint Death, Reinfarction, Recurrent Severe Ischemia at 30 Days.

  6. Reinfarction Recurrent ischemic symptoms at rest lasting at least 30 min and accompanied by • New or recurrent ST-segment elevation of ≥1 mm (0.1 mV) in any contiguous leads or • New left bundle branch block or • Re-elevation in serum CK level > twice the upper limit of normal and at least 50% above the lowest level measured post-infarction.

  7. Recurrent Severe Ischemia Recurrent symptoms of ischemia at rest associated with any one of the following • New ST-segment deviation (elevation at least 0.1 mV or depression > 0.05 mV measured 80 ms after the J-point in at least 2 contiguous leads). • An episode of acute pulmonary edema, sustained ventricular arrhythmias or hemodynamic instability. • The need for urgent revascularization. • Recurrent myocardial infarction.

  8. Exclusion Criteria • Active bleeding • Stroke within 90 days or intracranial bleeding at any time • Major surgery or trauma within six weeks • Systolic blood pressure > 200 mm Hg • Diastolic blood pressure > 110 mm Hg • Prolonged CPR (>10 min) • PCI within 30 days • Fibrinolytic or GP 2b/3a within 7 days • Coagulation disorder / warfarin therapy

  9. Exclusion Criteria (2) • Known severe renal impairment (creatinine > 200 mol/L) • Contrast allergy • LMWH within 12 hrs • Cardiogenic shock • Intolerance to aspirin or clopidogrel • Medical condition likely to result in death within 12 months • Participation in another study • Pregnancy

  10. Sample Size • Estimated the incidence of the primary endpoint at 30 days in pts assigned to PCI with heparin alone at 15% and in pts assigned to PCI with heparin plus eptifibatide at 5%. • -level: 0.05 (two-sided); -error: 0.10 • Anticipated a loss to follow-up rate of 5%. • The number of pts required was 200 per group.

  11. Timeline • Open label study design 400 pts were randomly assigned: • 201 to PCI with heparin plus eptifibatide • 199 to PCI with heparin alone • Enrollment started August 2005 • Enrollment completed March 2008 • Final 6-month follow-up September 2008

  12. Baseline Characteristics

  13. Baseline Characteristics (2)

  14. Initial Medications * Duration of eptifibatide infusion > 16 hrs in 82% pts; 94% received eptifibatide before cardiac catheterization.

  15. Median Time Intervals (min)

  16. Angiographic Results

  17. Infarct-Related Artery

  18. PCI Procedure

  19. Prior to PCI After PCI % % Heparinplus eptifibatide Heparin plus eptifibatide Heparin alone Heparin alone TIMI 3 TIMI 2 TIMI 0-1 Infarct-Related Artery TIMI Flow Rates p = 0.16 p = 0.43

  20. p = 0.54 p = 0.62 p = 0.76 p = 0.69 Events Within 30 Days % pts

  21. 6.5% 5.5% Kaplan-Meier Estimates30 days Log-Rankp = 0.70

  22. Clinical Events at 30 Days

  23. p = 0.54 p = 0.62 p = 0.97 p = 0.75 Events Within Six Months % pts

  24. Kaplan-Meier Estimates180 days 8.0% Log-Rank p = 0.76 7.1%

  25. Clinical Events at Six Months

  26. Subgroup Heparin plus Heparin Relative Risk Risk ratio and 95% CI Eptifibatide Alone (95%CI) All patients 13 / 201 11 / 199 1.18 (0.52 - 2.70) Female sex 2 / 39 6 / 56 0.48 (0.10 - 2.25) Male Sex 11 / 162 5 / 143 1.94 (0.69 - 5.46) Age < 75 yrs 9 / 170 8 / 174 1.15 (0.45 - 2.91) Age ≥ 75 yrs 4 / 31 3 / 25 1.08 (0.26 - 4.37) No Diabetes 8 / 172 7 / 163 1.08 (0.40 - 2.92) Diabetes 5 / 29 4 / 36 1.55 (0.46 - 5.26) Location of infarct anterior 6 / 73 5 / 75 1.23 (0.39 - 3.86) Location of infarct non-anterior 7 / 128 6 / 124 1.13 (0.39 - 3.27) Killip class I 11 / 182 8 / 172 1.30 (0.54 - 3.15) Killip class > I 2 / 19 3 / 27 0.95 (0.17 - 5.14) Initial TIMI flow grade < 3 13 / 150 8 / 152 1.65 (0.70 - 3.86) Initial TIMI flow grade 3 0 / 51 3 / 47 0.13 (0.01 - 2.49) Symptom to randomization < 180 min 9 / 164 6 / 151 1.38 (0.50 - 3.79) Symptom to randomization ≥ 180 min 4 / 37 5 / 48 1.04 (0.30 - 3.60) Symptom onset to balloon < 180 min 4 / 94 4 / 97 1.03 (0.27 - 4.01) Symptom onset to balloon ≥ 180 min 9 / 107 7 / 102 1.23 (0.47 - 3.17) Hospital arrival to balloon < 90 min 5 / 96 6 / 94 0.82 (0.26 - 2.58) Hospital arrival to balloon ≥ 90 min 8 / 105 5 / 105 1.60 (0.54 - 4.73) Clopidogrel to balloon < 75 min 5 / 105 8 / 105 0.63 (0.21 - 1.85) Clopidogrel to balloon ≥ 75 min 8 / 96 3 / 94 2.61 (0.71 - 9.54) TIMI not high risk 4 / 87 2 / 70 1.61 (0.30 - 8.53) TIMI high risk 9 / 114 9 / 129 1.13 (0.47 - 2.75) 0.1 0.2 0.5 1 2 5 10 Heparin plus Eptifibatide Better Heparin Alone Better Primary OutcomeSubgroup Analysis

  27. TIMI Bleeding Events During Initial Hospitalization % pts p = 0.14 p = 0. 21 p = 0.04

  28. RevascularizationInitial Hospitalization

  29. Revascularization30 Days and Six Months

  30. Limitations • Relatively small sample size. • Study was performed after the establishment of an integrated city-wide rapid response STEMI system that resulted in relatively short ischemic time intervals. • Relatively high percentage of PCI to a non–infarct-related artery performed later during the initial hospitalization may have contributed to the low event rates.

  31. Conclusions In pts with acute STEMI pre-treated with high dose clopidogrel, as compared with PCI with heparin alone, PCI with eptifibatide initiated before catheterization 1) does not improve clinical outcomes and 2) is associated with more bleeding.

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