Time to Integrilin Therapy in Acute myocardial infarctioN ...
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  • 5 5 5 Dr. Eugene Braunwald was the study chairman and Ms. Carolyn McCabe the project director. Drs. Skene and Wilcox coordinated the Eastern hemisphere and the data coordinating center.
  • 5 5 5 Dr. Eugene Braunwald was the study chairman and Ms. Carolyn McCabe the project director. Drs. Skene and Wilcox coordinated the Eastern hemisphere and the data coordinating center.
  • 5 5 5 Dr. Eugene Braunwald was the study chairman and Ms. Carolyn McCabe the project director. Drs. Skene and Wilcox coordinated the Eastern hemisphere and the data coordinating center.
  • 5 5 5 Dr. Eugene Braunwald was the study chairman and Ms. Carolyn McCabe the project director. Drs. Skene and Wilcox coordinated the Eastern hemisphere and the data coordinating center.
  • 5 5 5 Dr. Eugene Braunwald was the study chairman and Ms. Carolyn McCabe the project director. Drs. Skene and Wilcox coordinated the Eastern hemisphere and the data coordinating center.
  • In order to improve upon the variability in the TIMI flow grades, the TIMI frame count was developed. Shown here is the TIMI frame count method. The number of frames required for dye to traverse the artery are counted. In the first frame, dye extends across the width of the artery. In the last frame, one of the standard distal landmarks is first opacified. These landmarks include the first branch off of the posterolateral in the RCA, the last branch off of the most distal obtuse marginal in the circumflex, and the pitchfork in the distal LAD. LAD frame counts are divided by 1.7 to account for the longer length of the LAD. Normal frame counts are 21 in the absence of acute MI.
  • 5 5 5 Dr. Eugene Braunwald was the study chairman and Ms. Carolyn McCabe the project director. Drs. Skene and Wilcox coordinated the Eastern hemisphere and the data coordinating center.
  • 5 5 5 Dr. Eugene Braunwald was the study chairman and Ms. Carolyn McCabe the project director. Drs. Skene and Wilcox coordinated the Eastern hemisphere and the data coordinating center.
  • 5 5 5 Dr. Eugene Braunwald was the study chairman and Ms. Carolyn McCabe the project director. Drs. Skene and Wilcox coordinated the Eastern hemisphere and the data coordinating center.
  • 5 5 5 Dr. Eugene Braunwald was the study chairman and Ms. Carolyn McCabe the project director. Drs. Skene and Wilcox coordinated the Eastern hemisphere and the data coordinating center.
  • 5 5 5 Dr. Eugene Braunwald was the study chairman and Ms. Carolyn McCabe the project director. Drs. Skene and Wilcox coordinated the Eastern hemisphere and the data coordinating center.
  • 5 5 5 Dr. Eugene Braunwald was the study chairman and Ms. Carolyn McCabe the project director. Drs. Skene and Wilcox coordinated the Eastern hemisphere and the data coordinating center.
  • 5 5 5 Dr. Eugene Braunwald was the study chairman and Ms. Carolyn McCabe the project director. Drs. Skene and Wilcox coordinated the Eastern hemisphere and the data coordinating center.
  • 5 5 5 Dr. Eugene Braunwald was the study chairman and Ms. Carolyn McCabe the project director. Drs. Skene and Wilcox coordinated the Eastern hemisphere and the data coordinating center.
  • 5 5 5 Dr. Eugene Braunwald was the study chairman and Ms. Carolyn McCabe the project director. Drs. Skene and Wilcox coordinated the Eastern hemisphere and the data coordinating center.
  • 5 5 5 Dr. Eugene Braunwald was the study chairman and Ms. Carolyn McCabe the project director. Drs. Skene and Wilcox coordinated the Eastern hemisphere and the data coordinating center.
  • 5 5 5 Dr. Eugene Braunwald was the study chairman and Ms. Carolyn McCabe the project director. Drs. Skene and Wilcox coordinated the Eastern hemisphere and the data coordinating center.
  • 5 5 5 Dr. Eugene Braunwald was the study chairman and Ms. Carolyn McCabe the project director. Drs. Skene and Wilcox coordinated the Eastern hemisphere and the data coordinating center.
  • 5 5 5 Dr. Eugene Braunwald was the study chairman and Ms. Carolyn McCabe the project director. Drs. Skene and Wilcox coordinated the Eastern hemisphere and the data coordinating center.
  • 5 5 5 Dr. Eugene Braunwald was the study chairman and Ms. Carolyn McCabe the project director. Drs. Skene and Wilcox coordinated the Eastern hemisphere and the data coordinating center.
  • 5 5 5 Dr. Eugene Braunwald was the study chairman and Ms. Carolyn McCabe the project director. Drs. Skene and Wilcox coordinated the Eastern hemisphere and the data coordinating center.
  • 5 5 5 Dr. Eugene Braunwald was the study chairman and Ms. Carolyn McCabe the project director. Drs. Skene and Wilcox coordinated the Eastern hemisphere and the data coordinating center.
  • 5 5 5 Dr. Eugene Braunwald was the study chairman and Ms. Carolyn McCabe the project director. Drs. Skene and Wilcox coordinated the Eastern hemisphere and the data coordinating center.
  • 5 5 5 Dr. Eugene Braunwald was the study chairman and Ms. Carolyn McCabe the project director. Drs. Skene and Wilcox coordinated the Eastern hemisphere and the data coordinating center.
  • 5 5 5 Dr. Eugene Braunwald was the study chairman and Ms. Carolyn McCabe the project director. Drs. Skene and Wilcox coordinated the Eastern hemisphere and the data coordinating center.

Time to Integrilin Therapy in Acute myocardial infarctioN ... Presentation Transcript

  • 1. TITAN T ime to I ntegrilin T herapy in A cute myocardial infarctio N (TITAN)-TIMI 34
  • 2. TITAN-TIMI 34: Goal To answer the following question: Among patients intended to undergo primary PCI, does a strategy of early initiation of eptifibatide in the ER prior to primary PCI yield superior pre-PCI angiographic outcomes compared to a strategy of initiating eptifibatide in the cardiac catheterization laboratory after diagnostic angiography? © TIMI 2005. Duplication prohibited by law
  • 3. TITAN-TIMI 34: Trial Organization TIMI Study Group Eugene Braunwald, M.D. (Chairman) Brigham and Women’s C. Michael Gibson, M.S., M.D. (Principal Investigator) Hospital Carolyn McCabe, B.S. (Director) Ajay Kirtane, M.D. (Co-Investigator) Christopher P. Cannon, M.D. (Co-Investigator) Polly Fish, B.S. (Project Manager) Data Coordinating Center TIMI Data Coordinating Center Sabina A. Murphy, M.P.H. (Director Biostatistics) Jacqueline L. Buros, B.A. (Director Data Management) Angiographic Core Lab TIMI Angiographic Core Lab Ajay Kirtane, M.D. (Principal Investigator) Lauren N. Ciaglo, B.A. EKG Core Lab TIMI EKG Core Lab Benjamin Scirica, M.D. (Director) © TIMI 2005. Duplication prohibited by law
  • 4. Primary PCI STEMI < 6 HRS Undergoing Primary PCI (n=343) TITAN TIMI 34: Study Design RANDOMIZE Open Label ASA 160-325 mg po HEPARIN 60 U/kg bolus (Max 4000U) and 7U/kg infusion (Max 800 U/hr) “ EARLY ER EPTIFIBATIDE” “ CATH LAB EPTIFIBATIDE” EPTIFIBATIDE 180/2.0/180 TRANSFER TO CATH LAB DIAGNOSTIC ANGIO PRIMARY ENDPOINT: Pre PCI TIMI Frame Count EPTIFIBATIDE 180/2.0/180 TRANSFER TO CATH LAB DIAGNOSTIC ANGIO © TIMI 2005. Duplication prohibited by law
  • 5. TITAN-TIMI 34: Enrollment Criteria
    • Inclusion Criteria:
      • > 18 years of age
      • Clinical diagnosis of AMI ( ischemic pain > 20 min. )
      • Onset of symptoms < 6 hours
      • ST elevation > 1 mm in 2 contiguous limb leads or > 2 mm in 2 contiguous precordial leads
    • Major Exclusion Criteria:
      • Hemorrhagic risk factors
      • Current episode previously treated by fibrinolytics
      • Cardiogenic shock or hemodynamically significant arrhythmias
    © TIMI 2005. Duplication prohibited by law
  • 6. LAD Frame 1: Dye Touches Both Borders & Moves Forward Frame 0: Dye Touches One or No Borders Last Frame Definition Frame 21: Dye first enters landmark First Frame Definition RCA LCX Distal Landmark Normal Flow in the Absence of MI : 21.0 + 3.1 frames 1st branch off posterolateral Last branch off most distal OM “ Whale’s tail” or “pitchfork” or most distal branch LAD at apex Gibson, Circulation 1996; 93: 879-888 TITAN: Primary Endpoint Corrected TIMI Frame Count © TIMI 2005. Duplication prohibited by law
  • 7. TITAN Other Angiographic Efficacy Endpoint: TIMI Myocardial Perfusion (TMP) Grades 6.2% 4.4% 2.0% n = 203 n = 46 n = 434 TMP Grade 3 p = 0.05 Mortality (%) n = 79 5.1% Gibson et al, Circulation 2000 Normal ground glass appearance of blush Dye mildly persistent at end of washout Dye strongly persistent at end of washout Gone by next injection Stain present Blush persists on next injection No or minimal blush TMP Grade 2 TMP Grade 1 TMP Grade 0 © TIMI 2005. Duplication prohibited by law
  • 8. TITAN-TIMI 34: Angiographic Perfusion Score
    • Integrates epicardial and myocardial perfusion
    • Integrates flow before and after PCI
    • Sum of the following:
      • TIMI Flow Grade Before PCI (0-3)
      • TIMI Myocardial Perfusion Grade Before PCI (0-3)
      • TIMI Flow Grade After PCI (0-3)
      • TIMI Myocardial Perfusion Grade After PCI (0-3)
    Total Angiographic Perfusion Score: 0 - 12 Gibson CM. Am Heart J. 2004 Aug;148(2):336-40. Failed 0-3; Partial 4-9; Full 10-12 © TIMI 2005. Duplication prohibited by law
  • 9. Relationship of Angiographic Perfusion Score to SPECT Infarct Size & Mortality © TIMI 2005. Duplication prohibited by law % SPECT Infarct Size Angiographic Perfusion Score 35.5% 16.2% 12.5% p=0.002 11.1% 1.9% 0.0% p=0.01 % Death by 30 days Gibson CM. Am Heart J. 2004 Aug;148(2):336-40.
  • 10. Global Perfusion Score Methodology Flow Grade: □ 0 □ 1 □ 2 □ 3 Blush Grade: □ 0 □ 1 □ 2 □ 3 Flow Grade: □ 0 □ 1 □ 2 □ 3 Blush Grade: □ 0 □ 1 □ 2 □ 3 Flow Grade: □ 0 □ 1 □ 2 □ 3 Blush Grade: □ 0 □ 1 □ 2 □ 3 Total Potential Score: 54 points © TIMI 2005. Duplication prohibited by law
  • 11. TITAN-TIMI 34: Top 10 Enrolling Sites © TIMI 2005. Duplication prohibited by law 14 Terri Campbell Abdulhay Albirini Genesis Healthcare System 10 14 Rachel Monbouquette Daniel Simon Brigham and Women's Hospital 9 15 Cindy Werner Saeb Khoury University Of Cincinnati 8 16 Karen Turnbull Mahesh Bikkina St. Joseph's Regional Medical Center 7 20 Caroline Sloane Nicolas Shammas Genesis Medical Center 6 27 Gretchen Kalenak Jeffrey Lins Tri-State Medical Group, Cardiology 5 30 Kanchana Karunaratne Ivan Rokos Northridge Hospital 4 31 Kim Wood Mauricio Cohen University of North Carolina 3 32 Tammy Hedrick Steve Rohrbeck Carolina Cardiology Associates, PA 2 37 Rebecca Richmond Samer Kazziha Mount Clemens General Hospital 1 Enrollment Research Coordinator Principal Investigator Site Name
  • 12. TITAN-TIMI 34: Top 11-20 Enrolling Sites © TIMI 2005. Duplication prohibited by law 5 Cindy Whited Peter Ver Lee Northeast Cardiology Associates 20 5 Jackie Edwards Saeb Khoury Veterans Affairs Medical Center (111C2) 19 6 Lynn Royal Thomas Amidon Seattle Cardiovascular Research 18 7 Cindy Brockway Mian Jan West Chester Cardiology 17 7 Rebecka Songer Peter Katsiyiannis Decatur Memorial Hospital 16 9 Stacey Mazzurco Tom Lassar University Hospitals of Cleveland 15 9 Kathy Jurden Greg Eaton MedCentral Mansfield 14 10 Kelly Glenn Barry Bertolet Cardiology Associates of Mississippi 13 10 Dawn Myers David Zhao Vanderbilt University Medical Center 12 11 Cynthia Antonio Aswartha Pothula Trinity Medical Center 11 Enrollment Research Coordinator Principal Investigator Site Name
  • 13. TITAN-TIMI 34: Baseline Characteristics © TIMI 2005. Duplication prohibited by law NS 39.6% 35.2% Anterior MI NS 40.1% 49.4% Current smoker NS 40.9% 42.2% Hypertension NS 18.3% 15.5% Diabetes 10.6% 31.2% 73.2% 60.1 +/- 12.6 yrs Cath Lab Eptifibatide n=142 NS NS NS NS P value 14.9% Prior MI 32.2% 74.7% 59.1 +/- 13.1 yrs ER Eptifibatide n=174 Male Hyperlipidemia Age (yrs + SD) Characteristic
  • 14. TITAN-TIMI 34 Primary Endpoint: Pre-PCI TIMI Frame Count © TIMI 2005. Duplication prohibited by law p < 0.05 p=0.046 adjusting for infarct location Primary Analysis: Modified Intent-to-Treat Frame Count ER Eptifibatide Cath Lab Eptifibatide CTFC p < 0.05 84.3 + 30.7 (n=137) 77.5 + 32.2 (n=168) ER Eptifibatide Cath Lab Eptifibatide
  • 15. © TIMI 2005. Duplication prohibited by law Pre - PCI TMPG 3 (%) ER Eptifibatide Cath Lab Eptifibatide 24.3% 14.2% p = 0.026 (41/169) (20/141) p=0.025 adjusting for infarct location Primary Analysis: Modified Intent-to-Treat TITAN-TIMI 34: Secondary Angiographic Endpoint TIMI Flow Grades Pre - PCI TIMI 2 or 3 Flow (%) ER Eptifibatide Cath Lab Eptifibatide 46.2% 36.6% (79/171) (52/142) TIMI 2 or 3 p = 0.087 24% 19% p=NS TIMI 3
  • 16. TITAN-TIMI 34: Pre-PCI Flow Throughout Heart © TIMI 2005. Duplication prohibited by law Primary Analysis: Modified Intent-to-Treat ER Eptifibatide Cath Lab Eptifibatide Global Perfusion Score n=125 n=99 p = 0.008 p = 0.03 ER Eptifibatide Cath Lab Eptifibatide Global Frame Count (Ave. 3 Arteries)
  • 17. © TIMI 2005. Duplication prohibited by law Pre - PCI MLD (mm) ER Eptifibatide Cath Lab Eptifibatide 0.33 0.21 p = 0.026 (n=169) (n=138) Pre - PCI % Stenosis ER Eptifibatide Cath Lab Eptifibatide 87.5% 91.0% p = 0.048 (n=169) (n=139) Primary Analysis: Modified Intent-to-Treat TITAN-TIMI 34 Pre-PCI Quantitative Angiography
  • 18. © TIMI 2005. Duplication prohibited by law Post - PCI CTFC ER Eptifibatide Cath Lab Eptifibatide 20 22 p = 0.14 Post - PCI TIMI 3 Flow (%) ER Eptifibatide Cath Lab Eptifibatide 86.7% 89.1% p = NS Post - PCI TMPG 3 (%) ER Eptifibatide Cath Lab Eptifibatide 37.0% 36.7% p = NS (47/128) (57/154) (n=138) (n=116) (137/158) (122/137) Primary Analysis: Modified Intent-to-Treat TITAN-TIMI 34 Post-PCI Flow
  • 19. TITAN-TIMI 34: Full Angiographic Perfusion © TIMI 2005. Duplication prohibited by law Full Angiographic Perfusion (APS 10-12) % ER Eptifibatide Cath Lab Eptifibatide 21.1% 12.5% p = 0.059 (32/152) (16/128) Primary Analysis: Modified Intent-to-Treat Full Angiographic Perfusion previously defined in Gibson CM. Am Heart J. 2004 Aug;148(2):336-40.
  • 20. TITAN-TIMI 34: Treated as Intended in Protocol Analysis © TIMI 2005. Duplication prohibited by law ER Group: Drug at least 15 minutes before 1 st injection on angio (n=127) Cath Lab Group: Drug after 1 st injection on angio (n=114) First Injection on Angio = Time 0
  • 21. © TIMI 2005. Duplication prohibited by law p = 0.021 p=0.024 adjusting for infarct location Secondary Analysis: Treated per Protocol TITAN-TIMI 34 Primary Endpoint: Pre-PCI TIMI Frame Count ER Eptifibatide Cath Lab Eptifibatide Frame Count 75.3 + 32.1 (n=124) 84.4 + 30.7 (n=109) CTFC p = 0.021 Cath Lab Eptifibatide ER Eptifibatide
  • 22. F A S T E R F L O W TITAN-TIMI 34: Duration of Therapy and Pre-PCI TIMI Frame Count n=165 n=111 n=17 Mean TIMI Frame Count Duration of Therapy Before First Injection p = 0.003 for linear trend In cath lab to 15 min prior 15 min to 60 min. prior > 60 min. prior 85.6 76.6 68.6 Earlier Treatment © TIMI 2005. Duplication prohibited by law
  • 23. TITAN-TIMI 34: Pre-PCI TIMI Grade 2 or 3 Flow and Full Perfusion © TIMI 2005. Duplication prohibited by law Pre - PCI TIMI 2 or 3 Flow (%) ER Eptifibatide Cath Lab Eptifibatide 46.8% 34.2% (59/126) (39/114) p = 0.047 Secondary Analysis: Treated per Protocol Full Angiographic Perfusion (%) ER Eptifibatide Cath Lab Eptifibatide 23.9% 13.2% p = 0.041 Full Angiographic Perfusion previously defined in Gibson CM. Am Heart J. 2004 Aug;148(2):336-40. (28/117) (14/106)
  • 24. © TIMI 2005. Duplication prohibited by law Death (%) ER Eptifibatide Cath Lab Eptifibatide Death p = NS CHF (%) ER Eptifibatide Cath Lab Eptifibatide n=173 n=142 Primary Analysis: Modified Intent-to-Treat TITAN-TIMI 34 Clinical Endpoints at Discharge/Day 5 CHF p = 0.082 n=173 n=142
  • 25. TITAN-TIMI 34: Bleeding Events © TIMI 2005. Duplication prohibited by law Non CABG Through Discharge; Site Assessment Primary Analysis: Modified Intent-to-Treat NS 0.0% 0.0% Stroke or ICH NS 7.0% 9.8% Transfusion PRBC 1.4% 7.8% 4.2% 3.5% Cath Lab Eptifibatide (n=142) NS NS NS NS P-value 2.3% Thrombocytopenia (Plt. < 100K) 6.9% 5.2% 1.7% ER Eptifibatide (n=174) TIMI Minor (Hgb  3-5 g/dL) TIMI Major or Minor TIMI Major (Hgb  >5 g/dL or ICH) Outcome
  • 26. TITAN-TIMI 34: Conclusions © TIMI 2005. Duplication prohibited by law A strategy of early initiation of eptifibatide in the emergency room prior to primary PCI for ST segment elevation MI yields superior pre-PCI TIMI frame counts (epicardial flow) and superior TIMI myocardial perfusion compared to a strategy of initiating eptifibatide in the cardiac catheterization laboratory
  • 27. TITAN-TIMI 34: Clinical Implications © TIMI 2005. Duplication prohibited by law Among patients who are to undergo primary PCI for STEMI, GP IIbIIIa inhibition should be initiated as soon as possible prior to cardiac catheterization.