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Global Trials: Challenges and Opportunities Case Study: The ExTRACT-TIMI 25 Trial

Global Trials: Challenges and Opportunities Case Study: The ExTRACT-TIMI 25 Trial. Elliott Antman, MD Brigham and Women’s Hospital Harvard Medical School Boston, MA. Disclosure.

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Global Trials: Challenges and Opportunities Case Study: The ExTRACT-TIMI 25 Trial

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  1. Global Trials: Challenges and OpportunitiesCase Study: The ExTRACT-TIMI 25 Trial Elliott Antman, MD Brigham and Women’s Hospital Harvard Medical School Boston, MA

  2. Disclosure The TIMI Study Group has received research / grant support in the past 2 yrs through the Brigham & Women’s Hospital with funding from (in alphabetical order): The National Institutes of Health Integrated Therapeutics Corporation KAI Pharmaceuticals Merck & Co., Inc. Millennium Pharmaceuticals, Inc. Novartis Pharmaceuticals Nuvelo, Inc. Ortho-Clinical Diagnostics, Inc. Pfizer, Inc. Roche Diagnostics Corporation Roche Diagnostics GmbH Sanofi-Aventis Sanofi-Synthelabo Recherche Schering-Plough Research Institute St Jude Medical Accumetrics, Inc. Amgen, Inc. AstraZeneca Pharmaceuticals LP Baxter Bayer Healthcare LLC Beckman Coulter, Inc. Biosite Incorporated Bristol-Myers Squibb CardioKinetix CV Therapeutics, Inc.Daiichi-Sankyo Eli Lilly and Company FoldRx GlaxoSmithKline INO Therapeutics LLC Inotek Pharmaceuticals Corporation

  3. Hamm Lancet 358:1533,2001 Ischemic Discomfort Presentation Acute Coronary Syndrome Working Dx Davies MJ Heart 83:361, 2000 No ST Elevation ST Elevation ECG NSTEMI Biochem. Marker Myocardial Infarction Unstable Angina NQMI Qw MI Final Dx

  4. Reperfusion Strategies for STEMI Pharmacologic PCI Limited Availability Treatment Delay More Effective Bleeding Risk Lower Widely Available Quickly Administered Less Effective Bleeding Risk

  5. Thrombosis of epicardial coronary artery…….. Thrombin Fibrin Lytic Rx Antithrombins Flow Antiplatelet Rx ……….the cause of STEMI

  6. Pharmacologic Reperfusion for STEMI: Components of Regimen FibrinolyticSK↓ Fibrin- specific↓ Bolus AntiplateletASA↓ GPIIb/IIIaThienopyridine AnticoagulantUFH↓ Alternative Agents

  7. X TF/VIIa Xa inhibitorsLMWH Xa TFPI UFH V, Ca2+ LMWH Thrombin UFH Prothrombin DTIs Clopidogrel ASA Platelet GP IIb/IIIaInhibitor

  8. Potential Advantages of Anticoagulation with LMWH vs UFH LMWH UFH Greater Inhibit thrombus generation Less Route IV SC No Monitor A/C Yes No Inhibition by Platelets Yes

  9. Enoxaparin for STEMI No Lytic RxTETAMI Adjunct to LyticHART IIAMI SKBaird et alASENOXENTIRE-TIMI 23 ASSENT 3ASSENT 3-PLUS

  10. ASSENT 3 Bleeding Stratified by Age < 75 yrs(N = 5328) >75 yrs(N = 767, 13%) P <0.0001 P =0.26 JACC 39: 306A, 2002

  11. Primary Hypothesis Am Heart J 2005;149:17-26. Compared toUFH, adjunctive antithrombin therapy withENOXreduces the composite end point of all-cause mortality or non-fatal re-MI within 30 days in patients with STEMI who are eligible to receive fibrinolytic therapy.

  12. Protocol Design Am Heart J 2005;149:17-26. STEMI < 6 hLytic eligible Lytic choice by MD(TNK, tPA, rPA, SK) ASA Double-blind, double-dummy ENOX < 75 y: 30 mg IV bolus SC 1.0 mg / kg q 12 h (Hosp DC) ≥ 75 y: No bolusSC 0.75 mg / kg q 12 h (Hosp DC) CrCl < 30: 1.0 mg / kg q 24h UFH60 U / kg bolus (4000 U) Inf 12 U / kg / h (1000 U / h)Duration: at least 48 hCont’d at MD discretion Day 301° Efficacy Endpoint: Death or Nonfatal MI1° Safety Endpoint: TIMI Major Hemorrhage

  13. Trial Features • Central Randomization Toll free phone Stratified by center • Double Blind • Double Dummy • Ratio 1:1 (Enox : UFH)

  14. Statistical Considerations • Sample Size UFH 10.5% RRD 13% Enox 9.13 % ARD 1.37% 2-sided  = 5% Power > 90% 2080 events (approx 21,000 pts) • Interim Stopping Rules 3 Interim looks (25,50,75% of events) If Mortality lower with UFH (P<0.01) at first 2 looks--consider stopping If Mortality lower with Enox (P<0.01) AND D/MI lower (P<0.02) at 3rd look-consider stopping Final P value = 0.043

  15. B B B B A A A A A A A A A A A Study Medication Kits Drug A32 single-use ampules (1 ml) Drug B4 multi-use vials (10 ml) A UFH (5000 U/ml) / Placebo Enox (100mg/ml) / Placebo IV bolus # A SC Injections IV bolus # B IV Infusion

  16. CBFComputer 7 digit codeReported Specimen Drawn Local encrypted measurement(7 digit code) True/MockValue Reported Back UFHNomogram Double Blind Dose Adjustment CBF ProceduresaPTT/ACT via Hemochron Jr.

  17. Enrollment: Oct 2002 - Oct 2005N = 20,479 (ITT) 48 Countries 674 Sites

  18. Top 10 Enrolling Countries-1 Country Lead Inv # Subjects • Russia • Poland • Spain • Turkey • 5. Israel Ruda Sadowski/ Budaj Lopez-Sendon Guneri Hod 4,887 1,792 1,281 953 870

  19. Top 10 Enrolling Countries-2 Country Lead Inv # Subjects 790 753 645 639 626 6. Ukraine 7. India 8. Netherlands 9. Great Britain 10. Italy Parkhomenko SomaRaju Molhoek Jacob Ardissino

  20. Other Countries-through 48 Country Lead Inv # Subjects 57 49 46 43 39 36. Belarus 37. United States 38. Lithuania 39. Norway 40. Latvia Polonetsky Antman Sanofi-Aventis Dickstein Sanofi-Aventis

  21. Baseline Characteristics ITT N = 20,479 N Engl J Med 2006;354:1477-88. Age (yrs)-median 59 CrCl (ml/min)-median 82 Male (%) 77 UFH within 3 h (%) 16 Hypertension (%) 44 LMWH within 7 d (%) 0.5 Hyperlipidemia (%) 18 Killip Class I (%) 89 Current smoker (%) 47 TIMI Risk Score (STEMI) Diabetes (%) 15 < 3 (%) 64 Prior MI (%) 13 > 3 (%) 36 Anterior MI (%) 44 ALL P = NS

  22. Medications ITT N = 20,479 N Engl J Med 2006;354:1477-88. Fibrinolytic 20 SK (%) Fibrin-specific (%) 80 ASA (%) 95 Beta Blocker (%) 86 ACEI / ARB (%) 80 Statin (%) 70 ALL P = NS

  23. Main Results NEJM 354:1477, 2006 Bleeding by 30 days Primary Endpoint: Death or non-fatal re-MI by 30 days UFH 12.0 ARD 0.7%RR 1.53P<0.0001 ARD 0.4%RR 1.84P = 0.001 ARD 0.1%RR 1.27P = 0.14 9.9 ENOX % Events % ARD = 0.021 = 2.1 %RR = 0.83 (0.77 to 0.90)RRR = 0.17 (0.23 to 0.10)NNT = 48 FatalMajor Bleed Major Bleed(Total) ICH Days 33% RRR in reMI by 48 h (P=0.002) 19% RRR in Death/MI by 72 h (P<0.001)

  24. Revised Pkg Insert for Enoxaparin

  25. Enox (%) UFH (%) 9.8% 11.4% Death or Reinfarction Across the ACS Spectrum Eur Heart J. 2007;28:2077-86. Odds ratio (95% CI) 7.7 9.6 ASSENT 3 0.78 (0.63,0.98) 8.0 8.0 HART II 1.00 (0.49,2.06) BAIRD 0.60 (0.35,1.01) 20.8 30.5 ENTIRE-TIMI 23 0.24 (0.09,0.64) 4.4 15.9 ASSENT 3 Plus 0.89 (0.65,1.22) 10.3 11.4 ExTRACT-TIMI 25 0.81 (0.74,0.88) 9.9 12.0 STEMI (p=0.002) 0.78 (0.67,0.91) 9.6 11.7 ESSENCE 0.76 (0.58,1.01) 5.8 7.5 TIMI 11B 0.88 (0.70,1.11) 7.4 8.3 ACUTE II 0.98 (0.51,1.86) 7.9 8.1 INTERACT 0.53 (0.30,0.95) 5.0 9.0 A TO Z 0.94 (0.73,1.20) 7.4 7.8 SYNERGY 0.96 (0.85,1.07) 13.9 14.5 NSTEACS (p=0.043) 0.90 (0.81,0.996) 10.0 11.0 0.84 (0.76,0.92) TOTAL p < 0.001 .2 1 5 Odds ratio Favors Enox Favors UFH

  26. 6.5 6.9 5.2 3.4 0.3 1.0 5.3 8.7 0.8 0.2 9.1 7.6 4.3% 3.4% Major Bleeding Across the ACS Spectrum Eur Heart J. 2007;28:2077-86. Odds ratio Enox (%) UFH (%) (95% CI) ASSENT 3 1.27 (0.90,1.79) 3.8 3.0 HART II 1.18 (0.39,3.57) 3.6 3.0 BAIRD 0.84 (0.25,2.81) 3.4 4.0 ENTIRE-TIMI 23 0.76 (0.13,4.67) 1.9 2.4 ASSENT 3 Plus 1.70 (1.07,2.68) 6.2 3.8 ExTRACT-TIMI 25 1.54 (1.24,1.91) 2.1 1.4 STEMI (p<0.001) 2.6 1.8 1.45 (1.23,1.72) ESSENCE 0.93 (0.70,1.23) TIMI 11B 1.56 (1.13,2.14) ACUTE II 0.33 (0.03,3.68) INTERACT 0.58 (0.33,1.03) A TO Z 3.78 (1.25,11.41) SYNERGY 1.21 (1.05,1.40) NSTEACS (p=0.42) 6.3 5.4 1.13 (0.84,1.54) TOTAL 1.25 (1.04,1.50) 1 p = 0.019 .2 5 Odds ratio Favors Enox Favors UFH

  27. STEMI Treatments & Outcomes Worldwide:Results from the Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction - Thrombolysis In Myocardial Infarction (ExTRACT-TIMI) 25 Registry Benjamin A. Steinberg, Elliott M. Antman, Nazanin Moghbeli, Jacqueline Buros, Sabina A. Murphy, Carolyn H. McCabe,C. Michael Gibson, David A. Morrow, Eugene Braunwald

  28. Background • Significant regional differences in mortality rates following STEMI • Lower mortality rates in clinical trials versus registries • Patients in clinical trials more likely to get life-saving medications Giugliano, et al. Eur Heart J. 2001;22:1702-15.Bahit, et al. Am Heart J 2003;145:109-17.

  29. Unanswered Questions • How do contemporary RCT subjects differ from STEMI patients in the general population? • How well can we generalize the results of the ExTRACT-TIMI 25 trial? • How does regional variation contribute to mortality from STEMI?

  30. Hypotheses • STEMI patients in contemporary clinical trials have lower baseline risk and better outcomes than patients not enrolled in RCTs • When adjusted for baseline risk and treatments received, regional variation in outcomes after STEMI is minimized

  31. ExTRACT-TIMI 25 Program STEMI Randomized inExTRACT-TIMI 25 Trial Entered inExTRACT-TIMI 25 Registry Major In-Hospital Outcomes:1°: Death At Discharge or Day 8

  32. ExTRACT-TIMI 25 Chronology ExTRACT-TIMI 25 Trial October 31, 2005 January 24 ,2006 October, 2002 ExTRACT-TIMI 25 Registry April 1, 2005 Registry Enrollment n=0 n=3,098 n=3,726

  33. Population Samples Trial Registry 3,726 Patients 20,479 (Intention-to-Treat) 109 674 25 48 Antman, et al. NEJM 2006;354:1477-88.

  34. Baseline Characteristics Antman, et al. NEJM 2006;354:1477-88.

  35. Baseline Characteristics Cont. Antman, et al. NEJM 2006;354:1477-88.

  36. STEMI Management Antman, et al. NEJM 2006;354:1477-88.

  37. In-Hospital Mortality P<0.001 HR = 1.35 UnadjustedMortality

  38. TIMI Risk Index (TRI) HR  (Age/10)2 SBP P(trend)<0.001 In-Hospital Mortality TRI Morrow, et al. Lancet. 2001;358:1571-5.Wiviott, et al. JACC. 2004;44:783-9.

  39. TIMI Risk Index (TRI) Profile P<0.001 % Patient Population HR  (Age/10)2 SBP

  40. In-Hospital Mortality by TIMI Risk Index (TRI) p=0.92 Mortality P(trend)<0.001 P(trend)<0.001

  41. Gross National Income • Gross national income (GNI) per capita, as a surrogate for “regionality” • Data from World Bank Development indicators database, 2004 statistics World Bank. World Development Indicators Database. Washington DC; 2004.Orlandini, et al. Eur Heart J. 2006; 27:527-33.

  42. Registry: TIMI Risk Index Profile By Gross National Income % Patient Population TRI

  43. Registry: Gross National Income (GNI) Corrected for TRI When adjusted for baseline risk, GNI does not predict in-hospital mortality.

  44. Registry: Multivariate Analysis for In-Hospital Mortality

  45. Risk of In-Hospital Mortality: Statistical Assessment TRI + Therapy c=0.85 +GNIc=0.85 TRI c=0.77 Sensitivity Coin Flipc=0.5 C statistic(AUC for ROC) 1 - Specificity

  46. Registry: Predictors of In-Hospital Mortality GNI Medical &ReperfusionTherapy Overall c=0.85 Baseline Risk (TRI)

  47. Limitations • Registry population not perfect representation of ‘general’ STEMI population • Reporting and survival biases

  48. Conclusions • TIMI Risk Index • A simple, robust risk-stratification tool • ExTRACT-TIMI 25 RCT • Patients at lower risk and have better outcomes than the general STEMI population • Mortality differences explained by baseline risk • Regional Variation • After adjusting for baseline risk (TRI) and in-hospital treatments, GNI does not predict in-hospital mortality after STEMI.

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