1. 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

2. Disclosure 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 FoldRxGlaxoSmithKline INO Therapeutics LLC Inotek Pharmaceuticals Corporation 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 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):

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

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

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

6. Pharmacologic Reperfusion for STEMI: Components of Regimen Fibrinolytic SK ↓ Fibrin- specific ↓ Bolus Antiplatelet ASA ↓ GPIIb/IIIa Thienopyridine GPIIb/IIIa Thienopyridine Anticoagulant UFH ↓ Alternative Agents

7. Prothrombin Thrombin Xa X TF/VIIa V, Ca 2+ Platelet Xa inhibitors LMWH UFH LMWH UFH DTIs GP IIb/IIIa Inhibitor ASA Clopidogrel TFPI

8. Potential Advantages of Anticoagulation with LMWH vs UFH LMWHUFH Inhibit thrombus generation Route Monitor A/C Inhibition by Platelets NoYes SC IV GreaterLess NoYes

9. Enoxaparin for STEMI Adjunct to Lytic HART II AMI SK Baird et al ASENOX ENTIRE-TIMI 23 ASSENT 3 ASSENT 3-PLUS No Lytic Rx TETAMI

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

11. Primary Hypothesis Compared to UFH, adjunctive antithrombin therapy with ENOX reduces 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. Am Heart J 2005;149:17-26.

12. STEMI < 6 h Lytic eligible Lytic choice by MD (TNK, tPA, rPA, SK) ENOX < 75 y: 30 mg IV bolus SC 1.0 mg / kg q 12 h (Hosp DC) ≥ 75 y: No bolus SC 0.75 mg / kg q 12 h (Hosp DC ) CrCl < 30: 1.0 mg / kg q 24 h Double-blind, double-dummy ASA Day 30 1° Efficacy Endpoint: Death or Nonfatal MI 1° Safety Endpoint: TIMI Major Hemorrhage Protocol Design UFH 60 U / kg bolus (4000 U) Inf 12 U / kg / h (1000 U / h) Duration: at least 48 h Cont’d at MD discretion Am Heart J 2005;149:17-26.

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. Study Medication Kits Enox (100mg/ml) / Placebo UFH (5000 U/ml) / Placebo Drug A Drug A 32 single-use ampules (1 ml) B IV bolus # A Drug B Drug B 4 multi-use vials (10 ml) BBB SC Injections IV bolus # B IV Infusion A A A A A A A A A A A A

16. CBF Procedures aPTT/ACT via Hemochron Jr. True/Mock Value Reported Back Local encrypted measurement (7 digit code) CBF Computer 7 digit code Reported 7 digit code Reported Specimen Drawn UFH Nomogram Double Blind Dose Adjustment

17. Enrollment: Oct 2002 - Oct 2005 N = 20,479 (ITT) 48 Countries674 Sites 48 Countries674 SitesArgentinaFinlandLatviaSingaporeAustraliaFranceLebanonSlovakia AustriaGermanyLithuania South Africa BelarusGreeceMalaysiaSpain Belgium Hong Kong MexicoSweden BrazilHungaryNetherlandsSwitzerland BulgariaIndia New Zealand Thailand CanadaIrelandNorwayTurkey ChileIsraelPolandUkraine ChinaItalyPortugal United Kingdom CroatiaJordanRomania United States Estonia Republic of Korea Russian Federation Uruguay

18. Top 10 Enrolling Countries-1 CountryLead Inv# Subjects 1.Russia 2.Poland 3.Spain 4.Turkey 5.Israel Ruda Sadowski/ Budaj Lopez-Sendon Guneri Hod 4,887 1,792 1,281 953 870

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

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

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

22. Medications ITT N = 20,479 Medications ITT N = 20,47980 86 95 80 20 ACEI / ARB (%) Fibrin-specific (%) ASA (%) Beta Blocker (%) SK (%) Fibrinolytic 70 Statin (%) ALL P = NS N Engl J Med 2006;354:1477-88.

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

24. Revised Pkg Insert for Enoxaparin

25. Death or Reinfarction Across the ACS Spectrum 0.78 (0.63,0.98) Odds ratio Favors EnoxFavors UFH.21 5 Odds ratio (95% CI) ASSENT 3 1.00 (0.49,2.06) HART II 0.60 (0.35,1.01) BAIRD 0.24 (0.09,0.64) ENTIRE-TIMI 23 0.89 (0.65,1.22) ASSENT 3 Plus 0.81 (0.74,0.88) ExTRACT-TIMI 25 0.76 (0.58,1.01) ESSENCE 0.88 (0.70,1.11) TIMI 11B 0.98 (0.51,1.86) ACUTE II 0.53 (0.30,0.95) INTERACT 0.94 (0.73,1.20) A TO Z 0.96 (0.85,1.07) SYNERGY 0.84 (0.76,0.92) TOTAL 9.8%11.4% p < 0.001 Enox (%)UFH (%) 7.79.6 8.0 20.830.5 4.415.9 10.311.4 9.912.0 5.87.5 7.48.3 7.98.1 5.09.0 7.47.8 13.914.5 STEMI (p=0.002) NSTEACS (p=0.043) 0.78 (0.67,0.91) 9.611.7 0.90 (0.81,0.996) 10.011.0 Eur Heart J. 2007;28:2077-86.

26. Major Bleeding Across the ACS Spectrum.2 1 5 Odds ratio (95% CI) 1.27 (0.90,1.79) ASSENT 3 1.18 (0.39,3.57) HART II 0.84 (0.25,2.81) BAIRD 0.76 (0.13,4.67) ENTIRE-TIMI 23 1.70 (1.07,2.68) ASSENT 3 Plus 1.54 (1.24,1.91) ExTRACT-TIMI 25 0.93 (0.70,1.23) ESSENCE 1.56 (1.13,2.14) TIMI 11B 0.33 (0.03,3.68) ACUTE II 0.58 (0.33,1.03) INTERACT 3.78 (1.25,11.41) A TO Z 1.21 (1.05,1.40) SYNERGY 1.25 (1.04,1.50) TOTAL Odds ratio Favors EnoxFavors UFH STEMI (p<0.001) NSTEACS (p=0.42) Enox (%)UFH (%) 3.83.0 3.63.0 3.44.0 1.92.4 6.23.8 2.11.4 1.45 (1.23,1.72) 2.61.8 1.13 (0.84,1.54) 6.35.4 p = 0.019 6.56.9 5.23.4 0.31.0 5.38.7 0.80.2 9.17.6 4.3%3.4% Eur Heart J. 2007;28:2077-86.

28. 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

29. 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.

30. 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?

31. 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

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

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

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

35. Baseline Characteristics Trial – All (n = 20,479) % Trial – Registry Sites (n = 7,819) % Registry (n = 3,726) % p (registry sites) Age – yr (median)596063<0.001 Female2325280.003 Hypertension445058<0.001 Hyperlipidemia181634<0.001 Current Smoker47 40<0.001 Diabetes151321<0.001 Prior MI1315170.04 Prior angina pectoris2834360.07 Prior PCI3.21.83.8<0.001 Prior CABG1.30.71.4<0.001 Antman, et al. NEJM 2006;354:1477-88.

36. Baseline Characteristics Cont. Trial – All (n = 20,479) % Trial – Registry Sites (n = 7,819) % Registry (n = 3,726) % p (registry sites) Anterior MI4447450.02 Chronic ASA131218<0.001 Creat. clearance – ml/min (median) 82 73<0.001 Killip II-IV111326<0.001 Rx In-Hosp Aspirin94 950.005 Beta-blockers818278<0.001 ACEIs or ARBs7475760.70 Statin645176<0.001

37. Trial – All (n = 20,479) % Trial – Registry Sites (n = 7,819) % Registry (n = 3,726) % p (registry sites) Reperfusion Therapy Fibrinolysis Fibrin-specific808661 }<0.001 Streptokinase201436 Fibrinolysis Only869480 }<0.001 Lytic  PCI 14620 Primary PCI--26 No Reperfusion0.2 29<0.001 Antman, et al. NEJM 2006;354:1477-88. STEMI Management

38. In-Hospital Mortality Unadjusted Mortality P<0.001 HR = 1.35

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

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

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

42. 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.

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

44. Registry: Gross National Income (GNI) Corrected for TRI N=3268 HR for In-Hospital Death P TRI (per 10 unit increase) 1.18 <0.00 1 GNI (log) 1.040.50 When adjusted for baseline risk, GNI does not predict in-hospital mortality.

45. Registry: Multivariate Analysis for In-Hospital Mortality n=3501 HR for In-Hospital Death p TRI (per 10 unit increase) 1.11<0.001 Any Reperfusion 0.740.02 ASA 0.690.04 Beta-blocker 0.24<0.001 ACE-I/ARB 0.24<0.001 Thienopyridine 0.44<0.001 Anticoagulation (antithrombin or warfarin) 0.56<0.001 GNI (log) 1.080.2

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

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

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

49. 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.