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

Accumetrics, Inc. Accumetrics, Inc. Amgen, Inc. Amgen, Inc. AstraZeneca Pharmaceuticals LPAstraZeneca Pharmaceuticals LPBaxterBaxterBayer Healthcare LLCBayer Healthcare LLCBeckman Coulter, Inc. Beckman Coulter, Inc. Biosite IncorporatedBiosite IncorporatedBristol-Myers SquibbBristol-Myers SquibbCardioKinetixCardioKinetixCV Therapeutics, Inc.CV Therapeutics, Inc.Daiichi-Sankyo Daiichi-Sankyo Eli Lilly and CompanyEli Lilly and CompanyFoldRxFoldRxGlaxoSmithKlineGlaxoSmithKlineINO Therapeutics LLCINO Therapeutics LLCInotek Pharmaceuticals CorporationInotek Pharmaceuticals Corporation

The National Institutes of HealthThe National Institutes of HealthIntegrated Therapeutics CorporationIntegrated Therapeutics CorporationKAI PharmaceuticalsKAI PharmaceuticalsMerck & Co., Inc.Merck & Co., Inc.Millennium Pharmaceuticals, Inc. Millennium Pharmaceuticals, Inc. Novartis PharmaceuticalsNovartis PharmaceuticalsNuvelo, Inc. Nuvelo, Inc. Ortho-Clinical Diagnostics, Inc. Ortho-Clinical Diagnostics, Inc. Pfizer, Inc. Pfizer, Inc. Roche Diagnostics CorporationRoche Diagnostics CorporationRoche Diagnostics GmbHRoche Diagnostics GmbHSanofi-AventisSanofi-AventisSanofi-Synthelabo RechercheSanofi-Synthelabo RechercheSchering-Plough Research InstituteSchering-Plough Research InstituteSt Jude MedicalSt Jude Medical

The TIMI Study Group has received research / grant support in the past 2 yrs The TIMI Study Group has received research / grant support in the past 2 yrs through the Brigham & Women’s Hospital with funding fromthrough the Brigham & Women’s Hospital with funding from (in alphabetical order): (in alphabetical order):

No ST ElevationNo ST Elevation ST ElevationST Elevation

Acute Coronary SyndromeAcute Coronary Syndrome

Unstable AnginaUnstable Angina NQMINQMI Qw MIQw MI

NSTEMINSTEMI

Myocardial InfarctionMyocardial Infarction

Davies MJ Davies MJ Heart 83:361, 2000Heart 83:361, 2000

Ischemic DiscomfortIschemic DiscomfortPresentationPresentation

Working DxWorking Dx

ECGECG

Biochem. Biochem. MarkerMarker

Final DxFinal Dx

Hamm Lancet 358:1533,2001Hamm Lancet 358:1533,2001

Reperfusion Strategies for STEMIReperfusion Strategies for STEMI

Widely AvailableWidely Available

Quickly AdministeredQuickly Administered

Less EffectiveLess Effective

Bleeding RiskBleeding Risk

Limited AvailabilityLimited Availability

Treatment Delay Treatment Delay

More EffectiveMore Effective

Bleeding Risk LowerBleeding Risk Lower

PharmacologicPharmacologic PCIPCI

Thrombosis of epicardial coronary artery……..

……….the cause of STEMI

ThrombinFibrin

AntithrombinsLytic Rx

Antiplatelet Rx

Flow

Pharmacologic Reperfusion for STEMI: Pharmacologic Reperfusion for STEMI: Components of RegimenComponents of Regimen

FibrinolyticFibrinolytic

SKSK

↓↓

Fibrin- Fibrin- specificspecific

↓↓BolusBolus

AntiplateletAntiplatelet

ASAASA

↓↓ GPIIb/IIIaGPIIb/IIIa

ThienopyridineThienopyridine

AnticoagulantAnticoagulant

UFHUFH

↓↓

Alternative Alternative AgentsAgents

Prothrombin Thrombin

Xa

XTF/VIIa

V, Ca2+

Platelet

Xa inhibitorsLMWHUFH

LMWHUFH

DTIs

GP IIb/IIIa

Inhibitor

ASAClopidogrel

TFPI

Potential Advantages of Anticoagulation with Potential Advantages of Anticoagulation with LMWH vs UFHLMWH vs UFH

LMWHLMWH UFHUFHInhibit thrombus Inhibit thrombus

generationgeneration

RouteRoute

Monitor A/C Monitor A/C

Inhibition by Inhibition by Platelets Platelets

No No Yes Yes

SC SC IV IV

Greater Greater Less Less

No No Yes Yes

Enoxaparin for STEMIEnoxaparin for STEMIAdjunct to LyticHART IIAMI SKBaird et alASENOXENTIRE-TIMI 23 ASSENT 3ASSENT 3-PLUS

No Lytic RxTETAMI

ASSENT 3ASSENT 3 Bleeding Stratified by Age Bleeding Stratified by Age

1.90.74

4.13.1 2.58

13.3

2.41.52

7.2

0.96 0.73 0.79

0

5

10

15

ICH MajorBleed

ICH MajorBleed

% Pts

UFHAbxEnox

P <0.0001

P =0.26

< 75 yrs(N = 5328)

>75 yrs(N = 767, 13%)

JACC 39: 306A, 2002

Primary HypothesisPrimary 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.

STEMI < 6 hSTEMI < 6 hLytic eligibleLytic eligible

Lytic choice by MDLytic choice by MD(TNK, tPA, rPA, SK)(TNK, tPA, rPA, SK)

ENOXENOX

< 75 y: 30 mg IV bolus < 75 y: 30 mg IV bolus SC 1.0 mg / kg q 12 h (Hosp DC)SC 1.0 mg / kg q 12 h (Hosp DC)

≥≥ 75 y: No bolus75 y: No bolus

SC 0.75 mg / kg q 12 h (Hosp DCSC 0.75 mg / kg q 12 h (Hosp DC))

CrCl CrCl << 30: 1.0 mg / kg q 24 30: 1.0 mg / kg q 24 hh

Double-blind, double-dummyDouble-blind, double-dummy

ASAASA

Day 30Day 3011°° Efficacy Endpoint: Death or Nonfatal MI Efficacy Endpoint: Death or Nonfatal MI1° Safety Endpoint: TIMI Major Hemorrhage1° Safety Endpoint: TIMI Major Hemorrhage

Protocol DesignProtocol Design

UFHUFH60 U / kg bolus (4000 U) 60 U / kg bolus (4000 U)

Inf 12 U / kg / h (1000 U / h)Inf 12 U / kg / h (1000 U / h)Duration: at least 48 hDuration: at least 48 hCont’d at MD discretionCont’d at MD discretion

Am Heart J 2005;149:17-26.

Trial FeaturesTrial Features

• Central Randomization Toll free phoneStratified by center

• Double Blind• Double Dummy• Ratio 1:1 (Enox : UFH)

Statistical ConsiderationsStatistical 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

Study Medication KitsStudy Medication Kits

Enox (100mg/ml) / PlaceboEnox (100mg/ml) / Placebo UFH (5000 U/ml) / PlaceboUFH (5000 U/ml) / Placebo

Drug ADrug A32 single-use ampules (1 ml)

BB

IV IV bolus # Abolus # A

Drug BDrug B4 multi-use vials (10

ml)

BB BB BB

SC SC InjectionsInjections

IV IV bolus # Bbolus # B

IV IV InfusionInfusion

AA AA AA AA AA AA

AA AA AA AA AA AA

CBF ProceduresCBF ProceduresaPTT/ACT via Hemochron Jr.aPTT/ACT via Hemochron Jr.

True/MockTrue/MockValue Reported Value Reported

BackBack

Local Local encrypted encrypted

measurementmeasurement(7 digit code)(7 digit code)

CBFCBFComputerComputer

7 digit 7 digit codecode

ReportedReportedSpecimen DrawnSpecimen Drawn

UFHUFHNomogramNomogram

Double Blind Double Blind Dose Dose

AdjustmentAdjustment

Enrollment: Enrollment: Oct 2002 - Oct 2005Oct 2002 - Oct 2005N = 20,479 (ITT)N = 20,479 (ITT)

48 Countries48 Countries 674 Sites674 Sites

ArgentinaArgentina FinlandFinland LatviaLatvia SingaporeSingapore

AustraliaAustralia FranceFrance LebanonLebanon SlovakiaSlovakia

AustriaAustria GermanyGermany LithuaniaLithuania South AfricaSouth Africa

BelarusBelarus GreeceGreece MalaysiaMalaysia SpainSpain

BelgiumBelgium Hong KongHong Kong MexicoMexico SwedenSweden

BrazilBrazil HungaryHungary NetherlandsNetherlands SwitzerlandSwitzerland

BulgariaBulgaria IndiaIndia New ZealandNew Zealand ThailandThailand

CanadaCanada IrelandIreland NorwayNorway TurkeyTurkey

ChileChile Israel Israel PolandPoland UkraineUkraine

ChinaChina ItalyItaly PortugalPortugal United KingdomUnited Kingdom

CroatiaCroatia JordanJordan RomaniaRomania United StatesUnited States

EstoniaEstonia Republic of KoreaRepublic of Korea Russian Russian FederationFederation

UruguayUruguay

Top 10 Enrolling Countries-1Top 10 Enrolling Countries-1

Country Lead 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

Top 10 Enrolling Countries-2Top 10 Enrolling Countries-2

Country Lead Inv # Subjects

6. Ukraine

7. India

8. Netherlands

9. Great Britain

10. Italy

Parkhomenko

SomaRaju

Molhoek

Jacob

Ardissino

790

753

645

639

626

Other Countries-through 48Other Countries-through 48

Country Lead 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

Baseline CharacteristicsBaseline Characteristics ITT ITT N = 20,479N = 20,479

4444

1313

1515

4747

1818

4444

7777

5959

Prior MI (%)Prior MI (%)

Hypertension (%)Hypertension (%)

Hyperlipidemia (%)Hyperlipidemia (%)

Current smoker (%)Current smoker (%)

Diabetes (%)Diabetes (%)

Anterior MI (%)Anterior MI (%)

Male (%)Male (%)

Age (yrs)-medianAge (yrs)-median

ALL P = NSALL P = NS

3636

6464

8989

0.50.5

1616

8282

> 3 (%)> 3 (%)

LMWH within 7 d (%)LMWH within 7 d (%)

Killip Class I (%)Killip Class I (%)

TIMI Risk Score (STEMI)TIMI Risk Score (STEMI)

<< 3 (%) 3 (%)

UFH within 3 h (%)UFH within 3 h (%)

CrCl (ml/min)-medianCrCl (ml/min)-median

N Engl J Med 2006;354:1477-88.

MedicationsMedications ITT ITT N = 20,479N = 20,479

808086869595

8080

2020

ACEI / ARB (%)ACEI / ARB (%)

Fibrin-specific (%)Fibrin-specific (%)

ASA (%)ASA (%)

Beta Blocker (%)Beta Blocker (%)

SK (%)SK (%)FibrinolyticFibrinolytic

7070Statin (%)Statin (%)

ALL P = NSALL P = NS

N Engl J Med 2006;354:1477-88.

Main ResultsMain 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, 2006NEJM 354:1477, 2006

1.4

0.40.7

2.1

0.8 0.8

0

1

2

3

4

5

% E

ven

ts%

Eve

nts

Major BleedMajor Bleed(Total)(Total)

ICH ICH

ARD 0.7%ARD 0.7%RR 1.53RR 1.53

P<0.0001P<0.0001

ARD 0.1%ARD 0.1%RR 1.27RR 1.27P = 0.14 P = 0.14

ARD 0.4%ARD 0.4%RR 1.84RR 1.84

P = 0.001P = 0.001

FatalFatalMajor BleedMajor Bleed

Bleeding by 30 daysBleeding by 30 days

ARD = 0.021 = 2.1 %ARD = 0.021 = 2.1 %RR = 0.83 (0.77 to 0.90)RR = 0.83 (0.77 to 0.90)

RRR = 0.17 (0.23 to 0.10)RRR = 0.17 (0.23 to 0.10)NNT = 48NNT = 48

Revised Pkg Insert for EnoxaparinRevised Pkg Insert for Enoxaparin

Death or Reinfarction Death or Reinfarction Across the ACS SpectrumAcross the ACS Spectrum

0.78 (0.63,0.98)

Odds ratioFavors Enox Favors UFH

.2 1 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 (%)

7.7 9.6

8.0 8.0

20.8 30.5

4.4 15.9

10.3 11.4

9.9 12.0

5.8 7.5

7.4 8.3

7.9 8.1

5.0 9.0

7.4 7.8

13.9 14.5

STEMI (p=0.002)

NSTEACS (p=0.043)

0.78 (0.67,0.91) 9.6 11.7

0.90 (0.81,0.996) 10.0 11.0

Eur Heart J. 2007;28:2077-86.

Major Bleeding Across Major Bleeding Across the ACS Spectrumthe ACS Spectrum

.21

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 ratioFavors Enox Favors UFH

STEMI (p<0.001)

NSTEACS (p=0.42)

Enox (%) UFH (%)

3.8 3.0

3.6 3.0

3.4 4.0

1.9 2.4

6.2 3.8

2.1 1.4

1.45 (1.23,1.72) 2.6 1.8

1.13 (0.84,1.54) 6.3 5.4

p = 0.019

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%

Eur Heart J. 2007;28:2077-86.

STEMI Treatments & Outcomes WorldwideSTEMI Treatments & Outcomes Worldwide::Results from the Results from the EEnonoxxaparin and aparin and TThrombolysis hrombolysis RReperfusion for eperfusion for AAcute Myocardial Infarcute Myocardial Infarctction - ion -

TThrombolysis hrombolysis IIn n MMyocardial yocardial IInfarction nfarction (ExTRACT-TIMI) 25 Registry(ExTRACT-TIMI) 25 Registry

Benjamin A. SteinbergBenjamin A. Steinberg, Elliott M. Antman, Nazanin Moghbeli, , Elliott M. Antman, Nazanin Moghbeli, Jacqueline Buros, Sabina A. Murphy, Carolyn H. McCabe,Jacqueline Buros, Sabina A. Murphy, Carolyn H. McCabe,C. Michael Gibson, David A. Morrow, Eugene BraunwaldC. Michael Gibson, David A. Morrow, Eugene Braunwald

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.

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?

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

ExTRACT-TIMI 25 ProgramExTRACT-TIMI 25 Program

STEMISTEMI

Entered inExTRACT-TIMI 25 Registry

Randomized inExTRACT-TIMI 25 Trial

Major In-Hospital Outcomes:Major In-Hospital Outcomes:

11°: °: Death At Discharge or Day 8Death At Discharge or Day 8

ExTRACT-TIMI 25 Chronology

ExTRACT-TIMI 25 Trial

ExTRACT-TIMI 25 Registry

April 1, 2005

October, 2002

October 31, 2005

January 24 ,2006

Registry Enrollment n=0 n=3,098 n=3,726

Countries

Sites

Population Samples

Patients

Trial Registry

3,726

25

109

20,479

674

48

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

(Intention-to-Treat)

Baseline CharacteristicsTrial – All

(n = 20,479)

%

Trial – Registry Sites

(n = 7,819)%

Registry

(n = 3,726)

%

p

(registry sites)

Age – yr (median) 59 60 63 <0.001

Female 23 25 28 0.003

Hypertension 44 50 58 <0.001

Hyperlipidemia 18 16 34 <0.001

Current Smoker 47 47 40 <0.001

Diabetes 15 13 21 <0.001

Prior MI 13 15 17 0.04

Prior angina pectoris 28 34 36 0.07

Prior PCI 3.2 1.8 3.8 <0.001

Prior CABG 1.3 0.7 1.4 <0.001

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

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

Baseline Characteristics Cont.Trial – All

(n = 20,479)

%

Trial – Registry Sites

(n = 7,819)%

Registry

(n = 3,726)

%

p

(registry sites)

Anterior MI 44 47 45 0.02

Chronic ASA 13 12 18 <0.001

Creat. clearance – ml/min (median)

82 82 73 <0.001

Killip II-IV 11 13 26 <0.001

Rx In-Hosp

Aspirin 94 94 95 0.005

Beta-blockers 81 82 78 <0.001

ACEIs or ARBs 74 75 76 0.70

Statin 64 51 76 <0.001

Trial – All

(n = 20,479)

%

Trial – Registry Sites

(n = 7,819)%

Registry

(n = 3,726)

%

p

(registry sites)

Reperfusion Therapy

Fibrinolysis

Fibrin-specific 80 86 61}<0.001

Streptokinase 20 14 36

Fibrinolysis Only 86 94 80}<0.001

LyticPCI 14 6 20

Primary PCI - - 26

No Reperfusion 0.2 0.2 29 <0.001

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

STEMI Management

In-Hospital Mortality

5.7%6.6%

8.5%

0%

5%

10%

Death

Trial - All (n=20,479) Trial Registry Sites (n=7,819) Registry (n=3,726)

UnadjustedMortality

P<0.001 HR = 1.35

TIMI Risk Index (TRI)

0%

20%

40%

60%

0 to <10 10 to <20 20 to <30 30 to <40 40 to <50 50 to <60 60 to <70 70 to <80 >80

NRMI STEMI (n=153,679)

In-H

osp

ital

Mo

rtal

ity

In-H

osp

ital

Mo

rtal

ity

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

TIMI Risk Index (TRI) Profile

10%

15%

20%

25%

30%

<=12.5 12.5-17.5 17.5-22.5 22.5-30 >30

Trial - All (n=20,474) Trial - Registry Sites (n=7,819) Registry (n=3,520)

% P

atie

nt

Po

pu

lati

on

% P

atie

nt

Po

pu

lati

on

P<

0.00

1

HR (Age/10)2

SBP

In-Hospital Mortality by TIMI In-Hospital Mortality by TIMI Risk Index (TRI)Risk Index (TRI)

1% 2%2% 2%3% 3%

8%7%

19% 19%

0%

5%

10%

15%

20%

Trial - Registry Sites (n=7819) Registry (n=3520)

<=12.5 12.5-17.5 17.5-22.5 22.5-30 >30

Mo

rtal

ity

Mo

rtal

ity

P(trend)<0.001

p=0.92

P(trend)<0.001

Gross National IncomeGross 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.

Registry: TIMI Risk Index Profile By Registry: TIMI Risk Index Profile By Gross National IncomeGross National Income

0%

5%

10%

15%

20%

25%

30%

35%

<=12.5 12.5-17.5 17.5-22.5 22.5-30 >30

Low GNI (<$2900) Medium GNI ($2900-$9000) High GNI (>$9000)

% P

atie

nt

Po

pu

lati

on

% P

atie

nt

Po

pu

lati

on

TRITRI

Registry: Registry: Gross National Income (GNI) Gross National Income (GNI)

Corrected for TRICorrected for TRI

N=3268 HR for In-Hospital Death

P

TRI (per 10 unit increase)

1.18<0.00

1

GNI (log) 1.04 0.50

When adjusted for baseline risk, GNI does not When adjusted for baseline risk, GNI does not predict in-hospital mortality.predict in-hospital mortality.

Registry: Multivariate Analysis for In-Hospital Mortality

n=3501 HR for In-Hospital Deathp

TRI (per 10 unit increase) 1.11 <0.001

Any Reperfusion 0.74 0.02

ASA 0.69 0.04

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) 1.08 0.2

Risk of In-Hospital Mortality: Statistical Assessment

0

0.5

1

0 0.5 1

C statisticC statistic(AUC for ROC)(AUC for ROC)

c=0.77c=0.77

1 - Specificity1 - Specificity

SensitivitySensitivity

TRI + Therapy c=0.85TRI + Therapy c=0.85

TRITRI

Coin FlipCoin Flipc=0.5c=0.5

+GNI+GNIc=0.85c=0.85

Registry: Predictors of In-Registry: Predictors of In-Hospital MortalityHospital Mortality

Overall c=0.85

Baseline Risk (TRI)

Medical &Reperfusion

Therapy

GNI

LimitationsLimitations

• Registry population not perfect representation of ‘general’ STEMI population

• Reporting and survival biases

ConclusionsConclusions• 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.