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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.