Transcript Document

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
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):
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
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
Hamm Lancet 358:1533,2001
Presentation
Ischemic Discomfort
Working Dx
Acute Coronary Syndrome
Davies MJ
Heart 83:361, 2000
ECG
No ST Elevation
NSTEMI
Biochem.
Marker
Final Dx Unstable Angina
ST Elevation
Myocardial Infarction
NQMI
Qw MI
Reperfusion Strategies for STEMI
Pharmacologic
PCI
Widely Available
Limited Availability
Quickly Administered
Treatment Delay
Less Effective
More Effective
Bleeding Risk
Bleeding Risk Lower
Thrombosis of epicardial coronary artery……..
Thrombin
Fibrin
Lytic
Rx
Antithrombins
Flow
Antiplatelet Rx
……….the cause of STEMI
Pharmacologic Reperfusion for STEMI:
Components of Regimen
Fibrinolytic
Antiplatelet
Anticoagulant
SK
ASA
UFH
↓
↓
↓
Fibrinspecific
GPIIb/IIIa
Thienopyridine
Alternative
Agents
↓
Bolus
X
TF/VIIa
TFPI
Xa inhibitors
Xa LMWH
UFH
V, Ca2+
Prothrombin
Thrombin
Clopidogrel ASA
Platelet
GP IIb/IIIa
Inhibitor
LMWH
UFH
DTIs
Potential Advantages of Anticoagulation with
LMWH vs UFH
LMWH
Greater
UFH
Inhibit thrombus Less
generation
Route
SC
IV
No
Monitor A/C
Yes
No
Inhibition by
Platelets
Yes
Enoxaparin for STEMI
Adjunct to Lytic
No Lytic Rx
HART II
TETAMI
AMI SK
Baird et al
ASENOX
ENTIRE-TIMI 23
ASSENT 3
ASSENT 3-PLUS
ASSENT 3
Bleeding Stratified by Age
< 75 yrs
(N = 5328)
>75 yrs
(N = 767, 13%)
P <0.0001
% Pts
15
13.3
UFH
Abx
Enox
10
7.2
P =0.26
5
3.1
1.9
2.4
0.96 0.73 0.79
4.1
2.58
1.52
0.74
0
ICH
Major
Bleed
ICH
Major
Bleed
JACC 39: 306A, 2002
Am Heart J 2005;149:17-26.
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.
Protocol Design
Am Heart J 2005;149:17-26.
STEMI < 6 h
Lytic eligible
ASA
Lytic choice by MD
(TNK, tPA, rPA, SK)
Double-blind, double-dummy
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)
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
CrCl < 30: 1.0 mg / kg q 24 h
Day 30
1° Efficacy Endpoint: Death or Nonfatal MI
1° Safety Endpoint: TIMI Major Hemorrhage
Trial Features
• Central Randomization
Toll free phone
Stratified by center
• Double Blind
• Double Dummy
• Ratio 1:1 (Enox : UFH)
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
Study Medication Kits
Drug A
Drug B
32 single-use ampules (1 ml)
4 multi-use vials (10 ml)
A
A
A
A
A
A
B
A
A
A
A
A
B
B
B
A
Enox (100mg/ml) / Placebo
IV
SC
bolus # A Injections
UFH (5000 U/ml) / Placebo
IV
bolus # B
IV
Infusion
CBF Procedures
aPTT/ACT via Hemochron Jr.
CBF
Computer
7 digit code
Reported
Specimen Drawn
Local encrypted
measurement
(7 digit code)
True/Mock
Value Reported Back
UFH
Nomogram
Double Blind Dose
Adjustment
Enrollment: Oct 2002 - Oct 2005
N = 20,479 (ITT)
Argentina
Finland
Latvia
Singapore
Australia
France
Lebanon
Slovakia
Austria
Germany
Lithuania
South Africa
Belarus
Greece
Malaysia
Spain
Belgium
Hong Kong
Mexico
Sweden
Brazil
Hungary
Netherlands
Switzerland
Bulgaria
India
New Zealand
Thailand
Canada
Ireland
Norway
Turkey
Chile
Israel
Poland
Ukraine
China
Italy
Portugal
United Kingdom
Croatia
Jordan
Romania
United States
Estonia
Republic of Korea
Russian
Federation
Uruguay
48 Countries
674 Sites
Top 10 Enrolling Countries-1
Country
Lead Inv
# Subjects
1. Russia
Ruda
4,887
2. Poland
Sadowski/ Budaj
1,792
3. Spain
Lopez-Sendon
1,281
4. Turkey
Guneri
953
Hod
870
5. Israel
Top 10 Enrolling Countries-2
Country
Lead Inv
# Subjects
Parkhomenko
790
SomaRaju
753
8. Netherlands
Molhoek
645
9. Great Britain
Jacob
639
Ardissino
626
6. Ukraine
7. India
10. Italy
Other Countries-through 48
Country
36. Belarus
37. United States
38. Lithuania
39. Norway
40. Latvia
Lead Inv
# Subjects
Polonetsky
57
Antman
49
Sanofi-Aventis
46
Dickstein
43
Sanofi-Aventis
39
N Engl J Med 2006;354:1477-88.
Baseline Characteristics
ITT
N = 20,479
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
N Engl J Med 2006;354:1477-88.
Medications
ITT
N = 20,479
Fibrinolytic
SK (%)
Fibrin-specific (%)
20
80
ASA (%)
Beta Blocker (%)
ACEI / ARB (%)
Statin (%)
95
86
80
70
ALL P = NS
Main Results
NEJM 354:1477, 2006
Primary Endpoint:
Death or non-fatal re-MI by 30 days
12.0
5
9.9
4
ENOX
%
ARD = 0.021 = 2.1 %
RR = 0.83 (0.77 to 0.90)
RRR = 0.17 (0.23 to 0.10)
NNT = 48
% Events
UFH
Bleeding by 30 days
ARD 0.7%
RR 1.53
P<0.0001
33% RRR in reMI by 48 h (P=0.002)
19% RRR in Death/MI by 72 h (P<0.001)
ARD 0.1%
RR 1.27
P = 0.14
3
2.1
2
1.4
0.8
1
0.4
0
Days
ARD 0.4%
RR 1.84
P = 0.001
Major Bleed
(Total)
Fatal
Major Bleed
0.7 0.8
ICH
Revised Pkg Insert for Enoxaparin
Eur Heart J. 2007;28:2077-86.
Death or Reinfarction
Across the ACS Spectrum
Odds ratio
(95% CI)
Enox (%)
UFH (%)
ASSENT 3
0.78 (0.63,0.98)
7.7
9.6
HART II
1.00 (0.49,2.06)
8.0
8.0
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
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
0.90 (0.81,0.996)
10.0
11.0
9.8%
11.4%
STEMI (p=0.002)
NSTEACS
(p=0.043)
0.84 (0.76,0.92)
TOTAL
.2
1
Favors Enox Odds ratio Favors UFH
5
p < 0.001
Eur Heart J. 2007;28:2077-86.
Major Bleeding Across
the ACS Spectrum
Odds ratio
(95% CI)
Enox (%) UFH (%)
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
1.45 (1.23,1.72)
2.6
1.8
ESSENCE
0.93 (0.70,1.23)
6.5
6.9
TIMI 11B
1.56 (1.13,2.14)
5.2
3.4
ACUTE II
0.33 (0.03,3.68)
0.3
1.0
INTERACT
0.58 (0.33,1.03)
5.3
8.7
A TO Z
3.78 (1.25,11.41)
0.8
0.2
SYNERGY
1.21 (1.05,1.40)
9.1
7.6
1.13 (0.84,1.54)
6.3
5.4
STEMI (p<0.001)
NSTEACS
(p=0.42)
TOTAL
1.25 (1.04,1.50) 4.3%
1
.2
Odds ratio
Favors Enox
5
Favors UFH
3.4%
p = 0.019
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
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 Program
STEMI
Randomized in
ExTRACT-TIMI 25 Trial
Entered in
ExTRACT-TIMI 25 Registry
Major In-Hospital Outcomes:
1°: Death At Discharge or Day 8
ExTRACT-TIMI 25 Chronology
October 31, 2005
ExTRACT-TIMI 25 Trial
January 24 ,2006
October, 2002
ExTRACT-TIMI 25 Registry
April 1, 2005
Registry Enrollment n=0
n=3,098
n=3,726
Population Samples
Trial
Registry
3,726
Patients
20,479
(Intention-to-Treat)
109
Sites
674
25
Countries
48
Antman, et al. NEJM 2006;354:1477-88.
Baseline Characteristics
Trial – All
(n = 20,479)
Registry
(n = 3,726)
%
Trial –
Registry Sites
(n = 7,819)
%
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
p
(registry sites)
%
Antman, et al. NEJM 2006;354:1477-88.
Baseline Characteristics Cont.
Trial – All
(n = 20,479)
Registry
(n = 3,726)
%
Trial –
Registry Sites
(n = 7,819)
%
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
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
p
(registry sites)
%
Rx In-Hosp
Antman, et al. NEJM 2006;354:1477-88.
STEMI Management
Trial – All
(n = 20,479)
Registry
(n = 3,726)
%
Trial –
Registry Sites
(n = 7,819)
%
Fibrin-specific
80
86
61
Streptokinase
20
14
36
Fibrinolysis Only
86
94
80
LyticPCI
14
6
20
Primary PCI
-
-
26
No Reperfusion
0.2
0.2
29
%
p
(registry
sites)
Reperfusion Therapy
Fibrinolysis
}<0.001
}<0.001
<0.001
Antman, et al. NEJM 2006;354:1477-88.
In-Hospital Mortality
Trial - All (n=20,479)
Trial Registry Sites (n=7,819)
P<0.001
HR = 1.35
10%
8.5%
Unadjusted
Mortality
6.6%
5.7%
5%
0%
Death
Registry (n=3,726)
TIMI Risk Index (TRI)
In-Hospital Mortality
60%
40%
HR  (Age/10)2
SBP
NRMI STEMI (n=153,679)
P(trend)<0.001
20%
0%
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
TRI
Morrow, et al. Lancet. 2001;358:1571-5.
Wiviott, et al. JACC. 2004;44:783-9.
TIMI Risk Index (TRI) Profile
T rial - All (n=20,474)
T rial - Registry Sites (n=7,819)
Registry (n=3,520)
P<0.001
% Patient Population
30%
25%
20%
15%
10%
<=12.5
12.5-17.5
17.5-22.5
HR  (Age/10)2
SBP
22.5-30
>30
In-Hospital Mortality by TIMI
Risk Index (TRI)
<=12.5
12.5-17.5
22.5-30
>30
19%
20%
Mortality
17.5-22.5
p=0.92
19%
15%
8%
10%
5%
1%
2% 3%
7%
2% 2% 3%
0%
T rial - Registry Sites (n=7819)
P(trend)<0.001
Registry (n=3520)
P(trend)<0.001
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.
Registry: TIMI Risk Index Profile By
Gross National Income
Low GNI (<$2900)
Medium GNI ($2900-$9000)
High GNI (>$9000)
% Patient Population
35%
30%
25%
20%
15%
10%
5%
0%
<=12.5
12.5-17.5
17.5-22.5
TRI
22.5-30
>30
Registry:
Gross National Income (GNI)
Corrected for TRI
N=3268
TRI (per 10 unit
increase)
GNI (log)
HR for In-Hospital
Death
1.18
1.04
P
<0.00
1
0.50
When adjusted for baseline risk, GNI does not
predict in-hospital mortality.
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
0.74
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
+GNI
c=0.85
1
TRI + Therapy c=0.85
TRI
c=0.77
Sensitivity
Coin Flip
c=0.5
0.5
C statistic
(AUC for ROC)
0
0
0.5
1 - Specificity
1
Registry: Predictors of InHospital Mortality
GNI
Medical &
Reperfusion
Therapy
Overall c=0.85
Baseline Risk (TRI)
Limitations
• Registry population not perfect
representation of ‘general’ STEMI
population
• Reporting and survival biases
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 inhospital treatments, GNI does not predict inhospital mortality after STEMI.