Transcript CREATE - Hamilton Health Sciences

TIMACS
Timing of Intervention
in patients with
Acute Coronary Syndromes
An International Randomized Trial of Early
Versus Delayed Invasive Strategies in
Patients with Non-ST Segment Elevation
Acute Coronary Syndromes
Preliminary Results
Funded by Canadian Institutes of Health Research
Additional support from GSK and Sanofi-Aventis
TIMACS
Background
•
Randomized trials and meta-analyses
have demonstrated that an invasive
strategy is superior to a conservative
strategy in higher risk patients
•
The timing of intervention varied greatly
among the individual RCT’s
•
Few data exist on the optimal timing of
intervention in patients with ACS
Preliminary Results as of Nov 7, 2008
TIMACS
Large Variations in Timing of
Intervention in Current RCT’s
Delayed Invasive
Early Invasive
FRISCII
RITA 3
ICTUS
TACTICS
Sample Size
2457
1810
1201
2220
Cath Timing
96 h
48 h
19 h
22 h
PCI Timing
96 h
72 h
23 h
24 h
CABG Timing
7d
22 d
9d
4d
Preliminary Results as of Nov 7, 2008
TIMACS
Study Objective
To determine whether early
intervention is superior to delayed
intervention in patients with high risk
non-ST segment elevation acute
coronary syndrome
Preliminary Results as of Nov 7, 2008
TIMACS
Design, Eligibility Criteria and Protocol
UA or NSTEMI
2 of 3 Criteria: Age > 60, ischemic ECG or biomarker
AND suitable for revascularization
RANDOMIZE*
*Randomization ratio 1:1, 1:2 or 2:1
Early Invasive
Delayed Invasive
Coronary angio as soon as
possible (<24 hours)
Coronary angio
>36 hrs
Follow-up up to 180 days
Preliminary Results as of Nov 7, 2008
TIMACS
Outcomes
Primary
Composite of Death, new MI or Stroke at 180 days
Secondary
Composite of:
1.
Death, new MI or refractory ischemia
2.
Death, new MI, stroke, refractory ischemia or
repeat revascularization
3.
Stroke
Preliminary Results as of Nov 7, 2008
TIMACS
Study Flow Chart
TIMACS
OASIS 5
N=1,633
+
TIMACS
Stand Alone
N=1,398
TIMACS
Total
N=3,031
Follow-up >99.9%
Preliminary Results as of Nov 7, 2008
TIMACS
Recommended Medical Treatment
1. ASA, clopidogrel
2. GP IIb/IIIa inhibitor at discretion of attending physician
(especially if pt is not on a thienopyridine)
3. Antithrombin:
OASIS 5: Either fondaparinux or enoxaparin
TIMACS stand alone: UFH or LMWH or fondaparinux
or bivalirudin (investigator discretion)
4. Beta blocker
5. Statin
Preliminary Results as of Nov 7, 2008
TIMACS
Participating Countries
Europe 1065
North America 650
Asia 846
South America 442
Australia 28
Preliminary Results as of Nov 7, 2008
TIMACS
TIMACS Steering Committee
A. Avezum – Brazil
C. Morillo -- Columbia
J-P. Bassand – France
L. Piegas – Brazil
W. Boden – USA
J. Probstfield – USA
J. Col – Belgium
S. Qiao -- China
R. Diaz – Argentina
H-J Rupprecht – Germany
D. Faxon – USA
P. G. Steg – France
C. Granger – USA
P. Widimsky – Czech Rep
C. Joyner -- Canada
J. Varigos – Australia
M. Kenda – Slovenia
S. Yusuf -- Canada
S. Mehta -- Canada
J. Zhu – China
T. Moccetti – Switzerland
TIMACS
Study Organization
• Coordinating Center: PHRI, McMaster University
S. Mehta, S. Yusuf, S. Jolly, C. Horsman, S.
Chrolavicius, B. Meeks
• DSMB: P. Sleight (chair), J. Anderson, D. DeMets,
D. Johnstone, D. Holmes
• Adjudication Committee: C. Joyner (chair), M.
Rokoss (co-chair), M. Lawrence (coordinator)
Preliminary Results as of Nov 7, 2008
TIMACS
Analysis
Study Power: 3000 patients
80% power to detect a RRR of 28%
Randomization: Central 24 hour computer
randomization
Analysis: Intention to treat; Log rank
statistic
Follow-up: > 99% vital Status
Preliminary Results as of Nov 7, 2008
TIMACS
Criteria for Crossover from
Delayed Group to Early Group
1. Refractory ischemia
2. New MI
3. Hemodynamic instability
Crossover from Early to Delayed: 11.9%
Crossover from Delayed to Early: 25%
Preliminary Results as of Nov 7, 2008
TIMACS
Interventions and Timing
Coronary Angiography (%)
Early
N=1,593
97.6
Delayed
N=1,438
95.5
Median time (h ± iqr)
14 (3-21)
50 (41-81)
59.6
55.0
16 (3-23)
52 (41-101)
14.7
13.6
7.7 (4.7-17.4)
10.8 (6.7-19.8)
PCI (%)
Median time (h ± iqr)
CABG (%)
Median time (d ± iqr)
iqr=interquartile range
Preliminary Results as of Nov 7, 2008
TIMACS
Baseline Characteristics
Early
N=1,593
65.1
34.8
26.5
19.7
13.8
Delayed
N=1,438
65.8
34.7
27.3
20.9
14.1
7.0
7.3
Prior Stroke
Ischemic ECG
7.2
80.5
7.5
79.9
Elevated Biomarker
77.2
76.9
Age
% Female
Diabetes
Prior MI
Prior PCI
Prior CABG
Preliminary Results as of Nov 7, 2008
TIMACS
In-Hospital Medications
Early
N=1,593
98.0
87.2
Delayed
N=1,438
98.1
86.7
Thienopyridine or GP IIb/IIIa inhibitor
88.2
88.4
GP IIb/IIIa Inhibitor
Anticoagulant
UFH
23.2
97%
24.6
22.5
97%
24.6
LMWH
Fondaparinux
Bivalirudin
Beta Blocker
Statin
64.0
41.9
0.5
86.8
85.0
64.6
41.3
0.4
86.9
84.3
ASA
Thienopyridine
Preliminary Results as of Nov 7, 2008
TIMACS
Primary and Secondary Outcomes
Early
Delayed
N=1,593
N=1,438
Death, MI, Stroke
9.7
Death, MI, refractory
ischemia
Death, MI, Stroke,
refractory ischemia +
repeat intervention
Death
HR
95% CI
P
11.4
0.85
0.68-1.06
0.15
9.6
13.1
0.72
0.58-0.89
0.002
16.7
19.7
0.84
0.71-0.99
0.039
4.9
6.0
0.81
0.60-1.11
0.19
MI
4.8
5.8
0.83
0.61-1.14
0.25
Stroke
1.3
1.4
0.90
0.48-1.68
0.74
Ref. Ischemia
1.0
3.3
0.30
0.17-0.53
<0.00001
Rep. Intervention*
8.8
8.6
1.04
0.82-1.34
0.73
*At 30 days: 5.9% vs 4.2%, HR 1.39, 95% CI 1.00-1.95, P=0.047
TIMACS
Primary Outcome
Death, MI, or Stroke
Death/MI/Stroke at 180 days
0.10
0.06
Early
HR 0.85
95% CI 0.68-1.06
P= 0.15
0.0 0.02
Cumulative Hazard
Delayed
0
30
60
Early
120
150
180
Days
No. at Risk
Delayed
90
1438
1328
1269
1254
1234
1229
1211
1593
1484
1413
1398
1391
1382
1363
Preliminary Results as of Nov 7, 2008
Secondary Outcome
Death, MI, or Refractory Ischemia
TIMACS
Death/MI/RI at 180 days
0.08
Early
0.04
HR 0.72
95% CI 0.58-0.79
P=0.002
0.0
Cumulative Hazard
0.12
Delayed
0
30
60
Early
120
150
180
Days
No. at Risk
Delayed
90
1438
1303
1243
1230
1209
1205
1187
1593
1485
1417
1402
1394
1386
1366
Preliminary Results as of Nov 7, 2008
Secondary Outcome
TIMACS
Death, MI, Stroke, RFI or Rep Intervention
Death/MI/RI/Stroke/Rep Intervention at 180 days
0.20
Delayed
0.15
0.10
0.05
HR 0.84
95% CI 0.71-0.99
P=0.039
0.0
Cumulative Hazard
Early
0
30
60
1438
1593
1250
1400
1166
1321
No. at Risk
Delayed
Early
90
Days
120
150
180
1150
1304
1128
1287
1118
1276
1097
1256
Preliminary Results as of Nov 7, 2008
TIMACS
Safety Outcomes
Early
Delayed
N=1,593
N=1,438
Major Bleed during
initial hospitalization
ICH
3.1
3.5
0
0.1
Surg Intervention
0.4
0.8
Retroperitoneal
0.1
0.2
↓ Hb >= 3 g/dL
2.3
2.6
Transfusion ≥ 2 U
2.2
2.9
HR
CI
P
0.88 0.60-1.31 0.53
Preliminary Results as of Nov 7, 2008
TIMACS
Pre-specified Subgroups
Characteristic
N
Early Delayed
%
%
HR (95% CI)
Interaction
p-Value
Overall
3031
9.7
11.4
0.85 ( 0.68 - 1.06 )
Age < 65
>=65
1293
1736
6.5
12.3
6.5
14.8
0.98 ( 0.64 - 1.52 )
0.83 ( 0.64 - 1.07 )
0.463
Female
Male
1052
1976
9.7
9.8
12.3
10.9
0.77 ( 0.54 - 1.12 )
0.89 ( 0.68 - 1.18 )
0.540
No ST deviation
ST deviation
1523
1508
7.6
11.7
8.7
14.3
0.88 ( 0.62 - 1.26 )
0.81 ( 0.61 - 1.07 )
0.722
No elevated marker 668
10.5
10.5
1.00 ( 0.62 - 1.60 )
Elevated marker
2363
9.5
11.7
0.81 ( 0.63 - 1.04 )
GRACE 0-140
GRACE >=141
2070
961
7.7
14.1
6.7
21.6
1.14 ( 0.82 - 1.58 )
0.65 ( 0.48 - 0.88 )
0.33 0.5 0.7 1.00 1.5 2.0 3.0
Early better
Delayed better
Hazard Ratio (95% CI)
0.423
0.0097
TIMACS
Conclusions
1. Overall, we found no significant difference between an
early and a delayed invasive strategy for prevention of
death, MI or stroke (primary outcome).
2. In the subgroup at highest risk (GRACE score > 140),
an early invasive strategy appears to be superior to a
delayed invasive strategy for prevention of death, MI or
stroke.
3. The early invasive strategy had a large impact on
reducing the rate of refractory ischemia by 70%.
4. There were no significant differences in major bleeding
or other safety concerns between the two strategies.
Preliminary Results as of Nov 7, 2008
TIMACS
Implications
1. Most patients with ACS can be managed safely with
either an early or a delayed invasive strategy
2. In a subset of patients at highest risk (GRACE
score>140), early intervention appears to be superior
and these patients should be considered for early
cath
3. In all other patients, the decision regarding timing of
intervention can depend on other factors, such as
cath lab availability and economic considerations.
Preliminary Results as of Nov 7, 2008