An International Randomized Trial of Early Versus Delayed Invasive Strategies in Patients with...

An International Randomized Trial of Early Versus Delayed

Invasive Strategies in Patients with Non-ST Segment Elevation

Acute Coronary Syndromes

TIMACS Timing of Intervention in patients with Acute Coronary Syndromes

Funded by Canadian Institutes of Health ResearchFunded by Canadian Institutes of Health ResearchAdditional support from GSK and Sanofi-AventisAdditional support from GSK and Sanofi-Aventis

Preliminary Results

TIMACSTIMACSTIMACSTIMACS

Preliminary Results as of Nov 7, 2008

BackgroundBackground

• 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



Early InvasiveEarly Invasive

Large Variations in Timing of Large Variations in Timing of Intervention in Current RCT’sIntervention in Current RCT’s

Delayed InvasiveDelayed Invasive

FRISCIIFRISCII RITA 3RITA 3 ICTUSICTUS TACTICSTACTICS

Sample SizeSample Size 24572457 18101810 12011201 22202220

Cath TimingCath Timing 96 h96 h 48 h48 h 19 h19 h 22 h22 h

PCI TimingPCI Timing 96 h96 h 72 h72 h 23 h23 h 24 h24 h

CABG TimingCABG Timing 7 d7 d 22 d22 d 9 d9 d 4 d4 d



Study ObjectiveStudy Objective

To determine whether early intervention is superior to delayed

intervention in patients with high risk non-ST segment elevation acute

coronary syndrome



Design, Eligibility Criteria and Design, Eligibility Criteria and ProtocolProtocol

UA or NSTEMI2 of 3 Criteria: Age > 60, ischemic ECG or biomarker

AND suitable for revascularization

RANDOMIZE*

Early Invasive

Coronary angio as soon as possible (<24 hours)

Delayed Invasive

Coronary angio >36 hrs

*Randomization ratio 1:1, 1:2 or 2:1

Follow-up up to 180 days



OutcomesOutcomes

Primary Primary

Composite of Death, new MI or Stroke at 180 daysComposite of Death, new MI or Stroke at 180 days

SecondarySecondary

Composite of: Composite of:

1.1. Death, new MI or refractory ischemiaDeath, new MI or refractory ischemia

2.2. Death, new MI, stroke, refractory ischemia or Death, new MI, stroke, refractory ischemia or repeat revascularizationrepeat revascularization

3.3. StrokeStroke



Study Flow ChartStudy Flow Chart

TIMACS Stand Alone

N=1,398

TIMACSTotal

N=3,031

TIMACS OASIS 5N=1,633 +

Follow-up >99.9%



Recommended Medical Recommended Medical TreatmentTreatment

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



Participating Participating CountriesCountries

North America 650

South America 442

Europe 1065

Asia 846

Australia 28


TIMACS Steering TIMACS Steering CommitteeCommittee

A. Avezum – A. Avezum – BrazilBrazil C. Morillo --C. Morillo -- Columbia Columbia

J-P. Bassand – J-P. Bassand – FranceFrance L. Piegas – L. Piegas – BrazilBrazil

W. Boden – W. Boden – USAUSA J. Probstfield – J. Probstfield – USAUSA

J. Col – J. Col – BelgiumBelgium S. Qiao -- S. Qiao -- ChinaChina

R. Diaz – R. Diaz – ArgentinaArgentina H-J Rupprecht – H-J Rupprecht – GermanyGermany

D. Faxon – D. Faxon – USAUSA P. G. Steg – P. G. Steg – FranceFrance

C. Granger – C. Granger – USAUSA P. Widimsky – P. Widimsky – Czech RepCzech Rep

C. Joyner --C. Joyner -- Canada Canada J. Varigos – J. Varigos – AustraliaAustralia

M. Kenda – M. Kenda – SloveniaSlovenia S. Yusuf -- S. Yusuf -- CanadaCanada

S. Mehta --S. Mehta -- Canada Canada J. Zhu – J. Zhu – ChinaChina

T. Moccetti – T. Moccetti – SwitzerlandSwitzerland



Study OrganizationStudy 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)



AnalysisAnalysis

Study Power:Study Power: 3000 patients 3000 patients

80% power to detect a RRR of 28%80% power to detect a RRR of 28%

Randomization:Randomization: Central 24 hour computer Central 24 hour computer randomizationrandomization

Analysis:Analysis: Intention to treat; Log rank Intention to treat; Log rank statisticstatistic

Follow-up:Follow-up: > 99% vital Status > 99% vital Status



Criteria for Crossover from Criteria for Crossover from Delayed Group to Early Delayed Group to Early GroupGroup

1.1. Refractory ischemiaRefractory ischemia

2.2. New MINew MI

3.3. Hemodynamic instabilityHemodynamic instability

Crossover from Early to DelayedCrossover from Early to Delayed: 11.9%: 11.9%

Crossover from Delayed to EarlyCrossover from Delayed to Early: 25% : 25%



Interventions and Interventions and TimingTiming

EarlyEarly

N=1,593N=1,593

DelayedDelayed

N=1,438N=1,438

Coronary Angiography (%)Coronary Angiography (%) 97.697.6 95.595.5

Median time (h Median time (h ± iqr± iqr)) 14 (3-21)14 (3-21) 50 (41-81)50 (41-81)

PCI (%)PCI (%) 59.659.6 55.055.0

Median time (h Median time (h ± iqr± iqr)) 16 (3-23)16 (3-23) 52 (41-101)52 (41-101)

CABG (%)CABG (%) 14.714.7 13.613.6

Median time (d Median time (d ± iqr± iqr)) 7.7 (4.7-17.4)7.7 (4.7-17.4) 10.8 (6.7-19.8)10.8 (6.7-19.8)

iqr=interquartile range



Baseline CharacteristicsBaseline Characteristics

EarlyEarly

N=1,593N=1,593

DelayedDelayed

N=1,438N=1,438

AgeAge 65.165.1 65.865.8

% Female% Female 34.834.8 34.734.7

DiabetesDiabetes 26.526.5 27.327.3

Prior MIPrior MI 19.719.7 20.920.9

Prior PCIPrior PCI 13.813.8 14.114.1

Prior CABGPrior CABG 7.07.0 7.37.3

Prior StrokePrior Stroke 7.27.2 7.57.5

Ischemic ECGIschemic ECG 80.580.5 79.979.9

Elevated BiomarkerElevated Biomarker 77.277.2 76.976.9



In-Hospital MedicationsIn-Hospital MedicationsEarlyEarly

N=1,593N=1,593

DelayedDelayed

N=1,438N=1,438

ASAASA 98.098.0 98.198.1

ThienopyridineThienopyridine 87.287.2 86.786.7

Thienopyridine or GP IIb/IIIa Thienopyridine or GP IIb/IIIa inhibitorinhibitor

88.288.2 88.488.4

GP IIb/IIIa InhibitorGP IIb/IIIa Inhibitor 23.223.2 22.522.5

AnticoagulantAnticoagulant 97%97% 97%97%

UFHUFH 24.624.6 24.624.6

LMWHLMWH 64.064.0 64.664.6

FondaparinuxFondaparinux 41.941.9 41.341.3

BivalirudinBivalirudin 0.50.5 0.40.4

Beta BlockerBeta Blocker 86.886.8 86.986.9

StatinStatin 85.085.0 84.384.3


Primary and Secondary Primary and Secondary OutcomesOutcomes

EarlyEarlyN=1,593N=1,593

DelayedDelayedN=1,438N=1,438

HR HR 95% CI95% CI PP

Death, MI, Stroke 9.79.7 11.411.4 0.850.85 0.68-1.060.68-1.06 0.150.15

Death, MI, refractory ischemia

9.69.6 13.113.1 0.720.72 0.58-0.890.58-0.89 0.0020.002

Death, MI, Stroke, refractory ischemia + repeat intervention

16.716.7 19.719.7 0.840.84 0.71-0.990.71-0.99 0.0390.039

Death 4.94.9 6.06.0 0.810.81 0.60-1.110.60-1.11 0.190.19

MI 4.84.8 5.85.8 0.830.83 0.61-1.140.61-1.14 0.250.25

Stroke 1.31.3 1.41.4 0.900.90 0.48-1.680.48-1.68 0.740.74

Ref. Ischemia 1.01.0 3.33.3 0.300.30 0.17-0.530.17-0.53 <0.00001<0.00001

Rep. Intervention* 8.88.8 8.68.6 1.041.04 0.82-1.340.82-1.34 0.730.73

*At 30 days: 5.9% vs 4.2%, HR 1.39, 95% CI 1.00-1.95, P=0.047



Primary OutcomePrimary OutcomeDeath, MI, or StrokeDeath, MI, or Stroke

Days

Cum

ula

tive

Haz

ard

0.0

0.02

0.06

0.10

0 30 60 90 120 150 180

Death/MI/Stroke at 180 days

Early

No. at Risk

Delayed

Early

1438 1328 1269 1254 1234 1229 1211

1593 1484 1413 1398 1391 1382 1363

Delayed

HR 0.8595% CI 0.68-1.06

P= 0.15



Secondary OutcomeSecondary OutcomeDeath, MI, or Refractory IschemiaDeath, MI, or Refractory Ischemia

Days

Cum

ulat

ive

Haz

ard

0.0

0.04

0.08

0.12

0 30 60 90 120 150 180

Death/MI/RI at 180 days

Delayed

Early

No. at Risk

Delayed

Early

1438 1303 1243 1230 1209 1205 1187

1593 1485 1417 1402 1394 1386 1366

HR 0.7295% CI 0.58-0.79

P=0.002



Secondary OutcomeSecondary OutcomeDeath, MI, Stroke, RFIDeath, MI, Stroke, RFI or or Rep InterventionRep Intervention

Death/MI/RI/Stroke/Rep Intervention at 180 days

Days

Cu

mu

lativ

e H

aza

rd

0.0

0.05

0.10

0.15

0.20

0 30 60 90 120 150 180

Delayed

Early

No. at Risk

Delayed

Early

1438 1250 1166 1150 1128 1118 1097

1593 1400 1321 1304 1287 1276 1256

HR 0.8495% CI 0.71-0.99

P=0.039



Safety OutcomesSafety Outcomes

EarlyEarlyN=1,593N=1,593

DelayedDelayedN=1,438N=1,438

HR HR CICI PP

Major Bleed during initial hospitalization

3.1 3.5 0.88 0.60-1.31 0.53

ICH 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

TIMACSTIMACSTIMACSTIMACS Pre-specified SubgroupsPre-specified Subgroups

Overall

Age < 65>=65

FemaleMale

No ST deviationST deviation

No elevated marker

Elevated marker

GRACE 0-140GRACE >=141

3031

12931736

10521976

15231508

668

2363

2070961

9.7

6.512.3

9.79.8

7.611.7

10.5

9.5

7.714.1

0.463

0.540

0.722

0.423

0.0097

0.85 ( 0.68 - 1.06 )

0.98 ( 0.64 - 1.52 )0.83 ( 0.64 - 1.07 )

0.77 ( 0.54 - 1.12 )0.89 ( 0.68 - 1.18 )

0.88 ( 0.62 - 1.26 )0.81 ( 0.61 - 1.07 )

1.00 ( 0.62 - 1.60 )

0.81 ( 0.63 - 1.04 )

1.14 ( 0.82 - 1.58 )

0.65 ( 0.48 - 0.88 )

NCharacteristic HR (95% CI) Interaction p-Value

0.33 0.5 0.7 1.00 1.5 2.0 3.0Early better Delayed better

Hazard Ratio (95% CI)

Early%

11.4

6.514.8

12.310.9

8.714.3

10.5

11.7

6.721.6

Delayed%



ConclusionsConclusions

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.



ImplicationsImplications

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.

An International Randomized Trial of Early Versus Delayed Invasive Strategies in Patients with...

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