1 ExTRACT-TIMI 25 : New Data Elliott M. Antman, MD This presentation reflects the views of the...
-
Upload
dora-osborne -
Category
Documents
-
view
216 -
download
0
Transcript of 1 ExTRACT-TIMI 25 : New Data Elliott M. Antman, MD This presentation reflects the views of the...
1
ExTRACT-TIMI 25ExTRACT-TIMI 25 : :
New DataNew Data
Elliott M. Antman, MDElliott M. Antman, MD
This presentation reflects the views of the presenter and does not necessarily reflect the views of the American College of Cardiology
Content Distributed by Cardiosource
2
DisclosureDisclosure
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. 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 from (in alphabetical order):through the Brigham & Women’s Hospital with funding from (in alphabetical order):
3
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
N Engl J Med 2006;354:1477-88.N Engl J Med 2006;354:1477-88.
4
Main ResultsMain Results
Primary Endpoint:Primary Endpoint:Death or non-fatal re-MI by 30 daysDeath or non-fatal re-MI by 30 days
Primary Endpoint:Primary Endpoint:Death or non-fatal re-MI by 30 daysDeath or non-fatal re-MI by 30 days
Main Secondary Endpoint:Main Secondary Endpoint:Death, non-fatal re-MI, urgent Death, non-fatal re-MI, urgent
revascularization by 30 daysrevascularization by 30 days
Main Secondary Endpoint:Main Secondary Endpoint:Death, non-fatal re-MI, urgent Death, non-fatal re-MI, urgent
revascularization by 30 daysrevascularization by 30 days
12.0
9.9
UFH UFH
ENOX ENOX
14.5
11.7
Days Days
%% RR = 0.83p = 0.000003
RR = 0.81p = 0.000001
N Engl J Med 2006;354:1477-88.N Engl J Med 2006;354:1477-88.
33% RRR in reMI by 48 h (P=0.002)33% RRR in reMI by 48 h (P=0.002)19% RRR in Death/MI by 72 h (P<0.001)19% RRR in Death/MI by 72 h (P<0.001)33% RRR in reMI by 48 h (P=0.002)33% RRR in reMI by 48 h (P=0.002)19% RRR in Death/MI by 72 h (P<0.001)19% RRR in Death/MI by 72 h (P<0.001)
12% RRR in by 48 h (P=0.02)12% RRR in by 48 h (P=0.02)12% RRR in by 48 h (P=0.02)12% RRR in by 48 h (P=0.02)
5
Death or Nonfatal MIDeath or Nonfatal MITreatment Effect Over TimeTreatment Effect Over Time
8
7
6
5
4
3
2
1
0.5 1 2
UFHUFH (%)(%)
ENOXENOX (%) (%)
RRRRRR (%) (%)
4.14.1 3.63.6 1111
ARDARD(%)(%)
0.50.5
NNTNNT
200200
5.25.2 4.74.7 1010 0.50.5 200200
6.76.7 5.45.4 1919 1.31.3 7777
7.57.5 5.95.9 2222 1.61.6 6363
8.28.2 6.46.4 2222 1.81.8 5656
8.78.7 6.86.8 2222 1.91.9 5353
9.29.2 7.17.1 2222 2.12.1 4848
9.39.3 7.27.2 2323 2.12.1 4848
Days From Rand.
RRRRENOX BetterENOX Better UFH BetterUFH Better
P<0.001P<0.001
6
Bleeding Endpoints (TIMI) Bleeding Endpoints (TIMI) 30 Days30 Days
1.4
0.40.9 0.7
2.1
0.81.3
0.8
0
1
2
3
4
5 UFHUFHENOXENOX
%
% E
ven
tsE
ven
ts
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 1.27
P = 0.14P = 0.14
NonfatalNonfatalMajor BleedMajor Bleed
ARD 0.4%ARD 0.4%RR 1.39RR 1.39
P = 0.014P = 0.014
ARD 0.4%ARD 0.4%RR 1.84RR 1.84
P = 0.001P = 0.001
FatalFatalMajor BleedMajor Bleed
N Engl J Med 2006;354:1477-88.N Engl J Med 2006;354:1477-88.
7
Net Clinical BenefitNet Clinical Benefit at 30 Days at 30 Days
11 1.251.250.90.90.80.8
Death or Nonfatal MI or Death or Nonfatal MI or Nonfatal ICHNonfatal ICH
Death or Nonfatal MI or Death or Nonfatal MI or Nonfatal Major BleedNonfatal Major Bleed
Death or Nonfatal MI orDeath or Nonfatal MI or Nonfatal Disabl. Stroke Nonfatal Disabl. Stroke
ENOX BetterENOX Better UFH BetterUFH BetterRRRR
UFH (%) ENOX (%) RRR (%)
12.3 10.1 18
12.8 11.0 14
12.2 10.1 17
Prespecified DefinitionsPrespecified Definitions
P <0.0001
P <0.0001
P <0.0001
N Engl J Med 2006;354:1477-88.N Engl J Med 2006;354:1477-88.
8
For Every 1000 Pts For Every 1000 Pts Treated with EnoxaparinTreated with Enoxaparin
-15
-7 -6
4
-20
-15
-10
-5
0
5
Eve
nts
/ 1
000
Pts
Eve
nts
/ 1
000
Pts
Nonfatal Nonfatal reMIreMI
UrgentUrgent Revasc. Revasc.
DeathDeath Nonfatal TIMI Nonfatal TIMI Major BleedMajor Bleed
(No increase in (No increase in nonfatal ICH)nonfatal ICH)
++
N Engl J Med 2006;354:1477-88.N Engl J Med 2006;354:1477-88.
9
For Every 1000 Pts For Every 1000 Pts Treated with EnoxaparinTreated with Enoxaparin
Age < 75 vs Age < 75 vs >> 75 75
-15
-7-5
4
-12
-7
-3
2
-20
-15
-10
-5
0
5 < 75>=75
Nonfatal Nonfatal reMIreMI
Nonfatal UrgentNonfatal Urgent Revasc. Revasc.
DeathDeath Nonfatal TIMI Nonfatal TIMI Major BleedMajor Bleed
Eve
nts
/ 1
000
Pts
Eve
nts
/ 1
000
Pts
AHA 2006AHA 2006
10
For Every 1000 Pts For Every 1000 Pts Treated with EnoxaparinTreated with Enoxaparin
GenderGender
-16
-13
-8
5
-3
-15
-8
3
-20
-15
-10
-5
0
5
10 Women (N=4783) 23%
Men ( N= 15,696) 77%
Eve
nts
/ 1
000
Pts
Eve
nts
/ 1
000
Pts
DeathDeath NFMINFMI URUR Nonfatal TIMI Nonfatal TIMI Major BleedMajor Bleed
(No increase in (No increase in nonfatal ICH)nonfatal ICH)
11
For Every 1000 Pts For Every 1000 Pts Treated with EnoxaparinTreated with Enoxaparin
DiabetesDiabetes
-23
-12
-2
5
-3
-15
-8
3
-25
-20
-15
-10
-5
0
5
10 DMNoDM
Eve
nts
/ 1
000
Pts
Eve
nts
/ 1
000
Pts
DeathDeathp = 0.039p = 0.039p = 0.39p = 0.39
NFMINFMIp = 0.011p = 0.011
p < 0.0001p < 0.0001
URURp = 0.76p = 0.76
p = 0.0006p = 0.0006
Nonfatal TIMI Nonfatal TIMI Major BleedMajor Bleed
p = 0.21p = 0.21p = 0.04p = 0.04
(No increase in (No increase in nonfatal ICH)nonfatal ICH)
DMDMNo DMNo DM
AHA 2006AHA 2006
12
For Every 1000 Pts For Every 1000 Pts Treated with EnoxaparinTreated with Enoxaparin
Clopidogrel Use (No PCI)Clopidogrel Use (No PCI)
-21
-31
4
10
-35
-30
-25
-20
-15
-10
-5
0
5
10
15
No ClopidogrelNo Clopidogrel Clopidogrel UsedClopidogrel Used
Eve
nts
/ 1
000
Pts
Eve
nts
/ 1
000
Pts
Death, MI, Rec Isch, StrokeDeath, MI, Rec Isch, Stroke
Nonfatal Major BleedNonfatal Major Bleed
AHA 2006AHA 2006
13
Death or Nonfatal MI - Day 30 Death or Nonfatal MI - Day 30 Lytic AdministeredLytic Administered
0.5 1 2ENOX BetterENOX Better UFH BetterUFH Better
RRRR
UFH (%) ENOX (%) RRR (%)
SK (N=4139)SK (N=4139)
TNK (N=3986)TNK (N=3986)
rPA (N=1122)rPA (N=1122)
tPA (N=11,175)tPA (N=11,175)
11.8 10.2 13
11.5 9.4 18
11.4 8.4 27
12.2 10.1 17
Interaction TestsInteraction TestsP = NSP = NS
AHA 2006AHA 2006
14
Clinical ImplicationClinical Implication
A strategy ofA strategy of ENOXENOX is is clearly preferable to the clearly preferable to the current standard of current standard of UFHUFH as as the antithrombin to support the antithrombin to support fibrinolysis, the most fibrinolysis, the most common form of reperfusion common form of reperfusion for STEMI used worldwide.for STEMI used worldwide.