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UFH is Superior to Placebo for Reducing Mortality and Reinfarction in MI Pts. Routine ASA 68,000 Pts 93% Lysis Rx. Effect / 1,000 Pts Rx’d. P = 0.03 0.04 0.4 0.01 < 0.001. Collins R, et al. N Engl J Med . 1997;336:847.

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ufh is superior to placebo for reducing mortality and reinfarction in mi pts
UFH is Superior to Placebo for Reducing Mortality and Reinfarction in MI Pts

Routine ASA68,000 Pts93% Lysis Rx

Effect / 1,000 Pts Rx’d

P = 0.03 0.04 0.4 0.01 < 0.001

Collins R, et al. N Engl J Med. 1997;336:847.

lmwh is superior to placebo for reducing mortality and reinfarction in stemi
LMWH is Superior to Placebo for Reducing Mortality and Reinfarction in STEMI

RCTs Total Total Pts. Events

LMWH Placebo

3 16,167 387 ReMI 0.76 (0.62 – 0.93)

3 16,167 1,687 Death 0.86 (0.62 – 0.93)

0.5 1 2

Favors LMWH

Favors Control

OR

Eikelboom JW, et al. Circulation. 2005;112:3855.

e no x aparin and t hrombolysis r eperfusion for a cute myocardial infar ct ion extract timi 25

Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial InfarctionExTRACT-TIMI 25

ACC 2006

Atlanta, GA

Disclosure Statement: Dr. Antman received research grant support via the Brigham and Women’s Hospital from sanofi-aventis

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.

background
Background
  • Advantages of ENOX over UFH Greater anti Xa:anti IIa activity Reliable A/C without monitoring Convenient sc administration
  • Prior trials suggestENOX may be superior to UFH
  • Pharmacologic reperfusion remains the most common treatment for STEMIDefinitive evaluation of ENOX vs UFH needed
primary hypothesis
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.

trial organization
Trial Organization

TIMI Study Group

Eugene BraunwaldElliott M. Antman

David A. Morrow Carolyn H. McCabe

Sabina Murphy Susan McHale

Sponsor: sanofi-aventis

Frank Jiang Christophe Gaudin

Paul Chew Sylvie Fontecave Lu Cui Kim Giordano

Data Safety Monitoring Board

Frans Van de Werf (chair) David DeMets

Desmond Julian Jean Rouleau

J. Ward Kennedy Jeffrey Anderson

protocol design
Protocol Design

STEMI < 6 hLytic eligible

Lytic choice by MD(TNK, tPA, rPA, SK)

ASA

Double-blind, double-dummy

ENOX

< 75 y: 30 mg IV bolus SC 1.0 mg / kg q 12 h (Hosp DC)

≥ 75 y: No bolusSC 0.75 mg / kg q 12 h (Hosp DC)

CrCl < 30: 1.0 mg / kg q 24h

UFH60 U / kg bolus (4000 U) Inf 12 U / kg / h (1000 U / h)Duration: at least 48 hCont’d at MD discretion

Day 301° Efficacy Endpoint: Death or Nonfatal MI1° Safety Endpoint: TIMI Major Hemorrhage

baseline characteristics 1
Baseline Characteristics-1

Characteristic

ENOX(n=10,256)

UFH(n=10,223)

Age (yrs)-median

59

59

Male (%)

77

77

Hypertension (%)

45

44

Hyperlipidemia (%)

18

18

Current smoker (%)

47

47

Diabetes (%)

15

15

Prior MI (%)

13

13

Anterior MI (%)

44

44

ALL P = NS

baseline characteristics 2
Baseline Characteristics-2

Characteristic

ENOX(n=10,256)

UFH(n=10,223)

CrCl (ml/min)-median

82

82

UFH within 3 h (%)

16

16

LMWH within 7 d (%)

0.4

0.5

Killip Class I (%)

89

89

TIMI Risk Score (STEMI)

< 3 (%)

64

64

> 3 (%)

36

36

ALL P = NS

medications
Medications

Characteristic

ENOX(n=10,256)

UFH(n=10,223)

Fibrinolytic

SK (%)

20

20

Fibrin-specific (%)

80

80

TNK (%)

19

19

tPA (%)

55

55

rPA (%)

6

6

ALL P = NS

medications1
Medications

Characteristic

ENOX(n=10,256)

UFH(n=10,223)

ASA (%)

95

95

Beta Blocker (%)

86

86

ACEI / ARB (%)

80

79

Statin (%)

70

70

ALL P = NS

primary end point itt death or nonfatal mi
Primary End Point (ITT)Death or Nonfatal MI

UFH

12.0%

17% RRR

9.9%

ENOX

Primary End Point (%)

Relative Risk0.83 (0.77 to 0.90)P<0.0001

Lost to follow up = 3

Days

treatment benefit over time itt death or nonfatal mi
Treatment Benefit over Time (ITT)Death or Nonfatal MI

48 h

UFH

12.0%(1223)

206 events

9.9%(1017)

ENOX

Primary End Point (%)

5.2%

4.7%

RR0.90 (0.80 to 1.01)P=0.08

UFH

ENOX

Days

major secondary end point death or nonfatal mi or urgent revascularization itt
Major Secondary End PointDeath or Nonfatal MI or Urgent Revascularization (ITT)

48 h

UFH

14.5% (1479)

280 events19% RRR

11.7% (1199)

ENOX

Secondary End Point (%)

RR 0.81 (0.75 to 0.87)P<0.0001

6.1%

5.3%

12% RRR

RR 0.88 (0.79 to 0.98)P=0.02

UFH

ENOX

Days

outcomes at 30 days itt

8%

33%

26%

Outcomes at 30 Days (ITT)

UFH

ENOX

%

RRP value

0.920.11

0.740.0008

0.67<0.0001

outcomes at 48 hours itt comparison of drugs

2%

33%

23%

Outcomes at 48 hours (ITT)Comparison of Drugs

UFH

ENOX

%

RRP value

0.980.76

0.770.086

0.670.002

death or nonfatal mi day 30 major subgroups
Death or Nonfatal MI - Day 30 Major Subgroups

Reduction In Risk (%)

18

Male

SEX

All Interaction TestsP = NS

16

Female

20

< 75

AGE (y)

6

>= 75

11

INFARCT

Anterior

LOCATION

23

Other

17

No DM

B

DIABETES

21

DM

17

No Prior MI

B

PRIOR MI

20

Prior MI

13

Streptokinase

FIBRINOLYTIC

18

Fibrin-specific

23

< Median

TIME TO Rx

12

> Median

B

17

P < 0.0001

20,479

OVERALL

0.5

1

2

Relative Risk

ENOX Better

UFH Better

death or nonfatal mi day 30 medical rx vs any pci
Death or Nonfatal MI - Day 30Medical Rx vs Any PCI

13.8

11.4

10.7RRR 23%

9.7RRR 16%

% Events

UFH

ENOX

Any PCI N = 4,676 (23%)

Medical Rx N = 15,223 (75%)

P Value

0.001

0.0004

death or nonfatal mi day 30 clopidogrel use
Death or Nonfatal MI - Day 30Clopidogrel Use

12.2

11.4

10.4

RRR15%

% Events

8.7

RRR24%

UFH

ENOX

No Clopidogrel N = 14,752 (78%)

Clopidogrel Used N = 5,727 (28%)

P Value

0.0005

0.0006

bleeding endpoints timi 30 days
Bleeding Endpoints (TIMI) 30 Days

UFH

ENOX

ARD 0.7%RR 1.53P<0.0001

ARD 0.4%RR 1.84P = 0.001

ARD 0.4%RR 1.39P = 0.014

ARD 0.1%RR 1.27P = 0.14

% Events

Major Bleed(Total)

FatalMajor Bleed

NonfatalMajor Bleed

ICH

net clinical benefit at 30 days
Net Clinical Benefit at 30 Days

Prespecified Definitions

UFH (%)

ENOX (%)

RRR (%)

Death or Nonfatal MI or Nonfatal Disabl. Stroke

10.1

18

12.3

P <0.0001

Death or Nonfatal MI or Nonfatal Major Bleed

11.0

14

12.8

P <0.0001

Death or Nonfatal MI or Nonfatal ICH

10.1

17

12.2

P <0.0001

0.8

0.9

1

1.25

ENOX Better

RR

UFH Better

for every 1000 pts treated with enoxaparin
For Every 1000 Pts Treated with Enoxaparin

+

(No increase in nonfatal ICH)

Events / 1000 Pts

Nonfatal reMI

Urgent Revasc.

Death

Nonfatal TIMI Major Bleed

major findings of extract timi 25
Major Findings of ExTRACT-TIMI 25
  • Superiority of Enoxaparin StrategySignificant reduction of ischemic events
  • Management of STEMIBeneficial across a wide range of subgroups Useful for medical Rx or PCI post lysis
  • Risks of EnoxaparinIncrease in major bleeding
  • Net Clinical Benefit (3 Prespecified Definitions) Significantly favors enoxaparin
potential explanations for trial results
Potential Explanations for Trial Results
  • Superior antithrombotic effect of ENOX
  • Longer duration of treatment with ENOX
  • Rebound increase in thrombotic events after discontinuingUFH
clinical implication
Clinical Implication

A strategy ofENOX is clearly preferable to the current standard of UFH as the antithrombin to support fibrinolysis, the most common form of reperfusion for STEMI used worldwide.

publication of primary results
Publication of Primary Results

www.NEJM.org

Slides and Full Listing of Trial Participants at www.TIMI.org

trial results in perspective major bleeding rates
Trial Results In Perspective: Major Bleeding Rates

Major Bleeds in Prior TrialsPooled Data

UFH

% Pts with Major Bleed

LMWH

UFH

ENOX

UFH

ENOX

UFH

KeeleyLancet 2003

EikelboomCirc. 2005

Major Bleed(Total)

NonfatalMajor Bleed

Lytic Arms

trial results in perspective pci vs lysis for stemi
Trial Results In Perspective:PCI vs Lysis for STEMI

Overview of 23 RCTs Keeley Lancet 2003

% Events(30-42 Days)

Lytic Arms (UFH)

PCI Arms

ENOX

Reinfarction

The significant advance in adjunctive therapy with enoxaparin has narrowed the gap between PCI and Lysis as reperfusion for STEMI.