The Evolving Role of LMWH in ACS

The Evolving Role of

LMWH in ACS

The Evolving Role of

LMWH in ACS

James J. Ferguson, MD

Texas Heart InstituteHouston, TX

James J. Ferguson, MD

Texas Heart InstituteHouston, TX

2

ObjectivesObjectives

• Assist peers in overcoming gaps in awareness of LMWH therapy in ACS

• Review emerging data for ACS• NICE-3• GUSTO-IV

• Discuss strategies for increasing early administration of LMWH therapy

• Discuss future directions for LMWH therapy in ACS

• Assist peers in overcoming gaps in awareness of LMWH therapy in ACS

• Review emerging data for ACS• NICE-3• GUSTO-IV

• Discuss strategies for increasing early administration of LMWH therapy

• Discuss future directions for LMWH therapy in ACS

3

TIMI 11B-ESSENCE Meta-Analysis Death/MITIMI 11B-ESSENCE Meta-Analysis Death/MI

0.5 1 20.6 0.7 0.8 0.9

Odds RatioEnox Better UFH Better

DayOR p

N UFH(%)

Enox (%)

OVERALL

ESSENCE8

0.77(0.62-0.96)

23 0.027081

3910

3171

B

B

5.3 4.1

OVERALL

ESSENCE14

0.79(0.65-0.96)

21 0.027081

3910

3171 B

B

6.5 5.2

OVERALL

ESSENCE430.82

(0.69-0.98)18 0.027081

3910

3171 B

B

8.6 7.1

%TIMI 11B

TIMI 11B

TIMI 11B

4

The ESSENCE Trial: 1-YearTime to First Triple Endpoint

The ESSENCE Trial: 1-YearTime to First Triple Endpoint

0

5

10

15

20

25

30

35

40

0 2 4 6 8 10 12 14

Months

Cu

mu

lati

ve e

ve

nt

rate

(%

)

Heparin

Enoxaparin

5

ParadoxParadox

• We have data strongly supporting a better form of therapy

• We are still not using it widely

Why?

• We have data strongly supporting a better form of therapy

• We are still not using it widely

Why?

Unfractionated HeparinUnfractionated Heparin LMW HeparinLMW Heparin

IIaATIIaAT

XaAT XaAT

UpstreamUpstreamUpstreamUpstream

DownstreamDownstreamDownstreamDownstream

7

0.00.0

0.20.2

0.40.4

0.60.6

0.80.8

1.01.0

1.21.2

1.41.4

1.61.6

1.81.8

2.02.0

22 66 1010 1414 1818 2222 2626 3030 3434Time (h)Time (h)

An

ti-X

a a

cti

vit

y (

IU/m

l)A

nti

-Xa

ac

tiv

ity

(IU

/ml) 1.0 mg/kg1.0 mg/kg 1.25 mg/kg1.25 mg/kg

1.5 mg/kg1.5 mg/kg 2.0 mg/kg2.0 mg/kg

Plasma Anti-Xa Activity after Ascending Single Doses ofPlasma Anti-Xa Activity after Ascending Single Doses of Subcutaneous Enoxaparin in Healthy VolunteersSubcutaneous Enoxaparin in Healthy Volunteers

% P

ts

Hours from Randomization

0

1

2

3

4

5

6

7

8

9

0 8 16 24 32 40 48 56 64 72

UFHUFH

ENOXENOX

5.2 %5.2 %

4.2 %4.2 %

RRR 18%RRR 18%P=0.21P=0.21

% P

ts%

Pts

Hours from RandomizationHours from Randomization

00

11

22

33

44

55

66

77

88

99

00 88 1616 2424 3232 4040 4848 5656 6464 7272

7.3 %7.3 %

5.5 %5.5 %

RRR 24%RRR 24%P=0.03P=0.03

UFHUFH

ENOXENOX

ESSENCEESSENCE TIMI 11BTIMI 11B

Death/MI/Urgent RevascDeath/MI/Urgent RevascEarly Rx PhaseEarly Rx Phase

Early Benefit

AventisParsippany, NJ

9

TIMI 11BTriple Endpoint at Day 43

10

Discussion Discussion

• How are you currently using LMWHs?

• What are you using?• When are you using it?• Why? Why not?

• How are you currently using LMWHs?

• What are you using?• When are you using it?• Why? Why not?

11

CAPTURE

GUSTO IV†

PRISM

PRISM-Plus

PURSUIT

PARAGON

Trial (LMWH)

ESSENCE

TIMI 11B

TESSMA‡

Trial (IIb/IIIa) Placebo IIb/IIIa

1252

7800

3231

1570

10,948

2282

3171

3910

7,081

N

9.0

8.0

7.0

11.9

15.7

11.7

Heparin

7.7

8.3

8.6

4.8

~8.6

5.7

8.7

14.2

10.3

Enoxaparin

6.2

7.4

7.1

Better Worse0.1 1 10

Clinical Event Rates in Unstable Angina Trials

Death / MI at 30 days

Odds Ratio & 95% CI

N

† Preliminary results - placebo vs abciximab bolus plus 24 and 48 hr infusion‡ Meta-analysis of TIMI 11B and ESSENCE at Day 43

(%) (%)

NICE-3NICE-3NNational ational IInvestigators nvestigators CCollaborating on ollaborating on

EEnoxaparinnoxaparin

NICE-3NICE-3NNational ational IInvestigators nvestigators CCollaborating on ollaborating on

EEnoxaparinnoxaparin

XXIIXXIIndnd Congress of the European Congress of the European Society of CardiologySociety of Cardiology

August 30, 2000August 30, 2000

Amsterdam, The NetherlandsAmsterdam, The Netherlands

XXIIXXIIndnd Congress of the European Congress of the European Society of CardiologySociety of Cardiology

August 30, 2000August 30, 2000

Amsterdam, The NetherlandsAmsterdam, The Netherlands

13

NICE-3 ObjectivesNICE-3

Objectives

• To assess the safety profile (primarily with respect to bleeding) of enoxaparin and a IIb/IIIa antagonist (abciximab, eptifibatide or tirofiban) in patients with ACS

• To assess the feasibility and safety of bringing patients to the cath laboratory on combination therapy (without the use of UFH)

• To assess the safety profile (primarily with respect to bleeding) of enoxaparin and a IIb/IIIa antagonist (abciximab, eptifibatide or tirofiban) in patients with ACS

• To assess the feasibility and safety of bringing patients to the cath laboratory on combination therapy (without the use of UFH)

14

NICE-3 Inclusion Criteria

NICE-3 Inclusion Criteria

• Recent (w/in 24 hours) unprovoked or rest angina

• Documented ischemic CAD• ECG changes• Abnormal biomarkers• Previously documented CAD

• Patients on prior UFH could be included

• Recent (w/in 24 hours) unprovoked or rest angina

• Documented ischemic CAD• ECG changes• Abnormal biomarkers• Previously documented CAD

• Patients on prior UFH could be included

15

NICE-3 Exclusion Criteria

NICE-3 Exclusion Criteria

• Evolving Q-wave MI

• Fibrinolytic Rx w/in 48 hours

• Cardiogenic shock

• Left main disease

• Valvular disease

• CABG w/in 2 mos.; revasc w/in 1 week

• Thrombocytopenia

• Evolving Q-wave MI

• Fibrinolytic Rx w/in 48 hours

• Cardiogenic shock

• Left main disease

• Valvular disease

• CABG w/in 2 mos.; revasc w/in 1 week

• Thrombocytopenia

16

NICE-3ProtocolNICE-3Protocol

Study Study Initiated Initiated

January 2000January 2000

46 clinical sites 46 clinical sites in US/Canadain US/Canada

In-hospital, 14-day, In-hospital, 14-day, and 30-day follow-and 30-day follow-

upup

661 patients 661 patients enrolledenrolled

[Enoxaparin [Enoxaparin alone]alone]

(n=45)(n=45)

Data Data available available

August 2000August 2000

All IIb/IIIa patientsAll IIb/IIIa patients(n=616)(n=616)

Enrollment Enrollment Completed May Completed May

20002000

AbciximabAbciximab

(n=147)(n=147)

EptifibatideEptifibatide

(n=252)(n=252)

TirofibanTirofiban

(n=217)(n=217)

All treated All treated with with

EnoxaparinEnoxaparin

If patients went to the cath lab, combination Rx continued; no UF heparin

used

If within 8 hrs of last enoxaparin, no additional

Rx

If > 8 hrs from last dose, 0.3 mg/kg enoxaparin iv

17

NICE-3ProtocolNICE-3Protocol

• Primary Endpoint• Non-CABG major bleeding (TIMI

criteria) during hospitalization

• Secondary Endpoints• Minor bleeding (TIMI criteria)• Clinical efficacy

•Composite of death, MI, ischemia-driven TVR

• Primary Endpoint• Non-CABG major bleeding (TIMI

criteria) during hospitalization

• Secondary Endpoints• Minor bleeding (TIMI criteria)• Clinical efficacy

•Composite of death, MI, ischemia-driven TVR

18

NICE-3Sample Size

NICE-3Sample Size

• Primary Hypothesis

• The 95% CI for major bleeding will not exceed the historical rate

• Agents examined as a whole and separately

• Example (Assuming major bleed rate of 2%):

• A 200 patient sample size has a 95% CI of approx 0.1-3.9%

• A 150 patient sample size has a 95% CI of approx 0-4.2%

• Primary Hypothesis

• The 95% CI for major bleeding will not exceed the historical rate

• Agents examined as a whole and separately

• Example (Assuming major bleed rate of 2%):

• A 200 patient sample size has a 95% CI of approx 0.1-3.9%

• A 150 patient sample size has a 95% CI of approx 0-4.2%

19

NICE-3Demographics

NICE-3Demographics

AgeAge 62.9 62.9 12.2 years12.2 years

WeightWeight 83.9 83.9 18.5 kg18.5 kg

M/F M/F approx 2:1approx 2:1

LOSLOS 5.9 5.9 4.2 days 4.2 days

AgeAge 62.9 62.9 12.2 years12.2 years

WeightWeight 83.9 83.9 18.5 kg18.5 kg

M/F M/F approx 2:1approx 2:1

LOSLOS 5.9 5.9 4.2 days 4.2 days

HistoryHistory

HTNHTN 63.5%63.5% Prior PCIPrior PCI 30.7%30.7%

DMDM 30.0%30.0% Prior CABGPrior CABG 20.9%20.9%

SmokingSmoking 28.1%28.1% Prior MIPrior MI 36.2%36.2%

CHF (on admin) 4.5%CHF (on admin) 4.5%

20

NICE-3Bleeding (%)

NICE-3Bleeding (%)

AbciximabAbciximab

(n=147)(n=147)


(n=252)(n=252)

TirofibanTirofiban

(n=217)(n=217)

EnoxapariEnoxaparinn

[Enoxaparin [Enoxaparin alone]alone]

(n=45)(n=45)

All All IIb/IIIaIIb/IIIa

(n=616)(n=616)

AllAll 17.817.8

Major Major 6.76.7

non-CABGnon-CABG

4.4 4.4

MinorMinor 13.313.3

XfusionXfusion 8.98.9

AllAll 27.227.2

Major Major 5.15.1

non-CABGnon-CABG

1.4 1.4

MinorMinor 24.024.0


AllAll 30.630.6

Major Major 4.44.4

non-CABGnon-CABG

3.2 3.2

MinorMinor 27.227.2


AllAll 24.524.5

Major Major 4.14.1

non-CABGnon-CABG

0.70.7

MinorMinor 22.422.4


AllAll 27.9 27.9

Major Major 4.5 4.5

non-CABG 1.9non-CABG 1.9

MinorMinor 25.0 25.0

XfusionXfusion 10.5 10.5

21

NICE-3In-Hospital Clinical Outcomes

(%)

NICE-3In-Hospital Clinical Outcomes

(%)

AbciximabAbciximab

(n=147)(n=147)


(n=252)(n=252)

TirofibanTirofiban

(n=217)(n=217)

[Enoxaparin [Enoxaparin alone]alone](n=45)(n=45)

All IIb/IIIaAll IIb/IIIa

(n=616)(n=616)

DeathDeath 0 0

MI MI 2.2 2.2

uTVRuTVR 2.2 2.2

D/MI/uTVR 4.4D/MI/uTVR 4.4

D/MID/MI 2.2 2.2

DeathDeath 0.30.3

MI MI 3.43.4

uTVRuTVR 2.1 2.1


D/MID/MI 3.63.6

DeathDeath 0.5 0.5

MI MI 4.1 4.1

uTVRuTVR 3.2 3.2


D/MID/MI 4.6 4.6

DeathDeath 0.40.4

MI MI 3.23.2

uTVRuTVR 2.0 2.0


D/MID/MI 3.23.2

DeathDeath 0 0

MI MI 2.7 2.7

uTVRuTVR 0.7 0.7


D/MID/MI 2.7 2.7

EnoxapariEnoxaparinn

22

NICE-330% in Platelet Count

NICE-330% in Platelet Count

9.4

4.7

3.8

5.5

00

2

4

6

8

10

Abciximab Eptifibatide Tirofiban All I Ib/ I I Ia No I Ib/ I I Ia

9.4

4.7

3.8

5.5

00

2

4

6

8

10

Abciximab Eptifibatide Tirofiban All I Ib/ I I Ia No I Ib/ I I Ia

0<100K 0.85%<100K 1.44%<100K 0.86%<100K

(n=138)(n=138) (n=235)(n=235) (n=208)(n=208) (n=581)(n=581) (n=38)(n=38)

23

NICE-3All Major Bleeding (%)

NICE-3All Major Bleeding (%)

1

4.8

3.6

4.8

3.1

0.9

4.3

1.7

0

2

4

6

Abciximab Eptifibatide Tirofiban All IIb/IIIa

Patients undergoing PCIPatients undergoing PCI Patients not undergoing PCI or CABG

Patients not undergoing PCI or CABG

24

NICE-3PCI Patients (n=292)

NICE-3PCI Patients (n=292)

Tirofiban 0.9%

Eptifibatide2.4%

Abciximab 0

All IIb/IIIa1.0%

Tirofiban 0.9%

Eptifibatide2.4%

Abciximab 0

All IIb/IIIa1.0%

Non-CABG Major BleedingNon-CABG Major Bleeding

25

NICE-3Conclusions

NICE-3Conclusions

• Combination of enoxaparin and IIb/IIIa• Does not result in excess major bleeding • Events (non-CABG)

• Patients on combination Rx can safely undergo PCI

• Clinical outcomes in NICE-3 were comparable to those noted in prior studies

• Therefore, not necessary to use UFH in:• UA/NSTEMI patients undergoing coronary • intervention who are treated with enoxaparin

and an IV IIb/IIIa antagonist

• Combination of enoxaparin and IIb/IIIa• Does not result in excess major bleeding • Events (non-CABG)

• Patients on combination Rx can safely undergo PCI

• Clinical outcomes in NICE-3 were comparable to those noted in prior studies

• Therefore, not necessary to use UFH in:• UA/NSTEMI patients undergoing coronary • intervention who are treated with enoxaparin

and an IV IIb/IIIa antagonist

26

NICE-3Clinical Implications

NICE-3Clinical Implications

• Real-world study• Broad distribution of patients and institutions• Safety data for all 3 commercially available

• IIb/IIIa antagonists

• Addresses safety concerns about combining enoxaparin and a IIb/IIIa antagonist

• Addresses logistical concerns about transition to cath lab

• Foundation for future investigations

• Real-world study• Broad distribution of patients and institutions• Safety data for all 3 commercially available

• IIb/IIIa antagonists

• Addresses safety concerns about combining enoxaparin and a IIb/IIIa antagonist

• Addresses logistical concerns about transition to cath lab

• Foundation for future investigations

27

Is it safe to combine enoxaparin Is it safe to combine enoxaparin

with IIb/IIIa blockers?with IIb/IIIa blockers?

How do we make the transition How do we make the transition

from the floor to the cath lab?from the floor to the cath lab?

Is it safe to combine enoxaparin Is it safe to combine enoxaparin

with IIb/IIIa blockers?with IIb/IIIa blockers?

How do we make the transition How do we make the transition

from the floor to the cath lab?from the floor to the cath lab?

No safety issues at No safety issues at presentpresent

Potential synergismPotential synergism

Good regimen for PCIGood regimen for PCI

No safety issues at No safety issues at presentpresent

Potential synergismPotential synergism

Good regimen for PCIGood regimen for PCI

Carefully but confidently, Carefully but confidently, within the limits of our within the limits of our

experienceexperience

Carefully but confidently, Carefully but confidently, within the limits of our within the limits of our

experienceexperience

Issues for Enoxaparin in ACS

Issues for Enoxaparin in ACS

28

Discussion Discussion

• How does NICE-3 help you?

• What questions doesn’t it answer?

• Is it going to affect your practice?

• What additional information do we

need?

• How does NICE-3 help you?

• What questions doesn’t it answer?

• Is it going to affect your practice?

• What additional information do we

need?

29

NICE-1NICE-1

NICE-4NICE-4

NICE-3NICE-3

? ? ?? ? ?

PI: Cindy GrinesPI: Cindy Grines

Enoxaparin (1 mg/kg iv) for PCIEnoxaparin (1 mg/kg iv) for PCI

PI: Cindy GrinesPI: Cindy Grines

Enoxaparin (1 mg/kg iv) for PCIEnoxaparin (1 mg/kg iv) for PCI

PI: Dean KereiakesPI: Dean Kereiakes

Enoxaparin (0.75 mg/kg iv) Enoxaparin (0.75 mg/kg iv)

with abciximab for PCIwith abciximab for PCI

PI: Dean KereiakesPI: Dean Kereiakes

Enoxaparin (0.75 mg/kg iv) Enoxaparin (0.75 mg/kg iv)

with abciximab for PCIwith abciximab for PCI

PI: James FergusonPI: James Ferguson

Enoxaparin (1 mg/kg sq) Enoxaparin (1 mg/kg sq)

with IIb/IIIa blocker for ACSwith IIb/IIIa blocker for ACS

(including PCI)(including PCI)

PI: James FergusonPI: James Ferguson

Enoxaparin (1 mg/kg sq) Enoxaparin (1 mg/kg sq)

with IIb/IIIa blocker for ACSwith IIb/IIIa blocker for ACS

(including PCI)(including PCI)

The NICE Trials TogetherThe NICE Trials Together

30

DiscussionDiscussion

Patient management strategies

when an ACS patient, who is a

candidate for LMWH, proceeds

to the cath lab

Patient management strategies

when an ACS patient, who is a

candidate for LMWH, proceeds

to the cath lab

31

Future DataFuture Data

GUSTO-IV ACSGUSTO-IV ACS

A to ZA to Z

ACUTE-2ACUTE-2

INTERACTINTERACT

CRUISECRUISE

[Pilot trial LMWH vs combo Rx][Pilot trial LMWH vs combo Rx]

[Efficacy trial LMWH vs UFH][Efficacy trial LMWH vs UFH]

GUSTO-IV ACSGUSTO-IV ACS

A to ZA to Z

ACUTE-2ACUTE-2

INTERACTINTERACT

CRUISECRUISE

[Pilot trial LMWH vs combo Rx][Pilot trial LMWH vs combo Rx]

[Efficacy trial LMWH vs UFH][Efficacy trial LMWH vs UFH]

32

GUSTO-IV ACSSimoons, ESC 2000GUSTO-IV ACS

Simoons, ESC 2000

• Multicenter study (458 sites in 24 countries)• ACS patients not undergoing

revascularization• Treated with ASA and UFH• Scandanavian subset got LMWH• 7800 patients randomized to

• abciximab (24 hours)• abciximab (48 hours) • placebo

• Primary Endpoint: Death or MI at 30 days

• Multicenter study (458 sites in 24 countries)• ACS patients not undergoing

revascularization• Treated with ASA and UFH• Scandanavian subset got LMWH• 7800 patients randomized to

• abciximab (24 hours)• abciximab (48 hours) • placebo

• Primary Endpoint: Death or MI at 30 days

33

GUSTO-IV ACSSimoons, ESC 2000GUSTO-IV ACS

Simoons, ESC 2000

• Definition of ACS: Rest angina with ST-segment (1/2 mm) or (+) troponin

• Coronary angiography only for recurrent ischemia• ~ 28% had evolving MI• 14% from US, 48% from Western Europe• ~80% had ST-segment • ~59% had + troponin• ~32% had both• Revasc performed in ~30% by day 30• Only 1.4% revasc in first 48 hours

• Definition of ACS: Rest angina with ST-segment (1/2 mm) or (+) troponin

• Coronary angiography only for recurrent ischemia• ~ 28% had evolving MI• 14% from US, 48% from Western Europe• ~80% had ST-segment • ~59% had + troponin• ~32% had both• Revasc performed in ~30% by day 30• Only 1.4% revasc in first 48 hours

GUSTO-IV ACSGUSTO-IV ACSGUSTO-IV ACSGUSTO-IV ACS

Placebo Abcix (24) Abcix (48)

Death/MI 1.5 1.9 2.2

Death 0.3 0.7 0.9


Death/MI 1.5 1.9 2.2

Death 0.3 0.7 0.9


Death/MI 4.5 4.0 4.1

Death 1.8 1.5 2.0


Death/MI 4.5 4.0 4.1

Death 1.8 1.5 2.0


Death/MI 8.0 8.2 9.1

Death 3.9 3.4 4.2


Death/MI 8.0 8.2 9.1

Death 3.9 3.4 4.2

48 Hours48 Hours

7 Days7 Days

30 Days30 Days

36

GUSTO-IV ACSGUSTO-IV ACSGUSTO-IV ACSGUSTO-IV ACS

UFH

Placebo (n = 2270)

Abciximab (n = 4556)

0.1% 0.15%

0.5% 0.5%

UFH

Placebo (n = 2270)

Abciximab (n = 4556)

0.1% 0.15%

0.5% 0.5%

ICHICH

Ischemic Stroke

Ischemic Stroke

LMWH SubstudyLMWH Substudy

Dalteparin

Placebo (n = 328)

Abciximab (n = 646)

0 0.3%

1.2% 0.8%

Dalteparin

Placebo (n = 328)

Abciximab (n = 646)

0 0.3%

1.2% 0.8%

39

Documents

The Evolving Role of LMWH in ACS