Advantages of LMWH over UFH

• No need for laboratory monitoring

– when given on a weight-adjusted basis, the LMWH anticoagulant response is predictable and reproducible

• Higher bioavailability - 90% vs 30%

• Longer plasma half-life

– 4 to 6 hours vs 0.5 to 1 hour

– renal clearance

LMWH in ACSLMWH in ACS

STEMI < 6 hLytic eligible

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

ENOX <75 y: 30 mg IV bolus

SC 1.0 mg / kg q 12 h (Hosp DC) ≥75 y: No bolus

SC 0.75 mg / kg q 12 h (Hosp DC)CrCl < 30: 1.0 mg / kg q 24 h

Double-blind, double-dummy

ASA

Day 301° Efficacy Endpoint: Death or Nonfatal MI

1° Safety Endpoint: TIMI Major Hemorrhage

Extract: Protocol Design

UFH60 U / kg bolus (4000 U)

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

Antman EA et al. NEJM 2006;354

ExTRACT-TIMI 25: Primary End Point (ITT) Death or Nonfatal MI

0

3

6

9

12

15

0 5 10 15 20 25 30

P

rim

ary

En

d P

oin

t

)%( Enoxaparin

UFH

Relative Risk0.83 (95% CI, 0.77 to

0.90)P<.001

Days after Randomization

9.9%

12.0%

Lost to follow-up = 3

17% RRR

Adapted with permission from Antman EM, et al. N Engl J Med. 2006;354:1477-1488 .

Bleeding Endpoints (TIMI) 30 Days

1.40.9 0.7

2.1

1.30.8

0

2

4UFHENOX

%Ev

ents

Major Bleed(fatal + nonfatal)

ICH

ARD 0.7%RR 1.53

P<0.0001 ARD 0.1%RR 1.27

P = 0.14

NonfatalMajor Bleed

ARD 0.4%RR 1.39

P = 0.014

Antman EA et al. NEJM 2006;354

ESSENCE

Study DesignStudy Design

Enoxaparin1 mg/kg every

12 h subcutaneous

+ ASA

UFHIV dose

adjusted + ASA

Unstable anginaUnstable anginaNonNon--QQ--wave MIwave MI

Treatment phaseminimum 48 h

maximum 8 days

Follow-up phaseMI, myocardial infarctionASA, acetylsalicylic acid UFH, unfractionated heparinIV, intravenous

Cohen M, et al. N Engl J Med 1997;337:447-52

‡Goodman SG, et al. J Am Coll Cardiol 2000 (in press)

FollowFollow--up up callcall

1 Year1 Year‡‡

FollowFollow--up up callcall

Day 30Day 30

FollowFollow--up up visitvisit

Day 14Day 14

FollowFollow--up up callcall

Day 30Day 30

FollowFollow--up up visitvisit

Day 14Day 14

FollowFollow--up up callcall

1 Year1 Year‡‡

2525

2020

1515

1010

55

00

22 44 66 88 1010 1212 1414 1616 1818 2020 2222 2424 2626 2828 3030

UFHEnoxaparin

Days from randomizationDays from randomization

% o

f pa

tient

s w

ith e

ven

ts%

of

patie

nts

with

eve

nts

P=0.019

P=0.017

Cohen M, et al. N Engl J Med 1997;337:447-52

MI, myocardial infarctionRA, recurrent anginaUFH, unfractionated heparin

Time to First Event over 30 Days: Death, MI, Recurrent AnginaTime to First Event over 30 Days: Death, MI, Recurrent AnginaSuperiority ofSuperiority of enoxaparinenoxaparin was maintained to 30 dayswas maintained to 30 days

15 % Risk Reduction

LMWH in ACS LMWH in ACS -- ESSENCE trail ESSENCE trail

ESSENCE

0

5

10

15

20

25

30

35

0 2 4 6 8 10 12 14

MonthsMonths

Cu

mu

lati

ve

eve

nt

rate

(%

)C

um

ula

tiv

e ev

en

t ra

te (

%)

1-YEAR FOLLOW-UP

MI, myocardial infarction

RA, recurrent angina

UFH, unfractionated heparin

Time to Event at 1 Year: Death, MI, Recurrent AnginaTime to Event at 1 Year: Death, MI, Recurrent Angina

Superior efficacy ofSuperior efficacy of enoxaparinenoxaparin was maintained to 1 yearwas maintained to 1 year

Enoxaparin

UFH

Fox KAA. Heart 1998;82: I12-I14

P = 0.02

P = 0.02

ESSENCE

SafetySafetyRisk of majorRisk of major haemorrhagichaemorrhagic events was similar in both groupsevents was similar in both groups

HaemorrhageHaemorrhageMajorMajor 107 (7.0%)107 (7.0%) 102 (6.5%)102 (6.5%) 0.570.57MinorMinor 110 (7.2%)110 (7.2%) 188 (11.9%)188 (11.9%) < 0.001< 0.001

StrokeStroke 7 (0.5%)7 (0.5%) 7 (0.4%)7 (0.4%) NSNSHaemorrhagicHaemorrhagic 1 (0.1%)1 (0.1%) 00 NSNSNonNon--haemorrhagichaemorrhagic 6 (0.4%)6 (0.4%) 7 (0.4%)7 (0.4%) NSNS

TransientTransient ischaemicischaemic attackattack 8 (0.5%)8 (0.5%) 1 (0.1%)1 (0.1%) NSNS

Drop in platelet countDrop in platelet count 56 (3.7%)56 (3.7%) 39 (2.5%)39 (2.5%) 0.080.08(> 50% from baseline)(> 50% from baseline)

UFHUFH EnoxaparinEnoxaparin P P valuevalue((nn=1529)=1529) ((nn=1578)=1578)

Cohen M, et al. N Engl J Med 1997;337:447-52UFH, unfractionated heparinNS, non-significant

TIMI 11BTime to First Event (Triple Endpoint): Acute PhaseTime to First Event (Triple Endpoint): Acute Phase

Event rate significantly reduced at 48 h in enoxaparin groupEvent rate significantly reduced at 48 h in enoxaparin group

10 10 –

8 8 –

6 6 –

4 4 –

2 2 –

0088 1616 3232 4040 4848 5656 7272

UFHEnoxaparin

Hours from randomizationHours from randomization

% o

f p

ati

en

ts w

ith

eve

nts

% o

f p

ati

en

ts w

ith

eve

nts 7.3%

5.5%

Relative risk reduction 23.8%

P=0.029

Triple endpoint, death/myocardial infarction/urgent revascularization UFH, unfractionated heparin

Antman EM, et al. Circulation

1999;100:1593-1601

TIMI 11B

Time to First Event (Triple Endpoint): Chronic PhaseTime to First Event (Triple Endpoint): Chronic PhaseEarly treatment benefit of enoxaparin sustained over 14 daysEarly treatment benefit of enoxaparin sustained over 14 days

UFHEnoxaparin

Days from randomizationDays from randomization

% o

f p

ati

en

ts w

ith

eve

nts

% o

f p

ati

en

ts w

ith

eve

nts 14.5%

12.4%

Relative risk reduction 15%P=0.048

16.7%

14.2%

44

88

1212

1616

2020

00 22 44 66 88 1010 1212 1414

Antman EM, et al.

Circulation 1999;100:1593-1601

Triple endpoint, death/myocardial infarction/urgent revascularization UFH, unfractionated heparin

TIMI 11B

Time to First Event (Triple Endpoint): Chronic PhaseTime to First Event (Triple Endpoint): Chronic PhaseSuperior efficacy of enoxaparin maintained to 43 daysSuperior efficacy of enoxaparin maintained to 43 days

UFHEnoxaparin

Days from randomizationDays from randomization

% o

f p

ati

en

ts w

ith

eve

nts

% o

f p

ati

en

ts w

ith

eve

nts

Relative risk reduction 12%P=0.048

19.7%

17.3%

44

88

1212

1616

2020

00 88 1616 2424 3232 4040 4343

Antman EM, et al.

Circulation 1999;100:1593-1601

Triple endpoint, death/myocardial infarction/urgent revascularization UFH, unfractionated heparin

Major Hemorrhagic Events (Acute Phase) No significant increase in rate of major hemorrhage

0

20

40

60

ESSENCEn = 3171

TIMI 11Bn = 3910

TESSMAn = 7081

UFHEnoxaparin

Antman EM et al. Circulation 1999;100:1602-8UFH, unfractionated heparin; NS, not significant

NS

NS

NS

Num

ber o

f pati

ents

GUSTO VBenefit vs. risk

Death or re-MISevere / moderate

hemorrhage

Reteplase

Abciximab+ reteplase

8.8%

7.4%

2.3%

4.6%

D = 2.3%P < 0.001

D = 1.4%P = 0.001

0 2 4 6 8 10246Percentage of patients

GUSTO V Investigators. Lancet. 2001;357:1905.

FRAXIS2 (nadroparin)n=3468

FRIC3 (dalteparin)n=1482

TIMI 11B4 (enoxaparin)n=3910

ESSENCE5 (enoxaparin)n=3171

RRR-20% -15% -10% -5% 0% 5% 10% 15% 20%

3.9%

0%

-14.9%

-16.2%

1. Cohen M. Semin Thromb Hemost 1999;25(suppl 3):113-212. The FRAXIS study group. Eur Heart J 1999;20:1553-62 3. Klein W, et al. Circulation 1997;96:61-8 4. Antman EM, et al. Circulation 1999;100:1593-601 5. Cohen M, et al N Engl J Med 1997;337:447-52

LMWH superior UFH superior

Non ST Elevation MI/ Unstable Angina Non ST Elevation MI/ Unstable Angina Myocardial Infarction: Composite Endpoints Myocardial Infarction: Composite Endpoints

at 14 Daysat 14 Days11

Relative RiskRatio (RRR) Significance

NS

P=0.03

P=0.02

NS

LowLow--MolecularMolecular--Weight HeparinsWeight HeparinsAnti-Facotr Xa : Anti - Factor IIa Ratios

Agent Trade Xa:IIa Mol Wt (d)

Enoxaparin Lovenox 3.8 : 1 4,200Dalteparin Fragmin 2.7 : 1 6,000Ardeparin Normiflo 1.9 : 1 6,000Nadroparin 3.6 : 1 4,500Reviparin 3.5 : 1 4,000Tinzaparin 1.9 : 1 4,500

MontalescotG, et al. JAmColl Cardiol2000;36:110-4

vWF(%)

100

80

60

40

20

0

P=0.0006

Dalteparin120 IU anti-Xa/kg bid

Enoxaparin1 mg/kg (100 IU anti-Xa/kg) bid

UFH 5000 IU anti-Xai.v. bolus thenaPTT-adjusted continuous infusion

NS

Release of vonRelease of vonWillebrandWillebrandFactor (Factor (vWFvWF))

Enoxaparinreleases lessvWF, resulting in reduced

platelet aggregation compared with UFH ordalteparinat approved treatment doses for unstable angina/

non-Q-wave myocardial infarction

UFH,unfractionatedheparin LMWH, low-molecular-weight heparinaPTT, activated partialthromboplastintime

Low-Molecular-Weight Heparin

Indirect thrombin inhibitorLess reversibleDifficult to monitor

(no aPTT or ACT)Renally clearedLong half-lifeRisk of HIT

DisadvantagesIncreased anti-Xa to anti-IIa

activity inhibits thrombin generation more effectively

Induces ↑ release of TFPI vs UFH

Not neutralized by platelet factor 4

Less binding to plasma proteins (eg, acute-phase reactant proteins) more

consistent anticoagulationLower rate of HIT vs UFH Lower fibrinogen levels Easy to administer (SC

administration)Long history of clinical

studies and experience, FDA-approved indications

Monitoring typically unnecessary

Advantages

Hirsh J, et al. Circulation. 2001;103:2994-3018. TFPI = tissue factor pathway inhibitor; UFH = unfractionated heparin; SC = subcutaneous; aPTT = activated partial thromboplastin time ;

ACT = activated coagulation time.

ATIIa

Hep

UFH

IIaS

C

Direct antithrombin

LMWH

AT Xa

Clot Burden in ACS patient

Heparin fails to effectively inhibit Clot-bound Thrombin

Bivalirudin inhibitsClot-Bound and Circulating Thrombin

Bivalirudin Does not activate Platelets

Bivalirudin: Unique mechanism of action overcomes the limitation of Heparin