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 pat

ient

s w

ith e

vent

s%

of p

atie

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 14MonthsMonths

Cum

ulat

ive

even

t rat

e (%

)C

umul

ativ

e ev

ent r

ate

(%)

1-YEAR FOLLOW-UP

MI, myocardial infarctionRA, recurrent anginaUFH, unfractionated heparin

Time to Event at 1 Year: Death, MI, Recurrent AnginaTime to Event at 1 Year: Death, MI, Recurrent AnginaSuperior efficacy ofSuperior efficacy of enoxaparinenoxaparin was maintained to 1 yearwas maintained to 1 year

EnoxaparinUFH

Fox KAA. Heart 1998;82: I12-I14

P = 0.02

P = 0.02

ESSENCESafetySafety

Risk 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 group10 10 –

8 8 –

6 6 –

4 4 –

2 2 –

0088 1616 3232 4040 4848 5656 7272

UFHEnoxaparin

Hours from randomizationHours from randomization

% o

f pat

ient

s w

ith e

vent

s%

of p

atie

nts

with

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 11BTime 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 pat

ient

s w

ith e

vent

s%

of p

atie

nts

with

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 1414Antman EM, et al.

Circulation 1999;100:1593-1601

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

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

Superior efficacy of enoxaparin maintained to 43 daysSuperior efficacy of enoxaparin maintained to 43 days

UFHEnoxaparin

Days from randomizationDays from randomization

% o

f pat

ient

s w

ith e

vent

s%

of p

atie

nts

with

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 / moderatehemorrhage

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 reducedplatelet 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

Compared to Heparin/Enoxaparin with GP IIb/IIa inhibitors,Bivalirudin monotherapy significantly reduces major bleeding while providing similar ischemic protection, and improves net clinical

outcome.

Bivalirudin Advantage

ATIIa

Hep

UFH

IIaS

C

Direct antithrombin

LMWH

AT Xa AT Xa

Pentasaccharide

IIa II

Fibrinogen Fibrin clot

Extrinsic pathway

Intrinsicpathway

AT XaAT AT

Fondaparinux

Xa

Antithrombin

Fondaparinux: A Synthetic Factor Xa Inhibitor

Adapted with permission from Turpie AGG et al. N Engl J Med. 2001;344:619.

THROMBIN

Key Steps in Coagulation Pathway

Inhibition of one molecule of factor Xa can inhibit the

generation of 50 molecules of thrombin2

Intrinsic pathway Extrinsic pathway

1 .Rosenberg RD, Aird WC. N Engl J Med 1999;340(20):1555–64.2 .Wessler S, Yin ET. Thrombo Diath Haemorrh 1974;32(1):71–8.

Intrinsic pathway

1

50

Xa X

IIFibrinFibrinogen

Clot

Xa

Va

PLCa2+

IIa

VIIIa

Ca2+

PL

IXa

Herbert JM et al. Cardiovasc Drug Rev. 1997;15:1 .van Boeckel CAA et al. Angew Chem, Int Ed Engl. 1993;32:1671 .

·Once daily administration ·Rapid onset (Cmax/2=25 min)·Half life: 15-18 h.·Effects reversible with administration

of activated Factor VII (Novoseven®)·No liver metabolism·Renal clearance·No protein binding (other than AT)·No reported cases of HIT·No dose adjustment necessary in

elderly

Fondaparinux: A Synthetic Inhibitor of Factor Xa

12,000 Patients with STEMI < 12 h of symptom onsetInclusion: ST 2 mm prec leads or 1 mm limb leads

Exclusion: Contra-ind. for anticoagulant, INR>1.8, pregnancy, ICH<12 mo.

UFH not indicated

OASIS-6: Randomized, Double Blind

Lytics (SK, TPA, TNK, RPA), Primary PCI or no reperfusion (eg. late)

Stratification

UFH indicatedRandomization Randomization

Fondaparinux2.5 mg Placebo Fondaparinux

2.5 mg UFH JAMA 2006;295:1519-30

Primary Efficacy OutcomeDeath/MI at 30 Days

Days

Cum

ulati

ve H

azar

d0.0

0.02

0.04

0.06

0.08

0.10

0.12

0 3 6 9 12 15 18 21 24 27 30

UFH/Placebo

Fondaparinux

HR 0.86 95% CI 0.77-0.96

P=0.008

The OASIS-6 Trial Group. JAMA 2006;295:1519-30

Death or MI 3 or 6 months

Days

Cum

ulati

ve H

azar

d

0.00.0

20.0

40.0

60.0

80.1

00.1

2

0 18 36 54 72 90 108 126 144 162 180

UFH/Placebo

Fondaparinux

HR 0.88 95% CI 0.79-0.99

P=0.029

The OASIS-6 Trial Group. JAMA 2006;295:1519-30

•Primary: Efficacy: Death, MI, refractory ischemia 9 day

Safety: Major bleeds

Risk benefit: Death, MI, refractory ischemia, major bleeds•Secondary: Above & each component (especially deaths) at 30 & 180 d•Hypothesis: First test non-inferiority, then test superiority

Death at 6 Months

Days

Cum

ulati

ve H

azar

d0.0

0.02

0.04

0.06

0 20 40 60 80 100 120 140 160 180

HR 0.8995% CI 0.79-0.99

p=0.037

Enoxaparin

Fondaparinux

Death or MI: 6 Months

Days

Cum

ulati

ve H

azar

d0.0

0.02

0.04

0.06

0.08

0.10

0.12

0 20 40 60 80 100 120 140 160 180

HR 0.9195% CI 0.84-0.99

p=0.036

Enoxaparin

Fondaparinux

Major Bleeding: 6 Months

Days

Cum

ulati

ve H

azar

d

0.00.0

10.0

20.0

30.0

40.0

50.0

6

0 20 40 60 80 100 120 140 160 180

HR 0.7295% CI 0.63-0.82

p<<0.00001

Enoxaparin

Fondaparinux

Death, MI, RI or Major Bleeding at 6 Months

Days

Cum

ulati

ve H

azar

d0.0

0.05

0.10

0.15

0 20 40 60 80 100 120 140 160 180

Enoxaparin

Fondaparinux

HR 0.8795% CI 0.81-0.93

p<<0.00001

Fondaparinux

•Difficult to monitor (no aPTT or ACT)

•Long half-life•Catheter thrombosis

during PCI

DisadvantagesAdvantages•SC administration

―Potential exists for outpatient

management•Once-daily

administration•Predictable

anticoagulant response•Fixed dose•No antigenicity•Potentially no need for

serologic parameters•Does not cross the

placenta•HIT antibodies do not

cross-react•Decreased bleeding

complications vs UFH or LMWH

Simoons ML, et al. J Am Coll Cardiol. 2004;43:2183-2190.Yusuf S, et al. N Engl J Med. 2066;354:1464-1476 .