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