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