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Transcript of Heparin manufacturing Combine 5,000 lbs. intestines, 200 gallons water, 10 gallons chloroform, and 5...
Heparin manufacturing
• Combine 5,000 lbs. intestines, 200 gallons water, 10 gallons chloroform, and 5 gallons toluene. Hold at 90°F for 17 hours.
• Add 30 gallons acetic acid, 35 gallons ammonia, sodium hydroxide to adjust pH, and 235 gallons water. Bring to a boil; then filter.
• Add 200 gallons hot water to filtrate and allow to stand overnight, then skim off the fat.
• Keep pancreatic extract at 100°F for three days, then bring to boil.
• Filter solids and assay for heparin content.
The Unfractionated Heparins - Limitations
variability of preparations unpredictable neutralization by PF-4 binds to endothelial cells, plasma proteins, macrophages poor clot penetration indirect anticoagulant - relies on AT III levels, structure stimulates platelet aggregation HIT(TS)!! made of beef and pork intestine (and sausage, manure) discovered by a medical student !
Adapted from Hirsh and Fuster, Circulation 1994;89:1449
Characteristics of UFH and LMWH ChainsCharacteristics of UFH and LMWH Chains
Molecular weight (daltons)10,000 15,000 20,0005,000
5,400
Anti-Xa Anti-IIa and anti-Xa Resistant to PF4 Sensitivity to PF4 Little non-specific binding Non-specific binding Inhibition of thrombin generation Less inhibition thrombin generation
Hirsh J, Levine MN. Blood. 1992; 79: 1-17
Sites of Anti-thrombotic Drug ActionSites of Anti-thrombotic Drug Action
Intrinsic, ExtrinsicPathways
Plasma clottingcascade
Prothrombin
Thrombin
Fibrinogen Fibrin
Thrombus
Platelet aggregation
Conformational activation of GPIIb/IIIa
Platelet Agonists
Thromboxane A2
ADP
AT III
FactorXa
Coagulationcascade
Coagulationcascade
PlateletcascadePlateletcascade
BivalirudinHirudin
ArgatrobanXimelagatran
UF HeparinFondaparinux
Thrombo-lytics
EnoxaparinDX-9065a
Aspirin
TiclopidineClopidogrel
GPIIb/IIIainhibitors
TIMI 11B
Study Design: Acute PhaseStudy Design: Acute Phase
EnoxaparinEnoxaparin30 mg IV bolus +30 mg IV bolus +1.0 mg/kg q 12 H1.0 mg/kg q 12 H
subcutaneoussubcutaneous
Unfractionated heparinUnfractionated heparin70 U/kg IV bolus +70 U/kg IV bolus +
15U/kg/hr IV15U/kg/hr IV
Unstable AnginaUnstable AnginaNon-Q Wave MINon-Q Wave MI
min 72 hoursmax 8 days
Treatment—LMWH: Enoxaparin for Non ST ACS TIMI 11B/ESSENCE Meta-Analysis of Death/MI
Treatment—LMWH: Enoxaparin for Non ST ACS TIMI 11B/ESSENCE Meta-Analysis of Death/MI
LMWH BetterLMWH Better UFH BetterUFH Better
0.50.5 11 220.60.6 0.70.7 0.80.8 0.90.9
UFH (%) Enox (%) p
5.3 4.1 0.02
6.5 5.2 0.02
8.6 7.1 0.02
UFH (%) Enox (%) p
5.3 4.1 0.02
6.5 5.2 0.02
8.6 7.1 0.02
TIMI 11BDay 8 ESSENCE
Overall
TIMI 11BDay 14 ESSENCE
Overall
TIMI 11BDay 43 ESSENCE
Overall
TIMI 11BDay 8 ESSENCE
Overall
TIMI 11BDay 14 ESSENCE
Overall
TIMI 11BDay 43 ESSENCE
Overall
—Antman. 1998—Antman. 1998
Enoxaparin OutcomesEnoxaparin Outcomes
51% RRR
Fox KAA, et al. Am J Cardiol 2002;90:477-82.
ESSENCE and TIMI 11B patients undergoingPCI during index hospitalization (n=924)
11.97%
6.26%
p=0.0030%2%4%6%8%
10%12%14%
LOVENOX
(n=431)
UFH
(n=493)
Death
/MI
TESSMA: TIMI 11B + ESSENCE
Meta-Analysis 1 Yr Follow-up
00
55
1010
1515
2020
2525
3030
00 22 44 66 88 1010 1212
BBD/MI/URD/MI/UR
Urg RevascUrg Revasc
MIMI
DeathDeath
0.50.5 11 22
MonthsMonths
% P
ts%
Pts
HazarHazard d
RatioRatio
HRHR
0.90 0.90 (0.75,1.08)(0.75,1.08)
0.91 0.91 (0.77,1.08)(0.77,1.08)
0.86 0.86 (0.76,0.98)(0.76,0.98)
0.88 0.88 (0.80,0.97)(0.80,0.97)
25.5%25.5%
22.9%22.9%
P=0.008P=0.008Log RankLog Rank
D/MI/Urg RevascD/MI/Urg Revasc
ENOXENOX
UFHUFH
Enoxbetter
UFHbetter
Study Design and ProtocolStudy Design and Protocol
EptifibatideEptifibatide180 180 g/kg IV bolus g/kg IV bolus 2.0 2.0 g/kg/min infusion for 48 hrsg/kg/min infusion for 48 hrs
EptifibatideEptifibatide180 180 g/kg IV bolus g/kg IV bolus 2.0 2.0 g/kg/min infusion for 48 hrsg/kg/min infusion for 48 hrs
ASA 160 mg initially ASA 160 mg initially 80-325 mg daily 80-325 mg dailyASA 160 mg initially ASA 160 mg initially 80-325 mg daily 80-325 mg daily
Unfractionated HeparinUnfractionated Heparin70 U/kg (max. 5000 U) IV bolus70 U/kg (max. 5000 U) IV bolus15 U/kg/hr infusion for 15 U/kg/hr infusion for >>48 hrs48 hrsTarget aPTT 1.5-2x (50-70 sec)Target aPTT 1.5-2x (50-70 sec)
Unfractionated HeparinUnfractionated Heparin70 U/kg (max. 5000 U) IV bolus70 U/kg (max. 5000 U) IV bolus15 U/kg/hr infusion for 15 U/kg/hr infusion for >>48 hrs48 hrsTarget aPTT 1.5-2x (50-70 sec)Target aPTT 1.5-2x (50-70 sec)
EnoxaparinEnoxaparin1 mg/kg (no max.) SC Q12H1 mg/kg (no max.) SC Q12H
for min. 48 hrs (4 doses)for min. 48 hrs (4 doses)
EnoxaparinEnoxaparin1 mg/kg (no max.) SC Q12H1 mg/kg (no max.) SC Q12H
for min. 48 hrs (4 doses)for min. 48 hrs (4 doses)
Other meds, cardiac catheterization, coronary revasc per MDOther meds, cardiac catheterization, coronary revasc per MDOther meds, cardiac catheterization, coronary revasc per MDOther meds, cardiac catheterization, coronary revasc per MD
ACS patients (n=746; 54 hospitals; 9/1/00-12/17/01) with significant ST ACS patients (n=746; 54 hospitals; 9/1/00-12/17/01) with significant ST deviation (deviation (0.1 mV ST0.1 mV ST or or transient STtransient ST in in 2 contiguous leads)2 contiguous leads) and/orand/or
positive serum marker (CK-MB >ULN or troponin I or T positive serum marker (CK-MB >ULN or troponin I or T 3x ULN)3x ULN)
ACS patients (n=746; 54 hospitals; 9/1/00-12/17/01) with significant ST ACS patients (n=746; 54 hospitals; 9/1/00-12/17/01) with significant ST deviation (deviation (0.1 mV ST0.1 mV ST or or transient STtransient ST in in 2 contiguous leads)2 contiguous leads) and/orand/or
positive serum marker (CK-MB >ULN or troponin I or T positive serum marker (CK-MB >ULN or troponin I or T 3x ULN)3x ULN)
Baseline, 48 and 96 hr 12-lead ECGsBaseline, 48 and 96 hr 12-lead ECGs96 hr Continuous ST Segment Monitoring96 hr Continuous ST Segment Monitoring
30-Day Bleeding and Ischemic Events30-Day Bleeding and Ischemic Events
Baseline, 48 and 96 hr 12-lead ECGsBaseline, 48 and 96 hr 12-lead ECGs96 hr Continuous ST Segment Monitoring96 hr Continuous ST Segment Monitoring
30-Day Bleeding and Ischemic Events30-Day Bleeding and Ischemic Events
30-Day Composite Endpoints30-Day Composite Endpoints
99
55
00
55
1010
1515
2020% of Patients% of Patients
Death or Death or (re)MI(re)MI
p=0.031p=0.031
16.216.2
13.513.5
% of Patients% of Patients
Death, (re)MI, orDeath, (re)MI, orRecurrent Recurrent IschemiaIschemia
p=0.30p=0.30
12.612.6
8.48.4
% of Patients% of Patients
Death, (re)MI, orDeath, (re)MI, orRI* with ECG RI* with ECG
changeschanges
p=0.064p=0.064
* RI = Recurrent * RI = Recurrent IschemiaIschemia
Enoxaparin (n=380)
UF Heparin (n=366)
30-Day Major Bleeding30-Day Major Bleeding
8.58.5
5.35.3
00
22
44
66
88
1010% of Patients% of Patients
AllAll
p=0.083p=0.083
5.55.5
2.92.9
00
22
44
66
88
1010% of Patients% of Patients
Non-CABG-relatedNon-CABG-related
p=0.079p=0.079
Enoxaparin (n=380)UF Heparin (n=366)
TIMI ScaleTIMI Scale
Enoxaparin Meta-analysisTriple Composite Event Rates
Enoxaparin Meta-analysisTriple Composite Event Rates
ENOX UFH
9.2 % 12.1 %
12.4 % 14.5 %
6.3 % 9.6 %8.4 % 9.4 %
ESSENCE (8 days)
INTERACT (7 days)A to Z (7 days)
Meta-analysis
Odds Ratio (95 % CI)
favors ENOX favors UFH
TIMI 11B (8 days)
0.3 1 2 3
SSuperioruperior
YYield of theield of the
NNew strategy ofew strategy of
EEnoxaparin,noxaparin,
RRevascularization &evascularization &
GGllYYcoprotein IIb/IIIa Inhibitorscoprotein IIb/IIIa Inhibitors
The SYNERGY Trial
Study DesignAt least 2 of 3 required:At least 2 of 3 required:
• Age Age 60 60
• ST ST (transient) or (transient) or • (+) CK-MB or Troponin(+) CK-MB or Troponin
Enoxaparin IV Heparin
Primary endpoint: Death or MI at 30 days
High-RiskHigh-RiskACS PatientsACS Patients
RandomizeRandomize(n = 10,000)(n = 10,000)
Early invasive strategyOther therapy per AHA/ACC Guidelines
(ASA, -blocker, ACE, clopidogrel, GP IIb/IIIa)
60 U/kg 60 U/kg 12 U/kg/hr 12 U/kg/hr (aPTT 50-70 sec)(aPTT 50-70 sec)1 mg/kg SC Q12H1 mg/kg SC Q12H
Statistical Assumptions
InferiorityInferiority
NoninferiorityNoninferiority
SuperioritySuperiority
0.60.6 11 1.21.2
Hazard Ratio (95% CI)
Enoxaparin Better UFH Better
Control group 15% death/MIControl group 15% death/MI
17% reduction primary endpoint17% reduction primary endpoint
Type I error of 5% (2-sided)Type I error of 5% (2-sided)
90% power 90% power
Sample size ~10,000 patientsSample size ~10,000 patients
Sample size:
8000 10,000 pts
For crossover and interim event rate
Sample size:
8000 10,000 pts
For crossover and interim event rate
1.1
zone of noninferiority
Primary Results (30 Days)
EnoxaparinEnoxaparin UFHUFH Unadjusted Unadjusted(n = 4993)(n = 4993) (n = 4985)(n = 4985) P-valueP-value
Death and MI (%) Death and MI (%) 14.014.0 14.514.5 0.396 0.396
Death (%)Death (%) 3.23.2 3.13.1 0.705 0.705
MI (%)MI (%) 11.711.7 12.712.7 0.135 0.135
Death and MI at 30 Days
30-Day Death/MI30-Day Death/MI
0.80.8 11 1.21.2
Hazard Ratio (95% CI)
Enoxaparin
Better
UFH
Better0 5 10 15 20 25 30
0.8
0.85
0.9
0.95
1.0
Free
dom
from
Dea
th /
MI
Days from Randomization
UFHUFHEnoxaparinEnoxaparin
HR 0.96 (0.86-1.06)HR 0.96 (0.86-1.06)
1.11.1
Hazard Ratio (95% CI)
Enox UFHBetter Better
0.60.6 11 22
Hazard Ratio (95% CI)
Enox UFHBetter Better
0.60.6 11 22
Prior Antithrombin Therapy: Efficacy and Safety
Enox UFH (%) (%)Enox UFH (%) (%)
30-DAY DEATH / MI
30-DAY DEATH / MI
BLEEDINGGUSTO Severe
TIMI Major
BLEEDINGGUSTO Severe
TIMI MajorEnox UFH (%) (%)Enox UFH (%) (%)
2.9 2.42.9 2.4Total(n = 9978)
14.0 14.514.0 14.59.1 7.69.1 7.6
3.1 1.83.1 1.8No Pre-rando(n = 2440)
12.6 14.812.6 14.89.7 6.99.7 6.9
3.1 2.23.1 2.2ConsistentTherapy*(n = 6138)
13.3 15.913.3 15.99.3 7.99.3 7.9
Crossovers: Relation to Bleeding
TIMI MajorGUSTO Severe
0
2
4
6
8
10
Total No Crossover Crossover
0
2
4
6
8
10
Total No Crossover Crossover
0
4
8
12
16
20
Total No Crossover Crossover
0
4
8
12
16
20
Total No Crossover Crossover
(n = 9978)(n = 9978) (n = 9180)(n = 9180) (n =798)(n =798) (n = 9978)(n = 9978) (n = 9180)(n = 9180) (n =798)(n =798)
Enoxaparin
UFH
Caution !!!
Crossovers: Relation to Outcome
Enoxaparin
UFH Consistent RxDeath / MI
Total PopulationDeath / MI
(n = 9978)(n = 9978) (n = 9180)(n = 9180) (n =798)(n =798) (n = 6130)(n = 6130) (n = 5637)(n = 5637) (n =493)(n =493)
0
5
10
15
20
25
Total No Crossover Crossover
0
5
10
15
20
25
Total No Crossover Crossover
0
5
10
15
20
25
Total No Crossover Crossover
Caution !!! Caution !!!
LMWH in ACS/AMI and PCI Pre-Treatment +/- GP IIb/IIIaPre-Treatment +/- GP IIb/IIIa
ESSENCE/TIMI-11b ESSENCE/TIMI-11b (n = 239)(n = 239) PEPCI PEPCI (n = 48) (n = 48) NICE – 3NICE – 3 (n = 661) (n = 661) Collet Trial Collet Trial (n = 132)(n = 132)
No Pre-Treatment +/- GP IIb/IIIaNo Pre-Treatment +/- GP IIb/IIIa NICE – 1 NICE – 1 (n = 828)(n = 828) NICE – 4 NICE – 4 (n = 818)(n = 818) CRUISE CRUISE (n = 129) (n = 129) Choussat Trial Choussat Trial (n = 242)(n = 242)
Post-Thrombolysis for AMIPost-Thrombolysis for AMI ASSENT – 3 ASSENT – 3 (n = 590)(n = 590) ENTIRE / TIMI – 23 ENTIRE / TIMI – 23 (n = 121 )(n = 121 )Total n = 3,808
Performing angioplasty is likeflying a jet airplane –
Performing angioplasty is likeflying a jet airplane –
hours and hours of boredom punctuated by brief moments of
sheer terror.
hours and hours of boredom punctuated by brief moments of
sheer terror.-- J. Tcheng (1988)-- J. Tcheng (1988)-- J. Tcheng (1988)-- J. Tcheng (1988)
PEPCIPEPCI 0.3 mg/kg0.3 mg/kg (none)(none)NICE-3NICE-3 0.3 mg/kg0.3 mg/kgNICE-3NICE-3 (none)(none)ColletCollet (none)(none) (none)(none)
NICE-1NICE-1 (none)(none) 1.0 mg/kg1.0 mg/kg (none)(none)NICE-4NICE-4 (none)(none) 0.75 mg/kg0.75 mg/kgCRUISECRUISE (none)(none) 0.75 mg/kg0.75 mg/kgChoussatChoussat (none)(none) 0.5 mg/kg0.5 mg/kg
Enoxaparin in PCIEnoxaparin in PCIEnoxaparin in PCIEnoxaparin in PCI
PCIPCI-12 hr-12 hr -8 hr-8 hr
Last dose of subqLast dose of subqenox before PCIenox before PCI
IV enoxIV enoxat PCIat PCI GP 2b/3aGP 2b/3aTrialTrial
selective
12 hr+12 hr+
NICE 1 and NICE 4NICE 1 and NICE 4
NICE 1 (n = 828)– Enoxaparin – 1 mg/kg IV– without GP
IIb/IIIa
NICE 4 (n = 818)– Enoxaparin– 0.75 mg/kg IV– with GP IIb/IIIa
Safety (bleeding, MACE)
Compare to EPILOG, EPISTENT
NICE-1 and 4: Enoxaparin in PCI
NICE-1 NICE-4
Patients 828 818Enoxaparin 1.0 mg/kg IV0.75 mg/kg IVGP IIb/IIIa None Abcix. B+I30 day Death 1.3% 0.4% MI 2.6% 1.7% U. Revasc. 1.9% 0.6% CK >3x 3.3% 2.7% Maj. Bleed 0.6% 1.1% Plt <20 K 0 0
J Invas Cardiol 2000;12:1A-5A
NICE 1 (n = 828)NICE 1 (n = 828)NICE 4 (n = 818)NICE 4 (n = 818)
1.11.1 0.50.5
2.72.7
1.31.3
0.40.4 0.20.2
1.81.81.21.2
00112233445566778899
1010
Major Major Major Non-Major Non- Any TransfusionAny TransfusionMajor Non-Major Non-CABGCABG
CABGCABG TransfusionTransfusion
NICE 1 and NICE 4NICE 1 and NICE 4Incidence of Major
Bleeding
EPILOGEPILOG EPISTENTEPISTENT
——————%———%———Major BleedingMajor Bleeding 2.02.0 1.51.5
Non-CABGNon-CABGBleedingBleeding 1.11.1 0.80.8
Any TransfusionAny Transfusion 2.82.8 2.82.8
Perc
en
tag
e o
f P
erc
en
tag
e o
f P
ati
en
tsP
ati
en
ts
46 clinical 46 clinical sites in sites in
USA/CanadaUSA/Canada
Inhospital, 14-day, Inhospital, 14-day, and 30-day follow-and 30-day follow-
upup
[Enoxaparin[Enoxaparin
alone]alone]
(n = 43)(n = 43)
Patients receiving Patients receiving GP IIb/IIIa (n = 628)GP IIb/IIIa (n = 628)
AbciximabAbciximab
(n = 127)(n = 127)
EptifibatideEptifibatide
(n = 272)(n = 272)
TirofibanTirofiban
(n = 229)(n = 229)
671 patients enrolled 671 patients enrolled All treated with All treated with
enoxaparinenoxaparin
NICE 3NICE 3ProtocolProtocol
If patients went to If patients went to the cath lab, the cath lab,
combination Rx combination Rx continued; no UFH continued; no UFH
usedused
If within 8 h of last If within 8 h of last enoxaparin, no enoxaparin, no additional Rxadditional Rx
If > 8 h from last If > 8 h from last dose, dose,
0.3 mg/kg 0.3 mg/kg enoxaparin IVenoxaparin IV
Sheath Sheath removal:removal:
If last If last enoxaparin enoxaparin
given IV: 4 – 6 given IV: 4 – 6 h after last h after last
dosedose
If last If last enoxaparin enoxaparin
given SC: 8 h given SC: 8 h after last doseafter last dose
NICE 3NICE 3
SafetySafety
Major (TIMI) 2.1 %
Non-CABG 1.4 %
Minor (TIMI) 4.5 %
Major (TIMI) 2.1 %
Non-CABG 1.4 %
Minor (TIMI) 4.5 %
BleedingBleedingDeath 0.7 % 1.0 %
MI 4.5 % 4.9 %
Death / MI 5.2 % 5.9 %
Urg revasc 2.1 % 6.6 %
Death 0.7 % 1.0 %
MI 4.5 % 4.9 %
Death / MI 5.2 % 5.9 %
Urg revasc 2.1 % 6.6 %
EfficacyEfficacy
InhospInhosp 30 day30 day
TACTICSTACTICS TACTICSTACTICS(inv)(inv) (cons)(cons)
ProtocolProtocol 5.5%5.5% 3.3%3.3%TIMI majorTIMI major1.9%1.9% 1.3%1.3%
TACTICSTACTICS TACTICSTACTICS(inv)(inv) (cons)(cons)
DeathDeath 2.2%2.2% 1.6%1.6%MIMI 3.1%3.1% 5.8%5.8%Death/MIDeath/MI 4.7%4.7% 7.0%7.0%
PCI Patients (n = 628)PCI Patients (n = 628)
CRUISE: Enoxaparin vs UFH CRUISE: Enoxaparin vs UFH in PCI with Eptifibatidein PCI with Eptifibatide
2.5
6.2
8.5
1.6
6.3
7.6
0
2
4
6
8
10
Maj. Bleed Angio. Compl. D, MI, UR
Enox.UFH
Bhatt D, JACC 2003;41:20
Eptifibatide: Eptifibatide: 180, 180 ug/kg bolus + 2 ug/kg/min, 18-24 hr180, 180 ug/kg bolus + 2 ug/kg/min, 18-24 hrEnoxaparin: Enoxaparin: 0.75 ug/kg IV, no monitoring0.75 ug/kg IV, no monitoringUFH: UFH: 60 U/kg IV, ACT >200sec.60 U/kg IV, ACT >200sec.
P=NS
P=NS
P=NS
% p
ati
ents
Anti-Xa Activity With LMW Heparin Administration
An
ti-X
a (
U/m
l)
Time (hours)
5 10 15 20 25
Enoxaparin 1 mg/kg IV bolusEnoxaparin 0.75 mg/kg IV bolusEnoxaparin 1 mg/kg SQ
0.5
1.0
1.5
Enoxaparin pK ModelingEnoxaparin pK Modeling1 mg/kg sc1 mg/kg sc
SC 1 mg/kg q12
0.0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
1.8
0 12 24 36 48 60 72
Time (h)
An
tiXa
(IU
/mL
)
Normal
Mild
Moderate
Severe
renal function
Enoxaparin in PCI in Enoxaparin in PCI in Patients with ACSPatients with ACS
451 pts with 451 pts with UA/NQWMI rx’d with UA/NQWMI rx’d with enoxaparin for 48 hrs.enoxaparin for 48 hrs.
293 underwent cath 293 underwent cath within 8 hrs of AM within 8 hrs of AM enox. doseenox. dose
132 132 ad hocad hoc PCI, no PCI, no additional UFH/LMWHadditional UFH/LMWH
30d: Death=1.5%, 30d: Death=1.5%, MI=3.0%, Maj. MI=3.0%, Maj. Bleeding = 0.8%Bleeding = 0.8%
Mean anti-Xa at Mean anti-Xa at PCI=0.98PCI=0.98++0.03 IU/ml, 0.03 IU/ml,
Collet JP Circ 2001;103:658Collet JP Circ 2001;103:658
2525
2020
1515
1010
55
0000 0.20.2 0.40.4 0.60.6 0.80.8 1.01.0 1.21.2 1.41.4
Anti-Xa Activity (IU/mL)Anti-Xa Activity (IU/mL)
% of Patients% of Patients
N = 293
Collet et al. Circulation 2001;103:658Collet et al. Circulation 2001;103:658
Enoxaparin in PCI
simulated curve1.0 mg/kg sc steady state + 0.3 mg/kg iv
0.0
0.2
0.4
0.6
0.8
1.0
1.2
1.4
1.6
1.8
2.0
0 2 4 6 8 10 12 14 16 18 20Time (h)
aX
a IU
/ml
0.3 mg/kg IV at 8 hours or more after last sc injection allows optimal therapeutic levels
Martin JL, et al. Presented at ESC 2001.
Rapidpoint ENOX Test
Monitoring of the anticoagulant effect (anti-Xa effect) of enoxaparin on clotting
MoliternoMoliterno
RapidPointRapidPoint
BaselineBaseline
After 1 mg/kg EnoxaparinAfter 1 mg/kg Enoxaparin
ENOX Clotting Time (sec)ENOX Clotting Time (sec)
00 200200 400400 600600
% of Samples% of Samples
MoliternoMoliterno
ELECTELECT
Citrated ENOXCitrated ENOXN = 445N = 445
Citrated ENOXCitrated ENOXN = 445N = 445
SC EnoxaparinSC EnoxaparinN = 33N = 33
SC EnoxaparinSC EnoxaparinN = 33N = 33
IV EnoxaparinIV EnoxaparinN = 412N = 412
IV EnoxaparinIV EnoxaparinN = 412N = 412
WithWithGP IIb/IIIa RxGP IIb/IIIa Rx
N = 31N = 31
WithWithGP IIb/IIIa RxGP IIb/IIIa Rx
N = 31N = 31
WithoutWithoutGP IIb/IIIa RxGP IIb/IIIa Rx
N = 2N = 2
WithoutWithoutGP IIb/IIIa RxGP IIb/IIIa Rx
N = 2N = 2
WithWithGP IIb/IIIa RxGP IIb/IIIa Rx
N = 305N = 305
WithWithGP IIb/IIIa RxGP IIb/IIIa Rx
N = 305N = 305
WithoutWithoutGP IIb/IIIa RxGP IIb/IIIa Rx
N = 107N = 107
WithoutWithoutGP IIb/IIIa RxGP IIb/IIIa Rx
N = 107N = 107
Non-citratedNon-citratedN = 228N = 228
Non-citratedNon-citratedN = 228N = 228
Elective PCIElective PCIN = 673N = 673
Elective PCIElective PCIN = 673N = 673
MoliternoMoliterno
ELECTELECT
SCSC SC SC IV IV IV IV All All+ IIb/IIIa+ IIb/IIIa - IIb/IIIa- IIb/IIIa + IIb/IIIa+ IIb/IIIa - IIb/IIIa- IIb/IIIa GroupsGroups
NN 31 31 2 2 305 305 107 107 445 445
TIMI MajorTIMI Major 0 0 0 0 0 0 0.9% 0.9% 0.2% 0.2%
TIMI MinorTIMI Minor 0 0 0 0 0.7% 0.7% 0.9% 0.9% 0.7% 0.7%
Any BleedAny Bleed 19.4% 19.4% 0 0 8.5% 8.5% 2.8% 2.8% 7.9% 7.9%
TransfusionTransfusion 6.5% 6.5% 0 0 1.0% 1.0% 0 0 1.3% 1.3%
Enoxaparin Treatment GroupsEnoxaparin Treatment Groups
BleedingBleeding
MoliternoMoliterno
MACEMACE
ELECTELECT
SCSC SC SC IV IV IV IV All All+ IIb/IIIa+ IIb/IIIa - IIb/IIIa- IIb/IIIa + IIb/IIIa+ IIb/IIIa - IIb/IIIa- IIb/IIIa GroupsGroups
NN 31 31 2 2 305 305 107 107 445 445
DeathDeath 1 (3.2%)1 (3.2%) - - 1 (0.3%) 1 (0.3%) - - 0.4% 0.4%
MIMI 2 (6.5%)2 (6.5%) - - 14 (4.7%) 14 (4.7%) 5 (4.7%) 5 (4.7%) 4.9% 4.9%
Urgent TVRUrgent TVR - - - - 5 (1.6%) 5 (1.6%) - - 1.1% 1.1%
CompositeComposite 2 (6.5%)2 (6.5%) - - 17 (5.6%)17 (5.6%) 5 (4.7%) 5 (4.7%) 5.4% 5.4%
Enoxaparin Treatment GroupsEnoxaparin Treatment Groups
MoliternoMoliterno
ELECTELECT
200200 250250 300300 350350 400400 450450 500500 550550 600600
Citrated ENOX Clotting Time (sec)Citrated ENOX Clotting Time (sec)
0.100.10
0.200.20
0.300.30
0.400.40
0.000.00
Probability of MACEProbability of MACE
Enoxaparin + IIb/IIIa RxEnoxaparin + IIb/IIIa Rx
EnoxaparinKey Principles
EnoxaparinKey Principles
Subcutaneous dosing delay between dose and effect (peak 3-4h) not therapeutic from dose 1 steady-state only after 3-4 doses ~5% of patients still <0.6 anti-Xa IU/ml
Cath lab considerations no monitoring available t½ of subq enox ~8h (sheath pull) adverse interactions between enox + UFH,
enox + GP IIb/IIIa (↑ anticoagulation → bleeding, adverse events)
pharmacodynamics of IV enox = IV UFH
Subcutaneous dosing delay between dose and effect (peak 3-4h) not therapeutic from dose 1 steady-state only after 3-4 doses ~5% of patients still <0.6 anti-Xa IU/ml
Cath lab considerations no monitoring available t½ of subq enox ~8h (sheath pull) adverse interactions between enox + UFH,
enox + GP IIb/IIIa (↑ anticoagulation → bleeding, adverse events)
pharmacodynamics of IV enox = IV UFH
EnoxaparinED to Diagnostic Cardiac Catheterization
EnoxaparinED to Diagnostic Cardiac Catheterization
ED (AMI, ACS): 1.0 mg/kg subq (0.75 mg/kg if age >75) (optional 30 mg IV bolus if age <75)
inpatient: 1.0 mg/kg subq q12° dx cath:
<12h since subq dose: no additional anticoagulation >12h since subq dose: manage anticoag as de novo
sheath pull timing: ~4 hrs after 1 subq dose ~6 hrs after 2 subq doses ~8 hrs after >2 subq doses
ED (AMI, ACS): 1.0 mg/kg subq (0.75 mg/kg if age >75) (optional 30 mg IV bolus if age <75)
inpatient: 1.0 mg/kg subq q12° dx cath:
<12h since subq dose: no additional anticoagulation >12h since subq dose: manage anticoag as de novo
sheath pull timing: ~4 hrs after 1 subq dose ~6 hrs after 2 subq doses ~8 hrs after >2 subq doses
www.discc.duke.edu/heart_it/enox.htmwww.discc.duke.edu/heart_it/enox.htm
PCI: 1 dose subq enoxaparin <8h: 0.3 mg/kg IV >2 doses subq, last dose <8h: 0.1 mg/kg IV
last subq enoxaparin 8-12h: 0.3 mg/kg IV >12h, or de novo:
• with GP IIb/IIIa: 0.5-0.6 mg/kg IV• without GP IIb/IIIa: 0.75-1.0 mg/kg IV
sheath pull timing (whichever is greater): IV enoxaparin only: ~4h after dose 1-2 doses of subq enoxaparin: ~6h after dose >3 doses of subq enoxaparin: ~8h after dose
PCI: 1 dose subq enoxaparin <8h: 0.3 mg/kg IV >2 doses subq, last dose <8h: 0.1 mg/kg IV
last subq enoxaparin 8-12h: 0.3 mg/kg IV >12h, or de novo:
• with GP IIb/IIIa: 0.5-0.6 mg/kg IV• without GP IIb/IIIa: 0.75-1.0 mg/kg IV
sheath pull timing (whichever is greater): IV enoxaparin only: ~4h after dose 1-2 doses of subq enoxaparin: ~6h after dose >3 doses of subq enoxaparin: ~8h after dose
EnoxaparinPercutaneous Coronary Intervention
EnoxaparinPercutaneous Coronary Intervention
www.discc.duke.edu/heart_it/enox.htmwww.discc.duke.edu/heart_it/enox.htm