heparin manufacturing

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


Overall


Overall


Overall


Overall


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


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


AllAll

p=0.083p=0.083

5.55.5

2.92.9

00

22

44

66

88


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


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


Enox UFHBetter Better

0.60.6 11 22


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


0

4

8

12

16

20


0

4

8

12

16

20


(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


0

5

10

15

20

25


0

5

10

15

20

25


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)


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


N = 31N = 31

WithoutWithoutGP IIb/IIIa RxGP IIb/IIIa Rx

N = 2N = 2


N = 2N = 2


N = 305N = 305


N = 305N = 305


N = 107N = 107


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

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