AntiThrombotic Therapy in the Cath Lab: Preliminary Results

from the NICE Trials

Cindy L. Grines, M.D.Cindy L. Grines, M.D.William Beaumont HospitalWilliam Beaumont Hospital

Royal Oak, MichiganRoyal Oak, Michigan

Advantages Of LMWH OverConventional Heparin

Pharmacologic EffectsPharmacologic Effects Quick and predictable SQ Quick and predictable SQ

absorptionabsorption More stable dose responseMore stable dose response More resistant to inhib. by More resistant to inhib. by

platelet factor 4platelet factor 4 generation of antiheparin generation of antiheparin

antibody by 70%antibody by 70% Greater anti-Xa activityGreater anti-Xa activity Less anti-IIa activityLess anti-IIa activity

Clinical BenefitClinical Benefit More reliable level of More reliable level of

anticoagulantsanticoagulants Eliminates need for Eliminates need for

monitoring anticoagulationmonitoring anticoagulation incidence of heparin-incidence of heparin-

induced thrombocytopeniainduced thrombocytopenia Greater antithrombotic Greater antithrombotic

effectseffects Potential to reduce bleedingPotential to reduce bleeding

Use Of LMWH For Coronary Interventions

Prevent restenosis - antiproliferative propertiesPrevent restenosis - antiproliferative properties

Post procedural anticoagulation - reduce Post procedural anticoagulation - reduce

thrombosisthrombosis

High dose intraprocedural use - (instead of heparin) High dose intraprocedural use - (instead of heparin)

- improve safety- improve safety

Why Use IV LMWH DuringCoronary Interventions?

More predictable dose response - no need to More predictable dose response - no need to monitor anticoagulationmonitor anticoagulation

Greater antithrombotic effect - potential to Greater antithrombotic effect - potential to reduce ischemic complicationsreduce ischemic complications

REDUCE Trial

625 patients randomized to reviparin (625 patients randomized to reviparin (IV bolus, IV bolus, 24 hr infusion and 28-day SQ)24 hr infusion and 28-day SQ) vs unfractionated vs unfractionated heparin heparin (bolus, 24 hr infusion)(bolus, 24 hr infusion)

Trial designed to assess restenosis - negative Trial designed to assess restenosis - negative result result

At 24 hrs, At 24 hrs, composite of death, MI, composite of death, MI, unplanned stent or reintervention in reviparin unplanned stent or reintervention in reviparin arm arm (3.9 vs 8.2%; p=.03)(3.9 vs 8.2%; p=.03)

Karsh, JACC 1996;28:1437Karsh, JACC 1996;28:1437

IV Enoxaparin For Elective PTCA

Pilot study randomizing 60 patients to Pilot study randomizing 60 patients to conventional heparin vs IV enoxaparin during conventional heparin vs IV enoxaparin during PTCAPTCA

1 mg/kg IV bolus selected to achieve anti-Xa levels 1 mg/kg IV bolus selected to achieve anti-Xa levels similar to 10,000 u bolus of conventional heparinsimilar to 10,000 u bolus of conventional heparin

Laboratory testing at baseline, 5 min and 4 hoursLaboratory testing at baseline, 5 min and 4 hours

Clinical events monitored, angiograms reviewedClinical events monitored, angiograms reviewed

IV Enoxaparin For Elective PTCA

Hypothesis:Hypothesis:

Single bolus of enoxaparin will consistently Single bolus of enoxaparin will consistently achieve antithrombotic effectachieve antithrombotic effect

Multiple dosing and close monitoring of levels Multiple dosing and close monitoring of levels will not be necessarywill not be necessary

Safety will be similar to (or better than) Safety will be similar to (or better than) conventional unfractionated heparinconventional unfractionated heparin

0

100

200

300

400Enoxaparin (n=30) Unfractionated Heparin (n=30)

0

100

200

0

300

600

900

0 5 min* 4 hrs

*30% of PTCA pts required additional heparin boluses*30% of PTCA pts required additional heparin boluses

††

††

††

††

††

† † p < .001p < .001

TFPI = tissue factor pathway inhibitorTFPI = tissue factor pathway inhibitor

AC

TA

CT

(s)

(s)

aPT

TaP

TT

(s)

(s)

TFP

IT

FPI

(ng/

ml)

(ng/

ml)

Anticoagulation Effect: IV Enoxaparin vs IV Heparin

Angiographic Analysis AndIn-hospital Events

CharacteristicCharacteristicEnoxaparinEnoxaparin

(n=30)(n=30)

UnfractionatedUnfractionatedHeparinHeparin(n=30)(n=30)

ppValueValue

Post-PTCA stenosis Post-PTCA stenosis (%)(%)

TIMI 3 flow TIMI 3 flow (% pts)(% pts)

Major dissection post-PTCA Major dissection post-PTCA (% pts)(% pts)

Ischemic complications Ischemic complications (% pts)(% pts)

Bleeding events Bleeding events (% pts)(% pts)

Vascular events Vascular events (% pts)(% pts)

14 ± 18.214 ± 18.2

9797

33

00

11

00

16 ± 18.116 ± 18.1

9393

00

33

00

11

0.700.70

1.001.00

0.240.24

0.240.24

0.490.49

1.001.00

IV Enoxaparin For Elective PTCA

Conclusions:Conclusions:

Compared to conventional unfractionated heparin, a Compared to conventional unfractionated heparin, a single bolus of IV enoxaparinsingle bolus of IV enoxaparin

was safewas safe

achieved more consistent antithrombotic effect achieved more consistent antithrombotic effect with less anticoagulant effectwith less anticoagulant effect

may eliminate need for hematologic monitoringmay eliminate need for hematologic monitoring

LMWH For Interventional Procedures

What is Yet To Be Determined?What is Yet To Be Determined?

Is IV LMWH clinically superior to conventional Is IV LMWH clinically superior to conventional heparin?heparin?

Are higher doses (greater anti-Xa effect) Are higher doses (greater anti-Xa effect) necessary to be superior to heparin?necessary to be superior to heparin?

What is the appropriate dose of LMWH if a SQ What is the appropriate dose of LMWH if a SQ dose has been given, or if IIb/IIIa agents are dose has been given, or if IIb/IIIa agents are given?given?

Ongoing Studies Of IV Enoxaparin Instead Of Conventional Heparin For Coronary Intervention

Study PI n Dose Goal

NICE 1

NICE 4

Grines

Kereiakes

810(complete)

818(complete)

1 mg/kg

0.75 mg/kgplus abciximab

Safety

Safety

Goals of NICE 1 and NICE 4 Safety - major bleeding, MACESafety - major bleeding, MACE

Large non-randomized data set Large non-randomized data set compare to compare to recent historical controls (EPILOG and recent historical controls (EPILOG and EPISTENT)EPISTENT)

Inclusion criteria - similar to EPILOGInclusion criteria - similar to EPILOG

NICE 1 and 4: Preliminary Results

NICE 1NICE 1 NICE 4NICE 4

Complete dataComplete dataEnoxaparin dose (mg)Enoxaparin dose (mg)Abciximab bolus (mg)Abciximab bolus (mg)

infusion (infusion (g/min)g/min)# Vessels PCI# Vessels PCI

1 (%)1 (%)2 (%)2 (%)3 (%)3 (%)4 (%)4 (%)5 (%)5 (%)

Stent utilization (%)Stent utilization (%)(any lesion)(any lesion)

309 (38%)309 (38%)86860000

50.250.230.730.713.313.33.23.21.91.9

84.884.8

310 (38%)310 (38%)6565

21.521.510.010.0

47.447.431.931.916.516.52.62.61.01.0

85.585.5

Safety Data

NICENICE11

NICENICE44

Major bleeding, 30d (%)Major bleeding, 30d (%)

Non CABG bleed (%)Non CABG bleed (%)

Any transfusion (%)Any transfusion (%)

> 30% > 30% in platelets (%) in platelets (%)

Platelets < 50,000Platelets < 50,000

0.60.6

0.30.3

1.61.6

2.62.6

00

0.30.3

00

1.31.3

8.98.9

1.61.6

EPI-EPI-LOGLOG

(Abciximab/(Abciximab/Low doseLow doseheparin)heparin)

EPI-EPI-STENTSTENT

(Stent/(Stent/abciximab)abciximab)

2.02.0

1.11.1

1.61.6

NRNR

NRNR

1.41.4

0.60.6

3.13.1

NRNR

NRNR

NICE 1 and 4: Clinical Outcomes at 30 Days

NICE 1NICE 1(Enoxaparin)(Enoxaparin)

(n=309)(n=309)

NICE 4NICE 4(Enoxaparin/Abciximab)(Enoxaparin/Abciximab)

(n=310)(n=310)

Death (%)Death (%)MI (%)MI (%)**Urgent Revasc. (%)Urgent Revasc. (%)Death + MI (%)Death + MI (%)Death, MI,Death, MI,

Urgent Revasc. (%)Urgent Revasc. (%)

1.31.32.62.61.91.93.63.6

4.94.9

0.30.31.91.90.60.62.32.3

2.32.3

* Investigator defined* Investigator defined

NICE 1 and 4: Myocardial Infarction

NICE 1NICE 1(Enoxaparin)(Enoxaparin)

(n=309)(n=309)

NICE 4NICE 4(Enoxaparin/Abciximab)(Enoxaparin/Abciximab)

(n=310)(n=310)

Clinical infarction (%)Clinical infarction (%)

Any CK Any CK 3 x normal 3 x normal

Any MB Any MB 3 x normal 3 x normal(CK may be normal)(CK may be normal)

2.62.6

3.33.3

7.87.8

1.91.9

4.24.2

12.412.4

Conclusions Based on Preliminary NICE Results

IV enoxaparin, used instead of UFH for IV enoxaparin, used instead of UFH for coronary interventions:coronary interventions: Is associated with low rate of major bleeding Is associated with low rate of major bleeding

Slightly higher rates of CKMB release may Slightly higher rates of CKMB release may represent more aggressive PCI (paradoxically represent more aggressive PCI (paradoxically higher with abciximab)higher with abciximab)

Appears safe and effectiveAppears safe and effective