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
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