1. AntiThrombotic Therapy in the Cath Lab: Preliminary Results from the NICE Trials Cindy L. Grines, M.D. William Beaumont Hospital Royal Oak, Michigan Cindy L. Grines, M.D. William Beaumont Hospital Royal Oak, Michigan

2. Advantages Of LMWH Over Conventional Heparin Pharmacologic Effects u Quick and predictable SQ absorption u More stable dose response u More resistant to inhib. by platelet factor 4   generation of antiheparin antibody by 70% u Greater anti-Xa activity u Less anti-IIa activity Clinical Benefit u More reliable level of anticoagulants u Eliminates need for monitoring anticoagulation   incidence of heparin- induced thrombocytopenia u Greater antithrombotic effects u Potential to reduce bleeding

3. Use Of LMWH For Coronary Interventions u Prevent restenosis - antiproliferative properties u Post procedural anticoagulation - reduce thrombosis u High dose intraprocedural use - (instead of heparin) - improve safety

4. Why Use IV LMWH During Coronary Interventions? u More predictable dose response - no need to monitor anticoagulation u Greater antithrombotic effect - potential to reduce ischemic complications

5. REDUCE Trial u 625 patients randomized to reviparin ( IV bolus, 24 hr infusion and 28-day SQ) vs unfractionated heparin (bolus, 24 hr infusion) u Trial designed to assess restenosis - negative result  At 24 hrs,  composite of death, MI, unplanned stent or reintervention in reviparin arm (3.9 vs 8.2%; p=.03) Karsh, JACC 1996;28:1437

6. IV Enoxaparin For Elective PTCA u Pilot study randomizing 60 patients to conventional heparin vs IV enoxaparin during PTCA u 1 mg/kg IV bolus selected to achieve anti-Xa levels similar to 10,000 u bolus of conventional heparin u Laboratory testing at baseline, 5 min and 4 hours u Clinical events monitored, angiograms reviewed

7. IV Enoxaparin For Elective PTCA Hypothesis: u Single bolus of enoxaparin will consistently achieve antithrombotic effect u Multiple dosing and close monitoring of levels will not be necessary u Safety will be similar to (or better than) conventional unfractionated heparin

8. *30% of PTCA pts required additional heparin boluses † † † † † † p <.001 TFPI = tissue factor pathway inhibitor ACT(s) aPTT(s) TFPI(ng/ml) Anticoagulation Effect: IV Enoxaparin vs IV Heparin

9. Angiographic Analysis And In-hospital Events Characteristic Enoxaparin(n=30) UnfractionatedHeparin(n=30) pValue Post-PTCA stenosis (%) TIMI 3 flow (% pts) Major dissection post-PTCA (% pts) Ischemic complications (% pts) Bleeding events (% pts) Vascular events (% pts) 14 ± 18.2 973010 16 ± 18.1 9303010.701.000.240.240.491.00

10. IV Enoxaparin For Elective PTCA Conclusions: Compared to conventional unfractionated heparin, a single bolus of IV enoxaparin u was safe u achieved more consistent antithrombotic effect with less anticoagulant effect u may eliminate need for hematologic monitoring Conclusions: Compared to conventional unfractionated heparin, a single bolus of IV enoxaparin u was safe u achieved more consistent antithrombotic effect with less anticoagulant effect u may eliminate need for hematologic monitoring

11. LMWH For Interventional Procedures What is Yet To Be Determined? l Is IV LMWH clinically superior to conventional heparin? l Are higher doses (greater anti-Xa effect) necessary to be superior to heparin? l What is the appropriate dose of LMWH if a SQ dose has been given, or if IIb/IIIa agents are given? What is Yet To Be Determined? l Is IV LMWH clinically superior to conventional heparin? l Are higher doses (greater anti-Xa effect) necessary to be superior to heparin? l What is the appropriate dose of LMWH if a SQ dose has been given, or if IIb/IIIa agents are given?

12. Ongoing Studies Of IV Enoxaparin Instead Of Conventional Heparin For Coronary Intervention StudyPInDoseGoal NICE 1 NICE 4 Grines Kereiakes 810 (complete) 818 (complete) 1 mg/kg 0.75 mg/kg plus abciximab Safety

13. Goals of NICE 1 and NICE 4 u Safety - major bleeding, MACE  Large non-randomized data set  compare to recent historical controls (EPILOG and EPISTENT) u Inclusion criteria - similar to EPILOG u Safety - major bleeding, MACE  Large non-randomized data set  compare to recent historical controls (EPILOG and EPISTENT) u Inclusion criteria - similar to EPILOG

14. NICE 1 and 4: Preliminary Results NICE 1 NICE 4 Complete data Enoxaparin dose (mg) Abciximab bolus (mg) infusion (  g/min) # Vessels PCI 1 (%) 2 (%) 3 (%) 4 (%) 5 (%) Stent utilization (%) (any lesion) 309 (38%) 860050.230.713.33.21.984.8 310 (38%) 6521.510.047.431.916.52.61.085.5

15. Safety Data NICE1NICE4 Major bleeding, 30d (%) Non CABG bleed (%) Any transfusion (%) > 30%  in platelets (%) Platelets < 50,000 0.60.31.62.600.301.38.91.6 EPI-LOG(Abciximab/ Low dose heparin) EPI-STENT(Stent/abciximab) 2.01.11.6NRNR1.40.63.1NRNR

16. NICE 1 and 4: Clinical Outcomes at 30 Days NICE 1 (Enoxaparin)(n=309) NICE 4 (Enoxaparin/Abciximab)(n=310) Death (%) MI (%)* Urgent Revasc. (%) Death + MI (%) Death, MI, Urgent Revasc. (%) 1.32.61.93.64.90.31.90.62.32.3 * Investigator defined

17. NICE 1 and 4: Myocardial Infarction NICE 1 (Enoxaparin)(n=309) NICE 4 (Enoxaparin/Abciximab)(n=310) Clinical infarction (%) Any CK  3 x normal Any MB  3 x normal (CK may be normal) 2.63.37.81.94.212.4

18. Conclusions Based on Preliminary NICE Results u IV enoxaparin, used instead of UFH for coronary interventions: l Is associated with low rate of major bleeding l Slightly higher rates of CKMB release may represent more aggressive PCI (paradoxically higher with abciximab) l Appears safe and effective u IV enoxaparin, used instead of UFH for coronary interventions: l Is associated with low rate of major bleeding l Slightly higher rates of CKMB release may represent more aggressive PCI (paradoxically higher with abciximab) l Appears safe and effective