Interventional Pharmacology (poster 497-508)

The American Journal of Cardiology® | October 22-27, 2006 | TCT Abstracts/ElECTrONIC 195M

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http://www.attendeeinteractive.com/shows/tct0601

Interventional PharmacologyMonday, October 23, 2006 - Friday, October 27, 2006

(abstract nos. 497-508)

TCT-497

The Effects of Unfractionated Heparin and Low-Molecular-Weight Heparin on Platelet Activation

Wei Cui, Jing-chao Lu, Nan Guo, Fan Liu, Rui-qin Xie, Guo-qiang Gu, Jun Du TCT-2nd Hospital of Hebei Medical University, Shijiazhuang, China

Background: to compare the difference in platelet activation between unfractionated heparin (UFH) and low-molecular-weight heparin (LMWH) Fragmin. Methods: one hundred and twenty seven patients were enrolled in this study and divided into coronary angiography (caG) group and non-caG group. Patients in non-caG group were all the newly admitted inpatients, and randomly assigned to UFH group (5000 IU ) or Fragmin group (5000 anti-Xa IU ). blood samples were obtained through venipuncture to measure plasma cd62P, vWF and platelet membrane GPIIb/IIIa at baseline, 30 minutes and 1 hour after UFH or Fragmin administration. Patients in caG group were also randomly assigned to UFH group and Fragmin group. blood samples were obtained through arterial sheath immediately after artery canalization, 10 and 20 minutes after intra-arterial injection of 5000IU UFH or 5000IU anti-Xa Fragmin to measure plasma cd62P, vWF and platelet membrane GPIIb/IIIa. Results: the non-caG UFH group were more likely to have higher expression of platelet membrane GPIIb/IIIa, plasma levels of cd62P and vWF than those in non-caG Fragmin group at 30 minutes after corresponding drug administration (p<0.05). Although there were no significant differences between the two groups with respect to the expression of GPIIb/IIIa and plasma level of cd62P at 1 hour (all p>0.05), the level of vWF in non-caG UFH group was still significantly higher than that in non-CAG Fragmin group (p<0.05). the caG UFH group also showed a trend to have higher expression of GPIIb/IIIa, higher plasma level of cd62P than those in caG Fragmin group at 10 minutes and 20 minutes after corresponding drug administration, but the differences between the two groups were not statistically significant ( p>0.05). the level of vWF in caG UFH group were higher than that in caG Fragmin group at 10 minutes after administration (p<0.05), but there were no statistically significant difference between the two groups at 20 minutes (p>0.05).Conclusions: both UFH and Fragmin given intravenously could activate the platelet. the effect of platelet activation induced by UFH was more obvious than by Fragmin both during coronary angiography and in routine clinical practice.

TCT-498

Cost-Effectiveness of Bivalirudin Monotherapy for Patients Undergoing an Early Invasive Mangement for Acute Coronary Syndromes without ST-Elevation: Results from the Randomized ACUITY Trial

Duane S Pinto1,2, Gregg W Stone3,4, Brent T McLaurin5, David A Cox6, Chunxue Shi2, Elizabeth A Schneider2, David A Machon2, Ronna H Berezin2, Roxana Mehran3,4, Jeffrey W Moses3,4, E. Magnus Ohman7, Harvey D White8, Michele E Bertrand9, A. Michael Lincoff10, David J Cohen1,2 1Beth Israel Deaconess Medical Center, Boston, MA;2Harvard Clinical Research Institute, Boston, MA;3Columbia University, New York, NY;4Cardiovascular Research Foundation, New York, NY;5Anderson Area Medical Center, Anderson, SC;6Methodist Cardiology Physicians, Indianapolis, IN;7Duke University, Durham, NC;8Green Lane Hospital, Auckland, New Zealand9Hospital Cardiologique, Lambersart, France10The Cleveland Clinic Foundation, Cleveland, OH

Background: the large-scale, multicenter, randomized acUIty trial demonstrated that in patients with non-St elevation acute coronary syndromes (nSte-acS) undergoing early invasive management, bivalirudin

(bIV) alone yields similar rates of ischemic complications and less major and minor bleeding than regimens incorporating glycoprotein IIb/IIIa receptor inhibitors (GPI). the economic impact of this strategy is unknown.Methods: We performed a prospective economic analysis in acUIty. In the U.S., 7851 patients at 246 sites were randomized to: 1) heparin (UFH or enoxaparin) + GPI, 2) bIV + GPI or 3) bIV only. Index hospitalization and 30-day f/u costs were assessed from a U.S. healthcare perspective using resource-based costing, Medicare fee schedules, and hospital billing data.Results: baseline characteristics matched well (see table). 30-day death, MI, or urgent revascularization rates were similar for all groups. Major bleeding was reduced in patients assigned to bIV monotherapy compared to the GPI groups (p<0.01 for both comparisons). Length of stay (LoS) was reduced for both bIV groups compared to heparin + GPI (p<0.02 for both comparisons).

Heparin plus GPI

Bivalirudin plusGPI

BivalirudinAlone

P-value For A vs B

P-value forA vs C

number of pts 2609 2627 2615

Male (%) 68.7 67.4 66.9 0.32 0.16

diabetic (%) 31.7 30.7 32.1 0.59 0.94

troponin positive 49.7 49.2 51.5 0.71 0.24Length of Hospital Stay (days) [IQr]

2.32 [1.7, 4.0] 2.17 [1.6, 3.8]2.17 [1.6, 3.8]

0.01 0.008

death (%) 1.1 1.3 1.3 0.54 0.53Myocardial Infarction (%)

5.6 5.6 6.2 0.95 0.33

Urgent revascularization (%)

2.0 2.9 2.3 0.03 0.45

death or MI (%) 6.4 6.7 7.1 0.75 0.36composite Ischemic endpoint (%)

7.7 8.3 8.2 0.46 0.49

Major bleeding (%) 5.3 5.5 3.2 0.71 <0.001

Minor bleeding (%) 24.1 24.9 13.4 0.49 <0.001

Conclusions: In U.S. patients from acUIty, treatment with bIV monotherapy (compared to heparin + GPI) was associated with similar protection from ischemic events, and reduced bleeding and LoS. Hospital and 30-day costs for the 3 primary treatment groups will be available by 10/06. overall cost-effectiveness will be assessed after 1-yr f/u is completed.

TCT-499

Safety and Efficacy of Bivalirudin in ACS Patients Undergoing PCI: Impact of Duration of Upstream Infusion in the ACUITY Trial

David A Cox1, Charles V Pollack2, James Hoekstra3, Harvey D White4, Ramin Ebrahimi5, Lars H Rasmussen6, Hans Jürgen Rupprecht7, Gregg W Stone8 1Methodist Hospital, Indianapolis, IN;2Pennsylvania Hopsital, Philadelphia, PA;3Wake Forest University, Winston-Salem, NC;4Auckland City Hospital, Auckland, New Zealand5University of California Los Angeles and the Greater Los Angeles VA Center, Los Angeles, CA;6Aarhus University Hospital, Aalborg Hospital, Aalborg, Denmark7GPR Klinikum Rüsselsheim, Rüsselsheim, Germany8Columbia University Medical Center and The Cardiovascular Research Foundation, New York, NY

Background: Patients with acS are typically managed medically for approx. 20h prior to revascularization during which ongoing ischemia may occur. We sought to examine the utility of bivalirudin (biv) as an antithrombin agent (at) started at the time of presentation and continued through percutaneous coronary intervention (PcI) in patients with delayed times to intervention.Methods: In acUIty, 13,819 moderate and high risk acS patients undergoing an invasive strategy were randomized to heparin (unfractionated or enoxaparin) + GPIIb/IIIa inhibition (H+GPI) vs. biv + GPI vs. biv monotherapy (mono). the 30d rates of composite ischemia, major bleeding and net clinical outcomes (ischemia + bleeding) were examined in patients undergoing PCI ≤24h vs. >24h from randomization (rand).Results: PcI was performed in 7,774 patients (56.3 %), 6,321 (81.3%) of whom had PCI within 24h. Patients receiving PCI >24h from rand had significantly

��M The American Journal of Cardiology® | October 22-27, 2006 | TCT Abstracts/ElECTrONIC

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higher 30d rates of composite ischemia (10.4% vs. 8.4%, p=0.014), major bleeding (7.1% vs. 5.7%, p=0.038), and net clinical outcomes (15.9% vs. 12.6%, p<0.001). outcomes by rand appear in the table.

≤ 24h to PCI > 24h to PCI

Outcome H + GPIN=2071

Biv + GPIN=2146

Biv monoN=2104

H + GPI N=484

Biv + GPIN=458

Biv monoN=511

net clinical outcomescomposite ischemiaMajor bleeding

12.4%tct-7.8%tct-6.3%

14.2%tct-8.9%tct-7.1%

11.2%tct-8.4%tct-3.6%*

16.7%tct-9.7%tct-8.9%

18.3%tct-11.4%tct-9.4%

12.9%*tct-10.2%tct-3.3%*

*p<0.05

Conclusions: a delay in intervention of >24h is associated with increased ischemia and bleeding compared to more rapid therapy in acS. compared with H+GPI, Biv mono significantly reduces major bleeding regardless of time to intervention and is especially effective in improving net clinical outcomes in patients with delays to treatment.

TCT-500

Bivaluridin and proximal endovascular clamping for carotid artery stenting: results from a prospective randomized study

Eugenio Stabile, Luigi Salemme, Tullio Tesorio, Giovanni Sorropago, Angelo Cioppa, Vittorio Ambrosini, Gregory Pupusoi, Salvatore Battaglia, Paolo Rubino Clinica Montevergine, Mercogliano, AV, Italy

Background: the use of proximal endovascular clamping (Pec) led to a significant reduction of microembolization, during carotid artery stenting (caS). this device requires a large femoral sheath. Sheath size is a strong predictor of bleeding after percutaneous procedures. the use of direct thrombin inhibitors, i.e. bivalirudin, reduces such complications after PcI. to evaluate, in a randomized prospective study, safety and efficacy of bivaluridin vs. heparin during caS, using Pec as distal protection device.Methods: From december 2005 to may 2006, 90 consecutive patients undergoing caS using Pec, have been randomly assigned to one of the study arm (control arm: 100 UI/Kg heparin or bivaluridin arm: 0.75 mg/kg IV bolus of bivalirudin and infusion at 2.5mg/kg/h). all patients were chronically on aspirin and a thyenopiridine. Femoral sheaths were removed after 2 hours in case of bivaluridin and after 4 hours (assuming that act < 150 s) in case of heparin administration.Results: Procedural success was 100%, without any intraprocedural complications. In hospital Macce included no deaths, no mayor strokes, 2 % of minor strokes and no aMI. no difference of Macce was observed between the study groups. Post procedural haemoglobin drop was significatively lower in patients receiving bivaluridin (1,9 ± 0,2 g/dl vs 2,4 ± 0,1 g/dl; p< 0,05). When bivaluridin was administered, femoral sheath could be safely removed two hours after the procedure. thus resulting in a lower number of patients experiencing sheath induced leg ischemia.Conclusions: The use of direct thrombin inhibitors is a safe and efficient anticoagulation regimen during caS, using Pec as a distal protection device. this treatment reduce post procedural haemoglobin loss and allows an earlier removal of the large femoral sheath, thus reducing the incidence of post procedural leg ischemia. the clinical relevance of these data should be confirmed by multicenter randomized study.

TCT-501

Outcomes in Patients with NSTE-ACS Undergoing PCI on a Novel Tissue Factor/Factor VIIa Inhibitor (rNAPc2) with Full, Half-Dose or No Heparin in the ANTHEM-TIMI 32 Trial

Tara Narula1, Matthew C. Southard1, C. Michael Gibson2, Alain Bouchard3, Vibhuti N. Singh4, Michael Goulder5, Steven R. Deitcher6, Robert P. Giugliano1 1Brigham and Women’s Hospital, Boston, MA;2Beth Israel-Deaconess Medical Center, Boston, MA;3Baptist Medical Center, Birmingham, AL;4U of S. Florida & Suncoast CV Center, St. Petersburg, FL;5Nottingham Clinical Research Ltd, Nottingham, United Kingdom6Nuvelo, Inc., San Carlos, CA

Background: This prospective analysis evaluated the safety and efficacy of rnaPc2, a potent tF/FVIIa inhibitor that blocks thrombin generation, during PcI.Methods: In the double-blind ascending dose-ranging phase 203 pts received UFH or enoxaparin and were randomized 4:1 to rnaPc2 (1.5-10 mcg/kg) vs placebo. In the heparin de-escalation phase pts received 10 mcg/kg rnaPc2 with either ½ dose UFH (n=26) or no UFH (n=26). We compared outcomes in PcI pts receiving placebo vs high-dose (7.5-10 mcg/kg) rnaPc2 since these higher-doses suppress new thrombin generation.Results: PcI predischarge (n=119, 47%) was associated with nSte-MI (p<0.0001), higher tIMI risk score (p=0.04), and St depressions (p=0.047) at baseline. Most PcI pts received triple antiplatelet therapy with aspirin (100%), clopidogrel (99.2%), and GP IIb/IIIa inhibitor (74%). no statistical differences in efficacy or safety at 42 days in PCI pts on placebo (n=23) vs higher-dose rnaPc2 (n=48) occurred, although the rate of Holter ischemia was <1/3 with rnaPc2(table). In 24 pts during heparin de-escalation phase who had PcI, there was 1 peri-PcI MI (no UFH), 2 minimal bleeds (½ dose UFH), and 4 cases of procedure-related thrombus (no UFH).PcI. Study drug Placebo Higher-dose rnaPc2anticoagulant UFH or enox UFH, enox, or none p-valuen (%) pts undergoing PcI 23 (58%) 48 (52%) 0.70death by day 42 0% 0% n/areinfarction by day 42 0% 2.1% >0.99repeat revascularization by day 42 0% 6.3% 0.55recurrent angina by day 42 4.4% 6.3% >0.99Holter ischemia day 0-7 15.8% 4.9% 0.31any of the above 21.1% 17.1% 0.73Major or minor bleeding 0% 2.1% >0.99any bleeding 17.4% 12.5% 0.72Conclusions: rnaPc2 across a wide-range of doses was well tolerated in pts undergoing PcI, although some heparin appears necessary to avoid procedure-related thrombus. These preliminary data require confirmation in large-scale studies to determine if rnaPc2 improves clinical outcome during

TCT-502

Impact of Enoxaparin on Coronary Flow and Myocardial Blush Grade After Early Invasive Treatment During Acute Coronary Syndrome (ACS) - Results From the SYNERGY Library

Ricardo A Costa1, Gregg W Stone1, Kenneth Mahaffey2, Robert Califf2, Harvey White2, James Ferguson2, Dietrich Gulba2, Jacques Col2, Alexandra J Lansky1 1Cardiovascular Research Foundation and Columbia University Medical Center, New York, NY;2Duke Clinical Research Institute, Durhan, NC

Background: enoxaparin, a Xa-inhibitor precursor, was shown to be safe and non-inferior (death and myocardial infarction) at 30 days compared to unfractionated heparin (UFH) in the treatment of high-risk pts with acS in the SynerGy trial. Whether enoxaparin affects angiographic coronary and myocardial perfusion is not known.


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Methods: among 9978 acS patients randomized between aug/01 and dec/03 in the SynerGy trial to subcutaneous enoxaparin vs. intravenous UFH, consecutive 256 underwent blinded angiographic analysis at an independent core lab as part of the SynerGy Library. Intention-to-treat analysis included complete quantitative and qualitative assessment of the coronary tree, including TIMI flow and frame count and myocardial blush grade (MbG, previously validated with KaPPa 0.78).Results: baseline clinical characteristics were comparable among both groups. UFH pts had more moderate/severe calcification (21.5 vs. 6.8%, p=0.04), but there were similar rates of lesion ulceration (7.5 vs. 11.9%, p=0.40). angiographic results are shown in the table.Variable UFH Enoxaparin P ValuePreprocedureTIMI flow (0/1/2/3), % 11.9/3/9/76.1 15.3/8.5/5.1/71.1 0.45MbG (0/1/2/3), % 17.9/7.5/31.3/43.3 20.7/6.9/25.9/46.6 0.23corrected tIMI frame count, frames 35.5 35 0.79thrombus, % 19.4 18.6 0.91Lesion length, mm 15.1 14 0.46reference diameter, mm 2.93 2.75 0.07Minimum lumen diameter, mm 0.89 0.83 0.48% diameter stenosis 69.6 70 0.83FinalTIMI flow (0/1/2/3), % 0/0/1.5/98.5 5.1/3.4/0/91.5 0.02MbG (0/1/2/3), % 3.1/1.6/15.6/79.7 5.8/1.9/11.5/80.1 0.84corrected tIMI frame count, frames 17 18 0.84thrombus, % 0 3.4 0.22reference diameter, mm 2.82 2.75 0.39Minimum lumen diameter, mm 2.26 2.20 0.28% diameter stenosis 20 22.1 0.54

Conclusions: In the angiographic substudy of the SynerGy trial, despite the fact that post PCI TIMI-3 flow was lower with enoxaparin than UFH, tIMI frame counts, myocardial perfusion and residual thrombus were similar with both anticoagulants. These findings translated into similar clinical outcomes in the entire cohort, reinforcing the equivalence of enoxaparin and unfractionated heparin in this setting.

TCT-503

Pretreatment with Intracoronary Adenosine Reduces the Incidence of Myonecrosis after Non-urgent Percutaneous Coronary Intervention - A Prospective Randomized Study

Chi-Hang Lee, Adrian Low, Bee-Choo Tai, Melissa Co, Mark Y Chan, Jimmy Lim, Yean-Teng Lim, Huay-Cheem Tan National University Hospital, Singapore, Singapore

Background: Percutaneous coronary intervention (PcI) is associated with up to 30% incidence of myonecrosis. We propose that the hyperemic effect of adenosine could ameliorate the distal embolization of platelet thrombi associated with non-urgent PcI, & reduce the incidence of post-PcI myonecrosis.Methods: this was a prospective, randomized, open-label study. Patients who were scheduled for non-urgent PcI in de novo native coronary arteries were eligible. all patients were adequately pretreated with aspirin, clopidogrel & statin. Myonecrosis was measured by creatine Kinase (cK)-Mb elevation 12-24 hours after PcI.Results: a total of 62 patients were recruited and randomized into the adenosine group (n=31) or standard group (n=31). the baseline characteristics were similar in both groups. the adenosine group received 50μg adenosine bolus through the guiding catheter before wiring of each lesion, while

the standard group did not. after adenosine administration, no patients developed significant bradycardia requiring pacing. Drug-eluting stents were implanted in 12 (39%) & 15 (48%) patients in the adenosine & standard groups, respectively. Multi-vessel stenting was performed in 9 (29%) & 10 (32%) patients in the adenosine & standard groups, respectively. Post-PcI myonecrosis occurred more frequently in the standard group (39% vs. 13%, or 0.23, 95% cI 0.05 - 0.95, p = 0.020). after adjustment for drug-eluting stent implantation & multi-vessel stenting, the or was 0.19 (95% cI 0.05 - 0.72, p = 0.015). the median peak values of cK-Mb in the adenosine & standard groups were 2 & 4 μg/L respectively (p = 0.033). the adjusted difference was 1.95 μg/L (95% cI 0.13 - 3.77, p = 0.037). the incidences of myocardial infarction (>3x cK-Mb) were 6% & 16% in the adenosine & standard groups respectively (or 0.36; 95% cI 0.03 - 2.46, p = 0.229). the results remained unaltered after adjusting for drug-eluting stent implantation & multi-vessel stenting.Conclusions: bolus administration of 50μg of adenosine through the guiding catheter is associated with a 77% reduction in the occurrence of myonecrosis following non-urgent PcI in patients already pretreated with dual antiplatelet agents & statins.

TCT-504

A Phase 1/2 Trial of TG100-115, a Phosphatidylinositol-3 Kinase Inhibitor, in Acute ST Segment Elevation Myocardial Infarction Patients Treated by Percutaneous Coronary Intervention Indicates Acceptable Safety at Expected Therapeutic Concentrations

David Rizik1, Samin Sharma2, Kenneth Kent3, Jeffrey L. Anderson4, Steven Goldberg5, Ehtisham Mahmud6, Paul Casale7, Ron Waksman8, Bruce Brent9, Ian Gilchrist10, Reda Ibrahim11, Evelyne Goudreau12, Jolene Shorr13, David McClure13, Charles Theuer13, David Holmes14, TG001-03 Study Group 1Scottsdale Healthcare Hospital, Scottsdale, AZ;2Mount Sinai Medical Center, New York, NY;3Suburban General Hospital, Bethesda, MD;4LDS Hospital, Salt Lake City, UT;5University of Washington, Seattle, WA;6UCSD, San Diego, CA;7Lancaster General Hospital, Lancaster, PA;8WashingtonHospital Center, Washington, DC;9California Pacific Medical Center, San Francisco, CA;10Penn State University, Hershey, PA;11Montreal Heart Institute, Montreal, PQ, Canada12Virginia Commonwealth University, Richmond, VA;13TargeGen, San Diego, CA;14Mayo Clinic, Rochester, MN

Background: tG100-115 is a new chemical entity designed to complement currently available treatments for SteMI by reducing the contribution of reperfusion injury to infarct size. tG100-115 inhibits phosphatidylinositol-3 kinase (PI3K), a key signaling element that mediates receptor-induced responses such as leukocyte and platelet activation, vascular permeability, and cardiomyocyte contractility. as such, the compound should reduce microvascular obstruction, leukocyte activation and platelet activation following ischemia. These potential benefits have been documented in animal models of acute infarction in which administration of tG100-115 resulted in a significant decrease in infarct size. The objective was to determine the optimal dose of tG100-115 given intravenously following PcI for SteMI.Methods: Phase 1/2 first-in-human, placebo-controlled, dose escalation trial in acute, first-time STEMI patients undergoing PCI. Patients are randomized (4:1) to tG100-115 or placebo and four doses are studied in sequence: 0.04, 0.2, 0.4 and 0.6 mg/kg. Safety is monitored in real time and prior to each planned dose escalation by a Data Monitoring Committee (DMC). Efficacy measures include infarct size (assessed by cardiac Mr and SPect) and ejection fraction (assessed by cardiac Mr and echocardiography).Results: 45 subjects (age range: 42 to 78) have been dosed. the dMc authorized dosing at the 0.2 mg/kg level based on a safety evaluation of 18 subjects dosed at 0.04 mg/kg and authorized dosing at the 0.4 mg/kg dose level based on safety evaluation of 25 subjects dosed at the 0.2 mg/kg dose level. the drug has been well tolerated in initial patients dosed at 0.4 mg/kg. Human exposure at 0.2 mg/kg exceeded expected therapeutic concentrations based on pre-clinical rodent

��M The American Journal of Cardiology® | October 22-27, 2006 | TCT Abstracts/ElECTrONIC

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data. Updated safety and PK results will be presented.Conclusions: A first-in-human clinical trial of a new chemical entity that complements existing treatments for SteMI indicates acceptable safety at expected therapeutic concentrations.

TCT-505

Is Oral Rapamycin Useful in Preventing Coronary Stent Restenosis? A Randomized Study

Ricardo A Sarmiento1, Alejandro Cherro1, Jorge L SZARFER2, Angeles Videla Lynch1, Raul Solerno1, Diego Grinfeld1, Pablo Ferrari1, Anibal Campo1 1Hospital Frances, Buenos aires, Argentina2Hospital Argerich, Buenos aires, Argentina

Background: drug-eluting stents (utilizing rapamycin) have shown the ability to limit restenosis. oral rapamycin is an alternative delivery strategy that can target coronary lesions.Methods: between March 2003 and august 2004, 100 patients (pts) undergoing de novo coronary stenting (bare) were randomized to either oral rapamycin (treated immediately after the PcI with 6 mg loading dose, followed by 2 mg per day for 30 days) vs. control. Primary end Points were angiographic binary restenosis (Ir) and late loss (LL) determined by an independent core laboratory blinded to treatment allocation, at 8 month of follow up. Secondary end points were target lesion revascularization (tLr), incidence of death, acute myocardial infarction (aMI) and side adverse effect (Sae) after 12 month of follow up. rapamycin plasma levels were dosed at 3 week.Results: Fifty pts were randomized to oral rapamycin and 50 pts to control. the two groups were well matched for baseline clinical, angiographic and procedural characteristics. rapamycin blood level was: 6.83±2.3. Sae related to oral rapamycin were present in 38% of pts, 5 (10%) required medication discontinuation at days 7, 10 and 18. clinical follow-up, complete in all 100 pts is shown in the table. angiographic follow up, available in all arteries, showed a restenosis of 22% in control vs. 18.2% in oral rapamycin group p= nS.

basal reference Vessel diameter

basal Minimal Lumen diameter

basal Stenosis %

aMI deathbinary restenosis

tLrLL milimeters

rapamycin 2.95±0.39 0.65±0.16 77.75±7.14 1 ptc 0 ptc 18,2 %5 ptc (10%)

0.72±0.61

control3.00±0.35 p=nS

0.63±0.34 p=nS

80.4±6.35 p=nS

0 pts p=nS

1 ptc p=nS

22% p=nS7 pts (14 %) p=nS

0.77±0.74 p=nS

Conclusions: the absence of reduction in Ir and the incidence of Sae make the oral rapamycin at these doses a non eligible therapy for this population.

TCT-506

Angiographic Outcomes in Patients with Non-STE ACS Undergoing PCI Using Adjunctive Recombinant Nematode Anticoagulant Protein c2 Versus Placebo: An ANTHEM-TIMI 32 Angiographic Core Lab Analysis

Adrian Fluture1, Gregory R Giugliano2, Mathew C Southard3, Marc J Schweiger2, C Michael Gibson4, Jacquelin Buros3, Michael Goulder5, Steven Deitcher6, Robert P Giugliano3 1Baystate Medical Center / Tufts University School of Medicine, Springfield, MA;2Baystate Medical Center /Tufts University School of Medicine, Springfield, MA;3Brigham and Women’s Hospital, Harvard Medical School, Boston, MA;4Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA;5Nottingham Clinical Research ltd., Nottingham, United Kingdom6Nuvelo Inc, San Carlos, CA

Background: recurrent ischemic events in pts with acS remain high despite early invasive management, possibly due to suboptimal anticoagulation. rnaPc2 is a potent tF/factor VIIa inhibitor that blocks thrombin generation and was previously shown to be safe in elective pts undergoing PcI.Methods: antHeM-tIMI 32 was a randomized, double-blinded, phase II

dose-escalation and heparin de-escalation study of IV rnaPc2 as an adjunct to heparin + clopidogrel and GP IIb/IIIa inhibitor in pts with nSte-acS. We evaluated 120 angiograms (56 with PcI) in a blinded central core lab for angiographic outcomes and complications.Results: There were no significant differences in baseline angiographic parameters, thrombus, or PcI complications in pts treated with rnaPc2 vs placebo (table). during the heparin de-escalation phase (n=52) there were no statistically significant differences in angiographic core lab outcomes with rnaPc2 10 mcg/kg and either half-dose heparin (n=26) or no heparin (n=26) compared to either rnaPc2 with standard anticoagulation or placebo with standard anticoagulation.

angiographic core Lab baseline angiogram and PcI outcomesBaseline Post-PCI

Placebon = 31

rnaPc2n = 89

p-valuePlacebon = 16

rnaPc2n = 40

p-value

TIMI flow 2-3, n (%) 20 (77) 60 (83) 0.47 16 (100) 37 (97) >0.99ctFc*, mean ±Sd 53 ± 33 48 ± 30 0.47 26 ± 14 29 ± 19 0.58tMFc**, mean ±Sd 66 ± 8 70 ± 26 0.76 78 ± 8.5 64 ± 9.8 0.11tMPG*** 2-3, n (%) 15 (60) 34 (49) 0.36 10 (67) 17 (50) 0.28thrombus score > 2, n (%)

10 (38) 21(28) 0.34 0 0 n/a

any complications, n (%) - - - 5 (31) 12 (30) >0.99*ctFc=corrected tIMI frame count ; **tMFc=tIMI myocardial frame count; ***tMPG = tIMI myocardial perfusion grade

Conclusions: IV rnaPc2 10 mcg/kg added to standard anticoagulant therapy appears safe and effective at preventing angiographic complications during PcI compared to placebo in pts with acS. Future PcI studies with low dose or no heparin in pts receiving rnaPc2 are warranted.

TCT-507

Impact of Lipid-lowering Therapy with Pitavastatin, a New HMG-CoA Reductase Inhibitor, on Regression of Coronary Artery Plaque: A Three-Dimensional Intravascular Ultrasound Study

Hiroaki Takashima1, Katsuhisa Waseda2, Kenji Asai1, Yoshinori Wakita1, Yasuo Kuroda1, Takashi Kosaka1, Yasushi Kuhara1, Daiki Kato1, Tatsuya Yasukawa3, Yukio Ozaki4, Takayuki Ito1 1Department of Cardiology, Aichi Medical University, Nagakute, Japan2Center for Research in Cardiovascular Interventions, Stanford University, Stanford, CA;3Yasukawa Clinic, Nagoya, Japan4Division of Cardiology, Fujita Health University, Toyoake, Japan

Background: recent lipid-lowering trials have reported that statin may retard progression or stimulate regression of human coronary plaque. the objective was to investigate the effect of pitavastatin, a newly developed statin, on regression of human coronary plaque.Methods: eighty two patients with successful percutaneous coronary intervention were assigned to either lipid-lowering therapy (n=41; pitavastatin 2 mg/day) or control group (n=41; diet only). Volumetric intravascular ultrasound analyses were performed at baseline and on average 9-month follow-up in matched left main coronary artery site.Results: Baseline lipids profile and IVUS measurements were similar between both groups. A significant reduction in LDL cholesterol (LDL-C) level of 33.2% (p<0.001) was observed in the pitavastatin group. Plaque volume index (PVI) was significantly reduced in the pitavastatin group (10.6±9.4% decrease) compared with the control group (8.1±14.0% increase, p<0.001). there were positive correlations between the percent change in PVI and follow-up LdL-c level (r=0.500, p<0.001) and the percent change in LdL-c level (r=0.479, p<0.001). regression of PVI was observed in all patients with follow-up LdL-c levels of <75 mg/dL.


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LdL-c and 3d-IVUS measurementsPitavastatin control p value

baseline LdL-c (mg/dL) 132.5±20.0 126.9±20.3 0.206Follow-up LdL-c (mg/dL) 87.4±18.1 124.2±18.3 <0.001change in LdL-c (%) -33.2±14.5 -0.2±19.0 <0.001baseline PVI (mm3/mm) 9.6±2.5 9.4±2.3 0.706Follow-up PVI (mm3/mm) 8.6±2.5 10.2±2.7 0.01change in PVI (%) -10.6±9.4 8.1±14.0 <0.001correlation between %change in LdL-c and %change in PVIy=0.3069x+3.8219, r=0.479, p<0.001

Conclusions: Lipid-lowering therapy with pitavastatin significantly induced coronary plaque regression associated with a significant reduction of LDL-C level. The percent change in PVI showed a significant positive correlation with the percent change in LdL-c level.

TCT-508

Safety and Efficacy of Combined Antiplatelet-Warfarin Therapy after Coronary Stenting

Pasi Karjalainen1, Antti Ylitalo1, Pekka Porela2, Tuukka Airaksinen2, Saila Vikman3, Matti Niemelä4, Kai Nyman5, Marianne Vaittinen6, Juhani Airaksinen2 1Department of Cardiology, Satakunta Central Hospital, Pori, Finland2Department of Internal Medicine, Turku University Hospital, Turku, Finland3Department of Cardiology, Tampere University Hospital, Tampere, Finland4Department of Cardiology, Oulu University Hospital, Oulu, Finland5Department of Cardiology, Jyväskylä Central Hospital, Jyväskylä, Finland6Department of Cardiology, Vaasa Central Hospital, Vaasa, Finland

Background: there is no evidence-based antiplatelet treatment strategy for patients receiving long-term warfarin therapy during coronary stenting, and the bleeding and thrombotic risks of various drug combinations are largely unknown.Methods: We analysed retrospectively all consecutive patients on warfarin therapy (n=239, mean age 70 years, men 74) who underwent percutaneous coronary intervention (PcI) in six hospitals in 2003-4. In each centre, an age- and sex-matched control group with similar disease was collected from the same study period. The primary end point was defined as the occurrence of death, myocardial infarction, target vessel revascularization or stent thrombosis at 12 months.Results: Patients in warfarin group were discharged with following drug combinations: warfarin and aspirin 21%; warfarin and clopidogrel 19%; warfarin, aspirin and clopidogrel 46%; aspirin and clopidogrel 13 %. the duration of hospitalization after PcI was longer in warfarin treated patients (3.6 vs. 2.4 days, p=0.005). the occurrence of primary end point was 21% in warfarin group and 11% in control group (Table, p=0.003). No significant difference in end points was observed between various drug combinations.

table. Summary of baseline data and outcome events during follow-up.Warfarin patients(n = 239)

Control patients(n = 239)

p value

baseline characteristicsdiabetes, n (%) 71 (30) 50 (21) 0.027Heart Failure, n (%) 58 (24) 12 (5) <0.001Previous Stroke, n (%) 49 (21) 13 (5) <0.001Previous MI, n (%) 99 (41) 73 (31) 0.013Gp IIb/IIIa inhibitor, n (%) 83 (35) 70 (29) 0.20deS patients, n (%) 101 (42) 98 (41) 0.7812 Months follow-upPrimary endpointsdeath, n (%) 17 (7) 6 (3) 0.019MI, n (%) 19 (8) 8 (3) 0.029tVr, n (%) 23 (10) 17 (7) 0.32Stent thrombosis, (%) 5 (2) 2 (1) 0.25overall, n (%) 50 (21) 26 (11) 0.003Secondary endpointsMajor bleeding, n (%) 14 (6) 7 (3) 0.12Stroke, n (%) 7 (3) 5 (2) 0.56

Conclusions: our study shows that the long-term prognosis is unsatisfactory in warfarin treated patients irrespective of used drug combinations.

Documents

Interventional Pharmacology (poster 497-508)