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ECLIPSE Trial: Ensures Vascular Closure Device Speeds Hemostasis S. Chiu Wong MD Director, Cardiac Catheterization Laboratories New York Presbyterian Hosp.- Cornell Campus Professor of Medicine Weill Medical College of Cornell University SCAI / ACCi2 2008 Late Breaking Trial April 2 nd Chicago, IL Slide 2 Presenter Disclosure Information ECLIPSE Trial: Ensures Vascular Closure Device Speeds Hemostasis The following relationships exist related to this presentation: S. Chiu Wong MD Consultant Cordis Modest Level James Hermiller Speakers Bureau Cordis Modest Level Dennis Donohoe EmployeeCordis Herbert HutmanEmployee Cordis William BachinskyNo relationships to disclose Patrick CambierNo relationships to disclose Robert StolerNo relationships to disclose Janah AjiNo relationships to disclose Jason RogersNo relationships to disclose Ravi NairNo relationships to disclose Slide 3 In 2007, it has been estimated that ~6 million interventional and diagnostic procedures (cardiac & Peripheral) were performed in the U.S.with 90% via the femoral approach The currently approved femoral closure devices account for about 33% of access site closures following these percutaneous invasive procedures ECLIPSE Trial Background (1) Slide 4 ECLIPSE Trial Background (2) Although most of the currently available access site closures devices have demonstrated reduced time to ambulation and hemostasis with similar complication rates compared to manual compression, the adoption rate is relatively low due to limitations associated with these devices Slide 5 ECLIPSE Trial Eclipse Closure Device The investigational ExoSeal device (Cordis, Miami FL) is a novel 3rd generation 6 Fr. extra- vascular closure device with an unique deployment mechanism that delivers a poly-glycolic acid (PGA) felt-like plug atop the femoral artery anchored by the neuro-vascular bundle sheath. Slide 6 ECLIPSE Trial Degradation of PGA The PGA plug undergoes hydrolysis in the body and is degraded into CO 2 and H 2 O via the Kreb Cycle over a 3-month period Slide 7 ECLIPSE Trial Pre-clinical Murine Gluteal Model: Evaluate Absorption & Tissue Reaction No adverse tissue reaction to plugs at 14, 30 or 60 days post- implantation The PGA Plugs were almost completely absorbed at 60 days 3-day7-day 30-day 60-day 14-day 90-day Slide 8 U.S. multicenter pivotal study comparing ExoSeal and manual compression with 2:1 randomization to assess the safety and efficacy of ExoSeal in patients undergoing 6Fr. diagnostic and interventional procedures in the coronary and peripheral vasculatures ECLIPSE Trial ECLIPSE Trial Design Slide 9 Two primary effectiveness endpoints to be tested for superiority: Time to hemostasis (TTH) Time to ambulation (TTA) Primary safety endpoint to be tested for non-inferiority: 30-day combined rate of access site related complications including bleeding, infection, ischemia or injury requiring medical or surgical treatment ECLIPSE Trial Objectives Slide 10 ECLIPSE Trial Sample Size Justification (1) A minimum sample size of 390 randomized patients (260 VCD patients and 130 MC patients) is required to: Detect a 5 minute reduction in mean TTH for VCD vs. MC with over 90% power and a 5% two-sided (2.5% one-sided) type I error Detect a 2-hour reduction in mean TTA for VCD vs. MC with over 90% power and a 5% two-sided (2.5% one-sided) type I error Slide 11 ECLIPSE Trial Sample Size Justification (2) Rule out 4% disadvantage for VCD vs. MC in the incidence of major complications using a 95% upper confidence bound with 80% power and a 5% one-sided type I error In order to ensure that a minimum of 390 patients enrolled into the trial with complete follow-up, a total of 400 patients study was proposed Slide 12 Age between 18 and 85 years Ability to undergo emergent vascular surgery if complication relates to VCD or MC occurs. Placement of a 6F arterial sheath in the common femoral artery Target vessel lumen diameter 5mm ECLIPSE Trial Key Inclusion Criteria Slide 13 Uncontrolled HTN at time of sheath removal (BP 180/110mmHg) BMI > 40 kg/m 2 Prior femoral vascular surgery or vascular graft Planned repeat arterial access at closure site 30 days post procedure Previous target femoral artery closure 30 days Calcium or atherosclerostic plaque 1 cm from the puncture site ECLIPSE Trial Key Exclusion Criteria Slide 14 Time to Hemostasis (TTH): Time to achieve no or minimal subcutaneous oozing and absence of expanding or developing hematoma following sheath removal Time to Ambulation (TTA): Time from sheath removal to patient able to stand and walk at least 10 meters without re-bleed Time to Eligibility for Hospital Discharge: Time of the access site closure to the time when patient is eligible for discharge as per the judgment of the treating physician Time to Discharge: Time of access site closure to time of patient actually being discharged ECLIPSE Trial Study Definitions Slide 15 Device Success: Successful deployment of PGA plug, removal of intact delivery system, and hemostasis achieved 5 minutes Procedural Success: Initial hemostasis achieved by assigned method with none of the primary safety endpoint related major adverse events on day of procedure and at 30 days ECLIPSE Trial Study Definitions Slide 16 Major Adverse Events: Vascular injury requiring vascular repair (via surgery, ultrasound-guided compression, transcatheter embolization, or stent graft) Access site-related bleeding requiring transfusion Access site-related infection requiring IV/IM antibiotics and/or extended hospitalization Any new ipsilateral lower extremity ischemia Permanent (>30 days) nerve injury at the access site or surgery for it ECLIPSE Trial Study Definitions Slide 17 ECLIPSE Trial Study Enrollment Investigational Site Study InvestigatorRandomizedRoll-inTotal Pinnacle Health at HarrisburgWilliam Bachinsky, MD65772 New York Presbyterian HospitalS. Chiu Wong, MD51657 Morton Plant HospitalPatrick Cambier, MD45550 Baylor Research InstituteRobert Stoler, MD39645 Cooper Health SystemsJanah Aji, MD35843 UC Davis Medical CenterJason Rogers, MD32638 Heart Center of IndianaJames Hermiller, MD26430 University Hospitals of ClevelandRavi Nair, MD23629 Wake Heart ResearchLee Jobe, MD18321 LDS HospitalsPeter Casterella, MD15520 Barnes-Jewish HospitalJohn Lasala, MD, PhD14620 Sutter memorial HospitalDavid Roberts, MD13417 St. Josephs Hospital Health CenterMike Fischi, MD9615 Hahnemann HospitalDaniel McCormick, DO6410 Mayo Clinic HospitalJohn Sweeny, MD459 Stanford University Medical CenterAlan Yeung, MD347 Swedish Medical CenterPaul Huang, MD325 Slide 18 ECLIPSE Trial Deployment Procedure Insert device into sheath to level of black marker band Retract sheath checking for pulsatile flow Retract while compressing green cowling to secure Retract sheath & device until non-pulsatile flow Indicator window changes to black, depress plug deployment button Remove ExoSeal device and sheath Slide 19 ECLIPSE Trial Patient Enrollment ExoSeal 6F VCD (17 U.S. Sites) N = 488 Randomized N = 401 Roll-in N = 87 ExoSeal (N=267)Manual Compression (n=134) Withdrawn N = 6 (4.5%) 30-day FU N=259 ( 97.0%) 30-day FU N=128 (95.5%) Withdrawn N = 8 (3.0%) Withdrawn N = 4 (4.6%) 30 day FU N = 83 (95.4%) Slide 20 ECLIPSE Trial Baseline Demographics Roll-in (N=87) ExoSeal (N=267) MC (N=134) p- value Mean Age (years)63.3 11.6163.3 11.1361.4 10.470.0896 Female (%)33.331.838.10.2206 Diabetes Mellitus (%)24.125.532.80.1265 Renal Insufficiency (%)8.18.66.70.5636 Body Mass Index (kg/m 2 )29.7 4.6428.9 4.9929.5 5.400.4445 Baseline Hematocrit (%)40.441.440.50.1654 GP IIb/IIIa Use Pre and/or During Procedure (%) 13.814.211.20.4379 P-values are based on the comparison of the two randomized cohorts Slide 21 ECLIPSE Trial Procedural Characteristics Roll-in (N=87) ExoSeal (N=267) MC (N=134) p-value Type of Procedure (%) Diagnostic Interventional 66.7 33.3 50.2 49.8 49.3 50.8 0.9158 Type of Catheterization(%) Cardiac Peripheral 92.0 8.1 91.0 9.0 94.8 5.2 0.2351 ACT Level (seconds) Prior to Sheath Removal 168.4 54.79181.3 56.01142.1 33.9430 min. for hemostasis 1.1% (1)0.4% (1)0.7% (1)1.0000 Access site hematoma 6cm 3.4% (3)1.9% (5)0.7% (1)0.6683 Transient access site-related nerve injury0.0% (0)0.4% (1)0.0% (0)1.0000 Retroperitoneal bleeding0.0% (0)0.8% (2)0.0% (0)0.5533 Ecchymosis 6cm 1.1% (1)0.0% (0)0.7% (1)0.3350 Decrease in pedal pulse1.1% (1)0.0% (0)0.0% (1) -- No incidence of pseudoaneurysm not requiring treatment; treated pseudoaneurysm; documented AV fistula; post-hospital discharge access site related bleeding; ipsilateral lower extremity arterial emboli; transient loss of ipsilateral lower extremity pulse; ipsilateral DVT; access site related vessel laceration; access site wound dehiscence; treated, localized access site infection; ipsilateral peripheral artery total occlusion; intraluminal plug delivery not requiring surgical intervention; or death. P-values are based on the comparison of the two randomized cohorts Slide 27 In this multi-center randomized trial in pts following 6 Fr. diagnostic/interventional procedures, a significant reduction in the TTH and TTA (primary effectiveness endpoints) was achieved in pts treated with the investigational ExoSeal device compared with MC Device deployment was achieved promptly in about 1 minute on average following procedure There was no difference in procedural success rates in both the ExoSeal and MC groups ECLIPSE Trial Conclusions (1) Slide 28 Remarkably, there were no 30-day combined access site related complications (primary safety endpoint) reported in either treatment cohort Exoseal is non-inferior to MC in composite major adverse event at the pre-specified 4% margin level Exoseal compares favorably to manual compression for arteriotomy site management post 6 Fr. invasive/interventional procedures. ECLIPSE Trial Conclusions (2) Slide 29 Treatment of Calcified Lesion Slide 30 Back-up Slides Slide 31 Retroperitoneal bleed in 2 patients (0.8%) in randomized VCD arm 1)First patient (interventional / cardiac): Diagnosed on CT scan / leg Ultrasound normal No documented back pain Ambulation was delayed No transfusion given HCT decreased from 41.3 to 32.1 at discharge Length of Hospital stay 4/17/07 - 4/20/07 2)Second patient (interventional / cardiac): Localized swelling noted on routine groin check (Pt complaining of right groin discomfort, no documented back pain, hypotension or nausea) CT confirmed small, confined retroperitoneal bleed HCT decrease from 27.8 to 25.4, HCT 31.3 at discharge No transfusion given Length of Hospital stay 5/22/07 - 5/26/07 ECLIPSE Trial Patients with Retroperitoneal Bleeding Slide 32 P=0.2420 P=0.6720 P=0.1257 P=0.9460 ECLIPSE Trial Time to Discharge: Diagnostic vs. Interventional Slide 33 ECLIPSE Trial Patient Disposition Roll-in (N=87) ExoSeal (N=267) MC (N=134) Treated Randomized (ITT)--267/267 (100.0%)134/134 (100.0%) Per Protocol--233/267 (87.3%)115/134 (85.8%) Safety Population87/87 (100.0%)266/267 (99.6%)134/134 (100.0%) Completed Study83/87 (95.4%)259/267 (97.0%)128/134 (95.5%) Withdrew from Treatment4/87 (4.6%)8/267 (3.0%)6/134 (4.5%) Reasons for Early Withdrawal Withdrew Consent1/87 (1.1%)0/267 (0.0%)1/134 (0.7%) Adverse Event0/87 (0.0%)1/267 (0.4%)0/134 (0.0%) Lost to Follow-up3/87 (3.4%)7/267 (2.6%)4/134 (3.0%) Death0/87 (0.0%)0/267 (0.0%)0/134 (0.0%) Other0/87 (0.0%)0/267 (0.0%)1/134 (0.7%) Slide 34 ECLIPSE Trial Device / Procedural Failures with ExoSeal SitePatientRandomized Treatment Time to HemostasisHemostasis Achieved MAEs 025003Roll-in7YesNo 025004Roll-in10YesNo 035002Roll-in21YesNo 266011VCD5YesNo 025031VCD9YesNo 401026VCD11YesNo 095009VCD12YesNo 266039VCD12YesNo 419009VCD14YesNo 266022VCD15YesNo 196010VCD20YesNo 417036VCD20YesNo 416028VCD23YesNo 025009VCD25YesNo 416026VCD25YesNo 280022VCD30YesNo 417012VCD30YesNo 416042VCD34YesNo Procedural failures were due to failure to achieve hemostasis by assigned method Slide 35 Other Vascular Closure Devices Definitions of Procedural & Device Success Mynx Device Success93.2% Deploy delivery system, deliver the sealant and achieve hemostasis Procedure Success99.5% Hemostasis using any method with freedom from major complications MATRIX Device Success90.5% Deploy delivery system, inject the precursor and achieve hemostasis Procedure Success97.9% Hemostasis using any method with freedom from major complications StarClose Device Success94.1% Hemostasis using StarClose or adjunctive compression in 5 minutes, and freedom from major vascular complications Procedure Success100% Hemostasis using any method and freedom from major vascular complications Slide 36 Other Vascular Closure Devices Published TTH and TTA Vascular Closure Device (VCD) N TTH (min) TTA (hrs) Major Complications Minor Complications VCDMCVCDMCVCDMCVCDMC Angiolink (6 Fr.) 505.921.23.16.30.0%5.3%9.7%15.8% Angioseal1002.010.6NA 12%14% Duett6307.020.05.111.83.6%1.7%NA Sponge1418.214.12.77.10.0% 5.9%8.9% Mynx non-randomized 1901.32.60.5%3.7% In the randomized studies, TTH and TTA were significantly improved with VCDs as compared with manual compression. Complication rates were not significantly different between both treatments in any of these randomized studies. Slide 37 ECLIPSE Trial Time to Ambulation: Randomized Patients ExoSeal (N=267) Manual Compression (N=134) P=0.0021 P=0.7299 Slide 38 P=0.2420 P=0.6720 P=0.1257 P=0.9460 ECLIPSE Trial Time to Discharge: Diagnostic vs. Interventional