ECLIPSE Trial: Ensure

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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 TrialApril 2nd
Chicago, IL
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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 Employee Cordis He
rbert Hutman Employee Cordis William
Bachinsky No relationships to disclose Patrick
Cambier No relationships to disclose Robert
Stoler No relationships to disclose Janah
Aji No relationships to disclose Jason
Rogers No relationships to disclose Ravi
Nair No relationships to disclose
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ECLIPSE TrialBackground (1)

• 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

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ECLIPSE TrialBackground (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

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ECLIPSE TrialEclipse 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.

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ECLIPSE TrialDegradation of PGA

• The PGA plug undergoes hydrolysis in the body and
  is degraded into CO2 and H2O via the Kreb Cycle
  over a 3-month period

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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-day
7-day
14-day
30-day
60-day
90-day
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ECLIPSE Trial ECLIPSE Trial Design

• U.S. multicenter pivotal study comparing ExoSeal?
  and manual compression with 21 randomization to
  assess the safety and efficacy of ExoSeal? in
  patients undergoing 6Fr. diagnostic and
  interventional procedures in the coronary and
  peripheral vasculatures

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ECLIPSE Trial Objectives

• 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

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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

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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

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ECLIPSE Trial Key Inclusion Criteria

• 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

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ECLIPSE Trial Key Exclusion Criteria

• Uncontrolled HTN at time of sheath removal (BP ?
  180/110mmHg)
• BMI gt 40 kg/m2
• 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

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ECLIPSE Trial Study Definitions

• 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

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ECLIPSE Trial Study Definitions

• 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

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ECLIPSE Trial Study Definitions

• 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 (gt30 days) nerve injury at the access
  site or surgery for it

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ECLIPSE Trial Study Enrollment
Investigational Site Study Investigator Randomized Roll-in Total
Pinnacle Health at Harrisburg William Bachinsky, MD 65 7 72
New York Presbyterian Hospital S. Chiu Wong, MD 51 6 57
Morton Plant Hospital Patrick Cambier, MD 45 5 50
Baylor Research Institute Robert Stoler, MD 39 6 45
Cooper Health Systems Janah Aji, MD 35 8 43
UC Davis Medical Center Jason Rogers, MD 32 6 38
Heart Center of Indiana James Hermiller, MD 26 4 30
University Hospitals of Cleveland Ravi Nair, MD 23 6 29
Wake Heart Research Lee Jobe, MD 18 3 21
LDS Hospitals Peter Casterella, MD 15 5 20
Barnes-Jewish Hospital John Lasala, MD, PhD 14 6 20
Sutter memorial Hospital David Roberts, MD 13 4 17
St. Josephs Hospital Health Center Mike Fischi, MD 9 6 15
Hahnemann Hospital Daniel McCormick, DO 6 4 10
Mayo Clinic Hospital John Sweeny, MD 4 5 9
Stanford University Medical Center Alan Yeung, MD 3 4 7
Swedish Medical Center Paul Huang , MD 3 2 5
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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
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ECLIPSE Trial Patient Enrollment
30-day FU N259 ( 97.0)
30-day FU N128 (95.5)
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ECLIPSE Trial Baseline Demographics
Roll-in(N87) ExoSeal(N267) MC(N134) p-value
Mean Age (years) 63.3 11.61 63.3 11.13 61.4 10.47 0.0896
Female () 33.3 31.8 38.1 0.2206
Diabetes Mellitus () 24.1 25.5 32.8 0.1265
Renal Insufficiency () 8.1 8.6 6.7 0.5636
Body Mass Index (kg/m2) 29.7 4.64 28.9 4.99 29.5 5.40 0.4445
Baseline Hematocrit () 40.4 41.4 40.5 0.1654
GP IIb/IIIa Use Pre and/or During Procedure () 13.8 14.2 11.2 0.4379
P-values are based on the comparison of the two
randomized cohorts
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ECLIPSE Trial Procedural Characteristics
Roll-in(N87) ExoSeal(N267) MC(N134) p-value
Type of Procedure () Diagnostic Interventional 66.733.3 50.249.8 49.350.8 0.9158
Type of Catheterization() Cardiac Peripheral 92.08.1 91.09.0 94.85.2 0.2351
ACT Level (seconds) Prior to Sheath Removal 168.4 54.79 181.3 56.01 142.1 33.94 lt0.0001
P-values are based on the comparison of the two
randomized cohorts
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ECLIPSE Trial Results Primary Effectiveness
Endpoints
Roll-in(N87) ExoSeal(N267) MC(N134) p-value
Procedure Success 95.4 91.8 91.0 0.8500
Device Success 95.4 89.1 - -
TTH (min.) 4.68 ? 19.4 4.38 ? 11.6 20.05 ? 22.5 lt0.0001
TTA (hr.) 1.98 ? 2.59 2.54 ? 5.02 6.24 ? 13.34 0.0028
TT Eligibility for Hospital Discharge (hr.) 9.72 ? 14.2 12.57 ? 13.9 16.26 ? 27.5 0.1540
TT Hospital Discharge (hr.) 13.64 ? 18.5 16.77 ? 19.8 19.35 ? 29.2 0.3612
TT Device Deployment (min.) 0.94 ? 1.13 1.01 ? 2.12 - -
1 Endpoint
P-values are based on the comparison of the two
randomized cohorts
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ECLIPSE Trial Time to Hemostasis Randomized
Patients
Manual Compression (N134)
ExoSeal (N267)
P0.0080
P0.1430
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ECLIPSE Trial TTH TTA Patients Receiving GP
IIb/IIIa During Procedure
P0.0125
P0.0220
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ECLIPSE Trial Results Primary 30-Day Safety
Endpoints
Roll-in(N87) ExoSeal(N266) MC(N134)
Composite Major Adverse Event 0.0 0.0 0.0
Vascular Repair 0.0 0.0 0.0
Access Site Related Bleeding Requiring Transfusion 0.0 0.0 0.0
Access Site Related Infection Requiring Treatment 0.0 0.0 0.0
Any New Documented Ipsilateral Lower Extremity Ischemia 0.0 0.0 0.0
Surgery for Access Site-Related Nerve Injury 0.0 0.0 0.0
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ECLIPSE Trial Results Secondary Safety Endpoints
Roll-in(N87) ExoSeal(N266) MC(N134) p-value
Rebleeding following initial hemostasis 3.4 (3) 5.3 (14) 2.2 (3) 0.1953
Access site related bleeding requiring gt30 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 injury 0.0 (0) 0.4 (1) 0.0 (0) 1.0000
Retroperitoneal bleeding 0.0 (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 pulse 1.1 (1) 0.0 (0) 0.0 (1) --
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ECLIPSE Trial Conclusions (1)

• 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

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ECLIPSE Trial Conclusions (2)

• 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.

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Treatment of Calcified Lesion
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Back-up Slides
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ECLIPSE Trial Patients with Retroperitoneal
Bleeding

• Retroperitoneal bleed in 2 patients (0.8) in
  randomized VCD arm
• 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
• 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

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ECLIPSE Trial Time to Discharge Diagnostic vs.
Interventional
P0.6720
P0.9460
P0.2420
P0.1257
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ECLIPSE TrialPatient Disposition
Roll-in(N87) ExoSeal(N267) MC(N134)
Treated
Randomized (ITT) -- 267/267 (100.0) 134/134 (100.0)
Per Protocol -- 233/267 (87.3) 115/134 (85.8)
Safety Population 87/87 (100.0) 266/267 (99.6) 134/134 (100.0)
Completed Study 83/87 (95.4) 259/267 (97.0) 128/134 (95.5)
Withdrew from Treatment 4/87 (4.6) 8/267 (3.0) 6/134 (4.5)
Reasons for Early Withdrawal
Withdrew Consent 1/87 (1.1) 0/267 (0.0) 1/134 (0.7)
Adverse Event 0/87 (0.0) 1/267 (0.4) 0/134 (0.0)
Lost to Follow-up 3/87 (3.4) 7/267 (2.6) 4/134 (3.0)
Death 0/87 (0.0) 0/267 (0.0) 0/134 (0.0)
Other 0/87 (0.0) 0/267 (0.0) 1/134 (0.7)
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ECLIPSE TrialDevice / Procedural Failures with
ExoSeal
Site Patient Randomized Treatment Time to Hemostasis Hemostasis Achieved MAEs
025 003 Roll-in 7 Yes No
025 004 Roll-in 10 Yes No
035 002 Roll-in 21 Yes No
266 011 VCD 5 Yes No
025 031 VCD 9 Yes No
401 026 VCD 11 Yes No
095 009 VCD 12 Yes No
266 039 VCD 12 Yes No
419 009 VCD 14 Yes No
266 022 VCD 15 Yes No
196 010 VCD 20 Yes No
417 036 VCD 20 Yes No
416 028 VCD 23 Yes No
025 009 VCD 25 Yes No
416 026 VCD 25 Yes No
280 022 VCD 30 Yes No
417 012 VCD 30 Yes No
416 042 VCD 34 Yes No
Procedural failures were due to failure to
achieve hemostasis by assigned method
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Other Vascular Closure DevicesDefinitions of
Procedural Device Success
Mynx Mynx Mynx
Device Success 93.2 Deploy delivery system, deliver the sealant and achieve hemostasis
Procedure Success 99.5 Hemostasis using any method with freedom from major complications
MATRIX MATRIX MATRIX
Device Success 90.5 Deploy delivery system, inject the precursor and achieve hemostasis
Procedure Success 97.9 Hemostasis using any method with freedom from major complications
StarClose StarClose StarClose
Device Success 94.1 Hemostasis using StarClose or adjunctive compression in ?5 minutes, and freedom from major vascular complications
Procedure Success 100 Hemostasis using any method and freedom from major vascular complications
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Other Vascular Closure DevicesPublished TTH and
TTA
Vascular Closure Device (VCD) N TTH(min) TTH(min) TTA(hrs) TTA(hrs) Major Complications Major Complications Minor Complications Minor Complications
Vascular Closure Device (VCD) N VCD MC VCD MC VCD MC VCD MC
Angiolink(6 Fr.) 50 5.9 21.2 3.1 6.3 0.0 5.3 9.7 15.8
Angioseal 100 2.0 10.6 NA NA NA NA 12 14
Duett 630 7.0 20.0 5.1 11.8 3.6 1.7 NA NA
Sponge 141 8.2 14.1 2.7 7.1 0.0 0.0 5.9 8.9
Mynxnon-randomized 190 1.3 2.6 0.5 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.
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ECLIPSE Trial Time to Ambulation Randomized
Patients
Manual Compression (N134)
ExoSeal (N267)
P0.0021
P0.7299
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ECLIPSE Trial Time to Discharge Diagnostic vs.
Interventional
P0.6720
P0.9460
P0.2420
P0.1257