Endovascular Valve Edge-to-Edge REpair Study (EVEREST II) Randomized Clinical Trial: Primary Safety and Efficacy Endpoints

1
Endovascular Valve Edge-to-Edge REpair Study
(EVEREST II)Randomized Clinical Trial Primary
Safety and Efficacy Endpoints
Ted Feldman, Laura Mauri, Elyse Foster, Don
Glower on behalf of the EVEREST II Investigators

• American College of Cardiology
• March 14, 2010
• Atlanta, GA

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Disclosures

• Research Grants Abbott, Edwards
• Consultant Abbott, Edwards

3
Perspective

• gt250,000 cases of significant Mitral
  Regurgitation diagnosed annually in the US
• Current therapeutic options
• Medical management
• Effective in symptom management
• Ineffective in treating underlying
  pathophysiology or disease progression
• Surgical Repair or Replacement (Standard of Care)
• Effective yet invasive with associated morbidity
• Only 20 of patients with significant MR undergo
  MV surgery
• Unmet need for an effective less invasive option

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Catheter-Based Mitral Valve Repair MitraClip
System
5
Clinical Experience
Study Population n
EVEREST I (Feasibility) Non-randomized 55
EVEREST II Pre-randomization 60
EVEREST II High Risk Registry 78
EVEREST II (Pivotal) Randomized patients (21 MitraClip to Surgery) 279 184 MitraClip 95 Surgery
REALISM (Continued Access) High Risk Non High Risk 266
European Experience 472
Total Total 1,115 MitraClip
Percutaneous Mitral Valve Repair Using the
Edge-to-Edge Repair Six months Results of the
EVEREST Phase I Clinical trial, JACC
2005462134-2140. Percutaneous Mitral Repair
with the MitraClip System Safety and Midterm
Durability in the Initial EVEREST Cohort, JACC
2009 54686-694.
Data as of 2/15/2010.
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EVEREST II Randomized Clinical TrialStudy Design
279 Patients enrolled at 37 sites
Significant MR (3-4) Specific Anatomical
Criteria
Randomized 21
Control Group Surgical Repair or Replacement N95
Device Group MitraClip System N184
Echocardiography Core Lab and Clinical Follow-Up
Baseline, 30 days, 6 months, 1 year, 18 months,
and annually through 5 years
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EVEREST II Randomized Clinical TrialStudy
Organization

• Principal Investigators Ted Feldman, MD
• Evanston NorthShore University
  HealthSystem
• Donald Glower, MD Duke University
  Medical Center
• Academic Research Organization Laura Mauri, MD
• Harvard Clinical Research Institute
• Data Safety Monitoring Board Richard Shemin,
  MD
• University of California, Los Angeles
• Clinical Events Committee Don Cutlip, MD
• Harvard Clinical Research Institute
• Echocardiography Core Lab Elyse Foster, MD
• University of California, San Francisco
• Sponsor Abbott Vascular Structural Heart
  (Evalve)
• Menlo Park, CA

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EVEREST Clinical Investigators

• T Feldman, J Alexander, R Curran, E Chedrawy, S
  Smart, M Lampert NorthShore University
  HealthSystem, Evanston, IL
• A Wang, D Glower, J Jollis Duke University,
  Durham, NC
• T Byrne, P Tibi, HK Fang, JM Morgan Banner Good
  Samaritan Medical Center, Phoenix, AZ
• R Quesada, J Lamelas, N Moreno, R Machado Baptist
  Hospital of Miami, Miami, FL
• P Grayburn, B Hamman, R Hebeler, M Mack, W
  Ryan Baylor University Medical Center, Dallas, TX
• A Eisenhauer, M Davidson, L Cohn, J Wu Brigham
  and Womens Hospital, Boston, MA
• J Hermiller, D Heimansohn, K Allen, D Segar The
  Care Group, Indianapolis, IN
• M Rinaldi, E Skipper, R Steigel, J Cook, G Rose
  Carolinas Medical Center, Charlotte, NC
• S Kar, G Fontana, A Trento, R Kass, W Cheng, R
  Siegel, K Tolstrup Cedars-Sinai Medical Center,
  Los Angeles, CA
• P Whitlow, T Mihaljevic, N Smidera, L Sevensson,
  E Roselli, L Rodriquez, W Stewart The Cleveland
  Clinic, Cleveland, OH
• H Wasserman, W Gray, A Stewart, M Williams, M
  Argenziano, S Homma, R Pizzarello, L
  Gillam Columbia University, New York, NY
  Danville, CT
• P Block, Z Ghazzal, T Vassiliades, R Martin, J
  Merlino, S Lerakis Emory University Hospital,
  Atlanta, GA
• B Whisenant, S Clayson, B Reid, S Horton, J
  Orford Latter Day Saints Hospital, Salt Lake
  City, UT
• R Smalling, G Letsou, J Walkes, C Loghin Memorial
  Hermann Hospital, Houston, TX
• W Pedersen, V Kshettry, F Eales, T Flavin, T
  Kroshus, R Bae Minneapolis Heart Institute,
  Minneapolis, MN
• O Nass, D Gangahar, R Jex, R Kacere Nebraska
  Heart Institute, Lincoln, NE
• SC Wong, OW Isom, L Girardi, K Krieger, R
  Devereux, R Mishra New York Presbyterian
  Hospital, New York, NY
• J Slater, A Galloway, G Perk, I Kronzon NYU
  Medical Center, New York, NY
• S Ramee, C Van Meter, P Parrino, C Lavie, Y
  Gilliland, VS Lucas Ochsner Clinic Foundation,
  New Orleans, LA

Interventional Cardiologist, Cardiac Surgeon,
Echocardiologist
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EVEREST II Randomized Clinical TrialKey
Inclusion/Exclusion Criteria

• Exclusion
• AMI within 12 weeks
• Need for other cardiac surgery
• Renal insufficiency
• Creatinine gt2.5mg/dl
• Endocarditis
• Rheumatic heart disease
• MV anatomical exclusions
• Mitral valve area lt4.0cm2
• Leaflet flail width (15mm) and gap (10mm)
• Leaflet tethering/coaptation depth (gt11mm) and
  length (lt2mm)

• Inclusion
• Candidate for MV Surgery
• Moderate to severe (3) or severe (4) MR
• Symptomatic
• gt25 EF LVESD 55mm
• Asymptomatic with one or more of the following
• LVEF 25-60
• LVESD 40mm
• New onset atrial fibrillation
• Pulmonary hypertension

ACC/AHA Guidelines JACC 52e1-e142, 2008
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EVEREST II Randomized Clinical TrialBaseline
Demographics Co-morbidities
Device () n184 Control () n95 P
Age (mean) 67.3 years 65.7 years 0.32
Male 62.5 66.3 0.60
Congestive heart failure 90.8 77.9 lt0.01
Coronary artery disease 47.0 46.3 gt0.99
Myocardial infarction 21.9 21.3 gt0.99
Angina 31.9 22.2 0.12
Atrial fibrillation 33.7 39.3 0.42
Cerebrovascular disease 7.6 5.3 0.62
Peripheral vascular disease 6.5 11.6 0.17
Cardiomyopathy 17.9 14.7 0.61
Hypercholesterolemia 61.0 62.8 0.80
Hypertension 72.3 78.9 0.25
Moderate to severe renal disease 3.3 2.1 0.72
Diabetes 7.6 10.5 0.50
Previous cardiovascular surgery 22.3 18.9 0.54
MR Severity 3 to 4 95.7 92.6 0.48
MR Etiology Degenerative / Functional 73 / 27 73 / 27 0.81
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EVEREST II Randomized Clinical TrialDemographic
Comparison
EVEREST II RCT n279 2008 STS Database 2008 STS Database Isolated 1st Elective Operation for MR
EVEREST II RCT n279 Repair Replace High Volume Hospitals (gt140/Yr)
Age yrs (mean) 68 60 61 59
65 yrs 58 37 45 n/a
75 yrs 32 n/a n/a 0
NYHA Class III or IV 50 26 45 n/a
CHF 86 41 58 n/a
Hypertension 75 60 67 43
Diabetes Mellitus 9 13 23 6.5
COPD / Chronic Lung Disease 15 17 29 n/a
EF (mean) 60 53 55 56
Gammie JS et al Influence of Hospital Procedural
Volume on Care Process and Mortality for Patients
Undergoing Elective Surgery for Mitral
Regurgitation. Circ 2007115881-887.
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EVEREST II Randomized Clinical TrialPrimary
Endpoints
Pre-Specified MAEs Death Major Stroke Re-operation
of Mitral Valve Urgent / Emergent CV
Surgery Myocardial Infarction Renal Failure Deep
Wound Infection Ventilation gt48 hrs New Onset
Permanent Atrial Fib Septicemia GI Complication
Requiring Surgery All Transfusions 2 units

• Safety
• Major Adverse Event Rate at 30 days
• Per protocol cohort
• Superiority hypothesis
• Effectiveness
• Clinical Success Rate
• Freedom from the combined outcome of
• Death
• MV surgery or re-operation for MV dysfunction
• MR gt2 at 12 months
• Per protocol cohort
• Non-inferiority hypothesis

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EVEREST II Randomized Clinical TrialAdditional
Analyses

• Intention to Treat
• Safety
• Major Adverse Event Rate at 30 days
• Effectiveness
• Freedom from the combined outcome of death, MV
  surgery gt90 days or re-operation for valve
  dysfunction gt90 days post Index procedure, and MR
  gt2 at 12 months
• Clinical Benefit (per protocol cohort)
• MR Severity
• Left Ventricular Function
• NYHA Functional Class
• Quality of Life (SF-36 Survey)

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EVEREST II RCT Patient FlowPer Protocol Cohort
Analysis of Device Performance
Randomized Cohort n279
Device Group n184
Control Group n95
Randomized, not treated Device, n6 Control, n15
Treated n178
Treated n80 (86 MV repair)
Acute Procedural Success Achieved n137
Acute Procedural Success (APS) MR 2 at
discharge
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EVEREST II RCT Patient FlowPost MitraClip
Procedure
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EVEREST II RCT Patient FlowIntention to Treat
Cohort Analysis of Treatment Strategy
Randomized Cohort n279
Patients randomized but not treated are included
in ITT analysis
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EVEREST II RCT Primary EndpointsPer Protocol
Cohort
Effectiveness Clinical Success Rate 12 months
Safety Major Adverse Events 30 days
Device Group, n136
Device Group, n134
72.4
9.6
pSUP lt0.0001
pNI 0.0012
Control Group, n79
Control Group, n74
57.0
87.8

• Met superiority hypothesis
• Pre-specified margin 6
• Observed difference 47.4
• 97.5 LCB 34.4

• Met non-inferiority hypothesis
• Pre-specified margin 31
• Observed difference 15.4
• 95 UCB 25.4

LCB lower confidence bound UCB upper
confidence bound
Freedom from the combined outcome of death, MV
surgery or re-operation for MV dysfunction, MR
gt2 at 12 months
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EVEREST II RCT Primary Safety EndpointPer
Protocol Cohort
Patients experiencing event Patients experiencing event
Device Group (n136) Control Group (n79)
Death 0 2 (2.5)
Major Stroke 0 2 (2.5)
Re-operation of Mitral Valve 0 1 (1.3)
Urgent / Emergent CV Surgery 0 4 (5.1)
Myocardial Infarction 0 0
Renal Failure 0 0
Deep Wound Infection 0 0
Ventilation gt48 hrs 0 4 (5.1)
New Onset Permanent Atrial Fib 0 0
Septicemia 0 0
GI Complication Requiring Surgery 1 (0.7) 0
All Transfusions 2 units 12 (8.8) 42 (53.2)
TOTAL of Patients with MAE 9.6 57.0
plt0.0001 (95 CI 34.4, 60.4) plt0.0001 (95 CI 34.4, 60.4)
30 Day MAE, non-hierarchical
plt0.0001 if include Major Bleeding only
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Additional Analyses

• Intention to Treat Safety Effectiveness
• Clinical Benefit (per protocol cohort)
• MR Severity
• Left Ventricular Function
• NYHA Functional Class
• Quality of Life

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EII RCT Safety Effectiveness
EndpointsIntention to Treat Cohort
Effectiveness Clinical Success Rate 12 months
Safety Major Adverse Events 30 days
Device Group, n180
Device Group, n175
15.0
66.9
pSUP lt0.0001
pNI 0.0005
Control Group, n94
Control Group, n89
47.9
74.2

• Met superiority hypothesis
• Pre-specified margin 2
• Observed difference 32.9
• 97.5 LCB 20.7

• Met non-inferiority hypothesis
• Pre-specified margin 25
• Observed difference 7.3
• 95 UCB 17.8

LCB lower confidence bound UCB upper
confidence bound
Freedom from the combined outcome of death, MV
surgery or re-operation for MV dysfunction gt90
days post Index procedure, MR gt2 at 12 months
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EVEREST II RCT MR ReductionPer Protocol Cohort
Device Group
Control Group
2
2
81.5
97.0
3/4
3/4
3/4
18.5
n137
n119
n80
n67
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EVEREST II RCT MR ReductionPer Protocol Cohort
Device Group
Control Group
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EVEREST II RCT Left Ventricular Volume Per
Protocol Cohort
Control Group n65, matched data
Device Group n118, matched data
LVEDV
LVESV
LVEDV
LVESV
LVEDV left ventricular end diastolic
volume LVESV left ventricular end systolic
volume
Pre-specified hypothesis for statistical analysis
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EVEREST II RCT Left Ventricular Dimension Per
Protocol Cohort
Control Group n65, matched data
Device Group n118, matched data
LVID systole
LVID diastole
LVID systole
LVID diastole
LVIDd left ventricular internal diameter,
diastole LVIDs left ventricular internal
diameter, systole
Pre-specified hypothesis for statistical analysis
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EVEREST II RCT NYHA Functional Class Per
Protocol Cohort
Control Group
Device Group
plt0.0001
plt0.0001
I
I
II
II
I
I
87.9 NYHA Class I/II
97.6 NYHA Class I/II
III
III
II
II
III
IV
IV
12 months
Baseline
Baseline
12 months
n124, Matched data
n66, Matched data
Hypothesis not pre-specified for statistical
analysis
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EVEREST II RCT Quality of Life, SF-36 SurveyPer
Protocol Cohort
30 Day Scores
Device Group
Control Group
PCS
MCS
PCS
MCS
n120, matched pairs
n64, matched pairs
Baseline
30 days
PSC Physical Component Summary MCS Mental
Component Summary
Hypothesis not pre-specified for statistical
analysis
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EVEREST II RCT Summary

• Safety effectiveness endpoints met
• Safety MAE rate at 30 days
• MitraClip device patients 9.6
• MV surgery patients 57
• Effectiveness Clinical Success Rate at 12 months
  
• MitraClip device patients 72
• MV Surgery patients 88
• Clinical benefit demonstrated for MitraClip
  System and MV surgery patients through 12 months
• Improved LV function
• Improved NYHA Functional Class
• Improved Quality of Life
• Surgery remains an option after the MitraClip
  procedure

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EVEREST II RCT Conclusion

• The MitraClip procedure is an important
  therapeutic option for selected patients with
  significant mitral regurgitation given the
  demonstrated safety, effectiveness and clinical
  benefit.