endovascular valve edge-to-edge repair study (everest ii) randomized clinical trial: primary safety...

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

Endpoints

American College of CardiologyMarch 14, 2010

Atlanta, GA

Ted Feldman, Laura Mauri, Elyse Foster, Don Glower on behalf of the EVEREST II Investigators

2Investigational Device only in the US; Not available for sale in the US

Disclosures

Research Grants – Abbott, Edwards

Consultant – Abbott, Edwards


Perspective

>250,000 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


Catheter-Based Mitral Valve Repair

MitraClip® System


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(2:1 MitraClip to Surgery)

279184 MitraClip95 Surgery

REALISM (Continued Access)

High Risk & Non High Risk

266

European Experience 472

Total 1,115 MitraClip

Data as of 2/15/2010.

*Percutaneous Mitral Valve Repair Using the Edge-to-Edge Repair: Six months Results of the EVEREST Phase I Clinical trial, JACC 2005;46:2134-2140. Percutaneous Mitral Repair with the MitraClip System: Safety and Midterm Durability in the Initial EVEREST Cohort, JACC 2009; 54:686-694.


EVEREST II Randomized Clinical Trial

Study Design279 Patients enrolled at 37 sites

Randomized 2:1

Echocardiography Core Lab and Clinical Follow-Up:

Baseline, 30 days, 6 months, 1 year, 18 months, and annually through 5 years

Control GroupSurgical Repair or Replacement

N=95

Significant MR (3+-4+)Specific Anatomical Criteria

Device GroupMitraClip System

N=184


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, MDUniversity of California, Los Angeles

Clinical Events Committee: Don Cutlip, MDHarvard Clinical Research Institute

Echocardiography Core Lab: Elyse Foster, MD University of California, San Francisco

Sponsor: Abbott Vascular Structural Heart (Evalve)Menlo Park, CA


EVEREST Clinical InvestigatorsT Feldman, J Alexander, R Curran, E Chedrawy, S Smart, M Lampert NorthShore University HealthSystem, Evanston, ILA Wang, D Glower, J Jollis Duke University, Durham, NCT Byrne, P Tibi, HK Fang, JM Morgan Banner Good Samaritan Medical Center, Phoenix, AZR Quesada, J Lamelas, N Moreno, R Machado Baptist Hospital of Miami, Miami, FLP Grayburn, B Hamman, R Hebeler, M Mack, W Ryan Baylor University Medical Center, Dallas, TXA Eisenhauer, M Davidson, L Cohn, J Wu Brigham and Women’s Hospital, Boston, MAJ Hermiller, D Heimansohn, K Allen, D Segar The Care Group, Indianapolis, INM Rinaldi, E Skipper, R Steigel, J Cook, G Rose Carolinas Medical Center, Charlotte, NCS Kar, G Fontana, A Trento, R Kass, W Cheng, R Siegel, K Tolstrup Cedars-Sinai Medical Center, Los Angeles, CAP Whitlow, T Mihaljevic, N Smidera, L Sevensson, E Roselli, L Rodriquez, W Stewart The Cleveland Clinic, Cleveland, OHH Wasserman, W Gray, A Stewart, M Williams, M Argenziano, S Homma, R Pizzarello, L Gillam Columbia University, New York, NY; Danville, CTP Block, Z Ghazzal, T Vassiliades, R Martin, J Merlino, S Lerakis Emory University Hospital, Atlanta, GAB Whisenant, S Clayson, B Reid, S Horton, J Orford Latter Day Saints Hospital, Salt Lake City, UTR Smalling, G Letsou, J Walkes, C Loghin Memorial Hermann Hospital, Houston, TXW Pedersen, V Kshettry, F Eales, T Flavin, T Kroshus, R Bae Minneapolis Heart Institute, Minneapolis, MNO Nass, D Gangahar, R Jex, R Kacere Nebraska Heart Institute, Lincoln, NESC Wong, OW Isom, L Girardi, K Krieger, R Devereux, R Mishra New York Presbyterian Hospital, New York, NYJ Slater, A Galloway, G Perk, I Kronzon NYU Medical Center, New York, NYS Ramee, C Van Meter, P Parrino, C Lavie, Y Gilliland, VS Lucas Ochsner Clinic Foundation, New Orleans, LAR Kipperman, S Lucas, RM Bodenhamer, J Randolph, J Williams Oklahoma Heart Hospital, Okalahoma City, OKR Leung, R MacArthur, J Mullen, D Ross, J Choy Royal Alexandra Hospital, Edmonton, AB, CanadaP Kramer, B Castlemain, A Schwartz, L Crouse, V Pasnoori Shawnee Mission Medical Center, Shawnee Mission, KSA Berke, N Robinson, R Colangelo, P Damus, H Fernandez, J Taylor, N Bercow, A KatzSt. Francis Hospital, Long Island, NYM O'Donnell, M Qureshi, A Pruitt, B Kong, B McAllister, S Girard St. Joseph’s Mercy Hospital, Ypsilanti, MIT Bajwa, D O’Hair, D Kress, K Sagar St. Luke’s Medical Center, Milwaukee, WIJT Maddux, M Sanz, S Tahta, JM Maxwell, B Berry, J Knapp St. Patrick's Hospital & Health Science Ctr, Missoula, MTW Gray, M Reisman, W Curtis, D Gartman, J Teply, D Warth, K Krabill Swedish Medical Center, Seattle, WA P Fail, K Paape, T Fudge, M Trotter, M Allam, E Feinberg, V Tedesco, D Solet Terrebonne General Medical Center, Houma, LAE Horlick, T David, M Borger, M Mezody Toronto General Hospital, Toronto, ON, CanadaR Low, N Young, K Shankar, R Calhoun, W Bommer University of California at Davis, Sacramento, CAJ Carroll, J Cleveland, R Quaife University of Colorado Health Sciences Center, Denver,

COH Herrmann, M Acker, YJ Woo, F Silvestry, S Wiegers University of Pennsylvania, Philadelphia, PA S Bailey, E Sako, J Erikson University of Texas Health Sciences Ctr, San Antonio, TXDS Lim, I Kron, J Kern, J Dent, H Gutgesell University of Virginia, Charlottesville, VAE Fretz, J Ofiesh, M Mann Victoria Heart Institute Foundation, Victoria BC, Canada K Kent, S Boyce. P Sears-Rogan Washington Hospital Center, Washington DCJ Lasala, M Moon, R Damiano, B Lindman, A Zajarias, J Madrazo Washington University Medical Center, St. Louis, MO G Hanzel, F Shannon, M Sakwa, A Abbas, M Gallagher, P Markovitz William Beaumont Hospital, Royal Oak, MI

Interventional Cardiologist, Cardiac Surgeon, Echocardiologist


EVEREST II Randomized Clinical TrialKey Inclusion/Exclusion Criteria

Inclusion• Candidate for MV Surgery• Moderate to severe (3+)

or severe (4+) MR– Symptomatic

o >25% EF & LVESD ≤55mm

– Asymptomatic with one or more of the following

o LVEF 25-60%o LVESD ≥40mmo New onset atrial

fibrillationo Pulmonary hypertension

Exclusion• AMI within 12 weeks• Need for other cardiac

surgery• Renal insufficiency

– Creatinine >2.5mg/dl• Endocarditis• Rheumatic heart disease• MV anatomical exclusions

– Mitral valve area <4.0cm2

– Leaflet flail width (≥15mm) and gap (≥10mm)

– Leaflet tethering/coaptation depth (>11mm) and length (<2mm)

ACC/AHA Guidelines JACC 52:e1-e142, 2008


Device (%)n=184

Control (%)n=95 P

Age (mean) 67.3 years 65.7 years 0.32Male 62.5 66.3 0.60Congestive heart failure 90.8 77.9 <0.01Coronary artery disease 47.0 46.3 >0.99Myocardial infarction 21.9 21.3 >0.99Angina 31.9 22.2 0.12Atrial fibrillation 33.7 39.3 0.42Cerebrovascular disease 7.6 5.3 0.62Peripheral vascular disease 6.5 11.6 0.17Cardiomyopathy 17.9 14.7 0.61Hypercholesterolemia 61.0 62.8 0.80Hypertension 72.3 78.9 0.25Moderate to severe renal disease 3.3 2.1 0.72Diabetes 7.6 10.5 0.50Previous cardiovascular surgery 22.3 18.9 0.54MR Severity: 3+ to 4+ 95.7 92.6 0.48MR Etiology: Degenerative / Functional

73 / 27 73 / 27 0.81

EVEREST II Randomized Clinical TrialBaseline Demographics & Co-morbidities


EVEREST II RCT

n=279

2008 STS Database

Isolated 1st Elective Operation for MR*

Repair Replace High Volume Hospitals (>140/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%

EVEREST II Randomized Clinical TrialDemographic Comparison

*Gammie JS et al Influence of Hospital Procedural Volume on Care Process and Mortality for Patients Undergoing Elective Surgery for Mitral Regurgitation. Circ 2007;115:881-887.


EVEREST II Randomized Clinical TrialPrimary Endpoints

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 >2+ at 12 months

Per protocol cohort Non-inferiority hypothesis

Pre-Specified MAEsDeathMajor StrokeRe-operation of Mitral ValveUrgent / Emergent CV SurgeryMyocardial InfarctionRenal FailureDeep Wound InfectionVentilation >48 hrsNew Onset Permanent Atrial FibSepticemiaGI Complication Requiring SurgeryAll Transfusions ≥2 units


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 >90 days or re-operation for valve dysfunction >90 days post Index procedure, and MR >2+ at 12 months

Clinical Benefit (per protocol cohort) MR Severity Left Ventricular Function NYHA Functional Class Quality of Life (SF-36 Survey)


EVEREST II RCT: Patient FlowPer Protocol Cohort: Analysis of Device

Performance

Acute Procedural Success (APS) = MR ≤2+ at

discharge

12 months n=134

98.5% Clinical Follow-up

98% Echo Follow-up

12 months n=74

94% Clinical Follow-up92% Echo Follow-up

30 daysn=136

99% Clinical Follow-up

30 daysn=79

99% Clinical Follow-up

Acute Procedural SuccessAchievedn=137

Randomized, not treated

Device, n=6Control, n=15

Treated n=178

Treated n=80

(86% MV repair)

Device Group n=184

Acute Procedural SuccessNot Achieved

n=41

Control Group n=95

Randomized Cohort n=279


EVEREST II RCT: Patient FlowPost MitraClip Procedure

2nd MitraClipProcedure

n=3

MV Surgery PostMitraClip

Proceduren=9

2nd MitraClip Procedure

n=2

No Additional Intervention

n=11

MV Surgery Post MitraClip

Proceduren=28

Acute Procedural Success

Not Achieved

n=41

Acute Procedural SuccessAchievedn=137

n=3781% Follow-up96% MR ≤2+ at 12 months


16

Patients randomized but not treated are included in ITT analysis

EVEREST II RCT: Patient FlowIntention to Treat Cohort: Analysis of Treatment

Strategy

Randomized Cohort n=279

Device Groupn=184

Control Groupn=95

12 monthsn=175

92% Follow-up

30 daysn=180

95% Follow-up

30 daysn=94

84% Follow-up

12 monthsn=89

78% Follow-up


0 20 40 60 80 100

EVEREST II RCT: Primary EndpointsPer Protocol Cohort

0 20 40 60

9.6%

Device Group, n=136

Control Group, n=79

57.0%

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

72.4%

87.8%

Control Group, n=74

Device Group, n=134

Met non-inferiority Met non-inferiority hypothesishypothesis

• Pre-specified margin = 31% • Observed difference = 15.4%• 95% UCB = 25.4%

SafetyMajor Adverse Events

30 days

EffectivenessClinical Success Rate*

12 months

LCB = lower confidence boundUCB = upper confidence bound

pSUP <0.0001 pNI =0.0012

* Freedom from the combined outcome of death, MV surgery or re-operation for MV dysfunction, MR >2+ at 12 months


# Patients experiencing eventDevice Group

(n=136)Control Group

(n=79)

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 >48 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%

p<0.0001*(95% CI 34.4%, 60.4%)

EVEREST II RCT: Primary Safety Endpoint

Per Protocol Cohort30 Day MAE, non-hierarchical

*p<0.0001 if include Major Bleeding only


Additional Analyses

Intention to Treat Safety & Effectiveness

Clinical Benefit (per protocol cohort)• MR Severity• Left Ventricular Function• NYHA Functional Class• Quality of Life


0 20 40 60 80 100

SafetyMajor Adverse Events

30 days

EffectivenessClinical Success Rate*

12 months

0 20 40 60

EII RCT: Safety & Effectiveness Endpoints

Intention to Treat Cohort

Device Group, n=180

Control Group, n=94

Met superiority Met superiority hypothesishypothesis

• Pre-specified margin =2%• Observed difference =

32.9%• 97.5% LCB = 20.7%

Control Group, n=89

Device Group, n=175

Met non-inferiority Met non-inferiority hypothesishypothesis

• Pre-specified margin = 25% • Observed difference = 7.3%• 95% UCB = 17.8%

66.9%

74.2%

15.0%

47.9%

LCB = lower confidence boundUCB = upper confidence bound

pSUP <0.0001 pNI =0.0005

* Freedom from the combined outcome of death, MV surgery or re-operation for MV dysfunction >90 days post Index procedure, MR >2+ at 12 months


0%

20%

40%

60%

80%

100%

Baseline 12 Months Baseline 12 Months

Device Group Control Group

EVEREST II RCT: MR ReductionPer Protocol Cohort

≤2+

n=137 n=119 n=80 n=67

3+/4+

≤2+

3+/4+

81.5%

18.5%3+/4+

97.0%


EVEREST II RCT: MR ReductionPer Protocol Cohort


7.7% (1/13) Replacement

13.4%

0%

20%

40%

60%

80%

100%

Baseline 12 Months Baseline 12 Months n=137 n=119 n=80 n=67

3+/4+

1+-2+

1+

2+

3+/4+

2+ 2+

2+

1+-2+

1+

0

36.1%

11.8%

33.6%

18.5%

17.9%

58.2%

7.5%

3.0%

18.4% (7/38) Replacement

3+/4+


0

40

80

120

160

200

Volu

me (

ml)

0

40

80

120

160

200

Volu

me (

ml)

EVEREST II RCT: Left Ventricular Volume Per Protocol Cohort

LVEDV LVESV

Control Groupn=65, matched data

LVEDV LVESV

Baseline 12 Months

Pre-specified hypothesis for statistical analysis

p<0.0001

Device Groupn=118, matched data

LVEDV = left ventricular end diastolic volumeLVESV = left ventricular end systolic volume

p=0.0005

p<0.0001

p=0.0255


0

1

2

3

4

5

6

Dim

ensi

on (

cm)

EVEREST II RCT: Left Ventricular Dimension

Per Protocol Cohort

0

1

2

3

4

5

6

Dim

ensi

on (

cm)

LVID systoleLVID diastole

p<0.0001

LVID systoleLVID diastole

Baseline 12 Months

Control Groupn=65, matched data

Device Groupn=118, matched data

LVIDd = left ventricular internal diameter, diastoleLVIDs = left ventricular internal diameter, systole Pre-specified hypothesis for statistical analysis

p=0.0564

p<0.0001

p=0.4785


0

20

40

60

80

100

Perc

ent

Pati

ents

EVEREST II RCT: NYHA Functional Class

Per Protocol Cohort

97.6%NYHA

Class I/II

87.9%NYHA

Class I/II

n=124, Matched data n=66, Matched data

I

II

III

I

II

III

IVIV

III

II

I

II

I


Baseline Baseline12 months 12 months

p<0.0001 p<0.0001

Hypothesis not pre-specified for statistical analysis


0

10

20

30

40

50

60

Sco

reEVEREST II RCT: Quality of Life, SF-36

SurveyPer Protocol Cohort

PCS MCS

Baseline

n=120, matched pairs n=64, matched pairs

30 days

Device Group

30 Day Scores

p<0.0001

PCS MCS

PSC = Physical Component SummaryMCS = Mental Component Summary Hypothesis not pre-specified for statistical analysis

Control Groupp<0.0001

P=0.0043

P=0.2910

0

10

20

30

40

50

60

12 Months

12 Month Scores

n=60, matched pairsn=110, matched pairsMCSMCS PCSPCS

Control GroupDevice Group

P<0.0001

P<0.0001

P=0.0017P=0.0057


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

EVEREST II RCT: Summary


The MitraClip procedure is an important therapeutic option for selected patients with significant

mitral regurgitation given the demonstrated safety, effectiveness

and clinical benefit.

EVEREST II RCT: Conclusion

endovascular valve edge-to-edge repair study (everest ii) randomized clinical trial: primary safety...

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