2016/10/13

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Saibal Kar, MD, FACC, FAHA, FSCAI

Director of Interventional Cardiac Research

Heart Institute, Cedars-Sinai Medical Center,

Los Angeles, CA

Mitral Valvular Disease: An explosion ofmultiple new non-surgical options

Disclosure Statement of Financial InterestSaibal Kar, MD, FACC

• Grant/Research Support

• Consulting Fees/Honoraria

• Other Financial Benefit

• Abbott Vascular,Boston Scientific, StJude Medical, Gore Medical

• Abbott Vascular, Boston Scientific,St Jude Medical, Gore

Within the past 12 months, I or my spouse/partner have had a financialWithin the past 12 months, I or my spouse/partner have had a financialinterest/arrangement or affiliation with the organization(s) listed below.interest/arrangement or affiliation with the organization(s) listed below.

Affiliation/Financial Relationship Company

Mitral valve apparatus• Mitral valve is an apparatus rather than a single structure

and each of the components may cause MV malfunction.

Posterolateralcommissure

Posteriorannulus

Anterolateralpapillary

muscle

Anterior annulus Anterior leaflet Anteromedialcommissure

Posteriorleaflet

Chordaetendineae

Posteromedialpapillarymuscle

Left ventricularfree wall

Functional Mitral Regurgitation

Otto N Engl J Med 2001:345:740-746

Mitral Regurgitation (MR)

Primary Disorder of the MitralValve Apparatus (annulus,

leaflets, chords, papillary muscle

Functional MR: Leafletsappear normal, MR due to

abnormal LV geometry

Valve makes the VentricleSick

Ventricle makes the ValveSick

Mechanical Solution: OpenSurgical /Transcatheter

repair/replacement

Medical treatment for LVdysfunction

Mechanical reduction ofMR ?

PercutaneousMitralApproaches

• Leaflet repair• MitraClip® ( Abbott Vascular )

• Leaflet folding( St Jude Medical)

• Coronary sinus annuloplasty• Cardiac Dimensions Carillon

• Direct annuloplasty• Mitralign Suture-Based Plication• Guided Delivery Anchor-Cinch Plication• Quantum Cor• Cardioband (Valtec Cardio, Or Yehuda, Israel)

• Chordal replacement• NeoChord, V-Chordal(Valtec)• MitraFlex

• Transcatheter Mitral ValveReplacement

Standard ofCare

Emergingoptions

PercutaneousMitralApproaches

• Leaflet repair• MitraClip® ( Abbott Vascular )

• Leaflet folding( St Jude Medical)

• Coronary sinus annuloplasty• Cardiac Dimensions Carillon

• Direct annuloplasty• Mitralign Suture-Based Plication• Guided Delivery Anchor-Cinch Plication• Quantum Cor• Cardioband (Valtec Cardio, Or Yehuda, Israel)

• Chordal replacement• NeoChord, V-Chordal(Valtec)• MitraFlex

• Transcatheter Mitral ValveReplacement

Standard ofCare

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MitraClip

• Concept

• Technical aspects

• Case selection

• Longterm data

Concept: Edge to Edge repair(Alfieri stitch)

•• Simple solution forSimple solution fora complex problema complex problem

•• Selected patientsSelected patientsof degenerativeof degenerativeand functional MRand functional MR

•• Not effective inNot effective inrheumatic MRrheumatic MR

MitraClip Creation of double orifice valve

MitraClip Concepts

• Coaptation of Leaflets• Reduces MR

• Creates tissue bridge• Limits dilatation of annulus• Septal-lateral (A-P) dimension• Supports durability of repair

• Restrains LV wall• Limits LV dilatation

MitraClip

• Concept

• Technical aspects

• Case selection

• Longterm data

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Case Selection: Suitable Anatomy

• Non rheumatic MR originatingfrom a localized area of thevalve

• Etiology: degenerative orfunctional

• Sufficient leaflet tissue formechanical coaptation

• Valve anatomic exclusions• Flail gap >10mm• Flail width >15mm• Calcified leaflet

• MVA ≥ 4 sq cm

Expanded indications of the MitraClip:Beyond the EVEREST criteria

• A1P1 or A3P3 flail or prolapse

• Failed surgical repair

– Ring annuloplasty, or snapping of artificialchord

• HOCM : Systolic anterior motion with MR

• End stage heart failure with MR

– Delay heart transplantation or VAD

Flail P2/P3segment

MitraClip for aFlail P2/P3

MitraClip Therapy Worldwide Experience(2003-2016)

> 35000 Cases

30| June | 2016

GLOBAL MITRACLIP EXPERIENCE

1. Includes clinical and commercial procedures as of 06/30/2016. Source: Data on file at Abbott Vascular

1200 cases in month of June

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Clinical summary using MitraClip

• > 35,000 cases performed worldwide

• Most patients are high surgical riskpatients

• In US

– Oct 2013: FDA approved the MitraClip forprohibitive risk primary MR (degenerative)

– Functional MR: Investigational

– Ongoing clinical trials for Functional MR .

Key MitraClip Data

• Safety

– Impeccably safe in experienced hands

– No early or late safety events

• Effective

– Selected patients with both degenerative orfunctional MR

• Durability

– New data supports durability .

Freedom From Mortality andMV Surgery/Re-operation

Kaplan-Meier Freedom FromMitral Valve Surgery/Re-operation

Kaplan-Meier Freedom FromMortality

EVEREST II RCT

Feldman et al ACC 2014

EVEREST II 5 year: Sustained reduction ofMR

N=149 N=106 N=66 N=41

p<0.005 p<0.00581% 82% 99% 98%

MitraClip (N=178)MR ≤ 2+ at 1 and 5 Years

Surgery (N=80)MR ≤ 2+ at 1 and 5 Years

4+

4+

4+

4+

3+

3+

3+

3+

2+

2+

2+

2+

1+ 1+

0+ 0+

0%

20%

40%

60%

80%

100%

BL 1 Year BL 5 Years

Pa

tie

nts

(%)

4+ 4+

3+

3+

3+

3+

2+

2+

2+

2+

1+1+

0+ 0+

0%

20%

40%

60%

80%

100%

BL 1 Year BL 5 Years

Pa

tie

nts

(%)

p<0.005 p<0.005

EVEREST II RCT

Feldman et al ACC 2014

MitraClip in High Risk patients

Final 5 Year Results of theEVEREST II High Risk Registry

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MR Grade and NYHA Functional Class

4+

4+

4+

3+

3+

3+

3+

2+

2+2+

1+1+

0%

20%

40%

60%

80%

100%

BL 1 Year BL 5Years

Pa

tie

nts

(%)

N=54 N=24

Mitral Regurgitation Grade NYHA Functional Class

p < 0.005 p = 0.01

IV

IV

IV

III

III

III

III

II

II

II

II

II

0%

20%

40%

60%

80%

100%

BL 1 Year BL 5 Years

Pa

tie

nts

(%)

N=54 N=24

p < 0.005 p = 0.00678% 75% 74% 83%

EVEREST II HRR

Kar et al ACC 2014

REALISM ( degenerative MR Cohort)

Freedom From MV Surgery in DMR:EVEREST II RCT, REALISM Non-High Risk and REALISM High Risk

100%

90%

80%

70%

60%

50%

40%

30%

20%

10%

0%

30 Days98.9%95.6%90.0%

1 Year97.8%89.9%75.1%

REALISM High Risk DMR

EVEREST II RCT DMR MitraClip

REALISM Non-High Risk DMR

# At Risk Baseline 30 Days 6 Months 12 Months

High Risk DMR 189 176 159 121

Non-High Risk DMR 185 173 162 151

RCT DMR MitraClip 130 117 98 92

Eve

nt

Fre

eS

urv

ival

Kar et al ESC 2015

Learning Curve Experience inthe MitraClip REALISM Trial:

An Analysis of 899 High Risk andNon-High Risk Subjects

See Important Safety Information Referenced Within. Not to be reproduced, distributed or excerpted.

©2015 Abbott. All rights reserved. AP2941763-US Rev. A

Acute Procedural Success Rate

79% 81% 80%93%

0%

20%

40%

60%

80%

100%

Cohort A(n=354)

Cohort B(n=250)

Cohort C(n=115)

Cohort D(n=180)

AP

SR

ate

p=0.020

p=0.038

p=0.033

Kar et al TCT 2015 See Important Safety Information Referenced Within. Not to be reproduced, distributed or excerpted.

©2015Abbott. All rights reserved. AP2941763-US Rev. A

No of cases ( 0 - 10) (11 – 20) (21 – 30) ( > 31 )

Surgery following failed MitraClip

Repair can be done following failed MitraClipeven upto 5 years later

The surgical risk is not increased

Surgical options are preserved since there isno loss leaflet tissue

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Robotic surgical repair;6 years following MitraClip What if a surgeon wants to replace

a valve following failed mitraclip

• Replace the surgeon, don’t replace thevalve

AHA/ACC Guideline 2014

Circulation. 2014 Mar 3]

ESC Guideline 2012

ESC/EACT S GUIDELIN ES

Guidelines on the management of valvular heartdisease (version 2012)

The Joint Task Force on the Managem ent of Valvular Hear t Diseaseof the European Society of Cardiology (ESC) and the EuropeanAssociation for Cardio-Thor acic Surgery (EACTS)

Authors/Task Force Member s: Alec Vahanian (Chairperson) (France) *, Ot tavio Alfier i

(Chairperson) * (Italy), Felicita Andreot t i (Italy), Manuel J. Antunes (Port ugal),Gonzalo Bar on-Esquivias (Spain), Helm ut Baum gartner (Germany),

Michael Andr ew Borger (Germany), Thierr y P. Carrel (Switzer land), Michele De Bonis

(Italy), A rtur o Evangelista (Spain), Volkmar Falk (Switzer land), Bernard Iung(France), Patr izio Lancellot t i (Belgium), Luc Pier ard (Belgium ), Susanna Pr ice (UK),

Hans-Joachim Schafers (Ger many), Gerhar d Schuler (Ger many), Janina Stepinska

(Poland), Kar l Swedber g (Sweden), Johanna Takkenberg (The N ether lands),Ulr ich Otto Von Oppell (UK), Stephan W indecker (Switzer land), Jose Luis Zam orano

(Spain), Mar ian Zembala (Poland)

ESC Commit tee for Pract ice Guidelines (CPG): Jeroen J. Bax (Chairperson) (T he N ether lands), Helmut Baumgartner

(Germany), Claudio Ceconi (Italy), Veronica Dean (France), Chr ist i Deaton (UK), Robert Fagard (Belgium),

Chr ist ian Funck-Brentano (France), David H asdai (Israel), Arno Hoes(The N ether lands), Paulus Kirchhof(United Kingdom), Juhani Knuut i (Finland), Phi lippe Kolh (Belgium), Theresa McDonagh (UK), Cyr il Moulin (France),

Bogdan A. Popescu (Romania), Zeljko Reiner (Croat ia), U do Sechtem (Germany), Per Anton Sirnes (Norway),Michal Tendera (Poland), Adam Torbicki (Poland), A lec Vahanian (France), Stephan W indecker (Switzer land)

Document Reviewers:: Bogdan A. Popescu (ESC CPG Review Coordinator ) (Romania), Ludwig Von Segesser (EACTSReview Coordinator ) (Switzerland), Luigi P. Badano (Italy), Mat jaz Bunc (Slovenia), Marc J. Claeys (Belgium),

N iksa Drinkovic (Croat ia), Gerasimos Filippatos (Greece) ,Gilbert H abib (France), A. Pieter Kappetein (The N ether lands),

Roland Kassab (Lebanon), Gregory Y.H. Lip (U K), N ei l Moat (U K), Georg Nickenig (Germany), Cather ine M. Ot to (USA),John Pepper, (UK), N icolo Piazza (Germany), Pet ronella G. Pieper (The Nether lands), Raphael Rosenhek (Aust r ia),

N alt in Shuka (Albania), Ehud Schwammenthal (Israel ), Juerg Schwit ter (Switzer land), Pilar Tornos Mas(Spain),Pedro T. Tr indade (Switzer land), Thomas W alther (Germany)

The disclosure forms of the authors and reviewers are avai lable on the ESC website www.escardio.org/guidelines

Online publish-ahead-of-print 24 August 2012

Ottavio Alfieri, S. Raffaele University Hospital, 20132 Milan, Italy. Tel: + 39 02 26437109; Fax: + 39 02 26437125. Email: ottavio.alfieri@hsr.it†Other ESC ent ities having participated in the development of this document :

Associations: European Association of Echocardiography (EAE), European Association of Percutaneous Cardiovascular Interventions (EAPCI), Heart Failure Association (HFA)

Working Groups: Acute Cardiac Care, Cardiovascular Surgery, Valvular Heart Disease, Thrombosis, Grown-up Congenital Heart Disease

Councils: Cardiology Practice, Cardiovascular ImagingThe content of these European Society of Cardiology (ESC) Guidelines hasbeen published for personal and educational use only. No commercial use isauthorized.No part of the

ESC Guidelines may be translated or reproduced in anyform without writ ten permission from the ESC. Permission can be obtained upon submission of awritten request to Oxford

University Press, the publisher of the European Heart Journal, and the party authorized to handle such permissions on behalf of the ESC.

* Correspondingauthors: Alec Vahanian, Service de Cardiologie, Hopital Bichat AP-HP,46 rue Henri Huchard, 75018 Paris,France. Tel: + 33 1 40 25 67 60;Fax:+ 33 1 40 25 67 32.

Email: alec.vahanian@bch.aphp.fr

Disclaimer . The ESC/EACTS Guidelines represent the views of the ESC and the EACTS and were arrived at after careful consideration of the available evidence at the time they

were written.Health professionals are encouraged to take them fully into account when exercising their clinical judgement. The guidelines do not, however, override the individual

responsibility of health professionals to make appropriate decisions in the circumstances of the individual pat ients, in consultation with that patient and, where appropriate and

necessary, the patient’s guardian or carer. It is also the health professional’s responsibility to verify the rules and regulations applicable to drugs and devices at the time ofprescription.

& The European Society of Cardiology 2012. All rights reserved. For permissions please email: journals.permissions@oup.com

European Heart Journal (2012) 33, 2451–2496doi:10.1093/eurheartj/ehs109

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“The guideline recommendsthe MitraClip therapy as classIIb indication for bothdegenerative and functionalMR”

What about Functional MR

Treatment of FMR

• Medical treatment is the mainstay

• The role of surgery is controversial

– Often high risk since patients have low EF

– Symptomatic improvement

– High recurrence

– No mortality benefit

– No census whether repair is better thanreplacement

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MitraClip for Functional MR

• Majority of patients outside US are highrisk functional MR

• Evidence of safety and possible efficacy

• No randomized studies in this subgroup todemonstrate survival benefit

Ongoing Studies for MitraClip forFMR

• COAPT Trial ( US and Canada)• RESHAPE trial (Europe)

430 patients enrolled at up to 85 US sites

Randomize 1:1

Clinical and TTE follow-up:

1, 6, 12, 18, 24, 36, 48, 60 months

Control group

Standard of careN=215

Deemed not suitable for mitral valve surgery

Specific valve anatomic criteria

MitraClipN=215

Significant FMR (≥3+ by core lab) treated per standard of ccare

Trial design

Study has been extended468 patients have been randomized

COAPT : TOP ENROLLERS HIGHLIGHT!

Case summaryPatient: 45-year-old man

Clinical Presentation:Shortness of breath (NYHA functional class IV)Acute decompensated CHF (Dopamine; 3 mg/kg/min)

Past Medical History:Endstage non-ischemic cardiomyopathyHypertension

Past Surgical History:CRT-D implantation [2012]

45 year old male with non ischemic dilatedcardiomyopathy Class IV on inotropes Destination

IA for transplant/VAD“Parasternal short axis view” “4ch view” “3ch view”

Severe functional MR with LV dysfunction EROA = 0.46 cm2

LVEF = 23%, LVID d/s = 63/59 mm

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MitraClip procedure“Post 3rd clip deployment”

“Cardiac output increased from 2.9 to 3.7 L/min”

12 Month Follow-up : NYHA I off thetransplant list

“Parasternal long axis view” “4ch view” “3ch view”

Cedars Sinai Experience

Cedars Sinai Experience ( 2005 to 2016)

• Total number of patients treated: 502

– Clinical Trials: 198

– EVEREST II

– REALISM

– COAPT

– Comercial(since Oct 2013) 304

• Total number of procedures: 519

210

159

4333

20

33

154 5 6

11

71

109

86

0

20

40

60

80

100

120

05 06 07 08 09 10 11 12 13 14 15 16

Number of MitraClip Procedures in CSMC

MitraClip Trials commercial

Commercial approval Oct 2013

Cedars Sinai Experience(Results)

• Total No patients treated 502

• Primary success 96%

• In hospital mortality ( 2 case) 0.4%

• Partial clip detachment 1%

• Stroke 0.6%

• No case of urgent open heart surgery

• Surgery for failed clip procedure 4%

– 30 day and 1 year mortality for 0%

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Conclusion• Transacatheter MV repair is a safe and effective

treatment for selected patients with MR who are athigh risk for surgery.

• MitraClip is the leader in the field, though othertechnologies are in development

• Limitation of transcatheter repair include

– Adverse leaflet pathology

– Residual MR

Conclusion• Transcatheter MV repair using the MitraClip is a

safe and effective treatment for selected patientssignificant MR

• Evidence of safety, efficacy and durability

• In US the MitraClip is approved for treatment ofhigh risk primary (degenerative) MR

• The true role of MitraClip is being evaluated in theongoing COAPT trial.

62 yr old male with flail P2 treated withMitraClip in May 2006

9years later NYHA I

Low risk patients

• Is MitraClip and effective and durable treatmentoption for intermediate risk degenerative MRpatients

Probably yes

In the right patient

In the right hands

In the right time

Heart Team