Mitral Regurgitation Treatment :

No need for an Incision.

Igor F. Palacios, MD

Director of Interventional Cardiology

Massachusetts General Hospital

Professor of Medicine

Harvard Medical School

Controversies in Mitral Regurgitation Therapy

MR Etiology

Normal Degenerative MR

—ProlapseDegenerative MR

—Flail

Functional MR

Ischemic vs.

nonischemic

Organic (Primary) vs. Functional

(Secondary) Mitral Regurgitation

Of surgical

candidates, up to 50%

of patients are not

referred to surgery,

even if a surgical

indication

exists 2

Factors prohibiting

Surgery include6:

• Impaired LVEF

• High operative risk

• Multiple

comorbidities

• Advanced age

Many patients are not considered appropriate

candidates for mitral valve surgery

Large portion of mitral regurgitation patients are left untreated—

ineligible for surgical treatment or denied surgical intervention1-2

1. Lung B, et al. Eur Heart J. 2003;24:1231-1243.

2. Mirabel M, et al. Eur Heart J. 2007;28:1358-1365.

3. U.S. Census Bureau, Statistical Abstract of the U.S.

4. Nkomo et al. Burden of Valvular Heart Diseases: A Population-based Study, Lancet, 2006; 368: 1005-11.

5. Patel, et al. Mitral Regurgitation in Patients with Advanced Systolic Heart Failure, J of Cardiac Failure, 2004.

6. Rankin, et al, J of Thoracic and Cardiovascular Surgery, March 2006.

49%High-Risk

Patients*,3-5

(860K)

49%Surgical

Candidates

(850K)

2%Surgical Patients (30K)

* Data on file Abbott Vascular.

All Patients NOT

Candidates for Surgery

• Multiple, serious co-morbidities increase risk of

surgical mortality and morbidity

• Benefits of surgery do not outweigh risks

• In the USA, these patients are left with no other

treatment option

• Physicians struggle with the management of

these high surgical risk patients

Treatment Options

in USA

• Medical Therapy

– First course of therapy – limited role

• Surgery

– Repair or replacement

– Class I indication for some

– Proven effective

• Percutaneous Interventions

Why Percutaneous

Valve Repair?

• Surgical repair is the gold standard

– Surgical Mortality is low

NYHA Class Mortality for

Repair (%)

Class I 0.64

Class II 0.87

Class III 1.80

Class IV 3.71

Percutaneous Repair of

MR Features

Percutaneous procedure. No need for an Incision

Venous puncture

Percutaneous Transseptal Left Atrial Access

Versatile Positioning Capabilities

Adaptability to varying patient anatomy

Precise Device Placement Control

Re-positioning capability

Allows multiple tissue releases and grasps

Allows optimal MR reduction

Provides option to do not deploy the Device

4-Years Follow-Up of

the EVEREST II Trial

Mauri et al, JACC 2013; 62: 317-328.

• Four year follow up results of the EVEREST II trial showed that at 4 years, patients with mitral valve regurgitation who undergo repair with a novel Mitral-Clip experience mortality rates and mitral regurgitation (MR) levels comparable to those that accompany surgery, according to updated data from the EVEREST II.

• While surgery continues to hold an early advantage in MR and need for surgical re-intervention, few differences between treatment groups were apparent beyond 1 year. Kaplan Miers for Event Free Survival showed no significant differences (84.1% vs. 82.3%; p= 0.7350) for Mitral Clip vs. Surgical Groups.

Mitral Valve Repair

Technology Summary

LeafletCoupling

Bowtie

• E Valve

• Edwards

Technology Approach Status

Clinical

CS Reshaping

Coronary Sinus

• Edwards

• Cardiac Dimensions

• Viacor Early Clinical

Annulus Plication

• Mitralign

• Guided Delivery Systems

PosteriorReshaping

Pre-Clinical

Internal Direct S-L

Pre-Clinical

LV Shape Change

• Myocor

(Surgical/Endovascular)

External LA/LV

Clinical/Pre-Clinical

PS3PS3 Ample Medical

Indirect annuloplasty: Coronary Sinus Devices

PTMA (Viacor)

CARILLON (Cardiac

Dimensions)

MONARC (Edwards

Lifesciences)

Indirect Annuloplasty

Coronary Sinus Devices

CARILLON

(Cardiac Dimensions)

PTMA

(Viacor)

MONARC

(Edwards Lifesciences)

Normal

S-L Expansion

Causes FMR

• Sheep CHF/FMR Model Strong Surrogate for Human Condition

Mitral Regurgitation in CHF

Diseased

FMR Ameliorated By Restoring S-L to Normalcy

Direct S-L Shortening

Stops FMR

The PS3 System

Percutaneous

Septal-Sinus Shortening

Rogers JH, Palacios, IF. Circulation. 2006;113:2329-2334.

Percutaneous Septal,

Sinus Shortening

Ample PS3 FIM Studies

in Caracas - Venezuela

• FIM experience in two

patients with severe MR

scheduled for cardiac

surgery.

•Safety and efficacy issues

• Significant changes in the

PS dimensions and MR

Phase I

SurgicalPhase II

Café Trial

• To assess the feasibility and

safety of the chronically

implanted Ample PS3 device in

patients with FMR

• 40 pts to be enrolled at 3

hospitals in Venezuela. Three

patients initially done.

•Study restarted on May 2014

Septal Sinus Shortening (The ARTO™ System) for the Treatment of Functional Mitral

Regurgitation: 6-Month MAVERIC Trial Results

Marie-Claude Morice, MD Institut Cardiovasculaire Paris Sud

Générale de Santé Massy, France

for the MAVERIC Investigators

Andrejs Erglis, Jason H. Rogers, Martyn Thomas, Marie Claude

Morice, Inga Narbute, Milana Zabunova, Thomas Hovasse, Mathieu Poupineau, Ainars Rudzitis, Ginta Kamzola, Ligita

Zvaigzne, Samantha Greene, Jason H. Rogers

Porcine model, 6M

MitraClip Concepts

Facilitates proper leaflet coaptation

• Mechanical solution to a mechanical problem

Etiology

• Degenerative - Anchor flail and prolapsed leaflets (similar to chordal transfer/replacement)

• Functional - Coapt tethered leaflets to reduce time and force required to close valve

Creates tissue bridge

The Alfiere

Operation 2000

Edge to Edge: Clinical Results

Freedom from Reoperation

Case Selection

Case Selection

Edge to Edge: First Case

Caracas - Venezuela

MitraClip System

Abbott Vascular

LAA

300

600

300

A1

A2A3

P1

P2

P3

FOSSA

AO

LATERAL

MEDIAL

ANTERIOR

POSTERIOR

Echo Related Valve

Anatomy

Use of common

anatomically

based vocabulary

reinforces clear

communication

MitraClip Therapy:

Clinical Development

2003 2004 20092008200720062005 2010 2011 2012

EVEREST I

55 patients enrolled from 2003 to 2006

EVEREST II

279 patients enrolled from 2005 to 2008REALISM – 859* On going

CE Mark

HR Study

78 patients

First

Implant

commercialTrial

2013

SAP

Global Commercial & ACCESS EU Registry

8,000+ patients treated

MitraClip available in Canada

Study Population N*

EVEREST I (Feasibility) Feasibility patients 55

EVEREST II (Pivotal) Pre-randomized patients 60

EVEREST II (Pivotal) Non-randomized patients

(High Risk Study)

78

EVEREST II (Pivotal) Randomized patients

(2:1 Clip to Surgery)

279 (184 Clip vs.

95 Surgery)

REALISM (Continued Access) Non-randomized patients 881

Compassionate/Emergency Use Non-randomized patients 66

ACCESS Europe Phase I Non-randomized patients 567

ACCESS Europe Phase II Non-randomized patients 286

Commercial Use Commercial patients 8,556

Total 10,733

+95 surgery

MitraClip Worldwide Experience

Commercial MitraClip

Implant Experience

–Treating Centers: 249

–Patients: 9,409

– Implant Rate: 96%

–Acute MR reduction: 99% of implants

–Etiology

• Functional MR 67%

• Degenerative MR 22%

• Mixed 11%

Etiology

Transseptal Crossing

Tenting: Junction Between the Muscular and

Membranous Septum - Imaging: Bi-caval

Other transseptal tools

Baylis NRG RF transseptal needle

SafeSept Transseptal guidewire

Line of

coaptation

Tenting: “Posterior - Mid” Aspect of

Fossa Imaging: Short Axis at the Base

3.5 - 4.0 cm

Tenting: “Superior” Aspect of Fossa

Imaging: 4 Chamber or 5 Chamber, Height 3.5-4.0cm

3.5 - 4.0 cm

Puncture and Cross Fossa

Imaging: Short Axis at the Base

MitraClip Steering to

Valve Plane

Device Steering

Leaflets

Grasping

Everest II Randomized TrialEVEREST II Randomized

Trial

Degenerative vs. Functional MR

30 day Major Adversed Cardiac Events

Degenerative vs. Functional MR

30-day Major Adverse Cardiac Events 3

0-d

ay M

AC

E

Freedom from MV Surgery. Everest II Randomized Trial. 2 year Results

NS

4-Years Follow-Up of

the EVEREST II Trial

Mauri et al, JACC 2013; 62: 317-328.

• Four year follow up results of the EVEREST II trial showed that at 4 years, patients with mitral valve regurgitation who undergo repair with a novel Mitral-Clip experience mortality rates and mitral regurgitation (MR) levels comparable to those that accompany surgery, according to updated data from the EVEREST II.

• While surgery continues to hold an early advantage in MR and need for surgical re-intervention, few differences between treatment groups were apparent beyond 1 year. Kaplan Miers for Event Free Survival showed no significant differences (84.1% vs. 82.3%; p= 0.7350) for Mitral Clip vs. Surgical Groups.

More Effective Reduction

in MR with Surgery

More effective reduction in MR with surgery

Favorable LV remodeling in both groups Better NYHA & SF-36 QOL with MitraClip

More effective reduction in MR with surgery

Favorable LV remodeling in both groups Better NYHA & SF-36 QOL with MitraClip

More effective reduction in MR with surgery

Favorable LV remodeling in both groups Better NYHA & SF-36 QOL with MitraClipFavorable LV remodeling in both groups

Better NYHA & SF-36 QOL with Mitral CLip

EVEREST II Final

Results

MitraClip Received

FDA approval

• The US Food and Drug Administration (FDA) has approved

the MitraClip for patients with symptomatic degenerative mitral

regurgitation deemed high risk for mitral-valve surgery.

• The FDA approval follows the recommendations of the advisory

committee, that the efficacy of the MitraClip exceeded the risks in

patients with a prohibitive risk for surgery.

• The FDA approval is based on the results of the Endovascular

Valve Edge-to-Edge Repair Study (EVEREST II) and other

registry data. In EVEREST II, two-year results showed the

percutaneous repair of the mitral valve was less effective in

reducing mitral regurgitation but was associated with superior

safety and similar improvements in clinical outcomes.

High Risk Eligibility Criteria

(at least one)

• STS Score ≥ 8

• Prior CABG

• Hepatic Cirrhosis.

• Functional MR and LVEF < 40%

• Prior chest surgery, LVEF < 35%, and creatinine

> 2.5 mg/dl

• Age > 75 and prior chest surgery and creatinine >

2.5 mg/dl

• Two (2) or more chest surgeries

Functional MR

COAPT Trial

• Evaluate the safety and effectiveness of the

MitraClip System for the treatment of moderate-

to-severe or severe functional mitral regurgitation

in symptomatic subjects that are extremely high

risk for mitral valve surgery.

• MitraClip vs. Medical therapy– 1:1 randomization – n~420 pts

COAPT Primary

Endpoints

• Safety: Composite of

– Death (all-cause)

– Stroke,

– Worsening kidney dysfunction

– Permanent left ventricular assist device (LVAD) implant

– Heart transplant at 12 months.

• Effectiveness:

– Recurrent heart failure (HF) hospitalizations

COAPT Secondary

Endpoints

• Secondary Safety:

– Composite of death (all-cause), stroke, myocardial infarction

(MI), or non-elective cardiovascular surgery for device related

complications at 30 days post- procedure in the Device group

– All-cause mortality at 12 months

• Secondary Effectiveness:

– Mitral Regurgitation (MR) severity at 12 months

– Change in quality of life (QoL) at 12 months over

– Change in Left Ventricular End Diastolic Volume

– (LVEDV) at 12 months from baseline

– New York Heart Association Functional Class I/II at 12 months

– Recurrent hospitalizations - all-cause

430 patients enrolled at up to 75 US sites

Randomize 1:1

Clinical and TTE follow-up:

Baseline, Treatment, 1-week (phone), 1, 6, 12,

18, 24, 36, 48, 60 months

Control Group

Standard of careN=215

Symptomatic heart failure subjects who are treated per standard of care

Determined by the site’s local heart team as not appropriate for mitral valve surgery

Specific valve anatomic criteria

MitraClip

N=215

Significant FMR (≥3+ by core lab)

COAPT Trial Design

KEY INCLUSION

CRITERIA

• Symptomatic, functional (ischemic or non-ischemic) MR

greater ≥ 3+

• Primary MR jet from central A2 / P2 scallops

• Not a suitable candidate for open MV surgery

• NYHA II,III or ambulatory IV

• At least 1 HF hospitalization and/or elevated BNP

Key Exclusion

Criteria

• ACC/AHA Stage D heart failure

• Prior HTX or HTX status 1

• HOCM, infiltrative CMPs

• Life expectancy < 12m due to non-cardiac

conditions

• Hemodynamic instability (inotrops / LVAD)

• Prior MV leaflet surgery; implanted prosthetic MV

Increased Referrals at Leading

Valvular Heart Centers

* Voluntary recall of MitraClip for 6 months+ Hendrik Treede et al. A Heart Teams Perspective on Interventional Mitral Valve Repair: Percutaneous clip implantation as

an important adjunct to a surgical mitral valve program for treatment of high-risk patients; The Journal of Thoracic and

Cardiovascular Surgery, 2011

^ H. Reichenspurner. MitraClip - Data analysis from a cardiac surgeon’s perspective. EACTS 2012

*

Referral volume increases after introduction of MitraClip therapy+

*

^

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Category 1 Category 2 Category 3 Category 4

Series 3

Series 2

Series 1

Increased Referrals at Leading

Valvular Heart Centers

Voluntary recall of MitraClip for 6 months

Hendrik Treede et al. A Heart Teams Perspective on Interventional Mitral Valve Repair: Percutaneous clip

implantation as an important adjunct to a surgical mitral valve program for treatment of high-risk patients; The

Journal of Thoracic and Cardiovascular Surgery, 2011

H. Reichenspurner. MitraClip - Data analysis from a cardiac surgeon’s perspective. EACTS 2012

*

Referral volume increases after introduction of MitraClip therapy

55 49 51 48 51 56 56 54 52 57

63 90 99 113 95 135 164 157 174 196

8

3075

89

64

0

50

100

150

200

250

300

350

2002 2003 2004 2005 2006 2007 2008 2009 2010 2011

Pat

ients

Percutaneous

Repair

Replacement

^

Patient Selection

Bottom Line

Degenerative Functional

Low Surgical

Risk

Surgical Mitral

Valve Repair

COAPT

High Surgical

Risk

MitraClip COAPT

Conclusion I

• The MGH has become a Premier Institute for the

treatment of patients afflicted with valvular heart

disease.

• We are already a leading center for a variety of

valvular heart disease percutaneous procedures

including pulmonic, aortic, tricuspid and mitral

balloon valvuloplasties, pulmonic valve replacement

(Melody Valve), Aortic Valve Replacement (TAVI

with Sapien and CoreValves).

• Introduction of the Mitral Clip technology has

improved our position in this competitive market.

• Two groups of patients with severe mitral

regurgitation will be considered for this therapy

as follow:

– (1) Commercial Group for patients with

“degenerative mitral regurgitation” deemed

high risk for mitral valve surgery.

– (2) COAPT Trial for those patients with

“functional severe MR” as part of an ongoing

randomized Clinical trial comparing the

MitraClip with optimal medical therapy.

Conclusion II