controversies in mitral regurgitation therapy mitral...
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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
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