Download Percutaneous Approaches to Valve Repair for Mitral Regurgitation

Journal of the American College of Cardiology
2014 by the American College of Cardiology Foundation
Published by Elsevier Inc.
Vol. 63, No. 20, 2014
ISSN 0735-1097/$36.00
http://dx.doi.org/10.1016/j.jacc.2014.01.039
STATE-OF-THE-ART PAPERS
Percutaneous Approaches to Valve Repair
for Mitral Regurgitation
Ted Feldman, MD, Amelia Young, MD
Evanston, Illinois
Percutaneous therapy has emerged as an option for treatment of mitral regurgitation for selected, predominantly
high-risk patients. Most of the percutaneous approaches are modifications of existing surgical approaches. Catheterbased devices mimic these surgical approaches with less procedural risk, due to their less-invasive nature.
Percutaneous annuloplasty can be achieved indirectly via the coronary sinus or directly from retrograde left
ventricular access. Catheter-based leaflet repair with the MitraClip (Abbott Laboratories, Abbott Park, Illinois) is
accomplished with an implantable clip to mimic the surgical edge-to-edge leaflet repair technique. A large
experience with MitraClip has been reported, and several other percutaneous approaches have been successfully
used in smaller numbers of patients to demonstrate proof of concept, whereas others have failed and are no longer
under development. There is increasing experience in both trials and practice to begin to define the clinical utility of
percutaneous leaflet repair, and annuloplasty approaches are undergoing significant development. Transcatheter
mitral valve replacement is still in early development. (J Am Coll Cardiol 2014;63:2057–68) ª 2014 by the
American College of Cardiology Foundation
Novel transcatheter therapies for valvular heart disease have
developed tremendously over the past decade. These innovative interventional methods are largely modeled from
established surgical heart valve procedures, which have
started to evolve to less-invasive approaches. Until a decade
ago, interventional valve procedures included only balloon
pulmonic, aortic, or mitral valvuloplasty, serving highlyselected patients. In 2000 and 2002, percutaneous valve
therapy advanced greatly with the first catheter-based pulmonic and aortic valve replacement procedures (1,2). Since
then, tens of thousands of high-risk patients have had
percutaneous pulmonic and aortic valve replacement
worldwide. Although a variety of mitral valve (MV) transcatheter therapies grew in parallel with aortic valve therapies,
the MV therapies have had a slower development path.
Challenges arising from the complex anatomy of the MV
and mitral apparatus and the interplay of the MV with the
left ventricle (LV) contribute to the greater difficulty in
conceiving of and evaluating mitral devices.
Severe mitral regurgitation (MR) is an insidious disorder
that develops gradually over many years and carries an
annual mortality rate of at least 5% (3,4). Medical therapy
relieves symptoms but does not reverse the underlying mitral
pathology. Those with degenerative MR have excellent
From the Cardiology Division, Evanston Hospital, Evanston, Illinois. Dr. Feldman
has served as consultant for and received research grants from Boston Scientific,
Abbott, and Edwards. Dr. Young has reported that she has no relationships relevant to
the contents of this paper to disclose.
Manuscript received October 2, 2013; revised manuscript received January 17, 2014,
accepted January 28, 2014.
outcomes with repair surgery (5). The long-term benefits of
surgical treatment of functional MR are harder to demonstrate and remain controversial (6–9).
A number of transcatheter MV therapies have been
adapted from surgical techniques and are being applied in
patients at high-risk for surgery as a result of coexisting
comorbidities, among whom there is a large unmet clinical
need (10). Catheter device approaches for leaflet repair,
indirect and direct annuloplasty, chordal replacement, and
LV remodeling for the treatment of MR are under development for these patients who otherwise do not have a good
therapy option.
Leaflet Repair
In 1991, Alfieri et al. (11) described a simple surgical
technique for suturing leaflets together to reduce MR in
patients with degenerative MR. This repair technique, also
known as the edge-to-edge leaflet repair, involves suturing
the anterior and posterior mitral leaflet edges together near
their midpoints, creating a double-orifice valve, and thereby
reducing MR. Alfieri performed this surgical procedure in
combination with mitral annuloplasty in most cases (12,13).
In a select group of patients who underwent isolated surgical
edge-to-edge repair without annuloplasty, longer-term
outcomes up to 12 years were excellent (14). This concept
is the basis of a catheter-based approach to mimic the edgeto-edge surgical repair.
MitraClip. The MitraClip (Abbott Laboratories, Abbott
Park, Illinois) is a novel transvenous percutaneous device
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Feldman and Young
Percutaneous Approaches for Mitral Regurgitation
that creates an edge-to-edge
repair for MR (15). The MitraClip remains investigational in
CRT = cardiac
the United States. It received
resynchronization therapy
CE mark approval in 2008.
EuroSCORE = European
Catheter-based mitral repair
System for Cardiac
with the MitraClip system was
Operative Risk Evaluation
first performed in patients in
LV = left ventricle/
ventricular
2003. To date, of the various
transcatheter MV therapies, the
MR = mitral regurgitation
largest clinical experience is with
MV = mitral valve
the MitraClip system, which has
NYHA = New York Heart
been implanted in over 10,000
Association
patients worldwide.
STS = Society of Thoracic
The MitraClip is a mechanSurgeons
ical clip that permanently opposes the middle of the anterior and posterior mitral
leaflets (Fig. 1). A double-orifice is formed, and the
subvalvular apparatus is spared. The procedure is performed in the cardiac catheterization laboratory in the
beating heart, under general anesthesia, and with fluoroscopic and transesophageal echocardiographic guidance.
The MitraClip system consists of the clip delivery system,
to which the device is mounted at its distal end, and
steerable guide catheter. The MitraClip comes in 1 size,
made of cobalt-chromium metal alloy covered by polypropylene fabric. The clip delivery system and clip are
passed through the steerable guide. The steerable catheter
is 24-F at the skin and 22-F when it gains access to the
left atrium at the level of the atrial septum through a
transseptal puncture. The arms of the MitraClip are 8 mm
long. With the arms extended, the MitraClip is navigated
from the left atrium, across the mitral orifice, and into the
LV at a point above the origin of the MR jet (Fig. 2).
Once across the orifice, the open clip is slowly pulled back,
allowing the leaflets to fall into the arms. The arms are
closed to grasp the leaflet edges. Successful grasping results in immediate reduction in the degree of MR. An
assessment of leaflet insertion is made to ensure stability of
the device and leaflets, and then the clip is closed. The
operator may release and re-adjust the position of the clip
to optimize MR reduction. In approximately 40% of the
cases a second clip might be required to achieve sufficient
reduction in MR if the degree of MR reduction from the
first device is insufficient. Three clips are used in approximately 1% of cases, and the use of as many as 4 clips
has been described (16). The use of 2 clips is an integral
part of the strategy of the procedure. The device manufacturer currently charges for the device on a perprocedure rather than a per-clip basis, so the expense of
the procedure is not different when multiple clips are used.
The MitraClip device was used in carefully-selected patients in the initial trial experience. In addition to clinical
selection criteria based verbatim on the valve guidelines (9),
careful anatomic criteria were also required. These anatomic
features were originally designed for degenerative MR.
Abbreviations
and Acronyms
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Subsequently, it has been recognized in real-world practice
that patients with functional MR might be treated with less
concern for the EVEREST (Endovascular Valve Edgeto-Edge Repair Study) criteria. Specifically, a jet origin that
extends beyond the central scallops of the line of coaptation,
or is even pan-orificial, might respond to MitraClip therapy
in patients with functional MR. The anatomic criteria are
ideal in approximately 20% to 35% of patients with severe
degenerative MR and acceptable in a larger proportion with
functional MR.
The EVEREST I clinical trial established safety of the
device and feasibility of the procedure (17). In the phase II
EVEREST trial, 279 patients selected by the guideline
criteria for mitral operation were randomized in a 2:1 ratio to
undergo percutaneous repair with MitraClip (n ¼ 184)
or conventional MV repair or replacement surgery (n ¼ 95)
(Table 1) (18). Most patients (73%) had degenerative MV as
the etiology of MR. In the intention-to-treat analysis, the
rates of death (6%) were similar for MitraClip and surgery at
1 year. The frequency of 2þ MR was significantly higher
after MitraClip, but the proportion of patients with grade
3þ or 4þ MR was not significantly different between the 2
groups at 2 years of follow-up (20% percutaneous group vs.
22% surgical group). The rate of surgery for MV dysfunction
was 20% for percutaneous group as compared with 2.2% in
the surgical group. The combined primary efficacy endpoint
of freedom from death, from surgery for MV dysfunction,
and from grade 3þ or 4þ MR was 55% in the percutaneousrepair group and 73% in the surgery group (p ¼ 0.007). This
difference was driven largely by the high rate of surgery after
the initial intervention in the MitraClip group. The
EVEREST II trial showed superior safety in the
percutaneous-repair group as compared with the surgery
group in an intention-to-treat analysis (19). This was driven
primarily by a higher rate of bleeding requiring transfusion in
the surgery group. Importantly, the safety of the procedure
even in high-risk patients has been a large part of the
acceptance of the therapy in commercial use around the
world. Device embolization was not observed, and mitral
stenosis was not reported. Having a MitraClip in place did
not take away the option for surgical MV reconstruction (20).
A number of studies have established favorable changes
in LV dimensions, loading conditions, and MR severity after
MitraClip implantation (21–24). Baseline versus 24-h echocardiographic measurements demonstrated significant reductions in MR grade (mean 3.3 to 1.6), regurgitant fraction
(mean 46% to 28%) and volume (mean 51 to 27 ml), and LV
end-systolic and -diastolic dimensions and volume (25).
Other signs of significant reversal in LV remodeling include
decrease in LV mass and LV wall stress (26). Left atrial volume
reduction was associated with reduction in vena contracta area
>50% (27). A novel mechanism for how the MitraClip might
alter LV remodeling has been proposed (28). Tissue growth
into the clip forms a bridge between the anterior and posterior
mitral leaflets. The anatomic formation of this bridge might
interact with adjacent myocardial tissue to enhance the
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Figure 1
Feldman and Young
Percutaneous Approaches for Mitral Regurgitation
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MitraClip System
(A) The partially open MitraClip (Abbott Laboratories, Abbott Park, Illinois) device is shown without its fabric covering. A fine wire runs through the barbed “grippers,” which is
used to raise the grippers. (B) The device in closed configuration. (C) The MitraClip is attached to the clip delivery system, which protrudes from the steerable guide catheter.
(D) Control knobs allow deflection of the guide and clip delivery system to steer the system through the left atrium and position the MitraClip above the mitral orifice.
fibromuscular continuity that generates enough force to
counteract or constrain the distending wall stress with retardation of adverse remodeling. Histopathological studies have
found progressive “healing” over the course of several months,
with eventual formation of mature collagen-rich matrix and
complete fibrous encapsulation on the outer surface of the
device that helps to maintain device integrity and stability (29).
Despite this healing process, conventional surgical MV
reconstruction can usually be done in patients who received
MitraClip as late as 5 years after the implantation. Most of
these cases have successful surgical repair (30). Due to the
Figure 2
fibrous tissue bridge, it is important to perform careful
dissection of and have a basic understanding of the mechanism to unlock the device such that the MitraClip can
be explanted safely during surgery to preserve the mitral
leaflets (31,32). Although occasionally MV replacement is
required after MitraClip implantation due to MV injury or
difficulty in removing the clip, presence of the MitraClip
itself was not a major predictor of valve replacement, rather
replacement was strongly associated with anterior or
bi-leaflet MV pathologydalso predictors for valve replacement during surgical repair (32).
Introducing the Clip
To introduce the clip, the clip delivery system is advanced through the guide into the left atrium (left). Under echocardiographic and fluoroscopic guidance, the clip is aligned
perpendicular to the valve plane, with the clip arms perpendicular to the line of coaptation. It is then advanced into the left and then slowly retracted to grasp the leaflets (right).
The clip is closed (right, inset), and if reduction of mitral regurgitation is satisfactory, it is released.
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Feldman and Young
Percutaneous Approaches for Mitral Regurgitation
Table 1
EVEREST II Randomized Trial
Description
Primary Effectiveness Endpoint
Primary Safety Endpoint
Key Inclusion Criteria
Key Exclusion Criteria
Completed and reported
prospective multicenter
trial comparing MitraClip
vs. control surgical repair
or replacement
279 patients enrolled
at 37 sites
Clinical success rate
Freedom from the combined
outcome of death, MV surgery
or re-operation for MV
dysfunction, and MR >2þ at
12 months
Noninferiority hypothesis
Major adverse event rate at
30 days
Superiority hypothesis
Candidate for MV surgery
Moderate to severe (3þ) or
severe (4þ) MR
Symptomatic >25% EF and
LVESD 55 mm
Asymptomatic with 1 or more
of the following:
LVEF 25%–60%
LVESD 40 mm
New-onset atrial fibrillation
Pulmonary hypertension
AMI within 12 weeks
Need for other cardiac
surgery
Renal insufficiency
Creatinine >2.5 mg/dl
Endocarditis
Rheumatic heart disease
MV anatomical exclusions
MV area <4.0 cm2
Leaflet flail width (15 mm)
and gap (10 mm)
Leaflet tethering/coaptation
depth (>11 mm)
and length (<2 mm)
MitraClip (Abbott Laboratories, Abbott Park, Illinois).
AMI ¼ acute myocardial infarction; EF ¼ ejection fraction; EVEREST ¼ Endovascular Valve Edge-to-Edge Repair Study; LV ¼ left ventricle/ventricular; LVEF ¼ left ventricular ejection fraction;
LVESD ¼ left ventricular end-systolic dimension; MR ¼ mitral regurgitation; MV ¼ mitral valve.
Historically, there has been concern for development of an
acute low output state after open heart MV surgery among
patents with poor LV function (33,34). A substudy of the
EVEREST II trial examined acute hemodynamic effects
and demonstrated that no patients developed an acute low
output state immediately after MitraClip implantation
(25). Favorable hemodynamic changes included improvement in forward stroke volume and cardiac index, lower
LV end-diastolic pressure, reduction in systemic vascular
resistance, and improvement in LV unloading conditions
(35). Improvements in left-sided filling pressures and pulmonary arterial pressures have been demonstrated in those
with elevated values at baseline (36).
Recently published 4-year EVEREST II follow-up
showed stability of the earlier results of MitraClip (37).
Freedom from death occurred in 83% of patients in
the percutaneous group and 82% in the surgery group
(p ¼ 0.91). Rates of MR 3 to 4þ were not significantly
different between the percutaneous repair group and the
surgery group up to 4 years. Echocardiographic analysis
demonstrated improved LV end-diastolic and -systolic volumes and dimensions, with significant improvements in
clinical measures of functional status.
High-risk subgroups. Subgroup analysis of the randomized EVEREST II results suggested that patients with older
age and functional rather than degenerative MR had outcomes most similar to conventional surgery. The EVEREST
I and II trials included only surgical candidates, and it was
recognized that many patients who were poor candidates for
surgery were being excluded. This observation led to the
EVEREST High Risk study in which patients with severe,
predominantly functional MR who were high risk (estimated surgical mortality rate of 12%) for surgical repair
or replacement were compared with a nonrandomized
concurrent control group treated with standard medical
therapy (38). At 1 year, there was a trend toward increased
survival rate in the MitraClip group. Survival in clip-treated
patients was 76% versus 55% in the control group. In
addition, a 45% reduction in rate of repeat hospital stay was
demonstrated. A prospective, multicenter registry involving
high-risk surgical patients, the REALISM (Real World
ExpAnded MuLticenter Study of the MitraClip System)
registry, has found similar results (39).
Similar findings were demonstrated in the ACCESS-EU
European registry for MitraClip, in which most patients
treated were elderly, had multiple comorbidities, and were
high-risk surgical candidates according to their European
System for Cardiac Operative Risk Evaluation score
(EuroSCORE) (39,40). One-year survival rate was 82%,
and 70% were classified as New York Heart Association
(NYHA) functional class I/II. Recently published findings
from the German TRAMI (TRAnscatheter Mitral valve
Interventions) registry demonstrated similar results in which
elderly patients (age >76 years) with LV dysfunction fared
similarly to their younger counterparts (41).
A number of studies have shown feasibility and efficacy of
the MitraClip device in patients who were deemed high risk
for surgery or were inoperable (42–46). In a small, select
group of 51 patients, acute outcomes of MitraClip therapy
for MR were assessed (42). The average logistic EuroSCORE
was 28%, and average Society of Thoracic Surgeons (STS)
score was 15%. These patients were older (mean age 73 years)
and had poorer LV function (mean LV ejection fraction
36%), functional MR (69%), complex valvular abnormalities,
and pre-existing comorbidities. In fact, nearly 70% of these
patients would have been excluded in the EVEREST trials.
Most (94%) were discharged with MR grade 2þ. All were
hemodynamically stable throughout the procedure, and no
major periprocedural complications were observed. Significant
improvement in NYHA functional class was achieved in
>90% who received the device.
The MitraClip device has been proven to have high
procedural success clinical efficacy even in high-risk and
critically ill patients (45). Short-term follow-up in a group
with logistic EuroSCORE 41% and STS score 24%
demonstrated a 92% successful MitraClip implantation rate,
with reduction in MR and significant clinical improvement.
Use in critically ill patients as a “bail-out” has been recently
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described with rapid improvement in hemodynamic status,
allowing de-escalation and discontinuation of inotropic
therapy with eventual discharge to home (44). A unique case
of MitraClip as a successful rescue therapy was described
in a patient with acute MR due to ruptured papillary muscle
after suffering an acute myocardial infarction (47). Similar
therapeutic efficacy has been demonstrated in inoperable
patients (46).
A recent meta-analysis of high-risk cohorts who underwent MitraClip implantation found safety and feasibility
of the device in patients with primarily functional MR
and STS scores 12% or equivalent logistic EuroSCORE
(48). Acute procedural success demonstrated MR
grade 2þ could be achieved between 73% and 100% of a
high-risk subpopulation that was sustained through 12
months. Need for MV surgery ranged from 0% to 6%.
Survival rate ranged from 75% to 90% at 1 year. At 12
months, clinical outcomes demonstrated approximately 75%
of patients in NYHA functional class I/II had significant
improvements in 6-min walk test and quality of life and
parallel improvements in echocardiographic measures.
An additional subgroup that has benefited from MitraClip therapy includes nonresponders to cardiac resynchronization therapy (CRT) (49). CRT improves morbidity,
mortality, and NYHA functional class and reduces MR in
advanced heart failure patients by reducing LV dyssynchrony
and thereby decreasing tethering forces of the mitral apparatus (50). However, patients with persistent severe MR
despite CRT have increased rates of hospital stay and major
arrhythmic events, lower ejection fraction, less reverse
remodeling, and a higher incidence of mortality (51–53). In
the European PERMIT-CARE (Percutaneous Mitral Valve
Repair in Cardiac Resynchronization Therapy) trial, patients
with symptomatic persistent severe MR despite optimal
pharmacologic therapy and a CRT device received MitraClip (50). These patients, with predominantly functional
MR and dilated ischemic cardiomyopathy (average LV
ejection fraction 27%), were considered ineligible for surgery. Those who underwent MitraClip repair demonstrated
a trend in significant MR improvement and reverse LV
remodeling. Additionally, 75% demonstrated improved
NYHA functional class I/II at 1 year.
A number of European registries have reported therapeutic success with the MitraClip in commercial practice
(39,41,49,54–57). Low rates of procedure-related mortality
or major complications are highly consistent across these
reports. There are significant reductions in MR grade and
improvements in exercise capacity lasting beyond 1 year in
most patients. Taken together, consistent safety and high
procedural success rates, high clinical efficacy, and improved
functional status and quality have been reported in patients
who are considered high risk for mitral surgery or for whom
there are no options. There remain questions with regard to
the magnitude and duration of the efficacy or MR reduction,
the durability of clinical improvements, and the optimal
selection of patients.
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Before the March 2013 Food and Drug Administration
(FDA) panel review on MitraClip therapy, the FDA
expressed several concerns on the basis of the available data at
that time. Although EVEREST II and registry experiences
are consistent with regard to the procedural safety and the
clinical benefits of MitraClip therapy, particularly in higherrisk-for-surgery patients, there are no current randomized
trial data in higher-risk patients. The FDA commented that
the REALISM and High Risk Registries were continued
access protocols not intended to be used as a pivotal dataset.
Thus, “FDA believes the evidence necessary for determination of safety and effectiveness sufficient for approval of a first
of a kind device should not be based on a retrospective
evaluation of registry data.” The FDA panel considered the
proposed indication for “MitraClip use in patients with
significant symptomatic MR who have been determined by a
cardiac surgeon to be too high-risk for open MV surgery and
in whom existing co-morbidities would not preclude the
expected benefit from correction of the MR.” Ultimately,
the FDA panel review resulted in a vote of 8 to 0 in favor
of a reasonable assurance of safety, 4 to 5 against reasonable assurance of effectiveness, and 5 to 3 that the benefits outweigh the risks. On October 24, 2013, the FDA
approved MitraClip in a carefully-defined patient subgroup
“for the percutaneous reduction of significant symptomatic
MR 3þ due to primary abnormality of the mitral apparatus
(degenerative MR) in patients who have been determined
to be at prohibitive risk for MV surgery by a heart team,
which includes a cardiac surgeon experienced in MV surgery
and a cardiologist experienced in MV disease and in whom
existing comorbidities would not preclude the expected
benefit from reduction of the mitral regurgitation” (58). An
important consideration after FDA approval is how the
therapy will be disseminated. The international experience
has shown that new sites can be initiated with a high level of
procedure success, demonstrating that the overall group
learning can be transmitted to new operators and teams. The
procedure technical success rate has improved from 90%
in the EVERST trial experience to 95% to 100% in recent
international reports (42,44).
Before the FDA panel review, a pivotal randomized trial
of MitraClip in a high-risk-for-surgery heart failure population was initiated. The COAPT (Clinical Outcomes
Assessment of the MitraClip Percutaneous Therapy for
Extremely High-Surgical-Risk Patients) trial is examining
the safety and effectiveness of the MitraClip device in highsurgical-risk patients with MR and heart failure who are
randomized to either percutaneous mitral repair or control
group with standard medical therapy alone (Table 2). A
similar trial in Europe, the RESHAPE-HF (A Randomized
Study of the MitraClip Device of Heart Failure Patients
with Clinically Significant Functional Mitral Regurgitation),
is taking place (Table 3). These randomized trials will add
considerably to our understanding of the role of MitraClip
therapy compared with medical therapy in a patient population that is too high risk to undergo MV surgery. These
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Table 2
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Feldman and Young
Percutaneous Approaches for Mitral Regurgitation
COAPT High Risk Randomized Trial
Description
Prospective U.S. randomized
multicenter comparison of
MitraClip vs. medical
therapy in extremely
high-risk patients with HF
420 patients to be enrolled at
up to 75 U.S. sites
Primary Effectiveness Endpoint
Superiority for recurrent HF
hospital stays at 1 yr
Primary Safety Endpoint
Key Inclusion Criteria
Key Exclusion Criteria
Noninferiority hypothesis
for composite of all-cause
death, stroke, worsening
kidney function, or LVAD
or cardiac transplant
at 1 yr
Functional MR 3þ
Ischemic or nonischemic
cardiomyopathy
Symptomatic NYHA functional
class II, III, or ambulatory IV
Local Site Heart Team
concludes that comorbidities
result in an extremely high
operative risk of stroke or
death
1 HF hospital stay during
prior yr and/or BNP 400
pg/ml or NT-proBNP 1,600
pg/ml 90 days treated per
standards for CAD, LV
dysfunction, MR, or HF
including CRT,
revascularization, OMT
LVEF 50%
Primary MR jet originates from
malcoaptation of A2-P2
scallops
Severe LV dysfunction
is defined as LVESD
>70 mm or LVEF <20%
MV area <4 cm2
MI 30 days
Untreated clinicallysignificant CAD requiring
revascularization
CVA or TIA within 6 months
or severe carotid stenosis
Any percutaneous coronary,
carotid, or endovascular
intervention or carotid
surgery within 30 days
or any coronary or
endovascular surgery
within 6 months
Untreated clinicallysignificant coronary
artery disease requiring
revascularization or
tricuspid or aortic valve
disease requiring surgery.
CRT and/or ICD implant or
revision within 90 days
MVA by planimetry <4.0 cm2
Leaflet anatomy that might
preclude MitraClip
implantation, proper
MitraClip positioning on
the leaflets, or sufficient
reduction in MR
Severe right ventricular
failure or severe tricuspid
regurgitation
CAD ¼ coronary artery disease; COAPT ¼ Clinical Outcomes Assessment of the MitraClip Percutaneous Therapy for Extremely High Surgical Risk Patients; CRT ¼ cardiac resynchronization therapy; CVA ¼
cardiovascular accident; HF ¼ heart failure; ICD ¼ implantable cardioverter-defibrillator; LVAD ¼ left ventricular assist device; MI ¼ myocardial infarction; MVA ¼ mitral valve area; NT-proBNP ¼ N-terminal
pro–B-type natriuretic peptide; NYHA ¼ New York Heart Association; OMT ¼ optimal medical therapy; TIA ¼ transient ischemic attack; other abbreviations as in Table 1.
Table 3
RESHAPE-HF Randomized Trial
Description
Primary Endpoint
Key Inclusion Criteria
Key Exclusion Criteria
Prospective, randomized,
parallel-controlled, multicenter
European clinical evaluation
of the MitraClip device plus
optimal standard-of-care
therapy (Device group)
compared with optimal
standard-of-care therapy
alone (Control group)
Eligible subjects will be
randomized in a 1:1 ratio
to the device group or
control group
Approximately 800 subjects will
be enrolled at up to 75 sites
across Europe
Composite of all-cause
mortality and recurrent
HF hospital stays in the
ITT randomized population
Moderate-to-severe MR, NYHA
functional class III–IV
Minimum of 1 documented hospital
stay for HF within 12 months or
BNP 350 pg/ml, or
NT-proBNP 1,400 pg/ml
LVEF 15% and 40%
LVEDD 55 mm
Degenerative MR
Cardiovascular hospital stay within the last 2 weeks
ACS, TIA, or CVA within 90 days
Any percutaneous cardiovascular intervention,
carotid surgery, cardiovascular surgery, or atrial
fibrillation ablation within 90 days before
randomization
Implant of any rhythm management device (i.e.,
pacemaker, CRT or CRT-D, or ICD) within 90 days
before randomization
6MWT distance >450 m
MVA by planimetry <4.0 cm2
Specific leaflet anatomy that might preclude
MitraClip device implantation (evidence of
calcification in the grasping area, presence of
significant cleft in the grasping area, lack of both
primary and secondary chordal support in the
grasping area, prior mitral valve surgery,
coaptation length 2 mm, leaflet mobility
length <1 cm)
ACS ¼ acute coronary syndrom(s); CRT-D ¼ cardiac resynchronization therapy defibrillator; ITT ¼ intent-to-treat; LVEDD ¼ left ventricular end-diastolic dimension; RESHAPE-HF ¼ Randomized Study of the
MitraClip Device in Heart Failure Patients With Clinically Significant Functional MR; 6MWT ¼ 6-min walk test; other abbreviations as in Tables 1 and 2.
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will be the first randomized clinical trials to compare
nonsurgical standard-of-care medical treatment with an
interventional therapy for MR. Notably, no such randomized comparison has been made for surgery compared with
medical therapy for functional MR, despite ongoing controversy about the efficacy of surgery for functional MR. The
COAPT and RESHAPE trials will not simply test the
feasibility of percutaneous repair in patients who are too sick
to undergo surgery, they also represent an important step in
understanding whether MV repair offers an advantage at all
in patients with failing ventricles.
Annuloplasty
Surgical plication of the mitral annulus with an undersized
ring is the standard surgical treatment for functional MR
(58,59). Annuloplasty reports describe restoration of MV
competency, improved LV performance, decreased LV
remodeling, and amelioration of symptoms in patients with
functional MR (60–63). Despite the reduction of MR, a
benefit of surgical annuloplasty on long-term mortality has
not been demonstrated (8). Development of less invasive
percutaneous devices has evolved over the years as an alternative to surgical annuloplasty, particularly in high-risk
patients. Novel catheter-based devices have made use of
the coronary sinus to achieve indirect annuloplasty, whereas
other devices achieve more direct annuloplasty.
Indirect annuloplasty. Coronary sinus annuloplasty takes
advantage of the proximity of the coronary sinus to the posterior and lateral mitral annulus (64–66). A device is placed
in the coronary sinus to create tension that is transmitted to
the annulus. Thus, the annular circumference is decreased,
and mitral leaflet coaptation improves. The Carillon Mitral
Contour System (Cardiac Dimension, Inc., Kirkland,
Washington) is the only technology still using this approach.
Figure 3
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Percutaneous Approaches for Mitral Regurgitation
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It is implanted via the internal jugular vein with a 9-F delivery
catheter (Fig. 3) (67). The nitinol device has a proximal and
distal anchor connected by a ribbon (68). The distal anchor is
released deep in the coronary sinus near the anterior
commissure, whereas the proximal anchor resides near the
coronary sinus ostium. To plicate tissue adjacent to the MV,
direct tension is placed on the delivery system. Immediate
assessment to determine its efficacy in reducing MR is
possible, such that if the reduction of MR is insufficient, the
device can be repositioned or removed.
A prospective, single arm feasibility study, AMADEUS
(CARILLON Mitral Annuloplasty Device European Union
Study), was performed to examine the safety and efficacy of
the Carillon device for treatment of functional MR (69).
Patients who received the device demonstrated significant
reduction in mitral annular diameter and MR by at least 1
grade and improvement in functional class and quality of
life during the follow-up period through 24 months. A
second-generation device was used in the TITAN (The
Transcatheter Implantation of the Carillon Mitral Annuloplasty Device) trial, a prospective, nonrandomized study of
patients with functional MR (70). Among the 53 patients
enrolled, 36 patients underwent successful permanent
device implantation. Patients who received the device had
significant benefit in reductions in quantitative measures of
functional MR, including regurgitant volume and effective
regurgitant orifice area, and favorable changes in LV remodeling sustained at 12 months. Positive clinical outcomes were
reflected in significant improvement in 6-min walk test,
functional class, and quality of life sustained at 24 months.
In 17 of the 53 patients, the device could not be permanently
implanted, due to difficulty cannulating the coronary sinus,
ineffective reduction in MR, or compression of a coronary
artery. The Carillon device received CE mark approval in
Europe in 2011.
Coronary Sinus Annuloplasty
The Cardiac Dimensions Carillon Device (Cardiac Dimension, Inc., Kirkland, Washington): the guide catheter is introduced through jugular venous access. The device is delivered
in the distal coronary sinus, and the distal anchor is released (left), and then the guide catheter is pulled back to release the proximal anchor in the coronary sinus ostium. The
right panel shows the wireform, made of nitinol wire, after release in the coronary sinus. Cinching of the mitral annulus results in compression of the septal-lateral dimension
and thus the regurgitant orifice.
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Figure 4
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JACC Vol. 63, No. 20, 2014
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Mitralign Annular Plication
(A) The retrograde guide catheter in the left ventricle (LV), with the distal catheter tip under the mitral annulus, behind the posterior leaflet (arrow). A wire has been passed from
the LV through the annulus and into the left atrium (LA) in B. Two pairs of wires are used to place pledgets near both commissures, shown from the LA side in C. The pledgets are
drawn together (arrows) to decrease the mitral annular circumference.
Despite its ease of use and immediate reduction in MR,
the Carillon device has several limitations. Some of the
failures to deliver the device in the early experience are
clearly related to the learning curve. Understanding the
coronary sinus anatomy in its relation to the MV apparatus
and coronary vessels is important to understanding the
implications of percutaneous device annuloplasty. Noninvasive imaging has demonstrated that the separation between the coronary sinus and mitral apparatus increases
significantly in dilated hearts compared with normal hearts,
with the coronary sinus occasionally coursing along the left
atrium, which might result in ineffective MR reduction
(71). Between 16% and 80% of patients had a coronary
vessel, particularly the left circumflex artery, that coursed
inferiorly to the coronary sinus (i.e., coursing between the
coronary sinus and mitral apparatus) (71–75). The implication of the close relationship between the coronary sinus
and circumflex artery is that the directed forces of “cinching”
the device has the potential to compress the circumflex artery or its major branches. This phenomenon was observed
in both the AMADEUS and TITAN trials, in which 17%
and 15% of the patients, respectively, did not receive a
device due to impingement of the left circumflex coronary
artery. With increasing experience, this limitation has
interfered less and less with device placement (70).
Another concern is wire fracture. Several patients had
fractures of the nitinol wire ribbon in both the AMADEUS
and TITAN trials. Importantly, wire fractures were not
associated with adverse clinical events. A third-generation of
the device has not had wire fractures when tested in a model
that reproduced the fractures seen in earlier versions.
Other earlier indirect percutaneous mitral annuloplasty
devices have fallen by the wayside, but they add to our
understanding of the complexity of the MV and apparatus
and the long-term implications of a device implantation
(75). The Monarc device (Edwards Lifesciences, Irvine,
California) had been studied in a human trial with most
patients showing reduction in MR by at least 1 grade, but
further study was subsequently stopped due to slow enrollment (76). The Viacor PTMA system (Viacor, Wilmington,
Massachusetts) has been taken off the market due to late,
fatal coronary sinus laceration (77,78).
JACC Vol. 63, No. 20, 2014
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Direct annuloplasty. Although indirect annuloplasty exploits the coronary sinus for its ease of use, transvascular
direct annuloplasty devices attempt to more closely reproduce surgical annuloplasty. Historically, surgical annular
plication by suturing (without placement of an annular
reduction ring) has demonstrated some efficacy in reducing
MR (79). The Mitralign system (Mitralign, Inc., Tewksbury, Massachusetts) takes a retrograde transventricular
approach to gain access to the mitral annulus on the basis
of the concept of suture annuloplasty. With radiofrequency
energy, guidewires penetrate the mitral annulus into the left
atrium, whereby pairs of pledgets are implanted in the
posterior mitral annulus near A1-P1 and A3-P3 target
points (Fig. 4). The pledgets are cinched together by a suture
to reduce the size of the mitral annulus and hence mitral
orifice area. Early human experience is promising, and a CE
approval study is underway (80). The Accucinch System
(Guided Delivery Systems, Santa Clara, California) is
another direct annuloplasty device that also uses the retrograde transventricular approach (Fig. 5). A series of anchors
are implanted beneath the MV in the basilar LV. These
anchors are connected by a nitinol wire in which tethering
the cord cinches the basal LV and mitral annulus. The
Accucinch System also causes remodeling of the basal
portion of the LV and is unique in this respect.
Also under development is a percutaneously implanted
annuloplasty ring that more closely resembles a surgical ring
(Fig. 6). Whereas the Mitralign and Accucinch devices take a
retrograde transventricular approach, the Valtech CardioBand
system (Valtech Cardio, Or Yehuda, Israel) is delivered via
transseptal atrial access. Thus, the ring is implanted in the atrial
side of the mitral annulus. The screw anchors are deployed
from the posteromedial commissure to the anterolateral
commissure in a counter-clockwise fashion, with the ring
extruded from a delivery catheter in small segments. Annular
circumference is reduced by controlling tension on the band,
thereby reducing the degree of MR. Early animal studies
demonstrated safety and feasibility in the device, and several
patients have had successful percutaneous implants (81).
Ventricular Remodeling
The aforementioned catheter-based MR therapies indirectly
produce favorable LV remodeling, but several novel systems
aim to directly remodel the LV. The iCoapsys device
(Myocor, Inc., Maple Grove, Minnesota) is a novel system
that aims to reduce ventricular dilation by directly remodeling the LV while also compressing the mitral annular
septal-lateral dimension. Through a pericardial subxiphoid
approach, 2 epicardial pads connected by a flexible suturelike cord are placed on the LV surface, 1 anterior and
1 posterior. The cord is passed through the LV between the
2 papillary muscles, bisecting the ventricle. Shortening of
the cord reduces LV size in an anteroposterior dimension
with a corresponding decrease in the mitral annular size
in the respective dimension. The Coapsys device not only
Feldman and Young
Percutaneous Approaches for Mitral Regurgitation
Figure 5
2065
Direct Annuloplasty
The Guided Delivery Systems Accucinch device (Guided Delivery Systems, Santa
Clara, California) is delivered through retrograde catheterization of the left ventricle
(top). The arrows highlight the separation of the leaflet edges, which define the
regurgitant orifice. Anchors are placed in the posterior mitral annulus and connected with a “drawstring” to cinch the annular circumference. When the cord is
tightened, the basilar myocardium and annulus draw the mitral leaflets together to
decrease the regurgitant orifice (bottom).
decreases annular size but reshapes the distorted LV.
The safety and feasibility of this device has been tested in
RESTOR-MV (Randomized Evaluation of a Surgical
Treatment for Off-Pump Repair of the Mitral Valve), a
randomized trial comparing the Coapsys device with surgical internal reduction annuloplasty. Patients who received
the Coapsys device demonstrated significant sustained reductions in LV chamber dimensions and volume, reduced
MR, and improved survival, compared with mitral annuloplasty (82–84). Shortly after this trial, the company
(Mycor, Inc.) failed financially, and the device is no longer
available; however, the approach merits mention, because of
the positive RESTOR-MV trial results. The study is one of
the only prospective, multicenter randomized trials to show
a survival benefit in the arena of MV therapy.
Another ventricular remodeling device is the Mardil
Medical BACE system (Basal Annuloplasty of the Cardia
Externally, Mardil Medical, Inc., Plymouth, Minnesota),
2066
Figure 6
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Feldman and Young
Percutaneous Approaches for Mitral Regurgitation
Valtech CardioBand
Valtech CardioBand system (Valtech Cardio, Or Yehuda, Israel). (A) Transseptal guide catheter delivering the annuloplasty ring in segments. Each segment is sequentially
anchored into the annulus. (B) Final annuloplasty ring encircling the posterior leaflet.
which is a novel, minimally-invasive surgical technique that
places a circular band with inflatable chambers around the base
of the beating heart. When the chamber gently fills with
saline, the annular and subannular structures are displaced and
brought closer together, changing the shape and size of the
distorted LV, diminishing posterior leaflet tethering, and
reducing MR (85). Yet another novel beating heart surgical
device implants artificial chordae tendineae anchored to the
LV apex to restore MV competency (NeoChord, Inc., Eden
Prairie, Minnesota). This procedure is performed through a
transapical, off-pump, beating heart approach, whereby
chordoplasty is effectively performed (86,87). It has been used
successfully in several patients. The technology might be
adaptable to a percutaneous system.
Percutaneous MV Replacement
The development of percutaneous MV replacement devices
is in its early stages. The challenges for mitral replacement
are more complex than for the aortic valve, and it is clear that
the development and testing of these devices will take more
time than with transcatheter aortic valve replacement.
Replacement devices for direct left atrial, antegrade transseptal, and apical delivery are being tested in bench and
pre-clinical models. The number of patients treated with
these devices remains small. Although the use of transcatheter aortic valve replacement valves for mitral replacement in patients with degenerated mitral bioprosthetic
valves or prior annuloplasty shows feasibility and proof of
concept, there remain many challenges in treating the
diseased native MV. Device delivery and anchoring and the
large size and eccentric geometry of the mitral orifice are the
main complexities. Although the concept that a percutaneous replacement might make repair approaches obsolete is
attractive, it is premature to make a conclusion.
Conclusions
Transcatheter-based techniques for the treatment of clinicallysignificant MR have evolved tremendously in the past
decade. These novel devices are primarily based upon wellknown surgical techniques that have subsequently progressed to less invasive approaches. It is important to
emphasize that novel percutaneous techniques in the
treatment of MR are not meant to replace surgical techniques in low-risk patients who are good candidates for
surgery. Among all catheter-based mitral therapies, the
leaflet repair MitraClip system to date has the largest
clinical experience worldwide, with established and reproducible safety profile and effective reduction of MR with
amelioration of symptoms and improved quality of life
in high-risk surgical patients. A randomized study of
MitraClip to standard medical therapy in high-risk patients with severe MR is underway. Indirect and direct
annuloplasty approaches are promising, and further investigations are pending. Financing for these new device
start-up companies remains challenging, and development
of some has gone in stops and starts as a consequence.
These studies will add to the armamentarium of catheterbased approaches for severe MR.
Reprint requests and correspondence: Dr. Ted Feldman, Cardiology Division, Evanston Hospital, Walgreen Building, 3rd Floor,
2650 Ridge Avenue, Evanston, Illinois 60201. E-mail: tfeldman@
tfeldman.org.
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Key Words: edge-to-edge leaflet repair - MitraClip - mitral
regurgitation - percutaneous annuloplasty - percutaneous mitral valve
repair - transcatheter mitral repair.