-
REVIEW
Mitraclip Plus Medical Therapy Versus MedicalTherapy Alone for
Functional Mitral Regurgitation:A Meta-Analysis
Sunny Goel . Ravi Teja Pasam . Karan Wats . Srilekha Chava .
Joseph Gotesman . Abhishek Sharma . Bilal Ahmad Malik .
Sergey Ayzenberg . Robert Frankel . Jacob Shani . Umesh
Gidwani
Received: August 29, 2019 / Published online: December 9, 2019�
The Author(s) 2019
ABSTRACT
Introduction: The purpose of this meta-analy-sis is to compare
the efficacy of MitraClip plusmedical therapy versus medical
therapy alonein patients with functional mitral regurgitation(FMR).
FMR caused by left ventricular dysfunc-tion is associated with poor
prognosis. WhetherMitraClip improves clinical outcomes in
thispatient population remains controversial.
Methods: We conducted an electronic databasesearch of PubMed,
CINAHL, Cochrane Central,Scopus, Google Scholar, and Web of Science
data-bases for randomized control trials (RCTs) andobservational
studies with propensity scorematching (PSM) that compared MitraClip
plusmedical therapy with medical therapy alone forpatients with FMR
and reported on subsequentmortality, heart failure
re-hospitalization, andother outcomes of interest. Event rates were
com-pared using a random-effects model with oddsratio as the effect
size.Results: Five studies (n = 1513; MitraClip = 796,medical
therapy = 717) were included in the finalanalysis. MitraClip plus
medical therapy com-pared to medical therapy alone was
associatedwith a significant reduction in overall mortality(OR =
0.66, 95% CI = 0.44–0.99, P = 0.04) andheart failure (HF)
re-hospitalization rates (OR =0.57, 95% CI = 0.36–0.91, P = 0.02).
There wasreduced need for heart transplantation ormechanical
support requirement (OR = 0.48,95% CI = 0.25–0.91, P = 0.02) and
unplannedmitral valve surgery (OR = 0.21, 95%CI = 0.07–0.61, P =
0.004) in the MitraClipgroup. No effect was observed on cardiac
mortal-ity (P = 0.42) between the two groups.Conclusions: MitraClip
plus medical therapyimproves overall mortality and reduces HF
re-hospitalization rates compared to medicaltherapy alone in
patients with FMR.
Enhanced digital features To view enhanced digitalfeatures for
this article go to
https://doi.org/10.6084/m9.figshare.10265168.
Electronic supplementary material The onlineversion of this
article (https://doi.org/10.1007/s40119-019-00157-3) contains
supplementary material, which isavailable to authorized users.
S. Goel � U. GidwaniDepartment of Cardiology, Icahn School
ofMedicine at Mount Sinai, New York, NY, USA
R. T. Pasam � K. Wats � S. Chava � J. Gotesman �B. A. Malik � S.
Ayzenberg � R. Frankel � J. ShaniDepartment of Cardiology,
Maimonides MedicalCenter, Brooklyn, New York, NY, USA
A. SharmaDivision of Cardiology, Gundersen Health System,La
Crosse, WI, USA
A. Sharma (&)Institute of Cardiovascular Science and
Technology,New York, NY, USAe-mail:
[email protected]
Cardiol Ther (2020) 9:5–17
https://doi.org/10.1007/s40119-019-00157-3
https://doi.org/10.6084/m9.figshare.10265168https://doi.org/10.6084/m9.figshare.10265168https://doi.org/10.6084/m9.figshare.10265168https://doi.org/10.6084/m9.figshare.10265168https://doi.org/10.1007/s40119-019-00157-3https://doi.org/10.1007/s40119-019-00157-3https://doi.org/10.1007/s40119-019-00157-3https://doi.org/10.1007/s40119-019-00157-3http://crossmark.crossref.org/dialog/?doi=10.1007/s40119-019-00157-3&domain=pdfhttps://doi.org/10.1007/s40119-019-00157-3
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Keywords: Functional mitral regurgitation;Heart failure; Medical
therapy; MitraClip
Key Summary Points
Functional mitral regurgitation caused byleft ventricular
dysfunction is associatedwith significant morbidity and
mortality.
Whether MitraClip improves clinicaloutcomes in this patient
populationremains controversial.
We conducted a meta-analysis of allpublished studies to compare
the efficacyof MitraClip plus medical therapy versusmedical therapy
alone in patients withfunctional mitral regurgitation.
Based on our pooled analysis, we foundthat MitraClip plus
medical therapycompared to medical therapy alone wasassociated with
a significant reduction inoverall mortality and heart failure
re-hospitalization rates.
There was reduced need for hearttransplantation or mechanical
supportrequirement and unplanned mitral valvesurgery in the
MitraClip group.
INTRODUCTION
Functional mitral regurgitation (FMR) is definedas mitral
insufficiency secondary to inadequateleaflet movement due to either
left ventricular(LV) wall motion abnormalities or to ventricularand
mitral annulus dilatation [1]. In FMR, themitral valve itself is
normal but LV abnormalitiescause tenting of the valve, thereby
preventing itsclosure. It is associated with poor clinical
out-comes, increased cardiovascular mortality, andfrequent
re-hospitalizations [2]. Studies haveshown that patients with FMR
receiving medicaltherapy alone have grim prognoses and have
amortality rate as high as 50% at 5 years [3].Although considered
curative for primary mitral
regurgitation, surgical approaches used for cor-rection of FMR
have not been successful as mea-sured by rates of mortality and
heart failure re-hospitalizations [4] and is frequently
prohibitivegiven depressed ejection fraction, advanced age,high
operative risk, and other comorbidities [5].Percutaneous mitral
valve repair usingMitraClip(Abbott Vascular, Santa Clara, CA, USA)
offers aninnovative solution for this subgroupof
patients.TheMitraClip creates adoubleorificebybringingtogether the
free edges of the anterior and pos-terior leaflets. It has gained
widespread popular-ity as aneffectiveway to treatpatientswith
severemitral regurgitation who are at high risk for sur-gery [6,
7]. In the randomized EndovascularValve Edge-to-Edge Repair Study
(EVEREST) IItrial [7], trans-catheter mitral-leaflet
approxima-tionwith theMitraClip devicewas found to havesimilar
clinical outcomes, significant reductionin re-hospitalization, and
improved symptomcontrol compared to surgical mitral-valve repairfor
patients with primarymitral regurgitation. Incontrast, the data for
patients with FMR is con-flicting with the Mitra-FR trial [8]
reporting noadvantage of MitraClip and the recently pub-lished
COAPT trial [9] showing significant clini-cal, as well as,
mortality benefits.
Therefore, we performed a meta-analysis ofall published
randomized control trials (RCTs)and observational studies with
propensity scorematching (PSM) to compare the efficacy ofMitraClip
plus medical therapy versus medicaltherapy alone in patients with
FMR.
METHODS
Study Design
A systematic review of the literature was per-formed according
to the Preferred ReportingItems for Systematic Reviews and
Meta-Analyses(PRISMA) statement [10].
Data Sources and Search Strategy
We systematically searched PubMed, CINAHL,Cochrane Central,
Scopus, Google Scholar, andWeb of Science databases for all studies
that
6 Cardiol Ther (2020) 9:5–17
-
compared MitraClip plus medical therapy withmedical therapy
alone. All relevant combina-tions of the following keywords related
toMitraClip and FMR were searched: ‘‘MitraClip’’,‘‘Functional
mitral regurgitation’’, ‘‘Secondarymitral regurgitation,’’ and
‘‘Medical Therapy’’.The search was conducted from the inception
ofthese databases to October 30, 2018. No lan-guage or age
restrictions were applied. Pertinenttrials were also searched in
http://www.clinicaltrials.gov, and in the proceedings ofmajor
international cardiology meetings(American College of Cardiology,
AmericanHeart Association, European Society of Cardi-ology, and
Transcatheter Cardiovascular Thera-peutics). We also manually
searched thereferences of these articles to find
additionalarticles. Two independent reviewers SG and RTconducted
the search.
Study Selection
Studies were included in the meta-analysis ifthey met the
following criteria: (1) a study onhuman subjects with participants
of any ageundergoing MitraClip implantation for FMRand, (2) studies
comparing the outcomesbetween MitraClip plus medical therapy
versusmedical therapy alone. The exclusion criteriaincluded single
case reports, reviews, editorials,and studies comparing MitraClip
to surgicalvalve replacement or repair.
The studies included were either RCTs orobservational studies,
which used PSM to creategroups with similar baseline
characteristics.
Data Extraction
Two independent reviewers (SG, RPT) screenedthe titles and
abstracts for relevance. Discrepan-cies between reviewers were
discussed untilconsensus was reached. The manuscripts ofselected
titles and abstracts were reviewed forinclusion and authors were
contacted if addi-tional data was needed. Using the
above-men-tioned selection criteria, the two reviewersindependently
determined which articles wereto be included and excluded, and the
data fromthe relevant articles were extracted using
predefined extraction forms. Any disagreementsin data
extractionwere discussed until consensuswas reached. Bibliographies
of relevant publica-tions were hand-searched to attempt
completeinclusion of all possible studies of interest.
Study End-Points
Theprimary end-pointswere overallmortality andHF
re-hospitalizations. The secondary end-pointswere cardiovascular
mortality, heart transplanta-tion, or mechanical circulatory
support require-ment and unplanned mitral valve surgery. Allevents
that occurred during follow-up were ana-lyzed using an intention
to-treat principle.
Data Analysis
To analyze the data, the authors used ReviewManager Software
(RevMan, version 5.3). A ran-dom-effects model was used to
calculate thepooled mean difference between the MitraClipplus
medical therapy and the medical therapyarm. Random-effects model
was used for ouranalysis. Heterogeneity between studies wasassessed
using Cochran’s Q test and I2 statistics,which denotes the
percentage of total variationacross studies that is a result of
heterogeneityrather
thanchance.Heterogeneitywasconsideredsignificant if the P value
was\0.05. Heterogene-ity was classified asmoderate if the I2
statistic was30–60%, substantial if 50–90%, and considerableif
75–100%. Pooled mean difference and oddsratio were the effect sizes
used for continuous andcategorical variables, respectively; 95%
confi-dence intervals were calculated and the level ofsignificance
was set to a P value of 0.05. Publica-tion bias was assessed by
visual interpretation offunnel plots. Sensitivity analysis was
performedwherever appropriate by including either onlyRCTs or only
propensity score matched studies.Risk of bias assessment was
evaluated usingROBINS-I tool for propensity score matchedstudies,
and RevMan software for RCTs [11].
Ethics Compliance
This article is based on previously conductedstudies and does
not contain any studies with
Cardiol Ther (2020) 9:5–17 7
http://www.clinicaltrials.govhttp://www.clinicaltrials.gov
-
Table1
Salient
features
ofthestudiesincluded
inthemeta-analysis
Stud
yArm
eniet
al.
Asgar
etal.
Giann
iniet
al.
Obadiaet
al.
Ston
eet
al.
MitraClip
1OMT
OMT
MitraClip
1OMT
OMT
MitraClip
1OMT
OMT
MitraClip
1OMT
OMT
MitraClip
1OMT
OMT
Yearof
study
2016
2016
2016
2017
2017
Typeof
study
Propensity
matched
study
Propensity
matched
study
Propensity
matched
study
Randomized
controltrial
Randomized
controltrial
Mean/medianfollow-up
12months
22±
15months
33±
21months
515days
[248–8
28]
12months
24months
Indication
forMitraclip
Moderate/severe
MR
3?/4
?MR
4?
MR
Severe
MR
3?/4
?MR
Num
berof
patients
232
151
5042
6060
152
152
302
312
Mean/medianage(years)
71±
1071
±11
75.4
±9
68.2
±15.5
74±
876
±8
70.1
±10.1
70.6
±9.9
71.7
±11.8
72.8
±10.5
Malesex
171(73%
)112 (74%
)
37(74%
)33
(77%
)42
(70%
)38
(63%
)120(78.9%
)107(70.4%
)201(66.6%
)192(61.5%
)
Bodymassindex
26±
425
±5
N/A
N/A
25±
426
±3
N/A
N/A
27.0
±5.8
27.1
±5.9
History
ofhypertension
191(82%
)74
(49%
)
29(58%
)24
(57%
)39
(65%
)32
(53%
)N/A
N/A
243(80.5%
)251(80.4%
)
History
ofhyperlipidem
ia140(61%
)43
(28%
)
N/A
N/A
N/A
N/A
N/A
N/A
166(55.0%
)163(52.2%
)
History
ofdiabetes
mellitus
67(30%
)44
(29%
)
21(42%
)13
(31%
)17
(28%
)18
(30%
)50
(32.9%
)39
(25.7%
)106(35.1%
)123(39.4%
)
History
ofcoronary
artery
disease
N/A
N/A
39(78%
)30
(71%
)27
(45%
)35
(58%
)N/A
N/A
N/A
N/A
Priormyocardial
infarction
105(45%
)75
(50%
)
N/A
N/A
22(37%
)23
(38%
)75
(49.3%
)52
(34.2%
)156(51.7%
)160(51.3%
)
Priorcoronary
revascularization
51(22%
)77
(50%
)
N/A
N/A
N/A
N/A
71(46.7%
)64
(42.4%
)N/A
N/A
Priorpercutaneous
coronary
intervention
N/A
N/A
20(40%
)14
(33%
)17
(28%
)21
(35%
)N/A
N/A
130(43.0%
)153(49.0%
)
Priorcoronary
artery
bypassgraft
N/A
N/A
26(52%
)20
(48%
)14
(23%
)16
(27%
)N/A
N/A
121(40.1%
)126(40.4%
)
8 Cardiol Ther (2020) 9:5–17
-
Table1
continued
Stud
yArm
eniet
al.
Asgar
etal.
Giann
iniet
al.
Obadiaet
al.
Ston
eet
al.
MitraClip
1OMT
OMT
MitraClip
1OMT
OMT
MitraClip
1OMT
OMT
MitraClip
1OMT
OMT
MitraClip
1OMT
OMT
History
ofchronic
obstructivepulmonary
disease
58(25%
)31
(21%
)
N/A
N/A
15(25%
)12
(20%
)N/A
N/A
71(23.5%
)72
(23.1%
)
History
ofatrial
fibrillation/atrialfl
utter
77(33%
)50
(33%
)
29(58%
)27
(64%
)21
(35%
)26
(43%
)49
(34.5%
)48
(32.7%
)173(57.3%
)166(53.2%
)
History
ofischem
ic
cardiomyopathy
N/A
N/A
N/A
N/A
N/A
N/A
95(62.5%
)85
(56.3%
)184(60.9%
)189(60.6%
)
History
ofnonischemic
cardiomyopathy
N/A
N/A
N/A
N/A
N/A
N/A
57(37.5%
)66
(43.7%
)118(39.1%
)123(39.4%
)
ACEainhibitors
125(54%
)106 (70%
)
22(44%
)18
(43%
)N/A
N/A
N/A
N/A
138(45.7%
)115(36.9%
)
ARBH
N/A
N/A
14(28%
)11
(26%
)N/A
N/A
N/A
N/A
66(21.9%
)72
(23.1%
)
ARNI=
N/A
N/A
N/A
N/A
N/A
N/A
14(10%
)17
(12.1%
)13
(4.3%)
9(2.9%)
ACEinhibitors/A
RB
N/A
N/A
N/A
N/A
42(70%
)35
(58%
)111(73.0%
)113(74.3%
)N/A
N/A
ACEinhibitors/A
RB/
ARNI
N/A
N/A
N/A
N/A
N/A
N/A
N/A
N/A
216(71.5%
)196(62.8%
)
Betablockers
158(68%
)128 (85%
)
43(86%
)35
(83%
)40
(67%
)41
(68%
)134(88.2%
)138(90.8%
)275(91.1%
)280(89.7%
)
Aldosterone
antagonists
153(66%
)98
(65%
)
25(50%
)26
(62%
)35
(58%
)27
(45%
)86
(56.6%
)80
(53%
)153(50.7%
)155(49.7%
)
Diuretics
N/A
N/A
44(88%
)36
(86%
)56
(93%
)52
(87%
)151(99.3%
)149(98%
)270(89.4%
)277(88.8%
)
History
ofcardiac
resynchronization
therapy
47(21%
)24
(16%
)
10(20%
)6(14%
)24
(40%
)18
(30%
)46
(30.5%
)35
(23.0%
)115(38.1%
)109(34.9%
)
LVejection
fraction
(%)
34±
1332
±10
38.3
±15.8
31.8
±13.6
33[26-49]
34[27-
41]
33.3
±6.5
32.9
±6.7
31.3
±9.1
31.3
±9.6
Cardiol Ther (2020) 9:5–17 9
-
Table1
continued
Stud
yArm
eniet
al.
Asgar
etal.
Giann
iniet
al.
Obadiaet
al.
Ston
eet
al.
MitraClip
1OMT
OMT
MitraClip
1OMT
OMT
MitraClip
1OMT
OMT
MitraClip
1OMT
OMT
MitraClip
1OMT
OMT
LVend-systolicvolume
(ml)
N/A
N/A
N/A
N/A
50±
1349
±10
N/A
N/A
135.5±
56.1
134.3±
60.3
LVend-diastolic
volume
(ml)
N/A
N/A
N/A
N/A
187±
70178±
54136.2±
37.4
134.5±
33.1
194.4±
69.2
191.0±
72.9
3?
MR
N/A
N/A
29(58%
)32
(76%
)N/A
N/A
N/A
N/A
148(49.0%
)172(55.3%
)
4?
MR
N/A
N/A
21(42%
)10
(24%
)60
(100%)
60
(100%)
152(100%)
152(100%)
154(51.0%
)139(44.7%
)
NYHA
ClassIII
N/A
N/A
16(32%
)9(21.4%
)36
(60%
)39
(66%
)82
(53.9%
)96
(63.2%
)154(51.0%
)168(54.0%
)
NYHA
ClassIV
N/A
N/A
33(66%
)0(0)
8(13%
)6(10%
)14
(9.2%)
12(7.9%)
18(6.0%)
33(10.6%
)
?Mitralregurgitation;aAngiotensin-convertingenzyme;
HAngiotensin
receptor
blocker;=Angiotensin
receptor
andneprilysininhibitors;*LVleftventricle;
�NYHA-New
York
HeartAssociation
10 Cardiol Ther (2020) 9:5–17
-
human participants or animals performed byany of the
authors.
RESULTS
Studies Included
A total of five studies were included in the finalanalysis [8,
9, 12–14] (Table 1 shows salientfeatures of the studies). Figure 1
shows thePRISMA flow diagram describing the searchstrategy. The
initial search yielded 3836abstracts of which 3743 were excluded
based ontitle and abstract. Ninety-three articles werereviewed with
their full text. Five articles met
the inclusion criteria, two RCTs and three PSMobservational
studies (total number ofpatients = 1513; MitraClip = 796 and
medicaltherapy = 717).
Baseline Characteristics
The mean age of patients was 71.6 ± 10.6 yearsin the MitraClip
group and 72.0 ± 10.8 years inthe medical therapy alone group;
71.7% of theMitraClip patients and 67.2% of the medicaltherapy
patients were males. A history of dia-betes mellitus was present in
32.8% of theMitraClip patients and 33.1% of the medicaltherapy
patients. Hypertension was prevalent in78.0% and 67.4% of the
MitraClip and medical
Fig. 1 Preferred reporting items for systematic reviews and
meta-analyses (PRISMA) flow diagram
Cardiol Ther (2020) 9:5–17 11
-
therapy groups, respectively; 43.8% of theMitraClip patients and
44.2% of the medicaltherapy patients had a history of atrial
fibrilla-tion or atrial flutter; 30.4% and 26.8% of theMitraClip
and medical therapy patients,respectively, received cardiac
resynchronizationtherapy. A past history of at least one episode
ofmyocardial infarction was noted in 45.9 and48.0% of the MitraClip
and medical therapygroups, respectively (Table 1).
Primary Outcomes
Overall MortalityAll but one study reported overall
mortalitywith a mean follow-up of 12–24 months and atotal of 1393
patients were included for thisanalysis [8, 9, 12, 13]. The overall
mortality ratewas 19.8% in the MitraClip arm, as compared to29.2%
in the medical therapy alone group, with
an odds ratio of 0.66 (95% CI 0.44–0.99,P = 0.04, I2 = 52%)
(Fig. 2a).
HF Re-HospitalizationThe HF re-hospitalization rate was reported
infour studies with a total of 1130 patients[8, 9, 13, 14]. One of
the studies did not providethe number of re-hospitalization events
but didprovide a log odds ratio, which was included forthe final
analysis [13]. In our pooled analysis,the odds ratio for rate of
re-hospitalization forHF was found to be 0.57 (95% CI 0.36–0.91,P =
0.02, I2 = 85%) favoring the MitraClipgroup (Fig. 2b).
Secondary Outcomes
Cardiovascular MortalityCardiovascular mortality was reported by
threestudies with a total of 1010 patients [8, 9, 13].The rate of
cardiac deaths was 20% in the
Fig. 2 a Forest plot showing overall mortality
comparingMitraClip plus medical therapy versus medical
therapyalone. b Forest plot showing rates of HF
re-hospitalization
rates comparing MitraClip plus medical therapy versusmedical
therapy alone
12 Cardiol Ther (2020) 9:5–17
-
MitraClip group, which was numerically lowerthan the 29.6%
reported in medical therapyalone group. However, the difference was
notstatistically significant (OR 0.55, 95% CI0.26–1.13, P = 0.10,
I2 = 80%) (Fig. 3a).
Heart Transplantation or MechanicalCirculatory Support
RequirementHeart transplant or mechanical circulatorysupport use
was reported in two studies with atotal of 918 patients. A
significantly lowernumber of patients required heart
transplanta-tion or mechanical circulatory support in theMitraClip
group compared to medical therapygroup [8, 9] (OR: 0.48, 95% CI
0.25–0.91,P = 0.02, I2 = 0%) (Fig. 3b).
Unplanned Mitral Valve SurgeryUnplanned mitral valve surgeries
were reportedin three studies with a total of 1010
patients.Unplanned mitral valve surgeries were per-formed in
significantly more number of patientsreceiving medical therapy as
compared to thosewho had MitraClip placed [8, 9, 13] (OR 0.21,95%
CI 0.07–0.61, P = 0.004, I2 = 0%) (Fig. 3c).
Publication Bias Assessment, SensitivityAnalysis, and Risk of
Bias Assessment
Based on visual interpretation of the funnelplots there was no
significant publication biasfor the primary and secondary endpoints
[Sup-plementary figure 1]. Unlike the results of thepooled
analysis, sensitivity analysis for overallmortality with RCTs [8,
9] did not show any
Fig. 3 a Forest plot showing cardiovascular mortalitycomparing
MitraClip plus medical therapy versus medicaltherapy alone. b
Forest plot showing heart transplantationor mechanical circulatory
support requirement comparing
MitraClip plus medical therapy versus medical therapyalone. c
Forest plot showing unplanned mitral valvesurgery comparing
MitraClip plus medical therapy versusmedical therapy alone
Cardiol Ther (2020) 9:5–17 13
-
significant differences between the two groups[Supplementary
figure 2A]. However, the anal-ysis with propensity score matched
studies[12, 13] did show significant mortality benefitwith
MitraClip versus medical therapy alone[Supplementary figure 2B].
While there was asignificant reduction in re-hospitalization dueto
heart failure in the initial analysis, there wereno significant
differences between the groups inthe sensitivity analyses with both
RCTs [8, 9][Supplementary figure 2C] and propensity scorematched
studies [13, 14] [Supplementary fig-ure 2D]. Analysis of cardiac
mortality with onlyRCTs [8, 9] did not show any significant
differ-ences between the two groups, which is similarto the initial
analysis [Supplementary fig-ures 2E]. Proportion of patients
undergoingunplanned mitral valve surgery were signifi-cantly lower
in the MitraClip group in the sen-sitivity analysis of propensity
score matchedstudies [13, 14], which is similar to the result
ofinitial analysis [Supplementary figure 2F]. Therisks of bias
assessments for these outcomes areincluded in the same forest plots
[Supplemen-tary figure 2].
The risks of bias assessments for the sensi-tivity analyses
using propensity score matchingare included in the supplementary
material.
DISCUSSION
The findings from our meta-analysis can besummarized as
follows:
1. MitraClip plus medical therapy comparedto medical therapy
alone is associated witha significant reduction in overall
mortalityand reduced rates of re-hospitalization forHF;
2. There is reduced need for heart transplan-tation or
mechanical circulatory supportand unplanned mitral valve surgery in
theMitraClip group; and,
3. There is no significant difference in cardiacmortality
between the two groups.
To our knowledge this is the first meta-analysis comparing
MitraClip along with med-ical therapy versus medical therapy
aloneselectively in FMR patients only. Previous meta-
analyses performed on the same topic haveincluded either
observational studies or inclu-ded patients with degenerative
mitral regurgi-tation (DMR) in their analysis [15, 16]. Giventhe
pathophysiology of DMR patients is funda-mentally distinct from
that of FMR patients, theinclusion of DMR patients along with
FMRpatients in these meta-analyses may potentiallyact as a
confounding factor and may, therefore,skew the overall results in
either direction.
We believe that the positive results on mor-tality, reduced HF
re-hospitalization rates, andreduced rates of heart transplant or
mitral valvesurgeries among patients who received Mitra-Clip
treatment in our analysis, are secondary tothe reduction in the
severity of secondary mitralregurgitation seen with the use of
MitraClip.The presence of even mild degrees of functionalMR in
patients with left ventricular dysfunctioncarries high mortality
risk than those withoutMR [17]. MitraClip use may reverse
cardiacremodeling, thus leading to significantimprovement in
functional class even in highlysymptomatic patients with severely
dilatedhearts [18]. The results of decreased mortalitywith
Mitraclip should be interpreted with cau-tion given the fact that
we included propensityscore matched studies in our analysis.
Weincluded PSM studies in our analysis because ofthe paucity of
randomized data on this subjectand given that inclusion of purely
observationaldata would have created an enormous biasgiven the
unequal distribution of confoundingvariables. With the use of
propensity matchedmodel, authors and statisticians can use
obser-vational data to control for treatment selectionbias.
Propensity score is estimated using logisticregression model for
each subject and thesesubjects are matched based on their scores
tocontrol confounding. With this kind of purelystatistical
analysis, there is always a chance thatan important variable might
have been missedout during propensity regression which maylead to
over or underestimation of treatmenteffect [19].
The contrasting results from the two majorrandomized trials,
Mitra-FR [8] and COAPT [9],included in our analysis could be
explained bythe following facts:
14 Cardiol Ther (2020) 9:5–17
-
1. The patient populations in these two trialsvaried
significantly due to differences inhow the European Society of
Cardiology(ESC) and European Association for Cardio-Thoracic
Surgery (EACTS), versus the Amer-ican College of Cardiology (ACC),
andAmerican Heart Association (AHA) definesevere FMR (Effective
Regurgitation OrificeArea [EROA][20 mm2 and RegurgitationVolume
[RV][30 ml/beat as per ESC/EACTS guidelines [20] and EROA[30
mm2
and RV[ 45 ml/beat as per ACC/AHAguidelines [21]). As such,
patients in theCOAPT trial who received MitraClip hadmore severe MR
(EROA of 41 mm2) at timeof MitraClip implantation as compared
toMitra-FR (EROA of 31 mm2) and, therefore,could have derived more
benefit [2];
2. Patients in the COAPT trial were already onoptimal medical
therapy pre-trial with onlyminute changes to medical therapy
duringfollow–up, while those in the Mitra-FR werenot medically
optimized at baseline andhad variable adjustments during
follow-upperiod. This may have masked the overallbenefit derived
from MitraClip [3];
3. The success rate of MitraClip placement andacute reduction of
2 ? MR was higher inthe COAPT trial (95% versus 91.9% inMitra-FR
trial); and,
4. The reduction of MR to a grade of 2 ? orless sustained at 12
months was muchhigher in the COAPT trial as compared toMitra-FR
group which may have con-tributed to persistent clinical and
mortalitybenefit.
5. It is also important to understand thesecondary or functional
MR can beexplained either because of distortion ifmitral valve
function secondary to leftventricular enlargement or those in
whomthe disease process disproportionatelyaffects the segment of
left ventricle respon-sible for mitral valve cooptation. The
firstgroup of patients are considered to haveproportionate MR and
clinically not severeand thus any intervention the valve mightnot
have any implication on the diseaseprocess. It appears that
patients included inthe COAPT trial had disproportionate MR as
is proposed by Grayburn et al. which likelyexplains the
significant difference in theresults of the two trials. [22].
The above-mentioned differences betweenthe patients groups of
COAPT and MITRA-FRtrials could have led to moderate to
highheterogeneity seen in our analysis and there-fore, the results
of our analysis should beinterpreted with caution. Although
observa-tional studies in the past have shown a positiveeffect of
MitraClip in FMR patients [12–14, 23],the first major RCT, Mitra-FR
[8] yielded disap-pointing results. However, the COAPT trial
[9]surprisingly showed a robust decrease in overallmortality,
re-hospitalizations due to heart fail-ure, and cardiac death. The
baseline echocar-diographic parameters indicate that the
patientsincluded in the COAPT study did not have sig-nificant
dilation of left ventricle (LVEDV of101 ml/m2 versus 135 ml/m2 in
Mitra-FR),which would indicate that these patients didnot have
severe remodeling of their LV at thetime of enrollment. Moreover,
all patients inthe COAPT trial were being optimally managedon
medical therapy and were followed veryclosely which is certainly
variable in real worldpopulations. This shows that patients
withoutadvanced remodeling of LV and who are onoptimal medical
therapy might be better can-didates for MitraClip. Real-world
experiencewith MitraClip may help us better assess thebenefits of
MitraClip in FMR patients. Lastly,the results of RESHAPE HF 2
trial(NCT02444338) may swing the pendulum ineither direction.
There are several limitations to our study:
1. The analysis is based on pooled data fromdifferent studies
and it shares the possiblelimitations of the included studies.
Further-more, we were unable to perform anysubgroup or survival
analysis as we did nothave the patient level data;
2. Inclusion of observational studies alongwith randomized
controlled trials in ourmeta-analysis is a major limitation
whichcould have led to the heterogeneity in theanalysis; however,
this was a direct result ofthe scarcity of data on this topic and
we did
Cardiol Ther (2020) 9:5–17 15
-
perform appropriate statistical analysis toevaluate sources of
bias and heterogeneity;
3. For the observational studies, it was notclear whether the
patients in MitraClipgroup were on optimal medical therapy
atbaseline or at follow-up and whether themedical therapy between
the two groupswere similar. We included these studies dueto paucity
of data;
4. Although, our pooled analysis shows mor-tality and heart
failure re-hospitalizationbenefits with use of MitraClip, there
wasmoderate heterogeneity between the stud-ies evaluating the
mortality outcomes andsubstantial heterogeneity between
studiesreporting the heart failure re-hospitaliza-tion outcomes.
When we performed a sen-sitivity analysis, the positive effect
ofMitraClip was not evident for mortality inRCT’s and for HF
re-hospitalization in bothRCT and PSM studies; and,
5. We were not able to perform a risk of biasanalysis as the
study designs were differentin these studies and there is no single
scalethat would assess risk of bias in both RCTsand PSM
studies.
CONCLUSIONS
Based on our meta-analysis, it can be concludedthat MitraClip
plus medical therapy comparedto medical therapy alone improves
overallmortality and reduces HF re-hospitalizationrates for
patients with FMR. As well, there isreduced need for heart
transplantation ormechanical circulatory support and
unplannedmitral valve surgery in the MitraClip group.However, there
is no difference in cardiacmortality between the two groups.
ACKNOWLEDGEMENTS
Funding. No funding or sponsorship wasreceived for this study or
publication of thisarticle.
Authorship. All named authors meet theInternational Committee of
Medical JournalEditors (ICMJE) criteria for authorship for
thisarticle, take responsibility for the integrity ofthe work as a
whole, and have given theirapproval for this version to be
published.
Disclosures. Sunny Goel, Ravi Teja Pasam,Karan Wats, Srilekha
Chava, Joseph Gotesman,Abhishek Sharma, Bilal Ahmad Malik,Sergey
Ayzenberg, Robert Frankel, Jacob Shaniand Umesh Gidwani have
nothing to disclose.
Compliance with Ethics Guidelines. Thisarticle is based on
previously conducted studiesand does not contain any studies with
humanparticipants or animals performed by any of theauthors.
Data Availability. The datasets during and/or analyzed during
the current study are avail-able from the corresponding author on
reason-able request.
Open Access. This article is distributedunder the terms of the
Creative CommonsAttribution-NonCommercial 4.0 InternationalLicense
(http://creativecommons.org/licenses/by-nc/4.0/), which permits any
noncommer-cial use, distribution, and reproduction in anymedium,
provided you give appropriate creditto the original author(s) and
the source, providea link to the Creative Commons license,
andindicate if changes were made.
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Mitraclip Plus Medical Therapy Versus Medical Therapy Alone for
Functional Mitral Regurgitation: A
Meta-AnalysisAbstractIntroductionMethodsResultsConclusions
IntroductionMethodsStudy DesignData Sources and Search
StrategyStudy SelectionData ExtractionStudy End-PointsData
AnalysisEthics Compliance
ResultsStudies IncludedBaseline CharacteristicsPrimary
OutcomesOverall MortalityHF Re-Hospitalization
Secondary OutcomesCardiovascular MortalityHeart Transplantation
or Mechanical Circulatory Support RequirementUnplanned Mitral Valve
Surgery
Publication Bias Assessment, Sensitivity Analysis, and Risk of
Bias Assessment
DiscussionConclusionsAcknowledgementsReferences