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: abhisheksharma4mamc@gmail.com

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

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