C

Review article

Does combined mitral valve surgery improve survival whencompared to revascularization alone in patients withischemic mitral regurgitation? A meta-analysis on2479 patientsUmberto Benedetto, Giovanni Melina, Antonino Roscitano, Brenno Fiorani,Fabio Capuano, Gianluca Sclafani, Cosimo Comito,Gian Domenico di Nucci and Riccardo Sinatra

Objectives Optimal treatment of significant (>–2R grade)

ischemic mitral regurgitation remains controversial, and the

impact of mitral valve surgery (MVS) at the time of coronary

artery bypass grafting (CABG) on early and late results has

to be still clarified.

Methods A systematic literature search for studies

comparing CABG combined to MVS (repair or replacement)

compared with CABG alone in patients with ischemic mitral

regurgitation and meta-analysis for late mortality,

postoperative New York Heart Association functional

class and late residual mitral regurgitation grade was

performed. Risk ratios and the standardized mean

difference (SMD) under the fixed or random effects model

were reported.

Results A total of nine observational nonrandomized

studies were identified including 2479 patients with

ischemic mitral regurgitation who underwent CABG alone

(n U 1515) and CABG combined to MVS (n U 964).

Meta-analysis of the pooled study population showed that

MVS did not have advantages on late mortality [risk ratio

1.02; 95% confidence interval (CI) 0.90 to 1.14; P U 0.73]

compared with CABG alone.

Combined MVS was significantly associated with a lower

residual mitral regurgitation grade compared with CABG

opyright © Italian Federation of Cardiology. Unau

1558-2027 � 2009 Italian Federation of Cardiology

alone (SMD U S0.9; 95% CI S1.250 to S0.559; P < 0.0001).

However, postoperative New York Heart Association class

was not significantly improved in the combined MVS group

(SMD U S0.26; 95% CI S0.766 to S0.24; P U 0.30).

Conclusion Most surgeons commonly use additional

mitral valve procedure to treat moderate or severe

ischemic mitral regurgitation, because it seems logical to

assume that the volume overload associated with mitral

regurgitation will be detrimental particularly to the patient

with compromised left ventricular function. However, until

definitive evidence about the superiority of this approach

will be available, a tailored surgical strategy should be

considered especially in mild ischemic mitral regurgitation.

J Cardiovasc Med 10:109–114 Q 2009 Italian Federation of

Cardiology.

Journal of Cardiovascular Medicine 2009, 10:109–114

Keywords: coronary artery bypass grafting, meta-analysis, ischemic mitralregurgitation

Cardiac Surgery Department, II School of Medicine, University of Rome LaSapienza, Policlinico S.Andrea, Rome, Italy

Correspondence to Umberto Benedetto, MD, Cardiac Surgery Department, IISchool of Medicine, University of Rome ‘La Sapienza’, Via di Grottarossa 1039Rome, ItalyTel: +39 06 33775311; fax: +39 06 33775481; e-mail: u2benedetto@libero.it

Received 22 July 2008 Revised 26 September 2008Accepted 6 October 2008

IntroductionThe striking, well documented association of ischemic

mitral regurgitation and late survival has resulted in the

hypothesis that eliminating significant mitral regurgita-

tion (�2þ grade) at revascularization improves outcomes

[1,2].

Commonly, patients with severe ischemic mitral regur-

gitation are treated with concomitant repair or replace-

ment and surgical approach. They have been recently

advocated also for moderate ischemic mitral regurgitation

on the assumption that the presence of moderate mitral

regurgitation following coronary artery bypass grafting

(CABG) is related with poorer survival [3].

However, optimal treatment of significant ischemic

mitral regurgitation remains controversial and the evi-

dence to support mitral valve surgery (MVS) at the time

of CABG is still weak [4]. Concomitant mitral valve

procedure has been consistently associated with signifi-

cant increase in operative risk requiring prolonged surgi-

cal time, and the supposed benefit on long-term survival

still needs to be demonstrated even in patients with

severe mitral regurgitation [5–16]. The reasons are

thorized reproduction of this article is prohibited.

DOI:10.2459/JCM.0b013e32831c84b0

Cop

110 Journal of Cardiovascular Medicine 2009, Vol 10 No 2

unclear, but may indicate that ischemic mitral regurgita-

tion is only a manifestation of advanced infarction-

induced ventricular remodeling and that survival of these

patients is primarily dictated by the extent of their

ischemic heart disease. In addition, the recurrence of a

significant mitral regurgitation may have a negative

impact on late survival following surgical repair.

Critical drawbacks of available studies comparing CABG

alone with combined procedure are their small sample

size, their retrospective design, heterogeneity and selec-

tion bias related with the high-risk condition of this

population and these aspects may partially explain dis-

cordant conclusions reported.

In this study, meta-analysis was used to summarize

information from nine studies in an attempt to clarify

the additional MVS on long-term results in patients with

ischemic moderate (2þ grade) or severe (�3þ) mitral

regurgitation compared with CABG alone and to high-

light the differences in outcomes between patients with

moderate and severe mitral regurgitation.

Material and methodsThe meta-analysis of observational studies in Epidemiol-

ogy guidelines was followed.

To identify studies eligible for this meta-analysis, a

computerized search was performed in PubMed and

Ovid databases for all English-only journals published

during the period between 1960 and February 2007. All

peer-reviewed studies that dealt with trials comparing

CABG alone with combined CABG and MVS (repair or

replacement) in patients with significant ischemic mitral

regurgitation [(�2þ grade) both prospective randomized

and retrospective observational studies were searched]

were identified and reviewed. The text string employed

(formatted for PubMed) was ischemic mitral valve regur-

gitation or functional mitral valve regurgitation or

ischemic mitral valve insufficiency or functional mitral

valve insufficiency and coronary bypass grafting or surgi-

cal revascularization or mitral valve repair or mitral valve

annuloplasty or mitral valve replacement or MVS.

The outcomes searched were late mortality, postopera-

tive New York Heart Association (NYHA) functional

class and late residual mitral regurgitation grade. The

outcome definition used by the original researchers

was accepted.

To minimize temporal bias and institutional variability,

the studies reporting both CABG alone and combined

procedure patient cohorts only were included in the

meta-analysis. When several articles reported on the

same patient material, only the most recent article was

included. Two authors (U.B. and G.M.) reviewed each

study and determined if each study had adequate repre-

yright © Italian Federation of Cardiology. Unauth

sentation of survival information to allow for calculation

of risk ratios for outcomes used in this study.

Statistical analysisComprehensive meta-analysis, Version 2 (Borenstein and

Rothstein) was used to analyze abstracted data and to

generate Forrest plots for displaying the results. Late

mortality from individual studies were analyzed accord-

ing to the Mantel–Haenszel model to compute individ-

ual risk ratios with pertinent 95% confidence interval

(CI), and a pooled summary effect estimate was calcu-

lated by means of a fixed or random effects model

according to heterogeneity. To investigate continuous

measures (postoperative NYHA functional class and late

residual mitral regurgitation grade), the Hedges g statistic

was used as a formulation for the standardized mean

difference (SMD) under the fixed or random effects

model. Heterogeneity of the risk ratios among the

included studies was assessed by Cochran’s Q statistic.

To quantitatively assess heterogeneity, sensitivity

analysis was undertaken by using subgroup analysis.

To do this, the following variables were evaluated: all

studies; studies with mitral valve annuloplasty only

included in the combined procedure group; studies with

severe mitral regurgitation (�3þ grade) as inclusion

criteria and studies including a higher number of patients

with left ventricular dysfunction [mean left ventricular

ejection fraction (LVEF)<40%]. Finally, publication bias

was evaluated using the funnel graph and the Egger et al.[17] regression asymmetry test. Statistical significance

was defined by P value of 0.05 or less.

ResultsThe search yielded 12 observational nonrandomized

candidate studies [5–16]; no randomized study was

found. Among them nine trials were identified [5–13]

and included in the analysis with a total of 2479 patients

with ischemic mitral regurgitation who underwent CABG

alone (n¼ 1515) and CABG combined to MVS [repair or

replacement (n¼ 964)]. The remaining three studies

were excluded for duplicate publication [14,15] and for

inclusion of patients with mild mitral regurgitation (1þgrade) in the study [16]. From the study by Bonacchi et al.[8], we excluded group III because patients with mild

mitral regurgitation (1þ grade) were included. All studies

included made possible the computation of the risk ratio

for late mortality. A total of five studies [6,7,9,10,12] made

possible the computation of the SMD for residual mitral

regurgitation grade following surgery; and five studies

[6,8–10,12] were allowed to obtain the SMD for post-

operative NYHA functional class.

Demographic characteristicsClinical features of all studies included in the analysis are

shown in Tables 1 and 2. The mean age of the pooled

study population was 68 years ranging from 62 to 73 years.

orized reproduction of this article is prohibited.

Copyright © Italian Federation of Cardiology. U

Meta-analysis for ischemic mitral regurgitation Benedetto et al. 111

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The mean percentage of women participants was 40%

ranging from 27 to 51%.

Mean follow-up ranged from 2.6 to 5.1 years. Mean

follow-up was not reported by Kim et al. [10].

Four studies [7,9,12,13] included only patients

with preoperative severe ischemic mitral regurgitation

(�3þ grade). Others [5,6,8,10,11] included patients

with moderate or severe ischemic mitral regurgitation

(�2þ grade). Mean preoperative mitral regurgitation

grade was 2.9 ranging from 2.2 to 3.9. Four studies

[5,6,8,12] included a higher number of patients with left

ventricular dysfunction (mean left ventricular ejection

fraction <40%). Six studies [6–8,10,12,13] included in

the combined procedure group had only those patients

who underwent mitral valve annuloplasty. Others

included repair and replacement in combined procedure

group [5,9,11].

Meta-analysisMeta-analysis of the pooled study population showed

that MVS did not have advantages on late mortality (ratio

risk 1.02; 95% CI 0.90–1.14; P¼ 0.73; Fig. 1) compared

with CABG alone.

Combined MVS was significantly associated with a lower

residual mitral regurgitation grade compared with

CABG alone (SMD¼�0.9; 95% CI �1.250 to �0.559;

P< 0.0001; Fig. 2). However, postoperative NYHA func-

tional class was not significantly improved in the com-

bined MVS group (SMD¼�0.26; 95% CI �0.766 to

�0.24; P¼ 0.30; Fig. 3). Post-hoc analysis restricted to

studies including exclusively mitral valve annuloplasty in

the MVS group showed no advantages on late mortality

after following the combined procedures (risk ratio 1.04;

95% CI 0.8–1.2; P¼ 0.6). Combined mitral valve annu-

loplasty was associated with a lower residual mitral regur-

gitation grade (SMD¼�0.70; 95% CI �0.92 to �0.49).

Any significant improvement on late NYHA functional

class could be demonstrated for combined mitral valve

repair patients (SMD¼ 0.09; 95% CI �0.151 to 0.306).

Post-hoc analysis restricted to studies with preoperative

severe ischemic mitral regurgitation as inclusion criteria

(�3þ grade) showed that combined procedure had

no advantages on late mortality (risk ratio 0.94; 95% CI

0.76–1.16; P¼ 0.57). However, combined MVS was

associated with a lower residual mitral regurgitation grade

(SMD¼�0.60; 95% CI �0.96 to �0.24) and with no

statistically significant improvement on late NYHA func-

tional class (SMD¼�0.29; 95% CI �0.65 to 0.05).

Analysis restricted to studies with a mean preoperative

LVEF less than 40% showed that combined procedure

had no advantages on late mortality (risk ratio 0.99; 95%

CI 0.76–1.29; P¼ 0.95). However, combined MVS was

associated with a lower residual mitral regurgitation

grade (SMD¼�0.81; 95% CI �1.17 to �0.46) and with

thorized reproduction of this article is prohibited.

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112 Journal of Cardiovascular Medicine 2009, Vol 10 No 2

Table 2 Clinical characteristics of patients included into analysis

Reference

Mean age (years)Tot–MVS–

CABG alone

Women (%)Tot–MVS–

CABG alone

Preoperative meanLVEF Tot–MVS–

CABG alone

Diabeticpatients (%)Tot–MVS–

CABG alone

Mean no. ofgrafts/patientTot–MVS–

CABG alone

Mean CPBtime (min)

Tot–MVS–CABG alone

Harris et al. [5] 68–65–68 48–55–45 38–38–38 48–50–45 3.6–3.5–3.7 203–134Trichon et al. [11] 68–68–68 47–47–47 43–42–45 31–27–32 NS NSDiodato et al. [12] 67–65–69 51–52–49 33–35–31 NS 2.9–2.8–3.0 176–140Wong et al. [7] 71–NS–NS 43–NS–NS 41–39–42 44–NS–NS NS NSKim et al. [10] 71–72–71 31–29–33 40–38–43 40–39–39 3.1–3.1–3.0 156–84Kang et al. [6] 62–61–63 27–26–31 36–36–36 54–52–56 3.8–3.7–3.8 183–145Buja et al. [9] 73–72–75 37–38–36 43–50–38 42–41–42 2.0–2.2–1.9 204–119Bonacchi et al. [8] 64–64–64 37–42–30 27–27–27 39–40–37 2.3–2.2–2.5 124–110Mihaljevic et al. [13] 66–65–68 35–31–46 NS 36–34–40 3.0–2.97–3.28 132–107

CABG alone: 34% severe LV dysfunction; MVS: 46% severe LV dysfunction. CABG, coronary artery bypass grafting; CPB, cardiopulmonary bypass; LVEF, left ventricularejection fraction; MV, mitral valve; MVS, mitral valve surgery; NS, not significant.

no statistically significant improvement on late NYHA

functional class (SMD¼�0.44; 95% CI �1.23 to 0.35).

No publication bias was detected, as tested using the

Egger method for late mortality including all studies

(P¼ 0.25), and restricting the analysis to studies with

preoperative severe ischemic mitral regurgitation (�3þgrade) as inclusion criteria (P¼ 0.41), or studies with a

higher number of patients with left ventricular dysfunc-

tion (P¼ 0.33).

DiscussionIschemic mitral regurgitation remains one of the major

unresolved issues in the management of ischemic heart

disease. Although the negative impact of residual mitral

regurgitation on late survival following CABG is well

documented [1,2], the benefits of an additional mitral

yright © Italian Federation of Cardiology. Unauth

Fig. 1

Meta-analysis of studies, denoted by first author and publication year,that evaluated operative mortality after combined mitral valve surgeryand coronary artery bypass grafting alone. The risk ratio and 95%confidence intervals for each study are displayed on a logarithmic scale.Squares indicating individual trial differences are scaled according totheir weightage in the meta-analysis. CABG, coronary artery bypassgrafting; CI, confidence interval; MVS, mitral valve surgery.

valve procedure are less convincingly established.

Optimal treatment of significant ischemic mitral regur-

gitation at the time of surgical revascularization remains

controversial [3,4]. Concomitant mitral valve annulo-

plasty or replacement is commonly advocated for severe

mitral regurgitation and repair is recently advocated for

moderate mitral regurgitation also [4]. Historically, the

debate over the prudence of adding a mitral valve pro-

cedure to coronary bypass has centered on the incremen-

tal increase in operative risk imposed by a more complex

procedure. However, discordant results have been

recently reported about the benefit of combined pro-

cedure on long-term results in both moderate and severe

ischemic mitral regurgitation [5–16].

This meta-analysis, summarizing information from nine

observational studies, demonstrated that in patients with

orized reproduction of this article is prohibited.

Fig. 2

Meta-analysis of studies, denoted by first author and publication year,that evaluated residual mitral regurgitation after combined mitral valvesurgery and coronary artery bypass grafting alone. The standardizedmean difference and 95% confidence intervals for each study arereported. Squares indicating individual trial differences are scaledaccording to their weightage in the meta-analysis. CABG, coronaryartery bypass grafting; CI, confidence interval; MVS, mitral valvesurgery.

C

Meta-analysis for ischemic mitral regurgitation Benedetto et al. 113

Fig. 3

Meta-analysis of studies, denoted by first author and publication year,that evaluated postoperative New York Heart Association functionalclass after combined mitral valve surgery and coronary artery bypassgrafting alone. The standardized mean difference and 95% confidenceintervals for each study are reported. Squares indicating individual trialdifferences are scaled according to their weightage in the meta-analysis. CABG, coronary artery bypass grafting; CI, confidenceinterval; MVS, mitral valve surgery.

ischemic mitral regurgitation, MVS at the time of

revascularization does not improve long-term survival

when compared with CABG alone. This result seem to

confirm the hypothesis advocated by some authors [13]

that ischemic mitral regurgitation represents only a mani-

festation of advanced infarction-induced ventricular

remodeling and that survival of these patients is primarily

dictated by extent of their ischemic left ventricular dis-

ease [13].

A high rate of significant residual mitral regurgitation

following surgical repair has been previously reported.

It should be argued that the recurrence of a significant

mitral regurgitation following surgical repair might par-

tially explain the lack of survival benefits following

combined procedures. We were able to show that com-

bined procedure achieved a better result in terms of

residual mitral regurgitation when compared with

CABG alone, even restricting the analysis to mitral

valve repair alone. But this result was not associated

with a better long-term survival. However, this con-

clusion is not robust due to the limited number of

patients with postoperative evaluation of residual

mitral regurgitation.

Even in the absence of survival benefit, MVS could be

justified if it leads to symptomatic improvement. We

failed to show a significant benefit in terms of sympto-

matic improvement in the pooled study population, but

when analysis was restricted to studies with severe mitral

regurgitation there was a trend toward symptomatic

improvement in the combined procedures group. How-

ever, it should be pointed out that all-cause mortality

opyright © Italian Federation of Cardiology. Unau

remains the most robust outcome in observational

studies, given that these studies lacked blinded out-

come assessment and systematic outcome surveillance.

Mitral valve annuloplasty was considered the standard to

correct mitral regurgitation [4], as it has been previously

reported to provide better results than replacement. In

the present study, a direct comparison between repair

and replacement was not performed due to the lack of

sufficient data details and also we could not demonstrate

any advantages of combined MVS restricting the analysis

to studies that included mitral valve annuloplasty but not

replacement. It has been recently suggested that in

the presence of ischemic mitral regurgitation, survival

advantages related with repair may be less evident as the

extension of ischemic disease primarily influences long-

term outcome [18]. In addition, repair is related with

increased rate of recurrent mitral regurgitation [3,4,20]

especially for severe grade mitral regurgitation and on the

basis of this finding, some authors advocated for biopros-

thetic mitral valve replacement in same cases (e.g. severe

bileaflet tethering) [19].

It has been recently demonstrated that preoperative

mitral regurgitation is deleterious to CABG patients with

compromised but not preserved left ventricular function

[20]. We tried to investigate this aspect by restricting the

analysis to studies with a higher number of patients with

left ventricular dysfunction, but we could not demon-

strate any advantages from combined MVS.

Taken together, these data underline the lack of defini-

tive evidence concerning the efficacy of MVS for

ischemic mitral regurgitation compared with CABG alone

and highlight the need for additional evidence. Most

surgeons commonly use additional mitral valve procedure

to treat moderate or severe ischemic mitral regurgitation,

because it seems logical to assume that the volume

overload associated with mitral regurgitation will be

detrimental particularly to the patient with compromised

left ventricular function. However, until definitive evi-

dence about the superiority of this approach will be

available, a tailored surgical strategy should be con-

sidered especially in mild ischemic mitral regurgitation.

LimitationsThe findings of this meta-analysis must be interpreted

with some caution. The design of the study lacks random

allocation to combined procedures or CABG alone, and

few studies included in the meta-analysis reported the

criteria considered by the individual surgeons to allocate

patients to either group. Treatment was not randomized,

and generally there was no formal policy within institu-

tions at that time for the management of this condition.

Opinions regarding aggressiveness of intervention on the

mitral valve were strongly divided among the practicing

surgeons. A subtle bias toward intervention on the more

thorized reproduction of this article is prohibited.

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114 Journal of Cardiovascular Medicine 2009, Vol 10 No 2

severely regurgitant valves was likely active, however,

the mean severity of mitral regurgitation was statistically

significantly worse in the combined group. The two

groups were not comparable for all the factors that can

alter the outcome of interest and confounding factors

cannot be excluded.

However, even if randomized controlled trials represent

the highest level of evidence-based medicine, they are

subject to trial design bias by preferentially enrolling low-

risk patients, often resulting in high degree of selectability.

In addition, they are often underpowered to detect any

potential advantages for low-rate events such as morality,

which frequently occurs in cardiac surgery trials. Observa-

tional studies allow us to gain new insights from the more

heterogeneous real world of clinical practice.

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