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\begin{document}

\title{Comparative efficacy of 5 surgical methods in the treatment of mitral
regurgitation: a systematic review and network meta-analysis}



\author[1]{Weimin Huang}%
\author[2]{Biao Hou}%
\author[2]{Yuhai Zhang}%
\author[2]{Qin Li}%
\author[2]{Liang Wang}%
\affil[1]{Baotou Clinical Medical College of Inner Mongolia Medical University}%
\affil[2]{Affiliation not available}%


\vspace{-1em}



  
  \date{May 24, 2024}


\begingroup
\let\center\flushleft
\let\endcenter\endflushleft
\maketitle
\endgroup





\selectlanguage{english}
\begin{abstract}
Objective This study has been compared the effectiveness of different
surgical methods in the treatment of mitral regurgitation (MR) in adults
by using network meta-analysis method, so as to provide reference for
clinical selection of the best surgical scheme. Methods The PubMed,
EMBASE, the Cochrane Library, CNKI and Chongqing VIP Information
databases were comprehensively searched until December 2020. We
collected retrospective comparative studies on surgical procedures
including 3D endoscopic mitral valve surgery(3D-MVS), robot assisted
mitral valve surgery(R-MVS); totally thoracoscopic mitral valve
surgery(T-MVS), small incision mitral valve surgery (M-MVS) and
traditional thoracotomy mitral valve surgery(C-MVS). Addis1.16.8
software was used for network meta-analysis. Results A total of 31
studies were included, 12998 patients, involving 5 surgical methods.
Network Meta analysis showed that: in terms of complications (OR: 0.65,
95\% CI: 0.13 to 3.00, probability rank = 0.37) and mitral regurgitation
(OR:0.03, 95\%CI: 0.0 to 8315, probability rank=0.64), the 3D-MVS group
had the lowest event rate. In terms of blood transfusion rate (OR: 0.55,
95\% CI: 0.16 to 1.84, probability rank=0.45), T-MVS had the lowest
event rate. In addition, with the exception of operation time and chest
drainage, the R-MVS group has the best curative effect. Conclusion These
minimally invasive surgery has their own advantages and disadvantages.
Overall, 3D-MVS is most satisfactory, but more samples are needed.%
\end{abstract}%



\sloppy


\textbf{Comparative efficacy of 5 surgical methods in the treatment of
mitral regurgitation: a systematic review and network meta-analysis}

Weimin Huang\textsuperscript{1}, Biao Hou\textsuperscript{1}, Qin
Li\textsuperscript{1},Yuhai Zhang\textsuperscript{1}, Liang
Wang\textsuperscript{2}

\emph{1. Baotou Clinical Medical College of Inner Mongolia Medical
University;}

\emph{2. Department of Cardiology, Baotou Central Hospital, Baotou
014040, China.}

Correspondence to:

Liang Wang;\emph{huang\_manlin2021@163.com}Phone number:
+86138-9086-2882

523, Angel Building, Baotou Central Hospital, Inner Mongolia Autonomous
Region

\begin{CJK}{UTF8}{gbsn}【\end{CJK}\selectlanguage{english}\textbf{Key words} \begin{CJK}{UTF8}{gbsn}】\end{CJK}\selectlanguage{english}Minimally invasive surgery; Mitral valve;
Thoracoscopy; Robot surgery; Traditional thoracotomy; Network
meta-analysis

>This is the first network meta-analysis focused on different surgical
treatments for mitral regurgitation to review all available literature.

> We employed rigorous methodology according to the Preferred Reporting
Items for Systematic Reviews and Meta-Analyses statement, and used the
Recommendations Assessment, using the software ADDIS 1.16.8 in the
review process.

>Due to special circumstances, the thoracoscopy assisted or robot
assisted surgery are not listed as separate surgical method to collect
data for subgroup analysis.

ABSTRACT

\textbf{Objective} This study has been compared the effectiveness of
different surgical methods in the treatment of mitral regurgitation (MR)
in adults by using network meta-analysis method, so as to provide
reference for clinical selection of the best surgical scheme.
\textbf{Methods} The PubMed, EMBASE, the Cochrane Library, CNKI and
Chongqing VIP Information databases were comprehensively searched until
December 2020. We collected retrospective comparative studies on
surgical procedures including 3D endoscopic mitral valve
surgery(3D-MVS), robot assisted mitral valve surgery(R-MVS); totally
thoracoscopic mitral valve surgery(T-MVS), small incision mitral valve
surgery (M-MVS) and traditional thoracotomy mitral valve surgery(C-MVS).
Addis1.16.8 software was used for network meta-analysis.
\textbf{Results} A total of 31 studies were included, 12998 patients,
involving 5 surgical methods. Network Meta analysis showed that: in
terms of complications (OR: 0.65, 95\% CI: 0.13 to 3.00, probability
rank = 0.37) and mitral regurgitation (OR:0.03, 95\%CI: 0.0 to 8315,
probability rank=0.64), the 3D-MVS group had the lowest event rate. In
terms of blood transfusion rate (OR: 0.55, 95\% CI: 0.16 to 1.84,
probability rank=0.45), T-MVS had the lowest event rate. In addition,
with the exception of operation time and chest drainage, the R-MVS group
has the best curative effect. \textbf{Conclusion} These minimally
invasive surgery has their own advantages and disadvantages. Overall,
3D-MVS is most satisfactory, but more samples are needed.

INPLASY registration number 202140138

\textbf{INTRODUCTION}

Mitral regurgitation (MR) is a common heart valve disease, in which the
mitral valve fails to close during the left ventricular systole and
causes blood to flow from the left ventricle to the left atrium,
including primary (degenerative) MR and secondary (functional)
MR.\textsuperscript{{[}1{]}} With the gradual aging of the global
population, the number of MR patients has shown an upward trend year by
year and the annual mortality rate was as high as
34\%.\textsuperscript{{[}2{]}} The treatment methods of MR mainly
include drug therapy, surgery and percutaneous interventional therapy.
Drug therapy can only improve the symptoms of the patient, but cannot
prolong the survival time; the surgical operation includes mainly valve
repair and valve replacement, which is considered to be the standard
treatment for MR. Percutaneous intervention technology has become a
supplementary treatment option for high-risk MR patients who cannot
withstand the blow of surgery. \textsuperscript{{[}3{]}} After 30 years
of development, Minimally invasive cardiac surgery (MICS) technology
reduces the trauma caused by the operation itself in the case of
providing the same curative effect as the C-MVS operation. In recent
years, there have been studies that directly compared different
minimally invasive options, such as R-MVS, 3D-MVS, T-MVS, M-MVS, C-MVS,
etc., but lack of network meta-analysis research. This study has been
used to systematically evaluates the respective advantages and mid-term
efficacy of different surgical procedures, discuss the best minimally
invasive MV surgery and provide clinical reference for the majority of
cardiac surgery colleagues.

MATERIALS AND METHODS

\textbf{Patient and public involvement} No patients were involved.

\textbf{Eligibility criteria}

Studies that meet the following inclusion criteria were included: (1)
the design of the study was a clinical retrospective cohort study about
MR; (2) The experimental group and the control group received different
surgical treatments; and (3) at least four of the data indicators for
the perioperative period. Exclusion criteria were as follows: (1)
irrelevant studies and duplicate literature; (2) unavailable data in the
literature;(3) letters, reviews, case reports. (4) The type of disease
involves other major diseases that may affect the efficacy of the
operation.

\textbf{Search methodology}

PubMed, EMBASE, The Cochrane Library, CNKI and VIP were comprehensively
searched up to December 2020. The search terms were a combination of
medical subject headings (MeSH) terms and the following free words:
Mitral Regurgitation, Mitral Valve Replacement, Mitral Valve Repair,
Endoscopes, Thoracoscopes, Robot-assisted, Robotic Surgical Procedures,
Minimally Invasive Surgical Procedures, Thoracotomy. In addition, we
manually searched for other potential and relevant references. There
were no limitations in the language of all publications. Take PubMed as
an example, its strategy is as follows:

\#1 Mitral regurgitation {[}Mesh{]}

\#2 Mitral valve replacement {[}Title/Abstract{]} OR Mitral valve repair
{[}Title/Abstract{]} OR Mitral valvuloplasty {[}Title/Abstract{]}

\#3 \#1 and \#2

\#4 surgical therapy {[}Mesh{]}

\#5 Robotic Surgical Procedures {[}Mesh{]} OR Video-Assisted Surgery
{[}Mesh{]} OR Thoracoscopes {[}Mesh{]} OR Thoracotomy {[}Mesh{]}

\#6 totally thoracoscopic {[}Title/Abstract{]} OR Traditional
thoracotomy {[}Title/Abstract{]} OR Conventional Surgery
{[}Title/Abstract{]}

\#7 \#4 OR \#5 OR \#6

\#8 \#3 AND \#7

\textbf{Study selection}

Two investigators (WMH and BH) filtered the original studies
independently. If the literature meets the eligibility criteria, the two
investigators will further read the full text to screen the study. Any
discrepancies were addressed by discussion or third party consensus.

\textbf{Data extraction and analysis}

All data were collected independently by two investigators (WMH and QL)
from eligible studies using a standardised form. The following
information was extracted: (1) study identification, including author
name and publication year; (2) country where the study was conducted;
(3) study subjects, number of participants and male to female ratio; (4)
settings of trial arms; (5) Main indicators: complications, blood
transfusion rate, 30-day mortality; mitral regurgitation and
paravalvular leakage; secondary indicators: operation time, mechanical
ventilation time, chest drainage, physiological score, psychological
score, recovery time, hospitalization Total cost. (The ''complication''
here refers to postoperative wound infection, pneumonia, liver and
kidney insufficiency, myocardial infarction, postoperative atrial
fibrillation, stroke, secondary thoracotomy, etc., ''Physiological score
or Psychological score'' is a score determined according to the quality
of life questionnaire (SF-12/SF-36) provided in the literature. The
higher the score, the better the effect.)

\textbf{Quality assessment}

Risk of bias was assessed using the Cochrane Collaboration's tool
addressing six domains: sequence generation, allocation concealment,
blinding of participants/outcome assessors, incomplete outcome,
selective outcome reporting and other source of bias. These articles are
almost non-randomized controlled (NRCT) studies, so the Newcastle Ottawa
scale (NOS) recommended by Cochrane Collaboration Network is used to
evaluate the quality of retrospective cohort studies.

\textbf{Statistical analysis}

Traditional pairwise meta-analysis with Review Manager 5.4.1For binary
data, odds ratio (OR) and 95\% CI are used as effect size indicators.
OR\textless{}1 indicates that one intervention may be worse than another
intervention; OR\textgreater{}1 indicates that one intervention may be
better than another intervention; 95\%CI containing 1 means that the
difference is not statistically significant. For continuous data,
standard mean difference (SMD) and 95\% CI were used as effect size
indicators. SMD\textless{}0 means that one intervention may be worse
than another; SMD\textgreater{}0 means that one intervention may be
better than another; 95\%CI containing 0 means that the difference is
not statistically significant. In direct Meta analysis, Q test and I2
index are used to evaluate the heterogeneity of each effect size. If
P\textgreater{}0.1 and I2\textless{}50\%, it indicates that the results
of each study have good homogeneity, then the fixed effects model is
used. If P[?]0.1 and/or I2[?]50\%, the results of the study are
statistically heterogeneous, and a random effects model is used.

Network meta-analysis with software ADDIS 1.16.8

The Node-split model is used to test the consistency in the network
meta-analysis. If there is no statistical difference between the studies
within the subgroup (P\textgreater{}0.05), it indicates that the
heterogeneity of the included studies is small, so the consistency model
is used for analysis; otherwise, an inconsistency model is used for
analysis. A ranking probability table is used to rank the pros and cons
of intervention measures (the value indicates the probability of
intervention measures in the nth position). Regarding the main
indicators of this article, the higher the ranking, the better.

\textbf{RESULTS}

\textbf{Study selection outcome and characteristics}

There were 1892 relevant articles retrieved ultimately, among which 272
were duplicate articles. After screening layer by layer,
31\textsuperscript{{[}4-33{]}} articles were finally included, including
24 in English and 7 in Chinese, including 18 propensity matching studies
and 4 master's thesis. Figure 1 shows the screening process.

The mean age of the included 12998 participants was 51.60 years. The
follow-up time range is 1--50.5 months. Table 1 displays the main
characteristics in detail.

\textbf{Study quality assessment}

The quality scores of the included observational studies were ranged
from 5 to 8 with a mean score of 6.5, which suggested the relatively
high quality in the meta analysis (Table 2, in online supplement 1). All
studies did not mention the allocation concealment and most of studies
did not Provide the information about the blinding method (in clinical
surgery, family members are required to obtain informed consent and
inform their plans). The lowest agreement was achieved in the incomplete
outcome data, while the perfect agreement was achieved in the selective
reporting. The risk of bias of each study was showed in Figures 2 A,B.

Primary outcomes

In terms of complications, the P values of Node-splitting analysis are
all\textgreater{} 0.05, which means that the difference is not
statistically significant. Therefore, the consistency test is used, and
the probabilistic ranking results (Figure 4 A) are in order:
3D-MVS\textgreater{}M
-MVS\textgreater{}T-MVS\textgreater{}R-MVS\textgreater{}C-MVS. Specific
values: 3D-MVS(OR:0.65, 95\%CI:0.13 to 3.00), M-MVS(OR=0.56, 95\%CI:0.35
to 0.90) ){]}, T-MVS (OR: 0.60, 95\% CI:0.32 to 1.15), R-MVS (OR: 0.76,
95\% CI:0.48 to 1.14)) are less than C-MVS.

In terms of blood transfusion rate, the ranking result is:
T-MVS\textgreater{}3D-MVS\textgreater{}M-MVS\textgreater{}R-MVS\textgreater{}C-MVS.
Specific value: T-MVS(OR:0.31, 95\%CI:0.07 to 1.40), 3D -MVS(OR:0.35,
95\%CI:0.05 to 2.62), M-MVS(OR:0.61, 95\%CI:0.27 to 1.34),
R-MVS(OR:0.77, 95\%CI:0.38 to 1.55) Lower than C-MVS.

In terms of MR and paravalvular leakage, the ranking result is:
3D-MVS\textgreater{}M-MVS\textgreater{}T-MVS\textgreater{}R-MVS\textgreater{}C-MVS.
The specific value is: 3D-MVS(OR:0.03, 95\%CI:0.00 to 8315 ), M-MVS(OR:
0.46, 95\%CI: 0.25 to 0.88), T-MVS(OR: 0.64, 95\%CI: 0.25 to 1.47),
R-MVS(OR: 0.69, 95\%CI: 0.35 to 1.24) are lower than C-MVS.

Regarding the 30-day mortality rate, we use the node-split model (NM)
for non-uniformity test. The last line indicates P\textless{}0.05, that
is, the difference is statistically significant. According to the
principles of statistical methods, we use non-uniformity test.
Consistency test (Figure 5) and analysis of the source of inconsistency.
The inconsistency suggests that there is a significant statistical
difference between direct comparison and indirect comparison, so we
should refer to the traditional direct comparison result to be more
reliable.

Secondary outcomes

In terms of mechanical ventilation time, the robot takes the shortest
time, and the ranking result is:
R-MVS\textgreater{}3D-MVS\textgreater{}T-MVS\textgreater{}M-MVS\textgreater{}C-MVS.

In terms of recovery time, the robot group recovers the fastest, and the
ranking results are:
R-MVS\textgreater{}M-MVS\textgreater{}T-MVS\textgreater{}C-MVS.

In terms of postoperative thoracic drainage, the small incision drainage
value is the smallest, and the ranking result (from less to more
drainage) is:
M-MVS\textgreater{}T-MVS\textgreater{}3D-MVS\textgreater{}R-MVS\textgreater{}C-MVS.

In terms of scoring, only 4 intervention measures were compared. In
terms of physiological score, the ranking results of superiority and
inferiority were as follows:
R-MVS\textgreater{}M-MVS\textgreater{}T-MVS\textgreater{}C-MVS. In terms
of psychological score, the order is:
R-MVS\textgreater{}T-MVS\textgreater{}C-MVS\textgreater{}M-MVS.

Publication bias

A funnel plot of all included studies in this network meta-analysis was
made for visual screening of any publication bias (figure 6). It
revealed that all included studies were distributed around the vertical
and oblique line within the 95\% CIs, suggesting no obvious publication
bias.

DISCUSSION

The above-mentioned surgical procedures have their own advantages and
disadvantages, and even C-MVS is still used as a routine operation
method in some institutions restricted by endoscopic conditions due to
its remarkable curative effect.\textsuperscript{{[}27{]}} The effect of
different surgical methods in the treatment of mitral regurgitation is
described, and the probabilistic results of their pros and cons are
given.

It should be emphasized that in terms of total hospitalization costs,
three of the studies \textsuperscript{{[}7,23,27{]}} involved and
performed statistical analysis, among which Zhu
Yilin\textsuperscript{{[}27{]}} (P=0.391, T-MVS vs M-MVS vs C- MVS),
Coyan\textsuperscript{{[}7{]}} (P=0.273, R-MVS vs C-MVS) directly
compared the results with no statistical difference; while Liu's
study\textsuperscript{{[}23{]}} suggested that the difference was
statistically significant (P=0.002, T -MVS vs C-MVS).
Perin\textsuperscript{{[}34{]}} and others abroad reported that the
total hospitalization cost of minimally invasive and C-MVS mitral valve
surgery is not different: the high surgical cost of minimally invasive
surgery is lowered by the lower postoperative cost. The cost is offset,
and the length of hospital stay is shortened by about 2 days, which is
consistent with the author's research results to a certain extent. In
addition, we can conclude that the minimally invasive surgery options
can reduce trauma to a certain extent by comparing them with C-MVS.
Saving blood products, reducing complications, and speeding up body
recovery are beneficial to improve the quality of life of patients after
surgery.

Although most of articles record the left ventricular ejection fraction
(LVEF) values before, due to the large clinical heterogeneity between
the studies, the postoperative EF value was not included in the outcome
indicators for comparison. A Meta study in
China\textsuperscript{{[}35{]}} once reported that the Percutaneous
Mitral Valve Clipping (Mitra-Clip treatment) can improve the cardiac
function of patients with mitral regurgitation and heart failure to a
certain extent, but further studies are still needed to prove its
conclusions; recent studies by Khader \textsuperscript{{[}36{]}} and
others in the UK have also repeatedly emphasized the mid-term durability
of MR valve surgical repair is better than Mitra-Clip.

Combined with this Network Meta, we believes that MR minimally invasive
surgery will still be the standard treatment plan for mitral valve
disease for a long period of time in the future. Which minimally
invasive program needs to be determined by the institution based on the
individual and the environment.

CONCLUSION

Based on the above network meta-analysis and ranking results, 3D-MVS
operation method can be used as the best choice in the surgical scheme
of mitral valve disease, followed by T-MVS and M-MVS. Of course, if
there are resource conditions, the combination of two minimally invasive
operations (such as small incision combined with thoracoscopy) can
ensure safer operation and faster recovery of patients.

Figure 1 Study flow diagram

Figure 2 A-B. (A) risk of bias summary; (B) risk of bias graph.

Figure 3 a-d. Network diagram of the treatments. (\textbf{a} ):
Complications; (\textbf{b} ): Blood transfusion rate; (\textbf{c} ) :
Mitral regurgitation and perivalvular leakage during follow-up;
(\textbf{d} ): Mortality within 30 days.

Figure 4 A-C. Rank probability of the best treatment. Rank 1 is worst,
rank N is best. (A): Complications; (B): Blood transfusion rate; (C):
Mitral regurgitation and perivalvular leakage during follow-up.

Figure 5 Node-splitting analysis of the 30-day mortality index. Data are
presented as relative effect (95\% credible interval).

Figure 6 A funnel plot of all included studies in this network
meta-analysis was made for visual screening of any publication bias.

\textbf{Author affiliations}

1. Baotou Clinical Medical College of Inner Mongolia Medical University,
Baotou, China

2. Department of Cardiology, Baotou Central Hospital, Baotou 014040,
China

\textbf{Acknowledgements} Our greatest acknowledgement goes to the
authors who made detailed data available for this meta-analysis and all
our colleagues in this study for their hard work.

\textbf{Contributors} WMH, BH and QL performed the search and drafted
the manuscript. WMH and YHZ performed the data extraction and analysed
the data. WMH, WL and YHZ designed the study and amended the original
draft.

\textbf{Funding} The authors have not declared a specific grant for this
research from any funding agency in the public, commercial or
not-for-profit sectors.

\textbf{Competing interests} None declared.

\textbf{Patient and public involvement} Patients and/or the public were
not involved in the design, or conduct, or reporting, or dissemination
plans of this research.

\textbf{Patient consent for publication} Not required.

\textbf{Provenance and peer review} Not commissioned; externally peer
reviewed.

\textbf{Data availability statement} All data relevant to the study are
included in the article or uploaded as supplementary information.

ORCID iD Weimin Huang\emph{https://orcid.org/0000-0003-2556-6214}

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regurgitation?{[}J{]}.\emph{J Card Surg} , 2021,36(3):1103-1119.\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Firgure-1-Flow-diagram-(MV)/Firgure-1-Flow-diagram-(MV)}

\end{center}
\end{figure}\selectlanguage{english}
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\includegraphics[width=0.70\columnwidth]{figures/Figure-2-A:Risk-of-bias-graph/Figure-2-A:Risk-of-bias-graph}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
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\includegraphics[width=0.70\columnwidth]{figures/Figure-2-(B)-Risk-of-bias-summary/Figure-2-(B)-Risk-of-bias-summary}

\end{center}
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\includegraphics[width=0.70\columnwidth]{figures/Figure-3--a-d/Figure-3--a-d}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-4--(A)-complications/Figure-4--(A)-complications}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-4-(B)-Blooding-Rate/Figure-4-(B)-Blooding-Rate}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-4-(C)-MR-leakage/Figure-4-(C)-MR-leakage}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-5-Node-splitting-analysis-of-the-30-day-mortality-index/Figure-5-Node-splitting-analysis-of-the-30-day-mortality-index}

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-6-A-funnel-plot-of--included-studies/Figure-6-A-funnel-plot-of--included-studies}

\end{center}
\end{figure}

\textbf{Hosted file}

\verb`Table 1  Main information of the studies included in the meta.docx`  available at \url{https://authorea.com/users/435929/articles/538623-comparative-efficacy-of-5-surgical-methods-in-the-treatment-of-mitral-regurgitation-a-systematic-review-and-network-meta-analysis}

\selectlanguage{english}
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