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\begin{document}

\title{Comparing Mid-Term Outcomes of Cox-Maze Procedure and Pulmonary Vein
Isolation for Atrial Fibrillation After Concomitant Mitral Valve
Surgery: A Systematic Review}



\author[1]{Davorin Sef}%
\author[2]{Vladimir Trkulja}%
\author[1]{Shahzad  Raja}%
\author[3]{Joanne Hooper}%
\author[4]{Marko Turina}%
\affil[1]{Royal Brompton and Harefield Hospitals}%
\affil[2]{Department of Pharmacology Zagreb University School of Medicine Zagreb Croatia EU}%
\affil[3]{University Hospitals Bristol and Weston NHS Foundation Trust}%
\affil[4]{UniversitatsSpital Zurich}%


\vspace{-1em}



  
  \date{May 04, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
\textbf{Background:} Although concomitant pulmonary vein isolation (PVI)
is used more frequently than the Cox-maze procedure, which is currently
the gold standard treatment for AF, data on the comparative
effectiveness of the two procedures after concomitant mitral valve (MV)
surgery are still limited. \textbf{Objective:} We conducted a systematic
review to identify randomized controlled trials (RCT) and observational
studies comparing the mid-term mortality and recurrence of atrial
fibrillation (AF) after concomitant Cox-Maze and PVI in patients with AF
undergoing MV surgery based on 12-month follow-up. \textbf{Methods:}
Medline, EMBASE databases, and the Cochrane Library were searched from
1987 up to March 2022 for studies comparing concomitant Cox-Maze and
PVI. A meta-analysis of RCTs was performed to compare the mid-term
clinical outcomes between these two surgical ablation techniques.
\textbf{Results:} Three RCTs and 3 observational studies meeting the
inclusion criteria were included in this systematic review with 790
patients in total (532 concomitant Cox-Maze and 258 PVI during MV
surgery). Most studies reported that concomitant Cox-Maze procedure was
associated with a higher freedom from AF at 12-month follow-up than PVI.
Regarding AF recurrence, estimate pooled across the 3 RCTs indicated
large heterogeneity and high uncertainty. In the largest and highest
quality RCT, 12-month AF recurrence was higher in the PVI arm (RR=1.58,
95\%CI 0.91-2.73). In 2 out of 3 higher quality observational studies,
12-month AF recurrence was higher in PVI than in Cox-Maze arm (estimated
adjusted probabilities 11\% vs. 8\% and 35\% vs. 17\%, respectively).
RCTs demonstrated comparable 12-month mortality between concomitant
Cox-Maze and PVI, while observational studies demonstrated survival
benefit of Cox-Maze. \textbf{Conclusions:} Concomitant Cox-Maze in AF
patients undergoing MV surgery is associated with better mid-term
freedom from AF when compared to PVI with comparable mid-term survival.
Large observational studies suggest that there might be a mid-term
survival benefit among patients after concomitant Cox-Maze. Further
large RCTs with longer standardized follow-up are required in order to
clarify benefits of concomitant Cox-Maze in AF patients during MV
surgery.%
\end{abstract}%



\sloppy


\textbf{1. Introduction}

Up to 50\% of patients undergoing mitral valve (MV) surgery experience
preoperative atrial fibrillation (AF) \textsuperscript{1}. Incidence of
stroke in patients with AF who are optimally anticoagulated remains
between 2-5\% per year, depending on the individual risk
factors\textsuperscript{2}. Surgical ablation during MV surgery has now
been clearly shown to be associated with a reduced 30-day mortality and
stroke and is recommended at the time of concomitant mitral operations
to restore sinus rhythm \textsuperscript{1,3-6}. {While there have been
many studies on concomitant surgical ablation in cardiac surgery,
analysis of mid-term or long-term outcomes of simultaneous Cox-Maze
procedure or pulmonary vein isolation (PVI) during MV surgery is still
lacking.\textsuperscript{1,5}} The performance rate of concomitant
surgical ablation in patients with AF at the time of MV surgery has
risen from 52\% to 62\% over the last decade\textsuperscript{7}.

The first maze procedure (Cox-Maze I) was performed by James Cox on
September 25, 1987 \textsuperscript{8}. The procedure evolved into the
Cox-Maze III and became the gold standard surgical treatment of
AF\textsuperscript{3,9}. In 2002, Damiano and associates have modified
the Cox-Maze III technique and replaced the majority of the incisions
with a combination of bipolar radiofrequency (RF) and cryothermal
ablation lines in a procedure termed the Cox-Maze IV, which has
shortened and simplified the operation and has decreased morbidity and
mortality\textsuperscript{10}. The Cox-Maze IV is currently the gold
standard surgical treatment for AF, with estimated freedom from AF and
from antiarrhythmic drugs (AAD) at 1 year postoperatively of 93\% and
85\%, respectively \textsuperscript{11}. However, concomitant pulmonary
vein isolation (PVI) is still being used more frequently than the
Cox-Maze procedure as it is the simplest and most rapidly completed set
of ablation lesions \textsuperscript{12}. In addition, PVI can be
performed without cardiopulmonary bypass in coronary artery bypass graft
surgery\textsuperscript{13}.

In the attempt to evaluate mid-term efficacy and safety of concomitant
Cox-Maze relative to PVI in patients with AF undergoing MV surgery, we
conducted a systematic review to critically evaluate randomized
controlled trials (RCTs) and non-randomized studies directly comparing
the two procedures in this setting with additional subgroup
meta-analysis of RCTs.

\textbf{2. Patients and Methods}

\textbf{2.1. Study Protocol}

This systematic review was conducted in line with PRISMA (Preferred
Reporting Items for Systematic Reviews and Meta-Analyses) and AMSTAR
(Assessing the methodological quality of systematic reviews) Guidelines.
The study protocol was registered with the PROSPERO register of
systematic reviews (PROSPERO ID: CRD42021250576) \textsuperscript{14}.

\textbf{2.2. Literature Search and Study Selection}

An initial scoping search and a systematic literature search were
performed by a medical librarian to identify RCTs and observational
studies that compared concomitant Cox-Maze and PVI in patients who
underwent MV surgery. Medline, EMBASE databases, and the Cochrane
Library were searched from 1987 up to 15\textsuperscript{th} of March
2022 using the following search terms: Maze surgery, Maze procedure,
Maze technique, maze or Cox-Maze vs. pulmonary vein isolation, ablation
surgery, ablation procedure, surgical ablation. Details of the search
strategy are provided in the Supplement.

We defined 12-month mortality and recurrence of AF postoperatively as
outcomes of interest. We expected that variety of outcomes illustrating
efficacy/safety would be reported, but they were not reported
consistently over the studies.

After deduplication, study eligibility was assessed independently by two
investigators. Any discrepancies were resolved by discussion between the
3 investigators. The studies were selected through the following two
levels of screening: in the first step studies were independently
screened based on titles and abstracts, and in the second step,
full-text reports were evaluated based on predefined criteria. Studies
were eligible if they compared outcomes in patients with AF undergoing
MV surgery and concomitant Cox-Maze procedure or PVI and met the
following inclusion criteria:

1. Population: adults or adolescents (12 years or older)

2. Comparator: Cox-Maze vs PVI

3. Provided outcomes: death, recurrence of AF at 12-month follow-up

4. Design: RCT or non-randomized studies of interventions (NRSI) with at
least 20 patients \emph{per} treatment of interest

5. Published in English language.

Studies were ineligible if they had follow-up shorter than 12 months and
if they were duplicates. For studies reported in more than one
publication, or when institutions reported subsequent studies with
accumulating numbers of patients or increased lengths of follow-up, only
the most complete reports (in terms of reported outcomes and control of
confounding) were included.

\textbf{2.3. Risk of bias -- study quality assessment}

Risk of bias in individual studies was assessed independently by two
investigators. Discrepancies were resolved through discussion between
three investigators. RCTs were assessed using the revised Cochrane
collaboration Risk of Bias tool 2 for randomized controlled trials
(RoB2) \textsuperscript{15}, and NRSI were assessed using Cochrane
collaboration Risk of bias in non-randomized studies of interventions
(ROBINS-I) tool (see Supplement for details) \textsuperscript{16}.

\textbf{2.4. Data Extraction and Outcomes}

We assessed and extracted data on study characteristics, patients'
baseline data and data regarding study outcomes independently by two
investigators with verification for accuracy by two other investigators.
The investigators looked for information on the sources of funding for
individual studies included in the review, but it was not required to be
reported. Digitizing software was used to recover graphically presented
data. For RCTs, we extracted n/N data. For NRSI, we intended to extract
adjusted effect measures; however, out of the 3 identified studies, one
provided no relevant quantitative data, while the other two reported
adjusted proportions (estimated probabilities from multivariate models).
Where necessary, study authors were contacted to obtain additional
information.

The primary outcomes were recurrence of AF and mortality after 12-month
follow-up. The secondary outcomes included aortic cross-clamp time
(XCT), cardiopulmonary bypass (CPB) time, rate of MV repair and duration
of preoperative AF.

\textbf{2.5. Subgroup Meta-analysis}

We intended to generate random-effects pooled effect estimates,
separately for RCTs and NRSIs, but only 3 RCTs and 2 NRSIs with
numerical data on primary outcomes were identified. Therefore: (i) we
generated frequentist (Mantel-Haenszel relative risk, Paul-Mandel for
\selectlanguage{greek}τ\selectlanguage{english}\textsuperscript{2}, Hartung-Knapp adjustment) and Bayesian {[}vaguely
informative prior for ln(RR) (mean=0, SD=4, half-normal for \selectlanguage{english}\selectlanguage{greek}τ{]}
random-effects pooled estimates and prediction intervals specifically to
illustrate uncertainty (CI width) and heterogeneity of the RCT outcomes
(width of prediction intervals); (ii) adjusted proportions retrieved
from two NRSIs were used to calculate individual study risk ratios
(PVI/Cox-Maze) by the Miettinen-Nurminen method for more intuitive
presentation \textsuperscript{17}. We used package \emph{meta} in
R\textsuperscript{18} for the frequentist and package
\emph{bayesmeta}for Bayesian meta-analysis in R (R Core Team (2020). R:
A language and environment for statistical computing. R Foundation for
Statistical Computing, Vienna, Austria. URL
https://www.R-project.org/)\textsuperscript{19,20}.

\textbf{3. Results}

\textbf{3.1. Identification of Studies}

A total of 409 studies were identified from the literature search, 7 of
which reporting on 3 RCTs and 3 NRSIs \textsuperscript{21-26} that met
the eligibility criteria and were included in the present systematic
review. The full PRISMA flow diagram outlining the study selection
process is available in Figure 1.

\textbf{3.2. Study Characteristics}

Details of individual studies and patients' baseline characteristics
including history of AF, intraoperative data and mid-term postoperative
outcomes are summarized in Table 1. Three out of 6 studies were
RCTs\textsuperscript{21-23}. The studies included a total of 790
patients (532 undergoing concomitant Cox-Maze and 258 undergoing PVI
during MV surgery). The proportion of patients who had preoperative
longstanding persistent AF was reported in 5 out of 6 studies, while
\emph{Gillinov et al.} reported duration of preoperative AF
\textsuperscript{26}. The proportion of longstanding persistent AF was
similar in both compared subgroups in most studies. The performance rate
of concomitant left atrial appendage occlusion was reported in 5/6
studies\textsuperscript{21,22,24-26} and was 100\% in all subgroups
apart from the PVI subgroup in one study with the rate of
70\%\textsuperscript{24}. The rate of MV repair was reported in 5/6
studies and was comparable between the subgroups \textsuperscript{24}.
All included studies reported concomitant Cox-Maze III or IV procedures
performed in a standardized fashion. XCT and CPB time across the studies
are demonstrated in Table 1.

\textbf{3.3. Risk of Bias}

Bias assessment of RCTs is demonstrated in Table 2. There were some
concerns about the risk of bias in the two single-center
trials\textsuperscript{22,23} (allocation concealment, postoperative use
of antiarrhythmics and anticoagulants), while CTSN trial had low risk of
bias (Table 2.) \textsuperscript{13,21}. In respect to baseline and
intraoperative characteristics, PVI (total N=127) and Cox-Maze patients
(total N=126) appeared reasonably balanced within individual trial. Bias
assessment of NRSIs is demonstrated in Table 3. Out of 3 NRSIs, one had
a serious risk of bias (Table 3) \textsuperscript{24}.

\textbf{3.4. Mortality after 12-month follow-up}

A lower 12-month mortality was observed in several studies, although the
difference was not statistically significant. Onorati and colleagues
reported higher adjusted 12-month mortality among patients who underwent
PVI (6.0\%) as compared to Cox-Maze (1.4\%) (risk ratio=4.29, 95\%CI
0.67-27.0) \textsuperscript{25}.

Because of the lack of RCTs and limited number of enrolled patients,
meta-analysis of RCTs comparing patients who underwent concomitant
Cox-Maze and PVI during MV surgery resulted in wide CI/CrI (2-3-fold
lower to 2-3-fold higher risk with PVI) (Figure 2A). Considering very
wide prediction intervals, there was high uncertainty when comparing the
12-month mortality between the patients who underwent concomitant
Cox-Maze and PVI.

\textbf{3.5. Recurrence of AF after 12-month follow-up}

~{Two single-center RCTs\textsuperscript{22,23} indicated comparable
results in AF recurrence during 12-month follow-up after the concomitant
Cox-Maze and PVI, while the CTSN trial clearly demonstrated higher risk
of AF recurrence after the concomitant PVI procedure during MV surgery
(Table 1).\textsuperscript{21} However,~} CI/CrI (from 3-4-fold lower to
3-4-fold higher risk after PVI) and prediction intervals around the
pooled estimates were very wide (Figure 2B) illustrating uncertainty
when comparing 12-month recurrence of AF among patients who underwent
Cox-Maze and PVI. However, Srivastava and colleagues excluded patients
with enlarged left atrium (\textgreater{}6 cm) or if they received
antiarrhythmic drugs preoperatively from their RCT, which are actually
subsets of patients that would benefit most from Cox-Maze
procedure\textsuperscript{23}.

Adjusted recurrence of AF at 12 months appeared comparable in a study by
Gillinov and colleagues (PVI 11\% vs. Cox-Maze 8\%), although patients
who underwent PVI had significantly shorter duration of preoperative AF
(Table 1) {[}18{]}. AF recurrence was significantly higher among
patients who underwent PVI in the study by Onorati and colleagues
(adjusted estimates PVI 35\% vs. Cox-Maze 17\%, risk ratio=2.13, 95\%CI
1.10-3.94) (Table 1) \textsuperscript{25}. Among additional reported
outcomes, the authors also demonstrated higher adjusted recurrence of AF
at 6 months, higher adjusted proportion of antiarrhythmics at 12 months,
and higher adjusted risk of death or hospitalization among patients who
underwent PVI \textsuperscript{25}. Furthermore, in the study of 324
patients who underwent isolated MV surgery, Stulak and colleagues
reported significantly higher recurrence of AF after 12-month follow-up
among patients who underwent concomitant PVI (30\% vs. 13\%
Cox-Maze)\textsuperscript{24}.

\textbf{4. Discussion}

The outcomes of concomitant Cox-Maze and PVI during MV surgery have been
extensively evaluated, but comparative data on the mortality and freedom
from AF are still limited. In this systematic review, we investigated
comparison of mid-term clinical outcomes between these two surgical
ablation techniques. Across most studies with included AF patients
undergoing MV surgery, concomitant Cox-Maze procedure was associated
with a higher freedom from AF at 12-month follow-up when compared with
concomitant PVI. Secondly, our systematic review suggested that RCTs
have demonstrated similar 12-month mortality between concomitant
Cox-Maze and PVI, while observational studies have shown survival
benefit of Cox-Maze at 12-month follow-up.

Importantly, several long-term studies demonstrated a survival benefit
of AF ablation surgery \textsuperscript{27}. Even more, risk-adjusted
analysis confirmed the safety of concomitant ablation surgery and found
that the additional procedure is not associated with increased Society
of Thoracic Surgeons morbidity or mortality \textsuperscript{1,28}.
Interestingly, Mehaffey and colleagues reported recently that surgeons
perform concomitant Cox-Maze IV surgery among 27-78\% of patients
depending on whether they reported barriers to implementation of
evidence-based recommendation \textsuperscript{29}. However, a clinical
practice guideline recommended that surgical ablation for symptomatic AF
in the setting of left atrial enlargement (\textgreater{}4.5 cm) and
more than moderate mitral regurgitation by PVI alone is not recommended
(Class III no benefit, Level C expert opinion) \textsuperscript{3}.

Although the association of concomitant Cox-Maze and freedom from AF is
evident, our results indicated that more RCTs with longer standardized
follow-up (at least 2-year) are required in order to clarify the
benefits of concomitant Cox-Maze in AF patients undergoing MV surgery.
In addition, institutional experience is of paramount importance due to
the fact that a center might have a higher morbidity or early
postoperative mortality while introducing the Cox-Maze technique.
Therefore, clear advantage of this technique remains valid for centers
with substantial experience in antiarrhythmic surgery. Furthermore, the
reviewed data strongly suggest that both XCT and CPB time did not seem
to be prolonged with concomitant Cox-Maze
procedure\textsuperscript{22,24,25}, although they were not consistently
reported across all the studies.

The benefit of concomitant Cox-Maze in mitral patients with AF is in
line with the results of other studies that have not only shown both
freedom from AF and mortality benefit, but have also demonstrated
improvement in quality of life \textsuperscript{30-33}. However, our
subgroup analysis with meta-analysis of RCTs did not suggest that there
is a significant survival benefit of concomitant Cox-Maze procedure
among RCTs. This can be explained by the fact that one of the RCTs was
potentially underpowered and biased as many cases were excluded from
randomization over the study period \textsuperscript{22}. Furthermore,
in the same RCT all patients with postoperative AF were intensely
treated in order to restore the sinus rhythm. However, it has also been
difficult to demonstrate a survival benefit in mitral patients after
concomitant Cox-Maze procedure in other reports \textsuperscript{34}.
This may be related to a few reasons such as limited cohorts and short
follow-up study periods in RCTs. On the other hand, several
observational studies with larger data sets have reported significant
survival benefits \textsuperscript{24,25}. However, given that AF has
been clearly demonstrated to be an independent predictor of mortality,
restoration of sinus rhythm is vital for quality of life and
survival.\textsuperscript{35}

Previous studies have also reported that the Cox-Maze procedure in AF
patients undergoing concomitant cardiac surgery has a potential
protective effect from stroke and thromboembolism in the long-term
period.{\textsuperscript{36}} Unfortunately, these clinical outcomes
along with other potential outcomes of interest (re-hospitalization,
permanent pacemaker implantation) were poorly reported in both RCTs and
observational studies included in this systematic review. The available
data from the studies included in our systematic review has demonstrated
that early postoperative morbidity related to the risk of stroke was not
increased with the performance of concomitant Cox-Maze
procedure.\textsuperscript{24,26} ~More importantly would be to see the
evidence in future trials whether restoration of sinus rhythm in these
patients with concomitant Cox-Maze procedure can improve long-term
survival and quality of life while reducing the risk of late stroke.
However, despite this reported efficacy of Cox-Maze, the widespread
acceptance has been limited due to the technical complexity of the
procedure and its possible complications such as the need for permanent
pacemaker.

Interestingly, we found concomitant Cox-Maze to be associated with
somewhat lower rates of MV repair. This can be partially explained by
the technical complexity of this procedure and, therefore, greater
likelihood of decision to proceed with valve replacement instead of
repair when considering performing more complex ablation procedure.
However, for optimal outcomes the surgeons should become more skilled in
the Cox-Maze technique through fellowship training, peer-to-peer
education, or proctorship \textsuperscript{3}.

There are certain limitations to this systematic review. Although all
the available literature has been examined, the quality of the studies
included must be considered. Several eligible studies were retrospective
cohort studies and only 3 RCTs comparing both concomitant ablation
procedures were found. Most studies did not report the outcomes of
long-term mortality (\textgreater{}12 months), postoperative stroke or
re-hospitalization rate due to AF as well as other relevant clinical
outcomes. {However, sufficient studies were available to evaluate
mid-term outcomes between both subgroups and standardized Cox-Maze
lesion set patterns were used in all the studies. On the other hand, the
available data was insufficient to allow a robust meta-analysis as a
primary goal of our study.} It is also well established that there is no
difference in outcomes between the cut-and-sew and a
cryoablation/bipolar technique of Cox-Maze
procedure\textsuperscript{37,38}. In addition, some studies did not
perform standardized follow-up screening for outcome assessment, nor did
they report antiarrhythmic and anticoagulation protocols, as recommended
by current professional organizations \textsuperscript{39-41}. In our
opinion, each patient should receive a standardized postoperative
treatment with amiodarone, if not contraindicated, for at least 6 weeks
of duration \textsuperscript{42,43}. The number of patients lost to
follow-up was not reported in all the studies, therefore the reported
outcomes might not reflect the true outcomes within the studies. Future
trials can be improved by adhering to this performance and reporting
standards to better evaluate the effect of concomitant AF surgery.
Therefore, we would like to emphasize that the standardized
postoperative follow-up protocol should include regular outpatient
visits during the first 24 months and annually
thereafter\textsuperscript{3}. A 12-lead electrocardiogram should be
obtained at every follow-up visit while a 24-hour Holter monitor at
every follow-up visit after 6 months, consistent with established
guidelines\textsuperscript{39,44}. Still, even with the follow-up Holter
monitoring, not all events may be captured. Long-term outcome assessment
may help evaluate whether type of concomitant AF surgery influences
mortality, neurological or thromboembolic risk, which are the primary
goals of AF treatment. Large high-quality randomized trials evaluating
the effect of different AF surgery types and lesion sets and comparing
outcomes within different AF subgroups could provide guidance about
which intervention has the most favorable efficacy and safety profile.

\textbf{5. Conclusions}

This systematic review found that concomitant Cox-Maze in AF patients
undergoing MV surgery is associated with a strong tendency of better
mid-term freedom from AF when compared to PVI with comparable mid-term
postoperative survival outcomes. Large observational studies suggested
that there might be a mid-term survival benefit for patients undergoing
concomitant Cox-Maze procedure, although large multicenter RCT are still
needed to assess the long-term survival benefit of Cox-Maze procedure.
Successful intraoperative ablation of AF improves outcomes and thus the
ideal operation would correct both MV dysfunction and AF.

\textbf{Ethical approval:} Not directly applicable since this is a
review article.

\textbf{Author contributions:} DS: conceptualization, formal analysis,
investigation, methodology, validation, resources, writing -- original
draft, critical revision and approval of the article. VT, SGR:
conceptualization, formal analysis, validation, resources, supervision,
writing -- reviewing and editing, critical revision and approval of the
article. JH: conceptualization, formal analysis, validation, resources.
MT: validation, supervision, writing -- reviewing and editing, critical
revision and approval of the article.

\textbf{Data Availability Statement:}

Data available on request due to privacy/ethical restrictions.

\textbf{Acknowledgments} : The authors would like to thank Prof. Dr.
Vinay Badhwar (Department of Cardiovascular and Thoracic Surgery, West
Virginia University, Morgantown, WV, USA) for providing his expert
opinion and constructive feedback in improving the article.

\textbf{FIGURE LEGENDS}

\textbf{Figure 1. PRISMA} (Preferred Reporting Items for Systematic
Reviews and Meta-analyses) flow diagram\textbf{.}

Abbreviation: RCT, randomized controlled trial.

\textbf{Figure 2.} Forest plot showing the effect of pulmonary vein
isolation (PVI) and Cox-Maze procedure for AF during the mitral valve
surgery on 12-month mortality and recurrence of AF in randomized
controlled trials.

Abbreviations: AF, atrial fibrillation; CI, confidence interval; M-H,
Mantel--Haenszel statistic; PVI, pulmonary vein isolation.

\textbf{Table 1:} Details of studies included in a systematic review.
Data are mean\selectlanguage{ngerman}±SD, count (\%).\selectlanguage{english}
\begin{longtable}[]{@{}lllllll@{}}
\toprule
\textbf{Characteristics} & \textbf{Blackstone et
al.\textsuperscript{21}} & \textbf{Albrecht et al.\textsuperscript{22}}
& \textbf{Srivastava et al.\textsuperscript{23}} & \textbf{Stulak et
al.\textsuperscript{24}} & \textbf{Onorati et al.\textsuperscript{25}} &
\textbf{Gillinov et al.\textsuperscript{26}}\tabularnewline
\midrule
\endhead
\textbf{Year} & 2019 & 2009 & 2008 & 2014 & 2011 & 2006\tabularnewline
\textbf{Country of origin} & USA & Brazil & India & USA & Italy &
USA\tabularnewline
\textbf{Type of study} & RCT & RCT & RCT & NRSI & NRSI &
NRSI\tabularnewline
\textbf{Study period} & 2010-2013 & 1999-2004 & 2000-2005 & 1993-2011 &
2003-2008 & 1993-2004\tabularnewline
\textbf{Follow-up, median, m} & 12 & 36 & 44 & 38 & 30 &
13.5\tabularnewline
\textbf{No. of patients} & & & & & &\tabularnewline
\textbf{Cox-Maze} & 66 & 20 & 40 & 256 & 109 & 41\tabularnewline
\textbf{PVI} & 67 & 20 & 40 & 68 & 32 & 31\tabularnewline
\selectlanguage{ngerman}\textbf{Age, mean±SD, y} & & & & & &\tabularnewline
\textbf{Cox-Maze} & 68.2\selectlanguage{ngerman}±10.4 & 51.7\selectlanguage{ngerman}±12.4 & 37.1\selectlanguage{ngerman}±11.1 & 62 & 64\selectlanguage{ngerman}±9 &
64\selectlanguage{ngerman}±9.3\tabularnewline
\textbf{PVI} & 71.3\selectlanguage{ngerman}±10.3 & 55.1\selectlanguage{ngerman}±9.2 & 40.9\selectlanguage{ngerman}±11.4 & 68 & 65\selectlanguage{ngerman}±8 &
66\selectlanguage{ngerman}±12\tabularnewline
\textbf{Female gender (\%)} & & & & & &\tabularnewline
\textbf{Cox-Maze} & 42.4 & 75 & 52.5 & NR & 28 & 51\tabularnewline
\textbf{PVI} & 43.3 & 70 & 50 & NR & 44 & 48\tabularnewline
\textbf{Longstanding persistent AF (\%)} & & & & & &\tabularnewline
\textbf{Cox-Maze} & 54.6 & 100 & 100 & 55 & 100 & *54m\tabularnewline
\textbf{PVI} & 50.8 & 100 & 100 & 19 & 100 & *3m\tabularnewline
\selectlanguage{ngerman}\textbf{XCT, mean±SD, min} & & & & & &\tabularnewline
\textbf{Cox-Maze} & 107.4\selectlanguage{ngerman}±44 & 78.5\selectlanguage{ngerman}±15.9 & NR & 59\selectlanguage{ngerman}±5 & 74\selectlanguage{ngerman}±6 &
NR\tabularnewline
\textbf{PVI} & 98.4\selectlanguage{ngerman}±38.7 & 74.8\selectlanguage{ngerman}±19.2 & NR & 65\selectlanguage{ngerman}±6 & 73\selectlanguage{ngerman}±7 &
NR\tabularnewline
\selectlanguage{ngerman}\textbf{CPB time, mean±SD, min} & & & & & &\tabularnewline
\textbf{Cox-Maze} & 152.4\selectlanguage{ngerman}±60.8 & 123\selectlanguage{ngerman}±21 & NR & 103\selectlanguage{ngerman}±7 & 112 &
NR\tabularnewline
\textbf{PVI} & 143.3\selectlanguage{ngerman}±65.9 & 99.9\selectlanguage{ngerman}±23.8 & NR & 90\selectlanguage{ngerman}±8 & 110 &
NR\tabularnewline
\textbf{Rate of MV repair (\%)} & & & & & &\tabularnewline
\textbf{Cox-Maze} & 56.1 & 55 & 2.5 & NR & 64 & 76\tabularnewline
\textbf{PVI} & 62.7 & 60 & 7.5 & NR & 72 & 68\tabularnewline
\textbf{LAAO (\%)} & & & & & &\tabularnewline
\textbf{Cox-Maze} & 100 & 100 & NR & 100 & 100 & 100\tabularnewline
\textbf{PVI} & 100 & 100 & NR & 70 & 100 & 100\tabularnewline
\textbf{Recurrence of AF at 12 m (\%)} & & & & & &\tabularnewline
\textbf{Cox-Maze} & 23 & 15 & 20 & 13 & 17 & 8\tabularnewline
\textbf{PVI} & 36 & 10 & 12.5 & 30 & 35 & 11\tabularnewline
\textbf{Mortality at 12 m (\%)} & & & & & &\tabularnewline
\textbf{Cox-Maze} & 6.1 & 15 & 10 & 2 & 1.4 & 2\tabularnewline
\textbf{PVI} & 7.5 & 5 & 10 & 10 & 6.0 & 2\tabularnewline
\textbf{Stroke at 12 m (\%)} & & & & & &\tabularnewline
\textbf{Cox-Maze} & 1.5 & NR & NR & 1 & NR & 2\tabularnewline
\textbf{PVI} & 4.5 & NR & NR & 1 & NR & 2\tabularnewline
\textbf{Follow-up monitoring protocol} & Transtelephonic monitoring &
ECG & ECG & ECG & 24h Holter ECG & ECG\tabularnewline
\bottomrule
\end{longtable}

*median; Abbreviations: AF=atrial fibrillation, CPB=cardiopulmonary
bypass, ECG=electrocardiogram, LAAO=left atrial appendage occlusion,
m=month, MV=mitral valve, NR=not reported, NRSI=nonrandomized study,
PVI=pulmonary vein isolation, RCT=randomized controlled trial, XCT=cross
clamp time

\textbf{Table 2} . Randomized controlled trials: main characteristics
and risk of bias assessment.\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
& \textbf{Srivastava 2008, India \textsuperscript{23}} &
\textbf{Albrecht 2009, Brazil \textsuperscript{22}} & \textbf{CTSN
2015/2019, USA \textsuperscript{13,21}}\tabularnewline
\midrule
\endhead
\textbf{General design} & Single-center, open-label, enrollment
2000-2005, 5-year follow-up with 3-month intervals; 4 treatment arms
including Cox-Maze IV and PVI. & Single-center, open-label, enrollment
1999-2004, 5-year follow-up with 6-month intervals; 3 treatment arms
including Cox-Maze III and PVI. & Multicentric, assessor-blind,
enrollment 2010-2013, 12-month follow-up with 3-month intervals; 3
treatment arms including Cox-Maze IV and PVI.\tabularnewline
\textbf{Patients} & Age 12-60 years, undergoing MV surgery, no active
CAD, no antiarrhythmics, LA [?]6 cm. & Age 18-79, LVEF \textgreater{}20\%,
undergoing MV surgery , no previous surgeries. & Age [?]18 years,
undergoing MV surgery, no previous ablations, no thyroid disease, life
expectancy \textgreater{}1 year.\tabularnewline
\textbf{Postoperatively} & If NSR not achieved: DC or amiodarone. & If
NSR not achieved: DC or amiodarone; anticoagulation as per indication. &
AAD first 3 months after surgery. Further ablation when needed. All
patients anticoagulated over 12-month period.\tabularnewline
\textbf{Declared endpoints} & Conversion to NSR, AF free survival at
1-year follow-up. & Not explicitly stated. & Primary: AF after 6 and 12
months (3-day Holter ECG). Secondary: composite of death, stroke, HF
hospitalization, NYHA class worsening and mitral valve reintervention;
mortality; need for rhythm-related interventions.\tabularnewline
\textbf{Patient evaluation} & Clinical symptoms, ECG, echo. & Clinical
symptoms, ECG, echo, treadmill. & Transtelephonic
monitoring.\tabularnewline
Risk of bias & & &\tabularnewline
\textbf{Randomization} & Some concern. & Some concern. & Low
risk.\tabularnewline
\textbf{Treatment deviations} & Some concern. & Some concern. & Low
risk.\tabularnewline
\textbf{Missing outcome data} & Low risk. & Low risk. & Low
risk.\tabularnewline
Other RoB2 biases\textsuperscript{1} & Low risk. & Low risk. & Low
risk.\tabularnewline
Overall risk of bias & Some concerns. & Some concerns. & Low
risk.\tabularnewline
\bottomrule
\end{longtable}

Abbreviations: AAD -- antiarrhythmic drugs, AF -- atrial fibrillation;
CAD -- coronary artery disease, DC -- direct cardioversion, ECG
--electrocardiography, HF -- heart failure, NYHA -- New Your Heart
Association, LA -- left atrium, LVEF -- left ventricular ejection
fraction, NSR -- normal sinus rhythm, OR -- operating room

\textsuperscript{1}Other RoB2 biases -- measurement of outcomes;
selection of reported results

\textbf{Table 3} . Observational (non-randomized controlled) studies:
main characteristics and risk of bias assessment.\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
& \textbf{Gillinov 2006, USA \textsuperscript{26}} & \textbf{Onorati
2011, Italy \textsuperscript{25}} & \textbf{Stulak 2014, USA
\textsuperscript{24}}\tabularnewline
\midrule
\endhead
\textbf{Declared objective} & Efficacy of treatment for paroxysmal AF
with concomitant MV surgery: Cox-Maze III, PVI and PVI with connecting
lesions. & Outcomes of ``limited'' (PVI) and ``extensive'' (Cox-Maze IV)
treatment for persistent AF with concomitant MV surgery. & Outcomes in
patients with surgically treated persistent/paroxysmal AF undergoing MV
surgery.\tabularnewline
\textbf{Outcomes} & Prevalence of AF at 1, 3, 6, 12 months and yearly
follow-up. & Prevalence of AF at 3, 6, 12, 18, 24 months and mid-term
mortality/hospitalizations. & Freedom from AF at 1, 1-5 and
\textgreater{}5-year follow-up.\tabularnewline
\textbf{General design} & Retrospective analysis of a single center
registry 1993-2004. Cox-Maze III (n=41), PVI (n=31)/PVI + left atrial
connection lesions (n=80). Standardized follow-up. & Prospective.
Consecutive patients (2003- 2008), concomitant PVI (n=32) and Cox-Maze
IV (n=105) during MV surgery. Standardized follow-up, 24-hour ECG
Holter. & Retrospective analysis of a single center registry 1993-2011.
Cox-Maze III (n=256) and PVI (n=68) with MV surgery as a subset of a
larger cohort.\tabularnewline
Risk of bias & & &\tabularnewline
\textbf{Confounding} & Low-moderate risk. Adjustment: demographic
characteristics, NYHA class, MV disease, AF duration, LV function, other
cardiac comorbidity, concomitant procedures. Chrono bias and
post-baseline confounding (AAD/anticoagulant use) possible. &
Low-moderate risk. PS baseline covariates: demographic characteristics,
AF duration, LV function, atrial size, habits, diabetes and other
comorbidity, previous surgery. Sextiles of PS stratification +
adjustment for AF at discharge. Chrono bias and post-baseline
confounding (AAD/anticoagulant use) possible. & Serious risk. Declared
use of a multivariable model, but no data on adjustments at all,
including the subset of interest: surgical treatment of AF + MV surgery.
Chrono bias and post-baseline confounding (AAD/anticoagulant use)
possible.\tabularnewline
\textbf{Selection bias} & Low risk. & Low risk. & Moderate
risk.\tabularnewline
\textbf{Missing data bias} & Low-moderate risk. & Low risk. & Moderate
risk.\tabularnewline
\textbf{Other biases\textsuperscript{1}} & Low risk. & Low risk. &
Moderate risk.\tabularnewline
\textbf{Overall risk of bias} & Moderate risk. & Moderate risk. &
Serious risk.\tabularnewline
\bottomrule
\end{longtable}

Abbreviations: AAD -- antiarrhythmic drugs, AF -- atrial fibrillation,
ECG -- electrocardiography, LV -- left ventricle, NYHA -- New York Heart
association, MV -- mitral valve, PS -- propensity score, PVI --pulmonary
vein isolation, RCT -- randomized controlled trial

\textsuperscript{1}Other ROBINS-I biases: misclassification, deviation
from intended treatments, measurement of outcomes, selection of reported
results

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\begin{figure}[H]
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\includegraphics[width=0.70\columnwidth]{figures/Figure-1-PRISMA/Figure-1-PRISMA}

\end{center}
\end{figure}\selectlanguage{english}
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\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-2-meta-analysis-RCTs/Figure-2-meta-analysis-RCTs}

\end{center}
\end{figure}

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