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\begin{document}

\title{Survival after aortic valve replacement vs. conservative management in
severe low-flow, low-gradient aortic stenosis}



\author[1]{Linda Renata Micali}%
\author[1]{Salma Emad Algaroosh}%
\author[1]{Orlando Parise}%
\author[1]{Francesco Matteucci}%
\author[1]{Gianmarco Parise}%
\author[1]{Monique de Jong}%
\author[1]{Amalia Ioanna Moula}%
\author[1]{Cecilia Tetta}%
\author[1]{Sandro Gelsomino}%
\affil[1]{Maastricht University}%


\vspace{-1em}



  
  \date{May 22, 2024}


\begingroup
\let\center\flushleft
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\selectlanguage{english}
\begin{abstract}
Background and aim. Classical and paradoxical low-flow, low-gradient
aortic stenosis (LFLGAS) are the most challenging aortic stenosis (AS)
subtypes. The current therapeutic options are aortic valve replacement
(AVR) and conservative management. The matter is controversial because
AVR promotes long-term survival, but it is invasive, while no aortic
valve replacement (noAVR) in non-invasive, but it is associated with
poor prognosis. This meta-analysis aims to investigate the survival rate
in patients with LFLGAS undergoing AVR versus noAVR interventions.
Methods. A meta-analysis was conducted comparing the outcomes of AVR and
noAVR in terms of survival. A meta-regression was carried out to
investigate the impact of preserved and reduced left ventricular
ejection fraction (LVEF) on survival in both the AVR and noAVR group.
Results. The log IRR of survival between AVR group and noAVR group was
0.58 {[}0.28, 0.87{]} (p-value = 0.0001), suggesting that survival is
significantly better in the AVR group compared to the noAVR group. The
meta-regression revealed that low LVEF is related to higher survival
rates in the AVR group (p-value = 0.04) when compared to preserved LVEF.
LVEF has no impact on survival in the noAVR group (p-value = 0.18).
Conclusions. Patients with LFLGAS have better survival in the AVR group
rather than in the noAVR group. Reduced LVEF was related to better
survival than preserved LVEF in the AVR, and no difference between low
and preserved LVEF was found in the noAVR group.%
\end{abstract}%



\sloppy


\section*{Introduction}

{\label{introduction}}

Low-flow, low-gradient aortic stenosis (LFLGAS) is the most challenging
aortic stenosis (AS) subtype, regardless of whether it is accompanied by
either depressed left ventricular ejection fraction (LVEF) or preserved
LVEF\textsuperscript{1,2}. The challenge derives from the inconsistency
between aortic valve area (AVA) and gradient, which does not allow a
realistic evaluation of the entity of the stenosis, fundamental in
choosing the right therapeutic approach \textsuperscript{3}.

Currently, the available therapeutic managements for LFLFAS are aortic
valve replacement (AVR) in symptomatic patients with left ventricular
(LV) dysfunction, and conservative management \textsuperscript{4}. AVR
promotes long-term survival and improvement of the functional status of
patients in both classical and paradoxical LFLGAS. Still, it is more
invasive, and it is associated with high operative mortality risk in
patients with reduced LV contractile reserve \textsuperscript{4-7}. On
the other hand, a noAVR approach mainly via medical management is
considered the treatment of choice in elderly patients and subjects with
high preoperative risk, as it is not invasive \textsuperscript{8}.
However, noAVR approaches predispose patients to a poorer prognosis in
both classical and paradoxical LFLGAS \textsuperscript{8}.

Since noAVR approach leads to a poor prognosis and AVR is burdened by a
high operative risk, literature reports controversial results about the
superiority of one type of management over the other.

Therefore, this meta-analysis aims to investigate the survival rate in
patients with LFLGAS undergoing AVR versus noAVR interventions.

\section*{Materials and methods}

{\label{materials-and-methods}}

\subsection*{Search strategy}

{\label{search-strategy}}

We conducted our study using the Preferred Reporting Items for
Systematic Reviews and Meta-Analyses (PRISMA) investigation guidelines.
We searched for all available articles that reported the survival rate
in patients with LF LG AS following either AVR or no
AVR\textsuperscript{9}. A literature search was conducted in Embase and
Medline databases through PubMed, as well as Google Scholar and Cochrane
library. Moreover, we checked the relevant articles which are suggested
on those databases as well as the references of the selected materials.
We used both free text words and MeSH terms.

The search terms were ``Therapy/Broad{[}filter{]}'' AND ``Aortic Valve
Stenosis'' OR ``Aortic Valve Stenosis {[}MeSH Terms{]}'' OR ``Aortic
Stenosis'' OR ``Aortic Stenosis {[}MeSH Terms{]}'' AND ``Low Flow'' OR
``Low-Flow'' AND ``Low Gradient'' OR ``Low-Gradient'' AND ``Aortic Valve
Replacement'' OR ``Aortic Valve Replacement {[}MeSH Terms{]}'' AND
``Conservative Management'' OR Conservative Management {[}MeSH
Terms{]}'' OR ``Medical Treatment'' OR ``Medical Treatment {[}MeSH
Terms{]}'' AND ``Surgical Intervention'' OR ``Surgical Intervention
{[}MeSH Terms{]}'' AND ``Low-Flow Low-Gradient'' OR Low Flow Low
Gradient.''

\subsection*{}

{\label{section}}

\subsection*{Selection criteria}

{\label{selection-criteria}}

We included articles that met the following criteria: (a) performed on
humans, (b) studies with more than 20 patients, (c) articles comparing
AVR to noAVR procedures, (d) articles focused on LF LG AS, (e) studies
published in English and (f) articles published within the last 15 years
(2004 - 2019). On the other hand, we excluded articles with the
following conditions: (a) performed on animals, (b) not in English, (c)
case reports (d) literature reviews and meta-analyses, (e) population
study of 20 or less, (f) articles that are older than 15 years, (g)
studies not focusing on LFLGAS (h) studies which did not report a
comparison between AVR and no AVR.

\subsection*{}

{\label{section-1}}

\subsection*{Methodological quality
assessment}

{\label{methodological-quality-assessment}}

To assess the quality of the included studies, we used a modified tool
of Down and Black's Checklist for Measuring Quality\textsuperscript{10}.
This tool consists of 18 questions evaluating five criteria: (a) the
overall quality of the study, (b) the external validity, (c) study bias,
(d) confounding and selection bias, and (e) power of the study. Each
question is graded on a binary basis (0 or 1) except for two items,
ranked out of 2 and out of 5, respectively.

Two researchers (SA And LM) conducted the evaluation. A third researcher
was involved in reviewing (OP). The agreement was quantified using
Cohen's kappa \textsuperscript{11}.

\subsection*{}

{\label{section-2}}

\subsection*{Endpoints}

{\label{endpoints}}

\subsection*{}

{\label{section-3}}

The primary endpoint of our study was the survival rate at follow up in
patients with LFLG AS, treated with AVR or noAVR. Also, we aimed to
investigate the impact of LVEF on survival. In the AVR group, we
included both surgical valve replacement (SAVR) and transcatheter valve
replacement (TAVR), while in the no AVR group, we included conservative
medical management and valvuloplasty\textsuperscript{3}.

LFLGAS was defined as an aortic valve area (AVA) of [?]1
cm\textsuperscript{2} or indexed AVA \textless{}0.6
cm\textsuperscript{2}/m\textsuperscript{2}, a stroke volume indexed
(SVI) [?] 35 mL/m\textsuperscript{2} and a transvalvular mean pressure
gradient [?] 40 mmHg. Preserved LVEF was identified as \textgreater{} 55\%
(paradoxical LFLGAS), while reduced LVEF was defined as \textless{} 50\%
(classical LFLGAS) \textsuperscript{3}.

\subsection*{Statistical analysis}

{\label{statistical-analysis}}

This meta-analysis was conducted using V.3.6.1 (R Foundation for
Statistical Computing, Vienna, Austria). We used Incidence Rate (IR) and
proportions as main statistical indexes. Since the follow-up time was
different in each article, we employed the IR test to analyze survival
rates in both groups. Heterogeneity was evaluated by using the I-square
test, and the publication bias was evaluated by using the Egger
regression test. Furthermore, meta-regression was performed to evaluate
the impact of LVEF on survival in both AVR and the noAVR group. We
defined statistical significance for P values \textless{} 0.05.

\section*{Results}

{\label{results}}

\subsection*{Characteristics of the
studies}

{\label{characteristics-of-the-studies}}

The steps that we followed in selecting the articles are shown in the
PRISMA flow diagram in \textbf{Figure 1} . In total, we found 49
articles. After the selection process, we retrieved four papers, and
nine articles were added manually from the references of the formers. In
the end, the final number of the included in our meta-analysis was 13
articles \textsuperscript{14-26}.

The overall population size was 2,013 patients, 1,066 (53\%), and 947
(47\%) in the AVR and noAVR group, respectively. The baseline
characteristics of the included patients are shown in \textbf{Table 1} .
Twelve papers defined whether their cohort of patients presented
preserved or reduced LVEF \textsuperscript{14-21,23-26}. Out of 1,533
patients, 952 (62.1\%) patients had preserved LVEF, and 581 (37.9\%) had
low LVEF. The mean age of the total population was 74.9 {[}73.3-76.6{]}
years old \textsuperscript{14-18,20-23,25,26}, particularly 73.2
{[}69.7-76.7{]} years old in the AVR group and 77.7 {[}74.8-80.7{]}
years old in the noAVR group. Overall AVA was 0.81 {[}0.77-0.84{]}
cm\textsuperscript{2} \textsuperscript{14-18,20-23,26}; overall mean
gradients was 27.21 {[}24.43-29.98{]}
mmHg\textsuperscript{14-18,20-23,26}; overall SVI was 34.82 {[}27.61-
42.04{]} mL/m\textsuperscript{2} \textsuperscript{15-18,20,21,23,26}.

The determination of the number of patients undergoing either SAVR or
TAVR was conducted on 11 papers \textsuperscript{14-21,23,25,26}. The
number of patients treated with SAVR was 607 (81.7\%), while 136
(18.3\%) patients received TAVR (\textbf{Table 2} ). In the noAVR group,
the majority of patients were treated medically rather than with
valvuloplasty (99.9\% vs. 0.1\%).

\par\null

Methodological quality

The average overall quality rating was 0.81 \selectlanguage{ngerman}± 0.53, with ratings ranging
from 0 to 1.81. \textbf{Appendix A} illustrates the average scores on
the elements of the checklist. The analysis revealed lower scores
related to the internal validity for both bias and selection bias, and
for power analysis, which is related to the quality of reporting. The
low values shown are due to the study type being a retrospective with no
randomized samples validity studies. Acceptable interrater agreement was
found (\selectlanguage{greek}κ \selectlanguage{english}= 0.89; \%-agree = 94.9).

\subsection*{}

{\label{section-4}}

\subsection*{Follow up}

{\label{follow-up}}

The mean follow up period, calculated in 9 papers, was 35.66 {[}27.50-
43.81{]} months \textsuperscript{14-18,20,21,25,26}. The longest follow
up period was 55.2 months \textsuperscript{17}. Follow up was 100\%
complete in 9 studies \textsuperscript{14-17,19,20,23-25}.

\subsection*{Main endpoints}

{\label{main-endpoints}}

\textbf{Figure 2A} shows that the log IRR of survival between AVR group
and noAVR group was 0.58 {[}0.28, 0.87{]} (p-value = 0.0001; I-square =
24.16\%, p-value = 0.25; Egger's test: 0.18 {[}-0.18, 0.55{]}, p-value =
0.002). This suggests that the overall survival is significantly better
in the AVR group compared to the noAVR group. The funnel plot is shown
in \textbf{Figure 2B} (funnel plot asymmetry test: p-value = 0.10).
Moreover, the meta regression revealed that low LVEF is related to
higher survival rates in the AVR group (p-value = 0.04) when compared to
preserved LVEF (\textbf{Figure 3A} ). Conversely, LVEF has no impact on
survival in the noAVR group (p-value = 0.18), as shown in \textbf{Figure
3B} .



\section*{Discussion}

{\label{discussion}}

Low flow, low gradient aortic stenosis (LFLGAS) is associated with a
higher risk of a cardiac event and heart failure, increasing the rate of
all-cause mortality, cardiovascular- and valvular-related
death\textsuperscript{27}. Aortic valve replacement (AVR) is effective
in either classical or paradoxical LFLGAS \textsuperscript{28}. AVR has
shown to be able to reduce the rate of adverse events and improve left
ventricle ejection fraction (LVEF), enhancing long-term survival when
compared to non-aortic valve replacement (noAVR) approaches. However, in
patients with concomitant coronary artery disease (CAD and reduced
contractile reserve (CR), the preoperative risk is too high to opt for
AVR \textsuperscript{29,30}. In these cases, medical management is the
recommended alternative approach, despite its reduced long-term survival
rates \textsuperscript{31}. The aim of techniques alternative to AVR is
to treat patients who are inoperable because of concomitant
life-threatening comorbidities and the reduced life
expectancy\textsuperscript{32}. The therapy has more palliative
purposes, and it is per se related to complications such as stroke,
aortic regurgitation, myocardial infarction \textsuperscript{33},
restenosis, and deterioration of the aortic valve (AV)
\textsuperscript{34,35}.

The main finding of your meta-analysis is the superiority of AVR over
noAVR in enhancing survival in patients with LFLGAS. Our result is
consistent with studies reporting improved outcomes following AVR rather
than noAVR \textsuperscript{36}. AVR bears an elevated preoperative
risk, but its benefits still outweigh the disadvantages when compared to
noAVR. This is attributable to the fact that in high-risk patients with
low life expectancy, medication with or without valvuloplasty represents
a mere palliative cure not aimed at achieving therapeutic responses.
NoAVR approach is mainly oriented towards the management of the
cardiovascular risk factors, which include controlling hypertension and
volume status. Furthermore, the low survival rate in the noAVR group
could be the result of the increased risk of restenosis after
valvuloplasty, which leads to deterioration of the valve already after
one year\textsuperscript{37,38}. Indeed, if, on the one hand,
valvuloplasty reduces the transvalvular pressure gradient and improves
symptoms, on the other hand, the post-valvuloplasty AVA does not exceed
1.0 cm\textsuperscript{2} \textsuperscript{33,39}. Moreover, our result
could have been influenced by the employment of the TAVR technique in
some of the patients included in our analysis, as TAVR has better
survival rates than SAVR as well as better LVEF
recovery\textsuperscript{3,40,41}.

The second finding of our meta-analysis was the increased survival at
follow up in patients with reduced LVEF compared to those with preserved
LVEF in the AVR group. Despite this could be initially counterintuitive,
it is critical to acknowledge that it has been widely proved that LV
dysfunction is present even with preserved LVEF. Indeed, studies
employing speckle-tracking echocardiography have shown that in patients
with LFLGAS and normal LVEF, LV systolic longitudinal dysfunction
manifests as a result of the increased afterload \textsuperscript{12}.
Additionally, in patients with a low LVEF undergoing coronary artery
bypass grafting (CABG) concomitantly to AVR, long-term survival appears
to be enhanced. CABG makes the myocardium in certain areas viable,
increasing LV function, and exerting a protective
effect\textsuperscript{35,42} leading to an improvement in LVEF that was
reduced consequently to CAD.

Being the majority of the patients in our meta-analysis operated on
AVR+CABG, we believe that the simultaneous CABG procedure might have
been beneficial for patients with low LVEF \textsuperscript{2}.

Furthermore, we found that LVEF does not impact survival in the noAVR
group. We believe that these results are attributable to the fact that
conservative management has palliative purposes, thus not improving
cardiac function but only dealing with symptoms \textsuperscript{31}.
This is because both classical and paradoxical LFLGAS can induce heart
failure via different mechanisms. Patients with classical LFLGAS have
low survival rates as the cardiac function is severely compromised by
the small LV cavity size due to LV hypertrophy, severe myocardial
fibrosis, and the restrictive pattern of LV filling \textsuperscript{2}.
On the other hand, some studies suggest that conservative management is
not particularly useful in increasing survival in the case of
paradoxical LFLGAS as a result of the advanced stage of myocardial
fibrosis, the systolic and diastolic dysfunction and the reduced stroke
volume index \textsuperscript{2}. Moreover, patients with paradoxical
aortic stenosis mostly have diffused atherosclerosis and increased
stiffness of arterial walls, which decreases arterial
compliance\textsuperscript{2}. In this situation, medical management is
only useful in treating resulting hypertension rather than affecting the
aortic valve \textsuperscript{3}.

\section*{Limitation}

{\label{limitation}}

This meta-analysis has some limitations that need to be addressed.
First, the number of patients is not high enough to draw definite
conclusions. Second, the majority of papers were retrospective studies,
so this might have led to inherent selection bias. Third, one included
review was an abstract so that we could retrieve limited data from it.
Fourth, the papers about reduced LVEF and preserved LVEF were not evenly
distributed.



\section*{Conclusion}

{\label{conclusion}}

Patients with LFLGAS have a better survival rate following AVR rather
than noAVR. Besides, patients with reduced LVEF seemed to have better
survival than patients with preserved LVEF in the AVR group. No
difference between low and protected LVEF was found in the noAVR group.

\textbf{Acknowledgments:} We thank Dr Judith Wilson for the English
revision of the paper.

\textbf{Funding:} None

\textbf{Conflict of Interest:} None to be disclosed



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and severe left ventricular dysfunction. \emph{J Am Coll
Cardiol.}2002;39(8):1356-1363.

37. Cribier A, Eltchaninoff H, Tron C, et al. Treatment of calcific
aortic stenosis with the percutaneous heart valve: mid-term follow-up
from the initial feasibility studies: the French experience. \emph{J Am
Coll Cardiol.} 2006;47(6):1214-1223.

38. Letac B, Cribier A, Eltchaninoff H, Koning R, Derumeaux G.
Evaluation of restenosis after balloon dilatation in adult aortic
stenosis by repeat catheterization. \emph{American heart
journal.}1991;122(1):55-60.

39. Lieberman EB, Bashore TM, Hermiller JB, et al. Balloon aortic
valvuloplasty in adults: failure of procedure to improve long-term
survival. \emph{J Am Coll Cardiol.} 1995;26(6):1522-1528.

40. Ben-Dor I, Maluenda G, Iyasu GD, et al. Comparison of outcome of
higher versus lower transvalvular gradients in patients with severe
aortic stenosis and low (\textless{} 40\%) left ventricular ejection
fraction. \emph{The American journal of
cardiology.}2012;109(7):1031-1037.

41. Clavel M-A, Webb JG, Rodés-Cabau J, et al. Comparison between
transcatheter and surgical prosthetic valve implantation in patients
with severe aortic stenosis and reduced left ventricular ejection
fraction. \emph{Circulation.} 2010;122(19):1928-1936.

42. Sathyamurthy I, Jayanthi K. Low flow low gradient aortic stenosis:
clinical pathways. \emph{Indian Heart J.} 2014;66(6):672-677.

\textbf{Table 1} . Patients' characteristics\selectlanguage{english}
\begin{longtable}[]{@{}llllllllllllllll@{}}
\toprule
\begin{minipage}[b]{0.06\columnwidth}\raggedright\strut
\textbf{Author (year)}\strut
\end{minipage} & \begin{minipage}[b]{0.06\columnwidth}\raggedright\strut
\textbf{Study design}\strut
\end{minipage} & \begin{minipage}[b]{0.06\columnwidth}\raggedright\strut
\textbf{No. patients}\strut
\end{minipage} & \begin{minipage}[b]{0.06\columnwidth}\raggedright\strut
\textbf{No. patients}\strut
\end{minipage} & \begin{minipage}[b]{0.06\columnwidth}\raggedright\strut
\textbf{No. patients}\strut
\end{minipage} & \begin{minipage}[b]{0.06\columnwidth}\raggedright\strut
\textbf{No. patients}\strut
\end{minipage} & \begin{minipage}[b]{0.06\columnwidth}\raggedright\strut
\textbf{Age}\strut
\end{minipage} & \begin{minipage}[b]{0.06\columnwidth}\raggedright\strut
\textbf{Female}\strut
\end{minipage} & \begin{minipage}[b]{0.06\columnwidth}\raggedright\strut
\textbf{Symptoms}\strut
\end{minipage} & \begin{minipage}[b]{0.06\columnwidth}\raggedright\strut
\textbf{AVA (cm\textsuperscript{2})}\strut
\end{minipage} & \begin{minipage}[b]{0.06\columnwidth}\raggedright\strut
\textbf{SVi (mL/m\textsuperscript{2})}\strut
\end{minipage} & \begin{minipage}[b]{0.06\columnwidth}\raggedright\strut
\textbf{Mean gradient (mmHg)}\strut
\end{minipage} & \begin{minipage}[b]{0.06\columnwidth}\raggedright\strut
\textbf{LVEF (\%)}\strut
\end{minipage} & \begin{minipage}[b]{0.06\columnwidth}\raggedright\strut
\textbf{Classical LFLGAS/Paradoxical LFLGAS}\strut
\end{minipage} & \begin{minipage}[b]{0.06\columnwidth}\raggedright\strut
\textbf{CAD}\strut
\end{minipage} & \begin{minipage}[b]{0.06\columnwidth}\raggedright\strut
\textbf{Follow up} \textbf{(months)}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
\textbf{AVR}\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
\textbf{AVR}\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
\textbf{noAVR}\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
Hachicha et al. (2007)\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
RCS\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
171\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
80\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
91\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
91\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
73\selectlanguage{ngerman}±13\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
92 (51)\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
0.76\selectlanguage{ngerman}±0.23\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
32\selectlanguage{ngerman}±17\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
62\selectlanguage{ngerman}±8\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
Paradoxical LFLGAS\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
46 (65)\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
60*\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
Clavel et al. (2008)\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
MPOS\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
101\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
44\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
57\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
57\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
71\selectlanguage{ngerman}±10\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
23 (23)\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
49 (49)\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
0.92\selectlanguage{ngerman}±0.24\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
21\selectlanguage{ngerman}±8\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
29\selectlanguage{ngerman}±9\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
Classical LFLGAS\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
76 (75)\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
20\selectlanguage{ngerman}±15\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
Pai et al. (2008)\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
RCS\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
167\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
46\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
121\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
121\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
72\selectlanguage{ngerman}±13\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
Classical LFLGAS: 115 (68.9) Paradoxical LFLGAS: 52 (31.1)\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
28.8\selectlanguage{ngerman}±32.4\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
Tarantini et al. (2011)\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
RCS\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
101\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
72\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
29\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
29\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
78 {[}72--81{]}\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
59 (58)\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
90 (88)\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
0.80 {[}0.70-0.89{]}\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
46 \selectlanguage{ngerman}±13\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
33 {[}27--38{]}\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
0.69 {[}0.61--0.74{]}\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
Paradoxical LFLGAS\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
63 (62.4)\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
42 {[}23-75{]}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
Clavel et al. (2012)\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
RCS\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
187\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
83\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
104\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
104\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
74 \selectlanguage{ngerman}±12\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
96 (51)\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
44 (22)+ 104 (56)++\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
0.82 \selectlanguage{ngerman}± 0.16\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
30 \selectlanguage{ngerman}± 4\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
22\selectlanguage{ngerman}±8\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
62\selectlanguage{ngerman}±8\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
Paradoxical LFLGAS\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
120 (64)\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
50.4\selectlanguage{ngerman}±28.8\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
Mohty et al. (2013)\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
RCS\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
99\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
83\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
16\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
16\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
77\selectlanguage{ngerman}±6\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
50 (51)\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
88 (89)\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
0.72\selectlanguage{ngerman}±0.17\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
29\selectlanguage{ngerman}±5\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
30\selectlanguage{ngerman}±7\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
70\selectlanguage{ngerman}±11\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
Paradoxical LFLGAS\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
54 (54.5)\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
55.2\selectlanguage{ngerman}±36\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
Melis et al. (2013)\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
RCS\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
40\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
18\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
22\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
22\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
78 {[}73.0-83.0{]}\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
25 (59.5)\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
0.77 {[}0.73-0.81{]}\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
31 {[}30-32{]}\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
26 {[}24-29{]}\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
64 {[}62-67{]}\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
Paradoxical LFLGAS\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
22 (55)\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
26.1 {[}14.6-36.1{]}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
Herrmann et al. (2013)\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
RCS\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
130\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
105\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
25\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
25\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
Classical LFLGAS\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
24*\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
Eleid et al. (2013)\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
RCS\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
53\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
27\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
26\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
26\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
77\selectlanguage{ngerman}±12\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
18 (34)\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
41 (77)\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
0.87\selectlanguage{ngerman}±0.11\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
31\selectlanguage{ngerman}±3\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
30\selectlanguage{ngerman}±6\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
60\selectlanguage{ngerman}±7\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
Paradoxical LFLGAS\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
23 (43)\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
27.6\selectlanguage{ngerman}±22.8\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
Ozkan et al. (2013)\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
PCS\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
135\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
54\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
81\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
81\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
Paradoxical LFLGAS\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
60*\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
Tribouilloy et al. (2015)\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
RCS\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
114\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
57\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
57\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
57\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
78.5 {[}73.5--86.3{]}\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
33 (57.9)\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
9 (15.8)\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
0.8 {[}0.7--0.9{]}\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
30.1 {[}27.2--32.2{]}\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
30 {[}20.5--34.5{]}\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
60 {[}55--67{]}\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
Paradoxical LFLGAS\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
22 (13.3)\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
39 {[}11-69{]}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
Annabi et al. (2019)\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
PCS\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
480\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
269\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
211\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
211\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
75 \selectlanguage{ngerman}± 10\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
136 (28.3)\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
0.79\selectlanguage{ngerman}±0.15\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
26\selectlanguage{ngerman}±7\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
Classical LFLGAS: 341 (71) Paradoxical LFLGAS: 139 (29)\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.06\columnwidth}\raggedright\strut
36*\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
Sato et al. (2019)\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
ROS\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
235\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
128\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
107\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
107\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
80 {[}73--85{]}\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
61 (26)\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
0.75 {[}0.65--0.92{]}\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
25 {[}20--33{]}\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
22\selectlanguage{ngerman}±7\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
29 {[}23--37{]}\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
Classical LFLGAS\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
172 (74)\strut
\end{minipage} & \begin{minipage}[t]{0.04\columnwidth}\raggedright\strut
27.6 {[}8.4-44.4{]}\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

Values are expressed as mean\selectlanguage{ngerman}±standard deviation, median {[}interquartile
range{]} or number (\%). Abbreviations: No= Number, AVR= Aortic Valve
Replacement, AVA= Aortic Valve Area, SVI= Stroke Volume Index, LVEF=
Left Ventricle Ejection Fraction, LFLGAS= Low-Flow, Low-Gradient Aortic
Stenosis, CAD= Coronary Artery Disease, MCD= Multivessel Coronary
Disease, RCS= Retrospective Cohort Study, MPOS= Multicenter Prospective
Observational Study, ROS= Retrospective Observational Study. * maximum
follow up, \selectlanguage{english}+mild symptoms, \selectlanguage{english}++ moderate/severe symptoms.\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
\begin{minipage}[b]{0.17\columnwidth}\raggedright\strut
\textbf{Author (year)}\strut
\end{minipage} & \begin{minipage}[b]{0.17\columnwidth}\raggedright\strut
\textbf{AVR}\strut
\end{minipage} & \begin{minipage}[b]{0.17\columnwidth}\raggedright\strut
\textbf{AVR}\strut
\end{minipage} & \begin{minipage}[b]{0.17\columnwidth}\raggedright\strut
\textbf{AVR}\strut
\end{minipage} & \begin{minipage}[b]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{TAVR/SAVR}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{Concomitant CABG}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{Operative mortality}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{Operative mortality}\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Hachicha et al. (2007)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
SAVR\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
-\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Clavel et al. (2008)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
SAVR\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
30 (68.2)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
-\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Pai et al. (2008)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
SAVR\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
-\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Tarantini et al. (2011)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
SAVR\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
38 (52)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
2 (2.7)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
2 (2.7)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Clavel et al. (2012)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
SAVR\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
44 (53)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
-\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Mohty et al. (2013)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
SAVR\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
8 (9.8)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
8 (9.8)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Melis et al. (2013)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
SAVR\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
1 (5.6)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
1 (5.6)\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Herrmann et al. (2013)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
SAVR: 56 (53.3) TAVR: 49 (46.7)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
-\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Eleid et al. (2013)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
SAVR 26 (98) TAVR 1 (2)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
12 (23)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
-\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Ozkan et al. (2013)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
SAVR: NS TAVR: NS\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
-\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Tribouilloy et al. (2015)\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
SAVR\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
-\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Annabi et al. (2019)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
SAVR: NS TAVR: NS\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
-\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
Sato et al. (2019)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
SAVR: 42 (32.8) TAVR: 86 (67.2)\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
-\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\textbf{Table 2.} Surgical data of AVR

Values are expressed as number (\%). Abbreviations: AVR= Aortic Valve
Replacement, SAVR = Surgical Aortic Valve Replacement, TAVR =
Transcatheter Aortic Valve Replacement, CABG= Coronary Artery Bypass
Grafting.

\section*{Figures Legend}

{\label{figures-legend}}

\textbf{Figure 1.} PRISMA flowchart of the selection process

\textbf{Figure 2.} Survival AVR vs noAVR. \textbf{A.} Forest
plot.\textbf{B.} Funnel plot. *LVEF\textless{} 35\%; **LVEF between 35\%
and 54\%; ***LVEF \textgreater{} 55\%.

\textbf{Figure 3} . Meta regression on the impact of LVEF on survival
in\textbf{A} . AVR and \textbf{B.} noAVR

\par\null

\section*{Appendix A. Quality
assessment}

{\label{appendix-a.-quality-assessment}}\selectlanguage{english}
\begin{longtable}[]{@{}llll@{}}
\toprule
\begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
\textbf{Item}\strut
\end{minipage} & \begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
\textbf{Mean}\strut
\end{minipage} & \begin{minipage}[b]{0.22\columnwidth}\raggedright\strut
\textbf{SD}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
1\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Study hypothesis/aim/objective described?\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.92\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.27\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
2\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Main outcomes described in the introduction or methods?\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1.00\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.00\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
3\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Participant characteristics described?\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
1.00\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.00\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
4\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Contacted participants representative?\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.04\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.20\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
5\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Prepared participants representative?\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.08\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.27\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
6\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Participants recruited from the same population?\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.50\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.51\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
7\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Participants recruited over the same time?\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.71\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.46\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
8\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Measures and experimental tasks described?\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.83\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.38\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
9\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Main outcome measures valid and reliable?\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
1.00\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.00\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
10\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Task engagement assessed?\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.33\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.48\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
11\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Confounders described and controlled for?\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
1.81\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.57\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
12\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Statistical tests appropriate?\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
1.00\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.00\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
13\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Main findings described?\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
1.00\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.00\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
14\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
Estimates of the random variability in data main outcomes?\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
1.00\strut
\end{minipage} & \begin{minipage}[t]{0.24\columnwidth}\raggedright\strut
0.00\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
15\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Probability values reported?\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.96\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.20\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
16\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Withdrawals and drop-outs reported?\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.27\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.45\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
17\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Data dredging made clear?\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.86\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.35\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
18\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
Sufficient power analysis provided?\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.00\strut
\end{minipage} & \begin{minipage}[t]{0.22\columnwidth}\raggedright\strut
0.00\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}\selectlanguage{english}
\begin{figure}[H]
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\includegraphics[width=0.70\columnwidth]{figures/Figure-1/Figure-1}

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

\end{center}
\end{figure}\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/Figure-3/Figure-3}

\end{center}
\end{figure}

\selectlanguage{english}
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