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\begin{document}

\title{Clinical outcome after bioprosthetic aortic root replacement: A
Meta-Analysis and Microsimulation model}



\author[1]{Bardia Arabkhani}%
\author[2]{Jonathan Etnel}%
\author[3]{Michiel Vriesendorp}%
\author[4]{Richard van Valen}%
\author[5]{Emmanuel Lansac}%
\author[6]{Thomas van Brakel}%
\author[4]{Ad Bogers}%
\author[7]{hanneke takkenberg}%
\affil[1]{Leiden University Medical Center}%
\affil[2]{Erasmus University Rotterdam}%
\affil[3]{LUMC}%
\affil[4]{ErasmusMC}%
\affil[5]{Institut Mutualiste Montsouris}%
\affil[6]{Leiden Universitair Medisch Centrum}%
\affil[7]{Erasmus MC}%


\vspace{-1em}



  
  \date{June 05, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
Background and aim of the study This study aims to provide an overview
of clinical outcome after bioprosthetic aortic root replacement and
lifetime event-risk estimates of mortality and valve-related events, and
the potential effect of type of prosthesis used. Methods A systematic
literature search was conducted between January 2000 and August 2019.
Inclusion criteria: aortic root replacement in adults. Data were pooled
by inverse-variance weighting and entered a microsimulation model to
calculate lifetime event-risk and (event-free) life expectancy. Results
Of 2.106 publications, 31 were included (N = 5.227 patients, 74\%
stentless valves). Mean age was 65.4 years (74\% male). Pooled early
mortality was 5.5\% (95\% CI: 4.3-7.2\%). During follow-up (mean 4.1
years, total 22.706 patient-years), late mortality was
4.8\%/patient-year and reoperation 0.9\%/patient-year.
Linearized-occurrence-rates for thromboembolism, endocarditis, and
hemorrhagic events:1.2; 0.9 and 0.5 \%/patient-year; no significant
difference between stented and stentless prosthesis. Translating into a
60-year-old patient, an estimated life expectancy of 14 years (general
population: 22 years) and lifetime risks of thromboembolism,
endocarditis and reintervention of 21\%, 13\%, and 8\%, respectively is
expected. Conclusions The study shows impaired survival and a notable
lifetime risk of valve-related events after bioprosthetic aortic root
replacement. The risk of thromboembolism is prominent, especially during
earlier follow-up, suggesting higher risk of thromboembolism early after
operation. Type of prosthesis, stented or stentless, is not associated
with higher valve-related events. Moreover, this study could be used as
a benchmark to compare outcome with other aortic root replacement
procedures.%
\end{abstract}%



\sloppy


\textbf{TITLE:} Clinical outcome after bioprosthetic aortic root
replacement: A Meta-Analysis and Microsimulation model

\textbf{Running title:} Bioprosthetic aortic root replacement

Bardia Arabkhani MD, PHD\selectlanguage{ngerman}¹\textsuperscript{,2}, Jonathan RG Etnel MD¹,
Michiel Vriesendorp MD\textsuperscript{2}, Richard van Valen MA, PHD¹,
Emmanuel Lansac MD, PhD\textsuperscript{3}, Thomas J. van Brakel MD,
PhD\textsuperscript{2}, Ad JJC Bogers MD, PhD¹, Johanna JM Takkenberg
MD, PhD¹

\textsuperscript{1} Erasmus University Medical Center, Rotterdam, The
Netherlands; \textsuperscript{2} Leiden University Medical Center, The
Netherlands \textsuperscript{3} Institut Mutualiste Montsouris, Paris,
France

* Address for correspondence

B. Arabkhani

E-mail: b.arabkhani@lumc.nl Postal address:

Department of Cardio-Thoracic Surgery, D-06-13

Leiden University Medical Centre

Albinusdreef 2, 2333 ZA Leiden, The Netherlands

Tel.: 0031 71 5264022

Keywords: Aortic root, Biological valve, Bioprostheses, Bio-Bentall,
Stented, Stentless

Abstract: 241

Text and references: 5,762

No funding



\textbf{ABSTRACT}

\emph{Background and aim of the study} This study aims to provide an
overview of clinical outcome after bioprosthetic aortic root replacement
and lifetime event-risk estimates of mortality and valve-related events,
and the potential effect of type of prosthesis used.

\emph{Methods}

A systematic literature search was conducted between January 2000 and
August 2019. Inclusion criteria: aortic root replacement in adults. Data
were pooled by inverse-variance weighting and entered a microsimulation
model to calculate lifetime event-risk and (event-free) life expectancy.

\emph{Results}

Of 2,106 publications, 31 were included (N = 5,227 patients, 74\%
stentless valves). Mean age was 65.4 years (74\% male). Pooled early
mortality was 5.5\% (95\% CI: 4.3-7.2\%). During follow-up (mean 4.1
years, total 22.706 patient-years), late mortality was
4.8\%/patient-year and reoperation 0.9\%/patient-year.
Linearized-occurrence-rates for thromboembolism, endocarditis, and
hemorrhagic events:1.2; 0.9 and 0.5 \%/patient-year; no significant
difference between stented and stentless prosthesis. Translating into a
60-year-old patient, an estimated life expectancy of 14 years (general
population: 22 years) and lifetime risks of thromboembolism,
endocarditis and reintervention of 21\%, 13\%, and 8\%, respectively is
expected.

\emph{Conclusions}

The study shows impaired survival and a notable lifetime risk of
valve-related events after bioprosthetic aortic root replacement. The
risk of thromboembolism is prominent, especially during earlier
follow-up, suggesting higher risk of thromboembolism early after
operation. Type of prosthesis, stented or stentless, is not associated
with higher valve-related events. Moreover, this study could be used as
a benchmark to compare outcome with other aortic root replacement
procedures.

\textbf{Background and aim of the study}

In young patients with aortic root disease, composite mechanical graft
replacement \selectlanguage{english}- Bentall-procedure\selectlanguage{english}- (1) is widely used due to its long-term
durability (2). In elderly, biological aortic root replacement is more
common, because reoperations are less prominent due to shorter
life-expectancy and less structural valve degeneration (SVD) (3, 4).
This age `turning-point' however is arbitrary and biological valves are
increasingly implanted in middle-aged patients recently. Interestingly,
there are no large studies presenting outcome after bioprosthetic aortic
root replacement and our knowledge is mainly based on data reported on
aortic valve replacement. Additionally, most published studies have
limited follow-up duration, which is a limitation for the interpretation
of the results, particularly regarding SVD and reoperation hazard (5).
Moreover, it is not known how a stentless biological valve prosthesis
compares to stented prosthesis with regard to durability and
valve-related outcome (6). Stentless valves may have hemodynamic
advantages, especially in smaller aortic annulus, however, survival and
long-term durability have not yet been proved (7).

Conspicuously, transcatheter aortic valve implantation (TAVI) procedures
are gaining ground and with satisfying results, indicating that surgical
aortic valve replacement will probably become limited in the near future
(8). Nevertheless, when the aortic root is affected and should be
replaced, surgery is still the only solution. To provide comprehensive
data on outcome after bioprosthetic aortic root replacement and the
possible effect of the type of prosthesis, we conducted a systematic
review of observational reports on patient characteristics and
valve-related morbidity, mortality and reintervention with both stented
and stentless prostheses and explored potential determinants of outcome.

\textbf{Materials and methods}

\emph{Search Strategy}

On 30 August 2019, a systematic literature search was conducted in
MEDLINE, Embase, The Cochrane Collaboration and Web of Science, and
Google Scholar (Supplementary file 1). Studies published from January
2000 onwards were screened by two independent reviewers (BA, RvV) using
the following inclusion criteria: reporting morbidity and mortality
after bioprosthetic aortic root replacement with stentless (no
homografts) or stented prosthesis, cohorts \selectlanguage{english}[?] 50 patients (to prevent
including early experience reports highlighting the learning curve), and
mean age at surgery \selectlanguage{english}[?] 18 years. Exclusion criteria were: \textgreater{}
25\% acute type A aortic dissection, studies limited to reintervention
or mechanical valve prosthesis, studies reporting only early results,
\textgreater{} 10\% use of subcoronary technique, \textgreater{} 50\%
children included (aged \textless{}18 years), and state of the art, case
reports, experimental studies and reviews. In case the same cohort was
published more than once, the most complete publication was selected.
All included studies were cross-referenced to identify additional
publications. In case of disagreement, studies were assessed by another,
independent reviewer (MV) and agreement was negotiated until consensus
was reached.

\emph{Data Extraction}

Data extraction was performed in duplicate with Microsoft Excel
(Microsoft Office 2010, Microsoft, Redmond, WA, USA) by two of the
authors (BA and JE) according to the guidelines for reporting mortality
and morbidity after cardiac valve interventions (9). Events were not
included in our database when adherence to the reporting guidelines
could not be ascertained. For each article with missing information on
important variables, the corresponding author was requested to provide
the missing data. An overview of extracted variables is presented in
Supplementary file 2.

\emph{Data Analysis}

Data analysis was performed with Microsoft Excel (Microsoft Office 2010,
Microsoft, Redmond, WA, USA) and IBM SPSS version 21.0 (IBM, Somers, NY,
USA) and in the R statistical software (version 3.1.0. R Development
Core Team, R Foundation for Statistical Computing, Vienna, Austria)
using the metaphor package. Pooled baseline patient characteristics were
calculated with the use of sample-size weighting. Early mortality and
linearized occurrence rates (LOR) of late valve-related complications
were pooled on a logarithmic scale with the use of inverse variance
weighting in a random-effects model. Reported study characteristics and
pre- and peri-operative patient characteristics are presented as mean +-
standard deviation for continuous variables and percentages for discrete
variables. For outcome variables, individual and pooled statistics are
presented as LOR and 95\% confidence interval (CI). In studies where
median and ranges instead of mean and variance were reported, the method
described by Hozo et al. (10) was used to calculate the mean. In case of
absence of total number of patient-years, this was calculated by
multiplying the number of patients with the mean follow-up duration in
years. In case a certain event did not occur in an individual study, we
assumed that 0.5 events occurred for that particular outcome for the
purpose of inverse variance weighting. When an event was not reported,
this study was excluded from the analysis of that event. For late
mortality and reintervention, subgroup analyses were performed
stratifying the root replacement by prosthesis type (stented vs.
stentless), follow-up duration (individual study mean follow-up less
than pooled mean follow-up versus individual study mean follow-up more
than pooled mean follow-up), and age at surgery. To assess the
association of these variables with late mortality and reintervention
rates, linear regression analyses were performed with weighting the
studies according to the inverse variance of the occurrence rate.
Heterogeneity between the studies was assessed using the
I\textsuperscript{2} test. Funnels plots were used to investigate
publication bias. To investigate the potential influence of publication
bias on pooled outcome, sensitivity analyses were conducted by
temporarily excluding the smallest quartile (by sample size) of included
studies. This systematic review and meta-analysis was conducted
according to the PRISMA guidelines (11).

\emph{Microsimulation model: the concept}

The microsimulation model is a computer application that simulates the
life of a patient after aortic valve replacement, considering the
morbidity and mortality events that the patient could experience. The
calculated mortality of a patient is composed of the background
mortality of the general population, operative mortality, mortality due
to valve-related events and an additional ``excess mortality''. This
so-called excess mortality in the patient compared to a matched person
in the general population reflects mortality associated with the
underlying left ventricular function, valve pathology, and the root
replacement procedure. All pooled and weighted occurrence rates of
(operative) mortality risk, the occurrence rate of valve-related events
together with the risk of mortality and reintervention directly due to
valve-related events were obtained from the meta-analysis. The
occurrence rates of all events were assumed to be linear and non-age
dependent.

For patients aged 61-70 and \textgreater{} 70 years, these ``excess
mortality`` hazard ratios were 1.2 and 0.8 for males, and 2.2 and 1.3
for females, respectively. The background mortality of the general
population was obtained from the 2004 United States Life Tables, as 2004
was the pooled median year of intervention, assuming a constant
incidence rate over time in each study (12).

To obtain age-specific estimates of life expectancy and lifetime risk of
valve-related morbidity, the microsimulation model was run for the ages
of 60, 65 and 70 years for 10,000 iterations each and separately for
males and females. The age-specific outcomes of both genders were then
pooled at the male/female ratio obtained from our meta-analysis. For the
internal validation of the model, we performed an additional run for
10,000 iterations at the pooled mean age (65.5 years) and male/female
ratio (70\%) of the meta-analysis. The actuarial survival obtained from
the microsimulation model for these data was then plotted against the
pooled (overall) mortality observed in the meta-analysis. A more
detailed account of the microsimulation and the methodology has been
supplied previously (13).

\textbf{Results}\emph{Study and baseline patient characteristics}The
initial literature search exposed 2,106 publications. The selection
procedure is illustrated in Figure 1. Cross-referencing did not result
in additional papers. Thirty-one studies were finally included in this
systematic review with a total number of 5,227 patients, mean follow-up
of 4.1 years (range 1-10 years), and total follow-up of 22,706
patient-years. Root replacements was performed with a stented prosthesis
in 26\% of patients and 74\% were stentless valve prostheses. In one
study the implantation period was missing, which was provided by the
authors (14). Supplementary file 3 shows an overview of the included
publications and study characteristics. Pooled pre- and peri-operative
characteristics are presented in Table 1.

\emph{Pooled outcome}

Early (30 day) mortality occurred in 339 patients, corresponding to a
weighted early mortality of 5.5\% (95\% CI: 4.3 -- 7.1\%). The
linearized occurrence rates (LOR) of mortality, reintervention on the
aortic root, hemorrhage, thromboembolism, endocarditis and major adverse
valve-related events are presented along with a measure of statistical
heterogeneity in Table 2.

Late mortality occurred in 1,037 patients (4.6\%/patient-year); in 41\%
the cause was unknown or not reported. The main cause of late mortality
was cardiac (52\%), of these were 51\% valve-related and 49\%
non-valve-related cardiac death.

\emph{Publication Bias}Analysis of the funnel plots revealed evidence of
underreporting of late mortality, reintervention on the aortic root, and
thromboembolism in studies with smaller patient numbers. For other
variables, no evidence of publication bias was found (Supplementary file
3).

Sensitivity analyses revealed that this potential publication bias did
not have a substantial effect on pooled outcomes, as these remained
generally unchanged after temporary exclusion of smallest quartile of
the studies.

\emph{Type of prosthesis}

Twenty-tree studies reported using solely a biological valve-containing
prosthesis (14-36): 13 studies with Freestyle bioprostheses, 3 Shelhigh
bioconduit, 2 studies Bio-Valsalva prosthesis, 1 Edwards S prima Plus, 2
with mixed stentless prosthesis. In one study the type of the biological
valve was unspecified (37). Two studies included both stentless and
stented bioprostheses (38, 39). Five studies used (almost) exclusively
self-made aortic root prosthesis using a stented bioprostheses
(bio-Bentall) to replace the aortic root. (40-44).

No associations were found between late mortality or reintervention, and
the type of prosthesis used. Table 3 shows detailed information on
valve-related outcome for ``stentless'' and ``stented''
subgroups.\emph{Duration of follow-up}

A subgroup analysis was performed with 12 studies with a mean follow-up
of at least 5 years~\selectlanguage{english} \selectlanguage{english}pooled weighted mean of 7.4 years (range 5.0 to
10.1 years)~ \selectlanguage{english}with a pooled mean age of 65.9 years, and compared to the
other 19 studies, with a mean follow-up of 2.56 years (1.0 to 4.8 years)
and pooled mean age of 65.8 were analyzed. Table 4 shows details on
outcome.

\emph{Microsimulation predictions of age-specific life expectancy and
outcome}Microsimulation-based estimates of life expectancy and lifetime
risk of valve-related morbidity for 60, 65 and 70 years old patients are
shown in Figure 2. The microsimulation model calibration with the pooled
mortality is shown is Supplementary file 4.



\textbf{Conclusions}

This study provides an overview of contemporary published studies on
outcome after aortic root replacement with biological valve prostheses
and provides age-specific prediction of valve-related outcome. Patient
survival is impaired. Type of prosthesis is not associated with
(valve-related) outcome. Notably, thromboembolic events occur frequent,
especially during early follow-up. This report may be used to benchmark
the potential therapeutic benefit of other surgical approaches.

\emph{Early mortality}

The observed pooled early mortality was 5.5\%. This is in accordance
with an older review on aortic root replacement (4.5 to 5.3\%) and with
the recent report of the Society of Thoracic Surgeons database from the
U.S. that estimates early mortality after bioprosthetic aortic root
replacement to be 6.2\% (45, 46). However, these studies include also
acute and emergent operative indication like endocarditis and aortic
dissection. Early mortality was mainly due to low cardiac output
(22.7\%) and multi-organ failure (18.1\%). Surgical indication was
endocarditis in 9.2\% of patients and type A aortic dissection in 7.2\%.
The high mortality could (partly) be explained by operation in emergent
setting and partly by the additional procedures (e.g. arch replacement,
CABG). Nevertheless, overall early mortality seems not changed
significantly last 2 decades.

\emph{Late mortality and reintervention outcome} There was a high
mortality rate (4.8\%/pt-year) for a pooled mean age of 65.9 years,
which is higher than the general population mortality. Translated to our
microsimulation-based life-expectancy, there is a life-expectancy of
14.3 year for a 60 year old patient receiving a bioprosthetic root
replacement, while there is a life-expectancy of 22.5 years for the 60
year old U.S. ``healthy'' population (12). From previous research there
is evidence of significant ``excess mortality'' in (elective) isolated
aortic valve replacement, compared to the age-matched general population
(47). Additionally, patients in this study were diagnosed with a dilated
aortic root as well, with about 13\% suffering from a dissection of the
root and/or connective tissue disease, which are conditions that may
influence patient survival due to complication other than valve-related
events.

This microsimulation model shows a life-time reintervention risk of 9\%
for patients older than 60 years, which is comparable to previous
predictions on biological aortic valve prostheses (3). It is known that
younger patients, especially younger than 60 years, are more likely to
have a reintervention after biological aortic valve replacement, mainly
due to progressive SVD (3, 48). Of the 8 studies that explicitly tested
association between age and reintervention, 3 found indeed that older
age is associated with lower reintervention hazard.

\emph{Thromboembolic events}We found a high incidence of thromboembolic
events, with a life-time risk of more than 20\% after bioprosthetic
aortic root replacement. Data on TE events are not comprehensive, thus
discriminating between TIA and disabling ischemic CVA is not possible.
However, a previous systematic review and microsimulation study on
aortic valve replacement with isolated biological stented valve,
published by Puvimanasinghe et al. (3), reports similar TE event rates
(1.4\%/patient-year). Additionally, the incidence of thromboembolic
events is known to increase with age (49, 50) and might partly explain
this high incidence of thromboembolic events.

Subsequently the question arises whether there is a difference with
patients receiving a classical Bentall prosthesis. Although this
comparison is hampered by the differences in patient characteristics,
mainly due to the younger age in patient receiving mechanical valves; a
recently published meta-analysis on the Bentall procedure (mean age 50
years), shows lower thromboembolic event rates (0.77\%/patient-year)
(51). Another study on mechanical valve replacement in non-elderly
showed suboptimal survival and considerable lifetime risk of
anticoagulation-related complications (52). However, the anticoagulation
therapy after mechanical valve implantation in these patients plays a
protective role in prevention of thromboembolic events, as it also
occurs irrespective of the aortic valve replacement due to the aging
process (50).

Additionally, TE hazard is less likely to occur during long-term
follow-up, suggesting a larger hazard in the early postoperative period,
which may be related to anticoagulation therapy. According to the
current US and European guidelines on the management of valvular heart
disease, antiplatelet therapy is reasonable and may be considered for
the first 3 months after biological valve replacement (2, 53).
Additionally, the European guidelines state that the need for a 3 months
postoperative period of anticoagulation therapy has been challenged in
patients with bioprostheses, with low-dose aspirin being favored as an
alternative.

Hence, it is questionable whether the proposed anticoagulation therapy
is appropriate in patient receiving a bioprosthetic aortic root
replacement. Nevertheless, due to a lack of data on the exact
anticoagulation therapy and patient compliance, it is not possible to
make broad inference about this possible association. Further studies
are needed to determine the most optimal anticoagulation therapy after
biological aortic valve replacement.\emph{Endocarditis and type of
prostheses}Although the rate of endocarditis after bioprosthetic aortic
root replacement varies widely in the literature (54), our findings are
comparable to an older study on biological aortic valve replacement
{[}3{]}. Additionally, we found 3 large studies with an endocarditis
rate of more than 2.8\%/patient-year (22, 26, 55), all including
stentless valve prostheses. However, these studies included a relatively
high proportion of patients with active endocarditis which may explain
the higher re-endocarditis rate, although the severity of endocarditis
was not provided. Hence, the trend toward more endocarditis in stentless
valves could possibly be explained by the latter. Based on these data it
is reasonable to assume that stented bioprosthetic grafts are at least
not inferior to stentless bioprosthetic grafts to be used in case of
endocarditis, although the extent of endocarditis may allow for
different inference. Moreover, we found no difference in other
valve-related events between stentless and stented prosthesis. We
believe that both prostheses are safe to use in the average patient
undergoing aortic root replacement.

\emph{The position of bioprosthetic aortic root replacement}

There is no perfect valve substitute for the individual patient with
aortic valve and/or root disease as all prostheses are associated with
certain valve-related events of varying nature. Careful weighting of the
advantages and disadvantages of biological and mechanical valve
substitutes tailored to the patient's unique characteristics and
preferences, is the current gold standard. Interestingly, there is a
trend toward using a biological valve in younger patients (5, 56).
Although evidence is lacking, perhaps this is emerging due to the
potential prospect of transcatheter valve-in-valve therapy as a future
solution for bioprosthetic SVD.

According to the ESC/EACTS guidelines on valvular heart disease, age
limits contain an arbitrary element, and the choice of prostheses type
should be individualized in a joint decision between the patient and
doctor. Although SVD is known to occur earlier in younger patients (57),
mechanical valve prostheses are not the preferred alternative in all
young patients. Nevertheless, as individual patient norms, values and
goals in life vary widely, the decision for a particular valve
prosthesis should be individualized in a shared decision making process,
and together with surgical experience, the most suitable surgical
approach should be determined (2, 53). Our systematic review adds to the
body of evidence by showing in a middle-aged patient population,
undergoing bioprosthetic aortic root replacement, acceptable
reintervention rates and valve-related event occurrence, and may be used
as a benchmark to compare outcome with other type of prosthesis, e.g.
Bentall and valve-sparing procedures.

\emph{Limitations}As in all systematic reviews and meta-analysis of
retrospective observational studies, limitations of this type of study
should be taken into consideration (58). Furthermore, recall bias
inherent to the retrospective design of all but one study and
publication bias may have affected the observed outcome. In addition,
the included studies represent a heterogeneous population of patients
with different patient characteristics, with patients operated in
different era spanning over 20 years, and considering improvements in
anticoagulation strategies, medical management of valvular heart disease
and surgical techniques over the past decades, which may have influenced
outcome. Moreover, a lack of uniform data reporting as proposed by the
guidelines (9) may have influenced the uniformity of the pooled data.

The pooled late outcome estimates are based on the linearity assumption,
while occurrence of outcome events may not be linear in nature. However,
due to the lack of randomized trials where homogeneous data are present,
this meta-analysis was performed to provide an overview of published
outcomes after bioprosthetic aortic root replacement.

\textbf{Conclusion}

This study provides an overview of contemporary outcome after
bioprosthetic aortic root replacement and demonstrates impaired survival
and notable valve-related events, irrespective of the type of valve
prosthesis. Thromboembolic events occur relatively frequent and may be
associated with higher thrombogenicity of the biological valve, at least
in the early postoperative period. This should be considered when
choosing the most optimal treatment, especially in younger patients.
Given the observed heterogeneity of the pooled study results, in-depth
analysis of potential risk factors remains challenging. It requires a
collective international effort employing uniform data definitions and
high quality data collection, to push forward the knowledge on outcomes
and provide clues toward optimization of treatment selection for
patients requiring aortic root replacement (59). Nevertheless, this
study provides comprehensive outcome and may be used as a benchmark to
compare with other types of procedures (e.g. Bentall or valve-sparing
procedures).

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of this collaborative working group on aortic valve and root treatment.
2014 {[}



\textbf{Tables}

Table 1. Pooled pre-operative and peri-operative characteristics.\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
\begin{minipage}[b]{0.17\columnwidth}\raggedright\strut
\textbf{Variable}\strut
\end{minipage} & \begin{minipage}[b]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.17\columnwidth}\raggedright\strut
\textbf{Pooled data}\strut
\end{minipage} & \begin{minipage}[b]{0.17\columnwidth}\raggedright\strut
\textbf{Range}\strut
\end{minipage} & \begin{minipage}[b]{0.17\columnwidth}\raggedright\strut
\textbf{Included studies (N)}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Total patient number\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{5227}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
50 - 421\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
31\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Surgical period\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{1992 - 2014}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
30\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Mean age\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{65.4 years}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
47 -- 73 years\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
30\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Gender\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Male\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{67.6\%}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
30 -- 85\%\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
31\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Etiology\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Valve pathology\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
18\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Aortic stenosis\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{49.8\%}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
3 -- 100\%\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Aortic regurgitation\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{37.7\%}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0 -- 92\%\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Stenosis \& regurgitation\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{17.9\%}\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
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Connective tissue disease\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{2.9\%}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0 -- 32\%\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
13\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Bicuspid aortic valve\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{28.0\%}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0 -- 42.6\%\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
14\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Prior surgery\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Cardiac\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{14.2\%}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0 -- 39\%\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
23\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Other indications\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Acute type A dissection\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{7.2\%}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0 -- 24\%\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
20\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Acute endocarditis\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{9.1\%}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
1 -- 11\%\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
9\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Valve type\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Stentless\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{99.7\%}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
95 -- 100\%\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
23\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Stented\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{92.8\%}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
84 -- 100\%\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
5\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Mixed\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{50\%}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
50 -- 50\%\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
2\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Concomitant procedures\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Aortic hemiarch repair\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{18.2\%}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0 -- 44\%\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
19\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Aortic arch repair\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{5.9\%}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
3 -- 21\%\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
19\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
CABG\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{28.9\%}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0 -- 44\%\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
19\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Mitral valve surgery\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{3.3\%}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0 -- 17\%\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
19\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Re-exploration for bleeding\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{10.8\%}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
1 -- 28\%\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
14\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Early mortality\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{5.5\%}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
0 -- 16\%\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
31\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
Causes of early mortality *\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\emph{Low cardiac output}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{22.7\%}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
1 -- 44\%\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
\emph{Multi-organ failure Hemorrhage}\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
\textbf{18.1\%} \textbf{7.5\%}\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
13 -- 100\% 0 -- 13\%\strut
\end{minipage} & \begin{minipage}[t]{0.19\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\emph{Sepsis} \emph{Myocardial infarction}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{5.0\%} \textbf{4.0\%}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
6 -- 25\% 0 -- 100\%\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\emph{Unknown / unreported}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\textbf{9.6\%}\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
10 -- 55\%\strut
\end{minipage} & \begin{minipage}[t]{0.17\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\emph{} CABG indicates coronary artery bypass grafting. * major causes
of early mortality. Data indicate the pooled mean \% of occurrence and
the pooled range of occurrence. Included studies are publications
reporting on the specific characteristic. The percentages mentioned are
means of the reported variables in the studies that provided these
variable numbers. The range indicates the lowest and the highest
reported \% of that specific variable within all studies, and N
indicates the number of studies reporting on that specific variable.

Table 2. Linearized occurrence rates of late outcome events.\selectlanguage{english}
\begin{longtable}[]{@{}llllll@{}}
\toprule
\textbf{Pooled late outcome events} & \textbf{LOR (\%/yr) + 95\% CI*} &
\textbf{Heterogeneity (I\textsuperscript{2})} & \textbf{Included studies
(N)} & \textbf{Events (N)} & \textbf{Patient years of follow-up
(N)}\tabularnewline
\midrule
\endhead
Late mortality & \textbf{4.61} (3.98 -- 5.36) & 71 & 31 & 1037 &
19413\tabularnewline
Root reintervention & \textbf{0.72} (0.47 -- 1.10) & 73 & 31 & 167 &
19413\tabularnewline
Hemorrhage & \textbf{0.56} (0.33 -- 0.94) & 68 & 27 & 83 &
17365\tabularnewline
Thromboembolism & \textbf{1.41} (0.96 -- 2.06) & 73 & 26 & 180 &
17735\tabularnewline
Endocarditis & \textbf{0.94} (0.69 -- 1.32) & 69 & 27 & 130 &
14588\tabularnewline
SVD* & \textbf{0.32} (0.16 -- 0.62) & 76 & 26 & 74 &
16375\tabularnewline
NSVD* & \textbf{0.21} (0.13 -- 0.34) & 49 & 21 & 15 &
12139\tabularnewline
\bottomrule
\end{longtable}

LOR indicates linearized occurrence rates; CI, confidence interval; SVD,
structural valve degeneration; MAVRE, major adverse valve-related
events. * not all (N)SVD led to reintervention

Table 3. Mortality and valve-related outcome for stentless and stented
valve prosthesis.\selectlanguage{english}
\begin{longtable}[]{@{}lllllllll@{}}
\toprule
& \textbf{Stentless} & \textbf{Stentless} & \textbf{Stentless} &
\textbf{Stentless} & \textbf{Stented} & \textbf{Stented} &
\textbf{Stented} & \textbf{Stented}\tabularnewline
\midrule
\endhead
& \textbf{LOR} & \textbf{95\% CI -} & \textbf{95\% CI +} & \textbf{N} &
\textbf{LOR} & \textbf{95\% CI -} & \textbf{95\% CI +} &
\textbf{N}\tabularnewline
\textbf{Early Mortality} & 6.5 & 5.1 & 8.4 & 23 & 5.5 & 4.0 & 7.6 &
5\tabularnewline
\textbf{Late Mortality} & 4.9 & 4.2 & 5.6 & 23 & 4.3 & 3.1 & 6.0 &
5\tabularnewline
\textbf{Reintervention} & 1.0 & 0.7 & 1.4 & 23 & 0.9 & 0.3 & 2.6 &
5\tabularnewline
\textbf{TE} & 1.5 & 1.1 & 2.2 & 20 & 0.5 & 0.2 & 1.4 & 5\tabularnewline
\textbf{Bleeding} & 0.3 & 0.2 & 0.6 & 19 & 0.6 & 0.2 & 1.9 &
5\tabularnewline
\textbf{Endocarditis} & 1.0 & 0.8 & 1.4 & 22 & 0.4 & 0.2 & 0.8 &
4\tabularnewline
\textbf{SVD} & 0.4 & 0.3 & 0.7 & 20 & 0.7 & 0.2 & 3.1 & 5\tabularnewline
\bottomrule
\end{longtable}

LOR indicates linearized occurrence rates; CI confidence interval; N
number of studies included in analysis

Table 4. Mortality and valve-related outcome for mean follow-up (FU)
more than 5 years and less than 5 years.\selectlanguage{english}
\begin{longtable}[]{@{}lllllllll@{}}
\toprule
& \textbf{FU \textless{} 5 yrs} & \textbf{FU \textless{} 5 yrs} &
\textbf{FU \textless{} 5 yrs} & \textbf{FU \textless{} 5 yrs} &
\textbf{FU \textgreater{} 5 yrs} & \textbf{FU \textgreater{} 5 yrs} &
\textbf{FU \textgreater{} 5 yrs} & \textbf{FU \textgreater{} 5
yrs}\tabularnewline
\midrule
\endhead
& \textbf{LOR} & \textbf{95\% CI -} & \textbf{95\% CI +} & \textbf{N} &
\textbf{LOR} & \textbf{95\% CI -} & \textbf{95\% CI +} &
\textbf{N}\tabularnewline
\textbf{Early Mortality} & 6.2 & 4.8 & 8.0 & 18 & 5.7 & 4.5 & 7.2 &
12\tabularnewline
\textbf{Late Mortality} & 4.4 & 3.5 & 5.6 & 18 & 4.8 & 3.9 & 5.8 &
12\tabularnewline
\textbf{Reintervention} & 1.2 & 0.7 & 1.9 & 15 & 0.4 & 0.2 & 0.7 &
10\tabularnewline
\textbf{TE} & 1.6 & 1.0 & 2.5 & 15 & 0.7 & 0.3 & 1.5 & 8\tabularnewline
\textbf{Bleeding} & 0.6 & 0.3 & 1.3 & 13 & 0.5 & 0.3 & 0.8 &
8\tabularnewline
\textbf{Endocarditis} & 1.4 & 1.0 & 1.9 & 15 & 0.5 & 0.3 & 0.8 &
8\tabularnewline
\textbf{SVD} & 0.3 & 0.2 & 0.5 & 12 & 0.3 & 0.2 & 0.5 & 9\tabularnewline
\bottomrule
\end{longtable}

LOR indicates linearized occurrence rates; CI confidence interval; N
number of studies included in analysis\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image1/image1}

\end{center}
\end{figure}

Figure 1. Flowchart of systematic search and included articles\selectlanguage{english}
\begin{figure}[H]
\begin{center}
\includegraphics[width=0.70\columnwidth]{figures/image2/image2}

\end{center}
\end{figure}

Figure 2. Microsimulation-based life expectancy and lifetime risk of
valve-related morbidity for 60, 65 and 70 years old patients.

\selectlanguage{english}
\FloatBarrier
\end{document}

