The best approach for functional tricuspid regurgitation.
data availability statement: the data associated with the paper are not
publicly available but are available from the corresponding author on
reasonable request
Michele Di Mauro, MD, PhD, MSc.
P. Debyelaan 25, 6202 AZ
ABSTRACTOBJECTIVE. For many years, functional tricuspid regurgitation (FTR) was
considered negligible after treatment of left-sided heart valve surgery.
The aim of the present network meta-analysis is to summarize the results
of four approaches in order to establish the possible gold standard.
METHODS A systematic search was performed to identify all publications
reporting the outcomes of four approach for FTR, not tricuspid
annuloplasty (no TA), suture annuloplasty (SA), flexible (FRA), rigid
rings (RRA). All studies reporting at least one the four endpoints
(early and late mortality, early and late moderate or more TFR) were
included in a Bayesian network meta-analysis.
RESULTS There were 31 included studies with 9,663 patients. Aggregate
early mortality was 5.3% no TA, 7.2% SA, 6.6% FRA and 6.4% RRA;
Early TR moderate-or-more was 9.6%, 4.8%, 4.6% and 3.8%; Late
mortality was 22.5%, 18.2%, 11.9% and 11.9%; Late TR
moderate-or-more was 27.9%, 18.3%, 14.3% and 6.4%. Rigid or
semirigid ring annuloplasty was the most effective approach for
decreasing the risk of late moderate or more FTR (–85% vs. no TA;
–64% vs. SA; –32% vs. FRA). Concerning late mortality, no
significant differences were found among different surgical approaches,
however, flexible or rigid rings reduced significantly the risk of late
mortality (78% and 47%, respectively) compared with not performing TA
mortality. No differences were found for early outcomes.
CONCLUSIONS. Ring annuloplasty seems to offer better late outcomes
compare to either suture annuloplasty or not performing TA. In
particular rigid or semirigid rings provides more stable FTR across
time.
Keywords. Tricuspid regurgitation; tricuspid annuloplasty; tricuspid
valve repair; suture annuloplasty; rigid ring; flexible ring.Abbreviation listFunctional tricuspid regurgitation (FTR)
Tricuspid valve (TV) disease
Tricuspid annular dilatation (TAD)
Pulmonary hypertension (PHT)
No tricuspid annuloplasty (no TA)
Suture annuloplasty (SA)
Flexible ring annuloplasty (FRA)
Semirigid/rigid ring annuloplasty (RRA)
Odds ratios (ORs)
Incidence rate ratios (IRRs)
Surface under the cumulative ranking curve (SUCRA)
Tricuspid annuloplasty (TA)INTRODUCTIONFunctional tricuspid regurgitation (FTR) is the most frequent picture
among tricuspid valve (TV) disease; it is mainly due to TV annular
dilatation alongside with leaflets tethering, and is commonly associated
with left-sided heart valve disease [1,2].
For many years, FTR was considered negligible after treatment of
left-sided heart valve surgery [3,4]. Since the mid of
two-thousands, Dreyfus et al. [5] emphasized the need to treat FTR,
even less than severe, otherwise it could worsen at 5 years. This
concept has also been confirmed by some recent meta-analytic studies
[6,7].
So, guidelines for the management of heart valve disease [8,9] as
well as surgical consensus [10], updated the indications for
treatment of FTR, suggesting to treat not only severe TR, but also FTR
graded less than severe, in presence of tricuspid annular dilatation
(TAD), right ventricular dysfunction or pulmonary hypertension (PHT).
On the other hand, the results of different surgical strategies, suture
annuloplasty versus flexible rings or rigid rings are still
controversial11-16. Some meta-analyses report pairwise
comparison14-16, however a global description of four
most common approaches for functional tricuspid regurgitation (no
tricuspid annuloplasty, suture annuloplasty, flexible and rigid ring
annuloplasty) is still missing.
Hence, the aim of the present network meta-analysis is to summarize the
results of these four approaches in order to establish the possible gold
standard.METHODSLITERATURE SEARCH STRATEGY.Following the PRISMA (Preferred Reporting Items for Systematic Reviews
and Meta-Analyses) Extension for Network
Meta-analysis17,
electronic searches were performed by 3 authors (JMR, FR, GB). Details
of the literature search strategy are provided in the Appendix.SELECTION CRITERIA. Eligible studies for the present systematic review and network
meta-analysis were those published in English that compared two or more
strategies in case of functional tricuspid regurgitation: no tricuspid
annuloplasty (no TA), suture annuloplasty (SA), flexible annuloplasty
(FRA) and semirigid/rigid ring (RRA). Studies that did not contain
comparison were excluded. Detailed selection criteria are provided in
the Appendix.DATA EXTRACTION AND CRITICAL APPRAISAL.All data were extracted from article texts, tables and figures. Two
investigators (MDM and FR) independently reviewed each included article.
Details of study appraisal and quality scoring are provided in the
Appendix. Discrepancies between the 2 investigators were resolved by
discussion and consensus with the senior authors (AMC, RL, AP and UB).STATISTICAL ANALYSIS. In the present network meta-analysis, dichotomous outcome variables were
compared with odds ratios (ORs) and 95% confidence intervals (CIs) for
early (within postoperative 30 days) mortality and FTR moderate or more.
For long-term outcomes with potentially different follow-up durations
between groups, we derived the log incidence and corresponding standard
error from numbers of reported events and accumulated person-years of
follow-up. For each eligible study, if the associated information was
present merely in figures, Engauge Digitizer was used to collect data
from the statistical graphs. Then log IRR and standard error were
extracted using an excel calculator sheet based on previous reported
literature18. Finally, IRR with 95% confidence
interval (95%CI) were reported for late mortality or late TR moderate
or more. Outcome variables were compared with incidence rate ratios
(IRRs) and 95% confidence intervals (CIs).
Analyses were performed using Bayesian Markov chain Monte Carlo
modeling19.To provide a comparative hierarchy of procedural efficacy and safety,
“Rankograms” with surface under the cumulative ranking curve (SUCRA)
probabilities were reported. A SUCRA of 90% means that the treatment of
interest achieves 90% of effectiveness or safety relative to other
interventions. Thus, the larger the SUCRA value, the higher the rank of
the treatment, indicating a safer or more effective treatment. The
analyses were performed with NetMetaXL 1.6.1 (Canadian Agency for Drugs
and Technologies in Health, Ottawa, Canada), R-studio version 1.1.463
(2009-2018) and WinBUGS 1.4.3 (MRC Biostatistics Unit, Cambridge, United
Kingdom).
Detailed statistical methods are provided in the Appendix.RESULTSLITERATURE SEARCH. A total of 7517 studies were initially identified (Figure 1
supplementary). After exclusion of duplicate or irrelevant references,
114 potentially relevant articles were retrieved. After application of
the inclusion and exclusion criteria, 31 relevant articles were included
in the study5,12,20-48: randomized trials (n
=3)23,41,44, propensity score-adjusted
(n=4)12,25,30,45 and observational non-adjusted
(n=24)5,20-22,24,26-29,31-43,45-48. A total of 9663 patients were included for analysis, Among them 1371 did
not receive concomitant TA (no TA), 1931 received suture annuloplasty,
3248 got a flexible and 3104 where a semirigid or rigid ring were used.
Study characteristics are summarized in Table 1. Study quality
assessment is summarized in Table 1 supplementary. Inspection of the
funnel plots did not show significant asymmetry to suggest publication
bias with outcomes selected (Figure 2 supplementary).
Network diagrams were reported in the figure 1. Network characteristics
are summarized in the table 2 supplementary.Early mortality. Estimates of early mortality were extracted from 25 studies (7383) with
469 events (Table 2 supplementary). In the network meta-analysis, no TA
showed aggregate early mortality of 5.3% (0.9-13.1), 7.2% (1.4-20.6)
for SA, 6.6% (0.8-14.2) for FRA and 6.4% (0.7-13.5) for RRA (Table 2).
No significant differences were found among the 4 different approaches
(Figure 2A). Inconsistency was low (Figure 3A suppl.). Heterogeneity was
very low (I2=0%).Early TR moderate or more. Estimates of FTR moderate or more were extracted from 16 studies (3543)
with 173 events (Table 2 supplementary). In the network meta-analysis,
no TA showed aggregate early rate of FTR moderate or more of 9.6%
(5.6-45.7), 4.8% (1.4-15.4) for SA, 4.6% (1.7-13.6) for FRA and 3.8%
(2.8-9.2) for RRA (Table 2). No significant differences were found among
the 4 different approaches (Figure 2B). Inconsistency was low (Figure 3B
suppl.). Heterogeneity was very low (I2=0%)Late mortality Estimates of late mortality were extracted from 21 studies (4600) with
636 events (Table 2 supplementary). In the network meta-analysis, no TA
showed aggregate late mortality of 22.5% (5.3-55.6), 18.2% (4.1-32.0),
for SA, 11.9% (2.6-13.6) for FRA and 11.9% (1.2-22.6) for RRA (Table
2). No significant differences were found among different surgical
approaches FRA vs SA (IRR 1.52, 0.99-2,34), RRA vs SA (IRR 1.10,
0.68-1.77), and RRA vs FRA (IRR 0.72, 0.45-1.15) (Figure 2C).
Conversely, prosthesis TA, either with flexible rings or rigid rings
reduced significantly the risk of late mortality (78% and 47%,
respectively) compared with not performing TA. Bayesian Markov chain
Monte Carlo modeling demonstrated that FRA had the highest probability
of having the lowest rate of late mortality (SUCRA 90%), followed by
RRA (70%), SA (20%), and no TA (19%) (Figure 3A). Inconsistency was
low (Figure 3C suppl.). Heterogeneity was moderate (I2=40%)Late TR moderate or more Estimates of late FTR moderate or more were extracted from 26 studies
(7373) with 636 events (Table 2 supplementary). In the network
meta-analysis, no TA showed aggregate late rate of FTR moderate or more
of 27.9% (3.1-77.1), 18.3% (4.1-45.2) for SA, 14.3% (13.3-55.6) for
FRA and 6.4% (0.25-37.3) for RRA (Table 2). Different risks among the 4
approaches are summarized in the league table (Figure 2D). Bayesian
Markov chain Monte Carlo modeling demonstrated that RRA had the highest
probability of having the lowest rate of late FTR moderate or more
(SUCRA 99%), followed by FRA (67%), SA (34%), and no TA (0%) (Figure
3B). Hence, RRA provides a significant risk reduction of 85%, 64%,
32% with respect to no TA, SA and FRA, respectively (Figure 4).
FRA provides a risk reduction of 78% and 47% with respect to no TA and
SA, respectively. Even SA is able to provide a risk reduction of 59%
with respect to no TA. Inconsistency was low (Figure 3D suppl.).
Heterogeneity was mild (I2=18%).DISCUSSIONThe present network meta-analysis confirms that treating FTR at the time
of left-sided heart valve surgery is absolutely crucial to achieve both
lower mortality and tricuspid regurgitation at follow up. In almost all
the studies, TA was performed according to
Guidelines8-10, even in presence of moderate or mild
FTR with tricuspid annulus dilatation or right ventricular dysfunction
or PHT.
In contrast with the study by David et al.3, FTR
recurrence is not so uncommon, accounting for 27.9% (3.1-77.1%)
without any TA. The rate decreased to 18.3% with suture annuloplasty,
to 14,3 with flexible rings and even to 6.4% with rigid ring implant
(Table 2).
The role of TA for FTR is summarized in recent
meta-analyses6,7. Tam et al6reported the results of 56,027 patients where tricuspid valve was
repaired at time of left-sided heart valve surgery compared with 11,787
patients where an observational approach was adopted, leaving untreated
FTR. The pooled effect evidenced a significant protective effect of TV
repair (IRR 0.28, 0.17-0.47) with respect to late FTR.
Paganesi7 analyzed the pooled effect of 15 studies,
confirming that surgery for FTR at the time of the left-sided heart
valve surgery provides a significant risk reduction (-81%) rather than
observational approach.
In those studies5,23,30,41 where TA was performed
prophylactically, the rate of late FTR moderate or more was very low
(2.8%) when compared to the rate collected in patients without TA
(48.7%).
However, the main finding of the present network meta-analysis is the
significant risk reduction for late FTR, implanting rigid rather than
flexible rings (-49%), or performing suture annuloplasty, mainly
DeVega, but also Kay or bicuspidalization, (-64%) and mostly with
respect to leaving untreated FTR when performing left-sided heart valve
surgery (-84%). Electing this procedure could be the best approach for
the stabilization of FTR over time. Veen KM et al14pooled the results of 14 studies comparing suture vs ring annuloplasty,
even if only 4 studies reported data for a pairwise comparison between
suture and ring annuloplasty, failing to found out any significant
differences between these two procedures in terms of late moderate or
more TR (RR 0.98, 0.72-1.32). Contrariwise, Parolari et
al15, in a meta-analysis of 9 studies, reported a
significant reduction of risk for TA failure performing ring rather than
suture annuloplasty (RR=0.76, 0.60-0.95).
The introduction of the flexible rings was driven by some features such
as the advantage for annular contraction during cardiac cycle due to
their flexibility, the simple design and implantation procedure.
Moreover, right coronary occlusion or damage due to flexible ring were
anecdotical49-51. Less device dehiscence rate may be
another possible benefit of flexible with respect to rigid
rings42.
Nevertheless, the stability of tricuspid annulus offered by rigid ring
seems to be greater than the one by flexible rings. In fact, if results
of comparison between suture and ring annuloplasty are still
controversial, the literature seems to be more concordant to recognize
the superiority of rigid over flexible ring14,16. In
fact, both meta-analyses by Veen14 (RR flexible versus
rigid: 1.84, 1.24-2.74) and by Wang16 (RR rigid versus
flexible: 0.44, 0.20-0.99) confirm a more stable FTR over time after
rigid versus flexible ring TA. The former pairwise comparison was
performed with data from 4 studies, but rigid ring was demonstrated to
be more effective than flexible rings (RR 1.84, 1.24-2.74).
The main argument invoked by the detractors of TA at the time of
left-sided heart valve surgery has been for years the possible increase
in the risk of postoperative mortality. This fear has been disproved by
many studies52 that have clearly reported similar
mortality rate either with or without TA. In the present network
meta-analysis, no differences were found among the four different
approaches.
No differences were found even in terms of FTR at discharge, inducing us
to some speculations. It is very likely that in the short-term,
performing only left-sided heart valve surgery can lead to a temporary
reduction in pulmonary pressure and right ventricular overload, which
can be an apparently satisfying result. Actually, this finding can be
the result of high dosages of diuretics in postoperative stay and so be
independent from TA or no TA.
Although any surgical treatment showed more stable FTR over time than
leaving untreated FTR, only ring implant guarantees lower risk of death
at follow-up. In particular, risk reduction was higher in case of
flexible rings than rigid rings, even if not statically significant.
This is very likely to be explained considering that late mortality is
not only driven by late FTR, but also by possible right ventricular
positive remodeling which can happen regardless the type of
surgery25.Study LimitationsAmong the enrolled studies, there are only three randomized trials with
small sample size. Unadjusted summary estimates were used for
meta-analysis and confounders could not be ruled out. However, the
network meta-analysis offers greater power and precision for rare events
while controlling for publication bias and small-study effects.
The network model was tested for consistency and heterogeneity. There
was a moderate amount of heterogeneity for late mortality, so these
results should be interpreted with caution.Conclusions.To our knowledge, this is the first network meta-analysis comparing
early and late outcomes following four different approaches in case of
FTR. The results suggest that more stable FTR over time can be achieved
only with ring TA, and in particular with rigid ring implant. Performing
or not TA at the time of left-sided heart valve surgery does not add any
early risk, but can provide better long-term survival.