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\begin{document}

\title{Single versus dual antiplatelet after transcatheter aortic valve
replacement: An updated meta - analysis of randomized controlled trials
and observational studies}



\author[1]{chen yan}%
\author[1]{Liman Wang}%
\author[1]{Yijun ke}%
\author[1]{Lili Xu}%
\author[1]{Mengfei Dai}%
\author[1]{Baoyan Wang}%
\author[1]{Lin Zhou}%
\author[1]{Hang Xu}%
\author[1]{yong feng }%
\author[1]{Weihong Ge}%
\affil[1]{Affiliation not available}%


\vspace{-1em}



  
  \date{June 11, 2024}


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





\selectlanguage{english}
\begin{abstract}
Aim: Although current guidelines recommend 3-6 months of dual
antiplatelet therapy (DAPT) for patients without indications for
anticoagulation after transcatheter aortic valve replacement (TAVR),
evidence-based evidence was lacking. Our aim was to review the most
recent evidence comparing the safety and efficacy of both treatment
modalities, single antiplatelet therapy (SAPT) and DAPT, after TAVR.
Methods: We systematically searched the literature on Embase, PubMed,
Cochrane and Medline until January 5, 2022. Our primary outcome
indicators were: all-cause mortality, stroke and total bleeding rates,
and secondary outcome indicators were: cardiovascular mortality,
myocardial infarction (MI) and the incidence of major and
life-threatening bleeding (LTB). A random-effects model was used, and
subgroup analyses were performed according to study type and follow-up
time. Results: A total of 14 studies (4 RCTs, 10 observational studies)
involving 21,546 patients were finally screened. Compared with the DAPT
treatment modality, patients in the SAPT group showed a significant
difference in short-term cardiovascular mortality after TAVR (RR {[}95\%
CI{]} =0.39 {[}0.19-0.78{]}, P = 0.008) and a significantly lower risk
of bleeding (RR {[}95\% CI{]} =0.56 {[}0.48-0.65{]}, P
\textless{}0.001). There was also a significant difference in the
incidence of major bleeding and LTB (RR {[}95\% CI{]}
=0.59{[}0.47-0.76{]}, P \textless{}0.0001), but no statistically
significant difference in other aspects. Conclusion: Compared with DAPT
treatment modalities, the choice of SAPT for patients without
anticoagulation indication after TAVR better reduces the risk of
postoperative bleeding and short-term cardiovascular death without
increasing the incidence of all-cause mortality, stroke, and MI.%
\end{abstract}%



\sloppy


\textbf{INTRODUCTION}

Transcatheter aortic valve replacement (TAVR) has emerged as a valuable
alternative to surgical aortic valve replacement (SAVR) in an increasing
number of patients with severe symptomatic aortic stenosis (AS) over the
past decade\textsuperscript{{[}1, 2{]}}. With improved surgeon skills
and better equipment\textsuperscript{{[}3{]}}, the success rate of TAVR
procedures is gradually increasing and the efficacy is no less than that
of SAVR. However, TAVR is still associated with serious major
cardiovascular complications such as all-cause mortality, myocardial
infarction (MI), stroke, life-threatening bleeding (LTB), and other
complications\textsuperscript{{[}4, 5{]}}. To reduce the risk of
thromboembolism, the American College of Cardiology (ACC)/American Heart
Association (AHA) 2020 guidelines recommend dual antiplatelet therapy
(DAPT) after TAVR for a few time\textsuperscript{{[}6{]}}. DAPT may
reduce the incidence of ischemic events and have a positive effect on
the valve, but DAPT may increase the risk of bleeding complications
compared with single antiplatelet therapy
(SAPT)\textsuperscript{{[}7{]}}, and the benefits of DAPT for valve
maintenance have not been clearly elucidated. The optimal antiplatelet
regimen is currently unclear and it is difficult to balance the risk
between bleeding and thrombotic events. Therefore, we conducted a
meta-analysis to compare the risks and benefits of two antiplatelet
therapy regimens after TAVR in randomized controlled trials (RCTs) and
observational studies.

\textbf{METHODS}

\textbf{Protocol and registration}

This systematic review was performed in accordance with the checklist of
the Preferred Reporting Items for Systematic Reviews and Meta-analysis
(PRISMA) extension statement for meta-analysis\textsuperscript{{[}8{]}},
and registered with PROSPERO (International Prospective Register of
Systematic Reviews, NO. CRD42022302109).

\textbf{Study Selection and Data Extraction}

We selected RCTs and observational studies published in Embase, PubMed,
Cochrane and Medline from inception to January 5, 2022. There were no
language restrictions applied. We searched with TAVR and interventions
(DAPT, dual antiplatelet therapy, SAPT, single antiplatelet therapy,
antithrombotic, antiplatelet, aspirin, clopidogrel, thienopyridines,
ticlopidine) as keywords and mesh terms. References to relevant articles
and studies were also manually screened in order to identify additional
relevant literature.

Studies meeting the following criteria were eligible for inclusion: (1)
be RCTs or observational studies; (2) patients treating with TAVR for
aortic stenosis or developing regurgitation; (3) literature examining
different antithrombotic strategies after TAVR, including SAPT, DAPT;
(4) studies that included at least one of death, MI, stroke, or bleeding
as an adverse event.

Studies meeting the following criteria were eligible for excluded: (1)
be reviews and meta-analysis; (2) unpublished clinical trials or
duplicate publications at the time of the search; (3) studies not
including patients receiving anticoagulant or antiplatelet therapy; (4)
no adverse events of all-cause mortality, MI, stroke or bleeding in the
study.

Two independent investigators reviewed the titles and abstracts of the
studies for assessment, meanwhile assessed the full text of articles
that met the inclusion criteria. Two investigators used the Cochrane
Collaboration Risk of Bias Instrument\textsuperscript{{[}9{]}} to assess
RCTs and the Newcastle-Ottawa Scale (NOS)\textsuperscript{{[}10{]}} to
assess the risk of bias in observational studies. Two investigators
performed literature data extraction, and a third investigator resolved
disagreements. The information we extracted from each study was (1)
basic information about the literature, including authors, year of
publication, study type, inclusion criteria, exclusion criteria, and
duration of follow-up; (2) baseline of the study subgroup; (3) detailed
occurrence of clinical adverse cardiovascular and cerebrovascular
events.

\textbf{Outcomes}

The primary outcome indicators were adverse cardiovascular events,
including all-cause mortality, stroke, all bleeding. Secondary outcome
indicators were cardiovascular mortality, MI, major bleeding and LTB.
All clinical events were defined. Of the studies with multiple follow-up
times, the longest follow-up was used to analyze outcomes. Subgroup
analyses were available for both study type (RCTs and observational
studies) and follow-up time ([?]6 months and \textgreater{} 6 months).

\textbf{Statistical analysis}

We performed a paired meta-analysis using the RevMan 5.4 (Cochrane
Collaboration, Copenhagen, Denmark) random effects model and calculated
Risk Ratio (RR) with 95\% confidence
intervals\textsuperscript{{[}11{]}}. When \emph{P} \textless{} 0.05,
they were considered statistically significant. Heterogeneity in the
studies was assessed using \emph{I} \textsuperscript{2}, and
heterogeneity was greater when \emph{I}
\textsuperscript{2}\textgreater{} 50\%\textsuperscript{{[}12{]}}. For
each outcome, we performed regression analysis using STATA 15.1 (Stata
Corp, College Station, TX, USA)\textsuperscript{{[}13{]}}. We assessed
publication bias in the research literature through making funnel plots
and performing Egger's tests. We assessed the sensitivity of the studies
by excluding them one at a time.

\textbf{RESULTS}

\textbf{Studies and participants}

The detailed process of the search is shown in Figure S1. To summarize,
we collected a total of 2631 articles, and after eliminating 627
duplicate articles, then we performed title and abstract screening. The
remaining 292 articles were read in full text. After excluding other
study types, those without full text, and those that did not meet the
inclusion criteria, we finally found 14 eligible studies (4 were
RCTs\textsuperscript{{[}14-17{]}}; 10 were observational
studies\textsuperscript{{[}18-27{]}}).

14 studies with a total of 21,546 patients participated in the
meta-analysis, in which 12 studies compared SAPT (aspirin/clopidogrel)
and DAPT (aspirin +ticlopidine / clopidogrel) and 2 studies compared
SAPT +OAC (aspirin +OAC) and DAPT+OAC (aspirin +clopidogrel +OAC). All
studies were published in English. All studies were published during the
decade 2011 to 2021 and their follow-up time ranged from 1 to 25 months,
with a mean follow-up time of 8.6 months. All included studies reported
all-cause mortality as the primary outcome indicator, with 12 studies
reporting stroke, 6 studies reporting cardiovascular mortality, and 9
studies reporting the incidence of MI, while 8 studies also reported the
rate of bleeding during the study. Three studies provided details of the
bleeding.

Both study groups were predominantly elderly (SAPT group: 81.51 years;
DAPT group: 82.22 years). The patients studied were moderately divided
between men and women, with 50.53\% female in the SAPT group and 48.86\%
in the DAPT group, that tended to suffer from multiple diseases,
including hypertension (80.62\% vs 81.29\%) and diabetes mellitus
(27.14\% vs 28.73\%). Data from two studies\textsuperscript{{[}18,
20{]}} were selected for baseline levels of participants after
propensity score matching because there were multiple baseline levels
that were statistically different. The remainder had one significant
difference with diabetes (\emph{P} = 0.046)\textsuperscript{{[}27{]}}and
one correlation with peripheral arterial disease (\emph{P} =
0.001)\textsuperscript{{[}19{]}} among the baselines included in the
study. There was no significant correlation in previous stroke, MI,
percutaneous coronary intervention and coronary artery disease in both
groups. Detailed baseline characteristics information of the study
literature is presented in Table S1.

\textbf{Quality Assessment}

Studies from RCTs were assessed for quality utilizing the Cochrane
Collaboration Risk of Bias Tool, as shown in Figure S2. The quality of
observational studies was assessed by the NOS, as shown in Table 1. The
results concluded that all RCTs and observational studies were of high
quality.

\textbf{Outcomes}

Five studies \textsuperscript{{[}14, 15, 17, 20, 26{]}} had clinical
events defined according to the Valve Academic Research Consortium
(VARC)\textsuperscript{{[}28{]}}, five studies \textsuperscript{{[}16,
18, 24, 25, 27{]}} had clinical events defined according to the Valve
Academic Research Consortium-2 (VARC-2)\textsuperscript{{[}29{]}}, three
others were not found\textsuperscript{{[}21-23{]}}, and there was one
study\textsuperscript{{[}19{]}} that cardiovascular adverse events by
the \emph{International Classification of Diseases} (Ninth
Revision)\textsuperscript{{[}30{]}}.

All-cause mortality

Pooled analysis showed no significant difference in the incidence of
all-cause mortality between SAPT and DAPT groups (RR {[}95\% CI{]} =
0.92 {[}0.70-1.20{]}, \emph{P} = 0.54), with large heterogeneity between
the two groups of studies (\emph{I} \textsuperscript{2} = 52\%,
\emph{P}= 0.01). Classifying them by study type subgroup, the incidence
of all-cause mortality in both RCTs and observational studies was not
statistically significant, with no significant within-group
heterogeneity (\emph{I} \textsuperscript{2} = 0\%, \emph{P} = 0.68).
There was no significant heterogeneity among RCTs studies (\emph{I}
\textsuperscript{2} = 0\%, \emph{P} = 0.77), and the major heterogeneity
was present in relation to observational studies (\emph{I}
\textsuperscript{2} = 65\%, \emph{P} = 0.0002), as shown in Figure 1.

Stoke

A random effects model was selected to analyze the data on the incidence
of stroke in the SAPT and DAPT groups, which showed no significant
difference between the two groups (RR {[}95\% CI{]}
=1.00{[}0.84-1.19{]}, \emph{P} = 1.00), while no significant
heterogeneity was found in this analysis (\emph{I} \textsuperscript{2} =
0\%, \emph{P} = 0.88). We then performed subgroup analysis by follow-up
time with study category, and no significant heterogeneity was found in
any of them (\emph{I} \textsuperscript{2} = 0\%), as shown in Figure S3.

All bleeding

Seven sets of data on the bleeding rate in SAPT and DAPT groups were
analyzed by random effects model, and it was found that the bleeding
rate in the DAPT group was significantly higher than that in the SAPT
group (RR {[}95\% CI{]} =0.56{[}0.48-0.65{]}, \emph{P} \textless{}
0.001), with a statistically significant difference, and no
heterogeneity was found between the two data groups (\emph{I}
\textsuperscript{2} = 0\%, \emph{P} = 0.69). Heterogeneity was also
small in all subgroups when they were analyzed by subgroup, as shown in
Figure 2.

Secondary outcome indicators

The results after combining statistics using the selected random effects
model showed no significant difference between SAPT and DAPT overall in
the incidence of cardiovascular mortality (RR {[}95\%CI{]}
=0.81{[}0.42-1.58{]}, \emph{P} = 0.54), with moderate heterogeneity
between the two groups (\emph{I} \textsuperscript{2} = 38\%, \emph{P} =
0.15). Then analysis of the data by follow-up time subgroup revealed a
significant difference in cardiovascular mortality over a short period
(RR {[}95\% CI{]} =0.39 {[}0.19-0.78{]}, \emph{P} = 0.008), but
within-group heterogeneity was greater (\emph{I} \textsuperscript{2} =
82.1\%, \emph{P} = 0.02) and the data may be more biased, as shown in
Figure S4. There was also no statistical difference in the incidence of
MI between the two data sets (RR {[}95\% CI{]}
=0.85{[}0.65-1.11{]},\emph{P} = 0.23), and no significant heterogeneity
was found in this analysis (\emph{I} \textsuperscript{2} = 0\%, \emph{P}
= 0.60), as shown in Figure S4. Data analysis revealed an equally
significant variability in the incidence of major bleeding and LTB
events (RR {[}95\%CI{]} =0.59{[}0.47-0.76{]}, \emph{P} \textless{}
0.0001) with less heterogeneity between data (\emph{I}
\textsuperscript{2} = 1\%, \emph{P}= 0.40), as shown in Figure 3.

\textbf{Publication bias}

Regarding publication bias, funnel plot analysis was performed for the
main outcome indicators (all-cause mortality, stroke, and all bleeding),
and no evidence of publication bias was found, as shown in Figure S6.
Egger's regression tests were also performed for the main outcome
indicators, and their test values all exceeded 0.05, indicating no
publication bias, as shown in Table S2.

\textbf{Meta regression}

Meta-regression analysis of mixed effects was performed with study type
(observational study VS RCTs), follow-up time and total sample size as
continuous moderating variables and random effects as study variables.
Meta-regression analysis showed no interaction between the moderating
variables and all-cause mortality, stroke, total bleeding rate, MI,
cardiovascular mortality, and major bleeding and LTB, as shown in Table
2.

\textbf{DISCUSSION}

In this meta-analysis, we retrieved all studies that met the inclusion
criteria as a way to compare the safety and efficacy of different
antiplatelet treatment strategies after TAVR. The results of data
analysis illustrated that bleeding including major bleeding and
life-threatening bleeding risks were increased in the choice of DAPT
treatment modality after TAVR, while there was no significant difference
between the two treatment modalities of SAPT and DAPT in terms of
all-cause mortality, stroke, and MI. Therefore, the conclusion of our
data analysis supports the choice of SAPT treatment modality as the
optimal antiplatelet strategy after TAVR, with superior safety to DAPT.

Patients after TAVR are prone to cerebrovascular events such as stroke,
mainly because of the formation of subclinical leaflet
thrombosis\textsuperscript{{[}31, 32{]}} and reduced aortic valve
motion\textsuperscript{{[}33{]}}, which alters valve hemodynamics and
thus increases the occurrence of cerebrovascular
events\textsuperscript{{[}34{]}}. In a comprehensive analysis, 12\% of
patients developed subclinical lobar thrombosis within 83 days after
TAVR, and thrombus formation was significantly correlated with stroke
events\textsuperscript{{[}35{]}}. Meanwhile,
Polzin\textsuperscript{{[}36{]}} found that antiplatelet therapy such as
postoperative DAPT did not alter the course of subclinical thrombosis,
which is similar to our findings. Of the three studies included with
short follow-up for cardiovascular mortality, two were RCTs with small
data sizes and one was an observational study with large data sizes,
high weights, and large biases. In the observational study, physicians
may have developed appropriate antiplatelet therapy regimens for
patients based on their postoperative performance and ischemic risk
(assigning patients at high risk for ischemia with a history of MI or
PCI to the DAPT group and patients at high risk for bleeding to the SAPT
group\textsuperscript{{[}37{]}}). It eventually emerged that patients in
the DAPT group were in worse condition, so that the two groups ended up
with more significant differences in the subgroups.

TAVR procedure has become the treatment of choice for patients with
moderate to severe aortic stenosis, with less invasive, higher safety
and faster patient recovery compared to SAVR\textsuperscript{{[}38{]}}.
However, since it is also an interventional treatment modality, it
inevitably carries a higher risk of stroke and
bleeding\textsuperscript{{[}39{]}}. The results of our meta-analysis
showed that the incidence of stroke after TAVR with different
antiplatelet therapy modalities did not differ significantly in both
subgroup cases in terms of follow-up time and study type. The causes of
bleeding in patients after TAVR are often composed of multiple factors:
(1) higher risk of gastrointestinal bleeding due to the mean age of the
patients undergoing the procedure itself, as well as susceptibility to
atherosclerotic occlusive disease and the development of femoral
arteriopathy and other vascular complications\textsuperscript{{[}40{]}};
(2) female patients are more prone to postoperative bleeding due to
their own estrogen, smaller femoral artery vessels,
etc.\textsuperscript{{[}41{]}}; (3) concurrent chronic kidney disease,
which predisposes to platelet dysfunction and abnormal enzyme
coagulation cascade, increasing the bioavailability of antiplatelet
drugs, reducing their excretion, and increasing the risk of
bleeding\textsuperscript{{[}42{]}}; (4) the influence of factors of the
surgery itself on postoperative bleeding , the results of a
meta-analysis showed\textsuperscript{{[}43{]}} that the mode of surgery
(transapical access/subclavian access), sheath diameter
(\textgreater{}19 Fr), and circulatory support are mechanical causes of
postoperative bleeding; (5) last but not least, the postoperative
antiplatelet strategy also has a greater impact on postoperative
bleeding in patients with TAVR. And considering the vulnerability to
device-related thromboembolic events after TAVR as the metal valve
becomes endothelialization. European guidelines recommend DAPT treatment
modalities (low-dose (75-100 mg once daily) acetylsalicylic acid and
clopidogrel (75 mg once daily)) for the first 3-6 months initially,
followed by lifelong SAPT antiplatelet
therapy\textsuperscript{{[}44{]}}. And the latest consensus recommends
that post-TAVR patients without coronary artery stenosis within three
months have a preference for antiplatelet therapy in the form of
SAPT\textsuperscript{{[}45{]}}, but the evidence supporting its
recommendation was not high grade. Analysis of our data showed that the
likelihood of bleeding was greater with either long-term DAPT
(\textgreater{}6mth) or short-term DAPT ([?]6mth) antiplatelet therapy
than with SAPT, but there was no significant difference in all-cause
mortality, stroke, or MI. This result is similar to the results of
several previous meta-analyses: Zhu et
al\textsuperscript{{[}46{]}}conducted a network meta-analysis of eight
studies examining the riskiness of death and bleeding in SAPT, DAPT, and
OAC, and the final results showed a significantly lower risk of bleeding
in SAPT compared with DAPT and OAC; Kuno et al\textsuperscript{{[}47{]}}
performed a meta-analysis of four RCTs and three retrospective studies,
and the results similarly showed that the SAPT treatment modality had a
smaller bleeding rate at either 3 or 6 months and did not increase the
risk of death or stroke compared to the DAPT group. The use of the DAPT
regimen comes at the cost of increased risk of bleeding in patients,
especially major bleeding and life-threatening severe bleeding.
Regardless of the length of follow-up and the type of study, DAPT
increases the risk of bleeding in patients.

\textbf{Limitations}

Our study has several limitations. First, this meta-analysis included 4
RCTs and 10 observational studies, and the observational studies had a
large weighting, making the analysis vulnerable to selection bias and
confounding factors. Second, the 14 studies were not more consistent in
their definitions of adverse events, with references to VARC, VARC-2, or
BARC, making the registration of events such as bleeding subject to
error. Finally, we included studies whose follow-up time ranged from 1
month to 25 months, a large time span, and divided them into two groups
for comparative analysis, the incidence of adverse events with longer
follow-up time was significantly more than short-term, making some
results not significantly different in the pooled analysis.

\textbf{CONCLUSION}

We retrieved the largest number of eligible studies as a recent
meta-analysis, and the results of the data analysis suggest that SAPT
may better reduce the risk of bleeding and short-term cardiovascular
mortality in patients after TAVR compared with DAPT treatment
modalities, without increasing the incidence of all-cause mortality,
stroke, or MI in patients. Although more clinical studies are needed to
evaluate this finding, SAPT is expected to be the preferred antiplatelet
therapy option recommended in the next guideline update for patients
without an indication for anticoagulation after TAVR.

\textbf{Acknowledgements}

The authors would like to thank all participating authors for they
valuable help in methodology.

\textbf{Conflict of interest statement}

None

\textbf{Founding information}

None

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