CARREV-02562; No of Pages 6

Cardiovascular Revascularization Medicine xxx (xxxx) xxx

Contents lists available at ScienceDirect

Cardiovascular Revascularization Medicine

Sex differences in the clinical outcomes after left atrial appendage

closure: A systematic review and meta-analysis
Waiel Abusnina a, Azka Latif a, Ahmad Al-abdouh b, Mostafa R. Mostafa c, Qais Radaideh a, Yazeid Alshebani a,
Ahmad Aboeata a, Itsik Ben-Dor d, Erin D. Michos e, Khagendra Dahal a,⁎
a
Department of Cardiology, Creighton University School of Medicine, NE, USA
b
Department of Medicine, University of Kentucky, KY, USA
c
Department of Medicine, Rochester Regional/Unity Hospital, NY, USA
d
Section of Interventional Cardiology, MedStar Washington Hospital Center, Washington, DC, USA
e
Division of Cardiology, Johns Hopkins University School of Medicine, Baltimore, MD, USA

a r t i c l e i n f o a b s t r a c t

Article history: Introduction: Left atrial appendage occlusion (LAAO) has emerged as a reasonable alternative to oral anticoagu-
Received 25 October 2021 lation in a selective group of patients with atrial fibrillation (AF). While women are known have higher risk of
Received in revised form 12 December 2021 AF-related stroke, the impact of sex differences on the clinical outcomes of LAAO has not been well studied.
Accepted 13 December 2021 Objective: We sought to perform a meta-analysis evaluating sex differences on the outcomes of patients under-
Available online xxxx
going LAAO.
Methods: We searched PubMed, EMBASE, Cochrane Central Register of Controlled Trials, and ClinicalTrials.gov
Keywords:
Atrial fibrillation
databases (from inception to October 2021) for studies evaluating the impact of sex difference on LAAO proce-
Non-valvular atrial fibrillation dural outcomes. We used a random-effect model to calculate risk ratio (RR) with 95% confidence intervals
Left atrial appendage (CI). In-hospital all-cause mortality and ischemic stroke were the primary endpoints. In-hospital pericardial effu-
Left atrial appendage occlusion sion/cardiac tamponade, major bleeding, technical success, device related thrombus and hospital length of stay
Watchman device were secondary outcomes.
Amulet Results: A total of 5 studies with 54,754 patients were included, of which 22,461 (41%) were females. Female sex
Plaato was associated with higher rates of in-hospital all-cause mortality (RR 2.18; 95% CI 1.46–3.26; P = 0.0001) and
Gender difference
in-hospital ischemic stroke (RR 1.67; 95% CI 1.06–2.61; P = 0.03) when compared with males. Females had
higher rates of in-hospital major bleeding (RR 1.93; 95% CI 1.40–2.67; P < 0.0001) and hospital length of stay
>1 day (RR 1.38; 95% CI 1.33–1.45; P < 0.00001). There was no differences between females and males in
terms of technical success and device related thrombus (RR 1.00; 95% CI 1.00–1.00; P = 1.00) and (RR 0.94,
95% CI 0.31–2.82; P = 0.91), respectively.
Conclusion: In conclusion, women are more likely to experience worse periprocedural outcomes with longer hos-
pital stay after LAA closure. Further efforts are needed to increase the participation of women in clinical studies
and to assess these differences to properly address the discrepancy in outcomes between men and women.
© 2021 Published by Elsevier Inc.

1. Introduction
Atrial fibrillation (AF) is the most common persistent cardiac ar-
rhythmia in men and women. It increases the risk of stroke by about 3
to 5 fold and is associated with higher morbidity and mortality [1].
Population based studies showed that women have higher risk of AF-
Abbreviations: AF, atrial fibrillation; LAAO, left atrial appendage occlusion (LAAO);
TLR, target lesion revascularization; DCB, drug coated balloon.
⁎ Corresponding author at: Department of Medicine, Division of Cardiology, Creighton
University School of Medicine, CHI Health, Omaha, USA.
E-mail address: khagendra.dahal@creighton.edu (K. Dahal).
associated stroke and mortality compared to men [2]. These findings
led to adding female sex as an additional risk factor to increase the accu-
racy of the CHADS2 stroke risk stratification model (Congestive heart
failure, Hypertension, Age 75 years or greater, Diabetes mellitus, and
previous history of Stroke or TIA). In addition to that, incorporating
the history of vascular disease and dichotomizing the age item resulted
in establishing the CHA2DS2-VASc schema [3].
Although chronic anticoagulation has been the standard pharmaco-
logic approach to decrease the risk of the stroke, left atrial appendage
occlusion (LAAO) has emerged as an alternative approach to decrease
the risk of stroke in patients who cannot tolerate chronic anticoagula-
tion [4]. The 5-year outcomes of the PROTECT AF (WATCHMAN Left
Atrial Appendage System for Embolic Protection in Patients with Atrial

https://doi.org/10.1016/j.carrev.2021.12.013
1553-8389/© 2021 Published by Elsevier Inc.

Please cite this article as: W. Abusnina, A. Latif, A. Al-abdouh, et al., Sex differences in the clinical outcomes after left atrial appendage closure: A
systematic review an..., Cardiovascular Revascularization Medicine, https://doi.org/10.1016/j.carrev.2021.12.013
W. Abusnina, A. Latif, A. Al-abdouh et al.
Fibrillation) trial and the PREVAIL (Evaluation of the WATCHMAN LAA
Closure Device in Patients with Atrial Fibrillation Versus Long Term
Warfarin Therapy) trial showed that using the Watchman device
(Boston Scientific, St. Paul, Minnesota) for LAAO was non-inferior to
warfarin in decreasing the risk of stroke with additional benefit in
decreasing the risk of bleeding [5]. Women with AF were reported to
have higher risk of stroke compared with men after anticoagulation
using warfarin and after atrial ablation procedure on continuous antico-
agulation [6,7].
Several recently published studies compared the sex differences in
outcomes for patients undergoing LAAO with conflicting results,
which limits the understanding of the safety and efficacy of this proce-
dure in women vs men [8–12]. By pooling all available data together,
the aim of this meta-analysis is to evaluate whether there are differ-
ences between men and women in terms of the procedural and long-
term outcomes following a LAAO procedure, which would have implica-
tions for recommendations for patients in clinical practice.
2. Methods
2.1. Search strategy and study selection
A meta-analysis was performed according to the Preferred Reporting
Items for Systematic Reviews and Meta-Analyses 2009 guidelines [13].
Two reviewers (WA & AL) independently identified the relevant studies
by an electronic search of the PubMed, EMBASE, Cochrane Central Reg-
ister of Controlled Trials, and ClinicalTrials.gov databases (from incep-
tion to October 2021) (Supplementary Table 1). References of the
retrieved studies were also screened further for relevant studies. The
following search terms and key words were used: “left atrial append-
age” OR “left atrial appendage occlusion” OR “left atrial appendage clo-
sure” OR “watchman device” OR “amulet” OR “plaato” AND “atrial
fibrillation” OR “non-valvular atrial fibrillation” AND “gender differ-
ence” OR “sex difference”. No language, publication date or publication
status restrictions were imposed.
Two reviewers (WA & AL) independently assessed trial eligibility
based on titles, abstracts, and full-text reports. Discrepancies in study
selection were discussed and resolved with another author (KD). Eligi-
ble studies had to satisfy the following prespecified criteria: (a) patients
undergoing left atrial appendage closure (b) studies evaluating the im-
pact of sex on outcomes and (c) availability of procedural and in-
hospital outcome data. Exclusion criteria were: (a) lack of any clinical
outcome data; (b) duplicate publications and (c) reviews, editorials, let-
ters, and non-human studies.
2.2. Data collection and risk of bias assessment
Two investigators (WA & QR) independently extracted data (base-
line characteristics, definition of outcomes and number of events)
Table 1
Characteristics of the involved studies.
First author Design Study's period Total Female
(publication year) number
Zhao et al. (2020) Retrospective February 2012 to
September 2018
De caterina et al. (2021) Prospective observational study June 2015 through
October 2018
Kleinecke et al. (2021) Prospective observational non- July 2014 and
randomized January 2016.
Sanjoy et al. (2021) Retrospective observational study January 2015 to
October 2017
Darden et al. (2021) Retrospective observational study January 2016, to 49,357
June 2019
2
Cardiovascular Revascularization Medicine xxx (xxxx) xxx
using a standardized data abstraction form. The same investigators in-
dependently and systematically assessed the studies' methodological
quality using the Newcastle-Ottawa Scale (Supplemental Table 2),
disagreements were resolved by a third author (KD). We assessed for
publication bias using the funnel plots for the outcomes (Supplemental
Fig. 1).
2.3. Outcome measures
The primary endpoint was in-hospital all-cause mortality and ische-
mic stroke. Additional, in-hospital outcomes were pericardial effusion/
cardiac tamponade, major bleeding, technical success, hospital stay,
and device-related thrombus. Long term outcomes included are all-
cause mortality, bleeding, cardiovascular death, and stroke. Two studies
[10,11] reported long term outcomes at average follow up of 2 years and
one study [12] reported 1 year follow up outcomes. Endpoints were at-
tributed according to the definition used in each study.
2.4. Data analysis
For the categorical outcomes, the risk ratios (RRs) with 95% confi-
dence intervals (CI) were calculated from the available data in the in-
cluded trial and trial-specific RR and were combined using the
DerSimonian and Laird random effects with the estimate of heterogene-
ity using the Mantel–Haenszel model. We used I2 statistic to measure
heterogeneity among the included trials; a value of 0% indicating no
observed heterogeneity, and larger values showing increasing hetero-
geneity. I2 values of 25%, 50%, 75% were low, moderate, and high hetero-
geneity, respectively. The presence of publication bias for each outcome
was investigated by visual estimation with the use of funnel plots when
data was available in at least three studies. Results were reported ac-
cording to the Preferred Reporting Items for Systematic Reviews and
Meta-Analyses Protocol (PRISMA-P) 2009 statement. Analyses were
performed using Review Manager (RevMan) Version 5.3 (The Nordic
Cochrane Centre, The Cochrane Collaboration, Copenhagen, Denmark).
Our meta-analysis registered through PROSPERO with acknowledge-
ment of receipt [283118].
3. Results
A total of 5 studies [8–12] with 54,754 patients undergoing LAAO
were included, of which 22,461 were females. The median follow-up
duration was 1.7 year for long term outcomes. The characteristics of
the included trials and the patients' demographic features are presented
in Tables 1 and 2, respectively.
In pooled analyses, female sex was associated with higher rates of
in-hospital all-cause mortality (RR 2.18; 95% CI 1.46–3.26; P =
0.0001; I2 = 0%; Fig. 1-A) and in-hospital ischemic stroke (RR 1.67;
95% CI 1.06–2.61; P = 0.03, I2 = 0%, Fig. 1-B) when compared with
Male Device type
377 126 251 Watchman device
(33.4%) (66.6%)
1088 386 702 Amplatzer ™ Amulet™
(35.5%) (64.5%)
638 248 390 Watchman device, Amplatzer cardiac plug and
(38.9%) (61.1%) Amulet, Occlutech, Lambre, Lariat
{Watchman device [females, 105 (42.3%) and males,
173 (44.5%)] or Amplatzer cardiac plug and amulet device
[females, 134 (54.0%) and males, 206 (52.8%)]}
3294 1313 1981 Watchman device
(39.9%) (60.1%)
20,388 28,969 Watchman device
(44.3%0 (55.7%)
W. Abusnina, A. Latif, A. Al-abdouh et al. Cardiovascular Revascularization Medicine xxx (xxxx) xxx

Table 2
Patient characteristics of the included trials.

Characteristic Zhao et al. (2020) De Caterina et al. (2021) Kleinecke et al. (2021) Sanjoy et al. (2021) Darden et al. (2021)

Female Male Female Male Female Male Female Male Female Male
(126) (251) (386) (702) (248) (390) (1313) (1981) (20388) (28969)

Age (years) 77.5 ± 6.2 74.1 ± 8.3 76.2 ± 7.9 74.6 ± 8.7 76.4 ± 8.2 75.6 ± 7.7 76.3 ± 7.7 75.2 ± 8.4 76.5 ± 7.9 75.8 ± 8.2
CHA2DS2-VASc score (mean 4.3 ± 1.6 3.6 ± 1.3 4.7 ± 1.5 3.9 ± 1.6 4.9 ± 1.5 4.3 ± 1.5 4.9 ± 1.4 3.9 ± 1.4 5.3 ± 1.5 4.5 ± 1.4
± SD)
HAS-BLED score (mean ± SD) 3.5 ± 1.0 3.6 ± 1.1 3.2 ± 1.0 3.4 ± 1.1 3.8 ± 1.1 3.9 ± 1.1 N/A N/A 2.96 ± 1.1 3.04 ± 1.1
Diabetes 37 (29.4%) 66 (26.3%) N/A N/A 75 (30.2%) 142 381 (29%) 711 (36%) 7088 (34.8%) 11,468
(36.4%) (39.7%)
Hypertension 105 198 320 593 231 362 1117 1679 18,736 26,719
(83.3%) (78.9%) (82.9%) (84.5%) (93.1%) (92.8%) (85%) (85%) (92.0%) (92.3%)
Previous stroke 31 (24.6%) 51 (20.3%) 97 (25.1%) 202 63 (25.4%) 110 409 (31%) 563 (28%) 5288 (26.0%) 7104 (24.6%)
(28.8%) (28.2%)
Previous major bleeding 49 (38.9%) 88 (35.1%) 263 517 203 304 51(3.9%) 78 (3.9%) 14,245 20,287
(68.1%) (73.6%) (81.9%) (77.9%) (70.0%) (70.1%)
Congestive heart failure 15 (11.9%) 44 (17.5%) 48 (12.4%) 139 61 (24.6%) 111 454(35%) 782 (39%) 7025 (34.5%) 11,493
(19.8%) (28.5%) (39.7%)

males. In-hospital pericardial effusion/cardiac tamponade was higher in 4. Discussion

females (RR 1.98; 95%CI 1.15–3.43; P = 0.01, I2 = 26%, Fig. 1-C). Simi-
larly, females had higher rates of in-hospital major bleeding (RR 1.93;
95% CI 1.40–2.67; P < 0.0001; I2 = 16%, Fig. 2-A), and hospital length
of stay >1 day (RR 1.38; 95% CI 1.33–1.45; P < 0.00001; I2 = 0%,
Fig. 2-B). There was no difference between females and males in
terms of technical success and device related thrombus (RR 1.00; 95%
CI 1.00–1.00; P = 1.00, I2 = 0%, Fig. 2-C) and (RR 0.94, 95% CI
0.31–2.82; P = 0.91; I2 = 0%, Fig. 2-D), respectively.
Over a median follow-up of 1.7 years, there was no statistically
significant difference between females and males in terms of long
term all-cause mortality (RR 0.72; 95% CI 0.49–1.06; P = 0.10,
I2 = 55%, Fig. 3-A), long-term cardiovascular mortality (RR 0.88;
95% CI 0.65–1.20; P = 0.43, I 2 = 0%, Fig. 3-B), long-term stroke
(RR 1.08; 95% CI 0.63–1.86; P = 0.78, I2 = 5%, Fig. 3-C), and
long-term bleeding (RR 1.02; 95% CI 0.44–1.34; P = 0.88, I 2 =
55%, Fig. 3-D). Overall, heterogeneity was low and there was no
evidence of publication bias on visual inspection of funnel plot
(Supplemental Fig. 1).
The main findings of our meta-analysis evaluating sex differences
after LAAO procedure are as follows: 1) Women have higher
periprocedural/in-hospital outcomes including all-cause mortality, is-
chemic stroke, major bleeding, and pericardial effusion/cardiac tampon-
ade; 2) There was no difference in procedural success rate when
compared between women and men; 3) Women have higher rates of
hospital stay >1 day when compared to men and 4) There was no differ-
ence in long-term all-cause mortality, cardiovascular mortality, stroke,
and bleeding.
The PROTECT AF trial reported no difference in terms of composite
endpoints between men and women. However, sex-related safety
events are not reported by either the PROTECT or PREVAIL AF trials
[14,15]. The inclusion criteria of major trials on LAA closure for AF in-
cluded patients with CHA2DS2-VASc score of ≥1, which is in contrast
with the requirement of CHA2DS2-VASc score of ≥2 in patients unable
to receive long term anticoagulation in order to get reimbursed by
Centers for Medicare and Medicaid Services (CMS) for LAAO device

Fig. 1. Forest plot illustrating the outcomes results of (A. In-hospital all-cause mortality, B. In-hospital ischemic stroke, C. In-hospital pericardial effusion/cardiac tamponade).

3
W. Abusnina, A. Latif, A. Al-abdouh et al. Cardiovascular Revascularization Medicine xxx (xxxx) xxx

Fig. 2. Forest plot illustrating the outcomes results of (A. In-hospital major bleeding, B. Hospital length of stay >1 day, C. Technical success, D. Device related thrombus).

placement [16]. There was no significant difference in the CHA2DS2-
VASc score between the 2 groups in the included studies. The difference
in most of the studies was 1 unit which is because of the female sex. Our
results suggest worse periprocedural/in-hospital outcomes after LAA
closure in women resonate with the results of prior studies highlighting
adverse in-hospital events for women undergoing invasive procedures
such as percutaneous coronary intervention, catheter ablation for AF
and transcatheter aortic valve implantation [17–19]. This can be related
to the higher prevalence of comorbid conditions including older age, hy-
pertension, diabetes mellitus, and kidney dysfunction in women [15,
20]. Secondly, women tend to have higher risk of stroke and systemic
thromboembolism, hence female sex is assigned one point on
CHA2DS2-VASc score as compared to men when evaluating for antico-
agulation [10]. Likewise, anatomical differences among women and

Fig. 3. Forest plot illustrating the outcomes results of (A. Long term all-cause mortality, B. Long term cardiovascular mortality, C. Long-term stroke, D. Long-term bleeding).

4
W. Abusnina, A. Latif, A. Al-abdouh et al.
men, for instance small diameter of arteries and thinner myocardium
could also be contributing to adverse events in women [21]. Boucebci
et al. [22] reported that men had wider and longer LAAs compared
with women in normal conditions, as seen on cardiac computed tomog-
raphy (CT) scans. Elzeneini et al. [23]. scanned 252 patients with coro-
nary CT angiography in 2017 and concluded that females have
relatively larger LAA with subsequent higher risk of embolic stroke
due to blood stasis, less length and higher orifice positions. Moreover,
at a given age, women are noted to be frailer than men [21], and a recent
study suggests that frail patients take longer to recover requiring pro-
longed hospital stay while suffering from significant postoperative com-
plications such as stroke, major bleeding, myocardial infarction, and
mortality [24].
Analysis of the in-hospital outcomes showed that the rates of all-
cause mortality and ischemic stroke were greatest in the De Catarina
et al. study compared to the other 3 studies (Fig. 2A, B). Interestingly
De Catarina et al. study population used the Amplatzer Amulet device
for LAAO, which is different when compared to the other studies that
used the Watchman device. This might warrant that the type of device
could play a major factor in the mortality and ischemic stroke outcome.
Interestingly, a recent randomized control trial by Lakkireddy et al. [25]
that compared Amplatzer Amulet left atrial appendage occluder versus
Watchman device for stroke prophylaxis in a total of 1878 patients were
enrolled in the study. The study data showed that all-cause mortality
and ischemic stroke were similar between the two groups. The ischemic
stroke rate was 1.67%/year for the Amulet occluder and 1.94%/year for
the Watchman device. The mortality rate was 3.9% for the Amulet
occluder vs 5.1% for the Watchman device [25]. Procedural technical
success was found to be similar between men and women in our
study. Additionally, no significant differences were found for long-
term outcomes between men and women. However, it is worth noting
women represent only 20–30% of patients in major cardiovascular trials
as well as registries [10,14,15]. This underrepresentation may lead to
the selection of women with less aggressive risk profiles to undergo
LAA closure making it difficult to compare outcomes between men
and women. Further efforts are needed to enhance the participation of
women in clinical trials and registries to make these results generaliz-
able for patients undergoing LAAO. Although we cannot fully explain
the causes of the increased risk of adverse events experienced by
women, there are several suggested strategies to reduce the procedural
risk including: 1) using ultrasonography-guided venous access; 2) pre-
procedural imaging to evaluate cardiac function, LAA size and morphol-
ogy to guide equipment and device selection; 3) further developing
proficiency with LAAO devices; 4) continuing to train structural inter-
ventional physicians to increase the experience level; and 5) continued
development of safer devices. Recently, the U.S. Food and Drug Admin-
istration (FDA) released a letter to the health care providers [26] regard-
ing the potential procedural outcome difference between men and
women associated with LAAO. The FDA's recommendations included
continuous monitoring of patients treated with LAAO devices as per
the current standard of care, discussing the risks and benefits of avail-
able options for stroke prevention in patients with AF and reporting of
adverse events or suspected adverse events experienced with the use
of LAAO devices. Lastly, increasing women representation in clinical tri-
als will help for better understanding of the clinical outcomes based on
the sex difference.
4.1. Limitation
There are a few limitations applicable to our meta-analysis. Firstly,
the included studies are retrospective without randomization; thus,
the generalizability of results is limited. Secondly, most studies are on
different databases, and unfortunately it was difficult to account for pos-
sible coding errors. Thirdly, the use of appropriate anticoagulants and
antiplatelets after LAA closure was not mentioned in most studies. Like-
wise, we were unable to account for confounders such as criteria for
5
Cardiovascular Revascularization Medicine xxx (xxxx) xxx
patients' selection, transesophageal echocardiogram measurements
and interpretation, and operator's experience to perform the procedure.
Only one study reported the size of the device, so we did not include it in
the basic characteristics table. One of the studies [8] used national inpa-
tient sample data, which could provide some limitation. The study by
Darden et al. [9] had total of 49,357 patients which is much higher
than the other studies and that might skew the result of the meta-
analysis. Despite these limitations, our meta-analysis provides an im-
portant insight into the sex differences in the outcomes after LAA clo-
sure procedures which warrant further study to mitigate these
disparities.
5. Conclusion
In conclusion, women are more likely to experience worse peripro-
cedural outcomes with longer hospital stay after LAA closure. Long-
term follow-up demonstrated no significant differences in the risk of
all-cause mortality, cardiovascular mortality, stroke, and bleeding. Fur-
ther efforts are needed to increase the participation of women in clinical
studies and to assess these differences to properly address the discrep-
ancy in outcomes between men and women.
Supplementary data to this article can be found online at https://doi.
org/10.1016/j.carrev.2021.12.013.
CRediT authorship contribution statement
Waiel Abusnina: Conceptualization, Methodology, Formal analysis,
Writing- Original draft preparation. Azka Latif: Data curation,
Writing- Original draft preparation. Ahmad Al-abdouh: Visualization,
Investigation. Mostafa R Mostafa: Investigation. Qais Radaideh: Inves-
tigation, Validation. Yazeid Alshebani: Writing - Review & Editing.
Ahmad Aboeata: Writing - Review & Editing. Itsik Ben-Dor: Writing -
Review & Editing. Erin Michos: Writing- Reviewing and Editing,
Khagendra Dahal: Conceptualization, Methodology, Supervision,
Writing- Reviewing and Editing.
Declaration of competing interest
The authors declare that they have no known competing financial
interests or personal relationships that could have appeared to influ-
ence the work reported in this paper.
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