Original article

Indications for percutaneous left atrial appendage occlusion

in hospitalized patients with atrial fibrillation
Eleni Vranaa, Anastasios Kartasa, Athanasios Samarasa, Dimitra Vasdekia,
Evropi Forozidoua, Evangelos Liampasa, Haralambos Karvounisa,
George Giannakoulasa and Apostolos Tzikasa,b

Aims Percutaneous left atrial appendage occlusion (LAAO)
is an alternative nonpharmacological therapeutic option for
stroke prevention in patients with NVAF. However, no data
exist on potential LAAO candidates’ prevalence among ‘real-
world’ NVAF patients. This study aimed to investigate the
indications for LAAO in hospitalized patients with comorbid
nonvalvular atrial fibrillation (NVAF).
Methods This is a post-hoc analysis of the MISOAC-AF
(Motivational Interviewing to Support OAC-AF,
ClinicalTrials.gov: NCT02941978), randomized controlled trial,
which enrolled NVAF patients hospitalized for any reason in a
tertiary cardiology department. In this analysis, patients with a
history of major bleeding or stroke under OAC therapy were
considered to have a strong indication for LAAO.
experienced an embolic stroke while being treated using
OAC. Overall, either of these events was prevalent in 173
(17.7%) patients, denoting a strong indication for LAAO.
Conclusion Almost one out of six patients hospitalized
with comorbid NVAF may be considered eligible for
percutaneous LAAO for stroke prevention.
Trial Identification: NCT02941978, https://clinicaltrials.gov/
ct2/show/NCT02941978.
J Cardiovasc Med 2022, 23:176–182
Keywords: atrial fibrillation, left atrial appendage closure, stroke
a
First Department of Cardiology, AHEPA University Hospital, Aristotle University
of Thessaloniki and bDepartment of Cardiology, Interbalkan European Medical
Center, Pylaia, Thessaloniki, Greece

Results A total of 980 patients with NVAF were studied Correspondence to Apostolos Tzikas, MD, PhD, St. Kiriakidi 1, 54636
(mean age 73.9 W 10.9 years, 54.7% men). Prior major Thessaloniki, Greece
E-mail: aptzikas@yahoo.com
bleeding occurred in 134 (13.7%) patients (intracranial
bleeding in 1%, upper and lower gastrointestinal bleeding in Received 7 January 2021 Revised 5 May 2021
6.4 and 8.9%, respectively). A total of 58 (5.9%) patients Accepted 19 June 2021

Introduction recommends potential indications for LAAO but also

suggests individual consideration of the use of LAAO.8,9
The majority of patients with nonvalvular atrial fibrilla-
Currently, the LAAO procedures are increasing expo-
tion (NVAF) require oral anticoagulation (OAC) therapy
nentially worldwide. According to the LAAO Registry
to prevent stroke and other systemic arterial thromboem-
(NCT02699957), almost 20 000 transcatheter LAAO pro-
bolisms.1,2 Despite its proven efficacy, OAC has been
cedures were performed during 2018 in the United
associated with severe bleeding complications, variable
States, with an anticipated 25 000 procedures per year
tolerability, and suboptimal compliance.3–5 Hence, some
in 2019 and thereafter. However, as the best recommen-
patients at high risk for stroke may be unable or unwilling
dation remains a class IIb, there are still potential eligible
to comply with proper lifelong OAC treatment. This
candidates for LAAO who are not offered the proce-
raises the need for alternative strategies for thrombopro-
dure.10 Therefore, choosing the right patients for trans-
phylaxis.6
catheter LAAO is a matter of great importance.
Left atrial appendage occlusion (LAAO) is a promising
In this study, we analyzed a ‘real-world’ contemporary
nonpharmacologic strategy for stroke prevention in
cohort of hospitalized patients with NVAF. We aimed to
patients with NVAF. Its rational arises from echocardi-
identify the potential indications for LAAO in this
ography, autopsy, and surgical observations showing that
specific population.
in patients with NVAF, more than 90% of thrombi are
found in the left atrial appendage (LAA).7 The latest
European Society of Cardiology (ESC) guidelines on Methods
NVAF suggest that LAA occlusion may be considered This was a post-hoc analysis of the MISOAC-AF trial11,12
for stroke prevention in patients with NVAF and contra- (Motivational Interviewing to Support Oral AntiCoagula-
indications for long-term anticoagulant treatment.1 A tion Adherence in patients with nonvalvular Atrial Fibril-
recently published ESC expert consensus paper not only lation, ClinicalTrials.gov identifier: NCT02941978),
1558-2027 ß 2021 Italian Federation of Cardiology - I.F.C. All rights reserved. DOI:10.2459/JCM.0000000000001226

© 2022 Italian Federation of Cardiology - I.F.C. All rights reserved.


which was a prospective, two-arm, randomized controlled
trial. MISOAC-AF included consecutive patients hospi-
talized for any reason in the cardiology ward of AHEPA
University Hospital between December 2015 and June
2018 with a primary or secondary diagnosis of atrial
fibrillation or atrial flutter (paroxysmal, persistent or
permanent). The trial’s baseline study population
included patients with nonvalvular atrial fibrillation;
patients with rheumatic mitral stenosis or presence of
mechanical valves were excluded.13 Its objective was to
investigate the impact of physician–patient motivational–
educational intervention in addition to usual care, in
terms of improving the adherence of patients with atrial
fibrillation to OAC treatment, in comparison with
patients who have been randomly assigned to stan-
dard-of-care. The study was carried out according to
the principles of Good Clinical Practice and the Declara-
tion of Helsinki.
The risk of systemic thromboembolism and the risk of
bleeding were assessed using the CHA2DS2-Vasc
(congestive heart failure, hypertension, age 75 years,
diabetes mellitus, stroke/transient ischemic attack, vas-
cular disease, age 65–74 years, sex category)14 and HAS-
BLED (hypertension, abnormal renal/liver function,
stroke, bleeding history or predisposition, labile INR,
elderly patients, drugs/alcohol)15 score, respectively. The
estimated glomerular filtration rate (eGFR) was assessed
using the Cockcroft–Gault formula.16
Bleeding events were categorized into major, clinically
relevant nonmajor and minor bleedings.17 As major bleed-
ing was considered any symptomatic bleeding in an area or
organ, such as intracranial and gastrointestinal bleeding
and/or bleeding causing a fall in the hemoglobin level of
2 g/dl (1.24 mmol/l) or more, or leading to transfusion of
two or more units of blood. In our cohort, the only reported
major bleedings were intracranial hemorrhages, upper and
lower gastrointestinal bleedings. Clinically relevant non-
major bleeding was considered an acute or subacute clini-
cally overt bleed that did not meet the criteria for a major
bleed but prompted a clinical response such that it led to
one of the following: hospital admission for bleeding;
physician-guided medical or surgical treatment for bleed-
ing; change in antithrombotic therapy (including interrup-
tion or discontinuation). Minor bleeding was considered
any epistaxis or bleeding of any other source, such as
gingival bleeding, that did not require hospital admission,
physician-guided treatment, or change in antithrombotic
therapy.18 Stroke on OAC was thought to be an acute
episode of focal or global neurological dysfunction while
on treatment with OAC [either vitamin K antagonist
(VKA) or nonvitamin K antagonist oral anticoagulant
(NOAC)], caused by brain, spinal cord, or retinal vascular
injury as a result of infarction, if symptoms or signs were
persistent for more than 24 h, or if documented by com-
puted tomography (CT) or MRI.17 All retrospective clini-
cal events were verified by medical records and
© 2022 Italian Federation of Cardiology - I.F.C. All rights reserved.
Percutaneous left atrial appendage occlusion Vrana et al. 177
adjudicated by independent physicians in the MISOAC-
AF trial.12 The patients’ adherence to OAC treatment at 1
year was the primary study outcome of the MISOAC-AF
trial. It was estimated prospectively by the ‘Proportion of
days covered’ (PDC), which is widely studied and one of
the most reliable indirect methods of measuring adherence
to therapy.19,20
Statistical analysis
Continuous data are presented as means with standard
deviation, CHA2DS2-Vasc, and HAS-BLED scores are
also presented as medians and interquartile range. Cate-
gorical data are presented as frequencies and percen-
tages. Missing data of the variables concerning LAAO
indications, that is, history of major bleeding events,
stroke on OACs, HAS-BLED score, and eGFR stages
at discharge, were handled using listwise deletion
(Fig. 1). Data management and statistical analysis were
performed using IBM SPSS Statistics version 23.0 (IBM
Corp, Armonk, New York, USA) software.
Fig. 1
Total number of patients with NVAF
1009
Listwise deletion of patients with
missing values in at least one of the
following variables:
1. Prior major bleeding
missing values: 9 (0.9%)
2. Stroke on OAC therapy
missing values: 11 (1.1%)
3. HAS-BLED score
missing values: 1 (0.1%)
4. eGFR stages at discharge
missing values: 20 (2.0%)
Final population for analysis
980
Excluded patients and final study population. AF, atrial fibrillation;
eGFR, estimated glomerular filtration rate; HAS-BLED (Hypertension,
Abnormal renal/liver function, Stroke, Bleeding history or
predisposition, Labile INR, Elderly, Drugs/alcohol); OAC, oral
anticoagulant.
178 Journal of Cardiovascular Medicine 2022, Vol 23 No 3

Table 1 Indications for left atrial appendage occlusion therapy

Strong indication Loose indication

1. History of life-threatening/disabling or major bleeding 1. Elevated bleeding risk

 Intracranial bleeding  HAS-BLED score 3
 Gastrointestinal bleeding
 Other major bleedings (intraocular, pulmonary, urogenital)
2. Patients with embolic stroke on adequate OAC therapy 2. End-stage renal disease as a contraindication to NOACs (eGFR < 15 ml/min/1.73 m2)
 Poor adherence to OAC treatment (PDC 0.8)

eGFR, estimated glomerular filtration rate; HAS-BLED (Hypertension, Abnormal renal/ liver function, Stroke, Bleeding history or predisposition, Labile INR, Elderly, Drugs/
alcohol); LAAO, left atrial appendage occlusion; NOAC, nonvitamin K antagonist oral anticoagulant; OAC, oral anticoagulant; PDC, proportion of days covered.

Indications for transcatheter left atrial appendage Particularly, previous intracranial bleeding occurred in
occlusion 10 (1.0%) patients, upper and lower gastrointestinal (GI)
According to the most recent ESC guidelines, LAAO may bleeding in 63 (6.4%), and 87 (8.9%) patients, respec-
be considered for stroke prevention in patients with tively. A history of any prior thromboembolic event was
NVAF and contraindications for long-term anticoagulant present in 162 (16.5%) patients, and 58 (5.9%) of them
treatment.1 Potential indications for LAAO were had experienced an embolic stroke while under OAC
reported in the Munich consensus document on defini- treatment at the time of the event. A HAS-BLED score at
tions, endpoints, and data collection requirements for discharge of at least 3 was found in 197 patients (20.1%).
clinical studies, regarding percutaneous LAAO8 and in A total of 19 (1.9%) patients had stage V chronic kidney
the more recent expert consensus update.9 For this study, disease (kidney failure), namely an eGFR under 15 ml/
we considered two categories of LAAO eligible candi- min/1.73 m2 at discharge. Poor adherence to OAC therapy
dates (Table 1): during the first year after discharge, defined as PDC 80%
or less,19,20 was recorded in 229 (45.0%) patients of the
(1) Strong indication: history of major bleeding and/or control group. The proportion of potentially eligible
history of stroke while under adequate OAC
treatment. Table 2 Baseline patient characteristics (n U 980)
(2) Loose indication: HAS-BLED score (3) and/or Age (years) 73.9 (10.9)
presence of end-stage renal failure (eGFR < 15 ml/ Gender (male) 536 (54.7%)
min/1.73 m2). BMI (kg/m2) 28.69 (5.59)
AF
First diagnosed 124 (12.7%)
Patients featuring both strong and loose indications for Paroxysmal 321 (32.8%)
Persistent 62 (6.3%)
LAAO were included only in the group of patients with Permanent 451 (46.0%)
strong indication. Atrial flutter 22 (2.2%)
CHA2DS2-Vasc
Patients’ adherence to OAC treatment has also been (mean, SD) 4.4 (1.9)
suggested as a considerable factor when deciding for (median, IQR) 4 (3–6)
More than one nongender-related stroke risk factors 878 (89.6%)
LAAO. Nonetheless, there are no conclusive or random- HAS-BLED
ized data sets as to whether noncompliant patients bene- Mean, SD 1.7 (1.0)
Median, IQR 2 (1–2)
fit from LAAO; thus, patients’ compliance with OACs has HAS-BLED at least 3 197 (20.1%)
been assessed separately. In order to present ‘real-life’ History of any thromboembolic event 162 (16.5%)
compliance with treatment, only the estimated adher- Ischemic stroke 91 (9.3%)
TIA 45 (4.6%)
ence of the control group of the MISOAC-AF trial Unknown type of embolic stroke 12 (1.2%)
(n ¼ 509) was taken into account. Systemic thromboembolic disease 57 (5.8%)
Stroke while on OAC therapy 58 (5.9%)
History of bleeding 297 (30.3%)
Results History of major bleeding 134 (13.7%)
Out of 1009 patients who were the main study population Intracranial bleeding 10 (1.0%)
Upper GI bleeding 63 (6.4%)
of the MISOAC-AF trial, 29 (2.9%) were excluded in the Lower GI bleeding 87 (8.9%)
current analysis because of the presence of missing values History of minor bleeding 206 (21.0%)
in at least one of the relevant LAAO eligibility variables History of bleeding while under OAC 261 (26.6%)
eGFR less than 15 ml/min/1.73 m2 19 (1.9%)
(Fig. 1). The overall missing rate was 1.8%. The remain- Proportion of days covered (PDC) 0.75 (0.31)
ing 980 patients were analyzed to assess potential eligi- Poor adherence to OAC (PDC 0.8) 229 (45.0%)
bility for percutaneous LAAO. The baseline patient
Values are % (n), mean  standard deviation or medians with interquartile range of
characteristics are summarized in Table 2. The mean valid cases. AF, atrial fibrillation; CHA2DS2-Vasc (congestive heart failure, hyper-
age was 73.9  10.9 years, and 536 (54.7%) of the patients tension, age 75 years, diabetes mellitus, stroke/transient ischemic attack,
vascular disease, age 65–74 years, sex category); eGFR, estimated glomerular
were men. filtration rate; GI, gastrointestinal; HAS-BLED (Hypertension, Abnormal renal/ liver
function, Stroke, Bleeding history or predisposition, Labile INR, Elderly, Drugs/
A total of 134 (13.7%) patients had experienced a alcohol); IQR, interquartile range; OAC, oral anticoagulant; PDC, proportion of
prior life-threatening, disabling, or major bleeding.8,21 days covered; SD, standard deviation; TIA, transient ischemic attack.

© 2022 Italian Federation of Cardiology - I.F.C. All rights reserved.

 Percutaneous left atrial appendage occlusion Vrana et al. 179

Fig. 2

(a)

Loose
Strong indication
Non-eligible Eligible indication 108 (11%)
699 (71.3%) 281 (28.7%) 173 (17.7%)

229
(b) (45.0%)
197
(20.1%)

134
(13.7%)

58
(5.9%)
19
(1.9%)

Prior major Stroke on HAS-BLED eGFR<15 Poor

bleeding OAC ≥3 ml/min/1.73 adherence to
m2 OAC

(a) Potentially eligible candidates for transcatheter LAAO. (b) Possible indications for transcatheter LAAO. eGFR, estimated glomerular filtration rate;
HAS-BLED (Hypertension, Abnormal renal/liver function, Stroke, Bleeding history or predisposition, Labile INR, Elderly, Drugs/alcohol); OAC, oral
anticoagulant; PDC, proportion of days covered.

patients and the aforementioned possible indications for
transcatheter LAAO are presented in Fig. 2a and
b, respectively.
Overall number of potential candidates for left atrial
appendage occlusion
A total of 173 (17.7%) patients had at least one strong
indication for LAAO, with 19 (1.9%) of them presenting
both a history of major bleeding event and a prior stroke
under OAC therapy, whereas 108 (11.0%) had only loose
indication for LAAO (Fig. 2). Overall, with the combina-
tion of these two categories of potential indications, 281
(28.7%) patients could be considered eligible for trans-
catheter LAAO (patients with combined indications).
Relevant to LAAO eligibility, patient characteristics of
these three main categories of potential candidates are
summarized in Table 3.
Discussion
This is the first study identifying potentially eligible
candidates for LAAO amongst an unselected hospitalized
population with a primary or secondary diagnosis of
NVAF. The main finding was that one out of six patients
with NVAF had a strong indication for percutaneous
LAAO, as estimated by the presence of prior major
bleeding event or stroke on adequate OAC treatment.
At the same time, 1 out of 10 patients may be considered
eligible for LAAO according to looser criteria exclusively,
such as the high HAS-BLED score (3) or the existence
of end-stage renal disease (eGFR < 15 ml/min/1.73 m2).
The proportion of potential candidates reached almost
30% when combining all the indications mentioned
above.
Although the effectiveness and safety of percutaneous
LAAO have been the subject of multiple studies,22,23
there is no scientific consensus on the definitions of
absolute or relative contraindications to OAC therapy
for patients with atrial fibrillation. In other words, the
exact indications for LAAO have yet to be clarified.
There are several atrial fibrillation patients in whom
long-term pharmacological stroke prophylaxis with OACs
is not considered a first-choice therapy24,25 or who may

© 2022 Italian Federation of Cardiology - I.F.C. All rights reserved.

180 Journal of Cardiovascular Medicine 2022, Vol 23 No 3
Table 3 Patient characteristics regarding left atrial appendage occlusion eligibility of potential candidates for left atrial appendage occlusion
(group 1, candidates with strong indication; group 2, candidates with loose indication; group 3, candidates with combined indications)
Strong indication for LAAO (n ¼ 173)
History of embolic stroke 66 (38.2%)
History of stroke while under OAC 58 (33.5%)
HAS-BLED at least 3 96 (55.3%)
History of bleeding 145 (83.8%)
History of major bleeding 134 (77.5%)
Intracranial bleeding 10 (5.8%)
Upper GI bleeding 63 (36.4%)
Lower GI bleeding 87 (50.3%)
History of minor bleeding 54 (31.2%)
History of bleeding while under OAC 109 (63.0%)
eGFR less than 15 ml/min/1.73 m2 5 (2.9%)
Poor adherence to OAC (PDC0.8) 20.5%
Values are % (n), mean  standard deviation or medians with interquartile range of valid cases. eGFR, estimated glomerular filtration rate; GI, gastrointestinal; HAS-BLED
(Hypertension, Abnormal renal/ liver function, Stroke, Bleeding history or predisposition, Labile INR, Elderly, Drugs/alcohol); IQR, interquartile range; LAAO, left atrial
appendage occlusion; OAC, oral anticoagulant; PDC, proportion of days covered; SD, standard deviation.
suffer a thromboembolic event despite adequate and
indicated anticoagulant treatment – a fact that could be
regarded as a ‘failure of treatment’. On the other hand, it is
well known that anticoagulant agents increase bleeding
risk,26 and although the overall risk may be lower with
NOACs compared with warfarin, it is still not zero.27
According to the 2018 European Heart Rhythm Associa-
tion (EHRA) guidelines on the use of NOACs in patients
with atrial fibrillation,13 routine use of NOACs in patients
with severe renal dysfunction (eGFR < 15 ml/min) should
be avoided28 and warfarin may generate more harm than
benefit if the anticoagulation control is poor. Thus, the
decision to anticoagulate remains a very individualized
one, requiring a multidisciplinary approach considering
and respecting the patient’s preferences.29,30
The potential indications for LAAO used in this study
were selected based on the last expert consensus state-
ment on catheter-based LAAO.9 Observational studies of
patients with previous major bleeding events, stroke on
OACs, or end-stage renal disease showed favorable out-
comes with LAAO treatment. According to data from the
Amplatzer Cardiac Plug Multi-Center and the Korean
LAAO registry, patients with previous intracranial bleed-
ing or resistant stroke, that is, stroke on adequate OAC
treatment, who underwent LAAO, presented similar
safety outcomes to patients without such history, as well
as a significant reduction in stroke/TIA and major bleed-
ing events at follow-up.31,32 Moreover, patients who
experienced ischemic cerebrovascular events during fol-
low-up had more favorable neurological and functional
outcomes if treated with LAAO compared with those
treated with warfarin.33 Furthermore, in patients with
CKD treated with LAAO, even in those with eGFR less
than 15 ml/min/1.73 m2, a significant reduction of almost
60% was observed in stroke/TIA rate and major bleeding
rate in comparison with the expected annual risk.34
Another critical aspect in the area of atrial fibrillation
treatment is the adherence to anticoagulant agents. A
© 2022 Italian Federation of Cardiology - I.F.C. All rights reserved.
Loose indication for LAAO (n ¼ 108) Combined indications for LAAO (n ¼ 281)
27 (25.0%) 93 (33.1%)
0 (0.0%) 58 (20.6%)
101 (93.5%) 188 (68.4%)
20 (18.5%) 165 (58.7%)
0 (0.0%) 134 (47.7%)
0 (0.0%) 10 (3.6%)
0 (0.0%) 63 (22.4%)
0 (0.0%) 87 (31.0%)
20 (18.5%) 74 (26.3%)
25 (23.1%) 134 (47.7%)
14 (13.0%) 19 (6.8%)
20.3% 20.4%
mixture of patients’ and clinicians’ nonadherence exists
even in the era of novel OACs,3–5,35 whereas compliance
with treatment is crucial, especially with NOACs as these
drugs have a relatively short half-life, such that patients
would be left without any anticoagulation protection if
more than one dose were missed.36 In our study, 45% of
the patients of the control group had poor adherence to
OAC therapy, and although there is no strong evidence
on whether noncompliant patients would benefit from
LAAO, excluding the LAA from the blood circulation in
patients with significant stroke risk may be advantageous
as compared with no treatment.9
New data support the importance of LAAO in stroke
prevention. A recent study by Cresti et al.37 revealed that
in 1420 patients who underwent echocardiography-
guided cardioversion for NVAF, the percentage of atrial
thrombi, which originated from the LAA, was 95%, with
the prevalence of extra-LAA thrombosis to be lower than
5% (3.5% of right appendage and 1% of left atrial cavity
thrombosis), whereas a LAA thrombus also accompanied
all extra-LAA thromboses.
Nonetheless, LAAO remains an invasive procedure,
which has its complications.8,38 Even in the era of
NOACs, in which many reliable pharmacologic
approaches to stroke prevention in atrial fibrillation exist,
LAAO procedures are being increased year by year. Last
but not least, elimination of stroke risk in patients after
catheter or surgical ablation for atrial fibrillation is a
matter that should be addressed. Currently, recommen-
dations support the continuation of systemic anticoagula-
tion postablation in accordance with atrial fibrillation
guidelines. However, maybe in the future, there will
be sufficient evidence of discontinuation of anticoagula-
tion therapy after a successful ablation procedure, which
would consequently lead to a reduction of eligible
patients for LAAO. Therefore, the selection of eligible
patients for LAAO should be made cautiously. In order
for this therapy to be established and become a viable

option for specific patient groups, additional clinical
evidence based on adequately powered randomized con-
trolled trials are needed.
Limitations
The generalizability of our results is confined by our
study’s single-center, retrospective design. Our study
included patients admitted to a cardiology ward for any
reason with coexisting atrial fibrillation. Thus, our popu-
lation cohort has a substantially higher number of comor-
bidities than a sample of patients with atrial fibrillation
from the general population or another clinical site (e.g.
outpatients department); yet it reflects a typical clinical
practice population with atrial fibrillation. Furthermore,
because of the retrospective nature, there were missing
variables, such as other major bleeding events, which
could constitute additional strong bleeding indications
(i.e. intraocular bleeding compromising vision, pulmo-
nary, or urogenital source of bleedings), patients’ prefer-
ence for stroke prophylaxis strategy, the existence of
tumor and hepatic insufficiency, documented thrombus
formation in the LAA on adequate OAC therapy, and so
forth. Some of the recorded major bleedings in our cohort
were treatable. The retrospective design of our study has
limited us on obtaining data regarding whether a treat-
able bleeding source was finally treated. Therefore, such
variables were not included in our analysis.
Conclusion
One out of six patients with nonvalvular atrial fibrillation,
who are admitted to the cardiology department of a
tertiary hospital for any reason, has a strong indication
for LAAO, namely previous major bleeding or a history of
stroke during adequate OAC therapy. When considering
on top of the above a high HAS-BLED score (3) and the
existence of end-stage renal disease, the number of
eligible patients rises to 30%. In the absence of large
randomized clinical trials comparing LAAO with NOAC
therapy, a cautious, multidisciplinary team approach is
required to choose the patient who may benefit more
from this invasive therapy.
Conflicts of interest
There are no conflicts of interest.
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