Clinical outcomes of left atrial appendage closure and post-operative antiplatelet therapy in patients with contraindication to anticoagulation: a systematic review

(1)

2019/2020

Catarina de Vasconcelos Peixoto Fonseca

Resultados da oclusão do apêndice auricular esquerdo com

terapia antiagregante plaquetária em pacientes com

contraindicação para hipocoagulação:

uma revisão sistemática.

Clinical outcomes of left atrial appendage closure and

post-operative antiplatelet therapy in patients with

contraindication to anticoagulation:

a systematic review

.

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Mestrado Integrado em Medicina

Área: Ciências Médicas e da saúde

Tipologia: Dissertação

Trabalho efetuado sob a Orientação de:

Doutor Manuel Belchior Campelo

Trabalho organizado de acordo com as normas da revista:

Ata Médica Portuguesa

Catarina de Vasconcelos Peixoto Fonseca

Resultados da oclusão do apêndice auricular esquerdo com

terapia antiagregante plaquetária em pacientes com

contraindicação para hipocoagulação:

uma revisão sistemática.

Clinical outcomes of left atrial appendage closure and

post-operative antiplatelet therapy in patients with

contraindication to anticoagulation:

a systematic review.

(3)

(4)

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Clinical outcomes of left atrial appendage closure and post-operative

antiplatelet therapy in patients with contraindication to

anticoagulation: a systematic review.

Resultados da oclusão do apêndice auricular esquerdo com terapia

antiagregante plaquetária em pacientes com contraindicação para

hipocoagulação: uma revisão sistemática.

Catarina Vasconcelos P. Fonseca

1

_{, Luís Azevedo}

2

_{, Daniel Dias}

3

_{, Manuel Campelo}

4a, b, c

1 Faculty of Medicine, University of Porto, Porto, Portugal

2 Center for Research in Health Technologies and Services (CINTESIS), Porto, Portugal

3 Center for Research in Health Technologies and Services (CINTESIS), Porto, Portugal

4 a) Department of Medicine, Faculty of Medicine, University of Porto, Portugal

b) Center for Research in Health Technologies and Services (CINTESIS), Porto, Portugal

c) Department of Cardiology, Centro Hospitalar Universitário de São João, E.P.E., Porto,

Portugal

This research received no specific grant from any funding agency in the public, commercial, or

not-for-profit sectors.

Correspondence: Catarina Vasconcelos P. Fonseca, Faculdade de Medicina, Universidade do Porto,

Alameda Prof. Hernani Monteiro, 4200 Porto, Portugal.

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Clinical outcomes of left atrial appendage closure and post-operative

antiplatelet therapy in patients with contraindication to anticoagulation:

a systematic review.

Abstract

Background Randomized clinical trials have been performed to analyze the efficacy and safety of left

atrial appendage closure in non-valvular atrial fibrillation versus medical management. This technique

emerged for patients with contraindication to anticoagulation therapy; nonetheless, those patients were

still medicated with anticoagulation strategies for a period of time, which gave rise to safety concerns.

Our systematic review aims to evaluate the feasibility of this intervention in patients with

contraindication to anticoagulation and post-operative antiplatelet therapy.

Methods A comprehensive search of the Medline and ISI Web of Knowledge databases was conducted

using pre-defined criteria. We included non-comparative cohort studies with at least 15 patients and a

follow-up time longer than 6 months.

Results We selected 21 eligible studies enrolling 3974 patients. The adjusted pooled incidence rate of

thromboembolic events was 1.99/100 person-years (95% CI: 1.66 to 2.38/100 person-years) and the

incidence rate of major bleeding corresponded to 2.07/100 person-years (95% CI: 1.40 to 3.06/100

person-years). These results were similar, if not better, than the outcomes of the clinical trials made so

far. The incidence rate of all-cause mortality was 6.13 per 100 person-years (95% CI: 5.18 to 7.27

person-years), with a higher proportion of mortality associated to non-cardiovascular causes. Among

patients that changed from antiplatelet therapy to anticoagulation, the incidence rate was 1.62/100

person-years (95% CI: 0.92 to 2.84 person-years).

Conclusions Our review sustains the feasibility of this technique in patients submitted to antiplatelet

therapy, on the prevention of thromboembolic and bleeding events, in comparison to anticoagulation

after procedure.

Resumo

Introdução Ensaios clínicos randomizados foram realizados para analisar a eficácia e segurança da

oclusão do apêndice auricular esquerdo na fibrilação auricular não-valvular versus terapia médica. Esta

técnica foi desenvolvida para doentes com contraindicação para anticoagulação, contudo esses pacientes

continuavam a ser hipocoagulados por um período de tempo, o que alça problemas relativos à sua

segurança. Na nossa revisão sistemática pretendemos avaliar a viabilidade desta intervenção com

terapia antiplaquetária após intervenção.

Métodos Uma pesquisa pela MedLine e ISI Web of Knowledge foi conduzida com base em critérios

pré-definidos. Nós incluímos estudos observacionais não-comparativos com pelo menos 15 pacientes e por

um período mínimo de 6 meses de seguimento.

Resultados Foram selecionados 21 estudos com 3974 pacientes na globalidade. A taxa de incidência

ajustada de eventos tromboembólicos corresponde a 1.99/ 100 pessoa-ano (95% CI: 1.66-2.38/100

pessoa-ano) e a taxa de incidência de eventos hemorrágicos major foi de 2.07/100 pessoa-ano (95% CI:

1.40-3.06/100 pessoa-ano). Os resultados foram similares, se não melhores, que os dados clínicos dos

ensaios clínicos realizados. A taxa de incidência de mortalidade corresponde a 6.13 per 100 pessoa-ano

(95% CI: 5.18-7.27 pessoa-ano), com a proporção mais elevada associada a causas não-cardiovasculares.

Uma pequena porção de pacientes mudaram a sua terapia inicial para anticoagulantes orais com uma

taxa de incidência de 1.62/100 pessoa-ano (95% CI: 0.92-2.84 pessoa-ano).

Conclusão A nossa revisão sustém a viabilidade desta técnica em pacientes submetidos a terapia

antiplaquetária após intervenção, na prevenção de eventos tromboembólicos e hemorrágicos,

comparando com a terapia anticoagulante selecionada nos ensaios clínicos.

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Introduction

Atrial fibrillation (AF) is the most common sustained arrhythmia affecting

approximately 3% of the population over 20 years old, with greater prevalence in older

persons and patients with high cardiovascular risk. [1]

The left atrial appendage (LAA), an embryonic reminiscent structure of the left atrium,

is the major site of thrombogenesis in the heart, responsible for more than 90% of the

cardioembolic strokes in non-valvular AF (NVAF) patients. Indeed, 20% of ischemic

strokes among the elderly are caused by AF, emphasizing the need of stroke prevention

in these patients.[2]

While anticoagulation therapy with warfarin is effective in stroke prevention, it is

associated with an increased risk of intracerebral and extracranial bleeding and may

be contraindicated in some patients. Previous studies found a prevalence of

contraindications of around 15% in clinical AF patients, hence percutaneous LAA

occlusion devices were developed to overcome this problem.[3]

The first technology created was the Percutaneous Left Atrial Appendage Occlusion

(PLAATO) device that proved to be safe and feasible in patients with contraindication

for anticoagulation therapy.[4] Since then, other devices had emerged, such as

Watchman, Amplatzer Cardiac plug, Amplatzer Amulet and Lambre devices, all

characterized in the studies included in this review. Of the five devices mentioned, the

Watchman was the only device approved by the US Food and Drug Administration

(FDA) and with a specific indication for the prevention of stroke in atrial fibrillation.

[5]

The Watchman Left Atrial Appendage System for Embolic Protection in Patients with

AF (PROTECT AF) clinical trial showed non-inferiority of the Watchman device for the

prevention of stroke, systemic embolism and cardiovascular death when compared to

warfarin therapy and also fewer haemorrhagic strokes in non-valvular AF patients

with a CHADS2-score ≥1.[6] In the PREVAIL (Prospective Randomized Evaluation of

the WATCHMAN Device in Patients With Atrial Fibrillation Versus Long Term

Warfarin Therapy) trial, non-inferiority was also confirmed and procedural safety

improved.[7]

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However, the patients in the LAA closure arm were still prescribed with warfarin

therapy for at least 6 weeks after procedure, which could be a real problem for patients

with contraindication for anticoagulation. Thus, there was

a necessity to find a

strategy that dispensed anticoagulation and reduced the bleeding risk during those

weeks; in recent years, some researchers had attempted to perform the percutaneous

occlusion of LAA, using only antiplatelet therapy.

The aim of this study was to perform a systematic review to compare clinical

outcomes, specifically adjusted rates of thromboembolic events, major bleeding,

all-cause mortality and modification of initial therapy in NVAF patients submitted to this

percutaneous procedure and then prescribed with antiplatelet therapy.

Methods

Search strategy

To identify relevant articles, the authors started with a search on Medline (PubMed)

and ISI Web of Knowledge databases during the month of September 2019. The query

used on both was “left atrial appendage closure” AND “stroke prevention” AND

“(antiplatelet therapy OR anticoagulation contraindication)”.

The search resulted in 38 articles on Medline database with the filter “clinical trial”,

“multicentre studies” and “observational studies” and 103 articles on ISI Web of

Knowledge, with the filter “clinical trial” (Figure 1).

Inclusion criteria

The studies included in this review were human studies in patients with non-valvular

atrial fibrillation submitted to left atrial appendage closure, with a CHADS

2

score

or CHA

2

DS

2

-VASc score ≥1 and a contraindication to anticoagulation therapy.

Exclusion criteria

Follow-up studies, systematic reviews and/or meta-analysis, duplicate studies, cost

analyses or surveys, comparison between devices and studies focusing on imaging and

planning were not included in this review.

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Studies with anticoagulation therapy after procedure (>5%), a number of patients

inferior to 15 and a follow-up period shorter than 6 months were excluded.

Data extraction and quality assessment of studies

Eligibility and quality of the studies were independently evaluated by two researchers.

If there was a disagreement regarding the inclusion of the articles, a consensus

between the authors was established through review and discussion. The clinical

studies were selected based on the inclusion criteria and methodological quality, by

means of the Quality Appraisal of Case Series Studies Checklist from the Institute of

Health Economics.(Supplement file 1) [8]

Outcome measures

We synthesized the clinical outcomes of the prospective studies regarding the

procedure and the antiplatelet therapy applied after intervention. The outcomes

evaluated were the incidence of thromboembolic events (stroke, TIA, systemic

embolism), major bleeding, all-cause mortality and the incidence of modification of

initial therapy, from antiplatelet therapy to anticoagulation. The reasons stated for this

alteration were varied; however, the most recurrent argument was a formation of a

device-related thrombus that required anticoagulation therapy.

Statistical Analysis

We used Poisson-normal models for the meta-analysis of incidence rates. [9] [10] [11]

These are generalized linear mixed models (GLMM) that have been shown to have

several relevant advantages when compared with the classical inverse variance weight

meta-analysis, particularly when including primary studies with sparse data as is the

case in the present meta-analysis.[10] The results are presented as expected number

of events per 100 person-years at risk. We used the log transformed incidence rate as

outcome measure and then back transformed the results by exponentiation in order

to present meta-analytical measures and construct forest plots. To calculate incidence

rates, we used the total number of events observed and the total person-years of

follow-up, based on the mean follow-up times and the total number of participants in

each study. Studies with zero events were handled by adding a 0.5 constant to the

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number of events (only in studies with zero events). Heterogeneity was assessed using

the heterogeneity Chi-square test and using the I-square statistic (an I-square above

50% was considered as relevant heterogeneity). Meta-analyses was conducted with

the metafor package [11] in R, version 3.6.2. [12] We used a 5% level of significance.

Results

We selected 21

non-comparative cohort studies [4, 13-32]

from the PubMed and ISI

Web of Knowledge databases in accordance with study inclusion criteria. A total of

3974 patients were enrolled in this review. Table 1 shows the baseline characteristics

of the included studies, including the follow-up time that varied from 6 to 48 months.

The mean CHADS

2

score or/and CHA

2

DS

2

-VASc score of each study was between

2.3-4.0 and 3.2-5.4, respectively (Table 1).

Data related to the number and proportion of clinical outcomes of each study, as

thromboembolic events, major bleeding, all-cause mortality and modification of initial

therapy, are represented on Table 2.

Among identified studies, we detected high percentages of implantation/procedure

success rates, with values that varied between 88% and 100%. Peri-procedural

complications were identified in almost all of the registries, even though in small

proportions; the causes were mainly due to cardiac tamponade, anatomic

particularities that invalidated the use of this devices and bleeding complications or

device-associated thrombus.

The adjusted pooled incidence rate of thromboembolic events in this analysis was

1.99/100 person-years (PY) (95% CI: 1.66 to 2.38/100 PY) (Figure 2-A), including

strokes, TIAs and systemic embolic events. The study with the highest proportion of

thromboembolic events in the review showed a proportion of 0.14%, that

corresponded to an incidence of 3.75/ 100 PY [14]. This value was attributed to an

early essay regarding the first device created, PLAATO, and therefore, one of the

earliest studies made with this new surgical technique. In the following studies, a

substantial decrease of thromboembolic events was noticeable with proportions that

varied between 0.02% and 0.05% and a value of 0.11% in one of the studies. This

improvement might be attributed to an increase of the operator experience and to the

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growth of literature explaining the technicalities of percutaneous device´s

implantation.

The adjusted incidence rate of major bleeding was 2.07/100 PY (95% CI: 1.40 to

3.06/100 PY) (Figure 2-B), with the highest proportion of major bleeding in the review

of 0.18%. [29]. This value was attributed mainly to gastrointestinal bleeding which

could be related to baseline comorbidities and antithrombotic therapy after procedure

in patients with high risk of hemorrhagic complications.

The incidence of all-cause mortality was 6.13 per 100 person-years (95% CI: 5.18 to

7.27 PY) (Figure 3-A). As explained in the studies, the major portion of deaths were

not associated to cardiovascular causes, but mainly related to the elevated rate of

comorbidities of these patients, such as hypertension, diabetes mellitus, cancer,

respiratory problems.

Regarding to the alteration of medication, from antiplatelet therapy to anticoagulation,

we detected an incidence rate of 1.62/100 PY (95% CI: 0.92 to 2.84 PY) (Figure 3-B).

We thought it was pertinent to include this data, since this meta-analysis focused on

patients that didn´t tolerate anticoagulation and so, were on antiplatelet therapy after

the procedure. As we could appreciate from the data, it was a small portion of patients

that changed their initial therapy.

Discussion

The emergence of percutaneous devices for occlusion of left atrial appendage, the

major site of thrombus formation, was required in NVAF patients with

contraindication for anticoagulation therapy. The WATCHMAN device is the most

methodically studied, represented in both randomized clinical trials made regarding

this matter (PROTECT-AF and PREVAIL trial [6, 7]). Nevertheless, since the devices

are fairly new, there is a scarce clinical evidence that proves their safety and efficacy.

We synthetized

non-comparative cohort studies that evaluated the clinical outcomes

of this procedure and the subsequent antiplatelet therapy used in patients with

contraindication to anticoagulation.

Regarding to stroke prophylaxis, we estimated the incidence rate of thromboembolic

events to be

1.99/100 PY (95% CI: 1.66 to 2.38/100 PY) (Figure 2-A). This value was

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similar to the stroke rate of the randomized clinical trial PROTECT-AF [6] (2.2/100 PY

[95% CI: 1.2 to 3.5/100 PY]), even with the inclusion of only stroke events. In the

PREVAIL study [7], the stroke rate reported was 0.7/100 PY (95%: 0.1 to 5.1/100 PY),

lower than the incidence rate of thromboembolic events in this review, mainly because

of the disperse follow-up times of the studies included. Therefore, the antiplatelet

therapy showed a parallel prevention of stroke events, in comparison to the

anticoagulation therapy studied in the clinical trials.

The major bleeding incidence rate of

2.07/100 PY (95% CI: 1.40 to 3.06/100 PY)

(Figure 2-B) was inferior to the incidence rate of the clinical trial PROTECT-AF [6],

with a value of 2.3/100 PY (calculated based on data of the study, number of

participants and follow-up time). So, it was fair to conclude the presence of fewer

hemorrhagic complications in patients with an inherent higher risk of bleeding that

were medicated with antiplatelet therapy, in comparison to anticoagulation.

Therefore, antiplatelet therapy was a more secure treatment after procedure for

patients submitted to LAA closure.

Accordingly, the outcomes of the observational studies showed to be similar, if not

better, than the PROTECT-AF study data, indicating this procedure with post-operative

antiplatelet therapy as a feasible and secure option for stroke prophylaxis in NVAF

patients.

The PROTECT-AF study showed an incidence rate of all-cause mortality of 3.0 per 100

person-years, inferior to the rate of this review (6.13 per 100 person-years (95% CI:

5.18 to 7.27)) (Figure 2-C). In both studies, the main causes of all-cause mortality were

non-cardiovascular and so, not deemed related to the LAA closure device. Therefore,

the most logic reason for the higher incidence rate in the review could be due poorest

clinical conditions of the patients, with more co-morbidities than the patients allocated

in the clinical trial.

Furthermore, the amendment of the initial therapy was required in a minor fraction

of patients because of post-procedural complications, specifically device-associated

thrombus and thromboembolic events. Nonetheless, the change to anticoagulation

therapy was temporary with a complete resolution of the complications in most of the

cases.

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Study limitations. The included studies with different baseline characteristics and the

non-uniformity of the follow-up time might introduce imprecise and disperse

outcomes, explaining the heterogeneity of the data. Because of the minor rate of

thromboembolic events after intervention, more events are more likely to appear on

studies with longer follow-up periods and larger samples, giving rise to disperse rates

of events among the studies of the review. Another limitation is related to the type of

studies inserted in this meta-analysis, linked to the inherent concerns associated to

observational cohort studies. As example, we may refer the lack of standardization of

patients and the under-reported events associated to this type of studies in comparison

to randomized clinical trials.

In spite of these limitations, this review seeks to combine and clarify the feasibility of

LAA closure for stroke prophylaxis in patients with contraindication for

anticoagulation and then submitted to antiplatelet therapy. It seems to be a different

and more secure therapeutic option that completely excludes anticoagulation therapy,

including for at least six weeks after procedure as seen in several studies.

Conclusion

In our systematic review, we included the studies available that specified the rate of

clinical outcomes in patients submitted to LAA closure and a post-operative

antiplatelet therapy. This approach may be a reasonable alternative to LAA closure

with anticoagulation after procedure for stroke prophylaxis in patients unable to

receive this therapy. Nonetheless, more randomized clinical trials are needed to

support the efficacy and safety of percutaneous left atrial appendage closure with

antiplatelet therapy.

Funding

This research received no specific grant from any funding agency in the public,

commercial, or not-for-profit sectors.

Declaration of conflicting interests

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appendage closure with different devices. EuroIntervention, 2018. 13(18): p.

e2138-e2146.

31. Bergmann, M.W., Ince, H., Kische, S., Schmitz, T., Meincke, F., Schmidt, B., et al.,

Real-world safety and efficacy of WATCHMAN LAA closure at one year in patients

on dual antiplatelet therapy: results of the DAPT subgroup from the EWOLUTION

all-comers study. EuroIntervention, 2018. 13(17): p. 2003-2011.

32. Phillips, K.P., Santoso, T., Sanders, P., Alison, J., Chan, J.L.K., Pak, H.N., et al., Left

atrial appendage closure with WATCHMAN in Asian patients: 2year outcomes

from the WASP registry. Int J Cardiol Heart Vasc, 2019. 23: p. 100358.

(17)

Table 1- Baseline characteristics of included studies

First

Author,

Year

(Ref.#)

Patients

Follow-up

(months)

Device used

Age

(years)

CHADS

2

score

CHA

2

DS

2

-VASc

score

Ostermayer,

2005

111

9.8 PLAATO

71(9)

2.5(1.3)

NA

Block, 2009

64

45 PLAATO

73 (NA)

2.6(NA)

NA

Bayard,

2010

180

9.6 PLAATO

70(9.7)

3.0(NA)

NA

Lam, 2012

20

12.7 ACP

68(9.0)

2.3(1.3)

NA

Mínguez,

2013

35

21.1 ACP

74.7(7.6)

2.4(1.5)

3.2(1.6)

Danna, 2013

37

12 ACP

73.4(8.3)

3.1(1.5)

4.3(1.5)

Reddy, 2013

150

14.4 Watchman

72.5(7.4)

2.8(1.2)

4.4(1.7)

Urena, 2013

52

20 ACP

74(8.0)

3.0(2-4)

5.0(4-6)

Wiebe, 2014

60

21.6 ACP

72.9(8.1)

2.6(1.4)

4.3(1.7)

Kebernik,

2015

96

9 ACP

76(7.0)

4.0(3-4.75)

5.0(4.25-7)

Karczewski,

2016

34

6 Amulet

72 (NA)

3.2(3-6)

5.4(3-9)

Berti, 2016

110

30 ACP+Amulet

77(6.0)

NA

4.3(1.3)

Tzikas,

2016

1047

13 ACP

75(8.0)

2.8(1.3)

4.5(1.6)

Jalal, 2017

76

13 Amplatzer

73(8.0)

NA

4.4(1.3)

Park, 2018

60

12 Lambre

74.4(8.0)

NA

4.0(1.6)

Regueiro,

2018

101

48 ACP+Watchman

76 (NA)

3.2(1.3)

4.8(1.6)

Weise, 2018

298

27.3 ACP+Amulet+Watchman

76(8.0)

2.5(1.2)

4.3(1.5)

Bergmann,

2018

605

12 Watchman

NA

4.6(NA)

Bertrand,

2019

39

21 ACP

77.7(7.0)

NA

5.0(3-6)

Mínguez,

2019

598

22.9 ACP+Amulet+Watchman

75.4 (NA)

2.8(1.6)

4.4(1.5)

Phillips,

2019

201

22.8 Watchman

70.8(9)

2.5(1.4)

3.9(1.7)

Values are n, mean, mean (SD) or mean (interquartile range). ACP= Amplatzer Cardiac Plug; CHADS2 = congestive

heart failure, hypertension, age>75, diabetes mellitus, and prior stroke or transient ischemic attack; CHA2DS2-VASc

(18)

Table 2- Clinical outcomes of included studies

First Author,

Year (Ref.#)

Patients

Thromboembolic

Events

Major

Bleeding

All-cause

Mortality

Modification of

initial therapy

N

P

N

P

N

P

N

P

Ostermayer,

2005

111

5

0.05 NA

NA

6

0.05 NA

NA

Block, 2009

64

9

0.14

1

0.01

17

0.27

0

0 Bayard, 2010

180

3

0.02 NA

NA

7

0.04

4

0.02 Lam, 2012

20

0

1

0.05 Mínguez,

2013

35

1

0.03

1

0.03

3

0.09

4

0.11 Danna, 2013

37

1

0.03

0

2

0.05

0

0 Reddy, 2013

150

3

0.02

2

0.01

9

0.06

4

0.03 Urena, 2013

52

2

0.04

1

0.02

4

0.08

0

0 Wiebe, 2014

60

0

2

0.03

5

0.08

2

0.03 Kebernik,

2015

96

3

0.03

1

0.01

9

0.09

2

0.02 Karczewski,

2016

34

0

0 ?

0

0 Berti, 2016

110

6

0.05

3

0.03

14

0.13

0

0 Jalal, 2016

76

3

0.04

1

0.01

2

0.03

2

0.03 Tzikas, 2016

1047

18

0.02

15

0.01

63

0.06

46

0.04 Park, 2018

60

1

0.02

0

2

0.03

3

0.05 Bertrand,

2018

39

0

4

0.10

7

0.18

4

0.10 Mínguez,

2018

598

17

0.03

43

0.07

76

0.13

27

0.05 Regueiro,

2018

101

11

0.11

18

0.18

34

0.33

0

0 Weise, 2018

298

13

0.04

32

0.11

50

0.17

23

0.08 Bergmann,

2018

605

14

0.02

19

0.03

58

0.10 -

0.05 Phillips,

2019

201

7

0.03

10

0.05

12

0.06

5

0.02

(19)

Figure 1. Flow Diagram of Studies Selection

LAA= left atrial appendage.

Records identified through

database searching

(n = 38 in PubMed and 103 in ISI

Web of Knowledge

Records after duplicates removed

(n = 135)

Records screened

(n = 135)

Records excluded

(n = 79)

Study design, Reviews,

Unrelated to topic,

Surgical closure of LAA,

Studies focusing on

imaging and planning

Full-text articles assessed

for eligibility

(n =56)

Full-text articles excluded,

with reasons

(n = 35)

Follow-up studies,

Anticoagulation after

procedure (>5%),

follow-up<6 months and N<15

patients

Studies included in

qualitative synthesis

(20)

Figure 2- A and B. Forrest Plots depicting adjusted incidence rates of clinical

outcomes.

(A)Thromboembolic Event Rates. Fixed effects meta-analysis. Test for Heterogeneity with p=0.353

and I-square of 0.0%. (B)Major Bleeding Event Rates. Random effects meta-analysis. Test for Heterogeneity with p<0.001 and I-square of 67.33%.

(21)

Figure 3- A and B. Forrest Plots depicting adjusted incidence rates of clinical

outcomes.

(A)All-cause Mortality Rates. Random effects meta-analysis. Test for Heterogeneity with p=0.010

and I-square of 43.48%. (B)Modification of initial therapy Event Rates. Random effects meta-analysis. Test for Heterogeneity with p<0.001 and I-square of 82.57%.

(22)

Supplement 1

Supplementary file 1. Article Quality Assessment

Study

Ostermayer

2005

Block

2009

Bayard

2010

Lam

2011

Mínguez

2012

Study

objective

1.Was

the

hypothesis/aim of the

study clearly stated?

Yes

Study design 2. Was the study

conducted

prospectively?

Yes

3. Were the cases

collected in more

than one centre?

Yes

No

4. Were

patients

recruited

consecutively?

Unclear

Yes

Unclear

Study

population

5. Were

the

characteristics of the

patients included in

the study described?

Yes

No

Yes

6. Were the eligibility

criteria (i.e. inclusion

and

exclusion

criteria) for entry into

the

study

clearly

stated?

Yes

Partial

7. Did patients enter

the study at a similar

point in the disease?

Yes

Unclear

Yes

Unclear

Intervention

and

co-intervention

8. Was

the

intervention

of

interest

clearly

described?

Yes

9. Were additional

interventions

(co-interventions) clearly

described?

Yes

Outcome

measures

10. Were relevant

outcome

measures

established a priori?

Yes

11. Were outcome

assessors blinded to

the intervention that

patients received?

Yes

12. Were the relevant

outcomes measured

using

appropriate

objective/subjective

methods?

Yes

(23)

outcome

measures

made before and after

the intervention?

Statistical

analysis

14. Were

the

statistical tests used

to assess the relevant

outcomes

appropriate?

Yes

Unclear

Results and

conclusions

15. Was follow-up

long

enough

for

important events and

outcomes to occur?

No

Yes

No

16. Were losses to

follow-up reported?

Yes

No

17. Did the study

provided estimates of

random variability in

the data analysis of

relevant outcomes?

Yes

No

Yes

No

Yes

18. Were the adverse

events reported?

Yes

19. Were

the

conclusions of the

study supported by

the results?

Yes

Competing

interests

and sources

of support

20. Were

both

competing interests

and

sources

of

support for the study

reported?

(24)

Supplementary file 1. (continued)

Study

Danna

2013

Reddy

2013

Urena

2013

Wiebe

2014

Kebernik

2015

Study

objective

1.Was

the

hypothesis/aim of the

study clearly stated?

Yes

Study design 2. Was the study

conducted

prospectively?

Unclear

Yes

No

3. Were the cases

collected in more

than one centre?

No

Yes

No

4. Were

patients

recruited

consecutively?

Unclear

Yes

Study

population

5. Were

the

characteristics of the

patients included in

the study described?

Yes

6. Were the eligibility

criteria (i.e. inclusion

and

exclusion

criteria) for entry into

the

study

clearly

stated?

Yes

Partial

Yes

Partial

7. Did patients enter

the study at a similar

point in the disease?

Yes

Unclear

Yes

Unclear

Intervention

and

co-intervention

8. Was

the

intervention

of

interest

clearly

described?

Yes

9. Were additional

interventions

(co-interventions) clearly

described?

Yes

Outcome

measures

10. Were relevant

outcome

measures

established a priori?

Yes

11. Were outcome

assessors blinded to

the intervention that

patients received?

Yes

12. Were the relevant

outcomes measured

using

appropriate

objective/subjective

methods?

Yes

13. Were the relevant

outcome

measures

made before and after

the intervention?

(25)

Statistical

analysis

14. Were

the

statistical tests used

to assess the relevant

outcomes

appropriate?

Yes

Results and

conclusions

15. Was follow-up

long

enough

for

important events and

outcomes to occur?

No

Yes

No

Yes

No

16. Were losses to

follow-up reported?

No

Yes

No

Yes

No

17. Did the study

provided estimates of

random variability in

the data analysis of

relevant outcomes?

Yes

No

Yes

18. Were the adverse

events reported?

Yes

19. Were

the

conclusions of the

study supported by

the results?

Yes

Competing

interests

and sources

of support

20. Were

both

competing interests

and

sources

of

support for the study

reported?

(26)

Supplementary file 1. (continued)

Study

Karczewski

2016

Berti

2016

Jalal

2016

Tzikas

2016

Park

2018

Study

objective

1.Was

the

hypothesis/aim of the

study clearly stated?

Yes

Study design 2. Was the study

conducted

prospectively?

Unclear

Yes

No

Yes

3. Were the cases

collected in more

than one centre?

Unclear

No

Yes

4. Were

patients

recruited

consecutively?

Unclear

Yes

Unclear

Study

population

5. Were

the

characteristics of the

patients included in

the study described?

Yes

6. Were the eligibility

criteria (i.e. inclusion

and

exclusion

criteria) for entry into

the

study

clearly

stated?

Yes

Partial

Yes

7. Did patients enter

the study at a similar

point in the disease?

Unclear

Unclear Unclear

Intervention

and

co-intervention

8. Was

the

intervention

of

interest

clearly

described?

Yes

9. Were additional

interventions

(co-interventions) clearly

described?

Yes

Outcome

measures

10. Were relevant

outcome

measures

established a priori?

No

Yes

11. Were outcome

assessors blinded to

the intervention that

patients received?

Yes

12. Were the relevant

outcomes measured

using

appropriate

objective/subjective

methods?

Yes

13. Were the relevant

outcome

measures

made before and after

the intervention?

(27)

Statistical

analysis

14. Were

the

statistical tests used

to assess the relevant

outcomes

appropriate?

Yes

Results and

conclusions

15. Was follow-up

long

enough

for

important events and

outcomes to occur?

No

Yes

16. Were losses to

follow-up reported?

No

Yes

17. Did the study

provided estimates of

random variability in

the data analysis of

relevant outcomes?

No

Yes

18. Were the adverse

events reported?

Yes

19. Were

the

conclusions of the

study supported by

the results?

Yes

Competing

interests

and sources

of support

20. Were

both

competing interests

and

sources

of

support for the study

reported?

(28)

Supplementary file 1. (continued)

Study

Bertrand

2018

Mínguez

2018

Regueiro

2018

Weise

2018

Bergmann

2018

Study

objective

1.Was

the

hypothesis/aim

of

the

study

clearly

stated?

Yes

Study

design

2. Was the study

conducted

prospectively?

Yes

3. Were the cases

collected in more

than one centre?

No

Yes

No

Yes

4. Were

patients

recruited

consecutively?

Uncear

Unclear

Yes

Study

population

5. Were

the

characteristics of the

patients included in

the study described?

Yes

6. Were the eligibility

criteria (i.e. inclusion

and

exclusion

criteria) for entry

into the study clearly

stated?

Partial

No

Partial

No

7. Did patients enter

the study at a similar

point in the disease?

Yes

Unclear

Intervention

and

co-intervention

8. Was

the

intervention

of

interest

clearly

described?

Yes

9. Were additional

interventions

(co-interventions)

clearly described?

Yes

Outcome

measures

10. Were relevant

outcome

measures

established a priori?

No

Yes

11. Were outcome

assessors blinded to

the intervention that

patients received?

Yes

12. Were the relevant

outcomes measured

using

appropriate

objective/subjective

methods?

Yes

13. Were the relevant

outcome

measures

made before and

after

the

(29)

intervention?

Statistical

analysis

14. Were

the

statistical tests used

to assess the relevant

outcomes

appropriate?

Yes

Results and

conclusions

15. Was follow-up

long

enough

for

important events and

outcomes to occur?

No

Yes

16. Were losses to

follow-up reported?

No

17. Did the study

provided estimates of

random variability in

the data analysis of

relevant outcomes?

Yes

18. Were the adverse

events reported?

Yes

19. Were

the

conclusions of the

study supported by

the results?

Yes

Competing

interests

and sources

of support

20. Were

both

competing interests

and

sources

of

support for the study

reported?

(30)

Supplementary file 1. (continued)

Study

Phillips,

2019

Study

objective

1.Was

the

hypothesis/aim

of

the

study

clearly

stated?

Yes

Study

design

2. Was the study

conducted

prospectively?

Yes

3. Were the cases

collected in more

than one centre?

Yes

4. Were

patients

recruited

consecutively?

Yes

Study

population

5. Were

the

characteristics of the

patients included in

the study described?

Yes

6. Were the eligibility

criteria (i.e. inclusion

and

exclusion

criteria) for entry

into the study clearly

stated?

No

7. Did patients enter

the study at a similar

point in the disease?

Unclear

Intervention

and

co-intervention

8. Was

the

intervention

of

interest

clearly

described?

Yes

9. Were additional

interventions

(co-interventions)

clearly described?

Yes

Outcome

measures

10. Were relevant

outcome

measures

established a priori?

No

11. Were outcome

assessors blinded to

the intervention that

patients received?

Yes

12. Were the relevant

outcomes measured

using

appropriate

objective/subjective

methods?

Yes

13. Were the relevant

outcome

measures

made before and

after

the

(31)

intervention?

Statistical

analysis

14. Were

the

statistical tests used

to assess the relevant

outcomes

appropriate?

Yes

Results and

conclusions

15. Was follow-up

long

enough

for

important events and

outcomes to occur?

Yes

16. Were losses to

follow-up reported?

No

17. Did the study

provided estimates of

random variability in

the data analysis of

relevant outcomes?

Yes

18. Were the adverse

events reported?

Yes

19. Were

the

conclusions of the

study supported by

the results?

Yes

Competing

interests

and sources

of support

20. Were

both

competing interests

and

sources

of

support for the study

reported?

(32)

(33)

Normas de Publicação da Acta Médica Portuguesa

Acta Médica Portuguesa’s Publishing Guidelines

Conselho Editorial ACTA MÉDICA PORTUGUESA

Acta Med Port 2016, 30 dezembro 2016

NORMAS PUBLICAÇÃO

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Para atingir estes objectivos a Acta Médica Portuguesa publica artigos originais, artigos de revisão, casos clínicos, editoriais, entre outros, comentando sobre os factores clí-nicos, científicos, sociais, políticos e económicos que afec-tam a saúde. A Acta Médica Portuguesa pode considerar artigos para publicação de autores de qualquer país.

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