Clínica Universitária de Neurologia

Miocardiopatia dilatada e o risco de AVC cardioembólico: uma revisão sistemática com meta-análise

Catarina Mateus Paulo de Sousa

JUNHO’2019

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JUNHO’2019

Clínica Universitária de Neurologia

Miocardiopatia dilatada e o risco de AVC cardioembólico: uma revisão sistemática com meta-análise

Catarina Mateus Paulo de Sousa

Orientado por:

Professora Doutora Ana Catarina Fonseca

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RESUMO

O risco de embolia sistémica em doentes com miocardiopatia dilatada permanece

desconhecido. Para responder a esta questão, realizámos uma revisão sistemática da

literatura com meta-análise para avaliar o risco de acidente vascular cerebral (AVC) em

doentes com miocardiopatia dilatada. Assim, realizámos uma pesquisa eletrónica nas

bases de dados MEDLINE e EMBASE (até setembro de 2018). Incluímos adultos com

miocardiopatia dilatada que foram avaliados relativamente a pelo menos um dos

seguintes desfechos: AVC, AVC silencioso ou acidente isquémico transitório (AIT). O

outcome primário foi a ocorrência de isquémia cerebral (AVC, AVC silencioso ou AIT).

Após a exclusão de duplicados, analisamos 1124 artigos pelo título e resumo, 50 por texto

integral, dos quais 6 foram incluídos na análise qualitativa e 2 na análise quantitativa. O

número de doentes variou entre 40 a 290, com um total de 1020 em todos os estudos

incluídos (944 com miocardiopatia dilatada e 76 controlos). A duração de seguimento foi

desde 12 meses a 129 meses, 32% dos doentes incluídos eram do sexo feminino (n=328)

e a idade média de todos os participantes foi de 59.6 anos. Os dois artigos que foram

selecionados para a análise quantitativa tinham como outcome primário o AVC

silencioso. A prevalência de AVC silencioso em 92 doentes com miocardiopatia dilatada

foi de 31.4% (95% CI: 21.92-40.88) vs 3.6% (95% CI: 0-7.79) no grupo controlo. A meta-

análise realizada demonstrou um risco significativamente superior de AVC silencioso em

doentes com miocardiopatia dilatada em comparação com os controlos (OR 13.66, IC

95%:3.59-51.95, p < 0.001), com baixa heterogeneidade entre estudos (I2 = 0%). Em

conclusão, doentes com miocardiopatia dilatada têm um risco aumentado de AVC

silencioso. No entanto, não é possível concluir definitivamente qual o risco de AVC

clínico ou acidente isquémico transitório, sendo necessários mais estudos para avaliar o

risco de AVC cardioembólico em doentes com esta patologia.

ABSTRACT

There is controversy about the actual risk of systemic embolism associated with dilated

cardiomyopathy (DCM). Therefore, we conducted a systematic review with meta-

analysis in order to appraise the true risk of cardioembolic stroke in patients with DCM.

We performed an electronic search through MEDLINE and EMBASE databases (until

september 2018). Inclusion criteria were adult patients with dilated cardiomyopathy who

were evaluated for one of the following endpoints: stroke, silent stroke or a transient

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ischemic attack. The primary outcome was the occurrence of cerebral ischaemia (silent

stroke, stroke or transient ischaemic attack). After excluding duplicates, title and abstract

screening included 1124 articles, 50 were assessed for full-text screening, with 6 being

included for qualitative synthesis and 2 for quantitative syntheses. The number of patients

enrolled in each study varied between 40 and 290, for a total of 1020 patients (944 with

DCM and 76 controls). The duration of follow-up ranged from 12 months to 129 months,

32% were female (n=328) and the mean age of all participants was 59.6 years. Both the

articles selected for the quantitative synthesis had silent stroke as primary outcome. The

overall prevalence of stroke observed in 92 patients with DCM was 31.4% (95% CI:

21.92-40.88) vs 3.6% (95% CI: 0-7.79) in the control group. Pooled analysis showed a

significant increase in the risk of stroke in patients with DCM (OR 13.66, 95% CI: 3.59-

51.95, p < 0.001) with very low heterogeneity between studies’ estimates (I2 = 0%). In

conclusion, patients with dilated cardiomyopathy have an increased risk of silent stroke.

However, no conclusions can be definitely drawn on the risk of stroke or TIA in patients

with DCM. Further studies are warranted to assess the true risk of cardioembolic stroke

in patients with this condition.

PALAVRAS-CHAVE

Miocardiopatia dilatada; acidente vascular cerebral; AVC isquémico; AVC silencioso.

KEYWORDS

Dilated cardiomyopathy; stroke; ischemic stroke; silent stroke.

O Trabalho Final exprime a opinião do autor e não da FMUL.

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ÍNDICE

1. Resumo do trabalho final…………………………………………………………… 6

2. Trabalho de Revisão…………………………………...…………………………… 11

3. Agradecimentos…………………………………………………………………….. 22

4. Bibliografia…………………………………………………………………………. 23

5. Material suplementar..……………………………………………………………… 26

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RESUMO DO TRABALHO FINAL

Introdução: Sendo considerado a segunda maior causa de morte e a terceira maior

causa de anos de vida perdidos prematuramente ajustados pela incapacidade (DALY) em

todo o mundo [1], o acidente vascular cerebral (AVC) é uma lesão neurológica aguda que

pode resultar de um insulto isquémico (~80%) ou hemorrágico (~20%) [2]. Anualmente,

existem mais de 15 milhões novos AVC’s em todo o mundo, dos quais resultam grandes

custos para a saúde e um impacto negativo na produtividade da população [3-5]. O AVC

pode ainda ser subdividido de acordo com a sua etiopatogenia, manifestações clínicas,

tratamento e gestão do doente. Em 1993, foi desenvolvido o sistema de classificação

TOAST como ferramenta auxiliar ao diagnóstico dos diferentes subtipos de AVC

isquémico, subdividindo-os em 5 categorias [6]. Dependendo do tipo de AVC, o

prognóstico associado varia significativamente. De facto, os AVC recorrentes são mais

comuns em doentes com AVC de origem cardioembólica, tendo por base, na maioria das

vezes, a estase sanguínea associada a episódios de fibrilhação auricular (FA) [6-9]. No

entanto, existem muitos outros mecanismos responsáveis por este tipo de eventos com

origem cardíaca. A miocardiopatia dilatada (MCD) é definida como uma dilatação do

ventrículo esquerdo (VE) acompanhado de disfunção sistólica, na ausência de doença

arterial coronária ou condições de aumento de pressão proporcionais ao grau de disfunção

do VE [10]. Apesar de esta patologia ser considerada por alguns autores como uma das

causas de elevado risco de AVC cardioembólico [6, 11, 12], é ainda controverso qual o

verdadeiro risco associado a esta doença e qual o papel da anticoagulação profilática.

Tendo em conta a incerteza sobre este tópico, o objetivo desta revisão sistemática com

meta-análise é avaliar qual o risco de acidente vascular cerebral em doentes com

miocardiopatia dilatada.

Métodos: Tendo como referência o PRISMA statement, foi realizada uma pesquisa

eletrónica nas bases de dados da MEDLINE e EMBASE, entre 1946 e setembro de 2018.

Foram incluídos adultos com miocardiopatia dilatada que foram avaliados relativamente

a pelo menos um dos seguintes desfechos: AVC, AVC silencioso ou acidente isquémico

transitório. Como critérios de exclusão consideramos: ter um enfarte agudo do miocárdio

nos 3 meses prévios, casos clínicos, revisões não sistemáticas da literatura, investigação

animal, artigos de opinião, editoriais e artigos escritos numa língua que não o Português,

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Francês, Inglês ou Espanhol. Numa primeira fase, títulos e resumos foram avaliados

independentemente por dois autores, passando os estudos potencialmente relevantes para

uma segunda fase com leitura integral do respetivo artigo. Informação relevante que não

se encontrava referida no artigo ou material suplementar do mesmo, foi requisitada por

email aos autores. A qualidade dos estudos foi analisada segundo a ‘Newcastle-Ottawa

Quality Assessment scale’. Foi considerado como outcome primário a ocorrência de

isquemia cerebral (AVC, AVC silencioso ou acidente isquémico transitório). A análise

estatística foi realizada com a ferramenta RevMan 5.3, tendo por base o odds ratio como

medida do risco. Os resultados foram considerados estatisticamente significativos se o

valor P < 0.05 e a heterogeneidade foi medida pelo teste I2.

Resultados: O esquema de seleção dos estudos pode ser consultado na figura 1. A

pesquisa obteve 1180 artigos (112 pela MEDLINE e 1068 pela EMBASE), sendo que 1

artigo extra foi introduzido através da consulta de referências de um dos artigos incluídos.

Após exclusão dos duplicados, analisamos 1124 artigos pelo título e pelo resumo, tendo

50 entrado na análise de texto integral, dos quais 6 entraram na análise qualitativa e 2 na

análise quantitativa. As características dos estudos incluídos na análise qualitativa pode

ser consultada na tabela suplementar 2. O número de participantes em cada estudo variou

entre 40 e 290, com um total de 1020 indivíduos (944 com MCD e 76 controlos). Os

estudos foram publicados entre 1994 e 2017. A duração de seguimento foi desde 12 meses

a 129 meses, 32% dos doentes incluídos eram do sexo feminino (n=328) e a idade média

de todos os participantes foi de 59.6 anos. Os dois artigos selecionados para a síntese

quantitativa, caracterizados na tabela 2, tinham como outcome primário a deteção de

enfarte cerebral por ressonância magnética (AVC silencioso). Todos os estudos incluídos

nesta revisão sistemática foram unicêntricos. Considerando apenas AVC silencioso como

outcome primário, Kozdag et al. [15] e Schmidt et al. [16] demonstraram uma prevalência

global de 31.4% num total de 92 doentes com MCD (95% CI: 21.92-40.88) vs 3.6% em

76 controlos (95% CI: 0-7.79). A meta-análise realizada demonstrou um risco

significativamente superior de AVC silencioso em doentes com miocardiopatia dilatada

em comparação com controlos (OR 13.66, IC 95%: 3.59-51.95, p < 0.001), com baixa

heterogeneidade entre estudos (I2 = 0%) (figura 2). O risco relativo estimado a partir do

odds ratio foi de 2,75 [20]. A qualidade metodológica dos estudos incluídos foi média,

sendo que todos os estudos desta revisão sistemática são observacionais.

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Discussão: Os resultados principais desta revisão sistemática foram: 1) a prevalência

de AVC silencioso em doentes com MCD é superior que na população controlo (31.4%

vs 3.6%); 2) o risco de AVC silencioso é significativamente superior em doentes com

MCD vs controlos (OR 13.66). Este aumento de risco de AVC em doentes com MCD

pode ser explicado por inúmeros mecanismos fisiopatológicos: (i) função ventricular

esquerda diminuída com consequente esvaziamento ventricular incompleto e estase

sanguínea resultando na formação de um trombo intraventricular; (ii) aumento do risco

de FA devido à dilatação da aurícula esquerda consequente ao aumento das pressões intra-

cavitárias do ventrículo esquerdo (ex. elevação da pressão de enchimento diastólico do

ventrículo esquerdo); (iii) estado pró-trombótico por alterações inflamatórias sistémicas

e (iv) hipoperfusão cerebral crónica resultante de insuficiência cardíaca com baixo débito

[12,21].

Um outro aspeto importante a realçar desta revisão sistemática prende-se com a

elevada incidência de AVC silencioso em doentes com MCD. Esta associação é de

extrema importância, uma vez que o AVC silencioso é frequentemente considerado como

um precursor do AVC sintomático. Na verdade, este pode ser visto como uma evidência

indireta de que a condição que lhe deu origem cria um ambiente propenso a estes

fenómenos cerebrovasculares que poderá culminar num AVC clínico. No entanto, a

verdadeira implicação clínica desta condição ainda é limitada [22], com um fator de

confundimento não desprezível, pois a prevalência de acidentes vasculares cerebrais

silenciosos aumenta com a idade [23]. Cumulativamente, esta condição mais do que

duplica o risco de demência e contribui para um declínio mais acentuado e precoce da

função cognitiva [24,25]. Isto é particularmente importante quando se considera que os

AVC silenciosos são mais comuns do que os AVC clinicamente evidentes [23,26]. À luz

dos nossos resultados, que demonstraram um risco aumentado de AVC silencioso em

doentes com MCD, é de extrema importância alertar para as consequências a médio e

longo prazo destes eventos. Isto deve ser tido em consideração ao avaliar o benefício

clínico global de terapêutica anti trombótica nestes doentes. Para além disso, é importante

salientar que o facto dos doentes com MCD terem um maior risco de eventos

cerebrovasculares numa idade mais jovem, por volta de 60 anos, pode diminuir

significativamente a sua capacidade funcional, levando a perda de produtividade.

A fibrilhação auricular é a arritmia mais comum, com uma prevalência aproximada de

1% na população em geral [25]. Aumenta com a idade, atingindo aproximadamente 6%

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em pessoas com mais de 65 anos [26]. No entanto, isto pode ser apenas uma subestimativa

da realidade, uma vez que uma proporção significativa de doentes tem FA subclínica [28].

Dado que há um aumento de risco de AVC de quase 5 vezes nos doentes com FA não

valvular, esta patologia pode ser, na verdade, um fator confundente importante a ter em

consideração nesta revisão sistemática [25].

A idade em si é, também, um forte fator de risco independente de AVC, com um

aumento de 1.5 vezes no risco por década [25]. Nesta revisão, a prevalência de AVC

aumenta com a idade da população estudada.

Considerando que a MCD tem características protrombóticas, tais como os níveis

aumentados de fibrinopeptido A, antitrombina III, D-dímero e fibrinogénio, a terapêutica

antitrombótica pode ser considerada uma arma atrativa para lidar com o aumento de risco

de AVC associado a esta condição [30]. A maioria dos estudos nesta área não

demonstraram benefício em anticoagular ou antiagregar estes doentes [30,31], o que se

pode dever à heterogeneidade dos participantes incluídos nestes estudos. Assim, após

avaliar o verdadeiro risco de AVC em doentes com MCD, são necessários ensaios clínicos

prospetivos, controlados e aleatorizados para avaliar os efeitos da terapêutica

antitrombótica no risco de AVC nos doentes com miocardiopatia dilatada.

Como limitações desta revisão sistemática, há que considerar as limitações inerentes

ao tipo de estudos incluídos que, por serem estudos observacionais, estão intrinsecamente

limitados por fatores confundentes. Adicionalmente, verificaram-se heterogeneidades na

definição de MCD, no estado de anticoagulação e nas comorbilidades dos doentes, tais

como fibrilhação auricular, hipertensão arterial, doença arterial coronária, diabetes

mellitus e obesidade. Foram também consideradas as diferentes etiologias de MCD sob a

suposição de um efeito comum destas patologias, o que pode ter enviesado os resultados

finais. Mais ainda, a meta-análise é composta apenas por dois estudos transversais com

um número reduzido de doentes, o que diminui a robustez dos dados. Outros fatores que

podem limitar a extrapolação dos resultados incluem: pequeno número de

estudos/doentes incluídos, diferentes tempos de seguimento, diferentes desenhos de

estudo e heterogeneidade na idade da população incluída, particularmente nos estudos da

análise quantitativa. O viés de publicação também é inerente a qualquer revisão

sistemática da literatura e pode ter resultado numa amostra parcial de todos os estudos

relevantes sobre o tema. Outra limitação em relação à análise estatística é o uso do odds

ratio em vez do risco relativo. O odds ratio é a medida mais adequada para estudos com

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desfechos raros e é a única que pode ser usada em todos tipos de estudos observacionais.

No entanto, pode sobrestimar o verdadeiro risco, particularmente quando a prevalência é

superior a 10%, o que é o caso nesta meta-análise [20]. Apesar de ter sido realizada uma

análise para avaliar o risco relativo e com isso minorar a hiperbolização dos resultados

finais, é importante considerar estes aspetos na análise final dos resultados.

Conclusão: Doentes com miocardiopatia dilatada apresentam um risco aumentado de

AVC silencioso comparativamente aos doentes sem miocardiopatia dilatada. Devido à

falta de estudos robustos direcionados para a avaliação do risco de AVC em doentes com

MCD, não é possível concluir com segurança qual o seu verdadeiro risco nestes doentes.

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TRABALHO DE REVISÃO

Dilated cardiomyopathy and the risk of cardioembolic stroke: a systematic review

with meta-analysis

INTRODUCTION

Being considered the second most common cause of death and the third most common

cause of disability-adjusted life-years (DALYs) worldwide [1], stroke is an acute

neurologic injury that occurs as a result of either brain ischemia (~80%) or brain

haemorrhage (~20%) [2]. There are more than 15 million strokes each year, with high

health-care costs and dramatic loss of labour productivity [3-5]. Stroke can be further

subdivided according to its aetiology, clinical course, treatment, outcomes and

subsequent management. In 1993, the TOAST classification developed a system for

diagnosis of subtypes of ischemic stroke, dividing them in 5 categories: 1) large-artery

atherosclerosis, 2) cardioembolism, 3) small-artery occlusion (lacune), 4) stroke of other

determined etiology, and 5) stroke of undetermined etiology [6].

Outcomes and likelihood of recurrence differs significantly by different ischemic

stroke subtypes. Recurrent strokes are more likely among patients with a stroke of cardiac

origin [6-8]. The underlying pathophysiological mechanism of cardioembolic stroke is

occlusion of cerebral vessels with debris from a cardiac source, resulting in an ischemic

injury. One of the most important causes of these insults arises from blood stasis due to

episodes of discoordinated atrial contraction, that can occur namely during atrial

fibrillation (AF) [9]. Nonetheless, several other mechanisms are responsible for the

development of cardiac emboli and have been further divided into high-risk or medium-

risk groups based on the evidence of their relative propensities for embolism (table 1).

Dilated Cardiomyopathy (DCM) is a chronic heart disease characterized by left

ventricular (LV) dilatation and systolic dysfunction in the absence of coronary artery

disease or abnormal loading conditions proportionate to the degree of LV impairment

[10]. It is considered to be one of the high-risk sources of a cardioembolic stroke [6,11,12].

However, there is still controversy about the actual risk of systemic embolism associated

with this condition and whether anticoagulation would be of benefit to these patients.

Acknowledging the gap in the evidence and uncertainty about this topic, we performed a

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systematic review with meta-analysis in order to appraise the true risk of cardioembolic

stroke in patients with dilated cardiomyopathy.

High-risk sources Medium-risk sources

Mechanical prosthetic valve Mitral valve prolapse

Mitral stenosis with atrial fibrillation Mitral annulus calcification

Atrial fibrillation Mitral stenosis without atrial fibrillation

Left atrial/atrial appendage thrombus Left atrial turbulence (smoke)

Sick sinus syndrome Atrial septal aneurysm

Recent myocardial infarction (<4

weeks)

Patent foramen ovale

Left ventricular thrombus Atrial flutter

Dilated cardiomyopathy Lone atrial fibrillation

Akinetic left ventricular segment Bioprosthetic cardiac valve

Atrial myxoma Nonbacterial thrombotic endocarditis

Infective endocarditis Congestive heart failure

Hypokinetic left ventricular segment

Myocardial infarction (> 4 weeks, < 6

months)

Table 1. TOAST classification of high- and medium-risk sources of cardioembolism.

Adapted form TOAST, Trial of Org 10172 in Acute Stroke Treatment.

METHODS

Search strategy and study selection

We conducted a systematic review and meta-analysis according to the Preferred

Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) Statement [13].

We performed an electronic search through MEDLINE and EMBASE databases, between

1946 and September 2018, using the following terms: ("Stroke"[Mesh] OR "Stroke,

Lacunar"[Mesh] OR "Infarction, Posterior Cerebral Artery"[Mesh] OR "Infarction,

Middle Cerebral Artery"[Mesh] OR "Infarction, Anterior Cerebral Artery"[Mesh] OR

"Brain Stem Infarctions"[Mesh] OR “Brain Infarction” OR “Cerebral embolism” OR

“Ischemic stroke” OR “Cerebral vascular disease”) AND “Dilated cardiomyopathy”. No

language or time restrictions were applied. Reference lists of retrieved studies and review

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papers were also cross-checked. Inclusion criteria were: adult patients with dilated

cardiomyopathy who were evaluated for one of the following endpoints: stroke, silent

stroke or a transient ischemic attack (TIA). Exclusion criteria were: having a myocardial

infarction in the previous 3 months, case series, case reports, reviews, animal research,

opinion articles, editorials and articles written in other language than Portuguese, French,

English or Spanish. We further excluded studies with incomplete data after having

searched for supplementary materials and contacted the authors by email. When more

than one publication with the same population was found, we used the one providing the

most detailed information. No studies were excluded a priori for weakness of design or

data quality.

Titles and abstracts of obtained records were screened independently by two authors.

Potentially relevant studies were assessed in full-text to determine its appropriateness for

inclusion. In case of disagreement, a consensus between the two reviewers was achieved

by group discussion. The same reviewers independently extracted data on study design,

sample size, patient clinical characteristics, follow-up time and outcome of interest. If not

achievable from the article, supplementary materials were used to find the information of

interest and additional data was requested by email to the corresponding author. Quality

of reporting was independently analysed by the two investigators using the Newcastle-

Ottawa Quality Assessment scale.

Study Outcome

The primary outcome was the occurrence of cerebral ischaemia (silent stroke, stroke

or transient ischaemic attack).

Statistical analysis

Statistical analysis was performed using RevMan 5.3 software (The Nordic Cochrane

Centre, The Cochrane Collaboration, 2011). Individual studies and meta-analysis

estimates were derived and presented in forest plots. For the meta-analysis, we used by

default the random-effects model (irrespectively of the heterogeneity) to estimate pooled

odds ratios and 95% confidence intervals (CIs). Odds ratios (OR) were chosen as the

measure to report the results. Overall results were statistically significant if P < 0.05.

Heterogeneity was measured through the I2 test that estimates the percentage of total

variation between studies.

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RESULTS

Search Results

The flowchart of study selection can be seen in Figure 1. The search returned 1180

records (112 through MEDLINE 1068 through EMBASE) and 1 article was added

through references of another included article, resulting in 1124 records after removing

all duplicates. After title and abstract screening 50 articles were assessed for full-text

screening, with 6 being included for qualitative synthesis and 2 for quantitative synthesis.

We excluded 19 unpublished trials, 11 articles with no usable data, 5 articles not available

in the full-text version, 3 reviews, 3 articles in a non-eligible language, 2 studies using

the same population and 1 opinion article.

Fig. 1 PRISMA flow diagram showing the selection of eligible studies.

Qualitative synthesis

Supplementary table 2 summarizes the characteristics of the studies included in the qualitative

synthesis.

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The number of patients enrolled in each study varied between 40 and 290, for a total

of 1020 patients (944 with DCM and 76 controls). The studies were published between

1994 and 2017. The duration of follow-up ranged from 12 months to 129 months, 32%

were female (n=328) and the mean age of all participants was 59.6 years. In the majority

of the included studies the diagnosis of DCM was achieved only by 2D transthoracic

echocardiography, except in Schmidt et al [16], and in Fruhwald et al [18]. in which left-

heart catheterization was necessary for the diagnosis. Both articles selected for the

quantitative synthesis had as primary outcome cerebral infarction detected by MRI (also

known as Silent Stroke). All the included studies in this systematic review were single-

centre.

Crawford et al. [14] published a single-centre prospective cohort study in 2004 that

correlates the echocardiographic finding of LV thrombus or other apical

echocardiographic abnormalities with the clinical outcomes of stroke, TIA, and death in

patients with DCM. 290 patients with DCM [109 females (36%), with an average age of

62.5 years] were followed during an average of 30.7 months (0.9-74). Information was

collected from Duke University’s computerized medical records searched through

December 2009 and neither the diagnosis nor the aetiology of the DCM were confirmed

or investigated. Ejection fraction at baseline was approximately 21%. Patients were

considered to have had stroke if that diagnosis was included in their clinical history,

regardless of neurologic sequelae or radiologic confirmation. Fifteen patients (5.2%) had

a stroke or TIA during follow-up [TIA occurred in 7 patients (9.0%) who had a thrombus

diagnosed on their echocardiogram and in 8 patients (3.8%) without thrombus]. The odds

ratio for stroke in the presence of LV thrombus was 3.41 (p = 0.027), after being adjusted

for the presence of diabetes mellitus, hypertension, and atrial fibrillation. 102 patients

(34%) had a diagnosis of atrial fibrillation, 6 of which had a stroke (40% of all stroke

patients). 108 patients (40%) were anticoagulated with warfarin, 8 of which had a stroke

(53% of all stroke patients).

Kozdag et al. [15] published in 2008 a cross-sectional single-centre study that

included 72 patients with DCM (53 male, 19 female, aged 62 ± 12 years) with the

objective of determining the prevalence and related parameters of silent cerebral

infarction (SCI) in patients with this condition. To achieve this goal, they also enrolled

56 age- and gender-match volunteers as the control group (36 males, 20 females, aged

61±10 years). Exclusion criteria included having a previous stroke or atrial fibrillation.

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Silent strokes were diagnosed by evidence of cerebral infarction in MRI studies. DCM

was documented by left ventricular enlargement (end-diastolic diameter ≥ 56mm) and

systolic dysfunction (ejection fraction ≤ 45%), using 2-dimensional and M-mode

transthoracic echocardiography. The aetiology of DCM was investigated in all patients

with coronary angiography, subdividing them in ischemic DCM (n=46) and non-ischemic

DCM (n=26). Ejection fraction between the two subgroups did not differ significantly (32

± 9 % ischemic DCM and 31 ± 10 % non-ischemic DCM). The prevalence of SCI was

39%, 27% and 3.6% in ischemic, nonischemic DCM and control group, respectively

(ischemic DCM vs control group, p < 0.001, nonischemic DCM vs control group, p =

0.02). No patients were on anticoagulant therapy. In multivariable logistic regression

analysis, restrictive type of diastolic filling pattern was found as an independent factor for

SCI occurrence on the whole patient population (OR: 16.5, 95% CI: 4.4–61.8, p < 0.001).

Schmidt et al. [16] study, published in 1991, was a single-centre cross-sectional study

intended to compare brain magnetic resonance imaging (MRI) and neuropsychological

performance in 20 asymptomatic patients suffering from DCM and 20 age-matched

controls [40.5 ±7.8 years (DCM) and 37.9±4.7 years (controls)]. To keep confounding

factors at a minimum, having a previous stroke was one of the exclusion criteria. The

diagnosis of DCM included 2-dimensional and M-mode transthoracic echocardiography

and left ventricle catheterization. Cerebral infarcts were detected by brain MRI in 4

patients with DCM (20%) vs 0 in the control group. Even though 4 patients had a previous

diagnosis of atrial fibrillation, only 1 of the patients who had a silent stroke did actually

have this condition. No patients were on anticoagulants. The mean ejection fraction was

27.9% in the group of patients with DCM. Echocardiography did not reveal left

ventricular thrombus in any patient.

Cho et al. [17] published a single-centre prospective cohort study in 2017 aimed at

identifying the predictors of left ventricular functional recovery (LVFR) and its impacts

on clinical outcomes in patients with newly diagnosed DCM. A total of 175 patients were

included in the analysis [65 (37.1%) females, aged 58.6 years]. The patients were further

subdivided into 2 groups according to the LVFR on follow up after 6 months: the

recovered group (n=54, with 54.3 ±18.5 years, 23 females) and the non-recovered group

(n=121, 60.5±15.1 years, 42 females). DCM was diagnosed using a 2D transthoracic

echocardiography (ventricular dilatation defined by > 55 mm and depressed LV systolic

function defined by the LV ejection fraction < 45%). The mean ejection fraction for the

17

all the patients included was 28.9%, with no statistically significance difference between

the baseline values of the recovered vs the non-recovered group (30.2 ± 9.6% and 28.3 ±

8.0%, respectively). During the 60 months of follow-up, 4 (2.3%) patients had a stroke.

42 (24%) had atrial fibrillation and 52 (29.7%) were anticoagulated with warfarin.

Fruhwald et al. [18] published a single-centre retrospective cohort observational

study to investigate long-term follow-up and identify prognostic factors in patients with

DCM. The investigators included 167 patients with DCM, with 23 (13,8%) females and

a mean age of 55±11 years. DCM was diagnosed by left- and right-heart catheterization

and echocardiography. The mean ejection fraction was 34.9%. During 93 ± 36 months of

follow-up, 3 (1.8%) patients had a stroke. No data was found on the number of patients

with AF or those on anticoagulant therapy.

Kim et al. [19] conducted a single-centre retrospective cohort, published in 2009, on

the prognostic usefulness of spontaneous echo contrast (SEC) in predicting a stroke in

patients with DCM. For this, 220 patients (136 men, aged 62.81±5.4 years) with DCM

were included. DCM was diagnosed based on 2D M-mode transthoracic

echocardiographic findings of LV dilation (LV end diastolic dimension ≥ 55 mm) and

systolic dysfunction (LV ejection fraction ≤40%). The mean left ventricular ejection

fraction was 27.8±7.8%. During 87 months of follow-up, stroke occurred in 13 (5.9%)

patients, 4 (16.7%) of which had AF. SEC was observed in 24 patients, 4 of which had a

stroke (30.8%). Of all the patients with SEC findings on echocardiography, 10 (41.7%)

were on anticoagulant therapy (7 on warfarin and 3 on heparin), with no reported data on

the association of anticoagulation and stroke. The incidence of previous antiplatelet or

anticoagulation therapies was not different between patients with stroke and without

stroke [75% (3/4) vs. 65% (13/20), p = 0.69].

Quantitative synthesis

Considering silent stroke as the primary outcome, Kozdag et al. [15] and Schmidt et

al. [16] showed an overall prevalence of 31.4% (95% CI: 21.92-40.88) in 92 patients with

DCM vs 3.6% in age- and gender-matched control population (95% CI: 0-7.79). Overall,

pooled analysis from Kozdag et al.[15] and Schmidt et al. [16] showed an odds ratio of

silent stroke among DCM patients of 13.66 (95% CI: 3.59-51.95, p < 0.001) with very

low heterogeneity between studies’ estimates (I2 = 0%) (fig.2). The overall relative risk

estimated from the OR is 2.75 [20].

18

Reference

Kozdag Y. et al.,

Vasc Health Risk Manag,

2008;4(2):463-9

Schmidt R. et al., Stroke,

1991;22(2):195-9

Nationality Turkish Austrian

Type of study Cross-sectional Cross-sectional

CONTROLS DCM CONTROLS DCM

Number of patients 56 72 20 20

Gender, female (%) 20 (36%) 19 (26%) 7 (35%) 1 (5%)

Age, years (mean) 61 ± 10 62 ± 12 37.9 ± 4.7 40.5 ± 7.8

Previous Stroke* 0 0 0 0

Known auricular

fibrillation+ 0 0 0 4 (20%)

Ejection Fraction > 55% 31.6% > 55% 27.9%

Stroke, silent (%) 2 (3.6%) 25 (34.7%) 0 4 (20%)

Odds ratio 14.36 11.18

Relative Ratio

(estimated based on the

OR)[19]

2.55 3.68

Anticoagulant Therapy 0 0

Table 2. Characteristics of the studies included in the quantitative synthesis. * This was one of the exclusion criteria of both studies.

+ This was an exclusion criteria for Kozdag Y et al. study.

Fig.2 Forest plot with pooled estimates regarding the odds ratio of silent stroke.

Quality assessment

Overall, the methodological/reporting quality was fair (2 studies with good quality, 2

with fair quality and 2 with poor quality). All included studies were observational and

19

therefore intrinsically highly prone to selective reporting bias. Following the Newcastle–

Ottawa Scale for quality reporting, studies’ scores ranged from 3 to 10 stars, and the most

common flaws were in the selection and comparability sections. All these aspects increase

the risk of bias of the included studies. Supplementary table 1 summarizes the risk of bias

evaluation of all studies.

DISCUSSION

This systematic review was planned and designed to evaluate the risk of cardioembolic

stroke in patients with dilated cardiomyopathy. The main findings of this systematic

review were: (i) the prevalence of silent stroke in patients with DCM is higher than in

age- and gender-matched control population (31.4% vs 3.6%); (ii) the risk of silent stroke

is significantly higher in patients with DCM vs age- and gender-matched control

population (OR 13.66).

One may speculate about the possible mechanisms behind this increased risk to be: (i)

impaired left ventricular function with induced intraventricular thrombus formation from

blood stasis and incomplete ventricular emptying; (ii) increased risk of atrial fibrillation

or silent AF due to dilated left atrium as a result of an increase in the diastolic filling

pressure in the left ventricle; (iii) prothrombotic state due to inflammatory systemic

changes; and (iv) chronic cerebral hypoperfusion from resulting low output heart failure

[12,21].

Silent stroke is often thought of as a precursor of symptomatic strokes, as it may be an

indirect evidence that the underlying condition creates a stroke-prone environment that

will ultimately result in a clinically evident cerebrovascular accident. However, the true

clinical implication of this condition is still limited [22]. Evidence suggests that

prevalence of silent stroke increases with age [23]. This condition more than doubles the

risk of dementia and contributes to a steeper decline in cognitive function [24,25]. This

is particularly important when one considers that silent strokes are more common than

clinically evident strokes [23,26]. In light of our results demonstrating an increased risk

of silent stroke in patients with DCM, it is of the utmost importance to raise awareness of

mid and long-term consequences of such events. This should also be taken into account

when evaluating the net clinical benefit of antithrombotic therapy in these patients.

Another important aspect to emphasize is the young average age of these patients, about

20

60 years old, which may decrease functional capacities or lead to loss of productivity

throughout life.

Atrial fibrillation is the most common atrial arrhythmia, with an approximate

prevalence of 1% in the general population [25] that increases with age, achieving

approximately 6% in people older than 65 years [26]. However, this estimate may be an

underestimation of its true burden, due to the significant proportion of subclinical AF

[28]. Given that there is nearly a 5-fold increase in patients with non-valvular AF, this

could be, in fact, a major confounding factor of this systematic review [25].

Age itself is a strong independent risk factor of stroke, with a 1.5-fold increase in risk

per decade [25,29]. In this review, the higher the mean age of the population studied the

higher the prevalence of stroke.

Considering that DCM has prothrombotic characteristics, such as higher levels of

fibrinopeptide A, antithrombin III, circulating fibrinogen and D-dimer, antithrombotic

therapy could be considered as an attractive weapon to deal with increased stroke risk

associated with this condition [30]. However, most studies in this area have not shown

benefit of anticoagulation or antiaggregation therapy in patients with chronic heart failure

[30,31]. The HELAS trial [32] and the WASH trial [33] showed no overall significant

difference between aspirin, warfarin or placebo regarding embolic events. In the WATCH

trial [34] and the WARCEF trial [35] warfarin lowered the percentage of stroke, at the

cost of an increased hemorrhage rate. DCM should not be considered a synonym for heart

failure (HF), but instead an individualized entity that may or may not result in HF. One

must consider the heterogeneity of patients included in this RCT as a potential factor of

bias. This heterogeneity might be due to including patients with HF regardless of its cause

or not excluding patients with other conditions known to independently elevate

thromboembolic risk, such as AF and valvular heart disease [30]. Inadequate statistical

power, study design flaws and short-period of follow-up may have also contributed to the

poor outcomes of these studies. Therefore, after assessing the true risk of stroke in patients

with DCM, a prospective randomized controlled trial to evaluate the effects of

antithrombotic therapy on these patients’ stroke outcome is warranted.

Limitations

Our results are limited by methodological issues associated to the individual studies

included, so that the key limitation of this review is consistent with the major limitation

21

of most observational research, the confounding factors. These include: heterogeneity in

the definition of DCM, the anticoagulation status and concurrent comorbidities, such as

atrial fibrillation, hypertension, coronary artery disease, diabetes mellitus and obesity. We

pooled together the different aetiologies of DCM under the assumption of a common

effect of the end stage of this pathologies, which may have distorted the results.

Furthermore, the meta-analysis is only composed by two cross-sectional studies with a

rather low number of included patients which downgrades the robustness of the data.

Other factors that might limit the extrapolation of the results include: small number of

included studies/patients, different follow-up times, different study designs and different

mean age of the population, particularly in the studies that were included in the

quantitative synthesis. Modern detection of Silent Stroke is dependent upon the sensitivity

and specificity of imaging and definition of the radiological appearance, which may be

major sources of heterogeneity with important implications for prevalence estimates [36].

Publication bias is also inherent in any systematic literature review and may have resulted

in a biased sample of all relevant studies on the topic. Specifically, it is well established

that studies reporting relatively large effects are more likely to be published than those

that do not, and this becomes more pertinent among studies with smaller sample

sizes [37]. Another limitation regarding statistical analysis is the use of the odds ratio

instead of the relative ratio. The OR is the most appropriate for studies with rare outcomes

and it is the only one that can be used in all the different types of observational studies.

However, odds ratio might overestimate the true risk, particularly when the prevalence is

higher than 10%, which is the case in this meta-analysis [20]. Even though we calculated

the overall relative risk of silent stroke to minimize the overestimation of the results, it is

important to consider this drawback when analysing the final results.

CONCLUSION

This meta-analysis shows that patients with dilated cardiomyopathy have an increased

risk of silent stroke compared to age- and gender-match volunteers without this

comorbidity. No conclusions can be definitely drawn on the risk of stroke or TIA in

patients with DCM as there are no robust studies to validate this hypothesis. In fact,

further proof of the true risk of cardioembolic stroke in patients with dilated

cardiomyopathy is needed.

22

AGRADECIMENTOS

“Se eu vi mais longe foi por estar de pé sobre o ombro de gigantes.”

Isaac Newton

À Professora Doutora Ana Catarina Fonseca pela sua orientação, pelo seu entusiasmo

e pelos ensinamentos que me proporcionou.

À minha família, em particular aos meus pais, pelo constante apoio, incentivo,

compreensão e acima de tudo pelo seu amor incondicional.

Aos meus colegas e amigos de curso pelo seu apoio e preocupação, pelas longas horas

de estudo em conjunto e por sempre terem acreditado em mim e nas minhas capacidades.

A todos o meu sincero obrigado.

23

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26

MATERIAL SUPLEMENTAR

KOZDAG SCHMIDT CRAWFORD CHO FRUHWALD KIM

Selection 5* 3* 2* 1* 1* 2*

Comparability 2* 1* 2* 2* 0* 2*

Results 3* 3* 2* 2* 2* 3*

Total 10* 7* 6* 5* 3* 7*

Supplementary table 1. Quality assessment of all the included studies using the

Newcastle-Ottawa assessment scale for observational studies.

Reference Nationality Type of

study

Patients

included

Gender,

female (%)

Age, years

(mean)

Previous

Stroke

Known

Atrial

Fibrillation

Ejection

Fraction

at baseline

Primary

outcome

Follow-

up time

On

anticoagula

nt therapy

Crawford TC. Et

al., Am. J. Cardiol Feb

2004;93(4):500-3

American

Prospecti

ve

Cohort

290 with

DCM

109 (36%) 62.5 years

No data

specifically

about those

with DCM.

102 (34%), 6

(5,9%) of

which had a

Stroke.

21%

15 (5.2%) strokes.

8 (53%) were

anticoagulated. 6

had AF (40%). 7

(47%) had a

thrombus in the left

ventricle.

30.7

months

(0.9-74)

108 (40%), 8

(7,4%) of

which had a

Stroke. All

were

anticoagulat

ed with

Warfarin.

Kozdag Y. et al.,

Vasc Health Risk

Manag,

2008;4(2):463-9

*

Turkish Cross-

sectional

72 with

DCM (46

ischemic

DCM

and 26

non-

ischemic

DCM)

and 56

controls

19 (26%)

with DCM

(9 ischemic

DCM and 10

non-

ischemic

DCM) and

20 (36%)

controls

DCM: 62 ±

12 years (64

± 10 years ischemic DCM

and 57 ± 13

years non-ischemic

DCM)

Controls: 61

± 10 years

(Exclusion

criteria)

(Exclusion

criteria)

31.6%

[32 ± 9 %

(Ischemic DCM) and 31

± 10 % (non-

ischemic DCM)]

25 (34.7%) silent

strokes (18

(39%) in the

ischemic DCM

group and 7

(27%) in the non-

ischemic DCM

group VS 2

(3.6%) in the

control group.

No

follow-

up 0

Schmidt R. et al.,

Stroke Feb

1991;22(2):195-9

*

Austrian Cross-

sectional

20 DCM

and 20

controls

1 (5%) DCM

and 7 (35%)

controls

40.5 ±7.8

years

(DCM) and

37.9±4.7

years

(controls)

(Exclusion

criteria)

4 (20%)

DCM and 0

in controls.

27.9%

(DCM)

4 (20%) silent

strokes in DCM

group and 0 in

the control group

No

follow-

up.

0

Cho JY, et al.,

Heart, Lung and

Circulation (2017)

xx, 1–9

Korean

Prospecti

ve

Cohort

175 DCM 65 (37.1%) 58.6 years No data 42 (24%) 28.9% 4 (2.3%) strokes 60

months

52 (29.7%)

with

Warfarin

Fruhwald FM, et

al., Angiology

1994; 45

(9): 763-770

Austrian

Retrospe

ctive

Cohort

167

DCM 23 (13,8%) 55±11 years No data No data 34.9% 3 (1.8%) strokes

93 ± 36

months No data

Kim MK, et al., J

Cardiovasc

Ultrasound

2009;17 (1):10-15

Korean

Retrospe

ctive

Cohort

220

DCM 84 (38.1%)

62.8 ±15.4

years No data 65 (29.5%) 27.8±7.8%

13 (5.9%)

strokes.

4 (30.8%) had

AF.

87

months No data+

Supplementary table 2. Characteristics of the studies included in the qualitative synthesis. * Studies included in the quantitative synthesis (meta-analysis). + The only data available is on the group of patients with SEC (see full-text).