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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
2
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
3
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
4
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.
5
ÍNDICE
1. Resumo do trabalho final…………………………………………………………… 6
2. Trabalho de Revisão…………………………………...…………………………… 11
3. Agradecimentos…………………………………………………………………….. 22
4. Bibliografia…………………………………………………………………………. 23
5. Material suplementar..……………………………………………………………… 26
6
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,
7
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.
8
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%
9
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
10
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
12
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
13
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.
14
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.
15
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.
16
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).
Recommended