Associação entre a doença de Chagas e a ocorrência de AVC: uma revisão sistemática com metanálise

Santos, Ana Clara de Jesus; Benitez, Juciane Fagundes Durães; Baldoni, Nayara Ragi; Ferreira, Ariela Mota; Silva, Jose Luiz Padilha da; Nunes, Maria do Carmo Pereira; Ribeiro, Antonio Luiz Pinho; Sabino, Ester Cerdeira; Haikal, Desirée Sant’Ana

doi:10.1590/0102-311XEN246125

person Ana Clara de Jesus Santos

study design · data collection · writing and review · approved the final version

school Programa de Pós-graduação em Ciências da Saúde, Universidade Estadual de Montes Claros, Montes Claros, Brasil.

0000-0003-1821-2338

person Juciane Fagundes Durães Benitez

data collection · review · approved the final version

school Programa de Pós-graduação em Ciências da Saúde, Universidade Estadual de Montes Claros, Montes Claros, Brasil.

0000-0001-8329-8831

person Nayara Ragi Baldoni

data collection and analyses · review · approved the final version

school Universidade de Itaúna, Itaúna, Brasil.

0000-0002-3400-0725

person Ariela Mota Ferreira

review · approved the final version

school Programa de Pós-graduação em Ciências da Saúde, Universidade Estadual de Montes Claros, Montes Claros, Brasil.

0000-0002-2315-5318

person Jose Luiz Padilha da Silva

data analyses and interpretation · review · approved the final version

school Departamento de Estatística, Universidade Federal do Paraná, Curitiba, Brasil.

0000-0002-3146-0793

person Maria do Carmo Pereira Nunes

review · approved the final version

school Universidade Federal de Minas Gerais, Belo Horizonte, Brasil.

0000-0001-8801-1828

person Antonio Luiz Pinho Ribeiro

review · approved the final version

school Universidade Federal de Minas Gerais, Belo Horizonte, Brasil.

0000-0002-2740-0042

person Ester Cerdeira Sabino

review · approved the final version

school Universidade de São Paulo, São Paulo, Brasil.

0000-0003-2623-5126

person Desirée Sant’Ana Haikal

study design · data interpretation · writing, and review · approved the final version

school Programa de Pós-graduação em Ciências da Saúde, Universidade Estadual de Montes Claros, Montes Claros, Brasil.

0000-0002-0331-0747

personCorrespondence A. C. J. Santos Rua Duzentos e Setenta 31, Janaúba, MG 39445-766, Brasil.
anaclarajesus418@gmail.com

Associate Editor

Evaluation coordinator: Edison Iglesias de Oliveira Vidal (0000-0002-1573-4678)

(“Chagas Disease”ENT#091;MeSH TermsENT#093; OR “American Trypanosomiasis”ENT#091;All FieldsENT#093; OR “trypanosomiasis american”ENT#091;All FieldsENT#093; OR “trypanosomiasis south american”ENT#091;All FieldsENT#093; OR “South American Trypanosomiasis”ENT#091;All FieldsENT#093; OR “Trypanosoma cruzi Infection”ENT#091;All FieldsENT#093; OR “infection trypanosoma cruzi”ENT#091;All FieldsENT#093; OR “infections trypanosoma cruzi”ENT#091;All FieldsENT#093; OR “Trypanosoma cruzi Infections”ENT#091;All FieldsENT#093; OR “Chagas Disease”ENT#091;All FieldsENT#093;) AND (“Stroke”ENT#091;MeSH TermsENT#093; OR (“Stroke”ENT#091;MeSH TermsENT#093; OR “Stroke”ENT#091;All FieldsENT#093; OR “strokes”ENT#091;All FieldsENT#093; OR “stroke s”ENT#091;All FieldsENT#093;) OR “cerebrovascular accident*”ENT#091;All FieldsENT#093; OR “cva cerebrovascular accident”ENT#091;All FieldsENT#093; OR “Cerebrovascular Apoplexy”ENT#091;All FieldsENT#093; OR “apoplexy cerebrovascular”ENT#091;All FieldsENT#093; OR “vascular accident brain”ENT#091;All FieldsENT#093; OR “brain vascular accident*”ENT#091;All FieldsENT#093; OR “cerebrovascular stroke*”ENT#091;All FieldsENT#093; OR “stroke* cerebrovascular”ENT#091;All FieldsENT#093; OR (“apoplexies”ENT#091;All FieldsENT#093; OR “Stroke”ENT#091;MeSH TermsENT#093; OR “Stroke”ENT#091;All FieldsENT#093; OR “apoplexy”ENT#091;All FieldsENT#093;) OR “cerebral stroke*”ENT#091;All FieldsENT#093; OR “stroke* cerebral”ENT#091;All FieldsENT#093; OR “stroke* acute”ENT#091;All FieldsENT#093; OR “acute stroke*”ENT#091;All FieldsENT#093; OR “cerebrovascular accident* acute”ENT#091;All FieldsENT#093; OR “acute cerebrovascular accident*”ENT#091;All FieldsENT#093; OR “ischemic stroke”ENT#091;All FieldsENT#093; OR “Brain Infarction”ENT#091;MeSH TermsENT#093; OR “brain infarction*”ENT#091;All FieldsENT#093; OR “infarction* brain”ENT#091;All FieldsENT#093; OR “brain infarct*”ENT#091;All FieldsENT#093; OR “infarct* brain”ENT#091;All FieldsENT#093; OR “venous infarction brain”ENT#091;All FieldsENT#093; OR “brain venous infarction*”ENT#091;All FieldsENT#093; OR “venous infarctions brain”ENT#091;All FieldsENT#093; OR “venous brain infarction*”ENT#091;All FieldsENT#093; OR “Anterior Cerebral Circulation Infarction”ENT#091;All FieldsENT#093; OR “Anterior Circulation Brain Infarction”ENT#091;All FieldsENT#093; OR “brain infarction posterior circulation”ENT#091;All FieldsENT#093; OR “Posterior Circulation Brain Infarction”ENT#091;All FieldsENT#093; OR “Embolic Stroke”ENT#091;MeSH TermsENT#093; OR “Embolic Strokes”ENT#091;All FieldsENT#093; OR “stroke* embolic”ENT#091;All FieldsENT#093; OR “cardioembolic stroke*”ENT#091;All FieldsENT#093; OR “stroke* cardioembolic”ENT#091;All FieldsENT#093; OR “cardio embolic stroke*”ENT#091;All FieldsENT#093; OR “Cardio embolic Stroke”ENT#091;All FieldsENT#093; OR “stroke* cardio embolic”ENT#091;All FieldsENT#093;)

Design (Study)	Population/Sample and setting	Sample size	Stroke prevalence or incidence	Main findings/Effect measure (95%CI)	Risk of bias/Methodological quality
Cohort
Cerqueira-Silva et al. ¹⁵ (2022)	Heart failure outpatient clinic at a university hospital. Bahia, Brazil	Total: 404 patients G1: heart failure with Chagas disease (n = 210) vs. G2: heart failure without Chagas disease (n = 194)	There were 25 cases of ischemic stroke (G1: 16 cases; G2: 9 cases)	Chagas disease was an independent predictor of first ischemic stroke (HR = 2.54; 95%CI: 1.01-6.42)	High risk of bias
Lima-Costa et al. ¹⁶ (2010)	Community-dwelling residents aged ≥ 60 years identified through a census. Bambuí, Brazil	Total: 1,398 participants G1: individuals with Chagas disease (n = 524) vs. G2: individuals without Chagas disease (n = 874)	There were 45 stroke-related deaths (G1: 25 cases; G2: 20 cases)	Individuals with Chagas disease had a higher risk of death from stroke compared with those without Chagas disease (HR = 2.35; 95%CI: 1.25-4.44)	High risk of bias
Cross-sectional
Matta et al. ¹⁸ (2012)	Medical records of consecutive patients from a cardiomyopathy outpatient clinic. Bahia, Brazil	Total: 790 patients G1: Chagas cardiomyopathy (n = 329) vs. G2: non-Chagas cardiomyopathy (n = 461)	There were 108 cases of ischemic stroke (G1: 57 cases; G2: 51 cases)	Stroke was more frequent among patients with Chagas disease (OR = 1.79; p = 0.012)	High methodological quality
Dias et al. ¹⁹ (2009)	Random sample of patients from a cardiomyopathy outpatient clinic at a university hospital. Bahia, Brazil	Total: 79 patients G1: Chagas cardiomyopathy (n = 37) vs. G2: other cardiomyopathies (n = 42)	There were 12 cases of ischemic stroke (G1: 6 cases; G2: 6 cases)	Cognitive dysfunction was common among patients with Chagas disease, and a history of stroke was more prevalent in this group, although not statistically significant (p = 0.81)	High methodological quality
Jesus et al. ²¹ (2011)	Cardiomyopathy outpatient clinic of the Federal University of Bahia. Bahia, Brazil	Total: 144 patients G1: CHF with Chagas disease (n = 62) vs. G2: CHF due to other etiologies (n = 82)	There were 13 cases of stroke (G1: 7 cases; G2: 6 cases)	Stroke was more frequent among patients with Chagas disease, although the association was not statistically significant (p = 0.563)	Moderate methodological quality
Oliveira-Filho et al. ²⁰ (2005)	Patients with heart disease treated at a tertiary care outpatient clinic. Bahia, Brazil	Total: 305 patients G1: patients with Chagas disease (n = 147) vs. G2: patients without Chagas disease (n = 158)	There were 32 cases of stroke (G1: 22 cases; G2: 10 cases)	Chagas disease was an independent risk factor for stroke (OR = 1.09; 95%CI: 1.02-1.17)	High methodological quality
Case-control
Montanaro et al. ¹⁷ (2019)	Neurological rehabilitation service at SARAH Hospital. Brasília, Brazil	Total: 115 patients G1: AF without Chagas disease (n = 49) vs. G2: indeterminate Chagas disease (n = 23) vs. G3: cardioembolic Chagas disease (n = 43)	There were 13 stroke cases (G1: 6 cases; G2: 3 cases; G3: 4 cases)	No differences were observed in stroke mortality or recurrence between groups (p = 0.073)	High risk of bias

Study	Population and clinical severity (Chagas group)	Operational definitions (exposure/comparator/outcome)	Inclusion/Exclusion criteria and diagnostic method	Follow-up (time and losses)	Effect measure and adjustments for confounders	Funding source
Cerqueira-Silva et al. ¹⁵ (2022)	LVEF: median 47%. AF: 7.8%. Apical aneurysm: 3.4%. Thrombus: not available in table	Exposure: ELISA test performed in duplicate. Comparator: non-Chagas heart failure etiologies. Outcome: ischemic stroke	Inclusion: age > 18 years, Framingham criteria for heart failure. Exclusion: previous stroke, anticoagulation, recent thrombotic event, terminal diseases, and neurodegenerative diseases. Diagnostic: questionnaire, echocardiogram, ECG, serology, CT/MRI	Time: cohort, mean 42.9 months. Losses: 145 patients lost to follow-up	HR: 2.54 (95%CI, 1.01-6.42). Adjustments: sex, age, Chagas disease, acetylsalicylic acid use, dyslipidemia, LVEF, and AF	Authors declare no financial support
Lima-Costa et al. ¹⁶ (2010)	LVEF: not evaluated (population-based). AF: 3.3%. Thrombus/Aneurysm: not available	Exposure: positivity in 3 assays (IHA and 2 ELISA). Comparator: Uninfected individuals. Outcome: death due to stroke (ICD-10)	Inclusion: residents aged ≥ 60 years in 1997. Exclusion: missing or inconclusive serology. Diagnostic: serology, ECG, death verification	Time: 10-year cohort (1997-2007). Losses: 6% of the original cohort	HR: 2.35 (95%CI, 1.25-4.44). Adjustments: age, sex, education, conventional risk factors, and CRP	FINEP, Brazilian Ministry of Health, and FAPEMIG
Matta et al. ¹⁸ (2012)	LVEF: < 45%. AF: 8.2%. Thrombus: 2.8%. Aneurysm: not available in table	Exposure: positive serology (two tests: IFA, HAI, or ELISA). Comparator: non-Chagas cardiomyopathy. Outcome: ischemic stroke (focal deficit > 24h)	Inclusion: Diagnosis of structural cardiomyopathy. Exclusion: epidural and subdural hemorrhage, poisoning, trauma, coma, and lack of information on stroke. Diagnostic: ECG, echocardiogram, serology, radiography, and other examinations	Time: cross-sectional (medical record review). Losses: 16 individuals without stroke data	OR: 1.79 (95%CI: 1.13-2.84). Adjustments: age, sex, hypertension, pacemaker, AF, CAD	Authors declare no support or funding
Dias et al. ¹⁹ (2009)	LVEF: mean 37.4%. AF: 13.5%. Thrombus/Aneurysm: not detailed in table, but thrombus cited as a disease marker	Exposure: serology (hemagglutination or immunofluorescence). Comparator: other cardiomyopathies. Outcome: cognitive dysfunction (MMSE and Rey Figure)	Inclusion: LVEF < 40% or 40-49% with dilated chambers. Exclusion: blindness, renal/hepatic failure, cardiac arrest, COPD, hypothyroidism. Diagnostic: serology, ECG, echocardiogram	Time: cross-sectional. Losses: 13 patients excluded after screening	OR: 4.63 for MMSE (p = 0.07) and 4.67 for Rey Figure. Adjustments: age, education, digoxin, hypertension, stroke, CAD	CAPES, NIH, and CNPq
Jesus et al. ²¹ (2011)	LVEF: mean 37.8% with Chagas disease and 36.4% without Chagas disease. AF: 3%. Pacemaker: 11%. Thrombus/Aneurysm: not available in table	Exposure: etiology defined by cardiologist and serology. Comparator: other causes of heart failure (hypertensive, ischemic, etc.). Outcome: SCM	Inclusion: patients with CHF, available echocardiogram. Exclusion: use of oral anticoagulants. Diagnostic: TCD, echocardiogram	Time: cross-sectional (TCD monitoring for 60min). Losses: not reported	OR: 1.15 (95%CI: 1.05-1.26). Adjustments: age and LVEF	Not reported
Oliveira-Filho et al. ²⁰ (2005)	LVEF: 40 to 49%. AF: 4.9%. Thrombus/Aneurysm: 4%	Exposure: positive serology in two tests. Comparator: individuals with other cardiomyopathies. Outcome: stroke	Inclusion: clinical signs suggestive of cardiomyopathy. Exclusion: not reported. Diagnostic: serology, ECG, echocardiogram, questionnaire, and neurological assessment	Time: cross-sectional (conducted between 2002 and 2003). Losses: not reported	HR: 2.36 (95%CI: 1.25-4.44). Adjustments: age, sex, education, conventional risk factors, and CRP	CNPq and NIH
Montanaro et al. ¹⁷ (2019)	LVEF: reduced in 11 patients (25.5%). Apical aneurysm: 10.6% (7/66). Thrombus: 4.5% (3/66)	Exposure: 2wo serological tests (ELISA and HAI). Comparator: AF without Chagas disease. Outcome: vascular topography of brain lesions in Chagas disease and stroke	Inclusion: stroke confirmed by imaging, diagnosis of Chagas disease or AF. Exclusion: < 18 years, conflicting serology, lack of imaging. Diagnostic: medical records, CT/MRI, ECG, echocardiogram	Time: case-control (retrospective, patients admitted 2009-2013; followed until 2017). Losses: 20% of the population with Chagas disease	Statistics: frequency comparison (chi-square) and Kaplan-Meier (no OR/HR for group effect in the excerpts)	No specific funding

Outcome and follow-up	Patients (studies)	Relative effect (95%CI)	Absolute effects (95%CI)			Certainty	What happens
Outcome and follow-up	Patients (studies)	Relative effect (95%CI)	Comparison	Intervention	Difference
Occurrence of stroke and stroke mortality	1,802 (2 cohort studies)	RR = 1.92 (95%CI: 1.20-3.06)	56 per 1.000	107 per 1,000 (67 to 171)	51 more per 1,000 (11 more to 115 more)	⨁◯◯◯ Very low * **	Individuals with Chagas disease have a higher risk of developing stroke during follow-up compared with those without the disease
Occurrence of stroke	1,318 (4 cross-sectional studies)	PR = 1.63 (95%CI: 1.22-2.18)	160 per 1.000	261 per 1,000 (195 to 349)	***	⨁◯◯◯ Very low ^#	Individuals with Chagas disease have a higher prevalence of stroke compared with those without the disease

[TFN1] 95%CI: 95% confidence interval; AF: atrial fibrillation; CHF: congestive heart failure; HR: hazard ratio; OR: odds ratio.

Associação entre a doença de Chagas e a ocorrência de AVC: uma revisão sistemática com metanálise

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