doi: 10.1161/CIRCULATIONAHA.106.627265
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(Circulation. 2007;115:1101-1108.)
© 2007 American Heart Association, Inc.
Heart Disease in Latin America |
Predictors of Mortality in Chronic Chagas Disease
A Systematic Review of Observational Studies
From the Division of Cardiology, Anis Rassi Hospital, Goiânia, Brazil.
Correspondence to Dr Anis Rassi Jr, Anis Rassi Hospital, Avenida José Alves 453, Setor Oeste, Goiânia (GO), Brazil. E-mail arassijr{at}terra.com.br or arassijr@arh.com.br
Received April 12, 2006; accepted September 1, 2006.
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Abstract |
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Background— Chagas disease is a major cause of morbidity and mortality in Latin America. Knowledge of the predictors of prognosis can help clinical decision making by identifying patients’ level of risk.
Methods and Results— We reviewed the published literature on prognostic factors in patients with Chagas disease by performing a PubMed search for articles published in any language between 1985 and February 2006 and hand searches of the reference lists of retrieved articles. Studies were selected if they included patients in the chronic phase of Chagas disease, analyzed a clearly defined outcome (all-cause mortality, sudden cardiac deaths, and/or cardiovascular deaths), and used multivariable regression models of prognosis. From 606 potentially relevant studies, 12 met the inclusion criteria: 8 clinic-based studies including 3928 patients and 4 hospital-based studies including 349 patients. Impaired left ventricular function by echocardiogram or cineventriculogram was found to be the most common and consistent independent predictor of death. New York Heart Association functional class III/IV and cardiomegaly on the chest radiography also were independently associated with higher mortality. More recently, strong evidence was found that nonsustained ventricular tachycardia on 24-hour Holter monitoring indicated an adverse prognosis. The typical ECG abnormalities showed limited additional prognostic value. Other often-mentioned risk factors, advanced age and male sex, showed inconsistent results. A formal meta-analysis was not feasible because of the heterogeneity of published studies and the lack of minimal standards in reporting results.
Conclusions— A systematic review of published studies indicates that impaired left ventricular function, New York Heart Association class III/IV, cardiomegaly, and nonsustained ventricular tachycardia indicate a poor prognosis in patients with chronic Chagas disease.
Key Words: cardiomyopathy • Chagas cardiomyopathy • Chagas disease • mortality • prognosis • review, systematic • risk factors
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Introduction |
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Almost a century after its discovery, Chagas disease continues to be a serious health and economic problem in most Latin American countries. Recent estimates from the World Health Organization indicate that 18 million persons are chronically infected with Trypanosoma cruzi and
200 000 new cases occur each year.1 This parasitic disease is transmitted to humans through the feces of infected bloodsucking insects in endemic areas and occasionally by nonvectorial mechanisms such as blood transfusion. Chagas disease has 2 successive phases: acute and chronic (Figure 1). Acute infection often is asymptomatic or may be manifested by a self-limited febrile illness that lasts 4 to 8 weeks. Once the acute phase subsides, the vast majority of infected patients recover an apparently healthy status, in which no organ damage can be demonstrated by 12-lead ECG and radiological examination of heart, esophagus, and colon. This form of the chronic phase of Chagas disease, called the indeterminate form, delimits a subgroup of patients with very low morbidity and good prognosis.2 Approximately half of the patients remain in the indeterminate form for life, whereas the other half will subsequently develop the cardiac and/or digestive (megaesophagus and megacolon) forms of chronic disease 10 to 30 years after the initial infection. The direct evolution from acute phase to a clinical chronic form also may occur in a few patients.
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Cardiac involvement, the most frequent and serious manifestation of chronic Chagas disease, typically produces atrial and ventricular arrhythmias, cardiac failure, and thromboembolic phenomena, resulting in at least 21 000 deaths each year.1 The clinical course of Chagas heart disease is diverse, and identifying patients who are at risk of dying remains a challenge. Several longitudinal studies performed in patients in the chronic phase of Chagas disease demonstrated that many individual characteristics predict an unfavorable prognosis. However, the results have been somewhat inconsistent in different studies, and the best combination of variables predictive of mortality has not yet been established. Moreover, the initial studies focused only on univariable predictors of death, which do not take into account the relationship among variables and cannot be considered definitive.
We therefore performed a systematic review of the literature to collate data on predictive factors for mortality in patients with chronic Chagas disease and to derive a risk stratification algorithm.
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Methods |
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All prognostic studies of Chagas disease were considered eligible for the present review if they fulfilled the following criteria: original articles or abstracts published between January 1985 and February 2006, inclusion of patients in the chronic phase of Chagas disease, performance of multivariable regression models of prognosis, and analysis of a clearly defined outcome: all-cause mortality, sudden cardiac deaths, and/or cardiovascular deaths. There were no restrictions in terms of language, sample size, or duration of follow-up, but we excluded studies of mixed populations unless separate results for chagasic patients were identified. Studies evaluating prognosis after specific therapies or procedures (eg, heart transplantation, dynamic cardiomyoplasty, and implantable cardioverter-defibrillator) and studies in which death was part of a composite end point were also excluded.
Data from the present review were identified by a PubMed search using the following terms: Chagas and (incidence[MeSH] or mortality[MeSH] or follow-up studies[MeSH] or prognos*[Text Word] or predict*[Text Word] or course*[Text Word]). The combination of these terms has been shown to maximize sensitivity3 because our initial goal was not to miss any relevant prognostic study. Two independent reviewers (A.R. Jr, S.G.R.) initially checked the lists of titles and abstracts identified by this search to determine whether an article contained relevant data. The selected articles were read in full to confirm eligibility and to extract data. Additional studies were located by a manual search using references from the retrieved articles. In case of disagreement on inclusion or exclusion of a study or on data extraction between the 2 reviewers, the differences were resolved by consensus or discussion with a third reviewer (A.R.). From the included articles, the following information was extracted: country and period of enrollment of each study; type of population included (clinic or hospital derived); overall sample size and number of subjects entered into the multivariable analysis; characteristics of chagasic patients (age, sex, presence of cardiopathy); design (retrospective, clinical database, or prospective) and other study characteristics (in particular, whether inclusion and exclusion criteria were mentioned, if the number of excluded patients was specified, if consecutive patients were enrolled, and if relevant baseline data were shown); statistical analysis (type of regression model, Cox or logistic; use of dichotomized and/or continuous variables; and measures of reporting the effect estimate); duration of follow-up and number of subjects lost to follow-up; survival analysis, causes of death, and outcome of interest; and prognostic variables assessed on each study and quality of the regression model (number of variables included in univariate and multivariate analysis and number of variables with independent prognostic value).
The authors had full access to and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.
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Results |
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Our PubMed search performed on February 25, 2006, identified 606 articles. Of these, 579 were excluded because they did not meet inclusion criteria by a reading of titles and abstracts. Seventeen more articles4–20 were excluded after reading the entire article: 154,5,7–13,15–20 because of ineligibility, and 26,14 because they were written on the same or overlapping data sets of a subsequent21 or previous22 report. Two articles from an external source were added to this overview: a manuscript that had just been accepted for publication in a peer-reviewed journal23 and a relevant study (published as an abstract)24 that was identified by searching for bibliographies in all retrieved articles. Thus, 12 studies21–32 satisfied the prespecified inclusion and exclusion criteria and constitute the basis of this investigation.
Studies, Patients, and Statistical Analysis
Table 1 summarizes the characteristics of the 12 studies. Year of publication21–32 ranged from 1991 to 2006. Investigators enrolled subjects over several years, and the most studies referred to Brazilian cohorts. Eight clinic-based studies including 3928 patients and 4 hospital-based studies including 349 patients assessed factors potentially associated with mortality in chronic Chagas disease. Half of these studies, however, did not report the number of cases used in the multivariable analysis. When the information was provided, the multivariable regression was performed on between 25 and 331 patients. Only 2 reports showed a complete set of variables for each patient and applied the multivariate analysis to the entire population. In the other studies, case deletion was used for handling missing covariate data, reducing the number of patients included in the multivariate model. Patients’ mean or median ages varied from 43 to 59 years, and there was a predominance of men in most studies.
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The chagasic population enrolled in this overview was very heterogeneous and included not only patients at different stages of cardiomyopathy but also patients without apparent cardiac lesions (defined by a normal ECG and normal chest radiography). Six studies (Espinosa et al,25 Hagar et al,26 Bestetti et al,27,29 Rodriguez-Salas et al,30 and Rassi et al23) enrolled overall patients with heart disease; 1 study (Mady et al28) included sole male patients with congestive heart failure; 1 study (Leite et al31) included patients with symptomatic ventricular tachycardia who underwent electrophysiological study; and 4 studies (Carrasco et al,21 Garzon et al,24 Salles et al,22 and Viotti et al32) enrolled patients with and without manifest cardiopathy. The corresponding percentages of patients with normal ECG in these 4 studies were 20%, not reported, 45%, and 59%, respectively.
Regarding study design and execution, most studies were described (or were supposed by us) as prospective or a clinical database analysis (set of data systematically gathered on all patients even though no specific analysis was prospectively planned). Only 3 reports were truly retrospective. In addition, although not specified in all studies, only a minority (25%) included consecutive patients.
In 9 studies, the statistical analysis was performed using the Cox proportional-hazard model, which is concerned with the duration and timing of the occurrence of the event. Such model measures the hazard ratio, ie, the relative effect of a prediction factor on an outcome, by assuming that this relation is constant over time. On the other hand, 3 studies used the less appropriate logistic regression technique, which focuses only on the occurrence (or not) of the event, regardless of time, and is expressed by the odds ratio. All studies used dichotomized variables, and 5 also used some continuous measures. However, the cutoff strategies for dichotomization were usually not specified.
Statistical quality and the presentation of methods and results were poor in many studies. Although regression analysis was performed in all studies, 9 of them reported only the probability value (and sometimes with an inexact estimation, ie, P<0.05 or P<0.01), the ß-regression coefficient, the survival curves, or a combination of these parameters. Only 3 reports provided the values of the hazard ratio and 95% CI. Also, few studies22,23 clearly stated that collinearity (ie, a high degree of correlation between 
2 predictor variables) was assessed, and only 1 study developed a risk score based on the multivariable results and validated it on another data set (external validation).
Follow-Up Duration and Mortality in Prognostic Studies
Mean lengths of follow-up varied from 1.5 to 9.9 years (Table 2). Two studies reported only the maximal duration of follow-up. Most studies failed to mention the number of patients lost to follow-up. Reported losses varied from 0% to 13%.
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In most studies, the primary outcome was all-cause mortality. Cardiovascular death was the end point in 2 studies; sudden cardiac death was the end point in 1 study. Another study22 used all-cause, Chagas disease–related, and sudden cardiac deaths as primary outcomes, but for the purpose of this review, only all-cause mortality was considered. Sudden cardiac death was the principal cause of death in 6 studies, and heart failure was the main cause in 4 reports. Two studies did not mention the causes of death. Overall, sudden cardiac death was the predominant mode of death (420 of 882 deaths, 47.6%), followed by heart failure deaths (327 of 882 deaths, 37.1%). The annual mortality rates varied from 0.2% to 19.2%. It was lower in the studies that involved mixed chagasic population (with and without cardiopathy) and was higher in the hospital-derived cohorts that included solely patients with heart disease.
Prognostic Variables
In the last decades, many variables (clinical, demographic, and those obtained at noninvasive and invasive methods) were evaluated by multivariable modeling (Tables 2 and 3). Demographic (in 10 studies), clinical (in 11 studies), ECG (in 11 studies), radiological (in 9 studies), and echocardiographic or invasive cineventriculographic (in 12 studies) variables were more frequently assessed. In contrast, exercise testing (in 3 studies), ambulatory ECG monitoring (in 2 studies), heart rate variability (in 1 study), and invasive electrophysiological testing (in 1 study) variables were less frequently evaluated.
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Only 6 studies reported the number of variables included in univariable analysis (range, 4 to 28; Table 2). Variables that were significant in univariate analysis were entered into the multivariate model. This observation was reported in 9 studies, and the number of variables that were included in the multivariable analysis varied from 3 to 19. The mean number of variables that were independently predictive of mortality in these 12 studies was 4 (range, 1 to 7). Of note, in many studies, too few events were observed for the model to be stable; ie, the ratio of the number of deaths to the number of variables was <10:1.
As shown in Table 3, the variable found to be the most common independent predictor of death was left ventricular (LV) dysfunction, expressed by different measures either on echocardiogram or on cineventriculogram (in 11 studies). These measures made up some qualitative indexes such as the presence of LV aneurysm26 or apical aneurysm,29 evidence of segmental or global LV wall motion abnormality,23,26 an increased LV systolic dimension,32 an increased LV diastolic dimension,29 and a reduced LV ejection fraction,24,28,32 as well as some quantitative indexes such as an LV end-diastolic volume >110 mL/m2,25 an ejection fraction <0.30,21,27 an end-systolic stress >120 g/cm2,21 an end-diastolic volume index >120 mL/m2;21 and the echocardiographic M-mode E-point septal separation 22 mm.30 Dyspnea, congestive heart failure, or New York Heart Association (NYHA) functional class III/IV (in 6 studies) and cardiomegaly as determined by chest radiography and defined by a cardiothoracic ratio of more than 0.50 to 0.55 (in 5 studies) also were consistently found to predict mortality. Although many distinct ECG abnormalities were independently associated with higher mortality (in 5 studies), no single alteration showed prognostic significance in >1 study. Other variables found to be predictive of worse outcome were increased heart rate (in 2 studies), low systolic blood pressure (in 1 study), appearance or progression of heart disease (in 1 study), decreased maximal oxygen consumption on exercise testing (in 1 study), nonsustained ventricular tachycardia (NSVT) on Holter monitoring (in 1 study), and inducibility of sustained ventricular tachycardia on electrophysiological testing (in 1 study). Additionally, male sex and advanced age were associated with poorer prognosis in 1 and 2 studies, respectively. Other studies did not reproduce these findings, however.
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Discussion |
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The present study is the first systematic review of prognostic factors that has been reported in Chagas disease. The search strategy used is likely to have identified most of the available literature, targeting in particular the relevant databases. We chose 1985 as our starting search point because, to the best of our knowledge, no study focusing on multivariable analysis of risk factors was published before this year.
A systematic review is the preferred tool for identifying and combining existing evidence, particularly when there are conflicting findings across a number of studies. During this systematic review, we screened 606 articles overall and ultimately identified 12 relevant articles, which showed diversity in the study population (eg, inclusion of patients at differing disease stages or inclusion in the same study of patients with and without manifest cardiopathy); in the prognostic variables included in the analysis; in the type of statistical analyses applied in the studies; in the methods used to define, measure, or classify the variables; and in primary outcome. These variations may have resulted in patient selection bias, low statistical power, and limited opportunity to integrate results.
In addition, the quality of published reports was heterogeneous and usually poor. Most studies were described in insufficient detail and/or lacked minimal standards in reporting results to allow a formal meta-analysis to be conducted. Of note, in most of the studies, the number of variables included in the final analysis did not allow for controlling of the risk of overfitting the data; ie, the ratio of the number of deaths to the number of variables was <10:1, increasing the risk of false-positive results. This may explain the lack of reproducibility of the results for some prognostic factors.
Another important observation from this systematic review is the wide range of reported annual mortality rates across the studies (varying from 0.2% to 19.2%), which, at least in part, should be interpreted as an expression of the heterogeneity of the included patients.
Despite limitations and methodological caveats, however, this systematic review allowed the identification of meaningful predictors of death in Chagas disease. In agreement with the results of studies in other cardiomyopathies, the most consistent independent risk predictor is impaired LV function. Echocardiographic or cineventriculographic evidence of decreased contractility and/or increased volume, either qualitatively or quantitatively expressed, was found to be strongly associated with an increased risk of mortality in 11 of the 12 studies reviewed. It is well known that these variables reflect a more refined and sensitive measure of LV dysfunction. Two other variables, NYHA functional class III/IV and cardiomegaly on the chest radiography, were identified as powerful determinants of prognosis in many studies. They reflect a more advanced degree of myocardial damage and provide independent and complementary information to the LV ejection fraction.
Regarding the other potential risk factors, 2 studies investigated the role of complex ventricular arrhythmias as an independent predictor of mortality in chagasic patients, ie, taking into account other factors such as LV function. In the study of Carrasco et al21 involving 172 patients, the presence of complex ventricular arrhythmias (Lown III/IV) on 24-hour Holter monitoring did not contribute significantly to the total variance and was not related to death in the multivariable modeling. However, survival curves calculated according to ejection fraction showed that the presence of these arrhythmias increased mortality significantly in patients with an ejection fraction 30%. Of note, the similar survival rate found for patients with an ejection fraction <30%, regardless of the complexity of ventricular arrhythmias, may be explained by the reduced number of patients ascribed to this subgroup. Recently, Rassi et al,23 studying 424 patients by routine noninvasive methods and using the multivariable Cox proportional-hazard analysis, identified 6 independent prognostic factors (in order of importance): NYHA class III or IV, cardiomegaly on chest radiography, segmental or global wall motion abnormality on echocardiogram, NSVT on Holter monitoring, low QRS voltage, and male sex. The presence of NSVT on Holter monitoring was associated with a 2.15-fold-increased risk of mortality. More important, the combination of NSVT and LV dysfunction was associated with a 15.1-fold-increased risk for subsequent death compared with patients without both risk markers (Figure 2).
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The results of our present study demonstrate that other variables such as the ECG repolarization parameters (eg, QT dispersion) and the inducibility of ventricular tachyarrhythmias on invasive electrophysiological studies also predicted mortality in chagasic patients. They have been investigated solely in single studies, however, and have not been evaluated in the context of all other well-established risk factors. Another important finding of this review is that all typical ECG abnormalities of Chagas heart disease, when analyzed jointly with other variables, appeared to be of limited value in predicting prognosis. Finally, there is still controversy on the prognostic value of advanced age22,30 and male sex,23 which have been demonstrated to be associated with a worse outcome in some studies but not in others.4,21,31
Clinical Implications
Chagas disease is a heterogeneous condition with wide variation in clinical course and prognosis. Typical features of chronic Chagas heart disease that may differentiate it from other cardiomyopathies include a predominance of male gender, age of 30 to 60 years, and childhood resident of endemic area of Latin America; symptoms of palpitations, syncope, chest pain, and/or heart failure; right bundle-branch block, often associated with left anterior hemiblock, premature ventricular beats, ST-T changes, abnormal Q waves, various degrees of atrioventricular block, sick sinus syndrome, and low QRS voltage on the ECG; complex and frequent ventricular arrhythmias on Holter monitoring and/or on exercise testing (usually asymptomatic); occurrence of both tachyarrhythmias and bradyarrhythmias; biventricular heart failure (predominance of right-sided failure in advanced stages); apical left ventricular aneurysm that may contain thrombus; common thromboembolic phenomena; associated megaesophagus and/or megacolon; substantial morbidity and mortality; and high frequency of sudden unexpected death.
The results of the present systematic review indicate that risk stratification for mortality in chagasic patients can be refined by combining prognostic factors related to 3 major clinical-pathophysiological characteristics of the disease: symptoms of heart failure, expressed by the NYHA functional class III/IV; measures of ventricular dysfunction (ie, cardiomegaly on the chest radiography and decreased LV contractility and/or increased LV diameter on echocardiography); and a measure of ventricular electrical instability (presence of NSVT on 24-hour Holter monitoring) (Figure 3).
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Patients who present with symptoms of heart failure (NYHA class III/IV) or have LV dysfunction on echocardiogram associated with episodes of NSVT on Holter monitoring are at the highest risk of death and should be regarded as candidates for aggressive therapeutic management. It is not uncommon for chagasic patients with ECG and marked LV segmental abnormalities to be asymptomatic hard workers. When heart failure symptoms occur (NYHA class III/IV), invariably all patients manifest associated cardiomegaly on the chest radiography, global systolic dysfunction on echocardiogram, and NSVT on Holter monitoring.
Conversely, patients with a normal or abnormal ECG but in NYHA class I/II with neither LV dysfunction on echocardiography nor NSVT on Holter are at low risk of death. These patients should be followed up annually or biannually. Between these 2 extremes are patients with either LV dysfunction or NSVT. In such patients, who are at intermediate risk, the optimal treatment strategies remain to be established.
Conclusion
A better understanding of prognostic factors in Chagas disease has evolved over the last decades. The present systematic review of all prognostic studies published since 1985 (using multivariable analysis) allowed us to recognize some major independent predictors of mortality. Knowledge of these predictors can help to identify patients at different degrees of risk, facilitate and direct treatment choices, and aid patient counseling. Lessons learned from the present study should also help to improve the quality and relevance of future studies on prognostic factors in Chagas disease.
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Acknowledgments |
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We are indebted to Dr William C. Little of the Section of Cardiology, Wake Forest University School of Medicine, Winston-Salem, for revising the manuscript.
Disclosures
None.
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