article: Sudden death has been considered the main cause of death in patients with Chagas heart disease. Nevertheless, this information comes from a period before the introduction of drugs that changed the natural history of heart failure. We sought to study the mode of death of patients with heart failure caused by Chagas heart disease, comparing with non-Chagas cardiomyopathy. We examined the REMADHE trial and grouped patients according to etiology (Chagas vs non-Chagas) and mode of death. The primary end-point was all-cause, heart failure and sudden death mortality; 342 patients were analyzed and 185 (54. 1%) died. Death occurred in 56. 4% Chagas patients and 53. 7% non-Chagas patients. The cumulative incidence of all-cause mortality and heart failure mortality was significantly higher in Chagas patients compared to non-Chagas. There was no difference in the cumulative incidence of sudden death mortality between the two groups. In the Cox regression model, Chagas etiology (HR 2. 76; CI 1. 34–5. 69; p = 0. 006), LVEDD (left ventricular end diastolic diameter) (HR 1. 07; CI 1. 04–1. 10; p<0. 001), creatinine clearance (HR 0. 98; CI 0. 97–0. 99; p = 0. 006) and use of amiodarone (HR 3. 05; CI 1. 47–6. 34; p = 0. 003) were independently associated with heart failure mortality. LVEDD (HR 1. 04; CI 1. 01–1. 07; p = 0. 005) and use of beta-blocker (HR 0. 52; CI 0. 34–0. 94; p = 0. 014) were independently associated with sudden death mortality. In severe Chagas heart disease, progressive heart failure is the most important mode of death. These data challenge the current understanding of Chagas heart disease and may have implications in the selection of treatment choices, considering the mode of death. ClinicalTrails. gov NCT00505050 (REMADHE) Chagas disease (American trypanosomiasis) remains a burden for public health systems in Latin American countries [1]. In fact, the global prevalence of Chagas disease has reached 9 million people and 25 million are estimated to be at risk worldwide [2]. As a result of globalization and migration, non-endemic countries have reported an increase in the prevalence of Chagas disease. It has been estimated that 47,000 T. cruzi-infected persons are now living in Spain and another 300,000 in the United States [3]. Sudden death has been considered the main cause of death in patients with Chagas heart disease [4]. Nevertheless, this information comes mainly from a period before the introduction of drugs that changed the natural history of heart failure such as beta-blockers, angiotensin-converting enzyme inhibitors (ACEI) and angiotensin II receptor blockers (ARB). Furthermore, many studies that support this finding include heterogeneous cohorts of patients, in particular patients without ventricular dysfunction [4]. To the best of our knowledge there is not a recent publication studying the mode of death in Chagas heart disease. The management of Chagas heart disease is complex and includes the treatment of complex arrhythmias and heart failure. The precise understanding of current natural history of patients presenting systolic dysfunction is indispensable to plan adequate health politics and improve survival. Therefore, we sought to study the mode of death of patients with heart failure caused by Chagas heart disease, comparing with non-Chagas cardiomyopathy.
  We examined the patients included in the REMADHE (Repetitive Education at Six-Month Intervals and Monitoring for Adherence in Heart Failure Outpatients) trial; For the purpose of current study, patients were grouped according to etiology (Chagas vs non-Chagas groups) and mode of death. REMADHE is a prospective, randomized, single-center open parallel trial controlled by nonintervention simple randomization and designed to compare a disease management program versus control in patients with chronic heart failure. Patients enrolled in the study were under ambulatory care in a tertiary referral center and were followed by a cardiologist with experience in heart failure. Inclusion elapsed from October 1999 until January 2005. Patients were aged 18 years or older with irreversible chronic heart failure of at least 6-months. Exclusion criteria included patients' inability to attend educational sessions and researchers' inability to monitor patients because of the patients' lack of transportation, social or communication barriers; myocardial infarction or unstable angina within 6 months before randomization; cardiac surgery or angioplasty within 6 months before randomization; hospitalized patients or recently discharged patients; any severe systemic disease that could impair expected survival; procedures that could influence follow-up; pregnancy or childbearing potential (figure 1). The REMADHE trial demonstrated that a disease management program was associated with reduction in unplanned hospitalization, total hospital days and need for emergency care, as well as improved quality of life [5], [6]. Patients were divided into two groups: Chagas and non-Chagas. The diagnosis of Chagas disease was based on epidemiological information along with serological tests (indirect immunofluorescence, passive haemaglutination, immunoenzymatic assay) positive for Trypanosoma cruzi [7]. Patients with an alternative diagnosis, or a mixed etiology for the cardiomyopathy were included in non-Chagas group. All deaths were classified according to specified definitions. The agreement of two members of the study on the cause of death was mandatory. Sudden death was defined as an unexpected death occurred within 1 hour of the onset of new symptoms or occurred unwitnessed in a previously stable patient [8]. Heart failure death was defined as a death that occurred because of worsening or intractable heart failure, which included cardiogenic shock, pulmonary edema and terminal arrhythmias during hospital stay for aggravated heart failure. Other cardiovascular death was defined as a death that occurred after a cerebrovascular accident, vascular disease, myocardial infarction or cardiovascular procedure. Cerebrovascular accident was defined as a persistent disturbance of neurological function. Diagnosis required characteristic history, physical examination, imaging techniques and/or autopsy data. Myocardial infarction (MI) death was defined as a death that occurred after a verified acute MI. Noncardasiovcular death was defined as a death resulting from a noncardiac reason. Unknown death was defined as a death that did not have a definitive cause. Patients were categorized according to the New York Heart Association functional class [9] during evaluation of the medical staff of our heart failure clinic. The primary end-point of the study was all-cause, heart failure and sudden death mortality that were obtained during follow-up, either from the trial database, from review of medical records or by telephone contact with family members. Additionally, Cox proportional-hazards regression models were used to explore the relationship of mode of death, etiology and other variables with survival time. For Cox proportional hazards model, each mode of death is looked at in turn and all other modes of death are censored. Results are presented as frequencies, mean (SD), or median (interquartile range), as appropriate. For effects of group comparison, the t test was used for normal distribution and Mann-Whitney test was used to compare variables without normal distribution. For categorical variables, chi-square test or the Fisher exact test was applied. Survival was estimated by the Kaplan–Meier method, and differences in survival between groups were assessed by the log-rank test. Cox proportional-hazards models were used to compare the rates of deaths for each mode of mortality. In the analysis, data on patients was censored at the time of implantation of a defibrillator or the time of heart transplantation. All analyses and graphs were performed with SPSS statistical software version 13. 0 and Graphpad Prism software version 5. 0. , The study protocol was approved by the institutional ethics committee of Hospital das Clinicas da Faculdade de Medicina da Universidade de Sao Paulo and all patients provided written informed consent. All data analyzed were anonymized.
  Altogether 185 (54. 1%) patients died. Death occurred in 31 (56. 4%) Chagas patients and 154 (53. 7%) non-Chagas patients. Kaplan-Meier cumulative event curves for all-cause, heart failure and sudden death mortality are shown in Figures 2,3 and 4. The cumulative incidence of all-cause mortality was higher in patients with Chagas heart disease compared to non-Chagas patients (figure 2). Additionally, the cumulative incidence of heart failure mortality was higher in Chagas patients compared to non-Chagas (figure 3). Nevertheless, when we analyzed the cumulative incidence of sudden death mortality, there was no difference between the two groups (figure 4). The influence of etiology on heart failure and sudden death mortality was further evaluated by Cox proportional-hazards regression. As we have information about New York Heart Association functional class (NYHA FC) only in 296 patients, we did two different models of Cox proportional-hazards regression; Model 1 without information about NYHA FC and Model 2 including NYHA FC (I/II vs III/IV). Other variables included were age, gender, etiology (Chagas vs non-Chagas), use of beta-blocker, use of angiotensin-converting enzyme inhibitor or angiotensin II receptor blocker, use of amiodarone, use of spironolactone, body mass index, left ventricular ejection fraction, left ventricular end diastolic diameter (LVEDD), group allocated (disease management program versus control), hemoglobin, serum sodium, creatinine clearance, number of hospitalizations, days of hospitalization and number of admissions to emergency care. Chagas etiology, LVEDD, creatinine clearance and use of amiodarone were independently associated with heart failure mortality on Model 1 and Model 2 (table 3). On the other hand, LVEDD and use of beta-blocker were independently associated with sudden death mortality on both Models 1 and 2 (table 4). Concerning the toxic effects of amiodarone, it is important to highlight that none patient died from lung toxicity. The relationship between mode of death and NYHA functional class at randomization was analyzed for each etiology. As mentioned before, information about NYHA functional class was available in 296 (87%) patients. In patients with Chagas heart disease, the proportion of patients who died of worsening heart failure increased substantially as increased functional class (38% vs 57%). On the other hand, the proportion of patients who died of sudden death decreased with the worsening of functional class (31% vs 15%). Furthermore, 23% of deaths in NYHA class I/II were secondary to other cardiovascular causes (Figure 5). In non-Chagas group, sudden death was the main cause of death throughout the spectrum of NYHA functional class; 47% in both class I/II and class III/IV (figure 5).
  This study contains some limitations that should be acknowledged. First, this study was a single center trial that included patients initially enrolled in another intervention trail. In addition, this was a retrospective analysis though the data were obtained prospectively in REMADHE trial. Concerning our cohort, Chagas group is considerably smaller than non-Chagas group and Kaplan-Meier curves result may have limited value after 1500 days since the number of Chagas patients at risk is very low. However, it is important to note that the difference in proportion between groups reflects the reality of our population. In few patients, the mode of death of patients was not clarified. However, it was less than 10%. Unfortunately, the gold standard autopsy studies were not available widespread to confirm certainly the cause of death. Therefore, in most randomized trials as in the REMADHE trial the autopsy is not routinely performed. Clinicians should keep in mind that in severe Chagas heart disease progressive heart failure plays an important role as the most important mode of death in a scenario of worse prognosis in comparison with other etiologies. The data from this analysis challenges the current understanding of Chagas heart disease and may have implications in the selection of treatment choices considering the mode of death. In addition, our results may influence the development of new strategies for prevention of chagasic heart failure. The amiodarone role in chagasic heart disease should be reevaluated. Moreover, prevention of thromboembolism must be emphatically pursued. Finally, priority should be given to enhance the research related to prevent and treat the progression of heart failure in Chagas disease.
summary: Chagas disease remains a burden for public health systems in Latin American countries. Several authors believe that sudden death is the main cause of death in this population. So many efforts have been made to prevent sudden death in Chagas disease. In order to verify if sudden death is the leading cause of death in Chagasic heart failure, we performed a subanalysis of the REMADHE prospective trial, which included a population of outpatients in a tertiary referral center for heart failure. We grouped patients according to etiology (Chagas vs non-Chagas) and modes of death that were classified as progressive heart failure death, sudden death, other cardiovascular death, noncardiovascular death or unknown death. Our study showed that in this end of the spectrum of presentation of Chagas disease, with systolic heart dysfunction, progressive heart failure is the main mode of death. These data have implications for the development of new strategies for prevention of chagasic heart failure.
keywords: medicine
  infectious diseases
  cardiomyopathies
  chagas disease
  neglected tropical diseases
  heart failure
  cardiovascular
title: Mode of Death on Chagas Heart Disease: Comparison with Other Etiologies. A Subanalysis of the REMADHE Prospective Trial