Version May 2024
INTRODUCTION — Chagas disease (CD) is caused by Trypanosoma cruzi, a protozoan parasite that can cause acute myopericarditis as well as chronic fibrosing myocarditis. Chagas myocarditis is the most common cause of non-ischemic cardiomyopathy in Latin America [1].
The management and prognosis of chronic Chagas cardiomyopathy (CCC) will be reviewed here. Other issues related to chronic CD, including clinical manifestations and diagnosis of chronic Chagas cardiomyopathy and noncardiac manifestations, are discussed separately. (See "Chronic Chagas cardiomyopathy: Clinical manifestations and diagnosis" and "Chagas gastrointestinal disease" and "Chagas disease: Antitrypanosomal drug therapy" and "Chagas disease: Chronic Trypanosoma cruzi infection".)
MANAGEMENT — Management of patients with CCC includes monitoring for progression, selective use of antitrypanosomal therapy and supportive care of cardiovascular complications including heart failure (HF), arrhythmia, and thromboembolism.
Monitoring for disease progression — The optimal approach to monitoring patients with CCC has not been established. The following recommendations for monitoring are largely consistent with recommendations in the 2018 American Heart Association (AHA) scientific statement on Chagas cardiomyopathy [2].
Baseline evaluation of patients with CCC or suspected CCC is discussed separately. (See "Chronic Chagas cardiomyopathy: Clinical manifestations and diagnosis", section on 'Diagnosis'.)
The following serial evaluation is recommended for patients with CCC (or suspected CCC) as defined separately (see "Chagas disease: Chronic Trypanosoma cruzi infection", section on 'Criteria'):
●An annual clinical evaluation including history, physical examination, and electrocardiogram (ECG) to assess for any changes in clinical status (eg, new or worsening HF or symptoms of arrhythmia) that might merit further evaluation or changes in management.
●The frequency of follow-up echocardiography is based upon global and regional left ventricular (LV) function. For patients with normal LV ejection fraction (LVEF) and normal regional wall motion, we suggest follow-up echocardiography every three to five years. For patients with an ejection fraction less than 50 percent or who have regional wall motion abnormalities, we suggest follow-up echocardiography every one to two years.
●The role of stress testing and coronary angiography in patients with chest pain is discussed separately. (See "Chronic Chagas cardiomyopathy: Clinical manifestations and diagnosis", section on 'Stress testing' and "Chronic Chagas cardiomyopathy: Clinical manifestations and diagnosis", section on 'Cardiac catheterization'.)
Monitoring in patients with chronic CD with the indeterminate form is discussed separately. (See "Chagas disease: Chronic Trypanosoma cruzi infection", section on 'Monitoring'.)
Antitrypanosomal therapy — For patients with AHA/American College of Cardiology (ACC) stage A or B HF (table 1) and who have a Rassi score <7 points, we suggest antitrypanosomal therapy with benznidazole or nifurtimox [3]. (See 'Rassi score for predicting mortality' below.) The doses for these drugs are outlined in a table (table 2).
For patients who were treated in the acute or indeterminate phase of disease with a complete course of benznidazole (ie, 60 days) or nifurtimox (ie, 90 days) but who have AHA/ACC stage B HF, we suggest treating with a full course of the alternative drug (ie, the drug not previously used) (table 2). If the initial course was incomplete, we suggest treating with a full course of the same drug used in the prior incomplete course. There is no need to reassess serology before repeating the trypanocidal treatment, since it typically takes decades for serology to become negative after treatment.
Antitrypanosomal therapy is generally not prescribed to patients who have AHA/ACC stage C or D HF; the clinical benefit of therapy is likely negligible, and there is significant risk of drug toxicity.
Benznidazole and nifurtimox are the only drugs recommended for the treatment of CD. Benznidazole has the better safety and efficacy profile, and therefore is viewed by most experts as the first-line treatment. Adverse effects of benznidazole include dermatitis, gastrointestinal symptoms, peripheral neuropathy, rarely angioedema, and bone marrow suppression. Either drug should preferably be given after meals [4]. Drug doses are outlined in the table (table 2). (See "Chagas disease: Antitrypanosomal drug therapy".)
The available evidence suggests that timely antitrypanosomal therapy may be beneficial in selected patients with AHA/ACC stage B HF or less severe chronic CD. In contrast, there is no clear benefit of trypanocidal therapy in patients with AHA/ACC stage C or more advanced CCC. The best data on antitrypanosomal therapy in patients with CCC come from the multicenter double-blind BENEFIT trial, which randomly assigned 2854 patients (mean age 55 years) with CCC to receive either benznidazole or placebo for up to 80 days with mean 5.4-year follow-up [5,6].
●No reduction on the primary composite outcome (the first of the following events: death, resuscitated cardiac arrest, sustained ventricular tachycardia (VT), insertion of a pacemaker or implantable cardioverter-defibrillator (ICD), cardiac transplantation, new HF, stroke, or other thromboembolic event) was observed (27.5 percent in the benznidazole group and 29.1 percent in the placebo group, hazard ratio [HR] 0.93, 95% CI 0.81-1.07).
●Despite the neutral overall result, all components of the primary composite end point were nominally less frequent in the treated group than in the placebo group, and the reduction in hospitalizations for cardiovascular causes in the benznidazole group was significant [7]. Also, subgroup analysis suggested a benefit in patients receiving amiodarone; further study is needed to determine the significance of this observation [6]. The efficacy of amiodarone as an antitrypanosomal agent is unknown. (See 'Antiarrhythmic therapy' below.)
●Benznidazole reduced blood parasite detection by polymerase-chain-reaction (PCR) conversion to negative in 46.7 versus 33.1 for placebo at five years or more. The PCR conversion rates were variable among the five countries involved in the trial, and it is possible that the clinical therapeutic effect may be influenced by the predominant T. cruzi strains found in each country [7], a hypothesis that unfortunately was not analyzed for the BENEFIT patients.
The following nonrandomized studies in patients with chronic CD or early CCC have suggested a clinical benefit, but these studies are subject to risk of bias.
●In a retrospective study that included 228 patients with indeterminate CD, disease progression was lower in patients treated with benznidazole than in matched patients who received no antitrypanosomal treatment (7.9 percent versus 21.1 percent; adjusted HR 0.44, 95% CI 0.2-0.99) [8]. Patients treated with benznidazole had a lower risk of death or a cardiovascular event (HF, stroke, cardiac electronic device implantation; 2 versus 8 percent).
●The SaMi-Trop prospective observational study enrolled 1813 CD patients (1320 untreated and 493 treated with benznidazole) of which the majority (83 percent) had an abnormal ECG at baseline. Mortality after two years of follow-up was lower in the treated than in the untreated patients (3 versus 8 percent; adjusted odds ratio [OR] 0.37, 95% CI 0.21-0.63) [9].
●Another observational study of 310 patients with chronic CD and a normal ECG at baseline found a significant lower rate of new ECG changes over 20 years of follow-up among 263 treated with benznidazole compared to 47 patients who were untreated (20.9 percent versus 53.2 percent) [10].
●An earlier unblinded, nonrandomized study in 566 individuals (mean age 39 years) with chronic CD included patients with indeterminate form or CCC without HF who were assigned to treatment with benznidazole for 30 days or no antitrypanosomal treatment [11]. The study found that benznidazole treatment was associated with less frequent clinical progression (change to a more advanced Kuschnir group or cardiac death; 4 versus 14 percent) compared with no treatment over median 9.8-year follow-up. There was a high rate of loss to follow-up (20 percent).
The role of antitrypanosomal therapy in patients with the indeterminate form is discussed in detail separately. (See "Chagas disease: Chronic Trypanosoma cruzi infection", section on 'Antitrypanosomal therapy'.)
Heart failure — HF due to CCC is treated as HF due to other causes. (See "Treatment and prognosis of heart failure with mildly reduced ejection fraction" and "Overview of the management of heart failure with reduced ejection fraction in adults" and "Treatment and prognosis of heart failure with preserved ejection fraction".)
Pharmacologic therapy — HF due to CCC is generally treated with standard pharmacologic treatment for HF with reduced ejection fraction (HFrEF) or HF with mid-range ejection fraction (HFmrEF). (See "Overview of the management of heart failure with reduced ejection fraction in adults", section on 'Pharmacologic therapy' and "Treatment and prognosis of heart failure with preserved ejection fraction", section on 'Pharmacotherapy' and "Treatment and prognosis of heart failure with mildly reduced ejection fraction".)
Limited data are available on the efficacy of HF therapies in patients with CCC. A systematic review of pharmacologic interventions for HF in patients with Chagas cardiomyopathy identified two trials with a total of 69 subjects comparing carvedilol against placebo [12] and one trial with 39 subjects comparing rosuvastatin versus placebo [13]. A meta-analysis of the two carvedilol trials yielded inconclusive results. The rosuvastatin trial was also inconclusive. Because all therapies employed in CD patients are empirically extrapolated from trials performed in patients with HF of other etiologies, the morbidity and mortality benefit from each class of drugs in CD patients is uncertain. This is especially relevant in the case of beta blockers, since CD patients often have bradycardia and/or different degrees of AV block that may limit their use, particularly with concomitant amiodarone therapy [3].
Cardiac transplantation — Cardiac transplantation is an accepted therapy for patients with refractory HF caused by CD, despite being associated with risk of reactivation of Trypanosoma cruzi infection [14-24]. As recommended in the 2016 listing criteria, heart transplant candidates from endemic areas should be screened for T. cruzi infection, and surveillance for reactivation is required after transplantation [25]. (See "Heart transplantation in adults: Indications and contraindications", section on 'Chagas disease'.)
●In one cohort study including 117 patients with CD who underwent cardiac transplantation, survival of patients with CD at 1, 4, 8, and 12 years after transplantation was better than the survival of patients with ischemic heart disease or idiopathic cardiomyopathy (71, 57, 55, and 46 percent for CD versus 69, 57, 40, and 32 percent for idiopathic dilated cardiomyopathy (DCM) and 59, 44, 34, and 22 percent for ischemic heart disease) [15]. Causes of death following transplantation included infection, rejection, and neoplasm (10, 10, and 4 percent, respectively); T. cruzi reactivation was a rare cause of death.
Among patients who undergo cardiac transplantation for management of Chagas cardiomyopathy, some experts favor administration of antitrypanosomal therapy prior to induction of immunosuppression, even though such treatment does not usually achieve a cure in patients with longstanding infection [18]. There is no consensus and no definitive indication for prophylaxis prior to induction of immunosuppression [26]. As indicated in the First Latin American Guidelines for the diagnosis and treatment of Chagas heart disease, the prevailing recommendation is that in patients infected by T. cruzi, immunosuppression should be adjusted to the lowest intensity that prevents rejection [27].
●In a cohort of 53 patients with CCC who underwent cardiac transplantation in Brazil between 1996 and 2014, the administration of prophylactic benznidazole (dose of 5 mg/kg/day, two times per day, for at least four weeks and for a maximum of eight weeks) was associated with a lower incidence of CD reactivation during the posttransplantation period (11 percent versus 46 percent; adjusted OR 0.12, 0.02-0.76) [28].
The cumulative risk of reactivation among heart transplant patients ranges from 29 to 50 percent [14,18-24]. The timeframe for reactivation ranged from 38 days to more than seven years after transplantation [18,19]. Risk factors associated with increased risk of reactivation included use of high-dose cyclosporine A or mycophenolate mofetil, frequent rejection episodes, and neoplasm [14,18]. In one cohort of 11 patients who underwent cardiac transplant for Chagas cardiomyopathy, five were diagnosed with reactivation disease; survival during a median follow-up time of 1.1 years was comparable for those with and without reactivation (80 versus 83 percent, respectively) [24].
Patients with CD receiving cardiac transplants should be monitored for reactivation of Chagas infection. In general, the schedule of monitoring for reactivation is the same as the schedule for monitoring rejection (eg, 1, 3, 6, 9, and 12 months after transplantation, one month after steroid treatment for rejection, and whenever fever or overt acute myocarditis occurs) [18].
Reactivation may be diagnosed based on detection of parasites on peripheral blood smears, rising blood parasite load by quantitative PCR, and/or findings of acute Chagas myocarditis observed on endomyocardial biopsy. Quantitative real time PCR demonstrating rising parasite numbers over time provides the earliest and most sensitive indicator of reactivation, but there is no established threshold/cutoff for meaningful results [29]. Characteristic biopsy findings consist of T. cruzi amastigotes with or without surrounding inflammatory infiltrate (picture 1). These findings may occur in the absence of microscopically detectable peripheral parasitemia and may precede development of clinical signs of myocarditis. The Centers for Disease Control and Prevention (CDC) provides consultation to health care providers on CD diagnosis and treatment [30].
Other therapies — The role of cardiac resynchronization therapy (CRT) in patients with CCC is uncertain. Most patients in the CRT trials had left bundle branch block. Among patients with CCC, right bundle branch block is much more common than left bundle branch block (eg, 42.9 versus 7.1 percent [31]). The efficacy of CRT in patients with right bundle branch block has not been established.
The utility of CRT in patients with CCC remains to be determined by randomized clinical trials but the available limited evidence suggests that CCC patients treated with CRT have worse outcomes than other patients treated with CRT. One observational study compared the effect of CRT on groups of patients with CCC (n = 115), DCM of other etiologies (n = 177), and ischemic cardiomyopathy (ICM, n = 134) [32]. The annual mortality rate was significantly higher for the group with CCC compared with the two other groups (25.4 versus 10.4 and 11.3 percent, respectively). Multivariate analysis showed that the CCC group had a more than twofold (HR 2.34; 95% CI 1.47-3.71) higher risk of death compared with the DCM group. Although rates of advanced HF (New York Heart Association [NYHA] functional class II or IV) were similar in the three groups at baseline (CCC, 81.7 percent, DCM 87.6 percent and ICM 82.1 percent), at 12 months advanced HF was significantly more frequent in the CCC group compared to the DCM and ICM groups (43.5, 26.0, and 26.1 percent, respectively). No improvement in echocardiographic indices of LV function was detected in the CCC group after one year of follow-up. (See "Cardiac resynchronization therapy in heart failure: Indications and choice of system", section on 'Factors associated with less benefit from CRT'.)
Asymptomatic left ventricular dysfunction — For patients with CCC and asymptomatic LV systolic dysfunction (LVEF ≤40 percent), standard pharmacologic treatment (neurohormonal blockade) is warranted to reduce the risk of progression to HF, as discussed in detail separately. (See "Management and prognosis of asymptomatic left ventricular systolic dysfunction", section on 'Approach to initial medical therapy'.)
Bradyarrhythmias and heart block — Patients with second (Mobitz 2 type or advanced)- or third-degree AV block or symptomatic sinus node dysfunction require permanent cardiac pacing. Indications for permanent pacing are discussed in detail separately. (See "Permanent cardiac pacing: Overview of devices and indications".)
Ventricular arrhythmia and SCA — The optimal approach for management of arrhythmia and sudden cardiac arrest (SCA) due to CCC is uncertain. Potentially beneficial treatment tools include HF therapy, antiarrhythmic drugs (mainly amiodarone), radiofrequency catheter ablation, ICD device placement, and surgical intervention.
Our approach — The first step in treating patients with CCC at risk for malignant arrhythmia is optimization of medical therapy for HF (including beta blockers as tolerated) since this may improve survival and reduce ventricular arrhythmias. (See "Overview of the management of heart failure with reduced ejection fraction in adults", section on 'Pharmacologic therapy'.)
Appropriate measures to reduce the risk of SCA in patients with CCC are uncertain due to paucity of data. A separate concern is that widespread use of ICDs would be hampered by socioeconomic limitations.
●For patients with CCC who survive an episode of SCA or have sustained VT, we suggest an ICD for secondary prevention of SCA. In patients who have an ICD and a high density of spontaneous ventricular premature beats (eg, nonsustained VT, couplets), we typically treat with amiodarone and beta blocker therapy to reduce the risk of ICD shocks.
●For patients with CCC who survive an episode of SCA or have sustained VT but who are not treated with ICDs, we typically treat with amiodarone and a beta blocker in addition to appropriate pharmacologic therapy for HFrEF (or for asymptomatic LV systolic dysfunction).
●Indications for catheter ablation in patients with CCC include symptomatic monomorphic sustained VT (including VT terminated by an ICD) that cannot be adequately managed with antiarrhythmic drug therapy (due to recurrent VT with antiarrhythmic therapy or because antiarrhythmic drug therapy is not tolerated). Recommendations for catheter ablation are discussed separately. (See "Overview of catheter ablation of cardiac arrhythmias".)
●For primary prevention of SCA or sustained VT (see 'Rassi score for predicting mortality' below):
•For patients with CCC with an LVEF ≤35 percent, a Rassi score of ≥10, and a reasonable likelihood of survival of at least one year, ICD implantation is suggested.
•For patients with CCC, LVEF >35 percent, a Rassi score of ≥10, and nonsustained VT on Holter, we suggest amiodarone with or without beta blocker therapy.
CCC-specific evidence — Limited data are available on the safety and efficacy of antiarrhythmic drugs, device, ablation, and surgical treatment in patients with CCC. Thus, the above recommendations are largely based upon data on patients at risk for SCA due to heart disease other than CCC. (See "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy".)
ICD therapy — Limited observational data are available on ICD therapy in patients with CCC treated with ICDs. In patients with CD treated with ICDs largely for secondary prevention of SCA, many patients received appropriate ICD therapy [33-39], but early studies yielded mixed results [33,34] and an impact on clinical outcomes has not been ascertained.
The limited data on ICD therapy in patients with CCC contrasts with the high-quality evidence of mortality benefit from ICD therapy for secondary prevention in patients with other causes of cardiomyopathy with prior SCA or sustained VT and moderate quality evidence of mortality benefit from ICD for primary prevention in selected patients with nonischemic cardiomyopathy. (See "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy" and "Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF".)
Some studies in patients with CCC have reported an association between mortality and number of shocks per patient, which raised concern that mortality and deterioration of LV function may be associated with multiple ICD shocks [33,34]. In a study of ICD use for secondary prevention of SCA, 90 patients with CCC with sustained VT or ventricular fibrillation (VF) underwent ICD implantation and were treated with amiodarone [33]. Baseline mean LVEF was 47 percent. Sixty-four percent of patients received an appropriate shock during mean follow-up of two years. Mortality was 18, 27, 40, 50, and 73 percent at one-, two-, three-, four-, and five-year follow-up. Nearly all deaths were due to pump failure despite only mildly depressed mean LVEF at the beginning of the study (including 28 percent of patients with normal LV systolic function at the start of the study). The only independent predictor of mortality was number of shocks per patient through 30 days.
Later series of patients with CCC receiving ICDs largely for secondary prevention have reported lower mortality rates with high rates of appropriate ICD therapy and variable rates of inappropriate shocks. A meta-analysis of pooled data from 13 observational studies assessed clinical outcomes in patients with CCC and an implanted ICD (mean age at implantation, 57±11 years; 64 percent men) [40]. Most patients (92 percent) received an ICD for secondary prevention. During a mean follow-up of 2.8 years, the annual rate of all-cause mortality was 9 percent. Appropriate ICD interventions (shocks and antitachycardia pacing) and electrical storm were common, occurring at rates of 25 percent and 9 percent per year, respectively. In addition, 5 percent of the patients received inappropriate shocks. This information may be helpful in discussing risks and benefits in patients considered for ICD therapy.
Limited data are available comparing ICD therapy with drug therapy for secondary prevention in patients with CCC. A systematic review included six observational studies of patients with CCC comparing a total of 115 patients treated with amiodarone with a total of 483 patients treated with an ICD [39]. The mortality outcome in the ICD population was 9.7 per 100 patient-years of follow-up (95% CI 5.7-13.7) and 9.6 per 100 patient-years in the amiodarone group (95% CI 6.7-12.4). Thus, ICD therapy for secondary prevention was not associated with a reduced rate of all-cause mortality compared to pharmacologic therapy in observational studies. Randomized studies are necessary to determine the efficacy of ICD therapy in patients with CCC.
Outcomes of combined ICD plus amiodarone therapy in 76 patients with CCC was compared to a historical control group of 28 patients with CD treated with amiodarone alone [41]. The two groups had comparable baseline characteristics. Appropriate shock therapy was reported in 72 percent of the 76 patients. In comparison with the group treated solely with amiodarone, therapy with ICD plus amiodarone was associated with lower all-cause mortality by 72 percent and risk of sudden death by 95 percent. Of note, patients treated with ICD plus amiodarone were also more frequently treated with beta blockers. The survival benefit associated with ICD plus amiodarone was more prominent in patients whose LVEF was <40 percent.
Since the impact of ICD implantation on survival remains uncertain, controlled trials of such therapy in CCC are warranted. One such study is presently recruiting patients for a randomized comparison of amiodarone versus ICD for primary prevention of death in patients with nonsustained VT (NSVT) and a Rassi score of 10 or more [42].
Antiarrhythmic therapy — Recommendations on antiarrhythmic therapy in patients with CCC are based upon extrapolation of data from other patient populations and limited observational data in patients with CCC. Case series of patients with CCC suggest that amiodarone suppresses asymptomatic ventricular arrhythmias but its effect on clinical outcomes has not been established [43-45]. A meta-analysis including nine studies with 365 patients evaluated the effects of amiodarone in patients with CCC. By analyzing two studies with a total of 38 patients that had the full dataset, allowing individual patient data analysis, the authors showed that amiodarone reduced the number of ventricular tachycardia episodes in 99.9 percent (95% CI 99.8-100), ventricular premature beats in 93.1 percent (95% CI 82-97.4) and the incidence of ventricular couplets in 79 percent (95% CI 61–89) in 24-hour Holter monitoring. Despite the evidence for arrhythmia reduction, studies did not provide enough information for the assessment of the effect of amiodarone on clinically relevant outcomes, such as mortality and hospitalization [43]. There is no conclusive evidence that pharmacologic treatment improves survival in patients with CCC [46]. Use of amiodarone in patients with CCC is based upon evidence that it improves survival free of cardiac arrest or ICD shocks in patients with other types of heart disease. (See "Pharmacologic therapy in survivors of sudden cardiac arrest", section on 'Empiric versus guided pharmacologic therapy'.)
Observations from in vitro and animal studies and a case report suggest that amiodarone may have an antitrypanosomal effect, although its efficacy as an antiparasitic agent has not been established [47,48]. Also, as noted above, antiparasitic treatment is unlikely to affect the prognosis of patients with established severe CCC. (See 'Antitrypanosomal therapy' above.)
Ablation — Observational studies have suggested that catheter ablation can reduce the risk of recurrent VT in patients with CCC and may contribute to improved survival in patients receiving ICDs [36,49-51]. As for other patients with structural heart disease with frequent episodes of VT and ICD shocks, catheter ablation is recommended as adjunctive therapy in patients with an ICD who have frequent episodes of VT and ICD shocks. (See "Sustained monomorphic ventricular tachycardia in patients with structural heart disease: Treatment and prognosis", section on 'Radiofrequency catheter ablation'.)
As the arrhythmogenic circuit is frequently epicardial in patients with CCC, a combined endocardial/epicardial approach to VT ablation is associated with greater freedom from recurrent ventricular arrhythmias than endocardial ablation alone [52]. Bilateral cervicothoracic sympathectomy and bilateral renal denervation may provide additional benefit in patients with recurrent VT after catheter ablation [53].
Recommendations of others — Major society guidelines and scientific statements have provided differing recommendations for the management of ventricular arrhythmias and risk of SCA in patients with CCC. (See "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy" and "Primary prevention of sudden cardiac death in patients with cardiomyopathy and heart failure with reduced LVEF".)
The 2018 American Heart Association (AHA) scientific statement does not include graded recommendations, but notes general consensus for high priority for ICD placement for secondary prevention in patients with CCC resuscitated from sudden cardiac death (SCD) and patients with LVEF <35 percent and documented syncope secondary to VT [2]. The statement notes that an ICD should be considered in patients with CCC with syncope and inducible sustained VT during electrophysiologic (EP) testing, and patients with LVEF >35 percent who have experienced syncope secondary to VT. This document also highlights the role of amiodarone as adjunctive therapy after ICD placement and the role of VT ablation in selected patients.
The 2017 AHA/ACC/Heart Rhythm Society (HRS) guidelines for management of patients with ventricular arrhythmias and prevention of SCA discuss management of patients with nonischemic cardiomyopathy [54]. These guidelines recommend an ICD for secondary prevention in patients with nonischemic cardiomyopathy who are survivors of SCA due to VF or who have spontaneous sustained VT. These guidelines also recommend an ICD for primary prevention in patients with nonischemic DCM with an LVEF ≤35 percent and NYHA functional class II or III despite guideline-directed medical therapy if meaningful survival greater than one year is expected. However, these guidelines include limited discussion of CCC.
The 2015 European Society of Cardiology (ESC) guidelines for the management of patients with ventricular arrhythmias and the prevention of SCA include a weak recommendation that an ICD should be considered in patients with CCC and an LVEF <40 percent with expected survival >1 year with good functional status [55].
The 2015 Brazilian Ministry of Health guidelines recommend ICD therapy for secondary prevention in the following situations: patients resuscitated from SCA due to documented sustained VT or VF, hemodynamically unstable VT, unexplained syncope with sustained VT/VF induced at electrophysiologic study, and stable sustained VT with LVEF <35 percent. For patients with well-tolerated sustained VT and LVEF >35 percent, an ICD or amiodarone could be used. These guidelines recommend amiodarone for primary prevention of SCD in general, and ICD implantation, with a weak recommendation, specifically for patients with nonsustained VT and LVEF <35 percent [26].
The 2011 Latin American guidelines for CCC do not recommend ICD therapy for primary prevention of SCA [27]. For secondary prevention, the guidelines note that pharmacologic therapy should be an adjunct to ICD in patients with sustained VT and LVEF <35 percent. For patients with well-tolerated sustained VT with preserved LVEF, the guidelines suggest ICD implantation as the safest option, with amiodarone and ablation as other options. These guidelines include recommendations for amiodarone similar to those above. (See "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy".)
Thromboembolism treatment — Patients with CD are at risk for systemic and pulmonary thromboembolism. Although data are limited, the risk of thromboembolism in patients with CCC appears to be higher than generally seen in patients with other types of cardiomyopathy with similar degrees of LV dysfunction. This increased risk may be due to a combination of factors such as severe systemic venous congestion and low cardiac output, cardiac chamber dilation, and prominent ventricular wall motion abnormalities with aneurysm formation, an early finding in the natural history of CCC. (See "Chronic Chagas cardiomyopathy: Clinical manifestations and diagnosis", section on 'Thromboembolism'.)
Patients with CCC who present with LV thrombus or symptoms or signs of systemic or pulmonic thromboembolism should receive the appropriate evaluation and management of these disorders.
●LV thrombus. (See "Antithrombotic therapy in patients with heart failure", section on 'Role of antithrombotic therapy'.)
●Stroke or transient ischemic attack. (See "Overview of the evaluation of stroke" and "Overview of secondary prevention of ischemic stroke".)
●Systemic embolism. (See "Clinical features and diagnosis of acute lower extremity ischemia", section on 'Embolism'.)
●Pulmonary embolism. (See "Epidemiology and pathogenesis of acute pulmonary embolism in adults".)
Thromboembolism prophylaxis — For patients with CCC who do not have atrial fibrillation, we do not suggest routine prophylaxis for thromboembolism. For patients with CCC who have atrial fibrillation, we use the same guidelines and agents for thromboembolism prophylaxis that are used in the general population. (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation", section on 'Approach to deciding whether to anticoagulate'.)
Thromboembolism prophylaxis in patients without atrial fibrillation is controversial [56,57]. Our approach differs from the CCC guidelines, which describe the use of a risk score to determine thromboembolism risk and the need for prophylaxis (table 3) [27]. Notably, the study that derived the risk score recommended by the guidelines had few stroke or bleeding events, and the risk score has not been extensively validated [58].
PROGNOSIS — Mortality associated with the chronic phase of Chagas disease (CD) is almost exclusively due to cardiovascular involvement with CCC. According to studies among patients with CCC, death is sudden in 55 to 65 percent, due to progressive HF in 25 to 30 percent and stroke in 10 to 15 percent [59]. In young patients with segmental wall motion abnormalities but preserved global LV function, SCD occurs more frequently than death from progressive HF [60].
In a recent meta-analysis of 52 longitudinal studies published between 1946 and 2018 that included a mixed population of patients with CCC, the annual all-cause mortality rate was 7.9 percent (95% CI 6.3-10.1) and the annual cardiovascular death rate was 6.3 percent (95% CI 4.9-8.0). The annual mortality rates for HF, sudden death, and stroke were 3.5, 2.6, and 0.4 percent, respectively. Meta-regression showed that low LVEF was associated with an increased mortality risk, and subgroup analysis based on the Latin American guidelines classification revealed pooled estimate rates of 4.8, 8.7, 13.9, and 22.4 percent for B1/B2, B2/C, C, and C/D stages of cardiomyopathy, respectively. This meta-analysis also revealed that the mode of death is conditioned by the characteristics of the studied populations. While the sudden annual death rates were higher than the HF rates in studies that included ambulatory asymptomatic patients, patients without ventricular dysfunction, patients predominantly in New York Heart Association (NYHA) class I/II, and patients with documented ventricular arrhythmias, not treated with an ICD, the contrary was observed in cohorts of patients with symptomatic CCC, with LV dysfunction or HF, and with an implanted ICD or cardiac resynchronization therapy [61].
Other major risk factors for mortality in patients with Chagas cardiomyopathy include HF, evidence of LV dilatation or systolic dysfunction, and nonsustained VT (NSVT) [62]. These risk factors and others are combined in the Rassi score for predicting mortality. (See 'Rassi score for predicting mortality' below.)
Comparative data from observational studies suggest that the mortality rate for patients presenting with HF due to CCC is higher than the mortality due to other etiologies of HF [63,64].
Rassi score for predicting mortality — We use the Rassi score to stratify mortality risk in patients with confirmed CCC, but outcomes for individual patients are variable. The Rassi score was developed in 424 patients with Chagas cardiomyopathy and was first validated in a separate cohort of 153 patients [31]. In the initial cohort, the mean patient age was 47 years and there were 130 deaths (31 percent) during a mean follow-up of 7.9 years. Death was sudden in 62 percent, due to progressive HF in 15 percent, due to other cardiovascular causes (mainly stroke) in 9 percent, due to noncardiovascular causes in 12 percent, and due to unknown causes in 1 percent. Multivariate analysis identified six independent predictors of mortality, and each predictor was assigned a point value:
●NYHA class III or IV (5 points)
●Cardiomegaly on chest radiograph (5 points)
●Segmental or global LV systolic dysfunction on echocardiogram (3 points)
●NSVT on 24-hour ambulatory ECG (Holter) monitoring (3 points)
●Low QRS voltage on 12-lead ECG (voltage in each limb lead ≤0.5 mV) (2 points)
●Male sex (2 points)
Ten-year mortality in patients with 12 to 20 points was 84 to 85 percent (for the original and validation cohorts, respectively); for patients with 7 to 11 points, it was 37 to 44 percent and for patients with 0 to 6 points, it was 9 to 10 percent. The combination of LV systolic dysfunction and NSVT was associated with particularly high risk (15.1-fold increased risk of death) [31]. The presence of NSVT alone was associated with a 2.15-fold increased risk of death.
Other evidence on prognosis — Other studies have identified prognostic factors largely similar to those included in the Rassi score as summarized by a systematic review of predictors of mortality from 12 observational studies with 4277 patients with chronic CD [62]. Although most studies focused on patients with established CCC, four of the studies included some patients with the classically defined indeterminate form (normal ECG and normal chest radiograph).
●The most common and consistent independent risk factor for death was impaired LV function, as identified by echocardiography or ventriculography. Evidence of LV dysfunction included presence of reduced LVEF, LV aneurysm, regional or global wall motion abnormality, increased LV end systolic and/or end diastolic dimension, increased LV end-diastolic volume or volume index, and M-mode increased E-point septal separation.
●Other independent risk factors for mortality were symptoms (dyspnea, HF, or NYHA functional class III/IV), cardiomegaly on chest radiography, and NSVT on Holter monitoring.
●Male sex was associated with worse prognosis in the study that defined the Rassi score [31], but was not an independent predictor in other studies. Similarly, advanced age was associated with worse prognosis in some studies, but not others [62].
Prognostic value of ECG — ECG findings may have prognostic significance in patients with CCC and low limb lead QRS voltage is included in the Rassi score, as described above (see 'Rassi score for predicting mortality' above). Individual observational studies have identified associations between differing ECG abnormalities and mortality or risk factors for mortality as illustrated by the following studies [62]:
●In a cohort of 738 adults with chronic CD followed for five years, QT dispersion and LV end-systolic dimension were the strongest independent predictors of mortality [65]. Other predictors included isolated left anterior fascicular block, frequent ventricular premature beats on 12-lead ECG, pathologic Q waves, and heart rate (per 10 beats increase per minute).
●In the Bambui cohort study of 1462 participants ≥60 years old at enrollment, 38 percent were diagnosed with CD by serology [66]. At mean follow-up of 8.7 years, ECG variables associated with mortality in CD included absence of sinus rhythm, frequent ventricular and supraventricular premature beats, atrial fibrillation, right bundle branch block, Q-waves (consistent with prior myocardial infarction [MI] or possible MI), and LV hypertrophy. The presence of any major ECG finding doubled the mortality rate in patients with CD (hazard ratio [HR] 2.18, 95% CI 1.36-3.53) and the risk increased with the number of major ECG abnormalities.
●An ECG QRS score correlated with NYHA functional class and the extent of myocardial scar as detected by late gadolinium enhancement on cardiac magnetic resonance (CMR) imaging [67]. (See 'Prognostic value of cardiovascular magnetic resonance' below.)
●Some studies have found that patients with CD with normal ECGs had a similar risk of cardiovascular death when compared with sex- and age-matched individuals without CD [60,65,68-70].
Prognostic value of echocardiography — Presence of moderate or severe LV dysfunction [65] or LV aneurysm predict worse outcomes. A substudy of the BENEFIT trial, of 1508 patients with CCC followed for a mean of over 5.5 years, found that LV wall motion score index, indexed left atrial volume, and LVEF were independent predictors of both death and a composite endpoint (death, resuscitated cardiac arrest, insertion of a pacemaker or an ICD, sustained VT, cardiac transplantation, new HF, stroke, transient ischemic attack, or a systemic or pulmonary embolic event) in a multivariate analysis [71].
Prognostic value of cardiovascular magnetic resonance — The relationship between extent of myocardial fibrosis detected by CMR and prognosis is illustrated by the following studies:
●A prospective study of 140 patients (median age 57 years) with CCC found that 71.4 percent had fibrosis identified by CMR, with lateral, inferolateral, and inferior walls most commonly affected [72]. At a median of 34 months of follow-up, there were 11 cardiovascular deaths, three episodes of sustained VT, and 20 cardiovascular hospitalizations. Patients with evidence of fibrosis had significantly higher rates of both the primary endpoint (composite of cardiovascular death and sustained VT) and the secondary endpoint (composite of cardiovascular death, sustained VT, or cardiovascular hospitalization) compared to patients without fibrosis. On multivariate analysis, myocardial fibrosis area (HR 1.06, 95% CI 1.01-1.12) and older age were independent predictors of the primary endpoint; older age and lower LVEF were independent predictors of the secondary endpoint.
●A retrospective study of 130 patients with CCC (mean age 54) found that 44.6 percent reached the primary outcome (a composite of all-cause mortality, heart transplantation, antitachycardia pacing or appropriate shock from an ICD, and aborted SCD) and 34.6 percent of patients died at median follow-up of 5.05 years [73]. Myocardial fibrosis as a continuous variable was an independent predictor of the primary outcome (HR 1.03; 95% CI 1.01 -1.05) and mortality (1.03; 95% CI 1.01-1.05). In addition, myocardial fibrosis of ≥12.3 grams was a predictor of the primary outcome (adjusted HR 1.943; 95% CI 1.053-3.587) independently from the Rassi risk score.
Prognostic value of EP testing — The prognostic value of electrophysiologic (EP) testing in patients with CCC has not been established. The available limited data suggest that EP testing does not have prognostic utility in patients with CCC with preserved LV function with NSVT or no spontaneous arrhythmia. In one study, including 72 patients with CD and preserved LV function and 400 to 1200 ventricular extrasystoles per hour, programmed stimulation did not induce sustained VT in any of the patients; 35 percent had NSVT on Holter monitoring [74]. During an average follow-up of 36 months, only 1 of the 72 patients had spontaneous sustained VT.
Some have proposed a potential role for EP testing for evaluation of patients with CCC who are survivors of sudden cardiac arrest (SCA) or have sustained VT to determine prognosis and to select an appropriate device and antiarrhythmic therapy [74-76], but limited data are available on the efficacy of such an approach. An observational study included 115 patients with CCC presenting with symptomatic VT [76]. Patients were divided into three groups based upon their responses to electrophysiology testing after loading with a Class III antiarrhythmic drug (sotalol or amiodarone). Patients in group one had no induced sustained VT, those in group two had inducible tolerated sustained VT, and those in group three had inducible hemodynamically unstable VT. After a mean follow-up of 52 months, the mortality rate was significantly higher in group three as compared to groups one and two (69 versus 26 and 22 percent).
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Arrhythmias in adults" and "Society guideline links: Heart failure in adults" and "Society guideline links: Chagas disease".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topic (see "Patient education: Chagas disease (The Basics)")
SUMMARY AND RECOMMENDATIONS
●Management – Management of patients with chronic Chagas cardiomyopathy (CCC) includes monitoring for progression, selective use of antitrypanosomal therapy and supportive care of cardiovascular complications including heart failure (HF), arrhythmia, and thromboembolism. (See 'Management' above.)
●Heart failure – HF due to CCC is generally treated as HF due to other causes except for some specific caveats including watching for marked bradycardia with beta blocker use, particularly with concurrent amiodarone therapy. (See 'Heart failure' above.)
●Antitrypanosomal therapy
•Initial treatment of patients with stage A or B HF symptoms – For patients with American Heart Association/American College of Cardiology (AHA/ACC) stage A or B HF (table 1) and who have a Rassi score <7 points, we suggest antitrypanosomal therapy with benznidazole or nifurtimox (table 2) (Grade 2C). (See 'Antitrypanosomal therapy' above and 'Rassi score for predicting mortality' above.)
•Patients previously treated – For patients who were treated in the acute or indeterminate phase of disease with a complete course of benznidazole (ie, 60 days) or nifurtimox (ie, 90 days) but who have AHA/ACC stage B HF, we suggest treating with a full course of the alternative drug (ie, the drug not previously used) (table 2). If the initial course was incomplete, we suggest treating with a full course of the same drug used in the prior incomplete course. There is no need to reassess serology before repeating the trypanocidal treatment, since it typically takes decades for serology to become negative after treatment. (See 'Antitrypanosomal therapy' above.)
•Patients with advanced HF – Antitrypanosomal therapy is generally not prescribed to patients with advanced disease, as any clinical benefit is likely negligible and there is significant risk of adverse effects. (See 'Antitrypanosomal therapy' above and "Chagas disease: Chronic Trypanosoma cruzi infection".)
●Management of arrhythmias – Treatment of patients with CCC at risk for sudden cardiac death (SCD) is controversial. Although implantable cardioverter-defibrillator (ICD) therapy has been empirically used for primary and secondary prevention of SCD, there may be potential adverse effects of ICD therapy on pump function. (See 'Ventricular arrhythmia and SCA' above.)
Our approach to prevention of sudden cardiac arrest (SCA) and sustained ventricular tachycardia (VT) in patients with CCC is as follows:
•Secondary prevention of sudden cardiac death – In patients with CCC who survive an episode of SCA or have sustained VT, we recommend an ICD for secondary prevention of SCA. (See "Secondary prevention of sudden cardiac death in heart failure and cardiomyopathy" and 'ICD therapy' above.)
In patients with CCC who survive an episode of SCA or have sustained VT but who are not treated with ICDs, we typically treat with amiodarone and a beta blocker in addition to appropriate pharmacologic therapy for HFrEF (or for asymptomatic LV systolic dysfunction). In patients who have an ICD and a high density of spontaneous ventricular premature beats (eg, nonsustained VT, couplets), we typically treat with amiodarone and beta blocker therapy to reduce the risk of ICD shocks. (See 'ICD therapy' above and 'Antiarrhythmic therapy' above.)
•Primary prevention of sudden cardiac death – For primary prevention of SCA or sustained VT (see 'Our approach' above and 'Rassi score for predicting mortality' above):
-For patients with CCC with a left ventricular ejection fraction (LVEF) ≤35 percent, a Rassi score of ≥10, and a reasonable likelihood of survival of at least one year, ICD implantation is suggested (Grade 2C).
-For patients with CCC, LVEF >35 percent, a Rassi score of ≥10, and nonsustained VT on Holter, we suggest amiodarone with or without beta blocker therapy (Grade 2C).
●Management and prevention of thromboembolism
•LV thrombus or pulmonary thromboembolism – Patients with CCC who present with LV thrombus or symptoms or signs of systemic or pulmonic thromboembolism should receive the appropriate evaluation and management of these disorders. (See 'Thromboembolism treatment' above.)
•Embolism prophylaxis – For patients with CCC who do not have atrial fibrillation, we do not suggest routine prophylaxis for thromboembolism. For patients with CCC who have atrial fibrillation, we use the same guidelines and agents for thromboembolism prophylaxis that are used in the general population. (See "Atrial fibrillation in adults: Selection of candidates for anticoagulation", section on 'Approach to deciding whether to anticoagulate'.)
●Prognosis – In patients with CCC, LV dysfunction (commonly identified by LV dilation and/or LV systolic dysfunction) is the most consistent independent predictor of mortality rate. (See 'Prognosis' above.)
ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Marcus Simões, MD, Benedito C Maciel, MD, FACC, and Leonard I Ganz, MD, FHRS, FACC, who contributed to previous versions of this topic review.
آیا می خواهید مدیلیب را به صفحه اصلی خود اضافه کنید؟
