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Medwave 2015;15(Suppl 2):e6291 doi: 10.5867/medwave.2015.6291

�Debe indicarse terapia antitripanos�mica a pacientes con enfermedad de Chagas en fase cr�nica?

Should trypanocidal therapy be used to treat patients in the chronic phase of Chagas disease?

Federico Popoff, Ariel Izcovich

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Abstract

Antiparasitic treatment of patients with Chagas� disease in chronic stage could prevent the complications related to the disease. Searching in Epistemonikos database, which is maintained by screening 30 databases, we identified five systematic reviews including eight randomized trials and 11 observational studies. We combined the evidence using meta-analysis and generated a summary of findings table following the GRADE approach. We concluded it is not clear whether antiparasitic treatment improves survival or reduces complications related to chronic Chagas� disease because the certainty of the evidence is very low.

Problem

Chagas' disease represents the third largest parasitic disease burden globally and the first in Latin America [1]. Chronic Chagas' cardiomyopathy is the most common form of non-ischemic cardiomyopathy worldwide, and one of the leading causes of morbidity and death in Latin America [2]. Chagas' disease has two clinical phases, acute infection that may be manifested by a self-limited febrile illness that lasts 4 to 8 weeks, and chronic phase characterized by an indeterminate stage in which patients are asymptomatic and free of complications that can last their whole life [3]. Ten to thirty years after the acute infection, about one third of the patients in chronic phase of Chagas’ disease develop cardiac or digestive complications. At the present time, the mechanism responsible for the mentioned complications is believed to be related to the presence of chronic parasitemia and its corresponding inflammatory reaction [4]. In this context, antiparasitic treatment for patients with Chagas’ disease in the chronic phase is proposed as a measure to prevent the disease’s visceral complications and their consequences.

Methods

We used Epistemonikos database, which is maintained by screening more than 30 databases, to identify systematic reviews and their included primary studies. With this information, we generated a structured summary using a pre-established format, which includes key messages, a summary of the body of evidence (presented as an evidence matrix in Epistemonikos), meta-analysis of the total of studies, a summary of findings table following the GRADE approach and a table of other considerations for decision-making.

Key messages

Trypanocidal therapy probably does not improve survival nor reduces cardiomyopathy progression in patients with chronic Chagas’ heart disease.
Trypanocidal therapy probably reduces the risk of congenital transmission in young women with chronic Chagas’ disease.
It is not clear whether antiparasitic treatment improves survival or reduces complications related to chronic Chagas’ disease in patients with early stages of chronic Chagas’ disease (no visceral involvement) because the certainty of the evidence in this scenario is very low.
Antiparasitic treatment probably increases the risk of adverse effects that leads to treatment discontinuation

About the body of evidence for this question

What is the evidence. See evidence matrix in Epistemonikos later	We found five systematic reviews [5],[6],[7],[8],[9] considering 19 primary studies [10],[11],[12],[13], [14],[15],[16],[17],[18],[19],[20],[21],[22],[23],[24], [25],[26],[27],[28], including eight randomized controlled trials [10],[11],[12],[13],[15],[18],[21],[26], and 11 observational studies. We also identified two recently published primary studies (one randomized [29] and one observational [30]), not included in any systematic review.
What types of patients were included	Patients with Chagas’ disease in chronic phase indeterminate stage or chronic phase with visceral compromise.
What types of interventions were included	Benznidazole, nifurtimox, allopurinol or itraconazole for 30 to 60 days.
What types of outcomes were measured	Death from any cause; cardiac disease progression; congenital transmission; electrocardiographic abnormalities; serological tests negativization; xenodiagnosis negativization; polymerase chain reaction negativization; adverse effects leading to treatment discontinuation

Summary of findings

The information about the antiparasitic effects is based on eight randomized controlled trials and eleven observational studies that included 7772 patients. Eight studies (one randomized and seven observational studies) reported death from any cause, six studies (one randomized and five observational studies) reported cardiac disease progression, one observational study reported congenital transmission, eleven studies (six randomized and five observational studies) reported adverse effects that lead to treatment discontinuation, four studies (three randomized and one observational study) reported electrocardiographic abnormalities, ten studies (three randomized and seven observational studies) reported serological tests negativization, four studies (two randomized and two observational studies) reported polymerase chain reaction negativization and seven studies (four randomized and three observational studies) reported xenodiagnosis negativization.

Benznidazole therapy probably does not improve survival in patients with chronic Chagas’ heart disease. It is no clear whether other antiparasitic drugs affect survival or cardiomyopathy progression because the certainty of the evidence is very low.
Benznidazole therapy probably does not reduce cardiomyopathy progression in patients with chronic Chagas’ heart disease. It is no clear whether other antiparasitic drugs affect cardiomyopathy progression because the certainty of the evidence is very low.
Trypanocidal therapy probably reduces the risk of congenital transmission in young women with chronic Chagas’ disease. The certainty of the evidence is moderate.
It is not clear whether antiparasitic treatment improves survival or reduces complications related to chronic Chagas’ disease in patients with early stages of chronic Chagas’ disease (no visceral involvement) because the certainty of the evidence in this scenario is very low.
Antiparasitic treatment probably increases the risk of adverse effects that leads to treatment discontinuation. The certainty of the evidence is moderate.

Other considerations for decision-making

To whom this evidence does and does not apply

The evidence applies to patients with Chagas’ disease in chronic phase.
The evidence does not apply to patients with Chagas’ disease in acute phase, early congenital Chagas’ disease or reactivated Chagas’ disease.

About the outcomes included in this summary

Two of the efficacy outcomes that we considered as critical (survival and viceral compromise) were reported by only one randomized controlled trial [29] that informed absence of significant benefits. However that study included patients with Chagas’ disease in chronic phase with confirmed cardiac compromise and the results are not directly aplicable to patients at early stage (no visceral compromise). The latter subgroup of patients was only included in observational studies with inconsistent results (very low certainty evidence) [14],[17],[20],[24],[27].
One observational study [30] compared the incidence of congenital Chagas’ disease in newborns of women with chronic Chagas’ disease that had received and not received antiparasitic treatment. The results showed a considerable reduction in congenital infections.
Most of the efficacy outcomes reported in the randomized controlled trials were surrogate, their results suggest antiparasitic treatment with benznidazole, nifurtimox or allopurinol probably reduces the chance of xenodiagnosis positivity (308 less per 1000; 95% CI 56 to 390 less, [MODERATE certainty]. Treatment with benznidazole also probably reduces the chance of polimerase chain reaction positivity (152 less per 1000; 95% CI 93 less to 178 less, [MODERATE certainty]).

Balance between benefits and risks, and certainty of the evidence

The absence of benefits in terms of survival or cardiac disease progression in patients with confirmed viceral compromise (MODERATE certainty) determines that the risks (increase in morbidity related to adverse effects, MODERATE certainty) predominate in the trade-off analysis.
In patients with early stage chronic Chagas’ disease (no visceral compromise) it is not clear if antiparasitic treatment affects clinically important outcomes (observational studies with inconsistent results or indirect evidence from surrogate outcomes).
In young women with Chronic Chagas’ disease antiparasitic treatment probably reduces the risk of congenital transmission (MODERATE certainty) hence the trade-off analysis favors benefits over risks.

What would patients and their doctors think about this intervention

Considering the existing uncertainty related to the efficacy of antiparastic treatment we assume that significant variability in patients values and preferences could exist. Although we consider that the majority would choose no to be exposed to an intervention related to significant adverse effects whose benefits have not been proved, some could put more weight in the possibility of obtaining those benefits and choose the opposite.

Resource considerations

In the context of an intervention whose benefits are dubious, costs could be relevant in reaching a decision.

Differences between this summary and other sources

The conclusions of the present analysis are consistent with the conclusions of most published systematic reviews [5],[6],[7],[8] but are discordant with one of them in which the authors recommend antiparasitic treatment for most Trypanosoma cruzi infected patients [9].
Our conclusions are partially discordant with the main clinical practice guidelines which recommend to consider antiparasitic treatment for children or young adults with Chagas’ disease in chronic phase [32],[33],[34].

Could this evidence change in the future?

The probability that future evidence significantly modifies the information presented in the present summary is high because of the uncertainty that exists in relation to the main outcomes in the subgroup of patients with early stage Chronic Chagas´ disease (no visceral compromise).

How we conducted this summary

Using automated and collaborative means, we compiled all the relevant evidence for the question of interest and we present it as a matrix of evidence.

Follow the link to access the interactive version: Trypanocidal therapy to prevent chagasic cardiomyopathy

Notes

The upper portion of the matrix of evidence will display a warning of “new evidence” if new systematic reviews are published after the publication of this summary. Even though the project considers the periodical update of these summaries, users are invited to comment in Medwave or to contact the authors through email if they find new evidence and the summary should be updated earlier. After creating an account in Epistemonikos, users will be able to save the matrixes and to receive automated notifications any time new evidence potentially relevant for the question appears.

The details about the methods used to produce these summaries are described here http://dx.doi.org/10.5867/medwave.2014.06.5997.

Epistemonikos foundation is a non-for-profit organization aiming to bring information closer to health decision-makers with technology. Its main development is Epistemonikos database (www.epistemonikos.org).

These summaries follow a rigorous process of internal peer review.

Conflicts of interest
The authors do not have relevant interests to declare.

Licencia Creative Commons

Esta obra de Medwave est� bajo una licencia Creative Commons Atribuci�n-NoComercial 3.0 Unported. Esta licencia permite el uso, distribuci�n y reproducci�n del art�culo en cualquier medio, siempre y cuando se otorgue el cr�dito correspondiente al autor del art�culo y al medio en que se publica, en este caso, Medwave.

Edici�n Julio 2022

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