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Long-Term Cardiac Outcomes of Treating Chronic Chagas Disease with Benznidazole versus No Treatment: A Nonrandomized Trial

Rodolfo Viotti, MD; Carlos Vigliano, MD; Bruno Lococo, MD; Graciela Bertocchi, MD; Marcos Petti, MD; María Gabriela Alvarez, MD; Miriam Postan, MD, PhD; and Alejandro Armenti, MD
[+] Article and Author Information

From Hospital Interzonal General de Agudos Eva Perón and Instituto Nacional de Parasitología Dr. Mario Fatala Chaben, Buenos Aires, Argentina.


Acknowledgments: The authors thank the directors at Hospital Eva Perón for providing a suitable setting for this research. Dr. Postan is a fellow of CONICET, Argentina.

Grant Support: None.

Potential Financial Conflicts of Interest: None disclosed.

Requests for Single Reprints: Rodolfo Viotti, MD, José Hernández 3440, Villa Ballester, Gral. San Martín, Buenos Aires ZC 1653, Argentina; e-mail, peron@millicom.com.ar.

Current Author Addresses: Dr. Viotti: José Hernández 3440, Villa Ballester, Gral. San Martín, Buenos Aires ZC 1653, Argentina.

Drs. Vigliano, Lococo, Bertocchi, Petti, Alvarez, and Armenti: Avenue Ricardo Balbin 900, San Martín, Buenos Aires ZC 1650, Argentina.

Dr. Postan: Avenue Paseo Colón 568, Buenos Aires ZC 1063, Argentina.

Author Contributions: Conception and design: R. Viotti, C. Vigliano, A. Armenti.

Analysis and interpretation of the data: R. Viotti, C. Vigliano, M. Petti, A. Armenti.

Drafting of the article: R. Viotti, C. Vigliano, G. Bertocchi, M. Postan.

Critical revision of the article for important intellectual content: B. Lococo, G. Bertocchi, M. Petti, M.G. Alvarez, M. Postan, A. Armenti.

Final approval of the article: R. Viotti, C. Vigliano, B. Lococo, G. Bertocchi, M. Petti, M. Postan, A. Armenti.

Provision of study materials or patients: R. Viotti, C. Vigliano, B. Lococo, M. Petti, M.G. Alvarez.

Statistical expertise: R. Viotti.

Administrative, technical, or logistic support: B. Lococo, G. Bertocchi, M.G. Alvarez, M. Postan.

Collection and assembly of data: R. Viotti, C. Vigliano, B. Lococo, G. Bertocchi, M. Petti, M.G. Alvarez, M. Postan.


Ann Intern Med. 2006;144(10):724-734. doi:10.7326/0003-4819-144-10-200605160-00006
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A flow diagram describing the phases of screening, enrollment, assignment, and follow-up of the participants is shown in Figure 1. The baseline characteristics of the 566 study participants (283 treated patients and 283 untreated patients) are summarized in Table 1. Median time to follow-up was 9.8 years (interquartile range, 5.24 to 14.2 years).

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Figures

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Figure 1.
Flow diagram of the screening process, reasons for nonenrollment, and follow-up.
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Figure 2.
Kaplan–Meier curves of cumulative percentage of patients who changed clinical group.
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Tables

References

Letters

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Comments

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Benznidazole in chronic Chagas disease: hype or hope?
Posted on June 4, 2006
Anis Rassi Jr.
Anis Rassi Hospital
Conflict of Interest: None Declared

We congratulate Viotti and colleagues (1) for presenting their nonrandomized experience with benznidazole for the treatment of patients with chronic Chagas disease. Although the 60-day period of treatment recommended by PAHO/WHO (2) was not used, 30-days of treatment with benznidazole (5 mg/kg/day) was associated with reduced progression of heart disease and increased negative seroconversion. Of note, the benefit seemed to be even greater in patients with cardiac lesions (Kuschnir groups I and II) when compared to those without apparent cardiac disease (Kuschnir group 0). Other important findings should be pointed out. First, the incidence of serious side effects requiring discontinuation of the drug was acceptable (13%). Second, none of the patients who achieved seroconversion changed clinical group during follow-up. Third, as shown previously by others (3), patients without cardiac lesion (Kuschnir group 0) had an excellent prognosis, with 100% survival after approximately 10 years of follow-up.

On the other hand, some issues merit further discussion: 1) Chagas disease has 2 phases only: acute and chronic, with the chronic phase being divided into 2 forms, indeterminate and determinate or clinical. Patients in the indeterminate form belong to the chronic phase of the disease and the term "indeterminate phase" should be avoided; 2) Kuschnir group 0 patients should not be viewed as patients in the indeterminate form. The definition of indeterminate form requires the documentation of a normal radiologic evaluation of esophagus and colon; 3) as Viotti and colleagues also documented in their study, sudden death and not heart failure is the principal mechanism of death in nonselected patients with Chagas disease (4); and 4) a word of caution should be placed when interpreting spontaneous negative seroconversion in a single point in time as demonstration of spontaneous cure. In our opinion, spontaneous cure in patients with chronic Chagas disease is extraordinarily rare, contrasting with the 6% rate observed in the present study. Last and more importantly, we agree with the investigators that a multicenter, randomized, controlled trial enrolling patients who already manifest cardiac alterations is urgently needed. Fortunately such a trial is underway.

References

1. Viotti R, Vigliano C, Lococo B, Bertocchi G, Petti M, Alvarez MG, et al. Long-term cardiac outcomes of treating chronic Chagas disease with benznidazole versus no treatment: a nonrandomized trial. Ann Intern Med. 2006;144:724-34.

2. OPAS/OMS. Tratamiento etiológico de la enfermedad de Chagas. Conclusiones de una consulta técnica. OPS/HCP/HCT/140/99, 1998, 32 pp (published in Rev Patol Trop 1999;28:247-79).

3. Ianni BM, Arteaga E, Frimm CC, Pereira Barretto AC, Mady C. Chagas' heart disease: evolutive evaluation of electrocardiographic and echocardiographic parameters in patients with the indeterminate form. Arq Bras Cardiol 2001;77:59-62.

4. Rassi A Jr, Rassi SG, Rassi A. Sudden death in Chagas' disease. Arq Bras Cardiol 2001;76:75-96.

Conflict of Interest:

None declared

Etiological treatment in chronic Chagas disease: hope or reality ?
Posted on June 19, 2006
Rodolfo J Viotti
Hospital Eva Perón, Buenos Aires, Argentina
Conflict of Interest: None Declared

-We appreciate your considerations about our paper recently published. -The investigation started some years previous to the recommendations by PAHO/WHO. On the other hand, the 30-day period of treatment used is supported by the studies of Dr. Cerisola in Argentina (2, 3), who showed that benznidazole for periods more than 30 days did not increase the efficacy in the reduction of the parasitemia, evaluated with consecutive xenodiagnosis tests. This treatment has been used since 1978 and it can be associated with a reduced rate of side effects, as you observed in our study. -The benefit of the treatment to prevent a progression in patients with previous heart disease appears to be logical if we have in mind that Chagas disease induce a chronic active myocarditis and the etiological agent has an important role on the pathogenesis of cardiac lesions. -With regard to the issues that merit further discussion: 1) According to our perspective, the patients in the indeterminate phase do not present cardiac manifestations if we evaluate heart disease with the more common studies, but they can present abnormalities when the studies are more profound. For these reasons, the Kuschnir classification used in the study does not distinguish between indeterminate and chronic phases. 2) We agree with you as regards the gastrointestinal lesions but the low rate in our country (the rate is larger in Brazil) does not justify the systematic search for all patients in our population. 3) The patients with heart failure were excluded and this explains the higher incidence of sudden death in the total causes of death. 4) Chagas disease is not an exception with respect to other chronic infectious diseases. The incidence of spontaneous cure may be the consequence of a long-term follow-up, the urban Chagas disease condition and the differences of virulence of Trypanosome cruzi. In our previous study, published in 1994, we observed a similar percentage of spontaneous negative seroconversion. The antibody titles frequently vary up and down the cut-off (lower titles). Nevertheless, the clinical significance of this finding is very important for the prognosis of these patients.

References

1. Cerisola J, Rohwedder R, Segura E, Del Prado C, Alvarez M, De Martini G. El xenodiagnóstico, normatización-utilidad. In: Premio Ciba Geigy. Ministerio de Bienestar Social, Buenos Aires, 1974.

2. Cerisola J. Results of the anti-trypanosome activity of benznidazole in chronic Chagas infection. X International Congress of Chemotherapy, Zurich, 1977.

Conflict of Interest:

None declared

The etiologic treatment of patients with chronic Chagas disease
Posted on July 12, 2006
Reinaldo B. Bestetti
Faculty of Medicine of São José do Rio Preto
Conflict of Interest: None Declared

TO THE EDITOR: We have read with great interest the article by Viotti et al. (1) in which the potential benefit of benznidazol to halt disease progression in a hospital-derived cohort of patients with chronic Chagas´ disease is presented. First of all, we must congratulate Viotti et al. (1) for performing a prospective study on 566 Chagas´ disease patients in a single center in Latin America, which is undoubtly a colossal work. Nevertheless, because this article may lead physicians working in areas where Chagas' disease is endemic to treat patients with this condition, we would like to make some comments on this article: 1) Viotti et al. (1) have assessed disease progression by either 12-lead electrocardiogram or chest X-Ray. The latter method has clearly been demonstrated not to be adequate to detect cardiac disease in patients with Chagas' disease (2), whereas electrocardiographic abnormalities have no power to predict all- cause mortality when analysed jointly with echocardiography (3). Certainly, it would be better to assess disease progression with Dopplerechocardiography, which might show segmental wall motion abnormalities, the most important predictor of disease progression in patients in the indeterminate phase of Chagas' disease. Nevertheless, echocardiography was performed only on patients found to have Chest X ray abnormalities. Thus, this detection bias, and not the population size studied as Viotti et al. claimed (1), might account for the discrepancy between the data obtained by Viotti et al. (1) and those reported by Lauria Pires et al. (4), which showed no difference regarding disease progression between benznidazol-treated and benznidazol not treated- patients. In this regard, it is important to emphasize that left ventricular ejection fraction and left ventricular diastolic dimension as detected by echocardiography were the powerful predictors of mortality and disease progression in the work by Viotti et al. (1); 2) Another important point is related to the fact that Viotti et al. (1) excluded patients over 50 years of age from the study. We have to bear in mind that patients at the fifth and sixth decades of life have increasingly been detected in hospital-derived cohorts of patients with Chagas´ disease (3). Thus, until which point the data reported by Viotti et al. (1) can be extrapolated for a general, unselected population of Chagas´ disease patients is unclear; 3) benznidazol has been associated with cancer in experimental models of Chagas´ disease and perhaps in immunosuppressive Chagas´ disease patients following heart transplantation (5). Therefore, it would be of utmost importance to know if cancer might have causally been related to about 20% patients lost to follow up in that study. Finally, the authors claimed that a double-blinded, placebo-controlled trial should be performed to assess the role of benznidazol in the treatment of patients with chronic Chagas´ disease. On the basis of the facts outlined above, we are not convinced about this need.

References 1. Viotti R, Vigliano C, Lococo B, Bertocchi G, Petti M, Alvarez G et al. long-term cardiac outcomes of treating cchronic Chagas disease with benznidazole versus no treatment. Ann Int Med 2006; 144: 724-34. 2. Perez AA, Ribeiro AL, Barros MV, de Souza MR, Bittencourt RJ, Machado FS, Rocha M0. Value of the radiological study of the thorax for diagnosing left ventricular dysfunction in Chagas´ disease. Arq Bras Cardiol 2003; 80: 208-13. 3. Bestetti RB, Dalbo CM, Freitas OC, Teno LAC, Castilho OT, Oliveira JSM. Noninvasive predictors of mortality for patients with Chagas´ heart disease: a multivariate stepwise logistic regression analysis. Cardiology 1994; 84: 261-7. 4. Lauria-Pires L, Braga MS, Vexenat AL, Nitz N, Simões-Barbosa A, Tinoco Jl et al. Progressive chronic Chagas´ heart disease ten years after treatment with anti-Trypanosoma cruzi nitroderivatives. Am J trop Med 2000; 63: 111-8. 5. Bocchi EA, Higushi ML, Vieira Ml, Stolf N, Bellotti G, Fiorelli A, Uip D, Jatene A, Pileggi F. High incidence of malignant neoplasm after heart transplantation for treatment of chronic Chagas´ heart disease. J Heart Lung Transplant 1998; 17: 399-405.

Conflict of Interest:

None declared

Re: The etiologic treatment of patients with chronic Chagas disease
Posted on July 24, 2006
Rodolfo J Viotti
Hospital Eva Perón
Conflict of Interest: None Declared

TO THE EDITOR: Benznidazole treatment for chronic chagasic patients is included in the guidelines of the Public Health of Argentina, Brazil and Chile among other countries. -We presented many references in our study (1) that show the change of thought about the role of the parasite in Chagas disease, as well as clinical evidence of benefit with the use of benznidazole or other drugs with anti-T cruzi effects. Only one paper shows the argument against the etiological treatment. However, this study had a small number of patients that is inadequate to find any difference between the groups in study. -Regarding the comments on our article: 1)the use of ECG and chest X-ray is historical in all heart diseases. The left anterior fascicular block and other conduction abnormalities were described for the first time by Dr Rosembaum in chronic chagasic patients. There are more accurate measurements like echocardiography, but the ECG and chest X-ray have a low -cost and proved correlation with pathologic and echocardiographic findings and should not be disqualified. A very good correlation of Kuschnir classification (ECG and chest X-ray) and echocardiography has been published (2), and the power of ECG abnormalities analyzed jointly with echocardiography to predict Chagas disease progression has been recently showed (3). -The benefit of Benznidazole treatment to reduce Chagas disease progression was maintained when it was adjusted for left ventricular ejection fraction, left ventricular diastolic dimension and other variables (included an unknown variable). Segmental wall motion abnormalities did not show predictive value for Chagas disease progression in our previous studies that included clinic, electrocardiographic and echocardiographic variables (2, 3). Also, Dr Bestetti published a case of complete A-V block in a patient with chronic Chagas disease and heart transplant, with reactivation of the disease and nests of T. cruzi in endomyocardial biopsy, who not received etiological treatment. -2)Patients over 50 years were excluded "to avoid misinterpretation of electrocardiographic changes" and constitute a more rigorous form to analyze the results. Several electrocardiographic abnormalities like left anterior fascicular block, atrial fibrillation, A-V blocks and other are more frequent in elderly patients. -3)We have had experience in benznidazole treatment since 1978 with 1031 treated patients and have neither observed any evidence of cancer associated nor has there been clinical evidence published of cancer related to benznidazole. The percentage of patients lost to follow-up in the study was similar for treated and untreated patients and is unlikely that only treated patients have presented cancer. -To conclude, two randomized trials are in development in Latin America and the results will be available in the near future.

References

1-Viotti R, Vigliano C, Lococo B, Bertocchi G, Petti M, Alvarez MG et al. Long-term Cardiac Outcomes of Treating Chronic Chgas Disease with Benznidazole versus No Treatment. A Nonrandomized Trial. Ann Intern Med 2006;144:724-34.

2-Viotti R, Vigliano C, Laucella S, Lococo B, Petti M, Bertocchi G, et al. Value of echocardiography for diagnosis and prognosis of chronic Chagas disease cardiomyopathy without heart failure. Heart 2004;90:655-60.

3-Viotti R, Vigliano C, Lococo B, Petti, M, Bertocchi G, Alvarez MG, Armenti A. Clinical predictors of chronic chagasic myocarditis progression. Rev Esp Cardiol 2005;58:1037-44.

Conflict of Interest:

None declared

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Summary for Patients

Long-Term Outcomes of Treating Nonacute Chagas Disease with Benznidazole

The summary below is from the full report titled “Long-Term Cardiac Outcomes of Treating Chronic Chagas Disease with Benznidazole versus No Treatment. A Nonrandomized Trial.” It is in the 16 May 2006 issue of Annals of Internal Medicine (volume 144, pages 724-734). The authors are R. Viotti, C. Vigliano, B. Lococo, G. Bertocchi, M. Petti, M.G. Alvarez, M. Postan, and A. Armenti.

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