Randomized Trial of Benznidazole for Chronic Chagas' Cardiomyopathy
Carlos A Morillo, Jose Antonio Marin-Neto, Alvaro Avezum, Sergio Sosa-Estani, Anis Rassi Jr, Fernando Rosas, Erick Villena, Roberto Quiroz, Rina Bonilla, Constança Britto, Felipe Guhl, Elsa Velazquez, Laura Bonilla, Brandi Meeks, Purnima Rao-Melacini, Janice Pogue, Antonio Mattos, Janis Lazdins, Anis Rassi, Stuart J Connolly, Salim Yusuf, BENEFIT Investigators, R E Carrizo Paez, M A Carrizo Paez, S G Corzo Lujan, L Mercado, C A Cuneo, C Hasner, N C Gutierrez, T E Smith, J Bonacina, B Jauregui, C Heredia, M del C Bangher, M Romero, R Pantich, W Garcia, M H Mallagray, J S Beloscar, J M Petrucci, K A Ramos, L Scaglione, G B Perez Prados, E G Gayet, P Y Epstein, F A Silva Nieto, C M Fink, A Ferreira, E Oshiro, E Carlucci, M G Leguizamón, H D Mujica, R E Manzur, P Yacheline, O A Reyes, C D Ariel, S C Lloveras, T A Orduna, M P Bernachea, L Di Paola, R J Fernandez, M L Moran, M A Auteri, G Mazo, L A Gomez, J Bonacina, V Volerg, E W Villena Fiengo, J Solis Ortiz, M Roman Arequipa, M Cervantes Mendoza, A Schmidt, H T Moreira, M Tonani, A C Silva, A Carraro, M Romano, B C Maciel, M E Hernandes, N A Lucas, R C Amorim, C A Misson Ferreira Filho, R Aras, U Silveira, S C Camaras, A S Sousa, R M Saraiva, A Rassi Jr, A Rassi, L E M da Silva, T Silva Jr, J Ferreira Silva, B Fatima Ferreira, A M Lorga, A M Lorga Filho, E Palmegiani, C S Queirantes, W Alves de Oliveira Jr, M G Aureliano deMelo, V M Barros de Lorena, S Marinho Martins, A O Luquetti, D E Campos, L A B de Sa, S B N Tavares, A Fragata Filho, A M Lourenco, C de CastroFaccini, L V Armaganijan, D A R Moreira, R Coury Pedrosa, R M Torres, S M Eloi Santos, E Dias Gontijo, G Soares Feitosa, J Alves Pinho Filho, J F KerrSaraiva, M K Costa, L Nigro Maia, M A Lemos, N Goes, M Arruda Nakazone, A R Prata, D Correia, R J Molina, L F Avezum Oliveira, A L D Santos Augusto, C Mady, C L P Cunha, M I Miyazaki, A A Steffens, A C Alves de Souza, A Rassi Jr, C J de C Bastos, F R Quiroz, C H Tibaduiza, M L Florez Archila, O L Ortiz, S Navarrete, L J Rincón, J G Pérez, L C Saenz, F A Rosas, F R Betancourt, R Onate, R Figueroa de Bonilla, R Bonilla, V Rodriguez, Carlos A Morillo, Jose Antonio Marin-Neto, Alvaro Avezum, Sergio Sosa-Estani, Anis Rassi Jr, Fernando Rosas, Erick Villena, Roberto Quiroz, Rina Bonilla, Constança Britto, Felipe Guhl, Elsa Velazquez, Laura Bonilla, Brandi Meeks, Purnima Rao-Melacini, Janice Pogue, Antonio Mattos, Janis Lazdins, Anis Rassi, Stuart J Connolly, Salim Yusuf, BENEFIT Investigators, R E Carrizo Paez, M A Carrizo Paez, S G Corzo Lujan, L Mercado, C A Cuneo, C Hasner, N C Gutierrez, T E Smith, J Bonacina, B Jauregui, C Heredia, M del C Bangher, M Romero, R Pantich, W Garcia, M H Mallagray, J S Beloscar, J M Petrucci, K A Ramos, L Scaglione, G B Perez Prados, E G Gayet, P Y Epstein, F A Silva Nieto, C M Fink, A Ferreira, E Oshiro, E Carlucci, M G Leguizamón, H D Mujica, R E Manzur, P Yacheline, O A Reyes, C D Ariel, S C Lloveras, T A Orduna, M P Bernachea, L Di Paola, R J Fernandez, M L Moran, M A Auteri, G Mazo, L A Gomez, J Bonacina, V Volerg, E W Villena Fiengo, J Solis Ortiz, M Roman Arequipa, M Cervantes Mendoza, A Schmidt, H T Moreira, M Tonani, A C Silva, A Carraro, M Romano, B C Maciel, M E Hernandes, N A Lucas, R C Amorim, C A Misson Ferreira Filho, R Aras, U Silveira, S C Camaras, A S Sousa, R M Saraiva, A Rassi Jr, A Rassi, L E M da Silva, T Silva Jr, J Ferreira Silva, B Fatima Ferreira, A M Lorga, A M Lorga Filho, E Palmegiani, C S Queirantes, W Alves de Oliveira Jr, M G Aureliano deMelo, V M Barros de Lorena, S Marinho Martins, A O Luquetti, D E Campos, L A B de Sa, S B N Tavares, A Fragata Filho, A M Lourenco, C de CastroFaccini, L V Armaganijan, D A R Moreira, R Coury Pedrosa, R M Torres, S M Eloi Santos, E Dias Gontijo, G Soares Feitosa, J Alves Pinho Filho, J F KerrSaraiva, M K Costa, L Nigro Maia, M A Lemos, N Goes, M Arruda Nakazone, A R Prata, D Correia, R J Molina, L F Avezum Oliveira, A L D Santos Augusto, C Mady, C L P Cunha, M I Miyazaki, A A Steffens, A C Alves de Souza, A Rassi Jr, C J de C Bastos, F R Quiroz, C H Tibaduiza, M L Florez Archila, O L Ortiz, S Navarrete, L J Rincón, J G Pérez, L C Saenz, F A Rosas, F R Betancourt, R Onate, R Figueroa de Bonilla, R Bonilla, V Rodriguez
Abstract
Background: The role of trypanocidal therapy in patients with established Chagas' cardiomyopathy is unproven.
Methods: We conducted a prospective, multicenter, randomized study involving 2854 patients with Chagas' cardiomyopathy who received benznidazole or placebo for up to 80 days and were followed for a mean of 5.4 years. The primary outcome in the time-to-event analysis was the first event of any of the components of the composite outcome of death, resuscitated cardiac arrest, sustained ventricular tachycardia, insertion of a pacemaker or implantable cardioverter-defibrillator, cardiac transplantation, new heart failure, stroke, or other thromboembolic event.
Results: The primary outcome occurred in 394 patients (27.5%) in the benznidazole group and in 414 (29.1%) in the placebo group (hazard ratio, 0.93; 95% confidence interval [CI], 0.81 to 1.07; P=0.31). At baseline, a polymerase-chain-reaction (PCR) assay was performed on blood samples obtained from 1896 patients; 60.5% had positive results for Trypanosoma cruzi on PCR. The rates of conversion to negative PCR results (PCR conversion) were 66.2% in the benznidazole group and 33.5% in the placebo group at the end of treatment, 55.4% and 35.3%, respectively, at 2 years, and 46.7% and 33.1%, respectively, at 5 years or more (P<0.001 for all comparisons). The effect of treatment on PCR conversion varied according to geographic region: in Brazil, the odds ratio for PCR conversion was 3.03 (95% CI, 2.12 to 4.34) at 2 years and 1.87 (95% CI, 1.33 to 2.63) at 5 or more years; in Colombia and El Salvador, the odds ratio was 1.33 (95% CI, 0.90 to 1.98) at 2 years and 0.96 (95% CI, 0.63 to 1.45) at 5 or more years; and in Argentina and Bolivia, the odds ratio was 2.63 (95% CI, 1.89 to 3.66) at 2 years and 2.79 (95% CI, 1.99 to 3.92) at 5 or more years (P<0.001 for interaction). However, the rates of PCR conversion did not correspond to effects on clinical outcome (P=0.16 for interaction).
Conclusions: Trypanocidal therapy with benznidazole in patients with established Chagas' cardiomyopathy significantly reduced serum parasite detection but did not significantly reduce cardiac clinical deterioration through 5 years of follow-up. (Funded by the Population Health Research Institute and others; ClinicalTrials.gov number, NCT00123916; Current Controlled Trials number, ISRCTN13967269.).
Source: PubMed