Randomized Trial of Benznidazole for Chronic Chagas' Cardiomyopathy.

Design: randomized, double-blind, multicenter, placebo-controlled trial at 49 centers in Argentina, Bolivia, Brazil, Colombia, and El Salvador; 2854 adults aged 18-75 with established chronic Chagas' cardiomyopathy; mean age 55 years; 97% NYHA class I-II; 50.7% male; mean left-ventricular ejection fraction about 55%; inclusion required two positive serologic tests for T. cruzi and cardiomyopathy; follow-up mean 5.4 years.

Benznidazole, oral; initial regimen: 5 mg/kg per day for 60 days; after February 2009, fixed dose of 300 mg per day with duration of 40-80 days depending on weight.

Benznidazole did not significantly reduce the primary composite clinical outcome over about 5 years (hazard ratio 0.93; 95% CI 0.81-1.07; P=0.31). Among baseline PCR-positive patients, conversion to negative at end of treatment occurred in 66.2% with benznidazole vs 33.5% with placebo; at 2 years 55.4% vs 35.3%; at 5 years or more 46.7% vs 33.1% (P<0.001 for all time points). However, PCR conversion did not translate into improved clinical outcomes (P=0.16 for interaction). Adverse events leading to drug interruption were higher with benznidazole (23.9% vs 9.5%); 13.4% discontinued; adherence 84% vs 94%. Authors conclude that parasite clearance was reduced but cardiac clinical deterioration was not significantly slowed in established Chagas' cardiomyopathy; early treatment remains recommended and more research on genotype effects or longer/alternative regimens is warranted.

Geographic heterogeneity in PCR response and lack of parasite-genotype data; power may be insufficient to detect small treatment effects; higher adverse events and drug discontinuations with benznidazole; adherence lower in the benznidazole group; multiple prespecified subgroup analyses raise risk of spurious findings; findings apply to established Chagas' cardiomyopathy and may not generalize to earlier disease stages.