Randomized Trial of Benznidazole for Chronic Chagas Cardiomyopathy

Susan Kellum, Mercer University College of Pharmacy

Chagas disease is a chronic, systemic, parasitic infection affecting an estimated eight million people in rural areas of Mexico, Central America, and South America.1 Chagas disease is transmitted to animals and people through insect vectors by the parasite Trypanosoma cruziI (T. cruzi). The disease presents in an acute or chronic phase, both of which can be symptom free or life threatening. 2

 Chronic Chagas cardiomyopathy (CCC) is the most important chronic form of Chagas disease due to its high morbidity and mortality and its significant medical and social impact. Despite its importance, CCC pathophysiology is poorly understood and the therapeutic approach of CCC is still transposed from the knowledge acquired from other cardiomyopathies. Specific treatment targeted at T. cruzi is effective in the acute phase with a chance of cure around 90%. However, results in the chronic phase are uncertain. There are two drugs under investigational use protocols for the treatment of CCC, but are not approved by the Food and Drug Administration (FDA) and include: nifurtimox (Lampit®) and benznidazole (Rochagan®). 3 This study aims to evaluate the efficacy and safety of benznidazole, as compared with placebo, in reducing clinical outcomes among patients with chronic Chagas cardiomyopathy. 4

Title: Randomized Trial of Benznidazole for Chronic Chagas Cardiomyopathy4
Design Prospective, multicenter, randomized study, N = 2854
Objective This study aims to evaluate the efficacy and safety of benznidazole, as compared with placebo, in reducing clinical outcomes among patients with chronic Chagas cardiomyopathy.
Study Groups Benznidazole or Placebo group
Methods Benznidazole or matching placebo was administered orally in 2854 patients for 40 to 80 days at 49 centers in Argentina, Bolivia, Brazil, Colombia, and El Salvador. A ten-milliliter blood sample was collected at baseline and the end of treatment to be used for polymerase chain reaction (PCR) assay detection of circulating T. cruzi kinetoplast DNA (kDNA). Adverse events, results of liver-function testing, and findings on 12-lead electrocardiography were recorded at baseline and during each follow-up visit during the treatment period.
Duration Duration of treatment lasted 80 days, patients followed for an average of 5.4 years
Primary Outcome Measure 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.
Baseline Characteristics The majority of the patients were recruited in Brazil (1358 patients), followed by Argentina (559), Colombia (502), Bolivia (357), and El Salvador (78). Most patients (97%) had New York Heart Association (NYHA) class I or II heart failure, and the mean ejection fraction was 55%. The mean (±SD) age was 55±11 years.
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). In a per-protocol analysis of data from patients who took at least 75% of the target dose, the hazard ratio was 0.90 (95% CI, 0.78 to 1.04; P = 0.16).
Adverse Events Common Adverse Events: The rate of drug interruption because of a common adverse event was significantly higher in the benznidazole group than in the placebo group (23.9% versus 9.5%, P<0.001). Cutaneous rash, gastrointestinal symptoms, and nervous system disorders were the most common reasons for drug interruptions.
Serious Adverse Events: 8.3% in benznidazole group versus 1.4% in placebo group
Percentage that Discontinued due to Adverse Events: 13.4% of patients in the benznidazole group
Study Author 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 five years of follow-up.

All negative kDNA results on PCR assay were amplified with human gene-specific primers, which minimized the possibility of false negative results. Follow-up data was available for 100% of the patients at 1 year, for 99% at 2 years, and for 99.5% at 7 years. A total of 14 patients (0.5%) were lost to follow-up at the end of the study. In conclusion, among patients with established Chagas cardiomyopathy, benznidazole treatment significantly reduced the detection of circulating parasites but did not reduce cardiac clinical progression. 4

References

  1. Rassi A Jr, Rassi A, Marin-Neto JA (2010) Chagas disease. Lancet 375:1388–1402
  2. Chagas Disease. Centers for Disease Control and Prevention website http://www.cdc.gov/parasites/chagas/. Updated July 13, 2013. Accessed October 1, 2015.
  3. Fernando A. Botoni, Antonio Luiz P. Ribeiro, Carolina Coimbra Marinho, Marcia Maria Oliveira Lima, Maria do Carmo Pereira Nunes, and Manoel Otávio C. Rocha, “Treatment of Chagas Cardiomyopathy,” BioMed Research International, vol. 2013, Article ID 849504, 9 pages, 2013.
  4. Morillo CA, Marin-neto JA, Avezum A, et al. Randomized Trial of Benznidazole for Chronic Chagas’ Cardiomyopathy. N Engl J Med. 2015;
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