BENEFIT: Treating the Parasite Doesn't Help Clinically in Chagas' Cardiomyopathy

September 04, 2015

LONDON, UK — People with established Chagas' cardiomyopathy did not benefit with fewer cardiovascular events over 5 years despite antimicrobial therapy that significantly reduced serologic detection of the parasite associated with the disease, in a randomized trial conducted in endemic regions of South America[1]

The Benznidazole Evaluation for Interrupting Trypanosomiasis (BENEFIT) trial randomized >2800 people positive for the parasite Trypanosoma cruzi by polymerase chain reaction (PCR) assay to receive benznidazole, an agent commonly given for the disease, or placebo for 60 days. At entry, all patients had electrocardiographic or other objective evidence of cardiomyopathy. Most had heart failure and were on standard heart-failure medications; a fifth were on amiodarone.

In the trial, by far the largest-ever prospective study in Chagas' heart disease, according to researchers, there was clear evidence the drug regimen significantly reduced the presence of the parasite from the circulation of most patients. Yet active therapy had no meaningful effect on clinical outcomes, a primary end point that included death, cardiac arrest, sustained ventricular arrhythmias, implantation of a first pacemaker or defibrillator, new onset of or new hospitalization for heart failure, cerebrovascular events, or systemic or pulmonary embolism, reported Dr Carlos Arturo Morillo (McMaster University, Hamilton, ON).

Dr Carlos Arturo Morillo

Morillo presented BENEFIT here at the European Society of Cardiology 2015 Congress and is lead author on its same-day publication in the New England Journal of Medicine.

One lesson from BENEFIT, according to Prof Piotr Ponikowski (Medical University, Clinical Military Hospital, Wrocław, Poland), is that "the specific way patients with Chagas' disease are now treated in everyday practice is actually ineffective."

As assigned discussant following Morillo's formal presentation of BENEFIT, Ponikowski said questions for the future include "whether complete parasite elimination is what we really want to achieve" and whom to treat. "I'd presume that the real challenge in Latin America is those who are affected but who are not yet at the level of signs and symptoms of the disease, and that may well be the next step," according to Ponikowski.

Chagas' Disease: The Big Picture

Chagas' disease is among the most common parasitic diseases in the world and a major cause of heart disease in Latin America, observed Morillo for heartwire from Medscape. Infected individuals have about a 20% to 30% chance of developing cardiomyopathy, he said, but it may take 2 or 3 decades to manifest.

"We still don't understand which patients will end up having heart failure," he said, making it difficult to study early interventions for cardiomyopathy prevention; nor is it known whether reducing serologic evidence of the parasite will affect the disease course or clinical outcomes.

"I think it's worth noting that this parasite is one of the largest causes of cardiomyopathy in the world, and there have been small trials, but this is the first really large trial with long-term follow-up," according to Dr Salim Yusuf (McMaster University), senior author on the BENEFIT publication, who led a press conference that featured the results. He pointed out as well that Chagas' disease is increasingly seen in North America and Europe with the expansion of international travel.

Of patients who were PCR-positive for the parasite at baseline, 1431 were randomized to receive benznidazole 300 mg/day and 1423 to get placebo, with treatment continued for 40 to 80 days. Patients were followed for at least 2 years in the trial, conducted at 49 centers in Argentina, Bolivia, Brazil, Colombia, and El Salvador.

Seroconversion rates (conversion to negative for T cruzi) were 33% to 35% for control patients at each of 60 days (the end of randomized therapy), 2 years, and >5 years—significantly less at each time point than in those who received benznidazole (66.2%, 55.4%, and 46.7%, respectively; P<0.001 for all differences).

Of patients receiving active therapy, 27.5% met the primary end point over a follow-up averaging 5.4 years, compared with 29.1% of control patients, for an adjusted hazard ratio (HR) of 0.92 (95% CI 0.81–1.06; P=0.26) by intention to treat. There were no significant differences in any component of the primary end point, nor within subgroups by baseline PCR status, age, sex, NYHA class, or LVEF.

Nor did a significant benefit from benznidazole emerge in a per-protocol analysis for patients who took at least 75% of their assigned treatment (HR 0.90, 95% CI 0.78–1.04; P=0.16).

Speaking with heartwire , Morillo remained coy about echocardiographic follow-up results but did say there was no structural or functional evidence of reverse ventricular remodeling at 2 or 5 years in the active-treatment group.

Variable Responses by Country

Of note in BENEFIT, there was a disconnect between suppression of the parasite as evidenced by seroconversion rates and clinical response to therapy. Seroconversion rates appeared to vary with the predominant genotypic form of T cruzi in each country, observed Morillo when interviewed.

For example, as described in his group's report, T cruzi 2 is dominant in Brazil. Patients in Brazil, who made up almost half the study population, had the highest rates of becoming serologically negative for the parasite after benznidazole treatment. Seroconversion rates were intermediate in Argentina and Bolivia (where T cruzi 5 and 6 predominate) and lowest in Columbia and El Salvador (where T cruzi 1 reigns).

The interaction between seroconversion rates and country was significant (P<0.001). Yet there was no such heterogeneity in clinical response rates to active therapy. Heterogeneity in serologic response to treatment may reflect variation in T cruzi pathogenicity by parasite subtype, Morillo told heartwire .

The rate of adherence to assigned treatment was 84% of actively treated patients and 94% of controls, while 23.9% of benznidazole patients and 9.5% of those on placebo (P<0.001) interrupted their treatment at some point due to adverse events. Interruptions were most often associated with development of cutaneous rashes, which occurred in 9.6% and 1.3% (P<0.001) of benznidazole and placebo patients, respectively.

Morillo agreed that whether to identify and treat patients in the "indeterminate" phase of a T cruzi infection, in which patients are serologically positive but don't have structural or clinical signs of disease, is "potentially the next step" in exploring therapy for Chagas' disease. "We need to understand a bit better what the groups are that may actually respond to this drug and maybe target those groups more specifically."

The trial could be seen as supporting the use of benznidazole by at least some criteria, according to Morillo. For example, it did suppress the parasite by serologic measures, and that may still be a good thing. "Some of our investigators say, well it's a neutral or negative trial, but I'm still going to treat. Why? A lot of people think this drug is very toxic. We showed that it's way less [toxic] than what's been reported in observational trials." And the BENEFIT findings should carry some weight: previously, he observed, all prospective trials of Chagas' cardiomyopathy encompassed <300 patients, and the current trial had nearly 10 times that number.

And, Morillo and his colleagues contend in their publication, "Our findings do not challenge current guidelines that recommend treatment with trypanocidal therapy in the early stages of chronic Chagas' infection, which are based on several studies," and shouldn't discourage explorations of "more effective or earlier treatments with new drugs or drug combinations."

Morillo discloses receiving lecture fees from Bayer and Boehringer Ingelheim and grant support from Boston Scientific and Merck; disclosures for the coauthors are listed on the journal website. Ponikowski has previously disclosed relationships with Vifor Pharma, Abbott Vascular, Bayer HealthCare, Corthera, Johnson & Johnson, and Novartis. Yusuf has previously disclosed relationships with Boehringer Ingelheim, Bayer, AstraZeneca, Cadila Pharma, and Sanofi.


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