The TRACER-HF trial demonstrated that therapy with a copper chelator may have beneficial effects in patients with heart failure (HF) and should be evaluated in further studies. In addition, the therapy did not affect blood pressure or heart rate.

Copper is an essential trace mineral with important roles in the myocardium. As James Januzzi, MD, described, it scavenges oxygen radicals, serves as a cofactor for ATP production, and promotes iron and zinc uptake. Trientine-HCL (INL 1) is an oral copper chelator that acts as a copper chaperone at low doses, restoring normal intracellular Cu concentrations that has shown to reverses cardiac remodeling in experimental models.

The phase 2a TRACER-HF trial (NCT03875183) examined multiple doses of trientine-HCL (from 50 mg twice daily to 300 mg twice daily) in participants with HF and reduced ejection fraction. In this trial, 190 participants were enrolled at 27 sites in North America and China. All patients had HF with a left ventricular ejection fraction of 40% or less and were randomized to treatment with trientine-HCL or placebo for 12 weeks. The primary study endpoint was the effect of trientine-HCL on the proportional NT-proBNP change from baseline to 12 weeks. In addition, cardiac remodeling indices, distance covered in the 6-minute walk test, and Kansas City Cardiomyopathy Questionnaire (KCCQ) overall summary score were assessed as secondary endpoints.

Dr. Januzzi explained that the trial was severely affected by the COVID-19 pandemic. A decision was made to shift to a China-focused enrollment in 2021, but the follow-up was also influenced by the surge of COVID-19 cases in late 2022.

In the highest dose group (300 mg trientine-HCL twice daily), a significant reduction in NT-proBNP was noted at 4 and 8 weeks, but not at 12 weeks compared with the placebo group. At week 4, the geometric mean ratio (GMR) least square mean difference was 0.82 in the highest dose group (vs 1.03; P=.05); at week 8, it was 0.79 (vs 1.02; P=.03). As for the secondary endpoints, trientine-HCL in the 150-mg and 300-mg dose groups improved left ventricular end-systolic volumes. Participants treated with the highest dose improved by 42 minutes in the 6-minute walk test and had better results on the KCCQ. “The 300 mg dose was most consistently associated with favorable KCCQ changes,” Dr. Januzzi commented.

Treatment with the chelating agent was generally well tolerated. Moreover, copper and iron concentrations were not significantly different across treatment arms. “Notably and interestingly, blood pressure and heart rate were not significantly affected by trientine-HCL,” Dr. Januzzi said.

When asked why NT-proBNP concentrations were not lowered at week 12, Dr. Januzzi explained that this conflicting result may have been influenced by the COVID-19 pandemic. He believes that further studies of trientine-HCL in HF are justified in the light of the current results.

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