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Copper chelating agent improves biomarkers and quality of life in HF patients

Presented By
Prof. James Januzzi, Harvard Medical School, USA
HFA 2023
Phase 2, TRACER-HF

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

Copper is an essential trace mineral with important roles in the myocardium. As Prof. James Januzzi (Harvard Medical School, MA, USA) pointed out, it scavenges oxygen free 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 remodelling 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 heart failure and reduced ejection fraction. In this trial, 190 participants were enrolled at 27 sites in North America and China. All patients had heart failure with a left ventricular ejection fraction ≤ 40% 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 remodelling indices, 6-minute walk distances, and Kansas City Cardiomyopathy Questionnaire (KCCQ) Overall Summary Score were assessed as secondary endpoints.

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

In the highest dose arm (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 to the placebo group. At week 4, the geometric mean ratio (GMR) least square mean difference was 0.82 in the highest dose group (versus 1.03; P = 0.05), at week 8 it was 0.79 (versus 1.02; P = 0.03). As for the secondary endpoints, trientine-HCL in the 150mg and 300 mg dose improved left ventricular end-systolic volumes. Participants treated with the highest dose improved by 42 m in the 6-minute walking distance and had better results in the Questionnaire. “The 300 mg dose was most consistently associated with favourable KCCQ changes”, Prof. 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”, Prof. Januzzi said.

To the question, why NT-proBNP concentrations were not lowered at week 12, Prof. commented that this conflicting result may have been influenced by the pandemic. He believes that further studies of trientine-HCL in heart failure are justified in the light of the current results.

  1. Januzzi J. A randomised, double-blind, placebo-controlled phase 2A study to evaluate the effects of trientine-HCL in patients with heart failure and reduced ejection fraction: the TRACER-HF trial. Session “Late breaking clinical trials: Chronic HF and cardiomyopathies”, Heart Failure 2023, 20–23 May, Prague, Czechia.

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