Effect Of Trientine-hydrochloride In Heart Failure With Lower Left Ventricular Ejection Fraction: The TRACER-HF Trial

Background

Intracellular copper depletion may cause cardiovascular dysfunction among those with heart failure with reduced ejection fraction (HFrEF). Copper depletion may be corrected by administration of the copper chaperone trientine-HCL. In a placebo-controlled multicenter Phase 2 trial of patients with HFrEF (TRACER-HF; NCT03875183), 150 and 300 mg doses of trientine-HCL treatment resulted in ∼20% reduction in N-terminal pro-B type natriuretic peptide (NT-proBNP) by 4 and 8 weeks, accompanied by favorable trends in change in LV remodeling, 6-minute walk distance (6MWD) and health status (assessed with the Kansas City Cardiomyopathy Questionnaire Overall Summary Score, KCCQ-OSS). Greater effects of trientine-HCL on NT-proBNP concentrations were observed in study participants with an LV ejection fraction (EF) ≤30% (P_interaction=0.05). The present analysis details effect of trientine-HCL on secondary outcomes in study participants with baseline LVEF ≤30%.

Methods

Effect of trientine-HCL was examined on proportional change in NT-proBNP, and changes in LVEF, LV end-systolic or end-diastolic volume (LVESV, LVEDV), 6MWD, and KCCQ-OSS among study participants with LVEF ≤30% (N=101).

Results

Trial participants with LVEF ≤30% had a mean ± standard deviation age of 57 ± 10 years, and approximately 20% were female. Medical management included beta blocker in 93%, sacubitril/valsartan in 83%, mineralocorticoid receptor antagonist in 91% and sodium/glucose cotransporter 2 inhibitor in 44%. Baseline median (Q1, Q3) NT-proBNP was 1474 (756, 2540) ng/L and mean LVEF was 26 ± 3%. The baseline median 6MWD was 387 (310, 467) meters and mean baseline KCCQ OSS was 73 ± 18. From baseline to week 12, among those with LVEF ≤30%, the 150 mg and 300 mg dose of trientine-HCL resulted in an average 20% NT-proBNP reduction from 2 weeks sustained to 12 weeks following enrollment. By 12 weeks, treatment with trientine-HCL resulted in significant improvement in LVEF (up to 6% absolute increase with the 300 mg dose), reduction in LVEDV and LVESV (up to -8.5 and -15.7 mL respectively with the 300 mg dose) (Figure). In study participants with LVEF ≤30%, treatment with trientine was associated with clinically-meaningful increases in KCCQ-OSS, particularly with the 150 mg (+8) and 300 mg (+15) doses (Figure). Treatment with trientine-HCL was not associated with excess risk for adverse events in those with lower LVEF compared to placebo.

Conclusions

Among study participants with a baseline LVEF ≤30%, treatment with trientine-HCL was well tolerated and associated with a significant reduction in NT-proBNP, considerable reverse cardiac remodeling, and large clinically relevant improvements in health status. Further studies of trientine-HCL in HFrEF are justified.