Verinurad and Allopurinol Combination Lowers SUA Levels but Fails to Improve HFpEF Outcomes, AMETHYST Trial Finds

The study, published in JAMA Cardiology, revealed that combining verinurad with allopurinol to lower SUA levels did not improve peak oxygen uptake or symptoms for patients with HFpEF.

"In this randomized clinical trial involving 159 patients, the combination of verinurad and allopurinol led to a significantly greater reduction in SUA levels after 32 weeks than allopurinol alone or placebo. However, this improvement in SUA levels did not translate into significant enhancements in peak oxygen uptake, symptoms, or key echocardiographic parameters in patients with HFpEF and elevated SUA," the researchers reported.

Elevated serum uric acid levels may play a role in endothelial dysfunction, making SUA a promising target for treating heart failure with preserved ejection fraction. However, to date, there have been no randomized clinical trials to assess the effects of SUA reduction specifically in HFpEF patients. To fill this knowledge gap, Dalane W. Kitzman, Wake Forest University School of Medicine, Winston-Salem, North Carolina, and colleagues aimed to investigate the safety and efficacy of the novel urate transporter–1 inhibitor, verinurad, in patients with HFpEF and elevated SUA level.

For this purpose, the researchers conducted a phase 2, double-blind, randomized clinical trial from May 2020 to April 2022, involving 59 centers across 12 countries and included patients aged 40 and older with HFpEF and SUA levels greater than 6 mg/dL.

The study, which lasted 32 weeks, randomized eligible participants to receive either once-daily oral verinurad (12 mg) plus allopurinol (300 mg), allopurinol alone (300 mg), or a placebo, following an 8-week titration period. Allopurinol was combined with verinurad to prevent potential urate nephropathy induced by verinurad, and the allopurinol monotherapy group was included to isolate the effects of allopurinol. Additionally, all participants received oral colchicine (0.5 to 0.6 mg) daily for the first 12 weeks.

Data analysis, conducted from August 2022 to May 2024, focused on key outcomes, including changes from baseline to week 32 in peak oxygen uptake (VO2), Kansas City Cardiomyopathy Questionnaire total symptom score (KCCQ-TSS), and SUA levels. The trial also evaluated safety and tolerability, including adjudicated cardiovascular events.

The following were the key findings of the study:

• Among 159 randomized patients (53 per treatment group; median age, 71 years; 65% males) with median (IQR) N-terminal pro-brain natriuretic peptide level of 527 pg/mL and SUA level of 7.5 mg/dL, verinurad plus allopurinol (mean change, −59.6%) lowered SUA level to a greater extent than allopurinol (mean change, −37.6%) or placebo (mean change, 0.8%).
• Changes in peak VO2 (verinurad plus allopurinol, 0.27 mL/kg/min; allopurinol, −0.17 mL/kg/min; placebo, 0.37 mL/kg/min) and KCCQ-TSS (verinurad plus allopurinol, 4.3; allopurinol, 4.5; placebo, 1.2) were similar across groups.
• There were no adverse safety signals.
• Deaths or cardiovascular events occurred in 5.7% of patients in the verinurad plus allopurinol group, 15.1% of patients in the allopurinol monotherapy group, and 11.3% in the placebo group.

"The overall results of the AMETHYST randomized clinical trial indicate that lowering SUA levels with verinurad does not lead to improvements in peak VO2 or symptoms for patients with HFpEF," the researchers concluded.

Reference:

Kitzman DW, Voors AA, Mentz RJ, et al. Verinurad Plus Allopurinol for Heart Failure With Preserved Ejection Fraction: The AMETHYST Randomized Clinical Trial. JAMA Cardiol. Published online August 14, 2024. doi:10.1001/jamacardio.2024.2435