Verinurad–allopurinol combo disappoints in HFpEF

Combining verinurad with allopurinol does not appear to boost oxygen uptake or improve symptoms in heart failure with preserved ejection fraction (HFpEF), despite yielding significant reductions in serum uric acid (SUA) levels, according to a phase II study.

The study included 159 adult patients (median age 71 years, 65 percent male) with HFpEF and SUA level greater than 6 mg/dL. These patients were randomly assigned to receive once daily, oral verinurad 12 mg plus allopurinol 300 mg (n=35), allopurinol 300 mg monotherapy (n=35), or placebo (n=35) for 24 weeks after an 8-week titration period. All patients received oral colchicine 0.5–0.6 mg daily for the first 12 weeks after randomization.

Allopurinol was combined with verinurad to prevent verinurad-induced urate nephropathy, while the allopurinol monotherapy group was included to account for allopurinol effects in the combination therapy group.

The main endpoints included changes from baseline to week 32 in peak oxygen uptake (VO2), Kansas City Cardiomyopathy Questionnaire total symptom score (KCCQ-TSS), and SUA level. Safety and tolerability, including adjudicated cardiovascular events, were also assessed.

At baseline, the median N-terminal pro–brain natriuretic peptide level was 527 pg/mL while the SUA level was 7.5 mg/dL. The reductions observed in SUA levels over 32 weeks were significantly  greater with verinurad plus allopurinol (mean change, −59.6 percent, 95 percent confidence interval [CI], −64.4 to −54.2) than with allopurinol alone (mean change, −37.6 percent, 95 percent CI, −45.3 to −28.9) or placebo (mean change, 0.8 percent, 95 percent CI, −11.8 to 15.2; p<0.001).

However, the three treatment groups were comparable in terms of changes in peak VO2 (verinurad plus allopurinol: 0.27 mL/kg/min; allopurinol monotherapy: −0.17 mL/kg/min; placebo: 0.37 mL/kg/min) and KCCQ-TSS (verinurad plus allopurinol: 4.3; allopurinol monotherapy: 4.5; placebo: 1.2).

No adverse safety signals were reported. Deaths or cardiovascular events occurred in three patients (5.7 percent) in the verinurad plus allopurinol group, eight (15.1 percent) in the allopurinol monotherapy group, and six (11.3 percent) in the placebo group.