Comparison between febuxostat and allopurinol uric acid-lowering therapy in patients with chronic heart failure and hyperuricemia: a multicenter randomized controlled trial

Abstract

Objective: Heart failure (HF) is a common and highly morbid cardiovascular disorder. Oxidative stress worsens HF, and uric acid (UA) is a useful oxidative stress marker. The novel anti-hyperuricemic drug febuxostat is a potent non-purine selective xanthine oxidase inhibitor. The present study examined the UA-lowering and prognostic effects of febuxostat in patients with HF compared with conventional allopurinol.

Methods: This multicenter, randomized trial included 263 patients with chronic HF who were randomly assigned to two groups and received allopurinol or febuxostat (UA >7.0 mg/dL). All patients were followed up for 3 years after enrollment.

Results: There were no significant differences in baseline clinical characteristics between the two groups. The UA level was significantly decreased after 3 years of drug administration compared with the baseline in both groups. Urine levels of the oxidative stress marker 8-hydroxy-2'-deoxyguanosine were lower in the febuxostat group than in the allopurinol group (11.0 ± 9.6 vs. 22.9 ± 15.9 ng/mL), and the rate of patients free from hospitalization due to worsening HF tended to be higher in the febuxostat group than in the allopurinol group (89.0% vs. 83.0%).

Conclusions: Febuxostat is potentially more effective than allopurinol for treating patients with chronic HF and hyperuricemia.This study was registered in the University Hospital Medical Information Network Clinical Trials Registry (https://www.umin.ac.jp/ctr/; ID: 000009817).

Keywords: Heart failure; febuxostat; oxidative stress; prognosis; uric acid; worsening heart failure.

Figure 1.

Patient selection flowchart according to CONSORT guidelines in this study.

Figure 2.

Comparison of urine 8-hydroxy-2′-deoxyguanosine (8-OHdG) levels at 3 years between the allopurinol (n = 135) and febuxostat groups (n = 128) (22.9 ± 15.9 vs. 11.0 ± 9.6 ng/mL, P < 0.001). 8-OHdG levels were measured using a commercially available enzyme-linked immunosorbent assay kit.

Figure 3.

Kaplan–Meier analyses for patients free from cardiovascular events in the febuxostat and allopurinol groups. During this study period, 12 cardiovascular deaths and 37 hospitalizations due to worsening heart failure occurred. Numbers of followed-up patients in respective groups were indicated at the bottom of the figure.

Figure 4.

Kaplan–Meier analyses for patients free from hospitalization due to worsening heart failure in the febuxostat and allopurinol groups. Numbers of followed-up patients in respective groups were indicated at the bottom of the figure.

Figure 5.

Comparison of urine 8-hydroxy-2′-deoxyguanosine (8-OHdG) levels at 3 years between allopurinol and febuxostat users divided into two groups based on the left ventricular ejection fraction. 8-OHdG levels were measured using a commercially available enzyme-linked immunosorbent assay kit. a) Heart failure with preserved ejection fraction (HFpEF) (n = 173) (24.1 ± 15.6 vs. 10.9 ± 8.9 ng/mL, P < 0.001). b) Heart failure with reduced ejection fraction (HFrEF) (n = 86) (17.9 ± 12.2 vs. 11.4 ± 10.5 ng/mL, P = 0.212).

Figure 6.

Kaplan–Meier analyses for patients free from hospitalization due to worsening heart failure in the febuxostat and allopurinol groups. Numbers of followed-up patients in respective groups were indicated at the bottom of the figure. (a) Heart failure with preserved ejection fraction (HFpEF) (log-rank, P = 0.037). (b) Heart failure with reduced ejection fraction (HFrEF) (log-rank, P = 0.467).