Allopurinol, Febuxostat, and Nonuse of Xanthine Oxidoreductase Inhibitor Treatment in Patients Receiving Hemodialysis: A Longitudinal Analysis

Abstract

Rationale & Objective

Allopurinol and febuxostat, which are xanthine oxidoreductase inhibitors, have been widely used as uric acid-lowering medications. However, evidence regarding their cardiovascular effects in hemodialysis is insufficient. This study compared the effects of allopurinol and febuxostat on mortality and cardiovascular outcomes in patients receiving hemodialysis.

Study Design

A retrospective observational cohort study.

Setting & Participants

Data of 6,791 patients who had no history of topiroxostat usage and underwent maintenance hemodialysis between March 2016 and March 2019 at Yokohama Daiichi Hospital, Zenjinkai, and its affiliated dialysis clinics in Japan’s Kanagawa and Tokyo metropolitan areas were collected.

Exposure

Allopurinol, febuxostat, and nontreatment.

Outcomes

All-cause mortality, cardiovascular disease (CVD) events, heart failure (HF), acute myocardial infarction (AMI), and stroke.

Analytical Approach

For the main analyses, marginal structural Cox proportional hazards models were used to estimate HRs adjusted for time-varying confounding and selection bias because of censoring.

Results

Allopurinol and febuxostat showed significantly better survival than nontreatment for all-cause mortality (HR, 0.40; 95% CI, 0.30-0.54 and HR, 0.49; 95% CI, 0.38-0.63, respectively), without significant difference between allopurinol and febuxostat. Allopurinol showed significantly better survival than nontreatment, whereas febuxostat did not for CVD events (HR, 0.89; 95% CI, 0.84-0.95 and HR, 1.01; 95% CI, 0.96-1.07, respectively), HF (HR, 0.71; 95% CI, 0.56-0.90 and HR, 1.03; 95% CI, 0.87-1.21, respectively), and AMI (HR, 0.48; 95% CI, 0.25-0.91 and HR, 0.76; 95% CI, 0.49-1.19, respectively). No comparisons showed significant results for stroke.

Limitations

The ratio of renal or intestinal excretion of uric acid and uremic toxins could not be elucidated, and we could not investigate gene polymorphism because of the large number of cases.

Conclusions

Allopurinol and febuxostat improved survival for all-cause mortality. Allopurinol and not febuxostat reduced the risk of CVD events, HF, and AMI.

Plain Language Summary

Uric acid-lowering therapy has been used to prevent gout attacks and protect organs by reducing inflammation by lowering uric acid levels. However, uric acid-lowering medications have recently been found to have a side effect of inhibiting a channel responsible for excreting toxins, such as adenosine triphosphate-binding cassette transporter G2; the effects of medications with a strong inhibitory effect, such as febuxostat, are currently under investigation. Patients with kidney failure or dialysis excrete toxins through feces from their intestines in addition to removing toxins through dialysis. If uric acid-lowering medications suppress the channels responsible for intestinal toxin excretion, could this lead to the development of heart failure or stroke? This study investigated this question.