Allopurinol and febuxostat are similarly effective in controlling flares in patients with gout, including those with stage 3 chronic kidney disease (CKD), according to trial results published in the New England Journal of Medicine.
In double-blind CSP594 Comparative Effectiveness in Gout: Allopurinol versus Febuxostat trial (ClinicalTrials.gov identifier, NCT02579096), investigators randomly assigned 940 patients with hyperuricemia to receive allopurinol or febuxostat at titrated doses to achieve a serum urate target of 6 mg/dL or lower (or 5 mg/dL or lower if tophi were present). Approximately a third of patients in both groups had stage 3 CKD (30-59 mL/min/1.73 m2 using the Modification of Diet in Renal Disease study formula for estimated glomerular filtration rate). The allopurinol and febuxostat groups received daily doses of 100 and 40 mg, respectively, to start, then therapies were titrated until attainment of target uric acid levels or maximal dose. Patients also received guideline-directed anti-inflammatory prophylaxis with colchicine, nonsteroidal anti-inflammatory drugs, or glucocorticoids. After the maintenance phase, no study drug dose adjustments were allowed, and all anti-inflammatory treatments were discontinued except in the event of gout flare.
Results showed that 36.5% the allopurinol group and 43.5% of the febuxostat group experienced the primary outcome of 1 or more gout flares during the observation phase — a 7% difference that met a criterion for noninferiority, James R. O’Dell, MD, of Veterans Affairs (VA) Nebraska-Western Iowa Health Care System in Omaha, Nebraska, and colleagues reported. Among patients with stage 3 CKD, allopurinol also proved noninferior to febuxostat with 31.9% vs 45.3% experiencing a gout flare, respectively, the investigators reported.
In both the allopurinol and febuxostat groups, 80% of patients – including those with stage 3 CKD — achieved and maintained target serum urate levels at 1 year.
“Our randomized double-blind trial demonstrates that allopurinol, when dosed appropriately as part of a titrate-to-target strategy, is noninferior to febuxostat with respect to flares of gout,” Dr O’Dell’s team wrote.
In 2019, the FDA issued a boxed warning concerning the cardiovascular safety of febuxostat based on results of the CARES (Cardiovascular Safety of Febuxostat and Allopurinol in Patients with Gout) trial. The 2020 FAST trial (Febuxostat versus Allopurinol Streamlined Trial), however, showed no increased risk for cardiovascular events. In the current study, the investigators found no evidence that febuxostat increases cardiovascular morbidity or overall mortality compared with allopurinol. Serious adverse events (26.7% vs 26.1%), including cardiovascular events (8.1% vs 6.8%) and death (8 patients in each group), occurred in comparable proportions of the allopurinol and febuxostat arms, respectively. Dr O’Dell and colleagues suggested that the nearly ubiquitous use of colchicine in the early phases of the trial might have mitigated cardiovascular risks.
Dr O’Dell’s team made other observations that also warrant additional research. Hospitalization for heart failure was numerically higher among patients treated with allopurinol (23 vs 10 hospitalizations). A post hoc analysis showed that acute kidney injury occurred in 15 allopurinol-treated patients compared with 4 febuxostat-treated patients who had stage 3 CKD. Most AKI events were related to volume depletion or congestive heart failure, the investigators noted. All but 3 AKI events were transient.
O’Dell JR, Brophy MT, Pillinger MH, et al. Comparative effectiveness of allopurinol and febuxostat in gout management. N Engl J Med. Published online February 3, 2022. doi:10.1056/EVIDoa2100028