Patients with comorbid conditions such as cardiovascular disease, obesity, diabetes, and chronic kidney disease commonly experience gout. Gout is associated with hyperuricemia and episodes of intense joint pain and swelling. There are several therapies designed to lower urate levels in patients with gout. The most common are the xanthine oxidase inhibitors febuxostat and allopurinol.
Estimates put the proportion of patients with gout and concomitant CKD stage 3 and above at 20% to 30%. Estimates with any degree of CKD stage (stage 1-5) reach 70%. Concerns regarding the risk of allopurinol hypersensitivity syndrome (AHS) limit the use and dosing of allopurinol in patients with CKD. Furthermore, the use of febuxostat has been associated with conflicting cardiovascular safety signals in that patient population.
The STOP Gout trial compared the efficacy and safety of allopurinol and febuxostat in the management of patients with gout using a treat-to-target approach. A team of researchers led by Lindsay N. Helget, MD, reported results of a preplanned secondary analysis of data from a subgroup of participants with stage 3 CKD in the STOP Gout trial online in the American Journal of Kidney Diseases.
STOP Gout was a multicenter, randomized, double-blind, noninferiority comparative effectiveness trial. Enrollment occurred at 21 sites in the United States between 2017 and 2019. The final study visit was conducted in August 2019. As specified in the trial protocol, a minimum of one-third of the participants had CKD stage 3 (eGFR 30-59 mL/min/1.73 m2). The primary outcome of interest was gout flare between weeks 49 and 72. Secondary outcomes included the achievement of the serum urate (sUA) goal and dosing of urate-lowering therapy, and serious adverse events.
Participants were randomized 1:1 to receive allopurinol or febuxostat. During weeks 0-24 (phase 1), urate-lowering therapy was titrated to achieve a goal of sUA concentrations of <6.0 mg/dL (<5.0 mg/dL with tophi). Dosing was maintained during weeks 24-48 (phase 2). Assessment of gout flares occurred between weeks 49 and 72 (phase 3).
Logistic regression models were used to compare binary outcomes between the two treatment groups and Poisson regression was used to compare flare rates. Multivariable models were used following adjustment for factors identified to be imbalanced.
Of the 940 participants in the study cohort, 37.3% (n=351) had CKD. Of them, 181 were randomized to the allopurinol treatment arm and 170 to the febuxostat arm. Mean age of the total CKD subgroup was 68.4 years, and 97.2% were male. Furthermore, 70.4% were White, 21.9% were Black, 2.0% were Asian, 0.6% were American Indian, 2.6 % were Native Hawaiian/Pacific Islander/Maori, and 2.6% were other race/ethnicity.
The mean eGFR was 47.7 mL/min/1,73 m2 overall (47.4 mL/min/1.73 m2 in the allopurinol arm and 48.1 mL/min/1.73 m2 in the febuxostat arm), with mean sUA concentrations of 8.8 (1.5) mg/dL. Marked hyperuricemia (defined as a sUA exceeding 9 mg/dL) was observed in 41.9% of participants with CKD.
The most common comorbidities in the allopurinol and febuxostat arms were hypertension (86.2% vs 85.9%), diabetes (45.9% vs 51.2%), and cardiovascular disease (48.6% vs 34.1%), respectively. In the allopurinol arm, 54.1% of participants used a diuretic compared to 57.1% in the febuxostat arm. Serum creatinine concentration, diabetes, cardiovascular disease, body mass index, and sUAs at baseline were defined as imbalanced factors between the two arms (standard difference >0.1).
The mean allopurinol dose in the subgroup with CKD was 394.6 mg (145.6) and the median dose was 400 mg (200 mg). In the febuxostat arm, mean dose was 63.7 mg (23.8 mg) and median dose was 80 mg (40 mg). At the discretion of the site investigator, 90.0% (n=316) of trial participants with CKD were administered colchicine alone, 6.6% (n=23) received glucocorticoids alone, 2.6% (n=9) received another (combination therapy or not specified), and 0.9% (n=3) received nonsteroidal anti-inflammatory drugs.
During phase 3, fewer patients in the allopurinol treatment arm experienced one or more gout flares than those in the febuxostat treatment arm (32% vs 45%; P=.02), despite similar attainment of sUA goal (79% vs 81%; P=.06) by the end of phase 2. Participants in both treatment arms who did not reach target sUA at the end of phase 2 were significantly more likely to experience a flare in phase 3 compared to those who did achieve the sUA goal (flare rate 2.99 versus 1.59; P<.001).
The occurrence of serious adverse events, defined as the proportion of participants with one or more serious adverse events reported, was similar in the two treatment arms. Rashes were more frequent in the allopurinol arm than in the febuxostat arm. Severe rashes resolved without evidence of AHS but led to study withdrawal.
Patients in the CKD subgroup in the allopurinol arm more commonly experienced acute kidney injury compared to those in the febuxostat arm (8% [n=15) vs 2% [n=4]; P=.02). The most common etiology of AKI was volume depletion (seven events in the allopurinol arm vs one event in the febuxostat arm), followed by cardiorenal syndrome (five in the allopurinol arm vs zero for febuxostat).
The authors cited limitations to the findings, including limited power to assess infrequent safety events, the largely male makeup of the study population, and the percentage of older participants in the study.
The researchers concluded that the prespecified subanalysis focused on individuals with stage 3 CKD demonstrated allopurinol and febuxostat to be similarly effective in flare prevention and in reaching target sUA thresholds when used as part of a treat-to-target strategy. The analysis also revealed similarly favorable safety profiles with similar incidence of cardiovascular disease and low incidence of severe rashes.
“The higher AKI incidence in the allopurinol group needs to be interpreted with caution given higher baseline of cardiovascular disease in the allopurinol group and warrants further investigation,” the researchers said. “Moreover, the clinical benefit gained from treat-to-target urate lowering therapy in gout management extends to those with CKD.”
Source: American Journal of Kidney Diseases.
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