Three hundred seventy-four subjects ≥65 years of age who met all of the inclusion and none of the exclusion criteria were enrolled in the CONFIRMS study. Of these, 115, 128, and 131 were randomized to receive daily febuxostat 40 mg, febuxostat 80 mg, or allopurinol 200/300 mg, respectively. Among those randomized to receive allopurinol, 80/131 (61.1%) subjects had moderate renal impairment and therefore received 200 mg daily.
Figure illustrates the flow of subjects ≥65 years of age through the study. Of the 374 subjects, 83 (22.2%) discontinued prematurely; 28 (7.5%) discontinuations occurred during the first 30 days. Premature discontinuation rates were similar across treatment groups. The primary reason for premature discontinuation was AEs (n = 53; 14.2%).
Flow of Subjects Through the Study.
Demographics, baseline characteristics, and medical histories were similar across treatment groups (Table ). Subjects were predominantly male (85.8%), Caucasian (84.8%), and obese (51.3%; body mass index ≥30 kg/m2), with a mean age of 71 years. Mean duration of gout was 14.6 years and mean baseline sUA was 9.4 mg/dL. Tophi and kidney stones were present in 19.3% and 19.8% of subjects, respectively. Mild or moderate renal impairment was determined in 139 (37.2%) and 229 (61.2%) subjects, respectively. Comorbidities were common; in addition to the predominance of renal impairment, the majority of subjects (87.2%) had some history of cardiovascular disease, inclusive of, but not limited to, hypertension (82.4%), coronary artery disease (24.3%), cardiac arrhythmia (21.1%), and myocardial infarction (10.7%). In addition, 59.6% of elderly subjects had a history of hyperlipidemia and 24.6% were diabetic.
Demographics, baseline characteristics, and comorbiditiesa
Concomitant medication use was high in this population and comparable across treatment groups (Table ). Sixty percent of elderly subjects were taking at least one medication that acted on the renin-angiotensin system, 50% were taking an antithrombotic agent, while 24% were taking at least 1 diuretic. Colchicine was the primary gout flare prophylaxis used by elderly subjects (83.7%), while 10.4% received naproxen. The remaining 5.9% of subjects received indomethacin, nabumetone, prednisone, or celecoxib as flare prophylaxis.
Selected concomitant medication use among elderly subjects during the CONFIRMS trial
Achievement of the primary efficacy endpoint, sUA <6.0 mg/dL at final visit, occurred in 47.3%, 61.7%, and 82.0% of subjects in the allopurinol 200/300 mg, febuxostat 40 mg, and febuxostat 80 mg groups, respectively (Figure ). Febuxostat 80 mg was significantly more efficacious than febuxostat 40 mg or allopurinol for achieving the primary efficacy endpoint (p < 0.001 for both comparisons). In addition, febuxostat 40 mg was superior to allopurinol in this elderly gout population (p = 0.029).
Figure 2 Achievement of sUA <6.0 mg/dL--All Subjects (Primary Endpoint) and by Renal Function. Data regarding the percentage of subjects with normal renal function with sUA <6.0 mg/dL is not presented due to the low number of subjects in this group (more ...)
In subjects with any renal impairment (mild or moderate), the urate-lowering efficacies (sUA of <6.0 mg/dL at final visit) of both febuxostat 40 mg (69/112; 61.6%) and febuxostat 80 mg (104/126; 82.5%) were significantly better than that of allopurinol 200/300 mg (61/130; 46.9%; p = 0.028 vs febuxostat 40 mg; p < 0.001 vs febuxostat 80 mg). Achievement of sUA <6.0 mg/dL by renal status is also illustrated in Figure . Febuxostat 80 mg was significantly more efficacious than both febuxostat 40 mg and allopurinol in subjects with moderate renal impairment (p ≤ 0.001) and superior to allopurinol in subjects with mild renal impairment (p = 0.004). Within the mild or within the moderate renal impairment categories the percentage of subjects achieving final visit sUA <6.0 mg/dL was numerically greater in the febuxostat 40 mg group than in the allopurinol group, but the differences were not statistically significant.
The mean percent change (±standard deviation) in sUA from baseline to the final visit for the febuxostat 40 mg, febuxostat 80 mg, and allopurinol 200/300 mg groups was -36.9% (±16.8), -48.1% (±20.0), and -31.1% (±16.0), respectively. The mean percent change in sUA from baseline at months 2, 4, and 6 are illustrated in Figure . These percent changes were significantly greater in the febuxostat 80 mg group compared with either the febuxostat 40 mg or allopurinol 200/300 mg groups (p < 0.001 for both comparisons) and also in the febuxostat 40 mg group compared with the allopurinol 200/300 mg group (p = 0.011).
Mean Percent Change From Baseline In Serum Urate at Each Scheduled Visit. ap < 0.001 vs allopurinol; bp < 0.001 vs febuxostat 40 mg; cp ≤ 0.027 vs allopurinol. Error bars represent standard deviation.
The proportion of subjects requiring treatment for gout flares declined in all treatment groups during the course of the study. In the febuxostat 40 mg and 80 mg treatment groups, flare rates during the first 2 months were 16.5% (19/115) and 18.0% (23/128), respectively. During the last 2 months of treatment, rates were 9.5% (9/95) and 6.6% (7/106), respectively. Treatment for gout flares was required by 4.6% (6/131) of subjects in the allopurinol 200/300 mg group during the first 2 months; this rate decreased to 0.9% (1/106) during the last 2 months. Flare rates were significantly higher in the febuxostat 40 mg and 80 mg groups compared with the allopurinol group (p ≤ 0.05) during the first 2 months of the study, and in the febuxostat 40 mg group compared with the allopurinol group (p ≤ 0.05) during the last 2 months.
Overall, rates of AEs were low and similar across treatment groups; the most frequently reported AEs were diarrhea (9.6%), upper respiratory tract infection (7.8%), and musculoskeletal and connective tissue signs and symptoms (6.1%) (Table ). Rates of abnormal liver function analyses were reported in 4.3%, 3.9%, and 2.3% of subjects in the febuxostat 40 mg, febuxostat 80 mg, and allopurinol 200/300 mg groups, respectively. The percentage of subjects who discontinued prematurely from the study due to abnormal liver function analyses was 0.9%, 1.6%, and 0 in the febuxostat 40 mg, febuxostat 80 mg, and allopurinol groups, respectively. Elevated liver function tests are listed by treatment group in Table . No subjects experienced concurrent elevated ALT/bilirubin, AST/bilirubin, ALT/alkaline phosphatase, AST/alkaline phosphatase, or ALT/AST/bilirubin levels. Serious AEs occurred in 7.8%, 6.3%, and 11.5% of subjects in the febuxostat 40 mg, febuxostat 80 mg, and allopurinol 200/300 mg groups, respectively. Cardiac disorders and infections were the most frequently reported serious AEs; in the febuxostat 40 mg, febuxostat 80 mg, and allopurinol groups, 0.9%, 1.6%, and 3.1% of subjects reported cardiac disorders and 1.7%, 0.8%, and 3.1% reported infections and infestations. Two subjects in this elderly population died during the study; both were in the allopurinol group. One subject died from hypertensive heart disease, and the other from postsurgical complications related to lung adenocarcinoma and lymphocytic leukemia.
Most frequently reported adverse eventsa and elevated serum liver function tests, by treatment group