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Prerequisites for the study

Gout is a chronic disease characterized by hyperuricemia, arthropathy, tophi, and urolithiasis, which is associated with an increased risk of cardiovascular disease (CVD) and chronic kidney disease [1]. In patients with gout, the risk of developing CVD complications, including the risk of death, is significantly higher than in individuals without gout [2, 3]. The publication by experts of the US Food and Drug Administration of a recommendation document, which emphasized the requirements for assessing the safety of hypoglycemic drugs for their effect on the risk of developing CVD complications [4], became the basis for testing the safety of other therapeutic agents in similar studies. including drugs for the treatment of patients with gout.

Febuxostat is a non-purine xanthine oxidase inhibitor that is used to reduce the severity of hyperuricemia in patients with gout. Febuxostat inhibits both oxidized and reduced forms of xanthine oxidase and reduces the formation of uric acid (UA) [5]. The use of febuxostat provides highly selective and potent inhibition of xanthine oxidase and more pronounced hypouricemic activity compared to the use of allopurinol at commonly used doses [6]. During its development, febuxostat was compared with placebo and allopurinol in clinical trials that included more than 5000 patients with gout [5-7]. The results of such studies suggested a slight increase in the incidence of CVD complications with the use of febuxostat.

Main results

Between April 2010 and May 2022, 6198 patients were included in the study. Eight patients did not take a single tablet of the study drug, so the modified analysis, which was performed on the assumption that all patients took the prescribed treatment, included data on 6190 patients. There were no significant differences between groups in baseline characteristics.

In the febuxostat group, the final dose of study drug was 40 and 80 mg in 61 and 39% of patients, respectively. In the allopurinol group, 21.8, 44.6, 25.2, 4.3, and 4.1% of patients, respectively, took allopurinol doses of 200, 400, 300, 500, and 600 mg in accordance with the specific protocol for the CCR study.

Overall, 56.6% of patients persistently stopped taking the study drug: in the febuxostat group and allopurinol group 57.3 and 55.9%, respectively. The proportion of patients who did not visit the study center for the next scheduled examination generally reached 45%: in the febuxostat group and allopurinol group 45 and 44.9%, respectively. The median duration of treatment with febuxostat and allopurinol was 728 and 719 days, respectively. The median duration of follow-up in the febuxostat group and allopurinol group was 968 and 942 days, respectively.

The proportion of patients whose blood UA concentration was less than 360 μmol/L 2 weeks after the start of therapy was higher in the febuxostat group compared to the allopurinol group; After this, during the course of the study, more patients in the febuxostat group compared with the allopurinol group had blood sUA concentrations less than 360 μmol/L according to most tests, despite the fact that the differences between the groups were small. In addition, in the febuxostat group, compared with the allopurinol group, there was generally a higher proportion of patients with a blood sUA level less than 300 μmol/L during the study. The incidence of gout flares was similar in the febuxostat group and the allopurinol group, being 0.68 and 0.63 cases per person per year, respectively.

During the study, there were no statistically significant differences between the groups in blood concentrations of electrolytes, glucose and lipids, as well as blood pressure levels and the frequency of use of medications for the treatment of CVD.

After 624 adverse clinical outcomes occurred that led to study termination and before database closure, additional adverse clinical outcomes occurred. The results of the full analysis showed a similar incidence of adverse outcomes included in the main outcome: such outcomes in the febuxostat group and the allopurinol group occurred in 10.8 and 10.4% of patients, respectively, during a median follow-up of 32 months (risk ratio 1 .03 with the upper limit of one-sided 98.5% CI 1.23; p=0.002 for the analysis performed to test the hypothesis of non-inferiority of febuxostat compared to allopurinol). When additional rates of nonfatal adverse events were analyzed, the risk ratios were similar to those in the study as a whole.

However, the risk of death from any cause and the risk of death from complications of CVD were higher in the febuxostat group compared with the allopurinol group. In the febuxostat group and allopurinol group, 7.8 and 6.4% of patients died from any cause, respectively (risk ratio 1.22 with 95% CI from 1.01 to 1.47; p = 0.04), and from complications of CVD - 4.3 and 3.2% of patients, respectively (risk ratio 1.34 with 95% CI from 1.03 to 1.73; p = 0.03). Among the causes of death from complications of CVD, the most common was sudden death from complications of heart disease: this cause of death in the febuxostat group and allopurinol group was observed in 2.7 and 1.8% of patients, respectively. The rates of hospitalization for heart failure and hospitalization for non-ischemic arrhythmias, as well as the incidence of thromboembolic complications and hospitalization for transient cerebrovascular accident were similar in the two groups.

The results of the analysis of the main indicator in the subgroups indicated the absence of heterogeneity in the subgroups of patients with certain baseline characteristics. For CVD mortality, there was an interaction between NSAID use and no low-dose aspirin use (unstandardized p < 0.05 for both comparisons).

According to a planned analysis of the incidence of adverse outcomes included in the main outcome that developed while taking the study drug or within 30 days after discontinuation of therapy, such outcomes in the febuxostat group and allopurinol group occurred in 7.8 and 7.7% of patients, respectively. (hazard ratio 1.00 with upper limit of one-sided 98.5% CI 1.22). This analysis found that mortality from CVD complications was statistically significantly higher in the febuxostat group compared with the allopurinol group (risk ratio 1.49; 95% CI 1.01 to 2.22; p=0.047).

The results of a secondary analysis of the incidence of adverse outcomes included in the main combined indicator that developed during the period of use of the study drugs indicated a similar incidence of such outcomes in the febuxostat group and the allopurinol group (such outcomes developed in 6.2 and 6.4% of patients, respectively; hazard ratio 0.94 with upper limit of one-sided 98.5% CI 1.17). The risk of death from any cause and the risk of death from complications of CVD were higher in the febuxostat group compared with the allopurinol group.

Intervention

Patients were assigned to the febuxostat group or the allopurinol group. Both drugs were prescribed once a day. Randomization was performed with stratification depending on the calculated creatinine clearance (CCr) at study entry (60 ml/min or more or ranging from 30 ml/min or more to less than 60 ml/min).

The dose of allopurinol was adjusted according to renal function. Patients whose calculated CCR was at least 60 ml/min began taking allopurinol 300 mg once daily, and then the dose was increased by 100 mg every month either until the sUA concentration was less than 360 μmol/l or the allopurinol dose was 600 mg. 1 time per day. Patients whose calculated CCR was in the range from 30 ml/min to less than 60 ml/min began taking allopurinol 200 mg once a day and then the dose was increased by 100 mg per month until the concentration of sUA in the blood was less than 360 μmol/ l or reaching a dose of allopurinol 400 mg 1 time per day.

The dose of febuxostat did not vary depending on renal function. Patients assigned to the phlebuxostat group began taking the drug at 40 mg once daily and continued to take this dose if the sUA concentration remained less than 360 μmol/L after 2 weeks of therapy. If the serum sUA level was more than 360 μmol/L at the study center visit 2 weeks after randomization, the dose of febuxostat was increased to 80 mg once daily and this dose was maintained until the end of the study.

Information on sUA concentrations was provided to investigators only during the 10-week dosing period to facilitate dose escalation of study drugs based on response as assessed by blood sUA levels. During this period, study drugs were administered according to a double-blind, double-placebo-controlled study protocol using an interactive voice system. This approach was used to prevent unblinding in patients who were not dosed with study drugs. After dosing was completed, information about blood levels of uric acid was concealed from both the investigators and the study funder, and the interactive voice system was used only to regulate drug dispensing during the course of the study.

At the first study site visit, all hypouricemic medications were discontinued and, in the absence of a history of unacceptable side effects from colchicine, colchicine 0.6 mg/day was prescribed to prevent gout exacerbation. All patients took prophylactic colchicine for the first 6 months after randomization. If colchicine resulted in unacceptable side effects and the calculated Cr was at least 50 ml/min, patients were prescribed naproxen (250 mg twice daily) in combination with lansoprazole (15 mg once daily). If the patient was unable to take either colchicine or naproxen, other nonsteroidal anti-inflammatory drugs (NSAIDs) or prednisone could be used for prophylaxis, or the investigator could choose to treat a gout flare.

Patients were required to visit the study center for the first examination and thereafter at 2, 4, 6, 8, 10 and 12 months, and then 24 months after randomization and then every 6 months until the end of the study. Patients with reduced renal function or patients aged 65 years or older at randomization also visited the study center 9 and 15 months after randomization to assess blood biochemical parameters. If the patient agreed to follow-up but did not attend the study center, the patient was contacted by telephone, but this approach was not considered preferred or recommended.

Sick

The study included patients who were diagnosed with gout according to the criteria of the American Association of Rheumatology [8] and had a history of CVD before randomization. In addition, for inclusion in the study, it was required that the concentration of sUA was at least 420 µmol/l or at least 360 µmol/l for insufficiently treated gout after a washout phase for 1-3 weeks, in which the patient did not take previously used drugs for treatment of gout. A history of CVD was a criterion for inclusion in the study if the patient had previously suffered a myocardial infarction (MI), been hospitalized for unstable angina, suffered a stroke, been hospitalized for a transient cerebrovascular accident, had peripheral vascular disease, and diabetes mellitus with signs of micro- or macrovascular disease. The baseline characteristics of the patients are presented in detail in the table.

Table. Baseline characteristics of patients included in the study Note. Data are presented as percentage of patients, mean ± standard deviation, or median (interquartile range) unless otherwise stated. CVD - cardiovascular diseases; CKD is a chronic kidney disease.