Cardiovascular safety of febuxostat versus allopurinol among the Asian patients with or without gout: A systematic review and meta-analysis.

The cardiovascular (CV) safety of febuxostat compared to allopurinol for the treatment of hyperuricemia among Asian patients is uncertain. In this study, we conducted a systematic review and meta-analysis to compare the CV safety profiles of febuxostat with allopurinol in Asian patients with hyperuricemia. A total of 13 studies were included. On the basis of the pooled results of cohort studies, febuxostat users were at a significantly higher risk for acute coronary syndrome (ACS; hazard ratio [HR]: 1.06, 95% confidence interval [CI]: 1.03-1.09, p < 0.01), atrial fibrillation (HR: 1.19, 95% CI: 1.05-1.35, p < 0.01) than allopurinol users, whereas no significant difference between febuxostat and allopurinol existed for urgent coronary revascularization (HR: 1.07, 95% CI: 0.98-1.16, p = 0.13), and stroke (HR: 0.96, 95% CI: 0.91-1.01, p = 0.13). Nevertheless, that difference in results of acute decompensated heart failure (ADHF; HR: 0.73, 95% CI: 0.35-1.53, p = 0.40) and all-cause death (HR = 0.86, 95% CI: 0.49-1.51, p = 0.60) was not significant based on randomized controlled trials. In the Chinese subgroup, febuxostat could increase the risk of ADHF (HR: 1.22, 95% CI: 1.01-1.48, p < 0.05), CV death (HR: 1.25, 95% CI: 1.03-1.50, p < 0.05), and all-cause mortality (HR: 1.07, 95% CI: 1.01-1.14, p < 0.05) compared to allopurinol. In conclusion, the use of febuxostat, compared with allopurinol among Asian patients, was associated with a significantly increased risk of adverse CV events.

Two cases report of febuxostat-induced acute liver injury: acute heart failure as a probable risk factor?

Drug induced liver injury, as a sub-type of hepatotoxicity, is rare but practical problem, producing challenges for clinicians. Within the recent two months, two patients with heart failure develop febuxostat-induced acute liver injury during hospital stay. To the best of our knowledge, very few cases of febuxostat-induced hepatotoxicity have been reported up to now. In this paper, two unusual cases of febuxostat-induced acute liver injury are herein described. The medical history, drug treatment, clinical symptoms, liver function tests, diagnosis and prognosis are fully given in this paper. It should be noticed that, two liver injury happen in patients of heart failure with reduced ejection fraction. Whether heart failure is a risk factor of febuxostat related liver injury, deserves further research. This paper reminds the clinicians that more attention should be paid to the acute liver injury caused by febuxostat, and liver function tests are suggested especially for patients of heart failure.

Study of hispidulin in the treatment of uric acid nephropathy based on NF-κB signaling pathway.

Uric acid nephropathy (UAN) is caused by purine metabolism disorders. UAN rat models were established in SD rats. The modeling rats received different doses of hispidulin (10, 20, 50 mg/mL). Febuxostat was applied as the positive drug. Serum creatinine, uric acid (UA), and cystatin-C (cys-C), neutrophil gelatinase-associated lipocalin (NGAL), IL-1ß, IL-8, TNF-α, and IL-6 in rats were detected. HE staining was done to assess kidney injury. UAN rats possessed prominent levels of serum creatinine, UA, cys-C, and NGAL, which all reduced after hispidulin treatment in a dose-dependent manner. HE staining determined the improvement of kidney injury after treatment, which was comparable to the efficacy of febuxostat. Hispidulin inhibited the release of IL-1ß, IL-8, TNF-α, and IL-6 in UAN rats. Hispidulin enhanced autophagy in UAN rats, presenting as ascending LC3II/I ratio and downregulated P62. The increasing trend of inflammasome-related proteins of NLRP3 and Caspase-1 was changeovered by hispidulin. The activation of NF-kB signaling was intercepted by hispidulin in UAN rats. Hispidulin can effectively improve renal function injury caused by UAN in rats. The mechanism may be related to the inhibition of inflammatory response induced by autophagy and activation of NF-κB pathway.

Cardiovascular Safety of Febuxostat in Patients With Gout or Hyperuricemia: A Systematic Review of Randomized Controlled Trials.

INTRODUCTION: To this date, a causal relationship between febuxostat and cardiovascular disease remains controversial as comparison between trials can be challenging and may lead to misleading conclusions, especially when facing heterogeneous cardiovascular outcomes. We aimed to compare the cardiovascular outcomes in the most pertinent trials of febuxostat compared with controls. METHODS: We searched electronic databases using a PICOS-style approach search strategy of randomized controlled trials (RCTs) on cardiovascular outcomes of febuxostat in patients with gout or hyperuricemia. We conducted a quality and risk of bias assessment of the included clinical trials. The definition of major adverse cardiovascular event as well as all reported cardiovascular outcomes were retrieved from every involved trial. RESULTS: Of the 1173 records identified from all sources, 20 RCTs were included in the analysis. The mean duration of follow-up was 69.7 ± 81.5 weeks, and febuxostat dose ranged from 10 to 240 mg with 80 mg being the most commonly used dosage. Overall, the quality of evidence deriving from all RCTs showed concerns in most studies (65%). Major adverse cardiovascular event was defined in 7 of the 20 RCTs (35%), and cardiovascular outcome reporting was very heterogeneous. Overall, the data of cardiovascular safety of febuxostat were reassuring. CONCLUSIONS: Our systematic review showed high level of concerns in quality assessment domains as well heterogeneous cardiovascular outcomes across included studies. Cardiovascular outcomes in the majority of White males with gout treated with febuxostat were reassuring when compared with allopurinol. Further studies are needed to draw conclusions in patients with severe cardiovascular disease.

Effectiveness and safety of different doses of febuxostat compared with allopurinol in the treatment of hyperuricemia: a meta-analysis of randomized controlled trials.

BACKGROUND: The prevalence of hyperuricemia has increased steadily with the continuous improvement of living standards. Some studies have reported the clinical effectiveness and safety of different doses of febuxostat in comparison with allopurinol in hyperuricemia treatment, but the sample sizes of the studies have been small, and the results have been inconsistent. We designed this meta-analysis to evaluate the effectiveness and safety of different doses of febuxostat compared with allopurinol in the treatment of hyperuricemia. METHODS: The Cochrane Library, Embase, PubMed, Web of Science and ClinicalTrials.gov databases were searched to identify randomized controlled trials (RCTs) comparing the use of febuxostat and allopurinol for the treatment of hyperuricemia. The effectiveness and safety of different doses of febuxostat and allopurinol in treating hyperuricemia were assessed using meta-analysis. RESULTS: A total of 11 randomized controlled trials were included in the meta-analysis. The results of the meta-analysis showed that the percentage of patients achieving serum uric acid levels of 6.0 mg/dL or less was higher among patients taking febuxostat (80 mg/d) than among patients taking allopurinol (200-300 mg/d) [RR = 1.79, 95% CI (1.55, 2.08), P < 0.00001]. However, there was no statistically significant difference in the percentage of patients achieving serum uric acid levels of 6.0 mg/dL or less between febuxostat (40 mg/d) and allopurinol (200-300 mg/d) [RR = 1.10, 95% CI (0.93, 1.31), P = 0.25]. There was also no statistically significant difference in the incidence of gout between the febuxostat (40 mg/d) and allopurinol (200-300 mg/d) [RR = 0.97, 95% CI (0.64, 1.49), P = 0.91] or between the febuxostat (80 mg/d) and allopurinol (200-300 mg/d) [RR = 1.13, 95% CI (0.81, 1.58), P = 0.48].No significant difference in the incidence of major adverse reactions as observed between the febuxostat (40 mg/d) and allopurinol (200-300 mg/d) [RR = 1.16; 95% CI (0.43, 3.16), P = 0.77] or between the febuxostat (80 mg/d) and allopurinol (200-300 mg/d) [RR = 1.06; 95% CI (0.79, 1.42), P = 0.70]. The incidence of adverse cardiovascular events did not differ significantly between the febuxostat (40 mg/d) and allopurinol (200-300 mg/d) [RR = 1.30; 95% CI (0.57, 2.95), P = 0.53] or between the febuxostat (80 mg/d) and allopurinol (200-300 mg/d) [RR = 1.79; 95% CI (0.74, 4.32), P = 0.20]. CONCLUSIONS: Febuxostat (80 mg/d) was associated with a higher percentage of patients achieving serum uric acid levels of 6.0 mg/dL or less than allopurinol (200-300 mg/d), however, febuxostat (80 mg/d) did not exhibit better efficacy in reducing the incidence of gout. More attention should be devoted to the adverse reactions caused by an increase in febuxostat doses.

Safety update: febuxostat and CVD.

Overview of: Medicines and Healthcare products Regulatory Agency. Febuxostat: updated advice for the treatment of patients with a history of major cardiovascular disease. Drug Safety Update 2023;16(10):3.

[Hyperuricemia and kidney damage in patients with cardiovascular disease: A review].

Many studies have been conducted confirming the effect of uric acid (UA) on kidney function. It is obvious that there is a relationship between the effect of UA not only on kidney function, but also on the cardiovascular system, increasing cardiovascular risk. The review article provides basic information about the pathogenesis, principles and features of prescribing therapy to patients with chronic kidney disease (CKD) and cardiovascular disease. A lot of data currently indicates that hyperuricemia, both with and without crystal deposition, is associated with high cardiovascular risk and decreased kidney function. A number of studies and meta-analyses indicate that urate-reducing therapy prevents and slows down the decline in kidney function in patients with CKD, many of whom suffer from cardiovascular diseases or at least have several risk factors. Despite the fact that currently the guidelines for the treatment of CKD do not include a recommendation for the start of urate-lowering therapy, a large amount of data has been accumulated on the potential benefits of such treatment even in the absence of a diagnosis of gout. The preferred group of drugs for this group of patients are xanthine oxidase inhibitors, and for patients with eGFR below 30 ml/min/1.73 m2, it seems that allopurinol currently has larger evidence base for the efficacy and safety of prescribing.

A Phase I Study to Evaluate the Pharmacokinetic Drug‒Drug Interaction of HP501, Febuxostat, and Colchicine in Male Chinese Patients with Hyperuricemia.

BACKGROUND AND OBJECTIVE: HP501 is a highly selective renal urate transporter 1 (URAT1) inhibitor that is being developed for the treatment of hyperuricemia and gout. The primary aim of the present study was to study the pharmacokinetic drug‒drug interactions (DDIs) of HP501, febuxostat, and colchicine in hyperuricemic patients. METHODS: Hyperuricemic patients were randomly divided into group A, receiving HP501 40 mg once daily on days 1 and 4-10, and group B, receiving febuxostat 40 mg once daily on day 1 and HP501 40 mg plus febuxostat 40 mg on days 4-10. All patients received 0.5 mg colchicine once daily from day 4 to 12. Blood samples were collected for measurement of drug concentrations and serum uric acid (sUA) levels. RESULTS: Coadministration of colchicine with HP501 or HP501 plus febuxostat did not affect steady-state exposure to colchicine. Coadministration of HP501 and febuxostat did not significantly change the pharmacokinetic profiles of either drug. Following multiple administrations of HP501 40 mg once daily for 7 days, the maximal percent sUA change from baseline in group A was - 24.77%. The coadministration of HP501 40 mg and febuxostat 40 mg in group B for 7 days resulted in a - 55.82% maximal sUA reduction from baseline, and all patients achieved the goal of sUA < 360 µmol/L. All adverse events (AEs) were either mild or moderate, and the most frequently reported AEs were diarrhea and elevated alanine aminotransferase (ALT) levels. CONCLUSIONS: The concomitant use of HP501, febuxostat, and colchicine did not produce clinically meaningful DDIs in terms of their pharmacokinetic properties. CLINICAL TRIAL REGISTRATION: No. CTR20212261 ( http://www.chinadrugtrials.org.cn/ ) registered September 2021.

Association between use of febuxostat and muscle injury: A disproportionality analysis and meta-analysis of randomized controlled trials.

AIMS: Several reports have suggested an association between febuxostat and muscle injury. The purpose of this study was to determine whether febuxostat increases the risk of muscle injury. This study included an analysis of the US Food and Drug Administration Adverse Event Reporting System (FAERS) database and a systematic review/meta-analysis of randomized controlled trials. METHODS: First, evaluation of the FAERS data included a disproportionality analysis that compared patients with and without rhabdomyolysis according to whether they were receiving febuxostat or allopurinol. Second, a systematic review/meta-analysis was performed to assess the risk of rhabdomyolysis and muscle injury in patients who used febuxostat or allopurinol. RESULTS: Analysis of the FAERS data revealed disproportionality for increasing rhabdomyolysis in patients who received febuxostat (reporting odds ratio 4.49, 95% confidence interval [CI] 3.72-5.38, P < .01) and allopurinol (reporting odds ratio 2.49, 95% CI 2.25-2.75, P < .01). Nineteen studies were eligible for inclusion in the systematic review/meta-analysis. Rhabdomyolysis was reported in only 1 study. The risk of any type of muscle damage was not significantly increased with febuxostat compared with placebo (risk ratio 0.92, 95% CI 0.73-1.17, P = .52, I2  = 0%; 8 studies including 2597 participants, high-certainty evidence) or allopurinol (risk ratio 1.03, 95% CI 0.94-1.11, P = .56, I2  = 0%; 9 studies including 17 644 participants, moderate-certainty evidence). CONCLUSION: Febuxostat does not seem to affect the risk of muscle injury. However, the findings of this meta-analysis indicate a need for further high-quality observational studies with long-term follow-up.

A retrospective observational study of the appropriate starting dose of febuxostat in patients with gout.

BACKGROUND/AIMS: The occurrence of gout attacks at the start of uric acid lowering treatment worsens compliance. We aimed to determine the appropriate dose of febuxostat to reduce the occurrence of gout attacks during the initial treatment period. METHODS: We retrospectively analyzed the data of patients diagnosed with gout who underwent treatment at Jeju National University Hospital between May 2018 and May 2020. RESULTS: Two-hundred and twenty-seven patients were included, with a mean age of 53.2 ± 16.4 years, and 219 (96.5%) were male. The patients were divided into two groups according to the starting dose of febuxostat (20 mg vs. 40 mg). There were no significant differences in mean age, disease duration, colchicine, estimated glomerular filtration rate (eGFR), initial uric acid levels, and presence of subcutaneous tophi between the two groups. Gout attacks occurred more frequently in the 20 mg group than in the 40 mg group during the first 3 months of treatment (32.0% vs. 14.3%, p = 0.002), particularly during the first month (21.3% vs. 7.5%, p = 0.005). Multivariate logistic regression analysis was conducted adjusting for the effects of disease duration, the presence of subcutaneous tophi, eGFR, and initial uric acid levels. A febuxostat starting dose of 40 mg (odds ratio, 0.464; 95% confidence interval [CI], 0.246 to 0.862; p = 0.015) and anti-inflammatory prophylaxis (odds ratio, 0.359; 95% CI, 0.158 to 0.813; p = 0.014) were found to be independent factors associated with a gout attack. CONCLUSION: Starting uric acid lowering treatment with febuxostat 40 mg rather than 20 mg may reduce the incidence of gout attacks in the early period of treatment in Korean patients with gout.

`Risk of cardiovascular disease associated with febuxostat versus allopurinol use in patients with gout: a retrospective cohort study in Korea.

Febuxostat is the drug used to treat hyperuricemia in patients with gout. Recently, the usage of Febuxostat has been controversial over the side effects in cardiovascular. The study aimed to comparatively analyze the risk of cardiovascular disease associated with febuxostat and allopurinol use in Korean patients with gout. A cohort study was conducted using national insurance claim data from the Health Insurance Review and Assessment Service (HIRA). Adult patients who were diagnosed with gout and prescribed febuxostat or allopurinol more than once from July 1, 2015, to June 30, 2018 were studied. The outcome was cardiovascular disease. Analysis was performed using Cox's proportional hazard model following 1:1 propensity score matching to estimate the hazard ratio with a 95% confidence interval. In total, 90,590 patients were defined as the final study cohort who had an average follow-up of 467 days, including 28,732 and 61,858 patients in the febuxostat and allopurinol groups, respectively. After the 1:1 propensity score matching, the risk of cardiovascular disease in the febuxostat group was significantly higher than in the allopurinol group (HR: 1.17; 95% CI: 1.10-1.24). In the sensitivity analysis, the risk of cardiovascular disease in the febuxostat group was significantly higher than in the allopurinol group (HR: 1.09; 95% CI: 1.04-1.15). However, further sensitivity analysis showed no statistically significant difference between the febuxostat group and allopurinol group after adjusting for cardiovascular disease history before the index date. Similarly, no statistically significant difference was found between the two drugs in the subgroup analysis. Febuxostat was not associated with a significantly increased risk of cardiovascular disease.

C-reactive Protein Levels and Cardiovascular Outcomes After Febuxostat Treatment in Patients with Asymptomatic Hyperuricemia: Post-hoc Analysis of a Randomized Controlled Study.

PURPOSE: Inflammation plays an important role in the initiation and progression of atherosclerosis, leading to poor clinical outcomes. Hyperuricemia is associated with the activation of the Nod-like receptor protein 3 inflammasome. Here, we investigated whether inhibition of inflammation using febuxostat lowered the risk of cardiovascular events. METHODS: This is a post-hoc analysis of the randomized trial, Febuxostat for Cerebral and CaRdiorenovascular Events PrEvEntion StuDy (FREED). In total, 1067 patients (736 men and 331 women) were included in the analysis. We compared the serial changes in high-sensitivity C-reactive protein (hs-CRP) levels between febuxostat and non-febuxostat groups and assessed the correlation between the changes in uric acid (UA) and hs-CRP levels after febuxostat treatment. We also determined whether febuxostat could reduce a hard endpoint, defined as a composite of cardiovascular events and all-cause mortality. RESULTS: Serum UA levels in the febuxostat group were significantly lower than those in the non-febuxostat group after randomization (p < 0.05). However, hs-CRP levels were comparable between the two groups during the study. No significant correlation was observed between the changes in UA and hs-CRP levels after febuxostat treatment. The hard endpoints did not differ significantly between the two groups. In patients with baseline hs-CRP levels > 0.2 mg/dL or those administered 40 mg of febuxostat, the drug did not reduce hs-CRP levels or decrease the hard endpoint. CONCLUSION: Febuxostat reduced the UA levels but did not affect the CRP levels, and therefore may fail to improve cardiovascular outcomes after treatment. TRIAL REGISTRATION: ClinicalTrial.gov (NCT01984749). https://clinicaltrials.gov/ct2/show/NCT01984749.

Effect of Febuxostat versus Allopurinol on the Glomerular Filtration Rate and Hyperuricemia in Patients with Chronic Kidney Disease.

Hyperuricemia is a risk factor for the progression of chronic kidney disease (CKD). We compared febuxostat versus allopurinol in the progression of CKD and hyperuricemia in 101 patients with Stage 3-4 CKD treated with febuxostat or allopurinol for at least 6 months for hyperuricemia (>7 mg/dL) between January 2012 and December 2016. Baseline characteristics, serum uric acid (SUA), serum creatinine, and estimated glomerular filtration rate (eGFR) at entry and 6 months were compared. The primary outcome was the decline in eGFR and the secondary outcomes were reductions in SUA and adverse events. Fifty-four were in the febuxostat group and 47 were in the allopurinol group. The baseline characteristics were comparable except for age. The mean dose of febuxostat and allopurinol was 43.70 ± 14.5 mg and 108.51 ± 40 mg, respectively. After 6 months, the median rate of decline in eGFR was 1.2 mL/min/1.73 m2 (IQR: 1.2, 5.5) in the febuxostat group and 3.1 mL/min/1.73 m2 (0.6, 6.2) in the allopurinol group, but this was not statistically significant (P = 0.136). The mean reduction in SUA was significantly better (P = 0.004) in the febuxostat group (3.9 ± 1.7 mg/dL) compared with the allopurinol group (2.1 ± 1.0 mg/dL). Both drugs had no serious adverse events. Febuxostat was better at reducing hyperuricemia than allopurinol, but there was no significant difference in the progression of CKD. Large randomized trials and long-term follow-up are necessary to see whether febuxostat has a favorable effect on the progression of CKD.

Risk of Erectile Dysfunction in Male Patients with Gout Treated with Febuxostat or Allopurinol: A Propensity Score-Matched Cohort Study.

OBJECTIVE: To evaluate and compare the risk of erectile dysfunction (ED) associated with the use of allopurinol and febuxostat in adult male gout patients. METHODS: We conducted a cohort study using TriNetX (Cambridge, MA, USA), a global federated health research network that provides real-time electronic medical record datasets. We analyzed and compared the associated risk of ED in gout patients who started taking allopurinol or febuxostat within 12 months. Propensity score matching was performed to adjust for demographic variables, comorbidities, and medication use. Kaplan-Meier analysis was used to estimate the probability of the outcome of interest. The hazard ratio (HR) and associated confidence intervals were calculated along with the proportionality test using R's Survival Package v3.2-3. RESULTS: We identified 679,862 patients with gout among 107,517,445 patients in the database. Of these patients, 24,000 were treated with febuxostat and 299,726 with allopurinol. After propensity matching, 9075 patients receiving febuxostat without allopurinol (febuxostat group) and 9075 corresponding patients receiving allopurinol without febuxostat (allopurinol group) were analyzed for comparison. Among all male patients over 19 years of age, febuxostat was associated with a significantly higher risk of ED versus allopurinol (HR 1.354; 95% confidence interval (CI) 1.003-1.829; log rank test, p = 0.047). After subgroup analysis, in gout patients aged 19-64 years, a significantly higher incidence of ED was observed in the febuxostat group than in the allopurinol group (HR 2.002, 95% CI 1.282-3.126). The risk of ED did not differ significantly between the allopurinol and febuxostat groups in gout patients older than 65 years. CONCLUSIONS: Febuxostat may be associated with a higher risk of ED than allopurinol in adult male patients with gout. Future large-scale prospective studies are warranted to confirm our results.

Low-dose febuxostat exhibits a superior renal-protective effect and non-inferior safety profile compared to allopurinol in chronic kidney disease patients complicated with hyperuricemia: A double-centre, randomized, controlled study.

WHAT IS KNOWN AND OBJECTIVE: The present study compared the efficacy and safety of low-dose febuxostat versus allopurinol in chronic kidney disease (CKD) patients complicated with hyperuricemia (HUA). METHODS: In this double-centre, randomized, controlled study, 120 CKD patients complicated with HUA were recruited and randomly assigned to low-dose febuxostat group (20 mg/day) or allopurinol group (200 mg/day) at 1:1 ratio. The serum creatinine (Scr), serum uric acid (SUA), and estimated glomerular filtration rate (eGFR) were measured at baseline (M0), month (M) 1, M3, and M6. Besides, the drug-related adverse events (AEs) were recorded. The primary outcome was the proportion of patients showing a > 10% decline in eGFR from M0 to M6. RESULTS: The eGFR level was increased at M6, but similar at M0, M1 and M3 in febuxostat group compared with allopurinol group. Notably, the proportion of patients with >10% decline in eGFR from M0 to M6 was decreased in febuxostat group compared with allopurinol group. However, there was no difference of Scr, SUA at M0, M1, M3 and M6 between febuxostat group and allopurinol group. Moreover, there was no difference of drug-related AEs between febuxostat group and allopurinol group. Further subgroup analysis exhibited that low-dose febuxostat presented superior effect on attenuating eGFR decline and lowering SUA level compared with allopurinol in CKD stage 3 subgroup, but not in CKD stage 2 subgroup. CONCLUSION: Low-dose febuxostat may exhibit a superior renal-protective effect, non-inferior SUA lowering ability and safety profile compared with allopurinol in CKD patients complicated with HUA.

A modified xanthine oxidase cell model for screening of antihyperuricemic functional compounds.

Hyperuricemia is a purine metabolism disorder, with increasing prevalence worldwide. Here, a high throughput cell model for screening of antihyperuricemic compounds was set up. Human kidney cells (HK2 cells) were stimulated with adenosine and the resulting supernatant and lysate were then analyzed using high performance liquid chromatography (HPLC). The results showed that hypoxanthine content was increased in both HK2 cells supernatant and xanthine oxidase (XO)-overexpressing HK2 cells lysate, but no uric acid was detected due to lower endogenous XO content in these cells. Exogenous XO was added to the supernatant, and then used to evaluate the antihyperuricemic activity of Febuxostat and two the previously identified peptides, Pro-Gly-Ala-Cys-Ser-Asn (PGACSN) and Trp-Met-Leu (WML). By adding exogenous XO, this combined-adenosine-XO-induced hyperuricemia model was optimized and established, and the Febuxostat and peptides were confirmed to significantly reduce uric acid production in the HK2 cells supernatant (p < 0.05). Therefore, this cell model could be recommended for screening potential bioactive antihyperuricemic compounds.

Cardiovascular safety associated with febuxostat versus allopurinol among patients with gout: Update with accumulated use of febuxostat.

BACKGROUND: To re-evaluate comparative cardiovascular (CV) safety of febuxostat versus allopurinol among patients with gout following recent accumulated use of febuxostat. METHODS: Using 2011-2019 Korea National Health Insurance database, we conducted a cohort study comparing gout patients initiating febuxostat versus allopurinol, 1:1 matched on a propensity-score (PS) for >60 covariates. The primary outcome was a composite endpoint of myocardial infarction, coronary revascularization, and stroke. Secondary outcomes were individual components of the primary outcome, hospitalized heart failure, and all-cause mortality. Subgroup analyses were done for those at high CV risk, long-term users (follow-up >3 years), and those without chronic kidney disease. We used Cox proportional hazard models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: We included 160,930 PS-matched pairs of febuxostat and allopurinol users (mean age 59.3 years, 79.6% male). Incidence rates of the primary outcome were 2.06 and 2.27 per 100 person-years for febuxostat and allopurinol users, respectively, with a HR [95% CI] of 1.03 [0.95-1.12] comparing febuxostat versus allopurinol initiators. We also observed similar risks for secondary outcomes, except for reduced all-cause mortality among febuxostat users (HR [95% CI] of 0.84 [0.78-0.91]). Subgroup analyses also showed non-inferior CV safety of febuxostat. CONCLUSION: In this population-based cohort study including the largest number of febuxostat users to date, we found non-inferior CV safety of febuxostat versus allopurinol. There was a 16% reduction in all-cause mortality among febuxostat users.

Increased risk of cardiovascular events and death in the initial phase after discontinuation of febuxostat or allopurinol: another story of the CARES trial.

OBJECTIVES: The Cardiovascular Safety of Febuxostat or Allopurinol in Patients with Gout (CARES) trial suggested a higher risk of cardiovascular (CV) death from febuxostat than from allopurinol. However, a significant number of patients died after discontinuation of febuxostat or allopurinol. We investigated whether major adverse cardiovascular events (MACE) and CV death were increased because of discontinuation of febuxostat or allopurinol using the CARES trial data. METHODS: We compared the MACE that occurred during administration and after discontinuation in the initial phase after discontinuation, and we compared the CV and non-CV mortality rates in the initial phase after discontinuation to determine the impact of discontinuation of febuxostat or allopurinol. RESULTS: Among 6190 patients, the incidence rate per 100 person-years for MACE was 3.11 during administration and 6.71 after discontinuation. MACE was significantly increased after discontinuation compared with that during administration within 1 month (HR 7.40; 95% CI 5.38 to 10.17) and 6 months (HR 5.22; 95% CI 4.26 to 6.39). In the analysis excluding death induced by adverse events that occurred up to 1 day after the last medication, the CV mortality rate was higher than the non-CV mortality rate within 6 months (45.7% vs 27.9%, p=0.0001). In addition, changes in serum uric acid levels from baseline to the last measurement before discontinuation were significantly associated with higher MACE risk after drug discontinuation (HR 1.14; 95% CI 1.04 to 1.26). CONCLUSIONS: MACE and CV death were increased in the initial stage after discontinuation of febuxostat or allopurinol in patients with gout.