Abstract
Background and objectives
Febuxostat, a nonpurine xanthine oxidase inhibitor, is widely used to treat hyperuricemia. Although febuxostat-associated rhabdomyolysis was reported in some patients with CKD, the association between CKD and febuxostat-associated myopathy remains uncertain.
Design, setting, participants, & measurements
Our retrospective cohort study included 1332 patients using febuxostat in Taipei Medical University–Wanfang Hospital from February of 2014 to January of 2016. The primary predictor was time-averaged eGFR as calculated by the equation proposed by the 2009 Chronic Kidney Disease Epidemiology Collaboration. The outcome was febuxostat-associated myopathy defined as elevated creatine kinase levels during febuxostat use that were not attributed to other muscular injuries.
Results
The median duration of febuxostat use was 224 days (25th, 75th percentiles: 86, 441.5 days). Of 1332 study participants, 1222 (91.7%) had CKD; the median eGFR was 20.8 ml/min per 1.73 m2 (25th, 75th percentiles: 9.0, 35.4 ml/min per 1.73 m2). Forty-one of the participants had febuxostat-associated myopathy (3.2%). All patients with myopathy had CKD, and the incident rate was 0.013 (95% confidence interval, 0.01 to 0.02) events per 100 patient-days in patients with CKD. Of 41 patients with myopathy, 37 had myositis, and four had rhabdomyolysis. Myopathy resolved in 17 patients who withdrew from treatment and eight patients who continued febuxostat treatment. Among the evaluated predictors, multivariate analysis showed that only the lowest eGFR tertile was significantly associated with myopathy in febuxostat users. The odds ratio of the lowest eGFR tertile to the highest tertile was 4.21 (95% confidence interval, 1.7 to 10.43). This finding remained consistent among subgroups stratified by age, sex, diabetes status, coronary artery disease, and statin or fibrate use.
Conclusions
Patients with severely reduced eGFR had higher risk of myopathy with treatment of febuxostat. Regular monitoring of creatine kinase level is suggested for early detection of febuxostat-associated myopathy, particularly in patients with CKD.
Keywords: chronic kidney disease; febuxostat; myopathy; Confidence Intervals; coronary artery disease; Creatine Kinase; diabetes mellitus; Febuxostat; Fibric Acids; glomerular filtration rate; Gout Suppressants; Humans; Hyperuricemia; Multivariate Analysis; Myositis; Odds Ratio; Renal Insufficiency, Chronic; Retrospective Studies; rhabdomyolysis; Universities; Xanthine Oxidase
Introduction
Hyperuricemia is highly prevalent in patients with CKD (1–3) and often accompanied by diabetes, hypertension, and hyperlipidemia. Accumulating evidence has revealed that hyperuricemia may contribute to progression of CKD rather than only being a consequence of renal insufficiency (1,4–7). Moreover, hyperuricemia is also associated with adverse outcomes in patients with CKD, regardless of the presence of gouty arthritis (8–10). Therapeutic strategies used to treat hyperuricemia include enhancement of urinary excretion of uric acid with uricosuric agents and reduction of the urate production with xanthine oxidase inhibitors (11,12). However, uricosuric agents are of limited efficacy for patients with a GFR of <30 ml/min per 1.73 m2, and hyperuricemia in patients with CKD is mainly treated with xanthine oxidase inhibitors (11,12). The purine analog xanthine oxidase inhibitor allopurinol has been widely prescribed for the treatment of hyperuricemia. Although the need for dose reduction of allopurinol in patients with CKD remains controversial (13), its prescription is limited due to reduced clearance of its metabolite oxypurinol in this population (14).
Febuxostat is a novel xanthine oxidase inhibitor mainly metabolized in the liver that became available clinically in 2009 (15,16). The safety of febuxostat in patients with advanced CKD was shown in clinical trials (17,18), and it has been considered to be as efficacious and safer than allopurinol in patients with CKD (19). Furthermore, the renoprotective effect of febuxostat in patients with CKD has been shown in an observational study (20) and randomized, controlled trials (21,22). On the basis of these findings, attention has been given to the treatment of asymptomatic hyperuricemia for its protective renal effect (23). Although febuxostat has been considered a safe and efficacious treatment of hyperuricemia in patients with CKD, some patients may have muscular symptoms ranging from muscular soreness, weakness, and cramping to overt rhabdomyolysis when using febuxostat. These observations are in line with a recent clinical study evaluating the safety of febuxostat in patients with CKD; these muscular symptoms were exhibited in their participants (22). Moreover, two case reports have described febuxostat-associated rhabdomyolysis in patients with CKD (24,25). Despite these articles, an association of CKD with muscular complications in febuxostat users remains unclear on the basis of a large clinical study. Muscular complications, albeit minor, do cause a withdrawal of febuxostat in some patients; thus, there is clinical significance. The purpose of this study was to test the hypothesis that the presence of CKD is associated with an increased risk of muscular complications in febuxostat users.
Materials and Methods
Study Participants and Study Design
We conducted a retrospective cohort study including consecutive febuxostat users in the outpatient department of Taipei Medical University–Wanfang Hospital from February of 2014 to January of 2016. The indication for febuxostat use was exclusively hyperuricemia in patients with gouty arthritis who had a GFR of <45 ml/min per 1.73 m2 (including those on RRT) or those failing to achieve a serum uric acid level of <6.0 mg/dl with uricosuric agents according to the reimbursement criteria of Taiwan National Health Insurance. Patients treated with febuxostat for >1 month were included. The date of febuxostat initiation was defined as the index date. Predictors and outcomes of the study were obtained by a review of patient profiles, medication use, and laboratory data of each participant from the index date to the end of the study period in January of 2016. This study was approved by the ethics committee of Taipei Medical University Institutional Review Board and conducted in accordance with the Declaration of Helsinki of 1975 as revised in 2000.
Clinical Evaluation
For all included patients, laboratory data were measured at the discretion of the attending physicians. Time-averaged laboratory data throughout the study period were used for statistical analysis. eGFR was calculated by the equation proposed by the Chronic Kidney Disease Epidemiology Collaboration in 2009. CKD was defined by a baseline eGFR of <60 ml/min per 1.73 m2, including dialysis therapy. The baseline eGFR was defined as the last eGFR obtained within the 6 months before the index date. For participants with missing baseline values (n=156), CKD was defined with the time-averaged eGFR. The daily dose of febuxostat was expressed in the defined daily dose suggested by the World Health Organization Collaborating Center for Drug Statistics Methodology. ESRD was defined as the implementation of hemodialysis or peritoneal dialysis for >3 months before the onset or during the study period. Diabetes mellitus (DM) was defined as use of insulin or antidiabetic agents during the study period. Coronary artery disease (CAD) and hypertension were defined as the presence of a related diagnostic code by the International Classification of Diseases, Ninth Revision. For those with an uncertain status of comorbidities, a review of medical records was used to complete the statistical data. Statin or fibrate use was defined as any prescription of these classes of drugs for >1 month during the study period.
Outcome
The outcome of this study is febuxostat-associated muscular complications defined by the modification of the statin-associated muscular complications defined by the American College of Cardiology/American Heart Association/National Heart, Lung and Blood Institute Clinical Advisory on the Use and Safety of Statins as follows. Myositis referred to muscle symptoms with increased creatine kinase (CK) levels. Rhabdomyolysis referred to muscle symptoms with CK elevation >10 times the upper limit of normal. Myopathy was a general term for any disease of muscle (26). In this study, the definition of febuxostat-associated muscular complications was modified as follows. Myositis was defined as elevation of serum CK level three- to tenfold over normal. Rabdomyolysis was defined as elevation of serum CK level >10 times the upper limit of normal. Myopathy referred to myositis and rhabdomyolysis collectively in this study. Events of elevated CK levels throughout the period of febuxostat use without concomitantly elevated troponin I were considered as myopathy. Furthermore, in all patients with myopathy, medical records were reviewed, and those with myopathy attributed to causes other than febuxostat use were excluded from the outcome events. The muscular symptoms and outcomes of patients with febuxostat-associated myopathy were also documented by a review of medical records. Because CK level assessment was prescribed only if it was clinically indicated, patients with absent CK levels were presumed to be free from myopathy.
Statistical Analyses
Continuous variables are expressed as mean±SD or median (25th, 75th percentiles) values as appropriate, whereas categorical variables are expressed in frequency and percentage. Comparisons of continuous variables are performed using two-tailed t test for unpaired samples or Welch t test as appropriate. Comparisons of categorical variables are performed using chi-squared test or Fisher exact test as appropriate. In the statistical analysis of serum creatinine levels, patients with ESRD were excluded, because serum creatinine levels reflect muscle mass and dialysis adequacy rather than residual renal function in this population. On logistic regression, eGFR was used to represent renal function for all participants, including patients with ESRD. A univariate logistic regression model was used to evaluate the association between candidate variables and myopathy in febuxostat users. Candidate variables with a P value <0.20 on univariate logistic regression were included in a multivariable logistic regression model to confirm the association with myopathy in febuxostat users. The significance of the association between predictors and outcome was expressed in odds ratios and 95% confidence intervals (95% CIs). The Cochran–Armitage Trend test was used to calculate the P value for trend. To test the consistency of findings from multivariate logistic regression models, subgroup analysis was implemented in groups defined by age, sex, statin or fibrate use, and presence of CAD and DM. Of note, our preliminary analysis showed that febuxostat-associated myopathy did not seem to be time dependent. Therefore, logistic regression rather than Cox proportional regression was used. Missing values were imputed using the last value carried forward method. Statistical analysis was carried out using SAS 9.4 (SAS Institute Inc.).
Results
Patient Characteristics
Among 1332 patients, the median duration of febuxostat use was 224 days (25th, 75th percentiles: 86, 441.5 days), and 41 patients were identified to have myopathy after the onset of febuxostat use. Of the study participants, 1222 (91.7%) patients had CKD, and the median eGFR was 20.8 ml/min per 1.73 m2 (25th, 75th percentiles: 9.0, 35.4 ml/min per 1.73 m2). All patients with myopathy had CKD, and the incident rate of myopathy was 0.013 (95% CI, 0.01 to 0.02) events per 100 patient-days in patients with CKD. During the period of febuxostat use, the creatinine test was prescribed 7.3 times per patient-year. Across the entire study period, CK tests were prescribed in 336 patients. The characteristics of the included patients are shown in Table 1. The age, sex, percentage of DM, CAD, hypertension, statin or fibrate user status, serum level of uric acid, total cholesterol, and daily dose of febuxostat were similar in patients with and without myopathy. Patients with myopathy exhibited significantly higher percentage of CKD, significantly higher percentage of ESRD, higher level of serum creatinine, and lower eGFR than those without myopathy. The patients with myopathy received CK and creatinine tests more frequently than those without myopathy.
Table 1.
Demographic characteristics and time-averaged laboratory data of febuxostat users with or without myopathy
| Characteristics | Total | Nonmyopathy | Myopathy | P Value |
|---|---|---|---|---|
| No. | 1332 | 1291 | 41 | — |
| Age, yr (mean ± SD) | 71.5±14.8 | 71.5±14.8 | 71.5±15.4 | 0.99 |
| Men, n (%) | 925 (69.4) | 894 (69.3) | 31 (75.6) | 0.38 |
| CKD, n (%) | 1222 (91.7) | 1181 (91.5) | 41 (100) | 0.04a |
| ESRD, n (%) | 99 (7.4) | 92 (7.1) | 7 (17.0) | 0.03a |
| DM, n (%) | 626 (47.0) | 604 (46.8) | 22 (53.7) | 0.39 |
| CAD, n (%) | 645 (48.4) | 626 (48.5) | 19 (46.3) | 0.79 |
| Hypertension, n (%) | 1208 (90.7) | 1168 (90.5) | 40 (97.6) | 0.17a |
| Statin or fibrate use, n (%) | 685 (51.4) | 661 (51.2) | 24 (58.5) | 0.35 |
| Serum creatinine,b mg/dl | 1.7 (1.4, 2.5) | 1.7 (1.4, 2.5) | 2.6 (1.7, 3.4) | 0.01 |
| eGFR,b ml/min per 1.73 m2 | 20.8 (9.0, 35.4) | 21.3 (9.4, 35.9) | 7.3 (2.5, 21.9) | <0.001 |
| Serum uric acid, mg/dl (mean ± SD) | 8.2±2.1 | 8.2±2.1 | 8.5±2.1 | 0.33 |
| T. chol, mg/dl (mean ± SD) | 172.4±44.7 | 172.0±44.4 | 179.3±50.5 | 0.45 |
| Duration,b d | 224 (86, 442) | 223 (84, 440) | 303 (166, 515) | 0.03 |
| Daily dose (DDD) (mean ± SD) | 0.8±0.6 | 0.8±0.6 | 0.8±0.3 | 0.50 |
| CK testsb | 0 (0, 1) | 0 (0, 0) | 3 (2, 5) | <0.001 |
| Creatinine testsb | 6 (3, 9) | 5 (3, 9) | 11 (7, 14) | <0.001 |
eGFR was calculated by the equation proposed by the Chronic Kidney Disease Epidemiology Collaboration in 2009. —, not applicable; DM, diabetes mellitus; CAD, coronary artery disease; T. chol, serum total cholesterol; DDD, defined daily dose suggested by the World Health Organization Collaborating Center for Drug Statistics Methodology.
Significance tested by Fisher exact test.
Expressed as median (25th, 75th percentiles).
Among the 41 patients with myopathy, 37 patients had myositis, and four patients had rhabdomyolysis. Among the 23 patients who were hospitalized at the time of abnormal CK level, only eight patients were admitted for muscular symptoms. Febuxostat was documented as the culprit agent of myopathy in only two patients, and the cause of myopathy was not defined in other patients. All four patients with rhabdomyolysis were hospitalized, and myopathy was resolved with intravenous infusion of isotonic saline. Four patients with myopathy and elevated CK level died later in the hospital. The causes of death included renal failure in two patients and severe sepsis in two patients. Among the four deceased patients, elevated CK levels were detected incidentally during an in-hospital general evaluation; they were not explained by myocardial ischemia or causes of muscle injury other than febuxostat use. At the conclusion of the study, myopathy resolved in 28 (68.3%) patients, whereas CK levels remained slightly elevated in five (11.9%) patients (Table 2).
Table 2.
Characteristics of patients with myopathy-associated febuxostat use
| Characteristics | Total | Myositis | Rhabdomyolysis |
|---|---|---|---|
| No. | 41 | 37 | 4 |
| Age, yr (mean ± SD) | 72.1±14.8 | 71.4±15.6 | 71.8±12.4 |
| Men, n (%) | 31 (75.6) | 29 (78.4) | 2 (50.0) |
| CKD, n (%) | 41 (100) | 37 (100) | 4 (100) |
| Hypertension, n (%) | 40 (97.6) | 36 (97.3) | 4 (100) |
| DM, n (%) | 22 (53.7) | 18 (48.7) | 4 (100) |
| CAD, n (%) | 19 (46.3) | 17 (46.0) | 2 (50.0) |
| ESRD, n (%) | 7 (17.0) | 6 (16.2) | 1 (25.0) |
| eGFR,a ml/min per 1.73 m2 | 7.3 (2.5, 21.9) | 7.3 (2.5, 22.1) | 7.5 (4.0, 9.9) |
| CK,a mg/dl | 458 (306, 923) | 419 (303, 684) | 12,876.5 (7378, 19,719.5) |
| CK tests, times | 3 (2, 5) | 3 (2, 4) | 5 (4.5, 6.5) |
| Withdrawal from treatment, n (%) | 20 (48.8) | 17 (46.0) | 3 (75) |
| Mortality, n (%) | 4 (9.8) | 4 (10.8) | 0 (0) |
| Hospitalization, n (%) | 23 (56.1) | 19 (51.4) | 4 (100) |
| Muscular symptoms, n (%) | 23 (54.8) | 18 (48.7) | 4 (100) |
| Outcomes, n (%) | |||
| Resolution | 28 (68.3) | 24 (64.9) | 4 (100) |
| Nonresolution | 5 (11.9) | 5 (13.5) | 0 (0) |
| Undefined | 8 (20.0) | 8 (21.6) | 0 (0) |
DM, diabetes mellitus; CAD, coronary artery disease; CK, creatine kinase.
Expressed as median (25th, 75th percentiles).
The Association between CKD and Incident Myopathy in Febuxostat Users
On logistic regression, eGFR tertiles were used to evaluate the association of low eGFR with the incidence of myopathy (first tertile: eGFR≥29.1 ml/min per 1.73 m2; second tertile: 29.1>eGFR≥12.4 ml/min per 1.73 m2; third tertile: eGFR <12.4 ml/min per 1.73 m2). On univariate analysis, hypertension exhibited no association with myopathy (P=0.15), whereas the third eGFR tertile showed a significantly increased risk of myopathy compared with the first eGFR tertile (P<0.001). As predefined, these two variables were included in the multivariate analysis. Of note, the daily dose of febuxostat was not associated with occurrence of myopathy. On multivariate analysis, only the third eGFR tertile exhibited a significantly higher risk of myopathy compared with the first tertile (odds ratio, 4.21; 95% CI, 1.7 to 10.43; P<0.001), indicating that severely reduced eGFR was a risk factor for febuxostat-associated myopathy (Table 3).
Table 3.
Univariate and multivariate logistic regression models to evaluate the association between predictors and myopathy in febuxostat users
| Predictors | Crude OR (95% CI) | P Value | Adjusted OR (95% CI) | P Value |
|---|---|---|---|---|
| Age per 10-yr increment | 1.03 (0.83 to 1.27) | 0.78 | ||
| Men | 1.38 (0.67 to 2.83) | 0.39 | ||
| DM | 1.32 (0.71 to 2.46) | 0.39 | ||
| CAD | 0.92 (0.49 to 1.71) | 0.79 | ||
| Hypertension | 4.21 (0.57 to 30.91) | 0.16 | 2.88 (0.38 to 21.61) | 0.30 |
| Statin of fibrate user | 1.35 (0.72 to 2.53) | 0.36 | ||
| Daily dose per one DDD increment | 0.85 (0.34 to 2.14) | 0.72 | ||
| eGFR tertilesa | ||||
| First | Reference | Reference | ||
| Second | 1.56 (0.55 to 4.42) | 0.42 | 1.41 (0.49 to 4.02) | 0.36 |
| Third | 4.68 (1.91 to 11.48) | <0.001 | 4.21 (1.7 to 10.43) | <0.001 |
| Uric acid per 1-mg/dl increment | 1.08 (0.93 to 1.25) | 0.33 | ||
| T. chol per 10-mg/dl increment | 1.00 (0.99 to 1.01) | 0.45 |
OR, odds ratio; 95% CI, 95% confidence interval; DM, diabetes mellitus; CAD, coronary artery disease, DDD, defined daily dose suggested by the World Health Organization Collaborating Center for Drug Statistics Methodology; T. chol, total cholesterol.
First tertile: eGFR≥29.1 ml/min per 1.73 m2; second tertile: 29.1>eGFR≥12.4 ml/min per 1.73 m2; third tertile: eGFR<12.4 ml/min per 1.73 m2.
To further confirm the consistency of the association between eGFR and febuxostat-associated myopathy across different subpopulations, subgroup analysis was performed by logistic regression in patients of different sexes, patients with different statin or fibrate user status, patients with and without CAD and DM, and patients older or younger than 65 years old. All P values for interaction in the subgroups were >0.05 (data not shown). Among all subgroups, the association between eGFR tertiles and myopathy in febuxostat user remained consistent, in which the third tertile exhibited a significant increased risk of myopathy (Table 4).
Table 4.
The subgroup analysis for the association between reduced GFR and myopathy in febuxostat users
| Subgroups | GFR Tertilesa OR (95% CI) | P Value for Trend | ||
|---|---|---|---|---|
| First | Second | Third | ||
| Age, yr | ||||
| <65 | Reference | 1.04 (0.06 to 16.76) | 12.34 (1.57 to 96.95) | <0.001 |
| ≥65 | Reference | 2.10 (0.63 to 7.05) | 4.29 (1.42 to 12.98) | 0.002 |
| Sex | ||||
| Men | Reference | 2.43 (0.62 to 9.47) | 7.67 (2.26 to 25.97) | <0.001 |
| Women | Reference | 1.05 (0.07 to 16.89) | 8.69 (1.07 to 70.48) | 0.003 |
| DM | ||||
| Yes | Reference | 1.03 (0.20 to 5.14) | 5.84 (1.67 to 20.34) | <0.001 |
| No | Reference | 2.02 (0.37 to 11.15) | 8.24 (1.87 to 36.31) | <0.001 |
| CAD | ||||
| Yes | Reference | 1.72 (0.41 to 7.30) | 3.94 (1.08 to 14.32) | 0.01 |
| No | Reference | 2.57 (0.49 to 13.37) | 8.06 (1.82 to 35.67) | <0.001 |
| Statin or fibrate | ||||
| Yes | Reference | 2.09 (0.52 to 8.46) | 5.45 (1.56 to 19.09) | <0.001 |
| No | Reference | 0.34 (0.04 to 3.31) | 4.68 (1.31 to 16.66) | <0.001 |
P value for trend was tested by the Cochran–Armitage trend test. All P values for interaction in the subgroups were >0.05 (data not shown). OR, odds ratio; 95% CI, 95% confidence interval; DM, diabetes mellitus; CAD, coronary artery disease.
GFR tertiles are in descending order. The tertile with highest GFR was used as the reference group.
Discussion
The main findings in this study showed that severely reduced GFR was independently associated with the occurrence of myopathy in patients undergoing febuxostat treatment (GFR of <12.4 ml/min per 1.73 m2 in this study). Our study also revealed that the myopathy in febuxostat users presents as a spectrum ranging from myositis to overt rhabdomyolysis. In this study, myopathy in febuxostat users improved with intravenous saline infusion, even in patients with continued use of febuxostat. Regarding asymptomatic patients with slightly elevated CK levels, myositis resolved spontaneously with continued febuxostat use. This inferred that myopathy in febuxostat users was possibly self-limited in mild cases or related to hydration status. Most clinicians are unaware of febuxostat-associated myopathy. Therefore, CK levels were prescribed infrequently. In addition, even in patients with myopathy, febuxostat was seldom considered as the culprit of muscular injury. This study indicated the significance of this concern; clinicians should be alert for muscular complications in patients on the treatment of febuxostat, especially those with reduced GFR.
In this study, although the daily dose of febuxostat was not associated with myopathy, the prescribed dose ranged from 40 to 80 mg daily in the vast majority of patients (median: 75.1 mg daily; 10%–90% quantiles: 33.3–86.2 mg daily). As a result, a dose effect may possibly be overlooked by the limited power of the statistical method to detect the difference in such a narrow dose range.
Elevated serum uric acid level is associated with development of hypertension (27,28), cardiovascular mortality (29), and decline of GFR (4,30). Observational studies revealed an association of serum uric acid level with CKD incidence (31–34) and ESRD (6) in the general population. Among these studies, Obermayr et al. (31) reported uric acid level to be a predictor of new-onset kidney disease in a prospective study involving 21,457 healthy volunteers followed for a period of 7 years in the Vienna Health Screening Project. In support of these clinical studies, other experimental studies reported that hyperuricemia resulted in preglomerular arteriolopathy and progression of CKD, independent of its hypertensive effect (5,35). Recently, several randomized, controlled trials showed that uric acid–lowering treatment may delay the progression of CKD (21,36,37). These studies suggest the causal role of hyperuricemia in CKD and provide evidence for treatment of asymptomatic hyperuricemia. Despite the accumulating evidence in support of treatment of asymptomatic hyperurecemia, the policy of Taiwan National Health Insurance takes a more conservative attitude in this area and provides uric-lowering agents only to patients who are hyperurecemic with gouty arthritis. In line with this policy, the findings of this study suggest that febuxostat should be used with caution in patients with severely reduced GFR at risk of myopathy.
To date, among the available treatment modalities of hyperuricemia, xanthine oxidase inhibitors remain the treatment of choice. Allopurinol, the prototypic agent of xanthine oxidase inhibitors, is limited by its fatal hypersensitivity reaction and need for dose reduction in patients with CKD (38). The introduction of febuxostat contributed to an advance in the treatment of hyperuricemia, especially in patients with CKD, in whom dose reduction was not required (39). Febuxostat had also been shown to exhibit greater efficacy to lower serum uric acid level in randomized clinical trials involving patients either with or without renal impairment (40–42). However, the most common adverse reaction causing withdrawal of febuxostat was an abnormal liver function test. Additionally, for patients using febuxostat long term, a slightly higher risk of adverse cardiac event was reported compared with in those undergoing treatment with allopurinol (43).
Febuxostat-associated rhabdomyolysis has not been reported in randomized initial trials but was infrequently mentioned in postmarketing surveillance (44). Recently, two case reports of severe febuxostat–associated rhabdomyolysis were published (24,25). However, the comprehensive picture of clinical manifestation and associated risk factors of febuxostat-associated myopathy have not been presented. To our knowledge, this study is the first to show the association between CKD and febuxostat-associated myopathy in a large retrospective cohort study. In the two previously published case reports describing febuxostat-associated rhabdomyolysis in patients with CKD, both of the patients were using statin or fibrate concomitantly, which also causes myopathy (24,25). Nonetheless, in this study, univariate logistic regression model showed that combined use of statin or fibrate was not significantly associated with febuxostat-associated myopathy, which implies that these two classes of lipid-lowering agents can be used safely in febuxostat users.
A recent randomized, controlled trial designed to evaluate the safety of febuxostat in patients with CKD (eGFR of 15–50 ml/min per 1.73 m2) had reported musculoskeletal connective tissue pain and related discomfort in the participants in a 12-month study period. The percentages of this complication were 12.5%, 15.6%, and 9.4% in patients using febuxostat at 30 mg twice daily, febuxostat at 40/80 mg twice daily, and placebo, respectively. Nonetheless, serum CK level was not reported in this trial (45). In our study, febuxostat-associated myopathy was identified in 41 of 1332 participants (3.1%). This lower percentage of febuxostat-associated myopathy was possibly due to an underestimation of the occurrence of febuxostat-associated myopathy in our study resulting from absence of CK measurement in some patients with asymptomatic or mild myopathy. This infers that the exact incident rate of febuxostat-associated myopathy may be higher than that presented in our study. Notably, topiroxostat, a novel nonpurine xanthine oxidase inhibitor analogous to febuxostat, had recently been tested in a phase 3 trial conducted in Japanese patients who are hyperurecemic (46). In this trial, rhabdomyolysis was also documented as an adverse effect, suggesting that myopathy may be a common adverse effect of topiroxostat and febuxostat use.
The limitations of this study are its retrospective design and the fact that all laboratory data were measured heterogeneously at the discretion of the attending physician. Thus, baseline measurements were missing for slightly >10% of patients. To compensate for this limitation, time-averaged data were used for statistical analysis to represent the comprehensive condition of each participant. Another limitation is that CK level was not measured routinely, and therefore, the occurrence of febuxostat-associated myopathy may be underestimated as mentioned previously. However, this infers that febuxostat-associated myopathy may be of larger significance than shown in this study. To fill this gap, we suggest that CK level and muscular symptoms be monitored in clinical trials of febuxostat in the future.
Disclosures
None.
Acknowledgments
This study was supported Taipei Medical University–Wanfang Hospital grant 102-wf-eva-32 and partially supported by Taiwan Ministry of Science and Technology Academic Excellence Program grants MOST 105-2633-B-009-003, VGH-V98B1-003, VGH-V100E2-002, and VGHUST103-G7-2-1 from Taipei Veterans General Hospital and a grant from the Ministry of Education “Aim for the Top University” Plan.
Funding institutions took no part in study design, data collection and analysis, publication intent, or manuscript preparation.
Footnotes
Published online ahead of print. Publication date available at www.cjasn.org.
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