Urate Lowering Efficacy of Febuxostat Versus Allopurinol in Hyperuricemic Patients with Gout

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1 Philippine Journal of Internal Medicine Meta-Analysis Urate Lowering Efficacy of Febuxostat Versus Allopurinol in Hyperuricemic Patients with Gout Erika Bianca S. Villazor-Isidro, M.D.*; John Carlo G. Brojan, M.D.*; Christine Joy R. Pega-Flores, M.D.*; Paul V. Santos-Estrella, M.D.* Abstract Background: The prescribed maximum dose of allopurinol is 300 mg/day to maintain a serum uric acid (sua) concentration of < 6.0 mg/dl. However, increasing evidence shows that 300 mg dose is ineffective in achieving the target sua level, limiting allopurinol s use in certain subsets of patients who are intolerant to allopurinol such as patients with chronic kidney disease, with multiple comorbidities and elderly patients. Objective: To determine the efficacy and safety of febuxostat compared with allopurinol in lowering sua level in patients with hyperuricemia in gout with a baseline sua 8 mg/ dl. and duration in each study. Analysis: All outcomes were examined using the random effects model. Dichotomous data were analyzed by calculating the odds ratio, with 95% confidence interval and a significant p value of 0.1 was used. Results: Pooled data showed significant decrease in sua level from baseline with febuxostat 80 mg than with allopurinol with OR 0.31 (95% CI, , p = ). The risk of developing any adverse event with allopurinol is greater compared to febuxostat with RR 0.90 (95% CI, , p = 0.002). Data sources: Electronic searches through COCHRANE, EMBASE, PUBMED, and Manual Search. Search terms included the following: febuxostat, allopurinol, hyperuricemia, gout. Study Selection: Randomized, double-blinded, parallelgroup clinical trials with meta-analysis quality scale of A-B were included. Intervention included administration of febuxostat and allopurinol in determined dosages Conclusion: Febuxostat has significant urate lowering efficacy than allopurinol, and in patients with renal impairment without requiring dose adjustment, with lower incidence of any adverse events. However, elevated liver enzymes brought about by febuxostat were noted. Keywords: Allopurinol, Febuxsostat, serum uric acid, hyperuricemia, gout Background of the Study In the Philippines, the prevalence of gout had increased from 0.5% and 0.13% in 1991 and 1997 respectively. To date, a prevalence of 1.6% in 2007 has been recorded. 1 The goal for long-term management of gout is to lower the serum uric acid (sua) level and maintain it below the saturation point in tissues (6.8 mg/dl or 410 umol/l) so that existing monosodium uric crystals dissolve and no further crystals form. A target level of sua <6 mg/dl is recommended by the European League against Rheumatism (EULAR). 2 Allopurinol is the cornerstone of urate-lowering therapy in the Philippines. The Philippine Rheumatology Association recommends to start allopurinol at 100 mg/day, with a maximum dose of 300 mg/day to maintain sua concentration of <6.0 mg/dl. 1 However, *Department of Medicine, St. Luke s Medical Center evidence shows that the 300 mg dose is relatively ineffective in achieving the target sua level and that higher doses or combination therapy may be needed to achieve goal. 3 Moreover, side effects including hypersensitivity reactions manifested as rashes have been noted in some patients receiving allopurinol. The use of allopurinol in its recommended dosage is limited in subsets of patients who cannot tolerate allopurinol, including patients with chronic kidney disease, with multiple comorbidities, and those who have persistently elevated uric acid despite previous uric-lowering therapy. Alternative uric-lowering therapies may benefit these patients. Thus, the aim of the current study was to perform a meta-analysis of randomized trials to compare the serum urate-lowering efficacy of febuxostat, recently approved drug for hyperuricemia in gout, with allopurinol. Objectives The objective of the study is to determine the efficacy and safety of febuxostat compared with Volume 52 Number 1 January-March,

2 Villazor-Isidro EB, et al Urate Lowering Efficacy of Febuxostat Versus Allopurinol allopurinol in lowering sua level in patients with hyperuricemia in gout with a baseline sua 8 mg/ dl. Materials and Methods Search strategy Published studies were identified by searching the following with no language restrictions: The COCHRANE Central Register of Controlled Trials, EMBASE, PUBMED, Clinical Trials, Medline, and Manual Search. Free texts used the following search terms: febuxostat, allopurinol, hyperuricemia, gout. Communication with specialists was done to search for unpublished articles or ongoing studies. Eligibility criteria Randomized, double-blinded, parallel-group clinical trials with meta-analysis quality scale of A-B, central randomization schedule for adequate allocation concealment, subjects with similar baseline characteristics at the start of the trial, and adequate follow-up rate were eligible for inclusion. Subjects were aged years, male or female, with a diagnosis of gout fulfilling American Rheumatology Association preliminary criteria, and baseline sua level 8 mg/ dl. Intervention included administration of febuxostat and allopurinol in determined dosages and duration in each study. Colchicine or naproxen was given as prophylaxis for gout flares. Primary outcomes included the proportion of subjects in each treatment group with sua <6 mg/dl at the final visit; secondary outcomes included the proportion of subjects who reported any common and serious adverse events. Data collection and extraction Three reviewers searched for relevant studies based on titles and abstracts. These studies were collated, appraised, and analyzed by three authors independently reviewing every study. All differences and discrepancies in the analyses were re-discussed after individual reviews. To ensure study quality, allocation concealment, blinding of the outcome assessors and investigators, intention-to-treat analyses, and adequacy of follow-up was extracted. A meta-analyses quality scale was utilized to identify different biases that may weaken the quality of the study such as selection, performance, exclusion, and detection bias. Raw scores were identified based on the direction of the above mentioned biases, depicting the overall quality of the study. Assessment of heterogeneity Data were assessed for heterogeneity. Quantitative syntheses of data were performed if clinical heterogeneity was negligible. Clinical heterogeneity may be caused by differences in study populations, interventions or definition of endpoints. Heterogeneity was analyzed using a chi-squared test on N-1 degrees of freedom, with an alpha of 0.05 used for statistical significance and with the I 2 test. I 2 values greater than 25, 50 and 75% were considered evidence of low, moderate and high levels of statistical heterogeneity. If substantial statistical heterogeneity was noted (I 2 >50%), the reviewers performed statistical analyses to explore the influence of statistical models on effect size and the influence of each study by excluding one study at a time to assess the robustness of results. Subgroup analyses were performed to assess the robustness of the results and to statistically compare subgroups, respectively. Measures of treatment effect Dichotomous outcomes were used as primary endpoints which include a final-visit sua level < 6.0 mg/dl. Statistical Method Analysis of individual data was intended when studies had negligible heterogeneity. The data were entered in the Cochrane Review Manager Software version 5.0. All outcomes were examined using the random effects model. Dichotomous data were analyzed by calculating the odds ratio. Odds Risk with 95% confidence interval and a significant p value of 0.1 was used. All analyses were according to intention-to-treat principle wherein all randomized patients were included in the analysis of data. Results Study selection Figure 1: Flow diagram of study selection Five articles were included to be appraised, three were eligible for inclusion, and the other two were excluded. 2 Volume 52 Number 1 January-March, 2014

3 Urate Lowering Efficacy of Febuxostat Versus Allopurinol Villazor-Isidro EB, et al Study characteristics Table I: Characteristics of studies in the meta-analysis evaluating the efficacy and safety of febuxostat compared with allopurinol in gout STUDY METHODS PARTICIPANTS INTERVENTIONS OUTCOMES NOTES Becker, M. (FACT) 2005 Randomized, 52-week multicenter trial 762 patients with acute arthritis of gout, with baseline sua concentration of 8.0 mg/dl Febuxostat 80 mg vs. Febuxostat 120 mg vs. Allopurinol 300 mg Primary: sua concentration< 6.0 mg/dl at the last three measurements Secondary: mean percentage reduction from baseline sua at each visit. Clinical: incidence of gout flares, percentage reduction in tophi numbers and sizes Safety: treatment-emergent, serious, treatment related adverse event Allocation concealment: computer generated central randomization schedule with a block size of three Blinding: Double-blinded Intention-to-treat analysis: YES Adequacy of follow-up rate: YES MQA: A Naproxen 250 mg BID or 0.6 colchicine OD was administered to all patients during the wash-out period and the first eight weeks of double-blind treatment as prophylaxis Becker, M., (CONFIRMS) 2010 Randomized, double-blinded 6-month trial 2,268 patients aged years old, with a diagnosis of gout and sua concentration of 8.0 mg/dl Febuxostat 40 mg vs Febuxostat 80 mg vs Allopurinol 300 mg, 200 mg Primary: sua 6.0 mg/dl at the final visit Secondary: proportion of subjects with mild or moderate renal impairment and final sua <6.0 mg/dl; and the proportion of subjects with sua <6.0 mg/ dl, 5.0 mg/dl, and 4.0 mg/dl at each visit Subgroup analysis of primary endpoint: baseline sua, renal functional status, presence of tophi at baseline, and prior participation in a ULT trial Safety: most frequently reported adverse events, and cardiovascular endpoints Randomized stratification based on baseline renal function and prior completion of either of two-open label extension trials Allocation concealment: Interactive voice response system Blinding: Double-blinded Intention-to-treat analysis: modified ITT because one subject randomized to the allopurinol treatment group was excluded from the efficacy analyses because baseline sua was <8.0 mg/dl Adequacy of follow-up: YES MQA: A 30 day wash-out period for subjects receiving prior ULT, and throughout the subsequent six month treatment period for all subjects Prophylaxis for gout flares: Colchicine 0.6 mg/tab 1 tab OD, or Naproxen 250 mg/tab 1 tab BID and Lansoprazole 15 mg/tab 1 tab OD Schumacher, H. (APEX) week, randomized, double-blind, allopurinol and placebocontrolled, multi-center, parallel group trial 1,072 patients, aged years old with a diagnosis of gout, and sua concentration of 8.0 mg/dl Febuxostat 80 mg vs. Febuxostat 120 mg vs. Allopurinol 300/100 mg vs. placebo Primary: proportion of subjects with the last 3 monthly sua level<6.0 mg/dl Secondary: proportion of subjects with a sua<6.0 mg/dl at each visit, the percent reduction of serum uric from baseline at each visit, the proportion of subjects requiring treatment for a self-reported gout flare, reduction in the number of tophi at each visit, and the percent reduction in primary tophus Safety: most frequently associated adverse events, and cardiovascular events Allocation concealment: Not stated Blinding: Double-blinded Intention-to-treat analysis: YES Adequacy of follow-up: YES MQA: YES Allopurinol dose dependent on renal function; subjects with serum creatinine level 1.5 mg/ dl received 300 mg, whereas subjects with renal impairment (>1.5 to 2.0 mg/dl), received 100 mg There was a 2-week washout period for those receiving previous urate-lowering therapy with Colchicine 0.6 mg OD or Naproxen 250 mg BID as prophylaxis for gout flares. Table II: Studies excluded from the meta-analysis Excluded Studies Becker, M., (EXCEL) Schumacher, H. (FOCUS) 2009 Reason for Exclusion This is an open-label extension study which aims to determine the long-term achievement of serum uric acid lowering efficacy in relation to incidence of gout flares and dissolution of tophaceous deposits which strictly includes patients who have been enrolled and completed one of the two Phase III double-blind trial. This is an open-label extension study which has similar aims and objectives with the study above that includes patients who have been enrolled and completed 28-day Phase 2 study. Urate lowering efficacy Data on primary and secondary outcomes were provided in the three trials included in the analysis. The febuxostat dose of 80 mg/tab was common in all three trials. Other doses used, but not common to all were 40 mg, 120 mg, and 240 mg. Compared to allopurinol, febuxostat was associated with significant urate-lowering efficacy. The event represents the number of subjects that did not reach the goal uric acid level of < 6.0 mg/dl. Analysis was done using the common dose of febuxostat Volume 52 Number 1 January-March,

4 Villazor-Isidro EB, et al Urate Lowering Efficacy of Febuxostat Versus Allopurinol 80 mg. Figure 2 shows that more subjects in the allopurinol group did not reach the target uric acid level compared with the febuxostat group (66% for allopurinol vs. 40% for febuxostat). All included studies lie on the left side favoring febuxostat with an overall effect of 9.50 and a p value of < Therefore, febuxostat has a significantly less number of subjects with elevated uric acid levels compared to allopurinol. Adverse events Adverse events that occurred in the population were compared between the two groups. These included any adverse event, and abnormal levels of liver function tests. Figures 5 and 6 show that there is a greater risk of developing any adverse event with allopurinol compared to both febuxostat 120 mg (p-value <0.002) and 80 mg (p-value 0.001). Figure 2: Uric Acid Level <6.0 with febuxostat 80 mg vs. allopurinol at the end of the study Subgroup analysis was also done with regard to renal function. Patients were categorized as having normal renal function or impaired renal function. Among patients with normal renal function, the uratelowering effect of febuxostat was significantly greater compared to allopurinol with a p-value of < The urate-lowering effect was also significantly greater in febuxostat compared with allopurinol in patients with impaired renal function, with a p-value of < Figure 5: Analysis on the risk of developing any adverse event with Febuxostat 120 mg Figure 6: Analysis on the risk of developing any adverse event with febuxostat 80 mg Figure 3: Uric Acid Level <6.0 with febuxostat 80 mg vs. allopurinol among patients with normal renal function The risk of having abnormal liver enzyme levels is higher with febuxostat 120 mg compared to allopurinol. However, the plot shows a p value of 0.17; hence, the difference between the two treatment groups is not significant (Figure 7). There is also higher risk for abnormal liver enzyme levels with febuxostat 80 mg compared to allopurinol, but the difference is not statistically significant (p=0.22) (Figure 8). Figure 4: Uric Acid Level <6.0 with febuxostat 80 mg vs. allopurinol among patients with impaired renal function Fig 7: Analysis on the risk of developing abnormal liver function test with Febuxostat 120 mg 4 Volume 52 Number 1 January-March, 2014

5 Urate Lowering Efficacy of Febuxostat Versus Allopurinol Villazor-Isidro EB, et al Figure 8: Analysis on the risk of developing abnormal liver function test with febuxostat 80 mg Discussion Febuxostat is a new oral non-purine xanthine oxidase inhibitor that has been recently approved for the treatment of chronic hyperuricemia in gout. It is structurally different from allopurinol as it excludes the purine ring. It is more selective and is a potent inhibitor of xanthine oxidase than allopurinol and has no effect on other enzymes involved in purine and pyrimidine metabolism. The onset of action of febuxostat is more rapid than allopurinol that sua levels can be re-determined within two weeks of initial dosing. The main route of elimination of febuxostat is metabolism in the liver followed by excretion of metabolites in the urine and feces. The pharmacokinetics of febuxostat in patients with mildto-moderate hepatic impairment (Child-Pugh Classes A and B) is unaffected. 4 Concurrently, no dose adjustment is required in patients with mild to moderate renal impairment. Alternative urate-lowering therapies are regarded as major progress in the treatment of gout. The results of this meta-analysis of three RCTs, including 4,102 patients with hyperurcemia in gout, showed that compared to a standard dose of allopurinol, febuxostat is associated with a significant lowering of sua to target levels of <6.0 mg/dl. In the CONFIRMS trial, urate lowering efficacy of febuxostat 80 mg exceeded that of febuxostat 40 mg and allopurinol. In the subset of subjects with mild to moderate renal impairment, both febuxostat 40 and 80 mg were more efficacious than allopurinol. In the FACT trial, 53% of patients receiving febuxostat 80 mg, 62% of patients receiving febuxostat 120 mg, and 21% receiving allopurinol, reached the primary endpoint were reached. The APEX trial showed that, 48%, 65%, and 69% achieved the primary endpoint with febuxostat 80 mg, 120 mg, and 240 mg, respectively, compared with 22% in the allopurinol group. In all three RCTs, there was a significant difference in the urate lowering efficacy of febuxostat and allopurinol. Oxypurinol, the main metabolite of allopurinol, is responsible for the urate-lowering effect, and is predominantly excreted by the kidneys. Allopurinol is recommended for dose reduction especially in patients with poor renal function. It was shown that in both patients with normal renal function and impaired renal function, febuxostat had significant urate-lowering effect than allopurinol. The incidence of adverse events was lower for the febuxostat group compared to the allopurinol group. Adverse events were categorized as common adverse events, or a serious adverse event. Common adverse events included upper respiratory infections, liver function test abnormalities, diarrhea, headaches, and dizziness. Serious adverse events are those which may have resulted in death, hospitalization or prolongation of hospitalization, or persistent disability, such as any cardiovascular events. Occurrence of rash-related adverse events, was very small in both febuxostat and allopurinol groups. There was also note of elevation in liver enzymes in the febuxostat group, which may be due to the hepatic metabolism of the drug. In a study of febuxostat on patients with mild and moderate hepatic impairment, once daily dosing for seven days with 80-mg febuxostat was safe and well tolerated in subjects with normal hepatic function and in those with mild and moderate hepatic impairment. 5 No raw data were included in all of the published studies for the incidence of gouty flares. In all of the studies, gouty flares were prevalent during the first eight weeks in the treatment group despite administration of the prophylaxis compared to the last few weeks of the studies involved. This can be attributed to the rapid decrease in the serum uric acid level thereby causing symptoms. Thus, febuxostat can be used in patients with gout, especially in patients with chronic kidney disease, elderly patients, and in patients with multiple comorbidities. However, elevated liver enzymes brought about by febuxostat should be noted. Conclusion This meta-analysis of randomized trials conducted in patients with hyperuricemia in gout showed that febuxostat is associated with significant urate-lowering efficacy than allopurinol, and in the subset of patients with renal impairment without requiring dose adjustment, with lower incidence of any adverse event favoring the febuxostat group. Limitations include small number of eligible studies. Further studies may be of significant value in expounding more on efficacy and safety of the drug in patients with severe renal and liver impairment, in elderly patients and in other hyperuricemic syndromes. A thorough study on the dosing regimen with the highest therapeutic benefit but with minimal adverse effects may be beneficial. Volume 52 Number 1 January-March,

6 Villazor-Isidro EB, et al Urate Lowering Efficacy of Febuxostat Versus Allopurinol Acknowledgements The authors would like to thank Dr. Carina Dalay- Dizon and Dr. Evelyn Esposo of St. Luke s Medical Center-Quezon City, Department of Medicine, for supporting us in this endeavor. We would also like to thank Dr. Pia Villanueva for assisting us in the manuscript preparation. References 1. Philippine Clinical Pratice Guidelines for the management of Gout. Gout%20CPG%20Manuscript%20_PJIM% _.pdf. 2. Edwards, N.L., Febuxostat: a new treatment for hyperuricemia in gout. Rheumatology. 2009; 48: ii15-ii19 3. Gaffo, A.L., et.al.: Febuxostat: the evidence for its use in the treatment of hyperuricemia and gout. Core Evidence. 2009; 4: Becker, M.A., et.al.: The urate-lowering efficacy and safety of febuxostat in the treatment of the hyperuricemia of gout: the CONFIRMS trial. Arthritis Research & Therapy. 2010; 12; R63 5. Khosravan, R., et.al.: The effect of Mild and Moderate Hepatic Impairment on Pharmacokinetics, Pharmacodynamics, and Safety of Febuxostat, a Novel Nonpurine Selective Inhibitor of Xanthine Oxidase. The Jour of Clin Pharmacology, 2006; 46; Becker, M.A., et.al.: Febuxostat Compared with Allopurinol in Patients with Hyperuricemia and Gout (FACT). N Eng J Med 2005; 353: Becker. M.A., et.al.: Clinical Efficacy and Safety of Successful Long-term Uric Lowering with Febuxostat or Allopurinol in Subjects with Gout (EXCEL). The Jour of Rheumatology 2009; 36: Schumacher, H.R., and et.al.: Febuxostat in the treatment of gout: 5-yr findings of the FOCUS efficacy and safety study. Rheumatology 2009; 48: Schumacher, H.R., et.al.: Effects of Febuxostat Versus Allopurinol and Placebo in Reducing Serum Urate in Subjects With Hyperuricemia and Gout: A 28-Week, Phase III, Randomized, Double-Blind, Parallel-Group Trial. 6 Volume 52 Number 1 January-March, 2014