Establishment of therapeutic goal and plan of gout and asymptomatic hyperuricemia

Gout is a crystal deposition disease. European and Japanese guidelines of management for gout recommend that serum urate concentration should be maintained below 6.0 mg/dL to promote crystal dissolution leading to prevention of recurrent gouty attack. Although allopurinol is recommended to be an adequate drug for urate lowering therapy in all gouty patients by European guideline, it is desirable that allopurinol is indicated in patients with overproduction type and benzbromarone in patients with underexcretion type, recommended by Japanese guideline. Asymptomatic hyperuricemia dose not equate to gout. As there is no evidence to support treatment of isolated hyperuricemia with urate lowering therapy currently, it is difficult to establish lowering goal of serum urate level in patients with asymptomatic hyperuricemia. Advice regarding lifestyle and treatment of associated comorbidity should be preferred to urate lowering therapy. However, urate lowering therapy may be indicated in high risk patients with hyperuricemia who are suffered from hypertension, diabetes mellitus, ischemic heart disease and renal insufficiency.     

Preservation of Renal Function during Gout Treatment with Febuxostat: A Quantitative Study

Abstract

Background: Hyperuricemia can accelerate renal decline associated with aging. Chronic kidney disease is frequently seen in patients with hyperuricemia and gout. Objectives: Assess the impact of urate–lowering therapy on renal function in subjects with gout who were treated with febuxostat for ≤ 48 months. Methods: Subjects from 2 phase 3 clinical studies were enrolled in the phase 3, long–term, open–label Febuxostat/Allopurinol Comparative Extension Long–Term (EXCEL) study. In the EXCEL study, 1086 subjects initially were treated with febuxostat 80 or 120 mg daily, or allopurinol 300 mg daily. The subjects were permitted to switch between doses of febuxostat and/or allopurinol during the first 6 months of treatment to achieve and maintain a serum uric acid (SUA) level ≥ 3 to < 6 mg/dL. For the analysis presented in this article, data from 551 subjects who received only febuxostat throughout the duration of both the phase 3 and EXCEL studies (≤ 48 months) were used to determine the impact of SUA reduction on estimated glomerular filtration rates (eGFRs). Results: At baseline of the 2 original phase 3 studies, subjects' mean SUA level was 9.8 mg/dL. Greater sustained decreases in subjects' SUA levels were associated with less renal function decline (P < 0.001)by statistical modeling. The study data predicted that for every 1 mg/dL of chronic reduction of SUA level in subjects with gout, there would be a preservation of 1.15 mL/min of eGFR. Conclusion: Sustained urate–lowering therapy with febuxostat appears to impede renal decline in patients with gout. The results discussed in this article support similar observations previously reported in 116 hyperuricemic subjects with gout who received febuxostat for ≤ 5 years.     

Rationale and design of the randomized evaluation of an Ambulatory Care Pharmacist-Led Intervention to Optimize Urate Lowering Pathways (RAmP-UP) Study

BackgroundDespite the availability of effective therapies, most gout patients achieve suboptimal treatment outcomes. Current best practices suggest gradual dose-escalation of urate lowering therapy and serial serum urate (sUA) measurement to achieve sUA < 6.0 mg/dl. However, this strategy is not routinely used. Here we present the study design rationale and development for a pharmacist-led intervention to promote sUA goal attainment.MethodsTo overcome barriers in achieving optimal outcomes, we planned and implemented the Randomized Evaluation of an Ambulatory Care Pharmacist-Led Intervention to Optimize Urate Lowering Pathways (RAmP-UP) study. This is a large pragmatic cluster-randomized trial designed to assess a highly automated, pharmacist-led intervention to optimize allopurinol treatment in gout. Ambulatory clinics (n = 101) from a large health system were randomized to deliver either the pharmacist-led intervention or usual care to gout patients over the age of 18 years newly initiating allopurinol. All participants received educational materials and could opt-out of the study. For intervention sites, pharmacists conducted outreach primarily via an automated telephone interactive voice recognition system. The outreach, guided by a gout care algorithm developed for this study, systematically promoted adherence assessment, facilitated sUA testing, provided education, and adjusted allopurinol dosing. The primary study outcomes are achievement of sUA < 6.0 mg/dl and treatment adherence determined after one year. With follow-up ongoing, study results will be reported subsequently.ConclusionAmbulatory care pharmacists and automated calling technology represent potentially important, underutilized resources for improving health outcomes for gout patients.     

Management of gout in the older adult

Background

Gout affects 3 million people in the United States, with rates almost 5 times higher in those aged 70 to 79 years compared with those aged <50 years. Management of gout in elderly subjects can be complicated by comorbidities and polypharmacy.

Objective

The purpose of this article was to review the unique clinical presentation, treatment, and prevention of gout in the older adult, with attention to the age-related factors that may affect outcomes in this population.

Methods

PubMed and the Iowa Drug Information Service were searched (1944–January 14, 2011) for clinical studies of gout using the following search terms: gout, elderly, colchicine, non-steroidal anti-inflammatory drugs (NSAIDs), corticosteroid, prednisone, prednisolone, methylprednisolone, triamcinolone, allopurinol, febuxostat, probenecid, sulfinpyrazone, uricosuric, fenofibrate, and losartan. Articles were limited to clinical trials in humans, published in English. Citations of these articles were analyzed for additional relevant studies, and current guidelines were also consulted.

Results

Twenty-nine citations were reviewed. Evidence suggests that colchicine, NSAIDs, and corticosteroids are all efficacious in the treatment of acute gout in the older adult. Relevant limitations to colchicine use in the older adult include high cost, dosing restrictions in severe renal and hepatic dysfunction, gastrointestinal intolerance, and potential drug interactions. NSAID therapy is not recommended in older patients with congestive heart failure, renal failure, or gastrointestinal problems. Corticosteroids pose little risk when used in the short-term and may be preferred in patients with contraindications to colchicine or NSAIDs. Urate lowering with allopurinol for prevention of gout is well tolerated and has minimal cost per month; however, dose reduction is recommended in patients with renal impairment, which often results in failure to achieve target serum urate concentrations. Febuxostat does not require dose adjustment in mild to moderate renal disease and may be preferred in older people with this condition.

Conclusion

Management of gout in the older adult involves careful selection of treatment based on potential benefits and consequences of therapy, considered in tandem with individual patient-specific characteristics. ClinicalTrials.gov identifiers NCT00549549, NCT01101035, NCT00241839, NCT01157936, NCT00997542, NCT00288158, and NCT00987415.     

Gout: an update

Arthritis caused by gout (i.e., gouty arthritis) accounts for millions of outpatient visits annually, and the prevalence is increasing. Gout is caused by monosodium urate crystal deposition in tissues leading to arthritis, soft tissue masses (i.e., tophi), nephrolithiasis, and urate nephropathy. The biologic precursor to gout is elevated serum uric acid levels (i.e., hyperuricemia). Asymptomatic hyperuricemia is common and usually does not progress to clinical gout. Acute gout most often presents as attacks of pain, erythema, and swelling of one or a few joints in the lower extremities. The diagnosis is confirmed if monosodium urate crystals are present in synovial fluid. First-line therapy for acute gout is nonsteroidal anti-inflammatory drugs or corticosteroids, depending on comorbidities; colchicine is second-line therapy. After the first gout attack, modifiable risk factors (e.g., high-purine diet, alcohol use, obesity, diuretic therapy) should be addressed. Urate-lowering therapy for gout is initiated after multiple attacks or after the development of tophi or urate nephrolithiasis. Allopurinol is the most common therapy for chronic gout. Uricosuric agents are alternative therapies in patients with preserved renal function and no history of nephrolithiasis. During urate-lowering therapy, the dose should be titrated upward until the serum uric acid level is less than 6 mg per dL (355 micromol per L). When initiating urate-lowering therapy, concurrent prophylactic therapy with low-dose colchicine for three to six months may reduce flare-ups.     

Relationship between serum urate and plasma oxypurinol in the management of gout: determination of minimum plasma oxypurinol concentration to achieve a target serum urate level

The treatment of gout requires a lowering of serum urate (SU) levels, and allopurinol is the drug that is most commonly used for this purpose. The objectives of this study were to define the relationships between allopurinol dose on the one hand and plasma oxypurinol, renal function, and SU levels on the other and to determine the minimum plasma oxypurinol concentration that would result in a target level of <6?mg/dl (0.36?mmol/l) of SU. For this purpose, 82 patients who had been receiving allopurinol for at least 1 month were recruited. Patients with SU <6?mg/dl were followed up quarterly for 12 months. In patients with SU ≥6?mg/dl, the dose of allopurinol was increased to bring the level of SU to <6?mg/dl. These patients were followed up once a month until the SU level remained at <6?mg/dl for 3 consecutive months; thereafter they were seen quarterly. SU, creatinine, and plasma oxypurinol were measured 6-9 hours after administration of the allopurinol dose. There were significant inverse correlations between creatinine clearance (CrCl) and plasma oxypurinol (P = 0.002), between allopurinol dose and SU (P < 0.0001) and between plasma oxypurinol and SU (P < 0.0001). Using receiver operating characteristic analysis, the target SU of <6?mg/dl was achieved in 75% of serum samples with plasma oxypurinol levels of >100?μmol/l (15.2 mg/l). Increasing the allopurinol dose resulted in increased plasma oxypurinol and reduced SU concentrations. Plasma oxypurinol concentrations >100?μmol/l were required to achieve SU <6?mg/dl.     

Febuxostat: A selective xanthine-oxidase/xanthine-dehydrogenase inhibitor for the management of hyperuricemia in adults with gout

Background: Febuxostat, a nonpurine selective inhibitor of both the oxidized and reduced forms of xanthine oxidase, was approved in February 2009 by the US Food and Drug Administration for the management of hyperuricemia in adults with gout.Objective: The purpose of this review was to summarize available information about the clinical use of febuxostat, including its chemistry, pharmacology, pharmacokinetics, pharmacodynamics, clinical efficacy, and safety profile.Methods: A search of the medical literature using PubMed (1949–August 2009) and the Iowa Drug Information Service (1966–August 2009) was performed to identify all published articles about febuxostat. Key search terms included febuxostat, hyperuricemia, gout, TMX-67, and TEI-6720. Articles were limited to those published in English. Reference lists of the primary set of articles identified were reviewed for pertinent articles and scientific meeting abstracts not identified in the original search.Results: A total of 88 published articles (including 14 human studies) were identified in the original search. Review of the references of these 88 articles yielded 7 additional trials published in abstract form. Clinical trial data from this review were obtained from these 21 studies. Dose-dependent reductions from baseline in serum urate occur with febuxostat. Clinical trials found that 40 mg/d of febuxostat was noninferior to conventionally dosed allopurinol (300 mg/d) in the percentage of subjects achieving the primary end point of serum urate <6.0 mg/dL (45% for febuxostat vs 42% for allopurinol), whereas 80 mg/d of febuxostat was reported to be superior (67% vs 42%; P < 0.001). Febuxostat 40 and 80 mg/d appeared to be well tolerated in the populations studied, with adverse events mostly limited to liver enzyme elevations (6.6% and 4.6%, respectively), nausea (1.1% and 1.3%), arthralgias (1.1% and 0.7%), and rash (0.5% and 1.6%). Febuxostat does not require dosage adjustment in patients with mild to moderate renal impairment (creatinine clearance, 30–89 mL/min). Because of the risk of acute gout flares occurring when febuxostat treatment is initiated, concomitant therapy with colchicine or an NSAID for ≥8 weeks is recommended.Conclusions: Febuxostat is the first agent marketed in the United States to treat hyperuricemia of gout since allopurinol was approved in 1964. In English-language published clinical trials, it was found to be noninferior to allopurinol and generally well tolerated.     

Adherence to oral antidiabetic therapy in a managed care organization: a comparison of monotherapy, combination therapy, and fixed-dose combination therapy

BACKGROUND: Although medication adherence is one of the most important aspects of the management of diabetes mellitus, low rates of adherence have been documented. OBJECTIVE: This study sought to examine medication adherence among patients with diabetes mellitus in a managed care organization who were receiving antidiabetic monotherapy (metformin or glyburide), combination therapy (metformin and glyburide), or fixed-dose combination therapy (glyburide/metformin). METHODS: Medication adherence was evaluated through a retrospective database analysis of pharmacy claims. The adherence rate was defined as the sum of the days' supply of oral antidiabetic medication obtained by the patient during the follow-up period divided by the total number of days in the designated follow-up period (180 days). Health plan members were included in the analysis if they had an index pharmacy claim for an oral antidiabetic medication between August 1 and December 31, 2000, were continuously enrolled in the health plan, and were aged > or =18 years. A 6-month pre-index period was used to classify patients as newly treated or previously treated. Patients were grouped according to their medication-use patterns. RESULTS: After adjustment for potential confounding factors, including overall medication burden at index, there were no significant differences in adherence rates among 6502 newly treated patients receiving monotherapy, combination therapy, or fixed-dose combination therapy. Among the 1815 previously treated patients receiving glyburide or metformin monotherapy who required the addition of the alternative agent, resulting in combination therapy, adherence rates were significantly lower (54.0%; 95% CI, 0.52-0.55) than in the 105 patients receiving monotherapy who were switched to fixed-dose combination therapy (77.0%; 95% CI, 0.72-0.82). The 59 previously treated patients receiving combination therapy who were switched to fixed-dose combination therapy had a significant improvement in adherence after the switch (71.0% vs 87.0%; P < 0.001). CONCLUSIONS: In a managed care organization, previously treated patients receiving monotherapy with an oral antidiabetic medication who required additional therapy exhibited significantly greater adherence when they were switched to fixed-dose combination therapy compared with combination therapy. Patients receiving combination therapy who were switched to fixed-dose combination therapy exhibited significantly greater adherence after the switch.     

Improving the use of allopurinol in chronic gout: monitoring oxypurinol levels to guide therapy

Urate-lowering therapy (ULT), adjusted to achieve and maintain a serum uric acid (SUA) of <6?mg/dl, remains the standard of care for the chronic management of gout. New urate-lowering medications are important options; however, these agents should be reserved for patients who do not tolerate or cannot achieve SUA <6?mg/dl on allopurinol. The result of oxypurinol monitoring to guide allopurinol therapy suggests that allopurinol should still be considered first-line ULT for gout.     

Reverse phase partition HPLC for determination of plasma purines and pyrimidines in subjects with gout and renal failure

A reverse phase partition mode of high pressure liquid chromatography was developed for the estimation of purine, pyrimidine and pyrazolopyrimidine nucleosides and bases. This method has been applied to the investigation of purine and pyrimidine metabolism in subjects with gout and/or renal failure during allopurinol therapy.Plasma levels of hypoxanthine and xanthine were quantitated in all subjects. No significant differences were observed between healthy males and gouty subjects with or without allopurinol medication. There was a significant increase in xanthine levels in patients with gout and renal failure, or renal failure on allopurinol, and plasma levels of oxipurinol were increased, but no correlation with glomerular filtration rate (GFR) was observed.The separation method was also used to examine urines from patients with known abnormalities of purine and pyrimidine metabolism in an attempt to evaluate its usefulness as a urine screening technique.     

Pharmacy data identify poorly adherent patients with schizophrenia at increased risk for admission

BACKGROUND: Health care organizations may be able to use pharmacy data to identify patients with schizophrenia and poor antipsychotic adherence. OBJECTIVE: To determine whether a pharmacy-based measure of outpatient adherence, the medication possession ratio (MPR), is associated with adverse outcomes among patients with schizophrenia, as evidenced by increased psychiatric admission. RESEARCH DESIGN: Cohort study linking pharmacy and utilization data for veterans with schizophrenia. MPRs were calculated by dividing the number of days' supply of antipsychotic medication the veteran had received by the number of days' supply they needed to receive to take their antipsychotic continuously. Using multivariate regression, the relationship between MPRs and psychiatric admission was examined. SUBJECTS: Sixty-seven thousand seventy-nine veterans who received a diagnosis of schizophrenia and had outpatient antipsychotic medication fills between October 1, 1998 and September 30, 1999. RESULTS: Patients with MPRs close to 1.0 had the lowest rates of admission. As patients secured progressively smaller proportions of required antipsychotic medication (and had smaller MPRs), rates of admission climbed. Among patients on one antipsychotic (n = 49,003), patients with poor adherence (MPRs < 0.8) were 2.4 times as likely to be admitted as patients with good adherence (MPRs from 0.8-1.1). 23% of poorly adherent patients but only 10% of adherent patients were admitted. Once admitted, poorly adherent patients had more hospital days. Patients who received excess medication also had higher admission rates. CONCLUSIONS: Many health care systems may be able to use pharmacy data to identify poorly adherent patients with schizophrenia. These patients are at-risk for admission and may benefit from intervention.     

A Second Enzyme Defect in Acquired Lactase Deficiency: Lack of Small-Intestinal Phlorizin-Hydrolase

Abstract To differentiate between extrarenal and renal causes of hyperuricaemia and gout, clearances of urate and creatinine were monitored for 31/2 days in fifty-two individuals (seven with a history of gout) with no gross impairment of renal function (creatinine clearance 52–137 ml/min). Dietary purine intake was kept constant. Monophasic circadian fluctuations of fractional urate excretion (= urate clearance over creatinine clearance) were observed with peak values in the afternoon, about 50% higher than during the night. Circadian fluctuations of urinary flow rate were almost identical. However, enhancement of urinary flow rate due to water diuresis had no effect on urate clearance. Despite wide variation of plasma urate concentrations among different individuals (±30% SD), daily urate excretion varied little (± 4% SD) and did not correlate with plasma urate ( r = 0–03). Thus extrarenal factors appear not to account for the occurrence of hyperuricaemia in these patients. In contrast, a clearcut negative correlation was apparent between plasma urate concentration and fractional urate clearance ( r = -0 72), which could fully account for the variations of plasma urate concentration. To elucidate further the mechanism responsible for antiuricosuria in hyperuricaemic patients, the effects of the uricosuric agents benzbromarone and probenecid were tested. A clearcut correlation was apparent between control fractional urate excretion and uricosuric effect of both benzbromarone and probenecid ( r = 0–83 and 0–88, respectively), suggesting that anti-uricosuria was due to defective secretion. In an additional series, the uricosuric effect of probenecid was tested in ten patients with renal insufficiency. In these patients the uricosuric effect was clearly blunted, indicating that urate reab-sorption is reduced in renal insufficiency.     

Renal handling of urate in healthy man in hyperuricaemia and renal insufficiency: circadian fluctuation, effect of water diuresis and of uricosuric agents

Abstract. To differentiate between extrarenal and renal causes of hyperuricaemia and gout, clearances of urate and creatinine were monitored for 31/2 days in fifty-two individuals (seven with a history of gout) with no gross impairment of renal function (creatinine clearance 52–137 ml/min). Dietary purine intake was kept constant. Monophasic circadian fluctuations of fractional urate excretion (= urate clearance over creatinine clearance) were observed with peak values in the afternoon, about 50% higher than during the night. Circadian fluctuations of urinary flow rate were almost identical. However, enhancement of urinary flow rate due to water diuresis had no effect on urate clearance. Despite wide variation of plasma urate concentrations among different individuals (±30% SD), daily urate excretion varied little (± 4% SD) and did not correlate with plasma urate ( r = 0–03). Thus extrarenal factors appear not to account for the occurrence of hyperuricaemia in these patients. In contrast, a clearcut negative correlation was apparent between plasma urate concentration and fractional urate clearance ( r = -0 72), which could fully account for the variations of plasma urate concentration. To elucidate further the mechanism responsible for antiuricosuria in hyperuricaemic patients, the effects of the uricosuric agents benzbromarone and probenecid were tested. A clearcut correlation was apparent between control fractional urate excretion and uricosuric effect of both benzbromarone and probenecid ( r = 0–83 and 0–88, respectively), suggesting that anti-uricosuria was due to defective secretion. In an additional series, the uricosuric effect of probenecid was tested in ten patients with renal insufficiency. In these patients the uricosuric effect was clearly blunted, indicating that urate reab-sorption is reduced in renal insufficiency.     

Drug-adherence questionnaires not valid for patients taking blood-pressure-lowering drugs in a primary health care setting

Purpose  To validate two established questionnaires [Morisky and Medication Adherence Report Scale (MARS-5)] for the measurement of medical adherence of patients treated with antihypertensive drugs in primary care in Germany.
Setting  General practitioners (GPs) and their patients in North Rhine-Westphalia, Germany.
Methods  GPs were asked to recruit 12 consecutive patients using blood-pressure-lowering medication for at least 12 months. Patients were asked to fill out both the Morisky and MARS-5 questionnaires. The medication possession ratio (MPR) was calculated as reference standard for patients' medication adherence by using GPs' electronic patient records. The results of the questionnaires were then compared with the reference standard.
Results  A total of 14 GPs recruited 163 patients of which 128 were included in the analysis. Of the 128 patients, 52% were females; the age ranged from 44 to 96 years (mean 71). The overall adherence rate measured by the MPR was 62.1%. Compared to the reference standard, the Morisky Scale had a sensitivity of 31.9%, a specificity of 72.8% and a positive likelihood ratio (+LR) of 1.18. The MARS-5 had a sensitivity of 8.5%, a specificity of 97.4% and a +LR of 3.28.
Conclusion  The Morisky Scale and the MARS-5 cannot be recommended for measuring the adherence to antihypertensive drugs in a general practice setting in Germany at this point. These results emphasize the necessity to validate questionnaires in a specific setting before using them as instruments within a trial different from the original setting(s) of validation.     

随机双盲三模拟对照多中心临床研究非布索坦降低痛风患者高尿酸水平的疗效和安全性

目的 研究比较非布索坦与别嘌醇降低痛风（GOUT）患者血尿酸（SUA）水平的疗效和安全性.方法 486例痛风患者随机分成试验组：非布索坦40 mg组（40mg,每日1次）,非布索坦组80mg组（80mg,每日1次）和别嘌醇对照组（100 mg,每日3次）,疗程24周.主要疗效指标为24周末血尿酸水平降低到360 μmol/L以下的患者比例,次要疗效指标为2周末血尿酸水平降低到360μmol/L以下的患者比例,24周治疗前后血尿酸下降的水平和痛风发作的次数.结果 非布索坦40 mg组、非布索坦80 mg组、别嘌醇组三组意向性分析集（ITT）分析受试者末次访视SUA≤360 μmol/L的达标率分别为49.06％、65.38％、43.67％,三组疗后24周SUA降低到360 mol/L以下的受试者达标率组间比较差异有统计学意义（P＜0.0001）,具体为非布索坦40mg组与非布索坦80mg组、非布索坦80 mg组与别嘌醇组组间差异有统计学意义（P＜0.05）,非布索坦40mg组与别嘌醇组组间差异无统计学意义（P＞0.05）.总不良反应发生率在三组间差异无统计学意义.结论 非布索坦40mg组等效于别嘌醇组;非布索坦80 mag组优效于别嘌醇组,且也优效于非布索坦40mg组.非布索坦长期用于降尿酸具有良好的耐受性.