Combining Model-Based Clinical Trial Simulation, Pharmacoeconomics, and Value of Information to Optimize Trial Design.

The Bayesian decision-analytic approach to trial design uses prior distributions for treatment effects, updated with likelihoods for proposed trial data. Prior distributions for treatment effects based on previous trial results risks sample selection bias and difficulties when a proposed trial differs in terms of patient characteristics, medication adherence, or treatment doses and regimens. The aim of this study was to demonstrate the utility of using pharmacometric-based clinical trial simulation (CTS) to generate prior distributions for use in Bayesian decision-theoretic trial design. The methods consisted of four principal stages: a CTS to predict the distribution of treatment response for a range of trial designs; Bayesian updating for a proposed sample size; a pharmacoeconomic model to represent the perspective of a reimbursement authority in which price is contingent on trial outcome; and a model of the pharmaceutical company return on investment linking drug prices to sales revenue. We used a case study of febuxostat versus allopurinol for the treatment of hyperuricemia in patients with gout. Trial design scenarios studied included alternative treatment doses, inclusion criteria, input uncertainty, and sample size. Optimal trial sample sizes varied depending on the uncertainty of model inputs, trial inclusion criteria, and treatment doses. This interdisciplinary framework for trial design and sample size calculation may have value in supporting decisions during later phases of drug development and in identifying costly sources of uncertainty, and thus inform future research and development strategies.

Comprehensive assessment of T cell receptor ß repertoire in Stevens-Johnson syndrome/toxic epidermal necrolysis patients using high-throughput sequencing.

Stevens-Johnson syndrome (SJS) /toxic epidermal necrolysis (TEN) are life-threatening severe cutaneous adverse drug reactions characterized by widespread epidermal necrosis. Recent studies have indicated that SJS/TEN is a specific immune reaction regulated by T cells. Certain drug serves as foreign antigens that are presented by major histocompatibility complex (MHC) and recognized by T cell receptors (TCRs), inducing adaptive immune responses. However, few studies have performed detailed characterization of TCR repertoire in SJS/TEN, and it remains unclear whether the particular types of TCRs expanded clonally are drug-specific, which would provide a potential underlying mechanism of SJS/TEN. In this study, using high-throughput sequencing, we comprehensively assessed the diversity, composition and molecular characteristics of the TCRß repertoires in 17 SJS/TEN patients associated with three different causative drugs including methazolamide (MZ), carbamazepine (CBZ) and allopurinol (ALP). Systematic analysis of the TCRß sequences revealed that SJS/TEN patients had more highly expanded clones and less TCR repertoire diversity, and the TCR repertoire diversity of these patients showed certain associations with the clinical severity of disease. Similar predominant clonotypes, shared-usage TRBV/TRBJ subtypes and combinations thereof were observed among different subjects with the same causative agent. Our observations provide enhanced understanding of the role of T lymphocytes in the pathogenesis of SJS/TEN and enumerate potential therapeutic targets.

Efficacy and cost-effectiveness of nurse-led care involving education and engagement of patients and a treat-to-target urate-lowering strategy versus usual care for gout: a randomised controlled trial.

BACKGROUND: In the UK, gout management is suboptimum, with only 40% of patients receiving urate-lowering therapy, usually without titration to achieve a target serum urate concentration. Nurses successfully manage many diseases in primary care. We compared nurse-led gout care to usual care led by general practitioners (GPs) for people in the community. METHODS: Research nurses were trained in best practice management of gout, including providing individualised information and engaging patients in shared decision making. Adults who had experienced a gout flare in the previous 12 months were randomly assigned 1:1 to receive nurse-led care or continue with GP-led usual care. We assessed patients at baseline and after 1 and 2 years. The primary outcome was the percentage of participants who achieved serum urate concentrations less than 360 µmol/L (6 mg/dL) at 2 years. Secondary outcomes were flare frequency in year 2, presence of tophi, quality of life, and cost per quality-adjusted life-year (QALY) gained. Risk ratios (RRs) and 95% CIs were calculated based on intention to treat with multiple imputation. This study is registered with www.ClinicalTrials.gov, number NCT01477346. FINDINGS: 517 patients were enrolled, of whom 255 were assigned nurse-led care and 262 usual care. Nurse-led care was associated with high uptake of and adherence to urate-lowering therapy. More patients receiving nurse-led care had serum urate concentrations less than 360 µmol/L at 2 years than those receiving usual care (95% vs 30%, RR 3·18, 95% CI 2·42-4·18, p<0·0001). At 2 years all secondary outcomes favoured the nurse-led group. The cost per QALY gained for the nurse-led intervention was £5066 at 2 years. INTERPRETATION: Nurse-led gout care is efficacious and cost-effective compared with usual care. Our findings illustrate the benefits of educating and engaging patients in gout management and reaffirm the importance of a treat-to-target urate-lowering treatment strategy to improve patient-centred outcomes. FUNDING: Arthritis Research UK.

Design and Rationale for the Veterans Affairs "Cooperative Study Program 594 Comparative Effectiveness in Gout: Allopurinol vs. Febuxostat" Trial.

BACKGROUND: Gout patients do not routinely achieve optimal outcomes related in part to suboptimal administration of urate lowering therapy (ULT) including first-line xanthine oxidase inhibitors allopurinol or febuxostat. Studies leading to the approval of febuxostat compared this agent to allopurinol in inappropriately low, fixed doses. We will compare allopurinol with febuxostat in gout using appropriately titrated doses of both agents and a "treat-to-target" strategy congruent with specialty guidelines. METHODS: We have planned and initiated the Veterans Affairs (VA) Cooperative Study Program (CSP) 594, Comparative Effectiveness in Gout: Allopurinol vs Febuxostat study. This large double-blind, non-inferiority trial will enroll 950 gout patients randomized to receive allopurinol or febuxostat. Patients will be followed for a total of 72 weeks encompassing 3 distinct 24-week study phases. During Phase I (0-24 weeks), participants will undergo gradual dose titration of ULT until achievement of serum uric acid (sUA) <6.0 mg/dL or <5.0 mg/dL if tophi are present. Dose escalation will not be allowed during final three study visits of Phase 2 (24-48 weeks) and during Phase 3 (48-72 weeks). The primary study outcome is the proportion of participants experiencing at least one gout flare during Phase 3. Subsequent to the 72-week study, participants will be followed passively for up to 10 years after the study to assess long-term health outcomes. CONCLUSION: With its completion, the VA Comparative Effectiveness in Gout: Allopurinol vs Febuxostat study will demonstrate the central role of gradual ULT dose escalation and a treat-to-target strategy in gout management.

Prioritizing Future Research on Allopurinol and Febuxostat for the Management of Gout: Value of Information Analysis.

OBJECTIVES: The aim of this study was to quantify the value of conducting additional research and reducing uncertainty regarding the cost effectiveness of allopurinol and febuxostat for the management of gout. METHODS: We used a previously developed Markov model that evaluated the cost effectiveness of nine urate-lowering strategies: no treatment, allopurinol-only fixed dose (300 mg), allopurinol-only dose escalation (up to 800 mg), febuxostat-only fixed dose (80 mg), febuxostat-only dose escalation (up to 120 mg), allopurinol-febuxostat sequential therapy fixed dose, allopurinol-febuxostat sequential therapy dose escalation, febuxostat-allopurinol sequential therapy fixed dose, and febuxostat-allopurinol sequential therapy dose escalation. Each strategy was evaluated over the lifetime of a hypothetical gout patient. We calculated population expected value of perfect information (EVPI). We used a linear regression meta-modeling approach to calculate population expected value of partial perfect information (EVPPI), and a Gaussian approximation to calculate the population expected value of sample information for parameters (EVSI) and the expected net benefit of sampling (ENBS) for four potential study designs: (1) an allopurinol efficacy trial; (2) a febuxostat efficacy trial; (3) a prospective observational study evaluating health utilities; and (4) a comprehensive study evaluating the efficacy of allopurinol and febuxostat and health utilities. A 5-year decision time horizon was used in the base-case analysis. RESULTS: EVPI varied by a decision maker's willingness-to-pay (WTP) per quality-adjusted life-year (QALY) and was $US900 million for WTP of $US60,000 per QALY. Population EVPPI was highest across all WTP values for study design #4. For study design #4 and a WTP of $US60,000 per QALY, the optimal sample size was 735 patients per study arm. CONCLUSIONS: Future studies are needed to evaluate the effectiveness of allopurinol and febuxostat dose escalation.

Comparative effectiveness of allopurinol versus febuxostat for preventing incident renal disease in older adults: an analysis of Medicare claims data.

OBJECTIVE: To assess the comparative effectiveness of allopurinol versus febuxostat for preventing incident renal disease in elderly. METHODS: In a retrospective cohort study using 2006-2012 Medicare claims data, we included patients newly treated with allopurinol or febuxostat (baseline period of 183 days without either medication). We used 5:1 propensity-matched Cox regression analyses to compare the HR of incident renal disease with allopurinol use (and dose) versus febuxostat (reference). Sensitivity analyses included multivariable-adjusted regression models. RESULTS: There were 31 465 new allopurinol or febuxostat treatment episodes in 26 443 patients; 8570 ended in incident renal disease. Crude rates of incident renal disease per 1000 person-years were 192 with allopurinol versus 338 with febuxostat. Crude rates of incident renal disease per 1000 person-years were lower with higher daily dose: allopurinol <200, 200-299 and ≥300 mg/day with 238, 176 and 155; and febuxostat 40 and 80 mg/day with 341 and 326, respectively. In propensity-matched analyses, compared with febuxostat, allopurinol use was associated with lower HR of incident renal disease, 0.61 (95% CI 0.49 to 0.77). Compared with febuxostat 40 mg/day, allopurinol doses <200, 200-299 and ≥300 mg/day were associated with lower HR of incident renal disease, 0.75 (95% CI 0.65 to 0.86), 0.61 (95% CI 0.52 to 0.73) and 0.48 (95% CI 0.41 to 0.55), respectively. Sensitivity analyses using multivariable-adjusted regression confirmed these findings. CONCLUSIONS: Allopurinol was associated with a lower risk of incident renal disease in elderly patients than febuxostat. Future studies need to examine the mechanism of this potential renal benefit of allopurinol.

Are allopurinol dose and duration of use nephroprotective in the elderly? A Medicare claims study of allopurinol use and incident renal failure.

OBJECTIVE: To assess the effect of allopurinol dose/duration on the risk of renal failure in the elderly with allopurinol use. METHODS: We used the 5% random Medicare claims data from 2006 to 2012. Multivariable-adjusted Cox regression analyses assessed the association of allopurinol dose/duration with subsequent risk of developing incident renal failure or end-stage renal disease (ESRD) (no prior diagnosis in last 183 days) in allopurinol users, controlling for age, sex, race and Charlson-Romano comorbidity index. HRs with 95% CIs were calculated. Sensitivity analyses considered a longer baseline period (365 days), controlled for gout or used more specific codes. RESULTS: Among the 30 022 allopurinol treatment episodes, 8314 incident renal failure episodes occurred. Compared with 1-199 mg/day, allopurinol dose of 200-299 mg/day (HR 0.81; 95% CI 0.75 to 0.87) and ≥300 mg/day, 0.71 (0.67 to 0.76), had significantly lower hazard of renal failure in multivariable-adjustment model, confirmed in multiple sensitivity analyses. Longer allopurinol use duration was significantly associated with lower hazards in sensitivity analyses (365-day look-back; reference, <0.5 year): 0.5-1 year, 1.00 (0.88, 1.15); >1-2 years, 0.85 (0.73 to 0.99); and >2 years, 0.81 (0.67 to 0.98). Allopurinol ≥300 mg/day was also associated with significantly lower risk of acute renal failure and ESRD with HR of 0.89 (0.83 to 0.94) and 0.57 (0.46 to 0.71), respectively. CONCLUSIONS: Higher allopurinol dose is independently protective against incident renal failure in the elderly allopurinol users. A longer duration of allopurinol use may be associated with lower risk of incident renal failure. Potential mechanisms of these effects need to be examined.

Cost-effectiveness of allopurinol and febuxostat for the management of gout.

BACKGROUND: Gout is the most common inflammatory arthritis in the United States. OBJECTIVE: To evaluate the cost-effectiveness of urate-lowering treatment strategies for the management of gout. DESIGN: Markov model. DATA SOURCES: Published literature and expert opinion. TARGET POPULATION: Patients for whom allopurinol or febuxostat is a suitable initial urate-lowering treatment. TIME HORIZON: Lifetime. PERSPECTIVE: Health care payer. INTERVENTION: 5 urate-lowering treatment strategies were evaluated: no treatment; allopurinol- or febuxostat-only therapy; allopurinol-febuxostat sequential therapy; and febuxostat-allopurinol sequential therapy. Two dosing scenarios were investigated: fixed dose (80 mg of febuxostat daily, 0.80 success rate; 300 mg of allopurinol daily, 0.39 success rate) and dose escalation (≤120 mg of febuxostat daily, 0.82 success rate; ≤800 mg of allopurinol daily, 0.78 success rate). OUTCOME MEASURES: Discounted costs, discounted quality-adjusted life-years, and incremental cost-effectiveness ratios. RESULTS OF BASE-CASE ANALYSIS: In both dosing scenarios, allopurinol-only therapy was cost-saving. Dose-escalation allopurinol-febuxostat sequential therapy was more costly but more effective than dose-escalation allopurinol therapy, with an incremental cost-effectiveness ratio of $39 400 per quality-adjusted life-year. RESULTS OF SENSITIVITY ANALYSIS: The relative rankings of treatments did not change. Our results were relatively sensitive to several potential variations of model assumptions; however, the cost-effectiveness ratios of dose escalation with allopurinol-febuxostat sequential therapy remained lower than the willingness-to-pay threshold of $109 000 per quality-adjusted life-year. LIMITATION: Long-term outcome data for patients with gout, including medication adherence, are limited. CONCLUSION: Allopurinol single therapy is cost-saving compared with no treatment. Dose-escalation allopurinol-febuxostat sequential therapy is cost-effective compared with accepted willingness-to-pay thresholds. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality.

Allopurinol for the treatment of chronic kidney disease: a systematic review.

BACKGROUND: The term chronic kidney disease (CKD) is used to describe abnormal kidney function (or structure). People with CKD have an increased prevalence of cardiovascular disease (CVD). Evidence is emerging that allopurinol may have a role to play in slowing down the progression of CKD and reducing the risk of CVD. OBJECTIVES: This systematic review addresses the research question: does allopurinol reduce mortality, the progression of chronic kidney disease or cardiovascular risk in people with CKD? DATA SOURCES: The following databases were searched on 7 January 2013: MEDLINE (1946 to 7 January 2013), EMBASE (1974 to 28 December 2012), The Cochrane Library (Issue 1, 2013) and ClinicalTrials.gov. Bibliographies of retrieved citations were also examined and two manufacturers of allopurinol were approached for data. REVIEW METHODS: Two reviewers independently screened all titles and abstracts to identify potentially relevant studies for inclusion in the review. Full-text copies were assessed independently by two reviewers. Data were extracted and assessed for risk of bias by one reviewer and independently checked for accuracy by a second. Summary statistics were extracted for each outcome and, where possible, data were pooled. Meta-analysis was carried out using fixed-effects models. RESULTS: Efficacy evidence was derived solely from four randomised controlled trials (RCTs). Adverse event (AE) data were derived from the RCTs and 21 observational studies. Progression of CKD was measured by estimated glomerular filtration rate (eGFR) in three trials and by changes in serum creatinine in the other. No significant differences in eGFR over time were reported. The only significant difference between groups was reported in one trial at 24 months favouring allopurinol [eGFR: 42.2 ml/minute/1.73 m(2), standard deviation (SD) 13.2 vs. 35.9 ml/minute/1.73 m(2), SD 12.3 ml/minute/1.73 m(2); p < 0.001]. In this same trial, there were twice as many cardiovascular events in the control arm (27%) as in the allopurinol arm (12%). Another trial reported an improvement in CKD progression as measured by serum creatinine in the allopurinol arm. No significant differences were reported in blood pressure between treatment groups in the meta-analyses. The incidence of AEs was estimated to be around 9% from all studies. The incidence of severe cutaneous adverse reactions (SCARs), which typically occurred within the first 2 months after allopurinol commencement, was reported to be 2% in two studies. Evidence for whether or not AEs and SCARs were dose related was conflicting. Not all patients had CKD in these studies. LIMITATIONS: None of the included studies reported concealment of allocation, one of the greatest risks to study validity. Relatively few (< 115) patients were enrolled in any RCT. For studies reporting AEs, the main limitation is the heterogeneity across studies. No studies examining quality-of-life measures were identified. CONCLUSIONS: There is limited evidence that allopurinol reduces CKD progression or cardiovascular events. It appears that AEs and in particular serious adverse events attributable to allopurinol are rare. However, the exact incidence of AEs in patients with CKD is unknown. Direct evidence for the impact of allopurinol on quality of life is lacking. Given the uncertainties in the evidence base, additional RCT evidence comparing allopurinol with usual care is required, accompanied by supporting data from observational studies of patients with CKD and using allopurinol. STUDY REGISTRATION: The study is registered as PROSPERO CRD42013003642. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Impact of noncompliance with urate-lowering drug on serum urate and gout-related healthcare costs: administrative claims analysis.

OBJECTIVE: To determine the association between allopurinol compliance and serum urate (sUA) level; and examine the association between sUA and gout-related healthcare costs in a large managed care population. RESEARCH DESIGN AND METHODS: This retrospective administrative claims analysis examined subjects with gout (> or = 2 medical claims with ICD-9-CM diagnosis code 274.xx or > or = 1 claim with a gout diagnosis and > or = 1 pharmacy claim for allopurinol, probenecid, colchicine, or sulfinpyrazone) between January 1, 2002 and March 31, 2004. Each subject was observed during 1-year pre-index and 1-year post-index periods. MAIN OUTCOME MEASURES: Outcomes were allopurinol medication possession ratio (MPR) and compliance (MPR > or = 0.80), sUA (mg/dL), and gout-related healthcare costs. 'Post-allopurinol' sUA was measured during three periods after the first observed allopurinol fill: 30-89 days; 90-149 days; > or = 150 days. A baseline sUA on or before the start of the post-index period was also identified. Outcomes were stratified by post-allopurinol or baseline sUA and compliance. Generalized linear modeling (GLM) regression measured the impact of baseline sUA on gout-related healthcare costs, controlling for demographic and health status variables. RESULTS: The study sample comprised 18,243 subjects with mean age of 53.9 years. In all, 55% (n = 10,073) of subjects used allopurinol. There were 1473 (8.1%) subjects with a post-allopurinol sUA and 2438 (13.4%) subjects with a baseline sUA result. Among all subjects with a post-allopurinol sUA, 45.6% were compliant; between 49.3% and 56.8% of compliant subjects had an sUA < 6.0 mg/dL compared with 22.5-27.8% of non-compliant subjects, depending on the post-allopurinol time period (all p < 0.001). GLM results showed gout-related costs associated with baseline sUA > or = 6.0 and < 9.0 mg/dL were 58% higher (95% confidence interval (CI): 1.012 -2.456; p = 0.044) than were costs for sUA < 6.0 mg/dL. There was no significant difference in gout-related costs between baseline sUA < 6.0 mg/dL and > or = 9.0 mg/dL. CONCLUSIONS: Analysis revealed an important associations between allopurinol compliance, sUA, and gout-related costs: compliance was positively associated with favorable sUA (<6.0 mg/dL) in unadjusted comparisons. GLM showed that baseline sUA < 6.0 was inversely associated with gout-related costs relative to baseline sUA > or = 6.0 and <9.0 mg/dL. Nevertheless, a substantial portion of subjects, even compliant ones, did not achieve sUA < 6.0 mg/dL. These results should be interpreted carefully in light of study limitations, including incomplete laboratory data, the potentially incorrect inference that medications were taken as prescribed, and lack of generalizability from Medicare managed care enrollees to the broader Medicare population.

A critical reappraisal of allopurinol dosing, safety, and efficacy for hyperuricemia in gout.

Allopurinol, the first-line drug for serum urate-lowering therapy in gout, is approved by the US Food and Drug Administration for a dose up to 800 mg/d and is available as a low-cost generic drug. However, the vast majority of allopurinol prescriptions are for doses < or = 300 mg/d, which often fails to adequately treat hyperuricemia in gout. This situation has been promoted by longstanding, non-evidence-based guidelines for allopurinol use calibrated to renal function (and oxypurinol levels) and designed, without proof of efficacy, to avoid allopurinol hypersensitivity syndrome. Severe allopurinol hypersensitivity reactions are not necessarily dose-dependent and do not always correlate with serum oxypurinol levels. Limiting allopurinol dosing to < or = 300 mg/d suboptimally controls hyperuricemia and fails to adequately prevent hypersensitivity reactions. However, the long-term safety of elevating allopurinol dosages in chronic kidney disease requires further study. The emergence of novel urate-lowering therapeutic options, such as febuxostat and uricase, makes timely this review of current allopurinol dosing guidelines, safety, and efficacy in gout hyperuricemia therapy, including patients with chronic kidney disease.

Gout in the UK and Germany: prevalence, comorbidities and management in general practice 2000-2005.

OBJECTIVE: To investigate and compare the prevalence, comorbidities and management of gout in practice in the UK and Germany. METHODS: A retrospective analysis of patients with gout, identified through the records of 2.5 million patients in UK general practices and 2.4 million patients attending GPs or internists in Germany, using the IMS Disease Analyzer. RESULTS: The prevalence of gout was 1.4% in the UK and Germany. Obesity was the most common comorbidity in the UK (27.7%), but in Germany the most common comorbidity was diabetes (25.9%). The prevalence of comorbidities tended to increase with serum uric acid (sUA) levels. There was a positive correlation between sUA level and the frequency of gout flares. Compared with those in whom sUA was <360 micromol/l (<6 mg/dl), odds ratios for a gout flare were 1.33 and 1.37 at sUA 360-420 micromol/l (6-7 mg/dl), and 2.15 and 2.48 at sUA >530 micromol/l ( >9 mg/dl) in the UK and Germany, respectively (p<0.01). CONCLUSIONS: The prevalence of gout in practice in the UK and Germany in the years 2000-5 was 1.4%, consistent with previous UK data for 1990-9. Chronic comorbidities were common among patients with gout and included conditions associated with an increased risk for cardiovascular disease, such as obesity, diabetes and hypertension. The importance of regular monitoring of sUA in order to tailor gout treatment was highlighted by data from this study showing that patients with sUA levels >or=360 micromol/l (>or=6 mg/dl) had an increased risk of gout flares.

Frequency of serum creatinine monitoring during allopurinol therapy in ambulatory patients.

BACKGROUND: Allopurinol dosage reduction is recommended in patients with renal dysfunction because drug toxicity risk is increased. Little information is available about serum creatinine (SCr) monitoring in ambulatory patients taking allopurinol. OBJECTIVE: To evaluate SCr monitoring among patients prescribed allopurinol, identify associated factors, and evaluate administrative data in assessing monitoring. METHODS: Information for this retrospective cohort study was drawn from a dataset of 2 020 037 individuals; approximately 200 000 members from each of 10 organizations. Study patients had received at least one year of ongoing allopurinol prescription dispensings. Patient variables analyzed included age, gender, chronic diseases, outpatient visits, hospitalizations, gout diagnosis, and SCr monitoring. A random sample of medical records was reviewed to assess the accuracy of the automated data. Statistical analysis included descriptive and logistic regression techniques. RESULTS: Overall, 1139 (26%) of 4357 patients did not have SCr monitoring. For individuals without recent hospitalization, factors protective against lack of monitoring were increasing age (OR 0.77 per 10 y; 95% CI 0.74 to 0.79), more chronic diseases (OR 0.81; 95% CI 0.78 to 0.83), more outpatient visits (OR 0.87 per 5 visits; 95% CI 0.83 to 0.91), and gout diagnosis (OR 0.74; 95% CI 0.65 to 0.85). The sensitivity and specificity of administrative data compared with medical records for SCr monitoring were 92% and 65%, respectively. CONCLUSIONS: More than one-fourth of patients dispensed allopurinol did not have SCr monitoring during one year of therapy. Lack of monitoring and lack of subsequent possible dosage adjustment put patients at increased risk of allopurinol toxicity.

Role of i.v. allopurinol and rasburicase in tumor lysis syndrome.

The role of i.v. allopurinol and rasburicase in tumor lysis syndrome (TLS) is described. The current standard management for TLS consists of oral allopurinol in conjunction with i.v. hydration with or without alkalinization. Despite this standard prophylactic regimen, some high-risk patients may still develop urate nephropathy from TLS. Recently, i.v. allopurinol and rasburicase became available for the management of TLS. Available data on i.v. allopurinol indicate that the administration schedule and the adverse-effect profile will be similar to the oral formulation. The primary advantage of i.v. allopurinol is the flexibility of administration for patients who cannot take anything by mouth, since there are no data indicating the superiority of the i.v. to the oral product. Rasburicase is the first agent that will oxidize uric acid to allantoin, a metabolite with 5-10-fold greater solubility than uric acid, and reduces serum uric acid (SUA) levels within four hours of administration. Rasburicase is considerably more expensive than standard management strategies and should be reserved for patients with either renal dysfunction, significant elevations in SUA values, or large tumor burdens. Preliminary evidence indicates that rasburicase offers cost savings in the treatment of TLS and is cost-effective as a strategy for preventing TLS for many cancer patients. Both i.v. allopurinol and rasburicase offer additional flexibility in the management of TLS and may allow for further avoidance of the consequences of inadequate management of this syndrome.

Exposure to allopurinol and the risk of cataract extraction in elderly patients.

OBJECTIVE: To determine whether exposure to allopurinol is associated with an increased risk of cataract extraction in elderly patients. METHODS: We conducted a case-control study using data from the Quebec universal health insurance program for all elderly patients. The 3677 cases were patients with a cataract extraction between 1992 and 1994. The 21,868 controls were randomly selected among patients not diagnosed with cataract and matched to cases on the date of the extraction. We determined the odds ratio of cataract extraction according to the cumulative dose and duration of allopurinol use relative to nonusers, using conditional logistic regression analysis. The analysis was adjusted for the effects of age, sex, diabetes mellitus, hypertension, glaucoma, and ophthalmic and oral corticosteroid exposure. RESULTS: A cumulative dose of allopurinol of more than 400 g or a duration of use of longer than 3 years were associated with an increased risk of cataract extraction, with odds ratios of 1.82 (95% confidence interval [CI], 1.18-2.80) and 1.53 (95% CI, 1.12-2.08), respectively. No increase in risk was observed for lower cumulative doses or shorter exposure periods. CONCLUSION: Long-term administration of allopurinol increases the risk of cataract extraction in elderly patients.