Allopurinol

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A critical reappraisal of allopurinol dosing, safety, and efficacy for hyperuricemia in gout.
Chao J, Terkeltaub R.
Curr Rheumatol Rep. 2009 Apr;11(2):135-40

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 </= 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 </= 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.

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Clinical Efficacy and Safety of Successful Longterm Urate Lowering with Febuxostat or Allopurinol in Subjects with Gout.
Becker MA, Schumacher HR, Macdonald PA, Lloyd E, Lademacher C.
J Rheumatol. 2009 Mar 13. [Epub ahead of print]

OBJECTIVE: To determine longterm urate-lowering efficacy and clinical benefits and safety of therapy with febuxostat or allopurinol in subjects with gout.

METHODS: Subjects (n = 1086) in this open-label extension study were assigned to fixed-dose daily urate-lowering treatment (ULT) with febuxostat (80 mg or 120 mg) or allopurinol (300 mg). ULT reassignment was permitted during months 1 to 6 to achieve serum urate (SUA) concentrations between 3.0 and < 6.0 mg/dl. Flares requiring treatment, tophus size, safety, and SUA levels were monitored during up to 40 months of ULT maintenance.

RESULTS: After 1 month initial treatment, > 80% of subjects receiving either febuxostat dose, but only 46% of subjects receiving allopurinol, achieved SUA < 6.0 mg/dl. After ULT reassignment, > 80% of all remaining subjects maintained the primary efficacy endpoint of SUA < 6.0 mg/dl at each visit. More subjects initially randomized to allopurinol required ULT reassignment to achieve SUA < 6.0 mg/dl compared with subjects receiving febuxostat. Maintenance of SUA < 6.0 mg/dl resulted in progressive reduction to nearly 0 in proportion of subjects requiring gout flare treatment. Baseline tophus resolution was achieved by 46%, 36%, and 29% of subjects maintained on febuxostat 80 mg, febuxostat 120 mg, and allopurinol, respectively. Overall adverse event rates (including cardiovascular adverse event rates), adjusted for 10-fold greater febuxostat than allopurinol exposure, did not differ significantly among treatment groups.

CONCLUSION: Durable maintenance of goal range SUA level with either dose of febuxostat or in smaller numbers of subjects with allopurinol resulted in near elimination of gout flares and improved tophus status over time

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Allopurinol and mortality in hyperuricaemic patients.
Luk AJ, Levin GP, Moore EE, Zhou XH, Kestenbaum BR, Choi HK.
Rheumatology (Oxford). 2009 May 15. [Epub ahead of print]

Objectives. While studies have suggested that gout and hyperuricaemia are associated with the risk of premature death, none has investigated the role of urate-lowering therapy on this critical outcome. We examined the impact of allopurinol, the most commonly used urate-lowering drug, on the risk of mortality in hyperuricaemic patients.

Methods. From a population of hyperuricaemic veterans of [serum urate level >416 mumol/l (7.0 mg/dl)] at least 40 years of age, we compared the risk of death between incident allopurinol users (n = 2483) and non-users (n = 7441). We estimated the multivariate mortality hazard ratio (HR) of allopurinol use with Cox proportional hazards models.

Results. Of the 9924 veterans (males, 98% and mean age 62.7 years), 1021 died during the follow-up. Patients who began treatment with allopurinol had worse prognostic factors for mortality, including higher BMI and comorbidities. After adjusting for baseline urate levels, allopurinol treatment was associated with a lower risk of all-cause mortality (HR 0.78; 95% CI 0.67, 0.91). Further adjustment with other prognostic factors did not appreciably alter this estimate (HR 0.77; 95% CI 0.65, 0.91). The mean change from baseline in serum urate within the allopurinol group was -111 mumol/l (-1.86 mg/dl). Adjusting for baseline urate level, allopurinol users had a 40 mumol/l (0.68 mg/dl) lower follow-up serum urate value than controls (95% CI -0.55, -0.81).

Conclusion. Our findings indicate that allopurinol treatment may provide a survival benefit among patients with hyperuricaemia.