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18-12-2014 | Gout | Article

Safety of allopurinol compared with other urate-lowering drugs in patients with gout: a systematic review and meta-analysis

Journal: Rheumatology International

Authors: Isabel Castrejon, Esther Toledano, María Piedad Rosario, Estíbaliz Loza, Fernando Pérez-Ruiz, Loreto Carmona

Publisher: Springer Berlin Heidelberg

Abstract

Allopurinol is the most widely used urate-lowering drug (ULD). Together with efficacy and cost, safety is an aspect that helps taking clinical decisions. This systematic review analyzes allopurinol safety. The literature search was performed in MEDLINE, EMBASE, and the Cochrane Library (January 2014). Selection criteria: (a) patients >18, (b) gout by the ACR criteria or evidence of urate crystal in synovial fluid, (c) comparator (placebo or other ULD), and (d) RCTs, cohorts, or meta-analysis. Primary outcomes: rate of adverse events and death. The quality was assessed with the Jadad’s scale. A meta-analysis with fixed effects was performed. From 544 studies, seven met the eligibility criteria and were included. All RCT presented a low power for safety. All RCTs included a mixed population of patients with gout and hyperuricemia. Allopurinol (300 mg) was compared to febuxostat (40–240 mg) in five RCTs, to benzbromarone and probenecid in two RCTs, and to placebo in one. In the RCTs comparing allopurinol with benzbromarone and probenecid, the highest discontinuation rate was with probenecid (26 %), followed by allopurinol (11 %) and benzbromarone (4 %). The incidence of adverse events was similar between allopurinol (range 38.6–85) and febuxostat (range 41.8–80). Six patients on febuxostat and three on allopurinol died during the studies; no deaths were judged related to drug. The combined risk of adverse events was RR = 1.04 (95 % CI 0.98, 1.11). Allopurinol is a safe option, slightly better than other ULDs. The grade of evidence is high, but further research is needed to evaluate higher doses and long-term safety.
Literature
1.
Tausche AK, Jansen TL, Schroder HE, Bornstein SR, Aringer M, Muller-Ladner U (2009) Gout—current diagnosis and treatment. Deutsches Arzteblatt Int 106(34–35):549–555. doi:10.​3238/​arztebl.​2009.​0549
2.
Weaver AL (2008) Epidemiology of gout. Cleve Clin J Med 75(Suppl 5):S9–S12CrossRefPubMed
3.
Lipworth W, Kerridge I, Brett J, Day R (2011) How clinical and research failures lead to suboptimal prescribing: the example of chronic gout. BMJ 343:d7459. doi:10.​1136/​bmj.​d7459 CrossRefPubMed
4.
Schlesinger N (2004) Management of acute and chronic gouty arthritis: present state-of-the-art. Drugs 64(21):2399–2416CrossRefPubMed
5.
Perez-Ruiz F, Calabozo M, Pijoan JI, Herrero-Beites AM, Ruibal A (2002) Effect of urate-lowering therapy on the velocity of size reduction of tophi in chronic gout. Arthritis Rheum 47(4):356–360. doi:10.​1002/​art.​10511 CrossRefPubMed
6.
Stamp LK, Taylor WJ, Jones PB, Dockerty JL, Drake J, Frampton C, Dalbeth N (2012) Starting dose is a risk factor for allopurinol hypersensitivity syndrome: a proposed safe starting dose of allopurinol. Arthritis Rheum 64(8):2529–2536. doi:10.​1002/​art.​34488 CrossRefPubMed
7.
Hande KR, Noone RM, Stone WJ (1984) Severe allopurinol toxicity. Description and guidelines for prevention in patients with renal insufficiency. Am J Med 76(1):47–56CrossRefPubMed
8.
Stamp LK, O’Donnell JL, Zhang M, James J, Frampton C, Barclay ML, Chapman PT (2011) Using allopurinol above the dose based on creatinine clearance is effective and safe in patients with chronic gout, including those with renal impairment. Arthritis Rheum 63(2):412–421. doi:10.​1002/​art.​30119 CrossRefPubMed
9.
Edwards NL (2009) Febuxostat: a new treatment for hyperuricaemia in gout. Rheumatology (Oxford) 48(Suppl 2):ii15–ii19. doi:10.​1093/​rheumatology/​kep088 CrossRef
10.
Pascual E, Sivera F (2007) Therapeutic advances in gout. Curr Opin Rheumatol 19(2):122–127. doi:10.​1097/​BOR.​0b013e32802106b9​ CrossRefPubMed
11.
van Tulder M, Furlan A, Bombardier C, Bouter L, Editorial Board of the Cochrane Collaboration Back Review G (2003) Updated method guidelines for systematic reviews in the Cochrane collaboration back review group. Spine 28(12):1290–1299. doi:10.​1097/​01.​BRS.​0000065484.​95996.​AF PubMed
12.
Jadad AR, Moore RA, Carroll D, Jenkinson C, Reynolds DJ, Gavaghan DJ, McQuay HJ (1996) Assessing the quality of reports of randomized clinical trials: is blinding necessary? Control Clin Trials 17(1):1–12CrossRefPubMed
13.
Stevenson M, Pandor A (2011) Febuxostat for the management of hyperuricaemia in patients with gout: a NICE single technology appraisal. Pharmacoeconomics 29(2):133–140. doi:10.​2165/​11535770-000000000-00000 CrossRefPubMed
14.
Stevenson M, Pandor A (2009) Febuxostat for the treatment of hyperuricaemia in people with gout: a single technology appraisal. Health Technol Assess 13(Suppl 3):37–42. doi:10.​3310/​hta13suppl3/​06 PubMed
15.
Yu KH (2007) Febuxostat: a novel non-purine selective inhibitor of xanthine oxidase for the treatment of hyperuricemia in gout. Recent Pat Inflamm Allergy Drug Discov 1(1):69–75CrossRefPubMed
16.
Singh JA (2010) Advances in gout: some answers, more questions. Arthritis Res Ther 12(5):136. doi:10.​1186/​ar3110 CrossRefPubMedCentralPubMed
17.
Schumacher HR Jr, Becker MA, Wortmann RL, Macdonald PA, Hunt B, Streit J, Lademacher C, Joseph-Ridge N (2008) 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. Arthritis Rheum 59(11):1540–1548. doi:10.​1002/​art.​24209 CrossRefPubMed
18.
Reinders MK, Haagsma C, Jansen TL, van Roon EN, Delsing J, van de Laar MA, Brouwers JR (2009) A randomised controlled trial on the efficacy and tolerability with dose escalation of allopurinol 300–600 mg/day versus benzbromarone 100–200 mg/day in patients with gout. Ann Rheum Dis 68(6):892–897. doi:10.​1136/​ard.​2008.​091462 CrossRefPubMed
19.
Reinders MK, van Roon EN, Jansen TL, Delsing J, Griep EN, Hoekstra M, van de Laar MA, Brouwers JR (2009) Efficacy and tolerability of urate-lowering drugs in gout: a randomised controlled trial of benzbromarone versus probenecid after failure of allopurinol. Ann Rheum Dis 68(1):51–56. doi:10.​1136/​ard.​2007.​083071 CrossRefPubMed
20.
Becker MA, Schumacher HR, Espinoza LR, Wells AF, MacDonald P, Lloyd E, Lademacher C (2010) The urate-lowering efficacy and safety of febuxostat in the treatment of the hyperuricemia of gout: the CONFIRMS trial. Arthritis Res Ther 12(2):R63. doi:10.​1186/​ar2978 CrossRefPubMedCentralPubMed
21.
Becker MA, Schumacher HR Jr, Wortmann RL, MacDonald PA, Eustace D, Palo WA, Streit J, Joseph-Ridge N (2005) Febuxostat compared with allopurinol in patients with hyperuricemia and gout. N Engl J Med 353(23):2450–2461. doi: doi:10.​1056/​NEJMoa050373 CrossRefPubMed
22.
Kamatani N, Fujimori S, Hada T, Hosoya T, Kohri K, Nakamura T, Ueda T, Yamamoto T, Yamanaka H, Matsuzawa Y (2011) Multicenter, open-label study of long-term administration of febuxostat (TMX-67) in Japanese patients with hyperuricemia including gout. J Clin Rheumatol 17(4 Suppl 2):S50–S56. doi:10.​1097/​RHU.​0b013e31822541d0​ CrossRefPubMed
23.
Kamatani N, Fujimori S, Hada T, Hosoya T, Kohri K, Nakamura T, Ueda T, Yamamoto T, Yamanaka H, Matsuzawa Y (2011) An allopurinol-controlled, randomized, double-dummy, double-blind, parallel between-group, comparative study of febuxostat (TMX-67), a non-purine-selective inhibitor of xanthine oxidase, in patients with hyperuricemia including those with gout in Japan: phase 3 clinical study. J Clin Rheumatol 17(4 Suppl 2):S13–S18. doi:10.​1097/​RHU.​0b013e31821d36cc​ CrossRefPubMed
24.
Wallace SL, Robinson H, Masi AT, Decker JL, McCarty DJ, Yu TF (1977) Preliminary criteria for the classification of the acute arthritis of primary gout. Arthritis Rheum 20(3):895–900CrossRefPubMed
25.
Wyngaarden JB, Rundles RW, Metz EN (1965) Allopurinol in the treatment of gout. Ann Intern Med 62:842–847CrossRefPubMed