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Evidence-based answers from the clinical inquiries Family Physicians Inquiries Network

Sarah White, PharmD; Anne Mounsey, MD Department of Family Which prophylactic therapies Medicine, University of North Carolina School of Medicine, Chapel Hill best prevent attacks?

Janine Tillett, MSLS, AHIP Wake Forest School of Evidence-based answer Medicine, Winston-Salem, NC and serum and gout attacks and im- Assistant EDITOR A reduce the frequency of gout at- proves quality of life (QOL) (SOR: A, 2 Paul Crawford, MD tacks equally after 8 weeks of treatment RCTs). Nellis Family Medicine Residency, Nellis Air Force (strength of recommendation [SOR]: B, reduces gout attacks when Base, Nev multiple randomized control trials [RCTs] combined with or allopurinol with limitations). at the start of urate-lowering therapy (SOR: Intravenous decreases B, 1 high-quality and 1 low-quality RCT).

Evidence summary <80 mL/min/1.73m2—also concluded that A 28-week RCT compared the effects of pla- febuxostat and allopurinol are equally ef- cebo, allopurinol (300 mg/d), and febuxo- fective in reducing gout attacks (incidence stat (80 mg, 120 mg, and 240 mg) on serum of gout flares during Weeks 9 to 52 was 64% uric acid levels (sUA) and gout attacks in with both febuxostat 80 mg and allopurinol 1067 patients with gout and 300 mg).2 The percentage of patients with sUA (94% male, 78% white, 18 to 85 years of age <6 mg/dL at the last 3 monthly visits was 53% with mean age ranging from 51 to 54 years in the febuxostat 80 mg group compared with ± 12 years in each group).1 Patients also re- 21% in the allopurinol 300 mg group (P<.001; ceived prophylaxis with either colchicine or number needed to treat [NNT]=4]). during the first 8 weeks of the study. One significant limitation of both RCTs During Weeks 1 through 8, investigators was the fixed dose of allopurinol (300 mg/d). found no statistically significant differences in US Food and Drug Administration-approved the percentage of patients requiring treatment dosing for allopurinol allows for titration to a for gout attacks between the febuxostat 80 mg, maximum of 800 mg/d to achieve serum uric allopurinol, and placebo groups (28%, 23%, and acid <6 mg/dL. 20%, respectively). During Weeks 8 through 28, no statistically significant differences in gout IV pegloticase decreases gout attacks attack rates occurred between the allopuri- after 3 months, improves quality of life nol and febuxostat groups, although the study Pegloticase is an intravenously administered, didn’t report specific attack rates for this period. recombinant form of uricase, the natural en- Both allopurinol and all doses of febuxo- zyme that converts uric acid to more soluble stat reduced sUA to <6 mg/dL more effective- allantoin. Two RCTs compared pegloticase ly than placebo; more patients treated with with placebo in a total of 212 patients with febuxostat than allopurinol achieved a uric gout (mean age 54 to 59 years; 70% to 90% acid level of less than <6 mg/dL. male) intolerant or refractory to allopurinol Another RCT of 762 mostly white, male (defined as baseline sUA of ≥8 mg/dL and at patients (mean age 52 years) with gout and least one of the following: ≥3 self-reported sUA >8 mg/dL—35% of whom had renal im- gout flares during the previous 18 months, pairment, defined as creatinine clearance ≥1 tophi, or gouty arthropathy. continued on page 221

216 The Journal of Family Practice | APRIL 2014 | Vol 63, No 4 clinical inquiries

continued from page 216 These trials found that treatment with treated with colchicine experienced a gout 8 mg of pegloticase every 2 weeks for 6 months flare compared with 77% of placebo-treated initially increased gout flares during Months patients (P=.008; NNT=3 over 6 months).5 1 to 3 (75% with pegloticase, 53% with We identified no RCTs that evaluated the placebo; P=.02; number needed to harm agent probenecid and no studies [NNH]=5) but then decreased the incidence that assessed the use of nonsteroidal anti- of acute gout attacks during Months 4 to inflammatory drugs (NSAIDs) to prevent re- 6 (41% with pegloticase, 67% with placebo; current gout attacks. P=.007; NNT=4).3 In addition, pegloticase resulted in statistically significant improve- ments in QOL measured at the final visit us- Recommendations ing the Health Assessment Questionnaire The American College of Rheumatology (HAQ) pain scale, the HAQ-Disability Index, (ACR) guidelines on managing gout recom- and the 36-item Short Form Health Survey. mend allopurinol or febuxostat as first-line pharmacologic urate-lowering therapy, Colchicine plus probenecid or allopurinol with a goal of reducing sUA to <6 mg/dL. reduces gout attacks They recommend probenecid as an alterna- One small, low-quality RCT (N=38) found tive if contraindications exist or the patient that colchicine 0.5 mg administered 3 times is intolerant to allopurinol and febuxostat.6 daily effectively prevented gout attacks when The guidelines note that allopurinol doses Eight weeks of administered concomitantly with probene- may exceed 300 mg/d, even in patients with treatment with cid initiated to lower urate (gout attacks per chronic disease. either allopurinol month in colchicine and placebo-treated The ACR recommends anti-inflamma- or febuxostat patients, respectively, were 0.19±0.05 and tory prophylaxis with colchicine or NSAIDs reduces the 0.48±0.12; P< .05).4 upon initiation of urate-lowering therapy. frequency of Another RCT that compared allopuri- Anti-inflammatory prophylaxis should be gout attacks nol with and without colchicine showed that continued as long as clinical evidence of con- equally. coadministration of colchicine 0.6 mg twice tinuing gout disease exists and until the sUA daily reduced gout attacks: 33% of patients target has been acheived.7 JFP

References 1. Schumacher HR Jr, Becker MA, Wortmann RL, et al. Effects of fe- 5. Borstad GC, Bryant LR, Abel MP, et al. Colchicine for buxostat versus allopurinol and placebo in reducing serum urate prophylaxis of acute flares when initiating allopuri- in subjects with hyperuricemia and gout: a 28-week, phase III, nol for chronic gouty arthritis. J Rheumatol. 2004;31: randomized, double-blind, parallel-group trial. Arthritis Rheum. 2429-2432. 2008;59:1540-1548. 6. Khanna D, Fitzgerald JD, Khanna PP, et al; American College 2. Becker MA, Schumacher HR Jr, Wortmann RL, et al. Febuxo- of Rheumatology. 2012 American College of Rheumatol- stat compared with allopurinol in patients with hyperuricemia ogy guidelines for management of gout. Part 1: systematic and gout. N Engl J Med. 2005;353:2450-2461. nonpharmacologic and pharmacologic therapeutic ap- 3. Sundy JS, Baraf HSB, Yood RA, et al. Efficacy and tolerability of proaches to hyperuricemia. Arthritis Care Res (Hoboken). pegloticase for the treatment of chronic gout in patients refrac- 2012;64:1431-1446. tory to conventional treatment: two randomized controlled 7. Khanna D, Khanna PP, Fitzgerald JD, et al; American Col- trials. JAMA. 2011;306:711-720. lege of Rheumatology. 2012 American College of Rheu- 4. Paulus HE, Schlosstein LH, Godfrey RG, et al. Prophylactic matology guidelines for management of gout. Part 2: colchicine therapy of intercritical gout: a placebo-controlled therapy and anti-inflammatory prophylaxis of acute study of probenecid-treated patients. Arthritis Rheum. gouty arthritis. Arthritis Care Res (Hoboken). 2012;64: 1974;17:609-614. 1447-1461.

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