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The effects of allopurinol treatment on mortality among patients with gout remain uncertain, with a new meta-analysis finding conflicting results.

In a systematic review of the literature that identified four studies assessing all-cause or cardiovascular mortality in patients with gout receiving allopurinol, two of the studies found protective effects, one found no significant association, and another found no benefits for patients with dose escalation, reported Edward Roddy, PhD, and colleagues from Keele University in Staffordshire, England.

As shown in their study online in , pooled data for all-cause mortality in the four studies demonstrated no significant association with allopurinol use in gout, with an adjusted hazard ratio of 0.80 (95% CI 0.60-1.05).

Effective treatment is available for gout, and international guidelines recommend that all patients with confirmed gout be offered urate-lowering therapy. Allopurinol is the first-line choice, starting in dosages of 100 mg/day or less and titrating upward until serum urate is below 6 mg/dL. At that urate target, urate crystals can resolve and new depositions can be prevented.

Aside from its efficacy in lowering urate levels and successfully treating gout, allopurinol has other beneficial effects, including reducing the risks of renal events such as doubling of serum creatinine and the initiation of dialysis in patients with chronic kidney disease. The drug also has demonstrated improvements in endothelial function in patients with heart failure.

Still, despite the evidence for benefit, fewer than one-third of patients receive allopurinol, and of those, only 40% undergo treatment escalation to the serum urate target. The reasons for suboptimal use of allopurinol are complex, but "one contributing factor relates to the apprehension of patients and clinicians to initiate lifelong treatment without a clear understanding of the long-term effects," Roddy and co-authors observed.

with hyperuricemia (serum urate above 7 mg/dL) with or without gout diagnoses, treatment with allopurinol was associated with a 25% reduced risk of death.

However, whether mortality is decreased among patients who have confirmed gout is still uncertain, so Roddy's group conducted a systematic review and meta-analysis of the available data in cohort studies, identifying four that were published through 2018.

• The first study, by , included 286 patients with gout whose medical insurance data were obtained from the MJ Health Screening Center in Taiwan from 1997 to 2002. Patients' mean age was 52.7, and, as in the other three studies, the majority of patients were male. The adjusted hazard ratio for all-cause mortality in this study was 0.39 (95% CI 0.22-0.70)

• A second study, by , conducted in the U.K. with data from the Health Improvement Network from 2000 to 2010 also found protective effects for allopurinol on all-cause mortality. This study included 483 patients with gout whose mean age was 67, and found an adjusted hazard ratio of 0.81 (95% CI 0.70-0.92)

• But in the third study, also from the U.K. and analyzing outcomes from the Clinical Practice Research Datalink from 1995 to 2013, found no association of all-cause mortality with allopurinol use. The sample included 3,519 patients with gout whose mean age was 64. In a 1-year landmark analysis, the adjusted hazard ratio for all-cause mortality was 0.99 (95% CI 0.87-1.12) and at 3 years, the hazard ratio was 1.01 (95% CI 0.92-1.09)

• The fourth study, by , included 6,428 patients with gout who escalated their allopurinol doses with a goal of serum urate below 6 mg/dL, comparing them with an equivalent number of patients who did not have dose escalation. Dose escalators had a significant increase in all-cause mortality, with a hazard ratio of 1.08 (95% CI 1.01-1.17), and in a sensitivity analysis that limited the analysis to patients who achieved the target serum urate level, a nonsignificant reduction of 7% was seen for cardiovascular mortality (HR 0.93, 95% CI 0.76-1.14)

As to why Roddy and colleagues were unable to detect any significant protective effects of allopurinol on mortality, they said their analysis focused on observational data in real-world clinical use rather than clinical trials. In routine use, the team noted, doses of allopurinol are often far below what is needed for optimal urate control, and previous studies that have demonstrated mortality benefits have involved the use of higher doses, up to and exceeding 600 mg/day, rather than the typical 100 to 300 mg/day.

"The small number of studies suitable for inclusion and the evidence from the wider literature that allopurinol may have cardiovascular and renal benefits, suggests that further studies into the effect of allopurinol use on mortality in people with gout are required, particularly regarding the role of allopurinol dose and the importance of reaching target serum urate levels," the researchers concluded.

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