Allopurinol and Mortality in Gout Treatment

Effective treatments with few side effects are a clinical gold mine. But what if one of those side effects—though rare—is mortality?

Gout is caused by an overproduction or under-excretion of uric acid, and it can be treated with NSAIDs, corticosteroids or colchicine to relieve pain and inflammation; medications that block uric acid production (such as allopurinol); or medications that improve uric acid removal.

The xanthine oxidase inhibitor allopurinol is the most commonly used urate-lowering therapy. It treats gout complications by limiting the amount of uric acid the body makes. Allopurinol-induced rash may be followed by more severe hypersensitivity reactions—including toxic epidermal necrolysis, vasculitis, and hepatotoxicity; in some rare cases, these hypersensitivity syndromes have been fatal. (Gout, regardless of treatment, has also been shown to have an increased risk of all-cause mortality and cardiovascular disease mortality in men compared with men without gout.)

Allopurinol’s overall impact on the risk of mortality has been studied but is not yet well-understood. Now, a study has shown that allopurinol’s benefit likely outweighs the risk of serious side effects. An incident user cohort study in Annals of the Rheumatic Diseases evaluated the impact of allopurinol on the risk of individuals with hyperuricemia and among those with gout in the general population and found that“allopurinol initiation was associated with a modestly reduced risk of death in patients with hyperuricaemia and patients with gout. The overall benefit of allopurinol on survival may outweigh the impact of rare serious adverse effects.”

The study population included individuals aged ≥40 years who had a record of hyperuricaemia (serum urate level >357 μmol/L for women and >416 μmol/L for men) between January 2000 and May 2010. Of 5,927 allopurinol initiators and 5,927 matched comparators, 654 and 718, respectively, died during the follow-up (mean=2.9 years). The baseline characteristics were well balanced in the two groups, including the prevalence of gout in each group (84%). Allopurinol initiation was associated with a lower risk of all-cause mortality.

The study mirrors findings from a 2014 study that showed low- to moderate-quality evidence indicating similar adverse events and severe adverse events from allopurinol to placebo and febuxostat. A 2009 study in Rheumatology that looked at hyperuricemia patients found that, after adjusting for baseline urate levels, allopurinol treatment was associated with a lower risk of all-cause mortality (hazard ratio 0.78; 95% CI 0.67, 0.91).