Allopurinol

Abstract

Allopurinol is licensed in the United Kingdom for the prophylaxis of gout as well as uric acid and calcium oxalate renal stones. It can also be prescribed for the prophylaxis of hyperuricaemia associated with cancer chemotherapy. Allopurinol effectively lowers serum uric acid levels and reduces the risk of recurrent gout symptoms. It is commenced after an acute attack has fully subsided to avoid precipitating a flare in symptoms. The recommended starting dose is 100mg to reduce the risk of adverse reactions and the dose is subsequently increased if the serum urate lowering response is unsatisfactory.1 The drug is well tolerated although skin reactions, which may occur at any time during treatment, are the most common adverse effects. Fortunately, hypersensitivity reactions such as Stevens-Johnson syndrome are rarely seen in clinical practice. Allopurinol is a structural analogue of the naturally-occurring purine base hypoxanthine. It is a competitive inhibitor of xanthine oxidase, the enzyme responsible for the conversion of hypoxanthine to xanthine and of xanthine to uric acid, the end product of purine metabolism. (See Figure 1.) Xanthine oxidase is an enzyme that generates reactive oxygen species, promoting oxidative stress which inactivates the anti-atherosclerotic substance nitric oxide. Allopurinol is about 90% absorbed from the gastrointestinal tract with peak plasma levels 1.5 hours post dose. There is negligible protein binding and the plasma half life is 1–-2 hours due to its rapid renal clearance with a lower dose used in the presence of renal impairment. After the ingestion of allopurinol the plasma level of uric acid is reduced. Hypoxanthine, xanthine and uric acid are excreted in the urine but because of their levels of solubility there is a decreased risk of crystalluria. With the use of allopurinol the plasma concentration of uric acid is reduced below its level of solubility, encouraging the dissolution of gouty tophi. Hyperuricaemia and gout are closely associated with insulin resistance syndrome and frequently coexist with metabolic syndrome and type 2 diabetes. Observational and animal studies have identified hyperuricaema as an independent risk factor for insulin resistance and prediabetes. Observational studies have indicated that raised urate levels are an independent predictor of albuminuria and early decline in renal function in those with either type 1 or type 2 diabetes. In animal studies, allopurinol has been shown to improve insulin resistance. The drug has also been shown to improve endothelial function in those with type 2 diabetes and associated mild hypertension in addition to those with heart failure, and in smokers. It also causes regression of left ventricular hypertrophy in those with type 2 diabetes. Lowering of urate levels with allopurinol has overall not shown an improvement in diabetic kidney disease outcomes. Allopurinol reduces oxidative stress by reducing superoxide anions and other free radicals which in turn reduces cardiac hypertrophy, increases tissue oxygenation and reduces atherosclerotic plaque rupture. It has also been shown to improve endothelial function. A systematic review published in 2021 reported on the effect of allopurinol on cardiovascular mortality, myocardial infarction and stroke in patients with hyperuricaemia and preserved renal function.2 Of the 26 randomised-controlled trials included, compared to placebo, allopurinol significantly reduced the combined cardiovascular outcome due to a benefit on myocardial infarction with no significant effect on stroke or cardiovascular mortality. The extensive literature, highlighted in this systematic review suggesting positive cardiovascular benefits from the use of allopurinol, led to a landmark outcome trial which began randomisation in early 2014 and was published in late 2022. The efficacy of allopurinol therapy in improving cardiovascular outcomes in patients with ischaemic heart disease (ALL-HEART) study was designed to determine whether there were indeed benefits from the drug in patients with cardiovascular disease but without gout or a raised uric acid.3 The primary objective of the trial was to determine whether the addition of 600mg allopurinol to usual therapies improved outcomes. This dose was chosen, if baseline renal function was normal, on the basis that this higher dose may be needed for a positive cardiovascular outcome. A total of 5721 patients were randomised to either the allopurinol group or the usual-care group and included in the intention-to-treat analysis. The mean duration of follow up was 4.8 years. The 600mg dose of allopurinol was taken by 84.8% of the treatment group.4 There was no evidence of a difference in rates between the randomised groups of non-fatal myocardial infarction, non-fatal stroke or cardiovascular death. Of the participants in the allopurinol group 11% compared with 11.3% in the usual care group had a primary endpoint (hazard ratio [HR] 1.04, 95% CI 0.89–1.21, p=0.65). The HR for death from any cause was 1.02 (95% CI 0.87–1.20, p=0.77). Results from the secondary time to event outcomes showed similarly no difference in the full range of cardiovascular related hospitalisations. There was no difference in serious adverse effects between the two groups and the average uric acid levels in the trial were within the normal range. In the trial, 21.7% of each group had diabetes and in the treatment group 0.8% had type 1 and 20.8% type 2 diabetes. There was similarly no difference in outcomes in those with diabetes. The scientific evidence would suggest the possibility of a benefit from allopurinol in ischaemic heart disease prevention at times of high oxidative stress. Based on the ALL-HEART study, allopurinol cannot be recommended for the secondary prevention of cardiovascular events in patients with ischaemic heart disease including those with diabetes. The CARES study in patients with gout and major cardiovascular disease showed a higher risk for cardiovascular-related death and for all-cause mortality in patients taking febuxostat, a newer xanthine oxidase inhibitor compared with allopurinol. On the basis of this trial, National Institute for Health and Care Exellence (NICE) national clinical guideline NG219 recommends avoiding febuxostat in patients with gout and major cardiovascular disease, with allopurinol being the drug of choice. Allopurinol, a drug in use since 1966, is a tried and tested effective uric acid lowering drug used for the prevention of chronic gout. It remains our first-line drug in the long-term management of the condition, with NICE recommending a treat-to-target strategy. It has not been shown to improve cardiovascular outcomes with or without diabetes or slow progression of diabetic kidney disease.