Allopurinol disappoints in ALL-HEART

The findings from the randomised, prospective ALL-HEART study showed that allopurinol, a medicine commonly used to treat gout, did not reduce composite primary endpoint events, including non-fatal myocardial infarction (MI), non-fatal stroke, or cardiovascular death, in patients with ischaemic heart disease.

Preclinical and observational data have suggested that allopurinol, a xanthine oxidase inhibitor involved in oxidative stress signalling and commonly prescribed as a treatment for gout, might confer cardiovascular benefits. “The importance of serum uric acid levels, which can be reduced by allopurinol, in cardiovascular disease is controversial, and there have been different reports over the years of how important they may be,” Prof. Isla Shelagh Mackenzie (University of Dundee, UK) explained [1].

The ALL-HEART (ISRCTN32017426) study randomised 5,721 patients with ischaemic heart disease but no history of gout 1:1 to receive 600 mg of allopurinol daily or usual care. The primary endpoint was a composite of non-fatal MI, non-fatal stroke, or cardiovascular death.

Mean serum uric acid levels were reduced from 0.34 mmol/L at baseline to 0.18 mmol/L at 6 weeks of treatment, “so we can see that the treatment was effective at lowering uric acid,” Prof. Mackenzie pointed out. However, the composite primary endpoint was not met (HR 1.04; 95% CI 0.89–1.21; P=0.65), nor were there any differences between the 2 arms on any of the individual components.

“ALL-HEART is the first large, prospective, randomised trial of the effect of allopurinol on major cardiovascular outcomes in patients with ischaemic heart disease and provides robust evidence on the role of allopurinol in these patients,” concluded Prof. Mackenzie.

The invited discussant, Prof. Leslie Cho (Cleveland Clinic, OH, USA), suggested many factors could have masked any real influence of allopurinol, namely pointing to the older age of the participants (average age of 72 years) and the fact that the average length of their disease had been 10 years, suggesting chronic angina. Moreover, she felt that xanthine oxidase may not be “a major player” in the oxidative stress signalling in ischaemic heart disease, questioning whether allopurinol was the right drug to test in this setting.

1. Mackenzie IS, et al. ALL-HEART – Allopurinol and cardiovascular outcomes in ischaemic heart disease. Hot Line Session 3, ESC Congress 2022, Barcelona, Spain, 26–29 August.

 

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Posted on 27 October, 202226 October, 2022