Xanthine oxidase inhibitors for prevention of cardiovascular events: a systematic review and meta-analysis of randomized controlled trials

TLDR: Purine-like XOI may reduce the incidence of adverse CV outcomes, however, higher doses of allopurinol (> 300 mg/day) may be associated with loss of CV protection.

Abstract: Xanthine oxidase inhibitors (XOI), classified as purine-like (allopurinol and oxypurinol) and non-purine (febuxostat and topiroxostat) XOI, present antioxidant properties by reducing the production of reactive oxygen species derived from purine metabolism Oxidative stress is an important factor related to endothelial dysfunction and ischemia-reperfusion injury, and may be implicated in the pathogenesis of heart failure, hypertension, and ischemic heart disease However, there is contradictory evidence regarding the possible cardiovascular (CV) protective effect exerted by XOI Our objective is to compare the incidence of major adverse cardiovascular events (MACE), mortality, total (TCE) and specific CV events in randomized controlled trials (RCTs) testing XOI against placebo or no treatment PubMed, EMBASE, Web of Science, Cochrane Central, Lilacs databases were searched from inception to Dec 30 2016, along with hand searching RCTs including exclusively adult individuals, lasting ≥ 4 weeks, with no language restriction, were eligible Independent paired researchers selected studies and extracted data Considering the expected rarity of events, Peto and DerSimonian/Laird odds ratios (OR), the latter in case of heterogeneity, were used for analysis Random-effects meta-regression was used to explore heterogeneity The analysis of MACE included 81 articles (10,684 patients, 6434 patient-years) XOI did not significantly reduce risk of MACE (ORP = 071, 95% CI 046–109) and death (089, 059–133), but reduced risk of TCE (060, 044–082; serious TCE: 064, 046 to 089), and hypertension (054, 037 to 080) There was protection for MACE in patients with previous ischemic events (042, 023–076) Allopurinol protected for myocardial infarction (038, 017–083), hypertension (032, 018–058), TCE (048, 031 to 075, I2 = 55%) and serious TCE (056, 036 to 086, I2 = 44%) Meta-regression associated increasing dose of allopurinol with higher risk of TCE and serious TCE (P   300 mg/day) may be associated with loss of CV protection