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

Abstract

Background: 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.

Methods: 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.

Results: The analysis of MACE included 81 articles (10,684 patients, 6434 patient-years). XOI did not significantly reduce risk of MACE (OR_P = 0.71, 95% CI 0.46-1.09) and death (0.89, 0.59-1.33), but reduced risk of TCE (0.60, 0.44-0.82; serious TCE: 0.64, 0.46 to 0.89), and hypertension (0.54, 0.37 to 0.80). There was protection for MACE in patients with previous ischemic events (0.42, 0.23-0.76). Allopurinol protected for myocardial infarction (0.38, 0.17-0.83), hypertension (0.32, 0.18-0.58), TCE (0.48, 0.31 to 0.75, I² = 55%) and serious TCE (0.56, 0.36 to 0.86, I² = 44%). Meta-regression associated increasing dose of allopurinol with higher risk of TCE and serious TCE (P < 0.05). Accordingly, lower doses (≤ 300 mg/day) of allopurinol reduced the risk of TCE, unlike higher doses. Non-purine-like XOI did not significantly reduce or increase the risk of adverse CV events, but confidence intervals were wide. Quality of evidence was generally low to moderate.

Conclusions: 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.

Keywords: Cardiovascular disease; Gout; Meta-analysis; Treatment; Xanthine Oxidase inhibitors.

Fig. 1

Forest plot analysis comparing the risk of major adverse cardiovascular events (MACE) between xanthine oxidase inhibitors and control. Numbers are Peto odds ratio and 95% CI. Heterogeneity: I² = 10%; Cochrans’s Q test, P = 0.324

Fig. 2

Meta-regression of dose of allopurinol* versus log odds ratio of heart failure (a)^a, total cardiovascular events (b)^b, and serious cardiovascular events (c)^c. * One oxypurinol study [19] contributing with events was excluded from metaregression due to the absence of direct comparisons of serum oxypurinol levels between oral preparations of allopurinol and oxypurinol (produced by Cardiome Pharma Corporation, Vancouver, British Columbia, Canada) used continuously in daily doses. ^aMeta-regression coefficient = 0.004, 95% confidence interval: 0.001 to 0.008, P = 0.008. ^b0.002, 0.001 to 0.004, P = 0.006. ^c 0.002, 0.000 to 0.003, P = 0.039