Background/Purpose: There is evidence suggesting that high levels of uric acid represent an independent cardiovascular risk factor and that the use of xanthine oxidase inhibitors (XOI) may reduce the risk of major adverse cardiovascular events (MACE) (1). To date, this evidence is based mainly on observational studies (2), which are frequently subject to selection and confounding bias. Our objective in this systematic review and meta-analysis is to compare the incidence of MACE and mortality in patients enrolled in randomized controlled trials (RCTs) comparing XOI with placebo or no treatment.

Methods: A systematic review of the literature searching for RCTs was held on September 9, 2014 using PubMed, EMBASE, Cochrane Library, Web of Science, and  Lilacs databases (from their inception), and hand search. The study was conducted and reported in accordance with the recommendations of the PRISMA statement (3), and the protocol was registered in PROSPERO (CRD42015016073).  All RCTs comparing XOIs with placebo (or no treatment) lasting four weeks or more were eligible, independent of the presence of comorbidities or outcomes of interest in each particular study. Studies including individuals under the age of 18, as well as treatment or follow-up lasting less than 4 weeks, were excluded from the meta-analysis. The primary outcomes were the incidence of MACE (cardiovascular death, non-fatal myocardial infarction, unstable angina requiring urgent revascularization, or non-fatal stroke) and mortality; total cardiovascular events (TCE), serious adverse events (SAE), and skin rash served as secondary outcomes. Statistical analysis was made using the REVMAN 5.2 software, and  associations were analyzed using the Peto or Mantel-Haenszel odds ratios (OR), depending on the frequency of events. A subgroup analysis was performed including only studies in which subjects were at high-risk for cardiovascular events.  

Results: In Total, 61 RCTs including approximately 5500 individuals were considered eligible for the meta-analysis. The use of XOI was not significantly associated with the risk of MACE (OR=1.24, 95% CI 0.54 to 2.85, P = 0.61), death (0.93, 0.49 to 1.75, P = 0.82), total cardiovascular events (0.85, 0.61 to 1.18, P=0.33), and SAE (0.98, 0.74 to 1.30, P=0.90). The risk of skin rash was higher in the XOI group (1.89, 1.16 to 3.08, P = 0.01). In a subgroup analysis performed in studies including mainly individuals with high cardiovascular risk profile, there was no significant difference in the risk for MACE (1.05, 0.44 to 2.50, P=0.92),  TCE (0.79, 0.57 to 1.11, P=0.18), and death  (0.88, 0.46 to 1.67, P=0.70). 

Conclusion: A meta-analytical pooling of the results of several RCTs performed in different clinical contexts failed to demonstrate that the use of XOIs is associated with reduced risk of major cardiovascular events, death, any adverse cardiovascular event, and serious adverse events. A small but statistically significant increase in the risk of skin rash was observed in the XOI group. 

References:

1. Richette P et al.  Nat Rev Rheumatol 2014;10:654-61.

2. Grimaldi-Bensouda L et al. Ann  Rheum Dis 2015;74:836-42.

3. Moher D, et al. BMJ 2009;339:b2535.

« Back to 2015 ACR/ARHP Annual Meeting

ACR Meeting Abstracts - https://acrabstracts.org/abstract/xanthine-oxidase-inhibitors-for-the-prevention-of-cardiovascular-events-a-systematic-review-and-meta-analysis-of-randomized-controlled-trials/