Febuxostat and Cardiovascular Events: A Systematic Review and Meta-Analysis

Abstract

Background. Febuxostat is approved in the United States for the management of hyperuricemia in patients with gout. In November 2017 the FDA released a warning alert on a possible link between febuxostat and cardiovascular disease (CVD) reported in a single clinical trial. Objective. To conduct a systematic review and meta-analysis and assess the risk of major adverse cardiovascular events (MACE) in patients receiving febuxostat compared to a control group. Methods. We searched the MEDLINE and EMBASE database for studies published up until March 2018. We included randomized clinical trials (RCTs) that compared febuxostat to control groups including placebo and allopurinol. We calculated the pooled relative risk (RR) of MACE and cardiovascular disease (CVD) mortality with the corresponding 95% confidence intervals (CI). Results. Our search yielded 374 potentially relevant studies. Among the 25 RCTs included in the systematic review, 10 qualified for the meta-analysis. Among the 14,402 subjects included, the median age was 54 years (IQR 52-67) and 90% were male (IQR 82-96); 8602 received febuxostat, 5118 allopurinol, and 643 placebo. The pooled RR of MACE for febuxostat was 0.9; 95% CI 0.6-1.5 (p= 0.96) compared to the control. The RR of CV-related death for febuxostat was 1.29; 95% CI 1.01-1.66 (p=0.03). Conclusions. Compared with other SU-lowering treatments, febuxostat does not increase or decrease the risk of cardiovascular disease but may increase the risk of CVD death. More RCTs measuring cardiovascular safety as a primary outcome are needed to adequately evaluate the risk of CVD with febuxostat.

Febuxostat does not delay progression of carotid atherosclerosis in patients with asymptomatic hyperuricemia: A randomized, controlled trial

“…Several previous studies investigated whether pharmacological urate-lowering therapy in patients with gout could improve cardiovascular outcomes, and the results were controversial [13,23,24]. A systematic review and meta-analysis using data based on conventional adverseevent reporting demonstrated that the clinical impact of febuxostat on the incidence of CVD was neutral compared with allopurinol or placebo, whereas there was an increased incidence of cardiovascular death with febuxostat treatment [25]. A large-scale cohort study also demonstrated no difference in the risk of CVD between febuxostat and allopurinol, but there was a trend towards an increased risk for all-cause mortality with long-term use of febuxostat [26].…”

<p>Uric Acid and Arterial Stiffness</p>

“…The authors recommend caution when deciding to give febuxostat to high cardiovascular risk patients. 146…”

Inhibition of Xanthine Oxidoreductase Enhances the Potential of Tyrosine Kinase Inhibitors against Chronic Myeloid Leukemia

“…In the future, it would be interesting to test the combination of XOR inhibitors and TKIs in clinical trials, as well as to test the effect of other recently discovered XOR inhibitors, such as febuxostat, which is more powerful and stable than allopurinol. Its use in the USA has recently been approved by the FDA [57].…”