Cardiovascular safety of febuxostat compared to allopurinol for the treatment of gout: A systematic and meta‐analysis

Abstract The cardiovascular safety of febuxostat compared to allopurinol for the treatment of gout remains equivocal. Febuxostat had a better safety outcome compared with allopurinol. In this systematic review and meta‐analysis, we searched MEDLINE and Embase for articles published between March 1, 2000 and April 4, 2021, without any language restrictions. We did a systematic review and meta‐analysis of included clinical trials to evaluate the cardiovascular safety of febuxostat compared to allopurinol for treatment of chronic gout. Two reviewers independently selected studies, assessed study quality, and extracted data. Risk ratios were calculated with random effects and were reported with corresponding 95% confidence intervals (CI). From 240 potentially relevant citations, 224 papers were excluded; 16 studies were ultimately included in the analysis. Febuxostat had a better safety outcome compared with allopurinol，which was the composite of urgent coronary revascularization (OR: 0.84, 95% CI: 0.77–0.90, p < .0001) and stroke (OR: 0.87, 95% CI: 0.79–0.97, p = .009). However, that difference was not found in nonfatal myocardial infarction (OR: 0.99, 95% CI: 0.80–1.22, p = .91), cardiovascular related mortality (OR: 0.98, 95% CI: 0.69–1.38, p = .89) and all‐cause mortality (OR: 0.93, 95% CI: 0.75–1.15, p = .52). No significant differences in cardiovascular related mortality and all‐cause mortality were observed across any subgroup. This meta‐analysis adds new evidence regarding the cardiovascular safety of febuxostat in patients. Initiation of febuxostat in patients was not associated with an increased risk of death or serious cardiovascular related adverse events compared with allopurinol.


| INTRODUCTION
Gout is a common clinical metabolic system disease and may contribute to many adverse health events. Evidence shows that the risk of hyperuricemia increased with advanced age in both sexes. 1,2 At present, drugs are the first choice for the treatment of gout in clinical practice.
Studies have found that the treatment of gout with xanthine oxidase inhibition (allopurinol, febuxostat) can increase uric acid excretion via the kidneys and achieve better results. Recent studies have shown that febuxostat, a novel non-purine selective inhibitor of xanthine oxidase (XO), is more effective than allopurinol in lowering the uric acid levels in patients with hyperuricemia and gout. 3,4 It is particularly useful in patients who are refractory or intolerant to allopurinol, and requires no dose limitation in stages 1-3 chronic kidney disease. 5 However, the Linggen Gao and Bin Wang contributed equally to this study. food and drug administration (FDA) issued a public safety alert, responding to results of cardiovascular safety of febuxostat and allopurinol in patients with gout and cardiovascular morbidities (CARES) trial. 6 The FDA public safety alert highlights the discussion of CV safety of febuxostat. [7][8][9] By contrast, the European Medicines Agency (EMA)required febuxostat versus allopurinol streamlined trial, a prospective, randomized, open-label, blinded-endpoint, non-inferiority trial of febuxostat (80-120 mg/day) versus allopurinol, does not support the finding of an increased cardiovascular risk of febuxostat. 10 The evidence for a causal relationship between xanthine oxidase inhibitors and cardiovascular diseases (CVD) remains equivocal. Therefore, this study intends to conduct a systematic review of the relevant clinical trials published in recent years to analyze the adverse cardiovascular events and death risks of febuxostat compared with allopurinol in patients.

| Search strategy and selection criteria
We followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines in this systematic review and meta-analysis. 11 We systematically searched clinical trials of febuxostat and allopurinol treatment of gout in the elderly in PubMed, EMBASE, the Cochrane Library database and reviews of relevant articles from January 2000 to April 4, 2021. The following terms were used: "Gout" "Febuxostat" "Allopurinol" OR "Clinical Trial" "adverse events." Language of publication did not influence article selection.
Titles and abstracts were screened to exclude ineligible studies.
Studies were included if they met the following criteria: (i) clinical trials; (ii) treatment status as treated with febuxostat and allopurinol; (iii) long-term follow up of patients.
Exclusion criteria: (i) Documents in languages other than Chinese and English. (ii) There are no statistics on cardiovascular and deathrelated adverse events for the outcome indicators, and the data is incomplete. (iii) Patients with severe liver and kidney dysfunction, unstable vital signs, long-term alcoholism, and other conditions that will affect the resolution of indicators (iv) Patients with secondary gout. Gao LG and Bin Wang screened titles, abstracts, and full text of papers identified in our search and assessed for risk of bias.
The titles of the primary 240 publications identified were reviewed and 224 were discarded although they were identified by our search terms. The studies were also discarded because the enrolled patients with acute hyperuricemia or secondary hyperuricemia (e.g., end-stage renal disease). Finally, 14 publications were chosen for the meta-analysis.

| Study groups and clinical evaluation
The study population in the present meta-analysis consisted of 257 851 patients. Patients were categorized by treatment status as treated with febuxostat or allopurinol. The details in the pharmacologic intervention were listed in Table 1. All patients underwent complete clinical evaluations and fulfilled the diagnostic criteria.
Outcomes of major events from each trial were selected, which were consisted of cardiovascular related mortality, major vascular events (including myocardial infarction or other acute coronary syndrome, coronary revascularization, or stroke, etc.) and all-cause mortality.

| Data extraction
Two authors (L.G. and B.W.) independently assessed and abstracted relevant trials that met the standardized, predefined criteria. Disagreements were identified computationally. Each was checked independently. If data could not be extracted or calculated from the article with confidence, no data were entered. Any discrepancies between the two reviewers were resolved through discussion. A data extraction form was used to collect the following information: (i) authors, study location, dates of study; (ii) number and age of participants; (iii) study design; (iv) comorbidities; (v) details of administration; (vi) follow-up time; (vii) outcomes. L.G. and B.W. extracted the data for patients using a standardized data form.

| Statistical analysis
The heterogeneity of the included studies was examined by Cochran chisquare tests (p < .1). The I 2 statistic was also examined, and we considered I 2 > 50% to indicate significant heterogeneity between the trials. 12 Publication bias was evaluated using both the Begg's funnel plot and the Egger plot. The Mantel-Haenszel 13 fixed-effect model or the random-effects model was chosen for meta-analysis of the comparison of efficacy and cardiovascular safety of and endpoint events between febuxostat -treated group and allopurinol -treated group.
Statistical analyses were carried out with Review Manager 5.0.
p values that were <.05 were considered statistically significant. All statistical tests were two-sided.
To examine the cardiovascular safety and identify the possible source of heterogeneity within these studies, previously defined subgroup analyses were performed (age, population and study design).    were common comorbidities in both groups. Begg's funnel plot indicated that there are no strong evidences of publication selection bias.

| Results of subgroup analyses
To clarify the heterogeneity, subgroup analyses were performed to investigate the source of heterogeneity (Table 2)  Febuxostat is a urate-lowering drug that was approved for the management of gout by the EMA, the US FDA and the China FDA (CFDA). The CARES reported an increased risk of death in patients in the febuxostat group, prompting the FDA to change febuxostat's approval status to be adopted only as a second-line urate-lowering drug. By contrast, several recent clinical trials do not support the finding of an increased all-cause mortality and cardiovascular risk of febuxostat. 10,14,24,26 Our meta-analysis found that febuxostat users did not have a significantly different risk of cardiovascular events or all-cause mortality compared with allopurinol users.
Older individuals have higher rates of major cardiovascular events, coexistence of multiple diseases, accompanied by multiple syndromes, multiple medications, and natural decline in body function.
Gout currently plagues many old patients. Febuxostat has minimal effects on other enzymes involved in purine and pyrimidine metabolism and is metabolized mainly by glucuronide formation and oxidation in the liver. Febuxostat has been shown to be safe according to the available clinical data and can be used in treating patients with allopurinol hypersensitivity and renal insufficiency. 27 Since the application of febuxostat to the clinic, there have been many meta-analysis on the effectiveness and safety of febuxostat compared with allopurinol in the treatment of patients with gout. [28][29][30][31][32] Cardiovascular events were important concern associated with febuxostat treatment. However, the meta-analysis of cardiovascular safety of febuxostat compared with allopurinol in the elderly was not reported. Several clinical trials were conducted to investigate the cardiovascular safety of febuxostat compared with allopurinol in patients with gout with known cardiovascular comorbidities, but the results have been conflicting. Some studies showed that the incidence of major adverse cardiovascular events in febuxostat group was numerically higher than allopurinol group, although it was not statistically significantly. 3,4,33 Some studies found that initiation of febuxostat compared with allopurinol was not associated with a change in risk of cardiovascular events. 14 The subgroup analysis according to age of our meta-analysis adds new evidence regarding the safety of febuxostat in older patients.
Although we believe that this meta-analysis provides useful infor-