Febuxostat Use Among Gout Asian Patients Linked to Increased Cardiovascular Risk

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A new study found febuxostat use among Asian patients with and without gout was linked to a greater cardiovascular risk than allopurinol, particularly for acute coronary syndrome and atrial fibrillation.¹

“…Our findings suggest that febuxostat treatment may offer disadvantages over the allopurinol treatment strategy in the context of secondary prevention for Asian population,” wrote investigators, led by Jian-hao Deng, from the pharmacy department at Longyan Second Hospital in China. “Consequently, febuxostat may be not considered as a viable therapeutic option for managing hyperuricemia in the Asian population.”

Xanthine oxidase inhibitors, such as febuxostat and allopurinol, are considered the preferred initial urate-lowering therapy, according to the 2020 American College of Rheumatology guideline.²

The US Food and Drug Administration (FDA) approved Febuxostat for the treatment of hyperuricemia in 2009, and the medication demonstrated efficacy and longer-lasting hypouricemic activity compared to allopurinol. Trials conducted from 2010 – 2017 evaluating the cardiovascular safety of febuxostat and allopurinol in patients with gout found the febuxostat group had greater rates of all-cause mortality and cardiovascular mortality than the allopurinol group.³ Due to the concerning data, the FDA issued a safety alert in 2017 and 2019 regarding the link between febuxostat and cardiovascular mortality.

However, another study conducted from 2011 – 2018 found the opposite—febuxostat did not have a greater risk of mortality or serious adverse events compared to allopurinol among patients with gout and a high cardiovascular risk.⁴

On top of the conflicting data, most of the trials had White patients. In 1 study, Asian patients represented only 3% of the total gout patient population.

Due to the lack of Asian representation, investigators conducted a systematic review and meta-analysis to compare the cardiovascular safety of febuxostat and allopurinol for the treatment of hyperuricemia among Asian patients with or without gout.¹

The team examined 13 studies including prospective or retrospective cohort studies, cross-sectional studies, case-control studies, or randomized control trials. Inclusion criteria included participants being > 18 years old among Asian populations with a hyperuricemia diagnosis with or without gout, and comparing or focusing on either febuxostat and allopurinol, assessing the outcomes of urgent coronary revascularization, acute coronary syndrome, acute decompensated heart failure, stroke, atrial fibrillation, all-cause mortality, and cardiovascular death. Studies were excluded if participants had acute gout or secondary gout, animal experiments, unavailable full texts, published in a language other than Chinese or English, and duplicate studies.

Participants in the 4 randomized controlled trials were solely from the Japanese population, and participants from cohort studies were Chinese (n = 5), Korean (n = 3), and Japanese (n = 1).

The pooled analysis showed febuxostat users were at a significantly greater risk for acute coronary syndrome (hazard ratio [HR], 1.06; 95% confidence interval [CI], 1.03 – 1.09; P < .01), atrial fibrillation (HR, 1.19; 95% CI, 1.05 – 1.35; P < .01) than allopurinol users. However, no significant difference between febuxostat and allopurinol existed for urgent coronary revascularization (HR, 1.07; 95% CI, 0.98 – 1.16; P = .13) and stroke (HR, 0.96; 95% CI, 0.91 – 1.01; P = .13). Additionally, the difference for acute decompensated heart failure (HR, 0.73; 95% CI, 0.35 – 1.53; P = .40) and all-cause death (HR, 0.86; 95% CI, 0.49 – 1.51; P = .60) was not significant based on randomized controlled trials.

Furthermore, in the Chinese subgroup, febuxostat had increased the risk of acute decompensated heart failure (HR, 1.22; 95% CI, 1.01 – 1.48; P < .05), cardiovascular death (HR, 1.25; 95% CI, 1.03 – 1.50; P < .05), and all-cause mortality (HR, 1.07; 95% CI, 1.01 – 1.14; P < .05), compared to allopurinol.

Thus, despite the insignificant differences in cardiovascular risk between febuxostat and allopurinol among Asian patients, the Chinese subgroup still had a greater cardiovascular risk with febuxostat.

“The underlying mechanism of febuxostat-related adverse CV outcomes remains undetermined,” investigators wrote.

The team continued to write how hyperuricemia is linked to greater susceptibility to hypertension, diabetes, ischemic heart disease, and heart failure. Additionally, an increased level of serum uric acid is significantly linked to an increased risk of unfavorable outcomes in individuals with cardiovascular disease.

“One potential explanation for the cardioprotective effects of allopurinol, as opposed to febuxostat, may be attributed to the disparity in their respective mechanisms of action,” investigators wrote. “Allopurinol functions as a purine analogue that can undergo metabolic processes involving various enzymes implicated in purine and pyrimidine synthesis metabolism. In contrast, febuxostat acts solely as a non-purine analogue inhibitor of xanthine oxidase.”

Investigators highlighted many limitations, such as including more retrospective observational studies than randomized controlled trials, they found within-group heterogeneity, the dose range varied from 100 – 600 mg/day for allopurinol but only 40 – 120 mg/day for febuxostat, studies had varied definitions of cardiovascular disease outcomes, all the cohort studies were retrospective, and all the randomized controlled trials included a Japanese population.

“…to substantiate this assertion, it is imperative that future investigations encompassing larger sample sizes, multiple medical centers, extended durations, randomized participant selection, and double-blind methodologies be conducted within the Asian population,” investigators concluded.

^References

1. ^{Deng JH, Lai PH, Xie LS, Qiu SS, Qiu DS, Zhang JX. Cardiovascular safety of febuxostat versus allopurinol among the Asian patients with or without gout: A systematic review and meta-analysis. Clin Transl Sci. 2024;17(3):e13757. doi:10.1111/cts.13757}
2. ^{FitzGerald JD, Dalbeth N, Mikuls T, et al. 2020 American College of Rheumatology Guideline for the Management of Gout [published correction appears in Arthritis Care Res (Hoboken). 2020 Aug;72(8):1187] [published correction appears in Arthritis Care Res (Hoboken). 2021 Mar;73(3):458]. Arthritis Care Res (Hoboken). 2020;72(6):744-760. doi:10.1002/acr.24180}
3. ^{White WB, Saag KG, Becker MA, et al. Cardiovascular Safety of Febuxostat or Allopurinol in Patients with Gout. N Engl J Med. 2018;378(13):1200-1210. doi:10.1056/NEJMoa1710895}
4. ^{Mackenzie IS, Ford I, Nuki G, et al. Long-term cardiovascular safety of febuxostat compared with allopurinol in patients with gout (FAST): a multicentre, prospective, randomised, open-label, non-inferiority trial. Lancet. 2020;396(10264):1745-1757. doi:10.1016/S0140-6736(20)32234-0}