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A new study found that the use of febuxostat in Asian patients with and without gout was associated with greater cardiovascular risks than allopurinol, particularly acute coronary syndrome and atrial fibrillation.1
“…our findings suggest that febuxostat treatment may be less favorable than allopurinol treatment strategy from the perspective of secondary prevention in Asian populations,” said Department of Pharmacy, Longyan Second Hospital, China. write the researchers, led by Jian-hao Deng. “As a result, febuxostat may not be considered a viable treatment option for managing hyperuricemia in Asians.”
According to the 2020 American College of Rheumatology guidelines, xanthine oxidase inhibitors, such as febuxostat and allopurinol, are considered the preferred initial urate-lowering therapy.2
The U.S. Food and Drug Administration (FDA) approved febuxostat for the treatment of hyperuricemia in 2009, and the drug demonstrated efficacy and long-lasting hypouricemic effects compared to allopurinol. In a study conducted from 2010 to 2017 evaluating the cardiovascular safety of febuxostat and allopurinol in patients with gout, all-cause and cardiovascular mortality was lower in the febuxostat group than in the allopurinol group. It turned out to be high.3 Due to concerning data, the FDA issued safety alerts in 2017 and 2019 regarding febuxostat’s association with cardiovascular mortality.
However, another study conducted between 2011 and 2018 found the opposite. In gout patients at high cardiovascular risk, febuxostat was not associated with an increased risk of mortality or serious adverse events compared with allopurinol.Four
In addition to conflicting data, most trials included white patients. In one study, Asian patients made up only 3% of the total gout patient population.
Due to the lack of Asian representation, researchers conducted a systematic review and meta-analysis comparing the cardiovascular safety of febuxostat and allopurinol in the treatment of hyperuricemia in Asian patients with and without gout. An analysis was conducted.1
The team looked at 13 studies, including prospective or retrospective cohort studies, cross-sectional studies, case-control studies, or randomized controlled trials. Inclusion criteria included participants aged 18 years or older in an Asian population diagnosed with hyperuricemia with or without gout, comparing or focusing on either febuxostat or allopurinol, and emergency 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 or secondary gout, animal studies, unavailable full text, published in languages other than Chinese or English, and duplicate studies.
Participants in the four randomized controlled trials were Japanese only, and participants in the cohort study were Chinese (n = 5), Korean (n = 3), and Japanese (n = 1).
Pooled analysis showed that febuxostat users had a significantly higher risk of 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) lower than allopurinol users. However, no significant difference existed between febuxostat and allopurinol regarding emergency coronary revascularization (HR, 1.07; 95% CI, 0.98 – 1.16; 95% CI, 0.98 – 1.16; P = .13) and stroke (HR, 0.96; 95% CI, 0.91 – 1.01; P = .13). In addition, differences in acute decompensated heart failure (HR, 0.73; 95% CI, 0.35–1.53; 95% CI, 0.35–1.53; P = .40) and all-cause mortality (HR, 0.86; 95% CI, 0.49 – 1.51; P = .60) was not significant based on the randomized controlled trial.
Furthermore, in the Chinese subgroup, febuxostat increased the risk of acute decompensated heart failure (HR, 1.22; 95% CI, 1.01–1.48; 95% CI, 1.01–1.48; P < .05), cardiovascular death (HR, 1.25; 95% CI, 1.03 – 1.50; P < .05), all-cause mortality (HR, 1.07; 95% CI, 1.01 – 1.14; P < .05) compared to allopurinol.
Therefore, although the difference in cardiovascular risk between febuxostat and allopurinol in Asian patients was small, the cardiovascular risk with febuxostat was still greater in the Chinese subgroup.
“The underlying mechanisms of febuxostat-related adverse cardiovascular outcomes remain unclear,” the researchers wrote.
The research team continued to study how hyperuricemia is associated with susceptibility to hypertension, diabetes, ischemic heart disease, and heart failure. Furthermore, elevated serum uric acid levels are significantly associated with an increased risk of unfavorable outcomes in people with cardiovascular disease.
“One potential explanation for the cardioprotective effects of allopurinol, as opposed to febuxostat, may be due to differences in their respective mechanisms of action,” the researchers wrote. “Allopurinol acts as a purine analog that undergoes metabolic processes involving various enzymes involved in the synthetic metabolism of purines and pyrimidines. In contrast, febuxostat only acts as a non-purine analogue inhibitor of xanthine oxidase. It works.”
The researchers highlighted a number of limitations, including the inclusion of a retrospective observational study rather than a randomized controlled trial, and found within-group heterogeneity, with a dose range varying from 100 to 600 mg/day for allopurinol. However, research results revealed that febuxostat was only administered at doses of 40 to 120 mg/day. Definitions of cardiovascular disease outcomes vary, all cohort studies were retrospective, and all randomized controlled trials included a Japanese population.
“…future studies including larger sample sizes, multiple medical centers, extended time periods, randomized participant selection, and double-blind designs are needed to substantiate this claim within the Asian population. “It is essential that this is implemented,” the researchers concluded.
References
- Deng JH, Lai PH, Xie LS, Chiu SS, Chiu DS, Zhang JX. Cardiovascular safety of febuxostat and allopurinol in Asian patients with and without gout: a systematic review and meta-analysis. clinical translation science. 2024;17(3):e13757. doi:10.1111/cts.13757
- Fitzgerald JD, Dalbez N, Mickles T, et al. 2020 American College of Rheumatology Guidelines 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
- White WB, Saag KG, Becker MA et al. Cardiovascular safety of febuxostat or allopurinol in patients with gout. N English J Medicine. 2018;378(13):1200-1210. doi:10.1056/NEJMoa1710895
- McKenzie IS, Ford I, Nuki G, et al. Long-term cardiovascular safety (FAST) of febuxostat compared with allopurinol in patients with gout: a multicenter, prospective, randomized, open-label, non-inferiority study. lancet. 2020;396(10264):1745-1757. doi:10.1016/S0140-6736(20)32234-0
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