Febuxostat in hyperuricaemia management: FAST trial results and insights from a cardiologist
Hyperuricaemia, commonly manifesting as gout, is a marker for cardiorenal and metabolic abnormalities. While allopurinol is indicated for treatment of hyperuricaemia, hypersensitivity has been reported, with severe forms of allopurinol hypersensitivity (AH) associated with a high mortality rate. Febuxostat, a newer urate-lowering therapy (ULT), is a treatment option for hyperuricaemia with comparable cardiovascular (CV) safety vs allopurinol. In an interview with MIMS Doctor, Dr Michael Pak-Hei Chan, Specialist in Cardiology in Hong Kong, discussed population cohort study findings and his experience supporting the use of febuxostat in the management of hyperuricaemia with gout.
Hyperuricaemia: Increased risks of cardiorenal and metabolic disorders
“Patients with hyperuricaemia commonly present to GPs with gout and/or uric acid nephrolithiasis. Their increased risks of cardiorenal and metabolic disorders have led to increased attention among internal medicine physicians and cardiologists,” said Chan. [BMC Med 2017;15:123; Curr Hypertens Rep 2013;15:175-181]
Animal and epidemiological studies have demonstrated an important role of hyperuricaemia in promoting insulin resistance, leading to the development of type 2 diabetes mellitus and cardiorenal-metabolic syndrome (CRS). Elevated serum uric acid (SUA) level promotes endothelial dysfunction and vascular stiffness, which are known to play a central role in the development and progression of hypertension, CV disease and chronic kidney disease. [Ann Rhuem Dis 2015;74:631-634; Cardiorenal Med 2013;3:208-220]
“In Chinese patients [n=22,983], hyperuricaemia was associated with CV risk factors such as dyslipidaemia [odds ratio (OR) for male, 1.58; 95 percent confidence interval (CI), 1.41 to 1.76] [OR for female, 1.70; 95 percent CI, 1.46 to 1.98], hypertension [OR for male, 1.15; 95 percent CI, 1.02 to 1.29] [OR for female, 1.37; 95 percent CI, 1.18 to 1.60], overweight [OR for male, 2.03; 95 percent CI, 1.82 to 2.25] [OR for female, 1.82; 95 percent CI, 1.42 to 2.34], and diabetes [OR for female, 1.82; 95 percent CI, 1.42 to 2.34] following multivariate adjustment,” noted Chan. [Sci Rep 2017;7:5456]
Management of gout
The American College of Rheumatology (ACR) 2020 guidelines recommend initiation of ULT, such as febuxostat or allopurinol, for all patients with tophaceous gout, radiographic damage attributable to gout, or frequent (ie, ≥2 annually) gout flares. ULT is recommended to be continued indefinitely to avoid a return or worsening of gout symptoms. [Arthritis Care Res (Hoboken) 2020;72:744-760]
The European League Against Rheumatism (EULAR) 2016 guidelines recommend continuous monitoring of SUA level with lifelong maintenance of SUA at <6 mg/dL (<0.357 mmol/L). [Ann Rheum Dis 2017;76:29-42] A cohort study in Taiwan showed that individuals with extreme SUA levels had a significantly increased risk of CV mortality (SUA ≤0.17 mmol/L: hazard ratio [HR], 2.24; 95 percent CI, 1.93 to 2.59) (SUA ≥0.66 mmol/L: HR, 2.53; 95 percent CI, 2.28 to 2.81). [Rheumatology (Oxford) 2013;52:127-134]
Allopurinol hypersensitivity in Asians
AH has been reported in 0.1 percent of patients and is characterized by a combination of cutaneous changes (ranging from relatively benign maculopapular rash to more lethal forms, such as erythema multiforme [EM], Stevens-Johnson syndrome [SJS] and toxic epidermal necrolysis [TEN]) and systemic manifestations. Patients diagnosed with EM, SJS and TEN had a signiﬁcantly higher mortality rate than those with milder hypersensitivity reactions (20.3 percent vs 8.9 percent; p<0.0001). [Drug Saf 2013;36:953-980]
Despite a lower prevalence of gout in Asians and Pacific Islanders vs Caucasians (6 percent vs 82 percent) in a US cross-sectional study, a recent review reported that 73 percent of those with AH were Asians. [J Rheumatol 2008;35:498-501; Drug Saf 2013;36:953-980]
A case-control study found that individuals of Chinese vs European ancestry had a significantly increased risk of developing AH (OR, 70.8; p=0.005), due to high carriage of the HLA-B*5801 allele (8.9 percent from the Major Histocompatibility Complex database [dbMHC] database). [Arthritis Rheum 2012;64:2529-2536, Drug Saf 2013;36:953-980]
In another case-control study in Taiwan, severe cutaneous adverse reactions (SCARs) due to allopurinol were reported in 100 percent of Han Chinese patients with the HLA-B*5801 allele vs 15 percent of allopurinol-tolerant controls (OR, 580.3; 95 percent Cl, 34.4 to 9,780.9; p=4.7 x 10-24). [Proc Natl Acad Sci USA 2005;102:4134-4139] The degree of HLA-B*5801 binding to allopurinol was found to occur at a dose-dependent manner. [J Allergy Clin Immunol 2015;135:1063-5.e5]
In addition, 48 percent and 42 percent of patients with AH (mean age, 59.8 years) had pre-existing renal impairment and hypertension, respectively. [Drug Saf 2013;36:953-980]
“Testing of the HLA-B*5801 allele is therefore needed to determine whether patients can start allopurinol treatment,” said Chan. “In patients with renal impairment, a lower starting dose of allopurinol may be required.”
Febuxostat: Less hypersensitivity, noninferior CV safety vs allopurinol
Febuxostat is associated with a significantly lower incidence of hypersensitivity vs allopurinol (0.2 vs 2.7 per 1,000 new users) among 17,687 patients who were new to both ULTs in a population-based cohort study in Taiwan. [Clin Pharmacol Ther 2019;106:391-401]
“Febuxostat can therefore be initiated immediately without the need to schedule another visit for HLA-B*5801 allele testing, offering greater convenience for patients,” said Chan. “In my experience, febuxostat can lower SUA level effectively and in a rapid manner.”
The long-term CV safety of febuxostat was demonstrated in the FAST trial, in which 6,128 patients (mean age, 71.0 years; male, 85.3 percent) with gout and ≥1 additional CV risk factor currently treated with allopurinol were randomized (1:1) to either continue allopurinol (at the optimized dose) or start febuxostat (starting dose 80 mg/day and increased to 120 mg/day if necessary to achieve target SUA of <6 mg/dL [<0.357 mmol/L]), following a lead-in phase in which allopurinol dose was increased by 100 mg/day every 2 weeks until the maximum licensed dose (900 mg/day) or until patients achieved urate concentration target. [Lancet 2020;396:1745-1757]
At baseline, 33.4 percent of patients had a history of CV disease and 58.6 percent were receiving statin treatment. The median duration of allopurinol therapy at the time of screening was 6.0 years.
Results of on-treatment analysis showed that febuxostat was noninferior to allopurinol for the incidence of the primary endpoint (composite of hospitalization for nonfatal MI or biomarker-positive acute coronary syndrome, nonfatal stroke or CV death) (1.723 events vs 2.054 events per 100 patient-years; HR, 0.85; 95 percent CI, 0.70 to 1.03; p<0.0001) at a median follow-up of 1,467 days. (Figure)
Death occurred in 7.2 percent vs 8.6 percent of patients in the febuxostat vs allopurinol group. Serious adverse events (AEs) and treatment-related SAEs were reported in 57.3 percent vs 59.4 percent and 0.6 percent vs 0.2 percent of the patients, respectively.
“Hyperuricaemia with gout should be treated as a cardiorenal and metabolic risk factor, in addition to prevention of further gout flares. Timely and effective management with a ULT helps protect patients at increased CRS risk. Results of the FAST trial confirmed that febuxostat is noninferior to allopurinol with respect to CV safety,” Chan concluded.