TY - JOUR
T1 - Long-term cardiovascular safety of febuxostat compared with allopurinol in patients with gout (FAST)
T2 - a multicentre, prospective, randomised, open-label, non-inferiority trial
AU - Mackenzie, Isla S.
AU - Ford, Ian
AU - Nuki, George
AU - Hallas, Jesper
AU - Hawkey, Christopher J.
AU - Webster, John
AU - Ralston, Stuart H.
AU - Walters, Matthew
AU - Robertson, Michele
AU - De Caterina, Raffaele
AU - Findlay, Evelyn
AU - Perez-Ruiz, Fernando
AU - McMurray, John J. V.
AU - MacDonald, Thomas M.
AU - FAST study group
AU - Pigazzani, Filippo
N1 - Funding Information:
ISM reports research grants from Novartis, National Institute for Health Research (NIHR) Health Technology Assessment programme, Amgen, Research Triangle Institute, Tenovus Scotland, George Clinical, European Medicines Agency, Sanofi, Health Data Research UK, and Innovative Medicines Initiative outside of the submitted work and from Menarini for the submitted work, and personal income from AstraZeneca outside of the submitted work. IF, MR, and GN report grants from Menarini via the University of Dundee for the submitted work. JH reports grants from Astellas, Pfizer, Almirall, Servier, Leo Pharma, and Novo Nordisk outside of the submitted work. MW reports personal fees from Portola Pharmaceuticals and Myokardia outside of the submitted work. RDC reports grants and personal fees from Bayer, Boehringer Ingelheim, BMS/Pfizer, Daiichi Sankyo, AstraZeneca, Menarini, and Novartis outside of the submitted work. FP-R reports speaker, advisory, or educational fees from Astellas, Grünenthal, Horizon, Menarini, Syneos, Springer, Wolters-Kluwer, and the Spanish Foundation of Rheumatology; investigation funds from Cruces Rheumatology Association; membership of the Pharmacy Corporative Commission of the Basque Health Service. JJVM reports payments to their employer, Glasgow University, for work on clinical trials, consulting, and other activities from Alnylam, Amgen, AstraZeneca, Bayer, BMS, Cardurion, Cytokinetics, Dal-Cor, GlaxoSmithKline, Novartis, Pfizer, and Theracos, and personal lecture fees from Abbott, Hickma, Sun Pharmaceuticals, and Servier. TMM reports grants from Novartis, Pfizer, GlaxoSmithKline, and Amgen outside of the submitted work, and from Menarini for the submitted work, and personal income for consultancy or speaker fees from Novartis, Takeda, Servier, Shire, Astellus, Menarini, and AstraZeneca. CJH, JW, SHR and EF declare no competing interests.
Funding Information:
The study was an investigator-led trial sponsored by the University of Dundee and funded by Menarini. Menarini received support from Ipsen and Teijin Pharma. We thank all the patients, physicians, nurses, and other staff who participated in FAST. We thank the Scottish Primary Care Research Network and NIHR Clinical Research Network for assistance with recruitment and other study activities and Public Health Scotland, NHS Digital, and the Danish Health Data Board for providing record-linkage data. We thank Wendy Saywood, the FAST senior project manager, for her dedication throughout this study.
Publisher Copyright:
© 2020 Elsevier Ltd
Copyright:
Copyright 2020 Elsevier B.V., All rights reserved.
PY - 2020/11/28
Y1 - 2020/11/28
N2 - Background: Febuxostat and allopurinol are urate-lowering therapies used to treat patients with gout. Following concerns about the cardiovascular safety of febuxostat, the European Medicines Agency recommended a post-licensing study assessing the cardiovascular safety of febuxostat compared with allopurinol.Methods: We did a prospective, randomised, open-label, blinded-endpoint, non-inferiority trial of febuxostat versus allopurinol in patients with gout in the UK, Denmark, and Sweden. Eligible patients were 60 years or older, already receiving allopurinol, and had at least one additional cardiovascular risk factor. Those who had myocardial infarction or stroke in the previous 6 months or who had severe congestive heart failure or severe renal impairment were excluded. After a lead-in phase in which allopurinol dose was optimised towards achieving a serum urate concentration of less than 0·357 mmol/L (<6 mg/dL), patients were randomly assigned (1:1, with stratification according to previous cardiovascular events) to continue allopurinol (at the optimised dose) or start febuxostat at 80 mg/day, increasing to 120 mg/day if necessary to achieve the target serum urate concentration. The primary outcome was a composite of hospitalisation for non-fatal myocardial infarction or biomarker-positive acute coronary syndrome; non-fatal stroke; or cardiovascular death. The hazard ratio (HR) for febuxostat versus allopurinol in a Cox proportional hazards model (adjusted for the stratification variable and country) was assessed for non-inferiority (HR limit 1·3) in an on-treatment analysis. This study is registered with the EU Clinical Trials Register (EudraCT 2011-001883-23) and ISRCTN (ISRCTN72443728) and is now closed.Findings: From Dec 20, 2011, to Jan 26, 2018, 6128 patients (mean age 71·0 years [SD 6·4], 5225 [85·3%] men, 903 [14·7%] women, 2046 [33·4%] with previous cardiovascular disease) were enrolled and randomly allocated to receive allopurinol (n=3065) or febuxostat (n=3063). By the study end date (Dec 31, 2019), 189 (6·2%) patients in the febuxostat group and 169 (5·5%) in the allopurinol group withdrew from all follow-up. Median follow-up time was 1467 days (IQR 1029-2052) and median on-treatment follow-up was 1324 days (IQR 870-1919). For incidence of the primary endpoint, on-treatment, febuxostat (172 patients [1·72 events per 100 patient-years]) was non-inferior to allopurinol (241 patients [2·05 events per 100 patient-years]; adjusted HR 0·85 [95% CI 0·70-1·03], p<0·0001). In the febuxostat group, 222 (7·2%) of 3063 patients died and 1720 (57·3%) of 3001 in the safety analysis set had at least one serious adverse event (with 23 events in 19 [0·6%] patients related to treatment). In the allopurinol group, 263 (8·6%) of 3065 patients died and 1812 (59·4%) of 3050 had one or more serious adverse events (with five events in five [0·2%] patients related to treatment). Randomised therapy was discontinued in 973 (32·4%) patients in the febuxostat group and 503 (16·5%) patients in the allopurinol group.Interpretation: Febuxostat is non-inferior to allopurinol therapy with respect to the primary cardiovascular endpoint, and its long-term use is not associated with an increased risk of death or serious adverse events compared with allopurinol.
AB - Background: Febuxostat and allopurinol are urate-lowering therapies used to treat patients with gout. Following concerns about the cardiovascular safety of febuxostat, the European Medicines Agency recommended a post-licensing study assessing the cardiovascular safety of febuxostat compared with allopurinol.Methods: We did a prospective, randomised, open-label, blinded-endpoint, non-inferiority trial of febuxostat versus allopurinol in patients with gout in the UK, Denmark, and Sweden. Eligible patients were 60 years or older, already receiving allopurinol, and had at least one additional cardiovascular risk factor. Those who had myocardial infarction or stroke in the previous 6 months or who had severe congestive heart failure or severe renal impairment were excluded. After a lead-in phase in which allopurinol dose was optimised towards achieving a serum urate concentration of less than 0·357 mmol/L (<6 mg/dL), patients were randomly assigned (1:1, with stratification according to previous cardiovascular events) to continue allopurinol (at the optimised dose) or start febuxostat at 80 mg/day, increasing to 120 mg/day if necessary to achieve the target serum urate concentration. The primary outcome was a composite of hospitalisation for non-fatal myocardial infarction or biomarker-positive acute coronary syndrome; non-fatal stroke; or cardiovascular death. The hazard ratio (HR) for febuxostat versus allopurinol in a Cox proportional hazards model (adjusted for the stratification variable and country) was assessed for non-inferiority (HR limit 1·3) in an on-treatment analysis. This study is registered with the EU Clinical Trials Register (EudraCT 2011-001883-23) and ISRCTN (ISRCTN72443728) and is now closed.Findings: From Dec 20, 2011, to Jan 26, 2018, 6128 patients (mean age 71·0 years [SD 6·4], 5225 [85·3%] men, 903 [14·7%] women, 2046 [33·4%] with previous cardiovascular disease) were enrolled and randomly allocated to receive allopurinol (n=3065) or febuxostat (n=3063). By the study end date (Dec 31, 2019), 189 (6·2%) patients in the febuxostat group and 169 (5·5%) in the allopurinol group withdrew from all follow-up. Median follow-up time was 1467 days (IQR 1029-2052) and median on-treatment follow-up was 1324 days (IQR 870-1919). For incidence of the primary endpoint, on-treatment, febuxostat (172 patients [1·72 events per 100 patient-years]) was non-inferior to allopurinol (241 patients [2·05 events per 100 patient-years]; adjusted HR 0·85 [95% CI 0·70-1·03], p<0·0001). In the febuxostat group, 222 (7·2%) of 3063 patients died and 1720 (57·3%) of 3001 in the safety analysis set had at least one serious adverse event (with 23 events in 19 [0·6%] patients related to treatment). In the allopurinol group, 263 (8·6%) of 3065 patients died and 1812 (59·4%) of 3050 had one or more serious adverse events (with five events in five [0·2%] patients related to treatment). Randomised therapy was discontinued in 973 (32·4%) patients in the febuxostat group and 503 (16·5%) patients in the allopurinol group.Interpretation: Febuxostat is non-inferior to allopurinol therapy with respect to the primary cardiovascular endpoint, and its long-term use is not associated with an increased risk of death or serious adverse events compared with allopurinol.
UR - http://www.scopus.com/inward/record.url?scp=85096335593&partnerID=8YFLogxK
U2 - 10.1016/S0140-6736(20)32234-0
DO - 10.1016/S0140-6736(20)32234-0
M3 - Article
C2 - 33181081
SN - 0140-6736
VL - 396
SP - 1745
EP - 1757
JO - Lancet
JF - Lancet
IS - 10264
ER -
