英国邓迪大学Thomas M MacDonald团队比较了非布索坦与别嘌醇治疗痛风患者的长期心血管安全性。2020年11月9日，该研究发表在《柳叶刀》杂志上。
非布索坦和别嘌醇可用于治疗痛风患者，降低尿酸盐。在注意到非布索坦的心血管安全性后，欧洲药物管理局建议进行许可后研究，以评估非布索坦与别嘌醇相比的心血管安全性。
研究组在英国、丹麦和瑞典进行了非布索坦与别嘌醇治疗痛风患者的前瞻性、随机、开放标签、双盲、非劣效性试验，2011年12月20日到2018年1月26日，共招募了6128例年龄为60岁及以上、已经接受别嘌醇治疗，且至少有另一种心血管危险因素的患者。排除过去6个月中有心肌梗塞或中风的患者，或患有严重充血性心力衰竭或严重肾功能不全的患者。
在引入阶段，研究组优化了别嘌醇剂量以使患者的血清尿酸盐浓度低于0.357 mmol / L（<6 mg / dL），然后根据以前的心血管疾病分层，将患者按1：1随机分配，其中3065例继续接受别嘌醇治疗，3063例接受非布索坦治疗，以达到目标血清尿酸盐浓度。主要结局为非致死性心肌梗死或生物标记阳性急性冠脉综合征住院治疗、非致命性中风或心血管死亡的综合结局。
6128例患者的平均年龄为71.0岁，男性占85.3%，女性占14.7%，33.4％先前患有心血管疾病。截至2019年12月31日，非布索坦组有189例患者（6.2％）失访，别嘌醇组有169例（5.5％）失访。 中位随访时间为1467天，中位治疗随访时间为1324天。
在治疗中，非布索坦组有172例患者发生主要结局，发生率为每100患者-年1.72事件，不逊于别嘌醇组（241例，每100患者-年2.05事件）。非布索坦组3063名患者中有222名（7.2％）死亡，接受安全分析的3001名患者中有1720名（57.3％）发生至少一项严重不良事件，其中19名（0.6%）与治疗有关。
别嘌醇组3065名患者中有263名（8.6％）死亡，接受安全分析的3050名患者中有1812名（59.4％）发生至少一项严重不良事件，其中5名（0.2%）与治疗有关。非布索坦组中有973名患者（32.4％）中止了随机治疗，别嘌醇组中有503名患者（16.5％）。
研究结果表明，非布索坦治疗痛风在主要心血管终点方面不逊于别嘌醇治疗，且长期使用未增加死亡或严重不良事件的风险。
附：英文原文
Title: Long-term cardiovascular safety of febuxostat compared with allopurinol in patients with gout (FAST): a multicentre, prospective, randomised, open-label, non-inferiority trial
Author: Isla S Mackenzie, Ian Ford, George Nuki, Jesper Hallas, Christopher J Hawkey, John Webster, Stuart H Ralston, Matthew Walters, Michele Robertson, Raffaele De Caterina, Evelyn Findlay, Fernando Perez-Ruiz, John J V McMurray, Thomas M MacDonald, J. Aziz, G. Dobson, A.S.F. Doney, R.W.V. Flynn, J. Furnace, J.W.K. Grieve, G. Guthrie, D. Jamieson, C.G. Jennings, S. Kean, L.C. Lund, A. McConnachie, F. Pigazzani, P.L. Riches, M. Rix Hanson, A Rogers, E.D.M. Rooke, J. Thomson, M. Warren, K. Wetherall, R. Wilson, C.P. Hall, A. Maseri, H.A. Bird, G. Murray, J.W. Dear, M. Petrie, M. MacDonald, P.S. Jhund, E. Connolly, D.J. Murphy, N. Paul, A. Olsson, P.T. Koskinen, A. Fuat, A. Foster, W. Saywood, R.J. Barr, L. McConnachie, L.F. Wilson, L. Larsen Rasmussen, A.R. McGinnis, H. Birrell, M. Keiller, I.S. Bremner, G.J. Forbes, J.S. Dumbleton, J. Rhodes, T. Waller
Issue&Volume: 2020-11-09
Abstract:
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.
DOI: 10.1016/S0140-6736(20)32234-0
Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)32234-0/fulltext
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