The National Institute for Health and Clinical Excellence (NICE) invited the manufacturer of dabigatran etexilate (Boehringer Ingelheim Ltd, UK) to submit evidence for the clinical and cost-effectiveness of this drug for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation (AF) as part of the NICE single technology appraisal process. The Centre for Reviews and Dissemination and the Centre for Health Economics at the University of York were commissioned to act as the evidence review group (ERG). This article presents a summary of the manufacturer's submission, the ERG report and the subsequent development of NICE guidance for the use of dabigatran within the UK National Health Service. Dabigatran was granted marketing authorisation by the European Medicines Agency for a sequential dosing regimen (DBG sequential), in which patients under 80 years are treated with dabigatran 150 mg twice daily (DBG150) and patients 80 years and over are given dabigatran 110 mg twice daily (DBG110). NICE decisions are bound by the marketing authorisation; therefore, the decision problem faced by the committee was whether the DBG sequential regimen was effective and cost-effective compared with warfarin or aspirin for patients with non-valvular AF and one or more risk factors. The RE-LY trial, a large multi-centre non-inferiority randomised clinical trial, was the primary source of clinical evidence. DBG150 was shown to be non-inferior, and subsequently superior to warfarin, for the primary outcome of all stroke/systemic embolism. DBG110 was found to be non-inferior to warfarin. Results were presented for a post hoc subgroup analysis for patients under and over 80 years of age, where DBG110 showed a statistically significant reduction of haemorrhagic stroke and intracranial haemorrhage in comparison to warfarin in patients over 80 years of age. This post hoc subgroup analysis by age was the basis for the licensed DBG sequential regimen. The economic evaluation compared the costs and outcomes of DBG110, DBG150 and DBG sequential against warfarin, aspirin, and aspirin plus clopidogrel. Across the three dosing regimens, dabigatran was associated with greater costs and better health outcomes than warfarin; however, DBG150 offered the most benefits and dominated DBG110 and DBG sequential (i.e. less costly and more effective). The cost-effectiveness of DBG150 was less favourable for patients well controlled on warfarin. In the first appraisal meeting, the committee issued a 'minded no' decision until additional analyses on the licensed DBG sequential regimen were presented by the manufacturer. These additional analyses indicated that the incremental cost-effectiveness ratio (ICER) of the DBG sequential regimen compared with warfarin ranged from £8,388 to £18,987 per quality-adjusted life year (QALY) gained depending on the level of monitoring costs assumed for warfarin. Patients on warfarin would need to be within therapeutic range 83-85 % of the time for the ICER to exceed £30,000 per additional QALY. Following consideration of the additional evidence and the responses from a large number of consultees and commentators, the committee recommended dabigatran as DBG sequential as an option for the prevention of stroke and systemic embolism in people with non-valvular AF with one or more risk factors for ischaemic stroke.

译文

国家健康和临床卓越研究所 (NICE) 邀请了达比加群酯的制造商 (勃林格殷格翰有限公司,作为NICE单一技术评估过程的一部分,该药物用于预防非瓣膜性房颤 (AF) 患者的中风和全身性栓塞的临床和成本效益的证据。约克大学的审查和传播中心和卫生经济学中心被委托担任证据审查小组 (ERG)。本文介绍了制造商提交的内容,ERG报告以及随后在英国国家卫生局内使用达比加群的NICE指南的开发摘要。达比加群获得了欧洲药品管理局的连续给药方案 (DBG sequential) 的上市许可,其中80岁以下的患者每天两次接受达比加群150 mg治疗 (DBG150),80岁及以上的患者每天两次接受达比加群110 mg治疗 (DBG110)。NICE的决定受营销授权的约束; 因此,委员会面临的决策问题是,对于非瓣膜性房颤和一种或多种危险因素的患者,与华法林或阿司匹林相比,DBG序贯方案是否有效且具有成本效益。RE-LY试验是一项大型的多中心非劣效性随机临床试验,是临床证据的主要来源。在所有卒中/全身性栓塞的主要结局中,DBG150显示非劣于华法林,随后优于华法林。发现DBG110不劣于华法林。结果是针对80岁以下和80岁以上的患者进行的事后亚组分析,其中与80岁以上的患者相比,DBG110显示出血性中风和颅内出血的统计学上显着减少。这项按年龄进行的事后亚组分析是许可的DBG序贯方案的基础。经济评估比较了DBG110,DBG150和DBG顺序对华法林,阿司匹林和阿司匹林加氯吡格雷的成本和结果。在三种给药方案中,达比加群比华法林具有更高的成本和更好的健康结果; 然而,DBG150提供了最大的益处,并且主导了DBG110和DBG顺序 (即成本更低且更有效)。对于华法林控制良好的患者,DBG150的成本效益较差。在第一次评估会议上,委员会发布了 “不考虑” 的决定,直到制造商对许可的DBG顺序方案进行了其他分析。这些额外的分析表明,与华法林相比,DBG序贯方案的增量成本效益比 (ICER) 在每个质量调整生命年 (QALY) 获得的8,388英镑至18,987英镑之间,这取决于华法林的监测成本水平。服用华法林的患者需要在83-85% 的治疗范围内,ICER每增加QALY超过30,000英镑。在考虑了其他证据以及大量咨询人员和评论员的回应之后,委员会建议达比加群作为DBG顺序疗法,作为预防具有一种或多种缺血性卒中危险因素的非瓣膜性房颤患者中风和全身性栓塞的一种选择。

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