英国利物浦大学Anthony Marson团队比较了丙戊酸钠与左乙拉西坦治疗新诊断的泛发性和未分类癫痫的有效性和成本-效益。2021年4月10日，该研究发表在《柳叶刀》杂志上。

丙戊酸钠是新诊断的特发性泛发性或未分类癫痫患者的一线治疗药物，但由于致畸性，不适用于有生育潜力的妇女。尽管缺乏临床疗效或成本效益的证据，左乙拉西坦却越来越多地用于治疗这些患者。

为了比较左乙拉西坦与丙戊酸钠在新诊断的泛发性或未分类癫痫患者中的长期临床疗效和成本-效益，研究组进行了一项开放性随机对照试验。在英国的69个成人和儿科神经内科中心招募了年龄在5岁及以上的患者，均有两次及以上泛发性或未分类癫痫发作。将其按1：1随机分配，分别接受左乙拉西坦或丙戊酸钠治疗。主要终点为左乙拉西坦与丙戊酸钠在12个月时缓解的非劣效性，非劣效性限值为1.314，相当于10%的绝对差异。

2013年4月30日至2016年8月2日，研究组共招募了520名参与者，并进行了2年的随访。其中260名接受左乙拉西坦治疗，260名接受丙戊酸钠治疗。意向治疗（ITT）分析包括所有参与者，按方案（PP）分析包括丙戊酸钠组的255名参与者和左乙拉西坦组的254名参与者。参与者的中位年龄为13.9岁，65%为男性，35%为女性，397名参与者患有泛发性癫痫，123名参与者患有未分类癫痫。

左乙拉西坦在12个月缓解时间的ITT分析中不符合非劣效性标准。PP分析显示丙戊酸钠治疗12个月的缓解率优于左乙拉西坦。共有两例患者死亡，每组一例，均与试验治疗无关。丙戊酸钠组中有96名（37%）受试者报告了不良反应，左乙拉西坦组有107名（42%）。在成本-效用分析中，丙戊酸钠优于左乙拉西坦，其净健康效益负增量为- 0.040，在每个质量调整生命年的门槛为2万英镑时，成本-效益的概率为0.17。成本-效益是基于治疗组间的成本和质量调整生命年的差异。

研究结果表明，对于泛发性或未分类癫痫患者，与丙戊酸钠相比，左乙拉西坦既无临床疗效，也无成本-效益，不值得临床推广。

附：英文原文

Title: The SANAD II study of the effectiveness and cost-effectiveness of valproate versus levetiracetam for newly diagnosed generalised and unclassifiable epilepsy: an open-label, non-inferiority, multicentre, phase 4, randomised controlled trial

Author: Anthony Marson, Girvan Burnside, Richard Appleton, Dave Smith, John Paul Leach, Graeme Sills, Catrin Tudur-Smith, Catrin Plumpton, Dyfrig A Hughes, Paula Williamson, Gus A Baker, Silviya Balabanova, Claire Taylor, Richard Brown, Dan Hindley, Stephen Howell, Melissa Maguire, Rajiv Mohanraj, Philip E Smith, Karen Lanyon, Mark Manford, Manali Chitre, Alasdair Parker, Nina Swiderska, Richard Appleton, James Pauling, Adrian Hughes, Rajat Gupta, Sadia Hanif, Mostafa Awadh, Sharmini Ragunathan, Nicola Cable, Paul Cooper, Daniel Hindley, Karl Rakshi, Sophie Molloy, Markus Reuber, Kunle Ayonrinde, Martin Wilson, Satyanarayana Saladi, John Gibb, Lesley-Ann Funston, Damhait Cassidy, Jonathan Boyd, Mal Ratnayaka, Hani Faza, Martin Sadler, Hassan Al-Moasseb, Clare Galtrey, Damien Wren, Anas Olabi, Geraint Fuller, Muhammed Khan, Chetana Kallappa, Ravi Chinthapalli, Baba Aji, Rhys Davies, Kathryn Foster, Nikolas Hitiris, Melissa Maguire, Nahin Hussain, Simon Dowson, Julie Ellison, Basil Sharrack, Vandna Gandhi, Rob Powell, Phil Tittensor, Beatrice Summers, Sastry Shashikiran, Penelope J Dison, Shanika Samarasekera, Doug McCorry, Kathleen White, Kannan Nithi, Martin Richardson, Richard Brown, Rupert Page, David Deekollu, Sean Slaght, Stephen Warriner, Mansoor Ahmed, Abhijit Chaudhuri, Gabriel Chow, Javier Artal, Danute Kucinskiene, Harish Sreenivasa, Singara Velmurugan,, Christos S Zipitis, Brendan McLean, Vaithianathar Lal, Angelous Gregoriou, Paul Maddison, Trevor Pickersgill, Joseph Anderson, Charlotte Lawthom, Stephen Howell, Gabriel Whitlingum, Wojtek Rakowicz, Lucy Kinton, Alisa McLellan, Nitish Vora, Sameer Zuberi, Andrew Kelso, Imelda Hughes, John Martland, Hedley Emsley, Christian de Goede, RP Singh, Carl-Christian Moor, Julia Aram, Rajiv Mohanraj, Kumar Sakthivel, Suresh Nelapatla, Chris Rittey, Ashwin Pinto, John Paul Leach, Hannah Cock, Anna Richardson, Erika Houston, Christopher Cooper, Geoff Lawson, Albert Massarano, Christine Burness, Anthony Marson, Dave Smith, Udo Wieshmann, Indranil Dey, Puthuval Sivakumar, Lap-Kong Yeung, Philip Smith

Issue&Volume: 2021/04/10

Abstract:

Background

Valproate is a first-line treatment for patients with newly diagnosed idiopathic generalised or difficult to classify epilepsy, but not for women of child-bearing potential because of teratogenicity. Levetiracetam is increasingly prescribed for these patient populations despite scarcity of evidence of clinical effectiveness or cost-effectiveness. We aimed to compare the long-term clinical effectiveness and cost-effectiveness of levetiracetam compared with valproate in participants with newly diagnosed generalised or unclassifiable epilepsy.

Methods

We did an open-label, randomised controlled trial to compare levetiracetam with valproate as first-line treatment for patients with generalised or unclassified epilepsy. Adult and paediatric neurology services (69 centres overall) across the UK recruited participants aged 5 years or older (with no upper age limit) with two or more unprovoked generalised or unclassifiable seizures. Participants were randomly allocated (1:1) to receive either levetiracetam or valproate, using a minimisation programme with a random element utilising factors. Participants and investigators were aware of treatment allocation. For participants aged 12 years or older, the initial advised maintenance doses were 500 mg twice per day for levetiracetam and valproate, and for children aged 5–12 years, the initial daily maintenance doses advised were 25 mg/kg for valproate and 40 mg/kg for levetiracetam. All drugs were administered orally. SANAD II was designed to assess the non-inferiority of levetiracetam compared with valproate for the primary outcome time to 12-month remission. The non-inferiority limit was a hazard ratio (HR) of 1·314, which equates to an absolute difference of 10%. A HR greater than 1 indicated that an event was more likely on valproate. All participants were included in the intention-to-treat (ITT) analysis. Per-protocol (PP) analyses excluded participants with major protocol deviations and those who were subsequently diagnosed as not having epilepsy. Safety analyses included all participants who received one dose of any study drug. This trial is registered with the ISRCTN registry, 30294119 (EudraCt number: 2012-001884-64).

Findings

520 participants were recruited between April 30, 2013, and Aug 2, 2016, and followed up for a further 2 years. 260 participants were randomly allocated to receive levetiracetam and 260 participants to receive valproate. The ITT analysis included all participants and the PP analysis included 255 participants randomly allocated to valproate and 254 randomly allocated to levetiracetam. Median age of participants was 13·9 years (range 5·0–94·4), 65% were male and 35% were female, 397 participants had generalised epilepsy, and 123 unclassified epilepsy. Levetiracetam did not meet the criteria for non-inferiority in the ITT analysis of time to 12-month remission (HR 1·19 [95% CI 0·96–1·47]); non-inferiority margin 1·314. The PP analysis showed that the 12-month remission was superior with valproate than with levetiracetam. There were two deaths, one in each group, that were unrelated to trial treatments. Adverse reactions were reported by 96 (37%) participants randomly assigned to valproate and 107 (42%) participants randomly assigned to levetiracetam. Levetiracetam was dominated by valproate in the cost-utility analysis, with a negative incremental net health benefit of 0·040 (95% central range 0·175 to 0·037) and a probability of 0·17 of being cost-effectiveness at a threshold of ￡20000 per quality-adjusted life-year. Cost-effectiveness was based on differences between treatment groups in costs and quality-adjusted life-years.

Interpretation

Compared with valproate, levetiracetam was found to be neither clinically effective nor cost-effective. For girls and women of child-bearing potential, these results inform discussions about benefit and harm of avoiding valproate.

DOI: 10.1016/S0140-6736(21)00246-4

Source: https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(21)00246-4/fulltext