Background: Levetiracetam (Keppra, UCB Pharma Ltd, Slough, UK) and zonisamide (Zonegran, Eisai Co. Ltd, Tokyo, Japan) are licensed as monotherapy for focal epilepsy, and levetiracetam is increasingly used as a first-line treatment for generalised epilepsy, particularly for women of childbearing age. However, there is uncertainty as to whether or not they should be recommended as first-line treatments owing to a lack of evidence of clinical effectiveness and cost-effectiveness.
Objectives: To compare the clinical effectiveness and cost-effectiveness of lamotrigine (Lamictal, GlaxoSmithKline plc, Brentford, UK) (standard treatment) with levetiracetam and zonisamide (new treatments) for focal epilepsy, and to compare valproate (Epilim, Sanofi SA, Paris, France) (standard treatment) with levetiracetam (new treatment) for generalised and unclassified epilepsy.
Design: Two pragmatic randomised unblinded non-inferiority trials run in parallel.
Setting: Outpatient services in NHS hospitals throughout the UK.
Participants: Those aged ≥ 5 years with two or more spontaneous seizures that require anti-seizure medication.
Interventions: Participants with focal epilepsy were randomised to receive lamotrigine, levetiracetam or zonisamide. Participants with generalised or unclassifiable epilepsy were randomised to receive valproate or levetiracetam. The randomisation method was minimisation using a web-based program.
Main Outcome Measures: The primary outcome was time to 12-month remission from seizures. For this outcome, and all other time-to-event outcomes, we report hazard ratios for the standard treatment compared with the new treatment. For the focal epilepsy trial, the non-inferiority limit (lamotrigine vs. new treatments) was 1.329. For the generalised and unclassified epilepsy trial, the non-inferiority limit (valproate vs. new treatments) was 1.314. Secondary outcomes included time to treatment failure, time to first seizure, time to 24-month remission, adverse reactions, quality of life and cost-effectiveness.
Results: . A total of 990 participants were recruited, of whom 330 were randomised to receive lamotrigine, 332 were randomised to receive levetiracetam and 328 were randomised to receive zonisamide. Levetiracetam did not meet the criteria for non-inferiority (hazard ratio 1.329) in the primary intention-to-treat analysis of time to 12-month remission (hazard ratio vs. lamotrigine 1.18, 97.5% confidence interval 0.95 to 1.47), but zonisamide did meet the criteria (hazard ratio vs. lamotrigine 1.03, 97.5% confidence interval 0.83 to 1.28). In the per-protocol analysis, lamotrigine was superior to both levetiracetam (hazard ratio 1.32, 95% confidence interval 1.05 to 1.66) and zonisamide (hazard ratio 1.37, 95% confidence interval 1.08 to 1.73). For time to treatment failure, lamotrigine was superior to levetiracetam (hazard ratio 0.60, 95% confidence interval 0.46 to 0.77) and zonisamide (hazard ratio 0.46, 95% confidence interval 0.36 to 0.60). Adverse reactions were reported by 33% of participants starting lamotrigine, 44% starting levetiracetam and 45% starting zonisamide. In the economic analysis, both levetiracetam and zonisamide were more costly and less effective than lamotrigine and were therefore dominated. . Of 520 patients recruited, 260 were randomised to receive valproate and 260 were randomised to receive to levetiracetam. A total of 397 patients had generalised epilepsy and 123 had unclassified epilepsy. Levetiracetam did not meet the criteria for non-inferiority in the primary intention-to-treat analysis of time to 12-month remission (hazard ratio 1.19, 95% confidence interval 0.96 to 1.47; non-inferiority margin 1.314). In the per-protocol analysis of time to 12-month remission, valproate was superior to levetiracetam (hazard ratio 1.68, 95% confidence interval 1.30 to 2.15). Valproate was superior to levetiracetam for time to treatment failure (hazard ratio 0.65, 95% confidence interval 0.50 to 0.83). Adverse reactions were reported by 37.4% of participants receiving valproate and 41.5% of those receiving levetiracetam. Levetiracetam was both more costly (incremental cost of £104, 95% central range -£587 to £1234) and less effective (incremental quality-adjusted life-year of -0.035, 95% central range -0.137 to 0.032) than valproate, and was therefore dominated. At a cost-effectiveness threshold of £20,000 per quality-adjusted life-year, levetiracetam was associated with a probability of 0.17 of being cost-effective.
Limitations: The SANAD II trial was unblinded, which could have biased results by influencing decisions about dosing, treatment failure and the attribution of adverse reactions.
Future Work: SANAD II data could now be included in an individual participant meta-analysis of similar trials, and future similar trials are required to assess the clinical effectiveness and cost-effectiveness of other new treatments, including lacosamide and perampanel.
Conclusions: - The SANAD II findings do not support the use of levetiracetam or zonisamide as first-line treatments in focal epilepsy. - The SANAD II findings do not support the use of levetiracetam as a first-line treatment for newly diagnosed generalised epilepsy. For women of childbearing potential, these results inform discussions about the benefit (lower teratogenicity) and harm (worse seizure outcomes and higher treatment failure rate) of levetiracetam compared with valproate.
Trial Registration: Current Controlled Trials ISRCTN30294119 and EudraCT 2012-001884-64.
Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in ; Vol. 25, No. 75. See the NIHR Journals Library website for further project information.
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http://dx.doi.org/10.3310/hta25750 | DOI Listing |
J Clin Oncol
January 2025
Department of Breast Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
Purpose: Trastuzumab-pertuzumab (HP) plus taxane is a current standard first-line therapy for recurrent or metastatic human epidermal growth factor 2 (HER2)+ breast cancer (BC). We investigated noninferiority of eribulin to a taxane when combined with dual HER2 blockade as first-line systemic treatment for locally advanced/metastatic HER2+ BC.
Methods: In the phase III EMERALD trial (target sample size, 480; ClinicalTrials.
Clin J Am Soc Nephrol
January 2025
Division of Endocrinology and Metabolism, Department of Internal Medicine, Korea University Ansan Hospital, Ansan, Republic of Korea.
Background: The effects of glomerular hyperfiltration (GHF) on cardiovascular disease (CVD) risk in patients with type 2 diabetes mellitus (T2DM) were explored.
Methods: This retrospective cohort study enrolled 1,952,053 patients with type 2 diabetes mellitus from the Korean National Health Insurance Service database between 2015 and 2016. Based on age- and sex-specific estimated glomerular filtration rate (eGFR) percentiles, patients were classified into five groups: <5 (low filtration), 5-40, 40-60, 60-95, and >95 (GHF).
J Cardiovasc Surg (Torino)
January 2025
Faculty of Medicine and Biomedical Sciences, Campus of Gambelas, University of Algarve, Faro, Portugal.
Background: Aortoiliac disease poses a significant cardiovascular (CV) risk, especially in individuals with chronic kidney disease. This study aimed to assess the predictive role of chronic kidney disease in long-term major adverse CV events in patients submitted to aortoiliac revascularization due to severe aortoiliac atherosclerotic disease.
Methods: From 2013 to 2023, patients who underwent aortoiliac revascularization for TASC II type D lesions, including those with chronic kidney disease, were selected from a prospective cohort study.
Rheumatology (Oxford)
January 2025
Inflammation and Immunology, Graduate School of Medical Science, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Objectives: To clarify the differences in clinical phenotypes, therapeutic patterns, and outcomes of patients with granulomatosis with polyangiitis (GPA) and microscopic polyangiitis (MPA) across geographic regions using a multinational cohort.
Methods: Data were collected from patients with newly diagnosed or relapsing GPA or MPA in Europe, Japan, and the United States (US) from January to July 2020. The composite outcome of kidney failure and/or death within 52 weeks after treatment was evaluated, and the hazard ratios across the regions were estimated using the Cox proportional hazard model.
JAMA Netw Open
January 2025
School of Life Course and Population Sciences, King's College London, London, United Kingdom.
Importance: Reducing the burden of stroke is a public health priority. While higher stroke incidence among ethnic minority populations (defined in the context of this study as individuals who are not White) is well established, reports on ethnic inequalities in care or outcomes are conflicting and often limited to hospital-admitted patients and short-term outcomes.
Objective: To investigate ethnic differences in stroke care and outcomes up to 5 years after stroke and describe temporal trends and contributory factors.
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