Stage at which riluzole treatment prolongs survival in patients with amyotrophic lateral sclerosis: a retrospective analysis of data from a dose-ranging study.

BACKGROUND: Riluzole is the only drug to prolong survival for amyotrophic lateral sclerosis (ALS) and, at a dose of 100 mg, was associated with a 35% reduction in mortality in a clinical trial. A key question is whether the survival benefit occurs at an early stage of disease, late stage, or is spread throughout the course of the disease. To address this question, we used the King's clinical staging system to do a retrospective analysis of data from the original dose-ranging clinical trial of riluzole. METHODS: In the original dose-ranging trial, patients were enrolled between December, 1992, and November, 1993, in Belgium, France, Germany, Spain, Canada, the USA, and the UK if they had probable or definite ALS as defined by the El Escorial criteria. The censor date for the riluzole survival data was set as the original study end date of Dec 31, 1994. For this analysis, King's clinical ALS stage was estimated from the electronic case record data of the modified Norris scale, UK Medical Research Council score for muscle strength, El Escorial category, vital capacity, and gastrostomy insertion data. The lowest allocated stage was 2 because the original trial only included patients with probable or definite ALS. We used a χ2 test to assess the independence of stage at trial enrolment and treatment group, Kaplan-Meier product limit distribution to test the transition from each stage to subsequent stages, and Cox regression to confirm an effect of treatment group on time in stage, controlling for covariates. We did sensitivity analyses by combining treatment groups, using alternative strategies to stage, stratifying by stage at trial enrolment, and using multistate outcome analysis of treatments (MOAT). FINDINGS: We analysed the case records of all 959 participants from the original dose-ranging trial, 237 assigned to 50 mg/day riluzole, 236 to 100 mg/day, 244 to 200 mg/day, and 242 to daily placebo. Clinical stage at enrolment did not significantly differ between treatment groups (p=0·22). Time in stage 4 was longer for patients receiving 100 mg/day riluzole than for those receiving placebo (hazard ratio [HR] 0·55, 95% CI 0·36-0·83; log-rank p=0·037). Combining treatment groups and stratifying by stage at enrolment showed a similar result (HR 0·638, 95% CI 0·464-0·878; p=0·006), as did analysis with MOAT where the mean number of days spent in stage 4 was numerically higher for patients given riluzole at higher doses compared with patients receiving placebo. Time from stages 2 or 3 to subsequent stages or death did not differ between riluzole treatment groups and placebo (p=0·83 for stage 2 and 0·88 for stage 3). INTERPRETATION: We showed that riluzole prolongs survival in the last clinical stage of ALS; this finding needs to be confirmed in a prospective study, and treatment effects at stage 1 still need to be analysed. The ALS stage at which benefit occurs is important for counselling of patients before starting treatment. Staging should be used in future ALS clinical trials to assess the stage at which survival benefit occurs, and a similar approach could be used for other neurodegenerative diseases. FUNDING: NIHR Maudsley Biomedical Research Centre, The European Union Joint Programme on Neurodegeneration, and the King's Summer Undergraduate Studentship.

Peri-operative treatment of sleep-disordered breathing and outcomes in bariatric patients.

BACKGROUND: Obstructive sleep apnoea (OSA) is increasingly common in bariatric patients undergoing sedation during elective surgery. However, it has not been established how significant a contributor it is to peri-operative respiratory complications and mortality. We sought to pre-operatively identify OSA in bariatric patients and record peri-operative complications during and after bariatric surgery. METHODS: Data were collected and analysed from June 2014 to March 2017 for 410 bariatric surgery patients referred to the sleep laboratory for pre-operative screening and treatment of OSA. The STOP-Bang questionnaire, Epworth Sleepiness Scale (ESS) and nocturnal pulse oximetry were recorded and treatment was allocated with continuous positive airway pressure (CPAP). Peri-operative complications and mortality were the primary outcome measures for patients receiving CPAP treatment for OSA, with patients who did not require CPAP used as control. The mean follow-up time for all patients was 433 and 732 days for the patients who had undergone bariatric surgery. The two groups were compared with Chi square test and unpaired two-tailed t-test. RESULTS: OSA was present in any form in 70% of the screened patients; 40% of patients involved in the study received CPAP treatment. Patients receiving CPAP treatment [49.5 (11.3) years old, 61% female, 50.3 (8.5) kg/m2] were older, had a lower percentage of females and had a higher body mass index (BMI) than those not receiving CPAP [44.9 (12.0), 81% female, 46.6 (7.7)]. No significant differences were observed between patients on CPAP and those not on CPAP, there was no significant difference in hospital stay or rate of respiratory complications. Out of 53 patients who had undergone bariatric surgery at the cut-off date, only 1 had suffered a respiratory complication. CONCLUSIONS: Bariatric patients who are screened pre-operatively for OSA and treated according to guidelines have no increased risk of respiratory complications compared to patients without OSA.