STeroids Against Radiculopathy (STAR) trial: a statistical analysis plan

Background Transforaminal epidural injections with steroids (TESI) are used increasingly for patients with sciatica. However, their safety, effectiveness, and cost-effectiveness are still a matter of debate. This a priori statistical analysis plan describes the methodology of the analysis for the STAR trial that assesses the (cost-)effectiveness of TESI during the acute stage of sciatica (< 8 weeks). Methods The STAR trial is a multicentre, randomized controlled, prospective trial (RCT) investigating the (cost-)effectiveness of TESI by making a three-group comparison among patients with acute sciatica due to a herniated lumbar disc (< 8 weeks): (1) TESI combined with levobupivacaine added to oral pain medication (intervention group 1) versus oral pain medication alone (control group), (2) intervention group 1 versus transforaminal epidural injection with levobupivacaine and saline solution added to oral pain medication (intervention group 2), and (3) intervention group 2 versus control group. Co-primary outcomes were physical functioning (Roland Morris Disability Questionnaire), pain intensity (10-point numerical rating scale), and global perceived recovery (7-point Likert scale, dichotomized into ‘recovered’ and ‘not recovered’). For all three comparisons, we defined the following minimal clinically relevant between-group differences: two points for pain intensity (range 0–10), four points for physical functioning (range 0–24) and a 20% difference in recovery rate. Secondary outcomes are health-related quality of life (EQ-5D-5L) and patient satisfaction (7-point Likert scale) and surgery rate. We also collected resource use data to perform an economic evaluation. Analyses will be conducted by intention-to-treat with p < 0.05 (two-tailed) for all three comparisons. Effects will be estimated using mixed models by maximum likelihood. For each comparison, mean differences, or difference in proportions, between groups will be tested per time point and an overall mean difference, or difference in proportions, between groups during the complete duration of follow-up (6 months) will be estimated. In the economic evaluation, Multivariate Imputation by Chained Equations will be used to handle missing data. Cost and effect differences will be estimated using seemingly unrelated regression, and uncertainty will be estimated using bootstrapping techniques. Discussion This statistical analysis plan provides detailed information on the intended analysis of the STAR trial, which aims to deliver evidence about the (cost-)effectiveness of TESI during the acute phase of sciatica (< 8 weeks). Trial registration Dutch National trial register NTR4457 (6 March 2014)

0710 Hypoglossal Neurostimulation In Rem- Vs. Nrem-predominant Obstructive Sleep Apnea

Introduction Obstructive sleep apnea (OSA) is a chronic condition that requires appropriate treatment strategies to optimize outcomes while minimizing risk. In addition to anatomy, physiologic factors such as arousal threshold and loop gain (i.e. “endotypes”) play a known role in the disease process. Because loop gain tends to be higher and arousal threshold lower in NREM sleep, we hypothesize that patients with NREM-predominance may achieve less success with anatomical therapy such as upper airway stimulation (UAS). Our study aims to evaluate baseline characteristics and objective results related to NREM-predominance in patients treated with UAS. Methods Using data from the STAR trial, we identified patients (n=103) with at least 20 minutes of REM on baseline testing and complete demographic and disease data at baseline and month 18. Baseline NREM-predominant disease (percent NREM events &gt; 50) was defined as a binary variable. We created two cohorts: 1) patients with REM-predominant disease and 2) those with NREM-predominant disease. ODI and AHI were evaluated at month 18. Results Overall 62% (n=64) of patients had NREM-predominant disease at baseline. Other baseline characteristics were similar between both groups. In univariate analysis, age was significantly associated with lower AHI in the NREM-predominant population (p&lt;0.05) but not in the REM-predominant group (p&gt;0.05). Results were similar for ODI. For both groups, increasing age was correlated negatively with increasing AHI; this correlation was stronger in the NREM-predominant group Conclusion A majority of patients in the STAR trial had NREM-predominant OSA at baseline. There appears to be an interaction between NREM-predominance and age as predictors of UAS outcomes. Support

Hypoglossal Nerve Stimulation and Heart Rate Variability: Analysis of STAR Trial Responders

Objective Hypoglossal nerve stimulation represents a novel therapy for the treatment of moderate-severe obstructive sleep apnea; nonetheless, its cardiovascular effects are not known. We examine the effects of hypoglossal nerve stimulation on heart rate variability, a measure of autonomic function. Study Design Substudy of the STAR trial (Stimulation Therapy for Apnea Reduction): a multicenter prospective single-group cohort. Setting Academic and private practice centers in the United States and Europe. Subjects and Methods A subset of responder participants (n = 46) from the STAR trial was randomized to therapy withdrawal or therapy maintenance 12 months after surgery. Heart rate variability analysis included standard deviation of the R-R interval (SDNN), low-frequency power of the R-R interval, and high-frequency power of the R-R interval. Analysis was performed by sleep with 5-minute sliding window epochs during baseline, 12 months, and the maintenance/withdrawal period. Results A significant improvement from baseline to 12 months in heart rate variability was seen for SDNN and low frequency across all sleep stages. SDNN analysis demonstrated no change in the wake period (mean ± SD: 0.042 ± 0.01 vs 0.077 ± 0.07, P = .19). Reduction in SDNN was correlated to improvement in apnea-hypopnea index ( r = 0.39, P = .03). In the therapy withdrawal group, no significant changes in SDNN were seen for N1/N2, N3, or rapid eye movement sleep. Conclusion Hypoglossal nerve stimulation therapy appears to reduce heart rate variability during sleep. This reduction was not affected by a 1-week withdrawal period. Larger prospective studies are required to better understand the effect of hypoglossal nerve stimulation on autonomic dysfunction in obstructive sleep apnea.