Transcatheter aortic valve replacement versus surgical valve replacement in intermediate-risk patients: a propensity score analysis.

BACKGROUND: Transcatheter aortic valve replacement (TAVR) with the SAPIEN 3 valve demonstrates good 30 day clinical outcomes in patients with severe aortic stenosis who are at intermediate risk of surgical mortality. Here we report longer-term data in intermediate-risk patients given SAPIEN 3 TAVR and compare outcomes to those of intermediate-risk patients given surgical aortic valve replacement. METHODS: In the SAPIEN 3 observational study, 1077 intermediate-risk patients at 51 sites in the USA and Canada were assigned to receive TAVR with the SAPIEN 3 valve [952 [88%] via transfemoral access) between Feb 17, 2014, and Sept 3, 2014. In this population we assessed all-cause mortality and incidence of strokes, re-intervention, and aortic valve regurgitation at 1 year after implantation. Then we compared 1 year outcomes in this population with those for intermediate-risk patients treated with surgical valve replacement in the PARTNER 2A trial between Dec 23, 2011, and Nov 6, 2013, using a prespecified propensity score analysis to account for between-trial differences in baseline characteristics. The clinical events committee and echocardiographic core laboratory methods were the same for both studies. The primary endpoint was the composite of death from any cause, all strokes, and incidence of moderate or severe aortic regurgitation. We did non-inferiority (margin 7·5%) and superiority analyses in propensity score quintiles to calculate pooled weighted proportion differences for outcomes. FINDINGS: At 1 year follow-up of the SAPIEN 3 observational study, 79 of 1077 patients who initiated the TAVR procedure had died (all-cause mortality 7·4%; 6·5% in the transfemoral access subgroup), and disabling strokes had occurred in 24 (2%), aortic valve re-intervention in six (1%), and moderate or severe paravalvular regurgitation in 13 (2%). In the propensity-score analysis we included 963 patients treated with SAPIEN 3 TAVR and 747 with surgical valve replacement. For the primary composite endpoint of mortality, strokes, and moderate or severe aortic regurgitation, TAVR was both non-inferior (pooled weighted proportion difference of -9·2%; 90% CI -12·4 to -6; p<0·0001) and superior (-9·2%, 95% CI -13·0 to -5·4; p<0·0001) to surgical valve replacement. INTERPRETATION: TAVR with SAPIEN 3 in intermediate-risk patients with severe aortic stenosis is associated with low mortality, strokes, and regurgitation at 1 year. The propensity score analysis indicates a significant superiority for our composite outcome with TAVR compared with surgery, suggesting that TAVR might be the preferred treatment alternative in intermediate-risk patients. FUNDING: None.

Angiographic predictors of 2-year stent thrombosis in patients receiving drug-eluting stents: Insights from the ADAPT-DES study.

OBJECTIVES: We sought to identify angiographic predictors of 2-year stent thrombosis (ST) in the ADAPT-DES study. BACKGROUND: A strong relationship between platelet reactivity and ST after implantation of drug-eluting stents (DES) was recently confirmed in the prospective, multicenter ADAPT-DES study. METHODS: In a pre-specified analysis of patients enrolled in ADAPT-DES, an independent angiographic core laboratory performed detailed angiographic analyses for all cases of ST. Patients with Academic Research Consortium definite/probable target-lesion ST were matched with controls in a 1:2 ratio, and multivariable Cox regression models identified angiographic predictors of 2-year ST. RESULTS: Among 8,582 patients who had successful percutaneous coronary intervention (PCI) and were included in the ADAPT-DES study, 92 (1.1%) patients had ST at 2-year follow-up. Target lesion-related ST was identified in 77 patients (82 lesions) who were clinically matched with 153 patients (196 lesions) without ST. Patients with ST were more likely to have longer target lesions, thrombus, moderate/severe calcification, American College of Cardiology/American Heart Association (ACC/AHA) type C lesions, and saphenous vein grafts. After adjustment for clinical covariates the angiographic variables that predicted ST were lesion complexity (ACC/AHA type C lesion, adjusted HR: 1.97, 95% CI: 1.19 to 3.26, P = 0.01) and presence of thrombus on index PCI (HR: 2.25, 95% CI: 1.40 to 3.59, P < 0.01). CONCLUSIONS: Anatomically complex lesions and the presence of thrombus are strong predictors of 2-year ST in the DES era. © 2016 Wiley Periodicals, Inc.

Tumor recurrence of keratinocyte carcinomas judged appropriate for Mohs micrographic surgery using Appropriate Use Criteria.

BACKGROUND: The use of Mohs micrographic surgery (MMS) has increased greatly to treat basal cell and cutaneous squamous cell carcinomas (keratinocyte carcinoma [KC]), and consensus-based Appropriate Use Criteria (AUC) were developed to identify tumors for which MMS is appropriate. OBJECTIVE: We sought to compare recurrence rates after different treatments in tumors judged appropriate for MMS. METHODS: We used data from an observational prospective cohort study and retrospectively categorized consecutive tumors as appropriate for MMS according to the AUC. Among appropriate tumors, we used survival analyses to compare 5-year recurrence rates after treatments. RESULTS: Among tumors appropriate for MMS (N = 1483), adjusted 5-year recurrence rates were 2.9% (range, 1.4-4.3%) after MMS, 5.5% (range, 3.1-7.9%) after excision, 4.0% (range, 0.6-7.2%) after destruction, and 5.9% (range, 1.5-10.2%) after other treatments. In tumors treated only with MMS or excision (the most similar subgroups), the adjusted hazard ratio of 5-year recurrence after MMS was 0.6 (95% confidence interval, 0.3-1.0; P = .06). LIMITATIONS: This study is limited by its uncertain generalizability, lack of randomization, and unmeasured characteristics. CONCLUSION: The AUC identified tumors for which recurrence would be less common after MMS than after excision, but the absolute difference in recurrence rates was small.

Effect of sodium oxybate on body mass index in pediatric patients with narcolepsy.

STUDY OBJECTIVES: We examined body mass index (BMI) changes associated with sodium oxybate treatment (SXB) in pediatric patients with narcolepsy with cataplexy who participated in a double-blind, placebo-controlled, randomized withdrawal study and an open-label continuation period. METHODS: Participants were aged 7-16 years at screening. SXB-naive participants titrated to twice-nightly dosing of SXB then entered a 2-week stable-dose period; participants taking SXB at study entry entered a 3-week stable-dose period. After a 2-week randomized withdrawal period, all participants entered an open-label safety period (OLP; main study duration: ≤ 52 weeks). Participants who completed the OLP were allowed to enter the open-label continuation period (an additional 1-2 years). BMI percentile categories were defined as underweight (< 5th), normal (5th to < 85th), overweight (≥ 85th to < 95th), and obese (≥ 95th). RESULTS: Median BMI percentile decreased from baseline to OLP week 52 in SXB-naive participants who were normal weight at baseline (decreased from 77.0 to 35.0) or overweight/obese at baseline (98.0 to 86.7). Median BMI percentile decreased to a lesser extent in participants taking twice-nightly SXB at study entry who were normal weight at baseline (54.6 to 53.0) or overweight/obese at baseline (96.5 to 88.9). Shifts in BMI category from baseline to week 52 were sometimes noted. In SXB-naive participants, 9/10 (90.0%) who were overweight became normal weight, 7/25 (28.0%) who were obese became normal weight, 3/25 (12.0%) who were obese became overweight, and 1/16 (6.3%) who was normal weight became obese. In participants taking SXB at baseline, 5/8 (62.5%) who were overweight became normal weight, 3/6 (50.0%) who were obese became overweight, 1/14 (7.1%) who was normal weight became overweight, and 2/14 (14.3%) who were normal weight became underweight. Median BMI percentiles at months 6 and 12 of the open-label continuation period were similar to those at OLP end (OLP week 52). In SXB-naive participants, the evident BMI z-score decrease over time was relative to the screening values. CONCLUSIONS: Decreases in BMI percentile and z-score, and downward shifts in BMI category, were observed within 1 year of SXB treatment in pediatric participants with narcolepsy with cataplexy. BMI decreases plateaued after approximately 1 year. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Name: A Multicenter Study of the Efficacy and Safety of Xyrem With an Open-Label Pharmacokinetic Evaluation and Safety Extension in Pediatric Subjects With Narcolepsy With Cataplexy; URL: https://clinicaltrials.gov/study/NCT02221869; Identifier: NCT02221869. CITATION: Dauvilliers Y, Lammers GJ, Lecendreux M, et al. Effect of sodium oxybate on body mass index in pediatric patients with narcolepsy. J Clin Sleep Med. 2024;20(3):445-454.

Long-term safety and maintenance of efficacy of sodium oxybate in the treatment of narcolepsy with cataplexy in pediatric patients.

STUDY OBJECTIVES: Evaluate long-term efficacy and safety of sodium oxybate (SXB) in children and adolescents (aged 7-16 years) with narcolepsy with cataplexy. METHODS: A double-blind randomized withdrawal study was conducted. Prior to randomization, SXB-naive participants were titrated to an efficacious and tolerable dose of SXB; participants taking SXB entered on their established dose. Following a 2-week stable-dose period and 2-week, double-blind, randomized withdrawal period, participants entered an open-label period (OLP; ≤ 47 weeks). Efficacy measures during the OLP included number of weekly cataplexy attacks, cataplexy-free days, and Epworth Sleepiness Scale for Children and Adolescents (ESS-CHAD). Safety outcomes included treatment-emergent adverse events; assessments of depression, anxiety, and suicidality; and polysomnography. RESULTS: Of 106 enrolled participants, 95 entered and 85 completed the OLP. In SXB-naive participants and participants previously taking SXB, efficacy of SXB established prior to the double-blind, randomized withdrawal period was maintained throughout the OLP for number of weekly cataplexy attacks (median [quartile 1, quartile 3] change from the stable-dose period to end of the OLP: 0.0 [-2.5, 4.9] and 0.0 [-3.4, 2.6], respectively) and ESS-CHAD scores (0.0 [-3.0, 2.5] and 1.0 [-3.0, 3.0], respectively). The median (quartile 1, quartile 3) number of cataplexy-free days per week was 2.3 (0.0, 6.0) in OLP week 1 and 3.8 (0.5, 5.5) in week 48. Treatment-emergent adverse events (≥ 5%) were enuresis, nausea, vomiting, headache, decreased weight, decreased appetite, nasopharyngitis, upper respiratory tract infection, and dizziness. CONCLUSIONS: SXB demonstrated long-term maintenance of efficacy in pediatric narcolepsy with cataplexy, with a safety profile consistent with that observed in adults. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Name: A Multicenter Study of the Efficacy and Safety of Xyrem with an Open-Label Pharmacokinetic Evaluation and Safety Extension in Pediatric Subjects with Narcolepsy with Cataplexy; URL: https://clinicaltrials.gov/ct2/show/NCT02221869; Identifier: NCT02221869. CITATION: Lecendreux M, Plazzi G, Dauvilliers Y, et al. Long-term safety and maintenance of efficacy of sodium oxybate in the treatment of narcolepsy with cataplexy in pediatric patients. J Clin Sleep Med. 2022;18(9):2217-2227.

Safety and efficacy of lower-sodium oxybate in adults with idiopathic hypersomnia: a phase 3, placebo-controlled, double-blind, randomised withdrawal study.

BACKGROUND: Idiopathic hypersomnia is a central hypersomnolence disorder mainly characterised by excessive daytime sleepiness, with prolonged night-time sleep and pronounced sleep inertia. Until August, 2021, no medication had regulatory approval for the treatment of idiopathic hypersomnia. This study aimed to evaluate the safety and efficacy of lower-sodium oxybate in idiopathic hypersomnia. METHODS: This was a phase 3, multicentre (50 specialist sleep centres; six EU countries and the USA), placebo-controlled, double-blind, randomised withdrawal study. Participants (aged 18-75 years) with idiopathic hypersomnia (meeting criteria from the International Classification of Sleep Disorders, 2nd or 3rd editions) began lower-sodium oxybate treatment (oral solution once or twice nightly) in an open-label titration and optimisation period (10-14 weeks), followed by a 2-week, open-label, stable-dose period. After these open-label periods, participants were randomised (1:1) by means of an interactive web recognition system, stratified by participants' baseline medication use, to either placebo or lower-sodium oxybate (individually optimised dose; range 2·5-9·0 g/night) during a 2-week, double-blind, randomised withdrawal period. To maintain masking of treatment assignment, placebo and lower-sodium oxybate oral solutions were matched in volume, appearance, and taste. During the double-blind, randomised withdrawal period, participants and investigators were unaware of treatment assignments. The primary efficacy endpoint was change in Epworth Sleepiness Scale (ESS) score from the end of the stable-dose period to the end of the double-blind, randomised withdrawal period, which was assessed in the modified intention-to-treat population (defined as all participants who were randomly assigned, took at least one dose of study medication during the double blind, randomised withdrawal period, and had at least one set of post-randomisation assessments for the primary or key secondary endpoints). Adverse events were assessed in the safety population (defined as all participants who took at least one dose of study medication). This study is registered at ClinicalTrials.gov, NCT03533114, and at EU Clinical Trials, 2018-001311-79, and is complete. FINDINGS: Between Nov 27, 2018, and March 6, 2020, 154 participants were enrolled and comprised the safety population. ESS scores decreased from a mean of 15·7 (SD 3·8) at baseline to 6·1 (4·0) by the end of the stable-dose period. After the open-label periods, 115 participants were randomly assigned either placebo (n=59) or lower-sodium oxybate (n=56) and comprised the modified intention-to-treat population. During the double-blind, randomised withdrawal period, ESS scores increased (worsened) in participants randomly assigned to placebo but remained stable in those assigned to lower-sodium oxybate (least squares mean difference -6·5; 95% CI -8·0 to -5·0; p<0·0001). Treatment-emergent adverse events included nausea (34 [22%] of 154), headache (27 [18%] of 154), dizziness (19 [12%] of 154), anxiety (17 [11%] 154), and vomiting (17 [11%] 154). No deaths were reported during the study. INTERPRETATION: Lower-sodium oxybate treatment resulted in a clinically meaningful improvement in idiopathic hypersomnia symptoms, with an overall safety profile consistent with that reported for narcolepsy. Lower-sodium oxybate was approved in August, 2021, by the US Food and Drug Administration for the treatment of idiopathic hypersomnia in adults. FUNDING: Jazz Pharmaceuticals.

Identifying the needs of brain tumor patients and their caregivers.

The purpose of this study is to identify the needs of brain tumor patients and their caregivers to provide improved health services to these populations. Two different questionnaires were designed for patients and caregivers. Both questionnaires contained questions pertaining to three realms: disease symptoms/treatment, health care provider, daily living/finances. The caregivers' questionnaires contained an additional domain on emotional needs. Each question was evaluated for the degree of importance and satisfaction. Exploratory analyses determined whether baseline characteristics affect responder importance or satisfaction. Also, areas of high agreement/disagreement in satisfaction between the participating patient-caregiver pairs were identified. Questions for which >50% of the patients and caregivers thought were "very important" but >30% were dissatisfied include: understanding the cause of brain tumors, dealing with patients' lower energy, identifying healthful foods and activities for patients, telephone access to health care providers, information on medical insurance coverage, and support from their employer. In the emotional realm, caregivers identified 9 out of 10 items as important but need further improvement. Areas of high disagreement in satisfaction between participating patient-caregiver pairs include: getting help with household chores (P value = 0.006) and finding time for personal needs (P value < 0.001). This study provides insights into areas to improve services for brain tumor patients and their caregivers. The caregivers' highest amount of burden is placed on their emotional needs, emphasizing the importance of providing appropriate medical and psychosocial support for caregivers to cope with emotional difficulties they face during the patients' treatment process.

Population and Noncompartmental Pharmacokinetics of Sodium Oxybate Support Weight-Based Dosing in Children and Adolescents With Narcolepsy With Cataplexy.

The pharmacokinetics (PKs) of sodium oxybate (SXB) was evaluated in a subset of participants from a study of SXB treatment in children (aged 7-11 years; n = 11) and adolescents (aged 12-17 years; n = 18) with narcolepsy with cataplexy. PK evaluation was conducted over 2 nights during the period when participants received a stable nightly SXB dose. The SXB dose on night 1 was half of night 2 and was administered in two equally divided doses: dose 1 was administered > 2 hours after the evening meal, and dose 2 was administered ≥ 4 hours after dose 1. Noncompartmental PK analysis demonstrated higher plasma concentrations post-dose 2 vs. post-dose 1, higher than dose-proportional increases in area under the concentration-time curve from 0 to 4 hours (AUC0-4h ) after dose 1, indicating nonlinear clearance, and better correlation between exposure and mg/kg than exposure and gram dose. To confirm the noncompartmental findings, identify factors affecting SXB PK, and compare with prior results in adults, a population PK (PopPK) model was established combining PK data from the current study with prior data from adults (132 healthy volunteers and 13 with narcolepsy). A two-compartment PopPK model with first-order absorption and nonlinear clearance from the central compartment described the data well. PopPK identified weight as the main intrinsic factor and food as the main extrinsic factor affecting SXB PK, and predicts similar PK profiles on a mg/kg basis across ages. These results, along with previously reported efficacy and safety outcomes, support weight-based SXB dose initiation in pediatric patients.

Treatment of paediatric narcolepsy with sodium oxybate: a double-blind, placebo-controlled, randomised-withdrawal multicentre study and open-label investigation.

BACKGROUND: Narcolepsy is a lifelong neurological disorder with onset commonly in childhood or adolescence. No drugs are indicated for cataplexy and excessive daytime sleepiness in paediatric patients with narcolepsy. Sodium oxybate is approved for use in adult patients with excessive daytime sleepiness or cataplexy, or both, in narcolepsy. We aimed to examine the safety and efficacy of sodium oxybate oral solution treatment in children and adolescents who have narcolepsy with cataplexy. METHODS: This was a prospective, double-blind, placebo-controlled, randomised-withdrawal, multisite study and open-label investigation done at 30 sites in five countries (USA, Finland, France, Italy, and the Netherlands). Eligible participants were aged 7-16 years at screening, had narcolepsy with cataplexy, and were either being treated with sodium oxybate or were sodium oxybate-naive at entry. Sodium oxybate-naive participants were titrated to an optimal dose. Participants were randomly assigned (1:1) with a dynamic randomisation algorithm to receive placebo or to remain on sodium oxybate for 2 weeks; they then entered an open-label sodium oxybate treatment period for a total study duration of up to 1 year. Random assignment to placebo was discontinued if early efficacy was shown in the preplanned interim analysis of the primary efficacy endpoint, which was change in weekly number of cataplexy attacks. Participants entering the study after the interim analysis would then be assigned to receive open-label sodium oxybate for 2 weeks. The primary analysis of efficacy and safety included data collected until the cutoff date of Feb 10, 2017. The efficacy population consisted of all participants randomly assigned to receive an intervention who completed at least 5 days of dosing in the double-blind treatment period, and the safety population consisted of all participants who took the study drug, including open-label sodium oxybate. This study is registered with ClinicalTrials.gov, number NCT02221869. FINDINGS: Between Oct 1, 2014, and Feb 10, 2017, we enrolled 106 participants, and 104 took the study drug (the safety population). 96 (92%) of these participants completed the stable-dose period, of whom 63 participants (the efficacy population) were randomly assigned to receive sodium oxybate (n=31) or placebo (n=32) for 2 weeks. A preplanned interim analysis of the primary endpoint showed efficacy (p=0·0002), resulting in discontinuation of the placebo arm following guidance from the data safety monitoring board; 33 participants then received sodium oxybate on an open-label basis during the double-blind period. Participants who were randomly assigned to receive placebo and who were withdrawn from sodium oxybate (32 [51%] of 63 patients) had increased weekly cataplexy attacks (median increase of 12·7 attacks per week [Q1, Q3=3·4, 19·8]) when compared with those randomly assigned to continue treatment with sodium oxybate (median increase of 0·3 attacks per week [-1·0, 2·5]; p<0·0001). Commonly reported (>5%) adverse events were enuresis (15 [21%] of 72 sodium oxybate-naive participants vs four [13%] of 32 participants taking sodium oxybate at study entry), nausea (16 [22%] vs two [6%]), vomiting (15 [21%] vs two [6%]), headache (13 [18%] vs four [13%]), decreased weight (11 [15%] vs one [3%]), decreased appetite (eight [11%] vs none), nasopharyngitis (seven [10%] vs none), and dizziness (five [7%] vs 1 [3%]). Two serious adverse events (one event of severe acute psychosis and one event of moderate suicidal ideation) were reported, and both were considered to be related to the study drug. There were no reported deaths. INTERPRETATION: These results support the clinical efficacy of sodium oxybate for the treatment of both excessive daytime sleepiness and cataplexy in narcolepsy in children. The safety profile of sodium oxybate was consistent with that observed in adult patients. FUNDING: Jazz Pharmaceuticals.