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The association between anemia at admission and adverse outcomes in patients with acute coronary syndrome (ACS) has been incompletely studied. Anemia was defined as serum hemoglobin <12 g/dl in women or <13 g/dl in men in 2 large trials of patients with ACS. We plotted hazard functions for major bleeding at 30 days and all-cause mortality, myocardial infarction, and stent thrombosis at 1 year according to baseline hemoglobin. Among 16,318 patients, 3070 (18.8%) had anemia at baseline. All-cause death at 1 year (2.9% vs 1.5%), major bleeding (7.6% vs 3.6%, p <0.001), and transfusions (6.7% vs 1.5%, p <0.001) were more common in patients with baseline anemia. Spline transformations of the hazard for adverse events as a function of hemoglobin level on admission showed that adverse outcomes increased in a nonlinear fashion with lower levels of baseline hemoglobin; the lowest rates were observed at a level of ∼14 g/dl. Baseline hemoglobin and anemia were independent predictors of major bleeding and death. In conclusion, in patients with ACS, baseline hemoglobin carries important independent prognostic information and demonstrates a nonlinear association with major bleeding and mortality.

Thin-cap fibroatheromas (TCFAs) are considered precursors for plaque rupture and subsequent acute coronary events. We investigated intravascular ultrasound (IVUS) and near-infrared spectroscopy (NIRS) characteristics of lesions that were histopathologic TCFAs. IVUS, NIRS, and histopathology were performed in 271 atherosclerotic lesions from 107 fresh coronary arteries from 54 patients at necropsy. The plaque burden and remodeling index calculated by IVUS and maximum lipid core burden index within any 4-mm segment (maxLCBI4mm) calculated by NIRS were compared among each plaque type based on histopathologic classifications but focusing on TCFA. Lesions classified as TCFAs had the largest plaque burden, the highest remodeling index, and the greatest maxLCBI4mm. Plaque burden ≥69% (90% sensitivity, 75% specificity, and area under the curve 0.87); remodeling index ≥1.07 (80% sensitivity, 79% specificity, and area under the curve 0.84); and maxLCBI4mm ≥323 (80% sensitivity, 85% specificity, and area under the curve 0.84) predicted a histopathologic TCFA. In conclusion, a large plaque burden and a high remodeling index assessed by IVUS and lipid-rich plaque determined by the NIRS maxLCBI4mm are useful predictive markers of TCFA.

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.

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. 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. 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. 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. Jazz Pharmaceuticals.

For most cutaneous basal cell and squamous cell carcinomas (nonmelanoma skin cancers (NMSCs)), data are insufficient to permit evidence-based choices among treatments. To compare tumor recurrence after treatments, we conducted a prospective cohort study of consecutive patients with primary NMSCs treated with the most common treatments, in two practices in 1999–2000. Recurrence was determined from medical records by observers blinded to treatment type. Follow-up was available for 1,174 patients with 1,488 tumors (93.8%) at median 7.4 years; of these tumors, 24.3% (N=361) were treated with destruction with electrodessication/curettage, 38.3% (N=571) with excision, and 37.4% (N=556) with histologically guided serial excision (Mohs surgery). The overall 5-year tumor recurrence rate (95% confidence interval) was 3.3% (2.3, 4.4). Unadjusted recurrence rates did not differ after treatments: 4.9% (2.3, 7.4) after destruction, 3.5% (1.8, 5.2) after excision, and 2.1% (0.6, 3.5) after Mohs surgery (P=0.26), and no difference was seen after adjustment for risk factors. In tumors treated only with excision or Mohs surgery, the hazard of recurrence was not significantly different, even after adjustment for propensity for treatment with Mohs surgery. These data indicate that common treatments for NMSCs were at least 95% effective, and further studies are needed to guide therapeutic choices for different clinical subgroups.

Introduction Idiopathic hypersomnia (IH) is a rare central hypersomnolence disorder. In a randomized, controlled study of lower-sodium oxybate (LXB; Xywav™) in adults with IH (NCT03533114), significant differences for LXB compared with placebo were observed in Epworth Sleepiness Scale (ESS; primary efficacy endpoint), self-reported Patient Global Impression of Change (PGIc), and IH Severity Scale (IHSS; key secondary endpoints). In this clinical study, investigators were permitted to initiate LXB dosing on a once-nightly or twice-nightly regimen. Methods Eligible participants aged 18–75 years began LXB treatment, administered once or twice nightly during an open-label treatment/titration and optimization period (OLTTOP; 10–14 weeks); dose amount/regimen could be adjusted during this period. Participants next entered a 2-week, open-label, stable-dose period (SDP), then were randomized to placebo or to continue LXB treatment during a 2-week, double-blind, randomized withdrawal period (DBRWP). P values are nominal for this exploratory analysis. Results Of 154 enrolled participants, 40 (26%) initiated LXB treatment on a once-nightly regimen. In the efficacy population (n=115), 27 participants were on a once-nightly regimen during SDP (48.1% of whom initiated treatment once nightly during OLTTOP) and 88 participants were on a twice-nightly regimen during SDP (86.4% of whom initiated treatment twice nightly during OLTTOP). During SDP, median (min, max) LXB total dose was 4.5 (2.5, 6) g/night (once-nightly group) and 7.5 (4.5, 9) g/night (twice-nightly group). ESS scores worsened in participants randomized to placebo vs those continuing LXB in the once-nightly group (n=11 and n=15, respectively; LS mean difference [95% CI]: −4.93 [−7.41, −2.46]; P=0.0004) and twice-nightly group (n=47 and n=41, respectively; LS mean difference [95% CI]: −7.44 [−9.15, −5.72]; P<0.0001). Worsening was also observed in PGIc (once-nightly: 81.8% [placebo] vs 26.7% [LXB]; P=0.0077; twice-nightly: 89.4% [placebo] vs 19.5% [LXB]; P<0.0001) and IHSS score (estimated median difference [95% CI], once-nightly: −9.00 [−16.0, −3.0]; P=0.0028; twice-nightly: −12.00 [−15.0, −8.0]; P<0.0001). Common adverse events included nausea (21.4%), headache (16.2%), anxiety (14.9%), dizziness (11.7%), insomnia (11.7%), and vomiting (10.4%). Conclusion The efficacy and safety of LXB in IH were demonstrated for both once-nightly and twice-nightly regimens. The majority of participants initiated and remained on a twice-nightly regimen. Support (if any) Jazz Pharmaceuticals

Introduction Idiopathic hypersomnia (IH) is a rare central hypersomnolence disorder characterized by excessive daytime sleepiness, prolonged nighttime sleep, and sleep inertia. No US/EU medication is approved for treatment of IH. Lower-sodium oxybate (LXB; Xywav™; previously designated JZP-258) is a novel oxybate treatment with 92% less sodium than sodium oxybate (Xyrem®). The efficacy and safety of LXB was evaluated in adults with IH. Methods Eligible participants aged 18–75 years with IH began once- or twice-nightly LXB treatment entering an open-label titration and optimization period (10–14 weeks), followed by a 2-week, open-label, stable-dose period (SDP); they were then randomized to placebo or to continue LXB treatment during a 2-week, double-blind, randomized withdrawal period (DBRWP). The primary efficacy endpoint was change in Epworth Sleepiness Scale (ESS) score; key secondary endpoints were proportion of participants who reported worsening (minimally/much/very much worse) on Patient Global Impression of Change (PGIc) and change in Idiopathic Hypersomnia Severity Scale (IHSS) score, all from end of SDP to end of DBRWP. Results The study enrolled 154 participants (mean±SD age, 40±14 years; 68% female; mean±SD ESS, 16±3.6); mean±SD dose was 6.0±1.6 g/night. Mean±SD ESS score (n=115) decreased over open-label titration/optimization (15.7±3.8 at baseline, 9.8±4.5 at week 4, and 6.1±4.0 at the end of the SDP). At the end of the DBRWP, significant worsening was observed in participants randomized to placebo, compared with maintenance of improvement in participants randomized to continue LXB, in ESS scores (n=115; LS mean difference [95% CI] in change from SDP, −6.51 [−7.99, −5.03]; P<0.0001), in the PGIc (88.1% for placebo vs 21.4% for LXB; P<0.0001), and in IHSS scores (estimated median difference [95% CI], −12.00 [−15.0, −8.0]; P<0.0001). Common adverse events (AEs) included nausea (21.4%), headache (16.2%), anxiety (14.9%), dizziness (11.7%), insomnia (11.7%), and vomiting (10.4%). Serious AEs occurred in 4 participants (non-cardiac chest pain, rhabdomyolysis, syncope, and nephrolithiasis/pyelonephritis); none were reported related to study drug. Conclusion In participants with IH, LXB demonstrated a clinically meaningful effect on excessive daytime sleepiness, self-reported global change, and overall IH symptom severity. The overall safety profile was consistent with that of LXB in narcolepsy. Support (if any) Jazz Pharmaceuticals

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.

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.

Introduction In a placebo-controlled, randomized withdrawal study with subsequent open-label investigation for up to 1 year, sodium oxybate (SXB) demonstrated efficacy and safety in the treatment of pediatric narcolepsy with cataplexy. In a further continuation period for up to 2 years, safety of SXB and effects on growth were assessed. Methods Participants who completed Part 1 (up to 52 weeks on study) could transition or re-enroll into the open-label continuation (Part 2) for up to an additional 2 years. Part 2 evaluations included body mass index (BMI), weight, height, treatment-emergent adverse events (TEAEs), and vital signs. Age- and sex-based percentiles for height, weight, and BMI at each assessment were determined using standardized growth charts (CDC, 2000). Results As of 30 April 2018, of the 44 participants in Part 2, 1 completed and 4 discontinued (3 withdrew consent, 1 lost to follow-up). Mean (SD) age at first SXB dose in Part 2 was 13.1 (2.2) years; 29.5% were 7-11 years, 70.5% 12-17 years; 68.2% male; and 65.9% white. In Part 1, mean baseline BMI was elevated relative to age-matched population means. In Part 1, there was slight initial decrease from baseline in median BMI and weight percentile values, which stabilized, and remained within normal range in Part 2 (median change from baseline to Part 2 month 3: BMI percentile -2.8%; weight percentile -2.4%). There was increase in absolute height and slight decrease in height percentile (median change from baseline to Part 2 month 3: height 9.0 cm, height percentile -2.0). In Part 2, TEAEs were reported in 18/44 (40.9%) participants; most frequent TEAEs were respiratory tract infection (6.8%), constipation (4.5%), diarrhea (4.5%), gamma-glutamyltransferase increased (4.5%), headache (4.5%), weight increased (4.5%). As of 30 April 2018, for Part 2, there were no serious AEs reported and no discontinuations due to TEAEs. Vital signs remained within normal range throughout the study. Conclusion Growth parameters remained stable overall, and no new safety findings were identified during the ≤2-year open-label continuation period (Part 2). Support (If Any) Jazz Pharmaceuticals