Central Sleep Apnea in Patients With Coronary Heart Disease Taking P2Y12 Inhibitors.

ABSTRACT: Central sleep apnea (CSA) is common in patients with heart failure. Recent studies link ticagrelor use with CSA. We aimed to evaluate CSA prevalence in patients with coronary heart disease (CHD) and whether ticagrelor use is associated with CSA. We reviewed consecutive patients with CHD who underwent a polysomnography (PSG) test over a 5-year period from 3 sleep centers. We sampled patients who were on ticagrelor or clopidogrel during a PSG test at a 1:4 ticagrelor:clopidogrel ratio. Patients with an active opioid prescription during PSG test were excluded. Age, left ventricle (LV) dysfunction, and P2Y12 inhibitor use were included in a multivariate logistic regression. A total of 135 patients were included with 26 on ticagrelor and 109 on clopidogrel (age 64.1 ± 11.4, 32% male). High CSA burden (12%) and strict CSA (4.4%) were more common in patients on ticagrelor than in those on clopidogrel (27% vs. 8.3% and 10.0% vs. 1.8%). Ticagrelor use (vs. clopidogrel) was associated with high CSA burden (OR 3.53, 95% CI 1.04-12.9, P = 0.039) and trended toward significance for strict CSA (OR 6.32, 95% CI 1.03-51.4, P = 0.052) when adjusting for age and LV dysfunction. In an additional analysis also adjusting for history of atrial fibrillation, ticagrelor use and strict CSA became significantly associated (OR 10.0, 95% CI 1.32-117, P = 0.035). CSA was uncommon in patients with CHD undergoing sleep studies. Ticagrelor use (vs. clopidogrel) was associated with high CSA burden and trended toward significance for strict CSA.

Adaptive servo-ventilation and mortality in patients with systolic heart failure and central sleep apnea: a single-center experience.

BACKGROUND: Central sleep apnea (CSA) is associated with increased mortality and morbidity in patients with heart failure with reduced ejection fraction (HFrEF). Treatment of CSA with a certain type of adaptive servo-ventilation (ASV) device that targets minute ventilation (ASVmv) was found to be harmful in these patients. A newer generation of ASV devices that target peak flow (ASVpf) is presumed to have different effects on ventilation and airway patency. We analyzed our registry of patients with HFrEF-CSA to examine the effect of exposure to ASV and role of each type of ASV device on mortality. METHODS: This is a retrospective cohort study in patients with HFrEF and CSA who were treated with ASV devices between 2008 and 2015 at a single institution. Mortality data were collected through the institutional data honest broker. Usage data were obtained from vendors' and manufacturers' servers. Median follow-up was 64 months. RESULTS: The registry included 90 patients with HFrEF-CSA who were prescribed ASV devices. Applying a 3-h-per-night usage cutoff, we found a survival advantage at 64 months for those who used the ASV device above the cutoff (n = 59; survival 76%) compared to those who did not (n = 31; survival 49%; hazard ratio 0.44; CI 95%, 0.20 to 0.97; P = 0.04). The majority (n = 77) of patients received ASVpf devices with automatically adjusting end-expiratory pressure (EPAP) and the remainder (n = 13) received ASVmv devices mostly with fixed EPAP (n = 12). There was a trend towards a negative correlation between ASVmv with fixed EPAP and survival. CONCLUSION: In this population of patients with HFrEF and CSA, there was no evidence that usage of ASV devices was associated with increased mortality. However, there was evidence of differential effects of type of ASV technology on mortality.

Clinical and financial impact of sleep disordered breathing on heart failure admissions.

BACKGROUND: The impact of sleep disordered breathing (SDB) on heart failure (HF) is increasingly recognized. However, limited data exist in support of quantification of the clinical and financial impact of SDB on HF hospitalizations. METHODS: A sleep-heart registry included all patients who underwent inpatient sleep testing during hospitalization for HF at a single cardiac center. Readmission data and actual costs of readmissions were obtained from the institutional honest broker. Patients were classified based on the inpatient sleep study as having no SDB, obstructive sleep apnea (OSA), or central sleep apnea (CSA). Cumulative cardiac readmission rates and costs through 3 and 6 months post-discharge were calculated. Unadjusted and adjusted (age, sex, body mass index, and left ventricular ejection fraction) modeling of cost was performed. RESULTS: The cohort consisted of 1547 patients, 393 (25%) had no SDB, 438 (28%) had CSA, and 716 (46%) had OSA. Within 6 months of discharge, 195 CSA patients (45%), 264 OSA patients (37%), and 109 no SDB patients (28%) required cardiovascular readmissions. Similarly, 3- and 6-month mortality rates were higher in both SDB groups than those with no SDB. Both unadjusted and adjusted readmission costs were higher in the OSA and CSA groups compared to no SDB group at 3 and 6 months post-discharge with the CSA and OSA group costs nearly double (~ $16,000) the no SDB group (~ $9000) through 6 months. INTERPRETATION: Previously undiagnosed OSA and CSA are common in patients hospitalized with HF and are associated with increased readmissions rate and mortality.

Research Priorities for Patients with Heart Failure and Central Sleep Apnea. An Official American Thoracic Society Research Statement.

Background: Central sleep apnea (CSA) is common among patients with heart failure and has been strongly linked to adverse outcomes. However, progress toward improving outcomes for such patients has been limited. The purpose of this official statement from the American Thoracic Society is to identify key areas to prioritize for future research regarding CSA in heart failure.Methods: An international multidisciplinary group with expertise in sleep medicine, pulmonary medicine, heart failure, clinical research, and health outcomes was convened. The group met at the American Thoracic Society 2019 International Conference to determine research priority areas. A statement summarizing the findings of the group was subsequently authored using input from all members.Results: The workgroup identified 11 specific research priorities in several key areas: 1) control of breathing and pathophysiology leading to CSA, 2) variability across individuals and over time, 3) techniques to examine CSA pathogenesis and outcomes, 4) impact of device and pharmacological treatment, and 5) implementing CSA treatment for all individualsConclusions: Advancing care for patients with CSA in the context of heart failure will require progress in the arenas of translational (basic through clinical), epidemiological, and patient-centered outcome research. Given the increasing prevalence of heart failure and its associated substantial burden to individuals, society, and the healthcare system, targeted research to improve knowledge of CSA pathogenesis and treatment is a priority.

Central sleep apnea treatment in patients with heart failure with reduced ejection fraction: a network meta-analysis.

PURPOSE: Adaptive servo-ventilation (ASV) is contraindicated for the treatment of central sleep apnea (CSA) in patients with heart failure with reduced ejection fraction (HFrEF), limiting treatment options. Though continuous positive airway pressure (CPAP), bi-level PAP with back-up rate (BPAP-BUR), and transvenous phrenic nerve stimulation (TPNS) are alternatives, not much is known about their comparative efficacies, which formed the basis of conducting this network meta-analysis. We sought to analyze their comparative effectiveness in reducing apnea hypopnea index (AHI). Additionally, we also studied their comparative effectiveness on subjective daytime sleepiness as assessed by Epworth sleepiness score (ESS). METHODS: Randomized controlled trials (RCTs) from PubMed were analyzed in a network meta-analysis and relative superiority was computed based on P-score ranking and Hasse diagrams. RESULTS: Network meta-analysis based on 8 RCTs showed that when compared to guideline-directed medical therapy (GDMT-used as a common comparator across trials), reduction in AHI by ASV (- 26.05 [- 38.80; - 13.31]), TPNS (- 24.90 [- 42.88; - 6.92]), BPAP-BUR (- 20.36 [- 36.47; - 4.25]), and CPAP (- 16.01 [- 25.42; - 6.60]) were statistically significant but not between the interventions. Based on 6 RCTs of all the interventions, only TPNS showed a statistically significant decrease in ESS (- 3.70 (- 5.58; - 1.82)) when compared to GDMT, while also showing significant differences when compared with ASV (- 3.20 (- 5.86; - 0.54)), BPAP-BUR (- 4.00 (- 7.33; - 0.68)), and CPAP (- 4.45 (- 7.75; - 1.14)). Ranking of treatments based on Hasse diagram, accounting for both AHI and ESS as outcomes for relative hierarchy showed relative superiority of both ASV and TPNS over BPAP-BUR and CPAP. CONCLUSIONS: Results indicated relative superiority of TPNS and ASV to BPAP-BUR and CPAP in their effects on AHI and ESS.

In-Hospital Management of Sleep Apnea During Heart Failure Hospitalization: A Randomized Controlled Trial.

BACKGROUND: Obstructive sleep apnea (OSA) is associated with increased mortality and readmissions in patients with heart failure (HF). The effect of in-hospital diagnosis and treatment of OSA during decompensated HF episodes remains unknown. METHODS AND RESULTS: A single-site, randomized, controlled trial of hospitalized patients with decompensated HF (n = 150) who were diagnosed with OSA during the hospitalization was undertaken. All participants received guideline-directed therapy for HF decompensation. Participants were randomized to an intervention arm which received positive airway pressure (PAP) therapy during the hospitalization (n = 75) and a control arm (n = 75). The primary outcome was discharge left ventricular ejection fraction (LVEF). The LVEF changed in the PAP arm from 25.5 ± 10.4 at baseline to 27.3 ± 11.9 at discharge. In the control group, LVEF was 27.3 ± 11.7 at baseline and 28.8 ± 10.5 at conclusion. There was no significant effect on LVEF of in-hospital PAP compared with controls (P = .84) in the intention-to-treat analysis. The on-treatment analysis in the intervention arm showed a significant increase in LVEF in participants who used PAP for ≥3 hours per night (n = 36, 48%) compared with those who used it less (P = .01). There was a dose effect with higher hours of use associated with more improvement in LVEF. Follow-up of readmissions at 6 months after discharge revealed a >60% decrease in readmissions for patients who used PAP ≥3 h/night compared with those who used it <3 h/night (P < .02) and compared with controls (P < .04). CONCLUSIONS: In-hospital treatment with PAP was safe but did not significantly improve discharge LVEF in patients with decompensated HF and newly diagnosed OSA. An exploratory analysis showed that adequate use of PAP was associated with higher discharge LVEF and decreased 6 months readmissions.

Periorbital desmoplastic squamous cell carcinoma.

Desmoplasia is the formation of a dense collagenous stroma around a neoplasm. It occurs in a variety of malignancies including squamous cell carcinoma (SCC). While desmoplasia is uncommonly seen in cutaneous SCC, it is an independent risk factor for recurrence and metastasis. We report a case series of desmoplastic SCC in the periorbital region. Seven cases were identified: the median age was 68, four were men. The mean follow-up was 48 months. Two patients (29%) had aggressive local recurrence: one required salvage surgery including orbital exenteration, parotidectomy, and neck dissection to excise involved parotid and cervical lymph nodes; the other required repeat excision and adjuvant radiotherapy. Desmoplastic SCC is an uncommon but highly aggressive subtype. In the periorbital region, due to the high risk of orbital invasion, it is potentially sight and life-threatening.

Bridge flap repair for central nasal dorsum defect.

Surgery of the nose to remove skin cancer often requires the use of local flaps. We present a defect after the extirpation of a previously incompletely excised infiltrative squamous cell carcinoma, which we repaired with a Bridge flap, a bipedicled and subcutaneous islanded flap whose excellent vascularity allows reliable reconstruction and rapid mobilisation, with dependable results.

Transvenous neurostimulation for central sleep apnoea: a randomised controlled trial.

BACKGROUND: Central sleep apnoea is a serious breathing disorder associated with poor outcomes. The remedé system (Respicardia Inc, Minnetonka, MN, USA) is an implantable device which transvenously stimulates a nerve causing diaphragmatic contraction similar to normal breathing. We evaluated the safety and effectiveness of unilateral neurostimulation in patients with central sleep apnoea. METHODS: We recruited patients from 31 hospital-based centres in Germany, Poland, and the USA in this prospective, multicentre, randomised trial. Participants had to have been medically stable for at least 30 days and have received appropriate guideline recommended therapy, be aged at least 18 years, be expected to tolerate study procedures, and willing and able to comply with study requirements. Eligible patients with an apnoea-hypopnoea index (AHI) of at least 20 events per h, tested by a polysomnography, underwent device implantation and were randomly assigned (1:1) by a computer-generated method stratified by site to either stimulation (treatment) or no stimulation (control) for 6 months. The primary effectiveness endpoint in the intention-to-treat population was the comparison of the proportions of patients in the treatment versus control groups achieving a 50% or greater AHI reduction from baseline to 6 months, measured by a full-night polysomnography assessed by masked investigators in a core laboratory. The primary safety endpoint of 12-month freedom from serious adverse events related to the procedure, system, or therapy was evaluated in all patients. This trial is active, but not recruiting, and is registered with ClinicalTrials.gov (NCT01816776). FINDINGS: Between April 17, 2013, and May 28, 2015, we randomly assigned 151 eligible patients to the treatment (n=73) or control (n=78) groups. In the analysis of the intention-to-treat population, significantly more patients in the treatment group (35 [51%] of 68) had an AHI reduction from baseline of 50% or greater at 6 months than had those in the control group (eight [11%] of 73; difference between groups 41%, 95% CI 25-54, p<0·0001). 138 (91%) of 151 patients had no serious-related adverse events at 12 months. Seven (9%) cases of related-serious adverse events occurred in the control group and six (8%) cases were reported in the treatment group. Seven patients died (unrelated to implant, system, or therapy), four deaths (two in treatment group and two in control group) during the 6-month randomisation period when neurostimulation was delivered to only the treatment group and was off in the control group, and three deaths between 6 months and 12 months of follow-up when all patients received neurostimulation. 27 (37%) of 73 patients in the treatment group reported non-serious therapy-related discomfort that was resolved with simple system reprogramming in 26 (36%) patients, but was unresolved in one (1%) patient. INTERPRETATION: Transvenous neurostimulation significantly reduced the severity of central sleep apnoea, including improvements in sleep metrics, and was well tolerated. The clinically meaningful effects of the therapy are supported by the concordant improvements in oxygenation and quality of life, making transvenous neurostimulation a promising therapeutic approach for central sleep apnoea. FUNDING: Respicardia Inc.

Sleep disordered breathing and post-discharge mortality in patients with acute heart failure.

BACKGROUND: Hospitalizations for heart failure are associated with a high post-discharge risk for mortality. Identification of modifiable predictors of post-discharge mortality during hospitalization may improve outcome. Sleep disordered breathing (SDB) is the most common co-morbidity in heart failure patients. DESIGN, SETTING, AND PARTICIPANTS: Prospective cohort study of patients hospitalized with acute heart failure (AHF) in a single academic heart hospital. Between January 2007 and December 2010, all patients hospitalized with AHF who have left ventricular ejection fraction (LVEF) ≤ 45% and were not already diagnosed with SDB were the target population. MAIN OUTCOMES AND MEASURES: Patients underwent in-hospital attended polygraphy testing for SDB and were followed for a median of 3 years post-discharge. Mortality was recorded using national and state vital statistics databases. RESULTS: During the study period, 1117 hospitalized AHF patients underwent successful sleep testing. Three hundred and forty-four patients (31%) had central sleep apnoea (CSA), 525(47%) patients had obstructive sleep apnoea (OSA), and 248 had no or minimal SDB (nmSDB). Of those, 1096 patients survived to discharge and were included in the mortality analysis. Central sleep apnoea was independently associated with mortality. The multivariable hazard ratio (HR) for time to death for CSA vs. nmSDB was 1.61 (95% CI: 1.1, 2.4, P = 0.02). Obstructive sleep apnoea was also independently associated with mortality with a multivariable HR vs. nmSDB of 1.53 (CI: 1.1, 2.2, P = 0.02). The Cox proportional hazards model adjusted for the following covariates: LVEF, age, BMI, sex, race, creatinine, diabetes, type of cardiomyopathy, coronary artery disease, chronic kidney disease, discharge systolic blood pressure <110, hypertension, discharge medications, initial length of stay, admission sodium, haemoglobin, and BUN. CONCLUSIONS: This is the largest study to date to evaluate the effect of SDB on post-discharge mortality in patients with AHF. Newly diagnosed CSA and OSA during AHF hospitalization are independently associated with post-discharge mortality.

Subungual Congenital Nevus with Recurrent Nevus Phenomenon.

Melanonychia is uncommon. We report the first case of histopathologic recurrence of a completely excised subungual congenital nevus that presented as congenital melanonychia.

Improved sleep stage predictions by deep learning of photoplethysmogram and respiration patterns.

Sleep staging is a crucial tool for diagnosing and monitoring sleep disorders, but the standard clinical approach using polysomnography (PSG) in a sleep lab is time-consuming, expensive, uncomfortable, and limited to a single night. Advancements in sensor technology have enabled home sleep monitoring, but existing devices still lack sufficient accuracy to inform clinical decisions. To address this challenge, we propose a deep learning architecture that combines a convolutional neural network and bidirectional long short-term memory to accurately classify sleep stages. By supplementing photoplethysmography (PPG) signals with respiratory sensor inputs, we demonstrated significant improvements in prediction accuracy and Cohen's kappa (k) for 2- (92.7 %; k = 0.768), 3- (80.2 %; k = 0.714), 4- (76.8 %, k = 0.550), and 5-stage (76.7 %, k = 0.616) sleep classification using raw data. This relatively translatable approach, with a less intensive AI model and leveraging only a few, inexpensive sensors, shows promise in accurately staging sleep. This has potential for diagnosing and managing sleep disorders in a more accessible and practical manner, possibly even at home.

Multidimensional phenotyping to distinguish among central (CSA), obstructive (OSA) and co-existing central and obstructive sleep apnea (CSA-OSA) phenotypes in real-world data.

PURPOSE: When navigating the landscape of obstructive sleep apnea (OSA), central sleep apnea (CSA) and intersection of the two diseases (co-existing CSA-OSA), there are significant knowledge gaps. Data are scarce regarding the respective prevalence and differences in clinical presentation of the three conditions. One major issue for characterization of the prevalence of the different sleep apnea entities is the scoring of central versus obstructive hypopneas which is not included in the routine practice of many sleep laboratories. METHOD: We prospectively assessed multidomain symptoms and collected data on comorbidities, medications and treatment indications in a large monocentric real-life dataset (n > 2400) of patients referred for suspicion of sleep apnea. We have systematically distinguished central versus obstructive hypopneas to define OSA, CSA and co-existing CSA-OSA. RESULTS: When CSA was defined by the proportion of central apneas (and hypopneas were considered obstructive by default), the prevalence of CSA was 4.59 % (co-existing CSA-OSA: 11.03 %, and OSA: 84.37 %). When the distinction between obstructive and central hypopneas was used to classify the sleep disordered breathing, the prevalence of CSA was fourfold higher at 19.69 % (co-existing: 19.16 %, OSA: 61.16 %). The burden of cardiovascular and metabolic comorbidities was the highest in the CSA and co-existing sleep apnea subgroups. The three sleep apnea groups exhibited different constellations of symptoms but most of the patients with CSA, co-existing and OSA were symptomatic after comprehensive evaluation. The CSA group exhibited the most severe disturbances in sleep architecture on polysomnography. Therapeutic indications differed depending on the subtype of respiratory events. CONCLUSION: Our findings imply that not differentiating between central and obstructive hypopneas will underestimate the severity of central sleep disordered breathing abnormalities that mislead therapeutic decisions and might limit improvements in quality of life and sleepiness that are expected in appropriately treated patients with CSA.

Win ratio analysis of transvenous phrenic nerve stimulation to treat central sleep apnoea in heart failure.

AIMS: Central sleep apnoea (CSA) is present in 20-40% of heart failure (HF) patients and is associated with poor clinical outcomes and health status. Transvenous phrenic nerve stimulation (TPNS) is an available treatment for CSA in HF patients. The impact on HF outcomes is incompletely understood. The win ratio (WR) allows inclusion of multiple endpoint components, considers the relative severity of each component, and permits assessment of recurrent events in evaluation of clinical benefit. METHODS AND RESULTS: A WR hierarchy was pre-defined for analysis of the HF subgroup of the remede® System Pivotal Trial. The analysis used three hierarchical components to compare all treated to all control subjects: longest survival, lowest HF hospitalization rate, and ≥2-category difference in Patient Global Assessment at 6 months. Sensitivity analyses were performed substituting Epworth Sleepiness Scale and 4% oxygen desaturation index for the third component, and a 4-component WR hierarchy was also evaluated. Ninety-one HF subjects, 43 receiving TPNS and 48 in the control group, provided 2064 pairwise comparisons. More patients treated with TPNS experienced clinical benefit compared with control (WR 4.92, 95% confidence interval 2.27-10.63, P < 0.0001). There were 1111 (53.83%) winning pairwise comparisons for the treatment group and 226 (10.95%) for the control group. Similarly, large WRs were observed for all additional WR hierarchies. CONCLUSIONS: This WR analysis of the remede® System Pivotal Trial suggests that TPNS may be superior to untreated CSA in HF patients with CSA using a hierarchical clinical benefit endpoint composed of mortality, HF hospitalization, and health status.

Insights, recommendations, and research priorities for central sleep apnea: report from an expert panel.

Central sleep apnea (CSA) is commonly encountered among patients with sleep-disordered breathing, however its clinical consequences are less well-characterized. We therefore convened an expert panel to discuss the common presentations of CSA, as well as challenges and knowledge gaps in the diagnosis and management of CSA. The panel identified several key research priorities essential for advancing our understanding of the disorder. Within the diagnostic realm, panel members discussed the utility of multi-night assessments, and importance of the development and validation of novel metrics and automated assessments for differentiating central versus obstructive hypopneas, such that their impact on clinical outcomes and management may be better evaluated. The panel also discussed the current therapeutic landscape for the management of CSA and agreed that therapies should primarily aim to alleviate sleep-related symptoms, after optimizing treatment to address the underlying cause. Most importantly, the panel concluded that there is a need to further investigate the clinical consequences of CSA, as well as the implications of therapy on clinical outcomes, particularly among those who are asymptomatic. Future research should focus on endo-phenotyping central events for a better mechanistic understanding of the disease, validating novel diagnostic methods for implementation in routine clinical practice, as well as the use of combination therapy and comparative effectiveness trials in elucidating the most efficacious interventions for managing CSA.

Sleep-disordered breathing in heart failure: identifying and treating an important but often unrecognized comorbidity in heart failure patients.

Sleep-disordered breathing (SDB) is the most common comorbidity in patients with heart failure (HF) and has a significant impact on quality of life, morbidity, and mortality. A number of therapeutic options have become available in recent years that can improve quality of life and potentially the outcomes of HF patients with SDB. Unfortunately, SDB is not part of the routine evaluation and management of HF, so it remains untreated in most HF patients. Although recognition of the role of SDB in HF is increasing, clinical guidelines for the management of SDB in HF patients continue to be absent. This article provides an overview of SDB in HF and proposes a clinical care pathway to help clinicians to better recognize and treat SDB in their HF patients.

Transvenous phrenic nerve stimulation for the treatment of central sleep apnoea in heart failure.

AIMS: Periodic breathing with central sleep apnoea (CSA) is common in heart failure patients and is associated with poor quality of life and increased risk of morbidity and mortality. We conducted a prospective, non-randomized, acute study to determine the feasibility of using unilateral transvenous phrenic nerve stimulation for the treatment of CSA in heart failure patients. METHODS AND RESULTS: Thirty-one patients from six centres underwent attempted transvenous lead placement. Of these, 16 qualified to undergo two successive nights of polysomnography-one night with and one night without phrenic nerve stimulation. Comparisons were made between the two nights using the following indices: apnoea-hypopnoea index (AHI), central apnoea index (CAI), obstructive apnoea index (OAI), hypopnoea index, arousal index, and 4% oxygen desaturation index (ODI4%). Patients underwent phrenic nerve stimulation from either the right brachiocephalic vein (n = 8) or the left brachiocephalic or pericardiophrenic vein (n = 8). Therapy period was (mean ± SD) 251 ± 71 min. Stimulation resulted in significant improvement in the AHI [median (inter-quartile range); 45 (39-59) vs. 23 (12-27) events/h, P = 0.002], CAI [27 (11-38) vs. 1 (0-5) events/h, P≤ 0.001], arousal index [32 (20-42) vs. 12 (9-27) events/h, P = 0.001], and ODI4% [31 (22-36) vs. 14 (7-20) events/h, P = 0.002]. No significant changes occurred in the OAI or hypopnoea index. Two adverse events occurred (lead thrombus and episode of ventricular tachycardia), though neither was directly related to phrenic nerve stimulation therapy. CONCLUSION: Unilateral transvenous phrenic nerve stimulation significantly reduces episodes of CSA and restores a more natural breathing pattern in patients with heart failure. This approach may represent a novel therapy for CSA and warrants further study.