Analysis by sex of safety and effectiveness of transvenous phrenic nerve stimulation.

PURPOSE: Little is known about sex differences in the treatment of central sleep apnea (CSA). Our post hoc analysis of the remede System Pivotal Trial aimed to determine sex-specific differences in the safety and effectiveness of treating moderate to severe CSA in adults with transvenous phrenic nerve stimulation (TPNS). METHODS: Men and women enrolled in the remede System Pivotal Trial were included in this post hoc analysis of the effect of TPNS on polysomnographic measures, Epworth Sleepiness Scale, and patient global assessment for quality of life. RESULTS: Women (n = 16) experienced improvement in CSA metrics that were comparable to the benefits experienced by men (n = 135), with central apneas being practically eliminated post TPNS. Women experienced improvement in sleep quality and architecture that was comparable to men post TPNS. While women had lower baseline apnea hypopnea index than men, their quality of life was worse at baseline. Additionally, women reported a 25-percentage point greater improvement in quality of life compared to men after 12 months of TPNS therapy. TPNS was found to be safe in women, with no related serious adverse events through 12 months post-implant, while men had a low rate of 10%. CONCLUSION: Although women had less prevalent and less severe CSA than men, they were more likely to report reduced quality of life. Transvenous phrenic nerve stimulation may be a safe and effective tool in the treatment of moderate to severe CSA in women. Larger studies of women with CSA are needed to confirm our findings. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov NCT01816776; March 22, 2013.

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.

Transvenous phrenic nerve stimulation improves central sleep apnea, sleep quality, and quality of life regardless of prior positive airway pressure treatment.

STUDY OBJECTIVE: Positive airway pressure (PAP) therapy for central sleep apnea (CSA) is often poorly tolerated, ineffective, or contraindicated. Transvenous phrenic nerve stimulation (TPNS) offers an alternative, although its impact on previously PAP-treated patients with CSA has not been examined. METHODS: TPNS responses among PAP-naïve and prior PAP-treated patients from the remede® System Pivotal Trial were assessed. Of 151, 56 (37%) used PAP therapy before enrolling in the trial. Patients were implanted with a TPNS device and randomized to either active or deferred (control) therapy for 6 months before therapy activation. Apnea-hypopnea index (AHI) and patient-reported outcomes (PRO) were assessed at baseline, and 6 and 12 months following active therapy. RESULTS: Patients had moderate-severe CSA at baseline, which was of greater severity and more symptomatic in the PAP-treated vs. PAP-naïve group (median AHI 52/h vs. 38, central apnea index (CAI) 32/h vs. 18, Epworth Sleepiness Scale 13 vs. 10, fatigue severity scale 5.2 vs. 4.5). Twelve months of TPNS decreased AHI to <20/h and CAI to ≤2/h. Both groups showed reductions in daytime sleepiness and fatigue, improved well-being by patient global assessment, and high therapeutic acceptance with 98% and 94% of PAP-treated and PAP-naïve patients indicating they would undergo the implant again. Stimulation produced discomfort in approximately one-third of patients, yet <5% of prior PAP-treated participants discontinued therapy. CONCLUSION: Polysomnographic and clinical responses to TPNS were comparable in PAP-naïve and prior PAP-treated CSA patients. TPNS is a viable therapy across a broad spectrum of CSA patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifier NCT01816776; March 22, 2013.

Phase I Study of CHK1 Inhibitor LY2603618 in Combination with Gemcitabine in Patients with Solid Tumors.

OBJECTIVE: LY2603618, a selective inhibitor of checkpoint kinase 1 (CHK1) and key regulator of the DNA damage checkpoint, may enhance the effects of antimetabolites. This phase I study defined the recommended phase II dose of LY2603618 combined with gemcitabine. PATIENTS AND METHODS: Patients with advanced/metastatic disease were administered doses of LY2603618 (70-250 mg/m2 or flat-fixed doses of 200 or 230 mg) after gemcitabine (1,000 mg/m2). Safety and pharmacokinetics (PK) were assessed. RESULTS: Among the 50 patients enrolled, frequent adverse events possibly related to study drug treatment included fatigue (44%), decreased platelets (42%), decreased neutrophils (32%), nausea (26%), and decreased hemoglobin (20%). Systemic exposure of LY2603618 increased dose dependently, while clearance was relatively dose independent. The mean LY2603618 half-life varied; however, the durations were still suitable for maintaining human exposures while minimizing accumulation. LY2603618 PK were not altered by gemcitabine administration. Plasma exposures that correlate with the maximal pharmacodynamic effect in nonclinical models were achieved for all doses. One patient with non-small cell lung cancer carcinoma achieved a partial response; 22 patients had stable disease. CONCLUSIONS: The maximum tolerated dose of LY2603618 combined with gemcitabine was 200 mg/m2, but a fixed LY2603618 dose of 230 mg combined with gemcitabine was selected as the recommended phase II dose.

Transvenous phrenic nerve stimulation for treating central sleep apnea may regulate sleep microstructure.

STUDY OBJECTIVES: To assess the impact of transvenous phrenic nerve stimulation (TPNS) on non-rapid eye movement sleep microstructure quantified by cyclic alternating pattern (CAP) in individuals with central sleep apnea (CSA). METHODS: We analyzed baseline and 6-month follow-up overnight polysomnograms (PSG) in 134 CSA patients enrolled in the remede System Pivotal Trial implanted with TPNS randomized (1:1) to neurostimulation (treatment group) or no stimulation (control group). Differences in CAP rate, A1 index, and A2+A3 index between study arms at follow-up were assessed using Analysis of Covariance adjusted for baseline values. RESULTS: On follow-up PSG, the treatment group showed a decrease in the frequency of A2+A3 phases compared to controls (-5.86 ± 11.82 vs. 0.67 ± 15.25, p = 0.006), while the frequency of A1 phases increased more in the treatment group (2.57 ± 11.67 vs. -2.47 ± 10.60, p = 0.011). The change in CAP rate at follow-up was comparable between study arms. CONCLUSIONS: TPNS treatment for central sleep apnea may affect sleep microstructure. Brief phases of rapid cortical activity appear to be replaced by short phases of slower cortical activity, which may promote sleep continuity. Further investigations are warranted to elucidate the mechanisms underlying the effect of TPNS on CAP.

Phase I dose-escalation study to examine the safety and tolerability of LY2603618, a checkpoint 1 kinase inhibitor, administered 1 day after pemetrexed 500 mg/m(2) every 21 days in patients with cancer.

PURPOSE: This phase I study aims at assessing the safety and tolerability of LY2603618, a selective inhibitor of Checkpoint Kinase 1, in combination with pemetrexed and determining the maximum tolerable dose and the pharmacokinetic parameters. EXPERIMENTAL DESIGN: This was an open-label, multicenter, dose-escalation study in patients with advanced solid tumors. Increasing doses of LY2603618 (40-195 mg/m(2)) were combined with 500 mg/m(2) of pemetrexed. LY2603618 was administered on Days 1 and 9 and pemetrexed on Day 8 in a 28-day cycle. For all subsequent 21-day cycles, pemetrexed was administered on Day 1 and LY2603618 on Day 2. Antitumor activity was evaluated as per Response Evaluation Criteria in Solid Tumors 1.0. RESULTS: A total of 31 patients were enrolled into six cohorts (three at 40 mg/m(2) over 4.5-hour infusion, 1-hour infusion in subsequent cohorts: three each at 40 mg/m(2), 70 mg/m(2), and 195 mg/m(2); 13 at 105 mg/m(2); six at 150 mg/m(2)). Four patients experienced a dose-limiting toxicity: diarrhea (105 mg/m(2)); reversible infusion-related reaction (150 mg/m(2)); thrombocytopenia (195 mg/m(2)); and fatigue (195 mg/m(2)). The maximum tolerated dose was defined as 150 mg/m(2). The pharmacokinetic data demonstrated that the exposure of LY2603618 increased in a dose-dependent manner, displayed a suitable half-life for maintaining required human exposures while minimizing the intra- and inter-cycle accumulation, and was unaffected by the pemetrexed administration. The pharmacokinetic-defined biologically efficacious dose was achieved at doses ≥105 mg/m(2). CONCLUSION: LY2603618 administered approximately 24 h after pemetrexed showed acceptable safety and pharmacokinetic profiles.

Transvenous phrenic nerve stimulation is associated with normalization of nocturnal heart rate perturbations in patients with central sleep apnea.

STUDY OBJECTIVES: To determine the effect of transvenous phrenic nerve stimulation (TPNS) on nocturnal heart rate perturbations in patients with CSA. METHODS: In this ancillary study of the remede System Pivotal Trial, we analyzed electrocardiograms from baseline and follow-up overnight polysomnograms (PSG) in 48 CSA patients in sinus rhythm with implanted TPNS randomized to stimulation (treatment group; TPNS on) or no stimulation (control group; TPNS off). We quantified heart rate variability in the time and frequency domain. Mean change from baseline and standard error is provided. RESULTS: TPNS titrated to reduce respiratory events is associated with reduced cyclical heart rate variations in the very low-frequency domain across REM (VLFI: 4.12 ± 0.79% vs. 6.87 ± 0.82%, p = 0.02) and NREM sleep (VLFI: 5.05 ± 0.68% vs. 6.74 ± 0.70%, p = 0.08) compared to the control group. Further, low-frequency oscillations were reduced in the treatment arm in REM (LFn: 0.67 ± 0.03 n.u. vs. 0.77 ± 0.03 n.u., p = 0.02) and NREM sleep (LFn: 0.70 ± 0.02 n.u. vs. 0.76 ± 0.02 n.u., p = 0.03). CONCLUSION: In adult patients with moderate to severe central sleep apnea, transvenous phrenic nerve stimulation reduces respiratory events and is associated with the normalization of nocturnal heart rate perturbations. Long-term follow-up studies could establish whether the reduction in heart rate perturbation by TPNS also translates into cardiovascular mortality reduction. CLINICAL TRIAL: A Randomized Trial Evaluating the Safety and Effectiveness of the remede® System in Patients With Central Sleep Apnea, ClinicalTrials.gov, NCT01816776.

Transvenous phrenic nerve stimulation for the treatment of central sleep apnea reduces episodic hypoxemic burden.

STUDY OBJECTIVES: To determine the effect of transvenous phrenic nerve stimulation (TPNS) on the composition of the nocturnal hypoxemic burden in patients with CSA. METHODS: We analysed oximetry data from baseline and follow-up overnight polysomnograms (PSG) in 134 CSA patients with implanted TPNS randomised (1:1) to neurostimulation (treatment group; TPNS on) or no stimulation (control group; TPNS off) from the remede System Pivotal Trial. The hypoxemic burden was quantified using a battery of metrics, including the oxygen desaturation index (ODI), the relative sleep time spent below 90% SpO2 (T90) due to acute episodic desaturations (T90desat) and due to non-specific and non-cyclic drifts of SpO2 (T90non-specific). Mean change from baseline is provided. RESULTS: TPNS titrated to reduce respiratory events significantly reduced the ODI in the treatment group by -15.85 h-1 ± 1.99 compared to the control group, which increased 1.32 h-1 ± 1.85 (p ã€ˆ0001) and shortened the relative T90 duration by -3.81 percentage points ± 1.23 vs. 0.49 percentage points ± 1.14 increase (p = 0.012). This shortening of T90 was primarily accomplished by reducing the brief cyclic desaturations (T90desaturation: -4.32 percentage points ± 0.98 vs. 0.52 percentage points ± 0.91, p = 0.0004) while notable non-specific drifts in SpO2 remained unchanged (T90non-specific: 0.18 percentage points ± 0.62 vs. -0.13 percentage points ± 0.57, p = 0.72). CONCLUSIONS: TPNS appears to significantly reduce the nocturnal hypoxemic burden due to sleep-disordered breathing, but a considerable nocturnal hypoxemic burden from other sources remains. Further investigations are warranted to identify the best strategy to reduce the nocturnal hypoxemic burden beyond preventing respiratory events.

Transvenous phrenic nerve stimulation to treat central sleep apnoea in patients with heart failure may improve sleep, quality of life, and symptoms.

AIMS: Sleep disorder breathing is an important non-cardiovascular comorbidity in patients with heart failure (HF). However, central sleep apnoea (CSA) remains poorly diagnosed and treated. This post hoc analysis examined symptoms and quality of life in patients with CSA and HF following 12 months of transvenous phrenic nerve stimulation (TPNS) therapy. METHODS AND RESULTS: Patients enrolled in the remede System Pivotal trial were invited to complete self-reported questionnaires. Symptoms and responses to three validated questionnaires were examined. Percentage of patients noting an impairment was calculated at baseline. At 12 months, % of patients experiencing improvement, no change, or worsening was calculated. Shifts from symptom presence at baseline to absence at 12 months were assessed for those symptoms experienced by ≥50% of patients at baseline. Seventy-five patients were included. Most frequently reported symptoms were fatigue and daytime sleepiness. Following 12 months of TPNS, a variety of subjective improvements were observed; 45% of patients indicating cessation of daytime sleepiness, 44% cessation of fatigue/weakness, and 52% no longer having difficulty falling/staying asleep. Specific questions related to tiredness/fatigue, motivation, and chance of dozing provided an insight into potential areas of improvement. Furthermore, at least 60% of patients reported resolution of insomnia/fragmented sleep and snoring on therapy. CONCLUSION: Adult patients with CSA and HF experience distressing symptoms and limitations. Transvenous phrenic nerve stimulation was found to improve many of these. Awareness of key symptoms or limitations patients experience can be used to inform the development of a CSA-specific patient questionnaire to identify CSA sooner and aid treatment decisions.

Design of the remede System Therapy (reST) study: A prospective non-randomized post-market study collecting clinical data on safety and effectiveness of the remede system for the treatment of central sleep apnea.

BACKGROUND: Central sleep apnea (CSA) is a disorder defined by lack of respiratory drive from the brain stem on breathing efforts. There is a lack of established therapies for CSA and most available therapies are limited by poor patient adherence, limited randomized controlled studies, and potentially adverse cardiovascular effects. The remede System (ZOLL Respicardia, Inc., Minnetonka, Minnesota) uses transvenous phrenic nerve stimulation to stimulate the diaphragm, thereby restoring a more normal breathing pattern throughout the sleep period. METHODS: The remede System Therapy (reST) Study is a prospective non-randomized multicenter international study evaluating long-term safety and effectiveness of the remede System in the post-market setting. Up to 500 adult patients with moderate to severe CSA will be enrolled and followed up to 5 years at approximately 50 sites in the United States and Europe. Safety objectives include evaluation of adverse events related to the implant procedure, device or delivered therapy, death, and hospitalizations. Effectiveness endpoints include assessment of changes in sleep-disordered breathing metrics from polysomnograms and home sleep tests, changes in daytime sleepiness using the Epworth Sleepiness Scale, and changes in QoL using the PROMIS-29 and Patient Global Assessment questionnaires. The subgroup of patients with heart failure will undergo additional assessments including echocardiography to assess cardiac reverse remodeling, 6-min walk distance, QoL assessment by Kansas City Cardiomyopathy Questionnaire and measurement of biomarkers. CONCLUSION: This will be the largest prospective study evaluating long-term safety and effectiveness of transvenous phrenic nerve stimulation for the treatment of moderate to severe CSA in adult patients.

Improving Nocturnal Hypoxemic Burden with Transvenous Phrenic Nerve Stimulation for the Treatment of Central Sleep Apnea.

Nocturnal hypoxemic burden is established as a robust prognostic metric of sleep-disordered breathing (SDB) to predict mortality and treating hypoxemic burden may improve prognosis. The aim of this study was to evaluate improvements in nocturnal hypoxemic burden using transvenous phrenic nerve stimulation (TPNS) to treat patients with central sleep apnea (CSA). The remede System Pivotal Trial population was examined for nocturnal hypoxemic burden. The minutes of sleep with oxygen saturation < 90% significantly improved in Treatment compared with control (p < .001), with the median improving from 33 min at baseline to 14 min at 6 months. Statistically significant improvements were also observed for average oxygen saturation and lowest oxygen saturation. Hypoxemic burden has been demonstrated to be more predictive for mortality than apnea-hypopnea index (AHI) and should be considered a key metric for therapies used to treat CSA. Transvenous phrenic nerve stimulation is capable of delivering meaningful improvements in nocturnal hypoxemic burden. There is increasing interest in endpoints other than apnea-hypopnea index in sleep-disordered breathing. Nocturnal hypoxemia burden may be more predictive for mortality than apnea-hypopnea index in patients with poor cardiac function. Transvenous phrenic nerve stimulation is capable of improving nocturnal hypoxemic burden. Graphical Abstract.

Transvenous Phrenic Nerve Stimulation for Treatment of Central Sleep Apnea: Five-Year Safety and Efficacy Outcomes.

BACKGROUND: The remede System Pivotal Trial was a prospective, multi-center, randomized trial demonstrating transvenous phrenic nerve stimulation (TPNS) therapy is safe and effectively treats central sleep apnea (CSA) and improves sleep architecture and daytime sleepiness. Subsequently, the remede System was approved by FDA in 2017. As a condition of approval, the Post Approval Study (PAS) collected clinical evidence regarding long-term safety and effectiveness in adults with moderate to severe CSA through five years post implant. METHODS: Patients remaining in the Pivotal Trial at the time of FDA approval were invited to enroll in the PAS and consented to undergo sleep studies (scored by a central laboratory), complete the Epworth Sleepiness Scale (ESS) questionnaire to assess daytime sleepiness, and safety assessment. All subjects (treatment and former control group) receiving active therapy were pooled; data from both trials were combined for analysis. RESULTS: Fifty-three of the original 151 Pivotal Trial patients consented to participate in the PAS and 52 completed the 5-year visit. Following TPNS therapy, the apnea-hypopnea index (AHI), central-apnea index (CAI), arousal index, oxygen desaturation index, and sleep architecture showed sustained improvements. Comparing 5 years to baseline, AHI and CAI decreased significantly (AHI baseline median 46 events/hour vs 17 at 5 years; CAI baseline median 23 events/hour vs 1 at 5 years), though residual hypopneas were present. In parallel, the arousal index, oxygen desaturation index and sleep architecture improved. The ESS improved by a statistically significant median reduction of 3 points at 5 years. Serious adverse events related to implant procedure, device or delivered therapy were reported by 14% of patients which include 16 (9%) patients who underwent a pulse generator reposition or lead revision (primarily in the first year). None of the events caused long-term harm. No unanticipated adverse device effects or related deaths occurred through 5 years. CONCLUSION: Long-term TPNS safely improves CSA, sleep architecture and daytime sleepiness through 5 years post implant. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01816776.

Transvenous phrenic nerve stimulation to treat idiopathic central sleep apnea.

STUDY OBJECTIVES: Idiopathic central sleep apnea (ICSA) is a rare disorder diagnosed when known causes of central sleep apnea are excluded. No established treatments exist for ICSA, and long-term studies are lacking. We assessed the long-term effectiveness and safety of transvenous phrenic nerve stimulation in patients with ICSA. METHODS: In the remede System Pivotal Trial, 16/151 (11%) participants with central sleep apnea were diagnosed as having ICSA. Patients were implanted and followed through 18 months of active therapy. Polysomnograms obtained at baseline and at 6, 12, and 18 months were scored by a central laboratory. Sleep metrics and patient-reported quality of life outcomes were assessed. RESULTS: Patients experienced moderate-severe central sleep apnea. The baseline AHI, central apnea index, and arousal index were 40, 25, and 32 events/h of sleep, respectively. These metrics improved at 6, 12, and 18 months of therapy: the AHI decreased by 25, 25, and 23 events/h (P < .001 at each visit), the central apnea index by 22, 23, and 22 events/h (P < .001 at each visit), and the arousal index by 12 (P = .005), 11 (P = .035), and 13 events/h (P < .001). Quality of life instruments showed clinically meaningful improvements in daytime somnolence, fatigue, general and mental health, and social functioning. The only related serious adverse event was lead component failure in 1 patient. CONCLUSIONS: This is the longest prospective study for the treatment of ICSA. Transvenous phrenic nerve stimulation significantly decreased sleep-disordered breathing metrics with consequent improvement in quality of life at 6 months, and all benefits were sustained through 18 months. CLINICAL TRIAL REGISTRATION: Registry: ClinicalTrials.gov; Name: Respicardia, Inc. Pivotal Trial of the remede System; URL: https://clinicaltrials.gov/ct2/show/NCT01816776; Identifier: NCT01816776.

Transvenous phrenic nerve stimulation for central sleep apnea is safe and effective in patients with concomitant cardiac devices.

BACKGROUND: Central sleep apnea is common in heart failure patients. Transvenous phrenic nerve stimulation (TPNS) requires placing a lead to stimulate the phrenic nerve and activate the diaphragm. Data are lacking concerning the safety and efficacy of TPNS in patients with concomitant cardiovascular implantable electronic devices (CIEDs). OBJECTIVE: To report the safety and efficacy of TPNS in patients with concomitant CIEDs. METHODS: In the remede System Pivotal Trial, 151 patients underwent TPNS device implant. This analysis compared patients with concomitant CIEDs to those without with respect to safety, implant metrics, and efficacy of TPNS. Safety was assessed using incidence of adverse events and device-device interactions. A detailed interaction protocol was followed. Implant metrics included overall TPNS implantation success. Efficacy endpoints included changes in the apnea-hypopnea index (AHI) and quality of life. RESULTS: Of 151 patients, 64 (42%) had a concomitant CIED. There were no significant differences between the groups with respect to safety. There were 4 CIED oversensing events in 3 patients leading to 1 inappropriate defibrillator shock and delivery of antitachycardia pacing. There was no difference in efficacy between the CIED and non-CIED subgroups receiving TPNS, with both having similar percentages of patients who achieved ≥50% reduction in AHI and quality-of-life improvement. CONCLUSION: Concomitant CIED and TPNS therapy is safe. The presence of a concomitant CIED did not seem to impact implant metrics, implantation success, and TPNS efficacy. A detailed interaction protocol should be followed to minimize the incidence of device-device interaction.

In patients with heart failure the burden of central sleep apnea increases in the late sleep hours.

Study Objectives: Periodic breathing with central sleep apnea (CSA) is common in patients with left ventricular systolic dysfunction. Based on the pathophysiological mechanisms underlying CSA, we hypothesized that the frequency of CSA episodes would increase in the late hours of non-rapid eye movement (NREM) of sleep. Methods: Forty-one patients with left ventricular ejection fraction <40% underwent full-night-attended polysomnography scored by a central core lab. Because central apneas occur primarily in NREM sleep, total NREM sleep time for each patient was divided into 8 equal duration segments. Segment event counts were normalized to an events/hour index based on sleep segment duration. Results: Central apnea index (CAI) varied among sleep segments (p = 0.001). As expected CAI was higher in segment 1 compared to segments 2 and 3, increasing during later segments. The minimum CAI occurred in segment 2 with mean ± SD of 21 ± 3 events/hour and maximum CAI was in segment 8 with 37 ± 4 events/hour. We also determined central apnea duration which varied among segments (p = 0.005), with longer durations later in the night (segment 1: 22 ± 1 seconds; segment 8: 26 ± 1 seconds, p < 0.001). Data were also analyzed including rapid eye movement (REM) sleep, with similar results. Further, comparison of CAI between the first and second half of the night showed a significant increase in the index. Circulation time did not change across the segments (p = 0.073). Conclusions: In patients with left ventricular dysfunction and CSA, central apnea burden (number and duration) increases during later hours of sleep. These findings have pathophysiological and therapeutic implications. Clinical Trial Registration: NCT01124370.

Long-term efficacy and safety of phrenic nerve stimulation for the treatment of central sleep apnea.

STUDY OBJECTIVE: To evaluate long-term efficacy and safety of phrenic nerve stimulation (PNS) in patients with moderate-to-severe central sleep apnea (CSA) through 3 years of therapy. METHODS: Patients in the remede System Pivotal Trial were observed every 3 months after implant until US Food and Drug Administration approval. At the time of approval and study closure, all patients completed 24 months of follow-up; 33 patients had not reached the 36-month visit. Sleep metrics (polysomnography) and echocardiographic parameters are reported at baseline, 12, 18, and 24 months, in addition to available 36-month sleep results from polygraphy. Safety was assessed through 36 months; however, analysis focused through 24 months and available 36-month results are provided. RESULTS: Patients were assessed at 24 (n = 109) and 36 (n = 60) months. Baseline characteristics included mean age 64 years, 91% male, and mean apnea-hypopnea index 47 events per hour. Sleep metrics (apnea-hypopnea index (AHI), central apnea index, arousal index, oxygen desaturation index, rapid eye movement sleep) remained improved through 24 and 36 months with continuous use of PNS therapy. At least 60% of patients in the treatment group achieved at least 50% reduction in AHI through 24 months. Serious adverse events (SAEs) related to the remede System implant procedure, device, or therapy through 24 months were reported by 10% of patients, no unanticipated adverse device effects or deaths, and all events resolved. No additional related SAEs were reported between 24 and 36 months. CONCLUSION: These data suggest beneficial effects of long-term PNS in patients with CSA appear to sustain through 36 months with no new safety concerns. TRIAL REGISTRATION: NCT01816776.

Phrenic Nerve Stimulation for the Treatment of Central Sleep Apnea: A Pooled Cohort Analysis.

STUDY OBJECTIVES: Early evidence with transvenous phrenic nerve stimulation (PNS) demonstrates improved disease severity and quality of life (QOL) in patients with central sleep apnea (CSA). The goal of this analysis is to evaluate the complete prospective experience with PNS in order to better characterize its efficacy and safety, including in patients with concomitant heart failure (HF). METHODS: Using pooled individual data from the pilot (n = 57) and pivotal (n = 151) studies of the remede System in patients with predominant moderate to severe CSA, we evaluated 12-month safety and 6- and 12-month effectiveness based on polysomnography data, QOL, and cardiac function. RESULTS: Among 208 combined patients (June 2010 to May 2015), a remede device implant was successful in 197 patients (95%), 50/57 pilot study patients (88%) and 147/151 pivotal trial patients (97%). The pooled cohort included patients with CSA of various etiologies, and 141 (68%) had concomitant HF. PNS reduced apnea-hypopnea index (AHI) at 6 months by a median of -22.6 episodes/h (25th and 75th percentile; -38.6 and -8.4, respectively) (median 58% reduction from baseline, P < .001). Improvement in sleep variables was maintained through 12 months of follow-up. In patients with HF and ejection fraction ≤ 45%, PNS was associated with improvement in systolic function from 27.0% (23.3, 36.0) to 31.1% (24.0, 41.5) at 12 months (P = .003). In the entire cohort, improvement in QOL was concordant with amelioration of sleep measures. CONCLUSIONS: Transvenous PNS significantly improves CSA severity, sleep quality, ventricular function, and QOL regardless of HF status. Improvements, which are independent of patient compliance, are sustained at 1 year and are associated with acceptable safety.

Phrenic nerve stimulation in patients with central sleep apnea: a single­center experience from pilot and pivotal trials evaluating the remede System.

BACKGROUND: Patients with central sleep apnea (CSA) have recently been shown to have improved sleep metrics and quality of life (QoL) with phrenic nerve stimulation (PNS). AIMS: The aim of this study was to report the results of a partnership between cardiology, sleep medicine, and electrophysiology in a single clinical center as well as the enrollment, implantation, and follow­up experience demonstrating both the safety and efficacy of PNS. METHODS: This analysis included data from the pilot and pivotal trials investigating the effect of PNS using an implantable transvenous system in patients with CSA. We present our experience and data on the enrollment processes, implantation feasibility and safety, sleep indices, and QoL at 6 and 12 months of follow­up. RESULTS: Between June 2010 and May 2015, cardiology patients were prescreened and 588 of them were sent for in­home sleep test. Ninety­six patients were referred for polysomnographic studies, and 33 were enrolled and had an implant attempt, with 31 successfully receiving an implant. The apnea-hypopnea index was reduced in the pilot trial (mean [SD] of 48.7 [15.5] events/h to 22.5 [13.2] events/h; P <0.001) and in the pivotal trial (mean [SD] of 48.3 [18.8] events/h to 26.0 [21.9] events/h; P <0.001). Improvement in QoL was also observed. CONCLUSIONS: We showed that PNS improved sleep metrics and QoL in patients with CSA, which is a result of multiple factors, including a comprehensive coordination between cardiology, sleep medicine, and electrophysiology. This ensures appropriate patient identification leading to safe implantation and full patient compliance during follow­up visits.

Phrenic nerve stimulation to treat patients with central sleep apnoea and heart failure.

AIMS: The presence of central sleep apnoea (CSA) is associated with poor prognosis in patients with heart failure (HF). The aim of this analysis was to evaluate if using phrenic nerve stimulation to treat CSA in patients with CSA and HF was associated with changes in HF-specific metrics. METHODS AND RESULTS: All patients randomized in the remede System Pivotal Trial and identified at baseline with HF were included (n = 96). Effectiveness data from treatment and former control groups were pooled based on months since therapy activation. Changes from baseline to 6 and 12 months in sleep metrics, Epworth Sleepiness Scale, patient global assessment health-related quality of life, Minnesota Living with Heart Failure Questionnaire (MLHFQ), and echocardiographic parameters are reported. HF hospitalization, cardiovascular death, and the composite of HF hospitalization or cardiovascular death within 6 months are reported by the original randomized group assignment for safety assessment. Sleep metrics and quality of life improved from baseline to 6 and 12 months. At 12 months, MLHFQ scores changed by -6.8 ± 20.0 (P = 0.005). The 6-month rate of HF hospitalization was 4.7% in treatment patients (standard error = 3.3) and 17.0% in control patients (standard error = 5.5) (P = 0.065). Reported adverse events were as expected for a transvenous implantable system. CONCLUSIONS: Phrenic nerve stimulation reduces CSA severity in patients with HF. In parallel, this CSA treatment was associated with benefits on HF quality of life.