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Transvenous phrenic nerve stimulation improved sleep metrics and quality of life after 6 months versus control in the remedē System Pivotal Trial. This analysis explored the effectiveness of phrenic nerve stimulation in patients with central sleep apnea after 12 months of therapy. Reproducibility of treatment effect was assessed in the former control group in whom the implanted device was initially inactive for the sixth month and subsequently activated when the randomized control assessments were complete. Patients with moderate-to-severe central sleep apnea implanted with the remedē System were randomized to therapy activation at 1 month (treatment) or after 6 months (control). Sleep indices were assessed from baseline to 12 months in the treatment group and from 6 to 12 months in former controls. In the treatment group, a ≥50% reduction in apnea-hypopnea index occurred in 60% of patients at 6 months (95% confidence interval CI 47% to 64%) and 67% (95% CI 53% to 78%) at 12 months. After 6 months of therapy, 55% of former controls (95% CI 43% to 67%) achieved ≥50%reduction in apnea-hypopnea index. Patient Global Assessment was markedly ormoderately improved at 6 and 12 months in 60% of treatment patients.Improvements persisted at 12 months. A serious adverse event within 12 months occurred in 13 patients (9%). Phrenic nerve stimulation produced sustained improvements in sleep indices and quality of life to at least 12 months in patients with central sleep apnea. The similar improvement of former controls after 6 months of active therapy confirms benefits are reproducible and reliable. Transvenous phrenic nerve stimulation improved sleep metrics and quality of life after 6 months versus control in the remedē System Pivotal Trial. This analysis explored the effectiveness of phrenic nerve stimulation in patients with central sleep apnea after 12 months of therapy. Reproducibility of treatment effect was assessed in the former control group in whom the implanted device was initially inactive for the sixth month and subsequently activated when the randomized control assessments were complete. Patients with moderate-to-severe central sleep apnea implanted with the remedē System were randomized to therapy activation at 1 month (treatment) or after 6 months (control). Sleep indices were assessed from baseline to 12 months in the treatment group and from 6 to 12 months in former controls. In the treatment group, a ≥50% reduction in apnea-hypopnea index occurred in 60% of patients at 6 months (95% confidence interval CI 47% to 64%) and 67% (95% CI 53% to 78%) at 12 months. After 6 months of therapy, 55% of former controls (95% CI 43% to 67%) achieved ≥50%reduction in apnea-hypopnea index. Patient Global Assessment was markedly ormoderately improved at 6 and 12 months in 60% of treatment patients.Improvements persisted at 12 months. A serious adverse event within 12 months occurred in 13 patients (9%). Phrenic nerve stimulation produced sustained improvements in sleep indices and quality of life to at least 12 months in patients with central sleep apnea. The similar improvement of former controls after 6 months of active therapy confirms benefits are reproducible and reliable. Central sleep apnea (CSA) occurs when there is a recurrent transient reduction in the respiratory control center's generation of breathing rhythm.1Javaheri S. Dempsey J.A. Central sleep apnea.Compr Physiol. 2013; 3: 141-163Crossref PubMed Scopus (120) Google Scholar, 2Muza R.T. Central sleep apnoea—a clinical review.J Thorac Dis. 2015; 7: 930-937PubMed Google Scholar, 3Orr J.E. Malhotra A. Sands S.A. Pathogenesis of central and complex sleep apnoea.Respirology. 2017; 22: 43-52Crossref PubMed Scopus (70) Google Scholar, 4Costanzo M.R. Khayat R. Ponikowski P. Augostini R. Stellbrink C. Mianulli M. Abraham W.T. Mechanisms and clinical consequences of untreated central sleep apnea in heart failure.J Am Coll Cardiol. 2015; 65: 72-84Crossref PubMed Scopus (84) Google Scholar The consequences of CSA may include increased sympathetic activity, inflammation, oxidative stress, and intermittent hypoxia,4Costanzo M.R. Khayat R. Ponikowski P. Augostini R. Stellbrink C. Mianulli M. Abraham W.T. Mechanisms and clinical consequences of untreated central sleep apnea in heart failure.J Am Coll Cardiol. 2015; 65: 72-84Crossref PubMed Scopus (84) Google Scholar which may contribute to the development and progression of cardiovascular disorders and confer an increased mortality risk.5Punjabi N.M. Caffo B.S. Goodwin J.L. Gottlieb D.J. Newman A.B. O'Connor G.T. Rapoport D.M. Redline S. Resnick H.E. Robbins J.A. Shahar E. Unruh M.L. Samet J.M. Sleep-disordered breathing and mortality: a prospective cohort study.PLoS Med. 2009; 6 (e1000132)Crossref PubMed Scopus (982) Google Scholar, 6Lavie P. Mortality in sleep apnoea syndrome: a review of the evidence.Eur Respir Rev. 2007; 16: 203-210Crossref Scopus (41) Google Scholar, 7Bitter T. Westerheide N. Prinz C. Hossain M.S. Vogt J. Langer C. Horstkotte D. Oldenburg O. Cheyne-stokes respiration and obstructive sleep apnoea are independent risk factors for malignant ventricular arrhythmias requiring appropriate cardioverter-defibrillator therapies in patients with congestive heart failure.Eur Heart J. 2011; 32: 61-74Crossref PubMed Scopus (224) Google Scholar, 8Javaheri S. Shukla R. Zeigler H. Wexler L. Central sleep apnea, right ventricular dysfunction, and low diastolic blood pressure are predictors of mortality in systolic heart failure.J Am Coll Cardiol. 2007; 49: 2028-2034Crossref PubMed Scopus (380) Google Scholar Therefore, it is essential that any treatment for CSA have long-lasting safety and effectiveness. The remedē System (Respicardia, Inc., Minnetonka, Minnesota) combines an implantable pulse generator and a transvenous lead for unilateral stimulation of the phrenic nerve. The remedē System delivers electrical impulses to the phrenic nerve automatically and continuously throughout the night, causing the diaphragm to contract and create negative pressure, similar to normal breathing. In the randomized controlled remedē System Pivotal trial, a greater proportion of patients treated with phrenic nerve stimulation experienced a ≥50% reduction in the apnea-hypopnea index (AHI) after 6 months compared with control.9Costanzo M.R. Ponikowski P. Javaheri S. Augostini R. Goldberg L. Holcomb R. Kao A. Khayat R.N. Oldenburg O. Stellbrink C. Abraham W.T. Transvenous neurostimulation for central sleep apnoea: a randomised controlled trial.Lancet. 2016; 388: 974-982Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar This analysis reports the 12-month results from the remedē System Pivotal trial to evaluate whether the benefits of this therapy are long-lasting. The study design and primary outcomes of the remedē System Pivotal trial have been reported.9Costanzo M.R. Ponikowski P. Javaheri S. Augostini R. Goldberg L. Holcomb R. Kao A. Khayat R.N. Oldenburg O. Stellbrink C. Abraham W.T. Transvenous neurostimulation for central sleep apnoea: a randomised controlled trial.Lancet. 2016; 388: 974-982Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar, 10Costanzo M.R. Augostini R. Goldberg L.R. Ponikowski P. Stellbrink C. Javaheri S. Design of the remedē system pivotal trial: a prospective, randomized study in the use of respiratory rhythm management to treat central sleep apnea.J Card Fail. 2015; 21: 892-902Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar The study was a prospective, multicenter, randomized, open-label controlled trial of transvenous unilateral phrenic nerve stimulation versus no stimulation in patients with moderate-to-severe CSA. The study was conducted in accordance with the amended Declaration of Helsinki and approved by local ethics committees or institutional review boards. All patients provided written informed consent for all procedural and data use aspects of study participation. Patients were eligible for the study if the qualifying polysomnogram scored by a core laboratory showed an AHI ≥20 events/hour of sleep, central apneas ≥50% of all apneas and at least 30 central apnea events throughout the night, and an obstructive apnea index (OAI) ≤20% of the total AHI. Patients with phrenic nerve palsy, Stage D heart failure, a cerebrovascular event within 12 months, or CSA secondary to opioids were excluded.9Costanzo M.R. Ponikowski P. Javaheri S. Augostini R. Goldberg L. Holcomb R. Kao A. Khayat R.N. Oldenburg O. Stellbrink C. Abraham W.T. Transvenous neurostimulation for central sleep apnoea: a randomised controlled trial.Lancet. 2016; 388: 974-982Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar, 10Costanzo M.R. Augostini R. Goldberg L.R. Ponikowski P. Stellbrink C. Javaheri S. Design of the remedē system pivotal trial: a prospective, randomized study in the use of respiratory rhythm management to treat central sleep apnea.J Card Fail. 2015; 21: 892-902Abstract Full Text Full Text PDF PubMed Scopus (36) Google Scholar This analysis includes all enrolled patients who met the per protocol population criteria. Patients who did not meet inclusion criteria, had therapy programmed to off, did not have 6-month polysomnogram results, or had unsuccessful implants were not included (Figure 1). The intention-to-treat population was used to evaluate safety (N = 151). All eligible patients underwent a remedē System implant attempt. At implantation, patients were randomized 1:1 to receive phrenic nerve stimulation (treatment) or control (device implanted, treatment not initiated). The system was activated in the treatment group at 1-month post implant.9Costanzo M.R. Ponikowski P. Javaheri S. Augostini R. Goldberg L. Holcomb R. Kao A. Khayat R.N. Oldenburg O. Stellbrink C. Abraham W.T. Transvenous neurostimulation for central sleep apnoea: a randomised controlled trial.Lancet. 2016; 388: 974-982Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar The system remained off in the control group until the primary 6-month effectiveness end point was assessed, after which therapy was initiated and titrated similarly to the original treatment group. The term “former control group” denotes patients in whom therapy was not activated until 6 months after implant. Therefore, at the time of the 12-month visit, the treatment and control group had 12 and 6 months of active therapy, respectively (Figure 2). A full night polysomnogram9Costanzo M.R. Ponikowski P. Javaheri S. Augostini R. Goldberg L. Holcomb R. Kao A. Khayat R.N. Oldenburg O. Stellbrink C. Abraham W.T. Transvenous neurostimulation for central sleep apnoea: a randomised controlled trial.Lancet. 2016; 388: 974-982Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar was completed 12 months after the 1-month post-implantation therapy initiation visit in all subjects to assess the continued impact of therapy in the treatment group and 6-month effectiveness of therapy in the former control group after 6 months of active therapy. In addition to the polysomnogram, the Patient Global Assessment health-related quality of life and Epworth Sleepiness Scale questionnaires were completed at the 6- and 12-month post-therapy initiation visits in both groups. The primary safety end point of the overall trial was freedom from serious adverse events associated with the implantation procedure, the system, or delivered therapy in the combined study groups through 12 months as previously reported.9Costanzo M.R. Ponikowski P. Javaheri S. Augostini R. Goldberg L. Holcomb R. Kao A. Khayat R.N. Oldenburg O. Stellbrink C. Abraham W.T. Transvenous neurostimulation for central sleep apnoea: a randomised controlled trial.Lancet. 2016; 388: 974-982Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar Related adverse events deemed nonserious by the Clinical Events Committee are reported herein for the first time for all subjects. Changes in sleep metrics and quality of life from baseline to the 12-month visit in the treatment group were analyzed to assess durability of the treatment effect. In addition, changes in these end points in the former control group were evaluated from therapy activation to 12 months to assess reproducibility of treatment effect. Exploratory subgroup analyses were also performed in the treatment group to evaluate the consistency of treatment effects for the primary end point. Results are presented as means (±standard deviation) and medians (interquartile range) in tabular displays. Within group, changes from baseline were tested using statistical tests appropriate to the distributional properties of the observed data, with paired t tests for AHI, central apnea index, OAI, mixed apnea index, arousal index, oxygen desaturation index 4%, and Epworth Sleepiness Scale and the Wilcoxon signed-rank test for hypopnea index, percent of sleep in rapid eye movement, and oxygen saturation <90%. All 12-month analyses are considered exploratory; therefore, all p-values are nominal and unadjusted for multiplicity. No imputations for missing data were performed. Statistical analyses were performed using SAS (version 9.4, Cary, North Carolina). Between April 17, 2013 and May 28, 2015, 151 patients (73 treatment, 78 control) were randomized. Patient flow and composition of the per protocol population through the 6- and 12-month post-therapy initiation visits are shown in Figure 1. Two patients in each group (4 of 151, 3%) had unsuccessful implant attempts (Figure 1). Baseline characteristics of the per protocol patients were similar between groups (Table 1). The baseline sleep indices and questionnaires indicate that the population had moderate-to-severe CSA. Co-morbidities were common in the per protocol population and similar to the intention-to-treat patients.Table 1Baseline characteristicsBaseline CharacteristicsPer ProtocolTreatment (n = 58)Control (n = 73)Age (years)63 ± 1264 ± 14Men51 (88%)68 (93%)White57 (98%)69 (95%)Body mass index (kg/m2)30 ± 531 ± 7Neck circumference (cm)42 ± 543 ± 5Heart rate (beats per minute)76 ± 1373 ± 14Systolic blood pressure (mm Hg)124 ± 18124 ± 18Diastolic blood pressure (mm Hg)74 ± 1175 ± 12Respiration rate (breaths per minute)18 ± 317 ± 3Apnea hypopnea index (events/hour)49.7 ± 18.943.9 ± 17.3 Central apnea index (events/hour)31.7 ± 18.626.2 ± 16.2 Obstructive apnea index (events/hour)2.1 ± 2.22.4 ± 2.8 Mixed apnea index (events/hour)3.0 ± 3.92.3 ± 3.4 Hypopnea index (events/hour)13.0 ± 11.413.1 ± 11.8Percent of sleep with oxygen saturation < 90% (%)16.5 ± 17.911.2 ± desaturation index ± ± Sleepiness Scale ± ± ventricular ± ± Heart therapy therapy are reported as ± in a are reported as ± In the per protocol 60% of patients in the treatment group of confidence interval CI 47% to 64%) experienced a ≥50% reduction in AHI from baseline to 6 months. At 12 months, the proportion was 67% of CI 53% to The reduction in AHI at 6 months in the treatment group was sustained at 12 months (Table 2). apnea and hypopnea events were observed at 12 months (Table and similar to at 6 months in AHI, central apnea index, and mixed apnea index continued to observed at 12 months (Table 2). was a in from baseline to 12 months in the treatment group (Table 2). Hypopnea events were not scored as central versus it is not if central or obstructive in sleep and quality of life observed at 6 months were not at 12 months (Table 2). effects were (Figure in the through 12 (n = months (n = months (n = Changes from Baseline to 12 months (n = index (events/hour)49.7 ± ± ± ± < from paired for from baseline to 12 apnea index (events/hour)31.7 ± ± ± ± < from paired for from baseline to 12 apnea index (events/hour)2.1 ± ± ± ± < from paired for from baseline to 12 apnea index (events/hour)3.0 ± ± ± ± < from paired for from baseline to 12 index (events/hour)13.0 ± ± ± ± = from Wilcoxon test for from baseline to 12 index ± ± ± ± < from paired for from baseline to 12 of sleep in rapid eye ± ± ± ± = from Wilcoxon test for from baseline to 12 with or improvement in Patient Global patients in to overall as compared to device no or markedly confidence desaturation index ± ± ± ± < from paired for from baseline to 12 with oxygen saturation < 90% (%)16.5 ± ± ± ± < from Wilcoxon test for from baseline to 12 Sleepiness Scale ± ± ± ± < from paired for from baseline to 12 are reported as deviation) and (interquartile range) from paired for from baseline to 12 from Wilcoxon test for from baseline to 12 patients in to overall as compared to device no or markedly in a are reported as deviation) and (interquartile range) of sleep indices and quality of life were also observed after 6 months of active therapy in the former control group therapy was active from 6 to 12 months, the proportion of former control patients who achieved a ≥50% reduction in AHI was 55% of CI 43% to and similar to that observed at 6 months in the treatment group (Figure the baseline to 6-month when the system was not activated in the control group, of control group patients achieved a ≥50% reduction in AHI from baseline to 6 months (Figure M.R. Ponikowski P. Javaheri S. Augostini R. Goldberg L. Holcomb R. Kao A. Khayat R.N. Oldenburg O. Stellbrink C. Abraham W.T. Transvenous neurostimulation for central sleep apnoea: a randomised controlled trial.Lancet. 2016; 388: 974-982Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar The of AHI improvement after 6 months of therapy was similar in the treatment and former control as shown in Figure and and The improvement in quality of life in the former control group by the Patient Global Assessment after 6 months of active therapy is shown in Figure in AHI after 12 months of therapy for each treatment group and 6 months of active therapy for each former control group the shown are from the therapy initiation visit to the 12-month post-therapy initiation visit for each in the treatment group. Patients with any in AHI from baseline are shown in and patients with any in AHI from baseline are shown in the shown are from the 6-month post-therapy initiation visit to the 12-month post-therapy initiation visit for each in the former control group. Patients with any in AHI from baseline are shown in and patients with any in AHI from baseline are shown in Figure of to the The of the are shown in the per protocol population of the original treatment group assessed at 6 and 12 months of active treatment and in the control group at 6 months therapy and former control group after 6 months of active therapy. Patients were in to overall as compared to device no or markedly Figure were reported through 12 months and were to the implant procedure, the or the delivered therapy. of these have been reported.9Costanzo M.R. Ponikowski P. Javaheri S. Augostini R. Goldberg L. Holcomb R. Kao A. Khayat R.N. Oldenburg O. Stellbrink C. Abraham W.T. Transvenous neurostimulation for central sleep apnoea: a randomised controlled trial.Lancet. 2016; 388: 974-982Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar The freedom from serious adverse events to the implantation procedure, the system, or the delivered therapy was of 151, CI to in the M.R. Ponikowski P. Javaheri S. Augostini R. Goldberg L. Holcomb R. Kao A. Khayat R.N. Oldenburg O. Stellbrink C. Abraham W.T. Transvenous neurostimulation for central sleep apnoea: a randomised controlled trial.Lancet. 2016; 388: 974-982Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar The nonserious events through 12 months are in The nonserious were the diaphragm and in from the events are with of the device and the for an The cardiovascular system for the proportion of serious adverse and these are shown by randomized group through 6 months time when the control group was not (Table system serious adverse events through 6 months in the per protocol (N = (N = of heart ventricular in a A was completed by each group after 6 months of active therapy at the of the and Patients were with the remedē System therapy, to have this device implanted In the treatment group with a 6-month visit, of patients CI to In the former control group with a 12-month visit months of active of patients CI 90% to also The of this analysis is that the effectiveness of phrenic nerve stimulation for the treatment of moderate-to-severe CSA at 6 months in the pivotal trial was at 12 months. was no of treatment effect between 6 and 12 months. The sustained was all secondary sleep of sleep and outcomes of 12-month of the pivotal trial are with of the 12-month of the D. Ponikowski P. Augostini R. A. Khayat R. Abraham W.T. Transvenous stimulation of the phrenic nerve for the treatment of central sleep apnoea: 12 with the Heart Fail. 2016; PubMed Scopus (36) Google Scholar The study design of the reproducibility of the treatment effect. At 12 months, after 6 months of active therapy, patients in the former control group a similar to the treatment group all sleep of sleep and sleep and quality of life This the reproducibility of the observed treatment effect in the population This consistency that phrenic nerve stimulation is an therapy for CSA the and No safety The nonserious adverse events reported herein for the first time had impact to the therapy. of effectiveness is essential for any treatment CSA this sleep is to throughout a the durability of any effectiveness clinical and for CSA occurs in patients with and cardiovascular This sleep treatment, and it may contribute to the progression of cardiovascular and associated T. Redline S. R. breathing in Respir Med. 2016; PubMed Scopus Google Scholar not it that and with phrenic nerve stimulation may the associated of or sympathetic oxidative stress, inflammation, and dysfunction, which may also the progression of as heart as previously M.R. Ponikowski P. Javaheri S. Augostini R. Goldberg L. Holcomb R. Kao A. Khayat R.N. Oldenburg O. Stellbrink C. Abraham W.T. Transvenous neurostimulation for central sleep apnoea: a randomised controlled trial.Lancet. 2016; 388: 974-982Abstract Full Text Full Text PDF PubMed Scopus (103) Google Scholar therapies with of that from phrenic nerve stimulation AHI have not improved or the end point of cardiovascular or mortality in patients with D. M. J. P. M. pressure for central sleep apnea and heart Med. PubMed Scopus Google Scholar, M.R. H. C. E. P. H. for central sleep apnea in systolic heart Med. 2015; PubMed Scopus Google Scholar of increased and cardiovascular mortality with M.R. H. C. E. P. H. for central sleep apnea in systolic heart Med. 2015; PubMed Scopus Google Scholar the was in the remedē System Pivotal an of time to for both the treatment and control groups showed no for increased risk of clinical to the impact of CSA and treatment The effectiveness of phrenic nerve stimulation 12 months by the of therapy throughout the night that is not In the pivotal trial, therapy automatically and continued throughout each night the was in a and the of therapy remained at the 6- and 12-month to phrenic nerve stimulation not as as therapy is programmed In 1 analysis of patients with obstructive sleep apnea who were pressure showed that initiated N. M. of in heart J. PubMed Scopus Google Scholar use of 3.4 been reported for pressure therapies in patients with M.R. H. C. E. P. H. for central sleep apnea in systolic heart Med. 2015; PubMed Scopus Google Scholar, M. D. M. J. P. M. C. of central sleep apnea by pressure and in heart a post analysis of the for Patients with Central Sleep and Heart trial 2007; PubMed Scopus Google Scholar and this of use M.R. H. C. E. P. H. for central sleep apnea in systolic heart Med. 2015; PubMed Scopus Google Scholar, N. M. H. R. M. with pressure in patients with obstructive sleep Respir J. PubMed Scopus Google Scholar of phrenic nerve stimulation have the results of the Patient Global Assessment or Epworth Sleepiness the consistency between improvement in sleep and outcomes is both and of the clinical of the effects of phrenic nerve of CSA with phrenic nerve stimulation sleep indices and health-related quality of life for at least 12 months with no that the effectiveness This is this therapy is for treatment of CSA. and were also the 12-month with no of safety through 12 months of was in the former control group when therapy was initiated at 6 months, which a treatment effect. the of the D. Ponikowski P. Augostini R. A. Khayat R. Abraham W.T. Transvenous stimulation of the phrenic nerve for the treatment of central sleep apnoea: 12 with the Heart Fail. 2016; PubMed Scopus (36) Google Scholar and phrenic nerve stimulation as an and treatment to sleep indices and in patients with CSA. The for who was by and the and of from and study for remedē System Pivotal Ponikowski from and and from and Javaheri from and Committee Augostini from of and from Goldberg from and from and Holcomb from for statistical and review of study Kao to from to the Oldenburg for from and and from Stellbrink from Inc., and and is an of T. Abraham to from and from The no of to The is the data to this with and
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