Nervus phrenicus stimulatie bij CSA
Uitgangsvraag
Wat is de rol van nervus phrenicus stimulatie in de behandeling van CSA patiënten?
Aanbeveling
Behandel niet standaard met nervus phrenicus stimulatie* bij patiënten met een symptomatisch CSA.
Overweeg nervus phrenicus stimulatie* alleen bij patiënten met een symptomatisch CSA ondanks cardiale optimalisatie, die eerder gefaald hebben op CPAP, zuurstof en ASV.
*Ten tijde van de ontwikkeling van de richtlijn is dit nog geen vergoede zorg.
Overwegingen
Balans tussen voor- en nadelen van de interventie
De literatuuranalyse is gebaseerd op één RCT (Costanzo 2016). Op basis van de samengevatte literatuur is het momenteel te onzeker om een definitieve conclusie te trekken over de effecten van nervus phrenicus stimulatie. Er lijkt mogelijk een voordeel te zijn ten aanzien van de AHI-score, de ESS-score en de PGA score in vergelijking met placebo/geen interventie, echter met zeer lage bewijskracht (131 patiënten).
Wat betreft de cruciale uitkomstmaat, de apneu-hypopneu-index (AHI), lieten 35 van de 68 patiënten (51%) in de interventiegroep een reductie van ≥50% in AHI zien ten opzichte van de uitgangswaarde. In de interventiegroep daalde de gemiddelde AHI van 31,7 (SD 18,6) bij baseline naar 6,0 (SD 9,2) na een follow-up periode van zes maanden. In de controlegroep werd deze reductie van ≥50% in AHI t.o.v. de uitgangswaarde gezien bij 8 van de 73 patiënten (11%). In de controlegroep daalde de gemiddelde AHI van 26,2 (SD 1,2) bij baseline naar 23,3 (SD 18,0) na een follow-upperiode van zes maanden. Ondanks dat de AHI aanzienlijk is, is deze daling niet klinisch relevant, met een zeer lage bewijskracht.
De impact op kwaliteit van leven werd door Costanzo (2016) onderzocht na zes maanden. Op de ESS-score werd een klinisch relevante verbetering waargenomen in de nervus phrenicus stimulatie groep. Op de PGA-score rapporteerde 60% van de patiënten in de interventiegroep een matige of aanzienlijke verbetering, tegenover slechts 6% in de controlegroep. Ook hier geldt dat het bewijs van zeer lage kwaliteit is.
Daarnaast zijn er meerdere resultaten uit de remedē studie gepubliceerd waarin kwaliteit van leven een belangrijke uitkomstmaat vormt. Een publicatie van Costanzo uit 2018 (remedē trial) liet zien dat de score op de Minnesota Living with Heart Failure Questionnaire (MLHFQ) significant verbeterde van baseline tot 12 maanden (-6.8 ± 20.0; p = 0.005). De netwerk meta-analyse van Iftikhar (2022) toonde bovendien aan dat nervus phrenicus stimulatie, naast adaptieve servo-ventilatie (ASV), één van de meest effectieve behandelingen is voor CSA bij patiënten met hartfalen, met name wat betreft AHI en ESS.
Tot slot voerde Hill (2023) een post-hoc analyse uit onder deelnemers van de remedē studie, waarbij patiënten vragenlijsten invulden. Hierbij werden symptomen en uitkomsten op drie gevalideerde vragenlijsten geëvalueerd. Na 12 maanden werd het aandeel patiënten berekend dat verbetering, geen verandering of verslechtering rapporteerde. De meest voorkomende klachten bij aanvang waren vermoeidheid en slaperigheid overdag. Na 12 maanden behandeling met nervus phrenicus stimulatie werd afname van klachten gezien: 45% van de patiënten gaf aan geen last meer te hebben van slaperigheid overdag, 44% ervoer geen vermoeidheid of zwakte meer en 52% had geen problemen meer met in- of doorslapen. Daarnaast rapporteerde minimaal 60% van de patiënten een betere slaapkwaliteit en gaf deze groep aan niet meer te snurken. In een andere post-hoc analyse van de remedē studie werden 91 patiënten met hartfalen en centrale slaapapneu geïncludeerd (43 behandeld met nervus phrenicus stimulatie en 48 controles) (Abraham 2024). Na zes maanden hadden patiënten behandeld met nervus phrenicus stimulatie een significant grotere kans op een gunstige klinische uitkomst dan controles (win ratio 4,92; 95% BI 2,27; 10,63; p<0,0001). De win ratio is een hiërarchische samengestelde uitkomstmaat voor klinisch voordeel. In deze studie bestond dit uit sterfte, ziekenhuisopnames wegens hartfalen en gezondheidsstatus. Deze gunstige uitkomst werd voornamelijk bepaald door minder ziekenhuisopnames wegens hartfalen en een betere door patiënten gerapporteerde gezondheidstoestand.
Zeven (9%) gevallen van ernstige therapiegerelateerde bijwerkingen traden op in de controlegroep en zes (8%) in de behandelgroep (Costanzo 2016). Zeven patiënten overleden door oorzaken die niet gerelateerd waren aan het implantaat, het systeem of de therapie: vier overlijdens tijdens de 6 maanden durende randomisatieperiode (twee in de behandelgroep en twee in de controlegroep) en drie overlijdens tussen 6 en 12 maanden follow-up, toen alle patiënten neurostimulatie ontvingen. Daarnaast meldden 27 (37%) van de 73 patiënten in de behandelgroep niet-ernstig therapiegerelateerd ongemak, dat bij 26 (36%) patiënten werd opgelost door eenvoudige herprogrammering van het systeem, maar bij één (1%) patiënt aanhield.
Op basis van de evidentie van één RCT en de prospectieve observationele studies concludeerde de American Academy of Sleep Medicine (AASM) in 2025 dat nervus phrenicus stimulatie klinisch significante verbeteringen liet zien in overmatige slaperigheid, ziekte-ernst (CAI) en cardiovasculaire uitkomsten (6MWD), maar geen effect op sterfte en linkerventrikel-ejectiefractie (LVEF) (Badr 2025).
In de AASM-guideline resulteerde dit in een voorwaardelijke aanbeveling voor het gebruik van nervus phrenicus stimulatie boven geen behandeling met nervus phrenicus stimulatie bij volwassenen met primaire CSA of CSA ten gevolge van hartfalen, waarbij de zekerheid van het bewijs als zeer laag werd beoordeeld (Badr 2025). Hierbij geciteerd:
“The AASM suggests using transvenous phrenic nerve stimulation over no transvenous phrenic nerve stimulation in adults with CSA due to the following etiologies: primary CSA and CSA due to heart failure. (Conditional recommendation, very low certainty of evidence)
Remarks: Given that transvenous phrenic nerve stimulation requires an invasive procedure, is not universally accessible, and is associated with high costs, it may be more appropriate to consider other treatments first.” (Badr, 2025)
De AASM plaatste hierbij dus de kanttekening dat nervus phrenicus stimulatie een invasieve behandeling betreft, niet overal beschikbaar is en gepaard gaat met aanzienlijke kosten. Daarnaast vereist implementatie gespecialiseerde infrastructuur en expertise van zowel cardiologen als slaapspecialisten.
De beschikbare literatuur en de AASM-richtlijn suggereren dat nervus phrenicus stimulatie vooral een plaats heeft bij patiënten met primaire CSA of CSA ten gevolge van hartfalen die ondanks optimale behandeling van de onderliggende aandoening persisterende klachten houden en bij wie andere behandelopties onvoldoende effectief, niet verdragen of niet geschikt zijn. Vanwege het invasieve karakter van de behandeling, de beperkte beschikbaarheid, de benodigde expertise en de hoge kosten beschouwt de de werkgroep nervus phrenicus stimulatie niet als eerstelijnsbehandeling, maar als een behandeloptie voor zorgvuldig geselecteerde patiënten met een hoge klachtenlast bij wie overige therapieen gefaald hebben. De ideale kandidaat heeft daarbij overwegend centrale ademhalingsevents en weinig obstructieve apneus.
Kwaliteit van bewijs
De overall kwaliteit van bewijs is zeer laag. Dit betekent dat we zeer onzeker zijn over het gevonden geschatte effect van de interventie op de cruciale uitkomstmaten.
Er is afgewaardeerd vanwege:
- Risk of Bias: in- en exclusiecriteria en mogelijke belangenverstrengelingen (2 niveaus).
- Imprecisie: onnauwkeurigheid door klein aantal geïncludeerde studies en participanten (1 niveau).
Waarden en voorkeuren van patiënten
Centraal slaapapneu (CSA) verstoort veelal de slaap en zal daardoor het dagelijks functioneren van patiënten beïnvloeden. Hoewel CSA bij meerdere ziektebeelden voorkomt is de prevalentie van CSA met name hoog bij patiënten bij hartfalen. Nervus phrenicus stimulatie laat een significante reductie zien ten opzichte van geen behandeling en zou van toegevoegde waarde kunnen zijn indien er PAP-intolerantie is dan wel werkzaamheidsfalen CPAP en een contra-indicatie voor ASV.
Kostenaspecten
De interventie leidt tot meer kosten ten opzichte van de huidige zorg. De werkgroep heeft dit verschil in kosten meegewogen en is van mening dat de kosten van nervus phrenicus stimulatie alleen te rechtvaardigen zijn bij patiënten met CSA en persisterende klachten waarbij alle andere interventies gefaald hebben. De totale kosten voor een nervus phrenicus implantaat worden in het eerste jaar geschat op circa €59.560 per patiënt.
Gezondheidsgelijkheid ((health) equity/equitable)
De interventie leidt tot een mogelijk afname van gezondheidsgelijkheid omdat de behandeling niet tot de reguliere verzekerde zorg behoort.
Aanvaardbaarheid
Ethische aanvaardbaarheid
De interventie is aanvaardbaar voor de betrokkenen. Er zijn geen ethische bezwaren voor het starten van deze behandeling aangezien het wordt gereserveerd voor een groep patiënten waarin andere behandelingen niet effectief zijn gebleken.
Duurzaamheid
Bij de productie en het uitzetten van medische apparatuur voor nervus phrenicus stimulatie spelen duurzaamheidsaspecten een rol. Maar omdat de werkgroep onvoldoende inzicht heeft in de duurzaamheidsaspecten die spelen rond nervus phrenicus stimulatie is dit aspect niet meegenomen in de formulering van de aanbevelingen.
Haalbaarheid
De haalbaarheid van nervus phrenicus stimulatie wordt laag ingeschat om meerdere redenen:
- er bestaat onzekerheid over het geschatte effect van de interventie op de belangrijkste uitkomstmaten;
- ten tijde van het opstellen van deze richtlijn valt deze behandeling niet onder de reguliere verzekerde zorg en is daarom geen onderdeel van het verzekerde pakket.
Rationale van de aanbeveling: weging van argumenten voor en tegen de interventies
Nervus phrenicus stimulatie leidt in één RCT tot een klinisch relevante daling van de ESS score en de Patient Global Assessment (PGA). Daarnaast liet de AHI een daling zien ten gunste van patiënten met nervus phrenicus stimulatie.
Daarnaast liet een prospectieve, open-labelstudie zien dat nervus phrenicusstimulatie leidde tot een verbetering van de 6-minutenloopafstand (6MWD) en en de mate van hypoxemie verbeterde. Hoewel de bewijskracht beperkt is, kan nervus phrenicusstimulatie worden overwogen bij patiënten met symptomatische CSA bij wie eerdere behandeling met CPAP, zuurstoftherapie en ASV onvoldoende effect heeft gehad en bij wie andere behandelopties onvoldoende effectief zijn, niet verdragen worden of niet geschikt zijn.
Eindoordeel:
Zwakke aanbeveling tegen.
Onderbouwing
Central sleep apnea (CSA) can be managed using various approaches including CPAP, medication, supplemental oxygen, and adaptive servo-ventilation (ASV). However, these treatments are not always effective due to incomplete apnea/hypopnea-reduction, PAP-intolerance and/or contraindications. In symptomatic patients there is therefore a need for additional treatment options. Nervus phrenicus stimulation (NPS) is a novel treatment comprised of an implantable pulse generator, a stimulation lead for unilateral phrenic nerve stimulation, an optional sensing lead to detect respirations and a programmer. The generator provides an electrical stimulus to the left or right phrenic nerve and monitors the patient’s respiration using transthoracic impedance. Stimulation of the left or right phrenic nerve causes the diaphragm to contract, thereby developing negative intrathoracic pressure and restoring regular breathing pattern.
|
Outcome
|
Study results and measurements |
Absolute effect estimates |
Certainty of the evidence (Quality of evidence) |
Summary |
|
|
Control |
N. phrenicus stimulation |
||||
|
Apnea-hypopnea index (crucial) |
Based on data from 131 participants in 1 RCT
|
Mean (±SD): 1.1 (17.6) |
Mean (±SD): -23.9 (18·6) |
Very low Due to serious risk of bias, Due to very serious imprecision1 |
The evidence is very uncertain about the effect of N. phrenicus stimulation on apnea-hypopnea index when compared with placebo in patients with central sleep apnea.
(Costanzo 2016) |
|
Between groep difference: -25 (18.1) |
|||||
|
Cardiovascular mortality (crucial) |
- |
- |
No GRADE (no evidence was found) |
No evidence was found regarding the effect of N. phrenicus stimulation on cardiovascular mortality when compared with no treatment in patients with central sleep apnea. |
|
|
All-cause mortality
|
- |
- |
No GRADE (no evidence was found) |
No evidence was found regarding the effect of N. phrenicus stimulation on all-cause mortality when compared with no treatment in patients with central sleep apnea. |
|
|
Epworth Sleepiness Scale score (ESS) |
Based on data from 131 participants in 1 RCT
Lower score = less daytime sleepiness (better)
|
Mean (±SD): 9.4 (±6.1) |
Mean (±SD): 7.1 (±4.1) |
Very low Due to serious risk of bias, Due to very serious imprecision2 |
The evidence is very uncertain about the effect of N. phrenicus stimulation on the Epworth Sleepiness Scale score (ESS) when compared with placebo in patients with central sleep apnea.
(Costanzo 2016)
|
|
Between-group difference: -3.7 (± 5.0) |
|||||
|
Patient global assessment (PGA) |
Based on data from 130 participants in 1 study
% reporting a markedly or moderately improvement
|
6% (95% CI 2 to 14) |
60% (95% CI 47 to 73) |
Very low Due to serious risk of bias, Due to very serious imprecision3 |
The evidence is very uncertain about the effect of N. phrenicus stimulation on the patient global assessment (PGA) when compared with placebo in patients with central sleep apnea.
(Costanzo 2016)
|
|
Absolute difference: 55% (40–68) |
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1Risk of Bias: serious. Strong involvement of industry; Imprecision: serious. Low number of patients and only one study reported on the outcome.
2Risk of Bias: serious. Strong involvement of industry; Imprecision: serious. Low number of patients and only one study reported on the outcome.
3Risk of Bias: serious. Strong involvement of industry; Imprecision: serious. Low number of patients and only one study reported on the outcome
Description of studies
One randomized controlled trial (RCT) was included in the analysis of the literature. Important study characteristics and results are summarized in table 2. The assessment of the risk of bias is summarized in the risk of bias tables (under the tab ‘Evidence tabellen’).
Costanzo (2016) conducted a prospective, multicenter, randomized controlled trial to evaluate the safety and efficacy of transvenous phrenic nerve stimulation for the treatment of severe CSA. Adult patients with predominantly central apneas were eligible for inclusion. This included [1] apnea-hypopnea index (AHI) ≥20 events/hour, [2] ≥50% of all apneas being central in nature, [3] ≥30 central nightly apnea events, and [4] maximum of 20% of the total AHI being obstructive apnea index. Key exclusion criteria included obstructive sleep apnea as the predominant sleep disordered breathing, recent myocardial infarction or cardiac surgery, severe chronic obstructive pulmonary disease, and conditions preventing implantation of the stimulation system. Participants were randomized to either immediate activation of the implanted transvenous neurostimulation device or to a control group with immediate implantation of the transvenous neurostimulation device and delayed activation after six months. The primary efficacy endpoint was the reduction in AHI at six months, assessed by polysomnography.
Table 2. Characteristics of included studies
|
Study |
Participants |
Comparison |
Follow-up |
Outcome measures |
Comments |
Risk of bias (per outcome measure)* |
|
Costanzo, 2016 |
N at baseline Intervention: 73 Control: 78
Age (mean, SD) Intervention: 65 (12) Control: 65 (13)
Sex (male %) Intervention: 63% Control: 72%
BMI (mean, SD) Intervention: 30.8 (5.3) Control: 31.3 (6.6)
AHI events per h, baseline (mean, SD) Intervention: 48.8 (19.3) Control: 43.7 (16.8)
Left ventricular ejection fraction (mean, SD) Intervention: 39.7 (12.1) Control: 39.4 (12.2) |
Intervention group:
Intervention group: All patients underwent implantation of the remedē® system, consisting of a pulse generator (similar to a cardiac pacemaker), a stimulation lead positioned in the pericardiophrenic or brachiocephalic vein to stimulate the phrenic nerve, and a sensing lead placed in a thoracic vein (e.g., the azygos vein) to detect respiration via thoracic impedance. In the intervention group, the system was activated one month after implantation. Night-time stimulation was delivered automatically according to a proprietary algorithm, and stimulation intensity was gradually increased over approximately 12 weeks until consistent diaphragmatic capture was achieved without disrupting sleep.
Control group: Patients in the control group also received implantation of the remedē® system; however, the device remained inactive during the first 6 months (the effectiveness assessment phase). After completion of the 6-month evaluation, therapy was activated and continued until the end of the trial. |
6 months |
Primary outcome: Reduction of AHI by 50%.
Secondary outcomes: If a 50% reduction in AHI was achieved, quality of life (QoL) was assessed. |
The funders of the study contributed to the study design and data interpretation.
9 out of 11 authors reported funding from Respicardia Inc. |
Strong concerns about potential risk of bias, due to grants and fees received by the authors from Respicardia Inc. and contribution of funders to study design.
Respicardia Inc. funded the study.
Inclusion and exclusion criteria: only patients who had a successful implantation were included |
AHI: Apnea-hypopnea index. CSA: Central sleep apnea. AASM: American Academy of Sleep Medicine. SD: standard deviation.
*For further details, see risk of bias table in the appendix
Results
Apnea-hypopnea index (AHI)
Costanzo reported a reduction in mean AHI from 49.7 events/hour at baseline to 25.9 events/hour at 6 months in the intervention group, corresponding to a 48% reduction. This reduction did not reach the predefined threshold for clinical relevance of ≥50%. Therefore, the effect was not considered clinically relevant.
Cardiovascular mortality
This included study did not report on cardiovascular mortality.
All-cause mortality
This included study did not report on all-cause mortality.
Symptoms
Epworth Sleepiness Scale (ESS), daytime sleepiness
Costanzo (2016) reported an improvement in the intervention group on the Epworth Sleepiness Scale (ESS) score after 6 months of follow-up. The ESS score improved in the intervention group from baseline 10.7 (±5.3) to 7.1 (±4.1) after 6 months. The ESS score in the control group showed a minor change from baseline 9.3 (±5.7) to 9.4 (±6.1) after 6 months.
The mean (±SD) between group difference 6 months’ follow-up was -3.7 (± 5.0). This difference was considered clinically relevant.
Quality of life
Patient global assessment (PGA)
The Patient Global Assessment (PGA) is a subjective, patient-reported outcome measure (PROM) where patients rate their overall disease activity or health status, typically over the past week.
In the intervention group, 35 out of 58 patients reported a markedly or moderately improved PGA (60%, 95% CI 47 to 73). In the control group, 4 out of 72 patients reported a markedly of moderately improved PGA (6%, 95% CI 2 to 14).
A systematic review of the literature was performed to answer the following question(s):
What is the effectiveness of phrenic nerve stimulation compared to standard care on AHI, QoL and mortality in patients with CSA?
Table 1. PICO
|
Patients |
Adult patients with central sleep apnea (CSA) |
|
Intervention |
Treatment with nervus phrenicus stimulation |
|
Control |
No treatment |
|
Outcomes |
Apnea-hypopnea Index (AHI), cardiovascular mortality, all-cause mortality, symptoms, quality of life |
|
Other selection criteria |
Study design: systematic reviews and randomized controlled trials.
Age range: 18+ |
Relevant outcome measures
The guideline panel considered apnea-hypopnea index (AHI), cardiovascular mortality and all-cause mortality as critical outcome measures for clinical decision making; and symptoms and quality of life as an important outcome measure for clinical decision making.
A priori, the guideline panel did not define the outcome measures listed above but used the definitions used in the studies.
The guideline panel defined the following values per outcome as a minimal clinically (patient) important difference.
- Apnea-hypopnea index (AHI): decrease by 50%;
- Cardiovascular mortality: Risk difference of 5% (0.95≥RR≥1.05);
- All-cause mortality: Risk difference of 5% (0.95≥RR≥1.05);
- Symptoms: Difference of ≥ 2 points on the ESS score;
- Quality of life (QoL): Patient Global Assessment (PGA) Difference of ≥ 2 points.
Search and select (Methods)
A systematic literature search was performed by a medical information specialist using the following bibliographic databases: Embase.com and Ovid/Medline. Both databases were searched from 2005 to May 2025 for systematic reviews and RCTs. Systematic searches were completed using a combination of controlled vocabulary/subject headings (e.g., Emtree-terms, MeSH) wherever they were available and natural language keywords. The overall search strategy was derived from two primary search concepts: (1) central sleep apnea (2) N. phrenicus stimulation. Duplicates were removed using EndNote software. After deduplication a total of 248 records were imported for title/abstract screening. Initially, 74 studies were selected based on title and abstract screening. After reading the full text, 73 studies were excluded (see the exclusion table under the tab ‘Evidence tables’), and one study was included.
- Abraham WT, Oldenburg O, Lainscak M, Khayat R, Asin J, Ponikowski P, Germany R, McKane S, Costanzo MR. Win ratio analysis of transvenous phrenic nerve stimulation to treat central sleep apnoea in heart failure. ESC Heart Fail. 2025 Feb;12(1):80-86. doi: 10.1002/ehf2.15074. Epub 2024 Oct 18. PMID: 39422417; PMCID: PMC11769632.
- Badr MS, Khayat RN, Allam JS, Hyer S, Mustafa RA, Naughton MT, Patil S, Pien GW, Randerath W, Won C. Treatment of central sleep apnea in adults: an American Academy of Sleep Medicine clinical practice guideline. J Clin Sleep Med. 2025 Dec 1;21(12):2181-2191. doi: 10.5664/jcsm.11858. PMID: 40820608; PMCID: PMC12670627.
- Costanzo MR, Ponikowski P, Javaheri S, Augostini R, Goldberg L, Holcomb R, Kao A, Khayat RN, Oldenburg O, Stellbrink C, Abraham WT; remedé System Pivotal Trial Study Group. Transvenous neurostimulation for central sleep apnoea: a randomised controlled trial. Lancet. 2016 Sep 3;388(10048):974-82. doi: 10.1016/S0140-6736(16)30961-8. Epub 2016 Sep 1. PMID: 27598679.
- Costanzo MR, Ponikowski P, Coats A, Javaheri S, Augostini R, Goldberg LR, Holcomb R, Kao A, Khayat RN, Oldenburg O, Stellbrink C, McKane S, Abraham WT; remedē® System Pivotal Trial Study Group. Phrenic nerve stimulation to treat patients with central sleep apnoea and heart failure. Eur J Heart Fail. 2018 Dec;20(12):1746-1754. doi: 10.1002/ejhf.1312. Epub 2018 Oct 10. PMID: 30303611; PMCID: PMC6607512.
- Hill L, Meyer T, McKane S, Lainscak M, Ahmed QA. Transvenous phrenic nerve stimulation to treat central sleep apnoea in patients with heart failure may improve sleep, quality of life, and symptoms. Eur J Cardiovasc Nurs. 2023 Jul 19;22(5):489-497. doi: 10.1093/eurjcn/zvac086. PMID: 36125322.
- Iftikhar IH, Khayat RN. Central sleep apnea treatment in patients with heart failure with reduced ejection fraction: a network meta-analysis. Sleep Breath. 2022 Sep;26(3):1227-1235. doi: 10.1007/s11325-021-02512-y. Epub 2021 Oct 26. PMID: 34698980.
Risk of Bias tables
|
Study reference
(first author, publication year) |
Was the allocation sequence adequately generated?
Definitely yes Probably yes Probably no Definitely no |
Was the allocation adequately concealed?
Definitely yes Probably yes Probably no Definitely no |
Blinding: Was knowledge of the allocated interventions adequately prevented?
Were patients blinded?
Were healthcare providers blinded?
Were data collectors blinded?
Were outcome assessors blinded?
Were data analysts blinded?
Definitely yes Probably yes Probably no Definitely no |
Was loss to follow-up (missing outcome data) infrequent?
Definitely yes Probably yes Probably no Definitely no |
Are reports of the study free of selective outcome reporting?
Definitely yes Probably yes Probably no Definitely no |
Was the study apparently free of other problems that could put it at a risk of bias?
Definitely yes Probably yes Probably no Definitely no |
Overall risk of bias If applicable/necessary, per outcome measure
LOW Some concerns HIGH
|
|
Costanzo, 2016 |
Probably yes
The randomisation schedule was loaded into the electronic data capture system as prepared by an independent, third-party statistician (Manya R Harsch, MS of Technomics Research, LLC, Minneapolis MN, USA). |
Probably yes
Random assignment of patients was based on computer-generated random numbers stratifi ed by site with random blocks of size two and four within each site. |
Definitely yes
Although patients and physicians were aware of treatment assignment, the polysomnography core laboratory remained masked throughout the study. Patients and physicians were aware of treatment assignment when the health-related qualityof-life assessments were completed. |
Definitely yes
Five patients were excluded in the intervention group (2 unrelated deaths, 1 patient exited study, 1 missed visit, 1 medical issues) and five in de control group (2 unrelated deaths, 2 patient exited study, 1 lost to follow-up) |
Unclear
Study protocol was published earlier (Costanzo 2015) |
Probably yes
Many authors of the study report grants (4 authors) and fees from Respicardia (6authors) and some were part of the advisory board. |
Some concerns
|
Table of excluded studies
|
Reference |
Reason for exclusion |
|
Luni FK, Daniels J, Link MS, Joglar JA, Zungsontiporn N, Wu R, et al. Meta-analysis of usefulness of phrenic nerve stimulation in central sleep apnea. Am J Cardiol. 2020;125(11):1738-1744. doi:10.1016/j.amjcard.2020.02.012. |
Comparison is no stimulation. Remaining individual studies still need to be checked for overlap with the search. |
|
Iftikhar IH, Khayat RN. Central sleep apnea treatment in patients with heart failure with reduced ejection fraction: a network meta-analysis. Sleep Breath. 2022;26:1227-1235. doi:10.1007/s11325-021-02512 y. |
The only study that included PNS is Costanzo et al. (2016). |
|
Fox H, Oldenburg O, Javaheri S, Ponikowski P, Augostini R, Stellbrink C, et al. Long-term efficacy and safety of phrenic nerve stimulation for the treatment of central sleep apnea. Sleep. 2019;42(11):zsz158. doi:10.1093/sleep/zsz158. |
Also uses the remedē System Pivotal Trial (long-term follow-up). |
|
Jagielski D, Ponikowski P, Augostini R, Kolodziej A, Khayat RN, Abraham WT, et al. Transvenous stimulation of the phrenic nerve for the treatment of central sleep apnoea: 12 months' experience with the remede System. Eur J Heart Fail. 2016;18(11):1386-1393. doi:10.1002/ejhf.593. |
Non-randomized, open-label, prospective pilot study without a control group (transvenous phrenic nerve stimulation); no comparison. |
|
Costanzo MR, Ponikowski P, Javaheri S, Augostini R, Goldberg L, Holcomb R, et al. Sustained 12 month benefit of phrenic nerve stimulation for central sleep apnea. Am J Cardiol. 2018;121(11):1400-1408. doi:10.1016/j.amjcard.2018.02.022. |
Also uses the remedē System Pivotal Trial (follow-up of the 2016 study). |
|
Costanzo MR, Javaheri S, Ponikowski P, Augostini R, Goldberg LR, Holcomb RG, et al. Transvenous phrenic nerve stimulation for treatment of central sleep apnea: five-year safety and efficacy outcomes. Nat Sci Sleep. 2021;13:515-526. doi:10.2147/NSS.S300713. |
Also uses the remedē System Pivotal Trial (observational study up to 5 years). |
|
Potratz M, Fox H, Oldenburg O, Bitter T, Horstkotte D, Gutleben KJ, et al. Phrenic nerve stimulation improves physical performance and hypoxemia in heart failure patients with central sleep apnea. J Clin Med. 2021;10(2):202. doi:10.3390/jcm10020202. |
Prospective open-label study without a control group. |
|
Baumert M, Hartmann S, Krachman S, Oldenburg O, Augostini R, Abraham WT, et al. Transvenous phrenic nerve stimulation for the treatment of central sleep apnea reduces episodic hypoxemic burden. Int J Cardiol. 2023. doi:10.1016/j.ijcard.2023.02.041. |
Also uses the remedē System Pivotal Trial (reanalysis with physiological markers). |
|
Wang X, Fox H, Schulz R, Oldenburg O, Bitter T, Horstkotte D, et al. Phrenic nerve stimulation for the treatment of central sleep apnea in patients with heart failure. Sleep Breath. 2023. doi:10.1007/s11325-022-02699-8. |
Prospective, non-randomized, open-label study without a control group. |
|
Sagalow B, Tang WHW, Fudim M. Transvenous phrenic nerve stimulation for central sleep apnea. Am J Cardiol. 2022. doi:10.1016/j.amjcard.2022.06.038. |
Combination of studies, including studies that do not meet our PICO. Relevant study (Costanzo, 2016) already included in the full-text selection. It is unclear which studies lack a control group (not consistently reported in tables); needs to be checked later whether all studies from the search were identified and whether overlap exists. Multiple publications are based on the same trial. |
|
Wang Y, Li X, Zhou J, Chen L, Wang Z, Liu Y, et al. Effect of phrenic nerve stimulation on patients with central sleep apnea: a meta-analysis. Sleep Med Rev. 2023;70:101819. doi:10.1016/j.smrv.2023.101819. |
Includes both RCTs and observational studies. Three RCTs potentially relevant: Costanzo et al. (2016); Costanzo et al. (2018); Oldenburg et al. (2021) (already included in full-text selection). |
|
Fox H, Bitter T, Horstkotte D, Oldenburg O. Long-term experience with first-generation implantable neurostimulation device in central sleep apnea treatment. Pacing Clin Electrophysiol. 2017. doi:10.1111/pace.13049. |
Small case series (n=3), no control group; evaluates effectiveness of remedē therapy during battery replacement. |
|
Costanzo MR, Javaheri S, Ponikowski P, Augostini R, Goldberg LR, Holcomb RG, et al. Phrenic nerve stimulation to treat patients with central sleep apnoea and heart failure. Eur J Heart Fail. 2018. doi:10.1002/ejhf.1312. |
Also uses the remedē System Pivotal Trial (post-hoc analysis; subgroup with CSA and heart failure). |
|
Costanzo MR, Khayat R, Ponikowski P, Augostini R, Stellbrink C, Mianulli M, et al. Central sleep apnea in patients with heart failure-how to screen, how to treat. Curr Heart Fail Rep. 2020;17(5):277-287. doi:10.1007/s11897-020-00472-0. |
Narrative review describing the remedē System Pivotal Trial. |
|
Javaheri S, Abraham WT, Oldenburg O, Augostini R, Khayat R, Goldberg LR, et al. Transvenous phrenic nerve stimulation to treat idiopathic central sleep apnea. J Clin Sleep Med. 2020. doi:10.5664/jcsm.8802. |
Also uses the remedē System Pivotal Trial; subanalysis in idiopathic CSA (ICSA). |
|
Oldenburg O, Costanzo MR, Germany R, McKane S, Abraham WT. Improving nocturnal hypoxemic burden with transvenous phrenic nerve stimulation for the treatment of central sleep apnea. Heart Lung Circ. 2020. doi:10.1007/s12265-020-10061-0. |
Post-hoc analysis of the remedē System Pivotal Trial; includes additional information on oxygen saturation (T90). |
|
Voigt J, Emani S, Gupta S, Germany R, Khayat R. Meta-analysis comparing outcomes of therapies for patients with central sleep apnea and heart failure with reduced ejection fraction. Am J Cardiol. 2020;127:73-83. doi:10.1016/j.amjcard.2020.04.011. |
Systematic review/meta-analysis: RCTs comparing therapies or placebo; untreated control groups defined as GDMT. Of the 12 included studies, only Costanzo et al. (2016) evaluated PNS. |
|
Hill NS, Costanzo MR, Goldberg LR, Abraham WT, Ponikowski P, Augostini R, et al. Transvenous phrenic nerve stimulation to treat central sleep apnoea in patients with heart failure may improve sleep, quality of life, and symptoms. Eur J Cardiovasc Nurs. 2023. doi:10.1093/eurjcn/zvac086. |
Also uses the remedē System Pivotal Trial; subgroup of 75 patients with CSA and heart failure; post-hoc analysis without a control group. |
|
Ponikowski P, Javaheri S, Michalkiewicz D, Bart BA, Czarnecka D, Jastrzebski M, et al. Transvenous phrenic nerve stimulation for the treatment of central sleep apnoea in heart failure. Eur Heart J. 2012;33(7):889-894. doi:10.1093/eurheartj/ehr298. |
Small feasibility study (n=16), within-subject comparison; non-randomized. |
|
Zhang XL, Ding N, Wang H, Li X, Wang D, Xu H, et al. Transvenous phrenic nerve stimulation in patients with Cheyne-Stokes respiration and congestive heart failure: a safety and proof-of-concept study. Chest. 2012. doi:10.1378/chest.11-1899. |
Short-term, prospective, open-label, non-randomized feasibility study; patients served as their own control. |
|
Abraham WT, Jagielski D, Oldenburg O, Augostini R, Krueger S, Kolodziej A, et al. Phrenic nerve stimulation for the treatment of central sleep apnea. JACC Heart Fail. 2015. doi:10.1016/j.jchf.2014.12.013. |
Prospective, multicenter, non-randomized study. |
|
Schwartz AR, Fox H, Oldenburg O, Javaheri S, Ponikowski P, Augostini R, et al. Transvenous phrenic nerve stimulation improves central sleep apnea, sleep quality, and quality of life regardless of prior positive airway pressure treatment. Sleep Breath. 2021. doi:10.1007/s11325-021-02335-x. |
Also uses the remedē System Pivotal Trial; subgroup of 56 patients with prior PAP use. |
|
Baumert M, Hartmann S, McKane S, Abraham WT, Augostini R, Goldberg LR, et al. Transvenous phrenic nerve stimulation is associated with normalization of nocturnal heart rate perturbations in patients with central sleep apnea. Sleep. 2023. doi:10.1093/sleep/zsad166. |
Also uses the remedē System Pivotal Trial; subgroup of 48 patients with outcome nocturnal heart rate perturbations (not relevant for this module). |
|
Murtaza G, Sharma S, Parikh V, Akella K, Khalid M, Khan MS, et al. Pacing therapies for sleep apnea and cardiovascular outcomes: a systematic review. J Interv Card Electrophysiol. 2021. doi:10.1007/s10840-020-00760-8. |
Included studies: Costanzo et al. (2016); Costanzo et al. (2018); Jagielski et al. (2016); Woodson et al. (2018); Zhu et al. (2018); Zhang et al. (2017). Woodson (2018) and Zhu (2018) evaluate hypoglossal nerve stimulation; relevant PNS studies already identified in our search. |
|
Jagielski D, Ponikowski P, Augostini R, Kolodziej A, Khayat RN, Abraham WT, et al. Phrenic nerve stimulation in patients with central sleep apnea: a single-center experience from pilot and pivotal trials evaluating the remede System. Kardiol Pol. 2019. doi:10.5603/KP.a2019.0061. |
Also uses the remedē System Pivotal Trial; retrospective analysis. |
|
Mease J, Patel A, Grigsby M, Singh P, Abraham WT, Walia H. Phrenic nerve stimulation for central sleep apnea: a single institution experience. Sleep Breath. 2024. doi:10.1007/s11325-024-03125-x. |
Also uses the remedē System Pivotal Trial; analysis of changes in LVEF. |
|
Azarbarzin A, Sands SA, Abraham WT, Javaheri S, Oldenburg O, Costanzo MR, et al. Determinants of transvenous phrenic nerve stimulation-induced improvements in LV function in central sleep apnea and heart failure. Sleep. 2025. doi:10.1093/sleep/zsaf085. |
Review (wrong design). |
|
Joseph V, Javaheri S. A novel therapeutic approach for central sleep apnea: phrenic nerve stimulation by the remede System. Int J Cardiol. 2016. doi:10.1016/j.ijcard.2016.02.121. |
Pooled cohort analysis (wrong design). |
|
Fudim M, Spector AR, Costanzo MR, Oldenburg O, Augostini R, Goldberg LR, et al. Phrenic nerve stimulation for the treatment of central sleep apnea: a pooled cohort analysis. J Clin Sleep Med. 2019. doi:10.5664/jcsm.8076. |
Review (wrong design). |
|
Randerath WJ, Arzt M, Javaheri S, Levy P, Patil SP, Rodenstein D, et al. Unilateral phrenic nerve stimulation in the therapeutical algorithm of central sleep apnoea in heart failure. Curr Opin Pulm Med. 2019. doi:10.1097/MCP.0000000000000606. |
Prospective non-randomized study. |
|
Hirschfeld S, Exner G, Luukkaala T, Baer GA. Phrenic nerve stimulation experiences: a single centre, controlled, prospective study. J Clin Neurosci. 2022. doi:10.1016/j.jocn.2022.04.037. |
Also uses the remedē System Pivotal Trial; analysis of baseline and 6-month PSG in 134 CSA patients randomized to neurostimulation vs. no stimulation. |
|
Hartmann S, Baumert M, Oldenburg O, Abraham WT, Augostini R, Costanzo MR, et al. Transvenous phrenic nerve stimulation for treating central sleep apnea may regulate sleep microstructure. Sleep Med. 2023. doi:10.1016/j.sleep.2023.11.005. |
Also uses the remedē System Pivotal Trial; potentially relevant for considerations (e.g., win ratio). |
|
Abraham WT, Costanzo MR, Augostini R, Goldberg LR, Holcomb RG, Khayat R, et al. Win ratio analysis of transvenous phrenic nerve stimulation to treat central sleep apnoea in heart failure. ESC Heart Fail. 2025. doi:10.1002/ehf2.15074. |
Wrong intervention (multipoint cardiac resynchronization therapy in heart failure). |
|
Bessa A, Borges FK, Ribeiro ALP, Rabelo ER, Biolo A. Effectiveness of multipoint cardiac resynchronizing therapy in heart failure: a systematic review and meta-analysis of randomized controlled trials. Expert Rev Med Devices. 2021. doi:10.1080/14779072.2021.1940961. |
Too old. |
|
Hunt CE, Matalon SV, Thompson TR, Demuth GR. Successful treatment of sleep dependent primary hypoventilation syndrome (Ondine's curse) with bilateral phrenic nerve pacing. Radiology. 1976. |
Too old. |
|
Zeluff BJ, Wilcox JB. Ondine's curse. Pediatr Pulmonol. 1977. |
Too old. |
|
Glenn WWL, Gee JBL, Cole DR, Farmer WC, Shaw RK, Beckman CB. Combined central alveolar hypoventilation and upper airway obstruction: treatment by tracheostomy and diaphragm pacing. J Pediatr Surg. 1978. |
Too old. |
|
Langou RA, Wolfson B, Cohen LS. Ondine's curse: hemodynamic response to diaphragm pacing (electrophrenic respiration). Chest. 1978. |
Too old. |
|
Makhija R, Kumar R, Ravin CE, Grimes MM, Glenn WWL. Ventilation patterns mimicking COPD in patients with diaphragmatic pacing for Ondine's curse. Radiology. 1978;129(1):111-116. doi:10.1148/129.1.111. |
Case reports and wrong intervention. |
|
Marzocchi M, Brouillette RT, Brooks LJ. Comparison of transthoracic impedance/heart rate monitoring and pulse oximetry for patients using diaphragm pacemakers. Pediatr Pulmonol. 1990;8(1):19-23. doi:10.1002/ppul.1950080109. |
Wrong intervention. |
|
Normand H. Diaphragmatic paralysis: diagnosis, prognostic evaluation, phrenic nerve stimulation. Rev Mal Respir. 1990. |
Wrong population and intervention. |
|
Shaul DB, Danielson PD, McComb JG, Keens TG. Thoracoscopic placement of phrenic nerve electrodes for diaphragmatic pacing in children. J Pediatr Surg. 2002. doi:10.1053/jpsu.2002.33821. |
Wrong intervention. |
|
Taira T, Hori T. Phrenic nerve stimulation for diaphragm pacing with a spinal cord stimulator: technical note. Surg Neurol. 2003. doi:10.1016/s0090-3019(02)00997-7. |
Wrong design (anatomical study). |
|
Bramante CT, DiMarco AF, Kowalski KE, Geertman RT, Hromyak DR. Suitability of the pericardiophrenic veins for phrenic nerve stimulation: an anatomic study. Neuromodulation. 2011. doi:10.1111/j.1525-1403.2011.00369.x. |
Wrong design. |
|
Le Pimpec-Barthes F, Legras A, Arame A, Pricopi C, Riquet M, Badia A, et al. Intrathoracic phrenic pacing: a 10-year experience in France. J Thorac Cardiovasc Surg. 2011. doi:10.1016/j.jtcvs.2011.04.033. |
Wrong design and intervention. |
|
Kasai T, Bradley TD. Sleep apnea and heart failure. J Cardiol. 2012. doi:10.1016/j.jjcc.2012.05.013. |
Wrong design. |
|
Mansukhani MP, Kolla BP, Wang Z, Morgenthaler TI. International classification of sleep disorders 2 and American Academy of Sleep Medicine practice parameters for central sleep apnea. Sleep Med Clin. 2014. doi:10.1016/j.jsmc.2013.10.006. |
Wrong intervention (Congenital Central Hypoventilation Syndrome) and wrong design (review of 18 patients). |
|
Diep B, Wang A, Kun S, McComb JG, Shaul DB, Shin CE, et al. Diaphragm pacing without tracheostomy in congenital central hypoventilation syndrome patients. Respiration. 2015. doi:10.1159/000381401. |
Wrong intervention (diaphragm pacing stimulation) and wrong design (retrospective analysis). |
|
Karacam V, Yilmaz A, Sonmezoglu Y, Gokce A, Yilmaz M. A practical technique in laparoscopic diaphragm pacing surgery: retrospective analysis of 43 patients. J Minim Access Surg. 2018. doi:10.4103/jmas.JMAS-165-17. |
Wrong intervention. |
|
Wang A, Kun S, Diep B, Davidson Ward SL, Keens TG, Perez IA. Obstructive sleep apnea in patients with congenital central hypoventilation syndrome ventilated by diaphragm pacing without tracheostomy. J Clin Sleep Med. 2018. doi:10.5664/jcsm.6948. |
Wrong intervention. |
|
52. Gutleben KJ, Fox H, Bitter T, Horstkotte D, Oldenburg O. Interventional techniques to increase implantation success of transvenous phrenic nerve stimulation for central sleep apnea treatment. Sleep Breath. 2019. doi:10.1007/s11325-019-01917-0. |
Wrong intervention. |
|
53. Gutleben KJ, Fox H, Bitter T, Horstkotte D, Oldenburg O. First interventional exchange of a left transvenous phrenic nerve stimulation lead from the novel remede system. J Cardiovasc Electrophysiol. 2021. doi:10.1111/jce.14725. |
Wrong intervention. |
|
54. Maloney JP, Bell EF, Hunt CE, Weese-Mayer DE. Pregnancy in congenital central hypoventilation syndrome. Am J Obstet Gynecol MFM. 2020. doi:10.1016/j.ajogmf.2020.100237. |
Wrong intervention. |
|
55. Tsolakis I, Nilsson D, Malmgren N, Lagercrantz H, Hellstrom-Westas L, Hjalmarson O, et al. Strategy of changing from tracheostomy and non-invasive mechanical ventilation to diaphragm pacing in children with congenital central hypoventilation syndrome. Acta Paediatr. 2022. doi:10.1111/apa.16256. |
Wrong intervention. |
|
56. Mitsuyama H, Taira T, Hori T. Diaphragm pacing with the spinal cord stimulator. Neurol Med Chir (Tokyo). 2003. |
Wrong intervention. |
|
57. European Sleep Research Society. Abstract proceedings: transvenous phrenic nerve stimulation to treat central sleep apnea in chronic heart failure - feasibility of accessing the left pericardiophrenic vein for lead placement from either the right or left subclavian vein. J Sleep Res. 2012. |
Wrong intervention. |
|
58. Hirschfeld S, Exner G, Luukkaala T, Baer GA. Threshold currents of platinum electrodes used for functional electrical stimulation of the phrenic nerves for treatment of central apnea. Pacing Clin Electrophysiol. 2013. doi:10.1111/pace.12073. |
Wrong intervention. |
|
59. Levy P, Ryan S, Oldenburg O, Parati G. Sleep apnoea and the heart. Eur Respir Rev. 2013. doi:10.1183/09059180.00004513. |
Also uses the remedē System Pivotal Trial. |
|
60. Costanzo MR, Ponikowski P, Coats A, Javaheri S, Augostini R, Goldberg LR, et al. Design of the remede System Pivotal Trial: a prospective, randomized study in the use of respiratory rhythm management to treat central sleep apnea. J Card Fail. 2015. doi:10.1016/j.cardfail.2015.08.344. |
Wrong design. |
|
61. Bekfani T, Abraham WT. Current and future developments in the field of central sleep apnoea. Europace. 2016. doi:10.1093/europace/euv435. |
Prospective non-randomized study. |
|
62. Zhang XL, Ding N, Wang H, Li X, Wang D, Xu H, et al. Safety and feasibility of chronic transvenous phrenic nerve stimulation for treatment of central sleep apnea in heart failure patients. Clin Respir J. 2017. doi:10.1111/crj.12320. |
Wrong design. |
|
63. Nayak HM, Patel K, Otusanya O, Augostini R, Abraham WT, Costanzo MR, et al. Transvenous phrenic nerve stimulation for central sleep apnea is safe and effective in patients with concomitant cardiac devices. Heart Rhythm. 2020. doi:10.1016/j.hrthm.2020.06.023. |
Also uses the remedē System Pivotal Trial (safety and efficacy). |
|
64. Goldberg LR, Ponikowski P, Costanzo MR, Augostini R, Abraham WT, Oldenburg O, et al. 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. Sleep Med. 2022. doi:10.1016/j.sleep.2022.08.026. |
Also uses the remedē System Pivotal Trial (safety and efficacy). |
|
65. Cleland JGF, Coletta AP, Freemantle N, Clark AL. Clinical trials update from the American College of Cardiology meeting: CARE-HF and the Remission of Heart Failure, Women's Health Study, TNT, COMPASS-HF, VERITAS, CANPAP, PEECH and PREMIER. Eur J Heart Fail. 2005. doi:10.1016/j.ejheart.2005.04.002. |
Wrong design. |
|
66. Parhizgar F, Nugent K, Raj R. Obstructive sleep apnea and respiratory complications associated with vagus nerve stimulators. J Clin Sleep Med. 2011. doi:10.5664/JCSM.1204. |
Wong population (OSA). |
|
67. Caples SM, Somers VK. Central sleep apnea and cardiovascular disease. Sleep Med Clin. 2014. doi:10.1016/j.jsmc.2013.10.007. |
Wrong design. |
|
68. Flageole H, Adolph VR, Davis GM, Laberge JM, Nguyen LT, Guttman FM. Diaphragmatic pacing in children with congenital central alveolar hypoventilation syndrome. Surgery. 1995. doi:10.1016/s0039-6060(05)80005-4. |
Wronmg intervention. |
|
69. Coniglio AC, Mentz RJ. Sleep breathing disorders in heart failure. Heart Fail Clin. 2020. doi:10.1016/j.hfc.2019.08.009. |
Wrong population. |
|
70. Steffen A, Heiser C, Maurer JT, Verse T, Stuck BA. Patient related outcome and therapy effects in stimulation treatment of sleep-related breathing disorders. Somnologie. 2022. doi:10.1055/a-1647-8601. |
Wrong population and intervention. |
|
71. Wang Y, Yu W, Li S, Huang L, Chen X, Zhang X, et al. Persistent treatment-emergent central sleep apnea following hypoglossal nerve stimulation. Nat Sci Sleep. 2022. doi:10.2147/NSS.S382710. |
Wrong intervention (hypoglossal nerve stimulation). |
|
72. Somers VK, White DP, Amin R, Abraham WT, Costa F, Culebras A, et al. Sleep apnea and cardiovascular disease: an American Heart Association/American College of Cardiology Foundation scientific statement. Circulation. 2008;118(10):1080-1111. doi:10.1161/CIRCULATIONAHA.107.189420. |
Wong design (statement). |
|
73. Yu C, Gupta M, Chen J, Morrell M. Vagus nerve stimulation: can it be used in adolescents or children with treatment-resistant depression? Curr Psychiatry Rep. 2008. doi:10.1007/s11920-008-0021-6. |
Wrong intervention. |
Beoordelingsdatum en geldigheid
Publicatiedatum : 03-11-2026
Beoordeeld op geldigheid : 03-11-2026
Samenstelling werkgroep
Werkgroep
- Dhr. dr. M. (Manuel) Sastry, voorzitter, longarts, Nederlands Slaapinstituut Nederland, NVALT
- Dhr. J. (Jerryll) Asin, vicevoorzitter, longarts, Amphia ziekenhuis, NVALT
- Mevr. dr. H.C.J.P. (Hennie) Janssen, longarts, Centrum voor Slaapgeneeskunde (CSG) Kempenhaeghe, NVALT
- Dhr. W.J.B. (Wouter) Blox, longarts, Albert Schweitzer ziekenhuis, NVALT
- Dhr. prof. dr. P.J. (Peter) Wijkstra, longarts, UMCG, NVALT
- Mevr. E.W. (Esther) Gieteling, neuroloog, SEIN, NVN
- Dhr. prof. dr. D. (Dominik) Linz, cardioloog, MUMC, NVVC
- Dhr. K.E. (Karel) Schreuder, patiëntenvertegenwoordiger, Apneuvereniging
Klankbordgroep
- Dhr. dr. J.M.J.A.A. (Jos) Straetmans, KNO-arts, Zuyderland, NVKNO
- Dhr. N.E. (Nils) van ’t Veer, ziekenhuisapotheker, Amphia, NVZA
Met ondersteuning van
- Dr. A.N. (Nynke) Kampstra, adviseur, Kennisinstituut van de Federatie Medisch Specialisten
- Dr. L.K. (Leanne) Küpers, adviseur, Kennisinstituut van de Federatie Medisch Specialisten
- Mevr. Fieke Pepping, junior adviseur, Kennisinstituut van de Federatie Medisch Specialisten
- Mevr. Joline Rohof, junior adviseur, Kennisinstituut van de Federatie Medisch Specialisten
- Mevr. E. (Esther) van der Bijl, medisch informatiespecialist, Kennisinstituut van de Federatie Medisch Specialisten
Belangenverklaringen
Een overzicht van de belangen van de clusterleden en het oordeel over het omgaan met eventuele belangen vindt u in onderstaande tabel. De ondertekende belangenverklaringen zijn op te vragen bij het secretariaat van het Kennisinstituut van de Federatie Medisch Specialisten via secretariaat@kennisinstituut.nl.
Werkgroepleden
Tabel 1 Gemelde (neven)functies en belangen stuurgroep
|
Naam |
Hoofdfunctie |
Nevenwerkzaamheden |
Persoonlijke financiële belangen |
Persoonlijke relaties |
Extern gefinancierd onderzoek |
Overige belangen |
Restrictie |
|
Manuel Sastry (vz.) |
Sinds 1-6-2024 ZZP longarts bij het Nederlands Slaap Instituut. Voorheen tot 30-11-2024 longarts Academisch Slaapcentrum Ciro en longarts in 0-aanstelling MUMC+, afdeling longziekten. |
De centra voor thuisbeademing (CTB) hebben aangegeven in hun richtlijn “Chronische beademing” (chronische beademing (2021) dat zij de zorg voor volwassenen patiënten met OSA als ook CSA willen overdragen aan daarvoor gekwalificeerde slaapcentra. De CTB en de NVALT Sectie Ademhalingsstoornissen tijdens de Slaap (SAS) hebben daartoe eind 2024 een gezamenlijk visiedocument opgesteld dat door de Nederlandse Vereniging voor Keel-Neus-Oorheelkunde van het Hoofd-Halsgebied (NvKNO), de Nederlandse Vereniging voor Neurologie (NVN) en de Apneuvereniging geaccordeerd is. Ik heb deelgenomen aan de gezamenlijke werkgroep van de CTB en SAS. Wetenschappelijke secretaris NVALT Sectie Ademhalingsstoornissen tijdens de Slaap (SAS) |
Bij mijn werkzaamheden als longarts in een slaapcentrum/ slaapinstituut behandel ik onder andere patiënten met centrale slaapapneu. Uitkomsten van de richtlijn leveren me geen financieel voordeel op. |
Geen |
Tot 30-11-2024 bij De Maastricht Studie (DMS) was ik voor de afdeling longziekten MUMC+ co-eigenaar van longziekten-/slaap- gegevens. DMS heeft 20 partners. Naast het MUMC+, de provincie Limburg en de gemeente Maastricht, zijn dit onder andere meerdere industrie en farmaceutische bedrijven. Meerdere groepen van andere afdelingen hebben gebruik gemaakt van data van de afdeling longziekten. Bij de betreffende publicaties was ik meermaals coauteur geweest, nooit eerste of laatste auteur. Geen van de publicaties had centrale slaapapneu als onderwerp. |
Geen |
Geen |
|
Jerryll Asin
|
Longarts, Amphia Breda |
Voormalig bestuurslid SAS NVALT |
Consultant: ondersteuning ReST-studie als PI bij opzetten twee andere studie/sites elders in Nederland |
Nee |
ReST-studie |
Geen |
Restricties op besluitvorming over N. Phrenicus stimulatie. |
|
Esther Gieteling |
Neuroloog, SEIN |
Werkgroep Slaap Waakstoornissen NVN (onbetaald) |
Geen |
Mijn echtgenoot is longarts met aandachtsgebied longoncologie (geen belangen bij deze richtlijn) |
Zie hieronder: |
Geen |
Geen |
|
Hennie Janssen |
Longarts/somnoloog, |
Voordracht gericht op educatie op een symposium georganiseerd door VIVISOL |
Geen |
Nee |
Deelname aan wetenschappelijk onderzoek binnen the |
Geen |
Geen |
|
Peter Wijkstra |
Longarts, UMCG |
Penning meester European Respiratory Society ( ERS), betaald |
Neen |
Neen |
RESMED - RECAPTURE , chronische beademing bij COPD - Projectleider |
Geen |
Geen |
|
Wouter Blox |
Longarts, Albert Schweitzer ziekenhuis |
Luscii Medical board (adviserende functie, onbezoldigd) |
Geen |
Geen |
Geen |
Geen |
Geen |
|
Dominik Linz |
Cardioloog, Maastricht University Medical Center (MUMC+) |
Geen |
Geen |
Geen |
Geen |
Geen |
Geen |
Betrokken klankbordgroepleden
Tabel 2 Gemelde (neven)functies en belangen expertisegroep
|
Naam |
Hoofdfunctie |
Nevenwerkzaamheden |
Persoonlijke financiële belangen |
Persoonlijke relaties |
Extern gefinancierd onderzoek |
Overige belangen |
Restrictie |
|
Jos Straetmans |
KNO-arts, vrijgevestigd, Zuyderland MC Sittard-Heerlen |
Medisch manager RVE Oncologie, Zuyderland MC Sittard-Heerlen |
Niet van toepassing |
Niet van toepassing |
Niet van toepassing |
Niet van toepassing |
Geen |
|
Nils van 't Veer |
Ziekenhuisapotheker, Amphia ziekenhuis |
Geen |
Geen |
Geen |
Geen |
Geen |
Geen |
Inbreng patiëntenperspectief
Het patiëntenperspectief is ingebracht door deelname van de Apneuvereniging aan het cluster.
Kwalitatieve raming van mogelijke financiële gevolgen in het kader van de Wkkgz
Bij de richtlijnmodule voerden de clusterleden conform de Wet kwaliteit, klachten en geschillen zorg (Wkkgz) een kwalitatieve raming uit om te beoordelen of de aanbevelingen mogelijk leiden tot substantiële financiële gevolgen. Bij het uitvoeren van deze beoordeling is de richtlijnmodule op verschillende domeinen getoetst (zie het stroomschema bij Werkwijze).
|
Module |
Uitkomst raming |
Toelichting |
|
Module Nervus phrenicus stimulatie bij CSA |
Geen substantiële financiële gevolgen. |
Uit de toetsing volgt dat de aanbevelingen niet breed toepasbaar zijn (<5.000 patiënten) en daarom naar verwachting geen substantiële financiële gevolgen zullen hebben voor de collectieve uitgaven. |
Werkwijze
Voor meer details over de gebruikte richtlijnmethodologie verwijzen wij u naar de Werkwijze. Relevante informatie voor de ontwikkeling/herziening van deze richtlijnmodule is hieronder weergegeven.
Zoekverantwoording
Zoekstrategie Embase.com 22 april 2025
|
No. |
Query |
Results |
|
#1 |
'central sleep apnea syndrome'/exp OR 'cheyne stokes breathing'/exp OR 'central hypoventilation syndrome'/exp OR ((csa NEAR/3 (central* OR sleep* OR apn*)):ti,ab,kw) OR ((periodic* NEAR/3 (breathing* OR respiration*)):ti,ab,kw) OR ((central NEAR/3 alveolar NEAR/3 hypoventilat*):ti,ab,kw) OR ((central NEAR/3 hypoventilat* NEAR/3 syndrome*):ti,ab,kw) OR ((ondine* NEAR/3 (syndrome OR curse)):ti,ab,kw) OR ((central* NEAR/3 sleep* NEAR/3 apn*):ti,ab,kw) OR ((central* NEAR/3 apn*):ti,ab,kw) OR ((central NEAR/3 sleep* NEAR/3 disorder* NEAR/3 breath*):ti,ab,kw) OR 'cheyn* stoke*':ti,ab,kw |
11779 |
|
#2 |
'phrenic nerve'/exp OR 'phrenic nerve stimulator'/exp OR 'phrenic nerve stimulation'/exp OR 'heart pacing'/exp OR 'pacing'/exp OR 'nerve stimulation'/de OR ((phrenic* NEAR/3 nerve*):ti,ab,kw) OR (((phrenic* OR nerve* OR implant*) NEAR/4 (stimulat* OR stimulus)):ti,ab,kw) OR pacing*:ti,ab,kw OR neurostimulat*:ti,ab,kw OR 'neuro stimulat*':ti,ab,kw OR pns:ti,ab,kw |
209872 |
|
#3 |
#1 AND #2 |
818 |
|
#4 |
#3 NOT ('conference abstract'/it OR 'editorial'/it OR 'letter'/it OR 'note'/it) NOT (('animal'/exp OR 'animal experiment'/exp OR 'animal model'/exp OR 'nonhuman'/exp) NOT 'human'/exp) |
478 |
|
#5 |
'meta analysis'/exp OR 'systematic review'/exp OR 'scoping review'/exp OR 'rapid review'/exp OR 'umbrella review'/exp OR 'cochrane database of systematic reviews'/jt OR 'network meta-analysis'/exp OR 'networkmeta analy*':ti,ab,kw OR 'networkmetaanaly*':ti,ab,kw OR metaanaly*:ti,ab,kw OR 'meta analy*':ti,ab,kw OR metanaly*:ti,ab,kw OR prisma:ti,ab,kw OR prospero:ti,ab,kw OR metaanali*:ti,ab,kw OR 'meta anali*':ti,ab,kw OR metanali*:ti,ab,kw OR (((systemati* OR scoping OR umbrella OR 'structured literature') NEAR/3 (review* OR overview*)):ti,ab,kw) OR (((structured OR systemic*) NEAR/3 (review* OR overview* OR synth*) NEAR/3 literature):ti,ab,kw) OR ((systemic* NEAR/1 review*):ti,ab,kw) OR (((systemati* OR literature OR database* OR 'data base*') NEAR/10 search*):ti,ab,kw) OR (((structured OR comprehensive* OR systemic*) NEAR/3 search*):ti,ab,kw) OR (((literature NEAR/3 (review* OR overview*)):ti,ab,kw) AND (search*:ti,ab,kw OR database*:ti,ab,kw OR 'data base*':ti,ab,kw)) OR (('data extraction*':ti,ab,kw OR 'data source*':ti,ab,kw) AND ('study selection*':ti,ab,kw OR 'studies selection*':ti,ab,kw)) OR ('search strateg*':ti,ab,kw AND 'selection criteria*':ti,ab,kw) OR ('data source*':ti,ab,kw AND 'data synth*':ti,ab,kw) OR medline*:ti,ab,kw OR pubmed*:ti,ab,kw OR 'pub med*':ti,ab,kw OR embase:ti,ab,kw OR cochrane*:ti,ab,kw OR (((critical* OR rapid*) NEAR/2 (review* OR overview* OR synth*)):ti) OR ((((critical* OR rapid*) NEAR/3 (review* OR overview* OR synth*)):ab) AND (search*:ab OR database*:ab OR 'data base*':ab)) OR metasynth*:ti,ab,kw OR 'meta synth*':ti,ab,kw OR 'review* of review*':ti,ab,kw |
1102379 |
|
#6 |
'randomized controlled trial'/exp OR 'clinical trial'/exp OR 'randomization'/de OR 'single blind procedure'/exp OR 'double blind procedure'/exp OR 'triple blind procedure'/exp OR 'crossover procedure'/exp OR 'placebo'/exp OR 'prospective study'/exp OR rct:ti,ab OR ((random* NEAR/2 (trial OR study)):ti,ab) OR ((random* NEAR/10 (trial OR trail OR 'clinical trial' OR 'clinical trail' OR 'clinical study' OR 'multicenter study' OR crossover OR 'cross over')):ti) OR (((randomised OR randomized) NEXT/6 study):ti) OR 'random* control* clinical trial':ti,ab OR 'random* control* clinical trail':ti,ab OR 'random* control* clinical study':ti,ab OR ((('single blind*' OR 'double blind*' OR 'triple blind*' OR 'quadruple blind*') NEAR/4 (study OR trial OR trail OR design)):ti,ab) OR placebo*:ti,ab OR randomly:ti,ab OR ((random* NEAR/3 distribut* NEAR/7 group*):ti,ab) OR (((pragmatic OR practical) NEXT/1 ('clinical trial' OR 'clinical trail')):ti,ab) OR ((('non inferiority' OR noninferiority OR superiority OR equivalence) NEXT/3 (trial OR trail)):ti,ab) OR ((random* NEAR/4 ('cross over*' OR crossover*)):ti,ab) OR ((phase NEAR/5 ('clinical trial' OR 'clinical trail' OR randomized OR randomised)):ti) OR ((random* NEAR/3 phase NEAR/3 (trial OR trail OR study)):ti,ab) |
3590771 |
|
#7 |
'major clinical study'/de OR 'clinical study'/de OR 'family study'/de OR 'longitudinal study'/de OR 'retrospective study'/de OR 'prospective study'/de OR 'cohort analysis'/de OR 'case control study'/de OR 'comparative study'/exp OR 'control group'/de OR 'controlled study'/de OR 'controlled clinical trial'/de OR 'crossover procedure'/de OR 'double blind procedure'/de OR 'phase 2 clinical trial'/de OR 'phase 3 clinical trial'/de OR 'phase 4 clinical trial'/de OR 'pretest posttest design'/de OR 'pretest posttest control group design'/de OR 'quasi experimental study'/de OR 'single blind procedure'/de OR 'triple blind procedure'/de OR ((cohort NEAR/1 (study OR studies)):ab,ti) OR (('case control' NEAR/1 (study OR studies)):ab,ti) OR (('follow up' NEAR/1 (study OR studies)):ab,ti) OR (observational NEAR/1 (study OR studies)) OR ((epidemiologic NEAR/1 (study OR studies)):ab,ti) OR (('cross sectional' NEAR/1 (study OR studies)):ab,ti) OR (((control OR controlled) NEAR/6 trial):ti,ab,kw) OR (((control OR controlled) NEAR/6 (study OR studies)):ti,ab,kw) OR (((control OR controlled) NEAR/1 active):ti,ab,kw) OR 'open label*':ti,ab,kw OR (((double OR two OR three OR multi OR trial) NEAR/1 (arm OR arms)):ti,ab,kw) OR ((allocat* NEAR/10 (arm OR arms)):ti,ab,kw) OR placebo*:ti,ab,kw OR 'sham-control*':ti,ab,kw OR (((single OR double OR triple OR assessor) NEAR/1 (blind* OR masked)):ti,ab,kw) OR nonrandom*:ti,ab,kw OR 'non-random*':ti,ab,kw OR 'quasi-experiment*':ti,ab,kw OR crossover:ti,ab,kw OR 'cross over':ti,ab,kw OR 'parallel group*':ti,ab,kw OR 'factorial trial':ti,ab,kw OR ((phase NEAR/5 (study OR trial)):ti,ab,kw) OR ((case* NEAR/6 (matched OR control*)):ti,ab,kw) OR ((match* NEAR/6 (pair OR pairs OR cohort* OR control* OR group* OR healthy OR age OR sex OR gender OR patient* OR subject* OR participant*)):ti,ab,kw) OR ((propensity NEAR/6 (scor* OR match*)):ti,ab,kw) OR versus:ti OR vs:ti OR compar*:ti OR ((compar* NEAR/1 study):ti,ab,kw) OR (('observational study'/de OR 'cross-sectional study'/de OR 'multicenter study'/de OR 'correlational study'/de OR 'follow up'/de OR cohort*:ti,ab,kw OR 'follow up':ti,ab,kw OR followup:ti,ab,kw OR longitudinal*:ti,ab,kw OR prospective*:ti,ab,kw OR retrospective*:ti,ab,kw OR observational*:ti,ab,kw OR 'cross sectional*':ti,ab,kw OR cross?ectional*:ti,ab,kw OR multicent*:ti,ab,kw OR 'multi-cent*':ti,ab,kw OR consecutive*:ti,ab,kw) AND (group:ti,ab,kw OR groups:ti,ab,kw OR subgroup*:ti,ab,kw OR versus:ti,ab,kw OR vs:ti,ab,kw OR compar*:ti,ab,kw OR 'odds ratio*':ab OR 'relative odds':ab OR 'risk ratio*':ab OR 'relative risk*':ab OR 'rate ratio':ab OR aor:ab OR arr:ab OR rrr:ab OR ((('or' OR 'rr') NEAR/6 ci):ab))) |
18024319 |
|
#8 |
#4 AND #5 - SR |
30 |
|
#9 |
#4 AND #6 NOT #8 - RCT |
82 |
|
#10 |
#4 AND #7 NOT (#8 OR #9) - Observationeel |
94 |
|
#11 |
#8 OR #9 OR #10 - Totaal |
206 |
Zoekstrategie Ovid/Medline 22 april 2025
|
# |
Searches |
Results |
|
1 |
exp Sleep Apnea, Central/ or exp Cheyne-Stokes Respiration/ or (csa adj3 (central* or sleep* or apn*)).ti,ab,kf. or (periodic* adj3 (breathing* or respiration*)).ti,ab,kf. or (central adj3 alveolar adj3 hypoventilat*).ti,ab,kf. or (central adj3 hypoventilat* adj3 syndrome*).ti,ab,kf. or (ondine* adj3 (syndrome or curse)).ti,ab,kf. or (central* adj3 sleep* adj3 apn*).ti,ab,kf. or (central* adj3 apn*).ti,ab,kf. or (central adj3 sleep* adj3 disorder* adj3 breath*).ti,ab,kf. or cheyn* stoke*.ti,ab,kf. |
6570 |
|
2 |
exp Phrenic Nerve/ or exp Transcutaneous Electric Nerve Stimulation/ or exp Electric Stimulation Therapy/ or Implantable Neurostimulators/ or (phrenic* adj3 nerve*).ti,ab,kf. or ((phrenic* or nerve* or implant*) adj4 (stimulat* or stimulus)).ti,ab,kf. or pacing*.ti,ab,kf. or neurostimulat*.ti,ab,kf. or neuro stimulat*.ti,ab,kf. or pns.ti,ab,kf. |
187342 |
|
3 |
1 and 2 |
407 |
|
4 |
3 not (comment/ or editorial/ or letter/) not ((exp animals/ or exp models, animal/) not humans/) |
343 |
|
5 |
exp Meta-Analysis/ or exp Network Meta-Analysis/ or exp Systematic Review/ or (networkmeta analy* or networkmetaanaly* or metaanaly* or meta analy* or metanaly* or prisma or prospero or metaanali* or meta anali* or metanali*).ti,ab,kf. or ((systemati* or scoping or umbrella or structured literature) adj3 (review* or overview*)).ti,ab,kf. or ((structured or systemic*) adj3 (review* or overview* or synth*) adj3 literature).ti,ab,kf. or (systemic* adj1 review*).ti,ab,kf. or ((systemati* or literature or database* or data base*) adj10 search*).ti,ab,kf. or ((structured or comprehensive* or systemic*) adj3 search*).ti,ab,kf. or ((literature adj3 (review* or overview*)) and (search* or database* or data base*)).ti,ab,kf. or ((data extraction* or data source*) and (study selection* or studies selection*)).ti,ab,kf. or (search strateg* and selection criteria*).ti,ab,kf. or (data source* and data synth*).ti,ab,kf. or (medline* or pubmed* or pub med* or embase or cochrane*).ti,ab,kf. or cochrane.jw. or ((critical* or rapid*) adj2 (review* or overview* or synth*)).ti. or (((critical* or rapid*) adj3 (review* or overview* or synth*)) and (search* or database* or data base*)).ab. or metasynth*.ti,ab,kf. or meta synth*.ti,ab,kf. |
821525 |
|
6 |
exp clinical trial/ or randomized controlled trial/ or exp clinical trials as topic/ or randomized controlled trials as topic/ or Random Allocation/ or Double-Blind Method/ or Single-Blind Method/ or (clinical trial, phase i or clinical trial, phase ii or clinical trial, phase iii or clinical trial, phase iv or controlled clinical trial or randomized controlled trial or multicenter study or clinical trial).pt. or random*.ti,ab. or (clinic* adj trial*).tw. or ((singl* or doubl* or treb* or tripl*) adj (blind$3 or mask$3)).tw. or Placebos/ or placebo*.tw. |
2873577 |
|
7 |
Case-control Studies/ or clinical trial, phase ii/ or clinical trial, phase iii/ or clinical trial, phase iv/ or comparative study/ or control groups/ or controlled before-after studies/ or controlled clinical trial/ or double-blind method/ or historically controlled study/ or matched-pair analysis/ or single-blind method/ or (((control or controlled) adj6 (study or studies or trial)) or (compar* adj (study or studies)) or ((control or controlled) adj1 active) or "open label*" or ((double or two or three or multi or trial) adj (arm or arms)) or (allocat* adj10 (arm or arms)) or placebo* or "sham-control*" or ((single or double or triple or assessor) adj1 (blind* or masked)) or nonrandom* or "non-random*" or "quasi-experiment*" or "parallel group*" or "factorial trial" or "pretest posttest" or (phase adj5 (study or trial)) or (case* adj6 (matched or control*)) or (match* adj6 (pair or pairs or cohort* or control* or group* or healthy or age or sex or gender or patient* or subject* or participant*)) or (propensity adj6 (scor* or match*))).ti,ab,kf. or (confounding adj6 adjust*).ti,ab. or (versus or vs or compar*).ti. or exp cohort studies/ or epidemiologic studies/ or ((multicenter study/ or observational study/ or seroepidemiologic studies/ or (cohort* or 'follow up' or followup or longitudinal* or prospective* or retrospective* or observational* or multicent* or 'multi-cent*' or consecutive*).ti,ab,kf.) and ((group or groups or subgroup* or versus or vs or compar*).ti,ab,kf. or ('odds ratio*' or 'relative odds' or 'risk ratio*' or 'relative risk*' or aor or arr or rrr).ab. or (("OR" or "RR") adj6 CI).ab.)) or Case control.tw. or cohort.tw. or Cohort analy$.tw. or (Follow up adj (study or studies)).tw. or (observational adj (study or studies)).tw. or Longitudinal.tw. or Retrospective*.tw. or prospective*.tw. or consecutive*.tw. or Cross sectional.tw. or Cross-sectional studies/ or historically controlled study/ or interrupted time series analysis/ |
7990865 |
|
8 |
4 and 5 - SR |
20 |
|
9 |
(4 and 6) not 8 - RCT |
69 |
|
10 |
(4 and 7) not (8 or 9) - Observationeel |
59 |
|
11 |
8 or 9 or 10 - Totaal |
148 |