Review Article

Revisiting Transvenous Phrenic Nerve Stimulation in Central Sleep Apnoea and Heart Failure: Emerging Innovations in Clinical Trials Analysis

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Abstract

Central sleep apnoea (CSA) is a common comorbidity in patients with heart failure. Due to its insidious and chronic nature, CSA often remains unrecognised. Patients with CSA typically present with symptoms, such as daytime fatigue, recurrent heart failure decompensations and cardiac arrhythmias. Although the pathophysiology of CSA is not yet fully understood, the most widely accepted theory suggests that fluctuations in PaCO2 levels, particularly crossing the apnoeic threshold, play a central role in its development. CSA is associated with various changes, including activation of the sympathetic nervous system, neurohormonal disturbances and haemodynamic perturbations, all of which contribute to increased morbidity and mortality. Transvenous phrenic nerve stimulation (TPNS) has been demonstrated to be a safe and effective therapy for reducing the apnoea– hypopnoea index and improving both left ventricular ejection fraction and quality of life in patients with CSA. These benefits have been validated in randomised clinical trials (RCTs). New methods of analysing RCTs were recently introduced. Applying the win ratio method in a post hoc analysis of the primary RCTs evaluating TPNS suggested that TPNS may also contribute to reduced mortality and fewer heart failure hospitalisations. In this article we explore the pathophysiology of CSA and evaluate the existing evidence on therapeutic options, with a particular focus on TPNS.

Keywords

Phrenic nerve stimulation, sleep apnoea, heart failure,

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Accepted:

Published online:

DOI: https://doi.org/10.15420/cfr.2025.07

Disclosure: WTA has received grants from the National Institutes of Health (National Heart, Lung, and Blood Institute), consulting fees from Abbott, AquaPass, Cordio, CVRx, Innoventric, Relief Cardiovascular, Sensible Medical, Vectorious, White Swell and Zoll Respicardia and honoraria from Impulse Dynamics; has applied for a patent for a mobile ultrawideband radar for monitoring thoracic fluid levels and cardio-respiratory function; is co-chair of the Regulatory Policy and Implementation Science Working Group for Heart Failure Collaboratory (HFC) and of the HFC Academic Research Consortium Group; has stock options in scPharmaceuticals and V-Wave; and is on the Cardiac Failure Review editorial board; this did not influence peer review. The authors have no other conflicts of interest to declare.

Correspondence: Tarek Bekfani, Universitätsklinikum Magdeburg, Leipziger Str. 44, 39120 Magdeburg, Germany. E: Tarek.bekfani@med.ovgu.de

Copyright:

© The Author(s). This work is open access and is licensed under CC-BY-NC 4.0. Users may copy, redistribute and make derivative works for non-commercial purposes, provided the original work is cited correctly.

Sleep apnoea, also referred to as sleep-disordered breathing (SDB), is among the most prevalent comorbidities in patients with heart failure (HF).1 SDB, particularly central sleep apnoea (CSA), is often overlooked because patients with CSA do not always present with typical signs and symptoms, such as snoring or obesity, which are more commonly associated with obstructive sleep apnoea (OSA).2,3 In addition, screening for SDB is not routinely incorporated into the standard evaluation and management of patients with HF.4 Regular screening for CSA in the HF population would likely reveal higher prevalence rates and could have important therapeutic and prognostic implications.

CSA primarily occurs due to a failure in signalling from the brainstem, whereas OSA is characterised by preserved central stimulation along with abdominal and thoracic efforts, with the issue being obstruction of the upper airway.5

In an observational study of a cohort of patients with HF with preserved (HFpEF) or reduced (HFrEF) ejection fraction, those with SDB presented with preclinical congestion.6 In all, 111 patients with HF were screened and water volume was measured concurrently using bioimpedance analysis. Total body water and extracellular water volumes were increased in patients with HF and sleep apnoea who were clinically compensated, indicating preclinical congestion. The volume of water was found to be associated with the severity of SDB, as measured by the apnoea–hypopnoea index (AHI).6

CSA may present either as a comorbidity to other conditions or syndromes, such as HF, AF, kidney disease and stroke, or as idiopathic CSA when no underlying cause can be identified.7

Each episode of apnoea or hypopnoea in CSA triggers a cascade of events, including hypoxia, arousals and activation of the sympathetic nervous system. These processes are associated with detrimental effects, such as worsened sleep quality, reduced concentration, dementia, ischaemic changes in myocardial and brain tissue and an increased risk of arrhythmias.5,8–10 Furthermore, CSA is associated independently with higher morbidity and mortality.11,12

This makes screening for SDB in patients with HF, and treating them appropriately, crucial for optimal management. In a previous paper, an algorithm was proposed outlining which patients should be screened for SDB and how they should be treated.4

Central Illustration

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Continuous positive airway pressure (CPAP) is an established therapy for OSA and, to a lesser extent, CSA.13 Adaptive servo-ventilation has been shown to be harmful for patients with HFrEF and was associated with increased cardiovascular mortality.14 In a recently well-conducted meta-analysis and systematic review, the outcomes of therapies for patients with CSA and HFrEF or HF with mildly reduced ejection fraction (HFmrEF) were investigated.15 Although there was a statistically significant improvement in left ventricular ejection fraction (LVEF), AHI and quality of life (QoL) during the first 3 months, these improvements diminished thereafter, with the exception of improvements in AHI.15 This was primarily attributed to reduced patient compliance, as reported in five of the 11 studies.15

Another established therapy for treating patients with CSA is transvenous phrenic nerve stimulation (TPNS). Several studies over the past decade have demonstrated the safety and efficacy of this technology, using the implanted remedē System, in improving sleep architecture and QoL in patients with CSA.16–18 Interestingly, recent post hoc analyses have suggested that TPNS may reduce mortality and HF hospitalisation rates, as well as improve patient global assessment (PGA) in patients with HF and CSA.16–18

The aim of this article is to explore the pathophysiology of CSA, describe the implanted remedē System and summarise the current evidence regarding TPNS in patients with CSA and HF.

Pathophysiology of Sleep Apnoea

The exact mechanism underlying CSA is still largely not understood. However, there is a consensus that changes in PaCO2 levels, both above and below the apnoeic threshold, play a central role in the development of CSA. Under normal conditions, breathing is initiated when PaCO2 exceeds a certain threshold.19,20 This level is tightly regulated through central (brain and brainstem) and peripheral (carotid sinus) chemoreceptors that interact with the chest wall, respiratory muscles (e.g. diaphragm), the lungs and arterial blood gases.21 These coordinated interactions lead to the regulation of PaCO2 levels in the blood.4,22,23

Patients with HF experience dyspnoea (hyperventilation) both during exercise and while asleep. In the latter case, this is likely related to volume redistribution in the supine position, which leads to hyperventilation and results in reduced PaCO2 concentrations in the blood.24–27 If PaCO2 decreases below the apnoeic threshold, mechanisms to correct the low PaCO2 are activated centrally, leading to the cessation of breathing (apnoea). This results in an elevation of PaCO2, which then triggers the initiation of breathing again. This repetitive cycle typically leads to Cheyne–Stokes breathing.28,29

In healthy individuals, the reduced muscular tone when falling asleep leads to an increase in airway resistance.30 In addition, ventilation decreases physiologically during sleep, resulting in elevated PaCO2 levels that exceed the apnoeic threshold, which ensures continued breathing. These changes help maintain a healthy sleep pattern.5

However, several changes, such as hyperventilation, circulatory delay and diminished cerebrovascular reactivity, occur in patients with HF, leading to respiratory instability. The lung-to-ear circulation serves as a surrogate parameter describing the circulatory delay resulting from reduced cardiac output. This delay affects the ability of chemoreceptors to detect changes in CO2, which, in turn, affects sleep architecture and worsens periodic breathing in patients with CSA and HF.31

A further limitation to normal breathing in patients with both HF and CSA is the diminished cerebrovascular reactivity, which refers to the delayed response of cerebral blood flow to changes in PaCO2 levels.32 This leads to a reduced ability of the central respiratory control centre to adequately regulate the undershoots or overshoots in PaCO2 levels resulting from sleep apnoea.

Each HF subtype, namely HFrEF, HFpEF and HFmrEF, is driven by distinct underlying pathophysiological mechanisms, highlighting their unique clinical and biological characteristics. HFrEF is primarily associated with impaired systolic function, often resulting from MI, dilated cardiomyopathy or direct myocyte loss.33–35 In contrast, HFpEF is largely characterised by diastolic dysfunction, increased myocardial stiffness and a strong association with systemic comorbidities such as hypertension, diabetes, obesity and chronic inflammation.35,36 These factors contribute to microvascular dysfunction and impaired ventricular relaxation. HFmrEF represents an intermediate phenotype with overlapping features from both HFrEF and HFpEF, and its pathophysiology is still being actively explored. For example, regarding ischaemic aetiology, HFmrEF appears to be more similar to HFrEF than HFpEF, with a higher prevalence of coronary artery disease.33,35,37 Recognising that these HF subtypes arise from fundamentally different molecular and structural disturbances is crucial for guiding more precise and effective treatment strategies, because a uniform therapeutic approach does not account for the heterogeneity inherent in the syndrome of HF.

However, existing evidence for the treatment of CSA in HF suggests that current therapies may offer benefits across the full spectrum of HF phenotypes (Table 1). Nevertheless, given that most clinical trials have predominantly enrolled patients with HFrEF (Table 1), there remains a pressing need to generate more robust data specifically for patients with HFpEF.

All the aforementioned factors and mechanisms highlight the complex pathophysiology of CSA in HF. Despite the availability of therapeutic options, treating patients with both CSA and HF remains challenging and therapeutic options are not widely offered.

Table 1: Summary of Trials on Transvenous Phrenic Nerve Stimulation Using the remedē System

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Options for the Management of Central Sleep Apnoea in Patients With Heart Failure

Mask-based Therapy

Although CPAP is the standard therapy for patients with OSA, there is insufficient evidence supporting its effectiveness in patients with CSA.38 CPAP works by increasing intrathoracic pressure to keep the alveoli open and push air into the lungs. Earlier trials have shown that this method may be effective in reducing the AHI, as well as improving LVEF and QoL only in the first 3 months.13,39,40 However, CPAP is associated with haemodynamic disadvantages, particularly on the right ventricle, which compromises the already reduced ventricular output in patients with HF, ultimately leading to further deterioration of cardiac function.41 In addition, studies have shown that CPAP led to reduced cardiac output in patients with HFrEF, particularly in those with reduced pulmonary wedge pressure.42

Nocturnal Oxygen Therapy

Nocturnal oxygen therapy represents a physiologically sound approach to the treatment of CSA in HFrEF. Some evidence supports the potential clinical benefit of nocturnal oxygen in patients with HFrEF,43–45 but there is no convincing proof of its effectiveness. Indeed, the results of the LOFT-HF trial (NCT03745898) suggest there is, at best, a neutral effect of nocturnal oxygen on clinical outcomes.46 However, that trial was terminated early due to poor enrolment, and was thus underpowered for the assessment of clinical outcomes.

The remedē Device: Description and Implantation Process

The remedē System is a fully implantable, lead-based device, typically implanted on the right side in the pectoral region. The system consists of a neurostimulator, similar to a pacemaker, along with stimulating leads. Depending on the patient’s anatomy, the stimulating lead is advanced into the pericardiophrenic vein or the right brachiocephalic vein. Respiration is sensed through the stimulation lead, which is usually placed in the azygos vein (Figures 1 and 2).47

Figure 1: The remedē System and the Program Used for Regular Interrogation of the Implanted Device

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Figure 2: Thorax X-ray Showing the Implanted remedē System With the Stimulation Lead

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The remedē System delivers unilateral TPNS to the diaphragm, causing it to contract and create a negative pressure that simulates physiological breathing. The system is typically activated 1 month after implantation and is designed to automatically stimulate the diaphragm when patients are asleep and in a reclining position, according to an individually programmed algorithm simulating physiological breathing (Figure 3).

Stimulation is programmed to increase automatically to achieve sufficient diaphragm stimulation while the patient is fully asleep (Figure 4). This typically occurs over a period of about 12 weeks. The goal is to reach a balance between the strength and effectiveness of the stimulation and the threshold at which the patient begins to feel discomfort from the stimulation.48

Figure 3: Normal Inspiration Versus Inspiration With Established Central Sleep Apnoea Therapies

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Figure 4: Effect of the remedē System on Central Sleep Apnoea as Shown on Polysomnography

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Approval Trial and Recent Analysis of the remedē System

In the remedē pivotal trial (NCT01816776), conducted between April 2013 and May 2015, 151 patients were randomised across 31 centres in Germany, Poland and the US. The trial recruited patients who were aged ≥18 years, had been clinically stable for the past month and had an AHI of ≥20. After implantation of the remedē device, patients were randomised 1:1 to receive either active therapy (device on) or usual care (device off) for the first 6 months. The results were analysed on an intention-to-treat principle.18

The primary outcome was defined as a reduction in AHI of at least 50%. In all, 51% of patients in the therapy arm met this criterion, compared with just 11% in the usual-care arm, representing a significant difference of 41% (p<0.0001). In addition, 91% of participants did not experience any serious adverse events over a period of 12 months. Non-serious adverse events occurred in 37% of patients, 36% of which were resolved through reprogramming of the remedē device.18

This first randomised controlled trial (RCT) demonstrated that phrenic nerve stimulation significantly improved AHI, sleep structure and QoL in patients on therapy compared with those not receiving therapy.18 The procedure and the device were found to be safe.49 A detailed comparison of trials that have been conducted using TPNS in patients with HF and CSA is presented in Table 1.

In the remedē pivotal trial, half the patients were randomised to the usual-care group (therapy off), whereas the other half were randomised to the intervention arm (therapy on).18 After a 6-month period, all randomised patients were switched to receive active therapy. The sustained benefits of 12 months of TPNS for CSA were demonstrated by Costanzo et al.16 In that analysis, sleep indices were evaluated from baseline to 12 months in the treatment group and from 6 to 12 months in the control group. Sixty per cent of patients in the treatment group achieved a reduction of ≥50% in AHI at 6 months, with 67% achieving this reduction at 12 months.16 In addition, 55% of patients who had started in the control group reached the same AHI reduction at 12 months. Similarly, a significant and persistent improvement in the PGA was observed under TPNS therapy.16 Importantly, the benefits of TPNS were not associated with any increase in serious adverse events.16 Similar results were shown for different durations of follow-up.50

The Food and Drug Administration (FDA) approved the use of unilateral TPNS via the remedē System as a therapy for moderate and severe CSA in 2017, based on the results of the aforementioned RCT.51 The 5-year post-approval study (PAS) collected data that emphasised the safety and efficacy of the remedē device, further supporting its use as a treatment for moderate to severe CSA.52 In all, 52 patients were included in the final analysis. The PAS confirmed that TPNS improves sleep architecture, QoL and daytime sleepiness 5 years after implantation, without any additional safety concerns.52 Based on these findings, the FDA recently concluded that the PAS met the required criteria for demonstrating long-term efficacy and safety of TPNS.53

Currently, a large prospective non-randomised multicentre international study is under way.54 The study will recruit up to 500 patients with moderate to severe CSA who have received the remedē device in a post-market setting and follow them for up to 5 years. The study will assess sleep structure and PGA. In addition, patients with HF will undergo echocardiography, the 6-minute walk test and the Kansas City Cardiomyopathy Questionnaire. The results of the study will provide real-life data regarding patient selection, additional benefits and potential risks that have not yet been observed.54

Because many HF patients who are candidates for TPNS also have concomitant cardiac implanted electronic devices (CIEDs), a justified concern arises about potential adverse interactions between the CIED and the remedē device. Nayak et al. investigated this issue by analysing data from the remedē pivotal study, which included 151 patients.55 Of these 151 patients, 42% had a concomitant CIED. Nayak et al. found no significant differences in safety or efficacy between patients with and without CIEDs.55 There were four instances of CIED oversensing in three patients, leading to one inappropriate shock and the delivery of antitachycardia pacing. Nayak et al. concluded that TPNS is safe for patients with CIEDs and recommended implementing a detailed protocol to avoid device–device interactions and inappropriate therapies.55 However, these data should be confirmed in further studies, because nearly 60% of the devices in the study cohort were manufactured by Medtronic. It would be advisable to include a wider spectrum of devices from different manufacturers to better assess the potential for device–device interactions across various models.

Several studies have been conducted subsequently on the group of patients included in the remedē pivotal study, each focusing on different hypothesis testing that explore various interesting aspects. In an ancillary study of the remedē pivotal trial, Baumert et al. demonstrated that TPNS is associated with the normalisation of nocturnal heart rate perturbations.56 Whether this normalisation of heart rate perturbations would be associated with reduced mortality needs to be further investigated in larger, randomised trials. Baumert et al. analysed heart rate perturbations in 48 patients with CSA and sinus rhythm who were randomised to active therapy (TPNS) or control.56 The analysis was performed on polysomnograms obtained at baseline and at the 6-month follow-up, as part of the pivotal study. Heart rate variability is often used as a surrogate marker for an intact autonomic system. In patients with HF and CSA, diminished vagal tone and increased sympathetic tone during arousals following an apnoeic episode led to an elevated heart rate and markedly cyclical heart rate variations.56 Studies have shown that the very low-frequency power index (VLFI), which refers to these altered heart rate patterns, is associated with cortical arousals and activation of the autonomic nervous system.57 This repeated activation of the autonomic nervous system during the night in patients with sleep apnoea leads to chronic alterations in cardiac response. Specifically, it lowers baroreflex sensitivity and increases sympathetic tone during the daytime. This phenomenon is observed in patients with HF and sleep apnoea, as well as in those with OSA alone. The persistent sympathetic activation contributes to worsened cardiovascular outcomes, including increased blood pressure and heart rate variability during the night, further exacerbating disease progression.58–60 Moreover, repetitive arousals increase myocardial stress, which may lead to arrhythmias.61,62

These findings highlight the importance of TPNS in patients with HF and CSA. By reducing the VLFI and normalising nocturnal heart rate perturbations, TPNS may play a significant role in improving autonomic regulation. This could potentially be linked to a reduction in mortality, offering a promising therapeutic avenue for these patients.

A further study showed that TPNS leads to a reduced hypoxaemic burden.63 In that analysis, the oxygen desaturation index (ODI) and the percentage of sleep time spent with O2 saturation <90% (T90%) were analysed using baseline and follow-up data from overnight polysomnograms in 134 patients with moderate to severe CSA, who were randomised 1:1 to receive either TPNS or usual care. The authors found that TPNS significantly reduced both the ODI and T90% compared with the control group.63 The nocturnal hypoxaemic burden was shown to be associated with increased cardiovascular mortality and worse long-term cardiovascular outcomes. This further emphasises the potential benefits of TPNS in reducing these harmful effects in patients with CSA and HF.64 In addition, the total nocturnal time spent in the T90% range was found to be an AHI-independent factor in predicting worse cardiovascular prognosis in older men with HF.63 Thus, addressing nocturnal hypoxaemia with therapies like TPNS could have important implications for improving cardiovascular outcomes in this patient population.65 This should be investigated further. These results may be very helpful in understanding the underlying reasons for the increased mortality in patients with CSA. By identifying the impact of nocturnal hypoxaemia and heart rate perturbations, these findings provide valuable insights into the mechanisms that contribute to adverse cardiovascular outcomes in this patient group. Addressing these factors through targeted therapies like TPNS may help mitigate some of the risks associated with CSA and improve long-term survival in patients with HF.

Recently, a novel method for analysing composite outcomes in clinical trials, known as the win ratio (WR), has been introduced.66 The WR enables the prioritisation of outcomes based on their clinical relevance and presents results in accordance with the importance of these outcomes. This approach allows for the evaluation of recurrent events and facilitates the integration of different types of outcomes, including categorical, continuous and time-to-event variables.66

Building on the advantages of the WR method, Abraham et al. conducted a post hoc analysis of the pivotal trial results.67 The analysis incorporated three hierarchical components: longest survival, lowest HF rehospitalisation rate and at least a two-category improvement in the PGA score over 6 months. In all, 91 patients were included in the analysis, with 43 receiving TPNS and 48 in the control group.67 The results demonstrated a significant benefit for patients in the TPNS group compared with the control group, with a WR of 4.92 (95% confidence interval [2.27–10.63]; p<0.0001).67 The authors proposed that analysing the pivotal trial results using the WR and a hierarchical composite outcome suggests that TPNS may be clinically superior to usual care in treating patients with CSA and HF.67

To address potential bias stemming from the unblinded use of the PGA as a parameter, a sensitivity analysis was conducted.67 This analysis substituted the PGA with an objective parameter, namely ODI <4%, evaluated by a blinded assessor. Notably, the results remained consistent, demonstrating no difference when ODI was used instead of PGA.67 As mentioned previously, ODI has been associated with worse cardiac outcomes.65 The WR of 4.92 is comparable to the findings of the recently retrospectively or prospectively analysed cardiovascular trials using WR.68–71 The authors acknowledged several limitations in their analysis. First, it was a post hoc analysis, not part of the initial trial protocol or the originally intended statistical approach, which may introduce retrospective bias. Second, the potential impact of sodium–glucose cotransporter 2 inhibitors on the outcomes was not evaluated, leaving uncertainty about whether their use may have influenced the observed benefits of TPNS.

Conclusion

CSA is a very common comorbidity in patients with HF, yet it is often overlooked because its symptoms overlap with those of HF. Therefore, including screening for CSA in the management of HF is crucial for the early detection of this detrimental condition.

TPNS represents a safe and effective therapeutic option for patients with CSA, with proven efficacy in reducing AHI and improving LVEF, the 6-minute walk distance and QoL. Some post hoc analyses suggest a potential reduction in mortality and HF hospitalisations, which should be confirmed in future RCTs.

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