Central sleep apnea is a fundamentally different beast from the far better-known obstructive form. In obstructive sleep apnea, the airway physically collapses even though the brain keeps issuing breathing commands; in the central form, the brain itself fails to send stable signals to the respiratory muscles, so the diaphragm simply stops contracting for stretches of ten, twenty, sometimes thirty seconds. The condition is especially common in patients with systolic heart failure, where unstable blood gases and heightened chemosensitivity make the respiratory control system oscillate like a poorly damped pendulum. Each apnea drains oxygen from the blood, jolts the sympathetic nervous system, and fragments sleep, and in heart failure populations this nocturnal burden is associated with worse outcomes.

Transvenous phrenic nerve stimulation, embodied commercially by the remedē System, was developed as an alternative to positive airway pressure therapy, which many central sleep apnea patients tolerate poorly or cannot use at all. The device is implanted much like a cardiac pacemaker: a lead is threaded into a vein and positioned adjacent to the phrenic nerve, and a pulse generator sewn beneath the skin in the upper chest delivers electrical bursts synchronized to inspiration. By recruiting the diaphragm directly, the stimulator stabilizes ventilation during sleep without requiring a mask, hose, or machine at the bedside. The pivotal randomized controlled trial published in The Lancet in 2016 by Costanzo, Ponikowski, Javaheri, and colleagues demonstrated significant reductions in the apnea-hypopnea index compared with a control group, and subsequent reports have extended safety and efficacy observations to five years.

The critique that provoked the reply, however, zeroes in on a subtle but important methodological point: the difference between how often patients use a therapy and whether the therapy actually changes the outcomes that matter. In drug research this distinction is familiar, since a prescription filled is not a prescription taken, and a pill taken is not necessarily a life prolonged. The commentators applied the same logic to neurostimulation, suggesting that high nightly usage figures, while impressive as measures of tolerability and adherence, do not by themselves establish that the device improves survival, cardiac function, or quality of life. Usage, in their framing, is a necessary but insufficient condition for efficacy, and conflating the two risks overstating what the evidence shows.

The reply authors counter that usage data in their studies were never offered as a substitute for efficacy endpoints but as a complement to them, and they point to the broader evidentiary record assembled over nearly a decade. That record includes the original randomized trial, long-term follow-up published in the journal Sleep by Fox, Oldenburg, Javaheri, and colleagues, the five-year safety and efficacy analysis in Nature and Science of Sleep, and, most recently, a win ratio analysis published in ESC Heart Failure by Abraham, Oldenburg, Lainscak, and colleagues that evaluated transvenous phrenic nerve stimulation against a composite hierarchy of clinical outcomes in heart failure patients. The win ratio method, increasingly popular in cardiology, ranks patients by a cascade of endpoints from death through worsening heart failure to symptom change, allowing a trial to detect clinically meaningful benefit even when individual components are individually underpowered.

The stakes of this statistical and conceptual argument are amplified by the checkered history of central sleep apnea treatment. Adaptive servo-ventilation, a sophisticated bilevel pressure machine that was once the dominant therapy for central apnea in heart failure, was dealt a devastating blow by the SERVE-HF trial published in the New England Journal of Medicine in 2015, in which Cowie, Woehrle, Wegscheider, and colleagues found that the therapy was associated with increased mortality in patients with predominant central apnea and systolic heart failure. That result transformed the field overnight: a device that measurably reduced apneas on paper turned out to harm the very patients it was meant to help. Ever since, the sleep medicine community has been rightly skeptical of surrogate endpoints, and any argument that leans on apnea index reductions or adherence statistics rather than hard clinical outcomes invites intense scrutiny.

It is against that backdrop that the American Academy of Sleep Medicine convened a clinical practice guideline, published in 2025 with Badr, Khayat, Allam, and colleagues as authors, to formalize recommendations for treating central sleep apnea in adults. Guideline panels must weigh exactly the tension at issue in this journal exchange: how much weight to give device usage and physiological endpoints, how much to randomized outcome data, and how to handle therapies whose evidence base is still maturing. The reply’s authors, several of whom participated in that guideline process, argue that the totality of evidence, including high nightly usage rates documented in their automatic activation study published earlier in 2026, supports a favorable risk-benefit profile for appropriately selected patients.

The automatic activation study itself deserves attention because it speaks directly to the usage question. Published in the Journal of Clinical Sleep Medicine with Khayat as first author, it examined a feature that allows the stimulator to activate itself when the patient falls asleep, removing the burden of remembering to turn the device on each night. The result was high nightly usage, which the investigators interpreted as evidence that the therapy integrates smoothly into patients’ lives, a prerequisite for any chronic implanted therapy to deliver benefit. Critics respond that usage, however high, remains an intermediate variable; defenders respond that no therapy, however efficacious in principle, can work if it is not actually running during the hours when central apneas occur.

Both positions contain legitimate technical truth, and the exchange illustrates a broader dilemma in device medicine that drug regulation solved decades ago with adherence-adjusted analyses and per-protocol versus intention-to-treat frameworks. An implanted stimulator is unusual among therapies in that usage can be logged objectively, second by second, by the device itself, producing adherence data of a fidelity that pill counts and self-report can never match. That transparency is a scientific asset, but it also creates a temptation, conscious or not, to foreground the numbers that look best. The commentators’ warning is essentially a caution against letting beautiful adherence dashboards substitute for the harder question of whether the therapy changes the trajectory of heart failure and survival.

The reply, received in April 2026 and published on 28 July 2026 as volume 22, article 126 of the journal, does not resolve the debate, and it was not designed to. What it does is clarify where the disagreement actually lies: not over the raw data, which both sides acknowledge, but over the inferential weight each category of evidence should carry. Readers should also note the declared interests shaping the discussion, since the remedē System Pivotal Trial was sponsored by ZOLL Respicardia, two of the reply’s authors are company employees, and two others serve as consultants, while Costanzo and Khan report no conflicts. For patients with central sleep apnea and failing hearts, the practical takeaway is that phrenic nerve stimulation remains a real option with a growing evidence base, but that the scientific community is still actively negotiating what its evidence means, and that negotiation, conducted in letters and replies like this one, is precisely how the field earns the right to call a therapy effective rather than merely used.

Subject of Research: Debate over usage versus efficacy evidence for transvenous phrenic nerve stimulation in central sleep apnea

Article Title: Reply to “Usage is not efficacy in transvenous phrenic nerve stimulation for central sleep apnea”

Article References: Khayat, R. N., Khan, M., Morgenthaler, T. I., McKane, S., Germany, R., & Costanzo, M. R. (2026). Reply to “Usage is not efficacy in transvenous phrenic nerve stimulation for central sleep apnea”. Journal of Clinical Sleep Medicine, 22(1), Article 126. https://doi.org/10.1007/s44470-026-00099-3

Image Credits: AI Generated

DOI: 10.1007/s44470-026-00099-3

Keywords: central sleep apnea, phrenic nerve stimulation, neurostimulation, heart failure, sleep medicine, remedē System, adaptive servo-ventilation, clinical trial evidence, device adherence, Journal of Clinical Sleep Medicine, win ratio analysis, AASM guideline