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Pauline Anderson
Pauline Anderson is a freelance writer for Medscape.
Disclosure: Pauline Anderson has disclosed no relevant financial relationships.
Nafeez Zawahir, MD
CME Clinical Director, Medscape, LLC
Disclosure: Nafeez Zawahir, MD, has disclosed no relevant financial relationships.
CME Author(s)
Laurie Barclay, MD
Freelance writer and reviewer, Medscape, LLC
Disclosure: Laurie Barclay, MD, has disclosed no relevant financial relationships.
CME Reviewer/Nurse Planner
Amy Bernard, MS, BSN, RN-BC
Lead Nurse Planner, Medscape, LLC
Disclosure: Amy Bernard, MS, BSN, RN-BC, has disclosed no relevant financial relationships.
FDA Panel: Upper Airway Device Beneficial for OSA
Authors: News Author: Pauline Anderson
CME Author: Laurie Barclay, MD
CME/CE Released: 4/15/2014
THIS ACTIVITY HAS EXPIRED
Valid for credit through: 4/15/2015
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Target Audience and Goal Statement
This article is intended for primary care clinicians, pulmonologists, neurologists, sleep disorder specialists, nurses, and other clinicians who care for patients with obstructive sleep apnea.
The goal of this activity is to provide medical news to primary care clinicians and other healthcare professionals in order to enhance patient care.
Upon completion of this activity, participants will be able to:
Describe recent findings of an FDA panel regarding efficacy and usefulness of an implantable stimulator for treatment of obstructive sleep apnea.
Discuss concerns of the FDA panel regarding safety of an implantable stimulator for treatment of obstructive sleep apnea.
Evaluate findings from a study reviewed by the FDA panel regarding an implantable stimulator for treatment of obstructive sleep apnea.
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From Medscape Education Clinical Briefs > FDA Approvals for CME
Authors: News Author: Pauline Anderson CME Author: Laurie Barclay, MDFaculty and Disclosures
Clinical Context
Obstructive sleep apnea (OSA) causes excessive daytime sleepiness, which may increase the risk for accidents, and it has also been associated with increased risks for obesity, hypertension, diabetes mellitus, and congestive heart failure. Although continuous positive airway pressure (CPAP) is effective as a first-line therapy, discomfort, noise, and other factors may result in noncompliance.
Success rates for surgery range from 40% to 60%, and other treatments, such as oral appliances, have varying success rates. Most surgical procedures target obstruction only at a single anatomic location of the throat, whereas patients often have multilevel airway obstructions.
Study Synopsis and Perspective
The Anesthesiology and Respiratory Therapy Medical Devices Panel of the US Food and Drug Administration's (FDA) Medical Devices Advisory Committee determined almost unanimously that the Inspire II Upper Airway System is safe and effective for treatment of OSA and that the benefits of the system outweigh the risks.
However, during a day-long meeting, panel members expressed concern that device-related adverse events such as tongue weakness persist in some patients who have undergoing implantation, that the device was tested almost exclusively in white participants, that it is incompatible with having magnetic resonance (MRI) imaging, and that clinicians will need training in implanting the device.
The company is seeking premarket FDA approval for the device, which stimulates the hypoglossal nerve during sleep in sync with a patient's inspiration. The stimulation contracts the patient's upper airway muscles, pulls the base of the tongue forward, and helps keep the airway open.
The system consists of implanted components, including a pulse generator, and stimulation and sensing leads. It also has an external programmer that stores therapy settings that clinicians can configure according to patient comfort and treatment targets, and a programmer with buttons for patients to turn the system on at night and off in the morning.
Innovative Technique
Various panel members commented that the device "offers another tool," addresses "an unmet need," and is an "important and innovative technique" to treat OSA. And members praised the company's data as "impressive," "compelling," and "robust," and for an "astonishing" 98% retention rate in a 12-month study.
They were referring to the company's pivotal Stimulation Therapy for Apnea Reduction (STAR) trial. The study included 126 adult patients, mean age 54.5 years, with moderate to severe OSA (a measurement of ≥ 15 on the apnea-hypopnea index [AHI]) at 15 sites in the United States and 7 in Europe. Almost all participants were white (there were no African American participants, a population that has a relatively high rate of OSA), and 83% were men.
All participants had failed or were intolerant of CPAP treatment; had a body mass index no greater than 32 kg/m2; and were confirmed not to have complete concentric collapse at the level of the soft palate, determined through drug-induced sleep endoscopy.
At 12 months, the median AHI score decreased 68% from 29.3 events per hour to 9.0 events per hour (P ˂ .001). The score for the other coprimary endpoint — oxygen desaturation index (ODI) — decreased 70%, from 25.4 events per hour to 7.4 events per hour (P ˂ .001).
Also at 12 months, the responder rate for the AHI was 66% (P = .0002). (A responder was defined as having a ≥ 50% reduction in the AHI compared with the mean of the preimplant screening and 1‐month visit — postimplant but before therapy activation — and an AHI > 20 events per hour.)
The responder rate for ODI was 75% (P ˂ .0001) at 12 months. (A responder was defined as having a ≥ 25% reduction in ODI.)
The positive results persisted to 18 months. At that point, the AHI responder rate was 65% (P = .0008). Also, the ODI rate had improved to 80% (P ˂ .0001).
There were also patient-reported improvements in sleep-related quality-of-life measurements — on the Epworth Sleepiness Scale questionnaire, and on the Functional Outcomes of Sleep Questionnaire and improvements on the percentage of sleep time with oxygen saturation less than 90%.
The company noted that although 34% of participants were considered nonresponders according to the AHI at 12 months, many of these were partial responders in that they did experience some improvement on both the primary and secondary outcomes.
The STAR trial also had a randomized controlled therapy withdrawal group that consisted of 43 consecutive responders. At 13 months, half of these participants had their stimulator turned off and half had it kept on. The 18-month analysis showed that those with the device turned off had regressed to having significant sleep apnea — with AHI levels almost triple that of the maintenance group — before levels dropped back to just above those of the maintenance group after the device was turned back on.
This trend, according to company officials, confirms that the improvements seen in the study were because of upper airway stimulation and not because of other factors (eg, weight loss).
Addresses Concerns
This withdrawal group addressed some of issues raised by the FDA in its report provided to panel members. One of the FDA's initial concerns was that because STAR had no control group, a participant's condition could have changed even if he or she had not been treated with the device. Regression to the mean could be another issue because participants entering the study had a relatively high AHI and may have been more likely to experience a decrease in AHI than participants with a lower AHI, regardless of whether they received the device.
Because the majority of study participants had prior surgical procedures (eg, uvulopalatopharyngoplasty, tonsillectomy/adenoidectomy), the panel considered whether such procedures should be a criteria for device implantation, but in the end agreed that this should not be mandated.
Also, because 4 of the 5 cases of palatal collapse occurred at a European site that was the first to start the implants, panel members reiterated the importance of clinician training in use of this new technology and that this might involve a significant learning curve.
The implanted device did not affect sleep architecture — for example, the amount of rapid eye movement sleep — so sleep quality was unaffected, according to the results of the study, which have been published in the New England Journal of Medicine.
There were, however, some adverse events — a total of 681 events during the 18-month postimplantation period, with an additional 43 reported beyond this 18-month period.
The rate of procedure-related serious adverse events, however, was less than 2%. In 2 participants, the device was removed, in 1 case (in a patient in whom an abscess had developed) possibly related to the device. There were 3 deaths, none apparently related to the implant.
Although some of the device-related adverse events — including tongue weakness, dry mouth, pain, numbness — did not resolve in some patients, the panel was generally not overly concerned about the adverse event profile because patients remained extremely compliant with the device.
However, they agreed that patients should be forewarned. "In making the decision whether or not to have surgery, patients need to be educated about the possibility of these side effects and managing their expectations will help to improve compliance," said panel chair Steven D. Nathan, MD, from Inova Fairfax Hospital, Falls Church, Virginia.
Dr. Nathan added that as part of "full disclosure about what the procedure entails," patients contemplating the implant should also know that the device is a second-line — not first-line — therapy, that it does not work in everyone, and that they may need to be closely monitored. Some patients in the study — 14 of the 126 — needed extra titrations (adjustments to the stimulation level) over and above the 2 titrations included in the protocol.
Robert Loeb, MD, from the University of Arizona, Tucson, emphasized that patient selection for the implant is "paramount," especially because some patients in the pivotal study "ended up worse with treatment," although this was not necessarily the result of the device, he said.
Some panel members, including Nirjaleswar Nikhar, MD, from The Neurology Clinic of Washington, Olney, Maryland, expressed concern that the device is incompatible with MRI. He pointed out that patients in the study were in their mid-50s, so the risk of further abnormalities — for example, myocardial infarction — will increase with time. "This might not be an issue now, but it could be 10 years down the road," he said.
More Inclusive
Although Dr. Loeb said that he "can't think of any mechanistic reason this device would work differently in different racial groups" and that the study results could be extrapolated to populations other than whites, he and the other panel members at the end of the day agreed to encourage the sponsor to be more inclusive in postmarket studies.
Going forward, the company is proposing to conduct 2 postapproval studies: an extended follow-up to 5 years of the premarket pivotal study cohort and a study of 127 new patients to evaluate "real-world" effectiveness, device safety, and the learning curve among newly trained clinicians. Panel members agreed that overall quality of life (in addition to sleep-related quality of life) would be important information to collect in future studies.
All but 1 of the 13 voting members agreed that the device was safe, with 1 abstention from Rosalie Dominik, DrPh, a biostatistician from the University of North Carolina at Chapel Hill, who was also the only abstainer on the benefit-vs-risk issue.
"Given that I'm not a clinician, it's hard to make a judgment about whether the device is safe and because I can't judge the safety that well, I feel I can't judge the risk benefit, so I limited my vote to efficacy," she said.
On that vote, again, all but 1 of the panel members determined that the company had demonstrated the device's efficacy. Here, the abstention was from Christopher John Lettieri, MD, from Walter Reed National Military Medical Center, Bethesda, Maryland. He said he abstained because "there was residual sleep apnea and functional impairment," although he considered the treatment was "clearly better" than untreated sleep apnea.
The most common symptom of OSA is excessive daytime sleepiness, which could lead to unintentional injuries. Recent studies have linked OSA with the development of obesity, hypertension, diabetes mellitus, and congestive heart failure.
Traditional therapies for OSA have varying success rates. CPAP is an effective first-line therapy, but patient nonadherence because of discomfort, noise, or other factors limits its beneficial effect. Patients can also try oral appliances.
As for surgical therapies, success rates range from 40% and 60%. Most of these approaches address obstruction at a single anatomic location of the throat, but patients typically have multilevel airway obstructions. Other drawbacks are that although surgeons commonly perform procedures on the soft palate in the mouth, they have limited options to remove obstructions at the base of the tongue, and available surgical options may compromise tongue function or alter facial anatomy.
Meeting of the Anesthesiology and Respiratory Therapy Devices Panel of the Medial Devices Advisory Committee, FDA, White Oak Campus, Silver Spring, Maryland, February 20, 2014.
N Engl J Med. 2014:370:139-149.
Clinical Implications
An FDA panel found almost unanimously that an implantable stimulator is safe and effective for treatment of OSA and that its benefits outweigh the risks. As the patient inspires during sleep, the device stimulates the hypoglossal nerve, which contracts the upper airway muscles, pulls the base of the tongue forward, and helps maintain airway opening.
Concerns of the FDA panel regarding safety of the implantable stimulator for OSA include persistent tongue weakness in some patients and contraindication for MRI in patients who have undergone implantation. In addition, the stimulator was tested almost exclusively in white participants, and clinicians will need training in implanting the device, which has a significant learning curve.
In the STAR trial of participants with OSA who had failed or who were intolerant of CPAP treatment, the responder rate at 12 months was 66% for AHI and 75% for ODI, and these positive results persisted to 18 months. Also noted were improvements on the percentage of sleep time with an oxygen saturation of less than 90%.
CME Test
The educational activity presented above may involve simulated case-based scenarios. The patients depicted in these scenarios are fictitious and no association with any actual patient is intended or should be inferred.
The material presented here does not necessarily reflect the views of Medscape, LLC, or companies that support educational programming on medscape.org. These materials may discuss therapeutic products that have not been approved by the US Food and Drug Administration and off-label uses of approved products. A qualified healthcare professional should be consulted before using any therapeutic product discussed. Readers should verify all information and data before treating patients or employing any therapies described in this educational activity.
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