A 5-year, post-approval study of the remedē System confirmed results of the pivotal trial.
Results from a 5-year, post-approval study (PAS) of the remedē System (NCT03425188), a transvenous phrenic nerve stimulation (TPNS) therapy device by ZOLL Respicardia, suggest that long-term TPNS safely improves central sleep apnea (CSA), sleep architecture, and daytime sleepiness through 5 years post implant.1
“Patients with CSA have historically been underserved, both in terms of research into the disease and the development of effective therapies designed to treat it,” Peter Sommerness, president and chief executive officer, Respicardia, which was acquired by ZOLL in April 2021, said in a statement.2 “TPNS continues to deliver remarkable results, giving clinicians and patients confidence in the long-term safety and efficacy of the therapy.”
The FDA approved the remedē System for the treatment of moderate to severe CSA in adults in 2017. In this PAS, investigators analyzed data from 53 of the 151 original patients from the remedē System pivotal trial (NCT01816776) that consented to participate in the PAS—52 of which completed the 5-year visit. At the time of trial enrollment, 64% of participants had heart failure (HF), 42% had atrial fibrillation, 8% previous stroke, and 11% had idiopathic CSA.
Baseline median apnea-hypopnea index (AHI) was 46 events per hour of sleep (interquartile range [IQR], 34-60), which was reduced to less than 20 events per hour at 1, 2 and 5 years following TPNS therapy. Median paired change was –22 events per hour (IQR, –42 to –7; P <.001) from baseline to 5 years. Central-apnea index (CAI) improved from a median of 23 events per hour (IQR, 13-39) at baseline to 1 per hour at each yearly follow-up. Mixed apnea index, obstructive apnea index, and hypopnea index were unchanged through 5 years.
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Researchers also saw improvements in other metrics, including oxygen desaturation index (ODI4), which improved from a median of 39 events per hour (IQR, 26-57) at baseline to 15 per hour (IQR, 6-26) at 5 years. Arousal index decreased from 39 events per hour (IQR, 27-57) at baseline to 23 events per hour (12-36) at 5 years. Percentage of sleep with oxygen saturation less than 90% improved from 9% (IQR, 3-21) at baseline to 4% (IQR, 1-17) at 5 years, although the median paired change from baseline at 5 years was a 2% (IQR, –12 to 6) decrease.
At baseline, participants had a median of 31% (IQR, 19-47) of N1 sleep, 47% (IQR, 40-58) of N2 sleep, 2% (IQR, 0-9) of N3 sleep, and 10% (IQR, 6-16) of REM sleep. Overall, sleep architecture improved at 5 years from baseline. Median paired absolute changes from baseline revealed that N1 decreased by 19% (IQR, –23 to –9), N2 increased by 9% (IQR, –2 to 23) and REM increased by 5% (IQR, 0-13). Median N3 did not change (IQR, –3 to 4).
Epworth Sleepiness Scale (ESS) improved from 9 (IQR, 5-14) at baseline to 6 (IQR, 4-11) at 5 years, representing a clinically meaningful 3-point reduction. In participants with excessive daytime sleepiness (EDS; ESS > 10), 62% (n = 16/26) had an ESS of no more than 10 at 5 years. Of participants that experienced a clinically meaningful improvement, 74% (n = 37/50) improved by at least 2 points and 62% (n = 31/50) improved by at least 3 points. In participants with EDS that experienced a clinically meaningful improvement, 96% (n = 25/26) improved by at least 2 points and 88% (n = 23) improved by at least 3 points.
Treatment-related serious adverse events (SAEs) occurred in 14% (N = 21) of participants through 5 years, with the majority occurring in the first year after implant and none occurring between years 2 and 3. The most common related SAEs were concomitant cardiac device interaction, implant site infection, lead dislodgement, lead displacement, and impending pocket erosion.
Related SAEs in years 3 through 5 included a stimulation lead dislocation after a fall, stimulation lead component failure, and implant site infection. All SAEs resolved with remedē System revisions and routine care. No deaths occurred in patients enrolled in the PAS and the 5-year survival estimate from Kaplan–Meier analysis was 78%. Deaths occurred during the pivotal trial due to non-cardiovascular reasons, pump failure, sudden cardiac death, fall-related intracranial bleed, or other cardiovascular reasons; no deaths were determined to be related to treatment.
A subgroup analysis of participants with HF compared to those without confirmed results of the primary analysis, with improvements in sleep disordered breathing events, sleep architecture, and daytime sleepiness. Left stimulation leads (n = 92) had a battery longevity estimate of 47 months and right stimulation leads (n = 55) had a battery longevity estimate of 35 months for a combined estimate of 41 months.
“It is an important milestone for a therapy to demonstrate sustained patient safety and benefit over five years,” added Robin Germany, MD, chief medical officer, ZOLL Respicardia, to the statement. “Phrenic nerve stimulation continues to show a significant and durable improvement in patient outcomes, including reduction in sleep apnea events, improvement in sleep architecture, and improvements in quality of life metrics. We congratulate all of the coauthors, study investigators, and patients who have contributed to the data collection and publication of this 5-year study. We will continue to advance research on central sleep apnea and transvenous phrenic nerve stimulation as we increase access to the therapy for patients in need.”