Phrenic Nerve Pacing: A Revolution in the Treatment of Central Sleep Apnea

Sleep apnea is increasingly recognized as a common comorbidity that contributes to adverse outcomes for patients with cardiovascular disease. While many cardiologists are aware of the need to screen and treat sleep apnea in their patients, the majority of attention to date has focused on obstructive sleep apnea (OSA). Central sleep apnea (CSA) is prevalent in 30%-50% of patients with heart failure¹ and is also common in patients with atrial fibrillation.² Heart failure patients with CSA have a higher risk of readmission to the hospital and a significantly increased risk of death, as compared to patients with no sleep disordered breathing.^3,4

Until recently, few effective treatment options existed for these patients. Traditional positive pressure ventilation is not only ineffective in some patients, but the recent SERVE-HF trial demonstrated that heart failure patients with a left ventricular ejection fraction of ≤45% who received adaptive servo-ventilation (ASV) had a 34% increase in cardiovascular mortality compared to patients in the control group who did not receive therapy.⁵

Transvenous phrenic nerve pacing (remedē^®, Respicardia, Inc.) has emerged as an entirely novel therapy for CSA. It restores physiologic nocturnal breathing via an implanted device without the use of positive pressure ventilation. Utilizing technology similar to pacemakers and neurostimulators, this device utilizes transvenous leads placed in the chest to detect apneas. The leads deliver electricity to directly stimulate the phrenic nerve and restore normal movement of the diaphragm.⁶

CENTRAL SLEEP APNEA

Central sleep apnea is a form of sleep disordered breathing characterized by at least a 10-second pause in ventilation without associated respiratory effort. CSA results from an intermittent neural drive to breathe, resulting in a periodic breathing pattern (Cheyne-Stokes). This is due to a delay in the brain’s response to changes in carbon dioxide (CO₂) levels whereby the brain does not initiate breathing until the CO₂ level has raised significantly above the normal level. This results in rapid, deep breathing to expel the excess CO₂ continuing until the CO₂ level is far below normal levels. In turn, this leads to a cessation of breathing (apnea) or shallow breathing (hypopnea).^7,8

Each apnea and hypopnea event contributes to a progressive cycle of arousals from sleep, hypoxia, ischemia, and inflammation, and an increased sympathetic drive. This cycle can be especially detrimental in patients with heart failure.¹ Included among its multiple deleterious effects are:

• Arousals. Arousals have shown to diminish sleep quality leading to fatigue and decreased mental acuity.¹
• Hypoxia. Hypoxia leads to myocardial ischemia and poor cerebral perfusion.⁹
• Inflammation. Inflammation leads to adverse cardiac remodeling, worsening heart failure.¹
• Increased sympathetic drive. This increased drive results in increased blood pressure, fluid retention, myocardial fibrosis, and ventricular and atrial arrhythmias.¹

Central sleep apnea can be difficult to recognize, particularly in patients with heart failure, as symptoms of the two conditions frequently overlap (eg, fatigue, cognitive impairment, inability to get restful sleep, and daytime somnolence). In contrast to OSA patients, many CSA patients are not overweight and do not snore, which also makes CSA challenging to identify. Therefore, it is necessary to have a high index of suspicion for CSA, particularly when evaluating patients with heart failure and/or atrial fibrillation who continue to complain of fatigue and poor quality of life despite optimal medical therapy.¹⁰

Diagnosis is typically made by a sleep study. This can be either a full overnight polysomnogram (PSG) or a home sleep study. Providers should note that not all home sleep study devices are equipped to diagnose central sleep apnea. They should specify that they are screening for CSA or verify that the home device is capable of diagnosing CSA. If a patient is found to have moderate to severe sleep apnea with at least 50% or more central apnea events, phrenic nerve stimulation may be appropriate.¹⁰

THE DEVICE AND IMPLANT PROCEDURE

The phrenic nerve stimulator system¹¹ is implanted by electrophysiologists using many of the same skills utilized in cardiac resychronization therapy device procedures. The device is placed in the right chest and has two leads inserted into the axillary vein. The leads resemble coronary sinus leads and utilize similar delivery systems. They are delivered over 0.014˝ guidewires. The sensing lead, used to measure transthoracic impedance as a means to detect diaphragm movement, is placed in the azygous vein, located posterior to the heart, and advanced into an intercostal vein at the level of the diaphragm. The stimulation lead is placed in the left pericardiophrenic vein, a vein of the pericardium that drains in the innominate vein, just across from the left internal jugular vein. This very small vein, approximately the size of a small branch of the coronary sinus, courses directly adjacent to the left phrenic nerve. It is the ideal location to selectively stimulate this nerve without cardiac stimulation. A 4 French quadripolar lead is placed in this vein at approximately the level of the left atrium. The leads are secured to the pectoralis muscle, attached to the header of the device, and then the device and excess leads are placed into a subcutaneous pocket, similar to a right-sided cardiac device implant (Figures 1 and 2). If the left pericardiophrenic vein is not accessible or suitable for lead placement, the stimulation lead can be placed in the right brachiocephalic, which is adjacent to the right phrenic nerve.

As with any new procedure, there is a steep learning curve. However, most electrophysiologists should be proficient after approximately three cases and very comfortable after six or seven cases. Respicardia offers implant training, including case observations and proctoring.

THE TECHNOLOGY

While the device resembles a pacemaker, it functions as a neurostimulator. It delivers electricity through a series of low amplitude (3-4 mAmp) pulses delivered over a very short duration (0.15 msec) at a rapid rate (20 Hz). These stimulation characteristics will selectively stimulate the phrenic nerve and create a smooth, physiologic diaphragm contraction. This is in contrast to the uncomfortable phrenic nerve stimulation inadvertently generated by cross talk from coronary sinus leads that are programmed to pace at comparatively higher outputs over longer durations and lower frequency. Because the two domes of the diaphragm are joined by the central tendon of the diaphragm, it is possible to have bilateral diaphragm movement from unilateral phrenic nerve stimulation.

Following implant and recovery, the device is programmed to the patient’s specific therapy needs. Therapy is initiated one month after implant to allow for healing and recovery as well as to collect data on baseline respiratory patterns detected via the sensing lead. The system activates automatically each night, negating the need for any patient interaction and ensuring compliance. Therapy activates when the following programmable conditions are met:¹¹

• The time is within the patient’s normal sleeping hours (e.g., 11 p.m. to 6 a.m.), AND
• The patient is in a reclined position, AND
• The patient is not moving.

If the patient rolls over, sits up, or gets out of bed, therapy pauses; it resumes once the three conditions are met. Device programming and diagnostics are provided via interaction with a tablet-based programmer.¹¹

THE PIVOTAL TRIAL

The Pivotal trial⁶ was a prospective, multicenter, randomized control study of phrenic nerve pacing for patients with CSA. Patients were eligible if they had an Apnea-Hypopnea Index (AHI) greater than 20 events/hour with at least 50% central apneas. A total of 151 patients were randomized to treatment or control at the time of implant. Of note, all patients underwent device implantation, but the control group had the stimulation component of their devices turned off for the first 6 months and then therapy was turned on for the remainder of the trial. The device was successfully implanted 97% of the time with an average procedure duration of 2.7 hours. Procedural risks were similar to other transvenous systems, and there was a 91% freedom from serious adverse events related to the therapy, device, or procedure. At 6 months post implant, 87% of patients had a reduction in the AHI, and this improvement was sustained throughout the trial. Recently, the 3-year safety and effectiveness outcomes were published, demonstrating a strong safety profile and a similar sustained effectiveness benefit.¹²

Post-hoc analysis of the Pivotal trial showed that heart failure was prevalent in 64% of patients, with an average left ventricular ejection fraction (LVEF) of 34.5%. These patients demonstrated similar improvements in AHI as the overall patient population in the trial. After 12 months of therapy, there was a 6.8 ± 20.0 point improvement in the Minnesota Living with Heart Failure questionnaire, an improvement in left ventricular ejection fraction, and a decrease in left ventricular end-systolic volume (LVESV). Concomitant cardiac electronic devices were present in 63% of patients. Interaction between the phrenic nerve stimulator and an implanted cardiac device was extremely rare; all events were resolved by reprogramming the phrenic nerve stimulator.¹³ Based on the results of the Pivotal trial, in October 2017, the U.S. Food and Drug Administration (FDA) approved phrenic nerve stimulation for moderate to severe central sleep apnea in adults.¹¹

THE SAINT LUKE’S EXPERIENCE

Our institution, Saint Luke’s Mid America Heart Institute, began participating in the Pivotal trial in 2013. We were the largest enrolling U.S. center in the trial. The success of our center was due to a collaborative approach between heart failure, sleep medicine, and electrophysiology, and the presence of a dedicated coordinator to facilitate communication and procedures as well as to advocate for the patient. To date, we have implanted over 24 devices in Saint Luke’s patients, and we continue to follow up in our device and heart failure clinics.

Case Study

A 43-year-old male, without known cardiovascular disease, was diagnosed with idiopathic severe CSA with an AHI of 34. He had a family history of the disease and his father died in his sleep, thought to be due to untreated CSA. In March 2013, he underwent placement of the phrenic nerve stimulator (Figures 3-6); after one month of healing, the therapy was turned on. A year after implant, the patient had 32 total episodes of apnea per night, down from 195 (fewer than 5 events per hour). At 2-year post-op, he had 23 total episodes per night. At his third anniversary, he was having just 4 total episodes per night. Despite having an erratic sleep schedule due to his work and frequent travel, he was surprised how flexible the device programming could be made to facilitate his need to sleep at various times of the day. Today, this patient and his wife are strong proponents for getting a sleep study and receiving the remedē^® System for appropriate indications. The patient has spoken with other patients who are unsure about getting an implant.

DISCUSSION

Central sleep apnea has potentially serious health outcomes when left untreated. Traditional positive airway pressure therapies are not only ineffective in some patients, they are potentially dangerous for patients with heart failure and a left ventricular ejection fraction ≤45%.¹⁴ This has left a substantial portion of patients untreated.

Phrenic nerve stimulation is a promising therapy to meet this clinical need. The largest obstacle to widespread adoption is the challenge in diagnosis. Because no single symptom or sign provides unequivocal indication of CSA, the most important thing for clinicians is to have a high index of suspicion for this condition. Ordering sleep studies in patients with heart failure and/or atrial fibrillation who continue to complain of fatigue despite optimal medical therapy can help identify patients who may benefit.

Another necessary component to establishing a successful program is to identify champions who are passionate about the treatment of CSA in the fields of heart failure and sleep medicine. By working together, it is possible to create a multidisciplinary patient-focused team that can be a very rewarding experience for all involved. While there are always obstacles in implementing a new program, the rewards for the patients are worth the effort. At some point, nearly every patient at our center has reported feeling better. Patients have expressed gratitude for not having to wear a CPAP mask, for having more energy, for less fatigue, and for being able to think more clearly. Many tell us that their jobs, home life, and relationships are all better after getting this therapy. They still have a primary diagnosis of congestive heart failure or atrial fibrillation, but they experience many positive changes in their daily lives by addressing the symptoms of CSA.

CONCLUSION

Transvenous phrenic nerve stimulation is an entirely novel therapy for central sleep apnea, an underrecognized and potentially serious condition. This is the only FDA-approved CSA therapy for patients with a left ventricular ejection fraction of ≤45%. The results are transformative for most patients. The advent of this therapy is an exciting opportunity for electrophysiologists to provide care in an entirely new manner, one that can be challenging at times, yet extremely rewarding. 

Disclosures: Dr. Gupta performs clinical research supported by grants from Medtronic, Boston Scientific, and Bristol-Myers Squibb. He consults for Medtronic, Boston Scientific, and Respicardia. Dr. Kao has no conflicts of interest to report regarding the content herein. Medical writer Margaret Gowan Mester, MA, helped edit this article; her services were paid by Respicardia.

This article is published with support from Respicardia, Inc.

1. Bekfani T, Abraham WT. Current and future developments in the field of central sleep apnoea. EP Europace. 2016;18(8):1123-1134.
2. Bitter T, Langer C, Vogt J, Lange M, Horstkotte D, Oldenburg O. Sleep-disordered breathing in patients with atrial fibrillation and normal systolic left ventricular function. Dtsch Arztebl Int. 2009;106(10):164-170.
3. Khayat R, Abraham W, Patt B, et al. Central sleep apnea is a predictor of cardiac readmission in hospitalized patients with systolic heart failure. J Card Fail. 2012;18(7):534-540.
4. Khayat R, Jarjoura D, Porter K, et al. Sleep disordered breathing and post-discharge mortality in patients with acute heart failure. Eur Heart J. 2015;36(23):1463-1469.
5. Cowie MR, Woehrle H, Wegscheider K, et al. Adaptive servo-ventilation for central sleep apnea in systolic heart failure. N Engl J Med. 2015;373:1095-1105.
6. Costanzo M, Ponikowski P, Javaheri S, et al. Transvenous neurostimulation for central sleep apnoea: a randomised controlled trial. Lancet. 2016;388:974-982.
7. Dempsey JA, Veasey SC, Morgan BJ, O'Donnell CP. Pathophysiology of sleep apnea. Physiol Rev. 2010;90(1):47-112. [Published correction appears in Physiol Rev. 2010;90(2):797-798].
8. Javaheri S. Central sleep apnea. Clin Chest Med. 2010;31:235-248.
9. Oldenburg O, Wellmann B, Buchholz A, et al. Nocturnal hypoxaemia is associated with increased mortality in stable heart failure patients. Eur Heart J. 2016; 37:1695-1703.
10. Abraham WT, Pleister A, Germany R. Identification and treatment of central sleep apnoea: beyond SERVE-HF. Card Fail Rev. 2018;4(1):50-53.
11. remedē^® System - P160039. U.S. FDA. Published October 23, 2017. Available at https://www.fda.gov/medical-devices/recently-approved-devices/remeder-system-p160039. Accessed October 2, 2019.
12. Fox H, Oldenburg O, Javaheri S, et al. Long-term efficacy and safety of phrenic nerve stimulation for the treatment of central sleep apnea. Sleep. Published July 8, 2019. doi.org/10.1093/sleep/zsz158.
13. Costanzo MR, Ponikowski P, Coats A, et al. Phrenic nerve stimulation to treat patients with central sleep apnoea and heart failure. Eur J Heart Fail. 2018;20:1746-1754.
14. Aurora RN, Bista SR, Casey KR, et al. Updated Adaptive Servo-Ventilation Recommendations for the 2012 AASM Guideline: “The Treatment of Central Sleep Apnea Syndromes in Adults: Practice Parameters with an Evidence-Based Literature Review and Meta-Analyses.” J Clin Sleep Med. 2016;12(5):757-761.