Central Apnea in Heart Failure: Physiological Mechanisms to Inform Treatment

Official Summary

Central sleep apnea (CSA) is common in patients with heart failure and those using opioid analgesics. Unfortunately, effective treatment of central apnea remains elusive, pressure therapy given the modest efficiency of positive airway pressure therapy. The focus of this proposal is to identify mechanistic pathways to guide future therapeutic interventions for central sleep apnea based on the strong premise that multi-modality therapy will normalize respiration and hence mitigate adverse long-term consequences of CSA. The investigators' proposed studies will test combination therapies, including positive airway pressure (PAP) plus a pharmacological agent who have heart failure or are using opioid analgesics. The investigators anticipate that findings will inform future clinical trials to improve care and quality of life among Veterans suffering from central sleep apnea, which remains difficult to treat using existing approaches.

Eligibility Requirements

• Minimum Age: 18 Years

Study Design

• Study Type: INTERVENTIONAL
• Allocation: RANDOMIZED
• Model: CROSSOVER
• Masking: DOUBLE
• Enrollment: 200 participants

Study Arms

• Trazodone (ACTIVE_COMPARATOR)
  To determine the effect of dampening respiratory arousals. The investigators hypothesize that PAP therapy with trazodone at 100 mg will be superior to CPAP alone in widening the CO2 reserve during sleep, decreasing respiratory arousals, and increasing the arousal threshold.
• Oxygen (ACTIVE_COMPARATOR)
  To determine the effect of dampening peripheral chemoreceptor sensitivity. The investigators hypothesize that supplemental oxygen will be superior to CPAP alone in widening the CO2 reserve during sleep. The secondary analysis will use CAI as supplemental oxygen, which may obscure the detection of hypopneas based on desaturation.

Interventions

• DRUG: Trazodone + PAP therapy — The central apnea index and the apneic threshold will be compared under two conditions: trazodone or placebo. In addition, participants will get PAP therapy during both the conditions.
• DRUG: Oxygen + PAP therapy — The central apnea index and the apneic threshold will be compared under two conditions: oxygen or room air. In addition, participants will get PAP therapy during both the conditions.

Primary Outcomes

• CO2 Reserve (120 days)

Secondary Outcomes

• Peripheral Chemoresponsiveness (120 days)
• Arousal Threshold (120 days)
• Carotid body function (120 days)
• Controller gain (120 days)
• Plant gain (120 days)

Eligibility Criteria

Inclusion Criteria:

* Men and Women Veterans with central sleep apnea, defined as Apnea Hypopnea Index (AHI)\>15/hour with CAHI\>5/hour, will be included with the experiments.
* Those with chronic, stable heart failure with reduced ejection fraction, receiving stable optimized guideline-based therapy and no hospitalizations or change in the medical regimen for the past 90 days before enrollment.

Exclusion Criteria:

* less than 18 years old
* pregnant or breastfeeding females
* moderate or severe obstructive or restrictive lung disease, including supplemental o2 use
* current treatment for CSA, including any form of PAP in the past three months, or phrenic nerve situation.
* too ill to engage in the study procedures, inability to provide consent for participation.
* a history of cardiac arrhythmia
* Alcohol or substance abuse (less than 90 days sobriety) or current participation in a treatment program
* depression or a history of suicidality
* severe insomnia (ISI\>21) or reported short sleep duration (\<6 hours)
* PAP-emergent central sleep apnea
* Lack of PAP acceptance/adherence after a one-week home PAP trial after enrollment.

Additional Trazodone Exclusions:

* Prolonged QT on baseline ECG, using medications that inhibit CYP3A4
* Patients with severe renal impairment (GFR \< 20ml/min/1.73m2) or end-stage renal disease

Trial Locations

• John D. Dingell VA Medical Center, Detroit, MI, Detroit, Michigan, United States

Contact Information

• M S Badr, MD — CONTACT
  Phone: (313) 576-1000
  Email: sbadr@med.wayne.edu

Study Officials

• M Safwan Badr, MD — PRINCIPAL_INVESTIGATOR
  John D. Dingell VA Medical Center, Detroit, MI

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