Predicting Successful Sleep Apnea Treatment With Acetazolamide in Heart Failure Patients (HF-ACZ)

Physiological Study to Predict Successful Sleep Apnea Treatment With Acetazolamide in Heart Failure Patients

The ultimate goal is to improve our understanding of the pathophysiology and resistance to effective treatment of sleep disordered breathing in patients with heart failure, with a focus on selecting patients that will benefit specifically from acetazolamide treatment.

The study addresses three primary hypotheses: 1) Acetazolamide treatment will reduce the apnea-hypopnea index and improve markers of heart-failure severity in heart-failure patients with sleep apnea. 2) Acetazolamide will provide the greatest improvement in patients with the most severe ventilatory control instability (strongest chemoreflex response to carbon dioxide; highest loop gain). 3) Acetazolamide will act primarily via stabilizing ventilatory control (reducing loop gain), rather than via improvement to upper airway anatomy, pulmonary congestion, and cardiac function.

Study Overview

• Status: Completed
• Conditions: Heart Failures
• Intervention / Treatment: Drug: Acetazolamide; Drug: Placebo

• Study Type: Interventional
• Enrollment (Actual): 29
• Phase: Not Applicable

Contacts and Locations

Study Locations

• United States
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Brigham and Women's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria (Heart failure patients)

• Left ventricular ejection fraction (EF) <50%, or heart failure with preserved EF
• Age 18-89

Exclusion Criteria:

• severe obstructive respiratory disease
• unstable heart failure status
• recent use of positive airway pressure therapy
• current use of opioids, benzodiazepines
• severe kidney disease
• severe anemia

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Basic Science
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Sugar pill	Drug: Placebo; 4 mg/kg, once daily before bed, for 7 days
Experimental: Acetazolamide	Drug: Acetazolamide; 4 mg/kg, once daily before bed, for 7 days; Other Names: Diamox

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The Severity of Sleep Disordered Breathing (Apnea-hypopnea Index, AHI)	The frequency of apneas and hypopneas (apnea-hypopnea index) was assessed. The primary measure was the value for non-REM supine sleep. A higher value indicates more severe sleep apnea. A value above 15 indicates the presence of moderate-to-severe sleep apnea.	1 week

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Ventilatory Chemoreflex Sensitivity, "Loop Gain" Using Carbon Dioxide Pulses	Chemoreflex "loop gain" was assessed according to Sands SA et al AJRCCM 2017 Jan 15;195(2):237-246. Loop gain is a unitless ratio measure that describes the magnitude of the increase in ventilation that occurs in response to a prior reduction in ventilation ("disturbance") and has units of L/min per L/min. A larger value indicates a more sensitive and unstable control system predisposing to oscillatory breathing. Loop gain was measured on the time scale of 1 min (i.e. response to a 1 cycle/min sinusoidal disturbance, referred to as "LG1"). The procedure involved brief administration of 7% carbon dioxide in air for 0.5 min ("pulses"); tests were repeated every 3 min for 30 min while measuring ventilation and carbon dioxide levels at the nose with patients awake and supine. measured using 0.5 min pulses of carbon dioxide.	1 week
Sympathetic Activity (Urinary Norepinephrine)	Urinary norepinephrine levels overnight	1 week
Left-atrial Volume	Left-atrial volume index, echocardiography, bi-plane method. Lower values were considered a favorable outcome. We considered values ≤28 mL/m^2 to indicate normal left atrial volume. Values indicating graded left atrial enlargement were described as follows: mild (29-33 mL/m^2), moderate (34-39 mL/m^2), severe (≥40 mL/m^2).	1 week
Brain Natriuretic Peptide (NT-proBNP)	Brain natriuretic peptide (NT-proBNP) in morning	1 week
Pittsburgh Sleep Quality Index	Pittsburgh Sleep Quality Index is a measure of self-reported sleep quality containing 19 questions that make up 7 component scores that are added to provide a total score. Total scores range from 0-21 (units on a scale) with higher scores representing reduced sleep quality. A score of 5 or more is interpreted as reduced sleep quality. The total score is reported.	1 week

Collaborators and Investigators

• Sponsor: David Andrew Wellman
• Collaborators: National Institutes of Health (NIH); American Heart Association
• Investigators: Principal Investigator: Atul Malhotra, MD, Brigham and Women's Hospital

Study record dates

Study Major Dates

• Study Start: August 1, 2011
• Primary Completion (Actual): December 1, 2016
• Study Completion (Actual): December 1, 2016

Study Registration Dates

• First Submitted: June 20, 2011
• First Submitted That Met QC Criteria: June 20, 2011
• First Posted (Estimate): June 22, 2011

Study Record Updates

• Last Update Posted (Actual): June 13, 2018
• Last Update Submitted That Met QC Criteria: May 16, 2018
• Last Verified: May 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Heart Failure; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Carbonic Anhydrase Inhibitors; Natriuretic Agents; Diuretics; Anticonvulsants; Acetazolamide
• Other Study ID Numbers: 2011-P-000049/1