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

• Sponsor: David Andrew Wellman (Other)
• Overall Status: Completed
• CT.gov ID: NCT01377987
• Collaborator: American Heart Association (Other), National Institutes of Health (NIH) (NIH)
• Enrollment: 29
• Location: 1
• Arms: 2
• Duration (Months): 64
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

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.

Condition or Disease	Intervention/Treatment	Phase
Heart Failures	Drug: Acetazolamide; Drug: Placebo	N/A

Study Design

• Study Type: Interventional
• Actual Enrollment: 29 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Basic Science
• Official Title: Physiological Study to Predict Successful Sleep Apnea Treatment With Acetazolamide in Heart Failure Patients
• Study Start Date: Aug 1, 2011
• Actual Primary Completion Date: Dec 1, 2016
• Actual Study Completion Date: Dec 1, 2016

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures

1. The Severity of Sleep Disordered Breathing (Apnea-hypopnea Index, AHI) [1 week]

   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.

Secondary Outcome Measures

1. Ventilatory Chemoreflex Sensitivity, "Loop Gain" Using Carbon Dioxide Pulses [1 week]

   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.

2. Sympathetic Activity (Urinary Norepinephrine) [1 week]

   Urinary norepinephrine levels overnight

3. Left-atrial Volume [1 week]

   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).

4. Brain Natriuretic Peptide (NT-proBNP) [1 week]

   Brain natriuretic peptide (NT-proBNP) in morning

5. Pittsburgh Sleep Quality Index [1 week]

   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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 89 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Brigham and Women's Hospital	Boston	Massachusetts	United States	02115

Sponsors and Collaborators

• David Andrew Wellman
• American Heart Association
• National Institutes of Health (NIH)

Investigators

• Principal Investigator: Andrew Wellman, MD, PhD, Brigham and Women's Hospital
• Principal Investigator: Atul Malhotra, MD, Brigham and Women's Hospital

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: David Andrew Wellman, Associate Professor of Medicine, Brigham and Women's Hospital
• ClinicalTrials.gov Identifier: NCT01377987
• Other Study ID Numbers: 2011-P-000049/1
• First Posted: Jun 22, 2011
• Last Update Posted: Jun 13, 2018
• Last Verified: May 1, 2018

• Additional relevant MeSH terms: Heart Failure; Acetazolamide

Study Results

Participant Flow

Arm/Group Title	Acetazolamide First, Then Placebo	Placebo First, Then Acetazolamide
Arm/Group Description	Acetazolamide: 4 mg/kg, once daily before bed, for 7 days 1 week washout Placebo: 4 mg/kg, once daily before bed, for 7 days	Placebo: 4 mg/kg, once daily before bed, for 7 days 1 week washout Acetazolamide: 4 mg/kg, once daily before bed, for 7 days
Period Title: First Intervention (7 Days)
STARTED	14	15
COMPLETED	14	15
NOT COMPLETED	0	0
Period Title: First Intervention (7 Days)
STARTED	14	15
COMPLETED	13	14
NOT COMPLETED	1	1
Period Title: First Intervention (7 Days)
STARTED	13	14
COMPLETED	13	14
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	All Patients
Arm/Group Description	All patients randomized
Overall Participants	29
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	60 (13)
Sex: Female, Male (Count of Participants)
Female	3 10.3%
Male	26 89.7%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	1 3.4%
White	28 96.6%
More than one race	0 0%
Unknown or Not Reported	0 0%

Outcome Measures

1. Primary Outcome

Title	The Severity of Sleep Disordered Breathing (Apnea-hypopnea Index, AHI)
Description	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.
Time Frame	1 week

Outcome Measure Data

Analysis Population Description

All participants who were randomized and completed the relevant study arm. Data are for non-REM supine sleep.

Arm/Group Title	Acetazolamide	Placebo
Arm/Group Description	Acetazolamide (active arm)	Placebo arm
Measure Participants	28	28
All participants	26.3 (22.7)	36.1 (27.8)
Patients with sleep apnea	32.3 (22.1)	44.6 (25.3)

2. Secondary Outcome

Title	Ventilatory Chemoreflex Sensitivity, "Loop Gain" Using Carbon Dioxide Pulses
Description	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.
Time Frame	1 week

Outcome Measure Data

Analysis Population Description

All participants who completed the relevant arm. Morning data are reported.

Arm/Group Title	Acetazolamide	Placebo
Arm/Group Description	Acetazolamide (active arm)	Placebo arm
Measure Participants	28	28
Mean (Standard Deviation) [unitless]	0.40 (0.16)	0.49 (0.14)

3. Secondary Outcome

Title	Sympathetic Activity (Urinary Norepinephrine)
Description	Urinary norepinephrine levels overnight
Time Frame	1 week

Outcome Measure Data

Analysis Population Description

All participants who completed the relevant study arm

Arm/Group Title	Acetazolamide	Placebo
Arm/Group Description	Acetazolamide (active arm)	Placebo arm
Measure Participants	28	28
Mean (Standard Deviation) [ug/g-creatinine]	40.8 (23.6)	35.0 (17.3)

4. Secondary Outcome

Title	Left-atrial Volume
Description	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).
Time Frame	1 week

Outcome Measure Data

Analysis Population Description

echocardiography could not be performed on one study due to rescheduling issues

Arm/Group Title	Acetazolamide	Placebo
Arm/Group Description	Acetazolamide (active arm)	Placebo arm
Measure Participants	27	28
Mean (Standard Deviation) [mL/m^2]	34.3 (12.1)	40.0 (13.5)

5. Secondary Outcome

Title	Brain Natriuretic Peptide (NT-proBNP)
Description	Brain natriuretic peptide (NT-proBNP) in morning
Time Frame	1 week

Outcome Measure Data

Analysis Population Description

All participants who completed the relevant arm

Arm/Group Title	Acetazolamide	Placebo
Arm/Group Description	Acetazolamide (active arm)	Placebo arm
Measure Participants	28	28
Mean (Standard Deviation) [pg/ml]	919 (1320)	932 (1403)

6. Secondary Outcome

Title	Pittsburgh Sleep Quality Index
Description	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.
Time Frame	1 week

Outcome Measure Data

Analysis Population Description

All participants who participated in the relevant study arm.

Arm/Group Title	Acetazolamide	Placebo
Arm/Group Description	Acetazolamide (active arm)	Placebo arm
Measure Participants	28	28
Mean (Standard Deviation) [units on a scale]	6.7 (3.6)	7.5 (3.8)

Adverse Events

Arm/Group Title	Acetazolamide		Placebo
Arm/Group Description	Acetazolamide (active arm)		Placebo arm
All Cause Mortality
	Acetazolamide		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/28 (0%)		0/28 (0%)
Serious Adverse Events
	Acetazolamide		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/28 (0%)		0/28 (0%)
Other (Not Including Serious) Adverse Events
	Acetazolamide		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	17/28 (60.7%)		6/28 (21.4%)
Eye disorders
Dry eyes	1/28 (3.6%)	1	0/28 (0%)	0
Gastrointestinal disorders
Gastrointestinal discomfort	2/28 (7.1%)	2	2/28 (7.1%)	2
General disorders
Fall without injury	1/28 (3.6%)	1	0/28 (0%)	0
Fatigue	3/28 (10.7%)	3	1/28 (3.6%)	1
Headache	0/28 (0%)	0	1/28 (3.6%)	1
Reduced exercise tolerance	0/28 (0%)	0	1/28 (3.6%)	1
Metabolism and nutrition disorders
Taste Disturbance	4/28 (14.3%)	4	0/28 (0%)	0
Nervous system disorders
Paresthesias	5/28 (17.9%)	5	0/28 (0%)	0
Renal and urinary disorders
Nocturia	12/28 (42.9%)	12	1/28 (3.6%)	1
Vascular disorders
Lightheadedness upon standing	1/28 (3.6%)	1	1/28 (3.6%)	1

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.