Heart Failure
Conditions
Keywords
Preserved Ejection Fraction
Brief summary
Heart failure with preserved ejection fraction (HFpEF) is a major public health problem that has no proven effective treatment. This study will assess the effects of nebulized inhaled nitrite administration on resting and exercise hemodynamics in patients with HFpEF referred to the catheterization lab.
Detailed description
Patients referred to the cardiac catheterization laboratory for invasive exercise stress testing will be prospectively recruited. Standard right heart catheterization using high fidelity micromanometers (Millar Instruments) will be performed at rest and during supine exercise with simultaneous expired gas analysis (Medgraphics) as is the investigator's current practice. The protocol is rest-passive leg elevation--20 Watts exercise x 5 minutes, and then graded workload increases in 10Watt increments (3 minute stages) to exhaustion. Hemodynamic, arterial and mixed venous blood gas and expired gas data are acquired at rest, during each exercise stage and at peak exercise. Venous blood samples will be obtained at rest and at peak exercise. Perceived symptoms of dyspnea and fatigue will be quantified using the Borg dyspnea and effort scores at each stage of exercise. After the initial exercise study and hemodynamics have returned to baseline, previously prepared study drug (normal saline placebo or Sodium Nitrite Inhalation Solution (AIR001) 90mg placed into the medication chamber) will be nebulized utilizing the Aerogen Solo-Idehaler over 10-15 minutes. After a 15 minute observation period post completion of nebulization, resting hemodynamic and expired gas data will be acquired exactly as in the initial run. Subjects will then repeat the leg elevation-20 Watt x 5 minutes exercise phase. Blood samples will be again obtained at rest and with exercise. Subjects will repeat exercise only at the 20 Watt stage, rather repeating the entire study. This is done to increase the feasibility and shorten the time of the case. The investigators have previously observed that the vast majority (\>85%) of the elevation in cardiac filling pressures and reduction in venous oxygen content in people with HFpEF occurs at the low 20 Watt workload, so repeating exercise hemodynamic assessment at this load should be sufficient to detect any clinically meaningful treatment effect.
Interventions
90mg of (nebulized) inhaled sodium nitrite will be administered (by inhalation) to participants prior to exercise.
OTHERPlacebo
Normal saline will be administered (by inhalation) to participants prior to exercise.
Sponsors
Aires Pharmaceuticals, Inc.
National Heart, Lung, and Blood Institute (NHLBI)
Mayo Clinic
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
DIAGNOSTIC
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Heart Failure with preserved Ejection Fraction (HFpEF) is defined by clinical symptoms of dyspnea and fatigue * Normal left ventricular ejection fraction (\>/=50%) * And elevated Left Ventricular (LV) filling pressure at cardiac catheterization (defined as resting Pulmonary Capillary Wedge Pressure (PCWP)\>15 mmHg and/or PCWP \>/=25 mmHg during exercise).
Exclusion criteria
* Systolic Blood Pressure \<120 mmHg (during catheterization) * Prior nitrate therapy (within previous 2 weeks) * Glucose-6-Phosphate Dehydrogenase (G6PD) deficiency * Other non-HFpEF specific causes of heart failure such as significant valvular disease (\>moderate left-sided regurgitation, \>mild stenosis) * Severe pulmonary disease * Unstable coronary disease or coronary spasm * Primary renal or hepatic disease (end stage renal failure/on dialysis or clinical diagnosis of hepatitis or hepatic cirrhosis) * Constrictive pericarditis, or infiltrative, restrictive, or hypertrophic cardiomyopathies * Pregnant
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Pulmonary Capillary Wedge Pressure During Exercise | Baseline, after study drug dosing, approximately 4 minutes after starting exercise | Pulmonary capillary wedge pressure is a measure of cardiac filling pressure, measured in millimeters of mercury (mmHg) |
Countries
United States
Participant flow
Recruitment details
Participants were referred to the Rochester, Minnesota Mayo Clinic cardiac catheterization laboratory for invasive hemodynamic exercise stress testing between December 2014 and December 2015.
Pre-assignment details
Of 70 patients screened, 32 were excluded based upon entry criteria and 12 were excluded based on hemodynamic criteria for Heart Failure with preserved Ejection Fraction (HFpEF) (n=10) or because arterial pressures were too low (n=2).
Participants by arm
| Arm | Count |
|---|---|
| Placebo (Saline) Participants receive normal saline, administered by inhalation over 10-15 minutes, using a nebulizer
Placebo: Normal saline will be administered (by inhalation) to participants prior to exercise. | 13 |
| Sodium Nitrite Participants receive Sodium Nitrite inhalation solution, administered by inhalation over 10-15 minutes, using a nebulizer
Sodium Nitrite Inhalation Solution: 90mg of (nebulized) inhaled sodium nitrite will be administered (by inhalation) to participants prior to exercise. | 13 |
| Total | 26 |
Baseline characteristics
| Characteristic | Placebo (Saline) | Total | Sodium Nitrite |
|---|---|---|---|
| Age, Continuous | 72 years STANDARD_DEVIATION 10 | 70 years STANDARD_DEVIATION 10 | 67 years STANDARD_DEVIATION 9 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 13 Participants | 26 Participants | 13 Participants |
| Region of Enrollment United States | 13 participants | 26 participants | 13 participants |
| Sex: Female, Male Female | 8 Participants | 14 Participants | 6 Participants |
| Sex: Female, Male Male | 5 Participants | 12 Participants | 7 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 1 / 13 | 1 / 13 |
| serious Total, serious adverse events | 0 / 13 | 0 / 13 |
Outcome results
Primary
Change in Pulmonary Capillary Wedge Pressure During Exercise
Pulmonary capillary wedge pressure is a measure of cardiac filling pressure, measured in millimeters of mercury (mmHg)
Time frame: Baseline, after study drug dosing, approximately 4 minutes after starting exercise
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo (Saline) | Change in Pulmonary Capillary Wedge Pressure During Exercise | -1 millimeters of mercury | Standard Deviation 2 |
| Sodium Nitrite | Change in Pulmonary Capillary Wedge Pressure During Exercise | -4 millimeters of mercury | Standard Deviation 3 |
p-value: 0.002t-test, 2 sided