A Phase 3 interventional study of Albuterol and Saline placebo in Congestive Heart Failure, Heart Failure, Left-Sided and Left-Sided Heart Failure, sponsored by Mayo Clinic. Completed at 1 site in United States. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2019-02-22.
Sponsored by Mayo Clinic · Phase 3, Interventional, and Treatment
The enormous and rapidly growing burden of Heart Failure with Preserved Ejection Fraction (HFpEF) has led to a need to understand the pathogenesis and treatment options for this morbid disease. Recent research from the investigator's group and others have shown that pulmonary hypertension (PH) is highly prevalent in HFpEF, and right ventricular (RV) dysfunction is present in both early and advanced stages of HFpEF.
These abnormalities in the RV and pulmonary vasculature are coupled with limitations in pulmonary vasodilation during exercise. There are no therapies directly targeted at the pulmonary vasculature that have been clearly shown to be effective in HFpEF. A recent study by Mayo Clinic Investigators has demonstrated pulmonary vasodilation with dobutamine (a beta 2 agonist) in HFpEF. As an intravenous therapy, this is not feasible for outpatient use.
In the proposed randomized, placebo-controlled double blinded trial, the investigators seek to evaluate whether the commonly used inhaled bronchodilator albuterol (a beta 2 agonist), administered through a high-efficiency nebulizer device that achieves true alveolar drug delivery, improves pulmonary vascular resistance (PVR) at rest and during exercise in patients with HFpEF as compared to placebo. This has the potential to lead to a simple cost effective intervention to improve symptoms in HFpEF, and potentially be tested in other World Health Organization (WHO) Pulmonary Hypertension groups. PVR is an excellent surrogate marker for pulmonary vasodilation and has been used in previous early trials of PH therapy.
Preliminary studies to support feasibility: Recent research from the investigator's group has shown that right ventricular (RV) dysfunction is present in a third of patients with HFpEF and the presence of pulmonary vascular disease and pulmonary hypertension (PH) is very high (related to both pulmonary venous hypertension as well as pulmonary vascular disease). Both of these have been associated with adverse outcomes and exercise intolerance but no therapy is currently available directly targeted at the pulmonary vasculature in HFpEF.
The investigators recently demonstrated significant improvements in pulmonary vascular function with dobutamine (a β2 agonist) administered acutely in HFpEF. As an intravenous therapy, this is not suitable for chronic outpatient use. Hospitalized patients with heart failure often demonstrate symptomatic improvement with inhaled β2 agonist therapy, even in the absence of pulmonary disease, and animal studies have also shown improved resolution of pulmonary edema with albuterol. In the proposed randomized, double blinded placebo-controlled trial, the investigators seek to evaluate whether the commonly used inhaled bronchodilator albuterol, administered through a high-efficiency nebulizer device, improves pulmonary vascular function in patients with HFpEF-PH as compared to placebo. This has the potential to lead to a simple cost effective intervention to improve symptoms in HFpEF-PH, and potentially be tested in other WHO PH groups.
In the absence of frank signs of congestive heart failure, patients with early HFpEF can only be reliably diagnosed by exercise right heart catheterization, which is routinely performed at Mayo Clinic as part of the evaluation of patients with unexplained dyspnea. The presence of elevated pulmonary capillary wedge pressures (PCWP) at rest (>15 mmHg) or with exercise (>25 mmHg); and elevated mean pulmonary artery pressures at rest (>25 mm Hg) and with exercise (>40 mmHg) has been used to invasively diagnose HFpEF with exercise pulmonary hypertension with a high degree of validity and reliability. Just as exercise stress unmasks abnormalities in left ventricular (LV) diastolic function in early stage HFpEF, the investigators have very recently shown that exercise stress reveals early abnormalities in pulmonary artery vascular function as compared to controls without HF that are not apparent from resting data alone.
Using objective diagnoses of HFpEF and exercise induced PH, the investigators seek to evaluate the hemodynamic changes with exercise in pulmonary vascular resistance, peak cardiac output and subjective dyspnea before and after inhaled albuterol therapy for pulmonary vasodilation.
Study design: This study will be performed in a randomized, double blind placebo-controlled fashion using inhaled albuterol or inhaled saline (prepared by research pharmacy) administered through a novel high-efficiency nebulizer in a 1:1 fashion. Patients will undergo right heart catheterization (RHC) with expired-gas analysis using high Fidelity micromanometer catheters at rest and with exercise, at baseline and following treatment with study drug, using a novel study design that the investigators have previously utilized and reported. Rest and exercise measurements will be repeated after receiving inhaled albuterol or control therapy.
Patients referred to the cardiac catheterization laboratory for invasive exercise stress testing will be prospectively recruited. Standard RHC using high fidelity micromanometers (Millar Instruments) will be performed at rest and during supine exercise with simultaneous expired gas analysis (MedGraphics) as is our current practice. The protocol is rest-20 Watts exercise x 5 minutes, and then graded workload increases in 10-20 Watt 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. Limited echocardiography will be performed by a cardiologist skilled in imaging focused on measures of RV morphology and function.
After the initial exercise study and hemodynamics have returned to baseline, study drug (normal saline placebo or albuterol 2.5 mg) will be inhaled through a high efficiency nebulizer over 5 minutes. After a 10 minute observation period, resting hemodynamic and expired gas data will be acquired exactly as in the initial run. Subjects will then repeat the 20 Watt x 5 minutes exercise phase. 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 from albuterol.
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Exclusion Criteria:
2.5 mg inhaled albuterol through a high efficiency nebulizer -single dose
Drug: Albuterol
Inhaled saline through a high efficiency nebulizer -single dose
Other: Saline placebo
: Experimental: Inhaled albuterol 2.5 mg inhaled albuterol through a high efficiency nebulizer as a single dose
Also known as: Proventil, AccuNeb, Proair, Ventolin, and Vospire
Saline inhaled through a nebulizer as a single dose
Change in 20 Watt Exercise Pulmonary Vascular Resistance (PVR)
The exercise PVR at 20 Watts after study drug relative to the exercise PVR at 20 Watts in the initial assessment prior to study drug. This measurement is made by subtracting pulmonary capillary wedge pressure from the mean pulmonary arterial pressure and dividing by cardiac output in liters per minute and reported as wood units. A decrease in PVR measured by wood units would be considered a favorable response.
Time frame: Baseline, 10 minutes after intervention during exercise
Change in Resting Pulmonary Vascular Resistance
The resting PVR after study drug relative to the resting PVR in the initial assessment prior to study drug. This measurement is made by subtracting pulmonary capillary wedge pressure from the mean pulmonary arterial pressure and dividing by cardiac output in liters per minute and reported as wood units.
Time frame: Baseline, 10 minutes after intervention
Change in Exercise Pulmonary Capillary Wedge Pressure (PCWP)
Pulmonary capillary wedge pressure was measured using a high-fidelity micromanometer advanced through the lumen of a fluid-filled catheter. PCWP position was confirmed by appearance on fluoroscopy, characteristic pressure waveforms, and oximetry.
Time frame: Baseline, 10 minutes after intervention during exercise
Change in Resting Pulmonary Capillary Wedge Pressure (PCWP)
Pulmonary capillary wedge pressure was measured using a high-fidelity micromanometer advanced through the lumen of a fluid-filled catheter. PCWP position was confirmed by appearance on fluoroscopy, characteristic pressure waveforms, and oximetry.
Time frame: Baseline, 10 minutes after intervention
Change in Exercise Pulmonary Artery Compliance
Pulmonary artery compliance was calculated as the ratio of stroke volume/pulmonary artery pulse pressure.
Time frame: Baseline, 10 minutes after intervention during exercise
Change in Resting Pulmonary Artery Compliance
Pulmonary artery compliance was calculated as the ratio of stroke volume/pulmonary artery pulse pressure.
Time frame: Baseline, 10 minutes after intervention
Change in Exercise Pulmonary Artery Pressure
Pulmonary artery pressure was measured using a high-fidelity micromanometer advanced through the lumen of a fluid-filled catheter.
Time frame: Baseline, 10 minutes after intervention during exercise
Change in Resting Pulmonary Artery Pressure
Pulmonary artery pressure was measured using a high-fidelity micromanometer advanced through the lumen of a fluid-filled catheter.
Time frame: Baseline, 10 minutes after intervention
Change in Exercise Right Atrial Pressure (RA)
RA was measured using a high-fidelity micromanometer advanced through the lumen of a fluid-filled catheter.
Time frame: Baseline, 10 minutes after intervention during exercise
Change in Resting Right Atrial Pressure (RA)
RA was measured using a high-fidelity micromanometer advanced through the lumen of a fluid-filled catheter.
Time frame: Baseline, 10 minutes after intervention
Change in Exercise Cardiac Output
Cardiac output was calculated using the direct Fick method of breath-by-breath oxygen consumption (V02)/arterial-venous oxygen content difference (AVO2 diff).
Time frame: Baseline, 10 minutes after intervention during exercise
Change in Resting Cardiac Output
Cardiac output was calculated using the direct Fick method of breath-by-breath oxygen consumption (V02)/arterial-venous oxygen content difference (AVO2 diff).
Time frame: Baseline, 10 minutes after intervention
Change in Exercise Pulmonary Elastance
Pulmonary elastance was calculated by the ratio of pulmonary artery systolic pressure/stroke volume.
Time frame: Baseline, 10 minutes after intervention during exercise
Change in Resting Pulmonary Elastance
Pulmonary elastance was calculated by the ratio of pulmonary artery systolic pressure/stroke volume.
Time frame: Baseline, 10 minutes after intervention
| Milestone | Inhaled Albuterol | Inhaled Saline Placebo |
|---|---|---|
| Started | 15 | 15 |
| Completed | 15 | 15 |
| Not completed | 0 | 0 |
The exercise PVR at 20 Watts after study drug relative to the exercise PVR at 20 Watts in the initial assessment prior to study drug. This measurement is made by subtracting pulmonary capillary wedge pressure from the mean pulmonary arterial pressure and dividing by cardiac output in liters per minute and reported as wood units. A decrease in PVR measured by wood units would be considered a favorable response.
| wood units | Inhaled Albuterol | Inhaled Saline Placebo |
|---|---|---|
| Change in 20 Watt Exercise Pulmonary Vascular Resistance (PVR) | -0.6 ± 0.5 | 0.1 ± 0.7 |
The resting PVR after study drug relative to the resting PVR in the initial assessment prior to study drug. This measurement is made by subtracting pulmonary capillary wedge pressure from the mean pulmonary arterial pressure and dividing by cardiac output in liters per minute and reported as wood units.
| wood units | Inhaled Albuterol | Inhaled Saline Placebo |
|---|---|---|
| Change in Resting Pulmonary Vascular Resistance | -0.6 ± 0.5 | -0.3 ± 0.8 |
Pulmonary capillary wedge pressure was measured using a high-fidelity micromanometer advanced through the lumen of a fluid-filled catheter. PCWP position was confirmed by appearance on fluoroscopy, characteristic pressure waveforms, and oximetry.
| mm Hg | Inhaled Albuterol | Inhaled Saline Placebo |
|---|---|---|
| Change in Exercise Pulmonary Capillary Wedge Pressure (PCWP) | -2 ± 6 | -3 ± 3 |
Pulmonary capillary wedge pressure was measured using a high-fidelity micromanometer advanced through the lumen of a fluid-filled catheter. PCWP position was confirmed by appearance on fluoroscopy, characteristic pressure waveforms, and oximetry.
| mm Hg | Inhaled Albuterol | Inhaled Saline Placebo |
|---|---|---|
| Change in Resting Pulmonary Capillary Wedge Pressure (PCWP) | -2 ± 2 | -2 ± 3 |
Pulmonary artery compliance was calculated as the ratio of stroke volume/pulmonary artery pulse pressure.
| mL/mm Hg | Inhaled Albuterol | Inhaled Saline Placebo |
|---|---|---|
| Change in Exercise Pulmonary Artery Compliance | 1.6 ± 1.6 | 0.0 ± 0.7 |
Pulmonary artery compliance was calculated as the ratio of stroke volume/pulmonary artery pulse pressure.
| mL/mm Hg | Inhaled Albuterol | Inhaled Saline Placebo |
|---|---|---|
| Change in Resting Pulmonary Artery Compliance | 1.2 ± 1.0 | 0.7 ± 1.0 |
Pulmonary artery pressure was measured using a high-fidelity micromanometer advanced through the lumen of a fluid-filled catheter.
| mm Hg | Inhaled Albuterol | Inhaled Saline Placebo |
|---|---|---|
| Change in Exercise Pulmonary Artery Pressure | -8 ± 4 | -2 ± 4 |
Pulmonary artery pressure was measured using a high-fidelity micromanometer advanced through the lumen of a fluid-filled catheter.
| mm Hg | Inhaled Albuterol | Inhaled Saline Placebo |
|---|---|---|
| Change in Resting Pulmonary Artery Pressure | -5 ± 3 | -3 ± 3 |
RA was measured using a high-fidelity micromanometer advanced through the lumen of a fluid-filled catheter.
| mm Hg | Inhaled Albuterol | Inhaled Saline Placebo |
|---|---|---|
| Change in Exercise Right Atrial Pressure (RA) | -5 ± 3 | -1 ± 2 |
RA was measured using a high-fidelity micromanometer advanced through the lumen of a fluid-filled catheter.
| mm Hg | Inhaled Albuterol | Inhaled Saline Placebo |
|---|---|---|
| Change in Resting Right Atrial Pressure (RA) | -3 ± 2 | -1 ± 2 |
Cardiac output was calculated using the direct Fick method of breath-by-breath oxygen consumption (V02)/arterial-venous oxygen content difference (AVO2 diff).
| L/min | Inhaled Albuterol | Inhaled Saline Placebo |
|---|---|---|
| Change in Exercise Cardiac Output | 2.0 ± 2.1 | 0.1 ± 1.0 |
Cardiac output was calculated using the direct Fick method of breath-by-breath oxygen consumption (V02)/arterial-venous oxygen content difference (AVO2 diff).
| L/min | Inhaled Albuterol | Inhaled Saline Placebo |
|---|---|---|
| Change in Resting Cardiac Output | 0.6 ± 1.2 | 0.4 ± 1.2 |
Pulmonary elastance was calculated by the ratio of pulmonary artery systolic pressure/stroke volume.
| mm Hg/mL | Inhaled Albuterol | Inhaled Saline Placebo |
|---|---|---|
| Change in Exercise Pulmonary Elastance | -0.17 ± 0.11 | -0.05 ± 0.11 |
Pulmonary elastance was calculated by the ratio of pulmonary artery systolic pressure/stroke volume.
| mm Hg/mL | Inhaled Albuterol | Inhaled Saline Placebo |
|---|---|---|
| Change in Resting Pulmonary Elastance | -0.11 ± 0.13 | -0.03 ± 0.13 |
Collected over Subjects were monitored in the recovery area for up to two hours after procedure.. Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Inhaled Albuterol | 0/15 (0%) | 0/15 (0%) | 0/15 (0%) |
| Inhaled Saline Placebo | 0/15 (0%) | 0/15 (0%) | 0/15 (0%) |
| Age, Continuous(years) | Inhaled Albuterol | Inhaled Saline Placebo | Total |
|---|---|---|---|
| Mean | 68 ± 8 | 64 ± 17 | 66 ± 12 |
| Sex: Female, Male(Participants) | Inhaled Albuterol | Inhaled Saline Placebo | Total |
|---|---|---|---|
| Female | 6 | 8 | 14 |
| Male | 9 | 7 | 16 |
| Race and Ethnicity Not Collected(Participants) | Inhaled Albuterol | Inhaled Saline Placebo | Total |
|---|---|---|---|
| Count of participants | — | — | 0 |
| Region of Enrollment(participants) | Inhaled Albuterol | Inhaled Saline Placebo | Total |
|---|---|---|---|
| United States | 15 | 15 | 30 |
| Body mass index(kg/m^2) | Inhaled Albuterol | Inhaled Saline Placebo | Total |
|---|---|---|---|
| Mean | 33.7 ± 7 | 35.6 ± 9.2 | 34.6 ± 8.1 |
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