Ignite Creation Date:
2024-05-06 @ 9:02 AM
Last Modification Date:
2024-10-26 @ 12:09 PM
Study NCT ID:
NCT02885636
Status:
COMPLETED
Last Update Posted:
2019-02-22
First Post:
2016-08-24
Brief Title:
Inhaled Beta-adrenergic Agonists to Treat Pulmonary Vascular Disease in Heart Failure With Preserved EF BEAT HFpEF A Randomized Controlled Trial
Sponsor:
Mayo Clinic
Organization:
Mayo Clinic
Study Overview
Official Title:
Inhaled Beta-adrenergic Agonists to Treat Pulmonary Vascular Disease in Heart Failure With Preserved EF BEAT HFpEF A Randomized Controlled Trial
Status:
COMPLETED
Status Verified Date:
2019-02
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
BEAT HFpEF
Brief Summary:
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 investigators 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
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
Detailed Description:
Preliminary studies to support feasibility Recent research from the investigators 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 11 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 25 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
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 11 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 25 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
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None
Secondary IDs
| Secondary ID | Type | Domain | Link |
|---|---|---|---|
| U10HL110262 | NIH | None | httpsreporternihgovquickSearchU10HL110262 |
| R01HL128526 | NIH | None | None |
| R01HL126638 | NIH | None | None |
| U01HL125205 | NIH | None | None |