Inhaled Beta-adrenergic Agonists to Treat Pulmonary Vascular Disease in Heart Failure With Preserved EF (BEAT HFpEF): A Randomized Controlled Trial (BEAT HFpEF)
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|ClinicalTrials.gov Identifier: NCT02885636|
Recruitment Status : Completed
First Posted : August 31, 2016
Results First Posted : February 5, 2019
Last Update Posted : February 22, 2019
|First Submitted Date ICMJE||August 24, 2016|
|First Posted Date ICMJE||August 31, 2016|
|Results First Submitted Date ICMJE||January 13, 2019|
|Results First Posted Date ICMJE||February 5, 2019|
|Last Update Posted Date||February 22, 2019|
|Study Start Date ICMJE||September 2016|
|Actual Primary Completion Date||September 2017 (Final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
||Change in 20 Watt Exercise Pulmonary Vascular Resistance (PVR) [ Time Frame: Baseline, 10 minutes after intervention during exercise ]
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.
|Original Primary Outcome Measures ICMJE
||20 Watt exercise Pulmonary Vascular Resistance (PVR) [ Time Frame: During exercise 10 minutes after intervention ]
The primary endpoint will be the PVR at 20 Watts exercise after study drug relative to the PVR at 20 Watts exercise in the initial assessment prior to study drug.
|Current Secondary Outcome Measures ICMJE
|Original Secondary Outcome Measures ICMJE
|Current Other Pre-specified Outcome Measures||Not Provided|
|Original Other Pre-specified Outcome Measures||Not Provided|
|Brief Title ICMJE||Inhaled Beta-adrenergic Agonists to Treat Pulmonary Vascular Disease in Heart Failure With Preserved EF (BEAT HFpEF): A Randomized Controlled Trial|
|Official Title ICMJE||Inhaled Beta-adrenergic Agonists to Treat Pulmonary Vascular Disease in Heart Failure With Preserved EF (BEAT HFpEF): A Randomized Controlled Trial|
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.
|Study Type ICMJE||Interventional|
|Study Phase ICMJE||Phase 3|
|Study Design ICMJE||Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
|Study Arms ICMJE||
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Completed|
|Actual Enrollment ICMJE
|Original Estimated Enrollment ICMJE||Same as current|
|Actual Study Completion Date ICMJE||September 2017|
|Actual Primary Completion Date||September 2017 (Final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
|Ages ICMJE||18 Years and older (Adult, Older Adult)|
|Accepts Healthy Volunteers ICMJE||No|
|Contacts ICMJE||Contact information is only displayed when the study is recruiting subjects|
|Listed Location Countries ICMJE||United States|
|Removed Location Countries|
|NCT Number ICMJE||NCT02885636|
|Other Study ID Numbers ICMJE||16-005140A
R01HL128526 ( U.S. NIH Grant/Contract )
R01HL126638 ( U.S. NIH Grant/Contract )
U01HL125205 ( U.S. NIH Grant/Contract )
U10HL110262 ( U.S. NIH Grant/Contract )
|Has Data Monitoring Committee||Yes|
|U.S. FDA-regulated Product||Not Provided|
|IPD Sharing Statement ICMJE||
|Responsible Party||Barry Borlaug, Mayo Clinic|
|Study Sponsor ICMJE||Mayo Clinic|
|Collaborators ICMJE||National Heart, Lung, and Blood Institute (NHLBI)|
|PRS Account||Mayo Clinic|
|Verification Date||February 2019|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP