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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
Sponsor:
Collaborator:
National Heart, Lung, and Blood Institute (NHLBI)
Information provided by (Responsible Party):
Barry Borlaug, Mayo Clinic

Tracking Information
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
 (submitted: February 4, 2019)
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
 (submitted: August 26, 2016)
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.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: January 13, 2019)
  • Change in Resting Pulmonary Vascular Resistance [ Time Frame: Baseline, 10 minutes after intervention ]
    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.
  • Change in Exercise Pulmonary Capillary Wedge Pressure (PCWP) [ Time Frame: Baseline, 10 minutes after intervention during exercise ]
    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.
  • Change in Resting Pulmonary Capillary Wedge Pressure (PCWP) [ Time Frame: Baseline, 10 minutes after intervention ]
    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.
  • Change in Exercise Pulmonary Artery Compliance [ Time Frame: Baseline, 10 minutes after intervention during exercise ]
    Pulmonary artery compliance was calculated as the ratio of stroke volume/pulmonary artery pulse pressure.
  • Change in Resting Pulmonary Artery Compliance [ Time Frame: Baseline, 10 minutes after intervention ]
    Pulmonary artery compliance was calculated as the ratio of stroke volume/pulmonary artery pulse pressure.
  • Change in Exercise Pulmonary Artery Pressure [ Time Frame: Baseline, 10 minutes after intervention during exercise ]
    Pulmonary artery pressure was measured using a high-fidelity micromanometer advanced through the lumen of a fluid-filled catheter.
  • Change in Resting Pulmonary Artery Pressure [ Time Frame: Baseline, 10 minutes after intervention ]
    Pulmonary artery pressure was measured using a high-fidelity micromanometer advanced through the lumen of a fluid-filled catheter.
  • Change in Exercise Right Atrial Pressure (RA) [ Time Frame: Baseline, 10 minutes after intervention during exercise ]
    RA was measured using a high-fidelity micromanometer advanced through the lumen of a fluid-filled catheter.
  • Change in Resting Right Atrial Pressure (RA) [ Time Frame: Baseline, 10 minutes after intervention ]
    RA was measured using a high-fidelity micromanometer advanced through the lumen of a fluid-filled catheter.
  • Change in Exercise Cardiac Output [ Time Frame: Baseline, 10 minutes after intervention during exercise ]
    Cardiac output was calculated using the direct Fick method of breath-by-breath oxygen consumption (V02)/arterial-venous oxygen content difference (AVO2 diff).
  • Change in Resting Cardiac Output [ Time Frame: Baseline, 10 minutes after intervention ]
    Cardiac output was calculated using the direct Fick method of breath-by-breath oxygen consumption (V02)/arterial-venous oxygen content difference (AVO2 diff).
  • Change in Exercise Pulmonary Elastance [ Time Frame: Baseline, 10 minutes after intervention during exercise ]
    Pulmonary elastance was calculated by the ratio of pulmonary artery systolic pressure/stroke volume.
  • Change in Resting Pulmonary Elastance [ Time Frame: Baseline, 10 minutes after intervention ]
    Pulmonary elastance was calculated by the ratio of pulmonary artery systolic pressure/stroke volume.
Original Secondary Outcome Measures  ICMJE
 (submitted: August 26, 2016)
  • Resting Pulmonary Vascular Resistance [ Time Frame: 10 minutes after intervention ]
  • Rest and exercise pulmonary artery compliance [ Time Frame: 10 minutes after intervention ]
  • Rest and exercise right atrial pressure [ Time Frame: 10 minutes after intervention ]
  • Rest and exercise pulmonary artery pressure [ Time Frame: 10 minutes after intervention ]
  • Rest and exercise cardiac output pressure [ Time Frame: 10 minutes after intervention ]
  • Rest and exercise right ventricular systolic and diastolic function [ Time Frame: 10 minutes after intervention ]
  • Rest and exercise pulmonary artery input impedance [ Time Frame: 10 minutes after intervention ]
  • Exercise borg effort [ Time Frame: During exercise 10 minutes after intervention ]
  • Exercise dyspnea scores [ Time Frame: During exercise 10 minutes after intervention ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
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
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 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.

Detailed Description

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
Condition  ICMJE
  • Congestive Heart Failure
  • Heart Failure, Left-Sided
  • Left-Sided Heart Failure
Intervention  ICMJE
  • Drug: Albuterol

    : Experimental: Inhaled albuterol

    2.5 mg inhaled albuterol through a high efficiency nebulizer as a single dose

    Other Name: Proventil, AccuNeb, Proair, Ventolin, and Vospire
  • Other: Saline placebo
    Saline inhaled through a nebulizer as a single dose
Study Arms  ICMJE
  • Experimental: Inhaled albuterol
    2.5 mg inhaled albuterol through a high efficiency nebulizer -single dose
    Intervention: Drug: Albuterol
  • Placebo Comparator: Inhaled saline placebo
    Inhaled saline through a high efficiency nebulizer -single dose
    Intervention: Other: Saline placebo
Publications *

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: August 26, 2016)
30
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

Inclusion Criteria:

  • Heart Failure with Preserved Ejection Fraction (HFpEF)
  • Normal left ventricular ejection fraction (≥50%)
  • Elevated Left Ventricular filling pressures at cardiac catheterization (defined as resting Pulmonary Capillary Wedge Pressure>15 mmHg and/or ≥25 mmHg during exercise).

Exclusion Criteria:

  • Prior albuterol therapy (within previous 48 hours)
  • Current long acting inhaled beta agonist use
  • Significant hypokalemia (<3meq/L)
  • Significant valvular disease (>moderate left-sided regurgitation, >mild stenosis)
  • High output heart failure
  • Severe pulmonary disease
  • Unstable coronary disease
  • Constrictive pericarditis
  • Restrictive cardiomyopathy
  • Hypertrophic cardiomyopathy
Sex/Gender  ICMJE
Sexes Eligible for Study: All
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  
 
Administrative Information
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
Plan to Share IPD: No
Responsible Party Barry Borlaug, Mayo Clinic
Study Sponsor  ICMJE Mayo Clinic
Collaborators  ICMJE National Heart, Lung, and Blood Institute (NHLBI)
Investigators  ICMJE
Principal Investigator: Barry A Borlaug, MD Mayo Clinic
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