Inhaled Beta-adrenergic Agonists to Treat Pulmonary Vascular Disease in Heart Failure With Preserved EF (BEAT HFpEF): A Randomized Controlled Trial

NCT02885636 | Completed Phase 3 Results DMC

• 5 other identifiers: 16-005140AR01HL128526R01HL126638U01HL125205U10HL110262
• Study Type: interventional
• Target: 30
• Locations: 1 country
• Sites: 1

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.

Conditions

Congestive Heart Failure; Heart Failure, Left-Sided; Left-Sided Heart Failure

Keywords

Heart Failure with Preserved Ejection Fraction; Pulmonary Hypertension

Outcome Measures

Primary Outcomes (1)

• 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.

  Baseline, 10 minutes after intervention during exercise

Secondary Outcomes (13)

• Change in Resting Pulmonary Vascular Resistance

  Baseline, 10 minutes after intervention

• Change in Exercise Pulmonary Capillary Wedge Pressure (PCWP)

  Baseline, 10 minutes after intervention during exercise

• Change in Resting Pulmonary Capillary Wedge Pressure (PCWP)

  Baseline, 10 minutes after intervention

• Change in Exercise Pulmonary Artery Compliance

  Baseline, 10 minutes after intervention during exercise

• Change in Resting Pulmonary Artery Compliance

  Baseline, 10 minutes after intervention

Study Arms (2)

Inhaled albuterol

EXPERIMENTAL

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

Drug: Albuterol

Inhaled saline placebo

PLACEBO COMPARATOR

Inhaled saline through a high efficiency nebulizer -single dose

Other: Saline placebo

Interventions

Albuterol DRUG

: 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

Inhaled albuterol

Saline placebo OTHER

Saline inhaled through a nebulizer as a single dose

Inhaled saline placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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).

You may not qualify if:

• 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

Sponsors & Collaborators

• Mayo Clinic: lead
• National Heart, Lung, and Blood Institute (NHLBI): collaborator

Study Sites (1)

Mayo Clinic

Rochester, Minnesota, 55905, United States

Location

Related Publications (2)

• Reddy YNV, Obokata M, Koepp KE, Egbe AC, Wiley B, Borlaug BA. The beta-Adrenergic Agonist Albuterol Improves Pulmonary Vascular Reserve in Heart Failure With Preserved Ejection Fraction. Circ Res. 2019 Jan 18;124(2):306-314. doi: 10.1161/CIRCRESAHA.118.313832.

  PMID: 30582447 BACKGROUND

• Reddy YNV, Obokata M, Wiley B, Koepp KE, Jorgenson CC, Egbe A, Melenovsky V, Carter RE, Borlaug BA. The haemodynamic basis of lung congestion during exercise in heart failure with preserved ejection fraction. Eur Heart J. 2019 Dec 1;40(45):3721-3730. doi: 10.1093/eurheartj/ehz713.

  PMID: 31609443 DERIVED

MeSH Terms

Conditions

Heart Failure; Hypertension, Pulmonary

Interventions

Albuterol; Procaterol

Condition Hierarchy (Ancestors)

Heart Diseases; Cardiovascular Diseases; Lung Diseases; Respiratory Tract Diseases; Hypertension; Vascular Diseases

Intervention Hierarchy (Ancestors)

Ethanolamines; Amino Alcohols; Alcohols; Organic Chemicals; Amines; Phenethylamines; Ethylamines; Hydroxyquinolines; Quinolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Limitations and Caveats

This was a proof-of-concept study and chronic effects of albuterol were not examined. Further studies testing more clinically meaningful end points are needed to determine whether beta-agonists will improve patient-centric outcomes.

Results Point of Contact

• Title: Dr. Barry Borlaug
• Organization: Mayo Clinic

borlaug.barry@mayo.edu

507-284-8846

Study Officials

• Barry A Borlaug, MD

  Mayo Clinic

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate Professor of Medicine

Study Record Dates

• First Submitted: August 24, 2016
• First Posted: August 31, 2016
• Study Start: September 1, 2016
• Primary Completion: September 1, 2017
• Study Completion: September 1, 2017
• Last Updated: February 22, 2019
• Results First Posted: February 5, 2019

Record last verified: 2019-02

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)