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Reduced Contractile Reserve: a Therapeutic Target in Heart Failure With Preserved Ejection Fraction(HFpEF)

Primary Purpose

Heart Failure With Preserved Ejection Fraction, Pulmonary Disease, Left Ventricular Hypertrophy/Hypertension

Status

Completed

Phase

Not Applicable

Locations

United States

Study Type

Interventional

Intervention

Dobutamine

Amlodipine

About this trial

This is an interventional treatment trial for Heart Failure With Preserved Ejection Fraction

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

Male or female; Age 18 or older.
Left ventricular ejection fraction ≥ 50%.
Symptomatic heart failure or appropriate comparator group criteria
Informed consent signed by the subject

Exclusion Criteria:

Symptoms of active ischemia.
Moderate or severe mitral or aortic stenosis, or severe aortic insufficiency.
Serum creatinine > 3.0 or chronic hemodialysis.
Known chronic hepatic disease; defined as aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels > 3.0 times the upper limit of normal as read at the local lab.
Severe renal dysfunction, i.e. glomerular filtration rate (GFR) <30 ml/min.
Atrial fibrillation
Myocardial infarction within the last year
Coronary bypass surgery within the last 6 months
Stroke within the last 6 months
Known aortic aneurysm
Contra-indication to withdrawal of beta blocker or antihypertensive medications
Resting or orthostatic hypotension (SBP < 90 mmHg)
Any gastrointestinal disorder which would interfere with drug absorption
Any significant valvular heart disease, including prior multiple valve replacement.
Pericardial Disease
Infiltrative or hypertrophic cardiomyopathy
Cor pulmonale
Unstable coronary disease
Pregnancy
Any condition which may prevent the subject from adhering to the study protocol, as determined by the investigator

Heart Failure with Preserved Ejection Fraction

Clinical evidence of heart failure with preserved ejection fraction, as manifest by at least 2 symptoms or signs, including dyspnea on exertion or at rest, orthopnea, jugular venous distention or hepatojugular reflux, rales or edema.
Controlled systolic BP (< 150 mmHg on the day of study)

Pulmonary Disease Group

Known obstructive airways disease with objective documentation of an isolated obstructive defect by pulmonary function testing.
No history of heart failure.
No history of cardiovascular disease, with the exception of hypertension or hyperlipidemia
History and physical examination free of signs and symptoms of heart failure, including elevated jugular venous pressure, hepatojugular reflux, rales or edema.
Baseline echocardiographic examination without evidence of heart failure, including systolic dysfunction of the LV or RV, or evidence of more than mild diastolic dysfunction on non-invasive assessment.

HTN/LVH Group

Known history of hypertension.
Echocardiographic evidence of left ventricular hypertrophy and diastolic dysfunction.
No history or physical examination evidence of heart failure, including excessive dyspnea on exertion, dyspnea at rest, orthopnea, PND, jugular venous distention, hepatojugular reflux, rales or edema.

Sites / Locations

UW - Madison

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Placebo Comparator

Arm Label

HFpEF

Pulmonary Disease

LVH/HTN

HFpEF placebo

Arm Description

25 patients with clinically diagnosed heart failure with preserved ejection fraction, confirmed by Framingham criteria, with EF > 50% and without evidence of active ischemia or known severe CAD, valvular or pericardial disease, infiltrative or hypertrophic cardiomyopathy, cor pulmonale, severe pulmonary disease, or primary renal disease. Subjects will receive amlodipine, oral administration for a period of 12 weeks.

20 patients with pulmonary disease and no clinical evidence of cardiovascular disease

20 subjects with known left ventricular hypertrophy and clinically diagnosed hypertension without the diagnosis of heart failure.

25 patients with clinically diagnosed heart failure with preserved ejection fraction, confirmed by Framingham criteria, with EF > 50% and without evidence of active ischemia or known severe CAD, valvular or pericardial disease, infiltrative or hypertrophic cardiomyopathy, cor pulmonale, severe pulmonary disease, or primary renal disease. Subjects will be administered a placebo for a period of 12 weeks.

Outcomes

Primary Outcome Measures

Change in ejection fraction with 5mcg/kg/min dobutamine

The primary outcome variable in this analysis will be change in ejection fraction from baseline at the 5 mcg dobutamine dose.

Change in pulse wave velocity

Change in carotid-femoral pulse wave velocity (PWV) with 12 weeks of therapy with amlodipine or placebo will be the primary outcome variable.

Secondary Outcome Measures

Full Information

NCT ID

NCT01354613

First Posted

May 5, 2011

Last Updated

April 9, 2019

Sponsor

University of Wisconsin, Madison

Collaborators

National Heart, Lung, and Blood Institute (NHLBI)

1. Study Identification

Unique Protocol Identification Number

NCT01354613

Brief Title

Reduced Contractile Reserve: a Therapeutic Target in Heart Failure With Preserved Ejection Fraction(HFpEF)

Official Title

Reduced Contractile Reserve: a Therapeutic Target in Heart Failure With Preserved Ejection Fraction

Study Type

Interventional

2. Study Status

Record Verification Date

April 2019

Overall Recruitment Status

Completed

Study Start Date

April 2011 (undefined)

Primary Completion Date

December 2013 (Actual)

Study Completion Date

December 2013 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

University of Wisconsin, Madison

Collaborators

National Heart, Lung, and Blood Institute (NHLBI)

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

Heart failure with preserved ejection fraction (HFpEF) accounts for over 50% of heart failure cases in the United States, affecting a primarily elderly population. No treatment has been shown to affect mortality in HFpEF, which is more than 50% at five years a hospitalization. This project explores the underlying cardiovascular physiology of patients with HFpEF with the goal of identifying new therapeutic targets that would allow improved treatment of this devastating disease.

Detailed Description

Heart failure with preserved ejection fraction (HFpEF) is a difficult disease to diagnose due to nonspecific symptoms and clinical findings. The disease occurs in the elderly, who often have other illnesses and signs of aging that make diagnosis of heart failure more difficult. Recently, it has been suggested that HFpEF, which has primarily been thought to be a diastolic disease, is in fact multifactorial, with elements of abnormal systolic function and increased vascular stiffness playing a role in disease pathology. No treatment has been shown to reduce the high mortality of the disease. However, few studies have evaluated this population of patients during periods of increased physiologic stress, despite the consistent clinical presentation of impaired exercise tolerance with few symptoms at rest. This study explores the multifactorial physiology of HFpEF, with a detailed investigation of the specificity of abnormalities in contractile reserve and vascular stiffness for this disease, and exploration of the modifiability of these abnormalities. The techniques used are non-invasive, involving echocardiographic evaluation of cardiac function, and measurement of arterial stiffness using tonometry. The first aim of the study is to explore the specificity of a potential diagnostic test for HFpEF by investigating the change in ejection fraction before and after β-adrenergic stimulation with low-dose dobutamine in HFpEF compared to other groups important to distinguish clinically, specifically patients with shortness of breath due to pulmonary disease, and those with hypertension and left ventricular hypertrophy without clinical heart failure. In the second aim, the study will investigate the ability of the calcium channel blocker, amlodipine, to restore normal contractile responses of the myocardium. In the third aim, the role of arterial stiffness in drug responses in HFpEF will be explored. It is anticipated that improved understanding of the complex physiology of this multifactorial disease gained through this study will lead to more rational design of large clinical trials studying promising agents for HFpEF that impact not only diastolic function, but contractile reserve and arterial properties as well.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Heart Failure With Preserved Ejection Fraction, Pulmonary Disease, Left Ventricular Hypertrophy/Hypertension

7. Study Design

Primary Purpose

Treatment

Study Phase

Not Applicable

Interventional Study Model

Parallel Assignment

Masking

ParticipantCare ProviderInvestigator

Allocation

Randomized

Enrollment

14 (Actual)

8. Arms, Groups, and Interventions

Arm Title

HFpEF

Arm Type

Experimental

Arm Description

Arm Title

Pulmonary Disease

Arm Type

Experimental

Arm Description

20 patients with pulmonary disease and no clinical evidence of cardiovascular disease

Arm Title

LVH/HTN

Arm Type

Experimental

Arm Description

20 subjects with known left ventricular hypertrophy and clinically diagnosed hypertension without the diagnosis of heart failure.

Arm Title

HFpEF placebo

Arm Type

Placebo Comparator

Arm Description

25 patients with clinically diagnosed heart failure with preserved ejection fraction, confirmed by Framingham criteria, with EF > 50% and without evidence of active ischemia or known severe CAD, valvular or pericardial disease, infiltrative or hypertrophic cardiomyopathy, cor pulmonale, severe pulmonary disease, or primary renal disease. Subjects will be administered a placebo for a period of 12 weeks.

Intervention Type

Drug

Intervention Name(s)

Dobutamine

Intervention Description

IV administration at the initial study visit (all groups) and at the final study visit for the drug intervention arm (HFpEF group only). Administration of low-dose dobutamine at 5mcg/kg/min and 10mcg/kg/min for periods of approximately 30minutes/dose for purposes of performing a low-dose stress exam on the heart.

Intervention Type

Drug

Intervention Name(s)

Amlodipine

Intervention Description

Participants will be randomized to treatment with either amlodipine 5 mg daily or placebo, in double-blind fashion, 25 patients in each group. 12 week oral administration of 5mg/day, uptitrated to 10mg/day, determined by PI.

Primary Outcome Measure Information:

Title

Change in ejection fraction with 5mcg/kg/min dobutamine

Description

The primary outcome variable in this analysis will be change in ejection fraction from baseline at the 5 mcg dobutamine dose.

Time Frame

day 0 and 12 week study visit

Title

Change in pulse wave velocity

Description

Change in carotid-femoral pulse wave velocity (PWV) with 12 weeks of therapy with amlodipine or placebo will be the primary outcome variable.

Time Frame

12 week study visit

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: Male or female; Age 18 or older. Left ventricular ejection fraction ≥ 50%. Symptomatic heart failure or appropriate comparator group criteria Informed consent signed by the subject Exclusion Criteria: Symptoms of active ischemia. Moderate or severe mitral or aortic stenosis, or severe aortic insufficiency. Serum creatinine > 3.0 or chronic hemodialysis. Known chronic hepatic disease; defined as aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels > 3.0 times the upper limit of normal as read at the local lab. Severe renal dysfunction, i.e. glomerular filtration rate (GFR) <30 ml/min. Atrial fibrillation Myocardial infarction within the last year Coronary bypass surgery within the last 6 months Stroke within the last 6 months Known aortic aneurysm Contra-indication to withdrawal of beta blocker or antihypertensive medications Resting or orthostatic hypotension (SBP < 90 mmHg) Any gastrointestinal disorder which would interfere with drug absorption Any significant valvular heart disease, including prior multiple valve replacement. Pericardial Disease Infiltrative or hypertrophic cardiomyopathy Cor pulmonale Unstable coronary disease Pregnancy Any condition which may prevent the subject from adhering to the study protocol, as determined by the investigator Heart Failure with Preserved Ejection Fraction Clinical evidence of heart failure with preserved ejection fraction, as manifest by at least 2 symptoms or signs, including dyspnea on exertion or at rest, orthopnea, jugular venous distention or hepatojugular reflux, rales or edema. Controlled systolic BP (< 150 mmHg on the day of study) Pulmonary Disease Group Known obstructive airways disease with objective documentation of an isolated obstructive defect by pulmonary function testing. No history of heart failure. No history of cardiovascular disease, with the exception of hypertension or hyperlipidemia History and physical examination free of signs and symptoms of heart failure, including elevated jugular venous pressure, hepatojugular reflux, rales or edema. Baseline echocardiographic examination without evidence of heart failure, including systolic dysfunction of the LV or RV, or evidence of more than mild diastolic dysfunction on non-invasive assessment. HTN/LVH Group Known history of hypertension. Echocardiographic evidence of left ventricular hypertrophy and diastolic dysfunction. No history or physical examination evidence of heart failure, including excessive dyspnea on exertion, dyspnea at rest, orthopnea, PND, jugular venous distention, hepatojugular reflux, rales or edema.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Nancy K Sweitzer, MD, PhD

Organizational Affiliation

UW-Madison

Official's Role

Principal Investigator

Facility Information:

Facility Name

UW - Madison

City

Madison

State/Province

Wisconsin

ZIP/Postal Code

53705

Country

United States

12. IPD Sharing Statement

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Reduced Contractile Reserve: a Therapeutic Target in Heart Failure With Preserved Ejection Fraction(HFpEF)

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