Aldosterone Antagonist Therapy for Adults With Heart Failure and Preserved Systolic Function

Phase 3

Completed

Conditions: Heart Diseases
Heart Failure, Congestive
Cardiovascular Diseases

Interventions: Drug: Placebo
Drug: Spironolactone

Registration Number: NCT00094302

Lead Sponsor: Carelon Research

Brief Summary: The purpose of this study is to evaluate the effectiveness of aldosterone antagonist therapy in reducing cardiovascular mortality, aborted cardiac arrest, and heart failure hospitalization in patients who have heart failure with preserved systolic function.

Detailed Description: BACKGROUND:

Heart failure (HF) is a major cause of morbidity and mortality, particularly in older people. Indeed, it is the most common discharge diagnosis in patients older than 65 years. As the United States population ages, heart failure will continue to grow as a public health concern. Therapeutic trials of heart failure have dealt almost exclusively with patients who have systolic dysfunction. However, there is now an emerging awareness that nearly half of the patients with heart failure have preserved systolic function and that the survival of these patients is adversely affected. This study is a randomized clinical trial of a novel therapeutic approach, specifically the use of spironolactone, an aldosterone antagonist, in treating these patients. While this treatment has been shown to be useful in treating heart failure with reduced systolic function, it has not been studied in patients with preserved systolic function.

Patients with heart failure and preserved systolic function have a poor prognosis. The annual mortality rate is intermediate between the prognosis for those without heart failure and for those with heart failure and reduced systolic function. For instance, Family Health Study participants with heart failure and preserved systolic function had a mortality rate of 9% compared to 3% for their age- and gender-matched controls. The mortality rate was 19% in heart failure patients with reduced systolic function heart failure compared to 4% for their matched controls.

As heart failure develops, neurohormones are released that initially improve cardiac output but ultimately contribute to progression of left ventricular dysfunction. The renin-angiotensin-aldosterone system is an important part of this compensatory response. Aldosterone levels may rise to 20 times normal levels in heart failure and aldosterone contributes to the development of myocardial fibrosis. Spironolactone is a potassium-sparing diuretic that acts on the distal tubule, inhibiting sodium and potassium ion exchange. There are several potential beneficial actions, including prevention of cardiac fibrosis. A recent trial evaluated spironolactone in patients with systolic dysfunction heart failure. Spironolactone treatment caused a 30% reduction in mortality compared to placebo (p\< 0.001). The improvement resulted from a reduction in all cause mortality. More recently, the Eplerenone Post-Myocardial Infarction (MI) study showed that this aldosterone antagonist significantly reduces mortality despite background treatment with an angiotensin-converting enzyme (ACE) inhibitor and beta-blocker. Advantages of using spironolactone in this study are that it is commercially available, inexpensive, and no longer under patent (therefore this study will not be done by industry). Also, there is a clear physiologic rationale for its use, and the side effect profile is well understood. The study enrolled subjects who had preserved systolic function with heart failure and who met clearly defined eligibility criteria that were selected to make the results widely generalizable to clinical practice.

DESIGN NARRATIVE:

This is a randomized, double-blinded, placebo-controlled trial of aldosterone antagonist therapy (15 mg dose spironolactone or placebo; titrated up to 30 or 45 mg/day) in 3,445 adult patients with heart failure and preserved systolic function. Patients were recruited from August 2006 through January 2012, treated, and will be followed through June 2013. Approximately 270 clinical sites in six countries were subcontracted by the clinical trial coordinating center. Subject visits to a clinical center will occur every four or six months. Data collected include demographic and clinical data, including the results of history and physical exams, laboratory and imaging data, repository specimens for special physiology studies, and genetic studies. Additionally, data regarding quality of life and compliance with assigned treatment will also be collected and assessed.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 3445

Inclusion Criteria

Not provided

Exclusion Criteria

Not provided

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Placebo	Placebo	Placebo of spironolactone
Spironolactone	Spironolactone	Spironolactone (an aldosterone antagonist) is supplied as 15 mg tablets. Drug is taken orally by subjects. The initial study drug dose is 15 mg/day (one tablet) and may be titrated up to 30 mg/day (two tablets) or 45 mg/day (three tablets). Subjects are on study drug for the duration of the trial.

Primary Outcome Measures

Name	Time	Method
Composite Outcome of Cardiovascular Mortality, Aborted Cardiac Arrest, or Hospitalization for the Management of Heart Failure, Whichever Occurred First	Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.

Secondary Outcome Measures

Name	Time	Method
Aborted Cardiac Arrest	Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.	First incidence of aborted cardiac arrest
All-cause Mortality	Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.
Composite Outcome of Cardiovascular Mortality or Cardiovascular-related Hospitalization (i.e., Hospitalization for Myocardial Infarction(MI), Stroke, or the Management of Heart Failure), Whichever Occurred First	Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.
Composite Outcome of Sudden Death or Aborted Cardiac Arrest, Whichever Occurred First	Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.
Hospitalization for Any Reason	Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.	First incidence of a hospitalization for any reason
Serum Creatinine	Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.	Average post-baseline serum creatinine, taking into consideration baseline serum creatinine, treatment group, the time between the post-baseline measures, and the correlation between repeated measures within an individual.
Myocardial Infarction	Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.	First incidence of myocardial infarction
Quality of Life, as Measured by the EuroQOL Visual Analog Scale.	Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.	Average post-baseline quality of life, taking into consideration baseline quality of life, treatment group, the time between the post-baseline measures, and the correlation between repeated measures within an individual. The EuroQOL visual analog scale (EQ5D) is a single-item, self-administered instrument that quantifies current health status. Scores can range from 0-100, in which higher scores reflect better health status. The EQ5D was administered at the following study visits: baseline, month 4, month 12 and annually thereafter.
Quality of Life, as Measured by McMaster Overall Treatment Evaluation Questionnaire.	Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.	Average post-baseline quality of life, taking into consideration baseline quality of life and treatment group. The McMaster Overall Treatment Evaluation questionnaire is a self-administered 3-item instrument that measures a patient's perception of change in their health-related quality of life since the start of therapy. The questionnaire consists of a single question - "Since treatment started, has there been any change in your activity limitation, symptoms and/or feelings related to your heart condition?" Scores can range from -7 to +7, and higher scores reflect better health status. The questionnaire was administered at the following study visits: month 4 and month 12. Valid translations of this questionnaire were only available for subjects enrolled in the United States, Canada and Argentina.
Potassium	Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.	Average post-baseline Potassium, taking into consideration baseline Potassium, treatment group, the time between the post-baseline measures, and the correlation between repeated measures within an individual.
Quality of Life, as Measured by the Kansas City Cardiomyopathy Questionnaire.	Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.	Average post-baseline quality of life, taking into consideration baseline quality of life, treatment group, the time between the post-baseline measures, and the correlation between repeated measures within an individual. The Kansas City Cardiomyopathy Questionnaire (KCCQ) is a 23-item, self-administered instrument that quantifies physical function, symptoms (frequency, severity and recent change), social function, self-efficacy and knowledge, and quality of life. Scores are transformed to a range of 0-100, in which higher scores reflect better health status. The KCCQ was administered at the following study visits: baseline, month 4, month 12 and annually thereafter.
Depression Symptoms, as Measured by Patient Health Questionnaire.	Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.	Average post-baseline depression, taking into consideration baseline depression, treatment group, the time between the post-baseline measures, and the correlation between repeated measures within an individual. The Patient Health Questionnaire (PHQ) is a 10-item, self-administered instrument for screening, diagnosing, monitoring and measuring the severity of depression. Scores can range from 0-27, in which lower scores reflect better mental health status. The PH-Q was administered at the following study visits: baseline, month 12 and annually thereafter. Valid translations of this questionnaire were only available for subjects enrolled in the United States and Canada.
Sodium	Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.	Average post-baseline Sodium, taking into consideration baseline Sodium, treatment group, the time between the post-baseline measures, and the correlation between repeated measures within an individual.
Estimated Glomerular Filtration Rate (GFR)	Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.	Average post-baseline GFR, taking into consideration baseline GFR, treatment group, the time between the post-baseline measures, and the correlation between repeated measures within an individual.
Cardiovascular Mortality	Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.
Total Hospitalizations (Including Repeat Hospitalizations) for the Management of Heart Failure	Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.
Deterioration of Renal Function	Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.	First incidence of a deterioration of renal function. The TOPCAT protocol defines deterioration of renal function as occurring if a subject has a serum creatinine value which is at least double the baseline value for that subject, and is also above the upper limit of normal (assumed to be 1.0 mg/dL for females and 1.2 mg/dL for males.)
Composite Outcome of Sudden Death, Aborted Cardiac Arrest, or Hospitalization for the Management of Ventricular Tachycardia, Whichever Occurred First	Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.
Cardiovascular-related Hospitalization	Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.	Hospitalization for MI, stroke or the management of heart failure, whichever occurred first
New Onset Diabetes Mellitus, Among Subjects Without a History of Diabetes Mellitus at Baseline.	Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.	First incidence of new onset diabetes mellitus among subjects without a history of diabetes mellitus at baseline.
Development of Atrial Fibrillation, Among Subjects Without a History of Atrial Fibrillation at Baseline.	Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.	First incidence of atrial fibrillation among subjects without a history of atrial fibrillation at baseline
Stroke	Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.	First incidence of stroke
Chloride	Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.	Average post-baseline Chloride, taking into consideration baseline Chloride, treatment group, the time between the post-baseline measures, and the correlation between repeated measures within an individual.
Hospitalization for the Management of Heart Failure	Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.	First incidence of a hospitalization for the management of heart failure

Trial Locations

Locations (269): University of Alabama at Birmingham
🇺🇸
Birmingham, Alabama, United States
Cardiovascular Consultants, Ltd.
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Glendale, Arizona, United States
Carl T. Hayden VA Medical Center
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Phoenix, Arizona, United States
Central Arkansas Veterans Healthcare System
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Little Rock, Arkansas, United States
Heart Clinic Arkansas
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Little Rock, Arkansas, United States
Cynthia Thaik
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Burbank, California, United States
Fresno VA Medical Center
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Fresno, California, United States
Clinica Medica San Miguel
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Los Angeles, California, United States
CAPRI
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Los Angeles, California, United States
VA Medical Center West Los Angeles
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Los Angeles, California, United States
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University of Alabama at Birmingham
🇺🇸Birmingham, Alabama, United States