Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT)

Brief Summary

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.

Primary Outcomes

Secondary Outcomes

• Aborted Cardiac Arrest(Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.)
• 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.)
• Serum Creatinine(Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.)
• 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.)
• Myocardial Infarction(Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.)
• 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.)
• 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.)
• Potassium(Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.)
• 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.)
• 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.)
• Sodium(Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.)
• Estimated Glomerular Filtration Rate (GFR)(Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.)
• 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.)
• 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.)
• 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.)
• 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.)
• Stroke(Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.)
• Chloride(Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.)