• Aborted cardiac arrest [ Time Frame: Measured at baseline, 1 week, 4 weeks, 8 weeks, 4 months, 8 months, 12 months, and every 6 months thereafter (last visit is at 54 months) ] [ Designated as safety issue: Yes ]
  
• Composite of hospitalization for the management of heart failure (i.e., hospitalization for non-fatal MI or non-fatal stroke) [ Time Frame: Measured at baseline, 1 week, 4 weeks, 8 weeks, 4 months, 8 months, 12 months, and every 6 months thereafter (last visit is at 54 months) ] [ Designated as safety issue: Yes ]
  

• All cause mortality [ Time Frame: Measured at baseline, 1 week, 4 weeks, 8 weeks, 4 months, 8 months, 12 months, and every 6 months thereafter (last visit is at 54 months) ] [ Designated as safety issue: Yes ]
  
• Composite of cardiovascular mortality or cardiovascular related hospitalization (i.e., hospitalization for non-fatal MI, non-fatal stroke, or the management of heart failure) [ Time Frame: Measured at baseline, 1 week, 4 weeks, 8 weeks, 4 months, 8 months, 12 months, and every 6 months thereafter (last visit is at 54 months) ] [ Designated as safety issue: Yes ]
  
• Hospitalization for the management of heart failure incidence rate [ Time Frame: Measured at baseline, 1 week, 4 weeks, 8 weeks, 4 months, 8 months, 12 months, and every 6 months thereafter (last visit is at 54 months) ] [ Designated as safety issue: Yes ]
  
• Sudden death or aborted cardiac arrest [ Time Frame: Measured at baseline, 1 week, 4 weeks, 8 weeks, 4 months, 8 months, 12 months, and every 6 months thereafter (last visit is at 54 months) ] [ Designated as safety issue: Yes ]
  

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 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 age- and gender-matched controls. The mortality rate was 19 % compared to 4 % for matched controls in heart failure patients with reduced systolic function heart failure.

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 is currently enrolling patients hospitalized with heart failure who have preserved systolic function and who meet clearly defined eligibility criteria that have been 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 45 mg/day) in 4,500 adult patients with heart failure and preserved systolic function. Patients will be recruited over two and a half years, treated, and followed for approximately two years. Approximately 150 clinical sites will be subcontracted to the clinical trial coordinating center. Patient visits to a clinical center will occur every four or six months. Data to be 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 cost-effectiveness, quality of life, and compliance with assigned treatment will also be collected and assessed. The protocol has been developed.

Enrollment began August 2006.