left ventricular ejection fraction greater than or equal to 45% (per local reading) the ejection fraction must have been obtained within 6 months prior to randomization and after any MI or other event that would affect ejection fraction.Heart failure as defined by at least one of symptom (paroxysmal nocturnal dyspnea orthopnea or dyspnea on mild or moderate exertion) at the time of screening and at least one sign (any rales post cough jugular venous pressure(JVP) greater than or equal to 10cm of water(H2O) lower extremity edema or chest x-ray demonstrating pleural effusion, pulmonary congestion, or cardiomegaly) within 12 months prior to study entry:.Additionally, data regarding quality of life and compliance with assigned treatment will also be collected and assessed. 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. Subject visits to a clinical center will occur every four or six months.
TOPCAT LIBRARY TRIAL
Approximately 270 clinical sites in six countries were subcontracted by the clinical trial coordinating center. Patients were recruited from August 2006 through January 2012, treated, and will be followed through June 2013.
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. 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. Also, there is a clear physiologic rationale for its use, and the side effect profile is well understood. 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). 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. The improvement resulted from a reduction in all cause mortality. Spironolactone treatment caused a 30% reduction in mortality compared to placebo (p< 0.001). A recent trial evaluated spironolactone in patients with systolic dysfunction heart failure. There are several potential beneficial actions, including prevention of cardiac fibrosis. Spironolactone is a potassium-sparing diuretic that acts on the distal tubule, inhibiting sodium and potassium ion exchange. Aldosterone levels may rise to 20 times normal levels in heart failure and aldosterone contributes to the development of myocardial fibrosis. The renin-angiotensin-aldosterone system is an important part of this compensatory response. The mortality rate was 19% in heart failure patients with reduced systolic function heart failure compared to 4% for their matched controls.Īs heart failure develops, neurohormones are released that initially improve cardiac output but ultimately contribute to progression of left ventricular dysfunction.
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 annual mortality rate is intermediate between the prognosis for those without heart failure and for those with heart failure and reduced systolic function. Patients with heart failure and preserved systolic function have a poor prognosis.
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. This study is a randomized clinical trial of a novel therapeutic approach, specifically the use of spironolactone, an aldosterone antagonist, in treating these patients.
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. Therapeutic trials of heart failure have dealt almost exclusively with patients who have systolic dysfunction. As the United States population ages, heart failure will continue to grow as a public health concern. Indeed, it is the most common discharge diagnosis in patients older than 65 years. Heart failure (HF) is a major cause of morbidity and mortality, particularly in older people.
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