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

• Cardiovascular Mortality [ Time Frame: Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject. ] [ Designated as safety issue: No ]
• Aborted Cardiac Arrest [ Time Frame: Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject. ] [ Designated as safety issue: No ]
  First incidence of aborted cardiac arrest
• Hospitalization for the Management of Heart Failure [ Time Frame: Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject. ] [ Designated as safety issue: No ]
  First incidence of a hospitalization for the management of heart failure
• All-cause Mortality [ Time Frame: Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject. ] [ Designated as safety issue: Yes ]
• 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 [ Time Frame: Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject. ] [ Designated as safety issue: No ]
• Cardiovascular-related Hospitalization [ Time Frame: Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject. ] [ Designated as safety issue: No ]
  Hospitalization for MI, stroke or the management of heart failure, whichever occurred first
• Total Hospitalizations (Including Repeat Hospitalizations) for the Management of Heart Failure [ Time Frame: Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject. ] [ Designated as safety issue: No ]
• Composite Outcome of Sudden Death or Aborted Cardiac Arrest, Whichever Occurred First [ Time Frame: Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject. ] [ Designated as safety issue: No ]
• New Onset Diabetes Mellitus, Among Subjects Without a History of Diabetes Mellitus at Baseline. [ Time Frame: Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject. ] [ Designated as safety issue: No ]
  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. [ Time Frame: Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject. ] [ Designated as safety issue: No ]
  First incidence of atrial fibrillation among subjects without a history of atrial fibrillation at baseline
• Myocardial Infarction [ Time Frame: Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject. ] [ Designated as safety issue: No ]
  First incidence of myocardial infarction
• Stroke [ Time Frame: Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject. ] [ Designated as safety issue: No ]
  First incidence of stroke
• Deterioration of Renal Function [ Time Frame: Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject. ] [ Designated as safety issue: Yes ]
  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 [ Time Frame: Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject. ] [ Designated as safety issue: No ]
• Quality of Life, as Measured by the Kansas City Cardiomyopathy Questionnaire. [ Time Frame: Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject. ] [ Designated as safety issue: No ]

  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.

• Quality of Life, as Measured by the EuroQOL Visual Analog Scale. [ Time Frame: Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject. ] [ Designated as safety issue: No ]

  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. [ Time Frame: Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject. ] [ Designated as safety issue: No ]

  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.

• Depression Symptoms, as Measured by Patient Health Questionnaire. [ Time Frame: Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject. ] [ Designated as safety issue: No ]

  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.

• Hospitalization for Any Reason [ Time Frame: Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject. ] [ Designated as safety issue: Yes ]
  First incidence of a hospitalization for any reason
• Potassium [ Time Frame: Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject. ] [ Designated as safety issue: Yes ]
  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.
• Serum Creatinine [ Time Frame: Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject. ] [ Designated as safety issue: Yes ]
  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.
• Sodium [ Time Frame: Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject. ] [ Designated as safety issue: Yes ]
  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.
• Chloride [ Time Frame: Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject. ] [ Designated as safety issue: Yes ]
  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.
• Estimated Glomerular Filtration Rate (GFR) [ Time Frame: Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject. ] [ Designated as safety issue: Yes ]
  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.

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.

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.

• Cardiovascular Diseases
• Heart Diseases
• Heart Failure, Congestive

• Drug: 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.
  Other Name: aldosterone antagonist
• Drug: Placebo
  Placebo of spironolactone
  Other Name: Placebo

• Placebo Comparator: Placebo
  Placebo of spironolactone
  Intervention: Drug: Placebo
• Experimental: 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.
  Intervention: Drug: Spironolactone

• Desai AS, Lewis EF, Li R, Solomon SD, Assmann SF, Boineau R, Clausell N, Diaz R, Fleg JL, Gordeev I, McKinlay S, O'Meara E, Shaburishvili T, Pitt B, Pfeffer MA. Rationale and design of the treatment of preserved cardiac function heart failure with an aldosterone antagonist trial: a randomized, controlled study of spironolactone in patients with symptomatic heart failure and preserved ejection fraction. Am Heart J. 2011 Dec;162(6):966-972.e10. doi: 10.1016/j.ahj.2011.09.007. Epub 2011 Nov 8.
• Shah SJ, Heitner JF, Sweitzer NK, Anand IS, Kim HY, Harty B, Boineau R, Clausell N, Desai AS, Diaz R, Fleg JL, Gordeev I, Lewis EF, Markov V, O'Meara E, Kobulia B, Shaburishvili T, Solomon SD, Pitt B, Pfeffer MA, Li R. Baseline characteristics of patients in the treatment of preserved cardiac function heart failure with an aldosterone antagonist trial. Circ Heart Fail. 2013 Mar;6(2):184-92. doi: 10.1161/CIRCHEARTFAILURE.112.972794. Epub 2012 Dec 20.
• Shah AM, Shah SJ, Anand IS, Sweitzer NK, O'Meara E, Heitner JF, Sopko G, Li G, Assmann SF, McKinlay SM, Pitt B, Pfeffer MA, Solomon SD; TOPCAT Investigators. Cardiac structure and function in heart failure with preserved ejection fraction: baseline findings from the echocardiographic study of the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist trial. Circ Heart Fail. 2014 Jan;7(1):104-15. doi: 10.1161/CIRCHEARTFAILURE.113.000887. Epub 2013 Nov 18.
• Pitt B, Pfeffer MA, Assmann SF, Boineau R, Anand IS, Claggett B, Clausell N, Desai AS, Diaz R, Fleg JL, Gordeev I, Harty B, Heitner JF, Kenwood CT, Lewis EF, O'Meara E, Probstfield JL, Shaburishvili T, Shah SJ, Solomon SD, Sweitzer NK, Yang S, McKinlay SM; TOPCAT Investigators. Spironolactone for heart failure with preserved ejection fraction. N Engl J Med. 2014 Apr 10;370(15):1383-92. doi: 10.1056/NEJMoa1313731.
• Shah AM, Claggett B, Sweitzer NK, Shah SJ, Anand IS, O'Meara E, Desai AS, Heitner JF, Li G, Fang J, Rouleau J, Zile MR, Markov V, Ryabov V, Reis G, Assmann SF, McKinlay SM, Pitt B, Pfeffer MA, Solomon SD. Cardiac structure and function and prognosis in heart failure with preserved ejection fraction: findings from the echocardiographic study of the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) Trial. Circ Heart Fail. 2014 Sep;7(5):740-51. doi: 10.1161/CIRCHEARTFAILURE.114.001583. Epub 2014 Aug 13.
• Pfeffer MA, Claggett B, Assmann SF, Boineau R, Anand IS, Clausell N, Desai AS, Diaz R, Fleg JL, Gordeev I, Heitner JF, Lewis EF, O'Meara E, Rouleau JL, Probstfield JL, Shaburishvili T, Shah SJ, Solomon SD, Sweitzer NK, McKinlay SM, Pitt B. Regional variation in patients and outcomes in the Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT) trial. Circulation. 2015 Jan 6;131(1):34-42. doi: 10.1161/CIRCULATIONAHA.114.013255. Epub 2014 Nov 18.
• Mak GJ, Ledwidge MT, Watson CJ, Phelan DM, Dawkins IR, Murphy NF, Patle AK, Baugh JA, McDonald KM. Natural history of markers of collagen turnover in patients with early diastolic dysfunction and impact of eplerenone. J Am Coll Cardiol. 2009 Oct 27;54(18):1674-82. doi: 10.1016/j.jacc.2009.08.021.

INCLUSION CRITERIA:

• 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:
• 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
• Controlled systolic blood pressure(BP), defined as a target systolic BP less than 140 mm Hg; participants with BP up to and including 160 mm Hg are eligible for enrollment if they are on three or more medications to control BP
• Serum potassium less than 5.0 mmol/L prior to randomization
• At least one hospital admission for which heart failure was a major component of the hospitalization some time within the 12 months prior to study entry OR brain natriuretic peptide (BNP) greater than or equal to 100pg/ml or N-terminal pro-BNP greater than or equal to 360pg/ml within the 60 days prior to study entry
• Women of child-bearing potential must have a negative serum/urine pregnancy test within 72 hours prior to randomization, must not be lactating, and must agree to use an effective method of contraception during the entire course of study participation
• Willing to comply with scheduled visits
• Informed consent form signed by the subject prior to participation in the trial

EXCLUSION CRITERIA:

• Severe systemic illness with an expected life expectancy of less than 3 years
• Chronic pulmonary disease requiring home O2, oral steroid therapy, or hospitalization for exacerbation within 12 months of study entry, or significant chronic pulmonary disease in the opinion of the investigator
• Known infiltrative or hypertrophic obstructive cardiomyopathy or known pericardial constriction
• Primary hemodynamically significant uncorrected valvular heart disease, obstructive or regurgitant, or any valvular disease expected to lead to surgery during the trial
• Atrial fibrillation with a resting heart rate greater than 90 bpm
• MI in the past 90 days
• Coronary artery bypass graft surgery in the past 90 days
• Percutaneous coronary intervention in the past 30 days
• Heart transplant recipient
• Currently implanted left ventricular assist device
• Stroke in past 90 days
• Systolic BP (SBP) greater than 160 mm Hg
• Known orthostatic hypotension
• Gastrointestinal disorder that could interfere with study drug absorption
• Use of any aldosterone antagonist or potassium sparing medication in the last 14 days or any known condition that would require the use of an aldosterone antagonist during study participation;
• Known intolerance to aldosterone antagonists
• Current lithium use
• Current participation (including prior 30 days) in any other therapeutic trial
• Any condition that, in the opinion of the investigator, may prevent the participant from adhering to the trial protocol
• History of hyperkalemia (serum potassium greater than or equal to 5.5mmol/L) in the past 6 months or serum potassium greater than or equal to 5.0mmol/L within the past 2 weeks
• Severe renal dysfunction, defined as an estimated glomerular filtration rate(GFR) less than 30ml/min. Participants with serum creatinine greater than or equal to 2.5mg/dl are also excluded even if their GFR is greater than or equal to 30ml/min
• Known chronic hepatic disease, defined as aspartate aminotransferase(AST) and alanine aminotransferase(ALT) levels greater than 3.0 times the upper limit of normal as read at the local lab.