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

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Information provided by (Responsible Party):
New England Research Institutes
ClinicalTrials.gov Identifier:
NCT00094302
First received: October 15, 2004
Last updated: November 29, 2012
Last verified: November 2012
  Purpose

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.


Condition Intervention Phase
Cardiovascular Diseases
Heart Diseases
Heart Failure, Congestive
Drug: Spironolactone (an aldosterone antagonist)
Drug: Placebo
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Parallel Assignment
Masking: Double Blind (Subject, Caregiver, Investigator)
Primary Purpose: Treatment
Official Title: Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist (TOPCAT)

Resource links provided by NLM:


Further study details as provided by New England Research Institutes:

Primary Outcome Measures:
  • Time to a composite outcome of cardiovascular mortality, aborted cardiac arrest, or hospitalization for the management of heart failure, whichever occurs first. [ Time Frame: Through each subject's last semi-annual visit, up to a maximum of 6 years per subject. ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Time to cardiovascular mortality. [ Time Frame: Through each subject's last semi-annual visit, up to a maximum of 6 years per subject. ] [ Designated as safety issue: No ]
  • Time to aborted cardiac arrest. [ Time Frame: Through each subject's last semi-annual visit, up to a maximum of 6 years per subject. ] [ Designated as safety issue: No ]
  • Time to first hospitalization for the management of heart failure. [ Time Frame: Through each subject's last semi-annual visit, up to a maximum of 6 years per subject. ] [ Designated as safety issue: No ]
  • Time to all cause mortality. [ Time Frame: Through each subject's last semi-annual visit, up to a maximum of 6 years per subject. ] [ Designated as safety issue: Yes ]
  • Time to 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: Through each subject's last semi-annual visit, up to a maximum of 6 years per subject. ] [ Designated as safety issue: No ]
  • Hospitalization for the management of heart failure incidence rate. [ Time Frame: Through each subject's last semi-annual visit, up to a maximum of 6 years per subject. ] [ Designated as safety issue: No ]
  • Time to sudden death or aborted cardiac arrest. [ Time Frame: Through each subject's last semi-annual visit, up to a maximum of 6 years per subject. ] [ Designated as safety issue: No ]
  • Time to new onset diabetes mellitus, in subjects without a history of diabetes mellitus at baseline. [ Time Frame: Through each subject's last semi-annual visit, up to a maximum of 6 years per subject. ] [ Designated as safety issue: No ]
  • Time to development of atrial fibrillation, in subjects without a history of atrial fibrillation at baseline. [ Time Frame: Through each subject's last semi-annual visit, up to a maximum of 6 years per subject. ] [ Designated as safety issue: No ]
  • Time to myocardial infarction. [ Time Frame: Through each subject's last semi-annual visit, up to a maximum of 6 years per subject. ] [ Designated as safety issue: No ]
  • Time to stroke. [ Time Frame: Through each subject's last semi-annual visit, up to a maximum of 6 years per subject. ] [ Designated as safety issue: No ]
  • Time to deterioration of renal function. [ Time Frame: Through each subject's last semi-annual visit, up to a maximum of 6 years per subject. ] [ Designated as safety issue: No ]
  • Time to a composite outcome of sudden death, aborted cardiac arrest, or hospitalization for the management of ventricular tachycardia. [ Time Frame: 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: Baseline, Month 4, Month 12 and annually thereafter. ] [ Designated as safety issue: No ]
  • Quality of life, as measured by the EuroQOL visual analog scale. [ Time Frame: Baseline, Month 4, Month 12 and annually thereafter. ] [ Designated as safety issue: No ]
  • Quality of life, as measured by McMaster Overall Treatment Evaluation questionnaire. [ Time Frame: Month 4 and Month 12. ] [ Designated as safety issue: No ]
  • Depression symptoms, as measured by Patient Health Questionnaire. [ Time Frame: Baseline, Month 12 and annually thereafter. ] [ Designated as safety issue: No ]
  • Time to hospitalization for any reason. [ Time Frame: Through each subject's last semi-annual visit, up to a maximum of 6 years per subject. ] [ Designated as safety issue: Yes ]
  • Serum Potassium [ Time Frame: Through each subject's last semi-annual visit, up to a maximum of 6 years per subject. ] [ Designated as safety issue: Yes ]
  • Serum Sodium [ Time Frame: Through each subject's last semi-annual visit, up to a maximum of 6 years per subject. ] [ Designated as safety issue: Yes ]
  • Serum Creatinine [ Time Frame: Through each subject's last semi-annual visit, up to a maximum of 6 years per subject. ] [ Designated as safety issue: Yes ]
  • Serum Chloride [ Time Frame: Through each subject's last semi-annual visit, up to a maximum of 6 years per subject. ] [ Designated as safety issue: Yes ]
  • Serum Bicarbonate [ Time Frame: Through each subject's last semi-annual visit, up to a maximum of 6 years per subject. ] [ Designated as safety issue: Yes ]
  • Serum Blood Urea Nitrogen (BUN) [ Time Frame: Through each subject's last semi-annual visit, up to a maximum of 6 years per subject. ] [ Designated as safety issue: Yes ]

Enrollment: 3445
Study Start Date: August 2006
Estimated Study Completion Date: June 2013
Estimated Primary Completion Date: June 2013 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Placebo Comparator: 1
Placebo
Drug: Placebo
Placebo of spironolactone
Experimental: 2
Spironolactone
Drug: Spironolactone (an aldosterone antagonist)
Spironolactone 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.

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.

  Eligibility

Ages Eligible for Study:   50 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

INCLUSION CRITERIA:

  • Heart failure as defined by at least one of the following symptoms at the time of screening and at least one of the following signs within 12 months prior to study entry:

    1. SYMPTOMS:

      1. Paroxysmal nocturnal dyspnea
      2. Orthopnea
      3. Dyspnea on mild or moderate exertion
    2. SIGNS:

      1. Any rales post cough
      2. Jugular venous pressure(JVP) greater than or equal to 10 cm H2O
      3. Lower extremity edema
      4. Chest x-ray demonstrating pleural effusion, pulmonary congestion, or cardiomegaly
  • Left ventricular ejection fraction (ideally obtained by echocardiography, although radionuclide ventriculography and angiography are acceptable) 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 (transient heart failure in the context of MI does not qualify) OR brain natriuretic peptide (BNP) greater than or equal to 100 pg/ml or N-terminal pro-BNP greater than or equal to 360 pg/ml (not explained by another disease entity) 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 5.5 mmol/L) in the past 6 months or serum potassium greater than or equal to 5.0 mmol/L within the past 2 weeks
  • Severe renal dysfunction, defined as an estimated glomerular filtration rate(GFR) less than 30 ml/min (per the Modification of Diet in Renal Disease (MDRD) 4-component study equation). Participants with serum creatinine greater than or equal to 2.5 mg/dl are also excluded even if their GFR is greater than or equal to 30 ml/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
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT00094302

  Show 270 Study Locations
Sponsors and Collaborators
New England Research Institutes
Investigators
Principal Investigator: Sonja M. McKinlay, PhD New England Research Institutes, Inc.
  More Information

Additional Information:
Publications:
Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
Responsible Party: New England Research Institutes
ClinicalTrials.gov Identifier: NCT00094302     History of Changes
Other Study ID Numbers: 160, HHSN268200425207C
Study First Received: October 15, 2004
Last Updated: November 29, 2012
Health Authority: United States: Food and Drug Administration

Keywords provided by New England Research Institutes:
Heart Failure
Diastolic Heart Failure
Preserved Ejection Fraction

Additional relevant MeSH terms:
Cardiovascular Diseases
Heart Diseases
Heart Failure
Aldosterone Antagonists
Spironolactone
Hormone Antagonists
Hormones, Hormone Substitutes, and Hormone Antagonists
Physiological Effects of Drugs
Pharmacologic Actions
Diuretics
Natriuretic Agents
Cardiovascular Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on April 16, 2014