Cardiovascular Diseases, Heart Diseases, Heart Failure, Congestive
Conditions
Keywords
Heart Failure, Diastolic Heart Failure, Preserved Ejection Fraction
Brief summary
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.
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.
Interventions
DRUGSpironolactone
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.
DRUGPlacebo
Placebo of spironolactone
Sponsors
National Heart, Lung, and Blood Institute (NHLBI)
Carelon Research
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
50 Years to No maximum
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Composite Outcome of Cardiovascular Mortality, Aborted Cardiac Arrest, or Hospitalization for 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Aborted Cardiac Arrest | Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject. | First incidence of aborted cardiac arrest |
| 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. | First incidence of a hospitalization for the management of heart failure |
| 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. | — |
| Cardiovascular-related Hospitalization | Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject. | Hospitalization for MI, stroke or the management of heart failure, whichever occurred first |
| 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. | — |
| 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. | — |
| 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. | 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. | Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject. | First incidence of atrial fibrillation among subjects without a history of atrial fibrillation at baseline |
| Myocardial Infarction | Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject. | First incidence of myocardial infarction |
| Stroke | Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject. | First incidence of stroke |
| Cardiovascular Mortality | 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. | — |
| 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. | 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. | Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject. | 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. | Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject. | 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. | Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject. | 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 | Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject. | First incidence of a hospitalization for any reason |
| Potassium | Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject. | 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 | Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject. | 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 | Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject. | 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 | Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject. | 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) | Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject. | 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. |
| Deterioration of Renal Function | Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject. | 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.) |
Countries
Argentina, Brazil, Canada, Georgia, Russia, United States
Participant flow
Recruitment details
TOPCAT enrolled 3445 patients with heart failure and preserved ejection fraction at 233 academic and community medical centers in 6 countries between August 2006 and January 2012. Trial follow-up ended in June 2013.
Pre-assignment details
Trial randomization was stratified by whether patients were enrolled into the study on the basis of having a hospitalization for heart failure within the past year (N=2,464) or having an elevated natriuretic peptide level within 60 days before randomization (N=981). The second criterion was considered only for those who did not meet the first.
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo of spironolactone | 1,723 |
| 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. | 1,722 |
| Total | 3,445 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Death | 266 | 246 |
| Overall Study | Lost to Follow-up | 43 | 41 |
| Overall Study | Physician Decision | 5 | 8 |
| Overall Study | Withdrawal by Subject | 103 | 111 |
Baseline characteristics
| Characteristic | Placebo | Spironolactone | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 1074 Participants | 1068 Participants | 2142 Participants |
| Age, Categorical Between 18 and 65 years | 649 Participants | 654 Participants | 1303 Participants |
| Age, Continuous | 68.7 years | 68.7 years | 68.7 years |
| Eligibility Stratum Elevated natriuretic peptide in previous 60 days | 491 participants | 490 participants | 981 participants |
| Eligibility Stratum Hospitalization in previous year for heart failure | 1232 participants | 1232 participants | 2464 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 3 Participants | 6 Participants | 9 Participants |
| Race (NIH/OMB) Asian | 9 Participants | 10 Participants | 19 Participants |
| Race (NIH/OMB) Black or African American | 149 Participants | 151 Participants | 300 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 2 Participants | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 25 Participants | 28 Participants | 53 Participants |
| Race (NIH/OMB) White | 1537 Participants | 1525 Participants | 3062 Participants |
| Region of Enrollment Argentina | 60 participants | 63 participants | 123 participants |
| Region of Enrollment Brazil | 82 participants | 85 participants | 167 participants |
| Region of Enrollment Canada | 160 participants | 166 participants | 326 participants |
| Region of Enrollment Georgia | 305 participants | 307 participants | 612 participants |
| Region of Enrollment Russian Federation | 537 participants | 529 participants | 1066 participants |
| Region of Enrollment United States | 579 participants | 572 participants | 1151 participants |
| Sex: Female, Male Female | 887 Participants | 888 Participants | 1775 Participants |
| Sex: Female, Male Male | 836 Participants | 834 Participants | 1670 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 1,086 / 1,723 | 1,152 / 1,722 |
| serious Total, serious adverse events | 855 / 1,723 | 835 / 1,722 |
Outcome results
Primary
Composite Outcome of Cardiovascular Mortality, Aborted Cardiac Arrest, or Hospitalization for 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.
Population: All Participants who were randomized were included in the analysis. The analysis was Intention to Treat, meaning all participants were analyzed based on their initial treatment assignment and not on the treatment eventually received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Composite Outcome of Cardiovascular Mortality, Aborted Cardiac Arrest, or Hospitalization for the Management of Heart Failure, Whichever Occurred First | 6.6 Events per 100 person-years |
| Spironolactone | Composite Outcome of Cardiovascular Mortality, Aborted Cardiac Arrest, or Hospitalization for the Management of Heart Failure, Whichever Occurred First | 5.9 Events per 100 person-years |
Comparison: Composite endpoint was compared by trial arm using logrank test of time to first event from time of randomization. Time to event was the time at which the first observed event component of the composite endpoint was observed. This endpoint was adjudicated by the TOPCAT clinical endpoints committee. There were 320 subjects in the Spironolactone group and 351 subjects in Placebo group with a confirmed event. Subjects who did not experience this endpoint were censored at time of last contact.p-value: 0.1495% CI: [0.77, 1.04]Log Rank
Secondary
Aborted Cardiac Arrest
First incidence of aborted cardiac arrest
Time frame: Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.
Population: All Participants who were randomized were included in the analysis. The analysis was Intention to Treat, meaning all participants were analyzed based on their initial treatment assignment and not on the treatment eventually received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Aborted Cardiac Arrest | 0.09 Events per 100 person-years |
| Spironolactone | Aborted Cardiac Arrest | 0.05 Events per 100 person-years |
Comparison: This endpoint was compared by trial arm (spironolactone vs. placebo) using a logrank test of time to first event from the time of randomization. Subjects who did not experience this endpoint were censored at the time of their last contact.~This endpoint was adjudicated by the TOPCAT clinical endpoints committee. There were 8 subjects (3 in the Spironolactone group and 5 in the Placebo group) with a confirmed event.p-value: 0.4895% CI: [0.14, 2.5]Log Rank
Secondary
All-cause Mortality
Time frame: Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.
Population: All Participants who were randomized were included in the analysis. The analysis was Intention to Treat, meaning all participants were analyzed based on their initial treatment assignment and not on the treatment eventually received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | All-cause Mortality | 4.6 Events per 100 person-years |
| Spironolactone | All-cause Mortality | 4.2 Events per 100 person-years |
Comparison: Endpoint compared by trial arm using logrank test of time to event from randomization. Subjects who did not experience endpoint were censored at time of last contact. Attempts were made to determine vital status as of each subject's last potential visit, based on randomization, even if the subject ended study participation before then. This outcome was adjudicated. There were 252 events over 6,022 patient-years in Spironolactone arm and 274 events over 5,981 patient-years in Placebo arm.p-value: 0.2995% CI: [0.77, 1.08]Log Rank
Secondary
Cardiovascular Mortality
Time frame: Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.
Population: All Participants who were randomized were included in the analysis. The analysis was Intention to Treat, meaning all participants were analyzed based on their initial treatment assignment and not on the treatment eventually received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Cardiovascular Mortality | 3.1 Events per 100 person-years |
| Spironolactone | Cardiovascular Mortality | 2.8 Events per 100 person-years |
Comparison: This endpoint was compared by trial arm (spironolactone vs. placebo) using a logrank test of time to event from the time of randomization. Subjects who did not experience this endpoint were censored at the time of their last contact.~This endpoint was adjudicated by the TOPCAT clinical endpoints committee. There were 336 subjects (160 in the Spironolactone group and 176 in the Placebo group) with a confirmed event.p-value: 0.3595% CI: [0.73, 1.12]Log Rank
Secondary
Cardiovascular-related Hospitalization
Hospitalization for 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.
Population: All Participants who were randomized were included in the analysis. The analysis was Intention to Treat, meaning all participants were analyzed based on their initial treatment assignment and not on the treatment eventually received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Cardiovascular-related Hospitalization | 6.2 Events per 100 person-years |
| Spironolactone | Cardiovascular-related Hospitalization | 5.5 Events per 100 person-years |
Comparison: Endpoint was compared by trial arm using logrank test of time to first event from time of randomization. Time to event was the time at which the first observed event component of the composite endpoint was observed. Component endpoints were adjudicated by the TOPCAT clinical endpoints committee. There were 291 subjects in Spironolactone group and 320 subjects in Placebo group with a confirmed event. Subjects who did not experience this endpoint were censored at time of last contact.p-value: 0.1595% CI: [0.76, 1.04]Log Rank
Secondary
Chloride
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.
Time frame: Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.
Population: All Participants who were randomized were included in the analysis. The analysis was Intention to Treat, meaning all participants were analyzed based on their initial treatment assignment and not on the treatment eventually received.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Chloride | 102.33 mEq/L | Standard Error 0.08 |
| Spironolactone | Chloride | 102.26 mEq/L | Standard Error 0.08 |
Comparison: A generalized linear model was fit, with the post-baseline laboratory value as the dependent variable, and the baseline laboratory value, treatment group, month of visit, and the interaction between treatment group and month of visit as predictor variables. This tests whether the slope of the post-baseline laboratory parameter differs by treatment group, taking into account that measurements in the same subject over time may be correlated.p-value: 0.59Regression, Linear
Comparison: Since the p-value for the preceding test (Statistical Analysis 1) was not significant at the 0.05 level, another generalized linear model was fit, omitting the interaction between treatment group and month of visit. This tests whether the value of the post-baseline laboratory parameter differs by treatment group, taking into account that measurements in the same subject over time may be correlated.p-value: 0.54Regression, Linear
Secondary
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.
Population: All Participants who were randomized were included in the analysis. The analysis was Intention to Treat, meaning all participants were analyzed based on their initial treatment assignment and not on the treatment eventually received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | 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 | 7.8 Events per 100 person-years |
| Spironolactone | 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 | 7.2 Events per 100 person-years |
Comparison: Composite endpoint was compared by trial arm using logrank test of time to first event from time of randomization. Time to event was the time at which the first observed event component of the composite endpoint was observed. Component endpoints were adjudicated by the TOPCAT clinical endpoints committee. There were 382 subjects in Spironolactone group and 404 subjects in Placebo group with a confirmed event. Subjects who did not experience this endpoint were censored at time of last contact.p-value: 0.2895% CI: [0.8, 1.06]Log Rank
Secondary
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.
Population: All Participants who were randomized were included in the analysis. The analysis was Intention to Treat, meaning all participants were analyzed based on their initial treatment assignment and not on the treatment eventually received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Composite Outcome of Sudden Death, Aborted Cardiac Arrest, or Hospitalization for the Management of Ventricular Tachycardia, Whichever Occurred First | 1.1 Events per 100 person-years |
| Spironolactone | Composite Outcome of Sudden Death, Aborted Cardiac Arrest, or Hospitalization for the Management of Ventricular Tachycardia, Whichever Occurred First | 1.0 Events per 100 person-years |
Comparison: Composite endpoint was compared by trial arm using logrank test of time to first event from time of randomization. Time to event was the time at which the first observed event component of the composite endpoint was observed. Component endpoints were adjudicated by the TOPCAT clinical endpoints committee. There were 58 subjects in the Spironolactone group and 61 subjects in Placebo group with a confirmed event. Subjects who did not experience this endpoint were censored at time of last contact.p-value: 0.7595% CI: [0.66, 1.35]Log Rank
Secondary
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.
Population: All Participants who were randomized were included in the analysis. The analysis was Intention to Treat, meaning all participants were analyzed based on their initial treatment assignment and not on the treatment eventually received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Composite Outcome of Sudden Death or Aborted Cardiac Arrest, Whichever Occurred First | 1.1 Events per 100 person-years |
| Spironolactone | Composite Outcome of Sudden Death or Aborted Cardiac Arrest, Whichever Occurred First | 1.0 Events per 100 person-years |
Comparison: Composite endpoint was compared by trial arm using logrank test of time to first event from time of randomization. Time to event was the time at which the first observed event component of the composite endpoint was observed. Component endpoints were adjudicated by the TOPCAT clinical endpoints committee. There were 58 subjects in the Spironolactone group and 60 subjects in Placebo group with a confirmed event. Subjects who did not experience this endpoint were censored at time of last contact.p-value: 0.8295% CI: [0.67, 1.38]Log Rank
Secondary
Depression Symptoms, as Measured by Patient Health Questionnaire.
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.
Time frame: Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.
Population: All Participants from the United States and Canada who were randomized were included in the analysis. The analysis was Intention to Treat, meaning all participants were analyzed based on their initial treatment assignment and not on the treatment eventually received.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Depression Symptoms, as Measured by Patient Health Questionnaire. | 5.6 units on a scale | Standard Error 0.1 |
| Spironolactone | Depression Symptoms, as Measured by Patient Health Questionnaire. | 5.1 units on a scale | Standard Error 0.2 |
Comparison: A generalized linear model was fit, with the post-baseline quality of life scores as the dependent variable, and the baseline quality of life score, treatment group, month of visit, and the interaction between treatment group and month of visit as predictor variables. This tests whether the slope of the post-baseline quality of life parameter differs by treatment group, taking into account that measurements in the same subject over time may be correlated.p-value: 0.39Regression, Linear
Comparison: Since the p-value for the preceding test (Statistical Analysis 1) was not significant at the 0.05 level, another generalized linear model was fit, omitting the interaction between treatment group and month of visit. This tests whether the value of the post-baseline quality of life parameter differs by treatment group, taking into account that measurements in the same subject over time may be correlated.p-value: 0.01Regression, Linear
Secondary
Deterioration of Renal Function
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.)
Time frame: Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.
Population: All Participants who were randomized were included in the analysis. The analysis was Intention to Treat, meaning all participants were analyzed based on their initial treatment assignment and not on the treatment eventually received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Deterioration of Renal Function | 2.2 Events per 100 person-years |
| Spironolactone | Deterioration of Renal Function | 3.2 Events per 100 person-years |
Comparison: This endpoint was compared by trial arm (spironolactone vs. placebo) using a logrank test of time to first event from the time of randomization. Subjects who did not experience this endpoint were censored at the time of their last contact.~There were 295 subjects (175 in the Spironolactone group and 120 in the Placebo group) experiencing this endpoint. This endpoint did not undergo adjudication by the TOPCAT clinical endpoints committee.p-value: <0.0195% CI: [1.18, 1.87]Log Rank
Secondary
Development of Atrial Fibrillation, Among Subjects Without a History of Atrial Fibrillation at Baseline.
First incidence 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.
Population: All Participants who were randomized and did not have a history of atrial fibrillation at baseline were included in the analysis. The analysis was Intention to Treat, meaning all participants were analyzed based on their initial treatment assignment and not on the treatment eventually received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Development of Atrial Fibrillation, Among Subjects Without a History of Atrial Fibrillation at Baseline. | 1.4 Events per 100 person-years |
| Spironolactone | Development of Atrial Fibrillation, Among Subjects Without a History of Atrial Fibrillation at Baseline. | 1.4 Events per 100 person-years |
Comparison: This endpoint was compared by trial arm (spironolactone vs. placebo) using a logrank test of time to first event from the time of randomization. Subjects who did not experience this endpoint were censored at the time of their last contact.~This endpoint was adjudicated by the TOPCAT clinical endpoints committee. There were 103 subjects (52 in the Spironolactone group and 51 in the Placebo group) with confirmed events.p-value: 0.9495% CI: [0.69, 1.5]Log Rank
Secondary
Estimated Glomerular Filtration Rate (GFR)
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.
Time frame: Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.
Population: All Participants who were randomized were included in the analysis. The analysis was Intention to Treat, meaning all participants were analyzed based on their initial treatment assignment and not on the treatment eventually received.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Estimated Glomerular Filtration Rate (GFR) | 67.50 mL/min/1.73m2 | Standard Error 0.29 |
| Spironolactone | Estimated Glomerular Filtration Rate (GFR) | 65.20 mL/min/1.73m2 | Standard Error 0.9 |
Comparison: A generalized linear model was fit, with the post-baseline laboratory value as the dependent variable, and the baseline laboratory value, treatment group, month of visit, and the interaction between treatment group and month of visit as predictor variables. This tests whether the slope of the post-baseline laboratory parameter differs by treatment group, taking into account that measurements in the same subject over time may be correlated.p-value: 0.98Regression, Linear
Comparison: Since the p-value for the preceding test (Statistical Analysis 1) was not significant at the 0.05 level, another generalized linear model was fit, omitting the interaction between treatment group and month of visit. This tests whether the value of the post-baseline laboratory parameter differs by treatment group, taking into account that measurements in the same subject over time may be correlated.p-value: 0.02Regression, Linear
Secondary
Hospitalization for Any Reason
First incidence of a hospitalization for any reason
Time frame: Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.
Population: All Participants who were randomized were included in the analysis. The analysis was Intention to Treat, meaning all participants were analyzed based on their initial treatment assignment and not on the treatment eventually received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Hospitalization for Any Reason | 20.0 Events per 100 person-years |
| Spironolactone | Hospitalization for Any Reason | 18.8 Events per 100 person-years |
Comparison: This endpoint was compared by trial arm (spironolactone vs. placebo) using a logrank test of time to first event from the time of randomization. Subjects who did not experience this endpoint were censored at the time of their last contact.~There were a total of 1558 subjects (766 subjects in the Spironolactone group and 792 subjects in the Placebo) who were hospitalized for any cause while on study. This endpoint was not adjudicated by the TOPCAT clinical endpoints committee.p-value: 0.2595% CI: [0.85, 1.04]Log Rank
Secondary
Hospitalization for the Management of Heart Failure
First incidence of a 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.
Population: All Participants who were randomized were included in the analysis. The analysis was Intention to Treat, meaning all participants were analyzed based on their initial treatment assignment and not on the treatment eventually received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Hospitalization for the Management of Heart Failure | 4.6 Events per 100 person-years |
| Spironolactone | Hospitalization for the Management of Heart Failure | 3.8 Events per 100 person-years |
Comparison: This endpoint was compared by trial arm (spironolactone vs. placebo) using a logrank test of time to first event from the time of randomization. Subjects who did not experience this endpoint were censored at the time of their last contact.~This endpoint was adjudicated by the TOPCAT clinical endpoints committee. There were 451 subjects (206 in the Spironolactone group and 245 in the Placebo group) who have been confirmed to have experienced the eventp-value: 0.0495% CI: [0.69, 0.99]Log Rank
Secondary
Myocardial Infarction
First incidence of myocardial infarction
Time frame: Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.
Population: All Participants who were randomized were included in the analysis. The analysis was Intention to Treat, meaning all participants were analyzed based on their initial treatment assignment and not on the treatment eventually received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Myocardial Infarction | 1.1 Events per 100 person-years |
| Spironolactone | Myocardial Infarction | 1.2 Events per 100 person-years |
Comparison: This endpoint was compared by trial arm (spironolactone vs. placebo) using a logrank test of time to first event from the time of randomization. Subjects who did not experience this endpoint were censored at the time of their last contact.~This endpoint was adjudicated by the TOPCAT clinical endpoints committee. There were 129 subjects (65 in the Spironolactone group and 64 in the Placebo group) with confirmed events.p-value: 0.9895% CI: [0.71, 1.42]Log Rank
Secondary
New Onset Diabetes Mellitus, Among Subjects Without a History of Diabetes Mellitus at Baseline.
First incidence of 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.
Population: All Participants who were randomized and did not have a history of diabetes mellitus at baseline were included in the analysis. The analysis was Intention to Treat, meaning all participants were analyzed based on their initial treatment assignment and not on the treatment eventually received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | New Onset Diabetes Mellitus, Among Subjects Without a History of Diabetes Mellitus at Baseline. | 0.7 Events per 100 person-years |
| Spironolactone | New Onset Diabetes Mellitus, Among Subjects Without a History of Diabetes Mellitus at Baseline. | 0.7 Events per 100 person-years |
Comparison: This endpoint was compared by trial arm (spironolactone vs. placebo) using a logrank test of time to first event from the time of randomization. Subjects who did not experience this endpoint were censored at the time of their last contact.~This endpoint was adjudicated by the TOPCAT clinical endpoints committee. There were 56 subjects (29 in the Spironolactone group and 27 in the Placebo group) with confirmed events.p-value: 0.7695% CI: [0.64, 1.83]Log Rank
Secondary
Potassium
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.
Time frame: Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.
Population: All Participants who were randomized were included in the analysis. The analysis was Intention to Treat, meaning all participants were analyzed based on their initial treatment assignment and not on the treatment eventually received.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Potassium | 4.32 mEq/L | Standard Error 0.01 |
| Spironolactone | Potassium | 4.49 mEq/L | Standard Error 0.01 |
Comparison: A generalized linear model was fit, with the post-baseline laboratory value as the dependent variable, and the baseline laboratory value, treatment group, month of visit, and the interaction between treatment group and month of visit as predictor variables. This tests whether the slope of the post-baseline laboratory parameter differs by treatment group, taking into account that measurements in the same subject over time may be correlated.p-value: 0.27Regression, Linear
Comparison: Since the p-value for the preceding test (Statistical Analysis 1) was not significant at the 0.05 level, another generalized linear model was fit, omitting the interaction between treatment group and month of visit. This tests whether the value of the post-baseline laboratory parameter differs by treatment group, taking into account that measurements in the same subject over time may be correlated.p-value: <0.01Regression, Linear
Secondary
Quality of Life, as Measured by McMaster Overall Treatment Evaluation Questionnaire.
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.
Time frame: Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.
Population: All Participants from United States, Canada and Argentina who were randomized were included in the analysis. The analysis was Intention to Treat, meaning all participants were analyzed based on their initial treatment assignment and not on the treatment eventually received.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Quality of Life, as Measured by McMaster Overall Treatment Evaluation Questionnaire. | 1.2 units on a scale | Standard Error 0.1 |
| Spironolactone | Quality of Life, as Measured by McMaster Overall Treatment Evaluation Questionnaire. | 1.2 units on a scale | Standard Error 0.1 |
Comparison: A generalized linear model was fit, with the post-baseline quality of life scores as the dependent variable, and the baseline quality of life score and treatment group as predictor variables. This tests whether the value of the post-baseline quality of life parameter differs by treatment group.p-value: 0.99Regression, Linear
Secondary
Quality of Life, as Measured by the EuroQOL Visual Analog Scale.
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.
Time frame: Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.
Population: All Participants who were randomized were included in the analysis. The analysis was Intention to Treat, meaning all participants were analyzed based on their initial treatment assignment and not on the treatment eventually received.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Quality of Life, as Measured by the EuroQOL Visual Analog Scale. | 65.9 units on a scale | Standard Error 0.3 |
| Spironolactone | Quality of Life, as Measured by the EuroQOL Visual Analog Scale. | 66.4 units on a scale | Standard Error 0.3 |
Comparison: A generalized linear model was fit, with the post-baseline quality of life scores as the dependent variable, and the baseline quality of life score, treatment group, month of visit, and the interaction between treatment group and month of visit as predictor variables. This tests whether the slope of the post-baseline quality of life parameter differs by treatment group, taking into account that measurements in the same subject over time may be correlated.p-value: 0.87Regression, Linear
Comparison: Since the p-value for the preceding test (Statistical Analysis 1) was not significant at the 0.05 level, another generalized linear model was fit, omitting the interaction between treatment group and month of visit. This tests whether the value of the post-baseline quality of life parameter differs by treatment group, taking into account that measurements in the same subject over time may be correlated.p-value: 0.16Regression, Linear
Secondary
Quality of Life, as Measured by the Kansas City Cardiomyopathy Questionnaire.
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.
Time frame: Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.
Population: All Participants who were randomized were included in the analysis. The analysis was Intention to Treat, meaning all participants were analyzed based on their initial treatment assignment and not on the treatment eventually received.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Quality of Life, as Measured by the Kansas City Cardiomyopathy Questionnaire. | 63.1 units on a scale | Standard Error 0.3 |
| Spironolactone | Quality of Life, as Measured by the Kansas City Cardiomyopathy Questionnaire. | 64.4 units on a scale | Standard Error 0.3 |
Comparison: A generalized linear model was fit, with the post-baseline quality of life scores as the dependent variable, and the baseline quality of life score, treatment group, month of visit, and the interaction between treatment group and month of visit as predictor variables. This tests whether the slope of the post-baseline quality of life parameter differs by treatment group, taking into account that measurements in the same subject over time may be correlated.p-value: 0.27Regression, Linear
Comparison: Since the p-value for the preceding test (Statistical Analysis 1) was not significant at the 0.05 level, another generalized linear model was fit, omitting the interaction between treatment group and month of visit. This tests whether the value of the post-baseline quality of life parameter differs by treatment group, taking into account that measurements in the same subject over time may be correlated.p-value: <0.01Regression, Linear
Secondary
Serum Creatinine
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.
Time frame: Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.
Population: All Participants who were randomized were included in the analysis. The analysis was Intention to Treat, meaning all participants were analyzed based on their initial treatment assignment and not on the treatment eventually received.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Serum Creatinine | 1.11 mg/dL | Standard Error 0.005 |
| Spironolactone | Serum Creatinine | 1.17 mg/dL | Standard Error 0.01 |
Comparison: A generalized linear model was fit, with the post-baseline laboratory value as the dependent variable, and the baseline laboratory value, treatment group, month of visit, and the interaction between treatment group and month of visit as predictor variables. This tests whether the slope of the post-baseline laboratory parameter differs by treatment group, taking into account that measurements in the same subject over time may be correlated.p-value: 0.53Regression, Linear
Comparison: Since the p-value for the preceding test (Statistical Analysis 1) was not significant at the 0.05 level, another generalized linear model was fit, omitting the interaction between treatment group and month of visit. This tests whether the value of the post-baseline laboratory parameter differs by treatment group, taking into account that measurements in the same subject over time may be correlated.p-value: <0.01Regression, Linear
Secondary
Sodium
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.
Time frame: Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.
Population: All Participants who were randomized were included in the analysis. The analysis was Intention to Treat, meaning all participants were analyzed based on their initial treatment assignment and not on the treatment eventually received.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Sodium | 140.95 mEq/L | Standard Error 0.06 |
| Spironolactone | Sodium | 140.33 mEq/L | Standard Error 0.06 |
Comparison: A generalized linear model was fit, with the post-baseline laboratory value as the dependent variable, and the baseline laboratory value, treatment group, month of visit, and the interaction between treatment group and month of visit as predictor variables. This tests whether the slope of the post-baseline laboratory parameter differs by treatment group, taking into account that measurements in the same subject over time may be correlated.p-value: 0.11Regression, Linear
Comparison: Since the p-value for the preceding test (Statistical Analysis 1) was not significant at the 0.05 level, another generalized linear model was fit, omitting the interaction between treatment group and month of visit. This tests whether the value of the post-baseline laboratory parameter differs by treatment group, taking into account that measurements in the same subject over time may be correlated.p-value: <0.01Regression, Linear
Secondary
Stroke
First incidence of stroke
Time frame: Randomization through each subject's last semi-annual visit, up to a maximum of 6 years per subject.
Population: All Participants who were randomized were included in the analysis. The analysis was Intention to Treat, meaning all participants were analyzed based on their initial treatment assignment and not on the treatment eventually received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Stroke | 1.1 Events per 100 person-years |
| Spironolactone | Stroke | 1.0 Events per 100 person-years |
Comparison: This endpoint was compared by trial arm (spironolactone vs. placebo) using a logrank test of time to first event from the time of randomization. Subjects who did not experience this endpoint were censored at the time of their last contact.~This endpoint was adjudicated by the TOPCAT clinical endpoints committee. There were 117 subjects (57 in the Spironolactone group and 60 in the Placebo group) with confirmed events.p-value: 0.7395% CI: [0.65, 1.35]Log Rank
Secondary
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.
Population: All Participants who were randomized were included in the analysis. The analysis was Intention to Treat, meaning all participants were analyzed based on their initial treatment assignment and not on the treatment eventually received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo | Total Hospitalizations (Including Repeat Hospitalizations) for the Management of Heart Failure | 8.3 Events per 100 person-years |
| Spironolactone | Total Hospitalizations (Including Repeat Hospitalizations) for the Management of Heart Failure | 6.8 Events per 100 person-years |
Comparison: There were a total of 869 confirmed heart failure hospitalizations (394 in the Spironolactone group and 475 in the Placebo group) during the 11,471 person-years collected over the course of the TOPCAT trial (5,755 person-years in the Spironolactone group and 5,716 person-years in the Placebo group). The incidence rate of heart failure hospitalizations for each treatment group was compared using a negative binomial regression with a p-value threshold of 0.05 for statistical significance.p-value: 0.0395% CI: [0.58, 0.97]Negative binomial regression