Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist - TOPCAT

Description:

Mineralocorticoid receptor antagonists have been shown to reduce the risk of death and other major cardiovascular (CV) events in patients with reduced ejection fraction (EF) heart failure (HF) and following myocardial infarction. The current trial sought to study the safety and efficacy of spironolactone in patients with HF with preserved EF (HFpEF).

Hypothesis:

Spironolactone would be superior to placebo in improving CV outcomes in patients with HFpEF.

Study Design

  • Blinded
  • Parallel
  • Placebo Controlled
  • Randomized
  • Stratified

Patient Populations:

  • Symptomatic CHF within 12 months
  • Age ≥50 years
  • Left ventricular EF (LVEF) ≥45%, assessed within 6 months
  • Controlled systolic BP, defined as a target systolic BP <140 mm Hg; participants with BP up to and including 160 mm Hg were eligible for enrollment if they were on three or more medications to control BP
  • Serum potassium <5.0 mmol/L
  • Stratified based on CHF hospitalization within 12 months (stratum I), or elevated BNP/proBNP within 60 days (stratum II)

    Number of enrollees: 3,445
    Duration of follow-up: 6 years (mean 3.3 years)
    Mean patient age: 69 years
    Percentage female: 52%
    LVEF: 56%
    NYHA class: II (64%), III (33%)

Exclusions:

  • Recent stroke
  • Recent coronary event
  • Uncontrolled hypertension
  • Estimated glomerular filtration rate <30 or serum creatinine >2.5 mg/dl
  • Hyperkalemia (≥5.0 mmol/L)
  • Restrictive, infiltrative, or hypertrophic cardiomyopathy
  • Life expectancy <3 years

Primary Endpoints:

  • Composite of CV mortality, aborted cardiac arrest, or hospitalization for the management of HF

Secondary Endpoints:

  • Individual components of the composite outcome
  • Quality-of-life assessments
  • Development of atrial fibrillation
  • Development of diabetes mellitus

Drug/Procedures Used:

Patients were randomized in 1:1 fashion to either spironolactone versus placebo. Spironolactone was initiated at a dose of 15 mg/day and uptitrated to a maximum of 45 mg daily during the first 4 months of randomization. The mean dose at 8 months was 25 mg.

Concomitant Medications:

Angiotensin-converting enzyme inhibitor (ACEI)/angiotensin-receptor blocker (ARB) (84%), diuretic (82%), and statin (53%)

Principal Findings:

A total of 3,445 patients were randomized at 233 sites in six countries: 1,722 to spironolactone and to 1,723 to placebo. Baseline characteristics were fairly similar between the two arms. The baseline EF was 56%, 52% were female, and nearly two-thirds of the patients had New York Heart Association (NYHA) class II symptoms. Hypertension was present in 92% of patients, with median blood pressure (BP) of 130/80 mm Hg. Coexisting coronary artery disease was noted in 59% and atrial fibrillation in 35%. The baseline potassium was 4.3 mEq/L. Close to 29% of patients were enrolled into stratum II (elevated B-type natriuretic peptide [BNP]/N-terminal proBNP).

The primary endpoint of CV death, chronic HF (CHF) hospitalization, or resuscitated cardiac arrest over 6 years was similar between the spironolactone and placebo arms (18.6% vs. 20.4%, hazard ratio = 0.89, 95% confidence interval 0.77-1.04, p = 0.14). Individual components including CV mortality (9.3% vs. 10.2%. p = 0.35) and aborted cardiac arrest (3 vs. 5 events, p = 0.48) were similar between the two arms. CHF hospitalizations were lower (12.0% vs. 14.2%, p = 0.042); all-hospitalizations were similar (44.5% vs. 46.0%; p = 0.25). Hyperkalemia (18.7% vs. 9.1%, p < 0.001) and renal failure, defined as doubling of creatinine >2 upper limit of normal were both significantly higher in the spironolactone arm.

Interpretation:

The results of the TOPCAT trial indicate that spironolactone is not superior to placebo in improving CV outcomes in patients with HFpEF. The majority of these patients were already on an ACEI/ARB. There was also a significantly higher rate of hyperkalemia and renal failure in patients treated with spironolactone. The reduction in CHF hospitalizations with spironolactone is hypothesis generating and deserves further study.

HFpEF has been notoriously hard to treat. No single agent has been identified as being effective in improving CV outcomes in these patients. Current recommendations support the treatment of underlying etiologies. The current findings do not support a role for mineralocorticoid receptor antagonists in these patients. It is also important to note that although historically considered a diagnosis of exclusion, recent guidelines suggest employing objective clinical and imaging criteria for HFpEF, which include protocols for excluding HFpEF. The exact characterization of patients with HFpEF in the current trial is not available. Heterogeneity among patients may have impacted the results as well. The results of the ongoing ALDO-HF trial are awaited.

References:

Pitt B, Pfeffer MA, Assmann SF, et al., on behalf of the TOPCAT Investigators. Spironolactone for Heart Failure With Preserved Ejection Fraction. N Engl J Med 2014;370:1383-92.

Presented by Dr. Marc A. Pfeffer at the American Heart Association Scientific Sessions, Dallas, TX, November 18, 2013.

Clinical Topics: Anticoagulation Management, Arrhythmias and Clinical EP, Heart Failure and Cardiomyopathies, Prevention, Implantable Devices, SCD/Ventricular Arrhythmias, Acute Heart Failure, Heart Failure and Cardiac Biomarkers, Hypertension

Keywords: Coronary Artery Disease, Myocardial Infarction, Mineralocorticoid Receptor Antagonists, Hyperkalemia, Heart Arrest, Creatinine, Spironolactone, Renal Insufficiency, Potassium, Heart Failure, Peptide Fragments, Confidence Intervals, Blood Pressure Determination, Hypertension, Natriuretic Peptide, Brain


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