Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist - TOPCAT
Contribution To Literature:
The TOPCAT trial showed that spironolactone is not superior to placebo in improving CV outcomes in patients with HFpEF, with higher rates of hyperkalemia and renal failure.
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).
- Placebo Controlled
- 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%
NYHA class: II (64%), III (33%)
- 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
- Composite of CV mortality, aborted cardiac arrest, or hospitalization for the management of HF
- Individual components of the composite outcome
- Quality-of-life assessments
- Development of atrial fibrillation
- Development of diabetes mellitus
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.
Angiotensin-converting enzyme inhibitor (ACEI)/angiotensin-receptor blocker (ARB) (84%), diuretic (82%), and statin (53%)
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 (AF) 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 [HR] 0.89, 95% confidence interval [CI] 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.
Influence of AF: AF was common, either based on ECG at enrollment (25%) or based on history (18%). These patients had higher left atrial volumes than patients without AF. Patients with any history/prevalent AF had numerically higher incidence of the primary endpoint (12.1% vs. 11.0%/100 patient-years, HR 1.19, 95% CI 0.99-1.43, p = 0.06). Post-randomization AF occurred in 6.3% of patients and was associated with an increased early risk of the primary outcome (HR 2.32, 95% CI 1.59-3.40, p < 0.0001). There was no effect modification by AF for the primary endpoint for spironolactone vs. placebo (p = 0.49).
Sex differences: 49.9% were women. Women were older with fewer comorbidities. Primary outcome for spironolactone vs. placebo based on gender: women, 25.1% vs. 29.5%; men, 29.5% vs. 34.0% (p for interaction = 0.84). All-cause mortality: women, 15.8% vs. 22.3% (p = 0.015); men, 25.2% vs. 24.3% (p for interaction = 0.02).
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. Similarly, a reduction in mortality for women 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.
Merrill M, Sweitzer NK, Lindenfeld J, Kao DP. Sex Differences in Outcomes and Responses to Spironolactone in Heart Failure With Preserved Ejection Fraction: A Secondary Analysis of TOPCAT Trial. JACC Heart Fail 2019;7:228-38.
Cikes M, Claggett B, Shah AM, et al. Atrial Fibrillation in Heart Failure With Preserved Ejection Fraction: The TOPCAT Trial. JACC Heart Fail 2018;6:689-97.
Editorial Comment: DeVore AD, Piccini JP. Mineralocorticoid Receptor Antagonism for the Treatment of AF and HFpEF: Preserving Hope. JACC Heart Fail 2018;6:698-700.
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, Atherosclerotic Disease (CAD/PAD), Anticoagulation Management and Atrial Fibrillation, Implantable Devices, SCD/Ventricular Arrhythmias, Atrial Fibrillation/Supraventricular 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, Blood Pressure Determination, Hypertension, Natriuretic Peptide, Brain, Atrial Fibrillation, Stroke Volume
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