What is the TOPCAT (Treatment Of Preserved Cardiac Function Heart Failure With An Aldosterone Antagonist Trial) clinical trial?

What is the TOPCAT Clinical Trial?

TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist Trial) was a randomized, double-blind, placebo-controlled trial that investigated whether spironolactone could reduce cardiovascular death, aborted cardiac arrest, and heart failure hospitalizations in patients with heart failure and preserved ejection fraction (HFpEF). 1

Trial Design and Patient Population

TOPCAT enrolled up to 3,515 patients with symptomatic HFpEF, defined as:

• Age ≥50 years 2
• Left ventricular ejection fraction ≥45% 1, 2
• Symptomatic heart failure 2
• Either a hospitalization for HF within the prior year OR elevated natriuretic peptide levels (BNP ≥100 pg/mL or NT-proBNP ≥360 pg/mL) within 60 days before randomization 2

Key exclusion criteria included:

• Serum potassium >5.0 mEq/L 1
• Serum creatinine >2.5 mg/dL or eGFR <30 mL/min 1
• Uncontrolled hypertension 2
• Known infiltrative or hypertrophic cardiomyopathy 2

Patients were randomized 1:1 to receive spironolactone (target dose 30 mg daily) or matching placebo. 2

Primary Results and Limitations

The trial showed a small, statistically non-significant reduction in the primary composite endpoint (HR=0.89), though heart failure hospitalization alone was significantly reduced (HR=0.83). 1 Known side effects of hyperkalemia and rising creatinine occurred more commonly in the spironolactone group. 1

Critical Regional Variation Problem

The most significant limitation of TOPCAT was marked regional variation in outcomes, with rates of the primary endpoint being 4-fold lower in Russia/Georgia compared to North and South America (the Americas). 1 This prompted post-hoc analyses that revealed:

• In the Americas cohort: spironolactone showed efficacy (HR=0.83) 1
• In Russia/Georgia cohort: no benefit was observed (HR=1.10) 1
• Critically, samples from the Russia/Georgia population in the active treatment arm had nondetectable levels of spironolactone metabolites, suggesting medication non-adherence or other trial conduct issues 1

Clinical Implications and Current Guideline Recommendations

Based on TOPCAT results, the ACC/AHA/HFSA guidelines assign spironolactone a Class IIb recommendation (Level B-R evidence) for HFpEF, meaning it "might be considered" to decrease hospitalizations, but is not strongly recommended. 1, 3 This weak recommendation reflects:

• No mortality benefit demonstrated 3
• Only modest reduction in hospitalizations 1
• Significant safety concerns regarding hyperkalemia and renal dysfunction 1
• Uncertainty due to regional variation and trial conduct issues 1

Patient Selection Based on TOPCAT

If spironolactone is considered for HFpEF, the ACC/AHA recommends strict patient selection criteria mirroring TOPCAT inclusion/exclusion criteria:

• EF ≥45% 1, 3
• Elevated BNP levels or HF hospitalization within 1 year 1, 3
• eGFR >30 mL/min 1, 3
• Creatinine <2.5 mg/dL in men or <2.0 mg/dL in women 1
• Potassium <5.0 mEq/L 1, 3

Post-hoc analyses suggest greatest benefit in patients with elevated BNP levels and those at the lower end of the HFpEF ejection fraction spectrum (closer to 45% than 65%). 3, 4 Paradoxically, patients with higher natriuretic peptide levels (indicating more severe disease) appeared to derive less benefit from spironolactone. 4

Mechanistic Insights from TOPCAT Substudies

A TOPCAT biorepository substudy demonstrated that spironolactone reduced NT-proBNP and BNP levels over 12 months compared to placebo, suggesting effects on cardiac wall stress or filling pressures. 5 However, no significant changes were observed in markers of myocardial injury (hs-cTnI), inflammation (hs-CRP), or proteinuria. 5

Echocardiographic substudies identified that left ventricular hypertrophy, elevated left ventricular filling pressure (E/E'), and higher pulmonary artery pressure predicted worse outcomes in HFpEF patients, independent of clinical variables. 6

Atrial Fibrillation Findings

TOPCAT found that 43% of HFpEF patients had a history of atrial fibrillation or AF on enrollment ECG, and AF at enrollment was associated with increased cardiovascular risk (HR=1.34). 7 Importantly, spironolactone did not reduce the incidence of new-onset AF, and post-randomization AF (occurring in 6.3% of patients) was associated with markedly increased early risk of adverse outcomes (HR=2.32). 7