New Trial Investigates Heart Failure and Preserved Left Ventricular Ejection Fraction

Dallas—For patients with heart failure and preserved left ventricular ejection fraction (HFpEF), there is no proven therapy to improve the prognosis. However, mineralcorticoid receptor antagonists have been shown to reduce the risk of death and other major cardiovascular events in patients with reduced ejection fraction (EF) heart failure following myocardial infarction.

The Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial was conducted to determine if treatment with spironolactone could produce a clinically meaningful reduction in the composite end point of cardiovascular mortality, aborted cardiac arrest, or hospitalization for the management of heart failure in adults with HFpEF.  

Marc A. Pfeffer, MD, PhD, Brigham & Women’s Hospital, Harvard, Boston, Massachusetts, presented the results of the TOPCAT trial at the AHA Scientific Sessions in a session titled Medical and Surgical Approaches to Improving Heart Failure Outcomes. The National Heart, Lung, and Blood Institute funded this trial. This was noted as the first public presentation of the TOPCAT trial results.

This was an international, multicenter, double-blind, randomized, placebo-controlled trial evaluating the safety and effectiveness of spironolactone compared with placebo. Patients were included if they had symptomatic heart failure, were age ≥50 years, and had a left ventricular (LV) EF ≥45%. Patients were also stratified into the study cohorts based on hospitalization within the past 12 months for the management of heart failure, or elevated brain natriuretic peptides (BNP; ≥100 pg/mL or N-terminal pro-BNP N-terminal pro-360 pg/mL).

Some major exclusion study criteria included recent stroke, coronary events, uncontrolled hypertension epidermal growth factor receptor <30, and hyperkalemia (≥5 mmol/L). A total of 3445 study participants were randomized 1:1 to receive either spironolactone 15 mg titrated to 45 mg, daily (n=1722) or placebo, daily (n=1723). Study participants were followed for approximately 3.4 years on average. The study included participants from the United States (n=1151), Russia (n=1066), Republic of Georgia (n=612), Canada (n=326), Brazil (n=167), and Argentina (n=123).

Primary end points included cardiovascular death, heart failure hospitalization, and resuscitated cardiac arrest. Secondary end points included safety assessments, nonfatal cardiovascular events, development of atrial fibrillation (AF), diabetes, and quality of life. Baseline comorbidities included hypertension (91%), coronary artery disease (59%), chronic kidney disease (38%), AF (35%), and diabetes (32%).

The study found spironolactone did not impact the primary outcomes—spironolactone (18.6%; n=320) and placebo (20.4%; n=351; hazard ratio, .89; P=.138). See Table (below) for breakout of primary components. Reductions in hospitalizations for heart failure were observed—spironolactone (12%; n=206) and placebo (14.2%; n=245).

No differences in series adverse events were found in either cohort—spironolactone (48.5%; n=835) and placebo (49.6%; n=855). However, the researchers noted that the use of spironolactone requires careful monitoring of potassium and creatinine at each dose change and follow-up visit. When serum potassium tests were conducted the following results occurred: for hyperkalemia (≥5.5 mmol/L)—spironolactone 18.7% (n=322) and placebo 9.1% (n=157)); for hypokalemia (<3.5 mmol/L)—spironolactone 16.2% (n=279) and placebo 22.9% (n=394; P<.001 for all). No deaths were reported related to hyperkalemia.