Can Spironolactone, a drug with multiple actions on the heart and blood vessels, improve outcomes in a hard-to-treat group of heart failure patients? This was a question addressed by the “Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT)” trial.
Currently, treatment is very challenging for heart failure patients who have normal or near-normal ejection fraction, a number that describes the percentage of blood pumped out of the left ventricle (the heart’s main pumping chamber) with each heart beat. Generally, above 50 percent is thought to be a normal ejection fraction, said Nancy K. Sweitzer, MD, PhD, director of the University of Arizona Sarver Heart Center and chief of the Division of Cardiology at the UA College of Medicine – Tucson, who serves on the TOPCAT executive committee.
Although many effective treatments are available for heart failure patients with a low ejection fraction, no therapy ever has been shown to significantly affect outcomes in heart failure with preserved ejection fraction, which accounts for about 50 percent of heart failure in the United States and is very prevalent among the elderly. According to an article and editorial published in the April 10, 2014, edition of the New England Journal of Medicine, the TOPCAT trial studied whether spironolactone vs. placebo would be more effective in reducing hospitalization and death in patients with heart failure and a preserved ejection fraction.
In more than 3,500 patients studied in North America, South America, Russia and the nation of Georgia there were no differences in outcomes between those on spironolactone and those on placebo. However, differences in patient profiles at different sites in the trial suggest that a more refined definition of this patient population may improve outcomes for heart failure patients with preserved ejection fraction, said Dr. Sweitzer.
The study enrolled patients with at least one symptom and one sign of heart failure if they had an ejection fraction of at least 45 percent, in addition to either an elevated natriuretic peptide level (a measurement of sodium in urine that indicates heart failure) in the previous 60 days or a hospital admission in the previous year “with management of heart failure a major component of the care provided.” These eligibility criteria were used to stratify patients in the randomization of spironolactone vs. placebo.
“Spironolactone seemed to benefit patients who were enrolled in the natriuretic peptide stratum, but not those in the hospitalization stratum,” said Dr. Sweitzer. “This was because those enrolled in the natriuretic peptide stratum appeared to be sicker, with higher mortality when given placebo. This is strange, since in all other heart failure trials, hospitalization typically identifies the sickest patients.”
“Looking at this result further, we found geographic differences. Patients from the United States, Canada, Argentina and Brazil had much higher mortality than those in Eastern Europe, and there was a suggestion that drug benefit was not uniform in the two populations. We still need to look further at the patients in whom the drug seemed to provide benefit, and understand the results of this trial in more detail. Preventing heart failure hospitalizations could go a long way toward lowering health care costs since it is a primary driver of Medicare hospital costs, accounting for 6.5 million hospital days each year in the United States,” said Dr. Sweitzer.
What does this mean for clinicians? “When we presented this evidence at the American Heart Association conference in November, a number of cardiologists commented that given the positive outcomes in the Americas, they felt spironolactone was a worthwhile treatment to try on their heart failure patients with preserved ejection fraction, despite the overall trial being negative,” said Dr. Sweitzer. “Physicians will need to look at these results and make their own decisions. Spironolactone is a drug that has had significant benefit in other forms of heart failure, and one with which clinicians have experience, but it does require close monitoring of potassium levels during therapy.”
Link to NEJM articles: http://opa.ahsc.arizona.edu/sites/opa.ahsc.arizona.edu/files/uploads/nejmarticles.4.9.14.pdf