WATERTOWN, Mass.--(BUSINESS WIRE)--Findings from the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial, have revealed that adding the inexpensive medication known as spironolactone to existing treatment does not significantly reduce the composite outcome from either death from cardiovascular causes, sudden cardiac arrest, or hospitalization to manage heart failure in patients with heart failure and a preserved ejection fraction, in a study funded by the National Heart, Lung and Blood Institute, National Institutes of Health.
The report of results is published April 10, 2014 in the New England Journal of Medicine.
Spironolactone has been used for decades to lower blood pressure and for other medical conditions. Previous studies showed that it reduced the risks of heart-related death and hospitalizations in people with heart failure and a dilated heart (not pumping efficiently). TOPCAT is the first large-scale study to look at whether the medication also works in people with heart failure, but with a heart able to pump reasonably efficiently.
Sonja McKinlay PhD, President of New England Research Institutes and co-senior author, emphasized that “TOPCAT was robust in its design and was well conducted, with a strong collaboration between the New England Research Institutes and clinical colleagues at Brigham and Women’s Hospital and the University of Michigan, thus ensuring that the results would be reliable”.
The TOPCAT trial enrolled 3,445 patients from 233 medical sites in six countries. Participants with symptomatic heart failure and a left ventricular ejection fraction (measurement of amount of blood pumped out of the left side of the heart) of 45 percent or more were randomized to receive either spironolactone (15 to 45 milligrams daily) or matching placebo, and were followed for an average of nearly 3.3 years.
The primary outcome consisted of death from cardiovascular causes, sudden cardiac arrest, or hospitalization for the management of heart failure – whichever happened first – and occurred in 320 of 1,722 patients in the spironolactone group (18.6 percent) and 351 of 1,723 patients in the placebo group (20.4 percent).
While spironolactone did not reduce the risk of having at least one of these three outcomes, it did significantly reduce the risk of one component – hospitalization specifically for heart failure. Only these hospitalizations had a significantly lower incidence for those taking spironolactone compared to placebo, with 206 patients (12 percent) in the spironolactone group undergoing hospitalization versus 245 patients (14.2 percent) in the placebo group.
“While the overall results failed to demonstrate a significant effect of spironolactone on the primary endpoint in TOPCAT, the study provides important insights into the potential efficacy of spironolactone in reducing the need for hospitalizations for heart failure in this population, as well as providing clues for more effectively designing future studies to reduce mortality,” said Bertram Pitt, MD, University of Michigan school of Medicine, co-senior author.
Neither total deaths nor hospitalizations for any reason were significantly reduced by spironolactone. There were no significant differences in the incidence of serious adverse events, a serum creatinine level of 3.0 milligrams per deciliter or higher, or dialysis.
Spironolactone was associated with increased serum creatinine levels. It was also associated with a doubling of the rate of hyperkalemia (high potassium concentration in the blood)—18.7 percent versus 9.1 percent in the placebo group—but was linked with reduced hypokalemia (low potassium concentration in the blood). According to the researchers, such findings underscore the importance of monitoring patients prescribed spironolactone.
“When treating patients, clinicians must balance risks and benefits," said Marc Pfeffer MD, PhD, BWH Division of Cardiovascular Medicine, Department of Medicine, co-senior author, “If clinicians decide to prescribe spironolactone to their patients, it is imperative that they monitor for serum markers of kidney and electrolyte disorders which can be exacerbated by spironolactone.”
ABOUT THE TOPCAT Trial
TOPCAT is a multi-center, international, randomized, double-blind, placebo-controlled trial of the aldosterone antagonist, spironolactone, in 3,445 adult subjects with heart failure and left ventricular ejection fraction of at least 45 percent, recruited internationally from over 200 clinical centers in the United States, Canada, Russia, Republic of Georgia, Argentina and Brazil.
The TOPCAT trial was led by a scientific team at New England Research Institutes, Watertown MA, under the direction of Sonja M. McKinlay, PhD, in collaboration with a clinical research team at Brigham and Women's Hospital (BWH), Boston MA, under the direction of Marc A. Pfeffer and with Bertram Pitt, MD, University of Michigan School of Medicine, Ann Arbor MI. The rationale for using spironolactone—an inexpensive, generic, medication—stems from the pioneering research of Dr Pitt, who showed the benefit of this class of drugs in patients with heart failure and reduced ejection fraction, and who also served as chair of the TOPCAT Steering Committee.
This research was supported by the National Heart, Lung and Blood Institute, National Institutes of Health (HHSN268200425207C).
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