• Heart Failure
• Cardiology Clinical Trials

• Heart Failure
• Cardiology & Cardiovascular Medicine
• Cardiology Clinical Trials

Spironolactone treatment of heart failure (HF) with preserved ejection fraction (HFpEF) did not significantly reduce cardiovascular death, hospitalization due to HF, or resuscitated cardiac arrest compared with placebo. Bertram Pitt, MD, University of Michigan School of Medicine, Ann Arbor, Michigan, USA, presented updated data from the Aldosterone Antagonist Therapy for Adults With Heart Failure and Preserved Systolic Function trial [TOPCAT; Shah SJ et al. Circ Heart Fail 2012].

Previous trials have demonstrated that mineralocorticoid receptor antagonists improve survival in patients with mild to severe reduced ejection fraction and postmyocardial infarction left ventricular dysfunction compared with placebo [Zannad F et al. N Engl J Med 2011; Pitt B et al. N Engl J Med 2003; Pitt B et al. N Engl J Med 1999]. The purpose of the TOPCAT trial was to evaluate the effect of spironolactone in patients with HFpEF.

In the multicenter TOPCAT trial, 3445 patients with HFpEF were randomly assigned to receive a target dose of 30 mg of spironolactone (n=1722) or placebo (n=1723) over a mean follow-up of 3.3 years [Desai AS et al. Am Heart J 2011]. Randomly assigned patients had a mean age of 69 years and a New York Health Association class II or III HF, with a mean left ventricular ejection fraction of 56% [Shah SJ et al. Circ Heart Fail 2012].

The primary outcome was a composite of cardiovascular death, hospitalization due to HF, or resuscitated cardiac arrest. In the spironolactone and placebo arms, 34.3% and 31.4% of patients prematurely discontinued the medication by the end of the study, respectively.

There was no significant difference in the primary outcome with spironolactone (18.6%) compared to placebo (20.4%) at 72 months (HR, 0.89; 95% CI, 0.77 to 1.04; p=0.138) [Pitt B et al. N Engl J Med 2014]. Although the primary end point was not significant, there were promising trends for the individual components, including a lower rate of HF hospitalization with spironolactone compared with placebo at 72 months (HR, 0.83; 95% CI, 0.69 to 0.99; p=0.042).

Interestingly, the rate of reaching the primary outcome varied by geographic region. Patients from the United States, Canada, Argentina, and Brazil had a rate of 12.6 per 100 patient-years, compared with 2.3 per 100 patient-years in patients from Russia and the Republic of Georgia. Similarly, the HR varied. In the United States, Canada, Argentina, and Brazil, the HR was 0.82 (95% CI, 0.69 to 0.98), compared with 1.10 (95% CI, 0.79 to 1.51) in Russia and the Republic of Georgia; however, these differences did not result in a statistically significant interaction (interaction p=0.122).

There were no significant differences in the number of patients who experienced serious adverse events or total reports of adverse events. However, hyperkalemia occurred in 18.7% of patients who received spironolactone, compared with 9.1% who received placebo (p<0.001). In contrast, the placebo arm demonstrated greater rates of hypokalemia compared with the spironolactone arm (p<0.001). In addition, creatinine above the upper limit of reference occurred more frequently in the spironolactone arm compared with the placebo arm (HR, 1.49; 95% CI, 1.18 to 1.87; p<0.001).

Dr. Pitt concluded by stating that the results of the TOPCAT trial do not show a benefit of spironolactone treatment in patients with HFpEF, although the observation of an associated decrease in hospitalization for HF as an individual component is promising and warrants further study. The geographic heterogeneity in patient risk complicates the conclusions of this study.

• © 2014 MD Conference Express®