• Heart Failure
• Hypertensive Disease
• Cardiology Clinical Trials

Results from the Aldosterone Receptor Blockade in Diastolic Heart Failure [Aldo-DHF; ISCRTN94726526] trial, presented by Burkert Mathias Pieske, MD, Medical University of Graz, Graz, Austria, showed that spironolactone significantly improves diastolic function and blood pressure (BP) control, but not exercise capacity, in patients with diastolic heart failure (DHF).

DHF accounts for more than 50% of all HF cases and clinical outcomes for these patients are poor. While no established therapy exists for DHF, there is strong evidence for a benefit from aldosterone antagonists in patients with reduced left ventricular ejection fraction (LVEF) [Chatterjee S et al. Am J Med 2012], and aldosterone has been implicated in the pathogenesis of DHF via aldosterone receptor mediated myocardial fibrosis, hypertrophy, and vascular stiffening.

Aldo-DHF was a multicenter, randomized, placebo-controlled, double-blind, parallel-group study conducted to assess the safety and efficacy of the aldosterone receptor antagonist spironolactone on diastolic function and exercise capacity in patients with DHF after 1 year of therapy. Subjects were required to have documented stable chronic HF (NYHA II/III), echocardiographic evidence of diastolic dysfunction ≥Grade 1 or atrial fibrillation, EF ≥50%, and peak VO₂ <25 mL/kg/min. Co-primary endpoints were change in diastolic function (mitral inflow E velocity to tissue Doppler e′ [E/e′ ratio]) and maximal exercise capacity (peak VO₂ on bicycle spiroergometry) at 12 months [Edelmann F et al. Eur J Heart Fail 2010].

Subjects (mean age 67 years, 52% women, ≥85% NYHA class II) were randomized to spironolactone (n=213) or placebo (n=209). Baseline E/e′ was 12.7±3.6 and 12.8±4.4 and peak VO₂ was 16.3±3.6 and 16.4±3.5 mL/kg/min in the spironolactone and placebo groups, respectively. Median NT-proBNP was 179 ng/L in the spironolactone group (range, 81 to 276) and 148 ng/L (range, 80 to 276) in the placebo group. Approximately 92% of patients had controlled hypertension at study entry. Mean estimated glomerular filtration rate was ∼78 mL/min/1.73 m².

Spironolactone (25 mg QD) significantly improved diastolic function (p<0.001) but did not improve exercise capacity. Treatment effects were consistent across all subgroups analyzed. Spironolactone induced significant structural reverse remodeling (LV mass index p=0.009) and significant reductions in NT-proBNP plasma levels (p=0.03), but did not improve NYHA class, left atrial volume index, or quality of life.

Spironolactone was also associated with significant reductions in both systolic and diastolic BP beginning at 3 months, yet the effects of spironolactone on cardiac structure and function remained significant after adjusting for BP changes. Adverse events occurred significantly more often with spironolactone, including mild worsening of renal function (36% of spironolactone subjects vs 21% of placebo subjects; p<0.001); new or worsening anemia (16% vs 9%; p=0.03), gynecomastia (4% vs <1%; p=0.02), and nonsevere (<5.0 mmol/L) increases in serum potassium levels (21% vs 11%; p=0.005). One patient in the spironolactone group died (vs none of the placebo subjects). There was no difference in the rate of hospitalization.

Additional data on the long-term efficacy and safety of spironolactone in patients with DHF will come from the Trial of Aldosterone Antagonist Therapy in Adults With Preserved Ejection Fraction Congestive Heart Failure [TOPCAT; NCT00094302] study, which is expected to report during 2013. TOPCAT is a multicenter, international, randomized, double-blind, placebo-controlled trial of spironolactone in 3515 adults with HF and LVEF ≥45%. The trial duration is ∼6 years with an expected average subject follow-up of 3.45 years. The primary endpoint is a composite of cardiovascular mortality, aborted cardiac arrest, or hospitalization for the management of HF.

• © 2012 MD Conference Express®