By Van Selby, MD

Assistant Professor of Medicine, University of California, San Francisco, Cardiology Division, Advanced Heart Failure Section

Dr. Selby reports no financial relationships relevant to this field of study.

SYNOPSIS: In a small randomized, controlled trial of patients presenting with heart failure with preserved ejection fraction, treatment with spironolactone was associated with improved exercise capacity and less exercise-induced increase in left ventricular filling pressures.

SOURCE: Kosmala W, Rojek A, Przewlocka-Kosmala M, et al. Effect of aldosterone antagonism on exercise tolerance in heart failure with preserved ejection fraction. J Am Coll Cardiol 2016;68:1823-1834.

There is long-standing interest in the use of mineralocorticoid receptor antagonists (MRA) for the treatment of heart failure with preserved ejection fraction (HFpEF), although to date no study has definitively demonstrated improvement in mortality. Exercise intolerance, often driven by increases in cardiac filling pressure, is the primary symptom of HFpEF and a major cause of impaired quality of life. Kosmala et al studied the effects of spironolactone on exercise capacity in patients with HFpEF and exercise-induced increase in left ventricular pressure.

The SpironolacTone in myocaRdial dysfUnCTion with redUced exeRcisE capacity (STRUCTURE) trial enrolled 150 subjects presenting with exertional dyspnea, left ventricular ejection fraction (EF) > 50%, and diastolic dysfunction. Diastolic dysfunction was diagnosed by a post-exercise ratio of the early mitral inflow velocity to mitral annular early diastolic velocity (E/e’) > 13, indicative of elevated left ventricular pressure during exertion. All subjects had New York Heart Association functional class 2-3 symptoms, and those with ischemic heart disease, serum creatinine > 1.5 mg/dL, and atrial fibrillation were excluded. Subjects were randomized to spironolactone 25 mg daily for six months or placebo. The primary endpoints were change in peak oxygen uptake (VO2, exercise capacity) and change in exertional E/e’ ratio. Subjects randomized to spironolactone showed significant improvement in exercise capacity (mean increase in VO2 2.9 mL/kg/min vs. 0.3 mL/kg/min in the placebo group, P < 0.001). There also was significant improvement in exercise-induced E/e’ (-3.0 vs. +0.5 in the placebo group, P < 0.001). Spironolactone-mediated improvement in E/e’ was directly correlated with improvement in exercise capacity (P = 0.039), and spironolactone was associated with improvement in other markers of improved exercise capacity. There was a small increase in serum potassium level associated with spironolactone treatment, but otherwise no significant adverse events were reported. The authors concluded that in patients with HFpEF and abnormal diastolic response to exertion, spironolactone is associated with improvements in exercise capacity mediated by improvement in exercise-induced E/e’.

COMMENTARY

Clearly proving the efficacy of MRAs or any other treatment for HFpEF has been difficult, with many negative clinical trials to date. This is related in part to the heterogeneous nature of the disease, with different pathophysiology in different subgroups of HFpEF patients. Therefore, identification of effective treatment may require targeting HFpEF patients most likely to respond to a particular therapy. Exercise-induced increases in left ventricular pressure occur in a large subgroup of patients with HFpEF and are thought to be related to reduced myocardial compliance resulting from fibrosis. Mineralocorticoid receptor antagonists have antifibrotic properties in heart failure, and the study authors hypothesized that by reducing fibrosis in this HFpEF subgroup, MRAs could improve diastolic function during exercise, and, therefore, exercise capacity. Their findings support this concept, as the subjects treated with spironolactone showed clear improvements in exercise-induced left ventricular filling pressure, and this improvement directly correlated to increases in exercise capacity.

Modern cardiology clinical trials focus on outcomes such as mortality and hospitalization to demonstrate the efficacy of a new treatment. However, in HFpEF, exertional dyspnea is the primary symptom and a major determinant of quality of life. It seems reasonable to target exercise capacity as a therapeutic goal, especially given the lack of therapeutic options with proven mortality benefit in this patient population.

This was a relatively small, single-center study and may not be generalizable to the general HFpEF population. Patients with atrial fibrillation and ischemic heart disease also were excluded, further limiting generalizability. The primary outcome of exercise-induced change in E/e’ is only a surrogate for left ventricular filling pressure.

So how do we incorporate STRUCTURE into clinical practice? It seems appropriate to use spironolactone in patients meeting enrollment criteria. However, in routine practice, most HFpEF patients do not undergo stress echocardiography. Although STRUCTURE did not prove the efficacy of universal exercise echocardiography in patients with HFpEF, it could be considered in those with significantly impaired functional capacity that limits quality of life. Alternatively, it may be appropriate to use MRAs more liberally in HFpEF. The Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial found no overall mortality benefit with spironolactone in HFpEF, but a secondary analysis limited to patients enrolled from the Americas showed clear improvement in outcomes. Based on that subgroup analysis, many cardiologists now routinely prescribe spironolactone for HFpEF, and the findings from STRUCTURE only increase the evidence base supporting this. Although we still lack definitive proof of a mortality benefit from MRAs in HFpEF, for now it seems to be our best option.