ALDO-DHF & Paramount

1. ALDO-DHF STUDY – A NEW INDICATION FOR AN OLD DRUG? Results of the ALDOsterone receptor blockade in Diastolic Heart Failure (ALDO-DHF) were recently presented at the European Society of Cardiology (ESC) meeting in Munich [1]. The multicenter, double-blind randomized, placebo-controlled phase IIb mechanistic study was conducted to test the hypothesis that 12 months treatment with spironolactone would improve cardiac function and structure as well as exercise capacity and quality of life in patients with heart failure with preserved ejection fraction (HFpEF). HFpEF continues to be a challenging form of heart failure – one in which no therapy has yet been proven to improve outcome and with a prevalence that continues to rise at an alarming rate. An extensive review on HFpEF – including various drugs in current use as well as those under trial – was published in the last issue of the journal [2]. The study randomized 422 patients with HFpEF to spironolactone 25mg/day or placebo on top of other medical therapy and was funded by the German government within the Clinical Trial Research Program. The two co-primary endpoints were changes in diastolic function (assessed by tissue-Doppler derived E/e0 – a validated echocardiographic marker of left ventricular filling pressures) and changes in maximal exercise capacity (assessed by peak oxygen consumption – VO2 max – during bicycle spiroergometry). Secondary endpoints included left ventricular mass index (LVMI), quality of life, NYHA class and levels of N-terminal pro-brain-type natriuretic peptide (NT-proBNP) as a marker of neuroendocrine activity. At one year, the group receiving spironolactone showed significant improvement in diastolic function (E/e0 – p , 0.001). There was significant reduction in LVMI (p 1⁄4 0.009) and NT-proBNP levels (p 1⁄4 0.03) in the spironolactone arm. Interestingly, changes in LV mass were independent of the modest blood pressure lowering effect that spironolactone had (mean 1⁄4 8/3mmHg). These beneficial cardiac functional and structural changes did not, however, translate into clinical gains with spironolactone failing to improve peak exercise capacity, NYHA class or quality of life at 12 months compared placebo. There were no serious adverse events related to spironolactone but its use was associated with worsening renal function (36% with spironolactone and 21% with placebo – p , 0.001) and persistent elevation of serum potassium levels. In addition spironolactone carried a greater risk of new or worsening anemia compared to placebo (16% vs. 9% p 1⁄4 0.03) and gynecomastia (4% vs , 1% p 1⁄4 0.02). While presenting the results at the ESC meeting, the investigators concluded that “spironolactone can be considered in patients with diastolic heart failure for improving cardiac function and blood pressure control”. The results of the study are difficult to interpret from the practicing physician’s point of view. Compared to “real life” HFpEF patient population, the patients recruited in this study were relatively younger (mean age 1⁄4 67 years), had lower NT-proBNP values, lower rates of atrial fibrillation (4%) and better baseline renal function (mean 1⁄4 79ml/min/1.73m2). These features, together with the fact that only 15% of patients had more than NYHA class II symptoms, raise some concerns as to whether the study population truly represents the broader HFpEF population. The lack of symptomatic improvement in the active treatment arm might be related to these baseline patient characteristics which probably represent the mild end of the spectrum of HFpEF. The results also highlight the complex and multifactorial cause of symptoms in HFpEF where a number of pathophysiological features – beyond diastolic dysfunction – interact to produce symptoms as previously shown in a number of studies [2,3].