In this 4 month prospective trial of spironolactone added to usual therapy, treatment was associated with improvements in exercise capacity, echocardiographic measures of diastolic function, and NYHA class in older women with isolated DHF. Peak exercise oxygen consumption and the anaerobicthreshold, objective measures of exercise capacity that are also predictors of mortality in heart failure,(33
) improved significantly. This was paralleled by improvements in heart failure symptoms as assessed by NYHA class. Minnesota Living with Heart Failure Questionnaire scores demonstrated a trend towards improvement in quality of life as well. A sub-diuretic dose of spironolactone was used, with no change in patient weight or blood pressure over the course of the study such that the observed improvements were not likely due to diuresis, but rather to improvement in the underlying pathophysiology. These findings are important because DHF is the most common form of heart failure among the older population, and exercise intolerance is the primary chronic symptom and primary determinant of poor quality of life in this disorder.
Along with improvements in exercise capacity and heart failure symptoms, diastolic filling of the left ventricle (LV) as assessed by Doppler echocardiography also improved. Tissue Doppler peak velocity of the mitral valve annulus during early diastole, E’ (also called Em
, or Ea
) declines with worsening diastolic function.(35
) At baseline, the patients had Doppler indices of impaired relaxation and had an abnormally reduced E’. With treatment, multiple indices of diastolic function improved or tended to improve, including E’, isovolumic relaxation time, and the ratio E/E’, which is a related to LV filling pressure.(31
) This was accompanied by a strong trend toward reduced thickness of the posterior LV wall with maintenance of LV diastolic size, suggesting improvement in the concentric hypertrophic LV remodeling that appears characteristic of older patients with DHF.(7
The results from the present study are supported by those of Mottram et al who conducted a placebo controlled study of 30 patients with hypertension, dyspnea on exertion, and delayed relaxation LV filling patterns by Doppler. Their data showed that strain rate and peak strain improved with spironolactone therapy.(36
) Though the study by Mottram addressed an LV function outcome relevant to potential mechanisms of DHF, there have previously been no data assessing outcomes that directly impact patient well-being, such as exercise capacity and quality of life.
DHF is a major public health problem associated with substantial morbidity and mortality in older adults, yet treatment of this condition remains largely empiric due to the relative lack of large, randomized clinical outcomes trials.(37
) While promising, these preliminary results regarding spironolactone, a generic aldosterone antagonist which has been in use for many years for other conditions, should be confirmed in larger, definitive randomized controlled trials.
In addition to the present study results, there are multiple lines of evidence to suggest the potential benefit from antagonism of aldosterone in patients with DHF.(38
) We previously showed that exercise intolerance in DHF is related to increased LV diastolic stiffness, and this has been confirmed by several others.(40
) Aldosterone is a potent promoter of myocardial hypertrophy and fibrosis, both of which are known to increase LV diastolic stiffness.(18
) In the 4E study of patients with hypertension, epleronone independently improved LV concentric remodeling.(48
) Lopez et showed that in hypertensive rats, spironolactone resulted in a histologically documented decrease in collagen volume in the myocardium and this was accompanied by improved LV concentric remodeling and diastolic stiffness.(49
) Notably, the decline in collagen volume was highly correlated with a decrease in the circulating collagen type 1 c-terminal propeptide (CICP).(51
) Ciciora et al reported that the strongest predictor of exercise intolerance in systolic heart failure was the degree of aldosterone “escape” during ACEI therapy.(53
) Ciciora et al also showed that in patients with systolic heart failure,12 month treatment with spironolactone resulted in significant improvements in exercise intolerance associated with improved LV remodeling and diastolic function.(54
Furthermore, in 2 large trials in systolic heart failure patients, RALES and EPHESUS, aldosterone antagonism significantly reduced mortality.(23
) In a subset analysis of the RALES trial, most of the survival improvement imparted by spironolactone appeared to occur in patients with the highest baseline concentrations of pro-collagen biomarkers of fibrosis, and these were reduced with chronic therapy.(24
) Finally, prevention and even reversal of the sequence from aldosterone excess to myocardial fibrosis, LV remodeling, and increased LV diastolic stiffness by agents that antagonize aldosterone have now been documented in a number of animal models and in human cardiovascular diseases, including hypertension, hypertrophic cardiomyopathy, aortic stenosis, and the most stark example, Conn’s syndrome (primary hyperaldosteronism).(18
) All of these disorders share common features with the phenotype associated with DHF.
The dose of spironolactone and the safety monitoring protocol in the present study was identical to that used in the RALES trial, which was associated with very good tolerability and safety.(23
) As in the present study, in RALES there was no evidence of diuretic effect from low dose spironolactone.(23
) Further, as in the present study, in RALES most (95%) of patients were already taking angiotensin-converting-enzyme inhibitors or angiotensin II receptor blockers. Several studies indicate that long-term treatment with these agents may not completely block aldosterone or its adverse effects on LV and arterial function.(18
This study has limitations inherent in the open-label, uncontrolled study design, including potential for participant and investigator bias. In order to minimize bias, assessments of exercise function, echocardiography, and quality of life were performed by personnel who were not involved with patient management, and they were not allowed to review baseline findings prior to completion of follow up visits. In addition, the ventilatory anaerobic threshold and echo-Doppler outcomes, both of which are effort-independent and cannot be altered volitionally by the patient, were analyzed in random, blinded, unpaired fashion by individuals unaware of patient identity or of whether they were viewing baseline or follow-up studies. Another important limitation is the small sample size, which raises the possibility that effects may be missed due to insufficient statistical power, or that effects could be magnified if there was a non-homogenous sample. However, even with the small sample size, improvements were observed in multiple, objective, clinically relevant outcomes. A final limitation is that, although we did not systematically exclude men during recruitment, all participants in this study were women. Thus, it is uncertain whether the study results apply to men with HFNEF. However, the present results should apply to the majority of persons with HFNEF since population-based studies have shown that approximately two-thirds or more of persons with this disorder are older women.(2
These results should be viewed as preliminary, requiring verification by definitive randomized, controlled clinical trials. Indeed, the study results presented in this report served as the pilot data for a trial that was recently funded by the National Institute on Aging (project #R37-AG18915), and has the acronym SPIFFIE (Spironolactone For Failure In the Elderly). SPIFFIE is a randomized, placebo controlled, 9-month double-blinded trial of 25 mg spironolactone in 80 patients ≥ 60 years who have DHF. The primary outcomes are exercise tolerance measured as peak VO2 during cardiopulmonary exercise testing and quality of life measured as the total score on the MLHF questionnaire. The study is also assessing potential mechanistic outcomes, including improvement in diastolic LV function by tissue Doppler, reversal of concentric hypertrophic LV remodeling measured by magnetic resonance imaging, and amelioration of myocardial fibrosis measured by circulating procollagen markers. In addition, a large, multi-center, international randomized, controlled trial of 30 mg/day spironolactone named TOPCAT (Treatment Of Preserved Cardiac Function Heart Failure with an Aldosterone anTagonist) funded by the National Heart, Lung, and Blood Institute has been launched. TOPCAT will enroll 4500 patients aged ≥50 yrs with heart failure and EF>45% and follow them for an average of 3.25 years. The primary outcome of the trial is a composite endpoint of cardiovascular mortality, aborted cardiac arrest, or hospitalization for the management of heart failure,
Although DHF is a common disorder among older Americans, therapy remains largely empiric. In this study, 4 months treatment with 25 mg per day of generic spironolactone was well tolerated and was associated with improvements in symptoms, exercise performance, echo-Doppler measures of diastolic function, and quality of life. These preliminary results lend support to the hypothesis that aldosterone may play a role in the pathophysiology of DHF. Two larger randomized clinical trials of aldosterone antagonism in DHF are currently underway in order to definitively test this hypothesis.