HF with preserved ejection fraction
The prevalence of HF with preserved ejection fraction (HFpEF) is increasing, mainly due to the aging populations, however, mortality remains unchanged. HFpEF, also referred to as diastolic HF, is a clinical entity characterized by signs and symptoms of HF with a normal or low-to-normal left ventricular (LV) ejection fraction. Clinical trials in patients with HFpEF so far have not produced clear-cut favorable results, and guidelines for patients with HFpEF do not suggest specific medications besides the control of symptoms using diuretics (Ponikowski et al., 2016). Women represent the majority of patients with HFpEF. Although the reason for the sex-differences in HFpEF are not well known, one of the causes could be the activation of the renin-angiotensin-aldosterone system after menopause (Yanes et al., 2010). Accordingly, MRA treatment may be more efficacious in women than in men regarding CV effects (Khosla et al., 2009). MRAs are of particular interest in the treatment of HFpEF due to their effects on interstitial fibrosis, myocardial stiffness, extracellular matrix expansion and vascular function, which are all key components in the pathogenesis of HFpEF.
The Aldo-DHF randomized controlled trial (Effects of Spironolactone on Diastolic Function and Exercise Capacity in Patients with Heart Failure with Preserved Ejection Fraction) demonstrated that treatment with spironolactone improved diastolic dysfunction and reduced blood pressure in HFpEF patients, however, maximal exercise capacity and symptoms were not significantly altered (Edelmann et al., 2013). A larger study, the TOPCAT trial (Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist) showed that spironolactone treatment promoted a decrease in hospitalization but not in mortality in HFpEF patients (Pitt et al., 2014; de Denus et al., 2017). Interestingly, a significant interaction between sex and MRA treatment has been described based on the reduction in all-cause mortality in women (Merrill et al., 2019). In a secondary analysis of TOPCAT, spironolactone in patients with HFpEF and resistant hypertension decreased the risk of composite CV events, whereas this was not the case in those without resistant hypertension (Tsujimoto and Kajio, 2020). In addition, spironolactone use in patients with HFpEF with resistant hypertension led to a decreased risk of all-cause death and hospitalization for HF. These results support the recommendation to use spironolactone in patients with hypertension resistant to standard medical treatment (Williams et al., 2018).
In a meta-analysis of 14 randomized controlled clinical trials, which included 6428 patients with HFpEF or MI with preserved ejection fraction, MRA therapy reduced the number of hospitalizations for HF by 17%, improved diastolic function, induced a reversal of cardiac remodeling and improved quality of life, but did not decrease all-cause mortality (Chen et al., 2015). Another meta-analysis including 11 studies, evaluated the effects of MRAs on LV structure and function among patients with diastolic dysfunction or HFpEF. MRA therapy in patients with asymptomatic diastolic dysfunction or HFpEF was associated with significant improvement in diastolic function, blood pressure, and markers of cardiac fibrosis without a significant change in LV mass or dimensions (Pandey et al., 2015).
In the STRUCTURE trial (Spironolactone in Myocardial Dysfunction with Reduced Exercise Capacity), spironolactone therapy significantly improved the exercise capacity in patients with HFpEF and abnormal diastolic response to exertion. The authors suggested that identification of an elevated LV filling pressure induced by exercise in subjects with HFpEF may select out a subgroup of patients with a higher likelihood of a beneficial response to spironolactone (Kosmala et al., 2016).
More recently, canrenone was supported for the management of congestive HF and preserved systolic function by the COFFEE-IT trial (Canrenone Effects on Cardiovascular Mortality in Patients With Congestive Heart Failure), which found an improvement in mortality with the additional use of canrenone compared with the conventional therapy group (Derosa et al., 2019). Investigators found that patients on canrenone displayed a decreased LV mass compared with the control group, as well as a decreased mortality in patients within the 68–83-year age range after 10 years of follow-up. Despite these positive findings, canrenone is not widely used.
Another study including HFpEF and HF with mid-range EF (HFmrEF) patients suggested a benefit from spironolactone treatment, showing reduced hospitalizations and BNP levels, improved NYHA functional class, alleviated myocardial fibrosis by decreasing serum collagen type I marker in HFmrEF and HFpEF, and decreased collagen type III marker levels only in HFpEF (Xiang et al., 2019).
Currently, three ongoing large trials investigate MRA treatment in patients with HFpEF. SPIRIT-HF (SPIRonolactone In the Treatment of Heart Failure; NCT04727073; EudraCT 2017-000697-11) compares spironolactone to placebo in reducing recurrent HF hospitalizations and CV death in HF patients (NYHA II-IV) with mid-range or preserved ejection fraction. The SPIRRIT trial (Spironolactone Initiation Registry Randomized Interventional Trial in Heart Failure With Preserved Ejection Fraction; NCT02901184) aims at investigating whether spironolactone compared to standard of care alone reduces the composite of CV mortality and HF hospitalization. Complementarily, the FINEARTS-HF trial (Study to Evaluate the Efficacy and Safety of Finerenone on Morbidity and Mortality in Participants With Heart Failure and Left Ventricular Ejection Fraction Greater or Equal to 40%, NCT04435626) has been designed to evaluate the effect of finerenone compared to placebo in the reduction of CV death and total HF events in HFpEF and HFmrEF patients. In patients with diabetic kidney disease without history of HFrEF in the FIDELIO-DKD trial (Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease), finerenone recently has been shown to reduce both a composite of renal events and a composite of CV events with an acceptable side-effect profile in this vulnerable patient population (Bakris et al., 2020).