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).