CE / CME
Physician Assistants/Physician Associates: 1.00 AAPA Category 1 CME credit
Nurse Practitioners/Nurses: 1.00 Nursing contact hour
Physicians: maximum of 1.00 AMA PRA Category 1 Credit™
Released: June 17, 2025
Expiration: June 16, 2026
HFmrEF and HFpEF: Real-world Challenges
It is important to realize that there are substantial needs that persist among our patients with HF, in particular, those with HFmrEF or HFpEF.
HFpEF accounts for at least 50% of all HF cases, and its prevalence continues to rise due to an aging population and a growing prevalence of obesity, HTN, and diabetes. Patients with HFmrEF, defined as an LVEF of 41% to 49%, often share clinical features that overlap with heart failure with reduced ejection fraction (HFrEF) and HFpEF. In addition, these patients fall into a treatment gray zone where they may be eligible for therapies for the other HF conditions. Patients with HFmrEF or HFpEF face an increased risk of hospital readmission, mortality, and multimorbidity, since a number of other comorbid conditions can influence their prognosis. Of note, patients with HFpEF see a hospitalization rate of 1.4 times annually. In addition, therapies approved for HFmrEF and HFpEF have improved composite outcomes in HF studies but have not yet established a clear mortality benefit.1-5
HFmrEF and HFpEF: Navigating Unmet Needs
In thinking about this patient population, HCPs need to figure out how to navigate the unmet needs patients face. These unmet needs revolve around several areas, including1,6-8:
Patient Spotlight: Bringing the Challenges to Life
Let us illustrate these points with a patient case. A 68-year-old man has HFmrEF. His LVEF is 43%, and he has New York Heart Association (NYHA) Class II symptoms. The patient has concomitant CKD, T2D, and HTN, which nicely outlines the multimorbidity associated with this condition. He is on several therapies, including a beta-blocker, ACE inhibitor, SGLT2 inhibitor, and loop diuretic. As is reflective of his NYHA Class II functional status, the patient currently has symptoms of mild fatigue with exertion but has a stable weight.
Patient Spotlight: Clinical Questions
There are clinical questions that HCPs may want to ask regarding this patient case. Is there evidence to support the addition of an MRA for this patient? Would a nonsteroidal MRA offer benefits with reduced risk relative to a steroidal MRA? How does the presence of comorbid CKD and to what extent does its severity alter or influence treatment decisions?
Teaching Point
In this patient case, there is a marked overlap with several cardiovascular-kidney-metabolic conditions that often coexist with HF. These include obesity, diabetes, sleep disordered breathing or obstructive sleep apnea, atrial fibrillation, and atherosclerotic cardiovascular disease to name a few. Of note, CKD is relatively prevalent in this patient population and may influence treatment decisions.
The patient case also highlights the uncertainty that may exist regarding the initiation of certain therapies, particularly in those with comorbid CKD. This is because there can be increased susceptibility to the development of hyperkalemia that is potentiated by the addition of an MRA.9
MR Overactivation: Key Driver of Cardio-Renal Damage in HF/CKD
It is critical that HCPs understand that the overactivation of the mineralocorticoid receptor can be a driver of unfavorable effects with these conditions. Again, the intersection of CKD in HF highlights the fact that there is a shared pathophysiology for both conditions, and overactivation of the mineralocorticoid receptor may be a driver of this.
This is pictorially displayed on the slide. The renin-angiotensin-aldosterone system is activated, including mineralocorticoid receptors, which can lead to a lot of unfavorable effects, such as endothelial dysfunction, fibrosis or stiffness, and an inflammatory process that affects multiple organ systems. While the kidneys, blood vessels, and heart are illustrated under each one of these individual components, there are examples of fibrosis and stiffness affecting the kidneys and heart. Collectively, this can be a driver of worsening kidney and/or cardiac function and is the rationale for using MRAs in HF treatment.10,11
MRA Biology and Beyond: Steroidal vs Nonsteroidal
There are steroidal and nonsteroidal MRAs. These agents block aldosterone by binding at the mineralocorticoid receptors in the kidney, heart, and vasculature. Aldosterone contributes to many unfavorable effects, such as sodium and water retention, potassium loss, fibrosis, and inflammation. Initiating an MRA decreases sodium and water retention in patients, leading to lowered preload and congestion, which alleviates some of the symptoms related to HF. These agents also decrease myocardial and vascular fibrosis, leading to improved remodeling, as well as the inflammatory cascade, including oxidative stress.
MRAs have multiple clinical benefits, with proven mortality and morbidity benefit established HFrEF studies. In contrast, there is limited, but emerging, evidence that supports the use of an MRA in patients with HFmrEF or HFpEF. Of course, we want to see this done without potentiating hyperkalemia or off-target effects via the hormonal system that could lead to unfavorable side effects vs some of the historically used HF therapies.12-14
Steroidal vs Nonsteroidal MRAs: Enhanced Selectivity and Reduced Risk?
Diving deeper into steroidal vs nonsteroidal MRAs begs the question: does the selectivity of the therapy help define the likelihood of experiencing some of these other effects overall? The table on the slide nicely displays the features of steroidal MRAs, namely spironolactone and eplerenone, vs the nonsteroidal MRA finerenone.
In terms of selectivity, finerenone has higher selectivity of the mineralocorticoid receptor than spironolactone or eplerenone. We do not have much in terms of large randomized clinical trials that compare steroidal with nonsteroidal MRAs head-to-head, but studies have observed higher rates of hyperkalemia with spironolactone vs eplerenone and finerenone. Hormonal effects can be a limiting factor in the tolerability and adherence of spironolactone and eplerenone, which is especially true in males or those sensitive to hormonal fluctuations. Side effects can include gynecomastia as well as decreased libido and sexual dysfunction—all being drivers of limited adherence to these therapies. In contrast, finerenone is associated with a lower risk of hormonal disturbances. There also are data suggesting cardiovascular benefit for all populations, with the majority focusing on spironolactone or eplerenone among those with HFrEF. Again, it is critical to understand the comorbid presence of CKD and/or T2D, which can potentiate an increased risk of hyperkalemia and, therefore, limits the use of these therapies.14-21
Comparative Binding and Pharmacologic Profiles of MR Antagonists
This slide provides an additional look at the differences between steroidal MRAs (spironolactone and eplerenone) vs a nonsteroidal MRA (finerenone), including potency, selectivity, risk for sexual side effects, half-life, and effect on blood pressure.22
MRAs in Heart Failure: Evidence, Evolution, and Gaps
What is the evidence base to date on using MRAs in HF? In 1999, the RALES trial evaluated spironolactone in patients with HFrEF. It found a clinically important and statistically significant reduction in mortality for those with NYHA Class III or IV functional status. It was the first trial to provide evidence on the value of using MRAs in HFrEF treatment. However, there was concern about the potential for hyperkalemia, especially among those taking concomitant ACE inhibitors.23
This was followed several years later by the EPHESUS trial, which looked at eplerenone in patients with HFrEF following a myocardial infarction (MI). Researchers established a consistency of benefit with this steroidal MRA, showing a reduction in mortality that is limited by the potential of developing hyperkalemia. Close monitoring and intervening where appropriate is necessary for patients who develop hyperkalemia.20
In 2011, the EMPHASIS-HF trial brought the use of MRAs into patients who were less functionally limited, namely those with a NYHA Class II functional status. It showed a significant and clinically meaningful reduction in the composite endpoint of cardiovascular death and HF hospitalization—substantiating the value of adding an MRA earlier in the HF disease course.24
Shortly after, the TOPCAT trial explored the use of spironolactone in patients with HFpEF. Of note, there were some interesting analyses done after the initial results were released because there was no significant reduction in the primary outcome. A post-hoc analysis found a clinically important and statistically significant benefit among patients enrolled in North and South America, but patients enrolled in other countries may have had a confounding effect on the overall interpretation for the trial. This raised questions about trial conduct and patient selection and unfortunately confounded the potential value of using MRAs in HFpEF. It also underscores its assignment in the HF guidelines, as a Class IIb recommendation suggest these agents may be considered. Steroidal MRAs, spironolactone in particular, may be used in the management of patients with HFpEF and HFmrEF.19,25
Persistent Gaps in Clinical Practice
In short, there are persistent gaps in clinical practice. What was not discussed but must be underscored is the fact that MRAs are substantially underutilized in HF management.14 To date, there is not enough clinical evidence or guidance to help drive the use of MRAs in treating HFmrEF and HFpEF. This is challenged by the study design and results of TOPCAT, which made it more challenging to ubiquitously apply MRAs to this patient population analogous to what is recommended for HFrEF.
In using MRAs, HCPs are still challenged by issues related to hyperkalemia and that is potentiated by comorbid CKD. In an ideal world, we would have more selective agents with improved safety profiles to choose from and therapies that maximize efficacy as well as minimize off-target effects.
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