Jul 2026· Journal of the Saudi Heart Association· Vol 38· 0 citations· 22 references
Medicine
TL;DR
The principal challenge in modern HFrEF management is no longer the absence of effective therapies, but failure to deliver proven therapies rapidly, comprehensively, and sustainably.
Abstract
Background Heart failure with reduced ejection fraction (HFrEF) remains a major cause of morbidity, mortality, and healthcare utilization worldwide despite substantial therapeutic advances. Over the past three decades, randomized clinical trials have established four foundational pharmacologic pillars of guideline-directed medical therapy (GDMT): renin—angiotensin system inhibition or angiotensin receptor—neprilysin inhibition, evidence-based beta-blockers, mineralocorticoid receptor antagonists, and sodium—glucose cotransporter 2 inhibitors. However, real-world implementation of these therapies remains suboptimal. Objectives To provide a contemporary state-of-the-art review of current evidence supporting GDMT in HFrEF, examine unresolved challenges in sequencing and optimization, and propose a practical phenotype-based framework to support individualized treatment decisions. Methods A structured narrative review was conducted using PubMed/MEDLINE, Embase, and Google Scholar to identify relevant publications from January 2000 to February 2026. Priority was given to randomized controlled trials, international guidelines, meta-analyses, and high-quality observational registries addressing GDMT initiation, sequencing, tolerability, and implementation. Results Robust evidence supports early and combined use of the four foundational GDMT classes, with substantial reductions in mortality and heart failure hospitalization. Emerging data favor rapid initiation of multiple therapies followed by structured uptitration rather than prolonged sequential strategies. Nevertheless, important barriers persist, including hypotension, renal dysfunction, hyperkalemia, frailty, polypharmacy, therapeutic inertia, and inequitable access to medications. Current guidelines provide limited practical direction regarding treatment prioritization in complex clinical phenotypes. A phenotype-based decision framework may facilitate earlier, safer, and more individualized implementation of GDMT in routine practice. Conclusions The principal challenge in modern HFrEF management is no longer the absence of effective therapies, but failure to deliver proven therapies rapidly, comprehensively, and sustainably. Future progress may depend less on development of new drug classes and more on optimizing implementation of currently available life-saving treatments through phenotype-informed and patient-centered strategies.
BACKGROUND
Despite robust evidence that quadruple guideline-directed medical therapy (GDMT), comprising angiotensin receptor-neprilysin inhibitors (ARNIs), evidence-based beta-blockers, mineralocorticoid receptor antagonists (MRAs), and sodium-glucose cotransporter 2 (SGLT2) inhibitors, reduces mortality and hospitalizations in heart failure with reduced ejection fraction (HFrEF), implementation in clinical practice remains markedly incomplete.
OBJECTIVES
This study aimed to provide updated national estimates of the eligible untreated HFrEF population and to quantify deaths and hospitalizations preventable with optimal implementation of quadruple GDMT in the United States.
METHODS
The authors performed a population-level decision analytic modeling study using contemporary U.S. epidemiologic data. National HFrEF prevalence estimates were derived from the American Heart Association Heart Disease and Stroke Statistics 2026 report, and annual HFrEF hospitalization counts were derived from the National Inpatient Sample 2022-2023. Eligible untreated populations were estimated after sequential exclusions and therapy-specific contraindication adjustments using primary treatment rates from Epic Cosmos 2023-2025, with sensitivity analyses using alternative treatment-rate sources. Trial-derived numbers needed to treat and relative risk reductions were applied to estimate deaths preventable over 12 months and annual heart failure (HF) hospitalizations prevented.
RESULTS
An estimated 2.76 million U.S. adults with chronic symptomatic HFrEF were eligible for quadruple GDMT, yet only 18.2% received it. Eligible untreated populations included 733,891 for beta-blockers, 1,856,531 for ARNIs, 1,543,967 for MRAs, and 1,717,444 for SGLT2 inhibitors. Class-specific projected deaths preventable over 12 months were 26,210 for beta-blockers, 34,495 for ARNIs, 26,620 for MRAs, and 26,422 for SGLT2 inhibitors; the aggregate estimate across treatment gaps was 113,747 (95% uncertainty interval [UI]: 90,173-149,875). Optimal implementation was also projected to prevent 357,332 HF hospitalizations annually (95% UI: 297,493-425,674).
CONCLUSIONS
Incomplete implementation of quadruple GDMT in HFrEF remains a major modifiable opportunity to reduce preventable deaths and HF hospitalizations in the United States.
Mohammad Keykhaei, A. T. Sandhu, Priscilla Y. Hsue et al.· JACC. Heart failure· 1 citation
Treatment for heart failure with mildly reduced ejection fraction (HFmrEF) and preserved ejection fraction (HFpEF) has evolved significantly in recent years. This period of therapeutic progress follows a span of over two decades during which randomized controlled trials (RCTs) of neurohormonal blockade and other therapies failed to definitively demonstrate clinical benefits. As such, traditionally, management guidelines for HFmrEF and HFpEF were limited to recommendations focused on optimization of volume status with diuretics, management of comorbidities, and consideration of certain medications such as angiotensin receptor-neprilysin inhibitor (ARNi) or steroidal mineralocorticoid receptor antagonists (MRA) to subsets of patients. After definitive results from multiple RCTs, sodium-glucose cotransporter 2 inhibitors (SGLT2i) are currently a main pillar in treating HFmrEF and HFpEF in European and American guidelines. However, other therapies, including non-steroidal mineralocorticoid receptor antagonists (nsMRA) and glucagon-like peptide-1 receptor agonists (GLP-1 RA), are proving to be additional effective treatments for HFmrEF and HFpEF and preventing the progression of cardiovascular-kidney-metabolic (CKM) syndrome. There is now increasing justification for combining multiple proven treatments for HFmrEF and HFpEF to maximize potential benefits. Treatment for different types of heart failure has improved significantly in recent years. For many years, there were few treatments that clearly helped people with heart failure whose heart still pumps normally or nearly normally. Care mainly focused on treating symptoms, helping the body remove excess fluid, and managing related health conditions such as high blood pressure, diabetes, and obesity. Today, research has expanded the available treatment options. One important group of medicines helps the body remove excess sugar and salt through the urine, which also reduces excess fluid and lowers the strain on the heart. Newer studies have shown that medicines that block the effects of a hormone called mineralocorticoid can improve outcomes while causing fewer side effects than older steroid-based treatments. For people who also have obesity, another newer group of medicines that acts on natural gut hormones has been shown to improve symptoms, physical activity, and quality of life. Overall, using a combination of these newer treatments may help people with heart failure whose heart still pumps normally or nearly normally feel better, improve their quality of life, and achieve better long-term health outcomes.
Craig J. Beavers, S. Greene· Heart Failure Reviews· 0 citations
Abstract Heart failure (HF) remains a major cause of morbidity and mortality despite significant advances in its management. This study aimed to synthesize recent advances in HF management, including the role of artificial intelligence (AI) and advances in gene therapy. PubMed, Embase, Web of Science, and Google Scholar were searched for original research (2020–January 2026) on recent advances in HF management, including AI and gene-based therapies. While guideline-directed management and therapy (GDMT) substantially reduce mortality and hospitalization in heart failure with reduced ejection fraction (HFrEF), utilization of such therapies is frequently constrained by delayed initiation, incomplete titration, noncompliance, and cost. Beyond foundational therapy, finerenone, sodium glucose cotransporter-2 inhibitors (SGLT2i) across the ejection fraction (EF) spectrum, and glucagon-like peptide-1 receptor agonist (GLP-1 RA) for obesity-related heart failure with preserved ejection fraction (HFpEF) extend phenotype-directed options. Transcatheter mitral and tricuspid repair/replacement has shifted mitral and tricuspid regurgitation from a bystander lesion to a treatable contributor to improvement of symptoms and quality of life. Adjunctive transcatheter mitral interventions have expanded treatment options for selected symptomatic HFrEF patients with secondary mitral regurgitation (MR) despite optimized GDMT, improving MR severity, functional status, and reducing HF hospitalizations. Donor-derived cell-free DNA rejection surveillance, donation after circulatory death to expand donor supply, and refinement of left ventricular assist device (LVAD) antithrombotic strategies are evolving in advanced HF. AI tools and gene therapies are showing promising results but require further large-scale studies for validation and clinical adoption. Contemporary HF management is increasingly phenotype- and trajectory-guided, but its clinical adoption is limited by optimal implementation and access barriers. Future research should focus on outcomes-based validation with a clear patient-selection framework to enable durable real-world implementation to improve outcomes further.
Lakshmi Kattamuri, Kunal Sharma, Debabrata Mukherjee· International Journal of Ang...· 0 citations
BACKGROUND
Heart failure with preserved ejection fraction (HFpEF) represents nearly half of all heart failure cases and is increasingly recognized as a complex clinical syndrome driven by diverse pathophysiological mechanisms and multiple comorbidities. Despite its growing prevalence, evidence supporting disease-modifying therapies in HFpEF remains limited. Beta-blockers continue to be widely used in this population, largely for indications such as hypertension, atrial fibrillation, ischemic heart disease, and elevated heart rate; however, their therapeutic value in HFpEF itself remains uncertain.
METHOD
This narrative review summarizes current clinical evidence on role of beta blocker in phenotype driven HFpEF management. A thorough search of Pubmed has been done using the key words "heart failure with preserved ejection fraction", "heart failure comorbidities", and "beta blockers in heart failure".
RESULT
It was found that an all HFpEF trials for new pharmacological agents like SGLT2I, ARNI, MRA and nsMRA, beta blocker therapy had been there during screening in 80-90% of patients with HFpEF. Neither the reasons were explored nor the Beta blockers were withdrawn for inclusion in the studies.
CONCLUSION
Current evidence suggests that beta-blockers can be prescribed based on comorbidity profiles rather than as HFpEF specific therapy. Well-designed randomized studies particularly those incorporating phenotype-based patient selection are needed to clarify the therapeutic role of beta-blockers.
S. Ray, Satyavir Yadav, Nitish Naik et al.· Indian Heart Journal· 0 citations
Introduction: Heart failure is a leading cause of hospitalization and mortality worldwide.
Adherence to the European Society of Cardiology (ESC) guidelines can significantly reduce
mortality and rehospitalization rates. However, many patients are discharged without optimal
guideline-directed therapy.
Aim: To evaluate the implementation of the 2021 ESC guidelines (with 2023 updates) for
heart failure management in clinical practice.
Material and methods: This prospective, observational study included 118 patients hospitalized for acute heart failure from December 1, 2024, to January 31, 2025. Prescription rates
at discharge for the four recommended drug classes were assessed: Angiotensin-converting
enzyme inhibitors (ACEIs), Angiotensin receptor blockers (ARBs), or Angiotensin receptor
neprilysin inhibitors (ARNIs), Beta-blockers (BBs), Mineralocorticoid receptor antagonists
(MRAs), Sodium-glucose cotransporter-2 inhibitors (SGLT2Is). Only patients without contraindications were considered eligible. Common clinical reasons for non-prescription were
also examined.
Results: The ACEI/ARB/ARNI therapy was prescribed to 92.7% of eligible patients, BBs to
79.1%, MRAs to 61.7%, and SGLT2Is to 46.7%. Only 38.1% of the total population received all four drug classes at discharge. Contraindications for ACEI/ARB/ARNI included renal
dysfunction, hyperkalemia, and hypotension. The MRAs were limited by renal insufficiency
and hyperkalemia. Beta-blockers were often withheld due to bradycardia, asthma, or hypotension. Also, SGLT2Is were avoided in patients with significantly impaired renal function or
hypotension.
Conclusion: Implementation of guideline-directed therapy in heart failure patients remains
suboptimal. Although ACEI/ARB/ARNI therapy showed high adherence, BBs and MRAs
were less frequently used, and SGLT2Is were under-prescribed. Greater efforts are needed to
improve adherence to ESC recommendations at discharge.
Andrijana Stošić, Marija Polovina· Medicinski Podmladak· 0 citations
Beta-blockers have long been a foundational pharmacotherapy in cardiovascular care across many disease conditions. However, the emergence of contemporary randomized trials and large population analyses has reshaped our understanding of their appropriate use. This review highlights well established indications, such as chronic heart failure with reduced ejection fraction and angina, while also examining recent studies that have questioned routine use in certain scenarios such as myocardial infarction in patients with preserved ejection fraction, stable coronary artery disease, heart failure with preserved ejection fraction, first-line antihypertensive therapy, and perioperative management. Evolving data suggest that benefits are more nuanced than previously recognized and must be individualized based on underlying pathology, ventricular function, and symptomatic burden. This article provides a practical, indication-focused framework and identifies areas where further evidence is needed to refine prescribing and deprescribing practices.
B. Sperry, Mohammad Abdel Jawad, Deepak L. Bhatt et al.· Journal of the American Coll...· 0 citations