Phenotype-Specific Guideline-Directed Therapy Across the Heart Failure Ejection Fraction Spectrum

Key Takeaways

• Although ejection fraction remains an operational criterion for selecting heart failure pharmacotherapy, it is a continuous and dynamic parameter with significant interobserver variability. A single echocardiographic value should never be considered an immutable phenotypic label, and reassessment three to six months after optimized therapy frequently reclassifies patients among the categories of reduced, mildly reduced, preserved, and improved ejection fraction.
• Four foundational drug classes—a renin-angiotensin system inhibitor or an angiotensin receptor-neprilysin inhibitor, a beta-blocker, a mineralocorticoid receptor antagonist, and a sodium-glucose cotransporter 2 inhibitor—form the cornerstone of therapy in patients with reduced ejection fraction. SGLT2 inhibitors are the only class to demonstrate consistent benefit across the entire ejection fraction spectrum, a feature that makes them the cornerstone agent in mildly reduced and preserved phenotypes.
• The speed and completeness of therapy implementation are more important than the chosen initiation sequence: initiating all four foundational drug classes at low doses within weeks, followed by goal-directed titration, yields superior outcomes to maximizing drug classes sequentially. Asymptomatic low blood pressure, a modest increase in creatinine, and potassium levels up to 5.5 mmol/L are rationales for closer patient monitoring, not for discontinuing therapy.
• Atrial fibrillation is comorbid in more than half of patients with heart failure; it worsens symptoms and prognosis, attenuates the measurable benefit of some drug classes, and raises the natriuretic peptide thresholds used for diagnosis. Rhythm control, particularly catheter ablation in appropriately selected patients, is no longer a rescue strategy but a foundational pillar of treatment.
• Mainstays of practical monitoring include: checking renal function and potassium levels one to two weeks after each change in a renin-angiotensin-aldosterone system agent; measuring blood pressure and heart rate at every titration visit; and reassessing ventricular function before any de-escalation of therapy is considered.

Introduction and Clinical Background

Heart failure is among the most common chronic cardiovascular syndromes worldwide, affecting an estimated 70 million people. Its prevalence is approximately 2% in Europe and North America and roughly 1% in Asia and South America; about half of all cases are attributed to reduced left ventricular systolic function^[1]. The remaining disease burden stems predominantly from heart failure with preserved ejection fraction; this phenotype accounts for nearly half of all cases, causes significant morbidity and mortality, and clusters closely with advanced age, diabetes, hypertension, obesity, and atrial fibrillation^[2].

The taxonomy that currently guides prescribing—reduced ejection fraction at 40% or below, mildly reduced between 41% and 49%, and preserved at 50% or above—arose historically from clinical trial inclusion criteria rather than from biology. Nevertheless, this classification has proven clinically indispensable, as the magnitude of benefit provided by most disease-modifying agents diminishes as ejection fraction rises. European registry data reveal how these phenotypes are distributed in practice: in the ESC EORP Heart Failure III Registry, which enrolled 10,162 patients from 220 centers in 41 countries, 57% of patients had reduced, 17% had mildly reduced, and 26% had preserved ejection fraction; 39% of patients presented with acute heart failure, while the remainder were ambulatory patients under follow-up^[3].

The fundamental clinical failure in this field is not a lack of effective drugs, but a failure to deliver them to patients. Despite clear guideline recommendations, major gaps persist in the use of foundational therapy in eligible patients, and heart failure with reduced ejection fraction continues to pose a clinical risk that exceeds that of many other cardiovascular and non-cardiovascular conditions^[4]. Further complicating this situation is the presence of atrial fibrillation in more than half of patients with heart failure; this diagnosis marks a transition to a heavier symptom burden, more frequent hospitalizations, and a worse prognosis, and it modifies the efficacy of various components of guideline-directed therapy^[5].

Thus, the missed opportunities can be grouped into three categories: failure to initiate all indicated drug classes, failure to titrate these drugs to evidence-based doses, and failure to recognize and treat the arrhythmic comorbidity that reshapes both diagnosis and response to medication. Each of these problems is solvable at the patient level within a single outpatient cycle.

Molecular and Pathophysiological Mechanisms

An important limitation must be stated at the outset: the literature screened for this review consists of clinical trials, registry data, consensus reports, and clinical reviews. It does not include any mechanistic, molecular, or preclinical studies. Therefore, the mechanistic discussion below is intentionally kept brief and is limited to the pathophysiological framework presented in the cited clinical reviews; readers seeking details on receptor-level or signal transduction pathways are advised to consult primary basic science sources, which are beyond the scope of the present review.

Structural and Hemodynamic Substrate of the Preserved Ejection Fraction Phenotype

Heart failure with preserved ejection fraction is a constellation of hemodynamic abnormalities rather than a single lesion: changes in left ventricular structure, diastolic and systolic dysfunction, left atrial myopathy, pulmonary hypertension, right ventricular dysfunction, chronotropic incompetence, and vascular dysfunction. At the cellular and molecular level, inflammation, fibrosis, impaired nitric oxide signaling, sarcomere dysfunction, and mitochondrial and metabolic defects have been identified as contributing processes, and this syndrome exerts effects far beyond the heart—on skeletal muscle, the peripheral vascular bed, the lungs, kidneys, and brain^[2]. This multi-organ involvement explains why pharmacological approaches targeting a single pathway have historically been inadequate in this phenotype.

Reverse Remodeling as a Common Therapeutic Target

In the reduced ejection fraction phenotype, the four foundational drug classes act on different but overlapping neurohormonal and metabolic axes, and their combined effect manifests clinically as reverse remodeling—improvement in ejection fraction, reduction in filling pressures, and attenuation of the arrhythmic burden. Registry data discussed below indicate that improvement in serial ejection fraction measurements is not an idiosyncratic response but an expected consequence of full therapy. Left atrial myopathy forms the mechanistic bridge to arrhythmic comorbidity, and disease-modifying therapy appears to slow the progression of this myopathy while also reducing the incidence of new-onset atrial fibrillation.

Clinical Evidence and Guideline Comparison

Quadruple Foundational Therapy and the 2023 Guideline Update

The contemporary treatment of heart failure with reduced ejection fraction is based on the early initiation and rapid uptitration of renin-angiotensin system inhibitors or angiotensin receptor-neprilysin inhibitors, beta-blockers, mineralocorticoid receptor antagonists, and SGLT2 inhibitors, with loop diuretics reserved for decongestion^[1]. The 2023 European focused update significantly expanded this treatment framework: SGLT2 inhibitors have become recommended across the entire left ventricular ejection fraction spectrum; finerenone, a non-steroidal selective mineralocorticoid receptor antagonist, has entered practice for the prevention of heart failure in diabetic chronic kidney disease; vericiguat is positioned as a potential fifth agent after a worsening heart failure event; and semaglutide 2.4 mg once weekly improved symptoms by reducing body weight in the STEP-HFpEF and STEP-HFpEF-DM programs^[6].

The biological mechanism of action and clinical indication for vericiguat warrant further detail in the context of post-decompensation patient management. An orally active soluble guanylate cyclase (sGC) stimulator, vericiguat directly stimulates the sGC enzyme independent of nitric oxide, which is depleted by chronic inflammation and oxidative stress in the cardiorenal axis; it activates the intracellular cyclic GMP-protein kinase G pathway, reduces myocardial stiffness, and corrects microvascular tone. In the landmark VICTORIA trial, vericiguat significantly reduced the primary endpoint of cardiovascular death and heart failure hospitalizations in a high-risk group of patients with an ejection fraction of <45% who had experienced a recent worsening heart failure event (hospitalization or need for outpatient intravenous diuretics within the last 6 months) despite optimal foundational therapy^[25]. Accordingly, both the ESC and ACC/AHA guidelines position vericiguat not as an alternative to the four foundational pillars but as a fifth hemodynamic agent with a Class 2b recommendation, added to the regimen particularly during the fragile period following a worsening heart failure event.

Critically, the clinical use of finerenone is no longer limited to diabetic kidney disease. The landmark FINEARTS-HF trial proved that finerenone significantly reduced worsening heart failure events and cardiovascular death in patients with heart failure with mildly reduced or preserved ejection fraction, regardless of baseline glycemic status or the presence of underlying kidney damage^[23]. Furthermore, for non-diabetic chronic kidney disease, the mechanistic rationale that receptor-mediated inflammation and tissue fibrosis drive organ damage independent of glycemia has been carried into large clinical trials, such as FIND-CKD, that directly target this patient population^[24]. Therefore, the decision to initiate therapy should be based on objective safety thresholds, such as a serum potassium of 5.0 mmol/L or less and an eGFR of at least 25 mL/min/1.73 m², rather than on the presence of diabetes or a kidney lesion.

The place of sacubitril/valsartan in the preserved ejection fraction spectrum warrants clarification. Although the pivotal PARAGON-HF trial narrowly missed statistical significance for its primary composite endpoint in the overall cohort, prespecified subgroup analyses showed a marked reduction in heart failure hospitalizations, particularly in patients with an ejection fraction below the median (specifically between 45% and 57%) and in women.^[22] In line with this, current guidelines offer a Class 2b recommendation for sacubitril/valsartan in HFpEF, positioning the drug as an individualized option, particularly for patients at the lower end of the preserved spectrum.

High-Intensity Care: The STRONG-HF Paradigm

The STRONG-HF trial demonstrated that aggressive, protocol-based post-discharge optimization is feasible. Applying a standard intensity score, indication-adjusted triple therapy use at day 90 increased from 4.5% to 36% under standard care, whereas under high-intensity care, this rate rose from 5.2% to 93.5%. Dose-adjusted use increased from 4.5% to 20.5% in the standard care arm and from 3.3% to 77.4% in the high-intensity care arm, with a p value of less than 0.001 for the between-group differences^[7]. These dose-adjusted figures warrant particular emphasis, as they reveal that even in a maximally supported study environment, approximately one in four patients failed to reach target doses.

Titration in Real-World Data: TITRATE-HF and OPTIPHARM-HF

The TITRATE-HF registry study in the Netherlands provided the most detailed contemporary picture of implementation. Among 1508 patients with de novo heart failure with reduced ejection fraction (median age 70, 31% women, median ejection fraction 30%), 46% were receiving quadruple therapy at six weeks and 66.3% at six months, and 84% of those who initiated quadruple therapy were still on it at day 180^[8]. The full primary analysis of 3367 patients confirmed progressively increasing uptake of therapy in de novo disease—47.2% at six weeks, 64.7% at three months, 69.5% at six months, and 64.4% at twelve months—and serial echocardiography documented the change in ejection fraction along with the composite endpoint of all-cause death or heart failure hospitalization^[9]. An earlier cross-sectional analysis of the same 4288-patient cohort strikingly illustrated the dose problem: while 44% of patients with chronic and worsening disease received quadruple therapy, only 1% reached target doses of all four drug classes, and quadruple therapy was prescribed more frequently in specialized heart failure clinics^[10].

The OPTIPHARM-HF registry study in Italy extended these observations across the full spectrum. In 3054 patients (mean age 69, 25% women; 56% with reduced, 21% with mildly reduced, and 23% with preserved ejection fraction), prescription rates in the reduced ejection fraction group were 90% for beta-blockers, 61% for angiotensin receptor-neprilysin inhibitors, 19% for ACE inhibitors or angiotensin receptor blockers, 72% for mineralocorticoid receptor antagonists, and 69% for SGLT2 inhibitors^[11]. The near-complete replacement of ACE inhibitors by neprilysin inhibition in specialist practice and the persistent one-third deficit in SGLT2 inhibitor use are noteworthy.

The Post-Discharge Gap: CONNECT-HF

The North American experience has been less promising. In the CONNECT-HF trial, among 4646 participants with heart failure with reduced ejection fraction (mean age 63, 34% women), no improvement in therapy use was observed between discharge and the twelfth month: beta-blocker use fell from 84% to 78%, renin-angiotensin system inhibitors or neprilysin inhibitors from 73% to 65%, and mineralocorticoid receptor antagonists from 39% to 36%, while SGLT2 inhibitors rose only from 1.5% to 2.1%; the rate of achieving at least 50% of the target dose similarly showed minimal change^[12]. Without a mandate for titration, mere participation in a registry and a quality improvement infrastructure does not alter these trajectories.

Heart Failure with Recovered Ejection Fraction

As therapies have improved, a fourth phenotype has gained numerical importance. Within a large, integrated health system in California, ejection fraction recovery was defined as an ejection fraction of greater than 40% and an absolute increase of more than 10% within twelve months of an incident diagnosis of heart failure with reduced ejection fraction; treatment patterns and rates of worsening heart failure events and death were then compared with those in patients whose function remained persistently low^[13]. The clinical implication is that recovery is a treatment effect requiring maintenance therapy, not a cure that permits discontinuation of treatment.

Atrial Fibrillation: Treatment Adherence, Ablation, and Reversibility

In patients with acute heart failure and documented atrial fibrillation from the Korean Acute Heart Failure registry (986 of 5625 patients), adherence to recommended discharge therapy, including anticoagulation, was found to be directly associated with survival: low treatment adherence carried a hazard ratio (HR) of 4.75 (95% CI 1.77 to 12.74) for 60-day mortality and 2.36 (95% CI 1.33 to 4.18) for the composite endpoint. The one-year mortality hazard ratios were 1.64 (95% CI 1.15 to 2.33) compared with moderate adherence and 2.34 (95% CI 1.39 to 3.97) compared with good adherence^[14]. Disease-modifying therapy, in turn, reduces the incidence of atrial fibrillation and slows the progression of atrial myopathy. Catheter ablation now has a Class 1A recommendation in selected patients with atrial fibrillation and heart failure, based mainly on cohorts with reduced ejection fraction and end-stage disease; randomized data in patients with preserved ejection fraction are still lacking^[15].

A secondary analysis of the CABANA trial has begun to fill this gap. In this analysis of 1763 patients, a modified H2FPEF score of 6 or higher, present in 55% of the cohort, was shown to significantly modify the effect of ablation therapy (p=0.027 for interaction): patients with a high probability of heart failure with preserved ejection fraction had a lower risk of cardiovascular hospitalization or death with ablation (HR 0.82, 95% CI 0.69 to 0.98, p=0.025), whereas no benefit was seen in those without this probability (HR 1.00, 95% CI 0.82 to 1.22)^[16]. This finding is hypothesis-generating but directionally important: the more diseased the atrium and ventricle, the greater the apparent value of rhythm control.

The question of reversibility was directly addressed by WITHDRAW-AF, a multicenter, randomized, crossover study of 60 patients with atrial fibrillation-mediated cardiomyopathy whose ejection fraction had normalized with rhythm control. Participants were randomized to early and phased withdrawal of heart failure pharmacotherapy or to continuation of therapy for six months followed by delayed withdrawal; the primary endpoint was the maintenance of an ejection fraction of 50% or greater as measured by cardiac magnetic resonance at six months^[17]. Regardless of the final effect estimate, the study’s small sample size makes caution mandatory before a de-escalation approach is generalized to routine practice.

Practical Implications and Safety Profile

Diagnostic Workflow and Phenotyping

Diagnosis requires typical signs and symptoms, elevated natriuretic peptide levels, and objective cardiac structural or functional abnormalities detected by imaging. In ambulatory patients, NT-proBNP levels above 125 pg/mL or BNP levels above 35 pg/mL support the diagnosis; in the acute setting, these thresholds are approximately 300 pg/mL and 100 pg/mL, respectively. Atrial fibrillation independently elevates natriuretic peptides; therefore, while a normal value in a patient with atrial fibrillation largely rules out the diagnosis, the specificity of a mildly elevated value is much lower. Many centers use thresholds two to three times higher in this setting. Obesity can lower natriuretic peptide concentrations, leading to false-negative results.

In suspected heart failure with preserved ejection fraction where resting investigations are non-diagnostic, sequential testing is appropriate: comprehensive echocardiography including E/e’ (E/e prime), left atrial volume index, and tricuspid regurgitation velocity, followed by a composite score (H2FPEF or HFA-PEFF), and, if the score is intermediate, diastolic stress echocardiography or invasive exercise hemodynamics. Confirmation of the diagnosis is based on a rise in pulmonary capillary wedge pressure to 25 mmHg or higher with exercise, or a resting wedge pressure of 15 mmHg or higher. Amyloidosis, constrictive physiology, valvular disease, and high-output states must be excluded before this diagnosis is made.

Initiation, Sequencing, and Titration Doses

No randomized trial has directly compared treatment sequencing strategies. A microsimulation study modeling six proposed strategies predicted that 15.3 of 100 untreated ambulatory patients would die within one year. This rate falls to 6.9 per 100 patients with conventional two-week sequencing, and to between 5.2 and 6.4 per 100 patients with rapid or simultaneous strategies. The study also modeled bradycardia, hyperkalemia, hypotension, and renal dysfunction^[18]. The practical takeaway is that a complete regimen is always superior to an incomplete one, and that more rapidly initiated therapy provides a modest additional benefit.

Reasonable starting and target doses, drawn from established prescribing practice rather than from cited article abstracts, are as follows. Sacubitril/valsartan 24/26 mg twice daily, with the dose doubled every two to four weeks to a target of 97/103 mg twice daily; a mandatory 36-hour washout period is required when switching from an ACE inhibitor. In the absence of a neprilysin inhibitor, enalapril is titrated from 2.5 mg twice daily to 10 to 20 mg twice daily, or ramipril from 1.25 mg daily to 10 mg daily. Bisoprolol from 1.25 mg to 10 mg daily, carvedilol from 3.125 mg twice daily to 25 mg twice daily (50 mg twice daily if over 85 kg), or metoprolol succinate from 12.5 to 25 mg to 200 mg daily. Spironolactone or eplerenone from 12.5 to 25 mg to 50 mg daily. Dapagliflozin or empagliflozin 10 mg daily; the lack of a need for titration explains precisely why this agent should be initiated first or simultaneously. Vericiguat may be added after a worsening heart failure event, titrated from 2.5 mg to 10 mg daily. Ivabradine 5 mg twice daily is reserved for patients in sinus rhythm with a resting heart rate of 70 beats per minute or higher on maximally tolerated beta-blocker therapy and has no role in atrial fibrillation.

Management of Low Blood Pressure and Intolerance

Low blood pressure is the most frequently cited barrier to treatment optimization. The consensus view of the Heart Failure Association is clear: outside of overt shock, the dominant clinical scenario is non-severe asymptomatic hypotension in a patient receiving foundational therapies, in which case premature dose reduction or discontinuation should be avoided^[19]. Before reducing the dose of a disease-modifying agent, non-essential vasodilators and calcium channel blockers should be reviewed and reduced, volume status should be reassessed, the loop diuretic dose should be lowered if the patient is euvolemic, and adjustment of medication timing should be considered.

Nevertheless, intolerance is a real problem. In a single-center prospective cohort study that screened 263 patients with acute heart failure, nearly half could not tolerate quadruple therapy before discharge; the dominant reasons were renal failure and hypotension. Patients who could tolerate quadruple therapy at discharge were far more likely to remain on it at the study endpoint (92.4% vs 27.8%), and only 13.4% of the entire population ultimately reached maximum doses of all four drugs^[20]. Discharge is therefore the point of intervention with the highest yield.

Safety Monitoring Intervals and Thresholds

Serum creatinine, electrolytes, and blood pressure should be checked one to two weeks after initiating or uptitrating any renin-angiotensin-aldosterone system agent, at one- to three-month intervals once stable, and within one week in patients with chronic kidney disease or diabetes. An early increase in creatinine of up to 30% or a similar-magnitude drop in eGFR after treatment initiation is expected and does not require drug discontinuation. If potassium is above 5.5 mmol/L, the mineralocorticoid receptor antagonist dose should be halved and rechecked within a week; if above 6.0 mmol/L, the drug should be stopped and the situation reassessed. SGLT2 inhibitors cause a small, early drop in eGFR that is reversible and does not require discontinuation; the patient should be counseled about genital mycotic infections, volume depletion, and “sick day rules,” and the drug should be held 3 days before major surgery or prolonged fasting due to the risk of euglycemic ketoacidosis. The loop diuretic dose should be reduced by 25% to 50% when starting an SGLT2 inhibitor in euvolemic patients.

Concomitant Atrial Fibrillation

The decision to anticoagulate is based on the CHA2DS2-VASc score, to which heart failure itself contributes a point; direct oral anticoagulants are preferred unless mechanical valve disease or moderate-to-severe mitral stenosis is present. Digoxin remains useful for rate control at a dose range of 0.0625 to 0.25 mg daily, with a narrow target serum concentration of 0.5 to 0.9 ng/mL and close monitoring of renal function to avoid toxicity. Non-dihydropyridine calcium channel blockers are contraindicated in low ejection fraction. Amiodarone is the only generally accepted antiarrhythmic in this population and requires thyroid and liver function tests every six months, as well as baseline and periodic pulmonary assessment. Structured remote titration is a feasible treatment model: the AIM-POWER trial randomized patients with sub-optimally treated disease to a digital platform that generated biweekly medication suggestions for clinicians based on 90 days of daily weight and twice-daily blood pressure and heart rate data^[21].

Future Perspectives and Open Questions

Many questions remain genuinely unresolved. The optimal sequencing of the four foundational drug classes has never been tested in a randomized trial, and current guidelines are based on simulation and expert consensus; a pragmatic randomized trial comparing simultaneous low-dose initiation with rapid sequential uptitration, powered for hard endpoints rather than prescribing rates, is the most important study still missing.

The phenotype of mildly reduced ejection fraction is something of a “no-man’s land” in terms of evidence. While registry data confirm that this phenotype constitutes about one-fifth of contemporary heart failure populations, nearly all supporting evidence comes from subgroup analyses of trials designed around adjacent phenotypes. Whether the same quadruple-drug approach should be applied indiscriminately, or whether beta-blockade and neprilysin inhibition should be individualized by etiology and atrial rhythm, has not been clarified.

In preserved ejection fraction, the therapeutic pipeline has pivoted decisively toward metabolic and anti-inflammatory targets; incretin-based therapies have been shown to produce weight loss and symptomatic benefit, and advanced programs are examining whether these benefits translate into reductions in hospitalization and mortality. Combination strategies pairing SGLT2 inhibition with GLP-1 receptor agonism or non-steroidal mineralocorticoid receptor antagonism are the logical next step, but a sufficiently powered endpoint trial of such combinations has not yet been reported.

The question of de-escalation is the most clinically urgent and poorly answered. As ejection fraction recovery becomes more common, clinicians are faced daily with requests to discontinue medications in asymptomatic patients with normalized function. In atrial fibrillation-mediated cardiomyopathy, the available randomized evidence comprises just 60 patients over twelve months; while informative, this is far from definitive for a decision with potentially irreversible consequences. Until larger-scale trials with multi-year follow-up and cardiac magnetic resonance endpoints are available, the default approach should be to continue therapy.

Finally, implementation science deserves equal billing with pharmacology. The consistent finding from registry studies across three continents is that specialist clinic care, protocolized follow-up, and structured remote monitoring are far superior to standard care; on the other hand, attainment of target dose remains the weakest link everywhere. The honestly acknowledged limitations of the current evidence base include the observational design of most implementation cohorts, their concentration in high-income health systems, and the near-total absence of data from populations with advanced renal failure, frailty, or age over 85 — precisely the patients most often deprived of full implementation.

References

1. Cannata A, Crespo-Leiro MG, Bromage DI, Ruschitzka F, McDonagh TA. Heart failure with reduced ejection fraction. Lancet. 2026;407(10527):529-542. doi:10.1016/S0140-6736(25)01851-3. PubMed
2. Hamo CE, DeJong C, Hartshorne-Evans N, Lund LH, Shah SJ, Solomon S, et al. Heart failure with preserved ejection fraction. Nat Rev Dis Primers. 2024;10(1):55. doi:10.1038/s41572-024-00540-y. PubMed
3. Lund LH, Crespo-Leiro MG, Laroche C, Zaliaduonyte D, Saad AM, Fonseca C, et al. Heart failure in Europe: Guideline-directed medical therapy use and decision making in chronic and acute, pre-existing and de novo, heart failure with reduced, mildly reduced, and preserved ejection fraction – the ESC EORP Heart Failure III Registry. Eur J Heart Fail. 2024;26(12):2487-2501. doi:10.1002/ejhf.3445. PubMed
4. Patolia H, Khan MS, Fonarow GC, Butler J, Greene SJ. Implementing Guideline-Directed Medical Therapy for Heart Failure: JACC Focus Seminar 1/3. J Am Coll Cardiol. 2023;82(6):529-543. doi:10.1016/j.jacc.2023.03.430. PubMed
5. Newman JD, O’Meara E, Böhm M, Savarese G, Kelly PR, Vardeny O, et al. Implications of Atrial Fibrillation for Guideline-Directed Therapy in Patients With Heart Failure: JACC State-of-the-Art Review. J Am Coll Cardiol. 2024;83(9):932-950. doi:10.1016/j.jacc.2023.12.033. PubMed
6. Beghini A, Sammartino AM, Papp Z, von Haehling S, Biegus J, Ponikowski P, et al. 2024 update in heart failure. ESC Heart Fail. 2025;12(1):8-42. doi:10.1002/ehf2.14857. PubMed
7. Zhang X, Davison B, Adamo M, Arrigo M, Biegus J, Chioncel O, et al. Guideline-Directed Medical Therapy Use in the STRONG-HF Trial. Circ Heart Fail. 2025;18(9):e012716. doi:10.1161/CIRCHEARTFAILURE.124.012716. PubMed
8. Malgie J, Wilde MI, Brunner-La Rocca HP, Emans ME, De Boer GA, Siegers CEP, et al. Newly diagnosed heart failure with reduced ejection fraction: timing, sequencing, and titration of guideline-recommended medical therapy. Eur Heart J. 2025;46(25):2394-2405. doi:10.1093/eurheartj/ehaf244. PubMed
9. Malgie J, Wilde MI, Koudstaal S, Denham R, da Fonseca CA, Swart HP, et al. Real-life implementation of guideline-recommended medical therapy in heart failure with reduced ejection fraction: Effects on prognosis and left ventricular ejection fraction. Primary results of TITRATE-HF. Eur J Heart Fail. 2025;27(12):2735-2746. doi:10.1002/ejhf.70006. PubMed
10. Malgie J, Wilde MI, Clephas PRD, Emans ME, Koudstaal S, Schaap J, et al. Contemporary guideline-directed medical therapy in de novo, chronic, and worsening heart failure patients: First data from the TITRATE-HF study. Eur J Heart Fail. 2024;26(7):1549-1560. doi:10.1002/ejhf.3267. PubMed
11. Inciardi RM, Volterrani M, Savarese G, Vaduganathan M, Oriecuia C, Lombardi CM, et al. Contemporary medical therapy for heart failure across the ejection fraction spectrum: The OPTIPHARM-HF registry. Eur J Heart Fail. 2025;27(12):2691-2704. doi:10.1002/ejhf.70074. PubMed
12. Shoji S, Kaltenbach L, Granger BB, Fonarow GC, Al-Khalidi HR, Albert NM, et al. Guideline-Directed Medical Therapy After Hospitalization for Acute Heart Failure: Insights From the CONNECT-HF. J Am Heart Assoc. 2024;13(24):e036998. doi:10.1161/JAHA.124.036998. PubMed
13. Min KH, Go AS, Lee K, Parikh RV, Horiuchi KM, Ambrosy AP, et al. Guideline-Directed Medical Therapy and Outcomes Among Patients With Heart Failure With Improved Ejection Fraction. J Am Coll Cardiol. 2025;86(5):338-350. doi:10.1016/j.jacc.2025.05.040. PubMed
14. Ahn MS, Yoo BS, Yoon J, Lee SH, Kim JY, Ahn SG, et al. Guideline-directed therapy at discharge in patients with heart failure and atrial fibrillation. Heart. 2020;106(4):292-298. doi:10.1136/heartjnl-2019-315240. PubMed
15. Bidaoui G, Assaf A, Marrouche N. Atrial Fibrillation in Heart Failure: Novel Insights, Challenges, and Treatment Opportunities. Curr Heart Fail Rep. 2024;22(1):3. doi:10.1007/s11897-024-00691-9. PubMed
16. Martens P, Augusto SN, Erzeel J, Pison L, Mullens W, Tang WHW. Effects of Atrial Fibrillation Ablation for Heart Failure With Preserved Ejection Fraction: Insights From CABANA. JACC Heart Fail. 2025;13(5):785-794. doi:10.1016/j.jchf.2025.01.029. PubMed
17. Segan L, Kistler PM, Nanayakkara S, Taylor A, Hare J, Costello B, et al. Withdrawal of heart failure therapy after atrial fibrillation rhythm control with ejection fraction normalization: the WITHDRAW-AF trial. Eur Heart J. 2026;47(2):250-262. doi:10.1093/eurheartj/ehaf563. PubMed
18. Turgeon RD, Van MT, Loewen P, Sadatsafavi M, Zhang W, MacDonald BJ, et al. Comparison of Quadruple Therapy Sequencing Strategies for Heart Failure With Reduced Ejection Fraction. J Am Heart Assoc. 2025;14(18):e042943. doi:10.1161/JAHA.125.042943. PubMed
19. Skouri H, Girerd N, Monzo L, Petrie MC, Böhm M, Adamo M, et al. Clinical management and therapeutic optimization of patients with heart failure with reduced ejection fraction and low blood pressure. A clinical consensus statement of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail. 2025;27(4):707-722. doi:10.1002/ejhf.3618. PubMed
20. Chen J, Xiao R, Gao L, Zhou Y, Qin S, Wang Y, et al. Real-world challenges for guideline-directed medical therapy intolerance in heart failure: A single-center prospective cohort study. Int J Cardiol. 2025;434:133367. doi:10.1016/j.ijcard.2025.133367. PubMed
21. DeVore AD, Majmudar M, Etters L, Xie J, Hao C, Lam PH, et al. Digital Platform to Optimize Guideline-Directed Heart Failure Therapy: Results of the AIM-POWER Trial. Circ Heart Fail. 2026;19(2):e013231. doi:10.1161/CIRCHEARTFAILURE.125.013231. PubMed
22. Solomon SD, McMurray JJV, Anand IS, Ge J, Lam CSP, Maggioni AP, et al. Angiotensin-Neprilysin Inhibition in Heart Failure with Preserved Ejection Fraction. N Engl J Med. 2019;381(17):1609-1620. doi:10.1056/NEJMoa1908655. PubMed
23. Solomon SD, McMurray JJV, Vaduganathan M, Claggett B, Jhund PS, Desai AS, et al. Finerenone in Heart Failure with Mildly Reduced or Preserved Ejection Fraction. N Engl J Med. 2024;391(16):1475-1485. doi:10.1056/NEJMoa2407107. PubMed
24. Heerspink H, et al. Finerenone in Persons with Chronic Kidney Disease without Diabetes. N Engl J Med. 2026 Aug 6;395(6):533-545. doi: 10.1056/NEJMoa2604625. PubMed
25. Armstrong PW, Pieske B, Anstrom KJ, Ezekowitz J, Hernandez AF, Butler J, et al. Vericiguat in Patients with Heart Failure and Reduced Ejection Fraction. N Engl J Med. 2020;382(20):1883-1893. doi:10.1056/NEJMoa2001765. PubMed

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