A 75-year-old man with a history of heart failure with reduced ejection fraction (HFrEF), hypertension, and type 2 diabetes presents to the clinic for follow-up. He was diagnosed with HFrEF 20 months earlier, with an initial left ventricular ejection fraction (LVEF) of 30%. At that time, coronary angiography showed nonobstructive coronary artery disease. He was started on guideline-directed medical therapy (GDMT) over the past year, consisting of a beta-blocker, angiotensin receptor-neprilysin inhibitor, mineralocorticoid receptor antagonist, and sodium-glucose cotransporter (SGLT) 2 inhibitor. Repeat echocardiography shows his LVEF has improved to 50%, and the patient reports significant improvement in symptoms and better exercise tolerance. He asks if he can stop taking GDMT now that his ejection fraction has improved.
Current guidelines recommend continuing GDMT in patients previously diagnosed with HFrEF who have improved LVEF (≥ 40%) to prevent relapse and reduce long-term morbidity and mortality.
See related editorial, page 673
WHAT IS HEART FAILURE WITH IMPROVED EJECTION FRACTION?
Heart failure is a complex clinical syndrome characterized by signs and symptoms due to structural or functional abnormalities of the heart and corroborated by high natriuretic peptide levels with or without objective evidence of vascular congestion.1 Common symptoms include dyspnea, cough, and lower-extremity swelling, and common signs include jugular venous distention, wheezing, pedal edema, and hepatojugular reflex.2 No single test is diagnostic of heart failure as it is primarily a clinical diagnosis.
There are various frameworks for classifying heart failure. The American College of Cardiology and American Heart Association classification3 emphasizes the development and progression of the disease, while the New York Heart Association classification categorizes patients based on symptoms and functional capacity. LVEF is important because most clinical trials select patients based on ejection fraction. The classifications of heart failure based on LVEF endorsed by major heart failure societies include the following1:
HFrEF: LVEF 40% or less
Heart failure with mildly reduced ejection fraction: LVEF 41% to 49%
Heart failure with preserved ejection fraction: LVEF 50% or greater
Heart failure with improved ejection fraction (HFimpEF): symptomatic heart failure with a baseline LVEF of 40% or less, a 10-point or more increase from baseline LVEF, and a second measurement of LVEF greater than 40%.4
Other terms used to describe HFimpEF include heart failure with recovered ejection fraction, heart failure with restored ejection fraction, and heart failure with better ejection fraction. However, HFimpEF became the preferred term because “recovered” suggests permanent improvement, while “improved” acknowledges the potential for recurrence.1,4
In a review and pooled analysis by Albakri,5 patients with HFimpEF had more favorable clinical, biomarker, and functional characteristics than patients with HFrEF but worse than healthy controls. Although the myocardial pathology of patients with HFimpEF shows less severe abnormalities, these patients still have many molecular features of a failing heart and face a high risk of heart failure recurrence over the long term.4
WHAT IS GDMT?
GDMT is the cornerstone of pharmacologic treatment for patients with HFrEF. It has been proven to provide symptomatic relief and significantly reduce hospitalization and mortality rates.3 It comprises 4 drug classes: evidence-based beta-blockers (bisoprolol, sustained-release metoprolol, and carvedilol), angiotensin receptor-neprilysin inhibitors as the preferred first-line renin-angiotensin-aldosterone system inhibitor, mineralocorticoid receptor antagonists, and SGLT-2 inhibitors.3 These medications target the key mechanisms that drive heart failure progression, relieving symptoms by reducing neurohormonal activation, preventing adverse ventricular remodeling, and improving cardiac efficiency.
The benefits of GDMT are maximized when the 4 main drug classes are used in unison and when the therapies are titrated to maximally tolerated doses.6
The impact of GDMT on left ventricle function has been well documented in landmark trials3:
Renin-angiotensin-aldosterone system inhibitors—CONSENSUS (Cooperative North Scandinavian Enalapril Survival Study),7 SOLVD (Study of Left Ventricle Dysfunction),8 and PARADIGM-HF (The Efficacy and Safety of LCZ696 Compared to Enalapril on Morbidity and Mortality of Patients With Chronic Heart Failure)9
Beta-blockers—MERIT-HF (Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure),10 CIBIS-II (Cardiac Insufficiency Bisoprolol Study II),11 and COPERNICUS (Carvedilol Prospective Randomized Cumulative Survival)12
Mineralocorticoid receptor antagonists—RALES (Randomized Aldactone Evaluation Study)13 and EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure)14
SGLT-2 inhibitors—DAPA-HF (Dapagliflozin in Patients With Heart Failure and Reduced Ejection Fraction)15 and EMPEROR-Reduced (Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Reduced Ejection Fraction).16
WHAT DOES THE EVIDENCE SAY ABOUT STOPPING GDMT WHEN EJECTION FRACTION IMPROVES?
There are no clear guidelines on the treatment strategy for patients with HFimpEF. Most of the evidence supporting the use of GDMT involves patients with HRrEF. Guidelines from the Journal of the American College of Cardiology4 and the American College of Cardiology and American Heart Association3 recommend that GDMT be continued indefinitely to reduce the risk of progression of left ventricle dysfunction or major cardiovascular events.
None of the GDMT trials7–16 evaluated the effects of continuing or stopping treatment specifically in patients with HFimpEF. Other studies have shown that improved LVEF can be transitory.5
Observational studies
A retrospective observational cohort study explored the recurrence of left ventricle dysfunction (LVEF < 40%) in 42 patients with dilated cardiomyopathy who had recovered from congestive heart failure after treatment with angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor blockers, or beta-blockers.17 During an average 48 months of follow-up after heart failure diagnosis, 8 patients experienced a decrease in LVEF, and 5 of them had discontinued at least some heart failure medications. Analysis showed that discontinuation was significantly associated with recurrence.
Cioffi et al18 reported that 11 of 20 patients with HFrEF on GDMT who achieved normalization of LVEF (> 51%) and clinical status during a mean 17-month follow-up subsequently experienced decreased LVEF, clinical disease progression, or both, despite continuing optimal GDMT, including beta-blockers and ACE inhibitors. This suggests that the decline in LVEF was primarily due to underlying etiologies rather than the withdrawal of medications.5
In another retrospective study, 16% of 581 patients with dilated cardiomyopathy reported apparent recovery after long-term optimized treatment with ACE inhibitors and beta-blockers.5,19 Over the long term, however, there was significant progression of clinical disease in 33% of patients, regardless of the initial clinical response to treatment and despite continued optimized medical therapy. Progression occurred particularly in those with advanced disease at presentation or underlying comorbidities.
These studies indicate that in patients who show improvement in symptoms and a return to normal ejection fraction, there remains a significant risk of relapse even under rigorous pharmacologic management.1,5
Randomized trials
TRED-HF (Therapy Withdrawal in Recovered Dilated Cardiomyopathy—Heart Failure)20 is the only randomized study that has investigated the effects of discontinuing heart failure therapy in patients with HFimpEF. This study directly examined the safety of withdrawing these medications in patients treated pharmacologically who had recovered from dilated cardiomyopathy, a key group in the HFimpEF population. The patients previously had an LVEF of 40% or lower but improved to an LVEF of 50% or higher, were symptom free, were on at least 1 heart failure medication, had a normal left ventricular end-diastolic volume index, and had a natriuretic peptide level below 250 ng/L.
Fifty-one patients were randomized to continue or stop their heart failure medications. Of the 25 in the stop group, 11 relapsed within 6 months. After 6 months, 25 of 26 patients from the continue group attempted withdrawal, with 9 relapsing within 6 months.
The TRED-HF trial20 showed that stopping GDMT carries a high relapse risk in patients with recovered heart function, highlighting the need to continue treatment for long-term stability. However, the follow-up period after therapy was withdrawn was only 6 months, and no long-term outcomes were reported. Also, the sample size was limited to 51 patients, whereas the foundational GDMT trials included thousands of participants.
While TRED-HF offers important insights, it is unclear whether certain medication classes could be selectively withdrawn while maintaining others. Additionally, there is no protocol for sequential discontinuation of GDMT. In TRED-HF, the order of medication withdrawal was loop diuretics, mineralocorticoid receptor antagonists, beta-blockers, followed by ACE inhibitors and angiotensin II receptor blockers.
The DELIVER (Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure) trial21 also offers valuable insight into the management of HFimpEF. This randomized controlled trial demonstrated that dapagliflozin significantly reduced the risk of worsening heart failure and cardiovascular death in patients with HFimpEF. These findings suggest that patients with improved ejection fraction still benefit from continued use of SGLT-2 inhibitors, reinforcing the importance of ongoing GDMT even after apparent functional recovery.21
WHY IMPROVEMENTS IN HEART FAILURE CAN BE TRANSITORY
A recent review by Kodur and Tang22 highlighted the growing body of evidence (ie, biomarker, imaging, and clinical outcome data) showing the persistence of underlying disease activity even in the setting of improved systolic function and the importance of indefinite continuation of GDMT unless contraindicated. In addition, the aforementioned GDMT trials have shown that improving LVEF does not guarantee full myocardial recovery or normalization of left ventricle function. HFimpEF recovery involves 2 processes: reversal of remodeling (structural recovery) and myocardial recovery (return to normal function and molecular composition).1 However, even after reversal of remodeling, many abnormal molecules remain dysregulated, and impaired cardiac mechanics persist, increasing the risk of relapse.5 During the reversal process, only about 5% of heart failure–related gene expressions normalize, and new gene expression changes emerge.23
Other factors associated with HFrEF recurrence include older age, longer heart failure duration, larger left ventricle end diastolic diameter, lower LVEF, left bundle branch block, slower heart rate, hypertension, and lower glomerular filtration rate.23
WHEN SHOULD GDMT BE TAPERED OR DISCONTINUED?
GDMT should be continued unless the risks of therapy outweigh the benefits. Adverse effects such as hyperkalemia, renal dysfunction, and hypotension are important considerations for GDMT discontinuation but are not absolute reasons.24 Prompt individualized risk-benefit assessments should guide the appropriate approach to management.
Discontinuing GDMT is primarily reserved for patients who are transitioning to palliative care, where the focus shifts to improving quality of life and managing symptoms rather than aggressive heart failure therapy.25 Current guidelines3 emphasize that patients with improved LVEF (> 40%) who were previously diagnosed with HFrEF should continue GDMT.
Discontinuing GDMT due to intolerance or adverse effects is associated with poorer outcomes.6 Medication intolerance may indicate advanced heart failure and is often associated with a poorer prognosis. If intolerance occurs, efforts should be made to reintroduce these medications at a lower dose in the future, provided there are no absolute contraindications.
FUTURE DIRECTIONS
There is a critical gap in understanding how to manage patients with HFimpEF, with a clear lack of consensus on terminology and management of GDMT in these patients. Further research of this patient population is needed given the transient nature of LVEF improvements observed in several studies. Evidence-based guidelines are needed as well so that clinicians can make informed treatment decisions and avoid putting patients at risk of relapse and heart failure progression.
THE BOTTOM LINE
Continuing GDMT in patients with HFimpEF is crucial. Although normalization or improvement of LVEF reflects a positive response to treatment, it does not guarantee a permanent recovery. A significant proportion of patients with normalized LVEF may only be in a state of remission rather than true recovery. Guidelines should provide more precise terminology, highlighting that restored ventricular function likely does not represent recovered ventricular function but rather is more like remission of ventricular dysfunction. Other than LVEF, no biomarkers or clinical profiles align with treatment response. We have no parameters to suggest that a previously indicated treatment for reduced ejection fraction is no longer necessary and can be safely discontinued. GDMT provides ongoing protection against the deterioration of heart structure and function, thus preventing the recurrence of heart failure symptoms.
DISCLOSURES
The authors report no relevant financial relationships which, in the context of their contributions, could be perceived as a potential conflict of interest.
- Copyright © 2025 The Cleveland Clinic Foundation. All Rights Reserved.
REFERENCES
- 1↵Bozkurt B, Coats AJ, Tsutsui H, et al. Universal definition and classification of heart failure: a report of the Heart Failure Society of America, Heart Failure Association of the European Society of Cardiology, Japanese Heart Failure Society and Writing Committee of the Universal Definition of Heart Failure. J Card Fail 2021; 27(4):387–413. doi:10.1016/j.cardfail.2021.01.022
- 2↵Watson RD, Gibbs CR, Lip GY. ABC of heart failure. Clinical features and complications. BMJ 2000; 320(7229):236–239. doi:10.1136/bmj.320.7229.236
- 3↵Heidenreich PA, Bozkurt B, Aguilar D, et al. 2022 AHA/ACC/HFSA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines [published correction appears in J Am Coll Cardiol 2023; 81(15):1551]. J Am Coll Cardiol 2022; 79(17):e263–e421. doi:10.1016/j.jacc.2021.12.012
- 4↵Wilcox JE, Fang JC, Margulies KB, Mann DL. Heart failure with recovered left ventricular ejection fraction: JACC Scientific Expert Panel. J Am Coll Cardiol 2020; 76(6):719–734. doi:10.1016/j.jacc.2020.05.075
- 5↵Albakri A. Heart failure with improved ejection fraction: a review and pooled analysis of pathophysiology, diagnosis and clinical management. Int Med Care 2020; 4:1–9.
- 6↵Maddox TM, Januzzi JL Jr, Allen LA, et al. 2024 ACC expert consensus decision pathway for treatment of heart failure with reduced ejection fraction: a report of the American College of Cardiology Solution Set Oversight Committee. J Am Coll Cardiol 2024; 83(15):1444–1488. doi:10.1016/j.jacc.2023.12.024
- 7↵CONSENSUS Trial Study Group. Effects of enalapril on mortality in severe congestive heart failure. Results of the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS). N Engl J Med 1987; 316(23):1429–1435. doi:10.1056/NEJM198706043162301
- 8↵SOLVD Investigators; Yusuf S, Pitt B, Davis CE, Hood WB, Cohn JN. Effect of enalapril on survival in patients with reduced left ventricular ejection fractions and congestive heart failure. N Engl J Med 1991; 325(5):293–302. doi:10.1056/NEJM199108013250501
- 9↵McMurray JJ, Packer M, Desai AS, et al; PARADIGM-HF Investigators and Committees. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014; 371(11):993–1004. doi:10.1056/NEJMoa1409077
- 10↵Effect of metoprolol CR/XL in chronic heart failure: Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT-HF). Lancet 1999; 353(9169):2001–2007. pmid:10376614
- 11↵The Cardiac Insufficiency Bisoprolol Study II (CIBIS-II): a randomised trial. Lancet 1999; 353(9146):9–13. pmid:10023943
- 12↵Eichhorn EJ, Bristow MR. The Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) trial. Curr Control Trials Cardiovasc Med 2001; 2(1):20–23. doi:10.1186/cvm-2-1-020
- 13↵Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med 1999; 341(10):709–717. doi:10.1056/NEJM199909023411001
- 14↵Zannad F, McMurray JJ, Krum H, et al; EMPHASIS-HF Study Group. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med 2011; 364(1):11–21. doi:10.1056/NEJMoa1009492
- 15↵McMurray JJV, Solomon SD, Inzucchi SE, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction. N Engl J Med 2019; 381(21):1995–2008. doi:10.1056/NEJMoa1911303
- 16↵Packer M, Anker SD, Butler J, et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med 2020; 383(15):1413–1424. doi:10.1056/NEJMoa2022190
- 17↵Moon J, Ko YG, Chung N, et al. Recovery and recurrence of left ventricular systolic dysfunction in patients with idiopathic dilated cardiomyopathy. Can J Cardiol 2009; 25:e147–e150.
- 18↵Cioffi G, Stefenelli C, Tarantini L, Opasich C. Chronic left ventricular failure in the community: prevalence, prognosis, and predictors of the complete clinical recovery with return of cardiac size and function to normal in patients undergoing optimal therapy. J Card Fail 2004; 10(3):250–257. doi:10.1016/j.cardfail.2003.10.002
- 19↵Di Lenarda A, Pinamonti B, Mestroni L, et al; Gruppo di Studio sulle Malattie del Miocardio. The natural history of dilated cardiomyopathy: a review of the Heart Muscle Disease Registry of Trieste. Ital Heart J Suppl 2004; 5(4):253–266. Italian. pmid:15346692
- 20↵Halliday BP, Wassall R, Lota AS, et al. Withdrawal of pharmacological treatment for heart failure in patients with recovered dilated cardiomyopathy (TRED-HF): an open-label, pilot, randomised trial. Lancet 2019; 393(10166):61–73. doi:10.1016/S0140-6736(18)32484-X
- 21↵Solomon SD, McMurray JJV, Claggett B, et al. Dapagliflozin in heart failure with mildly reduced or preserved ejection fraction. N Engl J Med 2022; 387(12):1089–1098. doi:10.1056/NEJMoa2206286
- 22↵Kodur N, Tang WHW. Management of heart failure with improved ejection fraction: current evidence and controversies. JACC Heart Fail 2025; 13(4):537–553. doi:10.1016/j.jchf.2025.02.007
- 23↵Chen X, Wu M. Heart failure with recovered ejection fraction: current understanding and future prospects. Am J Med Sci 2023; 365(1):1–8. doi:10.1016/j.amjms.2022.07.018
- 24↵Vardeny O, Miller R, Solomon SD. Combined neprilysin and reninangiotensin system inhibition for the treatment of heart failure. JACC Heart Fail 2014; 2(6):663–670. doi:10.1016/j.jchf.2014.09.001
- 25↵Allen LA, Stevenson LW, Grady KL, et al. Decision making in advanced heart failure: a scientific statement from the American Heart Association. Circulation 2012; 125(15):1928–1952. doi:10.1161/CIR.0b013e31824f2173
