Current Treatment of Heart Failure with Preserved Ejection Fraction
Abstract
1. Introduction
2. Sodium–Glucose Cotransporter-2 Inhibitors as First Pillar of HFpEF Treatment
3. Angiotensin Receptor–Neprilysin Inhibitors as an Integrated Therapy in Specific Settings
4. Glucagon-Like Peptide-1 Receptor Agonist as a Tailored Therapy for Obese HFpEF
5. Non-Steroidal Mineralocorticoid Receptor Antagonists as a New Frontier in HFpEF Treatment
6. Upfront Treatment Approach for HFpEF Patients
7. Future Perspectives
8. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
References
- Bozkurt, B.; Coats, A.J.S.; Tsutsui, H.; WRITING COMMITTEE MEMBERS. 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: Endorsed by the Canadian Heart Failure Society, Heart Failure Association of India, Cardiac Society of Australia and New Zealand, and Chinese Heart Failure Association. Eur. J. Heart Fail. 2021, 23, 352–380. [Google Scholar] [CrossRef]
- Riccardi, M.; Sammartino, A.M.; Piepoli, M.; Adamo, M.; Pagnesi, M.; Rosano, G.; Metra, M.; von Haehling, S.; Tomasoni, D. Heart failure: An update from the last years and a look at the near future. ESC Heart Fail. 2022, 9, 3667–3693. [Google Scholar] [CrossRef]
- Borlaug, B.A.; Sharma, K.; Shah, S.J.; Ho, J.E. Heart Failure With Preserved Ejection Fraction: JACC Scientific Statement. J. Am. Coll. Cardiol. 2023, 81, 1810–1834. [Google Scholar] [CrossRef]
- Redfield, M.M.; Borlaug, B.A. Heart Failure With Preserved Ejection Fraction: A Review. JAMA 2023, 329, 827–838. [Google Scholar] [CrossRef] [PubMed]
- Lam, C.S.P.; Docherty, K.F.; Ho, J.E.; McMurray, J.J.V.; Myhre, P.L.; Omland, T. Recent successes in heart failure treatment. Nat. Med. 2023, 29, 2424–2437. [Google Scholar] [CrossRef] [PubMed]
- McDonagh, T.A.; Metra, M.; Adamo, M.; Gardner, R.S.; Baumbach, A.; Böhm, M.; Burri, H.; Butler, J.; Čelutkienė, J.; Chioncel, O.; et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: Developed by the Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). With the special contribution of the Heart Failure Association (HFA) of the ESC. Eur. J. Heart Fail. 2022, 24, 4–131. [Google Scholar] [CrossRef] [PubMed]
- Heidenreich, P.A.; Bozkurt, B.; Aguilar, D.; Allen, L.A.; Byun, J.J.; Colvin, M.M.; Deswal, A.; Drazner, M.H.; Dunlay, S.M.; Evers, L.R.; 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. Circulation 2022, 145, e895–e1032. [Google Scholar] [CrossRef]
- Butler, J.; Shah, S.J.; Petrie, M.C.; Borlaug, B.A.; Abildstrøm, S.Z.; Davies, M.J.; Hovingh, G.K.; Kitzman, D.W.; Møller, D.V.; Verma, S.; et al. Semaglutide versus placebo in people with obesity-related heart failure with preserved ejection fraction: A pooled analysis of the STEP-HFpEF and STEP-HFpEF DM randomised trials. Lancet 2024, 403, 1635–1648. [Google Scholar] [CrossRef]
- Packer, M.; Zile, M.R.; Kramer, C.M.; Baum, S.J.; Litwin, S.E.; Menon, V.; Ge, J.; Weerakkody, G.J.; Ou, Y.; Bunck, M.C.; et al. Tirzepatide for Heart Failure with Preserved Ejection Fraction and Obesity. N. Engl. J. Med. 2024, 392, 427–437. [Google Scholar] [CrossRef]
- McDonagh, T.A.; Metra, M.; Adamo, M.; Gardner, R.S.; Baumbach, A.; Böhm, M.; Burri, H.; Butler, J.; Čelutkienė, J.; Chioncel, O.; et al. 2023 Focused Update of the 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur. Heart J. 2023, 44, 3627–3639. [Google Scholar] [CrossRef]
- Anker, S.D.; Butler, J.; Filippatos, G.; Ferreira, J.P.; Bocchi, E.; Böhm, M.; Brunner–La Rocca, H.-P.; Choi, D.-J.; Chopra, V.; Chuquiure-Valenzuela, E.; et al. Empagliflozin in Heart Failure with a Preserved Ejection Fraction. N. Engl. J. Med. 2021, 385, 1451–1461. [Google Scholar] [CrossRef] [PubMed]
- Solomon, S.D.; McMurray, J.J.; Claggett, B.; de Boer, R.A.; DeMets, D.; Hernandez, A.F.; Inzucchi, S.E.; Kosiborod, M.N.; Lam, C.S.; Martinez, F.; et al. Dapagliflozin in Heart Failure with Mildly Reduced or Preserved Ejection Fraction. N. Engl. J. Med. 2022, 387, 1089–1098. [Google Scholar] [CrossRef] [PubMed]
- Vaduganathan, M.; Docherty, K.F.; Claggett, B.L.; Jhund, P.S.; de Boer, R.A.; Hernandez, A.F.; Inzucchi, S.E.; Kosiborod, M.N.; Lam, C.S.P.; Martinez, F.; et al. SGLT-2 inhibitors in patients with heart failure: A comprehensive meta-analysis of five randomised controlled trials. Lancet 2022, 400, 757–767. [Google Scholar] [CrossRef] [PubMed]
- Butler, J.; Siddiqi, T.J.; Filippatos, G.; Ferreira, J.P.; Pocock, S.J.; Zannad, F.; Anker, S.D. Early benefit with empagliflozin in heart failure with preserved ejection fraction: Insights from the EMPEROR-Preserved trial. Eur. J. Heart Fail. 2022, 24, 245–248. [Google Scholar] [CrossRef]
- Vaduganathan, M.; Claggett, B.L.; Jhund, P.; de Boer, R.A.; Hernandez, A.F.; Inzucchi, S.E.; Kosiborod, M.N.; Lam, C.S.P.; Martinez, F.; Shah, S.J.; et al. Time to Clinical Benefit of Dapagliflozin in Patients With Heart Failure With Mildly Reduced or Preserved Ejection Fraction: A Prespecified Secondary Analysis of the DELIVER Randomized Clinical Trial. JAMA Cardiol. 2022, 7, 1259–1263. [Google Scholar] [CrossRef]
- Biegus, J.; Voors, A.A.; Collins, S.P.; Kosiborod, M.N.; Teerlink, J.R.; Angermann, C.E.; Tromp, J.; Ferreira, J.P.; Nassif, M.E.; Psotka, M.A.; et al. Impact of empagliflozin on decongestion in acute heart failure: The EMPULSE trial. Eur. Heart J. 2023, 44, 41–50. [Google Scholar] [CrossRef]
- Kosiborod, M.N.; Angermann, C.E.; Collins, S.P.; Teerlink, J.R.; Ponikowski, P.; Biegus, J.; Comin-Colet, J.; Ferreira, J.P.; Mentz, R.J.; Nassif, M.E.; et al. Effects of Empagliflozin on Symptoms, Physical Limitations, and Quality of Life in Patients Hospitalized for Acute Heart Failure: Results From the EMPULSE Trial. Circulation 2022, 146, 279–288. [Google Scholar] [CrossRef]
- Tromp, J.; Kosiborod, M.N.; Angermann, C.E.; Collins, S.P.; Teerlink, J.R.; Ponikowski, P.; Biegus, J.; Ferreira, J.P.; Nassif, M.E.; Psotka, M.A.; et al. Treatment effects of empagliflozin in hospitalized heart failure patients across the range of left ventricular ejection fraction–Results from the EMPULSE trial. Eur. J. Heart Fail. 2024, 26, 963–970. [Google Scholar] [CrossRef]
- Cox, Z.L.; Collins, S.P.; Hernandez, G.A.; McRae, A.T.; Davidson, B.T.; Adams, K.; Aaron, M.; Cunningham, L.; Jenkins, C.A.; Lindsell, C.J.; et al. Efficacy and Safety of Dapagliflozin in Patients With Acute Heart Failure. J. Am. Coll. Cardiol. 2024, 83, 1295–1306. [Google Scholar] [CrossRef]
- Inciardi, R.M.; Riccardi, M.; Savarese, G.; Metra, M.; Vaduganathan, M.; Solomon, S.D. Tailoring medical therapy for heart failure with preserved ejection fraction. Eur. J. Heart Fail. 2024, 27, 190–193. [Google Scholar] [CrossRef]
- Solomon, S.D.; McMurray, J.J.V.; Anand, I.S.; Junbo Ge, D.P.; Lam, C.S.P.; Maggioni, A.P.; Martinez, F.; Packer, M.; Pfeffer, M.A.; Pieske, B.; et al. Angiotensin-Neprilysin Inhibition in Heart Failure with Preserved Ejection Fraction. N. Engl. J. Med. 2019, 381, 1609–1620. [Google Scholar] [CrossRef]
- McMurray, J.J.V.; Jackson, A.M.; Lam, C.S.; Redfield, M.M.; Anand, I.S.; Ge, J.; Lefkowitz, M.P.; Maggioni, A.P.; Martinez, F.; Packer, M.; et al. Effects of Sacubitril-Valsartan Versus Valsartan in Women Compared With Men With Heart Failure and Preserved Ejection Fraction: Insights From PARAGON-HF. Circulation 2020, 141, 338–351. [Google Scholar] [CrossRef]
- Mentz, R.J.; Ward, J.H.; Hernandez, A.F.; Lepage, S.; Morrow, D.A.; Sarwat, S.; Sharma, K.; Starling, R.C.; Velazquez, E.J.; Williamson, K.M.; et al. Angiotensin-Neprilysin Inhibition in Patients With Mildly Reduced or Preserved Ejection Fraction and Worsening Heart Failure. J. Am. Coll. Cardiol. 2023, 82, 1–12. [Google Scholar] [CrossRef]
- Vaduganathan, M.; Mentz, R.J.; Claggett, B.L.; Miao, Z.M.; Kulac, I.J.; Ward, J.H.; Hernandez, A.F.; Morrow, D.A.; Starling, R.C.; Velazquez, E.J.; et al. Sacubitril/valsartan in heart failure with mildly reduced or preserved ejection fraction: A pre-specified participant-level pooled analysis of PARAGLIDE-HF and PARAGON-HF. Eur. Heart J. 2023, 44, 2982–2993. [Google Scholar] [CrossRef]
- Sattar, N.; Lee, M.M.Y.; Kristensen, S.L.; Branch, K.R.H.; Del Prato, S.; Khurmi, N.S.; Lam, C.S.P.; Lopes, R.D.; McMurray, J.J.V.; Pratley, R.E.; et al. Cardiovascular, mortality, and kidney outcomes with GLP-1 receptor agonists in patients with type 2 diabetes: A systematic review and meta-analysis of randomised trials. Lancet Diabetes Endocrinol. 2021, 9, 653–662. [Google Scholar] [CrossRef]
- Kosiborod, M.N.; Abildstrøm, S.Z.; Borlaug, B.A.; Butler, J.; Rasmussen, S.; Davies, M.; Hovingh, G.K.; Kitzman, D.W.; Lindegaard, M.L.; Møller, D.V.; et al. Semaglutide in Patients with Heart Failure with Preserved Ejection Fraction and Obesity. N. Engl. J. Med. 2023, 389, 1069–1084. [Google Scholar] [CrossRef]
- Kosiborod, M.N.; Petrie, M.C.; Borlaug, B.A.; Butler, J.; Davies, M.J.; Hovingh, G.K.; Kitzman, D.W.; Møller, D.V.; Treppendahl, M.B.; Verma, S.; et al. Semaglutide in Patients with Obesity-Related Heart Failure and Type 2 Diabetes. N. Engl. J. Med. 2024, 390, 1394–1407. [Google Scholar] [CrossRef] [PubMed]
- Petrie, M.C.; Borlaug, B.A.; Butler, J.; Davies, M.J.; Kitzman, D.W.; Shah, S.J.; Verma, S.; Jensen, T.J.; Einfeldt, M.N.; Liisberg, K.; et al. Semaglutide and NT-proBNP in Obesity-Related HFpEF: Insights From the STEP-HfpEF Program. J. Am. Coll. Cardiol. 2024, 84, 27–40. [Google Scholar] [CrossRef] [PubMed]
- Verma, S.; Butler, J.; Borlaug, B.A.; Davies, M.J.; Kitzman, D.W.; Petrie, M.C.; Shah, S.J.; Jensen, T.J.; Rasmussen, S.; Rönnbäck, C.; et al. Atrial Fibrillation and Semaglutide Effects in Obesity-Related Heart Failure With Preserved Ejection Fraction: STEP-HFpEF Program. J. Am. Coll. Cardiol. 2024, 84, 1603–1614. [Google Scholar] [CrossRef] [PubMed]
- Shah, S.J.; Sharma, K.; Borlaug, B.A.; Butler, J.; Davies, M.; Kitzman, D.W.; Petrie, M.C.; Verma, S.; Patel, S.; Chinnakondepalli, K.M.; et al. Semaglutide and diuretic use in obesity-related heart failure with preserved ejection fraction: A pooled analysis of the STEP-HFpEF and STEP-HFpEF-DM trials. Eur. Heart J. 2024, 45, 3254–3269. [Google Scholar] [CrossRef]
- Kosiborod, M.N.; Deanfield, J.; Pratley, R.; Borlaug, B.A.; Butler, J.; Davies, M.J.; Emerson, S.S.; Kahn, S.E.; Kitzman, D.W.; Lingvay, I.; et al. Semaglutide versus placebo in patients with heart failure and mildly reduced or preserved ejection fraction: A pooled analysis of the SELECT, FLOW, STEP-HFpEF, and STEP-HFpEF DM randomised trials. Lancet 2024, 404, 949–961. [Google Scholar] [CrossRef]
- Verma, S.; Petrie, M.C.; Borlaug, B.A.; Butler, J.; Davies, M.J.; Kitzman, D.W.; Shah, S.J.; Rönnbäck, C.; Abildstrøm, S.Z.; Liisberg, K.; et al. Inflammation in Obesity-Related HFpEF: The STEP-HFpEF Program. J. Am. Coll. Cardiol. 2024, 84, 1646–1662. [Google Scholar] [CrossRef]
- Zile, M.R.; Borlaug, B.A.; Kramer, C.M.; Baum, S.J.; Litwin, S.E.; Menon, V.; Ou, Y.; Weerakkody, G.J.; Hurt, K.C.; Kanu, C.; et al. Effects of Tirzepatide on the Clinical Trajectory of Patients with Heart Failure, a Preserved Ejection Fraction, and Obesity. Circulation 2024, 151, 10. [Google Scholar] [CrossRef] [PubMed]
- Borlaug, B.A.; Zile, M.R.; Kramer, C.M.; Baum, S.J.; Hurt, K.; Litwin, S.E.; Murakami, M.; Ou, Y.; Upadhyay, N.; Packer, M. Effects of tirzepatide on circulatory overload and end-organ damage in heart failure with preserved ejection fraction and obesity: A secondary analysis of the SUMMIT trial. Nat. Med. 2024, 31, 544–551. [Google Scholar] [CrossRef] [PubMed]
- Kramer, C.M.; Borlaug, B.A.; Zile, M.R.; Ruff, D.; DiMaria, J.M.; Menon, V.; Ou, Y.; Zarante, A.M.; Hurt, K.C.; Murakami, M.; et al. Tirzepatide Reduces LV Mass and Paracardiac Adipose Tissue in Obesity-Related Heart Failure: SUMMIT CMR Substudy. J. Am. Coll. Cardiol. 2025, 85, 699–706. [Google Scholar] [CrossRef] [PubMed]
- Pitt, B.; Pfeffer, M.A.; Assmann, S.F.; Boineau, R.; Anand, I.S.; Claggett, B.; Clausell, N.; Desai, A.S.; Diaz, R.; Fleg, J.L.; et al. Spironolactone for heart failure with preserved ejection fraction. N. Engl. J. Med. 2014, 370, 1383–1392. [Google Scholar] [CrossRef]
- Agarwal, R.; Filippatos, G.; Pitt, B.; Anker, S.D.; Rossing, P.; Joseph, A.; Kolkhof, P.; Nowack, C.; Gebel, M.; Ruilope, L.M.; et al. Cardiovascular and kidney outcomes with finerenone in patients with type 2 diabetes and chronic kidney disease: The FIDELITY pooled analysis. Eur. Heart J. 2022, 43, 474–484. [Google Scholar] [CrossRef]
- Vaduganathan, M.; Claggett, B.L.; Lam, C.S.; Pitt, B.; Senni, M.; Shah, S.J.; Voors, A.A.; Zannad, F.; Desai, A.S.; Jhund, P.S.; et al. Finerenone in patients with heart failure with mildly reduced or preserved ejection fraction: Rationale and design of the FINEARTS-HF trial. Eur. J. Heart Fail. 2024, 26, 1324–1333. [Google Scholar] [CrossRef]
- Solomon, S.D.; McMurray, J.J.; Vaduganathan, M.; Claggett, B.; Jhund, P.S.; Desai, A.S.; Henderson, A.D.; Lam, C.S.; Pitt, B.; Senni, M.; et al. Finerenone in Heart Failure with Mildly Reduced or Preserved Ejection Fraction. N. Engl. J. Med. 2024, 391, 1475–1485. [Google Scholar] [CrossRef]
- Vaduganathan, M.; Claggett, B.L.; Desai, A.S.; Jhund, P.S.; Lam, C.S.P.; Senni, M.; Shah, S.J.; Voors, A.A.; Zannad, F.; Pitt, B.; et al. Estimated Long-Term Benefits of Finerenone in Heart Failure: A Prespecified Secondary Analysis of the FINEARTS-HF Randomized Clinical Trial. JAMA Cardiol. 2024, 10, 176–181. [Google Scholar] [CrossRef]
- Docherty, K.F.; Henderson, A.D.; Jhund, P.S.; Claggett, B.L.; Desai, A.S.; Mueller, K.; Viswanathan, P.; Scalise, A.; Lam, C.S.; Senni, M.; et al. Efficacy and Safety of Finerenone Across the Ejection Fraction Spectrum in Heart Failure With Mildly Reduced or Preserved Ejection Fraction: A Prespecified Analysis of the FINEARTS-HF Trial. Circulation 2025, 151, 45–58. [Google Scholar] [CrossRef]
- Chimura, M.; Wang, X.; Jhund, P.S.; Henderson, A.D.; Claggett, B.L.; Desai, A.S.; Fonseca, C.; Goncalvesova, E.; Katova, T.; Mueller, K.; et al. Finerenone in Women and Men With Heart Failure With Mildly Reduced or Preserved Ejection Fraction: A Secondary Analysis of the FINEARTS-HF Randomized Clinical Trial. JAMA Cardiol. 2024, 10, 59–70. [Google Scholar] [CrossRef] [PubMed]
- Vardeny, O.; Vaduganathan, M.; Claggett, B.L.; Desai, A.S.; Jhund, P.S.; Lam, C.S.P.; Senni, M.; Shah, S.J.; Voors, A.A.; Zannad, F.; et al. Finerenone, Serum Potassium, and Clinical Outcomes in Heart Failure With Mildly Reduced or Preserved Ejection Fraction. JAMA Cardiol. 2024, 10, 12–18. [Google Scholar] [CrossRef] [PubMed]
- Mc Causland, F.R.; Vaduganathan, M.; Claggett, B.L.; Kulac, I.J.; Desai, A.S.; Jhund, P.S.; Henderson, A.D.; Brinker, M.; Perkins, R.; Scheerer, M.F.; et al. Finerenone and Kidney Outcomes in Patients with Heart Failure: The FINEARTS-HF Trial. J. Am. Coll. Cardiol. 2024, 85, 2. [Google Scholar] [CrossRef]
- Vaduganathan, M.; Claggett, B.L.; Kulac, I.J.; Miao, Z.M.; Desai, A.S.; Jhund, P.S.; Henderson, A.D.; Brinker, M.; Lay-Flurrie, J.; Viswanathan, P.; et al. Effects of the Non-Steroidal MRA Finerenone with and without Concomitant SGLT2 Inhibitor Use in Heart Failure. Circulation 2024, 151, 2. [Google Scholar] [CrossRef]
- Kittleson, M.M.; Panjrath, G.S.; Amancherla, K.; Davis, L.L.; Deswal, A.; Dixon, D.L.; Januzzi, J.L.; Yancy, C.W. 2023 ACC Expert Consensus Decision Pathway on Management of Heart Failure With Preserved Ejection Fraction: A Report of the American College of Cardiology Solution Set Oversight Committee. J. Am. Coll. Cardiol. 2023, 81, 1835–1878. [Google Scholar] [CrossRef]
- Kondo, T.; Henderson, A.D.; Docherty, K.F.; Jhund, P.S.; Vaduganathan, M.; Solomon, S.D.; McMurray, J.J. Why Have We Not Been Able to Demonstrate Reduced Mortality in Patients With HFmrEF/HFpEF? J. Am. Coll. Cardiol. 2024, 84, 2233–2240. [Google Scholar] [CrossRef]
- von Haehling, S.; Doehner, W.; Evertz, R.; Garfias-Veitl, T.; Derad, C.; Diek, M.; Karakas, M.; Birkemeyer, R.; Fillippatos, G.; Lainscak, M.; et al. Ferric carboxymaltose and exercise capacity in heart failure with preserved ejection fraction and iron deficiency: The FAIR-HFpEF trial. Eur. Heart J. 2024, 45, 3789–3800. [Google Scholar] [CrossRef]
- Byrne, R.A.; Rossello, X.; Coughlan, J.J.; Barbato, E.; Berry, C.; Chieffo, A.; Claeys, M.J.; Dan, G.-A.; Dweck, M.R.; Galbraith, M.; et al. 2023 ESC Guidelines for the management of acute coronary syndromes. Eur. Heart J. 2023, 44, 3720–3826. [Google Scholar] [CrossRef]
- Vrints, C.; Andreotti, F.; Koskinas, K.C.; Rossello, X.; Adamo, M.; Ainslie, J.; Banning, A.P.; Budaj, A.; Buechel, R.R.; Chiariello, G.A.; et al. 2024 ESC Guidelines for the management of chronic coronary syndromes. Eur. Heart J. 2024, 45, 3415–3537. [Google Scholar] [CrossRef]
- Shah, S.J.; Rigolli, M.; Javidialsaadi, A.; Patel, R.B.; Khadra, S.; Goyal, P.; Little, S.; Wever-Pinzon, O.; Owens, A.T.; Skali, H.; et al. Cardiac Myosin Inhibition in Heart Failure with Normal and Supranormal Ejection Fraction. JAMA Cardiol. 2024, 10, 170–175. [Google Scholar] [CrossRef]
- Kalra, P.R.; Cleland, J.G.F.; Petrie, M.C.; Thomson, E.A.; Kalra, P.A.; Squire, I.B.; Ahmed, F.Z.; Al-Mohammad, A.; Cowburn, P.J.; Foley, P.W.X.; et al. Intravenous ferric derisomaltose in patients with heart failure and iron deficiency in the UK (IRONMAN): An investigator-initiated, prospective, randomised, open-label, blinded-endpoint trial. Lancet 2022, 400, 2199–2209. [Google Scholar] [CrossRef]
DELIVER | EMPEROR-Preserved | Pooled PARAGON-HF/PARAGLIDE-HF | STEP-HFpEF | STEP-HFpEF DM | FINEARTS-HF | SUMMIT | |
---|---|---|---|---|---|---|---|
Size | N = 6263 | N = 5988 | N = 5262 | N = 529 | N = 616 | N = 6001 | N = 731 |
Agent | Dapagliflozin | Empagliflozin | Sacubitril/valsartan | Semaglutide | Semaglutide | Finerenone | Tirzepatide |
Age, year | 72 | 72 | 72 | 69 | 69 | 72 | 65 |
Baseline EF (%) | 54 | 54 | 57 | 57 | 56 | 53 | 61 |
Primary outcome | Worsening HF and CV death: HR 0.82 (95% CI 0.73–0.92) | Hospitalization for HF and CV death: HR: 0.79 (95% CI 0.69–0.90) | Total hospitalizations for HF and CV death: RR 0.86 (95% CI 0.75–0.98) | Change in KCCQ-CSS (difference 7.8 points; 95% CI 4.8–10.9) and change in body weight (difference −10.7%, 95% CI −11.9–−9.4) | Change in KCCQ-CSS (difference 7.3 points; 95% CI 4.1–10.4) and change in body weight (difference −6.4%, 95% CI −7.6–−5.2) | Total worsening HF events and CV death: RR 0.84 (95% CI 0.74–0.95) | A composite of death from cardiovascular causes or a worsening heart-failure event, and the change at 52 weeks in the KCCQ-CSS |
Hospitalization for HF | HR 0.77 (95% CI 0.67–0.89) | HR 0.71 (95% CI 0.60–0.83) | - | HR 0.08 (95% CI 0.00–0.42) | HR 0.40 (95% CI 0.15–0.92 | RR 0.82 (95% CI 0.71–0.94) | HR 0.44 (95% CI 0.22–0.87) |
CV death | HR 0.88 (95% CI 0.74–1.05) | HR 0.91 (95% CI 0.76–1.09) | HR 0.93 (95% CI 0.77–1.12) | - | - | HR 0.93 (95% CI 0.78–1.11) | HR 1.58 (95% CI 0.52–4.83) |
Abbreviations: CI, Confidence Interval; CV, Cardiovascular; EF, Ejection Fraction; HF, Heart Failure; HR, Hazard ratio; KCCQ-CSS, Kansan City Cardiomyopathy Questionnaire—Clinical Summary Score; NR, Not Reported; RR, Rate Ratio. | DELIVER (Dapagliflozin vs. Placebo) | EMPEROR-Preserved (Empagliflozin vs. Placebo) | Pooled PARAGON-HF/ PARAGLIDE-HF (Sacubitril/Valsartan vs. Valsartan) | STEP-HFpEF (Semaglutide vs. Placebo) | STEP-HFpEF DM (Semaglutide vs. Placebo) | FINEARTS-HF (Finerenone vs. Placebo) | SUMMIT (Tirzepatide vs. Placebo) |
---|---|---|---|---|---|---|---|
Any Serious AEs (%) | 43.5 vs. 45.5 | 47.9 vs. 51.6 | - | 13.3 vs. 26.7 | 17.7 vs. 28.8 | 38.7 vs. 40.5 | 26.4 vs. 25.6 |
Hypotension | - | 6.6 vs. 5.2 | 23.4 vs. 16.9 | - | - | 18.5 vs. 12.4 | 6.0 vs. 3.0 |
Renal adverse events | 2.3 vs. 2.5 | 12.1 vs. 12.8 | 2.2 vs. 3.7 | 2.3 vs. 1.5 | 0.6 vs. 2.6 | 2.0 vs. 1.2 | 1.4 vs. 0.8 |
Hypoglycemic events | - | 2.4 vs. 2.6 | - | - | - | - | |
Hyperkaliemia (≥5.5 mEq/L) | - | - | 18.5 vs. 18.1 | - | - | 14.3 vs. 6.9 | |
Lower Limb Amputation | - | 0.5 vs. 0.8 | - | - | - | - | |
Gastrointestinal disorder | - | - | - | 2.7 vs. 2.6 | 1.6 vs. 1.6 | - | Diarrhea 18.6 vs. 6.3 Vomiting 10.4 vs. 2.2 |
Urinary tract infections | 1 vs. 1 | 9.9 vs. 8.1 | - | - | - | - | 1.4 vs. 0.3 |
Genital infections | - | 2.2 vs. 0.7 | - | - | - | - | - |
AEs leading to treatment discontinuation (%) | 5.8 vs. 5.8 | 19.1 vs. 18.4 | - | 2.3 vs. 2.3 | 1.9 vs. 3.6 | - | 6.3 vs. 1.4 |
Trial | Registration Number | Trial Design | Arms | Estimate Enrolment | Primary Endpoint |
---|---|---|---|---|---|
SPIRIT-HF | NCT04727073 | Randomized | Spironolactone vs. Placebo | N = 1300 | Cumulative number of primary composite events of CV death and total HFH |
SPIRRIT-HFpEF | NCT02901184 | Randomized | Spironolactone vs. standard care | N = 2000 | Incidence rate for total HFH or CV death |
HERMES | NCT06200207 | Randomized | Ziltivekimab vs. Placebo | N = 680 | A composite of CV death, HFH or urgent HF visit |
RENEU-HF | NCT06369298 | Randomized | JK07 vs. Placebo | N = 282 | Safety and efficacy |
CARE-Preserved HF | NCT05553314 | Randomized | Carvedilol vs. Placebo | N = 100 | Change in NT-proBNP and GLS |
CADENCE | NCT04945460 | Randomized | Sotatercept vs. Placebo | N = 150 | Change in PVR |
IMPROVE-DiCE | NCT04826159 | Single-group | IMB-1018972 | N = 50 | Cardiac energetic reserve at rest and during stress |
AURORA-HFpEF | NCT06122779 | Randomized | BMS-986435 vs. Placebo | N = 48 | Safety and tolerability |
SOTA-P-CARDIA | NCT05562063 | Randomized | Sotagliflozin vs. Placebo | N = 100 | Change in LV mass in cardiac magnetic resonance |
Low Dose Colchicine among Patients With Chronic Stable HFpEF and Systemic Inflammation | NCT06130059 | Randomized | Low-dose colchicine vs. Placebo | N = 60 | Change in VO2 peak indexed to body weight |
Colchicine in Patients With Heart Failure and Preserved Left Ventricular Ejection Fraction | NCT05637398 | Randomized | Colchicine vs. Placebo | N = 40 | Change in sST2 |
Efficacy and Safety of LY3540378 in Adults With Worsening Chronic Heart Failure With Preserved Ejection Fraction | NCT05592275 | Randomized | LY3540378 vs. Placebo | N = 432 | Change in LA Reservoir Strain |
IRONMET HFpEF | NCT04945707 | Randomized | Ferric Derisomaltose vs. Placebo | N = 66 | Change in VO2 peak |
COREVIVE-HFpEF | NCT05991128 | Randomized | Ferric Derisomaltose vs. Placebo | N = 170 | Change in 6MWD |
Cycle-2-PEF | NCT06215586 | Randomized | Tovinontrine vs. Placebo | N = 240 | Change in NT-proBNP |
INABLE-Training | NCT02713126 | Randomized | Sodium nitrite vs. placebo | N = 92 | Change in VO2 peak |
KNO3CK OUT HFpEF | NCT02840799 | Randomized | Potassium nitrate vs. potassium chloride | N = 84 | Change in VO2 peak |
EASi-HF | NCT06424288 | Randomized | Vicadrostat + empagliflozin vs. placebo | N = 6000 | Time to first event of CV death or HFH |
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content. |
© 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Riccardi, M.; D’Elia, E.; Lombardi, C.M.; Savarese, G.; Gori, M.; Oliva, F.; Volterrani, M.; Senni, M.; Metra, M.; Inciardi, R.M. Current Treatment of Heart Failure with Preserved Ejection Fraction. J. Clin. Med. 2025, 14, 5406. https://doi.org/10.3390/jcm14155406
Riccardi M, D’Elia E, Lombardi CM, Savarese G, Gori M, Oliva F, Volterrani M, Senni M, Metra M, Inciardi RM. Current Treatment of Heart Failure with Preserved Ejection Fraction. Journal of Clinical Medicine. 2025; 14(15):5406. https://doi.org/10.3390/jcm14155406
Chicago/Turabian StyleRiccardi, Mauro, Emilia D’Elia, Carlo M. Lombardi, Gianluigi Savarese, Mauro Gori, Fabrizio Oliva, Maurizio Volterrani, Michele Senni, Marco Metra, and Riccardo M. Inciardi. 2025. "Current Treatment of Heart Failure with Preserved Ejection Fraction" Journal of Clinical Medicine 14, no. 15: 5406. https://doi.org/10.3390/jcm14155406
APA StyleRiccardi, M., D’Elia, E., Lombardi, C. M., Savarese, G., Gori, M., Oliva, F., Volterrani, M., Senni, M., Metra, M., & Inciardi, R. M. (2025). Current Treatment of Heart Failure with Preserved Ejection Fraction. Journal of Clinical Medicine, 14(15), 5406. https://doi.org/10.3390/jcm14155406