Advances in Heart Failure with Preserved Ejection Fraction Management -
The Role of Sacubitril-Valsartan, Pirfenidone, Spironolactone and Empagliflozin:
Is Success a Series of Small Victories?

Georgios      Giannopoulos; Maria      Kousta; Ioannis      Anagnostopoulos; Sofia      Karageorgiou; Evangelia      Myrovali; Gerasimos      Deftereos; Nikolaos      Fragakis; Gerasimos      Siasos; Vassilios   P.   Vassilikos

doi:10.2174/1381612829666230202141437

Abstract

Background: Heart failure with preserved ejection fraction (HFpEF) is a syndrome characterized by marked heterogeneity in comorbidities and etiopathology substrates, leading to a diverse range of clinical manifestations and courses. Treatment options have been extremely limited and up to this day, there are virtually no pharmaceutical agents proven to reduce mortality in these patients.

Objective: The primary objective of this narrative review is to critically summarize existing evidence regarding the use of Angiotensin Receptor-Neprilysin Inhibitor (ARNI), spironolactone, pirfenidone and empagliflozin in HFpEF.

Methods: Medline (via PubMed) and Scopus were searched - from inception up to May 2022- using adequately selected keywords. Additional hand-search was also performed using the references of the articles identified as relevant (snowball strategy).

Results: Angiotensin Receptor-Neprilysin Inhibitor (ARNI) and spironolactone, despite being very successful in HFrEF, did not do well in clinical trials of HFpEF, although there appear to be certain subsets of patients who may derive benefit. Data regarding pirfenidone are limited and come from small trials; as a result, it would be premature to draw firm conclusions, although it seems improbable that this agent will ever become a mainstay in the general population of HFpEF patients, while there may be a niche for the drug in individuals with comorbidities associated with an intense fibrotic activity. Finally, empagliflozin, largely welcomed as the first agent to have a “positive” randomized clinical trial in HFpEF, does not seem to evade the general pattern of reduced hospitalizations for HF with no substantial effect on mortality, seen in ARNI and spironolactone HFpEF trials.

Conclusion: Recent research in drug treatment for HFpEF has resulted in an overall mixed picture, with trials showing potential benefits from certain classes of drugs, such as sodium-glucose co-transporter 2 inhibitors, and no benefit from other drugs, which have shown to be effective in patients with reduced ejection fraction. However, small steps may be the way to go in HFpEF, and success is sometimes just a series of small victories.

« Previous Next »

[1]
Ambrosy AP, Fonarow GC, Butler J, et al. The global health and economic burden of hospitalizations for heart failure: Lessons learned from hospitalized heart failure registries. J Am Coll Cardiol  2014; 63(12): 1123-33.
 [http://dx.doi.org/10.1016/j.jacc.2013.11.053] [PMID: 24491689]

[2]
McDonagh TA, Metra M, Adamo M, et al. 2021 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure. Eur Heart J  2021; 42(36): 3599-726.
 [http://dx.doi.org/10.1093/eurheartj/ehab368] [PMID: 34447992]

[3]
Bleumink G, Knetsch A, Sturkenboom M, et al. Quantifying the heart failure epidemic: Prevalence, incidence rate, lifetime risk and prognosis of heart failure: The rotterdam study.  Eur Heart J  2004; 25(18): 1614-9.
 [http://dx.doi.org/10.1016/j.ehj.2004.06.038] [PMID: 15351160]

[4]
Pfeffer MA, Swedberg K, Granger CB, et al. Effects of candesartan on mortality and morbidity in patients with chronic heart failure: The CHARM-Overall programme. Lancet  2003; 362(9386): 759-66.
 [http://dx.doi.org/10.1016/S0140-6736(03)14282-1] [PMID: 13678868]

[5]
Pieske B, Tschöpe C, de Boer RA, et al. How to diagnose heart failure with preserved ejection fraction: the HFA–PEFF diagnostic algorithm: A consensus recommendation from the Heart Failure Association (HFA) of the European Society of Cardiology (ESC). Eur Heart J  2019; 40(40): 3297-317.
 [http://dx.doi.org/10.1093/eurheartj/ehz641] [PMID: 31504452]

[6]
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. Circulation  2022; 145(18): e895-e1032.
 [http://dx.doi.org/10.1161/CIR.0000000000001063] [PMID: 35363499]

[7]
Meier ML, Pierce KN. New therapies for the treatment of heart failure with preserved ejection fraction. Am J Health Syst Pharm  2022; 79(17): 1424-30.
 [http://dx.doi.org/10.1093/ajhp/zxac129] [PMID: 35524990]

[8]
McMurray JJ, Packer M, Desai AS, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med  2014; 371: 993-1004.

[9]
Mullens W, Martens P. Exploiting the natriuretic peptide pathway to preserve glomerular filtration in heart failure. JACC Heart Fail  2018; 6(6): 499-502.
 [http://dx.doi.org/10.1016/j.jchf.2018.02.017] [PMID: 29655826]

[10]
Obtułowicz K. Bradykinin-mediated angioedema. Pol Arch Med Wewn  2016; 126(1-2): 76-85.
 [PMID: 26842379]

[11]
Vasquez N, Carter S, Grodin JL. Angiotensin receptor–neprilysin inhibitors and the natriuretic peptide axis. Curr Heart Fail Rep  2020; 17(3): 67-76.
 [http://dx.doi.org/10.1007/s11897-020-00458-y] [PMID: 32394149]

[12]
Velazquez EJ, Morrow DA, DeVore AD, et al. Angiotensin–neprilysin inhibition in acute decompensated heart failure. N Engl J Med  2019; 380(6): 539-48.
 [http://dx.doi.org/10.1056/NEJMoa1812851] [PMID: 30415601]

[13]
Solomon SD, Vaduganathan M, L Claggett B, et al. Sacubitril/valsartan across the spectrum of ejection fraction in heart failure. Circulation  2020; 141(5): 352-61.
 [http://dx.doi.org/10.1161/CIRCULATIONAHA.119.044586] [PMID: 31736342]

[14]
Solomon SD, Zile M, Pieske B, et al. The angiotensin receptor neprilysin inhibitor LCZ696 in heart failure with preserved ejection fraction: A phase 2 double-blind randomised controlled trial. Lancet  2012; 380(9851): 1387-95.
 [http://dx.doi.org/10.1016/S0140-6736(12)61227-6] [PMID: 22932717]

[15]
Solomon SD, McMurray JJV, Anand IS, et al. Angiotensin–neprilysin inhibition in heart failure with preserved ejection fraction. N Engl J Med  2019; 381(17): 1609-20.
 [http://dx.doi.org/10.1056/NEJMoa1908655] [PMID: 31475794]

[16]
Cikes M, Planinc I, Claggett B, et al. Atrial fibrillation in heart failure with preserved ejection fraction. JACC Heart Fail  2022; 10(5): 336-46.
 [http://dx.doi.org/10.1016/j.jchf.2022.01.018] [PMID: 35483796]

[17]
Jia R, Zhang X, Xu Y, et al. Effect of Sacubitril/Valsartan on renal function in patients with chronic kidney disease and heart failure with preserved ejection fraction: A real-world 12-week study. Eur J Pharmacol  2022; 928: 175053.
 [http://dx.doi.org/10.1016/j.ejphar.2022.175053] [PMID: 35709921]

[18]
Malik J, Shahid AW, Shah M, Rana G, Kamal A, Naeem H. Outcome of angiotensin receptor-neprilysin inhibitor on anxiety and depression in heart failure with reduced ejection fraction vs. heart failure with preserved ejection fraction. J Community Hosp Intern Med Perspect  2021; 11(5): 629-34.
 [http://dx.doi.org/10.1080/20009666.2021.1942623] [PMID: 34567453]

[19]
Vaz-Salvador P, Adão R, Vasconcelos I, Leite-Moreira AF, Brás-Silva C. Heart failure with preserved ejection fraction: A pharmacotherapeutic update.  Cardiovasc Drugs Ther 2022; 1-8. 
 [http://dx.doi.org/10.1007/s10557-021-07306-8] [PMID: 35098432]

[20]
Bouros D. Pirfenidone for idiopathic pulmonary fibrosis. Lancet  2011; 377(9779): 1727-9.
 [http://dx.doi.org/10.1016/S0140-6736(11)60546-1] [PMID: 21571363]

[21]
Nathan SD, Albera C, Bradford WZ, et al. Effect of pirfenidone on mortality: Pooled analyses and meta-analyses of clinical trials in idiopathic pulmonary fibrosis. Lancet Respir Med  2017; 5(1): 33-41.
 [http://dx.doi.org/10.1016/S2213-2600(16)30326-5] [PMID: 27876247]

[22]
Strieter RM, Mehrad B. New mechanisms of pulmonary fibrosis. Chest  2009; 136(5): 1364-70.
 [http://dx.doi.org/10.1378/chest.09-0510] [PMID: 19892675]

[23]
Cottin V, Koschel D, Günther A, et al. Long-term safety of pirfenidone: Results of the prospective, observational passport study. ERJ Open Res  2018; 4(4): 00084-2018.
 [http://dx.doi.org/10.1183/23120541.00084-2018] [PMID: 30364407]

[24]
Oku H, Shimizu T, Kawabata T, et al. Antifibrotic action of pirfenidone and prednisolone: Different effects on pulmonary cytokines and growth factors in bleomycin-induced murine pulmonary fibrosis. Eur J Pharmacol  2008; 590(1-3): 400-8.
 [http://dx.doi.org/10.1016/j.ejphar.2008.06.046] [PMID: 18598692]

[25]
Aimo A, Cerbai E, Bartolucci G, et al. Pirfenidone is a cardioprotective drug: Mechanisms of action and preclinical evidence. Pharmacol Res  2020; 155: 104694.
 [http://dx.doi.org/10.1016/j.phrs.2020.104694] [PMID: 32061664]

[26]
Shi Q, Liu X, Bai Y, et al. In vitro effects of pirfenidone on cardiac fibroblasts: proliferation, myofibroblast differentiation, migration and cytokine secretion. PLoS One  2011; 6(11): e28134.
 [http://dx.doi.org/10.1371/journal.pone.0028134] [PMID: 22132230]

[27]
Hisatomi K, Mukae H, Sakamoto N, et al. Pirfenidone inhibits TGF-β1-induced over-expression of collagen type I and heat shock protein 47 in A549 cells. BMC Pulm Med  2012; 12(1): 24.
 [http://dx.doi.org/10.1186/1471-2466-12-24] [PMID: 22694981]

[28]
Lewis GA, Schelbert EB, Naish JH, et al. Pirfenidone in heart failure with preserved ejection fraction—rationale and design of the PIROUETTE trial. Cardiovasc Drugs Ther  2019; 33(4): 461-70.
 [http://dx.doi.org/10.1007/s10557-019-06876-y] [PMID: 31069575]

[29]
Al-Ansari S, Borowski A, Fuad A, et al. Effects of pirfenidone on echocardiographic parameters of left ventricular structure and function in patients with idiopathic pulmonary fibrosis. J Interdiscip Med  2020; 5(2): 35-42.
 [http://dx.doi.org/10.2478/jim-2020-0009]

[30]
Pitt B, Zannad F, Remme WJ, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. N Engl J Med  1999; 341(10): 709-17.
 [http://dx.doi.org/10.1056/NEJM199909023411001] [PMID: 10471456]

[31]
Zannad F, McMurray JJV, Krum H, et al. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med  2011; 364(1): 11-21.
 [http://dx.doi.org/10.1056/NEJMoa1009492] [PMID: 21073363]

[32]
McDonagh TA, Metra M, Adamo M, 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. Rev Esp Cardiol (Engl Ed)  2022; 75(6): 523.
 [http://dx.doi.org/10.1016/j.rec.2022.05.005] [PMID: 35636830]

[33]
Edelmann F, Wachter R, Schmidt AG, et al. Effect of spironolactone on diastolic function and exercise capacity in patients with heart failure with preserved ejection fraction: The Aldo-DHF randomized controlled trial. JAMA  2013; 309(8): 781-91.
 [http://dx.doi.org/10.1001/jama.2013.905] [PMID: 23443441]

[34]
Choy M, Liang W, He J, et al. Phenotypes of heart failure with preserved ejection fraction and effect of spironolactone treatment. ESC Heart Fail  2022; 9(4): 2567-75.
 [http://dx.doi.org/10.1002/ehf2.13969] [PMID: 35587714]

[35]
Elkholey K, Papadimitriou L, Butler J, Thadani U, Stavrakis S. Effect of obesity on response to spironolactone in patients with heart failure with preserved ejection fraction. Am J Cardiol  2021; 146: 36-47.
 [http://dx.doi.org/10.1016/j.amjcard.2021.01.018] [PMID: 33529620]

[36]
Beldhuis IE, Myhre PL, Bristow M, et al. Spironolactone in patients with heart failure, preserved ejection fraction, and worsening renal function. J Am Coll Cardiol  2021; 77(9): 1211-21.
 [http://dx.doi.org/10.1016/j.jacc.2020.12.057] [PMID: 33663739]

[37]
Shantsila E, Shahid F, Sun Y, et al. Spironolactone in atrial fibrillation with preserved cardiac fraction: The IMPRESS-AF trial. J Am Heart Assoc  2020; 9(18): e016239.
 [http://dx.doi.org/10.1161/JAHA.119.016239] [PMID: 32909497]

[38]
Rieg T, Vallon V. Development of SGLT1 and SGLT2 inhibitors. Diabetologia  2018; 61(10): 2079-86.
 [http://dx.doi.org/10.1007/s00125-018-4654-7] [PMID: 30132033]

[39]
McMurray JJ, Solomon SD, Inzucchi SE, et al. Dapagliflozin in patients with heart failure and reduced ejection fraction.  N Engl J Med  2019; 381: 1995-2008.

[40]
Lopaschuk GD, Verma S. Mechanisms of cardiovascular benefits of sodium glucose Co-Transporter 2 (SGLT2) inhibitors. JACC Basic Transl Sci  2020; 5(6): 632-44.
 [http://dx.doi.org/10.1016/j.jacbts.2020.02.004] [PMID: 32613148]

[41]
Packer M, Anker SD, Butler J, et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med  2020; 383(15): 1413-24.
 [http://dx.doi.org/10.1056/NEJMoa2022190] [PMID: 32865377]

[42]
Jackson AM, Dewan P, Anand IS, et al. Dapagliflozin and diuretic use in patients with heart failure and reduced ejection fraction in DAPA-HF. Circulation  2020; 142(11): 1040-54.
 [http://dx.doi.org/10.1161/CIRCULATIONAHA.120.047077] [PMID: 32673497]

[43]
Anker SD, Butler J, Filippatos G, et al. Empagliflozin in heart failure with a preserved ejection fraction. N Engl J Med  2021; 385(16): 1451-61.
 [http://dx.doi.org/10.1056/NEJMoa2107038] [PMID: 34449189]

[44]
Butler J, Filippatos G, Jamal Siddiqi T, et al. Empagliflozin, health status, and quality of life in patients with heart failure and preserved ejection fraction: The emperor-preserved trial. Circulation  2022; 145(3): 184-93.
 [http://dx.doi.org/10.1161/CIRCULATIONAHA.121.057812] [PMID: 34779658]

[45]
Packer M, Anker SD, Butler J, et al. Effect of empagliflozin on the clinical stability of patients with heart failure and a reduced ejection fraction. Circulation  2021; 143(4): 326-36.
 [http://dx.doi.org/10.1161/CIRCULATIONAHA.120.051783] [PMID: 33081531]

[46]
Butler J, Packer M, Filippatos G, et al. Effect of empagliflozin in patients with heart failure across the spectrum of left ventricular ejection fraction. Eur Heart J  2022; 43(5): 416-24.
 [http://dx.doi.org/10.1093/eurheartj/ehab798] [PMID: 34878502]

[47]
Heath R, Johnsen H, Strain WD, Evans M. Emerging horizons in heart failure with preserved ejection fraction: The role of SGLT2 inhibitors. Diabetes Ther  2022; 13(2): 241-50.
 [http://dx.doi.org/10.1007/s13300-022-01204-4] [PMID: 35084695]

[48]
Böhm M, Butler J, Filippatos G, et al. Empagliflozin improves outcomes in patients with heart failure and preserved ejection fraction irrespective of age. J Am Coll Cardiol  2022; 80(1): 1-18.
 [http://dx.doi.org/10.1016/j.jacc.2022.04.040] [PMID: 35772911]

Rights & Permissions Print Cite

Journal Information

For Authors

For Editors

For Reviewers

Explore Articles

Open Access

Open Access Articles

For Visitors

DOI https://dx.doi.org/10.2174/1381612829666230202141437	Print ISSN 1381-6128
Publisher Name Bentham Science Publisher	Online ISSN 1873-4286

Current Pharmaceutical Design

Advances in Heart Failure with Preserved Ejection Fraction Management - The Role of Sacubitril-Valsartan, Pirfenidone, Spironolactone and Empagliflozin: Is Success a Series of Small Victories?

Abstract Play Pause

Related Journals

Related Books

Abstract