New Clinical Aspects of Eplerenone Use in Clinical Practice
Abstract
The problem of the discrepancy between convincing evidences of the effectiveness of the use of mineralocorticoid receptor antagonists in patients with heart failure with reduced left ventricular ejection fraction and insufficiently frequent their use in clinical practice for the treatment of these patients is considered in the article. Experts opinions on the reasons for this discrepancy are also presented. New data on the effectiveness of the use of the mineralocorticoid receptor antagonist, eplerenone, in some clinical situations identified in the analysis of subgroups of participants in a large randomized clinical trial EMPHASIS-HF are discussed. The main goal of this study was to evaluate the efficacy of eplerenone compared with placebo in patients with heart failure and reduced left ventricular function. In addition, experimental animal studies, which may indicate the pleiotropic effects of eplerenone in patients with vascular diseases, are presented. The new data on the effectiveness of eplerenone in subgroups of patients with heart failure and certain characteristics may be an additional reason to draw the attention of physicians to the benefits of its use and, accordingly, its more frequent application in clinical practice for the treatment of patients with clear indications for this therapy.
About the Authors
S. R. Gilyarevskiy
Russian Medical Academy of Continuing Professional Education
Russian Federation
Sergey R. Gilyarevskiy – MD, PhD, Professor, Chair of Clinical Pharmacology and Therapy
Russian Federation
Sergey R. Gilyarevskiy – MD, PhD, Professor, Chair of Clinical Pharmacology and Therapy
N. G. Bendeliani
A.N. Bakulev National Medical Research Center of Cardiovascular Surgery
Russian Federation
Nana G. Bendeliani – MD, PhD, Senior Researcher, Scientific-Advisory Department, Institute of Coronary and Vascular Surgery, Consultative and Diagnostic Center
Russian Federation
Nana G. Bendeliani – MD, PhD, Senior Researcher, Scientific-Advisory Department, Institute of Coronary and Vascular Surgery, Consultative and Diagnostic Center
M. V. Golshmid
Russian Medical Academy of Continuing Professional Education
Russian Federation
Russian Federation
Maria V. Golshmid – MD, PhD, Associate Professor, Chair of Clinical Pharmacology and Therapy
Barrikadnaya ul. 2/1, Moscow, 125993
I. M. Kuzmina
Sklifosovsky Research Institute of Emergency Medicine
Russian Federation
Russian Federation
Irina M. Kuzmina – MD, PhD, Leading Researcher, Department of Emergency Cardiology
Bolshaya Sukharevskaya pl. 3, Moscow, 129090
References
1. Zannad F., McMurray J.J., Krum H., et al; EMPHASIS-HF Study Group. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med. 2011;364:11-21. doi: 10.1056/NEJMoa1009492.
2. Pitt B., Williams G., Remme W., et al. The EPHESUS trial: eplerenone in patients with heart failure due to systolic dysfunction complicating acute myocardial infarction. Eplerenone Post-AMI Heart Failure Efficacy and Survival Study. Cardiovasc Drugs Ther. 2001;15:79-87.
3. Albert N.M, Yancy C.W., Liang L., et al. Use of aldosterone antagonists in heart failure. JAMA. 2009;302:1658-65. doi: 10.1001/jama.2009.1493.
4. Fonarow G.C., Yancy C.W., Hernandez A.F., et al. Potential impact of optimal implementation of evidence-based heart failure therapies on mortality. Am Heart J. 2011;161:1024-30.e3. doi: 10.1016/j.ahj.2011.01.027.
5. Dev S., Lacy M.E., Masoudi F.A., Wu W.C. Temporal trends and hospital variation in mineralocorticoid receptor antagonist use in veterans discharged with heart failure. J Am Heart Assoc. 2015;4:e002268. doi: 10.1161/JAHA.115.002268.
6. Vardeny O., Claggett B., Anand I., et al; Randomized Aldactone Evaluation Study (RALES) Investigators. Incidence, predictors, and outcomes related to hypoand hyperkalemia in patients with severe heart failure treated with a mineralocorticoid receptor antagonist. Circ Heart Fail. 2014;7:573-9. doi: 10.1161/CIRCHEARTFAILURE.114.001104.
7. Rossignol P., Dobre D., Gregory D., et al. Incident hyperkalemia may be an independent therapeutic target in low ejection fraction heart failure patients: insights from the HEAAL study. Int J Cardiol. 2014;173:380-7. doi: 10.1016/j.ijcard.2014.02.034.
8. Pitt B., Rossignol P. Potassium lowering agents: Recommendations for physician and patient education, treatment reappraisal, and serial monitoring of potassium in patients with chronic hyperkalemia. Pharmacol Res. 2016;118:2-4. doi: 10.1016/j.phrs.2016.07.032.
9. Ferreira J.P., Rossignol P., Machu J.L., et al. Mineralocorticoid receptor antagonist pattern of use in heart failure with reduced ejection fraction: findings from BIOSTAT-CHF. Eur J Heart Fail. 2017;19:1284-93. doi: 10.1002/ejhf.900.
10. Mailey J., Nicholl D. A retrospective audit of mineralocorticoid receptor antagonist (MRA) and device therapy following myocardial infarction (MI) complicated by left ventricular (LV) systolic dysfunction. Heart 2017;103(Suppl 5):A2.1-A2. doi: 10.1136/heartjnl-2017-311726.3.
11. Unwin R.J., Luft F.C., Shirley D.G. Pathophysiology and management of hypokalemia: a clinical perspective. Nat Rev Nephrol. 2011;7:75-84. doi: 10.1038/nrneph.2010.175.
12. Nilsson E., Gasparini A., Arnlov J., et al. Incidence and determinants of hyperkalemia and hypokalemia in a large healthcare system. Int J Cardiol. 2017;245:277-84. doi: 10.1016/j.ijcard.2017.07.035.
13. Kovesdy C.P., Matsushita K., Sang Y., et al; CKD Prognosis Consortium. Serum potassium and adverse outcomes across the range of kidney function: a CKD Prognosis Consortium meta-analysis. Eur Heart J. 2018;39:1535-42. doi: 10.1093/eurheartj/ehy100.
14. Rossignol P., Girerd N., Bakris G., et al. Impact of eplerenone on cardiovascular outcomes in heart failure patients with hypokalaemia. Eur J Heart Fail. 2017;19:792-9. doi: 10.1002/ejhf.688.
15. Lastra G., Sowers J.R. Obesity and cardiovascular disease: role of adipose tissue, inflammation, and the renin-angiotensin-aldosterone system. Horm Mol Biol Clin Investig. 2013;15:49-57. doi: 10.1515/hmbci-2013-0025.
16. Pitt B., Remme W., Zannad F., et al. Eplerenone, a Selective Aldosterone Blocker, in Patients with Left Ventricular Dysfunction after Myocardial Infarction. N Engl J Med. 2003;348:1309-21. doi: 10.1056/NEJMoa030207.
17. Olivier A., Girerd N., Michel J.B., et al; EPHESUS Investigators. Combined baseline and one-month changes in big endothelin-1 and brain natriuretic peptide plasma concentrations predict clinical outcomes in patients with left ventricular dysfunction after acute myocardial infarction: Insights from the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) study. Int J Cardiol. 2017;241:344-50. doi:10.1016/j.ijcard.2017.02.018.
18. Ibanez B., James S., Agewall S., et al. 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: The Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J. 2018;39:119-77. doi: 10.1093/eurheartj/ehx393.
19. Montalescot G., Pitt B., Lopez de Sa E., et al; REMINDER Investigators. Early eplerenone treatment in patients with acute ST-elevation myocardial infarction without heart failure: the Randomized Double-Blind Reminder Study. Eur Heart J. 2014;35:2295-302. doi: 10.1093/eurheartj/ehu164.
20. Beygui F., Cayla G., Roule V., et al. Early Aldosterone Blockade in Acute Myocardial Infarction: The ALBATROSS Randomized Clinical Trial. J Am Coll Cardiol. 2016;67:1917-27. doi: 10.1016/j.jacc.2016.02.033.
21. Packer M. Are Meta-Analyses a Form of Medical Fake News? Thoughts About How They Should Contribute to Medical Science and Practice. Circulation. 2017;136:2097-9. doi: 10.1161/CIRCULATIONAHA.117.030209.
22. Dahal K., Hendrani A., Sharma S.P., et al. Aldosterone Antagonist Therapy and Mortality in Patients With ST-Segment Elevation Myocardial Infarction Without Heart Failure: A Systematic Review and Meta-analysis. JAMA Intern Med. 2018 May 21. doi: 10.1001/jamainternmed.2018.0850.
23. Chin K.L., Collier T.J., Pitt B., et al. Aspirin does not reduce the clinical benefits of the mineralocorticoid receptor antagonist eplerenone in patients with systolic heart failure and mild symptoms: an analysis of the EMPHASIS-HF study. Eur J Heart Fail. 2016;18:1175-81. doi: 10.1002/ejhf.485.
24. Al-Khadra A.S., Salem D.N., Rand W.M., et al. Antiplatelet agents and survival: a cohort analysis from the Studies of Left Ventricular Dysfunction (SOLVD) Trial. J Am Coll Cardiol. 1998;31:419-25. Doi: 10.1016/S0735-1097(97)00502-0.
25. Nguyen K.N., Aursnes I., Kjekshus J. Interaction between enalapril and aspirin on mortality after acute myocardial infarction: subgroup analysis of the Cooperative New Scandinavian Enalapril Survival Study II (CONSENSUS II). Am J Cardiol. 1997;79:115-9. doi: 10.1016/S00029149(96)00696-0.
26. Pfeffer M.A., Braunwald E., Moyé L.A., et al, on behalf of the SAVE Investigators. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction — results of the Survival and Ventricular Enlargement Trial. N Engl J Med. 1992;327:669-677. doi: 10.1056/NEJM199209033271001.
27. The Acute Infarction Ramipril Efficacy (AIRE) Study Investigators. Effect of ramipril on mortality and morbidity of survivors of acute myocardial infarction with clinical evidence of heart failure. Lancet. 1993;342:821-8. doi: 10.1016/0140-6736(93)92693-N.
28. Aumé geat V., Lamblin N., De Groote P., et al. Aspirin does not adversely affect survival in patients with stable congestive heart failure treated with angiotensin-converting enzyme inhibitors. Chest. 2003;124:1250-8.
29. Masoudi F.A., Wolfe P., Havranek E.P., et al. Aspirin use in older patients with heart failure and coronary artery disease: national prescription patterns and relationship with outcomes. J Am Coll Cardiol. 2005;46:955-62. doi: 10.1016/j.jacc.2004.07.062.
30. Teo K.K., Yusuf S., Pfeffer M., et al, for the ACE Inhibitors Collaborative Group. Effects of long-term treatment with angiotensin-converting enzyme inhibitors in the presence or absence of aspirin: a systematic review. Lancet. 2002;360:1037-43. doi: 10.1016/S0140-6736(02)11138-X.
31. Papanicolaou N., Lefkos N., Massourides E., et al. Interaction between aldosterone and renomedullary prostaglandins. Competitive action between aspirin and spironolactone. Experientia. 1977;33:1632-5.
32. Tweeddale M.G,. Ogilvie R.I. Antagonism of spironolactone-induced natriuresis by aspirin in man. N Engl J Med. 1973;289:198-200.
33. Ramsay L.E., Harrison I.R., Shelton J.R., Vose C.W. Influence of acetylsalicylic acid on the renal handling of a spironolactone metabolite in healthy subjects. Eur J Clin Pharmacol. 1976;10:43-8.
34. De Pergola G., Nardecchia A., Giagulli V.A., et al. Obesity and heart failure. Endocr Metab Immune Disord Drug Targets. 2013;13:51-7. doi: 10.2174/1871530311313010007.
35. Kenchaiah S., Pocock S.J., Wang D., et al. Body mass index and prognosis in patients with chronic heart failure: insights from the Candesartan in Heart failure: Assessment of Reduction in Mortality and morbidity (CHARM) program. Circulation. 2007;116:627-36. doi: 10.1161/CIRCULATIONAHA.106.679779.
36. Schocken D.D., Benjamin E.J., Fonarow G.C., et al. Prevention of heart failure: a scientific statement from the American Heart Association Councils on Epidemiology and Prevention, Clinical Cardiology, Cardiovascular Nursing, and High Blood Pressure Research; Quality of Care and Outcomes Research Interdisciplinary Working Group; and Functional Genomics and Translational Biology Interdisciplinary Working Group. Circulation. 2008;117:2544-65. doi: 10.1161/CIRCULATIONAHA.107.188965.
37. Olivier A., Pitt B., Girerd N., et al. Effect of eplerenone in patients with heart failure and reduced ejection fraction: potential effect modification by abdominal obesity. Insight from the EMPHASIS-HF trial. Eur J Heart Fail. 2017;19:1186-97. doi: 10.1002/ejhf.792.
38. Deuchar G.A., McLean D., Hadoke P.W., et al. 11beta-hydroxysteroid dehydrogenase type 2 deficiency accelerates atherogenesis and causes proinflammatory changes in the endothelium in apoe/mice. Endocrinology. 2011;152:236-46. doi: 10.1210/en.2010-0925.
39. Kratz M.T., Schirmer S.H., Baumhakel M., Bohm M. Improvement of endothelial function in a murine model of mild cholesterol-induced atherosclerosis by mineralocorticoid antagonism. Atherosclerosis. 2016;251:291-8. doi: 10.1016/j.atherosclerosis.2016.06.018.
40. Takai S., Jin D., Muramatsu M., et al. Eplerenone inhibits atherosclerosis in nonhuman primates. Hypertension. 2005;46:1135-9. doi: 10.1161/01.HYP.0000184640.81730.22.
41. Rajagopalan S., Duquaine D., King S., et al. Mineralocorticoid receptor antagonism in experimental atherosclerosis. Circulation. 2002;105:2212-6.
42. Schafer N., Lohmann C., Winnik S., et al. Endothelial mineralocorticoid receptor activation mediates endothelial dysfunction in diet-induced obesity. Eur Heart J. 2013;34:3515-24. doi: 10.1093/eurheartj/eht095.
43. Suzuki J., Iwai M., Mogi M., et al. Eplerenone with valsartan effectively reduces atherosclerotic lesion by attenuation of oxidative stress and inflammation. Arterioscler Thromb Vasc Biol. 2006;26:91721. doi: 10.1161/01.ATV.0000204635.75748.0f.
44. Schupp N., Queisser N., Wolf M., et al. Aldosterone causes DNA strand breaks and chromosomal damage in renal cells, which are prevented by mineralocorticoid receptor antagonists. Horm Metab Res. 2010;42:458-65. doi: 10.1055/s-0029-1243253.
45. Keidar S., Kaplan M., Pavlotzky E., et al. Aldosterone administration to mice stimulates macrophage NADPH oxidase and increases atherosclerosis development: a possible role for angiotensin-converting enzyme and the receptors for angiotensin II and aldosterone. Circulation. 2004;109:2213-20. doi: 10.1161/01.CIR.0000127949.05756.9D.
46. Wakabayashi K., Suzuki H., Sato T., et al. Eplerenone suppresses neointimal formation after coronary stent implantation in swine. Int J Cardiol. 2006;107:260-6. doi: 10.1016/j.ijcard.2005.03.078.
47. Ward M.R., Kanellakis P, Ramsey D, Funder J, Bobik A. Eplerenone suppresses constrictive remodeling and collagen accumulation after angioplasty in porcine coronary arteries. Circulation. 2001;104:467-72.
48. Iqbal J., Macdonald L.J., Low L., et al. Contribution of endogenous glucocorticoids and their intravascular metabolism by 11beta-HSDs to postangioplasty neointimal proliferation in mice. Endocrinology. 2012;153:5896-905. doi: 10.1210/en.2012-1481.
Review
For citations:
Gilyarevskiy S.R., Bendeliani N.G., Golshmid M.V., Kuzmina I.M. New Clinical Aspects of Eplerenone Use in Clinical Practice. Rational Pharmacotherapy in Cardiology. 2018;14(4):612-620. (In Russ.) https://doi.org/10.20996/1819-6446-2018-14-4-612-620
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