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Inhibition of mineralocorticoid receptors in treatment of cardiovascular diseases: clinical and pharmacological aspects of the eplerenone therapy

Gilyarevsky S. R.1, Golshmid M. V.1, Kuzmina I. M.2
1 – State Budgetary Educational Institution of Advanced Professional Education, “Russian Medical Academy of Postgraduate Education” of the RF Ministry of Health Care, Barrikadnaya 2/1, Moscow 123995
2 – N. V. Sklifosovsky Research Institute of Emergency Medicine, B. Sukharevskaya Pl. 3, Moscow 129090

Keywords: treatment, cardiovascular diseases

DOI: 10.18087/rhj.2016.3.2198

The article discusses current aspects of clinical use of a selective mineralocorticoid antagonist, eplerenone, for treatment of patients with CVDs. The authors provided an evidence base for using eplerenone in treatment of different diseases. Approaches to providing safety and tolerability of mineralocorticoid antagonists are discussed.
  1. Guichard JL, Clark D 3rd, Calhoun DA, Ahmed MI. Aldosterone receptor antagonists: current perspectives and therapies. Vasc Health Risk Manag. 2013;9:321–31.
  2. Funder JW. Minireview: aldosterone and mineralocorticoid receptors: past, present, and future. Endocrinology. 2010 Nov;151 (11):5098–102.
  3. Deinum J, Riksen NP, Lenders JW. Pharmacological treatment of aldosterone excess. Pharmacol Ther. 2015 Oct;154:120–33.
  4. Viengchareun S, Le Menuet D, Martinerie L, Munier M, Pascual-Le Tallec L, Lombes M. The mineralocorticoid receptor: insights into its molecular and (patho) physiological biology. Nucl Recept Signal. 2007 Nov 30;5: e012.
  5. Funder JW. Minireview: aldosterone and the cardiovascular system: genomic and nongenomic effects. Endocrinology. 2006 Dec;147 (12):5564–7.
  6. Armanini D, Sabbadin C, Donà G, Clari G, Bordin L. Aldosterone receptor blockers spironolactone and canrenone: two multivalent drugs. Expert Opin Pharmacother. 2014 May;15 (7):909–12.
  7. Funder JW, Carey RM, Fardella C, Gomez-Sanchez CE, Mantero F, Stowasser M et al. Case detection, diagnosis, and treatment of pati­ents with primary aldosteronism: an endocrine society clinical practice guideline. J Clin Endocrinol Metab. 2008 Sep;93 (9):3266–81.
  8. Mosso L, Carvajal C, Gonzalez A, Barraza A, Avila F, Montero J et al. Primary aldosteronism and hypertensive disease. Hypertension. 2003 Aug;42 (2):161–5.
  9. Rossi GP, Di Bello V, Ganzaroli C, Sacchetto A, Cesari M, Bertini A et al. Excess aldosterone is associated with alterations of myocardial texture in primary aldosteronism. Hypertension. 2002 Jul;40 (1):23–7.
  10. Muiesan ML, Salvetti M, Paini A, Agabiti-Rosei C, Monteduro C, Galbassini G et al. Inappropriate left ventricular mass in patients with primary aldosteronism. Hypertension. 2008 Sep;52 (3):529–34.
  11. Milliez P, Girerd X, Plouin PF, Blacher J, Safar ME, Mourad JJ. Evidence for an increased rate of cardiovascular events in patients with primary aldosteronism. J Am Coll Cardiol. 2005 Apr 19;45 (8):1243–8.
  12. Catena C, Colussi G, Nadalini E, Chiuch A, Baroselli S, Lapenna R, Sechi LA. Cardiovascular outcomes in patients with primary aldosteronism after treatment. Arch Intern Med. 2008 Jan 14;168 (1):80–5.
  13. Born-Frontsberg E, Reincke M, Rump LC, Hahner S, Diederich S, Lorenz R et al. Cardiovascular and cerebrovascular comorbidities of hypokalemic and normokalemic primary aldosteronism: results of the German Conn’s Registry. J Clin Endocrinol Metab. 2009 Apr;94 (4):1125–30.
  14. Catena C, Colussi G, Lapenna R, Nadalini E, Chiuch A, Gianfagna P, Sechi LA. Long-term cardiac effects of adrenalectomy or mineralocorticoid antagonists in patients with primary aldosteronism. Hypertension. 2007 Nov;50 (5):911–8.
  15. Catena C, Colussi G, Di Fabio A, Valeri M, Marzano L, Uzzau A, Sechi LA. Mineralocorticoid antagonists treatment versus surgery in primary aldosteronism. Horm Metab Res. 2010 Jun;42 (6):440–5.
  16. Steichen O, Lorthioir A, Zinzindohoue F, Plouin PF, Amar L. Outcomes of drug-based and surgical treatments for primary aldosteronism. Adv Chronic Kidney Dis. 2015 May;22 (3):196–203.
  17. Vasan RS, Evans JC, Larson MG, Wilson PW, Meigs JB, Rifai N et al. Serum aldosterone and the incidence of hypertension in nonhypertensive persons. N Engl J Med. 2004 Jul 1;351 (1):33–41.
  18. Rossi GP, Bernini G, Caliumi C, Desideri G, Fabris B, Ferri C et al. A prospective study of the prevalence of primary aldosteronism in 1,125 hypertensive patients. J Am Coll Cardiol. 2006 Dec 5;48 (11):2293–300.
  19. Calhoun DA, Nishizaka MK, Zaman MA, Thakkar RB, Weissmann P. Hyperaldosteronism among black and white subjects with resistant hypertension. Hypertension. 2002 Dec;40 (6):892–6.
  20. Pratt-Ubunama MN, Nishizaka MK, Boedefeld RL, Cofield SS, Harding SM, Calhoun DA. Plasma aldosterone is related to severity of obstructive sleep apnea in subjects with resistant hypertension. Chest. 2007 Feb;131 (2):453–9.
  21. Jeunemaitre X, Chatellier G, Kreft-Jais C, Charru A, DeVires C, Plouin PF et al. Efficacy and tolerance of spironolactone in essential hypertension. Am J Cardiol. 1987 Oct 1;60 (10):820–5.
  22. Flack JM, Oparil S, Pratt JH, Roniker B, Garthwaite S, Kleiman JH et al. Efficacy and tolerability of eplerenone and losartan in hypertensive black and white patients. J Am Coll Cardiol. 2003 Apr 2;41 (7):1148–55.
  23. Krum H, Nolly H, Workman D, He W, Roniker B, Krause S, Fakouhi K. Efficacy of eplerenone added to renin-angiotensin blockade in hypertensive patients. Hypertension. 2002 Aug;40 (2):117–23.
  24. Pitt B, Reichek N, Willenbrock R, Zannad F, Phillips RA, Roniker B et al. Effects of eplerenone, enalapril, and eplerenone / enalapril in patients with essential hypertension and left ventricular hypertrophy: the 4E-left ventricular hypertrophy study. Circulation. 2003 Oct 14;108 (15):1831–8.
  25. Savoia C, Touyz RM, Amiri F, Schiffrin EL. Selective mineralocorticoid receptor blocker eplerenone reduces resistance artery stiffness in hypertensive patients. Hypertension. 2008 Feb;51 (2):432–9.
  26. Calhoun DA, Jones D, Textor S, Goff DC, Murphy TP, Toto RD et al. Resistant hypertension: diagnosis, evaluation, and treatment: a scientific statement from the American Heart Association Professional Education Committee of the Council for High Blood Pressure Research. Circulation. 2008 Jun 24;117 (25):e510–26.
  27. Kumbhani DJ, Steg PG, Cannon CP, Eagle KA, Smith SC Jr, Crowley K et al. Resistant hypertension: a frequent and ominous finding among hypertensive patients with atherothrombosis. Eur Heart J. 2013 Apr;34 (16):1204–14.
  28. Strauch B, Zelinka T, Hampf M, Bernhardt R, Widimsky J Jr. Prevalence of primary hyperaldosteronism in moderate to severe hypertension in the Central Europe region. J Hum Hypertens. 2003 May;17 (5):349–52.
  29. Gaddam KK, Nishizaka MK, Pratt-Ubunama MN, Pimenta E, Aban I, Oparil S, Calhoun DA. Characterization of resistant hypertension: association between resistant hypertension, aldosterone, and persistent intravascular volume expansion. Arch Intern Med. 2008 Jun 9;168 (11):1159–64.
  30. Gaddam K, Corros C, Pimenta E, Ahmed M, Denney T, Aban I et al. Rapid reversal of left ventricular hypertrophy and intracardiac volume overload in patients with resistant hypertension and hyperaldosteronism: a prospective clinical study. Hypertension. 2010 May;55 (5):1137–42.
  31. Pelliccia F, Rosano G, Patti G, Volterrani M, Greco C, Gaudio C. Efficacy and safety of mineralocorticoid receptors in mild to mode­rate arterial hypertension. Int J Cardiol. 2015 Dec 1;200:8–11.
  32. Dahal K, Kunwar S, Rijal J, Alqatahni F, Panta R, Ishak N, Russell RP. The effects of aldosterone antagonists in patients with resistant hypertension: a meta-analysis of randomized and nonrandomized studies. Am J Hypertens. 2015 Nov;28 (11):1376–85.
  33. Calhoun DA, White WB. Effectiveness of the selective aldosterone blocker, eplerenone, in patients with resistant hypertension. J Am Soc Hypertens. 2008 Nov-Dec;2 (6):462–8.
  34. Williams B. The principal results of the Prevention and Treatment of Hypertension With Algorithm-based Therapy (PATHWAY) – Optimal treatment of drug resistant hypertension – PATHWAY 2. European Society of Cardiology 2015 Congress. August 31, 2015; London, GB. Abstract 4137.
  35. Williams B, MacDonald TM, Caulfield M, Cruickshank JK, McInnes G, Sever P et al. Prevention And Treatment of Hypertension With Algorithm-based therapy (PATHWAY) number 2: protocol for a randomised crossover trial to determine optimal treatment for drug-resistant hypertension. BMJ Open. 2015 Aug 7;5 (8):e008951.
  36. Weber KT. Aldosterone in congestive heart failure. N Engl J Med. 2001 Dec 6;345 (23):1689–97.
  37. Pitt B. “Escape” of aldosterone production in patients with left ventricular dysfunction treated with an angiotensin converting enzyme inhibitor: implications for therapy. Cardiovasc Drugs Ther. 1995 Feb;9 (1):145–9.
  38. Jorde UP, Vittorio T, Katz SD, Colombo PC, Atif F, Jemtel TH. Elevated plasma aldosterone levels despite complete inhibition of the vascular angiotensin-converting enzyme in chronic heart failure. Circulation. 2002 Aug 27;106 (9):1055–7.
  39. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A 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 Sep 2;341 (10):709–17.
  40. Zannad F, Alla F, Dousset B, Perez A, Pitt B. Limitation of excessive extracellular matrix turnover may contribute to survival benefit of spironolactone therapy in patients with congestive heart failure: insights from the randomized aldactone evaluation study (RALES). Rales Investigators. Circulation. 2000 Nov 28;102 (22):2700–6.
  41. Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med. 2003 Apr 3;348 (14):1309–21.
  42. Zannad F, McMurray JJ, Krum H, van Veldhuisen DJ, Swedberg K, Shi H et al. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med. 2011 Jan 6;364 (1):11–21.
  43. Rogers JK, McMurray JJ, Pocock SJ, Zannad F, Krum H, van Veldhuisen DJ et al. Eplerenone in patients with systolic heart failure and mild symptoms: analysis of repeat hospitalizations. Circulation. 2012 Nov 6;126 (19):2317–23.
  44. Rossignol P, Menard J, Fay R, Gustafsson F, Pitt B, Zannad F. Eplerenone survival benefits in heart failure patients post-myocardial infarction are independent from its diuretic and potassium-sparing effects. Insights from an EPHESUS (Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study) substudy. J Am Coll Cardiol. 2011 Nov 1;58 (19):1958–66.
  45. Zannad F, Gattis Stough W, Rossignol P, Bauersachs J, McMurray JJ, Swedberg K et al. Mineralocorticoid receptor antagonists for heart failure with reduced ejection fraction: integrating evidence into clinical practice. Eur Heart J. 2012 Nov;33 (22):2782–95.
  46. Fonarow GC, Yancy CW, Hernandez AF, Peterson ED, Spertus JA, Heidenreich PA. Potential impact of optimal implementation of evidence-based heart failure therapies on mortality. Am Heart J. 2011 Jun;161 (6):1024–30.
  47. Edelmann F, Wachter R, Schmidt AG, Kraigher-Krainer E, Colantonio C, Kamke W 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 Feb 27;309 (8):781–91.
  48. Pitt B, Pfeffer MA, Assmann SF, Boineau R, Anand IS, Claggett B et al. Spironolactone for heart failure with preserved ejection fraction. N Engl J Med. 2014 Apr 10;370 (15):1383–92.
  49. Sechi LA, Novello M, Lapenna R, Baroselli S, Nadalini E, Colussi GL, Catena C. Long-term renal outcomes in patients with primary aldosteronism. JAMA. 2006 Jun 14;295 (22):2638–45.
  50. Epstein M. Aldosterone blockade: an emerging strategy for abroga­ting progressive renal disease. Am J Med. 2006 Nov;119 (11):912–9.
  51. Abboud H, Henrich WL. Clinical practice. Stage IV chronic kidney disease. N Engl J Med. 2010 Jan 7;362 (1):56–65.
  52. White WB, Duprez D, St Hillaire R, Krause S, Roniker B, Kuse-Hamilton J, Weber MA. Effects of the selective aldosterone blocker eplerenone versus the calcium antagonist amlodipine in systolic hypertension. Hypertension. 2003 May;41 (5):1021–6.
  53. Furumatsu Y, Nagasawa Y, Tomida K, Mikami S, Kaneko T, Okada N et al. Effect of renin-angiotensin- aldosterone system triple blocka­de on non-diabetic renal disease: addition of an aldosterone blocker, spironolactone, to combination treatment with an angiotensin-converting enzyme inhibitor and angiotensin II receptor blocker. Hypertens Res. 2008 Jan;31 (1):59–67.
  54. Navaneethan SD, Nigwekar SU, Sehgal AR, Strippoli GF. Aldo­sterone antagonists for preventing the progression of chronic kidney disease: a systematic review and meta-analysis. Clin J Am Soc Nephrol. 2009 Mar;4 (3):542–51.
  55. Pitt B, Kober L, Ponikowski P, Gheorghiade M, Filippatos G, Krum H et al. Safety and tolerability of the novel non-steroidal mineralocorticoid receptor antagonist BAY 94–8862 in patients with chronic heart failure and mild or moderate chronic kidney disease: a randomized, double-blind trial. Eur Heart J. 2013 Aug;34 (31):2453–63.
  56. Edwards NC, Steeds R, Chue CD, Stewart PM, Ferro CJ, Townend JN. The safety and tolerability of spironolactone in patients with mild to moderate chronic kidney disease. Br J Clin Pharmacol. 2012 Mar;73 (3):447–54.
  57. Shavit L, Lifschitz MD, Epstein M. Aldosterone blockade and the mineralocorticoid receptor in the management of chronic kidney disease: current concepts and emerging treatment paradigms. Kidney Int. 2012 May;81 (10):955–68.
  58. Gosse P, Macfadyen RJ. Does eplerenone have a future in the mana­gement of hypertension in Europe? J Hum Hypertens. 2006 Nov;20 (11):829–32.
Gilyarevsky S. R., Golshmid M. V., Kuzmina I. M. Inhibition of mineralocorticoid receptors in treatment of cardiovascular diseases: clinical and pharmacological aspects of the eplerenone therapy. Russian Heart Journal. 2016;15 (3):143–150

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