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Eplerenone (Inspra™) is a selective aldosterone blocker. Oral eplerenone is approved for use in patients with left ventricular (LV) systolic dysfunction and clinical evidence of heart failure following acute myocardial infarction (MI) in the US and in European countries (e.g. the UK and The Netherlands).
The addition of eplerenone to standard medical therapy significantly improved mortality and morbidity in patients with LV systolic dysfunction and clinical evidence of heart failure following acute MI in the large, well designed EPHESUS (Eplerenone Post-acute myocardial infarction Heart failure Efficacy and SUrvival Study) trial. The beneficial effects of eplerenone on all-cause mortality and cardiovascular mortality were seen within 30 days of randomisation. Eplerenone was generally well tolerated. Although a higher incidence of hyperkalaemia occurred with eplerenone than with placebo, the incidence of hypokalaemia was significantly lower with eplerenone treatment. Thus, the addition of eplerenone to standard medical therapy is an important new strategy for further improving mortality and morbidity in post-MI patients with LV systolic dysfunction and heart failure.
Eplerenone is a 9α, 11α-epoxy-derivative of mexrenone that binds preferentially to the mineralocorticoid receptor. Compared with spironolactone, eplerenone was ≈370-fold less potent at inhibiting activation of the androgen receptor and devoid of agonist activity at the progesterone receptor in vitro and, unlike spironolactone, eplerenone did not have antiandrogenic or progestagenic effects in animal models.
Eplerenone ameliorated maladaptive LV remodelling in rat models of MI, with the greatest benefits occurring in rats receiving eplerenone plus the ACE inhibitor trandolapril compared with rats receiving placebo. Increases in LV end-diastolic pressure and volume were significantly attenuated with eplerenone versus placebo. Moreover, eplerenone attenuated reactive fibrosis, without exacerbating infarct expansion or impairing infarct healing. Eplerenone demonstrated additional effects in animal models that may contribute to its cardioprotective effects, including attenuating increases in neurohormone and natriuretic peptide levels, and ameliorating platelet activation, endothelial dysfunction and Superoxide production.
In healthy volunteers, a mean maximum plasma concentration (Cmax) of 1.72 μg/mL was reached after 1.3 hours with a mean area under the plasma concentration-time curve (AUC) of 9.54 μg · h/mL following a single oral dose of eplerenone 100mg. Steady-state eplerenone concentrations are reached within 2 days. In patients with stable heart failure receiving eplerenone 50mg, the steady-state Cmax and AUC were 30% and 38% higher than in healthy volunteers receiving the same dose. Eplerenone is extensively metabolised; this metabolism is primarily mediated by the cytochrome P450 (CYP) isozyme CYP3A4, with no active metabolites detected in human plasma. The eplerenone elimination half-life was ≈4–6 hours. The potent CYP3A4 inhibitor ketoconazole increased the eplerenone AUC 5-fold; concomitant administration of eplerenone and potent CYP3A4 inhibitors is contraindicated. European prescribing information recommends that eplerenone not be coadministered with strong inducers of CYP3A4 such as St John’s wort, rifampicin (rifampin), carbamazepine, phenytoin and phenobarbital, due to the risk of decreased efficacy.
The addition of eplerenone (target dosage 50 mg/day) to standard medical therapy significantly improved mortality and morbidity in patients with LV systolic dysfunction and clinical evidence of heart failure following acute MI, according to the results of the large (n = 6632), well designed EPHESUS study. Compared with placebo recipients, eplerenone recipients had significant reductions in all-cause mortality and the combined endpoint of cardiovascular mortality or first hospitalisation for a cardiovascular event (primary endpoints) and in cardiovascular mortality and the combined endpoint of all-cause mortality or any hospitalisation (major secondary endpoints) after a mean 16 months of follow-up. The reduction in cardiovascular mortality was largely due to a significantly lower incidence of sudden death from cardiac causes with eplerenone than with placebo. The beneficial effects of eplerenone on all-cause mortality and cardiovascular mortality were seen within 30 days of randomisation.
Eplerenone recipients were significantly less likely than placebo recipients to be hospitalised for heart failure, and eplerenone recipients experienced significantly fewer hospitalisation episodes for cardiovascular events than placebo recipients.
Additional retrospective analyses of the EPHESUS study revealed that the mean length of hospital stay was significantly shorter with eplerenone than with placebo, and that eplerenone had beneficial effects on morbidity and mortality in patients with a history of hypertension at baseline and in patients with diabetes mellitus and signs of heart failure. In addition, eplerenone improved morbidity and mortality to a similar extent regardless of whether or not patients received reperfusion therapy. Moreover, eplerenone was a cost-effective option in patients with LV systolic dysfunction and heart failure following acute MI.
Eplerenone was generally well tolerated in patients with LV systolic dysfunction and heart failure following acute MI in the EPHESUS study. Gastrointestinal disorders occurred significantly more frequently in eplerenone than in placebo recipients, and respiratory disorders such as cough, dyspnoea and pneumonia occurred significantly less frequently.
There were no significant differences between eplerenone and placebo recipients in the proportion of men experiencing gynaecomastia or impotence, or women experiencing breast pain (incidence <1%).
Overall, metabolic and nutritional disorders occurred significantly less frequently in eplerenone than in placebo recipients; specifically, hypokalaemia, serious hypokalaemia and hypoglycaemia occurred significantly less frequently with eplerenone than with placebo. Hyperkalaemia and serious hyperkalaemia occurred significantly more frequently with eplerenone than with placebo. A post hoc analysis found that the hyperkalaemia that occurred with eplerenone in the EPHESUS study was predictable, manageable and nonfatal.
- Delyani JA, Robinson EL, Rudolph AE. Effect of a selective aldosterone receptor antagonist in myocardial infarction. Am J Physiol Heart Circ Physiol 2001 Aug; 50: H647–54
- Fraccarollo D, Galuppo P, Hildemann S, et al. Additive improvement of left ventricular remodeling and neurohormonal activation by aldosterone receptor blockade with eplerenone and ACE inhibition in rats with myocardial infarction. J Am Coll Cardiol 2003; 42(9): 1666–73 CrossRef
- Køber L, Torp-Pedersen C, Carlsen JE, et al. A clinical trial of the angiotension-converting-enzyme inhibitor trandolapril in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 1995 Dec 21; 333(25): 1670–6 CrossRef
- 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 Oct 2; 342: 821–8
- Pfeffer MA, Braunwald E, Moyé LA, et al. Effect of captopril on mortality and morbidity in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 1992 Sep 3; 327(10): 669–77 CrossRef
- Pfeffer MA, McMurray JV. Myocardial infarct: no one size fits all. Circulation 2002 Jun 4; 105: 2577–9 CrossRef
- Solomon SD, Pfeffer MA. Aldosterone antagonism and myocardial infarction: from animals to man and back. J Am Coll Cardiol 2003 Nov 5; 42(9): 1674–6 CrossRef
- Vantrimpont P, Rouleau JL, Ciampi A, et al. Two-year time course and significance of neurohormonal activation in the Survival and Ventricular Enlargement (SAVE) study. Eur Heart J 1998; 19: 1552–63 CrossRef
- Sica DA. Aldosterone receptor blockade: a therapy resurrected. Heart Dis 2003 Mar–Apr 30; 5(2): 85–8 CrossRef
- Moore TD, Nawarskas JJ, Anderson JR. Eplerenone: a selective aldosterone receptor antagonist for hypertension and heart failure. Heart Dis 2003 Sep–Oct; 5(5): 354–63 CrossRef
- McKelvie RS, Yusuf S, Pericak D, et al. Comparison of candesartan, enalapril, and their combination in congestive heart failure: Randomized Evaluation of Strategies for Left Ventricular Dysfunction (RESOLVD) pilot study. Circulation 1999 Sep 7; 100: 1056–64 CrossRef
- Stassen J, Lijnen P, Fagard R, et al. Rise in plasma concentration of aldosterone during long-term angiotensin II suppression. J Endocrinol 1981; 91: 457–65 CrossRef
- Funder JW. Is aldosterone bad for the heart? Trends Endocrinol Metab 2004 May; 15(4): 139–42 CrossRef
- Ketelslegers J-M, Schiffrin E, Williams G, et al. Biomarkers of prognosis in patients with post-acute myocardial infarction heart failure: results from a EPHESUS sub-study [abstract no. 3420 plus poster]. ESC Congress 2004: Annual Congress of the European Society of Cardiology; 2004 Aug 28–Sep 1; Munich
- Schäfer A, Fraccarollo D, Hildemann S, et al. Inhibition of platelet activation in congestive heart failure by aldosterone receptor antagonism and ACE inhibition. Thromb Haemost 2003; 89: 1024–30
- Schäfer A, Fraccarollo D, Hildemann SK, et al. Addition of the selective aldosterone receptor antagonist eplerenone to ACE inhibition in heart failure: effect on endothelial dysfunction. Cardiovasc Res 2003 Jun 1; 58(3): 655–62 CrossRef
- de Gasparo M, Whitebread SE, Preiswerk G, et al. Antialdoster-ones: incidence and prevention of sexual side effects. J Steroid Biochem 1989; 32(IB): 223–7 CrossRef
- Pitt B, Roniker B, Eplerenone Heart Failure Investigators. Eplerenone, a novel selective aldosterone receptor antagonist (SARA): dose finding study in patients with heart failure [abstract no. 825-4]. J Am Coll Cardiol 1999 Feb; 33 (2 Suppl. A): 188–9
- Ménard J. The 45-year old story of the development of an anti-aldosterone more specific than spironolactone. Mol Cell Endocrinol 2004 Mar 31; 217(1–2): 45–52 CrossRef
- de Gasparo M, Joss U, Ramjoue HP, et al. Three new epoxy-spironolactone derivatives: characterization in vivo and in vitro. J Pharmacol Exp Ther 1987; 240(2): 650–6
- Garthwaite SM, McMahon EG. The evolution of aldosterone antagonists. Mol Cell Endocrinol 2004; 217: 27–31 CrossRef
- Qin W, Rudolph AE, Bond BR, et al. Transgenic model of aldosterone-driven cardiac hypertrophy and heart failure. Circ Res 2003 Jul 11; 93: 69–76 CrossRef
- Suzuki G, Morita H, Mishima T, et al. Effects of long-term monotherapy with eplerenone, a novel aldosterone blocker, on progression of left ventricular dysfunction and remodeling in dogs with heart failure. Circulation 2002 Dec 3; 106(23): 2967–72 CrossRef
- Keidar S, Hayek T, Kaplan M, et al. Effect of eplerenone, a selective aldosterone blocker, on blood pressure, serum and macrophage oxidative stress, and atherosclerosis in apoli-poprotein E-deficient mice. J Cardiovasc Pharmacol 2003 Jun; 41(6): 955–63 CrossRef
- Rajagopalan S, Duquaine D, King S, et al. Mineralocorticoid receptor antagonism in experimental atherosclerosis. Circulation 2002 May 7; 105(18): 2212–6 CrossRef
- Rocha R, Rudolph AE, Frierdich GE, et al. Aldosterone induces a vascular inflammatory phenotype in the rat heart. Am J Physiol Heart Circ Physiol 2002; 283: H1802–10
- Rocha R, Martin-Berger CL, Yang P, et al. Selective aldosterone blockade prevents angiotensin II/salt-induced vascular inflammation in the rat heart. Endocrinology 2002 Dec; 143(12): 4828–36 CrossRef
- Cook CS, Berry LM, Bible RH, et al. Pharmacokinetics and metabolism of [14C]eplerenone after oral administration to humans. Drug Metab Dispos 2003 Nov; 31(11): 1448–55 CrossRef
- Reid SE, Hutmacher MM, Tolbert DS, et al. The pharmacokinetics of eplerenone in patients with left ventricular dysfunction/heart failure [abstract no. 27]. Pharmacotherapy 2003 Oct; 23(10): 1332
- Tolbert DS, Reid SE, Roniker B. Safety, tolerability, and pharmacokinetics of eplerenone, a selective aldosterone blocker [abstract no. 45]. Pharmacotherapy 2002 Oct; 22(10): 1331–2
- Tolbert DS, Reid SE, Roniker B. Pharmacokinetics of eplerenone in special populations [abstract no. 46]. Pharmacotherapy 2002 Oct; 22(10): 1332
- Reid SE, Tolbert DS, Ferry J. The effect of age on the pharmacokinetic of eplerenone [abstract no. 212]. Pharmacotherapy 2003 Oct; 23(10): 1359
- Tolbert DS, Reid SE, Roniker B. Pharmacokinetics of eplerenone coadministered with other medications [abstract no. 44]. Pharmacotherapy 2002 Oct; 22(10): 1331
- Tolbert DS, Reid SE, Qian J, et al. Effects of St. John’s wort on the pharmacokinetics of eplerenone [abstract no. T2267]. AAPSPharmSci 2002; 4 (4)
- Tolbert DS, Reid SE, Qian J, et al. Effects of eplerenone on the pharmacokinetics of cisapride [abstract no. T2266]. AAPSPharmSci 2002; 4 (4)
- Tolbert DS, Reid SE, Qian J, et al. Effects of erythromycin on the pharmacokinetics of eplerenone [abstract no. T2264]. AAPSPharmSci 2002; 4 (4)
- G.D. Searle LLC. INSPRA™ (eplerenone) tablets: prescribing information [online]. Available from URL: http://www.inspra.com [Accessed 2004 Aug 13]
- G.D. Searle and Co. Final report for evaluation of the single-and multiple-dose pharmacokinetics of eplerenone in subjects with and without renal impairment. Report no. NE3-01-06-034. US: G.D. Searle and Co., 2001 Oct19. (Data on file)
- Pfizer UK. Inspra: summary of product characteristics. 2004
- 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 Apr 3; 348(14): 1309–21 CrossRef
- Pitt B, Kram H, Nicolau JC, et al. The EPHESUS trial: effect of eplerenone in patients with a baseline history of hypertension [abstract no. 2727]. Circulation 2003 Oct 28; 108 Suppl. 17: 599
- Ketelslegers J-M, Zannad F, Schiffrin E, et al. The effect of eplerenone on the cytokine osteopontin in post-AMI heart failure: an EPHESUS substudy [poster]. ESC Congress 2004: Annual Congress of the European Society of Cardiology; 2004 Aug 28–Sep 1; Munich
- O’Keefe J, Zarich S, Felicetta J, et al. Eplerenone is safe and effective in diabetic patients with post-acute myocardial infarction heart failure: results from EPHESUS [abstract no. 491-P]. Diabetes 2004 Jun; 53 Suppl. 2: A116
- Gheorghiade M, Kram H, Chu T-C, et al. Concurrent treatment with eplerenone and standard HF therapy reduces the duration of heart failure hospitalization in patients with post AMI heart failure [abstract]. European Society of Cardiology Heart Failure Update; 2004 Jun 12–15; Wroclaw
- Anderson JL, Dietz R, Nicolau JC, et al. The impact of reperfusion status on the efficacy of eplerenone: results from EPHESUS [abstract]. 77th Scientific Sessions of the American Heart Association; 2004 Nov 7–10; New Orleans
- Zhang Z, Spertus JA, Pitt B, et al. Cost-effectiveness of eplerenone by age and gender subgroups in patients with heart failure after acute myocardial infarction: results from EPHESUS [abstract]. 77th Scientific Sessions of the American Heart Association; 2004 Nov 7–10; New Orleans
- Zhang Z, Weintraub WS. Cost-effectiveness of eplerenone in patients with heart failure post myocardial infarction: results from EPHESUS applied to the Netherlands [poster]. ESC Congress 2004: Annual Congress of the European Society of Cardiology; 2004 Aug 28–Sep 1; Munich
- Pitt B, Zannad F, Kram H, et al. Effect of eplerenone on early mortality in patients with heart failure and left ventricular systolic dysfunction post-myocardial infarction (EPHESUS) [abstract]. European Society of Cardiology Acute Cardiac Care Meeting; 2004 Oct 17–20; Rome
- Bakris G, Ruilope L, DiCarlo L, et al. Risk/benefit analysis of hyperkalemia on clinical outcomes in EPHESUS [abstract]. European Society of Cardiology Heart Failure Update; 2004 Jun 12–15; Wroclaw
- Spencer FA, Meyer TE, Gore JM, et al. Heterogeneity in the management and outcomes of patients with acute myocardial infarction complicated by heart failure: the National Registry of Myocardial Infarction. Circulation 2002 Jun 4; 105: 2605–10 CrossRef
- Wu AH, Parsons L, Every NR, et al. Hospital outcomes in patients presenting with congestive heart failure complicating acute myocardial infarction: a report from the second National Registry of Myocardial Infarction (NRMI-2). J Am Coll Cardiol 2002; 40(8): 1389–94 CrossRef
- Steg PG, Dabbous OM, Feldman LJ, et al. Determinants and prognostic implications of heart failure complicating acute coronary syndromes: observations from the Global Registry of Acute Coronary Events (GRACE). Circulation 2004 Feb 3; 109: 494–9 CrossRef
- Pfeffer MA, McMurray JJV, Velazquez EJ, et al. Valsartan, captopril, or both in myocardial infarction complicated by heart failure, left ventricular dysfunction, or both. N Engl J Med 2003 Nov 13; 349(20): 1893–906 CrossRef
- Dargie H, Colucci W, Ford I, et al. Effect of carvedilol on outcome after myocardial infarction in patients with left-ventricular dysfunction: the CAPRICORN randomised trial. Lancet 2001 May 5; 357: 1385–90 CrossRef
- Pitt B. Aldosterone blockade in patients with acute myocardial infarction. Circulation 2003 May 27; 107: 2525–7 CrossRef
- Antman EM, Anbe DT, Armstrong PW, et al. ACC/AHA guidelines for the management of patients with ST-elevation myocardial infarction — executive summary: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (writing committee to revise the 1999 guidelines for the management of patients with acute myocardial infarction). J Am Coll Cardiol 2004 Aug 4; 44(3): 671–719 CrossRef
- Fonarow GC, Gawlinski A, Moughrabi S, et al. Improved treatment of coronary heart disease by implementation of a Cardiac Hospitalization Athersclerosis Program (CHAMP). Am J Cardiol 2001 Apr 1; 87: 819–22 CrossRef
- Pitt B. Aldosterone blockade in patients with systolic left ventricular dysfunction. Circulation 2003 Oct 14; 108(15): 1790–4 CrossRef
- Jessup M. Aldosterone blockade and heart failure. N Engl J Med 2003 Apr 3; 348(14): 1380–2 CrossRef
- 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 Sep 2; 341(10): 709–17 CrossRef
- Juurlink DN, Mamdani MM, Lee DS, et al. Rates of hyperkalemia after publication of the Randomized Aldactone Evaluation Study. N Engl J Med 2004 Aug 5; 351(6): 543–51 CrossRef
- Pitt B. Eplerenone in patients with left ventricular dysfunction [letter]. N Engl J Med 2003 Jul 3; 349(1): 89
- Palmer BF. Managing hyperkalemia caused by inhibitors of the renin-angiotensin-aldosterone system. N Engl J Med 2004 Aug 5; 351(6): 585–92 CrossRef
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