The Importance of a Higher Dose of a Mineralocorticoid Receptor

Cor et Vasa

Available online at www.sciencedirect.com

journal homepage: www.elsevier.com/locate/crvasa

Kasuistika | Case report The importance of a higher dose of a mineralocorticoid receptor antagonist in reducing risk of reccurent hospitalization in a patient with advanced chronic heart failure – A case report

Ghada Mairgania, Václav Málaa, Filip Málekb

a Oddělení Interna I, Nemocnice Teplice, Krajská zdravotní, a.s., Teplice, Česká republika b Kardiocentrum, Nemocnice Na Homolce, Praha, Česká republika

ARTICLE INFO SOUHRN

Article history: Autoři upozorňují na význam podávání vyšší dávky antagonisty mineralokortikoidních receptorů pro snížení Received: 10. 3. 2017 frekvence hospitalizací 67letého pacienta s pokročilým chronickým srdečním selháním. Received in revised form: 9. 8. 2017 © 2017, ČKS. Published by Elsevier Sp. z o.o. All rights reserved. Accepted: 19. 8. 2017 Available online: 22. 9. 2017

Klíčová slova: Antagonisté mineralokortikoidních receptorů Eplerenon Pokročilé chronické srdeční selhání

Keywords: ABSTRACT Advanced chronic heart failure Eplerenone The authors present the signiﬁ cance of a higher dose of a mineralocorticoid receptor antagonist in reducing Mineral corticoid receptor the frequency of hospitalizations for decompensated heart failure in the 67-year-old patient suffering from antagonists advanced chronic heart failure.

Address: MUDr. Ghada Mairgani, Oddělení Interna I, Nemocnice Teplice, Krajská zdravotní, a.s., Duchcovská 53, 415 29 Teplice, e-mail: [email protected] DOI: 10.1016/j.crvasa.2017.08.004

Please cite this article as: G. Mairgani, et al., The importance of a higher dose of a mineralocorticoid receptor antagonist in reducing risk of reccurent hospitalization in a patient with advanced chronic heart failure – A case report, Cor et Vasa 60 (2018) e527–e530 as published in the online version of Cor et Vasa available at https://www.sciencedirect.com/science/ article/pii/S0010865017300425

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Introduction

Heart failure is deﬁ ned as a state when the heart is unable to pump blood with normal venous return accord-

ing to the needs of tissue metabolism or a state when it p is only able to do so with an increased ventricular fi lling pressure. The human body deals with a heart function disorder through adaptation mechanisms that are harm- ful if they are active over the long-term, mainly concerns the activation of the sympathetic nervous system and the renin–angiotensin–aldosterone system (RAAS). The short- term effects include increased heart activity, vasoconstriction and fl uid retention, and the long-term effects are myocyte hypertrophy, apoptosis and myocard fi brosis (left ventricular remodeling). There is also an increase in the production of vasodilatation mediators (prostaglan- dins, natriuretic peptides, bradykinin and others); however, these are unable to compensate for the adverse effects of vasoconstriction mediators. Diuretics are well- established in treatment, as are positive inotropic agents

administered in the short-term for acute or decompen- al infarction; MRA – mineral corticoid receptor antagonists. sated chronic heart failure. However, the highest success End-point Result Hospitalization for HF –35% <0.001 rate has been achieved through the administration of CV mortality –17% 0.005 medication that affects the sympathetic nervous system and the RAAS. Three groups of RAAS blocker are used in the clinical practice: inhibitors of the angiotensin-converting enzyme (median)

(ACE inhibitors), angiotensin II AT1 receptor blockers (AT1 blockers) and mineralocorticoid receptor blockers (MRA). Neither ACE inhibitors, nor AT1 blockers have a suf- fi cient effect on the increased aldosterone production. The prolonged activity of aldosterone causes fi brosis in Characteristics Follow-up LVEF ≤35% Mortality –31% <0.001 LVEF 33% Mortality –13% 0.008 the heart, the development of cardiac remodeling and LVEF ≤35% Mortality –24% 0.008 ventricular arrhythmias. Spironolactone is the basic medication in the group of mineralocorticoid receptor blockers. In some patients, its administration is limited due to adverse endocrine effects. These complications have been Average Average age eliminated by eplerenone, a spironolactone derivative that has been verifi ed in clinical studies in patients post– myocardial infarction left ventricular dysfunction as well as in patients with less advanced CHF. The verifi cation of patients the positive effects of mineralocorticoid receptor block- 1663 71 NYHA III–IV 24 M CV mortality –30.00% <0.001 ers has been confi rmed by several clinical studies – RALES with spironolactone, EPHESUS and EMPHASIS-HF with a eplerenone [1–3] (Table 1). In 1999, the RALES study proved a decrease in the mortality with a reduction in the hospitalization rate for patients with NYHA III and IV heart failure treated with spironolactone compared to placebo. The EPHESUS study published in 2003 contributed to the expanded indication of aldosterone antagonists; adding eplerenone to the es-

tablished medication for left ventricular dysfunction in Design Number of post-myocardial infarction patients resulted in a decrease in both the mortality and the frequency of hospitalizations. The EMPHASIS-HF clinical study published in 2011 shifted the use of eplerenone towards patients with chro nic heart failure and left ventricular systolic dysfunc- publication tion with mild symptoms (NYHA II). Eplerenone was developed in the effort to eliminate the adverse effects of the secondary hormonal effects of spironolactone. Chemically, it is 9D,11-epoxy-mexrenone Acronym Year of 1 – Clinical trials of MRAs in heart failure. Table Year Acronym RALES 1999 Spironolacton vs. placebo EPHESUS 2003 Eplerenone vs. placebo 6632 64 Post-MI HF 16 M CV mortality/CV hospitalization –13% 0.002 EMPHASIS-HF 2011 Eplerenone vs. placebo 2737 69 NYHA II 21 M CV mortality/hospitalization for HF –37% 0.001 Placebo – standard treatment including ACEI, potentially beta-blockers; CV cardiovascular; HF heart failure; MI myocardi

(CGP 30383) with the generic name eplerenone. In ex- a

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periments conducted on animals and healthy volunteers, selective coronary angiography and angioplasty of LAD the effectiveness of the doses 25 mg, 50 mg and 75 mg took place in 2003. In 2007, the patient was indicated for was proved, the dependence of natrium excretion on the heart resynchronization therapy and an ICD implantation dose was confi rmed and the equipotence of the 50 mg in primary prevention of sudden cardiac death. dose of eplerenone with 50 mg of commercial spirono- The patient had many comorbidities – chronic atrial lactone was determined. It was patented in 1985 and put fi brillation, type 2 diabetes mellitus, chronic renal insuffi - on the market in the form of 25 mg and 50 mg coated ciency, chronic obstructive pulmonary disease, metabolic tablets, and it was indicated so far exclusively as a supple- syndrome and hypothyreosis. Patient was contraindicated ment to standard therapy (including beta-blockers) for for heart transplantation because of the comorbidities. post-myocardial infarction left ventricular dysfunction In 2011, he was indicated for cardiac surgery due to when the ejection fraction falls below 40% and clinical signifi cant ischemic mitral and functional tricuspid re- symptoms of heart failure. gurgitation. CABG (coronary artery bypass grafting), In clinical trials, its use resulted in a decrease in both MVR (bioprosthetic mitral valve replacement), TVR (bio- the mortality and the frequency of hospitalizations; how- prosthetic tricuspid valve replacement) and Cryo MAZE ever, unlike spironolactone, the occurrence of hormon- were performed. For further treatment management and ally mediated disorders such as gynecomastia and erec- therapy titration, the patient was sent to a heart failure tile dysfunction is nearly twenty times lower after the clinic. Here, titration of the set therapy was performed; administration of eplerenone. The paracrine blockade of nonetheless, the patient’s condition required repeated aldosterone, in particular the reduction in collagen pro- hospital treatment for cardial decompensation. duction and perivascular fi brosis, is interpreted as a ben- The patient did not tolerate the treatment with an- efi cial effect of long-term eplerenone administration. giotensin converting enzyme inhibitors for symptomatic The bioavailability of eplerenone exceeds 90%, and the hypotension in concurrent therapy with BB and diuretics. excretion half-time is 3.5–5 hours; just as spironolactone, The recurrent signs of cardial decompensation and hy- it is metabolised by cytochrome P450 in the liver, and two pervolemia have been established in the course of further thirds are excreted in urine. Eplerenone has a lower affi n- patient monitoring. Diuretic treatment was increased in ity for mineralocorticoid receptors compared to spirono- the therapy, spironolactone was replaced with eplere- lactone, but its affi nity for androgen and progesterone none (intolerance of spironolactone – gynecomastia – receptors is lower by orders of magnitude. The occurrence had been documented for the patient) and the eplere- of gynecomastia was much lower in the EPHESUS study none dose was up-titrated. The patient was repeatedly compared to the RALES study (0.5%/0.6% compared to reeducated on the necessity to follow diet and regimen 9%/1%), and it was basically at the level of a placebo. As measures (fl uid and salt restrictions). After setting the for natrium excretion and impact on the Na/K quotient, therapy, clinical stabilization was achieved, and the pa- the effect of both medications is the same; it is easier to tient’s condition improved. Progression of his condition regulate in eplerenone – thanks to pharmacokinetics. The with heart failure decompensation occurred, and the occurrence of hyperkalemia with eplerenone administra- need for hospitalization arose in March 2015; diuretic tion was signifi cantly higher than with the placebo ad- therapy was intensifi ed. The dose of eplerenone was ministration; the statistical difference in the occurrence increased to 200 mg/day with frequent renal function of other adverse effects was insignifi cant. controls. The condition stabilized after that, enabling The reason for use of mineralocorticoid receptor an- discharge. The patient was followed on regular basis in tagonists is based on the fact that the long-term applica- a tertiary care clinic; chronic heart failure medication in- tion of ACE inhibitors and AT1 blockers results in a higher cluded carvedilol 12.5 mg 1-0-1, eplerenone 50 mg 2-0-2, concentration of aldosterone, which is undesirable ac- furosemide 250 mg 1-1-0, hydrochlorothiazid 25mg 1-0- cording to all the indications. Therefore, any treatment 0). His status remained stable until March 2016, requiring based on MRA becomes ineffective at a certain point. i.v. diuretic treatment in the hospital. He was discharged When the dose is chosen correctly, MRAs also contrib- clinically stable, functionally at NYHA II. From March 2016 ute to the correction of the potassium depletion known to January 2017 the patient’s status did not require re- to be caused by the ingestion of loop diuretics used in peated hospitalization. CHF therapy. In terms of clinical pharmacology, eplere- Unfortunately, the patient was admitted again to the none has obvious advantages in comparison with spi- hospital in January 2017 and in March 2017 the heart fail- ronolactone. ure progressed to refractory stage and the patient died in the hospital of multiorgan failure as a consequence of advanced heart failure. Case report

A male patient, born in 1950, with chronic heart failure Conclusion caused by coincidence of ischemic heart disease (IHD) and dilated cardiomyopathy (DCM). In 1999, he was diagnosed The clinical studies followed by the clinical practice have with IHD after a transmural infarction of the inferior wall shown an improvement in morbidity, mortality and a re- that was solved with a PTCA. He had already been dia- duction in the number of hospitalizations for heart failu- gnosed with heart failure at that point; the echocardio- re after eplerenone was added to the standard treatment gram conﬁ rmed a systolic function depression in a dilated of patients with chronic heart failure and left ventricular left ventricle with a 30-35% ejection fraction. Repeated systolic dysfunction. For safe treatment with eplerenone,

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Table 2 – Diuretic dose in chronic heart failure (modiﬁ ed from [5]) Loading dose Target dose Loop diuretic Furosemide 20–40 40–240 (250 mg) Thiazid diuretic Hydrochlorothiazide 25 12.5–100 Indapamid 2.5 2.5–5 Potassium sparing diuretic Regular and (–ACEI/ARB) Regular and (–ACEI/ARB) Spironolactone/eplerenone 12.5–25 50 50 100–200 Amiloride 2.5 5 5–10 10–20

(–ACEI/ARB) – diuretic dose in absence of ACEI or AT1 blocker (intolerance or contraindication)

an optimum dosage with regard to the current potassi- Ethical statement um level, renal function and careful laboratory monito- Authors state that the research was conducted according ring is essential. According to the ESC practice guidelines to ethical standards. for acute and chronic heart failure diagnostics and treatment, the administration of MRA (spironolactone and Informed consent eplerenone) is recommended to all symptomatic patients The authors declare that informed consent was obtained (regardless of ACEI and beta-blocker treatment) with from the patient participating in this study. HFrEF and LVEF at ≤ 35% with the aim to decrease mortality and hospitalization for heart failure. Caution must be taken in cases when MRA is administered to patients with References impaired renal function and patients with serum potassi- [1] B. Pitt, F. Zannad, W.J. Remme, et al., The effect of um concentrations at > 5.0 mmol/l. spironolactone on morbidity and mortality in patients with High initial and maintenance doses of MRA are neces- severe heart failure, New England Journal of Medicine 341 sary in patients with contraindications or patients who do (1999) 709–717. [2] B. Pitt, W. Remme, F. Zannad, et al., for the Eplerenone Post- not tolerate ACEI or ARB treatment [4,5] (Table 2). Acute Myocardial Infarction Heart Failure Efﬁcacy and Survival Our case report demonstrates that use of higher dose Study Investigators, Eplerenone, a selective aldosteron blocker, of MRA in addition to other drug therapy might be use- in patients with left ventricular dysfunction after myocardial ful in patients with advanced heart failure without other infarction, New England Journal of Medicine 348 (2003) 1309–1321. treatment options. High doses of eplerenone were associ- [3] F. Zannad, J.J.V. McMurray, H. Krum, et al., Eplerenone in ated with reduction of the frequency of hospital admis- patients with systolic heart failure and mild symptoms, New sions and need of i.v. diuretic treatment. This approach England Journal of Medicine 364 (2011) 11–21. probably also delayed the inevitable fatal course of the [4] P. Ponikowski, A.A. Voors, S.D. Anker, et al., ESC Guidelines disease. for the diagnosis and treatment of acute and chronic heart failure. The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Conﬂict of interest Cardiology (ESC), European Heart Journal 18 (2016) 891–975. None declared. [5] J. Špinar, J. Hradec, L. Špinarova, J. Vitovec, Souhrn Doporučených postupů ESC pro diagnostiku a léčbu akutního Funding body a chronického srdečního selhání z roku 2016, Cor et Vasa 58 (2016) e530–e568. None.

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