Place (25 mg/day, titrable upto 50 mg/day) or

Place of Eplerenone in heartfailure treatment in JapanBackgroundThe mineralocorticoid aldosterone has been implicated in thepathophysiology of heart failure. Aldosterone binds to the mineralocorticoidreceptor (MR) which retains sodium thereby increasing plasma volume leading tohypertension. Aldosterone also causes loss of magnesium and potassium,dysregulation of peripheral nervous system, baroreflex impairment, myocardialand vascular fibrosis, vascular damage and arterial compliance (1). Hence,drugs targeting aldosterone or its receptor have been explored for treatment ofcardiac disorders (2). Eplerenone is a mineralocorticoid receptor antagonist (MRA) belonging tothe spirolactone group of steroids. While other spirolactone steroids such asspironolactone may also bind androgen receptor, eplerenone displays bindingspecificity to mineralocorticoid receptor (MR). Eplerenone (marketed as Inspra® in US and EU and as Selara® inJapan) was approved by US Food and Drug Administration in 2002 for use inreducing cardiovascular mortality. The Eplerenone Post–Acute Myocardial InfarctionHeart Failure Efficacy and Survival Study (EPHESUS) study conducted on westernpopulation assessed the benefit of adding eplerenone to standard post-acute myocardialinfarction drug regimen.

Patients (N= 6642) were randomized within 3 to 14 daysof myocardial infarction to receive either eplereonone (25 mg/day, titrable upto50 mg/day) or matching placebo. At the end of trial, eplerenone significantlyreduced total mortality as well as death due to cardiovascular causes orhospitalization for cardiovascular events (3). The Eplerenone in Mild PatientsHospitalization and Survival Study in Heart Failure (EMPHASIS-HF) studyassessed whether use of eplerenone in addition to standard therapy isbeneficial in patients with systolic heart failure and mild symptoms (4).Patients (N= 2737) suffering from NYHA functional class II symptoms wererandomized within six months after hospitalization for cardiovascular reason.Patients received either eplerenone (25 mg once daily for first 4 weeks and 50mg once daily till completion of trial) or matching placebo on top ofrecommended medication for systolic heart failure. Mortality due to cardiovascularcauses or hospitalization for heart failure (primary outcome) was significantlylower in eplerenone treated patients.

Patients receiving eplerenone were alsosignificantly protected from death and hospitalization due to any cause. Thesestudies established safety and efficacy of eplerenone in management of heartfailure regardless of severity of symptoms. Consequently, European Society ofCardiology and American College of Cardiology recommend eplerenone for therapyto reduce mortality and hospitalization due to heart failure (5, 6).Eplerenone in JapanThe Pharmaceuticals and Medical Devices Agency (PMDA) of Japan requires clinicalstudies to be performed in Japanese population before approval for a new drugor new indication of a previously available drug. As eplerenone was initiallyindicated for hypertension in US and Europe, a clinical study was conducted toassess efficacy and safety of eplerenone Japanese patients suffering fromhypertension (7). A total of 193 adult and elderly patients were randomized toreceive either eplerenone (50 mg, 100 mg or 200 mg per day) or placebo for 8weeks. Inclusion criteria included seated cuff diastolic blood pressure ?95 mm Hg and < 115 mgHg and serum potassium level ?3.

5 mmol/L to ? 5 mmol/L. Patients suffering from arrhythmia,severe hypertension, heart failure, other cardiac disorders, cancer, diabetes,liver and kidney disorders were excluded. Results showed that all the doses ofeplerenone reduced systolic and diastolic blood pressure in a dose dependentmanner. Although more patients in eplerenone group experienced adverse eventswhich may be linked to study medication than the placebo group, clinicallyrelevant differences in incidence of adverse events were not observed. Nopatient reported hyperkalemia (potassium levels >5.

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5 mmol/L on two consecutivemeasures, 24 to 72 hours apart). Overall, eplerenone was well tolerated.  Eplerenone was hence approved for hypertensionby the PMDA of Japan in November 2007 (8).Although eplerenone up to a dose of 200 mg per day was safe and welltolerated in Japanese hypertensive patients, its efficacy and safety in patientswith heart failure was not known. To fulfil the regulatory requirement ofevidence in Japanese population, a clinical trial with a small number ofpatients (N = 221) was undertaken by Pfizer (Eplerenonein Mild Patients Hospitalization and Survival Study in Heart Failure, J-EMPHASIS-HF) (9). The trial (NCT01115855) was performed with small patient population as it isdifficult to recruit large number of patients in a single country like Japan.This multicenter, randomized, double-blind, placebo controlled study wasdesigned to evaluate consistency of results with those from EMPHASIS-HF.

Japanese patients ? 55 years of age wererecruited and randomized if they had – i.                    chronicheart failure (ischemic or non-ischemic) for atleast 4 weeksii.                  symptoms ofNYHA functional class II to IViii.                leftventricular ejection volume (LVEF) ?30 % (or ?35% inaddition to QRS duration >130 ms on ECG)iv.                treatmentwith ACE inhibitor, ARB, ?-blocker or diureticv.                  plasmalevel of B-type natriuretic peptide (BNP) ? 250 pg/mL or plasma level of N-terminal proBNP? 500ng/ml (men) and ? 750 ng/mL (women) only if they had not been hospitalized six monthsprior to randomization for non-cardiovascular cause.The patients were excluded if they had –i.

                    acutemyocardial infarction or stroke within 30 days prior to randomization (post-acutecases) orii.                   serum potassium level (> 5 mEq/L) oriii.                estimated glomerular filtrationrate (eGFR) <30 mL/min/1.73 m2 within 24 h prior torandomization, iv.                need for a potassium-sparingdiuretic such as spironolactonev.

                  any otherclinically significant coexisting conditionsPatients were stratified on NYHA class symptoms (class II and III/IV)and eGFR (30 to <50 mL/min/1.73 m2 and?50 mL/min/1.73 m2) within 24 h before randomization to receiveeither eplerenone or placebo.

The dose of eplerenone was initiated at 25 mgonce daily for first 4 weeks and increased to 50 mg once daily if the serum potassium level was < 5 mEq/L.In patients with eGFR 30 to <50 mL/min/1.73 m2,dose was initiated at 25 mg every alternate day for first 4 weeks and it wasincreased to 25 mg once daily thereafter. Serum potassium levels were monitoredat each hospital visit (except months 2, 3 and 4). Dose of eplerenone was titrateddown if serum potassium levels were found to be 5.5 to 5.9 mEq/L. Patients withserum potassium level ? 6 mEq/L, were askedto withhold drug and the drug was started if serum potassium levels reduced to< 5 mEq/L within 72 hours of stopping the drug.

The maximum duration oftreatment was 48 months and the study was completed when the last recruitedpatient had been followed for 1 year.Analysis of results revealed that the demographic and base linecharacteristics (age, gender, BMI, heart rate, systolic and diastolic bloodpressure, LVEF, NYHA class symptoms and principal causes of heart failure,serum levels of therapeutically important markers, medication and medicalhistory) were similar in placebo and eplerenone treated groups. As compared tobase line characteristics of EMPHASIS-HF study, Japanese patients had lowerBMI, eGFR, prevalence of ischemic heart failure, and use of ACE inhibitor. Theprevalence of idiopathic dilated cardiomyopathy of use of ARB were found to behigher in Japanese patients.Eplerenone reduced death/hospitalization from cardiovascular causes ascompared to placebo. However, this reduction did not reach statistical significance(P= 0.5).

Eplerenone significantly reduced hospitalization due to for any cause(hazard ratio, 0.65; 95% CI, 0.44–0.97, P=0.

03) (Fig. 1). The protective effect of eplerenonewas observed across NYHA and eGFR subgroups.                   Fig. 1: Kaplan- Meier plots for death/hospitalizationdue to cardiovascular cause (A), hospitalization for any cause (B),hospitalization for heart failure (C) and death from any cause (D). The numbersbelow the graphs represent number of patients at that time point.

CI –confidence interval. The hazard ratios for death or hospitalization due to cardiovascularcause appeared to be higher in patients not using ACE inhibitor/ARB orundergoing atrial fibrillation. However, owing to small sample size, nodefinite conclusion could be drawn.  Primary analysis of data also revealed that although the rate of deathfrom cardiovascular causes or any cause to be higher in eplerenone treatedgroup, it was not statistically significant. On-treatment analysis performedafter unblinding of data revealed lower hazard ratios in patients who completedtherapy.

This was true for death from any cause (1.36 vs 1.77 in primary analysis)and death from cardiovascular causes (1.74 vs 2.40 in primary analysis). Thistrial also measured plasma BNP and LVEF levels which was not done in EMPHASIStrial.

Eplerenone reduced plasma BNP levels and increased LVEF. Fig. 2: Plasma BNP levels (A) and left ventricularejection fraction (LVEF) (B) across duration of study trial. Values are mean ± S.E. * represents P<0.

05. From each group, 36 patients discontinued from the study. The majorreason for discontinuation was adverse events (16 patients in eplerenone and 18in placebo) followed by death (6 in eplerenone and 5 in placebo). The incidenceof adverse events was similar between the two groups except for hypokalemia(1.8% in eplerenone vs 10 % in placebo, P=0.01). Overall, eplerenone was welltolerated in Japanese patients and showed consistent results as obtained fromsimilar studies performed in the western population (i.e.

EMPHASIS-HF). Uponcompletion of this study, the PMDA approved use of eplerenone for heart failurein December 2016 (Ref.). Currently, Selara® is listed for Early Post-marketing PhaseVigilance (EPPV) by PMDA. Selara® is also undergoing two clinical trials inJapan. The first trial (NCT03342690), sponsored byPfizer, is studying safety and effectiveness of Selara® underJapanese medical practices. This observational study with estimated enrollmentof 1000 participants uses the same dosing strategy as that for J-EMPHASIS-HF.The primary outcome of this study is adverse events in patients suffering frommoderate renal impairment while secondary outcomes include percentage of subjectswith adverse event in participants as well as incidence of deaths due tocardiovascular or non-cardiovascular reasons.

The second study funded by Japanese government is a double-blind,randomized multicentre trial assessing benefits of eplerenone in patientssuffering from acute heart failure (study abbreviated as EARLIER) (10). Thisstudy, similar to EPHESUS trial, enrols patients within 72 hours of hospitalvisit and patients are randomized to receive eplerenone (25 to 50 mg) orplacebo. The primary outcome of this trial is a composite of death orhospitalization due to cardiac reasons. This is the first study to assess theeffect of eplerenone on quality of life by monitoring exercise capacity.

Theresults of these two studies are expected to provide further evidence regardingsafety and efficacy of eplerenone in management of heart failure among Japanesepopulation.