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

Place of Eplerenone in heart
failure treatment in Japan

Background

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The mineralocorticoid aldosterone has been implicated in the
pathophysiology of heart failure. Aldosterone binds to the mineralocorticoid
receptor (MR) which retains sodium thereby increasing plasma volume leading to
hypertension. Aldosterone also causes loss of magnesium and potassium,
dysregulation of peripheral nervous system, baroreflex impairment, myocardial
and vascular fibrosis, vascular damage and arterial compliance (1). Hence,
drugs targeting aldosterone or its receptor have been explored for treatment of
cardiac disorders (2).

Eplerenone is a mineralocorticoid receptor antagonist (MRA) belonging to
the spirolactone group of steroids. While other spirolactone steroids such as
spironolactone may also bind androgen receptor, eplerenone displays binding
specificity to mineralocorticoid receptor (MR). Eplerenone (marketed as Inspra® in US and EU and as Selara® in
Japan) was approved by US Food and Drug Administration in 2002 for use in
reducing cardiovascular mortality.

The Eplerenone Post–Acute Myocardial Infarction
Heart Failure Efficacy and Survival Study (EPHESUS) study conducted on western
population assessed the benefit of adding eplerenone to standard post-acute myocardial
infarction drug regimen. Patients (N= 6642) were randomized within 3 to 14 days
of myocardial infarction to receive either eplereonone (25 mg/day, titrable upto
50 mg/day) or matching placebo. At the end of trial, eplerenone significantly
reduced total mortality as well as death due to cardiovascular causes or
hospitalization for cardiovascular events (3). The Eplerenone in Mild Patients
Hospitalization and Survival Study in Heart Failure (EMPHASIS-HF) study
assessed whether use of eplerenone in addition to standard therapy is
beneficial in patients with systolic heart failure and mild symptoms (4).
Patients (N= 2737) suffering from NYHA functional class II symptoms were
randomized within six months after hospitalization for cardiovascular reason.
Patients received either eplerenone (25 mg once daily for first 4 weeks and 50
mg once daily till completion of trial) or matching placebo on top of
recommended medication for systolic heart failure. Mortality due to cardiovascular
causes or hospitalization for heart failure (primary outcome) was significantly
lower in eplerenone treated patients. Patients receiving eplerenone were also
significantly protected from death and hospitalization due to any cause. These
studies established safety and efficacy of eplerenone in management of heart
failure regardless of severity of symptoms. Consequently, European Society of
Cardiology and American College of Cardiology recommend eplerenone for therapy
to reduce mortality and hospitalization due to heart failure (5, 6).

Eplerenone in Japan

The Pharmaceuticals and Medical Devices Agency (PMDA) of Japan requires clinical
studies to be performed in Japanese population before approval for a new drug
or new indication of a previously available drug. As eplerenone was initially
indicated for hypertension in US and Europe, a clinical study was conducted to
assess efficacy and safety of eplerenone Japanese patients suffering from
hypertension (7). A total of 193 adult and elderly patients were randomized to
receive either eplerenone (50 mg, 100 mg or 200 mg per day) or placebo for 8
weeks. Inclusion criteria included seated cuff diastolic blood pressure ?95 mm Hg and < 115 mg Hg 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 of eplerenone reduced systolic and diastolic blood pressure in a dose dependent manner. Although more patients in eplerenone group experienced adverse events which may be linked to study medication than the placebo group, clinically relevant differences in incidence of adverse events were not observed. No patient reported hyperkalemia (potassium levels >5.5 mmol/L on two consecutive
measures, 24 to 72 hours apart). Overall, eplerenone was well tolerated.  Eplerenone was hence approved for hypertension
by the PMDA of Japan in November 2007 (8).

Although eplerenone up to a dose of 200 mg per day was safe and well
tolerated in Japanese hypertensive patients, its efficacy and safety in patients
with heart failure was not known. To fulfil the regulatory requirement of
evidence in Japanese population, a clinical trial with a small number of
patients (N = 221) was undertaken by Pfizer (Eplerenone
in Mild Patients Hospitalization and Survival Study in Heart Failure, J-EMPHASIS-HF) (9). The trial (NCT01115855) was performed with small patient population as it is
difficult to recruit large number of patients in a single country like Japan.
This multicenter, randomized, double-blind, placebo controlled study was
designed to evaluate consistency of results with those from EMPHASIS-HF.
Japanese patients ? 55 years of age were
recruited and randomized if they had –

i.                    
chronic
heart failure (ischemic or non-ischemic) for atleast 4 weeks

ii.                  
symptoms of
NYHA functional class II to IV

iii.                
left
ventricular ejection volume (LVEF) ?30 % (or ?35% in
addition to QRS duration >130 ms on ECG)

iv.                
treatment
with ACE inhibitor, ARB, ?-blocker or diuretic

v.                  
plasma
level of B-type natriuretic peptide (BNP) ? 250 pg/mL or plasma level of N-terminal proBNP
? 500
ng/ml (men) and ? 750 ng/mL (women) only if they had not been hospitalized six months
prior to randomization for non-cardiovascular cause.

The patients were excluded if they had –

i.                    
acute
myocardial infarction or stroke within 30 days prior to randomization (post-acute
cases) or

ii.                  
 serum potassium level (> 5 mEq/L) or

iii.                
estimated glomerular filtration
rate (eGFR) <30 mL/min/1.73 m2 within 24 h prior to randomization, iv.                 need for a potassium-sparing diuretic such as spironolactone v.                   any other clinically significant coexisting conditions Patients 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 receive either eplerenone or placebo. The dose of eplerenone was initiated at 25 mg once 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 was increased to 25 mg once daily thereafter. Serum potassium levels were monitored at each hospital visit (except months 2, 3 and 4). Dose of eplerenone was titrated down if serum potassium levels were found to be 5.5 to 5.9 mEq/L. Patients with serum potassium level ? 6 mEq/L, were asked to 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 of treatment was 48 months and the study was completed when the last recruited patient had been followed for 1 year. Analysis of results revealed that the demographic and base line characteristics (age, gender, BMI, heart rate, systolic and diastolic blood pressure, LVEF, NYHA class symptoms and principal causes of heart failure, serum levels of therapeutically important markers, medication and medical history) were similar in placebo and eplerenone treated groups. As compared to base line characteristics of EMPHASIS-HF study, Japanese patients had lower BMI, eGFR, prevalence of ischemic heart failure, and use of ACE inhibitor. The prevalence of idiopathic dilated cardiomyopathy of use of ARB were found to be higher in Japanese patients. Eplerenone reduced death/hospitalization from cardiovascular causes as compared 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 eplerenone was observed across NYHA and eGFR subgroups.                                     Fig. 1: Kaplan- Meier plots for death/hospitalization due to cardiovascular cause (A), hospitalization for any cause (B), hospitalization for heart failure (C) and death from any cause (D). The numbers below the graphs represent number of patients at that time point. CI – confidence interval.   The hazard ratios for death or hospitalization due to cardiovascular cause appeared to be higher in patients not using ACE inhibitor/ARB or undergoing atrial fibrillation. However, owing to small sample size, no definite conclusion could be drawn.   Primary analysis of data also revealed that although the rate of death from cardiovascular causes or any cause to be higher in eplerenone treated group, it was not statistically significant. On-treatment analysis performed after unblinding of data revealed lower hazard ratios in patients who completed therapy. 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). This trial also measured plasma BNP and LVEF levels which was not done in EMPHASIS trial. Eplerenone reduced plasma BNP levels and increased LVEF.   Fig. 2: Plasma BNP levels (A) and left ventricular ejection 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 major reason for discontinuation was adverse events (16 patients in eplerenone and 18 in placebo) followed by death (6 in eplerenone and 5 in placebo). The incidence of 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 well tolerated in Japanese patients and showed consistent results as obtained from similar studies performed in the western population (i.e. EMPHASIS-HF). Upon completion of this study, the PMDA approved use of eplerenone for heart failure in December 2016 (Ref.). Currently, Selara® is listed for Early Post-marketing Phase Vigilance (EPPV) by PMDA. Selara® is also undergoing two clinical trials in Japan. The first trial (NCT03342690), sponsored by Pfizer, is studying safety and effectiveness of Selara® under Japanese medical practices. This observational study with estimated enrollment of 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 from moderate renal impairment while secondary outcomes include percentage of subjects with adverse event in participants as well as incidence of deaths due to cardiovascular or non-cardiovascular reasons. The second study funded by Japanese government is a double-blind, randomized multicentre trial assessing benefits of eplerenone in patients suffering from acute heart failure (study abbreviated as EARLIER) (10). This study, similar to EPHESUS trial, enrols patients within 72 hours of hospital visit and patients are randomized to receive eplerenone (25 to 50 mg) or placebo. The primary outcome of this trial is a composite of death or hospitalization due to cardiac reasons. This is the first study to assess the effect of eplerenone on quality of life by monitoring exercise capacity. The results of these two studies are expected to provide further evidence regarding safety and efficacy of eplerenone in management of heart failure among Japanese population.