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 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)