A Randomized Controlled Study of Finerenone vs. Eplerenone in Japanese Patients With Worsening Chronic Heart Failure and Diabetes and/or Chronic Kidney Disease

Naoki Sato; Masayoshi Ajioka; Takahisa Yamada; Masaharu Kato; Masafumi Myoishi; Takashi Yamada; So-Young Kim; Christina Nowack; Peter Kolkhof; Tsuyoshi Shiga; on behalf of the ARTS-HF Japan study group

doi:10.1253/circj.CJ-16-0122

Abstract

Background: Finerenone, a nonsteroidal mineralocorticoid receptor antagonist, was evaluated in Japanese patients with heart failure (HF) with reduced ejection fraction and chronic kidney disease and/or diabetes mellitus.

Methods and Results: ARTS-HF Japan was a randomized, double-blind, phase 2b study. Patients (n=72) received oral, once-daily (o.d.) finerenone (2.5, 5, 7.5, 10 or 15 mg, up-titrated to 5, 10, 15, 20, or 20 mg, respectively, on day 30) or eplerenone (25 mg every other day, increased to 25 mg o.d. on day 30, and 50 mg on day 60) for 90 days. The primary endpoint was the proportion of individuals with a decrease of >30% in plasma NT-proBNP at day 90. Safety endpoints included the incidence of hyperkalemia. Decreases in NT-proBNP occurred in 23.1% of patients in the eplerenone group and 15.4%, 23.1%, 45.5%, 27.3% and 45.5% in the 2.5→5 mg, 5→10 mg, 7.5→15 mg, 10→20 mg and 15→20 mg finerenone groups, respectively (all P=NS). Mean changes in serum potassium levels were similar between groups.

Conclusions: Because of the small sample size, limited conclusions can be drawn. Considering the results of ARTS-HF and that finerenone was well tolerated in Japanese patients in ARTS-HF Japan, the safety and efficacy of finerenone should be further explored in a large outcomes trial including Japanese patients. (Circ J 2016; 80: 1113–1122)

Anti-aldosterone therapy is recommended in Japanese guidelines for the treatment of chronic heart failure (CHF).¹ The steroidal mineralocorticoid receptor antagonists (MRAs) spironolactone² and eplerenone³ reduce mortality and hospitalizations in patients with HF with reduced ejection fraction (HFrEF), and are recommended in European and US guidelines for symptomatic patients with HFrEF.⁴^–⁶ However, fear of inducing hyperkalemia and the worsening renal function that are associated with the use of steroidal MRAs⁷^,⁸ is the leading cause for suboptimal use in clinical practice,⁹ particularly for patients sensitive to developing hyperkalemia, including those with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD). A drug that is as effective as the steroidal MRAs but induces a lower risk of serious side effects could improve outcomes for patients HF.

Finerenone (BAY 94-8862) is a novel nonsteroidal MRA that combines high potency and selectivity for the MR.¹⁰ Based on its nonsteroidal structure, finerenone has different physicochemical properties, tissue distribution and mode of MR inactivation than steroidal MRAs.¹¹^,¹² These different molecular properties of finerenone translate into specific pharmacodynamic properties; for example, finerenone reduces cardiac and renal hypertrophy, the plasma prohormone of B-type natriuretic peptide (BNP), and proteinuria more effectively than the steroidal MRA eplerenone, when comparing equi-natriuretic doses in rats.¹³

In the international phase 2a minerAlocorticoid Receptor antagonist Tolerability Study (ARTS), finerenone (5.0–10.0 mg/day) had a comparable efficacy to that of spironolactone (25 mg/day or 50 mg/day) in patients with HFrEF and CKD. Smaller increases in serum potassium level and smaller decreases in estimated glomerular filtration rate (eGFR) were observed in the finerenone group than in the spironolactone group.¹⁴ Furthermore, the international phase 2b trial ARTS-Heart Failure (ARTS-HF) in patients with worsening CHF and T2DM and/or CKD showed that finerenone was well tolerated and the proportion of patients with a decrease in N-terminal pro-BNP (NT-proBNP) of 30% from baseline to day 90 was similar in the finerenone groups to that in the eplerenone group.¹⁵

The international phase 2b ARTS-Diabetic Nephropathy (ARTS-DN) conducted in patients with diabetic kidney disease showed that finerenone therapy led to improvements in the urinary-albumin-creatinine ratio, with a similar safety profile as placebo.¹⁶

Based on the international ARTS-HF, the ARTS-HF Japan (Clinicaltrials.gov Identifier: NCT01955694) was designed to investigate the safety and efficacy of 5 treatment regimens of once-daily (o.d.) oral doses of finerenone in Japanese patients with concomitant T2DM and/or CKD, who presented to emergency departments with worsening chronic HFrEF.

Methods

Study Design

As this was the first study to investigate finerenone in Japanese patients with HFrEF and CKD and/or diabetes, the Pharmaceuticals and Medical Devices Agency (PMDA) requested the study design of ARTS-HF include additional mandatory visits in the first month of treatment in order to assure careful monitoring of serum potassium as was performed in the first global ARTS study.¹¹ In addition, a gradual introduction in the high-dose treatment groups was requested. Both requests made it necessary to set up a stand-alone study in Japan and not include Japanese patients in the globally conducted ARTS-HF study.

The design of ARTS-HF Japan is based on the design of the international ARTS-HF,¹⁷ and was a randomized, double-blind, active-comparator-controlled, parallel-group, phase 2b, dose-finding study conducted at 31 centers in Japan. The study protocol was developed by the sponsor (Bayer Yakuhin Ltd), and was approved by independent ethics committees and/or institutional review boards for all participating centers before the study began. The study was carried out in accordance with Good Clinical Practice guidelines, the guiding principles of the Declaration of Helsinki, and applicable local laws and regulations. All participating patients gave written informed consent. Safety and tolerability were monitored by an independent Data Safety Monitoring Committee (DMC).

The key differences in the design of ARTS-HF Japan and ARTS-HF were the following: the sample size was much smaller (up to 72 patients randomized vs. ≤1,060 in ARTS-HF), reflecting the fact that this was a single-country study rather than a global study; there were 2 dose decision meetings rather than 1 to decide whether to introduce higher doses of finerenone to the study; there were 6 mandatory study visits during the acute/vulnerable phase of the study (up to day 30), compared with 5 visits (only 2 of which were mandatory for all patients) in the same phase of ARTS-HF.

Patients

The main inclusion and exclusion criteria are shown in Table 1. Briefly, patients were eligible for inclusion in the study if they were at least 18 years old and had worsening chronic HFrEF requiring emergency presentation to hospital and treatment with intravenous diuretics. They also had to have T2DM and/or CKD, have been receiving treatment with evidence-based therapy for CHF for at least 3 months, and have a medical history of a left ventricular EF ≤40% within the previous 12 months. Patients receiving treatment with spironolactone, eplerenone, renin inhibitors, or potassium-sparing diuretics at presentation had to be able to discontinue those treatments for 24 h before randomization (48 h for spironolactone) and for the duration of the study treatment period.

Table 1. Inclusion and Exclusion Criteria in ARTS-HF Japan

Main inclusion criteria	Main exclusion criteria
Written informed consent signed before any study-specific procedure	Acute de novo HF or acute inflammatory heart disease
Men and non-pregnant, non-lactating women aged ≥18 years	ACS^c in the 30 days prior to the screening visit
Women of childbearing potential must agree to use adequate contraception (a combination of ≥2 effective methods of birth c ontrol, of which ≥1 is a physical barrier)	Cardiogenic shock
Worsening of chronic HF requiring emergency presentation to hospital and treatment with IV diuretics at hospital	Valvular heart disease requiring surgical intervention during the course of the study
Treatment with ≥1 of the following for ≥3 months prior to emergency presentation to hospital: β-blocker, ACEI or ARB (not both), MRA or diuretic	Patients with a left ventricular assistance device or awaiting heart transplantation
Medical history of LVEF ≤40% measured by any modality within the past 12 months without intervening revascularization or cardiac surgery in the meantime; for individuals with cardiac intervention, LVEF must be reassessed and LVEF ≤40% must be reconfirmed after the intervention	Stroke or TIA ≤3 months before the screening visit
BNP concentration >255 pg/ml or plasma NT-proBNP concentration >1,200 pg/ml at any time during emergency presentation to hospital, but at the latest at the screening visit	Known hypersensitivity to the study drug (active substance or excipients) or eplerenone
Patients with T2DM must fulfil ≥1 of the following:	Addison’s disease
• Receiving oral antidiabetics and/or insulin	Acute infectious disease requiring IV antibiotics within the last 24h before randomization
• Documented fasting glucose concentration ≥7.0 mmol/L in their medical history	Dialysis for acute renal failure within the previous 3 months prior to emergency presentation to hospital
• 2-h plasma glucose concentration ≥11.1 mmol/L during an OGTT	Hepatic insufficiency (Child-Pugh B or C)
• Medical history of HbA_1c concentration ≥6.5%^a	Requirement for any IV vasodilator, any IV natriuretic peptide within the 24 h prior to randomization, or any IV positive inotrope within the 14 days prior to dosing with study drug
and have an eGFR^b ≥30 ml/min/1.73 m²	Treatment with either spironolactone or eplerenone that cannot be discontinued 48 h or 24 h, respectively, before randomization and for the duration of the treatment period
Patients without T2DM must have an eGFR^b of 30–60 ml/min/1.73 m² at screening	Treatment with any renin inhibitor or potassium-sparing diuretic that cannot be discontinued 24 h before randomization and for the duration of the treatment period
Blood potassium concentration ≤5.0 mmol/L at screening	Treatment with high-dose ASA (>500 mg/day) or another NSAID
SBP ≥90 mmHg without signs or symptoms of hypotension	Treatment with potent CYP3A4 inhibitors or inducers or strong CYP2C8 inhibitors (all must be stopped ≥7 days before randomization)
Ability to understand and follow study-related instructions

^aAs defined in the National Glycohemoglobin Standardization Program or the Diabetes Control and Complications Trial. ^bAs measured using the Modification of Diet in Renal Disease equation. ^cAs defined by the European Society of Cardiology⁴² and American College of Cardiology/American Heart Association⁴³ guidelines. ACEI, angiotensin-converting enzyme inhibitor; ACS, acute coronary syndromes; ARB, angiotensin-receptor blocker; ASA, acetylsalicylic acid; BNP, B-type natriuretic peptide; CKD, chronic kidney disease; CYP, cytochrome P450; eGFR, estimated glomerular filtration rate; HbA_1c, glycated hemoglobin; HF, heart failure; IV, intravenous; LVEF, left ventricular ejection fraction; MRA, mineralocorticoid receptor antagonist; NSAID, non-steroidal anti-inflammatory drug; NT-proBNP, N-terminal proBNP; OGTT, oral glucose tolerance test; SBP, systolic blood pressure; T2DM, type 2 diabetes mellitus; TIA, transient ischemic attack.

Dosing, Randomization, and Masking

The randomization listings were generated by the Randomization Management Group of the sponsor using a computer program, and participants, investigators and the sponsor’s clinical team were blinded to treatment allocation. The daily doses in the 5 preplanned finerenone treatment arms (presented as “initial dose→maintenance dose”; see Procedures section) were 2.5→5 mg, 5→10 mg, 7.5→15 mg, 10→20 mg and 15→20 mg. The initial dose in the eplerenone treatment arm was 25 mg every other day; this could be increased to 25 mg o.d. and then to 50 mg o.d. if both uptitration steps were performed. Uptitration of both study drugs in all dose groups was performed if serum potassium levels remained at 5.0 mmol/L or less.

Patients were initially randomized 1:1:1 during the 7 days following hospital presentation to 1 of the 2 lowest preplanned finerenone doses (2.5→5 mg or 5→10 mg o.d.) or eplerenone. The first DMC assessed safety and tolerability in the initial treatment arms after 10 patients had been treated for 60 days and the finerenone 7.5→15 mg group was introduced into the study based on the DMC recommendation. Following further assessment and recommendation by a second DMC meeting of safety and tolerability in all treatment arms after 27 patients had been treated for 60 days, the 2 remaining finerenone arms (10→20 mg, and 15→20 mg) were also introduced. Thus, in total 6 treatment arms were tested in the study. The randomization scheme was adapted to achieve a final randomization ratio of approximately 1:1 between each finerenone dose group and the eplerenone group.

Procedures

Finerenone or eplerenone was administered on top of standard therapy for HF. The planned treatment duration was 90 days, with an additional follow-up period after the cessation of study drug for 30 days.

If the blood potassium concentration was ≤5.0 mmol/L, the initial dose of finerenone or eplerenone was uptitrated at the end of the acute/vulnerable phase (day 30), and an additional uptitration (eplerenone) or sham uptitration (finerenone) was performed at day 60. Treatment with the study drug was required by the protocol to be terminated if the patient had a confirmed blood potassium concentration ≥5.6 mmol/L.

Outcomes

The primary efficacy endpoint was the percentage of subjects with a relative decrease in NT-proBNP >30% from baseline to day 90.

Further exploratory efficacy endpoints included: deaths and hospitalizations for cardiovascular causes and emergency presentation for worsening CHF (these events were defined by the sponsor); effects of each dose on BNP, and NT-proBNP at days 30, 60 and 90; and change in health-related quality of life from baseline to day 30 and day 90 using the Kansas City Cardiomyopathy Questionnaire (KCCQ) and EuroQol Group 5-dimension, 3-level questionnaire (EQ-5D-3L).

Safety outcomes were the incidence of adverse events, including those of special interest (ie, emergency presentation for worsening CHF and an increase in serum potassium concentration to ≥5.6 mmol/L leading to discontinuation of study drug); laboratory parameters (including potassium and serum creatinine concentrations and eGFR [measured using the Modification of Diet in Renal Disease equation¹⁸]); vital signs; and results of ECGs.

Statistical Analysis

Analyses were performed in 3 data sets: the safety-analysis set (all randomized patients who took at least 1 dose of study drug with data after the start beginning of treatment), full-analysis set (all patients from the safety-analysis set who had baseline and at least 1 post-baseline NT-proBNP value or who died or who experienced permanent [≥5 consecutive days] withdrawal of study drug after cardiovascular hospitalization or after emergency presentation for worsening CHF), and per-protocol set (all patients in the full-analysis set who had valid NT-proBNP data at day 60 or later and had no major protocol deviations).

The primary endpoint was assessed in the full-analysis set, with missing data imputed using a last observation carried forward approach in combination with the non-responder imputation: the highest NT-proBNP value from the premature discontinuation measurement and the follow-up measurement were used for subjects discontinuing study treatment and for whom the non-responder imputation was not applicable; a supportive analysis was performed in the per-protocol set and sensitivity analyses of the imputation method were performed in the full-analysis set. For the primary endpoint, each finerenone group was compared with the eplerenone group using Fisher’s exact test at a nominal one-sided significance level of 5%. Exploratory two-sided 90% confidence intervals (CIs) were provided for each treatment group and treatment differences.

Patients who died before day 90, or who permanently discontinued (≥5 consecutive days) the study drug after cardiovascular hospitalization or after emergency hospital presentation for worsening CHF, were considered non-responders to avoid biasing the primary efficacy analysis towards treatment responders.

The log-transformed ratio to baseline of NT-proBNP at day 90 was analyzed by ANCOVA with treatment group as the main effect and the factors comorbidities, MRA use at emergency presentation to hospital, atrial fibrillation, and the log-transformed baseline value as covariate. The treatment effect was tested at a nominal two-sided significance level of 5%. Pairwise ratios between each finerenone treatment group and the eplerenone treatment group were calculated, and corresponding exploratory two-sided 95% CIs were computed.

This was an exploratory study; no confirmatory testing of the primary efficacy variable or other variables was performed. No formal sample size calculation was performed. The sample size was chosen for reasons of feasibility rather than any power calculation; 12 patients per dose arm were considered sufficient to investigate finerenone’s safety and efficacy in the target population.

Results

Patients

The disposition of the patients throughout the study is shown in Figure 1.

Figure 1.

Patient disposition in ARTS-HF Japan. All patients from the safety-analysis set were considered for the full-analysis set. Patients were excluded from the full-analysis set if they: did not have baseline and at least one post-baseline plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) level value; died; experienced permanent (≥5 consecutive days) withdrawal of study drug after cardiovascular hospitalization or after emergency presentation for worsening chronic heart failure. The per-protocol set comprised all patients from the full-analysis set with valid plasma NT-proBNP data at day 60 or later and no major protocol deviations.

Of the 72 randomized patients, 45 (62.5%) were receiving an angiotensin-converting enzyme inhibitor (ACEI) or an angiotensin-receptor blocker (ARB) and 63 (87.5%) were receiving a β-blocker at baseline (Table 2). Mean age was 73.1 years. Median NT-proBNP concentration at baseline was highest in the finerenone 15→20 mg dose group (4,627.4 [range 2,593–16,348] pg/ml) and lowest in the finerenone 5→10 mg dose group (1,873.0 [range 674–18,247] pg/ml). Mean eGFR at baseline was highest in the eplerenone group (47.2 ml/min/1.73 m²) and lowest in the finerenone 15→20 mg dose group (37.5 ml/min/1.73 m²). Mean potassium concentration at baseline was highest in the finerenone 2.5→5 mg dose group (4.1 mmol/L) and lowest in the eplerenone group (3.8 mmol/L).

Table 2. Patient Demographics and Clinical Characteristics (Safety-Analysis Set) in ARTS-HF Japan

Parameter	Eplerenone (n=13)	Finerenone 2.5→5 mg (n=13)	Finerenone 5→10 mg (n=13)	Finerenone 7.5→15 mg (n=11)	Finerenone 10→20 mg (n=11)	Finerenone 15→20 mg (n=11)	Total (n=72)
Mean age (years)	76.5	73.2	71.2	78.2	65.9	73.5	73.1
Male sex, n (%)	12 (92.3)	11 (84.6)	9 (69.2)	6 (54.5)	8 (72.7)	7 (63.6)	53 (73.6)
NYHA functional class before worsening, n (%)
II	7 (53.8)	9 (69.2)	11 (84.6)	10 (90.9)	10 (90.9)	10 (90.9)	57 (79.2)
III	5 (38.5)	3 (23.1)	2 (15.4)	0	1 (9.1)	1 (9.1)	12 (16.7)
IV	1 (7.7)	1 (7.7)	0	1 (9.1)	0	0	3 (4.2)
Risk factors, n (%)
Type 2 DM without CKD	3 (23.1)	2 (15.4)	2 (15.4)	3 (27.3)	1 (9.1)	1 (9.1)	12 (16.7)
Type 2 DM with CKD	3 (23.1)	6 (46.2)	4 (30.8)	5 (45.5)	7 (63.6)	5 (45.5)	30 (41.7)
CKD without type 2 DM	7 (53.8)	5 (38.5)	7 (53.8)	3 (27.3)	3 (27.3)	5 (45.5)	30 (41.7)
Ischemic heart disease	7 (53.8)	4 (30.8)	4 (30.8)	7 (63.6)	6 (54.5)	5 (45.5)	33 (45.8)
Arterial hypertension	10 (76.9)	7 (53.8)	9 (69.2)	10 (90.9)	7 (63.6)	8 (72.7)	51 (70.8)
Atrial fibrillation-ECG at baseline	5 (38.5)	5 (38.5)	3 (23.1)	4 (36.4)	2 (18.2)	5 (45.5)	24 (33.3)
Heart failure medications, n (%)
ACEI/ARB at baseline	9 (69.2)	9 (69.2)	8 (61.5)	9 (81.8)	5 (45.5)	5 (45.5)	45 (62.5)
β-blocker at baseline	11 (84.6)	12 (92.3)	13 (100.0)	7 (63.6)	11 (100.0)	9 (81.8)	63 (87.5)
Median NT-proBNP concentration, pg/ml	3,847.7	1,966.2	1,873.0	3,762.9	4,508.7	4,627.4	3,407.0
Median BNP concentration, pg/ml	741.0	598.0	565.0	586.0	935.0	555.0	662.0
Mean K concentration, mmol/L	3.8	4.1	4.0	4.0	4.0	4.1	4.0
Mean eGFR*, ml/min/1.73 m²	47.2	41.7	42.3	44.9	39.4	37.5	42.3
eGFR* ≤60 ml/min/1.73 m², n (%)	11 (84.6)	13 (100)	12 (92.3)	9 (81.8)	10 (90.9)	10 (90.9)	65 (90.3)
Mean creatinine concentration, mg/dl	1.3	1.3	1.3	1.2	1.4	1.4	1.3
Mean urinary albumin:creatinine ratio, g/kg	96.1	169.4	27.7	72.2	99.4	339.7	131.0
High/very high albuminuria, n (%)	6 (46.2)	5 (38.5)	3 (23.1)	7 (63.6)	7 (63.6)	9 (81.8)	37 (51.4)
Mean SBP, mmHg	110.9	113.6	105.1	113.1	109.3	124.2	112.5
Mean heart rate, beats/min	63.3	79.2	70.2	69.6	72.8	72.6	71.3
Mean ejection fraction, %	30.2	30.0	27.1	27.6	30.7	30.7	29.4

*eGFR was calculated using the Modification of Diet in Renal Disease equation. DM, diabetes mellitus; NYHA, New York Heart Association. Other abbreviations as in Table 1.

Dosing

In the safety-analysis set the target maintenance doses were reached by 10/13 (77%) of patients in the finerenone 2.5→5 mg group, 12/13 (92%) of the 5→10 mg group, 9/11 (82%) of the 7.5→15 mg group, 6/11 (55%) of the 10→20 mg group, and 9/11 (82%) of the 15→20 mg group. In the eplerenone group, 10/13 patients (77%) reached the 50 mg/day dose, 2/13 (15%) reached the 25 mg/day dose, and 1/13 (7%) remained on eplerenone 25 mg every other day.

Efficacy

Primary Efficacy Endpoint The number of patients who had an NT-proBNP level decrease of >30% at day 90 compared with baseline in the full-analysis set was numerically higher in the 3 highest finerenone dose groups compared with the eplerenone group: 3/13 (23.1%) in the eplerenone group, 2/13 (15.4%) in the finerenone 2.5→5 mg group, 3/13 (23.1%) in the finerenone 5→10 mg group, 5/11 (45.5%) in the finerenone 7.5→15 mg group, 3/11 (27.3%) in the finerenone 10→20 mg group and 5/11 (45.5%) in the finerenone 15→20 mg group (Figure 2); the equivalent data for the per-protocol set are shown in Figure S1. The proportion of patients who had an NT-proBNP decrease of >30% at days 30 and 60 are shown in Table S1. Sensitivity analyses on the imputation method indicated no relevant effect on the results by the imputation method (data not shown).

Figure 2.

Mean percentage (90% confidence interval) of patients with a decrease of >30% in plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentration from baseline at day 90 (full-analysis set) in ARTS-HF Japan. Patients who died before day 90 or who experienced permanent (≥5 consecutive days) withdrawal of study drug after a cardiovascular hospitalization or emergency presentation for worsening chronic heart failure were counted as non-responders for the primary efficacy analysis.

The NT-proBNP decrease from baseline to day 90 is shown in Table S2. The geometric mean ratios of NT-proBNP at day 90 relative to baseline were below 1 in all groups.

Least-squares (LS) mean ratios of NT-proBNP at day 90 relative to baseline were below 1 for the finerenone 7.5→15 mg and 15→20 mg groups (Table S3).

Further Exploratory Efficacy Endpoints In total, 15 patients (20.8%) were hospitalized for cardiovascular causes and all of them had 1 such event; 17 patients (23.6%) presented for worsening CHF and of them, 13 had 1 event, 3 had 2 events and 1 had 3 events; 2 patients (2.8%) died of cardiovascular causes.

The changes in concentrations of BNP from baseline to day 90 are shown in Table S4. Mean scores on the KCCQ and the EQ-5D-3L questionnaires are shown in Table S5.

Safety

All doses of finerenone had a similar safety profile to that of eplerenone, including the incidence of treatment-emergency adverse events (Table 3). Mean serum potassium changes from baseline were similar in the finerenone and eplerenone groups (Figure 3). The maximum serum potassium value recorded during treatment was 5.7 mmol/L, an increase from 4.5 mmol/L at baseline, observed in a patient in the finerenone 7.5→15 mg group at day 21.

Figure 3.

Mean change (standard deviation) in serum potassium concentration from baseline to day 90 in patients with worsening chronic HFrEF receiving eplerenone or different doses of finerenone in ARTS-HF Japan. HFrEF, heart failure with reduced ejection fraction.

Table 3. Incidence of Treatment-Emergency Adverse Events and Hyperkalemia in Patients With Worsening of Chronic Heart Failure With Reduced Ejection Fraction Receiving Eplerenone or Finerenone (Safety-Analysis Set) in ARTS-HF Japan

Adverse event parameter, n (%)	Incidence, n (%)
Adverse event parameter, n (%)	Eplerenone (n=13)	Finerenone 2.5→5 mg (n=13)	Finerenone 5→10 mg (n=13)	Finerenone 7.5→15 mg (n=11)	Finerenone 10→20 mg (n=11)	Finerenone 15→20 mg (n=11)	Total (n=72)
Any treatment-emergency adverse event	13 (100)	9 (69.2)	11 (84.6)	8 (72.7)	8 (72.7)	9 (81.8)	58 (80.6)
Any treatment-emergency serious adverse event	3 (23.1)	5 (38.5)	3 (23.1)	3 (27.3)	3 (27.3)	3 (27.3)	20 (27.8)
Discontinuation because of treatment- emergency adverse event	0	1 (7.7)	0	4 (36.4)	2 (18.2)	2 (18.2)	9 (12.5)
Study-drug-related treatment-emergency adverse event	1 (7.7)	3 (23.1)	3 (23.1)	4 (36.4)	1 (9.1)	3 (27.3)	15 (20.8)
Study-drug-related treatment-emergency serious adverse event	0	1 (7.7)	0	0	0	0	1 (1.4)
Treatment-emergency adverse events of special interest
Hyperkalemia to day 30*	0	0	0	1 (9.1)	0	0	1 (1.4)
Hyperkalemia at any time post-baseline*	0	0	0	2 (18.2)	0	0	2 (2.8)
Blood potassium increased*	0	0	0	0	0	1 (9.1)	1 (1.4)
Emergency presentation for worsening chronic heart failure	2 (15.4)	4 (30.8)	3 (23.1)	1 (9.1)	4 (36.4)	3 (27.3)	17 (23.6)
Emergency presentation for worsening chronic heart failure leading to hospitalization	1 (7.7)	3 (23.1)	1 (7.7)	1 (9.1)	1 (9.1)	3 (27.3)	10 (13.9)
Any adverse event of special interest leading to discontinuation	0	1 (7.7)	0	2 (18.2)	1 (9.1)	1 (9.1)	5 (6.9)

*Defined as a blood potassium concentration ≥5.6 mmol/L with subsequent discontinuation of study drug.

The change in mean systolic blood pressure from baseline to day 90 is shown in Table S6. Treatment-emergency adverse events associated with decreased blood pressure reported were “blood pressure decreased” in 6 patients (2 in the finerenone 2.5→5 mg group, 3 in the finerenone 5→10 mg group and 1 in the finerenone 7.5→15 mg group) and “hypotension” in 1 patient (in the finerenone 5→10 mg group). These events were considered mild by the investigators and the dose of study drug was unchanged. As for other actions taken for these adverse events, the doses of ARB, β-blocker or diuretics were reduced or stopped in 3 of these 7 patients and the events had resolved or improved by the end of the study period.

Changes in mean eGFR are shown in Table S7. The proportions of patients experiencing a decrease in eGFR ≥25%, >30%, ≥40%, and ≥57% are shown in Table S8. Treatment-emergency adverse events associated with a decrease in eGFR reported were “renal impairment” in 4 patients (2 in the eplerenone group and 2 in the finerenone 7.5→15 mg group), “renal failure chronic” in 1 patient (in the finerenone 2.5→5 mg group), “urinary retention” in 2 patients (1 in the eplerenone group and 1 in the finerenone 2.5→5 mg group) and “blood creatinine increased” in 3 patients (1 each in the finerenone 7.5→15 mg group, 10→20 mg group and 15→20 mg group).

Discussion

Because patients with worsening CHF requiring emergency presentation to hospital²^–⁴^,¹⁹^–²² or with CKD²³ or diabetes mellitus²⁴ have high morbidity and mortality despite current therapy, the MR may be an important therapeutic target in these vulnerable patients. ARTS-HF Japan was a small study designed to test the response to finerenone in Japanese patients. As this has been the first study to investigate finerenone in Japanese patients with HFrEF and CKD and/or diabetes, the PMDA requested to that the study design of ARTS-HF include additional mandatory visits in the first month of treatment in order to assure careful monitoring of serum potassium as was performed in the first global ARTS study.¹¹ This made it necessary to set up a stand-alone study in Japan. The design of ARTS-HF Japan is based on that of the international ARTS-HF, which was the first clinical trial to investigate the novel nonsteroidal MRA finerenone in comparison with eplerenone in patients with worsening HFrEF requiring emergency treatment and who also had T2DM and/or CKD.¹⁵ This will allow data from the 2 studies to be pooled for further analyses.

Use of MRAs in patients with HF who have T2DM and/or CKD has been limited by safety concerns; however, previous studies have shown their clinical benefits. For example, the cumulative rate of the primary endpoint (HF hospitalization or cardiovascular mortality) in EMPHASIS-HF remained significantly reduced in the eplerenone group compared with the placebo group in the subset of patients with diabetes or renal dysfunction, although there was an increase in the incidence of potassium >5.5 mmol/L with eplerenone in patients with diabetes and CKD (eGFR <60 ml/min/1.73 m²) of 14.1% and 16.6%, respectively, vs. placebo (8.5 and 9.3%, respectively).⁸ Data from RALES showed that spironolactone efficacy was maintained in patients with an eGFR <60 ml/min/1.73 m².²⁵ In EPHESUS, a history of diabetes and an eGFR ≤60 ml/min/1.73 m² were each identified as risk factors for developing a serum potassium concentration ≥6.0 mmol/L, but did not affect the cardiovascular benefit of eplerenone.²⁶

The key findings of the international ARTS-HF were that the proportion of patients who experienced a decrease in NT-proBNP >30% from baseline was similar across all treatment groups. Except for the 2.5→5 mg finerenone group, the composite clinical endpoint occurred numerically less frequently in finerenone-treated patients than in those receiving eplerenone; this difference reached statistical significance in the 10→20 mg group. A potassium level increase to ≥5.6 mmol/L at any time point occurred in 4.3% of patients, with a balanced distribution among all treatment groups. The authors concluded that the finding of reduced clinical events in the finerenone 10→20 mg group should be further explored in a large outcomes trial.

In ARTS-HF Japan the responder rate, defined as the proportion of individuals with a decrease in NT-proBNP >30% from baseline at day 90, was numerically higher in the 3 highest finerenone groups (7.5→15, 10→20 and 15→20 mg o.d.) compared with the eplerenone group. All investigated doses of finerenone were well tolerated, without any adverse safety signals. Adverse events occurring at any time post-baseline that were associated with a blood potassium ≥5.6 mmol/L were “hyperkalemia leading to discontinuation of study drug,” observed in 2 patients overall (2.8%), both in the finerenone 7.5→15 mg group, and “blood potassium increased to ≥5.6 mmol/L leading to discontinuation of study drug,” reported in 1 patient overall (1.4%), in the finerenone 15→20 mg group. The maximum serum potassium value recorded during treatment was 5.7 mmol/L, observed in the finerenone 7.5→15 mg group at day 21. Given the small number of individuals per treatment group, no robust conclusions could be drawn from these results. Nevertheless, the results indicated that Japanese patients with worsening HFrEF requiring hospitalization and who also had T2DM and/or CKD can be included in larger outcomes trials of finerenone.

MRAs, including eplerenone, are recommended in Japanese guidelines for HF patients in New York Heart Association class III or more also receiving diuretics and an ACEI.¹ Eplerenone was chosen as the active comparator in ARTS-HF Japan because the study design was to mirror as closely as possible that of ARTS-HF, and eplerenone is considered more suitable than spironolactone for patients with T2DM (owing to the metabolic effects of spironolactone)²⁷^,²⁸ or CKD (owing to the safety profile of spironolactone in patients with moderate CKD).¹⁷^,²⁹ As 90% of the study population had an eGFR ≤60 ml/min/1.73 m² at baseline, the starting dose of eplerenone chosen (25 mg every other day) is in line with the recommended starting dose of eplerenone in stable patients with HFrEF and CKD.³^,³⁰

Study Limitations

The principal limitation of this study is the small sample size, which makes interpretation of results difficult. The primary efficacy endpoint was the proportion of patients experiencing a decrease in NT-proBNP level >30% from baseline. Prospective observational studies have shown that decreases ≥30% in this surrogate marker of efficacy correlate with improved prognosis³¹^–³³ and treatment of patients with CHF tends to lead to a decrease in natriuretic peptide levels over time.³⁴^–⁴¹

A potential confounding factor is that NT-proBNP levels may be increased in patients with atrial fibrillation and CHF compared with those without atrial fibrillation. However, atrial fibrillation was accounted for when performing an analysis of covariance for the absolute change in NT-proBNP levels.

Conclusions

ARTS-HF Japan is the first clinical trial to compare the novel nonsteroidal MRA finerenone with eplerenone in Japanese patients with worsening CHF. The results confirmed that Japanese patients with worsening HFrEF requiring hospitalization and who also had T2DM and/or CKD can be safely included in larger outcomes trials of finerenone. Together, the results of ARTS-HF Japan and the international ARTS-HF indicate that further investigations of finerenone in a larger clinical outcomes study are warranted.

Acknowledgments

This study was funded by Bayer Yakuhin Ltd. Charlotte Cookson, DPhil, of Oxford PharmaGenesis, Oxford, UK provided medical writing support, which was funded by Bayer Yakuhin Ltd. The authors thank the members of the data monitoring committee (Professor Yoshihiko Seino, [Nippon Medical School, Inza-city, Japan], Dr Enyu Imai [Nakayamadera Imai Clinic, Hyogo, Japan], Professor Hideki Origasa [University of Toyama School of Medicine, Toyama-city, Japan] and Professor Marco Metra [University and Civil Hospital, Brescia, Italy]), as well as Matthew Do (ALMAC Pharmaceutical Services), Guo Jing and Loh Sze Yin (Covance Central Laboratory Services), Biana Piot (Biomedical Systems) and Wolfgang Marter (Bayer Pharma) for their support in this study.

Role of the Funding Source

The sponsor, Bayer Yakuhin Ltd, provided financial support for the conduct of the research and preparation of the article. The sponsor could not veto decisions made by the authors in the production of this article. The sponsor designed and conducted the study, including collection, management, and analysis of data. The authors and employees of the sponsor interpreted the data and prepared, reviewed, and approved the manuscript; the sponsor was not involved in the decision to submit the manuscript for publication. N.S. had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Declaration of Conflicts of Interest

M.A. and Takahisa Y. have no financial conflicts of interest to disclose concerning this study.

M.K., M.M. and Takashi Y. are employees of Bayer Yakuhin Ltd.

P.K., S.-Y.K. and C.N. are employees of Bayer HealthCare AG.

N.S. has received honoraria and a consulting fee from Bayer Yakuhin Ltd.

T.S. has received lecture fees and research funding from Bayer Yakuhin Ltd.

Supplementary Files

Supplementary File 1

Appendix

Figure S1. Percentage of patients at day 90 with a decrease >30% in plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) concentration from baseline (per-protocol set) in ARTS-HF Japan.

Table S1. Percentage of patients with a decrease >30% in plasma NT-proBNP concentration from baseline at days 30 and 60 (FAS) in ARTS-HF Japan

Table S2. NT-proBNP concentrations at baseline and days 30, 60 and 90 and day 90: baseline ratio of NT-proBNP concentration (FAS) in ARTS-HF Japan

Table S3. ANCOVA model of the ratio of NT-proBNP concentrations at day 90 to baseline (FAS) in ARTS-HF Japan

Table S4. Geometric mean ratio to baseline of BNP concentration from baseline to day 90 in patients with worsening of HF with reduced ejection fraction receiving eplerenone or finerenone (FAS) in ARTS-HF Japan

Table S5. Change from baseline in (A) KCCQ and (B) EuroQol scores at day 90 (FAS) in ARTS-HF Japan

Table S6. Change in systolic blood pressure from baseline to days 30, 60 and 90 in patients with worsening of HF with reduced ejection fraction receiving eplerenone or finerenone (safety-analysis set) in ARTS-HF Japan

Table S7. Change in eGFR (according to the modification of diet in renal disease equation) from baseline to days 30, 60 and 90 in patients with worsening of HF with reduced ejection fraction receiving eplerenone or finerenone (safety-analysis set) in ARTS-HF Japan

Table S8. Number (%) of patients with a decrease in eGFR (according to the modification of diet in renal disease equation) of ≥25%, ≥30%, ≥40% and ≥57% from baseline to day 90 (safety-analysis set) in ARTS-HF Japan

Please find supplementary file(s);

http://dx.doi.org/10.1253/circj.CJ-16-0122

References

1. Japanese Circulation Society. Guidelines for treatment of chronic heart failure. http://www.j-circ.or.jp/guideline/pdf/JCS2010_matsuzaki_h.pdf (in Japanese).
2. Pitt B, Zannad F, Remme WJ, Cody R, Castaigne A, Perez A, et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure: Randomized Aldactone Evaluation Study Investigators. N Engl J Med 1999; 341: 709–717.
3. Zannad F, McMurray JJ, Krum H, van Veldhuisen DJ, Swedberg K, Shi H, et al. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med 2011; 364: 11–21.
4. McMurray JJ, Adamopoulos S, Anker SD, Auricchio A, Bohm M, Dickstein K, et al. ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure 2012: The Task Force for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012 of the European Society of Cardiology: Developed in collaboration with the Heart Failure Association (HFA) of the ESC. Eur Heart J 2012; 33: 1787–1847.
5. Yancy CW, Jessup M, Bozkurt B, Butler J, Casey DE Jr, Drazner MH, et al. 2013 ACCF/AHA guideline for the management of heart failure: Executive summary: A report of the American College of Cardiology Foundation/American Heart Association Task Force on practice guidelines. Circulation 2013; 128: 1810–1852.
6. Komajda M. Current challenges in the management of heart failure. Circ J 2015; 79: 948–953.
7. Juurlink DN, Mamdani MM, Lee DS, Kopp A, Austin PC, Laupacis A, et al. Rates of hyperkalemia after publication of the Randomized Aldactone Evaluation Study. N Engl J Med 2004; 351: 543–551.
8. Eschalier R, McMurray JJ, Swedberg K, van Veldhuisen DJ, Krum H, Pocock SJ, et al. Safety and efficacy of eplerenone in patients at high risk for hyperkalemia and/or worsening renal function: Analyses of the EMPHASIS-HF study subgroups (Eplerenone in Mild Patients Hospitalization And SurvIval Study in Heart Failure). J Am Coll Cardiol 2013; 62: 1585–1593.
9. Albert NM, Yancy CW, Liang L, Zhao X, Hernandez AF, Peterson ED, et al. Use of aldosterone antagonists in heart failure. JAMA 2009; 302: 1658–1665.
10. Bärfacker L, Kuhl A, Hillisch A, Grosser R, Figueroa-Perez S, Heckroth H, et al. Discovery of BAY 94-8862: A nonsteroidal antagonist of the mineralocorticoid receptor for the treatment of cardiorenal diseases. Chem Med Chem 2012; 7: 1385–1403.
11. Amazit L, Le Billan F, Kolkhof P, Lamribet K, Viengchareun S, Fay MR, et al. Finerenone impedes aldosterone-dependent nuclear import of the mineralocorticoid receptor and prevents genomic recruitment of steroid receptor coactivator-1. J Biol Chem 2015; 290: 21876–21889.
12. Kolkhof P, Nowack C, Eitner F. Nonsteroidal antagonists of the mineralocorticoid receptor. Curr Opin Nephrol Hypertens 2015; 24: 417–424.
13. Kolkhof P, Delbeck M, Kretschmer A, Steinke W, Hartmann E, Barfacker L, et al. Finerenone, a novel selective nonsteroidal mineralocorticoid receptor antagonist protects from rat cardiorenal injury. J Cardiovasc Pharmacol 2014; 64: 69–78.
14. Pitt B, Kober L, Ponikowski P, Gheorghiade M, Filippatos G, Krum H, et al. Safety and tolerability of the novel non-steroidal mineralocorticoid receptor antagonist BAY 94-8862 in patients with chronic heart failure and mild or moderate chronic kidney disease: A randomized, double-blind trial. Eur Heart J 2013; 34: 2453–2463.
15. Filippatos G, Anker SD, Böhm M, Gheorghiade M, Køber L, Krum H, et al. A randomized controlled study of finerenone versus eplerenone in patients with worsening chronic heart failure and diabetes and/or chronic kidney disease. Eur Heart J 2016 (in press).
16. Bakris GL, Agarwal R, Chan JC, Cooper ME, Gansevoort RT, Haller H, et al. Effect of finerenone on albuminuria in patients with diabetic nephropathy: A randomized clinical trial. JAMA 2015; 314: 884–894.
17. Pitt B, Anker SD, Bohm M, Gheorghiade M, Kober L, Krum H, et al. Rationale and design of MinerAlocorticoid Receptor antagonist Tolerability Study-Heart Failure (ARTS-HF): A randomized study of finerenone vs. eplerenone in patients who have worsening chronic heart failure with diabetes and/or chronic kidney disease. Eur J Heart Fail 2015; 17: 224–232.
18. Matsuo S, Imai E, Horio M, Yasuda Y, Tomita K, Nitta K, et al. Revised equations for estimated GFR from serum creatinine in Japan. Am J Kidney Dis 2009; 53: 982–992.
19. Pitt B, Remme W, Zannad F, Neaton J, Martinez F, Roniker B, et al. Eplerenone, a selective aldosterone blocker, in patients with left ventricular dysfunction after myocardial infarction. N Engl J Med 2003; 348: 1309–1321.
20. Girerd N, Pang PS, Swedberg K, Fought A, Kwasny MJ, Subacius H, et al. Serum aldosterone is associated with mortality and re-hospitalization in patients with reduced ejection fraction hospitalized for acute heart failure: Analysis from the EVEREST trial. Eur J Heart Fail 2013; 15: 1228–1235.
21. Ushigome R, Sakata Y, Nochioka K, Miyata S, Miura M, Tadaki S, et al. Temporal trends in clinical characteristics, management and prognosis of patients with symptomatic heart failure in Japan: Report from the CHART Studies. Circ J 2015; 79: 2396–2407.
22. Parikh KS, Felker GM, Metra M. Mode of death after acute heart failure hospitalization: A clue to possible mechanisms. Circ J 2016; 80: 17–23.
23. Lentini S, Heinig R, Kimmeskamp-Kirschbaum N, Wensing G. Pharmacokinetics, safety and tolerability of the novel, selective mineralocorticoid receptor antagonist finerenone: Results from first-in-man and relative bioavailability studies. Fundam Clin Pharmacol 2016; 30: 172–184.
24. Sarma S, Mentz RJ, Kwasny MJ, Fought AJ, Huffman M, Subacius H, et al. Association between diabetes mellitus and post-discharge outcomes in patients hospitalized with heart failure: Findings from the EVEREST trial. Eur J Heart Fail 2013; 15: 194–202.
25. Vardeny O, Wu DH, Desai A, Rossignol P, Zannad F, Pitt B, et al. Influence of baseline and worsening renal function on efficacy of spironolactone in patients With severe heart failure: Insights from RALES (Randomized Aldactone Evaluation Study). J Am Coll Cardiol 2012; 60: 2082–2089.
26. Pitt B, Bakris G, Ruilope LM, DiCarlo L, Mukherjee R. Serum potassium and clinical outcomes in the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS). Circulation 2008; 118: 1643–1650.
27. Yamaji M, Tsutamoto T, Kawahara C, Nishiyama K, Yamamoto T, Fujii M, et al. Serum cortisol as a useful predictor of cardiac events in patients with chronic heart failure: The impact of oxidative stress. Circ Heart Fail 2009; 2: 608–615.
28. Yamaji M, Tsutamoto T, Kawahara C, Nishiyama K, Yamamoto T, Fujii M, et al. Effect of eplerenone versus spironolactone on cortisol and hemoglobin A₁(c) levels in patients with chronic heart failure. Am Heart J 2010; 160: 915–921.
29. Pitt B, Anker SD, Bushinsky DA, Kitzman DW, Zannad F, Huang IZ. Evaluation of the efficacy and safety of RLY5016, a polymeric potassium binder, in a double-blind, placebo-controlled study in patients with chronic heart failure (the PEARL-HF) trial. Eur Heart J 2011; 32: 820–828.
30. Electronic Medicines Compendium (emc). Eplerenone 25 mg film-coated tablets [SPC]. https://www.medicines.org.uk/emc/medicine/29837 (accessed March 25, 2016).
31. Pascual-Figal DA, Domingo M, Casas T, Gich I, Ordonez-Llanos J, Martinez P, et al. Usefulness of clinical and NT-proBNP monitoring for prognostic guidance in destabilized heart failure outpatients. Eur Heart J 2008; 29: 1011–1018.
32. Verdiani V, Ognibene A, Rutili MS, Lombardo C, Bacci F, Terreni A, et al. NT-ProBNP reduction percentage during hospital stay predicts long-term mortality and readmission in heart failure patients. J Cardiovasc Med (Hagerstown) 2008; 9: 694–699.
33. Bettencourt P, Azevedo A, Pimenta J, Frioes F, Ferreira S, Ferreira A. N-terminal-pro-brain natriuretic peptide predicts outcome after hospital discharge in heart failure patients. Circulation 2004; 110: 2168–2174.
34. Berry C, Murphy NF, De Vito G, Galloway S, Seed A, Fisher C, et al. Effects of aldosterone receptor blockade in patients with mild-moderate heart failure taking a beta-blocker. Eur J Heart Fail 2007; 9: 429–434.
35. Frantz RP, Olson LJ, Grill D, Moualla SK, Nelson SM, Nobrega TP, et al. Carvedilol therapy is associated with a sustained decline in brain natriuretic peptide levels in patients with congestive heart failure. Am Heart J 2005; 149: 541–547.
36. Fruhwald FM, Fahrleitner-Pammer A, Berger R, Leyva F, Freemantle N, Erdmann E, et al. Early and sustained effects of cardiac resynchronization therapy on N-terminal pro-B-type natriuretic peptide in patients with moderate to severe heart failure and cardiac dyssynchrony. Eur Heart J 2007; 28: 1592–1597.
37. Hartmann F, Packer M, Coats AJ, Fowler MB, Krum H, Mohacsi P, et al. Prognostic impact of plasma N-terminal pro-brain natriuretic peptide in severe chronic congestive heart failure: A substudy of the Carvedilol Prospective Randomized Cumulative Survival (COPERNICUS) trial. Circulation 2004; 110: 1780–1786.
38. Iraqi W, Rossignol P, Angioi M, Fay R, Nuee J, Ketelslegers JM, et al. Extracellular cardiac matrix biomarkers in patients with acute myocardial infarction complicated by left ventricular dysfunction and heart failure: Insights from the Eplerenone Post-Acute Myocardial Infarction Heart Failure Efficacy and Survival Study (EPHESUS) study. Circulation 2009; 119: 2471–2479.
39. Maggioni AP, Anand I, Gottlieb SO, Latini R, Tognoni G, Cohn JN. Effects of valsartan on morbidity and mortality in patients with heart failure not receiving angiotensin-converting enzyme inhibitors. J Am Coll Cardiol 2002; 40: 1414–1421.
40. Tsutamoto T, Wada A, Maeda K, Mabuchi N, Hayashi M, Tsutsui T, et al. Effect of spironolactone on plasma brain natriuretic peptide and left ventricular remodeling in patients with congestive heart failure. J Am Coll Cardiol 2001; 37: 1228–1233.
41. Udelson JE, Feldman AM, Greenberg B, Pitt B, Mukherjee R, Solomon HA, et al. Randomized, double-blind, multicenter, placebo-controlled study evaluating the effect of aldosterone antagonism with eplerenone on ventricular remodeling in patients with mild-to-moderate heart failure and left ventricular systolic dysfunction. Circ Heart Fail 2010; 3: 347–353.
42. Hamm CW, Bassand JP, Agewall S, Bax J, Boersma E, Bueno H, et al. ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: The Task Force for the management of acute coronary syndromes (ACS) in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J 2011; 32: 2999–3054.
43. Wright RS, Anderson JL, Adams CD, Bridges CR, Casey DE Jr, Ettinger SM, et al. 2011 ACCF/AHA Focused Update of the Guidelines for the Management of Patients With Unstable Angina/ Non-ST-Elevation Myocardial Infarction (Updating the 2007 Guideline): A report of the American College of Cardiology Foundation/American Heart Association Task Force on Practice Guidelines. Circulation 2011; 123: 2022–2060.

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