Results of ARTS-HF: finerenone versus eplerenone in patients with worsening chronic heart failure and diabetes and/or chronic kidney disease Gerasimos Filippatos Stefan D Anker, Michael Böhm, Mihai Gheorghiade, Lars Køber, Henry Krum, Aldo P Maggioni, Piotr Ponikowski, Adriaan A Voors, Faiez Zannad, So- Young Kim, Christina Nowack, Giovanni Palombo, Peter Kolkhof, Nina Kimmeskamp- Kirschbaum, Alexander Pieper and Bertram Pitt, for the MinerAlocorticoid Receptor AnTagonist Study In Heart Failure (ARTS-HF) Committees and Investigators
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Results of ARTS-HF: finerenone versus eplerenone in patients with worsening chronic heart failure and diabetes and/or chronic kidney disease
Gerasimos Filippatos Stefan D Anker, Michael Böhm, Mihai Gheorghiade, Lars Køber,
Henry Krum, Aldo P Maggioni, Piotr Ponikowski, Adriaan A Voors, Faiez Zannad, So-Young Kim, Christina Nowack, Giovanni Palombo, Peter Kolkhof, Nina Kimmeskamp-
Kirschbaum, Alexander Pieper and Bertram Pitt,
for the MinerAlocorticoid Receptor AnTagonist Study In Heart Failure (ARTS-HF) Committees and Investigators
Study sponsor and presenter conflict of interest statement
• ClinicalTrials.gov Identifier: NCT01807221
• This study was funded by Bayer Healthcare AG
• G Filippatos has been a speaker and adviser for Bayer HealthCare AG
• Conflicts of interest for all other authors are listed in the full manuscript
Background
• Mineralocorticoid receptor antagonists (MRAs) such as eplerenone and spironolactone reduce mortality and hospitalizations in patients with heart failure with reduced ejection fraction (HFrEF) and are recommended by treatment guidelines1,2
• Spironolactone is not specific for the mineralocorticoid receptor and eplerenone is less tightly bound to the MR than spironolactone
• Underuse of MRAs may be due to fear of inducing hyperkalemia or worsening renal function in high-risk patients
• Despite current treatment mortality and morbidity remains high, especially after hospitalization for worsening heart failure
1. McMurray JJ et al. Eur J Heart Fail 2012;14:803–69; 2. Yancy CW et al. 2013 Circulation 2013;128:1810–52
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Study objective
• Finerenone (BAY 94-8862) is a novel non-steroidal MRA that has greater receptor selectivity than spironolactone and better receptor affinity than eplerenone in vitro1
Study objective: to compare the safety and efficacy of different
once-daily oral doses of finerenone with eplerenone in patients
who presented in emergency departments with worsening
chronic HFrEF with type 2 diabetes mellitus and/or chronic
kidney disease (CKD)
1. Pitt B et al. Eur Heart J 2013;34:2453–63
Study design
DMC, Data Monitoring Committee; e.o.d., every other day; o.d. once daily
Pre-specified additional treatment groups introduced following a recommendation from the DMC
Treatment groups at study start
Initial stabilization and screening
Safety follow-up
Emergency presentation (in the 7 days before randomization
Finerenone 20 mg o.d.
Finerenone 20 mg o.d.
Finerenone 15 mg o.d.
Finerenone 10 mg o.d.
Finerenone 5 mg o.d.
Eplerenone 25 mg o.d.
Finerenone 15 mg o.d.
Finerenone 10 mg o.d.
Finerenone 7.5 mg o.d.
Finerenone 5 mg o.d.
Finerenone 2.5 mg o.d.
Eplerenone 25 mg e.o.d.
Eplerenone 50 mg o.d.
Acute/vulnerable phase up to day 30
Chronic phase: days 31–90
Up-titration if serum potassium ≤ 5.0 mmol/L
Up-titration/sham up-titration if serum potassium ≤ 5.0 mmol/L Randomization
Day 1 Day 30 Day 90 Day 60
Study endpoints
Endpoint Outcome variable
Primary endpoint 1. Proportion of patients with a relative decrease in NT-proBNP of > 30% from baseline to day 90
Further exploratory endpoints
1. Composite endpoint of death from any cause, CV hospitalization or emergency presentation for worsening chronic heart failure (until day 90)
2. Change in efficacy biomarker levels from baseline (BNP and NT-proBNP) to days 30, 60 and 90
3. Change in health-related quality of life from baseline to days 30 and 90 • Kansas City Cardiomyopathy Questionnaire • 5-dimension EuroQol questionnaire
Table 14.3.4/107 and Table 14.3.4/109; Post hoc table 1/68 eGFR, estimated glomerular filtration rate (mL/min/1.73 m2); SAF, safety analysis set
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Mean change in potassium from baseline
*Statistically significant Table 14.3.4/102 ANCOVA with treatment group, comorbidities, MRA use at emergency presentation and region as factors and baseline value as covariate ANCOVA, analysis of covariance; MRA, mineralocorticoid receptor antagonist
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0.00
0.04
0.08
0.12
0.16
0.20
0.24
0.28
Ch
ange
in p
ota
ssiu
m (
mm
ol/
L)
Day 90
* * * p = 0.016 p = 0.016
p = 0.030
Eplerenone (n = 143)
Finerenone 2.5–5 mg (n = 116)
Finerenone 5–10 mg (n = 117)
Finerenone 7.5–15 mg (n = 120)
Finerenone 10–20 mg (n = 128)
Finerenone 15–20 mg (n = 118)
0.262
0.119 0.119 0.134
0.202 0.200
Summary I
• In patients hospitalized for worsening chronic HFrEF with type 2 diabetes mellitus and/or CKD, the proportion of patients with a relative decrease in NT-proBNP of more than 30% from baseline to day 90 was similar in the eplerenone group and the finerenone groups
• The incidence of the clinical composite endpoint (all-cause death, cardiovascular hospitalization or emergency presentation for worsening chronic heart failure) at day 90 was lower with all finerenone doses (except 2.5–5 mg) than with eplerenone, with the lowest incidence observed in the finerenone 10–20 mg dose group
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Summary II
• All doses of finerenone were well tolerated, with a similar incidence of treatment-emergent adverse events in the eplerenone group and finerenone groups
• Hyperkalaemia (serum potassium ≥ 5.6 mmol/L) was observed in 44 patients (4.3%) at any time post-baseline
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Back-up
Trial Committees
• Data Monitoring Committee members
– Marco Metra – Chairman (Italy), Barry Greenberg (USA), Meinhard Kieser (Germany), Eberhard Ritz (Germany), Pantelis Sarafidis (Greece), Guntram Schernthaner (Austria)
• Steering Committee members
– Bertram Pitt – Chairman (USA), Gerasimos Filippatos – Chairman (Greece), Stefan D Anker (Germany), Michael Böhm (Germany), Mihai Gheorghiade (USA), Lars Kober (Denmark), Henry Krum (Australia), Aldo Maggioni (Italy), Piotr Ponikowski (Poland), Adrian Voors (Netherlands), Faiez Zannad (France)
• Adjudication Committee members
– Stefan D Anker (Germany), Aldo Maggioni (Italy), Piotr Ponikowski (Poland)
Austria Andrea Podczeck-Schweighofer, Uta Hoppe, Armin Böhmer, Peter Siostrzonek, Dieter Botegal, Friedrich Fruhwald, Gerhard Pölzl, Gabriele Jakl-Kotauschek, Giorgio Giacomini
Australia Henry Krum, Carmine DePasquale, Andrew Sindone, Eugene Kotlyar, John Atherton, John Amerena
Canada Gordon Moe, Serge Lepage, Haissam Haddad, Richard Sheppard, Mark Liszkowski, Daniel Savard, Debra Isaac, Sebastien Bergeron, Dominique Auger, Imad Nadra, Sean Virani, Simon Kou
Czech Republic Filip Malek, Radim Kryza, Lubomir Ballek, Jan Macha, Tomas Brabec
Germany Johann Bauersachs, Stefan Anker, Michael Böhm, Jürgen vom Dahl, Harald Lapp, Rolf Wachter, Stefan Stoerk, Olaf Oldenburg, Sebastian Philipp, Holger Eggebrecht, Stephan Steiner, A Mügge, T Gori, A Sandek
Denmark Lars Køber, Gunnar Gislason, OlavWendelboe Nielsen, Niels Jørgen Frandsen, KnudSkagen, Kenneth Egstrup, Jacob Eifer Møller, Tonny Nielsen, Jens Refsgaard, Ole Nyvad, Jørgen Jeppesen
Spain Domingo A Pascual Figal, Julio Núñez, Luís Almenar Bonet, Juan Delgado, Enrique Galve Basilio, SoniaRuíz Bustillo, Josep Bisbe, Pablo García Pavía
Finland Johan Lassus, Anna-Mari Hekkala, Heikki Ukkonen, Kai Nyman, Alexandre Hadjikov
France Fabrice Bauer, Michel Galinier, Richard Isnard, Nathan Mewton, Philippe Le Corvoisier, Alain Cohen-Solal, Faïez Zannad, Pierre Gibelin
Greece John Parissis, John Nanas, Apostolos Karavidas, Sotirios Patsilinakos, Filippos Triposkiadis
USA Phillip Levy, David Lanfear, Robert Cole, Liviu Klein, Jalal Ghali, Frank Smart, Paul Mather, Stephen Gottlieb, Marc Klapholz, Jorge Silva Enciso, Douglas Chapman, Hector Ventura, Salman Khan, Steven Isserman, Suzanne Oparil, Lynne Wagoner, Joshua Larned
South Africa Richard Siebert, Mohamed Sarvan, Naresh Ranjith, Johannes Engelbrecht, Louis van Zyl, Saleem Dawood, Fayzal Ahmed, Jan Saaiman, Hans Prozesky, Thomas Mabin
Participating countries
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Europe
North America
Asia
Others (Australia, Israel, South Africa)
Treatment-emergent adverse events
Eplerenone Finerenone Total
(n = 221)
2.5–5 mg (n = 172)
5–10 mg (n = 163)
7.5–15 mg (n = 167)
10–20 mg (n = 169)
15–20 mg (n = 163)
(N = 1055)
Any AE, n (%) 170 (76.9) 132 (76.7) 124 (76.1) 105 (62.9) 120 (71.0) 128 (78.5) 779 (73.8)
Any SAE, n (%) 77 (34.8) 72 (41.9) 47 (28.8) 52 (31.1) 46 (27.2) 57 (35.0) 351 (33.3)
AE of special interest,a n (%) 44 (19.9) 38 (22.1) 28 (17.2) 34 (20.4) 25 (14.8) 35 (21.5) 204 (19.3)
Data are from the safety analysis set aAn increase in serum potassium concentration to at least 5.6 mmol/L leading to discontinuation and emergency presentation for worsening chronic heart failure after start of study drug that requires intravenous treatment with diuretics and/or positive inotropic agents AE, adverse event; SAE, serious adverse event
eGFR, estimated glomerular filtration rate (mL/min/1.73 m2); MDRD, Modification of Diet in Renal Disease
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Study flow
AE, adverse event; FAS, full analysis set; PPS, per protocol analysis set; SAF, safety analysis set
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Enrolment
Allocation
Follow-up
PPS
Assessed for eligibility (n = 1286)
Randomized (n = 1066)
• Excluded (n = 220) – Did not meet inclusion criteria (n = 191) – Declined to participate (n = 21)
– Other reasons (n = 8)
Discontinued study drug (n = 298 [AE, n = 145; death, n = 29; patient withdrawal, n = 99; other reasons, n = 25])
Finerenone 2.5–5 mg n = 173
Finerenone 5–10 mg n = 165
Finerenone 7.5–15 mg
n = 169
Finerenone 10–20 mg
n = 170
Finerenone 15–20 mg
n = 165
SAF
FAS
Eplerenone n = 224
Finerenone 2.5–5 mg n = 121
Finerenone 5–10 mg n = 122
Finerenone 7.5–15 mg
n = 123
Finerenone 10–20 mg
n = 134
Finerenone 15–20 mg
n = 124
Eplerenone
n = 144
n = 97 n = 107 n = 104 n = 115 n = 100 n = 131
n = 162 n = 157 n = 158 n = 160 n = 158 n = 207
n = 172 n = 163 n = 167 n = 169 n = 163 n = 221
Completed (n = 768)
Death from any cause, cardiovascular hospitalization, or emergency presentation for worsening CHF
Data are from the full analysis set. Composite endpoint – first of the following events: death from any cause, cardiovascular hospitalization or emergency presentation for heart failure worsening
Worsening chronic heart failure requiring emergency presentation to hospital and treatment with intravenous diuretics at hospital
Treatment with at least one of the following for ≥ 3 months before emergency presentation to hospital: β-blocker, ACE inhibitor or ARB (not both), MRA or diuretic
Medical history of LVEF ≤ 40% measured by any modality within the last 12 months without intervening revascularization or cardiac surgery in the meantime; for individuals with cardiac intervention, LVEF must be reassessed and a LVEF ≤ 40% must be reconfirmed after the intervention
BNP concentration > 400 pg/mL or plasma NT-proBNP concentration > 1200 pg/mL at any time during emergency presentation to hospital, but at the latest at the screening visit
Patients with T2DM must fulfil at least one of the following criteria: • receiving oral antidiabetics and/or insulin • documented fasting glucose concentration ≥ 7.0 mmol/L in their medical history • 2-hour plasma glucose concentration ≥ 11.1 mmol/L during an OGTT • medical history of HbA1c concentration ≥ 6.5%a and an eGFRb ≥ 30 mL/min/1.73 m2
Patients without T2DM must have an eGFRb of 30–60 mL/min/1.73 m2 at screening
Blood potassium concentration ≤ 5.0 mmol/L at screening and systolic blood pressure ≥ 90mmHg without signs or symptoms of hypotension
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 ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blocker; BNP, B-type natriuretic peptide; eGFR, estimated glomerular filtration rate; HbA1c, glycated haemoglobin; LVEF, left ventricular ejection fraction; MRA, mineralocorticoid receptor antagonist; NT-proBNP, N-terminal proBNP; OGTT, oral glucose tolerance test; T2DM, type 2 diabetes mellitus
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Adapted from Pitt et al. Eur J Heart Fail 2015;17:224–32
Inclusion and exclusion criteria
aAs defined by the European Society of Cardiology and American College of Cardiology/American Heart Association guidelines ACS, acute coronary syndromes; CYP, cytochrome P450; NSAID, non-steroidal anti-inflammatory drug; TIA, transient ischaemic attack
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Main exclusion criteria
Acute de novo heart failure or acute inflammatory heart disease or ACSa in the last 30 days before the screening visit
Cardiogenic shock, Addison’s disease, valvular heart disease requiring surgical intervention during the course of the study, or patients with a left ventricular assistance device or those awaiting heart transplantation
Stroke or TIA ≤ 3 months before the screening visit, known hypersensitivity to the study drug (active substance or excipients) or eplerenone, or acute infectious disease requiring intravenous antibiotics within the last 24 hours before randomization
Dialysis for acute renal failure within the previous 3 months before emergency presentation to hospital, or hepatic insufficiency (Child–Pugh B or C)
Requirement for any intravenous vasodilator, any intravenous natriuretic peptide ≤ 24 hours before randomization, or any intravenous positive inotrope ≤ 14 days before dosing with study drug
Treatment with either spironolactone or eplerenone that cannot be discontinued 48 hours or 24 hours, respectively, before randomization and for the duration of the treatment period
Treatment with any renin inhibitor or potassium-sparing diuretic that cannot be discontinued 24 hours before randomization and for the duration of the treatment period
Treatment with high-dose acetylsalicylic acid (> 500 mg/day) or another NSAID
Treatment with potent CYP3A4 inhibitors or inducers, or strong CYP2C8 inhibitors (all must be stopped ≥ 7 days before randomization)
Adapted from Pitt et al. Eur J Heart Fail 2015;17:224–32