1. 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

2. Study sponsor and presenter conflict of interest statement
ClinicalTrials.gov Identifier: NCT
This study was funded by Bayer Healthcare AG
G Filippatos has been adviser for Bayer HealthCare AG
Conflicts of interest for all other authors are listed in the full manuscript

3. 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 Circulation 2013;128:1810–52

4. Study objective
Finerenone (BAY ) 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

5. Study design
Pre-specified additional treatment groups introduced following a recommendation from the DMC
Finerenone 20 mg o.d.
Finerenone 15 mg o.d.
Finerenone 20 mg o.d.
Finerenone 10 mg o.d.
Finerenone 15 mg o.d.
Finerenone 7.5 mg o.d.
Treatment groups at study start
Emergency presentation (in the 7 days before randomization
Finerenone 10 mg o.d.
Finerenone 5 mg o.d.
Finerenone 5 mg o.d.
Finerenone 2.5 mg o.d.
Initial stabilization and screening
Eplerenone 50 mg o.d.
Eplerenone 25 mg o.d.
Eplerenone 25 mg e.o.d.
Note: this slide contains an animation
Safety follow-up
Up-titration if serum potassium ≤ 5.0 mmol/L
Up-titration/sham up-titration if serum potassium ≤ 5.0 mmol/L
Randomization
Acute/vulnerable phase up to day 30
Chronic phase: days 31–90
Day 1
Day 30
Day 60
Day 90
DMC, Data Monitoring Committee; e.o.d., every other day; o.d. once daily

6. Study endpoints Endpoint Outcome variable Primary endpoint
Proportion of patients with a relative decrease in NT-proBNP of > 30% from baseline to day 90
Further exploratory endpoints
Composite endpoint of death from any cause, CV hospitalization or emergency presentation for worsening chronic heart failure (until day 90)
Change in efficacy biomarker levels from baseline (BNP and NT-proBNP) to days 30, 60 and 90
Change in health-related quality of life from baseline to days 30 and 90
Kansas City Cardiomyopathy Questionnaire
5-dimension EuroQol questionnaire
BNP, B-type natriuretic peptide; CV, cardiovascular; NT-proBNP, N-terminal of prohormone B-type natriuretic peptide

7. Baseline demographics (I)
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 = 1055
Mean age, years (SD)
72.4 (9.9)
72.5 (9.7)
71.8 (10.6)
69.3 (9.8)
71.3 (10.3)
69.2 (10.2)
71.2 (10.1)
Men, n (%)
170 (76.9)
135 (78.5)
126 (77.3)
124 (74.3)
128 (75.7)
132 (81.0)
816 (77.3)
Risk factors, % DM
24.9
22.7
22.1
29.3
28.4
32.5
26.5
DM + CKD
38.0
39.5
43.6
35.3
35.5
34.4
37.7
CKD
37.1
36.6
33.7
34.1
36.1
31.9
35.1
Mean
potassium, mmol/L
4.2 ± 0.5
4.1 ± 0.5
4.2 ± 0.4
Mean eGFR, MDRD
52 ± 18
52 ± 16
55 ± 20
53 ± 17
55 ± 19
53 ± 18
eGFR < 60, MDRD
72%
70%
78%
67%
71%
eGFR, estimated glomerular filtration rate (mL/min/1.73 m2); MDRD, Modification of Diet in Renal Disease

8. Baseline demographics (II)
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 = 1055
NT-proBNP, median, pg/mL
5331
5000
4386
4085
4543 
3750
4517
BNP, median, pg/mL
645
715
559
572
646
570
625
Mean last LVEF, % (SD)
29.8 (7.5)
29.3 (7.8) 
28.7 (7.4)
28.5 (7.4)
29.0 (8.0)
29.0 (7.5)
29.1 (7.6)
ACEI/ARB, n (%)
173 (78.3)
131 (76.2)
129 (79.1)
130 (77.8)
127 (75.1)
134 (82.2)
824 (78.1)
β-blocker, n (%)
189 (85.5)
137 (79.7)
141 (86.5)
146 (87.4)
148 (87.6)
146 (89.6)
907 (86.0)
ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; BNP, B-type natriuretic peptide; CKD, chronic kidney disease; DM, diabetes mellitus; LVEF, left ventricular ejection fraction; NT-proBNP, N-terminal of prohormone B-type natriuretic peptide; SD, standard deviation

9. Primary endpoint results
The proportion of patients who had an NT-proBNP decrease of more than 30% at day 90 compared with baseline was similar in the finerenone groups and the eplerenone group in the full analysis set 50
38.8
37.3
37.2
34.2
32.5 40
30.9 30
Proportion of patients with > 30% reduction
in NT-proBNP from baseline to day 90 (%) 20 10
Eplerenone
(n = 207)
Finerenone
2.5–5 mg
(n = 162)
Finerenone
5–10 mg
(n = 157)
Finerenone
7.5–15 mg
(n = 158)
Finerenone
10–20 mg
(n = 160)
Finerenone
15–20 mg
(n = 158)
Error bars show 90% confidence intervals NT-proBNP, N-terminal of prohormone B-type natriuretic peptide

10. Probability of no event (%)
Death from any cause, cardiovascular hospitalization, or emergency presentation for worsening CHF
Study period
Follow-up
100 90 80
Probability of no event (%) 70
Eplerenone (n = 207)
Finerenone 7.5–15 mg (n = 158) 60
Finerenone 2.5–5 mg (n = 162)
Finerenone 10–20 mg (n = 160) 50
Finerenone 5–10 mg (n = 157)
Finerenone 15–20 mg (n = 158) 10 20 30 40 50 60 70 80 90
100
110
120
Time (days)
Number at risk:
Eplerenone
Finerenone 2.5–5 mg
Finerenone 5–10 mg
Finerenone 7.5–15 mg
Finerenone 10–20 mg
Finerenone 15–20 mg
207
162
157
158
160
161
122
130
138
139
129
134
103
113
117
126
118
121 90
105 96
107 95

11. Finerenone: all-cause death and cardiovascular hospitalization
Finerenone 10–20 mg/eplerenone HR: 0.14; 95% CI: 0.02–1.07
Pooled finerenone/eplerenone HR: 0.52; 95% CI: 0.23–1.19
Cardiovascular hospitalization
Finerenone 10–20 mg/eplerenone HR: 0.56; 95% CI: 0.34–0.93
Pooled finerenone/eplerenone HR: 0.70; 95% CI: 0.49–0.98 8 30 6 20
Cumulative probability (%) 4
Cumulative probability (%) 10 2
Day 0
Day 30
Day 60
Day 90 FU
Day 0
Day 30
Day 60
Day 90 FU
Eplerenone (n = 207)
Finerenone 10–20 mg (n = 160)
Pooled finerenone (n = 633)
Pooled finerenone included 5–10 mg, 7.5–15 mg, 10–20 mg and 15–20 mg CI, confidence interval; HR, hazard ratio

12. Change in health-related quality of life
Kansas City Cardiomyopathy Questionnaire 60
29.3
24.3
28.3
22.2
24.5
21.3 50 40 30
Mean change from baseline in Total Symptom score 20 10
–10
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)
Error bars show standard deviations

13. 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 = 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 causing discontinuation, n (%)
32 (14.5)
21 (12.2)
25 (15.3)
25 (15.0)
17 (10.1)
21 (12.9)
141 (13.4)
SAE causing discontinuation, n (%)
19 (8.6)
13 (7.6)
13 (8.0)
17 (10.2)
11 (6.5)
86 (8.2)
Study-drug-related AE, n (%)
39 (17.6)
34 (19.8)
28 (17.2)
32 (19.2)
27 (16.0)
29 (17.8)
189 (17.9)
Study-drug-related SAE, n (%)
9 (4.1)
10 (5.8)
7 (4.3)
11 (6.6)
6 (3.6)
11 (6.7)
54 (5.1)
AE of special interest,a n (%)
44 (19.9)
38 (22.1)
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

14. Patients with hyperkalemia or eGFR decrease > 40% at any time post-baseline
SAF
Eplerenone
Finerenone 2.5–5 mg
Finerenone 5–10 mg
Finerenone 7.5–15 mg
Finerenone 10–20 mg
Finerenone 15–20 mg
Total
Hyperkalaemia, n (%)
n = 212
n = 165
n = 157
n = 164
n = 160
n = 1023
≥ 5.6 mmol/L
10 (4.7)
6 (3.6)
6 (3.8)
6 (3.7)
10 (6.3)
44 (4.3)
> 6.0 mmol/L
1 (0.5)
1 (0.6)
3 (1.9)
5 (0.5)
eGFR decrease, n (%)
n = 167
n = 1025
> 40 %
20 (9.4)
21 (12.6)
14 (8.9)
12 (7.3)
7 (4.2)
19 (11.9)
93 (9.1)
eGFR, estimated glomerular filtration rate (mL/min/1.73 m2); SAF, safety analysis set

15. Mean change in potassium from baseline
0.262
0.202
0.200
p = 0.030
p = 0.016
p = 0.016 * * *
0.134
0.119
0.119
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)
*Statistically significant
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

16. 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

17. 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

18. 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)

19. Investigators 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
Bulgaria
Lyubomir Lyubenov, Yoto Yotov, Petyo Georgiev, Elina Blatadzhieva-Trendafilova, Temenuga Donova, Valentina Mincheva, Mariana Konteva
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
Hungary
Ebrahim Noori, Janos Tomcsanyi, Andras Vertes, Bela Merkely, Andras Matoltsy
Israel
Alon Marmor, Amos Katz, Tuvia Ben Gal, Sorel Goland, Avraham Shotan, Haim Shmilovich, Yoav Turgeman, Tanya Weitsman, Basil Lewis, Shaul Atar, Morris Mosseri, Zvi Vered
Italy
Michele Senni, Andrea Mortara, Gianfranco Parati, Matteo Di Biase, Maurizio Volterrani, FrancoCosmi, Mario Marzilli, Gianfranco Alunni, Antonello Gavazzi
South Korea
Jae-Joong Kim, Hae-Young Lee, Byung Su Yoo, Sang-Hong Baek, Seok-Min Kang
Lithuania
Jelena Celutkiene, Ausra Kavoliuniene, Alfredas Bagdonas, Gintautas Gumbrevicius, Sigitas Stonkus, Sigute, Norkiene
Netherlands
Adriaan Voors, MA Brouwer, GL Bartels, C de Nooijer, RGEJ Groutars, PR Nierop, E Ronner, SHK The, NYY Al Windy
Norway
Stein Ørn, Jan Erik Otterstad, Roar Thorshaug, Aina Brekk
Poland
Joanna Szachniewicz, Ewa Mirek-Bryniarska, Aleksander Goch, Waldemar Krysiak, Marcin Gruchala, Janina Stepinska, Michal Tendera, Beata Wozakowska-Kaplon, Wlodzimierz Musial
Portugal
José Carlos Silva Cardoso, Pedro Moraes Sarmento, Hélder Pereira, Cândida Fonseca, Dulce Brito, Jorge Mimoso, Carlos Cotrim
Sweden
Maria Schaufelberger, Jens Olson, Inger Hagerman, Hans Persson, Thomas Kronvall, Stefan Berglund, Bengt Johansson
Turkey
Sadi Gulec, Bulent Boyaci, Cemil Gurgun, Sema Guneri, Ahmet Temizhan, Aytül Belgi Yildirim
Taiwan
Chern-En Chiang, Wen-Jone Chen, Kou-Gi Shyu, Kwo-Chang Ueng, Yen-Wen Wu
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

20. Participating countries
North America
Europe
Asia
Others (Australia, Israel, South Africa)

21. Back-up

22. Inclusion and exclusion criteria
Main inclusion criteria
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
Adapted from Pitt et al. Eur J Heart Fail 2015;17:224–32
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

23. Inclusion and exclusion criteria
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
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