Results of ARTS-HF: finerenone versus eplerenone in

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

3

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.





Eplerenone 25 mg o.d.



Finerenone 7.5 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

BNP, B-type natriuretic peptide; CV, cardiovascular; NT-proBNP, N-terminal of prohormone B-type natriuretic peptide

6

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

Error bars show 90% confidence intervals NT-proBNP, N-terminal of prohormone B-type natriuretic peptide

Pro

po

rtio

n o

f p

atie

nts

wit

h >

30

% r

edu

ctio

n

in N

T-p

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NP

fro

m b

asel

ine

to d

ay 9

0 (

%) 50

30

20

10

0 Eplerenone

(n = 207) Finerenone 2.5–5 mg (n = 162)

Finerenone 5–10 mg (n = 157)

Finerenone 7.5–15 mg (n = 158)



37.2

30.9 32.5

37.3 38.8

34.2

40

Death from any cause, cardiovascular hospitalization, or emergency presentation

for worsening CHF

8

Pro

bab

ility

(%

)

100

90

80

50

0 0


Time (days)



Eplerenone (n = 207)



70

60

10 20 30 40 50 60 70 80 90 100 110 120

207 162 157 158 160 158

161 122 130 138 139 129

134 103 113 117 126 118

121 90

105 96

107 95

Study period Follow-up

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

Patients with hyperkalemia or eGFR decrease >

40% at any time post-baseline SAF Eplerenone

Finerenone 2.5–5 mg

Finerenone 5–10 mg




Total

Hyperkalaemia, n (%)

n = 212 n = 165 n = 157 n = 164 n = 165 n = 160 n = 1023

≥ 5.6 mmol/L 10 (4.7) 6 (3.6) 6 (3.8) 6 (3.7) 6 (3.6) 10 (6.3) 44 (4.3)

> 6.0 mmol/L 1 (0.5) 0 0 1 (0.6) 0 3 (1.9) 5 (0.5)

eGFR decrease, n (%)

n = 212 n = 167 n = 157 n = 164 n = 165 n = 160 n = 1025

> 40 % 20 (9.4) 21 (12.6) 14 (8.9) 12 (7.3) 7 (4.2) 19 (11.9) 93 (9.1)

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

10

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







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)

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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 = 163)

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

15

Investigators

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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

Participating countries

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Europe

North America

Asia

Others (Australia, Israel, South Africa)

Treatment-emergent adverse events


(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 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) 13 (8.0) 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) 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

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Baseline demographics (I)


(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

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 ± 0.5 4.2 ± 0.4 4.1 ± 0.5 4.1 ± 0.5 4.2 ± 0.5

Mean eGFR, MDRD 52 ± 18 52 ± 16 52 ± 16 55 ± 20 53 ± 17 55 ± 19 53 ± 18

eGFR < 60, MDRD 72% 70% 78% 70% 70% 67% 71%

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

20

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


n = 169


n = 170


n = 165

SAF

FAS

Eplerenone n = 224

Finerenone 2.5–5 mg n = 121

Finerenone 5–10 mg n = 122


n = 123


n = 134


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

21

Cum

ula

tive

pro

ba

bili

ty (

%)

40

30

20

10

0 Day 0


Day 30 Day 60 Day 90 Follow-up



Eplerenone



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

Finerenone vs Eplerenone: all-cause death and cardiovascular hospitalization

Pooled finerenone included 5–10 mg, 7.5–15 mg, 10–20 mg and 15–20 mg CI, confidence interval; HR, hazard ratio

22

All-cause death

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

Cu

mu

lati

ve p

rob

abili

ty (%

)

6

4

2

8

0

Cu

mu

lati

ve p

rob

abili

ty (%

)

20

10

30

0

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)

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

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

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

Change in health-related quality of life

Error bars show standard deviations

25

Mea

n c

han

ge f

rom

bas

elin

e in

To

tal S

ymp

tom

sco

re

60

30

20

10

–10

24.3 21.3

24.5

29.3

28.3 22.2

Kansas City Cardiomyopathy Questionnaire

40

50

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Documents

Results of ARTS-HF: finerenone versus eplerenone in