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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 Bhm, Mihai Gheorghiade, Lars Kber, Henry Krum, Aldo P


  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: NCT01807221 • 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 guidelines 1,2 • 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

  4. 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 vitro 1 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 Emergency presentation at study start Finerenone 10 mg o.d. (in the 7 days before Finerenone 5 mg o.d. randomization Finerenone 5 mg o.d. Finerenone 2.5 mg o.d. Initial stabilization Eplerenone 50 mg o.d. and screening Eplerenone 25 mg o.d. Eplerenone 25 mg e.o.d. Safety Up-titration if serum Up-titration/sham up-titration if follow-up Randomization potassium ≤ 5.0 mmol/L serum potassium ≤ 5.0 mmol/L Acute/vulnerable phase Chronic phase: days 31–90 up to day 30 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 1. Proportion of patients with a relative decrease in Primary endpoint NT-proBNP of > 30% from baseline to day 90 Further exploratory 1. Composite endpoint of death from any cause, endpoints 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

  7. Baseline demographics (I) Eplerenone Finerenone Total 2.5–5 mg 5–10 mg 7.5–15 mg 10–20 mg 15–20 mg (n = 221) (n = 172) (n = 163) (n = 167) (n = 169) (n = 163) N = 1055 71.8 69.2 71.2 Mean age, years (SD) 72.4 (9.9) 72.5 (9.7) 69.3 (9.8) 71.3 (10.3) (10.6) (10.2) (10.1) 816 Men, n (%) 170 (76.9) 135 (78.5) 126 (77.3) 124 (74.3) 128 (75.7) 132 (81.0) (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 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 potassium, mmol/L 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 m 2 ); MDRD, Modification of Diet in Renal Disease

  8. Baseline demographics (II) Eplerenone Finerenone Total 2.5–5 mg 5–10 mg 7.5–15 mg 10–20 mg 15–20 mg (n = 221) (n = 172) (n = 163) (n = 167) (n = 169) (n = 163) N = 1055 NT-proBNP, 5331 5000 4386 4085 4543 3750 4517 median, pg/mL BNP, median, pg/mL 645 715 559 572 646 570 625 Mean last LVEF, % 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) (SD) 127 ACEI/ARB, n (%) 173 (78.3) 131 (76.2) 129 (79.1) 130 (77.8) 134 (82.2) 824 (78.1) (75.1) 148 β-blocker, n (%) 189 (85.5) 137 (79.7) 141 (86.5) 146 (87.4) 146 (89.6) 907 (86.0) (87.6) 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 Proportion of patients with > 30% reduction 50 in NT-proBNP from baseline to day 90 (%) 38.8 37.3 37.2 34.2 32.5 30.9 40 30 20 10 0 Eplerenone Finerenone Finerenone Finerenone Finerenone Finerenone (n = 207) 2.5–5 mg 5–10 mg 7.5–15 mg 10–20 mg 15–20 mg (n = 162) (n = 157) (n = 158) (n = 160) (n = 158) • 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

  10. Death from any cause, cardiovascular hospitalization, or emergency presentation for worsening CHF Study period Follow-up 100 90 Probability (%) 80 70 Finerenone 7.5–15 mg (n = 158) Eplerenone (n = 207) 60 Finerenone 10–20 mg (n = 160) Finerenone 2.5–5 mg (n = 162) 50 Finerenone 5–10 mg (n = 157) Finerenone 15–20 mg (n = 158) 0 0 10 20 30 40 50 60 70 80 90 100 110 120 Time (days) Number at risk: 207 161 134 121 Eplerenone 162 122 103 90 Finerenone 2.5–5 mg 157 130 113 105 Finerenone 5–10 mg Finerenone 7.5–15 mg 158 138 117 96 Finerenone 10–20 mg 160 139 126 107 158 129 118 95 Finerenone 15–20 mg

  11. Finerenone: all-cause death and cardiovascular hospitalization All-cause death Cardiovascular hospitalization Finerenone 10–20 mg/eplerenone Finerenone 10–20 mg/eplerenone HR: 0.14; 95% CI: 0.02–1.07 HR: 0.56; 95% CI: 0.34–0.93 Pooled finerenone/eplerenone Pooled finerenone/eplerenone HR: 0.52; 95% CI: 0.23–1.19 HR: 0.70; 95% CI: 0.49–0.98 8 30 Cumulative probability (%) Cumulative probability (%) 6 20 4 10 2 0 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) 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 29.3 60 24.3 22.2 28.3 24.5 21.3 50 Mean change from baseline in 40 Total Symptom score 30 20 10 0 –10 Eplerenone Finerenone Finerenone Finerenone Finerenone Finerenone (n = 143) 2.5–5 mg 5–10 mg 7.5–15 mg 10–20 mg 15–20 mg (n = 116) (n = 117) (n = 120) (n = 128) (n = 118) Error bars show standard deviations

  13. Treatment-emergent adverse events Eplerenone Finerenone Total 2.5–5 mg 5–10 mg 7.5–15 mg 10–20 mg 15–20 mg (n = 221) (n = 172) (n = 163) (n = 167) (n = 169) (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, 19 (8.6) 13 (7.6) 13 (8.0) 17 (10.2) 11 (6.5) 13 (8.0) 86 (8.2) n (%) 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 a An 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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