Duke Clinical Research Institute

Duke Clinical Research Institute

Aldosterone Targeted NeuroHormonal CombinEd with Natriuresis TherApy Heart Failure Trial ATHENA-HF Trial Javed Butler, M.D., M.P.H, M.B.A. On behalf of the NHLBI Heart Failure Clinical Research Network Persistent Congestion and Outcomes in Acute Heart Failure Persistent clinical and sub-clinical congestion at discharge after AHF hospitalization is associated with worse outcomes. Pulmonary Capillary Natriuretic Peptide Levels Signs and symptoms Wedge Pressure Lucas C, et al. Am Heart J. 2000;140:840847. Fonarow GC, et al. Circulation. 1994;90(pt. 2):1-488. Logeart D, et al. J Am Coll Cardiol. 2004;43:635-641 Acute Heart Failure

Aldosterone levels and highdoseAHF MRA Patients with have elevated aldosterone levels that are associated with diuretic resistance and worse post-discharge outcomes Eur J Heart Fail. 2013;15(11):1228-35 High-dose mineralocorticoid receptor antagonists (MRA) therapy has been shown to overcome diuretic resistance in HF. Circ Heart Fail 2009; 2: pp. 370-376 In a single blind randomized trial of 100 patients, 50-100mg spironolactone use in AHF was associated with improved congestion and Study Aim and Design To test the hypothesis that high-dose spironolactone use in patients with AHF will lead to greater reductions in NT-proBNP levels from randomization to 96 hr. Randomized, double blind, placebo-controlled, multicenter trial.

Patients not on MRA at baseline were randomized to spironolactone 100 mg or placebo Those on low-dose spironolactone (12.5 or 25 mg) were randomized to 100 mg Other Objectives 96 1. Congestion score (dyspnea, orthopnea, fatigue, JVP, hours rales, edema) 2. Dyspnea relief 3. Net urine output 4. Net weight change 5. Loop diuretic dose requirement 6. In-hospital worsening of HF Day 1. All-cause mortality 30 2. All-cause readmissions 3. Outpatient worsening HF (HF readmissions or ED visits or observational unit stays for HF or need for outpatients IV diuretics) 4. MRA use 5. Loop diuretic dose 6. Index hospitalization length of stay Day 1. Vital status 60 Safety 1. Change in serum creatinine Key Inclusion Criteria

Age 21 yrs At least 1 symptom and 1 sign of congestion eGFR of 30 mL/min/1.73m2 Serum K+ 5.0 mmol/l NT-proBNP 1000 pg/mL or BNP 250 pg/mL within 24h of randomization Not on MRA or on low-dose spironolactone (12.5 mg or 25 mg daily) at baseline Randomized within 24 hours of first IV diuretic dose Key Exclusion Criteria Eplerenone or >25 mg spironolactone at home Systolic blood pressure <90 mmHg Significant arrhythmias or ICD shock within 1 wk

ACS currently suspected or within the past 4 wk Current or planned LVAD within 30 days Post transplant or expected to receive one within 30d Study Flow and Enrollment 12/2014 to 4/2016 360 patients enrolled from 22 sites. 182 patients randomized to highdose spironolactone 178 to usual care 132 placebo 46 continued low dose spironolactone Clinical Characteristics Placebo Spironolactone 65 (54, 74) 65 (57, 76) 36 36 56/43 55/41 Myocardial Infarction (%)

30 28 Hypertension (%) 81 87 Atrial fibrillation (%) 48 50 Diabetes Mellitus (%) 42 40 Chronic Kidney Disease 31 24 30 (20, 45) 35 (21, 50) 79 69

Age (yr.) Female (%) White/Black (%) (%) LVEF (%) Proportion <45% (%) Baseline Treatment Placebo (%) Spironolactone (%) ACEI or ARB 63 58 Beta blockers 74 74 MRA 28 27 Loop diuretics 95 97

Hydralazine 26 24 Nitrates 19 19 Implanted 42 35 Vitals and Laboratory Data Baseline Characteristics SBP - mmHg Placebo Spironolactone 123 (108, 138) 120 (106, 138) Heart rate - bpm 80 (70, 94) 78 (70, 90) Body mass index

32 (27, 38) 30 (25, 35) Sodium - mEq/L 140 (138, 142) 140 (138, 142) Potassium - mEq/L 4 (3.6, 4.3) 3.9 (3.6, 4.3) Blood urea nitrogen - 22 (17, 31) 23 (16, 33) 1.3 (1.0, 1.5) 1.2 (1.0, 1.5) 55 (46, 71) 58 (45, 75) mg/dL Creatinine - mg/dL eGFR - ml/min/1.73 m2 Results - Primary Endpoint Placebo

Spironolactone Baseline 8.23 (7.58, 8.94) 8.43 (7.90, 9.17) 96 h (or 7.64 (6.93, 7.89 (7.19, 8.45) 8.68) Log NTproBNP discharge) Change -0.49 (-0.98, - peptide, -0.55 (-0.92, N-terminal pro B-type natriuretic pg/ml Baseline 96 h (or 0.14) 3753 (1968,

0.18) 4601 (2697, 7633) 9596) 2080 (1025, 2672 (1326, P 0.57 Dyspnea and Congestion Placebo Spironolacto P ne Dyspnea - Likert Score 2 (1, 3) 2 (1, 3) Baseline 65 (40, 75) 60 (45, 75) 96 h

83 (70, 90) 80 (65, 90) 15 (5, 30) Placebo 15 (2, 30) Spironolacto 0.30 Dyspnea Visual Analog Scale 96 h Change ne Clinical congestion score Baseline 96 h 11 (9, 12) 10 (9, 12) 4 (2, 6) 4 (2, 7) 0.61 P Urine Output and Weight Change Placebo

Spironolactone P Net urine output, mL 24 h 48 h 1183 (510, 1955) 1100 (483, 2131) 0.76 2282 (1155, 4135) 2484 (1203, 0.44 4411) 72 h 3810 (2011, 5565) 4171 (2053, 0.53 6040) Weight change, Ibs 96 h Baseline 96 h or early discharge 5584 (2924, 8132) 207.1 (171.0, 250.4) 6086 (2780, 195.0 (162.6,

8420) 237.0) 198.9 (167.6, 185.1 (158.5, 243.6) 230.8) 0.57 Diuretic Use and Worsening Heart Failure Placebo Spironolactone P Furosemide equivalent diuretic dose, mg Baseline 96 h 96 h change 160 (120, 160 (100, 320) 320) 80 (40, 240) 80.0 (40,

Placebo -80 (-160, 0.0) Worsening heart failure (%) Inpatient 18 200) Spironolacton P -80.0 (-160, 0.7 e 0) 7 19 0.7 Hyperkalemia Placebo Spironolactone P Change in serum potassium mEq/L. Median (25th, 75th 24 h 48 h 0.00 (-0.40, 0.00 (-0.30, 0.30)

0.30) 0.10 (-0.3, 0.40) 0.10 (-0.10, 0.50 0.02 One patient in the placebo group developed serum K 0.40) levels between 5.5-5.9 mmol/L 72 h 0.20 (-0.40, 0.20 (-0.20, 0.08 No one developed K concentration > 6.0 mmol/L Renal Function Placebo Spironolactone P Change in serum creatinine - mg/dL. Median (25th, 75th) 24 h 0.05 (-0.05, 0.20)

0.05 (-0.03, 0.17) 0.76 48 h 0.02 (-1.10, 0.20) 0.10 (-0.03, 0.20) 0.67 72 h 0.08 (-0.08, 0.22) 0.10 (-0.03, 0.28) 0.85 96 h 0.10 (-0.02, 0.33) 0.10 (-0.05, 0.27) 0.77 Change in eGFR- ml/min/1.73 m2. Median (25th, 75th) 24 h -1.95 (-8.46, 2.79) -2.58 (-7.83, 1.53) 0.87

48 h -1.59 (-9.65, 3.71) -4.12 (-8.87, 1.89) 0.95 72 h -3.70 (-12.06, 4.09) -3.71 (-10.67, 0.87) 0.82 96 h -5.53 (-13.11, 0.79) -4.35 (-11.06, 1.74) 0.56 Post Discharge Outcomes Median time to discharge:

4 (2, 7) days in both groups. Two patients in each arm died in-hospital 7 patients in placebo and 5 in spironolactone arm died by day 30. No significant difference in post-discharge mortality, HF hospitalization, or ED visit. 47% in placebo and 43% Sub-group analysis No differences in the primary endpoint between patients stratified by Age (< or > 65 years) Gender Baseline use of low dose vs. no spironolactone Change in log NTproBNP in the spironolactone and placebo groups respectively was EF< 45% was -0.55 (-0.92, -0.19) and -0.54 (0.99, -0.15), EF >45% was -0.53 (-1.03, -0.14) and -0.42 (0.64, -0.03) (interaction P=0.078) Conclusion In ATHENA-HF, 100mg/day spironolactone for 96 hr in

AHF did not achieve its primary aim of reducing NTproBNP level more than usual care alone None of the secondary endpoints differed between the 2 groups Dyspnea relief, clinical congestion, net urine output, weight lose, or clinical events High dose spironolactone was well tolerated No significant difference in worsening renal function or hyperkalemia between the two groups These data do not support the routine use of high dose spironolactone in AHF. The role of high dose MRA targeted to patients

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