Introduction
Methods
Patient population
Study procedures
Renal function
Treatment effect of serelaxin in patients with renal impairment
Statistical analysis
Results
Variables | eGFR <60 ml/min/1.73 m2 (N = 817)a
| eGFR ≥60 ml/min/1.73 m2 (N = 315)a
|
p valueb
|
---|---|---|---|
Demographics and heart failure characteristics | |||
Age (years) | 73.3 (10.6) | 68.8 (12.1) | <0.001x
|
Male | 505 (61.8) | 200 (63.5) | 0.601†
|
White/Caucasian | 772 (94.5) | 301 (95.6) | 0.471†
|
Left ventricular ejection fraction (%) | 39.2 (14.6) | 37.0 (14.3) | 0.027*
|
Ischemic heart disease | 443 (54.2) | 146 (46.3) | 0.018†
|
NYHA class (I/II/III/IV) 30 days before admission | 0.130†
| ||
I | 216 (26.7) | 100 (31.9) | |
II | 210 (26.0) | 84 (26.8) | |
III | 289 (35.7) | 90 (28.8) | |
IV | 94 (11.6) | 39 (12.5) | |
Clinical signs | |||
Body mass index (kg/m2) | 29.3 (5.7) | 29.2 (5.8) | 0.918*
|
Syst. blood pressure (mmHg) | 142.4 (16.7) | 141.6 (15.8) | 0.507*
|
Diast. blood pressure (mmHg) | 78.4 (14.3) | 80.7 (13.8) | 0.012*
|
Heart rate, beat per minute | 78.9 (14.7) | 82.1 (15.2) | 0.002*
|
Serelaxin administration (%) | 409 (50.1) | 155 (49.2) | 0.797†
|
Medical history | |||
Hypertension | 720 (88.1) | 258 (81.9) | 0.006†
|
Hyperlipidemia | 454 (55.6) | 146 (46.3) | 0.005†
|
Diabetes mellitus | 414 (50.7) | 125 (39.7) | 0.001†
|
Cigarette smoking | 96 (11.8) | 51 (16.2) | 0.046†
|
Stroke or other cerebrovascular event | 111 (13.6) | 42 (13.3) | 0.911†
|
Peripheral vascular disease | 115 (14.1) | 35 (11.1) | 0.187†
|
Asthma, bronchitis, or COPD | 135 (16.5) | 42 (13.3) | 0.185†
|
Atrial fibrillation at screening | 344 (42.2) | 122 (38.7) | 0.287†
|
History of Atrial fibrillation or flutter | 439 (53.7) | 149 (47.3) | 0.052†
|
History of CRT or ICD procedures | 228 (27.9) | 61 (19.4) | 0.003†
|
Myocardial infarction | 291 (35.6) | 101 (32.1) | 0.260†
|
Depression | 39 (4.8) | 19 (6.0) | 0.390†
|
Baseline laboratory | |||
Hemoglobin (g/dL) | 12.58 (1.89) | 13.31 (1.67) | <0.001x
|
Sodium (mmol/L) | 140.84 (3.61) | 140.80 (3.53) | 0.853*
|
Potassium (mmol/L) | 4.33 (0.64) | 4.12 (0.59) | <0.001*
|
Uric acid (μmol/L) | 490.8 (135.8) | 436.9 (128.5) | <0.001*
|
BUN (mmol/L) | 10.82 (4.02) | 7.09 (2.53) | <0.001x
|
Cystatine C (mg/L)c
| 1.60 (1.57, 1.63) | 1.14 (1.11, 1.17) | <0.001*
|
NT-proBNP (ng/L)c
| 5567 (5236, 5920) | 3883 (3521, 4281) | <0.001*
|
hsTnT (ng/L)c
| 0.037 (0.035, 0.040) | 0.029 (0.026, 0.032) | <0.001*
|
Medication (day 0) | |||
ACE inhibitor | 431 (52.8) | 189 (60.0) | 0.028†
|
ACEi or ARBs | 546 (66.8) | 227 (72.1) | 0.090†
|
Angiotensin-receptor blocker | 136 (16.6) | 46 (14.6) | 0.402†
|
Beta-blocker | 565 (69.2) | 214 (67.9) | 0.692†
|
Aldosterone antagonist | 252 (30.8) | 105 (33.3) | 0.419†
|
Digoxin | 167 (20.4) | 60 (19.0) | 0.600†
|
Association between renal impairment and clinical outcomes
All patients (n = 1132)a
| Serelaxin (n = 564)a
| Placebo (n = 568)a
| Interaction p valueb
| |
---|---|---|---|---|
Dyspnea relief by VAS AUC to day 5 | −139.39 (−510.72, 231.95) | −30.03 (−556.94, 496.88) | −253.80 (−774.89, 267.28) | 0.554 |
Dyspnea relief by Likert scale at 6, 12 and 24 h | 0.99 (0.74, 1.33) | 1.14 (0.74, 1.73) | 0.87 (0.58, 1.32) | 0.384 |
Worsening heart failure through day 5 | 1.16 (0.75, 1.80) | 1.48 (0.68, 3.22) | 1.04 (0.61, 1.76) | 0.460 |
Worsening heart failure through day 14 | 1.28 (0.88, 1.86) | 1.70 (0.91, 3.19) | 1.07 (0.67, 1.71) | 0.246 |
CV death/re-hospitalization for HF/RF through day 60 (days) | 1.39 (0.94, 2.06) | 1.14 (0.67, 1.95) | 1.72 (0.96, 3.08) | 0.311 |
CV death through day 60 (days) | 1.21 (0.61, 2.38) | 0.65 (0.26, 1.66) | 2.20 (0.76, 6.38) | 0.093 |
CV death through day 180 | 2.00 (1.13, 3.54) | 1.19 (0.54, 2.64) | 3.12 (1.33, 7.30) | 0.106 |
All-cause mortality day 180 | 1.86 (1.12, 3.10) | 1.15 (0.56, 2.34) | 2.81 (1.34, 5.89) | 0.088 |
Effects of serelaxin in acute heart failure patients with renal impairment
All patients (n = 1132) | eGFR <60 (n = 817) | eGFR ≥60 (n = 315) | Treatment effect of serelaxin | Interaction p valuec
| ||||||
---|---|---|---|---|---|---|---|---|---|---|
Serelaxin (n = 564)a
| Placebo (n = 568)a
| Serelaxin (n = 409)a
| Placebo (n = 408)a
| Serelaxin (n = 155)a
| Placebo (n = 160)a
| All patients | eGFR <60b
| eGFR ≥60b
| ||
Dyspnea relief by Likert scale at 6, 12 and 24 h (number of patients, %) | 152 (26.95) | 149 (26.23) | 113 (27.63) | 104 (25.49) | 39 (25.16) | 45 (28.13) | 1.04 (0.80, 1.35) | 1.12 (0.82, 1.52) | 0.86 (0.52, 1.42) | 0.384 |
Total dose of IV diuretic to day 5 (mg) | 161 (135, 187) | 211 (185, 237) | 170 (139, 201) | 226 (195, 257) | 136 (86, 187) | 171 (122, 220) | −50 (−87, −13) | −56 (−100, −13) | −34 (−105, 36) | 0.608 |
Total dose of oral diuretic to day 5 (mg) | 193 (177, 209) | 184 (168, 200) | 197 (178, 216) | 187 (168, 206) | 183 (152, 213) | 177 (147, 207) | 9 (−14, 32) | 10 (−16, 37) | 5 (−38, 48) | 0.849 |
Worsening heart failure through day 5 | 39 (6.94) | 69 (12.15) | 31 (7.60) | 50 (12.25) | 8 (5.19) | 19 (11.88) | 0.55 (0.37, 0.82) | 0.60 (0.38, 0.94) | 0.42 (0.18, 0.96) | 0.460 |
Worsening heart failure through day 14 | 65 (11.58) | 89 (15.68) | 53 (13.01) | 65 (15.95) | 12 (7.79) | 24 (15.00) | 0.71 (0.52, 0.98) | 0.79 (0.55, 1.13) | 0.50 (0.25, 0.99) | 0.246 |
Length of initial hospital stay (days) | 9.66 (8.89, 10.43) | 10.40 (9.64, 11.17) | 9.55 (8.64, 10.45) | 10.61 (9.71, 11.52) | 9.95 (8.49, 11.42) | 9.86 (8.42, 11.30) | −0.74 (−1.83, 0.34) | −1.07 (−2.34, 0.21) | 0.09 (−1.96, 2.15) | 0.347 |
Length of stay in ICU/CCU (days) | 3.55 (2.97, 4.12) | 3.80 (3.23, 4.38) | 3.42 (2.74, 4.10) | 3.88 (3.20, 4.56) | 3.87 (2.76, 4.98) | 3.61 (2.53, 4.70) | −0.26 (−1.07, 0.56) | −0.46 (−1.42, 0.51) | 0.26 (−1.29, 1.81) | 0.444 |
Days alive out of hospital through day 60 (days) | 48.28 (47.31, 49.26) | 47.74 (46.77, 48.71) | 48.32 (47.17, 49.47) | 47.42 (46.27, 48.57) | 48.19 (46.32, 50.05) | 48.55 (46.71, 50.39) | 0.54 (−0.84, 1.92) | 0.90 (−0.73, 2.52) | −0.36 (−2.98, 2.25) | 0.422 |
CV death through day 60 | 19 (3.40) | 26 (4.61) | 12 (2.97) | 22 (5.43) | 7 (4.55) | 4 (2.51) | 0.73 (0.41, 1.32) | 0.54 (0.27, 1.09) | 1.82 (0.53, 6.21) | 0.093 |
All-cause mortality day 180 | 40 (7.19) | 63 (11.18) | 30 (7.43) | 55 (13.61) | 10 (6.56) | 8 (5.01) | 0.63 (0.42, 0.94) | 0.53 (0.34, 0.83) | 1.30 (0.51, 3.29) | 0.088 |
Number needed to treat
Safety of serelaxin
Adverse event (AE) subset; n (%) | eGFR category | |||||
---|---|---|---|---|---|---|
All patientsa
| eGFR <60 mL/min/1.73 m2
| eGFR ≥60 mL/min/1.73 m2
| ||||
Serelaxin (N = 568) | Placebo (N = 570) | Serelaxin (N = 403) | Placebo (N = 406) | Serelaxin (N = 155) | Placebo (N = 157) | |
AEs through day 5 | ||||||
Any AEs | 280 (49.3) | 305 (53.5) | 209 (51.9) | 231 (56.9) | 66 (42.6) | 70 (44.6) |
Any AEs leading to drug discontinuation | 26 (4.6) | 22 (3.9) | 16 (4.0) | 16 (3.9) | 10 (6.5) | 5 (3.2) |
SAEs | 36 (6.3) | 38 (6.7) | 27 (6.7) | 29 (7.1) | 8 (5.2) | 7 (4.5) |
SAEs with an outcome of death | 6 (1.1) | 9 (1.6) | 4 (1.0) | 6 (1.5) | 2 (1.3) | 2 (1.3) |
AEs through day 14 | ||||||
All-treatment emergent AEs | 305 (53.7) | 320 (56.1) | 229 (56.8) | 243 (59.9) | 70 (45.2) | 73 (46.5) |
SAEs | 86 (15.1) | 78 (13.7) | 68 (16.9) | 58 (14.3) | 16 (10.3) | 18 (11.5) |
SAEs with an outcome of death | 10 (1.8) | 15 (2.6) | 7 (1.7) | 10 (2.5) | 3 (1.9) | 4 (2.5) |
AEs indicative of renal impairment through day 5 | ||||||
Subjects with any AE | 26 (4.6) | 49 (8.6) | 24 (6.0) | 44 (10.8) | 2 (1.3) | 4 (2.5) |
Azotaemia | 1 (0.2) | 1 (0.2) | 1 (0.2) | 1 (0.2) | – | – |
Blood creatinine increased | 14 (2.5) | 22 (3.9) | 12 (3.0) | 19 (4.7) | 2 (1.3) | 3 (1.9) |
Oliguria | 0 | 1 (0.2) | – | – | 0 | 1 (0.6) |
Proteinuria | 0 | 2 (0.4) | 0 | 2 (0.5) | – | – |
Renal failure | 9 (1.6) | 23 (4.0) | 9 (2.2) | 21 (5.2) | 0 | 1 (0.6) |
Renal failure acute | 1 (0.2) | 0 | 1 (0.2) | 0 | – | – |
Renal impairment | 1 (0.2) | 1 (0.2) | 1 (0.2) | 1 (0.2) | – | – |
AEs indicative of renal impairment through day 14 | ||||||
Subjects with any AE | 32 (5.6) | 51 (8.9) | 30 (7.4) | 46 (11.3) | 2 (1.3) | 4 (2.5) |
Azotaemia | 1 (0.2) | 1 (0.2) | 1 (0.2) | 1 (0.2) | – | – |
Blood creatinine increased | 14 (2.5) | 23 (4.0) | 12 (3.0) | 20 (4.9) | 2 (1.3) | 3 (1.9) |
Oliguria | 0 | 1 (0.2) | – | – | 0 | 1 (0.6) |
Proteinuria | 0 | 2 (0.4) | 0 | 2 (0.5) | – | – |
Renal failure | 14 (2.5) | 25 (4.4) | 14 (3.5) | 23 (5.7) | 0 | 1 (0.6) |
Renal failure acute | 2 (0.4) | 0 | 2 (0.5) | 0 | – | – |
Renal impairment | 1 (0.2) | 1 (0.2) | 1 (0.2) | 1 (0.2) | – | – |