Introduction
Patients and methods
Study design, population and treatment
Ethics
Statistical analyses
Results
Baseline characteristics
Variables | Totala (n = 1161) | Mena (n = 725) | Womena (n = 436) |
p valueb
|
---|---|---|---|---|
Demographics and HF characteristics | ||||
Age (years) | 72.0 (11.2) | 69.8 (11.7) | 75.8 (9.2) | <0.0001 [S] |
Serelaxin administration (%) | 581 (50.0%) | 368 (50.8%) | 213 (48.9%) | 0.5295 [2] |
White | 1096 (94.4%) | 680 (93.8%) | 416 (95.4%) | 0.2450 [2] |
Geographic region | 0.0001 [2] | |||
Eastern EU | 562 (48.4%) | 315 (43.4%) | 247 (56.7%) | |
Western EU | 204 (17.6%) | 144 (19.9%) | 60 (13.8%) | |
South America | 71 (6.1%) | 45 (6.2%) | 26 (6.0%) | |
North America | 114 (9.8%) | 85 (11.7%) | 29 (6.7%) | |
Israel | 210 (18.1%) | 136 (18.8%) | 74 (17.0%) | |
US-Likec
| 786 (67.7%) | 540 (74.5%) | 246 (56.4%) | <0.0001 [2] |
Left ventricular EF (%) | 38.6 (14.6) | 35.1 (13.2) | 44.7 (14.9) | <0.0001 [S] |
EF <40% | 598 (54.8%) | 446 (64.8%) | 152 (37.7%) | <0.0001 [2] |
Ischemic heart disease | 603 (51.9%) | 419 (57.8%) | 184 (42.2%) | <0.0001 [2] |
Time to randomization (h) | 7.9 (4.6) | 7.7 (4.8) | 8.2 (4.4) | 0.0384 [1] |
CHF 1 month prior | 861 (74.2%) | 557 (76.8%) | 304 (69.7%) | 0.0074 [2] |
HF hospitalization past year | 397 (34.2%) | 260 (35.9%) | 137 (31.4%) | 0.1225 [2] |
NYHA class 30 days before admission | 0.0014 [2] | |||
I | 323 (28.1%) | 186 (25.8%) | 137 (31.8%) | |
II | 304 (26.4%) | 174 (24.2%) | 130 (30.2%) | |
III | 389 (33.8%) | 268 (37.2%) | 121 (28.1%) | |
IV | 135 (11.7%) | 92 (12.8%) | 43 (10.0%) | |
Clinical variables | ||||
Body mass index (kg/m2) | 29.3 (5.7) | 29.3 (5.3) | 29.3 (6.3) | 0.8964 [S] |
Syst. blood pressure (mmHg) | 142.2 (16.6) | 141.2 (16.5) | 143.8 (16.7) | 0.0110 [1] |
Diast. blood pressure (mmHg) | 79.0 (14.2) | 79.8 (14.0) | 77.7 (14.5) | 0.0125 [1] |
Heart rate (beats/min) | 79.7 (14.9) | 79.1 (14.5) | 80.6 (15.6) | 0.1093 [1] |
Respiratory rate (breaths/min) | 21.9 (4.6) | 21.7 (4.6) | 22.3 (4.6) | 0.0299 [1] |
Congestion at baseline | ||||
Edema | 910 (78.9%) | 578 (80.4%) | 332 (76.3%) | 0.1010 [2] |
Orthopnea | 1106 (95.8%) | 689 (95.8%) | 417 (95.9%) | 0.9773 [2] |
JVP | 850 (75.5%) | 533 (76.0%) | 317 (74.6%) | 0.5845 [2] |
Dyspnea on exertion | 1136 (99.6%) | 708 (99.7%) | 428 (99.5%) | 0.6351 [3] |
Dyspnea by VAS | 44.2 (20.0) | 44.7 (19.9) | 43.4 (20.1) | 0.2839 [1] |
Rales | 1095 (94.8%) | 679 (94.3%) | 416 (95.6%) | 0.3249 [2] |
Comorbidities | ||||
Hypertension | 1006 (86.6%) | 602 (83.0%) | 404 (92.7%) | <0.0001 [2] |
Hyperlipidemia | 617 (53.1%) | 405 (55.9%) | 212 (48.6%) | 0.0167 [2] |
Diabetes mellitus | 551 (47.5%) | 347 (47.9%) | 204 (46.8%) | 0.7229 [2] |
Cigarette smoking | 153 (13.2%) | 127 (17.5%) | 26 (6.0%) | <0.0001 [2] |
Stroke or other cerebrovascular event | 157 (13.5%) | 101 (13.9%) | 56 (12.8%) | 0.5999 [2] |
Peripheral vascular disease | 155 (13.4%) | 115 (15.9%) | 40 (9.2%) | 0.0012 [2] |
Asthma, bronchitis, or COPD | 184 (15.8%) | 138 (19.0%) | 46 (10.6%) | 0.0001 [2] |
Atrial fibrillation at screening | 479 (41.3%) | 284 (39.2%) | 195 (44.8%) | 0.0608 [2] |
History of atrial fibrillation or flutter | 602 (51.9%) | 354 (48.8%) | 248 (56.9%) | 0.0078 [2] |
History of CRT or ICD procedures | 294 (25.3%) | 218 (30.1%) | 76 (17.4%) | <0.0001 [2] |
Myocardial infarction | 403 (34.7%) | 286 (39.4%) | 117 (26.8%) | <0.0001 [2] |
Depression | 60 (5.2%) | 34 (4.7%) | 26 (6.0%) | 0.3425 [2] |
Devices | ||||
Pacemaker | 121 (10.4%) | 70 (9.7%) | 51 (11.7%) | 0.2701 [2] |
Implantable cardiac defibrillator | 154 (13.3%) | 136 (18.8%) | 18 (4.1%) | <0.0001 [2] |
Biventricular pacing | 113 (9.7%) | 96 (13.2%) | 17 (3.9%) | <0.0001 [2] |
Medication | ||||
ACE inhibitor | 633 (54.5%) | 392 (54.1%) | 241 (55.3%) | 0.6894 [2] |
ACEi or ARBs | 788 (67.9%) | 492 (67.9%) | 296 (67.9%) | 0.9922 [2] |
Angiotensin-receptor blocker | 185 (15.9%) | 112 (15.4%) | 73 (16.7%) | 0.5594 [2] |
Beta-blocker | 794 (68.4%) | 507 (69.9%) | 287 (65.8%) | 0.1451 [2] |
Aldosterone antagonist | 365 (31.4%) | 240 (33.1%) | 125 (28.7%) | 0.1151 [2] |
Oral loop diuretic 30 days prior | 44.7 (65.2) | 50.5 (72.3) | 34.9 (49.6) | <0.0001 [S] |
Digoxin | 228 (19.6%) | 116 (16.0%) | 112 (25.7%) | <0.0001 [2] |
Nitrates at randomization | 81 (7.0%) | 42 (5.8%) | 39 (8.9%) | 0.0412 [2] |
Baseline laboratory data | ||||
Sodium (mmol/L) | 140.82 (3.59) | 140.76 (3.60) | 140.93 (3.57) | 0.4183 [1] |
Phosphate (mmol/L) | 1.19 (0.32) | 1.18 (0.36) | 1.20 (0.23) | 0.3547 [S] |
Calcium (mmol/L) | 2.26 (0.15) | 2.26 (0.16) | 2.27 (0.14) | 0.8622 [S] |
Hemoglobin (g/dL) | 12.79 (1.86) | 13.11 (1.89) | 12.27 (1.68) | <0.0001 [S] |
White blood cell count (×10/L) | 8.179 (2.843) | 8.022 (2.637) | 8.439 (3.142) | 0.0243 [S] |
Lymphocyte (%) | 18.17 (7.81) | 18.50 (7.81) | 17.64 (7.78) | 0.0803 [1] |
Potassium (mmol/L) | 4.27 (0.63) | 4.31 (0.64) | 4.21 (0.61) | 0.0098 [1] |
Creatinine (μmol/L) | 116.58 (33.15) | 126.28 (32.81) | 100.58 (26.94) | <0.0001 [S] |
Uric acid (μmol/L) | 475.8 (135.9) | 488.1 (137.7) | 455.4 (130.6) | <0.0001 [1] |
Troponin T (μg/Ld) | 0.035 (0.033, 0.037) | 0.037 (0.035, 0.040) | 0.031 (0.029, 0.034) | 0.0015 [S] |
BUN (mmol/L) | 9.78 (4.03) | 10.01 (3.96) | 9.40 (4.10) | 0.0132 [1] |
Cystatin-C (mg/Ld) | 1.45 (1.43, 1.48) | 1.46 (1.43, 1.49) | 1.44 (1.40, 1.48) | 0.4950 [1] |
Alanine aminotransferase (U/Ld) | 23.5 (22.7, 24.4) | 23.8 (22.7, 25.0) | 23.1 (21.8, 24.5) | 0.4078 [1] |
NT-proBNP (ng/Ld) | 5054 (4795, 5326) | 4936 (4615, 5279) | 5253 (4830, 5714) | 0.2579 [1] |
eGFR (mL/min per 1.73 m2) | 53.49 (13.03) | 54.81 (12.84) | 51.32 (13.06) | <0.0001 [1] |
Total cholesterol (mmol/L) | 4.09 (1.17) | 3.97 (1.13) | 4.30 (1.20) | <0.0001 [1] |
Glucose (mmol/L) | 7.75 (3.57) | 7.62 (3.48) | 7.96 (3.71) | 0.1202 [1] |
Albumin (g/L) | 40.23 (4.33) | 40.28 (4.57) | 40.15 (3.91) | 0.6229 [S] |
Symptomatic response by sex
Total cohorta (n = 1161) | Mena (n = 725) | Womena (n = 436) |
p valueb
| |
---|---|---|---|---|
Change from baseline VAS score (mm) | ||||
Hour 6 | 9.55 (16.51) | 8.92 (16.21) | 10.60 (16.97) | 0.0933 [1] |
Hour 12 | 14.20 (19.33) | 13.35 (19.74) | 15.63 (18.57) | 0.0518 [1] |
Day 1 | 18.74 (23.49) | 17.77 (23.35) | 20.35 (23.66) | 0.0701 [1] |
Day 2 | 22.35 (26.55) | 21.46 (27.02) | 23.82 (25.70) | 0.1420 [1] |
Day 5 | 25.94 (30.77) | 24.88 (31.02) | 27.68 (30.30) | 0.1334 [1] |
Day 14 | 22.72 (34.52) | 22.01 (34.56) | 23.90 (34.46) | 0.3661 [1] |
Dyspnea VAS AUC (mm × h) | ||||
Baseline to day 14 | 7786.82 (9333.49) | 7482.07 (9410.64) | 8293.56 (9192.12) | 0.1515 [1] |
Day 1 to day 5 | 2234.37 (2549.18) | 2137.14 (2566.48) | 2396.04 (2514.75) | 0.0938 [1] |
Day 1 to day 14 | 7489.24 (9077.60) | 7201.79 (9152.91) | 7967.23 (8940.94) | 0.1642 [1] |
Dyspnea markedly or moderately improved per Likert scale, n (%) | ||||
Hour 6 | 385 (33.6%) | 221 (31.0%) | 164 (38.0%) | 0.0156 [2] |
Hour 12 | 544 (47.5%) | 313 (43.8%) | 231 (53.5%) | 0.0015 [2] |
Day 1 | 751 (65.5%) | 443 (62.0%) | 308 (71.1%) | 0.0017 [2] |
Day 2 | 850 (74.0%) | 510 (71.3%) | 340 (78.5%) | 0.0070 [2] |
Day 5 | 915 (79.5%) | 555 (77.4%) | 360 (82.9%) | 0.0240 [2] |
Day 14 | 857 (74.4%) | 523 (72.8%) | 334 (77.0%) | 0.1208 [2] |
General wellbeing, change from baseline in VAS score (mm) | ||||
Hour 6 | 9.12 (16.48) | 8.63 (16.12) | 9.93 (17.06) | 0.1933 [1] |
Hour 12 | 13.61 (18.85) | 13.04 (18.64) | 14.56 (19.19) | 0.1843 [1] |
Day 1 | 18.20 (22.72) | 17.45 (22.14) | 19.44 (23.63) | 0.1491 [1] |
Day 2 | 21.19 (25.77) | 20.47 (25.86) | 22.39 (25.61) | 0.2194 [1] |
Day 5 | 24.82 (30.43) | 23.50 (30.25) | 27.00 (30.64) | 0.0579 [1] |
Day 14 | 21.35 (33.67) | 20.48 (33.28) | 22.81 (34.30) | 0.2530 [1] |
General wellbeing Likert score | ||||
Hour 6 | 0.99 (1.11) | 0.94 (1.09) | 1.07 (1.12) | 0.0324 [W] |
Hour 12 | 1.31 (1.17) | 1.23 (1.19) | 1.44 (1.13) | 0.0018 [W] |
Day 1 | 1.60 (1.36) | 1.53 (1.36) | 1.71 (1.35) | 0.0040 [W] |
Day 2 | 1.75 (1.49) | 1.64 (1.55) | 1.91 (1.38) | 0.0012 [W] |
Day 5 | 1.84 (1.77) | 1.77 (1.83) | 1.97 (1.67) | 0.0434 [W] |
Day 14 | 1.56 (2.07) | 1.51 (2.11) | 1.65 (2.01) | 0.3751 [W] |
Diuretic doses, treatment response and post-discharge outcome by sex
Total cohorta (n = 1161) | Mena (n = 725) | Womena (n = 436) |
p valueb
| |
---|---|---|---|---|
Inotrope/vasoactive medication | ||||
All IV inotrope/vasoactive agents through day 5 | 161 (13.9) | 93 (12.8) | 68 (15.6) | 0.1862 [C] |
Nitroglycerin | 127 (10.9) | 66 (9.1) | 61 (14.0) | 0.0098 [C] |
Diuretic doses and treatment response | ||||
Total IV loop diuretic dose through day 5 (mg) | 187.21 (316.02) | 215.36 (364.91) | 140.76 (204.10) | <0.0001 [S] |
Total oral loop diuretic dose through day 5 (mg) | 187.70 (191.79) | 199.12 (204.05) | 168.86 (168.20) | 0.0067 [S] |
Treatment response | ||||
Study day of moderately or markedly improved dyspnea through day 5 | 1.72 (2.00) | 1.87 (2.07) | 1.48 (1.85) | 0.0005 [W] |
Study day of worsening HF through day 5 | 5.65 (1.19) | 5.61 (1.25) | 5.71 (1.08) | 0.1395 [W] |
Worsening HF through day 14 | 157 (13.56%) | 106 (14.67%) | 51 (11.71%) | 0.1522 [L] |
Change in bodyweight from baseline (kg) | ||||
Day 1 | −1.48 (1.98) | −1.56 (2.11) | −1.33 (1.73) | 0.0433 [S] |
Day 2 | −2.03 (2.46) | −2.13 (2.65) | −1.87 (2.09) | 0.0752 [S] |
Day 5 | −2.86 (3.34) | −2.93 (3.50) | −2.76 (3.05) | 0.4210 [S] |
Day 14 | −3.31 (4.26) | −3.49 (4.60) | −3.02 (3.64) | 0.0642 [S] |
Relative change in bodyweight from baseline (%) | ||||
Day 1 | −1.82 (2.38) | −1.83 (2.44) | −1.81 (2.28) | 0.8637 [1] |
Day 2 | −2.48 (2.90) | −2.45 (2.97) | −2.53 (2.80) | 0.6483 [1] |
Day 5 | −3.46 (3.91) | −3.30 (3.84) | −3.72 (4.01) | 0.0797 [1] |
Day 14 | −3.87 (4.75) | −3.82 (4.89) | −3.95 (4.53) | 0.6780 [1] |
Outcome | ||||
Uncontrolled blood pressurec
| 271 (23.3%) | 157 (21.7%) | 114 (26.1%) | 0.0798 [C] |
Length of ICU/CCU stay (days) | 3.71 (7.04) | 3.51 (6.63) | 4.05 (7.67) | 0.0248 [W] |
Length of initial hospital stay (days) | 10.06 (9.34) | 9.87 (9.17) | 10.37 (9.62) | 0.0258 [W] |
Days alive and out of hospital before day 30 | 20.61 (6.64) | 20.68 (6.80) | 20.47 (6.38) | 0.1001 [W] |
Death or worsening HF or readmission to hospital for HF through day 30 | 200 (17.30%) | 129 (17.87%) | 71 (16.34%) | 0.4556 [L] |
CV death or readmission to hospital for HF or renal failure through day 30 | 83 (7.20%) | 50 (6.95%) | 33 (7.62%) | 0.6769 [L] |
CV death or readmission to hospital for HF or renal failure through day 30 after discharge | 92 (8.17%) | 55 (7.82%) | 37 (8.76%) | 0.5790 [L] |
All-cause death through day 30 | 31 (2.68%) | 16 (2.22%) | 15 (3.46%) | 0.2100 [L] |
All-cause death or readmission to hospital for HF or renal failure through day 60 | 154 (13.36%) | 97 (13.48%) | 57 (13.17%) | 0.9028 [L] |
CV death through day 180 | 88 (7.68%) | 57 (7.98%) | 31 (7.20%) | 0.6484 [L] |
All-cause death through day 180 | 107 (9.31%) | 68 (9.46%) | 39 (9.06%) | 0.8059 [L] |
Interaction analyses of differential effects by sex
Effect of selected characteristics on early dyspnea improvement
Covariates | Coefficient (95% CI) | Std. err | Odds ratio (95% CI) |
p value |
---|---|---|---|---|
Male | −0.5032 (−0.8053, −0.2011) | 0.1541 | 0.605 (0.447, 0.818) | 0.0011 |
HFpEF (LVEF ≥50) | −0.1579 (−0.4959, 0.1801) | 0.1725 | 0.854 (0.609, 1.197) | 0.3598 |
Age | −0.0200 (−0.0330, −0.0070) | 0.0066 | 0.980 (0.968, 0.993) | 0.0026 |
Pulse pressure | −0.0025 (−0.0113, 0.0064) | 0.0045 | 0.998 (0.989, 1.006) | 0.5861 |
Heart rate | 0.0055 (−0.0041, 0.0152) | 0.0049 | 1.006 (0.996, 1.015) | 0.2607 |
Total diuretic dosea
| −0.0031 (−0.0053, −0.0009) | 0.0011 | 0.997 (0.995, 0.999) | 0.0067 |