1. Subgroup Placebo n/N (%) Serelaxin n/N (%)Favours placeboFavours serelaxin Odds ratio Estimate (95%CI) Interaction P value Total population150/580 (25.9)156/581 (26.9)1.05 (0.81, 1.37) Gender Male85/357 (23.8)85/368 (23.1) 0.96 (0.68, 1.36)0.3867 Female65/223 (29.2)71/213 (33.3) 1.22 (0.81, 1.82) Age <65 years32/119 (26.9)50/145 (34.5) 1.43 (0.84, 2.43)0.1706 ≥65 years118/461 (25.6)106/436 (24.3) 0.93 (0.69, 1.26) <75 years78/296 (26.4)93/315 (29.5) 1.17 (0.82, 1.67)0.3559 ≥75 years72/284 (25.4)63/266 (23.7) 0.91 (0.62, 1.35) Region Eastern Europe89/282 (31.6)87/280 (31.1) 0.98 (0.68, 1.40)0.9358 Western Europe17/101 (16.8)20/103 (19.4) 1.19 (0.58, 2.43) South America18/37 (48.7)16/34 (47.1) 0.94 (0.37, 2.38) North America20/55 (36.4)25/59 (42.4) 1.29 (0.61, 2.73) Israel6/105 (5.7)8/105 (7.6) 1.36 (0.46, 4.07) Race White / Caucasian142/552 (25.7)139/544 (25.6) 0.99 (0.76, 1.30)0.1656 Other8/28 (28.6)17/37 (50.0) 2.13 (0.75, 6.04) Hosp. for CHF in past year P Yes43/181 (23.8)56/216 (25.9) 1.12 (0.71, 1.78)0.7604 No107/399 (26.8)100/365 (27.4) 1.03 (0.75, 1.42) SBP <140 mmHg66/284 (23.2)68/298 (22.8) 0.98 (0.66, 1.44)0.4985 ≥140 mmHg83/294 (28.2)88/279 (31.5) 1.17 (0.82, 1.68) Heart rate P <80 bpm78/296 (26.4)72/314 (22.9) 0.83 (0.58, 1.20)0.0691 ≥80 bpm72/284 (25.4)84/267 (31.5) 1.35 (0.93, 1.96) LVEF <40%79/295 (26.8)76/303 (25.1) 0.92 (0.63, 1.32) 0.4556 ≥40%62/244 (25.4)69/249 (27.7) 1.13 (0.75, 1.68) History of IHD Yes69/307 (22.5)64/296 (21.6) 0.95 (0.65, 1.40)0.5226 No81/273 (29.7)92/285 (32.3) 1.13 (0.79, 1.62) History of ICD or CRT Yes27/141 (19.2)35/153 (22.9) 1.25 (0.71, 2.20)0.5142 No123/439 (28.0)121/428 (28.3) 1.01 (0.75, 1.36) History of DM Yes63/272 (23.2)76/279 (27.2) 1.24 (0.84, 1.83)0.2547 No87/308 (28.3)80/302 (26.5) 0.92 (0.64, 1.31) History of AF Yes69/305 (22.6)74/297 (24.9) 1.13 (0.78, 1.65)0.5625 No81/275 (29.5)82/284 (28.9) 0.97 (0.68, 1.40) AF at screening Yes55/246 (22.4)55/233 (23.6) 1.07 (0.70, 1.64)0.8382 No95/333 (28.5)100/347 (28.8) 1.01 (0.73, 1.41) Time from present. to rand. <6 h58/266 (21.8)65/275 (23.6) 1.11 (0.74, 1.66)0.7585 ≥6 h92/314 (29.3)91/306 (29.7) 1.02 (0.72, 1.44) ACEI/ARB use at baseline P Yes103/398 (25.9)97/390 (24.9) 0.95 (0.69, 1.31)0.2840 No47/182 (25.8)59/191 (30.9) 1.28 (0.82, 2.02) Beta-blocker use at baseline P Yes89/407 (21.9)96/387 (24.8) 1.18 (0.85, 1.64)0.1959 No61/173 (35.3)60/194 (30.9) 0.82 (0.53, 1.27) MRA use at baseline P Yes43/173 (24.9)48/192 (25.0) 1.01 (0.63, 1.62)0.8174 No107/407 (26.3)108/389 (27.8) 1.08 (0.79, 1.47) IV nitrates at baseline Yes14/42 (33.3)16/39 (41.0) 1.39 (0.56, 3.44)0.5315 No136/538 (25.3)140/542 (25.8) 1.03 (0.78, 1.35) Lymphocytes at baseline P ≤12%32/127 (25.2)24/110 (21.8) 0.83 (0.45, 1.52)0.5269 >12%113/409 (27.6)120/425 (28.2) 1.03 (0.76, 1.39) Troponin T at baseline M ≤0.024 μg/L 44/165 (26.7)42/176 (23.9) 0.86 (0.53, 1.41)0.8953 0.025–0.045 μg/L 53/196 (27.0)47/182 (25.8) 0.94 (0.59, 1.48) >0.045 μg/L 52/180 (28.9)51/175 (29.1) 1.01 (0.64, 1.60) NT-proBNP at baseline <5000 ng/L73/279 (26.2)74/288 (25.7) 0.98 (0.67, 1.42)0.7799 ≥5000 ng/L76/272 (27.9)68/262 (26.0) 0.90 (0.62, 1.33) ≤3346 ng/L 50/190 (26.3)48/177 (27.1) 1.04 (0.66, 1.65)0.4540 3347–7281 ng/L 43/174 (24.7)51/194 (26.3) 1.09 (0.68, 1.74) >7281 ng/L 56/187 (30.0)43/179 (24.0) 0.74 (0.46, 1.18) Cystatin C at baseline ≤1.26 mg/L 47/180 (26.1)50/189 (26.5) 1.02 (0.64, 1.62)0.9215 1.27–1.65 mg/L 57/191 (29.8)50/180 (27.8) 0.90 (0.58, 1.42) >1.65 mg/L 45/180 (25.0)42/181 (23.2) 0.91 (0.56, 1.47) eGFR at baseline <60 ml/min/1.73m 2 104/408 (25.5)113/409 (27.6) 1.12 (0.82, 1.52)0.3844 ≥60 ml/min/1.73m 2 45/160 (28.1)39/155 (25.2) 0.86 (0.52, 1.42) <50 ml/min/1.73m 2 74/272 (27.2)72/268 (26.9) 0.98 (0.67, 1.44)0.6976 ≥50 ml/min/1.73m 2 75/296 (25.3)80/296 (27.0) 1.09 (0.76, 1.57) Odds ratio (95%CI) for moderate or marked improvement in dyspnoea at 6,12 and 24 hours (Likert) 0.1 1 10

2. Abbreviations for the figure legend ACEI = angiotensin converting enzyme inhibitor; AF = atrial fibrillation; ARB = angiotensin receptor blocker; bpm = beats per minute; CRT = cardiac resynchronization therapy; DM = diabetes mellitus; eGFR = estimated glomerular filtration rate; h = hours; hosp. = hospitalization; ICD = implantable cardioverter defibrillator; IHD = ischemic heart disease; IV = intravenous; LVEF = left ventricular ejection fraction; NT-proBNP = N-terminal prohormone B-type natriuretic peptide; MRA = mineralocorticoid receptor antagonist; present. = presentation; rand. = randomization; SBP = systolic blood pressure