SUPPLEMENTAL MATERIALS
Online Table 1. Characteristics of patients included in the analysis cohort compared with those excluded due to missing biomarker or outcome
data.
Excluded
(N=56)
Included
(N=427)
P-value
67 (50.5 - 77)
68 (58 - 78)
0.1585
Male sex
66
75
0.1552
White race
50
76
<0.0001
24 (16.5 - 46.5)
32 (20 - 55)
0.0087
Ejection fraction <50%
77
69
0.2417
New York Heart Association Class IV
29
35
0.3951
Hospitalization for HF in the past year
84
74
0.1004
Ischemic etiology
46
60
0.0580
Atrial fibrillation/flutter
45
54
0.1937
Diabetes mellitus
55
57
0.8256
Implantable cardioverter defibrillator
43
34
0.1892
ACE inhibitor or ARB
59
56
0.6510
Beta-blocker
79
82
0.5678
Aldosterone antagonist
34
25
0.1675
Nitrates
29
31
0.6691
Nitrates and hydralazine
14
11
0.5399
120 (80 - 160)
120 (80 - 160)
0.8644
201 (172 - 243)
209 (179 - 257)
0.4385
33.1 (26.9 - 38.2)
31.9 (26.9 - 38.4)
0.9750
115 (103 - 129)
114 (104 - 129)
0.8780
Variable
Age, years
Ejection fraction, %
Baseline Medications (at randomization)
Furosemide equivalent dose, mg/day
Physical Examination
Weight, lbs
BMI,
kg/m2
Systolic blood pressure, mmHg
1
Excluded
(N=56)
Included
(N=427)
P-value
74 (68.5 - 90.5)
76 (68 - 85)
0.8819
JVP ≥ 8 cm water
96
93
0.7592
Orthopnea
98
91
0.1606
Peripheral edema grade ≥ 2+
80
83
0.6692
PRA, ng/ml/h [mean ± SD]
4.1 (1.5 - 18.3)
5.0 (0.9 - 16.6)
0.7455
Aldosterone, pg/ml [mean ± SD]
194 (134 - 480)
211 (111 - 364)
0.4876
Sodium, mg/l
138 (135 - 141)
138 (135 - 141)
0.6449
Blood urea nitrogen, mg/dl
30.4 (19.5 - 50.5)
40.0 (25.5 - 57.0)
0.0076
Creatinine, mg/dl
1.25 (0.97 - 1.62)
1.70 (1.23 - 2.17)
0.0004
54.4 (36.8 - 66.9)
40.0 (29.4 - 56.6)
0.0002
5200 (3113 - 10305)
4307 (2273 - 9823)
0.3178
Variable
Heart rate, beats/min
Laboratories
Estimate glomerular filtration rate,
ml/min/1.73m2
NT-proBNP, pg/ml
Presented as % or median (IQR) unless otherwise noted.
Abbreviations: RAAS indicates renin-angiotensin-aldosterone system; PRA, plasma renin activity; HF, heart failure; ACE-I, angiotensin converting
enzyme inhibitor; ARB, angiotensin receptor blocker; JVP, jugular venous pressure; SD, standard deviation; NT-proBNP, N-terminal pro Brain
Natriuretic Peptide.
2
Online Table 2. RAAS levels based on baseline medication use.
Baseline PRA (ng/ml/hr)
N
Median
(25th, 75th percentile)
Yes
238
4.4 (0.5, 17.4)
No
189
5.4 (1.6, 14.8)
108
10.0 (3.4, 24.6)
Baseline Medication Use
Baseline Aldosterone (pg/ml)
p-value*
Median
(25th, 75th percentile)
p-value*
ACE-I/ARB
0.18
168 (93, 278)
283 (161, 494)
<0.001
Aldosterone antagonist
Yes
No
319
* P-values come from Wilcoxon rank sum tests.
3.2 (0.8, 14.0)
<0.001
327 (194, 551)
175 (100, 309)
<0.001
Abbreviations: ACE-I indicates angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker; PRA, plasma renin activity, RAAS,
renin-angiotensin-aldosterone system.
OnlineTable 3. RAAS levels in patients with reduced (EF<50%) vs. preserved EF (≥50%) based on decongestion strategy.
Baseline Biomarker
Biomarker Change at
72 or 96 h
Baseline Biomarker
Biomarker Change at
72 or 96 h
Treatment
p-value
EF
p-value
0.0224
0.0427
0.6477
0.0542
0.0162
0.8731
0.5627
0.0128
0.7310
0.0148
0.9700
0.2209
PRA (ng/ml/h)
DOSE-AHF
Bolus Furosemide (N=110)
Continuous Infusion (N=96)
Reduced EF
5.9 (1.0, 21.2)
0.46 (-.25, 5.46)
5.0 (0.7, 15.3)
0.65 (-2.1, 7.79)
Preserved EF
2.5 (0.8, 15.2)
1.03 (-1.0, 6.11)
1.46 (0.63, 7.45)
3.5 (0.2, 15.4)
Low-dose Furosemide (N=95)
High-dose Furosemide (N=111)
Reduced EF
5.6 (0.9, 20.8)
0.48 (-1.6, 5.70)
5.6 (0.9, 18.4)
1.03 (-.26, 6.57)
Preserved EF
2.25 (0.78, 8.80)
3.8 (0.2, 16.4)
1.9 (0.6, 13.5)
1.04 (-.05, 6.11)
CARRESS
Stepped Pharmacologic Care (N=78)
Ultrafiltration (N=76)
Reduced EF
3.5 (0.9, 14.4)
0.72 (-1.3, 7.15)
5.7 (3.1, 12.7)
3.0 (-0.5, 13.5)
Preserved EF
3.8 (0.9, 14.8)
0.09 (-3.2, 1.30)
6.2 (1.7, 24.1)
4.6 (0.2, 14.8)
Aldosterone (pg/ml)
DOSE-AHF
Bolus Furosemide (N=113)
Continuous Infusion (N=102)
Reduced EF
241 (131, 400)
-2.0 (-89, 76.1)
165 (95, 343)
2 (-58, 104)
Preserved EF
149 (93, 321)
-7.3 (-102, 32.6)
200 (126, 362)
18 (-84, 106)
Low-dose Furosemide (N=102)
High-dose Furosemide (N=113)
Reduced EF
215 (110, 358)
8 (-54, 115)
201 (95, 364)
-6.0 (-91, 47.9)
Preserved EF
153 (93, 247)
31.3 (-78, 81.7)
154 (108, 352)
-11 (-105, 42.5)
CARRESS
Stepped Pharmacologic Care (N=79)
Ultrafiltration (N=76)
Reduced EF
271 (124, 375)
-4 (-112, 114)
264 (164, 485)
-28 (-161, 50.8)
Preserved EF
184 (98, 358)
34.9 (-77, 95.0)
175 (113, 282)
0.0 (-46, 93.4)
* P-values for treatment and EF effect come from linear regression models for 72 or 96 hour RAAS adjusted for baseline RAAS value, baseline
ACE/ARB use, and baseline aldosterone antagonist use where a log transformation is applied to both the baseline and follow-up RAAS measure.
Online Table 4. Net volume loss (ml) from baseline to 72 hours (DOSE-AHF) or 96 hours (CARRESS-HF) by decongestion strategy.
Treatment
Median
(25 , 75th percentile)
[ml]
th
p-value*
DOSE-AHF
Bolus dose furosemide
3700 (2012, 5875)
Continuous infusion furosemide
4151 (1872, 6180)
Low-dose furosemide
2912 (1714, 4880)
High-dose furosemide
4452 (2347, 7147)
0.94
0.005
CARRESS-HF
Ultrafiltration
7112 (4192, 10567)
Stepped pharmacologic therapy
6255 (3999, 9445)
* P-values come from Wilcoxon rank sum tests.
0.28
OnlineTable 5. Association between baseline RAAS biomarker quartile with time to death or HF hospitalization (reference=quartile 4).
RAAS marker
PRA
N
Events
427
134
Hazard Ratio* (95% CI)
0.40
Quartile 1
0.73 (0.44, 1.22)
Quartile 2
0.68 (0.42, 1.08)
Quartile 3
0.81 (0.51, 1.29)
Quartile 4
1.00
Aldosterone
427
p-value
134
0.29
Quartile 1
0.64 (0.38, 1.09)
Quartile 2
0.82 (0.50, 1.35)
Quartile 3
1.03 (0.65, 1.62)
Quartile 4
1.00
*Hazard ratio adjusted for trial, and baseline ACE-inhibitor/ARB and aldosterone antagonist use.