1
SUPPLEMENTAL MATERIAL
Supplemental Table 1. The ASCEND-HF Risk Model
List of covariates for adjusted models for each endpoint of interest. Covariates derived from
modeling in overall ASCEND-HF population.
Covariates derived from modeling in overall ASCEND-HF population:
•
Death at 30 days: age, blood urea nitrogen (BUN), sodium, amount systolic blood
pressure (SBP) <140 mmHg, dyspnea at rest
•
Death or rehospitalization at 30 days: amount SBP <140 mmHg, dyspnea at rest,
sodium, amount age <55 years, amount age >55 years, BUN, baseline cerebrovascular
disease, creatinine, baseline depression, jugular venous pressure (JVP), baseline chronic
respiratory disease
•
Death 180 days: BUN, amount SBP <140 mmHg, age
•
Dyspnea at 6 hours: age, sodium, respiratory rate, chest x-ray (CXR) showing edema,
race, amount SBP <140 mmHg, BUN, hemoglobin, NYHA class
•
Dyspnea at 24 hours: age, sodium, respiratory rate, CXR showing edema, race, amount
SBP <140 mmHg, BUN, hemoglobin, NYHA class
•
Death or worsening HF in hospital: amount SBP <140 mmHg, BUN, amount age <55
years, amount age >55 years, baseline cerebrovascular disease, creatinine, baseline
depression, CXR showing edema, dyspnea at rest, baseline chronic respiratory disease,
sodium
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Supplemental Table 2. Comparison of Prognostic Value of Baseline sST2 vs. NT-proBNP
as Dichotomous Variables
30-day Death/ HF
180-day Death
Hospitalization
OR
p-value
HR
p-value
Baseline sST2 vs. baseline NT-proBNP
Model 1
sST2 ≥71.2 ng/mL
1.81 (1.17-2.78) 0.0073 2.22 (1.45-3.4) 0.0002
Model 2 (unadjusted)
sST2 ≥71.2 ng/mL
1.41 (0.88-2.24) 0.1516 1.46 (0.93-2.3) 0.1036
NT-proBNP ≥5,000 pg/mL
1.79 (1.11-2.88) 0.0174 2.63 (1.59-4.35) 0.0002
Model 3* (adjusted)
sST2 ≥71.2 ng/mL
1.27 (0.79-2.02) 0.3252 1.21 (0.77-1.9) 0.4011
NT-proBNP ≥5,000 pg/mL
1.91 (1.19-3.07) 0.0072 1.79 (1.07-3.02) 0.0277
48–72 hr sST2 vs. 48–72 hr NT-proBNP
Model 1
sST2 ≥71.2 ng/mL
2.09 (1.28-3.41) 0.0032 2.90 (1.81-4.63) <0.0001
Model 2 (unadjusted)
sST2 ≥71.2 ng/mL
1.76 (1.06-2.93) 0.0302 2.11 (1.29-3.43) 0.0027
NT-proBNP ≥5,000 pg/mL
1.71 (1.05-2.8)
0.032 2.76 (1.68-4.53) 0.0001
sST2 ≥71.2 ng/mL
1.26 (0.73-2.2)
0.4047 1.77 (1.09-2.87) 0.0214
NT-proBNP ≥5,000 pg/mL
1.58 (0.94-2.65) 0.0832 1.86 (1.08-3.21) 0.0256
Model 3* (adjusted)
30-day sST2 vs. 30-day NT-proBNP
Model 1
--
--
sST2 ≥71.2 ng/mL
Model 2 (unadjusted)
2.23 (1.17-4.25) 0.0145
--
--
sST2 ≥71.2 ng/mL
1.26 (0.61-2.61) 0.539
NT-proBNP ≥5,000 pg/mL
5.82 (2.64-12.8) <0.0001
Model 3* (adjusted)
--
--
1.13 (0.54-2.37) 0.7515
3
sST2 ≥71.2 ng/mL
NT-proBNP ≥5,000 pg/mL
*
3.59 (1.50-8.59) 0.0041
Model 3 also adjusted with blood urea nitrogen, age, and systolic blood pressure as covariate
adjustments.
HF = heart failure; HR = heart rate; NT-proBNP = aminoterminal pro-B-type natriuretic
peptide; OR = odds ratio; sST2 = soluble growth stimulation expressed gene 2
4
Supplemental Table 3. Net Reclassification for Baseline and 48–72 Hour Follow-Up sST2
Levels
Category-free net reclassification improvement and integrated discrimination improvement to
quantify improvement in model performance. The risk of death at 180 days was estimated using
the Cox model; p-values compare models with/without sST2. All models were adjusted for age,
blood urea nitrogen, systolic blood pressure, and NT-proBNP (at corresponding timepoints).
A. Baseline sST2
Without vs. With Baseline sST2
AUC
Value (%)
p-value
78.33 vs 78.5
0.911
23
<0.001
10.76
0.001
Integrated discrimination improvement
Net reclassification improvement
Events correctly reclassified (%)
8.64
Non-events correctly reclassified (%)
2.12
AUC = area under the curve; NT-proBNP = aminoterminal pro-B-type natriuretic
peptide; sST2 = soluble growth stimulation expressed gene 2
B. 48-72 hour Follow-up sST2
Without vs. With 48–72 Hour Follow-up sST2
AUC
Value (%)
p-value
73.94 vs. 76.08
0.227
18
<0.001
15.6
0.027
Integrated discrimination improvement
Net reclassification improvement
Events correctly reclassified (%)
13.85
Non-events correctly reclassified (%)
1.75
All abbreviations can be found in Supplemental Table 3A.
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C. 30-day Follow-up sST2
Without vs. With 30-day Follow-up sST2
AUC
Value (%)
p-value
80.03 vs 82.02
0.38
30
<0.001
15.2
0.035
Integrated discrimination improvement
Net reclassification improvement
Events correctly reclassified (%)
13.89
Non-events correctly reclassified (%)
1.31
All abbreviations can be found in Supplemental Table 3A.
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Supplemental Table 4. Checking Independency Between Baseline sST2 and NT-proBNP as Continuous Variables
30-Day Death
p-value 30-Day Death/HF p-value
180-Day Death
OR (95% CI)
Rehospitalization
HR (95% CI)
p-value
OR (95% CI)
Unadjusted Model
Baseline sST2
1.75 (0.79, 3.89)
0.168
1.32 (0.87, 2.01)
0.196
1.40 (0.92, 2.13)
0.11
Baseline NT-proBNP
1.57 (0.99, 2.49)
0.054
1.23 (0.97, 1.55)
0.084
1.87 (1.51, 2.32)
<0.0001
Baseline sST2
0.63 (0.001, 496.8)
0.890
0.07 (0.006, 1.11)
0.059
0.82 (0.03, 25.83)
0.908
Baseline NT-proBNP
0.94 (0.04, 23.48)
0.971
0.29 (0.07, 1.12)
0.072
1.44 (0.25, 8.43)
0.686
Interaction: sST2/NT-proBNP
1.12 (0.54, 2.35)
0.761
1.41 (1.02, 1.94)
0.036
1.06 (0.72, 1.56)
0.766
Baseline sST2
0.19 (0.001,114.2)
0.608
0.05 (0.001, 0.810)
0.035
0.37 (0.01, 11.94)
0.576
Baseline NT-proBNP
0.45 (0.02-11.53)
0.631
0.26 (0.07, 0.99)
0.049
0.84 (0.14-5.03)
0.848
Interaction: sST2/NT-proBNP
1.26 (0.62-2.57)
0.527
1.39 (1.04, 1.95)
0.028
1.15 (0.78-1.69)
0.492
Interaction Model
Adjusted Interaction Model
CI = confidence interval; NT-proBNP = aminoterminal pro-B-type natriuretic peptide; OR = odds ratio; sST2 = soluble
growth stimulation expressed gene 2
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Supplemental Table 5. Baseline Characteristics Across Changes of sST2 Levels From
Baseline to 48–72 Hour sST2 Levels (at 71.2 ng/mL cut-off, n=680 With Both Baseline and
48–72 Hour Samples)
sST2 Levels
Low-Low
High-Low
Low-High
High-High
(n=318)
(n=199)
(n=15)
(n=148)
Age (years)
62.8±14.8
67.9±14.6
70.8±12.5
67.3±15.6
<0.001
Female (%)
34.3
29.6
13.3
37.0
0.168
Race (%)
63.5
69.3
66.7
72.3
0.249
Systolic BP (mmHg)
129.0±21.1
128.0±17.4
133.1±23.7
121.9±18.5
0.002
Heart rate (bpm)
79.8±15.2
81.5±17.4
76.6±15.5
78.4±16.3
0.265
Atrial fibrillation (%)
32.7
45.2
53.3
51.4
<0.001
Hypertension (%)
82.1
76.9
66.7
73.0
0.088
25.0±14.2
27.3±13.8
28.3±13.9
34.6±17.8
<0.001
Creatinine (mg/dL)
1.4±0.5
1.4±0.6
1.5±0.5
1.6±0.6
<0.001
Sodium (mmol/L)
139.2±3.2
138.3±4.1
139.4±5.2
138.2±4.5
0.038
3,878
6,999
8,512
8,464
<0.001
BUN (mg/dL)
NT-proBNP (pg/mL)
p-value
(2,193-7,865) (3,625-13,033) (3,178-11,207) (4,612-15,058)
LVEF (%)
27 (20-40)
25 (20-40)
35 (25-45)
25 (15-35)
0.041
Time from presentation
17.2±10.2
14.6±8.3
16.9±7.9
17.1±9.8
0.023
Beta-blockers (%)
76.1
75.4
80.0
79.7
0.774
ACEi or ARB (%)
65.4
63.8
76.7
62.8
0.317
MRA (%)
23.9
19.6
26.7
32.4
0.052
to randomization (hr)
Values in mean ± standard deviation or median (interquartile range)
ACEi = angiotensin-converting enzyme inhibitor; ARB = angiotensin receptor blocker; BP =
blood pressure; bpm = beats per minute; BUN = blood urea nitrogen; LVEF = left ventricular
ejection fraction; MRA = mineralocorticoid receptor antagonist; NT-proBNP = aminoterminal
pro-B-type natriuretic peptide; sST2 = soluble growth stimulation expressed gene 2
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Supplemental Figure 1. Interaction Plot Between Baseline sST2 and NT-proBNP
Interaction plot between baseline sST2 and NT-proBNP using restricted cubic splines, stratified
by median baseline NT-proBNP levels.
HF = heart failure; NT-proBNP = aminoterminal pro-B-type natriuretic peptide; sST2 = soluble
growth stimulation expressed gene 2
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Supplemental Figure 2. Kaplan-Meier Analysis for 180-Day Survival
Kaplan-Meier analysis for 180-day survival stratified by median baseline sST2 and NT-proBNP
levels. Median levels for sST2 = 71.2 ng/mL; median levels of NT-proBNP = 5,756 pg/mL
(median from whole cohort and not analytical set).
HF = heart failure; NT-proBNP = aminoterminal pro-B-type natriuretic peptide; sST2 = soluble
growth stimulation expressed gene 2
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Supplemental Figure 3. Kaplan-Meier Curves of 180-Day Death
Kaplan-Meier curves of 180-day death stratified by tertiles of ST2 levels at 30 days.
30-day sST2 quartile (Q) ranges: Quartile 1 = <28.0 ng/mL; Quartile 2 = 28.0–39.47 ng/mL;
Tertile 3 = 39.474–63.9 ng/mL; Quartile 4 >63.9 ng/mL.
sST2 = soluble growth stimulation expressed gene 2
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Supplemental Figure 4. Comparison of Adverse Clinical Outcomes
Comparison of adverse clinical outcomes in patients with a >30% (n=377) versus ≤30% (n=303)
reduction in sST2 levels from baseline to 48–72 hours.
HF = heart failure; sST2 = soluble growth stimulation expressed gene 2
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Supplemental Figure 5. CONSORT Diagram of Subgroup Distribution
CONSORT diagram of subgroup distribution according to baseline and follow-up sST2 levels.
sST2 = soluble growth stimulation expressed gene 2
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Supplemental Figure 6. Kaplan-Meier Curves of 180-Day Death
Kaplan-Meier survival analysis stratified by high versus low baseline and follow-up (48–72
hour) sST2 levels (cut-off at 71.2 ng/mL) with all subgroups included.