This study evaluated 103 high-risk chronic heart failure patients after acute decompensation who were randomized to either NT-proBNP guided therapy or standard therapy. Biomarkers including NT-proBNP, sST2, copeptin, galectin-3, and troponin T were measured at baseline, 3 months, and 6 months. NT-proBNP guided therapy aimed to reduce NT-proBNP levels by at least 50% from baseline. NT-proBNP guided therapy resulted in greater reductions in biomarkers and lower rates of cardiovascular events compared to standard therapy over 10 months of follow-up. Biomarker changes correlated with improvements in left ventricular function and filling pressures, suggesting guided

1. Biomarkers activity and the effect of NT-proBNP guided
therapy in high risk patients with chronic heart failure after
acute decompensation
D. Koshkina,
A. Skvortsov, V. Protasov, O. Narusov, V. Masenko, S.
Tereschenko
Russian Cardiology Research and Production Complex,
Moscow, Russian Federation
Sevilla-2015

3. Purpose of the study
to evaluate the change of the biomarkers
concentration in the group of heart failure (HF)
therapy guided by NT-proBNP versus standard
treatment of CHF patients at high risk after acute
decompensation

4. 103 hospitalized pts with ADHF III-IV FC NYHA and LV EF < 40% due to coronary artery disease, arterial hypertension
and dilated cardiomyopathy.
NT-proBNP-guided group
(n=35)
Group of standard therapy
(n=35)
• The goal of treatment was to reduce NT-proBNP concentration < 1000 pg/ml, or at least 50% of the initial
Active therapy (up-titration) – 6 months, mean follow-up - 10±2,5 months
• Blood sampling to determine the biomarkers concentrations (NT-proBNP, soluble ST2 receptor, copeptin,
galectin-3, high sensitive Troponin T and NGAL) were collected at discharge from the hospital, and 3 and 6
months after.
• Filling pressure was assessed by E/E’
• The primary end point - total cardiovascular events: cardiovascular (CV) death, hospitalization due to HF,
and episodes of HF deterioration needed additional i/v diuretics
“High risk” group, at discharge NT-proBNP >1400pg/ml,
n=70 (randomized 1:1)
“Low risk”, at discharge NT-proBNP <1400pg/ml,
n=33
*Uncomplaining group (protocol demands)
(n=10)
2 8

5. Baseline characteristics for “high risk” HF patients
Characteristics
NT-proBNP-guided
group (n=31)
Standard therapy
group(n=26)
Uncomplaining
group (protocol
demands)(n=10)
P*
Male, n (%) 20 (64,5) 22 (84,6) 8(80%) 0,063
Age (years) 63,3±8,7 64,1±12,7 60,1±8,7 0,64
Cause of HF:
 CAD, n (%) 21 (67,7) 18 (69,2) 8(80,0%) 0,76
 DCMP, n (%) 4 (11,4) 6 (23,1) 1(10,0%) 0,49
 Hypertension, n (%) 6 (19,4) 2 (7,7) 1(10,0%) 0,41
DM type 2, n (%) 8 (25,8) 8 (30,8) 4(40,0) 0,69
Post MI, n (%) 21 (67,7) 17 (65,4) 8(80,0) 0,69
CRT-D, n (%) 4 (12,9) 4 (15,4) 1(10,0) 0,9
AF, n (%) 14 (45,2) 15 (57,7) 3(30,0) 0,3
LV EF (%) 29,4±5,9 29,6±6,2 33,9±5,8 0,84
Creatinine (µmol/L) 101,54±28,02 104,2±33,1 100,7±30,3 0,16
Systolic BP (mmHg) 114,6±5,4 111,4±8,0 111,5±6,4 0,34
NT-proBNP (discharge) (pg/ml) 3651,0
(2196,0; 6613,0)
2801,0
(2108,0; 4833,0)
3158,0
(1847,0;8154,0)
0,32

6. Baseline concentration of biomarkers in patients with CHF in
«high risk» group and «low risk» group at discharge
801
NT-proBNP
0
500
1000
1500
2000
2500
3000
3500
80
12.1
28.4
31.3
39.5
67
12.5
21.4
14.1
22.3
NGAL Galectin-3 hsTpT Copeptin sST2
0
10
20
30
40
50
60
70
80
90
High risk group Low risk group 0
3000
2500
2000
1500
1000
100
3208
(ng/ml) (pg/ml)
p < 0.05 for all biomarkers except Galectin-3

7. Medication mean dosages at baseline (mg)
6,4
8,0
2.9
32.7
64.4
15.6
0.13
5.2 7,0 3.3
29.5
51.4
16.7
0.14
5 4 3.1
35
90
17.9
0.08
ACE-i ARB Beta-blocker MRA Torasemide Furosemide Digoxin
0
20
40
60
80
100
NT-proBNP-guided group Standard therapy group Uncomplaining group
(mg)
ACE-i- Enalapril, Perindopril, Fosinopril
ARB- Candesartan, Valsartan, Losartan
Beta-blocker- Bisoprolol, Metoprolola succinate, Carvedilol
MRA- Spironolactone, Eplerenone
(n=31) (n=26) (n=10)

8. Medication mean dosages after 6 months of treatment (mg)
19.2
23.5
8.5
44.6
55.6
11.2
0.09
15.4 18
7,0
35.3
72,0
18.5
0.13
7.9
0
4.1
35.7
80
18.6
0.13
ACE-i ARB Beta-blocker MRA Furosemide Torasemide Digoxin
0
10
20
30
40
50
60
70
80
90
NT-proBNP-guided group (n=31) Standard therapy group (n=26)
Uncomplaining group (n=10)
mg
р=0,0001
р=0,0001 р=0,017

9. NT-proBNP values changes after 6 months of treatment
Δ% NT-proBNP
NT-proBNP-guided group
(n=31)
Standard therapy group
(n=26)
Uncomplaining group
(n=10)
-53.1
-11.1
17.3
-60
-50
-40
-30
-20
-10
0
10
20
30
р=0.001
NT-proBNP, pg/ml
Baseline
6 month
р=0,001
р=0,036
р=0,018
p=0,0001
Uncomplaining
group
(n=10)
NT-proBNP-
guided group
(n=31)
Standard
therapy
group
(n=26)
3651
1585
NT-proBNP value after 6 months of treatment
≥ 50% = 78% and
< 1000 pg/ml = 30%
in NT-proBNP-guided group pts

10. Change of copeptin concentration in high risk patients with
CHF during follow-up
Copeptin
pmol/l
p=0,0001
23,5
34,6
32,1
30,7
53,7
34,3
Uncomplaining
group
(n=10)
NT-proBNP-guided
group (n=31)
Standard therapy
group
(n=26)
Baseline
6 month

11. sST2Galectin-3
Change of concentration of fibrosis and inflammation
biomarkers in high risk patients with CHF during follow-up
Ng/ml
11,8
9,2
12,2
11,6 12,2
14,2
p=0,0001
Uncomplaining
group
(n=10)
NT-proBNP-
guided group
(n=31)
Standard
therapy
group
(n=26)
Исходно
6 месяцев
Baseline
6 month
Uncomplaining
group
(n=10)
NT-proBNP-
guided group
(n=31)
Standard
therapy
group
(n=26)
Baseline
6 month
Ng/ml
38,4
22,9
39,7
30,9
45,3
70,8
p=0,0001 p=0,023
p=0,043p=0,0001

12. Change of concentration of cellular damage biomarkers in
high risk patients with CHF during follow-up
Pg/ml
NGALhsTroponin T
p=0,003
Ng/ml
29,3
21,8 24,9 22,3
31,5
49,5
Uncomplaining
group
(n=10)
NT-proBNP-
guided group
(n=31)
Standard
therapy
group
(n=26)
Baseline
6 month
NT-proBNP-
guided group
(n=31)
p=0,001
85,2
77,1 75,6
77,1
83,0
132,0
Uncomplaining
group
(n=10)
Standard
therapy
group
(n=26)
Baseline
6 month

13. Correlations between sST2 and Copeptin concentration changes
and changes of LV EF and LV filling pressure during follow-up
(n=103)
r=-0.552;
p<0,001
r=-0.722
p<0,001
∆% ST2
∆% LV EF
∆% Copeptin
∆% LV EF
r=0.573
p<0,001
∆% ST2
∆% Е/Е’
r=0.692
p<0,001
∆% Copeptin
∆% Е/Е’
r = 0,536
p<0,001
∆% Е/Е’
∆% NT-proBNP

14. Correlations between biomarkers concentration
changes and changes of the main patients clinical and
functional parameters
Biomarkers
(n=103) Δ% FC NYHA Δ% 6-minWT Δ% MLQHF Δ% LV EF Δ% Е/Е'
Δ% NT-proBNP ,517*** -0,672*** ,606*** -,630*** ,536***
Δ% sST2 ,518*** -,529*** ,579*** -,552*** ,573***
Δ% Copeptin ,475*** -,581*** ,717*** -,722*** ,692***
Δ% hsTnT ,252 -,318* ,552*** -,244 ,219
Δ %Galectin-3 ,470** -,392*** ,397*** -,392*** ,401*
Δ% NGAL ,278* -,283* ,355*** -,173 ,114

15. NT-proBNP group(n=31)
Standard therapy group (n=26)
“Low risk” group (n=32)
Uncomplaining group (n=10)
Total number and frequency (%) of CV events in HF patients
during the study period (10,5±2,1months)
32
107
140
22
0
20
40
60
80
100
120
140
160
p=0.01
(%)
CV outcomes, %
10
28
14
7
0
5
10
15
20
25
30
p=0.016
Events number
CV outcomes

16. 2
4 4
0
43
9
14
1
10
2
7
9
0
3
1
3 4
0
2
0
5
10
15
HF worsening
without
hospitalization
1-st HF
hospitalization
All HF
hospitalizations
Successful
resuscitation
CV death
р=0,001
р=0,018
р=0,025
7
13 13
0
1312
34
54
3
38.5
20
70
90
0
30
3
9 13
0 6
0
25
50
75
100
р=0,001
р=0,018
р=0,025
Frequency, % Events number
NT-proBNP group(n=31) Standard therapy group (n=26) Uncomplaining group (n=10)
“Low risk” group (n=32)
Cardiovascular outcomes

17. Risk of CV events in HF pts as a function of NT-proBNP change
(follow-up 10,5±2,1months)
0000
99.4
Baseline 6 months
-80
-60
-40
-20
0
20
40
60
80
100
120
NT-proBNP
<50%
NT-proBNP
<50%
NT-proBNP
≥50%
NT-proBNP
≥50%
4,55
(1,14-18,24)
р=0,03
1,7 (0,66-
4,4) NS
1,03 (0,4-
2,5) NS
0,1 (0,023-
0,505) р=0,001
HR (95% CI)
Δ% NT-proBNP
Significance in risk reduction of CV events
appeared only when NT-proBNP value
decreased at the follow-up > 40%
[∆% NT-proBNP = -48,0(-42,8;-53,0)]
HR (95% CI) = 0.1(0.01-0.8), р=0.01

18. Risk of CV events in HF pts as a function of ST2 change
(follow-up 10,5±2,1months)
0000
48.1
Baseline 6 months
-50
-40
-30
-20
-10
0
10
20
30
40
50
60
ST2<25%
ST2<25%
ST2≥25%
ST2≥25%
1,13
(0,95-1,35)
р=0,2
1,55 (1,1
-2,2)
p=0,006
0.94 (0,24
-3,65) p=1,0
0,1
(0,02-0,5)
р=0,004
HR (95% CI)
Δ% ST2

19. 1.0
0.8
0.6
0.4
0.2
0.0
Sensitivity
1-Specificity
0.0 0.2 0.4 0.6 0.8 1.0
∆%ST2 = - 24,9%
ST2 ≥ 25%
HR (95% CI) = 0.1 (0.02-0.5), p=0.004
AUC= 0.8, р=0.002
Sensitivity 82,4%
Specificity 66,7%
Optimal value ST2 change for risk reduction of CV events in HF pts
(follow-up 10,5±2,1months)

20. Conclusion
In NT-proBNP-guided therapy group was found more
significant reduction of concentrations of
biomarkers, especially sST2 and copeptin compared
with standard HF therapy and change of these
biomarkers were closely associated with the filling
pressure decrease
NT-proBNP-guided therapy was superior to standard
therapy in reduction of CV mortality and HF
hospitalization
Declaration of interest-no