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New Biomarkers for the
management of heart failure
J. Parissis
Attikon University Hospital
Athens, Greece
Disclosures related to this presentation: Horonaria from Roche Diagnostics
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Morrow D. Circulation 2007; 115: 949
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Multimarkers in chronic HF
MPO, GGT, urate,
oxLDL, isoprostanes
BNP, NTproBNP
MR-proANP, ET-1
Adrenomedullin,
copeptin
...
eGFR, BUN,
cystatin C, NGAL...
Hs-CRP, GDF-15, ST2, TNF-,
IL1,2,6,8,18, adipokynes,
Procalcitonin, neopterin, pentraxin-
3, CD40-CD154 ...
ST2, Gal-3, PICP, PIIP, MMPs,
TIMPs, osteopontin,
osteoprotegerin ...
hs-cTnT, hs-cTnI, H-FABP,
pentraxin-3, Fas (Apo1) ...
BNP ,NTproBNP, MR-proANP, adrenomedullin, ST2, GDF15 ...
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Value of clinical exam for diagnosis of HF
Am J Med.2002;112:437– 445
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Diagnostic pitfalls: radiology Chest hyperinflation reduces cardiothoracic ratio
Pulmonary vascular remodelling and radiolucent lung fields mask typical alveolar shadowing in pulmonary oedema
Asymetric, regional and reticular patterns of pulmonary oedema
Vascular bed loss with upper lobe venous diversion mimics HF
20-30 % of pts with AHF had negative chest X ray for pulmonary congestion (ADHERE, ALARM)
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Diagnostic pitfalls: echocardiography, CMR
Inadequate visualisation related to air trapping (10-50%)
Inadequate collaboration with dyspneic patient
High cost of comprehnsive echo-Doppler cardiac examination
(need for new sophisticated echo TDI markers )
Limited efficacy of LV filling pressure estimation in patients with high HR.
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Diagnostic flowchart for patients with suspected HF
ESC Guidelines for the Diagnosis and Treatment of Acute and Chronic Heart Failure 2012
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Established biomarkers for
diagnosis: Greater value as a rule –
out approach
BNP/NT-proBNP for diagnosis of CHF and ADHF
Hs troponin for diagnosis of new ACS complicating HF
Procalcitonin for diagnosis of infection
MR-proANP for diagnosis of HF in grey zones of NPs
N-gaL/ Cystatin-C for early diagnosis of acute kidney injury
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Limitations of biomarkers for
diagnosis of HF
Their levels are affected by:
- Age, gender, BMI,
- Renal function, Hb levels
- Timing of evaluation,
- Type of HF (systolic vs diastolic, backward
vs forward)
- Severity of disease and background
treatment (e.g beta blockers)
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BNP Cut Off-Points
According to Body Mass Index
Daniels et al. Am Heart J 2006;151:999 –1005.
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MR-proANP is a stable and reliable surrogate
marker of the mature hormone
SS
MM
NHNH22--
FFGG
CC
RR
LLYY
DD
NN
AA
II
OO
NHNH22
--CC
RR
SSSS
CC
GGRR
RRGG
GG
GGLL
SSFFRR
SSSS
MMMM
NHNH22--
FFFFGGGG
CCCC
RRRR
LLLLYYYY
QQQQ
DDDD
NNNN
AAAA
IIII
OO
NHNH22
--CC
OO
NHNH22
--CC
RRRR
SSSSSSSS
CCCC
GGGGRRRR
RRRRGGGG
GGGG
GGGGLLLL
SSSSFFFFRRRR
ANP
(diuretic,
vasodilator)
Peptides are instable in vivo
and ex vivo, therefore not
suitable for clinical diagnosis.
MR MR - - proANP proANP
ANP
Mid-regional -
proANP
MR MR - - proANP proANP MR - - proANP
• prohormone (fragment)
• can be easily measured by standard
sandwich immunoassay technology
• stable & reliable surrogate marker of
the mature hormone
Morgenthaler NG et al., Clin Chem. 2004;50:234-6.
Morgenthaler NG et al., Clin Chem. 2005;51:1823-9.
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Patient suspected to have LVD
Echocardiogram
BNP
Increased
Normal LVD
unlikely
Future diagnostic algorithm
Grey Zone
Low MR-
proANP
LVD
unlikely
High MR-
proANP
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Strength of evidence for individual biomarkers for
diagnosis and prognosis of HF
Maisel. Cardiovasc Diagn Ther 2012;2(2):147-164
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Prognostic value of hs- troponin T in patients with ADHF
and non-detectable conventional troponin T levels
Parissis et al. IJC 2012
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Kaplan–Meier survival curves according to the presence of
none (n= 18), one (n= 26), two (n= 25), or three biomarkers (n=
38) above optimal cut-off points
Pascual-Figal D A et al. Eur J Heart Fail 2011;13:718-725
•NT pro BNP
•hs Troponin
•ST2
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Prognostic role of liver congestion in
ADHF: A SURVIVE subanalysis
AP (U\l)
Days
Su
rviv
al p
rob
ab
ility
0 20 40 60 80 100 120 140 160 180
0.5
0.6
0.7
0.8
0.9
1.0
AP (U\l) =<149
AP (U\l) >149
Nikolaou M, Parissis J, …, Mebazaa A. EHJ 2013;34:742-749
Evidence for cardio-hepatic syndrome
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Additive values of abnormal transaminases and
abnormal alkaline phosphatase on a short- andlong-term
outcome
Nikolaou M, Parissis J, …, Mebazaa A. EHJ 2013;34:742-749
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Clinical Assessment of Acute Heart Failure
Syndromes
Nohria et al. Am J Cardiol 2005;96[suppl]:32G–40G
High
Transaminas
es plus ALP
High
Transaminases
High ALP Normal
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GGT levels in ADHF: prognostic value and
relationship with renal function
Serum creatinine
Parissis et al. Int J Cardiol 2014
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Biomarker-guided therapy: which molecules?
Cardiac stress
- BNP/ NT-pro-BNP
- MR-proANP
- Copeptin
- ST2
Cardiac injury
- Hs troponins
Cardiac fibrosis/remodeling
- Galectin-3
- PNIII/CT1
Co-morbidities
- NGAL (renal)
- cystatin-c
- Pro-calcitonin (respiratory)
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At Day 2, a decrease in NT-proBNP ≥30% below baseline, indicative of
decongestion, more than halved the risk of mortality through Day 180
RELAX-AHF: decreases from baseline in NT-proBNP
levels are associated with decreased mortality in patients
with AHF
395 376 372 365 357 351 349 341 339 288
Number at risk:
<30% decrease
≥30% decrease
AHF=acute heart failure; CI=confidence interval; HR=hazard ratio;
NT-proBNP=N-terminal pro B-type natriuretic peptide; RELAX-AHF=RELAXin in Acute Heart Failure
Metra et al. J Am Coll Cardiol 2013;61:196–206
Study day
0.20
0.15
0.10
0.05
0.00
0 20 40 60 80 100 120 140 160 180
HR 0.47 (95%CI 0.31, 0.69)
p=0.0001
<30% decrease
≥30% decrease
Cum
ula
tive r
isk
(all-
ca
use
mo
rta
lity) NT-proBNP
686 677 668 663 656 652 647 642 638 559
RELAX-AHF
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Algorithms for determining decompensation.
Maisel A S et al. Nephrol. Dial. Transplant. 2010;ndt.gfq647
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A Maisel JACC 2013
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RELAX AHF: increases from baseline in hs-
cTnT levels are associated with increased
mortality in patients with AHF
AHF=acute heart failure; CI=confidence interval; HR=hazard ratio; hs-cTnT=high sensitivity cardiac troponin T;
KM=Kaplan-Meier; RELAX-AHF=RELAXin in Acute Heart Failure
Metra et al. J Am Coll Cardiol 2013;61:196–206
Increased hs-cTnT levels from baseline were associated with increased 180-day
mortality
At Day 2, an increase in hs-cTnT ≥20% over baseline, indicative of substantial
additional myocardial necrosis, nearly doubled the risk of mortality through Day 180
0 20 40 60 80 100 120 140 160 180
Cum
ula
tive r
isk
(all-
cause m
ort
alit
y)
0.20 Troponin T
0.00
0.15
0.10
0.05
Number at risk:
<20% increase 825 810 799 790 782 775 771 762 759 654
≥20% increase 231 219 218 216 210 207 204 200 199 174
HR 1.80 (95%CI 1.16, 2.78)
p=0.0076
<20% increase
≥20% increase
Study day
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RELAX-AHF: Vasoactive treatment lowered the
incidence of increased hs-cTnT levels in patients with
AHF
AHF=acute heart failure; hs-cTnT=high sensitivity cardiac troponin T;
RELAX-AHF=RELAXin in Acute Heart Failure
Metra et al. J Am Coll Cardiol 2013;61:196–206
hs-cTnT ≥20% from baseline
p<0.0001
Placebo Serelaxin
16.5%
27.2%
Patients
(%
) Fewer patients had increased hs-cTnT ≥20% with serelaxin compared with
placebo at Day 2
n/N = 145/534 86/522 0
5
10
15
20
25
30
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NPs vs Clinical Judgment guided
therapy in Heart Failure Current evidence
Study STARS-BNP TIME-CHF BATTLESCARRED
N 220 499 364
Fixed target 100 pg/ml 400 / 800 pg/ml 1300 pg/ml
Reduction: primary endpoint yes no no
overall mortality no no no
Mortality < 75 years ----------------- yes yes, 10.9% vs 21.7%
Target reached 33% minority minority
Benefit in subjects younger than 75 years
Jourdain P et al. JACC 2007; 49:1733
TIME-CHF Pfisterer M et al. JAMA 2009;301:383
BATTLESCARRED Richards M et al. JACC 2009
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TIME-CHF sub-analysis: NT-proBNP
guided therapy in patients with HFpEF
Maeder et al. Eur J Heart Fail 2013;15:1148–1156
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NP-guided treatment in CHF:
unsolved issues
Cut-off limits of therapeutic target ?
BNP or NT-proBNP or something else ?
One biomarker or multi-marker strategy ?
Biomarker alone or combined with “hard”
clinical end –points ?
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PROTECT TRIAL: Study Design
Patient with Class II-IV symptoms, EF 40%, recent HF event
Randomization echocardiogram
Standard of Care
Minnesota Living With HF Questionnaire quarterly
Standard of Care + NT-proBNP
Minnesota Living With HF Questionnaire quarterly
Therapy adjusted to achieve optimal drug targets
Visits q3 months
Extra visits as needed for treatment goals
Therapy adjusted to achieve optimal drug targets PLUS NT-proBNP 1000 pg/mL
Visits q3 months
Extra visits as needed for treatment goals
Close-out echocardiogram
Total cardiovascular events assessed
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Age and outcomes
0
0,2
0,4
0,6
0,8
1
1,2
1,4
1,6
1,8
Age ≥ 75 years Age < 75 years
Mean
nu
mb
er
of
even
ts
SOC
NT-proBNP
P =.008 P =.005
*No interaction between age and NT-proBNP guided care was found (P =.11)
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Meta-analysis of NP guided therapy
Troughton et al. Eur Heart J 2013 November
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Follath et al. Int Care Med 2011
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BACH TRIAL: Combining BNP and PCT in differential diagnosis of dyspnea
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A. Maisel BACH trial
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Copeptin in Heart Failure
Xue et al. from the BACH Trial
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ACTIVATE
Acute heart failure patients with high
Copeptin levels treated with Tolvaptan
targets Increased aVp Activation for
Treatment Efficacy
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Galectin-3 a biomarker of cardiac
fibrosis
De Boer et al. Eur J Heart Fail 2013;15: 1095–1101
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The Kaplan–Meier estimates for the primary endpoint (cardiovascular death and non-fatal
myocardial infarction and stroke) (A) and for total mortality (B) by galectin-3 category (above
and at or below the median level, 19.0 ng/mL).
Gullestad L et al. Eur Heart J 2012;33:2290-2296
Galectin-3 predicts response to statin therapy in the Controlled
Rosuvastatin Multinational Trial in Heart Failure (CORONA)
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ST2 levels and beta-blocker up-titration in CHF
Gaggin et al. Circ Heart Fail. 2013;6:1206-1213
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Days
0 5 10 15 20 25 30
Eve
nt F
ree
Su
rviv
al
0.65
0.70
0.75
0.80
0.85
0.90
0.95
1.00
NGAL < 100, BNP < 330
NGAL < 100, BNP > 330
NGAL > 100, BNP < 330
NGAL > 100, BNP > 330
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NGAL may provide the “sweet spot”
A. Maisel Courtesy
Creatinine
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Recommendations for Biomarkers in HF Biomarker, Application Setting COR LOE
Natriuretic peptides
Diagnosis or exclusion of HF Ambulatory, Acute I A
Prognosis of HF Ambulatory, Acute I A
Achieve GDMT Ambulatory IIa B
Guidance of acutely decompensated HF
therapy Acute IIb C
Biomarkers of myocardial injury
Additive risk stratification
Acute, Ambulatory
I A
Biomarkers of myocardial fibrosis
Additive risk stratification
Ambulatory
IIb B
Acute
IIb A
ΑΗΑ/ ACC guidelines on HF 2013
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Packer M et al. Circulation. Online Nov 2014
PARADIGM-HF biomarker profile
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Packer M et al. Circulation. Online Nov 2014
PARADIGM-HF biomarker profile
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Post Paradigm NP Biomarkers
Diagnosis
Prognosis and risk stratification
Monitoring
Guided-therapy
BNP NTproBNP
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sNEP: soluble circulating NEP
sNEP in Serum/Plasma
? NEP
sNEP as a target for LCZ696 treatment monitoring ?
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sNEP events curves
Bayes-Genis A et al. JACC 2014 In Press
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The Ideal Biomarker 2001 2014
A. Maisel . JACC 2014