Transcript NT-proBNP and BNP

Biomarcadores en ICC
Ileana L. Piña, MD, MPH
Professor of Medicine, Epidemiology/Population Health
Albert Einstein College of Medicine
Associate Chief for Academic Affairs -- Cardiology
Montefiore-Einstein Medical Center
Bronx, NY
What Is a Biomarker: NIH Definition
“A characteristic that is objectively measured and
evaluated as an indicator of normal biologic
processes, pathogenic processes, or the
response to a therapeutic intervention.”
Atkinson et al, Clin Pharmacol Ther 2001
Clinical Value of Cardiac Biomarkers
• Screening for preclinical disease in
asymptomatic subjects
• Diagnosis of clinical disease in patients
with uncertain symptoms
• Risk stratification in patients with clinical
disease
• Therapeutic guidance in selection or
titration of agents in patient with know
disease
The Differential Diagnosis of an
Elevated NT-proBNP
Besides Acute Heart Failure
• Coronary ischemia
• Pulmonary heart disease
• Prior heart failure
 Sleep apnea
• Heart muscle disease
 Pulmonary embolism
 Left ventricular hypertrophy
 Restrictive myopathies
 Apical ballooning syndrome
 Pulmonary hypertension
• High output (shunts)
• Anemia
 Myocarditis
• Renal dysfunction
 Toxic insults, like chemotherapy
• Critical illness
• Valvular heart disease
• Atrial fibrillation or flutter
• Congenital heart disease
 Bacterial sepsis
 Burns
 ARDS
• Stroke
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Take Home: Biology
• The natriuretic peptide system has complex genetic
regulation
• Synthesis of an intracellular precursor, proBNP1-108,
precedes release of BNP1-32 and NT-proBNP1-76
• The kidneys clear NT-proBNP and BNP equally
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Expected NT-proBNP Values by Age
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*From Elecsys NT-proBNP package insert.
The Importance of Serial NP Measurement
for Prognosis in Chronic HF
Mortality
(%)
Hospitalization
for HF (%)
HighHigh
25.6
26.8
n=368
LowHigh
17.2
21.1
n=180
HighLow
13.6
10.1
n=1618
LowLow
8.6
6.7
2500
NT-proBNP (pg/mL)
n=1322
2000
1500
1000
500
0
4
0
Months
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Januzzi JL, Troughton R. Circulation. 2013; 127(4):500. Reproduced from Masson S, Latini R, Anand IS, et al. J Am Coll Cardiol. 2008;52(12):997-1003.
Prognosis in Chronic Heart Failure
Patients
• Risk prediction in chronic HF is
challenging
• Variables traditionally predictive
of risk include age, ejection
fraction, renal function, and
maximal oxygen consumption
• Similar to its value in acute HF,
concentrations of NT-proBNP
are powerfully prognostic for
adverse outcome in chronic
stable HF
• This is independent of multiple
other covariates of risk, such as
age or ejection fraction
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NT-proBNP or BNP and Stage C
HF Prognosis
All-cause Mortality
Hospitalization for HF
BNP
NT-proBNP
Masson S, Latini R, Anand IS, et al. Clin Chem, 2006;52(8):1528-1538.
Latini R, Masson S, Anand I, et al. Eur Heart J. 2004;25(4):292-299.
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



N=3916
Identify variables assoc with both
All cause mortality, morbidity and HF hospitalization
Both-most powerful predictors of all cause mortality
NT-BNP better for mortality and HF hospitalization
 Men >70 and GFR 30-60

Masson et al. Clinical Chemistry 52:8; 1528–1538 (2006)





19% of pts stop trastuzumab due to drop in EF
36 pts with normal EF at least 3 weeks after
trastuzumab
BNP and troponin at baseline at 24 hours
No elevation in troponin
39% had elevation of proBNP, 8 at both baseline and 24
hrs, 11 had previous anthracycline, 3 hx of HTN
Goel et al. Asia–Pac J Clin Oncol 2011; 7: 276–280
Therapies With Effects on B-type
Natriuretic Peptide Levels
Therapy
Effect on BNP/NT-proBNP
Diuresis1

ACE-I1

ARB1

-blockers1

Aldosterone antagonists1

BiV pacing4

Exercise2

Rate control of AF3

1. de Lemos, et al. Lancet. 2003;362:316.
2. Scharhag, et al. Am Heart J. 2005;150:1128.
3. Ulimoen, et al. Eur Heart Journal. 2014;35:517
4. Delgado, et al. Congestive Heart Failure. 2006;12:250
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Natriuretic Peptides and LVEF
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Januzzi, et al. Eur Heart JournaL.2006;27:330.
HFpEF Versus HFrEF and NP Levels
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O’Donoghue, et al. J Card Failure. 2005;11:S9.
Diagnostic Uncertainty Is Common
in Dyspnea Evaluation
Following full evaluation, managing physician asked to provide an estimate
from 0% to 100% for the likelihood for heart failure as the cause of dyspnea
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Green, et al. Arch Int Medicine. 2008;168:741.
Diagnostic Uncertainty Is Associated
with Poor Prognosis in Acute Dyspnea
• 31% of subjects in a
study were judged
uncertainly by the
managing physician
• Their prognosis was
significantly worse, with
higher rates of death and
re-hospitalization and
longer lengths of stay
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Green, et al. Arch Int Medicine. 2008;168:741.
Interpreting NT-proBNP in Those
With Prior Heart Failure
• Those with prior HF who are not decompensated at the
time of evaluation usually have considerably lower NTproBNP values than those who are decompensated
• It is useful to have a comparison to “dry” NT-proBNP
values (i.e., a measurement taken in the office when the
patient appears stable)
• A change >25% from the “dry” NT-proBNP generally
suggests a clinical change
• Irrespective of clinical stability, the “dry” NT-proBNP value
is prognostic
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Januzzi JL, Bayes-Genis A. Evolution of amino-terminal pro-B type natriuretic peptide testing in heart failure. Drug News Perspect. 2009;22(5):267-273.
The BNP Puzzle
Triage in ED
Observationals
BATTLESCARRED*
TIME-CHF*
– STARS-BNP
Protect
2010
Study flow
151 consented and randomized
Standard of care
plus NT-proBNP
(N=75)
Standard of care
alone
(N=76)
6 elective
withdrawals
6 elective
withdrawals
75 analyzed
0 excluded
76 analyzed
0 excluded
Drugs: Baseline
Medication
Baseline
NT-proBNP (N=75) SOC (N=76)
P
ACE Inhibitors (%)
53 (70.7)
47 (61.8)
.21
Angiotensin receptor blocker (%)
8 (10.7)
15 (19.7)
.11
β blocker (%)
74 (98.7)
71 (93.4)
.19
Aldosterone antagonist (%)
37 (49.3)
26 (34.2)
.10
Loop Diuretics (%)
67 (89.3)
71 (93.4)
.27
5 (6.7)
3 (4.0)
.48
22 (29.3)
25 (32.9)
.89
Hydralazine (%)
4 (5.3)
4 (5.3)
.89
Nitrates (%)
8 (10.7)
16 (21.1)
.07
Thiazide Diuretic (%)
Digoxin (%)
Drugs: Titration
Medication
Titration
NT-proBNP (N=75) SOC (N=76)
P
ACE Inhibitors (%)
+25.4%
+18.1%
.15
Angiotensin receptor blocker (%)
+5.8%
+22.3%
.01
β blocker (%)
+46.0%
+34.5%
.05
Aldosterone antagonist (%)
+22.7%
+5.8%
<.001
Loop Diuretics (%)
+23.7%
+25.6%
.65
Thiazide Diuretic (%)*
-16.7%
-12.5%
.88
Digoxin (%)*
-10.9%
+2.0%
.78
Hydralazine (%)*
+27.5%
-50.0%
.20
Nitrates (%)*
+59.4%
-3.7%
.08
*Limited number of observations
NT-proBNP Concentrations
Overall
Baseline
Follow-up
P
2118 [1122-3831] 1321 [554-3197] .02
By treatment allocation
Treatment
Baseline
Follow-up
P
SOC
1946 [951-3488] 1844 [583-3603] .61
NT-proBNP 2344 [1193-4381] 1125 [369-2537] .01
P = .03 for SOC follow-up versus NT-proBNP follow-up
44.3% of NT-proBNP subjects 1000 pg/mL
Primary Endpoint
P =.009
120
Number of events
100
100 events
80
60
40
20
58 events
Adjusted Logistic Odds= 0.44
(95% CI= .22-.84; P =.019)
0
Total CV Events
SOC
NT-proBNP
Mean Number of Events/Patient
P =.03
1.4
1.3 events
Number of events
1.2
1
0.8
0.6
0.4
0.2
0
0.77 events
SOC
NT-proBNP
Individual Endpoints
60
NB: 0 cerebral ischemia events in either arm
SOC
NT-proBNP
Number of events
50
40
NB: 3 of 4 CV deaths in NT-proBNP arm
occurred AFTER elective withdrawal from study
30
20
P =.001
P =.002
P =.72
P =.41
P =.52
Worsening HF
HF hosp
ACS
VT/VF
CV death
10
0
Angiotensin Receptor Neprilysin
Inhibition (ARNI): LCZ696
LCZ696
valsartan
sacubitril
Natriuretic Peptides
Angiotensin II
BK, ADM
Subs-P, VIP, CGRP
•
•
•
•
Vasodilation
Natriuresis
Diuresis
Inhibition of pathologic
growth/fibrosis
Neprilysin
AT1Receptor
Degradation
products
• Vasoconstriction
• Sodium/water retention
• Fibrosis/hypertrophy
PARADIGM-HF: NT-proBNP and BNP
Concentration of Natriuretic Peptides
LCZ696
Enalapril
“…because BNP
(but not NT-proBNP)
is a substrate for
neprilysin, levels of
BNP will reflect the
action of the drug,
whereas levels of
NT-proBNP will
reflect the effects of
the drug on the
heart.”
NT-proBNP
BNP
0
0
2
4
6
8
Months
Data adapted from Packer, et al. Circulation. 2015.
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Recommendations for Biomarkers in HF
Biomarker, Application
Setting
COR
LOE
Diagnosis or exclusion of HF
Ambulatory,
Acute
I
A
Prognosis of HF
Ambulatory,
Acute
I
A
Ambulatory
IIa
B
Acute
IIb
C
Acute,
Ambulatory
I
A
IIb
B
IIb
A
Natriuretic peptides
Achieve GDMT
Guidance of acutely decompensated
HF therapy
Biomarkers of myocardial injury
Additive risk stratification
Biomarkers of myocardial fibrosis
Ambulatory
Additive risk stratification
Acute
Causes for Elevated Natriuretic
Peptide Levels
Cardiac
 Heart failure, including RV
syndromes
 Acute coronary syndrome
 Heart muscle disease, including
LVH
 Valvular heart disease
 Pericardial disease
 Atrial fibrillation
 Myocarditis
 Cardiac surgery
 Cardioversion
Noncardiac
 Advancing age
 Anemia
 Renal failure
 Pulmonary causes: obstructive
sleep apnea, severe pneumonia,
pulmonary hypertension
 Critical illness
 Bacterial sepsis
 Severe burns
 Toxic-metabolic insults, including
cancer chemotherapy and
envenomation
Biomarker Guided Therapy and All-Cause Mortality
Adjusted HR = 0.69 (0.55-0.86)
N=
1627
Felker GM et al. Am Heart J 2009
Primary Hypothesis of GUIDE-IT
n
In high risk heart failure patients with LV systolic
dysfunction, a strategy of titrating medical therapy
based on minimizing natriuretic peptide levels will
be superior to usual care with regard to the
composite endpoint of heart failure hospitalizations
or CV mortality
GUIDE IT Study Design Overview
Patient Population
n
Chronic HF due to LV systolic dysfunction
l Ejection fraction < 40
n
Identified at the time of hospitalization for ADHF
n
NTproBNP > 2000 pg/mL or BNP > 400 pg/mL at
any time during index hospitalization
Intervention
n
Randomized 1:1 to either:
l Biomarker Guided Arm
Treatment Titrated to Achieve Target
NTproBNP < 1000 pg/mL
l OR
l Usual Care
Treatment titrated based on published
guidelines
Achieving NTproBNP Goals:
Guidance for Investigators
n
Up-titrate/add ACE-inhibitor or ARB
n
Up-titrate/add beta-blocker (if not clinically congested)
n
Up-titrate/add hydranazine-isosorbide dinitrate in African-American patients
n
Increase loop diuretic dosage (if clinically congested or NTproBNP > 5000 pg/mL)
n
Up-titrate/add spironolactone if tolerated by renal function/potassium
n
Add oral thiazide diuretic
n
Add digoxin
n
Consider adding ARB to ACE-I (if not on spironolactone)
n
Consider hydranazine-isosorbide dinitrate in non-African-American patients
n
Consider optimization of cardiac resynchronization therapy (if CRT device
implanted)
n
Reconsider potential indications for CRT (if not previously implanted)
n
If in atrial fibrillation, maximize rate control or more aggressive attempts at NSR
Endpoints
n
Primary Endpoint
l
n
Time to cardiovascular death or first heart failure
hospitalization
Secondary Endpoints
l
l
l
l
l
l
l
Total days alive and out of hospital over follow up
Time to all-cause mortality
Time to death or rehospitalization (all cause)
HRQOL
Resource use, costs and cost effectiveness
Global rank score based on death, hospitalization, and quality
of life
Changes in adherence and self-management
What’s New?
n
Galectin-3
n
ST-2
n
GDF-15
n
Mid-regional peptides (MRproANP, MRproADM,
copeptin)
n
Renal function and renal injury (Cystatin C, NGAL)
n
Altered forms of BNP
n
High sensitivity troponin
n
MPO, uric acid, RDW, many many others…
Galectin-3 as a Candidate Marker for Remodeling?
Beta-galactoside binding
lectin
Secreted by
macrophages
Mechanistic role in
fibrosis
The “switch” that turns
quiescent fibroblasts into
activated, matrixsecreting myofibroblasts
Galectin-3 Biology
Galectin-3 and NTproBNP in AHF
Acute Heart Failure: PRIDE –
Investigation of Dyspnea in
Emergency Room1
N = 209 (ADHF)
60-day mortality: OR = 10.3 (p<0.01)
60-day death/recurrent HF: OR = 14.3
(p<0.001)
Independent of NT-proBNP
Acutely Destabilized Heart
Failure2
N = 310 (ADHF)
Follow-up = 800 days
HR = 2.19 (p<0.001)
Independent of age/race/CRP/NTproBNP
1 van
Kimmenade RR, et al. J Am Coll Cardiol 2006
C, et al. J Card Fail 2009
2 DeFilippi
A similar increase in galectin-3 causes a much more
pronounced increase in risk in patients with HFPEF
compared to patients with HFREF
De Boer RA Annals of Medicine, 2011; 43: 60–68
Galectin 3 and CV Mortality: HF ACTION
N = 895
Felker et al. ESC 2010
Does Galectin-3 identify a specific HF Phenotype?
Low Galectin 3 = “Non-remodeling” HF
•
Relatively good prognosis
•
More likely to be responsive to traditional treatments?
High Galectin 3 = “Remodeling” HF
•
Relatively poor prognosis
•
May need earlier referral for advanced HF therapies
•
Should we consider specific anti-remodeling agents?
Lambert JM, et al. Int J Cardiol 2008
ST2 Background
ST2 is a member of the interleukin-1 receptor family
ST2 protein is found both as a trans-membrane form
as well as a soluble form in serum
The ligand for ST2 was recently identified to be IL-33
Links inflammation, hemodynamic stress, and
remodeling
Abnormalities in ST2 lead to a phenotype
of remodeling
Interruption of ST2 results in increased LV mass, LVH,
more dilated LV chambers, and worse LV function
ST2 Trends as a Function of Mortality
0.7
0.6
sST2 (ng/mL)
0.5
Death
0.4
0.3
0.2
Survival
0.1
First
Day 2
Day 3
Day 4
Day 5
Last
Time
Boisot, et al, J Card Failure, 2008
Acute HF:
ST2 Relationship to Time of All Cause Mortality Event
Chronic HF:
ST2 Relationship to Time of All Cause Mortality
ST2 predicts remodeling and response to
aldosterone blockade in acute MI
13
11
% change
9
7
Low/placebo
Low/eplerenone
High/placebo
High/eplerenone
5
3
1
-1
-3
-5
Left ventricular
end systolic volume index
Left ventricular
end diastolic volume index
Weir et al, JACC, 2010
What are the Unmet Needs in Heart Failure?
Diagnostic markers?
Natriuretic peptides are already extremely good
for diagnosis of ADHF
Prognostic markers?
> 150 prognostic markers have already been
identified in heart failure, very few of which are
employed by clinicians
Markers that tell us what we should do (ie, what is
likely to work) or what we shouldn’t do (ie, what is
unlikely to work) for an individual patient
Markers that may lead to new therapeutic targets
Maximal Medical Therapy for Systolic Heart Failure
Beta-blocker
2
ACE-inhibitor
1
Diuretic
2
Aldosterone antagonist
1
Digoxin
1
ISDN/Hydralazine in AA pts
6+
? Add ARB to ACE
1
14+
Do all our our HF pts really needs all of these drugs?
Biomarker Targeted Therapy
Marker not
elevated
Marker elevated
McLeod, H. Ann Rev of Pharmacol and Toxicol 2001.
Personalized Medicine: The Future?
Genomic Data
SNPs
Genome-scale sequence
Gene Expression Profiles
Clinical Data
Treatments
Family history
Demographics
Environmental
Patterns
Integration
Models
Metabolomic Data
Proteomic Data
Imaging
Known Biomarkers
Predictions:
Risk
Individualized Prognosis & Diagnosis
Drug/Device Response
Environmental Response
The Path to Personalized Medicine
“…focusing on the best ways to develop new
therapies and optimize prescribing by
steering patients to the right drug at the right
dose at the right time.”
Hamburg and Collins, New Eng J Med 2010
Conclusion
El peptido BNP o pro BNP indicador de la
severidad IC
El cambio durante el ingreso
La prediccion del reingreso
El responso al cambio en farmacoterapia
El estudio GUIDE-IT
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