Transcript B-Natriuretic Peptide (BNP)

2008 China-Western
BNP Consensus
Alan Maisel MD, FACC, ACP
Professor of Medicine,
University of California, San Diego
Director Coronary Care Unit and Heart
Failure Program,
San Diego Veterans Hospital
2008 China-Western BNP Consensus
Introductions
International meeting:
• China 15, USA 2, Greece 1 and Switzerland 1
Interdisciplinary experts:
• Cardiology 9, Nephrology 2, Emergency Medicine 5, Laboratory
Medicine 2 and Gerontology 1
Scientific Organizers:
• Chinese College of Cardiovascular Physician
• Chinese Laboratory Medicine Doctor Association
• Chinese Medical Doctor Association-Evidence-Based Medicine
Committee
• University of California at San Diego
Aim of the Meeting
•
•
•
To review the latest key literature on B-type natriuretic
peptide (BNP) measurements and utilization in clinical
application?
To discuss in the following topics:
BNP guidelines adherence
BNP for dyspnea patients (CHF & AHF)
BNP and Cardio-Renal Syndrome
Point-of-care-testing (POCT) with BNP
Economic & Operational Benefits
and make consensus statement?
To revise 2004 BNP consensus
Medical Board for the Consensus
Chairman
Prof. Hu Dayi
China
Co-chairman
Prof. Alan Maisel
U.S.A
Board of the Consensus

Prof. Chen Nan














First affiliated hospital, Sun yat-sen
university
Emergency Department

First Hospital of Peking University
Department of Gerontology


People’s Hospital of Peking University
Department of Cardiology

Mr. Ning Tianhai


Shanghai Ruijin hospital
Editorial Department
Beijing FuWai Hospital
Department of Cardiology
Prof. Zhang Wen



Beijing FuWai Hospital
Department of Cardiology
Prof. Zhang Jian


China-Japan Friendship Hospital
Clinical laboratory
Prof. Yang Yuejin


People’s Hospital of Peking
University
Department of Cardiology
Prof. Yan Shengkai


Chinese Journal of Laboratory
Editorial Department
Prof. Sun Yihong


Shanghai Ruijin hospital
Department of Cardiology
Ms. Shi Hong

Prof. Liu Meiyan



Prof. Liu Meilin



People’s Hospital of Jiangsu province
Department of Cardiology
Prof. Liao Xiaoxing
Prof. Qi Wenhang

People’s Hospital of Jiangsu province
Department of Cardiology
Prof. Gui Ming


General Hospital of the Chinese People's
Liberation Army
Clinical laboratory
Prof. Huang Jun


Shanghai Ruijin hospital
Department of Nephrology
Prof. Cong Yulong


Shanghai Ruijin Hospital
Department of Nephrology
Prof. Zhu Jihong


People’s Hospital of Peking
University
Emergency Department
Prevalence of CHF in China
Adult Population
Urban
1.1%
Rural
0.8%
P
0.054
North
1.4%
South
0.5%
P
< 0.01
Female
1.0%
Male
0.7%
P
< 0.05
GU Dongfeng et al. Chin J Cardiol. 2003;31:3-6
Prevalence of Chronic Heart Failure
in China
Male n=7,518
1.5
1.3
1.2
Female n=8,000
1.5
1.3 1.4
1.1
P<0.05
P<0.05
1.0
0.9
0.5
0.6
0.3
0.7
0.6
0.3
0
35-44
45-54
55-64
65-74
sum
Age (Years)
Sample data were collected from 10 provinces
GU Dongfeng et al. Chin J Cardiol. 2003;31:3-6
Duration of HF in Hospital Mortality
74.2
75
1980
2000
1990
60
Percent (%)
54.2
55
46.2
45
45.5
39.6
30
16.2
8.2
15
10.0
6.2
0
<5 years
5-10 years
> 10 years
GU Dongfeng et al. Chin J Cardiol. 2003;31:3-6
Age of Hospitalized Heart Failure
Patients
P<0.05
75
67.8
4
years
70
Age (year)
65
63.8
63.1
60
55
0
1980
1990
2000
GU Dongfeng et al. Chin J Cardiol. 2003;31:3-6
Mortality In Hospitalized HF Patients
%
Percent (%)
1980
1990
2000
25
20
15.4
15
12.3
10
6.2
5
0
Mortality
1980
1990
2000
GU Dongfeng et al. Chin J Cardiol. 2003;31:3-6
Cardiovascular Mortality vs. HF Mortality
%
6.0
3.0
Whole cardiac
mortality
Heart failure
mortality
GU Dongfeng et al. Chin J Cardiol. 2003;31:3-6
Long term survival of HF
in China
1. 0
_
_
_
Survival
.8
.6
.4
.2
0. 0
0
20
40
60
80
100
Time± º‰
(month)
£®‘¬ £©
N=92, follow-up 47 months (37-71)
Chin J Cardiol, 2002; 30: 450-454
Etiology of Heart Failure
Framingham† - SOLVD*
Total
African-American
Hypertension
77%
CAD
39%–50%
Rheumatic/Valvular 2%–20%
Idiopathic
5%–15%
White
32%
36%
11%
13%
4%
73%
10%
12%
†Framingham Heart Study.
.
*Bourassa et al. J Am Coll Cardiol. 1993;22:14A-19A
Changes of Etiology of Hospitalized HF
Patients In China
50
45
40
35
30
25
20
15
10
5
0
45.6
36.8
1980
N=10,714
33.8
1990
2000
34.4 34.3
18.6
8.0
CAD
10.4
HTN
18.7 18.9
20.5
12.9
Rheumatic
others
valvular heart disease
Data were taken from 42 hospitals in different city in China
Chin J Cardiol, 2002; 30: 450-454
Etiology of Hospitalized Patients With HF
Others
CAD
20.5%
RHD
45.6%
18.6%
HT
12.9%
Year 2000
CAD: Coronary Artery Disease; HT: Hypertension; RVHD: Rheumatic valvular heart disease; Others including congenital heart disease, nonrheumatic valvular heart disease, cardiomyopathy, etc.
Utilization of BNP Test
An important diagnostic tool for HF
 U.S.A —
Over 80%
hospitals
 Europe — Over 50%
hospital
 China — Over 10%
hospitals, which is 400 total
BNP: Quantitative Marker of Heart Failure
Volume 
Pressure 
ANP
Suppression of
renin-angiotensin
and endothelin
CNP
BNP =
Decreased
peripheral vascular
resistance (decreased
blood pressure)
LV Systolic Dysfunction
+
LV Diastolic Dysfunction
+
Valvular Dysfunction
+
RV Dysfunction
Increased
natriuresis
Iwanaga Y et al. JACC. 2006;47:742-8.
The Cardiovascular Disease Continuum
Endothelial
Dysfunction
Pathological
Remodeling
(LVH)
BNP
BNP
Vascular Disease
(Atherosclerosis)
Endothelial
BNP
Dysfunction
Risk Factors:
BNP
Obesity,
Insulin Resistance
Heart Attack
(Myocardial
Dysfunction)
BNP
Maladaptive
Remodeling
BNP
Left Ventricular
Enlargement
Heart Failure
BNP
DEATH
BNP = 0
Adapted from Dzau V et al. Am Heart J.1991;121:1244-63.
BNP by Staged HF Classification
BNP (pg/mL)
Stage C & D
100
Stage B
Stage A
20
Normal
20
40
60
80
Age (years)
Daniels LB & Maisel AS. Heart Failure Clin. 2006;2(3):299-309.
The Short of Breath Pie
Heart Failure
BNP in Dyspnea
Secondary to CHF or COPD
138 +/- 1076
1200
BNP pg/mL
1000
800
600
400
200
86 +/- 39
0
COPD
CHF
N=56 Cause of Dyspnea N=94
Dao, Q., Maisel, A. et al. J. American College of Cardiology, Vol 37, No. 2, 2001
Consensus Statement
•
BNP accurately differentiates
respiratory and cardiac etiologies
of dyspnea
Frequency Histogram
Clinical Probability of CHF
(Blinded to BNP)
Significant Indecision Exists
43%
Number of Cases
350
300
250
200
150
100
50
0
0
10.0 20.0 30.0 40.0 50.0 60.0 70.0 80.0 90.0 100.0
Pretest Probability of CHF
Adapted with permission from McCullough P et al. Circulation. 2002;106:416−422.
Specificity, Sensitivity, & Accuracy of
BNP Cutoff Value
Optimal cut-off point determined @ 100 pg/mL
BNP=50 pg/mL
BNP=80 pg/mL
BNP=100 pg/mL
BNP=125 pg/mL
BNP=150 pg/mL
1.0
Sensitivity
0.8
0.6
• Final
Diagnosis
HF
0.4
•
673
•
227
0.2
•
71
Sensitivity
=90%
•
0.0
• BNP <100
pg/mL
“Test negative”
615
Specificity
=73%
0.2
Positive
predictive
value=75
•
Negative
predictive
value=90
%
• Final Diagnosis
NOT HF
•BNP 100 pg/mL
“Test positive”
0.0
•
0.4 0.6
0.8
1.0
1-Specificity
Maisel AS et al. N Engl J Med. 2002;347:161-167.
Clarification of Diagnosis & BNP
BNP reduces clinical
indecision by 74%
45%
40%
Indecision
35%
43%
30%
25%
*P <0.0001
20%
15%
10%
11%
5%
0%
Clinical
Evaluation
Clinical Evaluation
and BNP
ROC Accuracy Improvement with BNP
Consensus Statement
•
The knowledge of BNP levels significantly
improves ED physician diagnostic
accuracy
Results of the BNP for Acute Shortness of Breath
Evaluation (BASEL) Study
Routine
Assessment
(n=227)
Routine
Assessment
+ BNP (n=225)
Time to treatment
(minutes, median, interquartile range)
90
(20-205)
63
(16-153)
0.03
Time to discharge
(days, median, interquartile range)
11.0
(5.0-18.0)
8.0
(1.0-16.0)
0.001
Hospitalization (%)
85
75
0.008
Intensive-care unit admission (%)
24
15
0.01
7264
(6301-8227)
5410
(4516-6304)
0.006
In-hospital mortality (%)
9
6
0.21
30-d mortality (%)
12
10
0.45
End Point
Total treatment cost
(S. median, 95% confidence intervals)
P Value
Mueller C et al. N Engl J Med 2004;350:647-54.
BNP Consensus Algorithm
Patients presenting
with Dyspnea
Physical examination,
Chest x-ray,
ECG, BNP Level
BNP 100-400 pg/mL
BNP<100pg/mL
HF very improbable (2%)
BNP >400 pg/mL
Clinical suspicion of HF
Or past History of HF
HF very Probable (95%)
HF probable (75%)
Silver M., Maisel AS et al. BNP Consensus Panel 2004 (Heart Failure 2004; (suppl. 3) S3-S14)
Revision, BNP Working Group, April 2007, Eur Heart Journal
Risk
Stratification
BNP Predicting Clinical Events
Death or Heart Failure Hospitalization
45%
40%
35%
BNP > 480 pg/ml
30%
25%
20%
BNP 230-480 pg/ml
15%
10%
BNP < 230 pg/ml
5%
0%
0
20
40
60
80
100 120 140 160 180
Days
Maisel A, et al. Annals of Emergency Medicine 2001 (in press)
Admission BNP and In-Hospital Mortality in
ADHF Distribution of BNP Values
pg/mL
(pg/mL)
48,629 (63%) out of 77,467 pt episodes had BNP assessment at initial evaluation.
Only 3.3% of patients in ADHERE with initial BNP < 100 pg/mL
Fonarow et al, JACC 2007 in press
Consensus Statement

BNP provides strong prognostic data in the
ED


Low BNP levels (< 200 pg/mL) are associated
with a very low rate of subsequent adverse
events
Very high BNP levels (> 1,700 pg/mL) are
associated with very high acute mortality
IN ACS--Time
Is Myocardium!
So we strive to
shorten door to
balloon time
So in Acute
Decompensated
Heart Failure,
why don’t we strive
to improve door to
Diuretic time!!
Sunday in the ED
Is speed important?
This is you
Delayed BNP Equals
Delayed Treatment
8
Time to BNP
7
6
<449
449-864
865-1738
>1738
5
4
3
2
1
0
<1.05
1.05-2.22
2.23-4.9
>4.9
Treatment Time
Maisel, Peacock, Fonarow, Jesse et al JACC 2008
BNP Levels with Diuretic Time
90
% Rales
85
80
75
<449
450-864
865-1738
>1738
70
65
60
55
50
<1.05
1.05-2.22
2.23-4.98
>4.98
Time to diuretic
Maisel, Peacock, Fonarow, Jesse et al JACC 2008
ED Time (hrs) vs. Quartiles of
Diuretic time & BNP level
8
7
ED Time
<449
450-864
865-1738
>1738
6
5
4
<1.05
1.05-2.22
2.23-4.98
Treatment Time
>4.98
Mortality (%)
Mortality and Diuretics
Time to IV Diuretic (hours)
Consensus Statement
•
Early knowledge of the BNP leads
to decreased hospital length of
stay
BNP Levels with either
Systolic or Diastolic Dysfunction
BNP (pg/mL)
1000
500
300
200
Median=
413 pg/mL
100
Median=
821 pg/mL
50
30
20
10
Median=
34 pg/mL
5
Non CHF
n=844
Diastolic
n=165
Systolic
n=287
J Am Coll Cardiol 2003;410(11):2010-17.
BNP Levels in Patients with Diastolic
Dysfunction
500
402 ± 66
BNP (pg/mL)
P < 0.001
400
294 ± 82
300
203 ± 30
200
100
0
33 ± 3
Normal
Impaired Pseudonormal Restrictive
Relaxation
Lubien and Maisel, Circulation. 2002; 105:595-601
Consensus Statement
Diastolic Dysfunction
•
In patients presenting with acute CHF with preservedLV function, BNP levels are always high although
usually not as high as patients with systolic
dysfunction (800 pg/mL vs. 400 pg/mL)
•
BNP levels cannot be used to differentiate systolic
from diastolic dysfunction in the emergency
department
•
In the outpatient setting-very few people have
diastolic dysfunction with BNP levels under 20-40
pg/mL.
Changes in BNP and PAW* Levels
33
31
29
27
25
23
21
19
17
15
baseline 4
1300
N = 15 (responders)
PAW
BNP
1200
1100
1000
900
BNP (pg/ml)
PAW (mm Hg)
During 24 Hours of Treatment
800
700
8
12
16
20
24
600
Hours
*Pulmonary artery wedge
Maisel, A. et al. J Cardiac Failure, Vol. 7, No. 1, 2001
In Volume Overloaded Patients:
BNP level = baseline BNP (dry) plus change due to increased volume (wet)
2500
BNP level (pg/ml)
Wet (Change due to volume overload)
Dry ( NYHA Euvolemic state)
2000
1500
1000
500
0
800
175
250
I
II
500
III
NYHA Class - Euvolemic (Dry) BNP
IV
Predischarge BNP for Identifying Patients at
High Risk of Re-Admission After
Decompensated HF
Death or readmission (%)
100
p <0.0001
Predischarge BNP >700ng/l
n =41, events =38
15.2
75
Predischarge BNP 350 - 700ng/l
n =50, events =30
p <0.0001
50
5.1
Predischarge BNP <350ng/l
n =111, events =18
25
1
0
0
30
60
90
120
150
Follow-up (days)
180
Hazard ratios
of 2nd and 3rd
versus 1st BNP range
Logeart D. et al. J Am Coll Cardiol. 2004 Feb 18;43(4):635-41
Consensus Statement
In-patient monitoring
•
BNP levels above baseline usually means volume
overload
•
With a half-life of 20 minutes, BNP levels from
volume overloaded heart failure patients drop
quickly
•
Patients whose BNP level do not drop in the hospital
have a poor prognosis
•
The lower the BNP levels are at the time of discharge,
the less likely the patient will be readmitted over the
short term
Consensus Statement
Achievement of Optimal BNP Levels
•
One must determine wet versus optivolemic BNP level
•
If BNP levels don’t fall after one day of treatment, one
should consider more aggressive therapy.
•
While a drop in BNP level is important it is not the
magnitude of the drop as much as it is the final BNP
level that relates to optivolemic status and prognosis.
•
At least two BNP levels should be measured during
hospitalization: admission, 24 hours after treatment
started, and at discharge.
BNP Utilization in the Out-patient
Setting
• Decompensation- Variability
• Driving Outpatient Therapy
• BNP as a Surrogate
• Screening
Reference Change Values for
BNP and NT-BNP
140
120
100
RCV %
80
BNP
NT-BNP
60
40
20
0
Wu
Bruin
O'Hanlon
Schou
O’Hanlon R et al. J Card Fail. 2007. Feb;13(1):50-5.
Reasons for Variability
• Relevant variables such as renal function, age
and gender did not influence variability
• Variability likely not ( all ) random; reflects
changes in the complex regulatory
environment
of BNP
–
Hemodynamic
–
Structural
–
Neuroendocrine
–
Renal
Weight Change ROC
1.00
Sensitivity
0.75
0.50
Source of the Curve
Reference Line
0.25
Percent
AUC: 0.65/0.63
Absolute
0.00
0.00
0.25
0.50
0.75
1.00
1-Specificity
Lewin J. Eur J Heart Fail. 2005 Oct;7(6):953-7.
Correlation Between ∆ in BNP and Weight
4000
R=0.002
BNP Change
3000
P=0.983 (NS)
2000
1000
0
-1000
-2000
-3000
-3
-2
-1
0
1
2
3
4
5
Weight Change
Lewin J. Eur J Heart Fail. 2005 Oct;7(6):953-7.
Algorithms for BNP Outpatient Management
TELEMEDICINE
Patient Reports Weight
Gain
3-5 lbs
Edema or Increased SOB
No
Symptomatic Changes
Draw BNP
Adjust Diuretic Over Phone
<25%
From Baseline
25-50%
From Baseline
>50%
From Baseline
Consider
Other Work-up
Clinical Decision
Adjust Diuretic
Algorithms for BNP Outpatient Management
OUTPATIENT CLINIC
Patient Arrives With
Worsening Symptoms
<25%
From Baseline
25-50%
From Baseline
Wt Gain
3-5 lbs
Wt Gain
3-5 lbs
Yes
Clinical
Decision
No
Other
Work-up
Yes
Adjust
Diuretic
>50%
From Baseline
No
Clinical
Decision
Adjust
Diuretic
What is “Biomarker Guided Therapy?”
•
A treatment strategy that integrates
measurement of a biomarker of biologic
response (or lack or response) into
treatment decisions
BNP Monitoring Trials –
Mortality
FAVORS BNP STRATEGY
FAVORS CLINICAL STRATEGY
Troughton
STARS-BNP
STARBRITE
Combined
(random effects)
0.01
0.1
1.0
10.0
Odds Ratio (95% Confidence Interval)
0.43 (0.183, 1.02); p=0.055
100.
Perspective
ALOFT
3 months
10
Val-HeFT
4 months
RALES
3 months
A-HeFT
6 months
n=51
n=340
+2
Change in BNP (pg/mL)
n=1890
0
n=137
n=148
n=1850
−10
−20
n=50
−6
n=343
−8
−12
−15
p=0.02
−30
−34
−40
−39
p<0.0001
p=0.05
−50
−60
−70
Baseline BNP
concentration
(pg/mL)
−61
p=0.016
291
181
Placebo
~70
Aliskiren
Valsartan
~300
Spironolactone
Hydralazine-isosorbide dinitrate
Consensus Statement
Out-patient Monitoring Impact of BNP Strategies
•
BNP-oriented strategies reduced heart failure related
hospitalizations and mortality.
•
Use of BNP oriented strategies could help clinicians
optimize medical therapy in patients with or without
beta blockers.
•
In CHF, BNP-oriented strategies are based on BNP
target value (100- 300 pg/ml) rather than on BNP
variation due to heterogeneity of basal BNP value.
These threshold values are only indicative due to low
number of randomized studies.
•
BNP-oriented strategies are safe and don’t lead to
hemodynamic or renal deterioration.
Potential Biomarker Targets in ACS
cTnT, cTnI, Myo, CK-MB, FABP
Necrosis
Ischemia
Plaque Rupture
IMA, uFFA
MMP’s, PAPP
sCD40L, PIGF
Arrhythmias
Thrombosis
PAI-1, sCD40L
vWF, D dimer
Neurohormone
Activation
BNP, NE
Inflammation
Endothelial
Activation
hs-CRP, Ox LDL
MCP-1, MPO, IL18
sICAM,
pSelectin
The Prognostic value of BNP in ACS
(preliminary results)
In-hospital mortality 4.28%
Median of BNP
5000
•ACS patients （N=327 ）
with or without ST
elevation between
Nov,2006 and Dec,2007,in
PUPH
4,487pg/ml
4000
3000
2000
1,434pg/ml
1000
Death (n=14)
No death
(n=313)
•BNP by Triage BNP Test
(Biosite, Inc., San Diego, CA)
Data not published
Consensus Statement
BNP with Chest Pain Presentation Additional Value
to Necrosis Biomarkers
•
A high BNP level in a troponin negative patient may herald a subsequent
troponin elevation.
•
In the patient with atypical chest pain, no ECG changes, and no troponin
elevation, the addition of a BNP level less than 100 pg/mL signifies a patient
who is especially low-risk.
•
A high BNP in the setting of ACS and NSTEMI is a significant predictor of
death, even in troponin negative patients. This provides physicians with
opportunity to provide more aggressive treatment to these patients.
•
High or rising BNP levels in patients presenting with ACS my herald the
imminent onset of acute HF.
BNP and Guidelines
• As with every new diagnostic
or treatment modality,
guidelines often lag behind
state-of-the-art practice
Suspected Acute Heart Failure
Assess Symptoms and Signs
Heart Disease?
ECG / BNP/ X-ray?
Abnormal
• It is very encouraging to see
that after only several years
of introduction into clinical practice,
the use of BNP is already
recommended by all
major guidelines
Normal
Consider other diagnosis
Evaluate function by
Echocardiography / other imaging
Normal
Abnormal
Heart Failure, assess by
Echocardiography
Selected tests
(angio, hemodynamic
monitoring, PAC)
Characterize type and severity
European Heart J. 2005;26:385-6.
Ten Key Messages for Physicians
• BNP is a quantitative marker of heart failure.
• BNP is highly accurate in the diagnosis of heart
failure.
• BNP may help risk stratify patients in the ED with
regard to admission or discharge.
• BNP testing improves patient management and
reduces total treatment costs.
• BNP testing has costs savings out to 6 months.
Ten Key Messages for Physicians
• BNP is the most powerful predictor of outcome heart
failure.
• BNP levels may be helpful in assessing safety for
discharge from the hospital
• BNP- guided therapy appears to improve outcome in
chronic heart failure.
• BNP levels, along with symptoms and weight gain are
the best way to ascertain clinical decompensation.
• BNP is the most powerful predictor of death in acute
coronary syndrome.
China-Western Consensus Group
2007 European-North American
BNP Consensus
THANK YOU !