Transcript Left ventricular dysfunction

Accuracy of brain natriuretic
peptides levels in the diagnosis of
systolic left ventricular dysfunctiona Systematic Review
Introduction to Medicine – 1st year
Class 11 2006-2007
3rd May 2007
Porto Medical Faculty
Introduction
• Left ventricular dysfunction.
• Type-B natriuretic peptides.
• Use of type-B natriuretic peptides on
diagnosis of left ventricular dysfunction.
Left ventricular dysfunction
• Left ventricular dysfunction or heart failure (HF) is the pathophysiologic
state in which the heart is unable to pump blood at a rate
commensurate with the requirements of the metabolizing tissues. [1]
• Complex clinical syndrome that can result from any structural or
functional cardiac disorders that impairs the ability of the ventricle to fill
with or eject blood. [2]
[1] - Braunwald. A textbook of Cardiovascular Medicine. Elsevier Saunders, 7th Edition
[2] - Hunt S. ACC/AHA 2005 Guideline for the Diagnosis and Management of CHF in the adult. JACC 2005
Left ventricular dysfunction
• 4,9 million people in USA are being treated for heart failure [3].
• 550,000 new cases diagnosed each year.
• 10% of patients older than 75 years have heart failure.
• Heart failure is the most common cause of hospitalization due to
cardiovascular disease in patients over 65 years of age [4].
• The number of HF deaths has increased steadly despite advances in
treatment, in part because of increasing numbers of patients with heart
failure [5].
[3] - Ho K. The epidemiology of heart failure: the Framingham Study. JACC 1993
[4] - Louis A. A systematic review of telemonitoring for the management of heart failure. Eur J Heart Failure 2003
[5] - American Heart Association. Heart disease and stroke statistics: 2005 update. Dallas; American Heart Association
Left ventricular dysfunction
• Is a major health care problem and one of the most frequent reasons
for patients to be admitted to hospital.
• Despite significant advances in treatment, the prognosis remains
poor. [6]
• A simple objective definition of CHF is currently impossible as there is
no cutoff value of cardiac or ventricular dysfunction or change in flow,
pressure, dimension, or volume that can be used reliably to identify
patients with heart failure. [7]
[6] – Sliwa, K. Heart Failure:Making a cardiac failure diagnosis as early as possible. The Medicine Journal,
2002
[7] - Denolin H. The definition of heart failure. Eur Heart J 1983.
Diagnosing Left Ventricular
Dysfunction
• The clinical diagnosis of heart failure or left ventricular dysfunction is
complex, especially in the presence of other pathologies such as
respiratory disease or obesity [8, 9]
• There are three types of tests for the diagnosis of this pathology:
– Echocardiography and Doppler flow studies;[10]
– ECG and Chest X-rays;
– Blood tests for heart failure. [11]
[8] – Remes J. Validity of clinical diagnosis of heart failure in primary health care. Eur Heart J 1991.
[9] – Stevenson LW. The limited reliability of physical signs for estimating hemodynamics in chronic heart failure. JAMA 1989.
[10] – Nielsen OW. Retrospective analysis of the cost-effectiveness of using plasma brain natiuretica peptide in screening for LVD in
the general population. JACC 2003.
[11] – McCullough PA. B tpe natriuretic peptide and clinical judgment in emergency diagnosis of HF: analysis from Breathing Not
Properly Multinational Study. Circulation 2002
Echocardiography and Doppler flow
studies
• The single most useful diagnostic test evaluating patients with suspected
heart failure is without doubt the 2-dimentional echocardiogram, coupled
with Doppler flow studies [12]
• With the help of echocardiography the degree of left ventricular systolic
dysfunction can be determined which has important prognostic
implications;
• Doppler echocardiography assists in the diagnosis of diastolic
dysfunction. [6]
• Its limited availability and high costs prohibit its use in general screening
test [13]
[12] – Sim V. The use of brain natriuretic peptide as a screening test for left ventricular systolic dysfunction –
cost-effectivenedd in relation to open access echocardiography. Fam Pract 2003.
[13] – Cheitlin MD. ACC/AHA/ASE 2003 Guideline update for clinical application of echocardiography. JACC
2003
ECG and Chest X-rays
• Both chest radiography and 12-lead electrocardiograms are important in
providing baseline information in most patients,
• Are both insensitive and nonspecific,
• Neither the ECG nor the chest radiograph should form the primary bases
for determining the specific cardiac abnormality responsible for the
development of heart failure. [6]
[6] – Sliwa K.Heart Failure: Making a cardiac failure diagnosis as early as possible, The Medicine Journal, March 2002
Blood tests for heart failure
• Recently the measurement of circulating levels of brain natriuretic peptide
(NT-proBNP by Roche diagnostics) has become available as a mean of
identifying patients with elevated left ventricular filling pressures who are
likely to have signs and symptoms of heart failure. [14]
[14] - Peacock W. The B-type natriuretic peptide assay: A rapid test for heart failure, Cleveland Clinic Journal of Medicine 2002
Natriuretic Peptides
• There are three types of natriuretic peptides (NP):
– Type-A: produced by atrials myocite cells;
– Type-B: produced by ventricular myocites cells;
– Type-C: predominantly secreted by noncardiac tissues (e.g.,
endothelium). [15]
• The most relevant type of NP for the diagnosis of left ventricular
dysfunction is the type-B. [16]
[15] – Vanderheyden M. Brain and other natriuretic peptides: molecular aspects. Eur J Heart Failure 2004
[16] – Pfister R. Use of NT-proBNP in routine testing and comparison to BNP. Eur J Heart Failure 2004
Type-B Natriuretic Peptides
• They are produced in the form of an inactive hormone, proBNP;
• This inactive hormone is enzimaticly cleaved to two peptides: one
active, BNP; and another inactive, NT-proBNP;
• In this reaction, NT-proBNP is produced in the same proportion as BNP
[17]
• This hormones are metabolized mostly in the kidneys;
• Although the proportion of this reaction is 1:1, the blood levels of NTproBNP are higher, since BNP is also metabolized by endopeptidases
and endotelial receptores.[18]
[17] – Hulsmann M. Incidence of normal values of natriuretic peptides in patients with chronic heart failure and impact on
survival: A direct comparison of N-terminal atrial natriuretic peptide, N-terminal brain natriuretic peptide and brain natriuretic
peptide.. Eur J Heart Failure 2005
[18] – Wu A. Biological variation of natriuretic peptides and their role in monitoring patients with heart failure. Eur J Heart Failure
2004
Type-B Natriuretic Peptides
• The active form, BNP, induces the relaxation of the cardiac muscle in
response to hemodinamic stress;
• The increase of the hemodinamic stress causes the rise of the
plasmatic levels of the NP;
• This rise is commonly a sign of heart failure.[19]
[19] – Larsen A. The effect of altering haemodynamics on the plasma concentrations of natriuretic peptides in heart failure. Eur J
Heart Failure 2006
Natriuretic Peptides on the
Diagnosis of Left Ventricular
Dysfunction
• The assay that determines the levels of NP consists on a blood test of
imunofluorescence that measures the plasmatic levels of BNP or NTproBNP;
• The cut value for the concentration of BNP is 100 pg/mL and for the
concentration of NT-proBNP is 175 pg/mL; above this levels, the patient
is considered in risk of suffering of an heart failure;
• It is economically viable and it is easy to perform.[14, 20]
[14] – Peacock W. The B-type natriuretic peptide assay: A rapid test for heart failure, Cleveland Clinic Journal
of Medicine 2002
[20] – Mueller C. Use of B-type natriuretic peptide in the evaluation and management of acute dyspnoea.
NEJM 2004.
Natriuretic Peptides on the
Diagnosis of Left Ventricular
Dysfunction
• The test is, nowadays used to diagnose patients in risk of heart failure
and to decide which patients need internment;
• It can also be used to stratify the patients, according to the severity of the
pathology;
• In the future, clinicians may be able to adjust the therapy bearing in mind
the levels of NP of the patients;
• This levels can also be used to predict the evolution (prognosis) of the
patient. [21]
[21] – Isakson S. Natriuretic peptides as prognosticators in congestive heart failure. BMJ
2006
Aim of the study
• To evaluate the sensitivity and specificity of
natriuretic peptide levels in the diagnosis of
systolic left ventricular dysfunction.
Pubmed’s new Query
(("Ventricular Dysfunction, Left"[MeSH] OR "Heart Failure,
Congestive"[MeSH] OR "Cardiac failure"[All Fields] OR "ventricular
dysfunction"[All Fields] OR "heart failure"[All Fields] OR "cardiac
dysfunction"[All Fields] OR "heart dysfunction"[All Fields]
AND
("Natriuretic Peptide, Brain"[MeSH] OR "natriuretic peptide"[All Fields] OR
"probnp"[All Fields] OR "bnp"[All Fields] OR "ntprobnp"[All Fields])
Pubmed’s new Query
AND
("Sensitivity and Specificity"[MeSH] OR (("sensitivity and specificity"[TIAB]
NOT Medline[SB]) OR "sensitivity and specificity"[MeSH Terms] OR
sensitivity[Text Word]) OR (("sensitivity and specificity"[TIAB] NOT
Medline[SB]) OR "sensitivity and specificity"[MeSH Terms] OR
specificity[Text Word]) OR "ROC Curve"[MeSH] OR "ROC Curve"[All
Fields] OR "likelihood ratio"[All Fields] OR accuracy[All Fields] OR
"predictive value"[All Fields]))
AND ((clinical[Title/Abstract] AND trial[Title/Abstract]) OR "clinical
trials"[MeSH Terms] OR clinical trial[Publication Type] OR
(random[Title/Abstract] OR random/aleatory[Title/Abstract] OR
random/and[Title/Abstract] OR random/arm[Title/Abstract] OR
random/basal[Title/Abstract] OR random/blind[Title/Abstract] OR
random/blocked[Title/Abstract] OR random/cdp[Title/Abstract] OR
random/ethanol…
• 763 articles found
Query used to search Cochrane
(("Ventricular Dysfunction, Left" OR "Heart Failure, Congestive" OR
"Cardiac failure" OR "ventricular dysfunction" OR "heart failure" OR
"cardiac dysfunction" OR "heart dysfunction")
AND
("Natriuretic Peptide, Brain” OR "natriuretic peptide" OR "probnp" OR
"bnp" OR "ntprobnp")
AND
("Sensitivity and Specificity" OR sensitivity OR specificity OR "ROC
Curve" OR "ROC Curve" OR "likelihood ratio" OR accuracy OR
"Predictive Value of Tests"))
• 26 articles found
Methods
• In an initial phase the titles and abstracts of the articles were
reviewed to identify all potential studies, without making restrictions
to the time of publication. Full text versions of these articles were
obtained, if considered necessarily.
• In the second phase we performed the exclusion of studies
Methods
• 1st phase – Inclusion of the articles
Selection made by 6 groups with 2 reviewers each;
The inclusion of the article was dependent on the approval of at least 2
reviewers.
INCLUSION CRITERIA
 Be written in English, Portuguese, French or Spanish.
 Publications on the accuracy or sensitivity and specificity of BNP
levels in the diagnosis of heart failure or left ventricular dysfunction.
 Compare the diagnostic accuracy of NTproBNP or BNP to the
traditional means of diagnosing the heart failure, such as
echocardiography, or clinical criterias.
Methods
•
2nd phase – exclusion
Selection made by 6 groups with 2 reviewers each.
EXCLUSION CRITERIA
 To evaluate diastolic dysfunction .

To be limited to very restrictive study groups such as patients with
Duchenne disease, Chagas disease or Brugada syndrome.

To be performed in non human population

To associate the cardiac failure to congenital or hereditary
diseases.
Articles’ Selection Flowchart
• Flowchart
Kappa’s Test
23
Descriptive Statistics
N
Concde
Valid N (lis twis e)
6
6
Minimum
,600
Maximum
,947
[23] Harold L. Kundel et al, Measurement of observer agreement, Radiology 2003
Mean
,77641
Data Extraction
• Data on study identification, year of publication, diagnostic cross
table, spectrum of patients and methodological aspects are to be
extracted from original studies;
• The study population data is going to incorporate the
inclusion/exclusion criteria, type of assay (extractive,
immunofluorescence) and the reference standard evaluated (cardiac
failure vs left ventricular systolic dysfunction)
• The methodological quality of the individual studies is going to be
appraised using QUADAS tool [22]
[22] – Whiting P. The development of QUADAS: a tool for the quality assessment of studies of diagnostic accuracy included in
systematic reviews. BMC Med Res Methodol 2003
Data Extraction
•
Table
•
Table of correspondence
Articles’ Characteristics
• Type of study – 12 articles are cohort studies, 7
randomized and 4 transversal (total=23)
• Total participants – 12082
• Female rate in population – 58%
• Mean age – 67.8 years
• Articles selected published after 2000
Results
Descriptive Statistics
N
number of participants
number of ill participants
number of non-ill
participants
number os female
participants
number of male
participants
Valid N (lis twis e)
23
14
Sum
12082
1933
14
3959
21
6383
21
4608
13
Descriptive Statistics
N
proportion of patients with
dys pnea
proportion of s mokers
proportion of patients with
hypertens ion antecedents
proportion of patients with
antecedents of is chaemic
heart dis eas e
proportion of patients with
antecedents of diabetes
Valid N (lis twis e)
Minimum
Maximum
7
,326
1,000
,70703
,285541
8
,019
,594
,34084
,206902
19
,012
,661
,38080
,206335
5
,010
,168
,12138
,063786
16
,005
,443
,17016
,123528
2
Mean
Std. Deviation
Results
Results
1 – 50yo or younger
2 – 50-60yo
3 – 60-65yo
4 – 65-70yo
5 – 70yo or older
Results
Scatterplots (sensitivity)
Scatterplot (specificity)
Scatterplot (positive predictive
value)
Scatterplot (negative predictive
value)
Scatterplot (accuracy)
Linear regression
Model Summary
Model
1
R
R Square
,500 a
,250
Adjus ted
R Square
,167
Std. Error of
the Es timate
,12943
a. Predictors : (Cons tant), mean of ages of the participants
Coefficientsa
Model
1
(Cons tant)
mean of ages of
the participants
Uns tandardized
Coefficients
B
Std. Error
1,473
,452
-,012
a. Dependent Variable: accuracy
,007
Standardized
Coefficients
Beta
-,500
t
3,261
Sig.
,010
-1,734
,117
Forest plot
Sources of heterogeneity
Forest plot of the OR for the
BNP test.
Forest plot of the OR for the
Nt-proBNP test.
Forest plot
Sensitivity and Specificity of BNP tests
Forest plot of the sensitivity
of BNP test
Forest plot of the specifity of
BNP test
Forest plot
Sensitivity and Specificity of NT-proBNP tests
Forest plot of the sensitivity
of NT-proBNP test
Forest plot of the specifity of
NT-proBNP test
ROC curves
Sensitivity
1
Sensitivity
1
SROC Curve
Symmetric SROC
AUC = 0,8271
SE(AUC) = 0,0491
Q* = 0,7600
SE(Q*) = 0,0446
0,9
0,8
SROC Curve
Symmetric SROC
AUC = 0,5000
SE(AUC) = 0,0000
Q* = 0,5000
SE(Q*) = 0,0000
0,9
0,8
0,7
0,7
0,6
0,6
0,5
0,5
0,4
0,4
0,3
0,3
0,2
0,2
0,1
0,1
0
0
0
0,2
0,4
0,6
0,8
1-specificity
0
0,2
0,4
0,6
0,8
1
1-specificity
ROC curve for BNP
ROC curve for Nt-proBNP
1
Discussion
Study limitations
• Slightly differences between studies’ aim were found;
• Data extraction: some studies didn’t present information necessary
for our statistical analyses;
• The heterogeneity presented by this studies complicated the carry
on of a meta-analysis.
Discussion
Limitations of BNP test
• There is a wide range of cutoffs values;
• There are considerable differences in the specificity and
sensitivity values for the same test.
• Accuracy values vary a lot for the same diagnosis test.
Discussion
Strengths of this review
• This review represents an up-to-date and comprehensive review of
primary research investigating the diagnostic accuracy of the
natriuretic peptides (BNP and NT-proBNP).
• It exposes the problems associated with the conduction of studies
heading the evaluation of the accuracy of BNP test in the diagnosis
of LVD, when trying to synthesize primary research in this area as a
result of clinical and methodological heterogeneity.
• Only high and good quality classified studies were included in our
systematic review.
Differences between the present systematic
review and the review published by Jaime et al
Present review
•
•
•
Jaime et al review
The search was made until
•The search was made from 1966 to 2004.
February 2007.
•Data
Data sources: Pubmed and
central, Medion, Embase
Cochrane central.
•Aim: accuracy of diagnosis of heart failure
Aim: to evaluate the accuracy of
BNP (or Nt-proBNP) test in the
diagnosis of systolic LVD.
•
[24]
sources:
Pubmed;
Cochrane
and explanation of source’s heterogeneity
•Reference standard: cardiac failure or
systolic left ventricular dysfunction and/or
diastolic.
Reference standard: systolic
left ventricular dysfunction.
•Studies using NT – proBNP were not
included.
[24] Jaime et al. Accuracy of B-type natriuretic peptide levels in the diagnosis of left ventricular dysfunction and heart
failure: A systematic review, 2005; Eur J Heart Fail. 2006 Jun;8(4):390-9. Epub 2005 Nov 21.
• Prospective, Transversal
studies and RCT were included.
•Gold standard:
echocardiography.
• Evaluation of methodological
quality: QUADAS tool.
• 23 of 789 articles selected.
• 12082 Patients
•Results-:
•Sources of Heterogeneity- a
wide range of cut-off points;
•Neither BNP nor Nt-proBNP test
are accurate for the diagnosis of
Left Ventricular Dysfunction
•Conclusion: Both the BNP and
Nt-proBNP test are not sufficient
for the discrimination between
patients who suffer from LVD
and those who don’t.
•Only prospective studies were included and no
case-control design.
•No gold standard was used as base of
comparison.
• Evaluation of methodological quality:
QUADAS tool.
• 52 of 272 articles were selected
• 16730 patients
• Results:
•Sources of Heterogeneity- Quality of studies ,
publication bias and reference standardized
•BNP levels were highly accurate for the
diagnosis of clinical heart failure
•The studies focused on the identification of left
ventricular dysfunction were heterogeneous,
with indications of publication bias, and showed
less overall diagnostic accuracy than studies
focused on heart failure.
Conclusion:BNP levels are useful for ruling out
heart failure. The accuracy of BNP for identifying
patients with systolic dysfunction is more limited.
(REM) Likelihood ratio
Type of
peptide
NT-proBNP
BNP
Pooled LR-(CI
95%)
0.283 (0.124 0.643)
0.386 (0.246 –
0.606)
P value of
heterogeneity*
Pooled LR+ (CI 95%)
P value of heterogeneity*
0.000
2.079 (1.250 -3.458)
0.000
0.000
4.143 (1.995 – 8,604)
0.000
•p<0,05- statistically significant
•CI- confidence interval
•REM- random effects model
•LR(-) – Negative Likelihood ratio
•LR (+) – Positive Likelihood ratio
•Negative LR’s were heterogeneous (p<0,05), wish means that
the wide range of cut-off points are a source of heterogeneity to
the evaluation of the accuracy of both BNP and Nt-proBNP test in
the diagnosis of LVD.
Conclusion
•The degree of heterogeneity present in all but a few small sub-groups of
our included studies would mean that both the BNP and the NT-proBNP
test are not good diagnostic tests to the discrimination between patients
with systolic LVD and patients with no systolic LVD, when compared to
echocardiography and radionuclide ventriculography.
•However both BNP and NT-proBNP might be useful in the ruling out of
systolic left ventricular dysfunction.
Gantt Chart
• Gantt chart
The Reviewers
• Leitão, A
•Correia, F
• Moreira, C
•Carvalho, J
• Pontes, J
• Lima, S
• Rodrigues, G
• Afonso, A
•Martinho, C
•Gaspar, R
•Martins, A
•Almendra, R
Acknowledgements
• Doctor Filipa Almeida
• Professor Altamiro da Costa Pereira
• Department of Biostatistic and informatic
(Porto Medical Faculty)