Accuracy of brain natriuretic peptides levels in the diagnosis of

systolic left ventricular dysfunction- a Systematic Review

Introduction to Medicine – 1st yearClass 11 2006-2007

3rd May 2007Porto Medical Faculty

IntroductionIntroduction

• Left ventricular dysfunction.

• Type-B natriuretic peptides.

• Use of type-B natriuretic peptides on diagnosis of 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]

Left ventricular dysfunctionLeft ventricular dysfunction

[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

• 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 dysfunctionLeft ventricular dysfunction

Left ventricular dysfunctionLeft 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 Diagnosing Left Ventricular DysfunctionDysfunction

• 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 Echocardiography and Doppler flow studiesstudies

• 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-raysECG 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 failureBlood 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 PeptidesNatriuretic 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 PeptidesType-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 NT-proBNP 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 PeptidesType-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 Natriuretic Peptides on the Diagnosis of Left Ventricular Diagnosis of Left Ventricular

DysfunctionDysfunction

• The assay that determines the levels of NP consists on a blood test of imunofluorescence that measures the plasmatic levels of BNP or NT-proBNP;

• 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 Natriuretic Peptides on the Diagnosis of Left Ventricular Diagnosis of Left Ventricular

DysfunctionDysfunction

• 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 studyAim of the study

• To evaluate the sensitivity and specificity of

natriuretic peptide levels in the diagnosis of

systolic left ventricular dysfunction.

Pubmed’s new QueryPubmed’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 QueryPubmed’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 CochraneQuery 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

MethodsMethods

• 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

MethodsMethods

• 1st phase – Inclusion of the articlesSelection 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.

MethodsMethods

• 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 FlowchartArticles’ Selection Flowchart

• Flowchart

Kappa’s TestKappa’s Test 23

Descriptive Statistics

6 ,600 ,947 ,77641

6

Concde

Valid N (listwise)

N Minimum Maximum Mean

[23] Harold L. Kundel et al, Measurement of observer agreement, Radiology 2003

Data ExtractionData 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 ExtractionData Extraction

• Table

• Table of correspondence

Articles’ CharacteristicsArticles’ 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

ResultsResultsDescriptive Statistics

23 12082

14 1933

14 3959

21 6383

21 4608

13

number of participants

number of ill participants

number of non-illparticipants

number os femaleparticipants

number of maleparticipants

Valid N (listwise)

N Sum

Descriptive Statistics

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

proportion of patients withdyspnea

proportion of smokers

proportion of patients withhypertension antecedents

proportion of patients withantecedents of ischaemicheart disease

proportion of patients withantecedents of diabetes

Valid N (listwise)

N Minimum Maximum Mean Std. Deviation

ResultsResults

ResultsResults

1 – 50yo or younger

2 – 50-60yo

3 – 60-65yo

4 – 65-70yo

5 – 70yo or older

ResultsResults

ScatterplotsScatterplots ( (sensitivitysensitivity))

Scatterplot (specificity)Scatterplot (specificity)

Scatterplot (positive predictive Scatterplot (positive predictive value)value)

Scatterplot (negative predictive Scatterplot (negative predictive value)value)

Scatterplot (accuracy)Scatterplot (accuracy)

Linear regressionLinear regression

Coefficientsa

1,473 ,452 3,261 ,010

-,012 ,007 -,500 -1,734 ,117

(Constant)

mean of ages ofthe participants

Model1

B Std. Error

UnstandardizedCoefficients

Beta

StandardizedCoefficients

t Sig.

Dependent Variable: accuracya.

Model Summary

,500a ,250 ,167 ,12943Model1

R R SquareAdjustedR Square

Std. Error ofthe Estimate

Predictors: (Constant), mean of ages of the participantsa.

Forest plotForest plot

Sources of heterogeneity

Forest plot of the OR for the BNP test.

Forest plot of the OR for the Nt-proBNP test.

Forest plotForest plot

Sensitivity and Specificity of BNP tests

Forest plot of the sensitivity of BNP test

Forest plot of the specifity of BNP test

Forest plotForest 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 curvesROC curves

ROC curve for BNP ROC curve for Nt-proBNP

Sensitivity SROC Curve

1-specificity0 0,2 0,4 0,6 0,8 1

0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

1

Symmetric SROCAUC = 0,8271SE(AUC) = 0,0491Q* = 0,7600SE(Q*) = 0,0446

Sensitivity SROC Curve

1-specificity0 0,2 0,4 0,6 0,8 1

0

0,1

0,2

0,3

0,4

0,5

0,6

0,7

0,8

0,9

1

Symmetric SROCAUC = 0,5000SE(AUC) = 0,0000Q* = 0,5000SE(Q*) = 0,0000

DiscussionDiscussion

• 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.

Study limitations

DiscussionDiscussion

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.

DiscussionDiscussion

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.

Present review

• The search was made until

February 2007.

• Data sources: Pubmed and

Cochrane central.

• Aim: to evaluate the accuracy of

BNP (or Nt-proBNP) test in the

diagnosis of systolic LVD.

• Reference standard: systolic

left ventricular dysfunction.

Jaime et al review

•The search was made from 1966 to 2004.

•Data sources: Pubmed; Cochrane

central, Medion, Embase

•Aim: accuracy of diagnosis of heart failure

and explanation of source’s heterogeneity

•Reference standard: cardiac failure or

systolic left ventricular dysfunction and/or

diastolic.

•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.

Differences between the present systematic Differences between the present systematic review and the review published by Jaime et alreview and the review published by Jaime et al [24]

• 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(REM) Likelihood ratio

•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.

Type of peptide

Pooled LR-(CI 95%)

P value of heterogeneity*

Pooled LR+ (CI 95%) P value of heterogeneity*

NT-proBNP 0.283 (0.124 - 0.643)

0.000 2.079 (1.250 -3.458) 0.000

BNP 0.386 (0.246 – 0.606)

0.000 4.143 (1.995 – 8,604) 0.000

ConclusionConclusion

•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 ChartGantt Chart

• Gantt chart

The ReviewersThe Reviewers

• Leitão, A

• Moreira, C

• Pontes, J

• Lima, S

• Rodrigues, G

• Afonso, A

•Correia, F

•Carvalho, J

•Martinho, C

•Gaspar, R

•Martins, A

•Almendra, R

AcknowledgementsAcknowledgements

• Doctor Filipa Almeida

• Professor Altamiro da Costa Pereira

• Department of Biostatistic and informatic

(Porto Medical Faculty)