Introduction to Medicine – 1st year Class 11 2006-2007 3rd May 2007 Porto Medical Faculty

1. Accuracy of brain natriuretic peptides levels in the diagnosis of systolic left ventricular dysfunction- a Systematic Review Introduction to Medicine – 1st year Class 11 2006-2007 3rd May 2007 Porto Medical Faculty

2. Introduction • Left ventricular dysfunction. • Type-B natriuretic peptides. • Use of type-B natriuretic peptides on diagnosis of left ventricular dysfunction.

3. 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

4. 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

5. 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.

6. 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

7. 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

8. 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

9. 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

10. 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

11. 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 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

12. 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

13. 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 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.

14. 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

15. Aim of the study • To evaluate the sensitivity and specificity of natriuretic peptide levels in the diagnosis of systolic left ventricular dysfunction.

16. 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])

17. 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

18. 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

19. 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

20. 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.

21. 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.

22. Articles’ Selection Flowchart • Flowchart

23. Kappa’s Test23 [23] Harold L. Kundel et al, Measurement of observer agreement, Radiology 2003

24. 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

25. Data Extraction • Table • Table of correspondence

26. 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

27. Results

28. Results

29. Results 1 – 50yo or younger 2 – 50-60yo 3 – 60-65yo 4 – 65-70yo 5 – 70yo or older

30. Results

31. Scatterplots (sensitivity)

32. Scatterplot (specificity)

33. Scatterplot (positive predictive value)

34. Scatterplot (negative predictive value)

35. Scatterplot (accuracy)

36. Linear regression

37. Forest plot Sources of heterogeneity Forest plot of the OR for the Nt-proBNP test. Forest plot of the OR for the BNP test.

38. Forest plot Sensitivity and Specificity of BNP tests Forest plot of the specifity of BNP test Forest plot of the sensitivity of BNP test

39. Forest plot Sensitivity and Specificity of NT-proBNP tests Forest plot of the specifity of NT-proBNP test Forest plot of the sensitivity of NT-proBNP test

40. ROC curves ROC curve for BNP ROC curve for Nt-proBNP

41. Discussion • 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

42. 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.

43. 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.

44. Differences between the present systematic review and the review published by Jaime et al[24] • 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. 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. [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.

45. 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.

46. (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.

47. 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.

48. Gantt Chart • Gantt chart

49. The 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

50. Acknowledgements • Doctor Filipa Almeida • Professor Altamiro da Costa Pereira • Department of Biostatistic and informatic (Porto Medical Faculty)