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Peter W Auld FRCPath Consultant Biochemist Department of Clinical Biochemistry RVH

ProBNP-Derived Peptides. A blood test to aid Heart failure diagnosis and the detection of mild cardiac dysfunction. Peter W Auld FRCPath Consultant Biochemist Department of Clinical Biochemistry RVH. January 2008. The Heart is an Endocrine Gland !.

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Peter W Auld FRCPath Consultant Biochemist Department of Clinical Biochemistry RVH

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  1. ProBNP-Derived Peptides A blood test to aid Heart failure diagnosis and the detection of mild cardiac dysfunction Peter W Auld FRCPath Consultant Biochemist Department of Clinical Biochemistry RVH January 2008

  2. The Heart is an Endocrine Gland! • 1963: “endocrine gland type” secretory granules seen in cardiac myocytes. • 1983: Factor inducing natriuresis, diuresis and lower BP identified in atrial tissue – ANF now ANP • 1988: Closely related peptide extracted from porcine brain - BNP

  3. The Natriuretic Peptides

  4. ProBNP Derived Peptides & Commercial Assays NT-proBNP:Roche Diagnostics Dade Behing BNP:Abbott Diagnostics Biosite Beckman Coulter Bayer

  5. Naturetic Peptide • Measurement of NT-Pro BNP on a simple blood sample is useful in the first line investigation of patients presenting with new symptoms suggestive of heart failure. • The result may rule out HF with a high degree of certainty, suggest that HF is not the major cause of the patients presentation or indicate the need for referral for further investigation. • May also be useful in assessment of the severity of HF, in the risk stratification of ACS and CHF and monitoring treatment in patients with LVD.

  6. Mechanisms of ProBNP Expression Ventricular dysfunction Reduced coronary blood flow Myocyte Stretch Myocardial Hypoxia BNP mRNA transcription Rapid ventricular ProBNP Circulating BNP and NT-ProBNP Goetze JP Scand J Clin Lab Invest 2004; 64: 497-510

  7. Actions of Natriuretic Peptides NPs RAAS / SNS • Natriuresis • Diuresis • Vasodilation • Inhibition of growth • Salt retention • Fluid retention • Vasoconstricton • Myocyte Growth NB. Natricor or Nesiritide for acute decompensation Adapted from Burnett JC, J Hypertens 1999;17(Suppl 1):S37-S43

  8. Diagnosis of Heart Failure • Clinical signs and symptoms are limited & non specific • Even experienced Physicians will disagree • < 50% of diagnoses made in Primary Care are confirmed on more detailed assessment. • Many patients with LVD/HF go unrecognised and receive no adequate treatment. • Patients my be treated with costly drugs unnecessarily • Objective confirmation requires ECHO cardiography • Timely intervention can increase quality of life and prognosis♥

  9. Diagnosis of Heart Failure • National Institute of Clinical Excellence (NICE) and European Society of Cardiology have recommended the use of proBNP derived Natriuretic peptides as a “rule-out” test for patients with new symptoms. • Locally CREST (clinical resource efficiency support team) “A normal 12 lead ECG and BNP virtually excludes CHF and alternative causes for symptoms should be considered”. • Cowie MR, Heart 2004,90, 725. & Guidelines on the Management of Chronic Heart failure in Northern Ireland, CREST 2005

  10. Investigative Strategy: Suspect Heart Failure . NORMAL Heart Failure Unlikely ECG, CXR, Natriuretic Peptides Abnormal NORMAL Heart Failure Unlikely ECHO Cardiography Abnormal Assess Aetiology Therapy ESC Guidelines, Eur Heart J 2001; 22: 1527-60

  11. Test Principle: • Roche Modular E170 analyser • “Sandwich assay” taking 18 mins • 1st incubation 20 ul sample + biotinylated polyclonal NT-proBNP specific antibody and anti NT-proBNP antibody Ruthenium label. • 2nd incubation binding to streptavidin coated microparticles • Magnetic capture of the bound complex and wash of unbound substances • Electrode induces chemiluminescence emission which is read by a photomultiplier. • Assay is calibrated using a 2 point calibrator and master curve (units pg/mL) Note: when evaluating data in the literature note assay characteristics and units may not be transferable

  12. SPECIMEN COLLECTION AND PREPARATION • Serum collected using standard “Gold top” gel tube • Lithium or NH4 heparin • KEDTA (#values ~10% lower) • Stable for 3 days @ 20-25o C • Stable for 6 days @ 2-8o C • 12 months @ -20o C Analytical Range 5-35 pg/mL

  13. Expected Values in Health

  14. Interpretation: • Values <125 ng/L exclude cardiac dysfunction with a high degree of certainty in patients with symptoms suggestive of heart failure. • Modest elevations above the age/sex reference range may indicate cardiac dysfunction. • Significant elevations are only seen in acute/chronic heart failure and correlate with severity/prognosis.

  15. Reference Values for NT-proBNP Roche Diagnostics 2007

  16. BNP & NT-ProBNP Reflect Heart Failure Severity McCullough el al Reviews in Cardiovascular Medicine2003 4 (2) 72-80

  17. Cut-off Values • Decision Threshold of 125 ng/L has a sensitivity of 88% and specificity of 92% ie a NPV of 97% and PPV of 80% for HF. • Decision threshold of 300 ng/L has a sensitivity of 99% and specifity of 60% ie a NPV of 98% and PPV 77% patients presenting with acute dyspnoea in A&E.

  18. Proforma for NT pro-BNP Requesting • PID • Relevant PMH • Alternative Causes • Symptoms / signs • ECG • Current medication • Comment (how will result influence your current management?) Designed to manage demand for the test and audit test use.

  19. Summary of results • Rule Out (<125) n = 246 (24%) • <reference value n = 447 (43%) • >reference value n = 708 (57%) • Markedly raised n = 421 (43%) • Total n = 1045

  20. MI CVA HT DM IHD Valve Disease Other (cardiomyopathy, raised lipids, Kawasaki) Past Medical History n = 806 (77%)

  21. Alternative Cause(s) • COPD 20% • Overweight 21% • Anaemia 6% • Obesity 8% • Respiratory 5% • Other 9% n = 680 (65%)

  22. Symptoms / Signs • Ankle Oedema • JVP • DOE • Fatigue • Chest Crackles • Orthopnoea • PND n = 977 (93%)

  23. ECG • Total recorded n = 547 (52%) • Abnormality n= 337 (62%) • No Abnormality n = 192 (35%)

  24. Medication • ACE/AIIRB • Beta Blocker • Digoxin • Diuretic • Other n = 855 (82%)

  25. Comment: • Diagnosis n = 302 (29%) • Treatment n = 229 (22%) • ECHO Referral n = 218 (21%) • Not Specified n= 191 (18%) • ?SOB/COPD n = 48 (16%) • Prognosis n = 93 (9 %) • Monitoring n = 68 (7%) • Other n = 49 (5%) n = 854 (82%)

  26. Audit of Primary Care Requesting Jan – Sept ’07(n = 699) • Practices Requesting 125/147 (85%) • GPs Requesting 201/449 (45%) • %<125 224 (32%) • %>1000 179 (25%) • %>2000 114 (16%) Uptake increased 165% in 9 months Form return rate 40%

  27. Conclusions: • Useful test • Requested appropriately • Uptake has now reached predicted levels • Contribution to optimised use of resources.

  28. Thank you !

  29. Average length of hospital admission by main diagnosis, National Health Service hospitals, 2000/01, England Hospital Episode Statistics (2001)

  30. Changes in patient management associated with BNP % reduction 60% 44% 76% 38% THE IMPACT OF INTRODUCING AN NT-proBNP SERVICE INTO CLINICAL PRACTICE S Knowles, S Burn, M Cassidy, P Wood, J Mayne, D Docherty, J S Harrop. Depts of Chemical Pathology and Cardiology, Derbyshire Royal Infirmary. Poster

  31. All patients - ability to predict EF <40% NTpBNP AUC 0.913 Collinson et al EJHF 2004; 6:365-8

  32. Clinical Utility of ProBNP derived Peptides • Screening for LVD • Prognosis / Risk stratification • Treatment Monitoring • Differential Diagnosis of Heart Failure

  33. The Diagnostic Accuracy of plasma BNP and NTproBNP in patients referred from primary care with suspected Heart Failure: Results of the UK Natriuretic peptide Study • Study reflected routine every day practice • Both peptides demonstrated favourable diagnostic utility as a “rule out” test for patients presenting with new symptoms suggestive of HF • Supports recommendations of NICE & ESC (& CREST !) • A high level does not confirm a diagnosis nor does it provide specific information about any underlying cardiac abnormality-further cardiological investigation is appropriate. Zaphiriou et al E J Heart 2005

  34. ProBNP-Derived Peptides Heart Failure Workshops For GPs, & practice nurses 7th and 8th June 2006 Introducing a new blood test for Heart failure diagnosis Peter W Auld MRCPath Consultant Biochemist Department of Clinical Biochemistry Belfast Link Laboratories RVH

  35. Uptake and Clinical Utility of the Test in Primary Care: The Story so far… • 33% of practices have requested one or more BNP tests (on average the typical practice would see 2.5 new patients /1000 patients/yr). • Using the 125 nmol/L general cut-off 34% of these patients had a result that ruled out HF as a cause of new symptoms. • Using the age/sex related reference values 74% of patients with normal renal function had a result making it unlikely that HF is a significant factor in their presentation.

  36. Cont. • 26% of patients had levels which were unequivocally raised indicating the presence of cardiac impairment requiring further investigation (echocardiography) to establish the aetiology. • In summary, measurement of NTpro-BNP on a simple blood sample is a useful part first line investigation of patients presenting with new symptoms suggesting HF.

  37. New Primary Care Blood Test for Heart Failure in EHSSB

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