Natriuretische Peptiden bij Diagnose en Monitoring Van Hartfalen

Transcription

1 Natriuretische Peptiden bij Diagnose en Monitoring Van Hartfalen Marc Vanderheyden, Cardiovascular Center,, OLV Ziekenhuis, Aalst, BE Cardiovascular Center, Aalst, Belgium VAKB Leuven, 5 juni-2007

2 Objectives Diagnosis of Congestive Heart Failure (CHF) Review the basic biology of brain natriuretic peptides Identify the area of Peptide testing utility for B-type Natriuretic Discuss further direction for B-type Natriuretic Peptide use

3 Diagnosis of CHF Still Very Difficult Symptoms and signs like shortness of breath and edema have a broad differential diagnosis Physical exam is neither sensitive nor specific for CHF and, even in good hands, there are often errors One third of patients with CHF have normal pumping function of the heart

4 Assessment of CHF Different ejection fraction, but both have CHF LV-EF = 65 % LV-EF = 15 %

5 Assessment of CHF No gold standard for the evaluation of CHF exists History Physical Examination Lab Evaluation

6 Heart Failure : Assessment Predictive Value of Clinical Features Sens Spec PPV NPV Past history of myocardial infarction Ingesting diuretic Dyspnoea on exertion Orthopnoea Paroxysmal nocturnal dyspnoea Oedema in history Jugular venous pressure distension Crackles Gallop rhythm Oedema on examination Davie AP et al QJM 1997;90:335-9

7 Diagnosis of CHF Still Very Difficult (cont d) A single blood test that differentiates a patient with heart failure from a patient without heart failure would be not only very helpful but also cost-effective

8 Objectives Diagnosis of Congestive Heart Failure (CHF) Review the basic biology of brain natriuretic peptides Identify the area of Peptide testing utility for B-type Natriuretic Discuss further direction for B-type Natriuretic Peptide use

9 Natriuretic Peptides: The Heart as a Secretory Organ Secretory granules found on EM of atria. Kisch, Exp Med Surg 1956 Balloon catheter in atria of dogs resulted in diuresis: Henry and Pearce, J Exp Phys 1956 Homogenized atrium injected IV causes natriuresis, diuresis. DeBold, Life Sciences, 1981 ANP identified in Kangawa BNP identified in 1988 in porcine brain. Nature, 1988 Amino acid sequence and DNA clones: Sudoh et al, 1988 and Seilhamer et al, 1989

10 y Arg y Ser y Arg Natriuretic Peptides: The Heart as a Secretory Organ H2N- Ser Pro Lys Met Met Asp BNP Val Gin Gly Ser Arg IIe Gly Phe Arg Lys Met Asp Gly Cys Gly Ala Gin Arg IIe S S Val Arg Ser Cys Lys Gly Ser Leu Leu Gly Ser Ser Arg HOOC- His Met Asp Arg IIe Gly H2N- Gly CNP 17 AA ring structure with 11 identical AA Leu Leu Lys Leu Gly disulfide bridgeser Asp Phe Ring structure islys essential for receptor binding Gly Cys S S Arg IIe

11 Comparing Natriuretic Peptides Features ANP BNP CNP Urodilatin Aminoacids or = ANP + 4 Main Source cardiac cardiac vascular kidney atrium ventricle endothelium Hormone type endocrine endocrine autocrine paracrine paracrine cardiac specific Main function Regulation of homeostasis of salt and H2O excretion (natriuretic, vasodilation, renin and aldosterone inhibitory properties Regulation of vascular tone Regulation of H2O and sodium reabsorption in collecting ducts

12 B-type Natriuretic Peptides Pre-Pro-BNP aa signal sequence Pro-BNP _ Wall stress N-terminal probnp 1-76 t 1/2 = 120 min BNP t 1/2 = 20 min

13 GC= Guanylate Cyclase Mode of Action andclearance Pathways GC-A Vascular Smooth Muscle Cell GTP G/C BNP GC-B G/C cgmp? Biological Effects NP-C NP=neutral endopeptidase Clearance receptor Nakao et al Can J Physiol Pharmacol, 1991, 69: clearance pathway

14 Physiology of Natriuretic Peptides + Cardiac Wall Stress - Neutral Endopeptidases Clearance CNP ANP+BNP NPR-A/NPR-B Urodilatin NPR-B?NPR-D NPR-C Decreased Vascular Growth Decreased Blood Pressure Increased Na/H 2 0 Excretion Adapted from Wilkins MR. Redondo J. Brown LA. Lancet 1997;349:

15 Objectives Diagnosis of Congestive Heart Failure (CHF) Review the basic biology of brain natriuretic peptides Identify the area of utility for B-type Natriuretic Peptide testing Discuss further direction for B-type Natriuretic Peptide use

16 B-type Natriuretic Peptide and Acute Patient Evaluation The ProBNP Investigation of Dyspnea in the Emergency Department (PRIDE) Study

17 PRIDE Trial Objectives To prospectively determine the role of NT-proBNP testing for the urgent evaluation of dyspnoeic patients in the Emergency Department Examine what NT-proBNP testing adds to standard clinical assessment To identify optimal cut-points for ruling out acute CHF Determine the costs (and potential cost-savings) from NT-proBNP testing

18 PRIDE Trial Study Procedures 600 dyspneic patients enrolled Following enrollment baseline clinical characteristics, results of history and physical as well as the results of standard diagnostic studies were collected The managing ED physician was asked to provide a clinical diagnosis as well as an estimate (from %) for the likelihood of acute CHF

19 PRIDE Trial Final Diagnoses Nr of Subjects Acute CHF COPD or asthma other pneumonia ACS Pulmonary Embolism 10 Acute Bronchitis Januzzi et al AJC 2005

20 PRIDE Trial Results: Nt-proBNP Levels Nt-proBNP (pg/ml) p < No prior CHF (n=355) 1175 Prior CHF (n=35) 4054 Acute CHF (n=209) Not acute CHF Januzzi et al AJC 2005

21 PRIDE Trial Nt-proBNP levels and Symptoms p < Nt-proBNP (pg/ml) class II(n=17) Class III(n=80) Class IV(n=12) NYHA functional class Januzzi et al AJC 2005

22 PRIDE Trial Results: Predictors of CHF Predictor Odds ratio 95 % Confidence interval p-value Elevated Nt-proBNP < Interstitial edema on chest X-ray < Orthopnea < Loop diuretics use at presentation Rales on pulmonary exam Age (per year) Cough Fever Januzzi et al AJC 2005

23 PRIDE Trial Results: Clinical Judgement nr of Patients % Likelihood for CHF

24 PRIDE Trial Results: Clinical Judgement nr of Patients Nt-proBNP Performance 0-25 % Certainty Sensitivity: 95 % Specificity: 85 % % Likelihood for CHF

25 PRIDE Trial Results: Clinical Judgement nr of Patients Nt-proBNP Performance % Certainty Sensitivity: 92 % Specificity: 84 % % Likelihood for CHF

26 PRIDE Trial Results: Clinical Judgement nr of Patients Nt-proBNP Performance > 75 % Certainty Sensitivity: 91 % Specificity: 83 % % Likelihood for CHF

27 PRIDE Trial Results: Primary Endpoint NT-proBNP vs clinical judgement, p =0.006 Combined vs NT-proBNP, p = 0.04 Combined vs Clinical Judgement, p < 0.001, AUC = 0.96, AUC = 0.94, AUC = 0.90

28 Clarification of Diagnosis and BNP Indecision (%) % Clinical Evaluation McCullough et al., Circulation 2002; 104:416 BNP reduces clinical indecision by 74 % 11 % Clinical Evaluation and BNP

29 Diagnostic Utility of NT-proBNP Testing Cut points

30 How Do You Want to Use Your Natriuretic Peptide Test? Rule out (d-dimer) Values below cut-off suggest disease is unlikely Values above the cut-off DO NOT NECESSARILY MEAN THE DISEASE IS PRESENT Rule in (troponin) Values above the cut-off suggest disease is likely

31 How Do You Want to Use Your Natriuretic Peptide Test? Cut-off Diagnosis Assessment Rule in (high cut-off high specificity) Clinically relevant heart failure likely > cut-off rule-out and < cut-off rule in Clinically relevant heart failure possible Patient at risk, other causes? Rule out (low cut-off high sensitivity) Heart failure unlikely Symptoms not of cardiac origin Confounding factors: gender; age, diuretics, other cardiac causes ( afib; diastolic HF;valve diseases) thyroid function; renal function;

32 Rule out cut-points Non-emergency pts Manufacturer recommended 125/450 pg/ml cut points (non acute setting) 125 pg/ml for patients < 75 years 99.7 % sensitive 51.7 % specific 99.6 % NPV 450 pg/ml for patients 75 years 99.0 % sensitive 33.0 % specific 89.7 % NPV

33 Optimal NT-proBNP Cut-points Emergency pts International NT-proBNP Collaboration data (acute setting) 300 pg/ml, age independent 99 % sensitive 60.0 % specific 99.0 % NPV

34 Optimal Nt-proBNP Cut-points Emergency Department Rule in Age Strata Optimal Cut-point Sensitivity Specificity PPV NPV Accuracy All < 50 years (n= 183) 450 pg/ml All years (n = 554) 900 pg/ml All > 75 years (n = 519 ) 1800 pg/ml Overall Average Rule out Optimal Cut-point Sensitivity Specificity PPV NPV Accuracy Rule out 300 pg/ml Note the cut-points are for ACUTE CHF DIAGNOSIS ONLY Januzi et al

35 Clinically Validated Algorithms Already Embedded in Clinical Practice Patient presenting with dyspnea Physical examination, chest X-ray, ECG, BNP level BNP < 100 pg/ml BNP pg/ml BNP >400 pg/ml CHF very unlikely (<10%) Grey zone-dry bnp,atrial fib,valve disease RV dysfunction, CHF very likely (>90%) Yes Possible exacerbation of CHF (25%) No CHF likely (75%) Maisel A. Reviews in Cardiovascular Medicine. 2002;3(4):S13.

36 The Costs of BNP Testing The PRIDE Economic analysis

37 Cost* of Heart Failure to Society $ 22,2 billion Hospital/nursing home Home health/other medical durables Indirect Costs Healthcare providers drugs * Direct and indirect costs in billion of $; estimated for year 2000 AHA 2000 Heart and Stroke Statistical Update

38 Effect of BNP Guided Treatment on Time to Discharge in Acute CHF Mueller et al NEJM 2004

39 PRIDE Study Economic Analysis $ 3,779 $ $ $ $ $ $ $ $ $ $ $ Standard Overall, $ /patient saved (14 %) Extended to the total study: $ 300, $ 3,289 Nt-proBNP Siebert, Januzzi, Beinfield, Cameron and Gazelle, 2005

40 PRIDE Study Economic Analysis Co-primary endpoint 2.5 % reduction of MAEs (urgent MD visits, ED presentations, and hospitalizations) 1.2 % reduction in 60-day mortality Secondary endpoints 13 % reduction of initial hospitalizations after ED 12 % reduction of overall length of hospital stay 58 % reduction of unnecessary echocardiograms performed

41 Optimizing Natriuretic Peptide Use in Acute Dyspnea Not everything with a high natriuretic peptide level is CHF

42 Wet versus Optivolemic BNP level: Definition Wet BNP level Any BNP level 25-50% over what the patients optivolemic BNP level is If patient comes to ER, often >600 pg/ml Falls rapidly with treatment Optivolemic BNP level BNP level once optimum fluid status is reached Correlated with functional class and prognosis May be 20-2,000 pg/mldepending on severity of disease Falls slowly with treatment

43 Non-CHF Causes of Elevated B-type Natriuretic Peptide Levels Dyspnea in patients with prior CHF Structural heart disease Acute coronary syndromes RV strain Critical illness Renal failure Gender Age False positive BNP Grey Zone : pg/ml

44 Combination of Nt-proBNP and Troponin T identifies a very high risk group T. Jernberg et al. Circulation Death (%) > 0.01 ug/l < 0.01 ug/l Troponin T < NT-proBNP (pg/ml) > 1653 During ischemia, release of NP s independent of LV dysfunction Pts with ischemia and high BNP are at higher risk

45 What causes False Negative B-type Natriuretic Peptides? It happens sometimes without any explanation CHF from causes upstream to the LV Right heart failure Mild CHF (Non-systolic CHF) Flash pulmonary edema Obesity BMI > 35 BNP x 2

46 Natriuretic Peptides: Future directions Acute Patient Evaluation Estimation of Prognosis Apparently normal subjects At risk for CHF Established Chronic heart Failure Acute CHF Monitoring and Guiding of CHF therapy

47 Predischarge BNP and 6 months risk of rehosp or death after decompensated heart failure Logeart D et al. JACC 2004

48 BNP Values (pg/ml) Acute Heart Failure-BNP levels and risk stratification from the ED to discharge <1,500 ABOVE 600 pg/ml PATIENT IS CONSIDERED STILL AT HIGH RISK pg/ml CONSIDER BNP IN THE CONTEXT OF CLINICAL SYMPTOMS 400/pg/ml UNDER 250 PATIENT IS AT LOW RISK AND MAY BE DISCHARGED SAFELY UNDER 100 HEART FAILURE UNLIKELY CAUSE OF SOB ED ADMISSION INPATIENT DISCHARGE ARRIVAL (Tiime)

49 BNP Guided Therapy? Event free (%) Cardiovascular events NT-proBNP Clinical 100 Heart failure or death NT-proBNP Clinical P = P = Time after randomisation (days) Time after randomisation (days) Troughton RW, Lancet 2000

50 Algorithms for BNP Outpatient Management Outpatient Clinic Telemedicine

51 Conclusion Indicates raised intracardiac pressure Something abnormal with cardiac function May be helpful for diagnosing dyspnea related to Acute HF RULE OUT HF: Good way to exclude Heart Failure Nt-proBNP < 300 pg/ml = No Heart Failure, so no need for Echo BNP < 100 pg/ml RULE IN HF: Age < 50 years: 450 pg/ml BNP > 400 pg/ml Age years: 900 pg/ml Age > 75 years: 1800 pg/ml BNP: cost saving and cost effective Important potential roles: LV dysfunction screening, guiding heart failure therapies, determining prognosis MORE WORK REQUIRED

52 Ten Key Messages for the Clinician 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 saving out to 6 months BNP is the most powerful predictor of outcome in heart failure BNP 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

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54 ALGORITHM FOR USE OF BNP TESTING IN A PRIMARY CARE SETTING IN PATIENTS WITH NO KNOWN HISTORY OF CHF Patient presents with signs and/ or symptoms of CHF. These include: -Shortness of breath, edema, fatigue, JVD, dyspnea on exertion, paroxysmal nocturnal dyspnea, unexplained weight gain, auscultatory rales or crackles Patients with hypertension, CAD, previous MI, obesity, and diabetes are at increased risk for development of HF. These risk factors should heighten suspicion for possible CHF. - Obtain Patient History - Perform Physical Examination - Perform EKG - Order BNP test - Order Chest X-Ray - Order standard laboratory testing studies Interpret BNP Patient is asymptomatic Patient is symptomatic If BNP < 20 Symptoms are not likely due to CHF If BNP 20 Consider MI, pulmonary embolism and pneumonia. If no suspicion of immediate life threatening disease, then If BNP < 40 Symptoms are not likely due to CHF BNP 40 and <400 Consider MI, pulmonary embolism and pneumonia. If no suspicion of immediate lifethreatening disease, then BNP 400 CHF is very likely Consider other etiologies for patient presentation Echocardiography; consider referral to a cardiologist for further work-up to screen for early LV dysfunction Consider other etiologies for patient presentation Echocardiography and strongly consider referral to a cardiologist for further work-up to screen for early LV dysfunction Consider referral to the ED or hospital admission References: Epsheteyn, V, Morrison, K, et. al. Utility of B-Type Natriuretic Peptide (BNP) as a Screen for Left Ventricular Dysfunction in Patients with Diabetes, Diabetes Care, Vol. 26, N. 7, July, Heidenreich, P, Gubens, M, et. al. Cost Effectiveness of Screening with B-Type Natriuretic Peptide to Identify Patients with Reduced Left Ventricular Ejection Fraction, Journal of the American College of Cardiology, Vol. 43, N. 6, March 17, Wang, T, Larson M, et. al. Plasma Natriuretic Peptide Levels and the Risk of Cardiovascular Events and Death, The New England Journal of Medicine, Vol. 350, N. 7, February 12, 2004.