Péptidos natriuréticos y derrame pleural José Manuel Porcel Grupo de Enfermedades de la Pleura IRBLLEIDA 19 septiembre 2007

Objetivos Reconocer las limitaciones existentes para diagnosticar la insuficiencia cardiaca (IC) Discutir el papel del BNP en el diagnóstico de la IC Valorar una aplicación adicional del BNP: diagnóstico de los derrames pleurales de causa cardiaca

Diagnóstico de la IC: un reto clínico Los síntomas y signos de IC, como disnea y edemas, tienen un amplio diagnóstico diferencial El examen físico no es ni sensible ni específico El ECG ofrece datos inespecíficos La radiografía de tórax tiene una eficacia limitada Cerca de la mitad de los pacientes tienen una función sistólica conservada Slide 11 The diagnosis of HF is a difficult one to make. Shortness of breath is a symptom associated with many disease states; physical examination is neither sensitive nor specific for CHF. One-third to one-half of patients with CHF have normal pumping function of the heart. Echocardiograms are useful for diagnosis of HF, and provide information to aid in estimating the ejection fraction. The procedure serves as an expensive means to rule in or rule out patients for HF. Echocardiograms are not always available, and require sophisticated technicians and interpretation. Maisel A et al. J Am Coll Cardiol. 2001;37:379-385.

Utilidad de la historia clínica y la exploración física en el diagnóstico de IC 250 pacientes con disnea (97 con IC) Dao Q et al. J Am Coll Cardiol 2001

Radiografía de tórax en la IC

Características operativas de la Rx de tórax en el diagnóstico de IC Variable Sensibilidad Especificidad LR+ Cardiomegalia 79% 80% 3,98 Cefalización 41% 96% 9,41 Edema intersticial 27% 98% 12,67 Edema alveolar 6% 99% 7 Derrame pleural 25% 92% 3,3 880 pacientes con disnea aguda (447 IC; 433 sin IC) Knudsen et al. Am J Med 2004;116:363-8

Ecocardiograma en la IC Un ecocardiograma normal excluye la IC Prueba de no fácil acceso Limitación de la prueba en obesos, EPOC

Péptidos natriuréticos Listed here are the three common natriuretic peptides. Structurally, the natriuretic peptides are similar. All have a 17 AA ring structure with 11 identical AA. This ring structure is essential for receptor binding (Guanylate cyclase linked receptor). The first natriuretic peptide that was identified in the late 1960s was the Atrial Natriuretic Peptide , a 28-amino acid hormone found predominantly in the atrium of the heart. ANP is increased in volume overload conditions in normal patients, as well as patients with CHF. The B-type, or formerly called Brain Natriuretic Peptide, has been found to be a more useful marker for congestive heart failure because the hormone is elevated in patients with congestive heart failure. BNP is secreted from the ventricles of the heart in response to ventricular stretch and volume overload. BNP has been synthesized and developed as a therapeutic tool for use in congestive heart failure. The C-type natriuretic peptide is found in the endothelium of the heart, has a very low concentration in plasma, and is not elevated in CHF. Other members of the natriuretic peptide family such as Urodilatin are still being identified and characterized. This family of hormonally active peptides clearly has a regulatory role in cardiovascular disease. The Triage® BNP Test is indicated for use as an aid in the diagnosis of congestive heart failure.

Natriuretic Peptides: Origin and Stimulus of Release Peptide Primary Origin Stimulus of Release ANP Cardiac atria Atrial distension BNP Ventricular myocardium Ventricular overload CNP Endothelium Endothelial stress This slide lists the origin and stimulus for the release of the natriuretic peptides. Note that BNP is specifically released from the ventricles of the heart in response to ventricular stretch and volume overload. The Triage® BNP Test is indicated for use as an aid in the diagnosis of congestive heart failure.

ventricular wall tension or stretch preproBNP (134 aa) Ventricular myocyte proBNP (108 aa) Signal peptide (26 aa) secretion Natriuresis/Diuresis Vasodilatation RAAS sympathetic tone NT-proBNP (1-76) BNP (77-108)

Utilidad de la medición de los péptidos natriuréticos Diagnóstico de la disnea de causa cardiaca Identificación de disfunción ventricular asintomática en poblaciones de alto riesgo Monitorizar la eficacia del tratamiento de la IC Estimar el pronóstico en pacientes con IC o SCA

BNP para diagnosticar IC en Urgencias 250 pacientes con disnea P<0.001 1400 1076 ± 138 1200 1000 800 Mean BNP Concentration (pg/mL) 600 400 141 ± 31 200 Slide 14 A study was conducted to assess the utility of a rapid bedside technique for measurement of B-type natriuretic peptide (BNP) in the diagnosis of CHF in an urgent care setting. BNP levels were measured in patients with acutely decompensated CHF and compared to patients without heart failure or with chronic left ventricular dysfunction. Patients with CHF have a higher level of BNP. Chronic heart failure can be diagnosed in asymptomatic patients by measuring plasma BNP levels. Generally, levels above 80 pg/mL are very sensitive and specific for the diagnosis of chronic heart failure. During acute exacerbations of heart failure, plasma BNP levels are further elevated. BNP levels can now be accurately measured with a point of a care test system manufactured by Biosite Diagnostics. In the multivariate analysis, the combined explanatory power of history, symptoms, signs, radiological studies and lab findings was evaluated. Additions of BNP levels to the regression substantially increased the explanatory power of the model, suggesting that BNP measurements provided meaningful diagnostic information not available from other clinical variables. 38 ± 4 Asymptomatic LV Dysfunction (n=14) No CHF (n=139) CHF (n=97) Dao Q, Maisel A, et al. J. Am Coll Cardiol 2001;37:379-385.

BNP en pacientes con disnea secundaria a IC o EPOC 1200 1076 +/- 138 1000 800 BNP (pg/mL) 600 400 200 86 +/- 39 The ability to differentiate dyspnea due to COPD vs. CHF is a major diagnostic dilemma in the E.D. The rapid whole blood assay provides a strong indication of symptom origin. Patients who presented with dyspnea from pulmonary origin without cardiac involvement had normal BNP levels in the blood, whereas patients with dyspnea as a symptom of congestive heart failure had markedly elevated BNP levels. COPD n=56 CHF n=97 Cause of Dyspnea Dao Q, Maisel A, et al. J. Am Coll Cardiol 2001;37:379-385. The Triage® BNP Test is indicated for use as an aid in the diagnosis of congestive heart failure.

BNP para diferenciar IC de enfermedades pulmonares 1000 758 900 800 700 600 BNP (pg/mL) 500 400 207 300 54 27 44 55 200 100 Slide 15 B-type natriuretic peptide (BNP) is elevated in HF. In this study, three tertiles exhibited a relative increase in BNP levels with increased severity of heart failure. An increase in BNP level in heart failure is a physiologic response to this condition. CHF COPD Asthma Acute Bronch Pneumonia PE Cause of Dyspnea (N=321) Morrison LK et al. J Am Coll Cardiol. 2002;39:202-209.

El BNP es útil para el diagnóstico de la insuficiencia cardiaca 675 110 346 Breathing Not Properly study (1586 pacientes con disnea) Maisel et al. N Engl J Med 2002;347:161-7

Maisel et al. N Engl J Med 2002;347:161-7 Eficacia comparativa entre BNP y criterios de Framingham y NHANES para diagnosticar IC Maisel et al. N Engl J Med 2002;347:161-7

Maisel et al. N Engl J Med 2002;347:161-7

BNP y disfunción ventricular 1200 1077+/-272 1000 800 567+/-113 BNP (pg/mL) 600 391+/-89 400 200 30 Patients with the highest BNP values were found to have systolic and diastolic dysfunction. Patients who were shown to be normal on echo also had a normal BNP value. One area of interest is the utility of BNP in the diagnosis of diastolic dysfunction. Diastolic congestive heart failure represents approximately 20% of all CHF, yet the majority of these patients are missed by the healthcare system. Diastolic dysfunction is difficult to diagnose on echocardiogram; however, BNP levels are abnormally elevated here, illustrating the value of BNP in identifying patients with diastolic dysfunction. Normal n=105 Systolic n=53 Diastolic n=42 Systolic & Diastolic n=14 200 patients referred for echocardiography to evaluate LV dysfunction. Maisel A, De Maria A, et al. Am Heart J 2001;141:367-374. The Triage® BNP Test is indicated for use as an aid in the diagnosis of congestive heart failure.

Heart Failure Diagnostic Algorithm Patient presenting with dyspnea Physical examination, chest x-ray, ECG, BNP level BNP <100 pg/mL BNP 100-500 pg/mL BNP > 500 pg/mL CHF very unlikely (2%) Baseline LV dysfunction, underlying cor pulmonale or acute pulmonary embolism? CHF very likely (95%) Yes No Possible exacerbation of CHF (25%) CHF likely (75%) European Society of Cardiology, 2003

Triage BNP® (Biosite Inc.)

BNP vs NT-proBNP NT-proBNP BNP Measuring range 5-35,000 pg/mL Total imprecision (coefficient of variation) 2.2-5.8% 10-16% Common sample types Serum, EDTA or heparinized plasma Whole blood, EDTA plasma Sample volume 20 μL 150 μL Throughput (test/hr) 50-170 4 Available at the point of care No Yes Increase with normal aging and renal failure ++ + Approved blood cutoff for HF diagnosis Age < 75 years: 125 pg/mL Age ≥ 75 years: 450 pg/mL 100 pg/mL

Correlación entre BNP y NT-BNP

¿Se puede aplicar el BNP al diagnóstico del derrame pleural?

¿Es el DP un trasudado o un exudado? Toracentesis Trasudado Exudado Causas limitadas: Insuficiencia cardiaca Cirrosis Causas múltiples: Cáncer Neumonía Tuberculosis Embolia pulmonar Exploraciones adicionales Tratar la causa

Distinción entre trasudados y exudados pleurales: Criterios de Light Proteínas LP/suero >0,5 LDH LP/suero > 0,6 LDH LP > 2/3 límite superior de LDH sérica

Posibles soluciones a la limitación de los criterios de Light Insuficiencia cardiaca + Derrame pleural Diuréticos!! “Exudado” según criterios de Light Gradiente proteínas suero-LP > 3,1 g/dL Gradiente albúmina suero-LP >1,2 g/dL TRASUDADO

2004;116:417-20

73 (62%) DP de causa no cardiaca Pacientes y Métodos 117 pacientes con derrame pleural 44 (38%) IC 25 (21%) Cáncer 20 (17%) Tuberculosis 13 (11%) Neumonía 10 (8%) Cirrosis 5 (4%) TEP NYHA III,IV 73 (62%) DP de causa no cardiaca Porcel et al. Am J Med 2004;116:417-20

Pacientes y Métodos (II) NT-proBNP Estadística LP conservado en tubos con EDTA a –80ºC hasta el ensayo NT-proBNP medido por electroquimoluminiscencia sobre Roche Elecsys 2010 CVI de 0,8% a 3% Rango de detección: 5 a 35.000 pg/mL Medianas (percentiles) Χ2 (variables cualitativas) y Kruskal-Wallis (variables cuantitativas) Análisis ROC Regresión logística múltiple Porcel et al. Am J Med 2004;116:417-20

Concentraciones pleurales de NT-proBNP en diferentes tipos de derrame 6931 551 514 347 346 101 Porcel et al. Am J Med 2004;116:417-20

AUC = 0.97 (95%CI 0.94 to 1.00) Optimal cut point 1500 pg/mL 1.0 0.8 0.6 0.4 0.2 0.0 proBNP, 750 pg/mL Optimal cut point 1500 pg/mL proBNP, 1000 pg/mL proBNP, 1500 pg/mL proBNP, 2000 pg/mL AUC = 0.97 (95%CI 0.94 to 1.00) proBNP, 3000 pg/mL NTproBNP, pg/mL Sens Spec Accuracy LR+ LR- 750 98 78 85 4 0,03 1000 95 89 6 0,05 1500 91 93 92 13 0,10 2000 94 16 0,12 3000 79 97 29 0,21 Sensitivity 0.0 0.2 0.4 0.6 0.8 1.0 1– Specificity Porcel et al. Am J Med 2004;116:417-20

10 de 35 (28,5%) DP cardíacos cumplían criterios estándar de exudado Eficacia del NT-proBNP pleural para diagnosticar derrame pleural cardiaco 10 de 35 (28,5%) DP cardíacos cumplían criterios estándar de exudado 8 de estos 10 pacientes recibían diuréticos 8 de los 10 pacientes mal clasificados (Light) tenían NT-proBNP > 1.500 pg/mL Porcel et al. Am J Med 2004;116:417-20

Conclusiones La medición de NT-proBNP en líquido pleural puede discriminar entre causas cardiacas y no cardiacas de DP El NT-proBNP pleural puede identificar trasudados cardiacos mal clasificados por los criterios de Light El NT-proBNP pleural distingue entre trasudados de causa cardiaca y hepática

¿Puede el BNP sanguíneo identificar a los pacientes con una causa cardiaca del derrame pleural? ¿Tiene el gradiente de albúmina o proteínas suero-líquido pleural el mismo poder discriminatorio que el BNP en los “trasudados” mal clasificados por criterios estándar? ¿Qué valor añadido tiene el BNP pleural sobre la presunción clínica de derrame de causa cardiaca?

¿Puede el BNP sanguíneo identificar derrames de causa cardiaca?

¿Puede el BNP sanguíneo identificar derrames de causa cardiaca? Chest 2005;128:1003-9 IC (31) vs DP no cardiacos (26) AUC=0,974

25 DP cardiacos vs 68 DP no cardiacos

Eur Respir J 2006;28:144-50 AUC=0,98

¿Puede el BNP medido en sangre diagnosticar derrames de causa cardiaca? Respirology 2007;12:654-9

La medición de NT-proBNP en líquido pleural probablemente es innecesaria, ya que las concentraciones séricas tienen el mismo valor

DP cardiacos mal clasificados BNP  en DP mal clasificados BNP en los derrames cardiacos mal clasificados por los criterios de Light Estudio DP cardiacos DP cardiacos mal clasificados BNP  en DP mal clasificados Porcel et al Am J Med 2004 35 10 (28%) 8 (80%) Gegenhuber et al Chest 2005* 31 10 (32%) 9 (90%) Kolditz et al Eur Resp J 2006 25 9 (36%) 9 (100%) Respirology 2007 53 8 (15%) 6 (75%)† TOTAL 144 37 (25%) 32 (86%) * plasma † Gradiente albúmina LP-S clasificó bien 6 y el gradiente de proteínas LP-S 4

Trasudados clasificados erróneamente como exudados Variable N DP correctamente clasificados NT-proBNP en LP 17 14 (82,4%) NT-proBNP en suero 7 6 (85,7%) Gradiente albúmina LP-S 12 9 (75%) Gradiente proteínas LP-S 60 33 (55%) Datos no publicados

Conclusiones El NT-proBNP (pleural o sérico) puede identificar trasudados cardiacos mal clasificados por los criterios de Light, probablemente con más precisión que el gradiente de albúmina o de proteínas entre líquido pleural y suero

Posibles soluciones a la limitación de los criterios de Light Insuficiencia cardiaca + Derrame pleural Diuréticos, DP hemáticos “Exudado” según criterios de Light Péptidos natriuréticos Gradiente albúmina suero-LP >1,2 g/dL Gradiente proteínas suero-LP > 3,1 g/dL TRASUDADO