Timing of NT-pro-BNP sampling for predicting adverse outcome after acute pulmonary embolism

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1 7 Frederikus A. Klok Noortje van der Bijl Inge C.M. Mos Albert de Roos Lucia J. M. Kroft Menno V. Huisman Timing of NT-pro-BNP sampling for predicting adverse outcome after acute pulmonary embolism Letter to the editor Thrombosis and Haemostasis ;104(1):

3 Timing of NT-pro-BNP in acute PE 149 The purpose of this study was to determine the optimal therapeutic management of patients with acute pulmonary embolism (PE), all patients diagnosed with this disease should be stratified rapidly according to their risk of mortality, starting with assessment of the patients hemodynamic status (1). Hemodynamically unstable patients have a very high risk of dying (30% or more) and therefore, benefit from treatment with thrombolytic drugs, except for those patients with very high bleeding risks (1). Further risk stratification of normotensive patients with PE allows differentiation between patients that might be considered for outpatient therapy, and patients who should be subjected to clinical treatment and surveillance (2). Blood levels of (N-terminal-pro-) brain-type natriuretic peptide, a peptide that is released in reaction to myocyte stress, can aid the physician in the risk stratification of normotensive patients with PE since high concentrations of (NT-pro-) BNP distinguish patients with higher risk of complicated in-hospital course and death from those with low BNP levels (3). Nonetheless, it has been suggested that (NT-pro-) BNP tests can be falsely negative in case of testing very early (< 24 hours) after onset of symptoms (3). This phenomenon can be explained by the low amounts of BNP prohormone that is stored in normal ventricular myocytes. As a consequence, it might take several hours for the plasma natriuretic peptide levels to significantly increase (4). As a consequence, NT-pro-BNP levels may be falsely low in patients who present very early in the course of disease. Therefore, we studied the influence of early presentation of patients with acute PE on NT-pro-BNP levels and the risk for falsely low NT-pro-BNP levels. We report on a post-hoc analysis of a prospective cohort study of consecutive normotensive patients with computed tomography (CT) proven acute PE (5). These patients were followed for 6 weeks for the occurrence of adverse events including all cause mortality, resuscitation after respiratory or cardiac arrest, admittance to intensive care unit, need for mechanical ventilation and administration of inotropic or thrombolytic agents. Blood samples were taken at clinical presentation and stored. After the study period was completed for all included patients, NT-pro-BNP levels were measured using a quantitative immunoassay (Elecsys 2010 analyzer, Roche Diagnostics, Mannheim, Germany) (5). Predefined threshold for elevated NT-pro-BNP levels was > 600 pg/ml. Researchers who measured NT-pro-BNP levels were blinded for the clinical outcome of the patients. In addition, and to evaluate ventricular function, we assessed the right-to-left ventricular dimension ratios (RV/LVratio) in reconstructed 4-chamber (4-CH) CT-views (5). For the present analysis, we determined the univariate associations of NT-pro-BNP levels and several clinical parameters including time from start of the symptoms to presentation to our hospital. Furthermore, we performed multivariate linear regression analysis to identify independent predictors of NT-pro-BNP concentration. In addition, we determined the risk for a low NT-pro-BNP level adjusted for all these latter independent predictors of NT-pro-BNP concentration in patients who presented to our hospital within 24 hours after onset of symptoms. Finally, we assessed the risk of falsely low NT-pro-BNP levels in patients who presented early in

4 the course of disease. This study was approved by the Institutional Review Board of our hospital and all patients provided written informed consent. In total, 113 normotensive patients with acute PE were included in the study (Table 1). Table 1. Demographics of 113 patients diagnosed with acute pulmonary embolism Age (mean ± SD) 56 ±17 Male sex 60 (53) History of venous thrombosis 25 (22) Active malignancy 24 (21) Recent immobilization, surgery or trauma 35 (31) Inpatient 20 (18) COPD 7 (6.2) Left heart failure 5 (4.4) Duration of complaints (hours; median, IQR) 48 (24-132) RV/LV-ratio (median, IQR) 1.0 ( ) Univariate analysis indicated that time from onset of complaints was not associated with NT-pro-BNP concentration, in contrast to age, active malignancy, inpatient status, previously diagnosed COPD, left heart failure and higher RV/LV-ratio (Table 2). Unless otherwise indicated, data are n (%). Chapter After multivariate backward conditional analysis, gender (p=0.012), previously diagnosed COPD (p=0.048), previously diagnosed left heart failure (p=0.043) and increased RV/LV-ratio (p < 0.001) were independently associated with NT-pro-BNP levels, whereas time from onset of symptoms to clinical presentation was not. Adjusted for these latter significant determinants of NT-pro-BNP levels, presentation within 24 hours after onset of symptoms was not associated with an increased risk for low NT-pro-BNP (n = 41; adjusted odds ratio (OR) 1.1, 95% confidence interval (CI) ). This finding was confirmed after performing the same analysis for patients who presented within 12 hours (n = 23; adjusted OR 1.4, 95%CI ) or within 6 hours (n =14; adjusted OR 1.2, 95%CI ) after start of the symptoms. After 6 weeks, 10 patients had reached a clinical endpoint: 5 patients developed respiratory or cardiac arrest after PE of whom 1 was successfully resuscitated, 1 patient received thrombolytic therapy because of a large saddle embolus, 1 had a major bleeding complication and was subsequently admitted to the intensive care unit and 3 patients died of progressive malignancy. Half of these patients presented to our hospital within 24 hours after onset of the symptoms. The first 7 patients all experienced their complications in the first 2 weeks after diagnosis, and all had clearly elevated NT-pro-BNP blood levels (range 1964 to 6540 pg/ml). The latter 3 patients died of cancer after this 2 week period. Two of these patients had elevated NT-pro-BNP levels at diagnosis. The final patient presented to our emergency ward 8 hours after he first noticed symptoms of acute PE, and had a NT-pro-BNP level beneath the predefined threshold at time of presentation (151 pg/ml). This patient died after 39 days of progressive metastatic prostate cancer. The overall risk for PE-related complications after a low NT-pro-BNP level at clinical presentation

5 Timing of NT-pro-BNP in acute PE 151 was 0% (0/81, 95%CI %), and for overall complications regardless of NT-pro-BNP level was 1.2% (1/81, 95%CI ). The risk for PE-related complications after a low NTpro-BNP level within 24 hours of onset of complaints was 0% (0/30, 95%CI ), and for overall complications 3.3% (1/30, 95%CI ). We conclude from this post hoc analysis that NT-pro-BNP levels with a threshold of 600 pg/ml can be used for risk stratification of patients diagnosed with PE, even in case of early presentation in the course of disease. This conclusion is based on 3 observations: 1) the time span between onset of symptoms and clinical presentation was not related to NT-pro-BNP blood levels; 2) we did not find an increased risk for NT-pro-BNP levels below 600 pg/ml in patients who presented to our hospital within 24, 12 or even 6 hours after start of the symptoms; and 3) the risk of PE related and overall complications after a normal NT-pro-BNP within 24 hours after onset of symptoms was very low. The main limitation of these observations was the relatively limited sample size of our study population. The use of prognostic tests in normotensive patients with confirmed PE is still debated, mainly because there is no clinical evidence that altered treatment strategies based on prognostic tests improve the prognosis or more general clinical outcome, i.e. mortality, patient satisfaction or medical costs, of these patients. In addition, it is not known what would be the most optimal test for this purpose. A recent report suggests that NT-pro-BNP might have superior sensitivity and specificity over Troponin levels, D-dimer levels or right ventricular dimension measurements on CT (5). Direct comparison of NT-pro-BNP with clinical scores are however lacking. Table 2. Correlations between NT-pro-BNP concentration and clinical parameters. Medians (interquartile range) of NT-pro- P value BNP concentration or regression coefficient [coefficient of determination(%)]* Age (per year)* (5.1) Sex (male vs. female) 201 (53 490) vs. 268 ( ) 0.24 Active malignancy (yes vs. no) 418 ( ) vs. 181 (45 586) Recent surgery or trauma (yes vs. no) 227 ( ) vs. 224 (58 661) 0.86 Inpatient (yes vs. no) 623 ( ) vs. 201 (45 519) COPD (yes vs. no) 2310 ( ) vs. 205 (48 674) Left heart failure (yes vs. no) 218 ( ) vs. 204 (52 729) Duration of complaints (per hour) (1.0) 0.31 RV/LV-ratio (median, IQR) 0.22 (5.0) * Regression coefficient from linear regression analysis for continuous parameters, medians and interquartile range for bivariate parameters (Mann-Whitney U test).

6 references 1. Torbicki A, Perrier A, Konstantinides S, Agnelli G, Galie N, Pruszczyk P, Bengel F, Brady AJ, Ferreira D, Janssens U, et al. Guidelines on the diagnosis and management of acute pulmonary embolism: the Task Force for the Diagnosis and Management of Acute Pulmonary Embolism of the European Society of Cardiology (ESC). Eur.Heart J Sep;29(18): Aujesky D, Hughes R, Jimenez D. Short-term prognosis of pulmonary embolism. J.Thromb. Haemost Jul;7 Suppl 1: Klok FA, Mos IC, Huisman MV. Brain-type natriuretic peptide levels in the prediction of adverse outcome in patients with pulmonary embolism: a systematic review and metaanalysis. Am.J.Respir.Crit Care Med Aug 15;178(4): Hama N, Itoh H, Shirakami G, Nakagawa O, Suga S, Ogawa Y, Masuda I, Nakanishi K, Yoshimasa T, Hashimoto Y, et al. Rapid ventricular induction of brain natriuretic peptide gene expression in experimental acute myocardial infarction. Circulation 1995 Sep 15;92(6): Klok FA, van der Bijl N, Eikenboom HC, Van Rooden CJ, de Roos A, Kroft LJ, Huisman MV. Comparison of CT assessed right ventricular size and cardiac biomarkers for predicting short-term clinical outcome in normotensive patients suspected of having acute pulmonary embolism. J.Thromb.Haemost Apr;8(4): Chapter 7 152

Chapter 6. F.A. Klok, N. van der Bijl, J. Eikenboom, C.J. van Rooden, A. de Roos, L.J.M. Kroft and M.V. Huisman. Equally contributed

Chapter 6. F.A. Klok, N. van der Bijl, J. Eikenboom, C.J. van Rooden, A. de Roos, L.J.M. Kroft and M.V. Huisman. Equally contributed Chapter 6 Comparison of CT assessed right ventricular size and cardiac biomarkers for predicting short term clinical outcome in normotensive patients suspected for having acute pulmonary embolism F.A.