Prognostic value of B-type natriuretic peptide in patients with left bundle-branch block admitted for acute heart failure

European Journal of Internal Medicine 22 (2011) e152–e154

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European Journal of Internal Medicine j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / e j i m

Letter to the Editor Prognostic value of B-type natriuretic peptide in patients with left bundle-branch block admitted for acute heart failure Keywords: Left bundle-branch block Acute heart failure BNP

Sirs, Congestive heart failure (HF) determines a 20–40% mortality within 1 year of diagnosis [1]; the management and the therapeutic approach to HF patients can be largely improved by the assessment of a good prognostic stratification, especially in the early period after hospital discharge [2,3]. Prolonged QRS duration (QRSd) due to delayed ventricular electrical activation, most commonly left bundle branch block (LBBB), is approximately represented in one third of patients with chronic HF [4,5]. This altered electrical activation results in mechanical dyssynchrony and, as consequence in reduced of systolic performance, functional mitral regurgitation and altered diastolic filling rate [6]. The prognosis of HF patients with LBBB has long been debated and previous studies showed that patients with LBBB tend to have a worse prognosis compared with others without LBBB [7]; moreover, this electrical delay predisposes heart failure patients to an increased risk of ventricular tachyarrhythmia and electrical death [8]. However, only few studies [9] analysed the prognostic role of BNP in patients with HF and a LBBB in 12leads ECG. Aim of this observational retrospective study was to gain further insight on the role of pre-discharge plasma BNP in patients discharged from hospital after an acute episode of HF (AHF) particularly in association with the presence of LBBB at ECG. The patient population was selected from a multicentre database prospectively collected from 2003 up to 2005 at 3 different clinics in Italy. Patients that presented a persistent prolonged duration of QRS (N0.12 s) with ECG patterns of left ventricular delayed depolarization were classified having a LBBB. Subjects who presented either concomitant acute coronary syndrome, severe renal dysfunction requiring haemodialysis treatment, or body mass index (BMI) N30 kg/m2 (in which the expression of BNP was lower for any given severity of HF) were excluded. All patients had been treated according to the principles laid down in the international guidelines on CHF and were enrolled in the study once clinical/instrumental finding of stability had been reached (between 0 and 21 days from acute failure). Discharge criteria were the following: a) subjective improvement on the basis of NYHA class, with no orthopnoea; b) 90 b SBPb 120 mmHg; c) heart rate b 100 bpm; d) pulse oxymetry in ambient air N 90%; e) diuresis N 1000 ml/day. Both serum creatinine and plasma BNP (BNP Triage method) were checked at discharge in all patients. Death by any cause and worsening heart failure requiring readmission to hospital were considered to be cardiovascular events and were scheduled as clinical endpoints of the study. Continuous variables were reported as mean± standard deviation, while BNP was reported as median, as well, due to its non-normal distribution. Variables proved to be significantly associated to the combined endpoint on Cox univariate regression and

were included in a Cox proportional hazard regression model (SPSS 13.0), in order to determine whether they added independent prognostic information. To compare the relationship between clinical events plasma BNP levels and the presence of LBBB, Kaplan–Meier curves were traced. BNP value was log-transformed before analysis, a ROC (receiver-operated curve) analysis was performed to show various cut-off values for BNP, to identify patients likely to suffer a cardiac event discharge. The population studied included 691 patients age 72 ± 11 years, males 60%), NYHA class 2.1 ± 0.4 and mean LVEF 41 ± 13%); 19% were in permanent atrial fibrillation and in 21% a complete LBBB emerged. The causes of the HF were: 41% ischemic heart disease, 22% hypertensive cardiomiopathy, and 9% valvular heart disease. The mean plasma BNP level at discharge was 157 (287 ± 418) ng/L and BNP levels differed according to left ventricular dysfunction (LVEF b 50%, 506 pts; 172 (308 ± 434) ng/L) than those with preserved LVEF and diastolic dysfunction (LVEF N 50%, 185 pts, 132 (229 ± 364) ng/L) (Mann–Whitney U-test; Z = −3.7; P b 0.001). At the 6-month clinical follow-up, 57 (8%) subjects died and 126 (18%) needed hospital re-admission for acute decompensation. The cardiovascular events registered were different in the group with systolic dysfunction and with diastolic dysfunction (and preserved LVEF) (29% and 18%, respectively; χ 2 = 8.5; P = 0.003) in the follow-up. Cox regression showed a significant correlation between LVEF, NYHA class, serum creatinine, restrictive pattern, age, atrial fibrillation, LBBB, diuretic prescription, digoxin prescription, BNP levels and the occurrence of death and/or re-admission (Table 1). Event rates were higher in patients with LBBB than in the remaining (35 vs 24%; Chi2 test; P b 0.01). We observed that BNP levels measured at discharge were associated with clinical events and they were significantly lower in event-free patients (n = 508) than in patients with events: 170 ± 212 (median 114) vs 609 ± 628 (median 443) ng/L (Mann–Whitney U-test; Z = −14.9; P = 0.0001). BNP values were higher in LBBB patients than the remaining (268± 380 (median 151) vs 358 ± 534 (median 194) ng/L; Mann–Whitney U-test; Z = −2.7; P = 0.006). The ROC analysis showed the ability of the BNP value on discharge to discriminate

Table 1 Cox regression between most important parameters and the occurrence of death and/or hospital readmission. LVEF = left ventricular ejection fraction, NYHA = New York Heart Association; LBBB = left bundle branch block; Log-BNP = Ln-transformed brain natriuretic peptide. Variable

Hazard ratio

Confidence intervals

P value

LVEF (%) NYHA class Serum creatinine (mg/dl) Restrictive pattern (yes vs no) Age (years) Atrial fibrillation (yes vs no) LBBB (yes vs no) Diuretic therapy (yes vs no) Digoxin therapy (yes vs no) Plasma BNP (pg/ml)

0.961 2.630 1.201 5.032 1.018 1.728 1.548 0.304 0.497 3.006

0.949–0.974 2.102–3.291 1.037–1.392 3.750–6.752 1.004–1033 1.246–2.397 1.121–2.139 0.124–0.746 0.343–0.720 2.662–3.447

0.000 0.000 0.015 0.000 0.015 0.001 0.008 0.009 0.000 0.000

0953-6205/$ – see front matter © 2011 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved. doi:10.1016/j.ejim.2011.07.020

Letter to the Editor

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200 ng/L Sens.: 85% Spec.: 76%

200 ng/L Sens.: 88% Spec.: 73%

400 ng/L Sens.: 67% Spec.: 92%

400 ng/L Sens.: 58% Spec.: 92%

500 ng/L Sens.: 51% Spec.: 93%

500 ng/L Sens.: 45% Spec.: 94%

AUC = 0.87; CI = 0.80 – 0.93

AUC = 0.87; CI = 0.84 – 0.90

Fig. 1. ROC (receiver operating curve) in patients studied to compare the sensitivity/specificity of the BNP cut-off values on discharge with the combined endpoint, in all patients (left panel) and in LBBB+ patients (right panel).

between patients with events and event-free: the AUC value was 0.87 (both for patients with and without LBBB) indicating good discriminating power (Fig. 1). In particular, the BNP values of 200 and 400 ng/L were found to have the best compromise between sensitivity and specificity (Fig. 1) for predicting events at six months, so that they may be proposed as cut-off values. According to such cut-off values, Kaplan– Meier curves depicted a significant increasing risk of events related to pre-discharge BNP in both HF population (with LBBB or without) (P b 0.001) (Fig. 2). Therefore, this observational study provides evidence that a predischarge plasma level of BNP in HF patients has a stronger prognostic value even if patients manifested a LBBB. In the prognostic role of LBBB in HF patients, the LBBB-related dyssynchrony associated with

pump failure and neurohormonal activation should be considered in term of increased risk of morbidity and mortality [10]. The principle observation that emerged from this study is that, independently from the presence/absence of LBBB, the degree of neurohormonal activation at discharge is the main determinant of short-term clinical outcome. Furthermore, the favourable prognosis in HF patients with conduction delay and plasma BNP ≤ 200 ng/l (8% of major cardiovascular event rate) appeared to be quite similar to those heart failure patients with low BNP plasma level without LBBB. These data seemed to suggest that neurohormonal activation at discharge (together with LVEF and NYHA class) might be considered in the clinical decision for the implantation of biventricular stimulation. This hypothesis deserves further and larger investigations.

BNP < 200 pg/ml; 7%

BNP < 200 pg/ml; 8%

BNP 201 -399 pg/ml; 37%

BNP 201 -399 pg/ml; 41%

BNP > 400 pg/ml; 70% BNP > 400 pg/ml; 79%

p<0.001

p<0.001

Fig. 2. Kaplan–Meier curves showing the cumulative incidence of death and readmission according to predischarge BNP levels in the whole study population (left panel) and in patients with LBBB (right panel).

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Letter to the Editor

References [1] Oh KK, Anderson KM, Kannel WB, Grossman W, Levy D. Survival after the onset of congestive heart failure in Framingham Heart Study subjects. Circulation 1993;88 (1):107–15. [2] Fonarow GC, Abraham WT, Albert NM, et al. Influence of a performance improvement initiative on quality of care for patients hospitalized with heart failure: results of the Organized Program to Initiate Lifesaving Treatment in Hospitalized Patients With Heart Failure (OPTIMIZE-HF). Arch Intern Med 2007;167(14):1493–502. [3] Gheorghiade M, Zannad F, Sopko G, et al. Acute heart failure syndromes: current state and framework for future research. Circulation 2005;112(25):3958–68. [4] Kashani A, Barold SS. Significance of QRS complex duration in patients with heart failure. J Am Coll Cardiol 2005;46(12):2183–92. [5] El-Menyar AA, Abdou SM. Impact of left bundle branch block and activation pattern on the heart. Expert Rev Cardiovasc Ther 2008;6(6):843–57. [6] van der Land V, Germans T, van Dijk J, et al. The effect of left bundle branch block on left ventricular remodeling, dyssynchrony and deformation of the mitral valve apparatus: an observational cardiovascular magnetic resonance imaging study. Int J Cardiovasc Imaging 2007;23(4):529–36. [7] Danciu SC, Gonzalez J, Gandhi N, Sadhu S, Herrera CJ, Kehoe R. Comparison of six month outcomes and hospitalization rates in heart failure patients with and without preserved left ventricular ejection fraction and with and without intraventricular conduction defect. Am J Cardiol 2006;97(2):256–9. [8] Baldasseroni S, Opasich C, Gorini M, et al. Left bundle-branch block is associated with increased 1-year sudden and total mortality rate in 5517 outpatients with congestive heart failure: a report from the Italian Network on Congestive Heart Failure. Am Heart J 2002;143(3):398–405. [9] Aspromonte N, Valle R, Peacock WF, Vanderheyden M, Maisel A. Inpatient monitoring and prognostic importance of B-type natriuretic peptide. Congest Heart Fail 2008;14(4 Suppl 1):30–4. [10] Zannad F, Huvelle E, Dickstein K, et al. Left bundle branch block as a risk factor for progression to heart failure. Eur J Heart Fail 2007;9(1):7–14.

Nadia Aspromonte Intensive Care Unit, Cardiovascular Department, San Filippo Neri Hospital, Rome, Italy Corresponding author at: via B. Cerretti,18, 00167 Rome, Italy. E-mail address: [email protected]. Roberto Valle Intensive Care Unit and Heart Failure Unit, Dept. of Cardiology, Ospedale Civile, Chioggia Italy Stefania Angela Di Fusco Massimo Santini Intensive Care Unit, Cardiovascular Department, San Filippo Neri Hospital, Rome, Italy Mauro Feola Cardiovascular Rehabilitation-Heart Failure Unit Ospedale SS Trinita' Fossano, Italy

13 July 2011