International Journal of Cardiology 179 (2015) 493–494
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
NT-proBNP in “low risk” patients with atrial fibrillation Jelena Kornej ⁎, Susanne Löbe, Elena Efimova, Daniela Husser, Gerhard Hindricks, Andreas Bollmann University of Leipzig Heart Center, Department of Electrophysiology, Germany
a r t i c l e
i n f o
Article history: Received 2 November 2014 Accepted 5 November 2014 Available online 6 November 2014 Keywords: Atrial fibrillation NT-proBNP CHA2DS2-VASc score
Atrial fibrillation (AF) increases the risk of stroke and death and constitutes a significant societal health and economic problem [1,2]. Prediction of thromboembolic risk is most commonly made using a clinical score such as the CHADS2 or CHA2DS2-VASc [3]. N-terminal pro-Btype natriuretic peptide (NT-proBNP) is associated with mortality and cardiovascular events in patients with AF and has been shown to improve risk stratification beyond the CHA2DS2-VASc score [4]. However, the association between NT-proBNP levels and the CHA2DS2-VASc score as well as the prevalence of high NT-proBNP levels indicating high risk in otherwise “low risk” patients is unknown in contemporary real-world AF patients referred for rhythm control strategies and was assessed in this pilot study. We recruited 94 consecutive patients (mean age 65 ± 11 years, 69% males, 71% persistent AF) with symptomatic AF who presented at Heart Center Leipzig, Germany in December 2013. The study was approved by the local ethics committee (Medical Faculty, University Leipzig) and patients provided written informed consent for participation. NT-proBNP was analyzed using commercially available assay. Statistical analyses were performed with SPSS statistical software version 17. To investigate the relationship between NT-proBNP plasma levels and clinical variables (Table 1), linear regression was performed with NT-proBNP plasma concentration as the dependent variable (univariable analysis, UV). Multivariable analyses (MV), which included variables with a p-value of b0.1 found on UV, were performed to identify independent associations between clinical variables and baseline NT-proBNP levels. The MV model 1 was performed for all clinical variables, while the MV model 2 — with the CHA2DS2-VASc score, but excluding age, since it is ⁎ Corresponding author at: University of Leipzig, Heart Center, Department of Electrophysiology, Strümpellstr. 39, 04289 Leipzig, Germany. E-mail address: [email protected] (J. Kornej).
http://dx.doi.org/10.1016/j.ijcard.2014.11.046 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.
already within the score. A p-value of b 0.05 was considered as statistically significant. The clinical characteristics of the study population are presented in Table 1. In univariable analysis, NT-proBNP level (median 588 [IQR 276–1052] ng/l) was associated with advanced age, persistent AF type, impaired renal function, larger left atrial and ventricular diameters, reduced left ventricular ejection fraction as well as with the CHA2DS2VASc score and EHRA class (all p b 0.05). However, in the multivariable models, only age and left ventricular diameter remained significantly associated with NT-proBNP levels while persistent AF did not reach significance (Table 2). Interestingly, even in patients with low CHA2DS2VASc score of 0 or 1 (n = 14), two patients (14.3%) had NT-proBNP levels in the highest quartile (N1052 ng/ml). Recently, Hijazi and co-workers demonstrated that NT-proBNP levels were elevated in AF and were independently associated with an increased risk of stroke and mortality [5]. Furthermore, the authors found that predictive value of NT-proBNP was incremental to the CHA2DS2-VASc score and even showed significant improvement beyond the risk stratification. Of importance, patients with the highest NT-proBNP levels were at increased risk despite having no cardiometabolic co-morbidities, i.e. CHA2DS2-VASc score of 0 (or 1 in females). In accordance to the previous study, our study also demonstrates significant associations between NT-proBNP and AF relevant clinical factors. However, in our study the percentage of low risk patients (accordingly to the CHA2DS2-VASc score) with highest NT-proBNP was much higher than in the study performed by Hijazi and colleagues (14.3% versus 4.8%, respectively). It might be partly explained by the relatively small cohort in our pilot study, while another study analyzed patients from large anticoagulation trials. Several studies have demonstrated the usefulness of adding blood biomarkers to established clinical risk scores [6,7] but the application of this approach to the daily clinical practice still remains uncertain and the latest AF management guidelines [8] stress the focus on the identification of ‘low’ and ‘truly low risk’ patients who do not need any antithrombotic therapy. Therefore, the use of NT-proBNP might be clinically relevant to stratify the patients within the low risk CHA2DS2VASc score 0 and 1. Our results can be seen as hypothesis generating and point out the potential clinical importance and scientific prominence of NT-proBNP assessment in planning treatment strategies in AF patients. Such combined approach of laboratory parameter and thromboembolic risk stratification would thus be a very important tool in guidance of antithrombotic prophylaxis and accurate patient selection for interventional AF treatment. However, larger prospective studies are needed to confirm that thesis.
494
J. Kornej et al. / International Journal of Cardiology 179 (2015) 493–494
Table 1 Baseline characteristics of the study population.
risk” patients. Whether or not rhythm control strategies improve outcomes in those patients needs to be determined.
Variables n (%)
Study population n = 94
Age, years Females Persistent AF BMI eGFR, ml/min/1.73 m2 Hypertension Diabetes mellitus Previous TE CHADS2, median (IQR) CHA2DS2-VASc, median (IQR) EF, % LA diameter, mm EHRA class 0 I II III IV
60 ± 10 434 (33) 480 (37) 29 ± 5 101 ± 32 942 (72) 210 (16) 97 (7) 2 (1–2) 3 (2–4) 59 ± 10 43 ± 6 2.5 (2–3) 1 (1) 13 (14) 33 (35) 43 (46) 4 (4)
Abbreviations: BMI — body mass index, eGFR — estimated glomerular filtration rate, TE — thromboembolic events, IQR — interquartile range, EF — ejection fraction, LA — left atrial.
Table 2 Clinical parameters associated with baseline NT-proBNP levels in study population. Variables
Age Males Persistent AF BMI eGFR LAD LV-EF LV-EDd CHA2DS2-VASc EHRA
UV Beta
P-value
.346 .030 .354 .143 −.301 .260 −.173 .332 .342 .186
0.001 0.775 b0.001 0.168 0.003 0.014 0.105 0.012 0.001 0.073
MV
Model 1
MV
Model 2
Beta
P-value
Beta
P-value
.393
0.008
.254
0.064
.249
0.093
−.101 −.095
0.430 0.531
−.222 .046
0.104 0.765
.355
0.012
.148
0.201
.189 .079 .150
0.157 0.574 0.227
In conclusion, although NT-proBNP levels associate with the CHA2DS2-VASc score, high levels may be detected in otherwise “low
Conflict of interest The authors report no relationships that could be construed as a conflict of interest.
References [1] E.J. Benjamin, P.A. Wolf, R.B. D'Agostino, H. Silbershatz, W.B. Kannel, D. Levy, Impact of atrial fibrillation on the risk of death: the Framingham Heart Study, Circulation 98 (10) (1998) 946–952. [2] P.A. Wolf, R.D. Abbot, W.B. Kannel, Atrial fibrillation as an independent risk factor for stroke: the Framingham Study, Stroke 22 (1991) 983–988. [3] G.Y. Lip, R. Nieuwlaat, R. Pisters, D.A. Lane, H.J. Crijns, Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the euro heart survey on atrial fibrillation, Chest 137 (2) (2010) 263–272. [4] Z. Hijazi, J. Oldgren, A. Siegbahn, C.B. Granger, L. Wallentin, Biomarkers in atrial fibrillation: a clinical review, Eur. Heart J. 34 (20) (2013) 1475–1480. [5] Z. Hijazi, J. Oldgren, U. Andersson, S.J. Connolly, M.D. Ezekowitz, S.H. Hohnloser, et al., Cardiac biomarkers are associated with an increased risk of stroke and death in patients with atrial fibrillation: a Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) substudy, Circulation 125 (13) (2012) 1605–1616. [6] V. Roldan, F. Marin, A. Garcia-Herola, G.Y. Lip, Correlation of plasma von Willebrand factor levels, an index of endothelial damage/dysfunction, with two point-based stroke risk stratification scores in atrial fibrillation, Thromb. Res. 116 (4) (2005) 321–325. [7] T. Sadanaga, S. Kohsaka, S. Ogawa, D-dimer levels in combination with clinical risk factors can effectively predict subsequent thromboembolic events in patients with atrial fibrillation during oral anticoagulant therapy, Cardiology 117 (1) (2010) 31–36. [8] A.J. Camm, G.Y. Lip, R. De Caterina, I. Savelieva, D. Atar, S.H. Hohnloser, et al., 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association, Eur. Heart J. 33 (21) (2012) 2719–2747.
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Letter to the Editor
NT-proBNP in “low risk” patients with atrial fibrillation Jelena Kornej ⁎, Susanne Löbe, Elena Efimova, Daniela Husser, Gerhard Hindricks, Andreas Bollmann University of Leipzig Heart Center, Department of Electrophysiology, Germany
a r t i c l e
i n f o
Article history: Received 2 November 2014 Accepted 5 November 2014 Available online 6 November 2014 Keywords: Atrial fibrillation NT-proBNP CHA2DS2-VASc score
Atrial fibrillation (AF) increases the risk of stroke and death and constitutes a significant societal health and economic problem [1,2]. Prediction of thromboembolic risk is most commonly made using a clinical score such as the CHADS2 or CHA2DS2-VASc [3]. N-terminal pro-Btype natriuretic peptide (NT-proBNP) is associated with mortality and cardiovascular events in patients with AF and has been shown to improve risk stratification beyond the CHA2DS2-VASc score [4]. However, the association between NT-proBNP levels and the CHA2DS2-VASc score as well as the prevalence of high NT-proBNP levels indicating high risk in otherwise “low risk” patients is unknown in contemporary real-world AF patients referred for rhythm control strategies and was assessed in this pilot study. We recruited 94 consecutive patients (mean age 65 ± 11 years, 69% males, 71% persistent AF) with symptomatic AF who presented at Heart Center Leipzig, Germany in December 2013. The study was approved by the local ethics committee (Medical Faculty, University Leipzig) and patients provided written informed consent for participation. NT-proBNP was analyzed using commercially available assay. Statistical analyses were performed with SPSS statistical software version 17. To investigate the relationship between NT-proBNP plasma levels and clinical variables (Table 1), linear regression was performed with NT-proBNP plasma concentration as the dependent variable (univariable analysis, UV). Multivariable analyses (MV), which included variables with a p-value of b0.1 found on UV, were performed to identify independent associations between clinical variables and baseline NT-proBNP levels. The MV model 1 was performed for all clinical variables, while the MV model 2 — with the CHA2DS2-VASc score, but excluding age, since it is ⁎ Corresponding author at: University of Leipzig, Heart Center, Department of Electrophysiology, Strümpellstr. 39, 04289 Leipzig, Germany. E-mail address: [email protected] (J. Kornej).
http://dx.doi.org/10.1016/j.ijcard.2014.11.046 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.
already within the score. A p-value of b 0.05 was considered as statistically significant. The clinical characteristics of the study population are presented in Table 1. In univariable analysis, NT-proBNP level (median 588 [IQR 276–1052] ng/l) was associated with advanced age, persistent AF type, impaired renal function, larger left atrial and ventricular diameters, reduced left ventricular ejection fraction as well as with the CHA2DS2VASc score and EHRA class (all p b 0.05). However, in the multivariable models, only age and left ventricular diameter remained significantly associated with NT-proBNP levels while persistent AF did not reach significance (Table 2). Interestingly, even in patients with low CHA2DS2VASc score of 0 or 1 (n = 14), two patients (14.3%) had NT-proBNP levels in the highest quartile (N1052 ng/ml). Recently, Hijazi and co-workers demonstrated that NT-proBNP levels were elevated in AF and were independently associated with an increased risk of stroke and mortality [5]. Furthermore, the authors found that predictive value of NT-proBNP was incremental to the CHA2DS2-VASc score and even showed significant improvement beyond the risk stratification. Of importance, patients with the highest NT-proBNP levels were at increased risk despite having no cardiometabolic co-morbidities, i.e. CHA2DS2-VASc score of 0 (or 1 in females). In accordance to the previous study, our study also demonstrates significant associations between NT-proBNP and AF relevant clinical factors. However, in our study the percentage of low risk patients (accordingly to the CHA2DS2-VASc score) with highest NT-proBNP was much higher than in the study performed by Hijazi and colleagues (14.3% versus 4.8%, respectively). It might be partly explained by the relatively small cohort in our pilot study, while another study analyzed patients from large anticoagulation trials. Several studies have demonstrated the usefulness of adding blood biomarkers to established clinical risk scores [6,7] but the application of this approach to the daily clinical practice still remains uncertain and the latest AF management guidelines [8] stress the focus on the identification of ‘low’ and ‘truly low risk’ patients who do not need any antithrombotic therapy. Therefore, the use of NT-proBNP might be clinically relevant to stratify the patients within the low risk CHA2DS2VASc score 0 and 1. Our results can be seen as hypothesis generating and point out the potential clinical importance and scientific prominence of NT-proBNP assessment in planning treatment strategies in AF patients. Such combined approach of laboratory parameter and thromboembolic risk stratification would thus be a very important tool in guidance of antithrombotic prophylaxis and accurate patient selection for interventional AF treatment. However, larger prospective studies are needed to confirm that thesis.
494
J. Kornej et al. / International Journal of Cardiology 179 (2015) 493–494
Table 1 Baseline characteristics of the study population.
risk” patients. Whether or not rhythm control strategies improve outcomes in those patients needs to be determined.
Variables n (%)
Study population n = 94
Age, years Females Persistent AF BMI eGFR, ml/min/1.73 m2 Hypertension Diabetes mellitus Previous TE CHADS2, median (IQR) CHA2DS2-VASc, median (IQR) EF, % LA diameter, mm EHRA class 0 I II III IV
60 ± 10 434 (33) 480 (37) 29 ± 5 101 ± 32 942 (72) 210 (16) 97 (7) 2 (1–2) 3 (2–4) 59 ± 10 43 ± 6 2.5 (2–3) 1 (1) 13 (14) 33 (35) 43 (46) 4 (4)
Abbreviations: BMI — body mass index, eGFR — estimated glomerular filtration rate, TE — thromboembolic events, IQR — interquartile range, EF — ejection fraction, LA — left atrial.
Table 2 Clinical parameters associated with baseline NT-proBNP levels in study population. Variables
Age Males Persistent AF BMI eGFR LAD LV-EF LV-EDd CHA2DS2-VASc EHRA
UV Beta
P-value
.346 .030 .354 .143 −.301 .260 −.173 .332 .342 .186
0.001 0.775 b0.001 0.168 0.003 0.014 0.105 0.012 0.001 0.073
MV
Model 1
MV
Model 2
Beta
P-value
Beta
P-value
.393
0.008
.254
0.064
.249
0.093
−.101 −.095
0.430 0.531
−.222 .046
0.104 0.765
.355
0.012
.148
0.201
.189 .079 .150
0.157 0.574 0.227
In conclusion, although NT-proBNP levels associate with the CHA2DS2-VASc score, high levels may be detected in otherwise “low
Conflict of interest The authors report no relationships that could be construed as a conflict of interest.
References [1] E.J. Benjamin, P.A. Wolf, R.B. D'Agostino, H. Silbershatz, W.B. Kannel, D. Levy, Impact of atrial fibrillation on the risk of death: the Framingham Heart Study, Circulation 98 (10) (1998) 946–952. [2] P.A. Wolf, R.D. Abbot, W.B. Kannel, Atrial fibrillation as an independent risk factor for stroke: the Framingham Study, Stroke 22 (1991) 983–988. [3] G.Y. Lip, R. Nieuwlaat, R. Pisters, D.A. Lane, H.J. Crijns, Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fibrillation using a novel risk factor-based approach: the euro heart survey on atrial fibrillation, Chest 137 (2) (2010) 263–272. [4] Z. Hijazi, J. Oldgren, A. Siegbahn, C.B. Granger, L. Wallentin, Biomarkers in atrial fibrillation: a clinical review, Eur. Heart J. 34 (20) (2013) 1475–1480. [5] Z. Hijazi, J. Oldgren, U. Andersson, S.J. Connolly, M.D. Ezekowitz, S.H. Hohnloser, et al., Cardiac biomarkers are associated with an increased risk of stroke and death in patients with atrial fibrillation: a Randomized Evaluation of Long-term Anticoagulation Therapy (RE-LY) substudy, Circulation 125 (13) (2012) 1605–1616. [6] V. Roldan, F. Marin, A. Garcia-Herola, G.Y. Lip, Correlation of plasma von Willebrand factor levels, an index of endothelial damage/dysfunction, with two point-based stroke risk stratification scores in atrial fibrillation, Thromb. Res. 116 (4) (2005) 321–325. [7] T. Sadanaga, S. Kohsaka, S. Ogawa, D-dimer levels in combination with clinical risk factors can effectively predict subsequent thromboembolic events in patients with atrial fibrillation during oral anticoagulant therapy, Cardiology 117 (1) (2010) 31–36. [8] A.J. Camm, G.Y. Lip, R. De Caterina, I. Savelieva, D. Atar, S.H. Hohnloser, et al., 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association, Eur. Heart J. 33 (21) (2012) 2719–2747.
