ORIGINAL ARTICLE
N-terminal pro-B-type natriuretic peptide and the risk of stroke and transient ischaemic attack: the Rotterdam Study M. L. P. Portegiesa,b, M. Kavousia, M. J. G. Leeninga,c, M. J. Bosa, A. H. van den Meirackerd, A. Hofmana, O. H. Francoa, P. J. Koudstaalb and M. A. Ikrama,b,e Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam; bDepartment of Neurology, Erasmus MC University Medical Center, Rotterdam; cDepartment of Cardiology, Erasmus MC University Medical Center, Rotterdam; dDepartment of Internal Medicine, Erasmus MC University Medical Center, Rotterdam; and eDepartment of Radiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
Keywords:
epidemiology, NTproBNP, risk factors, stroke, transient ischaemic attack Received 27 June 2014 Accepted 27 October 2014 European Journal of Neurology 2015, 22: 695–701 doi:10.1111/ene.12633
Background and purpose: Amino-terminal pro-B-type natriuretic peptide (NTproBNP) is a predictor of heart disease. It has also been related to stroke, but its association with transient ischaemic attacks (TIAs) is unclear. Moreover, it is unknown how clinical heart disease influences this relation. Within the prospective population-based Rotterdam Study, the association of NT-proBNP with stroke and TIA was examined and the role of heart disease on this association was investigated. Methods: NT-proBNP was measured in 1997–2001 in 5611 participants (mean age 68.7 years; 57.7% women) without a history of stroke, TIA or heart failure. Follow-up for stroke and TIA finished in 2012. Models were adjusted for age and cardiovascular risk factors, and were stratified by sex. Results: During 22 058 person-years 195 men suffered a stroke and 118 a TIA. During 31 825 person-years 230 women suffered a stroke and 187 a TIA. Higher NT-proBNP was associated with a higher risk of stroke in men [hazard ratio (HR) per SD increase 1.50; 95% confidence interval (CI) 1.29–1.76] and in women (HR 1.24; 95% CI 1.05–1.46). Associations with TIA were only present in women (HR 1.51; 95% CI 1.26–1.82) but not in men (HR 1.02; 95% CI 0.83–1.26). Excluding persons with a history of clinical coronary heart disease, heart failure or atrial fibrillation and censoring for clinical heart disease during follow-up did not change the associations. Conclusions: Higher NT-proBNP is associated with incident stroke in men and women and with incident TIA only in women. These associations are independent of clinical heart disease preceding cerebrovascular disease.
Introduction An important cornerstone of research on cardiovascular diseases is to identify subclinical markers that can elucidate etiology or serve as predictive markers. Amino-terminal pro-B-type natriuretic peptide (NTproBNP) is an emerging marker that is excreted in response to cardiac wall stress [1,2] and has recently been shown to predict heart disease [3,4]. Importantly, Correspondence: M. A. Ikram, MD, PhD, Department of Epidemiology, Erasmus MC University Medical Center, PO Box 2040, 3000 CA Rotterdam, The Netherlands (tel.: +31107043489; fax: +31107044657; e-mail: [email protected]).
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NT-proBNP provides information on cardiac overload and dysfunction even in the absence of clinical heart failure and therefore could serve as a subclinical marker [5]. Previous studies have also shown an increased risk of stroke in persons with high NT-proBNP [3,6–10], but there are still some knowledge gaps. First, it remains unclear how clinical heart disease (e.g. coronary heart disease, heart failure and atrial fibrillation) affects the reported association between NT-proBNP and stroke. It is conceivable that persons with high NT-proBNP, reflecting subclinical heart disease, first suffer from clinical heart disease during follow-up
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which subsequently leads to a stroke [11–13]. Secondly, if NT-proBNP truly could act as a subclinical marker of stroke, it is important to study its role in the earliest clinical manifestation of cerebrovascular disease, which is often a transient ischaemic attack (TIA). Importantly, at the time of TIA effective therapy can still be installed to prevent subsequent stroke [14]. Finally, given the differences in occurrence and risk factor profiles of cardiovascular disease between men and women [15,16], the association between NTproBNP and cerebrovascular disease merits further investigation for sex differences. Therefore, the association of NT-proBNP with stroke and TIA in men and women separately was investigated. Furthermore, the role of prevalent and incident heart disease on this association was studied.
Materials and methods Setting and study population
This study was embedded within the Rotterdam Study, a prospective population-based cohort study amongst persons aged 55 years and older residing in Ommoord, a suburb of Rotterdam, the Netherlands [17]. The study started in 1990 with 7983 participants and was extended in 2000 with 3011 persons. Followup examinations take place every 3–4 years. For the current study, baseline data were collected between 1997 and 2001. NT-proBNP was measured in 3923 participants of the original cohort and 2566 participants of the second cohort. After excluding 804 participants with a history of stroke, TIA or heart failure, and 74 participants with NT-proBNP above the age-specific heart failure limit (50–75 years, 108 pmol/l; >75 years, 216 pmol/l) [18], a total of 5611 participants (2374 men and 3237 women) were eligible for analysis. The Rotterdam Study has been approved by the medical ethics committee according to the Population Study Act Rotterdam Study. Written informed consent was obtained from all participants. Amino-terminal pro-B-type natriuretic peptide measurement
Blood samples for NT-proBNP assessment were collected in glass tubes containing clot activator and gel for serum separation and stored at 80°C. NT-proBNP was measured using a commercially available electrochemiluminescence immunoassay (Elecsys proBNP; F Hoffman-La Roche Ltd., Basel, Switzerland) on an Elecsys 2010 analyzer [6]. Precision, analytical sensitivity and stability of the system have been described [19].
Assessment of cerebrovascular events
At study entry, history of stroke and TIA was assessed using home interviews and confirmed by reviewing medical records. Subsequently, participants were continuously followed up for stroke and TIA through digital linkage of general practitioners’ files with the study database. Furthermore, nursing home physicians’ files and files from general practitioners of participants who moved out of the district were checked on a regular basis [20]. For all potential strokes and TIAs, hospital discharge letters and information from general practitioners was collected. Research physicians reviewed the information and an experienced neurologist verified the strokes and TIAs [21,22]. Strokes were further classified into ischaemic or hemorrhagic based on neuroimaging reports. Subarachnoid hemorrhages were excluded. Infarcts that turned hemorrhagic were classified as ischaemic stroke. If neuroimaging was lacking, a stroke was classified as unspecified. TIAs were further classified into focal or mixed. An event was focal if only symptoms attributable to dysfunction of one arterial territory of the brain were reported. An event was classified as mixed if diffuse non-localizing cerebral symptoms were reported as well [22]. Purely non-focal events were not analyzed as they are currently not included in the internationally used definition of TIA [23]. Follow-up was completed until 1 January 2012 for 95.6% of potential person-years. Covariates
Details on assessment of anthropometrics, cardiovascular risk factors (blood pressure, total cholesterol, high-density cholesterol, creatinine, diabetes mellitus and smoking) and use of medication have been described previously [4]. Within the heart disease definition the following were included: heart failure, coronary heart disease (defined as myocardial infarction or coronary revascularization procedure) and atrial fibrillation. Heart diseases were assessed through active follow-up and adjudicated using standardized definitions similar to the follow-up for stroke and TIA [20]. Statistical analyses
Amino-terminal pro-B-type natriuretic peptide values were natural-log-transformed and entered per standard deviation (SD) increase into Cox proportional hazards models. Hazard ratios (HRs) were also calculated for sex-specific tertiles of NT-proBNP. The association of NT-proBNP with any cerebrovascular event (stroke or TIA) and with stroke or TIA separately,
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censoring follow-up at the date of the other event if that occurred first, was examined. Thus, participants were censored at date of stroke, date of TIA, date of death, last date of follow-up or 1 January 2012, whichever came first. All models were adjusted for age and were stratified by sex to allow for sex-specific effects. Interaction terms were tested to identify significant differences between men and women. In multivariate adjusted models, additional adjustments for cardiovascular risk factors and blood-pressure-lowering, lipid-lowering and antithrombotic (including antiplatelet and anticoagulant) drugs were made. Missing data on covariates (for all covariates 4.6% or less) were imputed based on the other covariates using multiple imputation with five imputation sets. In sensitivity analyses, associations between NTproBNP and stroke were investigated without censoring for TIA, stratification was done for antiplatelet and anticoagulant drug use, and associations between NT-proBNP and stroke and TIA were investigated after additionally excluding participants with a history of atrial fibrillation or coronary heart disease at baseline and censoring for incident atrial fibrillation, coronary heart disease and heart failure during follow-up. Follow-up for atrial fibrillation and heart failure was available until 2008 and 2010, respectively. Therefore a final sensitivity analysis for stroke and TIA with follow-up ending in 2008 was done. All analyses were done using IBM SPSS Statistics version 21.0 (IBM Corp., Armonk, NY, USA).
Results The baseline characteristics of the study population are presented in Table 1. A total of 2374 men and 3237 women were eligible for analysis. Mean age (SD) was 67.9 (7.5) years in men and 69.2 (8.4) years in women. After a mean follow-up of 9.3 (3.4) years the first presentation of a cerebrovascular event was stroke in 195 men and TIA in 118 men. After a mean follow-up of 9.8 (3.3) years the first presentation of a cerebrovascular event was stroke in 230 women and TIA in 187 women. In Table 2 associations between NT-proBNP levels and cerebrovascular events are presented. The risk of any cerebrovascular event was similar in men and women: multivariate adjusted HR per SD increase in NT-proBNP in men 1.31 [95% confidence interval (CI) 1.15–1.48] and in women 1.36 (95% CI 1.20– 1.53). Associations with stroke were stronger in men (HR 1.50, 95% CI 1.29–1.76) compared to women (HR 1.24, 95% CI 1.05–1.46), but this difference was not statistically significant (P = 0.21). Associations were found for both ischaemic and hemorrhagic
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stroke. Associations with TIA were only present in women (HR 1.51, 95% CI 1.26–1.82) but not in men (HR 1.02, 95% CI 0.83–1.26), which was a statistically significant interaction (P < 0.01) (Table 2). With NT-proBNP levels in tertiles associations with stroke in men and women and with TIA only in women were again found (Table 3; Fig. 1). Without censoring for TIA, the effect size for stroke in women was higher (HR 1.36, 95% CI 1.16–1.59) (Table 4). Associations with hemorrhagic stroke and mixed TIA attenuated after excluding participants with a history of heart disease and censoring at time of incident heart disease (Table 5). Other associations remained similar. Ending the study follow-up in 2008 did not change the lack of an effect of preceding heart disease on the associations (data not shown). Associations were slightly weaker in persons who used anticoagulant or antiplatelet drugs (Table S1).
Discussion Higher levels of NT-proBNP were associated with a higher risk of cerebrovascular events. Associations with stroke were present for both men and women, whereas associations with TIA were only present in women. Associations were independent of clinical heart disease preceding cerebrovascular disease. Several other population-based studies have shown that an increased NT-proBNP level is related to a higher risk of cerebrovascular events [3,6–10]. However, these studies did not exclude all participants with history of heart disease or account for the occurrence of heart disease during follow-up. One study adjusted for the presence of coronary heart disease, heart failure and atrial fibrillation and found that the association remained unchanged [7]. This was consistent with our finding that associations were independent of clinical heart disease preceding the cerebrovascular disease, suggesting that a higher NT-proBNP as marker of subclinical heart disease is associated with a higher risk of cerebrovascular events. Subclinical heart disease might cause TIA or ischaemic stroke through intracardiac thrombus formation, the most important reason for stroke in persons with overt heart disease [11–13]. Another potential mechanism is that TIA or ischaemic stroke in persons with an increased NTproBNP is caused by paroxysmal atrial fibrillation which is not picked up by diagnostic electrocardiograms [24]. Associations with hemorrhagic stroke might be the consequence of antithrombotic drug use. Furthermore, the associations with any cerebrovascular event might reflect the shared effect of cardiovascular risk factors on NT-proBNP and cerebrovascular events, although after adjusting for cardiovascular risk
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factors the associations were similar. Still, residual confounding cannot be excluded. Previous studies found that the effect of NT-proBNP on cerebrovascular disease was similar for men and women [3,6–10]. However, those studies did not examine associations with only TIA or with stroke independent from TIA. In our study a higher NT-proBNP led to a higher risk of TIA in women, whereas in men there was only a higher risk of stroke. This suggests that subclinical heart disease, indicated by a higher NT-proBNP, leads to a cerebrovascular event that at its first presentation is already more severe in men than in women. A reason might be that men have more atherosclerosis [25] and therefore an additional thrombus from the heart possibly has a greater impact. Women might also recover better after a cerebrovascular event caused by subclinical heart disease and therefore suffer a TIA instead of a stroke. Furthermore, this might be an indication of diagnostic bias; a similar event might be reported as a stroke more often in men and in women more often as a TIA. This might happen if men are more likely to have magnetic resonance imaging compared to women, because a short-lasting event is more likely to be classified as a stroke if a relevant acute infarct is seen. Moreover, sex differences might have occurred by chance. Our findings have several implications for future research. The mechanism by which NT-proBNP relates to ischaemic stroke, hemorrhagic stroke and TIA needs to be elucidated further. As associations with focal TIA were different compared to mixed TIA, differences in etiology of those attacks should also be identified. Furthermore, NT-proBNP needs to be investigated for its predictive role in stroke, even in
Table 1 Baseline characteristics
Age, years Systolic blood pressure, mmHg Diastolic blood pressure, mmHg Blood-pressurelowering drugs, % Total cholesterol, mmol/l High-density lipoprotein cholesterol, mmol/l Lipid-lowering drugs, % Anticoagulant drugs, % Antiplatelet drugs, % Creatinine, lmol/l Diabetes mellitus, % Smoking Never, % Former, % Current, % NT-proBNP, pmol/la NT-proBNP, pmol/lb Tertile 1 Tertile 2 Tertile 3
Men N = 2374
Women N = 3237
67.9 (7.5) 144 (21)
69.2 (8.4) 142 (21)
79 (11)
76 (11)
459 (20.1)
738 (24.0)
5.6 (1.0)
6.0 (0.9)
1.2 (0.3)
1.5 (0.4)
296 (12.9)
367 (11.8)
85 (3.7)
44 (1.4)
373 (16.3) 88 (16) 284 (12.0)
333 (10.7) 70 (13) 322 (10.0)
275 1530 552 7.7
(11.7) (64.9) (23.4) (4.1–15.8)
1375 1272 541 10.5
0.59–5.06 5.06–12.30 12.30–210.10
(43.1) (39.9) (17.0) (5.9–18.3)
0.59–7.30 7.30–15.38 15.38–212.20
NT-proBNP, amino-terminal pro-B-type natriuretic peptide. Data are presented as mean (standard deviations) or counts (percentages). a Median and interquartile range; brange in each tertile.
Table 2 Amino-terminal pro-B-type natriuretic peptide (NT-proBNP) and the risk of cerebrovascular events Men N = 2374
Any cerebrovascular event Any stroke Ischaemic stroke Hemorrhagic stroke Unspecified stroke Any transient ischaemic attack Focal TIA Mixed TIA
Women N = 3237
n
Model I HR (95% CI)
Model II HR (95% CI)
n
Model I HR (95% CI)
Model II HR (95% CI)
313 195 139 18 38 118
1.37 1.60 1.68 1.86 1.31 1.05
1.31 1.50 1.59 1.70 1.14 1.02
1.48) 1.76) 1.92) 2.84) 1.63) 1.26)
417 230 143 26 61 187
1.36 1.28 1.31 1.43 1.15 1.47
1.36 1.24 1.30 1.17 1.11 1.51
101 17
1.08 (0.88; 1.34) 0.85 (0.50; 1.45)
1.05 (0.83; 1.31) 0.88 (0.52; 1.49)
145 42
1.48 (1.21; 1.81) 1.42 (0.98; 2.06)
(1.22; (1.39; (1.41; (1.16; (0.95; (0.86;
1.54) 1.85) 1.99) 2.97) 1.81) 1.27)
(1.15; (1.29; (1.32; (1.02; (0.80; (0.83;
(1.21; (1.09; (1.07; (0.90; (0.84; (1.23;
1.53) 1.51) 1.61) 2.30) 1.58) 1.75)
(1.20; (1.05; (1.05; (0.72; (0.80; (1.26;
1.53) 1.46) 1.61) 1.90) 1.53) 1.82)
1.55 (1.26; 1.90) 1.41 (0.96; 2.06)
n, number of events; N, number of persons at risk; values are hazard ratios (HRs) per SD increase in natural-log-transformed NT-proBNP level (SD 0.96) with 95% confidence intervals (CIs); analyses with stroke were censored for incident transient ischaemic attack (TIA) and analyses with TIA were censored for incident stroke. Model I, adjusted for age; model II, adjusted for age, systolic blood pressure, diastolic blood pressure, blood-pressure-lowering drugs, total cholesterol, high-density lipoprotein cholesterol, lipid-lowering drugs, antithrombotic drugs, creatinine, smoking and diabetes mellitus.
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Table 3 Amino-terminal pro-B-type natriuretic peptide (NT-proBNP) in tertiles and the risk of cerebrovascular events Men
n/N Any cerebrovascular event Tertile 1 61/790 Tertile 2 97/793 Tertile 3 155/791 Any stroke Tertile 1 29/790 Tertile 2 55/793 Tertile 3 111/791 Any transient ischaemic attack Tertile 1 32/790 Tertile 2 42/793 Tertile 3 44/791
Women Model I HR (95% CI)
Model II HR (95% CI)
n/N
Model I HR (95% CI)
Model II HR (95% CI)
1 (reference) 1.35 (0.98; 1.88) 2.00 (1.44; 2.76)
1 (reference) 1.29 (0.93; 1.80) 1.81 (1.29; 2.53)
85/1080 115/1076 217/1081
1 (reference) 1.07 (0.81; 1.42) 1.78 (1.35; 2.33)
1 (reference) 1.08 (0.81; 1.43) 1.77 (1.34; 2.33)
1 (reference) 1.59 (1.01; 2.51) 2.91 (1.87; 4.52)
1 (reference) 1.51 (0.95; 2.39) 2.57 (1.63; 4.06)
50/1080 63/1076 117/1081
1 (reference) 0.94 (0.65; 1.37) 1.45 (1.01; 2.08)
1 (reference) 0.94 (0.64; 1.37) 1.37 (0.94; 1.99)
1 (reference) 1.15 (0.72; 1.84) 1.14 (0.69; 1.89)
1 (reference) 1.11 (0.69; 1.79) 1.09 (0.64; 1.83)
35/1080 52/1076 100/1081
1 (reference) 1.26 (0.82; 1.95) 2.29 (1.51; 3.46)
1 (reference) 1.28 (0.83; 1.98) 2.40 (1.57; 3.66)
n, number of events; N, number of persons at risk; values are hazard ratios (HRs) per sex-specific tertile of NT-proBNP level with 95% confidence intervals (CIs); analyses with stroke were censored for incident transient ischaemic attack (TIA) and analyses with TIA were censored for incident stroke. Model I, adjusted for age; model II, adjusted for age, systolic blood pressure, diastolic blood pressure, blood-pressure-lowering drugs, total cholesterol, high-density lipoprotein cholesterol, lipid-lowering drugs, antithrombotic drugs, creatinine, smoking and diabetes mellitus.
persons free of heart disease. In our study NT-proBNP was merely used as a marker for subclinical heart disease, but it might even be a target for therapy, as is shown in the PARADIGM HF trial [26]. Additionally, studies should disentangle the exact role of antithrombotic medication in the associations of
Figure 1 Cumulative incidence of cerebrovascular events in men and women by tertiles of amino-terminal pro-B-type natriuretic peptide levels. Stroke was censored for incident transient ischaemic attack (TIA). TIA was censored for incident stroke.
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NT-proBNP with cerebrovascular events. Finally, future research should confirm whether subclinical heart disease is indeed a more important cause of TIA in women compared to men and whether future strokes in women can be prevented with more attention towards subclinical heart disease after TIA.
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Table 4 Amino-terminal pro-B-type natriuretic peptide (NT-proBNP) and the risk of stroke, without censoring for transient ischaemic attack (TIA) Men N = 2374
Any stroke Ischaemic stroke Hemorrhagic stroke Unspecified stroke
Women N = 3237
n
Model I HR (95% CI)
Model II HR (95% CI)
n
Model I HR (95% CI)
Model II HR (95% CI)
208 149 18 41
1.59 1.63 1.85 1.40
1.51 1.56 1.71 1.29
261 162 28 71
1.41 1.46 1.40 1.31
1.36 1.45 1.15 1.22
(1.38; (1.38; (1.16; (1.02;
1.82) 1.92) 2.96) 1.90)
(1.30; (1.30; (1.02; (0.92;
1.76) 1.86) 2.85) 1.81)
(1.22; (1.20; (0.89; (0.97;
1.64) 1.76) 2.21) 1.75)
(1.16; (1.19; (0.72; (0.90;
1.59) 1.77) 1.83) 1.66)
n, number of events; N, number of persons at risk; values are hazard ratios (HRs) per SD increase in natural-log-transformed NT-proBNP level (SD 0.96) with 95% confidence intervals (CIs). Model I, adjusted for age; model II, adjusted for age, systolic blood pressure, diastolic blood pressure, blood-pressure-lowering drugs, total cholesterol, high-density lipoprotein cholesterol, lipid-lowering drugs, antithrombotic drugs, creatinine, smoking and diabetes mellitus. Table 5 Amino-terminal pro-B-type natriuretic peptide (NT-proNBP) and the risk of cerebrovascular events, censored at the occurrence of incident heart disease Men N = 1805
Any cerebrovascular event Any stroke Ischaemic stroke Hemorrhagic stroke Unspecified stroke Any transient ischaemic attack Focal TIA Mixed TIA
Women N = 2725
n
Model I HR (95% CI)
Model II HR (95% CI)
n
Model I HR (95% CI)
Model II HR (95% CI)
198 118 88 7 23 80 69 11
1.52 1.98 2.09 1.08 1.98 1.01 1.03 0.91
1.46 1.86 2.02 1.15 1.61 1.01 1.00 1.06
318 174 110 20 44 144 112 32
1.38 1.32 1.30 1.33 1.33 1.45 1.53 1.20
1.37 1.26 1.28 1.17 1.28 1.53 1.62 1.24
(1.29; (1.61; (1.65; (0.44; (1.25; (0.77; (0.77; (0.45;
1.79) 2.43) 2.65) 2.68) 3.13) 1.32) 1.37) 1.86)
(1.22; (1.48; (1.55; (0.42; (0.94; (0.76; (0.74; (0.52;
1.74) 2.34) 2.62) 3.11) 2.75) 1.34) 1.35) 2.18)
(1.20; (1.09; (1.02; (0.76; (0.91; (1.18; (1.21; (0.77;
1.59) 1.60) 1.66) 2.34) 1.96) 1.79) 1.94) 1.89)
(1.19; (1.03; (0.99; (0.66; (0.86; (1.23; (1.27; (0.77;
1.59) 1.54) 1.64) 2.08) 1.92) 1.90) 2.08) 1.99)
n, number of events; N, number of persons at risk; values are hazard ratios (HRs) per SD increase in natural-log-transformed NT-proBNP level (SD 0.96) with 95% confidence intervals (CIs); analyses with stroke were censored for incident transient ischaemic attack (TIA) and analyses with TIA were censored for incident stroke. Model I, adjusted for age; model II, adjusted for age, systolic blood pressure, diastolic blood pressure, blood-pressure-lowering drugs, total cholesterol, high-density lipoprotein cholesterol, lipid-lowering drugs, antithrombotic drugs, creatinine, smoking and diabetes mellitus.
The strengths of this study are the population-based setting, the large study population and the thorough collection of events. A limitation is that follow-up for heart failure and atrial fibrillation was incomplete. Events in the last years of follow-up could therefore not be censored. However, also with shorter follow-up until 2008 censoring at the time of incident heart disease did not attenuate the results. Another limitation is that valvular heart disease was not systematically measured as a potential confounding factor [12,27].
Conclusion Our results show that higher levels of NT-proBNP are associated with a higher risk of cerebrovascular events. For stroke this risk was present in men and women, for TIA only in women. These associations were independent of prevalent and incident heart disease during follow-up, suggesting that a high NT-proBNP as marker of subclinical heart disease
leads to an increased risk of stroke in men and women and of TIA in women.
Acknowledgements The Rotterdam Study is supported by the Erasmus MC University Medical Center and Erasmus University Rotterdam; the Netherlands Organization for Scientific Research (NWO); the Netherlands Organization for Health Research and Development (ZonMW); the Research Institute for Diseases in the Elderly (RIDE); the Netherlands Genomics Initiative (NGI); the Ministry of Education, Culture and Science; the Ministry of Health, Welfare and Sports; the European Commission (DG XII); and the Municipality of Rotterdam. Further support was obtained from the Netherlands Consortium for Healthy Ageing (NCHA), Netherlands Heart Foundation (2012T008) and Erasmus MC Fellowship 2013. Oscar H. Franco works in ErasmusAGE, a center for ageing research
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within the Department of Epidemiology, Erasmus MC, funded by Nestle Nutrition (Nestec Ltd), Metagenics Inc. and AXA. Maryam Kavousi is supported by the AXA Research Fund. None of the funding organizations or sponsors were involved in the design and conduct of the study; collection, management analysis and interpretation of the data; and preparation, review or approval of the manuscript.
Disclosure of conflicts of interest Dr Leening received grants from the European Society of Cardiology (ESC), Erasmus University Trustfonds and Prins Bernhard Cultuurfonds. Dr Franco received grants from Nestle and Metagenics.
Supporting Information Additional Supporting Information may be found in the online version of this article: Table S1. NT-proBNP and the risk of any cerebrovascular event, stratified for antithrombotic drug use.
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10. Wang TJ, Larson MG, Levy D, et al. Plasma natriuretic peptide levels and the risk of cardiovascular events and death. N Engl J Med 2004; 350: 655–663. 11. Dutta M, Hanna E, Das P, Steinhubl SR. Incidence and prevention of ischemic stroke following myocardial infarction: review of current literature. Cerebrovasc Dis 2006; 22: 331–339. 12. Ferro JM. Cardioembolic stroke: an update. Lancet Neurol 2003; 2: 177–188. 13. Alberts VP, Bos MJ, Koudstaal P, et al. Heart failure and the risk of stroke: the Rotterdam Study. Eur J Epidemiol 2010; 25: 807–812. 14. de Lau LM, den Hertog HM, van den Herik EG, Koudstaal PJ. Predicting and preventing stroke after transient ischemic attack. Expert Rev Neurother 2009; 9: 1159–1170. 15. Lenzen MJ, Rosengren A, Scholte op Reimer WJ, et al. Management of patients with heart failure in clinical practice: differences between men and women. Heart 2008; 94: e10. 16. Mosca L, Barrett-Connor E, Wenger NK. Sex/gender differences in cardiovascular disease prevention: what a difference a decade makes. Circulation 2011; 124: 2145– 2154. 17. Hofman A, Darwish Murad S, van Duijn CM, et al. The Rotterdam Study: 2014 objectives and design update. Eur J Epidemiol 2013; 28: 889–926. 18. Januzzi JL, van Kimmenade R, Lainchbury J, et al. NTproBNP testing for diagnosis and short-term prognosis in acute destabilized heart failure: an international pooled analysis of 1256 patients: the International Collaborative of NT-proBNP Study. Eur Heart J 2006; 27: 330–337. 19. Yeo KT, Wu AH, Apple FS, et al. Multicenter evaluation of the Roche NT-proBNP assay and comparison to the Biosite Triage BNP assay. Clin Chim Acta 2003; 338: 107–115. 20. Leening MJ, Kavousi M, Heeringa J, et al. Methods of data collection and definitions of cardiac outcomes in the Rotterdam Study. Eur J Epidemiol 2012; 27: 173–185. 21. Wieberdink RG, Ikram MA, Hofman A, Koudstaal PJ, Breteler MM. Trends in stroke incidence rates and stroke risk factors in Rotterdam, the Netherlands, from 1990 to 2008. Eur J Epidemiol 2012; 27: 287–295. 22. Bos MJ, van Rijn MJ, Witteman JC, Hofman A, Koudstaal PJ, Breteler MM. Incidence and prognosis of transient neurological attacks. JAMA 2007; 298: 2877–2885. 23. Special report from the National Institute of Neurological Disorders and Stroke. Classification of cerebrovascular diseases III. Stroke 1990; 21: 637–676. 24. Wachter R, Lahno R, Haase B, et al. Natriuretic peptides for the detection of paroxysmal atrial fibrillation in patients with cerebral ischemia – the Find-AF study. PLoS ONE 2012; 7: e34351. 25. Kardys I, Vliegenthart R, Oudkerk M, Hofman A, Witteman JC. The female advantage in cardiovascular disease: do vascular beds contribute equally? Am J Epidemiol 2007; 166: 403–412. 26. McMurray JJ, Packer M, Desai AS, et al. Angiotensinneprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014; 371: 993–1004. 27. Gerber IL, Stewart RA, Legget ME, et al. Increased plasma natriuretic peptide levels reflect symptom onset in aortic stenosis. Circulation 2003; 107: 1884–1890.
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N-terminal pro-B-type natriuretic peptide and the risk of stroke and transient ischaemic attack: the Rotterdam Study M. L. P. Portegiesa,b, M. Kavousia, M. J. G. Leeninga,c, M. J. Bosa, A. H. van den Meirackerd, A. Hofmana, O. H. Francoa, P. J. Koudstaalb and M. A. Ikrama,b,e Department of Epidemiology, Erasmus MC University Medical Center, Rotterdam; bDepartment of Neurology, Erasmus MC University Medical Center, Rotterdam; cDepartment of Cardiology, Erasmus MC University Medical Center, Rotterdam; dDepartment of Internal Medicine, Erasmus MC University Medical Center, Rotterdam; and eDepartment of Radiology, Erasmus MC University Medical Center, Rotterdam, The Netherlands
Keywords:
epidemiology, NTproBNP, risk factors, stroke, transient ischaemic attack Received 27 June 2014 Accepted 27 October 2014 European Journal of Neurology 2015, 22: 695–701 doi:10.1111/ene.12633
Background and purpose: Amino-terminal pro-B-type natriuretic peptide (NTproBNP) is a predictor of heart disease. It has also been related to stroke, but its association with transient ischaemic attacks (TIAs) is unclear. Moreover, it is unknown how clinical heart disease influences this relation. Within the prospective population-based Rotterdam Study, the association of NT-proBNP with stroke and TIA was examined and the role of heart disease on this association was investigated. Methods: NT-proBNP was measured in 1997–2001 in 5611 participants (mean age 68.7 years; 57.7% women) without a history of stroke, TIA or heart failure. Follow-up for stroke and TIA finished in 2012. Models were adjusted for age and cardiovascular risk factors, and were stratified by sex. Results: During 22 058 person-years 195 men suffered a stroke and 118 a TIA. During 31 825 person-years 230 women suffered a stroke and 187 a TIA. Higher NT-proBNP was associated with a higher risk of stroke in men [hazard ratio (HR) per SD increase 1.50; 95% confidence interval (CI) 1.29–1.76] and in women (HR 1.24; 95% CI 1.05–1.46). Associations with TIA were only present in women (HR 1.51; 95% CI 1.26–1.82) but not in men (HR 1.02; 95% CI 0.83–1.26). Excluding persons with a history of clinical coronary heart disease, heart failure or atrial fibrillation and censoring for clinical heart disease during follow-up did not change the associations. Conclusions: Higher NT-proBNP is associated with incident stroke in men and women and with incident TIA only in women. These associations are independent of clinical heart disease preceding cerebrovascular disease.
Introduction An important cornerstone of research on cardiovascular diseases is to identify subclinical markers that can elucidate etiology or serve as predictive markers. Amino-terminal pro-B-type natriuretic peptide (NTproBNP) is an emerging marker that is excreted in response to cardiac wall stress [1,2] and has recently been shown to predict heart disease [3,4]. Importantly, Correspondence: M. A. Ikram, MD, PhD, Department of Epidemiology, Erasmus MC University Medical Center, PO Box 2040, 3000 CA Rotterdam, The Netherlands (tel.: +31107043489; fax: +31107044657; e-mail: [email protected]).
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NT-proBNP provides information on cardiac overload and dysfunction even in the absence of clinical heart failure and therefore could serve as a subclinical marker [5]. Previous studies have also shown an increased risk of stroke in persons with high NT-proBNP [3,6–10], but there are still some knowledge gaps. First, it remains unclear how clinical heart disease (e.g. coronary heart disease, heart failure and atrial fibrillation) affects the reported association between NT-proBNP and stroke. It is conceivable that persons with high NT-proBNP, reflecting subclinical heart disease, first suffer from clinical heart disease during follow-up
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which subsequently leads to a stroke [11–13]. Secondly, if NT-proBNP truly could act as a subclinical marker of stroke, it is important to study its role in the earliest clinical manifestation of cerebrovascular disease, which is often a transient ischaemic attack (TIA). Importantly, at the time of TIA effective therapy can still be installed to prevent subsequent stroke [14]. Finally, given the differences in occurrence and risk factor profiles of cardiovascular disease between men and women [15,16], the association between NTproBNP and cerebrovascular disease merits further investigation for sex differences. Therefore, the association of NT-proBNP with stroke and TIA in men and women separately was investigated. Furthermore, the role of prevalent and incident heart disease on this association was studied.
Materials and methods Setting and study population
This study was embedded within the Rotterdam Study, a prospective population-based cohort study amongst persons aged 55 years and older residing in Ommoord, a suburb of Rotterdam, the Netherlands [17]. The study started in 1990 with 7983 participants and was extended in 2000 with 3011 persons. Followup examinations take place every 3–4 years. For the current study, baseline data were collected between 1997 and 2001. NT-proBNP was measured in 3923 participants of the original cohort and 2566 participants of the second cohort. After excluding 804 participants with a history of stroke, TIA or heart failure, and 74 participants with NT-proBNP above the age-specific heart failure limit (50–75 years, 108 pmol/l; >75 years, 216 pmol/l) [18], a total of 5611 participants (2374 men and 3237 women) were eligible for analysis. The Rotterdam Study has been approved by the medical ethics committee according to the Population Study Act Rotterdam Study. Written informed consent was obtained from all participants. Amino-terminal pro-B-type natriuretic peptide measurement
Blood samples for NT-proBNP assessment were collected in glass tubes containing clot activator and gel for serum separation and stored at 80°C. NT-proBNP was measured using a commercially available electrochemiluminescence immunoassay (Elecsys proBNP; F Hoffman-La Roche Ltd., Basel, Switzerland) on an Elecsys 2010 analyzer [6]. Precision, analytical sensitivity and stability of the system have been described [19].
Assessment of cerebrovascular events
At study entry, history of stroke and TIA was assessed using home interviews and confirmed by reviewing medical records. Subsequently, participants were continuously followed up for stroke and TIA through digital linkage of general practitioners’ files with the study database. Furthermore, nursing home physicians’ files and files from general practitioners of participants who moved out of the district were checked on a regular basis [20]. For all potential strokes and TIAs, hospital discharge letters and information from general practitioners was collected. Research physicians reviewed the information and an experienced neurologist verified the strokes and TIAs [21,22]. Strokes were further classified into ischaemic or hemorrhagic based on neuroimaging reports. Subarachnoid hemorrhages were excluded. Infarcts that turned hemorrhagic were classified as ischaemic stroke. If neuroimaging was lacking, a stroke was classified as unspecified. TIAs were further classified into focal or mixed. An event was focal if only symptoms attributable to dysfunction of one arterial territory of the brain were reported. An event was classified as mixed if diffuse non-localizing cerebral symptoms were reported as well [22]. Purely non-focal events were not analyzed as they are currently not included in the internationally used definition of TIA [23]. Follow-up was completed until 1 January 2012 for 95.6% of potential person-years. Covariates
Details on assessment of anthropometrics, cardiovascular risk factors (blood pressure, total cholesterol, high-density cholesterol, creatinine, diabetes mellitus and smoking) and use of medication have been described previously [4]. Within the heart disease definition the following were included: heart failure, coronary heart disease (defined as myocardial infarction or coronary revascularization procedure) and atrial fibrillation. Heart diseases were assessed through active follow-up and adjudicated using standardized definitions similar to the follow-up for stroke and TIA [20]. Statistical analyses
Amino-terminal pro-B-type natriuretic peptide values were natural-log-transformed and entered per standard deviation (SD) increase into Cox proportional hazards models. Hazard ratios (HRs) were also calculated for sex-specific tertiles of NT-proBNP. The association of NT-proBNP with any cerebrovascular event (stroke or TIA) and with stroke or TIA separately,
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censoring follow-up at the date of the other event if that occurred first, was examined. Thus, participants were censored at date of stroke, date of TIA, date of death, last date of follow-up or 1 January 2012, whichever came first. All models were adjusted for age and were stratified by sex to allow for sex-specific effects. Interaction terms were tested to identify significant differences between men and women. In multivariate adjusted models, additional adjustments for cardiovascular risk factors and blood-pressure-lowering, lipid-lowering and antithrombotic (including antiplatelet and anticoagulant) drugs were made. Missing data on covariates (for all covariates 4.6% or less) were imputed based on the other covariates using multiple imputation with five imputation sets. In sensitivity analyses, associations between NTproBNP and stroke were investigated without censoring for TIA, stratification was done for antiplatelet and anticoagulant drug use, and associations between NT-proBNP and stroke and TIA were investigated after additionally excluding participants with a history of atrial fibrillation or coronary heart disease at baseline and censoring for incident atrial fibrillation, coronary heart disease and heart failure during follow-up. Follow-up for atrial fibrillation and heart failure was available until 2008 and 2010, respectively. Therefore a final sensitivity analysis for stroke and TIA with follow-up ending in 2008 was done. All analyses were done using IBM SPSS Statistics version 21.0 (IBM Corp., Armonk, NY, USA).
Results The baseline characteristics of the study population are presented in Table 1. A total of 2374 men and 3237 women were eligible for analysis. Mean age (SD) was 67.9 (7.5) years in men and 69.2 (8.4) years in women. After a mean follow-up of 9.3 (3.4) years the first presentation of a cerebrovascular event was stroke in 195 men and TIA in 118 men. After a mean follow-up of 9.8 (3.3) years the first presentation of a cerebrovascular event was stroke in 230 women and TIA in 187 women. In Table 2 associations between NT-proBNP levels and cerebrovascular events are presented. The risk of any cerebrovascular event was similar in men and women: multivariate adjusted HR per SD increase in NT-proBNP in men 1.31 [95% confidence interval (CI) 1.15–1.48] and in women 1.36 (95% CI 1.20– 1.53). Associations with stroke were stronger in men (HR 1.50, 95% CI 1.29–1.76) compared to women (HR 1.24, 95% CI 1.05–1.46), but this difference was not statistically significant (P = 0.21). Associations were found for both ischaemic and hemorrhagic
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stroke. Associations with TIA were only present in women (HR 1.51, 95% CI 1.26–1.82) but not in men (HR 1.02, 95% CI 0.83–1.26), which was a statistically significant interaction (P < 0.01) (Table 2). With NT-proBNP levels in tertiles associations with stroke in men and women and with TIA only in women were again found (Table 3; Fig. 1). Without censoring for TIA, the effect size for stroke in women was higher (HR 1.36, 95% CI 1.16–1.59) (Table 4). Associations with hemorrhagic stroke and mixed TIA attenuated after excluding participants with a history of heart disease and censoring at time of incident heart disease (Table 5). Other associations remained similar. Ending the study follow-up in 2008 did not change the lack of an effect of preceding heart disease on the associations (data not shown). Associations were slightly weaker in persons who used anticoagulant or antiplatelet drugs (Table S1).
Discussion Higher levels of NT-proBNP were associated with a higher risk of cerebrovascular events. Associations with stroke were present for both men and women, whereas associations with TIA were only present in women. Associations were independent of clinical heart disease preceding cerebrovascular disease. Several other population-based studies have shown that an increased NT-proBNP level is related to a higher risk of cerebrovascular events [3,6–10]. However, these studies did not exclude all participants with history of heart disease or account for the occurrence of heart disease during follow-up. One study adjusted for the presence of coronary heart disease, heart failure and atrial fibrillation and found that the association remained unchanged [7]. This was consistent with our finding that associations were independent of clinical heart disease preceding the cerebrovascular disease, suggesting that a higher NT-proBNP as marker of subclinical heart disease is associated with a higher risk of cerebrovascular events. Subclinical heart disease might cause TIA or ischaemic stroke through intracardiac thrombus formation, the most important reason for stroke in persons with overt heart disease [11–13]. Another potential mechanism is that TIA or ischaemic stroke in persons with an increased NTproBNP is caused by paroxysmal atrial fibrillation which is not picked up by diagnostic electrocardiograms [24]. Associations with hemorrhagic stroke might be the consequence of antithrombotic drug use. Furthermore, the associations with any cerebrovascular event might reflect the shared effect of cardiovascular risk factors on NT-proBNP and cerebrovascular events, although after adjusting for cardiovascular risk
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factors the associations were similar. Still, residual confounding cannot be excluded. Previous studies found that the effect of NT-proBNP on cerebrovascular disease was similar for men and women [3,6–10]. However, those studies did not examine associations with only TIA or with stroke independent from TIA. In our study a higher NT-proBNP led to a higher risk of TIA in women, whereas in men there was only a higher risk of stroke. This suggests that subclinical heart disease, indicated by a higher NT-proBNP, leads to a cerebrovascular event that at its first presentation is already more severe in men than in women. A reason might be that men have more atherosclerosis [25] and therefore an additional thrombus from the heart possibly has a greater impact. Women might also recover better after a cerebrovascular event caused by subclinical heart disease and therefore suffer a TIA instead of a stroke. Furthermore, this might be an indication of diagnostic bias; a similar event might be reported as a stroke more often in men and in women more often as a TIA. This might happen if men are more likely to have magnetic resonance imaging compared to women, because a short-lasting event is more likely to be classified as a stroke if a relevant acute infarct is seen. Moreover, sex differences might have occurred by chance. Our findings have several implications for future research. The mechanism by which NT-proBNP relates to ischaemic stroke, hemorrhagic stroke and TIA needs to be elucidated further. As associations with focal TIA were different compared to mixed TIA, differences in etiology of those attacks should also be identified. Furthermore, NT-proBNP needs to be investigated for its predictive role in stroke, even in
Table 1 Baseline characteristics
Age, years Systolic blood pressure, mmHg Diastolic blood pressure, mmHg Blood-pressurelowering drugs, % Total cholesterol, mmol/l High-density lipoprotein cholesterol, mmol/l Lipid-lowering drugs, % Anticoagulant drugs, % Antiplatelet drugs, % Creatinine, lmol/l Diabetes mellitus, % Smoking Never, % Former, % Current, % NT-proBNP, pmol/la NT-proBNP, pmol/lb Tertile 1 Tertile 2 Tertile 3
Men N = 2374
Women N = 3237
67.9 (7.5) 144 (21)
69.2 (8.4) 142 (21)
79 (11)
76 (11)
459 (20.1)
738 (24.0)
5.6 (1.0)
6.0 (0.9)
1.2 (0.3)
1.5 (0.4)
296 (12.9)
367 (11.8)
85 (3.7)
44 (1.4)
373 (16.3) 88 (16) 284 (12.0)
333 (10.7) 70 (13) 322 (10.0)
275 1530 552 7.7
(11.7) (64.9) (23.4) (4.1–15.8)
1375 1272 541 10.5
0.59–5.06 5.06–12.30 12.30–210.10
(43.1) (39.9) (17.0) (5.9–18.3)
0.59–7.30 7.30–15.38 15.38–212.20
NT-proBNP, amino-terminal pro-B-type natriuretic peptide. Data are presented as mean (standard deviations) or counts (percentages). a Median and interquartile range; brange in each tertile.
Table 2 Amino-terminal pro-B-type natriuretic peptide (NT-proBNP) and the risk of cerebrovascular events Men N = 2374
Any cerebrovascular event Any stroke Ischaemic stroke Hemorrhagic stroke Unspecified stroke Any transient ischaemic attack Focal TIA Mixed TIA
Women N = 3237
n
Model I HR (95% CI)
Model II HR (95% CI)
n
Model I HR (95% CI)
Model II HR (95% CI)
313 195 139 18 38 118
1.37 1.60 1.68 1.86 1.31 1.05
1.31 1.50 1.59 1.70 1.14 1.02
1.48) 1.76) 1.92) 2.84) 1.63) 1.26)
417 230 143 26 61 187
1.36 1.28 1.31 1.43 1.15 1.47
1.36 1.24 1.30 1.17 1.11 1.51
101 17
1.08 (0.88; 1.34) 0.85 (0.50; 1.45)
1.05 (0.83; 1.31) 0.88 (0.52; 1.49)
145 42
1.48 (1.21; 1.81) 1.42 (0.98; 2.06)
(1.22; (1.39; (1.41; (1.16; (0.95; (0.86;
1.54) 1.85) 1.99) 2.97) 1.81) 1.27)
(1.15; (1.29; (1.32; (1.02; (0.80; (0.83;
(1.21; (1.09; (1.07; (0.90; (0.84; (1.23;
1.53) 1.51) 1.61) 2.30) 1.58) 1.75)
(1.20; (1.05; (1.05; (0.72; (0.80; (1.26;
1.53) 1.46) 1.61) 1.90) 1.53) 1.82)
1.55 (1.26; 1.90) 1.41 (0.96; 2.06)
n, number of events; N, number of persons at risk; values are hazard ratios (HRs) per SD increase in natural-log-transformed NT-proBNP level (SD 0.96) with 95% confidence intervals (CIs); analyses with stroke were censored for incident transient ischaemic attack (TIA) and analyses with TIA were censored for incident stroke. Model I, adjusted for age; model II, adjusted for age, systolic blood pressure, diastolic blood pressure, blood-pressure-lowering drugs, total cholesterol, high-density lipoprotein cholesterol, lipid-lowering drugs, antithrombotic drugs, creatinine, smoking and diabetes mellitus.
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Table 3 Amino-terminal pro-B-type natriuretic peptide (NT-proBNP) in tertiles and the risk of cerebrovascular events Men
n/N Any cerebrovascular event Tertile 1 61/790 Tertile 2 97/793 Tertile 3 155/791 Any stroke Tertile 1 29/790 Tertile 2 55/793 Tertile 3 111/791 Any transient ischaemic attack Tertile 1 32/790 Tertile 2 42/793 Tertile 3 44/791
Women Model I HR (95% CI)
Model II HR (95% CI)
n/N
Model I HR (95% CI)
Model II HR (95% CI)
1 (reference) 1.35 (0.98; 1.88) 2.00 (1.44; 2.76)
1 (reference) 1.29 (0.93; 1.80) 1.81 (1.29; 2.53)
85/1080 115/1076 217/1081
1 (reference) 1.07 (0.81; 1.42) 1.78 (1.35; 2.33)
1 (reference) 1.08 (0.81; 1.43) 1.77 (1.34; 2.33)
1 (reference) 1.59 (1.01; 2.51) 2.91 (1.87; 4.52)
1 (reference) 1.51 (0.95; 2.39) 2.57 (1.63; 4.06)
50/1080 63/1076 117/1081
1 (reference) 0.94 (0.65; 1.37) 1.45 (1.01; 2.08)
1 (reference) 0.94 (0.64; 1.37) 1.37 (0.94; 1.99)
1 (reference) 1.15 (0.72; 1.84) 1.14 (0.69; 1.89)
1 (reference) 1.11 (0.69; 1.79) 1.09 (0.64; 1.83)
35/1080 52/1076 100/1081
1 (reference) 1.26 (0.82; 1.95) 2.29 (1.51; 3.46)
1 (reference) 1.28 (0.83; 1.98) 2.40 (1.57; 3.66)
n, number of events; N, number of persons at risk; values are hazard ratios (HRs) per sex-specific tertile of NT-proBNP level with 95% confidence intervals (CIs); analyses with stroke were censored for incident transient ischaemic attack (TIA) and analyses with TIA were censored for incident stroke. Model I, adjusted for age; model II, adjusted for age, systolic blood pressure, diastolic blood pressure, blood-pressure-lowering drugs, total cholesterol, high-density lipoprotein cholesterol, lipid-lowering drugs, antithrombotic drugs, creatinine, smoking and diabetes mellitus.
persons free of heart disease. In our study NT-proBNP was merely used as a marker for subclinical heart disease, but it might even be a target for therapy, as is shown in the PARADIGM HF trial [26]. Additionally, studies should disentangle the exact role of antithrombotic medication in the associations of
Figure 1 Cumulative incidence of cerebrovascular events in men and women by tertiles of amino-terminal pro-B-type natriuretic peptide levels. Stroke was censored for incident transient ischaemic attack (TIA). TIA was censored for incident stroke.
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NT-proBNP with cerebrovascular events. Finally, future research should confirm whether subclinical heart disease is indeed a more important cause of TIA in women compared to men and whether future strokes in women can be prevented with more attention towards subclinical heart disease after TIA.
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Table 4 Amino-terminal pro-B-type natriuretic peptide (NT-proBNP) and the risk of stroke, without censoring for transient ischaemic attack (TIA) Men N = 2374
Any stroke Ischaemic stroke Hemorrhagic stroke Unspecified stroke
Women N = 3237
n
Model I HR (95% CI)
Model II HR (95% CI)
n
Model I HR (95% CI)
Model II HR (95% CI)
208 149 18 41
1.59 1.63 1.85 1.40
1.51 1.56 1.71 1.29
261 162 28 71
1.41 1.46 1.40 1.31
1.36 1.45 1.15 1.22
(1.38; (1.38; (1.16; (1.02;
1.82) 1.92) 2.96) 1.90)
(1.30; (1.30; (1.02; (0.92;
1.76) 1.86) 2.85) 1.81)
(1.22; (1.20; (0.89; (0.97;
1.64) 1.76) 2.21) 1.75)
(1.16; (1.19; (0.72; (0.90;
1.59) 1.77) 1.83) 1.66)
n, number of events; N, number of persons at risk; values are hazard ratios (HRs) per SD increase in natural-log-transformed NT-proBNP level (SD 0.96) with 95% confidence intervals (CIs). Model I, adjusted for age; model II, adjusted for age, systolic blood pressure, diastolic blood pressure, blood-pressure-lowering drugs, total cholesterol, high-density lipoprotein cholesterol, lipid-lowering drugs, antithrombotic drugs, creatinine, smoking and diabetes mellitus. Table 5 Amino-terminal pro-B-type natriuretic peptide (NT-proNBP) and the risk of cerebrovascular events, censored at the occurrence of incident heart disease Men N = 1805
Any cerebrovascular event Any stroke Ischaemic stroke Hemorrhagic stroke Unspecified stroke Any transient ischaemic attack Focal TIA Mixed TIA
Women N = 2725
n
Model I HR (95% CI)
Model II HR (95% CI)
n
Model I HR (95% CI)
Model II HR (95% CI)
198 118 88 7 23 80 69 11
1.52 1.98 2.09 1.08 1.98 1.01 1.03 0.91
1.46 1.86 2.02 1.15 1.61 1.01 1.00 1.06
318 174 110 20 44 144 112 32
1.38 1.32 1.30 1.33 1.33 1.45 1.53 1.20
1.37 1.26 1.28 1.17 1.28 1.53 1.62 1.24
(1.29; (1.61; (1.65; (0.44; (1.25; (0.77; (0.77; (0.45;
1.79) 2.43) 2.65) 2.68) 3.13) 1.32) 1.37) 1.86)
(1.22; (1.48; (1.55; (0.42; (0.94; (0.76; (0.74; (0.52;
1.74) 2.34) 2.62) 3.11) 2.75) 1.34) 1.35) 2.18)
(1.20; (1.09; (1.02; (0.76; (0.91; (1.18; (1.21; (0.77;
1.59) 1.60) 1.66) 2.34) 1.96) 1.79) 1.94) 1.89)
(1.19; (1.03; (0.99; (0.66; (0.86; (1.23; (1.27; (0.77;
1.59) 1.54) 1.64) 2.08) 1.92) 1.90) 2.08) 1.99)
n, number of events; N, number of persons at risk; values are hazard ratios (HRs) per SD increase in natural-log-transformed NT-proBNP level (SD 0.96) with 95% confidence intervals (CIs); analyses with stroke were censored for incident transient ischaemic attack (TIA) and analyses with TIA were censored for incident stroke. Model I, adjusted for age; model II, adjusted for age, systolic blood pressure, diastolic blood pressure, blood-pressure-lowering drugs, total cholesterol, high-density lipoprotein cholesterol, lipid-lowering drugs, antithrombotic drugs, creatinine, smoking and diabetes mellitus.
The strengths of this study are the population-based setting, the large study population and the thorough collection of events. A limitation is that follow-up for heart failure and atrial fibrillation was incomplete. Events in the last years of follow-up could therefore not be censored. However, also with shorter follow-up until 2008 censoring at the time of incident heart disease did not attenuate the results. Another limitation is that valvular heart disease was not systematically measured as a potential confounding factor [12,27].
Conclusion Our results show that higher levels of NT-proBNP are associated with a higher risk of cerebrovascular events. For stroke this risk was present in men and women, for TIA only in women. These associations were independent of prevalent and incident heart disease during follow-up, suggesting that a high NT-proBNP as marker of subclinical heart disease
leads to an increased risk of stroke in men and women and of TIA in women.
Acknowledgements The Rotterdam Study is supported by the Erasmus MC University Medical Center and Erasmus University Rotterdam; the Netherlands Organization for Scientific Research (NWO); the Netherlands Organization for Health Research and Development (ZonMW); the Research Institute for Diseases in the Elderly (RIDE); the Netherlands Genomics Initiative (NGI); the Ministry of Education, Culture and Science; the Ministry of Health, Welfare and Sports; the European Commission (DG XII); and the Municipality of Rotterdam. Further support was obtained from the Netherlands Consortium for Healthy Ageing (NCHA), Netherlands Heart Foundation (2012T008) and Erasmus MC Fellowship 2013. Oscar H. Franco works in ErasmusAGE, a center for ageing research
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NT-PROBNP AND THE RISK OF STROKE AND TIA
within the Department of Epidemiology, Erasmus MC, funded by Nestle Nutrition (Nestec Ltd), Metagenics Inc. and AXA. Maryam Kavousi is supported by the AXA Research Fund. None of the funding organizations or sponsors were involved in the design and conduct of the study; collection, management analysis and interpretation of the data; and preparation, review or approval of the manuscript.
Disclosure of conflicts of interest Dr Leening received grants from the European Society of Cardiology (ESC), Erasmus University Trustfonds and Prins Bernhard Cultuurfonds. Dr Franco received grants from Nestle and Metagenics.
Supporting Information Additional Supporting Information may be found in the online version of this article: Table S1. NT-proBNP and the risk of any cerebrovascular event, stratified for antithrombotic drug use.
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