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Multimarker strategy for risk prediction in patients presenting with acute dyspnea to the emergency department
International Journal of Cardiology 126 (2008) 73 – 78 www.elsevier.com/locate/ijcard
Multimarker strategy for risk prediction in patients presenting with acute dyspnea to the emergency department Michael Christ ⁎, Kirsten Laule, Theresia Klima, Willibald Hochholzer, Tobias Breidthardt, Andre P. Perruchoud, Christian Mueller Department of Internal Medicine, University Hospital, Petersgraben 4, CH-4031 Basel, Switzerland Received 3 October 2006; received in revised form 19 February 2007; accepted 30 March 2007 Available online 3 May 2007
Abstract Background: Multimarker approaches improve risk prediction in patients presenting with acute coronary syndrome. We hypothesized that simultaneous assessment of B-type natriuretic peptide (BNP), cardiac troponin I (cTNI) and C-reactive protein (CRP) enables clinicians to better predict risk among patients with acute dyspnea presenting to the emergency department. Methods and results: In this post-hoc analysis of the B-Type natriuretic peptide for Acute Shortness of Breath Evaluation (BASEL) study, above biomarkers were available in 305 patients. Death occurred in 123 (40%) patients within 24 months of follow-up. Using prospectively defined cutoff points (BNP N 100 pg/mL; cTNIN 0.8 μg/L; CRP N 5 mg/L) and categorizing patients by the number of elevated cardiac biomarkers, the 24 months risk of death increased in proportion to the number of cardiac biomarkers elevated (p b 0.001 for trend). Elevated biomarkers significantly predicted increased risk of death at 24 months of follow-up in univariate Cox models (BNP: RR 4.78, 95%CI: 2.51–9.14; p b 0.001; cTNI: RR: 2.29, 95%CI: 1.61–3.26, p b 0.001; CRP: RR 1.98, 95%CI: 1.28–3.08; p = 0.002). Multivariable Cox regression analysis revealed that elevated levels of BNP (p b 0.001) and TNI levels (p b 0.002) indicated increased risk of death during long-term follow-up, while only a statistical trend was seen for elevated CRP (p = 0.09). Comparably, risk of death or rehospitalization significantly increased with the number of elevated biomarkers. Conclusions: Our findings suggest that a simple multimarker approach with simultaneous assessment of BNP, and cTNI demonstrates potential to assist clinicians in predicting risk of death and/or rehospitalization in patients presenting with acute dyspnea in the emergency department. © 2007 Elsevier Ireland Ltd. All rights reserved. Keywords: Natriuretic peptides; Troponin I; C-reactive protein; Acute dyspnea; Prognosis; Mortality
Cardiac and pulmonary disorders are the reason for more than 75% of patients presenting with acute dyspnea to the emergency department [1,2]. Unfortunately, a significant subjective component impedes the clinical staging of the severity of dyspnea and associated risk of death. Patient history and physical examination remain the cornerstones of clinical evaluation [3], while scoring tools [4] and non-invasive blood markers such as natriuretic peptide levels have been introduced to assist the clinician in assessment [1,5].
⁎ Corresponding author. Tel.: +41 61 32 86696; fax: +41 61 265 5353. E-mail address: [email protected] (M. Christ). 0167-5273/$ - see front matter © 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2007.03.119
Elevated levels of cardiac troponin I (cTNI), creatine kinase myocardial band, and myoglobin in addition to measurement of C-reactive protein (CRP) and B-type natriuretic peptide (BNP) emerged as important predictors of risk among patients presenting with acute coronary syndrome to the emergency department [6–8]. Subsequently, a multimarker approach, in which patients are categorized based on the number of elevated biomarkers, has been introduced and demonstrated superior risk stratification for patients with acute coronary syndrome [9]. Elevated levels of biomarkers including BNP, CRP, and cTNI are associated with increased risk of death in patients presenting with acute dyspnea related to cardiac causes
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[10–12]. Importantly, each of those markers assesses different pathophysiological mechanisms: BNP is elevated in response to myocardial stretch following myocardial volume overload [13], while elevation in troponin indicates myocardial cell necrosis [14], and CRP is a marker of inflammation [12,15]. We hypothesized that simultaneous assessment of multiple markers including BNP, cTNI and CRP levels will provide complimentary information and enable clinicians to stratify risk more effectively among consecutive dyspneic patients, irrespective whether dyspnea was related or not related to cardiac causes.
1. Methods 1.1. Setting and study population This analysis evaluated the impact of biomarker levels (BNP, cTNI, CRP) at initial presentation on mortality in patients with a subjective complaint of acute dyspnea recruited in the B-type natriuretic peptide for Acute Shortness of Breath Evaluation (BASEL) study [1]. The BASEL study was a prospective, randomized, single-blind study conducted in the emergency department at the University
Table 1 Demographic and laboratory characteristics in patients presenting with acute dyspnea to the emergency department Variables
All patients
Number of biomarkers elevated 0
1
2
3
Numbers Age, years Gender, male (%) Body mass index, kg/m2 Heart rate, bpm Presence of atrial fibrillation Systolic blood pressure, mm Hg, (%) Sodium, mmol/L Hemoglobin, g/L Creatinine clearance, mL/min/1.73 m2 LV ejection fraction, % (n = 161) New York Heart Association Class (%) II III IV Breathing rate, per minute Past medical history Coronary artery disease, (%) Hypertension, (%) Diabetes mellitus, (%) Chronic obstructive lung disease, (%) Any pulmonary disease, (%) Cause of acute dyspnea Acute heart failure, (%) Due to acute NSTEMI, (%) COPD/asthma bronchiale, (%) Pulmonary embolism, (%) Pneumonia, (%) Other causes, (%) Discharge medication Aspirin, (%) Diuretics, (%) Betablockers, (%) ACE-inhibitors/ARBs, (%) Digoxin, (%) Amiodarone, (%) Calcium antagonists, (%) Laboratory markers BNP levels, pg/mL; median (IQR) cTNI levels, ng/mL; median (IQR) CRP levels, mg/L; median (IQR) Endpoints at 24 months of follow-up Death, n (%) Time to death, days; median (IQR) Death or rehospitalization, n (%) Time to death or rehospitalization, days; median (IQR)
305 71 ± 14 180 (59) 26.0 ± 5.2 96 ± 24 71 (23) 144 ± 29 136 ± 5 131 ± 22 61 ± 33 44 ± 16 47 (16) 174 (57) 84 (27) 24 ± 8
31 60 ± 17 17 (55) 27.4 ± 5.0 89 ± 16 2 (6) 149 ± 17 138 ± 3 143 ± 16 87 ± 31 59 ± 12 10 (32) 16 (52) 5 (16) 20 ± 5
77 68 ± 14 51 (66) 27.4 ± 6.4 96 ± 22 14 (18) 145 ± 26 137 ± 5 139 ± 23 74 ± 33 46 ± 14 14 (18) 48 (62) 15 (19) 22 ± 6
117 74 ± 13 65 (56) 25.3 ± 4.9 99 ± 27 36 (31) 146 ± 30 136 ± 6 128 ± 23 56 ± 34 42 ± 17 16 (14) 68 (58) 33 (28) 23 ± 9
80 75 ± 14 47 (59) 25.3 ± 4.5 96 ± 25 19 (24) 138 ± 32 137 ± 5 124 ± 21 47 ± 20 41 ± 17 7 (9) 42 (53) 31 (39) 24 ± 9
183 (60) 170 (56) 78 (26) 84 (28) 140 (46)
8 (26) 8 (26) 5 (16) 7 (23) 17 (55)
43 (56) 47 (61) 11 (13) 25 (30) 31 (38)
76 (65) 65 (56) 34 (29) 33 (28) 56 (48)
56 (70) 50 (63) 28 (35) 19 (24) 36 (45)
b0.001 0.003 0.005 0.59 0.53
170 (56) 49 (16) 36 (12) 15 (5) 41 (13) 43 (14)
2 (6) 0 (0) 9 (29) 1 (3) 0 (0) 15 (48)
35 (47) 2 (3) 15 (19) 1 (3) 11 (14) 12 (16)
71 (61) 13 (13) 8 (7) 6 (5) 24 (21) 13 (11)
62 (78) 34 (43) 4 (5) 7 (9) 6 (8) 3 (4)
b0.001 b0.001 b0.001 0.18 0.04 b0.001
107 (35) 182 (60) 128 (42) 173 (57) 20 (6) 34 (11) 36 (12)
3 (10) 5 (16) 3 (10) 8 (26) 0 (0) 1 (3) 2 (6)
30 (39) 39 (51) 31 (40) 39 (51) 4 (5) 9 (12) 9 (12)
44 (38) 86 (74) 62 (53) 76 (65) 12 (10) 15 (13) 18 (15)
30 (38) 52 (65) 32 (40) 50 (63) 4 (5) 9 (11) 7 (9)
0.004 b0.001 b0.001 b0.001 0.14 0.42 0.41
448 (99–1175) 30 (10–67) 0.4 (0.3–1.7) 0.3 (0–0.3) 16 (5–54) 3 (3–5)
92 (35–432) 0.3 (0.3–0.4) 5 (3–25)
665 (249–1290) 1050 (594–1300) b0.001 0.4 (0.3–0.7) 3.3 (1.5–15) b0.001 22 (10–66) 39 (17–82) b0.001
123 (40) 166 (26–367) 179 (59) 82 (30–320)
16 (21) 204 (42–485) 33 (43) 131 (45–408)
58 (50) 111 (33–365) 80 (68) 62 (29–284)
2 (6) 219 (77–361) 9 (29) 323 (120–361)
Data are presented for patients receiving or not receiving all measurements of non-invasive biomarkers.
47 (59) 75 (9–320) 57 (71) 77 (14–262)
p value b0.001 0.48 0.013 0.31 0.03 0.17 0.19 b0.001 b0.001 0.01 0.005
0.45
b0.001 0.21 b0.001 0.40
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1.2. BNP measurement BNP was measured with the use of a rapid fluorescence immunoassay within 15 min after presentation (Biosite Inc., San Diego, CA) [1]. The coefficient of variation within a given assay has been reported to be 9.5%, 12.0%, and 13.9% for levels of 28.8, 584.0, and 1180.0 pg/mL. The limit of analytic sensitivity was less than 5.0 pg/mL with a measurable range of 0 to 1300 pg/mL [16]. The clinically established cut-off point of 100 pg/mL BNP was used for analysis. 1.3. Troponin I measurement After presentation serum specimens were immediately processed and analyzed for cTNI with the AxSYM immunoanalyzer (Abbott Laboratories, Baar/Zug, Switzerland). The limit of detection for this 1st generation AxSYM cTNI assay was 0.3 μg/L. Because the 99th percentile for this cTNI assay (0.5 μg/L) cannot be measured with ≤ 10% imprecision, the lowest cut-off value at which 10% imprecision is achieved (0.8 μg/L) was considered indicative of cardiac injury as suggested by current ESC/ACC guidelines for the definition of myocardial infarction [17]. Non-ST-elevation myocardial infarction was retrospectively established by two cardiologists (M.C. and C.M.) using all clinical information available, which included cTNI levels. Fig. 1. Mortality risks after 30 days (A) and 24 months (B) of follow-up in 305 patients presenting with acute dyspnea to the emergency department. Patients have been stratified by the number of elevated cardiac biomarkers. The chi-square test was used for comparison of frequencies.
Hospital Basel, Switzerland, from May 2001 to April 2002 [1]. Patients with severe renal dysfunction (serum creatinine N 250 μmol/L), or cardiogenic shock at presentation were excluded. The study was approved by the institutional review board, and written informed consent was obtained by each enrolled patient. All 3 biomarkers have been assessed in 305 patients of the overall study cohort. Thus, results of this post-hoc analysis included 67% of patients originally enrolled in the BASEL trial.
1.4. CRP measurement Levels of CRP were determined by a particle-enhanced turbidimetric immunoassay (Dade Behring Inc., Newark, DE) on hospital admission. The lower detection limit of this test is 3 mg/L. A cut-off point of 5 mg/L was used for analysis. 1.5. Endpoints The primary endpoint of this analysis was overall mortality. Death or rehospitalization for acute dyspnea during follow-up was defined as the secondary endpoint. Patients were contacted at specified intervals (3, 6, 12, and 24 months)
Table 2 Univariate and multivariable Cox regression models to predict the primary endpoint (time to death) Variables
B-type natriuretic peptide level Troponin I C-reactive protein
30 days mortality
24 months mortality
Relative risk (95%CI)
p univariate
p multivariable
Relative risk (95%CI)
p univariate
p multivariable
11.6 (1.59–84.91) 2.46 (1.25–4.85) 3.39 (1.20–9.63)
0.02 0.009 0.02
0.04 0.09 0.08
4.78 (2.51–9.14) 2.29 (1.61–3.26) 1.98 (1.28–3.08)
b0.001 b0.001 0.002
b0.001 b0.002 0.09
30 days mortality B-type natriuretic peptide level Troponin I C-reactive protein History of CAD
8.84 (1.16–67.1) 1.80 (0.91–3.56) 2.40 (0.84–6.91) 0.84 (0.41–1.72)
24 months mortality 0.04 0.09 0.10 0.63
2.92 (1.48–5.77) 1.68 (1.17–2.42) 1.55 (0.99–2.43) 2.00 (1.29–3.12)
0.002 0.005 0.06 0.002
Clinically used cut-off points have been used for B-type natriuretic peptide (N100 pg/mL), troponin I (N0.8 pg/L) and C-reactive protein levels (N5 mg/L). In further multivariable Cox regression models history of coronary artery disease (CAD) was included [4].
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Fig. 2. Survival analysis of dyspneic patients presenting to the emergency department. A Kaplan–Meier plot showing survival stratified by the number of elevated cardiac biomarkers is displayed. For comparison of curves the log-rank test was used.
by telephone interview performed by a single trained researcher, who was blinded to the results of cardiac biomarker testing. Referring physicians were contacted in case of uncertainties regarding health status. The administrative databases of the respective hometowns were assessed to ascertain the vital status of those patients who could not be contacted by telephone.
heart failure in 170 patients, of whom 29% had retrospectively established acute non-ST-elevation myocardial infarction (Table 1). Death occurred in 123 patients (40%) within 24 months of follow-up, while 42 of 146 patients (29%) died in the subgroup of patients, who were not included in this analysis due to the unavailability of all 3 biomarkers ( p = 0.02 for difference). A simple scoring system was devised in which patients were categorized on the basis of the number of elevated biomarkers. The 30 days and 24 months risk of death increased in proportion to the number of cardiac biomarkers elevated at baseline ( p b 0.001 for trend; Fig. 1), with more than doubling of the mortality risk for each additional biomarker. This risk increase was evident for an elevation of 2 biomarkers after 24 months of follow-up, while elevation of 3 biomarkers did not significantly indicate a further increase of mortality ( p = 0.25; Fig. 1). Univariate Cox regression analysis revealed that elevation of each biomarker significantly contributed to the model predicting increased risk of death at 30 days and at 24 months of follow-up (Table 2). In a multivariable regression model including all 3 biomarkers, only BNP emerged as an independent predictor of the death after 30 days of follow-up. Increased BNP and TNI independently predicted death after 24 months of follow-up, while a statistical trend was seen for elevated CRP levels. Results were not considerably changed in multivariable Cox regression analyses after including past medical history of CAD in the models (Table 2). Survival analysis using the Kaplan–Meier method indicated that elevation of 1 or 2 biomarkers significantly
1.6. Statistical analysis Results are expressed as number, frequency, median (interquartile range, IQR) and point estimate (95% confidence intervals, 95%CI) as indicated. Univariate and multivariable Cox proportional hazard models were used to evaluate the associations between the outcome measures. For building a first regression model, we thereby used a stepwise procedure with an entry level of 0.05. Event-free survival probabilities were estimated with the Kaplan–Meier method and the log-rank test was used for comparisons of curves. The chi-square test was used for comparison of frequencies of measures at baseline. Parametric or non-parametric tests were used for comparison of variables where applicable. All p values reported are two-sided, a p value b 0.05 was considered significant. All statistical calculations were performed using the SPSS statistical software package (version 13.0; SPSS Inc., Chicago, IL). 2. Results Demographic and clinical characteristics of the study patients are displayed in Table 1. Acute dyspnea was due to
Fig. 3. Kaplan–Meier analysis of dyspneic patients presenting to the emergency department. Time to death or rehospitalization for acute dyspnea has been used as a combined endpoint. Event-free survival stratified by the number of elevated cardiac biomarkers is displayed. For comparison of curves the log-rank test was used.
M. Christ et al. / International Journal of Cardiology 126 (2008) 73–78
increased the risk of death within 24 months of follow-up, while patients with an elevation of 3 biomarkers display a comparable risk of death as patients with an elevation of 2 biomarkers ( p = 0.13; Fig. 2). Comparable results of this multimarker strategy were obtained when a combined endpoint was used (time to death or first rehospitalization due to acute dyspnea). Risk of death or rehospitalization significantly increases with the number of elevated biomarkers. Again, elevation of 3 biomarkers did not add further information compared to the elevation of 2 biomarkers ( p = 0.38; Fig. 3). 3. Discussion This study examined whether a multimarker strategy including BNP, cTNI, and CRP levels contributes valuable information for risk stratification in patients with acute dyspnea presenting to the emergency department. The major results of our study are the following: i) Patients presenting with acute dyspnea to the emergency department display extraordinary high mortality. ii) Using prospectively defined cut-off points and categorizing patients by the number of elevated cardiac biomarkers, we found that risk of death increased in proportion to the number of cardiac biomarkers elevated at baseline with more than doubling of the mortality risk for each additional biomarker. Elevation of 3 biomarkers did not significantly indicate a further increase of mortality elevation compared to the elevation of 2 biomarkers. iii) Cox regression models revealed that elevated BNP and cTNI levels indicate increased long-term risk of death, while only a trend was seen for increased CRP levels. Our results are of clinical importance: Incorporating this powerful risk prediction in the management of patients with acute dyspnea may potentially help improve their dismal prognosis. Options for tailored treatment include more intense monitoring, specialist care and intensified, diseasespecific pharmacotherapy. Recent research on cardiac biomarkers has been primarily focused on selected patient cohorts with a primary diagnosis of acute coronary syndrome, pulmonary embolization and/or acute heart failure [2,9,18,19]. In clinical practice, patients are presenting with subjective symptoms such as acute dyspnea, which may be related or not related to cardiac causes. Diagnosis of cardiac related dyspnea is demanding [20] and risk stratification using elevation of single biomarkers or simple scoring systems in patients with acute heart failure display moderate sensitivity and specificity [4,21]. Multimarker approaches have been introduced to facilitate clinical care and aid the development of new therapies in acute coronary syndromes [9]. We extend those strategies to patients presenting with acute dyspnea: Risk of death is highest in patients with elevation of 2 or 3 biomarkers, while patients without increased biomarkers display a good prognosis and patients with elevation of one biomarker show an intermediate prognosis. Importantly, risk of death in this cohort of patients with acute dyspnea and elevation of 2
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biomarkers at 6 months of follow-up is more than 6 fold higher than the 6 months risk of death in patients of the TACTICS-TIMI 18 trial with acute coronary syndrome [9]. The suggested multimarker approach covering different aspects of interrelated pathophysiological processes appears suitable to designate this high-risk group of patients. Our analysis highlights that patients presenting with acute dyspnea and increased troponin I levels display elevated risk of death and/or rehospitalization. Only patients with the primary complaint of acute dyspnea have been enrolled in the BASEL trial [1], while patients with acute chest pain, instable angina and/or ST-elevation myocardial infarction have been excluded. Increases of troponin levels are specific for myocardial cell necrosis [22] and increased troponin levels are associated with increased risk of death in patients presenting with instable angina and/or non-ST-elevation myocardial infarction [23]. Of note, elevated troponin levels may indicate subendocardial myocyte death due to increased myocardial strain present during acute heart failure, reduced subendocardial perfusion and/or structural damage [24,25]. In addition, 16% of enrolled patients retrospectively had established acute non-ST-elevation myocardial infarction by clinical reevaluation including cTNI results supporting the notion that troponin levels should be determined in patients presenting with acute dyspnea to the emergency department. Comparably, patients with acute pulmonary embolization and increased troponin levels are at increased risk of adverse events and troponin levels may reflect ischemia due to increased right ventricular wall strain and subsequent reduction of coronary perfusion [19]. Inflammatory cytokines play an important role in the pathophysiology of many disorders underlying acute dyspnea including acute heart failure, chronic obstructive pulmonary disease or pneumonia [26]. We have recently demonstrated that elevation of CRP at the time of acute heart failure presentation is associated with adverse short- and long-term clinical outcomes [12] suggesting that increased CRP is either a result of hemodynamic deterioration or a reflection of a great burden of proinflammatory cytokines [15]. In the current analysis, we extend the above findings to the overall group of patients presenting with acute dyspnea. However, multivariable Cox regression analysis revealed only a statistical trend for CRP levels to predict risk of death and/or rehospitalization in this population. 3.1. Study limitations Several limitations of this analysis merit consideration: i) This is a post-hoc analysis of the BASEL study including patients, in whom measurement of all 3 biomarkers were available. Risk of death was lower in patients not meeting this criterion indicating that our study included a cohort of dyspneic patients at high risk of death. Therefore, our findings have to be considered hypothesis generating than definite and need to be confirmed in future studies. ii) Classification of cardiac or non-cardiac causes of death including sudden
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cardiac death would offer interesting insights into the potentially pathophysiological distinct role of biomarkers. However, we decided to record all-cause mortality, since classification of death in clinical practice is unreliable [27]. iii) The number of endpoints in this trial is of moderate size limiting the statistical power in this post-hoc analysis of a previous prospective cohort study. The careful long-term follow-up supports the validity of our results.
[9]
[10]
[11]
3.2. Conclusions [12]
Our findings suggest that this simple multimarker approach with simultaneous assessment of BNP, and cTNI demonstrates the potential to assist clinicians in predicting prognosis of patients presenting with acute dyspnea. Future study is needed to show whether this simple multimarker approach allows clinicians to improve patient management and prognosis. Acknowledgements This study was supported by research grants from the Swiss National Science Foundation, the Swiss Heart Foundation, and the Novartis Foundation (to C.M.). References [1] Mueller C, Scholer A, Laule-Kilian K, et al. Use of B-type natriuretic peptide in the evaluation and management of acute dyspnea. N Engl J Med 2004;350:647–54. [2] Maisel AS, Krishnaswamy P, Nowak RM, et al. Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure. N Engl J Med 2002;347:161–7. [3] Anonymous. Dyspnea. Mechanisms, assessment, and management: a consensus statement. American Thoracic Society. Am J Respir Crit Care Med 1999;159:321–40. [4] Fonarow GC, Adams Jr KF, Abraham WT, Yancy CW, Boscardin WJ. Risk stratification for in-hospital mortality in acutely decompensated heart failure: classification and regression tree analysis. JAMA 2005;293: 572–80. [5] McCullough PA, Nowak RM, McCord J, et al. B-type natriuretic peptide and clinical judgment in emergency diagnosis of heart failure: analysis from Breathing Not Properly (BNP) Multinational Study. Circulation 2002;106:416–22. [6] de Lemos JA, Morrow DA, Bentley JH, et al. The prognostic value of B-type natriuretic peptide in patients with acute coronary syndromes. N Engl J Med 2001;345:1014–21. [7] Lindahl B, Toss H, Siegbahn A, Venge P, Wallentin L. Markers of myocardial damage and inflammation in relation to long-term mortality in unstable coronary artery disease. FRISC Study Group. Fragmin during Instability in Coronary Artery Disease. N Engl J Med 2000;343:1139–47. [8] Mueller C, Buettner HJ, Hodgson JM, et al. Inflammation and long-term mortality after non-ST elevation acute coronary syndrome treated with a
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Multimarker strategy for risk prediction in patients presenting with acute dyspnea to the emergency department Michael Christ ⁎, Kirsten Laule, Theresia Klima, Willibald Hochholzer, Tobias Breidthardt, Andre P. Perruchoud, Christian Mueller Department of Internal Medicine, University Hospital, Petersgraben 4, CH-4031 Basel, Switzerland Received 3 October 2006; received in revised form 19 February 2007; accepted 30 March 2007 Available online 3 May 2007
Abstract Background: Multimarker approaches improve risk prediction in patients presenting with acute coronary syndrome. We hypothesized that simultaneous assessment of B-type natriuretic peptide (BNP), cardiac troponin I (cTNI) and C-reactive protein (CRP) enables clinicians to better predict risk among patients with acute dyspnea presenting to the emergency department. Methods and results: In this post-hoc analysis of the B-Type natriuretic peptide for Acute Shortness of Breath Evaluation (BASEL) study, above biomarkers were available in 305 patients. Death occurred in 123 (40%) patients within 24 months of follow-up. Using prospectively defined cutoff points (BNP N 100 pg/mL; cTNIN 0.8 μg/L; CRP N 5 mg/L) and categorizing patients by the number of elevated cardiac biomarkers, the 24 months risk of death increased in proportion to the number of cardiac biomarkers elevated (p b 0.001 for trend). Elevated biomarkers significantly predicted increased risk of death at 24 months of follow-up in univariate Cox models (BNP: RR 4.78, 95%CI: 2.51–9.14; p b 0.001; cTNI: RR: 2.29, 95%CI: 1.61–3.26, p b 0.001; CRP: RR 1.98, 95%CI: 1.28–3.08; p = 0.002). Multivariable Cox regression analysis revealed that elevated levels of BNP (p b 0.001) and TNI levels (p b 0.002) indicated increased risk of death during long-term follow-up, while only a statistical trend was seen for elevated CRP (p = 0.09). Comparably, risk of death or rehospitalization significantly increased with the number of elevated biomarkers. Conclusions: Our findings suggest that a simple multimarker approach with simultaneous assessment of BNP, and cTNI demonstrates potential to assist clinicians in predicting risk of death and/or rehospitalization in patients presenting with acute dyspnea in the emergency department. © 2007 Elsevier Ireland Ltd. All rights reserved. Keywords: Natriuretic peptides; Troponin I; C-reactive protein; Acute dyspnea; Prognosis; Mortality
Cardiac and pulmonary disorders are the reason for more than 75% of patients presenting with acute dyspnea to the emergency department [1,2]. Unfortunately, a significant subjective component impedes the clinical staging of the severity of dyspnea and associated risk of death. Patient history and physical examination remain the cornerstones of clinical evaluation [3], while scoring tools [4] and non-invasive blood markers such as natriuretic peptide levels have been introduced to assist the clinician in assessment [1,5].
⁎ Corresponding author. Tel.: +41 61 32 86696; fax: +41 61 265 5353. E-mail address: [email protected] (M. Christ). 0167-5273/$ - see front matter © 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.ijcard.2007.03.119
Elevated levels of cardiac troponin I (cTNI), creatine kinase myocardial band, and myoglobin in addition to measurement of C-reactive protein (CRP) and B-type natriuretic peptide (BNP) emerged as important predictors of risk among patients presenting with acute coronary syndrome to the emergency department [6–8]. Subsequently, a multimarker approach, in which patients are categorized based on the number of elevated biomarkers, has been introduced and demonstrated superior risk stratification for patients with acute coronary syndrome [9]. Elevated levels of biomarkers including BNP, CRP, and cTNI are associated with increased risk of death in patients presenting with acute dyspnea related to cardiac causes
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[10–12]. Importantly, each of those markers assesses different pathophysiological mechanisms: BNP is elevated in response to myocardial stretch following myocardial volume overload [13], while elevation in troponin indicates myocardial cell necrosis [14], and CRP is a marker of inflammation [12,15]. We hypothesized that simultaneous assessment of multiple markers including BNP, cTNI and CRP levels will provide complimentary information and enable clinicians to stratify risk more effectively among consecutive dyspneic patients, irrespective whether dyspnea was related or not related to cardiac causes.
1. Methods 1.1. Setting and study population This analysis evaluated the impact of biomarker levels (BNP, cTNI, CRP) at initial presentation on mortality in patients with a subjective complaint of acute dyspnea recruited in the B-type natriuretic peptide for Acute Shortness of Breath Evaluation (BASEL) study [1]. The BASEL study was a prospective, randomized, single-blind study conducted in the emergency department at the University
Table 1 Demographic and laboratory characteristics in patients presenting with acute dyspnea to the emergency department Variables
All patients
Number of biomarkers elevated 0
1
2
3
Numbers Age, years Gender, male (%) Body mass index, kg/m2 Heart rate, bpm Presence of atrial fibrillation Systolic blood pressure, mm Hg, (%) Sodium, mmol/L Hemoglobin, g/L Creatinine clearance, mL/min/1.73 m2 LV ejection fraction, % (n = 161) New York Heart Association Class (%) II III IV Breathing rate, per minute Past medical history Coronary artery disease, (%) Hypertension, (%) Diabetes mellitus, (%) Chronic obstructive lung disease, (%) Any pulmonary disease, (%) Cause of acute dyspnea Acute heart failure, (%) Due to acute NSTEMI, (%) COPD/asthma bronchiale, (%) Pulmonary embolism, (%) Pneumonia, (%) Other causes, (%) Discharge medication Aspirin, (%) Diuretics, (%) Betablockers, (%) ACE-inhibitors/ARBs, (%) Digoxin, (%) Amiodarone, (%) Calcium antagonists, (%) Laboratory markers BNP levels, pg/mL; median (IQR) cTNI levels, ng/mL; median (IQR) CRP levels, mg/L; median (IQR) Endpoints at 24 months of follow-up Death, n (%) Time to death, days; median (IQR) Death or rehospitalization, n (%) Time to death or rehospitalization, days; median (IQR)
305 71 ± 14 180 (59) 26.0 ± 5.2 96 ± 24 71 (23) 144 ± 29 136 ± 5 131 ± 22 61 ± 33 44 ± 16 47 (16) 174 (57) 84 (27) 24 ± 8
31 60 ± 17 17 (55) 27.4 ± 5.0 89 ± 16 2 (6) 149 ± 17 138 ± 3 143 ± 16 87 ± 31 59 ± 12 10 (32) 16 (52) 5 (16) 20 ± 5
77 68 ± 14 51 (66) 27.4 ± 6.4 96 ± 22 14 (18) 145 ± 26 137 ± 5 139 ± 23 74 ± 33 46 ± 14 14 (18) 48 (62) 15 (19) 22 ± 6
117 74 ± 13 65 (56) 25.3 ± 4.9 99 ± 27 36 (31) 146 ± 30 136 ± 6 128 ± 23 56 ± 34 42 ± 17 16 (14) 68 (58) 33 (28) 23 ± 9
80 75 ± 14 47 (59) 25.3 ± 4.5 96 ± 25 19 (24) 138 ± 32 137 ± 5 124 ± 21 47 ± 20 41 ± 17 7 (9) 42 (53) 31 (39) 24 ± 9
183 (60) 170 (56) 78 (26) 84 (28) 140 (46)
8 (26) 8 (26) 5 (16) 7 (23) 17 (55)
43 (56) 47 (61) 11 (13) 25 (30) 31 (38)
76 (65) 65 (56) 34 (29) 33 (28) 56 (48)
56 (70) 50 (63) 28 (35) 19 (24) 36 (45)
b0.001 0.003 0.005 0.59 0.53
170 (56) 49 (16) 36 (12) 15 (5) 41 (13) 43 (14)
2 (6) 0 (0) 9 (29) 1 (3) 0 (0) 15 (48)
35 (47) 2 (3) 15 (19) 1 (3) 11 (14) 12 (16)
71 (61) 13 (13) 8 (7) 6 (5) 24 (21) 13 (11)
62 (78) 34 (43) 4 (5) 7 (9) 6 (8) 3 (4)
b0.001 b0.001 b0.001 0.18 0.04 b0.001
107 (35) 182 (60) 128 (42) 173 (57) 20 (6) 34 (11) 36 (12)
3 (10) 5 (16) 3 (10) 8 (26) 0 (0) 1 (3) 2 (6)
30 (39) 39 (51) 31 (40) 39 (51) 4 (5) 9 (12) 9 (12)
44 (38) 86 (74) 62 (53) 76 (65) 12 (10) 15 (13) 18 (15)
30 (38) 52 (65) 32 (40) 50 (63) 4 (5) 9 (11) 7 (9)
0.004 b0.001 b0.001 b0.001 0.14 0.42 0.41
448 (99–1175) 30 (10–67) 0.4 (0.3–1.7) 0.3 (0–0.3) 16 (5–54) 3 (3–5)
92 (35–432) 0.3 (0.3–0.4) 5 (3–25)
665 (249–1290) 1050 (594–1300) b0.001 0.4 (0.3–0.7) 3.3 (1.5–15) b0.001 22 (10–66) 39 (17–82) b0.001
123 (40) 166 (26–367) 179 (59) 82 (30–320)
16 (21) 204 (42–485) 33 (43) 131 (45–408)
58 (50) 111 (33–365) 80 (68) 62 (29–284)
2 (6) 219 (77–361) 9 (29) 323 (120–361)
Data are presented for patients receiving or not receiving all measurements of non-invasive biomarkers.
47 (59) 75 (9–320) 57 (71) 77 (14–262)
p value b0.001 0.48 0.013 0.31 0.03 0.17 0.19 b0.001 b0.001 0.01 0.005
0.45
b0.001 0.21 b0.001 0.40
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1.2. BNP measurement BNP was measured with the use of a rapid fluorescence immunoassay within 15 min after presentation (Biosite Inc., San Diego, CA) [1]. The coefficient of variation within a given assay has been reported to be 9.5%, 12.0%, and 13.9% for levels of 28.8, 584.0, and 1180.0 pg/mL. The limit of analytic sensitivity was less than 5.0 pg/mL with a measurable range of 0 to 1300 pg/mL [16]. The clinically established cut-off point of 100 pg/mL BNP was used for analysis. 1.3. Troponin I measurement After presentation serum specimens were immediately processed and analyzed for cTNI with the AxSYM immunoanalyzer (Abbott Laboratories, Baar/Zug, Switzerland). The limit of detection for this 1st generation AxSYM cTNI assay was 0.3 μg/L. Because the 99th percentile for this cTNI assay (0.5 μg/L) cannot be measured with ≤ 10% imprecision, the lowest cut-off value at which 10% imprecision is achieved (0.8 μg/L) was considered indicative of cardiac injury as suggested by current ESC/ACC guidelines for the definition of myocardial infarction [17]. Non-ST-elevation myocardial infarction was retrospectively established by two cardiologists (M.C. and C.M.) using all clinical information available, which included cTNI levels. Fig. 1. Mortality risks after 30 days (A) and 24 months (B) of follow-up in 305 patients presenting with acute dyspnea to the emergency department. Patients have been stratified by the number of elevated cardiac biomarkers. The chi-square test was used for comparison of frequencies.
Hospital Basel, Switzerland, from May 2001 to April 2002 [1]. Patients with severe renal dysfunction (serum creatinine N 250 μmol/L), or cardiogenic shock at presentation were excluded. The study was approved by the institutional review board, and written informed consent was obtained by each enrolled patient. All 3 biomarkers have been assessed in 305 patients of the overall study cohort. Thus, results of this post-hoc analysis included 67% of patients originally enrolled in the BASEL trial.
1.4. CRP measurement Levels of CRP were determined by a particle-enhanced turbidimetric immunoassay (Dade Behring Inc., Newark, DE) on hospital admission. The lower detection limit of this test is 3 mg/L. A cut-off point of 5 mg/L was used for analysis. 1.5. Endpoints The primary endpoint of this analysis was overall mortality. Death or rehospitalization for acute dyspnea during follow-up was defined as the secondary endpoint. Patients were contacted at specified intervals (3, 6, 12, and 24 months)
Table 2 Univariate and multivariable Cox regression models to predict the primary endpoint (time to death) Variables
B-type natriuretic peptide level Troponin I C-reactive protein
30 days mortality
24 months mortality
Relative risk (95%CI)
p univariate
p multivariable
Relative risk (95%CI)
p univariate
p multivariable
11.6 (1.59–84.91) 2.46 (1.25–4.85) 3.39 (1.20–9.63)
0.02 0.009 0.02
0.04 0.09 0.08
4.78 (2.51–9.14) 2.29 (1.61–3.26) 1.98 (1.28–3.08)
b0.001 b0.001 0.002
b0.001 b0.002 0.09
30 days mortality B-type natriuretic peptide level Troponin I C-reactive protein History of CAD
8.84 (1.16–67.1) 1.80 (0.91–3.56) 2.40 (0.84–6.91) 0.84 (0.41–1.72)
24 months mortality 0.04 0.09 0.10 0.63
2.92 (1.48–5.77) 1.68 (1.17–2.42) 1.55 (0.99–2.43) 2.00 (1.29–3.12)
0.002 0.005 0.06 0.002
Clinically used cut-off points have been used for B-type natriuretic peptide (N100 pg/mL), troponin I (N0.8 pg/L) and C-reactive protein levels (N5 mg/L). In further multivariable Cox regression models history of coronary artery disease (CAD) was included [4].
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Fig. 2. Survival analysis of dyspneic patients presenting to the emergency department. A Kaplan–Meier plot showing survival stratified by the number of elevated cardiac biomarkers is displayed. For comparison of curves the log-rank test was used.
by telephone interview performed by a single trained researcher, who was blinded to the results of cardiac biomarker testing. Referring physicians were contacted in case of uncertainties regarding health status. The administrative databases of the respective hometowns were assessed to ascertain the vital status of those patients who could not be contacted by telephone.
heart failure in 170 patients, of whom 29% had retrospectively established acute non-ST-elevation myocardial infarction (Table 1). Death occurred in 123 patients (40%) within 24 months of follow-up, while 42 of 146 patients (29%) died in the subgroup of patients, who were not included in this analysis due to the unavailability of all 3 biomarkers ( p = 0.02 for difference). A simple scoring system was devised in which patients were categorized on the basis of the number of elevated biomarkers. The 30 days and 24 months risk of death increased in proportion to the number of cardiac biomarkers elevated at baseline ( p b 0.001 for trend; Fig. 1), with more than doubling of the mortality risk for each additional biomarker. This risk increase was evident for an elevation of 2 biomarkers after 24 months of follow-up, while elevation of 3 biomarkers did not significantly indicate a further increase of mortality ( p = 0.25; Fig. 1). Univariate Cox regression analysis revealed that elevation of each biomarker significantly contributed to the model predicting increased risk of death at 30 days and at 24 months of follow-up (Table 2). In a multivariable regression model including all 3 biomarkers, only BNP emerged as an independent predictor of the death after 30 days of follow-up. Increased BNP and TNI independently predicted death after 24 months of follow-up, while a statistical trend was seen for elevated CRP levels. Results were not considerably changed in multivariable Cox regression analyses after including past medical history of CAD in the models (Table 2). Survival analysis using the Kaplan–Meier method indicated that elevation of 1 or 2 biomarkers significantly
1.6. Statistical analysis Results are expressed as number, frequency, median (interquartile range, IQR) and point estimate (95% confidence intervals, 95%CI) as indicated. Univariate and multivariable Cox proportional hazard models were used to evaluate the associations between the outcome measures. For building a first regression model, we thereby used a stepwise procedure with an entry level of 0.05. Event-free survival probabilities were estimated with the Kaplan–Meier method and the log-rank test was used for comparisons of curves. The chi-square test was used for comparison of frequencies of measures at baseline. Parametric or non-parametric tests were used for comparison of variables where applicable. All p values reported are two-sided, a p value b 0.05 was considered significant. All statistical calculations were performed using the SPSS statistical software package (version 13.0; SPSS Inc., Chicago, IL). 2. Results Demographic and clinical characteristics of the study patients are displayed in Table 1. Acute dyspnea was due to
Fig. 3. Kaplan–Meier analysis of dyspneic patients presenting to the emergency department. Time to death or rehospitalization for acute dyspnea has been used as a combined endpoint. Event-free survival stratified by the number of elevated cardiac biomarkers is displayed. For comparison of curves the log-rank test was used.
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increased the risk of death within 24 months of follow-up, while patients with an elevation of 3 biomarkers display a comparable risk of death as patients with an elevation of 2 biomarkers ( p = 0.13; Fig. 2). Comparable results of this multimarker strategy were obtained when a combined endpoint was used (time to death or first rehospitalization due to acute dyspnea). Risk of death or rehospitalization significantly increases with the number of elevated biomarkers. Again, elevation of 3 biomarkers did not add further information compared to the elevation of 2 biomarkers ( p = 0.38; Fig. 3). 3. Discussion This study examined whether a multimarker strategy including BNP, cTNI, and CRP levels contributes valuable information for risk stratification in patients with acute dyspnea presenting to the emergency department. The major results of our study are the following: i) Patients presenting with acute dyspnea to the emergency department display extraordinary high mortality. ii) Using prospectively defined cut-off points and categorizing patients by the number of elevated cardiac biomarkers, we found that risk of death increased in proportion to the number of cardiac biomarkers elevated at baseline with more than doubling of the mortality risk for each additional biomarker. Elevation of 3 biomarkers did not significantly indicate a further increase of mortality elevation compared to the elevation of 2 biomarkers. iii) Cox regression models revealed that elevated BNP and cTNI levels indicate increased long-term risk of death, while only a trend was seen for increased CRP levels. Our results are of clinical importance: Incorporating this powerful risk prediction in the management of patients with acute dyspnea may potentially help improve their dismal prognosis. Options for tailored treatment include more intense monitoring, specialist care and intensified, diseasespecific pharmacotherapy. Recent research on cardiac biomarkers has been primarily focused on selected patient cohorts with a primary diagnosis of acute coronary syndrome, pulmonary embolization and/or acute heart failure [2,9,18,19]. In clinical practice, patients are presenting with subjective symptoms such as acute dyspnea, which may be related or not related to cardiac causes. Diagnosis of cardiac related dyspnea is demanding [20] and risk stratification using elevation of single biomarkers or simple scoring systems in patients with acute heart failure display moderate sensitivity and specificity [4,21]. Multimarker approaches have been introduced to facilitate clinical care and aid the development of new therapies in acute coronary syndromes [9]. We extend those strategies to patients presenting with acute dyspnea: Risk of death is highest in patients with elevation of 2 or 3 biomarkers, while patients without increased biomarkers display a good prognosis and patients with elevation of one biomarker show an intermediate prognosis. Importantly, risk of death in this cohort of patients with acute dyspnea and elevation of 2
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biomarkers at 6 months of follow-up is more than 6 fold higher than the 6 months risk of death in patients of the TACTICS-TIMI 18 trial with acute coronary syndrome [9]. The suggested multimarker approach covering different aspects of interrelated pathophysiological processes appears suitable to designate this high-risk group of patients. Our analysis highlights that patients presenting with acute dyspnea and increased troponin I levels display elevated risk of death and/or rehospitalization. Only patients with the primary complaint of acute dyspnea have been enrolled in the BASEL trial [1], while patients with acute chest pain, instable angina and/or ST-elevation myocardial infarction have been excluded. Increases of troponin levels are specific for myocardial cell necrosis [22] and increased troponin levels are associated with increased risk of death in patients presenting with instable angina and/or non-ST-elevation myocardial infarction [23]. Of note, elevated troponin levels may indicate subendocardial myocyte death due to increased myocardial strain present during acute heart failure, reduced subendocardial perfusion and/or structural damage [24,25]. In addition, 16% of enrolled patients retrospectively had established acute non-ST-elevation myocardial infarction by clinical reevaluation including cTNI results supporting the notion that troponin levels should be determined in patients presenting with acute dyspnea to the emergency department. Comparably, patients with acute pulmonary embolization and increased troponin levels are at increased risk of adverse events and troponin levels may reflect ischemia due to increased right ventricular wall strain and subsequent reduction of coronary perfusion [19]. Inflammatory cytokines play an important role in the pathophysiology of many disorders underlying acute dyspnea including acute heart failure, chronic obstructive pulmonary disease or pneumonia [26]. We have recently demonstrated that elevation of CRP at the time of acute heart failure presentation is associated with adverse short- and long-term clinical outcomes [12] suggesting that increased CRP is either a result of hemodynamic deterioration or a reflection of a great burden of proinflammatory cytokines [15]. In the current analysis, we extend the above findings to the overall group of patients presenting with acute dyspnea. However, multivariable Cox regression analysis revealed only a statistical trend for CRP levels to predict risk of death and/or rehospitalization in this population. 3.1. Study limitations Several limitations of this analysis merit consideration: i) This is a post-hoc analysis of the BASEL study including patients, in whom measurement of all 3 biomarkers were available. Risk of death was lower in patients not meeting this criterion indicating that our study included a cohort of dyspneic patients at high risk of death. Therefore, our findings have to be considered hypothesis generating than definite and need to be confirmed in future studies. ii) Classification of cardiac or non-cardiac causes of death including sudden
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cardiac death would offer interesting insights into the potentially pathophysiological distinct role of biomarkers. However, we decided to record all-cause mortality, since classification of death in clinical practice is unreliable [27]. iii) The number of endpoints in this trial is of moderate size limiting the statistical power in this post-hoc analysis of a previous prospective cohort study. The careful long-term follow-up supports the validity of our results.
[9]
[10]
[11]
3.2. Conclusions [12]
Our findings suggest that this simple multimarker approach with simultaneous assessment of BNP, and cTNI demonstrates the potential to assist clinicians in predicting prognosis of patients presenting with acute dyspnea. Future study is needed to show whether this simple multimarker approach allows clinicians to improve patient management and prognosis. Acknowledgements This study was supported by research grants from the Swiss National Science Foundation, the Swiss Heart Foundation, and the Novartis Foundation (to C.M.). References [1] Mueller C, Scholer A, Laule-Kilian K, et al. Use of B-type natriuretic peptide in the evaluation and management of acute dyspnea. N Engl J Med 2004;350:647–54. [2] Maisel AS, Krishnaswamy P, Nowak RM, et al. Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure. N Engl J Med 2002;347:161–7. [3] Anonymous. Dyspnea. Mechanisms, assessment, and management: a consensus statement. American Thoracic Society. Am J Respir Crit Care Med 1999;159:321–40. [4] Fonarow GC, Adams Jr KF, Abraham WT, Yancy CW, Boscardin WJ. Risk stratification for in-hospital mortality in acutely decompensated heart failure: classification and regression tree analysis. JAMA 2005;293: 572–80. [5] McCullough PA, Nowak RM, McCord J, et al. B-type natriuretic peptide and clinical judgment in emergency diagnosis of heart failure: analysis from Breathing Not Properly (BNP) Multinational Study. Circulation 2002;106:416–22. [6] de Lemos JA, Morrow DA, Bentley JH, et al. The prognostic value of B-type natriuretic peptide in patients with acute coronary syndromes. N Engl J Med 2001;345:1014–21. [7] Lindahl B, Toss H, Siegbahn A, Venge P, Wallentin L. Markers of myocardial damage and inflammation in relation to long-term mortality in unstable coronary artery disease. FRISC Study Group. Fragmin during Instability in Coronary Artery Disease. N Engl J Med 2000;343:1139–47. [8] Mueller C, Buettner HJ, Hodgson JM, et al. Inflammation and long-term mortality after non-ST elevation acute coronary syndrome treated with a
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