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B-type natriuretic peptide at presentation and prognosis in patients with ST-segment elevation myocardial infarction
Journal of the American College of Cardiology © 2004 by the American College of Cardiology Foundation Published by Elsevier Inc.
Vol. 44, No. 2, 2004 ISSN 0735-1097/04/$30.00 doi:10.1016/j.jacc.2004.04.033
B-Type Natriuretic Peptide at Presentation and Prognosis in Patients With ST-Segment Elevation Myocardial Infarction An ENTIRE–TIMI-23 Substudy Jessica L. Mega, MD,* David A. Morrow, MD, MPH, FACC,*† James A. de Lemos, MD, FACC,‡ Marc S. Sabatine, MD, MPH,*† Sabina A. Murphy, MPH,* Nader Rifai, PHD,§ C. Michael Gibson, MD, FACC,* Elliott M. Antman, MD, FACC,*† Eugene Braunwald, MD, FACC*† Boston, Massachusetts; and Dallas, Texas We sought to evaluate B-type natriuretic peptide (BNP), alone and in comparison to cardiac troponin I (cTnI) and high-sensitivity C-reactive protein (hs-CRP), for risk assessment at initial presentation with ST-segment elevation myocardial infarction (STEMI). BACKGROUND Elevated levels of BNP drawn two to four days after acute myocardial infarction are associated with higher mortality. Sparse data are available on its use at first presentation with STEMI. METHODS We obtained samples from 438 patients presenting within 6 h of STEMI enrolled in the Enoxaparin Tenecteplase-Tissue-Type Plasminogen Activator With or Without Glycoprotein IIb/IIIa Inhibitor as Reperfusion Strategy in ST-Segment Elevation Myocardial Infarction (ENTIRE)–Thrombolysis In Myocardial Infarction (TIMI)-23 trial. Outcomes were assessed through 30 days. RESULTS Median BNP was higher in patients who died (89 pg/ml, 25th to 75th percentile: 40 to 192), compared with survivors (15 pg/ml, 25th to 75th percentile: 8.8 to 32, p ⬍ 0.0001). Patients with BNP ⬎80 pg/ml were at significantly higher risk of death (17.4% vs. 1.8%, p ⬍ 0.0001). Cardiac troponin established a gradient of mortality between the highest and lowest quartile (7.9% vs. 0%, p ⫽ 0.007). C-reactive protein was not associated with outcome. After adjustment for cTnI, hs-CRP, and major clinical predictors, including age, heart failure, anterior myocardial infarction location, heart rate, and blood pressure, a BNP level ⬎80 pg/ml was associated with a seven-fold higher mortality risk (odds ratio 7.2, 95% confidence interval 2.1 to 24.5, p ⫽ 0.001). Patients with BNP ⬎80 pg/ml were also more likely to have impaired coronary flow (p ⫽ 0.049) and incomplete resolution of ST-segment elevation (p ⫽ 0.05). CONCLUSIONS Increased concentrations of BNP at initial presentation of patients with STEMI are associated with impaired reperfusion after fibrinolysis and higher short-term risk of mortality. These data support the value of combining markers of hemodynamic stress with traditional approaches to risk assessment in acute myocardial infarction. (J Am Coll Cardiol 2004;44: 335–9) © 2004 by the American College of Cardiology Foundation OBJECTIVES
B-type natriuretic peptide (BNP) is released from the cardiac ventricles in response to increased wall stress (1). It has emerged as an aid to diagnosing congestive heart failure (CHF) (2) and has subsequently been studied in the setting of acute coronary syndromes, where the plasma concentration rises rapidly over 24 h after ST-segment elevation myocardial infarction (STEMI) (3–5). When measured two to seven days after infarction, elevated levels of BNP identify patients with lower survival (6 –9). Because of the time-dependent rise in BNP, the value of very early determinations is less clear, and there are sparse data addressing the prognostic implications of BNP drawn at the time of presentation with STEMI (4). Moreover, the prognostic From the *TIMI Study Group, †Cardiovascular Division, Brigham and Women’s Hospital, Boston, Massachusetts; ‡University of Texas Southwestern Medical Center, Dallas, Texas; and §Children’s Hospital, Boston, Massachusetts. Aventis supported ENTIRE-TIMI 23. Bayer supported reagents and analysis costs. Drs. Mega and Morrow contributed equally to the drafting/editing of this manuscript. Manuscript received February 6, 2004; revised manuscript received March 27, 2004, accepted April 6, 2004.
value of BNP relative to other biomarkers has not been assessed in this setting. We thus evaluated the prognostic performance and clinical correlates of BNP, assessed at the time of presentation, along with cardiac troponin I (cTnI) and high-sensitivity C-reactive protein (hs-CRP) among patients with STEMI in the Enoxaparin Tenecteplase-Tissue-Type Plasminogen Activator With or Without Glycoprotein IIb/IIIa Inhibitor as Reperfusion Strategy in ST-Segment Elevation Myocardial Infarction (ENTIRE)–Thrombolysis In Myocardial Infarction (TIMI)-23 trial.
METHODS Study population. The ENTIRE–TIMI-23 trial randomized 483 patients with STEMI to either full-dose tenecteplase (TNK)–tissue-type plasminogen activator (tPA) or half-dose TNK-tPA plus abciximab and to either unfractionated heparin or enoxaparin (10). Patients age 21 to 75 years presenting within 6 h were eligible. Exclusion criteria included shock, pulmonary edema requiring intubation, and
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Abbreviations and Acronyms BNP ⫽ B-type natriuretic peptide CHF ⫽ congestive heart failure cTnI ⫽ cardiac troponin I ENTIRE–TIMI-23 ⫽ Enoxaparin Tenecteplase-TissueType Plasminogen Activator With or Without Glycoprotein IIb/IIIa Inhibitor as Reperfusion Strategy in ST-Segment Elevation Myocardial Infarction (ENTIRE)– Thrombolysis In Myocardial Infarction (TIMI)-23 trial hs-CRP ⫽ high-sensitivity C-reactive protein MI ⫽ myocardial infarction ROC ⫽ receiver-operating characteristics STEMI ⫽ ST-segment elevation myocardial infarction TNK-tPA ⫽ tenecteplase–tissue-type plasminogen activator
creatinine clearance ⱕ30 ml/min. The protocol and biomarker substudy were approved by the institutional review board at each institution, and all patients provided written, informed consent. Procedures. Angiography performed 55 to 75 min after reperfusion therapy was interpreted by the TIMI Angiographic Core Laboratory in Boston. Myocardial tissue-level reperfusion was categorized by the TIMI myocardial perfusion grade. ST-segment resolution was assessed using predefined criteria at 180 min after fibrinolysis (11). Blood samples were obtained before fibrinolysis for analysis of cardiac biomarkers. Patients were followed through 30 days (10). Biomarker testing. B-type natriuretic peptide was measured in EDTA-anticoagulated plasma using the ADVIA Centaur BNP assay (Bayer, Tarrytown, New York). This assay has a minimal detectable concentration of ⬍2.0 pg/ml and a total imprecision of 4.7% and 2.8% at 29 pg/ml and 410 pg/ml, respectively. The assay is calibrated to have the same cut-point for diagnosis of CHF as an existing method (2). Troponin I was measured using the ACS:180 (Bayer) with a decision limit of 0.1 ng/ml (12). High-sensitivity testing for CRP was performed using an immunonephelometric assay (Dade-Behring, Newark, Delaware). The decision limit (15 mg/l) was prespecified (13). Statistical analysis. The plasma levels of BNP were described by the median (interquartile range). The concentration of BNP was also categorized into quartiles and dichotomized using a prespecified decision limit (80 pg/ml) (14,15). An exploratory evaluation of additional cut-points was performed using receiver-operating characteristics (ROC). The baseline characteristics of patients with and without elevated BNP were compared using the Wilcoxon rank-sum test for continuous variables and the chi-square test for categorical variables. The association between each biomarker and clinical outcomes was evaluated using the chi-square or Fisher exact test for dichotomized comparisons and the chi-square test for trend across
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quartiles. Multivariate analyses of the association between BNP and outcomes were performed using logistic regression to adjust for the other biomarkers and for major clinical predictors of mortality (age, anterior myocardial infarction [MI] location, time from symptom onset, heart rate, blood pressure, and CHF at presentation), as captured by the TIMI risk score for STEMI. All analyses were performed using STATA v7intercooled (STATA Corp., College Station, Texas).
RESULTS The BNP results were available for 438 patients (91%). The median concentration of BNP at presentation was 15.6 pg/ml (25th to 75th percentile: 9.1 to 32.6). Patients with elevated levels (⬎80 pg/ml) were older and more likely to have a history of hypertension, angina, and CHF (Table 1). Consistent with the greater prevalence of angina and CHF, they were also more likely to be receiving beta-blockers and angiotensin-converting enzyme inhibitors at presentation. The proportion of patients with elevated BNP did not differ between men and women. The median time from symptom onset was longer in patients with elevated BNP. Prognosis and BNP. The baseline concentration of BNP was significantly higher in the 15 patients who died by 30 days (89 pg/ml, 25th to 75th percentile: 40 to 192), compared with the 423 survivors (15 pg/ml, 25th to 75th percentile: 8.8 to 32, p ⬍ 0.0001). The relationships between the baseline concentration of BNP (quartiles) and clinical outcomes are detailed in Table 2. Patients with BNP in the highest quartile had an 11-fold higher risk of death compared to quartiles 1 to 3 (p ⬍ 0.0001). When treated dichotomously, BNP ⬎80 pg/ml was associated with a significantly higher risk of death through 30 days (p ⬍ 0.0001) (Figs. 1 and 2). A trend toward more frequent new or worsening CHF was also apparent among those with BNP ⬎80 pg/ml (8.7% vs. 3.3%, p ⫽ 0.09), with a consequently increased risk of death or CHF (23.9% vs. 5.1, p ⬍ 0.0001). In addition to evaluating the prespecified decision limit, we performed an exploratory analysis of alternative cutpoints. The ROC analysis indicated an optimal cut-point in this data set of ⬍80 pg/ml (Fig. 3). Using a decision limit of 40 pg/ml, an elevated BNP was associated with a ⬎10-fold higher risk of death (13.5% vs. 0.86%, p ⬍ 0.0001) and a nearly five-fold higher risk of death/CHF (19.1% vs. 4.0%, p ⬍ 0.0001). Notably, as a single predictor for mortality, BNP performed very well (c statistic ⫽ 0.81). Clinical predictors and BNP and other biomarkers. Compared with cTnI and hs-CRP, BNP was a substantially more robust marker of 30-day mortality (Fig. 1). C-reactive protein was not associated with mortality or recurrent MI in this study. Patients with cTnI in the highest quartile were at increased risk of death (Table 2). However, cTnI did not offer prognostic information independent of BNP (p ⫽ 0.9, adjusted for BNP). In contrast, BNP maintained an independent contribution to risk assessment. Among patients
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Table 1. Univariate Associations With Elevated Levels of BNP
Demographics Age (yrs) Female (%) Risk factors Hypertension (%) Smoking (%) Diabetes (%) Dyslipidemia (%) Previous angina (%) Previous CHF (%) Presenting characteristics Anterior MI (%) Heart rate (beats/min) Systolic BP (mm Hg) Time from symptom onset (h) Previous medications Aspirin (%) Beta-blocker (%) ACE inhibitor (%) Antihyperlipidemic agent (%)
BNP <80 pg/ml (n ⴝ 390)
BNP >80 pg/ml (n ⴝ 46)
p Value
57 (50, 65) 17.4
67 (59, 70) 21.7
⬍0.0001 0.5
24.7 54.6 13.5 30.1 28.6 0.3
41.3 39.1 13.0 37.0 47.8 6.5
0.016 0.5 0.9 0.3 0.007 ⬍0.0001
35.7 70 (60, 80) 136 (120, 150) 2.8 (2.0, 3.8)
32.6 80 (65, 91) 146 (133, 160) 3.6 (2.6, 4.8)
0.7 0.008 0.003 ⬍0.0001
14.8 15.6 10.2 13.5
40.0 43.5 34.8 23.9
⬍0.0001 ⬍0.0001 ⬍0.0001 0.06
Data are presented as a percentage for dichotomous variables and median value (25th, 75th percentile) for continuous variables. ACE ⫽ angiotensin-converting enzyme; BNP ⫽ B-type natriuretic peptide; BP ⫽ blood pressure; CHF ⫽ congestive heart failure; MI ⫽ myocardial infarction.
with positive cTnI results, those with BNP ⬎80 pg/ml were at significantly higher risk of death at 30 days (p ⬍ 0.0001) (Fig. 4). In addition, although few patients with negative initial cTnI results had elevated BNP, a trend toward higher mortality was also evident among this group (p ⫽ 0.081). Moreover, assessed using logistic regression, BNP remained independently associated with mortality (odds ratio [OR] 7.2, 95% confidence interval [CI] 2.1 to 24.5, p ⫽ 0.001) after adjustment for cTnI and hs-CRP (evaluated as dichotomous and continuous variables), as well as major clinical predictors of mortality (age, anterior MI location, time from symptom onset to fibrinolysis, heart rate, blood pressure, and CHF at presentation). This independent risk relationship with BNP was unaltered (OR 8.2, 95% CI 2.3 to 28.4, p ⫽ 0.001) when the population was restricted to
those with no history of CHF. The prognostic association between BNP and mortality was even stronger using a cut-point of 40 pg/ml (OR 15.9, 95% CI 3.1 to 81, p ⫽ 0.001; likelihood ratio test vs. 80 pg/ml, p ⫽ 0.02). Angiographic and electrocardiographic observations. Elevated BNP at presentation was associated with evidence of subsequent impaired epicardial and myocardial reperfusion. Specifically, patients with BNP ⬎80 pg/ml were more likely to have incomplete reperfusion of the infarct-related artery (Table 3). In addition, elevated BNP was associated with incomplete (⬍70%) resolution of ST-segment elevation, an indicator of impaired myocardial tissue-level reperfusion (95.8% vs. 79.2%, p ⫽ 0.05) (Table 3) (11). The baseline concentration of BNP was not a surrogate for extent of necrosis (Spearman’s rho ⫽ ⫺0.065 for creatine kinase-MB fraction, p ⫽ 0.19).
Table 2. Association Between Biomarkers and Clinical Outcomes
BNP Concentration (pg/ml) Death (%) Re-infarction (%) CHF (%) cTnI Concentration (ng/ml) Death (%) Re-infarction (%) CHF (%) hs-CRP Concentration (mg/l) Death (%) Re-infarction (%) CHF (%)
Q1
Q2
Q3
Q4
p Value
⬍9 1.8 5.5 2.7
9–15 0 2.8 1.8
16–32 0.9 3.6 5.5
⬎32 11.1 3.7 5.5
⬍0.0001 0.8 0.4
⬍0.08 0 2.7 3.5
0.08–0.23 2.7 5.4 2.7
0.24–0.79 2.7 4.5 4.5
⬎0.79 7.9 2.6 6.1
0.007 0.7 0.6
⬍1.1 4.4 4.4 3.5
1.1–2.7 1.8 4.5 3.6
2.8–6.0 1.8 2.7 3.6
⬎6.0 3.3 3.6 6.3
0.4 0.9 0.7
BNP ⫽ B-type natriuretic peptide; CHF ⫽ congestive heart failure; cTnI ⫽ cardiac troponin I; hs-CRP ⫽ high-sensitivity C-reactive protein; Q ⫽ quartile.
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Figure 1. Relationship between elevated biomarkers and mortality at 30 days. Positive results (solid bars) were defined as B-type natriuretic peptide (BNP) ⬎80 pg/ml, cardiac troponin ⱖ0.1 ng/ml, and high sensitivity C-reactive protein (CRP) ⱖ15 mg/l (negative results ⫽ open bars).
DISCUSSION In this study of concurrent assessment of BNP, cTnI, and hs-CRP at the time of presentation with STEMI, we found that BNP was a robust and independent indicator of mortality risk, with risk assessment performance superior to cTnI or hs-CRP. Even when assessed early after symptom onset, BNP maintained the strong prognostic relationship evident in previous studies with later sample acquisition (1). Clinical application of biomarkers in STEMI. Cardiac biomarkers provide prognostic information that is incremental to clinical predictors in patients with STEMI. Patients with elevated cTnT at the time of presentation have two- to three-fold higher mortality risk at 30 days, independent of the time from symptom onset (16). Sparse data exist on the prognostic importance of hs-CRP in STEMI. In one study, patients with elevated CRP were more likely to suffer complications of acute MI (myocardial rupture, ventricular aneurysm, and death by one year) (17). The contrasting absence of a relationship between hs-CRP and outcome in the ENTIRE–TIMI-23 trial may relate both to the very early sample acquisition and the assessment of short- rather than long-term outcomes. Including our present analysis, BNP has been evaluated in at least seven studies of patients with STEMI (1,3,4, 6 – 8). Together, these studies provide consistent evidence
Figure 2. Probability of death through 30 days stratified by B-type natriuretic peptide (BNP).
Figure 3. The receiver-operator characteristic curve for B-type natriuretic peptide at 10-pg/ml intervals for predicting death at 30 days.
for the additive prognostic value of BNP. Although BNP levels are correlated with age, gender, intracardiac pressures, ejection fraction, and renal function, BNP provides prognostic information that is independent of these variables. Moreover, whether measured at presentation, as in the present report, or later during recovery, BNP is one of the most robust indicators of mortality risk. This strong prognostic association in STEMI parallels that among patients with non–ST-segment elevation acute coronary syndromes (15). An important and, as yet, unanswered question is whether biomarkers, such as BNP, evaluated in STEMI should be used to select specific therapies. Mechanistic information provided in this and other studies (18) points toward hypotheses regarding interventions that may ameliorate this risk. We have shown that an elevated BNP level before fibrinolysis is associated with a lower likelihood of successful epicardial and myocardial reperfusion. Although not directly addressed in this study, we may speculate that underlying left ventricular hypertrophy, unrecognized left ventricular dysfunction, and/or a large territory of infarct/ischemia may be contributing to the increased concentration of BNP and are associated with
Figure 4. Association of B-type natriuretic peptide (BNP), in conjunction with cardiac troponin and high sensitivity C-reactive protein (CRP), with mortality at 30 days. Positive results (solid bars) were defined as BNP ⬎80 pg/ml, cardiac troponin ⱖ0.1 ng/ml, and high sensitivity CRP ⱖ15 mg/l (negative results ⫽ open bars).
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JACC Vol. 44, No. 2, 2004 July 21, 2004:335–9 Table 3. Association Between Biomarkers, Coronary Flow, and Electrocardiographic Abnormalities
BNP (%) ⱕ80 pg/ml ⬎80 pg/ml p Value ⱕ40 pg/ml ⬎40 pg/ml p Value cTnI (%) ⬍0.1 ng/ml ⱖ0.1 ng/ml p Value hs-CRP (%) ⬍15 mg/l ⱖ15 mg/l p Value
Impaired Flow
Poor Myocardial Perfusion
Failed ST-Segment Resolution
47.5 64.1 0.049 46.5 59.5 0.04
46.1 53.8 0.362 44.5 56.4 0.06
79.2 95.8 0.05 77.2 95.6 0.005
43.3 51.3 0.157
46.9 47.5 0.923
72.8 83.2 0.072
48.6 50.0 0.887
47.3 46.4 0.926
79.6 84.2 0.632
Abbreviations as in Table 2.
impaired reperfusion and increased mortality. Therefore, patients with elevated BNP may be particularly appropriate candidates for primary angioplasty and for transfer when presenting to hospitals without available catheterization facilities. Others have shown that when measured subacutely after MI, elevated BNP identifies patients at risk of adverse left ventricular remodeling, chronic left ventricular dysfunction, and CHF (1). In this setting, routine treatment, even among patients without evident left ventricular dysfunction or CHF, with afterload-reducing agents or novel agents that may improve infarct healing or ventricular remodeling after MI, may be particularly beneficial. Study limitations. Limitations to this analysis should be considered. First, given the relatively low mortality rate in this study, it is possible that an association between hs-CRP and short-term mortality could not be detected. However, the observations regarding the relative strength of the risk relationships for BNP compared with cTnI and hs-CRP are unlikely to be altered in a larger population. Second, although this study provides interesting data on the association of BNP with impaired reperfusion, it does not provide direct insight into the underlying pathobiology. Third, the prevalence of pre-existing CHF among patients presenting with STEMI in the community is higher than that observed in this trial. It is possible that the prognostic implications of elevated BNP in patients with chronic CHF presenting with STEMI differ from those of patients without chronic CHF. Also, the lower cut-point (40 pg/ml) may not be optimal in populations with a greater proportion of women and elderly. For these reasons, additional community-based studies with STEMI will be valuable. Conclusions. In patients with STEMI, elevated levels of BNP at initial presentation are associated with impaired reperfusion after fibrinolysis and increased risk of shortterm mortality. These data support the value of combining markers of hemodynamic stress, such as BNP, with estab-
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lished biomarkers of necrosis, for risk assessment at the time of presentation with acute MI. Reprint requests and correspondence: Dr. David A. Morrow, TIMI Study Group/Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis Street, Boston, Massachusetts 02115. E-mail: [email protected].
REFERENCES 1. de Lemos JA, McGuire DK, Drazner MH. B-type natriuretic peptide in cardiovascular disease. Lancet 2003;362:316 –22. 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. Talwar S, Squire IB, Downie PF, et al. Profile of plasma N-terminal proBNP following acute myocardial infarction: correlation with left ventricular systolic dysfunction. Eur Heart J 2000;21:1514 –21. 4. Morita E, Yasue H, Yoshimura M, et al. Increased plasma levels of brain natriuretic peptide in patients with acute myocardial infarction. Circulation 1993;88:82–91. 5. Motwani JG, McAlpine H, Kennedy N, Struthers AD. Plasma brain natriuretic peptide as an indicator for angiotensin-converting enzyme inhibition after myocardial infarction. Lancet 1993;341:1109 –13. 6. Omland T, Aakvaag A, Bonarjee VV, et al. Plasma brain natriuretic peptide as an indicator of left ventricular systolic function and long-term survival after acute myocardial infarction: comparison with plasma atrial natriuretic peptide and N-terminal proatrial natriuretic peptide. Circulation 1996;93:1963–9. 7. Arakawa N, Nakamura M, Aoki H, Hiramori K. Plasma brain natriuretic peptide concentrations predict survival after acute myocardial infarction. J Am Coll Cardiol 1996;27:1656 –61. 8. Richards AM, Nicholls MG, Yandle TG, et al. Plasma N-terminal pro-brain natriuretic peptide and adrenomedullin: new neurohormonal predictors of left ventricular function and prognosis after myocardial infarction. Circulation 1998;97:1921–9. 9. Richards AM, Nicholls MG, Yandle TG, et al., the Christchurch Cardioendocrine Research Group. Neuroendocrine prediction of left ventricular function and heart failure after acute myocardial infarction. Heart 1999;81:114 –20. 10. Antman EM, Louwerenburg HW, Baars HF, et al. Enoxaparin as adjunctive antithrombin therapy for ST-elevation myocardial infarction: results of the ENTIRE-(TIMI) 23 trial. Circulation 2002;105: 1642–9. 11. de Lemos JA, Braunwald E. ST segment resolution as a tool for assessing the efficacy of reperfusion therapy. J Am Coll Cardiol 2001;38:1283–94. 12. Morrow DA, Rifai N, Tanasijevic MJ, Wybenga DR, de Lemos JA, Antman EM. Clinical efficacy of three assays for cardiac troponin I for risk stratification in acute coronary syndromes: a TIMI 11B substudy. Clin Chem 2000;46:453–60. 13. Morrow DA, Rifai N, Antman EM, et al. C-reactive protein is a potent predictor of mortality independently of and in combination with troponin T in acute coronary syndromes: a TIMI 11A substudy. J Am Coll Cardiol 1998;31:1460 –5. 14. 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. 15. Morrow DA, de Lemos JA, Sabatine MS, et al. Evaluation of B-type natriuretic peptide for risk assessment in unstable angina/non–STelevation myocardial infarction: B-type natriuretic peptide and prognosis in TACTICS-TIMI 18. J Am Coll Cardiol 2003;41:1264 –72. 16. Ohman EM, Armstrong PW, White HD, et al., the GUSTO III Investigators. Risk stratification with a point-of-care cardiac troponin T test in acute myocardial infarction. Am J Cardiol 1999;84:1281–6. 17. Anzai T, Yoshikawa T, Shiraki H, et al. C-reactive protein as a predictor of infarct expansion and cardiac rupture after a first Q-wave acute myocardial infarction. Circulation 1997;96:778 –84. 18. Richards AM, Nicholls MG, Espiner EA, et al. B-type natriuretic peptides and ejection fraction for prognosis after myocardial infarction. Circulation 2003;107:2786 –92.
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B-Type Natriuretic Peptide at Presentation and Prognosis in Patients With ST-Segment Elevation Myocardial Infarction An ENTIRE–TIMI-23 Substudy Jessica L. Mega, MD,* David A. Morrow, MD, MPH, FACC,*† James A. de Lemos, MD, FACC,‡ Marc S. Sabatine, MD, MPH,*† Sabina A. Murphy, MPH,* Nader Rifai, PHD,§ C. Michael Gibson, MD, FACC,* Elliott M. Antman, MD, FACC,*† Eugene Braunwald, MD, FACC*† Boston, Massachusetts; and Dallas, Texas We sought to evaluate B-type natriuretic peptide (BNP), alone and in comparison to cardiac troponin I (cTnI) and high-sensitivity C-reactive protein (hs-CRP), for risk assessment at initial presentation with ST-segment elevation myocardial infarction (STEMI). BACKGROUND Elevated levels of BNP drawn two to four days after acute myocardial infarction are associated with higher mortality. Sparse data are available on its use at first presentation with STEMI. METHODS We obtained samples from 438 patients presenting within 6 h of STEMI enrolled in the Enoxaparin Tenecteplase-Tissue-Type Plasminogen Activator With or Without Glycoprotein IIb/IIIa Inhibitor as Reperfusion Strategy in ST-Segment Elevation Myocardial Infarction (ENTIRE)–Thrombolysis In Myocardial Infarction (TIMI)-23 trial. Outcomes were assessed through 30 days. RESULTS Median BNP was higher in patients who died (89 pg/ml, 25th to 75th percentile: 40 to 192), compared with survivors (15 pg/ml, 25th to 75th percentile: 8.8 to 32, p ⬍ 0.0001). Patients with BNP ⬎80 pg/ml were at significantly higher risk of death (17.4% vs. 1.8%, p ⬍ 0.0001). Cardiac troponin established a gradient of mortality between the highest and lowest quartile (7.9% vs. 0%, p ⫽ 0.007). C-reactive protein was not associated with outcome. After adjustment for cTnI, hs-CRP, and major clinical predictors, including age, heart failure, anterior myocardial infarction location, heart rate, and blood pressure, a BNP level ⬎80 pg/ml was associated with a seven-fold higher mortality risk (odds ratio 7.2, 95% confidence interval 2.1 to 24.5, p ⫽ 0.001). Patients with BNP ⬎80 pg/ml were also more likely to have impaired coronary flow (p ⫽ 0.049) and incomplete resolution of ST-segment elevation (p ⫽ 0.05). CONCLUSIONS Increased concentrations of BNP at initial presentation of patients with STEMI are associated with impaired reperfusion after fibrinolysis and higher short-term risk of mortality. These data support the value of combining markers of hemodynamic stress with traditional approaches to risk assessment in acute myocardial infarction. (J Am Coll Cardiol 2004;44: 335–9) © 2004 by the American College of Cardiology Foundation OBJECTIVES
B-type natriuretic peptide (BNP) is released from the cardiac ventricles in response to increased wall stress (1). It has emerged as an aid to diagnosing congestive heart failure (CHF) (2) and has subsequently been studied in the setting of acute coronary syndromes, where the plasma concentration rises rapidly over 24 h after ST-segment elevation myocardial infarction (STEMI) (3–5). When measured two to seven days after infarction, elevated levels of BNP identify patients with lower survival (6 –9). Because of the time-dependent rise in BNP, the value of very early determinations is less clear, and there are sparse data addressing the prognostic implications of BNP drawn at the time of presentation with STEMI (4). Moreover, the prognostic From the *TIMI Study Group, †Cardiovascular Division, Brigham and Women’s Hospital, Boston, Massachusetts; ‡University of Texas Southwestern Medical Center, Dallas, Texas; and §Children’s Hospital, Boston, Massachusetts. Aventis supported ENTIRE-TIMI 23. Bayer supported reagents and analysis costs. Drs. Mega and Morrow contributed equally to the drafting/editing of this manuscript. Manuscript received February 6, 2004; revised manuscript received March 27, 2004, accepted April 6, 2004.
value of BNP relative to other biomarkers has not been assessed in this setting. We thus evaluated the prognostic performance and clinical correlates of BNP, assessed at the time of presentation, along with cardiac troponin I (cTnI) and high-sensitivity C-reactive protein (hs-CRP) among patients with STEMI in the Enoxaparin Tenecteplase-Tissue-Type Plasminogen Activator With or Without Glycoprotein IIb/IIIa Inhibitor as Reperfusion Strategy in ST-Segment Elevation Myocardial Infarction (ENTIRE)–Thrombolysis In Myocardial Infarction (TIMI)-23 trial.
METHODS Study population. The ENTIRE–TIMI-23 trial randomized 483 patients with STEMI to either full-dose tenecteplase (TNK)–tissue-type plasminogen activator (tPA) or half-dose TNK-tPA plus abciximab and to either unfractionated heparin or enoxaparin (10). Patients age 21 to 75 years presenting within 6 h were eligible. Exclusion criteria included shock, pulmonary edema requiring intubation, and
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Mega et al. BNP at Presentation in STEMI
Abbreviations and Acronyms BNP ⫽ B-type natriuretic peptide CHF ⫽ congestive heart failure cTnI ⫽ cardiac troponin I ENTIRE–TIMI-23 ⫽ Enoxaparin Tenecteplase-TissueType Plasminogen Activator With or Without Glycoprotein IIb/IIIa Inhibitor as Reperfusion Strategy in ST-Segment Elevation Myocardial Infarction (ENTIRE)– Thrombolysis In Myocardial Infarction (TIMI)-23 trial hs-CRP ⫽ high-sensitivity C-reactive protein MI ⫽ myocardial infarction ROC ⫽ receiver-operating characteristics STEMI ⫽ ST-segment elevation myocardial infarction TNK-tPA ⫽ tenecteplase–tissue-type plasminogen activator
creatinine clearance ⱕ30 ml/min. The protocol and biomarker substudy were approved by the institutional review board at each institution, and all patients provided written, informed consent. Procedures. Angiography performed 55 to 75 min after reperfusion therapy was interpreted by the TIMI Angiographic Core Laboratory in Boston. Myocardial tissue-level reperfusion was categorized by the TIMI myocardial perfusion grade. ST-segment resolution was assessed using predefined criteria at 180 min after fibrinolysis (11). Blood samples were obtained before fibrinolysis for analysis of cardiac biomarkers. Patients were followed through 30 days (10). Biomarker testing. B-type natriuretic peptide was measured in EDTA-anticoagulated plasma using the ADVIA Centaur BNP assay (Bayer, Tarrytown, New York). This assay has a minimal detectable concentration of ⬍2.0 pg/ml and a total imprecision of 4.7% and 2.8% at 29 pg/ml and 410 pg/ml, respectively. The assay is calibrated to have the same cut-point for diagnosis of CHF as an existing method (2). Troponin I was measured using the ACS:180 (Bayer) with a decision limit of 0.1 ng/ml (12). High-sensitivity testing for CRP was performed using an immunonephelometric assay (Dade-Behring, Newark, Delaware). The decision limit (15 mg/l) was prespecified (13). Statistical analysis. The plasma levels of BNP were described by the median (interquartile range). The concentration of BNP was also categorized into quartiles and dichotomized using a prespecified decision limit (80 pg/ml) (14,15). An exploratory evaluation of additional cut-points was performed using receiver-operating characteristics (ROC). The baseline characteristics of patients with and without elevated BNP were compared using the Wilcoxon rank-sum test for continuous variables and the chi-square test for categorical variables. The association between each biomarker and clinical outcomes was evaluated using the chi-square or Fisher exact test for dichotomized comparisons and the chi-square test for trend across
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quartiles. Multivariate analyses of the association between BNP and outcomes were performed using logistic regression to adjust for the other biomarkers and for major clinical predictors of mortality (age, anterior myocardial infarction [MI] location, time from symptom onset, heart rate, blood pressure, and CHF at presentation), as captured by the TIMI risk score for STEMI. All analyses were performed using STATA v7intercooled (STATA Corp., College Station, Texas).
RESULTS The BNP results were available for 438 patients (91%). The median concentration of BNP at presentation was 15.6 pg/ml (25th to 75th percentile: 9.1 to 32.6). Patients with elevated levels (⬎80 pg/ml) were older and more likely to have a history of hypertension, angina, and CHF (Table 1). Consistent with the greater prevalence of angina and CHF, they were also more likely to be receiving beta-blockers and angiotensin-converting enzyme inhibitors at presentation. The proportion of patients with elevated BNP did not differ between men and women. The median time from symptom onset was longer in patients with elevated BNP. Prognosis and BNP. The baseline concentration of BNP was significantly higher in the 15 patients who died by 30 days (89 pg/ml, 25th to 75th percentile: 40 to 192), compared with the 423 survivors (15 pg/ml, 25th to 75th percentile: 8.8 to 32, p ⬍ 0.0001). The relationships between the baseline concentration of BNP (quartiles) and clinical outcomes are detailed in Table 2. Patients with BNP in the highest quartile had an 11-fold higher risk of death compared to quartiles 1 to 3 (p ⬍ 0.0001). When treated dichotomously, BNP ⬎80 pg/ml was associated with a significantly higher risk of death through 30 days (p ⬍ 0.0001) (Figs. 1 and 2). A trend toward more frequent new or worsening CHF was also apparent among those with BNP ⬎80 pg/ml (8.7% vs. 3.3%, p ⫽ 0.09), with a consequently increased risk of death or CHF (23.9% vs. 5.1, p ⬍ 0.0001). In addition to evaluating the prespecified decision limit, we performed an exploratory analysis of alternative cutpoints. The ROC analysis indicated an optimal cut-point in this data set of ⬍80 pg/ml (Fig. 3). Using a decision limit of 40 pg/ml, an elevated BNP was associated with a ⬎10-fold higher risk of death (13.5% vs. 0.86%, p ⬍ 0.0001) and a nearly five-fold higher risk of death/CHF (19.1% vs. 4.0%, p ⬍ 0.0001). Notably, as a single predictor for mortality, BNP performed very well (c statistic ⫽ 0.81). Clinical predictors and BNP and other biomarkers. Compared with cTnI and hs-CRP, BNP was a substantially more robust marker of 30-day mortality (Fig. 1). C-reactive protein was not associated with mortality or recurrent MI in this study. Patients with cTnI in the highest quartile were at increased risk of death (Table 2). However, cTnI did not offer prognostic information independent of BNP (p ⫽ 0.9, adjusted for BNP). In contrast, BNP maintained an independent contribution to risk assessment. Among patients
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Table 1. Univariate Associations With Elevated Levels of BNP
Demographics Age (yrs) Female (%) Risk factors Hypertension (%) Smoking (%) Diabetes (%) Dyslipidemia (%) Previous angina (%) Previous CHF (%) Presenting characteristics Anterior MI (%) Heart rate (beats/min) Systolic BP (mm Hg) Time from symptom onset (h) Previous medications Aspirin (%) Beta-blocker (%) ACE inhibitor (%) Antihyperlipidemic agent (%)
BNP <80 pg/ml (n ⴝ 390)
BNP >80 pg/ml (n ⴝ 46)
p Value
57 (50, 65) 17.4
67 (59, 70) 21.7
⬍0.0001 0.5
24.7 54.6 13.5 30.1 28.6 0.3
41.3 39.1 13.0 37.0 47.8 6.5
0.016 0.5 0.9 0.3 0.007 ⬍0.0001
35.7 70 (60, 80) 136 (120, 150) 2.8 (2.0, 3.8)
32.6 80 (65, 91) 146 (133, 160) 3.6 (2.6, 4.8)
0.7 0.008 0.003 ⬍0.0001
14.8 15.6 10.2 13.5
40.0 43.5 34.8 23.9
⬍0.0001 ⬍0.0001 ⬍0.0001 0.06
Data are presented as a percentage for dichotomous variables and median value (25th, 75th percentile) for continuous variables. ACE ⫽ angiotensin-converting enzyme; BNP ⫽ B-type natriuretic peptide; BP ⫽ blood pressure; CHF ⫽ congestive heart failure; MI ⫽ myocardial infarction.
with positive cTnI results, those with BNP ⬎80 pg/ml were at significantly higher risk of death at 30 days (p ⬍ 0.0001) (Fig. 4). In addition, although few patients with negative initial cTnI results had elevated BNP, a trend toward higher mortality was also evident among this group (p ⫽ 0.081). Moreover, assessed using logistic regression, BNP remained independently associated with mortality (odds ratio [OR] 7.2, 95% confidence interval [CI] 2.1 to 24.5, p ⫽ 0.001) after adjustment for cTnI and hs-CRP (evaluated as dichotomous and continuous variables), as well as major clinical predictors of mortality (age, anterior MI location, time from symptom onset to fibrinolysis, heart rate, blood pressure, and CHF at presentation). This independent risk relationship with BNP was unaltered (OR 8.2, 95% CI 2.3 to 28.4, p ⫽ 0.001) when the population was restricted to
those with no history of CHF. The prognostic association between BNP and mortality was even stronger using a cut-point of 40 pg/ml (OR 15.9, 95% CI 3.1 to 81, p ⫽ 0.001; likelihood ratio test vs. 80 pg/ml, p ⫽ 0.02). Angiographic and electrocardiographic observations. Elevated BNP at presentation was associated with evidence of subsequent impaired epicardial and myocardial reperfusion. Specifically, patients with BNP ⬎80 pg/ml were more likely to have incomplete reperfusion of the infarct-related artery (Table 3). In addition, elevated BNP was associated with incomplete (⬍70%) resolution of ST-segment elevation, an indicator of impaired myocardial tissue-level reperfusion (95.8% vs. 79.2%, p ⫽ 0.05) (Table 3) (11). The baseline concentration of BNP was not a surrogate for extent of necrosis (Spearman’s rho ⫽ ⫺0.065 for creatine kinase-MB fraction, p ⫽ 0.19).
Table 2. Association Between Biomarkers and Clinical Outcomes
BNP Concentration (pg/ml) Death (%) Re-infarction (%) CHF (%) cTnI Concentration (ng/ml) Death (%) Re-infarction (%) CHF (%) hs-CRP Concentration (mg/l) Death (%) Re-infarction (%) CHF (%)
Q1
Q2
Q3
Q4
p Value
⬍9 1.8 5.5 2.7
9–15 0 2.8 1.8
16–32 0.9 3.6 5.5
⬎32 11.1 3.7 5.5
⬍0.0001 0.8 0.4
⬍0.08 0 2.7 3.5
0.08–0.23 2.7 5.4 2.7
0.24–0.79 2.7 4.5 4.5
⬎0.79 7.9 2.6 6.1
0.007 0.7 0.6
⬍1.1 4.4 4.4 3.5
1.1–2.7 1.8 4.5 3.6
2.8–6.0 1.8 2.7 3.6
⬎6.0 3.3 3.6 6.3
0.4 0.9 0.7
BNP ⫽ B-type natriuretic peptide; CHF ⫽ congestive heart failure; cTnI ⫽ cardiac troponin I; hs-CRP ⫽ high-sensitivity C-reactive protein; Q ⫽ quartile.
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Figure 1. Relationship between elevated biomarkers and mortality at 30 days. Positive results (solid bars) were defined as B-type natriuretic peptide (BNP) ⬎80 pg/ml, cardiac troponin ⱖ0.1 ng/ml, and high sensitivity C-reactive protein (CRP) ⱖ15 mg/l (negative results ⫽ open bars).
DISCUSSION In this study of concurrent assessment of BNP, cTnI, and hs-CRP at the time of presentation with STEMI, we found that BNP was a robust and independent indicator of mortality risk, with risk assessment performance superior to cTnI or hs-CRP. Even when assessed early after symptom onset, BNP maintained the strong prognostic relationship evident in previous studies with later sample acquisition (1). Clinical application of biomarkers in STEMI. Cardiac biomarkers provide prognostic information that is incremental to clinical predictors in patients with STEMI. Patients with elevated cTnT at the time of presentation have two- to three-fold higher mortality risk at 30 days, independent of the time from symptom onset (16). Sparse data exist on the prognostic importance of hs-CRP in STEMI. In one study, patients with elevated CRP were more likely to suffer complications of acute MI (myocardial rupture, ventricular aneurysm, and death by one year) (17). The contrasting absence of a relationship between hs-CRP and outcome in the ENTIRE–TIMI-23 trial may relate both to the very early sample acquisition and the assessment of short- rather than long-term outcomes. Including our present analysis, BNP has been evaluated in at least seven studies of patients with STEMI (1,3,4, 6 – 8). Together, these studies provide consistent evidence
Figure 2. Probability of death through 30 days stratified by B-type natriuretic peptide (BNP).
Figure 3. The receiver-operator characteristic curve for B-type natriuretic peptide at 10-pg/ml intervals for predicting death at 30 days.
for the additive prognostic value of BNP. Although BNP levels are correlated with age, gender, intracardiac pressures, ejection fraction, and renal function, BNP provides prognostic information that is independent of these variables. Moreover, whether measured at presentation, as in the present report, or later during recovery, BNP is one of the most robust indicators of mortality risk. This strong prognostic association in STEMI parallels that among patients with non–ST-segment elevation acute coronary syndromes (15). An important and, as yet, unanswered question is whether biomarkers, such as BNP, evaluated in STEMI should be used to select specific therapies. Mechanistic information provided in this and other studies (18) points toward hypotheses regarding interventions that may ameliorate this risk. We have shown that an elevated BNP level before fibrinolysis is associated with a lower likelihood of successful epicardial and myocardial reperfusion. Although not directly addressed in this study, we may speculate that underlying left ventricular hypertrophy, unrecognized left ventricular dysfunction, and/or a large territory of infarct/ischemia may be contributing to the increased concentration of BNP and are associated with
Figure 4. Association of B-type natriuretic peptide (BNP), in conjunction with cardiac troponin and high sensitivity C-reactive protein (CRP), with mortality at 30 days. Positive results (solid bars) were defined as BNP ⬎80 pg/ml, cardiac troponin ⱖ0.1 ng/ml, and high sensitivity CRP ⱖ15 mg/l (negative results ⫽ open bars).
Mega et al. BNP at Presentation in STEMI
JACC Vol. 44, No. 2, 2004 July 21, 2004:335–9 Table 3. Association Between Biomarkers, Coronary Flow, and Electrocardiographic Abnormalities
BNP (%) ⱕ80 pg/ml ⬎80 pg/ml p Value ⱕ40 pg/ml ⬎40 pg/ml p Value cTnI (%) ⬍0.1 ng/ml ⱖ0.1 ng/ml p Value hs-CRP (%) ⬍15 mg/l ⱖ15 mg/l p Value
Impaired Flow
Poor Myocardial Perfusion
Failed ST-Segment Resolution
47.5 64.1 0.049 46.5 59.5 0.04
46.1 53.8 0.362 44.5 56.4 0.06
79.2 95.8 0.05 77.2 95.6 0.005
43.3 51.3 0.157
46.9 47.5 0.923
72.8 83.2 0.072
48.6 50.0 0.887
47.3 46.4 0.926
79.6 84.2 0.632
Abbreviations as in Table 2.
impaired reperfusion and increased mortality. Therefore, patients with elevated BNP may be particularly appropriate candidates for primary angioplasty and for transfer when presenting to hospitals without available catheterization facilities. Others have shown that when measured subacutely after MI, elevated BNP identifies patients at risk of adverse left ventricular remodeling, chronic left ventricular dysfunction, and CHF (1). In this setting, routine treatment, even among patients without evident left ventricular dysfunction or CHF, with afterload-reducing agents or novel agents that may improve infarct healing or ventricular remodeling after MI, may be particularly beneficial. Study limitations. Limitations to this analysis should be considered. First, given the relatively low mortality rate in this study, it is possible that an association between hs-CRP and short-term mortality could not be detected. However, the observations regarding the relative strength of the risk relationships for BNP compared with cTnI and hs-CRP are unlikely to be altered in a larger population. Second, although this study provides interesting data on the association of BNP with impaired reperfusion, it does not provide direct insight into the underlying pathobiology. Third, the prevalence of pre-existing CHF among patients presenting with STEMI in the community is higher than that observed in this trial. It is possible that the prognostic implications of elevated BNP in patients with chronic CHF presenting with STEMI differ from those of patients without chronic CHF. Also, the lower cut-point (40 pg/ml) may not be optimal in populations with a greater proportion of women and elderly. For these reasons, additional community-based studies with STEMI will be valuable. Conclusions. In patients with STEMI, elevated levels of BNP at initial presentation are associated with impaired reperfusion after fibrinolysis and increased risk of shortterm mortality. These data support the value of combining markers of hemodynamic stress, such as BNP, with estab-
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lished biomarkers of necrosis, for risk assessment at the time of presentation with acute MI. Reprint requests and correspondence: Dr. David A. Morrow, TIMI Study Group/Cardiovascular Division, Brigham and Women’s Hospital, 75 Francis Street, Boston, Massachusetts 02115. E-mail: [email protected].
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