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US20030022235A1 - Use of B-type natriuretic peptide as a prognostic indicator in acute coronary syndromes - Google Patents
Use of B-type natriuretic peptide as a prognostic indicator in acute coronary syndromes Download PDF
US20030022235A1
US20030022235A1 US09835298 US83529801A US2003022235A1 US 20030022235 A1 US20030022235 A1 US 20030022235A1 US 09835298 US09835298 US 09835298 US 83529801 A US83529801 A US 83529801A US 2003022235 A1 US2003022235 A1 US 2003022235A1
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US7632647B2 (en )
The seriousness of ACS is underlined by the morbidity and mortality that follow the ischemic insult. For example, workers have estimated that within four to six weeks of presentation with ACS, the risk of death or a subsequent MI is 8-14%, and the rate of death, MI, or refractory ischemia is 15-25%. Theroux and Fuster, Circulation 97: 1195-1206 (1998) Given that the total number of deaths in the U.S. from acute MI is about 600,000, the search within the art for information that relates to the diagnosis, prognosis, and management of ACS has understandably been extensive. Several potential markers that may provide such information in certain patient populations have been identified, including circulating cardiac troponin levels (see, e.g., Antman et al., N. Eng. J. Med. 335: 1342-9 (1996); see also U.S. Pat. Nos. 6,147,688, 6,156,521, 5,947,124, and 5,795,725, each of which is hereby incorporated by reference in its entirety), ST-segment depression (see, e.g., Savonitto et al., JAMA 281: 707-13 (1999)), circulating creatine kinase levels (see, e.g., Alexander et al., Circulation (Suppl.) 1629 (1998)), and circulating c-reactive protein levels (see, e.g., Morrow et al., J. Am. Coll. Cardiol. 31: 1460-5 (1998)).
B-type natriuretic peptide (“BNP” or “BNP-32”) is a 32-amino acid neurohormone that is synthesized in ventricular myocardium and released into the circulation in response to ventricular dilation and pressure overload. The functions of BNP, like atrial natriuretic peptide, include natriuresis, vasodilation, inhibition of the renin-angiotensin-aldosterone axis, and inhibition of sympathetic nerve activity. The plasma concentration of BNP is elevated among patients with congestive heart failure (CHF), and increases in proportion to the degree of left ventricular dysfunction and the severity of CHF symptoms. For review, see, e.g., Wiese et al., Circulation 102: 3074-9 (2000); Yasue et al., Circulation 90: 195-203 (1994); Yoshimura et al., Circulation 87: 464-9 (1993); Stein and Levin, Am. Heart J. 135: 914-23 (1998); and Omland et al., Heart 76: 232-7 (1996).
The precursor to BNP is synthesized as a 108-amino acid molecule, referred to as “pre pro BNP,” that is proteolytically processed into a 76-amino acid N-terminal peptide (amino acids 1-76), referred to as “NT pro BNP” and the 32-amino acid mature hormone, referred to as BNP or BNP 32 (amino acids 77-108). It has been suggested that each of these species—NT pro-BNP, BNP-32, and the pre pro BNP—can circulate in human plasma. See, e.g., Tateyama et al., Biochem. Biophys. Res. Commun. 185: 760-7 (1992); Hunt et al., Biochem. Biophys. Res. Commun. 214: 1175-83 (1995). Pre pro BNP and NT pro BNP, and peptides which are derived from BNP, pre pro BNP and NT pro BNP that are present in the blood as a result of proteolyses of BNP, NT pro BNP and pre pro BNP, are collectively described herein as “markers related to or associated with BNP.”
Following the onset of acute MI, the plasma concentration of BNP has been shown to rise rapidly over the first 24 hours, and then to stabilize; patients with large infarcts may have a second peak in BNP concentration several days later. The concentration of BNP, when measured between 1 and 4 days following a transmural infarct, can provide prognostic information that is independent of the left ventricular ejection fraction (LVEF) and other important baseline variables. See, e.g., Talwar et al., Eur. Heart J. 21: 1514-21 (2000); Darbar et al., Am. J Cardiol. 78: 284-7 (1996); Richards et al., Heart 81: 114-20 (1999); Omland et al., Circulation 93: 1963-9 (1996); Arakawa et al., J. Am. Coll. Cardiol. 27: 1656-61 (1996); and Richards et al., Circulation 97: 1921-9 (1998).
The term “BNP” as used herein refers to the mature 32-amino acid BNP molecule itself. As described herein, levels of BNP in patient samples can provide an important prognostic indication of future morbidity and mortality in patients presenting with ACS. As the skilled artisan will recognize, however, other markers related to BNP may also serve as prognostic indicators in such patients. For example, BNP is synthesized as a 108-amino acid pre pro-BNP molecule that is proteolytically processed into a 76-amino acid “NT pro BNP” and the 32-amino acid BNP molecule. Because of its relationship to BNP, the concentration of NT pro-BNP molecule can also provide prognostic information in patients. See, e.g., Fischer et al., Clin. Chem. 47: 591-594 (2001); Berger et al., J. Heart Lung Transplant. 20: 251-(2001).
In certain embodiments, a prognostic indicator is correlated to a patient prognosis by merely its presence or absence. For example, the presence or absence of ST-segment depression in an electrocardiogram can be correlated with a predisposition to certain conditions. See, e.g., Savonitto et al., JAMA 281: 707-13 (1999).
The phrase “acute coronary syndromes” as used herein refers to a group of coronary disorders that result from ischemic insult to the heart. ACS includes unstable angina, non-ST-elevation non-Q wave MI, ST-elevation non-Q wave MI, and transmural (Q-wave) MI. ACS can be divided into non-ST-elevation ACS and ST-elevation ACS, each of which may be associated with certain prognostic indicators and prognoses, as described herein. The phrase “non-ST-elevation acute coronary syndrome” refers to those ACS not associated with an elevated ST component in an electrocardiogram. Non-ST-elevation ACS include unstable angina and non-ST-elevation non-Q wave MI. See, e.g., Nyman et al., Very early risk stratification by electrocardiogram at rest in men with suspected unstable coronary heart disease. The RISC Study Group, J. Intern. Med. 1993; 234: 293-301 (1993); Patel et al., Early continuous ST segment monitoring in unstable angina: prognostic value additional to the clinical characteristics and the admission electrocardiogram, Heart 75: 222-28 (1996); Patel et al., Long-term prognosis in unstable angina. The importance of early risk stratification using continuous ST segment monitoring, Eur. Heart J. 19: 240-49 (1998); and Lloyd-Jones et al., Electrocardiographic and clinical predictors of acute myocardial infarction in patients with unstable angina pectoris, Am. J Cardiol. 81: 1182-86 (1998), each of which is hereby incorporated by reference in its entirety.
Diagnosis of ACS generally, and non-ST-elevation ACS in particular, is well known to the skilled artisan. See, e.g., Braunwald et al., Unstable angina: diagnosis and management, Clinical practice guideline no. 10 (amended), AHCPR publication no. 94-0602. Rockville, Md.: Department of Health and Human Services, (1994); Yusuf et al., Variations between countries in invasive cardiac procedures and outcomes in patients with suspected unstable angina or myocardial infarction without ST elevation-OASIS (Organisation to Assess Strategies for Ischaemic Syndromes) Registry Investigators, Lancet 352:507-514 (1998); Savonitto et al., Prognostic value of the admission electrocardiogram in acute coronary syndromes, JAMA 281:707-713 (1999); Klootwijk and Hamm, Acute coronary syndromes: diagnosis, Lancet 353 (suppl II): 10-15 (1999), each of which is hereby incorporated by reference in its entirety.
[0035]FIG. 1 shows Kaplan-Meier curves relating BNP concentration to 10-month mortality. Patients were divided into quartiles based on the concentration of BNP at enrollment.
[0036]FIG. 2 shows the association between BNP concentration and 10-month mortality. Patients were divided into quartiles based on the concentration of BNP at enrollment. Quartiles were recalibrated for each of the subgroups shown. STEMI=ST elevation myocardial infarction; NSTEMI=non ST elevation myocardial infarction; UA=unstable angina.
[0037]FIG. 3 shows a stepwise logistic regression model showing the relationship between selected baseline clinical variables and 10-month mortality. Cardiac troponin I (cTnI) and BNP quartiles were forced into the final model. Odds ratios and 95% confidence intervals are shown. In addition to the variables shown in the figure, the final model included history of hyperlipidemia or peripheral vascular disease; prior therapy with diuretics, ACE inhibitors, nitrates, or heparin; heart rate; blood pressure; and creatinine clearance.
[0038]FIG. 4 shows the numbers of patients in 3 adverse outcome groups (death, congestive heart failure (CHF), and myocardial infarction (MI)) at 30 days and 10 months, among patients with a BNP concentration above and below a prespecified threshold of 80 pg/mL.
[0039]FIG. 5 shows the relationship between BNP concentration and 10-month mortality, using a threshold of 80 pg/mL to define BNP elevation. STEMI=ST elevation myocardial infarction; NSTEMI=non ST elevation myocardial infarction; UA—unstable angina.
[0040]FIG. 6 shows the numbers of patients in 3 adverse outcome groups (death, congestive heart failure (CHF), and myocardial infarction (MI)) at 30 days and 10 months, among patients with a BNP concentration above and below a threshold of 100 pg/mL.
[0041]FIG. 7 shows the relationship between BNP concentration and 10-month mortality, using a threshold of 100 pg/mL to define BNP elevation. STEMI=ST elevation myocardial infarction; NSTEACS=non ST elevation acute coronary syndrome; UA—unstable angina.
Previous cohort studies have demonstrated that following acute MI, higher plasma concentrations of BNP and the N-terminal fragment of its prohormone (NT-pro BNP) are associated with larger infarct size (Arakawa et al., Cardiology 85: 334-40 (1994); Horio et al., Am. Heart J. 126: 293-9 (1993)), adverse ventricular remodeling (Nagaya et al., Am. Heart J. 135: 21-8 (1998)), and lower ejection fraction and an increased risk for the development of congestive heart failure and death (Talwar et al., Eur. Heart J. 21: 1514-21 (2000); Darbar et al., Am. J. Cardiol. 78: 284-7 (1996); Richards et al., Heart 81: 114-20 (1999); Omland et al., Circulation 93: 1963-9 (1996); Arakawa et al., J. Am. Coll. Cardiol. 27: 1656-61 (1996); Richards et al., Circulation 97: 1921-9 (1998)). These prior studies have each included fewer than 150 patients, and focused on relatively homogenous groups of patients with ST elevation MI. The following exemplary embodiments extend these findings in patients with non-ST elevation acute coronary syndromes, including unstable angina.
Also, unlike traditional cardiac biomarkers used to predict risk among patients with ACS, and particularly non-ST elevation ACS, BNP has a putative role in the counter-regulatory response to ischemic injury. As such, it may act as an index of the size or severity of the ischemic insult, as well as the degree of underlying impairment in left ventricular function. For example, in an animal model of transmural myocardial infarction, BNP gene expression was augmented 3-fold in the left ventricle within 4 hours after the onset of coronary artery ligation, and importantly, tissue concentrations of BNP were increased in non-infarcted as well as infarcted regions. Hama et al., Circulation 92: 1558-64 (1995). Moreover, it has been demonstrated that BNP increases rapidly, and transiently, following exercise testing in patients with chronic stable angina, and that the degree of BNP elevation is closely correlated with the size of the ischemic territory as measured using nuclear SPECT imaging. Marumoto et al., Clin. Sci. (Colch.) 88: 551-6 (1995).
Furthermore, BNP increases transiently following uncomplicated percutaneous transluminal coronary angioplasty even in the absence of changes in pulmonary capillary wedge pressure. Tateishi et al. Clin. Cardiol. 23: 776-80 (2000); Kyriakides et al., Clin. Cardiol. 23: 285-8 (2000). Several small cross-sectional studies have shown that BNP and Nt-pro BNP concentrations are higher among patients with unstable angina than among patients with stable angina or among healthy controls. Talwar et al., Heart 84: 421-4 (2000); Kikuta et al., Am. Heart J. 132: 101-7 (1996). In one of these studies (Kikuta et al.), BNP elevation appeared to correlate with echocardiographic findings of regional wall motion abnormalities but not with hemodynamic data obtained at the time of simultaneous cardiac catheterization; furthermore, after medical stabilization, wall motion abnormalities improved and BNP levels fell significantly. Taken together, these prior studies suggest that myocardial ischemia may augment BNP synthesis and release, even in the absence of myocardial necrosis or pre-existing left ventricular dysfunction. Reversible ischemia may lead to a transient increase in left ventricular wall stress, which may be sufficient to cause BNP elevation.
A useful prognostic indicator such as BNP can help clinicians select between alternative therapeutic regimens. For example, patients with elevation in cardiac troponin T or I following an acute coronary syndrome appear to derive specific benefit from an early aggressive strategy that includes potent antiplatelet and antithrombotic therapy, and early revascularization. Hamm et al., N. Engl. J. Med. 340: 1623-9 (1999); Morrow et al., J. Am. Coll. Cardiol. 36: 1812-7 (2000); Cannon et al., Am. J. Cardiol. 82: 731-6 (1998). Additionally, patients with elevation in C-reactive protein following myocardial infarction appear to derive particular benefit from HMG-CoA Reductase Inhibitor therapy. Ridker et al., Circulation 98: 839-44 (1998). Among patients with congestive heart failure, pilot studies suggest that ACE inhibitors may reduce BNP levels in a dose dependent manner. Van Veldhuisen et al., J. Am. Coll. Cardiol. 32: 1811-8 (1998).
Similarly, “tailoring” diuretic and vasodilator therapy based on Nt-pro BNP levels may improve outcomes. Troughton et al., Lancet 355: 1126-30 (2000). Finally, in a single pilot study of 16 patients found that randomization to an ACE inhibitor rather than placebo following Q-wave MI was associated with reduced BNP levels over the subsequent 6-month period. Motwani et al., Lancet 341: 1109-13 (1993). Because BNP is a counter-regulatory hormone with beneficial cardiac and renal effects, it is likely that a change in BNP concentration reflects improved ventricular function and reduced ventricular wall stress. A recent article demonstrates the correlation of NT pro-BNP and BNP assays (Fischer et al., Clin. Chem. 47: 591-594 (2001). It is a further objective of this invention that the concentration of BNP can be used to guide diuretic and vasodilator therapy to improve patient outcome. Additionally, the measurement of one or more markers related to BNP, such as NT-proBNP, for use as a prognostic indicator for patients suffering from acute coronary syndromes, is within the scope of the present invention.
Recent studies in patients hospitalized with congestive heart failure suggest that serial BNP measurements may provide incremental prognositic information as compared to a single measurement; that is, assays can demonstrate an improving prognosis when BNP falls after therapy than when it remains persistently elevated. Cheng et al., J. Am. Coll. Cardiol. 37: 386-91 (2001). Thus, serial measurements may increase the prognostic value of a marker in patients with non-ST elevation ACS as well.
Example 1 Validation of BNP as a Prognostic Indicator in ACS
The Oral Glycoprotein IIb/IIIa Inhibition with Orbofiban in Patients with Unstable Coronary Syndromes (OPUS-TIMI 16) Trial was a randomized multicenter trial comparing an oral glycoprotcin IIb/IIIa inhibitor, orbofiban, with placebo in 10,288 patients with acute coronary syndromes. Patients were included if they presented within 72 hours of the onset of ischemic discomfort and met one or more of the following criteria: dynamic ECG changes (ST deviation ≧0.5 mm, T-mm, T-wave inversion ≧3 mm in ≧3 leads, or left bundle branch block); positive cardiac markers; prior history of coronary artery disease; or age ≧65 with evidence of diabetes or vascular disease. See, e.g., Cannon et al., Circulation 102: 149-56 (2000).
The study population described in the Examples herein consisted of a subpopulation of 2525 patients from the OPUS-TIMI 16 study, of whom 825 were enrolled following an index ST elevation MI, 565 following a non-ST elevation MI, and 1133 following a diagnosis of unstable angina. BNP concentration ranged from 0-1456 pg/mL, with a mean of 114±3 pg/mL, a median of 81 pg/mL, and 25th and 75th percentiles of 44 and 138 pg/mL. Mean time from the onset of ischemic symptoms to randomization was 40±20 hours (median 40 hours).
Blood specimens were collected by trained study personnel in citrate tubes and centrifuged for ≧12 minutes. The plasma component was transferred into a sterile cryovial and frozen at −20° C. or colder.
Troponin I, CKMB, CRP, and BNP were measured using standard immunoassay techniques. These techniques involved the use of antibodies to specifically bind the protein targets. CRP was measured using the N Latex CRP assay (Dade Behring) and fibrinogen was assayed using the Dade Behring Assay on the BN II analyzer. In the case of BNP measurements, an antibody directed against BNP was biotinylated using N-hydroxysuccinimide biotin (NHS-biotin) at a ratio of about 5 NHS-biotin moieties per antibody. The biotinylated antibody was then added to wells of a standard avidin 384 well microtiter plate, and biotinylated antibody not bound to the plate was removed. This formed an anti-BNP solid phase in the microtiter plate. Another anti-BNP antibody was conjugated to alkaline phosphatase using standard techniques, using SMCC and SPDP (Pierce, Rockford, Ill.). The immunoassays were performed on a TECAN Genesis RSP 200/8 Workstation. The plasma samples (10 μL) were pipeted into the microtiter plate wells, and incubated for 60 min. The sample was then removed and the wells were washed with a wash buffer, consisting of 20 mM borate (pH 7.42) containing 150 mM NaCl, 0.1% sodium azide, and 0.02% Tween-20. The alkaline phosphatase-antibody conjugate was then added to the wells and incubated for an additional 60 min, after which time, the antibody conjugate was removed and the wells were washed with a wash buffer. A substrate, (AttoPhos®, Promega, Madison, Wis.) was added to the wells, and the rate of formation of the fluorescent product was related to the concentration of the BNP in the patient samples.
All-cause mortality and nonfatal myocardial infarction were evaluated through 30 days, and the end of the follow up period (10 months). Myocardial infarction was defined using previously reported criteria based on CKMB elevation (Antman et al., Circulation 100: 1593-601 (1999)), and all cases of suspected myocardial infarction were adjudicated by a Clinical Events Committee. The endpoint of new or worsening CHF or cardiogenic shock was collected from case record forms.
Subjects were divided into quartiles based on their concentration of BNP at the time of enrollment in the trial. Means and proportions for baseline variables were compared across quartiles using ANOVA for continuous variables and the χ2 trend test for categorical variables. The direct correlation between BNP and other continuous baseline variables was assessed using Pearson's test. Mean concentration of BNP was compared between patients who met a study endpoint and those who did not using the Student t test. Cox regression analysis was used to evaluate the association between increasing concentration of BNP and adverse cardiovascular outcomes through 30 days and 10 months. Stratified analyses were performed among patients with a cTnI level>0.1 ng/ml and a cTnI≦0.1 ng/ml, as well as those with and without a clinical diagnosis of congestive heart failure. Subgroup analyses were performed in groups defined by the following index diagnoses: ST elevation MI, non-ST elevation ACS, and unstable angina. Quartile ranges were recalculated for each of these subgroups. For the endpoint of all-cause mortality through the end of follow-up (10 months), a logistic regression model was constructed using forward stepwise selection. Clinical variables that were assessed in >75% of the population were entered into the model, provided they had a univariate p value <0.1; variables were removed from the model if they had a multivariate p value >0.1. Baseline concentrations of cTnI and BNP were then forced into the completed model. Finally, analyses were performed using a BNP threshold of 80 and 100 pg/mL (Dao et al., J. Am. Coll. Cardiol. 37: 379-85 (2001)).
Quartile 1 Quartile 2 Quartile 3 Quartile 4 p trend p Q4 vs Q1
Range of BNP levels, 0-43.6 43.7-81.2 81.3-137.8 137.9-1456.6
n 631 632 632 630
Time to 39 ± 21 40 ± 21 41 ± 20 41 ± 19 0.04 0.10
Age (years) 57 ± 10 59 ± 11 61 ± 12 66 ± 11 <0.0001 <0.0001
Male 474 (75%) 465 (74%) 472 (75%) 405 (64%) 0.0001 <0.0001
White 575 (91%) 592 (94%) 605 (96%) 603 (96%) 0.0002 0.001
Hypertension 246 (39%) 254 (40%) 263 (42%) 298 (47%) 0.003 0.003
Congestive Heart 26 (4%) 28 (4%) 26 (4%) 56 (9%) 0.0006 0.0008
Coronary artery 329 (52%) 312 (49%) 294 (47%) 327 (52%) 0.7 0.9
Peripheral vascular 33 (5%) 43 (7%) 48 (8%) 57 (9%) 0.008 0.009
Cerebrovascular 24 (4%) 32 (5%) 39 (6%) 60 (10%) <0.0001 0.0001
Diabetes 138 (22%) 133 (21%) 132 (21%) 152 (24%) 0.4 0.3
199 (32%) 191 (30%) 173 (28%) 149 (24%) 0.0009 0.002
Current smoker 233 (37%) 263 (42%) 236 (38%) 189 (30%)
Index Diagnosis: <0.0001 <0.0001
ST elevation MI 141 (22%) 189 (30%) 231 (37%) 264 (42%)
Non ST elevation 87 (14%) 137 (22%) 159 (25%) 182 (29%)
Unstable angina 402 (64%) 306 (48%) 241 (38%) 184 (29%)
BMI kg/m2 29 ± 5  28 ± 5  28 ± 14 28 ± 12 0.1 0.08
Systolic BP (mm 130 ± 20  129 ± 19  128 ± 22  129 ± 21  0.3 0.4
Killip Class II-IV 31 (5%) 36 (6%) 56 (9%) 109 (18%) <0.0001 <0.0001
Creatinine clearance ≦ 146 (24%) 185 (31%) 229 (38%) 350 (58%) <0.0001 <0.0001
CK-MB > ULN 212 (58%) 308 (72%) 349 (79%) 388 (86%) <0.0001 <0.0001
ST depression ≧ 0.5 mm 270 (43%) 297 (47%) 311 (49%) 356 (57%) <0.0001 <0.0001
Association between cardiac test results and BNP concentration
Test 1. Result n BNP (Mean ± SD) p value
Coronary Angiography: None 103 58 [32,111] 90 ± 104 <0.0001
No. vessels with ≧ 1 433 73 [41,118] 92 ± 75
50% stenosis 2 368 70 [41,120] 104 ± 112
≧3 405 93 [49,154] 136 ± 168
LV Ejection Fraction >50% 718 73 [41,128] 99 ± 94 <0.0001
≦50% 554 110 [59,184]  160 ± 182
Stress test Negative 374 65 [39,106] 91 ± 95 0.003
Indeterminate 118 88 [49,143] 118 ± 128
Positive 296 88 [44,145] 118 ± 118
Outcome n Median [25,75] Mean ± SD p value*
Dead 39 153 [79,294] 226 ± 204 <0.0001
CHF 43 159 [79,317] 252 ± 269 <0.0001
Dead 85 143 [88,308] 228 ± 228 <0.0001
Alive 2440 79 [43,133] 110 ± 120
CHF 78 158 [82,313] 256 ± 278 <0.0001
No CHF 2447 79 [43,133] 110 ± 116
ST elevation MI 825 96 [56,161] 131 ± 125
Dead by 30 days 13 153 [77,265] 236 ± 220 0.003
Alive at 30 days 812 95 [56,161]
Dead by 10 months 23 150 [90,227] 199 ± 176 0.008
Alive at 10 months 802 95 [55,161) 129 ± 123
Dead by 30 days 12 176 [149,327] 265 ± 206 0.001
Alive at 30 days 553 97 [56,155] 134 ± 145
Dead by 10 months 28 176 [123,322] 245 ± 176 <0.0001
Alive at 10 months 537 95 [56,152] 131 ± 144
Dead by 30 days 14 94 [69,237] 182 ± 195 0.02
Alive at 30 days 1119 60 [33,105] 90 ± 109
Dead by 10 months 34 96 [70,265] 233 ± 292 <0.0001
Alive at 10 months 1099 58 [33,104] 87 ± 97
When stratification was performed based on the concentration of cTnI at the time of enrollment, increasing BNP concentration remained associated with higher 10-month mortality, both among those with a cTnI<0.1 ng/mL (n=882; p=0.01) and those with a cTnI≧0.1 ng/mL (n—1630; p<0.0001) (FIG. 2). After adjustment for other independent predictors of long-term mortality, including ST deviation and cTnI, increasing concentration of BNP remained associated with a higher rate of death by 10 months (FIG. 3). The adjusted odds ratios for 10-month mortality were 3.9 (1.1-13.6), 4.3 (1.3-15.0), and 6.7 (2.0-22.6) for patients with BNP concentrations in the second, third, and fourth quartile, respectively (FIG. 3). Evaluation of 80 and 100 pg/mL BNP Threshold Analyses were performed using prospectively defined BNP thresholds of 80 and 100 pg/mL. Patients with a plasma concentration of BNP greater than 80 or 100 pg/mL were significantly more likely to suffer death, myocardial infarction, or new/progressive CHF than those with a BNP level lower than the selected threshold (80 pg/mL threshold: p<0.005 for each at 30 days and 10 months; FIG. 4; 100 pg/mL threshold: p<0.005 for each at 30 days and 10 months; FIG. 6). In subgroups of patients with ST elevation MI, non-ST elevation ACS, and unstable angina, a BNP level greater than either 80 or 100 pg/mL was associated with a significant increase in the risk for 10-month mortality (FIGS. 5 and 7).
1. A method of determining a prognosis of a patient diagnosed with a non-ST-elevation acute coronary syndrome, the method comprising:
determining a level of B-type natriuretic peptide (BNP) in a sample obtained from said patient; and
correlating said BNP level to said patient prognosis by determining if said BNP level is associated with a predisposition to an adverse outcome of said non-ST-elevation acute coronary syndrome.
8. A method according to claim 1, further comprising determining a level of cardiac-specific troponin I in a sample obtained from said patient, and correlating both said BNP level and said cardiac-specific troponin I level to said patient prognosis, whereby the combination of said BNP level with said cardiac-specific troponin I level increases the predictive value of said BNP level for said adverse outcome.
9. A method of determining a prognostic panel consisting of a plurality of prognostic markers that predict an increased risk of an adverse outcome in a patient diagnosed with a non-ST-elevation acute coronary syndrome, the method comprising:
determining a first prognostic marker comprising a level of BNP that is associated with a predisposition to said adverse outcome; and
determining one or more second prognostic markers that increase the predictive value of said first prognostic marker for said adverse outcome.
10. A method of determining a treatment regimen for a patient diagnosed with a non-ST-elevation acute coronary syndrome, the method comprising:
determining a level of BNP in a sample obtained from said patient;
correlating said BNP level to a predisposition to an adverse outcome of said non-ST-elevation acute coronary syndrome; and
determining a treatment regimen that reduces said predisposition to said adverse outcome.
11. A method of determining a prognosis of a patient diagnosed with a non-ST-elevation acute coronary syndrome, the method comprising:
determining a level of a marker related to BNP in a sample obtained from said patient; and
correlating said BNP-related marker level to said patient prognosis by determining if said BNP-related marker level is associated with a predisposition to an adverse outcome of said non-ST-elevation acute coronary syndrome.
13. A method according to claim 11, wherein said correlating step comprises comparing said BNP-related marker level to a threshold BNP-related marker level, whereby, when said BNP-related marker level exceeds said threshold BNP-related marker level, said patient is predisposed to said adverse outcome.
18. A method according to claim 1 1, further comprising determining a level of cardiac-specific troponin I in a sample obtained from said patient, and correlating both said BNP-related marker level and said cardiac-specific troponin I level to said patient prognosis, whereby the combination of said BNP-related marker level with said cardiac-specific troponin I level increases the predictive value of said BNP-related marker level for said adverse outcome.
19. A method of determining a prognostic panel consisting of a plurality of prognostic markers that predict an increased risk of an adverse outcome in a patient diagnosed with a non-ST-elevation acute coronary syndrome, the method comprising:
determining a first prognostic marker comprising a level of a marker related to BNP that is associated with a predisposition to said adverse outcome; and
20. A method of determining a treatment regimen for a patient diagnosed with a non-ST-elevation acute coronary syndrome, the method comprising:
determining a level of a marker related to BNP in a sample obtained from said patient;
correlating said BNP-related marker level to a predisposition to an adverse outcome of said non-ST-elevation acute coronary syndrome; and
determining a treatment regimen that reduces said increase predisposition to said adverse outcome.
21. A method according to any one of claims 11-20, wherein said BNP-related marker is NT pro-BNP.
US09835298 2001-04-13 2001-04-13 Use of B-type natriuretic peptide as a prognostic indicator in acute coronary syndromes Active 2026-02-01 US7632647B2 (en)
US09835298 US7632647B2 (en) 2001-04-13 2001-04-13 Use of B-type natriuretic peptide as a prognostic indicator in acute coronary syndromes
CA 2412648 CA2412648C (en) 2001-04-13 2002-04-11 Use of b-type natriuretic peptide as a prognostic indicator in acute coronary syndromes
EP20080160527 EP1983058B1 (en) 2001-04-13 2002-04-11 Use of B-type natriuretic peptide as a prognostic indicator in acute coronary syndromes
EP20020721720 EP1311701B1 (en) 2001-04-13 2002-04-11 Use of b-type natriuretic peptide as a prognostic indicator in acute coronary syndromes
DK02721720T DK1311701T3 (en) 2001-04-13 2002-04-11 Use of a natriuretic peptide B-type as a prognostic indicator in acute coronary syndromes
PCT/US2002/011441 WO2002083913A1 (en) 2001-04-13 2002-04-11 Use of b-type natriuretic peptide as a prognostic indicator in acute coronary syndromes
DE2002627763 DE60227763D1 (en) 2001-04-13 2002-04-11 Use of a natriuretic peptide from the B-type as a prognostic indicator in acute coronary syndromes
JP2002582250A JP3749225B2 (en) 2001-04-13 2002-04-11 The use of b-type natriuretic promoting peptide as a prognostic indicator of acute coronary syndromes
ES02721720T ES2310590T3 (en) 2001-04-13 2002-04-11 Using b-type natriuretic peptide as a prognostic indicator of acute coronary syndromes.
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