a Department of Cardiology, Hospital Italiano de Buenos Aires, Buenos Aires, Argentina
b Department of Cardiology, CEMIC, Buenos Aires, Argentina
c Department of Cardiology, Instituto Cardiovascular de Buenos Aires, Buenos Aires, Argentina
d Department of Biochemistry, CEMIC, Buenos Aires, Argentina
* Corresponding author. Tel./fax: +54-11-4958-2623
E-mail address: oscar.bazzino{at}hospitaliano.org.ar
Received 1 October 2003; revised 24 February 2004; accepted 4 March 2004
Abstract
Aims We prospectively studied the additive value of N-terminal probrain natriuretic peptide (NT-proBNP) in relation to the Thrombolysis in Myocardial Infarction (TIMI) risk score and the American College of Cardiology/American Heart Association (ACC/AHA) joint prognostic classification, and compared the predictive capacity of NT-proBNP, troponin T (TnT), C-reactive protein (hsCRP), myoglobin, and creatine kinase-MB (CK-MB) concentrations in a cohort of 1483 consecutive patients with non-ST-segment-elevation acute coronary syndromes (NSTE-ACS).
Methods and results Centralised measurements of NT-proBNP, TnT, myoglobin, and hsCRP were performed 3 h (median) after admission.
Adjusting by clinical, ECG variables, and biomarkers, NT-proBNP concentration was the strongest independent predictor of in-hospital (OR 1.7, 95% CI: 1.312.20, ) and 180-day mortality (OR 1.67, 95% CI: 1.411.99,
), and added significant prognostic information to the TIMI and ACC/AHA prognostic categories. NT-proBNP was not an independent predictor of risk of new myocardial infarction, even in the acute or long term.
Conclusions In NSTE-ACS, NT-proBNP adds substantial information to the TIMI risk score and the ACC/AHA classification. Compared to other biomarkers, NT-proBNP is the strongest independent predictor of in-hospital and 180-day mortality.
Key Words: N-terminal probrain natriuretic peptide Acute coronary syndromes Cardiac markers Prognosis Risk stratification
Introduction
Brain natriuretic peptide (BNP) and N-terminal probrain natriuretic peptide (NT-proBNP) have recently shown promise for risk stratification in patients with non-ST-elevation acute coronary syndromes (NSTE-ACS).16 In patients with unstable angina and non-ST-elevation myocardial infarction, high levels of these markers were accompanied by a two- to threefold greater risk of death at 10 months.2. Also, BNP was associated with the occurrence of subsequent heart failure1,2,3 and added information to concentrations of troponin T and I, and other biomarkers.16
However, further assessment of the utility of NT-proBNP is required. Most of the information available comes from subsidiary analysis of randomised controlled trials. More importantly, the predictive value of BNP has not been studied over a prognostication scheme. Thus, we analysed the additive value of NT-proBNP concentration in relation to the Thrombolysis in Myocardial Infarction (TIMI) risk score and the American Cardiology College/American Heart Association (ACC/AHA) classification, and studied the predictive capacity of NT-proBNP in relation to troponin T (TnT), high-sensitivity C-reactive protein (hsCRP), myoglobin, and creatine kinase-MB (CK-MB) concentrations in a large cohort of patients with NSTE-ACS.
Methods
Study design
This is a prospective, multicentre (see Appendix A), cohort study. We included 1483 consecutive patients admitted to coronary care units with resting chest pain within 24 h of admission. The enrolment period was from December 1999 to July 2001. We excluded patients who were candidates for reperfusion therapy on admission because of ischaemic chest pain 20 min with ST-segment elevation, who had undergone coronary angioplasty during the previous six months, and patients with active cancer or autoimmune inflammatory disease.
After informed consent had been obtained, serum samples for a single measurement of troponin T (TnT), high-sensitivity C-reactive protein (hsCRP), myoglobin, and NT-proBNP were drawn. Samples were stored at 70 °C until they were analysed at a core laboratory (see Appendix A). The investigators were blinded to the test results until the study was completed. Simultaneous levels of CK-MB (activity or mass) were measured at each centre and used for the prognostic analysis. All patients were followed up from hospital admission until day 180 or death, whichever occurred first.
Study organisation
The Ethics Committee of each centre approved the study protocol and patients provided written informed consent. All major events were adjudicated by a clinical event committee that did not know the results of the serum biomarker determinations or the identities of patients and centres. All case report forms were reviewed automatically and manually to ensure the consistency and quality of the data.
Definitions
The outcome measurements were specified previously as the in-hospital and 180-day rates of the composite of death due to either any cause or new non-fatal myocardial infarction, and the corresponding rates of death and new non-fatal myocardial infarction individually. New myocardial infarction was defined as the occurrence of a new episode of ischaemic chest pain, characteristic electrocardiographic (ECG) alterations (new ST-segment depression or elevation 0.1 mV, T-wave inversion
0.2 mV, appearance of pathologic Q waves or new left bundle-branch block), and a peak creatine kinase (CK) level more than twice the normal concentration or the previously elevated value, and CK-MB (activity or mass) above the upper limit of normal at each centre. Non-ST-segment-elevation myocardial infarction already present at admission was defined by elevation of the CK and CK-MB levels (same criteria as above) at any time during the first 12 h of admission. Postangioplasty infarction was recognised by the appearance of new Q waves and/or a CK increase of three times the upper limit of normal, with elevated CK-MB. Infarction after coronary artery bypass surgery required the appearance of new Q waves. Severe angina was defined as two or more episodes of ischaemic chest pain at rest within 24 h before admission. The TIMI risk score was used for the assessment of clinical risk7 (Fig. 1). The following categories of risk were defined by the TIMI score: low (scores 0, 1, and 2), moderate (scores 3 and 4), and high risk (scores 5, 6, and 7). Each patient was categorised according to the ACC/AHA classification following previously published guidelines8 (Fig. 1). Prior aspirin use was defined as daily administration of aspirin for at least one month before admission.
|
Statistical analysis
All results for continuous variables are expressed as means±SD, and skewed variables are expressed as the median and interquartile range. Differences between mean or median values for continuous variables were evaluated with one-way ANOVA or the KruskalWallis test, as appropriate. We established a cutoff point between low and high levels of NT-proBNP, relating NT-proBNP concentrations and the corresponding 6-month mortality rates via a receiver-operating characteristic (ROC) curve. The NT-proBNP value showing the maximum likelihood ratio was defined as the cutoff point between low and high NT-proBNP concentrations. To compare the patient characteristics defined by the groups with low and high levels of NT-proBNP, we used the test. The degree of univariate association between clinical data and events at 180 days was assessed with the
test and Yates' correction for dichotomised comparisons, and with the t-test or Wilcoxon rank sum test for continuous variables with a normal or non-normal distribution. For univariate analysis, all tests were two-sided and a significance level of
was used. The correlations between NT-proBNP levels and other cardiac markers were examined with the Spearman correlation coefficient.
Stepwise logistic regression models were developed to analyse the effect of baseline characteristics and other biomarkers on any observed associations between NT-proBNP levels and the in-hospital and 180-day risk of the combined endpoint of either death or non-fatal infarction, and the individual endpoints of mortality and new, non-fatal myocardial infarction. For the assessment of linearity, we grouped concentrations of NT-proBNP and other cardiac markers into quartiles. Then we fitted a logistic regression model for the prediction of mortality, with the lowest quartile serving as the reference group, and plotted the average value of each quartile versus the coefficient of the quartile. The plot was then examined with respect to the shape of the resulting curve. Due to the lack of linearity, NT-proBNP, TnT, hsCRP, myoglobin, and CK-MB concentrations were logarithmically transformed. Variables with a significant partial regression coefficient of were added to the model, and those with
in the stepwise procedure were retained. The Wald
and likelihood ratio statistics tests were used to assess the statistical significance of the individual coefficients. The standard errors of the coefficients were used to calculate the confidence intervals. To assess the statistical significance of NT-proBNP in logistic regression analysis, we adjusted the p-values using the Bonferroni correction, dividing the usual p-value
by the number of variables in the model. To facilitate clinical interpretation, we repeated the multivariate logistic regression analysis, entering NT-proBNP and the other biomarkers as dichotomous variables. For this purpose we used the same NT-proBNP cutoff point that had been established earlier by ROC curve analysis, whereas for TnT, myoglobin, hsCRP, and CK-MB, we used the reference limits provided by the manufacturers. We also tested for interaction between NT-proBNP, hsCRP, and CK-MB levels.
The areas under the ROC curves for the TIMI risk score, with and without the addition of NT-proBNP values, were compared. Statistical analyses were performed with SPSS software version 10.0 (Statistical Package for the Social Sciences, Chicago, IL).
Results
Baseline characteristics
The study population consisted of 1483 consecutive patients with NSTE-ACS: 1226 with unstable angina and 257 with non-ST-elevation myocardial infarction. The mean age of the patients was 66±12 years, 63.6% were male, 21.1% had prior myocardial infarction, 16.9% had been previously treated with coronary revascularisation, 67.0% were being treated for hypertension, 27.0% were active smokers, and 18.5% had a history of diabetes. With regard to prior pharmacological treatment; 51.1% were receiving aspirin, 43.0% ß-blockers, 17.3% statins, and 26.3% angiotensin-converting enzyme inhibitors. The admission ECG showed ST-segment depression 0.1 mV in 18.0% of patients, transitory ST-segment elevation
0.1 mV in 9.8%, bundle-branch block in 17.9%, and isolated T-wave inversion in 22.5%. Overall, 50.9% of the patients had STT changes interpreted as ischaemic. TIMI low-, intermediate-, and high-risk categories were observed in 53.3%, 40.2%, and 6.5 % of all patients, respectively. The proportion of patients considered at low, medium, and high risk by ACC/AHA criteria were 5.7%, 24.8%, and 69.5%, respectively. Hospital treatment consisted of aspirin in 99.6% of patients, clopidogrel in 21.3%, ß-blockers in 91.0%, and heparin in 68.5%. The total rate of coronary revascularisation during hospitalisation and up to 180 days was 29.5%.
NT-proBNP and other cardiac biomarker levels
The median time from onset of the index episode of chest pain to admission was 3.2 h. In turn, measurements of NT-proBNP, TnT, hsCRP, and myoglobin were performed within a median time of 3 h (interquartile range, 07 h) from admission. Elevated levels of TnT (0.03 ng/mL), TnT (
0.1 ng/mL), hsCRP (
3 mg/L), and myoglobin (male,
72 ng/mL; female,
51 ng/mL) were observed in 36.5% (
), 28.1% (
), 58.6% (
), and 16.9% (
), respectively, of the overall population. Elevated CK-MB at baseline was observed in 214 patients (14.4%). NT-proBNP concentration ranged from 10 to 74,450 pg/mL, with a median of 232 pg/mL (interquartile range, 84755 pg/mL). The area of the ROC curve relating NT-proBNP level with 6-month mortality was 0.78 (95% CI: 0.730.83), and the highest likelihood ratio corresponded to a value of 586 pg/mL. NT-proBNP concentration over 586 pg/mL was associated with older age, prior aspirin use, female sex, diabetes, hypertension, not smoking, myocardial infarction, stroke, peripheral vascular disease, coronary artery bypass grafting, ST-segment depression at entry, severe angina within the last 24 h, lower creatinine clearance at baseline (
50 mL/min), and elevated levels of CK-MB, TnT, myoglobin, and hsCRP (Table 1). NT-proBNP was moderately correlated with TnT (
,
), myoglobin (
), and hsCRP (
) and poorly correlated with CK-MB (
).
|
Correlation with events during hospitalisation
Baseline characteristics associated with the risk of in-hospital death or new myocardial infarction were: age 75 years (9% vs. 4%, p<0.001), diabetes (9% vs. 4%,
), prior peripheral vascular disease (9% vs. 5%,
), high-risk characteristics (ACC/AHA) (6% vs. 2%,
), ST-segment depression
0.1 mV (8% vs. 4%,p=0.021), NT-proBNP above 586 pg/mL (7% vs. 3%,
), TnT
0.03 ng/mL (10% vs. 2%,
), positive myoglobin (13% vs. 3%,
), hsCRP
3 mg/L (6% vs. 3%,
), and elevated CK-MB (14% vs. 3%,
).
All these variables were included in a logistic regression analysis for the prediction of in-hospital death or new myocardial infarction. In the forward stepwise procedure, age, diabetes, and TnT and CK-MB concentrations were retained as independent predictors of the combined endpoint of in-hospital death or new myocardial infarction (Table 2).
|
Correlation with events at 180 days
Baseline characteristics associated with death or new myocardial infarction at 180 days were: age 75 years (16% vs. 6%,
), high-risk characteristics (ACC/AHA high risk 11% vs. non-high risk 5%,
), history of hypertension (10% vs. 6%,
), diabetes (15% vs. 7%,
), and prior myocardial infarction (12% vs. 8%,
), stroke (18% vs. 8%,
), or peripheral vascular disease (16% vs. 8%,
), ST-segment depression
0.1 mV (27% vs. 17%,
), severe angina (12% vs. 7%,
), and lower creatinine clearance (16% vs. 8%,
). Death or new, non-fatal myocardial infarction at 180 days were also more frequent in patients with elevated concentration (
586 pg/mL) (Fig. 2(a)) or increasing quartiles of NT-proBNP (Fig. 2(b)), TnT
0.03 ng/mL (15% vs. 5%,
), positive myoglobin (20% vs. 7%,
), hsCRP
3 mg/L (11% vs. 5%,
), and elevated CK-MB (20% vs. 7%,
).
|
When the logistic regression model was tested for the prediction of 6-month mortality, NT-proBNP concentration was an independent predictor, along with age, diabetes, severe angina, hypertension, and CK-MB concentration (Table 2). In a different model, age, diabetes and TnT and CK-MB concentrations independently predicted the risk at 180 days of new, non-fatal myocardial infarction. NT-proBNP levels were not associated with increased risk of new, non-fatal myocardial infarction at 180 days (Table 2).
When all cardiac markers were entered in the multivariate analysis as categorical variables, only NT-proBNP 586 pg/mL, hsCRP
3 mg/L and elevated CKMB were independently associated with 180-day mortality (OR 3.42, 95% CI: 1.955.98,
, hsCRP 2.00, 95% CI: 1.092.4,
, and 2.00, 95% CI: 1.183.6,
, respectively). Accordingly, we further evaluated the prognostic value of the combination of these markers. For patients with NT-proBNP
586 pg/mL, hsCRP
3 mg/L was associated with a significant increase in mortality (14.8% vs. 6.8%, OR 2.4, 95% CI: 1.145.00,
for interaction test, Fig. 3). Conversely, no interaction was observed between NT-proBNP
586 pg/mL and CK-MB levels (
for interaction test).
|
|
Discussion
In this cohort of patients with NSTE-ACS at a broad spectrum of risk, baseline levels of NT-proBNP were strongly predictive of in-hospital and 180-day mortality after adjustment for clinical and electrocardiographic markers and for concomitant measurements of TnT, hsCRP, myoglobin, and CK-MB.
Even in this relatively lower-risk population, we also showed the additive prognostic value of NT-proBNP in relation to the TIMI risk score and ACC/AHA classification scheme. It should be noted that for this purpose we refined the use of the TIMI risk score, assessing in all cases for the presence of myocardial necrosis with measurements of the level of TnT, a very sensitive biomarker.
After an episode of myocardial infarction with ST-segment elevation, higher levels of BNP are associated with a worse outcome10,11. These findings have recently been extended to patients with NSTE-ACS, showing that BNP as well as NT-proBNP, measured in the first few days after admission, are independent predictors of mortality and progression to heart failure.16
In accordance to prior reports, our data showed no association between NT-proBNP level and the risk of new, non-fatal myocardial infarction. BNP and NT-proBNP are released into circulation in response to ventricular dilatation or pressure overload.1214 Accordingly, NT-proBNP seems to be a marker of severe myocardial injury resulting in heart failure and death, rather than a manifestation of minimal and incomplete necrosis prone to early recurrent ischaemia. As observed in previous reports and in the present study, the mechanism by which a coronary thrombus leads to downstream embolisation and recurrent myocardial necrosis is better reflected by other markers, such as troponin or CK-MB.1617
The pathophysiologic link between NT-proBNP elevation and left ventricular dysfunction provides an explanation for the additive value of NT-proBNP concentration in prognostication schemes: neither the TIMI risk score nor the ACC/AHA classification schemes include sensitive variables that indicate the presence or severity of disturbances in left ventricular function.7,8
An important question remains about the potential usefulness of NT-proBNP for the selection of specific therapies. In our study, death was the most frequent event between discharge and 180 days, with a fivefold increase relative to myocardial infarction. In this phase, left ventricular dysfunction associated to adverse left ventricular remodelling and severe residual ischaemia may precipitate heart failure, malignant arrhythmias, and death. Owing to its greater sensitivity for the recognition of altered left ventricular function, NT-proBNP could be of great help in guiding the management of pharmacologic and interventional treatment of patients with left ventricular dysfunction. In TACTICS-TIMI-18,2 revascularisation did not benefit patients with elevated BNP level (80 ng/L) at admission. However, in a FRISC II substudy, the combination of NT-proBNP and interleukin-6 seems to be useful for the identification of patients with a survival benefit from an early invasive strategy.18 Consistent with that finding, in our study NT-proBNP and hsCRP concentrations, analysed as categorical variables, had complementary value in predicting the risk of 6-month mortality. Future studies are needed to confirm the ability of NT-proBNP to identify specific treatments that may reduce the risk of mortality.
Limitations
We did not adjust the prognostic value of NT-proBNP for the level of left ventricular function. In addition, we cannot provide data on the utility of BNP and NT-proBNP concentration to predict risk of subsequent heart failure because we did not collect this information during follow-up. In addition, we cannot exclude the possibility that serial measurements of cardiac markers may provide more complete prognostic information than a single baseline determination. It should be noted that we used a traditional definition of myocardial infarction based on CK-MB elevation because the joint recommendation from the European Society of Cardiology and American College of Cardiology about the use of troponin for this purpose was published after enrolment in the study began.15
Conclusions
Our findings confirmed that baseline NT-proBNP concentration adds substantial information to the clinical risk stratification systems recommended for patients with NSTE-ACS. The current study also provides further insight into the meaning of cardiac markers in the natural history of acute coronary syndromes. TnT and CK-MB concentrations indicate the early risk of recurrent ischaemic events, whereas NT-proBNP level is more useful for predicting early and late mortality.
Further prospective studies are needed to test the impact of multimarker strategies that include NT-proBNP in the management and prognosis of patients with acute coronary syndromes.
Steering Committee: Chairman: Oscar Bazzino. Members: J.L. Navarro Estrada, M.I. Sosa Liprandi, J.J. Fuselli, F. Botto, L. Guzmán, R. Ahuad, J. Gant López, M. Pérez, R. Nordaby, F. Sokn, J. Santopinto, C. Bruno, S. Salzberg, A. Farrás, M. Russo, and A. Hirschson Prado.
Core Lab for cardiac markers: CEMIC: J. Dadone.
Centres and Investigators: Antártida Hosp. Privado: R. Ahuad, P. Schygiel. Hospital Francés: R. Nordaby, M. Brito, C. Dizeo. CEMIC: J.J. Fuselli, J. Guetta. Hospital Italiano: J.L. Navarro Estrada, E. Natale. Clínica Sagrada Familia: F. Sokn, C. Rapallo. Hospital Leónidas Lucero: J. Santopinto, N. Budassi, F. Rocoma. Clínica Suizo Argentina: C. Bruno, F. Peñaloza. Hospital Rivadavia: E. Dominé, A. Hirschson Prado. Corp. Médica San Martín: A. Farrás, R. Memoli. ICBA: L. Guzmán, F. Botto. Hospital Alemán: J. Gant López, F. Meiller, F. Novo, G. Nau. Inst. Card. Hosp. Español: M. Russo, E. Berlante. Hospital Británico: M. Pérez, J. Ubaldini. Sanatorio Mitre: M.I. Sosa Liprandi, A. Sosa Liprandi. Hospital Fernández: S. Salzberg, and P. Gitelman.
Acknowledgments
Funding sources: Roche Diagnostics provided the troponin T, myoglobin, and NT-ProBNP assay kits and Dade Behring, the hsCRP assay kits.
Footnotes
Participating institutions: Antártida Hospital Privado, Hospital Francés, CEMIC, Hospital Italiano de Buenos Aires, Clínica Sagrada Familia, Hospital Leónidas Lucero, Clínica Suizo Argentina, Hospital Rivadavia, Corporación Médica San Martín, Instituto Cardiovascular de Buenos Aires, Hospital Alemán, Instituto de Cardiología del Hospital Español, Hospital Británico, Sanatorio Mitre, Hospital Fernández.
References