Prognostic Value of N-Terminal Pro–Brain Natriuretic Peptide in Patients With Chronic Stable Angina
Background— Patients with chronic stable angina are poorly characterized in terms of biomarkers that help in the assessment of prognosis. We investigated whether plasma levels of N-terminal pro–brain natriuretic peptide (NT-proBNP) may be used as a prognostic marker in patients with chronic stable angina treated with coronary stenting.
Methods and Results— Plasma levels of NT-proBNP were measured in 1059 patients with chronic stable angina and coronary angiographic confirmation of significant coronary artery disease. The primary end point of the study was mortality. After a median of 3.6 years (interquartile range, 3.3 to 4.5 years), there were 106 deaths. Kaplan-Meier estimates of 5-year mortality were 4.7% in the first quartile, 7.8% in the second quartile, 11.4% in the third quartile, and 32.7% in the fourth quartile of NT-proBNP (P<0.001). A Cox proportional hazards model showed that NT-proBNP was the strongest correlate of mortality (adjusted hazards ratio [HR], 5.83 [95% confidence interval: 2.07 to 16.44] for the fourth versus the first quartile). A similar prognostic value of NT-proBNP was demonstrated for cardiovascular mortality (HR, 5.98 [1.55 to 23.13] for the fourth versus the first quartile) and for patients with New York Heart Association class I and II (HR, 6.03 [2.07 to 17.52] for the fourth versus the first quartile).
Conclusions— Circulating levels of NT-proBNP are a strong prognostic biomarker for patients with chronic stable angina.
Received October 14, 2004; de novo received March 21, 2005; revision received June 29, 2005; accepted July 6, 2005.
Recently, several novel and sensitive biomarkers of myocyte necrosis, inflammation, vascular damage, and hemodynamic stress have become available to characterize patients with acute coronary syndromes.1 In contrast to the patients with acute coronary syndromes, there is a paucity of biomarkers that can be used in clinical practice to characterize patients with chronic stable angina. Angina is often the symptom that brings patients to medical attention because it is the initial manifestation of ischemic heart disease in approximately one half of the patients.2,3 Patients with chronic stable angina constitute up to two thirds of the patients that undergo percutaneous coronary interventions in Western countries.4,5 A recent study in US veterans has concluded that a substantial proportion of patients with chronic stable angina receive inadequate treatment,6 further emphasizing the need of markers to better characterize this group of patients.
Several recent studies have demonstrated that circulating levels of brain-type natriuretic peptide (BNP) or N-terminal fragment of the prohormone (NT-proBNP) are increased in patients with acute myocardial infarction and predict mortality in these patients.7,8 Furthermore, a robust association between BNP or NT-proBNP and the short- and long-term risk of death across the spectrum of non–ST-segment elevation acute coronary syndromes has been demonstrated9–13 even in patients without evidence of myocardial necrosis or clinical heart failure.9 A recent study has demonstrated that NT-proBNP is a long-term predictor of mortality in patients with stable coronary artery disease.14 However, because of the time period in which these patients were recruited (1991–1993), this study does not reflect the current practice of invasive and medical treatment of patients with stable chronic angina.
We conducted this study to assess whether elevated plasma levels of NT-proBNP predict an increased risk of death in an unselected consecutive series of patients with chronic stable angina treated with coronary artery stenting.
The study was conducted between September 1999 and February 2002 in Deutsches Herzzentrum Munich, Munich, Germany. For the purposes of this prospective study, plasma was collected with the intention to investigate the prognostic value of NT-proBNP. Patients eligible for the study were those with a clinical diagnosis of stable angina pectoris with coronary angiographic confirmation of significant coronary artery disease. The diagnosis of stable angina was based on the presence of chest pain that did not change its pattern during the preceding 2 months. We did not include patients who presented with acute coronary syndromes on the basis of ST-segment changes on ECG or abnormal creatine kinase or cardiac troponin tests. We did not include patients with unstable angina, which was defined on the basis of a history of crescendo angina, angina at rest or with minimal exertion, or angina of new onset (within 1 month), in the absence of clear-cut electrocardiographic and cardiac enzyme changes diagnostic of an acute myocardial infarction.15 Furthermore, patients with end-stage renal disease or malignancies were excluded. All patients gave informed consent before recruitment into the study. The study protocol was approved by the institutional ethics committee.
Stent implantation and periprocedural care were performed according to standard criteria. Bare metal stents were used. Antiplatelet therapy consisted of clopidogrel (600 mg as a loading dose followed by 75 mg/d for at least 4 weeks) and aspirin (200 mg/d administered orally and continued indefinitely). As a standard practice in our institution, all patients were scheduled to undergo coronary angiography 6 months after the procedure or whenever they showed symptoms or signs of myocardial ischemia.
Coronary artery disease was diagnosed in the presence of coronary stenoses ≥50% lumen obstruction in at least 1 of the 3 major coronary arteries. Congestive heart failure was graded according to New York Heart Association (NYHA) classification. Arterial hypertension was defined in the presence of active treatment with antihypertensive agents or otherwise as a systolic blood pressure of >140 mm Hg and/or diastolic blood pressure of >90 mm Hg on at least 2 separate occasions. Hypercholesterolemia was defined as a documented total cholesterol value ≥240 mg/dL. Smokers were defined as those currently smoking any tobacco. Diabetes mellitus was defined if patients were under active treatment with insulin or oral hypoglycemic agents. For patients on dietary treatment alone, documentation of abnormal fasting blood glucose or glucose tolerance test according to the World Health Organization criteria was required for the diagnosis of diabetes.16
Blood was collected before angiography in tubes containing EDTA (Sarstedt) and promptly centrifuged at 1550g for 10 minutes. After separation, plasma aliquots were stored frozen at −80°C until assayed within batches. Blood count, serum lipids, and other metabolites were determined immediately after collection by standard methods.
NT-proBNP measurements were performed on a Roche Elecsys 1010 automated analyser (Roche Diagnostics). The measuring range, defined by the lower detection limit and the maximum of the master curve, provided by the manufacturer is 5 to 35 000 pg/mL (Roche Diagnostics ProBNP technical bulletin for Elecsys systems). The functional sensitivity, ie, the lowest analyte concentration that can be reproducibly measured with a between-run coefficient of variation of 20%, is <50 pg/mL.17
Plasma concentrations of high-sensitivity C-reactive protein (CRP) were measured fully automated with a latex-enhanced immunoturbidimetric assay on a Cobas Integra system (Roche Diagnostics). The CRP assay has an analytical sensitivity of 0.085 mg/L and a measuring range up to 160 mg/L. The upper limit of the reference range in healthy adults is 5 mg/L.
Laboratory personnel involved in the laboratory measurements were unaware of clinical or angiographic outcome of the patients.
Digital angiograms were analyzed offline with an automated edge detection system (CMS; Medis Medical Imaging Systems). The complexity of lesions was defined according to the modified American College of Cardiology/American Heart Association grading system.18 Class B2 and C lesions were considered complex. Restenosis was defined as a diameter stenosis ≥50% at the target lesion at follow-up angiography. Left ventricular ejection fraction was calculated with the use of left ventricular angiograms. Left ventricular end-diastolic pressure was measured before angiography.
Study End Points and Follow-Up
The primary end point of the study was all-cause mortality. On the basis of the information obtained from hospital records, death certificates, or telephone contact with relatives of the patient or attending physician, deaths were classified as cardiovascular or noncardiovascular. Other adverse events assessed were myocardial infarction and target vessel revascularization. The diagnosis of myocardial infarction was based on the presence of typical chest pain accompanied by either the appearance of pathological Q waves on ECG or an increase of creatine kinase/creatine kinase MB isoenzyme >3 times the upper limit of normal. Target vessel revascularization was defined as coronary bypass surgery or repeated percutaneous transluminal coronary angioplasty performed during the follow-up period because of symptoms or signs of myocardial ischemia in the presence of angiographic restenosis. Clinical follow-up consisted of telephone interviews at 1 month, 1 year, and 3 to 5 years after the initial procedure. All patients were advised to contact our outpatient clinic or their referring physicians whenever they experienced cardiac symptoms. In case of symptoms, at least 1 clinical and electrocardiographic checkup was performed. Collection of baseline characteristics of the patients, follow-up information, and adjudication of adverse events was performed by medical staff unaware of NT-proBNP levels.
Data are presented as median (with 25th and 75th percentiles) or counts and proportions (percentages). The distribution of the data was analyzed with 1-sample Kolmogorov-Smirnov test. Categorical data were compared with χ2 test. Continuous data were compared with Kruskal-Wallis or Wilcoxon rank sum test. Survival analysis was performed by applying the Kaplan-Meier method. Differences in survival were assessed with the log-rank test. The Cox proportional hazards model was used to assess the correlates of mortality and calculate the adjusted hazard ratios and 95% confidence intervals (95% CI). All analyses were performed with the use of S-PLUS statistical package (S-PLUS, Insightful Corp). A probability value <0.05 was considered to indicate statistical significance.
A total of 1059 patients with chronic stable angina were included in the study. Quartiles of NT-proBNP concentrations were as follows: 10.2 to <120.6 ng/L (first quartile), 120.6 to <301.7 ng/L (second quartile), 301.7 to <808.4 ng/L (third quartile), and 808.4 to 35000.0 ng/L (fourth quartile).
Table 1 shows baseline characteristics according to quartiles of NT-proBNP. Patients in the upper NT-proBNP quartile were older, were more often women, and had more often atrial fibrillation and a history of previous myocardial infarction. High-sensitivity CRP and creatinine concentrations were higher in patients in the upper quartile of NT-proBNP, whereas body mass index and proportion of patients with hypercholesterolemia were lower among patients in the upper quartile of NT-proBNP than among those in lower quartiles of NT-proBNP. The proportion of patients with diabetes, arterial hypertension, and previous coronary bypass graft surgery was higher in patients in the third and fourth quartiles of NT-proBNP. A progressive increase in the NYHA class was observed with the increase in the quartiles of NT-proBNP. With regard to therapy at discharge, angiotensin-converting enzyme inhibitors were more often prescribed in patients in the upper quartiles of NT-proBNP.
Table 2 shows the main angiographic and procedural data. Patients in the upper quartile of NT-proBNP had lower left ventricular ejection fraction and higher left ventricular end-diastolic pressure than patients in the lower quartiles of NT-proBNP. Furthermore, the proportion of patients with more advanced coronary artery disease was higher among patients in the upper quartiles of NT-proBNP.
Follow-up coronary angiography was performed in 227 patients (85.6%) in the first quartile, 207 patients (78.4%) in the second quartile, 201 patients (75.8%) in the third quartile, and 187 (70.6%) in the fourth quartile of the NT-proBNP concentration. Angiographic restenosis was found in 71 patients (31.3%) in the first quartile, 63 patients (30.4%) in the second quartile, 53 patients (26.4%) in the third quartile, and 59 patients (31.6%) in the fourth quartile of the NT-proBNP concentration (P=0.64).
The median follow-up was 3.6 years (interquartile range, 3.3 to 4.5 years) without differences in patients in different quartiles of NT-proBNP (P=0.31). The 1-year follow-up was complete in 98.0% of the patients, and the 3-year follow-up was complete in 94.0% of the patients. During the follow-up period, there were 106 deaths. NT-proBNP concentration was 271.0 ng/L (113.0 to 635.4 ng/L) in survivors and 1254.0 ng/L (398.5 to 2249.8 ng/L) in nonsurvivors (P<0.001). There were 5 deaths in the first quartile, 15 deaths in the second quartile, 18 deaths in the third quartile, and 68 deaths in the fourth quartile. Kaplan-Meier estimates of mortality were 4.7% in the first quartile, 7.8% in the second quartile, 11.4% in the third quartile, and 32.7% in the fourth quartile of NT-proBNP (P<0.001; Figure). A separation in the estimates of mortality between patients in the fourth quartile of NT-proBNP concentration compared with patients in the first, second, and third quartiles (curves more closely spaced for these 3 quartiles) was observed. Myocardial infarction occurred in 9 patients in the first quartile, 19 patients in the second quartile, 19 patients in the third quartile, and 19 patients in the fourth quartile of NT-proBNP (Kaplan-Meier estimates, 3.5%, 7.3%, 7.7%, and 9.0%, respectively; P=0.18). Target vessel revascularization was required in 63 patients in the first quartile, 75 patients in the second quartile, 51 patients in the third quartile, and 67 patients in the fourth quartile (Kaplan-Meier estimates, 24.6%, 28.9%, 20.1%, and 27.9%, respectively; P=0.11).
A Cox proportional hazards model was used to identify the correlates of mortality. All variables in Tables 1 and 2⇑ that showed a probability value <0.10 were entered into the multivariable analysis. The NT-proBNP was entered as quartile categories. Because of skewed distribution, log values of CRP were entered into the models. The model showed that NT-proBNP was the strongest correlate of mortality (adjusted hazard ratio [HR], 5.83 [95% CI: 2.07 to 16.44], P<0.001, for the fourth versus the first quartile; HR, 2.09 [95% CI: 0.73 to 5.94], P=0.16, for the second versus the first quartile; HR, 2.24 [95% CI: 0.79 to 6.41], P=0.13, for the third versus the first quartile]). Other correlates of mortality along with their adjusted HR are shown in Table 3.
Seventy of 106 deaths (66.0%) were defined as of cardiovascular origin. Cardiovascular deaths according to quartiles of NT-proBNP were as follows: 3 deaths in the first quartile, 8 deaths in the second quartile, 13 deaths in the third quartile, and 46 deaths in the fourth quartile (odds ratio, 17.2 [7.3 to 40.2], P<0.001 for the fourth versus the first quartile). After adjustment in the Cox proportional hazards model (the same variables as for all-cause mortality were entered into the model), NT-proBNP was a strong correlate of cardiac mortality (adjusted HR, 5.98 [1.55 to 23.13], P=0.009, for the fourth versus the first quartile); other correlates were age (adjusted HR, 1.56 [1.14 to 2.13], P=0.005), female sex (adjusted HR, 0.39 [0.18 to 0.84], P=0.01), NYHA class (adjusted HR, 1.40 [1.02 to 1.95], P=0.04, for 1-class increase in NYHA), and diabetes (adjusted HR, 1.67 [1.01 to 2.81], P=0.04).
Of the total study cohort, 70 patients were in NYHA class III and IV, and 989 patients were in NYHA class I and II. Among the 989 patients with NYHA class I and II, there were 85 deaths: 5 deaths in the first quartile of NT-proBNP, 13 deaths in the second quartile, 16 deaths in the third quartile, and 51 deaths in the fourth quartile (P<0.001). Adjustment in the multivariable model (the same variables as for all-cause mortality were entered into the model) showed that NT-proBNP level was again the strongest predictor of mortality (adjusted HR, 6.03 [2.07 to 17.52], P<0.001, for the fourth versus the first quartile). Other correlates of mortality were age (adjusted HR, 1.66 [1.24 to 2.21], P<0.001, for a 10-year increase in age), CRP (adjusted HR, 1.35 [1.08 to 1.68], P=0.009, for 1-SD increase in the log variable), female sex (adjusted HR, 0.51 [0.27 to 0.95], P=0.03), and NYHA class (adjusted HR, 1.73 [1.05 to 2.83], P=0.03, for 1-class increase in NYHA class).
Patients with chronic stable angina are poorly characterized in terms of biomarkers that may help in the assessment of prognosis or in the selection of therapeutic approaches or titration of therapeutic agents. We included in this study a large cohort with stable angina pectoris and were able to collect multiple data, including left ventricular ejection fraction and end-diastolic pressure as well as creatinine and high-sensitivity CRP, that are highly relevant during the assessment of prognosis in this population.
Our findings demonstrate that NT-proBNP is a powerful predictor of mortality. Plasma NT-proBNP levels enabled the identification of a group of patients with stable angina (those in the upper quartile of NT-proBNP) who were at a particularly high risk of death after coronary intervention with stenting. As the mortality curves show, mortality was higher particularly among the patients in the upper quartile of NT-proBNP, whereas differences in mortality were less pronounced among the patients in other quartiles of NT-proBNP. This distribution pattern in the estimates of mortality may indicate that NT-proBNP measurements may be particularly helpful in identifying a subgroup of patients with stable angina who are at a particularly high risk of death after coronary stenting. In the study by Kragelund et al,14 however, differences in the mortality estimates were nearly evenly distributed in the quartiles of NT-proBNP. Whether the differences in the distribution pattern of the mortality estimates in our study and the study by Kragelund et al14 reflect differences in the treatment of patients, including invasive and chronic medical therapy, is not known.
The mechanisms underlying the observed strong association between elevated levels of NT-proBNP and the increased risk of death in patients with chronic stable angina are not well defined. Similar rates of coronary restenosis in different quartiles of NT-proBNP indicate that coronary restenosis is not related to and cannot be used to explain the observed differences in mortality. Increased levels of NT-proBNP reflect a greater degree of myocardial dysfunction, and hence increased levels of NT-proBNP are associated with greater risk of death or congestive heart failure. Although left ventricular ejection fraction, as an estimate of myocardial dysfunction, is a predictor of mortality, the findings of this study and the findings of previous studies in patients with acute coronary syndromes11,12 have shown that the association between elevated levels of BNP or NT-proBNP and all-cause or cardiovascular mortality is independent of left ventricular ejection fraction, suggesting that natriuretic peptides contain information beyond that provided by left ventricular ejection fraction. Another potential explanation for the association between elevated levels of NT-proBNP and increased risk of death in patients with chronic stable angina may involve myocardial ischemia. Previous experimental19,20 and clinical21,22 studies have demonstrated that myocardial ischemia increases the circulating levels of natriuretic peptides. A recent report from the Treat Angina with Aggrastat and Determine Cost of Therapy with an Invasive or Conservative Strategy–Thrombolysis In Myocardial Infarction–18 study (TACTICS-TIMI-18) has demonstrated that in patients with unstable angina or non–ST-segment elevation myocardial infarction, elevated levels of BNP were associated with more severe coronary artery stenoses, slower blood flow in the culprit artery, and a more proximal culprit lesion.23 In agreement with these findings, complex coronary lesions in our study were more often observed in patients in the upper quartiles of NT-proBNP. A recent study has demonstrated that nearly one third of patients with chronic stable angina experience anginal attacks >1 or 2 times per week.6 Another study by Bibbins-Domingo et al24 in patients with stable angina showed that elevated levels of BNP were associated with inducible ischemia, suggesting that elevated levels of BNP may predict the increased risk for future coronary events. Thus, it may be hypothesized that repetitive myocardial ischemia in patients with stable angina may increase the expression of BNP gene and, as a consequence, the levels of circulating natriuretic peptides. Finally, another factor that may help to explain the strong association between the elevated levels of NT-proBNP and mortality may be related to the nature of information contained in the NT-proBNP itself. Multivariable analysis models may provide insight into decoding the information contained in the NT-proBNP. A recent publication from the Global Utilization of Strategies to Open occluded arteries-IV (GUSTO-IV) has demonstrated that increased levels of NT-proBNP were independently and positively associated with various factors of adverse cardiovascular risk.10 Several other variables, such as left ventricular ejection fraction, age, left ventricular end-diastolic pressure, and CRP, have the ability to predict mortality in patients with cardiovascular disease. Inclusion in the model of NT-proBNP diminishes the predictive value of these factors, even abolishing their association with mortality. Thus, NT-proBNP accumulates information from multiple sources. In this sense, circulating NT-proBNP may be considered an integrative index of the increased cardiovascular risk in general.
Our findings provide support to circulating levels of NT-proBNP as a unique strong prognostic biomarker for patients with chronic stable angina. Further studies are needed to investigate how NT-proBNP can be used to guide the therapy of these patients.
We thank Roche Diagnostics for providing the assay kits for NT-proBNP determinations.
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