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European Journal of Heart Failure 2004 6(3):319-325; doi:10.1016/j.ejheart.2004.01.007
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© 2004 European Society of Cardiology

NT-proBNP in unstable coronary artery disease—experiences from the FAST, GUSTO IV and FRISC II trials

Tomas Jernberga,*, Stefan Jamesa, Bertil Lindahla, Mats Stridsbergb, Per Vengeb and Lars Wallentina

a Department of Medical Sciences, Cardiology and Uppsala Clinical Research Center University Hospital, Uppsala 751 85, Sweden
b Department of Medical Sciences, Clinical Chemistry University Hospital, Uppsala 751 85, Sweden

* Corresponding author. Tel.: +46-18-611-0232; Fax: +46-18-50-66-38 E-mail address: tomas.jernberg{at}medsci.uu.se


   Abstract
Top
 Abstract
1. Introduction
 2. FAST
 3. GUSTO IV ACS
 4. FRISC II
 5. Conclusions
 References
 
Background: Risk stratification is important in patients with unstable coronary artery disease (CAD), i.e. unstable angina or non-ST-elevation myocardial infarction. This article focuses on the emerging role of N-terminal pro brain natriuretic peptide (NT-proBNP) and the results from the FAST, GUSTO IV and FRISC II trials.

Methods: In the FAST study, NT-proBNP was measured on admission in 755 patients admitted because of symptoms suggestive of unstable CAD. Follow up was performed after 40 months. The GUSTO IV and the FRISC II-trials included patients with unstable CAD and NT-proBNP was analyzed in 6806 and 2019 patients, with follow up after 1 and 2 years, respectively.

Results: In the FAST study, patients in the 2nd, 3rd, and 4th NT-proBNP quartile had a relative risk of subsequent death of 4.2 (1.6–11.1), 10.7 (4.2–26.8) and 26.6 (10.8–65.5), respectively. In the GUSTO IV trial, increasing quartiles of NT-proBNP were related to short and long term mortality which at 1 year was; 1.8%, 3.9%, 7.7% and 19.2% (P<0.001), respectively. In multivariable analyses including well-known predictors of outcome, NT-proBNP level was independently associated to mortality in all three studies. In the FRISC II trial, the NT-proBNP level, especially if combined with a marker of inflammation, identified those with the greatest benefit from an early invasive strategy.

Conclusion: NT-proBNP is strongly associated with mortality in patients with suspected or confirmed unstable CAD and, combined with a marker of inflammation, seems helpful in identifying those with greatest benefit from an early invasive strategy.

Key Words: Natriuretic peptide • Coronary artery disease • Acute coronary syndrome • Myocardial infarction

Received December 2, 2003; Accepted January 13, 2004


   1. Introduction
Top
 Abstract
 1. Introduction
2. FAST
 3. GUSTO IV ACS
 4. FRISC II
 5. Conclusions
 References
 
Approximately 60–70% of all admissions because of acute coronary syndrome are caused by unstable coronary artery disease (CAD), i.e. unstable angina or non-ST-elevation myocardial infarction (MI) [1,2]. In recent years, there have been major changes in the treatment of these patients. Recommendations for antithrombotic treatment now include several drugs targeting different aspects of the thrombotic process [3]. Awareness of a role for neurohormonal antagonism and possibly early initiation of lipid lowering therapy has increased [4–6], and now, there are three large trials supporting an early invasive strategy in this population [7–9]. Although sharing key pathophysiological mechanisms, patients with unstable CAD vary widely regarding clinical presentation, prognosis and response to treatment. To select appropriate therapy, risk stratification has become increasingly important.

Traditionally, risk stratification is performed by the use of the medical history, clinical presentation, electrocardiography, and biochemical markers of myocardial damage [3]. Also, markers of inflammation and renal function may be included in this process [10–12]. In addition, measurements of cardiac performance, such as left ventricular ejection fraction, have been shown to be important prognostic markers in this population [13,14]. It has been known for some years that plasma levels of natriuretic peptides can be used for the detection of left ventricular dysfunction after MI and that these levels are related to the outcome [15–19]. However, the first studies included mainly patients with ST-elevation MI. Only recently, have studies including patients with unstable CAD been published. The present article focuses on the emerging role of N-terminal pro brain (B-type) natriuretic peptide (NT-proBNP) and the results from the FAST, GUSTO IV ACS, and FRISC II trials [20–22]. The Elecsys proBNP assay was used in all trials.


   2. FAST
Top
 Abstract
 1. Introduction
 2. FAST
3. GUSTO IV ACS
 4. FRISC II
 5. Conclusions
 References
 
The Fast Assessment in Thoracic Pain (FAST) study [20] was the first study to prospectively evaluate the prognostic value of NT-proBNP in patients with suspected or confirmed unstable CAD. This was a single center study including patients admitted to the coronary care unit at the Uppsala University hospital between March 1997 and February 1998. The inclusion criteria were a history of chest pain or other symptoms suggestive of an acute coronary syndrome. Exclusion criteria were prehospital thrombolysis, presence of ST-segment elevation on admission ECG, and previous enrollment in the study. For the first 2 months, only patients arriving during office hours were included (run in period). Thereafter all consecutive patients admitted to CCU were included. Plasma NT-proBNP was determined from samples obtained on admission and the median follow up time was 40 months (3.3 years), ranging from 35 to 47 months.

Out of 775 patients, 407 (53%) had unstable CAD. The median value of NT-proBNP on admission was 400 (111–1646) ng/l. During follow up, the mortality increased with increasing levels of NT-proBNP. Compared to the lowest quartile, patients in the 2nd, 3rd, and 4th quartile had a relative risk (95%CI) of subsequent death of 4.2 (1.6–11.1), 10.7 (4.2–26.8) and 26.6 (10.8–65.5), respectively. Patients with elevated NT-proBNP had an increased risk regardless of diagnosis (Fig. 1). In a Cox regression analysis, including well known predictors of outcome, such as increasing age, presence of diabetes, history of previous myocardial infarction, ECG changes, elevated levels of cTnT and plasma creatinine, levels of NT-proBNP was one of the most important predictors of outcome.


Figure 1
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  		Fig. 1 Cumulative probability of death in patients with (a) acute myocardial infarction (n1–3=51, 57, 67) pooled log-rank P<0.001, (b) angina or unstable angina (n1–4=50, 64, 74, 44) pooled log-rank P<0.001, (c) other cardiac causes (n1–3=23, 23, 51) pooled log-rank P=0.004, (d) other non-cardiac or unknown causes (n1–4=124, 76, 40, 31) pooled log-rank P<0.001. The curves are terminated when less than 10 remain at risk. NT-proBNP: N-terminal pro brain natriuretic peptide. (Data from the FAST study.) Reprinted from ref [20] with permission from the American College of Cardiology Foundation.

 

   3. GUSTO IV ACS
Top
 Abstract
 1. Introduction
 2. FAST
 3. GUSTO IV ACS
4. FRISC II
 5. Conclusions
 References
 
The Global Utilization of Strategies To open Occluded arteries-IV (GUSTO-IV) trial included 7800 patients with acute coronary syndromes without ST-segment elevations at 458 centers in 24 countries during 1999 and 2000. Patients were randomized to receive 24 or 48 h of abciximab infusion or corresponding placebo and coronary angiography was discouraged during or within 12 h after the completion of study agent infusion. Determinations of NT-proBNP levels in serum samples obtained at randomization were available from 6809 (87.3%) of the patients [21]. The NT-proBNP levels ranged from 5.3 to 35000 ng/l with a median level of 669 (interquartile range 237–1869) ng/l.

Increasing levels of NT-proBNP were independently and positively associated with age, female gender, diabetes mellitus, angina pectoris, hypertension, previous myocardial infarction, heart failure and heart rate, and ST-depression but negatively with body-weight and hypercholesterolemia. NT-proBNP levels were also associated with time from symptom onset and the magnitude of myocardial necrosis, i.e. troponin elevation. In addition, NT-proBNP levels were associated with renal dysfunction and inflammatory activity as reflected by levels of creatinine and CRP. The relationships can partly be explained by the secretion of NT-proBNP as a response to volume overload and raised intra-cardiac pressure. The fact that NT-proBNP was independently related to clinical factors indicating myocardial damage or dysfunction supports that NT-proBNP is a general marker of reduced cardiac performance rather than systolic dysfunction.

There was an increased mortality among patients in increasing quartiles of NT-proBNP (Fig. 2). The Kaplan–Meier survival curves for the quartiles separated early. Already, at 48 h after randomization the difference in mortality between the quartiles was statistically significant (P=0.001), with a mortality of 0.2%, 0.4%, 0.4% and 1.4%, respectively. The separation of the curves continued throughout the first year after the index event (P<0.001, log rank). Thus, at one-year follow-up the mortality was 1.8%, 3.9%, 7.7% and 19.2% in the respective quartile. At one year there was an exponentially increasing mortality in the entire spectrum of NT-proBNP levels with a mortality of 0.4% in the lowest decile (<98 ng/l) and 27.1% in the highest decile (>4634 ng/l). Despite the fact that the level of NT-proBNP was independently related to several risk factors, the NT-proBNP level still was the strongest independent indicator of mortality in the multivariate analysis (Fig. 3).


Figure 2
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  		Fig. 2 Kaplan–Meier survival curves regarding probability of death during 1-year of follow-up for patient strata based on quartiles of NT-proBNP in patients with unstable coronary artery syndromes. (Data from the GUSTO-IV study.) Reproduced with permission from Ref. [21].

 


Figure 3
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  		Fig. 3 Multiple logistic regression analyses for the prediction of death at 1-year follow-up in patients with unstable coronary artery syndromes. (Data from the GUSTO-IV study.) Reproduced with permission from Ref. [21].

 
Elevations of Troponin-T and CRP as well as reduced creatinine clearance rate also independently predicted an increased mortality. Accordingly, the combination of NT-proBNP and these markers allowed an even better risk stratification than either marker alone (Fig. 4). A very low mortality was found in patients with NT-proBNP in the bottom quartile in combination with creatinine clearance in the top quartile (0.3%) or in combination of NT-proBNP with Troponin-T or CRP in the bottom quartile (1.6%) (Fig. 4). The highest 1-year mortality, 25.7%, was found in patients with levels of NT-proBNP in the top and creatinine clearance in the bottom quartile. A similar high mortality was found in patients with NT-proBNP in combination with Troponin-T or CRP levels in the top quartiles, 22.3 or 23.4%.


Figure 4
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  		Fig. 4 Mortality at 1-year follow-up among strata of patients based on quartiles of NT-proBNP and quartiles of creatinine clearance (a) Troponin-T (b) and C-reactive protein (c). (Data from the GUSTO-IV study.) Reproduced with permission from Ref. [21].

 
The risk of subsequent MI after the index event also increased with increasing quartiles of NT-proBNP with an MI rate of 2.7%, 5.4%, 5.7% and 7.5% (P<0.001) for the respective quartile at 30-days follow-up. However, in a multivariable logistic regression analysis the level of NT-proBNP did not constitute an independent predictor of myocardial infarction at 30 days. The reason for this finding might be that BNP is a regulatory myocardial hormone, which is not involved in the processes related to the rupture of coronary plaques or formation of coronary thrombi.


   4. FRISC II
Top
 Abstract
 1. Introduction
 2. FAST
 3. GUSTO IV ACS
 4. FRISC II
5. Conclusions
 References
 
The FRISC II trial was a multicenter trial, designed to compare an early invasive to an early non-invasive strategy in patients with unstable CAD [7]. In the invasive strategy the aim was to perform coronary angiography, and if appropriate revascularization within 7 days from admission, whereas patients randomized to a non-invasive strategy underwent coronary angiography only if refractory or recurrent symptoms occurred or if they showed signs of severe ischemia at a pre-discharge exercise test. The aim of the NT-proBNP substudy of this trial was two-fold [22]. Firstly, to investigate the prognostic value of NT-proBNP in relation to other important predictors of outcome, including left ventricular ejection fraction determined by echocardiography. Secondly, to examine whether NT-proBNP in addition to other prognostic markers could improve the selection of patients who benefit from an early invasive strategy.

A total of 2019 patients had NT-proBNP measured at randomization, after a median time of 39 (27–54) h from the last episode of symptoms. The median value of NT-proBNP was 535 (212–1192) ng/l for men and 672 (283–1820) ng/l for women. When men and women were separately divided into tertiles according to NT-proBNP level, patients in the 3rd tertile had a 4.1 (95%CI: 2.4–7.2) fold and 3.5 (95%CI: 1.8–6.8) fold higher mortality in the non-invasive and invasive group, respectively. In a logistic regression analysis including well known predictors of outcome, the level of NT-proBNP was independently associated with mortality.

LVEF did not affect the association between NT-proBNP and mortality. Of the patients with LVEF<0.45, only those with raised levels of NT-proBNP had an increased mortality, whereas patients with raised levels of NT-proBNP had increased mortality regardless of LVEF and treatment strategy (Fig. 5). There are several possible reasons why NT-proBNP is a more important predictor of outcome than LVEF determined by echocardiography in the present population. As previously stated, NT-proBNP seems to be a marker of overall cardiac performance rather than systolic dysfunction. Previous studies have shown that the neurohormonal response, including raised levels of NT-proBNP, is independently associated with mortality in patients with left ventricular dysfunction [23]. High levels of NT-proBNP may reflect temporary left ventricular dysfunction secondary to transient ischemia jeopardizing a large part of the myocardium. Elevations of BNP have also been demonstrated shortly after percutaneous coronary intervention [24]. A raised level of NT-proBNP in patients with normal or slightly depressed LVEF may also indicate diastolic dysfunction [25] which also can contribute to prognosis. Finally, the performance and interpretation of echocardiography are operator-dependent, which might have contributed to the superiority of NT-proBNP in the present setting.


Figure 5
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  		Fig. 5 Two year mortality in relation to level of NT-proBNP, graded left ventricular ejection fraction (LVEF) and treatment strategy. (Data from the FRISC II study.) Reprinted from ref. [22] with permission from the American College of Cardiology.

 
The mortality benefit of an early invasive strategy was greater in patients with raised NT-proBNP levels. The absolute reduction in mortality in the invasive group was 3.6% [RR(95%CI): 0.67 (0.41–1.10)] in the 3rd tertile and 0.6% [RR (95%CI): 0.78 (0.39–1.57)] in the 1st and 2nd tertile (Fig. 6a). An obvious reason is the low mortality in patients with low NT-proBNP levels, making further improvements difficult. Another reason is probably that a high NT-proBNP level was associated both with more severe coronary artery disease and a reduced LVEF. Interestingly, the improved survival of an invasive strategy was found only in patients with simultaneously high levels of NT-proBNP and IL-6 (Fig. 6b–c). This suggests that patients with increased NT-proBNP and with an inflammatory response have a reversible condition that can be improved by revascularization. Those with high NT-proBNP levels but without inflammatory response, on the other hand, may have an irreversible myocardial dysfunction that will not be affected by an intervention. Several possible mechanisms might explain these findings. An increase in inflammatory activity has been associated with both stunned and hibernating myocardium [26–29]. Therefore, it can be hypothesized that patients with increased NT-proBNP and IL-6 levels more often have areas of stunned or hibernating myocardium that may be improved by revascularization. The inflammatory response to the ischemic insult may also have long-lasting negative effects on myocardial performance [30–32] that might be reduced by revascularization.


Figure 6
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  		Fig. 6 Cumulative probability of death in relation to level of NT-proBNP and treatment strategy in (a) all patients, (b) patients with IL-6<5 ng/l, and (c) patients with IL-6≥5 ng/l. (1) 1st or 2nd tertile NT-proBNP+non-invasive strategy. (2) 1st or 2nd tertile NT-proBNP+invasive strategy. (3) 3rd tertile NT-proBNP+non-invasive strategy. (4) 3rd tertile NT-proBNP+invasive strategy. The whole group: (n=655, 691, 353, 320) IL-6<5 ng/l group: (n=520, 540, 190, 187). IL-6≥5 ng/l group: (n=122, 140, 156, 129). Reprinted from ref. [22] with permission from the American College of Cardiology.

 

   5. Conclusions
Top
 Abstract
 1. Introduction
 2. FAST
 3. GUSTO IV ACS
 4. FRISC II
 5. Conclusions
References
 
The FAST-study and the NT-proBNP substudies of the GUSTO IV ACS and FRISC II trials have convincingly shown that the level of NT-proBNP predicts short- and long-term mortality in patients with suspected or confirmed unstable CAD. The association between NT-proBNP level and mortality is independent of other well-known predictors of outcome, such as age, presence of diabetes, previous myocardial infarction, heart failure, ECG-changes, elevated troponin T, C-reactive protein, Interleukin-6, creatinine clearance and left ventricular ejection fraction determined by echocardiography. The substudy of FRISC II also suggests that the level of NT-proBNP, especially when combined with a marker of inflammation can be helpful in the selection of patients for an early invasive strategy.


   References
Top
 Abstract
 1. Introduction
 2. FAST
 3. GUSTO IV ACS
 4. FRISC II
 5. Conclusions
 References
 

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Serum NT-proBNP Concentrations in the Early Phase Do Not Predict the Severity of Systolic or Diastolic Left Ventricular Dysfunction Among Patients With ST-Elevation Acute Myocardial Infarction
Angiology, January 1, 2007; 57(6): 686 - 693.
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M. Mockel, R. Muller, J. O. Vollert, C. Muller, A. Carl, D. Peetz, F. Post, J. K. Kohse, and K. J. Lackner
Role of N-Terminal Pro-B-Type Natriuretic Peptide in Risk Stratification in Patients Presenting in the Emergency Room
Clin. Chem., September 1, 2005; 51(9): 1624 - 1631.
[Abstract] [Full Text] [PDF]

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