Article

B-type Natriuretic Peptides in the Management of Acute Heart Failure and Acute Coronary Syndromes

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DOI:https://doi.org/10.15420/apc.2007:1:1:22

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Acute coronary syndromes (ACS) and heart failure (HF) are both associated with complex neurohormonal activation. Commensurate with advances in pharmacological and device therapies for both conditions, the concept of using circulating biomarkers for diagnosis and risk stratification, as well as for targeting and monitoring therapy, has received great attention. Although many novel biomarkers have been identified and evaluated, few have been documented to provide clinically useful incremental information to existing risk markers.1 However, in patients with suspected acute HF, B-type natriuretic peptide (BNP) and N-terminal proBNP have been widely accepted as clinically useful tools. Moreover, among a large number of potential novel prognostic biomarkers in ACS, the BNPs have emerged as the strongest candidates for routine use as a supplement to cardiac-specific troponins.

Acute Heart Failure

The clinical diagnosis of HF can be challenging, particularly in patients presenting with acute shortness of breath in the urgent care setting. Information obtained from clinical history and physical examination, as well as from the electrocardiogram and chest radiograph, may provide valuable clues as to whether HF is the cause of symptoms, but additional diagnostic tests, including echocardiography, may be required to obtain a more definite diagnosis. Currently, the best documented and most widely used clinical application of BNP testing is for the emergency diagnosis of HF in patients presenting with acute dyspnoea. Following the publication of the results of The Breathing Not Properly Multinational study in 2002, BNP measurements have rapidly entered the clinical arena. This multicentre diagnostic test evaluation trial, which included 1,586 patients who visited the emergency department (ED) with a main complaint of acute dyspnoea, used a rapid point-of-care fluorescence immunoassay for BNP determination.2 Diagnosis of HF was adjudicated by cardiologists blinded to the BNP results. BNP levels were found to provide strong and incremental diagnostic information to conventional historical, clinical or other laboratory tests and to have greater diagnostic accuracy for the diagnosis of heart failure than the ED physician using all other available information. Importantly, BNP performed well in patients with an intermediate (20–80%) pre-test probability of HF as evaluated by the ED physician.3 In the subsequent N-terminal Pro-BNP Investigation of Dyspnea in the Emergency Department (PRIDE) study, similar results were published for NT-proBNP. This study included 599 patients presenting to the ED of Massachusetts General Hospital in Boston with acute dyspnoea.4

The primary aim was to compare the diagnostic accuracy of NT-proBNP with that of clinical assessment for diagnosing acute HF. In this trial, NT-proBNP again performed slightly better than clinical assessment alone as a diagnostic tool. However, the combined use of NT-proBNP and clinical assessment performed better than either alone. A decision threshold for NT-proBNP of 900pg/ml was found to provide optimal discrimination for diagnosing heart failure, with an overall diagnostic accuracy of 87% (sensitivity 90%, specificity 85%). Lowering the decision threshold to 450pg/ml resulted in increased sensitivity (98%), but at the cost of decreased specificity (76%) and a slight reduction in overall diagnostic accuracy (83%). Based on a pooled analysis of studies evaluating the diagnostic value of NT-proBNP in acutely dyspnoeic patients, optimal confirmatory and exclusionary cut-off values for acute HF have been presented.5

Measurement of BNPs on presentation to the ED may result not only in an enhanced initial diagnostic approach to the patient, but also in a shorter hospital stay and reduced cost. The effect of rapid point-of-care BNP testing on time to discharge and total cost of treatment was first evaluated in the B-type Natriuretic Peptide for Acute Shortness of Breath Evaluation (BASEL) study, a prospective, non-blinded, randomised trial of 452 acutely dyspnoeic patients.6 BNP measurement in the ED resulted in reduced need for intensive care and reduced length of hospitalisation, which together translated into reduced total cost of treatment. The results of the BASEL trial have recently been corroborated and extended by the Canadian IMPROVE-CHF study, a randomised trial of 501 patients presenting with shortness of breath to seven EDs across Canada.7 Knowledge of NT-proBNP levels was associated with a shorter stay in the ED (on average 42 minutes), but the likelihood of being admitted to hospital, duration of hospitalisation or in-hospital mortality were not significantly different between the NT-proBNP and the conventional care groups. Importantly, re-hospitalisation rates at two months following discharge and direct hospital costs were significantly reduced when NT-proBNP levels were known to providers.

Although this study suggests that NT-proBNP testing provides clinically useful diagnostic information, it is not clear whether the better outcomes and savings were related to better and more rapid triage and initiation of adequate therapy or to less use of diagnostic testing. Although serial sampling of NT-proBNP was performed in hospitalised patients (at 72 hours), these results have not yet been published.

The value of repeated testing therefore remains uncertain. Despite the shortcomings of IMPROVE-CHF, including unblinded design and relatively modest statistical power, its results strongly support the routine use of BNPs in the initial evaluation of patients presenting with acute dyspnoea.

Acute Coronary Syndromes

Following acute ischaemic injury, the cardiac natriuretic peptide system is rapidly activated. A variety of factors may cause increased production of BNPs following episodes of acute ischaemia. Increased myocardial stretch secondary to ischaemia-induced ventricular dysfunction may quantitatively be the most important stimulus. Ischaemia and cellular hypoxia may also augment the production of BNP and NT-proBNP in the absence of haemodynamic changes. Pro-inflammatory cytokines and neurohormones with vasoconstrictive, antidiuretic, hypertrophic and cytoproliferative effects may also stimulate natriuretic peptide synthesis during ischaemia. In clinical studies, increased concentrations of BNPs have been observed in patients with unstable angina and during and after percutaneous coronary intervention. The rise in BNP concentration is proportional to the size of the reversible perfusion defect in patients with coronary artery disease.8 Plasma concentrations of BNPs increase in proportion to myocardial infarct size and degree of subsequent left ventricular dysfunction. Reversible ischaemic episodes may also result in transient release of BNPs. Still, BNPs are poorly suited to diagnostic purposes in suspected acute coronary syndromes, as both sensitivity and specificity are relatively low. Circulating levels of BNPs are determined by a variety of cardiac and non-cardiac factors (e.g. age, gender, renal function). Accordingly, there is relatively high inter-subject variability. Since the magnitude of increase in BNP and NT-proBNP levels is usually considerably lower in patients with acute coronary syndromes than in patients with acute decompensated HF, the signal-to-noise ratio is relatively low and unfavourable for diagnostic purposes.

A number of large-scale observational studies during the past five years have convincingly documented that levels of BNPs obtained in the acute or sub-acute phase following non-ST-elevation acute coronary syndromes are independently associated with both cardiovascular and total mortality.9–12 This relationship is independent of conventional risk factors, including the presence of clinical HF and left ventricular impairment. Conversely, after adjustment for potential confounders only a weak or non-existent association has been observed between BNPs and recurrent ischaemic events.

Whether repeated measurement of BNPs in patients with suspected acute coronary syndromes provides incremental prognostic value has not been extensively studied. Recent data from the Fragmin and Fast Revascularization during Instability in Coronary Artery Disease-II (FRISC-II) study demonstrate that NT-proBNP levels are highest on admission, decrease markedly during the first 24 hours and then fall more gradually over the following six months.13 Data from the Platelet Receptor Inhibition in Ischemic Syndrome Management (PRISM) study suggest that the addition of a second NT-proBNP value 72 hours following admission improves risk prediction.12 Regardless of the NT-proBNP value on admissison, an NT-proBNP concentration >250ng/l at 72 hours was associated with markedly increased risk of the combined end-point of death or recurrent myocardial infarction at 30 days. However, as most patients presenting with acute coronary syndromes in 2007 will be referred to coronary angiography within 72 hours of presentation, the clinical implications of these findings are not clear. Whether BNP levels on admission are predictive of the effect of specific therapeutic interventions is another important question.

Currently, the evidence in support of such a relationship is limited, one reason for which is that few contemporary clinical trials in patients with acute coronary syndromes document a significant effect of intervention on mortality. Data from the FRISC-II trial suggest that mortality reduction following an early invasive strategy is greater in patients with higher NT-proBNP levels, although the interaction was of only borderline statistical significance.14 These findings were recently confirmed and extended by data from the GUSTO-IV trial showing that patients with elevated troponin and NT-proBNP levels undergoing coronary revascularisation had a lower mortality rate at one year than those not revascularised.15 Conversely, patients without concomitant elevation in troponin and NT-proBNP did not appear to benefit from revascularisation. Indeed, in patients with low levels of both biomarkers, revascularisation was associated with a significant increase in mortality at one year. However, findings from other studies contradict these results. In the TACTICS-TIMI 18 trial16 and in the ICTUS trial,17 no interaction between baseline levels of BNPs and mortality reduction with early invasive therapy was apparent. Differing rates of cross-over to an invasive strategy from the conservative arms of the respective trials may have contributed to the discrepant results of these trials.

Conclusion

In conclusion, current data support the measurement of BNPs in acute HF for diagnostic, prognostic and cost-saving purposes and in ACS for prognostic assesment. Because only limited and partially conflicting retrospective data exist concerning the use of BNPs as a guide for therapeutic interventions, no general recommendation for this use can yet be made. However, in the case of concomitant troponin elevation, current data seem to suggest that an elevated initial BNP or NT-proBNP measurement should prompt consideration of an early invasive management approach. Ôûá Acute coronary syndromes (ACS) and heart failure (HF) are both associated with complex neurohormonal activation. Commensurate with advances in pharmacological and device therapies for both conditions, the concept of using circulating biomarkers for diagnosis and risk stratification, as well as for targeting and monitoring therapy, has received great attention. Although many novel biomarkers have been identified and evaluated, few have been documented to provide clinically useful incremental information to existing risk markers.1 However, in patients with suspected acute HF, B-type natriuretic peptide (BNP) and N-terminal proBNP have been widely accepted as clinically useful tools. Moreover, among a large number of potential novel prognostic biomarkers in ACS, the BNPs have emerged as the strongest candidates for routine use as a supplement to cardiac-specific troponins.

Acute Heart Failure

The clinical diagnosis of HF can be challenging, particularly in patients presenting with acute shortness of breath in the urgent care setting. Information obtained from clinical history and physical examination, as well as from the electrocardiogram and chest radiograph, may provide valuable clues as to whether HF is the cause of symptoms, but additional diagnostic tests, including echocardiography, may be required to obtain a more definite diagnosis. Currently, the best documented and most widely used clinical application of BNP testing is for the emergency diagnosis of HF in patients presenting with acute dyspnoea. Following the publication of the results of The Breathing Not Properly Multinational study in 2002, BNP measurements have rapidly entered the clinical arena. This multicentre diagnostic test evaluation trial, which included 1,586 patients who visited the emergency department (ED) with a main complaint of acute dyspnoea, used a rapid point-of-care fluorescence immunoassay for BNP determination.2

Diagnosis of HF was adjudicated by cardiologists blinded to the BNP results. BNP levels were found to provide strong and incremental diagnostic information to conventional historical, clinical or other laboratory tests and to have greater diagnostic accuracy for the diagnosis of heart failure than the ED physician using all other available information. Importantly, BNP performed well in patients with an intermediate (20–80%) pre-test probability of HF as evaluated by the ED physician.3 In the subsequent N-terminal Pro-BNP Investigation of Dyspnea in the Emergency Department (PRIDE) study, similar results were published for NT-proBNP. This study included 599 patients presenting to the ED of Massachusetts General Hospital in Boston with acute dyspnoea.4 The primary aim was to compare the diagnostic accuracy of NT-proBNP with that of clinical assessment for diagnosing acute HF. In this trial, NT-proBNP again performed slightly better than clinical assessment alone as a diagnostic tool. However, the combined use of NT-proBNP and clinical assessment performed better than either alone. A decision threshold for NT-proBNP of 900pg/ml was found to provide optimal discrimination for diagnosing heart failure, with an overall diagnostic accuracy of 87% (sensitivity 90%, specificity 85%). Lowering the decision threshold to 450pg/ml resulted in increased sensitivity (98%), but at the cost of decreased specificity (76%) and a slight reduction in overall diagnostic accuracy (83%). Based on a pooled analysis of studies evaluating the diagnostic value of NT-proBNP in acutely dyspnoeic patients, optimal confirmatory and exclusionary cut-off values for acute HF have been presented.5

Measurement of BNPs on presentation to the ED may result not only in an enhanced initial diagnostic approach to the patient, but also in a shorter hospital stay and reduced cost. The effect of rapid point-of-care BNP testing on time to discharge and total cost of treatment was first evaluated in the B-type Natriuretic Peptide for Acute Shortness of Breath Evaluation (BASEL) study, a prospective, non-blinded, randomised trial of 452 acutely dyspnoeic patients.6 BNP measurement in the ED resulted in reduced need for intensive care and reduced length of hospitalisation, which together translated into reduced total cost of treatment. The results of the BASEL trial have recently been corroborated and extended by the Canadian IMPROVE-CHF study, a randomised trial of 501 patients presenting with shortness of breath to seven EDs across Canada.7 Knowledge of NT-proBNP levels was associated with a shorter stay in the ED (on average 42 minutes), but the likelihood of being admitted to hospital, duration of hospitalisation or in-hospital mortality were not significantly different between the NT-proBNP and the conventional care groups. Importantly, re-hospitalisation rates at two months following discharge and direct hospital costs were significantly reduced when NT-proBNP levels were known to providers.

Although this study suggests that NT-proBNP testing provides clinically useful diagnostic information, it is not clear whether the better outcomes and savings were related to better and more rapid triage and initiation of adequate therapy or to less use of diagnostic testing. Although serial sampling of NT-proBNP was performed in hospitalised patients (at 72 hours), these results have not yet been published. The value of repeated testing therefore remains uncertain. Despite the shortcomings of IMPROVE-CHF, including unblinded design and relatively modest statistical power, its results strongly support the routine use of BNPs in the initial evaluation of patients presenting with acute dyspnoea.

Acute Coronary Syndromes

Following acute ischaemic injury, the cardiac natriuretic peptide system is rapidly activated. A variety of factors may cause increased production of BNPs following episodes of acute ischaemia. Increased myocardial stretch secondary to ischaemia-induced ventricular dysfunction may quantitatively be the most important stimulus. Ischaemia and cellular hypoxia may also augment the production of BNP and NT-proBNP in the absence of haemodynamic changes. Pro-inflammatory cytokines and neurohormones with vasoconstrictive, antidiuretic, hypertrophic and cytoproliferative effects may also stimulate natriuretic peptide synthesis during ischaemia. In clinical studies, increased concentrations of BNPs have been observed in patients with unstable angina and during and after percutaneous coronary intervention. The rise in BNP concentration is proportional to the size of the reversible perfusion defect in patients with coronary artery disease.8 Plasma concentrations of BNPs increase in proportion to myocardial infarct size and degree of subsequent left ventricular dysfunction. Reversible ischaemic episodes may also result in transient release of BNPs. Still, BNPs are poorly suited to diagnostic purposes in suspected acute coronary syndromes, as both sensitivity and specificity are relatively low. Circulating levels of BNPs are determined by a variety of cardiac and non-cardiac factors (e.g. age, gender, renal function). Accordingly, there is relatively high inter-subject variability. Since the magnitude of increase in BNP and NT-proBNP levels is usually considerably lower in patients with acute coronary syndromes than in patients with acute decompensated HF, the signal-to-noise ratio is relatively low and unfavourable for diagnostic purposes.

A number of large-scale observational studies during the past five years have convincingly documented that levels of BNPs obtained in the acute or sub-acute phase following non-ST-elevation acute coronary syndromes are independently associated with both cardiovascular and total mortality.9–12 This relationship is independent of conventional risk factors, including the presence of clinical HF and left ventricular impairment. Conversely, after adjustment for potential confounders only a weak or non-existent association has been observed between BNPs and recurrent ischaemic events. Whether repeated measurement of BNPs in patients with suspected acute coronary syndromes provides incremental prognostic value has not been extensively studied. Recent data from the Fragmin and Fast Revascularization during Instability in Coronary Artery Disease-II (FRISC-II) study demonstrate that NT-proBNP levels are highest on admission, decrease markedly during the first 24 hours and then fall more gradually over the following six months.13 Data from the Platelet Receptor Inhibition in Ischemic Syndrome Management (PRISM) study suggest that the addition of a second NT-proBNP value 72 hours following admission improves risk prediction.12 Regardless of the NT-proBNP value on admissison, an NT-proBNP concentration >250ng/l at 72 hours was associated with markedly increased risk of the combined end-point of death or recurrent myocardial infarction at 30 days. However, as most patients presenting with acute coronary syndromes in 2007 will be referred to coronary angiography within 72 hours of presentation, the clinical implications of these findings are not clear. Whether BNP levels on admission are predictive of the effect of specific therapeutic interventions is another important question.

Currently, the evidence in support of such a relationship is limited, one reason for which is that few contemporary clinical trials in patients with acute coronary syndromes document a significant effect of intervention on mortality. Data from the FRISC-II trial suggest that mortality reduction following an early invasive strategy is greater in patients with higher NT-proBNP levels, although the interaction was of only borderline statistical significance.14 These findings were recently confirmed and extended by data from the GUSTO-IV trial showing that patients with elevated troponin and NT-proBNP levels undergoing coronary revascularisation had a lower mortality rate at one year than those not revascularised.15

Conversely, patients without concomitant elevation in troponin and NT-proBNP did not appear to benefit from revascularisation. Indeed, in patients with low levels of both biomarkers, revascularisation was associated with a significant increase in mortality at one year. However, findings from other studies contradict these results. In the TACTICS-TIMI 18 trial16 and in the ICTUS trial,17 no interaction between baseline levels of BNPs and mortality reduction with early invasive therapy was apparent. Differing rates of cross-over to an invasive strategy from the conservative arms of the respective trials may have contributed to the discrepant results of these trials.

Conclusion

In conclusion, current data support the measurement of BNPs in acute HF for diagnostic, prognostic and cost-saving purposes and in ACS for prognostic assesment. Because only limited and partially conflicting retrospective data exist concerning the use of BNPs as a guide for therapeutic interventions, no general recommendation for this use can yet be made. However, in the case of concomitant troponin elevation, current data seem to suggest that an elevated initial BNP or NT-proBNP measurement should prompt consideration of an early invasive management approach.

References

  1. Vasan RS, Biomarkers of cardiovascular disease: molecular basis and practical considerations, Circulation, 2006;113(19):2335–62.
  2. Maisel AS, Krishnaswamy P, Nowak RM, et al., Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure, N Engl J Med, 2002;347(3):161–7.
  3. McCullough PA, Nowak RM, McCord J, et al., B-type natriuretic peptide and clinical judgment in emergency diagnosis of heart failure: analysis from Breathing Not Properly (BNP) Multinational Study, Circulation, 2002;106(4):416–22.
  4. Januzzi JL, Jr., Camargo CA, Anwaruddin S, et al., The Nterminal Pro-BNP investigation of dyspnea in the emergency department (PRIDE) study, Am J Cardiol, 2005;95(8):948–54.
  5. Januzzi JL, et al., NT-proBNP testing for diagnosis and short-term prognosis in acute destabilized heart failure: an international pooled analysis of 1256 patients: the International Collaborative of NT-proBNP Study, Eur Heart J, 2006;27(3):330–37.
  6. Mueller C, Scholer A, Laule-Kilian K, et al., Use of B-Type Natriuretic Peptide in the Evaluation and Management of Acute Dyspnea, N Engl J Med, 2004;350(7):647–54.
  7. Moe GW, Howlett J, Januzzi JL, Zowall H, N-terminal pro-B-type natriuretic peptide testing improves the management of patients with suspected acute heart failure: primary results of the Canadian prospective randomized multicenter IMPROVECHF study, Circulation, 2007;115(24):3103–10.
  8. Sabatine MS, Morrow DA, de Lemos JA, et al., Acute changes in circulating natriuretic peptide levels in relation to myocardial ischemia, J Am Coll Cardiol, 2004;44(10):1988–95.
  9. de Lemos JA, Morrow DA, Bentley JH, et al., The prognostic value of B-type natriuretic peptide in patients with acute coronary syndromes, N Engl J Med, 2001;345(14):1014–21.
  10. Omland T, Persson A, Ng L, et al., N-terminal pro-B-type natriuretic peptide and long-term mortality in acute coronary syndromes, Circulation, 2002;106(23):2913–18.
  11. James SK, Lindahl B, Siegbahn A, et al., N-terminal pro-brain natriuretic peptide and other risk markers for the separate prediction of mortality and subsequent myocardial infarction in patients with unstable coronary artery disease: a Global Utilization of Strategies To Open occluded arteries (GUSTO)-IV substudy, Circulation, 2003;108(3):275–81.
  12. Heeschen C, et al., N-terminal pro-B-type natriuretic peptide levels for dynamic risk stratification of patients with acute coronary syndromes, Circulation, 2004;110(20):3206–12.
  13. Lindahl B, Lindback J, Jernberg T, et al., Serial analyses of Nterminal pro-B-type natriuretic peptide in patients with non-STsegment elevation acute coronary syndromes: a Fragmin and fast Revascularisation during In Stability in Coronary artery disease (FRISC)-II substudy, J Am Coll Cardiol, 2005;45(4):533–41.
  14. Jernberg T, Lindahl B, Siegbahn A, et al., N-terminal pro-brain natriuretic peptide in relation to inflammation, myocardial necrosis, and the effect of an invasive strategy in unstable coronary artery disease, J Am Coll Cardiol, 2003;42(11):1909–16.
  15. James SK, Lindback J, Tilly J, et al., Troponin-T and N-terminal pro-B-type natriuretic peptide predict mortality benefit from coronary revascularization in acute coronary syndromes: a GUSTO-IV substudy, J Am Coll Cardiol, 2006;48(6):1146-–54.
  16. Morrow DA, de Lemos JA, Sabatine MS, et al., Evaluation of B-type natriuretic peptide for risk assessment in unstable angina/non-ST-elevation myocardial infarction: B-type natriuretic peptide and prognosis in TACTICS-TIMI 18, J Am Coll Cardiol, 2003;41(8):1264–72.
  17. Windhausen F, Hirsch A, Sanders GT, et al., N-terminal probrain natriuretic peptide for additional risk stratification in patients with non-ST-elevation acute coronary syndrome and an elevated troponin T: an Invasive versus Conservative Treatment in Unstable coronary Syndromes (ICTUS) substudy, Am Heart J, 2007;153(4):485–92.
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