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Three Part Question

In [patients with suspected cardiac chest pain] does [measurement of brain natriuretic peptide] enable [exclusion of acute coronary syndromes]?

Clinical Scenario

A previously healthy sixty year-old lady presents with a thirty-minute history of left-sided chest discomfort, also felt in the left arm. Examination and initial ECG are normal. You refer her for troponin testing at 12 hours but recognise that this strategy has three major limitations: (1) The patient may be unnecessarily alarmed or receive inappropriate treatment for what turns out to be an erroneous diagnosis; (2) The patient's condition has not been diagnosed in the initial 12-hour period, when intensive guided therapy may have been most beneficial; (3) troponins merely mark myocardial necrosis and cannot inform you as to whether the patient has an unstable coronary atheromatous plaque.
Having heard a rumour about brain natriuretic peptide (BNP) as an early cardiac marker, you wonder if it would help to avoid such disadvantages in this clinical situation.

Search Strategy

OVID Medline 1966 - 2005 July Week 4
OVID Embase 1980 - 2005 Week 32
The Cochrane Library 2005 Issue 2
Medline and Embase:
(exp Myocardial Infarction/ OR exp Coronary Thrombosis/ OR exp Angina, Unstable/ OR (myocard$ adj (infarct$ OR ischaem$ OR ischem$)).mp. OR (acute coronary syndrome OR ACS OR MI OR AMI).mp.) AND (exp Natriuretic Peptide, Brain/ OR $BNP.mp. OR ((brain OR B) adj natriuretic peptide$).mp.) limit to human and English language
Cochrane:
(Myocardial Infarction [MeSH] OR Angina, Unstable [MeSH] OR (myocard* NEAR (infarct* OR ischaem* OR ischem*)) OR acute coronary syndrome OR ACS OR MI OR AMI) AND (Natriuretic Peptide, Brain [MeSH] OR BNP OR ((brain OR B) NEAR (natriuretic peptide*)))

Search Outcome

Medline: 294 papers were identified, of which eight were relevant.
Embase: 354 papers were identified, of which eight were relevant.
Cochrane: 37 papers were identified, of which one was relevant.
Altogether eight relevant papers were identified. Papers investigating the value of N-terminal-pro-BNP were excluded but a separate review has been undertaken.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Bassan et al 2005 Brazil	631 consecutive patients presenting to the Emergency Department with suspected cardiac chest pain <12 hours and no ST elevation on ECG. Blood taken on admission. Follow-up through in-patient stay.	Prospective observational cohort	Association between BNP and diagnosis	Significantly higher BNP in MI patients (P<0.0001). Increasing risk of MI with increasing BNP (divided into quartiles; P<0.0001).	No follow-up following hospital discharge. 30-day and 6-month follow-up would be desirable. No firm diagnosis in 202 (32%) patients (MI excluded but not UA).
			Diagnostic accuracy of BNP for MI (optimal 100pg/ml cut-off)	Area under ROC curve 0.710. Sensitivity 70.8%; Specificity 68.9%; PPV 22.7%; NPV 94.8%; LR+ 2.28; LR- 0.42. RR 4.38
			Raised BNP, CK-MB or TnI (on admission) for diagnosis of MI	Sensitivity 87.3%; Specificity 65.7%; PPV 27.0%; NPV 97.3%; LR+ 2.55; LR- 0.19. RR 9.91
			Logistic regression model for association with MI	BNP an independent predictor for diagnosis of MI (P=0.0026).
			Clinical utility of BNP to rule in MI	Authors' note: 72 patients had MI, 37 of whom had raised CK-MB or TnI on admission. Raised BNP would have allowed detection of 22 more MI's [albeit at a cost of 163 false +ve diagnoses!]
			Value of BNP in ruling out MI (calculated)	For every 100 patients treated according to BNP levels on admission (cut-off 100pg/ml), 3 MI's would be missed.
Morrow et al 2003 United States	1676 patients (of 2220), enrolled in TACTICS-TIMI 18 (early invasive v. conservative strategy), with non-ST elevation acute coronary syndromes (NSTACS) and symptoms in the last 24 hours. Blood taken "at enrollment". Follow-up at 6 months.	Nested prospective observational cohort	Elevated plasma BNP in UA (>80pg/ml)	Raised in 15.6% (n=167) [i.e. sensitivity 15.6%], and 10.1% (n=67) of those with -ve baseline TnI. Elevated BNP in 13.6% (n=135) of patients with UA and no history or current evidence of HF.	Patients enrolled having already been diagnosed with ACS (an undifferentiated group of patients would have enabled more clinically relevant conclusions to be drawn). Insufficient data reported to allow calculation of specificities, PPV's, NPV's or LR's.
			Elevated plasma BNP in NSTEMI (>80pg/ml)	Raised in 25.2% [i.e. sensitivity 25.2%] (n=153)
			Death at 30 days (BNP cut-off 80pg/ml)	5.0% raised v. 1.2% not raised (P<0.0001). Calculated sensitivity 80.6%.
			Death at 6 months (BNP cut-off 80pg/ml)	8.4% raised v. 1.8% not raised (P<0.0001). Calculated sensitivity 82%.
			Death at 7 days (BNP cut-off 80pg/ml)	2.5% raised v. 0.74% not raised. Calculated sensitivity 77%.
			Association between BNP and 6/12 mortality after adjustment for important clinical predictors available at presentation	Remained an independent predictor of mortality (OR 3.3, 95% CI 1.7-6.3).
			BNP for prediction of recurrent MI	Not predictive (5.3% v. 5.2%, p=1.0)
			BNP for prediction of hospitilisation with recurrent ACS	Not predictive (13.4% v. 12.2%, p=0.6).
			BNP for prediction of new or worsening CHF	30 days: Significantly increased risk with raised BNP (5.9% v. 1.0%, p<0.0001). 6 months: Risk persisted (9.1% v. 1.8%, P<0.0001).
			BNP + TnI for prediction of 6/12 mortality	Both -ve: 0.7% risk of death.
			Death with conservative/early invasive treatment according to BNP results	No appreciable difference (p=0.6 for 6/12 mortality).
de Lemos et al 2001 United States	2525 patients with ACS (825 STEMI, 565 NSTEMI, 1133 UA) enrolled into another study investigating GPIIb/IIIa inhibitors. Blood sent at a mean of 40+/-20 hours from symptom onset.	Prospective observational cohort	Baseline characteristics	Patients with higher BNP more likely to be older (P<0.001), male (P<0.001), hypertensive (P<0.003), have CHF (P<0.001, hypercholesterolaemia (P<0.001), smokers (P<0.001), to have reduced creatinine clearance (P<0.001), CK-MB > upper limit of normal (P<0.001) or ST segment depression (P<0.001).	Very late sampling time. ACS had already been ruled in for this patient group at time of inclusion (by ECG or cardiac marker testing). Inadequate reporting of data to allow calculation of sensitivities, specificities, PPVs, NPVs or likelihood ratios.
			Correlation of BNP with angiography/stress test	Patients with higher BNP more likely to have >50% stenosis (P<0.001) or +ve stress test (P<0.01) than patients with low levels
			BNP as an independent predictor of death (after adjustment using logistic regression)	Adjusted OR's for death at 10 months in 2nd, 3rd & 4th quartiles of BNP were 3.8 (95% CI 1.1-13.3), 4.0 (1.2-13.7) and 5.8 (1.7-19.7), respectively.
			Value of a BNP cutoff of 80pg/ml as an independent predictor of mortality (adjusted)	BNP remain significantly associated with increased 10-month mortality (P=0.04).
Mega et al 2004 United States	438 eligible (of 483) patients enrolled in the ENTIRE-TIMI 23 trial (full v. half dose thrombolysis + abciximab and LMWH or heparin in STEMI < 6hours). Blood sampling on admission, before thrombolysis.	Nested prospective observational cohort	30-day mortality (reported results)	Significantly higher BNP among those who died (P<0.0001). BNP>80pg/ml associated with significantly higher risk of death (P<0.0001).	All patients had STEMI already ruled in by ECG - the study is not helpful to evaluate BNP as a diagnostic test for MI.
			30-day mortality (values calculated using reported data)	BNP>80pg/ml: Sensitivity 53%, specificity 91%, PPV 17%, NPV 98.2% (i.e. 1.8% chance of death despite -ve BNP); LR+ 5.9; LR- 0.5
			New or worsening CHF at 30 days	More frequent if BNP>80pg/ml (8.7% v. 3.3%, p=0.09).
			New or worsening CHF at 30 days (calculated)	BNP>80pg/ml: Sensitivity 23.5%; Specificity 90%; PPV 8.7%; NPV 96.7% (i.e. probability of CHF despite -ve BNP 3.3%); LR+ 2.35; LR- 0.7.
			Independent predictors of mortality following logistic regression	BNP remained independently associated with mortality (OR 7.2, 95% CI 2.1-24.5, P=0.001).
			BNP as a predictor of successful myocardial reperfusion	Elevated BNP associated with incomplete reperfusion (impaired flow, P=0.04; poor myocardial perfusion, P=0.06; Failed ST-segment resolution, P=0.005).
Mukoyama et al 1991 Japan	13 consecutive patients with AMI < 12 hours from symptom onset. Blood samples at enrollment and every 4-24 hours over 4 days.	Prospective diagnostic cohort	BNP levels	Rose after AMI (within "hours" of onset of AMI).	Small numbers Subopimal reporting of results. Little statistical analysis. Meaningful conclusions cannot be drawn about the value of BNP as a diagnostic test.
			Correlation of BNP with PCWP and CIn	No correlation with PCWP. Highly correlated inversely with CIn (r=-0.81, P<0.01).
Morita et al 1993 Japan	50 consecutive patients with AMI within 8 hours of symptom onset. 30 age- and sex-matched controls. Blood taken on admission. All patients had coronary angiography on admission. 10 had intracoronary thrombolysis, 11 had IV thrombolysis; 26 had PTCA.	Prospective diagnostic cohort	BNP level on admission	Significantly increased with AMI v. controls (92+/-28 v. 5.2+/-0.5pg/ml; P<0.01)	Diagnosis of MI had already been ruled in at enrollment. Investigating application in an undifferentiated group would be more clinically relevant.
			Peak BNP level in MI patients	Peak level at 16.4+/-0.7 hours after admission
			BNP levels at four weeks	Still significantly higher in MI group than controls (149+/-47 v. 5.2+/-0.5pg/ml; P<0.001).
			Correlation between BNP and haemodynamic parameters	No correlation with PCWP; No correlation with CIn in 1st 2 days; Significant inverse correlation with CIn at time of peak BNP level (r=-0.476, P<0.01).
Kikuta et al 1995 Japan	73 patients (already diagnosed) with either UA (n=33), SA (n=20) or atypical chest pain with normal coronary angiogram, stress test and hyperventilation test (n=20). Blood taken within 24 hours of last attack in UA group.	Prospective diagnostic cohort	BNP levels	Significantly higher in UA group compared with SA and controls (P<0.01 for each). No significant difference between SA and controls.	16 of UA group had ST elevation on ECG. CK-MB < twice normal but no troponin testing. These patients may actually have had MI. Results not useful for clinical evaluation of BNP as a diagnostic test (sensitivities, specificities, etc, cannot be calculated; patients had already been diagnosed at enrollment).
			BNP levels according to ST elevation or depression	No significant difference
			BNP levels following treatment	BNP decreased significantly (P<0.01) in UA group but not SA group.
			Regional wall motion abnormalities on echocardiography	Significantly higher BNP if +ve for this outcome (P<0.01).
Horio et al 1993 Japan	16 patients admitted to CCU with AMI within 9 hours of symptom onset. All patients had right-sided cardiac catheterisation, coronary angiography and primary angioplasty. 16 normal subjects. Blood taken on admission and serially on days 3, 7, 14 and 28	Prospective observational cohort	BNP levels on day 1	Higher in AMI patients than controls (4.5 fold on day 1). No P value.	Small numbers Method of identification of normal subjects not described. Not all pertinent P values given. This study suggests raised BNP in AMI but, because of the design, data cannot be used to evaluate BNP as a diagnostic test for AMI.
			BNP levels at follow up	Significantly elevated in AMI patients at 14 days; still "abnormally elevated" at 4 weeks (no P values).
			Correlation between BNP and haemodynamic variables	No correlation with PCWP, right atrial pressure or CIn. Significant inverse correlation with LVEF (r=-0.67, P<0.01).

Comment(s)

BNP was first isolated from porcine brains but it has since been recognised as a cardiac hormone synthesised predominantly by the ventricles in response to ventricular wall stress. Together with atrial natriuretic peptide, which is secreted primarily by the atria, BNP belongs to the natriuretic peptide family that is involved in cardiac homeostasis. Biological effects include diuresis, vasodilatation, inhibition of the renin–aldosterone system and of cardiac and vascular myocyte growth (Hall et al, 2003). BNP is known to be a marker of acute and chronic left ventricular dysfunction and may be useful for the Emergency Department diagnosis of the former (Maisel et al, 2002; Morrison et al, 2002). It has been used as a marker of left ventricular systolic dysfunction following AMI, where it rovides prognostic information (Omland 1996). BNP is also expressed in ischaemic human myocardium and plasma levels may rise during periods of ischaemia (Ruck et al, 2004; Goetze et al, 2003; Marumoto et al, 1995). All of the studies identified demonstrated a rise of BNP in acute coronary syndromes (ACS). It would also seem that elevated BNP is an independent predictor of adverse prognosis following ACS. However, the data does not suggest that BNP can be utilised to rule out ACS in the emergency department. The well-designed study by Bassan et al demonstrated an NPV of 94.8% for the diagnosis of AMI. Therefore the posttest probability of AMI following a negative test would be 5.2%, meaning that an unacceptably high proportion of AMI's would still be missed. In addition, the test would result in over three false positive diagnoses for every true positive. Combining BNP with CK-MB and troponin I improved sensitivity but PPV remained low (27%) and 3% of all AMI's would still be missed using this strategy. Despite these limitations, BNP has potential as a cardiac marker for use in the Emergency Department but it is likely to be necessary to incorporate BNP into a multimarker strategy, together with other promising early markers, in order to increase diagnostic accuracy. Future investigations may also focus on whether detection of raised BNP can be used to guide therapy, for example by selecting a patient group likely to derive particular benefit from ACE inhibition (Motwani et al, 1993).

Editor Comment

Abbreviations: MI: myocardial infarction; STEMI: ST-elevation MI; NSTEMI: non-ST elevation MI; UA: unstable angina; SA: stable angina; ACS: acute coronary syndrome; LMWH: low molecular-weight heparin; CHF: congestive heart failure; HF: heart failure; PPV: positive predictive value; NPV: negative predictive value; CI: Confidence interval; LR: likelihood ratio; ROC: receiver operating characteristic; CIn: cardiac index; PCWP: pulmonary capillary wedge pressure; LVEF: left ventricular ejection fraction; AMI: acute myocardial infarction

Clinical Bottom Line

BNP has shown promise as an early cardiac marker and may aid prognostic stratification, although NPV and PPV may be unacceptably low to enable use as a sole cardiac marker. Incorporation into multimarker strategy is likely to be necessary. Serial estimations may enhance clinical utility.

Level of Evidence

Level 2 - Studies considered were neither 1 or 3.

References

1. Bassan R; Potsch A; Maisel A; Tura B; Villacorta H; Nogueira MV; Campos A; Gamarski R; Masetto AC; Moutinho MA B-type natriuretic peptide: a novel early blood marker of acute myocardial infarction in patients with chest pain and no ST-segment elevation European Heart Journal 2005; 26: 234-240
2. Morrow DA; de Lemos JA; Sbatine MS; Murphy A; Demopoulous LA; DiBattiste PM; McCabe CH; Gibon M; Cannon C; Braunwald E Evaluation fo B-type natriuretic peptide for risk assessment in unstable angina/non-ST-elevation myocardial infarction. B-type natriuretic peptide and prognosis in TACTICS-TIMI Journal of the American College of Cardiology 2003; 41(8): 1264-1272
3. de Lemos JA; Morrow DA; Bentley JH; Omland T; Sabatine MS; McCabe CH; Hall C; Cannon CP; Braunwald E The prognostic value of B-type natriuretic peptide in patients with acute coronary syndromes New England Journal of Medicine 2001; 345: 1014-1021
4. Mega JL; Morrow DA; de Lemos JA; Sabatine MS; Murphy SA; Rifai N; Gibson CM; Antman EM; Braunwald E B-type natriuretic peptide at presentation and prognosis in patients with ST-segment elevation myocardial infarction. An ENTIRE-TIMI-23 substudy Journal of the American College of Cardiology 2004; 44(2): 335-339
5. Mukoyama M; Nakao K; Obata K; Jougasaki M; Yoshimura M; Morita E; Hosoda K; Suga SI; Ogawa Y; Yasue H; Imura H Augmented secretion of brian natriuretic peptide in acute myocardial infarction Biochemical and Biophysical Research Communications 1991; 180(1): 431-436
6. Morita E; Hirofumi Y; Michihiro Y; Ogawa H; Jougasaki M; Matsumura T; Mukoyama M; Nakao K Myocardial injury/infarction: increased plasma levels of brain natriuretic peptide in patients with acute myocardial infarction Circulation 1991; 88(1): 82-91
7. Kikuta K; Yasue H; Yoshimura M; Morita E; Sumida H; Kato H; Kugiyama K; Ogawa H; Okumura K; Ogawa Y; Nakao K Increased plasma levels of B-type natriuretic peptide in patients with unstable angina American Heart Journal 1996; 132: 101-107
8. Horio T; Shimada KE; Hokno M; Yoshimura T; Kawarabayashi T; Yasunari K; Murakawa KI; Yokokawa K; Ikeda M; Fukui T; Takeda T Serial changes in atrial and brain natriuretic peptides in patients with acute myocardial infarction treated with early coronary angioplasty American Heart Journal 1993; 126: 293-299
9. Hall C Essential biochemistry and physiology of (NT-pro) BNP. European Journal of Heart Failure 2004; 6: 257-260
10. Maisel AS; Krishnaswamy P; Nowak RM; McCord J; Hollander JE; Duc P; Omland T; Storrow AB; Abraham WT; Wu AH; Clopton P; Steg PG; Westheim A; Knudsen CW; Perez A; Kazanegra R; Herrmann HC; McCullogh PA Rapid measurement of B-type natriuretic peptide in the emergency diagnosis of heart failure New England Journal of Medicine 2002; 347: 161-167
11. Morrison LK; Harrison A; Krishnaswamy P; Kazanegra R; Clopton P; Maisel A Utility of a rapid B-natriuretic peptide assay in differentiating congestive heart failure from lung disease in patients presenting with dyspnea Journal of the American College of Cardiology 2002; 39(2): 202-209
12. Omland T; Aakvaag A; Bonarjee WS; Caidahl K; Lie RT; Nilsen DWT; Sundsfjord JA; Dickstein K Plasma brain natriuretic peptide as an indicator of left ventricular systolic function and long-term survival after acute myocardial infarction Circulation 1996; 93: 1963-1969
13. Ruck A; Gustaffson T; Norrborn J; Nowak J; Kallner G; Soderberg M; Sylven C; Drvota V ANP and BNP but not VEGF are regionally overexpressed in ischemic human myocardium Biochemical and Biophysical Research Communications 2004; 322: 287-291
14. Goetze JP; Gore A; Moller CH; Steinbruchel DA; Rehfeld JF; Nielsen LB Acute myocardial hypoxia increases BNP gene expression FASEB Journal 2004; 18(15): 1928-1930
15. Marumoto K; Hamada M; Hiwada K Increased secretion of atrial and brain natriuretic peptides during acute myocardial ischaemia induced by dynamic exercise in patients with angina pectoris Clinical Science 1995; 88: 551-556
16. Motwani JG; McAlpine H; Kennedy N; Struthers AD Plasma brain natriuretic peptide as an indicator for angiotensin-converting enzyme inhibition after myocardial infarction Lancet 1993; 341(8853): 1109-1113