Brain natriuretic peptide as a potential marker of acute coronary syndromes

Brain natriuretic peptide as a potential marker of acute coronary syndromes

Report by Richard Body, Clinical Research Fellow

Checked by Catherine Roberts, SHO, Emergency Medicine Rotation

Manchester Royal Infirmary

Abstract

A short cut review was carried out to establish whether brain natriuretic peptide (BNP) can be used as a marker for acute coronary syndromes. 685 citations were found, of which eight presented the best evidence to answer the clinical question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses of these best papers are tabulated. The clinical bottom line is that BNP shows promise as an early cardiac marker and may enhance prognostic stratification. NPV and PPV may be unacceptably low to enable use as a sole cardiac marker. Incorporation into a multimarker strategy and serial estimations may be necessary.

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 60 year old lady presents with a 30 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 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, and 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 identified 294 papers, of which eight were relevant. Embase identified 354 papers, of which eight were relevant. Cochrane identified 37 papers, of which one was relevant. Altogether eight relevant papers were identified (see table 3). Papers investigating the value of N‐terminal‐pro‐BNP were excluded but a separate review has been undertaken.

Table 3.

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study weaknesses
Mukoyama et al, 1991, Japan	13 consecutive patients with AMI <12 hours from symptom onset.	Prospective diagnostic cohort	BNP levels	Rose after AMI (within “hours” of onset of AMI).	Small numbers
	Blood samples at enrollment and every 4–24 hours over 4 days.		Correlation of BNP with PCWP and CIn	No correlation with PCWP. Highly correlated inversely with CIn (r = −0.81, P<0.01).	Subopimal reporting of results. Little statistical analysis. Meaningful conclusions cannot be drawn about the value of BNP as a diagnostic test.
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.	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
			BNP levels at follow up	Significantly elevated in AMI patients at 14 days; still “abnormally elevated” at 4 weeks (no P values).	Method of identification of normal subjects not described.
	Blood taken on admission and serially on days 3, 7, 14 and 28		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).	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.
Morita et al, 1993, Japan	50 consecutive patients with AMI within 8 hours of symptom onset. 30 age‐ and sex‐matched controls.	Prospective diagnostic cohort	BNP level on admission	Significantly increased with AMI v. controls (92+/−28 v. 5.2+/−0.5 pg/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
	Blood taken on admission. All patients had coronary angiography on admission. 10 had intracoronary thrombolysis, 11 had IV thrombolysis; 26 had PTCA.		BNP levels at four weeks	Still significantly higher in MI group than controls (149+/−47 v. 5.2+/−0.5 pg/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).	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.
			BNP levels according to ST elevation or depression	No significant difference
	Blood taken within 24 hours of last attack in UA group.		BNP levels following treatment	BNP decreased significantly (P<0.01) in UA group but not SA group.	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).
			Regional wall motion abnormalities on echocardiography	Significantly higher BNP if +ve for this outcome (P<0.01).
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.	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.
			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	ACS had already been ruled in for this patient group at time of inclusion (by ECG or cardiac marker testing).
	Blood sent at a mean of 40+/−20 hours from symptom onset.		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.	Inadequate reporting of data to allow calculation of sensitivities, specificities, PPVs, NPVs or likelihood ratios.
			Value of a BNP cutoff of 80 pg/ml as an independent predictor of mortality (adjusted)	BNP remain significantly associated with increased 10‐month mortality (P = 0.04).
Morrow et al, 2003, USA	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.	Nested prospective observational cohort	Elevated plasma BNP in UA (>80 pg/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).
	Blood taken “at enrolment”. Follow‐up at 6 months.		Elevated plasma BNP in NSTEMI (>80 pg/ml)	Raised in 25.2% [i.e. sensitivity 25.2%] (n = 153)	Insufficient data reported to allow calculation of specificities, PPV's, NPV's or LR's.
			Death at 30 days (BNP cut‐off 80 pg/ml)	5.0% raised v. 1.2% not raised (P<0.0001). Calculated sensitivity 80.6%.
			Death at 6 months (BNP cut‐off 80 pg/ml)	8.4% raised v. 1.8% not raised (P<0.0001). Calculated sensitivity 82%.
			Death at 7 days (BNP cut‐off 80 pg/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).
Mega et al, 2004, USA	438 eligible (of 483) patients enrolled in the ENTIRE‐TIMI 23 trial (full v. half dose thrombolysis + abciximab and LMWH or heparin in STEMI <6 hours). 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>80 pg/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>80 pg/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>80 pg/ml (8.7% v. 3.3%, p = 0.09).
			New or worsening CHF at 30 days (calculated)	BNP>80 pg/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).
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.	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.
			Diagnostic accuracy of BNP for MI (optimal 100 pg/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
	Follow‐up through in‐patient stay.		Logistic regression model for association with MI	BNP an independent predictor for diagnosis of MI (P = 0.0026).	No firm diagnosis in 202 (32%) patients (MI excluded but not UA).
			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 100 pg/ml), 3 MI's would be missed.

AMI, acute myocardial infarction; CCU, coronary care unit; PTCA, per cutaneous coronary angioplasty; IV, intravenous; UA, unstable angina; BNP, brain natriuretic peptide; PCWP, pulmonary capillary wedge pressure; MI, myocardial infarction; SA, stable angina

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 provides 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 post‐test 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).

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 stratcgy is likely to be necessary. Serial estimations may enhance clinical utility.