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Three Part Question

In [Emergency Department patients with chest pain of suspected cardiac aetiology] does [measurement of serum myeloperoxidase on admission] allow [exclusion of acute coronary syndromes]?

Clinical Scenario

A fifty year-old man with no previous medical history presents to the Emergency Department with two hours of vague dull central chest pain. Initial ECG is normal. You arrange admission for troponin T testing at 12 hours but can't help thinking that there must be a better and quicker way to exclude acute coronary syndromes. A colleague tells you that myeloperoxidase (MPO) is set to make world headlines as a new definitive early cardiac marker.

Search Strategy

OVID Medline 1966 - June 2005
EMBASE 1974 - June 2005 via the Dialog Datastar Interface
The Cochrane Library 2005 Issue 2
OVID: [exp Myocardial Infarction/ OR exp Angina, Unstable/ OR unstable angina.mp. OR (myocard$ ADJ infarct$).mp. OR (myocard$ ADJ ischaem$).mp. OR (myocard$ ADJ ischem$).mp. OR acute coronary syndrome.mp. OR MI.mp. OR AMI.mp.] AND [myeloperoxidase.mp. OR MPO.mp.] limit to human and English language
EMBASE:
[exp heart-infarction/ OR exp acute-heart-infarction/ OR exp heart-muscle-ischemia/ OR exp ST-segment-elevation/ OR (heart ADJ attack).mp. OR (myocard$ ADJ infarct$).mp. OR MI.mp. OR AMI.mp. OR exp unstable-angina-pectoris/ OR (unstable ADJ angina).mp. OR (acute ADJ coronary ADJ syndrome).mp. OR (myocard$ ADJ ischaem$).mp. OR (myocard$ ADJ ischem$).mp. OR (acute ADJ coronary ADJ syndrome).mp.] AND [exp myeloperoxidase/ OR myeloperoxidase.mp. OR MPO.mp.] limit to human and English language
Cochrane: myeloperoxidase

Search Outcome

OVID: 52 papers were identified using the reported search, two of which were relevant to the three-part question.
EMBASE: 158 papers were identified, two of which were relevant to the three-part question.
Cochrane: 152 papers were identified, none of which were relevant to the three-part question.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
Baldus et al 2003 Germany	547 patients with available baseline blood samples, who had been enrolled in the CAPTURE trial with acute coronary syndrome (recurrent chest pain at rest associated with ECG changes during treatment with intravenous nitroglycerin and heparin). All patients underwent coronary angiography before randomisation, which demonstrated a stenosis >=70%, and subsequently underwent angioplasty. The CAPTURE trial had randomised patients to receive either abciximab or placebo. The abciximab group was excluded from this study as abciximab has been shown to interact with troponin T and sCD40L, both of which were also measured in this study. Blood had been taken 8.7+/- 4.9 hours after the last episode of chest pain. MPO results were split into tertiles for statistical analysis.	Retrospective observational cohort	Death or nonfatal myocardial infarction within 24 hours	Trend towards increasing MPO with increasing incidence of outcome (p=0.17).	Retrospective; abciximab group were excluded and this group had fewer cardiac events both before PTCA (p=0.07), after PTCA (p=0.001) and at 30 days (p=0.001). The study population is a very specific group. The results cannot be applied to patients with undifferentiated chest pain in the Emergency Department. Patients with high MPO were more likely to have had a history of previous coronary events (p=0.022 for infarction within 30 days of enrolment). The blood samples were apparently taken following coronary intstrumentation. This may have affected the results.
			Death or nonfatal myocardial infarction within 72 hours, 30 days and 6 months	Increasing incidence with rising MPO at all times (p<0.001 for all).
			Correlation of MPO with other cardiac markers	Poor correlation with troponin T (r=0.04) and CRP (r=0.02). However, MPO remained an independent predictor of outcome on multivariate analysis. In conjunction with troponin T, MPO identified 95% of all events.
Brennan et al 2003 USA	604 sequential patients presenting to ED within 24 hours of onset of chest pain of suspected cardiac origin. All patients had myeloperoxidase measured on admission, serial troponin T for 16 hours and were followed up at 30 days and 6 months.	Prospective observational cohort	Diagnosis of myocardial infarction	MPO higher in those with MI (p<0.001). Sensitivity for MI (if MPO result is above the first quartile) can be calculated to be 66%	Raw data were not adequately described, precluding meaningful calculation of sensitivities, specificities and likelihood ratios. The results are not clinically meaningful as it is not possible to calculate how many false negative and false positive diagnoses would result if myeloperoxidase was implemented in practice. There is no mention of patients lost to follow up. Although the data suggest that no patients were lost, it would be surprising if adequate follow-up data had been obtained for each of 604 sequential Emergency Department patients.
			Diagnosis of myocardial infarction or unstable angina	Higher incidence with increasing MPO (p<0.001 for trend). Sensitivity (if MPO above the first quartile) can be calculated to be 67%
			Major adverse cardiac event (MACE) or revascularisation within 30 days	MPO higher in those who had a MACE or required revascularisation (p<0.001). Sensitivity (MPO above first quartile) 67%
			MACE or revascularisation within 6 months	MPO higher in those who had a MACE or required revascularisation (p<0.001).
			MACE within 30 days for patients with negative troponin T	Sensitivity 63%. MPO higher in the group who went on to have a MACE (median 268pM (interquartile range 152-444) vs. 158pM (interquartile range 100-307), p<0.001). Among patients who were negative for troponin T, 22.3% still had a MACE within 30 days; however, with the addition of MPO measurement, this was significantly reduced to 14.8% (P<0.01).

Comment(s)

In recent years there has been growing recognition of the role played by inflammation in the aetiology of acute coronary syndromes. Neutrophils undergo degranulation in the coronary circulation in acute coronary syndromes (Buffon et al, 200) and release myeloperoxidase, which may be proatherogenic (Podrez et al, 2002) and may play a role in destabilising the atherosclerotic plaque preceding rupture (Fu et al, 2001). Early evidence suggests that myeloperoxidase may be a useful early marker of acute coronary syndromes, although further evidence is needed before it can be implemented into clinical practice. Interestingly, myeloperoxidase may identify a subgroup of patients who are troponin negative yet still at risk for adverse cardiac events in the near future. It may then be possible to target specific therapy at this group in order to prevent complications. The sensitivity of myeloperoxidase for detection of myocardial infarction or unstable angina was 67% in the study by Brennan et al. If this is a true figure, it is clearly not acceptable to institute MPO as an early rule out strategy for acute coronary syndromes in the Emergency Department. Incorporation of MPO into a multimarker strategy may have greater potential for future use in the Emergency Department.

Clinical Bottom Line

Myeloperoxidase appears to be insufficiently sensitive as a sole rule out strategy for acute coronary syndromes in the Emergency Department. However, more evidence from well-designed prospective cohort studies is required.

References

1. Baldus S; Heeschen C; Meinertz T; Zeiher AM; Eiserich JP; Munzel T; Simoons ML; Hamm MD; on behalf of the CAPTURE Investigators Myeloperoxidase serum level predicts risk in patients with acute coronary syndromes Circulation 2003; 108: 1440-1445
2. Brennan ML; Penn MS; Van Lente F; Nambi V; Shshehbor MH; Aviles RJ; Goormastic M; Pepoy ML; McErlean ES; Topol EJ; Nissen SE; Hazen SL Prognostic value of myeloperoxidase in patients with chest pain New England Journal of Medicine 2003; 349(17):1595-1604
3. Buffon A; Biasucci LM; Liuzzo G; D'Onofrio G; Crea F; Maseri A Widespread coronary inflammation in unstable angina New England Journal of Medicine 2002; 347(1): 5-12
4. Fu X; Kassim SY; Parks WC; Heinecke JW Hypochlorous acid oxygenates the cysteine switch domain of pro-matrilysin (MMP-7) Journal of Biological Chemistry 2001; 276(44): 41279-41287
5. Podrez EA; Poliakov E; Shen Z; Zhang R; Deng Y; Sun M; Finton PJ; Shan L; Febbraio M; Hajjar DP; Silverstein RL; Hoff HF; Salomon RG; Hazen SL A novel family of atherogenic oxidized phospholipids promotes macrophage foam cell formation via the scavenger receptor CD36 and is enriched in atherosclerotic lesions Journal of Biological Chemistry 2002; 277(41): 38517-38523