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Three Part Question

In [patients with suspected myocardial ischaemia] does [measurements of plasma soluble VCAM-1] enable [accurate exclusion of acute coronary syndromes]?

Clinical Scenario

A sixty year-old lady presents to the Emergency Department with a thirty minute history of intermittent resting central chest pain that seems likely to be ischaemic. Examination, baseline obserations and ECG are normal. You follow your department's rapid rule-out protocol, with serial CK-MBmass estimations and continuous ST segment monitoring for 6 hours. The lady completes the protocol and tests negative.
You feel rather uneasy about sending her home. As CK-MBmass is a marker of myocardial necrosis, you realise that you have excluded infarction but not necessarily unstable angina. You wonder if there are any novel markers that would help to identify the vulnerable patient, who is at high risk for adverse cardiac events in the near future. Hearing that VCAM-1 has such potential, you wonder if the evidence suggests that it is suitable for clinical implementation.

Search Strategy

OVID Medline 1966 - 2005 September Week 1
OVID Embase 1980 - 2005 Week 38
(exp Vascular Cell Adhesion Molecule-1 OR $VCAM$.mp. OR $V CAM$.mp.) AND (exp Myocardial Infarction/ OR exp Coronary Thrombosis/ OR exp Angina, Unstable/ OR exp Chest Pain/ OR ((myocard$ adj (infarct$ OR ischem$ OR ischaem$)).mp. OR (AMI OR MI OR ACS OR acute coronary syndrome OR heart attack).mp.) limit to human and English language

Search Outcome

Altogether 90 papers were identified using the reported Medline search and 162 using Embase. In total, three papers addressed were directly relevant to the three-part question. Additional papers that are also of relevance are discussed.

Relevant Paper(s)

Author, date and country	Patient group	Study type (level of evidence)	Outcomes	Key results	Study Weaknesses
O'Malley et al, 2001 2001 Scotland	241 men aged <65 years presenting to the Emergency Department with chest pain. Blood taken at presentation (mean 7.4 hours from symptom onset). Follow up at 30 days. VCAM-1 levels were compared to those of 82 (of 300 invited) healthy controls randomly selected from a general practice database.	Prospective observational cohort	VCAM levels on admission	UA 450+/-139ng/ml, AMI 450+/-138ng/ml, chest pain without evidence of IHD 426+/-126ng/ml, controls 426+/-126ng/ml. No significant differences between groups.	Only men included. Results may not be applicable to women, which would effectively preclude clinical implementation. The authors did not justify the exclusion of women. Imperfect gold standards for diagnosis: subjective criteria for diagnosis of UA, modified outdated WHO criteria for diagnosis of AMI. Multiple exclusion criteria but numbers excluded not stated. ROC curve analysis, sensitivities, specificities, PPV's and NPV's, which would enable evaluation of VCAM-1 as a diagnostic test, were not reported. Despite following patients up at 30 days, value of VCAM-1 levels for prediction of adverse events not reported.
Hillis et al 2002 United States	126 consecutive patients presenting to the Emergency Department with chest pain suspicious of myocardial ischaemia. Blood taken at presentation. 113 patients (89.7%) completed follow up at 3 months.	Prospective observational cohort	VCAM-1 for prediction of adverse events at 3 months	No significant correlation	No sample size calculation; relatively small numbers. The value of VCAM-1 for diagnosing ACS not evaluated.
Menown et al 2003 Ireland	195 patients (of 626 consecutive patients, 235 of whom had received anticoagulants and 196 had a positive TnI or CKMBmass) with ischaemic-type chest pain, who presented to either a mobile coronary care unit, Emergency Department or medical ward. Blood taken on admission for VCAM-1, TnI and CK-MBmass and at 12 hours for TnI and CK-MBmass. Follow up at 1 year.	Prospective observational cohort	CK-MBmass and TnI results	196/391 patients had either raised TnI or CK-MBmass (both raised in 36%, only TnI raised in 14%). Of those in whom both TnI and CK-MBmass were normal, 77/195 (39%) had an adverse cardiac event at follow up.	In total 69% of eligible patients were effectivley excluded from analysis, which is a considerable drawback. No sample size calculation. CI's were wide, even for the composite end-point; the study may be underpowered. VCAM-1 was not evaluated as a diagnostic marker of AMI or for prognostic stratification in AMI. VCAM-1 was measured in serum, whereas the majority of groups have reportedly measured VCAM-1 in plasma. This potential source of bias should be taken into account.
			VCAM-1 for prediction of adverse cardiac events	Non-significant trend to higher VCAM-1 in patients with death/MI (P=0.37). Using the 75th percentile of results as a cut-off, VCAM-1 did not predict adverse events (OR 0.3, 95% CI 0.04-2.6, P=0.27).

Comment(s)

The problem of suspected cardiac chest pain is a significant challenge for the Emergency physician, accounting for 2-4% of all attendances (Herren et al, 2001). As clinical features and ECG findings are insufficiently sensitive to enable immediate exclusion of ACS, biochemical markers are essential triage tools. Current gold standard biochemical markers are insufficiently sensitive to exclude ACS from an admission blood sample (Richell-Herren et al, 2000). In addition, troponin and CK-MBmass are markers of myocardial necrosis. Many patients without necrosis may have a vulnerable coronary atherosclerotic plaque and be at risk for cardiac events occurring in the near future. Interestingly, Menown et al (tabulated) reported that 39% of patients who tested negative for both CK-MBmass and TnI had an adverse cardiac event within one year. VCAM-1 is a cell adhesion molecule belonging to the immunoglobulin gene superfamily. Its presence is necessary for circulating leucocytes to migrate across the endothelium (Springer, 1994). In coronary atherosclerosis, the recruitment of leucocytes into atheroma leads to plaque expansion, secretion of procoagulant substances including tissue factor and destabilisation of the fibrous cap, rendering the plaque vulnerable to rupture or erosion. Upon plaque rupture, exposure of circulating blood to procoagulant contents of the lipid core of the plaque leads to activation of the coagulation system, thrombus formation and an acute coronary syndrome may ensue (Ross, 1999; Libby, 1995; Corti et al, 2004). Elevated levels of VCAM-1 are detectable in peripheral vascular disease and levels may correlate with disease severity (Peter et al, 1997; De Caterina et al, 1997; Blann et al, 2002). Unlike ICAM-1, VCAM-1 is not known to be elevated in stable angina (Morisaki et al, 1997; Oishi et al, 2000), nor can it be used to predict cardiac events in apparently healthy men (De Lemos et al, 2000; Luc et al, 2003). However, the detection of elevated levels of VCAM-1 in patients with stable angina may predict adverse events (Wallen et al, 1999). Levels of VCAM-1 in peripheral blood correlate with levels in the coronary circulation (Mulvihill et al, 2001). Several groups have demonstrated elevated VCAM-1 levels in ACS (Xie et al, 2000; Peng et al, 2002; Nomoto et al, 2003; Mulvihill et al, 1999; Guray et al, 2004; Zeitler et al, 1997; Parissis et al, 2004; Gurbel et al, 1998; Miza-Stec et al, 2002; Clausell et al, 1999). Levels have been shown to predict adverse events after admission for UA or NSTEMI (Mulvihill et al, 2001; Rallidis et al, 2003), survival following AMI (Zeitler et al, 1997), resistance to thrombolysis in AMI (Murphy et al, 2002) and LV dysfunction following AMI (Parissis et al, 2004). Other groups have reported conflicting results. Li et al found no difference in VCAM-1 levels between AMI and controls, although they measured serum and not plasma levels. Tekin et al (2005) found no difference between ACS and stable angina, although it is unclear whether they measured plasma or serum levels. Parker et al (2001) reported no difference in VCAM-1 levels between patients with ACS and stable angina, although the study included consecutive patients referred for cardiac catheterisation and took blood at the time of catheterisation. Other studies found no difference in VCAM-1 levels between patients with ACS and apparently non-cardiac chest pain but did not provide clinical follow-up data or completely exclude cardiac pain (Hope et al, 2002; Ghaisas et al, 1997). Although the balance of evidence suggests that VCAM-1 is probably elevated in the early stages of ACS, the evidence for its use in the Emergency Department is disappointing. Although they all had significant weaknesses, none of the three relevant papers identified a use for VCAM-1 in the Emergency Department. O'Malley et al failed to detect a significant difference in levels between UA, AMI and apparently non-cardiac chest pain. Hillis et al and Menown et al found that VCAM-1 did not predict adverse cardiac events at follow-up. No groups have investigated the sensitivity, specificity, PPV and NPV of VCAM-1 for the detection of ACS. However, the early evidence suggests that it is unlikely that VCAM-1 could be used for exclusion of ACS in the Emergency Department. As there is clearly a need for new early markers of ACS, future research is likely to investigate the value of incorporating promising cardiac markers into a multimarker strategy. VCAM-1 may have be potentially useful as part of such a strategy but other markers may be superior.

Editor Comment

Abbreviations: AMI: acute myocardial infarction; UA: unstable angina; ACS: acute coronary syndrome; CI: confidence interval; VCAM-1: vascular cell adhesion molecule-1; ICAM-1: intercellular adhesion molecule-1; PPV: positive predictive value; NPV: negative predictive value; LV: left ventricular

Clinical Bottom Line

VCAM-1 cannot be used to exclude ACS in the Emergency Department. There is the possibility that it may be useful if incorporated into a multimarker strategy but other markers may be superior.

Level of Evidence

Level 3 - Small numbers of small studies or great heterogeneity or very different population.

References

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