Impact of soluble fms-like tyrosine kinase-1 and placental growth factor serum levels for risk stratification and early diagnosis in patients with suspected acute myocardial infarction. Hochholzer W, Reichlin T, Stelzig C, et al. Eur Heart J. 2010 Dec 7. [Epub ahead of print]

Cardiac troponin (cTn) is the gold standard for risk stratification and diagnosis of emergency department (ED) chest pain patients due to its high sensitivity, specificity and important prognostic information. However, as a result of its limited early sensitivity, a large proportion of patients with suspected acute myocardial infarction (AMI) require further monitoring and testing until AMI can be excluded. Thus, novel biomarkers that can improve early diagnosis would be useful.

Two such markers were studied in the current study: placental growth factor (PlGF) and soluble Flt-1 (sFlt-1). Both are angiogenic factors that appear important in the development and progression of atherosclerosis, and also seem to be involved in the pathogenesis of AMI. PlGF is a platelet-derived protein that appears to promote the inflammatory process of atherosclerosis. In patients with acute coronary syndrome (ACS), PlGF is increased regardless of the cardiac troponin concentration. Vascular endothelial growth factor receptor-1, known as Flt-1, is expressed on endothelial cells and macrophages. sFlt-1 is a potential endogenous antagonist of PlGF that can capture PlGF, reducing the amount available to bind to the receptor located on macrophages and endothelial cells. Because both sFlt-1 and PlGF have been demonstrated to increase with AMI, they represent potentially useful biomarkers for early MI diagnosis.

Both markers were studied in the Advantageous Predictors of Acute Coronary Syndrome Evaluation trial, a prospective, observational multicenter study of patients presenting to the ED with possible ACS. Levels of sFlt-1 and PlGF were compared to TnT, and a novel high-sensitive troponin (hsTnT) assay for early diagnosis of MI. In addition, both were assessed for their ability to predict one-year mortality against TnT, hsTnT and N-terminal pro-B-type natriuretic peptide (NT-proBNP).

MI was diagnosed in 132 of the 763 patients (17%) included. For diagnosing MI, the area under the curve for sFlt-1 (0.70) and PlGF (0.60) was low, and suboptimal compared to TnT (0.88). The combination of troponin T and sFlt-1 improved the performance of TnT alone and led to a negative predictive value of 98.3% at time of presentation. However, if hsTnT was used, sFlt-1 and PlGF non-significantly improved early diagnosis.
For prognosis, the novel markers performed a little better. A sFlt-1 >84 ng/L [hazard ratios (HR) 2.6, 95% confidence intervals (CI) 1.2–5.4, P=0.01] and PlGF >20 ng/L (HR 3.6, 95% CI 1.3–10.4, P=0.02) predicted one-year mortality, independent from TnT and NT-proBNP, although when hsTnT was included, only sFlt-1 persisted as independent predictor for mortality.

The authors concluded that sFlt-1 but not PlGF provided independent prognostic information in patients presenting with symptoms suggestive of AMI. If hsTnT was used instead of TnT, sFlt-1 and PlGF added limited diagnostic information for the detection or exclusion of AMI.

Discussion

This study brings up a number of important considerations when new markers are evaluated for identifying high risk ED chest pain patients. How does this study do when compared to standards?

1. For most markers, the trade-off for having a high sensitivity and negative predictive value (NPV) is a low specificity and positive predictive value (PPV). Frequently this trade-off is substantial.
2. Most studies evaluating new biomarkers are performed in a high risk population, so that this trade-off may not be immediately evident. When used in a lower risk population, the false positives often substantially outnumber the true positives, negating any advantage of the marker from the increased diagnostic confusion.
3. Any new maker should be evaluated in context of markers currently used. If it does not add value, then it is unlikely to be adopted, especially in the current more cost conscious era.
4. For early diagnosis of MI, the new standard has now become a very high sensitive troponin assay. The addition of the new Tn assays has substantially upped the ante, making it increasingly difficult for any new marker to beat it without a significant cost in specificity.
5. The choice of diagnostic value for troponin has frequently been inappropriately high, falsely improving the diagnostic accuracy of a new assay. Further, use of relatively insensitive troponins further “stacked the deck,” making it easier to demonstrate overall efficacy of a new biomarker.
6. The goals of a new marker are usually twofold: to rapidly diagnosis MI, and to predict cardiac outcomes, both short and long term. Frequently, a marker will meet one but not both of these objectives. For example, many new markers have incremental prognostic power, but few have been able to improve early sensitivity for MI.

How do sFlt-1 and PIGF do against these metrics? A limitation was that the study population was relatively high risk, with an MI rate of 17%, more than twice United States ED chest pain populations. Additionally, patients with ST elevation were not excluded, a group in whom markers are not used for early diagnosis. These two factors will inflate the diagnostic value of the new biomarkers. Strengths included the comparator used: TnT, is a standard, well validated troponin assay, and the diagnostic value was consistent with current guidelines. For prognosis, both TnT and NT-proBNP, two established markers, were used as comparators.

When compared to TnT, neither added significant diagnostic value for early detection of MI; Although the NPV was not unreasonable at 88-90%, PPV was low at only 14-27%. One point not brought out is that although hsTnT is likely to be the new diagnostic standard, it is not necessarily a panacea for diagnosis, as its higher earlier sensitivity came at a cost of a reduction in PPV from 66% to 34%. These two markers did perform better as prognostic markers, although only sFlt-1 was significant in a multivariate analysis.

What the current study demonstrates is that for diagnosis, troponin will be a very hard standard to beat; for mortality, troponin and NT-proBNP are also a high benchmark that will be difficult to improve on.

A final limitation of this study is the use of death as the only long-term outcome event. Although predicting death is an important goal, the information gained does not provide us a means of altering the outcome. The ultimate goal of any new marker is to allow us to target therapy appropriately, rather than treating everyone with everything. We have had some small successes in that direction (eg, selective use of glycoprotein IIb/IIIa antagonists in Tn (+) patients, therapy targeted towards reductions in natriuretic peptides [although not a consistent finding]). To reach this point, trials, that identify specific treatments that reduce a marker, and demonstrate that the reduction in a marker is correlated with improved outcomes, are needed. Hopefully, ongoing trials will be more successful than the current one.

Keywords: Acute Coronary Syndrome, Angiogenesis Inducing Agents, Atherosclerosis, Biomarkers, Blood Platelets, Chest Pain, Myocardial Infarction, Pregnancy Proteins, Troponin, Vascular Endothelial Growth Factor A, Vascular Endothelial Growth Factor Receptor-1

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