Editor’s Note: This article is in response to Keller T, Zeller T, Ojeda F, Tzikas S, Lillpopp L, Sinning C, et al. Serial Changes in Highly Sensitive Troponin I Assay and Early Diagnosis of Myocardial Infarction. JAMA. 2011; 28;306:2684-93.

Article Summary

The utility of highly sensitive troponin (hsTn) assays for evaluating patients with chest pain has been a subject of ongoing investigation. However, a number of issues remain. Is there an advantage of serial changes for diagnosis? Is there a utility of other biomarkers if hsTn is used? To address these questions, the authors evaluated the diagnostic performance of a hsTnI assay compared with a contemporary cTnI assay, the role of serial changes, and the added value of other biomarkers for the diagnosis of acute MI.

In this study, 1818 consecutive patients with suspected ACS, of whom 413 (23%) were diagnosed as having MI, underwent evaluation with 12 biomarkers which have been found to improve early diagnosis. These included hsTnI (level of detection, 3.4 pg/mL) and cTnI (level of detection, 10 pg/mL). All markers were measured on admission and at 3 and 6 hours. Among the additional markers studied were copeptin, fatty acid binding protein (HFABP), myeloperoxidase, GDF 15,and endothelial growth factor receptor-1 (sFLT-1).

For discrimination of MI at time of initial evaluation, the area under the receiver operating characteristic (ROC) curve was 0.96 for hsTnI and 0.92 for standard cTnI. Both were superior to all other biomarkers. hsTnI had higher diagnostic utility than cTnI in patients with chest pain onset <2 hours (AUC hsTnI vs cTnI 0.97 vs 0.89 (P < .001)). The use of hsTnI at admission (diagnostic cutoff value at the 99th percentile=30 pg/mL) compared to the standard cTnI had a sensitivity of 82% vs 79% and a negative predictive value (NPV) of 95% vs 94%. Sensitivity and NPV at 3 hours increased to 98% and 99.4% for both cTnI assays.

Other markers added little value to hsTnI. The AUC of hsTnI at presentation of 0.962 was increased to 0.968 (P = .01) with copeptin, to an AUC of 0.967 with H-FABP ( P = .02), and to 0.966 with sFLT-1 (P = .03). The 3 biomarkers improved the relative integrated discrimination improvement model based on hsTnI by 5.6%, 7.4%, and 4.0%, respectively (all P < .001).

The authors concluded that in patients with suspected ACS, hsTnI or cTnI determination at time of evaluation and 3 hours later accurately excludes MI. A serial change in hsTnI or cTnI levels from admission (using the 99th percentile diagnostic cutoff value) to 3 hours after admission accurately diagnosed AMI.

Discussion

The ability to rapidly and accurately identify patients who do and who do not have MI who present to the ED has been an ongoing goal for >20 years, leading to numerous investigations of a wide variety of different markers and marker combinations. During this time, the gold standard for identifying myocardial necrosis, cTn, has continued to evolve, with more sensitive assays being developed. The higher accuracy at lower levels of the newer assays offers the ability to improve early sensitivity for identifying patients with MI, and may negate the necessity of having other markers. In this regard, a study from Keller et al provides a wealth of useful information that can be summarized as follows:

1. Their results confirm prior ones, in that in a large number of patients (over 1800) they confirmed the early sensitivity of a hscTnI compared to a standard cTnI.
2. They found that serial changes over a time period of 3 hours was sufficient to exclude MI in the vast majority of patients, with a NPV of 99.4% (using either type of cTnI assay).
3. The advantage of hsTnI was primarily limited to early diagnosis, as by 3 hours, sensitivity, specificity, PPV and NPV were similar for the 2 assays.
4. Novel markers added little to hsTnI , with utility being primarily limited to early MI exclusion on the first sample.

In this well done study, the authors found that novel markers added only to the initial sample; even then the improvement when combined with the best performing marker, copeptin, was only from a NPV of 94% to 97%, with a net reclassification index of only 5.6%. Whether the loss in specificity that is likely to occur with the increased false positive rate is a reasonable compromise will remain to be seen. In addition, education around the different marker characteristics, particularly considering the addition of an hsTnI assay, will be required.

There are some limitations to consider. First, the population was relatively high risk, with 23% having MI, a rate 4-5x (or more) of the typical US low risk population. If used in a lower risk population, PPV is likely to decrease. They did not exclude patients with STEMI (13% of the MI patients), a population that should be excluded from marker studies, as initial triage and treatment is driven by the ECG and not markers. However, they did report no differences in the patients without STEMI. It would have been interesting to see if the novel markers added to the traditional cTnI assay.

In conclusion, in patients with suspected ACS, hsTnI or cTnI determination at time of evaluation and 3 hours later accurately excludes AMI. If a hsTnI assay is used, addition of novel markers has only a small additional benefit when combined at the time of presentation.

Keywords: Biomarkers, Troponin I, Early Diagnosis, Chest Pain, Fatty Acid-Binding Proteins, Growth Differentiation Factor 15, Myocardial Infarction, Receptors, Vascular Endothelial Growth Factor, Troponin

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