JAMA Feature: More sensitive troponin test IDs more at risk of MI

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Double immunostaining of transplanted cells. Cardiac troponin T (red) and GFP (green) are overlapped on one CM of three in this field (arrow).
Image source: Proceedings of the National Academy of Science 
In patients with suspected acute coronary syndrome (ACS), implementation of a sensitive troponin assay increased the diagnosis of MI and identified patients at high risk of recurrent MI and death in the following year, according to a study in the March 23/30 issue of the Journal of the American Medical Association. However, one researcher expresses caution about lowering the troponin threshold for MI.

Recent reports have indicated that the latest tests for improving the sensitivity for detecting troponin can increase diagnostic performance and improve the early diagnosis of MI.

"Lowering the threshold for detecting cardiac troponin is a highly controversial issue among clinicians with cardiologists, physicians and clinical biochemists uncertain as to whether the benefits of small improvements in sensitivity will outweigh the problems that may arise as a result of reduced specificity. Furthermore, whether lowering the threshold for detection of plasma troponin improves clinical outcomes in patients with suspected ACS is unknown," the authors wrote.

To help determine whether a more sensitive troponin assay could be prognostic in terms of MI and death, Nicholas L. Mills, MD, PhD, of the University of Edinburgh, Scotland, and colleagues evaluated 2,092 patients with suspected ACS.

The study was divided into two phases: validation and implementation. Although plasma troponin I was measured using a reformulated sensitive assay throughout both phases, only concentrations above the original diagnostic threshold (0.20 ng/mL or greater) were reported in the validation phase, and concentrations above the revised diagnostic threshold (0.05 ng/mL or greater) were reported during the implementation phase.

Patients were stratified into three groups (less than 0.05 ng/ml, 0.05-0.19 ng/mL, and 0.20 ng/mL or greater). Of the 2,092 patients, 64 percent had troponin concentrations of less than 0.05 ng/mL, 8 percent had concentrations of 0.05 to 0.19 ng/mL, and 28 percent had concentrations of 0.20 ng/mL or more.

During the validation phase, at 12 months, a greater proportion of patients with troponin concentrations of 0.05 to 0.19 ng/mL had died or been readmitted with an MI (39 percent) compared with those with troponin concentrations of less than 0.05 ng/mL (7 percent) or 0.20 ng/mL or more (24 percent).

The researchers said, however, that in the validation phase, patients admitted with troponin concentrations of 0.05 to 0.19 ng/mL were less likely to be referred to a cardiologist (44 vs. 93 percent), receive dual-antiplatelet therapy (27 vs. 80 percent) or undergo coronary revascularization (17 vs. 59 percent) compared with those patients with troponin concentrations of 0.20 ng/mL or more. They say that this lack of treatment in the validation phase could be the reason for the larger numbers of death and MI in the implementation phase.

James de Lemos, MD, director of the coronary care unit at Parkland Memorial Hospital in Dallas, who was not involved in the study, disagrees with this reasoning. "It's a stretch to say the lack of treatment in the validation phase led to the increase in detection in the implementation phase, as the difference in outcomes between the validation and implementation phases is implausibly large," he told Cardiovascular Business News.

In order for 0.05 ng/mL to be a valid cut-off point, Mills and colleagues "would need to look at levels between 0.01 and 0.05 ng/mL to address whether even lower levels are prognostic," de Lemos said. "The researchers combined all patients with less than 0.05 ng/mL as 'negative,' even though most clinicians would call anything above the 99th percentile—0.01—elevated."

During the implementation phase of the study, lowering the diagnostic threshold to 0.05 ng/mL was associated with a lower risk of death and recurrent MI (from 39 to 21 percent) in patients with troponin concentrations of 0.05 to 0.19 ng/mL.

Mills and colleagues concluded, "In patients presenting with suspected ACS, the use of a sensitive troponin I assay increased the detection of MI by 29 percent and identified patients who were at the highest risk of recurrent MI and death. Implementation of this assay and the diagnostic reclassification of these patients was associated with improved clinical management, fewer deaths and fewer admissions with recurrent MI."

They noted that continuing to lower the threshold of troponin assay concentration to define increasing numbers of patients with MI may be questioned, which could increase false positives.

"Our study supports the contention that this is not the case, rather the concern relates to the potential for misclassification of high-risk patients through the use of outdated diagnostic thresholds," the researchers wrote. "The next generation of assays may define progressively lower thresholds for detection of plasma troponin that ultimately may lead to the definition of a normal reference range. These assays are necessary to assess whether further reductions in the diagnostic threshold are indicated."

"This study tests differences between an obsolete troponin assay and a contemporary one and does not evaluate newer highly sensitive troponin assays that have recently been the focus of a number of research studies," de Lemos said.

"It seems obvious that an assay as insensitive as the one the authors were previously using would perform poorly and misclassify individuals with actual MIs. However, it is less clear that continued movement toward even greater sensitivity will improve care of patients with chest pain," he added.

"In the U.S., the typical 'rule out MI' patient that is admitted to a low-risk observation unit has a probability of 'ruling in' for MI well below 5 percent. This contrasts sharply with the MI rate in this study of greater than 30 percent. Thus, in a typical chest pain observation unit, the balance of false-positive vs. true-positive diagnoses may be quite unfavorable with highly sensitive assays," de Lemos said. "In the end, it is certainly reasonable to upgrade to contemporary troponin assays and to define MI at the 99th percentile cut-point from a normal population. However, whether even more sensitive assays will improve care in the ER or cause confusion remains to be seen."