Rapid Rule-Out Strategy With High-Sensitivity Troponin Shows Promise Ahead of US Commercial Availability of Test

With questions swirling on how best to use a new high-sensitivity cardiac troponin T assay soon to be released in the United States, a new study suggests that a single blood draw and measurement in conjunction with ECG may be sufficient to rapidly rule out acute MI in up to 30% of patients and provide for earlier decision-making.

“The numbers of patients this affects is vast given the huge numbers who present to emergency departments and are investigated for possible acute coronary syndrome,” the study’s lead author, John W. Pickering, PhD (Christchurch Hospital, New Zealand), told TCTMD in an email.

Based on a meta-analysis that was inclusive for clinically and geographically diverse patients, Pickering and colleagues found that those who had no or very low levels of detectable cardiac troponin T on the high-sensitivity assay plus a nonischemic ECG had very low risk for acute MI or MACE within 30 days.

High-sensitivity assays for cardiac troponin have been available for years in multiple countries to help in diagnosing patients with suspected MI. In the United States, the first high-sensitivity or “new-generation” troponin assay received 501(k) clearance for use in January and is expected to be commercially available by the end of this month.

High Sensitivity for Death and MACE

For the collaborative meta-analysis, published online April 17, 2017, ahead of print in Annals of Internal Medicine, Pickering and colleagues examined 11 studies published between 2009 and 2016 that had a combined total of 9,241 participants from 10 countries. All presented to an emergency department for possible ACS and had available data for ECG and high-sensitivity troponin measurement. Principal investigators and lead authors of each study were contacted to provide additional data on the number of low-risk patients, and the number who had acute MI during hospitalization (primary outcome) or who experienced a MACE or death within 30 days (secondary outcomes). In seven of the 10 studies, a second blood draw occurred at least 6 hours after symptom onset.

Overall, 30.6% of the cohort—ranging from 3.8% to 73.5% across studies—had a troponin level less than 0.005 µg/L and were classified as being at low risk for acute MI. Among those classified as low risk, acute MI occurred in 0.5%.

Use of the assay plus ECG had a pooled sensitivity estimate of 98.7%, with sensitivities of the individual study cohorts ranging from 87.5% to 100%. Heterogeneity among cohorts was 90.3%. The pooled sensitivity estimate for MACE, which occurred in 21 patients, was 98.0%, with sensitivities in individual cohorts ranging from 87.9% to 100%. Of the 1.3% of patients who died within 30 days, none were in the low-risk group.

How Low Can You Go?

According to Pickering and colleagues, use of so-called undetectable levels on high-sensitivity troponin assays to rule out acute MI in patients with chest pain has been shown to be an effective method in other studies, including a registry study of nearly 9,000 patients that reported an acute MI rate of 0.17% at 30 days for patients with initial troponin concentrations less than 0.005 µg/L in combination with no signs of ischemia on ECG. The negative predictive value for MI in that study was 99.8%.

The authors also note that recent guidelines from the National Institute for Health and Care Excellence and the European Society of Cardiology include diagnostic pathways that begin with ruling out acute MI if the initial troponin is less than the limit of detection (< 0.005 µg/L) or the limit of “blank” (< 0.003 µg/L).

In an interview with TCTMD, James Januzzi Jr, MD (Massachusetts General Hospital, Boston), said identifying the lowest-risk patients and triaging them out of the emergency department is a worthwhile goal, but he added some caveats.

“What this study says is that you can exclude acute MI very quickly in a substantial percentage—about one in three—and even if they had a cardiac syndrome of some kind, their likelihood of having a complication is very, very low,” he said. “This is a reasonable strategy, recognizing that it is, by definition, attached to other ways of ruling out MI in patients who don’t meet criteria for low risk.”

But Januzzi said there is another issue pertinent to the United States. Although the assay has been approved in other countries with the full measuring range down to the level of blank, the US Food and Drug Administration (FDA) has approved the assay only down to 6 ng/L (0.006 µg/L).

“What this means is that the data, though interesting and compelling, would not be usable here in the United States because the marker is not approved for measuring down to that level,” Januzzi said. “Unfortunately, that 1 ng/L difference is going to make all the difference in the world for us in terms of the ability to use the assay in this way.”

Januzzi said the FDA chose to be conservative based on concerns about imprecision for numbers in the very low range, but added that “on the basis of the extent that we have abundant data pointing toward the value of this very low concentration measurement of high-sensitivity troponin T, the inability for us to measure down to this concentration needs to be reconsidered.” Otherwise, “you’re losing one of the great advantages of high-sensitivity troponin in that the ‘one-and-done’ approach could be applied in a high percentage of patients and that could shorten length of stay and speed triage decision-making.”

Piece of the Puzzle

“I think this is a piece of the puzzle,” said James de Lemos, MD (University of Texas Southwestern Medical Center, Dallas), in an interview with TCTMD. “The other piece is that in a substantial proportion of these patients, MI may be able to be ruled out in 1 or 2 hours with serial monitoring that shows persistent low measurements with minimal change between the two.”

But for de Lemos, the most important message is that when the high-sensitivity assay becomes available to US physicians, it should not be seen as a substitute for the current assay. “It’s only of value if it comes with the kind of process change that allows new protocols to be implemented in the [emergency department] to allow earlier discharge,” he noted.

Although practices regarding what to pair the assay with as part of a protocol “package” vary widely, Pickering and colleagues say recent guidelines have emphasized the possibility of combining ECG, high-sensitivity troponin, and some type of standardized risk score. “New Zealand has become the first country in the world to adopt such a strategy in every emergency department, with most using the EDACS risk assessment tool, and a few using the TIMI score,” Pickering noted.  

As for the United States, de Lemos said centers will likely choose their own options with regard to the risk assessment and monitoring strategies they use and, “over time, as has happened in Europe, things will harmonize and then hopefully there will be other assays, too, to provide flexibility.”

Januzzi added that his center is going live with an accelerated diagnostic protocol utilizing the HEART score along with high-sensitivity troponin and ECG “because we really feel this is the optimal approach for patient care.”