hs-Troponins and the Chest Pain Guidelines: Experts Call for Clarification

Guidelines on the evaluation and diagnosis of stable chest pain put out last year by the American College of Cardiology and American Heart Association (ACC/AHA) may have endorsed the use of high-sensitivity cardiac troponin (hs-cTn) testing as the preferred biomarker, but a group of concerned physicians says the document is lacking detailed advice as to how to incorporate this assay in clinical practice.

In their paper, published online last week in Circulation, Yader Sandoval, MD (Mayo Clinic, Rochester, MN), and colleagues outline several analytical aspects of hs-cTn testing as well as issues with the commonly used thresholds for diagnosing myocardial injury, among other areas in need of clarification.

“This is an appraisal that is trying, without calling names or suggesting any degree of bad intentions, to point out that there were some major areas that really weren't as good as they could have been in these guidelines,” senior author Allan S. Jaffe, MD (Mayo Clinic), told TCTMD. “We felt that we should, in the interest of helping clinicians, point out some of these errors so that they would not be promulgated by clinicians who might be using these guidelines.”

Further, he continued, while more data are needed in areas such as hs-cTn testing in patients with type 2 MI as well as sex-specific 99th percentiles effect on outcomes, “there are other places where there is more than enough data and the data were either ignored or at times put in in a way that made it confusing at best and maybe even inaccurate.”

Taken as a whole, the guidelines do not offer guidance “that can be functionally operationalized in any way,” Jaffe said.

In response, writing committee chair Martha Gulati, MD (Cedars-Sinai Medical Center, Los Angeles, CA), told TCTMD that while she considers this paper “a good supplement,” guidelines in general “have to be practical and simple and understandable to everyone who reads them. And not everybody who reads our guidelines is a biomarker expert.”

She hopes that laboratories which process hs-cTn assays are aware of all the details discussed by Sandoval et al, but “that was too much information for us to put into the guidelines.”

What Level to Use?

For example, while the guidelines advocate for the use of single-sample rule out—ruling out MI in a patient with chest pain who has a very low level of troponins on admission—both the ACC/AHA and European Society of Cardiology guidelines suggest using a value below the limit of detection (LoD) of the assay. However, the US Food and Drug Administration prohibits clinical reporting below a slightly higher threshold called the level of quantification (LoQ).

“For many assays, the value that allows you to exclude MI is much higher than the limit of detection,” Jaffe explained. “So the idea that you have to use the limit of detection, which you can't do, and therefore making this suggestion unusable is really not only incorrect but misses the fact that for a large number of assays one can’t use values that are allowed to be reported by the FDA.”

He cited his recently published study that demonstrated that using a concentration of less than 6 ng/L—higher than the LoQ—in conjunction with a normal ECG was safe to rapidly triage patients without acute MI using the hs-cTnT assay.

Further, the authors point out that the guidelines don’t give enough recommendations for patients with both unstable angina as well as type 2 MI, which may outnumber type 1 MIs in the US.

“Unstable angina is diagnosed less frequently using hs-cTn assays, but the entity has not yet disappeared,” Sandoval and colleagues write. “Education on this fact would be helpful because it alerts clinicians that although hs-cTn assays are excellent in ruling out acute MI, unstable angina presentations and severe stable obstructive coronary artery disease still occur.”

As for risk stratification, the ACC/AHA guidelines suggest imaging for all patients deemed to be at intermediate risk. “Well, the reality is that you could get to be intermediate risk, for example, by having a high risk score . . . or you could be at intermediate risk because your troponin is elevated,” Jaffe said. “We would argue strongly that the latter is a situation which is much more associated with information that suggests markedly abnormal risk than the situation where the risk score pins somebody as intermediate.”

The problem with sending patients with normal or even low troponins for imaging is that it will only “delay the ability of people to move out of the emergency room,” he continued. “One of the best benefits of high-sensitivity assays has been the ability to rapidly triage people and move them out quickly, reducing overcrowding.” However, with a lack of “precision” in the guidelines about what to do for a patient considered intermediate risk solely by a risk score, “you actually might lose a lot of that,” Jaffe argued.

There are likely subsets of patients—perhaps those with an elevated troponins—who would benefit from imaging, he said, but these are fundamentally different from “the group that reaches that intermediate status by having a higher risk score but has totally normal troponins.”

Appropriate Metrics

Sandoval and colleagues also highlight the use of appropriate metrics for hs-cTn assays, which they claim are glossed over by the guidelines.

The guidelines do endorse use of the 99th percentile upper reference limit, but the authors point out that these thresholds have varied in many studies depending on patient selection. “Support by the guidelines for a consistent approach in this area would have helped the standardization of the 99th percentile upper reference limits,” they write.

The lack of advocacy for sex-specific cutoffs was also disappointing, Jaffe said. “It would have been good for them to have embraced the idea that men and women need different metrics. They sort of talked about it, but they never said it,” he said. “Many of us believe that that would improve care of women.”

Here, Gulati specifically agreed with Sandoval and colleagues, saying that the guidelines writing committee did debate this issue. “We felt like we at the time when we wrote these, we didn't have a lot of information in the United States yet,” she said. “When we started writing these guidelines, that's when troponins were being rolled out.”

Gulati said that, in her view, “we should have sex-specific cutoffs,” which is why she was happy to at least have a class 1b recommendation to acknowledge them. “We just know that a lot of places aren't doing it, and if we could just start communicating in one manner and we have solid evidence in the United States, perhaps it would be more endorsed,” she added.

Ultimately, “we're interested in helping clinicians get it right. Whether the guidelines [authors] choose . . . to update things that we point out might be done better is their decision, not ours,” Jaffe said. “What's really important is not whether they change or don't change, but that clinicians understand how to do this properly and how to implement these guidelines.”

Gulati acknowledged that if the guidelines are updated, “there's probably a few things I would take from this to add into our update.”

The paper was endorsed by the International Federation of Clinical Chemistry and Laboratory Medicine Committee on the Clinical Application of Cardiac Biomarkers, an entity focused in part on setting global standards for laboratory tests in collaboration with other international organizations.