Sherrie Rice
June 2025—Patients who present to the ED with an elevated cardiac troponin above the 99th percentile and suspected acute coronary syndrome but in whom myocardial infarction is not diagnosed are at risk for future cardiac events. But how much risk?
Last fall, the Food and Drug Administration cleared Siemens Healthineers’ Atellica IM High-Sensitivity Troponin I assay for prognostic risk stratification, an expanded intended use claim. Now, with this newly cleared use, “novel information is created from traditional indications,” said Christopher deFilippi, MD, who was recently director of the Biocore research laboratory and vice chair of academic affairs, Inova Schar Heart and Vascular in Fairfax, Va., and is now, since June 1, at the University of Maryland.
He spoke in March with Alan H.B. Wu, PhD, D(ABCC), co-director of the core laboratory at Zuckerberg San Francisco General Hospital, in a CAP TODAY webinar on prognostic risk in cardiac patients using the Atellica high-sensitivity assay. (The webinar, sponsored by Siemens Healthineers, is online at https://bit.ly/CT_031925-WOD.)
“We can use it as an aid for prognosis to detect major adverse cardiac events,” Dr. Wu said of the Atellica assay. Those events are defined as urgent revascularization, myocardial infarction, heart failure hospitalization, or cardiac death.
The Atellica IM High-Sensitivity Troponin I assay is the first in the U.S. to include prognostic risk as part of an expanded intended use claim, which says the assay can be used as an aid in prognosis for 30-, 90-, 182-, and 365-day all-cause mortality and major adverse cardiac events in patients who present with signs and symptoms suggestive of ACS.
Nine of 10 patients who present to the ED with chest pain are not diagnosed with acute myocardial infarction, according to American Heart Association data, leaving only 10 percent of such patients diagnosed with AMI.
“Most of the time you’re ruling out, and that puts a lot of stress on assays that have high-sensitivity because you don’t want to miss anyone,” Dr. Wu said.
He described the first-generation cardiac troponin assay as “woefully insensitive and not much better than our previous standby, CK-MB.” And to those who are still using the second-generation troponin assays, he says: “You are providing a substandard performance because today everybody needs to be using a high-sensitivity troponin assay.” The reason: “We can now measure troponin reliably in healthy individuals, which was not possible with the two previous generation assays.”
The International Federation of Clinical Chemistry and Laboratory Medicine decided that high-sensitivity refers to an assay’s performance characteristics such that the 99th percentile has a coefficient of variation of less than or equal to 10 percent and that measurable troponins must exceed the limit of detection for the assay for at least 50 percent of healthy individuals. “It is a challenge for some so-called high-sensitivity assays to measure healthy individuals among women in particular with this target of 50 percent,” Dr. Wu said, noting the slightly lower troponin levels of women than men.
A study performed on samples collected from healthy people who attended the AACC (now ADLM) meeting several years ago found varying degrees of assay sensitivity in this healthy population. With the Siemens Healthineers Atellica assay, 59 percent of women had measurable concentrations above the limit of detection and below the 99th percentile. “The other assays, including high-sensitivity troponin T, fall short of the 50 percent mark,” Dr. Wu said.
The Atellica assay has a 10-minute turnaround time—“as fast as any central laboratory assay for high-sensitivity”—and “minimal impact from common interference,” he said. The 99th percentile cutoffs are 34.11 ng/L (women) and 53.48 ng/L (men). “Some labs have chosen to use a combined cutoff,” one that’s user-defined, he said. For the Atellica assay, it’s 45.20 ng/L.
Dr. Wu is coauthor of a soon-to-be-published prospective study of about 1,800 patients who presented to the ED with signs and symptoms suggestive of ACS. They were divided into three subpopulations and followed up for 30-, 90-, 182-, and 365-day progression to all-cause mortality and MACE.
Population No. 1 is the entire population, excluding subjects with adjudicated AMI. At every time interval, the patients in this population who tested greater than the 99th percentile had a 39.5 percent post-test risk of all-cause mortality/MACE within one year (subjects with levels below the 99th percentile: 12.9 percent post-test risk within one year).
Population No. 2 is the entire population, excluding not only the subjects with adjudicated AMI but also a history of incident or prior MACE. In this group, those who tested greater than the 99th percentile had a 15.1 percent post-test risk of ACM/MACE within one year. “It’s not 39 percent at one year; it’s 15 percent. So that’s the good news,” Dr. Wu said. In the absence of a history of prior myocardial events and no AMI at the present time, “your risk for developing adverse events is lower but not zero.”
There is separation between subjects who have a normal, less than 99th percentile baseline level—4.4 percent at one year—versus the 15.1 percent who have an elevated troponin, he added. “For the first time, we have FDA clearance to identify these individuals and to hopefully mitigate their risks moving forward.” Already known is how to mitigate risk for patients with AMI. “Now we can do the same with patients who have no history of AMI and no history of any prior cardiac event,” Dr. Wu said.
Population No. 3 is the entire population, excluding those with AMI and including patients with a history of incident or prior MACE. Here, those who tested greater than the 99th percentile had a 48.9 percent post-test risk of a cardiac event/death within one year (subjects with levels below the 99th percentile: 26.1 percent post-test risk). “Now we are jumping up in terms of adverse cardiac risk—50 percent, not 40 percent,” Dr. Wu said. “These are people who are going to have trouble if we don’t intervene. So this test allows us to determine who’s going to be at greatest risk.”
Dr. deFilippi has long been interested in the prognosis for those who are not experiencing acute coronary syndromes.
(At the University of Maryland, he is professor of medicine and pathology, co-director of the clinical chemistry research laboratory, and director of cardiovascular and biomarker research for the university’s Institute for Health Computing.) His take on the newly cleared claim: “I think it’s going to do a lot in the field.”
“Siemens, by including this prognostic claim, is going to raise awareness for its troponin assay and probably all troponin assays that individuals who are not having myocardial infarctions but have an elevated troponin above the 99th percentile presenting to the emergency department are in fact at risk for major adverse cardiovascular events.”
Identifying these people is important, he said, whether their further workup takes place in the hospital setting in the same encounter or in the near term.
“What Siemens has done by obtaining this FDA claim is rigorously evaluate the information from its own study,” Dr. deFilippi said, citing another such study from 2019.
In that retrospective registry-based cohort study (Eggers KM, et al. J Am Coll Cardiol. 2019;73[1]:1–9), the authors investigated the associations of cardiac troponin levels with clinical findings and long-term outcomes in acutely evaluated patients with suspected ACS who had been discharged without a specified diagnosis. They concluded: “cTn elevation is associated with cardiovascular and noncardiovascular comorbidities and predicts major adverse events” in these patients, in whom no definitive acute cardiovascular diagnosis was established. A subsequent cardiovascular workup is often required in these patients, they added.
In this study, the 48,872 ED patients evaluated in Sweden did not have an AMI. However, a cardiac troponin level greater than the 99th percentile was noted in 9,800 patients. In total, 7,529 of the 48,872 patients (15.4 percent) had a major adverse event, defined as the composite of all-cause mortality, MI, readmission for heart failure, or stroke (median follow-up 4.9 years). The risk for such events was significantly higher in those with a high-sensitivity cardiac troponin value greater than the 99th percentile, ranging from 1.3- to 2.6-fold higher than for those with levels below the 99th percentile based on progressively higher hs-cTn values when first seen in the ED despite the absence of an initial MI diagnosis. “Higher cTn levels were associated with constantly increasing MAE rates during long-term follow-up,” the authors wrote.
In response to listeners’ questions, the following points were made:
- The laboratory provides results but typically no interpretive comments about risk stratification. “But it is our responsibility,” Dr. Wu said, “to educate our providers and other medical staff about the availability of this testing and that it is cleared for risk stratification use.” Dr. deFilippi said awareness of the test’s prognostic claim in tertiary and quaternary hospitals is likely already reasonable or high, “though defining it more carefully is important.” He notes the variation in how closely physicians, even cardiologists or emergency physicians, follow the troponin literature, and thus advises disseminating the new information outside the literature as well. “For many hospitals, I think this is going to be new information or at least reinforcing information,” that the at-risk patients need not remain in the hospital, Dr. deFilippi said, “but they do need follow-up over the next couple of weeks and probably additional diagnostic testing with imaging.”
- For risk stratification, delta values are not important, Drs. Wu and deFilippi note, because the prognostic claim is not related to change but instead to the elevation of a single value above the 99th percentile with the exclusion of AMI.
- Melanie Pollan, PhD, senior director of medical and scientific affairs for lab diagnostics, Siemens Healthineers, said in the webinar that serum or heparinized plasma can be used for testing. “Use the same one throughout your serial collection protocol,” she advised.
- In adopting a high-sensitivity cardiac troponin assay, the laboratory at San Francisco General followed the model of a colleague, James de Lemos, MD, chief of the Division of Cardiology at UT Southwestern Medical Center. Said Dr. Wu: “We have a zero-, one-, and three-hour rule-out protocol. The delta cutoffs would be a bit different because the testing frequency is a bit faster. This puts tremendous stress on the laboratory to get a result of the baseline value within one hour.” For that, he added, the Atellica assay’s 10-minute TAT is helpful. The conversion to a high-sensitivity assay at Inova Schar Heart and Vascular took place in late 2022, and there they went with a zero/two-hour protocol, not zero/one, because of turnaround time. “We were going from a zero/six on the traditional assay, so that was still light speed in our minds,” Dr. deFilippi said. For patients who fall into an intermediate zone (with an elevated value), typically an additional test will be performed between three and six hours.
- The new ability to risk stratify with cardiac troponin testing, Dr. Pollan said, “gives us the opportunity to use this test for the 90 percent of people who are getting it and did not have a heart attack. That sets a good direction for the future, for the utility of the assay and for the treatment of patients.”
Sherrie Rice is editor of CAP TODAY.