Studying laboratory measures of circulating cardiac troponin (cTn), a protein released from myocardial injury, for years has been the standard of practice for diagnosing heart attack, as well as stratifying risk among patients presenting with acute coronary syndrome (Clin Chem 2017;63:73-81). High-sensitivity assays to detect cTn (hs-cTn), cleared by the Food and Drug Administration just in the past few years, have been gaining favor among some cardiologists and labs to further stratify patients’ risk of poor cardiac outcomes, even those with stable disease. These assays have opened a management window on individuals with mildly elevated levels well below the 99th percentile that signals myocardial infarction (MI), causing some debate as to whether such patients might benefit from more aggressive interventions.

“We know that many individuals have measurable levels of troponin in day-to-day living, and that the higher the value is, the worse they do with regard to cardiovascular complications,” said James de Lemos, MD, a professor of cardiology at the University of Texas Southwestern Medical Center in Dallas. “But what’s been missing largely is the clinical context—what do you do with that information?”

What to do differently among these patients, and how to ameliorate their risk, remains “the $64,000 question,” added Fred Apple, PhD, DABCC, medical director of clinical laboratories at Hennepin Healthcare, and professor of laboratory medicine and pathology at the University of Minnesota in Minneapolis.

Emerging and Reinforcing Evidence

One recent study adds a possible twist to the ongoing dialogue (JAMA Cardiol 2020;5:1255-62). Researchers at Brigham and Women’s Hospital in Boston investigated how hs-cTn I measurements would impact risk classification of patients with atherosclerotic cardiovascular disease (ASCVD) from the prior PEGASUS-TIMI 54 trial (N Engl J Med 2015;372:1791-800).

In the newer study, the investigators first assigned patients to groups of very high-risk ASCVD or lower-risk ASCVD based on their cardiovascular history and comorbidities, in line with the 2018 American Heart Association (AHA)/American College of Cardiology (ACC) cholesterol management guidelines criteria (J Am Coll Cardiol 2019;73:e285-350). The researchers further stratified the 8,635 study participants by hs-cTn I level with Abbott’s ARCHITECT assay, using cut points of 2 ng/L (the assay’s limit of detection) and 6 ng/L (a proposed risk threshold). All patients had had an MI 1 to 3 years before study enrollment, were at least 50 years old, and had at least one high-risk feature.

When patients in the very high-risk ASCVD group were further risk stratified by hs-cTn I level, 9% with levels below the assay’s limit of detection had a 3-year event rate of 2.7%, less than the overall rate in the lower-risk ASCVD group. Conversely, 22.6% of those in the lower-risk ASCVD group with an hs-cTn I level exceeding 6 ng/L had an event rate of 9.1%, comparable to the overall rate in the very high-risk ASCVD group. In total, the use of hs-cTn I measurements reclassified about 12% of patients, said lead study author Nicholas Marston, MD, MPH, a cardiologist at Brigham and Women’s Hospital.

“Most notably, it upclassified one in four patients in the lower-risk ASCVD group into the very high-risk ASCVD group,” he said. “So that’s potentially 25% of these lower-risk patients who could or should be getting more aggressive therapies. It adds a clinical application that could provide value in helping manage patients.”

The data are showing that cTn “is a powerful risk-stratifying tool, independent of everything else going on there,” Apple said. “That’s been shown for years now, so this is just another rendition of how troponin independently predicts risk.”

A New Strategy—Perhaps

An accompanying editorial suggested that cTn levels should not just be viewed as a marker for myocardial injury but also used more frequently for assessing CVD risk in stable patients with heart disease (JAMA Cardiol 2020;5:1263-4). In this way, reclassified individuals potentially could receive more intensive statin therapy or start taking potent PCSK9 inhibitors. Marston said he and his colleagues already monitor patients’ cTn levels to help guide their management decisions. Apple said he totally agrees with this approach, and he could see where cTn could be monitored as commonly as cholesterol.

de Lemos, admittedly an early adopter, said he also thinks it’s a reasonable strategy that can provide further information on when to be more aggressive with additional therapies in patients with established disease. The readings could be even more beneficial in people who don’t have diagnosed CVD, he said.

But others are more cautious.

“I think it’s premature to say that we would do this routinely,” said Donald Lloyd-Jones, MD, professor of preventive medicine, cardiology, and pediatrics and chair of preventive medicine at Northwestern University Feinberg School of Medicine in Chicago. While the Boston study does shuffle the deck a bit, he would do something different for a fairly small number of patients.

Drilling down on the numbers, the lower-risk group was roughly 20% of the total population from this trial, explained Lloyd-Jones, who also coauthored the 2018 AHA/ACC guidelines and is president-elect of AHA. About one in four of those patients fell in the high cTn group, who would be reclassified upwards.

“In this particular study, it was only about 5% of patients where I would do something different by knowing their troponin level,” he said. “It’s an important 5%, but it’s only 5%. On the flip side, I would not decrease the intensity of therapy for the large group (80%) of higher risk patients just because their troponin is low today. While these data are interesting and point the way to how we might use these biomarkers for the future, I think we need to get a little bit better at figuring out who we need to do this testing on, because I’m not sure running this on everybody all the time is going to be a very cost-effective strategy.”

Several caveats would need to be considered before implementing this type of testing wide-scale, cautioned Allan S. Jaffe, MD, chair of the division of clinical core laboratory services and a consultant in cardiovascular medicine at the Mayo Clinic in Rochester, Minnesota. “As you get way down into low laboratory values, where you have a more diverse group who may or may not have underlying cardiovascular disease, some of these patients will end up having values that look like they may have increased risk for disease, and could be misclassified due to the tiny changes that exist between those at risk and those not at risk.” Factors like biological and analytical variation can cause such alterations. In addition, he said, things such as exercise can increase cTn modestly, just enough to confuse the results.

“You have to have the sort of study that definitively says this works, before you can worry about these other implementation details,” Jaffe said. “That is not a knock on the study, but it’s a caution in regard to taking the next step.”

Additionally, he said, the study results are only applicable to Abbott’s assay. More cutoff points would have to be determined for each hs-cTn assay.

cTn is a marker of interest as a signal of heart damage, but the mechanism of injury has yet to be determined, Apple said. Once that issue has been sorted out, physicians can think about implementing more accurate therapies based on cTn results.

Information like the results of this study will be considered in future guidelines produced by AHA and ACC, Lloyd-Jones said, but they’re not strong enough to influence a revision as of now. A clinical trial that compares this testing strategy versus usual care would be interesting evidence but an expensive undertaking, he noted.

Here and Now

Meanwhile, clinical laboratory professionals can take several actions to help clinicians at their home institutions. One is to be aware of the availability of these tests, Marston said. The field needs to move toward using hs-cTn assays as an overall strategy, Jaffe added. Despite the Fourth Universal Definition of MI, different approaches persist even for diagnosing acute MI. Lab professionals also need to help clinicians understand how to interpret and act on hs-cTn results for individual patients. Verbiage is important here, Lloyd-Jones stressed: It’s key to educate clinicians that not everyone with a low cTn level is low-risk, and not everyone with a high cTn level is high risk.

Jaffe concurred: “I think we need to be careful to make sure that the advice we give makes this useful, and isn’t just a way of selling testing that doesn’t end up really helping.”

While both science and laboratory technology evolve, cTn remains an important indicator to watch. “It is a very consistently powerful test for risk assessment for cardiac disease across the spectrum,” de Lemos said. “Wherever you measure it, it seems to provide very important additional information.”

Labs in the future might be able to generate hazard ratio data from their own populations, Apple suggested. Jaffe said he and others in the field appreciate that more useful cTn measurements are a coming benefit.

“This is eventually going to be applicable to large numbers of patients with and without atherosclerotic disease,” Jaffe said. “But we need to do the sorts of studies done here to define what those cutoff values are … Eventually, we will get all those metrics right. And this will work not only for patients with stable ASCVD but in a whole lot of other instances for prevention.”

Marston and Lloyd-Jones reported no relevant financial disclosures.

de Lemos has grant support from Roche and Abbott, and has consulted for Siemens, Ortho Clinical Diagnostics, and Quidel.

Apple and the Hennepin Healthcare Research Institute receive research funding from several companies that have cTn assays. Apple sits on the board of directors for Hytest, and on an advisory board for Siemens and Instrumentation Laboratory.

Jaffe has consulted for multiple diagnostic companies that make hs-cTn assays.

Karen Blum is a freelance medical and science writer who lives in Owings Mills, Maryland. +Email: [email protected]