High-Sensitivity Troponin Test Predicts Poor Outcomes in Stable Patients With Chest Pain

High-sensitivity cardiac troponin assays may eventually play a part in an overall strategy for evaluating patients who present with stable chest pain symptoms and possible coronary disease, an analysis from the PROMISE trial suggests.

Higher levels of troponin I measured at enrollment—even within the normal range—were associated with a significantly greater risk of a composite of death, acute MI, or hospitalization for unstable angina as well as an elevated risk of CV death or acute MI at 1 year, according to researchers led by James Januzzi Jr, MD (Massachusetts General Hospital, Boston).

The relationships were particularly strong in the first 90 days after enrollment, they report in a study published online ahead of the January 29, 2019, issue of the Journal of the American College of Cardiology.

It’s possible, Januzzi told TCTMD, that “the troponin was detecting a signal that was active at the time of enrollment, perhaps identifying a small amount of myocardial injury related to the unstable coronary syndrome that was present in this relatively small number of patients in PROMISE but, nonetheless, a high-risk patient population.”

Overall, the findings suggest “that among patients with stable symptoms in whom suspicion for a coronary cause may be present, high-sensitivity troponin testing, together with a physical exam and electrocardiography, may help support clinical judgment for identifying the specific patients in whom a more directed diagnostic and therapeutic strategy might be taken,” Januzzi said.

Troponin Testing Outside the Emergency Department

Although high-sensitivity troponin testing—which became available in the United States only in the past 2 years but has been employed in Europe and elsewhere for much longer—is well established for sorting out the diagnosis of acute MI, there is mounting evidence supporting its ability to identify patients outside of the acute setting who have an elevated risk for CV events. An analysis of the ARIC study, for example, showed that high-sensitivity cardiac troponin T measurements identified apparently healthy people with greater risks of coronary heart disease, death, and heart failure.

This new analysis is unique in that the PROMISE population was made up of outpatients with stable chest pain, many of whom turned out to not have coronary disease.

“This really created an opportunity to examine the question of how use of a very highly sensitive troponin assay—such as the one we used in the study—might help to support clinical judgment when evaluating a patient with an ambiguous diagnosis,” Januzzi said.

In a prior analysis of PROMISE participants who were imaged with coronary CT angiography, investigators showed that higher levels of troponin I were associated with higher prevalence and severity of underlying coronary disease. This new analysis takes the evaluation a step further by expanding to include all patients with troponin measurements available at enrollment.

The assay used in PROMISE, which has not been approved for this use and is not widely available, is a highly sensitive method that tallies individual molecules of troponin I (SMC TnI; Singulex). It “provides somewhat higher precision at very low concentrations of troponin than commercially available assays can deliver,” Januzzi explained. Using this test, troponin was detected in 98.6% of the 4,021 patients who provided blood samples. The median level was 1.6 ng/L (levels below 6 ng/L are considered normal).

Patients were divided into quartiles according to troponin level, and those in the upper quartiles had higher-risk clinical profiles. For example, Framingham risk score increased from 15.8% in the lowest quartile to 26.4% in the top.

Higher troponin levels were also associated with poorer outcomes in the first year of follow-up. The estimated probability of death, acute MI, or hospitalization for unstable angina (primary outcome) was 0.8%, 1.5%, 2.3%, and 3.1% across increasing troponin quartiles. Corresponding figures for CV death or acute MI were 0.4%, 0.6%, 0.8%, and 1.2%.

On multivariate analysis, increases in troponin were independently associated with both composite endpoints (P < 0.001), with similar findings in both men and women. The associations remained significant for events occurring up to 90 days after enrollment, with hazard ratios falling off after that.

“These results suggest a possible role for measurement of troponin I using a very highly sensitive assay as a part of an overall strategy for evaluation of stable chest symptoms and possible coronary artery disease,” the authors say.

Improving Triage

Incorporating high-sensitivity troponin testing into the decision-making process might help streamline the evaluation of outpatients with stable chest pain, a common clinical scenario, Januzzi said. But further studies are needed before implementing that approach, he added.

“The goal here would be to better understand how we can utilize high-sensitivity troponin in a cost-effective strategy together with clinical judgment to best identify which patients should be referred for which tests, rather than the broader approach that we take where patients may go through numerous steps before the final diagnosis is identified,” he said. “So, it may help to refine and focus the diagnostic and therapeutic approach.”

It’s not unreasonable to expect that in the near future we’ll be incorporating these tests in the office much the way we do in the emergency department setting. James Januzzi Jr

Commenting for TCTMD, Vijay Nambi, MD (Michael E. DeBakey VA Medical Center and Baylor College of Medicine, Houston, TX), said this new PROMISE analysis adds to a string of studies that have been exploring the utility of high-sensitivity troponin testing in a non-ACS setting and “showing the value of high-sensitivity troponin across the spectrum.”

High-sensitivity troponin assays represent another tool, in addition to physical examination, stress testing, and coronary CT angiography, that could potentially be used to evaluate patients with chest pain, Nambi said, adding that if the troponin level is high, it might identify a higher-risk patient who requires a more extensive workup.

Still, Nambi agreed with Januzzi that additional research is needed before rolling out this strategy in a routine fashion. In particular, more information is needed on the best course of action after a high troponin level is identified.

“Eventually, for it to be a mainstream thing for you to be able to use the information to further manage your patients, you would want to see clinical studies using this strategy to help you go further,” he said.

Nambi noted, too, that high-sensitivity troponin testing has not been approved for routine risk stratification and prognostication. “But I think that’s definitely the way this is headed, because any measurement of troponin identifies some kind of subclinical myocardial injury or damage and that’s basically telling you the heart is not happy,” he said. “So as a clinician you have to figure out at that point in time what you can do . . . and that’s a fertile area of ongoing research.”

Any measurement of troponin identifies some kind of subclinical myocardial injury or damage and that’s basically telling you the heart is not happy. Vijay Nambi

Ultimately, Nambi said, “I think [in the] long term high-sensitivity troponin will be incorporated into several risk prediction algorithms and several approaches for routine care beyond acute coronary syndromes.”

Januzzi agreed, saying that “it’s not unreasonable to expect that in the near future we’ll be incorporating these tests in the office much the way we do in the emergency department setting.”

As Paul Collinson, MB BChir, MD (St. George’s, University of London, England), puts it in an accompanying editorial, “Are we therefore looking at another paradigm for troponin as the biomarker for detection of developing coronary artery disease and monitoring of treatment of established disease? Time will tell, but it is looking very promising.”