hs-Troponin Fails to ID Ischemia in Symptomatic Stable CAD
Some experts are questioning whether exclusion of inducible ischemia is all that important anyway in the post-ISCHEMIA era.
In patients with stable CAD who are experiencing symptoms, very low levels of cardiac troponin I measured with a high-sensitivity assay do not reliably exclude the presence of inducible myocardial ischemia on stress testing, new Swiss data show. But after seeing results from ISCHEMIA and other trials, some experts are questioning how important it is to rule out ischemia in the first place.
None of the evaluated troponin cutoffs, including the 2.5-ng/L standard used in a prior study of mostly asymptomatic patients, provided both a negative predictive value and a sensitivity of 90%, the predefined target performance criteria, lead author Joan Walter, MD, PhD (University Hospital Basel, Switzerland), and colleagues report.
Results were similar when a high-sensitivity assay for troponin T and an alternative high-sensitivity troponin I assay were used.
The study, published January 6, 2020, ahead of print in the Annals of Internal Medicine, “shows that this previously proposed 2.5-ng/L high-sensitivity cardiac troponin I cutoff for asymptomatic patients should not be employed in symptomatic patients,” Walter told TCTMD, adding that “even in patients with very low circulating high-sensitivity cardiac troponin concentrations, a clinician should not defer cardiac stress testing for inducible ischemia if he or she suspects it clinically.”
There’s some question, however, about whether there is a great need to rule out inducible myocardial ischemia in patients with stable CAD considering the results of ISCHEMIA and other trials, a point raised in an accompanying editorial written by Katy Bell, MBChB, PhD (University of Sydney, Australia), and colleagues.
Walter suggested that there are two factors to consider. “On the one hand, from the clinician’s side, it is potentially partly true that sometimes the less-aggressive strategy does not impact hard outcomes for a patient, so maybe we do not need to stress that much as a clinician,” he said.
“But on the other hand, we also need to see that mostly we are dealing with symptomatic patients and these patients have known coronary artery disease, so a large proportion might even have had a myocardial infarction and for them having these kinds of symptoms, they might want to have some sort of assurance that, at the moment, their heart is not the problem,” Walter continued.
Clinically speaking, he added, there remains “a very big need to rule out stress-induced myocardial ischemia. However, I completely agree that we should limit invasive testing and also unnecessary noninvasive testing, and that’s why I still think a cheap and easy and fast strategy to exclude inducible myocardial ischemia as a reason for the symptoms of a patient is highly needed in current clinical practice.”
Avoiding the Expense, Downsides of Stress Testing
Walter pointed out that the noninvasive workup of patients with symptoms suggestive of myocardial ischemia—typically a combination of clinical judgment and cardiac stress imaging—is costly and carries the risk of further unnecessary testing.
Finding an alternate approach could avoid some of those issues, and the previous study in mostly asymptomatic patients with stable CAD showed that very low high-sensitivity troponin I levels—specifically below 2.5 ng/L—excluded any inducible myocardial ischemia with a negative predictive value of 90%.
But there was still a remaining question about how the strategy would fare in symptomatic patients.
In this prospective study conducted at the University Hospital Basel, Walter et al sought to validate the approach using the same troponin cutoff but in 1,896 patients with stable CAD (median age 69 years; 19% women) who were referred for stress testing due to the presence of symptoms possibly related to inducible myocardial ischemia.
Troponin, a marker that every clinician knows and most clinicians trust in a related phenotype of acute coronary syndromes, does not work in a chronic setting in patients with known coronary artery disease. Joan Walter
Based on myocardial perfusion imaging with single-photon emission CT combined with CT, as well as coronary angiography and fractional flow reserve measurements when available, the investigators determined that 46% of the cohort in fact had inducible ischemia.
The diagnostic accuracy of using troponin I concentrations measured with the Architect Stat high-sensitivity assay (Abbott) to identify inducible ischemia was low both overall and across patient subgroups, the authors report.
Using the 2.5-ng/L cutoff to rule out ischemia provided a negative predictive value of 70% and a sensitivity of 90%, falling short of the predefined goals of at least 90% for both measures. None of the other thresholds evaluated achieved those goals either. Sensitivity analyses using troponin values obtained using a high-sensitivity troponin T assay and another high-sensitivity troponin I assay gave similar results.
The results show that “troponin, a marker that every clinician knows and most clinicians trust in a related phenotype of acute coronary syndromes, does not work in a chronic setting in patients with known coronary artery disease,” Walter said.
James de Lemos, MD (UT Southwestern Medical Center, Dallas, TX), who was not involved in the study, told TCTMD “that’s not an unexpected result. It’s what one would expect in this group of individuals without [an acute] heart attack and who are referred for elective stress testing, because troponins are muscle markers and not markers of the extent of atherosclerosis. . . . I wouldn’t have expected the troponins to work well for this purpose and that’s what the authors found.”
Prognostic Value Confirmed
Both Walter and de Lemos pointed out, though, that the study affirmed the value high-sensitivity troponin concentrations have in estimating risk of adverse clinical outcomes.
Through a median follow-up of 3.1 years in this study, higher troponin I and T concentrations were associated with higher rates of CV death, all-cause death, and nonfatal MI, regardless of the presence of inducible ischemia, providing “very important and very precise prognostic performance,” Walter said.
De Lemos said there’s definitely a role for high-sensitivity troponins in terms of risk assessment, as supported by this and prior studies.
“High-sensitivity troponins are powerful prognostic markers in patients with stable ischemic heart disease, probably better even than the results of the stress test, but they’re not telling you how much ischemia the patient has,” he said. “They’re telling you basically what the consequences are on the heart muscle.”
So overall, de Lemos said, the findings of the study were not particularly surprising, and he predicted that Walter et al would look at other biomarkers that might correlate better with the presence of inducible ischemia in future analyses.
Walter said it’s possible that a strategy incorporating other biomarkers, in addition to troponin, could pay dividends in this area, something on which his group is currently focusing.
Walter J, du Fay de Lavallaz J, Koechlin L, et al. Using high-sensitivity cardiac troponin for exclusion of inducible myocardial ischemia in symptomatic patients: a cohort study. Ann Intern Med. 2020;Epub ahead of print.
Bell KJL, Semsarian C, Doust J. Why we might not need to stress about ruling out inducible myocardial ischemia._ Ann Intern Med_. 2020;Epub ahead of print.
- The study was funded by research grants from the European Union, the Swiss National Science Foundation, the Kommission für Technologie und Innovation, the Swiss Heart Foundation, the Cardiovascular Research Foundation Basel, the University of Basel, the University Hospital Basel, Abbott, Roche, Schiller, and Singulex.
- Walter reports receiving grants from the Swiss Academy of Medical Sciences and the Swiss Heart Foundation during the conduct of the study.
- Bell reports being the recipient of a National Health and Medical Research Council Investigator Grant.
- De Lemos reports receiving grants from Abbott and Roche; consulting for Quidel; and serving on endpoint committees for Ortho Clinical Diagnostics and Siemens.