High sensitivity cardiac troponin I (hs-cTnI) assays routinely used to help exclude or diagnose acute myocardial infarction (MI) can be misleading, researchers caution in a paper online in The BMJ March 13, 2019.

In a study of 20,000 consecutive patients at University Hospital Southampton NHS Foundation Trust, about one in 20 had a hs-cTnI concentration above the recommended upper limit of normal (ULN), despite most of them having no clinical suspicion of acute MI.

“This paper should raise questions about the routine use of this test in hospitals,” study chief Dr. Nick Curzen, a consultant cardiologist at University Hospital Southampton, told Reuters Health by email. “This study shows the need for medical staff to interpret troponin levels carefully in order to avoid misdiagnosis of a heart attack and inappropriate treatment.”

Manufacturers of troponin assays provide a recommended “99th centile” based on values from healthy individuals. This level is often used as the ULN when applied to patients in hospitals.

A troponin value above the 99th centile is considered abnormal and indicative of acute MI in appropriate circumstances. But the distribution of troponin levels across the whole hospital population (inpatients, outpatients, patients undergoing surgery, in intensive care, etc.) is largely unknown.

Dr. Curzen’s team measured hs-cTnI in 20,000 inpatients and outpatients undergoing blood tests for any reason at their hospital. Their average age was 61 and 53 percent were women.

The 99th centile of troponin for the whole study population was 296 ng/L, compared with the manufacturer’s recommended ULN of 40 ng/L. Troponin levels were above 40 ng/L in 1,080 individuals, or 5.4 percent, of the total population. After excluding 122 individuals diagnosed with acute MI and 1,707 for whom hs-cTnI was requested for clinical reasons, the 99th centile was 189 ng/L for the remaining 18,171 individuals.

Overall, 39 percent of critical care patients, 14 percent of medical inpatients, and 6 percent of emergency department patients had a troponin concentration greater than the recommended ULN.

This study suggests that the ULN, “which is derived from a group of relatively healthy people, may not be suitable for a hospital population in general,” Dr. Curzen told Reuters Health. “This is of significant concern because if it is measured in patients without a classic heart attack presentation, the level may appear raised and such patients may end up being incorrectly diagnosed as having had a heart attack. They may then receive inappropriate treatment which could be potentially harmful outside of this context.”

He added, “The results can be used to stimulate debate about the way troponin measurements are requested and interpreted in the future because it is certainly not quite right at the moment.”

The cardiac troponin I assay used at University Hospital Southampton is the Beckman Coulter Access AccuTnI+3 assay, but the findings are “almost certainly relevant to the application of all modern hs-cTn assays,” Dr. Curzen and his colleagues note in their article.

This study is “very important,” Dr. Jay Giri, director of peripheral intervention and assistant professor of cardiovascular medicine in the Perelman School of Medicine at the University of Pennsylvania, told Reuters Health by email.

“Specifically, there has been a several-decades long push to improve the sensitivity of cardiac biomarkers for the detection of heart attacks. This has been primarily driven by a fear of missing any developing heart attacks, especially in the emergency room. But the unintended consequence of this is that a growing number of hospitalized patients are seen to have ‘positive’ cardiac biomarkers in the absence of a heart attack,” Dr. Giri explained.

“This consequence is not trivial as these patients often undergo workups that involve consultations, imaging tests, and invasive procedures to adjudicate the meaning of the abnormal biomarker. This imposes a significant burden on hospital resources and also exposes the patient to procedures that may be unnecessary or harmful,” said Dr. Giri. “The current study demonstrates that, while we have been dealing with this issue for some time, the promulgation of hs-troponin is likely to put this problem on steroids since large proportions of patients are in the hospital with hs-troponin values that are ‘abnormal’ despite no active cardiac complaints.”

Dr. Giri also mentioned that proponents of hs-troponin have said health care providers need to be educated in how to interpret the test in the context of a patient’s overall clinical presentation. “This is a commonsense approach, but I would argue that this has always been the case even in the days when we used slightly less sensitive biomarkers for heart attacks,” said Dr. Giri.

“An experienced clinical assessment with a cardiac biomarker as supporting information has always been the best way to diagnose a developing heart attack. So I am skeptical that having an ultrasensitive biomarker incrementally adds much to this optimal care pattern when its available. And when experienced clinicians are not available for rapid assessment of patients, I am worried that the all-too-common algorithms which base decisions on biomarker results will more often lead to unnecessary workups,” Dr. Giri concluded.

Beckman Coulter provided an unrestricted research grant for the study. The company had no involvement in the data collection, analysis or interpretation, trial design, patient recruitment, writing of the manuscript or decision to submit it for publication. Dr. Curzen received unrestricted research grants from Beckmann Coulter, Boston Scientific, Haemonetics and Heartflow, and speaker fees or consultancy fees from Haemonetics, Abbot Vascular, Heartflow, and Boston Scientific.