‘Mishmash’ of Troponin Cutoffs Being Used to Diagnose MI
Most centers are not sticking to recommended thresholds found on the troponin assays’ package inserts, a recent survey found.
Inconsistency abounds when it comes to the troponin thresholds that centers are using to diagnose MI, a survey of sites participating in the international ISCHEMIA trial reveals.
In fact, only 31.6% of laboratories said they were using the manufacturer-determined 99th percentile upper reference limit (URL) as the cutoff for diagnosis, researchers led by Akshay Bagai, MD (St. Michael’s Hospital, Toronto, Canada), report in a study recently published online ahead of print in the American Heart Journal.
Some centers were using values below that threshold, whereas most were using higher values, sometimes greater than 10 times the 99th percentile URL.
“So there’s a mishmash of different thresholds,” Bagai told TCTMD, pointing out that this can cause problems both for daily patient care and for event ascertainment in clinical trials. “We do need to have consistency across sites.”
Centers “should follow what’s recommended by the universal definition of MI guidelines, which is to make the 99th percentile for that troponin assay as the upper limit of normal,” he continued. Sites should have a good reason for not using the recommended cutoff, he added, “but they should do their best to make it consistent with what’s recommended by the experts in this field.”
Bagai said it became apparent during the conduct of the ongoing ISCHEMIA trial, which is evaluating management strategies in patients with stable ischemic heart disease, that centers were using a wide range of different assays and troponin thresholds, so the investigators decided to take a look at the issue in a more systematic way.
They sent surveys to participating centers, receiving responses from 276 sites in 31 countries; 101 centers were in the United States. About two-thirds of centers were using troponin I assays, 31.9% were using troponin T assays, and 2.5% were using both. High-sensitivity assays were used in about one-quarter of sites.
Across study sites, 21 unique assays from nine manufacturers were used. Variability in the thresholds employed to diagnose MI was seen regardless of geography and sensitivity of the assay, although sites using high-sensitivity assays were more likely to adhere to recommended cutoffs.
Bagai said that he was not surprised to see small variations across sites, but added, “I was surprised at the fact that there were large variations when using the same troponin assay.”
One example provided by the authors involved the Abbott Architect troponin I assay, which has a recommended 99th percentile URL of 0.028 ng/mL. Diagnostic thresholds used by study sites, however, ranged widely from 0.012 to 0.50 ng/mL. Thus, an individual patient could be diagnosed with an MI at one center but not at another.
“This has considerable implications for patient management in clinical practice, as well as over- and underreporting of MI events in clinical trials,” the authors say.
Although the survey did not ask centers about how they chose their diagnostic cutoffs, Bagai said that based on discussions with colleagues and published studies, the observed variation could be due to several factors. Centers might not be confident that the manufacturer-recommended thresholds are relevant to their local populations, leading them to derive their own values based on a reference population. Some sites might be using a higher cutoff to make the test more specific rather than sensitive. And others might be using thresholds found in the literature.
In an accompanying editorial, Robert Christenson, PhD (University of Maryland Medical Center, Baltimore), and Christopher deFilippi, MD (Inova Heart and Vascular Institute, Falls Church, VA), point out that use of the 99th percentile URL has been shown to be associated with better patient outcomes and discuss possible reasons for suboptimal adoption of that threshold for diagnosis.
Awareness of the recommendation to use that cutoff doesn’t seem to be the problem, they note.
“The reality is that there is some rationale for skepticism about use of the 99th percentile cut point. The stringency needed for defining the normal population is a hotly debated issue,” Christenson and deFilippi say. Cutoff values will depend on what criteria are used, they say.
Nevertheless, “that two-thirds of the institutions were noncompliant with using the 99th percentile potentiates inconsistency, confusion in either the over- and underreporting of MI, and a false sense of security at a majority of institutions participating in the ISCHEMIA study,” the editorialists write. “Use of the 99th percentile of healthy, normal individuals is certainly complicated. However, we do know that use of this decision is better for patients, and now that we know better, we should do better.”
Bagai et al predict that “with the recent approval of high-sensitivity assays in the US, many US laboratories are likely to switch troponin assays in the very near future. As more laboratories make this change, further efforts are required to encourage the adoption of 99th percentile URL as the [cardiac troponin] threshold to diagnose MI, and for clinical societies/regulators to establish a recommendation for the best and universally accepted methodology to establish the 99th percentile for [troponin] assays.”
Bagai A, Alexander KP, Berger JS, et al. Use of troponin assay 99th percentile as the decision level for myocardial infarction diagnosis. Am Heart J. 2017;Epub ahead of print.
Christenson RH, deFilippi CR. The troponin decision-point dilemma: the 99th percentile solution “do the best you can [with cardiac troponin] until you know better. Then when you know better, do better.” Maya Angelou, poet, dancer, producer, playwright, director, author. Am Heart J. 2017;Epub ahead of print.
- The ISCHEMIA trial is supported by a grant from the National Heart, Lung, and Blood Institute; in-kind donations from Abbott Vascular, Medtronic, St. Jude Medical, Volcano Corporation, Arbor Pharmaceuticals, AstraZeneca Pharmaceuticals, Merck Sharp & Dohme, and Omron Healthcare; and financial donations from Arbor Pharmaceuticals and AstraZeneca Pharmaceuticals.
- Bagai reports no relevant conflicts of interest.
- Christenson and deFilippi did not make any disclosures.