With high-sensitivity troponins, watching and waiting continue

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Dr. Jaffe

Dr. Jaffe of Mayo Clinic says he’s an advocate of using sex-specific cutoffs for high-sensitivity troponin. It’s known that women who have heart disease or have had an MI do worse than men despite the effective therapies seeming to help women just as much as they help men, he says. One reason women don’t fare as well, Dr. Jaffe adds, is they aren’t as rapidly detected and treated or in some cases they’re not treated at all.

“In almost all of the studies with high-sensitivity troponin, there are substantial differences in the normal ranges between men and women, with men having higher values than women.”

In addition, women have a higher percentage of nonobstructive coronary artery disease and therefore are less likely to have higher troponin values, Dr. Jaffe says. “So women with ischemic heart disease are enriched with that subset that can be hard to detect. In order to bring that out, you need to have large numbers of women who are having heart attacks, and most studies do not have adequate numbers to document the need for sex-specific cutoff values.” The large studies show, he adds, that the use of sex-specific cutoffs markedly improves the diagnosis of acute MI and, with treatment, lives are saved.

Dr. Apple reports that Hennepin County Medical Center recently closed the database on a clinical trial called UTROPIA (Use of Abbott High Sensitivity Troponin I Assay in Acute Coronary Syndromes), funded partially by Abbott. In the study of 1,700 patients, they found that the assay’s cutoff of 16 ng/L for females and 34 ng/L for males resulted in more women being diagnosed with MIs. “The male MI rate didn’t really change compared to the contemporary [Abbott] assay,” he says.

Dr. Apple

In the AACC session last year, however, Dr. Apple presented the case of a 56-year-old woman who was thought to have acute MI based on the contemporary troponin assay. Using the overall cutoff for the high-sensitivity troponin I assay, the patient’s troponin values seemed to be normal. But in applying the sex-specific cutoff for a female, they saw a trend in which all the values were abnormal without a rising or falling pattern. The patient had a chronic troponin elevation that would be diagnosed as a non-ACS myocardial injury.

Dr. Apple explains that the “analytical noise of imprecision” of the contemporary assays may show false troponin elevations that might be, and in the aforementioned case were, interpreted differently compared with the more precise analytics of the high-sensitivity troponin assay, which would not have shown imprecision-related changes. He says that in their study, they probably saw five to 10 cases like that out of the approximately 200 MIs identified by the contemporary assay that wouldn’t have been MIs if adjudicated based on the high-sensitivity troponin I assay.

Dr. Jaffe presented the case of a 78-year-old male with a history of coronary bypass who had an aortic aneurysm repair. The man “had claudication, so was living with angina but in point of fact really wasn’t exerting himself very much,” he says. His chest X-ray and creatinine were okay and a high-sensitivity troponin was at the upper limit of normal. A baseline NT-proBNP was in line with someone with heart disease. The patient was taking numerous cardiac medications and had a lengthy surgery.

“On day two something went wrong, and when we got some additional values, his troponin was elevated, his NT-proBNP was elevated, his ECG was unchanged. So what’s the diagnosis? Well, you could argue this is heart failure, acute heart failure,” he said. “But you could also argue that this guy had had some ischemic injury.”

Although not yet proven, “one of the interesting and likely good strategies that will evolve,” Dr. Jaffe predicts, is getting a baseline high-sensitivity troponin result in patients going to surgery who are thought to be at possibly high risk so that it’s known whether they have a rising and/or falling pattern postoperatively. “This is critical because there can be chronic elevations of cardiac troponin associated with chronic structural heart disease. And one always should try to distinguish elevations that are new and acute from those that are due to structural heart disease,” he adds.

This is especially important for older individuals, who tend to have higher troponin values, he says.

Though he favors sex-specific cut-offs, Dr. Jaffe is not an advocate of developing age-specific cutoffs. “Sex isn’t a comorbidity. We could argue about that—but let’s not.” He does believe, based on research he and colleagues have done, that the troponin changes that occur with age reflect comorbidities. “If you start trying to correct for every comorbidity and use different cutoff values, it would confound the field because there are so many things that increase troponin,” Dr. Jaffe says. The better way, he adds, is to rely on a changing pattern of values.

Dr. Apple says it’s important to keep in mind that an elderly person may have increases above the current 99th percentile upper reference limits. “However if you are going to rule in MI, you still have to look for a rising and/or falling pattern. That’s the key to ruling in.”

Dr. Apple predicts that as high-sensitivity assays become better studied, age-related cutoffs will be considered if appropriate reference individuals can be identified. “We already know something happens when you hit 60. You start observing increases above the published 99th percentile that was likely defined in subjects under the age of 60. The problem is, how do you define normality in 60, 70, 80 year olds? Not an easy clinical task.”

Margot LeClair, product manager at Beckman Coulter, which has in development a high-sensitivity troponin assay, says the 99th percentile is specific to each troponin assay. “Unfortunately, troponin assays aren’t standardized across the board, and another issue you get into is that the 99th percentile upper reference limit can vary based on how you set up your reference population study.” Based on two schools of thought, a patient population more representative of an ED population can be selected, or a healthier population can be selected, LeClair says. The 99th percentile upper reference limit will be higher in the former instance, lower in the latter. LeClair notes that a high-sensitivity troponin assay has to be capable of detecting troponin values in more than 50 percent of the healthy population.

It’s likely to be up to each hospital’s ED, cardiology department, and laboratory to work together to determine what reference intervals they want to establish, she says. The manufacturers establish a 99th percentile for their assays based on the reference populations they studied, which laboratories can use.

Is it possible to have an MI with a troponin value that doesn’t exceed the upper reference limit? According to the Third Universal Definition of Myocardial Infarction, a rising and/or falling cardiac troponin pattern must include a cardiac troponin concentration with at least one value above the 99th percentile, Dr. Apple points out. “However, with the new high-sensitivity assays, a rising and/or falling cardiac troponin pattern that remains within the 99th percentile range [with all measurements providing interpretable numbers] should be carefully considered as a potential etiology for a small myocardial injury that may include an MI,” he cautions. In evaluating these patients, clinicians need to consider imaging, ECG, and clinical presentation.

Dr. Hollander

When using the high-sensitivity assays, Dr. Hollander says, “we will be detecting myocardial injury much, much earlier and at smaller values. So in effect what we used to call ischemia, we might now call myocardial injury, but it’s a small degree of myocardial injury.”

Most MI patients have atypical rather than classic chest pain, he adds. “So once you take everybody who rolls through the door with some type of chest pain and you say, ‘Well, the [troponin] markers are negative, it might still be ischemia,’ it’s impossible to get out of that loop,” Dr. Hollander says. “But if everybody with ischemia actually had a small degree of injury and the [troponin] markers were either positive, meaning you have the disease, or negative, meaning you don’t, everything gets much easier.” With the high-sensivity assays, “I think we are going to get really, really close to that.”
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Karen Lusky is a writer in Brentwood, Tenn.