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With high-sensitivity troponins, watching and waiting continue

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Karen Lusky

May 2016—Laboratories and hospitals in the U.S. continue to look forward to high-sensitivity troponin assays. Judd E. Hollander, MD, says all he’s heard for the past five years is that an assay will be out at the end of the year. “And once you get halfway through the year, it will be out next year,” says Dr. Hollander, chair of the Department of Emergency Medicine and associate dean of strategic health initiatives at Sidney Kimmel Medical College of Thomas Jefferson University.

Robert Christenson, PhD, DABCC, professor of pathology at the University of Maryland School of Medicine, sees the odds as good that the FDA will clear one such assay this year. He predicts it will be a Roche or an Abbott assay.

Agim Beshiri, MD, Abbott’s senior medical director of global medical and scientific affairs for diagnostics, says, “The requirements for U.S. regulatory approval for any troponin test are very high, and the complexity is enhanced with high-sensitivity troponin methods. It is not possible to predict when these tests will become available.”

Dr. deFilippi

Dr. deFilippi

The FDA appears to have two concerns, says cardiologist Christopher deFilippi, MD. “First, there is the whole ‘false-positive’ issue for diagnosis of acute myocardial infarction.” The FDA fears too many patients will receive unneeded testing, which could potentially include cardiac catheterization. Second, by excluding patients with recent MIs, end-stage renal disease, or cardiac procedures, prior studies may not have reflected the all-comers population that presents to the ED, which implicitly decreased the number of subjects who had elevated cardiac troponin values without an acute MI, says Dr. deFilippi, vice chair of academic affairs, Inova Heart and Vascular Institute, Fairfax, Va.

Fred S. Apple, PhD, medical director of clinical laboratories at Hennepin County Medical Center in Minneapolis, says he’s concerned about the FDA’s slowness to clear high-sensitivity cardiac troponin I and T assays. “The evidence-based literature on these assays is overwhelmingly positive for improving patient management and outcomes,” he says. “Internationally, hospitals are replacing contemporary assays. Only the U.S. hasn’t been allowed to bring these high-sensitivity assays into the mix.”

Dr. Apple doesn’t know whether the problem lies with the FDA or the companies or both. He proposes that the FDA have a white paper to hand to every company that details the basics of analytical and clinical studies that need to be performed for the FDA to look at a high-sensitivity troponin submission for 510(k) clearance. “Imagine the positive impression this would have on diagnostics and clinical research allowing for uniform submission and better comparisons between assays,” he says.

Experts agree that getting the tests to market soon is important.

“Getting to use high-sensitivity troponin in the U.S. is terribly important and will revolutionize the ability to detect patients who have chronic comorbidities and improve the ability to ferret out those who have acute myocardial infarction from those who do not,” says Allan S. Jaffe, MD, professor of medicine and cardiology and professor of laboratory medicine and pathology, Mayo Clinic, Rochester, Minn.

Speaking last year in an AACC session on troponin, Dr. Hollander said the high-sensitivity troponins from the emergency department perspective “can be a game-changer, but we need to be smart.”

“The way that I think we need to think about this, particularly in the emergency department, is troponin is myocardial injury if it’s elevated—always,” he said. “We need to determine acute from chronic.” Acute myocardial injury has a changing troponin value. “It’s going up or it’s going down. But not all acute myocardial injury is acute myocardial infarction.

“Probably most acute myocardial infarction needs a cardiologist. Not all acute myocardial injury may need a cardiologist,” he added. There may be, for example, a pneumonia or sepsis to treat. “So we need to determine acute MI from other causes of acute injury, and I think that’s our challenge as we look at this.”

Dr. deFilippi said in a talk at CAP ’15 that looking at the change in high-sensitivity cardiac troponin and the absolute value of change may be “what saves the day” and differentiates patients who have underlying cardiovascular disease that’s not acute coronary syndrome from those who have ACS.

Aside from acute MI, most elevations of cardiac troponin are due to chronic etiologies, but suspicion should be maintained for other causes of an acute elevation, Dr. deFilippi says, such as a pulmonary embolism.

Dr. Christenson

Dr. Christenson

“All the information,” Dr. Christenson tells CAP TODAY, “is that an elevated troponin is bad whatever the cause,” whether it’s heart failure, MI, myocarditis, or trauma. “They all portend a worse diagnosis.” Thus, clinicians would look for some reason for the elevated troponin even if it’s a suspected interference, which would mean a false-positive. Will interferences be a problem with high-sensitivity troponin? Yes, he says, “at least to some extent, and possibly the diagnostic specificity may be lower. We must remember that even high-sensitivity cardiac troponin is an organ-specific marker and not a disease-specific biomarker.” Manufacturers will do everything they can to mitigate interferences, he says, but eliminating 100 percent of interferences is going to be complicated.

Dr. Hollander believes a pathway and guidelines need to be developed that say it’s acceptable to discharge patients from the ED with elevated troponins or to put them in observation. “We’re not going to go overnight from admitting everybody with a whiff of troponin to sending home a bunch of people with elevated troponin,” he says. “So we need to bridge the gap.” Using a contemporary sensitive assay with an upper reference limit of .01 ng/mL, Jefferson is putting patients in observation as long as troponin levels are below 0.1 ng/mL and not rising. “People get used to that really fast,” he says. “But that’s a bridge to ultimately being able to send some of those people home.”

The Royal Wolverhampton NHS Trust (RWT) in the United Kingdom has been using the Abbott Architect Stat High Sensitive Troponin-I assay with a chest pain pathway since April 2013, say Kate Willmer, MBBS, FRCP, consultant acute physician, and Clare Ford, PhD, consultant clinical scientist, in the Department of Clinical Chemistry at RWT. “The way the pathway has been developed means that we have a reliable method of assessing those patients with elevated troponin levels for any cause which has meant the number of negative workups has not increased significantly,” they told CAP TODAY in an email.

Before bringing the high-sensitivity troponin I assay on board, RWT used a high-sensitivity cardiac troponin T assay with a 12-hour pathway that had been for contemporary sensitive assays, they explained.

According to an updated abstract on the new chest pain pathway, which Dr. Willmer made available to CAP TODAY, RWT has an admission high-sensitivity troponin I of ≤1.9 ng/L cutoff for discharging patients with suspected ACS. They do not discharge patients whose first troponin value was obtained within one hour after their chest pain began, Dr. Willmer noted. “The troponin may not yet have had time to go up, as evidenced by the patient who had her troponin taken 15 minutes after collapsing with a cardiac arrest outside the ED and had a troponin less than 2 ng/L,” she said.

The abstract says that low-risk patients who have a high-sensitivity troponin I above the cutoff go to a clinical decision unit to wait for a troponin result from another specimen, which initially was drawn six hours after admission. Now the interval between samples is three hours based on the October 2014 NICE (National Institute for Health and Care Excellence) guidance for early rule out of MI. Patients determined to be high risk go to the acute medical unit.

Using the pathway with the Abbott assay reined in hospital admissions for chest pain from 60.9 percent to 38.4 percent. The authors write in the abstract: “The negative predictive value of hs-cTnI ≤1.9 ng/l on admission for MACE [major adverse cardiac events] at 30 days and 9 months was 99.6 percent (95 percent CI 98.9–99.9) and 98.4 percent (95 percent CI 97.2–99.1) respectively.”

In addition to the rapid triage approaches that can be adopted when using high-sensitivity troponin assays, there are already “hints,” Dr. deFilippi says, that the lower troponin values they detect can be used to guide treatment. For example, the PLATO study showed that the antiplatelet drug ticagrelor was superior overall to the generally lower-cost generic clopidogrel in treating patients with acute MI, he says. An abstract of a study published in Circulation, however, says: “Ticagrelor versus clopidogrel reduced the rate of cardiovascular death, myocardial infarction, and stroke in patients with NSTE-ACS [non-ST-elevation acute coronary syndrome] and hs-TnT ≥14.0 ng/L in both invasively and noninvasively managed patients; in patients with hs-TnT Circulation. 2014;129:293–303). Although the research is a post-hoc retrospective analysis, Dr. deFilippi says, “it raises the possibility that care can be directed by [troponin] levels only measurable with high-sensitive assays. More studies will be forthcoming.”

The more sensitive testing could be a plus for women. Dr. Apple, who is also a professor of laboratory medicine and pathology at the University of Minnesota, says laboratorians and clinicians who know the cardiac biomarker area sufficiently well should understand that men usually have larger hearts than women, and with the natural turnover of cells, different distributions of cardiac troponin can be expected to be seen. “We haven’t been able to see that male-female difference because the contemporary assays currently used only measure less than 20 percent of the normal population and even a smaller percentage of women,” he says.

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