INDIANAPOLIS, IN ( UPDATED ) — The recent 501(k) clearance of the Elecsys Troponin T Gen 5 STAT assay (Roche Diagnostics) long used outside the US to rule out MI is a big step forward for US cardiologists but not without its questions.
Commenting to heartwire from Medscape, biomarker expert Dr James Januzzi (Massachusetts General Hospital, Boston) said in an email, "It's unclear to me why there hasn't been more of a reaction in the press. Clinicians should know about the approval of high-sensitivity troponin T, particularly since approval of other highly sensitive troponin methods are soon to follow.
"This means the United States will be going through a sea change in how we use troponin, a test we use daily in thousands of patients."
High-sensitivity cardiac troponin assays allow for earlier recognition of cardiomyocyte necrosis and can detect changes more rapidly than contemporary troponin assays.
Another advantage of high-sensitivity methods "is the ability to exclude acute myocardial infarction at first draw if values are very, very low, such as below the limit of detection, and particularly when combined with reassuring clinical variables, such as a very low TIMI risk score," he said.
In its January 19, 2017 news release, Roche said the "next-generation" troponin test, available in the rest of the world for the past 7 years, has a turnaround time of only 9 minutes and "is able to provide accuracy at lower levels of troponin to aid in correctly identifying patients having an AMI."
Dr Allan Jaffe (Mayo Clinic, Rochester, MN) told heartwire the data in the decision summary for the assay, posted today by the FDA, show clearly that the 99th-percentile upper-reference-limit values are different between Europe and the US. The values are 15 ng/L vs 19 ng/L overall and 11 ng/L for women and 15 ng/L for men in most European studies but 14 ng/L and 22 ng/L for the respective sexes in the US studies. "Thus, for whatever reason, the values to use will be different and that raises questions about whether we can use the prior research in this area for US patients," he said.
After publication of this article, senior Roche officials reached out to heartwire and explained, "It is important to understand that sex-specific cutoffs were determined to address the potential variances in troponin values between males and females experiencing MI. Importantly, this is the first time sex-specific cutoffs have been included in troponin product indications, not just in the US but also worldwide."
Several years ago, Jaffe and other biomarker experts approached the FDA asking that cardiac troponin assay values be reported down to a value called the limit of quantification (LoQ), or a coefficient of variation (CV) <20%. This sort of standard is achievable only with the more sensitive iterations of assays. Most contemporary assays cannot achieve a 10% CV upper reference limit and some even have a CV as high as 20% at that value.
"It looks like the LoQ for this assay is 6 ng/L, which means that assuming that will be the lowest level that is reported, then the studies in Europe using a low value, as low as 3 ng/L and 5 ng/L, to rule out AMI in initial samples will not be translatable to the US population. That would be unfortunate," Jaffe said. "Perhaps when US studies are done, the differences in the performance of the assay will be such that 6 ng/L will work just as well, but that is not known at this time."
The Roche officials told heartwire , "The LoQ value reported in the 510(k) FDA decision summary stems from FDA recommendations that in vitro diagnostic manufacturers report down only to the LoQ and no lower. If the guidance had been different, Roche would have readily provided that data."
On learning of the Roche approval, Jaffe and roughly a dozen other biomarker experts contacted Roche for more information and were told it would be provided "as soon as that was feasible," he said. In the meantime, the manufacturer's package alert has not yet been released.
The devil is in the details, agreed Dr Fred Apple (Hennepin County Medical Center, University of Minnesota, Minneapolis), who was among those reaching out to Roche and who chairs the International Federation of Clinical Chemistry (IFCC) Task Force on Clinical Applications of Cardio Biomarkers.
"There are two sets of clinical data shown in the decision summary; one from the APACE trial in European patients and one from an unpublished multicenter US study, confirming that European data do not look the same as the American data," he told heartwire .
"The European data look much better, as you would expect than [if the analysis had been ] based on US data, which likely comprises a more heterogeneous population of patients presenting to US emergency departments."
He noted that predominantly all of the European diagnostic studies on the assay to date have also been done based on a single cardiac troponin T cut point (14 ng/L), which can vary from lab to lab and from country to country, and now verified by Roche.
"A 99th percentile of predominantly white subjects is going to be very different than a 99th percentile based on a more ethnically diverse population in your town of Chicago, for example," he said.
"In addition, Roche has never supported sex-derived 99th percentiles. It has always said it's only 14 [ng/L], where the rest of the world understands that men and women have substantially different cut points, women being lower, men being higher," he said.
Christina Vysma, a communications partner for Roche Diagnostics (Indianapolis, IN), told heartwire in an email that the company is "finalizing the package insert with the FDA and unfortunately cannot share the specifics at this time" regarding what studies were conducted or whether the metrics used for the assay are the same as those in Europe.
As for why the term "high sensitivity" is conspicuously absent from its news release describing the new assay, she said, "This is based on guidance from the FDA, as the FDA believes that 'high sensitivity' is an analytical claim and is not appropriate for the nomenclature of a product."
Apple said he hopes Roche provides the appropriate data in its package insert and applauds the approval of the fifth-generation assay as a huge improvement over its predecessor.
"It's a step forward for the FDA. If it's as good as they say it is, it's going to be a beast," he said. "It's going to take over the cardiac troponin T market."
Apple also agreed that the approval may open the door for other next-generation assays, including a high-sensitivity troponin I assay from Abbott Laboratories currently under FDA review and used globally except for the US and another from Siemens expected to be submitted in the coming months. In a recent study, Apple and colleagues reported that a single high-sensitivity cardiac troponin I test at presentation was able to rule out any acute myocardial injury including MI, regardless of the etiology or ECG findings.
Although there may be some confusion ahead, Januzzi told heartwire that US physicians have the benefit of years of experience with the assay in Europe and Asia/Pacific. "It's up to us in the United States to rapidly adapt based on those prior experiences. I am confident that while there'll be a learning curve, the transition will not be as difficult as some may fear."
Januzzi reports consulting for Roche, Abbott, Singulex, and Phillips; and grants from Roche and Singulex. Jaffe reports a consultant or advisory role with Beckman Coulter, Alere, Abbott, Roche, Siemens, ET Healthcare, NeuorgenomiX, Lpath, Singulex, and Novartis. Apple reports a consultant or advisory role with HyTest, Philips Healthcare Incubator, and Metanomics; honoraria from Instrumentation Laboratory and Abbott; and research funding from Abbott, Siemens, Singulex, Roche, and Beckman Coulter.
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Heartwire from Medscape © 2017 Medscape, LLC
Cite this: US Debut of 'High-Sensitivity' Troponin Assay Signals Sea Change in Acute MI - Medscape - Jan 25, 2017.