American Association for Clinical Chemistry
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April 2009 Clinical Laboratory News: cTn and MI—What’s the Diagnosis?

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April 2009: Volume 35, Number 4


cTn and MI—What’s the Diagnosis?
Chronic Elevations, Improving Analytic Performance Confound Interpretation
By Gina Rollins

Cardiac troponin (cTnI and cTnT) was established in 2000 by guidelines of the European Society of Cardiology and ACC as the preferred biomarker for diagnosing MI and for risk stratification of acute coronary syndrome (ACS). Other guidelines of major professional organizations, including NACB, have endorsed cTn for those purposes and provided updated recommendations for the diagnostic cutoffs and CVs for the marker. Yet even with guideline concurrence, clinical and analytical challenges continue to impact the use of cTn as a biomarker of myocardial injury. Emerging evidence on both these fronts ultimately is expected to crystallize the role of cTn, but in the near term laboratorians and clinicians will need to join forces to navigate the changing cTn landscape.

Both groups need a better understanding of the operating characteristics and clinical implications of cTn assays, according to Fred Apple, PhD, professor of laboratory medicine and pathology at the University of Minnesota School of Medicine, and medical director of clinical laboratories at Hennepin County Medical Center in Minneapolis. “There’s a huge educational curve that has to be effected even at the lab level,” he noted. “Laboratorians have to understand the assay they operate, its strengths and weaknesses. Then they need to put together evidence-based literature that supports all the applications of that assay, sit down with cardiology and emergency physicians, and be a proponent of why the 99th percentile should be used. It’s important to explain the analytic characteristics of the assay and what they can expect from it.”

Universal Definition of MI

Guidelines on the Universal Definition of MI issued in 2007 by the ESC, ACC Foundation, American Heart Association, and World Heart Foundation called for a cTn measurement exceeding the 99th percentile of a normal reference population with a CV ≤10% as an element of diagnosing MI, along with at least one additional criterion: symptoms or ECG changes indicative of ischemia; development of pathological Q waves in the ECG; or imaging evidence of new loss of viable myocardium or regional wall motion abnormality. The guidelines also note the importance of rising and/or falling cTn values in discerning MI. Measurements should be taken at the time of first assessment and 6 to 9 hours later to detect any pattern. CK-MB by mass assay is an acceptable alternative when cTn values are not available, according to the guidelines.

Even though this guidance is straightforward and endorsed by key professional organizations, there have been problems implementing it. As Drs. David Morrow and Elliott Antman noted in their editorial in the January 2009 issue of Clinical Chemistry, “Despite this clear recommendation and evidence establishing therapeutic implications at this cutoff, we are surprised to see in our practice that a substantial proportion of medical centers have maintained the approach of reporting more than one decision limit and/or one that is higher than the 99th percentile” (Clin Chem 2009;55:5–8). A survey conducted in conjunction with a November 2008 AACC audioconference bears this out. Slightly more than one-third of participants indicated that they used a 10% CV cutoff strategy, about one-third reported using the 99th percentile, while 18% used the ROC cutpoint, and 13% were unsure of the cutoff strategy.

Part of the confusion emanates from changes in recommended cutoffs over time, as the analytic performance of cTn assays improved. For example, the first iteration of NACB guidelines for cardiac biomarkers, published in 1999, called for two cutpoints, with the ROC curve used to establish acute MI decision limits. “That set the stage for using whatever cutoff you want, and the field has never recovered from it,” contended Allan Jaffe, MD, professor of medicine and laboratory medicine at the Mayo Clinic.

New Assays, Lower Disease Thresholds

Keeping abreast of the evolving analytical performance of cTn assays likewise has been an ongoing challenge. In early studies, first-generation assays did not consistently out-perform the then-gold standard CK-MB in sensitivity or analytical precision. Since then, however, the cTn assays have improved steadily and a substantial body of evidence has documented their superior analytic capabilities for identifying cardiac ischemia. Not only are the commercially available assays able to reliably detect at the recommended 99th percentile with a ≤10% CV, many are precise at lower limits of detection (see table, below). For example, the most sensitive assays today have a limit of detection as low as 0.006µ/L, according to Alan Wu, PhD, director of clinical chemistry and toxicology at the University of California at San Francisco. New ultra-sensitive research assays that are not yet commercially available can go even lower, by another 10- to 100-fold. As a result, the assays will detect virtually all cTn elevations and even normal levels, he indicated.

Analytical Characteristics of cTn I and T assays*

Company/platform

LoD†
μg/L

99th centile
μg/L

10% CV
μg/L

Abbott AxSYM ADV

0.02

0.04

0.16

Abbott Architect

0.009

0.012

0.032

Abbott i-STAT

0.02

0.08

0.10

Beckman Access

0.01

0.04

0.06

BioMerieux Vidas Ultra

0.01

0.01

NA

Innotrac Aio!**

0.012

0.023

0.036

Inverness Biosite Triage

0.05

<0.05

NA

Mitsubishi PATHFAST**

0.008

0.029

NA

Ortho Vitros ES

0.012

0.034

0.034

Radiometer AQT90**

0.0095

0.023

0.039

Response Biomedical RAMP

0.03

<0.01

0.21

Roche E170

0.01

<0.01

0.03

Roche Elecsys 2010

0.01

<0.01

0.03

Siemens Centaur -Ultra

0.006

0.04

0.03

Siemens Dimension

0.04

0.07

0.14

Siemens Immulite 2500 STAT

0.1

0.2

0.42

Siemens Immulite 1000 Turbo

0.15

NA

0.64

Siemens Stratus CS

0.03

0.07

0.06

Siemens VISTA

0.015

0.045

0.04

Tosoh AIA

0.06

<0.06

0.09

Source: IFCC Committee on Standardization of Markers of Cardiac Damage, www.ifcc.org

* As stated by the manufacturers
** Not available in the U.S.
† Limit of detection

Already, the improved performance of cTn assays has changed the diagnostic scope of the biomarker. “We can now detect many more cases previously called normal that we didn't have the sensitivity to detect before,” said Wu. “We're seeing true cardiac injury that we didn't see before which is not related to an ischemic event.”

It is this group of patients with cTn elevations, either at or above the 99th percentile, but without other signs and symptoms of MI, that is causing the most consternation among clinicians. At issue is that while cTn is a very sensitive marker of myocardial necrosis, it is not specific for MI. “The diagnosis of MI is predicated on an elevated troponin above the 99th percentile. That is correct. But an elevated troponin does not necessarily mean the patient has had an MI,” explained Wu. A host of other conditions also can cause cTn elevations, including myocarditis, renal failure, drug toxicities, congestive heart failure, and pulmonary embolism.

An Amazing Quandary

Nowhere does the diagnostic workup of patients with chronic elevations of cTn present more of a dilemma than in the emergency setting. Emergency physicians in particular face the need to move patients quickly, but appropriately, through the system for either inpatient admission or further diagnostic workup before admission or discharge. “It’s the most amazing quandary,” said Francis Fesmire, MD, FACEP, director of the Chest Pain Center at Erlanger Medical Center, and associate professor and research director of the department of emergency medicine at the University of Tennessee College of Medicine in Chattanooga. “People don’t understand all the different disease processes and that you have to take troponin levels in context with the clinical situation and with a degree of rise or fall over whatever time period,” he noted.

Fesmire chaired the writing group committee for the American College of Emergency Physicians’ guidelines on evaluating and managing patients with Non-STEMI ACS, and as such, receives feedback from emergency physicians across the country. "There are a lot of places where doctors admit every single person with troponin elevations, and the admitting physicians are reflexively consulting cardiologists. When the cardiologists see these patients, they ask, ‘why am I being consulted? because this patient clearly doesn't have cardiac ischemia’," he explained. Fesmire also is a board member of the Society of Chest Pain Centers, and said that the organization has been “flooded with people wanting to know how to deal with low-level troponin levels.”

The confusion about how to use and interpret cTn results is so significant that the assay is being misused, according to Kristin Newby, MD, MHS, associate professor of medicine at Duke University Medical Center. “It’s almost being drawn for all emergency patients and people are using the assay in a way that wasn’t intended,” she observed. A cardinal misuse of the assay is that it is ordered often in patients with an extremely low pre-test likelihood of ACS, according to Robert Christenson, PhD, professor of pathology and medical and research technology at the University of Maryland School of Medicine in Baltimore. “If the doctor thinks the patient has extremely low odds of having ACS, then he shouldn’t order the test. That’s what gets you in trouble, particularly in terms of false positive results,” he said.

Fesmire estimates that 20% of chest pain patients with elevated troponin levels seen in the Erlanger Medical Center emergency department do not have ACS. “Every day we discharge from our ER patients with troponin greater than the 99th percentile that is their normal background for whatever disease state they may have but which is not MI,” he said. Erlanger Medical Center has adopted an approach of looking for at least a 0.1ng/mL rise in cTn in a 2-hour period as an indicator of MI. “We're saying that if they don't do that then they don't have AMI. They may still have unstable angina but that's where we make our clinical decision point,” Fesmire explained.

Reporting a Delta Change

The concept of using a specific "delta change" in interpreting any rise or fall in serial cTn measurements is gaining currency but hasn't been adopted universally. Like Erlanger Medical Center, the Mayo Clinic also has implemented a specific delta change protocol. cTn measurements are taken at 0, 3, and 6 hours, and a delta is reported as being significant or not between the 0 to 3 and 0 to 6 hour time points. Analytically significant changes are defined as at least 0.03 ng/mL for values <0.20 ng/mL, or at least 20% for values >0.20 ng/mL. “The change over time is important, but if clinicians are not careful they can misinterpret what a changing pattern is. Clinicians who are not as knowledgeable can take tiny changes as significant and it might lead them astray,” noted Jaffe.

Evidence is still evolving about what should be considered a significant delta change with higher-sensitivity assays. A study recently published by Wu and colleagues found that the prototype cTnI assay being developed by Singulex produced same-day CVs between individuals, within individuals, and analytically, of 57%, 9.7%, and 8.3%, respectively. Between-day CVs between individuals, within individuals, and analytically were 63%, 14% and 15%, respectively (Clin Chem 2007;55:52–58). A study by Apple and colleagues, which has been accepted but not published by Clinical Chemistry, indicates that a 30% delta increase over 6 hours results in a specificity for MI of about 90%. “We're going to see the delta change over time become very important,” said Apple. “Right now it's a moving target with improving assays and looking at them in combination with lower cutoffs below the 99th percentile.”

The Need for a Reference Method, Material

Yet another evolving analytical issue is a joint effort between the IFCC and NIST to develop a standard reference method and serum-based reference material for cTnI. A working group will meet during the AACC annual meeting in July to finalize a pilot project to determine the best method for collecting the reference material, according to David Bunk, PhD, a research chemist at NIST. Collection of the reference material will take considerable time and effort, since cTnI cannot be collected in large quantities from a single source and most likely will have to be procured from hospitals worldwide.

As a result, Bunk has not established a timetable for when the reference material will be available. He anticipates that the reference method, which NIST is developing in collaboration with the National Physical Laboratory (UK), will be in place much sooner. cTnT is effectively standardized in that there is only one manufacturer, Roche Diagnostics.

Guidelines Re-examined

Even as the cTn assays have improved over time, there continues to be confusion about the evidence of cTn’s diagnostic significance in relation to other cardiac biomarkers. The ACEP guidelines, which were released in 2006 just prior to publication of the Universal Definition of MI, determined that there was insufficient evidence at that time to make any recommendations regarding the use of cardiac serum markers to exclude non-STEMI AMI using then-current ESC/ACC criteria for AMI. Fesmire said the group had been concerned that the 99th percentile was based on a normal reference population. “We were referring to the fact that there's not many good studies in the low positive group that's at the 99th percentile. That's not a reliable measurement because it's based on healthy individuals. But that's not what we see in the real world,” he said.

Fesmire’s point is well-taken, according to Christenson. "Most studies have been done in ACS-enriched populations," he agreed. However, a large number of robust studies of patients without a high pre-test probability of ACS but with high cTn elev-ations are unlikely to be conducted, because the event rate is quite low and would require a very large, multicenter study to detect outcomes with sufficient statistical power. “The trick is, what do you do when you lack evidence? Just do nothing, or go with the best you have? Right now the best we have is cohorts of ACS patients with measurements of cTn that clearly indicated they're at increased risk. These data are being extrapolated to the non-ACS population with cTn elevations where it is deduced that they are at risk as well,” said Christenson.

 Troponin and MI-related Guidelines

Key professional organizations have published guidelines on the use and interpretation of cardiac biomarkers in ACS, including:

ACC/AHA 2007 Guidelines for the Management of Patients with Unstable Angina/Non-ST-Elevation Myocardial Infarction, J Am Coll Cardiol 2007;50:e1–157.

Clinical Policy: Critical Issues in the Evaluation and Management of Adult Patients with Non-ST-Segment Elevation Acute Coronary Syndromes, Annals of Emergency Medicine 2006; 48:270–301.

NACB Laboratory Medicine Practice Guidelines for Utilization of Biochemical Markers in Acute Coronary Syndromes and Heart Failure, Clin Chem 2007;53:2086–2096.

Universal Definition of Myocardial Infarction, J Am Coll Cardiol 2007;50:2173–2195. 

 

Jaffe believes the continued use of CK-MB is an impediment to using cTn as recommended by current guidelines. “As long as clinicians rely on something they think works even though the data is very clear about its inadequacies, then they don't have to learn something new, and it's a busy world,” he noted. “If organizations eliminated CK-MB then people would be forced to learn what they desperately need to learn.” Indeed, the AACC audioconference survey revealed that there is considerable variation in the use of cTn and other cardiac biomarkers. Approximately 22% of respondents reported using cTn only, 39% said they used cTn and CK-MB, 23% reported using cTn, CK-MB and myoglobin, while 14% reported using a different combination of biomarkers. Mayo Clinic removed CK-MB from the lab’s cardiac biomarker panel in 2007, while Hennepin County Medical Center discontinued CK-MB in 1996 and performs only about 300 of the tests per year, according to Apple.

In recognition of the challenge in implementing cTn in practice, the ACC Foundation has convened a working group to develop an expert consensus document on practical considerations in the interpretation of troponin elevations. In addition to the ACCF, the committee has representation from several other professional organizations. Christenson is the AACC representative. Newby, who is co-chair of the group, expects to have the document published by the end of the year. “Our hope is that we'll be helping the non-troponin expert understand what troponin means when elevations are detected and how best to use it in clinical practice, and to some extent even when the test should be ordered,” she explained.

AACC also has taken steps to advance understanding of cTn. The association sponsored a session, Demystifying Clinical use of Cardiac Markers, at the ACC Annual Scientific meeting in March. In addition, Clinical Chemistry papers of significance to cardiology practice will be available free-of-charge to ACC members on ACC’s educational website, with an accompanying summary by Jaffe.

Improving Performance

As the cTn picture sharpens, laboratorians have a seminal responsibility in selecting robust assays and knowing their nuances, according to Newby. “They need to insist on tight CVs and those things that make for high quality, even when cost is an issue,” she said. “We’d like them involved in making sure everyone understands the assay and its operating characteristics.” Laboratorians also can make important contributions in helping establish testing protocols, and in developing reports that help with interpretations. For example, cTn results at Erlanger Medical Center come with an explanation that in patients with ischemic symptoms, a cutoff value of 0.1 ng/mL suggests being consistent with ESC/ACC/AHA criteria for AMI. “Ideally, which we don’t have, there would be another statement that there are multiple causes of troponin elevations and interpretation must be taken in context with the patient’s clinical circumstances,” said Fesmire.

While emergency physicians perform the delicate balancing act between swift diagnosis, discharge, admission, or further work-up, labs should review procedures to ensure they are meeting turnaround time requirements. Wu suggests re-engineering steps such as using pneumatic tubes rather than couriers, using plasma samples rather than serum, and combining lab informatics with alert mechanisms to track processing times better. Although POC testing is less sensitive than central lab-based assays, it is faster, and may be a consideration when aspects of turnaround times outside the lab’s control can’t be improved, Wu advised.

Continued expansion of the evidence base and improvements in analytical performance, coupled with a better understanding of cTn’s diagnostic parameters, will secure its place as the workhorse of cardiac biomarkers.