Clinical Laboratory Strategies: December 11, 2008

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Retiring CK-MB
Troponin’s Diagnostic Advantages May Make CK-MB Redundant

By Gina Rollins

The advent of rapid, accurate testing for CK-MB transformed acute cardiac care in the 1970s and 80s, and the marker has been a mainstay of cardiac diagnostics since then. However, as assay methods changed and overall accuracy of the test improved, some shortcomings became apparent as well. Meanwhile, cardiac troponin I and T assays, developed in the 1990s and improved since then, have shown that elevated troponin levels are almost completely specific for cardiac injury and have better sensitivity than CK-MB. Despite these advantages, CK-MB still is part of the standard cardiac work-up in many institutions. The authors of a recently published special report argue that it is time to put CK-MB to rest in favor of troponin. This issue of Strategies examines that report and the authors’ experience in removing CK-MB from the cardiac biomarker panel at their institution.

Elevated CK-MB levels in concert with a thorough clinical examination and ECG findings became the gold standard for detecting cardiac injury shortly after the CK-MB test was introduced. Over time, the advent of mass assays for CK-MB showcased some issues with the test that are well-known to both laboratorians and clinicians. Most notably, CK-MB levels also rise in the event of skeletal muscular injuries, renal failure, and numerous other conditions, thereby reducing its specificity for cardiac injury.

Troponin has much higher sensitivity and specificity for cardiac injury than CK-MB, so that even in the event of minor damage, increased troponin values correlate with adverse short- and long-term outcomes. However, before the body of evidence on troponin was as substantial as it is today, many clinicians stuck with the more familiar CK-MB. “Clinicians didn’t realize how much more sensitive and specific troponin was and didn’t know how to use it, so they held on and kept using CK-MB,” said Allan Jaffe, MD, co-author of the special report published in Circulation (2008; 118:2200-2206). Jaffe is professor of medicine and laboratory medicine at the Mayo Clinic.

As a result, the authors argue, CK-MB remains on the cardiac biomarker panel at many institutions and is ordered frequently. ”CK-MB doesn’t add anything additional to troponin. It lacks both sensitivity and specificity in comparison to modern troponin assays,” noted co-author Amy Saenger, PhD, director, central clinical laboratory and central processing at the Mayo Clinic. In fact, a survey conducted during a November 6 AACC audioconference, Low Level Troponin Results: Clinical Applications and Analytical Challenges, gives a good indication of how many institutions still run CK-MB. Nearly 40% of participants indicated that their lab measures both troponin and CK-MB; 23% measure troponin, CK-MB and myoglobin; 14.5% measure a different combination of markers; and 22.2% measure troponin only.

Based on evidence from a literature search and recommendations from the American College of Cardiology/European Society of Cardiology/American Heart Association and the National Academy of Clinical Biochemistry, the authors lead an effort at the Mayo Clinic to remove CK-MB from the lab’s cardiac biomarker panel, a change that was implemented in late 2007. A protocol to test for troponin at 0, 3, and 6 hours was introduced at the same time, with abnormal values defined as >99th percentile cut-off value of <0.01 ng/mL, and a delta was also reported as being significant or not significant between the 0–3 and 0–6 hour timepoints. 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.

According to Jaffe, the key to implementing the change was educating physicians about the role of troponin in a variety of clinical situations, including diagnosis of AMI and reinfarction, estimation of infarct size, and evaluation of patients post-PCI and post-CABG, and with renal failure, chronic elevations not associated with renal failure, critical illness, and extreme exercise.  In their Circulation report, Jaffe and Saenger suggest criteria for using troponin for these purposes. They argue that troponin is a superior marker in all cases, in comparison to CK-MB.

Other experts agree that troponin measurements are preferred over CK-MB for the majority of these applications, but they believe more evidence is needed in support of its role in diagnosing reinfarctions and measuring infarct size. “I believe troponin may be useful for those purposes, but we just need more complete evidence. The available studies are of relatively small size,” observed Robert Christenson, PhD, professor of pathology and professor of medical and research technology at the University of Maryland School of Medicine in Baltimore.

That type of review and discussion of evidence is critical to making a decision to remove CK-MB from an organization’s cardiac marker panel, agreed Saenger. “I’ve found that if you have data from your own patients and can prove that another test does not add anything to the diagnosis you will have an easier time getting buy-in from your clinicians,” Saenger said. It is equally important to educate laboratorians about why such a change is being considered, she added.

Saenger and Jaffe had “extensive dialogue” with clinicians, particularly cardiologists and emergency physicians, to discover how they were using both troponin and CK-MB levels in care decisions, according to Saenger. Feedback from this process revealed that clinicians were unsure about the significance of chronic, low-level troponin levels, which lead Saenger and Jaffe to implement the protocol to measure troponin levels over a 6-hour interval. “It’s the change over time that provides information about the underlying significance,” Saenger noted.

A better understanding of how to use troponin is essential to gaining support for using it rather than CK-MB, according to Jaffe. “It’s not the marker that is a problem. It’s sometimes the lack of interpretation of the marker that is a challenge, and that needs to be distinguished from the adequacy of the marker,” he explained.

The University of Maryland also recently removed CK-MB from its cardiac biomarker panel. Christenson and his cardiology colleagues made the move in order to comply with ACC/ESC/AHA and NACB guidance. An earlier attempt some years ago to retire CK-MB was not successful despite potential diagnostic and prognostic issues related to CK-MB in patients with both cardiac and skeletal muscular injuries, according to Christenson.

Both Mayo and Maryland informed physicians in advance of the change, and both reported receiving little feedback. At Maryland, orders for CK-MB have dropped to about two requests per day, down from pre-change levels of about 40 per day; at Mayo, the annualized number of orders now is approximately one-third the pre-change level, about 9,500 versus 33,000. “We would like to obsolete CK-MB altogether as we have done with myoglobin. But right now, it can still be ordered; it’s just not as easy to do so as it was before,” Saenger said.

Overall, the authors believe the removal of CK-MB has had no “discernable negative effects on clinical care,” and has advanced Mayo’s objectives to provide cost-effective care. “Especially today, if a test is adding unnecessary costs for labs or patients, one should think about eliminating it,” said Saenger.

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