Study Proposes New CK-MB Threshold for Periprocedural MI

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Definitions for what constitutes elevation of creatine kinase-MB (CK-MB) vary widely among centers. Setting absolute rather than relative thresholds may help pinpoint clinically relevant levels of the biomarker, asserts a paper published online October 4, 2011, ahead of print in Circulation: Cardiovascular Interventions.

To better understand the impact of varying CK-MB thresholds on periprocedural MI incidence and mortality outcomes, David J. Cohen, MD, MSc, of Saint Luke’s Mid America Heart Institute (Kansas City, MO), and colleagues looked at data from 6,347 patients in the EVENT (Evaluation of Drug-Eluting Stents and Ischemic Events) registry who had normal CK-MB levels at baseline and subsequently underwent nonemergent PCI (34% for unstable angina and 59% for stable CAD).

Universal Definition Not So Universal

Among the study’s 59 participating sites, the CK-MB value chosen as the upper limit of normal (ULN) varied widely, from 2.6 ng/mL to 10.4 ng/mL (median 5.0 ng/mL). Because the universal definition of periprocedural MI—at least 3 times the ULN—considers relative changes in CK-MB, the number of patients diagnosed with that event also varied among the centers.

Peak postprocedural CK-MB values were:

• < 5 ng/mL in 74.5% of subjects
• 5 to < 15 ng/mL in 17.6%
• 15 to < 25 mg in 3.9%
• 25 to < 50 ng/mL in 2.5%
• ≥ 50 ng/mL in 1.5%

At 1 year, the overall mortality rate was 2.8%, ranging from 2.0% in patients with peak CK-MB less than 5 ng/mL to 12.0% in those with peak CK-MB of 50 ng/mL or higher. Multivariable analyses using the 5 ng/mL-group as reference found that only CK-MB elevations of 50 ng/mL or above independently predicted higher 1-year mortality (adjusted HR 4.71; 95% CI 2.42-9.13; P < 0.001). The degree of excess risk was modest and not statistically significant in the remaining groups.

Further analysis using peak CK-MB as a continuous variable showed that 1-year mortality first appears to spike at 30 ng/mL and then maintains an upward trajectory.

“Our findings suggest that use of absolute (rather than relative) CK-MB levels and a higher threshold for defining [periprocedural] MI (eg, 30-50 ng/mL) would enhance both the ability to compare results across studies and the clinical relevance of any observed therapeutic differences,” the researchers conclude. “To further enhance precision of endpoint determination, use of a centralized core laboratory for CK-MB assessment would be optimal.”

Setting the Standard

In a telephone interview, Dr. Cohen told TCTMD that such widespread changes may require an organized effort to standardize the endpoint, “because in this field consensus is often more important than having the perfect definition. As we acknowledge in the paper, no definition is going to be ideal for all circumstances, because we’re always making a trade-off. We can identify very, very tiny MIs these days, but whether these are important to identify is another matter.”

The range of 30 to 50 ng/mL and above appears to capture which MIs are most clinically relevant, he noted.

That inflection in risk also caught the attention of Morton J. Kern, MD, of the University of California, Irvine (Irvine, CA). “Something really big happens there at [30 to 50 ng/mL],” he said in a telephone interview with TCTMD. Other than that, however, the study simply “told us what we already know, which is higher CK-MB means more events,” he added.

Sorin J. Brener, MD, of Weill Cornell Medical College (New York, NY), said that the ULN came into fashion “because for a long period of time, the assays were not standardized, so it was easier.”

In an interview with TCTMD, Dr. Brener agreed that an absolute rather than relative definition would be preferred, by virtue of improving statistical power, but emphasized that such a cutoff would be meaningless until centers begin consistently using mass spectrometry to assess CK-MB. Another issue, he said, is whether the inflection at 30 ng/mL indicates an abrupt change in risk or if the reality is more continuous.

But What About Patients?

For physicians treating patients, the impact of these nuances in CK-MB measurement is less clear. Few measure the biomarker, Dr. Cohen said, “because we don’t know any way to alter therapy on the basis of the observation that CK-MB goes up. There are things we can do in our practice every day to lower the frequency of this event, but they all have to be done before PCI.” These include aggressive use of antiplatelet drugs prior to intervention, the use of glycoprotein IIb/IIIa inhibitors, and possibly preloading with atorvastatin, he noted, as well as making sure to address side branch occlusion.

Moreover, “[c]linicians read research studies that use these endpoints,” Dr. Cohen added. “Drugs and devices that we use in daily practice are approved based on these endpoints. That’s why it’s important for clinicians to understand this.”

Dr. Brener also stressed that clinicians should not write off CK-MB. “We should still measure it. It [not only] is a very useful research and quality assurance tool [but also can be used to] separate the people who have very large MIs from those who have little MIs. And I think it does help to tailor therapy, such that patients with larger MIs should be followed more carefully” after discharge, he advised.

In addition, registries should require participating hospitals to measure and report CK-MB levels, Dr. Brener said, so as not to put those institutions that choose to do so voluntarily at a disadvantage.

Understanding “prognosis is always good,” Dr. Kern noted, “but does it change what you’re going to do?” Probably not in the case of CK-MB, since there are no obvious ways to alter therapy, he said, adding that the main interest may be to those developing new devices.

Rise in CK-MB: Surrogate or Real Event?

Another issue the study does not resolve, said Dr. Cohen, is the long-standing debate over whether CK-MB elevations are just markers of more severe disease or if they represent real, stand-alone events.“[P]eople have difficulty accepting the concept that a very small MI that damages just a few myocytes could truly be something that adversely affects long-term mortality in these patients,” he explained.

Dr. Brener counted himself a member of this camp, noting, “It’s hard to believe that [increased CK-MB] represents the actual loss of muscle, which is usually trivial. . . . What is it? It’s unclear. My belief has always been that it’s a marker of severe coronary disease.”

 

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Source:
Lindsey JB, Kennedy KF, Stolker JM, et al. Prognostic implications of creatine kinase-MB elevation after percutaneous coronary intervention: Results from the Evaluation of Drug-Eluting Stents and Ischemic Events (EVENT) registry. Circ Cardiovasc Interv. 2011;Epub ahead of print.

 

 

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