Are You Worried About Re-Infarction or Rhabdo: Does CK-MB matter?

It seems like only yesterday, I was writing about the silliness of some order set (link) with a one-click stop for amylase, lipase, and ketones. Now, for another.

In some hospitals, a single, “cardiac markers” click orders troponin I and a CK with a reflex to CK-MB. Two tests in the time it takes to just order one. What efficiency! At this rate, a button labeled “labs” should automatically order an amylase, D-Dimer, cholesterol panel, and PSA along with the usual troponin, CK, CMP, CBC. It would be the most efficient click ever.

And yet, the fancily named American Heart Association surprised me with their newest guidelines on NSTEMI [1] in which they pontificate, “With contemporary troponin assays, creatine kinase myocardial isoenzyme (CK-MB) and myoglobin are not useful for diagnosis of ACS. (Level of Evidence: A)” and give it a score of “No Benefit”. They continue that CK-MB is much less sensitive than trop, and doesn’t add benefit to a troponin value. But this is the same organization that recommends stress tests for low risk chest pain (really?) – so let’s look at the evidence.

Let’s start with some statistics.

An anaylsis of ROC curves [2] for troponin, CK-MB, myoglobin, and various combinations of these showed the expected increased sensitivity and specificity of trop I. They also demonstrated no added sensitivity with the addition of CK-MB or myoglobin to the troponin at peak concentrations.

But statistics shmetistics, how did actual patients do?

A retrospective study [3] looked at outcomes with patients that had both troponin and CK sent. They found no difference in mortality or percent taken to cath between the CK-MB neg/trop neg group and the CK-MB pos/trop neg patients. They conclude that “An elevated troponin level identifies patients at increased acute risk regardless of CK-MB status, but an isolated CK-MB+ status has limited prognostic value.”

Our Swedish colleagues have looked at this as well [4]. They prospectively tested trop I, CK-MB, and myoglobin q 30 minutes for the first 2 hours, then at 3, 6, and 12 hours after ED presentation. Out of 197 patients, troponin was more sensitive than either CK-MB or myoglobin, and, in two separate strategies, adding CK-MB or myoglobin to the troponin did NOT statistically significantly improve sensitivity or specificity. A trop I < 0.1ug/L as a single cut-off resulted in less false positives without changing sensitivity compared to combining trop with CK-MB and myglobin.

Another [5], retrospectively identified 11,092 patients with trop and CK-MB index, and found only 7 (0.06%) patients with trop (-)/ CK-MBi (+). None of these patients underwent catheterization, had an MI, or died in the next 30 days. Out of an additional 4,910 patients who received trop as an inpatient, 4 patients had CK-MBi (+) with trop (-). From the total 11 patients identified, 4 received stress tests (all negative). The rate of true positive CK-MB index with negative troponin here was 0% (99% CI, 0-0.4%). They conclude that with a negative troponin, an added CK-MB index is of no benefit.

What percent of people should be helped by a test for you to order it? Even if the pos CK-MB index with a neg trop helped people, here it was only found in 0.06% of cases. That’s a NNT of 1,584!

So, CK-MB is not helpful in negative troponins. Logically, it’s not helpful in positive troponins, but what about in intermediate troponins?

The same first author [6], looked at the CK-MB index in intermediate troponin (values between 0.01 and 0.09). Out of 2,512 intermediate troponins, 28 had a positive CK-MB index.

Of these 28 –

…..21 had no increase in trop on repeat testing and were judged by the treating physician to not have MI

…..1 had an intracranial hemorrhage and no further testing was done.

…..1 had hyperkalemia, and the inpatient team did not repeat the troponin or pursue a cardiac work-up.

Even if the CK-MB helps the remaining 5 patients, the NNT is 502. But does it help?

…..4 had an elevated second trop and were urgently cath’d AFTER the positive troponin. One had no CAD, three did.

…..1 was cath’d for hyperacute T waves, a concerning clinical picture, and a significant history of CAD. He had CAD without an acute blockage or stentable lesion and his second troponin was also negative.

The final rate of true positive CK-MB index with an intermediate troponin was 0.16% (95% CI, 0.04%-0.41%).

When to send CK/CK-MB?

1. For re-infarction! Trop stays elevated for over a week while CK-MB levels usually return to normal by day 4. If someone has another NSTEMI after day 4, but before the trop has decreased, a rising CK-MB can help diagnose MI.

2. Rhabdo is diagnosed by an elevated CK.

Any other uses for CK/CK-MB you can think of?

Lastly, this review was made extra complicated as the troponin assay, and even which troponin protein is being measured, changes between each paper. At the same time, some papers looked at CK-MB index, while others just at the CK.

To paraphrase from Joe Lex – This is my best, most honest, but imperfect interpretation of an imperfect literature.

By Dr. Andrew Grock

References

[1] Richard W. Smalling and Susan J. Zieman Glenn N. Levine, Philip R. Liebson, Debabrata Mukherjee, Eric D. Peterson, Marc S. Sabatine, Ganiats, David R. Holmes, Jr., Allan S. Jaffe, Hani Jneid, Rosemary F. Kelly, Michael C. Kontos, Ezra A. Amsterdam, Nanette K. Wenger, Ralph G. Brindis, Donald E. Casey, Jr., Theodore G. 2014 AHA/ACC Guideline for the Management of Patients With Non-ST-Elevation Acute Coronary Syndromes: A Report of the American College of Cardiology/American Heart   Association Task Force on Practice Guidelines. Circulation. published online September 23, 2014

[2] Apple et al. Simultaneous rapid measurement of whole blood myoglobin creatine kinase MB, and cardiac troponin I by the triage cardiac panel for detection of myocardial infarction. Clin Chem. 1999; 45:199-205

[3] Newby LK, Roe MT, Chen AY, et al. Frequency and clinical implications of discordant creatine kinase-MB and troponin measurements in acute coronary syndromes. J Am Coll Cardiol. 2006;47:312-8

[4] Eggers KM, Oldgren J, Nordenskjold A, et al. Diagnostic value of serial measurement of cardiac markers in patients with chest pain: limited value of adding myoglobin to troponin I for exclusion of myocardial infarction. Am Heart J. 2004;148:574-81.

[5] Volz KA, McGillicuddy DC, Horowitz GL, et al. Creatine kinase-MB does not add additional benefit to a negative troponin in the evaluation of chest pain. Am J Emerg Med. 2012;30:188-90.

[6] Volz et al. Should Creatine Kinase-MB Index be Eliminated in Patients with Indeterminate Troponins in the ED. The American Journal of Emergency Medicine.2012;30,1574-1576