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For assessing myocardial injury following percutaneous coronary intervention (PCI), troponin I is overly sensitive and fails to distinguish procedure-related myocardial infarction (MI) from minor injury when the ‘universal definition’ is applied, according to a small study published in the February 8, 2011, issue of the Journal of the American College of Cardiology. The authors conclude that measuring CK-MB is more relevant for clinical management.

Investigators led by Adrian P. Banning, MD, of John Radcliffe Hospital (Oxford, United Kingdom), looked at periprocedural myocardial injury in 32 patients who received multivessel PCI as part of the randomized MICASA (Myocardial Injury following Coronary Artery Surgery versus Angioplasty) trial. Myocardial necrosis was assessed using the universal definition, or cardiac biomarker levels above the upper reference limit (URL) of the 99^th percentile of the normal population.

All patients underwent late gadolinium enhancement cardiac magnetic resonance (CMR) imaging—the gold standard for evaluating myocardial necrosis—2 weeks before PCI and 4 to 10 days after revascularization. In addition, using plasma samples obtained at baseline and 1, 6, 12, and 24 hours after the procedure, cardiac troponin I and CK-MB were measured, as were the inflammatory markers tumor necrosis factor (TNF) alpha, myeloperoxidase, high-sensitivity C-reactive protein (CRP), and serum amyloid A.

Patients were stratified into 3 groups of myocardial injury based on the universal definition:

• No injury = biomarker normal or less than the 99th percentile URL
• Periprocedural necrosis = biomarker 1-3 times the 99th percentile URL
• MI type 4a or PCI-related MI = biomarker more than 3 times the 99th percentile URL

Significant Discrepancy Seen

Baseline CK-MB and troponin I values were similar for the 3 groups. Five of 32 patients (15%) showed CMR evidence of necrosis following PCI. The mean peak troponin I value in these patients was 13.4 µg/l vs. 0.93 µg/l in those without CMR evidence (P < 0.001), while the mean peak CK-MB value was 28.3 µg/l in CMR-positive patients vs. 4.7 µg/l in CMR-negative patients (P < 0.001). All 5 CMR-positive patients met the criteria for procedure-related MI by troponin I definitions, while only 3 were classified as having MI and 2 as having periprocedural myocardial necrosis using CK-MB definitions.

The distributions of patients into myocardial injury groups differed markedly depending on the biomarker used, with many more patients categorized as having procedure-related MI when troponin was used compared with CK-MB (table 1).

Table 1. Distribution of Patients by Biomarker Level Using the Universal Definition

With only 5 of the 26 patients in the troponin I-defined MI group showing CMR evidence of necrosis, use of that biomarker yielded a positive predictive value of only 19% and a specificity of 22%. By contrast, with 3 of 5 patients in the CK-MB MI group exhibiting CMR necrosis, that biomarker yielded a positive predictive value of 60% and a specificity of 93%.

Reinforcing the discrepancy between the biomarkers, CMR-positive patients had greater elevations of 2 key inflammatory makers, CRP (18.6 mg/ml vs. 3.6 mg/m; P < 0.01) and amyloid A (34.5 mg/ml vs. 5.3 mg/ml; P < 0.05)—though not of myeloperoxidase or TNF alpha—compared with those without CMR-detected necrosis. Changes in both CRP and amyloid A increased along with the severity of CK-MB-defined injury (P < 0.05 for both markers). By contrast, levels of these markers did not track with the troponin I-defined injury groups.

Recalibrating Troponin Might Help

According to the investigators, receiver-operator characteristic analysis suggests that both troponin I and CK-MB can be used to diagnose periprocedural injury provided the current troponin I thresholds are revised so that the categories of injury are in sync with the CK-MB definitions. They propose an “ideal” troponin I cutoff of more than 12 times the 99th percentile URL (0.8 µg/l) for periprocedural injury and more than 40 times the 99th percentile URL (2.4 µg/l) for procedure-related MI, with the latter threshold yielding 100% sensitivity and 93% specificity.

According to the authors, there has been ongoing debate about the clinical significance of lower levels of troponin elevation.

Dr. Banning and colleagues conclude that “when applying the current universal definition of MI to periprocedural injury, CK-MB should . . . be the preferred biomarker. Under the current definition criteria, troponin is oversensitive with the arbitrary limit of 3 times the 99th percentile failing to discriminate between necrosis and procedure-related MI. Redefining the troponin I thresholds for necrosis and MI will allow a more-standardized diagnostic approach to diagnosing [periprocedural myocardial injury].”

Low MI Threshold Has Patient, Trial Implications

In an accompanying editorial, Cindy L. Grines, MD, and Simon Dixon, MBChB, both of William Beaumont Hospital (Royal Oak, MI), caution that the “extremely low threshold for diagnosis of PCI-related MI [using the recommended universal definition] has far-reaching implications for patient care, outcome reporting, and clinical trial design. . . . [G]iven the high frequency of troponin leak after coronary intervention, the key question should be: ‘When is a post-PCI troponin elevation clinically meaningful?’”

Although the investigators’ suggested “optimal” threshold for troponin I-defined periprocedural MI seems reasonable, the editorialists say, “this will require validation in a larger cohort of patients with long-term outcome data.”

Meanwhile, they conclude, until minor troponin leaks detected with high-sensitivity assays are shown to mechanistically impact patient outcome, their routine measurement in patients undergoing PCI is of limited value.

In an email communication with TCTMD, David A. Cox, MD, of Lehigh Valley Hospital (Allentown, PA), praised the study, commenting that its strength lies in the serial biomarker and CMR assessments and the fact that the inflammatory markers support the enzyme findings. Nonetheless, he said, it is difficult to draw firm conclusions from such a small number of patients.

Biomarkers in the Real World

“Most doctors will continue to believe that troponin is great for assessing ACS but will use CK-MB post PCI,” he added. “That’s because the data for CK-MB from large respected centers such as the Cleveland Clinic, the Washington Hospital Center, and Columbia University Medical Center all verify that large CK-MB rises—on the order of 5 to 8 times the upper limit of normal—post PCI do translate into worse clinical outcomes.”

In the real world, however, the great majority of clinicians do not check biomarkers after PCI, Dr. Cox said. “If we suddenly started using troponin, there would be a lot of patients with high [values] post PCI, and some doctors might get nervous and decide to keep their patient an extra day when that isn’t clinically warranted,” he observed.

“This study did a good job of making sure that what we accept as guidelines is truly based on science,” Dr. Cox concluded. “For now, most interventionalists are going to say, ‘I’m not going to use troponin. If I’m worried about my patient post PCI, I’ll measure CK-MB.’”

Ajay J. Kirtane, SM, of Columbia University Medical Center (New York, NY), suggested that the adoption of the universal definition was not entirely arbitrary. In a telephone interview with TCTMD, noted that some prior MI data showed that troponin elevations were associated with myonecrosis as seen on CMR. “Now, however, you’re seeing that troponin elevations are not necessarily correlated with CMR findings, so that calls into question exactly what we’re seeing with troponin elevations,” he said.

Results of Trials Using the Universal Definition Problematic

“The reason this is important,” he noted, “is that . . . about 10 years ago, a lot of pharmacology trials that had periprocedural MI as measured by CK-MB as an endpoint were showing you could reduce [these events], and there was a big debate as to whether that really changed anything prognostically for the patient. Now with the universal definition using troponin, [the uncertainty is taken] one step further. If it was debated whether or not CK-MB was important, it’s an even more of a stretch with troponin.”

According to Dr. Kirtane, “the big issue this article raises is that there are a lot of newer clinical trials powered and tailored with primary endpoints based on the universal MI definition, and now it appears from these data that the applicability of those trial results is in doubt.”

Echoing a point made by the editorialists, Dr. Kirtane said that the message of the study is not that biomarkers should not be measured, because labs that do so appear to have better outcomes, he noted. “However, for everyday practice, [these findings] reinforce the value of CK-MB over troponin. And for clinical trials, this is going to give researchers pause in interpreting trial results based on the universal definition,” he said, adding, “We’re going to have to take this very seriously.”

2. Grines CL, Dixon S. A nail in the coffin of troponin measurements after percutaneous coronary intervention. J Am Coll Cardiol. 2011;57:662-663.

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