Determining myocardial infarction after PCI: CK-MB, troponin, both, or neither?

Cardiac troponins (cTn) are the most sensitive and specific markers available for the diagnosis of myocardial injury.¹ Because these are highly desirable characteristics for diagnostic markers, cTn has been universally accepted as the gold standard to diagnose myocardial tissue injury.¹ Current guidelines recommend that values above the 99th percentile of a normal reference population should be used to diagnose myocardial necrosis and, in the appropriate clinical scenario, myocardial infarction (MI).¹ Despite some resistance related to the sensitivity of this marker resulting in many patients presenting with positive values as compared with the less sensitive and specific creatine kinase (CK)-MB, cTn has become the key diagnostic test, with significant therapeutic implications, in patients presenting with suspected spontaneous myocardial ischemia.²

cTn and CK-MB

In the context of percutaneous coronary intervention (PCI), the issue of diagnosing myocardial necrosis and infarction is more complex and controversial.³ There is uncertainty on what constitutes a PCI-related MI (i.e., type 4a MI), and whether biomarker alone is sufficient to define an MI in the absence of clinical or angiographic evidence of ischemia. The majority of data indicating an association between elevated post-PCI myocardial necrosis biomarkers and mortality have originally been obtained with CK-MB and standard thresholds to define PCI-related MI, typically three to five times the upper limit of normal.⁴ While it is inarguable that PCI-related elevation of myocardial necrosis biomarkers indicates some degree of myocardial cell damage, many factors fuel the controversy on the clinical relevance of PCI-related myocardial injury and whether isolated PCI-associated biomarker elevation should be considered an MI.

First, unlike spontaneous MI, in which there is a unifying mechanism leading to the event (i.e., acute plaque rupture with superimposed thrombosis), there is not a common process causing peri-procedural biomarker elevation.³ Side branch occlusions, distal embolization of plaques disrupted by the balloon or stent, platelet-rich microthrombi, vasospasm, and transient ischemia due to balloon inflation are among the proposed mechanisms.^{1, 3} Second, PCI-related biomarker elevation are often “silent” events, without associated clinical or angiographic features consistent with acute myocardial ischemia.⁵ 

Nonetheless, MRI studies have demonstrated that CK-MB and cTn post-PCI increases correlate with MRI-detected myocardial necrosis.⁶ In addition to imaging studies, there is an extensive literature evaluating the correlation between CK-MB elevation post-procedure and outcomes.⁷ While the results of studies correlating CK-MB and long-term mortality have not been consistent, overall they have established a graded association between extent of increase of CK-MB post-PCI and mortality that become clearer above thresholds of three to five times the ULN, with smaller increases having less consistent statistical association with mortality.³ These findings have laid the basis for a widely adopted definition of PCI-related MI in clinical trials.⁸

A third issue that has contributed to questions regarding clinical relevance of PCI-related myocardial necrosis is the lack of specific therapies to treat these events. However, in view of the observed association between PCI-related MI and outcomes, therapies to reduce the occurrence of PCI-related MI have been developed, and PCI-related MI has been a key outcome measure in trials with novel antiplatelet medications.⁸ 

The question of “equivalency”

CK-MB and cTn assays are used to detect the same phenomenon (i.e., myocardial cell injury), and therefore one would expect that if a correlation exists between per-PCI CK-MB elevation and prognosis, a similar one should exist for cTn. In addition, cTn assays have the advantage of being more sensitive, thus being capable of detecting a smaller amount of myocardial necrosis, and are more specific, thus providing near certainty of a myocardial origin of the increased values. For these reasons, replacing CK-MB with cTn for the definition of PCI-related MI has been advocated.⁹ There is also a practical advantage in using cTn-based definition, as cTn assays are currently nearly ubiquitous and use of CK-MB is becoming less common.¹⁰ Because of their sensitivity, concerns regarding clinical significance of cTn elevation after PCI have been raised. With cTn, at the same thresholds as those used for CK-MB (3-5x ULN), the prevalence of PCI-related MI is substantially higher, but is indicative of a smaller amount of cellular damage, with uncertain clinical consequences.⁵

The 2007 version of the Universal MI definition recommend values >3 times the 99th percentile of the reference range for both cTn and CK-MB, which was then raised to above five times the 99th percentile in the most recent update.¹ The document recognizes that these thresholds are arbitrary. Because of different sensitivity, it is questionable whether the same threshold which had been used for CK-MB should also apply to cTn, because at the same relative increase above the 99th percentile, cTn likely reflects a much smaller amount of injured myocardium. The point of “equivalency” between cTn and CK-MB remains unclear, and is likely to vary by cTn assay.

To assess clinical relevance of cTn elevation post-PCI, several studies have been conducted to assess the association with prognosis, with very inconsistent results: some, but not all, show an association with mortality.³ A common limitation of the studies is they have not systematically addressed the issue of elevated pre-PCI cTn values, which is often the case in patients with acute coronary syndromes. In some of those studies patients with elevated cTn prior to PCI were simply excluded (thus excluding patients at higher risk of subsequent ischemic events) or it was not specifically identified if the cTn elevation post-PCI represented a new episode of myocardial necrosis separate from the initial ACS presentation.

A critical point emphasized by the definition is that in order to detect PCI-related MI, cTn values have to be normal or descending prior to the procedure; otherwise it is not possible to distinguish new post-PCI elevation from natural evolution of preceding MI.

Despite the contradictory evidence, the last two versions of the Universal MI Definition have recommended cTn as the biomarker of choice for the detection of myocardial cell injury related to PCI.^1,11 Despite the recommendation, the adoption of a cTn-based PCI-related MI definition has been very limited in clinical trials.⁸ Reported reasons by surveyed principal investigators were 1) that the recommended diagnostic threshold for cTn was thought to be too low; 2) a belief that there was a lack of clinical relevance of asymptomatic cTn elevations after procedures; and 3) the lack of proof of independent relationship with mortality.⁸

Troponin levels and mortality

To address some of the important issues described above we recently evaluated the association between post-PCI cTn and mortality at one year in a large cohort of patients with NSTE-ACS undergoing PCI who participated in the EARLY ACS and the SYNERGY trials.⁵ A key methodological aspect of our study is the systematic assessment of temporal trends of cTn prior to PCI. For each patient, cTn-time trends curves were created and reviewed to identify those patients in which cTn was positive and still ascending prior to PCI. Those patients were excluded from analysis because it is not possible to distinguish new post-PCI elevation from the natural evolution of the presenting spontaneous MI. By limiting the population analyzed to NSTE-ACS patients with stable or falling cTn pre-PCI using this novel methodology, we observed a highly significant and independent association between post-PCI cTn peak and one-year mortality, with a 7% relative increase in the hazard of mortality for each 10xULN increase in peak cTn (HR: 1.07, 95% CI: 1.02 to 1.11; p = 0.0038). 

We also compared the risk of mortality associated with CK-MB and found that the threshold to reach the same mortality was markedly different with these two biomarkers. The risk of predicted mortality with CK-MB of 3xULN or above was reached by cTn at a threshold of approximately 60xULN. With a CK-MB threshold of >5x ULN, a cTn >100xULN was required to have a similar mortality risk. Interestingly, the proportion of patients who had values above these corresponding thresholds was similar (i.e., 13.5% had cTn >60 xULN and 14.5% had CK-MB >3xULN; 8.8% had cTn >100xULN and 8.2% had CK-MB >3xULN), suggesting that the amount of injured myocardium might also have been similar at these thresholds. 

Consistent with our findings were the data published by Novack and colleagues in elective PCI patients, in which a cTn of >20xULN provided a similar risk of one-year mortality and similar frequency of MI as CK-MB>3xULN.¹² While the cTn to CK-MB equivalency threshold in our two studies varies (60xULN vs. 20xULN), which may be due to different populations (i.e., ACS patients in our study, elective patients in the Novack study), the two studies deliver a consistent message: both cTn and CK-MB elevation post-PCI are associated with mortality, but the thresholds are much higher if cTn is used compared to CK-MB.

In summary, PCI-associated myocardial injury detected by either CK-MB and cTn elevation post-PCI has significant prognostic implication on long-term mortality. CK-MB and cTn provide similar information, and we concur with the current guideline recommendation that cTn should represent the marker of choice to detect post-PCI myocardial necrosis, given higher specificity and sensitivity and the lack of incremental information provided by CK-MB, with CK-MB used when cTn is not available. The cTn threshold to define MI should be much higher than the CK-MB threshold. Consensus and additional data are needed to define clinically meaningful thresholds in the diagnosis of PCI-associated MI and whether additional clinical or angiographic criteria are needed.

References

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