Editor's Note: This article is in response to Cavallini C, Verdecchia P, Savonitto S,et al. Prognostic value of isolated troponin I elevation after percutaneous coronary intervention. Circ Cardiovasc Interv. 2010 Oct;3(5):431-5.

The prognostic value of elevated CK and CK-MB after percutaneous coronary intervention (PCI) is reasonably established;^{1, 2} however, the impact on long-term outcome of elevations in cardiac troponin (cTn) not associated with a concomitant rise in CK-MB is less clear. This issue is of particular interest given the recommendations that an increase in cTn exceeding three times the 99th percentile of a normal reference population (upper reference limit, URL) should define PCI-related myocardial infarction.³

In the largest such study performed thus far, Cavallini et al. sought to determine whether “isolated” cTnI elevations (ie, not associated with a concomitant elevation in CK-MB levels) after PCI was predictive of long term mortality.⁴ To do so, the authors performed a retrospective analysis of data collected from a prior CK-MB and PCI study,⁵ a prospective, multicenter, cohort study that enrolled 3494 consecutive patients without ST elevation undergoing PCI in 16 Italian hospitals. Blood samples were drawn in each patient immediately before PCI (baseline) and at 12 and 24 hours after the procedure. Cardiac markers included CK-MB (upper reference value 5.0 ng/mL) and cTnI (upper reference value 0.15 ng/mL; this represented the 99th percentile).

To determine the effects of isolated cTnI increases, their analysis was restricted to patients with 1) normal baseline values (<URL) of both cTnI and CK-MB; and 2) normal (<URL) post-PCI values of CK-MB. A multivariate analysis was performed to correct for baseline characteristics, and included both patient and procedural variables known to influence mortality.

A total of 2,362 patients were included that had normal pre and post-procedure CK-MB and pre-procedure cTnI values. An isolated postprocedure cTnI >1×URL was observed in 932 patients (39%), and 467 patients (20%) had cTnI >3×URL, meeting the diagnostic criteria of periprocedural myocardial infarction.

cTnI elevation >3×URL was associated with a significantly worse baseline risk profile, as these patients were older, more likely to have unstable angina, chronic renal insufficiency, multivessel disease, longer stenosis length, and coronary thrombosis. In addition, patients with a post-PCI cTnI >3×URL had a significantly higher rate of procedural complications.

During the two-year follow-up period, 73 patients (3.1%) died. Compared with patients with normal cTnI levels, those with cTnI elevation >1×URL had a slightly higher, although not statistically significant, two-year mortality (3.8% versus 2.6%; HR 1.5; 95% CI, 0.97 to 2.4; P=0.07). In contrast, a cTnI elevation >3×URL was associated with a significant increase in two-year mortality (4.5% versus 2.7%; HR, 1.7; 95% CI, 1.01 to 2.8; P=0.044). However, after baseline and procedural variables were taken into account, it was no longer significant (HR, 1.45; 95% CI, 0.9 to 2.5; P=0.16). Results did not change when the analysis was restricted to patients (n=2,176) who did not have any angiographic complications (side branch closure, transient abrupt vessel closure, distal thromboembolism, and transient slow flow).

Commentary

In this study, a number of issues that are of increasingly important were reported. First, consistent with prior studies,^{6, 7} they found that cTn elevations are relatively common after PCI, occurring in 40% of the patients. Second, in the absence of concomitant CK-MB elevation, low cTnI elevations, those <3×URL, were not associated with worse outcomes. Finally, cTnI values >3×URL, although associated with higher long term mortality, appear to reflect patient and procedural factors associated with worse outcomes, rather than being an independent predictor of mortality.

A strength of this study is that patients with pre-procedural cTnI elevations were excluded, a group which in the past has been associated with worse outcomes.⁸ Additionally, they focused primarily on patients who had cTnI elevations without CKMB elevations, a group in whom outcomes data is less clear. As the sensitivity of assays has improved, we are increasingly detectingcTn elevations post procedure. Newer evidence, such as that provided by Cavallini et al.,⁴ indicate these low level marker elevations may not be as adversely prognostic as previously reported. Additional strengths include the large number of patients included, inclusion of patient and procedural variables into the prediction model, use of standardized definition and use of a single assay at a core site for measurement of cTn.

Why does cTn appear to be less predictive? First, many previous studies did not differentiate between patients who had pre-procedural cTn elevations, a group whom has subsequently been found to be at increased risk.⁸ A second reason is that as the sensitivity of assays has improved, cTn elevations post procedure are increasingly being detected. Newer generation assays are both more sensitive and specific; therefore, small amounts of myocardial damage that were below the range of older assays can now be quantitated. Newer evidence, such as provided by Cavallini et al⁴ indicates these low level marker elevations may not be as detrimental as previously thought.

Additional data supporting this comes from studies using cardiac magnetic resonance imaging (cMRI). In one of the first studies of this type, post procedural cTn elevations were associated with evidence of MI with a mean myocardial mass of approximately 5 gm of infracted tissue.⁹ In contrast, a more recent study, using a more sensitive cTn assay, found that evidence of infarction was present in only 45% of patients with cTnI elevations, with a mean infarcted LV mass of only 0.8 gm.¹⁰ Thus, it appears that with current assays, minor post-procedure cTn elevations are more benign than previously thought.

Risk factors for post PCI marker increase include patient factors, lesion characteristics and procedural complications. Given the multitude of possible etiologies, cTn elevations in the absence of CK-MB elevations likely do not serve as a valid quality measure, as higher risk, more complex patients are more likely to have marker elevations, irrespective of the procedural success. In addition, any such analysis is confounded if patients with pre-procedural elevations, a known high risk group,⁸ are not analyzed separately.

The lack of side branch occlusion or abrupt vessel closure, or other obvious complications, and failure to demonstrate infarction by cMRI, indicate the cTn elevations that occur post PCI result from distal embolization of proximal platelet-thrombi aggregates, with distal showering down stream, resulting in small amounts of patchy necrosis, below the detection threshold of current imaging techniques. Therefore, although not a valid PCI quality measure, cTn elevations post procedure could be a valid end-point for clinical trials designed to compare acute coronary syndrome treatments.

The implications of this study are important as we shift towards a cTn definition, with less use of CK-MB, and will require improved standardization of assays and cut-off values. The wide variation in assays and reported URLs that are used has significant implications for reporting and comparing outcomes if cTn values are used. For example, two centers, each using cTnT, but one with an URL of 0.01 ng/ml and the other 0.03 ng/ml, would have markedly different rates of post procedural MIs. In the first center, values >0.03 ng/ml would be considered an MI; in the second, it would take a value >0.09 ng/ml, 9 x that of the first center, to be considered an MI. Thus, it is critical that any study using post procedural MI as an end-point will need to standardize both the assay and the URL that is used.

References

1. Akkerhuis KM, Alexander JH, Tardiff BE, et al. Minor myocardial damage and prognosis: are spontaneous and percutaneous coronary intervention-related events different? Circulation 2002;105:554–6.
2. Simoons ML, van den Brand M, Lincoff M. Minimal myocardial damage during coronary intervention is associated with impaired outcome. Eur Heart J 1999;20:1112–9.
3. Thygesen K, Alpert JS, White HD, on behalf of the Joint ESC/ACCF/AHA/WHF Task Force for the Redefinition of Myocardial Infarction. Universal definition of myocardial infarction. Circulation 2007;116:2634–53.
4. Cavallini C, Verdecchia P, Savonitto S,et al. Prognostic value of isolated troponin I elevation after percutaneous coronary intervention. Circ Cardiovasc Interv 2010 Oct;3(5):431-5.
5. Cavallini C, Savonitto S, Violini R, et al. , on behalf of the Italian “Atherosclerosis, Thrombosis, and Vascular Biology” and “Society for Invasive Cardiology–GISE” Investigators. Impact of the elevation of biochemical markers of myocardial damage on long-term mortality after percutaneous coronary intervention: results of the CK-MB and PCI study. Eur Heart J 2005;26:1494–8.
6. The SYMPHONY and II SYMPHONY Cardiac Markers Substudy Investigators. Prognostic significance of elevated troponin I after percutaneous coronary intervention. J Am Coll Cardiol 2002;39:1738–44.
7. Prasad A, Singh M, Lerman A, et al. Isolated elevation in troponin T after percutaneous coronary intervention is associated with higher long term mortality. J Am Coll Cardiol 2006;48:1765–70.
8. Prasad A, Rihal CS, Singh M, et al. . Significance of periprocedural myonecrosis for outcomes following percutaneous coronary intervention: an analysis of pre and post intervention troponin T levels in 5487 patients. Circ Cardiovasc Intervent 2008;1:10–9.
9. Selvanayagam JB, Porto I, Channon K, et al. Troponin elevation after percutaneous coronary intervention directly represents the extent of irreversible myocardial injury: insights from cardiovascular magnetic resonance imaging. Circulation 2005;111:1027-32.
10. Locca D, Bucciarelli-Ducci C, Ferrante G, et al. New Universal Definition of Myocardial Infarction: Applicable After Complex Percutaneous Coronary Interventions? J Am Coll Cardiol Intv 2010 3: 950-8.

Keywords: Creatine Kinase, MB Form, Myocardial Infarction, Troponin, Percutaneous Coronary Intervention

< Back to Listings