Prognostic Significance of Post-CABG Enzyme Elevations

In this issue, Mauermann et al1 examine the prognostic value of high-sensitivity troponin T (hsTnT) elevation after coronary artery bypass grafting (CABG). To put this article into the proper perspective, a review of what we know about post-CABG enzyme elevations is useful. Enzyme elevations after CABG are common and were, at one time, believed to be a benign concomitant of the surgery. A number of smaller studies,2–5 and then a large meta-analysis,6 examined the prognostic significance of these postoperative enzyme elevations. The meta-analysis examined 18,908 patients, by far the largest study of this subject, and showed a strong, graded, independent association of creatine kinase-MB and troponin with mortality for all ratios of postprocedure enzyme level to the upper limit of normal greater than 1.0. Interestingly, in this study, enzyme elevations in the first 24 hours after surgery continued to be significant indicators of late prognosis for those surviving 30 days and also for those surviving for 1 year. These data made clear that even small enzyme elevations after CABG have prognostic importance. Other smaller studies, not included in this meta-analysis, lead to qualitatively similar conclusions, and quantitative differences likely represent differences in study design, study populations, and study size.7 That even modest enzyme elevations post-CABG are predictive of long-term prognosis and the graded association of worsening prognosis with the degree of enzyme elevation has relevance for a number of reasons, including the potential to use enzyme elevation determinations as surrogate end points in clinical trials and perhaps even as a metric of surgical quality. An improved understanding of the clinical relevance of elevated enzymes post-CABG requires a more complete understanding of the reasons for both the long-term prognostic significance of small enzyme elevations and the basis for the graded association of elevation with outcome. Are postoperative elevations simply markers of more aggressive disease or is the necrosis that results in enzyme elevation in the pathophysiologic train of events leading to death? If enzyme elevations are just markers of disease independent of the consequences of physiologic damage due to necrosis, then some mechanism would be needed that quantitatively links enzyme elevation after CABG to long-term prognosis independent of severity of physiologic damage due to necrosis. From first principles, this seems unlikely. Additionally, a graded relationship of enzyme elevation to prognosis also exists for percutaneous intervention.8 In the absence of sudden occlusion of a vessel, the mechanism of necrosis is different in these 2 procedures and yet the graded prognostic significance of enzyme elevations is qualitatively similar. The conclusion most likely to be correct is that the necrosis produced by these procedures is causally related to prognosis and not just a marker of aggressive disease. The observed relationship of post-CABG enzyme elevation to long-term prognosis offers the possibility of using the occurrence and severity of enzyme elevation as a surrogate end point in clinical trials or as a metric of CABG quality. However, use as a quality metric will require clarity regarding the mechanism by which even a small enzyme rise detriments prognosis to assure that the increased mortality is primarily related to the surgery and not to patient characteristics that would have resulted in a rise regardless of the quality of the operation. The next fundamental question is not whether post-CABG enzyme elevations have prognostic significance, this is now established, but rather why do even small amounts of necrosis predict late prognosis? This is the context surrounding the article by Mauermann et al.1 They included a total of 1155 patients who underwent on-pump CABG, valve surgery, or combined valve and coronary surgery. The study used an hsTnT assay and found, as expected, that enzyme elevations independently predict 30-day and 1-year prognosis. Although anticipated based on prior work, the article confirms that when newer assays of troponin are used, enzyme elevations continue to have prognostic significance. In this article, a number of the patients who had only valvular disease were included. An analysis of this subgroup might have provided an indication of whether troponin elevation is just a marker of aggressive coronary disease or, instead, directly in the pathophysiologic pathway. The authors also make the point that hsTnT determinations add to the prognostic significance of the European System for Cardiac Operative Risk Evaluation Score (EuroSCORE). In this context, it is to be noted that, while the EuroSCORE predicts outcome using a series of variables, correcting for EuroSCORE is not necessarily the same as correcting individually for the variables that compose the score. Such an approach would have resulted in a more compelling analysis. The article leaves to the future any attempt to define the mechanism by which enzyme elevation, particularly modest elevations, contribute to mortality. One approach would be a larger but similar cohort of valvular heart disease patients in whom the prognostic significance of modest troponin elevations could be compared to the prognosis in patients with valvular heart disease and no postoperative enzyme elevation. DISCLOSURES Name: Michael J. Domanski, MD. Contribution: This author helped analyze the evidence and write the manuscript. Name: Michael E. Farkouh, MD, MSc. Contribution: This author helped analyze the evidence and write the manuscript. This manuscript was handled by: W. Scott Beattie, PhD, MD, FRCPC.

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