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Journal of the American College of Cardiology Vol. 48, No.

9, 2006
© 2006 by the American College of Cardiology Foundation ISSN 0735-1097/06/$32.00
Published by Elsevier Inc. doi:10.1016/j.jacc.2006.08.008

EDITORIAL COMMENT to 4 g of myocardial tissue, or how critical is a marker of


plaque instability once the plaque is “sealed” with a stent?
Measuring In this issue of the Journal, Prasad et al. (7) examine the
Troponin Elevation After significance of isolated elevation in plasma troponin T after
uncomplicated percutaneous cardiac intervention (PCI).
Percutaneous Coronary Intervention Among 4,760 patients undergoing PCI, 1,949 had normal
baseline CK-MB and troponin T and had their post-
Ready for Prime Time?* procedure troponin levels evaluated; 383 (19.6%) of these
Neal S. Kleiman, MD patients had elevation in troponin T but not CK-MB after
Houston, Texas the procedure. This occurred despite nearly 50% use of
glycoprotein (GP) IIb/IIIa antagonists and 90% stent place-
Since the description by Klein et al. (1) of unexpected rise in ment. As expected, the degree of underlying illness in these
plasma creatine kinase muscle-brain fraction (CK-MB) patients was greater than in patients in whom circulating
following percutaneous transluminal angioplasty, debate has troponin T was undetectable. The number of in-hospital
ensued concerning the mechanisms, meaning, and impor- events was relatively small, and only at about the first year
tance of this phenomenon. Postulated mechanisms for its was the rate of death or myocardial infarction observed to be
occurrence have included transient balloon-induced isch- higher in the troponin-positive group. At 3 years, mortality
emia, side branch occlusion, and embolization of platelet- in this seemingly low-risk group of patients was 13%,
compared with 7% in patients without troponin T elevation
fibrin aggregates along with atherosclerotic debris. Data
(partial hazard ratio 1.2, 95% confidence interval 1.02 to
extracted from several large databases have indicated that
1.40). Among the variables studied, troponin T elevation
when levels of CK-MB release are high, the relationship
was found to be an independent predictor of long-term
with ensuing events, particularly mortality, is clear; the
mortality. Commonly quoted rates of myocardial infarction
largest of these databases (those with the most statistical
after PCI, as defined using CK-MB, range from 6% to 10%,
power) have also indicated that the long-term relative risk of
depending on the underlying risk of the patient population.
mortality is increased even when the levels of enzyme
The data of Prasad et al. (7) indicate that infarction (based
elevation are relatively low (2). A study by Kong et al. (3)
on European Society of Cardiology/American College of
suggested that the diffuse nature of microinfarction repre-
Cardiology standards, which include troponin elevation [8])
sented by CK-MB elevation might provide the substrate for
occurs in an additional 20% of patients. These figures are
sudden cardiac death as a mechanism of mortality. Other concordant with observations made in multicenter registries
authors, however, have suggested that CK-MB elevation (EVENT [A Multicenter Registry for the Evaluation of
may be most important as a covariate of lesion complexity Drug Eluting Stents and Ischemic Events] Investigators,
and the extent of coronary atherosclerosis (4). Now that the 2006). Clearly, myocardial infarction after PCI is more
troponins and other markers of myocardial necrosis have common than is readily believed. As the number of markers
become available, similar questions about their importance available to detect myocyte injury continues to grow, and as
in the prognostication of patients following percutaneous the sensitivity for detecting them increases, the observed
procedures are arising. rates will likely increase.
What do these findings mean? The answer is 2-fold.
See page 1765 First, it must be recognized that clinical events continue to
occur after patients who have had successful PCI are
Recent evidence, obtained using diffusion-weighted mag- discharged from the hospital. Although hospital mortality is
netic resonance image scanning has confirmed the near low, mortality continues to accrue after hospital discharge.
universal finding that CK-MB and troponin elevations are The e-Cypher Investigators recently reported that among a
associated with areas of reduced perfusion consistent with broad population of more than 14,000 patients undergoing
myocardial infarction (5,6). Few observers would seriously placement of a sirolimus-eluting stent in late 2004 and
argue that release of either marker is not associated with 2005, mortality rose from 0.6% at 30 days to 1.4% at 6
infarction at the cellular level. Of course, the clinical months and 2.2% at 1 year (9). Although CK-MB elevation
significance of these events needs to be resolved. In the age has been a useful surrogate for mortality, not all deaths
of near-universal stenting, more complete revascularization, during follow-up can be predicted on the basis of CK-MB
and low restenosis rates, how important is an infarction of 3 elevation; some authors have argued that rather than a
surrogate, it should be viewed as one of many risk factors
(4). Because the attributable risk associated with CK-MB
*Editorials published in the Journal of the American College of Cardiology reflect the elevation greater than 3-fold is approximately 14% (10), it is
views of the authors and do not necessarily represent the views of JACC or the
American College of Cardiology. almost certain that additional factors are involved. Addi-
From the Methodist DeBakey Heart Center, Houston, Texas. tional markers may be useful to help refine risk estimates.
1772 Kleiman JACC Vol. 48, No. 9, 2006
Editorial Comment November 7, 2006:1771–3

The second part of the answer lies in the additional troponin, determination would involve little additional ef-
prognostic information obtained from examining additional fort. Second, new trials of therapies designed to reduce
markers after PCI. In principle, it is likely that an associa- periprocedural infarction (defined using CK-MB) should
tion can be found between elevation of any abnormal also include data collection concerning the frequency of
protein in the blood after PCI and worse outcomes. Most troponin elevation and the effect of the treatment on it.
studies that have examined the significance of troponin Correlation of clinical outcomes with changes in troponin-
elevation were relatively small and did not include long term defined infarction should follow. Such observations would
follow-up. In the largest of these studies, Kini et al. (11) be useful in determining whether troponin is a useful
observed that approximately 25% of patients with normal surrogate for mortality after PCI. Formal rules are evolving
post-procedure CK-MB had elevations in the levels of for acceptance of an end point as a valid surrogate (15), and
troponin I. In contrast with the present study, follow-up these will need to be applied to newly recognized biomar-
was for 12 months; CK-MB was the most powerful predic- kers.
tor of events during this period. Unlike the observations At least one novel experimental use also exists for
made by Prasad et al. (7), only elevations of troponin troponin measurement after PCI. Data from a number of
exceeding 5-fold predicted events during follow-up. Inter- sources indicate that endothelialization is delayed after
estingly, the estimated hazard ratios for troponin I elevation placement of drug-eluting stents compared with bare-metal
(1.1 to 1.4, depending on the level of elevation) were very stents (16); there has been concern about the effect of this
similar to those of Prasad et al. (7). phenomenon on subacute and late stent thrombosis (17). It
At the current time, the findings of Prasad et al. (7) is also possible that delayed endothelialization exposes the
should be viewed as proof of principle rather than as a recipients of drug-eluting stents to a longer risk period for
dictum for altering practice. Over the last 15 years, a wealth microinfarction. Although periprocedural infarction is gen-
of information has accumulated concerning the prognostic erally stated to occur within ⬍24 h after stent placement, it
information surrounding CK-MB elevation. This body of is worth noting that measurement of CK-MB is rarely
knowledge does not yet exist for the troponins. The latest performed after this period. Current assessments are inad-
iteration of American College of Cardiology/American equate to test this hypothesis, and asking patients to return
Heart Association guidelines for PCI now assigns a class I to the hospital for daily measurements of CK-MB is clearly
indication for determination of CK-MB or troponin after impractical. Because troponin levels remain elevated in the
PCI complicated by evidence of ischemia and a class IIa blood for days to weeks, 1 or 2 late measurements of
indication for routine collection of either marker (12). troponin several days after hospital discharge might help
During preparation for a number of clinical trials and shed light on this situation. All these steps would be useful
registries, we have learned that about half of the PCI centers in determining whether troponin is useful as a surrogate for
in the U.S. have adopted the latter practice. However, mortality after PCI.
because there is no specific therapy for such patients (other The present report should help refocus the stage light on
than aspirin, clopidogrel, and statins, which are routinely post-procedural infarction. We now know that it happens,
used in post-PCI patients anyway) the utility of the test for even in the context of modern techniques (i.e., well-
clinical decision making rather than for informational pur- developed technical skills, aggressive use of GP IIb/IIIa
poses remains in question. The recognition of CK-MB antagonists, clopidogrel, and modern stents). If we are to
elevation as an important prognostic indicator, and its continue to reduce the long-term morbidity and mortality in
acceptance as a surrogate for catastrophic clinical events was patients who have had interventions, we will need to
instrumental in the development of “adjunctive” therapies recognize that there are new markers of risk that merit our
designed to reduce the rate of periprocedural infarction. attention.
Post hoc analyses of these treatments has confirmed the
relationship between reductions in enzyme release with Reprint requests and correspondence: Dr. Neal S. Kleiman,
reduction in mortality (13,14). Perhaps the recognition that Methodist DeBakey Heart Center, 6565 Fannin MS F-1090,
troponin T elevations occur after otherwise uncomplicated Houston, Texas 77030. E-mail: nkleiman@tmh.tmc.edu.
procedures and are associated with a 20% increase in
long-term mortality ought to prompt the development of
new strategies, both short- and long-term. As has been the REFERENCES
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JACC Vol. 48, No. 9, 2006 Kleiman 1773
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