This Article Abstract Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Abdelmeguid, A. E. Articles by Ellis, S. G. Search for Related Content PubMed PubMed Citation Articles by Abdelmeguid, A. E. Articles by Ellis, S. G.

(Circulation. 1996;94:1528-1536.)
© 1996 American Heart Association, Inc.

Articles

Significance of Mild Transient Release of Creatine Kinase–MB Fraction After Percutaneous Coronary Interventions

Alaa E. Abdelmeguid, MD, PhD; Eric J. Topol, MD; Patrick L. Whitlow, MD; Shelly K. Sapp, MS; Stephen G. Ellis, MD

the Department of Cardiology, the Cleveland Clinic Foundation, Cleveland, Ohio.

Correspondence to Stephen G. Ellis, MD, Director, Sones Cardiac Cath Labs, The Cleveland Clinic Foundation, 9500 Euclid Ave, F-25, Cleveland, OH 44195 or to Alaa E. Abdelmeguid, MD, PhD, Henry Ford Medical Center, Cardiac Catheterization Laboratory (K-2), 2799 W Grand Blvd, Detroit, MI 48202.

	Abstract

Top Abstract Introduction Methods Results Discussion References

 
Background The clinical significance of minor elevations in creatine kinase–myocardial band isoenzyme (CK-MB) after coronary interventions has not been systematically evaluated.

Methods and Results We examined 4484 patients who underwent successful percutaneous transluminal coronary angioplasty or directional coronary atherectomy and whose peak CK levels did not exceed twice the upper limit of laboratory normal. Group 1 (3776 patients) had no CK or MB elevation after the procedure (ie, CK 180 IU/L, with MB fraction 4%). Group 2 (450 patients) had a peak CK level between 100 and 180 IU/L, with MB fraction >4%, and group 3 (258 patients) had a peak CK level between 181 and 360 IU/L, with MB fraction >4%. The strongest correlate of postprocedure CK-MB elevation was the performance of directional coronary atherectomy (odds ratio, 4.1; P<.0001), followed by the development of 1 in-lab minor procedural complication (odds ratio, 2.6; P<.0001). Clinical follow-up was available in 4461 patients (99.5%), with a mean duration of 36±22 months. Survival analysis, adjusted with Cox proportional hazards regression model, showed that the groups with elevated CK-MB had a significantly higher incidence of cardiac death (risk ratio, 1.3; P=.04) and myocardial infarction (risk ratio, 1.3; P=.03). Major ischemic complications (death, myocardial infarction, and coronary revascularization) occurred more frequently in the groups with increased CK-MB (groups 1 versus 2 versus 3, 37.3% versus 43.3% versus 48.9%; P=.01).

Conclusions This study shows that minor elevations of CK-MB after successful coronary interventions identify a population with a worse long-term prognosis compared with patients with no enzyme elevations and appear to have an adverse effect on long-term prognosis. Future studies of percutaneous coronary revascularization should include routine measurements of biochemical cardiac markers as important predictors of long-term prognosis.

Key Words: creatine kinase • angioplasty • revascularization • enzymes

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
In contrast to the major complications of percutaneous coronary interventions (death, Q-wave myocardial infarction, and coronary artery bypass surgery), the causes, incidence, and clinical significance of elevation of cardiac enzymes have not been systematically studied. This is surprising, given the numerous studies emphasizing the significance and short- and long-term features of spontaneous elevations of cardiac enzymes in different clinical settings.^{1 2 3 4}

Minor elevations in cardiac enzymes after apparently successful percutaneous coronary interventions are common (15% to 26%).^{5 6 7 8 9} Only a few small observational studies with limited follow-up have evaluated the clinical significance of enzyme "leaks" in this setting.^{5 6 10} The conclusion of these studies was that enzyme elevations are frequent after coronary interventions but that they are not associated with adverse short- or long-term events. However, these studies might have lacked the power to detect a subtle yet important sequela from this degree of enzyme elevation.⁶ This is particularly important since any effect that minor changes in creatine kinase–myocardial band isoenzymes (CK-MB) might cause would be expected, statistically, to require a large number of patients followed for a long period of time. This study was undertaken to evaluate the clinical, morphological, and procedural correlates of mild CK-MB elevations after successful percutaneous transluminal coronary angioplasty (PTCA) or directional coronary atherectomy (DCA) in the largest series reported to date. The long-term follow-up of these patients and its relation to CK-MB elevation are also presented.

	Methods

Top Abstract Introduction Methods Results Discussion References

 
Patient Population
This study comprised all patients who underwent successful PTCA or DCA at the Cleveland Clinic between January 1984 and December 1991 and whose postprocedure peak CK levels did not exceed twice the upper limit of laboratory normal (ie, 2x180 IU/L). Patients with acute myocardial infarction within 36 hours, those undergoing a salvage atherectomy for failed PTCA, and those with a procedure for chronic total occlusions were excluded from this analysis. All patients gave informed consent before the procedure.

From an initial population of 5204 consecutive patients, 44 patients (0.8%) were excluded because of missing CK and/or CK-MB data. Major ischemic complications (death, Q-wave infarction, and bypass surgery) occurred in 111 patients (2.1%), and 121 patients (2.4%) had an unsuccessful procedure on 1 stenosis. CK elevation >360 IU/L was present in 273 patients (5.2%). Another 171 patients had a peak CK between 181 and 360 IU/L, with an MB fraction 4% (3.3%). These exclusions left 4484 patients (86.2%) who met the study criteria and constituted the population of this study. The patients were divided into three groups according to the peak CK and MB isoenzyme levels after the procedure. Group 1 (3776 patients) had no CK or MB elevation after the procedure (ie, CK 180 IU/L, with MB fraction 4%). Group 2 (450 patients) had a peak CK level between 100 and 180 IU/L, with MB fraction >4%. Group 3 (258 patients) had a peak CK level between 181 and 360 IU/L, with MB fraction >4%.

Techniques of Angioplasty and Directional Atherectomy
The angioplasty and atherectomy procedures were performed as described in detail elsewhere.^{10 11 12 13} Routine preprocedure and postprocedure care was followed for all patients, including pretreatment with aspirin and a calcium channel blocker. Intravenous heparin (10 000 and 15 000 U) was administered at the beginning of the procedure, followed by additional boluses as needed. After completion of the procedure, the patients were monitored in an intensive care unit or a postprocedure telemetry ward. A 12-lead ECG was routinely obtained after the procedure, on the following day, and in the event of any chest pain. Patients were maintained on aspirin, and a calcium channel blocker was administered for 48 hours after the procedure.

Cardiac Enzyme and Isoenzyme Determination
All patients in this study left the laboratory with a "successful" procedure and underwent postprocedure CK determination under a protocol followed at our institution that calls for routine CK determination 6 to 8 hours after the procedure, on the following day, and in the event of symptoms suggestive of ischemia. Myocardial isoenzyme (CK-MB) determination was performed on CK values >100 IU/L. When the CK was elevated, it was followed every 8 hours until it returned to normal values. The peak CK activity was taken as the maximum value after the procedure in excess of both initial and final values. Total CK activity in serum was determined spectrophotometrically by the standard method of the Scandinavian Committee on Enzymes.¹⁴ The CK-MB isoenzyme values were determined by agarose gel electrophoresis with fluorometric quantification and were expressed as a percent of total enzyme activity.

Clinical and Procedural Variables
Clinical information at the time of the initial presentation and data obtained at the time of the procedure and at discharge were recorded prospectively on standard case report forms and entered in the Interventional Registry Database. An experienced angiographer reviewed the cineangiograms to code for lesion-related morphological variables. Angiographic data were also entered prospectively in the database.

Follow-up
Clinical follow-up data were obtained by trained registry personnel who made telephone contact with the referral patients and by visits of patients followed at our institution. The patients were contacted on a yearly basis and were questioned through the use of a standardized format as to the recurrence of symptoms, cardiac hospitalization (for angina, heart failure, or arrhythmias), repeat revascularization, or myocardial infarction. Follow-up events were analyzed and classified by a physician. The families or physicians (or both) of deceased patients were interviewed to ascertain the cause of death. Autopsy results were reviewed when available. Myocardial infarction was defined as prolonged chest pain with a documented rise in CK greater than twice the upper limit of laboratory normal with a positive MB fraction, or development of new Q waves. Each death was categorized as cardiac or noncardiac. Cardiac death included (1) sudden cardiac death: witnessed, or death occurring within 1 hour of onset of cardiac symptoms, or if the patient was found dead, having previously appeared in normal health, (2) death from arrhythmias, (3) death from documented myocardial infarction, (4) death from progressive heart failure, (5) death after cardiac surgery, and (6) death from other cardiac causes.

Definitions
Success
All patients included in this study had a successful procedure. Success was defined as an increase of 20% in luminal diameter with a final percent diameter stenosis of <50% and no major complications. Bypass surgery, Q-wave myocardial infarction, or death, as defined elsewhere,¹⁶ were considered major complications.

Angiographic definitions
The angiographic definitions used in this analysis have been used in the evaluation of the results of PTCA and DCA and were previously published elsewhere.^{17 18}

Minor procedural complications
The following were considered minor complications: transient in-lab vessel closure, side branch compromise, large dissection, hypotension requiring intravenous vasopressors or intra-aortic balloon counterpulsation, and coronary embolism.

Statistical Analysis
Statistical analysis was performed with the use of a computerized statistical program (SAS Institute Inc). The three groups were compared with the use of the ² or an exact test as defined by Mehta and Patel¹⁹ for categorical variables. One-way ANOVA was used to assess differences in continuous variables. All clinical, morphological, and procedural variables that had a univariate association with CK-MB at a value of P.10 were included in a multivariate proportional odds model²⁰ to identify the factors independently associated with CK-MB. Survival curves were calculated according to the Kaplan-Meier estimates of survival. Univariate time-to-event analyses of CK-MB and the factors independently associated with CK-MB (P.10) were carried out with the use of the Wald ² and the Cox proportional hazards regression model. The stepwise Cox proportional hazard procedure was used to identify the CK-MB covariates that were independently associated with adverse events.²¹ The effect of CK-MB on adverse events adjusted for the factors associated with both CK-MB and adverse events was investigated with the use of the Wald ² and the Cox proportional hazards model. The robustness of the effect of CK-MB was verified for the factors that had a univariate but not a multivariate association with CK-MB and found not to significantly alter the results.

Percentages were computed with the use of the set of nonmissing data as the denominator. Patients with missing data for one or more of the potential predictor variables in the Cox proportional hazards model were omitted from the analysis. To include the maximal number of patients in the analyses, the potential predicator variables were limited to those that correlated with CK-MB, since these variables represented the potential confounders.

	Results

Top Abstract Introduction Methods Results Discussion References

 
Patient Population
Baseline patient information for the three groups is presented in Table 1. The majority of the patients were men with unstable angina and multivessel disease. Risk factors for coronary artery disease were prevalent in this population. There was no difference in the frequency of diabetic patients among the three groups. Notably, multivessel disease and left ventricular dysfunction were also equally distributed among the three groups.

View this table: [in this window] [in a new window]   Table 1. Clinical Demographics for the Study Population

Morphological Characteristics
Limited morphological characteristics are described in Table 2. Most of the stenoses attempted were discrete, noncalcified, and eccentric. In the groups with CK-MB elevation, there was a significantly lower incidence of single, discrete stenoses (P=.03) and a higher incidence of thrombus-associated lesions (P=.02).

View this table: [in this window] [in a new window]   Table 2. Lesion Morphology

Procedural Characteristics
Multivessel procedures and procedures performed on saphenous vein grafts were more frequent in the groups with elevated CK-MB (P<.0001). Similarly, DCA was performed more frequently in the same groups (P<.0001). See Table 3.

View this table: [in this window] [in a new window]   Table 3. Procedural Characteristics

Procedural Complications
Complications in this study are limited to minor complications that were more common in groups 2 and 3 (Table 4). When all the minor complications were added together, more patients in these groups had 1 minor complication (P<.0001).

View this table: [in this window] [in a new window]   Table 4. Minor Procedural Complications

Correlates of CK-MB Elevation
The strongest correlate of postprocedure CK-MB leak was the performance of DCA, followed by the incidence of 1 in-lab minor complication. Other important correlates included side branch compromise, transient in-lab vessel closure, a multivessel procedure, and higher residual stenosis. See Table 5.

View this table: [in this window] [in a new window]   Table 5. Correlates of CK and MB Isoenzyme Elevation After Coronary Interventions

Follow-up
Clinical follow-up was available in 4461 of 4484 patients (99.5%), with a mean duration of 36±22 months (median, 26.4 months; range, 1 to 104 months). The incidence of noncardiac death was equally distributed among the three groups (Fig 1B). In terms of absolute events, there was a 2% to 3% cardiac mortality in the first year, with a 12% to 18% incidence of other major ischemic events (myocardial infarction, 1% to 3%; bypass surgery, 4% to 6%; repeat percutaneous coronary interventions, 6% to 10%). During years 2 to 5, these complications occurred at an annual rate of 1% to 2% for cardiac mortality, 1% to 1.5% for infarction, 1% to 2% for bypass surgery, and 1% to 2% for percutaneous interventions, with all the events consistently higher in the groups with high CK-MB. Beyond the fifth year, the annual cardiac mortality rate was 0% to 0.2%; myocardial infarction, 0.5% to 1.0%; bypass surgery, 0.5% to 1.0%; and repeat percutaneous revascularization, 0.5% to 1.5%. Cardiac death and myocardial infarction occurred more frequently in the groups with elevated CK-MB (Figs 1A and 2A). There was a trend toward more bypass surgery, repeat percutaneous revascularization, and cardiac hospitalization in the same groups (Fig 2, B, C, and D). Fig 3 shows the event-free survival curves (from death, infarction, and coronary revascularization) for the three groups. At the end of the follow-up period, 14% of the surviving patients in group 1 had class III or class IV angina compared with 19% for group 2 and 13% for group 3 (P=.12). Class III or IV congestive heart failure was present in 9% of the surviving patients in group 1 compared with 11% for group 2 and 7% for group 3 (P=NS).

View larger version (34K): [in this window] [in a new window]   Figure 1. Plots showing freedom from cardiac (A) and noncardiac (B) death according to postprocedure cardiac enzyme level.

View larger version (71K): [in this window] [in a new window]   Figure 2. Plots showing freedom from myocardial infarction (A), coronary artery bypass surgery (CABG) (B), repeat percutaneous revascularization (C), and cardiac hospitalization (D) for the three study groups.

View larger version (18K): [in this window] [in a new window]   Figure 3. Graph showing freedom from major cardiac events (death, myocardial infarction, bypass surgery, and repeat percutaneous coronary intervention) according to postprocedure cardiac enzyme level.

Long-term Complications: CK-MB and CK-MB Covariates
Table 6 provides the univariate time-to-event analyses for CK-MB and the factors associated with CK-MB (given in Table 5). Only CK-MB and the factors associated with both CK-MB and long-term complications were used in the multivariate analyses (Table 7). If a factor is associated with either CK-MB or long-term prognosis, then the effect of the factor on the "significance" of CK-MB will be minimal.

View this table: [in this window] [in a new window]   Table 6. Long-term Complications: CK-MB and CK-MB Covariates (Univariate Analysis: Wald 2 (P)/[Risk Ratio (95% CI)]

View this table: [in this window] [in a new window]   Table 7. Long-term Complications: CK-MB and CK-MB Covariates (Multivariate Analysis)

Death
A rise in CK-MB was a strong correlate of cardiac death (risk ratio, 1.27; P=.04). Increased CK-MB was not a good predictor of noncardiac death (P=.44).

Myocardial infarction
CK-MB elevation was also a strong correlate of myocardial infarction on follow-up (risk ratio, 1.31; P=.03).

Coronary bypass surgery
A multivessel procedure and transient in-lab vessel closure were correlates of bypass surgery on follow-up (risk ratio, 1.28 and 2.18; P=.06 and .02, respectively).

Repeat percutaneous coronary interventions
There were two strong correlates of percutaneous revascularization on follow-up: a DCA procedure (risk ratio, 1.81; P=.001) and a multivessel procedure (risk ratio, 1.39; P=.004).

Cardiac hospitalization
There were two strong correlates of cardiac hospitalization on follow-up: a multivessel procedure (risk ratio, 1.18; P=.01) and CK-MB elevation (risk ratio, 1.10; P=.05).

Major ischemic complications
When all the major ischemic complications were taken together (death, Q-wave infarction, bypass surgery, and repeat percutaneous interventions), there were four important correlates of these complications: a DCA procedure (risk ratio, 1.47; P=.004), CK-MB elevation (risk ratio, 1.15; P=.01), a higher residual stenosis (risk ratio, 1.01; P=.02), and a multivessel procedure (risk ratio, 1.19; P=.03). These complications were more frequent in the groups with CK-MB elevation (Fig 3).

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
In clinical practice, demonstration of elevated cardiac enzyme activity has been used as an important criterion for the diagnosis of myocardial necrosis. This practice stems from the assumption that once intracellular enzymes start leaking from myocardial cells, cellular injury has reached a stage of irreversibility.^{22 23 24 25 26} The present study is the first large-scale study to show in the era of percutaneous interventions that such enzymatic leakage, in the face of an apparently successful procedure, carries an independent adverse long-term prognosis.

Several reports have described the appearance of CK-MB in the absence of an abnormal elevation of total CK activity.^{27 28 29 30 31} Unfortunately, the qualitative and quantitative definitions of this diagnostic "gray zone" and its prognostic significance are not well understood. These equivocal changes in CK-MB are usually attributed to myocardial fiber injury resulting in a small nontransmural infarct^{1 27 28 29 32} ; however, reversible ischemia, sampling deficiencies, or artifact has been implicated as cause.^{4 24 33} Our finding that a number of coronary interventions fulfilling both clinical and angiographic criteria for success are associated with abnormal enzyme elevations is similar to that of previous studies.^{5 6 7 34} In our study, 708 of 4484 (15.8%) patients had elevation of CK-MB with normal or elevated total CK, and 258 (5.8%) had clear elevation of total CK. These values completely confirm previous reports.^{5 6 7 34} These minor elevations of CK-MB have been shown to uncover clinically and electrically inapparent minor myocardial damage in 26% of patients after visually successful PTCA.^{7 34}

Our results identify the performance of directional atherectomy as the strongest predictor of CK-MB "leak" after a successful procedure. These results are consistent with our recently published atherectomy series³⁵ and with those of the CAVEAT (Coronary Angioplasty Versus Excisional Atherectomy Trial) study, which reported a higher incidence of CK release after DCA compared with PTCA.³⁶ The reason for this enzyme "leak" is not known. It is possible that DCA is associated with an increased rate of distal embolization resulting from a bulkier device compared with smaller-sized PTCA catheters. Waksman et al³⁷ recently reported distal embolization in 22% of DCA procedures performed on native coronaries and in 48% of procedures performed on saphenous vein grafts. DCA has also been associated with a higher incidence of non–Q-wave infarction, abrupt vessel closure, and side branch occlusion compared with PTCA.³⁸ Since all patients in this study had a successful procedure as defined previously, there was no difference in in-hospital outcome among the three groups. However, an apparent in-lab minor clinical event was identified in 20% of patients with elevated CK-MB, suggesting that events currently judged by interventionalists to have little permanent clinical sequelae nevertheless are associated with release of cardiac enzymes. Evaluation of these minor clinical events reveals a high prevalence of conditions that potentially precipitate the clinical entity of acute coronary insufficiency that can cause myocardial necrosis. Our study also identified a multivessel procedure as a strong correlate of CK-MB elevation. A similar finding has been reported by Gaul et al,³⁹ who found that peak CK after PTCA was significantly higher after multivessel compared with single-vessel procedures. CK elevations after interventions on vein grafts were also more frequent and are probably related to distal microembolization from friable material.^{37 40}

Enzyme elevation may occur for a variety of reasons in the setting of percutaneous interventions. Prolonged ischemia caused by balloon inflations in the absence of clinical or pathological evidence of myocardial infarction can result in relatively minor increases in CK-MB.³³ On the other hand, several studies suggest that minor increases in CK-MB are indeed associated with myocardial necrosis.^{1 7 34} Histological data confirmed that elevated CK-MB without an abnormal elevation of total CK activity could be associated with several small areas of myocardial necrosis that correlate chronologically with the appearance of CK-MB.¹ Recent studies using very specific measures of myocardial necrosis (cardiac-specific troponin-T [Tn-T]) also show that minor increases in CK-MB after PTCA might indeed reflect myocardial damage, especially that the release kinetics of Tn-T in these studies indicate an ongoing release from necrotizing myocytes.^{7 34} Myocardial necrosis in this setting could result from embolization of plaque microparticles, debris of intravascular friable material, clots, or cholesterol crystals. Also, minor in-lab complications (eg, transient vessel closure, side branch compromise, coronary dissection, embolism) are all conditions that can cause small zones of necrosis because of sudden mismatch between metabolic requirements of the myocardium and coronary blood flow. Thus, there is clear evidence that a number of patients with normal total CK activity and a positive MB have myocardial necrosis. Histological confirmation of necrosis in the absence of ECG or lactate dehydrogenase (LDH) level changes strengthens this concept.¹ It is likely that elevated CK-MB in the presence of normal total CK activity does indicate myocardial necrosis, although the extent of the damage may be limited and therefore results in no ECG or LDH changes.

Analysis of our long-term clinical follow-up shows that the clinical events were higher in the first 2 years after the procedure. In other words, the divergence of the survival curves occurred primarily in the first 2 years. This divergence persisted in the following years. This initial divergence probably reflects the PTCA or DCA event. The steady attrition over time in all groups probably reflects the natural history of patients with complex coronary disease.

This is the crucial question: If the release of CK-MB represents mild myocardial injury, what is the clinical significance of this finding? Oh et al⁶ followed 23 patients with increased CK after successful PTCA for a mean of 10 months and found no adverse effects on prognosis. However, because of the small number of patients and the relatively short follow-up, valid statistical comparisons could not be performed, leading the authors to state that "a subtle, yet important sequela from a mild degree of CK-MB elevation might not have been apparent from their small number of patients and limited clinical follow-up." Indeed, two recent reports suggest that postprocedural cardiac enzyme elevations are associated with a worse clinical outcome.^{41 42} Tauke et al⁴¹ evaluated the long-term prognosis in 250 consecutive patients who developed CK elevations after coronary interventions and showed that these elevations are associated with an increased risk of cardiac death on follow-up. Harrington et al⁴² also showed that postprocedural cardiac enzyme elevation was predictive of mortality, bypass surgery, and repeat coronary interventions.

The present study demonstrates a prognostic significance for minor elevations of CK-MB after percutaneous interventions but does not establish the mechanism(s) by which increased CK-MB affects long-term prognosis. Yet, it is important to identify the possible mechanisms that have support in the literature to determine whether any of them are consistent with our observations. The possibility that increased CK-MB reflects small zones of necrosis caused by a sudden mismatch between the metabolic requirements of the myocardium and coronary blood flow, which is precipitated by minor in-lab complications or by microembolization of intravascular particles, has been raised. Animal studies of coronary microembolization reveal numerous small infarcts with angiographically normal epicardial coronary arteries.⁴³ These microinfarcts can create zones of slow conduction that increase the susceptibility to ventricular arrhythmias via microreentrant circuits.^{44 45 46} Additionally, ventricular arrhythmias after microembolization also may be triggered by a focal mechanism.⁴⁷ Thus, it is conceivable that microinfarcts associated with minor increases in CK-MB provide a nidus for ventricular arrhythmias via a microreentry or a focal mechanism.^{44 46 47} Another potential mechanism by which microembolization could increase the likelihood of myocardial infarction and cardiac death is through the compromise of coronary collaterals. The interruption of collateral blood flow by embolization has been shown to potentiate the ischemic effects of subsequent coronary occlusion.⁴⁵ This can lead to a higher incidence of ventricular arrhythmias and a larger size of infarct. In other terms, the initial microembolization event "sensitizes" the heart to the effect of a subsequent ischemic insult.⁴⁵ It is thus possible that a "vulnerable" subset of patients is identified who experienced enzymatic leaks during their periprocedural phase and had subsequent events in the same distribution during follow-up. In a sense, these myocardial segments could be viewed as "watershed" zones that are vulnerable to subsequent ischemic insults. Alternatively, the elevated CK-MB might represent a marker of a high-risk population with other risk factors that can adversely affect long-term prognosis. Some reports claim that these patients are older and that they have other medical problems that adversely affect their prognosis.^{4 48 49} However, this was not the case in this population with minimal CK-MB elevation. Moreover, the lack of impact of increased CK-MB on the incidence of noncardiac death points to a cardiac mechanism by which increased CK-MB influences long-term outcome.

Our results raise a flag of caution about the prognostic value of cardiac enzyme elevation after percutaneous procedures, especially with new devices that tend to be associated with release of CK-MB. The results show a clear association between low-level CK-MB elevations and late cardiac events. However, this does not prove actual causation of these events by elevated CK-MB, and we propose that future interventional studies take a closer look at the relation of CK-MB or other cardiac biochemical markers to short- and long-term prognoses.

Because of the retrospective nature of this analysis, it is possible that other known risk factors, not assessed in this study, might have added prognostic information to the factors we identified or might have modified their interaction. For example, we did not routinely perform exercise testing or assess inducible ischemia with nuclear imaging. Also, because of the retrospective nature of this study, we cannot exclude a potential source of bias related to the possibility that clinically ill–appearing patients who might otherwise sustain late cardiac events might have been treated differently with different frequency and intervals of sampling of cardiac enzymes than were routine patients. Also, we cannot exclude with certainty a follow-up censoring bias that might have affected our conclusions. Moreover, the duration and aggressiveness of periprocedural heparinization were not standardized. Also, because the study was carried out over a prolonged period of percutaneous interventions, the evolution of the procedure, equipment, and practice are not standardized. We do not know with absolute certainty if the patients who displayed elevated enzyme levels after the procedures had myocardial necrosis, transient myocardial ischemia, or enzyme release from a traumatized coronary artery, since we have not measured specific cardiac biochemical markers such as Tn-T. However, conclusions from studies that correlated measurements of CK-MB and Tn-T after PTCA support the hypothesis that this group represents patients with microinfarcts that involve few myofibrils.^{7 34} The increased number of cardiac complications in the groups with increased CK-MB in our study (and the lack of impact of grouping by CK-MB on noncardiac death) indirectly supports a cardiac origin of this enzyme release.

This study confirms that mild elevations of CK-MB after successful PTCA and DCA are common, are associated with distinct clinical, morphological, and procedural variables, and identify a population with a worse long-term prognosis compared with patients with no enzyme elevations. Mild CK-MB elevations also appear to have an adverse effect on long-term prognosis of these patients that cannot be explained by differences in baseline variables.

	Acknowledgments

 
We gratefully acknowledge Gan Howell, Deborah Lynch, Freddie Ford, J. Patrick Lang, and all the staff of the Interventional Registry at the Cleveland Clinic for their effort in the collection of data.

Received November 16, 1995; revision received April 11, 1996; accepted April 15, 1996.

	References

Top Abstract Introduction Methods Results Discussion References

 

1. Dillon MC, Calbreath DF, Dixon AM, Rivin BE, Roark SF, Ideker RE, Wagner GS. Diagnostic problems in acute myocardial infarction: CK-MB in the absence of abnormally elevated total creatine kinase levels. Arch Intern Med. 1982;142:33-38.[Abstract]
   
2. Petterson T, Ohlsson O, Tryding N. Increased CKMB (mass concentration) in patients without traditional evidence of acute myocardial infarction: a risk indicator of coronary death. Eur Heart J. 1992;13:1387-1392.[Abstract/Free Full Text]
   
3. Ravkilde J, Hansen AB, Horder M, Jorgensen PJ, Thygesen K. Risk stratification in suspected acute myocardial infarction based on sensitive immunoassay for serum creatine kinase isoenzyme MB. Cardiology. 1992;80:143-151.[Medline] [Order article via Infotrieve]
   
4. White RD, Grande P, Califf L, Palmeri ST, Califf RM, Wagner GS. Diagnostic and prognostic significance of minimally elevated creatine kinase-MB in suspected acute myocardial infarction. Am J Cardiol. 1985;55:1478-1484.[Medline] [Order article via Infotrieve]
   
5. Klein LW, Kramer BL, Howard E, Lesch M. Incidence and clinical significance of transient creatine kinase elevations and the diagnosis of non-Q wave myocardial infarction associated with coronary angioplasty. J Am Coll Cardiol. 1991;17:621-626.[Abstract]
   
6. Oh JK, Shub C, Ilstrup DM, Reeder GS. Creatine kinase release after successful percutaneous transluminal coronary angioplasty. Am Heart J. 1985;109:1225-1231.[Medline] [Order article via Infotrieve]
   
7. Ravkilde J, Nissen H, Mickley H, Andersen PE, Thayssen P, Horder M. Cardiac troponin T and CK-MB mass release after visually successful percutaneous transluminal coronary angioplasty in stable angina pectoris. Am Heart J. 1994;127:13-20.[Medline] [Order article via Infotrieve]
   
8. Spadaro JJ, Ludbrook PA, Tiefenbrunn AJ, Kurnik PB, Jaffe AS. Paucity of subtle myocardial injury after angioplasty delineated with MB CK. Cathet Cardiovasc Diagn. 1986;12:230-234.[Medline] [Order article via Infotrieve]
   
9. Pauletto P, Piccolo D, Scannapieco G, Vescovo G, Zaninotto M, Corbara F, Cuman G, Chioin R, Casiglia E, Maddalena F, Pessina AC, Palu C. Changes in myoglobin, creatine kinase-MB after percutaneous transluminal coronary angioplasty for stable angina pectoris. Am J Cardiol. 1987;59:999-1000.[Medline] [Order article via Infotrieve]
   
10. Kugelmass AD, Cohen CJ, Moscucci M, Piana RN, Senerchia C, Kuntz RE, Baim DS. Elevation of creatine kinase myocardial isoform following otherwise successful directional coronary atherectomy and stenting. Am J Cardiol. 1994;74;748-754.
    
11. Ellis SG, Roubin GS, King SB, Douglas JS, Weintraub WS, Thomas RG, Cox WR. Angiographic and clinical predictors of acute closure after native vessel coronary angioplasty. Circulation. 1988;77:372-379.[Abstract/Free Full Text]
    
12. Detre KM, Holmes DR, Holubkov R, Cowley MJ, Bourassa MG, Faxon DP, Dorros GR, Bentivoglio LG, Kent KM, Myler RK. Incidence and consequences of periprocedural occlusion: the 1985-1986 National Heart, Lung, and Blood Institute PTCA Registry. Circulation. 1990;82:739-750.[Abstract/Free Full Text]
    
13. Hinohara T, Rowe MH, Robertson GC, Selmon MR, Braden L, Legget JH, Vetter JW, Simpson JS. Effect of lesion characteristics on outcome of directional coronary atherectomy. J Am Coll Cardiol. 1991;17:1112-1120.[Abstract]
    
14. Hinohara T, Selmon MR, Robertson GC, Braden L, Simpson JS. Directional atherectomy: new approaches for treatment of obstructive coronary and peripheral vascular disease. Circulation. 1990;81(suppl IV):IV-79-IV-91.
    
15. The Committee on Enzymes of the Scandinavian Society for Clinical Chemistry and Clinical Physiology (SCE). Recommended method for the determination of creatine kinase in blood modified by the inclusion of EDTA. Scand J Clin Lab Invest. 1979;39:1-5.[Medline] [Order article via Infotrieve]
    
16. Dorros G, Cowley MJ, Simpson J, Bentivoglio LG, Block PC, Bourassa M, Detre K, Gosselin AJ, Gruentzig AR, Keley SF, Kent KM, Mock MB, Mullin SM, Myler RK, Passamani ER, Stertzer SH, Williams DO. PTCA: report of complications from the National Heart, Lung, and Blood Institute PTCA Registry. Circulation. 1983;67:723-730.[Abstract/Free Full Text]
    
17. Ellis SG, De Cesare NB, Pinkerton CA, Whitlow P, King SB, Ghazzal ZMB, Kereiakes DJ, Popma JJ, Menke KK, Topol EJ, Holmes DR. Relation of stenosis morphology and clinical presentation to the procedural results of directional coronary atherectomy. Circulation. 1991;84:644-653.[Abstract/Free Full Text]
    
18. Ellis SG, Vandormael MG, Cowley MJ, DiSciascio G, Deligonul U, Topol EJ, Bulle TM. Coronary morphologic and clinical determinants of procedural outcome with angioplasty for multivessel coronary disease: implications for patient selection. Circulation. 1990;82:1193-1202.[Abstract/Free Full Text]
    
19. Mehta CR, Patel NR. A network algorithm for performing Fisher's Exact Test in r x c contingency tables. J Am Stat Assoc. 1983;78:427-434.
    
20. McCullagh P. Regression models for ordinal data (with discussion). J R Stat Soc. 1980;B42:109-142.
    
21. Cox DR. Regression models and life tables. J R Stat Soc B. 1972;34:187-220.
    
22. Sobel BE, Shell WE. Serum enzyme determination in the diagnosis and assessment of myocardial infarction. Circulation. 1972;45:471-482.[Free Full Text]
    
23. Ahmed SA, Williamson JR, Roberts R, Clark RE, Sobel BE. The association of increased plasma MB CPK activity and irreversible ischemic myocardial injury in the dog. Circulation. 1976;54:187-193.[Abstract/Free Full Text]
    
24. Geft IL, Fishbein MC, Ninomiya K, Hashida J, Chaux E, Yano J, Y-Rit J, Genov T, Shell W, Ganz W. Intermittent brief periods of ischemia have a cumulative effect and may cause myocardial necrosis. Circulation. 1982;66:1150-1153.[Abstract/Free Full Text]
    
25. Shell WE, Kjekshus JK, Sobel BE. Quantitative assessment of the extent of myocardial infarction in the conscious dog by means of analysis of serial changes in serum creatine phosphokinase activity. J Clin Invest. 1971;50:2614-2625.
    
26. Shell WE, Sobel BE. Biochemical markers of ischemic injury. Circulation. 1976;53(suppl I):I-98-I-106.
    
27. Varat MA, Mercer DW. Cardiac specific creatine phosphokinase isoenzyme in the diagnosis of acute myocardial infarction. Circulation. 1975;51:855-859.[Abstract/Free Full Text]
    
28. Mercer DW, Varat MA. Detection of cardiac specific creatine kinase isoenzyme in sera with normal or slightly increased total creatine kinase activity. Clin Chem. 1975;21:1088-1092.[Abstract]
    
29. D'Souza JP, Sine HE, Horvitz RA, Kubasik NP, Brody BB, Barold SS. The significance of the MB isoenzyme in patients with acute cardiovascular disease with a normal or borderline CPK activity. Clin Biochem. 1978;11:204-209.[Medline] [Order article via Infotrieve]
    
30. Grande P, Christiansen C, Naestoft J. Creatine kinase isoenzyme MB assay by electrophoresis. Scan J Clin Lab Invest. 1979;39:607-612.[Medline] [Order article via Infotrieve]
    
31. Grande P, Christiansen C, Pederson A, Christiansen MS. Optimal diagnosis in acute myocardial infarction: a cost-effectiveness study. Circulation. 1980;61:723-728.[Abstract/Free Full Text]
    
32. Shell WE, Kligerman M, Porke MP, Burnam M. Sensitivity and specificity of MB creatine kinase activity determined by column chromatography. Am J Cardiol. 1979;44:67-75.[Medline] [Order article via Infotrieve]
    
33. Heyndrickx GR, Amano J, Kenna T, Fallon JT, Patrick TA, Manders T, Rogers GG, Rosendorff C, Vatner SF. Creatine kinase release not associated with myocardial necrosis after short periods of coronary artery occlusion in conscious baboons. J Am Coll Cardiol. 1985;6:1299-1303.[Abstract]
    
34. Talasz H, Genser N, Mair J, Dworzak EA, Friedrich G, Moes N, Muhlberger V, Puschendorf B. Side-branch occlusion during percutaneous transluminal coronary angioplasty. Lancet. 1992;339:1380-1382.[Medline] [Order article via Infotrieve]
    
35. Abdelmeguid AE, Ellis SE, Sapp SK, Simpfendorfer C, Franco I, Whitlow PL. Directional coronary atherectomy in unstable angina. J Am Coll Cardiol. 1994;24:46-54.[Abstract]
    
36. Topol EJ, Leya F, Pinkerton CA, Whitlow PL, Hoffling B, Simonton CA, Masden RR, Serruys PW, Leon MB, Williams DO, King SB, Mark DB, Isner JM, Holmes DR, Ellis SG, Lee KL, Keeler GP, Berdan LG, Hinohara T, Califf RM. A comparison of directional atherectomy with coronary angioplasty in patients with coronary disease. N Engl J Med. 1993;329:221-227.[Abstract/Free Full Text]
    
37. Waksman R, Scott NA, Douglas JS, Mays R, Peterson J, King SB. Distal embolization is common after directional atherectomy in coronary arteries and vein grafts. Circulation. 1993;88(suppl I):I-299. Abstract.
    
38. Garratt KN, Hinohara T. Complication rates: directional atherectomy versus coronary angioplasty: the Coronary Angioplasty Versus Excisional Atherectomy Trial (CAVEAT). Circulation. 1993;88(suppl I):I-586. Abstract.
    
39. Gaul G, Hollman J, Simpfendorfer C, Franco I. Acute occlusion in multiple lesion coronary angioplasty: frequency and management. J Am Coll Cardiol. 1989;13:283-288.[Abstract]
    
40. Altmann DB, Popma JJ, Hong MK, Salter LF, Pichard AD, Kent KM, Leon MB. CK-MB elevation after angioplasty of saphenous vein grafts. J Am Coll Cardiol. 1993;21:232A. Abstract.
    
41. Tauke TT, Kong TO, Meyers SN, Srinivisan G, Niemyski PR, Parker MA, Davidson CJ. Prognostic value of creatine kinase elevation following elective coronary artery interventions. J Am Coll Cardiol. 1995:269A. Abstract. Special issue.
    
42. Harrington RA, Lincoff AM, Califf RM, Holmes DR, Berdan L, O'Hanesian MA, Keeler GP, Garratt KN, Ohman EM, Mark DB, Jacobs AK, Topol EJ. Characteristics and consequences of myocardial infarction after percutaneous coronary interventions: insights from the Coronary Angioplasty Versus Excisional Atherectomy Trial (CAVEAT). J Am Coll Cardiol. 1995;25:1693-1699.[Abstract]
    
43. Jacobey JA, Taylor WJ, Smith GT, Gorlin R, Harken DE. A new therapeutic approach to acute coronary occlusion. Am J Cardiol. 1962;9:60-73.[Medline] [Order article via Infotrieve]
    
44. Euler DE, Prood CE, Spear JF, Moore EN. The interruption of collateral blood flow to the ischemic myocardium by embolization of a coronary artery with latex: effects on conduction delay and ventricular arrhythmias. Circ Res. 1981;49:97-108.[Free Full Text]
    
45. Marcus E, Katz LN, Pick R, Stamler J. The production of myocardial infarction, chronic coronary insufficiency and chronic coronary heart disease in the dog. Acta Cardiol. 1958;13:190-198.[Medline] [Order article via Infotrieve]
    
46. Kaplinsky E, Ogawa S, Balke W, Dreifus L. Two periods of early ventricular arrhythmia in the canine acute myocardial infarction model. Circulation. 1979;60:397-403.[Abstract/Free Full Text]
    
47. Pogwizd SM. Focal mechanisms underlying ventricular tachycardia during prolonged ischemic cardiomyopathy. Circulation. 1994;90:1141-1158.[Abstract/Free Full Text]
    
48. Lipsitz LA, Pluchino FC, Wei JY. The prevalence and prognosis of minimally elevated creatine kinase-myocardial band activity in elderly patients with syncope. Arch Intern Med. 1987;147:1321-1323.[Abstract]
    
49. Heller GV, Blaustein AS, Wei JY. Implications of increased myocardial isoenzyme level in the presence of normal serum creatine kinase activity. Am J Cardiol. 1983;51:24-27.[Medline] [Order article via Infotrieve]
    

This article has been cited by other articles:

				T. Uetani, T. Amano, H. Ando, K. Yokoi, K. Arai, M. Kato, N. Marui, M. Nanki, T. Matsubara, H. Ishii, et al. The correlation between lipid volume in the target lesion, measured by integrated backscatter intravascular ultrasound, and post-procedural myocardial infarction in patients with elective stent implantation Eur. Heart J., July 2, 2008; 29(14): 1714 - 1720. [Abstract] [Full Text] [PDF]

				T. Y. Wang, E. D. Peterson, D. Dai, H. V. Anderson, S. V. Rao, R. G. Brindis, M. T. Roe, and on behalf of the National Cardiovascular Data Regi Patterns of Cardiac Marker Surveillance After Elective Percutaneous Coronary Intervention and Implications for the Use of Periprocedural Myocardial Infarction as a Quality Metric: A Report From the National Cardiovascular Data Registry (NCDR) J. Am. Coll. Cardiol., May 27, 2008; 51(21): 2068 - 2074. [Full Text] [PDF]

				A. Nusca, R. Melfi, and G. Di Sciascio Review: Percutaneous coronary interventions and statins therapy Therapeutic Advances in Cardiovascular Disease, April 1, 2008; 2(2): 101 - 107. [Abstract] [PDF]

				W. D Cahoon Jr and M. A Crouch Preprocedural Statin Therapy in Percutaneous Coronary Intervention Ann. Pharmacother., October 1, 2007; 41(10): 1687 - 1693. [Abstract] [Full Text] [PDF]

				A. Prasad, M. Singh, A. Lerman, R. J. Lennon, D. R. Holmes Jr, and C. S. Rihal Isolated Elevation in Troponin T After Percutaneous Coronary Intervention Is Associated With Higher Long-Term Mortality J. Am. Coll. Cardiol., November 7, 2006; 48(9): 1765 - 1770. [Abstract] [Full Text] [PDF]

				V. Balian, M. Galli, C. Marcassa, G. Cecchin, M. Child, F. Barlocco, E. Petrucci, G. Filippini, R. Michi, and M. Onofri Intracoronary ST-Segment Shift Soon After Elective Percutaneous Coronary Intervention Accurately Predicts Periprocedural Myocardial Injury Circulation, October 31, 2006; 114(18): 1948 - 1954. [Abstract] [Full Text] [PDF]

				M. Kuduvalli, N. Newall, A. Stott, A. D. Grayson, and B. M. Fabri Impact of avoiding cardiopulmonary bypass for coronary surgery on perioperative cardiac enzyme release and survival. Eur. J. Cardiothorac. Surg., May 1, 2006; 29(5): 729 - 735. [Abstract] [Full Text] [PDF]

				E. Okmen, N. Cam, A. Sanli, S. Unal, Z. Tartan, and M. Vural Cardiac Troponin I Increase After Successful Percutaneous Coronary Angioplasty: Predictors and Long-Term Prognostic Value Angiology, March 1, 2006; 57(2): 161 - 169. [Abstract] [PDF]

				R. Glaser, H. A. Glick, H. C. Herrmann, and S. E. Kimmel The Role of Risk Stratification in the Decision to Provide Upstream Versus Selective Glycoprotein IIb/IIIa Inhibitors for Acute Coronary Syndromes: A Cost-Effectiveness Analysis J. Am. Coll. Cardiol., February 7, 2006; 47(3): 529 - 537. [Abstract] [Full Text] [PDF]

				J. Herrmann Peri-procedural myocardial injury: 2005 update Eur. Heart J., December 1, 2005; 26(23): 2493 - 2519. [Abstract] [Full Text] [PDF]

				K. Arakawa, Y. Kawai, T. Kumamoto, N. Morikawa, M. Yoshida, H. Tada, R. Kawaguchi, K. Taniguchi, I. Miyamori, Y. Kominato, et al. Serum deoxyribonuclease I activity can be used as a sensitive marker for detection of transient myocardial ischaemia induced by percutaneous coronary intervention Eur. Heart J., November 2, 2005; 26(22): 2375 - 2380. [Abstract] [Full Text] [PDF]

				G. M. Tadros, K. Broder, and F. Bachour Intracoronary Macrothrombus Formation During Percutaneous Coronary Intervention Despite Optimal Activated Clotting Time Using Bivalirudin: A Case Report Angiology, November 1, 2005; 56(6): 761 - 765. [Abstract] [PDF]

				D. Paparella, G. Cappabianca, G. Visicchio, A. Galeone, A. Marzovillo, N. Gallo, C. Memmola, and L. d. L. T. Schinosa Cardiac Troponin I Release After Coronary Artery Bypass Grafting Operation: Effects on Operative and Midterm Survival Ann. Thorac. Surg., November 1, 2005; 80(5): 1758 - 1764. [Abstract] [Full Text] [PDF]

				W. E. Boden Acute Coronary Syndromes without ST-Segment Elevation -- What Is the Role of Early Intervention? N. Engl. J. Med., September 15, 2005; 353(11): 1159 - 1161. [Full Text] [PDF]

				T Nageh, R A Sherwood, B M Harris, and M R Thomas Prognostic role of cardiac troponin I after percutaneous coronary intervention in stable coronary disease Heart, September 1, 2005; 91(9): 1181 - 1185. [Abstract] [Full Text] [PDF]