Author + information
- Received November 9, 1998
- Revision received October 21, 1999
- Accepted December 15, 1999
- Published online April 1, 2000.
- Jorge F Saucedo, MD∗,
- Roxana Mehran, MD, FACC, FESC†,
- George Dangas, MD, FACC, FESC†,
- Mun K Hong, MD, FACC†,
- Alexandra Lansky, MD†,
- Kenneth M Kent, MD, PhD, FACC, FESC†,
- Lowell F Satler, MD, FACC†,
- Augusto D Pichard, MD, FACC†,
- Gregg W Stone, MD, FACC† and
- Martin B Leon, MD, FACC†,* ()
- ↵*Reprint requests and correspondence: Dr. Martin B. Leon, Cardiovascular Research Foundation, 110 Irving Street NW, Suite 4B-1, Washington, DC 20010
We sought to evaluate the impact of intermediate creatine kinase–myocardial band isoenzyme (CK-MB) elevation on late clinical outcomes in patients undergoing successful stent implantation in native coronary arteries.
Elevations of CK-MB after percutaneous coronary interventions are frequent. An association between high level of CK-MB elevation (>5 times normal) and late mortality after balloon and new device angioplasty has been reported previously. However, significant controversy remains on the long-term clinical importance of lower CK-MB elevations (one to five times normal) after percutaneous coronary revascularization. Moreover, the incidence and prognostic importance of cardiac enzyme elevation after coronary stenting have not been well established.
Prospectively collected data from 900 consecutive patients (1,213 lesions) undergoing successful stenting in native vessels were analyzed. Based on the CK-MB levels after coronary stenting, patients were classified into three groups: normal group 1 (n = 585), elevation of >1 to 5 times normal group 2 (n = 238) and elevation of >5 times normal group 3 (n = 77).
Patients in group 3 had more in-hospital recurrent ischemia (p = 0.001) and pulmonary edema (p = 0.01) than patients in groups 1 and 2. Long-term clinical end points were similar between groups 1 and 2. However, patients in group 3 had an increased incidence of late mortality compared with patients in groups 2 and 1 (6.9%, 1.2% and 1.7%, respectively, p = 0.01). Multivariate analysis showed that patients with CK-MB >5 times normal after coronary stenting had an increased risk of major adverse clinical events (relative risk: 1.70, p < 0.05) and death (relative risk: 3.25, p < 0.05) that was not observed in patients with lower CK-MB rise.
Patients with CK-MB elevation >5 times normal had higher late mortality and more unfavorable event-free survival than those patients with normal or lower CK-MB rise after coronary stenting. While intermediate CK-MB elevation (>1 to 5 times normal) is frequent after coronary stenting (26%), this was not associated with an increased risk of late mortality or major adverse clinical events.
There is significant controversy regarding the prognostic importance of mild-to-moderate creatine kinase–myocardial band isoenzyme (CK-MB) increase (>1 to 5 times normal) after percutaneous coronary interventions of native coronary lesions. This issue requires further evaluation, especially as abnormal elevation of enzyme markers occurs frequently after instrumentation of coronary arteries. Creatine kinase–myocardial band isoenzyme elevation has been reported in up to 22% of overall coronary interventions (1–9) and even as high as 47% following successful vein graft angioplasty (10). Recent studies have reported that intermediate creatine kinase (CK) elevations in patients undergoing successful coronary angioplasty or directional atherectomy are associated with an adverse long-term outcome, including cardiac death (11,12). Other reports, however, have shown that modest CK-MB isoform elevation after coronary stenting or directional atherectomy has no adverse clinical consequences and therefore should not be considered a major complication (13). Thus, the objective of the present study was to evaluate the incidence and long-term clinical outcome of patients with CK-MB elevation after stenting of native coronary arteries, and to determine whether rise of CK-MB levels after elective stenting is an independent predictor of unfavorable long-term clinical outcomes.
All 900 patients (1,213 lesions) who underwent successful, elective native coronary artery stenting between January 1994 and December 1995 were selected for this analysis. Stents used in this cohort included the Gianturco-Roubin, the coronary Palmaz-Schatz and the biliary Palmaz stents.
Techniques of coronary stenting
Patients were selected for coronary stenting by the operator based on preintervention lesion characteristics. All patients were premedicated with 325 mg of aspirin prior to the procedure, unless contraindicated. Bolus intravenous (IV) heparin, 10,000 to 15,000 U, was given after sheath insertion. Additional heparin boluses were given to maintain the HemoTech activated clotting time >300 s. Patients also received ticlopidine with or without the addition of low-molecular-weight heparin or warfarin (Coumadin) at the end of the procedure. Patients were excluded for this analysis if they had received glycoprotein IIb/IIIa inhibitor.
All patients had serial measurements of CK-MB isoform at baseline, 6 h and 18 to 24 h after coronary intervention. Patients with baseline CK-MB isoform elevation were excluded from this analysis if the levels were elevated. Absolute CK-MB levels were determined by radioimmunoassay (normal ≤4 ng/ml) (Dade Behring Inc., Miami, Florida). When the CK-MB level was elevated, it was monitored every 8 h until it came back to normal values. Patients were classified according to the peak CK-MB values into three groups: group 1 had no CK-MB elevation following the procedure, group 2 had an elevation of CK-MB >1 to 5 times normal (5 to 20 ng/ml) and group 3 had a CK-MB increase >5 times normal (>20 ng/ml).
Clinical and procedural variables
Baseline demographic and procedural variables were recorded prospectively and entered in the Cardiology Research Foundation Database. All patients included in this analysis underwent successful coronary intervention as defined by <50% residual diameter stenosis and the absence of death, Q-wave myocardial infarction or emergency or urgent coronary bypass surgery. The occurrence of minor or major complications, including subacute closure, recurrent chest pain, ischemia or repeat coronary intervention, was also recorded.
All cineangiograms were analyzed in blinded manner with regard to the acute clinical outcome and CK-MB level. Flow was graded according to Thrombolysis in Myocardial Infarction (TIMI) study criteria; TIMI flow grade 0 or 1 was considered representative of a total occlusion. The rest of the angiographic definitions used in this study have been published previously (3). Angiographic measurements before and after the procedure were performed using hand-held calipers in the projection showing the most severe stenosis (worst view), with the guiding catheter serving as the reference standard.
Clinical follow-up and end points
Trained personnel followed up patients in outpatient visits and by telephone calls. The patients were contacted three, six and 12 months after their procedure and yearly thereafter. The patients were questioned as to recurrence or presence of cardiovascular symptoms (myocardial infarction [MI], angina, heart failure and arrhythmias) or the need for repeat coronary revascularization. For patients with clinical events, their medical records were reviewed and the events were adjudicated. The families or the physicians of deceased patients were interviewed to try to determine the cause of death. Patients were followed up for a mean of 14 months and data were obtained in 96% of patients. The primary end point of the study was the occurrence of death at one year. Secondary end points included TLR and the combined occurrence of death/Q-wave MI/and death/Q-wave MI/coronary artery bypass grafting (CABG) percutaneous transluminal coronary angioplasty (PTCA) at one year.
All statistical analyses were performed using statistical software (SAS; SAS Institute; Cary, North Carolina). Continuous variables are presented as mean ± SD and categorical variables are presented as percentages. One-way analysis of variance (ANOVA) was used to determine differences in the three groups. Comparisons between two groups were made using the chi-square test or the Fisher exact test to analyze differences in categorical variables, and t test for continuous variables with a Bonferroni correction. Clinical, configuration and procedural variables that had demonstrated statistically significant difference at the 0.1 level were initially included in the multivariate logistic regression analyses to identify the factors associated with adverse long-term outcomes and death. Intermediate elevation of CK-MB was forced into the model. Survival curves were calculated according to the Kaplan-Meier estimates of survival. A p < 0.05 was considered significant.
We studied 900 consecutive patients who underwent successful native coronary artery stenting of 1,213 lesions. Two hundred thirty-eight patients (26.4%) sustained a minor postprocedural CK-MB elevation (>1 to 5 times normal) and 77 patients (8.5%) had a CK-MB elevation >5 times normal. Baseline clinical characteristics are presented in Table 1. Most patients were men with unstable angina and a high prevalence of risk factors. Patients in group 1 were younger (p < 0.01), more frequently male (p < 0.01), had higher left ventricular ejection fraction (p = 0.02), more often had a history of PTCA (p = 0.04) and presented less frequently with unstable angina (p = 0.006) and history of MI (p = 0.05) than patients in either group 2 or 3.
Lesion configuration is summarized in Table 2. Patients in group 3 presented with more de novo lesions (p = 0.001), totally occluded vessels (p = 0.001) and type C lesions than those in group 1. Patients in group 2 had more ostial lesions (p = 0.03), a trend toward more total occlusions (p = 0.19) and less restenotic (p = 0.02) and eccentric lesions (p = 0.005) than patients in group 1.
In Table 3, procedural variables are shown. Patients in group 1 had more lesions treated in the right coronary artery (p < 0.01), less number of stents per lesion (p < 0.01) and more Palmaz-Schatz coronary stents used (p < 0.01) than patients in the other two groups. Patients in group 3 had a larger final minimal lumen diameter (p = 0.05), smaller final percent diameter stenosis (p = 0.01), more stents per lesion (p = 0.002) and more Gianturco-Roubin flexible coronary stents (p = 0.001) than patients in group 1. No differences were observed in the reference vessel diameter in any of the three groups.
In-hospital outcome by CK-MB level is presented in Table 4. By inclusion criteria, all patients in this analysis had a successful procedure defined as an increase of >20% in luminal diameter with final percent diameter stenosis of <50%, without the occurrence of any major complication (death, Q-wave MI and CABG). The peak CK-MB levels were 1.1 ± 1.0 ng/ml, 8.1 ± 3.8 ng/ml and 53.5 ± 41.7 ng/ml in groups 1, 2 and 3, respectively. Compared with group 1, patients in group 3 had more subacute closure (p = 0.03), recurrent ischemia (p < 0.001), repeat catheterization (p < 0.001), target lesion PTCA (p < 0.001) and pulmonary edema (p = 0.001). Patients in group 2 had more recurrent ischemia (p = 0.02), repeat catheterization (p = 0.03), pulmonary edema (p = 0.01) and number of lesion treated (p < 0.001) than patients in group 1.
The late clinical events are summarized in Table 5. Long-term clinical end points were similar in patients in groups 1 and 2. A trend toward more CABG but less PTCA was observed in group 2. However, patients in group 3 had an increased incidence of late mortality when compared with those in group 2 and 1 (6.9%, 1.2% and 1.7%, respectively, p = 0.01 by ANOVA). Q-wave MI was also more common in this group (4.1%, 0.8% and 1.0%, respectively, p < 0.01) as it was also the composite end point of death/Q-wave MI/CABG/PTCA (37.5%, 24.3% and 24.9%, p < 0.05). Multivariate analysis (Table 6)showed that patients with CK-MB >5 times normal after coronary stenting had an increased risk of major adverse clinical events (relative risk [RR]: 1.70, p < 0.05), which was not observed in patients with minor CK-MB elevation (RR: 0.89, p = 0.5). Also, patients in group 3 had a higher risk of death (p = 0.04) or death and MI (p = 0.03) by logistic regression analysis.
The results of the present study indicate that the incidence of CK-MB elevation following successful stenting in native coronary arteries is relatively high (35%). Most of these patients (26.4%) experienced a CK-MB rise between 1 to 5 times normal. We found that while major elevation of CK-MB (>5 times normal) predicts a higher risk of death and late major adverse clinical events, lower elevations are not associated with an unfavorable long-term outcome.
The importance of this issue is emphasized by the fact that new drugs (i.e., glycoprotein IIb/IIIa antagonists) have been shown to improve clinical outcomes following percutaneous coronary revascularization mainly by reducing the incidence of non-Q-wave MI (14–16).
Unfavorable prognostic importance of CK or CK-MB elevations on late clinical outcomes after percutaneous coronary revascularization has been reported in three studies (1,12,17). Harrington et al. (1) reported the consequences of MI in 1,012 patients enrolled in the Coronary Angioplasty versus Excisional Atherectomy Trial (CAVEAT). Myocardial infarction was defined as new pathologic Q waves, CK-MB levels three or more times the upper limit of normal or total CK levels two or more times the upper limit of normal (when CK-MB levels were not available). The authors reported an increased risk of death at one year in patients with MI when baseline characteristics were considered (p = 0.038). However, only borderline significance was observed when baseline characteristics and procedural complications were considered (p = 0.055) (1). Moreover, in another long-term analysis on the same patients, late cardiac events were not influenced by postprocedural CK elevation by multivariate analyses (18). Abdelmeguid et al. (12) examined 4,484 patients who underwent successful PTCA or directional atherectomy. Patients were classified according to the CK level into three groups: group 1 had no CK or CK-MB elevation, group 2 had a CK <180 IU/liter with MB fraction >4% and group 3 had a peak CK level between 181 and 360 IU/liter with MB fraction >4%. It was shown that patients with elevated CK-MB had a significantly higher incidence of cardiac death (p = 0.04). Very recently, Kong et al. (17) followed up 253 patients with total CK and CK-MB fraction elevation and 120 control patients without CK elevation after PTCA. They found that late cardiac mortality was greater (p = 0.02) for patients with CK elevation after PTCA. It was also reported that when patients were categorized according to peak CK elevation, cardiac mortality was significantly higher with high (>3.0 times normal) and minor (1.5 to 3.0 times normal) CK rise (p = 0.007) (17).
Comparison between this and other studies
Even though previous studies included a broad range of interventional devices, patients with coronary stents were not included in their analysis. No quantitative coronary angiography data were presented, thus the influence of final minimal lumen diameter or final percent diameter stenosis on clinical end points could not be assessed, and patients with interventions in saphenous vein grafts were not excluded. Finally, data from the IMPACT II trial associated increased levels of CK-MB with major adverse clinical events, but the death rate did not seem to be higher for patients with CK-MB elevation >5 times normal (19). Our results disagree with the increased mortality associated with mild-to-moderate elevation of CK or CK-MB after PTCA observed in these studies (12,17). However, our report confirms the increased risk of death and major clinical events seen in patients with major CK-MB elevation (>5 times normal) (12,13,17,19). However, significant data have shown no association between cardiac enzyme elevation after percutaneous coronary revascularization and adverse clinical outcomes. Oh et al. (7) reported on 25 of 128 patients (20%) who had CK-MB elevation following PTCA. At a mean follow-up of 10 months, no early or late mortality was observed in any patient with or without elevation of CK-MB (8). Similarly, in the study by Klein et al. (8), 38 of 272 patients (15%) with CK or CK-MB elevation did not have important clinical consequences early after PTCA. Very recently, Cutlip et al. (20) studied the influence of postprocedural MI on late clinical outcomes in 1,865 patients from the Stent Anti-Thrombotic Regimen Study (STARS) Registry and randomized trial. Patients were classified into three MI categories: type 1, CK-MB ratio >1 and <3; type 2, CK-MB ratio >2 and <3 with ST abnormality or CK-MB ≥3 and ≤8; and type 3, Q-wave MI or CK-MB ≥8. Follow-up between 6 and 12 months revealed no association between any type of MI and death (p = 0.54). In a similar analysis, Cutlip et al. (21) analyzed the pooled data from 3,387 patients enrolled in Balloon versus Optimal Atherectomy Trial (BOAT), STARS and the Study to determine Rotablator and Transluminal Angioplasty Strategy (STRATAS) trials. Patients were classified into the same three MI category types as above. Likewise, no association between any cardiac enzyme elevation and late mortality was established. An intriguing finding was that even large MI (type 3) was not associated with an adverse late clinical outcome. A similar observation was reported in the subanalysis of the surgical arm from the Emory Angioplasty versus Surgical Trial (EAST). In this study, 10.3% of the patients identified with perioperative Q-wave MI did not have an adverse clinical outcome when compared with those who did not develop this complication. In fact, the authors concluded that Q-wave MI identified in the postoperative period following CABG seemed to be a weak end point with little prognostic significance and therefore not valuable for future randomized trials (22). Further data may be needed to determine the importance of very high enzyme elevation after percutaneous intervention. Nevertheless, our observations support the view that small non-Q-wave MI after revascularization with stents as seen in patients in group 2 (mean CK-MB elevation two times greater than normal) is not associated with an increased risk of late mortality. However, contrary to the observation by Cutlip et al., we did find an association between CK-MB elevation >5 times normal with all major late clinical events (death, death/MI and death/MI/PTCA/CABG). Our results, indeed, are more in accordance with those of Kugelmass et al. (13) who explored the incidence and importance of elevation of CK-MB isoform in a consecutive series of 565 patients who underwent successful directional atherectomy (274 patients) or stenting (291 patients). After a mean of two years of follow-up, the patients with intermediate elevation of CK-MB (>10 IU/liter to 50 IU/liter) did not show any adverse long-term sequelae (death, recurrent MI or repeat revascularization) compared with patients without elevation of CK-MB isoform. However, patients with CK-MB >50 IU/liter demonstrated a trend toward decreased late survival when compared with patients with normal levels of CK-MB (p = 0.08) (13). An important controversial issue is the prognostic importance of three to five times rise in CK-MB following coronary interventions. We believe that no definite conclusions can be drawn from this analysis regarding this group of patients, as most patients included in group 2 had only mild CK-MB elevations (>1 to 3 times normal).
CK-MB elevation as a marker of high risk patients
Our observations agree with the view that identifying a mild CK-MB rise as a major complication after percutaneous coronary revascularization may be inaccurate. We and others believe that it is likely that cardiac enzyme elevation is a marker of high risk patients who can be identified by their clinical, angiographic and procedural characteristics (23). Indeed, in our report, patients with CK-MB elevation seemed to be a population at higher risk of complications. When compared with group 1, patients in group 2 had higher incidence of diabetes (p = 0.12) and unstable angina (p = 0.006), both strongly associated with a higher risk of major adverse clinical events in our multivariate analysis. Furthermore, patients in group 2 had a higher incidence of in-hospital ischemic events (recurrent typical chest pain, repeat catheterization and pulmonary edema). Similarly, patients in group 3 had lower left ventricular function, higher incidence of adverse lesion characteristics and marked increase of early complications and thus greater number of late ischemic events (Tables 4 and 5). Thus, it may be that despite adjusting for all known risk factors for cardiac mortality, patients with very high CK elevation had more extensive disease that could not be accounted for by standard methods (24). It must be noted in our results, however, that despite all these clinical disadvantages of patients in group 2 (intermediate elevation of CK-MB), the late occurrence of death, MI or the composite end point (death, MI, CABG and PTCA) was almost identical to that of patients in group 1.
Native vessels versus saphenous vein graft
Our study differs from previous reports in that only consecutive patients undergoing stenting of native vessels were included. It must be noted that in previous analyses, patients who had higher CK or CK-MB elevations had interventions more frequently in saphenous vein grafts (12,17). Late mortality after percutaneous revascularization of saphenous vein conduits is higher than that of native coronary arteries (25). In the study of Kong et al. (17), saphenous vein graft PTCA was the most important predictor of long-term cardiac mortality or subsequent MI (RR 3.59, p < 0.001). Indeed, if we compare our report (native vessels) with that of patients undergoing revascularization of vein grafts during the same time period and by the same operators, the incidence of late mortality seems to be much higher in the latter for each level of CK-MB (normal CK-MB 1.7% vs. 4.8%, CK-MB 5 to 20 ng/ml 1.2% vs. 6.5%, CK-MB >20 ng/ml 6.9% vs. 11.7%) (10). Thus, by analyzing only interventions in native vessels, we were able to exclude the important potential confounding effect of saphenous vein graft revascularization.
Stents and CK-MB elevation
According to a national cardiovascular network, while the use of directional and rotational atherectomy decreased 30% to 50% between 1994 and 1996, that of coronary stents increased fivefold during the same time period (26) and its use will most likely increase in the future, especially with improved designs. Despite this, little is known about the incidence and significance of cardiac enzyme marker elevation after coronary stenting. In fact, as most previous reports have not included patients undergoing coronary stenting in their analyses, their findings cannot necessarily be extrapolated to this revascularization technique (1,11,12,17). We report an incidence of 26% intermediate CK-MB elevation and 8% of high CK-MB elevation after stenting in native coronary arteries. This incidence is higher than 11.5% CK-MB elevation >10 IU/liter reported following directional atherectomy and stenting in one series (13) or to the more recent 22% in patients enrolled in the STARS trial (20). We believe that our results may represent more accurately the incidence of any CK-MB elevation after successful native coronary artery stenting in a daily and more current interventional practice. However, it must be kept in mind that the definition of CK-MB was very strict and that patients treated with Gp IIb/IIIa inhibitors were excluded from this analysis. Finally, despite the difference in the stent model used in each group, we did not observe an association between stent model and late clinical events by multivariate analysis.
Creatine kinase–myocardial band isoenzyme elevation occurs frequently following stenting in native coronary arteries. Patients with CK-MB elevation >5 times normal had higher mortality rate and lower event-free survival at follow-up than those patients with normal or intermediate CK-MB elevation. Despite unfavorable baseline clinical characteristics, patients with intermediate CK-MB elevation did not experience an increased risk of late mortality or major adverse clinical events after coronary stenting when compared to patients with no CK-MB elevation.
- analysis of variance
- Balloon versus optimal Atherectomy Trial
- coronary artery bypass grafting
- Coronary Angioplasty versus Excisional Atherectomy Trial
- creatine kinase
- CK-myocardial band isoenzyme
- Emory Angioplasty versus Surgical Trial
- myocardial infarction
- percutaneous transluminal coronary angioplasty
- relative risk
- Stent Anti-Thrombotic Regimen Study
- Study to determine Rotablator and Transluminal Angioplasty Strategy
- Thrombolysis in Myocardial Infarction
- Received November 9, 1998.
- Revision received October 21, 1999.
- Accepted December 15, 1999.
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