Increased CK-MB release is a “trade-off” for optimal stent implantationan intravascular ultrasound study
Author + information
- Received March 19, 2003
- Revision received June 1, 2003
- Accepted June 3, 2003
- Published online December 3, 2003.
Author Information
- Ioannis Iakovou, MD*,
- Gary S Mintz, MD*,
- George Dangas, MD, PhD*,* (gdangas{at}crf.org),
- Alexandre Abizaid, MD*,
- Roxana Mehran, MD*,
- Yoshio Kobayashi, MD*,
- Alexandra J Lansky, MD*,
- Eve D Aymong, MD, MSc*,
- Eugenia Nikolsky, MD*,
- Gregg W Stone, MD*,
- Jeffrey W Moses, MD* and
- Martin B Leon, MD*
- ↵*Reprint requests and correspondence:
Dr. George Dangas, Lenox Hill Heart and Vascular Institute, Cardiovascular Research Foundation, 55 East 59th Street, 6th Floor, New York, New York 10022, USA.
This study was presented at the 52nd Annual Scientific Session of the American College of Cardiology, Atlanta, Georgia, March 2002.
Abstract
Objectives We sought to determine the impact of aggressive stent expansion on creatine kinase-MB isoenzyme (CK-MB) release and clinical restenosis.
Background Elevation of CK-MB after percutaneous coronary interventions has been associated with late mortality.
Methods We identified 989 consecutive patients who underwent intravascular ultrasound-guided stenting of 1,015 coronary lesions. Patients were divided into three groups according to stent expansion, defined as the ratio of final lumen over the reference lumen cross-sectional areas: Group 1 (ratio <70%, n = 117 patients with 126 lesions); Group 2 (ratio 70% to 100%, n = 551 patients with 562 lesions); Group 3 (ratio >100%, n = 321 patients with 327 lesions).
Results The peak CK-MB values increased significantly with increasing stent expansion: CK-MB = 3 to 5× normal occurred 16%, 18%, and 25% in Groups 1, 2, and 3, respectively, p = 0.02; CK-MB >5 times normal occurred 9%, 13%, and 16% respectively, p = 0.02. Conversely, at one year follow-up there was a stepwise decrease in target lesion revascularization (11% vs. 19% and 17%, respectively, p = 0.04) and major adverse cardiac events with increasing stent expansion. In addition, there was a trend toward lower mortality in Group 3 (9% vs. 4.4% vs. 4.0%, p = 0.07).
Conclusions Intravascular ultrasound-guided stent overexpansion (final lumen greater than reference lumen cross-sectional area) is accompanied by a higher periprocedural CK-MB release but a lower target lesion revascularization and a trend toward lower mortality at one year. Increased periprocedural CK-MB release appears as a trade-off for optimal stent implantation and lower clinical restenosis.
Percutaneous interventional techniques continue to evolve, including optimization of stent implantation. The final lumen dimension achieved after stenting is one of the most powerful predictors of restenosis (1–3). Even though routine high-pressure balloon inflation affords a better lumen at the end of the intervention, its systematic use during coronary stent placement has not been associated with significant improvement in one-year outcome (4). On the contrary, routine high-pressure inflation may be accompanied by a higher creatine kinase-MB isoenzyme (CK-MB) elevation (4). We have previously shown that CK-MB elevation after percutaneous coronary intervention (PCI) is associated with an increased atherosclerotic plaque burden and calcification (5); it occurs after 6% to 30% of otherwise successful PCI (6,7)and may be associated with increased late mortality (8,9).
Several intravascular ultrasound (IVUS) criteria have been used to optimize stent expansion in an attempt to reduce clinical and angiographic restenosis. The purpose of the current study was to determine the relationship between stent expansion, as assessed by IVUS, and both post-PCI CK-MB elevation and clinical restenosis.
Methods
Patient population
The Cardiovascular Research Foundation Database was queried to identify 989 consecutive patients who underwent IVUS-guided stenting of 1,015 native coronary lesions between January 1994 and June 1999. Patients with acute myocardial infarction (MI), pre-PCI elevation, and restenotic lesions were excluded. Events were recorded at 30-day and one-year clinical follow-up. Patients were divided into three groups according to stent expansion, defined as a ratio represented by the final lumen divided by the reference lumen cross-sectional area (CSA): Group 1 (stent expansion ratio <70%) with 117 patients and 126 lesions; Group 2 (ratio 70% to 100%) with 551 patients and 562 lesions; and Group 3 (ratio >100%) with 321 patients and 327 lesions. Stents were used for elective indications, suboptimal angioplasty results, and abrupt or threatened closure.
Procedures
All procedures were performed after written informed consent. All patients underwent PCI according to current stent-implantation guidelines and techniques (10). All patients received aspirin 325 mg daily at least 24 h before the procedure and indefinitely afterwards. Patients were treated concomitantly with a thienopyridine: either ticlopidine 250 mg twice daily or clopidogrel 75 mg daily for four weeks. Weight-adjusted heparin was administered during the procedure and was routinely discontinued at the end of the procedure. Platelet glycoprotein IIb/IIIa inhibitors were used in <4% of cases.
Angiographic analysis
Cineangiograms were analyzed using a validated system (ARTEK, Quantitative Cardiac Systems, Ann Arbor, Michigan) by a dedicated core laboratory blinded to the IVUS and clinical data. Using the contrast-filled catheter as the calibration standard, minimal lumen diameter, reference diameter, and percent diameter stenosis before and after PCI were obtained from the single “worst” and least foreshortened view. The reference segment diameter was averaged from user-defined, 5-mm-long angiographically normal segments proximal and distal to the stenosis in the projection with the least amount of foreshortening. Ostial lesions were within 3 mm of the coronary ostia or <3 mm distal to a major proximal side branch. These are standard qualitative and quantitative analyses and definitions, and they have been published previously (11).
IVUS imaging and analysis
Intravascular ultrasound imaging was performed after administration of 0.2 mg of intracoronary nitroglycerin, using a system made by one of the following manufacturers: CVIS/Inter Therapy, Hewlett-Packard and Boston Scientific Corporation, or Cardiovascular Imaging Systems/Boston Scientific Corporation. The IVUS catheter was advanced approximately 10 mm distal to the lesion, the video recorder was turned on, the transducer and pullback device was activated, and the entire artery was imaged and recorded on 0.5-inch high-resolution s-VHS for off-line analysis.
Validations of normal coronary anatomy, plaque composition, and measurements using IVUS have been reported (12). Using computer planimetry (TapeMeasure, Indec Systems), the following lesion and reference measurements were made in diastole (13,14). The external elastic membrane (EEM) CSA was measured by tracing the leading edge of the adventitia. The lesion site was the cross-sectional slice with the smallest lumen; among sections with the same lumen area, the one with the most plaque was selected. If the plaque was “packed” around the catheter, the lumen was assumed to be the physical (not acoustical) size of the catheter. Because IVUS cannot measure media thickness accurately, plaque and media were the measure of plaque mass. Cross-sectional narrowing (plaque and media CSA divided by EEM CSA) has also been called the plaque burden or percent plaque area. The reference segment averaged the most visually normal cross-sections (largest lumen with least plaque) within 10 mm proximal and distal to the lesion but between major branches; a distal reference was used for ostial lesions. Percent stent expansion was measured as final stent CSA divided by the average of the proximal and distal reference lumen CSA. These IVUS methods have been validated and published previously (15,16).
Clinical definitions and follow-up
Pre-specified clinical and laboratory demographic information was obtained from hospital charts that were reviewed by independent research personnel who were unaware of the objectives of the study; data were entered prospectively into a database. Standard definitions included: 1) Q-wave MI—the presence of new pathologic Q-waves associated with an elevation of CK or CK-MB at least two times the upper normal value and 2) non–Q-wave MI—CK-MB elevation at least five times the upper normal value without new Q-waves.
CK-MB levels were systematically evaluated before intervention and at 6 h and 24 h after the procedure. If CK-MB levels were elevated, serial measurements were performed every 8 h and the peak level was recorded. All CK-MB determinations were performed in the clinical chemistry laboratory by the mass-determination method (normal range 0 to 4 ng/ml). For this study, only the peak CK-MB values post-PCI were used.
One-year clinical follow-up was performed by either telephone contact or office visit. Multiple adverse cardiac events (MACE) were recorded, including death (all-cause), Q-wave MI, and target lesion revascularization (TLR) (whether PCI or surgical). These data collection methods have been published previously (17).
Statistical analysis
Statistical analysis was performed using SAS (Statistical Analysis Systems, SAS Institute Inc, Cary, North Carolina) by a dedicated data analysis center. Continuous variables are expressed as mean ± 1 SD and categorical variables as frequency (%). Continuous variables were compared using analysis of variance or the unpaired Student ttest. Categorical variables were compared with chi-squared statistics. A p value <0.05 was considered statistically significant.
Results
Baseline patient and lesion characteristics were similar among the three groups, except from a higher percentage of men in Group 2, as shown in Table 1. There were no significant differences in high-risk lesion characteristics such as ostial location, bifurcation, thrombus, and Thrombolysis in Myocardial Infarction 0 to 2 flow among the three groups.
Patient Demographic and Lesion Characteristics
Procedural data and quantitative coronary angiography
As shown in Table 2, angiographic reference was larger and lesion length was longer in Group 1. Atheroablation use was more frequent in Group 1, and the balloon-to-artery ratio was greater in Group 3. There were no other statistically significant differences among the three groups regarding procedural data and complications.
Procedural Data and Quantitative Coronary Angiographic Analysis
IVUS analysis
Intravascular ultrasound findings are shown in Table 3. Group 1 had larger proximal reference EEMs, lumen CSAs, distal reference EEMs, pre-intervention EEMs, and plaque and media CSAs at the lesion site. However, there were no statistically significant differences regarding pre-PCI arc of calcium, lumen CSA, minimal lumen diameter, CSA, and cross-sectional narrowing among the groups. Post-stent implantation, Group 3 had larger lumen dimensions than the other two groups.
Intravascular Ultrasound Findings
In-hospital outcome
Procedural success was 98% to 99% in all the groups. Table 4summarizes the major in-hospital complications. There were no statistically significant differences among the three groups. Group 3 patients had a higher CK-MB release rate than the other two groups, regardless of the level of CK-MB elevation examined (Fig. 1).
Creatine kinase-MB isoenzyme elevation (CK-MB) post percutaneous coronary intervention according to stent expansion. CK-MB release one to three times normal was similar in Group 1 (stent expansion <70%) vs. Group 2 (stent expansion 70% to 100%) vs. Group 3 (stent expansion >100%). However, there was a stepwise increase in CK-MB 3 to 5 times and >5 times normal in Group 1 vs. Group 2 vs. Group 3.
In-Hospital Events
Clinical follow-up
Cumulative clinical events at one-year follow-up are shown in Figure 2. There were no statistically significant differences regarding death or Q-wave MI among the three groups. However, Group 3 patients had lower TLR and MACE rates than the other groups (p = 0.04 and 0.01 respectively). In addition, there was a trend toward lower mortality in Group 3 (9% vs. 4.4% vs. 4.0%, p = 0.07). Figure 3displays one-year TLR according to percent stent expansion. Higher percent stent expansion (>90%) resulted in significantly lower TLR at one year compared with lower stent expansion (<90%).
One-year cumulative outcome. There was a stepwise decrease in death, multiple adverse cardiac events, and target lesion revascularization in Group 1 (stent expansion <70%) vs. Group 2 (stent expansion 70% to 100%) vs. Group 3 (stent expansion >100%). MACE = multiple adverse cardiac events; Q-W MI = Q-wave myocardial infarction; TLR = target lesion revascularization.
The occurrence of any target lesion revascularization event decreased with increasing percent stent expansion (% stent expansion = final stent CSA/[proximal CSA + distal CSA]/2). CSA = cross-sectional area.
Discussion
The main finding of the current study is that stent overexpansion is accompanied by significantly lower TLR and MACE rate at one year, but at the expense of a higher post-PCI CK-MB elevation.
Relatively low-level release of cardiac enzymes occurs after 6% to 30% of otherwise successful PCIs (6–8). It has also been shown that elevation of CK-MB is associated with increased late mortality (6,18–21). However, the impact of CK-MB release on clinical outcome is rather small in the absence of new Q-waves or elevation less than eight times the upper limit of normal (20,22–24). It has also been suggested that a larger post-PCI lumen dimension, attained after successful new device PCI, primarily determines subsequent cardiac events and is associated with lower TLR (25,26); thus, the potentially adverse influence of CK-MB elevation may be overshadowed by the other favorable outcomes after optimal PCI stent (22).
In the present study, the aggressive stent expansion strategy was associated with higher CK-MB elevation post PCI. It is of note that atheroablation was more frequent, and plaque and media were larger, in Group 1 (least stent expansion group). As previously reported, periprocedural enzyme release varies markedly with different devices, being most common with combined stenting and atheroablation (20). We have also suggested that the increased incidence of CK-MB elevation after stenting and atheroablation may simply reflect the baseline presence of more diffuse atherosclerotic disease and greater plaque burden (5).
Stent overexpansion had been considered elsewhere to result in an increased late loss or even higher restenosis rates (27). Indeed, we documented potentially greater vessel wall trauma, as suggested by the greater balloon-to-artery ratio in Group 3; however, this finding was not associated with an increased rate of late events. To the contrary, increased stent expansion correlated with reduced one-year event rates and, in particular, an arithmetically lower one-year mortality. This finding is in accordance with studies in which stent overexpansion resulted in larger final lumen dimensions that were maintained at follow-up, despite greater lumen loss due to exaggerated intimal hyperplasia in response to the greater vessel wall trauma (28,29).
It is of note that Group 1 lesions were longer than lesions in the other two groups. Conversely, Group 3 vessels were smaller, as suggested by the smaller EEM CSA. Longer lesion length and smaller vessel size are well-recognized risk factors for in-stent restenosis (30). There are two main determinants of the final stent CSA: vessel size and implantation technique (30). Intravascular ultrasound guidance can be used to optimize final stent implantation results, mainly because of bigger balloons (greater balloon-to-artery ratio, as seen in this study) or higher inflation pressures (30,31). After IVUS-guided overdilation, minimal stent lumen CSA and diameter have been shown to increase by as much as 11% to 80% (16,29,32). In the present study, we examined various IVUS-derived stent expansion cutoff values in relation to clinical restenosis and found that percent stent expansion >90% had the lowest one-year TLR rate.
Limitations
First, this was a retrospective analysis; in an attempt to offset this limitation, the data were collected prospectively by independent monitors and entered into a dedicated database, and independent laboratories interpreted all angiographic and IVUS studies. Second, complete follow-up was available in 92% of the whole patient population (89%, 92%, and 93% for Groups 1, 2, and 3, respectively). We did not use more sensitive markers of myocardial damage such as troponin T or I tests. However, measurement of CK-MB release is an accepted, widely used method of assessment of myocardial injury after PCI, used in a large number of previous studies (5,8,9,18,22). In addition, we do not report data on time of ischemia and information about side branch occlusion. Nevertheless, the absence of reporting these data does not alter the basic hypothesis of the current study.
Conclusions
Stent overexpansion (final lumen greater than reference lumen CSA) is accompanied by a higher periprocedural CK-MB release but a lower TLR and a trend toward lower mortality at one year. Increased periprocedural CK-MB release appears as a trade-off for optimal stent implantation and lower clinical restenosis and one-year MACE.
- Abbreviations
- CK-MB
- creatine kinase-MB isoenzyme
- CSA
- cross-sectional area
- EEM
- external elastic membrane
- IVUS
- intravascular ultrasound
- MACE
- multiple adverse cardiac events
- MI
- myocardial infarction
- PCI
- percutaneous coronary intervention
- TLR
- target lesion revascularization
- Received March 19, 2003.
- Revision received June 1, 2003.
- Accepted June 3, 2003.
- American College of Cardiology Foundation
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