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J Am Coll Cardiol, 1999; 34:40-48 © 1999 by the American College of Cardiology Foundation |
* Cardiac Unit, Department of Medicine, Massachusetts General Hospital, Boston, Massachusetts, USA
Medizinische Klinik und Poliklinik für Innere Medizin II, Universität Regensburg, Regensburg, Germany
Manuscript received July 23, 1998; revised manuscript received January 7, 1999, accepted March 29, 1999.
Reprint requests and correspondence: Dr. Igor F. Palacios, Director, Cardiac Catheterization Laboratory and Interventional Cardiology, Cardiac Unit, Bulfinch 105, Massachusetts General Hospital, Fruit Street, Boston, Massachusetts 02114
palacios.igor{at}mgh.harvard.edu
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Abstract |
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The purpose of this study was to determine whether small reference diameter of the culprit coronary artery influences the outcome of an attempted percutaneous revascularization procedure in the current era of interventional cardiology.
BACKGROUND
Although the interventional strategy is largely determined by the size of the culprit coronary artery, earlier quantitative studies have not shown a worse acute outcome for small reference vessel diameter (
2.5 mm).
METHODS
A total of 2,306 patients undergoing percutaneous coronary revascularization was divided in groups with reference diameters 2.5 mm (n = 813) or >2.5 mm (n = 1,493). Success and in-hospital major adverse cardiac event (death, Q-wave myocardial infarction and emergency coronary artery bypass graft) rates between both groups were compared.
RESULTS
Patients with lesions in small vessels were older and presented more frequently with female gender, diabetes mellitus, heart failure, peripheral vascular, multivessel coronary disease and American Heart Association/American College of Cardiology (AHA/ACC) lesion type C (p 0.01, each). Further, utilization of interventional devices differed markedly. In contrast to stents (18.5% vs. 41.9%) and directional atherectomy (3.7% vs. 13.5%), conventional balloon angioplasty (73% vs. 50%) and rotational atherectomy (16.1% vs. 8.3%) were used more often in smaller vessels (p 0.0001, each). Success rate was lower in the small vessel group (92% vs. 95%; p = 0.006). Major adverse cardiac events occurred more frequently in small than large vessels (univariate 3.4% vs. 2.0%, p = 0.03; multivariate odds ratio 2.1, p = 0.02), particularly when proximal coronary segments were compared.
CONCLUSIONS
Lesions in vessels with small reference diameter represent a distinct group with respect to clinical and morphologic characteristics as well as device utilization. These lesions have lower chances of successful percutaneous intervention and carry relatively higher risks, specifically when located in proximal coronary segments.
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Since 1988, device technology employed for transluminal coronary revascularization experienced considerable improvements. In parallel, success rates increased and complication rates declined substantially (5–8). However, most of these new devices were preferentially used in larger vessels (9,10). In particular, stent deployment, currently the most frequently used strategy in many institutions (7), has been shown to be most effective in vessels with reference diameters >2.5 mm (11,12). Thus, small coronary vessels were partially exempted from recent shifts in device technology. We therefore reconsidered reference diameter of the coronary artery as a potential factor influencing the outcome of an attempted revascularization procedure. In particular, we tested the predictive value of an angiographically small culprit vessel size in 2,306 consecutive patients scheduled for coronary intervention at a single institution who were prospectively analyzed by quantitative digitized coronary angiography.
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Methods |
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2.5 mm and 1,493 patients had culprit lesion(s) treated in vessels with reference diameters >2.5 mm. A total of 2,840 lesions were treated in this patient cohort. Clinical and periprocedural variables. Demographic, clinical and preprocedural data were determined as part of the routine evaluation before attempted coronary intervention and entered prospectively in the interventional database of the Massachusetts General Hospital (13). Patient demographics, coronary risk factors, preprocedural associated major comorbidities and clinical admission syndrome including chronic stable angina, unstable angina (includes new onset, worsening and rest), post–myocardial infarction angina, cardiogenic shock, evolving myocardial infarction and congestive heart failure were prospectively collected as part of the routine evaluation before attempted coronary intervention.
Coronary intervention was considered to be complicated by a major adverse cardiac event (MACE) when death (cardiac and noncardiac) or Q-wave myocardial infarction occurred during the hospital stay irrespective of the time that elapsed between the procedure and the event. Coronary bypass surgery was considered to be a major adverse event when performed within the first 24 h after the procedure (emergency coronary artery bypass graft). This definition of combined events (death, Q-wave myocardial infarction and emergency coronary artery bypass graft) is the most frequently used for analysis of adverse outcome after interventional procedures (6,8,10,14). Cardiac enzymes, creatine kinase (CK) and CK MB fraction (CK-MB) were obtained before and at 8 and 16 h after the procedure and reviewed daily as a part of the critical pathway of our institution. A 
2-fold increase in CK-MB above the upper limit of normal (10 ng/ml) irrespective of total CK in the absence of new Q waves in the electrocardiogram was considered to indicate a non–Q-wave infarction. The combination of major adverse events and non–Q-wave infarction constituted a secondary end point in this study. Patient charts were reviewed daily for adverse events until hospital discharge or death.
Procedural variables and quantitative coronary angiography.
Lesion morphology was classified according to the American Heart Association/American College of Cardiology (AHA/ACC) Classification Task Force with the exception that type B lesions were further stratified into B1 and B2 lesions according to Ellis et al. (14). It was the responsibility of the operator to record device strategy and utilization, intraprocedural adverse events and procedural outcome on detailed forms. A lesion treatment was considered to be successful when there was a 20% gain in luminal diameter and less than 50% residual diameter stenosis in the absence of severe complications including death, Q-wave myocardial infarction or emergency bypass surgery.
Vessel segments were classified according to the AHA/ACC task force guidelines (15). Segments 1, 12 and 18 were considered to be proximal in location. Segments 2 and 13 were by definition at midlocations and segments 3–10, 14–17 and 19–28 were considered distal in location. All baseline angiograms were analyzed by a single technician who was blinded for clinical data. The percent degree of stenosis, reference and minimal luminal diameter were determined after intracoronary administration of 100 µg of nitroglycerin using a computer-assisted, automated edge detection algorithm (Computer Measurements System, MEDIS, Nuenen, The Netherlands) (16). Absolute reference diameter and minimal luminal diameter in millimeters were determined using the guiding catheter filled with contrast agent for calibration. Reference diameter was determined automatically at the site of the obstruction using an iterative linear regression technique. This automated approach represented a reconstruction of the estimated size of the vessel before the occurrence of a focal obstruction.
Statistical analysis.
Continuous variables are expressed as mean ± SD and categorical variables as percent. Student t test and chi-square analysis were carried out for comparison of continuous and categorical variables, respectively. P values 0.05 were considered significant. All analyses were performed using SAS software version 6.10 (SAS Institute, Cary, North Carolina). Reference diameters (2.5 mm or >2.5 mm) were entered as categorical variables. Demographic, clinical, procedural, angiographic and periprocedural variables were tested to determine significant univariate correlates of combined major adverse events. Univariate correlates with p values 0.05 were considered significant. A multiple stepwise logistic regression analysis of all significant univariate factors was performed to determine independent correlates of combined major events. Patients with small and large reference diameters were further stratified into those with lesions treated at proximal, mid-, or distal coronary segments, to compare the rate of major events between the two groups with respect to treatment location. To analyze whether stent utilization affected the relationship between small reference artery diameter and major adverse events, a subgroup analysis was performed on patients receiving coronary stent placement.
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Results |
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Table 1 displays baseline demographic and clinical characteristics and major in-hospital outcomes for patients with reference diameters 2.5 mm (n = 813 patients) and >2.5 mm (n = 1,493 patients). As compared with the large vessel group, patients with lesions in small vessels were older, more often female and more often affected by diabetes, multivessel coronary disease, vascular disease, heart failure and unstable angina (p 0.01, each). Furthermore, patients in the small vessel group presented less frequently with evolving myocardial infarction, whereas history of myocardial infarction, bypass grafting and prior coronary intervention was observed more often (p < 0.01, each) in this group.
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20% in diameter stenosis and a residual stenosis of less than 50% without occurrence of a major adverse event during the procedure was achieved in 92% of lesions in small vessels and 95% of lesions in large vessels attempted for coronary intervention (p = 0.0006). Additionally, there were also differences in device utilization between both groups. Specifically, large vessels were more than twice as likely to be treated with directional atherectomy or coronary stenting (p 0.0001, each), whereas those with small vessels were more likely to be treated with conventional balloon percutaneous transluminal coronary angioplasty or rotational atherectomy (p 0.0001, each). Furthermore, lesions in vessels with small reference diameters were preferentially found in distal coronary segments, whereas reference diameters >2.5 mm were characteristic for proximal vessel segments (p 0.0001, each). During the course of this study two important pharmacologic interventions were introduced. First, the routine use of periprocedural ticlopidine for patients receiving coronary stents was introduced in May of 1995. Second, in this study cohort a total of 65 patients received the glycoprotein receptor antagonist ReoPro after April of 1996. There were no significant differences in the utilization of this drug between both groups of patients (2.2% vs. 3.2% for patients with reference diameters 2.5 mm and >2.5 mm, respectively; p = 0.19).
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Major recent trends.
Between 1994 and 1996, the rate of combined major adverse events declined significantly from 3.5% to 1.3% (p = 0.01). Table 5 displays annual rates of combined major adverse events and lesion treatment success rates by reference vessel group. Whereas the complication rate decreased significantly over time in the large vessel group, the improvement in the group with reference diameters 2.5 mm was only modest and statistically not significant. Likewise, the increase in lesion treatment success over time was significant only in the large vessel group. In parallel, the rate of stent utilization increased significantly from 8% to 63% (p 0.0001) during this three-year observational period. Since stent treatment was preferentially used in the large vessel group (Table 2), the lower rate of stent utilization in the small vessel group may have contributed to the higher periprocedural risk of these patients. To test this hypothesis we studied a subgroup of 835 patients receiving stents (167 patients with reference vessel diameters of 2.5 mm and 668 patients with reference vessel diameter >2.5 mm) to determine whether small reference artery diameter is also a risk predictor in patients receiving stents. As shown in Table 3, major adverse events were infrequent in patients receiving stents (1.3% vs. 3.2%; p = 0.005 for patients receiving and not receiving stents, respectively). Interestingly, small reference artery diameter was not found to be a correlate of in-hospital MACEs, in this subgroup of 835 patients receiving stents.
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Discussion |
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2.5 mm are associated with lower rates of procedural success and higher rates of subsequent in-hospital major events. A novel discovery of this study is that coronary interventions involving proximal vessels of small caliber appear to be a major adverse prognostic factor. Moreover, patients with such small coronary vessels are characterized by other unfavorable comorbid or lesion-specific conditions. Altogether, it appears that a small luminal reference diameter at the lesion site constitutes a prognostic factor that may provide refined information to predict the outcome of an attempted interventional coronary revascularization procedure. Small vessels and associated risk factors for coronary interventions. Previous studies have identified a number of patient- and coronary artery–related factors that predict elevated risks of attempted percutaneous coronary revascularization procedures (7,17–21). It is of interest that some of these conditions, such as female gender and diabetes mellitus, are associated with smaller epicardial arterial diameters (22,23). In agreement with those studies, patients with small luminal reference diameters of the present registry were found to be older, more often female or characterized by diabetes mellitus, peripheral vascular disease, carotid disease, multivessel coronary disease or history of myocardial infarction or bypass grafting. In addition, small reference diameters were often associated with unfavorable AHA/ACC type C lesion morphology, which is another powerful factor to predict both a decreased success rate and an elevated periprocedural risk (14,20). To account for enhanced patient comorbidities and unfavorable lesion morphologies in the small vessel group, we adjusted for these factors using a stepwise logistic regression model. The analysis revealed that small luminal reference diameter appeared to predict lower rates of procedural success and higher rates of subsequent major adverse events independently from these group-specific cofactors. In fact, some clinical predictors such as female gender were not found to be associated with major adverse events after correction for vessel size in this analysis. Thus, it may be hypothesized that some of the risks associated with these clinical predictors may be secondary to the fact that these patients often present with small coronary arteries and therefore, unfavorable coronary artery morphology. It has to be noted, however, that these conclusions are based on a retrospective analysis of a prospectively established angioplasty registry. Furthermore, although patient anatomic and procedural variables have been included in the model, multivariate analysis does not account for all differences between groups. Therefore, further confirmation from prospective trials is required to firmly establish this information.
Proximal vessels of small caliber, a major adverse prognostic factor.
The present study demonstrated that the risk for major events is particularly high when a proximal or midcoronary segment has a luminal diameter 2.5 mm. In fact, the rate of periprocedural major adverse events was sevenfold higher in patients with small proximal left anterior descending arteries than in those with large proximal left anterior descending arteries. This elevated risk is most likely due to the absence of adequate bailout techniques available to treat suboptimal angioplasty results in small vessels, even though vessels at proximal locations perfuse large areas of myocardium. In contrast, a small reference diameter at a distal location was without predictive value. Furthermore, it may be speculated that a small reference diameter at a proximal or midsegment location is a marker for the presence of more severe coronary artery disease. For example, patients with diabetes mellitus have been shown to have small reference diameters as a consequence of higher plaque burden and more diffuse disease (24,25). Thus, the association of unfavorable comorbid factors with small reference diameters may reflect diffuse coronary artery disease that is more likely to result in major complications such as death, Q-wave or non–Q-wave myocardial infarctions, emergency coronary artery bypass grafting or, as previously demonstrated, subsequent restenosis (26,27). This opinion receives further support from experience with surgical revascularization that indicates a substantial increase in perioperative mortality if a left anterior descending artery in patients undergoing coronary bypass surgery is smaller than 2.5 mm in luminal diameter (28,29).
Small vessel interventions in the new device era.
The present association between small luminal reference diameter and adverse in-hospital events appears to contrast with previous registries of patients undergoing interventional coronary revascularization procedures (2,3). However, previous studies as well as the experience that led to the AHA/ACC stratification of coronary morphologies were based on the predominant use of conventional balloon angioplasty. More recently, profound changes in interventional technology have taken place and were related to an increase in procedural success rates and a decrease in the rate of major adverse events (5,6,8). The present registry confirms this trend (7). However, some new devices such as stents or directional coronary atherectomy catheters have specific limitations in the treatment of small vessels (9–12). Indeed, in this registry only a minority of patients with vessel diameter of 2.5 mm have been treated with these devices. Hence, it may be postulated that the benefit of the new device era is largely confined to patients with coronary arteries >2.5 mm. In accordance with this hypothesis are two trends observed in this registry. Namely, the increase in procedural success rate and decrease in major adverse event rate were significant only for lesions located in large coronary arteries.
With the continued refinement in angioplasty techniques and new device evolution, lesion morphologic determinants of angioplasty outcome may have changed significantly. One may speculate, for example, that the progress in the interventional treatment of complex lesions is largely confined to vessels with the appropriate size to harbor a stent. Although this hypothesis requires confirmation by controlled studies, two potential clinical implications may deserve consideration. First, the observation that interventional treatment of small vessels carries higher risks and is associated with a lower chance of success clearly defines a coronary morphology that may benefit from further improvements in device technology or interventional strategies. Second, the current practice to largely limit the use of stents to vessels >2.5 mm requires reevaluation. Our results of no significant differences in the rate of major adverse events in patients receiving stent placement regardless of the reference vessel diameter are encouraging. Thus, it appears from the present data that there is a need for the development of stents appropriately designed to treat small diameter vessels, as the utilization of stents was limited to 18% of patients with small vessels as compared with 43% of those with large vessels. However, a prospective, randomized trial comparing balloon angioplasty with stent placement using specifically designed stents for smaller coronary arteries (2.5 mm) is necessary. Since there may be an increased risk for stent thrombosis in small vessels (30,31), the impact of these devices needs to be investigated prospectively not only with respect to restenosis rates (11,12), but also with respect to the rates of periprocedural success and major adverse events.
Vessel size is a critical anatomic factor inversely related to restenosis rate. In the M-HEART study of patients undergoing conventional balloon angioplasty, Hirshfeld et al. reported a significantly higher restenosis rate of 44% in vessels <2.9 mm compared with 34% in vessels >2.9 mm (32). Therefore, interventions designed to reduce restenosis such as coronary stents would have a greater impact if applicable to smaller vessels. In fact in a substudy analysis of the STRESS trial (33), Savage et al. reported a restenosis rate of 33% in 139 patients with a mean reference vessel diameter of 2.69 ± 0.21 mm treated with stenting and a restenosis rate of 54% in 121 patients with a mean reference vessel diameter of 2.64 ± 0.24 mm treated with conventional balloon angioplasty (p = 0.001). The corresponding target artery revascularization was 19% and 31% for the stent and the angioplasty groups, respectively (p = 0.019). These findings suggest that elective stent placement may be highly effective for smaller vessels. Since in the present study 36% of percutaneous interventional procedures were performed in vessels 2.5 mm in diameter, demonstration of the efficacy of stents in this subgroup would significantly enlarge the patient population who would benefit from this technique.
Conclusions. The present study suggests that the luminal reference diameter of the coronary artery that carries the culprit lesion, particularly when it is located in the proximal segments of the coronary arteries, is a powerful predictor of periprocedural risks and success rates.
Study limitations. We recognize certain limitations of this study. First, the present study addressed only in-hospital events (success, in-hospital MACEs and non–Q-wave myocardial infarction). Although previous studies have demonstrated that small vessels treated with conventional balloon angioplasty have an inferior long-term follow-up outcome (32,33), it is possible that long-term follow-up may also differ in these patients in the current device era. Second, our conclusions are based on a retrospective analysis of a prospectively established angioplasty registry and further confirmation from prospective trials is required to firmly establish this information. Finally, although stent implantation seems to be the more likely reason for the decrease of the in-hospital major complication rate, other factors such as the periprocedural administration of ticlopidine or ReoPro may have also contributed to the decrease of the in-hospital MACEs. A prospective randomized trial of balloon angioplasty versus coronary stenting in a small vessel group is necessary to address these important but yet unanswered questions.
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