CLINICAL RESEARCH: ACUTE CORONARY SYNDROME
In Unstable Angina or Non–ST-Segment Acute Coronary Syndrome, Should Patients With Multivessel Coronary Artery Disease Undergo Multivessel or Culprit-Only Stenting?
Mehdi H. Shishehbor, DO, MPH*,1,
Michael S. Lauer, MD, FACC*,
Inder M. Singh, MD, MS ,
Derek P. Chew, MBBS, MPH ,
Juhana Karha, MD*,
Sorin J. Brener, MD, FACC*,
David J. Moliterno, MD, FACC ,2,
Stephen G. Ellis, MD, FACC*,
Eric J. Topol, MD, FACC|| and
Deepak L. Bhatt, MD, FACC*,3,*
* Department of Cardiovascular Medicine, Cleveland Clinic, Cleveland, Ohio
Department of Internal Medicine, Cleveland Clinic, Cleveland, Ohio
Department of Cardiology, Flinders Medical Center, South Australia, Australia
Gill Heart Institute and Division of Cardiovascular Medicine, University of Kentucky, Lexington, Kentucky
|| Department of Genetics, Case Western Reserve University, Cleveland, Ohio
Manuscript received August 15, 2006;
revised manuscript received October 12, 2006,
accepted October 17, 2006.
* Reprint requests and correspondence to: Dr. Deepak L. Bhatt, Department of Cardiovascular Medicine, Desk F-25, 9500 Euclid Avenue, Cleveland, Ohio 44195. (Email: bhattd{at}ccf.org).
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Abstract
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OBJECTIVES: We examined the safety and efficacy of nonculprit multivessel compared with culprit-only stenting in patients with multivessel disease presenting with unstable angina or non–ST-segment elevation myocardial infarction (non–ST-segment elevation acute coronary syndromes [NSTE-ACS]).
BACKGROUND: In patients presenting with NSTE-ACS, multivessel coronary artery disease (CAD) is associated with adverse outcome.
METHODS: Patients with multivessel CAD and NSTE-ACS that underwent percutaneous coronary intervention were included. The culprit lesion was defined by reviewing each patient’s angiographic report, electrocardiogram, echocardiogram and, if available, nuclear stress test. All patients had at least 2 vessels with  50% stenosis, and the angiographic severity of CAD was assessed using the Duke Prognostic Angiographic Score. Patients with coronary bypass grafts, chronic total occlusions, and those with uncertain culprit lesions were excluded. Our end point was the composite of death, myocardial infarction, or any target vessel revascularization.
RESULTS: From January 1995 to June 2005, 1,240 patients with ACS and multivessel CAD underwent percutaneous coronary intervention with bare-metal stenting and met our study criteria. Of these, 479 underwent multivessel and 761 underwent culprit-only stenting. There were 442 events during a median follow-up of 2.3 years. Multivessel intervention was associated with lower death, myocardial infarction, or revascularization after both adjusting for baseline and angiographic characteristics (hazard ratio 0.80; 95% confidence interval 0.64 to 0.99; p = 0.04) and propensity matched analysis (hazard ratio 0.67; 95% confidence interval 0.51 to 0.88; p = 0.004).
CONCLUSIONS: In patients with multivessel CAD presenting with NSTE-ACS, multivessel intervention was significantly associated with a lower revascularization rate, which translated to a lower incidence of the composite end point compared with culprit-only stenting.
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Abbreviations and Acronyms
| | CAD = coronary artery disease | | MI = myocardial infarction | | NSTE-ACS = non–ST-segment elevation acute coronary syndromes (unstable angina and non–ST-segment myocardial infarction) | | NSTEMI = non–ST-segment elevation myocardial infarction | | PCI = percutaneous coronary intervention |
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Coronary artery disease (CAD) is a diffuse process and, often, patients presenting with unstable angina or non–ST-segment elevation myocardial infarction (NSTEMI) have multiple lesions that may be suitable for percutaneous coronary intervention (PCI) (1–3). In the era of contemporary medical therapy, it is not clear whether intervening on stable chronic nonculprit lesions in patients with non–ST-segment elevation acute coronary syndromes (NSTE-ACS) can prevent major adverse cardiovascular events. In addition, multivessel stenting in this setting could potentially be associated with greater dye load and periprocedural myocardial infarction (MI) secondary to side branch closure and distal embolization (4,5).
The American College of Cardiology/American Heart Association guidelines for multivessel PCI in patients presenting with NSTE-ACS recommend that "it be performed when there is a high likelihood of success and a low risk of morbidity and the vessel(s) to be dilated subtend a moderate or large area of viable myocardium and have high risk by noninvasive testing" (6). We sought to examine the clinical outcomes in patients with multivessel CAD presenting with NSTE-ACS who had undergone multivessel versus culprit-only stenting.
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Methods
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Study population.
The study participants are from an ongoing registry of patients undergoing PCI at the Cleveland Clinic. For the purpose of this study, we included all patients from January 1995 to June 2005 who underwent PCI with bare-metal stents. Baseline characteristics, angiographic data, medication use, and other data were prospectively obtained and recorded by trained research coordinators. Patients with chronic total occlusions, staged procedures, and those who had prior bypass graft surgery were excluded. Non–ST-segment elevation acute coronary syndromes were defined as unstable angina or NSTEMI. Unstable angina was defined as rest, new-onset, progressive, or postinfarct chest pain, and NSTEMI was defined as the occurrence of troponin elevation with electrocardiographic changes or angina. The institutional review board of the Cleveland Clinic waived requirements for informed consent for the institutional PCI registry.
Angiographic characteristics and definitions.
A diameter stenosis of 50% was considered significant. All patients had at least two major coronary vessels with a stenosis of 50%. The culprit lesion was defined by reviewing each patient’s angiographic report, electrocardiogram, echocardiogram and, if available, nuclear stress test. A lesion was considered culprit if an obvious thrombus or ruptured plaque was present, or if 2 of the aforementioned diagnostic tests implicated the same coronary territory. Location of the culprit lesion was defined as proximal, middle, or distal left anterior descending, right coronary artery, or left circumflex coronary artery. All patients received bare-metal stents. In addition, we calculated the percent of each operator’s volume for the number of patients with multivessel disease and multivessel intervention in our study cohort.
Duke Prognostic Angiographic Score.
The severity of CAD was assessed by using the Duke CAD Prognostic Score (7). In brief, 2 investigators (M.H.S. and I.M.S.) reviewed all cardiac catheterization reports and assigned a percent stenosis based on a 17-segment coronary model. Subsequently, using the validated Duke Prognostic Score, a prognostic weight of 0 to 100 based on the degree and location of stenosis was generated. For example, a 75% lesion in left main trunk is assigned a score of 82, whereas a 95% lesion in the proximal left anterior descending artery is given a score of 48.
Clinical end points.
The primary end point was the composite of death, MI requiring hospitalization (excluding periprocedural MI), or any target or nontarget vessel revascularization (PCI or coronary artery bypass grafting). All patients were prospectively followed for adverse cardiovascular events by research coordinators through hospital record review, telephone contact, and the U.S. Social Security Administration Death Index up to July 2005. Secondary end points were the components of the composite end point in addition to periprocedural MI and decreased renal function, which were defined as an increase in creatine kinase-myocardial band 3 times the upper limit of normal (8.8 ng/ml) and decreased renal function defined as a rise in creatinine >1 mg/dl or 50% increase in creatinine post procedure, respectively (4). Cardiac enzymes were routinely drawn on the morning after the procedure and when indicated were serially repeated.
Statistical analysis.
Continuous variables are presented as mean ± standard deviation. Differences in baseline and angiographic characteristics were compared using the Wilcoxon Rank sum test for continuous variables and the chi-square test for categorical variables. We used Kaplan-Meier curves and Cox proportional hazards modeling to examine the association between multivessel stenting and clinical end points accounting for the differences in baseline demographic features, angiographic variables, treatment assignment, and other confounders. The proportional hazards assumption was confirmed by testing the weighted Schoenfeld residuals and by plotting hazard ratio against time plots for selected variables. Additionally, time-dependent analyses were performed to examine the potential effect of subsequent revascularization on later death or MI.
To minimize the impact of confounding by risk factors, we used the technique of propensity analysis. We used nonparsimonious logistic regression model to generate a propensity score for individuals who had undergone multivessel stenting. We considered all variables listed in Table 1
for this model. We then matched each subject from the multivessel stented group to an individual that had undergone culprit-only stenting using the derived propensity score. Subsequently, we performed a Cox proportional hazards modeling in which we incorporated all baseline characteristics in addition to the propensity score for the propensity-matched patients (version 9.1, SAS Institute, Cary, North Carolina).
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Table 1 Baseline and Target Lesion Characteristics of Patients With Multivessel CAD Based on Multivessel Versus Culprit-Only Stenting
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Results
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Baseline characteristics.
Baseline and target lesion characteristics of patients stratified by multivessel and culprit-only coronary intervention are shown in Table 1. In general, the 2 groups were similar regarding risk factors for CAD and medical history.
Clinical outcomes.
There were a total of 442 events during a median follow-up of 2.3 years (interquartile range 0.2 to 4.3 years). Although in unadjusted analysis no significant differences were noted between the 2 groups, in multivariable model after adjusting for baselines characteristics, medical history, angiographic data, Duke Prognostic Score, operator volume, and location of culprit lesion, multivessel intervention was associated with lower incidence of composite end point of death, MI, or revascularization (Table 2, Fig. 1A). However, there were no differences observed for composite end point of death or MI (Table 2, Fig. 1B), or death (Table 2, Fig. 1C), whereas there was a trend toward lower revascularization (Table 2, Fig. 1D). In addition, no significant differences were found in the rate of postprocedural CK increase (7.3% vs. 5.0%, p = 0.09) or creatinine increase (4% vs. 3%, p = 0.32) among the 2 groups. However, in a subset of patients in which fluoroscopy time was available (n = 254), patients undergoing multivessel PCI had significantly higher fluoroscopy time compared with those that underwent culprit-only PCI (46 ± 190 min vs. 25 ± 22 min, p < 0.001).
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Figure 1 Kaplan-Meier Curves for Patients Undergoing Multivessel Versus Culprit-Only Stenting
(A) Kaplan-Meier curves for the composite end point of death, myocardial infarction (MI), or revascularization for patients undergoing multivessel versus culprit-only stenting (n = 1,240). (B) Kaplan-Meier curves for the composite end point of death or MI for patients undergoing multivessel versus culprit-only stenting (n = 1,240). (C) Kaplan-Meier mortality curves for patients undergoing multivessel versus culprit-only stenting (n = 1,240). (D) Kaplan-Meier curves for revascularization for patients undergoing multivessel versus culprit-only stenting (n = 1,240).
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Propensity-matched analysis.
To account for multiple confounding features that are associated with multivessel stenting, such as higher prevalence of proximal left anterior descending artery disease and worse Duke Prognostic Score, we generated a propensity matched cohort using all variables shown in Table 1. After generating a propensity score (c-statistic = 0.78), 315 of the 479 patients who underwent multivessel stenting were matched with a patient who underwent culprit-only stenting. There were no differences in more than 20 baseline characteristics for the propensity matched subjects.
There were 222 events for a median follow-up of 2.7 years. Even after propensity-matched analysis, multivessel intervention remained associated with lower incidence of composite end point of death, MI, or revascularization in both unadjusted and multivariable adjusted analyses (Table 2, Fig. 2A). However, there were no differences seen for composite end point of death or MI (Table 2, Fig. 2B), death (Table 2, Fig. 2C); whereas there was a significantly lower rate of revascularization in patients undergoing multivessel intervention (Table 2, Fig. 2D). In addition, no significant differences were observed between multivessel versus culprit-only stenting in the rate of postprocedural CK elevation (7% vs. 5%, p = 0.31) or creatinine rise (4% vs. 3%, p = 0.68).
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Figure 2 Kaplan-Meier Curves for Propensity-Matched Patients Undergoing Multivessel Versus Culprit-Only Stenting
(A) Kaplan-Meier curves for the composite end point of death, myocardial infarction (MI), or revascularization for propensity-matched patients undergoing multivessel versus culprit-only stenting (n = 630). (B) Kaplan-Meier curves for the composite end point of death or MI for propensity-matched patients undergoing multivessel versus culprit-only stenting (n = 630). (C) Kaplan-Meier mortality curves for propensity-matched patients undergoing multivessel versus culprit-only stenting (n = 630). (D) Kaplan-Meier curves for revascularization for propensity-matched patients undergoing multivessel versus culprit-only stenting (n = 630).
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To further examine the impact of future revascularization on mortality, we treated revascularization as a time-dependent covariate. In this analysis, future revascularization did not have an impact on mortality (adjusted hazard ratio, 1.38; 95% confidence interval 0.90 to 2.09; p = 0.14).
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Discussion
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In a large cohort of patients with unstable angina or NSTEMI undergoing PCI, nonculprit multivessel bare-metal stenting was associated with lower incidence of death, MI, or revascularization, which was mainly driven by significantly lower incidence of revascularization in the multivessel intervention group. To our knowledge, this is the largest study to examine systematically the safety and efficacy of multivessel compared with culprit-only stenting in patients with multivessel CAD presenting with NSTE-ACS while accounting for both baseline and angiographic characteristics.
In U.S. in 2001, there were more than 1.6 million patients discharged from hospital with the diagnosis of NSTE-ACS. The invasive approach is the preferred method for treating such patients (8–10). Although interventions to culprit lesions have clinical benefit (8–10), little is known about the safety and efficacy of nonculprit multivessel stenting in the setting of NSTE-ACS. Furthermore, multivessel stenting could potentially have adverse effects secondary to increased contrast load and side branch closure, leading to renal dysfunction and periprocedural MI, respectively (4). Additionally, patients with NSTE-ACS are in a heightened thrombotic and inflammatory state and may be more prone to adverse effects of multivessel PCI (11). Finally, multivessel disease is associated with increased in-stent restenosis, and placing multiple stents may be associated with increased revascularization secondary to in-stent restenosis (11).
The safety and efficacy of multivessel PCI was examined in a subpopulation of the TACTICS–TIMI-18 (Treat angina with Aggrastat and determine Cost of Therapy with an Invasive or Conservative Strategy–Thrombolysis in Myocardial Infarction-18) trial. Of the 290 patients with multivessel disease, 224 underwent culprit lesion and 66 multivessel stenting (12). There were no significant differences for the 6-month composite end point of death or MI. Other studies have looked at the safety and efficacy of multivessel stenting, but none have been in the setting of unstable angina or NSTEMI (13–16).
Study limitations.
Our study has several limitations. First, it is an observational study. Second, the mindset of the operator and the procedure progression are very important but very difficult to measure in an observational study. A potential culprit-only procedure in which the culprit goes smoothly can turn into a multivessel procedure, whereas a planned multivessel procedure that is more difficult than predicted can become a culprit only procedure. Third, individuals who underwent multivessel PCI may get more follow-up procedures as well as differential ascertainment of events. However, these differences would most likely lead to more revascularization in patients with multivessel PCI. Fourth, all patients in our study had bare-metal stents; however, these data could most likely be extrapolated to drug-eluting stents, as these devices have a significantly lower restenosis rate and have not yet been shown to decrease death or MI. Fifth, we had limited data on contrast volume and fluoroscopy time.
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Conclusions
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In the current study, nonculprit multivessel stenting reduced future revascularization rate but was not associated with lower death or MI. Although the current study does not support multivessel stenting to reduce mortality on angiographically significant lesions in patients with stable CAD, future technologies that allow the in vivo assessment of vulnerable plaques may at some point provide an opportunity to decrease death or MI in these patients. The cumulative event rate for death, MI, or revascularization over a median of 2.3 years in our study was high, which suggests that there is a need for better therapies in this population. Future randomized studies that examine the safety and efficacy of multivessel stenting using drug-eluting stents in patients with unstable angina and NSTEMI, perhaps in conjunction with methods to identify vulnerable plaque, are warranted.
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Footnotes
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1 Dr. Shishehbor is supported in part by the National Institutes of Health, National Institute of Child Health and Human Development, Multidisciplinary Clinical Research Career Development Programs Grant K12 HD049091 and the National Institutes of Health Loan Repayment Program. 
2 Dr. Moliterno has served on Data and Safety Monitoring Committees for stent manufacturers, including Boston Scientific and Guidant.
3 Dr. Bhatt has received honoraria and has served as a consultant and/or on the advisory board of AstraZeneca, Bristol Myers Squibb, Eisai, Eli Lilly, GlaxoSmithKline, Millennium, Paringenix, PDL, Sanofi Aventis, Schering Plough, and The Medicines Company.
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Abstract
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