Stenting for bifurcation lesions is still challenging, and the effect of intravascular ultrasound (IVUS) guidance on long-term outcomes has not been evaluated. We assessed the long-term outcomes of IVUS-guided stenting in bifurcation lesions. We evaluated 758 patients with de novo nonleft main coronary bifurcation lesions who underwent stent implantation from January 1998 to February 2006. We compared the adverse outcomes (i.e., death, stent thrombosis, and target lesion revascularization) within 4 years, after adjustment using a multivariate Cox proportional hazard model and propensity scoring. IVUS-guided stenting significantly reduced the long-term all-cause mortality (hazard ratio [HR] 0.31, 95% confidence interval [CI] 0.13 to 0.74, p = 0.008) in the total population and in the patients receiving drug-eluting stents (DESs) (HR 0.24, 95% CI 0.06 to 0.86, p = 0.03), but not in the patients receiving bare metal stents (HR 0.41, 95% CI 0.13 to 1.26, p = 0.12). IVUS-guided stenting had no effect on the rate of stent thrombosis (HR 0.48, 95% CI 0.16 to 1.43, p = 0.19) or target lesion revascularization (HR 1.47, 95% CI 0.79 to 2.71, p = 0.21). In patients receiving DESs, however, IVUS guidance reduced the development of very late stent thrombosis (0.4% vs 2.8%, p = 0.03, log-rank test). In conclusion, in patients receiving DESs, IVUS-guided stenting for treatment of bifurcation lesions significantly reduced the 4-year mortality compared to conventional angiographically guided stenting. In addition, IVUS guidance reduced the development of very late stent thrombosis in patients receiving DESs.
Intravascular ultrasonography provides useful information on vessel anatomy and can result in optimal stent deployment. A large cohort study reported that intravascular ultrasound (IVUS) guidance during drug-eluting stent (DES) implantation significantly reduced the thrombosis rate and showed a favorable trend for repeat revascularization. IVUS guidance might be even more useful in complex lesions such as bifurcation lesions. In addition, the long-term effect of IVUS guidance on bifurcation stenting has not been determined. Therefore, we evaluated the effect of IVUS-guided stenting on the long-term outcomes in patients with bifurcation lesions.
Methods
From January 3, 1998 to February 28, 2006, 7,221 patients underwent percutaneous coronary intervention with stenting at the Asan Medical Center (Seoul and Gangneung, Korea). Of these, 758 consecutive patients underwent stenting for de novo nonleft main coronary bifurcation lesions with a side branch >2.0 mm in diameter, by visual estimation. The performance of IVUS-guided stenting was left to the physician’s discretion. Patients were classified as having undergone IVUS-guided stenting if an IVUS examination was performed during any stenting procedure for the targeted lesions. Bare metal stents (BMSs) were the default treatment from January 1998 to January 2003, and DESs were the default choice beginning in February 2003. Qualitative and quantitative angiographic measurements were performed using standard techniques with automated edge-detection algorithms (CASS-5, Pie Medical, Maastricht, The Netherlands) in the angiographic analysis center of the Cardiovascular Research Foundation, Seoul, Korea. Any patient who received ≥1 DES in the treatment of targeted bifurcation lesions was assigned to the DES group. All patients were prescribed aspirin indefinitely, with additional clopidogrel at the physician’s discretion.
The primary end point was death from any cause within the 4 years after index stenting. The secondary end points were stent thrombosis and target lesion revascularization during the same period. Stent thrombosis was assessed using the Academic Research Consortium definitions, including all levels of certainty, and by the timing of the event as early, late, or very late after the index coronary intervention. Target lesion revascularization was defined as revascularization for a stenosis within the stent or within a region 5 mm adjacent to the stent. Target lesion revascularization was performed on the basis of clinical decision making, not angiographically, and was assessed after long-term follow-up, not dichotomously at 6 months. All clinical outcomes of interest were adjudicated by independent clinicians.
The baseline clinical and procedural characteristics were recorded in our institution’s dedicated database by the clinical research nurses. Clinical follow-up was performed by office visit or telephone interview at 1, 6, and 12 months after the procedure and every 6 months thereafter. To reduce follow-up bias, the clinical outcomes were censored at 4 years in 2 sequential cohorts of patients with BMS or DES implantation. These data were used for the present study. The institutional review board at Asan Medical Center, Seoul and Gangneung, Korea, approved the present study, and all patients provided written informed consent for the use of the clinical and procedural data.
Categorical variables are presented as raw numbers and frequencies and were compared using the chi-square test to ensure equality of proportions. Continuous variables are presented as the mean ± SD and were compared using Student’s t test. Kaplan-Meier analysis was used to determine the adverse event-free survival rate, and differences were analyzed using the log-rank test. We adjusted the results for significant differences in patient characteristics using Cox proportional hazards regression models that included all significant variables with p <0.2 on univariate analysis. The covariates of the baseline demographic, clinical, angiographic, and procedural characteristics included all variables listed in Tables 1 and 2 . The second multivariate Cox model, to identify the predictors of adverse outcomes, used backward elimination until only factors with p <0.1 remained. Each propensity score was estimated from a logistic regression model for IVUS-guided versus angiographically guided stenting. The propensity scores were incorporated into the Cox proportional hazards regression model as covariates. The discrimination and calibration ability of the propensity score model was assessed by c-statistics and Hosmer-Lemeshow statistics. The c-statistic of the regression model for the propensity score was 0.72 (0.74 for DESs, 0.71 for BMSs). To evaluate the risk factors for very late stent thrombosis, the events were accessed beginning at the 1-year point. The patients who were event free at 1 year were assigned to a landmark analysis of 4 groups (by stent type and guidance method), and the effect of IVUS guidance for each stent type was separately analyzed. All analyses were performed on a per-patient basis. A p value <0.05 was considered statistically significant. The Statistical Package for Social Sciences for Windows, version 12.0 (SPSS, Chicago, Illinois) was used for all analyses.
| Variable | IVUS Guidance (n = 473) | Angiographic Guidance (n = 285) | p Value |
|---|---|---|---|
| Clinical characteristics | |||
| Age (years) | 59 ± 10 | 60 ± 11 | 0.08 |
| Men | 344 (73%) | 204 (72%) | 0.73 |
| Diabetes mellitus | 95 (20%) | 63 (22%) | 0.51 |
| Hypertension | 205 (43%) | 132 (46%) | 0.43 |
| Smoker | 171 (36%) | 102 (36%) | 0.92 |
| Hypercholesterolemia | 134 (28%) | 99 (35%) | 0.06 |
| Previous percutaneous coronary intervention | 49 (10%) | 21 (7%) | 0.17 |
| Previous coronary bypass | 1 (0.2%) | 1 (0.4%) | 0.72 |
| Acute coronary syndrome | 248 (52%) | 181 (64%) | 0.003 |
| Acute myocardial infarction | 54 (11%) | 42 (15%) | 0.18 |
| Primary percutaneous coronary intervention | 24 (5%) | 8 (3%) | 0.13 |
| Renal failure | 5 (1.1%) | 1 (0.4%) | 0.29 |
| Left ventricular ejection fraction (%) | 60 ± 8 | 59 ± 10 | 0.61 |
| Left ventricular dysfunction | 36 (8%) | 27 (10%) | 0.28 |
| Procedural characteristics | |||
| Drug-eluting stent implantation | 308 (65%) | 112 (39%) | <0.001 |
| Sirolimus-eluting stents | 259 (84%) | 94 (84%) | 0.97 |
| Paclitaxel-eluting stents | 49 (16%) | 18 (16%) | |
| One-stent strategy | 386 (82%) | 263 (92%) | <0.001 |
| Multivessel percutaneous coronary intervention | 137 (29%) | 97 (34%) | 0.14 |
| Restenosis lesion | 25 (5%) | 11 (4%) | 0.37 |
| Ostial lesion | 61 (13%) | 9 (3%) | <0.001 |
| Chronic total occlusion | 12 (3%) | 7 (3%) | 0.95 |
| Long lesion (≥30 mm) | 279 (59%) | 131 (46%) | <0.001 |
| Use of glycoprotein IIb/IIIa inhibitor | 18 (4%) | 8 (3%) | 0.46 |
| Discontinuation of clopidogrel within 6 mo | 29 (6%) | 16 (6%) | 0.77 |
| Total stent length per lesion (mm) | 34 ± 19 | 26 ± 14 | <0.001 |
| Stents used per lesion (n) | 1.4 ± 0.7 | 1.2 ± 0.5 | <0.001 |
| Variable | IVUS Guidance (n = 473) | Angiographic Guidance (n = 285) | p Value |
|---|---|---|---|
| Reference diameter | |||
| Before procedure | |||
| Proximal (mm) | 3.3 ± 0.5 | 3.1 ± 0.5 | 0.004 |
| Distal (mm) | 2.7 ± 0.5 | 2.6 ± 0.4 | 0.16 |
| Mean (mm) | 3.1 ± 0.5 | 3.0 ± 0.5 | 0.02 |
| After procedure | |||
| Proximal (mm) | 3.4 ± 0.5 | 3.2 ± 0.5 | 0.001 |
| Distal (mm) | 2.6 ± 0.4 | 2.5 ± 0.4 | 0.06 |
| At 4-year follow-up | |||
| Proximal (mm) | 3.1 ± 0.5 | 3.2 ± 0.4 | 0.49 |
| Distal (mm) | 2.6 ± 0.4 | 2.5 ± 0.3 | 0.80 |
| Mean (mm) | 2.8 ± 0.4 | 2.8 ± 0.5 | 0.57 |
| Minimal luminal diameter | |||
| Preprocedure (mm) | 0.9 ± 0.5 | 0.8 ± 0.5 | <0.001 |
| Postprocedure (mm) | 3.0 ± 0.5 | 2.8 ± 0.5 | 0.002 |
| At follow-up (mm) | 2.3 ± 0.8 | 2.1 ± 1.6 | 0.21 |
| Acute gain (mm) | 2.1 ± 0.6 | 2.1 ± 0.6 | 0.69 |
| Late loss (mm) | 0.7 ± 0.8 | 0.7 ± 1.7 | 0.78 |
| Diameter stenosis (%) | |||
| Preprocedure | 70 ± 16% | 74 ± 15% | 0.003 |
| Postprocedure | 2 ± 12% | 4 ± 12% | 0.08 |
| At follow-up | 10 ± 27% | 18 ± 49% | 0.16 |
| Lesion length (mm) | 25 ± 14 | 21 ± 10 | <0.001 |
| Maximum balloon size | 3.6 ± 0.4 | 3.4 ± 0.5 | <0.001 |
Results
A total of 758 patients were treated with stenting for nonleft main coronary bifurcation lesions. Of these, 473 underwent IVUS-guided and 285 underwent angiographically guided stenting. Patients who received IVUS-guided stenting were more likely to be implanted with DESs, to undergo complex stenting with 2 stents, to have ostial lesions, and to have longer lesions than the patients who underwent angiographically guided stenting ( Table 1 ). Of the 420 patients implanted with DESs, 353 (84%) received sirolimus-eluting stents (Cypher, Cordis, Johnson & Johnson, New Brunswick, New Jersey) and 67 (16%) received paclitaxel-eluting stents (Taxus Express; Boston Scientific, Boston, Massachusetts). Although treatment with clopidogrel was at the physicians’ discretion, only 4 patients who received DESs took clopidogrel for <3 months, with most patients (94%) prescribed clopidogrel for >6 months. Of the 420 patients receiving DESs, 62 (15%) were treated with cilostazol. Quantitative angiographic analysis showed that patients who underwent IVUS-guided stenting had longer lesions, larger reference diameters, larger postprocedural minimal luminal diameters, smaller preprocedure diameter stenosis, and maximum balloon sizes ( Table 2 ). When the follow-up period was truncated at 4 years, the mean length of follow-up was 3.9 ± 0.6 years in the BMS group and 3.5 ± 0.7 years in the DES group. No significant difference was found in the follow-up duration between patients who underwent IVUS-guided and those who underwent angiographically guided stenting (3.7 ± 0.6 years vs 3.7 ± 0.8 years, p = 0.90).
During the 4 years of follow-up, 30 (4.0%) of the 758 patients died. On multivariate-adjusted Cox regression analysis, the IVUS-guided group had a significantly lower rate of all-cause mortality than did the angiographically guided group for the overall group, a difference observed in patients treated with DESs but not BMSs ( Figure 1 and Table 3 ). In the second multivariate-adjusted Cox regression analysis, the independent risk factors for death were older age (hazard ratio [HR] 1.06, 95% confidence interval [CI] 1.02 to 1.10, p = 0.001), diabetes mellitus (HR 2.68, 95% CI 1.29 to 5.58, p = 0.01), and angiographically guided stenting (HR 3.92, 95% CI 1.74 to 8.84, p = 0.001). In the DES group, older age (HR 1.10, 95% CI 1.02 to 1.17, p = 0.006), discontinuation of clopidogrel within 6 months after the index procedure (HR 9.45, 95% CI 2.84 to 31.38, p = 0.0002), and angiographically guided stenting (HR 4.15, 95% CI 1.20 to 14.29, p = 0.02) were independent risk factors for death from any cause. In the BMS group, however, IVUS-guided stenting did not affect the all-cause mortality rate. In these patients, older age (HR 1.07, 95% CI 1.01 to 1.12, p = 0.01), diabetes mellitus (HR 2.73, 95% CI 1.10 to 6.83, p = 0.03), and presentation with acute coronary syndrome (HR 8.02, 95% CI 1.07 to 60.27, p = 0.04) were independent risk factors for death from any cause. When we assessed the causes of death, we found that 12 patients died from cardiovascular causes. IVUS-guided stenting significantly reduced the 4-year cardiovascular mortality rate compared to angiographically guided stenting (0.4% vs 3.6%, p = 0.001, using the log-rank method), an effect sustained after multivariate-adjusted analysis (HR 0.17, 95% CI 0.04 to 0.81). However, IVUS-guided stenting did not affect the noncardiovascular mortality rate (3.2% vs 5.4%, p = 0.09, log-rank method).
