Three-Year Outcomes After Sirolimus-Eluting Stent Implantation for Unprotected Left Main Coronary Artery Disease
Insights From the j-Cypher Registry
Background— Long-term outcomes after stenting of an unprotected left main coronary artery (ULMCA) with drug-eluting stents have not been addressed adequately despite the growing popularity of this procedure.
Methods and Results— j-Cypher is a multicenter prospective registry of consecutive patients undergoing sirolimus-eluting stent implantation in Japan. Among 12 824 patients enrolled in the j-Cypher registry, the unadjusted mortality rate at 3 years was significantly higher in patients with ULMCA stenting (n=582) than in patients without ULMCA stenting (n=12 242; 14.6% versus 9.2%, respectively; P<0.0001); however, there was no significant difference between the 2 groups in the adjusted risk of death (hazard ratio 1.23, 95% confidence interval 0.95 to 1.60, P=0.12). Among 476 patients whose ULMCA lesions were treated exclusively with a sirolimus-eluting stent, patients with ostial/shaft lesions (n=96) compared with those with bifurcation lesions (n=380) had a significantly lower rate of target-lesion revascularization for the ULMCA lesions (3.6% versus 17.1%, P=0.005), with similar cardiac death rates at 3 years (9.8% versus 7.6%, P=0.41). Among patients with bifurcation lesions, patients with stenting of both the main and side branches (n=119) had significantly higher rates of cardiac death (12.2% versus 5.5%; P=0.02) and target-lesion revascularization (30.9% versus 11.1%; P<0.0001) than those with main-branch stenting alone (n=261).
Conclusions— The higher unadjusted mortality rate of patients undergoing ULMCA stenting with a sirolimus-eluting stent did not appear to be related to ULMCA treatment itself but rather to the patients’ high-risk profile. Although long-term outcomes in patients with ostial/shaft ULMCA lesions were favorable, outcomes in patients with bifurcation lesions treated with stenting of both the main and side branches appeared unacceptable.
Received April 27, 2009; accepted September 1, 2009.
Although coronary artery bypass graft surgery has long been considered the “gold standard” for revascularization of patients with unprotected left main coronary artery (ULMCA) disease, drug-eluting stents (DES) have been used with increasing frequency for the percutaneous coronary intervention (PCI) of ULMCA disease.1,2 However, recent reports have questioned the long-term safety of DES on the basis of a concern about increased rates of very late stent thrombosis (ST) compared with that found with bare-metal stents (BMS).3 In patients undergoing ULMCA stenting, stent failure manifesting as restenosis or thrombosis may be associated with a large area of myocardium in jeopardy and subsequent fatal myocardial infarction or sudden death; therefore, the long-term performance of DES in ULMCA disease is considered to be more closely linked to survival outcome than in non-ULMCA disease. To assess long-term outcomes of ULMCA PCI with sirolimus-eluting stents (SES) in the real world, we investigated the 3-year clinical outcomes of patients undergoing SES implantation for ULMCA lesions in a large multicenter registry.
Clinical Perspective on p 1874
Study Design and Patient Population
The study design and patient enrollment for the j-Cypher registry has been described in detail elsewhere.4 In brief, the j-Cypher registry is a physician-directed prospective multicenter registry in Japan enrolling consecutive patients undergoing SES implantation. From August 2004 to November 2006, 12 824 patients were enrolled in the j-Cypher registry for the first time, and 10 784 patients were treated exclusively with SES. The recommended antiplatelet regimen was aspirin (≥81 mg/d) indefinitely and a thienopyridine (200 mg of ticlopidine or 75 mg of clopidogrel daily) for at least 3 months. The duration of dual-antiplatelet therapy was left to the discretion of each attending physician.
The relevant review boards in all 37 participating centers approved the study protocol. Written informed consent was obtained from all patients enrolled.
Among the 12 824 patients enrolled in the j-Cypher registry, 582 underwent PCI for ULMCA disease (ULMCA group), and 12 242 patients underwent PCI for non-ULMCA lesions only (non-ULMCA group; Figure 1). Baseline characteristics, clinical outcomes, and causes of death in the ULMCA group were compared with those in the non-ULMCA group. Patients undergoing PCI for protected left main coronary artery lesions (n=101) were included in the non-ULMCA group.
Subgroup analysis was also conducted in 476 patients whose ULMCA lesion was treated exclusively by SES (Figure 1). Clinical outcomes in the subgroup study population were analyzed according to lesion location (ostial/shaft or bifurcation), stenting strategy (bifurcation 1-stent strategy or bifurcation 2-stent strategy), and number of diseased vessels other than ULMCA.
The left main coronary artery was defined as “unprotected” when no surgical grafts to the left coronary system were patent. Renal insufficiency was defined as estimated glomerular filtration rate <30 mL · min−1 · 1.73 m−2 according to the Modification of Diet in Renal Disease study equation modified for Japanese patients.5 Coronary angiographic parameters were assessed in each participating center either by visual assessment or by quantitative angiographic measurement. Bifurcation lesion was defined as that which involved a side branch ≥2.2 mm in diameter. Bifurcation 2-stent treatment was defined as stenting of both the main and side branches and 1-stent treatment as stenting of the main branch alone. When stenting for the side-branch ostium (circumflex in the vast majority of the cases) was performed before stenting of the main branch, the procedure was regarded as an elective 2-stent strategy. When stenting for the side-branch ostium was performed after stenting of the main branch, the procedure was regarded as a provisional 2-stent strategy.
During follow-up, death was regarded as cardiac in origin unless obvious noncardiac causes could be identified. Any death during the index hospitalization was regarded as cardiac death. Myocardial infarction was adjudicated according to the definition in the Arterial Revascularization Therapy Study.6 ST was defined according to the Academic Research Consortium definition.7 Both Academic Research Consortium “definite ST” and “definite/probable ST” on a patient basis were used as the end points for ST. Definite ST of the ULMCA lesion was also assessed separately. Target-lesion revascularization (TLR) was defined as either PCI or coronary artery bypass graft surgery due to restenosis or thrombosis of the target lesion that included the proximal and distal edge segments and the ostium of the side branches.
Categorical variables are presented as counts and/or percentages and were compared with the χ2 test. Continuous variables were expressed as mean±SD unless otherwise indicated. Continuous variables were compared with the Student t test, ANOVA, or Wilcoxon rank sum test on the basis of their distribution. Cumulative incidences of adverse events were estimated by the Kaplan-Meier method, and curves were compared with the log-rank test.
We used the Cox proportional hazard model to identify risk factors for end points such as death, cardiac death, and TLR. Proportional hazard assumptions were assessed by the plot of log (time) versus log [−log (survival)] stratified by risk factor variables. All variables in Table 1 were used as candidates for risk factors, and we selected those with P<0.10. We then conducted a backward-selection procedure on the multivariable Cox proportional hazard model with all selected risk factors and identified the independent risk factors with P<0.05. Lastly, we added ULMCA intervention as a risk factor and developed the final model.
We conducted a similar backward selection for multivariable Cox proportional hazard models to assess the effect of lesion location and bifurcation stenting strategy on all-cause death, cardiac death, or TLR in the subgroup of patients with ULMCA stenting. Then, we reached the final model with independent risk factors and bifurcation lesion or 2-stent strategy.
Adjusted survival curves were drawn for the 2 groups of patients with or without ULMCA stenting by use of the Cox proportional hazard model in conjunction with methods described by Ghali et al,8 with adjustment for the above-mentioned variables selected by the backward-selection procedure.
Probability was significant at a level of <0.05. All statistical tests were 2-tailed. Statistical analyses were conducted by a physician (M. Toyofuku) and by an independent statistician (T.M.) with the use of JMP5.1.1 (SAS Institute Inc, Cary, NC) and SAS 9.1 (SAS Institute Inc) software. The study sponsor was not involved in the study design; the collection, analysis, and interpretation of data; the writing of the report; or the decision to submit the article for publication.
The authors had full access to and take full responsibility for the integrity of the data. All authors have read and agree to the manuscript as written.
Baseline and Procedural Characteristics
Patients in the ULMCA group were significantly older and sicker than those in the non-ULMCA group, as reflected by the higher incidences of stroke, heart failure, renal insufficiency, unstable angina, shock, and bifurcation disease (Table 1). However, 53% of the patients in the ULMCA group had a EuroSCORE <6, and the procedures were performed electively in 79% of the patients.
Aspirin and thienopyridines were prescribed in 98.7% and 99.2% of patients with ULMCA stenting and 97.8% and 98.6% of patients with non-ULMCA stenting, respectively (online-only Data Supplement Table I). The proportion of patients with dual-antiplatelet therapy longer than 1 year was significantly greater in the ULMCA group than in the non-ULMCA group (73% versus 62%, P<0.0001).
Outcomes of Patients With or Without ULMCA Stenting
The median follow-up intervals were 942 days in the ULMCA group and 924 days in the non-ULMCA group, with complete 1-year follow-up in 97.0% and 96.5% (P=0.62) of patients, respectively. The crude rates of all-cause death and cardiac death up to 3 years were significantly higher in patients with ULMCA disease (Table 2; Figure 2; online-only Data Supplement Table II). Significant risk factors for all-cause death by multivariable Cox proportional hazard model included age >75 years, male gender, shock, heart failure, renal insufficiency, extracoronary arteriopathy, triple-vessel disease, diabetes mellitus, no statin use, absence of intravascular ultrasound guidance, and EuroSCORE ≥6 (online-only Data Supplement Table III). After adjustment for these confounders, there were no significant differences between the ULMCA group and the non-ULMCA group for all-cause death risk (hazard ratio 1.23, 95% confidence interval 0.95 to 1.60, P=0.12) or cardiac death risk (hazard ratio 1.10, 95% confidence interval 0.71 to 1.63, P=0.64). The adjusted 3-year survival rates were not different between the 2 groups (92.6% versus 93.9%, P=0.12; Figure 2).
Distributions of the causes of death were comparable between patients with and without ULMCA treatment (Table 3). There was no excess of patients with documented ventricular fibrillation and/or sudden death in the ULMCA group.
Rates of ST (both definite and definite/probable) were significantly higher in the ULMCA group than in the non-ULMCA group; however, the incidence of definite ST of the ULMCA lesion was relatively low (0.9% at 3 years). Furthermore, the cumulative incidence of myocardial infarction was not different between the ULMCA group and the non-ULMCA group. Angiograms and details of 4 patients with definite ST of ULMCA lesions treated exclusively by SES are shown in Figure 3 and online-only Data Supplement Table IV. No ST occurred in the main body of the ULMCA.
The rate of stroke was not different between the 2 groups with and without ULMCA treatment. The rate of TLR also was not different between the 2 groups, although the rate of any repeated revascularization was slightly but significantly higher in the ULMCA group than in the non-ULMCA group.
Clinical Outcomes According to Left Main Lesion Location
Among 476 patients whose ULMCA lesions were treated exclusively with SES, 96 (20%) had ostial/shaft left main lesions, whereas 380 patients (80%) had distal left main bifurcation lesions. With regard to lesion and procedural characteristics, patients with ostial/shaft lesions had less calcification, shorter stent length, and higher maximal balloon inflation pressure (Table 4).
Clinical outcomes were markedly favorable in the ostial/shaft group (Table 5; online-only Data Supplement Table V). There was no definite ST of the ULMCA lesion among 97 patients in the ostial/shaft group. The incidence of TLR at 3 years in that group was remarkably lower than in the bifurcation group. (3.6% versus 17.1%, P=0.0047; Figure 4). After adjustment for dialysis, small diameter (<3 mm), and diabetes mellitus, the hazard ratio for TLR with ostial/shaft lesions was 0.22 (0.07 to 0.70, P=0.011).
There was no difference in the rates of cardiac death between the 2 groups (Figure 4). After adjustment for confounders of heart failure, renal insufficiency, shock, elderly age, and intravascular ultrasound guidance, the hazard ratio for ostial/shaft lesions was 1.10 (95% confidence interval 0.60 to 2.00, P=0.76) for all-cause death and 1.40 (0.65 to 3.04, P=0.39) for cardiac death.
Clinical Outcomes According to Left Main Bifurcation Stenting Strategies and Extent of Coronary Artery Disease
Among 380 patients treated for ULMCA bifurcation lesions, 261 (69%) underwent bifurcation 1-stent procedures, whereas 119 patients (31%) were treated with 2-stent procedures (Table 6). Among 119 patients with 2-stent procedures, elective and provisional 2-stent strategies were adopted in 99 and 20 patients, respectively. Compared with patients undergoing bifurcation 1-stent procedure, patients with 2-stent procedures had more severe stenosis of the origin of the circumflex and larger vessel diameter of the circumflex.
Patients in the 2-stent group showed a trend toward a higher incidence of all-cause death and a significantly higher rate of cardiac death than patients in the 1-stent group (Table 7; Figure 5; online-only Data Supplement Table VI). After adjustment for confounders, the hazard ratio of bifurcation 2-stent treatment was 1.64 (95% confidence interval 0.93 to 2.90, P=0.088) for all-cause death and 2.78 (1.27 to 6.05, P=0.010) for cardiac death. The prevalence of documented ventricular fibrillation or sudden cardiac death among patients who died throughout the 3-year follow-up period was 4 (19%) of 21 patients in the bifurcation 2-stent group and 2 (6.7%) of 30 patients in the bifurcation 1-stent group. The rate of definite ST in the ULMCA lesion also tended to be higher in patients with bifurcation 2-stent treatment than in patients with bifurcation 1-stent treatment (2.8% versus 0.4%; P=0.050).
Furthermore, the rate of TLR in the 2-stent group was markedly higher than that in the 1-stent group (30.9% versus 11.1%, P<0.0001; Figure 5). After adjustment for confounders, the hazard ratio for TLR with bifurcation 2-stent treatment was 3.17 (95% confidence interval 1.82 to 5.52, P<0.0001). When analyzed according to the number of diseased vessels other than the left main coronary artery, the rates of cardiac death, definite/probable ST and any revascularization were significantly higher in patients with ULMCA plus 3-vessel disease (Table 8).
The main findings of this study are as follows: (1) PCI for ULMCA lesions was relatively safe, with adjusted mortality rates similar to those with non-ULMCA lesions, which indicates that fatal events due to stent failure manifesting as thrombosis or restenosis were rare; (2) SES implantation in ostial/shaft left main lesions was associated with an excellent 3-year TLR rate; and (3) bifurcation 2-stent treatment was associated with significantly higher rates of cardiac death and TLR.
Mortality Rate After ULMCA Stenting
In patients with ULMCA disease, surgical revascularization has significantly improved the survival rate compared with medical management.9 Therefore, PCI in patients with ULMCA disease should demonstrate at least comparable mortality rates to those with surgical revascularization, if PCI is a clinically acceptable alternative.
Recent reports comparing percutaneous and surgical revascularization for ULMCA disease have shown similar survival rates between the 2 therapies.10,11 Likewise, 1-year results of the SYNTAX (Synergy Between PCI With TAXUS and Cardiac Surgery) trial showed comparable mortality rates after PCI with DES or coronary artery bypass graft.12
In the present study, the crude mortality rate was 1.7% and 14.6% at 30 days and 3 years, respectively. The 30-day mortality rate was comparable to that in a recent systematic review of ULMCA stenting with DES13 and current benchmarks with coronary artery bypass graft for ULMCA14,15; however, the late mortality rates appeared to be higher in the present series. The prevalence of comorbidities in the present study population may explain the relatively high late mortality rates. Indeed, the 1-year mortality rate of 4.2% in low-risk patients (EuroSCORE <6) in the present study was similar to the 4.8% seen in the low-risk patients in the systematic review mentioned above.13 Moreover, after adjustment for confounders, there was no significant difference in the risk of all-cause death at 3 years between the 2 groups of patients with or without ULMCA stenting. These results suggest that fatal events were secondary to clinical presentation and comorbidities rather than to the performance of the implanted device. This finding is consistent with recent reports11,16,17 that the occurrence of fatal events owing to stent failure such as thrombosis or restenosis after ULMCA stenting is rare.
The present study population included high-risk conditions for ST, such as renal failure, heart failure, diabetes mellitus, and bifurcation lesions; however, the incidence of definite ST of the ULMCA lesion was relatively low (0.9% at 3 years). Moreover, no ST occurred in the main body of the ULMCA. This result is consistent with some reports that have suggested that the incidence of definite ST after ULMCA stenting is relatively lower than in other lesion subsets.16,17 However, the ST rate tended to be higher with the bifurcation 2-stent strategy than with the bifurcation 1-stent strategy.
Lesion Location and Bifurcation Stenting Strategy
Experiences with DES implantation for ULMCA showed marked reduction of restenosis rates compared with bare-metal stents.1,2 Chieffo et al18 recently showed that SES or paclitaxel-eluting stent implantation in ostial or mid-shaft lesions is associated with an excellent long-term restenosis rate of 0.9%, a finding that is consistent with the 3-year TLR rate of 3.6% seen in the present study. Patients with ostial and mid-shaft left main coronary artery lesions that did not require bifurcation treatment appeared to be good candidates for percutaneous treatment with DES.
However, distal left main disease has been reported to be associated with relatively high TLR rates of 13% to 38%, particularly when a bifurcation 2-stent procedure was undertaken.19,20 In the present study, SES deployment with a bifurcation 2-stent strategy was the strongest predictor of TLR after ULMCA stenting (3-year TLR rate of 30.9%), a finding that is in line with previous reports. The present results also point to an increased incidence of thrombotic events and a significantly higher incidence of cardiac death in patients treated with bifurcation 2-stent strategies, although the statistical power is obviously insufficient to detect differences in the incidences of these hard events. Also, survival analysis of cardiac death could be seen as a competing risk situation, because there are multiple types of death. Use of the Kaplan-Meier method in this situation may result in an overestimation of the true cumulative incidence of cardiac death.21
Because the patients with bifurcation 1-stent treatment had relatively favorable outcomes in terms of survival and need for TLR, one should make every effort to finish with main-branch stenting alone when treating left main bifurcation lesions. Also, foreseeing the likelihood of the need for a 2-stent approach appears to be important in selecting patients for ULMCA stenting. The use of DES in patients with distal bifurcation lesions that are likely to require a 2-stent strategy is probably premature. Future innovative solutions are crucial for the percutaneous treatment of left main true bifurcation lesions.
The higher rates of cardiac death and any revascularization in patients with ULMCA plus 3-vessel disease observed in the present study are consistent with the findings from the SYNTAX trial.12 Therefore, serious consideration must be given to the indication for PCI in this subgroup of patients with the most complex coronary anatomy.
Relative to the selection of revascularization strategies in patients with extensive coronary artery disease, the SYNTAX trial highlighted the lower incidence of stroke after PCI than after coronary artery bypass graft. Although the rate of stroke in the ULMCA group in the present study (2.8% at 1 year) appeared to be higher than in the PCI arm of the SYNTAX trial (0.6% at 1 year), the rates of stroke were similar between the 2 groups with or without ULMCA stenting. The relatively high incidence of stroke in the present study cohort might be related to the high prevalence of stroke at baseline.
There are several limitations to the present study. First, this was an observational study, and comparison of the clinical outcomes between patients treated for ULMCA and those treated for non-ULMCA disease might be biased even after adjustment for known confounders. Furthermore, the treatment strategy for bifurcation lesions was not based on randomized assignment. Second, TLR events in the present study included both clinically driven and angiographically driven events. The clinical significance of angiographically driven TLR of ULMCA remains unclear. Third, the length of clinical follow-up is still limited. Fourth, although the number of study patients was larger than reported previously, the present study population included heterogeneous patients with a high prevalence of elderly age, renal failure, and heart failure. Cautious interpretation is required to generalize our results. Fifth, we could not incorporate the SYNTAX score, which would have helped us to stratify the risk among patients undergoing ULMCA stenting. Finally, the relatively lower rate of ST (1.3% at 1 year) in the present study than reported in the SYNTAX trial (3.3% at 1 year) might result from the much more complex anatomic characteristics of patients in the SYNTAX trial. Alternatively, the different rates of ST could be derived from differences related to ethnicity. Therefore, it might be difficult to extrapolate the present study results outside Japan.
The higher unadjusted mortality rate in patients undergoing ULMCA stenting did not appear to be related to treatment of ULMCA itself but rather to the high-risk profile of the ULMCA patients treated by PCI in real-world clinical practice. Although long-term outcomes of patients with ostial/shaft ULMCA lesions were favorable, outcomes of patients who underwent bifurcation 2-stent treatments appeared unacceptable.
A complete list of investigators and committees of the j-Cypher registry has been published previously.11
We thank the members of the cardiac catheterization laboratories of the participating centers and the clinical research coordinators.
Sources of Funding
This study was supported in part by Cordis Cardiology Japan, Johnson & Johnson.
Drs Kimura and Isshiki have served as advisory board members and have received honoraria from Cordis Cardiology, Japan, Johnson & Johnson. Dr Mitsudo has received honoraria from Cordis Cardiology, Japan, Johnson & Johnson. The remaining authors report no conflicts.
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Despite the growing popularity of stenting unprotected left main coronary arteries with drug-eluting stents, long-term outcomes have not been assessed adequately. This large multicenter registry in Japan (the j-Cypher registry) compared the 3-year clinical outcomes of 582 patients undergoing percutaneous coronary intervention for unprotected left main coronary artery (ULMCA) lesions with those of 12 242 patients undergoing percutaneous coronary intervention for non-ULMCA lesions only. The influence of lesion location and bifurcation stenting strategy on clinical outcomes was also assessed in 476 patients whose ULMCA lesions were treated exclusively with sirolimus-eluting stents. The main findings of this study are as follows: (1) Percutaneous coronary intervention for ULMCA lesions was associated with a higher late mortality rate than for lesions located elsewhere, but this finding was mainly related to factors other than the left main being the treatment site; (2) sirolimus-eluting stent implantation in ostial/shaft left main lesions was associated with a better 3-year target-lesion revascularization rate than in distal bifurcation lesions; and (3) patients with ULMCA plus 3-vessel disease had poor long-term outcome in terms of coronary revascularization, stent thrombosis, and cardiac death. Therefore, although ULMCA stenting with a sirolimus-eluting stent is an attractive option, clinical outcomes are less satisfactory in patients who need bifurcation 2-stent treatment or who have extensive coronary artery disease outside the ULMCA. Consideration of the individual patient’s risk stratification is important when selecting coronary revascularization strategies in patients with ULMCA disease.
The online-only Data Supplement is available with this article at http://circ.ahajournals.org/cgi/content/full/CIRCULATIONAHA.109.873349/DC1.