Percutaneous Treatment With Drug-Eluting Stent Implantation Versus Bypass Surgery for Unprotected Left Main Stenosis
A Single-Center Experience
Background— Improvements in results with percutaneous coronary intervention (PCI) with drug-eluting stents (DES) may extend their use in patients with left main coronary artery (LMCA) stenosis.
Methods and Results— Two hundred forty-nine patients with LMCA stenosis were treated with PCI and DES implantation (n=107) or coronary artery bypass grafting (CABG) (n=142), in a single center, between March 2002 and July 2004. A propensity analysis was performed to adjust for baseline differences between the two cohorts. At 1 year, there was no statistical difference in the occurrence of death in PCI versus CABG both for the unadjusted (OR=0.291; 95% CI=0.054 to 1.085; P=0.0710) and adjusted analyses (OR=0.331; 95% CI=0.055 to 1.404; P=0.1673). PCI was correlated to a lower occurrence of the composite end points of death and myocardial infarction (unadjusted OR=0.235; 95% CI=0.048 to 0.580; P=0.0002; adjusted OR=0.260; 95% CI=0.078 to 0.597; P=0.0005) and death, myocardial infarction, and cerebrovascular events (unadjusted OR=0.300; 95% CI=0.102 to 0.617; P=0.0004; adjusted OR=0.385; 95% CI=0.180 to 0.819; P=0.01). No difference was detected in the occurrence of major adverse cardiac and cerebrovascular event at the unadjusted (OR=0.675; 95% CI=0.371 to 1.189; P=0.1891) and adjusted analyses (OR=0.568; 95% CI=0.229 to 1.344; P=0.2266).
Conclusions— At 1 year, in this single-center, retrospective experience, there was no difference in the degree of protection against death, stroke, myocardial infarction, and revascularization between PCI with DES and CABG for LMCA disease. (Circulation. 2006;113:2542-2547.)
Received October 15, 2005; revision received February 27, 2006; accepted March 2, 2006.
The treatment of unprotected left main coronary artery (LMCA) disease by percutaneous coronary intervention (PCI) represents a considerable challenge for interventional cardiologists. Surgical revascularization is currently recommended for this disorder,1 and PCI has thus far only been performed in selected cases, albeit with encouraging results.2–6 Technical limitations, stent restenosis, and the risk of thrombosis limit the widespread application of this technique. The availability of drug-eluting stents (DES), associated with single-digit angiographic restenosis, prompted renewed interest in the percutaneous treatment of LMCA lesions. Preliminary results from registries show that the implantation of DES for unprotected LMCA lesions is a feasible and safe approach.7–10 Until now, no study has analyzed the treatment of LMCA stenosis with PCI versus coronary artery bypass grafting (CABG). The aim of the present study was to compare the treatment of LMCA stenosis with PCI and DES implantation versus surgical revascularization in a single center.
Editorial p 2480
Clinical Perspective p 2547
All patients with LMCA stenosis treated with PCI and DES implantation or (CABG) between March 2002 and July 2004 were analyzed. The decision to perform PCI or CABG was dependent on patient and/or physician choice. In all cases, the revascularization approach selected appeared suitable to guarantee complete revascularization. Hierarchical study end points were the composite occurrence, during hospitalization, and at 1 year of death; death or myocardial infarction (MI); death, MI or stroke; repeat revascularization; death, MI, stroke, or repeat revascularization, major adverse cardiac cerebrovascular events (MACCE). Coronary angioplasty and DES implantation in LMCA stenosis was performed with the objective of fully covering the diseased segment.11–13 Clinical follow-up was scheduled for all patients at 12 months. Angiographic follow-up was scheduled in the PCI group between 4 and 8 months or earlier if noninvasive evaluation or clinical presentation suggested ischemia.
Non–Q-wave MI was defined as elevation of serum creatine kinase MB isoenzyme that was 5 times the upper limit of normal (>40 ng/mL) in the absence of pathological Q waves.1,14 The choice of a cutoff of 5 times the upper limit of normal creatine kinase MB was made by considering the current CABG guidelines, which identifies in this subset of patient the highest risk in terms of development of subsequent events (Class IIb indication).1
Target lesion revascularization (TLR) was defined as any revascularization performed on the treated segment; target vessel revascularization (TVR) was defined as any reintervention performed on the treated vessel, considering also treatment of any segment in the left anterior descending and circumflex arteries. Cerebrovascular events were defined as stroke, transient ischemic attacks, and reversible ischemic neurological deficits adjudicated by a neurologist and confirmed by CT scanning.
The European system for cardiac operative risk evaluation (Euroscore), which is based on patient-, cardiac-, and operation-related factors, was used to stratify the risk of death at 30 days.15,16 According to the scoring system, the patients were stratified as high risk in the presence of a Euroscore ≥6 and as very high risk if Euroscore was ≥13. Full access on how to calculate the Euroscore is available at http://www.euroscore.org/calc.html.
Data are presented as percentages and mean±SD. In general, differences in proportions were tested with the χ2 test or Fisher’s exact test, and differences in location parameters of continuous variables were tested with a Student t test. Because of the nonrandomized nature of the study, the propensity score analysis was performed to minimize any selection bias due to the differences in clinical characteristics between the two treatment groups. Briefly, for each patient, a propensity score, indicating the likelihood of having PCI, was calculated by the use of a multivariable logistic regression that identifies variables independently associated with PCI. Variables included in the logistic regression analysis were age, sex, diabetes, hypertension, hypercholesterolemia, smoking, family history of coronary artery disease, unstable angina, renal failure, left ventricular ejection fraction, Euroscore, Euroscore ≥6, right coronary artery (RCA) disease, RCA treatment during the index procedure and angiographic follow-up (only for MACCE with revascularization). Patients were subsequently divided into 4 subgroups, according to the quartiles of the propensity score. The impact of PCI on death; death or MI; death, MI, or stroke; and repeat revascularization and MACCE during hospital stay and at 1 year follow-up was investigated in all 4 subgroups of patients with similar characteristics between PCI and CABG. Exact logistic regression models based on permutation resampling were used to perform unadjusted univariate analyses, stratified analyses using the propensity score quartiles as variable, and the subgroup analyses performed within each propensity score quartile. Results were reported as odds ratios (OR), together with associated exact 95% CI. The Statistical Analysis System Program version 9.1 (SAS Institute) was used for the analysis.
The authors had full access to the data and take full responsibility for its integrity. All authors have read and agree to the manuscript as written.
Baseline clinical characteristics are summarized in Table 1.
Two hundred forty-nine patients were treated: 142 with CABG and 107 with PCI with DES implantation (PCI). In the PCI group, 52 patients had paclitaxel-eluting stent implantation and 55 had sirolimus-eluting stent implantation. Patients treated with PCI were younger (63.6±10.3 versus 67.5±9.7 years; P=0.002) and less frequently had hypertension (58.8% versus 76.0%; P=0.006) and renal failure (1.9% versus 8.4%; P=0.02) but more often presented with unstable angina (31.8% versus 21.8%; P=0.08). Diabetes mellitus was present in 20 (18.7%) of the PCI group versus 33 (23.2%) of the CABG group (P=0.44). More patients treated with CABG had additional disease in the RCA (69.0% versus 40.4%); this was treated during the index procedure in 48.3% versus 16.9% of the patients, respectively (P=0.0001 for both comparison). All other variables were similar.
Eighty-seven (81.3%) patients treated with PCI had distal LMCA stenosis: 77 were bifurcations and 10 were trifurcations. Procedural characteristics of the patients treated with PCI are illustrated in Table 2.
During hospitalization, MI occurred in 10 (9.3%) patients after PCI versus 37 (26.05%) in the CABG group (P=0.0009); of these, Q-wave MI occurred in 5 patients after CABG versus none after PCI (P=0.07). Three (2.1%) patients died after CABG, whereas there were no deaths in the PCI group. Two patients had cerebrovascular events after CABG and none after PCI.
At 1 year, 9 (6.4%) in the CABG group versus 3 (2.8%) in the PCI group died, and 1 (0.9%) patient had MI versus 2 (1.4%) in the CABG group. The rate of angiographic follow-up was significantly higher in the PCI group (85% versus 6% in CABG; P<0.0001). There was a lower rate of TLR (3.6% in CABG versus 15.8% in PCI, respectively; P=0.001) as well as TVR (3.6% in the CABG group versus 19.6% in the PCI group; P=0.0001) in the CABG group. Characteristics of the patients who died during the study period are illustrated in Table 3. MACCE are reported in Table 4.
Study End Points
At 1 year, death occurred in 8.4% of the patients after CABG versus 2.8% after PCI (unadjusted OR=0.291; 95% CI=0.054 to 1.085; P=0.0710). This statistical trend was not confirmed at the adjusted analysis, where no statistical difference was present between the two study treatments (adjusted OR=0.331; 95% CI=0.055 to 1.404; P=0.1673).
PCI was correlated with a lower occurrence of the composite end points of death and MI (unadjusted OR=0.235; 95% CI=0.048 to 0.580; P=0.0002; adjusted OR=0.260; 95% CI=0.078 to 0.597; P=0.0005) and death, MI, and cerebrovascular events (unadjusted OR=0.300; CI 95%=0.102 to 0.617; P=0.0004: adjusted OR=0.385; 95% CI=0.180 to 0.819; P=0.01) (Figure 1). Conversely, CABG was correlated with a lower occurrence of TVR at both adjusted (OR=3.33; 95% CI=1.321 to 8.960; P=0.008) and adjusted analysis (OR=4.22; 95% CI=1.486 to 14.549; P=0.0046).
There was no difference in the occurrence of MACCE in PCI versus CABG both for the unadjusted (OR=0.675; 95% CI=0.371 to 1.189; P=0.1891) and adjusted analyses (OR=0.568; 95% CI=0.229 to 1.344; P=0.2266) (Figure 2).
On-Pump Versus Off-Pump Surgery
Eighty-six (60.5%) patients had on-pump versus 56 off-pump surgery. In-hospital MACCE were lower in patients with off-pump surgery (19.6% versus 36.0%; P=0.04). The benefit of off-pump surgery was maintained at 1 year: MACCE were 30.3% versus 43.0% (P=0.15) and MACCE without revascularization were 21.4% versus 39.5% (P=0.02). MACCE are reported in Table 4.
The main finding of this single-center, retrospective study is that in our experience there is no difference in the degree of protection against death, stroke, MI, and revascularization at 1 year between PCI with DES and CABG for unprotected LMCA disease.
Current guidelines recommend surgical revascularization for LMCA stenosis.1 Some retrospective studies evaluating surgical treatment for this disease reported an in-hospital mortality rate varying from 1.7% to 7.0% and a 1-year mortality rate of 6% to 14%.17–20 Conversely, the treatment of LMCA stenosis by PCI is still debated. In these patients, PCI has thus far been performed only in exceptional cases, albeit with positive results.2–6 The availability of DES, associated with a reduction in angiographic restenosis, prompted renewed interest in the percutaneous treatment of LMCA stenosis. Recently, encouraging results have been reported with elective DES implantation in LMCA, with a 1-year mortality rate from 0% to 4%.7–10
This is the first study to compare surgical revascularization with PCI with DES implantation in the treatment of LMCA stenosis. Because of the nonrandomized nature of the study, an adjusted analysis using the propensity score was performed to take into account differences in baseline clinical characteristics between the study groups. This adjustment by propensity score analysis, which takes into account baseline differences in risk factors, showed that there is no statistical difference in the occurrence of death and MACCE at 1 year in both unadjusted and adjusted analysis between CABG and PCI, mainly because of the increased risk of revascularization with PCI. Conversely, PCI was associated with a lower occurrence of the composite end points of death and MI and death, MI, and cerebrovascular events compared with CABG, which was significant at 1-year follow-up.
The lower need for revascularization in CABG demonstrates that current DES are still an imperfect solution unable to completely eliminate restenosis in complex settings such as bifurcational lesions and multivessel disease.7–10
It might, however, be fair to point out that routine angiographic follow-up was part of this initial protocol to detect early left main stent restenosis and that many TVR were angiographically rather than clinically driven (Table 4). Because CABG patients have no such routine follow-up, the parallel ability to detect asymptomatic graft closure or restenosis may be underestimated in the present study. We should take into account that patients with LMCA stenosis treated with DES do not undergo routine angiographic follow-up when enrolled in the “Synergy between Percutaneous Intervention with TAXUS (Boston Scientific Corporation, Natick, MA) and Cardiac Surgery” (the SYNTAX trial), unless enrolled in a specific substudy or as routine practice of many European Institutions (M.C. Morice and P.W. Serruys, personal communication, Paris, 2005). Nevertheless, we cannot ignore the fact that among the 16 patients who had restenosis after PCI (in all cases the restenosis was focal), only 5 required CABG and all the others were successfully treated with PCI. Although there were insufficient numbers of ostial/mid shaft lesions in this series, none of those patients required TLR; all TLR were in the patients with distal stenting, typically through repeat PCI. The restenosis occurred in 7 patients in the ostium of the side branch (circumflex artery), in 4 in the ostium of the main branch (left anterior descending artery), and in all other cases proximal or distal to bifurcation. It may be possible that a more conservative use of provisional stenting of the circumflex could have further improved the results of the patients treated with PCI.
Among the 3 patients in the PCI cohort who died (Table 3), only 1 death was due to the presence of a stent in the left main because of early discontinuation of antiplatelet therapy. This fact stresses the importance of careful screening of each patient before considering PCI to rule out any risk of premature discontinuation of antiplatelet therapy.21,22 One persisting problem is for how long the patients need to continue double-antiplatelet therapy. In this series, almost 70% of the patients were still taking 2 antiplatelet agents at 1 year. We could therefore assume, even if not demonstrated, that the extended 1-year therapy could be sufficient in the more complex anatomical setting such as bifurcational stenting.
Another aspect to be taken into account is the different incidence of complications between on-pump and off-pump CABG with an in-hospital incidence of MACCE 2 times higher for on-pump surgery. This finding, in accordance with the current literature,17,20 is quite important in planning any future trial in which the use of off-pump revascularization should be encouraged.
It is our belief that only a prospective, randomized trial with extended follow-up at least until 5 years will give any conclusive information about the optimal treatment of LMCA. The SYNTAX trial is at the present time ongoing and will include 1800 patients with either left main or triple-vessel disease, randomly assigned to receive paclitaxel-eluting stent implantation or CABG.
The major limitation is that this is an observational not a randomized study. Consequently, the choice of the treatment was left to the physician and/or patient. This limit was mainly due to the exploratory nature of the study, which is the first to compare surgical revascularization to PCI with DES implantation in the treatment of LMCA stenosis. Although the small number of patients enrolled in the present study represents an important limitation, we nevertheless performed a propensity score adjustment to reduce the disadvantage caused by the higher-risk profile of the patients treated with CABG. Moreover, despite the numerical difference, the small sample size allows us to detect as statistically significant only very relevant differences in mortality rate between the two study groups. Furthermore, the MI definition of our study could have penalized the CABG group. Another limitation is the duration of the follow-up (1 year), which could have penalized the CABG group because of the higher occurrence of periprocedural MACCE in this type of treatment. A longer follow-up will give us further information to evaluate the optimal treatment of LMCA.
At 1 year, in this single-center, retrospective experience, there was no difference in the degree of protection against death, stroke, MI, and revascularization between PCI with DES and CABG for LMCA disease.
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Surgical revascularization is currently recommended for left main coronary artery (LMCA) stenosis, and percutaneous coronary intervention (PCI) has thus far only been performed in selected cases, albeit with encouraging results. Improvements in results with PCI with drug-eluting stents (DES) may extend their use in this subset of patients. In the present study, 249 consecutive patients with LMCA stenosis electively treated in our center with PCI and DES implantation (n=107) or coronary artery bypass grafting (CABG) (n=142) were analyzed. A propensity analysis was performed to adjust for baseline differences between the two cohorts. The hierarchical study end points were the occurrence, during hospitalization and at 1 year, of: death; death or myocardial infarction (MI); death, MI, or stroke; repeat revascularization (TVR); death, MI, stroke, or repeat revascularization, major adverse cardiac cerebrovascular events (MACCE). At 1 year, there was no statistical difference in the occurrence of death in PCI versus CABG. No difference was detected in the occurrence of MACCE at 1-year follow-up. In conclusion, in this single-center, retrospective experience, there was no difference at 1 year in the degree of protection against death, stroke, MI, and revascularization between PCI with DES and CABG for LMCA disease. A prospective, randomized study with longer clinical follow-up is needed to define the optimal revascularization strategy for LMCA disease.