Clinical Outcomes after Multilesion Percutaneous Coronary
Intervention: Comparison between Exclusive and Selective
Use of Drug

Drug-eluting stents (DES) have revolutionized modern interventional cardiology by providing distinct advantages over bare-metal stents (BMS) in reducing the risk of in-stent restenosis. Several randomized clinical trials have consistently demonstrated improved clinical results for polymer-based DES as compared to BMS in low-, moderate- and high-risk lesions.¹ Large registries have also confirmed the superiority of DES in the real world and all-comers.^2,3 At the same time, the benefit of DES appears confined in lowering the risks of repeat intervention as mortality and the risks of myocardial infarction have not been altered by DES.^2,3 Therefore, the costeffectiveness of DES remains an important issue.⁴ Furthermore, recent data looking at longer follow up (> 4 years) have suggested late thrombosis after DES in a small but significant number of patients.^5–7 Further analysis on late follow up with DES has been advocated.⁸ In this regard, the role of prolonged combined therapy with aspirin and clopidogrel to limit the risk of delayed stent thrombosis is currently much debated.⁹
A complex related issue remains to define the best strategy for patients with multiple coronary lesions. Indeed, some authors have suggested that DES should be reserved for higherrisk lesions and BMS could be still used for lower-risk lesions.¹⁰ Other authors have disputed this view.¹¹ Therefore, it remains important to evaluate the optimal strategy to revascularize patients with multiple lesions. Due primarily to cost constraints, DES are not used in every lesion, and this provides a unique opportunity to evaluate clinical results according to the initial strategy of revascularization. Our objective was to compare acute and late results in a consecutive series of unselected patients with multiple coronary lesions that were treated with DES-only (Exclusive DES group) versus DES and BMS (Selective DES group), guided by clinical and angiographic criteria.

Materials and Methods
Population and percutaneous coronary intervention (PCI) procedures. Patients treated with ≥ 2 coronary lesions were identified from our catheterization laboratory database from February 2005 to February 2006. In accordance with our routine practice, procedures were mostly performed by the transradial approach. Interventional strategy including direct stenting, pre- and postdilatation, stent types and periprocedural glycoprotein IIb/IIIa receptor inhibitors were left to the choice of operators. The BMS included the Express2 and Liberté (Boston Scientific, Corp. Natick, Massachusetts), Driver (Medtronic, Inc., Minneapolis, Minnesota) and Mini-Vision (Abbott Vascular, Abbott Park, Illinois) stents. The primary DES was Taxus^® Express2 (Boston Scientific). Heparin (70 U/kg) was administered at the beginning of the diagnostic procedure. Patients were pretreated with aspirin, which was continued afterwards indefinitely. Clopidogrel wasinitiated prior to the procedure with a minimal loading dose of 300 mg and prescribed for a minimum of 12 months.
In 2003, at the request of the government which was concerned by the costs of DES, a group of experts in Québec Province of Canada issued recommendations to limit the use of DES, and 4 criteria were chosen to guide DES use in our institution. Criteria 1 is the presence of diabetes, Criteria 2 is a reference diameter < 2.9 mm, Criteria 3 is a lesion length 3 15 mm and Criteria 4 is a lesion located in proximal left anterior descending artery lesion. The choice of exclusive DES strategy or selective DES strategy was left to the operator’s discretion and visual assessment. All patients signed an informed consent prior to the index procedure.
Study protocol. Acute and late outcomes were assessed using hospital charts and structured case report forms, and clinical follow up was performed by telephone contact either with patients or referring physicians as required. The primary endpoint was the incidence of a major adverse cardiovascular event (MACE) including death from any cause, myocardial infarction (MI) and revascularization (PCI or coronary artery bypass surgery [CABG]). Secondary endpoints were revascularization rate (per patient) and TLR rate. Postprocedure MI was adjudicated after 3 3 times CK-MB values above the upper limit of normal (ULN) value. Follow-up MI was adjudicated using standard criteria, i.e., prolonged chest pain with troponin/ CK-MB rise above ULN value with or without new Qwave on the electrocardiogram. Revascularization was defined as any new intervention either, PCI or CABG involving the treated vessel. TLR was defined as any repeat intervention involving the initially treated segment. Quantitative angiographic analysis of all index lesions was performed using a previously validated software package (CMS 6.0, Medis, Leiden). Stent thrombosis was evaluated according to the Academic Research Consortium (ARC) criteria.¹² Briefly, stent thrombosis was classified as definite, probable or possible. The timing of stent thrombosis was evaluated as early (£ 30 days), late (> 30 days–1 year) or very late (> 1 year).¹² Rehospitalization for cardiac reason, cardiovascular medications and angina status according to Canadian Cardiovascular Classification were also assessed during follow up.
Data analysis. Data are presented as mean values ± standard deviation or medians or as percentages. Continuous variables were compared using the unpaired Student’s t-test or the Wilcoxon rank-sum test. Categorical values were compared using the Fischer’s exact test or the Pearson Chi-Square test as appropriate. Time-to-event was calculated using the Kaplan-Meier method and compared using the log-rank test. Because of the observed differences in baseline characteristics between the two treatment groups, propensity score analyses were carried out by use of a multivariable logistic regression model for treatment strategy of exclusive DES versus selective DES. Variables with significant univariate associations, along with a number of clinical, angiographic and procedural variables that differed among the two treatment groups at p < 0.25 were candidates for multivariable analysis. Multivariable logistic regression was performed using backward variable selection in a stepwise fashion with the exit criteria set at p < 0.05. Variables not selected by the automated procedure were added back into models individually to evaluate for residual confounding. Seven variables (gender, diabetes, prior CABG, ST-elevation MI, reference vessel diameter < 2.9 mm, lesion numbers and length 3 15 mm) met criteria for inclusion in the propensity score. The goodness-of-fit of the propensity score model was assessed by the c-statistic and showed good discrimination value (0.75). The propensity score was then incorporated into the Cox proportional hazards model as a covariate. The Cox proportional hazard model was used to assess the relative risks of adverse outcomes. Inclusion of the propensity score as a covariate accounts for the likelihood of treatment and may adjust for unobserved confounding and selection bias. A p-value < 0.05 was considered significant. All analyses were performed using JMP 5.1 statistical software (SAS Institute, Cary, North Carolina).

Results

During the study period, we treated a total of 362 patients with 900 coronary lesions. Clinical follow up at 412 ± 110 days was completed in 100% of the study population. Patients in the exclusive DES group (n = 161) were less often men, had more diabetes, more previous CABG and presented less often with ST-elevation MI than patients in the selective DES group (n = 201) (Table 1). There were less bifurcations, less multivessel disease, and less lesions/patient treated in the exclusive DES group compared to the selective DES group (Table 2). Accordingly, there were less stents/patient used in the exclusive DES group compared to the selective DES group (2.72 ± 1.04 vs. 3.22 ± 1.35; p < 0.0001). In contrast, the rate of stent/lesion was similar in both groups (1.20 ± 0.34 vs. 1.21 ± 0.33; p = 0.74). Patients in the exclusive DES group received 2.72 ± 1.04 DES compared to 1.67 ± 1.02 DES in the selective DES group (p < 0.0001). Taxus Express2 stents were the DES used in most cases, followed by Cypher^™ stents (Cordis Corp, Miami Lakes, Florida). Using the clinical and angiographic criteria, patients in the exclusive DES group had more diabetes, less lesions with length 3 15 mm (36% vs. 52%; p < 0.0001), and less lesions located in the proximal left anterior descending artery (16% vs. 31%; p < 0.0001) than patients in the selective DES group. Overall, lesions treated with DES had ≥ 2 criteria in 65% of patients in the exclusive DES group and 70% in the selective DES group (p = 0.25) (Table 3). More than 75% of the lesions in both groups were type B or C lesions (Table 4). In contrast, there were less type B or C lesions treated with BMS than lesions treated with DES in the selective DES group (p < 0.0001).

At 30 days, clinical outcomes were similar in the 2 groups (Table 5). At late follow up, the MACE rate was similar in the 2 groups: 16.8% in the exclusive DES group versus 18.4% in the selective DES group (p = 0.78) (Table 5) (Figure 1). There were no differences in death or MI rates between the 2 groups. Importantly, the rates of revascularization including CABG and repeat PCI were similar in the 2 groups: 9.9% versus 10.5%, p = 1.00, respectively. Cardiac death occurred in 4 cases (mean delay 218 days) in the exclusive DES group and 8 cases (mean delay 47 days) in the selective DES group (p = 0.12). Stent thrombosis occurred in 6/161 (3.7%) cases in the exclusive DES group, and in 1/201 (0.5%) case in the DES selective group (p = 0.03). In the exclusive DES group, definite stent thrombosis was angiographically observed in 3 cases (2 early and 1 late), and in 3 others was associated with sudden death (2 late and 1 very late). In the selective DES group, the sudden death resulted from late possible stent thrombosis.

Per lesion analysis, 5.5% lesions were revascularized in the exclusive DES group compared to 6.2% in the selective DES group (p = 0.77). In the selective DES group, 2.8% TLR involved lesions with DES and 3.4% TLR involved lesions with BMS (p = 0.84). Unadjusted hazard ratios (HR) did not suggest a significant role for the initial strategy of exclusive or selective DES use, for MACE (HR 0.92; 95% CI 0.72–1.18), revascularization (HR 0.93; 95% CI 0.67–1.29) or for target lesion revascularization (HR 0.89; 95% CI 0.67–1.18). Even after adjustment, Cox proportional HR did not indicate a significant influence of the initial strategy on the occurrence of MACE (HR 0.94; 95% CI 0.72–1.23), revascularization (HR 0.91; 95% CI 0.64–1.29) or TLR (HR 0.81; 95% CI 0.59–1.08). In subgroups analysis, male gender (HR 0.69; 95% CI 0.47–0.98; p = 0.037), prior CABG (HR 0.50; 95% CI 0.23–1.00; p = 0.049) and number of lesions 3 3 (HR 0.58; 95% CI 0.30–1.00; p = 0.048) were identified with significantly less risk of TLR with the exclusive DES strategy compared with the selective DES strategy (Figure 2).

Significant predictors for increased risk of MACE rates were lesion length 3 15 mm (HR 1.36; 95% CI 1.02–1.88; p = 0.03), and serum creatinine levels > 2 mg/dL (HR 2.25; 95% CI 1.39–3.30; p = 0.002). Significant predictors for increased risk of revascularization rates were unstable angina (HR 1.72; 95% CI 1.23–2.42; p = 0.001), and total stent length > 68 mm (HR 1.49, 95% CI 1.03–2.14; p = 0.017). Significant predictors for TLR were dyslipidemia (HR 1.59; 95% CI 1.14–2.36; p = 0.006), and unstable angina (HR 1.50; 95% CI 1.14–1.98; p = 0.004).
At 12-month follow up, the majority of patients were taking aspirin and clopidogrel combination (> 95%) and at the end of the study follow up, 63% of patients in the exclusive DES group and 65% of patients in the selective DES group were still taking clopidogrel (p = 0.74). Similarly, there was no difference in other cardiovascular medications in the 2 groups. The rate of repeat hospitalizations for cardiac reasons was also similar in the 2 groups. More patients were anginafree or in class I of Canadian Cardiovascular Society angina class at the end of follow up in the selective DES group compared to the exclusive DES group.

Discussion
In this study, we showed that patients with multiple coronary lesions who were treated with a selective DES strategy guided by 4 angiographic and clinical criteria had similar acute and late clinical outcomes than patients treated with an exclusive DES strategy. DES have been a major breakthrough in interventional cardiology. Large international, double-blind, randomized studies have largely demonstrated the benefit of DES compared to BMS in lowering the rates of in-stent restenosis and hence of repeat interventions.^1,7 Yet no significant benefit in terms of risks of mortality and/or MI has been demonstrated with DES compared to BMS. Moreover, the increasing use of DES in socalled off-label indications, i.e., the majority of lesions in everyday practice have been associated with recent concerns related to long-term safety.5 Lastly, the issue of cost of DES has further complicated the worldwide adoption of these devices.^10,13–17 The issue of discontinuing the combination of aspirin and clopidogrel months after DES implantation has also been recently discussed.⁹ Following a special U.S. Food and Drug Administration meeting in December 2006, it has been suggested that additional data related to DES use in nonapproved indications and all-comers are eagerly awaited.¹⁸
Although data comparing exclusive and selective DES use have been previously reported, important biases including different periods of implantation, unbalanced numbers of DES and BMS or incomplete angiographic follow ups have been generally associated with these reports.^11,19,20 In order to limit the costs associated with DES use, the governments of Canadian provinces have requested experts to make recommendations to guide clinicians in their DES use.^21,22 In Québec province of Canada, the Tertiary Cardiology Network formed by interventional cardiologists, noninterventional cardiologists and representatives from government and health agencies, published reports in 2003 and 2004 with several recommendations to guide the use of DES.²² Based on these reports, we summarized these recommendations into 4 angiographic and clinical criteria. Other Canadian and foreign health agencies have used similar criteria to guide DES use.^13,23
Our results indicate that both strategies are safe since death and MI rates were similar in the 2 treatment groups. It should be emphasized that since the beginning of DES use, it was recommended to prescribe the combination of aspirin and clopidogrel for a period of 12 months. Indeed, at 12-month follow up, > 95% of our study population was still on dual therapy. Furthermore, at the end of follow up, > 66% of the patients were still taking aspirin and clopidogrel. This might underscore that with off-label DES use, physicians are becoming reluctant to stop clopidogrel 12 months post PCI. Despite the high level of dual therapy use, it is noteworthy that stent thrombosis using the ARC definitions (definite, probable and possible) occurred more often in the exclusive DES group compared to the selective DES group.
Limitations of DES use as advocated by health agencies and governments is primarily due to cost constraints.¹⁴ No data on DES cost-effectiveness have been reported yet for the treatment of patients with multiple coronary lesions. The use of specific criteria defining high-risk lesions for repeat intervention or bearing severe clinical consequences in the event of restenosis/reocclusion intends to limit the use of DES from 20% to ~40% of the cases.^{13,17,21–26} In general, proposed criteria are based on lesion diameter and length, lesion location, i.e., the proximal left anterior descending artery, and the presence of diabetes. These factors have been associated with higher risk of in-stent restenosis, hence, repeat revascularization. In our experience, more than two-thirds of lesions that were treated with DES in the 2 treatment groups had ≥ 2 high-risk criteria. Patients in the selective DES group had similar rates of revascularization and TLR compared to patients in the exclusive DES group. Overall, the rates of revascularization and TLR in our study population are consistent with several other experiences with exclusive use of DES.³ Furthermore, our results also agree with other experiences with selective use of DES.^9,16,19 Whereas the theoretical advantage of DES is not disputed, this should not obscure the fact that BMS with more recent designs have also greatly improved clinical outcomes.^10,27,28 Our experience suggests also that some subgroups such as males, post-CABG patients or patients with ≥ 3 coronary lesions might benefit more from an exclusive DES strategy.
Study limitations. Our single-center study is limited by its retrospective and nonrandomized nature with its inherent potential bias. The initial strategy was left to the operators’ discretion, which introduced a bias. Despite adjustment by propensity score, it remains possible that some confounding variables were ignored. Despite a mean follow-up period > 12 months in both groups, the follow-up duration was shorter in the selective DES group, and this may have affected the rates of revascularization and TLR compared to the exclusive DES group. Indeed, the HR for TLR, although not significant, was associated with a 19% benefit in favor of the exclusive strategy. Larger sample sizes are required to better clarify this issue. Our results should only be interpreted as hypothesisgenerating, and ultimately, a large, prospective, multicenter, randomized study is required to validate a selective strategy guided by angiographic and clinical criteria as an alternative to the exclusive strategy. Lastly, the cost-effectiveness of selective and exclusive DES strategies should be also investigated.

Conclusion
In conclusion, in this study selective and exclusive DES use were both effective strategies for revascularization of patients with multiple coronary lesions, the latter being possibly associated with less risks of TLR in some subgroups and with an increased risk of stent thrombosis compared to the selective strategy.

Acknowledgements.
Dr. Olivier F. Bertrand is a researchscholar supported by the Quebec Foundation for Health Research. Support from Servier Inc. for the clinical management of the catheterization laboratory database is gratefully acknowledged. Dr. Benjamin Faurie was supported by a fellowship grant from the Fédération Française de Cardiologie.

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