Two-Year Clinical Follow Up of Coronary Drug-Eluting Stent in
Patients at High Risk for Coronary Restenosis

Drug-eluting stents (DES), compared with bare-metal stents (BMS), have shown a clear superiority in the prevention of restenosis and the need for further revascularization in randomized, controlled trials.^1–5 Accordingly, the superiority of DES over BMS was confirmed in large registries.^6,7 A major finding regarding the use of DES is that although the safety of DES is not different from that of BMS in the shortto- medium term, concern has arisen about the potential for late stent thrombosis related to delayed endothelialization of the stent struts.^8,9 Although there was not a significant increase in neointimal thickness at 4-year follow up in the first-in-human trial regarding DES,¹⁰ other data have suggested a possible late restenotic phenomenon due to delayed neointimal growth and stent fracture with local tissue proliferation.^11,12 Therefore, we evaluated the 2-year clinical outcomes of the selective use of DES in a group of patients at high risk for coronary restenosis.

Methods
Patient population. Among 495 patients who underwent a percutaneous coronary intervention (PCI) between June 2004 and March 2005 in our tertiary referral hospital, we retrospectively selected a subset of 150 patients (30%) on the basis of the following angiographic characteristics: ostial lesion, proximal lesion if the reference vessel diameter was £ 2.75 mm, long lesion (³ 20 mm), recent or chronic total occlusion (lesion of at least 1 month’s duration with thrombolysis in myocardial infarction [TIMI] grade 0 or 1 flow), the need for multivessel angioplasty, the presence of a bifurcation lesion, left main disease, in-stent restenosis, or bypass graft disease. On the basis of stent availability, the patients were treated exclusively with Cypher stents (Cordis Corp., Miami Lakes, Florida) between June and December 2004, while only Taxus stents (Boston Scientific Corp., Natick, Massachusetts) were used between January and March 2005. Written, informed consent to coronary intervention was obtained from all patients.
Procedure and medications. The interventional strategy and the use of glycoprotein (GP) IIb/IIIa inhibitors were left entirely to the discretion of the operator. A loading dose of 300–600 mg of clopidogrel was given to all patients before the procedure. Lifelong aspirin was prescribed to all patients, in addition to clopidogrel (75 mg/day) or ticlopidine (250 mg bid) for 6–12 months.
Follow up. We evaluated the incidence rate and the risk of major adverse cardiac events (MACEs), death (cardiac and noncardiac), nonfatal acute myocardial infarction (MI), target lesion revascularization (TLR), target vessel revascularization (TVR) and nontarget vessel revascularization during a 2-year follow up period. MACE were defined as a composite of all-cause death, nonfatal acute MI, or TVR. Acute MI during follow up was diagnosed by local cardiologists at the hospital of admission according to standard criteria (increased levels of troponin or creatinine kinase-MB fraction in association with chest pain and/or ischemic electrocardiographic changes). TLR was defined as a repeat intervention (percutaneous or surgical) to treat a luminal stenosis occurring within the stent or in the 5 mm proximal or distal segments adjacent to the stent. TVR was defined as a repeat intervention (percutaneous or surgical) to treat a luminal stenosis occurring in the same coronary vessel treated at the index procedure within and beyond the target lesion limits. Coronary angiography procedures performed at baseline and postprocedurally were visually estimated. The American College of Cardiology (ACC)/American Heart Association (AHA) lesion classification was used.¹³ All patients were followed up by telephone interview and the information about clinical outcomes was confirmed by review of hospital records or by the referring physicians. Data on all repeat interventions and repeat hospitalizations were prospectively collected.

Statistical analysis. Continuous variables were expressed as mean ± standard deviation (SD). Categorical variables were expressed as counts and percentages. The cumulative incidence of adverse events was estimated according to the Kaplan- Meier method. We assessed the proportional hazard of covariates listed in Tables 1 and 2 and univariate Cox regression analyses were performed to evaluate the risk of adverse events. Covariates with a p-value < 0.05 were considered significant and are reported in Table 3. Patients lost to follow up were considered at risk until thedate of final contact, at which point they were censored. In all cases, p < 0.05 was considered significant.

Results
The clinical, angiographic and procedural characteristics of the 150 patients enrolled are shown in Tables 1 and 2. Overall, 31% of the patients had diabetes mellitus, 43% prior MI, and more than 50% of the patients were admitted with acute coronary syndromes (12% of acute ST-segment elevation MI). The more frequent selection criteria observed were the presence of a long lesion (73% of patients) and the execution of multivessel angioplasty (43% of patients). We treated 284 lesions (1.9 lesions/patient), and 318 stents were implanted (2 stents/patient). Before the procedure, the reference diameter was 2.9 ± 0.3 mm, the minimum lumen diameter was 0.7 ± 0.6 mm, the diameter stenosis was 83 ± 11%, the lesion length was 18.2 ± 6.2 mm, and the TIMI flow was 0 to 1 in 34 patients (23%). After the procedure, the minimum lumen diameter was 2.9 ± 0.4 mm, the diameter stenosis was 0.4 ± 2.8%, and the TIMI flow was 0 to 1 in 2 patients (1.3%). Periprocedural glycoprotein IIb/IIIa inhibition was used in 25 patients (17%). Procedural success was achieved in 99% of the procedures.

The 30-day, 1-year and 2-year results are shown in Figure 1. Two-year cumulative incidence of the combined endpoint of death or MI, TVR, MACE and TLR were 7.3%, 10%, 16% and 7.3%, respectively (Figures 1 and 2). Clinical follow up was 100% at 1 month, 95% at 1 year and 95% at 2 years. A total of 6 deaths (4%) occurred. Three patients died during the index hospitalization; all of them had a history of previous MI and were admitted with an acute coronary syndrome (2 died the same day ofthe procedure and the other one at day 6 as a result of progressive hemodynamic deterioration). One patient died of a noncardiac cause 10 days after hospital discharge. A 71-year-old male with previous MI, three-vessel disease, prior coronary bypass graft surgery (CABG), 3 of 4 coronary bypasses occluded, and poor left ventricular function (ejection fraction 18%), who was admitted with unstable angina and treated with stenting of the circumflex artery, died as result of heart failure 62 days after hospital discharge. There was 1 case of fatal acute MI attributable to stent thrombosis in a 77-year-old female 88 days after hospital discharge, and 8 days after discontinuation of antiplatelet therapy due to noncardiac surgery. A total of 5 nonfatal acute MIs (3%) occurred. One patient had a postprocedural MI. Two patients experienced an acute MI in territories unrelated to the target vessel. One patient experienced acute stent thrombosis (< 24 hours). The last patient had a stent thrombosis in a saphenous vein graft 2 years after stent implantation. A total of 11 TLRs (7.3%) were necessary. TVR and nontarget vessel revascularization were necessary in 15 patients (10%) and 9 patients (6%), respectively. In 23 of 24 cases, the reintervention was successfully performed percutaneously, while 1 patient underwent CABG.

To identify independent predictors of MACE and TVR at 2 years, Cox regression analyses were performed for all baseline and procedural characteristics listed in Tables 1 and 2, and those who were found to be significant are reported in Table 3. Total occlusion, number of lesions treated and age were significant predictors of MACEs at 2 years. Furthermore, bypass graft treatment, total occlusion, number of stents implanted and number of lesions treated were significant predictors of TVR. A stent thrombosis occurred in 3 patients (2%); 1 of them died.

Discussion
The major finding of this report is that in real-world patients at high risk for coronary restenosis, the use of DES was associated with a low incidence of cardiac events over a long-term followup period. Indeed, a late restenotic phenomenon was not shown in this series as confirmed by a low incidence of clinically- driven TLR of 7.3% at 2 years. Our findings are in accordance with the results of large registries which showed that the selective use of DES in realworld patients who have high-risk clinical and angiographic characteristics is associated with a significant decrease in MACE and repeat revascularization compared with BMS.^14,15 Thus, the suppression of neointimal hyperplasia seems to be extremely important for complex lesions and patients such as those in our population.
The number of lesions treated was an independent predictor of worse MACE outcomes, as shown by the MACE rate and the need for TVR at 2 years. A previous metaanalysis of controlled trials of PCI versus CABG showed improvement for these patients with extensive forms of coronary artery disease who underwent surgical revascularization.¹⁶ Today, there are reasons to doubt the current trend towards the increasing use of PCI in such patients. Finally, the observed low incidence of stent thrombosis over 2 years (2% of the patients) confirms previous data from randomized trials¹⁷ and large registries,¹⁸ underlining the importance of prescribing long-term dual antiplatelet therapy.
Study limitations. This report suffers from several limitations. First, among our patients, there was significant variation in the types of interventional procedures and techniques used; second, a limited number of the patients enrolled in this study were unable to be compared with other patient subgroups. Nonetheless, this study provides interesting information derived from “real-world” PCI and DES in patients treated for very complex lesions who are usually excluded from randomized trials.

Conclusions
This study confirms, once again, the effectiveness of DES in the prevention of restenosis and new clinically-driven revascularization procedures. Indeed, in these real-world patients at high risk for coronary restenosis, the use of DES was associated with a low incidence of cardiac events.

References

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