Treatment of Multilesion Coronary Artery Disease with Simultaneous Drug-Eluting (Full title below)

From the Department of Cardiology, Ferrarotto Hospital, University of Catania, Catania, Italy. The authors report no conflicts of interest regarding the content herein. Manuscript submitted October 29, 2008, provisional acceptance given December 2, 2008, final version accepted January 5, 2009. Address for correspondence: Prof. Corrado Tamburino, MD, FSCAI, FESC, Cardiology Chair and Division, Ferrarotto Hospital, via Citelli 6, 95124 Catania, Italy. E-mail: tambucor@unict.it _________________________________

Treatment of Multilesion Coronary Artery Disease with Simultaneous Drug-Eluting and Bare-Metal Stent Implantation: Clinical Follow Up and Angiographic Mid-Term Results

ABSTRACT: Objectives. We sought to evaluate clinical and angiographic outcomes of percutaneous coronary intervention (PCI) in patients receiving both bare-metal stents (BMS) and drug-eluting stents (DES). Background. Few data are available about the safety and efficacy of the practice namely called “hybrid PCI”. Methods. One hundred and eighty-six patients, 502 de novo lesions, received during PCI both BMS (n = 266) and DES (316), with a mean of 3.1 ± 1.2 stents/patient. Cumulative major adverse cardiac events were analyzed at 24 ± 22 months. Results. Clinical follow up was carried out in 100% of eligible patients. Angiographic follow up at 8.6 ± 4.4 months was achieved in 70.4% of patients, 71.6% of stents and 72.5% of lesions. Binary restenosis was 12.9% vs. 20.6% (p = 0.034) in DES vs. BMS, respectively; late loss was significantly higher in BMS than in DES (0.67 ± 0.73 vs. 0.35 ± 0.71 mm; p Methods Population. From the Ferrarotto DES database, a prospective, single-center registry with the primary purpose of evaluating safety and efficacy of DES in daily practice, we retrospectively analyzed 186 patients with CAD who were referred to our institution for myocardial ischemia and underwent hybrid PCI between May 2002 and May 2006. Interventional procedures and medical therapy. Since this study was based on current clinical practice, it required only ordinary written informed consent to the procedure, which was obtained from every patient. The study was in accordance with the Declaration of Helsinki. All interventions were performed according to current standard guidelines.12 The interventional strategy and administration of glycoprotein (GP) IIb/IIIa inhibitors were left to the discretion of the operators. An intravenous (IV) bolus of unfractioned heparin (UFH) was administered at a dose of 70 UI/kg immediately before PCI, and an additional bolus was given to achieve a target activated clotting time (ACT) between 250 and 300 seconds. In cases of abciximab administration, the loading dose of UFH was 50 UI/Kg and the target ACT was 250 seconds. All patients were on aspirin (100 mg daily), which was continued indefinitely. A loading dose of 300–600 mg of clopidogrel was given the day before PCI in elective procedures, or in the catheterization laboratory in emergent revascularizations, and was followed by a 75 mg daily dose for at least 6 months. Alternatively, ticlopidine, at a dose of 250 mg twice daily, was administered. Follow up, endpoint and definitions. Information about in-hospital outcomes was obtained from an electronic centralized clinical database. After discharge, all clinical follow-up data were prospectively collected by scheduled clinic evaluations or direct telephone interviews. The referring physicians and institutions were contacted whenever necessary for additional information. Angiographic follow up was suggested at 6–9 months after the index procedure, especially in patients with complex bifurcation lesions, chronic total occlusions (CTO), left main lesions, ostial lesions, small vessels, long lesions and more than 2 implanted stents. It was performed at an earlier time if clinically indicated. Angiographic data were evaluated visually by 2 independent operators using the same angiographic views from the index procedure. In cases of discordance, a split decision was resolved by consensus. An independent internal clinical events committee was responsible for reviewing all adverse events and adjudicated the relationship between the device and the severity of the events. Cardiac death was defined as any death due to sudden death, fatal MI or refractory congestive heart failure. The diagnosis of MI was based on the ESC/ACCF/AHA/WHF 2007 definition13 as a total creatinine kinase-MB elevation ≥ 3 times normal with or without new pathological Q waves in ≥ 2 contiguous leads. TLR included any repeat revascularization within the stent or in the 5 mm proximal or distal segments adjacent to the stent. Major adverse cardiac events (MACE) were defined as a composite of cardiac death, nonfatal MI or TLR. Binary restenosis was defined as a diameter stenosis of > 50% occurring in the segment inside the stent or a 5 mm segment proximal or distal to the stent at follow-up angiography. Stent thrombosis was classified according to the Academic Research Consortium (ARC) definitions14 as acute if it occurred within 24 hours after the index procedure, subacute if it occurred between 1 and 30 days after the index procedure and late if it occurred between 31 days and 1 year after the procedure. Stent thrombosis was considered definite if there was angiographic confirmation of thrombus, with or without vessel occlusion, associated with clinical or electrocardiographic signs of acute ischemia. Stent thrombosis was classified as probable if unexplained death occurred ≤ 30 days after the index procedure or if a MI, occurring at any time after the index procedure, was documented in an area irrigated by the stented vessel in the absence of angiographic confirmation of stent thrombosis. Stent thrombosis was classified as possible in cases of unexplained death occurring > 30 days after the index procedure. Angiographic analysis. Angiograms suitable for quantitative analysis were obtained before and after stent implantation and at follow up using at least two orthogonal views. Angiographic analysis was performed using a computer-assisted system with an automated edge-detection algorithm (QCA-CMS® version 5.2, MEDIS, The Netherlands). The complexity of lesions was defined according to a modified grading system of the American College of Cardiology/American Heart Association. When the angiogram was not reliable for computer-assisted analysis, the stenosis was visually estimated by two senior interventional cardiologists. Statistical analysis. Continuous variables are presented as mean ± standard deviations and compared using the Student’s unpaired t-test. Categorical variables are presented as counts and percentages and were compared with the chi-square test when appropriate (expected frequency > 5). Otherwise, Fisher’s exact test was used. All statistical tests were two-tailed. MACE were analyzed using the Kaplan-Meier method. A p-value Results Baseline and procedural characteristics. Of 5,350 patients who underwent PCI with stent implantation between May 2002 and May 2006 at our Institution, 186 (3.5%) met the criteria for “hybrid PCI”, receiving at least 1 DES and 1 BMS in either the same (22.0%) or different vessels to treat a total of 506 de novo lesions located in native coronary arteries or saphenous vein grafts. A total of 582 stents were implanted, of which 266 (45.7%) were BMS and 316 (54.3%) were DES. Of the DES, 187 (59%) were Cypher™ stents (Johnson & Johnson-Cordis Unit, Cordis Europe NV) and 129 (41%) were Taxus® stents (Boston Scientific Corp., Natick, Massachusetts). Multivessel disease was observed in 89.8% of patients (6% of them also had left main disease) and ≥ 1 CTO was treated in 7 (3.4%) patients. Of note, because in the study period the vast majority of bifurcation lesions treated occurred in patients who received only DES during the procedure, it is not surprising that in this series, ≥ 1 bifurcation lesions were treated in only 9 (4.8%) patients. Baseline clinical, angiographic and procedural characteristics are reported in Table 1. The average number of stents implanted was 3.1 ± 1.2 per patient, and 1.2 ± 0.4 per lesion. Three or more stents were implanted in 62.4% of patients and GP IIb/IIIa inhibitors (abciximab 31.2%, and tirofiban 11.8%) were administered in 43.0% of patients. Angiographic success was achieved in 97.6% of PCIs. DES were more often used in the left anterior descending artery (LAD) (DES 50.3% vs. BMS 32.7%; p 20 mm in length, and 20.5% versus 14.5% (p = 0.37) for stents Discussion DES have shown to reduce restenosis and the need of revascularization in all subsets of patients and lesions when compared with BMS. Nevertheless, the use of DES increases costs and shows a potential risk of late events related to thienopyridine discontinuation. For these reasons, BMS should not be abandoned and their use should be encouraged when results can be predicted to be similar or close to those offered by DES. There is a paucity of data regarding angiographic comparisons of DES and BMS11 in the same patient and on long-term clinical follow up in this population.15,16 In fact, all randomized trials and other studies have compared two different populations with either DES or BMS, and we cannot exclude some of the potential differences on an individual patient basis after stenting (i.e., platelet reactivity, drug resistance, operator technique, symptom referral). In our study, we retrospectively analyzed 186 patients who received — during the same procedure — 1 or more DES and 1 or more BMS. This population was arbitrarily divided into two subgroups in order to discriminate between the lesion types and to correlate them with the results. The main findings of this study are: 1) The simultaneous use of both DES and BMS is safe and provides similar results between the 2 stents in simple lesion types (A/B1); 2) In complex lesions (B2/C), BMS showed a significantly higher restenosis rate than DES. When DES and BMS implanted in A/B1 lesions were compared, differences in late loss and binary restenosis were not significant, while comparing DES and BMS implanted in complex lesions (B2/C) showed a significant difference, with the binary restenosis rate twice that with BMS than with DES. Interestingly, the correlation is evident when a criterion for complexity is established according to lesion characteristics, but is denied when it is determined according to procedural characteristics such as stent size. In fact, even when 2 lesions are treated with the same stent, it is well known that their characteristics and propensity for restenosis may differ when the following are present: greater amounts of tortuosity; angulation of the segment; presence of occlusions; issues with side branches; and potential for protection. This stresses the importance of referring to the validated ACC/AHA lesion classifications in clinical practice instead of searching for other surrogate, but less reliable, markers of complexity. Thus, in patients with more than one complex lesion, the hybrid PCI approach should be discouraged and DES use preferred. Conversely, the hybrid approach can be employed in patients with heterogeneous lesions, as the use of BMS to treat simple lesions does not increase the risk for restenosis compared to DES. Of note, the overall rate of repeat revascularization (26%) was higher than that previously reported in other studies (Table 5).11,15,16 This was primarily due to higher rates of diabetes, ACC/AHA Type C lesions and follow-up angiography in our population in which > 100 Type B2/C lesions were treated with BMS; however, the mortality and MI rates remained low (4% and 1%, respectively), confirming that the selective use of DES may be reasonably safe. Stent thrombosis. A suspected stent thrombosis occurred in 2 cases during the entire follow-up period up to 12 months after stent implantation. In 1 angiographically confirmed case, a BMS was demonstrated to be responsible for the event. No suspected late or very late stent thrombosis occurred after scheduled thienopyridine discontinuation. Study limitations. This study has several limitations, notably the small number of patients studied, the retrospective and non-predetermined identification of the different strata, the open-label design, the forced use of BMS depending on shelf availability of DES and the lack of a blinded follow up. Moreover, we recognize that two different types of DES with different late lumen loss and restenosis rates were utilized. We cannot exclude the possibility that the lack of difference in restenosis rates in the Type A and B1 lesions may be due to the lack of power that a greater number of patients would have conferred. Angiographic follow up, which is known to accentuate the rates of repeat revascularization compared with clinical follow up alone, despite careful attempts to adjudicate and include only those events that were truly driven by ischemia, may have distorted the results relative to routine clinical practice. Intravascular ultrasound evaluation was not routinely performed after PCI, but both groups suffer this limitation. On the other hand, it is possible to exclude any bias due to the operator-dependent technique, because both stent types were implanted during the same procedure. Conclusions In real-world patients, the simultaneous use of both DES and BMS is safe and provides similar results for the 2 stents only in simple lesions. In complex lesions, BMS offer significantly greater restenosis and TLR rates comparison to DES. Prospective studies are needed to confirm our results and to produce a cost-benefit analysis in the setting of multivessel or multilesion PCI where at least one large vessel is treated. Acknowledgment. This research was supported in part by a research grant from the Associazione Cuore e Ricerca of Catania.

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