First Clinical Experience With a Paclitaxel Derivate–Eluting Polymer Stent System Implantation for In-Stent Restenosis
Immediate and Long-Term Clinical and Angiographic Outcome
Background— It has been shown that antiproliferative drugs such as paclitaxel lower the amount of intimal hyperplasia after stent implantation. We report the first clinical experience of 7-hexanoyltaxol (QP2)–eluting polymer stent system (QuaDS) implantation for in-stent restenosis.
Methods and Results— Fifteen consecutive patients with elective indication to percutaneous coronary intervention for in-stent restenosis were treated with the QuaDS-QP2 stent implantation. The QuaDS-QP2 stent was successfully implanted in all but 2 target lesions. In one lesion, the restenotic segment could not be completely covered by the stent, and in another lesion, a bare metal stent was implanted distally to the QuaDS-QP2 stent. One patient suffered from postprocedural non–Q-wave myocardial infarction (NQWMI). No other adverse events were observed during hospital stay. Six- and 12-month angiographic and clinical follow-up was scheduled for all patients. At 6 months, 3 patients had target lesion revascularization (20%). Two patients had restenosis (13.3%); one experienced restenosis in a gap between 2 drug-eluting stents, and the other had stent occlusion leading to NQWMI. Minimal intimal hyperplasia was observed in all the segments covered by drug-eluting stents (late loss=0.47±1.01 mm with a loss index=0.17±0.39). At 12 months, 1 patient suffered from NQWMI, and 8 of 13 patients (61.5%) had angiographic restenosis (late loss=1.36±0.94 mm with a loss index=0.62±0.44).
Conclusion— This first experience with QuaDS-QP2 stent implantation for in-stent restenosis revealed minimal intimal hyperplasia at the 6-month follow-up. However, the antiproliferative effect was not maintained at the 12-month follow-up, resulting in delayed occurrence of angiographic restenosis.
Received January 10, 2002; revision received March 1, 2002; accepted March 6, 2002.
The widespread use of stents has brought about the increasing emergence of in-stent restenosis (ISR). Postintervention and follow-up intravascular ultrasound studies have shown that ISR is secondary to intimal hyperplasia.1,2⇓ The knowledge of biomolecular aspects of cell cycle regulation has made possible the development an antiproliferative approach to restenosis that aims to control cell proliferation.3 The new concept of local drug delivery via coated stents couples the biological and mechanical solutions necessary to maximize the angiographic result and facilitate the recovery of the vessel from the injury caused by the stent implantation itself. Paclitaxel, a microtubule inhibitor, has been shown to reduce and prevent intimal hyperplasia in animal models of vascular injury, as well as in the first human experience in de novo lesions.4,5⇓ Our registry includes a limited number of patients but is the first clinical experience of a paclitaxel derivate–eluting stent implantation for treatment of ISR.
Between December 2000 and January 2001, 15 consecutive patients with ISR were treated with 7-hexanoyltaxol–eluting polymer stent implantation (QuaDS-QP2; Quanam Medical Corp) in San Raffaele hospital and Centro Cuore Columbus, Milan, Italy. All the patients had an elective indication to percutaneous coronary intervention, received detailed information about potential risks and benefits of the procedure, and signed an informed consent approved by the Ethics Committees at both institutions.
Combined antiplatelet therapy with aspirin (at least 100 mg/d) and ticlopidine 500 mg/d (or clopidogrel 75 mg/d) was started at least 48 hours before procedure and continued for at least 6 months.
The stent used was a 316L stainless steel slotted tube with 50% of its surface area covered by multiple polymer sleeves that released QP2. The drug was loaded into the polyacrylate sleeve at 800 μg of QP2 per 2.4 mm of sleeve. The number of sleeves varied with the size of the stent, with a maximum number of 4 sleeves on the 17-mm stent. In this registry, either 13- or 17-mm stents were used. Kinetic studies in animals have shown drug release up to 180 days into subjacent tissues (personal communication from Dr E. Grube, Heart Center, Siegburg, Germany, March 2001).
A bolus of unfractionated heparin was administered at dose of 70 IU/kg. Balloon predilation was performed in all target lesions with at least a 2.5×20-mm balloon aimed to provide sufficient coronary lumen to limit friction between the lesion and the stent’s drug-eluting membrane.
Coronary angiograms were analyzed by a semiautomated edge contour detection computer analysis system (MEDIS QCA CMS, version 4). ISR was classified according to the angiographic patterns reported by Mehran et al.2 Reference diameter (RD), minimal lumen diameter (MLD), percentage diameter stenosis (DS), and lesion lengths were measured before and at the end of the procedure, as well as at follow-up. Acute gain, late loss, and loss index were calculated.
Clinical and angiographic follow-up was planned for all patients 6 and 12 months from the index procedure. Major adverse cardiac events (MACE) were defined as death from any cause, myocardial infarction (MI), coronary artery bypass grafting (CABG,) or repeated percutaneous coronary angioplasty (Re-PTCA), either in the hospital or during follow-up. MI was defined as Q-wave MI (development of new regional pathological Q waves) or non–Q-wave MI (total creatine kinase >2 times upper normal limit with elevated myocardial brain (MB) fraction).
Baseline clinical characteristics are reported in Table 1. Procedural and lesion characteristics are presented in Table 2, and baseline and follow-up angiographic characteristics are presented in Table 3. Sixty percent of lesions had an ostial-proximal location, and diffuse ISR pattern was present in 60% of target lesions. Almost 30% of the patients had 3-vessel disease that explained the need for multivessel intervention in 5 of 15 patients. Among these patients, the QuaDS-QP2 stent was implanted only in one of the treated vessels. Two patients with long lesions required 2 QuaDS-QP2 stents each. In 1 patient, the QuaDS-QP2 stents were implanted with a gap left unintentionally between the 2 stents. In 1 patient with a protected left main and ISR of the proximal circumflex, the QuaDS-QP2 stent could not be correctly positioned because of the angulated take-off of the vessel. The stent was finally deployed to cover only part of the target lesion. In another patient, a regular bare metal stent was implanted partially overlapping with the QuaDS-QP2 stent to treat a distal dissection.
In-Hospital, 6-Month, and 12-Month Clinical Outcome
Cumulative in-hospital, 6-month, and 12-month follow-up MACE were obtained in all patients and are reported in Tables 4 and 5⇓. One patient had postprocedural non–Q-MI with a creatine kinase (CK) peak value of 657 U/L and a CK-MB value of 63 U/L, which were due to the occlusion of a small side branch. No other events occurred during hospital stay.
Acute MI occurred in 1 patient in whom the QuaDS-QP2 stent occluded 2 months after the procedure. That stent was originally implanted without complete coverage of the target lesion. Target lesion revascularization (TLR) occurred in 3 patients. One patient had restenosis in a gap between 2 QuaDS-QP2 stents, and another patient had re-PTCA in a metallic stent (DS= 40%) overlapping with the distal edge of a QuaDS-QP2 stent. This patient had no proliferation inside the QuaDS-QP2 stent. The third patient underwent CABG for the presence of a new lesion in the proximal segment of the left anterior descending artery; however, the QuaDS-QP2 stent implanted in the mid-segment showed no restenosis.
Between 6 and 12 months, 1 patient suffered from a non–Q-wave MI, and 8 patients underwent TLR (2 had already repeated the procedure at the 6-month follow-up). All patients were taking combined antiplatelet therapy with aspirin and ticlopidine. Total incidence of TLR at 12 months was therefore 60%.
Six-Month and 12-Month Angiographic Follow-Up Results
Angiographic restenosis occurred in 2 lesions (13.3%), with stent occlusion in one. At the time of the index procedure, the QuaDS-QP2 stent could not be advanced to fully cover the lesion. The other patient had restenosis at a gap site between 2 QuaDS-QP2 stents. Taking into account the patient who developed total occlusion, late loss was 0.47±1.01 mm and late loss index was 0.17±0.39.
Twelve-month follow-up was performed in 13 of the 15 patients. One patient had stent occlusion that was not re-treated, and another who underwent CABG repeat angiography was not followed up. Angiographic restenosis occurred in 8 lesions (61.5%), with a late loss of 1.36±0.94 mm and late loss index of 0.62±0.44.
The aim of the present study was to evaluate the first clinical experience with 7-hexanoyltaxol–eluting polymer stent system implantation for ISR. Repeated balloon angioplasty and stent implantation for ISR are associated with a high rate of recurrence.6 Other mechanical devices experimented with for this purpose either failed to demonstrate clear benefit or showed advantages only in selected cases.7–9⇓⇓ Although intracoronary radiation can almost abolish neointimal cell proliferation and lower the restenosis rate,10 this approach has been shown not to be free of complications, such as edge restenosis and late thrombosis.11,12⇓ The initial positive results of 0% to 4% restenosis rate (loss index of 0 to 0.20) reported in 3 recently presented randomized trials using antiproliferative drug-eluting stents in de novo lesions prompted the evaluation of this strategy for the treatment of ISR.
In our present study, the encouraging positive results in terms of low MACE rate at 6 months obtained using the QuaDS-QP2 stent are almost eliminated at 12 months. Six-month angiographic results in our patients revealed a low loss index (0.17±0.39), resembling those reported using the same drug-eluting stent for the treatment of de novo lesions.5 It is important to note that the only 2 instances of angiographic restenosis at 6 months occurred in 2 lesions not completely covered by the drug-eluting stent during the index procedure. However, at the 12-month follow-up, an angiographic restenosis rate of 61.5% was found, with a loss index of 0.62±0.44, showing clear disease progression from 6 to 12 months and suggesting that QuaDS-QP2 drug-eluting stents actually delayed rather than prevented neointimal growth. Several factors may be operative in this loss of effect. The high dose of drug loaded in the stents and the presence of plastic sleeves are important features of the drug-eluting stent used in this study, and both might contribute to the development of late cell proliferation. Prior studies with paclitaxel-eluting stents showed not only dose-dependent reduction in neointimal hyperplasia but also histological signs of delayed healing and local toxicity after high-dose paclitaxel exposure.13 In addition, the presence of plastic sleeves could result in a foreign-body reaction that triggers inflammation and cell proliferation.
We cannot draw conclusions with regard to the thrombogenicity of this stent because of the small number of patients enrolled in this study and the continuation of combined antiplatelet therapy for at least 6 months. It is reasonable to assume that the patient who had late stent occlusion developed restenosis distal to the stent at the site of the uncovered target lesion.
This first experience with QuaDS-QP2 stent implantation for ISR revealed minimal intimal hyperplasia at the 6-month follow-up. However, the antiproliferative effect was not maintained at the 12-month follow-up, resulting in delayed occurrence of angiographic restenosis.
This study has been partially supported by Quanam Corporation, Santa Clara, Calif.
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