Novel paclitaxel-eluting, biodegradable polymer coated stent in the treatment of de novo coronary lesions: A prospective multicenter registry

Abstract

Objectives: The purpose of the present study was to evaluate the efficacy and safety of a biodegradable polymer coated, paclitaxel eluting stent (Luc-Chopin²) based on 9-months angiographic and 12-months clinical follow-up results. Background: First-generation drug-eluting stents utilize nonbioabsorbable polymeric coatings, whose persistent presence in the arterial wall may negatively affect long-term outcomes. Bioabsorbable coatings with a degradation period matched to that of the drug elution may be a better alternative, clinically and economically. Methods: We conducted a prospective, multicenter first-in-man registry of a novel, locally developed, bioabsorbable-coated, paclitaxel-eluting coronary stent in 116 patients with single-lesion de novo coronary disease. Results: Major adverse cardiac events occurred in 7.8% patients within 12 months. There were no late thrombotic events, death, stroke, or surgical revascularization in that period. There were two myocardial infarctions, one related to recent subacute stent thrombosis and another associated with restenosis. By 12 months, target vessel revascularization was performed in 7.8%; 2.9% were ischemia-driven and the rest were mandated at 9 months in accordance with a control angiography protocol. Core-lab assessed binary in-stent restenosis (≥50% DS) was noted in 11.9% patients and mean late loss was 0.46 ± 0.47 mm. Conclusions: This first-in-man experience obtained in a multicenter registry of real-world de novo lesions (almost half of lesions were class B2 or C by AHA classification) showed a favorable safety profile and acceptable efficacy through 12 months. Randomized comparison with a benchmark nonbioabsorbable polymer coated paclitaxel eluting stent should be undertaken to validate this initial positive experience. © 2008 Wiley-Liss, Inc.

INTRODUCTION

The efficacy of drug eluting stents (DES) for prevention of restenosis and for reduction of the risk of revascularization has been proven in numerous clinical trials [1–5]. On the other hand, these stents simultaneously inhibit the physiological healing process of the vessel wall, prolong the inflammatory reaction and adversely affect the restoration of correctly functioning endothelium [6–9]. It is believed that one possible cause for these adverse reactions might be a negative influence of the permanent presence of the polymer used to coat the stent surface and elute the drug. After the drug elution, polymer stays on the stent surface and may continue to incite a local inflammatory reaction, impair healing, and eventually contribute to late thrombosis [1, 6, 10–13]. This scenario could be potentially averted with the use of a biodegradable polymer, which would be absorbed from the stent surface shortly after the drug has been eluted. Biodegradation ensures that both drug and coating are absorbed from the stent surface after their function is accomplished, leaving only a metal stent covered by neointima and endothelium without further continuous irritation of the arterial wall. Theoretically, this may improve arterial healing as well as reduce the need for prolonged antiplatelet therapy.

Recently, a novel, locally developed stent became available in our region of Europe that elutes paclitaxel from a biodegradable coating with a relatively short lifetime. It uses a stainless steel “Chopin²” stent (Balton, Warszawa, Poland) as a platform, widely used in clinical practice, and reported previously [14]. The purpose of the present study was to evaluate the efficacy and safety of this biodegradable polymer coated, paclitaxel eluting stent (Luc-Chopin²) based on 9-months angiographic and 12-months clinical follow-up results.

MATERIAL AND METHODS

The Luc-Chopin² stent (Balton, Warszawa, Poland) is covered with a multilayer structure containing a copolymer of lactic and glycolic acid, paclitaxel and auxiliary substances. The total mass of polymer on a 3.0 × 15 mm² stent does not exceed 360 μg. In vitro evaluations suggest that the coating degrades entirely in 8 weeks. Analysis of Luc-Chopin² stent's surface structure before and after expansion shows uniform coating without peeling or fractures (Figs. 1 and 2). Paclitaxel in a dose of 1.0 μg/mm² was chosen as a drug inhibiting neointimal proliferation.

Figure 1. Microscopic pictures of Luc-Chopin² stent surface showed uniform biodegradable polymer coating without fractures or peeling.

Figure 2. Microscopic picture (with 1,000× enlargement) of the expanded Luc-Chopin² stent surface. The polymer covers the whole surface as a homogenous layer, despite microcrackings in the stent struts.

The study was a prospective, multicenter registry for the assessment of safety and efficacy of the treatment of patients with the use of the Luc-Chopin² coronary stent system. Patients were enrolled in the study after signing the informed consent form. The registry protocol was approved by a local Institutional Review Board and the Ministry of Health. Between July 2005 and October 2005 in 11 cardiac centers in Poland, 116 patients with angiographically diagnosed de novo coronary stenosis (>50% DS) referred for coronary stent implantation were enrolled in the registry. From 116 patients enrolled to the study 73.9% were men. The average age of the studied population was 54 ± 21 years. Stable angina was present in 85.2% of patients and diabetes in 21.7%. More demographic data of the studied population are showed in Table I.

Table I. Demographic Data (n = 115)

	N	%
Male	85	74
Hypercholesterolemia	69	60
Family history of CAD	28	24
Smoking	65	57
Diabetes	25	22
Hypertension	80	70
Previous myocardial infarction	43	37
Stable angina	98	85
Unstable angina	15	13
STEMI, NSTEMI	2	2

Adult patients (>18 years) with symptomatic coronary artery disease who had single “de novo” lesions in a native coronary artery with reference diameter of 2.8–4.0 mm and lesion length <18 mm were considered for enrollment. Patients with contraindications to aspirin, ticlopidine or clopidogrel, with active ulcer disease, hemorrhagic diathesis, and noncardiac disease, which could limit long-term survival, were excluded from the study. Ostial lesions, unprotected left main disease, or total occlusions were also excluded.

After signing the informed consent form for participation in the study, patients meeting the entry criteria received 150 mg aspirin and 2 × 250 mg ticlopidine or 75 mg clopidogrel at least 48 h before the procedure (with the exception of emergent cases of unstable angina, who were saturated immediately prior to percutaneous coronary angioplasty (PCI) with 300 or 600 mg of clopidogrel). During the procedure patients received 100 IU/kg i.v. unfractionated heparin, which was corrected to maintain an ACT >300 sec. Use of GP IIb/IIIa receptor inhibitors was left to the operator's discretion. Dual oral antiplatelet treatment was continued for 6 months.

Percutaneous coronary intervention was performed using standard techniques. Predilation was not obligatory and depended on the operator's preferences. The study protocol included an angiographic follow-up 9 months after the index procedure. In case the clinically driven PCI was performed earlier, angiograms were used for follow-up analysis if done later than 6 months after the index procedure. An assessment of the clinical status and adverse events was made at 1, 3, 6, and 12 months after stent implantation. Clinical data analysis was made based on a case report form filled electronically by investigators on a study website. All serious adverse events were adjudicated by an independent committee, based on complete medical documentation available from sites.

Angiograms of the stented segment in all cases were obtained in at least two orthogonal views after intracoronary nitroglycerin application; baseline angiogram—directly before intervention, second—directly after stent implantation, and third—during the 9-month angiographic follow-up. All angiograms were recorded digitally on CD in DICOM format and subjected to analysis at an independent core laboratory (KCRI, Krakow, Poland). Measurements were made based on calibration of a contrast-filled catheter and automatic contour detection of treated segment using NewQuant32 QCA software package (Sanders Data Systems, Palo Alto, CA). Reference vessel diameter (RVD) was calculated as an arithmetical mean of vessel diameter in segments proximal and distal to the target lesion. Percent diameter stenosis (%DS) was defined as the difference between RVD and minimal lumen diameter (MLD) divided by the reference diameter multiplied by 100. Late loss (LL) was defined as the difference between MLD in the angiogram obtained after stent implantation and at the 9-month follow-up. Binary restenosis was defined as stenosis of 50% or greater of the MLD in the target lesion at angiographic follow-up (≥50% DS).

Primary endpoints of study were angiographic features of restenosis in the stented segment, evaluated with the 9-month follow-up coronary angiography, and clinically driven revascularization of the study stent including 5-mm margins (target lesion revascularization, TLR) in the 12-month clinical observation. Clinically driven TLR was defined as: any stenosis >70% in a target lesion or stenoses between 50 and 70% in a target lesion accompanied by stenocardial signs or symptoms. Secondary endpoints of the study were defined as the incidence of major adverse cardiovascular events (MACE) such as death, stroke, myocardial infarction with or without ST elevation (STEMI, NSTEMI), and stent thrombosis.

RESULTS

Procedural Outcomes

Of 116 patients who had PCI with Luc-Chopin² stent implantation, protocol violation occurred in one case. The patient was not included in the study population but was closely followed-up. Eventually 115 patients in whom 118 study stents were implanted were enrolled in the study. The average preprocedural %DS was 63 ± 15% with an average lesion length of 13.9 ± 3.4 mm. The implanted stent diameter was 3.1 ± 0.3 mm and length was 16.2 ± 3.7 mm. Eighty one procedures (70.4%) were accomplished with direct stenting and 34 (29.5%) with predilatation. In 78 procedures (67.8%) additional postdilatation was done. Lesion characteristics and their localization are presented in Table II.

Table II. Lesions Characteristics (n = 115)

		Number (N)	%
Location	LAD	51	44.3
	RCA	40	34.8
	CX	20	17.4
	Other (OM, PDA)	4	3.5
Disease	Single-vessel	52	45.2
	Double-vessel	56	48.7
	Tri-vessel	7	6.1
Lesion type	A	12	10.4
	B1	49	42.6
	B2	45	39.1
	C	9	7.9
Calcified lesions	–	15	13.0
TIMI flow = I	–	15	13.0
TIMI flow = II	–	31	26.9
TIMI flow = III	–	69	60.0

In three cases during the procedure dissection in stented segments occurred. They were provided with additional Luc-Chopin² stents according to the protocol. Procedural success defined as satisfactory angiographic outcome in the absence of periprocedural MACE was achieved in 99.1%. During hospitalization one patient (0.9%) on the fourth day after the index procedure experienced myocardial infarction due to subacute in-stent thrombosis. This patient was successfully treated with balloon angioplasty.

Long-Term Outcomes

During 12 months of clinical follow-up no case of death, stroke, or surgical revascularization occurred (Table III). Prior to the control angiography at 9 months, one patient had stent thrombosis with myocardial infarction as described above. In another case, during the third month after the procedure, myocardial infarction occurred and angiography revealed in-stent restenosis. A third patient who demonstrated acute anginal symptoms at 4 months after stent implantation had restenosis in the stent. Thus, up to 9 months after implantation only one case of in-stent thrombosis (0.9%) and two cases of restenosis occurred. All three events were treated successfully with repeat PCI (TLR = 2.6%, MACE = 2.6%). None of these three patients showed recurrence in the 12 months of follow-up.

Table III. Clinical Events in 12-Months Observation (n = 115)

	No. of patients	% of patients
Death	0	0
Myocardial infarction	2	1.9
Stroke	0	0
Thrombosis	1	0.9
During hospitalization	1	0.9
Since discharge to 12 months	0	0
TLR before planned coronarography	3	2.6
TVR before planned coronarography	3	2.6
MACE before planned coronarography	3	2.6
TLR based on control coronarography	5	4.9
TVR based on control coronarography	6	5.9
TLR (all)	8	7.0
TVR (all)	9	7.8
MACE (all)	9	7.8

Angiographic 9-month follow-up was available in 101 (87.8%) patients. Eleven patients without clinical symptoms of angina refused control angiography, and three patients met the study endpoint before the 9-months follow-up. Following 9-month coronarography, six patients were diagnosed with restenosis requiring revascularization in stented segments that yielded total TLR of 7.8% (total MACE = 7.8%). In patients who had control angiography, binary in-stent restenosis (≥50% DS) was noted in 12 cases (11.9%). Average LL in this group was 0.46 ± 0.47 mm and average in-stent %DS was 27% ± 16%. Results of quantitative angiographic analysis are presented in Table IV, while the distribution of stenosis severity is shown in Fig. 2. V

Table IV. QCA Analysis Results in 101 Patients at 9-Month Follow-Up Angiography

	Before implantation	After implantation	After 270 days
RD (mm)	2.9 ± 0.45	3.1 ± 0.43	3.0 ± 0.45
MLD (mm)	1.1 ± 0.47	2.7 ± 0.35	2.2 ± 0.61
%DS (%)	63 ± 15	13 ± 10	27 ± 16
Lesion length (mm)	13.9 ± 4.71	16.0 ± 4.26	16.0 ± 4.08
Acute gain (mm)	–	1.6 ± 0.41	–
Late loss (mm)	–	–	0.46 ± 0.47
Binary restenosis	–	–	11.9 % (n = 12)

Table V. Mehran Classification of Restenosis Type

	Number (n = 12)	%
Focal	5	41.7
Intrastent	6	50.0
Diffuse	1	8.3
Total occlusion	0	0.0

DISCUSSION

First generation DES effectively limited the rate of restenosis and the need for revascularization (TLR) compared to bare metal stents (BMS) [1–5]. Unfortunately, lots of doubts regarding their long term safety have recently appeared, specifically regarding the possibility of increased risk of late and very late stent thrombosis in comparison to BMS [1, 10–13]. Experimental studies have shown that the first generation DES may impair endothelialization and cause an excessive and prolonged inflammatory process in comparison to BMS. Similar conclusions arise from autopsy investigations in which Taxus and Cypher stents were compared to their stainless steel counterparts. A recent study of human pathology specimens confirmed that both Cypher and Taxus stents delayed arterial healing in comparison to BMS, presenting persistent fibrin deposits and lack of or incomplete endothelialization [6]. It seems that the polymer itself could be at least partially responsible for delayed healing, because it permanently remains on the stent surface after the drug has been eluted. Conversely, it is believed that improved outcomes could be achieved if the coating was temporary and could degrade in parallel with the drug elution so that both would no longer be present in the artery wall once the antirestenotic effect is accomplished and the stented segment is healed.

With this goal in mind, the LUC-Chopin² stent covered with biodegradable polymer, eluting paclitaxel from its surface, was developed. The copolymeric (lactic and glycolic acid-based) multilayer absorbable coating is fully degraded in vitro in ∼8 weeks, closely following complete elution of paclitaxel from it. Preclinical studies in a porcine coronary overstretch model demonstrated favorable safety with endothelialization appearing complete and inflammation significantly decreased between 1 and 3 months [15]. At 1 month in the porcine model Luc-Chopin² stents effectively limited neointimal hyperplasia in comparison to the control group (LL = 0.48 ± 0.06 mm for steel stents vs. 0.15 ± 0.05 mm for Luc-Chopin² stents; P < 0.05). At 3 months, a “catch-up” effect in neointimal formation was observed similar to other preclinical studies evaluating stents eluting paclitaxel, sirolimus, or tacrolimus [16–18]. It is known that this lack of late efficacy in the pig coronary model does not preclude sustained efficacy in clinical trials [19–21].

The present first-in-man feasibility muliticenter registry confirms, clinically and angiographically, the acceptable safety and efficacy of Luc-Chopin² stents in the treatment of de novo coronary lesions. Device success was 100%. The angiographic binary restenosis rate was 11.9% and LL was 0.46 ± 0.47 mm at the 9-month angiographic observation in this first-in-man feasibility registry. These results are satisfactory in view of rather complex lesions (47% were AHA class B₂ and C). In the benchmark randomized Taxus IV and Taxus V clinical trials, in which paclitaxel eluting stents were also evaluated angiographically after 9 months, LL was 0.39 ± 0.50 mm and 0.49 ± 0.61 mm, and binary restenosis was 7.9% and 13.7%, respectively [22, 23]. A comparison to the Infinnium stent registry (Sahajanand Medical Technologies) seems more adequate, since it features a similar concept and technology (biodegradable polymer coated, paclitaxel eluting stents at a dose of 1.4 μg/mm²). In this registry (with a short angiographic follow-up made after 6 months), results were comparable to ours with a LL of 0.38 ± 0.49 mm and a restenosis rate of 7.3% [24].

Clinically, the total incidence of MACE was 7.8% at 12 months, which is also comparable to previously reported rates for paclitaxel eluting stents (8.5% for Taxus stents and 9.7% for Infinnium stents). There was no occurrence of death, stroke, or necessity for surgical revascularization (CABG). Two cases of myocardial infarction occurred (1.9%). One was related to stent thrombosis and another to restenosis. The early stent thrombosis was subacute and therefore did not seem to be related to degradation of the coating, which is projected to last at least 8 weeks. Moreover, during the observation time after Luc-Chopin² implantation, a low revascularization rate in stented vessel segments (TLR = 7.8%) was observed and only three of these patients (2.6%) required reintervention due to refractory angina. In the remaining six patients coronary angioplasty was primarily driven by angiographically confirmed restenosis at 9-months follow-up. The restenosis pattern was mild overall, with the majority of affected patients showing %DS of 50–70% by quantitative angiography (Fig. 3). Only in two cases were %DS values >70%. Qualitatively, among 12 cases of angiographic restenosis none was a total occlusion and only one was proliferative. Focal restenosis was found in 41.7% of cases.

Figure 3. Distribution of percent diameter stenosis (%DS) in treated arteries among 101 patients with angiographic follow-up.

In summary, this first-in-man experience obtained in a multicenter registry of real-world de novo lesions treated with a novel Luc-Chopin² stent eluting paclitaxel from bioabsorbable polymer has been positive. The safety profile appeared excellent as there were no incidents of late thrombosis between 30 and 365 days of clinical follow-up. This is always encouraging for a new DES concept in view of recent concerns about excess late events with DES [1, 10–13]. Angiographically documented restenosis was comparable to previous experiences with paclitaxel and the ischemia-driven revascularization rate was low. Conceptually, use of a biodegradable polymer whose duration on the stent surface matches the period of anti-restenotic action of the drug may provide an improved safety profile by reducing late events related to the persistent presence of polymer on the surface of the first-generation stents. It may consequently also shorten the obligatory period of double antiplatelet therapy, enhancing overall clinical and economical benefit. Obviously, however, larger, more adequately powered studies would have to support this initial impression.

A randomized head-to-head comparison against the benchmark Taxus stent (which uses the same drug but a nonbiodegradable polymer) is planned to elucidate some of these concepts.