EXPRESS PUBLICATION
First human experience with the 17-beta-estradiol–eluting stent
The estrogen and stents to eliminate restenosis (EASTER) trial
Alexandre Abizaid, MD, PhD*,*,
Mariano Albertal, MD, PhD*,
Marco A. Costa, MD, PhD ,
Andrea S. Abizaid, MD, PhD*,
Rodolfo Staico, MD*,
Fausto Feres, MD, PhD*,
Luiz A. Mattos, MD, PhD*,
Amanda G. M. R. Sousa, MD, PhD*,
Jeffrey Moses, MD ,
Nicholas Kipshidize, MD,
Gary S. Roubin, MD,
Roxana Mehran, MD ,
Gishel New, MD||,
Martin B. Leon, MD and
J. Eduardo Sousa, MD, PhD*
* Institute Dante Pazzanese of Cardiology, São Paulo, Brazil
University of Florida-Shands, Jacksonville, Florida, USA
Lenox Hill Hospital, New York, New York, USA
Cardiovascular Research Foundation, New York, New York, USA
|| Box Hill Hospital, Melbourne, Australia
Manuscript received August 5, 2003;
revised manuscript received December 4, 2003,
accepted December 9, 2003.
* Reprint requests and correspondence: Dr. Alexandre Abizaid, Av. Dr. Dante Pazzanese 500, Ibirapuera, São Paulo, SP, Brazil, CEP: 04012-909.
aabizaid{at}uol.com.br
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Abstract
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OBJECTIVES: The purpose of the study was to examine the safety and efficacy of 17-beta-estradiol–eluting stent implantation on coronary de novo lesions.
BACKGROUND: Recent animal data indicate that local delivery of 17-beta-estradiol promotes re-endothelialization, inhibits cell migration and proliferation, and prevents restenosis.
METHODS: A total of 30 consecutive patients underwent 17-beta-estradiol–eluting BiodVysio (Biocompatibles Ltd., London, United Kingdom) stent implantation for the treatment of coronary de novo lesions. Clinical, angiographic, and intravascular ultrasound (IVUS) analysis was performed at six-month follow-up.
RESULTS: All stents were successfully deployed and patients were discharged home without clinical events. A total of two patients exceeded 50% intra-stent narrowing by angiography, whereas no patients experienced edge restenosis. One patient had focal intra-stent restenosis (60% diameter stenosis) with no symptoms and negative stress test, whereas the other patient had diffuse restenosis, requiring target vessel revascularization. No other patient experienced any major adverse cardiac event. Follow-up IVUS revealed a neointimal hyperplasia volume of 32.3 ± 16.4 mm3, whereas the stent volume was 143.7 ± 43.7 mm3, resulting in a neointimal volume obstruction of 23.5 ± 12.5%. None of the patients had  50% volume obstruction by IVUS.
CONCLUSIONS: Implantation of 17-beta-estradiol–eluted BiodVysio stents appears feasible and safe, showing low rates of binary restenosis and revascularization. These results warrant further confirmation with a large, randomized multicenter trial.
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Abbreviations and Acronyms
| | IVUS | = intravascular ultrasound | | PC | = phosphorylcholine | | QCA | = quantitative coronary angiography |
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Coronary stent implantation has been proven superior to conventional balloon angioplasty for the treatment of coronary de novo lesions (1–4). However, coronary stenting procedures are still burdened with an unacceptable high restenosis rate. Utilization of antiproliferative agents delivered locally via drug-eluting stents has dramatically reduced these rates (5–7) . However, as in the case of brachytherapy, concern remains regarding delayed healing of the arterial wall and the long-term effects of cell-cycle inhibitors. An alternative approach for the prevention of in-stent restenosis involves the use of a naturally occurring vasculoprotective hormone such as 17-beta-estradiol, which has a low molecular weight and is hydrophobic and lipophilic, making it pharmacokinetically suitable for loading on a stent delivery system. Recent animal data suggest that the local delivery of 17-beta-estradiol either via an infusion catheter or impregnated on a stent inhibits neointimal proliferation without affecting endothelial repair and function (8–10). To date, the safety and efficacy of the 17-beta-estradiol–eluting stent system on neointimal proliferation in human coronaries has not been reported. The purpose of the Estrogen And Stents To Eliminate Restenosis (EASTER) study was to evaluate the feasibility of 17-beta-estradiol–eluting stents to inhibit restenosis in humans.
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Methods
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This was a single-center prospective trial of 30 patients who were scheduled to undergo elective percutaneous intervention for single, short (<18 mm in length), de novo lesions in native coronary arteries having a diameter between 2.5 and 3.5 mm. All patients received aspirin (325 mg/day, indefinitely) at least 12 h before the procedure, and clopidogrel (300 mg at least 6 h prior to stent implantation and 75 mg daily continued for 60 days). All patients underwent angiographic and intravascular ultrasound (IVUS) follow-up at six months. The patients returned for clinical visits at 30 days, 6 months, and 12 months, during which time the physicians were blinded to the angiographic and ultrasonographic data. The protocol was approved by the Medical Ethics Committee of the Institute Dante Pazzanese of Cardiology, and informed consent was obtained from every patient.
Loading 17-beta-estradiol stents.
The BiodivYsio stent delivery system (Biocompatibles Ltd., London, United Kingdom) is a laser cut, 316L stainless steel balloon-expandable stent coated with phosphorylcholine (PC), a naturally occurring biological substance. The biocompatible PC coating constitutes a 50- to 100-µm thick double layer of synthetic PC headgroup coating that is able to adsorb a drug via a "sponge-like" mechanism. Safety of this PC headgroup coating has been previously reported (11). The method of impregnating the PC coating involves three steps. First, immersing the stent into a solution of 17-beta-estradiol (in ethanol) for 5 min. After removal of the stent from the solution and allowing it to dry for 1 min, a second step whereby 10 µl of the same solution is pipetted onto the stent. The PC polymer absorbs the solution like a sponge. The stent is again allowed to air-dry for 1 min. This process is repeated, but with 5 min of air-drying (total preparation time, 12 min). The stent is then immediately deployed. Laboratory testing has demonstrated that a consistent amount of drug (2.52 µg/mm2) can be impregnated using this method.
Procedure.
Each patient received one 18-mm stent (3.0 to 3.5 mm in diameter). All lesions were pre-dilated. Stents were deployed at high pressure (>14 atm) and the need for post-dilation was guided by IVUS.
Quantitative measurements.
Baseline, post-procedure, and six-month follow-up quantitative coronary angiography (QCA) analysis was performed in all patients by an independent core laboratory (Cardiovascular Imaging Core Laboratories, University of Florida, Jacksonville, Florida). Quantitative measurements of the in-stent and in-lesion segments (in-stent segment plus 5-mm edge proximally and distally) were performed in two orthogonal projections. The IVUS imaging was performed in all patients post-procedure and at follow-up. The IVUS images were acquired using motorized pullback at a constant speed of 0.5 mm/s (Galaxy, Boston Scientific, Natick, Massachusetts). Three-dimensional IVUS volumetric analysis was performed by an independent core laboratory (Cardiovascular Imaging Core Laboratories, University of Florida). Percent volume obstruction was defined as the ratio of the volume of neointimal hyperplasia to the volume of the stent multiplied by 100.
Statistical analysis.
Statistical analysis was performed with the aid of the commercially available software (SPSS Version 11, SPSS Inc., Chicago, Illinois). Quantitative data are presented as rates or mean value ± SD. Probability values are two-sided from the Student t test for continuous variables and the Fisher exact test for categorical variables. A value of p < 0.05 was considered significant.
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Results
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The mean age of the patients was 61 ± 12 years. A total of 21 patients (70%) were men. Systemic hypertension was the most frequent coronary risk factor, involving 15 patients (50%), followed by smoking in 10 patients (33%), and dyslipidemia in 8 patients (27%), whereas only 3 patients (10%) were diabetics. Eleven patients (37%) had a prior history of myocardial infarction. The procedure was successful in all patients. There were no in-hospital events, including no elevation of cardiac enzymes post-procedure. One patient underwent target lesion revascularization at six-month follow-up due to symptomatic angiographic restenosis. All other patients were asymptomatic at six-month angiographic follow-up. No stent thrombosis occurred, there were no other major cardiovascular events (including death, myocardial infarction, stroke, or target vessel revascularization) up to 12-month clinical follow-up.
Angiographic follow-up.
Angiographic results are presented in Table 1 and Figure 1. Mean lesion length was 9.1 ± 2.4 mm. Two patients developed in-stent restenosis (>50% diameter stenosis). One patient with a 60% lesion was asymptomatic with negative noninvasive stress test and did not undergo repeat revascularization. No restenosis occurred at the stent-edge segments, and in-segment late loss was only 0.34 mm.
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Figure 1 Cumulative distribution curves of in-stent (A) and in-lesion (B) percentage diameter stenosis (%DS) and in-stent late loss (C) at six-month angiographic follow-up.
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Six-month IVUS analysis.
The neointimal hyperplasia volume amounted to 32.3 ± 16.4 mm3 with a stent volume of 143.7 ± 43.7 mm3, resulting in a mean neointimal volume obstruction of 23.5 ± 12.5%. No patient had 50% volume obstruction by IVUS. No evidence was seen of stent malapposition or echolucent images ("black-hole").
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Discussion
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This study is the first human experience with 17-beta-estradiol–eluting stents for the prevention of restenosis. Clinical outcomes up to one-year follow-up suggest that the use of 17-beta-estradiol–eluted PC-coated stents is safe and feasible, with a low incidence of restenosis and without associated local or systemic toxicity. Only one patient (out of 30 patients) required target vessel revascularization. The angiographic and IVUS follow-up results at six months demonstrated a low amount of intimal hyperplasia and late loss, which compares favorably with previous studies testing the same PC-coated BiodivYsio (Biocompatibles Ltd.) stents without estradiol (Fig. 2). In addition, there was minimal in-segment late loss and no edge restenosis. Nevertheless, neointimal proliferation was not completely abolished by estradiol-eluting stents. It is possible that drug dosing, absorption, and elution kinetics may have influenced our results and partially limited the anti-proliferative effects of estradiol. Estradiol eluting from "hand"-loaded PC-coated stents is only carried out within the first 24-h interval (Fig. 3). Nonetheless, the amount of intimal hyperplasia detected by IVUS in the present study compares favorably with bare metal stents (12) suggesting an anti-restenotic effect of estradiol despite the suboptimal stent elution.
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Figure 2 Late-loss comparison between phosphorylcholine (PC)-coated stent trials with and without estradiol.
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Figure 3 Graph showing the phosphorylcholine polymer local delivery pharmacokinetics of 17-beta-estradiol. Total drug delivery is completed within the first 24 h.
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Estradiol is the most potent naturally occurring female hormone. It is well known that premenopausal women have a low incidence of coronary heart disease (13). Many experimental studies have demonstrated that estradiol has a vasculoprotective effect mediated via a number of cellular mechanisms (14). In particular, estradiol can inhibit smooth muscle cell proliferation and migration (15), accelerate re-endothelialization (16), and restore normal endothelial function following balloon artery injury (8,17). Inhibition of neointimal proliferation and accelerated re-endothelialization and function with the injection of 17-beta-estradiol following balloon angioplasty in a pig model has been recently reported (8). In addition, pre-clinical work with the same stent, dose, and loading process of 17-beta-estradiol as in this study, suggests a 40% reduction in in-stent neo-intimal formation (11). Estradiol is known to have pleomorphic properties. It has anti-atherogenic, anti-inflammatory, and antioxidant properties, and has a wide therapeutic window. These features may contribute to its vasculoprotective effect and may also make it a potential agent in the treatment of vulnerable plaque.
No stent thrombosis occurred despite the short duration of antiplatelet therapy in the present study. In addition, late-stent malapposition was not detected by IVUS, late-loss at the stent margins (in-segment analysis) was minimal, and no edge restenosis was found at six-month follow-up. Hence, an adequate safety profile of the 17-beta-estradiol–eluted stent was demonstrated in the present study.
Study limitations.
As most pilot studies, this "First-in-Man" experience included only 30 patients with de novo, single-vessel coronary lesions. However, the present data provide important information about the safety and potential of this technology to prevent restenosis. Whether similar results are reproducible in a larger population with more complex lesion morphology in a randomized trial remains to be tested.
The loading of 17-beta-estradiol onto the stent was performed in the catheterization laboratory just prior to stent insertion. Although a strict recipe for loading was adhered to, because this process was a "manual" method, lack of good reproducibility by this technique could result in varying doses of the hormone being loaded onto the stent. This "manual" loading process is also not practical, and pre-loaded stents would eliminate this problem. Theoretically, pre-loaded stents with different pharmacokinetics, higher drug doses, and more homogeneous and programmed drug release may further improve the results observed in the present study. A second phase of EASTER with pre-loaded 17-beta-estradiol–eluting stents is ongoing in Europe.
Conclusions.
This is the first study in humans to demonstrate that 17-beta-estradiol–eluting stents are feasible and safe. Low rates of restenosis and revascularization were observed. At 1-year follow-up, these results appear to be sustained. These seminal observations suggest that vasculoprotective agents such as estradiol may provide an alternative approach to anti-proliferative agents in the prevention of restenosis and warrant further investigation with a large, randomized multicenter trial.
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Abstract
Methods