Six- and Twelve-Month Results From First Human Experience Using Everolimus-Eluting Stents With Bioabsorbable Polymer
Background— Everolimus, an active immunosuppressive and antiproliferative agent of the same family as sirolimus (rapamycin), has demonstrated significant reduction of neointimal proliferation in animal studies. The First Use To Underscore restenosis Reduction with Everolimus (FUTURE) I trial was the first in-human experience to evaluate the safety and efficacy of everolimus-eluting stents (EES), coated with a bioabsorbable polymer, compared with bare metal stents (BMS).
Methods and Results— FUTURE I was a prospective, single-blind, randomized trial that enrolled 42 patients with de novo coronary lesions (EES 27, BMS 15). Patient and lesion characteristics were comparable between the groups. Major adverse cardiac event rates were low at 30 days and 6 months, without any early or late stent thrombosis for either group (P=NS). Between 6 and 12 months, there were no additional reports of major adverse cardiac events. The 6-month angiographic in-stent restenosis rate was 0% versus 9.1% (1 patient) (P=NS), with an associated late loss of 0.11 mm versus 0.85 mm (P<0.001), and the in-segment restenosis rate was 4% (1 patient) and 9.1% (1 patient) (P=NS) for EES and BMS, respectively. Intravascular ultrasound analysis revealed a significant reduction of percent neointimal volume in EES compared with BMS (2.9±1.9 mm3/mm versus 22.4±9.4 mm3/mm, P<0.001). There was no late stent malapposition in either group. The safety and efficacy of the EES appeared to be sustained at 12 months.
Conclusions— In this initial clinical experience, EES with bioabsorbable polymer demonstrated a safe and efficacious method to reduce in-stent neointimal hyperplasia and restenosis.
Received September 2, 2003; de novo received January 7, 2004; revision received March 18, 2004; accepted March 23, 2004.
Currently, percutaneous coronary intervention with the use of antiproliferative drug–coated stents appears to be a most promising approach to both mechanically remodel target lesions and biologically reduce neointimal hyperplasia. Recent success with stents eluting sirolimus (rapamycin) and paclitaxel, both potent inhibitors of smooth muscle proliferation, has provided clues for future drug development. Everolimus (SDZ-RAD, C53H83NO14), an active immunosuppressive and antiproliferative compound of the same macrocyclic lactone family as sirolimus, has shown promise in preventing rejection in kidney and heart transplantation.1,2 The effect is mediated by binding to a specific intracellular receptor, FK506-binding protein 12 (FKBP12), with subsequent inactivation of the enzyme, the mammalian target of rapamycin (mTOR). In addition, it has been shown to reduce smooth muscle cell proliferation in human transplant allografts.3,4
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The purpose of the present study was to provide the first in-human safety and efficacy evaluations of everolimus-eluting stents (EES), coated with a bioabsorbable polymer, compared with bare metal stents (BMS).
The FUTURE (First Use To Underscore restenosis Reduction with Everolimus) I trial was a prospective, randomized, single-center (Heart Center Siegburg, Germany), single-blinded trial of EES to reduce in-stent restenosis. Forty-two patients were randomly assigned to either EES or BMS (2:1). The institutional review board at the investigational site had approved the study protocol, and written informed consent was obtained from all patients. De novo coronary lesions with a reference diameter between 2.75 and 4.0 mm with lesion length <18 mm were enrolled, with mandatory predilatation before stent placement. Multiple stent placement was permitted to treat the target lesion. All patients received aspirin (325 mg/d) and clopidogrel (300 mg loading dose immediately and 75 mg/d for 6 months).
Absorbable composite coatings were applied onto the abluminal surface of the S-Stent (Biosensors International), a stainless steel, balloon-expandable stent.5 The coating consists of everolimus (197 μg everolimus/mm2), which is combined with a polyhydroxyacid bioabsorbable polymer (polylactic acid, PLA) matrix in a 1:1 ratio. The in vivo assays have shown that ∼70% of the drug has eluted at 30 days. A pharmacokinetic substudy has shown the circulating levels of everolimus were undetectable at 30 days of follow-up in whole blood. The lengths for both types of stents were 14 mm and 18 mm, with diameters of 2.5, 3.0, 3.5, and 4.0 mm.
Clinical evaluation was scheduled at 1, 6, and 12 months after implantation. Angiographic and intravascular ultrasound (IVUS) imaging was obtained at baseline and at 6-month follow-up.
Study End Points
The primary end point was major adverse cardiac events (MACE), including death, CABG to the target vessel, Q-wave and non–Q-wave myocardial infarction, and target lesion revascularization at 30 days. Non–Q-wave myocardial infarction was defined as elevation of creatine kinase levels >2 times normal with detectable creatine kinase-MB in the absence of new pathological Q-waves. The secondary end point was to compare quantitative angiographic and IVUS observation within the vessel as well as the clinical performance of the EES with regard to device success, MACE, and restenosis rate at 6-month follow-up.
Angiographic and IVUS Analysis
All cineangiograms and IVUS images were independently analyzed at independent core laboratories blinded to the treatment protocol. After intracoronary nitrate administration, coronary angiograms were obtained in multiple views. Quantitative angiographic end points included binary restenosis, defined as >50% diameter stenosis, minimum lumen diameter (MLD), percent diameter stenosis, and late lumen loss. Late lumen loss was measured as the difference between postprocedural MLD and follow-up MLD. Segment analysis included the stented segment as well as their margins, 5 mm proximal and distal to the stent. IVUS images were acquired by using automated pullback at 0.5 mm/s after intracoronary nitrates with one of two commercially available imaging systems (Boston Scientific/Jomed). Two-dimensional and volumetric IVUS analysis was performed with the use of commercially available planimetry software (TapeMeasure/EchoPlaque, Indec Systems), according to previously validated and published protocols. Vessel, stent, lumen, and neointimal volumes were computed for the stented segment as well as stent margins 5 mm distal and proximal to the stent. To adjust for different stent lengths, volume index was calculated as volume data divided by stent length (VVI, vessel volume index; SVI, stent volume index; LVI, lumen volume index; and NVI, neointimal volume index). Percent neointimal volume (%NV) was defined as NVI divided by SVI.
Data are presented as mean±SD or frequencies. Statistical analyses were performed with the use of StatView 5.0 (SAS Institute). For comparisons of continuous variables, a 2-tailed, unpaired t test was used. Categorical data were compared by means of the χ2 test or Fisher’s exact test. A value of P<0.05 was considered significant.
Baseline patient and lesion characteristics were similar in both groups (Table 1). Multiple stents were implanted to optimize results in 2 EES patients and 5 BMS patients. One EES patient died on day 138 from chronic obstructive pulmonary disease. Clinical follow-up rate was 95% up to 12 months. Five asymptomatic patients refused follow-up angiography. As a result, 36 patients completed the 6-month angiographic follow-up, 35 of whom underwent IVUS.
Clinical MACE and Angiographic Results
The procedural success rate was 100% for both groups. MACE rates were low at 30 days and 6 months, without any early or late stent thrombosis for both groups (P=NS). Furthermore, there was no additional MACE between 6 and 12 months. The 6-month angiographic in-stent restenosis rate for EES was 0% and 9.1% for BMS (P=NS). The in-segment restenosis rate for EES was 4% and 18.2% for BMS (P=NS). One EES patient required revascularization for a lesion distal to the stented area. For the analysis of the entire stented segment, EES showed 87% reduction in late lumen loss compared with BMS (Table 2). At the proximal and distal edges, no significant differences in late lumen loss were observed between the two groups. Lumen diameters in a subset of 8 EES patients remained virtually unchanged from their baseline measurements at 12 months.
Qualitative IVUS analysis showed there was no evidence of stent thrombosis or late stent malapposition in either group. In the 2-dimensional analysis, EES showed a larger minimum lumen area than BMS at 6- month follow-up (P<0.01). For the volumetric analysis, EES showed 87% volume reduction in neointimal formation compared with BMS (Table 2). At adjacent reference segments, neither exaggerated plaque increase nor negative vessel remodeling were observed after EES compared with BMS. The 12-month IVUS analysis showed sustained inhibition of neointimal tissue proliferation within the stent (Δ%NV, 1.5±1.9%), with no significant dimensional changes at stent margins.
In this trial, EES showed promise for the prevention of neointimal proliferation, restenosis, and associated clinical events despite the small number of patients and excellent results in BMS. The acute procedural and in-hospital outcome was uneventful. Furthermore, the safety and efficacy of the EES appeared to be sustained at 12 months.
Everolimus has increased solubility in organic solvents compared with sirolimus and has shown similar ability to inhibit smooth muscle cell proliferation despite a 2- to 3-fold lower affinity for FKBP12.2 Slightly more lipophilic than sirolimus, everolimus is more rapidly absorbed into the arterial wall where it is “warehoused” in fatty tissue membranes and plaque core close to the injury site. Experimental investigations have demonstrated that EES, through the use of a biodegradable polymer–coated stent, significantly inhibits smooth muscle cell proliferation without obvious delayed vessel wall healing in an overstretched stent restenosis model (equivalent efficacy compared with sirolimus) (Saibal Kar, MD, unpublished data, 2003). The RAVEL (RAndomized study with the sirolimus-eluting VElocity balloon-expandable stent in the treatment of patients with de novo native coronary artery Lesions) and SIRIUS (a multicenter, randomized, double-blind study of the SIRolImUS-eluting balloon-expandable stent in the treatment of patients with de novo native coronary artery lesions) trials showed significant reduction of neointimal growth (%NV, 1.0% to 2.9%), similar to the magnitude found in the present study. Significant and concordant improvements in the quantitative assessments support the efficacy of this drug-eluting stent. To minimize polymer loading in the vessel, absorbable composite coatings have been developed for this stent platform, which contain an ∼1:1 ratio of everolimus to a polyhydroxyacid biodegradable polymer (PLA) matrix. This unique and newly used bioabsorbable polymer may reduce and minimize long-term inflammation and restenosis. The present study is the first report to compare this unique type of drug-eluting stent with BMS in a prospective, randomized fashion. Because these data in a small number of patients are very limited, the results need to be confirmed by larger multicenter studies for more complex lesions.
The present study was a single-center, single-blind trial, including only 42 patients with standard-risk lesions. The BMS group had excellent clinical and angiographic outcomes that may have limited the ability to identify significant differences with the EES.
In this initial clinical experience, EES with bioabsorbable polymer demonstrated a safe and efficacious method to reduce in-stent neointimal hyperplasia and restenosis. Subsequent larger studies are needed to confirm these findings.
FUTURE-1: E. Grube, MD, Principle Investigator; R. Muller, MD, G. Techen, MD, Co-Investigators, Department of Cardiology/Angiology, Heart Center Siegburg; M. Hepper, MD, Monitor, Pharmaconsult; Biosensors International, Sponsor; Promedt Consulting GmbH, Sponsor’s Authorized Representative. Data from this trial acquired by Guidant Corporation, Vascular Interventions. Core Lab, intravascular ultrasound: Stanford University Medical Center; Angiographic Core Lab and Data Management: Cardiovascular Research Foundation. Clinical Events Committee: G. Dangas, MD (Chairman), F. Feit, MD, E. Nikolsky, MD.
The authors thank Heidi N. Bonneau, RN, MS, for her careful review of the manuscript.
↵*Drs Grube and Sonoda contributed equally to this study.
Dr Lansky has received research support from Guidant, and Dr Fitzgerald has served as a consultant to Guidant.