Paclitaxel Coating Reduces In-Stent Intimal Hyperplasia in Human Coronary Arteries
A Serial Volumetric Intravascular Ultrasound Analysis From the ASian Paclitaxel-Eluting Stent Clinical Trial (ASPECT)
Background— The aim of this study was to use serial volumetric intravascular ultrasound (IVUS) to evaluate the effect of a paclitaxel coating on in-stent intimal hyperplasia (IH).
Methods and Results— Patients were randomized to placebo (bare metal stents) or 1 of 2 doses of paclitaxel (low dose: 1.28 μg/mm2; high dose: 3.10 μg/mm2). Complete post-stent implantation and follow-up IVUS were available in 81 patients, including 25 control patients and in 28 receiving a low-dose and 28 receiving a high dose. Volumetric analysis of the stented segment and of both reference segments was performed. Baseline stent measurements and both reference measurements were similar among the groups. With increasing doses, there was a stepwise reduction in IH accumulation within the stented segment (31±22 mm3 in control, 18±15 mm3 in low dose, and 13±14 mm3 in high dose, P<0.001). Post hoc analysis showed less IH accumulation when low- and high-dose patients were compared with control (P=0.009 and P<0.001, respectively), but not when low-dose patients were compared with high-dose patients (P=0.2). Focal late malapposition was seen in 1 high-dose patient. With increasing doses, there was no significant change in the reference segments.
Conclusions— Paclitaxel-coated stents are effective in reducing in-stent neointimal tissue proliferation in humans. They are not associated with edge restenosis or significant late malapposition.
Received October 7, 2002; revision received December 5, 2002; accepted December 5, 2002.
The major limitation of coronary stenting is in-stent restenosis (ISR) secondary to intimal hyperplasia (IH).1 Various treatment modalities, including radiation at the time of stent implantation, have not reduced first-time ISR.1 However, recent studies of sirolimus-eluting stents have reported a dramatic reduction of first-time ISR.2,3 The aim of the current study was to use serial volumetric intravascular ultrasound (IVUS) to evaluate the efficacy of paclitaxel coating in inhibiting IH after stenting in humans.
ASPECT (ASian Paclitaxel-Eluting Stent Clinical Trial) was a three-center, triple-blind, randomized, placebo-controlled trial of paclitaxel-coated stents to reduce ISR. Single de novo lesions in 177 patients were randomized to placebo (bare metal stents) or 1 of 2 doses (low dose: 1.28 μg/mm2 stent surface area and high dose: 3.10 μg/mm2; overall dose 54 to 60 μg and 130 to 146 μg, respectively, depending on stent diameter). SupraG stents (Cook Cardiology), which are 316L stainless-steel slotted-tube design, 15 mm in length and stent diameters in 2.5 to 3.5 mm, were used in this study. Preclinical testing using a porcine coronary model showed inhibition of IH at 1 and 6 months with acceptable safety. On the basis of animal studies, doses of 3.10 μg/mm2and 1.28 μg/mm2 were considered reasonable for study in a human trial. Low- and high-dose stents were coated with pure paclitaxel using a proprietary process. No polymer was used. After the release of paclitaxel, only a bare metal stent remained. Patients were treated with antiplatelet agents for 6 months. The current IVUS analysis was a single center (Asan Medical Center) substudy of ASPECT. Ninety-eight patients were enrolled in this IVUS substudy. All patients gave their written, informed consent. This study was approved by Asan Medical Center Institutional Review Board.
Complete serial (post-stent implantation and 6-month follow-up) IVUS was available in 81 patients, including 25 control, 28 low-dose, and 28 high-dose patients. No differences existed in baseline characteristics when comparing patients in the IVUS substudy versus the total cohort or when comparing paclitaxel-coated stents versus placebo patients in the IVUS substudy (Table 1).
IVUS Imaging and Analysis
IVUS imaging was performed after intracoronary administration of 0.2 mg nitroglycerin by use of a motorized transducer pullback system (0.5 mm/s) and commercial scanner (SCIMED) consisting of a 30 MHz transducer within 3.2Fr imaging sheath.
Quantitative volumetric IVUS analysis was performed in an independent core laboratory (N.J.W.). With the use of computerized planimetry, stent and reference segments were measured every 1 mm. Reference segment external elastic membrane (EEM), lumen, and plaque and media (P&M=EEM − lumen) areas were measured over a 5-mm length adjacent to stent edge and averaged. Stent, lumen, and IH (stent − lumen) areas were measured every 1 mm within the stented segment; volumes were calculated using Simpson’s rule. The minimum lumen area was also measured. These methods have been reported and used previously.4 Late malapposition was defined as a separation of stent struts from the intimal surface of the arterial wall that was not present postimplantation.4 The primary endpoint of this analysis was intra-stent IH accumulation at follow-up.
Statistical analysis was performed with Statview 4.5 (SAS Institute). Data are presented as frequencies or mean±1SD. Comparison was performed with a Pearson’s χ2 test, unpaired or paired t test, and factorial ANOVA with post hoc comparison using the Bonferroni correction.
IVUS-guided stenting was successfully performed in all patients without additional stenting or any complications. Adjunct balloon angioplasty after IVUS was performed for stent optimization in 9 patients (3 patients in each groups); in these patients, IVUS was repeated as the last step in the procedure. Serial IVUS measurements are shown in Table 2. Baseline stent and reference measurements were similar among the 3 groups. Follow-up lumen area and changes (after intervention to follow-up) in reference segment EEM, lumen, and P&M area and intra-stent lumen and IH area in the 3 groups are shown in Figure 1.
In the stented segment of all 3 groups from after implantation to follow-up, there was a decrease in lumen volume and an increase in IH volume (P<0.0001 for all comparisons). With increasing doses of paclitaxel, however, there was a stepwise reduction in IH accumulation within the stented segment (31±22 mm3 in control, 18±15 mm3 in low-dose, and 13±14 mm3 in high-dose patients; P<0.001). Post hoc analysis showed less IH accumulation when low- and high-dose patients were compared with placebo patients (P=0.009 and P<0.001, respectively), but not when low-dose patients were compared with high-dose patients (P=0.2). Similar findings were seen in the follow-up minimum lumen area. With increasing doses, there were no significant changes in reference segment measurements.
When postintervention and follow-up IVUS studies were compared side-by-side, focal (less than 1 quadrant in circumference and less than 2 mm in length) late malapposition was seen in 1 high-dose patient (Figure 2), but in no low-dose or placebo patients. In this 1 patient, late malapposition was associated with positive remodeling (increase in EEM).
The current IVUS study demonstrated that a paclitaxel coating reduces in-stent neointimal tissue proliferation. These data are consistent with the results of previous serial IVUS studies of sirolimus-eluting stents.2,3 The RAndomized study with the sirolimus-eluting Bx VELocity balloon-expandable stent (RAVEL) trial reported dramatic results of a 0% angiographic restenosis rate in the sirolimus-stent group.3 The ASPECT trial showed similar findings; angiographic restenosis was reduced from 27% in the control group to 4% in the high-dose group.
Paclitaxel and sirolimus have been reported to reduce vascular cell proliferation and intimal thickening in models of vascular injury.5,6 The reported mechanisms of action might also lead to late vessel enlargement (positive remodeling) at the stented segment, similar to intracoronary brachytherapy.7 Positive remodeling coupled with inhibition of IH can cause late malapposition. Late malapposition must be differentiated from malapposition present at implantation that was only detected at follow-up. The higher overall dose (in the high-dose stent group) might be the cause of the 1 case of late malapposition.6 The follow-up IVUS substudy of RAVEL showed a 21% incidence of late malcomplete apposition in the sirolimus group.8 However, there was only 1 case of focal late malapposition in the high dose group in this study. Therefore, it is imperative that IVUS be performed both at implantation and at follow-up, as was done in the current study.
The current study also assessed the impact of paclitaxel on nearby reference segments. Serial IVUS analysis of patients treated as part of brachytherapy protocols identified focal edge lumen loss, termed the “candy-wrapper effect,” resulting from a focal increase in neointima at the stent edge.7 This was not seen in the current study.
Serial IVUS study was performed in only a subset of the 177 patients enrolled in ASPECT.
Paclitaxel-coated stent implantation is effective in reducing in-stent neointimal proliferation in humans. It is not associated with significant late malapposition or edge lumen loss.
This study was supported by Cardiovascular Research Foundation, Seoul, Korea and Cook Cardiology.
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