Richard Rapoza

Evaluation of the Second Generation of a Bioresorbable Everolimus Drug-Eluting Vascular Scaffold for Treatment of De Novo Coronary Artery Stenosis Six-Month Clinical and Imaging Outcomes

OBJECTIVES The aim of this study was to demonstrate that the prevention of early scaffold area shrinkage of the ABSORB BVS (Rev.1.1, Abbott Vascular, Santa Clara, California) was sustained and not simply delayed by a few months. BACKGROUND With improved scaffold design and modified manufacturing process of its polymer, the second iteration of ABSORB (BVS 1.1) has improved performance to prevent a scaffold area reduction at 6 months. METHODS Fifty-six patients were enrolled and received 57 ABSORB scaffolds. Quantitative coronary angiography, intravascular ultrasound (IVUS), analysis of radiofrequency backscattering, echogenicity and optical coherence tomography (OCT) were performed at baseline and at 12-month follow-up. RESULTS Overall the scaffold area remained unchanged with IVUS as well as with OCT, whereas the radiofrequency backscattering and the echogenicity of the struts decreased by 16.8% (p < 0.001) and 20% (p < 0.001), respectively; more specifically, the strut core area on OCT decreased by 11.4% (p = 0.003). Despite the absence of scaffold area loss, pharmacological vasomotion was restored. On an intention-to-treat basis, the angiographic late lumen loss amounted to 0.27 ± 0.32 mm with an IVUS relative decrease in minimal lumen area of 1.94% (p = 0.12), without significant changes in mean lumen area. The OCT at follow-up showed that 96.69% of the struts were covered and that malapposition, initially observed in 18 scaffolds was only detected at follow-up in 4 scaffolds. Two patients experienced peri-procedural and iatrogenic myocardial infarction, respectively, whereas 2 underwent repeat intervention, resulting in the major adverse cardiac event rate of 7.1% (4 of 56). CONCLUSIONS The 12-month performance of the second-generation ABSORB bioresorbable everolimus-eluting scaffold justifies the conduct of a randomized trial against current best standards. (A Clinical Evaluation of the Bioabsorbable Everolimus Eluting Coronary Stent System [BVS EECSS] in the Treatment of Patients With de Novo Native Coronary Artery Lesions; NCT00856856).

Evaluation of the Second Generation of a Bioresorbable Everolimus Drug-Eluting Vascular Scaffold for Treatment of De Novo Coronary Artery StenosisClinical Perspective

Background— The first generation of the bioresorbable everolimus drug-eluting vascular scaffold showed signs of shrinkage at 6 months, which largely contributed to late luminal loss. Nevertheless, late luminal loss was less than that observed with bare metal stents. To maintain the mechanical integrity of the device up to 6 months, the scaffold design and manufacturing process of its polymer were modified. Methods and Results— Quantitative coronary angiography, intravascular ultrasound with analysis of radiofrequency backscattering, and as an optional assessment, optical coherence tomography (OCT) were performed at baseline and at a 6-month follow-up. Forty-five patients successfully received a single bioresorbable everolimus drug-eluting vascular scaffold. One patient had postprocedural release of myocardial enzyme without Q-wave occurrence; 1 patient with OCT-diagnosed disruption of the scaffold caused by excessive postdilatation was treated 1 month later with a metallic drug-eluting stent. At follow-up, 3 patients declined recatheterization, 42 patients had quantitative coronary angiography, 37 had quantitative intravascular ultrasound, and 25 had OCT. Quantitative coronary angiography disclosed 1 edge restenosis (1 of 42; in-segment binary restenosis, 2.4%). At variance with the ultrasonic changes seen with the first generation of bioresorbable everolimus drug-eluting vascular scaffold at 6 months, the backscattering of the polymeric struts did not decrease over time, the scaffold area was reduced by only 2.0% with intravascular ultrasound, and no change was noted with OCT. On an intention-to-treat basis, the late lumen loss amounted to 0.19±0.18 mm with a limited relative decrease in minimal luminal area of 5.4% on intravascular ultrasound. OCT showed at follow-up that 96.8% of the struts were covered and that malapposition of at least 1 strut, initially observed in 12 scaffolds, was detected at follow-up in only 3 scaffolds. Mean neointimal growth measured by OCT between and on top of the polymeric struts equaled 1.25 mm2, or 16.6% of the scaffold area. Conclusion— Modified manufacturing process of the polymer and geometric changes in the polymeric platform have substantially improved the medium-term performance of this new generation of drug-eluting scaffold to become comparable to those of current drug eluting stents. Clinical Trial Registration— URL: http://clinicaltrials.gov. Unique identifier: NCT00856856.

Dynamics of vessel wall changes following the implantation of the Absorb everolimus-eluting bioresorbable vascular scaffold: a multi-imaging modality study at 6, 12, 24 and 36 months

AIMS To assess observations with multimodality imaging of the Absorb bioresorbable everolimus-eluting vascular scaffold performed in two consecutive cohorts of patients who were serially investigated either at 6 and 24 months or at 12 and 36 months. METHODS AND RESULTS In the ABSORB multicentre single-arm trial, 45 patients (cohort B1) and 56 patients (cohort B2) underwent serial invasive imaging, specifically quantitative coronary angiography (QCA), intravascular ultrasound (IVUS), radiofrequency backscattering (IVUS-VH) and optical coherence tomography (OCT). Between one and three years, late luminal loss remained unchanged (6 months: 0.19 mm, 1 year: 0.27 mm, 2 years: 0.27 mm, 3 years: 0.29 mm) and the in-segment angiographic restenosis rate for the entire cohort B (n=101) at three years was 6%. On IVUS, mean lumen, scaffold, plaque and vessel area showed enlargement up to two years. Mean lumen and scaffold area remained stable between two and three years whereas significant reduction in plaque behind the struts occurred with a trend toward adaptive restrictive remodelling of EEM. Hyperechogenicity of the vessel wall, a surrogate of the bioresorption process, decreased from 23.1% to 10.4% with a reduction of radiofrequency backscattering for dense calcium and necrotic core. At three years, the count of strut cores detected on OCT increased significantly, probably reflecting the dismantling of the scaffold; 98% of struts were covered. In the entire cohort B (n=101), the three-year major adverse cardiac event rate was 10.0% without any scaffold thrombosis. CONCLUSIONS The current investigation demonstrated the dynamics of vessel wall changes after implantation of a bioresorbable scaffold, resulting at three years in stable luminal dimensions, a low restenosis rate and a low clinical major adverse cardiac events rate. CLINICAL TRIAL REGISTRATION INFORMATION http://www.clinicaltrials.gov/ct2/show/NCT00856856.

First Serial Assessment at 6 Months and 2 Years of the Second Generation of Absorb Everolimus-Eluting Bioresorbable Vascular Scaffold A Multi-Imaging Modality Study

Background—Nonserial observations have shown this bioresorbable scaffold to have no signs of area reduction at 6 months and recovery of vasomotion at 1 year. Serial observations at 6 months and 2 years have to confirm the absence of late restenosis or unfavorable imaging outcomes. Methods and Results—The ABSORB trial is a multicenter single-arm trial assessing the safety and performance of an everolimus-eluting bioresorbable vascular scaffold. Forty-five patients underwent serial invasive imaging, such as quantitative coronary angiography, intravascular ultrasound, and optical coherence tomography at 6 and 24 months of follow-up. From 6 to 24 months, late luminal loss increased from 0.16±0.18 to 0.27±0.20 mm on quantitative coronary angiography, with an increase in neointima of 0.68±0.43 mm2 on optical coherence tomography and 0.17±0.26 mm2 on intravascular ultrasound. Struts still recognizable on optical coherence tomography at 2 years showed 99% of neointimal coverage with optical and ultrasonic signs of bioresorption accompanied by increase in mean scaffold area compared with baseline (0.54±1.09 mm2 on intravascular ultrasound, P=0.003 and 0.77±1.33 m2 on optical coherence tomography, P=0.016). Two-year major adverse cardiac event rate was 6.8% without any scaffold thrombosis. Conclusions—This serial analysis of the second generation of the everolimus-eluting bioresorbable vascular scaffold confirmed, at medium term, the safety and efficacy of the new device. Clinical Trial Registration—URL: http://www.clinicaltrials.gov. Unique identifier: NCT00856856.

Endothelial-dependent vasomotion in a coronary segment treated by ABSORB everolimus-eluting bioresorbable vascular scaffold system is related to plaque composition at the time of bioresorption of the polymer: indirect finding of vascular reparative therapy?

AIMS To analyse the vasoreactivity of a coronary segment, previously scaffolded by the ABSORB bioresorbable vascular scaffold (BVS) device, in relationship to its intravascular ultrasound-virtual histology (IVUS-VH) composition and reduction in greyscale echogenicity of the struts. Coronary segments, transiently scaffolded by a polymeric device, may in the long-term recover a normal vasomotor tone. Recovery of a normal endothelial-dependent vasomotion may be enabled by scaffold bioresorption, composition of the underlying tissue, or a combination of both mechanisms. METHODS AND RESULTS All patients from the ABSORB Cohort A and B trials, who underwent a vasomotion test and IVUS-VH investigation at 12 and 24 months, were included. Acetylcholine (Ach) and nitroglycerin were used to test either the endothelial-dependent or -independent vasomotion of the treated segment. Changes in polymeric strut echogenicity-a surrogate for bioresorption-IVUS-VH composition of the tissue underneath the scaffold and their relationship with the pharmacologically induced vasomotion were all evaluated. Overall, 26 patients underwent the vasomotion test (18 at 12 and 8 at 24 months). Vasodilatory response to Ach was quantitatively associated with larger reductions over time in polymeric strut echogenicity (y= -0.159x- 6.85; r= -0.781, P< 0.001). Scaffolded segments with vasoconstriction to Ach had larger vessel areas (14.37 ± 2.50 vs. 11.85 ± 2.54 mm(2), P= 0.030), larger plaque burden (57.31 ± 5.96 vs. 49.09 ± 9.10%, P= 0.018), and larger necrotic core (NC) areas [1.39 (+1.14, +1.74) vs. 0.78 mm(2) (+0.20, +0.98), P= 0.006] compared with those with vasodilation. CONCLUSION Vasodilatory response to Ach, in coronary segments scaffolded by the ABSORB BVS device, is associated with a reduction in echogenicity of the scaffold over time, and a low amount of NC. In particular, the latter finding resembles the behaviour of a native coronary artery not caged by an intracoronary device.

Design principles and performance of bioresorbable polymeric vascular scaffolds

AIMS Bioresorbable polymeric vascular scaffolds may spawn a fourth revolution in percutaneous coronary intervention (PCI) and a novel treatment termed vascular restoration therapy. The principal design considerations for bioresorbable scaffolds are discussed in the context of physiological behaviour using the Bioabsorbable Vascular Solutions (BVS) ABSORB Cohort B scaffold (Abbott Vascular) as an example. METHODS AND RESULTS The lifecycle of a bioresorbable scaffold is divided into three phases: (1) revascularisation; (2) restoration; and (3) resorption. In the revascularisation phase spanning the first three months after intervention, the bioresorbable scaffold should perform comparably to metallic drug-eluting stents (DES) in terms of deliverability, radial strength, recoil, and neointimal thickening. The ensuing restoration phase is characterised by gradual erosion of radial strength and a loss of structural continuity, where the time scale at which each occurs is related to the hydrolytic degradation rate of the polymer. Natural vasomotion in response to external stimuli is theoretically possible at the end of this phase. Finally, in the resorption phase, the passive implant is systematically resorbed and processed by the body. CONCLUSIONS Limited clinical data speak to the potential of bioresorbable scaffolds as a new therapy, and future studies will prove critical to inspiring a fourth revolution in PCI.

Three-year results of clinical follow-up after a bioresorbable everolimus-eluting scaffold in patients with de novo coronary artery disease: The ABSORB trial

AIMS Multimodality imaging of the first-in-man trial using a fully resorbable everolimus-eluting scaffold (BVS, Abbott Vascular, Santa Clara, CA, USA) demonstrated at two years the bioresorption of the device while preventing restenosis. Nevertheless, the long-term safety and efficacy of this novel therapy remain to be documented. METHODS AND RESULTS The ABSORB trial completed in July 2006 at four clinical sites in Europe and New Zealand the enrolment of 30 patients with a single de novo native coronary artery lesion. The major clinical endpoint was ischaemia-driven major adverse cardiac events (ID-MACE) defined as a composite of cardiac death, myocardial infarction, or ischaemia-driven target lesion revascularisation. Clinical follow-up was available in 29 patients since one patient withdrew consent. At 46 days, one patient experienced a single episode of chest pain and underwent a diagnostic optical coherence tomography and subsequently a target lesion revascularisation with slight troponin rise after the procedure. At 3-year the hierarchical ID-MACE of 3.4% remained unchanged. Clopidogrel therapy was discontinued in all but one patient. There has been no stent thrombosis reported. Two non-cardiac deaths were reported; one from duodenal perforation, the other from Hodgkin disease. Two patients underwent non-ischaemia driven target vessel revascularisation. CONCLUSIONS Three-year clinical results have demonstrated a sustained low MACE rate (3.4%) without any late complication such as stent thrombosis.

Circumferential evaluation of the neointima by optical coherence tomography after ABSORB bioresorbable vascular scaffold implantation: can the scaffold cap the plaque?

OBJECTIVE To quantify the circumferential healing process at 6 and 12 months following scaffold implantation. BACKGROUND The healing process following stent implantation consists of tissue growing on the top of and in the space between each strut. With the ABSORB bioresorbable vascular scaffold (BVS), the outer circumference of the scaffold is detectable by optical coherence tomography (OCT), allowing a more accurate and complete evaluation of the intra-scaffold neointima. METHODS A total of 58 patients (59 lesions), who received an ABSORB BVS 1.1 implantation and a subsequent OCT investigation at 6 (n=28 patients/lesions) or 12 (n=30 patients with 31 lesions) months follow-up were included in the analysis. The thickness of the neointima was calculated circumferentially in the area between the abluminal side of the scaffold and the lumen by means of an automated detection algorithm. The symmetry of the neointima thickness in each cross section was evaluated as the ratio between minimum and maximum thickness. RESULTS The neointima area was not different between 6 and 12 months follow-up (1.57±0.42 mm(2) vs. 1.64±0.77 mm(2); p=0.691). No difference was also found in the mean thickness of the neointima (median [IQR]) between the two follow-up time points (210 μm [180-260]) vs. 220 μm [150-260]; p=0.904). However, the symmetry of the neointima thickness was higher at 12 than at 6 months follow-up (0.23 [0.13-0.28] vs. 0.16 [0.08-0.21], p=0.019). CONCLUSIONS A circumferential evaluation of the healing process following ABSORB implantation is feasible, showing the formation of a neointima layer, that resembles a thick fibrous cap, known for its contribution to plaque stability.

ABSORB II randomized controlled trial. A clinical evaluation to compare the safety, efficacy, and performance of the Absorb everolimus-eluting bioresorbable vascular scaffold system against the XIENCE everolimus-eluting coronary stent system in the treatment of subjects with ischemic heart disease caused by de novo native coronary artery lesions: Rationale and study design

BACKGROUND Currently, no data are available on the direct comparison between the Absorb everolimus-eluting bioresorbable vascular scaffold (Absorb BVS) and conventional metallic drug-eluting stents. METHODS The ABSORB II study is a randomized, active-controlled, single-blinded, multicenter clinical trial aiming to compare the second-generation Absorb BVS with the XIENCE everolimus-eluting metallic stent. Approximately 501 subjects will be enrolled on a 2:1 randomization basis (Absorb BVS/XIENCE stent) in approximately 40 investigational sites across Europe and New Zealand. Treated lesions will be up to 2 de novo native coronary artery lesions, each located in different major epicardial vessels, all with an angiographic maximal luminal diameter between 2.25 and 3.8 mm as estimated by online quantitative coronary angiography (QCA) and a lesion length of ≤48 mm. Clinical follow-up is planned at 30 and 180 days and at 1, 2, and 3 years. All subjects will undergo coronary angiography, intravascular ultrasound (IVUS) and IVUS-virtual histology at baseline (pre-device and post-device implantation) and at 2-year angiographic follow-up. The primary end point is superiority of the Absorb BVS vs XIENCE stent in terms of vasomotor reactivity of the treated segment at 2 years, defined as the QCA quantified change in the mean lumen diameter prenitrate and postnitrate administration. The coprimary end point is the noninferiority (reflex to superiority) of the QCA-derived minimum lumen diameter at 2 years postnitrate minus minimum lumen diameter postprocedure postnitrate by QCA. In addition, all subjects allocated to the Absorb BVS group will undergo multislice computed tomography imaging at 3 years. CONCLUSIONS The ABSORB II randomized controlled trial (ClinicalTrials.gov NCT01425281) is designed to compare the safety, efficacy, and performance of Absorb BVS against the XIENCE everolimus-eluting stent in the treatment of de novo native coronary artery lesions.

Long-Term Safety of an Everolimus-Eluting Bioresorbable Vascular Scaffold and the Cobalt-Chromium XIENCE V Stent in a Porcine Coronary Artery Model

Background—The Absorb everolimus-eluting bioresorbable vascular scaffold (Absorb) has shown promising clinical results; however, only limited preclinical data have been published. We sought to investigate detailed pathological responses to the Absorb versus XIENCE V (XV) in a porcine coronary model with duration of implant extending from 1 to 42 months. Methods and Results—A total of 335 devices (263 Absorb and 72 XV) were implanted in 2 or 3 main coronary arteries of 136 nonatherosclerotic swine and examined by light microscopy, scanning electron microscopy, pharmacokinetics, and gel permeation chromatography analyses at various time points. Vascular responses to Absorb and XV were largely comparable at all time points, with struts being sequestered within the neointima. Inflammation was mild to moderate (with absence of inflammation at 1 month) for both devices, although the scores were greater in Absorb at 6 to 36 months. Percent area stenosis was significantly greater in Absorb than XV at all time points except at 3 months. The extent of fibrin deposition was similar between Absorb and XV, which peaked at 1 month and decreased rapidly thereafter. Histomorphometry showed expansile remodeling of Absorb-implanted arteries starting after 12 months, and lumen area was significantly greater in Absorb than XV at 36 and 42 months. These changes correlated with dismantling of Absorb seen after 12 months. Gel permeation chromatography analysis confirmed that degradation of Absorb was complete by 36 months. Conclusions—Absorb demonstrates comparable long-term safety to XV in porcine coronary arteries with mild to moderate inflammation. Although Absorb was associated with greater percent stenosis relative to XV, expansile remodeling was observed after 12 months in Absorb with significantly greater lumen area at ≥36 months. Resorption is considered complete at 36 months.