Stefan Verheye

Effects of the direct lipoprotein-associated phospholipase A2 inhibitor darapladib on human coronary atherosclerotic plaque

Background— Lipoprotein-associated phospholipase A2 (Lp-PLA2) is expressed abundantly in the necrotic core of coronary lesions, and products of its enzymatic activity may contribute to inflammation and cell death, rendering plaque vulnerable to rupture. Methods and Results— This study compared the effects of 12 months of treatment with darapladib (an oral Lp-PLA2 inhibitor, 160 mg daily) or placebo on coronary atheroma deformability (intravascular ultrasound palpography) and plasma high-sensitivity C-reactive protein in 330 patients with angiographically documented coronary disease. Secondary end points included changes in necrotic core size (intravascular ultrasound radiofrequency), atheroma size (intravascular ultrasound gray scale), and blood biomarkers. Background therapy was comparable between groups, with no difference in low-density lipoprotein cholesterol at 12 months (placebo, 88±34 mg/dL; darapladib, 84±31 mg/dL; P=0.37). In contrast, Lp-PLA2 activity was inhibited by 59% with darapladib (P<0.001 versus placebo). After 12 months, there were no significant differences between groups in plaque deformability (P=0.22) or plasma high-sensitivity C-reactive protein (P=0.35). In the placebo-treated group, however, necrotic core volume increased significantly (4.5±17.9 mm3; P=0.009), whereas darapladib halted this increase (−0.5±13.9 mm3; P=0.71), resulting in a significant treatment difference of −5.2 mm3 (P=0.012). These intraplaque compositional changes occurred without a significant treatment difference in total atheroma volume (P=0.95). Conclusions— Despite adherence to a high level of standard-of-care treatment, the necrotic core continued to expand among patients receiving placebo. In contrast, Lp-PLA2 inhibition with darapladib prevented necrotic core expansion, a key determinant of plaque vulnerability. These findings suggest that Lp-PLA2 inhibition may represent a novel therapeutic approach.

Safety and performance of the drug-eluting absorbable metal scaffold (DREAMS) in patients with de-novo coronary lesions: 12 month results of the prospective, multicentre, first-in-man BIOSOLVE-I trial

BACKGROUND Bioabsorbable vascular scaffolds were developed to overcome limitations of permanent bare-metal or drug-eluting coronary stents—ie, stent thrombosis (despite prolonged dual antiplatelet therapy), the life-long presence of a caged vessel segment that does not allow vasomotion or remodelling, and chronic vessel wall inflammation. We assessed the safety and performance of a new magnesium-based paclitaxel-eluting absorbable metal scaffold in symptomatic patients with de-novo coronary lesions. METHODS We did a prospective, multicentre, first-in-man trial (BIOSOLVE-1) of the drug-eluting absorbable metal scaffold (DREAMS). 46 patients with 47 lesions were enrolled at five European centres. The primary endpoint was target lesion failure, a composite of cardiac death, target vessel myocardial infarction, and clinically driven target lesion revascularisation, at 6 and 12 months. Clinical follow-up was scheduled at 1, 6, 12, 24, and 36 months. Patients were consecutively assigned to angiographic and intravascular ultrasonographic follow-up at 6 months or 12 months. Optical coherence tomography was done in some patients. All patients were recommended to take dual antiplatelet therapy for at least 12 months. This trial is registered with ClinicalTrials.gov, number NCT01168830. FINDINGS Overall device and procedural success was 100%. Two of 46 (4%) patients had target lesion failure at 6 months (both clinically driven target lesion revascularisations), which rose to three of 43 (7%) at 12 months (one periprocedural target vessel myocardial infarction occurred during angiography at the 12 month follow-up visit). We noted no cardiac death or scaffold thrombosis. INTERPRETATION Our results show feasibility, a good safety profile, and promising clinical and angiographic performance results up to 12 months for DREAMS. Our promising clinical results show that absorbable metal scaffolds might be an alternative to polymeric absorbable scaffolds. FUNDING Biotronik.

In Vivo Temperature Heterogeneity of Atherosclerotic Plaques Is Determined by Plaque Composition

Background—Temperature heterogeneity of atherosclerotic plaques has been associated with macrophage accumulation in ex vivo studies. We investigated in vivo whether modifying the cell composition of rabbit atherosclerotic plaques by dietary cholesterol lowering can influence temperature heterogeneity. Methods and Results—Twenty New Zealand rabbits were randomized to either a normal (n=10) or cholesterol-rich (0.3%) diet (n=10) for 6 months. Thereafter, intravascular ultrasound and intravascular catheter-based thermography of the surface of aortic arch and descending aorta were performed in all animals. Ten control and 5 hypercholesterolemic rabbits were euthanized, and their aortas were analyzed histologically. The 5 remaining rabbits received a normal diet for 3 months and underwent repeat ultrasound and thermography before euthanasia followed by histology. Ex vivo temperature was measured in 3 additional rabbits at 6 months to correlate local temperature with local plaque composition. In control animals, plaque formation and temperature heterogeneity were absent. In hypercholesterolemic rabbits, plaque formation was prominent in the thoracic aorta. Plaques were composed of fibromuscular tissue and contained, underneath endothelial cells, an accumulation of foam cells of macrophage origin. Temperature heterogeneity was markedly elevated and increased with plaque thickness. Importantly, after 3 months of cholesterol lowering, plaque thickness remained unchanged, but temperature heterogeneity was significantly decreased. This paralleled plaque histology, which showed a marked loss of macrophages. The ex vivo experiments demonstrated the relation between local temperature and local total macrophage mass. Conclusions—In vivo temperature heterogeneity of rabbit atherosclerotic plaques is determined by plaque composition. In vivo thermography may have important clinical implications in the assessment of plaque composition.

Primary endpoint results of the EVOLVE trial: a randomized evaluation of a novel bioabsorbable polymer-coated, everolimus-eluting coronary stent.

OBJECTIVES This study sought to compare the safety and efficacy of 2 dose formulations of SYNERGY, a novel bioabsorbable polymer everolimus-eluting stent (EES) (Boston Scientific Corp., Natick, Massachusetts) compared with the durable polymer PROMUS Element EES (Boston Scientific Corp.). BACKGROUND Durable polymer coatings on drug-eluting stents have been associated with chronic inflammation and impaired healing. Bioabsorbable polymer-coated drug-delivery systems may reduce the risk of late adverse events, including stent thrombosis, and thus the need for prolonged dual-antiplatelet therapy. METHODS A total of 291 patients with a de novo lesion ≤28 mm in length, in a coronary artery of ≥2.25 to ≤3.5 mm diameter, were enrolled in the EVOLVE study, a prospective, randomized, single-blind, noninferiority trial. Patients were randomly assigned in a 1:1:1 ratio to PROMUS Element, SYNERGY, or SYNERGY half dose. The primary clinical endpoint was the 30-day rate of target lesion failure, defined as cardiac death or myocardial infarction related to the target vessel, or target lesion revascularization. The primary angiographic endpoint was 6-month in-stent late loss measured by quantitative coronary angiography. RESULTS The 30-day primary clinical endpoint of target lesion failure occurred in 0%, 1.1%, and 3.1% of patients in the PROMUS Element, SYNERGY, and SYNERGY half dose groups, respectively. The 6-month in-stent late loss was 0.15 ± 0.34 mm for PROMUS Element, 0.10 ± 0.25 mm for SYNERGY, and 0.13 ± 0.26 mm for SYNERGY half dose (SYNERGY, difference -0.06, upper 95.2% confidence limit: 0.02, p for noninferiority <0.001; SYNERGY half dose, difference -0.03, upper 95.2% confidence limit: 0.05, p for noninferiority <0.001). Clinical event rates remained low and comparable between groups, with no stent thromboses in any group at 6 months. CONCLUSIONS The EVOLVE trial confirms the effective delivery of everolimus by a unique directional bioabsorbable polymer system utilizing the SYNERGY stent. (A Prospective Randomized Multicenter Single-Blind Noninferiority Trial to Assess the Safety and Performance of the Evolution Everolimus-Eluting Monorail Coronary Stent System [Evolution Stent System] for the Treatment of a De Novo Atherosclerotic Lesion [EVOLVE]; NCT01135225).

Accelerated vascular repair following percutaneous coronary intervention by capture of endothelial progenitor cells promotes regression of neointimal growth at long term follow-up: final results of the Healing II trial using an endothelial progenitor cell capturing stent (Genous R stent).

AIMS The study sought to define the long-term angiographic and clinical outcome of a bio-engineered stent, able to sequester endothelial progenitor cells (EPC) to the stent to promote the post-stenting vascular repair response. METHODS AND RESULTS The HEALING-II was a multicentre, prospective registry, including 63 patients treated with the implantation of a Genous EPC capture stent. Serial quantitative coronary angiography (QCA) and intravascular ultrasound (IVUS) analysis was performed at 6 and 18 month. The 18 month composite MACE rate was 7.9%, whereas 6.3% clinically justified target lesion revascularisations were observed. Although patients received one month of clopidogrel, no (sub)acute or late angiographic stent thrombosis occurred. At 6 month follow-up, in-stent late luminal loss was 0.78+/-0.39 mm and percent in-stent volume obstruction was 22.9+/-13.7% (mean+/-sd). Serial angiographic and IVUS analyses were available in 30 event-free patients at post-procedure, 6 months and 18 months. From 6 months to 18 months follow-up, a significant late regression of neointimal hyperplasia was observed on QCA (late luminal loss 0.59+/-0.31, 24.4% reduction or 16.9% by matched serial analysis) and IVUS (percent in-stent volume obstruction 20.3+/-14.3%, 11.4% reduction or 9.6% by matched serial analysis). The relative increase in circulating EPC titers at long-term follow-up correlated with neointimal compaction in individual patients, suggestive of an EPC-mediated vascular repair response. CONCLUSIONS The HEALING II study suggests that the EPC capture stent, aimed to stimulate the coronary vascular repair response, significantly promotes late regression of neointimal hyperplasia up to 18 months after stent implantation.

A novel bioresorbable polymer paclitaxel-eluting stent for the treatment of single and multivessel coronary disease: primary results of the COSTAR (Cobalt Chromium Stent With Antiproliferative for Restenosis) II study.

OBJECTIVES The aim was to compare safety and effectiveness of the CoStar drug-eluting stent (DES) (Conor MedSystems, Menlo Park, California) with those of the Taxus DES (Boston Scientific, Maple Grove, Minnesota) in de novo single- and multivessel percutaneous coronary intervention (PCI). BACKGROUND Paclitaxel elution from a stent coated with biostable polymer (Taxus) reduces restenosis after PCI. The CoStar DES is a novel stent with laser-cut reservoirs containing bioresorbable polymer loaded to elute 10 microg paclitaxel/30 days. METHODS Patients undergoing PCI for a single target lesion per vessel in up to 3 native epicardial vessels were randomly assigned 3:2 to CoStar or Taxus. Primary end point was 8-month major adverse cardiac events (MACE), defined as adjudicated death, myocardial infarction (MI), or clinically driven target vessel revascularization (TVR). Protocol-specified 9-month angiographic follow-up included 457 vessels in 286 patients. RESULTS Of the 1,700 patients enrolled, 1,675 (98.5%) were evaluable (CoStar = 989; Taxus = 686), including 1,330 (79%) single-vessel and 345 (21%) multivessel PCI. The MACE rate at 8 months was 11.0% for CoStar versus 6.9% for Taxus (p < 0.005), including adjudicated death (0.5% vs. 0.7%, respectively), MI (3.4% vs. 2.4%, respectively), and TVR (8.1% vs. 4.3%, respectively). Per-vessel 9-month in-segment late loss was 0.49 mm with CoStar and 0.18 mm with Taxus (p < 0.0001). Findings were consistent across pre-specified subgroups. CONCLUSIONS The CoStar DES is not noninferior to the Taxus DES based on per-patient clinical and per-vessel angiographic analyses. The relative benefit of Taxus is primarily attributable to reduction in TVR. Follow-up to 9 months showed no apparent difference in death, MI, or stent thrombosis rates.

A next-generation bioresorbable coronary scaffold system: from bench to first clinical evaluation: 6- and 12-month clinical and multimodality imaging results.

OBJECTIVES This study sought to perform clinical and imaging assessments of the DESolve Bioresorbable Coronary Scaffold (BCS). BACKGROUND BCS, which is drug eluting, may have potential advantages compared with conventional metallic drug-eluting stents. The DESolve system, designed to provide vessel support and neointimal suppression, combines a poly-l-lactic acid-based scaffold with the antiproliferative myolimus. METHODS The DESolve First-in-Man (a non-randomized, consecutive enrollment evaluation of the DESolve myolimus eluting bioresorbable coronary stent in the treatment of patients with de novo native coronary artery lesions) trial was a prospective multicenter study enrolling 16 patients eligible for treatment. The principal safety endpoint was a composite of cardiac death, myocardial infarction, and clinically indicated target lesion revascularization. The principal imaging endpoint was in-scaffold late lumen loss (LLL) assessed by quantitative coronary angiography (QCA) at 6 months. Intravascular ultrasound (IVUS) and optical coherence tomography (OCT) imaging was performed at baseline and 6 months; multislice computed tomography (MSCT) was performed at 12 months. RESULTS Acute procedural success was achieved in 15 of 15 patients receiving a study scaffold. At 12 months, there was no scaffold thrombosis and no major adverse cardiac events directly attributable to the scaffold. At 6 months, in-scaffold LLL (by QCA) was 0.19 ± 0.19 mm; neointimal volume (by IVUS) was 7.19 ± 3.56%, with no evidence of scaffold recoil or late malapposition. Findings were confirmed with OCT and showed uniform, thin neointimal coverage (0.12 ± 0.04 mm). At 12 months, MSCT demonstrated excellent vessel patency. CONCLUSIONS This study demonstrated the feasibility and efficacy of the DESolve BCS. Results showing low in-scaffold LLL, low % neointimal volume at 6 months, no chronic recoil, and maintenance of lumen patency at 12 months prompt further study. (DESolve First-in-Man; EudraCT number 2011-000027-32).

Quantitative Ex Vivo and In Vivo Comparison of Lumen Dimensions Measured by Optical Coherence Tomography and Intravascular Ultrasound in Human Coronary Arteries

INTRODUCTION AND OBJECTIVES The relationship between the lumen dimensions obtained in human coronary arteries using intravascular ultrasound (IVUS) and those obtained using optical coherence tomography (OCT) is not well understood. The objectives were to compare the lumen measurements obtained ex vivo in human coronary arteries using IVUS, OCT and histomorphometry, and in vivo in patients using IVUS and OCT with and without balloon occlusion. METHODS Ex vivo study: the lumen areas of matched anatomical sections of human coronary arteries were measured using IVUS, OCT and histology. In vivo study: the lumen areas in matched sections were measured using IVUS and OCT with and without occlusion. RESULTS Ex vivo: in the eight specimens studied, the lumen area obtained using OCT and IVUS was larger than that obtained using histomorphometry: mean difference 0.8+/-1 mm(2) (28%) for OCT and 1.3+/-1.1 mm(2) (40%) for IVUS. In vivo: in the five vessels analyzed, the lumen area obtained using IVUS was larger than that obtained using OCT: mean difference 1.67+/-0.54 mm(2) (33.7%) for IVUS relative to OCT with occlusion and 1.11+/-0.53 mm(2) (21.5%) relative to OCT without occlusion. The lumen area obtained using OCT without occlusion was larger than that obtained using OCT with occlusion: mean difference 0.61+/-0.23 mm(2) (13%). CONCLUSIONS In fixed human coronary arteries, both IVUS and OCT overestimated the lumen area compared with histomorphometry. In vivo the lumen dimensions obtained using IVUS were larger than those obtained using OCT, with or without occlusion. Moreover, the OCT image acquisition technique (i.e. with or without occlusion) also had an impact on lumen measurement.

9-Month Clinical, Angiographic, and Intravascular Ultrasound Results of a Prospective Evaluation of the Axxess Self-Expanding Biolimus A9-Eluting Stent in Coronary Bifurcation Lesions : The DIVERGE (Drug-Eluting Stent Intervention for Treating Side Branches Effectively) Study

OBJECTIVES This study sought to assess the safety and performance of the Axxess (Devax Inc., Lake Forest, California) self-expanding drug-eluting stent in coronary bifurcation lesions. BACKGROUND Percutaneous treatment of coronary bifurcations is a predictor of adverse late outcomes, in part because of the lack of dedicated devices. METHODS Patients with de novo bifurcation lesions were prospectively enrolled in a multicenter study. The Axxess stent was deployed at the level of the carina followed by additional sirolimus-eluting stents in the distal parent vessel (PV) and/or side branch (SB). All patients underwent clinical follow-up at 9 months; 150 were to receive control angiography and 76 were to receive intravascular ultrasound. The primary end point was the rate of major adverse cardiac events (MACE): a composite of death, myocardial infarction (MI), and target lesion revascularization (TLR). Secondary end points included in-segment restenosis, late loss, and percent neointimal volume obstruction. RESULTS Overall, 302 patients were treated with 299 Axxess stents (99%). Additional stenting of 1 branch was performed in 21.7% of patients (17.7% PV, 4% SB), and of both branches in 64.7%. At 9 months, 99.3% of patients returned for clinical follow-up; from the angiographic and IVUS substudies, 93.3% and 89.4% returned. The cumulative 9-month MACE rate was 7.7% (0.7% death, 3.3% non-Q-wave MI, 1.0% Q-wave MI, 4.3% TLR). Subacute and late stent thrombosis occurred in 0.7% and 0.3% of patients. Total restenosis was 6.4% (3.6% PV, 4.3% SB), late loss was 0.20 +/- 0.41 mm in the PV and 0.17 +/- 0.34 mm in the SB. In the Axxess stent segment, percent neointimal volume obstruction was 4.3 +/- 5.2%. CONCLUSIONS This prospective multicenter study confirms the safety and performance of the Axxess stent in bifurcation lesions. (Drug-Eluting Stent Intervention for Treating Side Branches Effectively; ACTRN12606000259549).

Quantification of coronary plaque by 64-slice computed tomography: a comparison with quantitative intracoronary ultrasound.

Background:Noninvasive assessment of coronary atherosclerotic plaque may be useful for risk stratification and treatment of atherosclerosis. Materials and Methods:We studied 47 patients to investigate the accuracy of coronary plaque volume measurement acquired with 64-slice multislice computed tomography (MSCT), using newly developed quantification software, when compared with quantitative intracoronary ultrasound (QCU). Quantitative MSCT coronary angiography (QMSCT-CA) was performed to determine plaque volume for a matched region of interest (regional plaque burden) and in significant plaque defined as a plaque with ≥50% area obstruction in QCU, and compared with QCU. Dataset with image blurring and heavy calcification were excluded from analysis. Results:In 100 comparable regions of interest, regional plaque burden was highly correlated (coefficient r = 0.96; P < 0.001) between QCU and QMSCT-CA, but QMSCT-CA overestimated the plaque burden by a mean difference of 7 ± 33 mm3 (P = 0.03). In 76 significant plaques detected within the regions of interest, plaque volume determined by QMSCT-CA was highly correlated (r = 0.98; P < 0.001) with a slight underestimation of 2 ± 17 mm3 (P = not significant) when compared with QCU. Calcified and mixed plaque volume was slightly overestimated by 4 ± 19 mm3 (P = ns) and noncalcified plaque volume was significantly underestimated by 9 ± 11 mm3 (P < 0.001) with QMSCT-CA. Overall, the limits of agreement for plaque burden/volume measurement between QCU and QMSCT-CA were relatively large. Reproducibility for the measurements of regional plaque burden with QMSCT-CA was good, with a mean intraobserver and interobserver variability of 0% ± 16% and 4% ± 24%, respectively. Conclusions:Quantification of coronary plaque within selected proximal or middle coronary segments without image blurring and heavy calcification with 64-slice CT was moderately accurate with respect to intravascular ultrasound and demonstrated good reproducibility. Further improvement in CT resolution is required for more reliable measurement of coronary plaques using quantification software.