Willem J. van der Giessen

Marked Inflammatory Sequelae to Implantation of Biodegradable and Nonbiodegradable Polymers in Porcine Coronary Arteries

BACKGROUND With the thrombogenic tendency and permanent implant nature of metallic stents, synthetic polymers have been proposed as candidate materials for stents and local drug delivery designs. We investigated the biocompatibility of several synthetic polymers after experimental placement in the coronary artery. METHODS AND RESULTS Five different biodegradable polymers (polyglycolic acid/polylactic acid [PGLA], polycaprolactone [PCL], polyhydroxybutyrate valerate [PHBV], polyorthoester [POE], and polyethyleneoxide/polybutylene terephthalate [PEO/ PBTP]) and three nonbiodegradable polymers (polyurethane [PUR], silicone [SIL], and polyethylene terephthalate [PETP]) were tested as strips deployed longitudinally across 90 degrees of the circumferential surface of coil wire stents. Appropriately sized polymer-loaded stents were implanted in porcine coronary arteries of 2.5- to 3.0-mm diameter. Four weeks after implantation, stent patency was assessed by angiography followed by microscopic examination of the coronary arteries. The biodegradable PCL, PHBV, and POE and the nonbiodegradable PUR and SIL evoked extensive inflammatory responses and fibrocellular proliferation (thickness of tissue response: 0.79 +/- 0.22, 1.12 +/- 0.01, 2.36 +/- 0.60, 1.24 +/- 0.36, and 1.43 +/- 0.15 mm, respectively). Less but still severe responses were observed for the biodegradable PGLA and PEO/PBTP (0.46 +/- 0.18 and 0.61 +/- 0.23 mm, respectively) and for the nonbiodegradable PETP (0.46 +/- 0.11 mm). CONCLUSIONS An array of both biodegradable and nonbiodegradable polymers has been demonstrated to induce a marked inflammatory reaction within the coronary artery with subsequent neointimal thickening, which was not expected on the basis of in vitro tests. The observed tissue response may be attributable to a combination of parent polymer compound, biodegradation products, and possibly implant geometry.

Unrestricted Utilization of Sirolimus-Eluting Stents Compared With Conventional Bare Stent Implantation in the “Real World” The Rapamycin-Eluting Stent Evaluated At Rotterdam Cardiology Hospital (RESEARCH) Registry

Background—The effectiveness of sirolimus-eluting stents in unselected patients treated in the daily practice is currently unknown. Methods and Results—Sirolimus-eluting stent implantation has been used as the default strategy for all percutaneous procedures in our hospital as part of the R apamycin-E luting S tent E valuated A t R otterdam C ardiology H ospital (RESEARCH) registry. Consecutive patients with de novo lesions (n=508) treated exclusively with sirolimus-eluting stents (SES group) were compared with 450 patients who received bare stents in the period just before (pre-SES group). Patients in the SES group more frequently had multivessel disease, more type C lesions, received more stents, and had more bifurcation stenting. At 1 year, the cumulative rate of major adverse cardiac events (death, myocardial infarction, or target vessel revascularization) was 9.7% in the SES group and 14.8% in the pre-SES group (hazard ratio [HR], 0.62 [95% CI, 0.44 to 0.89]; P =0.008). The 1-year risk of clinically driven target vessel revascularization in the SES group and in the pre-SES group was 3.7% versus 10.9%, respectively (HR, 0.35 [95% CI, 0.21 to 0.57]; P <0.001). Conclusions—Unrestricted utilization of sirolimus-eluting stents in the “real world” is safe and effective in reducing both repeat revascularization and major adverse cardiac events at 1 year compared with bare stent implantation.

TAXUS III Trial In-Stent Restenosis Treated With Stent-Based Delivery of Paclitaxel Incorporated in a Slow-Release Polymer Formulation

Background—The first clinical study of paclitaxel-eluting stent for de novo lesions showed promising results. We performed the TAXUS III trial to evaluate the feasibility and safety of paclitaxel-eluting stent for the treatment of in-stent restenosis (ISR). Methods and Results—The TAXUS III trial was a single-arm, 2-center study that enrolled 28 patients with ISR meeting the criteria of lesion length ≤30 mm, 50% to 99% diameter stenosis, and vessel diameter 3.0 to 3.5 mm. They were treated with one or more TAXUS NIRx paclitaxel-eluting stents. Twenty-five patients completed the angiographic follow-up at 6 months, and 17 of these underwent intravascular ultrasound (IVUS) examination. No subacute stent thrombosis occurred up to 12 months, but there was one late chronic total occlusion, and additional 3 patients showed angiographic restenosis. The mean late loss was 0.54 mm, with neointimal hyperplasia volume of 20.3 mm3. The major adverse cardiac event rate was 29% (8 patients; 1 non-Q-wave myocardial infarction, 1 coronary artery bypass grafting, and 6 target lesion revascularization [TLR]). Of the patients with TLR, 1 had restenosis in a bare stent implanted for edge dissection and 2 had restenosis in a gap between 2 paclitaxel-eluting stents. Two patients without angiographic restenosis underwent TLR as a result of the IVUS assessment at follow-up (1 incomplete apposition and 1 insufficient expansion of the stent). Conclusions—Paclitaxel-eluting stent implantation is considered safe and potentially efficacious in the treatment of ISR. IVUS guidance to ensure good stent deployment with complete coverage of target lesion may reduce reintervention.

Short- and Long-Term Clinical Outcome After Drug-Eluting Stent Implantation for the Percutaneous Treatment of Left Main Coronary Artery Disease Insights From the Rapamycin-Eluting and Taxus Stent Evaluated At Rotterdam Cardiology Hospital Registries (RESEARCH and T-SEARCH)

Background—The impact of drug-eluting stent (DES) implantation on the incidence of major adverse cardiovascular events in patients undergoing percutaneous intervention for left main (LM) coronary disease is largely unknown. Methods and Results—From April 2001 to December 2003, 181 patients underwent percutaneous coronary intervention for LM stenosis at our institution. The first cohort consisted of 86 patients (19 protected LM) treated with bare metal stents (pre-DES group); the second cohort comprised 95 patients (15 protected LM) treated exclusively with DES. The 2 cohorts were well balanced for all baseline characteristics. At a median follow-up of 503 days (range, 331 to 873 days), the cumulative incidence of major adverse cardiovascular events was lower in the DES cohort than in patients in the pre-DES group (24% versus 45%, respectively; hazard ratio [HR], 0.52 [95% CI, 0.31 to 0.88]; P=0.01). Total mortality did not differ between cohorts; however, there were significantly lower rates of both myocardial infarction (4% versus 12%, respectively; HR, 0.22 [95% CI, 0.07 to 0.65]; P=0.006) and target vessel revascularization (6% versus 23%, respectively; HR, 0.26 [95% CI, 0.10 to 0.65]; P=0.004) in the DES group. On multivariate analysis, use of DES, Parsonnet classification, troponin elevation at entry, distal LM location, and reference vessel diameter were independent predictors of major adverse cardiovascular events. Conclusions—When percutaneous coronary intervention is undertaken at LM lesions, routine DES implantation, which reduces the cumulative incidence of myocardial infarction and the need for target vessel revascularization compared with bare metal stents, should currently be the preferred strategy.

Clinical, Angiographic, and Procedural Predictors of Angiographic Restenosis After Sirolimus-Eluting Stent Implantation in Complex Patients An Evaluation From the Rapamycin-Eluting Stent Evaluated At Rotterdam Cardiology Hospital (RESEARCH) Study

Background—The factors associated with the occurrence of restenosis after sirolimus-eluting stent (SES) implantation in complex cases are currently unknown. Methods and Results—A cohort of consecutive complex patients treated with SES implantation was selected according to the following criteria: (1) treatment of acute myocardial infarction, (2) treatment of in-stent restenosis, (3) 2.25-mm diameter SES, (4) left main coronary stenting, (5) chronic total occlusion, (6) stented segment >36 mm, and (7) bifurcation stenting. The present study population was composed of 238 patients (441 lesions) for whom 6-month angiographic follow-up data were obtained (70% of eligible patients). Significant clinical, angiographic, and procedural predictors of post-SES restenosis were evaluated. Binary in-segment restenosis was diagnosed in 7.9% of lesions (6.3% in-stent, 0.9% at the proximal edge, 0.7% at the distal edge). The following characteristics were identified as independent multivariate predictors: treatment of in-stent restenosis (OR 4.16, 95% CI 1.63 to 11.01; P <0.01), ostial location (OR 4.84, 95% CI 1.81 to 12.07; P <0.01), diabetes (OR 2.63, 95% CI 1.14 to 6.31; P =0.02), total stented length (per 10-mm increase; OR 1.42, 95% CI 1.21 to 1.68; P <0.01), reference diameter (per 1.0-mm increase; OR 0.46, 95% CI 0.24 to 0.87; P =0.03), and left anterior descending artery (OR 0.30, 95% CI 0.10 to 0.69; P <0.01). Conclusions—Angiographic restenosis after SES implantation in complex patients is an infrequent event, occurring mainly in association with lesion-based characteristics and diabetes mellitus.

Relationship Between Neointimal Thickness and Shear Stress After Wallstent Implantation in Human Coronary Arteries

BackgroundIn-stent restenosis by excessive intimal hyperplasia reduces the long-term clinical efficacy of coronary stents. Because shear stress (SS) is related to plaque growth in atherosclerosis, we investigated whether variations in SS distribution are related to variations in neointima formation. Methods and ResultsIn 14 patients, at 6-month follow-up after coronary Wallstent implantation, 3D stent and vessel reconstruction was performed with a combined angiographic and intravascular ultrasound technique (ANGUS). The bare stent reconstruction was used to calculate in-stent SS at implantation, applying computational fluid dynamics. The flow was selected to deliver an average SS of 1.5 N/m2. SS and neointimal thickness (Th) values were obtained with a resolution of 90° in the circumferential and 2.5 mm in the longitudinal direction. For each vessel, the relationship between Th and SS was obtained by linear regression analysis. Averaging the individual slopes and intercepts of the regression lines summarized the overall relationship. Average Th was 0.44±0.20 mm. Th was inversely related to SS: Th=(0.59±0.24)−(0.08±0.10)×SS (mm) (P <0.05). ConclusionsThese data show for the first time in vivo that the Th variations in Wallstents at 6-month follow-up are inversely related to the relative SS distribution. These findings support a hemodynamic mechanism underlying in-stent neointimal hyperplasia formation.

Coronary Restenosis After Sirolimus-Eluting Stent Implantation Morphological Description and Mechanistic Analysis From a Consecutive Series of Cases

Background We describe the clinical and morphological patterns of restenosis after sirolimus‐eluting stent (SES) implantation. Methods and Results From 121 patients with coronary angiography obtained >30 days after SES implantation, restenosis (diameter stenosis >50%) was identified in 19 patients and 20 lesions (located at the proximal 5‐mm segment in 30% or within the stent in 70%). Residual dissection after the procedure or balloon trauma outside the stent was identified in 83% of the proximal edge lesions. Lesions within the stent were focal, and stent discontinuity was identified in some lesions evaluated by intravascular ultrasound. Conclusions Sirolimus‐eluting stent edge restenosis is frequently associated with local trauma outside the stent. In‐stent restenosis occurs as a localized lesion, commonly associated with a discontinuity in stent coverage. Local conditions instead of intrinsic drug‐resistance to sirolimus are likely to play a major role in post‐SES restenosis. (Circulation. 2003; 108:257‐260.)

Sirolimus-eluting stent for treatment of complex in-stent restenosis: the first clinical experience.

OBJECTIVES In this study, we assess the value of sirolimus eluting stent (SES) implantation in patients with complex in-stent restenosis (ISR). BACKGROUND The treatment of ISR remains a therapeutic challenge, since many pharmacological and mechanical approaches have shown disappointing results. The SESs have been reported to be effective in de-novo coronary lesions. METHODS Sixteen patients with severe, recurrent ISR in a native coronary artery (average lesion length 18.4 mm) and objective evidence of ischemia were included. They received one or more 18 mm Bx VELOCITY SESs (Cordis Waterloo, Belgium). Quantitative angiographic and three-dimensional intravascular ultrasound (IVUS) follow-up was performed at four months, and clinical follow-up at nine months. RESULTS The SES implantation (n = 26) was successful in all 16 patients. Four patients had recurrent restenosis following brachytherapy, and three patients had totally occluded vessels preprocedure. At four months follow-up, one patient had died and three patients had angiographic evidence of restenosis (one in-stent and two in-lesion). In-stent late lumen loss averaged 0.21 mm and the volume obstruction of the stent by IVUS was 1.1%. At nine months clinical follow-up, three patients had experienced four major adverse cardiac events (two deaths and one acute myocardial infarction necessitating repeat target vessel angioplasty). CONCLUSIONS The SES implantation in patients with severe ISR lesions effectively prevents neointima formation and recurrent restenosis at four months angiographic follow-up.

An optical coherence tomography study of a biodegradable vs. durable polymer-coated limus-eluting stent: A LEADERS trial sub-study

AIMS Incomplete endothelialization has been found to be associated with late stent thrombosis, a rare but devastating phenomenon, more frequent after drug-eluting stent implantation. Optical coherence tomography (OCT) has 10 times greater resolution than intravascular ultrasound and thus appears to be a valuable modality for the assessment of stent strut coverage. The LEADERS trial was a multi-centre, randomized comparison of a biolimus-eluting stent (BES) with biodegradable polymer with a sirolimus-eluting stent (SES) using a durable polymer. This study sought to evaluate tissue coverage and apposition of stents using OCT in a group of patients from the randomized LEADERS trial. METHODS AND RESULTS Fifty-six consecutive patients underwent OCT during angiographic follow-up at 9 months. OCT images were acquired using a non-occlusive technique at a pullback speed of 3 mm/s. Data were analysed using a Bayesian hierarchical random-effects model, which accounted for the correlation of lesion characteristics within patients and implicitly assigned analytical weights to each lesion depending on the number of struts observed per lesion. Primary outcome was the difference in percentage of uncovered struts between BESs and SESs. Twenty patients were included in the analysis in the BES group (29 lesions with 4592 struts) and 26 patients in the SES group (35 lesions with 6476 struts). A total of 83 struts were uncovered in the BES group and 407 out of 6476 struts were uncovered in the SES group [weighted difference -1.4%, 95% confidence interval (CI) -3.7 to 0.0, P = 0.04]. Results were similar after adjustment for pre-procedure lesion length, reference vessel diameter, number of implanted study stents, and presence of stent overlap. There were three lesions in the BES group and 15 lesions in the SES group that had > or =5% of all struts uncovered (difference -33.1%, 95% CI -61.7 to -10.3, P < 0.01). CONCLUSION Strut coverage at an average follow-up of 9 months appears to be more complete in patients allocated to BESs when compared with SESs. The impact of this difference on clinical outcome and, in particular, on the risk of late stent thrombosis is yet to be determined.

Reduction in Thrombotic Events With Heparin-Coated Palmaz-Schatz Stents in Normal Porcine Coronary Arteries.

BACKGROUND The use of stents improves the result after balloon coronary angioplasty. Thrombogenicity of stents is, however, a concern. In the present study, we compared stents with an antithrombotic coating with regular stents. METHODS AND RESULTS Regular stents were placed in coronary arteries of pigs receiving no aspirin (group 1; n = 8) or aspirin over 4 weeks (group 2, n = 10) or 12 weeks (group 3, n = 9). Stents coated with heparin (antithrombin III uptake, 5 pmol/stent) were placed in 7 pigs that did not receive aspirin (group 4). The other animals received aspirin and coated stents with a heparin activity of 12 pmol antithrombin III/stent (group 5, n = 10) or 20 pmol/stent (group 6, n = 10; group 7, n = 10). Quantitative arteriography was performed at implantation and after 4 (groups 1, 2, and 4 through 6) or 12 weeks (groups 3 and 7). In an additional 5 animals, five regular and five coated stents (20 pmol/stent) were placed and explanted after 5 days for examination of the early responses to the implants. Thrombotic occlusion of the regular stent occurred in 9 of 27 in groups 1 through 3. However, in 0 of 30 of the animals receiving high-activity heparin-coated stents (groups 5 through 7), thrombotic stent occlusion was observed (P < .001). Histological analysis at 4 weeks showed that the neointima in group 6 was thicker compared with its control group 2 (259 +/- 104 and 117 +/- 36 microns, P < .01), but at 12 weeks the thickness was similar (152 +/- 61 and 198 +/- 49 microns, respectively). Comparison at 5 days suggested delayed endothelialization of the coating. CONCLUSIONS High-activity heparin coating of stents eliminates subacute thrombosis in porcine coronary arteries.