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Parenteral and enteral nutrition support are key components of care for various medical and physiological conditions in infants, children, and adults. Nutrition support practices have advanced over time, driven by the goals of safe and sufficient delivery of needed nutrients and improved patient outcomes. These advances have been, and continue to be, dependent on research and development studies. Such studies address aspects of enteral and parenteral nutrition support: formulations, delivery devices, health outcomes, cost-effectiveness, and related metabolism. The studies are supported by public funding from the government and by private funding from foundations and from the nutrition support industry. To build public trust in nutrition support research findings, it is important to underscore ethical research conduct and reporting of results for all studies, including those with industry sponsors. In 2019, American Society for Parenteral and Enteral Nutrition's (ASPEN's) Board of Directors established a task force to ensure integrity in nutrition support research that is done as collaborative partnerships between the public (government and individuals) and private groups (foundations, academia, and industry). In this ASPEN Position Paper, the Task Force presents principles of ethical research to guide administrators, researchers, and funders. The Task Force identifies ways to curtail bias and to minimize actual or perceived conflict of interests, as related to funding sources and research conduct. Notably, this paper includes a Position Statement to describe the Task Force's guidance on Public-Private Partnerships for research and funding. This paper has been approved by the ASPEN Board of Directors.

Context: Metatarsal stress fractures are common in cleated-sport athletes. Previous authors have shown that plantar loading varies with footwear, sex, and the athletic task. Objective: To examine the effects of shoe type and sex on plantar loading in the medial midfoot (MMF), lateral midfoot (LMF), medial forefoot (MFF), middle forefoot (MidFF), and lateral forefoot (LFF) during a jump-landing task. Design: Crossover study. Setting: Laboratory. Patients or Other Participants: Twenty-seven recreational athletes (14 men, 13 women) with no history of lower extremity injury in the last 6 months and no history of foot or ankle surgery. Main Outcome Measure(s): The athletes completed 7 jumping trials while wearing bladed-cleat, turf-cleat, and running shoes. Maximum force, contact area, contact time, and the force-time integral were analyzed in each foot region. We calculated 2 × 3 analyses of variance (α = .05) to identify shoe-condition and sex differences. Results: We found no shoe × sex interactions, but the MMF, LMF, MFF, and LFF force-time integrals were greater in men (P < .03). The MMF maximum force was less with the bladed-cleat shoes (P = .02). Total foot and MidFF maximum force was less with the running shoes (P < .01). The MFF and LFF maximum forces were different among all shoe conditions (P < .01). Total foot contact area was less in the bladed-cleat shoes (P = .01). The MMF contact area was greatest in the running shoes (P < .01). The LFF contact area was less in the running shoes (P = .03). The MFF and LFF force-time integrals were greater with the bladed-cleat shoes (P < .01). The MidFF force-time integral was less in the running shoes (P < .01). Conclusions: Independent of shoe, men and women loaded the foot differently during a jump landing. The bladed cleat increased forefoot loading, which may increase the risk for forefoot injury. The type of shoe should be considered when choosing footwear for athletes returning to activity after metatarsal stress fractures.

Background— Early clinical studies demonstrated the feasibility of local paclitaxel delivery in reducing restenosis after treatment of de novo coronary lesions in small patient populations. Methods and Results— We conducted a randomized, double-blind trial of 536 patients at 38 medical centers evaluating slow-release (SR) and moderate-release (MR) formulations of a polymer-based paclitaxel-eluting stent (TAXUS) for revascularization of single, primary lesions in native coronary arteries. Cohort I compared TAXUS-SR with control stents, and Cohort II compared TAXUS-MR with a second control group. The primary end point was 6-month percent in-stent net volume obstruction measured by intravascular ultrasound. Secondary end points were 6-month angiographic restenosis and 6- and 12-month incidence of major adverse cardiac events, a composite of cardiac death, myocardial infarction, and repeat revascularization. At 6 months, percent net volume obstruction within the stent was significantly lower for TAXUS stents (7.9% SR and 7.8% MR) than for respective controls (23.2% and 20.5%; P P P =0.0002). The incidence of major adverse cardiac events at 12 months was significantly lower ( P =0.0192) in the TAXUS-SR (10.9%) and TAXUS-MR (9.9%) groups than in controls (22.0% and 21.4%, respectively), predominantly because of a significant reduction in repeat revascularization of the target lesion in TAXUS-treated patients. Conclusions— Compared with a bare metal stent, paclitaxel-eluting stents reduced in-stent neointimal formation and restenosis and improved 12-month clinical outcome of patients with single de novo coronary lesions.

Lower-extremity injury is common in soccer. A number of studies have begun to assess why specific lower-extremity injuries occur. However, currently few studies have examined how footwear affects lower-extremity mechanics. In order to address this question, 14 male (age: 22.1 ± 3.9 years, height: 1.77 ± 0.06 m, and mass: 73.3 ± 11.5 kg) and 14 female (age: 22.8 ± 3.1 years, height: 1.68 ± 0.07 m and mass: 64.4 ± 9.2 kg) competitive soccer players underwent a motion analysis assessment while performing a jump heading task. Each subject performed the task in three different footwear conditions (running shoe, bladed cleat, and turf shoe). Two-way analyses of variance were used to examine statistical differences in landing mechanics between the footwear conditions while controlling for gender differences. These comparisons were made during two different parts (prior to and following) of a soccer-specific jump heading task. A statistically significant interaction for the peak dorsiflexion angle (P = 0.02) and peak knee flexion angle (P = 0.05) was observed. Male soccer players exhibited a degree increase in dorsiflexion in the bladed cleat while female soccer players exhibited a three-degree reduction in peak knee flexion in the bladed cleat condition. Other main effects for gender and footwear were also observed. The results suggest that landing mechanics differ based upon gender, footwear, and the type of landing. Therefore, training interventions aimed at reducing lower-extremity injury should consider utilizing sport-specific footwear when assessing movement patterns.

Objectives: The multicenter, single-arm BEACH (Boston Scientific EPI: A Carotid Stenting Trial for High-Risk Surgical Patients) evaluated outcomes in high-surgical-risk patients with carotid artery stenosis treated with the Carotid WALLSTENT plus FilterWire EX/EZ Emboli Protection System (Boston Scientific, Natick, Massachusetts). Background: Carotid artery stent (CAS) placement offers a less invasive alternative for high-risk surgical carotid endarterectomy (CEA) patients. Methods: The trial enrolled 480 pivotal patients who were candidates for carotid revascularization but considered high surgical risk due to pre-specified anatomic criteria and/or medical comorbidities. The primary end point (all stroke, death, or Q-wave myocardial infarction [MI] through 30 days; non-Q-wave MI through 24 h; and ipsilateral stroke or neurologic death through 1 year) was compared with a proportionally weighted objective performance criterion (OPC) of 12.6% for published surgical endarterectomy results in similar patients, plus a pre-specified noninferiority margin of 4%. Results: Among pivotal patients, 41.2% were at high surgical risk due to comorbid risk factors, and 58.8% due to anatomic risk factors; 76.7% were asymptomatic with flow-limiting carotid stenosis >80%. At 1 year, the composite primary end point occurred in 8.9% (40 of 447), with a repeat revascularization rate of 4.7%. With an upper 95% confidence limit of 11.5% for the primary composite end point, the BEACH trial results met the pre-specified criteria for noninferiority relative to the calculated OPC plus noninferiority margin (16.6%) for historical surgical CEA outcomes in similar patients (p < 0.0001 for noninferiority). Conclusions: The BEACH trial results demonstrate that CAS with the WALLSTENT plus FilterWire embolic protection is non-inferior (equivalent or better than) to CEA at 1-year in high-surgical-risk patients (Boston Scientific Embolic Protection, Inc. [EPI]: A Carotid Stenting Trial for High-Risk Surgical Patients [BEACH]; http://clinicaltrials.gov/ct2/show/NCT00316108?term=NCT00316108r NCT00316108).

Late loss has been used as a reliable surrogate end point for evaluation and differentiation of short-term performance of drug-eluting stents. This study investigated the consistency between angiographic and intravascular ultrasound (IVUS) outcomes of late lumen loss (late loss) and neointimal growth to measure restenotic plaque load in TAXUS and bare metal stents. The randomized TAXUS II trial evaluates the polymer-based paclitaxel-eluting TAXUS stent in slow- and moderate-release formulations. Serial angiographic and IVUS analyses were available in 155 event-free patients (bare metal stent, 74; TAXUS stent, 81) after the procedure, at 6 months, and at 2 years. For this subanalysis, quantitative coronary angiographic (QCA) and IVUS measurements were used to derive late loss and neointimal volume. From after the procedure to 6 months, quantitative coronary angiography and IVUS showed matching results for the 2 groups with significant decreases in late loss and neointimal volume in the TAXUS versus the control group. From 6 months to 2 years, QCA and IVUS measurements also showed results similar to those in the control group, demonstrating neointimal compaction over time. However, in the TAXUS group, QCA late loss showed a nonsignificant decrease from 6 months to 2 years, whereas IVUS neointimal volume increased. In conclusion, although QCA and IVUS results were similar over the first 6 months, long-term assessment of changes in restenotic plaque load showed discrepant findings for the TAXUS. These findings suggest the need for critical reevaluation of current end points and the use of more precise techniques to detect lumen and stent boundaries.

The use of a medical device outside of its approved label is commonly referred to as “off-label use.” Off-label use arises when physicians see the opportunity to leverage an approved therapy for an unmet patient need. This practice typically occurs on a case by case basis without clear documentation of indication, frequency, or outcomes. Sponsors have a responsibility to consider formal indication expansion depending on the actual use, how well the therapy fits the unmet need, product iteration cycles, adoption speed, resource demands, and the clinical risk to benefit ratio. This responsibility is particularly relevant for breakthrough technologies where adoption patterns can span a variety of uses. For Boston Scientific's drug-eluting stent program, a surveillance program was developed in collaboration with the FDA to compile information on practice patterns and safety outcomes for the TAXUS® Express2™ Paclitaxel-Eluting Coronary Stent System. The ARRIVE program has used a Web-based format to collect real-time data on TAXUS stent use. This >7,000 patient registry documents both on-label and off-label use and key safety measures for the TAXUS stent. This real-world registry has successfully provided a data-driven approach to BSC's product development strategy, including the initiation of formal label expansion programs. For complex or combination products, more innovative ways of capturing risk to benefit data are needed to define off-label use and to maximize the potential therapeutic utility as supported by safety data.

Objectives This study sought to compare aggregate medical care costs for patients undergoing percutaneous coronary intervention with paclitaxel-eluting stents (PES) and bare-metal stents (BMS) and to formally evaluate the incremental cost effectiveness of PES for patients undergoing single-vessel percutaneous coronary intervention. Background Although the cost effectiveness of SES has been studied in both clinical trials and decision-analytic models, few data exist on the cost effectiveness of alternative drug-eluting stent (DES) designs. In addition, no clinical trials have specifically examined the cost effectiveness of DES among patients managed without mandatory angiographic follow-up. Methods We performed a prospective economic evaluation among 1,314 patients undergoing percutaneous coronary revascularization randomized to either PES (N = 662) or BMS (N = 652) in the TAXUS-IV trial. Clinical outcomes, resource use, and costs (from a societal perspective) were assessed prospectively for all patients over a 1-year follow-up period. Cost effectiveness was defined as the incremental cost per target vessel revascularization (TVR) event avoided and was analyzed separately among cohorts assigned to mandatory angiographic follow-up (n = 732) or clinical follow-up alone (n = 582). Results The PES reduced TVR by 12.2 events per 100 patients treated, resulting in a 1-year cost difference of $572 per patient with incremental cost-effectiveness ratios of $4,678 per TVR avoided and $47,798/quality-adjusted life year (QALY) gained. Among patients assigned to clinical follow-up alone, the net 1-year cost difference was $97 per patient with cost-effectiveness ratios of $760 per TVR event avoided and $5,105/QALY gained. Conclusions In the TAXUS-IV trial, treatment with PES led to substantial reductions in the need for repeat revascularization while increasing 1-year costs only modestly. The cost-effectiveness ratio for PES in the study population compares reasonably with that for other treatments that reduce coronary restenosis, including alternative drug-eluting stent platforms.

Objectives The objectives of the study were to evaluate the effect of angiographic follow-up on revascularization rates in the TAXUS-IV trial and to determine whether the relative benefit of paclitaxel-eluting stent implantation compared with bare metal stent implantation was modified by angiographic follow-up. Background Although several clinical trials have demonstrated that drug-eluting stents (DES) reduce restenosis compared with bare-metal stents (BMS), virtually all of these studies have incorporated angiographic follow-up. Methods In the TAXUS-IV trial, 1,314 percutaneous coronary intervention patients were randomized to receive paclitaxel-eluting stents (PES) (n = 662) or identical-appearing BMS (n = 652). Clinical outcomes were compared, stratified by assignment to angiographic follow-up or clinical follow-up alone. Results Compared with clinical follow-up alone, angiographic follow-up patients had a significantly higher rate of target vessel revascularization (TVR) at 1 year (adjusted hazard ratio [HR] 1.46; p = 0.04), with similar relative increases in PES and BMS patients. Because PES reduced TVR by ∼60% regardless of type of follow-up, assignment to angiographic follow-up tended to overestimate the absolute benefit of PES relative to clinical follow-up alone. In contrast, assessment of end points immediately before the time of follow-up angiography led to substantial underestimation of the absolute benefit of PES implantation. Conclusions Performance of mandatory angiographic follow-up increases rates of TVR among patients receiving both BMS and PES and overestimates the absolute clinical benefits of PES relative to clinical follow-up alone. Nonetheless, PES substantially reduces TVR regardless of assignment to mandatory angiographic follow-up or not. Future studies designed to determine the true clinical benefits of DES should either forgo routine angiographic follow-up or separate the time of repeat angiography from the primary clinical end point by as long as possible.

OBJECTIVES To address the safety and efficacy of drug-eluting stents (DES) in the treatment of intermediate lesions, we performed a pooled analysis of four randomized DES versus bare-metal stent (BMS) trials and assessed outcomes among patients with intermediate lesions. BACKGROUND Before the introduction of DES, intermediate coronary lesions were commonly managed based on physiologic or anatomic assessment of lesion severity. The DES may challenge this paradigm. METHODS The study population involved 167 of 2,478 randomized patients (6.7%) with intermediate lesions (diameter stenosis

Background— Intracoronary polymer-based stent delivery of paclitaxel has been shown to be effective in reducing restenosis in simple coronary lesions, but the evidence base for contemporary use in longer, more complex coronary stenoses is lacking. Methods and Results— TAXUS VI is a prospective, multicenter, double-blind, randomized trial assessing clinical and angiographic outcomes of the TAXUS Moderate Release paclitaxel-eluting stent in the treatment of long, complex coronary artery lesions. Four hundred forty-eight patients at 44 sites were randomized (1:1) between a drug-eluting TAXUS Express 2 and an uncoated Express 2 control stent. Per protocol, the 9-month follow-up included an angiographic reevaluation in all patients. The primary end point was the rate of target-vessel revascularization 9 months after the study procedure; secondary end points included the rate of target-lesion revascularization and binary restenosis at follow-up. Mean lesion length in the study was 20.6 mm, with a mean stent-covered length of 33.4 mm. Of all lesions, 55.6% were classified as complex lesions (type C of the AHA/ACC classification). At 9 months, target-vessel revascularization was 9.1% in the TAXUS group and 19.4% in the control group ( P =0.0027; relative reduction, 53%). Target-lesion revascularization was reduced from 18.9% to 6.8%, respectively ( P =0.0001). The incidence of major adverse cardiac events was similar in the 2 groups, 16.4% and 22.5% in TAXUS and control, respectively ( P =0.12), including comparable rates for acute myocardial infarction. Binary restenosis in the stented area was reduced from 32.9% in the control group to 9.1% in the TAXUS patients ( P Conclusions— The finding that the TAXUS Moderate Release stent system is safe and effective in the treatment of long, complex coronary artery lesions provides the evidence base for the more widespread use of drug-eluting stents in contemporary clinical practice.

Objectives We sought to examine the efficacy of paclitaxel-eluting stent implantation in the left anterior descending coronary artery (LAD). Background Restenosis and recurrent cardiac events after percutaneous intervention are more common for lesions in the LAD than other native coronary arteries, and often necessitate bypass surgery. Drug-eluting stents may improve the long-term prognosis of this high-risk group. Methods In the TAXUS-IV trial, 1,314 patients with single de novo coronary lesions were assigned to implantation of the slow-release, polymer-based, paclitaxel-eluting TAXUS stent or an identical bare-metal stent; 536 (41%) randomized patients had LAD lesions. Results Baseline characteristics of patients with LAD lesions were well-matched between the randomized groups. Late lumen loss at nine months after paclitaxel-eluting and control stent implantation were 0.28 ± 0.51 mm and 0.54 ± 0.57 mm, respectively (p = 0.0004), and binary restenosis rates were 11.3% and 26.9%, respectively (p = 0.004). At one year, major adverse cardiac events (MACE) occurred in 13.5% of TAXUS-treated patients versus 21.2% treated with the control stent (p = 0.01). The need for bypass surgery at one year was reduced among patients randomized to the TAXUS stent (2.6% vs. 6.3%, p = 0.02). In the proximal LAD subgroup (n = 126), the one-year target vessel revascularization rate was 7.9% with the TAXUS stent and 18.6% with the bare-metal stent (p = 0.009). Conclusions Compared to bare-metal stents, implantation of polymer-based, paclitaxel-eluting stents in LAD lesions is safe, and reduces angiographic restenosis and MACE one year. Notably, the need for bypass graft surgery due to restenosis is reduced after TAXUS stent implantation in LAD lesions.

Objectives We sought to determine the safety and efficacy of polymer-regulated site-specific delivery of paclitaxel in patients with diabetes mellitus undergoing stent implantation. Background Percutaneous coronary intervention in patients with diabetes is associated with high rates of restenosis and repeat revascularization due to excessive neointimal proliferation, a process that may be blunted with the site-specific delivery of paclitaxel. Methods In the TAXUS-IV trial, 1,314 patients were prospectively randomized to the slow rate-release polymer-based paclitaxel-eluting TAXUS stent or the bare-metal EXPRESS stent (Boston Scientific Corp., Natick, Massachusetts). Medically treated diabetes was present in 318 patients (24%), 105 of whom required insulin. Results Among patients with diabetes, the TAXUS stent, compared to the bare-metal stent, reduced the rate of 9-month binary angiographic restenosis by 81% (6.4% vs. 34.5%, p Conclusions The site-specific delivery of paclitaxel after coronary stent implantation is highly effective in reducing clinical and angiographic restenosis in patients with diabetes mellitus.

Objectives The aim of this study was to use serial volumetric intravascular ultrasound (IVUS) to evaluate the effects of polymer-based, paclitaxel-eluting stents on in-stent neointima formation and late incomplete stent apposition. Background The TAXUS-IV trial demonstrated that the slow-release, polymer-based, paclitaxel-eluting stent reduces angiographic restenosis and the need for repeat revascularization procedures. Serial IVUS studies reveal details of the pattern of vascular responses provoked by stent implantation that provide insight into device safety and efficacy. Methods In the TAXUS-IV trial, patients were randomized to the slow-release, polymer-based, paclitaxel-eluting TAXUS stent or a bare-metal EXPRESS stent (Boston Scientific Corp., Natick, Massachusetts). As part of a formal substudy, complete volumetric IVUS data were available in 170 patients, including 88 TAXUS patients and 82 controls, at implantation and at nine-month follow-up. Results No baseline differences were present in the clinical characteristics or IVUS parameters between the control and TAXUS groups. At nine-month follow-up, IVUS lumen volumes were larger in the TAXUS group (123 ± 43 mm3vs. 104 ± 44 mm3, p = 0.005), due to a reduction in neointimal volume (18 ± 18 mm3vs. 41 ± 23 mm3, p Conclusions Polymer-based, paclitaxel-eluting TAXUS stents are effective in inhibiting neointimal tissue proliferation, and do not result in late incomplete stent apposition.

Objectives We sought to investigate the outcomes of paclitaxel-eluting stent implantation in patients with unstable angina or non-ST-segment elevation myocardial infarction undergoing percutaneous coronary intervention (PCI). Background Whether the paclitaxel-eluting stent is safe and effective in patients with acute coronary syndromes (ACS) is unknown. Methods In the TAXUS-IV trial, 1,314 patients with stable or unstable ischemic syndromes undergoing PCI were randomized to treatment with either the slow-release, polymer-based, paclitaxel-eluting TAXUS stent or a bare-metal EXPRESS stent (Boston Scientific Corp., Natick, Massachusetts). The results were stratified by the acuity of the presenting clinical syndrome. Results Acute coronary syndromes were present in 450 patients (34.2%), 237 of whom were assigned to paclitaxel-eluting stents and 213 to bare-metal stents. The baseline and procedural characteristics were well matched between the groups. Clinical outcomes at 30 days were similar with both stents. At one-year follow-up, patients with ACS assigned to the paclitaxel-eluting stent compared to the control stent had strikingly lower rates of target lesion revascularization (TLR) (3.9% vs. 16.0%, p Conclusions The use of the paclitaxel-eluting TAXUS stent was safe in patients with unstable ischemic syndromes, and was associated with marked reduction of ischemia-driven TLR and adverse cardiac events at one year.

Background— The purpose of this study was to evaluate long-term vascular responses as long as 2 years after implantation of polymer-based, paclitaxel-eluting stents in contrast to uncoated stents. Methods and Results— TAXUS II is a randomized, double-blind trial comparing slow-release (SR) and moderate-release (MR) TAXUS stents with bare-metal control stents (BMSs). One hundred sixty-one event-free patients (SR, 43; MR, 41; and BMS, 77) underwent serial intravascular ultrasound (IVUS) analysis after the procedure and at 6 months and 2 years. At 2 years, neointimal responses continued to be significantly suppressed in the SR and MR groups when compared with the BMS group (BMS, 1.49±1.12 mm 2 ; SR, 0.94±0.76 mm 2 [ P =0.004]; and MR, 1.06±0.90 mm 2 [ P =0.02]). Between 6 months and 2 years, the BMS group showed compaction of the neointima (Δ, −0.22±1.05 mm 2 [ P =0.08]). In contrast, both the SR and MR groups exhibited an increase (Δ SR, 0.30±0.76 mm 2 ( P =0.01); MR, 0.41±0.94 mm 2 [ P =0.009]). Between 6 months and 2 years, the initial increase in plaque outside the stent regressed in the BMS and SR groups to levels comparable to those after the procedure, whereas expansive remodeling partially regressed in the MR group (Δ between after the procedure and 2 years BMS, −0.34±1.28 mm 2 [ P =0.05]; SR, −0.02±1.40 mm 2 [ P =0.93]; MR, 0.32±1.56 mm 2 [ P =0.27]). Conclusions— The 2-year follow-up demonstrates that neointimal suppression was dose independent and that this effect was still sustained at 2 years. However, the increase in area outside the stent seen at 6 months regressed to different extents in a dose-dependent manner at 2 years.

Background— The clinical impact of late incomplete stent apposition (ISA) for drug-eluting stents is unknown. We sought to prospectively investigate the incidence and extent of ISA after the procedure and at 6-month follow-up of paclitaxel-eluting stents in comparison with bare metal stents (BMS) and survey the clinical significance of ISA over a period of 12 months. Methods and Results— TAXUS II was a randomized, double-blind study with 536 patients in 2 consecutive cohorts comparing slow-release (SR; 131 patients) and moderate-release (MR; 135 patients) paclitaxel-eluting stents with BMS (270 patients). This intravascular ultrasound (IVUS) substudy included patients who underwent serial IVUS examination after the procedure and at 6 months (BMS, 240 patients; SR, 113; MR, 116). The qualitative and quantitative analyses of ISA were performed by an independent, blinded core laboratory. More than half of the instances of ISA observed after the procedure resolved at 6 months in all groups. No difference in the incidence of late-acquired ISA was observed among the 3 groups (BMS, 5.4%; SR, 8.0%; MR, 9.5%; P =0.306), with a similar ISA volume (BMS, 11.4 mm 3 ; SR, 21.7 mm 3 ; MR, 8.5 mm 3 ; P =0.18). Late-acquired ISA was the result of an increase of vessel area without change in plaque behind the stent. Predictive factors of late-acquired ISA were lesion length, unstable angina, and absence of diabetes. No stent thrombosis occurred in the patients diagnosed with ISA over a period of 12 months. Conclusions— The incidence and extent of late-acquired ISA are comparable in paclitaxel-eluting stents and BMS. ISA is a pure IVUS finding without clinical repercussions.

Objectives The Study to COmpare REstenosis Rate between QueST and QuaDDS-QP2 (SCORE) trial was a multicenter, randomized, open-label trial comparing the safety and performance of 13- and 17-mm QuaDDS stents (n = 126) (Quanam Medical Corp., Santa Clara, California/Boston Scientific Corp., Natick, Massachusetts) versus uncoated control stents (n = 140) in focal, de novo coronary lesions. Background The pioneering drug-delivery QuaDDS stent used four to six acrylate polymer sleeves, each loaded with 800 μg of the paclitaxel derivative 7-hexanoyltaxol. Methods Clinical end points were assessed at 1, 6, and 12 months post procedure. Quantitative coronary angiography and intravascular ultrasound were performed post procedure and at six-month follow-up. Results In the QuaDDS group, early stent thrombosis and myocardial infarction (MI) rates were significantly higher, leading to premature cessation of enrollment. For the QuaDDS group, the stent thrombosis rate increased from 3.2% to 10.3% between 1 and 12 months, associated with increased non–Q-wave MI and death rates. The angiographic restenosis rate at six months was reduced from 32.7% (control) to 7.4% (p Conclusions Despite angiographic indications of potential anti-restenotic benefit, increased rates of stent thrombosis, MI, and cardiac death associated with the QuaDDS stent show an unacceptable safety profile.

Background— The safety and efficacy of the slow-release, polymer-based, paclitaxel-eluting stent after implantation in a broad cross section of de novo coronary lesions at 1 year are unknown. Methods and Results— In the TAXUS-IV trial, 1314 patients with single de novo coronary lesions 10 to 28 mm in length, with reference-vessel diameter 2.5 to 3.75 mm, coverable by a single study stent, were prospectively randomized to the slow-release, polymer-based, paclitaxel-eluting TAXUS stent or an identical-appearing bare-metal EXPRESS stent. By actuarial analysis, the TAXUS stent compared with the bare-metal stent reduced the 12-month rates of target-lesion revascularization by 73% (4.4% versus 15.1%, P P P P P =0.007), target-vessel revascularizations (2.4% versus 5.8%, P =0.002), and major adverse cardiac events (2.4% versus 6.3%, P =0.0009) in the paclitaxel-eluting stent than in the control stent group, respectively. Conclusions— The relative efficacy reported at 9 months for the polymer-based, paclitaxel-eluting TAXUS stent compared with the EXPRESS stent is preserved and continues to increase at 1 year, with no safety concerns apparent.

Background— On the basis of brachytherapy experience, edge stenosis has been raised as a potential limitation for drug-eluting stents. We used serial intravascular ultrasound (IVUS) to prospectively analyze vessel responses in adjacent reference segments after implantation of polymer-controlled paclitaxel-eluting stents. Methods and Results— TAXUS II was a randomized, double-blind trial with 2 consecutive patient cohorts that compared slow-release (SR) and moderate-release (MR) paclitaxel-eluting stents with control bare metal stents (BMS). By protocol, all patients had postprocedure and 6-month follow-up IVUS. Quantitative IVUS analysis was performed by an independent core laboratory, blinded to treatment allocation, in 5-mm vessel segments immediately proximal and distal to the stent. Serial IVUS was available for 106 SR, 107 MR, and 214 BMS patients. For all 3 groups, a significant decrease in proximal-edge lumen area was observed at 6 months. The decrease was comparable (by ANOVA, P =0.194) for patients in the SR (−0.54±2.1 mm 2 ) and MR (−0.88±1.9 mm 2 ) groups compared with the BMS (−1.02±1.9 mm 2 ) group. For the distal edge, a significant decrease in lumen area was only observed with BMS (−0.91±2.0 mm 2 , P 2 ) and MR (−0.19±1.7 mm 2 ) stents ( P 2 , P =0.011) but not the distal edges of BMS and at neither edge of SR or MR stents. Conclusions— The marked reduction in in-stent restenosis with SR or MR stents is not associated with increased edge stenosis at 6-month follow-up IVUS. In fact, compared with BMS, there is instead a significant reduction in late lumen loss at the distal edge with TAXUS stents.

Background— The TAXUS NIRx stent (Boston Scientific Corp) provides local delivery of paclitaxel via a slow-release polymer coating. The TAXUS I trial was the first in-human experience evaluating safety and feasibility of the TAXUS NIRx stent system compared with bare NIR stents (control) (Boston Scientific Corp) for treatment of coronary lesions. Methods and Results— The TAXUS I trial was a prospective, double-blind, three-center study randomizing 61 patients with de novo or restenotic lesions (≤12 mm) to receive a TAXUS (n=31) versus control (n=30) stent (diameter 3.0 or 3.5 mm). Demographics, lesion characteristics, clinical outcomes were comparable between the groups. The 30-day major adverse cardiac event (MACE) rate was 0% in both groups ( P =NS). No stent thromboses were reported at 1, 6, 9, or 12 months. At 12 months, the MACE rate was 3% (1 event) in the TAXUS group and 10% (4 events in 3 patients) in the control group ( P =NS). Six-month angiographic restenosis rates were 0% for TAXUS versus 10% for control ( P =NS) patients. There were significant improvements in minimal lumen diameter (2.60±0.49 versus 2.19±0.65 mm), diameter stenosis (13.56±11.77 versus 27.23±16.69), and late lumen loss (0.36±0.48 versus 0.71±0.48 mm) in the TAXUS group (all P 3 ) group compared with the control group (21.6 mm 3 ) ( P Conclusions— In this feasibility trial, the TAXUS slow-release stent was well tolerated and showed promise for treatment of coronary lesions, with significant reductions in angiographic and intravascular ultrasound measures of restenosis.

Provision of adequate T cell costimulation is critical for the development of acute and chronic allograft rejection. We have previously reported that early blockade of CD28-B7 T cell costimulation prevents the development of graft arteriosclerosis, in the LEW into F344 rat cardiac transplant model. In this study, we used the same model to examine the requirement for CD28-B7-mediated T cell costimulation in the progression of established chronic rejection and examined the individual roles of B7-1 (CD80) and B7-2 (CD86) costimulatory molecules. Late blockade of CD28-B7 T cell costimulation by the fusion protein CTLA4Ig, which binds both CD80 and CD86, attenuated the development of transplant arteriosclerosis, mononuclear cell infiltration, and parenchymal fibrosis in this model. Selective blockade of CD80 using the mutant fusion protein Y100F was as effective as CTLA4Ig in this regard. In contrast to CTLA4Ig, blockade of CD80 alone by Y100F was ineffective at preventing early graft loss and prolonging graft survival when given early after transplantation. This study is the first to demonstrate that late blockade of CD28-B7 T cell costimulation interrupts chronic cardiac allograft rejection, and it indicates the importance of continued T cell activation in this process. This study further defines functional differences between CD80 and CD86 costimulatory molecules in vivo.

Background —To study transcription factor signaling pathways that mediate cardiac allograft vasculopathy, we used mice with targeted gene deletion of signal transducer and activator of transcription (STAT)4 and STAT6 as recipients in our mouse cardiac transplant model of chronic rejection. Methods and Results —At day 55 after transplantation, cardiac grafts placed into STAT4 −/− (n=10) had reduced frequency (24±2%) and severity (9±4%) of vascular occlusion compared with wild-type controls (n=7, frequency 70±12% [ P P 32 P RT-PCR and immunohistochemistry) of the Th1 signature cytokines interferon-γ ( P P + mononuclear cells (99±27 cells/mm 3 compared with 551±168 cells/mm 3 in wild-type controls [ P P P Conclusions —Hence, we show that immune responses mediated by STAT4, but not STAT6, contribute to the development of cardiac allograft vasculopathy. We speculate that when present, STAT4-mediated signaling pathways may promote cardiac allograft vasculopathy by directing Th1-specific lymphocyte recruitment, activation, and effector functions.

It has been reported previously that one-third of protocol renal biopsies in asymptomatic, biochemically stable renal transplant recipients in the first 6 mo show unsuspected subclinical graft rejection (both infiltrate and tubulitis) and that subclinical rejection is a risk factor for chronic renal dysfunction. This study was performed to determine whether differences in phenotype or activation status of graft-infiltrating cells underlie these different manifestations of acute rejection. Biopsies with normal histology (n = 10), subclinical rejection (n = 13), and clinical rejection (n = 9) were studied using immunohistochemistry and computerized image analysis. Subclinical and clinical rejections had similar histologic Banff scores. Univariate analysis showed a trend for a higher infiltration with CD8+ (P = 0.053) and CD68+(P = 0.06) cells in clinical rejection. Of the activation markers studied (CD25, perforin, tumor necrosis factor-alpha), only allograft inflammatory factor-1+-activated macrophages were significantly (P = 0.014) increased in the infiltrate of clinical rejection biopsies. These data suggest that activated macrophages or their products are responsible for acute renal dysfunction associated with clinical rejection episodes.

To investigate the role of interleukin (IL)-10 in late graft outcomes, we compared BALB/c donor hearts transplanted into immunosuppressed wild-type or IL-10 gene-deficient (−/−) C57BL recipients (n = 49) at 50 ± 5 days. There was prominent leukocyte infiltration and parenchymal destruction with more severe vascular occlusion in grafts from IL-10 −/− recipients. An occlusive CD45+ arteritis with medial necrosis occurred with IL-10 deficiency instead of the α-smooth muscle actin-rich arteriosclerosis seen in wild-type recipients. Increased interferon (IFN)-γ as well as Mac-1, inducible nitric oxide synthase, and allograft inflammatory factor-1 (but not CD3 and IL-4) transcript levels were seen in allografts from IL-10 −/− recipients as assessed by 32P reverse transcription polymerase chain reaction. We then evaluated the contribution of IFN-γ-mediated responses by neutralizing IFN-γ. Anti-IFN-γ monoclonal antibody (MAb) treatment of IL-10 −/− recipients did not improve graft survival, parenchymal rejection, or occlusive arteritis, indicating that these processes are IFN-γ independent. However, medial smooth muscle cell loss in IL-10 −/− recipients was attenuated by anti-IFN-γ MAb. Hence, in this transplant model, IL-10 suppresses T cell and macrophage responses in the parenchyma and vasculature and confers a protective effect against late rejection.

To compare regulatory effects of NOS2 in acute and chronic cardiac allograft rejection, we used NOS2 knockout mice as recipients in a cardiac transplant model. To study acute and chronic rejection separately but within the same genetic strain combination, we compared allografts placed into recipients without or with immunosuppression (anti-CD4/8 for 28 days). NOS2 mRNA and protein expression were compared using 32 P-RT-PCR and immunohistochemistry. In our acute rejection model, NOS2 was predominately localized to graft-infiltrating immune cells. At day 7, grafts in NOS2-deficient recipients ( n = 7) showed reduced inflammatory infiltrates and myocyte damage resulting in significantly lower rejection scores (1.6 ± 0.4) compared to wild-type controls ( n = 18; 2.8 ± 0.2, P = 0.002). In contrast, in our chronic rejection model, additional NOS2 expression was localized to graft-parenchymal cells. At day 55, grafts in NOS2-deficient recipients ( n = 12) showed more parenchymal infiltration and parenchymal destruction (rejection score 3.8 ± 0.1) than wild-type controls ( n = 15; 1.6 ± 0.2, P P

Background —Inducible NO synthase (NOS2, or iNOS) is upregulated in grafts with transplant arteriosclerosis. However, the functional role of NOS2 in the pathogenesis of transplant arteriosclerosis remains unclear. NOS2 may regulate lesion development by modulating the early alloimmune response and/or late myointimal thickening. Methods and Results —To determine whether NOS2-mediated pathways protect against or promote transplant arteriosclerosis, we used NOS2-deficient mice as recipients in our vascularized chronic cardiac rejection model. The severity of vascular thickening in 55-day grafts placed into NOS2 −/− recipients (n=13) was compared with that in wild-type recipients (n=15). Computer-assisted analysis of all elastin-stained vessels (n=283) showed significantly increased luminal occlusion (77.1±9.4% versus 40.8±13.6%, P P =.0002). To elucidate potential mechanisms, we studied NOS2 effects on T-cell differentiation (Th 1 /Th 2 ) and neointimal smooth muscle cell accumulation. Normalized mRNA levels for Th 1 - (signal transducer and activator of transcription [STAT] 4, interleukin [IL]-2, interferon-γ) and Th 2 - (STAT 6, IL-4, and IL-5) associated factors were comparable in both groups. In contrast, quantitative analysis of the α-actin–positive area showed a significant increase in the contribution of smooth muscle cells within the neointima in allografts from NOS2 −/− recipients (28.2±2.0%) compared with wild-type controls (13.2±2.3%; P Conclusions —NOS2 plays a protective role in the development of transplant arteriosclerosis, suppressing neointimal smooth muscle cell accumulation.

To study the role of cytokines in long-term cardiac allografts we have used recipient mice with targeted gene deletions (-/-) in IFN-gamma, IL-4, or IL-10. In wild-type and IL-4 -/- recipients immunosuppressed with a 30-d course of anti-CD4 and anti-CD8, graft survival was > 87 d. This time was significantly reduced in IFN-gamma -/- (62 +/- 19 d, P < 0.05) and IL-10 -/- recipients (55 +/- 4 d, P < 0.0001). Histology showed mononuclear cell infiltration, patchy necrosis, fibrosis, and vascular thickening in all groups. Intragraft transcript levels measured by 32P-reverse transcriptase PCR showed different inflammatory patterns. IFN-gamma -/- recipients had higher IL-2 transcripts and selective alteration in macrophage activation that may have contributed to decreased graft survival. Decreased graft survival in IL-10 -/- recipients was associated with increases in iNOS and IFN-gamma-driven responses. Finally, in grafts from IL-4 -/- recipients, there were increases in CD3 transcripts concurrent with TNF-alpha levels. This increase suggests that IL-4 may regulate T cell infiltration through TNF-alpha-mediated inflammatory cell recruitment. Concurrent evaluation of these three isolated cytokine deletions has shown that the recipient environment caused distinct graft modifications.

Abstract We evaluated inflammatory activation and vascular thickening in a heterotopic murine heart transplant model. C57BL/6J recipient mice received anti-CD4 therapy (days 1 to 4 after transplantation) or sustained, combined anti-CD4/CD8 therapy (days 1 to 4, weekly thereafter). Morphometric analysis of grafts (>95 days) found the mean percentage of vessel occlusion to be 51.7% in allografts treated with anti-CD4, 8.3% in allografts treated with sustained anti-CD4/CD8, and 6.7% in isografts. Mean transcript levels of the adhesion molecules P-selectin, intercellular adhesion molecule 1 (ICAM-1), and leukocyte function-associated antigen 1 (LFA-1) and the cytokines interleukin 4 (IL-4), interferon-γ (IFN-γ), inducible nitric oxide synthase (iNOS), allograft inflammatory factor 1 (AIF-1), and monocyte chemoattractant protein 1 (MCP-1) were measured with reverse transcription–polymerase chain reaction [RT-PCR] assays using deoxycytidine triphosphate radiolabeled with phosphorus 32 [ 32 P-dCTP]. The assays were normalized against glyceraldehyde-3-phosphate dehydrogenase [G3PDH] Levels were found to be significantly higher in the anti-CD4 group than in the anti-CD4/CD8 group. A strong correlation was also found between the percentage of luminal occlusion and the expression of these markers of inflammation ( r =.92-.99, P

CTLA4Ig, a fusion protein that blocks CD28-B7 costimulation, was studied in a LEW to F344 rat model of chronic cardiac rejection. In rats treated with a single dose of CTLA4Ig (0.5 mg intraperitoneally) 2 d after transplantation, allografts survived significantly longer ( > 70 d in 64%) than in untreated controls or rats treated with control Ig (all rejected within 25 d). Only 25% of grafts from rats treated with a single, high dose of cyclosporine A (25 mg/kg, 2 d after transplantation) survived longer than 70 d. Reverse transcriptase PCR and immunostaining analyses of tissue from 75-d, CTLA4Ig-treated allografts showed reduced expression of the T cell factor IFN-gamma and macrophage activation factors monocyte chemoattractant protein-1, inducible nitric oxide synthase, and galactose/N-acetylgalactosamine macrophage lectin, as well as TGF-beta. Grafts from longterm survivors ( > 120 d) treated with CTLA4Ig showed significant reductions in the frequency and severity of arteriosclerosis in comparison with cyclosporine A-treated rats. Thus, T cell activation is a proximal event in the cascade that culminates in the arteriosclerosis of chronic rejection. Strategies for blocking T cell costimulation may help prevent chronic rejection in clinical transplantation.

The development of arteriosclerotic lesions in the Lewis to F344 rat model of chronic cardiac rejection is characterized by macrophage adhesion to the vessel lumen and macrophage infiltration in the neointima prior to smooth muscle cell accumulation. We report the cloning and characterization of allograft inflammatory factor-1 (AIF-1), a novel cDNA that is expressed early and persistently in chronically rejecting cardiac allografts but is absent in cardiac syngrafts and host hearts. The full-length cDNA codes for a hydrophilic polypeptide of 17 kD that contains a 12-amino acid region similar to an EF-hand (calcium-binding) domain. In cardiac allografts AIF-1 transcripts and protein localized to infiltrating mononuclear cells. Analysis of isolated cell populations confirmed that AIF-1 was selectively expressed in macrophages and neutrophils and demonstrated that AIF-1 transcripts could be upregulated by sixfold after stimulation with the T cell-derived cytokine IFN-gamma. Treatment with a diet deficient in essential fatty acids (which attenuates arteriosclerosis) or CTLA-4 Ig (which blocks lymphocyte activation) significantly decreased AIF-1 transcript levels. Upregulation of AIF-1 in the setting of T cell activation suggests that it may play a role in macrophage activation and function.

Blocking the CD28-B7 T cell costimulatory pathway with the fusion protein CTLA4Ig inhibits alloimmune responses in vitro and in vivo and induces tolerance to cardiac allografts in mice and rats, but the mechanisms mediating the tolerant state in vivo are unknown. Here, we report the effects and potential mechanisms of CTLA4Ig in the rat renal allograft model. LEW rats were nephrectomized and received renal allografts from major histocompatibility complex-incompatible WF rats. While all untreated and control immunoglobulin (Ig)-treated animals acutely rejected their allografts and died, 86% of rats that received a single injection of CTLA4Ig on day 2 after transplantation had prolonged survival (> 60-100 days) with preserved renal function. By contrast, only 29% of animals that received CTLA4Ig on the day of engraftment had prolonged survival. Long-term survivors (> 100 days) exhibited donor-specific tolerance, accepting donor-matched WF but acutely rejecting third-party BN cardiac allografts. Immunohistological analysis of grafts sampled at 1 week after transplantation showed that both control and CTLA4Ig-treated animals had mononuclear cell infiltrates, with a higher percentage of CD4+ cells in the CTLA4Ig-treated group. However, while this was associated with vasculitis and tubulitis in control grafts, there was no evidence of tissue injury in CTLA4Ig-treated animals. The immune response leading to graft rejection in control animals was characterized by expression of the T helper (Th) type 1 cytokines interleukin (IL)-2 and interferon-gamma. In contrast, the persistent CD4+ infiltrate without graft rejection in CTLA4Ig-treated animals was associated with increased staining for the Th2-related cytokines IL-4 and IL-10. Furthermore, grafts from CTLA4Ig-treated animals had marked upregulation of intragraft staining for IgG1, but not IgG2a or IgG2b. Administration of rIL-2 to CTLA4Ig-treated animals restored allograft rejection in 50% of animals tested. These results confirm that blockade of the CD28-B7 pathway after alloantigenic challenge induces donor-specific acceptance of vascularized organ allografts, and indicates in this model that CTLA4Ig inhibits Th1 but spares Th2 cytokines in vivo.

Background:For persons with unicompartment knee osteoarthritis (OA), off-unloader braces are a mechanical intervention designed to reduce pain, improve physical function, and possibly slow disease progression. Pain relief is thought to be mediated by distracting the involved compartment via external varus or valgus forces applied to the knee. In so doing, tibiofemoral alignment is improved, and load is shifted off the degenerative compartment, where exposure to potentially damaging and provocative mechanical stresses are reduced.Objectives:To provide a synopsis of the evidence documented in the scientific literature concerning the efficacy of offloader knee braces for improving symptomatology associated with painful disabling medial compartment knee OA.Search Strategy:Relevant peer-reviewed publications were retrieved from a MEDLINE search using the terms with the reference terms osteoarthritis, knee, and braces (per Medical Subject Headings), plus a manual search of bibliographies from original and review articles and appropriate Internet resources.Results:For persons with combined unicompartment knee OA and mild to moderate instability, the strength of recommendation reported by the Osteoarthritis Research Society International in the ability of off-loader knee braces to reduce pain, improve stability, and diminish the risk of falling was 76% (95% confidence interval, 69%–83%). The more evidence the treatment is effective, the higher the percentage.Conclusions:Given the encouraging evidence that off-loader braces are effective in mediating pain relief in conjunction with knee OA and malalignment, bracing should be fully used before joint realignment or replacement surgery is considered. With the number of patients with varus deformities and knee pain predicted to increase as the population ages, a reduction of patient morbidity for this widespread chronic condition in combination with this treatment modality could have a positive impact on health care costs and the economic productivity and quality of life of the affected individuals.

Using differential mRNA display to uncover potential mediators associated with chronic rejection, we identified a cDNA fragment induced in Lewis to F344 rat cardiac allografts with arteriosclerosis but not Lewis syngrafts. The full-length cDNA (1.4 kb) isolated from a rat cardiac allograft cDNA library was 99% identical to galactose/N-acetylgalactosamine (Gal/GalNAc) macrophage lectin, a cell-surface receptor. This cDNA hybridized in Northern analysis with total RNA from eight cardiac allografts but not with host hearts, syngrafts, or other organs. There was a significant allograft-specific increase in transcript levels measured by reverse transcriptase PCR at days 7, 14, 28, and 75 in comparison with paired F344 host hearts (subject to same circulation but histologically normal), day-0 hearts, and syngrafts (P < 0.008, n = 4 at each time). Transcript levels in cardiac allografts were higher than those in paired host spleens (a major source of inflammatory cells) (P < 0.0001), indicating the localized nature of Gal/GalNAc lectin induction. By in situ hybridization and immunostaining, Gal/GalNAc lectin expression localized to a subset of inflammatory cells in cardiac allografts. These findings link Gal/GalNAc macrophage lectin to the chronic rejection process, as a possible mediator of macrophage infiltration.

These studies sought to evaluate the clinical outcomes of the slow-release Taxus paclitaxel-eluting stent (PES) versus an otherwise identical bare-metal stent (BMS).Prior studies were not individually powered to generate reliable estimates of low-frequency safety endpoints or to characterize the long-term safety and efficacy profile of PES.The completed 5-year databases from the prospective, randomized, double-blind TAXUS I, II, IV, and V trials were pooled for a patient-level analysis.The study population comprised 2,797 randomized patients (1,400 PES and 1,397 BMS). At the end of the 5-year study period, PES compared with BMS significantly reduced the rate of ischemia-driven target lesion revascularization (12.3% vs. 21.0%, p0.0001), with consistent reductions across high-risk subgroups and in patients with and without routine angiographic follow-up. There were no significant differences between the stent types in the 1-year or cumulative 5-year rates of death or myocardial infarction (MI). However, cardiac death or MI between 1 and 5 years was increased with PES (6.7% vs. 4.5%, p = 0.01), as was stent thrombosis (protocol definition: 0.9% vs. 0.2%, p = 0.007; ARC definition: 1.4% vs. 0.9%, p = 0.18).In this pooled patient-level analysis from the prospective, randomized, double-blind TAXUS trials, PES compared with BMS resulted in a durable 47% reduction in the 5-year rate of ischemia-driven target lesion revascularization in simple and complex lesions, with nonsignificant differences in the cumulative 5-year rates of death or MI. Between 1 and 5 years, however, the rates of cardiac death or MI and protocol-defined stent thrombosis were increased with PES.

The early response gene for monocyte chemoattractant protein 1 (MCP-1) encodes a potent chemotactic factor that is specific for monocytes. To determine whether MCP-1 is involved in macrophage recruitment in cardiac allografts, we studied time-dependent MCP-1 gene and protein expression patterns in the heterotopic, Lewis to F-344 rat transplantation model (by reverse transcription-PCR and immunohistochemistry). There was a significant increase (8- to 12-fold) in MCP-1 gene transcripts in cardiac allografts compared with host hearts at 7, 14, and 28 days after transplantation. This induction was not observed with syngeneic transplants or hosts exposed to the same circulating cells and blood products. The MCP-1 gene product was expressed predominantly by mononuclear cells that double-stained with antimacrophage antibody (ED1) and localized to the interstitial and vascular spaces of the allografts. Immunocytochemical cell counting revealed significant increases in both MCP-1- and ED1-immunopositive cells in 7-, 14-, and 28-day allografts (in comparison with day 0 hearts). The absolute number of MCP-1-positive cells (5-7%) was lower than that of ED1-positive cells (25-34%) at all time points, suggesting that MCP-1-positive cells represent a subpopulation of activated macrophages. The persistent expression of MCP-1 in association with increased macrophage localization suggests that this inducible mediator contributes to the chronic inflammatory response following cardiac transplantation and that it may play a role in the pathogenesis of transplant arteriosclerosis.

Aims: To provide insight on the patients with long lesions that received multiple, overlapping stents by reporting clinical outcomes, together with a detailed angiographic and intravascular ultrasound analysis of the overlap zone. Methods and results: TAXUS VI is a prospective, multicentre, double-blind, trial, specifically designed to assess outcomes of paclitaxel-eluting stents in longer lesions by randomising 446 patients (1:1) between a drug-eluting TAXUS™ Express 2 Moderate Release (MR) and an uncoated Express 2 control stent. Multiple overlapping stents were implanted in 124 patients (27.8%) and are the subject of this report. Clinical, angiographic and IVUS outcomes at nine months were compared in the overlap group for patients receiving the TAXUS™ Express 2 MR stent and the uncoated Express 2 stent. In the overlap group, mean lesion length was 25.1 mm with a mean stent length of 43.6 mm. At nine months, TVR was reduced by 94% from 25.0% to 1.6% in the TAXUS patients compared with control (p=

The multicenter, single-arm BEACH (Boston Scientific EPI: A Carotid Stenting Trial for High-Risk Surgical Patients) evaluated outcomes in high-surgical-risk patients with carotid artery stenosis treated with the Carotid WALLSTENT plus FilterWire EX/EZ Emboli Protection System (Boston Scientific, Natick, Massachusetts).Carotid artery stent (CAS) placement offers a less invasive alternative for high-risk surgical carotid endarterectomy (CEA) patients.The trial enrolled 480 pivotal patients who were candidates for carotid revascularization but considered high surgical risk due to pre-specified anatomic criteria and/or medical comorbidities. The primary end point (all stroke, death, or Q-wave myocardial infarction [MI] through 30 days; non-Q-wave MI through 24 h; and ipsilateral stroke or neurologic death through 1 year) was compared with a proportionally weighted objective performance criterion (OPC) of 12.6% for published surgical endarterectomy results in similar patients, plus a pre-specified noninferiority margin of 4%.Among pivotal patients, 41.2% were at high surgical risk due to comorbid risk factors, and 58.8% due to anatomic risk factors; 76.7% were asymptomatic with flow-limiting carotid stenosis80%. At 1 year, the composite primary end point occurred in 8.9% (40 of 447), with a repeat revascularization rate of 4.7%. With an upper 95% confidence limit of 11.5% for the primary composite end point, the BEACH trial results met the pre-specified criteria for noninferiority relative to the calculated OPC plus noninferiority margin (16.6%) for historical surgical CEA outcomes in similar patients (p0.0001 for noninferiority).The BEACH trial results demonstrate that CAS with the WALLSTENT plus FilterWire embolic protection is non-inferior (equivalent or better than) to CEA at 1-year in high-surgical-risk patients.

BackgroundDevelopmental dysplasia of the hip (DDH) is a condition in which bone growth irregularities subject articular cartilage to higher mechanical stresses, increase susceptibility to subluxation, and elevate the risk of early osteoarthritis. Study objectives were to calculate three-dimensional cartilage contact stresses and to examine increases of accumulated pressure exposure over a gait cycle that may initiate the osteoarthritic process in the human hip, in the absence of trauma or surgical intervention.MethodsPatient-specific, non-linear, contact finite element models, constructed from computed tomography arthrograms using a custom-built meshing program, were subjected to normal gait cycle loads.ResultsPeak contact pressures for dysplastic and asymptomatic hips ranged from 3.56 – 9.88 MPa. Spatially discriminatory cumulative contact pressures ranged from 2.45 – 6.62 MPa per gait cycle. Chronic over-pressure doses, for 2 million cycles per year over 20 years, ranged from 0.463 – 5.85 MPa-years using a 2-MPa damage threshold.ConclusionThere were significant differences between the normal control and the asymptomatic hips, and a trend towards significance between the asymptomatic and symptomatic hips of patients afflicted with developmental dysplasia of the hip. The magnitudes of peak cumulative contact pressure differed between apposed articular surfaces. Bone irregularities caused localized pressure elevations and an upward trend between chronic over-pressure exposure and increasing Severin classification.

ContextRestenosis within bare-metal stents is often treated with repeat percutaneous coronary intervention, although subsequent recurrence rates are high, with vascular brachytherapy (VBT) affording the best results. The effectiveness of drug-eluting stents in this setting has not been established.ObjectiveTo investigate the safety and efficacy of the polymer-based, slow-release paclitaxel-eluting stent in patients with restenotic lesions after prior stent implantation in native coronary arteries.Design, Setting, and PatientsProspective, multicenter, randomized trial conducted between June 6, 2003, and July 16, 2004, at 37 North American academic and community-based institutions in 396 patients with in-stent restenosis of a previously implanted bare-metal coronary stent (vessel diameter, 2.5-3.75 mm; lesion length, ≤46 mm).InterventionsPatients were randomly assigned to undergo angioplasty followed by VBT with a β source (n = 201) or paclitaxel-eluting stent implantation (n = 195). Clinical and angiographic follow-up at 9 months was scheduled in all patients.Main Outcome MeasureIschemia-driven target vessel revascularization at 9 months.ResultsDiabetes mellitus was present in 139 patients (35.1%). Median reference vessel diameter was 2.65 mm and median lesion length was 15.3 mm. In the VBT group, new stents were implanted in 22 patients (10.9%) and in the paclitaxel-eluting stent group, multiple stents were required in 57 patients (29.2%), with median stent length of 24 mm. Follow-up at 9 months was complete in 194 patients in the VBT group and 191 patients in the paclitaxel-eluting stent group (96.5% and 97.9%, respectively). For VBT and paclitaxel-eluting stents, respectively, the number of events and 9-month rates for ischemic target lesion revascularization were 27 (13.9%) vs 12 (6.3%) (relative risk [RR], 0.45; 95% confidence interval [CI], 0.24-0.86; P = .01); for ischemic target vessel revascularization, 34 (17.5%) vs 20 (10.5%) (RR, 0.60; 95% CI, 0.36-1.00; P = .046); and for overall major adverse cardiac events, 39 (20.1%) vs 22 (11.5%) (RR, 0.57; 95% CI, 0.35-0.93; P = .02), with similar rates of cardiac death or myocardial infarction (10 [5.2%] vs 7 [3.7%]; RR, 0.71; 95% CI, 0.28-1.83; P = .48) and target vessel thrombosis (5 [2.6%] vs 3 [1.6%]; RR, 0.61; 95% CI, 0.15-2.50; P = .72). Angiographic restenosis at 9 months was 31.2% (53 of 170 patients) with VBT and 14.5% (25 of 172 patients) with paclitaxel-eluting stents (RR, 0.47; 95% CI, 0.30-0.71; P

The objectives of the study were to evaluate the effect of angiographic follow-up on revascularization rates in the TAXUS-IV trial and to determine whether the relative benefit of paclitaxel-eluting stent implantation compared with bare metal stent implantation was modified by angiographic follow-up.Although several clinical trials have demonstrated that drug-eluting stents (DES) reduce restenosis compared with bare-metal stents (BMS), virtually all of these studies have incorporated angiographic follow-up.In the TAXUS-IV trial, 1,314 percutaneous coronary intervention patients were randomized to receive paclitaxel-eluting stents (PES) (n = 662) or identical-appearing BMS (n = 652). Clinical outcomes were compared, stratified by assignment to angiographic follow-up or clinical follow-up alone.Compared with clinical follow-up alone, angiographic follow-up patients had a significantly higher rate of target vessel revascularization (TVR) at 1 year (adjusted hazard ratio [HR] 1.46; p = 0.04), with similar relative increases in PES and BMS patients. Because PES reduced TVR by approximately 60% regardless of type of follow-up, assignment to angiographic follow-up tended to overestimate the absolute benefit of PES relative to clinical follow-up alone. In contrast, assessment of end points immediately before the time of follow-up angiography led to substantial underestimation of the absolute benefit of PES implantation.Performance of mandatory angiographic follow-up increases rates of TVR among patients receiving both BMS and PES and overestimates the absolute clinical benefits of PES relative to clinical follow-up alone. Nonetheless, PES substantially reduces TVR regardless of assignment to mandatory angiographic follow-up or not. Future studies designed to determine the true clinical benefits of DES should either forgo routine angiographic follow-up or separate the time of repeat angiography from the primary clinical end point by as long as possible.

To address the safety and efficacy of drug-eluting stents (DES) in the treatment of intermediate lesions, we performed a pooled analysis of four randomized DES versus bare-metal stent (BMS) trials and assessed outcomes among patients with intermediate lesions.Before the introduction of DES, intermediate coronary lesions were commonly managed based on physiologic or anatomic assessment of lesion severity. The DES may challenge this paradigm.The study population involved 167 of 2,478 randomized patients (6.7%) with intermediate lesions (diameter stenosis50% [mean 44%] by quantitative coronary angiography) from the Sirolimus-coated Bx Velocity Balloon Expandable Stent in the Treatment of Patients with De Novo Coronary Artery Lesions (SIRIUS), TAXUS-IV, and the First and Second First Use to Underscore Restenosis Reduction with Everolimus (FUTURE-I and -II) trials. End points examined included early (in-hospital and 30-day) and late (1-year) major adverse cardiac events (MACE), including cardiac death, myocardial infarction (MI), target vessel revascularization (TVR), stent thrombosis, and follow-up angiographic restenosis.Patients with intermediate lesions randomized to DES versus BMS had low rates of 30-day MACE (1.1% vs. 4.0% respectively; p = 0.22). At one-year follow-up, patients treated with DES versus BMS had similar rates of cardiac death (0% vs. 2.7%, respectively; p = 0.11) and MI (3.4% vs. 5.4%; p = 0.49) but markedly lower rates of TVR (3.4% vs. 20.3%; p = 0.0004), MACE (5.6% vs. 25.4%; p = 0.0003), and binary angiographic restenosis (1.8% vs. 34.0%; p0.0001). No patient in either group developed stent thrombosis.Compared with BMS, treatment of intermediate lesions with DES appears safe and results in a marked reduction in clinical and angiographic restenosis. The efficacy of DES may require a reevaluation of current treatment paradigms for intermediate lesions.

ContextCompared with bare metal stents, drug-eluting stents reduce restenosis in noncomplex lesions. The utility of drug-eluting stents has not been evaluated in more difficult stenoses.ObjectiveTo investigate the safety and efficacy of the polymer-based, slow-release paclitaxel-eluting stent in a patient population with more complex lesions than previously studied.Design, Setting, and PatientsProspective, placebo-controlled, double-blind, multicenter randomized trial conducted from February 2003 to March 2004 at 66 academic and community-based institutions with 1156 patients who underwent stent implantation in a single coronary artery stenosis (vessel diameter, 2.25-4.0 mm; lesion length, 10-46 mm), including 664 patients (57.4%) with complex or previously unstudied lesions (requiring 2.25-mm, 4.0-mm, and/or multiple stents) and 9-month clinical and angiographic follow-up.InterventionsPatients were randomly assigned to receive 1 or more bare metal stents (n = 579) or identical-appearing paclitaxel-eluting stents (n = 577).Main Outcome MeasureIschemia-driven target vessel revascularization at 9 months.ResultsBaseline characteristics were well matched. Diabetes was present in 31% of patients. The mean (SD) reference vessel diameter was 2.69 (0.57) mm, the reference lesion length was 17.2 (9.2) mm, and 78% of lesions were type B2/C. A mean (SD) of 1.38 (0.58) stents (total mean [SD] length, 28.4 [13.1] mm) were implanted per lesion; 33% of lesions required multiple stents. Stents that were 2.25 mm and 4.0 mm in diameter were used in 18% and 17% of lesions, respectively. Compared with bare metal stents, paclitaxel-eluting stents reduced the 9-month rate of target lesion revascularization from 15.7% to 8.6% (P

This study sought to compare aggregate medical care costs for patients undergoing percutaneous coronary intervention with paclitaxel-eluting stents (PES) and bare-metal stents (BMS) and to formally evaluate the incremental cost effectiveness of PES for patients undergoing single-vessel percutaneous coronary intervention.Although the cost effectiveness of SES has been studied in both clinical trials and decision-analytic models, few data exist on the cost effectiveness of alternative drug-eluting stent (DES) designs. In addition, no clinical trials have specifically examined the cost effectiveness of DES among patients managed without mandatory angiographic follow-up.We performed a prospective economic evaluation among 1,314 patients undergoing percutaneous coronary revascularization randomized to either PES (N = 662) or BMS (N = 652) in the TAXUS-IV trial. Clinical outcomes, resource use, and costs (from a societal perspective) were assessed prospectively for all patients over a 1-year follow-up period. Cost effectiveness was defined as the incremental cost per target vessel revascularization (TVR) event avoided and was analyzed separately among cohorts assigned to mandatory angiographic follow-up (n = 732) or clinical follow-up alone (n = 582).The PES reduced TVR by 12.2 events per 100 patients treated, resulting in a 1-year cost difference of 572 dollars per patient with incremental cost-effectiveness ratios of 4,678 dollars per TVR avoided and 47,798 dollars/quality-adjusted life year (QALY) gained. Among patients assigned to clinical follow-up alone, the net 1-year cost difference was 97 dollars per patient with cost-effectiveness ratios of 760 dollars per TVR event avoided and $5,105/QALY gained.In the TAXUS-IV trial, treatment with PES led to substantial reductions in the need for repeat revascularization while increasing 1-year costs only modestly. The cost-effectiveness ratio for PES in the study population compares reasonably with that for other treatments that reduce coronary restenosis, including alternative drug-eluting stent platforms.

The Study to COmpare REstenosis Rate between QueST and QuaDDS-QP2 (SCORE) trial was a multicenter, randomized, open-label trial comparing the safety and performance of 13- and 17-mm QuaDDS stents (n = 126) (Quanam Medical Corp., Santa Clara, California/Boston Scientific Corp., Natick, Massachusetts) versus uncoated control stents (n = 140) in focal, de novo coronary lesions.The pioneering drug-delivery QuaDDS stent used four to six acrylate polymer sleeves, each loaded with 800 microg of the paclitaxel derivative 7-hexanoyltaxol.Clinical end points were assessed at 1, 6, and 12 months post procedure. Quantitative coronary angiography and intravascular ultrasound were performed post procedure and at six-month follow-up.In the QuaDDS group, early stent thrombosis and myocardial infarction (MI) rates were significantly higher, leading to premature cessation of enrollment. For the QuaDDS group, the stent thrombosis rate increased from 3.2% to 10.3% between 1 and 12 months, associated with increased non-Q-wave MI and death rates. The angiographic restenosis rate at six months was reduced from 32.7% (control) to 7.4% (p0.0001). However, the primary end point was not met with six-month target vessel revascularization (TVR) rate as well as the composite major adverse cardiac event rates (cardiac death, MI, and TVR) comparable between groups.Despite angiographic indications of potential anti-restenotic benefit, increased rates of stent thrombosis, MI, and cardiac death associated with the QuaDDS stent show an unacceptable safety profile.