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Context: The Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy (ESPRIT) trial showed the efficacy of adjunctive, double-bolus eptifibatide therapy in reducing ischemic complications of nonurgent coronary stent implantation at 48 hours and at 30 days.Objective: To determine whether the beneficial effects of eptifibatide persist at 6 months after treatment.Design: Follow-up study of a randomized, double-blind, placebo-controlled, crossover-permitted trial conducted from June 1999 through February 2000.Setting: Ninety-two tertiary care centers in the United States and Canada.Participants: A total of 2064 patients scheduled to undergo nonurgent percutaneous coronary intervention with stent implantation.Intervention: Patients were randomly assigned to receive placebo or eptifibatide (two 180-microg/kg boluses 10 minutes apart and continuous infusion of 2.0 microg/kg per minute), started immediately before stent implantation and continued for 18 to 24 hours. Complete follow-up data were available for 988 (95.0%) of 1040 patients given eptifibatide and 977 (95.4%) of 1024 patients given placebo.Main Outcome Measures: Composite rates of death or myocardial infarction (MI); death, MI, or target vessel revascularization; and their individual components 6 months after enrollment, compared between the 2 groups.Results: By 6 months, the composite end point of death or MI had occurred in 7.5% of eptifibatide-treated patients and in 11.5% of placebo-treated patients (hazard ratio [HR], 0.63; 95% confidence interval [CI], 0.47-0.84; P =.002). The composite of death, MI, or target vessel revascularization was 14.2% in eptifibatide-treated patients vs 18.3% in placebo-treated patients (HR, 0.75; 95% CI, 0.60-0.93; P =.008). Most of this benefit accrued early (<48 hours after initiation of therapy) and was maintained through 6 months. Six-month mortality in the eptifibatide group was 0.8% vs 1.4% in the placebo group (HR, 0.56; 95% CI, 0.24-1.34; P =.19) and target vessel revascularization occurred in 8.6% of the eptifibatide group vs 9.4% of the placebo group (HR, 0.91; 95% CI, 0.68-1.22; P =.51).Conclusion: Adjunctive eptifibatide therapy during coronary stent implantation provides benefit through 6-month follow-up. [ABSTRACT FROM AUTHOR]

We describe Leucocytozoon polynuclearis n. sp. (Haemosporida: Leucocytozoidae) from two North American woodpeckers, the northern flicker (Colaptes auratus Linnaeus) and white-headed woodpecker (Dryobates albolarvatus Boie, 1826), based on the morphology of its blood stages and portions of the mitochondrial cytochrome b gene. The most distinctive features of Leucocytozoon polynuclearis n. sp. development are the triangular-shaped host cell nuclei and position of host cell nuclei above gametocytes. This parasite inhabits thrombocytes. Leucocytozoon squamatus Nandi, 1986, the only other Leucocytozoon species detected from Picidae birds, lacks features that are commonly found with L. polynuclearis n. sp. infections. Phylogenetic analysis identified DNA lineages associated with L. polynuclearis n. sp. and showed that this parasite is more closely related to other North American Leucocytozoon species than to L. squamatus, whose initial description was from infected Old World Picidae species. Although there are reports of L. squamatus in North American Picidae species, these detections were based only on microscopic examinations, remain genetically non-characterized, and might be misidentifications with regards to L. polynuclearis n. sp. Available parasite distribution data indicate that L. polynuclearis n. sp. infects Picidae species throughout North America and L. squamatus distribution probably is restricted to Old World Piciformes birds., (© 2021. The Author(s), under exclusive licence to Springer Nature B.V.)

Pyrodiversity, defined as variation in fire history and characteristics, has been shown to catalyse post-fire biodiversity in a variety of systems. However, the demographic and behavioural mechanisms driving the responses of individual species to pyrodiversity remain largely unexplored. We used a model post-fire specialist, the black-backed woodpecker (Picoides arcticus), to examine the relationship between fire characteristics and juvenile survival while controlling for confounding factors. We radio-tracked fledgling black-backed woodpeckers in burned forests of California and Washington, USA, and derived information on habitat characteristics using ground surveys and satellite data. We used hierarchical Bayesian mixed-effects models to determine the factors that influence both fledgling and annual juvenile survival, and we tested for effects of fledgling age on movement rates. Burn severity strongly affected fledgling survival, with lower survival in patches created by high-severity fire compared to patches burned at medium to low severity or left unburned. Time since leaving the nest was also a strong predictor of fledgling survival, annual juvenile survival and fledgling movement rates. Our results support the role of habitat complementation in generating species-specific benefits from variation in spatial fire characteristics-one axis of pyrodiversity-and highlight the importance of this variation under shifting fire regimes. High-severity fire provides foraging and nesting sites that support the needs of adult black-backed woodpeckers, but fledgling survival is greater in areas burned at lower severity. By linking breeding and foraging habitat with neighbouring areas of reduced predation risk, pyrodiversity may enhance the survival and persistence of animals that thrive in post-fire habitat., (Published 2021. This article is a U.S. Government work and is in the public domain in the USA.)

The majority of landbird species feed their nestlings arthropods and variation in arthropod populations can impact reproductive outcomes in these species. Arthropod populations in turn are influenced by climate because temperature affects survival and reproduction, and larval development. Thus, climate factors have the potential to influence many bird species during their reproductive phases. In this study, we assessed climate factors that impact the diet of nestling White-headed Woodpecker ( Dryobates albolarvatus ), an at-risk keystone species in much of its range in western North America. To do this, we measured stable isotope signatures (δ 13 C and δ 15 N) in 152 nestlings across six years and linked variation in isotopic values to winter (December-February) and spring (June) precipitation and temperature using mixed effects models. We also explored habitat factors that may impact δ 13 C and δ 15 N and the relationship between δ 15 N and nest productivity. Last, we estimated isotopic niche width for nestlings in different watersheds and years using Bayesian standard ellipses, which allowed us to compare dietary niche width and overlap. We found that colder winter temperatures were associated with an increase in δ 15 N and δ 15 N levels had a weak positive relationship with nest productivity. We also found that sites with a more diverse tree community were associated with a broader isotopic niche width in nestlings. Our findings suggest that nestling diet is affected by climate, and under future warming climate scenarios, White-headed Woodpecker nestling diet may shift in favor of lower trophic level prey (prey with lower δ 15 N levels). The impact of such changes on woodpecker populations merits further study., Competing Interests: None declared., (© 2020 The Authors. Ecology and Evolution published by John Wiley & Sons Ltd This article has been contributed to by US Government employees and their work is in the public domain in the USA.)

A juvenile White-headed woodpecker ( Dryobates albolarvatus ) fitted with a radio tag was located dead at approximately 22-days post-fledging in Yakima county in central Washington in July 2015. Postmortem examination revealed an enlarged liver and spleen plus evidence of iron sequestration. Microscopic examination observed young gametocytes within the cytoplasm of erythrocytes, and exo-erythrocytic meronts within the cytoplasm of capillary endothelial cells, hepatocytes, and myocytes, and free in the tissues. These attributes implicated a haemosporidian infection that likely resulted in mortality. Subsequent sampling results of local woodpecker species in the same area during the breeding season in June-July 2016 and May-July 2017 showed other individuals infected with Haemoproteus parasites. Nested Polymerase Chain Reaction (PCR), sequencing, and microscopic analyses for avian haemosporidians revealed infections with Haemoproteus velans (Haemosporida, Haemoproteidae). This parasite was characterized molecularly and morphologically. This is the first report of a haemosporidian infection in a White-headed woodpecker anywhere in its range, and the first reported suspected mortality from haemoproteosis for a woodpecker (Piciformes, Picidae). The use of radio-tagged birds is an asset in wildlife haemosporidian studies because the effect of the pathogen can be monitored in real time. Additionally, this methodology provides opportunities to collect fresh material for microscopic and histological examination from wild birds that have died from natural causes., Competing Interests: None.

Tree cavities provide critical roosting and breeding sites for multiple species, and thermal environments in these cavities are important to understand. Our objectives were to (1) describe thermal characteristics in cavities between June 3 and August 9, 2014, and (2) investigate the environmental factors that influence cavity temperatures. We placed iButtons in 84 different cavities in ponderosa pine (Pinus ponderosa) forests in central Washington, and took hourly measurements for at least 8 days in each cavity. Temperatures above 40 °C are generally lethal to developing avian embryos, and ~ 18% of the cavities had internal temperatures of ≥ 40 °C for at least 1 h of each day. We modeled daily maximum cavity temperature, the amplitude of daily cavity temperatures, and the difference between the mean internal cavity and mean ambient temperatures as a function of several environmental variables. These variables included canopy cover, tree diameter at cavity height, cavity volume, entrance area, the hardness of the cavity body, the hardness of the cavity sill (which is the wood below the cavity entrance which forms the barrier between the cavity and the external environment), and sill width. Ambient temperature had the largest effect size for maximum cavity temperature and amplitude. Larger trees with harder sills may provide more thermally stable cavity environments, and decayed sills were positively associated with maximum cavity temperatures. Summer temperatures are projected to increase in this region, and additional research is needed to determine how the thermal environments of cavities will influence species occupancy, breeding, and survival.

The marbled murrelet (Brachyramphus marmoratus) is a declining seabird that is well-known for nesting in coastal old-growth forests in the Pacific Northwest. Most studies of habitat selection have focused on modeling terrestrial nesting habitat even though marine habitat is believed to be a major contributor to population declines in some regions. To address this information gap, we conducted a 5-year study of marine resource selection by murrelets in Washington, which contains a population experiencing the steepest documented declines and where marine habitat is believed to be compromised. Across five years we tracked 157 radio-tagged murrelets during the breeding season (May to August), and used discrete choice models to examine habitat selection. Using an information theoretic approach, our global model had the most support, suggesting that murrelet resource selection at-sea is affected by many factors, both terrestrial and marine. Locations with higher amounts of nesting habitat (β = 21.49, P < 0.001) that were closer to shore (β = -0.0007, P < 0.001) and in cool waters (β = -0.2026, P < 0.001) with low footprint (β = -0.0087, P < 0.001) had higher probabilities of use. While past conservation efforts have focused on protecting terrestrial nesting habitat, we echo many past studies calling for future efforts to protect marine habitat for murrelets, as the current emphasis on terrestrial habitat alone may be insufficient for conserving populations. In particular, marine areas in close proximity to old-growth nesting habitat appear important for murrelets during the breeding season and should be priorities for protection., Competing Interests: The authors have declared that no competing interests exist.

Woodpeckers and other primary cavity excavators (PCEs) are important worldwide for excavating cavities in trees, and a large number of studies have examined their nesting preferences. However, quantitative measures of wood hardness have been omitted from most studies, and ecologists have focused on the effects of external tree- and habitat-level features on nesting. Moreover, information is lacking on the role of wood hardness in limiting nesting opportunities for this important guild. Here, we used an information theoretic approach to examine the role of wood hardness in multi-scale nest site selection and in limiting nesting opportunities for six species of North American PCEs. We found that interior wood hardness at nests (n = 259) differed from that at random sites, and all six species of PCE had nests with significantly softer interior wood than random trees (F1,517 = 106.15, P < 0.0001). Accordingly, interior wood hardness was the most influential factor in our models of nest site selection at both spatial scales that we examined: in the selection of trees within territories and in the selection of nest locations on trees. Moreover, regardless of hypothesized excavation abilities, all the species in our study appeared constrained by interior wood hardness, and only 4-14% of random sites were actually suitable for nesting. Our findings suggest that past studies that did not measure wood hardness counted many sites as available to PCEs when they were actually unsuitable, potentially biasing results. Moreover, by not accounting for nest site limitations in PCEs, managers may overestimate the amount of suitable habitat. We therefore urge ecologists to incorporate quantitative measures of wood hardness into PCE nest site selection studies, and to consider the limitations faced by avian cavity excavators in forest management decisions.

Randomized clinical trials have identified a population of acute medically ill patients who remain at risk for venous thromboembolism (VTE) beyond the standard duration of therapy and hospital discharge. The aim of the APEX study is to determine whether extended administration of oral betrixaban (35-42 days) is superior to a standard short course of prophylaxis with subcutaneous enoxaparin (10 ± 4 days followed by placebo) in patients with known risk factors for post-discharge VTE. Patients initially are randomized to receive either betrixaban or enoxaparin (and matching placebo) in a double dummy design. Following a standard duration period of enoxaparin treatment (with placebo tablets) or betrixaban (with placebo injections), patients receive only betrixaban (or alternative matching placebo). Patients are considered for enrollment if they are older than 40 years, have a specified medical illness, and restricted mobility. They must also meet the APEX criteria for increased VTE risk (aged ≥75 years, baseline D-Dimer ≥2× upper the limit of "normal", or 2 additional ancillary risk factors for VTE). The primary efficacy end point is the composite of asymptomatic proximal deep venous thrombosis, symptomatic deep venous thrombosis, non-fatal (pulmonary embolus) pulmonary embolism, or VTE-related death through day 35. The primary safety outcome is the occurrence of major bleeding. We hypothesize that extended duration betrixaban VTE prophylaxis will be safe and more effective than standard short duration enoxaparin in preventing VTE in acute medically ill patients with known risk factors for post hospital discharge VTE., (Copyright © 2014 The Authors. Published by Mosby, Inc. All rights reserved.)

Background: Edifoligide, an E2F transcription factor decoy, does not prevent vein graft failure or adverse clinical outcomes at 1 year in patients undergoing coronary artery bypass grafting (CABG). We compared the 5-year clinical outcomes of patients in PREVENT IV treated with edifoligide and placebo to identify predictors of long-term clinical outcomes., Methods: A total of 3,014 patients undergoing CABG with at least 2 planned vein grafts were enrolled. Kaplan-Meier curves were generated to compare the long-term effects of edifoligide and placebo. A Cox proportional hazards model was constructed to identify factors associated with 5-year post-CABG outcomes. The main outcome measures were death, myocardial infarction (MI), repeat revascularization, and rehospitalization through 5 years., Results: Five-year follow-up was complete in 2,865 patients (95.1%). At 5 years, patients randomized to edifoligide and placebo had similar rates of death (11.7% and 10.7%, respectively), MI (2.3% and 3.2%), revascularization (14.1% and 13.9%), and rehospitalization (61.6% and 62.5%). The composite outcome of death, MI, or revascularization occurred at similar frequency in patients assigned to edifoligide and placebo (26.3% and 25.5%, respectively; hazard ratio 1.03 [95% CI 0.89-1.18], P = .721). Factors associated with death, MI, or revascularization at 5 years included peripheral and/or cerebrovascular disease, time on cardiopulmonary bypass, lung disease, diabetes mellitus, and congestive heart failure., Conclusions: Up to a quarter of patients undergoing CABG will have a major cardiac event or repeat revascularization procedure within 5 years of surgery. Edifoligide does not affect outcomes after CABG; however, common identifiable baseline and procedural risk factors are associated with long-term outcomes after CABG., (Copyright © 2012 Mosby, Inc. All rights reserved.)

Background: Acute decompensated heart failure (ADHF) is a major public health burden with significant mortality and morbidity. Nesiritide is a recombinantly produced intravenous formulation of human B-type natriuretic peptide that promotes vasodilation and increases salt and water excretion, which results in reduced cardiac filling pressures. Prior studies have shown that dyspnea is improved in patients with ADHF 3 hours after nesiritide infusion with significant dose-related reductions in cardiac filling pressures and systemic vascular resistance without significant arrhythmias. However, the effect of nesiritide on dyspnea at 6 or 24 hours is unknown, and no clinical outcome trials have been done to provide a reliable estimate of the effect of nesiritide on morbidity and mortality., Methods: The Acute Study of Clinical Effectiveness of Nesiritide in Decompensated Heart Failure trial (ASCEND-HF) is a phase III study evaluating the efficacy and safety of nesiritide in patients with ADHF. Patients hospitalized for hear failure will be randomly assigned to receive either intravenous nesiritide or matching placebo for 24 hours to 7 days. The 2 coprimary end points are (1) assessment of acute dyspnea at 6 or 24 hours and (2) death or rehospitalization for hear failure within 30 days. A total of 7,000 patients will be enrolled worldwide between 2007 and 2010., Conclusions: The data from the ASCEND-HF trial will establish whether nesiritide safely improves acute dyspnea as well as morbidity and mortality at 30 days.

Objective: The PREVENT III study was a prospective, randomized, double-blinded, multicenter phase III trial of a novel molecular therapy (edifoligide; E2F decoy) for the prevention of vein graft failure in patients undergoing infrainguinal revascularization for critical limb ischemia (CLI)., Methods: From November 2001 through October 2003, 1404 patients with CLI were randomized to a single intraoperative ex vivo vein graft treatment with edifoligide or placebo. After surgery, patients underwent graft surveillance by duplex ultrasonography and were followed up for index graft and limb end points to 1 year. A blinded Clinical Events Classification committee reviewed all index graft end points. The primary study end point was the time to nontechnical index graft reintervention or major amputation due to index graft failure. Secondary end points included all-cause graft failure, clinically significant graft stenosis (>70% by angiography or severe stenosis by ultrasonography), amputation/reintervention-free survival, and nontechnical primary graft patency. Event rates were based on Kaplan-Meier estimates. Time-to-event end points were compared by using the log-rank test., Results: Demographics, comorbidities, and procedural details reflected a population with CLI and diffuse atherosclerosis. Tissue loss was the presenting symptom in 75% of patients. High-risk conduits were used in 24% of cases, including an alternative vein in 20% (15% spliced vein and 5% non-great saphenous vein) and 6% less than 3 mm in diameter; 14% of the cases were reoperative bypass grafts. Most (65%) grafts were placed to infrapopliteal targets. Perioperative (30-day) mortality occurred in 2.7% of patients. Major morbidity included myocardial infarction in 4.7% and early graft occlusion in 5.2% of patients. Ex vivo treatment with edifoligide was well tolerated. There was no significant difference between the treatment groups in the primary or secondary trial end points, primary graft patency, or limb salvage. A statistically significant improvement was observed in secondary graft patency (estimated Kaplan-Meier rates were 83% edifoligide and 78% placebo; P = .016) within 1 year. The reduction in secondary patency events was manifest within 30 days of surgery (the relative risk for a 30-day event for edifoligide was 0.45; 95% confidence interval, 0.27-0.76; P = .005). For the overall cohort at 1 year, the estimated Kaplan-Meier rate for survival was 84%, that for primary patency was 61%, that for primary assisted patency was 77%, that for secondary patency was 80%, and that for limb salvage was 88%., Conclusions: In this prospective, randomized, placebo-controlled clinical trial, ex vivo treatment of lower extremity vein grafts with edifoligide did not confer protection from reintervention for graft failure.

Context: Coronary artery bypass graft (CABG) surgery with autologous vein grafting is commonly performed. Progressive neointimal hyperplasia, however, contributes to considerable vein graft failure. Edifoligide is an oligonucleotide decoy that binds to and inhibits E2F transcription factors and thus may prevent neointimal hyperplasia and vein graft failure., Objective: To assess the efficacy and safety of pretreating vein grafts with edifoligide for patients undergoing CABG surgery., Design, Setting, and Participants: A phase 3 randomized, double-blind, placebo-controlled trial of 3014 patients undergoing primary CABG surgery with at least 2 planned saphenous vein grafts and without concomitant valve surgery, who were enrolled between August 2002 and October 2003 at 107 US sites., Intervention: Vein grafts were treated ex vivo with either edifoligide or placebo in a pressure-mediated delivery system. The first 2400 patients enrolled were scheduled for 12- to 18-month follow-up angiography., Main Outcome Measures: The primary efficacy end point was angiographic vein graft failure (> or =75% vein graft stenosis) occurring 12 to 18 months after CABG surgery. Other end points included other angiographic variables, adverse events through 30 days, and major adverse cardiac events., Results: A total of 1920 patients (80%) either died (n = 91) or underwent follow-up angiography (n = 1829). Edifoligide had no effect on the primary end point of per patient vein graft failure (436 [45.2%] of 965 patients in the edifoligide group vs 442 [46.3%] of 955 patients in the placebo group; odds ratio, 0.96 [95% confidence interval {CI}, 0.80-1.14]; P = .66), on any secondary angiographic end point, or on the incidence of major adverse cardiac events at 1 year (101 [6.7%] of 1508 patients in the edifoligide group vs 121 [8.1%] of 1506 patients in the placebo group; hazard ratio, 0.83 [95% CI, 0.64-1.08]; P = .16)., Conclusions: Failure of at least 1 vein graft is quite common within 12 to 18 months after CABG surgery. Edifoligide is no more effective than placebo in preventing these events. Longer-term follow-up and additional research are needed to determine whether edifoligide has delayed beneficial effects, to understand the mechanisms and clinical consequences of vein graft failure, and to improve the durability of CABG surgery. Clinical Trial Registration ClinicalTrials.gov Identifier: NCT00042081.

Up to 20% of saphenous vein grafts (SVGs) fail within 2 years of coronary artery bypass grafting (CABG). The long-term effects of early SVG failure on major clinical events remain undefined in contemporary patient populations. We sought to examine the relation between early SVG failure and long-term outcomes after CABG. Using the Duke Cardiovascular Databank, we examined baseline clinical and angiographic characteristics and clinical outcomes among patients who underwent catheterization 1 to 18 months after their first CABG from 1986 to 2004. Patients were classified on the basis of their worst SVG stenosis as having no (<25%), noncritical (25% to 74%), critical (75% to 99%), or occlusive (100%) SVG disease. Our primary outcome measure was the composite of death, myocardial infarction, or repeat revascularization after catheterization. Of 1,243 patients included in the analysis, 27.9% had no, 11.9% had noncritical, 20.8% had critical, and 39.3% had occlusive SVG disease. At 10 years, the corresponding adjusted composite event rates were 41.2%, 56.2%, 81.2%, and 67.1%, respectively (p <0.0001). Most events occurred immediately after catheterization in patients with critical and occlusive SVG disease and were primarily repeat revascularization. On multivariate analysis, critical, nonocclusive SVG disease was the strongest predictor of the composite outcome (hazard ratio 2.36, 95% confidence interval 2.00 to 2.79, p <0.0001). In conclusion, in contemporary clinical practice, early SVG failure is associated with worse long-term outcomes after CABG.

Background: Coronary artery bypass graft (CABG) surgery with autologous vein graft (VG) conduit is one of the most frequently performed operations in the United States. Unfortunately, many VGs become occluded during long-term follow-up largely because of neointimal hyperplasia. A novel approach to preventing neointimal hyperplasia is with the double-stranded oligonucleotide edifoligide (Corgentech Inc, South San Francisco, Calif). Edifoligide inhibits E2F, a transcription factor that activates cell-cycle genes responsible for neointimal hyperplasia., Methods: PREVENT IV is a phase-III, multicenter, randomized double-blind placebo-controlled trial of ex vivo treatment of autologous VGs with edifoligide in patients undergoing initial CABG surgery. The primary end point is VG failure, defined as death or > or =75% stenosis in a treated VG at 12- to 18-month angiographic follow-up. Secondary end points include major adverse cardiac events through at least 5 years and adverse events through 30 days., Results: Enrollment of 3014 patients from 107 sites was completed on October 22, 2003. The baseline and procedural characteristics of the PREVENT IV population are generally well matched to a contemporary population of patients undergoing initial CABG from the Society of Thoracic Surgeons National Database. Angiographic follow-up is ongoing and scheduled to be completed in March 2005., Conclusions: The PREVENT IV data will establish whether VG pretreatment with an E2F transcription factor decoy, edifoligide, can improve graft patency and reduce the long-term morbidity and mortality of patients undergoing CABG surgery.

Surgical bypass of peripheral arterial occlusive disease with autologous vein grafts provides an effective means of restoring blood flow to the lower extremity, and has been a standard therapy for patients with disabling claudication or critical limb ischemia (CLI). However, failure rates may run as high as 50% within 5 years. These graft failures occur as a result of neointimal hyperplasia, a ubiquitous biologic response of blood vessel walls to injury, which is characterized by the migration and proliferation of smooth muscle cells (SMC). The E2F family of transcription factors regulates the expression of genes controlling SMC proliferation. Edifoligide (E2F Decoy) is a novel therapy that inhibits E2F function, thus attenuating neointimal hyperplasia. Its use in conjunction with a patented drug delivery pressurization chamber is under investigation. Using this system, edifoligide is administered to vein grafts in a single, ex vivo treatment following vein harvest and before implantation, resulting in minimal systemic drug exposure and excellent patient compliance. This Phase 3, randomized, double-blind, multicenter clinical trial is designed to evaluate the safety and efficacy of edifoligide in a population of approximately 1400 patients with CLI undergoing infrainguinal bypass for peripheral arterial disease (PAD). The primary outcome measure will be the time to occurrence of non-technical graft failure resulting in either graft revision or major amputation at 12 months after enrollment. A governing Clinical Events Classification committee (CEC) will adjudicate each graft failure to determine its etiology. The PREVENT III trial is the largest multicenter trial ever performed in patients receiving autologous vein bypass grafts for CLI. This landmark study will determine if edifoligide is safe and effective at preventing vein graft failure in patients undergoing lower extremity bypass, but it also provides a unique opportunity to observe current treatment practices in vascular surgery.

Rarely is it straightforward to specify the design and parameters of a clinical trial investigating an alternative therapy where effective therapies already exist. If existing therapeutic interventions are highly efficacious, safe, inexpensive, and firmly entrenched, an active-control design becomes the logical first choice. Short of this absolute condition, however, the merits and realities of the scientific, clinical, corporate, and regulatory environments need to be weighed before determining the appropriate approach. A state of clinical equipoise with regard to the use of glycoprotein (GP) IIb/IIIa therapy in percutaneous coronary intervention (PCI) provided the unique opportunity to address the complexities in selecting a placebo-controlled design for the Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Trial (ESPRIT). ESPRIT investigators assessed whether a high dose of eptifibatide would improve the outcomes of patients undergoing coronary stenting. By using the example of the ESPRIT trial, we examine factors warranting the need for this trial and evaluate the process whereby the United States Food and Drug Administration (FDA) gave approval for a placebo-controlled design. Although the focus of this trial is GP IIb/IIIa inhibition therapy, the issues pertaining to the trial and how they were resolved are general enough to be applied to the design and conduct of clinical trials across a broad spectrum of illnesses and therapeutic modalities.

Objective: The study was done to determine whether eptifibatide, a platelet glycoprotein (GP) IIb/IIIa antagonist, prevents ischemic complications following percutaneous coronary interventions (PCIs) in women as well as in men., Background: Eptifibatide reduces ischemic complications after nonurgent coronary stent interventions., Methods: We compared outcomes in women (n = 562) and men (n = 1,502) enrolled in the Enhanced Suppression of the Platelet GP IIb/IIIa Receptor with Integrilin Therapy (ESPRIT) trial of double-bolus eptifibatide during PCI., Results: Women in the ESPRIT trial were older, and more frequently had hypertension, diabetes mellitus, or acute coronary syndromes, but were less likely to have prior PCI or coronary artery bypass graft surgery. The primary end point, a composite at 48 h of death, myocardial infarction (MI), urgent target vessel revascularization (TVR), and unplanned GP IIb/IIIa use, occurred in 10.5% of women and 7.9% of men (p = 0.082). The composite of death, MI, or TVR after one year occurred in 24.5% of women compared with 18% of men (p = 0.0008). At 48 h, eptifibatide reduced the composite of death, MI, and TVR from 14.5% to 6.0% in women versus 9.0% to 6.8% in men. At one year, these differences persisted: 28.9% versus 20.0% for women and 19.5% versus 16.6% for men. No statistical interaction existed between treatment and gender at either 48 h (p = 0.063) or one year (p = 0.2). Bleeding occurred more commonly in women (5.5% vs. 2.6%, p = 0.002), and was more common in eptifibatide-treated women. After adjustment for age, weight, and hypertension, no interaction between treatment and gender was present., Conclusion: Eptifibatide is effective to prevent ischemic complications of PCI in women and may eliminate gender-related differences in PCI outcomes.

Background: The etiology of creatine kinase-myocardial band (CK-MB) release after percutaneous coronary intervention (PCI) remains unclear. The goal of this study was to evaluate the relationship of both epicardial and tissue level perfusion at the completion of stent placement to CK-MB release after the procedure. Given the high rates of Thrombolysis in Myocardial Infarction (TIMI) grade 3 flow after PCI, we hypothesized that abnormalities in tissue level perfusion would instead explain CK-MB release., Methods: Data were drawn from the angiographic substudy of the Enhanced Suppression of the Platelet IIb/IIIa Receptor With Integrilin Therapy (ESPRIT) trial of eptifibatide versus placebo in patients undergoing planned coronary stent implantation. In the substudy, cinefilms of 65 patients were analyzed by an angiographic core laboratory blinded to enzymatic and clinical outcomes., Results: The release of CK-MB was not associated with TIMI grade 3 flow or the corrected TIMI frame count; 100% of patients had TIMI grade 3 flow at the completion of PCI. In contrast, tissue level perfusion using the TIMI myocardial perfusion grade (TMPG) was related to postintervention CK-MB release: patients with a closed myocardium (TMPG 0/1) or delayed myocardial perfusion (TMPG 2) had an average CK-MB release 2.2 +/- 2.7 times the upper limit of normal (n = 34), whereas those patients with normal myocardial perfusion (TMPG 3, n = 24) had CK-MB 0.8 +/- 0.6 times the upper limit of normal (P =.01). Although no patients with TMPG 3 sustained death/myocardial infarction/urgent target vessel revascularization or thrombotic bailout, 17.7% of patients with TMPG 0/1/2 did by 48 hours (P =.037)., Conclusions: Impaired tissue level perfusion as assessed by the TMPG and not epicardial coronary blood flow is associated with CK-MB elevation after PCI. These data provide a pathophysiologic link between impaired tissue level perfusion, post-PCI infarction, and adverse clinical outcomes.

This study describes the dose-exploration phase of the PRIDE trial, an investigation of the clinical pharmacology of higher dose eptifibatide in patients who underwent elective percutaneous coronary intervention (PCI). Outcomes of treatment with the platelet glycoprotein IIb/IIIa inhibitors were dependent upon proper dosing selection. In this multicenter, placebo-controlled clinical study, 127 patients were randomized 1:1:2:2 into 1 of the following treatment groups: placebo; eptifibatide as a 135 microg/kg bolus followed by a 0.75 microg/kg/min infusion; eptifibatide as a 180 microg/kg bolus with a 2.0 microg/kg/min infusion; or eptifibatide as a 250 microg/kg bolus with a 3.0 microg/kg/min infusion. Light transmission aggregometry was used to determine platelet aggregation in response to 20 microM adenosine diphosphate, and platelet receptor occupancy was also determined. Eptifibatide exhibited linear pharmacokinetics over the dose range studied. Inhibition of platelet aggregation was greater in samples collected in sodium citrate compared with those collected in D-phenylalanyl-L-prolyl-L-arginine chloromethyl ketone. The 180/2.0 dosing regimen achieved 90% inhibition of platelet aggregation immediately (5 minutes) and at steady state (8 to 24 hours). At 1 hour, mean inhibition of platelet aggregation was 80%. Eptifibatide exhibited dose-dependent pharmacodynamics that were dependent upon choice of anticoagulant. A 180 microg/kg bolus followed by a 2.0 microg/kg/min infusion at steady state achieved >80% inhibition of platelet aggregation. With the single-bolus regimen, however, there was an early loss of the inhibition of platelet aggregation before steady state was reached. Additional dose-exploration studies may further optimize eptifibatide dosing.

Background: Pharmacodynamics of eptifibatide, a cyclic heptapeptide antagonist of platelet glycoprotein IIb/IIIa, are substantially altered by anticoagulants that chelate calcium, resulting in overestimation ex vivo of the in vivo effects of this agent. We conducted a dose-ranging study to characterize the pharmacodynamics and pharmacokinetics of eptifibatide under physiological conditions., Methods and Results: Patients (n=39) undergoing elective percutaneous coronary intervention were randomly assigned to an eptifibatide bolus followed by an infusion (180-microgram/kg bolus followed by 2 microgram/kg per minute or 250-microgram/kg bolus followed by 3 microgram/kg per minute) for 18 to 24 hours. In a 2:1 ratio, these patients received either a second bolus of eptifibatide (90 microgram/kg or 125 microgram/kg for the initial 180-microgram/kg or 250-microgram/kg groups, respectively) or placebo 30 minutes after the initial bolus. Bleeding times, ex vivo platelet aggregation, receptor occupancy, and plasma eptifibatide levels at baseline and at 1, 2, 3, 4, 6, and 8 hours were evaluated. Platelet inhibition was dose dependent and >80% in all groups by steady state. The single-bolus regimens had a transient loss of inhibition at 1 hour, consistent with rapid distribution and drug elimination. Pharmacokinetic modeling suggested that optimal dosing of eptifibatide would be obtained with a 180-microgram/kg bolus and a 2-microgram/kg per minute infusion followed by a second 180-microgram/kg bolus 10 minutes later., Conclusions: A novel higher-dose, double-bolus regimen of eptifibatide in coronary intervention attains and maintains >90% inhibition of platelet aggregation in >90% of patients, providing the pharmacodynamic construct for the design of the Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy (ESPRIT) trial of adjunctive eptifibatide in coronary stent implantation.

Background: Clinical trials of the glycoprotein (GP) IIb/IIIa inhibitors have shown that these potent antiplatelet agents are effective in reducing the ischemic complications of percutaneous coronary interventions. However, even though stents are now implanted in >75% of percutaneous interventional procedures, only one study, a trial of the monoclonal antibody abciximab, has formally evaluated adjunctive GP IIb/IIIa inhibition in this setting., Methods and Results: Eptifibatide, a nonimmunogenic and rapidly reversible inhibitor of the platelet receptor integrin IIb/IIIa, has also undergone evaluation as an adjunct to coronary intervention. In clinical trials performed heretofore, however, it has appeared to have less relative clinical efficacy than the monoclonal antibody abciximab. Since the early seminal trials, it has been recognized that the doses of eptifibatide previously used achieved only 30% to 50% of maximal platelet GP IIb/IIIa integrin inhibition. This is considerably less than the 80% level of receptor inhibition that has been proposed to prevent coronary thrombus formation in animal models and that has been achieved in clinical trials with abciximab., Conclusions: The Enhanced Suppression of the Platelet IIb/IIIa Receptor with Integrilin Therapy (ESPRIT) trial was designed to test the safety and efficacy of a high-dose, "180/2.0/180" double-bolus regimen of eptifibatide (a 180-microg/kg bolus followed 10 minutes later by a second 180-microg/kg bolus of eptifibatide combined with a 2.0-microg/kg per minute infusion) as an adjunct to nonacute percutaneous coronary intervention with stent implantation. In this report, we review the rationale, design, and methods of this clinical investigation.

Background: The platelet GP IIb/IIIa inhibitor eptifibatide improves outcomes in patients with acute coronary syndromes. Patients requiring emergent coronary artery bypass grafting, however, may be at increased risk for bleeding if exposed to eptifibatide. Data from the PURSUIT trial were reviewed to assess this risk in patients undergoing coronary surgery immediately after exposure to eptifibatide., Methods: In PURSUIT, 10,948 patients who presented with non-ST segment elevation acute coronary syndromes were prospectively randomized to receive eptifibatide (180 microg/kg bolus plus 2 microg/kg/min infusion) or placebo. A total of 78 patients underwent immediate coronary artery bypass surgery within 2 hours of cessation of study drug (placebo, n = 46; eptifibatide, n = 32). Clinical outcome, bleeding, and transfusion requirements within this subset were examined., Results: Major bleeding was not different between groups, occurring in 64% of patients receiving placebo and 63% of patients receiving eptifibatide. The incidence of blood transfusion was similar as well (57% vs 59%). Postoperative thrombocytopenia occurred less often after eptifibatide exposure. Perioperative myocardial infarction was significantly reduced in patients who received eptifibatide (46% vs 22%, p < 0.05). There was no difference in perioperative stroke (2.2% vs 6.3%) or mortality (6.3% vs 6.5%)., Conclusions: Patients may safely undergo coronary artery bypass surgery within 2 hours of discontinuation of eptifibatide. Eptifibatide infusion in the immediate preoperative period had no adverse clinical effects, but did significantly decrease the incidence of perioperative myocardial infarction. Additionally, platelet counts after surgery were higher in the group of patients who received eptifibatide, perhaps indicative of a platelet-sparing effect during cardiopulmonary bypass.

Background: Platelet glycoprotein (GP) IIb/IIIa antagonists prevent the composite end point of death or myocardial infarction (MI) in patients with acute coronary syndromes. There is uncertainty about whether this effect is confined to patients who have percutaneous coronary interventions (PCIs) and whether PCIs further prevent death or MI in patients already treated with GP IIb/IIIa antagonists., Methods and Results: PURSUIT patients were treated with the GP IIb/IIIa antagonist eptifibatide or placebo; PCIs were performed according to physician practices. In 2253 of 9641 patients (23.4%), PCI was performed by 30 days. Early (<72 hours) PCI was performed in 1228 (12.7%). In 34 placebo patients (5.5%) and 10 treated with eptifibatide (1.7%) (P=0.001), MI preceded early PCI. In patients censored for PCI across the 30-day period, there was a significant reduction in the primary composite end point in eptifibatide patients (P=0.035). Eptifibatide reduced 30-day events in patients who had early PCI (11.6% versus 16.7%, P=0.01) and in patients who did not (14.6% versus 15.6%, P=0.23). After adjustment for PCI propensity, there was no evidence that eptifibatide treatment effect differed between patients with or without early PCI (P for interaction=0.634). PCI was not associated with a reduction of the primary composite end point but was associated with a reduced (nonspecified) composite of death or Q-wave MI. This association disappeared after adjustment for propensity for early PCI., Conclusions: Eptifibatide reduced the composite rates of death or MI in PCI patients and those managed conservatively.

Inhibitors of platelet glycoprotein (GP) IIb-IIIa have been demonstrated to be effective in controlling acute cardiac complications in patients presenting with acute ischemic coronary syndromes (AICS). Since patients with atherosclerotic coronary vascular disease may present with AICS on multiple occasions, it is important to have documented evidence that novel antithrombotic agents are nonimmunogenic and thus safe for repeated administration. Eptifibatide (Integrilin) is a cyclic heptapeptide inhibitor that contains a modified lysine-glycine-aspartic acid sequence that recognizes the binding site of platelet GP IIb-IIIa, resulting in potent and selective inhibition of its binding to fibrinogen. An enzyme-linked immunosorbent assay sensitive to all classes of immunoglobulins was developed to test the immunogenicity of eptifibatide in humans. In two clinical studies, Integrilin to Minimize and Prevent Acute Coronary Thrombosis (IMPACT) and IMPACT II, samples were obtained from 414 patients undergoing coronary angioplasty to determine anti-eptifibatide antibodies at baseline and 30 days after treatment. In a separate clinical pharmacology study, 28 healthy volunteers received 2 infusions of eptifibatide 28 days apart and were monitored at baseline (immediately before the first infusion), at 28 days (immediately before the second infusion), and at 42, 56, 84, and 112 days after enrollment to monitor for an anamnestic anti-eptifibatide response. Eptifibatide administration did not result in an antibody response in any of the 3 studies, even after repeated administration. Eptifibatide represents a potent, specific inhibitor of the platelet GP IIb-IIIa complex that has not been observed to be immunogenic in clinical studies and is thus safe for repeated administration. This finding suggests that small, peptide-based therapeutic agents, which are becoming increasingly common, may be used in humans without inciting an immune response.

To investigate the effects of a recombinant endotoxin-binding protein, bactericidal/permeability-increasing protein (rBPI23), on cytokine release and neutrophil activation in endotoxemia in humans, 8 volunteers were challenged twice with endotoxin and concurrently received either rBPI23 or placebo in a randomized, placebo controlled, double-blind crossover study, rBPI23 treatment significantly lowered circulating endotoxin levels (P = .02) and resulted in a significant reduction in the release of tumor necrosis factor (TNF), soluble TNF receptors p55 and p75, interleukin (IL)-6, IL-8 (P < .01 for each), and IL-10 levels (P = .02) but did not prevent the endotoxin-induced rise in body temperature. The early endotoxin-induced leukopenia was blunted (P = .08), and neutrophil degranulation, as measured by circulating levels of elastase/alpha 1-antitrypsin complexes (P = .03) and lactoferrin (P < .01), was largely prevented by rBPI23. The results of this study indicate that rBPI23 is capable of neutralizing many of the biologic effects of endotoxin in humans.

Type-I (insulin-dependent) diabetes mellitus is an immunologically mediated disease that results in destruction of the insulin secreting beta cells of the pancreas. T cells have been implicated in the pathogenesis of this disease. One novel form of anti-T-cell therapy is the immunoconjugate CD5-Plus. This agent is composed of the murine IgG1 monoclonal antibody H65, which is directed toward the CD5+ antigen; and ricin A chain, a ribosomal inhibitor protein. We performed a pilot study to evaluate the safety of the immunoconjugate in subjects with type-I diabetes mellitus. We conducted a dose-escalation study using CD5-Plus given as an intravenous infusion for 5 consecutive days. Fifteen subjects (12 men and 3 women) with a mean age of 26 years, a mean duration of diabetes of 4.8 months, and a minimum stimulated C peptide of 0.3 pmol/mL were entered. Six subjects each were treated at the 0.1 and 0.2 mg/kg/day dosage levels, and three subjects were treated at the 0.33 mg/kg/day dose. Glycemic control was determined monthly by recording the glycohemoglobin, total daily insulin requirements, and fasting blood glucoses. Beta-cell function was measured by determining the C-peptide response to a mixed formula meal (Sustacal) at baseline and at 1,3,6,9, and 12 months after treatment. The area under the curve (AUC) of the C-peptide response was calculated and, to reduce variability, related to that of the same subject at baseline. An analysis of subjects who retained at least 80% of their baseline beta-cell function as measured by the AUC was performed.(ABSTRACT TRUNCATED AT 250 WORDS)

Objective: To evaluate the safety and activity of an immunoconjugate of ricin A chain and anti-CD5 monoclonal antibody (anti-CD5 IC), with and without concomitant methotrexate and/or azathioprine, in the treatment of rheumatoid arthritis (RA)., Methods: Seventy-nine patients with active RA were enrolled in 2 prospective open-label protocols., Results: Using composite criteria, response rates were 50-68% at 1 month and 22-25% at 6 months. Transient depletion of CD3/CD5 T cells was observed on days 2 and 5 of treatment, with reconstitution on day 15 or day 29. Treatment-associated adverse effects were common but resolved rapidly without sequelae., Conclusion: These findings suggest activity of anti-CD5 IC in active RA and warrant confirmation in a multicenter randomized study (currently underway).