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Background: Blinding is a fundamental design strengthening feature in randomized clinical trials. Blinding is particularly important in trials whose outcome measures include subjective assessment of signs and symptoms, such as trials investigating the post-thrombotic syndrome, a frequent chronic complication of deep vein thrombosis., Purpose: To determine whether strategies used to blind site investigators, research coordinators and patients were successful in a specific device trial, a multicenter trial of active versus placebo elastic compression stockings worn for 2 years to prevent post-thrombotic syndrome in patients with a first deep vein thrombosis (the SOX Trial)., Methods: Patients were randomized to the active or placebo stocking intervention, which were indistinguishable in appearance at baseline. Replacement stockings were shipped directly to patients' homes and were not worn to any of the study visits during the study. Guesstimates of treatment group assignment were completed by site investigators, research coordinators and patients at the end of study follow-up. Statistical assessments of blinding were performed using the James and Bang blinding indices., Results: Overall rates of correct responses were 10.4% for site investigators, 17.8% for research coordinators and 29.4% for patients. James blinding index values suggest that blinding was achieved for site investigators, research coordinators and patients. The treatment specific Bang blinding index values suggest that blinding was achieved for site investigators and research coordinators, but detected possible unblinding and opposite guess for patients in the active and placebo elastic compression stocking groups, respectively., Limitations: Post-study assessment of blinding, as was done for the SOX Trial, cannot distinguish between degree of blinding and hunches about an intervention's efficacy. However, as rates of post-thrombotic syndrome along with adverse events in the SOX Trial were similar between treatment groups, it is unlikely that hunches would have interfered with our end-of-trial assessment for blinding., Conclusion: Blinding strategies used in our trial were successful overall and appeared to be most effective for site investigators and research coordinators. For patients, there may have been some degree of unblinding in the active stocking group. However, as the trial results were negative with active elastic compression stocking showing no benefit over placebo elastic compression stocking, this potential unblinding has minimal impact on the overall conclusions of the trial., (© The Author(s) 2014.)

In this article, we provide the rationale for the ELOPE (Evaluation of Long-term Outcomes after Pulmonary Embolism) Study, a prospective, observational, multicenter cohort study of patients with a newly diagnosed, first episode of pulmonary embolism (www.clinicaltrials.govNCT01174628) that aims to identify clinical, anatomic, physiologic and biomarker determinants of poor outcome after pulmonary embolism.Pulmonary embolism, the most serious form of venous thromboembolism (VTE), leads to the hospitalization or death of over 30,000 Canadians, 225,000 Americans and 300,000 Europeans each year, numbers that have risen over the past decade. Although numerous studies have evaluated optimal approaches to the diagnosis and treatment of pulmonary embolism, their focus has primarily been on short-term outcomes such as mortality and recurrent VTE in the days, weeks or months after pulmonary embolism diagnosis. However, it is increasingly recognized that pulmonary embolism may have long-lasting sequelae that impact on patients' health. The objective of this article was to review the available evidence on long-term clinical, functional, anatomic and physiologic outcomes after pulmonary embolism, and discuss avenues for research in this field, including the ELOPE Study. Residual pulmonary vascular abnormalities on follow-up imaging and echocardiogram are frequent in pulmonary embolism patients, but the clinical significance of these abnormalities is poorly understood. Whether initial and/or residual clot burden, recurrent pulmonary embolism, altered pulmonary artery or right ventricular hemodynamics or other prognostic factors such as biomarker levels contribute to long-term morbidity after pulmonary embolism is as yet unknown. The ELOPE Study will describe and identify the predictors of long-term outcomes after pulmonary embolism in the setting of a rigorous, multicenter cohort study in which long-term clinical, anatomic, physiologic and functional sequelae such as quality of life, return to work and loss of productivity after pulmonary embolism are systematically evaluated.

Background: Post-thrombotic syndrome (PTS) is a common and burdensome complication of deep venous thrombosis (DVT). Previous trials suggesting benefit of elastic compression stockings (ECS) to prevent PTS were small, single-centre studies without placebo control. We aimed to assess the efficacy of ECS, compared with placebo stockings, for the prevention of PTS., Methods: We did a multicentre randomised placebo-controlled trial of active versus placebo ECS used for 2 years to prevent PTS after a first proximal DVT in centres in Canada and the USA. Patients were randomly assigned to study groups with a web-based randomisation system. Patients presenting with a first symptomatic, proximal DVT were potentially eligible to participate. They were excluded if the use of compression stockings was contraindicated, they had an expected lifespan of less than 6 months, geographical inaccessibility precluded return for follow-up visits, they were unable to apply stockings, or they received thrombolytic therapy for the initial treatment of acute DVT. The primary outcome was PTS diagnosed at 6 months or later using Ginsberg's criteria (leg pain and swelling of ≥1 month duration). We used a modified intention to treat Cox regression analysis, supplemented by a prespecified per-protocol analysis of patients who reported frequent use of their allocated treatment. This study is registered with ClinicalTrials.gov, number NCT00143598, and Current Controlled Trials, number ISRCTN71334751., Findings: From 2004 to 2010, 410 patients were randomly assigned to receive active ECS and 396 placebo ECS. The cumulative incidence of PTS was 14·2% in active ECS versus 12·7% in placebo ECS (hazard ratio adjusted for centre 1·13, 95% CI 0·73-1·76; p=0·58). Results were similar in a prespecified per-protocol analysis of patients who reported frequent use of stockings., Interpretation: ECS did not prevent PTS after a first proximal DVT, hence our findings do not support routine wearing of ECS after DVT., Funding: Canadian Institutes of Health Research., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: The relationship between plant sterol (PS) absorption and circulatory concentrations with cholesterol absorption and biosynthesis during PS consumption has yet to be clearly elucidated in humans. It is therefore essential to examine campesterol, β-sitosterol, and cholesterol absorption and cholesterol fractional synthesis rate (FSR) following PS consumption in individuals with high versus low basal circulatory PS concentrations., Design: A randomized, crossover trial was conducted in 82 hypercholesterolemic men consuming spreads with or without 2 g/d of PS for two 4-week periods, each separated by a 4-week washout. Endpoint tracer enrichments after ingestion of (2)H-labeled campesterol or β-sitosterol and (13)C-labeled cholesterol were determined by isotope ratio mass spectrometry., Results: For both phases of dietary intervention, the endpoint cholesterol absorption index was positively correlated with campesterol (r = 0.5864, p < 0.0001) and β-sitosterol (r = 0.4676, p < 0.0001) absorption indices; inversely, endpoint cholesterol FSR correlated negatively with the absorption indices of campesterol (r = -0.5004, p < 0.0009), β-sitosterol (r = -0.4154, p < 0.05), and cholesterol (r = -0.4056, p < 0.0001). PS intervention reduced absorption indices of campesterol, β-sitosterol, and cholesterol by 36.5% ± 2.7%, 39.3% ± 2.9%, and 34.3% ± 1.9%, respectively, but increased cholesterol FSR by 33.0% ± 3.3% relative to control. Endpoint circulatory PS levels (cholesterol adjusted) were positively associated with endpoint absorption indices of campesterol (r = 0.5586, p < 0.0001, for placebo; r = 0.6530, p < 0.0001, for PS intake) and cholesterol (r = 0.3683, p < 0.001 for placebo; r = 0.3469, p < 0.002, for PS intake) and were negatively associated with cholesterol FSR (r = -0.3551, p < 0.002, for placebo; r = -0.3643, p < 0.001, for PS intake). The cholesterol-lowering effect of PS was most pronounced among individuals falling within the 50th-75th percentiles of basal PS concentrations., Conclusion: These data suggest that basal PS concentrations indicate not only sterol absorption efficiency but also the extent of PS-induced cholesterol reduction and thus might be clinically useful to predict the extent of cholesterol response to PS intervention within a given individual.

Background: Exercise training may have the potential to improve post-thrombotic syndrome, a frequent, chronic complication of deep venous thrombosis. We conducted a randomized controlled two-centre pilot trial to assess the feasibility of a multicentre-based evaluation of a six-month exercise training program to treat post-thrombotic syndrome and to obtain preliminary data on the effectiveness of such a program., Methods: Patients were randomized to receive exercise training (a six-month trainer-supervised program) or control treatment (an education session with monthly phone follow-ups). Levels of eligibility, consent, adherence and retention were used as indicators of study feasibility. Primary outcomes were change from baseline to six months in venous disease-specific quality of life (as measured using the Venous Insufficiency Epidemiological and Economic Study Quality of Life [VEINES-QOL] questionnaire) and severity of post-thrombotic syndrome (as measured by scores on the Villalta scale) in the exercise training group versus the control group, assessed by t tests. Secondary outcomes were change in generic quality of life (as measured using the Short-Form Health Survey-36 [SF-36] questionnaire), category of severity of post-thrombotic syndrome, leg strength, leg flexibility and time on treadmill., Results: Of 95 patients with post-thrombotic syndrome, 69 were eligible, 43 consented and were randomized, and 39 completed the study. Exercise training was associated with improvement in VEINES-QOL scores (exercise training mean change 6.0, standard deviation [SD] 5.1 v. control mean change 1.4, SD 7.2; difference 4.6, 95% CI 0.54 to 8.7; p = 0.027) and improvement in scores on the Villalta scale (exercise training mean change -3.6, SD 3.7 v. control mean change -1.6, SD 4.3; difference -2.0, 95% CI -4.6 to 0.6; p = 0.14). Most secondary outcomes also showed greater improvement in the exercise training group., Interpretation: Exercise training may improve post-thrombotic syndrome. It would be feasible to definitively evaluate exercise training as a treatment for post-thrombotic syndrome in a large multicentre trial.

ATP-binding cassette hetero-dimeric transporters G5 and G8 (ABCG5/G8) have been postulated to mediate intestinal cholesterol efflux, whereas Niemann-Pick C1 Like 1 (NPC1L1) protein is believed to be essential for intestinal cholesterol influx. The individual or combined genetic markers, such as single nuclear polymorphisms (SNPs), of these two transporter genes may explain inter-individual variations in plasma cholesterol response following plant sterol (PS) intervention. The present study was aimed at investigating the association between ABCG5/G8 and NPC1L1 genotype SNPs with sterol absorption and corresponding plasma concentrations. The study used a 4-week crossover design with 82 hypercholesterolemic men characterized by high vs. low basal plasma PS concentrations consuming spreads with or without 2 g/day of PS. For the ABCG8 1289 C > A (T400 K) polymorphism, the A allele carriers with high basal plasma PS concentrations demonstrated a 3.9-fold greater reduction (p < 0.05) in serum low density lipoprotein cholesterol (LDL-C) than their low basal plasma PS counterparts. For the NPC1L1 haplotype of 872 C > G (L272L) and 3929 G > A (Y1291Y), individuals carrying mutant alleles showed a 2.4-fold greater (p < 0.05) reduction in LDL-C levels, compared to wild type counterparts. Results suggest that genetic and metabolic biomarkers together may predict inter-individual lipid level responsiveness to PS-intervention, and thus could be useful in devising individualized cholesterol lowering strategies.

Plant sterols combined with exercise beneficially alter lipid profiles in hypercholesterolemic adults. Although the mechanism by which plant sterols favorably modulate lipid levels is well established, no trial to date has examined the effect of exercise, alone or combined with plant sterols, on cholesterol kinetics. Thus, the current objective was to examine the effects of exercise, plant sterols, and the combination of exercise and plant sterols on cholesterol absorption and synthesis. In an 8-week, parallel-arm trial, 84 subjects were randomized to 1 of 4 interventions: plant sterols combined with exercise, plant sterols, exercise, or control. Diets were not controlled. Total cholesterol and triglyceride levels decreased (P<0.01) by 7.7% and 11.8%, respectively, whereas high-density lipoprotein (HDL) cholesterol levels increased (P<0.01) by 7.5% in the combination group. Mean posttreatment low-density lipoprotein (LDL) cholesterol levels decreased (P<0.01) by 0.30 mmol/L in the combination group. Cholesterol absorption was 16% lower (P<0.01) in the combination group and 18% lower (P<0.01) in the plant sterol group, when compared with control. Exercise had no effect on cholesterol absorption. Nonsignificant increases in cholesterol synthesis rates of 63% (0.084+/-0.014 pools/day), 59% (0.075+/-0.013 pools/day), and 57% (0.072+/-0.011 pools/day) were observed in the combination, exercise, and plant sterol groups, respectively, relative to the control group (0.031+/-0.019 pools/day). LDL cholesterol levels correlated with cholesterol absorption, as represented by the area under the deuterium enrichment curve (r=0.23, P=0.05), and with percent absorption relative to control (r=0.25, P=0.03). These findings suggest that exercise does not modulate lipid levels by altering to cholesterol absorption or synthesis, whereas plant sterols favorably alter levels of LDL cholesterol by suppressing intestinal absorption.