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1.
N Engl J Med ; 382(20): 1916-1925, 2020 05 14.
Article in English | MEDLINE | ID: mdl-32223113

ABSTRACT

BACKGROUND: Nonmajor orthopedic surgery of the lower limbs that results in transient reduced mobility places patients at risk for venous thromboembolism. Rivaroxaban may be noninferior to enoxaparin with regard to the prevention of major venous thromboembolism in these patients. METHODS: In this international, parallel-group, randomized, double-blind, noninferiority trial, we randomly assigned adult patients undergoing lower-limb nonmajor orthopedic surgery who were considered to be at risk for venous thromboembolism on the basis of the investigator's judgment to receive either rivaroxaban or enoxaparin. The primary efficacy outcome of major venous thromboembolism was a composite of symptomatic distal or proximal deep-vein thrombosis, pulmonary embolism, or venous thromboembolism-related death during the treatment period or asymptomatic proximal deep-vein thrombosis at the end of treatment. A test for superiority was planned if rivaroxaban proved to be noninferior to enoxaparin. For all outcomes, multiple imputation was used to account for missing data. Prespecified safety outcomes included major bleeding (fatal, critical, or clinically overt bleeding or bleeding at the surgical site leading to intervention) and nonmajor clinically relevant bleeding. RESULTS: A total of 3604 patients underwent randomization; 1809 patients were assigned to receive rivaroxaban, and 1795 to receive enoxaparin. Major venous thromboembolism occurred in 4 of 1661 patients (0.2%) in the rivaroxaban group and in 18 of 1640 patients (1.1%) in the enoxaparin group (risk ratio with multiple imputation, 0.25; 95% confidence interval, 0.09 to 0.75; P<0.001 for noninferiority; P = 0.01 for superiority). The incidence of bleeding did not differ significantly between the rivaroxaban group and the enoxaparin group (1.1% and 1.0%, respectively, for major bleeding or nonmajor clinically relevant bleeding; 0.6% and 0.7%, respectively, for major bleeding). CONCLUSIONS: Rivaroxaban was more effective than enoxaparin in the prevention of venous thromboembolic events during a period of immobilization after nonmajor orthopedic surgery of the lower limbs. (Funded by Centre Hospitalier Universitaire de Saint-Etienne and Bayer; PRONOMOS ClinicalTrials.gov number, NCT02401594.).


Subject(s)
Anticoagulants/therapeutic use , Enoxaparin/therapeutic use , Lower Extremity/surgery , Orthopedic Procedures , Postoperative Complications/prevention & control , Rivaroxaban/therapeutic use , Venous Thromboembolism/prevention & control , Administration, Oral , Adult , Anticoagulants/adverse effects , Double-Blind Method , Enoxaparin/adverse effects , Female , Hemorrhage/chemically induced , Humans , Injections, Subcutaneous , Male , Middle Aged , Pulmonary Embolism/prevention & control , Rivaroxaban/adverse effects , Venous Thromboembolism/mortality , Venous Thrombosis/prevention & control
2.
Br J Clin Pharmacol ; 80(5): 1010-20, 2015 Nov.
Article in English | MEDLINE | ID: mdl-26147763

ABSTRACT

AIMS: The aim was to evaluate the comprehension of participants of an improved informed consent document (ICD). METHOD: This was a randomized controlled French multicentre study performed in real conditions. Participants were adult patients undergoing screening for enrolment in biomedical research studies, who agreed to answer a validated questionnaire evaluating objective and subjective comprehension scored from 0 (no comprehension) to 100 (excellent comprehension). Patients were provided either the original ICD or an ICD modified in terms of structure and readability. The primary end point was the score of objective comprehension. The secondary end-points were the enrolment rate in the clinical study and patient characteristics associated with the score of objective comprehension. RESULTS: Four hundred and eighty-one patients were included, 241 patients in the original ICD group and 240 patients in the modified ICD group. There was no difference between the two groups for the score of objective comprehension (original ICD 72.7 (95% CI 71.3, 74.1) vs. modified ICD 72.5 (95% CI 71.0, 74.0); P = 0.81). However, the rate of enrolment in the clinical study was lower in the group who received the modified ICD (64.4% (95% CI 58.3, 70.5)) than for the original ICD (73.0% (95% CI 67.4, 78.7)) (P = 0.042). Only female gender and high educational level were associated with a better objective comprehension. CONCLUSIONS: Improving ICDs had no effect on participants' understanding, whereas the rate of enrolment was lower in this group. In attempts at improving potential participants' understanding of clinical research information, efforts and future trials should focus on other ways to improve comprehension.


Subject(s)
Biomedical Research/methods , Comprehension , Consent Forms/standards , Informed Consent/psychology , Research Subjects/psychology , Research Subjects/statistics & numerical data , Female , Humans , Male , Middle Aged , Patient Selection
3.
Thromb Haemost ; 107(6): 1151-60, 2012 Jun.
Article in English | MEDLINE | ID: mdl-22476471

ABSTRACT

Despite the need for effective and safe thromboprophylactic drugs for patients with renal impairment, clinical trial data on anticoagulant agents are limited in this population. The study aim was to assess in the real-world setting the use of the once-daily 1.5 mg reduced dosage regimen of fondaparinux available for this context. In this prospective cohort study, patients with a creatinine clearance (CrCl) of 20-50 ml/minute, undergoing total hip (THR) or knee (TKR) replacement or hip fracture surgery (HFS) received fondaparinux thromboprophylaxis. Main clinical outcomes were bleeding (major/clinically relevant non-major), symptomatic venous thromboembolism (VTE) and death. Overall, 442 patients (353 women; median age: 82 years; 39.4% in ASA class ≥3; mean ± SD CrCl: 39.0 ± 8.0 ml/minute; 78% with additional risk factors for bleeding), undergoing THR (43.7%), TKR (27.6%), or HFS (28.7%) received fondaparinux 1.5 mg for a mean ± SD duration of 16.0 ± 12.5 days. At postoperative day 10, the rates (95% confidence interval) of major bleeding, clinically relevant bleeding and symptomatic VTE were 4.5% (2.8-6.9), 0.5% (0.1-1.6) and 0.5% (0.05-1.62), respectively; no fatal bleeding, bleeding into a critical organ, pulmonary embolism or proximal deep-vein thrombosis occurred. Corresponding rates at one month were 5.2%, 0.7% and 0.7%. One-month mortality was 2.3% (0.9-3.6). This large clinical prospective study provides for the first time, under conditions reflecting "real-world" routine clinical practice, data on the bleeding and VTE risks of thromboprophylaxis with fondaparinux 1.5 mg after major orthopaedic surgery in renally impaired patients. It shows that these patients constitute a very elderly and fragile population.


Subject(s)
Anticoagulants/administration & dosage , Kidney/physiopathology , Orthopedic Procedures/adverse effects , Polysaccharides/administration & dosage , Renal Insufficiency/complications , Venous Thromboembolism/prevention & control , Age Factors , Aged , Aged, 80 and over , Anticoagulants/adverse effects , Arthroplasty, Replacement, Hip/adverse effects , Arthroplasty, Replacement, Knee/adverse effects , Biomarkers/blood , Creatinine/blood , Female , Fondaparinux , Fracture Fixation/adverse effects , France , Hemorrhage/chemically induced , Hip Fractures/complications , Hip Fractures/surgery , Humans , Kidney/metabolism , Logistic Models , Male , Middle Aged , Multivariate Analysis , Orthopedic Procedures/mortality , Polysaccharides/adverse effects , Prospective Studies , Renal Insufficiency/blood , Renal Insufficiency/mortality , Renal Insufficiency/physiopathology , Risk Assessment , Risk Factors , Time Factors , Treatment Outcome , Venous Thromboembolism/etiology , Venous Thromboembolism/mortality
4.
Thromb Haemost ; 104(2): 252-60, 2010 Aug.
Article in English | MEDLINE | ID: mdl-20539905

ABSTRACT

Fondaparinux is a synthetic antithrombotic agent with specific anti-factor Xa activity. A population pharmacokinetic model of fondaparinux, based on data obtained in patients included in phase II/III trials, has been described. However, the validity of this model in everyday practice needed to be confirmed. This study was a multicenter, prospective cohort study in consecutive orthopaedic patients treated with 2.5 mg of fondaparinux. Anti-Xa activities were recorded in 809 patients. Population parameters and inter-individual variability were estimated using NONMEM VI software. A two-compartment model with first-order absorption best described fondaparinux pharmacokinetics. Covariates partly explaining inter-individual variability were body weight, age and creatinine clearance estimated by the simplified Modification of Diet in Renal Disease formula (MDRD). A body weight less than 50 kg and moderate renal failure increased drug exposure. Although the population pharmacokinetic model of fondaparinux was described, this one requires to be validated in everyday practice.


Subject(s)
Anticoagulants/pharmacokinetics , Computer Simulation , Factor Xa Inhibitors , Fibrinolytic Agents/pharmacokinetics , Models, Biological , Orthopedic Procedures , Polysaccharides/pharmacokinetics , Venous Thromboembolism/prevention & control , Adult , Age Factors , Aged , Aged, 80 and over , Anticoagulants/administration & dosage , Anticoagulants/adverse effects , Body Weight , Creatinine/metabolism , Female , Fibrinolytic Agents/administration & dosage , Fibrinolytic Agents/adverse effects , Fondaparinux , France , Hemorrhage/chemically induced , Humans , Kidney/metabolism , Kidney/physiopathology , Male , Middle Aged , Nonlinear Dynamics , Orthopedic Procedures/adverse effects , Polysaccharides/administration & dosage , Polysaccharides/adverse effects , Prospective Studies , Reproducibility of Results , Treatment Outcome , Venous Thromboembolism/blood , Venous Thromboembolism/etiology , Young Adult
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