ALBERT

Beschreibung: BACKGROUND: Oral DVT prophylaxis not requiring monitoring is an advantage in orthopaedic patients. Dabigatran etexilate is an oral direct thrombin inhibitor undergoing evaluation for the prevention of venous thromboembolic events (VTE) following orthopaedic surgery. METHODS: In a phase III, multicenter, non-inferiority, double-blind study, patients undergoing total knee replacement were randomized to 3 treatments. The patients received 8±2 days of oral dabigatran etexilate, 150 or 220 mg once daily starting with a half dose (i.e.75 or 110 mg) 1–4 hours after surgery, or subcutaneous enoxaparin 40 mg once daily starting 12 hours prior to surgery. The primary efficacy outcome was the composite of total VTE and all causes of mortality during the treatment period. All efficacy and safety outcome events were adjudicated by blinded independent committees. RESULTS: Efficacy could be evaluated for 1541 (75%) treated and operated patients. Total VTE and death occurred in 40.5%, 36.4% and 37.7% of patients assigned to dabigatran etexilate 150 or 220mg once daily or enoxaparin, respectively. Proximal DVT and/or PE occurred in 3.8%, 2.6% and 3.5% of patients receiving dabigatran 150 or 220mg or enoxaparin, respectively. Three deaths occurred during the treatment period, one in each of the treatment groups. Safety was evaluated for all 2076 patients receiving study treatment. The rate of major bleeding was 1.3%, 1.5% and 1.3% of patients receiving dabigatran 150 or 220mg or enoxaparin. Elevated LFTs (ALT 〉3xULN) occurred in 3.7%, 2.8% and 4.0% of the patients treated with 150 and 220 mg dabigatran or enoxaparin during the study. A late temporary rise in LFTs was observed in 6 patients (0.5%) who had received dabigatran. CONCLUSIONS: Non-inferiority for the primary efficacy endpoint was met for both doses of dabigatran etexilate compared to enoxaparin. There was no difference in bleeding rates between the treatment groups. Oral administration of dabigatran etexilate once daily, given early in the postoperative period, was effective and safe for the prevention of total VTE in patients undergoing total knee replacement surgery.

Beschreibung: Abstract 1160 Background: Dabigatran etexilate (DE) 220 mg once daily (qd) was as effective as enoxaparin 40 mg qd in phase III trials for the prevention of venous thromboembolism (VTE) in orthopaedic surgery patients, with a favourable safety profile. Recommendations from the European Medicines Agency state that DE 110 mg should be administered 1–4 hours after surgery and 220 mg thereafter, in patients ≤ 75 years and without moderate renal impairment or concomitant verapamil, amiodarone or quinidine. The aim of this prospective, international, observational, single-arm study was to evaluate the safety and efficacy of DE in a real-world setting, with a particular focus on pre-specified subgroups that may represent an increased risk of bleeding and/or VTE. We report here a prespecified analysis of the results for additional subgroups with different body mass index (BMI), creatinine clearance (CrCL) and age. Methods: Patients were included if aged ≥ 18 years and undergoing elective total hip or knee replacement (THR, TKR). Patients also had to be eligible for DE 220 mg qd according to the European label. The primary safety endpoint was the incidence of major bleeding events (MBEs) as defined in the pivotal clinical trials of DE; the primary efficacy endpoint was documented symptomatic VTE (sVTE) (the composite of symptomatic proximal and distal deep vein thrombosis and symptomatic non-fatal pulmonary embolism) and all-cause mortality. The observation period was from the first dose to 24 hours after the last dose of DE. We examined the incidence of these endpoints stratified by baseline BMI, CrCL and age, all characteristics with potential influence on bleeding and/or efficacy. Results: 5292 patients were included in the study. Median BMI was 28.4 kg/m2. Median CrCL was 95.4 mL/min, with 70.4% of patients having CrCL ≥ 80 mL/min and 26.0% with CrCL 50 to 〈 80 mL/min. Median age was 64 years. A small proportion of patients were treated who had moderate renal impairment (1.1%) or were 〉 75 years old (0.8%); no differences in primary efficacy or safety results were seen in these underpowered groups. The incidence of MBEs for all patients was 0.72% (95% CI: 0.51, 0.98%).Occurrence of MBEs was comparable for subgroups of patients with BMI ≤ 35 kg/m2 and numerically higher for severely obese patients with BMI 〉 35 kg/m2 (1.47%). The rate of MBE was not affected by age 〈 65 or ≥ 65 years. There were no differences for patients with CrCL ≥ 80 or those with CrCL 50 to 〈 80 mL/min. Incidence of sVTE and all-cause mortality in patients treated in the total population was 1.04% (95% CI: 0.78, 1.35%). The rates were comparable in patients stratified according to their BMI, age and CrCL. Overall, the type of surgery, THR or TKR, did not impact on the incidence of MBEs (0.69% [95% CI 0.42%, 1.08%] and 0.74% [95% CI 0.45%, 1.16%], respectively), whereas the composite of sVTE and death was more common in the TKR group (1.56% [95% CI 1.12%, 2.12%]) than the THR group (0.55% [95% CI 0.31%, 0.90%]), as expected. The stratified analysis by surgery type did not show differences in incidence rates of the primary efficacy or safety endpoints across BMI, age or CrCL sugroups. Conclusion: DE 220 mg qd administered to patients undergoing TKR or THR according to the European label showed a favourable safety profile in a real-world clinical setting irrespective of their BMI, renal function and age. Disclosures: Rosencher: BMS (Hemostasis, thrombosis and transfusion): Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim (Hemostasis, thrombosis and transfusion): Membership on an entity's Board of Directors or advisory committees; Pfizer (Hemostasis, thrombosis and transfusion): Membership on an entity's Board of Directors or advisory committees; Sanofi (Hemostasis, thrombosis and transfusion): Membership on an entity's Board of Directors or advisory committees; GSK (Hemostasis, thrombosis and transfusion): Membership on an entity's Board of Directors or advisory committees; Bayer (Hemostasis, thrombosis and transfusion): Membership on an entity's Board of Directors or advisory committees. Frostick:DePuy: Research Funding; Pfizer: Speakers Bureau; Bristol-Myers Squibb: Speakers Bureau; Biomet: Speakers Bureau; Boehringer Ingelheim: Speakers Bureau; DePuy: Consultancy; Boehringer Ingelheim: Consultancy; Biomet: Consultancy; Johnson & Johnson: Research Funding. Feuring:Boehringer Ingelheim (Anticoagulant Therapy): Employment. Kleine:Boehringer Ingelheim (Anticoagulant Therapy): Employment. Brueckmann:Boehringer Ingelheim Pharma GmbH & cO.kg: Employment. Clemens:Boehringer Ingelheim (Anticoagulant Therapy): Employment. Samama:Cordis (product development and education): Honoraria; LFB (anticoagulant therapy): Honoraria; Boehringer Ingelheim (anticoagulant therapy): Honoraria; Bayer (anticoagulant therapy): Honoraria; Biotest (anticoagulant therapy): Honoraria; CSL Behring (anticoagulant therapy): Honoraria; Sanofi-Aventis (anticoagulant therapy): Membership on an entity's Board of Directors or advisory committees; GSK (anticoagulant therapy): Membership on an entity's Board of Directors or advisory committees; Pfizer (anticoagulant therapy): Membership on an entity's Board of Directors or advisory committees; BMS (anticoagulant therapy): Membership on an entity's Board of Directors or advisory committees; Lilly (anticoagulant therapy): Membership on an entity's Board of Directors or advisory committees; Baxter (anticoagulant therapy): Membership on an entity's Board of Directors or advisory committees; Bayer (anticoagulant therapy): Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Curacyte (anticoagulant therapy): Membership on an entity's Board of Directors or advisory committees; Fresenius: Membership on an entity's Board of Directors or advisory committees; LFB (anticoagulant therapy): Primary Investigator, Primary Investigator Other; GSK (anticoagulant therapy): Primary Investigator Other; Sanofi (anticoagulant therapy): Primary Investigator, Primary Investigator Other.

Beschreibung: Abstract 2269 Background: In randomized, double-blind, phase III trials, dabigatran etexilate (DE) 220 mg once daily (qd) was as effective as enoxaparin 40 mg qd in preventing venous thromboembolism (VTE) following total hip or knee replacement (THR, TKR), with a favourable safety profile. As patient populations in clinical practice may differ from those in clinical trials, we conducted an international, observational, single-arm study to evaluate the safety and efficacy of DE in a real-world setting. A prespecified secondary objective was to generate epidemiological data on the incidence of co-morbidities and co-medications in TKR and THR patients treated with DE in a routine clinical setting. We present here these epidemiological results as well as the patient characteristics observed in phase III clinical trials of DE and historical population studies. Methods: Patients were recruited at 110 sites in 9 countries in the European Union. The protocol required that patients were aged ≥ 18 years, undergoing elective THR or TKR and eligible for DE 220 mg qd (first dose 110 mg 1–4 hours after surgery) according to the European label (≤ 75 years old with creatinine clearance [CrCL] 〉 50 mL/min). Baseline data were collected at the screening visit prior to surgery. In the phase III clinical trials of DE, randomization to DE 220 mg qd or 150 mg qd was irrespective of age and renal function. Results: Of the 5292 patients treated in this observational study, 2734 underwent THR and 2558 TKR. Table 1 shows the baseline demographics and medical history and the concomitant use of non-steroidal anti-inflammatory drugs (NSAIDs) and acetylsalicylic acid (ASA). Patients undergoing TKR were more often female and mean BMI was higher than THR patients. With the exception of diabetes, other co-morbidities and co-medications were comparable between TKR and THR patients. Mean CrCL and mean age at baseline were influenced by the inclusion and exclusion criteria for the study and therefore differed from those in the Phase III DE trials (Table 2). Regarding gender, BMI, diabetes and history of VTE, the data from the observational study are generally comparable to those found in other large observational studies (e.g., White, et al. Arch Intern Med. 1998;158:1525–1531; Andersen, et al. Chest. 2003;124:349–356; Warwick, et al. J Bone Joint Surg Br. 2007;89-B:799–807). The incidences of the primary endpoints for efficacy (symptomatic VTE and all-cause mortality) and safety (major bleeding events) in the observational study are reassuring and supportive of the evidence seen in the clinical trials. Conclusions: Demographic characteristics of the patients included in the observational study are broadly aligned with previously published real-world data sets and add detail on co-morbidities. Patients included in this observational study were in general similar to those of the phase III TKR and THR trials of DE but a valid direct comparison between these data should take into account the differences in age and renal function due to study design. Disclosures: Rosencher: Sanofi (haemostasis, thrombosis and transfusion): Membership on an entity's Board of Directors or advisory committees; Pfizer (haemostasis, thrombosis and transfusion): Membership on an entity's Board of Directors or advisory committees; Boehringer Ingelheim (haemostasis, thrombosis and transfusion): Membership on an entity's Board of Directors or advisory committees; BMS (haemostasis, thrombosis and transfusion): Membership on an entity's Board of Directors or advisory committees; Bayer (haemostasis, thrombosis and transfusion): Membership on an entity's Board of Directors or advisory committees; GSK (haemostasis, thrombosis and transfusion): Membership on an entity's Board of Directors or advisory committees. Frostick:Pfizer (anticoagulant therapy): Speakers Bureau; Bristol-Myers Squibb (anticoagulant therapy): Speakers Bureau; Biomet (product development and education): Speakers Bureau; Boehringer Ingelheim (anticoagulant therapy): Speakers Bureau; DePuy (product development and education): Consultancy; Boehringer Ingelheim (anticoagulant therapy): Consultancy; Biomet (product development and education): Consultancy; DePuy (product development and education): Research Funding; Johnson & Johnson (anticoagulant therapy): Research Funding. Feuring:Boehringer Ingelheim (anticoagulant therapy): Employment. Kleine:Boehringer Ingelheim (anticoagulant therapy): Employment. Brueckmann:Boehringer Ingelheim (anticoagulant therapy): Employment. Clemens:Boehringer Ingelheim (anticoagulant therapy): Employment. Samama:GSK (anticoagulant therapy): Primary Investigator Other; LFB (anticoagulant therapy): Primary Investigator, Primary Investigator Other; Fresenius: Membership on an entity's Board of Directors or advisory committees; Curacyte (anticoagulant therapy): Membership on an entity's Board of Directors or advisory committees; Bayer (anticoagulant therapy): Membership on an entity's Board of Directors or advisory committees; Baxter (anticoagulant therapy): Membership on an entity's Board of Directors or advisory committees; Lilly (anticoagulant therapy): Membership on an entity's Board of Directors or advisory committees; BMS (anticoagulant therapy): Membership on an entity's Board of Directors or advisory committees; Pfizer (anticoagulant therapy): Membership on an entity's Board of Directors or advisory committees; GSK (anticoagulant therapy): Membership on an entity's Board of Directors or advisory committees; Sanofi-Aventis (anticoagulant therapy): Membership on an entity's Board of Directors or advisory committees; CSL Behring (anticoagulant therapy): Honoraria; Biotest (anticoagulant therapy): Honoraria; Bayer (anticoagulant therapy): Honoraria; Boehringer Ingelheim (anticoagulant therapy): Honoraria; LFB (anticoagulant therapy): Honoraria; Cordis (product development and education): Honoraria; Sanofi (anticoagulant therapy): Primary Investigator, Primary Investigator Other.

Beschreibung: This study assesses the impact of a decrease in air quality and the risk of hospital admissions to a public hospital for chronic respiratory diseases for residents of Petaling Jaya, a city in the Greater Kuala Lumpur area in Malaysia. Data on hospital admissions for asthma, bronchitis, emphysema and other chronic obstructive pulmonary disease, weather conditions and the Malaysian Air Pollution Index, a composite indicator of air quality, were collated. An unconstrained distributed lag model to obtain risk of hospitalization for a 10 μg/m3 increase in the API. The lag cumulative effect for a 10 μg/m3 increase in the API was calculated to test for harvesting in the short term. Findings indicate that after an initial decrease in admissions (days 3 and 4), admissions increased again at day 7 and 8 and this relationship was significant. We therefore conclude that a 10 μg/m3 increase has a greater effect on admissions for respiratory health in the short term than a harvesting effect alone would suggest. These results suggest that while air quality is improving in the Greater Kuala Lumpur area, no level of air pollution can be deemed safe.

Beschreibung: Background Type 2 diabetes mellitus (T2DM) had been reported to be associated with tendinopathy. However, the underlying mechanisms of diabetic tendinopathy still remain largely to be discovered. The purpose of this study was to develop insulin resistance (IR) model on primary human tenocytes (hTeno) culture with tumour necrosis factor-alpha (TNF-α) treatment to study tenocytes homeostasis as an implication for diabetic tendinopathy. Methods hTenowere isolated from human hamstring tendon. Presence of insulin receptor beta (INSR-β) on normal tendon tissues and the hTeno monolayer culture were analyzed by immunofluorescence staining. The presence of Glucose Transporter Type 1 (GLUT1) and Glucose Transporter Type 4 (GLUT4) on the hTeno monolayer culture were also analyzed by immunofluorescence staining. Primary hTeno were treated with 0.008, 0.08, 0.8 and 8.0 µM of TNF-α, with and without insulin supplement. Outcome measures include 2-[N-(7-nitrobenz-2-oxa-1,3-diazol-4-yl) amino]-2-deoxy-d-glucose (2-NBDG) assay to determine the glucose uptake activity; colourimetric total collagen assay to quantify the total collagen expression levels; COL-I ELISA assay to measure the COL-I expression levels and real-time qPCR to analyze the mRNA gene expressions levels of Scleraxis (SCX), Mohawk (MKX), type I collagen (COL1A1), type III collagen (COL3A1), matrix metalloproteinases (MMP)-9 and MMP-13 in hTeno when treated with TNF-α. Apoptosis assay for hTeno induced with TNF-α was conducted using Annexin-V FITC flow cytometry analysis. Results Immunofluorescence imaging showed the presence of INSR-β on the hTeno in the human Achilles tendon tissues and in the hTeno in monolayer culture. GLUT1 and GLUT4 were both positively expressed in the hTeno. TNF-α significantly reduced the insulin-mediated 2-NBDG uptake in all the tested concentrations, especially at 0.008 µM. Total collagen expression levels and COL-I expression levels in hTeno were also significantly reduced in hTeno treated with 0.008 µM of TNF-α. The SCX, MKX and COL1A1 mRNA expression levels were significantly downregulated in all TNF-α treated hTeno, whereas the COL3A1, MMP-9 and MMP-13 were significantly upregulated in the TNF–α treated cells. TNF-α progressively increased the apoptotic cells at 48 and 72 h. Conclusion At0.008 µM of TNF-α, an IR condition was induced in hTeno, supported with the significant reduction in glucose uptake, as well as significantly reduced total collagen, specifically COL-I expression levels, downregulation of candidate tenogenic markers genes (SCX and MKX), and upregulation of ECM catabolic genes (MMP-9 and MMP-13). Development of novel IR model in hTeno provides an insight on how tendon homeostasis could be affected and can be used as a tool for further discovering the effects on downstream molecular pathways, as the implication for diabetic tendinopathy.

Beschreibung: In exercising muscle, creatine kinase ensures that mismatch between ATP supply and ATP use results in net phosphocreatine (PCr) splitting. This,inter alia, makes31P magnetic resonance spectroscopy a useful tool for studying muscle ‘energy metabolism’ noninvasivelyin vivo. We combined this with near–infrared spectroscopy (NIRS) to study ATP synthesis and oxygenation in calf muscle of normal subjects and patients with peripheral vascular disease. Experimental and clinical details and basic data have been published elsewhere (G.J. Kemp et al.,Journal of Vascular Surgery34 (2001), 1103–10); we here propose an analysis of interactions between metabolic ‘error signals’ and cellular PO2(estimated from NIRS changes, provisionally assumed to reflect deoxymyoglobin). Post–exercise PCr recovery is monoexponential, and the linear relationship between PCr resynthesis rate (= oxidative ATP synthesis) and the perturbation in PCr (conceptually the simplest error signal) is consistent with negative feedback. In patients the inferred ‘mitochondrial capacity’ (= oxidative ATP synthesis at ‘zero’ PCr) is decreased by 53±6%, leading to reduced oxidative ATP contribution in exercise, because of increased deoxygenation. Increased PCr perturbation partially outweighs cellular hypoxia, but as low cellular PO2is required for capillary–mitochondrion O2diffusion, rate–signal relationships may overstate maximum oxidative ATP synthesis rate.