Objective: We here aimed to characterize changes of Matrix Gla Protein (MGP) expression in relation to its recently identified OA risk allele rs1800801-T in OA cartilage, subchondral bone and human... Show moreObjective: We here aimed to characterize changes of Matrix Gla Protein (MGP) expression in relation to its recently identified OA risk allele rs1800801-T in OA cartilage, subchondral bone and human ex vivo osteochondral explants subjected to OA related stimuli. Given that MGP function depends on vitamin K bioavailability, we studied the effect of frequently prescribed vitamin K antagonist warfarin. Methods: Differential (allelic) mRNA expression of MGP was analyzed using RNA-sequencing data of human OA cartilage and subchondral bone. Human osteochondral explants were used to study exposures to interleukin one beta (IL-1b; inflammation), triiodothyronine (T3; Hypertrophy), warfarin, or 65% mechanical stress (65%MS) as function of rs1800801 genotypes. Results: We confirmed that the MGP risk allele rs1800801-T was associated with lower expression and that MGP was significantly upregulated in lesioned as compared to preserved OA tissues, mainly in risk allele carriers, in both cartilage and subchondral bone. Moreover, MGP expression was downregulated in response to OA like triggers in cartilage and subchondral bone and this effect might be reduced in carriers of the rs1800801-T risk allele. Finally, warfarin treatment in cartilage increased COL10A1 and reduced SOX9 and MMP3 expression and in subchondral bone reduced COL1A1 and POSTN expression. Discussion & conclusions: Our data highlights that the genetic risk allele lowers MGP expression and upon OA relevant triggers may hamper adequate dynamic changes in MGP expression, mainly in carti-lage. The determined direct negative effect of warfarin on human explant cultures functionally un-derscores the previously found association between vitamin K deficiency and OA. (c) 2021 The Authors. Published by Elsevier Ltd on behalf of Osteoarthritis Research Society International. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/). Show less
Background: In patients with active cancer and atrial fibrillation (AF) anticoagulation, thrombotic and bleeding risk still entail uncertainty.Aim: We explored the results of an international... Show moreBackground: In patients with active cancer and atrial fibrillation (AF) anticoagulation, thrombotic and bleeding risk still entail uncertainty.Aim: We explored the results of an international survey examining the knowledge and behaviours of a large group of physicians.Methods and results: A web-based survey was completed by 960 physicians (82.4% cardiologists, 75.5% from Europe). Among the currently available anticoagulants for stroke prevention in patients with active cancer, direct oral anticoagulants (DOACs) were preferred by 62.6%, with lower values for low molecular weight heparin (LMWH) (24.1%) and for warfarin (only 7.3%). About 46% of respondents considered that DOACs should be used in all types of cancers except in non-operable gastrointestinal cancers. The lack of controlled studies on bleeding risk (33.5% of respondents) and the risk of drug interactions (31.5%) were perceived as problematic issues associated with use of anticoagulants in cancer. The decision on anticoagulation involved a cardiologist in 27.8% of cases, a cardiologist and an oncologist in 41.1%, and a team approach in 21.6%. The patient also was involved in decision-making, according to similar to 60% of the respondents. For risk stratification, use of CHA2DS2-VASc and HAS-BLED scores was considered appropriate, although not specifically validated in cancer patients, by 66.7% and 56.4%, respectively.Conclusion: This survey highlights that management of anticoagulation in patients with AF and active cancer is challenging, with substantial heterogeneity in therapeutic choices. Direct oral anticoagulants seems having an emerging role but still the use of LMWH remains substantial, despite the absence of long-term data on thromboprophylaxis in AF. Show less
Background: Patients on prehospital anticoagulation with warfarin or direct oral anticoagulants (DOACs) represent a vulnerable subset of the trauma population. While protocolized warfarin reversal... Show moreBackground: Patients on prehospital anticoagulation with warfarin or direct oral anticoagulants (DOACs) represent a vulnerable subset of the trauma population. While protocolized warfarin reversal is widely available and easily implemented, prehospital anticoagulation with DOAC is cost prohibitive with only a few reversal options. This study aims to compare hospital outcomes of non-head injured trauma patients taking pre-injury DOAC versus warfarin.Methods: A retrospective cohort study at a level 1 trauma center was performed. All adult trauma patients with pre-injury anticoagulation admitted between January 2015 and December 2018, were stratified into DOAC-using and warfarin-using groups. Patients were excluded if they had traumatic brain injury (TBI). Univariate and multivariable analyses were performed. Outcomes measures included inhospital mortality, blood transfusion requirements, ICU length of stay (LOS), hospital LOS and discharge disposition.Results: 374 non-TBI trauma patients on anticoagulation were identified, of which 134 were on DOACs and 240 on warfarin. Patients on DOACs had a higher ISS (9 [IQR, 9-10] vs. 9 [IQR, 5-9]; p<0.001), and lower admission INR values (1.2 [IQR, 1.1-1.3] vs 2.4 [IQR, 1.8-2.7]; p<0.001) than warfarin users. Use of reversal agents was higher in warfarin users (p< 0.001). Relative to warfarin, DOAC users did not differ significantly with respect to hospital mortality (OR 0.47, 95% CI [0.13-1.73]). Multivariable analysis (not possible for mortality) did not show significant difference for RBC transfusion requirements (OR 0.92 [0.51-1.67]), ICU LOS (OR 1.08 [0.53-2.19]), hospital LOS (OR 1.10 [0.70-1.74]) or discharge disposition (OR 0.56 [0.29-1.11]) between the groups.Conclusion: Despite lower reversal rates and higher ISS, non-TBI trauma patients with pre-injury DOAC use had similar outcomes as patients on pre-injury warfarin. There may be equipoise to have larger, prospective studies evaluating the comparative safety of DOACs and warfarin in the population prone to low energy fall type injuries. (C) 2020 Elsevier Ltd. All rights reserved. Show less
Purpose To study whether polypharmacy or drug-drug interactions have differential effect on safety and efficacy in patients treated with direct oral anticoagulants (DOACs) versus warfarin.Methods... Show morePurpose To study whether polypharmacy or drug-drug interactions have differential effect on safety and efficacy in patients treated with direct oral anticoagulants (DOACs) versus warfarin.Methods We performed a systematic review and meta-analysis of studies that randomized patients with atrial fibrillation to DOACs or warfarin stratified by the number of concomitant drugs. Outcomes included stroke or systemic embolism (SE), all-cause mortality, major bleeding, and intracranial hemorrhage. Risk ratios (RR) were calculated and Mantel-Haenszel random effects were applied.Results Two high-quality studies were eligible, including 32,465 participants who received apixaban, rivaroxaban, or warfarin, with a median follow-up of 1.9 years. Of participants, 29% used < 5 drugs, 55% used 5-9 drugs, and 16% used >= 10 drugs. Drugs interacting with DOACs (P-glycoprotein/CYP3A4) were used by 6460 (20%) of patients. Patients with higher number of drugs (0-4 vs 5-9 vs >= 10) had higher rates of mortality (5.8%, 7.9%, 10.0%) and major bleeding (3.4%, 4.8%, 7.7%). Comparative efficacy or safety of DOACs versus warfarin was not affected by polypharmacy status or P-glycoprotein/CYP3A4 inhibitor use. However, the presence of polypharmacy (p = 0.001) or glycoprotein/CYP3A4-modulating drugs (p = 0.03) was correlated with increased risk of major bleeding when compared with warfarin. Overall, DOAC use was associated with a lower risk of stroke/SE (RR, 0.84; 95%CI, 0.74-0.94), all-cause mortality (RR, 0.91; 95%CI, 0.84-0.98), and intracranial hemorrhage (RR, 0.51; 95%CI, 0.38-0.70) compared with warfarin.Conclusions DOACs were more effective than warfarin, and at least as safe. Polypharmacy was associated with adverse outcomes and attenuated the advantage in risk of major bleeding among rivaroxaban users, particularly in the presence of P-glycoprotein/CYP3A4-modulating drugs. Show less
Kooiman, J.; Rein, N. van; Hagen, N. van; Cannegieter, S.C.; Meer, F.M. van der; Huisman, M.V. 2013
