Dataset Information

Differential Effects of Dabigatran and Warfarin on Bone Volume and Structure in Rats with Normal Renal Function.

ABSTRACT:

Background

Warfarin, a widely used anticoagulant, is a vitamin K antagonist impairing the activity of vitamin K-dependent Bone Gla Protein (BGP or Osteocalcin) and Matrix Gla Protein (MGP). Because dabigatran, a new anticoagulant, has no effect on vitamin K metabolism, the aim of this study was to compare the impact of warfarin and dabigatran administration on bone structure and vascular calcification.

Methods

Rats with normal renal function received for 6 weeks warfarin, dabigatran or placebo. Bone was evaluated immuno-histochemically and hystomorphometrically after double labelling with declomycin and calcein. Aorta and iliac arteries were examined histologically.

Results

Histomorphometric analysis of femur and vertebrae showed significantly decreased bone volume and increased trabecular separation in rats treated with warfarin. Vertebra analysis showed that the trabecular number was higher in dabigatran treated rats. Osteoblast activity and resorption parameters were similar among groups, except for maximum erosion depth, which was higher in warfarin treated rats, suggesting a higher osteoclastic activity. Therefore, warfarin treatment was also associated with higher bone formation rate/bone surface and activation frequency. Warfarin treatment may cause an increased bone turnover characterized by increased remodelling cycles, with stronger osteoclast activity compared to the other groups. There were no differences among experimental groups in calcium deposition either in aortic or iliac arteries.

Conclusions

These findings suggest for the first time that dabigatran has a better bone safety profile than warfarin, as warfarin treatment affects bone by reducing trabecular size and structure, increasing turnover and reducing mineralization. These differences could potentially result in a lower incidence of fractures in dabigatran treated patients.

SUBMITTER: Fusaro M

PROVIDER: S-EPMC4524674 | biostudies-literature | 2015

REPOSITORIES: biostudies-literature

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Publications

Differential Effects of Dabigatran and Warfarin on Bone Volume and Structure in Rats with Normal Renal Function.

Fusaro Maria M Dalle Carbonare Luca L Dusso Adriana A Arcidiacono Maria Vittoria MV Valenti Maria Teresa MT Aghi Andrea A Pasho Sabina S Gallieni Maurizio M

PloS one 20150804 8

<h4>Background</h4>Warfarin, a widely used anticoagulant, is a vitamin K antagonist impairing the activity of vitamin K-dependent Bone Gla Protein (BGP or Osteocalcin) and Matrix Gla Protein (MGP). Because dabigatran, a new anticoagulant, has no effect on vitamin K metabolism, the aim of this study was to compare the impact of warfarin and dabigatran administration on bone structure and vascular calcification.<h4>Methods</h4>Rats with normal renal function received for 6 weeks warfarin, dabigatr ...[more]

PMID: 26241483

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Project description:ObjectiveTo determine the real world risk of gastrointestinal bleeding associated with the use of the novel oral anticoagulants dabigatran and rivaroxaban compared with warfarin.DesignRetrospective, propensity matched cohort study.SettingOptum Labs Data Warehouse, a large database including administrative claims data on privately insured and Medicare Advantage enrollees.ParticipantsNew users of dabigatran, rivaroxaban, and warfarin from 1 November 2010 to 30 September 2013.Main outcome measuresIncidence rates (events/100 patient years) and propensity score matched Cox proportional hazards models were used to estimate rates of total gastrointestinal bleeds, upper gastrointestinal bleeds, and lower gastrointestinal bleeds for the novel oral anticoagulants compared with warfarin in patients with and without atrial fibrillation. Heterogeneity of treatment effect related to age was examined using a marginal effects model.ResultsThe incidence of gastrointestinal bleeding associated with dabigatran was 2.29 (95% confidence interval 1.88 to 2.79) per 100 patient years and that associated with warfarin was 2.87 (2.41 to 3.41) per 100 patient years in patients with atrial fibrillation. In non-atrial fibrillation patients, the incidence of gastrointestinal bleeding was 4.10 (2.47 to 6.80) per 100 patient years with dabigatran and 3.71 (2.16 to 6.40) per 100 patient years with warfarin. With rivaroxaban, 2.84 (2.30 to 3.52) gastrointestinal bleeding events per 100 patient years occurred in atrial fibrillation patients (warfarin 3.06 (2.49 to 3.77)/100 patient years) and 1.66 (1.23 to 2.24) per 100 patient years in non-atrial fibrillation patients (warfarin 1.57 (1.25 to 1.99)/100 patient years). In propensity score matched models, the risk of gastrointestinal bleeding with novel oral anticoagulants was similar to that with warfarin in atrial fibrillation patients (dabigatran v warfarin, hazard ratio 0.79 (0.61 to 1.03); rivaroxaban v warfarin, 0.93 (0.69 to 1.25)) and in non-AF patients (dabigatran v warfarin, hazard ratio 1.14 (0.54 to 2.39); rivaroxaban v warfarin, 0.89 (0.60 to 1.32)). The risk of gastrointestinal bleeding increased after age 65, such that by age 76 the risk exceeded that with warfarin among atrial fibrillation patients taking dabigatran (hazard ratio 2.49 (1.61 to 3.83)) and patients with and without atrial fibrillation taking rivaroxaban (2.91 (1.65 to 4.81) and 4.58 (2.40 to 8.72), respectively).ConclusionsThe risk of gastrointestinal bleeding related to novel oral anticoagulants was similar to that for warfarin. Caution should be used when prescribing novel oral anticoagulants to older people, particularly those over 75 years of age.

Project description:BackgroundWarfarin and similar vitamin K antagonists have been the standard therapy for patients with mechanical or biological valve prosthesis and atrial fibrillation (AF). Even with the appropriate use of therapy, some studies have reported that there is a high incidence of thromboembolic events, 1%-4% per year. Furthermore, a bleeding risk is significant, ranging from 2% to 9% per year, according to some studies.ObjectiveThe objective of our study was to examine the effect of dabigatran etexilate versus dose-adjusted warfarin for the prevention of intracardiac thrombus in persistent or permanent AF at least 3 months after aortic and/or mitral bioprosthesis replacement.MethodsDabigatran versus warfarin after bioprosthesis valve replacement for the management of atrial fibrillation postoperatively (DAWA) is a phase 2, prospective, open label, randomized exploratory pilot study. The main variable to be observed in this study is intracardiac thrombus. From August 2013 to April 2015, 100 patients, at least 3 months after aortic and/or mitral bioprosthesis replacement and permanent or persistent AF postoperatively, who match eligibility criteria will be selected from Ana Nery Hospital in Salvador-Bahia with a follow-up of three months. Patients were randomly assigned in a 1:1 ratio to receive either dabigatran etexilate or warfarin.ResultsAlthough the present study has no statistic power to proof non-inferiority, it is expected that the dabigatran etexilate group will be protected as well as the warfarin group from intracardiac thrombus, without increasing the bleeding rates, since we are using safer doses (110 mg bid). The lack of necessity of monitoring INR is also another factor that contributes to a better adherence to the new drug and it can make all the difference in the manner of doing anticoagulation for patients with similar clinical characteristics.ConclusionsThe study is in the recruitment phase. It is possible that dabigatran etexilate is as effective as warfarin in preventing the emergence of intracardiac thrombus in patients with AF and mitral and/or aortic bioprosthesis.Trial registrationClinicaltrials.gov NCT01868243; http://clinicaltrials.gov/ct2/show/NCT01868243 (Archived by WebCite at http://www.webcitation/6OABiuasd).

Dataset Information

Differential Effects of Dabigatran and Warfarin on Bone Volume and Structure in Rats with Normal Renal Function.

Background

Methods

Results

Conclusions

Publications

Differential Effects of Dabigatran and Warfarin on Bone Volume and Structure in Rats with Normal Renal Function.

Similar Datasets

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