BACKGROUND: The use of warfarin for the treatment of atrial fibrillation (AF) is often complicated by the associated narrow therapeutic index and frequent monitoring. Dabigatran, an oral direct thrombin inhibitor, does not require routine monitoring, produces rapid therapeutic anticoagulation, and has the potential to improve thromboprophylaxis through increased adherence. As such, it is important to evaluate adherence and the incidence of bleeding and systemic embolism with dabigatran in a real-world population with AF. OBJECTIVE: To measure adherence and incidence of bleeding and systemic embolism with dabigatran in a state Medicaid population with AF. METHODS: Medicaid members >18 years of age with AF were included if they had >1 paid claim for dabigatran between February 1, 2011 and September 30, 2011. Members were excluded if they had breaks in Medicaid coverage, supplemental insurance or were a female of childbearing age. The index date was defined as the date of the first pharmacy claim for dabigatran. Adherence was measured using medication possession ratios (MPR) for members with >2 paid claims for dabigatran and members with an MPR >0.8 were considered adherent. The incidences of bleeding, stroke and all-cause hospitalization were determined using medical claims data for one year post-index date. Pharmacy claims data was used to report changes in anticoagulant therapy within one year post-index date. RESULTS: The average MPR was 0.87 and 69% of members were considered adherent. Of the members that started dabigatran, 42.9% continued dabigatran while 21.4% switched to warfarin. Overall, 16.7% of members experienced a systemic embolism and only one bleeding event occurred during the study period. While chest pain and dyspepsia were the most common adverse events, 45.2% of members had no adverse events. CONCLUSIONS: This evaluation found that while members were adherent to dabigatran therapy, the discontinuation rate suggests poor tolerance to therapy.

Mdm2 is required to negatively regulate p53 activity at the peri-implantation stage of early mouse development. However, the absolute requirement for Mdm2 throughout embryogenesis and in organogenesis is unknown. To explore Mdm2-p53 signaling in osteogenesis, Mdm2-conditional mice were bred with Col3.6-Cre-transgenic mice that express Cre recombinase in osteoblast lineage cells. Mdm2-conditional Col3.6-Cre mice die at birth and display multiple skeletal defects. Osteoblast progenitor cells deleted for Mdm2 have elevated p53 activity, reduced proliferation, reduced levels of the master osteoblast transcriptional regulator Runx2, and reduced differentiation. In contrast, p53-null osteoprogenitor cells have increased proliferation, increased expression of Runx2, increased osteoblast maturation, and increased tumorigenic potential, as mice specifically deleted for p53 in osteoblasts develop osteosarcomas. These results demonstrate that p53 plays a critical role in bone organogenesis and homeostasis by negatively regulating bone development and growth and by suppressing bone neoplasia and that Mdm2-mediated inhibition of p53 function is a prerequisite for Runx2 activation, osteoblast differentiation, and proper skeletal formation.