No abstract

Angiogenesis is a key feature of liver fibrosis. Although sinusoidal remodeling is believed to contribute to fibrogenesis, the impact of sinusoidal angiogenesis on the resolution of liver fibrosis remains undefined. Myeloid cells, particularly macrophages, constantly infiltrate the fibrotic liver and can profoundly contribute to remodeling of liver sinusoids. We observe that the development of fibrosis is associated with decreased hepatic vascular endothelial growth factor (VEGF) expression as well as sinusoidal rarefication of the fibrotic scar. In contrast, the resolution of fibrosis is characterized by a rise in hepatic VEGF levels and revascularization of the fibrotic tissue. Genetic ablation of VEGF in myeloid cells or pharmacological inhibition of VEGF receptor 2 signaling prevents this angiogenic response and the resolution of liver fibrosis. We observe increased expression of matrix metalloproteases as well as decreased expression of tissue inhibitor of metalloproteases confined to sinusoidal endothelial cells in response to myeloid cell VEGF. Remarkably, reintroduction of myeloid cell–derived VEGF upon recovery restores collagenolytic acitivity and the resolution of fibrosis. Conclusion: We identify myeloid cell–derived VEGF as a critical regulator of extracellular matrix degradation by liver endothelial cells, thereby unmasking an unanticipated link between angiogenesis and the resolution of fibrosis. (Hepatology 2015;61:2042–2055)

Study ObjectivePatients with nonvalvular atrial fibrillation (NVAF) often have multiple comorbidities requiring concomitant medications in addition to their oral anticoagulant (OAC). The objective of this study was to evaluate the impact of polypharmacy on the effectiveness and safety of rivaroxaban versus warfarin in patients with NVAF managed in routine clinical practice.DesignRetrospective claims analysis.Data SourceUnited States Truven MarketScan database (November 2012–March 2017).PatientsAdults who were OAC naïve during the 12 months before the day of the first qualifying rivaroxaban or warfarin dispensing (index date); had at least two International Classification of Diseases, Ninth or Tenth Revision diagnosis codes for atrial fibrillation without codes suggesting valvular heart disease; had at least 12 months of continuous insurance coverage prior to the qualifying OAC dispensing; and were experiencing polypharmacy (concomitant prescription claims for five or more unique chronic medication claims) were included. Patients who had concomitant prescription claims for ≥ 10 unique chronic medication claims constituted the substantial polypharmacy cohort used in the secondary analysis. Patients receiving rivaroxaban were propensity‐score matched in a 1:1 ratio to patients receiving warfarin (13,981 patients in each polypharmacy OAC group, and 1765 patients in each substantial polypharmacy OAC group).Measurements and Main ResultsPatients were followed until occurrence of an event (stroke or systemic embolism [SSE] combined [primary effectiveness outcome] or major bleeding [primary safety outcome]), OAC discontinuation or switch (30‐day permissible gap), insurance disenrollment, or end of follow‐up period. Rates of SSE, ischemic stroke, and major bleeding were compared by using Cox regression, reported as hazard ratios (HRs) and 95% confidence intervals (CIs). In patients with NVAF taking five or more chronic medications, rivaroxaban was associated with a 34% (95% CI 12–50) and 40% (95% CI 16–57) hazard reduction of SSE and ischemic stroke, respectively. Occurrence of major bleeding was similar between OAC cohorts (HR 1.08, 95% CI 0.92–1.28). A secondary analysis in patients with NVAF with substantial polypharmacy (taking ≥ 10 chronic medications) was also performed. Similar trends in SSE (HR 0.44), ischemic stroke alone (HR 0.62), and major bleeding (HR 1.07) were observed in patients with NVAF who had substantial polypharmacy, although 95% CIs crossed 1.0 for each outcome in this smaller study cohort.ConclusionThis real‐world study suggests that in the setting of polypharmacy and NVAF, rivaroxaban is an effective and safe alternative to warfarin.

Aims  Vascular calcification is common in diabetic patients. Warfarin has been associated with renovascular calcification and worsening renal function; rivaroxaban may provide renopreservation by decreasing vascular inflammation. We compared the impact of rivaroxaban and warfarin on renal outcomes in diabetic patients with non-valvular atrial fibrillation (NVAF). Methods and results  Using United States IBM MarketScan data from January 2011 to December 2017, we identified adults with both NVAF and diabetes, newly-initiated on rivaroxaban or warfarin with ≥12-month insurance coverage prior to anticoagulation initiation. Patients with Stage 5 chronic kidney disease (CKD) or undergoing haemodialysis at baseline were excluded. Differences in baseline covariates between cohorts were adjusted using inverse probability-of-treatment weighting (IPTW) based on propensity scores (absolute standardized differences <0.1 achieved for all after adjustment). Outcomes included incidence rates of emergency department/hospital admissions for acute kidney injury (AKI) and the composite of the development of Stage 5 CKD or need for haemodialysis. Patients were followed until an event, index anticoagulant discontinuation/switch, insurance disenrollment, or end-of-data availability. Hazard ratios (HRs) with 95% confidence intervals (CIs) were estimated using Cox regression. We assessed 10 017 rivaroxaban (22.6% received a reduced dose) and 11 665 warfarin users. In comparison to warfarin, rivaroxaban was associated with lower risks of AKI (HR = 0.83, 95% CI = 0.74–0.92) and development of Stage 5 CKD or need for haemodialysis (HR = 0.82, 95% CI = 0.70–0.96). Sensitivity and subgroup analyses had similar effects as the base-case analysis. Conclusion  Rivaroxaban appears to be associated with lower risks of undesirable renal outcomes vs. warfarin in diabetic NVAF patients.