We investigated the beneficial effects of midazolam against vascular endothelial growth factor (VEGF)-induced vascular leakage and its molecular mechanism of action in human retinal endothelial cells (HRECs) and the retinas of diabetic mice. Midazolam inhibited VEGF-induced elevation of intracellular Ca, generation of reactive oxygen species (ROS), and transglutaminase activation in HRECs; these effects were reversed by the GABA, type A (GABA) receptor antagonist flumazenil but not by the translocator protein antagonist PK11195. Midazolam also prevented VEGF-induced disassembly of adherens junctions and in vitro permeability. Intravitreal injection of midazolam prevented hyperglycemia-induced ROS generation, transglutaminase activation, and subsequent vascular leakage in the retinas of diabetic mice, and those effects were reversed by flumazenil. The roles of flumazenil were further supported by identifying GABA receptors in mouse retinas. Thus, midazolam prevents hyperglycemia-induced vascular leakage by inhibiting VEGF-induced intracellular events in the retinas of diabetic mice.-Lee, Y.-J., Kim, M., Lee, J.-Y., Jung, S.-H., Jeon, H.-Y., Lee, S.-A., Kang, S., Han, E.-T., Park, W. S., Hong, S.-H., Kim, Y.-M., Ha, K.-S. The benzodiazepine anesthetic midazolam prevents hyperglycemia-induced microvascular leakage in the retinas of diabetic mice.

Background Although randomized trials provide a high level of evidence regarding the efficacy of non-vitamin K oral anticoagulants (NOACs), the results of such trials may differ from those observed in day-to-day clinical practice. Aims To compare the risk of stroke/systemic embolism (S/SE) and major bleeding (MB) between NOAC and warfarin in clinical practice. Methods Patients with non-valvular atrial fibrillation (NVAF) who started warfarin/NOACs between January 2015 and November 2016 were retrospectively identified from Korea’s nationwide health insurance claims database. Using inpatient diagnosis and imaging records, the Cox models with inverse probability of treatment weighting using propensity scores were used to estimate hazard ratios (HRs) for NOACs relative to warfarin. Results Of the 48,389 patients, 10,548, 11,414, 17,779 and 8,648 were administered apixaban, dabigatran, rivaroxaban and warfarin, respectively. Many patients had suffered prior strokes (36.7%, 37.7%, 31.4%, and 32.2% in apixaban, dabigatran, rivaroxaban, and warfarin group, respectively), exhibited high CHA2DS2-VASc (4.8, 4.6, 4.6, and 4.1 in apixaban, dabigatran, rivaroxaban, and warfarin group, respectively) and HAS-BLED (3.7, 3.6, 3.6, and 3.3 in apixaban, dabigatran, rivaroxaban, and warfarin group, respectively) scores, had received antiplatelet therapy (75.4%, 75.7%, 76.8%, and 70.1% in apixaban, dabigatran, rivaroxaban, and warfarin group, respectively), or were administered reduced doses of NOACs (49.8%, 52.9%, and 42.8% in apixaban, dabigatran, and rivaroxaban group, respectively). Apixaban, dabigatran and rivaroxaban showed a significantly lower S/SE risk [HR, 95% confidence intervals (CI): 0.62, 0.54–0.71; 0.60, 0.53–0.69; and 0.71, 0.56–0.88, respectively] than warfarin. Apixaban and dabigatran (HR, 95% CI: 0.58, 0.51–0.66 and 0.75, 0.60–0.95, respectively), but not rivaroxaban (HR, 95% CI: 0.84, 0.69–1.04), showed a significantly lower MB risk than warfarin. Conclusions Among Asian patients who were associated with higher bleeding risk, low adherence, and receiving reduced NOAC dose than that provided in randomised controlled trials, all NOACs were associated with a significantly lower S/SE risk and apixaban and dabigatran with a significantly lower MB risk than warfarin.

Background Studies have shown that the concomitant use of a vitamin K antagonist (VKA) and an antiplatelet (APL) drug increased the bleeding risk and was less effective at preventing ischemic events. This study aimed to investigate the control status of international normalized ratio (INR) and the discontinuation rate of a VKA in patients taking VKA plus an APL drug compared with those taking a VKA alone. Methods Data were extracted from the KORean Atrial Fibrillation Investigation II registry, a multicenter noninterventional prospective observational study. Nonvalvular atrial fibrillation (NVAF) patients with CHADS2 scores ≥ 1 who newly started (within 3 months) a VKA were enrolled and followed up for 1 year. Results A total of 866 NVAF patients (mean age, 67.7 years; 60.3% men) without a bleeding history were divided into the VKA+APL (n = 229) and VKA alone (n = 637) groups. During follow‐up, mean INR level was lower in the VKA+APL group than in the VKA alone group (1.7 ± 0.8 vs 1.9 ± 0.9, P = 0.0005). INR levels were poorly controlled in both groups (66.1% and 64.7%, respectively). Patients in the VKA+APL group more frequently discontinued VKA than patients in the VKA alone group (28.8% vs 24.2%, P = 0.045). Major causes of VKA discontinuation were uncontrolled INR level and patient dissatisfaction or concerns. Conclusions The conditions of NVAF patients were inadequately controlled with VKA with or without an APL. These findings suggest that other antithrombotic treatment options are warranted in NVAF patients to achieve INR control.

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