Effectiveness and safety of direct oral anticoagulants in patients with venous thromboembolism and creatinine clearance < 30 mL/min.

The few studies that compared direct oral anticoagulants (DOAC) vs. warfarin in the setting of advanced renal insufficiency have focused on patients with atrial fibrillation. The purpose of this observational, matched, cohort study of patients was to assess the effectiveness and safety of DOAC vs. warfarin for the treatment of venous thromboembolism (VTE) among patients with a creatinine clearance (CrCl) < 30 mL/min. This observational, cohort study included patients with VTE and CrCl < 30 mL/min who were newly initiated on a DOAC or warfarin between January 1, 2016 and December 31, 2020. DOAC patients were matched up to 1:2 to warfarin patients. Primary outcome was a composite of recurrent VTE, clinically-relevant bleeding, ischemic stroke, and all-cause mortality. Adjusted conditional, multivariate Cox proportional hazards modeling was used to assess outcomes. 626 DOAC patients were matched to 1071 warfarin patients. DOAC patients had a higher mean age, higher mean baseline CrCl, and were less likely to have been receiving dialysis. There was no statistically significant difference in the composite outcome between groups (adjusted hazard ratio [aHR] 1.13, 95% confidence interval [CI] 0.87-1.47) or in the individual components of the composite (all HR 95% CI crossed 1.00). Identification of statistically non-significant rates of bleeding and thromboembolic outcomes suggest that the use of DOAC or warfarin is reasonable in patients with VTE and CrCl < 30 mL/min.

Investigating Substrate Analogues for Mycobacterial MenJ: Truncated and Partially Saturated Menaquinones.

Menaquinones (MKs) are essential for electron transport in prokaryotes, and importantly, partially saturated MKs represent a novel virulence factor. However, little is known regarding how the degree of saturation in the isoprenyl side chain influences conformation or quinone redox potential. MenJ is an enzyme that selectively reduces the second isoprene unit on MK-9 and is contextually essential for the survival of Mycobacterium tuberculosis in J774A.1 macrophage-like cells, suggesting that MenJ may be a conditional drug target for pathogenic mycobacteria. Therefore, fundamental information about the properties of this system is important, and we synthesized the simplest MKs, unsaturated MK-1 and the saturated analogue, MK-1(H2). Using two-dimensional nuclear magnetic resonance spectroscopy, we established that MK-1 and MK-1(H2) adopted similar folded-extended conformations (i.e., the isoprenyl side chain folds upward) in each solvent examined but the folded-extended conformations differed slightly between organic solvents. Saturation of the isoprenyl side chain slightly altered the MK-1 analogue conformation in each solvent. We used molecular mechanics to illustrate the MK-1 analogue conformations. The measured quinone redox potentials of MK-1 and MK-1(H2) differed between organic solvents (presumably due to differences in dielectric constants), and remarkably, an ∼20 mV semiquinone redox potential difference was observed between MK-1 and MK-1(H2) in pyridine, acetonitrile, and dimethyl sulfoxide, demonstrating that the degree of saturation in the isoprenyl side chain of MK-1 influences the quinone redox potential. Finally, MK-1 and MK-1(H2) interacted with Langmuir phospholipid monolayers and Aerosol-OT reverse micelle (RM) model membrane interfaces, where MK-1 adopted a slightly different folded conformation within the RM model membrane interface.