Edoxaban: an update on the new oral direct factor Xa inhibitor.

Edoxaban is a once-daily oral anticoagulant that rapidly and selectively inhibits factor Xa in a concentration-dependent manner. This review describes the extensive clinical development program of edoxaban, including phase III studies in patients with non-valvular atrial fibrillation (NVAF) and symptomatic venous thromboembolism (VTE). The ENGAGE AF-TIMI 48 study (N = 21,105; mean CHADS2 score 2.8) compared edoxaban 60 mg once daily (high-dose regimen) and edoxaban 30 mg once daily (low-dose regimen) with dose-adjusted warfarin [international normalized ratio (INR) 2.0-3.0] and found that both regimens were non-inferior to warfarin in the prevention of stroke and systemic embolism in patients with NVAF. Both edoxaban regimens also provided significant reductions in the risk of hemorrhagic stroke, cardiovascular mortality, major bleeding and intracranial bleeding. The Hokusai-VTE study (N = 8,292) in patients with symptomatic VTE had a flexible treatment duration of 3-12 months and found that following initial heparin, edoxaban 60 mg once daily was non-inferior to dose-adjusted warfarin (INR 2.0-3.0) for the prevention of recurrent VTE, and also had a significantly lower risk of bleeding events. Both studies randomized patients at moderate-to-high risk of thromboembolic events and were further designed to simulate routine clinical practice as much as possible, with edoxaban dose reduction (halving dose) at randomisation or during the study if required, a frequently monitored and well-controlled warfarin group, a well-monitored transition period at study end and a flexible treatment duration in Hokusai-VTE. Given the phase III results obtained, once-daily edoxaban may soon be a key addition to the range of antithrombotic treatment options

Reversal Agents in Development for the New Oral Anticoagulants

The new oral anticoagulants have many advantages over vitamin K antagonists, but they are still associated with a troublesome incidence of major bleeding. Additionally, the absence of a reversal agent for the new oral anticoagulants is a barrier to their more widespread use. Currently, there are 3 potential reversal agents in development: idarucizumab is a humanized murine monoclonal antibody fragment directed specifically at dabigatran; andexanet alfa is a recombinant modified decoy factor Xa that binds to factor Xa inhibitors; and PER977 is a small molecule that binds to factor Xa and IIa inhibitors and to heparin-based anticoagulants through charge interaction. These agents have undergone phase I clinical testing, appear to be well tolerated in healthy volunteers, and are effective in neutralizing their respective targets. All 3 are currently undergoing or entering into a phase II or III clinical study. This article reviews the available data for idarucizumab, andexanet alfa, and PER977

Understanding gastric forces calculated from high-resolution pill tracking

Although other methods exist for monitoring gastrointestinal motility and contractility, this study exclusively provides direct and quantitative measurements of the forces experienced by an orally ingested pill. We report motive forces and torques calculated from real-time, in vivo measurements of the movement of a magnetic pill in the stomachs of fasted and fed humans. Three-dimensional net force and two-dimensional net torque vectors as a function of time data during gastric residence are evaluated using instantaneous translational and rotational position data. Additionally, the net force calculations described can be applied to high-resolution pill tracking acquired by any modality. The fraction of time pills experience ranges of forces and torques are analyzed and correlate with the physiological phases of gastric digestion. We also report the maximum forces and torques experienced in vivo by pills as a quantitative measure of the amount of force pills experience during the muscular contractions leading to gastric emptying. Results calculated from human data are compared with small and large animal models with a translational research focus. The reported magnitude and direction of gastric forces experienced by pills in healthy stomachs serves as a baseline for comparison with pathophysiological states. Of clinical significance, the directionality associated with force vector data may be useful in determining the muscle groups associated with gastrointestinal dysmotility. Additionally, the quantitative comparison between human and animal models improves insight into comparative gastric contractility that will aid rational pill design and provide a quantitative framework for interpreting gastroretentive oral formulation test results