Background Emerging safety and efficacy data for rivaroxaban suggest traditional therapy and rivaroxaban are comparable in the morbidly obese. However, real‐world data that indicate pharmacokinetic (PK) parameters are comparable at the extremes of body size are lacking. The International Society of Thrombosis and Haemostasis Scientific and Standardisation Committee (ISTH SSC) suggests avoiding the use of direct oral anticoagulants (DOACs) in patients weighing >120 kg or with a body mass index >40 kg/m2 and gives no recommendation on the use of DOACs in those <50 kg. Objectives To generate a population PK model to understand the influence of bodyweight on rivaroxaban exposure from clinical practice data. Method Rivaroxaban plasma concentrations and patient characteristics were collated between 2013 and 2018 at King's College Hospital anticoagulation clinic. A population PK model was developed using a nonlinear mixed effects approach and then used to simulate rivaroxaban concentrations at the extremes of bodyweight. Results A robust population PK model derived from 913 patients weighing between 39 kg and 172 kg was developed. The model included data from n = 86 >120 kg, n = 74 BMI >40 kg/m2, and n = 30 <50 kg. A one‐compartment model with between‐subject variability on clearance and a proportional error model best described the data. Creatinine clearance calculated by Cockcroft‐Gault, with lean bodyweight as the weight descriptor in this equation, was the most significant covariate influencing rivaroxaban exposure. Conclusions Our work demonstrates rivaroxaban can be used at extremes of bodyweight provided renal function is satisfactory. We recommend that the ISTH SSC revises the current guidance with respect to rivaroxaban at extremes of body size.

Summary The availability of direct oral anticoagulants (DOACs) has led to a paradigm shift in the field of anticoagulation, with DOACs increasingly being prescribed for patients in preference to vitamin K antagonists and low molecular weight heparin. Despite good experience with the use of these agents at fixed doses, there are clinical scenarios where monitoring is recommended. Data from phase III studies of the DOACs and small real‐world studies suggest a relationship between DOAC concentration and clinical events. The DOACs have differing impacts on the common tests of haemostasis and it is important that clinicians are familiar with the sensitivity of the reagents used in their laboratory to individual DOACs. The specific DOAC drug concentrations can be assayed in the laboratory, when required, to guide appropriate clinical decision‐making. Studies from the real world with sufficient numbers evaluating the association of DOAC concentrations with outcomes should be a research priority in order to understand if we could do better through dose individualisation.

King's College Hospital hosts a busy anticoagulation clinic in south London within the epicentre of the COVID-19 outbreak in the UK [1]. After the UK entered a period of 'lockdown' from 23/03/2020, the Government advised shielding of elderly and vulnerable patients and limiting hospital visits. UK guidance for anticoagulation services was issued (Guidance for the safe switching of warfarin to direct oral anticoagulants (DOACs) for patients with non-valvular AF and venous thromboembolism (DVT / PE) during the coronavirus pandemic) with recommendations around maintaining safe anticoagulation whilst minimising exposure to COVID-19 infection [2]. These included switching to direct oral anticoagulants (DOACs) where appropriate, self-testing INRs, increasing the INR test interval for previously stable patients, and temporarily suspending anticoagulation with VKA therapy where this could no longer be safely continued. Despite implementation of these recommendations, we noted frequent high INR readings in clinical practice during this period. Routine practice at our institution is to perform root cause analysis on all INR results above > 8.0. We report on the frequency of supra-therapeutic INR values during the COVID-19 pandemic compared to the previous year and during lockdown and describe the findings of the root cause analysis. Methods

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The physiological disposition of two nitrofuran derivatives used as antimicrobial agents for the treatment of acute infectious diarrhoea was evaluated in humans and animals. Upon administration of a single oral dose (600 mg) of nifurzide or nifuroxazide, no unchanged parent drug was detected in human blood or urine. In rats given 14C-nifurzide and 14C-nifuroxazide at a dose of 10 mg kg-1, 5 per cent and 17 per cent of the dose of nifurzide and nifuroxazide, respectively, were excreted in urine over a 48-hour period. None of this radioactivity was present as unchanged drug, indicating that renal excretion of both drugs occurs as metabolites. In the faeces 20 per cent of the radioactivity recovered was associated with unchanged nifuroxazide as compared with 100 per cent for nifurzide. Whole body autoradiography using rats showed that after oral administration of 14C-nifurzide and 14C-nifuroxazide, most of the radioactivity remained in the gastrointestinal lumen.

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the junior doctors in the prescription of MRAs however (p£0.05). Self-reported competency in initiating and up-titrating HF medications is reported in table 2. Of participants who felt comfortable with initiation and up-titration of beta blockers (N=89), only 26% (N=27) correctly identified an optimal target heart rate of less than 70 beats per minute. Twenty-four percent of respondents (N=28) were unaware of a specialist HF service that catered to their institution, and how to refer to it, but 97% (N=113) felt that their practice would benefit from further education on HF pharmacotherapy. ConclusionThe high prevalence of HF in Ireland and costs associated with admission for decompensation necessitates a sound knowledge of its management amongst generalists. Results of this survey suggest a need, and indeed a demand, for further education and support surrounding pharmacotherapy of stable heart failure.

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