J. Graham Davies

Efficacy and Harms of Direct Oral Anticoagulants in the Elderly for Stroke Prevention in Atrial Fibrillation and Secondary Prevention of Venous Thromboembolism: Systematic Review and Meta-Analysis

Background— Evidence regarding the use of direct oral anticoagulants (DOACs) in the elderly, particularly bleeding risks, is unclear despite the presence of greater comorbidities, polypharmacy, and altered pharmacokinetics in this age group. Methods and Results— We performed a systematic review and meta-analysis of randomized trials of DOACs (dabigatran, apixaban, rivaroxaban, and edoxaban) for efficacy and bleeding outcomes in comparison with vitamin K antagonists (VKA) in elderly participants (aged ≥75 years) treated for acute venous thromboembolism or stroke prevention in atrial fibrillation. Nineteen studies were eligible for inclusion, but only 11 reported data specifically for elderly participants. The efficacy in managing thrombotic risks for each DOAC was similar or superior to VKA in elderly patients. A nonsignificantly higher risk of major bleeding than with VKA was observed with dabigatran 150 mg (odds ratio, 1.18; 95% confidence interval, 0.97–1.44) but not with the 110-mg dose. Significantly higher gastrointestinal bleeding risks with dabigatran 150 mg (1.78, 1.35–2.35) and dabigatran 110 mg (1.40, 1.04–1.90) and lower intracranial bleeding risks than VKA for dabigatran 150 mg (0.43, 0.26–0.72) and dabigatran 110 mg (0.36, 0.22–0.61) were also observed. A significantly lower major bleeding risk in comparison with VKA was observed for apixaban (0.63, 0.51–0.77), edoxaban 60 mg (0.81, 0.67–0.98), and 30 mg (0.46, 0.38–0.57), whereas rivaroxaban showed similar risks. Conclusions— DOACs demonstrated at least equal efficacy to VKA in managing thrombotic risks in the elderly, but bleeding patterns were distinct. In particular, dabigatran was associated with a higher risk of gastrointestinal bleeding than VKA. Insufficient published data for apixaban, edoxaban, and rivaroxaban indicate that further work is needed to clarify the bleeding risks of these DOACs in the elderly. Systematic Review Registration— http://www.crd.york.ac.uk/PROSPERO. Unique identifier: PROSPERO CRD42014007171/

Inflammatory cytokine removal by an activated carbon device in a flowing system

A prototype in-line filtration/adsorption device has been developed using novel synthetic pyrolysed carbon monoliths with controlled mesoporous domains of 2-50nm. Porosity was characterized by SEM and porosimetry. Removal of inflammatory cytokines TNF, IL-6, IL-1beta and IL-8 was assessed by filtering cytokine spiked human plasma through the walls of the carbon modules under pressure. The effect of carbon filtration on plasma clotting response and total plasma protein concentration was also assessed. Significant removal of the cytokines IL-6, IL-1beta and IL-8 was observed. Initially marked TNF removal diminished over time. The coagulation studies indicated that the carbon device does not exacerbate the propensity of blood plasma to clot. The total plasma protein concentration remained constant. The device offers a broader approach to the treatment of systemic inflammatory response syndrome (SIRS) by the removal of inflammatory mediators central to its progression.

Adverse Drug Reactions in a Population of Hospitalized Very Elderly Patients

OBJECTIVES The aims of the study were to determine the rates, types, severity and preventability of adverse drug reactions (ADRs) in a hospitalized population of very elderly patients (over 80 years of age) and to identify factors that predispose the very elderly to an ADR. METHODS An observational study was conducted in patients over 80 years of age admitted to four care of the elderly wards in Brighton and Sussex University Hospitals NHS Trust. The main outcome measures were the incidence of ADRs during inpatient stay in older patients and the identification of the major drug classes involved and the risk factors contributing to the occurrence of ADRs. RESULTS A total of 560 very elderly patients were recruited, 74 of whom experienced one or more ADR (83 in total), representing an incidence of 13.2% (95% CI 10.4, 16). Sixty-three percent of all ADRs were considered preventable, with 57 classified as serious and three as life threatening. The drug classes frequently implicated in ADRs were cardiovascular agents (34%), analgesic medications (18%) and anti-diabetic drugs (10%). Five variables were established as independent predictors of ADRs: number of medications, use of hypoglycaemic agents, history of hyperlipidaemia, raised white cell count on admission, and length of stay. CONCLUSIONS The ADR incidence reported in this population was no greater than that seen in other studies for both general medical patients and those elderly patients over 65 years of age. A significant proportion of ADRs were preventable, and this suggests that closer monitoring of high-risk elderly patients is needed to address this problem.

Population Pharmacokinetics of Enoxaparin During the Antenatal Period

Background— The optimal dosing strategy of low-molecular-weight heparins for the treatment of antenatal venous thromboembolism is not known. The physiological changes associated with pregnancy alter the pharmacokinetic profile of low-molecular-weight heparins, which has led to controversy and subsequent variation in practice, when pregnant women with venous thromboembolism are treated with low-molecular-weight heparins. Our objective was to develop a robust pharmacokinetic model of enoxaparin during the antenatal period to address this problem. Method and Results— Women prescribed antenatal enoxaparin were eligible to enroll in the study. Recruited women were reviewed monthly and had up to 3 anti-Xa activities (trough and 1 and 3 hours after dose) drawn at each clinic attendance. Compartmental pharmacokinetic modeling was conducted using nonlinear mixed-effects modeling. One hundred twenty-three patients contributed 795 anti-Xa activities for pharmacokinetic modeling purposes. Both enoxaparin clearance and volume of distribution were increased during pregnancy. Simulations of once- versus twice-daily enoxaparin administration demonstrated that both dosing regimens would reach target 3-hour plasma concentrations throughout the duration of the pregnancy. When trough anti-Xa activity was simulated, both once- and twice-daily regimens exhibited an increase in trough anti-Xa activity with the progression of pregnancy. This is explained by the significant increase in volume of distribution observed during pregnancy. Conclusions— The half-life of enoxaparin is prolonged with the progression of pregnancy, and our work provides compelling evidence for prescribing once-daily enoxaparin for the treatment of antenatal venous thromboembolism. National and international guideline recommendations should be reconsidered.

Dosing regimen of meropenem for adults with severe burns: a population pharmacokinetic study with Monte Carlo simulations

OBJECTIVES To develop a population model to describe the pharmacokinetics (PK) of intravenous meropenem in adult patients with severe burns and investigate potential relationships between dosage regimens and antimicrobial efficacy. PATIENTS AND METHODS A dose of 1 g every 8 h was administered to adult patients with total body surface area burns of ≥15%. Doses for subsequent courses were determined using results from the initial course and the patients clinical condition. Five plasma meropenem concentrations were typically measured over the dosage interval on one to four occasions. An open, two-compartment PK model was fitted to the meropenem concentrations using NONMEM and the effect of covariates on meropenem PK was investigated. Monte Carlo simulations investigated dosage regimens to achieve a target T>MIC for ≥40%, ≥60% or ≥80% of the dose interval. RESULTS Data comprised 113 meropenem concentration measurements from 20 dosage intervals in 12 patients. The parameters were CL (L/h) = 0.196 L/h/kg × [1 - 0.023 × (age - 46)] × [1 - 0.049 × (albumin - 15)], V1 = 0.273 L/kg × [1 - 0.049 × (albumin - 15)], Q = 0.199 L/h/kg and V2 = 0.309 L/kg × [1 - 0.049 × (albumin - 15)]. For a target of ≥80% T>MIC, the breakpoint was 8 mg/L for doses of 1 g every 4 h and 2 g every 8 h given over 3 h, but only 4 mg/L if given over 5 min. CONCLUSIONS Although 1 g 8 hourly should be effective against Escherichia coli and CoNS, higher doses, ideally with a longer infusion time, would be more appropriate for empirical therapy, mixed infections and bacteria with MIC values ≥4 mg/L.

A Framework for Assessing the Continuous Professional Development Needs of Community Pharmacists

This paper describes and evaluates a process by which the professional development needs of community pharmacists (CPs) were identified and recommendations made as to how they might be addressed. Twenty CPs were recruited onto the Continuing Professional Development (CPD) programme and asked to complete a reflective logbook over a four-week period. Day one of the programme involved participation in seven skills evaluation workstations, a focus group to explore their views about CPD and a one-to-one interview with a facilitator to review the reflective logbooks and individual perceived training needs. Day two involved the presentation of the results of pharmacists’ performance in the skills workstations, followed by individual feedback to inform their personal development plans (PDPs). Fourteen pharmacists completed the CPD programme. Three key training needs were identified from the skills assessment workstations and six themes from the focus groups. Evaluation of the CPD programme indicated that it was highly rated and improved their understanding of the CPD process.

The effect of training and service provision on the self-assessed competence of community pharmacists

Objective The purpose of this study was to explore self‐assessed competence of community pharmacists who had completed additional clinical pharmacy training at certificate level and were accredited to provide a clinical medication review service to primary care patients (the ‘trained’ group). The self‐assessed competence of these pharmacists was compared with others who had not undertaken the training (the ‘untrained’ group).

Changes in thrombin generation and D-dimer concentrations in women injecting enoxaparin during pregnancy and the puerperium

BackgroundIt is well accepted that the gravid state is hypercoagulable and a significant cause of both maternal morbidity and mortality in the Western world. Although thrombin generation is reported to be increased in pregnant women, uncertainty exists on the pattern of thrombin generation change during this time. The aim of this study is to describe thrombin generation changes and D-dimer concentrations in women injecting enoxaparin during pregnancy the postnatal period.MethodsOne hundred and twenty-three women injecting enoxaparin had their thrombin generation, as measured by Calibrated Automated Thombinography (CAT), repeatedly assayed during pregnancy, once in each trimester, at delivery and 8 weeks post-partum. Furthermore, to understand the impact enoxaparin has on D-dimer concentrations during pregnancy, D-dimer concentrations were measured monthly in the recruited women.ResultsThrombin generation was found to increase in the first trimester (mean endogenous thrombin potential (ETP): 1391 nmol/L.min), further increasing during the second trimester (mean ETP: 1757 nmol/L.min), after which it plateaued through to delivery, where it peaked (mean ETP: 1857 nmol/L.min) and then fell back at 8 weeks post-partum (ETP: 1293 nmol/L.min). In contrast D-dimer concentrations increased exponentially during the antenatal period, despite the enoxaparin prescription.ConclusionOur results provide further evidence on alterations of thrombin generation during pregnancy and the postnatal period.

Piloting an Objective Structured Clinical Examination to Evaluate the Clinical Competency of Pre‐Registration Pharmacists

Objectives: The primary aim of the study was to pilot the Objective Structured Clinical Examination (OSCE) as a method of evaluating the clinical competency of pre‐registration pharmacists trained in Brisbane and nearby hospitals. A secondary aim was to demonstrate that this model of assessment is transferable when used to evaluate preregistration pharmacists from the UK.

Incidence and cost of medication harm in older adults following hospital discharge: a multicentre prospective study in the UK

Polypharmacy is increasingly common in older adults, placing them at risk of medication‐related harm (MRH). Patients are particularly vulnerable to problems with their medications in the period following hospital discharge due to medication changes and poor information transfer between hospital and primary care. The aim of the present study was to investigate the incidence, severity, preventability and cost of MRH in older adults in England postdischarge.