Michael Barras

Recurrent readmissions in medical patients: A prospective study

BACKGROUND Hospital readmissions are common and costly. A recent previous hospitalization preceding the index admission is a marker of increased risk of future readmission. OBJECTIVES To identify factors associated with an increased risk of recurrent readmission in medical patients with 2 or more hospitalizations in the past 6 months. DESIGN Prospective cohort study. SETTING Australian teaching hospital acute medical wards, February 2006-February 2007. PARTICIPANTS 142 inpatients aged ≥ 50 years with a previous hospitalization ≤ 6 months preceding the index admission. Patients from residential care, with terminal illness, or with serious cognitive or language difficulties were excluded. VARIABLES OF INTEREST Demographics, previous hospitalizations, diagnosis, comorbidities and nutritional status were recorded in hospital. Participants were assessed at home within 2 weeks of hospital discharge using validated questionnaires for cognition, literacy, activities of daily living (ADL)/instrumental activities of daily living (IADL) function, depression, anxiety, alcohol use, medication adherence, social support, and financial status. MAIN OUTCOME MEASURE Unplanned readmission to the study hospital within 6 months. RESULTS A total of 55 participants (38.7%) had a further unplanned hospital admission within 6 months. In multivariate analysis, chronic disease (adjusted odds ratio [OR] 3.4; 95% confidence interval [CI], 1.3-9.3, P = 0.002), depressive symptoms (adjusted OR, 3.0; 95% CI, 1.3-6.8, P = 0.01), and underweight (adjusted OR, 12.7; 95% CI, 2.3-70.7, P = 0.004) were significant predictors of readmission after adjusting for age, length of stay and functional status. CONCLUSIONS In this high-risk patient group, multiple chronic conditions are common and predict increased risk of readmission. Post-hospital interventions should consider targeting nutritional and mood status in this population.

Individualized compared with conventional dosing of enoxaparin

The aim of this study was to compare an individualized dosing regimen for enoxaparin to conventional dosing. Patients in the individualized arm were initially dosed according to weight: patients <100 kg using total body weight; patients ⩾100 kg using lean body weight. Doses were adjusted at 48 h according to renal function. Patients in the conventional arm received enoxaparin according to current practice. Dose‐individualized patients had fewer bleeding events (primary end point; relative risk (RR)=0.12, 95% confidence interval (CI)=0.01–0.89, P=0.03) and composite bleeding and bruising events (secondary end point; RR=0.30, 95% CI=0.12–0.71, P=0.003) than those who received conventional dosing. In both arms of the study, there were no recurrent thromboembolic events during treatment and no deaths had occurred at 30 days. Dose individualization of enoxaparin significantly reduces the prevalence of bleeding and bruising events, without apparent loss in effectiveness.

Current Status of Therapeutic Drug Monitoring in Australia and New Zealand: A Need for Improved Assay Evaluation, Best Practice Guidelines, and Professional Development

The measurement of drug concentrations, for clinical purposes, occurs in many diagnostic laboratories throughout Australia and New Zealand. However, the provision of a comprehensive therapeutic drug monitoring (TDM) service requires the additional elements of pre- and postanalytical advice to ensure that concentrations reported are meaningful, interpretable, and clinically applicable to the individual patient. The aim of this project was to assess the status of TDM services in Australia and New Zealand. A range of professions involved in key aspects of TDM was surveyed by questionnaire in late 2007. Information gathered included: the list of drugs assayed; analytical methods used; interpretation services offered; interpretative methods used; and further monitoring advice provided. Fifty-seven responses were received, of which 42% were from hospitals (public and/or private); 11% a hospital (public and/or private) and pathology provider; and 47% a pathology provider only (public and/or private). Results showed that TDM is applied to a large number of different drugs. Poorly performing assay methods were used in some cases, even when published guidelines recommended alternative practices. Although there was a wide array of assays available, the evidence suggested a need for better selection of assay methods. In addition, only limited advice and/or interpretation of results was offered. Of concern, less than 50% of those providing advice on aminoglycoside dosing in adults used pharmacokinetic tools with six of 37 (16.2%) respondents using Bayesian pharmacokinetic tools, the method recommended in the Australian Therapeutic Guidelines: Antibiotic. In conclusion, the survey highlighted deficiencies in the provision of TDM services, in particular assay method selection and both quality and quantity of postanalytical advice. A range of recommendations, some of which may have international implications, are discussed. There is a need to include measures of impact on clinical decision-making when assessing assay methodologies. Best practice guidelines and professional standards of practice in TDM are needed, supported by an active program of professional development to ensure the benefits of TDM are realized. This will require significant partnerships between the various professions involved.

Modelling the occurrence and severity of enoxaparin-induced bleeding and bruising events

AIMS To develop a population pharmacokinetic-pharmacodynamic model to describe the occurrence and severity of bleeding or bruising as a function of enoxaparin exposure. METHODS Data were obtained from a randomized controlled trial (n = 118) that compared conventional dosing of enoxaparin (product label) with an individualized dosing regimen. Anti-Xa concentrations were sampled using a sparse design and the size, location and type of bruising and bleeding event, during enoxaparin therapy, were collected daily. A population pharmacokinetic-pharmacodynamic analysis was performed using nonlinear mixed effects techniques. The final model was used to explore how the probability of events in patients with obesity and/or renal impairment varied under differing dosing strategies. RESULTS Three hundred and forty-nine anti-Xa concentrations were available for analysis. A two-compartment first-order absorption and elimination model best fit the data, with lean body weight describing between-subject variability in clearance and central volume of distribution. A three-category proportional-odds model described the occurrence and severity of events as a function of both cumulative enoxaparin AUC (cAUC) and subject age. Simulations showed that individualized dosing decreased the probability of a bleeding or major bruising event when compared with conventional dosing, which was most noticeable in subjects with obesity and renal impairment. CONCLUSIONS The occurrence and severity of a bleeding or major bruising event to enoxaparin, administered for the treatment of a thromboembolic disease, can be described as a function of both cAUC and subject age. Individualized dosing of enoxaparin will reduce the probability of an event.

New oral anticoagulants: appropriateness of prescribing in real-world setting.

The new oral anticoagulants (NOAC) have been extensively studied in the clinical trial setting; however, concerns remain about the safety of prescribing in the elderly and patients with renal impairment.

Individualized dosing of enoxaparin for subjects with renal impairment is superior to conventional dosing at achieving therapeutic concentrations.

Introduction: Enoxaparin is an anticoagulant used in the treatment of thromboembolic diseases. It is a hydrophilic molecule that is, predominantly, eliminated renally with few data to support dosing for subjects with renal impairment and/or obesity. A recently conducted randomized controlled clinical trial compared individualized enoxaparin doses based on lean body weight and renal function to conventional dosing. During this trial, anti-Xa concentrations were collected using a sparse sampling design and a population pharmacokinetic model was developed to describe the data. Methods: The current study evaluated the ability of the individualized dose to achieve and maintain anti-Xa concentrations within the therapeutic range (0.5-1.0 IU/mL) in subjects with renal impairment and/or obesity. A matched comparison of the two dosing strategies was undertaken using individual model predicted anti-Xa concentrations generated every 30 minutes to 120 hours post initiation of therapy. Concentration-time curves were generated for each subject and the proportion of time in the therapeutic, supratherapeutic, and subtherapeutic ranges were determined. Results: When compared with conventional dosing, individualized dosing in subjects with renal impairment resulted in a significantly greater proportion of time in the therapeutic range (median [range] = 69.9% (11.3-91.8) versus 42.6% [13.9-71.4], P = 0.02) and a significantly reduced proportion of time in the supratherapeutic range (median [range] = 9.3% (0%-67.0%) versus 37.1% (0%-85.7%), P = 0.02). Although there was a trend toward a greater proportion of time in the therapeutic range in obese subjects, this did not achieve statistical significance. Conclusions: Individualized dosing in subjects with renal impairment is more effective than conventional dosing at achieving and maintaining therapeutic anti-Xa concentrations, which could decrease the risk of bleeding events and mortality in these subjects.

Current dosing of low-molecular-weight heparins does not reflect licensed product labels: an international survey

AIMS Low-molecular-weight heparins (LMWHs) are used globally to treat thromboembolic diseases; however, there is much debate on how to prescribe effectively for patients who have renal impairment and/or obesity. We aimed to investigate the strategies used to dose-individualize LMWH therapy. METHODS We conducted an online survey of selected hospitals in Australia, New Zealand (NZ), United Kingdom (UK) and the United States (US). Outcome measures included: the percentage of hospitals which recommended that LMWHs were prescribed according to the product label (PL), the percentage of hospitals that dose-individualized LMWHs outside the PL based on renal function, body weight and anti-Xa activity and a summary of methods used to dose-individualize therapy. RESULTS A total of 257 surveys were suitable for analysis: 84 (33%) from Australia, 79 (31%) from the UK, 73 (28%) from the US and 21 (8%) from NZ. Formal dosing protocols were used in 207 (81%) hospitals, of which 198 (96%) did not adhere to the PL. Of these 198 hospitals, 175 (87%) preferred to dose-individualize based on renal function, 128 (62%) on body weight and 48 (23%) by monitoring anti-Xa activity. All three of these variables were used in 29 (14%) hospitals, 98 (47%) used two variables and 71 (34%) used only one variable. CONCLUSIONS Dose-individualization strategies for LMWHs, which contravene the PL, were present in 96% of surveyed hospitals. Common individualization methods included dose-capping, use of lean body size descriptors to calculate renal function and the starting dose, followed by post dose anti-Xa monitoring.

Reporting a Population Pharmacokinetic–Pharmacodynamic Study: A Journal’s Perspective

The key purpose of performing pharmacometric research is to aid optimization of drug dosing strategies. The statistical techniques required for this research are advanced, which can make interpretation of results difficult to convey to the target audience if they are unfamiliar with pharmacometric concepts. This article provides a basic guide for authors who wish to publish pharmacometric analyses in peer-reviewed journals. This guide is intended to enhance the readability, reproducibility and understanding of the work for a general readership, which may include clinicians, pharmacists and pharmacometricians. Presentation techniques and examples are offered, as well as a checklist of suggested contents for the manuscript.

Bayesian Estimation of Tobramycin Exposure in Patients with Cystic Fibrosis

ABSTRACT Fixed tobramycin (mg/kg) dosing is often inappropriate in patients with cystic fibrosis (CF), as pharmacokinetics are highly variable. The area under the concentration-time curve (AUC) is an exposure metric suited to monitoring in this population. Bayesian strategies to estimate AUC have been available for over 20 years but are not standard practice in the clinical setting. To assess their suitability for use in clinical practice, three AUC estimation methods using limited sampling were compared to measured true exposure by using intensive sampling tobramycin data. Adults prescribed once daily intravenous tobramycin had eight concentrations taken over 24 h. An estimate of true exposure within one dosing interval was calculated using the trapezoidal method and compared to three alternate estimates determined using (i) a two-sample log-linear regression (LLR) method (local hospital practice); (ii) a Bayesian estimate using one concentration (AUC1); and (iii) a Bayesian estimate using two concentrations (AUC2). Each method was evaluated against the true measured exposure by a Bland-Altman analysis. Twelve patients with a median (range) age and weight of 25 (18 to 36) years and 66.5 (51 to 76) kg, respectively, were recruited. There was good agreement between the true exposure and the three alternate estimates of AUC, with a mean AUC bias of <10 mg/liter · h in each case, i.e., −8.2 (LLR), 3.8 (AUC1), and 1.0 (AUC2). Bayesian analysis-based and LLR estimation methods of tobramycin AUC are equivalent to true exposure estimation. All three methods may be suitable for use in the clinical setting; however, a one-sample Bayesian method may be most useful in ambulatory patients for which coordinating blood samples is difficult. Suitably powered, randomized clinical trials are required to assess patient outcomes.

Routine plasma anti-Xa monitoring is required for low-molecular-weight heparins.

Low-molecular-weight heparins are anticoagulants used in the treatment of thrombosis. They have effectiveness and safety profiles similar to those of unfractionated heparin but are considered an attractive alternative because of their predictable pharmacokinetic characteristics. In this article, we demonstrate the need for therapeutic monitoring of low-molecular-weight heparins by addressing evidence arising from the literature and from modelling and simulation. First, treatment targets for unfractionated heparin and enoxaparin sodium were identified. Then, 10 000 virtual patients were simulated and the rate of treatment success was calculated. Treatment success was found to be similar between the two drugs (48% with unfractionated heparin and 54% with enoxaparin sodium). These results are consistent with empirical evidence from the literature and reflect the inadequacy of current dosing strategies in achieving desired biomarker targets. These results, along with recent advances in Bayesian forecasting techniques, support the need for routine monitoring and dose individualization of enoxaparin sodium in order to improve treatment success.