Rationale and Design of the Genotype-Blinded Trial of Torasemide for the Treatment of Hypertension (BHF UMOD).

BACKGROUND: Genome-wide association studies have identified single nucleotide polymorphisms (SNPs) near the uromodulin gene (UMOD) affecting uromodulin excretion and blood pressure (BP). Uromodulin is almost exclusively expressed in the thick ascending limb (TAL) of the loop of Henle and its effect on BP appears to be mediated via the TAL sodium transporter, NKCC2. Loop-diuretics block NKCC2 but are not commonly used in hypertension management. Volume overload is one of the primary drivers for uncontrolled hypertension, so targeting loop-diuretics to individuals who are more likely to respond to this drug class, using the UMOD genotype, could be an efficient precision medicine strategy. METHODS: The BHF UMOD Trial is a genotype-blinded, multicenter trial comparing BP response to torasemide between individuals possessing the AA genotype of the SNP rs13333226 and those possessing the G allele. 240 participants (≥18 years) with uncontrolled BP, on ≥1 antihypertensive agent for ≥3 months, will receive treatment with Torasemide, 5 mg daily for 16 weeks. Uncontrolled BP is average home systolic BP (SBP) >135 mmHg and/or diastolic BP >85 mmHg. The primary outcome is the change in 24-hour ambulatory SBP area under the curve between baseline and end of treatment. Sample size was calculated to detect a 4 mmHg difference between groups at 90% power. Approval by West of Scotland Research Ethics Committee 5 (16/WS/0160). RESULTS: The study should conclude August 2021. CONCLUSIONS: If our hypothesis is confirmed, a genotype-based treatment strategy for loop diuretics would help reduce the burden of uncontrolled hypertension. CLINICAL TRIALS REGISTRATION: https://clinicaltrials.gov/ct2/show/NCT03354897.

Longitudinal Assessment of the Effect of Atrasentan on Thoracic Bioimpedance in Diabetic Nephropathy: A Randomized, Double-Blind, Placebo-Controlled Trial.

BACKGROUND: Fluid retention is a common adverse event in patients who receive endothelin (ET) receptor antagonist therapy, including the highly selective ETA receptor antagonist, atrasentan. OBJECTIVE: We performed longitudinal assessments of thoracic bioimpedance in patients with type 2 diabetes mellitus and nephropathy to determine whether a decrease in bioimpedance accurately reflected fluid retention during treatment with atrasentan. STUDY DESIGN: We conducted a randomized, double-blind, placebo-controlled study in 48 patients with type 2 diabetes mellitus and nephropathy who were receiving stable doses of renin angiotensin system inhibitors and diuretics. METHODS: Patients were randomized 1:1:1 to placebo, atrasentan 0.5 mg, or atrasentan 1.25 mg once daily for 8 weeks. Thoracic bioimpedance, vital signs, clinical exams, and serologies were taken at weeks 1, 2, 4, 6, and 8, with the exception of serum hemoglobin, which was not taken at week 1, and serum brain natriuretic peptide, which was only taken at baseline, week 4, and week 8. RESULTS: Alterations in bioimpedance were more often present in those who received atrasentan than in those who received placebo, though overall differences were not statistically significant. Transient declines in thoracic bioimpedance during the first 2 weeks of atrasentan exposure occurred before or during peak increases in body weight and hemodilution (decreased serum hemoglobin). CONCLUSIONS: We conclude that thoracic bioimpedance did not reflect changes in weight gain or edema with atrasentan treatment in this study. However, the sample size was small, and it may be of interest to explore the use of thoracic bioimpedance in a larger population to understand its potential clinical use in monitoring fluid retention in patients with chronic kidney disease who receive ET receptor antagonists.

Prescribing Safety Assessment 2016: Delivery of a national prescribing assessment to 7343 UK final-year medical students.

AIMS: Newly graduated doctors write a large proportion of prescriptions in UK hospitals but recent studies have shown that they frequently make prescribing errors. The prescribing safety assessment (PSA) has been developed as an assessment of competence in relation to prescribing and supervising the use of medicines. This report describes the delivery of the PSA to all UK final-year medical students in 2016 (PSA2016). METHODS: The PSA is a 2-hour online assessment comprising eight sections which cover various aspects of prescribing defined within the outcomes of undergraduate education identified by the UK General Medical Council. Students sat one of four PSA 'papers', which had been standard-set using a modified Angoff process. RESULTS: A total of 7343 final-year medical students in all 31 UK medical schools sat the PSA. The overall pass rate was 95% with the pass rates for the individual papers ranging from 93 to 97%. The PSA was re-sat by 261 students who had failed and 80% of those candidates passed. The internal consistency (Cronbach's alpha) of the four papers ranged from 0.74 to 0.77 (standard error of measurement 4.13-4.24%). There was a statistically significant variation in performance between medical school cohorts (F = 32.6, P < 0.001) and a strongly positive correlation in performance for individual schools between PSA2015 and PSA2016 (r = 0.79, 95% CI 0.61-0.90; P < 0.01). CONCLUSIONS: PSA2016 demonstrated the feasibility of delivering a standardized national prescribing assessment online. The vast majority of UK final-year medical students were able to meet a prespecified standard of prescribing competence.

Modelling estimates of the burden of respiratory syncytial virus infection in children in the UK.

OBJECTIVE: The burden of respiratory syncytial virus (RSV) illness is not well characterised in primary care. We estimated the burden of disease attributable to RSV in children in the UK between 1995 and 2009. DESIGN: Time-series regression modelling. SETTING: A multiple linear regression model based on weekly viral surveillance (RSV and influenza, Public Health England), and controlled for non-specific seasonal drivers of disease, estimated the proportion of general practitioner (GP) episodes of care (counted as first visit in a series within 28 days; Clinical Practice Research Datalink, CPRD), hospitalisations (Hospital Episode Statistics, HES) and deaths (Office of National Statistics, ONS) attributable to RSV each season. PARTICIPANTS: Children 0-17 years registered with a GP in CPRD, or with a respiratory disease outcome in the HES or ONS databases. PRIMARY OUTCOME MEASURES: RSV-attributable burden of GP episodes, hospitalisations and deaths due to respiratory disease by age. RSV-attributable burden associated with selected antibiotic prescriptions. RESULTS: RSV-attributable respiratory disease in the UK resulted in an estimated 450 158 GP episodes, 29 160 hospitalisations and 83 deaths per average season in children and adolescents, with the highest proportions in children <6 months of age (14 441/100 000 population, 4184/100 000 and 6/100 000, respectively). In an average season, there were an estimated 125 478 GP episodes for otitis media and 416 133 prescriptions for antibiotics attributable to RSV. More GP episodes, hospitalisations and deaths from respiratory disease were attributable to RSV than to influenza in children under 5 years. CONCLUSIONS: The burden of RSV in children in the UK exceeds that of influenza. RSV in children and adolescents contributes substantially to GP office visits for a diverse range of illnesses, and was associated with an average 416 133 prescribed antibiotic courses per season. Effective antiviral treatments and preventive vaccines are urgently needed for the management of RSV infection in children. TRIAL REGISTRATION NUMBER: NCT01706302.

Prevalence and causes of prescribing errors: the PRescribing Outcomes for Trainee Doctors Engaged in Clinical Training (PROTECT) study.

OBJECTIVES: Study objectives were to investigate the prevalence and causes of prescribing errors amongst foundation doctors (i.e. junior doctors in their first (F1) or second (F2) year of post-graduate training), describe their knowledge and experience of prescribing errors, and explore their self-efficacy (i.e. confidence) in prescribing. METHOD: A three-part mixed-methods design was used, comprising: prospective observational study; semi-structured interviews and cross-sectional survey. All doctors prescribing in eight purposively selected hospitals in Scotland participated. All foundation doctors throughout Scotland participated in the survey. The number of prescribing errors per patient, doctor, ward and hospital, perceived causes of errors and a measure of doctors' self-efficacy were established. RESULTS: 4710 patient charts and 44,726 prescribed medicines were reviewed. There were 3364 errors, affecting 1700 (36.1%) charts (overall error rate: 7.5%; F1:7.4%; F2:8.6%; consultants:6.3%). Higher error rates were associated with : teaching hospitals (p<0.001), surgical (p = <0.001) or mixed wards (0.008) rather thanmedical ward, higher patient turnover wards (p<0.001), a greater number of prescribed medicines (p<0.001) and the months December and June (p<0.001). One hundred errors were discussed in 40 interviews. Error causation was multi-factorial; work environment and team factors were particularly noted. Of 548 completed questionnaires (national response rate of 35.4%), 508 (92.7% of respondents) reported errors, most of which (328 (64.6%) did not reach the patient. Pressure from other staff, workload and interruptions were cited as the main causes of errors. Foundation year 2 doctors reported greater confidence than year 1 doctors in deciding the most appropriate medication regimen. CONCLUSIONS: Prescribing errors are frequent and of complex causation. Foundation doctors made more errors than other doctors, but undertook the majority of prescribing, making them a key target for intervention. Contributing causes included work environment, team, task, individual and patient factors. Further work is needed to develop and assess interventions that address these.

Junior doctors' perceptions of their self-efficacy in prescribing, their prescribing errors and the possible causes of errors.

AIMS: The aim of the study was to explore and compare junior doctors' perceptions of their self-efficacy in prescribing, their prescribing errors and the possible causes of those errors. METHODS: A cross-sectional questionnaire study was distributed to foundation doctors throughout Scotland, based on Bandura's Social Cognitive Theory and Human Error Theory (HET). RESULTS: Five hundred and forty-eight questionnaires were completed (35.0% of the national cohort). F1s estimated a higher daytime error rate [median 6.7 (IQR 2-12.4)] than F2s [4.0 IQR (0-10) (P = 0.002)], calculated based on the total number of medicines prescribed. The majority of self-reported errors (250, 49.2%) resulted from unintentional actions. Interruptions and pressure from other staff were commonly cited causes of errors. F1s were more likely to report insufficient prescribing skills as a potential cause of error than F2s (P = 0.002). The prescribers did not believe that the outcomes of their errors were serious. F2s reported higher self-efficacy scores than F1s in most aspects of prescribing (P < 0.001). CONCLUSION: Foundation doctors were aware of their prescribing errors, yet were confident in their prescribing skills and apparently complacent about the potential consequences of prescribing errors. Error causation is multi-factorial often due to environmental factors, but with lack of knowledge also contributing. Therefore interventions are needed at all levels, including environmental changes, improving knowledge, providing feedback and changing attitudes towards the role of prescribing as a major influence on patient outcome.

Learning curves, taking instructions, and patient safety: using a theoretical domains framework in an interview study to investigate prescribing errors among trainee doctors.

BACKGROUND: Prescribing errors are a major source of morbidity and mortality and represent a significant patient safety concern. Evidence suggests that trainee doctors are responsible for most prescribing errors. Understanding the factors that influence prescribing behavior may lead to effective interventions to reduce errors. Existing investigations of prescribing errors have been based on Human Error Theory but not on other relevant behavioral theories. The aim of this study was to apply a broad theory-based approach using the Theoretical Domains Framework (TDF) to investigate prescribing in the hospital context among a sample of trainee doctors. METHOD: Semistructured interviews, based on 12 theoretical domains, were conducted with 22 trainee doctors to explore views, opinions, and experiences of prescribing and prescribing errors. Content analysis was conducted, followed by applying relevance criteria and a novel stage of critical appraisal, to identify which theoretical domains could be targeted in interventions to improve prescribing. RESULTS: Seven theoretical domains met the criteria of relevance: "social professional role and identity," "environmental context and resources," "social influences," "knowledge," "skills," "memory, attention, and decision making," and "behavioral regulation." From critical appraisal of the interview data, "beliefs about consequences" and "beliefs about capabilities" were also identified as potentially important domains. Interrelationships between domains were evident. Additionally, the data supported theoretical elaboration of the domain behavioral regulation. CONCLUSIONS: In this investigation of hospital-based prescribing, participants' attributions about causes of errors were used to identify domains that could be targeted in interventions to improve prescribing. In a departure from previous TDF practice, critical appraisal was used to identify additional domains that should also be targeted, despite participants' perceptions that they were not relevant to prescribing errors. These were beliefs about consequences and beliefs about capabilities. Specifically, in the light of the documented high error rate, beliefs that prescribing errors were not likely to have consequences for patients and that trainee doctors are capable of prescribing without error should also be targeted in an intervention. This study is the first to suggest critical appraisal for domain identification and to use interview data to propose theoretical elaborations and interrelationships between domains.

UK medicines policy: the role of clinical pharmacologists.

Clinical pharmacologists are the only medical specialists whose training focuses specifically on the safe, effective and cost-effective use of medicines, underpinned by an understanding of drug discovery, drug regulation, pharmacology, translational medicine and the performance of clinical trials. This unique perspective has allowed them to provide expertise and leadership in medicines regulation, medicines policy, health technology assessment and drug pricing. Clinical pharmacologists assisted in the creation of the Committee on Safety of Medicines (now the Commission on Human Medicines), the Yellow Card Scheme, the National Institute of Health and Clinical Excellence (NICE) and related organizations in Scotland and Wales, and contributed to clinical guidelines (through the Scottish Intercollegiate Guidelines Network) and the British National Formulary. Their research work has contributed substantially, through translational medicine and therapeutics, to the development of new medicines and, as a result, creation of health and wealth in the UK. Their work in medicines policy has served to protect patients from harms associated with the use of medicines. A reduction in the number of able junior doctors attracted to a career in clinical pharmacology, a reduction in the number of training posts, and an ageing population of academic trainers, puts the future of the specialty, and its contribution to patient safety and UK wealth creation, at substantial risk. Urgent measures are needed to convince the NHS and government that these essential skills should be protected and nurtured.

An investigation into the effect of advice from the Scottish Medicines Consortium on the use of medicines in Scotland's Health Service.

AIMS: The aims of the study were to determine the effect of advice from the Scottish Medicines Consortium (SMC) on the use of medicines within Scotland's National Health Service (NHS) and generate hypotheses that may explain differences in the impact of advice on the use of individual medicines. METHODS: A retrospective analysis of medicine advice issued between January 2002 and December 2005 was performed. The inclusion criterion was medicines with a 'not recommended for use' decision (NRD) from the SMC (57 out of 207 medicines submitted). The exclusion criteria were medicines used predominately in secondary care and medicines with multiple indications. In total, 20 medicines fulfilled these criteria. The volume of prescribing was measured by each medicine's gross ingredient cost to the prescribing budget. RESULTS: Before the SMC published advice there was use, though limited, of all 20 medicines. After an NRD, the pattern of use was variable, with the use of some medicines stabilizing or declining but others increasing. We identified factors to help explain unexpected use in some cases. These included delays between medicine launch and initial SMC advice, the publication of conflicting advice from different national bodies and failure to engage with relevant clinical experts early in the medicine review process. CONCLUSIONS: This study demonstrates the complex relationship between advice following health technology assessment and change in clinical practice. When this study was done there were significant limitations in the collection of prescribing data within the NHS, which recent changes promise to improve.

Predictors of placebo group decline in the Alzheimer's disease Assessment Scale-cognitive subscale (ADAS-Cog) in 24 week clinical trials of Alzheimer's disease.

One limitation of several recent 24 week Alzheimer's disease (AD) clinical trials was the lack of cognitive decline detected by the AD Assessment Scale-cognitive subscale (ADAS-cog) in the placebo groups, possibly obscuring true medication effects. Data from 733 individuals in the placebo arms of six AD clinical trials performed 1996-1997 were pooled to examine the relationship of clinical, demographic, and genetic characteristics with the 24 week change in ADAS-cog. Baseline cognitive and functional status and the screening-to-baseline change in ADAS-cog were the strongest independent predictors of the 24 week change in ADAS-cog. The ADAS-cog did not detect progression in patients with mild dementia (screening Mini-Mental State Exam, MMSE, >or=20). The change in ADAS-cog from screening to baseline was inversely correlated with the 24 week change score; it was more difficult to detect cognitive decline at 24 weeks if individuals markedly worsened from screening to baseline. The effects of baseline MMSE and screening-to-baseline change in ADAS-cog generalized to the placebo group (N=106) of another AD study performed in 2004-2005. Overcoming lack of placebo decline in AD clinical trials will require scales more sensitive to cognitive decline in mild AD and strategies to reduce within-person variability in outcome measures.

Undergraduate preparation for prescribing: the views of 2413 UK medical students and recent graduates.

AIMS: To gather opinions from UK medical students and recent graduates about their undergraduate training to prescribe and their confidence about meeting the relevant competencies identified by the General Medical Council (GMC). METHODS: We designed a web-based survey that was distributed to UK medical students and first year Foundation doctors (graduation years 2006-2008) via medical schools and postgraduate networks. RESULTS: Analysis was restricted to 2413 responses from students graduating in 2006-2008 from the 25 UK medical schools (mean 96.5 per school) with a complete undergraduate curriculum. Distinct courses and assessments in 'clinical pharmacology & therapeutics (or equivalent)' were identified by 17% and 13%, respectively, with mode of learning described most commonly as 'opportunistic learning during clinical attachments' (41%). Only 38% felt 'confident' about prescription writing and only a minority (35%) had filled in a hospital prescription chart more than three times during training. The majority (74%) felt that the amount of teaching in this area was 'too little' or 'far too little', and most tended to disagree or disagreed that their assessment 'thoroughly tested knowledge and skills' (56%). When asked if they were confident that they would be able to achieve the prescribing competencies set out by the GMC, 42% disagreed or tended to disagree, whereas only 29% agreed or tended to agree. CONCLUSIONS: Many respondents clearly perceived a lack of learning opportunities and assessment related to the safe and effective use of drugs and had little confidence that they would meet the competencies identified by the GMC. There is an urgent need to review undergraduate training in this area.

The impact of prognosis without treatment on doctors' and patients' resource allocation decisions and its relevance to new drug recommendation processes.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT: The dominant health economic units upon which new treatment funding decisions are made are the incremental cost per life year gained (LYG) or the cost per quality-adjusted life year (QALY) gained. Neither of these units modifies the amount of health gained, by the amount of health patients would have had if they had not been given the treatment under consideration, which may unfairly undervalue the treatments for poor prognosis conditions. How certain patients make decisions about their own treatment has previously been explored, but not how they, or doctors, would allocate hypothetical resource within a healthcare system given information on disease-treatment scenarios' prognoses with and without treatment. WHAT THIS STUDY ADDS: Information on prognosis without treatment is used within the resource allocation strategies of many doctors and most patients. Individuals use this information in a variety of different ways and a single dominant strategy for quantitative modification of health units is not apparent. Information on prognosis without treatment, or prognosis with standard treatment, is available from the control arm of randomized controlled clinical trials and should be used qualitatively to facilitate decision-making around the second inflexion point on cost per QALY/LYG acceptability curves. AIMS: Health economic assessments increasingly contribute to funding decisions on new treatments. Treatments for many poor prognosis conditions perform badly in such assessments because of high costs and modest effects on survival. We aimed to determine whether underlying shortness of prognosis should also be considered as a modifier in such assessments. METHODS: Two hundred and eighty-three doctors and 201 oncology patients were asked to allocate treatment resource between hypothetical patients with unspecified life-shortening diseases. The prognoses with and without treatment were varied such that consistent use of one of four potential allocation strategies could be deduced: life years gained (LYGs) - which did not incorporate prognosis without treatment information; percentage increase in life years (PILY); life expectancy with treatment (LEWT) or immediate risk of death (IRD). RESULTS: Random choices were rare; 47% and 64% of doctors and patients, respectively, used prognosis without treatment in their strategies; while 50% and 32%, respectively, used pure LYG-based strategies. Ranking orders were LYG > PILY > IRD > LEWT (doctors) and LEWT > LYG > IRD > PILY (patients). When LYG information alone could not be used, 76% of doctors prioritized shorter prognoses, compared with 45% of patients. CONCLUSIONS: Information on prognosis without treatment is used within the resource allocation strategies of many doctors and most patients, and should be considered as a qualitative modifier during the health economic assessments of new treatments for life-shortening diseases. A single dominant strategy incorporating this information for any quantitative modification of health units is not apparent.

The influence of primary care prescribing rates for new drugs on spontaneous reporting of adverse drug reactions.

INTRODUCTION: Adverse drug reaction (ADR) reporting makes a vital contribution to pharmacovigilance, although the factors that influence the reporting rate remain unclear. The aim of this study was to investigate whether the variation in the rate of reporting of suspected ADRs in different regions of Scotland was explained by differences in local prescribing practice and to quantify the extent of this influence. METHODS: Population and primary care prescribing data were obtained for ten geographical areas based on the 15 administrative regions of the National Health Service in Scotland. All reports of suspected ADRs received from within Scotland for 2000 and 2001 were available from the regional monitoring centre (Committee on Safety of Medicines, Scotland). The primary analysis was based on 14 medications that appeared in the 'top ten' list for the frequency of reported ADRs for either year. Reporting rates for each area were expressed both in terms of population (reports per million people) and in terms of estimated exposure to those medications in primary care (reports per 1000 prescriptions). For each analysis, the Pearson correlation coefficient between reporting and prescribing data was calculated using SPSS software. RESULTS: The 'top ten' medications accounted for 1715 of 2817 (60.9%, 95% CI 59.1, 62.7) ADR reports but only 2.2 million out of a total of 128 million primary care prescriptions (1.7%). Although there was a 3-fold geographical variation in the per-population ADR reporting rate, there was a close correlation between local reporting of ADRs and prescribing of the index medications (p = 0.66, p = 0.04, respectively). This implies that 44% of the observed variation in reporting rate can be attributed to variation in prescribing within the same population. DISCUSSION: Spontaneous ADR reporting in Scotland over the 2 years studied was highly concentrated on a small number of medications that were under intensive surveillance. Although there was a 3-fold variation in reporting rates from individual geographic areas when corrected for the size of the population, primary care prescribing data showed nearly half of this local variation in reporting rates could be explained by differences in prescribing. This study highlights the importance of considering prescribing practice when interpreting spontaneous ADR reporting data.