BackgroundAntihypertensives are effective at reducing the risk of cardiovascular disease, but limited data exist quantifying their association with serious adverse events, particularly in older people with frailty. This study aimed to examine this association using nationally representative electronic health record data.Methods and findingsThis was a retrospective cohort study utilising linked data from 1,256 general practices across England held within the Clinical Practice Research Datalink between 1998 and 2018. Included patients were aged 40+ years, with a systolic blood pressure reading between 130 and 179 mm Hg, and not previously prescribed antihypertensive treatment. The main exposure was defined as a first prescription of antihypertensive treatment. The primary outcome was hospitalisation or death within 10 years from falls. Secondary outcomes were hypotension, syncope, fractures, acute kidney injury, electrolyte abnormalities, and primary care attendance with gout. The association between treatment and these serious adverse events was examined by Cox regression adjusted for propensity score. This propensity score was generated from a multivariable logistic regression model with patient characteristics, medical history and medication prescriptions as covariates, and new antihypertensive treatment as the outcome. Subgroup analyses were undertaken by age and frailty. of 3,834,056 patients followed for a median of 7.1 years, 484,187 (12.6%) were prescribed new antihypertensive treatment in the 12 months before the index date (baseline). Antihypertensives were associated with an increased risk of hospitalisation or death from falls (adjusted hazard ratio [aHR] 1.23, 95% confidence interval (CI) 1.21 to 1.26), hypotension (aHR 1.32, 95% CI 1.29 to 1.35), syncope (aHR 1.20, 95% CI 1.17 to 1.22), acute kidney injury (aHR 1.44, 95% CI 1.41 to 1.47), electrolyte abnormalities (aHR 1.45, 95% CI 1.43 to 1.48), and primary care attendance with gout (aHR 1.35, 95% CI 1.32 to 1.37). The absolute risk of serious adverse events with treatment was very low, with 6 fall events per 10,000 patients treated per year. In older patients (80 to 89 years) and those with severe frailty, this absolute risk was increased, with 61 and 84 fall events per 10,000 patients treated per year (respectively). Findings were consistent in sensitivity analyses using different approaches to address confounding and taking into account the competing risk of death. A strength of this analysis is that it provides evidence regarding the association between antihypertensive treatment and serious adverse events, in a population of patients more representative than those enrolled in previous randomised controlled trials. Although treatment effect estimates fell within the 95% CIs of those from such trials, these analyses were observational in nature and so bias from unmeasured confounding cannot be ruled out.ConclusionsAntihypertensive treatment was associated with serious adverse events. Overall, the absolute risk of this harm was low, with the exception of older patients and those with moderate to severe frailty, where the risks were similar to the likelihood of benefit from treatment. In these populations, physicians may want to consider alternative approaches to management of blood pressure and refrain from prescribing new treatment.

BACKGROUND: Antidepressants are one of the most widely prescribed drugs in the global north. However, little is known about the health consequences of long-term treatment. AIMS: This study aimed to investigate the association between antidepressant use and adverse events. METHOD: the study cohort consisted of UK Biobank participants whose data was linked to primary care records (N = 222 121). We assessed the association between antidepressant use by drug class (selective serotonin reuptake inhibitors (SSRIs) and 'other') and four morbidity (diabetes, hypertension, coronary heart disease (CHD), cerebrovascular disease (CV)) and two mortality (cardiovascular disease (CVD) and all-cause) outcomes, using Cox's proportional hazards model at 5- and 10-year follow-up. RESULTS: SSRI treatment was associated with decreased risk of diabetes at 5 years (hazard ratio 0.64, 95% CI 0.49-0.83) and 10 years (hazard ratio 0.68, 95% CI 0.53-0.87), and hypertension at 10 years (hazard ratio 0.77, 95% CI 0.66-0.89). At 10-year follow-up, SSRI treatment was associated with increased risks of CV (hazard ratio 1.34, 95% CI 1.02-1.77), CVD mortality (hazard ratio 1.87, 95% CI 1.38-2.53) and all-cause mortality (hazard ratio 1.73, 95% CI 1.48-2.03), and 'other' class treatment was associated with increased risk of CHD (hazard ratio 1.99, 95% CI 1.31-3.01), CVD (hazard ratio 1.86, 95% CI 1.10-3.15) and all-cause mortality (hazard ratio 2.20, 95% CI 1.71-2.84). CONCLUSIONS: Our findings indicate an association between long-term antidepressant usage and elevated risks of CHD, CVD mortality and all-cause mortality. Further research is needed to assess whether the observed associations are causal, and elucidate the underlying mechanisms.

Objectives to investigate whether better continuity of care is associated with increased prescribing of clinically relevant medication and improved medication adherence. Setting Random sample of 300 000 patients aged 30+ in 2017 within 83 English general practitioner (GP) practices from the Clinical Practice Research Datalink. Design Patients were assigned to a randomly selected index date in 2017 on which medication use and continuity of care were determined. Adjusted associations between continuity of care and the prescribing and adherence of five cardiovascular medication groups were examined using logistic regression. Participants Continuity of Care Index was calculated for 173 993 patients with 4+ GP consultations 2 years prior to their index date and divided into five categories: absence of continuity, below-average continuity, average, above-average continuity and perfect continuity. Main outcome measures (A) Prescription for statins (primary or secondary prevention separately), anticoagulants, antiplatelet agents and antihypertensives covering the patient's index date. (B) Adherence (>80%) estimated using medication possession ratio. Results There was strong evidence (p

BACKGROUND: Hypertensive disorders of pregnancy are common pregnancy complications that are associated with greater cardiovascular disease risk for mothers. However, risk of cardiovascular disease subtypes associated with gestational hypertension or pre-eclampsia is unclear. The present study aims to compare the risk of cardiovascular disease outcomes for women with and without a history of gestational hypertension and pre-eclampsia using national hospital admissions data. METHODS: This was a retrospective cohort study of national medical records from all National Health Service hospitals in England. Women who had one or more singleton live births in England between 1997 and 2015 were included in the analysis. Risk of total cardiovascular disease and 19 pre-specified cardiovascular disease subtypes, including stroke, coronary heart disease, cardiomyopathy and peripheral arterial disease, was calculated separately for women with a history of gestational hypertension and pre-eclampsia compared to normotensive pregnancies. RESULTS: Amongst 2,359,386 first live births, there were 85,277 and 74,542 hospital admissions with a diagnosis of gestational hypertension and pre-eclampsia, respectively. During 18 years (16,309,386 person-years) of follow-up, the number and incidence of total CVD for normotensive women, women with prior gestational hypertension and women with prior pre-eclampsia were n = 8668, 57.1 (95% CI: 55.9-58.3) per 100,000 person-years; n = 521, 85.8 (78.6-93.5) per 100,000 person-years; and n = 518, 99.3 (90.9-108.2) per 100,000 person-years, respectively. Adjusted HRs (aHR) for total CVD were aHR (95% CI) = 1.45 (1.33-1.59) for women with prior gestational hypertension and aHR = 1.62 (1.48-1.78) for women with prior pre-eclampsia. Gestational hypertension was strongly associated with dilated cardiomyopathy, aHR = 2.85 (1.67-4.86), and unstable angina, aHR = 1.92 (1.33-2.77). Pre-eclampsia was strongly associated with hypertrophic cardiomyopathy, aHR = 3.27 (1.49-7.19), and acute myocardial infarction, aHR = 2.46 (1.72-3.53). Associations were broadly homogenous across cardiovascular disease subtypes and increased with a greater number of affected pregnancies. CONCLUSIONS: Women with either previous gestational hypertension or pre-eclampsia are at greater risk of a range of cardiovascular outcomes. These women may benefit from clinical risk assessment or early interventions to mitigate their greater risk of various cardiovascular outcomes.

Background: Updatable estimates of COVID-19 onset, progression, and trajectories underpin pandemic mitigation efforts. To identify and characterise disease trajectories, we aimed to define and validate ten COVID-19 phenotypes from nationwide linked electronic health records (EHR) using an extensible framework. Methods: in this cohort study, we used eight linked National Health Service (NHS) datasets for people in England alive on Jan 23, 2020. Data on COVID-19 testing, vaccination, primary and secondary care records, and death registrations were collected until Nov 30, 2021. We defined ten COVID-19 phenotypes reflecting clinically relevant stages of disease severity and encompassing five categories: positive SARS-CoV-2 test, primary care diagnosis, hospital admission, ventilation modality (four phenotypes), and death (three phenotypes). We constructed patient trajectories illustrating transition frequency and duration between phenotypes. Analyses were stratified by pandemic waves and vaccination status. Findings: Among 57 032 174 individuals included in the cohort, 13 990 423 COVID-19 events were identified in 7 244 925 individuals, equating to an infection rate of 12·7% during the study period. of 7 244 925 individuals, 460 737 (6·4%) were admitted to hospital and 158 020 (2·2%) died. of 460 737 individuals who were admitted to hospital, 48 847 (10·6%) were admitted to the intensive care unit (ICU), 69 090 (15·0%) received non-invasive ventilation, and 25 928 (5·6%) received invasive ventilation. Among 384 135 patients who were admitted to hospital but did not require ventilation, mortality was higher in wave 1 (23 485 [30·4%] of 77 202 patients) than wave 2 (44 220 [23·1%] of 191 528 patients), but remained unchanged for patients admitted to the ICU. Mortality was highest among patients who received ventilatory support outside of the ICU in wave 1 (2569 [50·7%] of 5063 patients). 15 486 (9·8%) of 158 020 COVID-19-related deaths occurred within 28 days of the first COVID-19 event without a COVID-19 diagnoses on the death certificate. 10 884 (6·9%) of 158 020 deaths were identified exclusively from mortality data with no previous COVID-19 phenotype recorded. We observed longer patient trajectories in wave 2 than wave 1. Interpretation: Our analyses illustrate the wide spectrum of disease trajectories as shown by differences in incidence, survival, and clinical pathways. We have provided a modular analytical framework that can be used to monitor the impact of the pandemic and generate evidence of clinical and policy relevance using multiple EHR sources. Funding: British Heart Foundation Data Science Centre, led by Health Data Research UK.

BACKGROUND: Deprescribing of antihypertensive medications for older patients with normal blood pressure is recommended by some clinical guidelines, where the potential harms of treatment may outweigh the benefits. This study aimed to assess the cost-effectiveness of this approach. METHODS: a Markov patient-level simulation was undertaken to model the effect of withdrawing one antihypertensive compared with usual care, over a life-time horizon. Model population characteristics were estimated using data from the OPTiMISE antihypertensive deprescribing trial, and the effects of blood pressure changes on outcomes were derived from the literature. Health-related quality of life was modeled in Quality-Adjusted Life Years (QALYs) and presented as costs per QALY gained. RESULTS: in the base-case analysis, medication reduction resulted in lower costs than usual care (mean difference £185), but also lower QALYs (mean difference 0.062) per patient over a life-time horizon. Usual care was cost-effective at £2975 per QALY gained (more costly, but more effective). Medication reduction resulted more heart failure and stroke/TIA events but fewer adverse events. Medication reduction may be the preferred strategy at a willingness-to-pay of £20 000/QALY, where the baseline absolute risk of serious drug-related adverse events was ≥7.7% a year (compared with 1.7% in the base-case). CONCLUSIONS: Although there was uncertainty around many of the assumptions underpinning this model, these findings suggest that antihypertensive medication reduction should not be attempted in many older patients with controlled systolic blood pressure. For populations at high risk of adverse effects, deprescribing may be beneficial, but a targeted approach would be required in routine practice.

OBJECTIVE: to develop and externally validate the STRAtifying Treatments in the multi-morbid Frail elderlY (STRATIFY)-Falls clinical prediction model to identify the risk of hospital admission or death from a fall in patients with an indication for antihypertensive treatment. DESIGN: Retrospective cohort study. SETTING: Primary care data from electronic health records contained within the UK Clinical Practice Research Datalink (CPRD). PARTICIPANTS: Patients aged 40 years or older with at least one blood pressure measurement between 130 mm Hg and 179 mm Hg. MAIN OUTCOME MEASURE: First serious fall, defined as hospital admission or death with a primary diagnosis of a fall within 10 years of the index date (12 months after cohort entry). Model development was conducted using a Fine-Gray approach in data from CPRD GOLD, accounting for the competing risk of death from other causes, with subsequent recalibration at one, five, and 10 years using pseudo values. External validation was conducted using data from CPRD Aurum, with performance assessed through calibration curves and the observed to expected ratio, C statistic, and D statistic, pooled across general practices, and clinical utility using decision curve analysis at thresholds around 10%. RESULTS: Analysis included 1 772 600 patients (experiencing 62 691 serious falls) from CPRD GOLD used in model development, and 3 805 366 (experiencing 206 956 serious falls) from CPRD Aurum in the external validation. The final model consisted of 24 predictors, including age, sex, ethnicity, alcohol consumption, living in an area of high social deprivation, a history of falls, multiple sclerosis, and prescriptions of antihypertensives, antidepressants, hypnotics, and anxiolytics. Upon external validation, the recalibrated model showed good discrimination, with pooled C statistics of 0.833 (95% confidence interval 0.831 to 0.835) and 0.843 (0.841 to 0.844) at five and 10 years, respectively. Original model calibration was poor on visual inspection and although this was improved with recalibration, under-prediction of risk remained (observed to expected ratio at 10 years 1.839, 95% confidence interval 1.811 to 1.865). Nevertheless, decision curve analysis suggests potential clinical utility, with net benefit larger than other strategies. CONCLUSIONS: This prediction model uses commonly recorded clinical characteristics and distinguishes well between patients at high and low risk of falls in the next 1-10 years. Although miscalibration was evident on external validation, the model still had potential clinical utility around risk thresholds of 10% and so could be useful in routine clinical practice to help identify those at high risk of falls who might benefit from closer monitoring or early intervention to prevent future falls. Further studies are needed to explore the appropriate thresholds that maximise the model's clinical utility and cost effectiveness.

Introduction: Polypharmacy is increasingly common, and associated with undesirable consequences. Polypharmacy management necessitates balancing therapeutic benefits and risks, and varying clinical and patient priorities. Current guidance for managing polypharmacy is not supported by high quality evidence. The aim of the Improving Medicines use in People with Polypharmacy in Primary Care (IMPPP) trial is to evaluate the effectiveness of an intervention to optimise medication use for patients with polypharmacy in a general practice setting. Methods: This trial will use a multicentre, open-label, cluster-randomised controlled approach, with two parallel groups. Practices will be randomised to a complex intervention comprising structured medication review (including interprofessional GP/pharmacist treatment planning and patient-facing review) supported by performance feedback, financial incentivisation, clinician training and clinical informatics (intervention), or usual care (control). Patients with polypharmacy and triggering potentially inappropriate prescribing (PIP) indicators will be recruited in each practice using a computerised search of health records. 37 practices will recruit 50 patients, and review them over a 26-week intervention delivery period. The primary outcome is the mean number of PIP indicators triggered per patient at 26 weeks follow-up, determined objectively from coded GP electronic health records. Secondary outcomes will include patient reported outcome measures, and health and care service use. The main intention-to-treat analysis will use linear mixed effects regression to compare number of PIP indicators triggered at 26 weeks post-review between groups, adjusted for baseline (pre-randomisation) values. A nested process evaluation will explore implementation of the intervention in primary care. Ethics and dissemination: the protocol and associated study materials have been approved by the Wales REC 6, NHS Research Ethics Committee (REC reference 19/WA/0090), host institution and Health Research Authority. Research outputs will be published in peer-reviewed journals and relevant conferences, and additionally disseminated to patients and the public, clinicians, commissioners and policy makers. ISRCTN Registration: 90146150 (28/03/2019)

BACKGROUND: General Practitioners (GPs) report high levels of burnout, job dissatisfaction, and turnover intention. The complexity of presenting problems to general practice makes diagnostic uncertainty a common occurrence that has been linked to burnout. The interrelationship between diagnostic uncertainty with other factors such as burnout, job satisfaction and turnover intention have not been previously examined. OBJECTIVES: to examine associations between diagnostic uncertainty, emotional exhaustion (EE), depersonalization (DP), job satisfaction, and turnover intention in GPs. METHODS: Seventy general practices in England were randomly selected through the Oxford-Royal College of General Practitioners Research and Surveillance Centre (RCGP-RSC). A total of 348 GPs within 67 these practices completed a 10-item online questionnaire which included questions on GP characteristics, work-life balance, job satisfaction, sickness presenteeism, diagnostic uncertainty, turnover intention as well as EE and DP. Associations between diagnostic uncertainty and each of EE, DP, job satisfaction, and turnover intention were evaluated in multivariate mixed-effect ordinal logistic regressions whilst adjusting for covariates, to account for the correlation in the three outcomes of interest. RESULTS: Almost one-third of GPs (n = 101; 29%) reported experiencing >10% of diagnostic uncertainty in their day-to-day practice over the past year. GPs reporting greater diagnostic uncertainty had higher levels of EE [OR = 3.90; 95% CI = (2.54, 5.99)], job dissatisfaction [OR = 2.01; 95% CI = (1.30, 3.13)] and turnover intention [OR = 4.51; 95% CI = (2.86, 7.11)]. GPs with no sickness presenteeism had lower levels of EE [OR = 0.53; 95% CI = (0.35, 0.82)], job dissatisfaction [OR = 0.56; 95% CI = (0.35, 0.88)], and turnover intention [OR = 0.61; 95% CI = (0.41, 0.91)]. CONCLUSION: Diagnostic uncertainty may not only negatively impact on the wellbeing of GPs, but could also have adverse implications on workforce retention in primary care.

Aims: Novel oral iron supplements may be associated with a reduced incidence of adverse drug reactions compared to standard treatments of iron deficiency anaemia. The aim was to establish their value-based price under conditions of uncertainty surrounding their tolerability. Methods: a discrete-time Markov model was developed to assess the value-based price of oral iron preparations based on their incremental cost per quality-adjusted life year (QALY) gained from the perspective of the NHS in the UK. Primary and secondary care resource use and health state occupancy probabilities were estimated from routine electronic health records; and unit costs and health state utilities were derived from published sources. Patients were pre-menopausal women with iron deficiency anaemia who were prescribed oral iron supplementation between 2000 and 2014. Results: the model reflecting current use of iron salts yielded a mean total cost to the NHS of £779, and 0.84 QALYs over 12 months. If a new iron preparation were to reduce the risk of adverse drug reactions by 30–40%, then its value-based price, based on a threshold of £20 000 per QALY, would be in the region of £10–£13 per month, or about 7–9 times the average price of basic iron salts. Conclusions: There are no adequate, direct comparisons of new oral iron supplements to ferrous iron salts, and therefore other approaches are needed to assess their value. Our modelling shows that they are potentially cost-effective at prices that are an order of magnitude higher than existing iron salts.

BACKGROUND: Clinical medication reviews are a recognised strategy to address polypharmacy, a key part of general practice and positively associated with patient safety and clinical effectiveness. To date there has been little investigation of the patient perspective of medication reviews. OBJECTIVE: to explore patient experiences of medication review including the processes and activities that led up to and shaped the review. METHODS: Qualitative interview study within 10 general practices in Bristol. Participants were adults with polypharmacy (≥ 4 medications) and ≥ 2 long-term conditions who had a record of medication review with either a GP or pharmacist. Interviews were transcribed verbatim and analysed thematically using a data driven approach. Co-design work was undertaken with four patient and public involvement advisers to design and develop resources to support patient preparation for medication review. RESULTS: Twenty-one patients were interviewed (10 female, mean age 73 years, range 59-88 years). Medication review was viewed as an opportunity to assess the effectiveness and need for medications. Participants expected the review to focus upon medication related concerns, side-effects and symptoms. Those who were newer to review, were uncertain of the intended purpose, and described their review as a box-ticking exercise. Some participants were unfamiliar with the role of the pharmacist and expressed a lack of confidence in their clinical skills and knowledge. Face-to-face consultation and relationship continuity were considered important for efficient and effective medication review. Results informed co-production of a patient information leaflet to facilitate greater patient engagement and involvement in medication review. CONCLUSIONS: a lack of understanding of the rationale for medication review can limit the value patients attach to these healthcare encounters. Improved prior communication and information around the intended purpose and potential benefits of medication review may enhance patient engagement and improve patient experience and outcomes.

Objectives: the study aims to explore the use of regression discontinuity analysis (RDA) to examine effects of prescription of statins on total cholesterol and adverse outcomes (type 2 diabetes, rhabdomyolysis and myopathy, myalgia and myositis, liver disease, CVD, and mortality). Study Design and Setting: We conducted a prospective cohort study using the Clinical Practice Research Datalink including patients with QRISK scores of 10 to 30 in 2010 to 2013 who were last followed-up in October 2016. Comparing patients with QRISK≥20 and QRISK

Abstract
. Background
. Up to 50% of medicines are not used as intended, resulting in poor health and economic outcomes. Medicines optimisation is ‘a person-centred approach to safe and effective medicines use, to ensure people obtain the best possible outcomes from their medicines’. The purpose of this exercise was to co-produce a prioritised research agenda for medicines optimisation using a multi-stakeholder (patient, researcher, public and health professionals) approach.
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. Methods
. A three-stage, multiple method process was used including: generation of preliminary research questions (Stage 1) using a modified Nominal Group Technique; electronic consultation and ranking with a wider multi-stakeholder group (Stage 2); a face-to-face, one-day consensus meeting involving representatives from all stakeholder groups (Stage 3).
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. Results
. In total, 92 research questions were identified during Stages 1 and 2 and ranked in order of priority during stage 3. Questions were categorised into four areas: ‘Patient Concerns’ [e.g. is there a shared decision (with patients) about using each medicine?], ‘Polypharmacy’ [e.g. how to design health services to cope with the challenge of multiple medicines use?], ‘Non-Medical Prescribing’ [e.g. how can the contribution of non-medical prescribers be optimised in primary care?], and ‘Deprescribing’ [e.g. what support is needed by prescribers to deprescribe?]. A significant number of the 92 questions were generated by Patient and Public Involvement representatives, which demonstrates the importance of including this stakeholder group when identifying research priorities.
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. Conclusions
. A wide range of research questions was generated reflecting concerns which affect patients, practitioners, the health service, as well the ethical and philosophical aspects of the prescribing and deprescribing of medicines. These questions should be used to set future research agendas and funding commissions.
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Objective to examine the association between antihypertensive treatment and specific adverse events. Design Systematic review and meta-analysis. Eligibility criteria Randomised controlled trials of adults receiving antihypertensives compared with placebo or no treatment, more antihypertensive drugs compared with fewer antihypertensive drugs, or higher blood pressure targets compared with lower targets. To avoid small early phase trials, studies were required to have at least 650 patient years of follow-up. Information sources Searches were conducted in Embase, Medline, CENTRAL, and the Science Citation Index databases from inception until 14 April 2020. Main outcome measures the primary outcome was falls during trial follow-up. Secondary outcomes were acute kidney injury, fractures, gout, hyperkalaemia, hypokalaemia, hypotension, and syncope. Additional outcomes related to death and major cardiovascular events were extracted. Risk of bias was assessed using the Cochrane risk of bias tool, and random effects meta-analysis was used to pool rate ratios, odds ratios, and hazard ratios across studies, allowing for between study heterogeneity (τ 2). Results of 15 023 articles screened for inclusion, 58 randomised controlled trials were identified, including 280 638 participants followed up for a median of 3 (interquartile range 2-4) years. Most of the trials (n=40, 69%) had a low risk of bias. Among seven trials reporting data for falls, no evidence was found of an association with antihypertensive treatment (summary risk ratio 1.05, 95% confidence interval 0.89 to 1.24, τ 2 =0.009). Antihypertensives were associated with an increased risk of acute kidney injury (1.18, 95% confidence interval 1.01 to 1.39, τ 2 =0.037, n=15), hyperkalaemia (1.89, 1.56 to 2.30, τ 2 =0.122, n=26), hypotension (1.97, 1.67 to 2.32, τ 2 =0.132, n=35), and syncope (1.28, 1.03 to 1.59, τ 2 =0.050, n=16). The heterogeneity between studies assessing acute kidney injury and hyperkalaemia events was reduced when focusing on drugs that affect the renin angiotensin-aldosterone system. Results were robust to sensitivity analyses focusing on adverse events leading to withdrawal from each trial. Antihypertensive treatment was associated with a reduced risk of all cause mortality, cardiovascular death, and stroke, but not of myocardial infarction. Conclusions This meta-analysis found no evidence to suggest that antihypertensive treatment is associated with falls but found evidence of an association with mild (hyperkalaemia, hypotension) and severe adverse events (acute kidney injury, syncope). These data could be used to inform shared decision making between doctors and patients about initiation and continuation of antihypertensive treatment, especially in patients at high risk of harm because of previous adverse events or poor renal function. Registration PROSPERO CRD42018116860.

BACKGROUND: Lymphopenia (reduced lymphocyte count) during infections, such as pneumonia, is common and is associated with increased mortality. Little is known about the relationship between lymphocyte count before developing infections and mortality risk. AIM: to identify whether patients with lymphopenia who develop pneumonia have increased risk of death. DESIGN AND SETTING: a cohort study set in the Clinical Practice Research Datalink (CPRD) linked to national death records, in primary care. This database is representative of the UK population and is extracted from routine records. METHOD: Patients aged >50 years with a pneumonia diagnosis were included from January 1998 until January 2019. The relationship between lymphocyte count and mortality was measured, using a time-to-event (multivariable Cox regression) approach, adjusted for age, sex, social factors, and potential causes of lymphopenia. The primary analysis used the most recent test before pneumonia. The primary outcome was 28-day, all-cause mortality. RESULTS: a total of 40 909 participants with pneumonia were included, with 28 556 having had a lymphocyte count test before pneumonia (median time between test and diagnosis was 677 days). When lymphocyte count was categorised (0-1 × 109 cells/L, 1-2 × 109 cells/L, 2-3 × 109 cells/L, >3 × 109 cells/L, never tested), both 28-day and 1-year mortality varied significantly: 14%, 9.2%, 6.5%, 6.1%, and 25%, respectively, for 28-day mortality, and 41%, 29%, 22%, 20%, and 52% for 1-year mortality. In multivariable Cox regression, lower lymphocyte count was consistently associated with increased hazard of death. CONCLUSION: Lymphopenia is an independent predictor of mortality in primary care pneumonia. Even low-normal lymphopenia (1-2 × 109 cells/L) is associated with an increase in short- and long-term mortality compared with higher counts.

Aims: Deprescribing of antihypertensive drugs is recommended for some older patients with polypharmacy, but there is little evidence to inform which drug (or dose) should be withdrawn. This study used data from the OPTiMISE trial to examine whether short-term outcomes of deprescribing vary by drug class and dose of medication withdrawn. Methods: the OPTiMISE trial included patients aged ≥80 years with controlled systolic blood pressure (SBP;

Background: Medication review is a core aspect of medicine optimisation, yet existing models of review vary substantially in structure and content and are not necessarily easy to implement in clinical practice. This study aimed to use evidence from the existing literature to identify key medication review components and use this to inform the design of an improved review model. Methods: a systematic review was conducted (PROSPERO: CRD42018109788) to identify randomised control trials of stand-alone medication review in adults (18+ years). The review updated that by Huiskes et al. (BMC Fam Pract. 18:5, 2017), using the same search strategy implemented in MEDLINE and Embase. Studies were assessed using the Cochrane risk of bias tool. Key review components were identified, alongside relevant clinical and health service outcomes. A working group (patients, doctors and pharmacists) developed the model through an iterative consensus process (appraisal of documents plus group discussions), working from the systematic review findings, brief evidence summaries for core review components and examples of previous models, to agree on the main purpose of the review model, overarching model structure, review components and supporting material. Results: We identified 28 unique studies, with moderate bias overall. Consistent medication review components included reconciliation (26 studies), safety assessment (22), suboptimal treatment (19), patient knowledge/preferences (18), adherence (14), over-the-counter therapy (13) and drug monitoring (10). There was limited evidence from studies for improvement in key clinical outcomes. The review structure was underpinned by patient values and preferences, with parallel information gathering and evaluation stages, feeding into the final decision-making and implementation. Most key components identified in the literature were included. The final model was considered to benefit from a patient-centred, holistic approach, which captured both patient-orientated and medication-focused problems, and aligned with traditional consultation methods thus facilitating implementation in practice. Conclusions: the Bristol Medication Review Model provides a framework for standardised delivery of structured reviews. The model has the potential for use by all healthcare professionals with relevant clinical experience and is designed to offer flexibility of implementation not limited to a particular healthcare setting.

Pleural empyema represents a significant healthcare burden due to extended hospital admissions and potential requirement for surgical intervention. This study aimed to assess changes in incidence and management of pleural empyema in England over the past 10 years and the potential impact of influenza on rates. Hospital Episode Statistics data were used to identify patients admitted to English hospitals with pleural empyema between 2008 and 2018. Linear regression was used to analyse the relationship between empyema rates and influenza incidence recorded by Public Health England. The relationship between influenza and empyema was further explored using serological data from a prospective cohort study of patients presenting with pleural empyema. Between April 2008 and March 2018 there were 55 530 patients admitted with pleural empyema. There was male predominance (67% versus 33%), which increased with age. Cases have increased significantly from 4447 in 2008 to 7268 in 2017. Peaks of incidence correlated moderately with rates of laboratoryconfirmed influenza in children and young adults (r=0.30). For nine of the 10 years studied, the highest annual point incidence of influenza coincided with the highest admission rate for empyema (with a 2-week lag). In a cohort study of patients presenting to a single UK hospital with pleural empyema/ infection, 24% (17 out of 72) had serological evidence of recent influenza infection, compared to 7% in seasonally matched controls with simple parapneumonic or cardiogenic effusions (p

Background Optimal management of hypertension in older patients with multimorbidity is a cornerstone of primary care practice. Despite emphasis on personalised approaches to treatment in older patients, there is little guidance on how to achieve medication reduction when GPs are concerned that possible risks outweigh potential benefits of treatment. Mindlines - tacit, internalised guidelines developed over time from multiple sources - may be of particular importance in such situations. Aim to explore GPs' decision-making on deprescribing antihypertensives in patients with multimorbidity aged ≥80 years, drawing on the concept of mindlines. Design and setting Qualitative interview study set in English general practice. Method Thematic analysis of face-to-face interviews with a sample of 15 GPs from seven practices in the East of England, using a chart-stimulated recall approach to explore approaches to treatment for older patients with multimorbidity with hypertension. Results GPs are typically confident making decisions to deprescribe antihypertensive medication in older patients with multimorbidity when prompted by a trigger, such as a fall or adverse drug event. GPs are less confident to attempt deprescribing in response to generalised concerns about polypharmacy, and work hard to make sense of multiple sources (including available evidence, shared experiential knowledge, and non-clinical factors) to guide decision-making. Conclusion in the absence of a clear evidence base on when and how to attempt medication reduction in response to concerns about polypharmacy, GPs develop 'mindlines' over time through practice-based experience. These tacit approaches to making complex decisions are critical to developing confidence to attempt deprescribing and may be strengthened through reflective practice.

Background: People with chronic kidney disease (CKD) are at high risk of polypharmacy. However, no previous study has investigated international prescribing patterns in this group. This article aims to examine prescribing and polypharmacy patterns among older people with advanced CKD across the countries involved in the European Quality (EQUAL) study. Methods: the EQUAL study is an international prospective cohort study of patients ≥65 years of age with advanced CKD. Baseline demographic, clinical and medication data were analysed and reported descriptively. Polypharmacy was defined as ≥5 medications and hyperpolypharmacy as ≥10. Univariable and multivariable linear regressions were used to determine associations between country and the number of prescribed medications. Univariable and multivariable logistic regression were used to determine associations between country and hyperpolypharmacy. Results: of the 1317 participants from five European countries, 91% were experiencing polypharmacy and 43% were experiencing hyperpolypharmacy. Cardiovascular medications were the most prescribed medications (mean 3.5 per person). There were international differences in prescribing, with significantly greater hyperpolypharmacy in Germany {odds ratio (OR) 2.75 [95% confidence interval (CI) 1.73-4.37]; P < 0.001, reference group UK}, the Netherlands [OR 1.91 (95% CI 1.32-2.76); P = 0.001] and Italy [OR 1.57 (95% CI 1.15-2.15); P = 0.004]. People in Poland experienced the least hyperpolypharmacy [OR 0.39 (95% CI 0.17-0.87); P = 0.021]. Conclusions: Hyperpolypharmacy is common among older people with advanced CKD, with significant international differences in the number of medications prescribed. Practice variation may represent a lack of consensus regarding appropriate prescribing for this high-risk group for whom pharmacological treatment has great potential for harm as well as benefit.

. Background
. Drug-related problems and potentially inappropriate prescribing impose a huge burden on patients and the health-care system. The most widely used tools for appropriate prescription in older adults in England and in other European countries are the Screening Tool of Older People’s Prescriptions (STOPP)/Screening Tool to Alert to the Right Treatment (START) tools. STOPP/START tools support medicines optimisation for older adults.
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. Objectives
. To identify, test and refine the programme theories underlying how interventions based on the STOPP/START tools are intended to work, for whom, in what circumstances and why, as well as the resource use and cost requirements or impacts.
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. Design
. A realist synthesis.
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. Setting
. Primary care, hospital care and nursing homes.
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. Patients
. Patients aged ≥ 65 years.
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. Interventions
. Any intervention based on the use of the STOPP/START tools.
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. Review methods
. Database and web-searching was carried out to retrieve relevant evidence to identify and test programme theories about how interventions based on the use of the STOPP/START tools work. A project reference group made up of health-care professionals, NHS decision-makers, older people, carers and members of the public was set up. In phase 1 we identified programme theories about STOPP/START interventions on how, for whom, in what contexts and why they are intended to work. We searched the peer-reviewed and grey literature to identify documents relevant to the research questions. We interviewed experts in the field in our reference group to gain input on our list of candidate context–mechanism–outcome configurations, to identify additional context–mechanism–outcome configurations and to identify additional literature and/or relevant concepts. In phase 2 we reviewed and synthesised relevant published and unpublished empirical evidence and tested the programme theories using evidence from a larger set of empirical studies.
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. Results
. We developed a single logic model structured around three key mechanisms: (1) personalisation, (2) systematisation and (3) evidence implementation. Personalisation: STOPP/START-based interventions are based on shared decision-making, taking into account patient preferences, experiences and expectations (mechanisms), leading to increased patient awareness, adherence, satisfaction, empowerment and quality of life (outcomes). Systematisation: STOPP/START tools provide a standardised/systematic approach for medication reviews (mechanisms), leading to changes in professional and organisational culture and burden/costs (outcomes). Evidence implementation: delivery of STOPP/START-based interventions is based on the implementation of best evidence (mechanisms), reducing adverse outcomes through appropriate prescribing/deprescribing (outcomes). For theory testing, we identified 40 studies of the impact of STOPP/START-based interventions in hospital settings, nursing homes, primary care and community pharmacies. Most of the interventions used multiple mechanisms. We found support for the impact of the personalisation and evidence implementation mechanisms on selected outcome variables, but similar impact was achieved by interventions not relying on these mechanisms. We also observed that the impact of interventions was linked to the proximity of the selected outcomes to the intervention in the logic model, resulting in a clearer benefit for appropriateness of prescribing, adverse drug events and prescription costs.
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. Limitations
. None of the available studies had been explicitly designed for evaluating underlying causal mechanisms, and qualitative information was sparse.
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. Conclusions
. No particular configuration of the interventions is associated with a greater likelihood of improved outcomes in given settings.
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. Study registration
. This study is registered as PROSPERO CRD42018110795.
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. Funding
. This project was funded by the National Institute for Health Research (NIHR) Health Services and Delivery Research programme and will be published in full in Health Services and Delivery Research; Vol. 9, No. 23. See the NIHR Journals Library website for further project information.
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The use of big data containing millions of primary care medical records provides an opportunity for rapid research to help inform patient care and policy deci-sions during the first and subsequent waves of the coronavirus disease 2019 (COVID-19) pandemic. Routinely collected primary care data have previously been used for national pandemic surveillance, quantifying associations between exposures and outcomes, identifying high risk populations, and examining the effects of interventions at scale, but there is no consensus on how to effectively conduct or report these data for COVID-19 research. A COVID-19 primary care database consortium was established in April 2020 and its researchers have ongoing COVID-19 projects in overlapping data sets with over 40 million primary care records in the United Kingdom that are variously linked to public health, secondary care, and vital status records. This consensus agreement is aimed at facilitating transparency and rigor in methodological approaches, and consis-tency in defining and reporting cases, exposures, confounders, stratification vari-ables, and outcomes in relation to the pharmacoepidemiology of COVID-19. This will facilitate comparison, validation, and meta-analyses of research during and after the pandemic.

BackgroundIschaemic stroke and myocardial infarction (MI) are common after pneumonia and are associated with long-term mortality. Aspirin may attenuate this risk and should be explored as a therapeutic option.MethodsWe extracted all patients with pneumonia (aged over 50â€
years) from the Clinical Practice Research Datalink (CPRD), a large UK primary care database, from inception until January 2019. We then performed a prior event rate ratio (PERR) analysis with propensity score matching (PSM), an approach that allows for control of measured and unmeasured confounding, with aspirin usage as the exposure and ischaemic events as the outcome. The primary outcome was the combined outcome of ischaemic stroke and MI. Secondary outcomes were ischaemic stroke and MI individually. Relevant confounders (smoking, comorbidities, age and gender) were included in the analysis.Findings48 743 patients were eligible for matching. of these, 9864 were aspirin users who were matched to 9864 non-users. Aspirin users had a reduced risk of the primary outcome (adjusted hazard ratio 0.64, 95% CI 0.52–0.79) in the PERR analysis. For both secondary outcomes, aspirin use was also associated with a reduced risk for MI (hazard ratio 0.46, 95% CI 0.30–0.72) and stroke (hazard ratio 0.70, 95% CI 0.55–0.91), respectively.InterpretationThis study provides supporting evidence that aspirin use is associated with reduced ischaemic events after pneumonia in a primary care setting. This drug may have a future clinical role in preventing this important complication.

Background: Multimorbidity is associated with mortality and service use, with specific types of multimorbidity having differential effects. Additionally, multimorbidity is often negatively associated with participation in research cohorts. Therefore, we set out to identify clusters of multimorbidity patients and how they are differentially associated with mortality and service use across age groups in a population-representative sample. Methods: Linked primary and secondary care electronic health records contributed by 382 general practices in England to the Clinical Practice Research Datalink (CPRD) were used. The study included a representative set of multimorbid adults (18 years old or more, N = 113,211) with two or more long-term conditions (a total of 38 conditions were included). A random set of 80% of the multimorbid patients (N = 90,571) were stratified by age groups and clustered using latent class analysis. Consistency between obtained multimorbidity phenotypes, classification quality and associations with demographic characteristics and primary outcomes (GP consultations, hospitalisations, regular medications and mortality) was validated in the remaining 20% of multimorbid patients (N = 22,640). Results: We identified 20 patient clusters across four age strata. The clusters with the highest mortality comprised psychoactive substance and alcohol misuse (aged 18-64); coronary heart disease, depression and pain (aged 65-84); and coronary heart disease, heart failure and atrial fibrillation (aged 85+). The clusters with the highest service use coincided with those with the highest mortality for people aged over 65. For people aged 18-64, the cluster with the highest service use comprised depression, anxiety and pain. The majority of 85+-year-old multimorbid patients belonged to the cluster with the lowest service use and mortality for that age range. Pain featured in 13 clusters. Conclusions: This work has highlighted patterns of multimorbidity that have implications for health services. These include the importance of psychoactive substance and alcohol misuse in people under the age of 65, of co-morbid depression and coronary heart disease in people aged 65-84 and of cardiovascular disease in people aged 85+.

Background: Health services have failed to respond to the pressures of multimorbidity. Improved measures of multimorbidity are needed for conducting research, planning services and allocating resources. Methods: We modelled the association between 37 morbidities and 3 key outcomes (primary care consultations, unplanned hospital admission, death) at 1 and 5 years. We extracted development (n = 300 000) and validation (n = 150 000) samples from the UK Clinical Practice Research Datalink. We constructed a general-outcome multimorbidity score by averaging the standardized weights of the separate outcome scores. We compared performance with the Charlson Comorbidity Index. RESULTS: Models that included all 37 conditions were acceptable predictors of general practitioner consultations (C-index 0.732, 95% confidence interval [CI] 0.731-0.734), unplanned hospital admission (C-index 0.742, 95% CI 0.737-0.747) and death at 1 year (C-index 0.912, 95% CI 0.905-0.918). Models reduced to the 20 conditions with the greatest combined prevalence/weight showed similar predictive ability (C-indices 0.727, 95% CI 0.725-0.728; 0.738, 95% CI 0.732-0.743; and 0.910, 95% CI 0.904-0.917, respectively). They also predicted 5-year outcomes similarly for consultations and death (C-indices 0.735, 95% CI 0.734-0.736, and 0.889, 95% CI 0.885-0.892, respectively) but performed less well for admissions (C-index 0.708, 95% CI 0.705-0.712). The performance of the generaloutcome score was similar to that of the outcome-specific models. These models performed significantly better than those based on the Charlson Comorbidity Index for consultations (C-index 0.691, 95% CI 0.690-0.693) and admissions (C-index 0.703, 95% CI 0.697-0.709) and similarly for mortality (C-index 0.907, 95% CI 0.900-0.914). INTERPRETATION: the Cambridge Multimorbidity Score is robust and can be either tailored or not tailored to specific health outcomes. It will be valuable to those planning clinical services, policymakers allocating resources and researchers seeking to account for the effect of multimorbidity.

OBJECTIVE: to examine the concordance between dates of death recorded in UK primary care and national mortality records. METHODS: UK primary care data from the Clinical Practice Research Datalink were linked to Office for National Statistics (ONS) data, for 118 571 patients who died between September 2010 and September 2015. Logistic regression was used to examine factors associated with discrepancy in death dates between data sets. RESULTS: Death dates matched in 76.8% of cases with primary care dates preceding ONS date in 2.9%, and following in 20.3% of cases; 92.2% of cases differed by 4 weeks later than ONS in 1.5% of cases and occurred more frequently with deaths categorised as 'external' (15.8% vs 0.8% for cancer), and in younger patients (15.9% vs 1% for 18-29 and 80-89 years, respectively). General practices with the greatest discrepancies (97.5th percentile) had around 200 times higher odds of recording substantially discordant dates than practices with the lowest discrepancies (2.5th percentile). CONCLUSION: Dates of death in primary care records often disagree with national records and should be treated with caution. There is marked variation between practices, and studies involving young patients, unexplained deaths and where precise date of death is important are particularly vulnerable to these issues.

Importance: Deprescribing of antihypertensive medications is recommended for some older patients with polypharmacy and multimorbidity when the benefits of continued treatment may not outweigh the harms. Objective: This study aimed to establish whether antihypertensive medication reduction is possible without significant changes in systolic blood pressure control or adverse events during 12-week follow-up. Design, Setting, and Participants: the Optimising Treatment for Mild Systolic Hypertension in the Elderly (OPTIMISE) study was a randomized, unblinded, noninferiority trial conducted in 69 primary care sites in England. Participants, whose primary care physician considered them appropriate for medication reduction, were aged 80 years and older, had systolic blood pressure lower than 150 mm Hg, and were receiving at least 2 antihypertensive medications were included. Participants enrolled between April 2017 and September 2018 and underwent follow-up until January 2019. Interventions: Participants were randomized (1:1 ratio) to a strategy of antihypertensive medication reduction (removal of 1 drug [intervention], n = 282) or usual care (control, n = 287), in which no medication changes were mandated. Main Outcomes and Measures: the primary outcome was systolic blood pressure lower than 150 mm Hg at 12-week follow-up. The prespecified noninferiority margin was a relative risk (RR) of 0.90. Secondary outcomes included the proportion of participants maintaining medication reduction and differences in blood pressure, frailty, quality of life, adverse effects, and serious adverse events. Results: Among 569 patients randomized (mean age, 84.8 years; 276 [48.5%] women; median of 2 antihypertensive medications prescribed at baseline), 534 (93.8%) completed the trial. Overall, 229 (86.4%) patients in the intervention group and 236 (87.7%) patients in the control group had a systolic blood pressure lower than 150 mm Hg at 12 weeks (adjusted RR, 0.98 [97.5% 1-sided CI, 0.92 to ∞]). of 7 prespecified secondary end points, 5 showed no significant difference. Medication reduction was sustained in 187 (66.3%) participants at 12 weeks. Mean change in systolic blood pressure was 3.4 mm Hg (95% CI, 1.1 to 5.8 mm Hg) higher in the intervention group compared with the control group. Twelve (4.3%) participants in the intervention group and 7 (2.4%) in the control group reported at least 1 serious adverse event (adjusted RR, 1.72 [95% CI, 0.7 to 4.3]). Conclusions and Relevance: Among older patients treated with multiple antihypertensive medications, a strategy of medication reduction, compared with usual care, was noninferior with regard to systolic blood pressure control at 12 weeks. The findings suggest antihypertensive medication reduction in some older patients with hypertension is not associated with substantial change in blood pressure control, although further research is needed to understand long-term clinical outcomes.

BACKGROUND/OBJECTIVES: Randomized controlled trials are used to inform clinical guidelines on the management of hypertension in older adults, but it is unclear to what extent these trials represent the general population attending routine clinical practice. This study aimed to define the proportion and characteristics of patients eligible for hypertension trials conducted in older people. DESIGN: Cross-sectional study. SETTING: a total of 24 general practices in England. PARTICIPANTS: Anonymized electronic health record data from all individuals aged 80 and older. MEASUREMENTS: Descriptive statistics were used to define the proportion and characteristics of patients eligible for two previous medication intensification trials (HYVET, SPRINT) and one medication reduction trial (OPTiMISE). A logistic regression model was constructed to estimate predictors of eligibility for each trial. RESULTS: of 15,376 patients identified, 268 (1.7%; 95% confidence interval [CI] = 1.5-2.0%), 5,290 (34.4%; 95%CI = 33.7-35.2%), and 3,940 (25.6%; 95%CI = 24.9-26.3%) were eligible for the HYVET, SPRINT, and OPTiMISE trials, respectively. Between 5.6% and 30.7% of exclusions from each trial were due to eligibility criteria excluding those with high or uncontrolled blood pressure. Frailty (odds ratio [OR] =. 44; 95%CI =. 36-.54 [OPTiMISE]), cardiovascular polypharmacy (OR =. 61; 95%CI =. 55-.68 [SPRINT]) and multimorbidity (OR =. 72; 95%CI =. 64-.82 [SPRINT]) were associated with a lower likelihood of being eligible for one or more of the trials. CONCLUSION: a possible unintended consequence of blood pressure criteria used by trials attempting to answer different primary questions is that for many older patients, no trial evidence exists to inform treatment decisions in routine practice. Caution should be exercised when applying results from existing trials to patients with frailty or multimorbidity.

BACKGROUND: Little is known about the impact of hospitalisation on prescribing in UK clinical practice. AIM: to investigate whether an emergency hospital admission drives increases in polypharmacy and potentially inappropriate prescriptions (PIPs). DESIGN AND SETTING: a retrospective cohort analysis set in primary and secondary care in England. METHOD: Changes in number of prescriptions and PIPs following an emergency hospital admission in 2014 (at admission and 4 weeks post-discharge), and 6 months post-discharge were calculated among 37 761 adult patients. Regression models were used to investigate changes in prescribing following an admission. RESULTS: Emergency attendees surviving 6 months (N = 32 657) had a mean of 4.4 (standard deviation [SD] = 4.6) prescriptions before admission, and a mean of 4.7 (SD = 4.7; P

Polypharmacy is a common issue in clinical practice, with 20% of adults given ≥5 regular medications. It particularly impacts elderly individuals and those with multiple morbidities, and is worsened by single-disease, guideline-driven prescribing and service pressures. Although sometimes appropriate, it can also be problematic, associated with a range of adverse outcomes including hazardous prescribing, excess treatment burden, poor quality of life, higher health service use, and increased morbidity and mortality. Polypharmacy management is complex because of the presence of multiple problems, competing priorities and clinical uncertainty. The mainstay of management is currently medication review, which should be holistic and patient centred, and employ shared decision-making. Key elements include addressing unnecessary prescribing, ineffective prescribing, drug safety and cost-effectiveness. Deprescribing is a core means of reducing polypharmacy, although there are several important barriers to its delivery, including a weak evidence base. In the longer term, preventing inappropriate polypharmacy requires a significant shift in prescribing culture, and is likely to take considerable time to achieve.

Background: Clinical trials indicate that direct oral anticoagulants (DOACs) are as effective as warfarin at preventing ischaemic stroke. It is unclear, however, whether relative changes in DOAC uptake have affected clinical and economic outcomes in practice. Aim: to investigate variations in DOAC uptake and the relationship with hospital admissions and cost. Design & setting: an ecological study using electronic administrative records from England, April 2012 to March 2017. Method: Multivariable regression was used to model practice variation in DOAC prescribing, and the relationship with clinical and economic outcomes. Results: in quarter 1 of 2017, 55.0% of the 2 695 262 patients dispensed an anticoagulant were given a DOAC. There was a two-fold difference in odds of dispensing DOACs between clinical commissioning groups (CCGs) between those with the highest and lowest usage of these drugs. Increases in the relative uptake of DOACs were not associated with hospital admissions for ischaemic stroke (adjusted incidence rate ratio [IRR] = 1.00; 95% confidence intervals [CI] = 0.999 to 1.001), nor gastrointestinal or intracranial bleeds (IRR = 1.001; 95% CI = 1.000 to 1.002). In 2017, quarter 1, CCGs spent £9247 (inter-quartile range £7751 to £10 853) per 1000 patients on anticoagulants. The marginal effect of a 5% increase in DOAC uptake was associated with a £17.95 (£8.75 to £27.15) increase in total costs, per 1000 patient population. Conclusion: There were significant differences in the relative uptake of DOACs across practices, with greater costs but no reduction in hospital admissions in those with higher levels of dispensing. Findings indicate that clinical and economic benefits of DOACs identified by clinical trials are not realised in practice.

BACKGROUND: Clinical trials indicate that direct oral anticoagulants (DOACs) are as effective as warfarin at preventing ischaemic stroke. It is unclear, however, whether relative changes in DOAC uptake have affected clinical and economic outcomes in practice. AIM: to investigate variations in DOAC uptake and the relationship with hospital admissions and cost. DESIGN & SETTING: an ecological study using electronic administrative records from England, April 2012 to March 2017. METHOD: Multivariable regression was used to model practice variation in DOAC prescribing, and the relationship with clinical and economic outcomes. RESULTS: in quarter 1 of 2017, 55.0% of the 2 695 262 patients dispensed an anticoagulant were given a DOAC. There was a two-fold difference in odds of dispensing DOACs between clinical commissioning groups (CCGs) between those with the highest and lowest usage of these drugs. Increases in the relative uptake of DOACs were not associated with hospital admissions for ischaemic stroke (adjusted incidence rate ratio [IRR] = 1.00; 95% confidence intervals [CI] = 0.999 to 1.001), nor gastrointestinal or intracranial bleeds (IRR = 1.001; 95% CI = 1.000 to 1.002). In 2017, quarter 1, CCGs spent £9247 (inter-quartile range £7751 to £10 853) per 1000 patients on anticoagulants. The marginal effect of a 5% increase in DOAC uptake was associated with a £17.95 (£8.75 to £27.15) increase in total costs, per 1000 patient population. CONCLUSION: There were significant differences in the relative uptake of DOACs across practices, with greater costs but no reduction in hospital admissions in those with higher levels of dispensing. Findings indicate that clinical and economic benefits of DOACs identified by clinical trials are not realised in practice.

BACKGROUND: Chronic obstructive pulmonary disease (COPD) accounts for 10% of emergency hospital admissions in the UK annually. Nearly 33% of patients are readmitted within 28 days of discharge. We evaluated the effectiveness of implementing standardised packages of care called 'care bundles' on COPD readmission, emergency department (ED) attendance, mortality, costs and process of care. METHODS: This is a mixed-methods, controlled before-and-after study with nested case studies. 31 acute hospitals in England and Wales which introduced COPD care bundles (implementation sites) or provided usual care (comparator sites) were recruited and provided monthly aggregate data. 14 sites provided additional individual patient data. Participants were adults admitted with an acute exacerbation of COPD. RESULTS: There was no evidence that care bundles reduced 28-day COPD readmission rates: OR=1.02 (95% CI 0.83 to 1.26). However, the rate of ED attendance was reduced in implementation sites over and above that in comparator sites (implementation: IRR=0.63 (95% CI 0.56 to 0.71); comparator: IRR=1.12 (95% CI 1.02 to 1.24); group-time interaction p

PURPOSE: to describe prescribing of medicines in primary care in the last year of life in patients with dementia. METHOD: a retrospective cohort analysis in UK primary care using routinely collected data from the Clinical Practice Research Datalink. Number of medications and potentially inappropriate medication prescribed one year prior to, and including death, was ascertained. RESULTS: Dementia patients (n = 6923) aged 86.6 ± 7.3 years (mean ± SD) were prescribed 4.8 ± 4.0 drugs 1 year prior to death, increasing to 5.6 ± 4.0 2 months prior, before falling to 4.9 ± 4.1 at death. One year prior to death, 50% of patients were prescribed a potentially inappropriate medication, falling to 41% at death. Cardiovascular medications were the most common, with decreases in drug count only occurring in the last month prior to death. Prescriptions for gastrointestinal and central nervous system medication increased throughout the year, particularly laxatives/analgaesics, antidepressants and hypnotic/antipsychotics. Women (vs. men) and patients with Alzheimer's (vs. vascular dementia) were prescribed 4.7% (95% CI 2.3%-7%) and 14.6% (11.7-17.3%) fewer medications, respectively. Prescribing decreased with age and increased with additional comorbidities. CONCLUSIONS: Dementia patients are prescribed high levels of medication, many potentially inappropriate, during their last year of life, with reductions occurring relatively late. Improvements to medication optimisation guidelines are needed to inform decision-making around deprescribing of long-term medications in patients with limited life-expectancy.

OBJECTIVE: to investigate whether the introduction of a named general practitioner (GP, family physician) improved patients' healthcare for patients aged 75 and over in England. SETTING: Random sample of 27 500 patients aged 65 to 84 in 2012 within 139 English practices from the Clinical Practice Research Datalink linked with Hospital Episode Statistics. DESIGN: Prospective cohort approach, measuring patients' GP consultations and emergency hospital admissions 2 years before/after the intervention. Patients were grouped in (i) aged over 74 and (ii) younger than 75 in both periods in order to compare who were or were not subject to the intervention. Adjusted associations between the named GP scheme, continuity of care and emergency hospital admission were examined using multilevel modelling. INTERVENTION: National Health Service policy to introduce a named accountable GP for patients aged over 74 in April 2014. MAIN OUTCOME MEASURES: (A) Continuity of care index-score, (B) risk of emergency hospital admissions, (C) number of emergency hospital admissions. RESULTS: the intervention was associated with a decrease in continuity index-scores of -0.024 (95% CI -0.030 to -0.018, p

Background: Coeliac disease affects approximately 1% of the population and is increasingly diagnosed in the United Kingdom. A nationwide consultation in England has recommend that state-funded provisions for gluten-free (GF) food should be restricted to bread and mixes but not banned, yet financial strain has prompted regions of England to begin partially or fully ceasing access to these provisions. The impact of these policy changes on different stakeholders remains unclear. Methods: Prescription data were collected for general practice services across England (n = 7176) to explore changes in National Health Service (NHS) expenditure on GF foods over time (2012-2017). The effects of sex, age, deprivation and rurality on GF product expenditure were estimated using a multi-level gamma regression model. Spending rate within NHS regions that had introduced a 'complete ban' or a 'complete ban with age-related exceptions' was compared to spending in the same time periods amongst NHS regions which continued to fund prescriptions for GF products. Results: Annual expenditure on GF products in 2012 (before bans were introduced in any area) was £25.1 million. Higher levels of GF product expenditure were found in general practices in areas with lower levels of deprivation, higher levels of rurality and higher proportions of patients aged under 18 and over 75. Expenditure on GF food within localities that introduced a 'complete ban' or a 'complete ban with age-related exceptions' were reduced by approximately 80% within the 3 months following policy changes. If all regions had introduced a 'complete ban' policy in 2014, the NHS in England would have made an annual cost-saving of £21.1 million (equivalent to 0.24% of the total primary care medicines expenditure), assuming no negative sequelae. Conclusions: the introduction of more restrictive GF prescribing policies has been associated with 'quick wins' for NHS regions under extreme financial pressure. However, these initial savings will be largely negated if GF product policies revert to recently published national recommendations. Better evidence of the long-term impact of restricting GF prescribing on patient health, expenses and use of NHS services is needed to inform policy.

Motivated by two case studies using primary care records from the Clinical Practice Research Datalink, we describe statistical methods that facilitate the analysis of tall data, with very large numbers of observations. Our focus is on investigating the association between patient characteristics and an outcome of interest, while allowing for variation among general practices. We explore ways to fit mixed-effects models to tall data, including predictors of interest and confounding factors as covariates, and including random intercepts to allow for heterogeneity in outcome among practices. We introduce (1) weighted regression and (2) meta-analysis of estimated regression coefficients from each practice. Both methods reduce the size of the dataset, thus decreasing the time required for statistical analysis. We compare the methods to an existing subsampling approach. All methods give similar point estimates, and weighted regression and meta-analysis give similar standard errors for point estimates to analysis of the entire dataset, but the subsampling method gives larger standard errors. Where all data are discrete, weighted regression is equivalent to fitting the mixed model to the entire dataset. In the presence of a continuous covariate, meta-analysis is useful. Both methods are easy to implement in standard statistical software.

Background: Risk assessment is central to primary prevention of cardiovascular disease (CVD), but there remains a need to better understand the use of evidence-based interventions in practice. This study examines: (i) the policies and guidelines for risk assessment in Europe, (ii) the use of risk assessment tools in clinical practice and (iii) the barriers to, and facilitators of, risk assessment. Methods: Data were collected from academics, clinicians and policymakers in an online questionnaire targeted at experts from all European Union member states, and in 8 indepth country case studies that were developed from a targeted literature review and 36 interviews. Results: the European Society of Cardiology (ESC) produces European guidelines for CVD risk assessment and recommends the Systematic COronary Risk Evaluation tool, which is the most widely used risk assessment tool in Europe. The use of risk assessment tools is variable. Lack of time and resources are important barriers. Integrating risk assessment tools into clinical systems and providing financial incentives to carry out risk assessments could increase implementation. Novel biomarkers would need to be supported by evidence of their clinical effectiveness and costeffectiveness to be introduced in clinical practice. These findings were consistent across Europe. Conclusions: Efforts to improve the assessment of CVD risk in clinical practice should be carried out by or in collaboration with, the ESC. Increasing the use of existing risk assessment tools is likely to offer greater gains in primary prevention than the development of novel biomarkers.

Background: Polypharmacy is an increasing challenge for primary care. Although sometimes clinically justified, polypharmacy can be inappropriate, leading to undesirable outcomes. Optimising care for polypharmacy necessitates effective targeting and monitoring of interventions. This requires a valid, reliable measure of polypharmacy, relevant for all patients, that considers clinical appropriateness and generic prescribing issues applicable across all medications. Whilst there are several existing measures of potentially inappropriate prescribing, these are not specifically designed with polypharmacy in mind, can require extensive clinical input to complete, and often cover a limited number of drugs. The aim of this study was to identify what experts consider to be the key elements of a measure of prescribing appropriateness in the context of polypharmacy. Methods: Firstly, we conducted a systematic review to identify generic (not drug specific) prescribing indicators relevant to polypharmacy appropriateness. Indicators were subject to content analysis to enable categorisation. Secondly, we convened a panel of 10 clinical experts to review the identified indicators and assess their relative clinical importance. For each indicator category, a brief evidence summary was developed, based on relevant clinical and indicator literature, clinical guidance, and opinions obtained from a separate patient discussion panel. A two-stage RAND/UCLA Appropriateness Method was used to reach consensus amongst the panel on a core set of indicators of polypharmacy appropriateness. Results: We identified 20,879 papers for title/abstract screening, obtaining 273 full papers. We extracted 189 generic indicators, and presented 160 to the panel grouped into 18 classifications (e.g. adherence, dosage, clinical efficacy). After two stages, during which the panel introduced 18 additional indicators, there was consensus that 134 indicators were of clinical importance. Following the application of decision rules and further panel consultation, 12 indicators were placed into the final selection. Panel members particularly valued indicators concerned with adverse drug reactions, contraindications, drug-drug interactions, and the conduct of medication reviews. Conclusions: We have identified a set of 12 indicators of clinical importance considered relevant to polypharmacy appropriateness. Use of these indicators in clinical practice and informatics systems is dependent on their operationalisation and their utility (e.g. risk stratification, targeting and monitoring polypharmacy interventions) requires subsequent evaluation.

Background Long-term conditions place a substantial burden on primary care services, with drug therapy being a core aspect of clinical management. However, the ideal frequency for issuing repeat prescriptions for these medications is unknown. Aim to examine the impact of longer-duration (2-4 months) versus shorter-duration (28-day) prescriptions. Design and setting Systematic review of primary care studies. Method Scientific and grey literature databases were searched from inception until 21 October 2015. Eligible studies were randomised controlled trials and observational studies that examined longer prescriptions (2-4 months) compared with shorter prescriptions (28 days) in patients with stable, chronic conditions being treated in primary care. Outcomes of interest were: health outcomes, adverse events, medication adherence, medication wastage, professional administration time, pharmacists' time and/or costs, patient experience, and patient out-of-pocket costs. Results from a search total of 24 876 records across all databases, 13 studies were eligible for review. Evidence of moderate quality from nine studies suggested that longer prescriptions are associated with increased medication adherence. Evidence from six studies suggested that longer prescriptions may increase medication waste, but results were not always statistically significant and were of very low quality. No eligible studies were identified that measured any of the other outcomes of interest, including health outcomes and adverse events. Conclusion There is insufficient evidence relating to the overall impact of differing prescription lengths on clinical and health service outcomes, although studies do suggest medication adherence may improve with longer prescriptions. UK recommendations to provide shorter prescriptions are not substantiated by the current evidence base.

BACKGROUND: the National Health Service (NHS) in England spends over £9 billion on prescription medicines dispensed in primary care, of which over two-thirds is accounted for by repeat prescriptions. Recently, GPs in England have been urged to limit the duration of repeat prescriptions, where clinically appropriate, to 28 days to reduce wastage and hence contain costs. However, shorter prescriptions will increase transaction costs and thus may not be cost saving. Furthermore, there is evidence to suggest that shorter prescriptions are associated with lower adherence, which would be expected to lead to lower clinical benefit. The objective of this study is to estimate the cost-effectiveness of 3-month versus 28-day repeat prescriptions from the perspective of the NHS. METHODS: We adapted three previously developed UK policy-relevant models, incorporating transaction (dispensing fees, prescriber time) and drug wastage costs associated with 3-month and 28-day prescriptions in three case studies: antihypertensive medications for prevention of cardiovascular events; drugs to improve glycaemic control in patients with type 2 diabetes; and treatments for depression. RESULTS: in all cases, 3-month prescriptions were associated with lower costs and higher QALYs than 28-day prescriptions. This is driven by assumptions that higher adherence leads to improved disease control, lower costs and improved QALYs. CONCLUSION: Longer repeat prescriptions may be cost-effective compared with shorter ones. However, the quality of the evidence base on which this modelling is based is poor. Any policy rollout should be within the context of a trial such as a stepped-wedge cluster design.

INTRODUCTION: Recent evidence suggests that larger blood pressure reductions and multiple antihypertensive drugs may be harmful in older people, particularly frail individuals with polypharmacy and multimorbidity. However, there is a lack of evidence to support deprescribing of antihypertensives, which limits the practice of medication reduction in routine clinical care. The aim of this trial is to examine whether antihypertensive medication reduction is possible in older patients without significant changes in blood pressure control at follow-up. METHODS AND ANALYSIS: This trial will use a primary care-based, open-label, randomised controlled trial design. A total of 540 participants will be recruited, aged ≥80 years, with systolic blood pressure

Elevated levels of prenatal testosterone may increase the risk for autism spectrum conditions (autism). Given that polycystic ovary syndrome (PCOS) is also associated with elevated prenatal testosterone and its precursor sex steroids, a hypothesis from the prenatal sex steroid theory is that women with PCOS should have elevated autistic traits and a higher rate of autism among their children. Using electronic health records obtained from the Clinical Practice Research Datalink (CPRD) in the UK between 1990 and 2014, we conducted three matched case-control studies. Studies 1 and 2 examined the risk of PCOS in women with autism (n = 971) and the risk of autism in women with PCOS (n = 26,263), respectively, compared with matched controls. Study 3 examined the odds ratio (OR) of autism in first-born children of women with PCOS (n = 8588), matched to 41,127 controls. In Studies 1 and 2 we found increased prevalence of PCOS in women with autism (2.3% vs. 1.1%; unadjusted OR: 2.01, 95% CI: 1.22–3.30) and elevated rates of autism in women with PCOS (0.17% vs. 0.09%, unadjusted OR: 1.94 CI: 1.37–2.76). In Study 3 we found the odds of having a child with autism were significantly increased, even after adjustment for maternal psychiatric diagnoses, obstetric complications, and maternal metabolic conditions (unadjusted OR: 1.60, 95% CI: 1.28–2.00; adjusted OR: 1.35, 95% CI: 1.06–1.73). These studies provide further evidence that women with PCOS and their children have a greater risk of autism.

BACKGROUND: Multimorbidity places a substantial burden on patients and the healthcare system, but few contemporary epidemiological data are available. AIM: to describe the epidemiology of multimorbidity in adults in England, and quantify associations between multimorbidity and health service utilisation. DESIGN AND SETTING: Retrospective cohort study, undertaken in England. METHOD: the study used a random sample of 403 985 adult patients (aged ≥18 years), who were registered with a general practice on 1 January 2012 and included in the Clinical Practice Research Datalink. Multimorbidity was defined as having two or more of 36 long-term conditions recorded in patients' medical records, and associations between multimorbidity and health service utilisation (GP consultations, prescriptions, and hospitalisations) over 4 years were quantified. RESULTS: in total, 27.2% of the patients involved in the study had multimorbidity. The most prevalent conditions were hypertension (18.2%), depression or anxiety (10.3%), and chronic pain (10.1%). The prevalence of multimorbidity was higher in females than males (30.0% versus 24.4% respectively) and among those with lower socioeconomic status (30.0% in the quintile with the greatest levels of deprivation versus 25.8% in that with the lowest). Physical-mental comorbidity constituted a much greater proportion of overall morbidity in both younger patients (18-44 years) and those patients with a lower socioeconomic status. Multimorbidity was strongly associated with health service utilisation. Patients with multimorbidity accounted for 52.9% of GP consultations, 78.7% of prescriptions, and 56.1% of hospital admissions. CONCLUSION: Multimorbidity is common, socially patterned, and associated with increased health service utilisation. These findings support the need to improve the quality and efficiency of health services providing care to patients with multimorbidity at both practice and national level.

Background: the majority of people with dementia have other long-term diseases, the presence of which may affect the progression and management of dementia. This study aimed to identify subgroups with higher healthcare needs, by analysing how primary care consultations, number of prescriptions and hospital admissions by people with dementia varies with having additional long-term diseases (comorbidity). Methods: a retrospective cohort study based on health data from the Clinical Practice Research Datalink (CPRD) was conducted. Incident cases of dementia diagnosed in the year starting 1/3/2008 were selected and followed for up to 5 years. The number of comorbidities was obtained from a set of 34 chronic health conditions. Service usage (primary care consultations, hospitalisations and prescriptions) and time-to-death were determined during follow-up. Multilevel negative binomial regression and Cox regression, adjusted for age and gender, were used to model differences in service usage and death between differing numbers of comorbidities. Results: Data from 4999 people (14 866 person-years of follow-up) were analysed. Overall, 91.7% of people had 1 or more additional comorbidities. Compared with those with 2 or 3 comorbidities, people with ≥ 6 comorbidities had higher rates of primary care consultations (rate ratio (RR) 1.31, 95% CI 1.25 to 1.36), prescriptions (RR 1.68, 95% CI 1.57 to 1.81), and hospitalisation (RR 1.62, 95% CI 1.44 to 1.83), and higher risk of death (HR 1.56, 95% CI 1.37 to 1.78). Discussion: in the UK, people with dementia with higher numbers of comorbidities die earlier and have considerably higher health service usage in terms of primary care consultations, hospital admissions and prescribing. This study provides strong evidence that comorbidity is a key factor that should be considered when allocating resources and planning care for people with dementia.

BACKGROUND: to reduce expenditure on, and wastage of, drugs, some commissioners have encouraged general practitioners to issue shorter prescriptions, typically 28 days in length; however, the evidence base for this recommendation is uncertain. OBJECTIVE: to evaluate the evidence of the clinical effectiveness and cost-effectiveness of shorter versus longer prescriptions for people with stable chronic conditions treated in primary care. DESIGN/DATA SOURCES: the design of the study comprised three elements. First, a systematic review comparing 28-day prescriptions with longer prescriptions in patients with chronic conditions treated in primary care, evaluating any relevant clinical outcomes, adherence to treatment, costs and cost-effectiveness. Databases searched included MEDLINE (PubMed), EMBASE, Cumulative Index to Nursing and Allied Health Literature, Web of Science and Cochrane Central Register of Controlled Trials. Searches were from database inception to October 2015 (updated search to June 2016 in PubMed). Second, a cost analysis of medication wastage associated with

Polypharmacy is an increasing and global issue affecting primary care. Although sometimes appropriate, polypharmacy can also be problematic, leading to a range of adverse consequences. Deprescribing is the process of supervised withdrawal of an inappropriate medication and has the potential to reduce some of the problems associated with polypharmacy. It is a complex and sensitive process. We examine the issue of deprescribing from the perspective of primary care. Key steps in the deprescribing process are a review of medications and corresponding indications, consideration of harms, assessment of eligibility for discontinuation, prioritisation of medications and implementation of a stopping plan with appropriate monitoring. Patient involvement is a key feature of this process. Deprescribing should be considered in the context of end-of-life care and medication safety, but approaches are also required to identify other situations where deprescribing is appropriate. General practitioners are well positioned to facilitate deprescribing, usually through formal medication review, with decisions informed by a range of other healthcare professionals. Guidelines are available that help guide these processes. A range of studies have explored attitudes towards deprescribing; patients are generally supportive of the concept, although clinician views are varied. The successful implementation of deprescribing strategies still requires important patient and clinician barriers to be overcome, and clinical trial evidence of effectiveness and safety is essential.

BACKGROUND: Web-based interventions provide the opportunity to combine the tailored approach of face-to-face interventions with the scalability and cost-effectiveness of public health interventions. This potential is often limited by low engagement. A number of studies have described the characteristics of individuals who engage more in Web-based interventions but few have explored the reasons for these variations. OBJECTIVE: We aimed to explore individual-level factors associated with different degrees of engagement with a Web-based behavior change intervention following provision of coronary heart disease (CHD) risk information, and the barriers and facilitators to engagement. METHODS: This study involved the secondary analysis of data from the Information and Risk Modification Trial, a randomized controlled trial of a Web-based lifestyle intervention alone, or alongside information on estimated CHD risk. The intervention consisted of three interactive sessions, each lasting up to 60 minutes, delivered at monthly intervals. Participants were characterized as high engagers if they completed all three sessions. Thematic analysis of qualitative data from interviews with 37 participants was combined with quantitative data on usage of the Web-based intervention using a mixed-methods matrix, and data on the views of the intervention itself were analyzed across all participants. RESULTS: Thirteen participants were characterized as low engagers and 24 as high engagers. There was no difference in age (P=.75), gender (P=.95), or level of risk (P=.65) between the groups. Low engagement was more often associated with: (1) reporting a negative emotional reaction in response to the risk score (P=.029), (2) perceiving that the intervention did not provide any new lifestyle information (P=.011), and (3) being less likely to have reported feeling an obligation to complete the intervention as part of the study (P=.019). The mixed-methods matrix suggested that there was also an association between low engagement and less success with previous behavior change attempts, but the statistical evidence for this association was weak (P=.16). No associations were seen between engagement and barriers or facilitators to health behavior change, or comments about the design of the intervention itself. The most commonly cited barriers related to issues with access to the intervention itself: either difficulties remembering the link to the site or passwords, a perceived lack of flexibility within the website, or lack of time. Facilitators included the nonjudgmental presentation of lifestyle information, the use of simple language, and the personalized nature of the intervention. CONCLUSIONS: This study shows that the level of engagement with a Web-based intervention following provision of CHD risk information is not influenced by the level of risk but by the individual's response to the risk information, their past experiences of behavior change, the extent to which they consider the lifestyle information helpful, and whether they felt obliged to complete the intervention as part of a research study. A number of facilitators and barriers to Web-based interventions were also identified, which should inform future interventions.

Objectives: Severe mental illness (SMI) is associated with premature cardiovascular disease, prompting the UK primary care payment-for-performance system (Quality and Outcomes Framework, QOF) to incentivise annual physical health reviews. This study aimed to assess the QOF's impact on detection and treatment of cardiovascular risk factors in people with SMI. Methods: a retrospective open cohort study of UK general practice was conducted between 1996 and 2014, using segmented logistic regression with 2004 and 2011 as break points, reflecting the introduction of relevant QOF incentives in these years. 67239 SMI cases and 359951 randomly-selected unmatched controls were extracted from the Clinical Practice Research Datalink (CPRD). Results: There was strong evidence (p≤0.015) the 2004 QOF indicator (general health) resulted in an immediate increase in recording of elevated cholesterol (odds ratio 1.37 (95% confidence interval 1.24 to 1.51)); obesity (OR 1.21 (1.06 to 1.38)); and hypertension (OR 1.19 (1.04 to 1.38)) in the SMI group compared with the control group, which was sustained in subsequent years. Similar findings were found for diabetes, although the evidence was weaker (p = 0.059; OR 1.21 (0.99 to 1.49)). There was evidence (p

OBJECTIVES: to investigate patterns of early repeat prescriptions and treatment switching over an 11-year period to estimate differences in the cost of medication wastage, dispensing fees and prescriber time for short (

Polypharmacy describes, in simplistic terms, the use of multiple medications in an individual. It has become a normal aspect of modern medicine, driven by an ageing, multimorbid population, the increasing availability of preventative medications and an increasing use of single-disease guidelines and adherence to evidence-based practice. However, polypharmacy is also associated with a range of adverse outcomes, and is considered an important and increasing challenge for clinical practice. Here, we consider the definitions of polypharmacy, the extent and nature of medication use in different settings, and the type of problems encountered as a consequence of polypharmacy.

OBJECTIVE: Developing primary care is an important current health policy goal in the U.S. and England. Information on patients’ experience can help to improve the care of people with diabetes. We describe the experiences of people with diabetes in primary care and examine how these experiences vary with increasing comorbidity. RESEARCH DESIGN AND METHODS: Using data from 906,578 responders to the 2012 General Practice Patient Survey (England), including 85,760 with self-reported diabetes, we used logistic regressions controlling for age, sex, ethnicity, and socioeconomic status to analyze patient experience using seven items covering three domains of primary care: access, continuity, and communication. RESULTS: People with diabetes were significantly more likely to report better experience on six out of seven primary care items than people without diabetes after adjusting for age, sex, ethnicity, and socioeconomic status (adjusted differences 0.88-3.20%; odds ratios [ORs] 1.07-1.18; P < 0.001). Those with diabetes and additional comorbid long-term conditions were more likely to report worse experiences, particularly for access to primary care appointments (patients with diabetes alone compared with patients without diabetes: OR 1.22 [95% CI 1.17-1.28] and patients with diabetes plus three or more conditions compared with patients without diabetes: OR 0.87 [95% CI 0.83-0.91]). CONCLUSIONS: People with diabetes in England report primary care experiences that are at least as good as those without diabetes for most domains of care. However, improvements in primary care are needed for diabetes patients with comorbid long-term conditions, including better access to appointments and improved communication.

Background: Multimorbidity, the presence of two or more chronic conditions, affects over 60 % of patients in primary care. Due to its association with polypharmacy, the development of interventions to optimise medication management in patients with multimorbidity is a priority. The Behaviour Change Wheel is a new approach for applying behavioural theory to intervention development. Here, we describe how we have used results from a review of previous research, original research of our own and the Behaviour Change Wheel to develop an intervention to improve medication management in multimorbidity by general practitioners (GPs), within the overarching UK Medical Research Council guidance on complex interventions. Methods: Following the steps of the Behaviour Change Wheel, we sought behaviours associated with medication management in multimorbidity by conducting a systematic review and qualitative study with GPs. From the modifiable GP behaviours identified, we selected one and conducted a focused behavioural analysis to explain why GPs were or were not engaging in this behaviour. We used the behavioural analysis to determine the intervention functions, behavioural change techniques and implementation plan most likely to effect behavioural change. Results: We identified numerous modifiable GP behaviours in the systematic review and qualitative study, from which active medication review (rather than passive maintaining the status quo) was chosen as the target behaviour. Behavioural analysis revealed GPs' capabilities, opportunities and motivations relating to active medication review. We combined the three intervention functions deemed most likely to effect behavioural change (enablement, environmental restructuring and incentivisation) to form the MultimorbiditY COllaborative Medication Review and DEcision Making (MY COMRADE) intervention. MY COMRADE primarily involves the technique of social support: two GPs review the medications prescribed to a complex multimorbid patient together. Four other behavioural change techniques are incorporated: restructuring the social environment, prompts/cues, action planning and self-incentives. Conclusions: This study is the first to use the Behaviour Change Wheel to develop an intervention targeting multimorbidity and confirms the usability and usefulness of the approach in a complex area of clinical care. The systematic development of the MY COMRADE intervention will facilitate a thorough evaluation of its effectiveness in the next phase of this work.

Background: Cardiovascular disease (CVD) remains the leading cause of death globally. Primary prevention of CVD requires cost-effective strategies to identify individuals at high risk in order to help target preventive interventions. An integral part of this approach is the use of CVD risk scores. Limitations in previous studies have prevented reliable inference about the potential advantages and the potential harms of using CVD risk scores as part of preventive strategies. We aim to evaluate short-term effects of providing different types of information about coronary heart disease (CHD) risk, alongside lifestyle advice, on health-related behaviours. Methods/Design: in a parallel-group, open randomised trial, we are allocating 932 male and female blood donors with no previous history of CVD aged 40-84 years in England to either no intervention (control group) or to one of three active intervention groups: i) lifestyle advice only; ii) lifestyle advice plus information on estimated 10-year CHD risk based on phenotypic characteristics; and iii) lifestyle advice plus information on estimated 10-year CHD risk based on phenotypic and genetic characteristics. The primary outcome is change in objectively measured physical activity. Secondary outcomes include: objectively measured dietary behaviours; cardiovascular risk factors; current medication and healthcare usage; perceived risk; cognitive evaluation of provision of CHD risk scores; and psychological outcomes. The follow-up assessment takes place 12 weeks after randomisation. The experiences, attitudes and concerns of a subset of participants will be also studied using individual interviews and focus groups. Discussion: the INFORM study has been designed to provide robust findings about the short-term effects of providing different types of information on estimated 10-year CHD risk and lifestyle advice on health-related behaviours. Trial registration: Current Controlled Trials ISRCTN17721237. Registered 12 January 2015.

In the second article of our polypharmacy series the authors explore the difference between appropriate and problematic polypharmacy, and illustrate how in some circumstances these two states can co-exist.

OBJECTIVES: to describe and explain the primary care experiences of people with multiple long-term conditions in England. DESIGN AND METHODS: Using questionnaire data from 906,578 responders to the English 2012 General Practice Patient Survey, we describe the primary care experiences of patients with long-term conditions, including 583,143 patients who reported one or more long-term conditions. We employed mixed effect logistic regressions to analyse data on six items covering three care domains (access, continuity and communication) and a single item on overall primary care experience. We controlled for sociodemographic characteristics, and for general practice using a random effect, and further, controlled for, and explored the importance of, health-related quality of life measured using the EuroQoL (EQ-5D) scale. RESULTS: Most patients with long-term conditions report a positive experience of care at their general practice (after adjusting for sociodemographic characteristics and general practice, range 74.0-93.1% reporting positive experience of care across seven questions) with only modest variation by type of condition. For all three domains of patient experience, an increasing number of comorbid conditions is associated with a reducing percentage of patients reporting a positive experience of care. For example, compared with respondents with no long-term condition, the OR for reporting a positive experience is 0.83 (95% CI 0.80 to 0.87) for respondents with four or more long-term conditions. However, this relationship is no longer observed after adjusting for health-related quality of life (OR (95% CI) single condition=1.23 (1.21 to 1.26); four or more conditions=1.31 (1.25 to 1.37)), with pain making the greatest difference among five quality of life variables included in the analysis. CONCLUSIONS: Patients with multiple long-term conditions more frequently report worse experiences in primary care. However, patient-centred measures of health-related quality of life, especially pain, are more important than the number of conditions in explaining why patients with multiple long-term conditions report worse experiences of care.

BACKGROUND: Polypharmacy is often considered suggestive of suboptimal prescribing, and is associated with adverse outcomes. It is particularly common in the context of cardiovascular disease, but it is unclear whether prescribing of multiple cardiovascular medicines, which may be entirely appropriate and consistent with clinical guidance, is associated with adverse outcome. The aim of this study was to assess the relationship between number of prescribed cardiovascular medicines and unplanned non-cardiovascular hospital admissions. METHODS: a retrospective cohort analysis of 180,815 adult patients was conducted using Scottish primary care data linked to hospital discharge data. Patients were followed up for one year for the outcome of unplanned non-cardiovascular hospital admission. The association between number of prescribed cardiovascular medicines and hospitalisation was modelled using logistic regression, adjusting for key confounding factors including cardiovascular and non-cardiovascular morbidity and non-cardiovascular prescribing. RESULTS: 25.4% patients were prescribed ≥1 cardiovascular medicine, and 5.7% were prescribed ≥5. At least one unplanned non-cardiovascular admission was experienced by 4.2% of patients. Admissions were more common in patients receiving multiple cardiovascular medicines (6.4% of patients prescribed 5 or 6 cardiovascular medicines) compared with those prescribed none (3.5%). However, after adjusting for key confounders, cardiovascular prescribing was associated with fewer non-cardiovascular admissions (OR 0.66 for 5 or 6 vs. no cardiovascular medicines, 95% CI 0.57-0.75). CONCLUSIONS: We found no evidence that increasing numbers of cardiovascular medicines were associated with an increased risk of unplanned non-cardiovascular hospitalisation, following adjustment for confounding. Assumptions that polypharmacy is hazardous and represents poor care should be moderated in the context of cardiovascular disease.

INTRODUCTION: Asthma is now one of the most common long-term conditions in the UK. It is therefore important to develop a comprehensive appreciation of the healthcare and societal costs in order to inform decisions on care provision and planning. We plan to build on our earlier estimates of national prevalence and costs from asthma by filling the data gaps previously identified in relation to healthcare and broadening the field of enquiry to include societal costs. This work will provide the first UK-wide estimates of the costs of asthma. In the context of asthma for the UK and its member countries (ie, England, Northern Ireland, Scotland and Wales), we seek to: (1) produce a detailed overview of estimates of incidence, prevalence and healthcare utilisation; (2) estimate health and societal costs; (3) identify any remaining information gaps and explore the feasibility of filling these and (4) provide insights into future research that has the potential to inform changes in policy leading to the provision of more cost-effective care. METHODS AND ANALYSIS: Secondary analyses of data from national health surveys, primary care, prescribing, emergency care, hospital, mortality and administrative data sources will be undertaken to estimate prevalence, healthcare utilisation and outcomes from asthma. Data linkages and economic modelling will be undertaken in an attempt to populate data gaps and estimate costs. Separate prevalence and cost estimates will be calculated for each of the UK-member countries and these will then be aggregated to generate UK-wide estimates. ETHICS AND DISSEMINATION: Approvals have been obtained from the NHS Scotland Information Services Division's Privacy Advisory Committee, the Secure Anonymised Information Linkage Collaboration Review System, the NHS South-East Scotland Research Ethics Service and the University of Edinburgh's Centre for Population Health Sciences Research Ethics Committee. We will produce a report for Asthma-UK, submit papers to peer-reviewed journals and construct an interactive map.

AIMS: Prescribing multiple medications is associated with various adverse outcomes, and polypharmacy is commonly considered suggestive of poor prescribing. Polypharmacy might thus be associated with unplanned hospitalization. We sought to test this assumption. METHODS: Scottish primary care data for 180 815 adults with long-term clinical conditions and numbers of regular medications were linked to national hospital admissions data for the following year. Using logistic regression (age, gender and deprivation adjusted), we modelled the association of prescribing with unplanned admission for patients with different numbers of long-term conditions. RESULTS: Admissions were more common in patients on multiple medications, but admission risk varied with the number of conditions. For patients with one condition, the odds ratio for unplanned admission for four to six medications was 1.25 (95% confidence interval 1.11-1.42) vs. one to three medications, and 3.42 (95% confidence interval 2.72-4.28) for ≥10 medications vs. one to three medications. However, this effect was greatly reduced for patients with multiple conditions; amongst patients with six or more conditions, those on four to six medications were no more likely to have unplanned admissions than those taking one to three medications (odds ratio 1.00; 95% confidence interval 0.88-1.14), and those taking ≥10 medications had a modestly increased risk of admission (odds ratio 1.50; 95% confidence interval 1.31-1.71). CONCLUSIONS: Unplanned hospitalization is strongly associated with the number of regular medications. However, the effect is reduced in patients with multiple conditions, in whom only the most extreme levels of polypharmacy are associated with increased admissions. Assumptions that polypharmacy is always hazardous and represents poor care should be tempered by clinical assessment of the conditions for which those drugs are being prescribed.

PURPOSE: Polypharmacy-the use of multiple medications by a single patient-is an important issue associated with various adverse clinical outcomes and rising costs. It is also a topic rarely addressed by clinical guidelines. We used routine Scottish health records to address the lack of data on the prevalence of polypharmacy in the broader, adult primary care population, particularly in relation to long-term conditions. METHODS: We conducted a cross-sectional analysis of adult electronic primary healthcare records and used linear regression models to examine the association between the number of medicines prescribed regularly and both multimorbidity and specific clinical conditions, adjusting for age, gender and socioeconomic deprivation. RESULTS: Overall, 16.9 % of the adults assessed were receiving four to nine medications, and 4.6 % were receiving ten or more medications, increasing with age (28.6 and 7.4 %, respectively, in those aged 60-69 years; 51.8 and 18.6 %, respectively, in those aged ≥ 80 years), but relatively unaffected by gender or deprivation. of those patients with two clinical conditions, 20.8 % were receiving four to nine medications, and 1.1 % were receiving ten or more medications; in those patients with six or more comorbidities, these values were 47.7 and 41.7 %, respectively. The number of medications varied considerably between clinical conditions, with cardiovascular conditions associated with the greatest number of additional medications. The accumulation of additional medicines was less with concordant conditions. CONCLUSIONS: Polypharmacy is common in UK primary care. The main factor associated with this is multimorbidity, although considerable variation exists between different conditions. The impact of clinical conditions on the number of medicines is generally less in the presence of co-existing concordant conditions.

BACKGROUND: ACE Inhibitors (ACE-I) and Angiotensin-Receptor Antagonists (ARAs) are commonly prescribed but can cause acute kidney injury (AKI) during intercurrent illness. Rates of hospitalization with AKI are increasing. We aimed to determine whether hospital AKI admission rates are associated with increased ACE-I/ARA prescribing. METHODS AND FINDINGS: English NHS prescribing data for ACE-I/ARA prescriptions were matched at the level of the general practice to numbers of hospital admissions with a primary diagnosis of AKI. Numbers of prescriptions were weighted for the demographic characteristics of general practices by expressing prescribing as rates where the denominator is Age, Sex, and Temporary Resident Originated Prescribing Units (ASTRO-PUs). We performed a mixed-effect Poisson regression to model the number of admissions for AKI occurring in each practice for each of 4 years from 1/4/2007. From 2007/8-2010/11, crude AKI admission rates increased from 0.38 to 0.57 per 1000 patients (51.6% increase), and national annual ACE-I/ARA prescribing rates increased by 0.032 from 0.202 to 0.234 (15.8% increase). There was strong evidence (p

BACKGROUND AND OBJECTIVE: Falls are a major cause of morbidity and mortality in the elderly. This study examined the frequency of hospital admission for falls or fractures, and the association with a recent change in the use of cardiovascular and psychotropic medications. METHODS: We conducted a retrospective case-cohort study of 39,813 patients aged >65 years from 40 Scottish general practices. Data on current prescriptions, dates of drug changes (defined as increases in dose or starting new drugs), diagnoses and clinical measurements were extracted from primary care electronic records, linked to national hospital admissions data. Multivariable logistic regression was used to model the association of change in prescribing of cardiovascular or psychotropic medication with admission to hospital for falls or fractures in the following 60 days. RESULTS: a total of 838 patients (2.1 %) were admitted in the 1-year study period. Following adjustment for factors including age, sex, socioeconomic deprivation, co-morbidity and current prescribing, changes in both cardiovascular and psychotropic medications were associated with subsequent admission for falls or fractures (odds ratio [OR] 1.54 [95 % confidence interval (CI) 1.17-2.03] and 1.68 [95 % CI 1.28-2.22], respectively). There was no evidence for a difference in the effect of change in medication for different cardiovascular drug types (p = 0.86), but there was evidence (p = 0.003) for variation in the association between change in different psychotropic medications and admission; the strongest associations were observed for changes in selective serotonin reuptake inhibitor (SSRI) antidepressants (OR 1.99 [95 % CI 1.29-3.08]), non-SSRI/tricyclic antidepressants (OR 4.39 [95 % CI 2.21-8.71]) and combination psychotropic medication (OR 3.05 [95 % CI 1.66-5.63]). CONCLUSIONS: Recent changes in psychotropic and cardiovascular medications are associated with a substantial increase in risk of hospital admission for falls and fractures. Caution should thus be taken when instigating prescribing changes in relation to these medicines, particularly in individuals already considered to be at high risk, such as those with multiple co-morbidities and the oldest old.

Background: Changing family practice (voluntary disenrollment) without changing address may indicate dissatisfaction with care. We investigate the potential to use voluntary disenrollment as a quality indicator for primary care. Methods. Data from the English national GP Patient Survey (2,169,718 respondents), the number of voluntary disenrollments without change of address, data relating to practice characteristics (ethnicity, deprivation, gender of patients, practice size and practice density) and doctor characteristics were obtained for all family practices in England (n = 8450). Poisson regression analyses examined associations between rates of voluntary disenrollment, patient experience, and practice and doctor characteristics. Results: Mean and median rates of annual voluntary disenrollment were 11.2 and 7.3 per 1000 patients respectively. Strongest associations with high rates of disenrollment were low practice scores for doctor-patient communication and confidence and trust in the doctor (rate ratios 4.63 and 4.85). In a fully adjusted model, overall satisfaction encompassed other measures of patient experience (rate ratio 3.46). Patients were more likely to move from small practices (single-handed doctors had 2.75 times the disenrollment rate of practices with 6-9 doctors) and where there were other local practices. After allowing for these, substantial unexplained variation remained in practice rates of voluntary disenrollment. Conclusion: Family practices with low levels of patient satisfaction, especially for doctor patient communication, are more likely to experience high rates of disenrollment. However substantial variation in disenrollment rates remains among practices with similar levels of patient satisfaction, limiting the utility of voluntary disenrollment as a performance indicator for primary care in England. © 2013 Nagraj et al.; licensee BioMed Central Ltd.

OBJECTIVE: Increased arterial stiffness, as measured by pulse wave velocity (PWV), is associated with increased cardiovascular risk in the general population. Few studies have examined factors associated with increased PWV in people with Type 2 diabetes. The aim of this study was to determine whether there was a link between PWV and clinical variables associated with central obesity, in men and women with Type 2 diabetes. RESEARCH DESIGNS AND METHODS: Eight hundred and sixty individuals [mean age (±SD) 69 (±4) years] from the Edinburgh Type 2 Diabetes Study, underwent applanation tonometry using a high-fidelity micromanometer. PWV was measured by sequentially recording electrocardiogram-gated carotid and femoral artery waveforms. RESULTS: Waist circumference (β = 0.10, P < 0.01) and waist: hip ratio (β = 0.10, P < 0.01) were independently associated with PWV, but not with BMI. In a stepwise multiple regression model, mean arterial pressure (β = 0.26, P < 0.01) and age (β = 0.23, P < 0.01) were strongly associated with PWV. The associations between the central obesity measures and PWV were independent of age, sex, duration of diabetes and metabolic factors associated with central obesity. Duration of diabetes (β = 0.10, P < 0.01) and glycated hemoglobin (β = 0.09, P < 0.01) were also found to be independent predictors of arterial stiffness. Obesity biomarkers such as C-reactive protein, leptin, tumour necrosis factor-α and interleukin-6 were not associated with arterial stiffness. CONCLUSION: Central obesity in people with Type 2 diabetes was associated with increased arterial stiffness. This association was independent of the conventional factors associated with central obesity and further studies are required to identify the mechanisms involved. © 2013 Wolters Kluwer Health | Lippincott Williams &Wilkins.

BACKGROUND: Acute kidney injury (AKI) is an independent risk factor for mortality and is responsible for a significant burden of healthcare expenditure, so accurate measurement of its incidence is important. Administrative coding data has been used for assessing AKI incidence, and shows an increasing proportion of hospital bed days attributable to AKI. However, the accuracy of coding for AKI and changes in coding over time have not been studied in England. METHODS: We studied a random sample of admissions from 2005 and 2010 where ICD-10 code N17 (acute renal failure) was recorded in the administrative coding data at one acute NHS Foundation Trust in England. Using the medical notes and computerised records we examined the demographic and clinical details of these admissions. RESULTS: Against a 6.3% (95% CI 4.8-7.9%) increase in all non-elective admissions, we found a 64% increase in acute renal failure admissions (95% CI 41%-92%, p < 0.001) in 2010 compared to 2005. Median age was 78 years (IQR 72-87), 11-25% had a relevant pre-admission co-morbidity and 64% (55-73%) were taking drugs known to be associated with AKI. Over both years, 95% (91-99%) of cases examined met the Kidney Disease: Improving Global Outcomes criteria for AKI. CONCLUSIONS: Patients with hospital admissions where AKI has been coded are elderly with multiple co-morbidities. Our results demonstrate a high positive predictive value of coding data for a clinical diagnosis of AKI, with no suggestion of marked changes in coding of AKI between 2005 and 2010.

Background: Multimorbidity, the presence of more than 1 long-term disorder, is associated with increased use of health services, but un - planned admissions to hospital may often be undesirable. Furthermore, socioeconomic de p - rivation and mental health comorbidity may lead to additional unplanned admissions. We examined the association between un planned admission to hospital and physical multi - morbidity, mental health and socioeconomic deprivation. Methods: We conducted a retrospective co - hort study using data from 180 815 patients aged 20 years and older who were registered with 40 general practices in Scotland. Details of 32 physical and 8 mental health morbidities were extracted from the patients’ electronic health records (as of Apr. 1, 2006) and linked to hospital admission data. We then recorded the occurrence of unplanned or potentially preventable unplanned acute (nonpsychiatric) admissions to hospital in the subsequent 12 months. We used logistic regression models, adjusting for age and sex, to determine associations between unplanned or potentially preventable unplanned admissions to hospital and physical multimorbidity, mental health and socioeconomic deprivation. Results: We identified 10 828 (6.0%) patients who had at least 1 unplanned admission to hospital and 2037 (1.1%) patients who had at least 1 potentially preventable unplanned admission to hospital. Both unplanned and potentially preventable unplanned admissions were independently associated with increasing physical multimorbidity (for = 4 v. 0 conditions, odds ratio [OR] 5.87 [95% confidence interval (CI) 5.45-6.32] for unplanned admissions, OR 14.38 [95% CI 11.87-17.43] for potentially preventable unplanned admissions), mental health conditions (for ≥ 1 v. 0 conditions, OR 2.01 [95% CI 1.92-2.09] for unplanned admissions, OR 1.80 [95% CI 1.64- 1.97] for potentially preventable unplanned admissions) and socioeconomic deprivation (for most v. least deprived quintile, OR 1.56 [95% CI 1.43-1.70] for unplanned admissions, OR 1.98 [95% CI 1.63-2.41] for potentially preventable unplanned admissions). Interpretation: Physical multimorbidity was strongly associated with unplanned admission to hospital, including admissions that were potentially preventable. The risk of admission to hospital was exacerbated by the coexistence of mental health conditions and socio - economic deprivation. © 2013 Canadian Medical Association or its licensors.

OBJECTIVES: Data linkage combines information from several clinical data sets. The authors examined whether coding inconsistencies for cardiovascular disease between components of linked data sets result in differences in apparent population characteristics. DESIGN: Retrospective cohort study. SETTING: Routine primary care data from 40 Scottish general practitioner (GP) surgeries linked to national hospital records. PARTICIPANTS: 240 846 patients, aged 20 years or older, registered at a GP surgery. OUTCOMES: Cases of myocardial infarction, ischaemic heart disease and stroke (cerebrovascular disease) were identified from GP and hospital records. Patient characteristics and incidence rates were assessed for all three clinical outcomes, based on GP, hospital, paired GP/hospital (similar diagnoses recorded simultaneously in both data sets) or pooled GP/hospital records (diagnosis recorded in either or both data sets). RESULTS: for all three outcomes, the authors found evidence (p

Cardiovascular disease is a major, growing, worldwide problem. It is important that individuals at risk of developing cardiovascular disease can be effectively identified and appropriately stratified according to risk. This review examines what we understand by the term risk, traditional and novel risk factors, clinical scoring systems, and the use of risk for informing prescribing decisions. Many different cardiovascular risk factors have been identified. Established, traditional factors such as ageing are powerful predictors of adverse outcome, and in the case of hypertension and dyslipidaemia are the major targets for therapeutic intervention. Numerous novel biomarkers have also been described, such as inflammatory and genetic markers. These have yet to be shown to be of value in improving risk prediction, but may represent potential therapeutic targets and facilitate more targeted use of existing therapies. Risk factors have been incorporated into several cardiovascular disease prediction algorithms, such as the Framingham equation, SCORE and QRISK. These have relatively poor predictive power, and uncertainties remain with regards to aspects such as choice of equation, different risk thresholds and the roles of relative risk, lifetime risk and reversible factors in identifying and treating at-risk individuals. Nonetheless, such scores provide objective and transparent means of quantifying risk and their integration into therapeutic guidelines enables equitable and cost-effective distribution of health service resources and improves the consistency and quality of clinical decision making. © 2012 the British Pharmacological Society.

Arterial generalized transfer functions (GTFs) are increasingly used to estimate central pressure from peripheral measurements. Analysis of derived central waveforms may be valuable in the assessment of patients with chronic kidney disease. The aim of this study was to assess whether the GTF is affected by renal disease. Ninety-four subjects with varying degrees of renal function (Kidney Disease Outcomes Quality Initiative stages 1 to 5; 14 controls) had simultaneous measurements of carotid and radial waveforms made by applanation tonometry. GTFs were calculated by Fourier analysis for each subject group. Derived carotid waveforms were obtained by applying an independently generated GTF to the radial waveform. Glomerular filtration rate inversely correlated with central systolic (R=-0.42; P

BACKGROUND/OBJECTIVES: Socioeconomic gradients exist in the prevalence of cardiovascular disease. This has prompted the development of risk scores such as ASSIGN and QRISK, which incorporate measures of deprivation, to address the issue of underprescribing of primary preventive medicines in the socially disadvantaged. The scores use area-based measures of deprivation rather than the socioeconomic status of the individual. We examined to what extent the decision to treat a patient might be influenced by where that individual lived. METHODS: on the basis of individual patient risk factor data from the Scottish Health Survey, we compared the theoretical level of deprivation [Scottish Index of Multiple Deprivation (SIMD)] required to give a person an ASSIGN risk of 20% (the treatment cut-off), with the person's actual SIMD quintile. We assumed that patients are more likely to move between areas of similar deprivation (i.e. the same SIMD quintile). If the theoretical SIMD value for that individual fell within their actual SIMD quintile, we assumed that prescribing decisions could be influenced by the area of residence. RESULTS: If the ASSIGN risk score was implemented, the area of residence would affect the decision to initiate statins in the case of 15.7% of the population (aged 30-74 years), and for borderline hypertension, in 3.0%. This corresponds to 407 000 and 15 000 people, respectively, in Scotland and 4.6 million and 169 000 in the entire UK. CONCLUSION: These findings demonstrate that by using cardiovascular risk scores based on area deprivation, primary prevention treatment decisions will be affected by the area of residence in a large number of individuals.

OBJECTIVES: to identify factors influencing hospital re-admission with self-poisoning. STUDY DESIGN: Retrospective cohort follow-up study using national linked hospital discharge data. METHODS: all Scottish adult hospital episodes with self-poisoning admissions were captured using NHS Scotland Information Services Division data, and first-time 'index' admissions between 1996 and 2002 were identified. Re-admission rate was defined as the proportion of index admissions who went on to have one or more further self-poisoning admissions within 2 years. The effects of various potential risk factors for re-admission were examined using logistic regression. RESULTS: in total, 50,891 index admissions were identified; of these, 8278 patients were re-admitted. The 1-year re-admission rate was 12.2%. Older patients (>65 years) were least likely to be re-admitted [odds ratio (OR) 0.40, P

OBJECTIVES: Peripheral exercise blood pressure and resting central blood pressure are considered more relevant to cardiovascular health than resting peripheral blood pressure. Central exercise blood pressure may well be an even more useful measure, but there is no simple non-invasive means of determining it. The aim of the present study was to establish whether the estimation of central blood pressure from peripheral blood pressure using a transfer function derived at rest, would hold after aerobic exercise. METHODS: Thirty healthy young men were studied before and immediately (< 1 min) and 10 min after 15 min bicycle exercise at 65-70% of maximum heart rate. Simultaneous carotid and radial artery waveforms were recorded, and radial-to-carotid generalized transfer functions (GTF) were calculated using Fourier analysis for rest and immediately postexercise. Central systolic blood pressure (SBP) and augmentation index (AIx) were calculated for measured and derived waves. RESULTS: the resting GTF underestimated central SBP and AIx immediately (-5.8 ± 2.1 mmHg, P = 0.01; -8.3 ± 2.9%, P = 0.008) and 10 min after (-2.0 ± 0.7 mmHg, P = 0.008; -7.0 ± 2.1%, P = 0.003) exercise. No significant bias was found between measured and derived (using resting GTF) carotid values at rest. The use of an exercise-specific GTF resulted in no specific bias immediately or 10 min after exercise, although it overestimated blood pressure and AIx at rest (2.5 ± 1.0 mmHg, P = 0.02; 11.3 ± 3.0%, P = 0.001). CONCLUSION: a peripheral-to-central arterial GTF derived at rest significantly underestimates key measures of central arterial pressure immediately after exercise, and pressure estimations may be improved by the use of an exercise-specific GTF. © 2007 Lippincott Williams & Wilkins, Inc.

Background: to examine whether augmentation index (AIx) is increased in Marfan syndrome (MFS) and associated with increased aortic root size, and whether a peripheral-to-central generalised transfer function (GTF) can be applied usefully in MFS. Methods: 10 MFS patients and 10 healthy controls (matched for sex, age and height) were studied before and after 400 μg sub-lingual GTN. Arterial waveforms were recorded using applanation tonometry. AIx and pulse pressure (PP) were determined for the radial and carotid arteries. Pulse wave velocity (PWV) was measured between carotid and femoral arteries. GTFs were generated to examine the relationship between radial and carotid waveforms. Results: AIx was greater in MFS compared to controls at radial (mean -31.4 (SD 14.3)% v -50.2(15.6)%, p = 0.003) and carotid (-7.6(11.2)% v -23.7(12.7)%, p = 0.004) sites. Baseline PP at all measurement sites, and PWV, did not differ between subject groups. Multivariate analysis demonstrated that PWV and carotid AIx were positively correlated with aortic root size (p < 0.001 and p = 0.012 respectively), independent of the presence of MFS. PP was not associated with aortic root size. GTN caused similar decreases in AIx in both controls and patients. Significant differences were found in GTFs between MFS and control subjects, which changed following GTN administration. However, when an independent GTF was used to derive carotid waves from radial waves, no differences were found in the degree of error between MFS and controls. Conclusion: AIx is sensitive to the vascular abnormalities present in MFS, and may have a role as an adjunct to measurement of central PP and PWV. Differences between MFS and controls in the nature of the peripheral-to-central GTF are present, although have little effect on the pulse contour. © 2007 Payne et al; licensee BioMed Central Ltd.

Background. Wideband external pulse (WEP) monitoring, using a broad bandwidth piezoelectric sensor located over the brachial artery under the distal edge of a sphygmomanometer cuff, can be used for evaluating the contour of the arterial pressure pulse wave. The pulse contour contains valuable information relating to cardiovascular function which may be of clinical use in addition to blood pressure measurements. The aim of this study was to compare the shape of the WEP signal during inflation of the cuff to suprasystolic pressure, with intra-arterial pressure waves, after the administration of vasoactive drugs. Methods. Radial intra-arterial and suprasystolic WEP waveforms were recorded in 11 healthy men (mean 23 yr) before and at the end of infusion of glyceryl trinitrate, angiotensin II, norepinephrine, and salbutamol. Waveform similarity was assessed by comparing the timing and pressure of incident and reflected waves and by root mean square error (RMSE). Results. The WEP signal was found to closely resemble the first derivative of intra-arterial pressure. The WEP signal could be used to derive an arterial pressure wave with minimal bias in the timing of incident [- 8 (18) ms, mean (sd)] and reflected [- 1 (24) ms] waves. Augmentation index was underestimated by WEP [- 7 (18)%]. WEP also provided a measure of compliance which correlated with pulse wave velocity (r = - 0.44). RMSE values after the administration of each of the four drugs mentioned earlier were 12.4 (3.8), 17.7 (5.0), 22.1 (11.7), and 28.9 (22.4) mm Hg, respectively. Changes in derived WEP signals were similar to those measured by arterial line with all drugs. Conclusions. The suprasystolic WEP signals can be used to derive arterial pressure waves which, although not identical, track changes in the intra-arterial pulse wave induced by vasoactive drugs. © the Board of Management and Trustees of the British Journal of Anaesthesia 2007. All rights reserved.

The arterial pulse-wave transit time can be measured between the ECG R-wave and the finger pulse (rPTT), and has been shown previously to have a linear correlation with blood pressure (BP). We hypothesized that the relationship between rPTT, preejection period (PEP; the R-wave/ mechanical cardiac delay), and BP would vary with different vasoactive drugs. Twelve healthy men (mean age 22 yr) were studied. Beat-to-beat measurements were made of rPTT (using ECG and photoplethysmograph finger probe), intra-arterial radial pressure, PEP (using cardiac bioimpedance), and transit time minus PEP (pPTT). Four drugs (glyceryl trinitrate, angiotensin II, norepinephrine, salbutamol) were administered intravenously over 15 min, with stepped dosage increase every 5 min and a 25-min saline washout between agents. All subjects in all conditions had a negative linear correlation (R2 = 0.39) between rPTT and systolic BP (SBP), generally constant between different drugs, apart from four subjects who had a positive rPTT/SBP correlation with salbutamol. The 95% limits of agreement between measured and rPTT-predicted SBP were ±17.0 mmHg. Beat-to-beat variability of rPTT showed better coherence with SBP variability than it did with heart rate variability (P < 0.001). PEP accounted for a substantial and variable proportion of rPTT (12-35%). Diastolic (DBP) and mean arterial BP (MAP) correlated poorly with rPTT (R2 = 0.02 and 0.08, respectively) but better with pPTT (rPTT corrected for PEP, R2 = 0.41 and 0.45, respectively). The 95% limits of agreement between measured and pPTT-predicted DBP were ± 17.3 mmHg. In conclusion, the negative correlation between rPTT and SBP is generally constant, even with marked hemodynamic perturbations. However, the relationship is not reliable enough for rPTT to be used as a surrogate marker of SBP, although it may be useful in assessing BP variability. DBP and MAP cannot be predicted from rPTT without correction for PEP. The significant contribution of PEP to rPTT means that rPTT should not be used as a marker of purely vascular function. Copyright © 2006 the American Physiological Society.

Background: Nonsteroidal anti-inflammatory drugs (NSAIDs) with increased selectivity for the cyclooxygenase-2 (COX-2) isoform reduce gastrotoxicity but may increase adverse cardiovascular events. Methods: We searched the literature for studies that reported the odds ratio (OR) for such events following exposure to NSAIDs. Results: for studies comparing NSAID use with no use, increased COX-2 selectivity was significantly related to cardiovascular risk (log OR) amongst observational studies (R = -0.34, P < 0.001) and randomized controlled trials (RCTs) (R = -0.56, P < 0.001). For studies comparing NSAIDs, difference in selectivity was related to risk for observational studies (R = -0.28, P = 0.005) but not for RCTs (R = -0.23, P = 0.15). Conclusions: Although increased COX-2 selectivity may reduce gastrotoxicity, this may be at the cost of increasing cardiovascular risk. © 2006 Blackwell Publishing Ltd.