Defining, identifying and addressing problematic polypharmacy within multimorbidity in primary care: a scoping review.

INTRODUCTION: Polypharmacy and multimorbidity pose escalating challenges. Despite numerous attempts, interventions have yet to show consistent improvements in health outcomes. A key factor may be varied approaches to targeting patients for intervention. OBJECTIVES: To explore how patients are targeted for intervention by examining the literature with respect to: understanding how polypharmacy is defined; identifying problematic polypharmacy in practice; and addressing problematic polypharmacy through interventions. DESIGN: We performed a scoping review as defined by the Joanna Briggs Institute. SETTING: The focus was on primary care settings. DATA SOURCES: Medline, Embase, Cumulative Index to Nursing and Allied Health Literature and Cochrane along with ClinicalTrials.gov, Science.gov and WorldCat.org were searched from January 2004 to February 2024. ELIGIBILITY CRITERIA: We included all articles that had a focus on problematic polypharmacy in multimorbidity and primary care, incorporating multiple types of evidence, such as reviews, quantitative trials, qualitative studies and policy documents. Articles focussing on a single index disease or not written in English were excluded. EXTRACTION AND ANALYSIS: We performed a narrative synthesis, comparing themes and findings across the collective evidence to draw contextualised insights and conclusions. RESULTS: In total, 157 articles were included. Case-finding methods often rely on basic medication counts (often five or more) without considering medical history or whether individual medications are clinically appropriate. Other approaches highlight specific drug indicators and interactions as potentially inappropriate prescribing, failing to capture a proportion of patients not fitting criteria. Different potentially inappropriate prescribing criteria also show significant inconsistencies in determining the appropriateness of medications, often neglecting to consider multimorbidity and underprescribing. This may hinder the identification of the precise population requiring intervention. CONCLUSIONS: Improved strategies are needed to target patients with polypharmacy, which should consider patient perspectives, individual factors and clinical appropriateness. The development of a cross-cutting measure of problematic polypharmacy that consistently incorporates adjustment for multimorbidity may be a valuable next step to address frequent confounding.

Educational inequality in multimorbidity: causality and causal pathways. A mendelian randomisation study in UK Biobank.

BACKGROUND: Multimorbidity, typically defined as having two or more long-term health conditions, is associated with reduced wellbeing and life expectancy. Understanding the determinants of multimorbidity, including whether they are causal, may help with the design and prioritisation of prevention interventions. This study seeks to assess the causality of education, BMI, smoking and alcohol as determinants of multimorbidity, and the degree to which BMI, smoking and alcohol mediate differences in multimorbidity by level of education. METHODS: Participants were 181,214 females and 155,677 males, mean ages 56.7 and 57.1 years respectively, from UK Biobank. We used a Mendelian randomization design; an approach that uses genetic variants as instrumental variables to interrogate causality. RESULTS: The prevalence of multimorbidity was 55.1%. Mendelian randomization suggests that lower education, higher BMI and higher levels of smoking causally increase the risk of multimorbidity. For example, one standard deviation (equivalent to 5.1 years) increase in genetically-predicted years of education decreases the risk of multimorbidity by 9.0% (95% CI: 6.5 to 11.4%). A 5 kg/m2 increase in genetically-predicted BMI increases the risk of multimorbidity by 9.2% (95% CI: 8.1 to 10.3%) and a one SD higher lifetime smoking index increases the risk of multimorbidity by 6.8% (95% CI: 3.3 to 10.4%). Evidence for a causal effect of genetically-predicted alcohol consumption on multimorbidity was less strong; an increase of 5 units of alcohol per week increases the risk of multimorbidity by 1.3% (95% CI: 0.2 to 2.5%). The proportions of the association between education and multimorbidity explained by BMI and smoking are 20.4% and 17.6% respectively. Collectively, BMI and smoking account for 31.8% of the educational inequality in multimorbidity. CONCLUSIONS: Education, BMI, smoking and alcohol consumption are intervenable causal risk factors for multimorbidity. Furthermore, BMI and lifetime smoking make a considerable contribution to the generation of educational inequalities in multimorbidity. Public health interventions that improve population-wide levels of these risk factors are likely to reduce multimorbidity and inequalities in its occurrence.

Association of strong opioids and antibiotics prescribing with GP burnout: a retrospective cross-sectional study.

BACKGROUND: Prescribing of strong opioids and antibiotics impacts patient safety, yet little is known about the effects GP wellness has on overprescribing of both medications in primary care. AIM: To examine associations between strong opioid and antibiotic prescribing and practice- weighted GP burnout and wellness. DESIGN AND SETTING: A retrospective cross-sectional study was undertaken using prescription data on strong opioids and antibiotics from the Oxford- Royal College of General Practitioners Research and Surveillance Centre linking to a GP wellbeing survey overlaying the same 4-month period from December 2019 to April 2020. METHOD: Patients prescribed strong opioids and antibiotics were the outcomes of interest. RESULTS: Data for 40 227 patients (13 483 strong opioids and 26 744 antibiotics) were linked to 57 practices and 351 GPs. Greater strong opioid prescribing was associated with increased emotional exhaustion (incidence risk ratio [IRR] 1.19, 95% confidence interval [CI] = 1.10 to 1.24), depersonalisation (IRR 1.10, 95% CI = 1.01 to 1.16), job dissatisfaction (IRR 1.25, 95% CI = 1.19 to 1.32), diagnostic uncertainty (IRR 1.12, 95% CI = 1.08 to 1.19), and turnover intention (IRR 1.32, 95% CI = 1.27 to 1.37) in GPs. Greater antibiotic prescribing was associated with increased emotional exhaustion (IRR 1.19, 95% CI = 1.05 to 1.37), depersonalisation (IRR 1.24, 95% CI = 1.08 to 1.49), job dissatisfaction (IRR 1.11, 95% CI = 1.04 to 1.19), sickness-presenteeism (IRR 1.18, 95% CI = 1.11 to 1.25), and turnover intention (IRR 1.38, 95% CI = 1.31 to 1.45) in GPs. Increased strong opioid and antibiotic prescribing was also found in GPs working longer hours (IRR 3.95, 95% CI = 3.39 to 4.61; IRR 5.02, 95% CI = 4.07 to 6.19, respectively) and in practices in the north of England (1.96, 95% CI = 1.61 to 2.33; 1.56, 95% CI = 1.12 to 3.70, respectively). CONCLUSION: This study found higher rates of prescribing of strong opioids and antibiotics in practices with GPs with more burnout symptoms, greater job dissatisfaction, and turnover intentions; working longer hours; and in practices in the north of England serving more deprived populations.

Using the Primary care Academic CollaboraTive to explore the characteristics and healthcare use of older housebound patients in England: protocol for a retrospective observational study and clinician survey (the CHiP study).

BACKGROUND: Older housebound people are an under-researched group for whom achieving good primary health care can be resource intensive. AIMS: To describe the characteristics and healthcare use of older (≥65 years) housebound people; explore clinician views on delivery of care to housebound people; and assess the feasibility of using a new network of healthcare professionals to deliver high quality research. DESIGN & SETTING: Retrospective observational study of electronic GP records and clinician survey in England. METHOD: Clinical members of a new UK research network called the Primary care Academic CollaboraTive (PACT) will collect the data. For part A, around 20 GP practices will be recruited and clinicians will identify 20 housebound and 20 non-housebound people, matched by age and gender (around 400 total in each group). Anonymised data will be collected on characteristics (age, gender, ethnicity, deprivation decile), long-term conditions, prescribed medicines, quality of healthcare (via Quality Outcomes Framework targets), and continuity of care. Reports with benchmarked practice-level data will be provided to practices to identify areas for quality improvement and to enhance engagement. For part B, 2-4 clinicians will be recruited from around 50 practices in England (around 150 clinicians) to complete a survey about delivery of healthcare for housebound people. For part C, data will be collected to assess the feasibility of using the PACT network to deliver primary care research. CONCLUSION: Older housebound people are a neglected group both in terms of research and clinical care. Understanding the characteristics and use of primary healthcare of housebound people will help identify how to improve their care.

Ideas, concerns, expectations, and effects on life (ICEE) in GP consultations: an observational study using video-recorded UK consultations.

BACKGROUND: Eliciting patients' ideas, concerns, expectations, and whether a problem has an 'effect' on their life (ICEE), is a widely recommended communication technique. However, it is not known how frequently ICEE components are raised in UK GP consultations. AIM: To assess the frequency of ICEE in routine GP consultations with adult patients and explore variables associated with ICEE. DESIGN & SETTING: An observational study was undertaken. It involved secondary analysis of a pre-existing archive of video-recorded, face-to-face GP consultations in the UK. METHOD: Observational coding of 92 consultations took place. Associations were assessed using binomial and ordered logistic regression. RESULTS: Most consultations included at least one ICEE component (90.2%). The most common ICEE component per consultation was patient ideas (79.3%), followed by concerns (55.4%), expectations (51.1%), and then effects on life (42.4%). For all ICEE components patients more commonly initiated the ICEE dialogue, and in only three consultations (3.3%) did GPs directly ask patients about their expectations. Problems that were acute (odds ratio [OR] 2.98, 95% confidence interval [CI] = 1.36 to 6.53, P = 0.007) or assessed by GPs aged ≥50 years (OR 2.10, 95% CI = 1.07 to 4.13, P = 0.030) were associated with more ICEE components. Problems assessed later in the consultation (OR 0.60 per problem order increase, 95% CI = 0.41 to 0.87, P = 0.007) by patients aged ≥75 years (OR 0.40, 95% CI = 0.16 to 0.98, P = 0.046) and from the most deprived cohort (OR 0.39, 95% CI = 0.17 to 0.92, P = 0.032) were associated with fewer ICEE components. Patient ideas were associated with more patients being 'very satisfied' post-consultation (OR 10.74, 95% CI = 1.60 to 72.0, P = 0.014) and the opposite was true of concerns (OR 0.14, 95% CI = 0.02 to 0.86, P = 0.034). CONCLUSION: ICEE components were associated with patient satisfaction and demographic variables. Further research is required to assess if the way ICEE are communicated affects these associations and other potential confounders.

Predicting the risk of acute kidney injury in primary care: derivation and validation of STRATIFY-AKI.

BACKGROUND: Antihypertensives reduce the risk of cardiovascular disease but are also associated with harms including acute kidney injury (AKI). Few data exist to guide clinical decision making regarding these risks. AIM: To develop a prediction model estimating the risk of AKI in people potentially indicated for antihypertensive treatment. DESIGN AND SETTING: Observational cohort study using routine primary care data from the Clinical Practice Research Datalink (CPRD) in England. METHOD: People aged ≥40 years, with at least one blood pressure measurement between 130 mmHg and 179 mmHg were included. Outcomes were admission to hospital or death with AKI within 1, 5, and 10 years. The model was derived with data from CPRD GOLD (n = 1 772 618), using a Fine-Gray competing risks approach, with subsequent recalibration using pseudo-values. External validation used data from CPRD Aurum (n = 3 805 322). RESULTS: The mean age of participants was 59.4 years and 52% were female. The final model consisted of 27 predictors and showed good discrimination at 1, 5, and 10 years (C-statistic for 10-year risk 0.821, 95% confidence interval [CI] = 0.818 to 0.823). There was some overprediction at the highest predicted probabilities (ratio of observed to expected event probability for 10-year risk 0.633, 95% CI = 0.621 to 0.645), affecting patients with the highest risk. Most patients (>95%) had a low 1- to 5-year risk of AKI, and at 10 years only 0.1% of the population had a high AKI and low CVD risk. CONCLUSION: This clinical prediction model enables GPs to accurately identify patients at high risk of AKI, which will aid treatment decisions. As the vast majority of patients were at low risk, such a model may provide useful reassurance that most antihypertensive treatment is safe and appropriate while flagging the few for whom this is not the case.

The association between antihypertensive treatment and serious adverse events by age and frailty: A cohort study.

BACKGROUND: Antihypertensives 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 FINDINGS: This 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. CONCLUSIONS: Antihypertensive 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.

Development and external validation of a risk prediction model for falls in patients with an indication for antihypertensive treatment: retrospective cohort study.

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.

Association between continuity of primary care and both prescribing and adherence of common cardiovascular medications: a cohort study among patients in England.

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<0.01) that prescription of all five cardiovascular medication groups increased with greater continuity of care. Patients with absence of continuity were less likely to be prescribed cardiovascular medications than patients with above-average continuity (statins primary prevention OR 0.73, 95% CI 0.59 to 0.85; statins secondary prevention 0.77, 95% CI 0.57 to 1.03; antiplatelets 0.55, 95% CI 0.33 to 0.92; antihypertensives 0.51, 95% CI 0.39 to 0.65). Furthermore, patients with perfect continuity were more likely to be prescribed cardiovascular medications than those with above-average continuity (statins primary prevention OR 1.23, 95% CI 1.01 to 1.49; statins secondary prevention 1.37, 95% CI 1.10 to 1.71; antiplatelets 1.37, 95% CI 1.08 to 1.74; antihypertensives 1.10, 95% CI 0.99 to 1.23). Continuity was generally not associated with medication adherence, except for adherence to statins for secondary prevention (OR 0.75, 95% CI 0.60 to 0.94 for average compared with above-average continuity). CONCLUSION: Better continuity of care is associated with improved prescribing of medication to patients at higher risk of cardiovascular disease but does not appear to be related to patient's medication adherence.

Antidepressant use and risk of adverse outcomes: population-based cohort study.

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.

Association between hypertensive disorders of pregnancy and later risk of cardiovascular outcomes.

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.

Improving Medicines use in People with Polypharmacy in Primary Care (IMPPP): Protocol for a multicentre cluster randomised trial comparing a complex intervention for medication optimization against usual care.

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).

Regression discontinuity analysis for pharmacovigilance: statin example reflected trial findings showing little evidence of harm.

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<20, we explored RDA assumptions, provided proof of concept analyses (total cholesterol as outcome), and investigated the effect of statins prescription on adverse outcomes. RESULT: RDA confirmed statin prescription reduced total cholesterol (Mean difference (MD) -1.33 mmol/L, 95%Confidence Interval (CI) -1.93 to -0.73). RDA provided little evidence for adverse effects on diabetes, myalgia and myositis, liver disease, CVD, or mortality. The RDA analysis findings are similar to RCT results. Findings from non-RDA analysis agree with published observational studies. CONCLUSION: RDA can be used with large routine clinical datasets to provide evidence on effects of medications which are prescribed according to a threshold. Testable RDA assumptions were satisfied, but confidence intervals were wide, partly due to the low compliance with the prescribing threshold.

Novel oral iron therapy for iron deficiency anaemia: How to value safety in a new drug?

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.

Blood Pressure Changes Following Antihypertensive Medication Reduction, by Drug Class and Dose Chosen for Withdrawal: Exploratory Analysis of Data From the OPTiMISE Trial.

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; <150 mmHg), receiving ≥2 antihypertensive medications. This study compared SBP control, mean change in SBP and frequency of adverse events after 12 weeks in participants stopping one medication vs. usual care, by drug class and equivalent dose of medication withdrawn. Equivalent dose was determined according to the defined daily dose (DDD) of each medication type. Drugs prescribed below the DDD were classed as low dose and those prescribed at ≥DDD were described as higher dose. Outcomes were examined by generalized linear mixed effects models. Results: A total of 569 participants were randomized, aged 85 ± 3 years with controlled blood pressure (mean 130/69 mmHg). Within patients prescribed calcium channel blockers, higher dose medications were more commonly selected for withdrawal (90 vs. 10%). In those prescribed beta-blockers, low dose medications were more commonly chosen (87 vs. 13%). Withdrawal of calcium channel blockers was associated with an increase in SBP (5 mmHg, 95%CI 0-10 mmHg) and reduced SBP control (adjusted RR 0.89, 95%CI 0.80-0.998) compared to usual care. In contrast, withdrawal of beta-blockers was associated with no change in SBP (-4 mmHg, 95%CI -10 to 2 mmHg) and no difference in SBP control (adjusted RR 1.15, 95%CI 0.96-1.37). Similarly, withdrawal of higher dose medications was associated with an increase in SBP but no change in BP control. Withdrawal of lower dose medications was not associated with a difference in SBP or SBP control. There was no association between withdrawal of specific drug classes and adverse events. Conclusion: These exploratory data suggest withdrawal of higher dose calcium channel blockers should be avoided if the goal is to maintain BP control. However, low dose beta-blockers may be removed with little impact on blood pressure over 12-weeks of follow-up. Larger studies are needed to confirm these associations.

GPs' mindlines on deprescribing antihypertensives in older patients with multimorbidity: a qualitative study in English general practice.

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 practicebased experience. These tacit approaches to making complex decisions are critical to developing confidence to attempt deprescribing and may be strengthened through reflective practice.

The Use of Primary Care Big Data in Understanding the Pharmacoepidemiology of COVID-19: A Consensus Statement From the COVID-19 Primary Care Database Consortium.

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 decisions 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 consistency in defining and reporting cases, exposures, confounders, stratification variables, 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.

Association between antihypertensive treatment and adverse events: systematic review and meta-analysis.

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 (τ2). 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, τ2=0.009). Antihypertensives were associated with an increased risk of acute kidney injury (1.18, 95% confidence interval 1.01 to 1.39, τ2=0.037, n=15), hyperkalaemia (1.89, 1.56 to 2.30, τ2=0.122, n=26), hypotension (1.97, 1.67 to 2.32, τ2=0.132, n=35), and syncope (1.28, 1.03 to 1.59, τ2=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.

A multi-stakeholder approach to the co-production of the research agenda for medicines optimisation.

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. 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). 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. 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.