Search

BackgroundAdverse drug reactions (ADRs) represent a significant barrier to achieve optimal treatment outcomes. Cardiovascular drugs, including antihypertensive drugs, lipid-lowering drugs, and antithrombotic drugs, are among the most prescribed medications in the primary care setting.ObjectivesTo estimate the prevalence of cardiovascular drug-related ADRs consultations in United Kingdom (UK) primary care and identify risk factors of these ADRs.MethodsThis was a cross-sectional study of cardiovascular drug users between 2000-2019 using UK IQVIA Medical Research Data. ADRs consultations were identified using database screening method employing standardised designated codes. The overall and annual age-standardised prevalence was estimated using direct standardisation method using 2019 mid-year UK population. Risk factors of ADRs consultations were estimated using logistic regression model stratified by therapeutic areas.ResultsThe standardised prevalence of consultations related to cardiovascular drugs ADRs was 10.60 (95% CI. 10.46, 10.75) per 1000 patients. Patients aged 70-79 years had the highest occurrence of ADRs consultations. The most frequently drug classes implicated in the ADRs consultations were statins (n = 9,993 events, 27.09%), beta-blockers (n = 8,538 events, 23.15%), ACEIs/ARBs (n = 8,345 events, 22.62%), and aspirin (n = 6,482 events, 17.57%). Risk factors of ADRs consultations were previous history of cardiovascular diseases, e.g., myocardial infarction and stroke; advanced age, comorbidities; diabetes and dyslipidaemia; and polypharmacy.ConclusionsThe burden of cardiovascular drug-related ADRs consultations in primary care was considerable. Statins, beta-blockers, ACEIs/ARBs, and aspirin were the most frequently implicated drug classes. Closer clinical monitoring should be performed for patients affected by the ADRs to mitigate the risk of suboptimal treatment outcomes.

Background Acamprosate is an effective and cost-effective medication for alcohol relapse prevention but poor adherence can limit its full benefit. Effective interventions to support adherence to acamprosate are therefore needed. Objectives To determine the effectiveness of Medication Management, with and without Contingency Management, compared to Standard Support alone in enhancing adherence to acamprosate and the impact of adherence to acamprosate on abstinence and reduced alcohol consumption. Design Multicentre, three-arm, parallel-group, randomised controlled clinical trial. Setting Specialist alcohol treatment services in five regions of England (South East London, Central and North West London, Wessex, Yorkshire and Humber and West Midlands). Participants Adults (aged 18 years or more), an International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, diagnosis of alcohol dependence, abstinent from alcohol at baseline assessment, in receipt of a prescription for acamprosate. Interventions (1) Standard Support, (2) Standard Support with adjunctive Medication Management provided by pharmacists via a clinical contact centre (12 sessions over 6 months), (3) Standard Support with adjunctive Medication Management plus Contingency Management that consisted of vouchers (up to £120) to reinforce participation in Medication Management. Consenting participants were randomised in a 2 : 1 : 1 ratio to one of the three groups using a stratified random permuted block method using a remote system. Participants and researchers were not blind to treatment allocation. Main outcome measures Primary outcome: self-reported percentage of medication taken in the previous 28 days at 6 months post randomisation. Economic outcome: EuroQol-5 Dimensions, a five-level version, used to calculate quality-adjusted life-years, with costs estimated using the Adult Service Use Schedule. Results Of the 1459 potential participants approached, 1019 (70%) were assessed and 739 (73 consented to participate in the study, 372 (50%) were allocated to Standard Support, 182 (25%) to Standard Support with Medication Management and 185 (25%) to Standard Support and Medication Management with Contingency Management. Data were available for 518 (70%) of participants at 6-month follow-up, 255 (68.5%) allocated to Standard Support, 122 (67.0%) to Standard Support and Medication Management and 141 (76.2%) to Standard Support and Medication Management with Contingency Management. The mean difference of per cent adherence to acamprosate was higher for those who received Standard Support and Medication Management with Contingency Management (10.6%, 95% confidence interval 19.6% to 1.6%) compared to Standard Support alone, at the primary end point (6-month follow-up). There was no significant difference in per cent days adherent when comparing Standard Support and Medication Management with Standard Support alone 3.1% (95% confidence interval 12.8% to −6.5%) or comparing Standard Support and Medication Management with Standard Support and Medication Management with Contingency Management 7.9% (95% confidence interval 18.7% to −2.8%). The primary economic analysis at 6 months found that Standard Support and Medication Management with Contingency Management was cost-effective compared to Standard Support alone, achieving small gains in quality-adjusted life-years at a lower cost per participant. Cost-effectiveness was not observed for adjunctive Medication Management compared to Standard Support alone. There were no serious adverse events related to the trial interventions reported. Limitations The trial’s primary outcome measure changed substantially due to data collection difficulties and therefore relied on a measure of self-reported adherence. A lower than anticipated follow-up rate at 12 months may have lowered the statistical power to detect differences in the secondary analyses, although the primary analysis was not impacted. Conclusions Medication Management enhanced with Contingency Management is beneficial to patients for supporting them to take acamprosate. Future work Given our findings in relation to Contingency Management enhancing Medication Management adherence, future trials should be developed to explore its effectiveness and cost-effectiveness with other alcohol interventions where there is evidence of poor adherence. Trial registration This trial is registered as ISRCTN17083622 https://doi.org/10.1186/ISRCTN17083622. Funding This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 27, No. 22. See the NIHR Journals Library website for further project information. Plain language summary What is the problem? Many people who are trying to stop drinking alcohol can find it difficult to remain alcohol free. There is a medication called acamprosate (Campral) that can reduce cravings thereby increasing the likelihood of abstinence. However, some people have trouble taking the right amount of acamprosate tablets needed every day at the right time, preferably at mealtimes. This means the medication is not as effective. We have tested some new ways to help support people taking acamprosate. What did we do? We tested three different strategies to find the best way to support people taking acamprosate. We recruited 739 people aged 18 and over who were receiving alcohol treatment to stop drinking and were taking acamprosate. We randomly allocated these people to three groups. The first was Standard Support, the usual support people receive when taking acamprosate. The second group received Standard Support plus Medication Management. This consisted of 12 telephone calls over 6 months with a trained pharmacist to discuss the importance of taking the right amount of the medication, how the medication works and strategies to help people take the medication correctly. The third group received Standard Support, Medication Management and Contingency Management. This involved giving people shopping vouchers for participating with Medication Management calls. The maximum value of vouchers per person was £120. What did we find out? People who were in the group receiving Medication Management and Contingency Management took a greater number of acamprosate tablets. We also found that Medication Management plus Contingency Management was more cost-effective; there were greater gains in health with a smaller cost per person compared to Standard Support alone. This shows that there is likely to be a benefit to patients of Medication Management plus Contingency Management for supporting people taking acamprosate. Scientific summary Background Alcohol is a significant risk factor for morbidity and mortality. In the UK there has been an increase in harm related to alcohol while also a reduction in funding to public health budgets, including alcohol services. While some individuals do successfully complete alcohol treatment, the majority will undergo frequent episodes of relapse. Providing effective treatment can reduce relapse rates and associated harms thus having a positive impact on cost-effectiveness. The National Institute for Health and Care Excellence (NICE) recommends acamprosate in combination with psychological intervention as a first-line treatment for relapse prevention in alcohol dependence, however, acamprosate adherence poses a problem for its effectiveness in clinical practice. The reasons for non-adherence are complex and often due to multiple influences. Currently there is insufficient evidence as to which forms of intervention are effective in increasing adherence. Psychosocial interventions to support medication adherence have the potential to promote positive beliefs about medication and any concerns. Medication Management (MM) is a psychosocial intervention which aims to improve medication and treatment adherence by providing education, support, and practical advice about drinking behaviour and medication. There has also been an increasing focus on extending the role of the community pharmacist and the delivery of MM to improve medication adherence compliments this expanding role. Engagement in psychological interventions and retention in treatment is often poor in alcohol dependence but there is evidence that Contingency Management (CM) improves engagement and retention in substance use disorder treatment. There is currently limited evidence of its effectiveness within alcohol treatment but if shown to be effective it has the potential to also be adopted within the NHS and community pharmacies. Objectives Our aim was to evaluate the effectiveness and cost-effectiveness of adjunctive MM with and without CM in improving adherence to acamprosate for relapse prevention in alcohol dependence. To conduct a definitive three-arm, randomised controlled trial (RCT) of the effectiveness of MM with and without CM compared to Standard Support (SS) alone in enhancing adherence to acamprosate in alcohol dependence relapse prevention. To estimate the cost-effectiveness of MM with and without CM compared to SS alone in enhancing adherence to acamprosate in alcohol dependence relapse prevention. To assess the impact of adherence to acamprosate for alcohol dependence relapse prevention on abstinence and reduced alcohol consumption. Methods Trial design This was a three-arm, parallel-group, pragmatic RCT, which began with an internal pilot phase to demonstrate recruitment, randomisation and interventions could be implemented as planned. Eligibility and recruitment Participants presenting to alcohol services in one of the trial sites (London, Southampton, Birmingham, Yorkshire and Humber) who met the trial inclusion criteria were recruited via service staff. Participants Inclusion criteria were: (1) adults, aged 18 years and over; (2) an International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, diagnosis of alcohol dependence; (3) abstinent from alcohol at baseline assessment; (4) in receipt of a prescription of acamprosate; and (5) willing and able to provide informed consent. Exclusion criteria were: (1) a diagnosis of a severe physical/mental illness likely to preclude active participation in treatment or follow-up, (2) unable to understand verbal English at a level necessary to engage in the intervention and follow-up and (3) concurrent dependence on an illicit substance (other than cannabis). Randomisation and interventions Participants were randomised in a 2 : 1 : 1 ratio to SS, SS + MM or SS + MM + CM using a stratified random permuted block method using a remote system. Participants and researchers were not blind to treatment allocation. SS typically comprised of monthly dispensing of prescribed acamprosate, monthly monitoring of the service user for 3 months by the specialist alcohol service, and then returned to the care of their GP for monthly monitoring in accordance with NICE guidelines and current clinical NHS clinical practice. SS + MM participants followed the same care pathway as those in SS, with the addition of MM delivered by a central telephone support service by trained pharmacists. MM was delivered once a week for the first 6 weeks, reducing to once a fortnight for the following 6 weeks, and then monthly for 3 months. SS + MM + CM participants followed the same care pathway as those in the SS + MM arm but with the addition of CM. Incentives in the form of vouchers were provided to reinforce attendance at MM sessions, up to a total of £120. Outcomes The primary outcome measure was the self-reported per cent of medication taken as prescribed during the 6-month target phase of prescribing, post randomisation. Data collection Data were collected at baseline, 2, 4, 6 and 12 months. Following an amendment, the 12-month follow-up was removed to maximise participant recruitment, and the recruitment period was extended without extending the trial end date. Data that had been collected at the 12-month follow-up were still included in the trial analysis plan. The primary outcome was collected at the 6-month follow-up. Sample size The sample size aimed to detect a clinically important effect size difference of 0.3, about 13% difference in per cent adherence. In order to make the study cost-efficient, we proposed to allocate twice as many to the SS group than to the SS + MM and SS + MM + CM groups. With power at 80%, alpha of 0.05 and a two-sided test, this required 524 to be followed up at the primary end point, 262 in the SS group and 131 in each of the other groups. We anticipated a loss to follow-up at month 6 of 30% and inflated the required sample at baseline to 748 to account for this. Sample sizes were calculated using Stata 12 (StataCorp LP, College Station, TX, USA). Statistical methods The primary analysis was an analysis by treatment allocated (ATA) and was based on all available data for participants who were randomised, irrespective of whether they complied with their allocation or not. The primary analysis was based on the ATA. Secondary analyses examined treatment effects under different scenarios for compliance with allocation/treatment: complier average causal effects (CACE). Two scenarios of compliance were defined in this trial. The first compliance for those in the SS + MM and SS + MM + CM group was defined as adhering to at least 50% of the MM calls. In the second, the threshold was increased to 100%. Both scenarios are modelled in the analysis. We considered missing data as being missing at random (MAR) or missing not at random (MNAR). We conducted a multiple imputation to address MAR and a sensitivity analysis to address MNAR. Fractional regression was conducted to model the relationship between pre-randomisation factors and per cent adherence to acamprosate and per cent days abstinent from alcohol at month 6. Interaction terms with treatment allocation were included in the model and a significance level of 0.1 was used as a threshold to determine which variables were maintained in the final model reported. Baseline variables included initially in the model include age, gender, marital status, ethnicity, employment status, number of children, age of first drink, weekly and daily drinking, frequency and quantity of alcohol consumption, severity of alcohol dependence, alcohol urges and alcohol-related problems. This analysis was augmented with an additional analysis for the SS + MM and SS + MM + CM groups where the same dependent variable was assessed with the same independent variables with the addition of therapeutic alliance. Method of economic evaluation The primary economic analysis was a cost-utility analysis where outcomes were expressed as quality-adjusted life-years (QALYs), as recommended by NICE. A secondary analysis explored cost-effectiveness in terms of the primary clinical outcome which was adherence to relapse prevention medication. The primary economic perspective was the NHS and personal social services (NHS/PSS) perspective preferred by NICE. The primary time horizon of the economic analyses using both QALYs and relapse medication adherence was the 6-month follow-up, consistent with the primary clinical analysis. A secondary analysis was carried out at the 12-month follow-up using QALYs. The primary economic outcome was QALYs calculated using the EuroQol-5 Dimensions, a five-level version measure of health-related quality-of-life scores at baseline, 6- and 12-month follow-ups. The primary economic analysis was composed of two separate comparisons: (1) SS + MM + CM versus SS alone; and (2) SS + MM versus SS alone, both at 6 months post randomisation, and assessed cost-effectiveness in terms of cost per QALY using the EuroQol-5 Dimensions measure of quality of life. Two secondary economic evaluations were carried out, a cost-utility analysis at 12 months post randomisation and a cost-effectiveness analysis using adherence to relapse medication which was the primary clinical outcome. Cost-effectiveness was explored using incremental cost-effectiveness ratios (difference in mean cost divided by difference in mean effect) and cost-effectiveness acceptability curves (CEACs), which show the probability that SS + MM + CM or SS + MM are cost-effective compared to SS alone for different levels of willingness to pay for improvements in outcome. Sensitivity analyses were carried out to test the impact of varying methods and assumptions on the relative cost-effectiveness of the interventions being compared. We planned three sensitivity analyses: (1) a broader analytical perspective to include the cost of crime (which was not completed as no crimes were reported), (2) a complete case analysis for comparison with the results that used multiple imputation for missing data and (3) a cost-utility analysis using QALYs calculated from EuroQol-5 Dimensions, three-level version tariffs. Results A total of 1459 potential participants were approached of whom 1019 (70%) were assessed. Of these 739 (73%) were eligible and consented to participate in the study. Allocation was in the ratio of 2 : 1 : 1, 372 (50%) were allocated to SS, 182 (25%) to SS + MM and 185 (25%) to SS + MM + CM. At the primary end point, 6 months post randomisation, 518 (70%) were successfully followed up with 255 (68.5%) allocated to SS, 122 (67.0%) to SS + MM and 141 (76.2%) to SS + MM + CM. There were no serious adverse events related to the trial interventions reported. The mean difference in per cent adherence to acamprosate at month 6 between those allocated to SS and SS + MM + CM versus SS was 10.6% [95% confidence interval (CI) 19.6% to 1.6%]; this difference was statistically significant. When the SS + MM group was compared to SS alone, the SS + MM group had a lower per cent days adherent than the SS group, mean difference 3.1% (95% CI 12.8% to −6.5%); this was not significant. A similar non-significant finding was seen when we compared the SS + MM and SS + MM + CM groups, mean difference 7.9% (95% CI 18.7% to −2.8%). Our secondary analysis included per cent days abstinent from alcohol at month 6. The ATA found differences favouring both intervention groups over SS alone but neither of these was significant. When a CACE analysis was conducted using scenario 2, both intervention groups had a significantly greater per cent days abstinent than SS alone. This analysis also highlighted the relationship between adherence to acamprosate and better outcomes, something additionally highlighted by a significant correlation between adherence to acamprosate and increased per cent days abstinent at month 6. CACE analysis: Under scenario 1, 50% adherence, the mean difference in per cent adherence increases from 10.6% (95% CI 19.6 to 1.62) to 12.4% (95% CI 17.8% to 7.1%) in the SS + MM + CM versus SS comparison, indicating that at 50% compliance those allocated to SS + MM + CM have a mean of 12.44% more adherence to acamprosate at month 6 than those allocated to SS alone. When comparing the SS + MM versus the SS group, a previous non-significant difference 3.14% (95% CI 12.8% to −6.5%) becomes a significant difference of 13.2% (25.4–1.15%). Under scenario 2, the differences are larger in magnitude, the SS + MM + CM group having 22.2% (95% CI 29.7% to 14.7%) more adherent days than the SS group alone. At the same time, the magnitude of difference is larger for the SS + MM versus SS comparison 31.8% (95–60.5% vs. 3.10%), although this comparison is based on a small number of participants, 20, and should be interpreted with caution. For SS + MM + CM versus SS, the primary economic analysis at 6-month follow-up using QALYs, the secondary economic analysis at 6-month follow-up using medication adherence and the economic modelling over a 20-year time horizon using QALYs all found SS + MM + CM to dominate SS (better outcomes at lower cost). At 12-month follow-up, although SS + MM + CM was not dominant, it generated more QALYs at an additional cost that was below the NICE cost per QALY threshold. CEACs also showed there was a higher probability of SS + MM + CM being cost-effective compared to SS alone in all analyses and at all time points. For SS + MM versus SS, at 6- and 12-month follow-up and when modelled over 20 years, SS + MM achieved better outcomes at higher cost compared to SS. In terms of cost-effectiveness, SS + MM was not found to be cost-effective at 6-month follow-up but had a higher probability of being cost-effective compared to SS at both the 12-month follow-up (using the higher £30,000 per QALY NICE threshold) and when modelled over 20 years (over the full £20,000–30,0000 cost per QALY threshold). Conclusions When comparing SS + MM + CM versus SS alone, we observed a significantly higher per cent adherence to acamprosate in the SS + MM + CM group, and the differences were of the magnitude that would indicate a clinically important difference. Differences were also observed when comparing SS + MM versus SS and SS + MM + CM versus SS + MM, but these were not significant. We explored how robust these findings were to assumptions about the nature of any missing data and we explored a missing data imputation model to explore the impact of data that may be MAR and a sensitivity analysis to explore data that may not be MAR. Neither of these analyses found any significant deviation from the analysis based on observed values, we can be confident that our findings from the ATA analysis are robust. To explore the effect of compliance to MM we conducted a CACE analysis using two scenarios of compliance, 50% and 100%. In both scenarios, we found greater benefits associated with SS + MM + CM and SS + MM versus SS alone and these benefits were significant and clinically important. There were several limitations to the current trial that should be taken into consideration. The trial’s primary outcome measure changed substantially due to data collection difficulties and therefore relied on a measure of self-reported adherence. A lower than anticipated follow-up rate at 12 months may have lowered the statistical power to detect differences in the secondary analyses, although the primary analysis was not impacted. The results of the primary economic analysis at the 6-month follow-up point suggest that MM was only cost-effective when supported by incentives to encourage support session uptake. This finding was heavily influenced by lower total costs in the SS + MM + CM group as a result of lower use of residential rehabilitation facilities compared to both SS + MM and SS alone, which may be related to the significantly higher medication adherence seen in the CM group. Over the medium (12 months) and longer term (20 years), SS + MM + CM remained cost-effective compared to SS and there was a higher probability of SS + MM being cost-effective compared to SS. These results support the addition of MM to SS for alcohol dependence, with or without CM. However, the economic benefit was stronger when CM was included. Trial registration This trial is registered as ISRCTN17083622 https://doi.org/10.1186/ISRCTN17083622. Funding This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 27, No. 22. See the NIHR Journals Library website for further project information.

Abstract Background Interprofessional education (IPE) at university level is an essential component of undergraduate healthcare curricula, as well as being a requirement of many associated regulatory bodies. In this study, the perception of pharmacy and medical students’ of remote IPE was evaluated. Methods A series of IPE sessions took place via Zoom and students’ feedback was collected after each session. Both qualitative and quantitative data were collected and analysed. Results 72% (23/32) of medical students strongly agreed that the sessions had helped to improve their appreciation of the role of pharmacists, whereas 37% (22/59) of pharmacy students strongly agreed, reporting a median response of ‘somewhat agreeing’, that their appreciation of the role of general practitioners had improved. This difference was found to be statistically significant (p = 0.0143). Amongst students who responded, 55% (53/97) identified remote teaching as their preferred mode of delivery for an IPE session. Conclusions The survey demonstrated that the students valued the development of their prescribing skills as well as the ancillary skills gained, such as communication and teamwork. Remote IPE can be a practical means of improving medical and pharmacy students’ understanding of each other’s professional roles, as well as improving the skills required for prescribing.

Abstract Background Adults with long-term health conditions (LTCs) are more likely to experience depressive symptoms which can worsen health outcomes and quality of life, and increase healthcare costs. Subthreshold depression may go undetected and/or untreated. The Community Pharmacies Mood Intervention Study (CHEMIST) explored whether community pharmacies represent a suitable setting to offer brief psychological support to people with LTCs and comorbid subthreshold depression. Methods A feasibility intervention study with a nested mixed methods evaluation was employed. Adults with subthreshold depression and a minimum of one LTC were recruited from community pharmacies/local general practices and offered a brief psychological support intervention (‘Enhanced Support Intervention’ (ESI)), based on behavioural activation within a Collaborative Care framework. The intervention included up to six sessions supported by pharmacy staff (‘ESI facilitators’) trained to deliver the ESI within the community pharmacy setting. Recruitment, retention rates and engagement with the ESI were assessed. Semi-structured, one-to-one interviews with pharmacy staff and study participants, and a focus group with pharmacy staff, explored experiences and acceptability of the study and the ESI. Themes were mapped onto constructs of the Theoretical Framework of Acceptability. Results Recruitment of ESI participants was challenging and slower than anticipated despite the varied methods of recruitment employed; although, this was useful in identifying barriers and enabling factors for participation. Engagament with the ESI was good with n=17 (71%) recruited participants commencing the ESI. The ESI was found to be acceptable to participants and ESI facilitators. Retention rate at 4 months was good n=20 (87.0%). The main barriers to identifying potential participants for pharmacy staff were lack of time, resources and limited experience in research. The ESI training and support manual were acceptable to ESI facilitators. The ESI and supporting patient workbook were acceptable to people with LTCs and subthreshold depression. Conclusions Community pharmacies were viewed as an acceptable setting in which to deliver preventative brief psychological support to people with LTCs at risk of depression. This feasibility study provided important data to inform the design of a pilot randomised controlled trial in this setting and highlighted important considerations for future pharmacy-based research. Trial registration ISRCTN11290592

Introduction Increasing collaborative and integrated working between General practice (GP) and Community pharmacy (CP) is a key priority of the UK National Health Service and has been proposed as a solution to reducing health system fragmentation, improving synergies and coordination of care. However, there is limited understanding regarding how and under which circumstances collaborative and integrated working between GP and CP can be achieved in practice and how regulatory, organisational and systemic barriers can be overcome.Methods and analysis The aim of our review is to understand how, when and why working arrangements between GP and CP can provide the conditions necessary for optimal communication, decision-making, and collaborative and integrated working. A realist review approach will be used to synthesise the evidence to make sense of the complexities inherent in the working relationships between GP and CP. Our review will follow Pawson’s five iterative stages: (1) finding existing theories; (2) searching for evidence (our main searches were conducted in April 2022); (3) article selection; (4) data extraction and (5) synthesising evidence and drawing conclusions. We will synthesise evidence from grey literature, qualitative, quantitative and mixed-methods research. The research team will work closely with key stakeholders and include patient and public involvement and engagement throughout the review process to refine the focus of the review and the programme theory. Collectively, our refined programme theory will explain how collaborative and integrated working between GP and CP works (or not), for whom, how and under which circumstances.Ethics and dissemination Formal ethical approval is not required for this review as it draws on secondary data from published articles and grey literature. Findings will be widely disseminated through: publication in peer-reviewed journals, seminars, international conference presentations, patients’ association channels, social media, symposia and user-friendly summaries.PROSPERO registration number CRD42022314280.

Abstract Background Alcohol is challenging to discuss, and patients may be reluctant to disclose drinking partly because of concern about being judged. This report presents an overview of the development of a medications review intervention co-produced with the pharmacy profession and with patients, which breaks new ground by seeking to give appropriate attention to alcohol within these consultations. Methods This intervention was developed in a series of stages and refined through conceptual discussion, literature review, observational and interview studies, and consultations with advisory groups. In this study we reflect on this process, paying particular attention to the methods used, where lessons may inform innovations in other complex clinical consultations. Results Early work with patients and pharmacists infused the entire process with a heightened sense of the complexity of consultations in everyday practice, prompting careful deliberation on the implications for intervention development. This required the research team to be highly responsive to both co-production inputs and data gathered in formally conducted studies, and to be committed to working through the implications for intervention design. The intervention thus evolved significantly over time, with the greatest transformations resulting from patient and pharmacist co-design workshops in the second stage of the process, where pharmacists elaborated on the nature of the need for training in particular. The original research plans provided a helpful structure, and unanticipated issues for investigation emerged throughout the process. This underscored the need to engage dynamically with changing contexts and contents and to avoid rigid adherence to any early prescribed plan. Conclusions Alcohol interventions are complex and require careful developmental research. This can be a messy enterprise, which can nonetheless shed new insights into the challenges involved in optimising interventions, and how to meet them, if embraced with an attitude of openness to learning. We found that exposing our own research plans to scrutiny resulted in changes to the intervention design that gained the confidence of different stakeholders. Our understanding of the methods used, and their consequences, may be bounded by the person-centred nature of this particular intervention.

ObjectiveTo investigate the association of concurrent use of oral anticoagulants (OACs) and sulfonylureas and the risk of hypoglycemia in individuals with type 2 diabetes mellitus (T2DM).Research Design and MethodsA retrospective cohort study was conducted between 2001 and 2017 using electronic primary healthcare data from the IQVIA Medical Research Data (IMRD) that incorporates data supplied by The Health Improvement Network (THIN), a propriety database of Cegedim SA. Individuals with T2DM who received OAC prescription and sulfonylureas were included. We compared the risk of hypoglycemia with sulfonylureas and OACs using propensity score matching and Cox regression.Results109,040 individuals using warfarin and sulfonylureas and 77,296 using direct oral anticoagulants (DOACs) and sulfonylureas were identified and included. There were 285 hypoglycemia events in the warfarin with sulfonylureas group (incidence rate = 17.8 per 1,000 person-years), while in the sulfonylureas only, 304 hypoglycemia events were observed (incidence rate = 14.4 per 1,000 person-years). There were 14 hypoglycemic events in the DOACs with sulfonylureas group (incidence rates = 14.8 per 1,000 person-years), while in the sulfonylureas alone group, 60 hypoglycemia events were observed (incidence rate =23.7 per 1,000 person-years). Concurrent use of warfarin and sulfonylureas was associated with increased risk of hypoglycemia compared with sulfonylureas alone (HR 1.38; 95% CI 1.10–1.75). However, we found no evidence of an association between concurrent use of DOACs and sulfonylureas and risk of hypoglycemia (HR 0.54; 95% CI, 0.27–1.10) when compared with sulfonylureas only.ConclusionsWe provide real-world evidence of possible drug-drug interactions between warfarin and sulfonylureas. The decision to prescribe warfarin with coexistent sulfonylureas to individuals with T2DM should be carefully evaluated in the context of other risk factors of hypoglycemia, and availability of alternative medications.

Abstract Background To manage the risk factors and to improve clinical outcomes, patients with stroke commonly receive multiple cardiovascular medications. However, there is a lack of evidence on the optimum combination of medication therapy in the primary care setting after ischemic stroke. Therefore, this study aimed to investigate the effect of multiple cardiovascular medications on long-term survival after an incident stroke event (ischemic stroke or transient ischemic attack (TIA)). Methods This study consisted of 52,619 patients aged 45 and above with an incident stroke event between 2007 and 2016 in The Health Improvement Network database. We estimated the risk of all-cause mortality in patients with multiple cardiovascular medications versus monotherapy using a marginal structural model. Results During an average follow-up of 3.6 years, there were 9230 deaths (7635 in multiple cardiovascular medication groups and 1595 in the monotherapy group). Compared with patients prescribed monotherapy only, the HRs of mortality were 0.82 (95% CI 0.75–0.89) for two medications, 0.65 (0.59–0.70) for three medications, 0.61 (0.56–0.67) for four medications, 0.60 (0.54–0.66) for five medications and 0.66 (0.59–0.74) for ≥ six medications. Patients with any four classes of antiplatelet agents (APAs), lipid-regulating medications (LRMs), angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs), beta-blockers, diuretics and calcium channel blockers (CCBs) had the lowest risk of mortality (HR 0.51, 95% CI 0.46–0.57) versus any one class. The combination containing APAs, LRMs, ACEIs/ARBs and CCBs was associated with a 61% (95% CI 53–68%) lower risk of mortality compared with APAs alone. Conclusion Our results suggested that combination therapy of four or five cardiovascular medications may be optimal to improve long-term survival after incident ischemic stroke or TIA. APAs, LRMs, ACEIs/ARBs and CCBs were the optimal constituents of combination therapy in the present study.

Abstract Background Alcohol interventions are important to the developing public health role of community pharmacies. The Medicines and Alcohol Consultation (MAC) is a new intervention, co-produced with community pharmacists (CPs) and patients, which involves a CP practice development programme designed to integrate discussion of alcohol within existing NHS medicine review services. We conducted a pilot trial of the MAC and its delivery to investigate all study procedures to inform progression to a definitive trial. Methods This cluster pilot RCT was conducted in 10 community pharmacies in Yorkshire, UK, with a CP from each who regularly conducted Medicine Use Review (MUR) and New Medicine Service (NMS) consultations. Randomisation was conducted using a secure remote randomisation service. Intervention CPs (n = 5) were trained to deliver the MAC in MUR/NMS consultations. Control CPs (n = 5) provided these services as usual. Consecutive MUR/NMS patients were asked by CPs to participate, screened for eligibility (consumption of alcohol at least twice per week), and baseline data collected for those eligible. A two-month follow-up telephone interview was conducted. Blinding of CPs was not possible, but patients were blinded to the alcohol focus of the trial. Primary outcomes were total weekly UK units (8 g of ethanol per unit) of alcohol consumption in the week prior to follow-up, and confidence in medications management. Trial procedures were assessed by recruitment, attrition, and follow-up rates. Results 260 patients were approached by CPs to take part in the trial, 68% (n = 178) were assessed for eligibility and 30% (n = 54) of these patients were eligible. Almost all eligible patients (n = 51; 94%) consented to participate, of whom 92% (n = 47) were followed-up at 2 months; alcohol consumption was lower in the intervention arm and confidence in medication management reduced slightly for both groups. Exploration of recall issues at follow-up showed a high level of agreement between a two-item quantity/frequency measure and 7-day guided recall of alcohol consumption. Conclusions The pilot trial demonstrates the feasibility of implementing the MAC in community pharmacy and trial recruitment and data collection procedures. However, decommissioning of MURs means that it is not possible to conduct a definitive trial of the intervention in this service. Trial registration ISRCTN57447996

Background: Depression is common in people with long-term health conditions, and this combination can lead to worsened health outcomes and increased health-care costs. Subthreshold depression, a risk factor for major depression, is prevalent in this population, but many people remain untreated due to the demand on services. The community pharmacy may be an alternative setting to offer mental health support; however, insufficient evidence exists to support implementation. Objectives: To conduct a feasibility study and pilot randomised controlled trial of a community pharmacy-delivered psychological intervention aimed at preventing depression in adults with long-term health conditions. Design: A feasibility study with nested qualitative evaluation and an external pilot, two-arm, 1 : 1 individually randomised controlled trial with nested process and economic evaluations. Setting: Community pharmacies in the north of England. Participants: Adults aged ≥ 18 years with subthreshold depression and at least one long-term health condition. Intervention: A bespoke enhanced support intervention (behavioural activation within a collaborative care framework) involving up to six sessions delivered by trained community pharmacy staff (intervention facilitators) compared with usual care. Main outcome measures: Recruitment and retention rates, completeness of outcome measures and intervention engagement. The intended primary outcome was depression severity at 4 months, assessed by the Patient Health Questionnaire-9. Results: In the feasibility study, 24 participants were recruited. Outcome measure completeness was 95–100%. Retention at 4 months was 83%. Seventeen participants (71%) commenced intervention sessions and all completed two or more sessions. Depression symptoms reduced slightly at 4 months. The process evaluation suggested that the intervention was acceptable to participants and intervention facilitators. In the pilot randomised controlled trial, 44 participants (target of 100 participants) were randomised (intervention, n = 24; usual care, n = 20). Outcome measure completeness was 100%. Retention at 4 months was 93%. Eighteen participants (75%) commenced intervention sessions and 16 completed two or more sessions. Depression symptoms reduced slightly at 4 months, with a slightly larger reduction in the usual-care arm, although the small sample size limits any conclusions. The process evaluation reported good acceptability of the intervention and identified barriers associated with study implementation and its impact on core pharmacy functions. The economic analysis revealed some indication of reduced resource use/costs associated with the intervention, but this is limited by the small sample size. Intervention costs were low. Limitations: The main limitation is the small sample size due to difficulties with recruitment and barriers to implementing the study within existing pharmacy practices. Conclusions: The community pharmacy represents a new setting to deliver a depression prevention intervention. Recruitment was a challenge and pharmacy staff encountered barriers to effective implementation of the study within busy pharmacy practice. Despite these challenges, good retention rates and intervention engagement were demonstrated, and process evaluation suggested that the intervention was acceptable in this setting. To the best of our knowledge, this is the first study to demonstrate that community pharmacy staff can be trained to deliver a depression prevention intervention. Future work: Further work is needed to address barriers to recruitment, intervention delivery and implementation of psychological interventions in the community pharmacy setting. Trial registration: This trial is registered as ISRCTN11290592. Funding: This project was funded by the National Institute for Health Research (NIHR) Public Health Research programme and will be published in full in Public Health Research; Vol. 10, No. 5. See the NIHR Journals Library website for further project information.

Objectives Chlamydia testing among young people in community pharmacies in North East England has been low compared with other remote settings offering testing for the past few years. To understand why this may be, to maximise service provision, the perceptions of young men and women about pharmacy testing and possible chlamydia treatment were gathered and interpreted.Design Indepth, semistructured interviews.Setting Four youth centres in North East England.Participants The study included 26 young people aged 16–23. The sample of participants comprised those with a history of chlamydia testing as well as those never tested.Interviews Face-to-face interviews were conducted between October 2018 and May 2019. The interview schedule covered young people’s perceptions of sexually transmitted infections, provision of pharmacy sexual and reproductive health and chlamydia testing, and potential chlamydia treatment. Data from the interviews were subjected to thematic analysis.Results The geographical accessibility and long opening times of community pharmacies in North East England were perceived benefits of the service. However, young people had concerns about being judged by pharmacy staff or overheard by customers when requesting the test. Men did not want to be seen by their peers accessing the pharmacy. These barriers were associated with a perceived stigma of chlamydia. Despite this, young people thought that pharmacist advice on the test kit would be important to ensure they complete it correctly. Those never tested favoured how the kit could be taken home to complete the urine sample. The option of including chlamydia treatment was reported to be convenient and comforting.Conclusion Supporting pharmacies in North East England to offer a confidential chlamydia testing service is necessary to overcome young people’s perceived barriers to testing. Delivering testing as an integrated sexual health package with other pharmacy services, together with treatment where suitable, will increase acceptance for testing and timely access to treatment.

Abstract Feasibility study Objectives:(a)Refine a bespoke enhanced support intervention (ESI) (including self-help materials, intervention manual and training) for implementation by community pharmacy (CP) staff to people with sub-threshold depression and long-term conditions (LTCs) based upon evidence-supported interventions in primary care(b)Develop and refine study procedures (recruitment strategies and set up, screening, participant recruitment, assessment, suitability of outcome measures and data collection procedures) for testing in the pilot study phase Design: A case series/qualitative study Setting: UK community pharmacy Population: Adults with long-term health conditions who screen-positive for depression but who do not reach the threshold for DSM IV Moderate Depressive disorder Intervention: Enhanced support intervention (ESI) delivered by an appropriately trained community pharmacy team member involving four to six sessions over four months. ESI is a modified form of an intervention within the collaborative care framework for sub-threshold depression validated in previous studies in UK primary care which appears suitable for implementation in community settings. Sample size: 20–30 participants Outcomes: Study implementation (recruitment and attrition rates), quality of data collection at baseline and 4 months and ESI adherence (number of contacts, DNA and drop out) as per objectives 1a/b Qualitative evaluation: Semi-structured interviews with up to 10 participants and ESI facilitators and focus group(s) (range of pharmacy staff n = 8–10) will be conducted to explore the acceptability of the intervention and feasibility of the study, training and study procedures. External pilot study Objectives:(a)Quantify the flow of participants (eligibility, recruitment and follow-up rate)(b)Evaluate proposed recruitment, assessment and outcome measure collection methods(c)Examine the delivery of the enhanced support intervention in a community pharmacy setting (intervention uptake, retention and dose) to inform process evaluation(d)Process evaluation, using semi-structured interviews with participants across a range of socio-economic settings, and pharmacy staff to explore the acceptability of the ESI within community pharmacy, elements of the intervention that were considered useful (or not) and appropriateness of study procedures Design: Pilot randomised controlled trial, including a prospective economic and qualitative evaluation Setting: As above Population: As above Intervention: As above with adaptations post feasibility study Comparator: Usual care Sample size: 100 participants Outcomes: Data will be used to estimate recruitment, intervention delivery and study completion rates as per objectives 2a–d. Definitive estimates of the effectiveness of ESI will not be made. Primary outcome: Depression severity (Patient Health Questionnaire 9) at four months. Secondary outcomes: Patient acceptance, uptake and attrition. ICD10 depression status, anxiety (GAD 7), health-related quality of life (SF-12v2) and health-state utility (EQ5D 3L) will be measured at four months. Economic evaluation: The incremental cost per QALY will be calculated from both the NHS and societal perspective. Process evaluation: Using mixed methods, potential mediators/moderators of the intervention, the acceptability (to participants and pharmacy staff), barriers and facilitators to the use of ESI in community pharmacy, and impact on usual practice will be examined. Semi-structured interviews with approximately 30 study participants, 20 pharmacy staff and eight GPs near participating pharmacies will be conducted. Trial registration ISRCTN: ISRCTN11290592 Protocol version number: Version 4.1 (dated 16th January 2018) Study Sponsor Tees Esk and Wear Valleys NHS Foundation Trust

Abstract Background Standardizing concentrations of intravenous infusions enables pre-preparation and is effective in improving patient safety by avoiding large deviations from the prescribed concentration that can occur when infusions are made individually in wards and theatres. The use of pre-prepared morphine standardized concentration infusions for paediatric nurse/patient-controlled analgesia (N/PCA) has not been previously investigated. We aimed to establish, implement and evaluate standardized concentrations of morphine in pre-filled syringes (PFS) for use in paediatric N/PCA. Methods Concentrations of morphine in PFS for N/PCA were identified that accommodated dosage variation across a 1–50 kg weight range. The use of infusions in PFS was implemented and evaluated using mixed methods involved direct observation of healthcare professionals (HCPs), focus groups and failure mode and effects analysis, a HCP survey and medication incident reports analysis. Results Standardized concentrations, 3 mg, 10 mg and 50 mg morphine in 50 mL sodium chloride 0.9%, delivered prescribed continuous and bolus doses using programmable smart pumps with variable infusion rates. During the implementation, 175 morphine pre-prepared infusions were administered to 157 children (9.4 ± 5.1 years) in theatres and wards. Time taken to set up a N/PCA was 3.7 ± 1.7 min, a reduction of one third compared with the previous system. The number of incidents associated with N/PCA infusions was reduced by 41.2%, and preparation errors were eliminated. HCPs reported using morphine PFS was an easier and safer system. Conclusion A system using pre-prepared standardized concentrations of morphine for paediatric N/PCA was implemented successfully and sustainably.

Objectives To investigate the perception and experience of patients and the public (PP) about community pharmacy (CP) services and other primary care services after hospital discharge back home.Design and setting A rapid review and qualitative study exploring PP perceptions of primary care, focusing on CP services in the UK.Methods A mixed-methods approach was adopted including a rapid review undertaken between 24 April and 8 May 2019 across four databases (MEDLINE, EMBASE, PsycINFO and CINAHL). Semistructured interviews were then conducted investigating for shifts in current PP perception, but also nuanced opinion pertaining to CP services. A convenience sampling technique was used through two online PP groups for recruitment. Thematic framework analysis was applied to interview transcripts.Participants Any consenting adults ≥18 years old were invited regardless of their medical condition, and whether they had used post-discharge services or not.Results Twenty-five studies met the inclusion criteria. Patients were generally supportive and satisfied with primary care services. However, some barriers to the use of these services included: resource limitations; poor communication between healthcare providers or between patient and healthcare providers; and patients’ lack of awareness of available services. From the 11 interviewees, there was a lack of awareness of CP post-discharge services. Nevertheless, there was general appreciation of the benefit of CP services to patients, professionals and wider healthcare system. Potential barriers to uptake and use included: accessibility, resource availability, lack of awareness, and privacy and confidentiality issues related to information-sharing. Several participants felt the uptake of such services should be improved.Conclusion There was alignment between the review and qualitative study about high patient acceptance, appreciation and satisfaction with primary care services post-discharge. Barriers to the use of CP post-discharge services identified from interviews resonated with the existing literature; this is despite developments in pharmacy practice in recent times towards clinical and public health services.

BackgroundAdverse drug reactions (ADRs) represent a major cause of iatrogenic morbidity and mortality in patient care. While a substantial body of work has been undertaken to characterise ADRs in the hospital setting, the overall burden of ADRs in the primary care remains unclear.ObjectivesTo investigate the prevalence of ADRs in the primary care setting and factors affecting the heterogeneity of the estimates.MethodsStudies were identified through searching of Medline, Embase, CINAHL and IPA databases. We included observational studies that reported information on the prevalence of ADRs in patients receiving primary care. Disease and treatment specific studies were excluded. Quality of the included studies were assessed using Smyth ADRs adapted scale. A random-effects model was used to calculate the pooled estimate. Potential source of heterogeneity, including age groups, ADRs definitions, ADRs detection methods, study setting, quality of the studies, and sample size, were investigated using sub-group analysis and meta-regression.ResultsThirty-three studies with a total study population of 1,568,164 individuals were included. The pooled prevalence of ADRs in the primary care setting was 8.32% (95% CI, 7.82, 8.83). The percentage of preventable ADRs ranged from 12.35-37.96%, with the pooled estimate of 22.96% (95% CI, 7.82, 38.09). Cardiovascular system drugs were the most commonly implicated medication class. Methods of ADRs detection, age group, setting, and sample size contributed significantly to the heterogeneity of the estimates.ConclusionADRs constitute a significant health problem in the primary care setting. Further research should focus on examining whether ADRs affect subsequent clinical outcomes, particularly in high-risk therapeutic areas. This information may better inform strategies to reduce the burden of ADRs in the primary care setting.

BackgroundPreventing hypoglycaemia is an essential component of diabetes self-management that is affected by patients' attitudes and perceptions. This study aimed to explore the hypoglycaemia problem-solving ability of patients who have diabetes mellitus and factors that determine their attitudes and perceptions towards their previous events.MethodologyA cross-sectional study was conducted between October 2017 and May 2018 in three Arab countries (Jordan, Saudi Arabia and Kuwait) in patients with diabetes mellitus, who were prescribed antidiabetic therapy and had experienced hypoglycaemic events in the past six months. The Hypoglycaemia Problem-Solving Scale was used in this study. This scale contains two subscales, problem orientation (six questions) and problem-solving skills (eighteen questions), using a five-point Likert scale (range 0-4). Multiple linear regression analysis was used to identify predictors of hypoglycaemia problem-solving abilities.ResultsA total of 895 patients participated in this study from the three countries (300 in Jordan, 302 in Saudi Arabia, and 293 in Kuwait). The average age of the patients was 53.5 years (standard deviation = 13.7) and 52.4% (n = 469) were males. Patients had moderate overall problem-solving ability with a median score of 63.00 (interquartile range = 13.00). Patients' problem-solving skills score (68.1%) was better than their problem-orientation skills score (58.3%). The highest sub-scale scores were for detection control, setting problem-solving goals, and evaluating strategies, 75.0%. The lowest sub-scale score was for problem-solving perception and immediate management, 50.0%. Older age, being educated, being married, having T2DM, prescribed insulin therapy, and not having been admitted to hospital for hypoglycaemia were important predictors of patients' problem-solving ability (p < 0.05).ConclusionsHealthcare professionals are advised to provide more education to patients on how to self-manage hypoglycaemic events. Specifically, they should focus on the overall problem-solving perception of hypoglycaemia and its immediate management.