Examining variations in prescribing safety in UK general practice: cross sectional study using the Clinical Practice Research Datalink

Study question: What is the prevalence of different types of potentially hazardous prescribing in general practice in the United Kingdom, and what is the variation between practices? Methods: A cross sectional study included all adult patients potentially at risk of a prescribing or monitoring error defined by a combination of diagnoses and prescriptions in 526 general practices contributing to the Clinical Practice Research Datalink (CPRD) up to 1 April 2013. Primary outcomes were the prevalence of potentially hazardous prescriptions of anticoagulants, anti-platelets, NSAIDs, β blockers, glitazones, metformin, digoxin, antipsychotics, combined hormonal contraceptives, and oestrogens and monitoring by blood test less frequently than recommended for patients with repeated prescriptions of angiotensin converting enzyme inhibitors and loop diuretics, amiodarone, methotrexate, lithium, or warfarin. Study answer and limitations: 49 927 of 949 552 patients at risk triggered at least one prescribing indicator (5.26%, 95% confidence interval 5.21% to 5.30%) and 21 501 of 182 721 (11.8%, 11.6% to 11.9%) triggered at least one monitoring indicator. The prevalence of different types of potentially hazardous prescribing ranged from almost zero to 10.2%, and for inadequate monitoring ranged from 10.4% to 41.9%. Older patients and those prescribed multiple repeat medications had significantly higher risks of triggering a prescribing indicator whereas younger patients with fewer repeat prescriptions had significantly higher risk of triggering a monitoring indicator. There was high variation between practices for some indicators. Though prescribing safety indicators describe prescribing patterns that can increase the risk of harm to the patient and should generally be avoided, there will always be exceptions where the indicator is clinically justified. Furthermore there is the possibility that some information is not captured by CPRD for some practices—for example, INR results in patients receiving warfarin. What this study adds: The high prevalence for certain indicators emphasises existing prescribing risks and the need for their appropriate consideration within primary care, particularly for older patients and those taking multiple medications. The high variation between practices indicates potential for improvement through targeted practice level intervention. Funding, competing interests, data sharing: National Institute for Health Research through the Greater Manchester Primary Care Patient Safety Translational Research Centre (grant No GMPSTRC-2012-1). Data from CPRD cannot be shared because of licensing restrictions

Antipsychotic prescribing to patients diagnosed with dementia without a diagnosis of psychosis in the context of national guidance and drug safety warnings: longitudinal study in UK general practice

Introduction: Policy interventions to address inappropriate prescribing of antipsychotic drugs to older people diagnosed with dementia are commonplace. In the UK, warnings were issued by the Medicines Healthcare products Regulatory Agency in 2004, 2009 and 2012 and the National Institute for Health and Care Excellence guidance was published in 2006. It is important to evaluate the impact of such interventions. Methods: We analysed routinely collected primary-care data from 111,346 patients attending one of 689 general practices contributing to the Clinical Practice Research Datalink to describe the temporal changes in the prescribing of antipsychotic drugs to patients aged 65 years or over diagnosed with dementia without a concomitant psychosis diagnosis from 2001 to 2014 using an interrupted time series and a before-and-after design. Logistic regression methods were used to quantify the impact of patient and practice level variables on prescribing prevalence. Results: Prescribing of first-generation antipsychotic drugs reduced from 8.9% in 2001 to 1.4% in 2014 (prevalence ratio 2014/2001 adjusted for age, sex and clustering within practices (0.14, 95% confidence interval 0.12–0.16), whereas there was little change for second-generation antipsychotic drugs (1.01, confidence interval 0.94–1.17). Between 2004 and 2012, several policy interventions coincided with a pattern of ups and downs, whereas the 2006 National Institute for Health and Care Excellence guidance was followed by a gradual longer term reduction. Since 2013, the decreasing trend in second-generation antipsychotic drug prescribing has plateaued largely driven by the increasing prescribing of risperidone. Conclusions: Increased surveillance and evaluation of drug safety warnings and guidance are needed to improve the impact of future interventions

Antitumour and antimalarial activity of artemisinin–acridine hybrids

Artemisinin–acridine hybrids were prepared and evaluated for their in vitro activity against tumour cell lines and a chloroquine sensitive strain of Plasmodium falciparum. They showed a 2–4-fold increase in activity against HL60, MDA-MB-231 and MCF-7 cells in comparison with dihydroartemisinin (DHA) and moderate antimalarial activity. Strong evidence that the compounds induce apoptosis in HL60 cells was obtained by flow cytometry, which indicated accumulation of cells in the G1 phase of the cell cycle

Predictors of agreement between general practitioner detection of dementia and the revised Cambridge Cognitive Assessment (CAMCOG-R)

BACKGROUND: Dementia is a complex and variable condition which makes recognition of it particularly difficult in a low prevalence primary care setting. This study examined the factors associated with agreement between an objective measure of cognitive function (the revised Cambridge Cognitive Assessment, CAMCOG-R) and general practitioner (GP) clinical judgment of dementia. METHODS: This was a cross-sectional study involving 165 GPs and 2,024 community-dwelling patients aged 75 years or older. GPs provided their clinical judgment in relation to each of their patient's dementia status. Each patient's cognitive function and depression status was measured by a research nurse using the CAMCOG-R and the 15-item Geriatric Depression Scale (GDS), respectively. RESULTS: GPs correctly identified 44.5% of patients with CAMCOG-R dementia and 90% of patients without CAMCOG-R dementia. In those patients with CAMCOG-R dementia, two patient-dependent factors were most important for predicting agreement between the CAMCOG-R and GP judgment: the CAMCOG-R score (p = 0.006) and patient's mention of subjective memory complaints (SMC) to the GP (p = 0.040). A higher CAMCOG-R (p < 0.001) score, female gender (p = 0.005), and larger practice size (p < 0.001) were positively associated with GP agreement that the patient did not have dementia. Subjective memory complaints (p < 0.001) were more likely to result in a false-positive diagnosis of dementia. CONCLUSIONS: Timely recognition of dementia is advocated for optimal dementia management, but early recognition of a possible dementia syndrome needs to be balanced with awareness of the likelihood of false positives in detection. Although GPs correctly agree with dimensions measured by the CAMCOG-R, improvements in sensitivity are required for earlier detection of dementia.C. Dimity Pond, Karen E. Mate, Jill Phillips, Nigel P. Stocks, Parker J. Magin, Natasha Weaver and Henry Brodat

Effects of antiplatelet therapy on stroke risk by brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases: subgroup analyses of the RESTART randomised, open-label trial

Background Findings from the RESTART trial suggest that starting antiplatelet therapy might reduce the risk of recurrent symptomatic intracerebral haemorrhage compared with avoiding antiplatelet therapy. Brain imaging features of intracerebral haemorrhage and cerebral small vessel diseases (such as cerebral microbleeds) are associated with greater risks of recurrent intracerebral haemorrhage. We did subgroup analyses of the RESTART trial to explore whether these brain imaging features modify the effects of antiplatelet therapy

The COVID-OUT study protocol: COVID-19 outbreak investigation to understand workplace SARS-CoV-2 transmission in the United Kingdom

Preventing SARS-CoV-2 transmission and protecting people from COVID-19 is the most significant public health challenge faced in recent years. COVID-19 outbreaks are occurring in workplaces and evidence is needed to support effective strategies to prevent and control these outbreaks. Investigations into these outbreaks are routinely undertaken by public health bodies and regulators in the United Kingdom (UK); however, such investigations are typically disparate in nature with a lack of consistency across all investigations, preventing meaningful analysis of the data collected. The COVID-OUT (COVID-19 Outbreak investigation to Understand Transmission) study aims to collect a consistent set of data in a systematic way from workplaces that are experiencing outbreaks, to understand SARS-CoV-2 transmission risk factors, transmission routes, and the role they play in the COVID-19 outbreaks. Suitable outbreak sites are identified from public health bodies. Following employer consent to participate, the study will recruit workers from workplaces where there are active outbreaks. The study will utilise data already collected as part of routine public health outbreak investigations and collect additional data through a comprehensive questionnaire, viral and serologic testing of workers, surface sampling, viral genome sequencing, and an environmental assessment of building plans, ventilation and current control measures. At each site, a detailed investigation will be carried out to evaluate transmission routes. A case-control approach will be used to compare workers who have and have not had SARS-CoV-2 infections during the outbreak period to assess transmission risk factors. Data from different outbreaks will be combined for pooled analyses to identify common risk factors, as well as factors that differ between outbreaks. The COVID-OUT study can contribute to a better understanding of why COVID-19 outbreaks associated with workplaces occur and how to prevent these outbreaks from happening in the future.</ns3:p

Temporal trends in antidepressant prescribing to children in UK primary care, 2000–2015

Background The prevalence of antidepressant prescribing in children and adolescents increased steadily in the United States and parts of Europe between 2005 and 2012 despite regulatory safety warnings. Little is known about the characteristics of those being prescribed antidepressants for the first time. Methods A longitudinal study of antidepressant prescribing in 3–17 year olds was carried out using data from the UK Clinical Practice Research Datalink (CPRD) between 2000 and 2015. Changes in the incidence of first ever antidepressant prescriptions and the characteristics of those being prescribed them was examined. Results Incidence of first ever prescriptions nearly doubled between 2006 and 2015 rising from 1.60 (95%CI: 1.51, 1.69) to 3.12 (3.00, 3.25) per 1000 person years. Only 21% of the 1721 patients with incident prescriptions in 2015 could be linked to a depression diagnosis, with an additional 22% of prescriptions linked to alternative indications. The incidence of prescriptions linked to a depression diagnosis increased between 2012 and 2015, with an adjusted incidence rate ratio of 1.46 (1.26, 1.70). Antidepressant prescribing for depression and other indications has been increasing most rapidly in 15 to 17 year old females. Limitations Diagnoses are not directly linked to prescriptions in CPRD, so linkage must be inferred by temporal proximity. Conclusions Antidepressant prescribing in children increased between 2006 and 2015. This is, at least in part, due to a rise in alternative uses of antidepressants, including the treatment of anxiety, chronic pain and migraines

Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): a randomised, open-label trial

Background: Antiplatelet therapy reduces the risk of major vascular events for people with occlusive vascular disease, although it might increase the risk of intracranial haemorrhage. Patients surviving the commonest subtype of intracranial haemorrhage, intracerebral haemorrhage, are at risk of both haemorrhagic and occlusive vascular events, but whether antiplatelet therapy can be used safely is unclear. We aimed to estimate the relative and absolute effects of antiplatelet therapy on recurrent intracerebral haemorrhage and whether this risk might exceed any reduction of occlusive vascular events. Methods: The REstart or STop Antithrombotics Randomised Trial (RESTART) was a prospective, randomised, open-label, blinded endpoint, parallel-group trial at 122 hospitals in the UK. We recruited adults (≥18 years) who were taking antithrombotic (antiplatelet or anticoagulant) therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage, discontinued antithrombotic therapy, and survived for 24 h. Computerised randomisation incorporating minimisation allocated participants (1:1) to start or avoid antiplatelet therapy. We followed participants for the primary outcome (recurrent symptomatic intracerebral haemorrhage) for up to 5 years. We analysed data from all randomised participants using Cox proportional hazards regression, adjusted for minimisation covariates. This trial is registered with ISRCTN (number ISRCTN71907627). Findings: Between May 22, 2013, and May 31, 2018, 537 participants were recruited a median of 76 days (IQR 29–146) after intracerebral haemorrhage onset: 268 were assigned to start and 269 (one withdrew) to avoid antiplatelet therapy. Participants were followed for a median of 2·0 years (IQR [1·0– 3·0]; completeness 99·3%). 12 (4%) of 268 participants allocated to antiplatelet therapy had recurrence of intracerebral haemorrhage compared with 23 (9%) of 268 participants allocated to avoid antiplatelet therapy (adjusted hazard ratio 0·51 [95% CI 0·25–1·03]; p=0·060). 18 (7%) participants allocated to antiplatelet therapy experienced major haemorrhagic events compared with 25 (9%) participants allocated to avoid antiplatelet therapy (0·71 [0·39–1·30]; p=0·27), and 39 [15%] participants allocated to antiplatelet therapy had major occlusive vascular events compared with 38 [14%] allocated to avoid antiplatelet therapy (1·02 [0·65–1·60]; p=0·92). Interpretation: These results exclude all but a very modest increase in the risk of recurrent intracerebral haemorrhage with antiplatelet therapy for patients on antithrombotic therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage. The risk of recurrent intracerebral haemorrhage is probably too small to exceed the established benefits of antiplatelet therapy for secondary prevention

Effects of antiplatelet therapy after stroke due to intracerebral haemorrhage (RESTART): a randomised, open-label trial

Background: Antiplatelet therapy reduces the risk of major vascular events for people with occlusive vascular disease, although it might increase the risk of intracranial haemorrhage. Patients surviving the commonest subtype of intracranial haemorrhage, intracerebral haemorrhage, are at risk of both haemorrhagic and occlusive vascular events, but whether antiplatelet therapy can be used safely is unclear. We aimed to estimate the relative and absolute effects of antiplatelet therapy on recurrent intracerebral haemorrhage and whether this risk might exceed any reduction of occlusive vascular events. Methods: The REstart or STop Antithrombotics Randomised Trial (RESTART) was a prospective, randomised, open-label, blinded endpoint, parallel-group trial at 122 hospitals in the UK. We recruited adults (≥18 years) who were taking antithrombotic (antiplatelet or anticoagulant) therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage, discontinued antithrombotic therapy, and survived for 24 h. Computerised randomisation incorporating minimisation allocated participants (1:1) to start or avoid antiplatelet therapy. We followed participants for the primary outcome (recurrent symptomatic intracerebral haemorrhage) for up to 5 years. We analysed data from all randomised participants using Cox proportional hazards regression, adjusted for minimisation covariates. This trial is registered with ISRCTN (number ISRCTN71907627). Findings: Between May 22, 2013, and May 31, 2018, 537 participants were recruited a median of 76 days (IQR 29–146) after intracerebral haemorrhage onset: 268 were assigned to start and 269 (one withdrew) to avoid antiplatelet therapy. Participants were followed for a median of 2·0 years (IQR [1·0– 3·0]; completeness 99·3%). 12 (4%) of 268 participants allocated to antiplatelet therapy had recurrence of intracerebral haemorrhage compared with 23 (9%) of 268 participants allocated to avoid antiplatelet therapy (adjusted hazard ratio 0·51 [95% CI 0·25–1·03]; p=0·060). 18 (7%) participants allocated to antiplatelet therapy experienced major haemorrhagic events compared with 25 (9%) participants allocated to avoid antiplatelet therapy (0·71 [0·39–1·30]; p=0·27), and 39 [15%] participants allocated to antiplatelet therapy had major occlusive vascular events compared with 38 [14%] allocated to avoid antiplatelet therapy (1·02 [0·65–1·60]; p=0·92). Interpretation: These results exclude all but a very modest increase in the risk of recurrent intracerebral haemorrhage with antiplatelet therapy for patients on antithrombotic therapy for the prevention of occlusive vascular disease when they developed intracerebral haemorrhage. The risk of recurrent intracerebral haemorrhage is probably too small to exceed the established benefits of antiplatelet therapy for secondary prevention