Antipsychotic drug prescribing and mortality in people with dementia before and during the COVID-19 pandemic: a retrospective cohort study in Wales, UK.

BACKGROUND: Concerns have been raised that antipsychotic drug prescribing, which has been associated with increased mortality in people with dementia, might have increased during the COVID-19 pandemic due to social restrictions imposed to limit the spread of SARS-CoV-2. We used multisource, routinely collected health-care data from Wales, UK to investigate prescribing and mortality variations in people with dementia before and during the COVID-19 pandemic. METHODS: In this retrospective cohort study, we used individual-level, anonymised, population-scale linked health data to identify adults aged 60 years and older with a diagnosis of dementia in Wales, UK. We used the CVD-COVID-UK initiative to access Welsh routinely collected electronic health record data from the Secure Anonymised Information Linkage (SAIL) Databank. Patients who were alive and registered with a SAIL general practice on Jan 1, 2016, and who received a dementia diagnosis before the age of 60 years and before or during the study period were included. We explored antipsychotic drug prescribing rate changes over 67 months, between Jan 1, 2016, and Aug 1, 2021, overall and stratified by age and dementia subtype. We used time-series analyses to examine all-cause and myocardial infarction and stroke mortality over the study period and identified the leading causes of death in people with dementia between Jan 1, 2020, and Aug 1, 2021. FINDINGS: Of 3 106 690 participants in SAIL between Jan 1, 2016 and Aug 1, 2021, 57 396 people (35 148 [61·2%] women and 22 248 [38·8%] men) met inclusion criteria for this study and contributed 101 428 person-years of follow-up. Of the 57 396 people with dementia, 11 929 (20·8%) were prescribed an antipsychotic drug at any point during follow-up. Accounting for seasonality, antipsychotic drug prescribing increased during the second half of 2019 and throughout 2020. However, the absolute difference in prescribing rates was small, ranging from 1253 prescriptions per 10 000 person-months in March, 2019, to 1305 per 10 000 person-months in September, 2020. All-cause mortality and stroke mortality increased throughout 2020, while myocardial infarction mortality declined. From Jan 1, 2020, to Aug 1, 2021, 1286 (17·1%) of 7508 participants who died had COVID-19 recorded as the underlying cause of death. INTERPRETATION: During the COVID-19 pandemic, antipsychotic drug prescribing in people with dementia in the UK increased slightly; however, it is unlikely that this was solely related to the pandemic and this increase was unlikely to be a major factor in the substantial increase in mortality during 2020. The long-term increase in antipsychotic drug prescribing in younger people and in those with Alzheimer's disease warrants further investigation using resources with access to more granular clinical data. Although deprescribing antipsychotic medications remains an essential aspect of dementia care, the results of this study suggest that changes in prescribing and deprescribing practices as a result of the COVID-19 pandemic are not required. FUNDING: British Heart Foundation (via the British Heart Foundation Data Science Centre led by Health Data Research UK), and the Scottish Neurological Research Fund.

Long-term mortality and recurrent vascular events in lacunar versus non-lacunar ischaemic stroke: A cohort study.

Introduction: Studies of differences in very long-term outcomes between people with lacunar/small vessel disease (SVD) versus other types of ischaemic stroke report mixed findings, with limited data on myocardial infarction (MI). We investigated whether long-term mortality, recurrent stroke and MI risks differ in people with versus without lacunar/SVD ischaemic stroke. Patients and methods: We included first-ever strokes from a hospital-based stroke cohort study recruited in 2002-2005. We compared risks of death, recurrent stroke and MI during follow-up among lacunar/SVD versus other ischaemic stroke subtypes using Cox regression, adjusting for confounding factors. Results: We included 812 participants, 283 with lacunar/SVD ischaemic stroke and 529 with other stroke. During a median of 9.2 years (interquartile range 3.1-11.8), there were 519 deaths, 181 recurrent strokes and 79 MIs. Lacunar/SVD stroke was associated with lower mortality (adjusted HR 0.79, 95% CI 0.65 to 0.95), largely due to markedly lower all-cause mortality in the first year. From one year onwards this difference attenuated, with all-cause mortality only slightly and not statistically significantly lower in the lacunar/SVD group (0.86, 95% CI 0.70 to 1.05). There was no clear difference in risk of recurrent stroke (HR 0.84, 95% CI 0.61-1.15) or MI (HR 0.83, 95% CI 0.52-1.34). Conclusion: Long-term risks of all-cause mortality, recurrent stroke and MI are similar, or only slightly lower, in patients with lacunar/SVD as compared to other ischaemic stroke. Patients and physicians should be as vigilant in optimising short- and long-term secondary prevention of vascular events in lacunar/SVD as for other stroke types.

Drug prescriptions and dementia incidence: a medication-wide association study of 17000 dementia cases among half a million participants.

BACKGROUND: Previous studies have suggested that some medications may influence dementia risk. We conducted a hypothesis-generating medication-wide association study to investigate systematically the association between all prescription medications and incident dementia. METHODS: We used a population-based cohort within the Secure Anonymised Information Linkage (SAIL) databank, comprising routinely-collected primary care, hospital admissions and mortality data from Wales, UK. We included all participants born after 1910 and registered with a SAIL general practice at ≤60 years old. Follow-up was from each participant's 60th birthday to the earliest of dementia diagnosis, deregistration from a SAIL general practice, death or the end of 2018. We considered participants exposed to a medication if they received ≥1 prescription for any of 744 medications before or during follow-up. We adjusted for sex, smoking and socioeconomic status. The outcome was any all-cause dementia code in primary care, hospital or mortality data during follow-up. We used Cox regression to calculate hazard ratios and Bonferroni-corrected p values. RESULTS: Of 551 344 participants, 16 998 (3%) developed dementia (median follow-up was 17 years for people who developed dementia, 10 years for those without dementia). Of 744 medications, 221 (30%) were associated with dementia. Of these, 217 (98%) were associated with increased dementia incidence, many clustering around certain indications. Four medications (all vaccines) were associated with a lower dementia incidence. CONCLUSIONS: Almost a third of medications were associated with dementia. The clustering of many drugs around certain indications may provide insights into early manifestations of dementia. We encourage further investigation of hypotheses generated by these results.

Impact of detecting potentially serious incidental findings during multi-modal imaging.

Background: There are limited data on the impact of feedback of incidental findings (IFs) from research imaging.  We evaluated the impact of UK Biobank's protocol for handling potentially serious IFs in a multi-modal imaging study of 100,000 participants (radiographer 'flagging' with radiologist confirmation of potentially serious IFs) compared with systematic radiologist review of all images. Methods: Brain, cardiac and body magnetic resonance, and dual-energy x-ray absorptiometry scans from the first 1000 imaged UK Biobank participants were independently assessed for potentially serious IFs using both protocols. We surveyed participants with potentially serious IFs and their GPs up to six months after imaging to determine subsequent clinical assessments, final diagnoses, emotional, financial and work or activity impacts. Results: Compared to systematic radiologist review, radiographer flagging resulted in substantially fewer participants with potentially serious IFs (179/1000 [17.9%] versus 18/1000 [1.8%]) and a higher proportion with serious final diagnoses (21/179 [11.7%] versus 5/18 [27.8%]). Radiographer flagging missed 16/21 serious final diagnoses (i.e., false negatives), while systematic radiologist review generated large numbers of non-serious final diagnoses (158/179) (i.e., false positives). Almost all (90%) participants had further clinical assessment (including invasive procedures in similar numbers with serious and non-serious final diagnoses [11 and 12 respectively]), with additional impact on emotional wellbeing (16.9%), finances (8.9%), and work or activities (5.6%). Conclusions: Compared with systematic radiologist review, radiographer flagging missed some serious diagnoses, but avoided adverse impacts for many participants with non-serious diagnoses. While systematic radiologist review may benefit some participants, UK Biobank's responsibility to avoid both unnecessary harm to larger numbers of participants and burdening of publicly-funded health services suggests that radiographer flagging is a justifiable approach in the UK Biobank imaging study. The potential scale of non-serious final diagnoses raises questions relating to handling IFs in other settings, such as commercial and public health screening.

Reliability of intracerebral hemorrhage classification systems: A systematic review.

BACKGROUND: Accurately distinguishing non-traumatic intracerebral hemorrhage (ICH) subtypes is important since they may have different risk factors, causal pathways, management, and prognosis. We systematically assessed the inter- and intra-rater reliability of ICH classification systems. METHODS: We sought all available reliability assessments of anatomical and mechanistic ICH classification systems from electronic databases and personal contacts until October 2014. We assessed included studies' characteristics, reporting quality and potential for bias; summarized reliability with kappa value forest plots; and performed meta-analyses of the proportion of cases classified into each subtype. SUMMARY OF REVIEW: We included 8 of 2152 studies identified. Inter- and intra-rater reliabilities were substantial to perfect for anatomical and mechanistic systems (inter-rater kappa values: anatomical 0.78-0.97 [six studies, 518 cases], mechanistic 0.89-0.93 [three studies, 510 cases]; intra-rater kappas: anatomical 0.80-1 [three studies, 137 cases], mechanistic 0.92-0.93 [two studies, 368 cases]). Reporting quality varied but no study fulfilled all criteria and none was free from potential bias. All reliability studies were performed with experienced raters in specialist centers. Proportions of ICH subtypes were largely consistent with previous reports suggesting that included studies are appropriately representative. CONCLUSIONS: Reliability of existing classification systems appears excellent but is unknown outside specialist centers with experienced raters. Future reliability comparisons should be facilitated by studies following recently published reporting guidelines.

Thienopyridine derivatives versus aspirin for preventing stroke and other serious vascular events in high vascular risk patients.

BACKGROUND: Aspirin is the most widely studied and prescribed antiplatelet agent for preventing serious vascular events, reducing the odds of such events among high vascular risk patients by about a quarter. Thienopyridine derivatives inhibit platelet activation by a different mechanism and so may be more effective. OBJECTIVES: To determine the effectiveness and safety of thienopyridine derivatives (ticlopidine and clopidogrel) versus aspirin for preventing serious vascular events (stroke, myocardial infarction (MI) or vascular death) in patients at high risk, and specifically in patients with a previous TIA or ischaemic stroke. SEARCH STRATEGY: We searched the trials registers of the Stroke, Heart and Peripheral Vascular Diseases Cochrane Review Groups (last searched July 2008), the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library Issue 3, 2008), MEDLINE (1966 to August 2008) and EMBASE (1980 to August 2008). We also searched reference lists of relevant papers, and contacted other researchers and the pharmaceutical company Sanofi-BMS (December 2008). SELECTION CRITERIA: All unconfounded, double blind, randomised trials directly comparing a thienopyridine derivative with aspirin in high vascular risk patients. DATA COLLECTION AND ANALYSIS: Two review authors independently extracted data and assessed trial quality. We sought additional data from the principal investigators of the largest trials. MAIN RESULTS: We included 10 trials involving 26,865 high vascular risk patients. The trials were generally of high quality. Aspirin was compared with ticlopidine in nine trials (7633 patients) and with clopidogrel in one trial (19,185 patients). Compared with aspirin, allocation to a thienopyridine produced a modest, just statistically significant, reduction in the odds of a serious vascular event (11.6% versus 12.5%; odds ratio (OR) 0.92, 95% confidence interval (CI) 0.85 to 0.99), corresponding to the avoidance of 10 (95% CI 0 to 20) serious vascular events per 1000 patients treated for about two years. However, the wide confidence interval includes the possibility of negligible additional benefit. Compared with aspirin, thienopyridines significantly reduced gastrointestinal adverse effects. However, thienopyridines increased the odds of skin rash and diarrhoea, ticlopidine more than clopidogrel. Allocation to ticlopidine, but not clopidogrel, significantly increased the odds of neutropenia. In patients with TIA/ischaemic stroke, the results were similar to those for all patients combined. AUTHORS' CONCLUSIONS: The thienopyridine derivatives are at least as effective as aspirin in preventing serious vascular events in patients at high risk, and possibly somewhat more so. However, the size of any additional benefit is uncertain and could be negligible. Clopidogrel has a more favourable adverse effects profile than ticlopidine and so is the thienopyridine of choice. It should be used as an alternative to aspirin in patients genuinely intolerant of or allergic to aspirin.