Effect of timed dosing of usual antihypertensives according to patient chronotype on cardiovascular outcomes: the Chronotype sub-study cohort of the Treatment in Morning versus Evening (TIME) study.

Background: Timing drug administration to endogenous circadian rhythms may enhance treatment efficacy. In the Chronotype sub-study of the Treatment in Morning versus Evening (TIME) clinical trial we examined whether timing of usual antihypertensive medications according to patient chronotype (a behavioural marker of personal circadian rhythm) may influence clinical cardiovascular outcomes. Methods: This was a cohort sub-study of TIME, a prospective, randomised, open-label, blinded-endpoint, UK clinical trial of morning versus evening dosing of usual antihypertensive medications and cardiovascular outcomes. On August 3rd, 2020, all active TIME participants were invited to complete a validated chronotype questionnaire. Chronotype was quantitatively assessed as the mid sleep time on free days corrected for sleep debt on workdays (MSFsc). We analysed associations between chronotype and antihypertensive dosing time and explored their combined effect on cardiovascular outcomes (a composite endpoint of hospitalisation for non-fatal myocardial infarction (MI) or non-fatal stroke, and single components) using proportional hazard time-to-event models adjusted for baseline covariates. These were used to specifically test for interactions between dosing time and chronotype. Findings: Between August 3, 2020, and March 31, 2021, 5358 TIME participants completed the online questionnaire. 2778 were previously randomised to morning dosing and 2580 to evening dosing of their usual antihypertensives. Chronotype was symmetrically distributed around a median MSFsc of 3:07 am. The composite endpoint increased for later MSFsc (later chronotype) dosed in the morning but not in those dosed in the evening (hazard ratios 1.46 [95% CI 1.14-1.86] and 0.96 [95% CI 0.70-1.30] per hour of MSFsc, respectively; interaction p = 0.036). Later chronotype was associated with increased risk of hospitalisation for non-fatal MI in the morning dosing group, and reduced risk in the evening dosing group (hazard ratios 1.62 [95% CI 1.18-2.22] and 0.66 [95% CI 0.44-1.00] per hour of MSFsc, respectively; interaction p < 0.001). No interaction between chronotype and antihypertensive dosing time was observed for stroke events. Interpretation: Alignment of dosing time of usual antihypertensives with personal chronotype could lower the incidence of non-fatal MI compared to a 'misaligned' dosing time regimen. Future studies are warranted to establish whether synchronizing administration time of antihypertensive therapy with individual chronotype reduces risk of MI. Funding: The TIME study was funded by the British Heart Foundation (CS/14/1/30659) with support from the British and Irish Hypertension Society.

Evaluating Diuretics in Normal Care (EVIDENCE): a feasibility report of a pilot cluster randomised trial of prescribing policy in primary care to compare the effectiveness of thiazide-type diuretics in hypertension.

BACKGROUND: Obtaining evidence on comparative effectiveness and safety of widely prescribed drugs in a timely and cost-effective way is a major challenge for healthcare systems. Here, we describe the feasibility of the Evaluating Diuretics in Normal Care (EVIDENCE) study that compares a thiazide and thiazide-like diuretics for hypertension as an exemplar of a more general framework for efficient generation of such evidence. In 2011, the UK NICE hypertension guideline included a recommendation that thiazide-like diuretics (such as indapamide) be used in preference to thiazide diuretics (such as bendroflumethiazide) for hypertension. There is sparse evidence backing this recommendation, and bendroflumethiazide remains widely used in the UK. METHODS: Patients prescribed indapamide or bendroflumethiazide regularly for hypertension were identified in participating general practices. Allocation of a prescribing policy favouring one of these drugs was then randomly applied to the practice and, where required to comply with the policy, repeat prescriptions switched by pharmacy staff. Patients were informed of the potential switch by letter and given the opportunity to opt out. Practice adherence to the randomised policy was assessed by measuring the amount of policy drug prescribed as a proportion of total combined indapamide and bendroflumethiazide. Routinely collected hospitalisation and death data in the NHS will be used to compare cardiovascular event rates between the two policies. RESULTS: This pilot recruited 30 primary care practices in five Scottish National Health Service (NHS) Boards. Fifteen practices were randomised to indapamide (2682 patients) and 15 to bendroflumethiazide (3437 patients), a study population of 6119 patients. Prior to randomisation, bendroflumethiazide was prescribed to 78% of patients prescribed either of these drugs. Only 1.6% of patients opted out of the proposed medication switch. CONCLUSION: The pilot and subsequent recruitment confirms the methodology is scalable within NHS Scotland for a fully powered larger study; currently, 102 GP practices (> 12,700 patients) are participating in this study. It has the potential to efficiently produce externally valid comparative effectiveness data with minimal disruption to practice staff or patients. Streamlining this pragmatic trial approach has demonstrated the feasibility of a random prescribing policy design framework that can be adapted to other therapeutic areas. TRIAL REGISTRATION: ISRCTN Registry, ISRCTN46635087 . Registered on 11 August 2017.

Factors influencing home blood pressure monitor ownership in a large clinical trial.

Home blood pressure monitor (HBPM) ownership prevalence and the factors that influence it are unclear. This study aimed to investigate factors associated with HBPM ownership among participants in the Treatment in Morning versus Evening (TIME) hypertension study. This study is a sub-analysis of the TIME study, a randomised trial investigating the effect of day-time versus night-time dosing of antihypertensive medication on cardiovascular outcomes in adults with hypertension. As part of the TIME study online registration process, participants were asked to indicate whether they owned an HBPM. A multivariable logistic regression model was constructed to determine factors associated with HBPM ownership. Of 21,104 randomised participants, 11,434 (54.2%) reported owning an HBPM. The mean age of all participants at enrolment was 67.7 ± 9.3 years, 12,134 (57.5%) were male, and 8892 (42.1%) reported a current or previous history of smoking. Factors associated with an increased likelihood of reporting HBPM owned include being male (OR:1.47; 95% CI 1.39-1.56) or residing in a less deprived socioeconomic region (IMD Decile 6-10) (OR:1.31; 95% CI 1.23-1.40). Participants with a history of diabetes mellitus (OR:0.74; 95% CI:0.64-0.86) or current smokers, compared to non-smokers, (OR:0.71; 95% CI:0.62-0.82) were less likely to report owning an HBPM. This study has identified important patient factors influencing HBPM ownership. Further qualitative research would be valuable to identify and explore potential patient-level barriers to engagement with self-monitoring of blood pressure.

Evaluating Diuretics in Normal Care (EVIDENCE): protocol of a cluster randomised controlled equivalence trial of prescribing policy to compare the effectiveness of thiazide-type diuretics in hypertension.

INTRODUCTION: Healthcare systems must use treatments that are effective and safe. Regulators licensed many currently used older medications before introducing the stringent evidential requirements imposed on modern treatments. Also, there has been little encouragement to carry out within-class, head-to-head comparisons of licensed medicines. For commonly prescribed drugs, even small differences in effectiveness or safety could have significant public health implications. However, conventional clinical trials that randomise individual subjects are costly and unwieldy. Such trials are also often criticised as having low external validity. We describe an approach to rapidly generate externally valid evidence of comparative safety and effectiveness using the example of two widely used diuretics for the management of hypertension. METHODS AND ANALYSIS: The EVIDENCE (Evaluating Diuretics in Normal Care) study has a prospective, cluster-randomised, open-label, blinded end-point design. By randomising prescribing policy in primary care practices, the study compares the safety and effectiveness of commonly used diuretics in treating hypertension. Participating practices are randomised 1:1 to a policy of prescribing either indapamide or bendroflumethiazide when clinically indicated. Suitable patients who are not already taking the policy diuretic are switched accordingly. All patients taking the study medications are written to explaining the rationale for changing the prescribing policy and notifying them they can opt-out of any switch. The prescribing policies' effectiveness and safety will be compared using rates of major adverse cardiovascular events (hospitalisation with myocardial infarction, heart failure or stroke or cardiovascular death), routinely collected in national healthcare administrative datasets. The study will seek to recruit 250 practices to provide a study population of approximately 50,000 individuals with a mean follow-up time of two years. A primary intention-to-treat time-to-event analysis will be used to estimate the relative effect of the two policies. ETHICS AND DISSEMINATION: EVIDENCE has been approved by the East of Scotland Research Ethics Service (17/ES/0016, current approved protocol version 5, 26 August 2021). The results will be disseminated widely in peer reviewed journals, guideline committees, National Health Service (NHS) organisations and patient groups. TRIAL REGISTRATION: ISRCTN 46635087 . Registered on 11 August 2017 (pre-recruitment).

Identification and Validation of Major Cardiovascular Events in the United Kingdom Data Sources Included in a Multi-database Post-authorization Safety Study of Prucalopride.

INTRODUCTION: A multinational post-authorization safety study assessed cardiovascular safety in initiators of prucalopride for chronic constipation compared with a matched cohort of polyethylene glycol 3350 initiators. The primary safety outcome was major adverse cardiovascular events (MACE), a composite of hospitalization for acute myocardial infarction, stroke, or in-hospital cardiovascular death. We report the validation process for MACE endpoints in United Kingdom (UK) data sources: Clinical Practice Research Datalink (CPRD GOLD), The Health Improvement Network (THIN), and the Information Services Division (ISD) Scotland. METHODS: Modified electronic algorithms from prior research identified potential MACE cases. Validation followed a common protocol, adapted for each database, with all information anonymized: (1) direct confirmation via linkage to hospital records (CPRD GOLD); (2) requests for additional clinical information through questionnaires (CPRD GOLD), free-text (THIN), or abstraction of hospital records (ISD); (3) manual review of electronic records of potential events retrieved by the algorithm (CPRD GOLD/THIN); and (4) event adjudication by three clinicians, blinded to exposure, for all remaining events. RESULTS: Electronic algorithms identified 260 potential MACE cases: 38 confirmed via linkage to hospital records (CPRD GOLD), 56 ruled out as non-cardiovascular death cases (THIN), and three unavailable for review (ISD), leaving 163 potential cases. After manual review with additional information (steps 2 and 3), 45 were considered noncases (CPRD GOLD/THIN). Upon final adjudication (step 4), remaining potential events were adjudicated as definite (n = 62), probable (n = 10), possible (n = 13), or noncases (n = 33). CONCLUSIONS: Given the limitations of relying solely on computer algorithms to identify cardiovascular outcomes, validation with clinical review is essential to guide interpretation.

Impact of EU regulatory label changes for diclofenac in people with cardiovascular disease in four countries: Interrupted time series regression analysis.

OBJECTIVE: Due to cardiovascular safety concerns, the European Medicines Agency (EMA) recommended new contraindications and changes to product information for diclofenac across Europe in 2013. This study aims to measure their impact among targeted populations. METHOD: Quarterly interrupted time series regression (ITS) analyses of diclofenac initiation among cohorts with contraindications (congestive cardiac failure [CHF], ischaemic heart disease [IHD], peripheral arterial disease [PAD], cerebrovascular disease [CVD]) and cautions (hypertension, hyperlipidaemia, diabetes) from Denmark, the Netherlands, England and Scotland. RESULTS: The regulatory action was associated with significant immediate absolute reductions in diclofenac initiation in all countries for IHD (Denmark -0.08%, 95%CI -0.13, -0.03; England -0.09%, 95%CI -0.13 to -0.06%; the Netherlands -1.84%, 95%CI -2.51 to -1.17%; Scotland -0.34%, 95%CI -0.38 to -0.30%), PAD and hyperlipidaemia, the Netherlands, England and Scotland for hypertension and diabetes, and England and Scotland for CHF and CVD. Post-intervention there was a significant negative trend in diclofenac initiation in the Netherlands for IHD (-0.12%, 95%CI -0.19 to -0.04), PAD (-0.13%, 95%CI -0.22 to -0.05), hypertension, hyperlipidaemia and diabetes, and in Scotland for CHF (-0.01%, 95%CI -0.02 to -0.007%), IHD (-0.017, 95%CI -0.02, -0.01%), PAD and hypertension. In England, diclofenac initiation rates fell less steeply. In Denmark changes were more strongly associated with the earlier EMA 2012 regulatory action. CONCLUSION: Although significant reductions in diclofenac initiation occurred, patients with contraindications continued to be prescribed diclofenac, the extent of which varied by country and target condition. Understanding reasons for such variation may help to guide the design or dissemination of future safety warnings.

Impact of EMA regulatory label changes on systemic diclofenac initiation, discontinuation, and switching to other pain medicines in Scotland, England, Denmark, and The Netherlands.

PURPOSE: In June 2013 a European Medicines Agency referral procedure concluded that diclofenac was associated with an elevated risk of acute cardiovascular events and contraindications, warnings, and changes to the product information were implemented across the European Union. This study measured the impact of the regulatory action on the prescribing of systemic diclofenac in Denmark, The Netherlands, England, and Scotland. METHODS: Quarterly time series analyses measuring diclofenac prescription initiation, discontinuation and switching to other systemic nonsteroidal anti-inflammatory (NSAIDs), topical NSAIDs, paracetamol, opioids, and other chronic pain medication in those who discontinued diclofenac. Absolute effects were estimated using interrupted time series regression. RESULTS: Overall, diclofenac prescription initiations fell during the observation periods of all countries. Compared with Denmark where there appeared to be a more limited effect, the regulatory action was associated with significant immediate reductions in diclofenac initiation in The Netherlands (-0.42%, 95% CI, -0.66% to -0.18%), England (-0.09%, 95% CI, -0.11% to -0.08%), and Scotland (-0.67%, 95% CI, -0.79% to -0.55%); and falling trends in diclofenac initiation in the Netherlands (-0.03%, 95% CI, -0.06% to -0.01% per quarter) and Scotland (-0.04%, 95% CI, -0.05% to -0.02% per quarter). There was no significant impact on diclofenac discontinuation in any country. The regulatory action was associated with modest differences in switching to other pain medicines following diclofenac discontinuation. CONCLUSIONS: The regulatory action was associated with significant reductions in overall diclofenac initiation which varied by country and type of exposure. There was no impact on discontinuation and variable impact on switching.

Cardiovascular Safety of Prucalopride in Patients with Chronic Constipation: A Multinational Population-Based Cohort Study.

INTRODUCTION: The serotonin 5-HT4 receptor agonist prucalopride is approved in the European Union for the treatment of chronic constipation. This offered the unique opportunity to include real-world observational data on cardiovascular safety in the new drug application for approval of prucalopride in the USA. METHODS: This observational population-based cohort study (EUPAS9200) conducted in five data sources (three in the UK, one in Sweden, and one in Germany [which was subsequently excluded from the pooled analyses]) aimed to estimate the pooled adjusted incidence rate ratio for major adverse cardiovascular events (defined as hospitalization for non-fatal acute myocardial infarction or stroke, and in-hospital cardiovascular death) in adult initiators of prucalopride compared with initiators of polyethylene glycol 3350 (PEG) following a common protocol. Standardized incidence rates and incidence rate ratios of major adverse cardiovascular events were derived using propensity score stratification. Sensitivity analyses explored the impact of exposure definition, outcome categories, interim cancer, and unmeasured confounding. RESULTS: The pooled analyses included 5715 initiators of prucalopride and 29,372 initiators of PEG. Average duration of use was 175 days for prucalopride and 82 days for PEG. The pooled standardized incidence rate per 1000 person-years (95% confidence interval) of major adverse cardiovascular events was 6.57 (3.90-10.39) for patients initiating prucalopride and 10.24 (6.97-14.13) for PEG. The pooled adjusted incidence rate ratio for major adverse cardiovascular events was 0.64 (95% confidence interval 0.36-1.14). Results remained consistent in various sensitivity analyses. CONCLUSIONS: The pooled incidence rate ratio estimate was consistent with no indication of an increased risk above the pre-specified safety threshold of 3.00 for major adverse cardiovascular events in patients with chronic constipation using prucalopride as compared with PEG.

Study Design and Cohort Comparability in a Study of Major Cardiovascular Events in New Users of Prucalopride Versus Polyethylene Glycol 3350.

INTRODUCTION: Given prior safety experience with other 5-HT4 agonists for chronic constipation, an observational, population-based cohort study in five data sources from Germany, Sweden, and the UK was conducted to evaluate the cardiovascular safety of prucalopride. OBJECTIVES: Our objective is to describe the methods and resulting comparability of cohorts in a multi-database, multinational study of prucalopride initiators and polyethylene glycol 3350 (PEG) initiators following a harmonized protocol. METHODS: Prucalopride initiators were matched on age, sex, and index date to PEG initiators (1:5 ratio). Study exposures, cardiovascular risk factors, and other covariates were identified from healthcare utilization codes harmonized across databases. Cardiovascular outcomes were identified using database-specific algorithms based on diagnosis codes. The propensity score (PS) in each database was estimated using logistic regression, with prucalopride versus PEG as the outcome and including clinically relevant variables associated with major adverse cardiovascular events. RESULTS: In total, 12,030 prucalopride initiators and 59,985 PEG initiators were identified. After matching and trimming, cohorts from the UK and Sweden were well-balanced for cardiovascular risk factors and cancer. However, in Germany, PEG initiators remained older and sicker than prucalopride initiators. The prevalence of these characteristics also differed from those in the UK and Sweden. The pooled analyses included only data from the UK and Sweden. CONCLUSIONS: Matching, trimming, and PS stratification yielded comparable cohorts in four of five data sources. Use of these methods could not achieve balance for key covariates within the German cohort, likely due to reimbursement differences in Germany.

Does the provision of a DVD-based audio-visual presentation improve recruitment in a clinical trial? A randomised trial of DVD trial invitations.

BACKGROUND: Recruitment to clinical trials can be challenging. Methods that improve the efficiency of trial recruitment are needed to increase successful study completions. The aim of this study was to ascertain whether sending an audio-visual presentation on a digital versatile disc (DVD), along with usual study invitation materials, would improve recruitment to the Febuxostat versus Allopurinol Streamlined Trial (FAST), a clinical trial in patients with established gout. METHODS: Potential participants for the FAST study who were identified by searches of GP records in Scottish primary care practices between August 2013 and July 2014 were included in this study. Individuals were randomly allocated to receive either a standard invitation (letter and information leaflet) or a standard invitation and a DVD containing an audio-visual presentation explaining the background and operation of FAST. Data on invitation response rates, screening attendances and randomisations were collected by research nurses. RESULTS: One thousand fifty potential participants were invited to take part in FAST during this period. 509 individuals were randomised to receive the DVD presentation and the standard invitation and 541 received a standard invitation only. DVD recipients were less likely to respond to the initial invitation (adjusted OR 0.76, CI 0.58-0.99) and marginally less likely to return a positive response (OR 0.75, CI 0.59-0.96). There was no statistically significant difference between the groups in attendance for screening or randomisation. The DVD did not influence the age, gender, or socioeconomic deprivation scores of those responding positively to a letter of invitation. CONCLUSIONS: The inclusion of a DVD presentation with FAST study invitations did not make any practical difference to the rate of positive response to invitation. Further innovation and evaluation will be required to improve recruitment to clinical trials. TRIAL REGISTRATION: EU Clinical Trials Register. EudraCT Number: 2011-001883-23 . ISRCTN registry.  ISRCTN72443278 .

The effect of indapamide vs. bendroflumethiazide for primary hypertension: a systematic review.

The aims of the current review were to compare the efficacy of monotherapy with bendroflumethiazide vs. indapamide on mortality, cardiovascular outcomes, blood pressure, need for intensification of treatment and treatment withdrawal. Two authors independently screened the results of a literature search, assessed the risk of bias and extracted relevant data. Randomized clinical trials of hypertensive patients of at least a 1-year duration were included. When there was disagreement, a third reviewer was consulted. Risk ratio (RR) and mean differences were used as measures of effect. Two trials comparing bendroflumethiazide against placebo, one comparing indapamide with placebo and three of short duration directly comparing indapamide and Bendroflumethiazide, were included. No statistically significant difference was found between indapamide and bendroflumethiazide for all deaths [RR 0.82; 95% confidence interval (CI) 0.57, 1.18], cardiovascular deaths (RR 0.82; 95% CI 0.55, 1.20), noncardiovascular deaths (0.81; 95% CI 0.54, 1.22), coronary events (RR 0.73; 95% CI 0.30, 1.79) or all cardiovascular events (RR 0.89; 95% CI 0.67, 1.18). Indapamide performed worse for stroke (RR 2.21; 95% CI 1.19, 4.11), even though a reduction in RR compared with placebo was observed in both groups. There was no statistically or clinically significant difference between indapamide and bendroflumethiazide in blood pressure reduction (mean absolute difference <1 mmHg). The present review highlights a lack of studies to answer the review question but also a lack of evidence of superiority of one drug over the other. Therefore, there is a clear need for new studies directly comparing the effect of these drugs on the outcomes of interest.

The effect of changes to GOLD severity stage on long term morbidity and mortality in COPD.

BACKGROUND: The Global Initiative for Chronic Obstructive Lung Disease (GOLD) severity stage classifies Chronic Obstructive Pulmonary Disease (COPD) into groups based on symptoms, exacerbations and forced expiratory volume in one second (FEV1). This allows patients to change to less severe COPD stages, a novel aspect of assessment not previously evaluated. We aimed to investigate the association between temporal changes in GOLD severity stage and outcomes in COPD patients. METHODS: This was a record-linkage study using patients registered with a Scottish regional COPD network 2000-2015. Annual spirometry & symptoms were recorded and linked to healthcare records to identify exacerbations, hospitalisations and mortality. Spirometry, modified Medical Research Council (mMRC) dyspnoea scale and acute exacerbations over the previous year were used to assign GOLD severity at each visit. A time-dependent Cox model was used to model time to death. Secondary outcomes were respiratory specific mortality and hospitalisations. Effect sizes are expressed as Hazard Ratios HR (95%CI). RESULTS: Four thousand, eight hundred and eighty-five patients (mean age 67.3 years; 51.3% female) with 21,348 visits were included. During a median 6.6 years follow-up there were 1530 deaths. For the secondary outcomes there were 712 respiratory deaths and 1629 first hospitalisations. Across 16,463 visit-pairs, improvement in COPD severity was seen in 2308 (14%), no change in 11,010 (66.9%) and worsening in 3145 (19.1). Compared to patients staying in GOLD stage A, those worsening had a stepwise increased mortality and hospitalisations. CONCLUSIONS: Improving COPD severity classification was associated with reduced mortality and worsening COPD severity was associated with increased mortality and hospitalisations. Change in GOLD group has potential as monitoring tool and outcome measure in clinical trials.

The Treatment In Morning versus Evening (TIME) study: analysis of recruitment, follow-up and retention rates post-recruitment.

BACKGROUND: The use of information technology (IT) is now the preferred method of capturing and storing clinical research data. The Treatment In Morning versus Evening (TIME) study predominantly uses electronic data capture and IT to compare morning dosing of hypertensive medication against evening dosing. Registration, consent, participant demographics and follow-up data are all captured via the study website. The aim of this article is to assess the success of the TIME methodology compared with similar studies. METHODS: To assess the TIME study, published literature on similar clinical trials was reviewed and compared against TIME recruitment, follow-up and email interaction data. RESULTS: The TIME website registered 31,695 individuals, 21,116 of whom were randomised. Recruitment cost per randomised participant varied by strategy: £17.40 by GP practice, £3.08 by UK Biobank and £58.82 for GoShare. Twelve-month follow-up retention rates were 96%. A total of 1089 participants have withdrawn from their assigned time of dosing, 2% of whom have declined follow-up by record linkage or further contact. When the TIME data are compared with similar study data, study recruitment is very successful. However, TIME suffers difficulties with participant follow-up and withdrawal rates similar to those of conventional studies. CONCLUSIONS: The TIME study has been successful in recruitment. Follow-up, retention rates and withdrawal rates are all acceptable, but ongoing work is required to ensure participants remain engaged with the study. Various recruitment strategies are necessary, and all viable options should be encouraged to maintain participant engagement throughout the life of studies using IT.

Electronic case report forms and electronic data capture within clinical trials and pharmacoepidemiology.

AIMS: Researchers in clinical and pharmacoepidemiology fields have adopted information technology (IT) and electronic data capture, but these remain underused despite the benefits. This review discusses electronic case report forms and electronic data capture, specifically within pharmacoepidemiology and clinical research. METHODS: The review used PubMed and the Institute of Electrical and Electronic Engineers library. Search terms used were agreed by the authors and documented. PubMed is medical and health based, whereas Institute of Electrical and Electronic Engineers is technology based. The review focuses on electronic case report forms and electronic data capture, but briefly considers other relevant topics; consent, ethics and security. RESULTS: There were 1126 papers found using the search terms. Manual filtering and reviewing of abstracts further condensed this number to 136 relevant manuscripts. The papers were further categorized: 17 contained study data; 40 observational data; 27 anecdotal data; 47 covering methodology or design of systems; one case study; one literature review; two feasibility studies; and one cost analysis. CONCLUSION: Electronic case report forms, electronic data capture and IT in general are viewed with enthusiasm and are seen as a cost-effective means of improving research efficiency, educating participants and improving trial recruitment, provided concerns about how data will be protected from misuse can be addressed. Clear operational guidelines and best practises are key for healthcare providers, and researchers adopting IT, and further work is needed on improving integration of new technologies with current systems. A robust method of evaluation for technical innovation is required.

Persistence, adherence and outcomes with antiplatelet regimens following cerebral infarction in the Tayside Stroke Cohort.

BACKGROUND: Co-prescribed aspirin and dipyridamole are more effective than aspirin alone following cerebral infarction; however, patients may struggle with this more complex regimen. The objectives of this study were: (1) to describe postdischarge prescribing of antiplatelet regimens, (2) to measure patient persistence with different antiplatelet regimens, and (3) to measure whether persistence impacts on outcomes. METHODS: We used record linkage of the Tayside Stroke Cohort with community dispensed prescribing data from 1994 to 2005. All patients had suffered a radiologically confirmed cerebral infarction and were excluded if they had previously used or had other indications for antiplatelet agents. We measured persistence to initial and any antiplatelet regimen using survival analysis. To assess the impact of therapy we used survival analysis to follow up until the APTC endpoint of serious vascular event (myocardial infarction, stroke or vascular death) or censored. Antiplatelet regimen was entered as a time-dependent covariate in a Cox model that also adjusted for age, sex, history of diabetes and baseline use of nitrates and statins. RESULTS: The study cohort contained 1,407 stroke patients (mean age 70.3 years, 46.8% male), with a total follow-up of 4,243 patient-years. Patients initiated on aspirin with dipyridamole had a worse persistence to their initial regimen compared with those initiated on aspirin alone (hazard ratio for non-persistence 1.62; 95% CI 1.37-1.92), but better persistence with any antiplatelet medication long term (hazard ratio 0.86; 95% CI 0.73-1.02). Compared to aspirin monotherapy, receiving no antiplatelet therapy was associated with significantly worse patient outcomes (hazard ratio 1.50; 95% CI 1.21-1.87), whilst receiving prescribed aspirin with dipyridamole was associated with better outcomes (hazard ratio 0.75; 95% CI 0.56-0.99). Only a few patients received clopidogrel or other antiplatelet regimens. CONCLUSIONS: Patients discharged on dual therapy have worse adherence to their initial regimen but better persistence to any antiplatelet agents in the long term. Continued exposure to antiplatelet regimens predicts good outcomes in patients with cerebral infarction.

Prescribing antiplatelet medicine and subsequent events after intracerebral hemorrhage.

BACKGROUND AND PURPOSE: Antiplatelet medicines are commonly perceived as contraindicated after intracerebral hemorrhage (ICH). Many ICH patients have or will have indications for antiplatelet therapy. This observational study describes the level of antiplatelet prescribing and rate of subsequent events after ICH in Tayside, Scotland. METHODS: This study used record-linkage of an existing stroke cohort with antiplatelet prescribing data from 1994 to 2005. Patients were followed-up from discharge after index event. The primary outcome was recurrent ICH. Other outcomes were subsequent ischemic stroke and a composite of ischemic stroke or myocardial infarction. Event rates were calculated as the number of events divided by patient-years of exposure. Univariate hazard ratios associated with antiplatelet exposure were derived from a Cox model using a time-dependent covariate. RESULTS: There were 417 ICH patients who survived to discharge. Of these, 120 patients were prescribed subsequent antiplatelet medicines (28.8%). The median time from discharge to antiplatelet use was 14.8 months (range, 2 days-7.5 years). Among all survivors, there were 14 recurrent ICH (rate, 9.7 per 1000 patient-years; 95% confidence interval [CI], 5.3-16.4), 29 subsequent ischemic strokes (rate, 20.6; 95% CI, 13.8-29.6), and 40 subsequent ischemic strokes or myocardial infarctions (rate, 28.7; 95% CI, 20.5-39.0). Hazard ratios associated with antiplatelet exposure were 1.07 (95% CI, 0.24-4.84) for recurrent ICH, 0.23 (95% CI, 0.03-1.68) for ischemic stroke, and 0.72 (95% CI, 0.25-2.02) for ischemic strokes or myocardial infarction. CONCLUSIONS: Antiplatelet prescribing was common after ICH. Subsequent ischemic strokes or myocardial infarctions were more common than recurrent ICH. Antiplatelet prescribing did not appear to have a clinically significant impact on outcomes measured. Despite being contraindicated, antiplatelet use was not a major hazard for recurrent ICH.

Automated data capture from free-text radiology reports to enhance accuracy of hospital inpatient stroke codes.

PURPOSE: Much potentially useful clinical information for pharmacoepidemiological research is contained in unstructured free-text documents and is not readily available for analysis. Routine health data such as Scottish Morbidity Records (SMR01) frequently use generic 'stroke' codes. Free-text Computerised Radiology Information System (CRIS) reports have potential to provide this missing detail. We aimed to increase the number of stroke-type-specific diagnoses by augmenting SMR01 with data derived from CRIS reports and to assess the accuracy of this methodology. METHODS: SMR01 codes describing first-ever-stroke admissions in Tayside, Scotland from 1994 to 2005 were linked to CRIS CT-brain scan reports occurring with 14 days of admission. Software was developed to parse the text and elicit details of stroke type using keyword matching. An algorithm was iteratively developed to differentiate intracerebral haemorrhage (ICH) from ischaemic stroke (IS) against a training set of reports with pathophysiologically precise SMR01 codes. This algorithm was then applied to CRIS reports associated with generic SMR01 codes. To establish the accuracy of the algorithm a sample of 150 ICH and 150 IS reports were independently classified by a stroke physician. RESULTS: There were 8419 SMR01 coded first-ever strokes. The proportion of patients with pathophysiologically clear diagnoses doubled from 2745 (32.6%) to 5614 (66.7%). The positive predictive value was 94.7% (95%CI 89.8-97.3) for IS and 76.7% (95%CI 69.3-82.7) for haemorrhagic stroke. CONCLUSIONS: A free-text processing approach was acceptably accurate at identifying IS, but not ICH. This approach could be adapted to other studies where radiology reports may be informative.

The Tayside Stroke Cohort: exploiting advanced regional medical informatics to create a region-wide database for studying the pharmacoepidemiology of stroke.

PURPOSE: Observational studies can provide valuable information where data from randomised controlled trials is lacking. We aimed to generate a region-wide longitudinal register of stroke patients using record-linkage of existing clinical and research datasets. METHODS: The population were residents of Tayside, Scotland from 1994-2005. Stroke cases were identified from hospital inpatient admission records, death certificates and prescribing data. These were augmented with data derived from free-text CT-brain scan reports. Strokes were classified as intracerebral haemorrhage (ICH), subarachnoid haemorrhage (SAH) or ischaemic stroke (IS). The methodology was validated by audit of patient case-records. The incidence was calculated using direct standardisation to the standard European population for ages 45-84. Twenty-eight day case-fatality rates were calculated as percentages. RESULTS: There were 12 620 all-cause incident strokes (ICH 1057; SAH 511; IS 6257; undetermined 4795). Standardised incidences per 100 000 by subtypes of stroke were: ICH 35 (95%CI 33-38), SAH 19 (17-22) and IS 210 (205-217). The 28-day case-fatality rates were: ICH 49% (95%CI 46-52), SAH 38% (34-43) and IS 19% (18-20). Comparisons with previous studies were favourable for ICH and SAH. For IS the incidence was lower and fatality rate higher than elsewhere. Three hundred and three sets of patient case records were audited. The positive predictive value (PPV) for identifying cases of stroke was 94.7% (95%CI 91.6-96.7). CONCLUSIONS: The case ascertainment in the TSC compares favourably to established stroke cohorts. This cost effective resource can now be linked with multiple other clinical and research datasets in Tayside to further understanding of stroke and its treatment.

Drugs dispensed in primary care during pregnancy: a record-linkage analysis in Tayside, Scotland.

BACKGROUND: For many regularly used drugs, evidence for safe use in pregnancy has not been established. Despite this, international studies have identified high levels of drug prescribing among pregnant women. OBJECTIVE: To investigate the patterns of prescribing of drugs to women who gave birth in Tayside, Scotland, in 2007. METHODS: Scottish maternity records were linked to dispensed prescribing data for all women who gave birth in Tayside in 2007. Drugs prescribed were coded according to the US FDA classification for risks of drugs in pregnancy. Patterns of prescribing were investigated during the 3 trimesters of pregnancy and the 3 months prior to conception. RESULTS: Prescribing in pregnancy was common, with 21 093 prescriptions dispensed to 3356 (85.2%) of the 3937 women. The most frequently prescribed drugs were antacids, antibacterials, oral iron, folic acid preparations and analgesics. Category A drugs (positive evidence of safety in pregnancy) and Category B drugs (some evidence of safety in pregnancy) accounted for 19.6% and 26.9% of all prescriptions dispensed, respectively. Prescribing of Category X drugs (evidence of risk to the fetus; use contraindicated in women who are or may become pregnant) during pregnancy was rare, with 112 prescriptions dispensed to 68 women (1.7%). Most of these were oral contraceptives or sex hormones. Prescribing of Category X drugs fell markedly during the first trimester and remained very low thereafter. Category D drugs (evidence of risk to the fetus but benefits of therapy may outweigh the potential risk) [432] were dispensed to 166 women (4.2%) during pregnancy. The most commonly prescribed Category D drugs were anxiolytics, nicotine replacement therapy and antiepileptic drugs. The frequency of prescribing of Category D drugs reduced in the third trimester. Prescribing of Category C drugs (insufficient evidence to know whether they are harmful) was common. Thirty percent of women received a total of 3641 Category C prescriptions, which accounted for 17.3% of all prescriptions issued during pregnancy. Prescribing of Category C drugs showed only a very modest decline during pregnancy. No FDA code was available for 4035 prescriptions issued (87 different items), the majority of which were for antacids and preparations for indigestion. More than 40% of women received such medications. CONCLUSIONS: Prescribing of drugs during pregnancy was very common, but the levels of prescribing of drugs that are known to be harmful were low. Much of the prescribing was for drugs related to the pregnancy. While this study provides some evidence that primary-care prescribers in Tayside are prescribing potentially harmful drugs appropriately and with caution during pregnancy, safety data during pregnancy are unavailable for many drugs that are commonly prescribed.