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AIMS: We profile the lack of specific regulation for direct-to-patient postal supply (DTP) of clinical trial medications (investigational medicinal products, IMPs) calling for increased efficiency of patient-centred multi-country remote clinical trials. METHODS: Questionnaires emailed to 28 European Economic Area (EEA) Medical Product Licensing Authorities (MPLAs) and Swissmedic MPLA were analysed in 2019/2020. The questionnaire asked whether DTP of IMPs was legal, followed by comparative legal analysis profiling relevant national civil and criminal liability provisions in 30 European jurisdictions (including The Netherlands), finally summarising accessible COVID-19-related guidance in searches of 30 official MPLA websites in January 2021. RESULTS: Twenty MPLAs responded. Twelve consented to response publication in 2021. DTP was not widely authorised, though different phrases were used to explain this. Our legal review of national laws in 29 EEA jurisdictions and Switzerland did not identify any specific sanctions for DTP of IMPs; however, we identified potential national civil and criminal liability provisions. Switzerland provides legal clarity where DTP of IMPs is conditionally legal. MPLA webpage searches for COVID-19 guidance noted conditional acceptance by 19 MPLAs. CONCLUSIONS: Specific national legislation authorising DTP of IMPs, defining IMP categories, and conditions permitting the postage and delivery by courier in an EEA-wide clinical trial, would support innovative patient-centred research for multi-country remote clinical trials. Despite it appearing more acceptable to do this between EU Member States, provided each EU MPLA and ethics board authorises it, temporary Covid-19 restrictions in national Good Clinical Practice (GCP) guidance discourages innovative research into the safety and effectiveness of clinical trial medications.

This study investigates factors associated with active participation, and long-term commitment, to home blood pressure monitoring (HBPM) in the TIME study, a remote clinical trial assessing the effectiveness of morning vs. evening dosing of antihypertensive medications on cardiovascular outcomes in adults with hypertension. Participants reporting HBPM ownership were invited to submit blood pressure (BP) measurements three-monthly. Factors associated with active participation (submitting at least one set of BP measurements), and longer-term commitment (at least six sets of BP measurements), were analysed using multivariable logistic regression. 11,059 participants agreed to provide BP measurements, of whom 7646 submitted. Active participation was associated with age (adjusted odds ratio (AOR) per decade, 1.29; 95% CI 1.23–1.36), positive family history of hypertension (AOR 1.11; 95% CI 1.01–1.21), number of antihypertensive medications (AOR, 1.10; 95% CI 1.04–1.16), and lower deprivation (AOR per decile, 1.03; 95% CI 1.01–1.05). People with higher body mass index (BMI) and smokers were less likely to participate (AOR, 0.91 (per increase of 5.0 kg/m2) and 0.63 respectively; all p 2, 0.89; 95% CI 0.85–0.93), smoking (AOR 0.60, 95% CI 0.44–0.82) and higher baseline systolic blood pressure (AOR per mmHg, 0.99; 95% CI 0.98–0.99) were negatively associated. This study provides insight into factors that influence HBPM use.

Allopurinol is a urate-lowering therapy used to treat patients with gout. Previous studies have shown that allopurinol has positive effects on several cardiovascular parameters. The ALL-HEART study aimed to determine whether allopurinol therapy improves major cardiovascular outcomes in patients with ischaemic heart disease.ALL-HEART was a multicentre, prospective, randomised, open-label, blinded-endpoint trial done in 18 regional centres in England and Scotland, with patients recruited from 424 primary care practices. Eligible patients were aged 60 years or older, with ischaemic heart disease but no history of gout. Participants were randomly assigned (1:1), using a central web-based randomisation system accessed via a web-based application or an interactive voice response system, to receive oral allopurinol up-titrated to a dose of 600 mg daily (300 mg daily in participants with moderate renal impairment at baseline) or to continue usual care. The primary outcome was the composite cardiovascular endpoint of non-fatal myocardial infarction, non-fatal stroke, or cardiovascular death. The hazard ratio (allopurinol vs usual care) in a Cox proportional hazards model was assessed for superiority in a modified intention-to-treat analysis (excluding randomly assigned patients later found to have met one of the exclusion criteria). The safety analysis population included all patients in the modified intention-to-treat usual care group and those who took at least one dose of randomised medication in the allopurinol group. This study is registered with the EU Clinical Trials Register, EudraCT 2013-003559-39, and ISRCTN, ISRCTN32017426.Between Feb 7, 2014, and Oct 2, 2017, 5937 participants were enrolled and then randomly assigned to receive allopurinol or usual care. After exclusion of 216 patients after randomisation, 5721 participants (mean age 72·0 years [SD 6·8], 4321 [75·5%] males, and 5676 [99·2%] white) were included in the modified intention-to-treat population, with 2853 in the allopurinol group and 2868 in the usual care group. Mean follow-up time in the study was 4·8 years (1·5). There was no evidence of a difference between the randomised treatment groups in the rates of the primary endpoint. 314 (11·0%) participants in the allopurinol group (2·47 events per 100 patient-years) and 325 (11·3%) in the usual care group (2·37 events per 100 patient-years) had a primary endpoint (hazard ratio [HR] 1·04 [95% CI 0·89-1·21], p=0·65). 288 (10·1%) participants in the allopurinol group and 303 (10·6%) participants in the usual care group died from any cause (HR 1·02 [95% CI 0·87-1·20], p=0·77).In this large, randomised clinical trial in patients aged 60 years or older with ischaemic heart disease but no history of gout, there was no difference in the primary outcome of non-fatal myocardial infarction, non-fatal stroke, or cardiovascular death between participants randomised to allopurinol therapy and those randomised to usual care.UK National Institute for Health and Care Research.

Various home blood pressure monitors (HBPMs) are available to the public for purchase but only some are validated against standardised protocols. This study aimed to assess whether HBPMs owned by participants taking part in a clinical trial were validated models. The TIME study is a decentralised randomised trial investigating the effect of antihypertensive medication dosing time on cardiovascular outcomes in adults with hypertension. No HBPMs were provided to participants in this trial but patients were asked to report if they already owned one. We identified the model of HBPM reported by participants, then cross-referenced this against lists of validated HBPMs produced by dabl Educational Trust and the British and Irish Hypertension Society (BIHS). Of 21,104 participants, 10,464 (49.6%) reported their model of HBPM. 7464 (71.3%) of these participants owned a monitor that could be identified from the participants’ entry. Of these, 6066 (81.3%) participants owned a monitor listed as validated by either dabl (n = 5903) or BIHS (n = 5491). Some were listed as validated by both. 1398 (18.7%) participants owned an identifiable HBPM that lacked clear evidence of validation. 6963 (93.3%) participants owned an upper arm HBPM and 501 (6.7%) owned a wrist HBPM. Validated HBPMs had a higher median online retail price of £45.00 compared to £20.00 for HBPMs lacking clear evidence of validation. A significant number of participants own HBPMs lacking evidence of validation.

AIMS The aim of this study was to investigate the initial cardiovascular prescription patterns in patients after their first cardiovascular events, and to identify factors associated with cardiovascular polypharmacy. METHODS This was a cross-sectional study including patients aged ≥ 45 years with the first record of coronary heart disease (CHD) or stroke between 2007 and 2016 using The Health Improvement Network database. This study investigated the patterns of cardiovascular drugs prescribed during the first 90 days after the first cardiovascular events. Logistic regression was used to examine the association between patients' baseline characteristics and cardiovascular polypharmacy (≥5 cardiovascular drugs). RESULTS A total of 121,600 (59,843 CHD and 61,757 stroke) patients were included in the study. The mean age was 69.5 ± 11.9 years. The proportion of patients who were prescribed 0-1, 2-3, 4-5 drugs and ≥6 drugs were 11.0%, 29.8%, 38.6% and 20.5%, respectively. Factors associated with cardiovascular polypharmacy were sex (female: OR 0.74, 95% CI 0.72-0.76 vs male), age (75-84 years old: OR 0.50, 0.47-0.53 vs 45-54 years old), smoking status (current smoking: OR 1.29, 1.15-1.24 vs never), body mass index (obesity: OR 1.38, 1.34-1.43 vs normal), deprivation status (most deprived: OR 1.09, 1.04-1.14 vs least deprived) and Charlson comorbidity index (index ≥5: OR 1.25, 1.16-1.35 vs index 0). CONCLUSION Multiple cardiovascular drugs treatment was common in patients with CVD in the UK. High-risk factors of CVD were also associated with cardiovascular polypharmacy. Further studies are warranted to assess the impact of cardiovascular polypharmacy and its interaction on CVD recurrence and mortality.

The COVID-19 pandemic significantly impacted the conduct of clinical trials through delay, interruption or cancellation. Decentralised methods in clinical trials could help to continue trials during a pandemic. This paper presents the results of an exploratory study conducted early in the pandemic to gain insight into and describe the experiences of organisations involved in clinical trials, with regard to the impact of COVID-19 on the conduct of trials, and the adoption of decentralised methods prior to, and as mitigation for the impact, of COVID-19.A survey with 11 open-ended and four multiple choice questions was conducted in June 2020 among member organisations of the public-private "Trials@Home" consortium. The survey investigated (1) the impact and challenges of COVID-19 on the continuation of ongoing clinical trials, (2) the adoption of decentralised methods in clinical trials prior to and as a mitigation strategy for COVID-19, (3) the challenges of conducting clinical trials during COVID-19, (4) the expected permanency of COVID-19-driven changes to the adoption of decentralised methods in clinical trials, and (5) lessons learned from conducting clinical trials during the COVID-19 pandemic. A thematic, inductive analysis of open survey questions was performed, complemented with descriptive statistics (frequencies and distributions).The survey had a response rate of 81%. All organisations included in the analysis (n = 18) implemented (some) decentralised methods in their clinical trials prior to COVID-19, and 15 (83%) implemented decentralised methods as mitigation for COVID-19. Decentralised methods for IMP supply, patient-health care provider interaction and communication, clinic visits and source document verification were used more often as mitigation strategies than they were used prior to COVID-19. Many respondents expect to maintain those decentralised methods they implemented during COVID-19 in ongoing trials, as well as implement them in future trials.Decentralised methods are a widely implemented mitigation strategy for trial conduct in the face of the COVID-19 pandemic. The results of this survey show that there is an interest to continue the use of decentralised methods in future trials, but important points of attention have been identified that need solutions to help guide the transition from the traditional trial model to a more decentralised trial model.

BackgroundObtaining 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.MethodsPatients 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 hospitalization and death data in the NHS will be used to compare cardiovascular event rates between the two policies.ResultsThis 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.ConclusionThe 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 numberISRCTN 46635087; registered pre-results, 11/08/2017.SummaryWe report on a Chief Scientist Office for Scotland-funded pilot of the feasibility of the (Evaluating Diuretics in Usual Care) EVIDENCE study. This report will describe:Recruitment and policy randomisation of 30 GP practices across 5 NHS health board regions in Scotland.Acceptability of study implementation information provided to primary healthcare practitioners and patients.Recruitment rates, staffing, training, and funding requirement estimations to inform the full-sized project.How knowledge and practical experience gained has informed scaling of activities to realise a fully powered EVIDENCE study, including 250 practices.Key messages regarding feasibilityWhat uncertainties existed regarding the feasibility?For widely prescribed medicines with similar mode of action and similar indications differences in effectiveness are likely to be quite small indicating the need for very large study sizes. Previous work has demonstrated that practices would be reluctant to take part in this kind of study if it involved any extra work within already limited practice capacity. Would NHS Primary Care leads be willing to endorse the study taking place in their region? In addition, the large size and geographically distributed nature of this study meant devising solutions for work to take place remotely or using pre-existing regional staff needed to be devised. There was also uncertainty about the overall acceptability for patients in having their medication changed for research purposes.What are the key feasibility findings?The experience from the pilot and subsequent successful expanded recruitment shows that the solutions we developed seemed to be acceptable and achievable both for general practice staff and the patients they care for. Obtaining endorsement from key stakeholders in NHS health boards improved recruitment success with the practices and sustained support for the study. Negotiations with pharmacy regional leads around workforce implications enabled us to approach practices with a range of solutions for study implementation. It was found that offering training for the EVIDENCE study along with general clinical trials training for regional Pharmacists was key to recruitment of pharmacy delegates on a large scale. We were able to develop the IT infrastructure around the study to allow remote delivery of both training and implementation providing a framework that could be delivered during the covid-19 pandemic. We found that concerns from patients constituted a very small minority indeed indicating overwhelming tacit support for the objectives of the studyWhat are the implications of the feasibility findings for the design of the main study?The initial engagement with a range of healthcare providers offered support for the study in areas that may otherwise have become a potential barrier to success. We will use this approach in the main study. Many of the practical skills required to undertake the EVIDENCE study were also useful skills for pharmacy teams in their everyday practice so acceptance of the study training and implementation was higher. We will continue to progress the study using this methodology as this provided beneficial professional development for pharmacy staff and a platform for a future research ready workforce. Demonstrating the success of this approach we have currently recruited over 100 practices and have 29 pharmacy delegates across Scotland outside the core study team. This indicates that recruiting the target of 250 practices (approximately 50,000 individuals is entirely feasible.

IntroductionHealthcare 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 AnalysisThe 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 2 years. The primary analysis will test for equivalence with a 30% margin in a per-protocol cohort.Ethics and DisseminationEVIDENCE has been approved by the East of Scotland Research Ethics Service (17/ES/0016, current approved protocol version 4, 28th September 2019). The results will be disseminated widely in peer review journals, guideline committees, National Health Service (NHS) organisations and patient groups.Trial registration numberISRCTN 46635087; registered pre-results, 11/08/2017.Strengths and limitations of this study designA cluster randomisation design maximises generalisability of results to UK NHS primary care.Study interventions with minimal impact on existing NHS workflows should encourage recruitment.Development of electronic study search tools and routinely collected data facilitates participation by remote and rural practices.One-off policy interventions may have a limited long-term effect on prescribing behaviour.

BACKGROUND: Hydroxyzine is indicated for the management of anxiety, skin and sleep disorders. In 2015, the European Medicines Agency (EMA) concluded that hydroxyzine was pro-arrhythmogenic and changes to the product information were implemented in Europe. This study aimed to evaluate their impact in Denmark, Scotland, England and the Netherlands.METHOD: Quarterly time series analyses measuring hydroxyzine initiation, discontinuation, and switching to other antihistamines, benzodiazepines and antidepressants in Denmark, England, Scotland and the Netherlands from 2009 to 2018. Data were analysed using interrupted time series regression.RESULTS: Hydroxyzine initiation in quarter one 2010 in Denmark, Scotland, England and the Netherlands per 100 000 was: 23.5, 91.5, 35.9 and 34.4 respectively. Regulatory action was associated with a significant: immediate fall in hydroxyzine initiation per 100 000 in England (-12.05, 95%CI -18.47 to -5.63) and Scotland (-19.01, 95%CI -26.99 to -11.02); change to a negative trend in hydroxyzine initiation per 100 000/quarter in England (-1.72, 95%CI -2.69 to -0.75) and Scotland (-2.38, 95%CI -3.32 to -1.44). Regulatory action was associated with a significant: immediate rise in hydroxyzine discontinuation per 100 000 in England (3850, 95%CI 440-7240). No consistent changes were observed in the Netherlands or Denmark. Regulatory action was associated with no switching to other antihistamines, benzodiazepines or antidepressants following hydroxyzine discontinuation in any country.CONCLUSION: The 2015 EMA regulatory action was associated with heterogeneous impact with reductions in hydroxyzine initiation varying by country. There was limited impact on discontinuation with no strong evidence suggesting unintended consequences of major switching to other antihistamines, benzodiazepines or antidepressants.

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.

ObjectiveEffervescent, soluble, dispersible formulations contain considerable amounts of sodium. In 2013, we previously confirmed the association between sodium-containing medications and cardiovascular risks. This study aimed to determine the changes in the prescribing pattern in clinical practice following this publication.DesignA longitudinal cross-sectional study.SettingPrimary care in the UK from 2009 to 2018.ParticipantsPrescribing information in The Health Improvement Network (THIN) and Prescription Cost Analysis (PCA) databases in the UK.Outcome measurementsPrescription rates per 10 000 inhabitants were calculated using the number of prescriptions or the number of drug-using patients over the total number of inhabitants, and the prescription rates were measured at annual intervals. Prescribing trends from 2009 to 2018 were indexed with yearly data from THIN and PCA. Interrupted time series analysis (ITSA) was conducted with monthly data in THIN.ResultsFrom the THIN database, a total of 3 651 419 prescription records from 446 233 patients were included. The prescribing rate of sodium-containing medications changed from 848.3/10 000 inhabitants in 2009 to 571.6/10 000 inhabitants in 2018. The corresponding figures from PCA data were of 631.0/10 000 inhabitants in 2009 and 423.8/10 000 inhabitants in 2018. ITSA showed the prescribing trend reduced significantly during the postpublication period (prescribing rate: slope change=−0.26; 95% CI −0.45 to –0.07; p=0.009; proportion of patients: slope change=−0.22; 95% CI −0.35 to –0.09; pConclusionsThe prescribing of sodium-containing medications in the UK primary care has declined significantly during the postpublication period. Changes in the prescribing trends for sodium-containing medications varied across regions of the UK and patient age groups.

AIMS The aim of the study was to identify actionable learning points from stakeholders in remote decentralised clinical trials (RDCTs) to inform their future design and conduct. METHODS Semistructured interviews were carried out with a purposive sample of stakeholders, including senior managers, trial managers, technology experts, principal investigators, clinical investigators, research scientists, research nurses, vendors, patient representatives and project assistants. The interview data were coded using a thematic approach, identifying similarities, differences and clustering to generate descriptive themes. Further refinement of themes was guided by empirical phenomenology, grounding explanation in the meanings that interviewees gave to their experiences. RESULTS Forty-eight stakeholders were interviewed. Actionable learning points were generated from the thematic analysis. Patient involvement and participant engagement were seen as critical to the success of RDCTs where in-person contact is minimal or nonexistent. Involving patients in identifying the research question, creating recruitment materials, apps and websites, and providing ongoing feedback to trial participants were regarded as facilitating recruitment and engagement. Building strong relationships early with trial partners was thought to support RDCT conduct. Multiple modes of capturing information, including patient-reported outcomes (PROs) and routinely collected data, were felt to contribute to data completeness. However, RDCTs may transfer trial activity burden onto participants and remote-working research staff, therefore additional support may be needed. CONCLUSION RDCTs will continue to face challenges in implementing novel technologies. However, maximising patient and partner involvement, reducing participant and staff burden, and simplifying how participants and staff interact with the RDCT may facilitate their implementation.

Background:\ud Febuxostat and allopurinol are urate-lowering therapies used to treat patients with gout. Following concerns about the cardiovascular safety of febuxostat, the European Medicines Agency recommended a post-licensing study assessing the cardiovascular safety of febuxostat compared with allopurinol.\ud \ud Methods:\ud We did a prospective, randomised, open-label, blinded-endpoint, non-inferiority trial of febuxostat versus allopurinol in patients with gout in the UK, Denmark, and Sweden. Eligible patients were 60 years or older, already receiving allopurinol, and had at least one additional cardiovascular risk factor. Those who had myocardial infarction or stroke in the previous 6 months or who had severe congestive heart failure or severe renal impairment were excluded. After a lead-in phase in which allopurinol dose was optimised towards achieving a serum urate concentration of less than 0·357 mmol/L (

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.

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.

For most chronic medical conditions, multiple medications are available and prescribers often have limited evidence about which therapy is likely to be the most effective and safe for an individual patient. As many patients are exposed every day to medicines that may be less effective than available alternatives, this is of public health importance. Cluster randomised trials of prescribing policy offer an opportunity to rapidly obtain evidence of comparative effectiveness and safety. These trials can pose a low risk to patients and cause minimal disruption to usual care. Despite the potential scientific value of this approach, there remain valid concerns about consent, medication switching and the use of routinely collected data in research. We discuss these concerns with reference to an ongoing pilot study (Evaluating Diuretics in Normal Care (EVIDENCE) - a cluster randomised evaluation of hypertension prescribing policy, ISRCTN 46635087, registered 11 August 2017).

This commentary refers to ‘Bedtime hypertension treatment improves cardiovascular risk reduction: the Hygia Chronotherapy Trial’, by R.C. Hermida et al., doi:10.1093/eurheartj/ehz754.

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.

Non-steroidal anti-inflammatory drugs are associated with a dose and duration-dependent coronary risk. There is little information concerning analgesic-dose ibuprofen, among the most widely used drugs worldwide.Our objective was to measure the risks of acute coronary syndrome (ACS) after dispensing of ibuprofen, versus paracetamol.Propensity score 1:2-matched cohorts of ibuprofen or paracetamol treatment episodes (TEs) in Echantillon Généraliste de Bénéficiaires (EGB), the 1/97 sample of Système National des Données de Santé (SNDS), the French nationwide claims database, from 2009 to 2014, were compared. Outcomes were hospital admissions for ACS during the 3 months after the dispensing of ibuprofen or paracetamol. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated overall and stratified on low-dose aspirin dispensing.A total of 315,269 ibuprofen TEs in 168,400 persons were matched to 630,457 paracetamol TEs in 395,952 patients. Event rates were 50-100 times higher in low-dose aspirin users (27 vs 0.28 per 1000 patient years). Overall there was no difference in risk of ACS at 3 months (HR 0.94, 95% CI 0.74-1.20) despite a transient increase in the first 2 weeks in ibuprofen users (HR 1.70, 95% CI 1.11-2.59). In the stratified analysis, this short-term risk was only found in aspirin users (5% of population, HR 1.84, 95% CI 1.24-3.24), but not in non-aspirin users (HR 1.09, 95% CI 0.40-2.94).There was no evidence for an increased risk of ACS in patients dispensed ibuprofen compared to paracetamol.

Aims To investigate whether acid-suppression medicines (ASMs) increase the risk of bacterial gastroenteritis. Methods A population-based, propensity-score matched cohort study using a record-linkage database in Tayside, UK. The study consisted of 188 323 exposed to ASMs (proton-pump inhibitors and histamine-2 receptor antagonists) and 376 646 controls (a propensity-score matched cohort from the rest of population who were not exposed to ASMs) between 1999 and 2013. The main outcome measure was a positive stool test for Clostridium difficile, Campylobacter, Salmonella, Shigella or Escherichia coli O157. The association between ASMs and risk of bacterial gastroenteritis was assessed by a Cox regression model. Results There were 22 705 positive test results (15 273 C. difficile [toxin positive], 6590 Campylobacter, 852 Salmonella, 129 Shigella and 193 E. coli O157, not mutually exclusive) with a total of 5 729 743 person-years follow up time in Tayside, 1999–2013. The adjusted hazard ratios for culture positive diarrhoea for the proton-pump inhibitors and histamine-2 receptor antagonists exposed vs. unexposed cohort were 2.72 (95% confidence interval [CI] 2.33, 3.17) during follow–up time for samples submitted from the community and 1.28 (95% CI 1.08, 1.52) for samples submitted from hospitals. Compared with the unexposed cohort, patients in the exposed group had increased risks of C. difficile and Campylobacter [adjusted hazard ratios of 1.70 (95% CI 1.28, 2.25), 3.71 (95% CI 3.04, 4.53) for community samples, and 1.42 (95% CI 1.17, 1.71), 4.53 (95% CI 1.75, 11.8) for hospital samples, respectively]. Conclusions The results suggest that community prescribed ASMs were associated with increased rates of C. difficile and Campylobacter positive gastroenteritis in both the community and hospital settings.

Aims Spironolactone is widely used to treat heart failure, hypertension and liver disease with increased usage in recent years. Spironolactone has endocrine effects that could influence cancer risks and historical reports suggest possible links with increased risk of certain types of cancer. The aim of this study was to assess the effect of spironolactone exposure on cancer incidence. Methods A pharmacoepidemiological propensity score-matched cohort study was performed to assess the effect of spironolactone exposure on cancer incidence. Cox proportional hazards models were used to analyse time to first diagnosis of each prespecified cancer and hazard ratios for spironolactone exposure are presented. The setting for the study was UK primary care using the Clinical Practice Research Datalink. The participants were 74 272 patients exposed to spironolactone between 1986 and 2013, matched 1:2 with unexposed controls. The prespecified primary outcomes were the first incidence of ovarian, endometrial, pancreatic, colorectal, prostate, renal cell, pharyngeal and thyroid cancers, and myelomonoblastic/-cytic leukaemias. Secondary outcomes were the remaining 27 types of cancer. Results There was no evidence of an increased risk of any cancer associated with spironolactone use. Spironolactone use was associated with a significantly lower risk of prostate cancer (hazard ratio 0.69; 95% confidence interval 0.60–0.80, P

Background Intensive systolic blood pressure ( SBP ) lowering significantly reduced cardiovascular disease ( CVD ) events in SPRINT (Systolic Blood Pressure Intervention Trial) but not in ACCORD BP (Action to Control Cardiovascular Risk in Diabetes Blood Pressure). Methods and Results SPRINT tested the effects of intensive (120 mm Hg) versus standard (140 mm Hg) SBP goals on CVD events and all-cause mortality. Using 2×2 factorial design, ACCORD BP tested the same SBP intervention in addition to an intensive versus standard glycemia intervention. We compared the effects of intensive SBP lowering on the composite CVD end point and all-cause mortality in SPRINT with its effects within each of the glycemia arms in ACCORD BP . Intensive SBP lowering decreased the hazard of the composite CVD end point similarly in SPRINT (hazard ratio: 0.75; 95% confidence interval, 0.64-0.89) and in the ACCORD BP standard glycemia arm (hazard ratio: 0.77; 95% confidence interval, 0.63-0.95; interaction P=0.87). However, the effect of intensive SBP lowering on the composite CVD end point in the ACCORD BP intensive glycemia arm (hazard ratio: 1.04; 95% confidence interval, 0.83-1.29) was significantly different from SPRINT (interaction P=0.023). Patterns were similar for all-cause mortality. Conclusions The effects of intensive SBP control on CVD events and all-cause mortality were similar in patients without diabetes mellitus and in those with diabetes mellitus on standard glycemic control. An interaction between intensive SBP lowering and intensive glycemic control may have masked beneficial effects of intensive SBP lowering in ACCORD BP . Clinical Trial Registration URL : http://www.clinicaltrials.gov . Unique identifiers: NCT 01206062, NCT 00000620.

IntroductionWe will use the existing online mechanisms of the Treatment in Morning versus Evening (TIME) study to collect patient-reported outcome measures of sleep quality to determine whether nocturnal dosing of antihypertensives affects sleep quality, when compared with morning dosing.The TIME study aims to determine if morning or evening dosing of antihypertensive medications is more effective in preventing heart attacks and strokes. The cardiovascular end points in TIME are identified by individual-level linkage to routinely collected hospital admissions and mortality data; these data are supplemented with participant-completed follow-up questionnaires, administered online.This substudy will provide information regarding the relative acceptability of morning and evening dosing of antihypertensives that will be essential should the TIME study results prompt doctors to consider advising particular dosing times to their patients.Methods and analysisTIME participants are aged over 18 years and prescribed at least one antihypertensive drug, taken once a day. They are self-enrolled and consented on the secure TIME website (www.timestudy.co.uk) and then randomised to dosing time. Study follow-up is conducted by automated email. Average participant follow-up is expected to be 4 years. Participants in the sleep substudy are asked to complete an online sleep quality questionnaire at baseline, after 3 months and annually. This includes a Pittsburgh Sleep Quality Index (PSQI), a Hospital Anxiety and Depression Scale and an Epworth Sleepiness Scale. The primary outcome of the TIME Sleep substudy is sleep quality as measured by the PSQI. Secondary outcomes include sleep quantity and duration, and an analysis of any association between sleep quality and the main outcome measures of the TIME study (heart attack, stroke and vascular death).Ethics and disseminationEthical approval has been obtained from the Tayside Committee on Medical Research Ethics (MREC reference: 11/AL/0309), and results will be published in a peer-reviewed journal.Protocol version9 (approved 19 July 2017).Trial registration numberUKCRN ID: 17071. ISRCTN:NCT18157641. Pre-results.

Background The Febuxostat versus Allopurinol Streamlined Trial (FAST) is a prospective, randomised, open-label, blinded endpoint trial comparing the cardiovascular safety of allopurinol and febuxostat in patients with symptomatic hyperuricaemia.1 The trial includes patients aged over 60 years who are taking chronic allopurinol therapy at baseline and have at least one additional cardiovascular risk factor. After uptitration on allopurinol to reach EULAR urate targets, patients are randomised to febuxostat or allopurinol then followed up for events. Patient recruitment to the trial completed in late 2017 and follow-up is ongoing. Objectives To describe the baseline characteristics of the patients randomised into the FAST study. Methods The primary endpoint of the FAST study is the composite of non-fatal myocardial infarction, non-fatal stroke or cardiovascular death. The primary analysis is a non-inferiority analysis with a non-inferiority upper limit for the hazard ratio for the primary outcome of 1.3. Results 6142 patients from UK, Denmark and Sweden have been randomised into the FAST study. The mean age at randomisation was 71.0±6.4 (SD) years. 85.3% of participants are male. 57.3% are former smokers and 7.9% current smokers. Mean systolic blood pressure was 138±18 mmHg and mean diastolic blood pressure 75±12 mmHg. Mean body mass index was 31.1±5.2 kg/m2. 10.7% of participants had a history of previous myocardial infarction, 5.0% a history of previous cerebrovascular accident and 4.8% a history of peripheral arterial disease. 22.5% had a history of diabetes mellitus and 4.6% a history of heart failure. 78.0% had a history of high blood pressure. 33.3% had a history of any cardiovascular disease (defined as history of myocardial infarction, cerebrovascular accident, transient ischaemic attack, acute coronary syndrome, coronary revascularisation, angina pectoris or heart failure). The mean baseline urate at study entry (screening) was 297±47 umol/L. The mean allopurinol dose being taken at study entry (screening) was 225±106 mg daily. 2206 patients (35.9%) had at least one uptitration of allopurinol dose prior to randomisation. Conclusions This ongoing European trial will report on the cardiovascular safety of febuxostat versus allopurinol in patients with symptomatic hyperuricaemia. Reference [1] MacDonald TM, Ford I, Nuki G, Mackenzie IS, et al. Protocol of the Febuxostat versus Allopurinol Streamlined Trial (FAST): a large, prospective, randomised, open, blinded-endpoint study comparing the cardiovascular safety of allopurinol and febuxostat in the management of symptomatic hyperuricaemia. BMJ Open2014;4:e005354. doi:10.1136/bmjopen-2014-005354 Acknowledgements The FAST study is funded by Menarini and sponsored by the University of Dundee. Disclosure of Interest None declared

Background Allopurinol is licensed for the prevention of gout. In recent years, several studies have suggested that allopurinol may have beneficial effects on cardiovascular parameters. The ALL-HEART study is a large outcome trial designed to investigate whether allopurinol improves cardiovascular outcomes in patients with ischaemic heart disease[.1 It is a multicentre, controlled, prospective, randomised, open-label, blinded endpoint trial of allopurinol (up to 600 mg daily) versus no treatment added to usual care in patients aged 60 and over with ischaemic heart disease. Patients are followed up by electronic record-linkage and annual questionnaires. Patient recruitment to the trial started in 2014 and completed in 2017 and follow-up is ongoing. Objectives To describe the baseline characteristics of the patients randomised into the ALL-HEART study. Methods The primary endpoint of the ALL-HEART study is the composite of non-fatal myocardial infarction, non-fatal stroke or cardiovascular death. Secondary outcomes include all-cause mortality, quality of life and cost-effectiveness of allopurinol. The study will end when 631 adjudicated primary outcomes have occurred. Results 5938 patients from the UK have been randomised into the ALL-HEART study. The mean age at randomisation was 72.1±6.8 (SD) years. 75.2% of participants are male. 56.5% are former smokers and 9.4% current smokers. Mean systolic blood pressure was 133±18 mmHg and mean diastolic blood pressure 72±11 mmHg. Mean body mass index was 28.9±5.3 kg/m2. The average duration of ischaemic heart disease was 11.5±7.9 years. 47.4% of participants had a history of previous myocardial infarction, 64.2% a history of angina, 56.4% a history of coronary revascularisation and 69.3% had other evidence of ischaemic heart disease. 57.6% had a history of hypertension. 3.9% had a history of previous cerebrovascular accident, 7.6% of peripheral arterial disease, 21.8% of diabetes mellitus, 8.9% of chronic obstructive pulmonary disease and 5.2% of heart failure. Conclusions This large ongoing trial will determine whether allopurinol improves major cardiovascular outcomes in patients with ischaemic heart disease. Reference [1] Mackenzie IS, Ford I, Walker A, et al. Multicentre, prospective, randomised, open-label, blinded endpoint trial of the efficacy of allopurinol therapy in improving cardiovascular outcomes in patients with ischaemic heart disease: protocol of the ALL-HEART study. BMJ Open2016;6:e13774. doi:10.1136/bmjopen-2016-013774. Acknowledgements This study is funded by the National Institute for Health Research, Health Technology Assessment programme (http://www.nihr.ac.uk) (HTA 11/36/41). The study is sponsored by the University of Dundee and NHS Tayside. The study is supported by the Scottish Primary Care Research Network, Support for Science in Scotland and the NIHR Local Clinical Research Networks. Disclosure of Interest None declared

Exaggerated blood pressure (BP) response to exercise predicts future hypertension. However, there is considerable lack of understanding regarding the mechanism of how this abnormal response is generated, and how it relates to the future establishment of cardiovascular disease. The authors studied 82 healthy male volunteers without cardiovascular risk factors. The participants were categorized into two age-matched groups depending on their exercise systolic BP (ExSBP) rise after 3 minutes of exercise using a submaximal step test: exaggerated ExSBP group (hyper-responders [peak SBP ≥180 mm Hg]) and low ExSBP responder group (hypo-responders [peak SBP

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.

It is widely recognized that excess sodium intake increases the risk of hypertension, and this subsequently increases the risk of cardiovascular disease. Although efforts are being made to reduce sodium intake in the population in general, there are concerns that a considerable sodium load can be ingested via certain effervescent, dispersible, and soluble formulations of medicines.Reducing dietary sodium intake in the general population has resulted in a significant reduction in cardiovascular disease outcomes. However, no previous studies have highlighted the potential risk of cardiovascular disease by taking sodium-containing medicines such as soluble forms of aspirin, paracetamol, ibuprofen, and other common drugs. We recently conducted a nested case-control study in the UK general population using the UK Clinical Practice Research Datalink to study the long-term use of sodium-containing medicines and cardiovascular outcomes. The results showed that compared with standard formulations, patients who took sodium-containing medicines were 16% more likely to develop cardiovascular events (OR = 1.16, 95% CI 1.12 - 1.21). The risks for stroke and hypertension were even higher, (1.22 [1.16 - 1.29] and 7.18 [6.74 - 7.65]), respectively.Sodium-containing formulations should be prescribed with caution only if the perceived benefits outweigh the risks.

Aims To measure the impact of newspaper advertising across Scotland on patient interest, and subsequent recruitment into the Standard Care vs. Celecoxib Outcome Trial (SCOT), a clinical trial investigating the cardiovascular safety of non-steroidal anti-inflammatory drugs in patients with osteoarthritis or rheumatoid arthritis. Methods Newspaper advertisements about the SCOT trial were placed sequentially in regional and national Scottish newspapers. The number of phone calls as a result of exposure to the advertisements and ongoing study recruitment rates were recorded before, during and after the advertising campaign. To enroll in SCOT individuals had to be registered with a participating GP practice. Results The total cost for the advertising campaign was £46 250 and 320 phone calls were received as a result of individuals responding to the newspaper advertisements. One hundred and seventy-two individuals were identified as possibly suitable to be included in the study. However only 36 were registered at participating GP practices, 17 completed a screening visit and 15 finally were randomized into the study. The average cost per respondent individual was £144 and the average cost per randomized patient was £3083. Analysis of recruitment rate trends showed that there was no impact of the newspaper advertising campaign on increasing recruitment into SCOT. Conclusions Advertisements placed in local and national newspapers were not an effective recruitment strategy for the SCOT trial. The advertisements attracted relatively small numbers of respondents, many of whom did not meet study inclusion criteria or were not registered at a participating GP practice.

Introduction Ischaemic heart disease (IHD) is one of the most common causes of death in the UK and treatment of patients with IHD costs the National Health System (NHS) billions of pounds each year. Allopurinol is a xanthine oxidase inhibitor used to prevent gout that also has several positive effects on the cardiovascular system. The ALL-HEART study aims to determine whether allopurinol improves cardiovascular outcomes in patients with IHD. Methods and analysis The ALL-HEART study is a multicentre, controlled, prospective, randomised, open-label blinded end point (PROBE) trial of allopurinol (up to 600 mg daily) versus no treatment in a 1:1 ratio, added to usual care, in 5215 patients aged 60 years and over with IHD. Patients are followed up by electronic record linkage and annual questionnaires for an average of 4 years. The primary outcome is the composite of non-fatal myocardial infarction, non-fatal stroke or cardiovascular death. Secondary outcomes include all-cause mortality, quality of life and cost-effectiveness of allopurinol. The study will end when 631 adjudicated primary outcomes have occurred. The study is powered at 80% to detect a 20% reduction in the primary end point for the intervention. Patient recruitment to the ALL-HEART study started in February 2014. Ethics and dissemination The study received ethical approval from the East of Scotland Research Ethics Service (EoSRES) REC 2 (13/ES/0104). The study is event-driven and results are expected after 2019. Results will be reported in peer-reviewed journals and at scientific meetings. Results will also be disseminated to guideline committees, NHS organisations and patient groups. Trial registration number 32017426, pre-results.

Background— Endothelial vasomotor dysfunction and markers of systemic inflammation are independent determinants of cardiovascular risk. However, the link between clinical inflammation and endothelial dysfunction is unclear. The aim of this study was to use anti–neutrophil cytoplasmic antibody–associated systemic vasculitis (AASV) as a model of systemic inflammation in which to test the hypothesis that inflammation is associated with endothelial dysfunction and can be reversed with anti–tumor necrosis factor-α (TNF-α) therapy. Methods and Results— Fourteen patients with active AASV and 21 age-matched control subjects were studied. Endothelial function was assessed through the use of forearm plethysmography and related to clinical disease activity: Birmingham Vasculitis Activity Score (BVAS) and serum levels of C-reactive protein (CRP), interleukin-6 (IL-6), and TNF-α. The effects of anti–TNF-α therapy (infliximab), either alone (n=6) or in combination with standard treatment (n=4), on endothelial function were subsequently determined. Patients had a mean BVAS of 11±1, and CRP and IL-6 were higher in the AASV group than in control subjects (34.8±10.5 versus 1.6±0.2 pg/mL, P P =0.02). Forearm blood flow response to acetylcholine (ACh) was reduced in the patients compared with control subjects ( P =0.002), but sodium nitroprusside (SNP) responses were not ( P =0.3). The response to ACh improved with infliximab treatment ( P =0.004) in particular, with infliximab alone ( P =0.03). Conclusions— AASV is associated with endothelial dysfunction. Anti–TNF-α therapy, alone or in combination with standard treatment, results in clinical remission, reduced inflammation, and improved endothelium-dependent vasomotor responses.

Background: Trials of investigational medicinal products are required to adhere to strict guidelines with regard to the handling and supply of medication. Information technology offers opportunities to approach clinical trial methodology in new ways. This report summarises a novel pharmacy system designed to supply trial medications directly to patients by post in the Febuxostat versus Allopurinol Streamlined Trial. Method: A bespoke web-based software package was designed to facilitate the direct supply of trial medications to Febuxostat versus Allopurinol Streamlined Trial participants from a pharmacy based in the Medicines Monitoring Unit, University of Dundee. Results: To date, 65,467 packs of medication have been dispensed using the system to 3978 patients. Up to 238 packs per day have been dispensed. Conclusion: The Medicines Monitoring Unit Febuxostat versus Allopurinol Streamlined Trial drug management system is an effective method of administering the complex drug supply requirements of a large-scale clinical trial with advantages over existing arrangements. A low rate of loss to follow-up in the Febuxostat versus Allopurinol Streamlined Trial may be attributable to the drug management system.

Aims To investigate whether acid‐suppression medicines (ASMs) increase the risk of bacterial gastroenteritis. Methods A population‐based, propensity‐score matched cohort study using a record‐linkage database in Tayside, UK. The study consisted of 188 323 exposed to ASMs (proton‐pump inhibitors and histamine‐2 receptor antagonists) and 376 646 controls (a propensity‐score matched cohort from the rest of population who were not exposed to ASMs) between 1999 and 2013. The main outcome measure was a positive stool test for Clostridium difficile , Campylobacter, Salmonella, Shigella or Escherichia coli O157. The association between ASMs and risk of bacterial gastroenteritis was assessed by a Cox regression model. Results There were 22 705 positive test results (15 273 C. difficile [toxin positive], 6590 Campylobacter, 852 Salmonella, 129 Shigella and 193 E. coli O157, not mutually exclusive) with a total of 5 729 743 person‐years follow up time in Tayside, 1999–2013. The adjusted hazard ratios for culture positive diarrhoea for the proton‐pump inhibitors and histamine‐2 receptor antagonists exposed vs. unexposed cohort were 2.72 (95% confidence interval [CI] 2.33, 3.17) during follow–up time for samples submitted from the community and 1.28 (95% CI 1.08, 1.52) for samples submitted from hospitals. Compared with the unexposed cohort, patients in the exposed group had increased risks of C. difficile and Campylobacter [adjusted hazard ratios of 1.70 (95% CI 1.28, 2.25), 3.71 (95% CI 3.04, 4.53) for community samples, and 1.42 (95% CI 1.17, 1.71), 4.53 (95% CI 1.75, 11.8) for hospital samples, respectively]. Conclusions The results suggest that community prescribed ASMs were associated with increased rates of C. difficile and Campylobacter positive gastroenteritis in both the community and hospital settings.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Pioglitazone is mainly used in combination with diet and exercise and other anti-diabetic medications to treat type 2 diabetes mellitus. • Long term use of pioglitazone (>24 months of therapy) may be associated with an increased risk of bladder cancer. WHAT THIS STUDY ADDS • In this study population, pioglitazone does not appear to be significantly associated with an increased risk of bladder cancer in patients with type 2 diabetes. AIM To examine whether exposure to pioglitazone use is associated with increased incidence of bladder cancer in patients with type 2 diabetes mellitus. METHOD A cohort study was done in the General Practice Research Database (GPRD) between 2001 and 2010. Two hundred and seven thousand seven hundred and fourteen patients aged ≥40 years with type 2 diabetes were studied (23 548 exposed to pioglitazone and 184 166 exposed to other antidiabetic medications but not pioglitazone). The association between pioglitazone and risk of bladder cancer was assessed by a Cox regression model. A propensity score matched analysis was done in a group of patients without missing baseline characteristics data. RESULTS Sixty-six and 803 new cases of bladder cancer occurred in the pioglitazone and other group, respectively (rates of 80.2 (95% CI 60.8, 99.5) and 81.8 (95% CI 76.2, 87.5) per 100 000 person-years respectively). Pioglitazone did not increase the risk of bladder cancer significantly compared with the other antidiabetic drugs treatment group, (adjusted hazard ratio (HR), 1.16, 95% CI 0.83, 1.62). In a matched propensity score analysis in which both groups had similar baseline characteristics (17 249 patients in each group), the adjusted HR was 1.22 (95% CI 0.80, 1.84). CONCLUSION The results suggest that pioglitazone may not be significantly associated with an increased risk of bladder cancer in patients with type 2 diabetes.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Cluster randomized trials (randomized policy design studies) can be used to compare the safety and effectiveness of different interventions. • Cluster randomized trials are relatively novel in the context of studying drug interventions. • Using cluster randomized trials to investigate drug safety and effectiveness would require public and primary-care practitioner co-operation. WHAT THIS STUDY ADDS • The general public in Scotland is broadly supportive of the concept of cluster randomized trials (randomized policy design studies) to improve understanding of comparative effectiveness and safety of medicines within the National Health Service. • There is a spread of opinion among general practitioners in Scotland regarding the acceptability of the concept of cluster randomized trials in the field of drug safety and effectiveness. • Of the general public participants, 97% agreed that the National Health Service has a duty to determine the safety and effectiveness of the medicines its doctors prescribe. AIMS To understand public and general practitioner (GP) opinion on the acceptability of randomized policy design (RPD) studies (cluster randomized trials) of prescription medicines in Scotland. METHODS We surveyed public opinion on the concept of RPD studies in a sample of 1040 adults to determine acceptability and understand how people feel when changes are made to their medicines. We also surveyed GPs (n = 1034) about the concept of RPD studies as a tool for improving understanding of comparative effectiveness and safety of medicines in the ‘usual care’ setting. RESULTS Thirty per cent of people would be happy to receive a letter about randomized policy changes to their therapy, 31% would not mind or had no opinion and 39% would be unhappy. This view was sensitive to the reason for change; effectiveness and safety reasons were most acceptable (96%) and cost saving least acceptable (39%). Only 19% thought randomized policy change was not an acceptable method of determining the best treatments. Eighty-one per cent of respondents were willing for their medical data to be followed up to compare drug treatments (further 10% undecided). Participants reporting long-term medical conditions and those reporting previous changes to drug therapy were more in favour of RPD studies than other participants. Thirty-three per cent (n = 341) of GPs responded to our survey. Of these, 45% were in favour of RPD studies, 19% were undecided and 36% not in favour. CONCLUSIONS The public in Scotland is broadly supportive of the concept of randomized policy design studies of medicines, while there is a spread of opinion among GPs.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • While the new H1N1 vaccines underwent the usual rigorous safety and efficacy testing, concerns remained that there may be unexpected side effects of the vaccines. • The strategy for H1N1 vaccine pharmacovigilance in the UK consisted of two patient studies by the two vaccine manufacturers, 14 small scale studies supported by the National Institute of Health Research, monitoring by specialist neurologists and the MHRA. • There were calls to investigate the feasibility of a large-scale prospective active surveillance system for ‘near real-time’ vaccine safety monitoring that would be complementary to the other aforementioned initiatives. WHAT THIS STUDY ADDS • This pilot study demonstrated that collecting ‘near real-time’ reporting of event data from patients who experienced side effects as well as those who reported no problems after swine flu vaccination is feasible. • The use of information technologies improves patient involvement in research as well as dramatically limiting the cost of the study. • The online methodology facilitates rapid surveillance in response to urgent safety issues. AIMS During the global H1N1 influenza A (swine flu) pandemic 2009–2010, swine flu vaccines were expeditiously licensed and a mass vaccination programme for high risk groups, including pregnant women, was introduced in the UK. This pilot active safety surveillance study was performed to establish the feasibility of rapidly monitoring the new swine flu vaccines in large patient numbers receiving or offered the vaccination under normal conditions of use within a short time frame. METHODS A cohort design with safety data capture through modern technologies was carried out in Scotland, UK during the winter swine flu vaccination programme 2009–2010 in individuals receiving or offered the swine flu vaccination. The main outcome measures were self-reported serious adverse events (SAEs) and pregnancy outcomes. RESULTS The cohort comprised 4066 people; 3754 vaccinated and 312 offered the vaccination but not vaccinated. There were 939 self-reported events (838 different events), 53 judged to fit SAE criteria by the investigators, with nine judged as possibly, probably or definitely vaccine related. None of the seven deaths (six in vaccinees) were judged as vaccine related. One hundred and twenty-eight women reported 130 pregnancies during the study with 117 pregnant at study start. There were reports of four miscarriages in three women and six possible congenital abnormalities in live births. CONCLUSIONS Overall, no significant safety issues were identified. The methodology and use of modern technologies to collect safety data from large numbers of patients was successful and could be used again in similar safety studies.

Identification of unilateral aldosterone-producing (Conn's) adenomas has traditionally required lateralization by the invasive and technically difficult procedure of adrenal vein sampling (AVS). (11)C-metomidate, a potent inhibitor of adrenal steroidogenic enzymes, is a positron emission tomography (PET) radiotracer that is selectively accumulated by Conn's adenomas.The objective of the study was to compare the sensitivity and specificity of (11)C-metomidate PET-computed tomography (CT) against the current gold standard of AVS.The design of the study was within-patient comparison of diagnostic techniques.The study was conducted at a single center-university teaching hospital.Thirty-nine patients with primary hyperaldosteronism (PHA) and five with nonfunctioning adenomas (incidentalomas) participated in the study.The first six PHA patients were studied on three occasions to determine whether steroid pretreatment reduced (11)C-metomidate uptake by normal adrenal. Subsequent patients received dexamethasone for 3 d prior to injection of (11)C-metomidate 150-500 MBq.Maximum standardized uptake values (SUV(max)) over regions of interest determined from 35-45 min after injection were measured.Dexamethasone increased tumor to normal adrenal SUV(max) ratio by 25.6 ± 5.0% (P0.01). PET-CT visualized subcentimeter adenomas and distinguished hot from cold adenomas within a gland. In 25 patients with PHA and AVS lateralization to the side of an adenoma, SUV(max) over tumor (mean ± sem) of 21.7 ± 1.6 was greater than over normal adrenal, 13.8 ± 0.6 (P = 0.00003); this difference was absent in 10 patients without lateralization on AVS (P = 0.28) and in four of five incidentalomas. On receiver-operator characteristics analysis, an SUV(max) ratio of 1.25:1 provided a specificity of 87% [95% confidence interval (69, 104)] and sensitivity of 76% (59, 93); in tumors with SUV(max) greater than 17, the specificity rose to 100%.(11)C-metomidate PET-CT is a sensitive and specific noninvasive alternative to AVS in the management of PHA.

WHAT IS ALREADY KNOWN ABOUT THIS SUBJECT • Guidelines recommend that the therapeutic goal of urate-lowering therapy (ULT) is to achieve a urate concentration of ≤6 mg dl−1. • High-dose allopurinol is associated with reduced cardiovascular events and mortality in heart failure patients. WHAT THIS STUDY ADDS • Less than 50% of patients taking allopurinol reached target urate concentration. • Higher doses of allopurinol were associated with better control of urate and lower risks of both cardiovascular events and mortality in all patients on allopurinol treatment. AIMS To characterize patients with urate measurements by urate-lowering therapy (ULT) use and to study the impact of allopurinol treatment on cardiovascular and mortality outcomes. METHODS A cohort study using a record-linkage database. The study included 7135 patients aged ≥60 years with urate measurements between 2000 and 2002 followed up until 2007. A Cox regression model was used. The association between urate levels, dispensed allopurinol and cardiovascular hospitalization and mortality was determined. RESULTS Six thousand and forty-two patients were not taking ULT and 45.9% of those (2774 of 6042) had urate concentrations ≤6 mg dl−1. Among 1035 allopurinol users, 44.7% (45.6% for men and 43.3% for women) reached target urate concentration. There was no significant increased risk of cardiovascular events for allopurinol users when compared with non-ULT users [adjusted hazard ratio (HR) 1.10, 95% confidence interval (CI) 0.95–1.26] and the non-ULT group with urate >6 mg dl−1 (adjusted HR 1.07, 95% CI 0.89–1.28). Within the allopurinol use cohort, cardiovascular event rates were 74.0 (95% CI 61.9–86.1) per 1000 person years for the 100 mg group, 69.7 (49.6–89.8) for the 200 mg group and 47.6 (38.4–56.9) for the ≥300 mg group. Compared with low-dose (100 mg) users, high-dose (≥300 mg) users had significant reductions in the risk of cardiovascular events (adjusted HR 0.69, 95% CI 0.50–0.94) and mortality (adjusted HR 0.75, 95% CI 0.59–0.94). CONCLUSIONS Less than 50% of patients taking allopurinol reached target urate concentration. Higher doses of allopurinol were associated with better control of urate and lower risks of both cardiovascular events and mortality.

Both laboratory studies in healthy volunteers and clinical studies have suggested adverse interactions between antiplatelet drugs and other commonly used medications. Interactions described include those between aspirin and ibuprofen, aspirin and other nonsteroidal anti-inflammatory drugs (NSAIDs), and the thienopyridine, clopidogrel, and drugs inhibiting CYP2C19, notably the proton pump inhibitors (PPI) omeprazole and esomeprazole. Other interactions between thienopyridines and CYP3A4/5 have also been reported for statins and calcium channel blockers. The ibuprofen/aspirin interaction is thought to be caused by ibuprofen blocking the access of aspirin to platelet cyclo-oxygenase. The thienopyridine interactions are caused by inhibition of microsomal enzymes that metabolize these pro-drugs to their active metabolites. We review the evidence for these interactions, assess their clinical importance and suggest strategies of how to deal with them in clinical practice. We conclude that ibuprofen is likely to interact with aspirin and reduce its anti-platelet action particularly in those patients who take ibuprofen chronically. This interaction is of greater relevance to those patients at high cardiovascular risk. A sensible strategy is to advise users of aspirin to avoid chronic ibuprofen or to ingest aspirin at least 2 h prior to ibuprofen. Clearly the use of NSAIDs that do not interact in this way is preferred. For the clopidogrel CYP2C19 and CYP3A4/5 interactions, there is good evidence that these interactions occur. However, there is less good evidence to support the clinical importance of these interactions. Again, a reasonable strategy is to avoid the chronic use of drugs that inhibit CYP2C19, notably PPIs, in subjects taking clopidogrel and use high dose H2 antagonists instead. Finally, anti-platelet agents probably interact with other drugs that affect platelet function such as selective serotonin reuptake inhibitors, and clinicians should probably judge patients taking such combination therapies as at high risk for bleeding.

Our new series on Prescribing challenges focuses on areas of therapeutics that can present a particular challenge in general practice. Here, the authors address the familiar problem of hypertension that remains above target despite treatment with three anti-hypertensives. Copyright © 2010 Wiley Interface Ltd