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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.

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.

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.

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.

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.

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 • 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 * Recruitment is key to the success of clinical trials. * Many clinical trials fail to achieve adequate recruitment. * Public understanding and engagement in clinical research could be improved. WHAT THIS STUDY ADDS * 'Get Randomised' is the first campaign of its kind in the UK. * It is possible to improve public awareness of clinical research using the media. * Further work is needed to determine whether improved public awareness leads to increased participation in clinical research in the future. AIM To increase public awareness and understanding of clinical research in Scotland. METHODS A generic media campaign to raise public awareness of clinical research was launched in 2008. The 'Get Randomised' campaign was a Scotland-wide initiative led by the University of Dundee in collaboration with other Scottish universities. Television, radio and newspaper advertising showed leading clinical researchers, general practitioners and patients informing the public about the importance of randomised clinical trials (RCTs). 'Get Randomised' was the central message and interested individuals were directed to the http://www.getrandomised.org website for more information. To assess the impact of the campaign, cross-sectional surveys were conducted in representative samples of 1040 adults in Scotland prior to campaign launch and again 6 months later. RESULTS There was an improvement in public awareness of clinical trials following the campaign; 56.7% [95% confidence interval (CI) 51.8, 61.6] of the sample recalled seeing or hearing advertising about RCTs following the campaign compared with 14.8% (10.8, 18.9) prior to the campaign launch (difference = 41.4%; 95% CI for difference 35.6, 48.3; P < 0.01). Of those who recalled the advertising, 49% felt that the main message was that people should take part more in medical research. However, on whether they would personally take part in a clinical trial if asked, there was little difference in response following the campaign ['yes' 31.3% (28.4, 34.1) prior; 30.4% (27.6, 33.2) following; difference =-0.9%; 95% CI for difference -4.8, 3.1%; P= 0.92]. CONCLUSIONS It is possible to raise public awareness of clinical research using the media, but further efforts may be required to influence individuals' decisions to take part in clinical research.

Osteoarthritis and hypertension commonly co-exist. Treatment of osteoarthritis in hypertensive patients is a therapeutic challenge due to the adverse effects of some analgesics, especially non-steroidal anti-inflammatory drugs (NSAIDs), on blood pressure. Even small drug-induced rises in blood pressure due to therapy may significantly increase cardiovascular risk in these patients if sustained over the long term. Patients treated with certain classes of antihypertensive agent may be at particular risk of deterioration in blood pressure control with NSAID therapy. NSAIDs may also increase cardiovascular risk due to mechanisms other than by raising blood pressure.We discuss the management of osteoarthritis in the hypertensive patient, review the evidence for the effects of paracetamol and NSAIDs on blood pressure and discuss novel therapeutic strategies for osteoarthritis that might diminish this problem. A literature search was undertaken in PubMed including the years 1980 - 2009.Insight will be gained into the complexity of treating patients with co-existent osteoarthritis and hypertension and into possible new approaches to treating osteoarthritis symptoms effectively in these patients while minimising any adverse impact on blood pressure control.There are ways to minimise the adverse impact of treatment of osteoarthritis on blood pressure control in hypertensive patients.

Isolated systolic hypertension is an important risk factor for cardiovascular disease and results primarily from elastic artery stiffening. Although various drug therapies are used to lower peripheral blood pressure (BP) in patients with isolated systolic hypertension, the effects of the 4 major classes of antihypertensive agents on central BP, pulse pressure (PP) amplification, and arterial stiffness in this condition are not clear. Fifty-nine patients over the age of 60 years with untreated isolated systolic hypertension (systolic BP ≥140 mm Hg and diastolic BP ≤90 mm Hg) were randomly assigned to receive 1 of the following 4 antihypertensive agents: perindopril, atenolol, lercanidipine, or bendrofluazide. BP was measured using a mercury sphygmomanometer, and augmentation index and carotid-femoral (aortic) pulse wave velocity were measured at baseline, after 2 weeks of placebo therapy, and at the end of 10 weeks of active therapy. Peripheral systolic BP and peripheral PP were reduced similarly after treatment with all 4 classes of drug. However, central PP was only reduced significantly by perindopril, lercanidipine, and bendrofluazide, whereas atenolol had no effect. Lercanidipine reduced the augmentation index, whereas atenolol increased it. Aortic pulse wave velocity was not changed by any of the drugs. In summary, despite similar reductions in peripheral systolic and PPs with the 4 classes of drug, changes in central pressure and augmentation index varied. Because central PP and increased wave reflections are considered important risk factors in patients with isolated systolic hypertension, the choice of therapy may be influenced by these findings in the future.

123I-Metaiodobenzylguanidine (123I-MIBG) scintigraphy scanning is commonly used in the imaging of phaeochromocytoma (and paraganglioma) to confirm the site of disease and whether any spread has occurred. However, 123I-MIBG imaging is negative in 15% of cases of benign phaeochromocytoma and around 50% of cases of malignant phaeochromocytoma. In recent years, positron emission tomography (PET) scanning using various different radiotracers has been shown to be a good alternative or supplementary investigation in phaeochromocytoma. We present the cases of four patients with symptoms and signs suggestive of phaeochromocytoma, but who had negative 123I-MIBG scans, and illustrate the usefulness of 18-fluoro-dihydroxyphenylalanine PET scanning in their assessment. In one of the patients, we illustrate how fluorodeoxyglucose PETscanning can provide useful information about the extent of malignant disease. These illustrative cases lend further support for the use of PET scanning in the assessment of phaeochromocytoma and suggest that it may have a particularly important role in the investigation of patients in whom 123I-MIBG scanning is negative.

Potassium depletion by thiazide diuretics is associated with a rise in blood glucose. We assessed whether addition or substitution of a potassium-sparing diuretic, amiloride, to treatment with a thiazide can prevent glucose intolerance and improve blood pressure control.We did a parallel-group, randomised, double-blind trial in 11 secondary and two primary care sites in the UK. Eligible patients were aged 18-80 years; had clinic systolic blood pressure of 140 mm Hg or higher and home systolic blood pressure of 130 mmHg or higher on permitted background drugs of angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, β blockers, calcium-channel blockers, or direct renin inhibitors (previously untreated patients were also eligible in specific circumstances); and had at least one component of the metabolic syndrome in addition to hypertension. Patients with known diabetes were excluded. Patients were randomly assigned (1:1:1) to 24 weeks of daily oral treatment with starting doses of 10 mg amiloride, 25 mg hydrochlorothiazide, or 5 mg amiloride plus 12·5 mg hydrochlorothiazide; all doses were doubled after 12 weeks. Random assignment was done via a central computer system. Both participants and investigators were masked to assignment. Our hierarchical primary endpoints, assessed on a modified intention-to-treat basis at 12 and 24 weeks, were the differences from baseline in blood glucose measured 2 h after a 75 g oral glucose tolerance test (OGTT), compared first between the hydrochlorothiazide and amiloride groups, and then between the hydrochlorothiazide and combination groups. A key secondary endpoint was change in home systolic blood pressure at 12 and 24 weeks. This trial is registered with ClinicalTrials.gov, number NCT00797862, and the MHRA, Eudract number 2009-010068-41, and is now complete.Between Nov 18, 2009, and Dec 15, 2014, 145 patients were randomly assigned to amiloride, 146 to hydrochlorothiazide, and 150 to the combination group. 132 participants in the amiloride group, 134 in the hydrochlorothiazide group, and 133 in the combination group were included in the modified intention-to-treat analysis. 2 h glucose concentrations after OGTT, averaged at 12 and 24 weeks, were significantly lower in the amiloride group than in the hydrochlorothiazide group (mean difference -0·55 mmol/L [95% CI -0·96 to -0·14]; p=0·0093) and in the combination group than in the hydrochlorothiazide group (-0·42 mmol/L [-0·84 to -0·004]; p=0·048). The mean reduction in home systolic blood pressure during 24 weeks did not differ significantly between the amiloride and hydrochlorothiazide groups, but the fall in blood pressure in the combination group was significantly greater than that in the hydrochlorothiazide group (p=0·0068). Hyperkalaemia was reported in seven (4·8%) patients in the amiloride group and three (2·3%) patients in the combination group; the highest recorded potassium concentration was 5·8 mmol/L in a patient in the amiloride group. 13 serious adverse events occurred but the frequency did not differ significantly between groups.The combination of amiloride with hydrochlorothiazide, at doses equipotent on blood pressure, prevents glucose intolerance and improves control of blood pressure compared with montherapy with either drug. These findings, together with previous data about morbidity and mortality for the combination, support first-line use of amiloride plus hydrochlorothiazide in hypertensive patients who need treatment with a diuretic.British Heart Foundation and National Institute for Health Research.

Introduction Previous studies have suggested that more intensive initial therapy for hypertension results in better long-term blood pressure (BP) control. We test this hypothesis comparing initial monotherapy with dual therapy in the management of essential hypertension. Methods and analysis The study is a prospective, multicentre, double-blind, active-controlled trial in patients with essential hypertension. Around 50% of patients studied will be newly diagnosed and the others will be known hypertensives who previously received only monotherapy. The trial is divided into three phases as follows: Phase 1 (Week 0–Week 16): Randomised, parallel-group, masked assignation to either combination or monotherapy. Phase 2 (Week 17–Week 32): Open-label combination therapy. Phase 3 (Week 33–Week 52): Open-label combination therapy plus open-label add-on (if BP is above 140/90 mm Hg). Hierarchical primary end points are: a comparison of home BP (home systolic blood pressure (HSBP)) averaged over the duration of phase 1 and 2 in the combination versus monotherapy arms. If combination is superior in this analysis, then the averaged mean HSBP between initial monotherapy and initial combination therapy at the end of phase 2 will be compared. Secondary end points include: BP control at 1 year; the role of age, baseline renin, sodium status, plasma volume, haemodynamic compensation and peripheral resistance on BP control; validation of the National Institute for Clinical Excellence/British Hypertension Society joint guideline algorithm; safety and tolerability of combination therapy; and the impact of combination versus monotherapy on left ventricular mass and aortic pulse wave velocity. A sample size of 536 (268 in each group) will have 90% power to detect a difference in means of 4 mm Hg. Ethics and dissemination PATHWAY 1 was approved by UK ethics (REC Reference 09/H0308/132). Trial results will be published and all participating subjects will be informed of the results. Trial registration number UKCRN 4499 and EudraCT number 2008-007749-29 registered 27/08/2009.

Patient recruitment into clinical trials is a major challenge, and the elderly, socially deprived and those with multiple comorbidities are often underrepresented. The idea of paying patients an incentive to participate in research is controversial, and evidence is needed to evaluate this as a recruitment strategy. In this study, we sought to assess the impact on clinical trial recruitment of a £100 incentive payment and whether the offer of this payment attracted more elderly and socially deprived patients. A total of 1,015 potential patients for five clinical trials (SCOT, FAST and PATHWAY 1, 2 and 3) were randomised to receive either a standard trial invitation letter or a trial invitation letter containing an incentive offer of £100. To receive payment, patients had to attend a screening visit and consent to be screened (that is, sign a consent form). To maintain equality, eventually all patients who signed a consent form were paid £100. The £100 incentive offer increased positive response to the first invitation letter from 24.7% to 31.6%, an increase of 6.9% (P

Background Stoma-related complication rates vary between 10% and 70%, possibly because of varying lengths of follow-up. It is thought that most of the complications improve with time. Furthermore, little is known about the commonly neglected but potentially quite distressing complications such as leakage, soiling and night-time emptying. The aim of this audit was to examine prospectively whether there was any difference in the complication rates at different time-points during the postoperative follow up period. Method A prospective study on 408 consecutive patients with either colostomy or ileostomy was conducted over a period of at least 2 years. Both emergency and elective procedures were included. Stoma related complications were analysed at 10 days, 3 months, 6 months, 1 year and 2 years postoperatively. Results Both elective and emergency stomas had similar complication rates. The percentage of patients who had stenosis (1–2%), retraction (8–22%), prolapse (1–3%) or odour (6–9%) did not significantly change with time. The complication rates for skin excoriation, leakage, soiling or night-time emptying were higher amongst the ileostomy patients, and these rates did not improve with time. The proportion of patients who had parastomal hernias increased with time (from 0 to 40% in the colostomy and 0 to 22% in the ileostomy group). Daytime leakage, night-time leakage, soiling and night-time emptying were more problematic in the ileostomy group. Conclusions The proportion of patients who had postoperative stoma-related complications did not improve with time, but the rate of parastomal hernias in both groups and night-time emptying in the ileostomy group was worse with time. Ileostomy patients had a higher incidence of skin excoriation, leakage, soiling, and night-time emptying, and they should receive additional support.

Objective— C-reactive protein (CRP) levels predict outcome in healthy individuals and patients with atherosclerosis. Arterial stiffness also independently predicts all-cause and cardiovascular mortality and may be involved in the process of atherosclerosis. The aim of this study was to investigate the relationship between stiffness and inflammation in a cohort of healthy individuals. Methods and Results— Pulse wave velocity (PWV) and blood pressure were assessed in 427 individuals. Subjects with cardiovascular disease, diabetes, hypercholesterolemia and those using medication were excluded. CRP correlated with age, mean arterial pressure (MAP), brachial and aortic PWV, and pulse pressures. In multiple regression models, aortic PWV correlated independently with age, CRP, male gender, and MAP ( R 2 =0.593; P R 2 =0.794; P Conclusion— Aortic and brachial PWV, and pulse pressure, relate to levels of inflammation in healthy individuals, suggesting that inflammation may be involved in arterial stiffening. Anti-inflammatory strategies may, therefore, be of benefit in reducing arterial stiffness and thus cardiovascular risk, especially in patients with premature arterial stiffening.

There is a greater choice of drug classes for hypertension than most other diseases, increasing paradoxically the difficulty of finding the right drug for individual patients. Systematic drug rotation studies have shown that the rank order of response to different drugs varies substantially among patients. However, two broad patterns of response emerge, named after the initials of the major drug classes. The AB pattern is seen in Type 1 (high-renin) hypertensives. These are younger Caucasians who respond best to angiotensin-converting enzyme (ACE) inhibitors, angiotensin blockers and beta-blockers. The CD pattern is seen in Type 2 (low-renin) patients. These are Afro-Caribbeans and older Caucasians, who respond best to calcium blockers and diuretics. This relative homogeneity of phenotype at each age group contrasts with a large heterogeneity of genotype on recent genome-wide scans, and suggests that most hypertension is due to interaction among multiple minor genetic variants. Genotype is unlikely therefore to be useful in selecting treatment for most patients. The exception is patients who have the atypical phenotype for their age, illustrated by the rare Na+ dependent monogenic syndromes of the young.

Background Inhaled corticosteroids (ICS), especially when prescribed in combination with long-acting β2 agonists have been shown to improve COPD outcomes. Although there is consistent evidence linking ICS with adverse effects such as pneumonia, the complete risk profile is unclear with conflicting evidence on any association between ICS and the incidence or worsening of existing diabetes, cataracts and fractures. We investigated this using record linkage in a Dundee COPD population. Methods A record linkage study linking COPD and diabetes datasets with prescription, hospitalisation and mortality data via a unique Community Health Index (CHI) number. A Cox regression model was used to determine the association between ICS use and new diabetes or worsening of existing diabetes and hospitalisations for pneumonia, fractures or cataracts after adjusting for potential confounders. A time dependent analysis of exposure comparing time on versus off ICS was used to take into account patients changing their exposure status during follow-up and to prevent immortal time bias. Results 4305 subjects (3243 exposed to ICS, total of 17,229 person-years of exposure and 1062 non exposed, with a follow-up of 4,508 patient-years) were eligible for the study. There were 239 cases of new diabetes (DM) and 265 cases of worsening DM, 550 admissions for pneumonia, 288 hospitalisations for fracture and 505 cataract related admissions. The hazard ratio for the association between cumulative ICS and outcomes were 0.70 (0.43-1.12), 0.57 (0.24-1.37), 1.38 (1.09-1.74), 1.08 (0.73-1.59) and 1.42 (1.07-1.88) after multivariate analysis respectively. Conclusion The use of ICS in our cohort was not associated with new onset of diabetes, worsening of existing diabetes or fracture hospitalisation. There was however an association with increased cataracts and pneumonia hospitalisations.

Adrenal masses vary in importance from being incidental findings of no clinical significance to having sinister consequences through malignancy. The importance in integrating the clinical history, biochemical findings and results of modern imaging techniques is illustrated in this case.

Low 25-hydroxyvitamin D levels are associated with higher prevalent blood pressure. We tested whether high-dose intermittent oral vitamin D therapy could reduce blood pressure and left ventricular mass in patients with hypertension resistant to conventional treatment. We conducted a parallel-group, double-blind, randomized placebo-controlled trial. Patients with supine office blood pressure >140/90 mm Hg on ≥3 antihypertensive agents received 100 000 U oral vitamin D3 or matching placebo every 2 months. Office and 24-hour ambulatory blood pressure, glucose, and cholesterol were measured at baseline, 2, 4, and 6 months; left ventricular mass index was measured by cardiac MRI on a subgroup at baseline and 6 months. The primary outcome was mean 24-hour ambulatory blood pressure at 6 months. A total of 68 participants were randomized, 34 in each group. Mean age was 63 (SD 11) years, mean baseline office blood pressure was 154/84 (13/10) mm Hg, and mean baseline 25-hydroxyvitamin D level was 42 (16) nmol/L. Treatment with vitamin D did not reduce 24-hour ambulatory blood pressure (adjusted treatment effects: systolic, +3 mm Hg; 95% confidence interval, –4 to +11; P =0.33; diastolic, –2 mm Hg; 95% confidence interval, –6 to +2; P =0.29); similar results were seen for office blood pressure. Left ventricular mass index was measured in a subgroup (n=25); no reduction was seen with vitamin D treatment (adjusted treatment effect, +4 g/m 2 ; 95% confidence interval, 0 to +7; P =0.04). There was no significant change in cholesterol or glucose levels. Thus, 6 months of intermittent, high-dose oral vitamin D3 did not reduce blood pressure or left ventricular mass in patients with resistant hypertension.

Objective To determine whether patients taking formulations of drugs that contain sodium have a higher incidence of cardiovascular events compared with patients on non-sodium formulations of the same drugs. Design Nested case-control study. Setting UK Primary Care Patients registered on the Clinical Practice Research Datalink (CPRD). Participants All patients aged 18 or over who were prescribed at least two prescriptions of sodium-containing formulations or matched standard formulations of the same drug between January 1987 and December 2010. Main outcome measures Composite primary outcome of incident non-fatal myocardial infarction, incident non-fatal stroke, or vascular death. We performed 1:1 incidence density sampling matched controls using the UK Clinical Practice Research Datalink (CPRD). For the secondary analyses, cases were patients with the individual components of the primary study composite endpoint of hypertension, incident heart failure, and all cause mortality. Results 1 292 337 patients were included in the study cohort. Mean follow-up time was 7.23 years. A total of 61 072 patients with an incident cardiovascular event were matched with controls. For the primary endpoint of incident non-fatal myocardial infarction, incident non-fatal stroke, or vascular death the adjusted odds ratio for exposure to sodium-containing drugs was 1.16 (95% confidence interval 1.12 to 1.21). The adjusted odds ratios for the secondary endpoints were 1.22 (1.16 to 1.29) for incident non-fatal stroke, 1.28 (1.23 to 1.33) for all cause mortality, 7.18 (6.74 to 7.65) for hypertension, 0.98 (0.93 to 1.04) for heart failure, 0.94 (0.88 to 1.00) for incident non-fatal myocardial infarction, and 0.70 (0.31 to 1.59) for vascular death. The median time from date of first prescription (that is, date of entry into cohort) to first event was 3.92 years. Conclusions Exposure to sodium-containing formulations of effervescent, dispersible, and soluble medicines was associated with significantly increased odds of adverse cardiovascular events compared with standard formulations of those same drugs. Sodium-containing formulations should be prescribed with caution only if the perceived benefits outweigh these risks.

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.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.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.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.

Issues surrounding data security and privacy are of great importance when handling sensitive health-related data for research. The emphasis in the past has been on balancing the risks to individuals with the benefit to society of the use of databases for research. However, a new way of looking at such issues is that by optimising procedures and policies regarding security and privacy of data to the extent that there is no appreciable risk to the privacy of individuals, we can create a 'win-win' situation in which everyone benefits, and pharmacoepidemiological research can flourish with public support. We discuss holistic measures, involving both information technology and people, taken to improve the security and privacy of data storage.After an internal review, we commissioned an external audit by an independent consultant with a view to optimising our data storage and handling procedures.Improvements to our policies and procedures were implemented as a result of the audit.By optimising our storage of data, we hope to inspire public confidence and hence cooperation with the use of health care data in research.

Interactions between the renin-angiotensin-aldosterone system and other mechanisms determining sodium balance are important in the pathophysiology of hypertension. Low-renin hypertension is a common type of resistant hypertension and is often associated with increased sodium retention. The importance of investigation, factors determining renin and aldosterone levels, and drug therapies in low-renin hypertension are reviewed.