Nick Freemantle

Cardiac resynchronization reduces symptoms and improves left ventricular function in many patients with heart failure due to left ventricular systolic dysfunction and cardiac dyssynchrony. We evaluated its effects on morbidity and mortality.Patients with New York Heart Association class III or IV heart failure due to left ventricular systolic dysfunction and cardiac dyssynchrony who were receiving standard pharmacologic therapy were randomly assigned to receive medical therapy alone or with cardiac resynchronization. The primary end point was the time to death from any cause or an unplanned hospitalization for a major cardiovascular event. The principal secondary end point was death from any cause.A total of 813 patients were enrolled and followed for a mean of 29.4 months. The primary end point was reached by 159 patients in the cardiac-resynchronization group, as compared with 224 patients in the medical-therapy group (39 percent vs. 55 percent; hazard ratio, 0.63; 95 percent confidence interval, 0.51 to 0.77; P<0.001). There were 82 deaths in the cardiac-resynchronization group, as compared with 120 in the medical-therapy group (20 percent vs. 30 percent; hazard ratio 0.64; 95 percent confidence interval, 0.48 to 0.85; P<0.002). As compared with medical therapy, cardiac resynchronization reduced the interventricular mechanical delay, the end-systolic volume index, and the area of the mitral regurgitant jet; increased the left ventricular ejection fraction; and improved symptoms and the quality of life (P<0.01 for all comparisons).In patients with heart failure and cardiac dyssynchrony, cardiac resynchronization improves symptoms and the quality of life and reduces complications and the risk of death. These benefits are in addition to those afforded by standard pharmacologic therapy. The implantation of a cardiac-resynchronization device should routinely be considered in such patients.

Guidelines •

Although physicians report spending a considerable amount of time in continuing medical education (CME) activities, studies have shown a sizable difference between real and ideal performance, suggesting a lack of effect of formal CME.To review, collate, and interpret the effect of formal CME interventions on physician performance and health care outcomes.Sources included searches of the complete Research and Development Resource Base in Continuing Medical Education and the Specialised Register of the Cochrane Effective Practice and Organisation of Care Group, supplemented by searches of MEDLINE from 1993 to January 1999.Studies were included in the analyses if they were randomized controlled trials of formal didactic and/or interactive CME interventions (conferences, courses, rounds, meetings, symposia, lectures, and other formats) in which at least 50% of the participants were practicing physicians. Fourteen of 64 studies identified met these criteria and were included in the analyses. Articles were reviewed independently by 3 of the authors.Determinations were made about the nature of the CME intervention (didactic, interactive, or mixed), its occurrence as a 1-time or sequenced event, and other information about its educational content and format. Two of 3 reviewers independently applied all inclusion/exclusion criteria. Data were then subjected to meta-analytic techniques.The 14 studies generated 17 interventions fitting our criteria. Nine generated positive changes in professional practice, and 3 of 4 interventions altered health care outcomes in 1 or more measures. In 7 studies, sufficient data were available for effect sizes to be calculated; overall, no significant effect of these educational methods was detected (standardized effect size, 0.34; 95% confidence interval [CI], -0.22 to 0.97). However, interactive and mixed educational sessions were associated with a significant effect on practice (standardized effect size, 0.67; 95% CI, 0.01-1.45).Our data show some evidence that interactive CME sessions that enhance participant activity and provide the opportunity to practice skills can effect change in professional practice and, on occasion, health care outcomes. Based on a small number of well-conducted trials, didactic sessions do not appear to be effective in changing physician performance.

<h3>Abstract</h3> <b>Objectives</b>: To assess the effectiveness of β blockers in short term treatment for acute myocardial infarction and in longer term secondary prevention; to examine predictive factors that may influence outcome and therefore choice of drug; and to examine the clinical importance of the results in the light of current treatment. <b>Design</b>:Systematic review of randomised controlled trials. <b>Setting</b>: Randomised controlled trials. <b>Subjects</b>: Patients with acute or past myocardial infarction. <b>Intervention</b>: βBlockers compared with control. <b>Main</b>:outcome measures All cause mortality and non-fatal reinfarction. <b>Results</b>: Overall, 5477 of 54 234 patients (10.1%) randomised to β blockers or control died. We identified a 23% reduction in the odds of death in long term trials (95% confidence interval 15% to 31%), but only a 4% reduction in the odds of death in short term trials (−8% to 15%). Meta regression in long term trials did not identify a significant reduction in effectiveness in drugs with cardioselectivity but did identify a near significant trend towards decreased benefit in drugs with intrinsic sympathomimetic activity. Most evidence is available for propranolol, timolol, and metoprolol. In long term trials, the number needed to treat for 2 years to avoid a death is 42, which compares favourably with other treatments for patients with acute or past myocardial infarction. <b>Conclusions</b>: β Blockers are effective in long term secondary prevention after myocardial infarction, but they are underused in such cases and lead to avoidable mortality and morbidity.

Many patients who receive a diagnosis of heart failure have neither a low left ventricular (LV) ejection fraction nor valve disease. Few substantial randomized controlled trials have been conducted in this population, none has focussed on patients with evidence of diastolic dysfunction and none has shown clear benefit on symptoms, morbidity, or mortality.This was a randomized double-blind trial, comparing placebo with perindopril, 4 mg/day in patients aged > or =70 years with a diagnosis of heart failure, treated with diuretics and an echocardiogram suggesting diastolic dysfunction and excluding substantial LV systolic dysfunction or valve disease. The primary endpoint was a composite of all-cause mortality and unplanned heart failure related hospitalization with a minimum follow-up of 1 year. A total of 850 patients were randomized. Their mean age was 76 (SD 5) years and 55% were women. Median follow-up was 2.1 (IQR 1.5-2.8) years. Enrollment and event rates were lower than anticipated, reducing the power of the study to show a difference in the primary endpoint to 35%. Many patients withdrew from perindopril (28%) and placebo (26%) after 1 year and started taking open-label ACE-inhibitors. Overall, 107 patients assigned to placebo and 100 assigned to perindopril reached the primary endpoint (HR 0.919: 95% CI 0.700-1.208; P = 0.545). By 1 year, reductions in the primary outcome (HR 0.692: 95% CI 0.474-1.010; P = 0.055) and hospitalization for heart failure (HR 0.628: 95% CI 0.408-0.966; P = 0.033) were observed and functional class (P < 0.030) and 6-min corridor walk distance (P = 0.011) had improved in those assigned to perindopril.Uncertainty remains about the effects of perindopril on long-term morbidity and mortality in this clinical setting since this study had insufficient power for its primary endpoint. However, improved symptoms and exercise capacity and fewer hospitalizations for heart failure in the first year were observed on perindopril, during which most patients were on assigned therapy, suggesting that it may be of benefit in this patient population.

Background The European Society of Cardiology (ESC) has published guidelines for the investigation of patients with suspected heart failure and, if the diagnosis is proven, their subsequent management. Hospitalisation provides a key point of care at which time diagnosis and treatment may be refined to improve outcome for a group of patients with a high morbidity and mortality. However, little international data exists to describe the features and management of such patients. Accordingly, the EuroHeart Failure survey was conducted to ascertain if appropriate tests were being performed with which to confirm or refute a diagnosis of heart failure and how this influenced subsequent management.

Objective To develop an evidence base for recommendations on the use of atypical antipsychotics for patients with schizophrenia.Design Systematic overview and meta-regression analyses of randomised controlled trials, as a basis for formal development of guidelines.Subjects 12 649 patients in 52 randomised trials comparing atypical antipsychotics (amisulpride, clozapine, olanzapine, quetiapine, risperidone, and sertindole) with conventional antipsychotics (usually haloperidol or chlorpromazine) or alternative atypical antipsychotics.Main outcome measures Overall symptom scores.Rate of drop out (as a proxy for tolerability) and of side effects, notably extrapyramidal side effects.Results For both symptom reduction and drop out, there was substantial heterogeneity between the results of trials, including those evaluating the same atypical antipsychotic and comparator drugs.Meta-regression suggested that dose of conventional antipsychotic explained the heterogeneity.When the dose was <12 mg/day of haloperidol (or equivalent), atypical antipsychotics had no benefits in terms of efficacy or overall tolerability, but they still caused fewer extrapyramidal side effects.Conclusions There is no clear evidence that atypical antipsychotics are more effective or are better tolerated than conventional antipsychotics.Conventional antipsychotics should usually be used in the initial treatment of an episode of schizophrenia unless the patient has previously not responded to these drugs or has unacceptable extrapyramidal side effects.

Educational outreach visits (EOVs) have been identified as an intervention that may improve the practice of healthcare professionals. This type of face-to-face visit has been referred to as university-based educational detailing, academic detailing, and educational visiting.To assess the effects of EOVs on health professional practice or patient outcomes.For this update, we searched the Cochrane EPOC register to March 2007. In the original review, we searched multiple bibliographic databases including MEDLINE and CINAHL.Randomised trials of EOVs that reported an objective measure of professional performance or healthcare outcomes. An EOV was defined as a personal visit by a trained person to healthcare professionals in their own settings.Two reviewers independently extracted data and assessed study quality. We used bubble plots and box plots to visually inspect the data. We conducted both quantitative and qualitative analyses. We used meta-regression to examine potential sources of heterogeneity determined a priori. We hypothesised eight factors to explain variation across effect estimates. In our primary visual and statistical analyses, we included only studies with dichotomous outcomes, with baseline data and with low or moderate risk of bias, in which the intervention included an EOV and was compared to no intervention.We included 69 studies involving more than 15,000 health professionals. Twenty-eight studies (34 comparisons) contributed to the calculation of the median and interquartile range for the main comparison. The median adjusted risk difference (RD) in compliance with desired practice was 5.6% (interquartile range 3.0% to 9.0%). The adjusted RDs were highly consistent for prescribing (median 4.8%, interquartile range 3.0% to 6.5% for 17 comparisons), but varied for other types of professional performance (median 6.0%, interquartile range 3.6% to 16.0% for 17 comparisons). Meta-regression was limited by the large number of potential explanatory factors (eight) with only 31 comparisons, and did not provide any compelling explanations for the observed variation in adjusted RDs. There were 18 comparisons with continuous outcomes, with a median adjusted relative improvement of 21% (interquartile range 11% to 41%). There were eight trials (12 comparisons) in which the intervention included an EOV and was compared to another type of intervention, usually audit and feedback. Interventions that included EOVs appeared to be slightly superior to audit and feedback. Only six studies evaluated different types of visits in head-to-head comparisons. When individual visits were compared to group visits (three trials), the results were mixed.EOVs alone or when combined with other interventions have effects on prescribing that are relatively consistent and small, but potentially important. Their effects on other types of professional performance vary from small to modest improvements, and it is not possible from this review to explain that variation.

Patients' beliefs about treatment influence treatment engagement and adherence. The Necessity-Concerns Framework postulates that adherence is influenced by implicit judgements of personal need for the treatment (necessity beliefs) and concerns about the potential adverse consequences of taking it.To assess the utility of the NCF in explaining nonadherence to prescribed medicines.We searched EMBASE, Medline, PsycInfo, CDSR/DARE/CCT and CINAHL from January 1999 to April 2013 and handsearched reference sections from relevant articles.Studies using the Beliefs about Medicines Questionnaire (BMQ) to examine perceptions of personal necessity for medication and concerns about potential adverse effects, in relation to a measure of adherence to medication.Patients with long-term conditions.Systematic review and meta-analysis of methodological quality was assessed by two independent reviewers. We pooled odds ratios for adherence using random effects models.We identified 3777 studies, of which 94 (N = 25,072) fulfilled the inclusion criteria. Across studies, higher adherence was associated with stronger perceptions of necessity of treatment, OR = 1.742, 95% CI [1.569, 1.934], p<0.0001, and fewer Concerns about treatment, OR = 0.504, 95% CI: [0.450, 0.564], p<0.0001. These relationships remained significant when data were stratified by study size, the country in which the research was conducted and the type of adherence measure used.Few prospective longitudinal studies using objective adherence measures were identified.The Necessity-Concerns Framework is a useful conceptual model for understanding patients' perspectives on prescribed medicines. Taking account of patients' necessity beliefs and concerns could enhance the quality of prescribing by helping clinicians to engage patients in treatment decisions and support optimal adherence to appropriate prescriptions.

National surveys suggest that treatment of heart failure in daily practice differs from guidelines and is characterized by underuse of recommended medications. Accordingly, the Euro Heart Failure Survey was conducted to ascertain how patients hospitalized for heart failure are managed in Europe and if national variations occur in the treatment of this condition.The survey screened discharge summaries of 11304 patients over a 6-week period in 115 hospitals from 24 countries belonging to the ESC to study their medical treatment.Diuretics (mainly loop diuretics) were prescribed in 86.9% followed by ACE inhibitors (61.8%), beta-blockers (36.9%), cardiac glycosides (35.7%), nitrates (32.1%), calcium channel blockers (21.2%) and spironolactone (20.5%). 44.6% of the population used four or more different drugs. Only 17.2% were under the combination of diuretic, ACE inhibitors and beta-blockers. Important local variations were found in the rate of prescription of ACE inhibitors and particularly beta-blockers. Daily dosage of ACE inhibitors and particularly of beta-blockers was on average below the recommended target dose. Modelling-analysis of the prescription of treatments indicated that the aetiology of heart failure, age, co-morbid factors and type of hospital ward influenced the rate of prescription. Age <70 years, male gender and ischaemic aetiology were associated with an increased odds ratio for receiving an ACE inhibitor. Prescription of ACE inhibitors was also greater in diabetic patients and in patients with low ejection fraction (<40%) and lower in patients with renal dysfunction. The odds ratio for receiving a beta-blocker was reduced in patients >70 years, in patients with respiratory disease and increased in cardiology wards, in ischaemic heart failure and in male subjects. Prescription of cardiac glycosides was significantly increased in patients with supraventricular tachycardia/atrial fibrillation. Finally, the rate of prescription of antithrombotic agents was increased in the presence of supraventricular arrhythmia, ischaemic heart disease, male subjects but was decreased in patients over 70.Our results suggest that the prescription of recommended medications including ACE inhibitors and beta-blockers remains limited and that the daily dosage remains low, particularly for beta-blockers. The survey also identifies several important factors including age, gender, type of hospital ward, co morbid factors which influence the prescription of heart failure medication at discharge.

Composite outcomes, in which multiple end points are combined, are frequently used as primary outcome measures in randomized trials and are often associated with increased statistical efficiency. However, such measures may prove challenging for the interpretation of results. In this article, we examine the use of composite outcomes in major clinical trials, assess the arguments for and against them, and provide guidance on their application and reporting. To assess incidence and quality of reporting, we systematically reviewed the use of composite end points in clinical trials in Annals of Internal Medicine, BMJ, Circulation, Clinical Infectious Diseases, Journal of the American College of Cardiology, JAMA, Lancet, New England Journal of Medicine, and Stroke from 1997 through 2001 using a sensitive search strategy. We selected for review 167 original reports of randomized trials (with a total of 300 276 patients) that included a composite primary outcome that incorporated all-cause mortality. Sixty-three trials (38%) were neutral both for the primary end point and the mortality component. Sixty trials (36%) reported significant results for the primary outcome measure but not for the mortality component. Only 6 trials (4%) were significant for the mortality component but not for the primary composite outcome, whereas 19 trials (11%) were significant for both. Twenty-two trials (13%) were inadequately reported. Our review suggests that reporting of composite outcomes is generally inadequate, implying that the results apply to the individual components of the composite outcome rather than only to the overall composite. Current guidelines for the undertaking and reporting of clinical trials could be revised to reflect the common use of composite outcomes in clinical trials.

In individual studies and limited meta-analyses venlafaxine has been reported to be more effective than comparator antidepressants, particularly selective serotonin reuptake inhibitors (SSRIs).To perform a systematic review of all such studies.We conducted a systematic review of double-blind, randomised trials comparing venlafaxine with alternative antidepressants in the treatment of depression. The primary outcome was the difference in final depression rating scale value, expressed as a standardised effect size. Secondary outcomes were response rate, remission rate and tolerability.A total of 32 randomised trials were included. Venlafaxine was more effective than other antidepressants (standardised effect size was -0.14, 95% Cl -0.07 to -0.22). A similar significant advantage was found against SSRIs (20 studies) but not tricyclic antidepressants (7 studies).Venlafaxine has greater efficacy than SSRIs although there is uncertainty in comparison with other antidepressants. Further studies are required to determine the clinical importance of this finding.

Background Heart failure is a prevalent condition that is generally treated in primary care. The aim of this study was to assess how primary-care physicians think that heart failure should be managed, how they implement their knowledge, and whether differences exist in practice between countries. Methods The survey was undertaken in 15 countries that had membership of the European Society of Cardiology (ESC) between Sept 1, 1999, and May 31, 2000. Primary-care physicians' knowledge and perceptions about the management of heart failure were assessed with a perception survey and how a representative sample of patients was managed with an actual practice survey. Findings 1363 physicians provided data for 11 062 patients, of whom 54% were older than 70 years and 45% were women. 82% of patients had had an echocardiogram but only 51% of these showed left ventricular systolic dysfunction. Ischaemic heart disease, hypertension, diabetes mellitus, atrial fibrillation, and major valve disease were all common. Physicians gave roughly equal priority to improvement of symptoms and prognosis. Most were aware of the benefits of ACE inhibitors and β blockers. 60% of patients were prescribed ACE inhibitors, 34% β blockers but only 20% received these drugs in combination. Doses given were about 50% of targets suggested in the ESC guidelines. If systolic dysfunction was documented, ACE inhibitors were more likely and β blockers less likely to be prescribed than when there was no evidence of systolic dysfunction. Interpretation Results from this survey suggest that most patients with heart failure are appropriately investigated, although this finding might be as a result of high rates of hospital admissions. However, treatment seems to be less than optimum, and there are substantial variations in practice between countries. The inconsistencies between physicians' knowledge and the treatment that they deliver suggests that improved organisation of care for heart failure is required.

The Effective Health Care bulletins have con- centrated on providing systematic reviews of the research evidence on clinical and cost effectiveness to help inform decision makers and clinicians in the NHS.However, providing information by itself is rarely sufficient to stimulate corresponding change in practice.Various implementation strategies can be used to promote the use of research evidence.One approach which has received growing attention and support is the development and implemen- tation of clinical practice guidelines.' 2 These

To examine whether gender differences in primary care consultation rates (1) vary by age and deprivation status and (2) diminish when consultation for reproductive reasons or common underlying morbidities are accounted for.Cross-sectional study of a cohort of patients registered with general practice.UK primary care.Patients (1 869 149 men and 1 916 898 women) registered with 446 eligible practices in 2010.Primary care consultation rate.This study analyses routinely collected primary care consultation data. The crude consultation rate was 32% lower in men than women. The magnitude of gender difference varied across the life course, and there was no 'excess' female consulting in early and later life. The greatest gender gap in primary care consultations was seen among those aged between 16 and 60 years. Gender differences in consulting were higher in people from more deprived areas than among those from more affluent areas. Accounting for reproductive-related consultations diminished but did not eradicate the gender gap. However, consultation rates in men and women who had comparable underlying morbidities (as assessed by receipt of medication) were similar; men in receipt of antidepressant medication were only 8% less likely to consult than women in receipt of antidepressant medication (relative risk (RR) 0.916, 95% CI 0.913 to 0.918), and men in receipt of medication to treat cardiovascular disease were just 5% less likely to consult (RR=0.950, 95% CI 0.948 to 0.952) than women receiving similar medication. These small gender differences diminished further, particularly for depression (RR=0.950, 95% CI 0.947 to 0.953), after also taking account of reproductive consultations.Overall gender differences in consulting are most marked between the ages of 16 and 60 years; these differences are only partially accounted for by consultations for reproductive reasons. Differences in consultation rates between men and women were largely eradicated when comparing men and women in receipt of medication for similar underlying morbidities.

The ESC/EACTS Guidelines represent the views of the ESC and the EACTS and were produced after careful consideration of the scientific and medical knowledge and the evidence available at the time of their publication.The ESC and the EACTS are not responsible in the event of any contradiction, discrepancy and/ or ambiguity between the ESC/EACTS Guidelines and any other official recommendations or guidelines issued by the relevant public health authorities, in particular in relation to good use of healthcare or therapeutic strategies.Health professionals are encouraged to take the ESC/EACTS Guidelines fully into account when exercising their clinical judgment, as well as in the determination and the implementation of preventive, diagnostic or therapeutic medical strategies; however, the ESC/ EACTS Guidelines do not override, in any way whatsoever, the individual responsibility of health professionals to make appropriate and accurate decisions in consideration of each patient's health condition and in consultation with that patient and, where appropriate and/or necessary, the patient's caregiver.Nor do the ESC/ EACTS Guidelines exempt health professionals from taking into full and careful consideration the relevant official updated recommendations or guidelines issued by the competent public health authorities, in order to manage each patient's case in light of the scientifically accepted data pursuant to their respective ethical and professional obligations.It is also the health professional's responsibility to verify the applicable rules and regulations relating to drugs and medical devices at the time of prescription.

To examine the evidence for using selective serotonin reuptake inhibitors instead of tricyclic antidepressants in the first line treatment of depression.Meta-analysis of 63 randomised controlled trials comparing the efficacy and acceptability of selective serotonin reuptake inhibitors with those of tricyclic and related antidepressants.Improvement in mean scores on Hamilton depression rating scale for 53 randomised controlled trials. Pooled drop out rates from the 58 trials which reported drop out by treatment group.Among the 20 studies reporting standard deviation for the Hamilton score no difference was found in efficacy between serotonin reuptake inhibitors and tricyclic and related antidepressants (standardised mean difference 0.004, 95% confidence interval -0.096 to 0.105). The difference remained insignificant when the remaining 33 studies that used the 17 item and 21 item Hamilton score were included by ascribing weighted standard deviations. The odds ratio for drop out rate in patients receiving serotonin reuptake inhibitors compared with those receiving tricyclic antidepressants was 0.95 (0.86 to 1.07). Similar proportions in both groups cited lack of efficacy as the reason for dropping out but slightly more patients in the tricyclic group cited side effects (18.8% v 15.4% in serotonin reuptake group).Routine use of selective serotonin reuptake inhibitors as the first line treatment of depressive illness may greatly increase cost with only questionable benefit.

<h3>Context</h3> Selective serotonin reuptake inhibitors (SSRIs) are often described as having a delayed onset of effect in the treatment of depression. However, some trials have reported clinical improvement as early as the first week of treatment. <h3>Objective</h3> To test the alternative hypotheses of delayed vs early onset of antidepressant action with SSRIs in patients with unipolar depression. <h3>Data Sources</h3> Trials identified by searching CENTRAL, The Cochrane Collaboration database of controlled trials (2005), and the reference lists of identified trials and other systematic reviews. <h3>Study Selection</h3> Randomized controlled trials of SSRIs vs placebo for the treatment of unipolar depression in adults that reported outcomes for at least 2 time points in the first 4 weeks of treatment (50 trials from &gt;500 citations identified). Trials were excluded if limited to participants older than 65 years or specific comorbidities. <h3>Data Extraction</h3> Data were extracted on trial design, participant characteristics, and outcomes by a single reviewer. <h3>Data Synthesis</h3> Pooled estimates of treatment effect on depressive symptom rating scales were calculated for weeks 1 through 6 of treatment. In the primary analysis, the pattern of response seen was tested against alternative models of onset of response. The primary analysis incorporated data from 28 randomized controlled trials (n = 5872). A model of early treatment response best fit the experimental data. Treatment with SSRIs rather than placebo was associated with clinical improvement by the end of the first week of use. A secondary analysis indicated an increased chance of achieving a 50% reduction in Hamilton Depression Rating Scale scores by 1 week (relative risk, 1.64; 95% confidence interval, 1.2-2.25) with SSRI treatment compared with placebo. <h3>Conclusions</h3> Treatment with SSRIs is associated with symptomatic improvement in depression by the end of the first week of use, and the improvement continues at a decreasing rate for at least 6 weeks.

to measure the impact of pharmacist-conducted clinical medication review with elderly care home residents.randomised controlled trial of clinical medication review by a pharmacist against usual care.sixty-five care homes for the elderly in Leeds, UK.a total of 661 residents aged 65+ years on one or more medicines.clinical medication review by a pharmacist with patient and clinical records. Recommendations to general practitioner for approval and implementation. Control patients received usual general practitioner care.primary: number of changes in medication per participant. Secondary: number and cost of repeat medicines per participant; medication review rate; mortality, falls, hospital admissions, general practitioner consultations, Barthel index, Standardised Mini-Mental State Examination (SMMSE).the pharmacist reviewed 315/331 (95.2%) patients in 6 months. A total of 62/330 (18.8%) control patients were reviewed by their general practitioner. The mean number of drug changes per patient were 3.1 for intervention and 2.4 for control group (P < 0.0001). There were respectively 0.8 and 1.3 falls per patient (P < 0.0001). There was no significant difference for GP consultations per patient (means 2.9 and 2.8 in 6 months, P = 0.5), hospitalisations (means 0.2 and 0.3, P = 0.11), deaths (51/331 and 48/330, P = 0.81), Barthel score (9.8 and 9.3, P = 0.06), SMMSE score (13.9 and 13.8, P = 0.62), number and cost of drugs per patient (6.7 and 6.9, P = 0.5) (pounds sterling 42.24 and pounds sterling 42.94 per 28 days). A total of 75.6% (565/747) of pharmacist recommendations were accepted by the general practitioner; and 76.6% (433/565) of accepted recommendations were implemented.general practitioners do not review most care home patients' medication. A clinical pharmacist can review them and make recommendations that are usually accepted. This leads to substantial change in patients' medication regimens without change in drug costs. There is a reduction in the number of falls. There is no significant change in consultations, hospitalisation, mortality, SMMSE or Barthel scores.

This article provides information and a commentary on trials presented at the American Heart Association meeting held in November 2005, relevant to the pathophysiology, prevention and treatment of heart failure. All reports should be considered as preliminary data, as analyses may change in the final publication. In REPAIR-AMI an improvement in ejection fraction was observed in post-MI patients following infusion of bone marrow stem cells. However, the ASTAMI study showed no benefit of stem cell implantation in a similar patient cohort. The JELIS study reported a reduction in major coronary events in patients receiving statins plus fish oil compared to statins alone. MEGA showed that low dose statins in a low risk population reduce the incidence of major cardiovascular events. Two studies of levosimendan in acute heart failure gave conflicting results, in the REVIVE-II study levosimendan was reported to have a superior effect on the composite primary outcome compared to placebo, however, in SURVIVE despite a trend to early benefit with levosimendan, there was no difference in effect on long-term outcome versus dobutamine. The PROACTIVE study showed encouraging results for the use of pioglitazone in post-myocardial infarction patients with concomitant type 2 diabetes.

To assess whether weekend admissions to hospital and/or already being an inpatient on weekend days were associated with any additional mortality risk.Retrospective observational survivorship study. We analysed all admissions to the English National Health Service (NHS) during the financial year 2009/10, following up all patients for 30 days after admission and accounting for risk of death associated with diagnosis, co-morbidities, admission history, age, sex, ethnicity, deprivation, seasonality, day of admission and hospital trust, including day of death as a time dependent covariate. The principal analysis was based on time to in-hospital death.National Health Service Hospitals in England.30 day mortality (in or out of hospital).There were 14,217,640 admissions included in the principal analysis, with 187,337 in-hospital deaths reported within 30 days of admission. Admission on weekend days was associated with a considerable increase in risk of subsequent death compared with admission on weekdays, hazard ratio for Sunday versus Wednesday 1.16 (95% CI 1.14 to 1.18; P < .0001), and for Saturday versus Wednesday 1.11 (95% CI 1.09 to 1.13; P < .0001). Hospital stays on weekend days were associated with a lower risk of death than midweek days, hazard ratio for being in hospital on Sunday versus Wednesday 0.92 (95% CI 0.91 to 0.94; P < .0001), and for Saturday versus Wednesday 0.95 (95% CI 0.93 to 0.96; P < .0001). Similar findings were observed on a smaller US data set.Admission at the weekend is associated with increased risk of subsequent death within 30 days of admission. The likelihood of death actually occurring is less on a weekend day than on a mid-week day.

The ESC Guidelines represent the views of the ESC and were produced after careful consideration of the scientific and medical knowledge and the evidence available at the time of their dating.The ESC is not responsible in the event of any contradiction, discrepancy and/or ambiguity between the ESC Guidelines and any other official recommendations or guidelines issued by the relevant public health authorities, in particular in relation to good use of health care or therapeutic strategies.Health professionals are encouraged to take the ESC Guidelines fully into account when exercising their clinical judgment as well as in the determination and the implementation of preventive, diagnostic or therapeutic medical strategies.However, the ESC Guidelines do not override in any way whatsoever the individual responsibility of health professionals to make appropriate and accurate decisions in consideration of each patient's health condition and in consultation with that patient and the patient's caregiver where appropriate and/or necessary.Nor do the ESC Guidelines exempt health professionals from taking careful and full consideration of the relevant official updated recommendations or guidelines issued by the competent public health authorities in order to manage each patient's case in light of the scientifically accepted data pursuant to their respective ethical and professional obligations.It is also the health professional's responsibility to verify the applicable rules and regulations relating to drugs and medical devices at the time of prescription.

The final analysis of this 2-year, randomized, crossover study showed that postmenopausal women with osteoporosis were more adherent, compliant, and persistent with subcutaneous denosumab injections every 6 months than with once-weekly alendronate tablets. After receiving both treatments, women reported greater satisfaction with injectable denosumab and preferred it over oral alendronate.Osteoporosis patients who are non-compliant or non-persistent with therapy may have suboptimal clinical outcomes. This 2-year, randomized, open-label, crossover study compared treatment adherence between subcutaneous denosumab, 60 mg every 6 months, and oral alendronate, 70 mg once weekly.Postmenopausal women at 25 centers in the USA and Canada with bone mineral density T-scores -4.0 to -2.0 and no prior bisphosphonate use received alendronate then denosumab, or denosumab then alendronate, over successive 12-month periods. Adherence required both compliance (denosumab injections 6 months apart or ≥ 80% of alendronate tablets) and persistence (both denosumab injections or ≥ 2 alendronate doses in the last month and completion of the treatment period).Of the 250 women enrolled (124 alendronate, 126 denosumab), 221 entered the second year (106 denosumab, 115 alendronate). Denosumab was associated with less non-adherence than alendronate (first year, 11.9% vs 23.4%; second year, 7.5% vs 36.5%). Risk ratios for non-adherence, non-compliance, and non-persistence favored denosumab in both years (p < 0.05). Of 198 subjects expressing treatment preference, 183 (92.4%) preferred the injections over the oral therapy. BMD improved further when subjects received denosumab after alendronate and remained stable when they received alendronate after denosumab.Based on the final results of this crossover study after women had received each treatment for up to 1 year, postmenopausal women with osteoporosis were more adherent, compliant, and persistent with subcutaneous denosumab injections every 6 months than with once-weekly alendronate tablets and reported increased treatment preference and satisfaction with injectable denosumab over oral alendronate.

Nick Freemantle and colleagues discuss the findings of their updated analysis of weekend admissions and the implications for service design

Generalised anxiety disorder is a disease that can be associated with substantial dysfunction. Pharmacological treatment is often the first choice for clinicians because of the cost and resource constraints of psychological alternatives, but there is a paucity of comparative information for the multiple available drug choices.A systematic review and network meta-analysis was performed on randomised trials in adult outpatients with generalised anxiety disorder identified from MEDLINE, Web of Science, Cochrane Library, ClinicalTrials.gov, Chinese National Knowledge Infrastructure (CNKI), Wanfang data, Drugs@FDA and commercial pharmaceutical registries. Placebo and active control trials were included. Data were extracted from all manuscripts and reports. Primary outcomes were efficacy (mean difference [MD] in change in Hamilton Anxiety Scale Score) and acceptability (study discontinuations for any cause). We estimated summary mean treatment differences and odds ratios using network meta-analyses with random effects. This study is registered with PROSPERO, number CRD42018087106.Studies were published between Jan 1, 1994 and Aug 1, 2017, in which 1992 potential studies were screened for inclusion. This analysis is based on 89 trials, which included 25 441 patients randomly assigned to 22 different active drugs or placebo. Duloxetine (MD -3·13, 95% credible interval [CrI] -4·13 to -2·13), pregabalin (MD -2·79, 95% CrI -3·69 to -1·91), venlafaxine (MD -2·69, 95% CrI -3·50 to -1·89), and escitalopram (MD -2·45, 95% CrI -3·27 to -1·63) were more efficacious than placebo with relatively good acceptability. Mirtazapine, sertraline, fluoxetine, buspirone, and agomelatine were also found to be efficacious and well tolerated but these findings were limited by small sample sizes. Quetiapine (MD -3·60 95% CrI -4·83 to -2·39) had the largest effect on HAM-A but it was poorly tolerated (odds ratio 1·44, 95% CrI 1·16-1·80) when compared with placebo. Likewise, paroxetine and benzodiazepines were effective but also poorly tolerated when compared with placebo. Risk of reporting bias was considered low, and when possible all completed studies were included to avoid publication bias.To our knowledge, this is the largest contemporary review of pharmacological agents for the treatment of generalised anxiety disorder by use of network analysis. There are several effective treatment choices for generalised anxiety disorder across classes of medication. The failure of initial pharmacological therapy might not be a reason to abandon a pharmacological treatment strategy.No funding was received for this research.

Mixed treatment comparisons (MTC) were performed to assess the relative efficacy and tolerability of the main anti-arrhythmic drugs used for the treatment of atrial fibrillation (AF)/flutter.Electronic databases were systematically searched to identify randomized controlled trials (RCTs) examining amiodarone, dronedarone, flecainide, propafenone, sotalol, or placebo for the treatment of AF. Thirty-nine RCTs met inclusion criteria and were combined using MTC models to provide direct and indirect comparisons in a single analysis. Results are presented vs. placebo. Amiodarone had the largest effect in reducing AF recurrence (OR 0.22, 95% CI 0.16-0.29). Amiodarone was associated with the highest rate of patients experiencing at least one serious adverse event (OR 2.41, 95% CI 0.96-6.06) and treatment withdrawals due to adverse events (OR 2.91, 95% CI 1.66-5.11). Dronedarone was associated with the lowest rate of proarrhythmic events including bradycardia (OR 1.45, 95% CI 1.02-2.08). Dronedarone significantly reduced the risk of stroke (OR 0.69, 95% CI 0.57-0.84). Trends towards increased mortality for sotalol (OR 3.44, 95% CI 1.02-11.59) and amiodarone (OR 2.17, 95% CI 0.63-7.51) were found, which were stronger when small studies randomizing <100 subjects per group were excluded.Amiodarone has been demonstrated to be the most effective drug in maintaining sinus rhythm. Differences in outcomes between the anti-antiarrhythmic drugs were reported, with sotalol and possibly amiodarone increasing mortality and dronedarone possibly decreasing the incidence of serious adverse events and proarrhythmia.

Infection and increased systemic inflammation cause organ dysfunction and death in patients with decompensated cirrhosis. Preclinical studies provide support for an antiinflammatory role of albumin, but confirmatory large-scale clinical trials are lacking. Whether targeting a serum albumin level of 30 g per liter or greater in these patients with repeated daily infusions of 20% human albumin solution, as compared with standard care, would reduce the incidences of infection, kidney dysfunction, and death is unknown.

Propensity score based methods are used increasingly to evaluate the effectiveness of treatments when evidence from randomised trials is not available. However, users need to be aware of their strengths and limitations

Heterogeneity in meta-analysis describes differences in treatment effects between trials that exceed those we may expect through chance alone. Accounting for heterogeneity drives different statistical methods for summarizing data and, if heterogeneity is anticipated, a random-effects model will be preferred to the fixed-effects model. Random-effects models assume that there may be different underlying true effects estimated in each trial which are distributed about an overall mean. The confidence intervals (CIs) around the mean include both within-study and between-study components of variance (uncertainty). Summary effects provide an estimation of the average treatment effect, and the CI depicts the uncertainty around this estimate. There are 5 statistics that are computed to identify and quantify heterogeneity. They have different meaning and give complementary information: Q statistic and its P-value simply test whether effect sizes depart from homogeneity, T2 and T quantify the amount of heterogeneity, and I2 expresses the proportion of dispersion due to heterogeneity. The point estimate and CIs for random-effects models describe the practical implications of the observed heterogeneity and may usefully be contrasted with the fixed-effects estimates.

A passage under the title "Indications for intervention" should read, "women with low BSA, TGFBR2 mutation, and severe extra-aortic features", instead of "women with low BSA, patients with a TGFBR2 mutation, or patients with severe extra-aortic features that appear to be at particularly high risk".Note 'e' from the legend for the table titled Recommendations on indications for surgery in (A) severe aortic regurgitation and (B) aortic root or tubular ascending aortic aneurysm (irrespective of the severity of aortic regurgitation) should read, "A lower threshold of 40 mm may be considered in women with low BSA" instead of "A lower threshold of 40 mm may be considered in women with low BSA, in patients with a TGFBR2 mutation or in patients with severe extra-aortic features".

Patients with depression who are treated in primary care practices may receive antidepressants for prolonged periods. Data are limited on the effects of maintaining or discontinuing antidepressant therapy in this setting.We conducted a randomized, double-blind trial involving adults who were being treated in 150 general practices in the United Kingdom. All the patients had a history of at least two depressive episodes or had been taking antidepressants for 2 years or longer and felt well enough to consider stopping antidepressants. Patients who had received citalopram, fluoxetine, sertraline, or mirtazapine were randomly assigned in a 1:1 ratio to maintain their current antidepressant therapy (maintenance group) or to taper and discontinue such therapy with the use of matching placebo (discontinuation group). The primary outcome was the first relapse of depression during the 52-week trial period, as evaluated in a time-to-event analysis. Secondary outcomes were depressive and anxiety symptoms, physical and withdrawal symptoms, quality of life, time to stopping an antidepressant or placebo, and global mood ratings.A total of 1466 patients underwent screening. Of these patients, 478 were enrolled in the trial (238 in the maintenance group and 240 in the discontinuation group). The average age of the patients was 54 years; 73% were women. Adherence to the trial assignment was 70% in the maintenance group and 52% in the discontinuation group. By 52 weeks, relapse occurred in 92 of 238 patients (39%) in the maintenance group and in 135 of 240 (56%) in the discontinuation group (hazard ratio, 2.06; 95% confidence interval, 1.56 to 2.70; P<0.001). Secondary outcomes were generally in the same direction as the primary outcome. Patients in the discontinuation group had more symptoms of depression, anxiety, and withdrawal than those in the maintenance group.Among patients in primary care practices who felt well enough to discontinue antidepressant therapy, those who were assigned to stop their medication had a higher risk of relapse of depression by 52 weeks than those who were assigned to maintain their current therapy. (Funded by the National Institute for Health Research; ANTLER ISRCTN number, ISRCTN15969819.).

Allergen immunotherapy (AIT) is the only causal treatment for respiratory allergy. Long-term real-life effectiveness of AIT remains to be demonstrated beyond the evidence from randomised controlled trials (RCTs).REACT (Real world effectiveness in allergy immunotherapy) is a retrospective cohort study using claims data between 2007 and 2017. Study eligibility was a confirmed diagnosis of allergic rhinitis (AR), with or without asthma, and AIT. To ensure comparable groups, AIT-treated subjects were propensity score matched 1:1 with control subjects, using characteristic and potential confounding variables. Outcomes were analysed as within (pre vs post AIT) and between (AIT vs control) group differences across 9 years of follow-up (ClinicalTrial.gov: NCT04125888).46,024 AIT-treated subjects were matched with control subjects and 14,614 were included in the pre-existing asthma cohort. AIT-treated subjects were 29·5 (16·3) years and 53% were male. Compared to pre-index year, AIT was consistently associated with greater reductions compared to control subjects in AR and asthma prescriptions, including both asthma controller and reliever prescriptions. Additionally, the AIT group had significantly greater likelihood of stepping down asthma treatment (P <0·0001). In addition to the reduction in asthma treatment in the AIT group, a greater reduction in severe asthma exacerbations was demonstrated (P<0·05). Reductions in pneumonia with antibiotic prescriptions, hospitalisations, and duration of inpatients stays were all in favour of AIT.The study extends the existing RCT evidence for AIT by demonstrating longer-term and sustained effectiveness of AIT in the real world. Additionally, in patients with concurrent asthma, AIT was associated with reduced likelihood of asthma exacerbations and pneumonia.The study was funded by ALK A/S.

Abstract Aims The aims of this study were to assess prescription patterns, dosages, discontinuation rates, and association with prognosis of conventional heart failure medications in patients with transthyretin cardiac amyloidosis (ATTR-CA). Methods and results A retrospective analysis of all consecutive patients diagnosed with ATTR-CA at the National Amyloidosis Centre between 2000 and 2022 identified 2371 patients with ATTR-CA. Prescription of heart failure medications was greater among patients with a more severe cardiac phenotype, comprising beta-blockers in 55.4%, angiotensin-converting enzyme inhibitors (ACEis)/angiotensin II receptor blockers (ARBs) in 57.4%, and mineralocorticoid receptor antagonists (MRAs) in 39.0% of cases. During a median follow-up of 27.8 months (interquartile range 10.6–51.3), 21.7% had beta-blockers discontinued, and 32.9% had ACEi/ARBs discontinued. In contrast, only 7.5% had MRAs discontinued. A propensity score-matched analysis demonstrated that treatment with MRAs was independently associated with a reduced risk of mortality in the overall population [hazard ratio (HR) 0.77 (95% confidence interval (CI) 0.66–0.89), P &amp;lt; .001] and in a pre-specified subgroup of patients with a left ventricular ejection fraction (LVEF) &amp;gt;40% [HR 0.75 (95% CI 0.63–0.90), P = .002]; and treatment with low-dose beta-blockers was independently associated with a reduced risk of mortality in a pre-specified subgroup of patients with a LVEF ≤40% [HR 0.61 (95% CI 0.45–0.83), P = .002]. No convincing differences were found for treatment with ACEi/ARBs. Conclusion Conventional heart failure medications are currently not widely prescribed in ATTR-CA, and those that received medication had more severe cardiac disease. Beta-blockers and ACEi/ARBs were often discontinued, but low-dose beta-blockers were associated with reduced risk of mortality in patients with a LVEF ≤40%. In contrast, MRAs were rarely discontinued and were associated with reduced risk of mortality in the overall population; but these findings require confirmation in prospective randomized controlled trials.

To review systematically the use of intravenous (IV) inotropic agents acting through the adrenergic signalling pathway, compared with placebo or an active agent, in patients with heart failure.Studies investigating the use of intravenous inotropes in patients with heart failure published between 1966 and 2000 were identified using MEDLINE, the Cochrane register and Embase databases. Reference lists from relevant papers and reviews were hand searched for further papers. In total, 21 trials, that included 632 patients receiving IV inotropic drugs, placebo or non-treatment control, were identified. Drugs of the following classes were included, the beta-agonists; dobutamine, high-dose (>2.5 microg/kg/min) dopamine, dopexamine and the phosphodiesterase (PDE) inhibitors; amrinone, milrinone, enoximone and toborinone. Sixteen trials (474 patients) contributed data from acute invasive haemodynamic studies of symptomatically severe heart failure. Five trials (158 patients) were based on intermittent inotropic therapy in an outpatient context.With few exceptions, trials of intravenous inotropic agents were small and often failed to report clinically important outcomes. Compared to placebo, intravenous inotropic agents acting through the adrenergic system tended to increase mortality (odds ratio 1.50 (95% CI=0.51 to 3.92) but this did not reach significance and insufficient data were available to determine whether symptoms improved. There appeared to be little difference in the effect of beta-agonists compared to PDE inhibitors on patient outcomes but this could be attributed to the paucity of data.Intravenous inotropic agents acting through the adrenergic pathway are often used in patients with worsening heart failure to achieve arbitrary haemodynamic targets. Our analyses show that there is very little evidence that such treatment improves symptoms or patient outcomes and may not be safe. This highlights the need for further well designed randomised clinical trials.

Background Educational meetings and printed educational materials are the two most common types of continuing education for health professionals. An important aim of continuing education is to improve professional practice so that patients can receive improved health care. Objectives To assess the effects of educational meetings on professional practice and health care outcomes. Search methods We searched the Cochrane Effective Practice and Organisation of Care Group specialised register, MEDLINE (from 1966), the Research and Development Resource Base in Continuing Medical Education in January 1999 and reference lists of articles. Selection criteria Randomised trials or well designed quasi‐experimental studies examining the effect of continuing education meetings (including lectures, workshops, and courses) on the clinical practice of health professionals or health care outcomes. Data collection and analysis Two reviewers independently applied inclusion criteria, assessed the quality of each study, and extracted study data. We attempted to collect missing data from investigators. We conducted both qualitative and quantitative analyses. Main results Thirty‐two studies were included with a total of 36 comparisons. The studies involved from 13 to 411 health professionals (total N= 2995) and were judged to be of moderate or high quality, although methods were generally poorly reported. There was substantial variation in the complexity of the targeted behaviours, baseline compliance, the characteristics of the interventions and the results. The heterogeneity of the results was best explained by differences in the interventions. For 10 comparisons of interactive workshops, there were moderate or moderately large effects in six (all of which were statistically significant) and small effects in four (one of which was statistically significant). For interventions that combined workshops and didactic presentations, there were moderate or moderately large effects in 12 comparisons (eleven of which were statistically significant) and small effects in seven comparisons (one of which was statistically significant). In seven comparisons of didactic presentations, there were no statistically significant effects, with the exception of one out of four outcome measures in one study. Authors' conclusions Interactive workshops can result in moderately large changes in professional practice. Didactic sessions alone are unlikely to change professional practice.

Objective To determine whether a pharmacist can effectively review repeat prescriptions through consultations with elderly patients in general practice.Design Randomised controlled trial of clinical medication review by a pharmacist against normal general practice review.Setting Four general practices.Participants 1188 patients aged 65 or over who were receiving at least one repeat prescription and living in the community.Intervention Patients were invited to a consultation at which the pharmacist reviewed their medical conditions and current treatment.Main outcome measures Number of changes to repeat prescriptions over one year, drug costs, and use of healthcare services.Results 590 (97%) patients in the intervention group were reviewed compared with 233 (44%) in the control group.Patients seen by the pharmacist were more likely to have changes made to their repeat prescriptions (mean number of changes per patient 2.2 v 1.9; difference = 0.31, 95% confidence interval 0.06 to 0.57; P = 0.02).Monthly drug costs rose in both groups over the year, but the rise was less in the intervention group (mean difference £4.72 per 28 days, -£7.04 to -£2.41); equivalent to £61 per patient a year.Intervention patients had a smaller rise in the number of drugs prescribed (0.2 v 0.4; mean difference -0.2, -0.4 to -0.1).There was no evidence that review of treatment by the pharmacist affected practice consultation rates, outpatient consultations, hospital admissions, or death rate.Conclusions A clinical pharmacist can conduct effective consultations with elderly patients in general practice to review their drugs.Such review results in significant changes in patients' drugs and saves more than the cost of the intervention without affecting the workload of general practitioners.

Abstract Background: Cardiac resynchronisation is a promising new intervention for patients with heart failure, left ventricular systolic dysfunction and ventricular dyssynchrony. Objective: The CARE‐HF trial is designed to evaluate the long‐term effects of cardiac (atrio‐bi‐ventricular) resynchronisation on the mortality and morbidity of patients with heart failure due to left ventricular systolic dysfunction already receiving diuretics and optimal medical therapy with ACE inhibitors and beta‐blockers (where indicated and tolerated). Methods and Results: Approximately 800 patients will be randomised to device therapy or control and followed for a minimum of 18 months. A pragmatic study design has been chosen that does not attempt to conceal allocation from investigators or patients because it is impossible to guarantee maintenance of blinding for the duration of the study. The end‐points committee will adjudicate events in a blinded fashion. Since cardiac resynchronisation may alter other aspects of the management of the patient, as would occur in clinical practice, the study should be considered a comparison of strategies rather than simply of a device. The primary end‐point is all‐cause mortality or unplanned cardiovascular hospitalisation. The study should complete recruitment during 2002 and report in 2004.

Abstract This article continues a series of reports on recent research developments in the field of heart failure. Key presentations made at the American College of Cardiology meeting, held in New Orleans, Louisiana, USA in March 2004 are reported. These new data have been added to existing data in cumulative meta‐analyses. The WATCH study randomised 1587 patients with heart failure and left ventricular systolic dysfunction to warfarin, aspirin or clopidogrel. The study showed no difference between the effects of these agents on mortality or myocardial infarction, but hospitalisations for heart failure were higher on aspirin (22.2%) compared to warfarin (16.1%). The SCD‐HeFT study showed that ICD therapy reduced all‐cause mortality at 5 years by 23% in patients with predominantly NYHA class II heart failure and left ventricular systolic dysfunction, but amiodarone was ineffective. The DINAMIT study showed that ICD therapy was not beneficial in patients with left ventricular dysfunction after a recent MI, even in those with risk factors for arrhythmic death. In CASINO, levosimendan improved survival compared with dobutamine or placebo in patients with decompensated heart failure. INSPIRE showed that SPECT imaging can be used to assess risk early after acute MI safely and accurately. Rimonabant was shown to be safe and effective in treating the combined cardiovascular risk factors of smoking and obesity. An overview of new developments in cardiac resynchronisation therapy (CRT) in heart failure is also reported.

In CARE-HF, cardiac resynchronization therapy (CRT) lowered morbidity and mortality in patients with moderate to severe heart failure. We examined whether baseline and follow-up electrocardiographic characteristics might predict long-term outcome.CARE-HF randomly assigned 409 patients to medical therapy (MT) plus CRT, and 404 patients to MT alone. Electrocardiographic measurements were made at baseline during sinus rhythm, and at 3 months during paced or spontaneous rhythm depending on treatment assignment. Favourable outcome was defined as freedom from death, urgent transplantation, or cardiovascular hospitalization. Among patients assigned to CRT, 39% had unfavourable outcomes including 55 deaths. By single variable analysis, (i) prolonged PR interval, left QRS axis (but not QRS duration), and left bundle branch block (BBB) at baseline, and (ii) heart rate, PR, and QRS duration at 3 months predicted unfavourable outcome. By multiple variable analysis, treatment assignment (P = 0.0001), PR (P = 0.0004), and right BBB (P < 0.00013) at baseline predicted outcome, whereas baseline JTc and QRS duration at 3 months predicted all-cause mortality and heart failure hospitalization (P = 0.0071).In CARE-HF, QRS duration at baseline did not predict outcome, but QRS at 3 months was a predictor by single variable analysis. Patients with prolonged PR interval and the 5% of patients with right BBB had a particularly high event rate.

This study was designed to investigate whether selected baseline variables and early response markers predict the effects of cardiac resynchronization therapy (CRT) on long-term mortality.Cardiac resynchronization therapy reduces long-term morbidity and mortality in patients with moderate or severe heart failure and markers of cardiac dyssynchrony, but not all patients respond to a similar extent.In the CARE-HF (Cardiac Resynchronization in Heart Failure) study, 813 patients with heart failure and markers of cardiac dyssynchrony were randomly assigned to receive or not receive CRT in addition to pharmacological treatment and were followed for a median of 37.6 months. A model including assigned treatment, 15 pre-specified baseline variables, and 8 markers of response at 3 months was constructed to predict all-cause mortality.On multivariable analysis, plasma concentration of amino terminal pro-brain natriuretic peptide (univariate and multivariable model chi-square test: 105.0 and 48.4; both p < 0.0001) and severity of mitral regurgitation (chi-square test: 44.0 and 17.9; both p < 0.0001) at 3 months, regardless of assigned treatment, were the strongest predictors of mortality. Ischemic heart disease as the cause of ventricular dysfunction (chi-square test: 34.9 and 7.4; p < 0.0001 and p = 0.0066), being in New York Heart Association functional class IV (chi-square test: 18.8 and 9.6; p < 0.0001 and p = 0.0020), or having less interventricular mechanical delay (chi-square test: 29.8 and 8.8; p < 0.0001 and p = 0.0029) at baseline all predicted a worse outcome. However, the reduction in mortality in patients assigned to CRT was similar before (hazard ratio: 0.602; 95% confidence interval: 0.468 to 0.774) and after (hazard ratio: 0.679; 95% confidence interval: 0.494 to 0.914) adjustment for variables measured at baseline and at 3 months.Patients who have more severe mitral regurgitation or persistently elevated amino terminal pro-brain natriuretic peptide despite treatment for heart failure, including CRT, have a higher mortality. However, patients assigned to CRT had a lower mortality even after adjusting for variables measured before and 3 months after intervention. The effect of CRT on mortality cannot be usefully predicted using such information. (CARE-HF CArdiac Resynchronization in Heart Failure; NCT00170300).

Aims Implantable loop recorders (ILR) provide an opportunity to record ECG data from a spontaneous syncopal event.We conducted a randomized study to investigate the impact of the Reveal Plus ILR on an unselected population of patients with recurrent syncope.Initial follow-up (at least 6 months) did not demonstrate a reduction in syncopal events or an improvement in quality of life.We report the planned extension of follow-up to 18 months.Methods and results All patients presenting acutely with recurrent unexplained syncope over a 16-month period, following a basic clinical work-up, were randomized to receive the ILR or conventional investigation and management.A total of 421 patients presented, 201 were eligible, median age 74, (IQ range 61-81) 54% female, with median syncopes 3 (IQ range 2-6).Median follow-up 17 months (IQ range 9-23).42 (43%) of ILR patients and 8 (6%) of conventional patients received an ECG diagnosis (hazard ratio 6.53, 95% CI 3.73-11.4,P , 0.001).Time to second syncope was significantly longer for ILR patients, although of borderline significance (P ¼ 0.04).A greater variety of diagnoses and treatments were seen in ILR patients.ILR patients had fewer post-randomization investigations and fewer days in hospital; however, cost savings were not statistically significant.There was improved quality of life in the ILR group (visual analogue scales, P ¼ 0.03) for general wellbeing.Overall mortality was 12% with no difference between the two groups.Conclusion Investigation by the ILR significantly increases the diagnostic rate and ECG directed treatments in a typical unselected syncopal population.Long-term follow-up has demonstrated a significant subsequent reduction in syncopal events with improved quality of life.

To assess the quality of life of patients with heart failure, due to left ventricular dysfunction (NYHA class III or IV), taking optimal medical therapy using baseline quality of life assessments from the CArdiac REsynchronisation in Heart Failure (CARE-HF) trial, and to evaluate the appropriateness of using the EQ-5D in patients with heart failure.The quality of life of patients enrolled in CARE-HF was evaluated using the EQ-5D and Minnesota Living with Heart Failure Questionnaire. Response rates for the instruments were >90% and statistical modelling revealed an association between EQ-5D and Minnesota Living with Heart Failure scores. Heart failure is shown to have an important impact on all aspects of quality of life, but particularly on patients' mobility and usual activities, and leads to significant reductions in comparison with a representative sample of the UK population.The impact of heart failure varies amongst patients but the overall burden of disease appears to be comparable to other chronic conditions such as motor neurone or Parkinson's disease. The EQ-5D appears to be an acceptable valid measure for use in patients with heart failure although further evidence of the responsiveness of this measure in such patients is required.

Atrial fibrillation/flutter (AF) and heart failure often coexist; however, the effect of cardiac resynchronization therapy (CRT) on the incidence of AF and on the outcome of patients with new-onset AF remains undefined.In the CArdiac REsynchronisation in Heart Failure (CARE-HF) trial, 813 patients with moderate or severe heart failure were randomly assigned to pharmacological therapy alone or with the addition of CRT. The incidence of AF was assessed by adverse event reporting and by ECGs during follow-up, and the impact of new-onset AF on the outcome and efficacy of CRT was evaluated. By the end of the study (mean duration of follow-up 29.4 months), AF had been documented in 66 patients in the CRT group compared with 58 who received medical therapy only (16.1% versus 14.4%; hazard ratio 1.05; 95% confidence interval, 0.73 to 1.50; P=0.79). There was no difference in the time until first onset of AF between groups. Mortality was higher in patients who developed AF, but AF was not a predictor in the multivariable model (hazard ratio 1.17; 95% confidence interval, 0.82 to 1.67; P=0.37). In patients with new-onset AF, CRT significantly reduced the risk for all-cause mortality and all other predefined end points and improved ejection fraction and symptoms (no interaction between AF and CRT; all P>0.2).Although CRT did not reduce the incidence of AF, CRT improved the outcome regardless of whether AF developed.

Aims The aim of the present study was to assess the long‐term effects of cardiac resynchronization therapy (CRT) on the reverse remodelling of the left ventricle (LV). Methods and results The effects of CRT compared with controls on LV dimensions and function were assessed at 3, 9, and 18 months and at the end of study (average 29 months) in 735 (90%) patients with adequate echocardiographic examinations, randomized in the CARE‐HF trial. Echocardiographic recordings were submitted to a core laboratory to ensure consistent quantitative analysis. LV volume decreased and ejection fraction increased substantially in the CRT group by 3 months and improved further at each assessment when compared with the control group. Effects were less marked in patients with ischaemic heart disease and those with right ventricular dysfunction, but not in patients with a restrictive LV filling pattern. The extent of reverse remodelling at 18 months showed a modest relationship with baseline interventricular mechanical delay (IVMD). Conclusion CRT induces sustained LV reverse remodelling with the most marked effects occurring within the first 3–9 months. The extent of remodelling in response to CRT is related to the aetiology of heart failure and, to a lesser extent, to the IVMD.

Randomised controlled trials generally suggest that cardiac resynchronisation improves outcomes in patients with heart failure due to left ventricular systolic dysfunction and cardiac dyssynchrony. Our objective was to provide a valid synthesis of the effects of CRT on mortality, major morbidity, quality of life and implantation success rates.Systematic overview and meta-analysis of randomised trials, both blinded and open, comparing cardiac resynchronisation with control. The primary outcome was all-cause mortality, and secondary outcomes included hospitalisation for worsening heart failure, quality of life and implantation success rates.We identified 8 randomised trials which included 3380 patients and observed a total of 524 deaths. Follow-up ranged from 1 month to a mean of 29.4 months. Most trials were of high quality, with centrally administered randomisation and few patients lost to follow-up. CRT reduced mortality in these trials (odds ratio 0.72, 95% CI 0.59 to 0.88). In addition CRT reduced hospitalisation for worsening heart failure (odds ratio 0.55, 95% CI 0.44 to 0.68) and improved quality of life as measured by the Minnesota Living with Heart Failure Questionnaire (weighted mean difference -7.1, 95% CI -2.9 to -11.4). Implantation success rates in the trials were 87% or greater.Cardiac resynchronisation in patients with heart failure characterised by dyssynchrony substantially reduces all-cause mortality, major morbidity and improves quality of life.

Aims Revascularization is frequently advocated to improve ventricular function and prognosis for patients with heart failure due to coronary artery disease, especially when there is evidence of extensive myocardial viability. Methods and results Patients with heart failure, coronary artery disease, and a left ventricular (LV) ejection fraction &lt;35%, who had a substantial volume of viable myocardium with contractile dysfunction assessed by any standard imaging technique, were randomly assigned to a strategy of conservative management vs. angiography with the intent of percutaneous or surgical revascularization. Patients requiring revascularization for angina or too frail for surgery were excluded. Only 138 of the planned 800 patients were enrolled because of withdrawal of funding due to slow recruitment. Also, a larger trial (The Surgical Treatment for Ischemic Heart Failure Trial) addressing a similar question became available, which investigators were encouraged to join. Of 69 patients assigned to the invasive strategy, 6 refused angiography, 2 died as a result of the diagnostic procedure, 14 were considered unsuitable for revascularization, 2 refused surgery, and 45 had revascularization. After a median follow‐up of 59 (inter‐quartile range: 33–63) months, there were 51 (37%) deaths; 25 (37%) in those assigned to the conservative strategy, and 26 (38%) in those assigned to the invasive strategy, 13 (29%) of whom had been revascularized. Conclusion A conservative management strategy may not be inferior to one of coronary arteriography with the intent to revascularize in patients with heart failure, LV systolic dysfunction, and extensive myocardial viability. However, this study was underpowered and, further, larger trials are required to settle this issue. Clinical trials Registration No: ISRCTN86284615

Quantitative evidence on the strength of the association between abdominal obesity and the incidence of type 2 diabetes was assessed.Systematic review of longitudinal studies assessing the relationship between measures reflecting abdominal obesity and the incidence of type 2 diabetes.There was a strong association between measures reflecting abdominal obesity and the incidence of type 2 diabetes, the pooled odds ratio was 2.14 (95% CI: 1.70-2.71; p < 0.0001). Waist circumference (WC) was at least as good as other measures in predicting outcome.There is a strong association between measures reflecting abdominal obesity and the development of type 2 diabetes. Reducing WC may reduce the risk of developing type 2 diabetes.

Cardiac resynchronization therapy (CRT-P) is an effective treatment for patients with heart failure and cardiac dyssynchrony with moderate or severe symptoms despite pharmacological therapy. The addition of an implantable cardioverter-defibrillator (ICD) function may further reduce the risk of sudden death. We assessed the cost-effectiveness of CRT-P compared with medical therapy (MT) alone, and the cost-effectiveness of CRT-ICD + MT compared with CRT-P + MT, on incremental cost per quality adjusted life year (QALY) and life year using data from two landmark clinical trials.A Markov model with Monte Carlo simulation to assess costs, life years, and QALYs associated with CRT (+/- ICD) and MT in patients with heart failure and cardiac dyssynchrony, on the basis of a UK healthcare perspective was constructed. NYHA class distribution and transitions, associated health utilities, rates and cause of hospitalization and death were estimated from individual patient data from the CArdiac REsychronization in Heart Failure (CARE-HF trial). The estimated additional benefit on survival of an ICD was based on results from COMPANION. The base case analysis used 10 000 individual life-time simulations assuming a battery life of 6 years for CRT-P and 7 years for CRT-ICD. From a life-time perspective in a 65-year-old patient, the incremental cost-effectiveness of CRT-P compared with MT is 7538 euros (95% CI 5325-11,784 euros) per QALY gained and 7011euros (95% CI 5346-10,003 euros) per life year gained. The incremental cost-effectiveness of CRT-ICD compared with CRT-P is 47,909 euros (95% CI 35,703-79,438 euros) per QALY gained, and 35,864 euros (95% CI 26,709-56,353 euros) per life year gained.Long-term treatment with CRT-P appears cost-effective compared with MT alone. From a life-time perspective, assuming a reasonable life expectancy when receiving effective treatment for heart failure, CRT-ICD may also be considered cost-effective when compared with CRT-P + MT.

Background The duration and cost of cancer clinical trials could be reduced if a surrogate endpoint were used in place of survival. We did a meta-analysis to assess the extent to which two surrogates, tumour response and time to progression, are predictive of mortality in metastatic colorectal cancer and non-small-cell lung cancer. Methods Summary data (median time to progression, proportion of patients responding to treatment, and median overall survival) from randomised trials of first-line treatment in colorectal cancer (146 trials) and lung cancer (191 trials) were identified. Data were extracted and analysed by linear regression. We used prediction bands for trials with 250, 500, and 750 patients to identify the surrogate threshold effect that would predict a significant difference in survival. Findings Response to treatment and time to progression correlated with improvement in survival for both lung cancer (p<0·0001 and p=0·0003, respectively) and colorectal cancer (p<0·0001 for both). To predict a significant survival gain in colorectal cancer trials, an improvement of 20% in the number of patients responding to treatment was required in trials with 750 patients, increasing to 26% in trials with 500 patients and 38% in trials with 250 patients. In lung cancer trials, the same prediction required differences in response of 18% for 750 patients, 21% for 500 patients, and 30% for 250 patients. For time to progression for both cancer types, the incremental gain needed to predict a survival improvement was a median of 1·8 months for trials with 750 patients, 2·2 months for 500 patients, and 3·3 months for 250 patients. Interpretation Irrespective of trial size, large differences in tumour response rate are needed to predict a significant survival benefit. If surrogates are chosen as the primary endpoint in a clinical trial, time to progression is the preferred measure because more modest and achievable differences are needed for a significant survival benefit. Trials in metastatic lung cancer and colorectal cancer should measure survival as their primary outcome unless the surrogate outcome difference is anticipated to exceed the threshold effect size.

Aims To assess procedural characteristics and adjudicated procedure-related (≤30 days) major adverse events among patients who underwent cardiac resynchronization therapy (CRT) implantation in the CARE-HF study. The CARE-HF study shows that CRT improves symptoms and reduces morbidity and mortality in New York Heart Association (NYHA) class III/IV chronic heart failure (CHF) patients. However, safe and proper implantation of pacing systems remains key to effective CRT delivery.

Objectives To examine the management of diabetes between 2001 and 2007 in the United Kingdom and to assess whether changes in the quality of care reflect existing temporal trends or are a direct result of the implementation of the quality and outcomes framework.Design Retrospective cohort study.Setting 147 general practices (annual list size over 1 million) across the UK.Patients People with type 1 or type 2 diabetes.Main outcome measures Annual prevalence of diabetes and attainment of process and clinical outcomes over the three years before and the three years after the introduction of the quality and outcomes framework.Results Significant improvements in process and intermediate outcome measures were observed during the six year period, with consecutive annual improvements observed before the introduction of incentives.However, the current diagnostic case definition for the quality and outcomes framework does not capture up to two thirds of people with type 1 diabetes and a third of people with type 2 diabetes.After the introduction of the quality and outcomes framework, existing trends of improvement in glycaemic control, cholesterol levels, and blood pressure were attenuated, particularly in people with diabetes who did not meet the case definition of the quality and outcomes framework.The introduction of the quality and outcomes framework did not lead to improvement in the management of patients with type 1 diabetes, nor to a reduction in the number of patients with type 2 diabetes who had HbA 1c levels greater than 10%.Introduction of the quality and outcomes framework may have increased the number of patients with type 2 diabetes with HbA 1c levels of ≤7.5%; odds ratio 1.05 (95% confidence interval 1.01 to 1.09; P=0.02).Conclusions The management of people with diabetes has improved since the late 1990s, but the impact of the quality and outcomes framework on care is not straightforward; upper thresholds may need to be removed or targets made more challenging if people are to benefit.Many patients in whom care may be suboptimal may not be captured in the quality and outcomes framework assessment.

The cardiac resynchronization therapy in heart failure trial (CARE-HF) demonstrated that cardiac resynchronization therapy (CRT) reduces morbidity and mortality in patients with heart failure and cardiac dyssynchrony. The aim of this study was to develop a prognostic model to evaluate the relationship between prospectively defined patient characteristics and treatment on the trial primary outcome of death from any cause or unplanned hospitalization for a major cardiovascular event.A total of 813 patients were enrolled in the CARE-HF study and were followed for a mean of 29.4 months. A Cox Proportional Hazards Model was fitted to identify predictors of the primary outcome and any predictors that modified the effect of CRT. Ischaemic aetiology, more severe mitral regurgitation and increased N-terminal pro-brain natriuretic peptide, were associated with an increased risk of death or unplanned cardiovascular hospitalization irrespective of cardiac resynchronization [Hazard ratio (HR) 1.89, 95% CI 1.45-2.46, HR 1.71, 95% CI 1.38-2.12 and HR 1.31, 95% CI 1.17-1.47, respectively] and increasing systolic blood pressure with a decreasing risk of an event (HR 0.99, 95% CI 0.98-1.00). The benefits of cardiac resynchronization were modified by systolic blood pressure and interventricular mechanical delay (IVMD). Patients with increasing systolic blood pressure appear to receive reduced benefit from CRT (HR 1.02, 95% CI 1.00-1.03), whereas those patients with more severe IVMD appear to benefit more from treatment (HR 0.99, 95% CI 0.98-1.00).Patients with echocardiographic evidence of more severe cardiac dyssynchrony and low systolic blood pressure obtain greater benefit from CRT, although benefits were substantial across the range of subjects included in the trial.

Cardiac dyssynchrony is common in patients with heart failure, whether or not they have ischaemic heart disease (IHD). The effect of the underlying cause of cardiac dysfunction on the response to cardiac resynchronization therapy (CRT) is unknown. This issue was addressed using data from the CARE-HF trial. Patients (n = 813) were grouped by heart failure aetiology (IHD n = 339 vs. non-IHD n = 473), and the primary composite (all-cause mortality or unplanned hospitalization for a major cardiovascular event) and principal secondary (all-cause mortality) endpoints analysed. Heart failure severity and the degree of dyssynchrony were compared between the groups by analysing baseline clinical and echocardiographic variables. Patients with IHD were more likely to be in NYHA class IV (7.5 vs. 4.0%; P = 0.03) and to have higher NT-proBNP levels (2182 vs. 1725 pg/L), indicating more advanced heart failure. The degree of dyssynchrony was more pronounced in patients without IHD (assessed using mean QRS duration, interventricular mechanical delay, and aorta-pulmonary pre-ejection time). Left ventricular ejection fraction and left ventricular end-systolic volume improved to a lesser extent in the IHD group (4.53 vs. 8.50% and −35.68 vs. –58.52 cm3). Despite these differences, CRT improved all-cause mortality, NYHA class, and hospitalization rates to a similar extent in patients with or without IHD. The benefits of CRT in patients with or without IHD were similar in relative terms in the CARE-HF study but as patients with IHD had a worse prognosis, the benefit in absolute terms may be greater.

Interventions to reduce treatment delay in first-episode psychosis have met with mixed results. Systematic reviews highlight the need for greater understanding of delays within the care pathway if successful strategies are to be developed.To document the care-pathway components of duration of untreated psychosis (DUP) and their link with delays in accessing specialised early intervention services (EIS). To model the likely impact on efforts to reduce DUP of targeted changes in the care pathway.Data for 343 individuals from the Birmingham, UK, lead site of the National EDEN cohort study were analysed.A third of the cohort had a DUP exceeding 6 months. The greatest contribution to DUP for the whole cohort came from delays within mental health services, followed by help-seeking delays. It was found that delay in reaching EIS was strongly correlated with longer DUP.Community education and awareness campaigns to reduce DUP may be constrained by later delays within mental health services, especially access to EIS. Our methodology, based on analysis of care pathways, will have international application when devising strategies to reduce DUP.

To examine the effect of setting, intensity, and timing of peer support on breast feeding.Systematic review and metaregression analysis of randomised controlled trials.Cochrane Library, Medline, CINAHL, the National Research Register, and British Nursing Index were searched from inception or from 1980 to 2011. Review methods Study selection, data abstraction, and quality assessment were carried out independently and in duplicate. Risk ratios and 95% confidence intervals were calculated for individual studies and pooled. Effects were estimated for studies grouped according to setting (high income countries, low or middle income countries, and the United Kingdom), intensity (<5 and ≥5 planned contacts), and timing of peer support (postnatal period with or without antenatal care), and analysed using metaregression for any and exclusive breast feeding at last study follow-up.Peer support interventions had a significantly greater effect on any breast feeding in low or middle income countries (P<0.001), reducing the risk of not breast feeding at all by 30% (relative risk 0.70, 95% confidence interval 0.60 to 0.82) compared with a reduction of 7% (0.93, 0.87 to 1.00) in high income countries. Similarly, the risk of non-exclusive breast feeding decreased significantly more in low or middle income countries than in high income countries: 37% (0.63, 0.52 to 0.78) compared with 10% (0.90, 0.85 to 0.97); P=0.01. No significant effect on breast feeding was observed in UK based studies. Peer support had a greater effect on any breastfeeding rates when given at higher intensity (P=0.02) and only delivered in the postnatal period (P<0.001), although no differences were observed of its effect on exclusive breastfeeding rates by intensity or timing.Although peer support interventions increase breastfeeding continuation in low or middle income countries, especially exclusive breast feeding, this does not seem to apply in high income countries, particularly the United Kingdom, where breastfeeding support is part of routine postnatal healthcare. Peer support of low intensity does not seem to be effective. Policy relating to provision of peer support should be based on more specific evidence on setting and any new peer services in high income countries need to undergo concurrent evaluation.

The Cardiac Resynchronization-Heart Failure (CARE-HF) study demonstrated that cardiac resynchronization therapy (CRT) could reduce morbidity and mortality and improve cardiac function in patients with moderate or severe heart failure secondary to left ventricular systolic dysfunction and markers of cardiac dyssynchrony. The purpose of this analysis was to investigate the effect of CRT on plasma concentrations of N-terminal pro-brain natriuretic peptide (NT-pro-BNP), a powerful marker of cardiac dysfunction and prognosis.Blood samples were collected routinely at baseline and 3 and 18 months. Plasma was separated by cool centrifugation and stored at -70 degrees C until transported to a central laboratory for analysis of NT-pro-BNP using a standard commercial assay. Cardiac function was assessed echocardiographically. At baseline, median plasma concentration of NT-pro-BNP was similar in patients assigned to CRT or medical therapy [1920 pg/mL (inter-quartile range (IQR) 744-4288) and 1809 pg/mL (IQR 719-3949), respectively]. The differences in medians between the CRT and medical therapy groups were highly significant at both 3 months (537 pg/mL; P < 0.0001) and 18 months of follow-up (567 pg/mL; P < 0.0001). These differences could not be accounted for by changes in pharmacological therapy or renal function but were associated with improvement in ventricular volumes and function.CRT exerts an early and sustained reduction in NT-pro-BNP. This appears to reflect improvements in ventricular function. NT-pro-BNP may be a simple method for monitoring the effects of CRT.

The efficacy of pharmaceuticals is most often demonstrated by randomised controlled trials (RCTs); however, in some cases, regulatory applications lack RCT evidence.To investigate the number and type of these approvals over the past 15 years by the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA).Drug approval data were downloaded from the EMA website and the 'Drugs@FDA' database for all decisions on pharmaceuticals published from 1 January 1999 to 8 May 2014. The details of eligible applications were extracted, including the therapeutic area, type of approval and review period.Over the period of the study, 76 unique indications were granted without RCT results (44 by the EMA and 60 by the FDA), demonstrating that a substantial number of treatments reach the market without undergoing an RCT. The majority was for haematological malignancies (34), with the next most common areas being oncology (15) and metabolic conditions (15). Of the applications made to both agencies with a comparable data package, the FDA granted more approvals (43/44 vs 35/44) and took less time to review products (8.7 vs 15.5 months). Products reached the market first in the USA in 30 of 34 cases (mean 13.1 months) due to companies making FDA submission before EMA submissions and faster FDA review time.Despite the frequency with which approvals are granted without RCT results, there is no systematic monitoring of such treatments to confirm their effectiveness or consistency regarding when this form of evidence is appropriate. We recommend a more open debate on the role of marketing authorisations granted without RCT results, and the development of guidelines on what constitutes an acceptable data package for regulators.

Network meta-analysis techniques (meta-analysis, adjusted indirect comparison, and mixed treatment comparison [MTC]) allow for treatment comparisons in the absence of head-to-head trials. In this study, conditional estimates of relative treatment efficacy derived through these techniques show important differences in the fracture risk reduction profiles of marketed pharmacologic therapies for postmenopausal osteoporosis. This study illustrates how network meta-analysis techniques (meta-analysis, adjusted indirect comparison, and MTC) can provide comparisons of the relative efficacy of postmenopausal osteoporosis therapies in the absence of comprehensive head-to-head trials. Source articles were identified in MEDLINE; EMBASE; Cochrane Central Register of Controlled Trials (CENTRAL) via Wiley Interscience; and Cumulative Index to Nursing and Allied Health Literature (CINAHL) between April 28, 2009 and November 4, 2009. Two reviewers identified English-language articles reporting randomized controlled trials (RCTs) with on-label dosing of marketed osteoporosis agents and fracture endpoints. Trial design, population characteristics, intervention and comparator, fracture outcomes, and adverse events were abstracted for analysis. Primary analyses included data from RCTs with fracture endpoints. Sensitivity analyses also included studies with fractures reported through adverse event reports. Meta-analysis compared fracture outcomes for pharmacological therapies vs. placebo (fixed and random effects models); adjusted indirect comparisons and MTC assessed fracture risk in postmenopausal women treated with denosumab vs. other agents. Using data from 34 studies, random effects meta-analysis showed that all agents except etidronate significantly reduced the risk of new vertebral fractures compared with placebo; denosumab, risedronate, and zoledronic acid significantly reduced the risk for nonvertebral and hip fracture, while alendronate, strontium ranelate, and teriparatide significantly reduced the risk for nonvertebral fractures. MTC showed denosumab to be more effective than strontium ranelate, raloxifene, alendronate, and risedronate in preventing new vertebral fractures. The conditional estimates of relative treatment efficacy indicate that there are important differences in fracture risk reduction profiles for marketed pharmacological therapies for postmenopausal osteoporosis.

Aims The Cardiac Resynchronization‐Heart Failure (CARE‐HF) study helped establish an important role for cardiac resynchronization therapy (CRT) in the management of selected patients with heart failure. We now report the long‐term outcome during and subsequent to the randomized trial. Methods and results Enrolment was completed in March 2003. After reporting the main study results in 2005, investigators were asked to inform patients of the results and implant a CRT device if still appropriate. Subsequently, investigators were asked to consent patients for long‐term follow‐up until 30 September 2009. Of 813 patients originally enrolled, 343 (42%) died prior to re‐consent, 111 patients (14%) were not or could not be contacted, 50 (6%) were alive but declined to participate, and 309 (38%) consented to long‐term follow‐up. Of patients originally assigned to the control group, &gt; 95% of survivors had received CRT by the time of re‐consent. From the time of randomization, 222 patients originally assigned to pharmacological therapy and 192 originally assigned to CRT were known to have died. The hazard ratio for mortality in patients originally assigned to CRT compared with those originally assigned to the control group was 0.77 (95% confidence interval 0.63–0.93; P = 0.007). No subgroup interactions were observed. Conclusion The effect of CRT on mortality observed during the randomized CARE‐HF trial persisted during long‐term follow‐up. A high rate of CRT device implantation in the control group after completion of the randomized phase of the study may have prevented further divergence of the survival curves.

Pancreatic cancer is the fifth most common cause of cancer death. Identification of defined patient groups based on a prognostic index may improve the prediction of survival and selection of therapy. Many prognostic factors have been identified often based on retrospective, underpowered studies with unclear analyses. Data from 653 patients were analysed. Continuous variables are often simplified assuming a linear relationship with log hazard or introducing a step function (dichotomising). Misspecification may lead to inappropriate conclusions but has not been previously investigated in pancreatic cancer studies. Models based on standard assumptions were compared with a novel approach using nonlinear fractional polynomial (FP) transformations. The model based on FP-transformed covariates was most appropriate and confirmed five previously reported prognostic factors: albumin, CA 19-9, alkaline phosphatase, LDH and metastases, and identified three additional factors not previously reported: WBC, AST and BUN. The effects of CA 19-9, alkaline phosphatase, AST and BUN may go unrecognised due to simplistic assumptions made in statistical modelling. We advocate a multivariable approach that uses information contained within continuous variables appropriately. The functional form of the relationship between continuous covariates and survival should always be assessed. Our model should aid individual patient risk stratification and the design and analysis of future trials in pancreatic cancer.

Background The global burden of hypertension and other non-communicable diseases (NCDs) is rapidly increasing, and the African continent seems to be the most affected region in the world. The prevalence of hypertension in Nigeria forms a substantial portion of the total burden in Africa because of the large population of the country currently estimated to be over 170 million. Objective The purpose of this systematic review is to summarise up to date data on the prevalence and distribution of hypertension in Nigeria from prevalence studies. Methods A search of the following databases: PubMed, EMBase and WHO cardiovascular InfoBase from 1968 till date was conducted to identify studies which provide estimates of prevalence of hypertension in Nigeria. Results The search yielded a total of 1748 hits from which 45 relevant studies met the inclusion criteria for the review. The overall crude prevalence of hypertension ranged from 0.1% (95%CI:-0.1 to 0.3) to 17.5% (95% CI: 13.6 to 21.4) in children and 2.1% (95%CI: 1.4 to 2.8) to 47.2% (95%CI: 43.6 to 50.8) in adults depending on the benchmark used for diagnosis of hypertension, the setting in which the study was conducted, sex and ethnic group. The crude prevalence of hypertension ranged from 6.2% (95%CI: 4.0 to 8.4) to 48.9% (95%CI: 42.3 to 55.5) for men and 10% (95%CI: 8.1 to 12) to 47.3% (95%CI: 43 to 51.6%) for women. In most studies, prevalence of hypertension was higher in males than females. In addition, prevalence across urban and rural ranged from 9.5% (95%CI: 13.6 to 21.4) to 51.6% (95%CI: 49.8 to 53.4) and 4.8% (95%CI: 2.9 to 6.7) to 43% (95%CI: 42.1 to 43.9) respectively. Conclusions The prevalence of hypertension is high among the Nigerian population. Appropriate interventions need to be developed and implemented to reduce the preventable burden of hypertension especially at Primary Health Care Centres which is the first point of call for over 55% of the Nigerian population.

Headline Evaluating service innovations in health care and public health requires flexibility, collaboration and pragmatism; this collection identifies robust, innovative and mixed methods to inform such evaluations.

The impact of individual antiarrhythmic drugs (AADs) on mortality and hospital stay in atrial fibrillation (AF) was evaluated.Cardiovascular (CV) outcomes in AF patients receiving pharmacologic rhythm control therapy have not been compared with rate control therapy on the basis of AAD selection.We compared CV outcomes in the AFFIRM (Atrial Fibrillation Follow-Up Investigation of Rhythm Management) trial in subgroups defined by the initial AAD selected with propensity score matched subgroups from the rate arm (Rate).Seven hundred twenty-nine amiodarone patients, 606 sotalol patients, and 268 Class 1C patients were matched. The composite outcome of mortality or cardiovascular hospital stays (CVH) showed better outcomes with Rate compared with amiodarone (hazard ratio [HR]: 1.18, 95% confidence interval [CI]: 1.03 to 1.36, p = 0.02), sotalol (HR: 1.32, 95% CI: 1.13 to 1.54, p < 0.001), and Class 1C (HR: 1.22, 95% CI: 0.97 to 1.56, p = 0.10). There was a nonsignificant increase in mortality with amiodarone (HR: 1.20, 95% CI: 0.94 to 1.53, p = 0.15) with the risk of non-CV death being significantly higher with amiodarone versus Rate (HR: 1.11, 95% CI: 1.01 to 1.24, p = 0.04). First CVH event rates at 3 years were 47% for amiodarone, 50% for sotalol, and 44% for Class 1C versus 40%, 40%, and 36%, respectively, for Rate (amiodarone HR: 1.20, 95% CI: 1.03 to 1.40, p = 0.02, sotalol HR: 1.364, 95% CI: 1.16 to 1.611, p < 0.001, Class 1C HR: 1.24, 95% CI: 0.96 to 1.60, p = 0.09). Time to CVH with intensive care unit stay or death was shorter with amiodarone (HR: 1.22, 95% CI: 1.02 to 1.46, p = 0.03).In AFFIRM, composite mortality and CVH outcomes differed for Rate and AADs due to differences in CVH; CVH event rates during follow-up were high for all cohorts, but they were higher for all groups on AADs. Death, intensive care unit hospital stay, and non-CV death were more frequent with amiodarone.

<h3>Importance</h3> Although many studies have explored the correlates of violence during first-episode psychosis (FEP), most have simply compared violent psychotic individuals with nonviolent psychotic individuals. Accumulating evidence suggests there may be subgroups within psychosis, differing in terms of developmental processes and proximal factors associated with violent behavior. <h3>Objective</h3> To determine whether there are subgroups of psychotic individuals characterized by different developmental trajectories to violent behavior. <h3>Design, Setting, and Participants</h3> The National EDEN (Evaluating the Development and Impact of Early Intervention Services in the West Midlands) Study longitudinal cohort assessed premorbid delinquency (premorbid adjustment adaptation subscale across childhood and adolescence), age at illness onset, duration of untreated psychosis, past drug use, positive symptoms, and violent behavior. Group trajectories of premorbid delinquency were estimated using latent class growth analysis, and associations with violent behavior were quantified. This study included 6 early intervention services in 5 geographical locations across England, with violent behavior information available for 670 first-episode psychosis cases. <h3>Main Outcomes and Measures</h3> Violent behavior at 6 or 12 months following early intervention services entry. <h3>Results</h3> Four groups of premorbid delinquency were identified: stable low, adolescent-onset high to moderate, stable moderate, and stable high. Logistic regression analysis, with stable low delinquency as the reference group, demonstrated that moderate (odds ratio, 1.97; 95% CI, 1.12-3.46) and high (odds ratio, 3.53; 95% CI, 1.85-6.73) premorbid delinquency trajectories increased the risk for violent behavior during FEP. After controlling for confounders, path analysis demonstrated that the increased risk for violence in the moderate delinquency group was indirect (ie, partially mediated by positive symptoms) (probit coefficient [β] = 0.12;<i>P</i> = .002); while stable high delinquency directly increased the risk for violence (β = 0.38;<i>P</i> = .05). <h3>Conclusions and Relevance</h3> There appear to be diverse pathways to violent behavior during FEP. Stable high premorbid delinquency from childhood onwards appears to directly increase the risk for violent behavior, independent of psychosis-related risk factors. In addition to tackling illness-related risks, treatments should directly address antisocial traits as a potent risk for violence during FEP.

When faced with a P value that has failed to reach some specific threshold (generally P&lt;0.05), authors of scientific articles may imply a "trend towards statistical significance" or otherwise suggest that the failure to achieve statistical significance was due to insufficient data. This paper presents a quantitative analysis to show that such descriptions give a misleading impression and undermine the principle of accurate reporting.

The aim of cost-utility analysis is to support decision making in healthcare by providing a standardised mechanism for comparing resource use and health outcomes across programmes of work. The focus of this paper is the denominator of the cost-utility analysis, specifically the methodology and statistical challenges associated with calculating QALYs from patient-level data collected as part of a trial. We provide a brief description of the most common questionnaire used to calculate patient level utility scores, the EQ-5D, followed by a discussion of other ways to calculate patient level utility scores alongside a trial including other generic measures of health-related quality of life and condition- and population-specific questionnaires. Detail is provided on how to calculate the mean QALYs per patient, including discounting, adjusting for baseline differences in utility scores and a discussion of the implications of different methods for handling missing data. The methods are demonstrated using data from a trial. As the methods chosen can systematically change the results of the analysis, it is important that standardised methods such as patient-level analysis are adhered to as best as possible. Regardless, researchers need to ensure that they are sufficiently transparent about the methods they use so as to provide the best possible information to aid in healthcare decision making.

Background Although many women treated with psychotropic medication become pregnant, no psychotropic medication has been licensed for use in pregnancy. This leaves women and their health-care professionals in a treatment dilemma, as they need to balance the health of the woman with that of the unborn child. The aim of this project was to investigate the risks and benefits of psychotropic medication in women treated for psychosis who become pregnant. Objective(s) (1) To provide a descriptive account of psychotropic medication prescribed before pregnancy, during pregnancy and up to 15 months after delivery in UK primary care from 1995 to 2012; (2) to identify risk factors predictive of discontinuation and restarting of lithium (multiple manufacturers), anticonvulsant mood stabilisers and antipsychotic medication; (3) to examine the extent to which pregnancy is a determinant for discontinuation of psychotropic medication; (4) to examine prevalence of records suggestive of adverse mental health, deterioration or relapse 18 months before and during pregnancy, and up to 15 months after delivery; and (5) to estimate absolute and relative risks of adverse maternal and child outcomes of psychotropic treatment in pregnancy. Design Retrospective cohort studies. Setting Primary care. Participants Women treated for psychosis who became pregnant, and their children. Interventions Treatment with antipsychotics, lithium or anticonvulsant mood stabilisers. Main outcome measures Discontinuation and restarting of treatment; worsening of mental health; acute pre-eclampsia/gestational hypertension; gestational diabetes; caesarean section; perinatal death; major congenital malformations; poor birth outcome (low birthweight, preterm birth, small for gestational age, low Apgar score); transient poor birth outcomes (tremor, agitation, breathing and muscle tone problems); and neurodevelopmental and behavioural disorders. Data sources Clinical Practice Research Datalink database and The Health Improvement Network primary care database. Results Prescribing of psychotropic medication was relatively constant before pregnancy, decreased sharply in early pregnancy and peaked after delivery. Antipsychotic and anticonvulsant treatment increased over the study period. The recording of markers of worsening mental health peaked after delivery. Pregnancy was a strong determinant for discontinuation of psychotropic medication. However, between 40% and 76% of women who discontinued psychotropic medication before or in early pregnancy restarted treatment by 15 months after delivery. The risk of major congenital malformations, and neurodevelopmental and behavioural outcomes in valproate (multiple manufacturers) users was twice that in users of other anticonvulsants. The risks of adverse maternal and child outcomes in women who continued antipsychotic use in pregnancy were not greater than in those who discontinued treatment before pregnancy. Limitations A few women would have received parts of their care outside primary care, which may not be captured in this analysis. Likewise, the analyses were based on prescribing data, which may differ from usage. Conclusions Psychotropic medication is prescribed before, during and after pregnancy. Many women discontinue treatment before or during early pregnancy and then restart again in late pregnancy or after delivery. Our results support previous associations between valproate and adverse child outcomes but we found no evidence of such an association for antipsychotics. Future work Future research should focus on (1) curtailing the use of sodium valproate; (2) estimating the benefits of psychotropic drug use in pregnancy; and (3) investigating the risks associated with lifestyle choices that are more prevalent among women using psychotropic drugs. Funding details The National Institute for Health Research Health Technology Assessment programme.

Objective:The use of cannabis during the early stage of psychosis has been linked with increased psychotic symptoms. This study aimed to examine the use of cannabis in the 12 months following a first-episode of psychosis (FEP) and the link with symptomatic course and outcome over 1 year post psychosis onset.

<h2>Summary</h2><h3>Background</h3> Provision of early intervention services has increased the rate of social recovery in patients with first-episode psychosis; however, many individuals have continuing severe and persistent problems with social functioning. We aimed to assess the efficacy of early intervention services augmented with social recovery therapy in patients with first-episode psychosis. The primary hypothesis was that social recovery therapy plus early intervention services would lead to improvements in social recovery. <h3>Methods</h3> We did this single-blind, phase 2, randomised controlled trial (SUPEREDEN3) at four specialist early intervention services in the UK. We included participants who were aged 16–35 years, had non-affective psychosis, had been clients of early intervention services for 12–30 months, and had persistent and severe social disability, defined as engagement in less than 30 h per week of structured activity. Participants were randomly assigned (1:1), via computer-generated randomisation with permuted blocks (sizes of four to six), to receive social recovery therapy plus early intervention services or early intervention services alone. Randomisation was stratified by sex and recruitment centre (Norfolk, Birmingham, Lancashire, and Sussex). By necessity, participants were not masked to group allocation, but allocation was concealed from outcome assessors. The primary outcome was time spent in structured activity at 9 months, as measured by the Time Use Survey. Analysis was by intention to treat. This trial is registered with ISRCTN, number ISRCTN61621571. <h3>Findings</h3> Between Oct 1, 2012, and June 20, 2014, we randomly assigned 155 participants to receive social recovery therapy plus early intervention services (n=76) or early intervention services alone (n=79); the intention-to-treat population comprised 154 patients. At 9 months, 143 (93%) participants had data for the primary outcome. Social recovery therapy plus early intervention services was associated with an increase in structured activity of 8·1 h (95% CI 2·5–13·6; p=0·0050) compared with early intervention services alone. No adverse events were deemed attributable to study therapy. <h3>Interpretation</h3> Our findings show a clinically important benefit of enhanced social recovery on structured activity in patients with first-episode psychosis who received social recovery therapy plus early intervention services. Social recovery therapy might be useful in improving functional outcomes in people with first-episode psychosis, particularly in individuals not motivated to engage in existing psychosocial interventions targeting functioning, or who have comorbid difficulties preventing them from doing so. <h3>Funding</h3> National Institute for Health Research.

BackgroundDelayed treatment for first episodes of psychosis predicts worse outcomes. We hypothesised that delaying treatment makes all symptoms more refractory, with harm worsening first quickly, then more slowly. We also hypothesised that although delay impairs treatment response, worse symptoms hasten treatment, which at presentation mitigates the detrimental effect of treatment delay on symptoms.MethodsIn this longitudinal analysis and modelling study, we included two longitudinal cohorts of patients with first-episode psychosis presenting to English early intervention services from defined catchments: NEDEN (recruiting 1003 patients aged 14–35 years from 14 services between Aug 1, 2005, and April 1, 2009) and Outlook (recruiting 399 patients aged 16–35 years from 11 services between April 1, 2006, and Feb 28, 2009). Patients were assessed at baseline, 6 months, and 12 months with the Positive and Negative Symptom Scale (PANSS), Calgary Depression Scale for Schizophrenia, Mania Rating Scale, Insight Scale, and Social and Occupational Functioning Assessment Scale. Regression was used to compare different models of the relationship between duration of untreated psychosis (DUP) and total symptoms at 6 months. Growth curve models of symptom subscales tested predictions arising from our hypotheses.FindingsWe included 948 patients from the NEDEN study and 332 patients from the Outlook study who completed baseline assessments and were prescribed dopamine antagonist antipsychotics. For both cohorts, the best-fitting models were logarithmic, describing a curvilinear relationship of DUP to symptom severity: longer DUP predicted reduced treatment response, but response worsened more slowly as DUP lengthened. Increasing DUP by ten times predicted reduced improvement in total symptoms (ie, PANSS total) by 7·339 (95% CI 5·762 to 8·916; p<0·0001) in NEDEN data and 3·846 (1·689 to 6·003; p=0·0005) in Outlook data. This was true of treatment response for all symptom types. Nevertheless, longer DUP was not associated with worse presentation for any symptoms except depression in NEDEN (coefficients 0·099 [95% CI 0·033 to 0·164]; p=0·0028 in NEDEN and 0·007 [−0·081 to 0·095]; p=0·88 in Outlook).InterpretationLong DUP was associated with reduced treatment response across subscales, consistent with a harmful process upstream of individual symptoms' mechanisms; response appeared to worsen quickly at first, then more slowly. These associations underscore the importance of rapid access to a comprehensive range of treatments, especially in the first weeks after psychosis onset.FundingUK Department of Health, National Institute of Health Research, and Medical Research Council.

Non-randomised clinical trial designs involving comparisons against external controls or specific standards can be used to support regulatory submissions for indications in diseases that are rare, with high unmet need, without approved therapies and/or where placebo is considered unethical. The objective of this review was to summarise the characteristics of non-randomised trials submitted to the European Medicines Agency (EMA) or Food and Drug Administration (FDA) for indications in haematological cancers, haematological non-malignant conditions, stem cell transplants or rare metabolic diseases.We conducted systematic searches of EMA databases of conditional approvals, exceptional circumstances, or orphan drug designations and FDA inventories of orphan drug designations, accelerated approvals, breakthrough therapy, fast-track and priority approvals. Products were included if reviewed by at least one agency between 2005 and 2017, the primary evidence base was non-randomised trial(s) and the indication was for haematological cancers, stem cell transplantation, haematological conditions or rare metabolic conditions.We identified 43 eligible indication-specific products using non-randomised study designs involving comparisons with external controls, submitted to the EMA (n=34) and/or FDA (n=41). Of the 43 indication-specific products, 4 involved matching external controls to the population of a non-randomised interventional study using individual patient-level data (IPD), 12 referred to external controls without IPD and 27 did not explicitly reference external controls. The FDA approved 98% of submissions, with 56% accelerated approvals; most required postapproval confirmatory randomised controlled trials (RCT). The EMA approved 79% of submissions, with a quarter of approvals conditional on completion of a postapproval RCT or additional non-randomised trials.There has been a large increase in submissions to the EMA and FDA using non-randomised study designs involving comparisons with external controls in recent years. This study demonstrated that regulators may be willing to approve such submissions, although approvals are often conditional on further confirmatory evidence from postapproval studies.

To determine the 5-year outcome in patients treated by isolated transcatheter aortic valve implantation (TAVI) or surgical aortic valve replacement (sAVR)-a prospective observational cohort study.A total of 18 010 patients were included (n = 8942 TAVI and n = 9068 sAVR) in the German Aortic Valve Registry (GARY) who were treated in 2011 and 2012 at 92 sites in central Germany. Eligible patients with TAVI and sAVR were matched using propensity scores in a nearest-neighbour approach. Patients with repeat procedures or unequivocal indication for one treatment option (e.g. frailty) were excluded (n = 4785 for TAVI and n = 2 for sAVR). This led to 13 223 patients (4157 TAVI and 9066 sAVR) as an unmatched subcohort. The main outcome measure was the 5-year all-cause mortality.TAVI patients were significantly older (80.9 ± 6.1 vs 68.5 ± 11.1 years, P < 0.001), had a higher Society of Thoracic Surgeons (STS) score (6.3 ± 4.9 vs 2.6 ± 3.0, P < 0.001) and a higher 5-year all-cause mortality (49.8% vs 16.5%, P < 0.0001). There was no major difference in in-hospital stroke, in-hospital myocardial infarction, or temporary and chronic dialysis. In the propensity score-matched group (n = 3640), there were 763 deaths (41.9%) among 1820 TAVI patients compared with 552 (30.3%) among 1820 treated with sAVR during the 5-year follow-up (hazard ratio 1.51, 95% confidence interval 1.35-1.68; P < 0.0001). New pacemaker implantation was performed in 448 patients (24.6%) after TAVI and in 201 (11.0%) after sAVR (P < 0.0001).The 5-year follow-up data show that TAVI patients were significantly older and had a higher STS score than sAVR patients. After propensity score matching, TAVI with early-generation prosthesis was associated with significantly higher 5-year all-cause mortality than sAVR.

Maintenance antipsychotic medication is recommended for people with schizophrenia or recurrent psychosis, but the adverse effects are burdensome, and evidence on long-term outcomes is sparse. We aimed to assess the benefits and harms of a gradual process of antipsychotic reduction compared with maintenance treatment. Our hypothesis was that antipsychotic reduction would improve social functioning with a short-term increase in relapse.RADAR was an open, parallel-group, randomised trial done in 19 National Health Service Trusts in England. Participants were aged 18 years and older, had a diagnosis of recurrent, non-affective psychotic disorder, and were prescribed an antipsychotic. Exclusion criteria included people who had a mental health crisis or hospital admission in the past month, were considered to pose a serious risk to themselves or others by a treating clinician, or were mandated to take antipsychotic medication under the Mental Health Act. Through an independent, internet-based system, participants were randomly assigned (1:1) to gradual, flexible antipsychotic reduction, overseen by treating clinicians, or to maintenance. Participants and clinicians were aware of treatment allocations, but assessors were masked to them. Follow-up was for 2 years. Social functioning, assessed by the Social Functioning Scale, was the primary outcome. The principal secondary outcome was severe relapse, defined as requiring admission to hospital. Analysis was done blind to group identity using intention-to-treat data. The trial is completed and has been registered with ISRCTN registry (ISRCTN90298520) and with ClinicalTrials.gov (NCT03559426).4157 people were screened, of whom 253 were randomly allocated, including 168 (66%) men, 82 (32%) women, and 3 (1%) transgender people, with a mean age of 46 years (SD 12, range 22-79). 171 (67%) participants were White, 52 (21%) were Black, 16 (6%) were Asian, and 12 (5%) were of other ethnicity. The median dose reduction at any point during the trial was 67% in the reduction group and zero in the maintenance group; at 24 months it was 33% versus zero. At the 24-month follow-up, we assessed 90 of 126 people assigned to the antipsychotic dose reduction group and 94 of 127 assigned to the maintenance group, finding no difference in the Social Functioning Scale (β 0·19, 95% CI -1·94 to 2·33; p=0·86). There were 93 serious adverse events in the reduction group affecting 49 individuals, mainly comprising admission for a mental health relapse, and 64 in the maintenance group, relating to 29 individuals.At 2-year follow-up, a gradual, supported process of antipsychotic dose reduction had no effect on social functioning. Our data can help to inform decisions about the use of long-term antipsychotic medication.National Institute for Health Research.

<h3>ABSTRACT</h3> Hematopoietic differentiation is controlled by both genetic and epigenetic regulators. Long non-coding RNAs (lncRNAs) have been demonstrated to be important for normal hematopoiesis, but their function in erythropoiesis needs to be further explored. We profiled the transcriptomes of 16 murine hematopoietic cell populations by deep RNA-sequencing and identified a novel lncRNA, <i>Gm15915</i>, that was highly expressed in erythroid-related progenitors and erythrocytes. For this reason, we named it <i>lncEry</i>. We also identified a novel <i>lncEry</i> isoform, which was also the principal transcript that has not been reported before. <i>LncEry</i> depletion impaired erythropoiesis, indicating the important role of the lncRNA in regulating erythroid differentiation and maturation. Mechanistically, we found that <i>lncEry</i> interacted with WD repeat-containing protein 82 (WDR82) to promote the transcription of <i>Klf1</i> and globin genes and thus control the early and late stages of erythropoiesis, respectively. These findings identified <i>lncEry</i> as an important player in the transcriptional regulation of erythropoiesis.

Other members of the guideline development and project groups are listed in the Appendix This guideline addresses the appropriate use of non-steroidal anti-inflammatory drugs in the primary care treatment of patients with joint pain believed to be caused by degenerative arthritis. It does not consider therapies other than drug treatment. General practitioners must use their professional knowledge and judgement when applying guideline recommendations to the management of individual patients. They should note the information, contraindications, interactions, and side effects contained in the British National Formulary.1 This is a summary of the full version of the guideline.2 In this article, the statements accompanied by categories of evidence (cited as Ia, Ib, IIa, IIb, III, and IV) and recommendations classified according to their strength (A, B, C, or D) are as described previously and are summarised in the box.3 ### Summary points The methods used to develop the guideline have been described previously.3Briefly, we searched the electronic databases Medline and Embase, using a combination of subject heading and free text terms aimed at locating systematic reviews, meta-analyses, randomised trials, quality of life studies, and economic studies. The search was backed up by the expert knowledge and experience of group members. ### Strength of recommendation

To determine the effectiveness of specialist nurse-led clinics for hypertension and hyperlipidemia provided for diabetic patients receiving hospital-based care.This study was a randomized controlled implementation trial at Hope Hospital, Salford, U.K. The subjects consisted of 1,407 subjects presenting for annual review with raised blood pressure(>or=140/80 mmHg), raised total cholesterol (>or=5.0 mmol/l), or both. Individuals with diabetes were randomized to usual care or usual care with subsequent invitation to attend specialist nurse-led clinics. Nurses provided clinics for participants, with attendance every 4-6 weeks, until targets were achieved. Lifestyle advice and titration of drug therapies were provided according to the locally agreed upon guidelines. Patients with both conditions were eligible for enrollment in either or both clinics. At subsequent annual review, blood pressure and total cholesterol values were obtained from the Salford electronic diabetes register. Data relating to deaths were obtained from the national strategic tracing service. The primary outcome was the odds ratio of achieving targets in hypertension and hyperlipidemia, attributable to the specialist nurse-led intervention.Overall, specialist nurse-led clinics were associated with a significant improvement in patients achieving the target after 1 year (odds ratio [OR] 1.37 [95% CI 1.11-1.69], P = 0.003). This primary analysis revealed a borderline difference in effect between the two types of clinics (test for interaction between groups: P = 0.06). Secondary analysis, consistent with the prior beliefs of the health care professionals involved, suggested that targets were achieved more frequently in patients enrolled in the specialist nurse-led clinic for hyperlipidemia (OR 1.69 [1.25-2.29], P = 0.0007) than for hypertension (OR 1.14 [0.86-1.51], P = 0.37). Intervention (enrolled to either or both clinics) was associated with a reduction in all-cause mortality (OR 0.55 [0.32-0.92], P = 0.02).This study provides good evidence to support the use of specialist nurse-led clinics as an effective adjunct to hospital-based care of patients with diabetes. If the standards of care recommended in the National Service Framework for Diabetes are to be achieved, then such proven methods for delivering care must be adopted.

Abstract Background: The prevalence of chronic heart failure (CHF) rises with increasing age, from &lt;1% in those below 65 years of age to &gt; 5% in those over 65 years of age and is a major cause of morbidity and mortality in older people. Recent European guidelines point to a major deficiency in our knowledge of how to treat diastolic chronic heart failure, and a lack of information on treatment for heart failure in the elderly in general. Aims: The aims of this trial are to assess the potential benefits of the ACE inhibitor perindopril to treat chronic heart failure in elderly people, in the absence of any major left ventricular systolic dysfunction. Subjects: One thousand people over the age of 70 years will be recruited into this study. Evidence of chronic heart failure will be confirmed by clinical criteria and echocardiography. Methods: Once a diagnosis of chronic heart failure has been confirmed, the patient will receive either perindopril or placebo in addition to their usual treatment. Death, and unplanned heart failure related hospitalisations, are the primary outcomes. Quality of life, as measured by the Guyatt questionnaire will be assessed at the beginning of the study and at 1 year. Sub‐studies of this trial include a 6‐min walking test and more detailed evaluation of ventricular function (as assessed by echocardiography). Both parameters will be measured at 8 weeks and 1 year, and analysed against baseline data. Cognitive function in this group of patients will also be evaluated at baseline and 1 year. This trial is due to report in the year 2001.

Abstract Background: The EUROHEART programme is a rolling programme of cardiovascular surveys among the member nations of the European Society of Cardiology (ESC). These surveys will provide information on the nature of cardiovascular disease and its management. This manuscript describes a survey into the nature and management of heart failure. Aims: The Euroheart Failure survey aims to describe the quality of hospital care, diagnostic and therapeutic, for patients with suspected or confirmed heart failure in ESC member countries. Patients will be interviewed subsequent to hospital discharge to assess their understanding of their condition, side effects from and their compliance with therapy and their satisfaction with the management for heart failure. The quality of management will be judged against the recommendations contained in the ESC guidelines on diagnosis and treatment of heart failure. Outcome will be further assessed by repeat interviews in 6–12 months time. A further survey of heart failure in 2001/2002 is also planned. Methods: A prospective survey of all deaths and discharges from medical (cardiology, internal medicine and geriatric medicine) and cardiac surgical wards to identify patients with heart failure, suspected or confirmed. Approximately 70 hospital clusters, comprising two to six hospitals in each cluster, in 24 member countries of the ESC are conducting the study. At the time of writing, approximately 30 000 deaths and discharges have been screened and approximately 4000 patients have been enrolled. Conclusions: The Euroheart Survey will allow actual practice to be compared to ESC guidelines on the diagnosis and treatment of heart failure. The surveys and guidelines should prove mutually informative. The main EuroHeart Failure project will be completed by late 2000. However, new centres volunteering to participate in the study (contact corresponding author) may be accepted providing they have the necessary research personnel and provided funding can be agreed for statistical support and administration.

Other members of the guideline development and project groups are listed at the end of the paper. This guideline aims to provide recommendations to assist general practitioners manage people with all forms of dementia and help their carers. This is a summary version of the full guideline.1 The areas covered were developed in conjunction with the guideline development group. They were felt to reflect areas that were important in daily clinical practice. The guideline is for the management of patients with dementia; although it covers the area of screening instruments, it is not meant to cover the area of differential diagnosis. All recommendations are for general practitioners and apply to patients attending general practice with dementia. The development group assumes that doctors will use their knowledge and judgment in applying the principles and recommendations given below in managing individual patients, since the recommendations may not be appropriate for all circumstances. Doctors must decide to adopt any particular recommendation in the light of available resources and the circumstances of individual patients. Throughout this guideline categories of evidence (cited as I, II, or III) and the strength of recommendations (A, B, C, or D) are as described in previous method papers and the full version of the guideline. 1 2 A summary of categories of evidence and strength of recommendations is given in the box. ### Summary points In general practice, dementia has an incidence of 1.6, a prevalence of 3.6, and a workload of 7.4 consultations per year General practitioners should use formal cognitive testing as well as clinical judgment in diagnosing dementia The impact of caring depends on factors such as behaviour and affect more than on the severity of the cognitive impairment The search strategy was carried out using Medline (covering 1966-96), BIDS-EMBASE(1980-96), and PsycLIT (1974-96). Searches were limited to English …

Both the theory of diffusion of innovations and the social influences model of behaviour change suggest that using local opinion leaders to transmit norms and model appropriate behaviour may improve health professional practice.To assess the effects using local opinion leaders on the practice of health professionals or patient outcomes.We searched MEDLINE to May 1998, the Research and Development Resource Base in Continuing Medical Education, and reference lists of related systematic reviews and articles.Randomised trials of the use of local opinion leaders (defined as health professionals nominated by their colleagues as being educationally influential). The participants were health care professionals responsible for patient care.Two reviewers independently extracted data and assessed study quality.Eight studies were included involving more than 296 health professionals. A variety of patient problems were targeted, including acute myocardial infarction, cancer pain, osteoarthritis, rheumatoid arthritis, chronic lung disease, vaginal birth after caesarean section, labour and delivery, and urinary catheter care. Six of seven trials that measured health professional practice demonstrated some improvement for at least one outcome variable, and in two trials, the results were statistically significant and clinically important. In three trials that measured patient outcomes, only one achieved an impact upon practice that was of practical importance: local opinion leaders were effective in improving the rate of vaginal birth after previous caesarean section.Using local opinion leaders results in mixed effects on professional practice. However, it is not always clear what local opinion leaders do and replicable descriptions are needed. Further research is required to determine if opinion leaders can be identified and in which circumstances they are likely to influence the practice of their peers.

Practice guidelines are valid if “they lead to the health gains and costs predicted for them.”1 When implemented, valid guidelines lead to changes in clinical practice and improvements in outcomes for patients.2-5 Invalid guidelines, however, may lead to the use of ineffective interventions that waste resources, or even to harm. Guidelines must offer recommendations for both effective and efficient care, and these have not previously been available in the United Kingdom. We have reported the development and content of guidelines for primary care in the United Kingdom based explicitly on evidence of effectiveness.6-9 Here, we present the methods used to develop evidence based guidelines on the use in primary care of four important groups of drugs—angiotensin converting enzyme inhibitors in patients with heart failure, choice of antidepressants, non-steroidal anti-inflammatory drugs in patients with osteoarthritis, and aspirin as an antithrombotic agent.10-13 Abridged versions of the guidelines on angiotensin converting enzyme inhibitors, aspirin, and non-steroidal anti-inflammatory drugs will be published in subsequent articles.14-16 #### Summary points Guideline development groups defined important clinical questions, produced search criteria, and drew up protocols for systematic review and, where appropriate, meta-analysis Medline and Embase were searched for systematic reviews and meta-analyses, randomised trials, quality of life studies, and economic studies Meta-analysis was used extensively by the group to answer specific clinical questions Statements on evidence were categorised in relation to study design, reflecting their susceptibility to bias Strength of recommendations was graded according to the category of evidence and its applicability, economic issues, values of the guideline group and society, and the groups' awareness of practical issues Recommendations cease to apply in December 1999, by which time relevant results that may affect recommendations may be known Guideline development groups comprised three broad classes of members—relevant healthcare professionals (up to five general practitioners (all with …

Background— Risk stratification algorithms for coronary artery bypass grafting (CABG) do not include a weighting for preoperative mild renal impairment defined as a serum creatinine 130 to 199 μmol/L (1.47 to 2.25 mg/dL), which may impact mortality and morbidity after CABG. Methods and Results— We reviewed prospectively collected data between 1997 and 2004 on 4403 consecutive patients undergoing first-time isolated CABG with a preoperative serum creatinine &lt;200 μmol/L (2.26 mg/dL)] in a single institution. The in-hospital mortality was 2.5% (112 of 4403), the need for new dialysis/hemofiltration was 1.3% (57 of 4403), and the stroke rate was 2.5% (108 of 4403). There were 458 patients with a serum creatinine 130 to 199 μmol/L or 1.47 to 2.25 mg/dL (mild renal dysfunction group) and 3945 patients with a serum creatinine &lt;130 μmol/L (&lt;1.47 mg/dL). Operative mortality was higher in the mild renal dysfunction group (2.1% versus 6.1%; P &lt;0.001) and increased with increasing preoperative serum creatinine level. New dialysis/hemofiltration (0.8%versus 5.2%; P &lt;0.001) and postoperative stroke (2.2% versus 5.0%; P &lt;0.01) were also more common in the patients with mild renal impairment. Multivariate analysis adjusting for known risk factors confirmed preoperative mild renal impairment (creatinine 130 to 199 μmol/L or 1.47 to 2.25 mg/dL; odd ratio, 1.91; 95% CI, 1.18 to 3.03; P =0.007) or glomerular filtration rate estimates &lt;60 mL/min per 1.73 m 2 , derived using the Cockroft-Gault formula, (odds ratio, 1.98; 95% CI, 1.16 to 3.48; P =0.015) as independent predictors of in-hospital mortality. Preoperative mild renal dysfunction adversely affected the 3-year survival probability after CABG (93% versus 81%; P &lt;0.001). Conclusions— Mild renal dysfunction is an important predictor of outcome in terms of in-hospital mortality, morbidity, and midterm survival in patients undergoing CABG.

Background Syncope is a common, disabling symptom.The most useful data for diagnosing and managing syncope is the recording of physical parameters such as the ECG and blood pressure during a spontaneous event.Implantable loop recorders (ILR) provide an opportunity to record ECG data from a spontaneous event.The purpose of the Eastbourne Syncope Assessment Study (EaSyAS) was to investigate the impact of ILRs on an unselected population of syncopal patients presenting acutely to our institution.Methods All patients presenting acutely with recurrent, unexplained syncope over a 16month period, were randomised after a basic clinical workup to receive the Reveal Plus ILR or conventional investigation.All patients were followed up for at least 6 months (mean 276 ± 134 days) following randomisation.The primary outcome measure was time to ECG diagnosis.Results Four hundred twenty-one patients presented, 201 were eligible, median age 74 years (interquartile range 61-81 years), 54% female, with a median of three previous syncopes (IQ range 2-6).Thirty-three percent of ILR patients and 4% of conventional patients had an ECG diagnosis (hazard ratio 8.93, 95% CI 3.17-25.2p 6 0:0001).Introduction of ECG-directed therapy was quicker for ILR patients (hazard ratio 7.9, 95% CI 2.8-22.3,p < 0:0001).ILR patients had fewer post-randomisation investigations and fewer hospital days, resulting in a saving of costs, £406 versus £1210 (mean difference £809, 95% CI £123-£2730).There was no difference in the number of subsequent syncopal episodes, mortality, or quality of life.Conclusions LR significantly increased the rate of diagnosis in an unselected Western population with recurrent syncope.There was a significant decrease in the rates of hospitalisation and investigation in patients receiving an ILR.

Editor—In their editorial on cluster randomised trials Campbell and Grimshaw correctly identify the importance of the appropriate choice of the unit of analysis.1 Unfortunately, they display a disappointingly poor grasp of the basis of estimation, and the specific recommendations that they make are inappropriate. The authors’ plea for a standardised approach to the analysis and reporting of cluster randomised trials is misguided. The framework that they describe has the patient as the principal unit of the experiment, with the correlation between patients in the same cluster having to be taken into account in the analysis. Following the recommendations in the editorial may, however, make investigators prey to the same errors that the authors are counselling them to guard against. Although some trials fall naturally into the framework that the authors describe, others do not. It is not helpful in their own example of an educational intervention to implement a clinical guideline. There, the clinician (whose behaviour is the target of the intervention) is clearly the principal unit of the experiment. We are interested in the change in his or her behaviour as a result of the intervention, the average size of the change, and how the size varied between clinicians. Focusing on the estimation of these quantities of direct interest should lead to a sensible and interpretable analysis. Recognising that such estimates should be fit for purpose should lead to a sensible design.2 Adjusting the analysis on the basis of the intracluster correlation coefficient assumes the observed covariance structure to be the true structure, without taking into account measurement error. It is robust only where a reasonable estimate of variability at the clinician level is available. Thus to suggest that such methods are more efficient than aggregated analyses at the level at which the intervention is targeted is incorrect. The authors’ quest for information on intracluster correlation coefficients is a search for an answer to the wrong problem. Thoughtless focus on correlation coefficients could lead to the use of values estimated in one study for calculations of sample size in quite a different area, which is probably worse than doing no such calculation at all. The authors also suggest incorrectly that covariates at the patient level may not be examined in aggregated analyses. Generalised linear modelling provides the opportunity of specifying covariates at the patient level while analysing at the level at which the intervention is targeted.3

The objective of health technology assessment (HTA) is to support decision making in health care. HTA does not claim to provide a definite solution to a health care problem, but to assist decision makers with evidence-based information about the clinical, ethical, social, and economic implications of the development, diffusion, and use of health care technology.

Inhaled insulin (INH, Exubera) is under investigation for preprandial treatment of patients with type 1 and type 2 diabetes (1–3). This dry-powder insulin formulation is delivered by aerosol, permitting the noninvasive administration of rapid-acting insulin (4). Preliminary studies have shown that INH provides reproducible and effective control of glycemia (1,5–7). This randomized controlled trial examined the extent to which the availability of INH affects the perceived acceptability of insulin therapy among patients with type 2 diabetes who failed to achieve target glycemia on current therapy. Male or female participants ( n = 779) aged 35–80 years with at least 3 months duration of type 2 diabetes and a HbA1c >8%, despite current therapy, were recruited from seven countries. Permitted current therapy included dietary measures and/or oral antidiabetic agents (OADs). Patients receiving insulin injections, smokers, or those who had significant pulmonary diseases were excluded. All patients gave informed consent, and local research ethics review boards approved the study. Participants were randomly assigned to receive either educational information about the potential risks and benefits of all currently licensed treatment options only (OADs and/or subcutaneous insulin, n = 388) or information about the potential risks and benefits of licensed treatments and INH ( n = 391). …

Cardiac resynchronization therapy (CRT) improves quality of life (QoL) when measured 3 to 6 months after implantation, but whether these effects are sustained is unknown. The CArdiac Resynchronisation-Heart Failure study is the only long-term randomized trial of CRT with repeated measures of QoL.Quality of life was measured at baseline and 3 months using generic European Quality of Life-5 Dimensions and disease-specific (Minnesota Living with Heart Failure) questionnaires and at 18 months and study-end using the latter instrument. Median follow-up was 29.6 (interquartile range 23.6-34.6) months.At baseline, patients had a substantially impaired QoL (mean European Quality of Life-5 Dimensions score 0.60, 95% confidence interval [CI] 0.58-0.62) compared to an age-matched general population (0.78, 95% CI 0.76-0.80). Quality of life improved to a greater extent in patients assigned to CRT at each time point (P < .0001). By 18 months, the mean difference in disease-specific QoL score was 10.7 (95% CI 7.6-13.8) in favor of CRT, mostly due to improved physical functioning. Differences were sustained thereafter. Quality-adjusted life-years at 18 months increased by 0.13 (95% CI 0.07-0.182) and by 0.23 (95% CI 0.13-0.33) at study-end (both P < .0001). Little heterogeneity of effect across subgroups was observed.Cardiac resynchronization therapy improves long-term QoL and survival in patients with moderate to severe heart failure. The effects appear sustained, and therefore, the gain in quality-adjusted life years with CRT should be even greater during longer term follow-up.

Abstract Background Most patients suspected of having heart failure (HF) will get a 12‐lead electrocardiogram (ECG) but its utility for excluding HF or assisting in its management has rarely been investigated. Methods The EuroHeart Failure survey identified 11,327 patients hospitalised with a suspected diagnosis of HF from 115 hospitals in 24 countries. ECGs were obtained from 9315 patients, of whom 5934 had cardiac imaging tests. The utility of the ECG was assessed for excluding or diagnosing major structural heart disease (MSHD) or major left ventricular systolic dysfunction (MLVSD) and for therapeutic decision making. Findings MSHD was present in 70% and MLVSD in 54% of patients overall but in only 21% and 5%, respectively, if the ECG was entirely normal. However, &lt;2% of patients had a normal ECG. No single ECG characteristic identified a probability &lt;25% of MSHD or &lt;20% of MLVSD. Patients with QRS width ≥120 ms or anterior pathological Q‐waves had a probability &gt;80% of MSHD and &gt;70% of MLVSD. Diagnostic models suggested that electrocardiographic criteria alone were not accurate for the diagnosis or exclusion of important heart disease in this population. However, 2468 patients (42%) had an electrocardiographic finding that should be used to guide the choice of therapy. Conclusions A normal ECG is rare in patients with suspected HF but has limited diagnostic value in this setting. The ECG has an important role in guiding therapy.

Patients undergoing aortic valve replacement for critical aortic stenosis often have significant left ventricular hypertrophy. Left ventricular hypertrophy has been identified as an independent predictor of poor outcome after aortic valve replacement as a result of a combination of maladaptive myocardial changes and inadequate myocardial protection at the time of surgery. Glucose-insulin-potassium (GIK) is a potentially useful adjunct to myocardial protection. This study was designed to evaluate the effects of GIK infusion in patients undergoing aortic valve replacement surgery.Patients undergoing aortic valve replacement for aortic stenosis with evidence of left ventricular hypertrophy were randomly assigned to GIK or placebo. The trial was double-blind and conducted at a single center. The primary outcome was the incidence of low cardiac output syndrome. Left ventricular biopsies were analyzed to assess changes in 5' adenosine monophosphate-activated protein kinase (AMPK), Akt phosphorylation, and protein O-linked β-N-acetylglucosamination (O-GlcNAcylation). Over a 4-year period, 217 patients were randomized (107 control, 110 GIK). GIK treatment was associated with a significant reduction in the incidence of low cardiac output state (odds ratio, 0.22; 95% confidence interval, 0.10 to 0.47; P=0.0001) and a significant reduction in inotrope use 6 to 12 hours postoperatively (odds ratio, 0.30; 95% confidence interval, 0.15 to 0.60; P=0.0007). These changes were associated with a substantial increase in AMPK and Akt phosphorylation and a significant increase in the O-GlcNAcylation of selected protein bands.Perioperative treatment with GIK was associated with a significant reduction in the incidence of low cardiac output state and the need for inotropic support. This benefit was associated with increased signaling protein phosphorylation and O-GlcNAcylation. Multicenter studies and late follow-up will determine whether routine use of GIK improves patient prognosis.

Abstract This study examines the relationship between psychometric changes in treatment and recidivism in a sample of 3773 sex offenders. All had completed treatment in a prison, between 1996 and 2006. Clinically significant changes were calculated for the psychometrics, and for the overarching psychological problems as represented by the four domains in the Structured Assessment of Risk and Need (Thornton, Sexual Abuse: A Journal of Research and Treatment, 14, 139–154, 2002): (1) sexual interests; (2) pro-offending attitudes; (3) socio-affective problems; and (4) self-regulation problems. Analyses indicate that those whose scores were in the ‘normal range’ before and after treatment were reconvicted at a significantly lower rate than those whose scores were not in the ‘normal range’ after treatment on selected psychometric scales. Additionally, participants who were deemed ‘changed’ overall on three of the four risk domains were reconvicted at a lower rate than those who were deemed not to have changed on these domains. An overall treatment change status was also computed, but this did not add significantly to the predictive validity of a modified version of an actuarial risk assessment tool (RM2000, Thornton et al., Annals of the New York Academy of Sciences, 989, 223–235, 2003) in a Cox regression. The results of the study indicate the potential role and limitations of clinical methodologies in ascertaining whether treatment has worked.

This prospective randomized controlled study evaluated the first-line use of a novel remotely monitored implantable loop recorder (ILR) in the initial investigation of unexplained syncope, and compared this to conventional therapy and a dedicated Syncope Clinic (SC).A total of 246 patients (mean age 70.3 years) were randomly allocated to conventional management, SC alone, ILR alone, or SC + ILR. Median follow-up was 20 months (IQR 15-25 months). Time to electrocardiogram (ECG) diagnosis was significantly shorter with ILR alone vs. conventional [hazard ratio (HR) 35.5, P = 0.0004] and with SC vs. conventional (HR 25.6, P = 0.002). Seventy-four per cent of first syncopal events documented in the SC groups occurred during provocative tilt testing. Twenty-two per cent of patients who received an ILR were found to have a bradycardia indication for permanent pacing, compared with 3% of patients who did not. Overall, more investigative tests were undertaken in the conventional group than in any other. Only patients who received an ILR had a significant increase in time to second syncope (P = 0.02), suggesting successful diagnosis and management of treatable causes of syncope.Implantable loop recorder monitoring achieved a more rapid diagnosis in unexplained syncope than usual care. Conventional management of syncope failed to achieve an ECG diagnosis despite a large number of investigative tests. Syncope Clinic and provocative tilt testing delivered a rapid ECG diagnosis, but did not prevent recurrent syncope. Implantable loop recorders offered rapid diagnosis, increased the likelihood of syncope being reported, demonstrated a high rate of intermittent bradycardia requiring pacing, and reduced recurrent syncope.

Moderate weight gain is usual after starting insulin therapy. The identification and quantification of factors associated with weight gain may help target strategies for avoidance of weight gain.The noninterventional CREDIT (Cardiovascular Risk Evaluation in people with type 2 Diabetes on Insulin Therapy) study included data from people with type 2 diabetes starting any insulin in 314 centers, in 12 countries. From a number of predefined candidate explanatory variables, analyses identified factors associated with weight gain 1 year after starting insulin treatment, after adjusting for investigational site as a random factor. A multivariable backward regression analysis selected a subset of these factors associated with weight gain.We studied the 2,179 people with data for body weight change at 1 year and for potential predictive factors. The mean weight gain was 1.78 kg, and 24% gained ≥5.0 kg. Baseline factors associated with weight gain were BMI, A1C, insulin regimen, insulin dose, other glucose-lowering therapies, and hypertension; at 1 year, additional factors were A1C, insulin regimen, insulin dose, and use of other glucose-lowering therapies. In multivariable analysis, weight gain at 1 year was associated with a higher A1C at baseline, a higher insulin dose at baseline and at 1 year, and a lower baseline BMI.By the time insulin was started, a high baseline A1C and insulin dose requirements were independently associated with greater weight gain, as was lower baseline BMI. Insulin regimen per se was not a predictive factor.

The aim of this study was to explore the relationships between plasma concentrations of N-terminal pro brain natriuretic peptide (NT-proBNP) and characteristics and prognosis of patients with heart failure and preserved (HFPEF) left ventricular ejection fraction (LVEF). No substantial trial has shown that treatment alters prognosis in patients with HFPEF due, in part, to much lower than anticipated event rates. The lack of a simple, objective test to identify patients with HFPEF at increased risk of cardiovascular events would be valuable.The Perindopril in Elderly People with Chronic Heart Failure Trial (PEP-CHF) was a randomized, controlled trial comparing perindopril and placebo in patients with symptoms and signs of heart failure who had an LVEF >40% and evidence of LV diastolic dysfunction. The primary endpoint was all-cause mortality or heart failure-related hospitalization. NT-proBNP was measured in 375 patients. Quartile thresholds were 176, 409, and 1035 pg/mL. Patients in the highest quartile of NT-proBNP were older, had lower body mass, more often had atrial fibrillation, had greater atrial and ventricular dimensions and a lower LVEF, and were more likely to receive loop diuretic therapy. Compared with the first quartile of NT-proBNP, the hazard ratios for the primary endpoint in the second {1.38 [95% confidence interval (CI) 0.64-2.99]}, third [2.84 (95% CI 1.42-5.72)], and fourth [4.47 (95% CI 2.30-8.72)] quartiles were increased. In a multivariable model, NT-proBNP, but not echocardiographic measures, was associated with outcome.NT-proBNP is a powerful prognostic marker in patients with HFPEF.

National EDEN aims to evaluate the implementation and impact on key outcomes of somewhat differently configured Early Intervention Services (EIS) across sites in England and to develop a model of variance in patient outcomes that includes key variables of duration of untreated psychosis (DUP), fidelity to the EIS model and service engagement. The cohort is being followed up for two further years as patients are discharged, to observe the stability of change and the impact of the discharge settings.A longitudinal cohort study of patients with a first episode of a psychosis, managed by EIS in six services across England. Patients are followed up 12 months after inception, then up to 2 years following discharge. Measures of DUP, psychosis, social functioning and relapse were taken. User and carer experience of EIS were monitored over time; as was the fidelity of each EIS to national guidelines. Service use is costed for a health economic evaluation.1027 people consented to the study of which 75% were successfully followed up at 12 months, with almost 100% data on treatment, relapse and recovery and service use.National EDEN is the largest cohort study of young people with psychosis receiving care under EIS. It will be able definitively to indicate whether this major investment in the United Kingdom in EI is achieving meaningful change for its users in practice and provide indications concerning who does well under this approach and who does not, and the long-term stability of any improvements.

Background Recruitment and retention challenges are very common in mental health randomised trials. Investigators utilise different methods to improve recruitment or retention. However, evidence of the effectiveness and efficiency of these strategies in mental health has not been synthesised. This systematic review is to investigate and assess the effectiveness and cost-effectiveness of different strategies to improve recruitment and retention in mental health randomised trials. Methods and materials MEDLINE, EMBASE, the Cochrane Methodology Register and PsycINFO were searched from beginning of record up to July 2016. Randomised trials involving participants with mental health problems which compared different strategies for recruitment or retention were selected. Two authors independently screened identified studies for eligibility. Results A total of 5,157 citations were identified. Thirteen articles were included, 11 on recruitment and 2 on retention. Three randomised controlled trials compared different recruitment strategies, none of which found statistically significant differences between the interventional recruitment strategies and the routine recruitment methods. Retrospective comparisons of recruitment methods showed that non-web-based advertisement and recruitment by clinical research staff each have advantages in efficiency. Web-based adverts had the lowest cost per person recruited (£13.41 per person recruited). Specialised care referral cost £183.24 per person, non-web-based adverts cost £372.03 per patient and recruitment via primary care cost £407.65 for each patient. Financial incentives, abridged questionnaires and pre-notification had a positive effect on retention rates. Conclusion The recruitment studies included showed differences in strategies, clinical settings, mental health conditions and study design. It is difficult to assess the overall effectiveness of any particular recruitment strategy as some strategies that worked well for a particular population may not work as well for others. Paying attention to the accessibility of information and consent materials may help improve recruitment. More research in this area is needed given its important implications.