Liraglutide and Cardiovascular Outcomes in Type 2 Diabetes

Background The cardiovascular effect of liraglutide, a glucagon-like peptide 1 analogue, when added to standard care in patients with type 2 diabetes, remains unknown. Methods In this double-blind trial, we randomly assigned patients with type 2 diabetes and high cardiovascular risk to receive liraglutide or placebo. The primary composite outcome in the time-to-event analysis was the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The primary hypothesis was that liraglutide would be noninferior to placebo with regard to the primary outcome, with a margin of 1.30 for the upper boundary of the 95% confidence interval of the hazard ratio. No adjustments for multiplicity were performed for the prespecified exploratory outcomes. Results A total of 9340 patients underwent randomization. The median follow-up was 3.8 years. The primary outcome occurred in significantly fewer patients in the liraglutide group (608 of 4668 patients [13.0%]) than in the placebo group (694 of 4672 [14.9%]) (hazard ratio, 0.87; 95% confidence interval [CI], 0.78 to 0.97; P<0.001 for noninferiority; P=0.01 for superiority). Fewer patients died from cardiovascular causes in the liraglutide group (219 patients [4.7%]) than in the placebo group (278 [6.0%]) (hazard ratio, 0.78; 95% CI, 0.66 to 0.93; P=0.007). The rate of death from any cause was lower in the liraglutide group (381 patients [8.2%]) than in the placebo group (447 [9.6%]) (hazard ratio, 0.85; 95% CI, 0.74 to 0.97; P=0.02). The rates of nonfatal myocardial infarction, nonfatal stroke, and hospitalization for heart failure were nonsignificantly lower in the liraglutide group than in the placebo group. The most common adverse events leading to the discontinuation of liraglutide were gastrointestinal events. The incidence of pancreatitis was nonsignificantly lower in the liraglutide group than in the placebo group. Conclusions In the time-to-event analysis, the rate of the first occurrence of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke among patients with type 2 diabetes mellitus was lower with liraglutide than with placebo. (Funded by Novo Nordisk and the National Institutes of Health; LEADER ClinicalTrials.gov number, NCT01179048 .)

Emergency contraception from the pharmacy 20 years on:a mystery shopper study

Background Emergency contraception (EC) was approved in the UK as a pharmacy medicine for purchase without prescription in 1991. Twenty years later we conducted a study to characterise routine practice pharmacy provision of EC. Study design Mystery shopper study of 30 pharmacies in Edinburgh, Dundee and London participating in a clinical trial of contraception after EC. Methods Mystery shoppers, aged ≥16 years, followed a standard scenario requesting EC. After the pharmacy visit, they completed a proforma recording the duration of the consultation, where it took place, and whether advice was given to them about the importance of ongoing contraception after EC. Results Fifty-five mystery shopper visits were conducted. The median reported duration of the consultation with the pharmacist was 6 (range 1–18) min. Consultations took place in a private room in 34 cases (62%) and at the shop counter in the remainder. In 27 cases (49%) women received advice about ongoing contraception. Eleven women (20%) left the pharmacy without EC due to lack of supplies or of a trained pharmacist. Most women were generally positive about the consultation. Conclusions While availability of EC from UK pharmacies has undoubtedly improved access, the necessity to have a consultation, however helpful, with a pharmacist introduces delays and around one in five of our mystery shoppers left without getting EC. Consultations in private are not always possible and little advice is given about ongoing contraception. It is time to make EC available without a pharmacy consultation

Characteristics of men responding to an invitation to undergo testing for prostate cancer as part of a randomised trial

Background: Sociodemographic characteristics are associated with participating in cancer screening and trials. We compared the characteristics of those responding with those not responding to a single invitation for prostate-specific antigen (PSA) testing for prostate cancer as part of the Cluster randomised triAl of PSA testing for Prostate cancer (CAP). / Methods: Age, rurality and deprivation among 197,763 men from 271 cluster-randomised primary care centres in the UK were compared between those responding (n = 90,300) and those not responding (n = 100,953) to a prostate cancer testing invitation. / Results: There was little difference in age between responders and nonresponders. Responders were slightly more likely to come from urban rather than rural areas and were slightly less deprived than those who did not respond. / Conclusion: These data indicate similarities in age and only minor differences in deprivation and urban location between responders and nonresponders. These differences were smaller, but in the same direction as those observed in other screening trials. / Trial registration: ISRCTN92187251. Registered on 29 November 2004

Ticagrelor versus Clopidogrel in Symptomatic Peripheral Artery Disease

International audienc

The use of interim data and Data Monitoring Committee recommendations in randomized controlled trial reports: frequency, implications and potential sources of bias

Background: Interim analysis of accumulating trial data is important to protect participant safety during randomized controlled trials (RCTs). Data Monitoring Committees (DMCs) often undertake such analyses, but their widening role may lead to extended use of interim analysis or recommendations that could potentially bias trial results.Methods: Systematic search of eight major publications: Annals of Internal Medicine, BMJ, Circulation, CID, JAMA, JCO, Lancet and NEJM, including all randomised controlled trials ( RCTs) between June 2000 and May 2005 to identify RCTs that reported use of interim analysis, with or without DMC involvement. Recommendations made by the DMC or based on interim analysis were identified and potential sources of bias assessed. Independent double data extraction was performed on all included trials.Results: We identified 1772 RCTs, of which 470 (27%; 470/1772) reported the use of a DMC and a further 116 (7%; 116/1772) trials reported some form of interim analysis without explicit mention of a DMC. There were 28 trials ( 24 with a formal DMC), randomizing a total of 79396 participants, identified as recommending changes to the trial that may have lead to biased results. In most of these, some form of sample size re-estimation was recommended with four trials also reporting changes to trial endpoints. The review relied on information reported in the primary publications and methods papers relating to the trials, higher rates of use may have occurred but not been reported.Conclusion: The reported use of interim analysis and DMCs in clinical trials has been increasing in recent years. It is reassuring that in most cases recommendations were made in the interest of participant safety. However, in practice, recommendations that may lead to potentially biased trial results are being made

Amylase, lipase, and acute pancreatitis in people with type 2 diabetes treatedwith liraglutide: Results from the LEADER randomized trial

Objective: To evaluate serum amylase and lipase levels and the rate of acute pancreatitis in patients with type 2 diabetes and high cardiovascular risk randomized to liraglutide or placebo and observed for 3.5-5.0 years. Research Design and Methods: Atotal of 9,340 patientswith type 2 diabeteswere randomized to either liraglutide or placebo (median observation time 3.84 years). Fasting serum lipase and amylase were monitored. Acute pancreatitis was adjudicated in a blinded manner. Results: Compared with the placebo group, liraglutide-treated patients had increases in serum lipase and amylase of 28.0% and 7.0%, respectively. Levels were increased at 6 months and then remained stable. During the study, 18 (0.4% [1.1 events/1,000 patient-years of observation] [PYO]) liraglutide-treated and 23 (0.5% [1.7 events/ 1,000 PYO]) placebo patients had acute pancreatitis confirmed by adjudication.Most acute pancreatitis cases occurred ≥12months after randomization. Liraglutide-treated patients with prior history of pancreatitis (n = 147) were not more likely to develop acute pancreatitis than similar patients in the placebo group (n = 120). Elevations of amylase and lipase levels did not predict future risk of acute pancreatitis (positive predictive value <1.0%) in patients treated with liraglutide. Conclusions: In a population with type 2 diabetes at high cardiovascular risk, there were numerically fewer events of acute pancreatitis among liraglutide-treated patients (regardless of previous history of pancreatitis) comparedwith the placebo group. Liraglutide was associated with increases in serum lipase and amylase, which were not predictive of an event of subsequent acute pancreatitis

Accuracy of healthcare systems data for identifying cardiovascular outcomes after stroke due to intracerebral haemorrhage in the United Kingdom

Funding: This work was funded by a British Heart Foundation Special Project grant (SP/12/2/20422).Background Healthcare systems data (HCSD) could improve the efficiency of clinical trials, but their accuracy and validity are uncertain. Our objective was to assess the accuracy of HCSD as the sole method of outcome detection in the REstart or STop Antithrombotics Randomised Trial (RESTART; ISRCTN71907627) compared with adjudicated questionnaire follow-up and compare estimates of treatment effect. Methods RESTART was a prospective, open, assessor-blind, parallel-group randomised controlled trial (RCT) of antiplatelet therapy after intracerebral haemorrhage (ICH) in the UK. We included 496 (92%) of 537 RESTART participants, who were resident in England or Scotland at randomisation. Computerised randomisation incorporating minimisation allocated participants (1:1) to start or avoid antiplatelet therapy. RESTART used annual questionnaires to detect its primary outcome (recurrent ICH) and secondary outcome (a composite of haemorrhagic or ischemic major adverse cardiovascular events [MACE]) over a median of 2.0 years; an independent adjudication committee verified outcomes using medical records and brain imaging. We obtained ICD10-coded HCSD on hospital admissions and deaths in England and Scotland to identify primary and secondary outcomes. We compared HCSD with a reference standard of adjudicated outcomes. We estimated the effects of antiplatelet therapy using HCSD alone in a Cox proportional hazards model adjusted for minimisation variables. Results In the original RESTART trial, 31 people experienced a primary outcome event. HCSD had sensitivity of 84% (95% CI 66 to 95%) and positive predictive value of 68% (51 to 82%) for recurrent ICH. HCSD estimated an effect of antiplatelet therapy (adjusted hazard ratio [aHR] 0.51, 95% CI 0.27 to 0.98; p = 0.044) that was almost identical to adjudicated outcomes (aHR 0.51, 95% CI 0.25 to 1.03; p = 0.060). HCSD had sensitivity of 84% (76 to 91%) and positive predictive value of 78% (69 to 85%) for MACE, on which HCSD estimated an effect of antiplatelet therapy (aHR 0.81, 95% CI 0.56 to 1.16; p = 0.247) that was similar to adjudicated outcomes (aHR 0.65, 95% CI 0.44 to 0.95; p = 0.025). Conclusions In a RCT of antiplatelet therapy for people with ICH, HCSD was reasonably accurate and provided similar estimates of treatment effect compared with adjudicated outcomes.Peer reviewe

Evidence for models of diagnostic service provision in the community: literature mapping exercise and focused rapid reviews

Background Current NHS policy favours the expansion of diagnostic testing services in community and primary care settings. Objectives Our objectives were to identify current models of community diagnostic services in the UK and internationally and to assess the evidence for quality, safety and clinical effectiveness of such services. We were also interested in whether or not there is any evidence to support a broader range of diagnostic tests being provided in the community. Review methods We performed an initial broad literature mapping exercise to assess the quantity and nature of the published research evidence. The results were used to inform selection of three areas for investigation in more detail. We chose to perform focused reviews on logistics of diagnostic modalities in primary care (because the relevant issues differ widely between different types of test); diagnostic ultrasound (a key diagnostic technology affected by developments in equipment); and a diagnostic pathway (assessment of breathlessness) typically delivered wholly or partly in primary care/community settings. Databases and other sources searched, and search dates, were decided individually for each review. Quantitative and qualitative systematic reviews and primary studies of any design were eligible for inclusion. Results We identified seven main models of service that are delivered in primary care/community settings and in most cases with the possible involvement of community/primary care staff. Not all of these models are relevant to all types of diagnostic test. Overall, the evidence base for community- and primary care-based diagnostic services was limited, with very few controlled studies comparing different models of service. We found evidence from different settings that these services can reduce referrals to secondary care and allow more patients to be managed in primary care, but the quality of the research was generally poor. Evidence on the quality (including diagnostic accuracy and appropriateness of test ordering) and safety of such services was mixed. Conclusions In the absence of clear evidence of superior clinical effectiveness and cost-effectiveness, the expansion of community-based services appears to be driven by other factors. These include policies to encourage moving services out of hospitals; the promise of reduced waiting times for diagnosis; the availability of a wider range of suitable tests and/or cheaper, more user-friendly equipment; and the ability of commercial providers to bid for NHS contracts. However, service development also faces a number of barriers, including issues related to staffing, training, governance and quality control. Limitations We have not attempted to cover all types of diagnostic technology in equal depth. Time and staff resources constrained our ability to carry out review processes in duplicate. Research in this field is limited by the difficulty of obtaining, from publicly available sources, up-to-date information about what models of service are commissioned, where and from which providers. Future work There is a need for research to compare the outcomes of different service models using robust study designs. Comparisons of ‘true’ community-based services with secondary care-based open-access services and rapid access clinics would be particularly valuable. There are specific needs for economic evaluations and for studies that incorporate effects on the wider health system. There appears to be no easy way of identifying what services are being commissioned from whom and keeping up with local evaluations of new services, suggesting a need to improve the availability of information in this area. Funding The National Institute for Health Research Health Services and Delivery Research programme

Does adjunctive clindamycin have a role in Staphylococcus aureus bacteremia? A protocol for the adjunctive treatment domain of the S. aureus Network Adaptive Platform (SNAP) randomized controlled trial.

INTRODUCTION: The use of adjunctive antibiotics directed against exotoxin production in Staphylococcus aureus bacteremia (SAB) is widespread, and is recommended in many guidelines, but there is limited evidence underpinning this. Existing guidelines are based on the theoretical premise of toxin suppression, as many strains of S. aureus produce toxins such as leucocidins (e.g., Panton-Valentine Leucocidin (PVL), toxic shock syndrome toxin 1 (TSST-1), exfoliative toxins, and various enterotoxins). Many clinicians therefore believe that limiting exotoxin production release by S. aureus could reduce its virulence and improve clinical outcomes. Clindamycin, a protein synthesis inhibitor antibiotic, is commonly used for this purpose. We report the domain-specific protocol, embedded in a large adaptive, platform trial, seeking to definitively answer this question. METHODS AND ANALYSIS: The Staphylococcus aureus Network Adaptive Platform (SNAP) trial is a pragmatic, randomized, multi-center adaptive platform trial that aims to compare different SAB therapies, simultaneously, for 90-day mortality. The adjunctive treatment domain aims to test the effectiveness of adjunctive antibiotics, initially comparing clindamycin to no adjunctive antibiotic, but future adaptations may include other agents. Individuals will be randomized to receive either five days of adjunctive clindamycin (or lincomycin) or no adjunctive antibiotic therapy alongside standard of care antibiotics. Most participants with SAB (within 72hr of index blood culture and not contraindicated) will be eligible to participate in this domain. Prespecified analyses are defined in the statistical appendix to the core protocol and domain-specific secondary analyses will be adjusted for resistance to clindamycin, disease phenotype (complicated or uncomplicated SAB) and PVL-positive isolate