Background: Glucagon-like peptide 1 agonists differ in chemical structure, duration of action and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. Methods: We randomly assigned patients with type 2 diabetes and cardiovascular disease to the addition of once-weekly subcutaneous injection of albiglutide (30 mg to 50 mg) or matching placebo to standard care. We hypothesized that albiglutide would be noninferior to placebo for the primary outcome of first occurrence of cardiovascular death, myocardial infarction, or stroke. If noninferiority was confirmed by an upper limit of the 95% confidence interval for the hazard ratio of less than 1.30, closed-testing for superiority was prespecified. Findings: Overall, 9463 participants were followed for a median of 1.6 years. The primary composite outcome occurred in 338 of 4731 patients (7.1%; 4.6 events per 100 person-years) in the albiglutide group and in 428 of 4732 patients (9.0%; 5.9 events per 100 person-years) in the placebo group (hazard ratio, 0.78; 95% confidence interval [CI ], 0.68 to 0.90), indicating that albiglutide, was superior to placebo (P<0.0001 for noninferiority, P=0.0006 for superiority). The incidence of acute pancreatitis (albiglutide 10 patients and placebo 7 patients), pancreatic cancer (6 and 5), medullary thyroid carcinoma (0 and 0), and other serious adverse events did not differ significantly between the two groups. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. (Funded by GlaxoSmithKline; Harmony Outcomes ClinicalTrials.gov number, NCT02465515.) noninferiority; P = 0.06 for superiority). There seems to be variation in the results of existing trials with GLP-1 receptor agonists, which if correct, might reflect drug structure or duration of action, patients studied, duration of follow-up or other factors.

UK National Institute for Health Research, Camelia Botnar Arterial Research Foundation.

Background Perineural and IV dexmedetomidine have each been suggested to prolong the duration of analgesia when administered in conjunction with peripheral nerve blocks. In the first randomized, triple-masked, placebo-controlled trial to date, the authors aimed to define and compare the efficacy of perineural and IV dexmedetomidine in prolonging the analgesic duration of single-injection interscalene brachial plexus block (ISB) for outpatient shoulder surgery. Methods Ninety-nine patients were randomized to receive ISB using 15 ml ropivacaine, 0.5%, with 0.5 μg/kg dexmedetomidine administered perineurally (DexP group), intravenously (DexIV group), or none (control group). The authors sequentially tested the joint hypothesis that dexmedetomidine prolongs the duration of analgesia and reduces the 24-h cumulative postoperative morphine consumption. Motor blockade, pain severity, hemodynamic variations, opioid-related side effects, postoperative neurologic symptoms, and patient satisfaction were also evaluated. Results Ninety-nine patients were analyzed. The duration of analgesia was 10.9 h (10.0 to 11.8 h) and 9.8 h (9.0 to 10.6 h) for the DexP and DexIV groups, respectively, compared with 6.7 h (5.6 to 7.8) for the control group (P &lt; 0.001). Dexmedetomidine also reduced the 24-h cumulative morphine consumption to 63.9 mg (58.8 to 69.0 mg) and 66.2 mg (60.6 to 71.8 mg) for the DexP and DexIV groups, respectively, compared with 81.9 mg (75.0 to 88.9 mg) for the control group (P &lt; 0.001). DexIV was noninferior to DexP for these outcomes. Both dexmedetomidine routes reduced the pain and opioid consumption up to 8 h postoperatively and did not prolong the duration of motor blockade. Conclusion Both perineural and IV dexmedetomidine can effectively prolong the ISB analgesic duration and reduce the opioid consumption without prolonging motor blockade.

BackgroundShort-term survival benefits of endovascular aneurysm repair (EVAR) compared with open repair (OR) of intact abdominal aortic aneurysms have been shown in randomised trials, but this early survival benefit is soon lost. Survival benefit of EVAR was unclear at follow-up to 10 years.ObjectiveTo assess the long-term efficacy of EVAR against OR in patients deemed fit and suitable for both procedures (EVAR trial 1; EVAR-1); and against no intervention in patients unfit for OR (EVAR trial 2; EVAR-2). To appraise the long-term significance of type II endoleak and define criteria for intervention.DesignTwo national, multicentre randomised controlled trials: EVAR-1 and EVAR-2.SettingPatients were recruited from 37 hospitals in the UK between 1 September 1999 and 31 August 2004.ParticipantsMen and women aged ≥ 60 years with an aneurysm of ≥ 5.5 cm (as identified by computed tomography scanning), anatomically suitable and fit for OR were randomly assigned 1 : 1 to either EVAR (n = 626) or OR (n = 626) in EVAR-1 using computer-generated sequences at the trial hub. Patients considered unfit were randomly assigned to EVAR (n = 197) or no intervention (n = 207) in EVAR-2. There was no blinding.InterventionsEVAR, OR or no intervention.Main outcome measuresThe primary end points were total and aneurysm-related mortality until mid-2015 for both trials. Secondary outcomes for EVAR-1 were reinterventions, costs and cost-effectiveness.ResultsIn EVAR-1, over a mean of 12.7 years (standard deviation 1.5 years; maximum 15.8 years), we recorded 9.3 deaths per 100 person-years in the EVAR group and 8.9 deaths per 100 person-years in the OR group [adjusted hazard ratio (HR) 1.11, 95% confidence interval (CI) 0.97 to 1.27;p = 0.14]. At 0–6 months after randomisation, patients in the EVAR group had a lower mortality (adjusted HR 0.61, 95% CI 0.37 to 1.02 for total mortality; HR 0.47, 95% CI 0.23 to 0.93 for aneurysm-related mortality;p = 0.031), but beyond 8 years of follow-up patients in the OR group had a significantly lower mortality (adjusted HR 1.25, 95% CI 1.00 to 1.56,p = 0.048 for total mortality; HR 5.82, 95% CI 1.64 to 20.65,p = 0.0064 for aneurysm-related mortality). The increased aneurysm-related mortality in the EVAR group after 8 years was mainly attributable to secondary aneurysm sac rupture, with increased cancer mortality also observed in the EVAR group. Overall, aneurysm reintervention rates were higher in the EVAR group than in the OR group, 4.1 and 1.7 per 100 person-years, respectively (p < 0.001), with reinterventions occurring throughout follow-up. The mean difference in costs over 14 years was £3798 (95% CI £2338 to £5258). Economic modelling based on the outcomes of the EVAR-1 trial showed that the cost per quality-adjusted life-year gained over the patient’s lifetime exceeds conventional thresholds used in the UK. In EVAR-2, patients died at the same rate in both groups, but there was suggestion of lower aneurysm mortality in those who actually underwent EVAR. Type II endoleak itself is not associated with a higher rate of mortality.LimitationsDevices used were implanted between 1999 and 2004. Newer devices might have better results. Later follow-up imaging declined, particularly for OR patients. Methodology to capture reinterventions changed mainly to record linkage through the Hospital Episode Statistics administrative data set from 2009.ConclusionsEVAR has an early survival benefit but an inferior late survival benefit compared with OR, which needs to be addressed by lifelong surveillance of EVAR and reintervention if necessary. EVAR does not prolong life in patients unfit for OR. Type II endoleak alone is relatively benign.Future workTo find easier ways to monitor sac expansion to trigger timely reintervention.Trial registrationCurrent Controlled Trials ISRCTN55703451.FundingThis project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and the results will be published in full inHealth Technology Assessment; Vol. 22, No. 5. See the NIHR Journals Library website for further project information.

The reproducibility of dual-energy X-ray absorptiometry (DXA) measurements of bone mineral density (BMD) is an important factor for longitudinal studies. We assessed the long-term precision of posteroanterior lumbar spine, femoral neck and total hip BMD in 40 postmenopausal women who formed the control arm of a clinical trial of tibolone. BMD was measured at 0, 6 and 12 months and thereafter every 12 months up to 7 years. For each subject the trend of BMD with time was analyzed using linear regression. Each residual was expressed as the percentage difference from predicted BMD and the validity of assuming linear change with time was checked using the mean residuals for each visit number. For spine BMD a chi-squared test showed that the mean residuals were not statistically significantly different from zero. Although statistically significant deviations from linearity were found for the femoral neck and total hip sites the weighted root mean square residuals were small compared with the precision errors. When residuals were binned into histograms a statistical test for skewness was not significant for all three sites. However, a test for kurtosis yielded a statistically significant result for each histogram due to outlying residuals. To determine the standard deviation (SD) of the core gaussian distribution, outliers were trimmed using the method of Melton et al. For lumbar spine BMD outliers with residuals exceeding +/- 3 SD arose mainly from subjects with a body mass index (BMI) >28 kg/m(2) or from subjects who had undergone a large change in BMI during the study. For femoral neck BMD and total hip BMD the outliers were frequently due to inconsistent rotation of the hip. Results for long-term precision calculated from the standard deviation of residuals using the trimmed (untrimmed) data were: lumbar spine BMD, 1.12% (1.65%); femoral neck BMD, 2.21% (2.48%); and total hip BMD, 1.32% (1.57%). These errors were only slightly worse than short-term errors despite changes of DXA scanner during the course of the study. However, obesity may have an adverse effect on precision errors in individual patients and particular care is necessary to ensure reproducible patient positioning for femur scans.