Generalised Anxiety Disorder: Incidence and Drug Treatment

This thesis focused on time trends for the incidence of generalised anxiety recording in UK primary care, initial pharmacologic treatment in this setting, and comparing available treatment options. The first study assessed the incidence of diagnoses of generalised anxiety and related illness recorded in UK primary care electronic notes. This analysis found a substantial increase in general practitioner consulting for generalised anxiety and depression recently, concentrated within younger people and in particular women. The second, related analysis examined trends in anxiolytic prescribing in UK primary care following diagnosis with generalised anxiety. This analysis showed that about half of psychotropic drug naïve patients receive pharmacologic therapy in the year following diagnosis, and that the most common initial therapy was a selective serotonin reuptake inhibitor. It also found that the rate of benzodiazepine prescribing has fallen over time. The third study was a systematic review and network meta-analysis of randomised trials in GAD. The objective of this study was to provide a comparison of the safety and efficacy of therapeutic options. This analysis was based on 89 trials, which included 25,441 patients randomly assigned to 22 different active drugs or placebo. Duloxetine, pregabalin, venlafaxine and escitalopram were shown to be 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 samples. Quetiapine had the largest impact on anxiety severity, but it was poorly tolerated when compared to placebo. Likewise, paroxetine and benzodiazepine were effective but also poorly tolerated when compared to placebo

Effects of canagliflozin on serum potassium in the CANagliflozin cardioVascular Assessment Study (CANVAS) Program

Background: The sodium-glucose cotransporter 2 inhibitor canagliflozin has been shown to reduce the risk of cardiovascular and renal events in patients with Type 2 diabetes mellitus and high risk. Pooled analyses of data from early studies and interim data from the CANagliflozin cardioVascular Assessment Study (CANVAS) suggested that canagliflozin might lead to increases in serum potassium, particularly the 300 mg dose in patients with renal impairment, which is important because high serum potassium is associated with increased cardiovascular and renal risk. We examined the effect of canagliflozin on serum potassium levels and hyperkalemia rates in the completed CANVAS Program. Methods: The CANVAS Program (n = 10,142) was comprised of two comparable double-blind, randomized, placebo-controlled trials (CANVAS and CANVAS-Renal). Participants received canagliflozin 100 or 300 mg or placebo. Serum potassium measurements were performed in a central laboratory0 and assessed at ∼6-month intervals. Results: In the CANVAS Program, mean potassium levels were generally consistent with canagliflozin and placebo, overall and by baseline estimated glomerular filtration rate (eGFR; ≥60, 45 to<60 and <45 mL/min/1.73 m2). The risk of increased or decreased potassium was similar with canagliflozin and placebo overall and by baseline eGFR (all P-heterogeneity ≥0.56) or use of renin-angiotensin-aldosterone system inhibitors (all P-heterogeneity ≥0.71); levels did not appear different by canagliflozin dose. Hyperkalemia {hazard ratio (HR) [95% confidence interval (CI)] 1.60 (0.92-2.81)} and serious hyperkalemia [HR (95% CI) 0.75 (0.27-2.11)] adverse events were not different across groups. Conclusions: In the CANVAS Program, there were no meaningful effects of canagliflozin on serum potassium in the overall population or key subgroups. Hyperkalemia adverse events were uncommon and occurred at comparable rates with canagliflozin and placebo

Effects of canagliflozin on initiation of insulin and other antihyperglycaemic agents in the CANVAS program

This study compared initiation of insulin and other AHAs with canagliflozin versus placebo for participants with type 2 diabetes and a history/high risk of cardiovascular disease in the CANagliflozin cardioVascular Assessment Study (CANVAS) Program. After 1 year fewer participants treated with canagliflozin versus placebo initiated any AHA (7% vs 16%), insulin (3% vs 9%;) or any non-insulin AHA (5% vs 12%; p<0.001 for all); overall AHA initiation rates increased over time but were consistently lower with canagliflozin compared with placebo. During the study, the likelihood of initiating insulin was 2.7 times lower for participants treated with canagliflozin compared with placebo (hazard ratio, 0.37; 95% CI: 0.31,0.43; p<0.001). The time difference between 10% of patients in the canagliflozin and placebo groups being initiated on insulin from the beginning of the trial was about two years. Time to initiation of other AHAs, including metformin, dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists and sulphonylureas, was also delayed for canagliflozin versus placebo (p<0.001 for each). Compared with placebo, canagliflozin delayed the need for initiation of other AHAs and delayed time to insulin therapy, an outcome that is important to many people with diabetes. Trial registration: ClinicalTrials.gov identifiers NCT01032629, NCT01989754. This article is protected by copyright. All rights reserved

Kidney protection with canagliflozin: A combined analysis of the randomized CANVAS program and CREDENCE trials

AIM: In the CANVAS Program and CREDENCE trials, the sodium glucose co-transporter 2 inhibitor canagliflozin reduced the risk of cardiovascular and kidney events in patients with type 2 diabetes. The current study analysed a pooled population to ascertain the kidney protection provided by canagliflozin across the full spectrum of kidney parameters. METHODS: This post-hoc pooled analysis of the CANVAS Program (N = 10 142) and CREDENCE trial (N = 4401), assessed the risk of the primary kidney composite (doubling of serum creatinine, end-stage kidney disease, renal death), in all patients and subgroups defined by baseline estimated glomerular filtration rate (300 mg/g (33.9 mg/mmol)] and 2012 Kidney Disease: Improving Global Outcomes (KDIGO) classification of chronic kidney disease (low/moderate, high and very high risk). RESULTS: In the overall population, the risk for the primary kidney composite outcome was 37% lower in the canagliflozin group versus placebo (HR: 0.63; 95% CI: 0.53, 0.77; p  .05). A statistically significant risk reduction of the primary kidney composite outcome was sustained by approximately 18 months after randomization. CONCLUSIONS: These results emphasize a critical role of canagliflozin in kidney protection across a broad spectrum of participants with type 2 diabetes with varying levels of kidney function

Impact of Canagliflozin Treatment on Health-Related Quality of Life among People with Type 2 Diabetes Mellitus: A Pooled Analysis of Patient-Reported Outcomes from Randomized Controlled Trials

Background: Evidence from patient-reported outcomes in clinical trials may explain health-related behaviors observed in the real world. Objective: The purpose of this analysis was to evaluate the effect of treatment with canagliflozin, a sodium glucose co-transporter 2 inhibitor, compared with placebo or sitagliptin on health-related quality-of-life outcomes in participants with type 2 diabetes mellitus from the clinical development program. Methods: Patient-reported outcomes data from four randomized controlled trials of canagliflozin (n = 2536) were pooled and analyzed to evaluate participants’ interest in continuing study medication; satisfaction with weight; and physical, mental, and emotional health after 26–52 weeks of treatment with canagliflozin vs. placebo or sitagliptin. Results: Upon trial completion, participants treated with canagliflozin were more likely to express interest in continuing study medication than participants treated with placebo or sitagliptin [odds ratio (95% confidence interval) of 1.54 (1.19–1.99); p = 0.001]. Those treated with canagliflozin were also more likely to be satisfied with their weight and report favorable outcomes (score improvement or maintenance of good scores) related to physical and emotional health. Conclusions: The results of this pooled analysis suggest that people with type 2 diabetes mellitus treated with canagliflozin generally had positive experiences with treatment and improvements in health-related quality of life. Future research is needed to determine if these improvements result in improved type 2 diabetes mellitus management and treatment adherence. ClinicalTrials.gov identifiers NCT01106625, NCT01106677, NCT01137812, NCT02025907. Electronic supplementary material The online version of this article (10.1007/s40271-017-0290-4) contains supplementary material, which is available to authorized users

Overnight auto-adjusting continuous airway pressure + standard care compared with standard care alone in the prevention of morbidity in sickle cell disease phase II (POMS2b): Study protocol for a randomised controlled trial

Background: In addition to pain, sickle cell anaemia (HbSS) complications include neurocognitive difficulties in attention and processing speed associated with low daytime and night-time oxygen saturation compounded by obstructive sleep apnoea (OSA). In the general population OSA is treated with continuous positive airways pressure (CPAP). The aim of this single-blind, randomised, controlled phase II trial is to compare auto-adjusting CPAP (APAP) with standard care to standard care alone in individuals with HbSS to determine whether the intervention improves attention and processing speed, brain structure, pain and quality of life. Methods/Design: Eligibility criteria include: ability to provide informed consent; age>8years; diagnosis of HbSS; and mean overnight saturation of23years); silent infarction on MRI; minimum overnight oxygen saturation>90% or<90%; and hydroxyurea use. For APAP individuals, the intervention is administered at home. Adherence and effectiveness are recorded using software documenting hours of use each night and overnight oximetry. Participant support in terms of appropriate facemask and facilitating adherence are provided by an unblinded sleep physiologist. The primary outcome is change in the cancellation subtest from the Wechsler scales. Secondary outcomes include general cognitive functioning, quantitative brain MRI, blood and urine chemistry, quality of life and daily pain via a smartphone App (GoMedSolutions, Inc) and, where possible MRI heart, echocardiography, and 6-min walk. These outcomes will be assessed at baseline and after six months of treatment by assessors blind to treatment assignment. Discussion: Altering oxygen saturation in HbSS may lead to bone marrow suppression. This risk will be reduced by monitoring full blood counts at baseline, two weeks, three months and six months, providing treatment as appropriate and reporting as safety events. Trial registration: ISRCTN46012373. Registered on 10 July 2015. Protocol Version: 6.0 Date: 24th December 2015 Sponsor: University Hospital Southampton. Sponsor's protocol code: RHMCHIOT53National Institute for Health Research (NIHR)NIHR Great Ormond Street Hospital Biomedical Research CentreGreat Ormond Street CharityResearch for Patient Benefit funding programm