Effectiveness and safety of menopause treatments: pitfalls of available evidence and future research need.

By 2050 more than 1.6 billion women worldwide will be of post-reproductive age, with >75% reporting severe menopausal symptoms. The last few years saw a gradual uplift in public awareness reaffirming the health needs of women with menopause. Still, effective translation of available evidence on menopause treatments is hindered by several methodological limitations and poor research conduct. We argue that a paradigm shift is required in menopause research to address the remaining knowledge gap and guide safe evidence-based care provision. A critical misconception across studies on menopause is the assumption that women represent a homogeneous group who respond similarly to a particular therapy irrespective of their exposure and individual risk factors. We highlight potential solutions to optimize the quality of future research in menopause including adopting robust trial methodology, standardize outcome reporting to capture quality-of-life measures, and improve lay patient and public involvement in future research.

Antidepressants Trial in Parkinson's Disease (ADepT-PD): protocol for a randomised placebo-controlled trial on the effectiveness of escitalopram and nortriptyline on depressive symptoms in Parkinson's disease.

BACKGROUND: Depressive symptoms are common in patients with Parkinson's disease and depression is a significant predictor of functional impairment, reduced quality of life and general well-being in Parkinson's disease. Despite the high prevalence of depression, evidence on the effectiveness and tolerability of antidepressants in this population is limited. The primary aim of this trial is to establish the clinical and cost effectiveness of escitalopram and nortriptyline for the treatment of depression in Parkinson's disease. METHODS: This is a multi-centre, double-blind, randomised placebo-controlled trial in 408 people with Parkinson's disease with subsyndromal depression, major depressive disorder or persistent depressive disorder and a Beck Depression Inventory-II (BDI-II) score of 14 or above. Participants will be randomised into one of three groups, receiving either escitalopram, nortriptyline or placebo for 12 months. Trial participation is face-to-face, hybrid or remote. The primary outcome measure is the BDI-II score following 8 weeks of treatment. Secondary outcomes will be collected at baseline, 8, 26 and 52 weeks and following withdrawal, including severity of anxiety and depression scores as well as Parkinson's disease motor severity, and ratings of non-motor symptoms, cognitive function, health-related quality of life, levodopa-equivalence dose, changes in medication, overall clinical effectiveness, capability, health and social care resource use, carer health-related quality of life, adverse effects and number of dropouts. DISCUSSION: This trial aims to determine the effectiveness of escitalopram and nortriptyline for reducing depressive symptoms in Parkinson's disease over 8 weeks, to provide information on the effect of these medications on anxiety and other non-motor symptoms in PD and on impact on patients and caregivers, and to examine their effect on change in motor severity. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03652870 Date of registration - 29th August 2018.

Sociodemographic inequalities in the management of depression in adults aged 55 and over: an analysis of English primary care data.

BACKGROUND: We do not know how primary care treatment of depression varies by age across both psychotropic medication and psychological therapies. METHODS: Cohort study including 19 710 people aged 55+ with GP recorded depression diagnoses and 26 276 people with recorded depression symptoms during the period 2009-2013, from 373 General Practices in The Health Improvement Network (THIN) database in England. Main outcomes were initiation of treatment with anti-depressants, anxiolytics, hypnotics, anti-psychotic drugs, referrals to psychological therapies within 6 months of onset. RESULTS: Treatment rates with antidepressants are high for those recorded with new depression diagnoses (87.1%) or symptoms of depression (58.7%). Treatment in those with depression diagnoses varies little by age. In those with depressive symptoms there was a J-shaped pattern with reduced antidepressant treatment in those in their 60s and 70s followed by increased treatment in the oldest age groups (85+ years), compared with those aged 55-59 years. Other psychotropic drug prescribing (hypnotics/anxiolytics, antipsychotics) all increase with increasing age. Recorded referrals for psychological therapies were low, and decreased steadily with increasing age, such that women aged 75-79 years with depression diagnoses had around six times lower odds of referral (OR 0.17, 95% CI 0.1-0.29) than those aged 55-59 years, and men aged 80-84 years had around seven times lower (OR 0.14, 95% CI 0.05-0.36). CONCLUSIONS: The oldest age groups with new depression diagnoses and symptoms have fewer recorded referrals to psychological therapies, and higher psychotropic drug treatment rates in primary care. This suggests potential inequalities in access to psychological therapies.

Short-term outcome of substance-induced psychotic disorder in a large UK first episode psychosis cohort.

OBJECTIVE: The incidence and outcome of first-episode substance-induced psychotic disorder (SIPD) are unclear. The study aimed to compare the 1-year outcomes of those given a SIPD diagnosis by clinicians compared to other psychosis diagnoses in a first-episode cohort. METHOD: Data were from a large (n = 1027) cohort of first-episode psychosis (FEP) patients admitted to early intervention services in the UK (National EDEN). Diagnosis, including that of SIPD, was made by treating psychiatrists at baseline using ICD10 criteria. Details on symptoms, functioning, quality of life, relapse and recovery were available at baseline and 12 months. RESULTS: There were 67 cases of SIPD (6.5% of the cohort). At baseline, SIPD patients were no different to other psychoses on symptoms, functioning and quality of life. At 12 months, there was no difference in SIPD and other psychoses on functioning, quality of life or relapse and recovery rates. Levels of psychotic and general symptomatology were similar but depressive symptoms were higher in the SIPD group. CONCLUSIONS: First-episode psychosis patients with a diagnosis of SIPD do not appear to have better outcomes than those with other primary psychotic diagnoses. The higher levels of depressive symptoms may be a specific marker in these patients.

Relationship of glycaemic control and hypoglycaemic episodes to 4-year cardiovascular outcomes in people with type 2 diabetes starting insulin.

AIMS: To examine the relationships between glycated haemoglobin (HbA1c) and cardiovascular (CV) events in people beginning insulin in routine clinical practice in Europe, North America and Asia in a non-interventional study, the Cardiovascular Risk Evaluation in people with Type 2 Diabetes on Insulin Therapy (CREDIT) study. METHODS: Data on 2999 people were collected prospectively over 4 years from physician reports. The primary outcome was the composite of stroke or myocardial infarction (MI) or CV-specific death. Events were blindly adjudicated. The relative hazards of CV events were described from Cox proportional hazards models incorporating patient risk factors, with updated average HbA1c as a time-dependent covariate. The relationship of severe and symptomatic hypoglycaemia (collected during the 6 months before yearly ascertainment) with CV and all-cause mortality was examined. RESULTS: A total of 147 primary events were accrued during up to 54 months of follow-up. In all, 60 CV-specific deaths, 44 non-fatal MIs and 57 non-fatal strokes occurred, totalling 161 events. There was a significant positive relationship between updated mean HbA1c and primary outcome: hazard ratio (HR) 1.25 [95% confidence interval (CI) 1.12-1.40; p < 0.0001]. CV death [HR 1.31 (95% CI 1.10-1.57); p = 0.0027] and stroke [HR 1.36 (95% CI 1.17-1.59); p < 0.0001] were both strongly associated with HbA1c, while MI was not [HR 1.05 (95% CI 0.83-1.32)]. One or more severe hypoglycaemic episodes affected 175 participants, while 1508 participants experienced one or more symptomatic hypoglycaemic events. We found no relationship between severe/symptomatic hypoglycaemic events and CV-specific/all-cause death. CONCLUSIONS: Ongoing poorer glucose control was associated with CV events; hypoglycaemia was not associated with CV-specific/all-cause death.

Pilot randomised trial of a brief intervention for comorbid substance misuse in psychiatric in-patient settings.

OBJECTIVE: This proof of principle study evaluated the effectiveness and feasibility of a brief motivational intervention, delivered in mental health in-patient settings, to improve engagement in treatment for drug and alcohol misuse. METHOD: A randomised controlled trial using concealed randomisation, blind, independent assessment of outcome at 3 months. Participants were 59 new adult admissions, to six acute mental health hospital units in one UK mental health service, with schizophrenia related or bipolar disorder diagnoses, users of community mental health services and also misusing alcohol and/or drugs. Participants were randomised to Brief Integrated Motivational Intervention (BIMI) with Treatment As Usual (TAU), or TAU alone. The BIMI took place over a 2-week period and encouraged participants to explore substance use and its impact on mental health. RESULTS: Fifty-nine in-patients (BIMI n = 30; TAU n = 29) were randomised, the BIMI was associated with a 63% relative odds increase in the primary outcome engagement in treatment [OR 1.63 (95% CI 1.01-2.65; P = 0.047)], at 3 months. Qualitative interviews with staff and participants indicated that the BIMI was both feasible and acceptable. CONCLUSION: Mental health hospital admissions present an opportunity for brief motivational interventions focussed on substance misuse and can lead to improvements in engagement.

The natural history of atrial fibrillation in patients with permanent pacemakers: is atrial fibrillation a progressive disease?

OBJECTIVES: Atrial fibrillation (AF) is thought to be a progressive arrhythmia, starting with short paroxysmal episodes, until eventually, it becomes permanent. Evidence for this is limited to studies with short follow-up or with minimal cardiac rhythm monitoring. We utilised the continuous rhythm monitoring capabilities of implanted pacemakers to define better the natural history of AF. METHODS: The study included 356 patients with pacemaker devices capable of continuous atrial rhythm monitoring (186 male, mean age (± SD) 79.5 ± 8.9 years). All clinical records, including history/physical examination reports, laboratory results, ECGs and Holter monitoring data were reviewed. Patients were included if AF episodes >30 s were documented. Permanent pacemaker diagnostic data were reviewed at least every 12 months. ACC/AHA/ESC guidelines were used to define AF episodes as paroxysmal, persistent or long-standing persistent/permanent. RESULTS: Study follow-up period (± SD) was 7.2 ± 3.1 years. Over the study period, 179 of 356 patients (50.3 %) had at least one episode of persistent AF. Of the 356 patients, 314 (88.2 %) had paroxysmal AF and 42 (11.8 %) had persistent AF at the time of diagnosis. The predominant AF subtype, at latest follow-up, was paroxysmal for 192 patients (53.9 %), persistent for 77 (21.6 %) and long-standing persistent/permanent for 87 (24.4 %). Univariable predictors of progression to persistent AF were (1) male gender, (2) increasing left atrial diameter (LAD), (3) reduced atrial pacing (AP) and (4) increasing ventricular pacing. CONCLUSIONS: Although many patients with AF will have persistent episodes, long-term continuous pacemaker follow-up demonstrates that the majority will have a paroxysmal, as opposed to persistent, form of the arrhythmia.

A propensity score matched comparison of different insulin regimens 1 year after beginning insulin in people with type 2 diabetes.

AIM: To compare using propensity score analysis the outcome of beginning insulin therapy with basal, premix, mealtime + basal or mealtime insulin on the basis of data from 3031 people from the observational CREDIT (Cardiovascular Risk Evaluation in People with Type 2 Diabetes on Insulin Therapy) study. This approach overcomes likely confounding in baseline and unknown characteristics common to observational studies. METHODS: Efficacy and safety outcomes were collected at baseline and at 1 year in previously insulin-naïve people. Propensity score matched groups using all available baseline data were defined to compare outcomes by pairs of insulin regimens. RESULTS: From 2659 people with available data, propensity score matches were achieved for 686 people starting premix or basal insulin, 542 starting basal + mealtime or premix insulin and 400 starting basal or basal + mealtime. HbA1c reduction did not differ between the three pairs of insulin regimens. However, the relative risk of overall and nocturnal hypoglycaemia was lower (p = 0.010 to p < 0.001) with basal or basal + mealtime compared with premix insulin, and for nocturnal (p = 0.021) but not overall hypoglycaemia for basal compared to basal + mealtime insulin. Body weight increase was less for basal versus premix insulin [-1.3 (95% CI -2.1, -0.6) kg, p < 0.001] or versus basal + mealtime insulin [-1.4 (-2.5, -0.3) kg, p = 0.016], but did not differ between basal + mealtime and premix. Smaller groups matching mealtime insulin had some residual mismatching of HbA1c. CONCLUSION: Comparing insulin regimens between individuals matched by propensity scores indicated differences in hypoglycaemia and body weight change, despite similar HbA1c reductions. Our findings are consistent with those from randomized controlled trials.

Fear of falling, fracture history, and comorbidities are associated with health-related quality of life among European and US women with osteoporosis in a large international study.

UNLABELLED: We studied 7,897 women with postmenopausal osteoporosis to assess factors that influence health-related quality of life (HRQoL). An increased number of comorbidities, fear of falling, and previous vertebral fracture were associated with significant reductions in HRQoL. Understanding the factors that affect HRQoL may improve management of these patients. INTRODUCTION: HRQoL is impaired in women treated for postmenopausal osteoporosis (PMO). The objective of this study was to examine the relationship between clinical characteristics, comorbidities, medical history, patient demographics, and HRQoL in women with PMO. METHODS: Baseline data were obtained and combined from two large and similar multinational observational studies: Prospective Observational Scientific Study Investigating Bone Loss Experience in Europe (POSSIBLE EU®) and in the US (POSSIBLE US™) including postmenopausal women in primary care settings initiating or switching bone loss treatment, or who had been on bone loss treatment for some time. HRQoL measured by health utility scores (EQ-5D™) were available for 7,897 women (94 % of study participants). The relationship between HRQoL and baseline clinical characteristics, medical history and patient demographics was assessed using parsimonious, multivariable, mixed-model analyses. RESULTS: Median health utility score was 0.80 (interquartile range 0.69-1.00). In multivariable analyses, young age, low body mass index, previous vertebral fracture, increased number of comorbidities, high fear of falling, and depression were associated with reduced HRQoL. Regression-based model estimates showed that previous vertebral fracture was associated with lower health utility scores by 0.08 (10.3 %) and demonstrated the impact of multiple comorbidities and of fear of falling on HRQoL. CONCLUSIONS: In this large observational study of women with PMO, there was substantial interindividual variability in HRQoL. An increased number of comorbidities, fear of falling, and previous vertebral fracture were associated with significant reductions in HRQoL.

A comparison of health-related quality of life (health utility) between insulin degludec and insulin glargine: a meta-analysis of phase 3 trials.

AIM: To evaluate health-related quality of life (health utility) scores in patients with diabetes receiving insulin degludec (IDeg) or insulin glargine (IGlar). METHODS: Patient-level data from six, randomized, controlled, open-label, multicentre, confirmatory, treat-to-target trials of 26- or 52 weeks' duration were pooled in this analysis. The Short Form 36 (SF-36) version-2 health questionnaire was completed by patients at baseline and end-of-trial. SF-36 scores for 4001 individual patients were then mapped onto the EuroQol-5D health utility scale, which has a range from -0.59 (a state worse than death) to 1.00 (perfect health). RESULTS: IDeg treatment exhibited a significant improvement in health status of 0.005 (CI: 0.0006; 0.009) points compared with IGlar (p < 0.024). Gender, region, trial and age also had a significant influence on estimated utility scores as did baseline utility scores, p < 0.05. Prior to the removal of interaction variables a difference of 0.008 points was observed, p < 0.045. Previous insulin treatment did not have an impact on the final outcome. CONCLUSION: This study shows that IDeg is associated with a modest, but statistically significant, improvement in health utility compared with IGlar in patients with diabetes.

Results of indirect and mixed treatment comparison of fracture efficacy for osteoporosis treatments: a meta-analysis.

UNLABELLED: 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. INTRODUCTION: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Insulin degludec improves health-related quality of life (SF-36® ) compared with insulin glargine in people with Type 2 diabetes starting on basal insulin: a meta-analysis of phase 3a trials.

AIM: To compare the effect of insulin degludec and insulin glargine on health-related quality of life in patients with Type 2 diabetes starting on insulin therapy. METHODS: Patient-level data from three open-label, randomized, treat-to-target trials of 26 or 52 weeks' duration were pooled using a weighted analysis in conjunction with a fixed-effects model. Insulin-naive patients received either insulin degludec (n = 1290) or insulin glargine (n = 632) once daily, in combination with oral anti-diabetic drugs. Glycaemic control was assessed via HbA(1c) and fasting plasma glucose concentrations. Rates of hypoglycaemia, defined as plasma glucose < 3.1 mmol/l (< 56 mg/dl), were recorded. Health-related quality of life was evaluated using the 36-item Short Form (SF-36(®) ) version 2 questionnaire. Statistical analysis was performed using a generalized linear model with treatment, trial, anti-diabetic therapy at baseline, gender, region and age as explanatory variables. RESULTS: Insulin degludec was confirmed as non-inferior to insulin glargine based on HbA(1c) concentrations. In each trial comprising the meta-analysis, fasting plasma glucose and confirmed overall and nocturnal (00.01-05.59 h) hypoglycaemia were all numerically or significantly lower with insulin degludec vs. insulin glargine. At endpoint, the overall physical health component score was significantly higher (better) with insulin degludec vs. insulin glargine [+0.66 (95% CI 0.04-1.28)], largely attributable to a difference [+1.10 (95% CI 0.22-1.98)] in the bodily pain domain score. In the mental domains, vitality was significantly higher with insulin degludec vs. insulin glargine [+0.81 (95% CI 0.01-1.59)]. CONCLUSIONS: Compared with insulin glargine, insulin degludec leads to improvements in both mental and physical health status for patients with Type 2 diabetes initiating insulin therapy.

Factors influencing initial choice of insulin therapy in a large international non-interventional study of people with type 2 diabetes.

AIM: To use baseline characteristics of the Cardiovascular Risk Evaluation in people with type 2 Diabetes on Insulin Therapy study population to identify factors that could explain the choice of insulin therapy when beginning insulin. METHODS: The source, non-interventional, longitudinal, long-term study involves 314 centres in 12 countries in five regions. People were enrolled having started any insulin regimen in the previous 12 months. To identify factors associated with the choice of insulin regimen, multivariable backward logistic regression was performed on eligible physician and participant explanatory variables. RESULTS: Participants (N = 3031) had mean age 62 years, diabetes duration 11 years, body mass index 29.3 kg/m² and an HbA1c of 9.5%. Participants in Japan had less hypertension, smoked more and used fewer concomitant medications than those of other regions. Only physician location (rural or urban) influenced the choice of insulin in Japan. In the other four-regions-combined, physician location, specialty, sex and practice type influenced choice of insulin as did participant location, baseline HbA1c, use of glucose-lowering therapies and prior insulin secretagogue use. CONCLUSION: Choice of initial insulin regimen was influenced by several physician and participant characteristics in Canada and Europe, but only by physician location in Japan.

Weekend hospitalization and additional risk of death: an analysis of inpatient data.

OBJECTIVE: To assess whether weekend admissions to hospital and/or already being an inpatient on weekend days were associated with any additional mortality risk. DESIGN: 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. PARTICIPANTS: National Health Service Hospitals in England. MAIN OUTCOME MEASURES: 30 day mortality (in or out of hospital). RESULTS: 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. CONCLUSIONS: 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.

Final results of the DAPS (Denosumab Adherence Preference Satisfaction) study: a 24-month, randomized, crossover comparison with alendronate in postmenopausal women.

UNLABELLED: 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. INTRODUCTION: 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. METHODS: 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). RESULTS: 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. CONCLUSION: 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.