The impact of Type 2 diabetes prevention programmes based on risk-identification and lifestyle intervention intensity strategies: a cost-effectiveness analysis.

AIMS: To develop a cost-effectiveness model to compare Type 2 diabetes prevention programmes targeting different at-risk population subgroups with a lifestyle intervention of varying intensity. METHODS: An individual patient simulation model was constructed to simulate the development of diabetes in a representative sample of adults without diabetes from the UK population. The model incorporates trajectories for HbA1c , 2-h glucose, fasting plasma glucose, BMI, systolic blood pressure, total cholesterol and HDL cholesterol. Patients can be diagnosed with diabetes, cardiovascular disease, microvascular complications of diabetes, cancer, osteoarthritis and depression, or can die. The model collects costs and utilities over a lifetime horizon. The perspective is the UK National Health Service and personal social services. We used the model to evaluate the population-wide impact of targeting a lifestyle intervention of varying intensity to six population subgroups defined as high risk for diabetes. RESULTS: The intervention produces 0.0003 to 0.0009 incremental quality-adjusted life years and saves up to £1.04 per person in the general population, depending upon the subgroup targeted. Cost-effectiveness increases with intervention intensity. The most cost-effective options are to target individuals with HbA1c > 42 mmol/mol (6%) or with a high Finnish Diabetes Risk (FINDRISC) probability score (> 0.1). CONCLUSION: The model indicates that diabetes prevention interventions are likely to be cost-effective and may be cost-saving over a lifetime. In the model, the criteria for selecting at-risk individuals differentially impact upon diabetes and cardiovascular disease outcomes, and on the timing of benefits. These findings have implications for deciding who should be targeted for diabetes prevention interventions

Clinical effectiveness and cost-effectiveness results from the randomised, Phase IIB trial in previously untreated patients with chronic lymphocytic leukaemia to compare fludarabine, cyclophosphamide and rituximab with fludarabine, cyclophosphamide, mitoxantrone and low-dose rituximab: the Attenuated dose Rituximab with ChemoTherapy In Chronic lymphocytic leukaemia (ARCTIC) trial

Background: The conventional frontline therapy for fit patients with chronic lymphocytic leukaemia (CLL) is fludarabine, cyclophosphamide and rituximab (FCR). Rituximab (Mabthera®, Roche Products Ltd) targets the CD20 antigen, which is expressed at low levels in CLL. The standard dose of rituximab in CLL (375 mg/m2 in cycle 1 and 500 mg/m2 in cycles 2–6) was selected based on toxicity data only. Small doses of rituximab (as low as 20 mg) have biological activity in CLL, with an immediate reduction in circulating CLL cells and down-regulation of CD20. Phase II trials had suggested improved efficacy with the addition of mitoxantrone to FCR. The key assumption for the Attenuated dose Rituximab with ChemoTherapy In CLL (ARCTIC) trial was that the addition of mitoxantrone to fludarabine, cyclophosphamide and low-dose rituximab would be more effective than conventional FCR. Objectives: To assess whether fludarabine, cyclophosphamide, mitoxantrone and low-dose rituximab (FCM-miniR) (100 mg of rituximab per cycle) was non-inferior to FCR in frontline CLL. Complete response (CR) rate was the primary end point, with the secondary end points being progression-free survival (PFS), overall survival (OS), overall response rate, eradication of minimal residual disease (MRD), safety and cost-effectiveness. Design: ARCTIC was a UK multicentre, randomised, controlled, open, Phase IIB non-inferiority trial in previously untreated CLL. A total of 206 patients with previously untreated CLL who required treatment, according to the International Workshop on Chronic Lymphocytic Leukaemia criteria, were to be randomised to FCR or FCM-miniR. There was an independent Data Monitoring and Ethics Committee (DMEC) with a pre-planned interim efficacy assessment on 103 participants. Results: The DMEC’s interim analysis led to early trial closure. Although the response rates in both arms were higher than anticipated, FCM-miniR had a lower CR rate than FCR. This was partly attributable to the higher toxicity associated with mitoxantrone. A total of 100 participants completed FCR, 79 completed FCM-miniR and 21 commenced FCM-miniR but switched to FCR following DMEC recommendations. The CR rate for participants receiving FCR was 76%, compared with 55% for FCM-miniR (adjusted odds ratio 0.37; 95% confidence interval 0.19 to 0.73). Key secondary end points also showed that FCR was superior, with more participants achieving MRD negativity (57% for FCR vs. 46% for FCM-miniR). More participants experienced a serious adverse reaction with FCM-miniR compared with FCR (50% vs. 41%). At a median of 37.3 months’ follow-up, the PFS and OS rates are good compared with previous studies, with no significant difference between the treatment arms. The economic analysis indicates that because FCM-miniR is less effective than FCR, FCM-miniR is not expected to be cost-effective over a lifetime horizon, producing a mean cost-saving of –£7723, a quality-adjusted life-year loss of –0.73 and a resulting incremental net monetary loss of –£6780. Conclusions: FCM-miniR is less well tolerated, with poorer response rates, than FCR, partly owing to the additional toxicity associated with mitoxantrone. In view of this, FCM-miniR will not be taken forward into a larger definitive Phase III trial. The trial demonstrated that oral FCR yields extremely high response rates compared with historical series with intravenous chemotherapy. Future work: We shall compare the results of ARCTIC with those of the ADMIRE (Does the ADdition of Mitoxantrone Improve Response to FCR chemotherapy in patients with CLL?) trial, which compared FCR with FCM-R to assess the efficacy of low- versus standard-dose rituximab, allowing for the toxicity associated with mitoxantrone. Trial registration: Current Controlled Trials ISRCTN16544962. Funding: This project was funded by the NIHR Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 21, No. 28. See the NIHR Journals Library website for further project information

Reasonable adjustments to provide equitable and inclusive assessment, screening and treatment of osteoporosis for adults with intellectual disabilities: a feasibility study

Background: People with intellectual disabilities are a high risk population for developing osteoporosis and fragility fractures, yet they experience barriers to accessing dual‐energy x‐ray absorptiometry (DXA) bone mineral density (BMD) screening and fracture assessment. Reasonable adjustments are a statutory requirement in the UK, but there is a paucity of evidence‐based examples to assist their identification, implementation and evaluation. Method: Thirty adults with intellectual disabilities underwent DXA BMD screening and fracture risk assessment. Reasonable adjustments were identified and implemented. Results: The presence of osteopenia or osteoporosis was detected in 23 out of 29 (79%) participants. Osteoporosis professionals report that 17 of 18 reasonable adjustments identified and implemented are both important and easy to implement. Conclusion: Adults across all levels of intellectual disabilities can complete DXA BMD screening with reasonable adjustments. Widely implementing these reasonable adjustments would contribute to reducing inequalities in health care for adults with intellectual disabilities

Breast cancer surgery in older women: outcomes of the bridging age gap in breast cancer study

Background In older women breast cancer (BC) surgery is often non-standard or omitted due to concerns about morbidity. The Age Gap prospective multi-centre cohort study aimed to determine factors influencing selection for and outcomes from surgery for older BC patients. Methods Women >70 with operable BC were recruited from 56 UK breast units between 2013-2018. Data on patient and tumour characteristics were correlated with type of surgery to the breast (breast conservation surgery [BCS], mastectomy) and axilla (axillary node clearance [ANC], sentinel node biopsy [SLNB] or no axillary surgery [NAS]) using univariate and multivariate analysis. Oncologic, adverse event and Quality of life (QoL) outcomes were monitored for 2 years. Results Of 3375 recruited women, surgery was performed in 2816. There were 62 bilateral tumours, giving 2854 surgical events. The median age was 76 (range 70-95). Breast surgery comprised mastectomy in 1138, BCS in 1798. Axillary surgery comprised 575 ANC, 2203 SLNB and 76 NAS. Age, frailty, dementia and comorbidities were predictors of mastectomy (RR 1.06, CI 1.05-1.08). Frailty and comorbidity were significant predictors of NAS (RR 0.91, CI 0.87-0.96). The rate of adverse events was moderate (551/2854, 19.3%) with no 30 day mortality. Long term QoL and functional independence were adversely affected by surgery. Conclusions Age, ill health and frailty all impact on surgical decision making for BC. BC surgery is safe with serious adverse events being rare and no mortality. However surgery has a negative impact on QoL and independence which must be considered when counselling patients about choices

Infection and wound breakdown in spontaneous second-degree perineal tears: An exploratory mixed methods study.

BACKGROUND: Perineal trauma affects large numbers of women who have a vaginal birth. This study explores the incidence, etiology and women's experiences of wound infection/breakdown associated with spontaneous second degree tears. METHODS: This was an exploratory mixed methods study set in an urban tertiary National Health Service hospital in 2014-2015. The study included a prospective observational study of second-degree tears using electronic patient records. Infection was defined using criteria adapted from Public Health England's Surgical Site Infection Surveillance Service. We also did a case-control study of maternity records to explore factors associated with perineal infection/wound breakdown, and semi-structured interviews with a purposeful sample of women who experienced wound infection/breakdown. RESULTS: Of 2892 vaginal births during the study period, 76.8% sustained perineal trauma, with second-degree tears most commonly recorded (n = 828/28.6%). Sixteen (1.9%) had a documented infection/wound breakdown which were associated with "compromised wound status" (increased severity of wound/poor suturing; P = 0.033) Women complained of a lack of information about their perineum and poor postnatal surveillance by midwives and physicians. Diagnosis and treatment were often delayed by clinicians' reliance on external signs of wound infection. Although the sample size was small, there were no differences in rates of infection between sutured and unsutured second-degree tears. CONCLUSIONS: Although second-degree tears were common after vaginal birth, wound infection/breakdown was relatively uncommon. Women who report feeling unwell or develop pyrexia postnatally should be assessed urgently. A prospective longitudinal study exploring the long-term sequelae of second-degree tears is needed

Canagliflozin, dapagliflozin and empagliflozin monotherapy for treating type 2 diabetes: systematic review and economic evaluation

Background: Most people with type 2 diabetes are overweight, so initial treatment is aimed at reducing weight and increasing physical activity. Even modest weight loss can improve control of blood glucose. If drug treatment is necessary, the drug of first choice is metformin. However, some people cannot tolerate metformin, which causes diarrhoea in about 10%, and it cannot be used in people with renal impairment. This review appraises three of the newest class of drugs for monotherapy when metformin cannot be used, the sodium–glucose co-transporter 2 (SGLT2) inhibitors. Objective: To review the clinical effectiveness and cost-effectiveness of dapagliflozin (Farxiga, Bristol-Myers Squibb, Luton, UK), canagliflozin (Invokana, Janssen, High Wycombe, UK) and empagliflozin (Jardiance, Merck & Co., Darmstadt, Germany), in monotherapy in people who cannot take metformin. Sources: MEDLINE (1946 to February 2015) and EMBASE (1974 to February 2015) for randomised controlled trials lasting 24 weeks or more. For adverse events, a wider range of studies was used. Three manufacturers provided submissions. Methods: Systematic review and economic evaluation. A network meta-analysis was carried out involving the three SGLT2 inhibitors and key comparators. Critical appraisal of submissions from three manufacturers. Results: We included three trials of dapagliflozin and two each for canagliflozin and empagliflozin. The trials were of good quality. The canagliflozin and dapagliflozin trials compared them with placebo, but the two empagliflozin trials included active comparators. All three drugs were shown to be effective in improving glycaemic control, promoting weight loss and lowering blood pressure (BP). Limitations: There were no head-to-head trials of the different flozins, and no long-term data on cardiovascular outcomes in this group of patients. Most trials were against placebo. The trials were done in patient groups that were not always comparable, for example in baseline glycated haemoglobin or body mass index. Data on elderly patients were lacking. Conclusions: Dapagliflozin, canagliflozin and empagliflozin are effective in improving glycaemic control, with added benefits of some reductions in BP and weight. Adverse effects are urinary and genital tract infections in a small proportion of users. In monotherapy, the three drugs do not appear cost-effective compared with gliclazide or pioglitazone, but may be competitive against sitagliptin (Januvia, Boehringer Ingelheim, Bracknell, UK). Funding: The National Institute for Health Research Health Technology Assessment programme

Corrigendum: A systematic review and economic evaluation of bisphosphonates for the prevention of fragility fractures

Abstract Background Fragility fractures are fractures that result from mechanical forces that would not ordinarily result in fracture. Objectives To evaluate the clinical effectiveness and safety of bisphosphonates [alendronic acid (Fosamax® and Fosamax® Once Weekly, Merck Sharp & Dohme Ltd), risedronic acid (Actonel® and Actonel Once a Week®, Warner Chilcott UK Ltd), ibandronic acid (Bonviva®, Roche Products Ltd) and zoledronic acid (Aclasta®, Novartis Pharmaceuticals UK Ltd)] for the prevention of fragility fracture and to assess their cost-effectiveness at varying levels of fracture risk. Data sources For the clinical effectiveness review, six electronic databases and two trial registries were searched: MEDLINE, EMBASE, The Cochrane Library, Cumulative Index to Nursing and Allied Health Literature, Web of Science and BIOSIS Previews, Clinicaltrials.gov and World Health Organization International Clinical Trials Registry Platform. Searches were limited by date from 2008 until September 2014. Review methods A systematic review and network meta-analysis (NMA) of effectiveness studies were conducted. A review of published economic analyses was undertaken and a de novo health economic model was constructed. Discrete event simulation was used to estimate lifetime costs and quality-adjusted life-years (QALYs) for each bisphosphonate treatment strategy and a strategy of no treatment for a simulated cohort of patients with heterogeneous characteristics. The model was populated with effectiveness evidence from the systematic review and NMA. All other parameters were estimated from published sources. A NHS and Personal Social Services perspective was taken, and costs and benefits were discounted at 3.5% per annum. Fracture risk was estimated from patient characteristics using the QFracture® (QFracture-2012 open source revision 38, Clinrisk Ltd, Leeds, UK) and FRAX® (web version 3.9, University of Sheffield, Sheffield, UK) tools. The relationship between fracture risk and incremental net benefit (INB) was estimated using non-parametric regression. Probabilistic sensitivity analysis (PSA) and scenario analyses were used to assess uncertainty. Results Forty-six randomised controlled trials (RCTs) were included in the clinical effectiveness systematic review, with 27 RCTs providing data for the fracture NMA and 35 RCTs providing data for the femoral neck bone mineral density (BMD) NMA. All treatments had beneficial effects on fractures versus placebo, with hazard ratios varying from 0.41 to 0.92 depending on treatment and fracture type. The effects on vertebral fractures and percentage change in BMD were statistically significant for all treatments. There was no evidence of a difference in effect on fractures between bisphosphonates. A statistically significant difference in the incidence of influenza-like symptoms was identified from the RCTs for zoledronic acid compared with placebo. Reviews of observational studies suggest that upper gastrointestinal symptoms are frequently reported in the first month of oral bisphosphonate treatment, but pooled analyses of placebo-controlled trials found no statistically significant difference. A strategy of no treatment was estimated to have the maximum INB for patients with a 10-year QFracture risk under 1.5%, whereas oral bisphosphonates provided maximum INB at higher levels of risk. However, the PSA suggested that there is considerable uncertainty regarding whether or not no treatment is the optimal strategy until the QFracture score is around 5.5%. In the model using FRAX, the mean INBs were positive for all oral bisphosphonate treatments across all risk categories. Intravenous bisphosphonates were estimated to have lower INBs than oral bisphosphonates across all levels of fracture risk when estimated using either QFracture or FRAX. Limitations We assumed that all treatment strategies are viable alternatives across the whole population. Conclusions Bisphosphonates are effective in preventing fragility fractures. However, the benefit-to-risk ratio in the lowest-risk patients may be debatable given the low absolute QALY gains and the potential for adverse events. We plan to extend the analysis to include non-bisphosphonate therapies. Study registration This study is registered as PROSPERO CRD42013006883. Funding The National Institute for Health Research Health Technology Assessment programme

Bridging the age gap: a prognostic model that predicts survival and aids in primary treatment decisions for older women with oestrogen receptor‐positive early breast cancer

Background A prognostic model was developed and validated using cancer registry data. This underpins an online decision support tool, informing primary treatment choice for women aged 70 years or older with hormone receptor‐positive early breast cancer. Methods Data from women diagnosed between 2002 and 2010 in the English Northern and Yorkshire and West Midlands regions were used to develop the model. Primary treatment options of surgery with adjuvant endocrine therapy or primary endocrine therapy were compared. Models predicting the hazard of breast cancer‐specific mortality and hazard of other‐cause mortality were combined to derive survival probabilities. The model was validated externally using data from the Eastern Cancer Registration and Information Centre. Results The model was developed using data from 23 842 women, and validated externally on a data set from 14 526 patients. The overall model calibration was good. At 2 and 5 years, predicted mortality from breast cancer and other causes differed from the observed rate by less than 1 per cent. At 5 years, there were slight overpredictions in breast cancer mortality (2629 predicted versus 2556 observed deaths; P  = 0·142) and mortality from all causes (6399 versus 6320 respectively; P  = 0·583). The discrepancy varied between subgroups. Model discrimination was 0·75 or above for all mortality measures. Conclusion A prognostic model for older women with oestrogen receptor‐positive early breast cancer was developed and validated in the present study. This forms a basis for an online decision support tool (https://agegap.shef.ac.uk/)

The management of type 2 diabetes with fixed‐ratio combination insulin degludec/liraglutide (IDegLira) versus basal‐bolus therapy (insulin glargine U100 plus insulin aspart): a short‐term cost‐effectiveness analysis in the UK setting

Aim: To evaluate the cost‐effectiveness of IDegLira versus basal‐bolus therapy (BBT) with insulin glargine U100 plus up to 4 times daily insulin aspart for the management of type 2 diabetes in the UK. Methods: A Microsoft Excel model was used to evaluate the cost‐utility of IDegLira versus BBT over a 1‐year time horizon. Clinical input data were taken from the treat‐to‐target DUAL VII trial, conducted in patients unable to achieve adequate glycaemic control (HbA1c <7.0%) with basal insulin, with IDegLira associated with lower rates of hypoglycaemia and reduced body mass index (BMI) in comparison with BBT, with similar HbA1c reductions. Costs (expressed in GBP) and event‐related disutilities were taken from published sources. Extensive sensitivity analyses were performed. Results: IDegLira was associated with an improvement of 0.05 quality‐adjusted life years (QALYs) versus BBT, due to reductions in non‐severe hypoglycaemic episodes and BMI with IDegLira. Costs were higher with IDegLira by GBP 303 per patient, leading to an incremental cost‐effectiveness ratio (ICER) of GBP 5924 per QALY gained for IDegLira versus BBT. ICERs remained below GBP 20 000 per QALY gained across a range of sensitivity analyses. Conclusions: IDegLira is a cost‐effective alternative to BBT with insulin glargine U100 plus insulin aspart, providing equivalent glycaemic control with a simpler treatment regimen for patients with type 2 diabetes inadequately controlled on basal insulin in the UK