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

Is antimicrobial stewardship cost-effective? A narrative review of the evidence

Aims This narrative review aimed to collate recent evidence on the cost-effectiveness and cost–benefit of antimicrobial stewardship (AMS) programmes, to address the question ‘is AMS cost-effective?’, while providing resources and guidance for future research in this area. Sources PubMed was searched for studies assessing the cost-effectiveness, cost–utility or cost–benefit of AMS interventions in humans, published from January 2000 to March 2017, with no setting inclusion/exclusion criteria specified. Reference lists of retrieved reviews were searched for additional articles. Content Recent evidence on the cost-effectiveness and cost–benefit of AMS is described, studies suggest persuasive and structural AMS interventions may provide health economic benefits to the hospital setting. However, overall, cost-effectiveness evidence for AMS is severely limited, especially for the community setting. Recommendations for future research in this area are therefore provided, including discussion of appropriate health economic methodological choice. Implications Health systems have a finite and decreasing resource, decision makers currently do not have necessary evidence to assess whether AMS programmes provide sufficient benefits. Although the evidence-base of the cost-effectiveness of AMS is increasing, it remains inadequate for investment decision-making. Robust health economics research needs to be completed to enhance the generalizability and usability of cost-effectiveness results

Optimal strategies for monitoring lipid levels in patients at risk or with cardiovascular disease: a systematic review with statistical and cost-effectiveness modelling

Background: Various lipid measurements in monitoring/screening programmes can be used, alone or in cardiovascular risk scores, to guide treatment for prevention of cardiovascular disease (CVD). Because some changes in lipids are due to variability rather than true change, the value of lipid-monitoring strategies needs evaluation. Objective: To determine clinical value and cost-effectiveness of different monitoring intervals and different lipid measures for primary and secondary prevention of CVD. Data sources: We searched databases and clinical trials registers from 2007 [including the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE, the Clinical Trials Register, the Current Controlled Trials (CCT) register, and the Cumulative Index to Nursing and Allied Health Literature (CINAHL)] to update and extend previous systematic reviews. Patient-level data from the Clinical Practice Research Datalink (CPRD) and St Luke’s Hospital, Japan, were used in statistical modelling. Utilities and health-care costs were drawn from the literature. Methods: In two meta-analyses, we used prospective studies to examine associations of lipids with CVD and mortality, and randomised controlled trials to estimate lipid-lowering effects of atorvastatin doses. Patient-level data were used to estimate progression and variability of lipid measurements over time, and hence to model lipid-monitoring strategies. Results are expressed as rates of true-/false-positive and true-/false-negative tests for high lipid or high CVD risk. We estimated incremental costs per quality-adjusted life-year. Results: A total of 115 publications reported strength of association between different lipid measures and CVD events in 138 data sets. The summary adjusted hazard ratio (HR) per standard deviation of total cholesterol (TC) to high-density lipoprotein (HDL) cholesterol ratio was 1.25 [95% confidence interval 1.15 to 1.35] for CVD in a primary prevention population but heterogeneity was high (I 2 = 98%); similar results were observed for non-HDL cholesterol, apolipoprotein B and other ratio measures. Associations were smaller for other single lipid measures. Across 10 trials, low-dose atorvastatin (10 and 20 mg) effects ranged from a TC reduction of 0.92 mmol/l to 2.07 mmol/l, and low-density lipoprotein reduction of between 0.88 mmol/l and 1.86 mmol/l. Effects of 40 mg and 80 mg were reported by one trial each. For primary prevention, over a 3-year period, we estimate annual monitoring would unnecessarily treat 9 per 1000 more men (28 vs. 19 per 1000) and 5 per 1000 more women (17 vs. 12 per 1000) than monitoring every 3 years. However, annual monitoring would also undertreat 9 per 1000 fewer men (7 vs. 16 per 1000) and 4 per 1000 fewer women (7 vs. 11 per 1000) than monitoring at 3-year intervals. For secondary prevention, over a 3-year period, annual monitoring would increase unnecessary treatment changes by 66 per 1000 men and 31 per 1000 women, and decrease undertreatment by 29 per 1000 men and 28 per 1000 men, compared with monitoring every 3 years. In cost-effectiveness, strategies with increased screening/monitoring dominate. Exploratory analyses found that any unknown harms of statins would need utility decrements as large as 0.08 (men) to 0.11 (women) per statin user to reverse this finding in primary prevention. Limitation: Heterogeneity in meta-analyses. Conclusions: While acknowledging known and potential unknown harms of statins, we find that more-frequent monitoring strategies are cost-effective compared with others. Regular lipid monitoring in those with and without CVD is likely to be beneficial to patients and to the health service. Future research should include trials of the benefits and harms of atorvastatin 40 and 80 mg, large-scale surveillance of statin safety, and investigation of the effect of monitoring on medication adherence