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

Adalimumab, etanercept, infliximab, certolizumab pegol, golimumab, tocilizumab and abatacept for the treatment of rheumatoid arthritis not previously treated with disease-modifying antirheumatic drugs and after the failure of conventional disease-modifying antirheumatic drugs only: systematic review and economic evaluation.

OBJECTIVES: Rheumatoid arthritis (RA) is a chronic inflammatory disease associated with increasing disability, reduced quality of life and substantial costs (as a result of both intervention acquisition and hospitalisation). The objective was to assess the clinical effectiveness and cost-effectiveness of seven biologic disease-modifying antirheumatic drugs (bDMARDs) compared with each other and conventional disease-modifying antirheumatic drugs (cDMARDs). The decision problem was divided into those patients who were cDMARD naive and those who were cDMARD experienced; whether a patient had severe or moderate to severe disease; and whether or not an individual could tolerate methotrexate (MTX). DATA SOURCES: The following databases were searched: MEDLINE from 1948 to July 2013; EMBASE from 1980 to July 2013; Cochrane Database of Systematic Reviews from 1996 to May 2013; Cochrane Central Register of Controlled Trials from 1898 to May 2013; Health Technology Assessment Database from 1995 to May 2013; Database of Abstracts of Reviews of Effects from 1995 to May 2013; Cumulative Index to Nursing and Allied Health Literature from 1982 to April 2013; and TOXLINE from 1840 to July 2013. Studies were eligible for inclusion if they evaluated the impact of a bDMARD used within licensed indications on an outcome of interest compared against an appropriate comparator in one of the stated population subgroups within a randomised controlled trial (RCT). Outcomes of interest included American College of Rheumatology (ACR) scores and European League Against Rheumatism (EULAR) response. Interrogation of Early Rheumatoid Arthritis Study (ERAS) data was undertaken to assess the Health Assessment Questionnaire (HAQ) progression while on cDMARDs. METHODS: Network meta-analyses (NMAs) were undertaken for patients who were cDMARD naive and for those who were cDMARD experienced. These were undertaken separately for EULAR and ACR data. Sensitivity analyses were undertaken to explore the impact of including RCTs with a small proportion of bDMARD experienced patients and where MTX exposure was deemed insufficient. A mathematical model was constructed to simulate the experiences of hypothetical patients. The model was based on EULAR response as this is commonly used in clinical practice in England. Observational databases, published literature and NMA results were used to populate the model. The outcome measure was cost per quality-adjusted life-year (QALY) gained. RESULTS: Sixty RCTs met the review inclusion criteria for clinical effectiveness, 38 of these trials provided ACR and/or EULAR response data for the NMA. Fourteen additional trials contributed data to sensitivity analyses. There was uncertainty in the relative effectiveness of the interventions. It was not clear whether or not formal ranking of interventions would result in clinically meaningful differences. Results from the analysis of ERAS data indicated that historical assumptions regarding HAQ progression had been pessimistic. The typical incremental cost per QALY of bDMARDs compared with cDMARDs alone for those with severe RA is > £40,000. This increases for those who cannot tolerate MTX (£50,000) and is > £60,000 per QALY when bDMARDs were used prior to cDMARDs. Values for individuals with moderate to severe RA were higher than those with severe RA. Results produced using EULAR and ACR data were similar. The key parameter that affected the results is the assumed HAQ progression while on cDMARDs. When historic assumptions were used typical incremental cost per QALY values fell to £38,000 for those with severe disease who could tolerate MTX. CONCLUSIONS: bDMARDs appear to have cost per QALY values greater than the thresholds stated by the National Institute for Health and Care Excellence for interventions to be cost-effective. Future research priorities include: the evaluation of the long-term HAQ trajectory while on cDMARDs; the relationship between HAQ direct medical costs; and whether or not bDMARDs could be stopped once a patient has achieved a stated target (e.g. remission). STUDY REGISTRATION: This study is registered as PROSPERO CRD42012003386. FUNDING: The National Institute for Health Research Health Technology Assessment programme

Post-injection delirium/sedation syndrome in patients with schizophrenia treated with olanzapine long-acting injection, I: analysis of cases

<p>Abstract</p> <p>Background</p> <p>An advance in the treatment of schizophrenia is the development of long-acting intramuscular formulations of antipsychotics, such as olanzapine long-acting injection (LAI). During clinical trials, a post-injection syndrome characterized by signs of delirium and/or excessive sedation was identified in a small percentage of patients following injection with olanzapine LAI.</p> <p>Methods</p> <p>Safety data from all completed and ongoing trials of olanzapine LAI were reviewed for possible cases of this post-injection syndrome. Descriptive analyses were conducted to characterize incidence, clinical presentation, and outcome. Regression analyses were conducted to assess possible risk factors.</p> <p>Results</p> <p>Based on approximately 45,000 olanzapine LAI injections given to 2054 patients in clinical trials through 14 October 2008, post-injection delirium/sedation syndrome occurred in approximately 0.07% of injections or 1.4% of patients (30 cases in 29 patients). Symptomatology was consistent with olanzapine overdose (e.g., sedation, confusion, slurred speech, altered gait, or unconsciousness). However, no clinically significant decreases in vital signs were observed. Symptom onset ranged from immediate to 3 to 5 hours post injection, with a median onset time of 25 minutes post injection. All patients recovered within 1.5 to 72 hours, and the majority continued to receive further olanzapine LAI injections following the event. No clear risk factors were identified.</p> <p>Conclusions</p> <p>Post-injection delirium/sedation syndrome can be readily identified based on symptom presentation, progression, and temporal relationship to the injection, and is consistent with olanzapine overdose following probable accidental intravascular injection of a portion of the olanzapine LAI dose. Although there is no specific antidote for olanzapine overdose, patients can be treated symptomatically as needed. Special precautions include use of proper injection technique and a post-injection observation period.</p> <p>Trial Registration</p> <p>ClinicalTrials.gov ID; URL: <url>http://http//www.clinicaltrials.gov/</url>: NCT00094640, NCT00088478, NCT00088491, NCT00088465, and NCT00320489.</p

An Insight into Z-Drug Abuse and Dependence: An Examination of Reports to the European Medicines Agency Database of Suspected Adverse Drug Reactions

© The Author(s) 2019. Published by Oxford University Press on behalf of CINP.BACKGROUND: Although originally marketed as safe alternatives to the habit-forming benzodiazepines, growing numbers of zaleplon, zolpidem, and zopiclone ("Z-drugs") clinical concerns relating to their potential of abuse, dependence, and withdrawal have been reported over time. We aimed here at assessing these issues analyzing datasets of adverse drug reactions provided by the European Medicines Agency through the EudraVigilance system. METHODS: Analyzing the adverse drug reactions databases of each Z-drug, descriptive analyses have been performed on cases and proportional reporting ratios (PRRs) computed. RESULTS: An overall number of 33 240 (e.g., 23 420 zolpidem; 9283 zopiclone; and 537 zaleplon) misuse-, abuse-, dependence-, and withdrawal-related adverse drug reactions, corresponding to some 6246 unique patients given Z-drugs, were here identified. Cases were studied and described, including demographic characteristics and clinical data such as concomitant drugs, doses, routes of administration, and outcomes of the reactions (being fatalities recorded). Considering PRR values and in comparison with zopiclone, zolpidem was more frequently involved in both misuse/abuse and withdrawal issues. Zolpidem and zopiclone presented with the same dependence risk, but zopiclone was most involved in overdose adverse drug reactions. Compared with zaleplon, zopiclone presented higher dependence and overdose-related issues but slightly lower misuse/abuse and withdrawal PRR values. CONCLUSION: Current data may only represent a gross underestimate of the real prevalence of Z-drug misuse. Caution should be exercised when prescribing those molecules, especially for patients with psychiatric illnesses and/or history of drug abuse. We recommend the need to invest in proactive pharmacovigilance activities to better and promptly detect, understand, and prevent any possible misuse potential of prescribed medications.Peer reviewe

Facet-joint injections for non-specific low back pain: a feasibility RCT

Background: Pain of lumbar facet-joint origin is a common cause of low back pain in adults and may lead to chronic pain and disability, with associated health and socioeconomic implications. The socioeconomic burden includes an inability to return to work resulting in loss of productivity in addition to direct and indirect health-care utilisation costs. Lumbar facet-joints are paired synovial joints between the superior and inferior articular processes of consecutive lumbar vertebrae and between the fifth lumbar vertebra and the sacrum. Facet-joint pain is defined as pain that arises from any structure that is part of the facet-joints, including the fibrous capsule, synovial membrane, hyaline cartilage and bone. This pain may be treated by intra-articular injections with local anaesthetic and steroid, although this treatment is not standardised. At present, there is no definitive research to support the use of targeted lumbar facet-joint injections to manage this pain. Because of the lack of high-quality, robust clinical evidence, the National Institute for Health and Care Excellence (NICE) guidelines on the management of chronic low back pain [NICE. Low Back Pain in Adults: Early Management. Clinical guideline (CG88). London: NICE; 2009] did not recommend the use of spinal injections despite their perceived potential to reduce pain intensity and improve rehabilitation, with NICE calling for further research to be undertaken. The updated guidelines [NICE. Low Back Pain and Sciatica in Over 16s: Assessment and Management. NICE guideline (NG59). London: NICE; 2016] again do not recommend the use of spinal injections. Objectives: To assess the feasibility of carrying out a definitive study to evaluate the clinical effectiveness and cost-effectiveness of lumbar facet-joint injections compared with a sham procedure in patients with non-specific low back pain of > 3 months’ duration. Design: Blinded parallel two-arm pilot randomised controlled trial. Setting: Initially planned as a multicentre study involving three NHS trusts in the UK, recruitment took place in the pain and spinal orthopaedic clinics at Barts Health NHS Trust only. Participants: Adult patients referred by their GP to the specialist clinics with non-specific low back pain of at least 3 months’ duration despite NICE-recommended best non-invasive care (education and one of a physical exercise programme, acupuncture or manual therapy). Patients who had already received lumbar facet-joint injections or who had had previous back surgery were excluded. Interventions: Participants who had a positive result following a diagnostic test (single medial branch nerve blocks) were randomised and blinded to receive either intra-articular lumbar facet-joint injections with steroids (intervention group) or a sham procedure (control group). All participants were invited to attend a group-based combined physical and psychological (CPP) programme. Main outcome measures: In addition to the primary outcome of feasibility, questionnaires were used to assess a range of pain-related (including the Brief Pain Inventory and Short-Form McGill Pain Questionnaire version 2) and disability-related (including the EuroQol-5 Dimensions five-level version and Oswestry Low Back Pain Questionnaire) issues. Health-care utilisation and cost data were also assessed. The questionnaire visits took place at baseline and at 6 weeks, 3 months and 6 months post randomisation. The outcome assessors were blinded to the allocation groups. Results: Of 628 participants screened for eligibility, nine were randomised to receive the study intervention (intervention group, n = 5; sham group, n = 4), six completed the CPP programme and eight completed the study. Limitations: Failure to achieve our expected recruitment targets led to early closure of the study by the funder. Conclusions: Because of the small number of participants recruited to the study, we were unable to draw any conclusions about the clinical effectiveness or cost-effectiveness of intra-articular lumbar facet-joint injections in the management of non-specific low back pain. Although we did not achieve the target recruitment rate from the pain clinics, we demonstrated our ability to develop a robust study protocol and deliver the intended interventions safely to all nine randomised participants, thus addressing many of the feasibility objectives. Future work: Stronger collaborations with primary care may improve the recruitment of patients earlier in their pain trajectory who are suitable for inclusion in a future trial. Trial registration: EudraCT 2014-003187-20 and Current Controlled Trials ISRCTN12191542. Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 21, No. 74. See the NIHR Journals Library website for further project information

A systematic review and economic evaluation of adalimumab and dexamethasone for treating non-infectious intermediate, posterior or panuveitis in adults

Background: Non-infectious intermediate uveitis, posterior uveitis and panuveitis are a heterogeneous group of inflammatory eye disorders. Management includes local and systemic corticosteroids, immunosuppressants and biologic drugs. Objectives: To evaluate clinical and cost-effectiveness of subcutaneous adalimumab and dexamethasone intravitreal implant in adults with non-infectious intermediate, posterior or panuveitis. Methods: Nine electronic databases were searched to June 2016. A Markov model was developed to assess cost-effectiveness of dexamethasone and adalimumab, each compared with current practice, from an NHS and PSS perspective over a lifetime horizon, parameterised with published evidence. Costs and benefits were discounted at 3.5%. Substantial sensitivity analyses were undertaken. Results: Two studies (VISUAL I, active uveitis; and VISUAL II, inactive uveitis) compared adalimumab against placebo, plus limited standard care in both arms. Time to treatment failure (reduced visual acuity, intraocular inflammation, new vascular lesions) was longer for adalimumab than placebo, with hazard ratio 0.50 (95% CI 0.36 to 0.70, p<0.001) in VISUAL I and 0.57 (0.39 to 0.84, p=0.004) in VISUAL II. Adalimumab provided significantly greater improvement in VFQ-25 composite score in VISUAL I (mean difference, 4.20; p=0.010) but not VISUAL II (mean difference, 2.12; p=0.16). Some systemic adverse effects occurred more frequently with adalimumab than placebo. One study (HURON, active uveitis) compared single 0.7mg dexamethasone implant against sham, plus limited standard care in both arms. Dexamethasone provided significant benefits over sham at 8 and 26 weeks in percentage of patients with vitreous haze score zero (p<0.014); mean BCVA improvement (p≤0.002); and percentage of patients with ≥5-point improvement in VFQ-25 (p<0.05). Raised intraocular pressure and cataracts occurred more frequently with dexamethasone than sham. The incremental cost-effectiveness ratio (ICER) of one dexamethasone implant in one eye for a combination of patients with unilateral and bilateral uveitis, compared with limited current practice as per the HURON trial, is estimated as £19,509 per quality-adjusted life year (QALY) gained. The ICER of adalimumab for patients with mainly bilateral uveitis, compared with limited current practice as per the VISUAL trials, is estimated as £94,523 and £317,547 per QALY gained in active and inactive uveitis respectively. Sensitivity analyses suggest rate of blindness has the biggest impact upon model results. The interventions may be more cost-effective in populations where there is a greater risk of blindness. Limitations: The clinical trials did not fully reflect clinical practice. Thirteen studies of clinically-relevant comparator treatments were identified; however, network meta-analysis was not feasible. The model results are highly uncertain due to the limited evidence base. Conclusions: Two RCTs of systemic adalimumab and one RCT of unilateral, single dexamethasone implant showed significant benefits over placebo or sham. The ICERs for adalimumab are estimated to be above generally accepted thresholds for cost-effectiveness. The cost-effectiveness of dexamethasone is estimated to fall below standard thresholds. However there is substantial uncertainty around the model assumptions. Future work: Primary research should compare dexamethasone and adalimumab with current treatments over the long term, and in important subgroups, and consider how short-term improvements relate to long-term effects on vision. Study registration: PROSPERO CRD42016041799 Funding details: NIHR HTA Programm