Juliet Hockenhull

The clinical effectiveness of central venous catheters treated with anti-infective agents in preventing catheter-related bloodstream infections : A systematic review

Objectives:To assess the clinical effectiveness of central venous catheters (CVCs) treated with anti-infective agents (AI-CVCs) in preventing catheter-related bloodstream infections (CRBSI). Data Sources:MEDLINE (OVID), EMBASE, SCI//Web of Science, SCI/ISI Proceedings, and the Cochrane Library. Study Selection:A systematic review of the literature was conducted using internationally recognized methodology. All included articles were reports of randomized controlled trials comparing the clinical effectiveness of CVCs treated with AI-CVCs with either standard CVCs or another anti-infective treated catheter. Articles requiring in-house preparation of catheters or that only reported interim data were excluded. Data Extraction:Data extraction was carried out independently and crosschecked by two reviewers using a pretested data extraction form. Data Synthesis:Meta-analyses were conducted to assess the effectiveness of AI-CVCs in preventing CRBSI, compared with standard CVCs. Results are presented in forest plots with 95% confidence intervals. Results:Thirty-eight randomized controlled trials met the inclusion criteria. Methodologic quality was generally poor. Meta-analyses of data from 27 trials assessing CRBSI showed a strong treatment effect in favor of AI-CVCs (odds ratio 0.49 (95% confidence interval 0.37–0.64) fixed effects, test for heterogeneity, chi-square = 28.78, df = 26, p = 0.321, I2 = 9.7). Results subgrouped by the different types of anti-infective treatments generally demonstrated treatment effects favoring the treated catheters. Sensitivity analyses investigating the effects of methodologic differences showed no differences to the overall conclusions of the primary analysis. Conclusion:AI-CVCs appear to be effective in reducing CRBSI compared with standard CVCs. However, it is important to establish whether this effect remains in settings where infection-prevention bundles of care are established as routine practice. This review does not address this question and further research is required.

Erlotinib monotherapy for the maintenance treatment of non-small cell lung cancer after previous platinum-containing chemotherapy: a NICE single technology appraisal.

The UK National Institute for Health and Clinical Excellence (NICE) invited the manufacturer of erlotinib (Roche) to submit evidence for the clinical and cost effectiveness of erlotinib as monotherapy for the maintenance treatment of patients with non-small cell lung cancer (NSCLC) and stable disease following previous treatment with four cycles of platinumcontaining therapy. The Liverpool Reviews and Implementation Group(LRiG) at the University of Liverpool was commissioned to act as the Evidence Review Group (ERG) for this appraisal.The ERG reviewed the clinical- and cost-effectiveness evidence in two stages and in accordance with the decision problem defined by NICE. The analysis of the submitted models assessed the appropriateness of the approach taken by the manufacturer in modelling the decision problem. Analysis also included reliability of model implementation and the extent of conformity to published standards and prevailing norms of practice within the health economics modelling community. Particular attention was paid to issues likely to have substantial impact on the base-case cost-effectiveness results.Clinical evidence was derived from a multi-centre, double-blind, randomized, phase III study designed to address the overall population of NSCLC patients. Outcomes included progression-free survival (PFS) and overall survival (OS). The recruited population was mainly from outside of Western Europe and no patients in the pivotal trial had received pemetrexed as a firstline therapy, which is now accepted clinical practice in the UK. The evidence considered in this article includes only the population for whom marketing authorizations has been received–that is, patients with stable disease following first-line therapy.The trial reported a small but statistically significant increase in both PFS and OS in patients with stable disease receiving erlotinib compared with placebo. However, no significant difference was identified in OS when patients with non-squamous disease and stable disease were considered as a subgroup.The economic evidence was focussed on the ERG’s assessment of three economic models that related to patients with stable disease and compared erlotinib with placebo in the squamous and non-squamous populations and erlotinib with pemetrexed in the non-squamous population. The incremental cost-effectiveness ratios (ICERs) reported by the manufacturer were £39 936 per QALY gained (stable disease, all); £35 491 per QALY gained (stable disease, squamous); and £40 020 per QALY gained (stable disease, nonsquamous). In comparison with pemetrexed, in the cases where erlotinib was considered to be superior or equivalent, erlotinib dominated. In the cases where erlotinib was considered to be slightly inferior, then the ICERs ranged between £91 789 and £511 351 per QALY gained; these ICERs appear in the south-west corner of a cost-effectiveness plane, i.e. erlotinib is cheaper but less effective than pemetrexed.The ERG recalculated the base-case cost-effectiveness results in the manufacturer’s submission, considering nine key areas where corrections and/or adjustments were required, related to time horizon, discounting logic, costs of erlotinib and pemetrexed, cost of second-line chemotherapy, unit costs, utility values, PFS and OS. This resulted in ERG-revised ICERs for the stable disease squamous population of £44 812 per QALY gained, in the stable disease non-squamous population of £68 120 per QALY gained, and, when erlotinib was compared with pemetrexed, the result was £84 029 per QALY gained. All values were above NICE’s perceived willingness-to-pay threshold. After the second Appraisal Committee meeting, the Committee did not recommend the use of erlotinib in this patient population.

Rituximab for the treatment of relapsed or refractory stage III or IV follicular non-Hodgkin's lymphoma.

This paper presents a summary of the evidence review group report into the clinical effectiveness and cost-effectiveness of rituximab for the treatment of relapsed or refractory stage III or IV follicular non-Hodgkins lymphoma (NHL), in accordance with the licensed indication, based upon the evidence submission from Roche Products Ltd to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal (STA) process. The submitted clinical evidence included two randomised controlled trials [European Organisation for Research and Treatment of Cancer (EORTC) and German Low Grade Lymphoma Study Group - Fludarabine, Cyclophosphamide and Mitoxantrone and (GLSG-FCM)] comparing the clinical effects of chemotherapy with or without rituximab in the induction of remission at first or second relapse and the clinical benefits of rituximab maintenance therapy versus the NHSs current clinical practice of observation for follicular lymphoma (FL) patients. Both trials showed that in patients with relapsed FL the addition of rituximab to chemotherapy induction treatment increased overall response rates. Furthermore, rituximab maintenance therapy increased the median length of remission when compared with observation only. Safety data from the two trials showed that while the majority of patients reported some adverse events, the number of patients withdrawing from treatment in the EORTC trial was low, with rates not being reported for the GLSG-FCM trial. The most commonly reported adverse events were blood/bone marrow toxicity, skin rashes and allergies. The ERG reran the manufacturers economic model after altering several of the assumptions and parameter values in order to recalculate the cost-utility ratios, quality-adjusted life-years (QALYs) and estimates of benefits. The manufacturer reported that maintenance therapy with rituximab was cost-effective compared with observation against commonly applied thresholds, with an incremental cost-effectiveness ratio of 7721 pounds per QALY gained. The greatest clinical effectiveness is achieved by R-CHOP followed by rituximab maintenance (R-CHOP>R) and this treatment strategy had the greatest probability of being cost-effective for a QALY of approximately 18,000 pounds or greater. The guidance issued by NICE as a result of the STA states that in people with relapsed stage III or IV follicular NHL, rituximab is now an option in combination with chemotherapy to induce remission or alone as maintenance therapy during remission. Rituximab monotherapy is also an option for people with relapsed or refractory disease when all alternative treatment options have been exhausted.

Erlotinib for the treatment of relapsed non-small cell lung cancer.

This paper presents a summary of the evidence review group (ERG) report into the clinical and cost-effectiveness of erlotinib for the treatment of relapsed non-small cell lung cancer (NSCLC), according to its licensed indication, based upon the evidence submission from Roche Products to the National Institute for Health and Clinical Excellence (NICE) as part of the single technology appraisal (STA) process. The submitted clinical evidence includes one randomised controlled trial (RCT) (BR21) investigating the effect of erlotinib versus placebo, which demonstrates that erlotinib significantly increases median overall survival, progression-free survival and response rate compared with placebo. The majority of patients in the trial experienced non-haematological drug-related adverse effects. Currently there are no trials that directly compare erlotinib with any other second-line chemotherapy agent. For the purposes of indirect comparison, the manufacturers submission provides a narrative discussion of data from 11 RCTs investigating the use of docetaxel. From these data the manufacturer concludes that erlotinib has similar clinical efficacy levels to docetaxel but results in fewer serious haematological adverse events; however, it is difficult to compare the results of BR21 with those of the docetaxel trials or with current UK clinical practice because, for example, the BR21 patient population is younger than that expected to present in UK clinical practice and almost half of the BR21 participants received erlotinib as third-line chemotherapy, with third-line chemotherapy being rare in the UK. The manufacturers submission included a three-state model comparing erlotinib with docetaxel, reporting an incremental cost-effectiveness ratio (ICER) of 1764 pounds per quality-adjusted life-year (QALY) gained for erlotinib compared with docetaxel. Rerunning the manufacturers economic model with varied parameters and assumptions increases the ICER to in excess of 52,000 pounds per QALY gained. There is still a large amount of unquantifiable uncertainty in the model and it is unlikely that erlotinib could be considered to be cost-effective compared with docetaxel at a willingness to pay of 30,000 pounds and there may even be the potential for docetaxel to dominate erlotinib. Because of the limitations of the indirect analysis undertaken by the manufacturer and the subsequent economic modelling exercise there is a need for a head-to-head trial comparing erlotinib with docetaxel. The guidance issued by NICE in February 2007 as a result of the STA states that erlotinib is not recommended for the treatment of locally advanced or metastatic NSCLC.

A systematic review of prevention and intervention strategies for populations at high risk of engaging in violent behaviour: update 2002-8.

BACKGROUND It has been estimated that violence accounts for more than 1.6 million deaths worldwide each year and these fatal assaults represent only a fraction of all assaults that actually occur. The problem has widespread consequences for the individual and for the wider society in physical, psychological, social and economic terms. A wide range of pharmacological, psychosocial and organisational interventions have been developed with the aim of addressing the problem. This review was designed to examine the effectiveness of these interventions when they are developed in mental health and criminal justice populations. OBJECTIVE To update a previous review that examined the evidence base up to 2002 for a wide range of pharmacological, psychosocial and organisational interventions aimed at reducing violence, and to identify the key variables associated with a significant reduction in violence. DATA SOURCES Nineteen bibliographic databases were searched from January 2002 to April 2008, including PsycINFO (CSA) MEDLINE (Ovid), Cumulative Index to Nursing and Allied Health Literature (CINAHL), Allied and Complementary Medicine Database (AMED), British Nursing Index/Royal College of Nursing, International Bibliography of the Social Sciences (IBSS), Education Resources Information Center (ERIC)/International ERIC, The Cochrane Library (Cochrane reviews, other reviews, clinical trials, methods studies, technology assessments, economic evaluations), Web of Science [Science Citation Index Expanded (SCIE), Social Sciences Citation Index (SSCI), Arts & Humanities Citation Index (A&HCI)]. REVIEW METHODS The assessment was carried out according to accepted procedures for conducting and reporting systematic reviews, including identification of studies, application of inclusion criteria, data extraction and appropriate analysis. Studies were included in meta-analyses (MAs) if they followed a randomised control trial (RCT) design and reported data that could be converted into odds ratios (ORs). For each MA, both a fixed-effects model and a random-effects model were fitted, and both Q statistic and I2 estimates of heterogeneity were performed. RESULTS A total of 198 studies were identified as meeting the inclusion criteria; of these, 51 (26%) were RCTs. Bivariate analyses exploring possible sources of variance in whether a study reported a statistically significant result or not, identified six variables with a significant association. An outcome was less likely to be positive if the primary intervention was something other than a psychological or pharmacological intervention, the study was conducted in an penal institution, the comparator was another active treatment or treatment as usual and if a between-groups design had been used. An outcome was more likely to be positive if it was conducted with people with a mental disorder. The variation attributable to these variables when added to a binary logistic regression was not large (Cox and Snell R(2) = 0.12), but not insignificant given the small number of variables included. The pooled results of all included RCTs suggested a statistically significant advantage for interventions over the various comparators [OR 0.59, 95% confidence interval (CI) 0.53 to 0.65, fixed effects; OR 0.35, 95% CI 0.26 to 0.49 random effects, 40 studies]. However, there was high heterogeneity {I(2) = 86, Q = 279 [degrees of freedom (df) = 39], p < 0.0001}, indicating the need for caution in interpreting the observed effect. Analysis by subgroups showed that most results followed a similar pattern, with statistically significant advantages of treatments over comparators being suggested in fixed- and/or random-effects models but in the context of large heterogeneity. Three exceptions were atypical antipsychotic drugs [OR 0.21, 95% CI 0.16 to 0.27, fixed effects; OR 0.24, 95% CI 0.14 to 0.43, random effects; 10 studies, I(2) = 72.2, Q = 32.4 (df = 9), p < 0.0001], psychological interventions [OR 0.63, 95% CI 0.48 to 0.83, fixed effects; OR 0.53, 95% CI 0.31 to 0.93, random effects; nine studies, I(2) = 62.1, Q = 21.1 (df = 8), p = 0.007] and cognitive behavioural therapy (CBT) as a primary intervention [OR 0.61, 95% CI 0.42 to 0.88, fixed effects; OR 0.61, 95% CI 0.37 to 0.99, random effects; seven studies, I(2) = 21.6, Q = 7.65 (df = 6), p = 0.26]. LIMITATIONS The heterogenity of the included studies inhibits both robust MA and the clear application of findings to establishing improvements in clinical practice. CONCLUSIONS Results from this review show small-to-moderate effects for CBT, for all psychological interventions combined, and larger effects for atypical antipsychotic drugs, with relatively low heterogeneity. There is also evidence that interventions targeted at mental health populations, and particularly male groups in community settings, are well supported, as they are more likely to achieve stronger effects than interventions with the other groups. Future work should focus on improving the quality of evidence available and should address the issue of heterogenity in the literature. FUNDING The National Institute for Health Research Health Technology Assessment programme and the Research for Patient Benefit programme.

A systematic review of risk assessment strategies for populations at high risk of engaging in violent behaviour: update 2002-8.

BACKGROUND This review systematically examines the research literature published in the period 2002-8 on structured violence risk assessment instruments designed for use in mental health services or the criminal justice system. It adopted much broader inclusion criteria than previous reviews in the same area in order to capture and summarise data on the widest possible range of available instruments. OBJECTIVES To address two questions: (1) what study characteristics are associated with a risk assessment instrument score being significantly associated with a violent outcome? and (2) which risk assessment instruments have the highest level of predictive validity for a violent outcome? DATA SOURCES Nineteen bibliographic databases were searched from January 2002 to April 2008, including PsycINFO, MEDLINE, Cumulative Index to Nursing and Allied Health Literature, Allied and Complementary Medicine Database, British Nursing Index, International Bibliography of the Social Sciences, Education Resources Information Centre, The Cochrane Library and Web of Knowledge. REVIEW METHODS Inclusion criteria for studies were (1) evaluation of a structured risk tool; (2) outcome measure of interpersonal violence; (3) participants aged 17 years or over; and (4) participants with a mental disorder and/or at least one offence and/or at least one indictable offence. A series of bivariate analyses using either a chi-squared test or Spearmans rank-order correlation were conducted to explore associations between study characteristics and outcomes. Data from a subset of studies reporting area under the curve (AUC) analysis were combined to provide estimates of mean validity. RESULTS For the overall set of included studies (n = 959), over three-quarters (77%) were conducted in the USA, Canada or the UK. Two-thirds of all studies were conducted with offenders who had either no formal mental health diagnosis (43%) or forensic samples with a formal diagnosis (25%). The Psychopathy Checklist-Revised was tested in the largest number of studies (n = 192). Most studies (78%) reported a statistically significant (p < 0.05) relationship between the instrument score and a violent outcome. Prospective data collection (chi-squared = 4.4, p = 0.035), number of people recruited (U = 27.8, p = 0.012) and number of participants at end point (U = 26.9, p = 0.04) were significantly associated with predictive validity. For those instruments tested in five or more studies reporting AUC values, the General Statistical Information on Recidivism instrument had the highest mean AUC (0.73). LIMITATIONS Agreement between pairs of reviewers in the initial pilot exercises was good but less than perfect, so discrepancies may be present given the complexity and subjectivity of some aspects of violence research. Only five of the seven calendar years (2003-7) are completely covered, with partial coverage of 2002 and 2008. There is no weighting for sample or effect sizes when results from studies are aggregated. CONCLUSIONS A very large number of studies examining the relationship between a structured instrument and a violent outcome were published in this relatively short 7-year period. The general quality of the literature is weak in places (e.g. over-reliance on cross-sectional designs) and a vast range of distinct instruments have been tested to varying degrees. However, there is evidence of some convergence around a small number of high-performing instruments and identification of the components of a high-quality evaluation approach, including AUC analysis. The upper limits (AUC ≥ 0.85) of instrument-based prediction have probably been achieved and are unlikely to be exceeded using instruments alone. FUNDING The National Institute for Health Research Health Technology Assessment and Research for Patient Benefit programmes.

The clinical effectiveness and cost-effectiveness of the PROGENSA® prostate cancer antigen 3 assay and the Prostate Health Index in the diagnosis of prostate cancer: a systematic review and economic evaluation

BACKGROUND There is no single definitive test to identify prostate cancer in men. Biopsies are commonly used to obtain samples of prostate tissue for histopathological examination. However, this approach frequently misses cases of cancer, meaning that repeat biopsies may be necessary to obtain a diagnosis. The PROGENSA(®) prostate cancer antigen 3 (PCA3) assay (Hologic Gen-Probe, Marlborough, MA, USA) and the Prostate Health Index (phi; Beckman Coulter Inc., Brea, CA, USA) are two new tests (a urine test and a blood test, respectively) that are designed to be used to help clinicians decide whether or not to recommend a repeat biopsy. OBJECTIVE To evaluate the clinical effectiveness and cost-effectiveness of the PCA3 assay and the phi in the diagnosis of prostate cancer. DATA SOURCES Multiple publication databases and trial registers were searched in May 2014 (from 2000 to May 2014), including MEDLINE, EMBASE, The Cochrane Library, ISI Web of Science, Medion, Aggressive Research Intelligence Facility database, ClinicalTrials.gov, International Standard Randomised Controlled Trial Number Register and World Health Organization International Clinical Trials Registry Platform. REVIEW METHODS The assessment of clinical effectiveness involved three separate systematic reviews, namely reviews of the analytical validity, the clinical validity of these tests and the clinical utility of these tests. The assessment of cost-effectiveness comprised a systematic review of full economic evaluations and the development of a de novo economic model. SETTING The perspective of the evaluation was the NHS in England and Wales. PARTICIPANTS Men suspected of having prostate cancer for whom the results of an initial prostate biopsy were negative or equivocal. INTERVENTIONS The use of the PCA3 score or phi in combination with existing tests (including histopathology results, prostate-specific antigen level and digital rectal examination), multiparametric magnetic resonance imaging and clinical judgement. RESULTS In addition to documents published by the manufacturers, six studies were identified for inclusion in the analytical validity review. The review identified issues concerning the precision of the PCA3 assay measurements. It also highlighted issues relating to the storage requirements and stability of samples intended for analysis using the phi assay. Fifteen studies met the inclusion criteria for the clinical validity review. These studies reported results for 10 different clinical comparisons. There was insufficient evidence to enable the identification of appropriate test threshold values for use in a clinical setting. In addition, the implications of adding either the PCA3 assay or the phi to clinical assessment were not clear. Furthermore, the addition of the PCA3 assay or the phi to clinical assessment plus magnetic resonance imaging was not found to improve discrimination. No published papers met the inclusion criteria for either the clinical utility review or the cost-effectiveness review. The results from the cost-effectiveness analyses indicated that using either the PCA3 assay or the phi in the NHS was not cost-effective. LIMITATIONS The main limitations of the systematic review of clinical validity are that the review conclusions are over-reliant on findings from one study, the descriptions of clinical assessment vary widely within reviewed studies and many of the reported results for the clinical validity outcomes do not include either standard errors or confidence intervals. CONCLUSIONS The clinical benefit of using the PCA3 assay or the phi in combination with existing tests, scans and clinical judgement has not yet been confirmed. The results from the cost-effectiveness analyses indicate that the use of these tests in the NHS would not be cost-effective. STUDY REGISTRATION This study is registered as PROSPERO CRD42014009595. FUNDING The National Institute for Health Research Health Technology Assessment programme.

Immunotherapy for Hymenoptera venom allergy: too expensive for European health care?

To the Editor: Insect venom allergy is the most frequent elicitor of severe anaphylaxis in central Europe (1), accounting for the majority of anaphylactic reactions in adults, and being second as elicitor of anaphylaxis in children (2). The prevalence of insect-sting anaphylaxis varies widely between children and adults ranging from 1.5% to 3.3% and more depending on the geographic and socioeconomic background (3). Venom immunotherapy (VIT) is highly effective to cure Hymenoptera venom allergy (4) and does also improve this disease-specific quality of life (5,6). Recently, a focus has been put on the cost-effectiveness of VIT used for treating bee and wasp venom allergy. Stimulated by the English National Health Service, the British National Institute for Health and Clinical Excellence (NICE) commissioned a study analysing the economic burden caused by VIT (7). A central aspect of this analysis was the calculation of additional costs arising from potential life-saving effects of VIT. To adjust to quality of life in gained years, Hockenhull et al. (7) used the age-dependent European Quality of Life-5 Dimensions (EQ-5D) Weighted Health Status Index population norms. Key finding of the analysis was that, compared to avoidance advice and supply with emergency kits only, VIT may cost up to £18 million per year gained if the focus is put on life-saving aspect of VIT. With this commentary, we would like to express our concerns regarding the authors’ strategy to focus on fatal reactions possibly prevented by VIT. How can it be explained that – when referred to qualityadjusted years of life – VIT results in such astronomical costs? In medicine, economic issues include the evaluation of therapy costs. As some treated patients will live longer without getting well again, it is also essential to refer the number of years gained to the resulting quality of life. To combine both variables, a QALY (quality-adjusted life year) is calculated by multiplying the number of years gained with score points reflecting the quality of life during these years. If, for example, a therapy would gain 10 extra years for a patient not suffering from any long-term morbidity (1 score point for optimal quality of life), a QALY of 10 would be calculated. With only 2 years gained and with a significant longterm morbidity (e.g. 0.5 score points for reduced quality of life), the QALY would be 1. To calculate cost-effectiveness, treatment costs arising from an additional therapy (incremental cost-effectiveness ratio, ICER) are then referred to one QALY. Thus, for example, in comparison with a wait-and-see strategy, after a lay cardiopulmonary resuscitation, up to US

Venom immunotherapy for preventing allergic reactions to insect stings

500.000 will be required per QALY (8). Compared to the numbers above calculated for VIT, this sum seems to be actually quite favourable. If, however, a disease is comparably common (and if many affected patients need a long-term therapy thereby further increasing costs), and if, simultaneously, the same disease (such as Hymenoptera venom allergy) is rarely lethal (with a low potential of saving lives), then it will be awfully expensive to gain even one extra year. The incidence of insect-sting mortality due to early anaphylaxis is known to be low ranging from 0.03 to 0.48 fatalities per 1000.000 inhabitants per year (3). These facts must have already been clear in advance of the above-mentioned analysis, which calculated a death rate following severe anaphylaxis of 1.25% (7), and make one wonder about the reasons making the initiators of the analysis commission such an evaluation of which catastrophic results for VIT were predictable. We acknowledge the fact that Hockenhull et al. (7) also performed a subgroup analysis, where VIT was found to be cost-effective in terms of preventing fatal reactions. This subgroup contained patients stung at least five times a year. Such a patient classification, however, is quite unrealistic, because there are – fortunately – hardly or even no patients who are stung that often each year. The approach to refer cost-effectiveness of a therapy just to survival and to a normalized quality of life (ICER per QALY) must be regarded as inappropriate for many therapies. Numerous, even very expensive, therapeutic measures are not primarily aiming at a prolongation of life, but rather at a specific improvement of quality of life. VIT also falls under this category, and assessment of cost-effectiveness is only justified against this background. It is important to note that the above NICE analysis initially assumed no VIT-related change in utility due to anxiety (1). There is, however, some evidence that VIT significantly improves quality of life (5,6). Unfortunately, there are no results obtained by a validated utility measure of quality of life. Consequently, Hockenhull et al. (7) concluded that any health benefit from VIT is entirely due to its effectiveness in reducing systemic reactions from sting and resulting deaths. We welcome the fact that the NICE analysis also contains a separate subgroup analysis assuming that fear of sting does affect the utility of some people and that VIT reduces this anxiety and so negates this loss in quality of life. For this specific subgroup (patients with sting anxiety), it was calculated that, compared to avoidance advice and supply with emergency kits only, VIT may cost up to £23,868 per QALY. These numbers are in the range of those derived, for example, for statins used to reduce cholesterol concentrations (9).