Cost-effectiveness of proton radiotherapy versus photon radiotherapy for non-small cell lung cancer patients: Exploring the model-based approach.

INTRODUCTION: Proton radiotherapy (PT) is a promising but more expensive strategy than photon radiotherapy (XRT) for the treatment of non-small cell lung cancer (NSCLC). PT is probably not cost-effective for all patients. Therefore, patients can be selected using normal tissue complication probability (NTCP) models with predefined criteria. This study aimed to explore the cost-effectiveness of three treatment strategies for patients with stage III NSCLC: 1. photon radiotherapy for all patients (XRTAll); 2. PT for all patients (PTAll); 3. PT for selected patients (PTIndividualized). METHODS: A decision-analytical model was constructed to estimate and compare costs and QALYs of all strategies. Three radiation-related toxicities were included: dyspnea, dysphagia and cardiotoxicity. Costs and QALY's were incorporated for grade 2 and ≥ 3 toxicities separately. Incremental Cost-Effectiven Ratios (ICERs) were calculated and compared to a threshold value of €80,000. Additionally, scenario, sensitivity and value of information analyses were performed. RESULTS: PTAll yielded most QALYs, but was also most expensive. XRTAll was the least effective and least expensive strategy, and the most cost-effective strategy. For thresholds higher than €163,467 per QALY gained, PTIndividualized was cost-effective. When assuming equal minutes per fraction (15 minutes) for PT and XRT, PTIndividualized was considered the most cost-effective strategy (ICER: €76,299). CONCLUSION: Currently, PT is not cost-effective for all patients, nor for patient selected on the current NTCP models used in the Dutch indication protocol. However, with improved clinical experience, personnel and treatment costs of PT can decrease over time, which potentially leads to PTIndividualized, with optimal patient selection, will becoming a cost-effective strategy.

Bilateral vestibulopathy: beyond imbalance and oscillopsia.

OBJECTIVE: To optimize the current diagnostic and treatment procedures for patients with bilateral vestibulopathy (BV), this study aimed to determine the complete spectrum of symptoms associated with BV. METHOD: A prospective mixed-method study design was used. Qualitative data were collected by performing semi-structured interviews about symptoms, context, and behavior. The interviews were recorded and transcribed until no new information was obtained. Transcriptions were analyzed in consensus by two independent researchers. In comparison to the qualitative results, quantitative data were collected using the Dizziness Handicap Inventory (DHI), Hospital Anxiety and Depression Scale (HADS) and a health-related quality of life questionnaire (EQ-5D-5L). RESULTS: Eighteen interviews were transcribed. Reported symptoms were divided into fourteen physical symptoms, four cognitive symptoms, and six emotions. Symptoms increased in many situations, such as darkness (100%), uneven ground (61%), cycling (94%) or driving a car (56%). These symptoms associated with BV often resulted in behavioral changes: activities were performed more slowly, with greater attention, or were avoided. The DHI showed a mean score of severe handicap (54.67). The HADS questionnaire showed on average normal results (anxiety = 7.67, depression = 6.22). The EQ-5D-5L demonstrated a mean index value of 0.680, which is lower compared to the Dutch age-adjusted reference 0.839 (60-70 years). CONCLUSION: BV frequently leads to physical, cognitive, and emotional complaints, which often results in a diminished quality of life. Importantly, this wide range of symptoms is currently underrated in literature and should be taken into consideration during the development of candidacy criteria and/or outcome measures for therapeutic interventions such as the vestibular implant.

Burden of disease of type 2 diabetes mellitus: cost of illness and quality of life estimated using the Maastricht Study.

AIMS: To estimate the societal costs and quality of life of people with type 2 diabetes and to compare these results with those of people with normal glucose tolerance or prediabetes. METHODS: Data from 2915 individuals from the population-based Maastricht Study were included. Costs were assessed through a resource-use questionnaire completed by the participants; cost prices were based on Dutch costing guidelines. Quality of life was expressed in utilities using the Dutch EuroQol 5D-3L questionnaire and the SF-36 health survey. Based on normal fasting glucose and 2-h plasma glucose values, participants were classified into three groups: normal glucose tolerance (n = 1701); prediabetes (n = 446); or type 2 diabetes (n = 768). RESULTS: Participants with type 2 diabetes had on average 2.2 times higher societal costs than those with normal glucose tolerance (€3,006 and €1,377 per 6 months, respectively) and had lower utilities (0.77 and 0.81, respectively). No significant differences were found between participants with normal glucose tolerance and those with prediabetes. Subgroup analyses showed that higher age, being female and having two or more diabetes-related complications resulted in higher costs (P < 0.05) and lower utilities. CONCLUSIONS: This study showed that people with type 2 diabetes have substantially higher societal costs and lower quality of life than people with normal glucose tolerance. The results provide important input for future model-based economic evaluations and for policy decision-making.

Clinical Outcomes of Soft Tissue Preservation Surgery With Hydroxyapatite-Coated Abutments Compared to Traditional Percutaneous Bone Conduction Hearing Implant Surgery-A Pragmatic Multi-Center Randomized Controlled Trial.

Background: Soft tissue preservation using a hydroxyapatite-coated abutment in bone conduction hearing implant surgery may lead to improved clinical outcomes over the short (1 year) and long term (3 years). Methods: In this open multi-center, randomized (1:1), controlled clinical trial, subjects with conductive, mixed hearing loss or single-sided sensorineural deafness were randomly assigned to receive the conventional intervention, a titanium abutment with soft tissue reduction surgery (control), or a new intervention, a hydroxyapatite-coated abutment with soft tissue preservation surgery (test). The primary efficacy outcome was the combined endpoint of numbness, pain, peri-abutment dermatitis, and soft tissue thickening/overgrowth after 1 and 3 years. Results: The Intention-to-treat (ITT) population consisted of 52 control subjects and 51 test subjects. The difference between the groups after 1 year of follow-up as measured by the primary efficacy outcome was not statistically significant (p = 0.12) in the ITT population (n = 103), but did reach statistical significance (p = 0.03) in the per-protocol (PP) population (n = 96). It showed an advantage for the test group, with over twice as many subjects (29%) without these medical events during the first year compared to the control group (13%). After 3 years, the difference between the two groups had declined and did not reach statistical significance (24 vs. 10%, ITT p = 0.45). Secondary outcome measures which showed a statistical significant difference during the first year, such as surgical time (15 vs. 25 minutes, p < 0.0001), numbness (90 vs. 69% of subjects experienced no numbness at 1 year, p < 0.01), neuropathic pain at 3 months (p = 0.0087) and the overall opinion of the esthetic outcome (observer POSAS scale at 3 months, p < 0.01) were favorable for the test group. More soft tissue thickening/overgrowth was observed at 3 weeks for the test group (p = 0.016). Similar results were achieved for the long term follow up. Conclusions: Soft tissue preservation with a hydroxyapatite-coated abutment leads to a reduction in the combined occurrence of complications over the first year which is not statistically significant in the ITT population but is in the PP population. This effect decreased for the long-term study follow up of 3 years and did also not reach statistical significance.

The relative effectiveness of eribulin for advanced breast cancer treatment: a study of the southeast Netherlands advanced breast cancer registry.

Background: Eribulin provided significant overall survival (OS) benefit in heavily pretreated advanced breast cancer patients in the EMBRACE trial. We investigated the use of eribulin in daily clinical practice, the relative effectiveness of eribulin versus non-eribulin chemotherapy, and the safety of eribulin in real-world patients included in the SOutheast Netherlands Advanced BREast cancer (SONABRE) registry.Material and methods: Patients treated with eribulin and eligible patients for eribulin who received a different chemotherapy (i.e., non-eribulin group) in ten hospitals in 2013-2017 were included. A multivariate matching algorithm was applied to correct for differences in baseline characteristics between the groups, including the number of previous treatment lines. Progression-free survival (PFS) and OS of eribulin were compared with the matched non-eribulin group through Kaplan-Meier curves and multivariate Cox proportional hazard models. The occurrence of dose delay and reduction was described.Results: Forty-five patients received eribulin according to its registration criteria and 74 patients were eligible for eribulin but received non-eribulin chemotherapy. Matching increased the similarity in baseline characteristics between the eribulin and non-eribulin groups. Median PFS was 3.5 months (95% confidence interval (CI): 2.7-5.5) in the eribulin group and 3.2 months (95% CI: 2.0-4.8) in the matched non-eribulin group (adjusted hazard ratio (HR): 0.83, 95% CI: 0.49-1.38). Median OS was 5.9 months (95% CI: 4.6-11.0) and 5.2 months (95% CI: 4.6-9.5) in the eribulin and non-eribulin groups, respectively (adjusted HR: 0.66, 95% CI: 0.38-1.13). Dose delay or reduction occurred in 14 patients (31%) receiving eribulin.Conclusions: No difference in PFS and OS was observed between eribulin and non-eribulin treated patients. Eribulin had a manageable toxicity profile.

Health-related quality of life after prophylactic cranial irradiation for stage III non-small cell lung cancer patients: Results from the NVALT-11/DLCRG-02 phase III study.

BACKGROUND AND PURPOSE: The NVALT-11/DLCRG-02 phase III trial (clinicaltrials.gov identifier: NCT01282437) showed that, after standard curative intent treatment, prophylactic cranial irradiation (PCI) decreased the incidence of symptomatic brain metastases (BM) in stage III non-small cell lung cancer (NSCLC) patients compared to observation. In this study we assessed the impact of PCI on health-related quality of life (HRQoL). In addition, an exploratory analysis was performed to assess the impact of neurocognitive symptoms and symptomatic BM on HRQoL. MATERIALS AND METHODS: Stage III NSCLC patients were randomized between PCI and observation. HRQoL was measured using the EuroQol 5D (EQ-5D-3L), EORTC QLQ-C30 and QLQ-BN20 instruments at completion of standard curative intent treatment and 4 weeks, 3, 6, 12, 24 and 36 months thereafter. Generalized linear mixed effects (GLM) models were used to assess the impact of PCI compared to observation over time on three HRQoL metrics: the EORTC QLQ-C30 global health status and the EQ-5D-3L utility and visual analogue scale (EQ VAS) scores. RESULTS: In total, 86 and 88 patients were included in the PCI and observation arm, with a median follow-up of 48.5 months (95% CI 39-54 months). Baseline mean HRQoL scores were comparable between the PCI and observation arm for the three HRQoL metrics. In the GLM models, none of the HRQoL metrics were clinically relevant or statistically significantly different between the PCI and the observation arm (p-values ranged between 0.641 and 0.914). CONCLUSION: No statistically significant nor a clinically relevant impact of PCI on HRQoL was observed.

Clinical and economic impact of compression in the acute phase of deep vein thrombosis.

Essentials The value of compression therapy in acute phase of deep vein thrombosis is still unclear. Patients with deep vein thrombosis received acute compression hosiery, bandaging, or none. Acute compression reduces irreversible skin signs related to post thrombotic syndrome. Compression hosiery may be the preferred choice for the acute phase SUMMARY: Background The effectiveness of compression therapy in the acute phase of deep vein thrombosis (DVT) is not yet determined. Objectives To investigate the impact of compression therapy in the acute phase of DVT on determinants of the Villalta score, health-related quality of life (HRQOL), and costs. Patients/Methods Eight hundred and sixty-five patients with proximal DVT (substudy of the IDEAL DVT study) received, immediately after DVT diagnosis, either no compression, multilayer bandaging, or hosiery. In the acute phase and 3 months after diagnosis, HRQOL was determined by use of the EQ-5D, SF6D, and VEINES-QoL intrinsic method (VEINES-QoLint ). At 3 months, signs and symptoms were assessed for the total and separate items of the Villalta score, and healthcare costs were calculated. Results The compression groups had lower overall objective Villalta scores than the no-compression group (1.47 [standard deviation (SD) 1.570] and 1.59 [SD 1.64] versus 2.21 [SD 2.15]). The differences were mainly attributable to irreversible skin signs (induration, hyperpigmentation, and venectasia) and pain on calf compression. Subjective and total Villalta scores were similar across groups. Differences in HRQOL were only observed at 1 month; HRQOL was better for hosiery (EQ-5D 0.86 [SD 0.18]; VEINES-QoLint  0.66 [SD 0.18]) than for multilayer compression bandaging (EQ-5D 0.81 [SD 0.23; VEINES-QoLint  0.62 [SD 0.19]). Mean healthcare costs per patient were €417.08 (€354.10 to €489.30) for bandaging, €114.25 (€92.50 to €198.43) for hosiery, and €105.86 (€34.63 to €199.30) for no compression. Conclusions Initial compression reduces irreversible skin signs, edema, and pain on calf compression. Multilayer bandaging is slightly more effective than hosiery, but has substantially higher costs, without a gain in HRQOL. From a patient and economic perspective, compression hosiery would be preferred when initial compression is applied. TRIAL REGISTRATION: IDEAL DVT study ClinicalTrials.gov number, NCT01429714.

Real-world and trial-based cost-effectiveness analysis of bevacizumab in HER2-negative metastatic breast cancer patients: a study of the Southeast Netherlands Breast Cancer Consortium.

INTRODUCTION: The aim of our analysis was to assess the real-world cost-effectiveness of bevacizumab in addition to taxane treatment versus taxane monotherapy for HER2-negative metastatic breast cancer compared with the cost-effectiveness based on the efficacy results from a trial. METHODS: A state transition model was built to estimate costs, life years (LYs) and quality-adjusted life years (QALYs) for both treatments. Two scenarios were examined: a real-world scenario and a trial-based scenario in which transition probabilities were primarily based on a real-world cohort study and the E2100 trial, respectively. In both scenarios, costs and utility parameter estimates were extracted from the real-world cohort study. Moreover, the Dutch health care perspective was adopted. RESULTS: In both the real-world and trial scenarios, bevacizumab-taxane is more expensive (incremental costs of €56,213 and €52,750, respectively) and more effective (incremental QALYs of 0.362 and 0.189, respectively) than taxane monotherapy. In the real-world scenario, bevacizumab-taxane compared to taxane monotherapy led to an incremental cost-effectiveness ratio (ICER) of €155,261 per QALY gained. In the trial scenario, the ICER amounted to €278,711 per QALY gained. CONCLUSION: According to the Dutch informal threshold, bevacizumab in addition to taxane treatment was not considered cost-effective for HER2-negative metastatic breast cancer both in a real-world and in a trial scenario.

The effects of school-based lifestyle interventions on body mass index and blood pressure: a multivariate multilevel meta-analysis of randomized controlled trials.

Primary prevention of childhood obesity and related hypertension is warrant given that both risk factors are intertwined and track into adulthood. This systematic review and meta-analysis assess the impact of school-based lifestyle interventions on children's body mass index (BMI) and blood pressure. We searched databases and prior reviews. Eligibility criteria were the following: randomized controlled trial design, evaluation of a school-based intervention, targeting children aged 4-12 years, reporting on BMI and/or related cardiovascular risk factors, reporting data on at least one follow-up moment. The effects on BMI, systolic blood pressure (SBP) and diastolic blood pressure (DBP) were evaluated by means of univariate and multivariate three-level random effects models. A total of 85 RCTs (91 papers) were included in the meta-analyses. In univariate models, the pooled effects were -0.072 (95%CI: -0.106; -0.038) for BMI, -0.183 (95%CI: -0.288; -0.078) for SBP and -0.071 (95%CI: -0.185; 0.044) for DBP. In multivariate analyses, the pooled effects of interventions were -0.054 (95%CI: -0.131; 0.022) for BMI, -0.182 (95%CI: -0.266; -0.098) for SBP and -0.144 (95%CI: -0.230; -0.057) for DBP. Parental involvement accentuated the beneficial effects of interventions. School-based lifestyle prevention interventions result in beneficial changes in children's BMI and blood pressure, and the effects on the latter may be stronger than and accrue independently from those in the former.

The Healthy Primary School of the Future: study protocol of a quasi-experimental study.

BACKGROUND: Unhealthy lifestyles in early childhood are a major global health challenge. These lifestyles often persist from generation to generation and contribute to a vicious cycle of health-related and social problems. This design article presents a study evaluating the effects of two novel healthy school interventions. The main outcome measure will be changes in children's body mass index (BMI). In addition, lifestyle behaviours, academic achievement, child well-being, socio-economic differences, and societal costs will be examined. METHODS: In close collaboration with various stakeholders, a quasi-experimental study was developed, for which children of four intervention schools (n = 1200) in the southern part of the Netherlands are compared with children of four control schools (n = 1200) in the same region. The interventions started in November 2015. In two of the four intervention schools, a whole-school approach named 'The Healthy Primary School of the Future', is implemented with the aim of improving physical activity and dietary behaviour. For this intervention, pupils are offered an extended curriculum, including a healthy lunch, more physical exercises, and social and educational activities, next to the regular school curriculum. In the two other intervention schools, a physical-activity school approach called 'The Physical Activity School', is implemented, which is essentially similar to the other intervention, except that no lunch is provided. The interventions proceed during a period of 4 years. Apart from the effectiveness of both interventions, the process, the cost-effectiveness, and the expected legal implications are studied. Data collection is conducted within the school system. The baseline measurements started in September 2015 and yearly follow-up measurements are taking place until 2019. DISCUSSION: A whole-school approach is a new concept in the Netherlands. Due to its innovative, multifaceted nature and sound scientific foundation, these integrated programmes have the potential to form a template for primary schools worldwide. The effects of this approach may extend further than the outcomes associated with well-being and academic achievement, potentially impacting legal and cultural aspects in our society. TRIAL REGISTRATION: The study protocol was registered in the database ClinicalTrials.gov on 14-06-2016 with the reference number NCT02800616 .

Eliciting patients' preferences for elastic compression stocking therapy after deep vein thrombosis: potential for improving compliance.

UNLABELLED: ESSENTIALS: Elastic compression stocking (ECS) therapy is used to prevent post-thrombotic syndrome (PTS). We aimed to elicit patient preferences regarding ECS therapy after deep vein thrombosis. The most valued attributes were PTS risk reduction and the ability to put on the ECS independently. Heterogeneous results with respect to education level stress the importance of proper counselling. BACKGROUND: Elastic compression stocking (ECS) therapy is used for prevention of post-thrombotic syndrome (PTS) after deep vein thrombosis (DVT). Current evidence on its effectiveness is conflicting. Compliance, a major determinant of the effectiveness of ECS therapy, remained largely ignored in former studies. OBJECTIVES: To gain insight into preferences regarding ECS therapy in patients after DVT. PATIENTS/METHODS: A discrete choice experiment was conducted 3 months after DVT in patients enrolled in the IDEAL DVT study, a randomized controlled trial comparing 2 years of ECS therapy with individually tailored duration of ECS therapy for the prevention of PTS. Nine unlabeled, forced-choice sets of two hypothetical types of ECS were presented to each patient. Data were analyzed with multinomial logit models. RESULTS: The respondent sample consisted of 81% (300/369) of invited patients. The most important determinants of preference were PTS risk reduction and putting on the ECS. Patients were willing to increase the duration of therapy by 1 year if this increases the PTS risk reduction with 10%. Patients accepted an increase in the risk of PTS of 29% if they were able to put on the ECS themselves. Preferences were heterogeneous with respect to education level. CONCLUSIONS: Reduction of the risk of PTS and the ability to put on the ECS without help are the most important characteristics of ECS therapy. Physicians should pay considerable attention to patient education regarding PTS. In addition, patients should be supported in their ability to put on and take off the ECS independently. These rather simple interventions could improve compliance.

Sample Size Estimation for Non-Inferiority Trials: Frequentist Approach versus Decision Theory Approach.

BACKGROUND: Non-inferiority trials are performed when the main therapeutic effect of the new therapy is expected to be not unacceptably worse than that of the standard therapy, and the new therapy is expected to have advantages over the standard therapy in costs or other (health) consequences. These advantages however are not included in the classic frequentist approach of sample size calculation for non-inferiority trials. In contrast, the decision theory approach of sample size calculation does include these factors. The objective of this study is to compare the conceptual and practical aspects of the frequentist approach and decision theory approach of sample size calculation for non-inferiority trials, thereby demonstrating that the decision theory approach is more appropriate for sample size calculation of non-inferiority trials. METHODS: The frequentist approach and decision theory approach of sample size calculation for non-inferiority trials are compared and applied to a case of a non-inferiority trial on individually tailored duration of elastic compression stocking therapy compared to two years elastic compression stocking therapy for the prevention of post thrombotic syndrome after deep vein thrombosis. RESULTS: The two approaches differ substantially in conceptual background, analytical approach, and input requirements. The sample size calculated according to the frequentist approach yielded 788 patients, using a power of 80% and a one-sided significance level of 5%. The decision theory approach indicated that the optimal sample size was 500 patients, with a net value of €92 million. CONCLUSIONS: This study demonstrates and explains the differences between the classic frequentist approach and the decision theory approach of sample size calculation for non-inferiority trials. We argue that the decision theory approach of sample size estimation is most suitable for sample size calculation of non-inferiority trials.

Should patients prescribed long-term low-dose aspirin receive proton pump inhibitors? A systematic review and meta-analysis.

BACKGROUND: Several clinical guidelines recommend the use of proton pump inhibitors (PPIs) in patients taking low-dose aspirin but report no or limited supporting data. We conducted a systematic review and meta-analysis to examine the effects of co-administration of PPIs in patients taking low-dose aspirin on the risks of adverse gastrointestinal (GI) and cardiovascular (CV) events, and on patient adherence to aspirin. METHODS: We searched PUBMED, EMBASE and Cochrane Central Register of Controlled Trials databases for relevant articles published through November 2013. We included randomised controlled trials (RCTs) and observational studies in patients taking low-dose aspirin with and without PPIs. Risk of bias was assessed using the Cochrane Collaboration's tool (for RCTs) and the Newcastle-Ottawa Scale (for observational studies). Pooled risk ratios (RRs) were computed using a random-effects model. RESULTS: We included 13 studies, of which 12 (2 RCTs and 10 observational studies) reported on GI events, and one (cohort study) on both GI bleeding and CV events. No study reported on adherence to aspirin. Co-administration of PPIs in patients receiving low-dose aspirin was associated with risk reductions of 73% (RR 0.27, 95% CI 0.17-0.42) and 50% (RR 0.50, 95% CI 0.32-0.80) in the occurrence of peptic ulcer and GI bleeding respectively. There was evidence of bias in publications reporting on the GI events. CONCLUSIONS: The practice of co-prescribing PPIs in patients taking low-dose aspirin is supported by some data, but the evidence is rather weak. It currently remains unclear whether the benefits of co-administration of PPIs in users of low-dose aspirin outweigh their potential harms.

Prospective cost-effectiveness analysis of genomic profiling in breast cancer.

BACKGROUND: The cost-effectiveness of the 70-gene signature (70-GS) (MammaPrint®) has earlier been estimated using retrospective validation data. Based on the prospective 5-year survival data of the microarRAy-prognoSTics-in-breast-cancER (RASTER) study, the aim here was to evaluate the cost-effectiveness reflecting the actual use in clinical practice, including reality-based compliance rates. METHODS: Costs and outcomes (quality-adjusted-life-years (QALYs)) were calculated in node-negative (N-) patients included in the RASTER study (n=427). Sensitivity and specificity of the 70-gene and Adjuvant! Online (AO) were based on 5-year distant-disease-free survival (DDFS). Subgroup analyses were performed for two groups for whom benefit of the 70-gene had earlier been reported: (1) ductal, oestrogen receptor-positive (ER+), tumour diameter 10-30 mm, grade II, age 40-70; (2) ductal, oestrogen receptor-positive, tumour diameter 5-30 mm, grade II/III and age 40-70. RESULTS: Based on 5-year survival data, the cost-effectiveness of the 70-gene signature versus AO was prospectively confirmed. The total health care costs per patient were €26,786 for the 70-gene and €29,187 for AO. The quality adjusted life years yielded 12.49 and 11.88, respectively. The subgroups retrieved slightly higher life gains and higher costs, but all resulted finally in a favourable position for the 70-gene signature. CONCLUSIONS: The use of the 70-gene signature, as judged appropriate by doctors and patients and supported by a low risk 70-gene signature as an oncological safe choice, was also found to be cost-effective.

The effects and costs of a hearing screening and rehabilitation program in residential care homes for the elderly in the Netherlands1.

PURPOSE: This study describes the effects and costs of hearing screening and rehabilitation in residential care homes for the elderly. It was hypothesized that offering an in-house hearing screening and rehabilitation program would be an effective strategy to increase hearing aid ownership among the residents. METHOD: All 705 residents of 8 residential care homes in the Netherlands were invited to participate in a hearing screening (pure-tone audiometry) and rehabilitation (hearing aids) program. Resident participation was analyzed, and the costs were calculated. RESULTS: A total of 243 residents (34%) participated in the screening, 222 (91%) of whom had hearing loss. Ninety-one (41%) of the screening participants with hearing loss started rehabilitation, which was successful for 50 (55%) of them. Hearing aid ownership among the residents with hearing loss increased from 28% at the start of the program to 33% at the end. The costs were €1,896 (US $2,480) per successfully rehabilitated resident. Hearing aid trials and hearing aids together accounted for 83% of the total costs. CONCLUSION: The effectiveness of the program was limited, as hearing aid ownership increased only slightly. Cost reduction measures should focus on decreasing the number of unsuccessful hearing aid trials.

Contrast-enhanced ultrasound using SonoVue® (sulphur hexafluoride microbubbles) compared with contrast-enhanced computed tomography and contrast-enhanced magnetic resonance imaging for the characterisation of focal liver lesions and detection of liver metastases: a systematic review and cost-effectiveness analysis.

BACKGROUND: Medical imaging techniques are important in the management of many patients with liver disease. Unenhanced ultrasound examinations sometimes identify focal abnormalities in the liver that may require further investigation, primarily to distinguish liver cancers from benign abnormalities. One important factor in selecting an imaging test is the ability to provide a rapid diagnosis. Options for additional imaging investigations include computed tomography (CT) and/or magnetic resonance imaging (MRI) and biopsy when the diagnosis remains uncertain. CT and MRI usually require referral with associated waiting time and are sometimes contraindicated. The use of contrast agents may improve the ability of ultrasound to distinguish between liver cancer and benign abnormalities and, because it can be performed at the same appointment as unenhanced ultrasound, more rapid diagnoses may be possible. OBJECTIVE: To compare the clinical effectiveness and cost-effectiveness of contrast-enhanced ultrasound (CEUS) using SonoVue(®) with that of contrast-enhanced computed tomography (CECT) and contrast-enhanced magnetic resonance imaging (CEMRI) for the assessment of adults with focal liver lesions (FLLs) in whom previous liver imaging is inconclusive. DATA SOURCES: Eight bibliographic databases including MEDLINE, EMBASE, Cochrane Database of Systematic Reviews and Database of Abstracts of Reviews of Effects were searched from 2000 to September/October 2011. Research registers and conference proceedings were also searched. REVIEW METHODS: Systematic review methods followed published guidance. Risk of bias was assessed using a modified version of the QUADAS-2 tool. Results were stratified by clinical indication for imaging (characterisation of FLLs detected on ultrasound surveillance of cirrhosis patients, detection of liver metastases, characterisation of incidentally detected FLLs, assessment of treatment response). For incidental FLLs, pooled estimates of sensitivity and specificity, with 95% CIs, were calculated using a random-effects model. For other clinical indications a narrative summary was used. The cost-effectiveness of CEUS was modelled separately for the three main clinical applications considered [characterisation of FLLs detected on ultrasound surveillance of cirrhosis patients, detection of liver metastases in patients with colorectal cancer (CRC), characterisation of incidentally detected FLLs]. RESULTS: Of the 854 references identified, 19 (describing 18 studies) were included in the review. Hand searching of conference proceedings identified a further three studies. Twenty of the 21 studies included in the systematic review were diagnostic test accuracy studies. Studies in cirrhosis patients reported varying estimates of test performance. There was no consistent evidence of a significant difference in performance between imaging modalities. It was unclear whether or not CEUS alone is adequate to rule out hepatocellular carcinoma (HCC) for FLLs of < 30 mm; one study indicated that CEUS may be better at ruling out HCC for FLLs of 11-30 mm [very small FLLs (< 10 mm) excluded]. There was no consistent evidence of a difference in test performance between imaging modalities for the detection of metastases; CEUS alone may be adequate to rule out liver metastases in colorectal cancer. In patients with incidentally detected FLLs, the pooled estimates of sensitivity for any malignancy using CEUS and CECT were 95.1% and 94.6%, respectively, and the corresponding specificity estimates were 93.8% and 93.1% respectively. One study comparing CEUS with CEMRI reported similar sensitivity and lower specificity for both modalities. In the surveillance of cirrhosis, CEUS was as effective as but £379 less costly than CECT. CEMRI was £1063 more costly than CEUS and gained 0.022 QALYs. In the detection of liver metastases from CRC, CEUS cost £1 more than CECT, and at a lifetime time horizon they yielded equal QALYs. CEMRI was dominated by CECT. In the characterisation of incidentally detected FLLs, CEUS was slightly more effective than CECT and CEMRI (by 0.0002 QALYs and 0.0026 QALYs respectively) and less costly (by £52 and £131 respectively). LIMITATIONS: There were a number of methodological issues specific to the studies included in this review. The main indication for liver imaging in the populations considered is likely to be to rule out primary liver cancer or metastases. Therefore, patient-level analyses of test performance are of particular interest. Some of the studies included in this review reported per-patient analyses; however, no study clearly stated how results were defined (e.g. was the presence of any positive lesion regarded as a positive test for the whole patient). In addition, a number of studies reported data for one lesion per patient (treated as per-patient data in this assessment). These studies generally selected the largest lesion or the lesion 'most suspicious for malignancy' for inclusion in analyses, with the consequence that estimates of test performance may have been exaggerated. The applicability of studies included in this review may be limited, as the majority of imaging studies were interpreted by multiple, experienced operators and the prevalence of malignancy in included studies appeared higher than might be expected in clinical practice. The cost-effectiveness analyses did not take into account the potential benefits of reduced anxiety that may arise from potentially shorter waiting times associated with SonoVue CEUS. CONCLUSIONS: SonoVue CEUS could provide similar diagnostic performance to other imaging modalities (CECT and CEMRI) for the assessment of FLLs. Economic analyses indicated that CEUS was a cost-effective replacement for CEMRI. The use of CEUS instead of CECT was considered cost-effective in the surveillance of cirrhosis and the characterisation of incidentally detected FLLs, with similar costs and effects for the detection of liver metastases from CRC. Further research is needed to compare the effects of different imaging modalities (SonoVue CEUS, CECT, CEMRI) on therapeutic planning, treatment and clinical outcomes. Future test accuracy studies should provide standardised definitions of a positive imaging test, and compare all three imaging modalities in the same patient group. STUDY REGISTRATION: PROSPERO: CRD42011001694. FUNDING: The National Institute for Health Research Health Technology Assessment programme.