Systematic reviews as a "lens of evidence": Determinants of participation in breast cancer screening.

OBJECTIVE: To assess the determinants of the participation rate in breast cancer screening programs by conducting a systematic review of reviews. METHODS: We conducted a systematic search in PubMed via Medline, Scopus, Embase, and Cochrane identifying the literature up to April 2019. Out of 2258 revealed unique abstracts, we included 31 reviews, from which 25 were considered as systematic. We applied the Walsh & McPhee Systems Model of Clinical Preventive Care to systematize the determinants of screening participation. RESULTS: The reviews, mainly in high-income settings, reported a wide range for breast cancer screening participation rate: 16-90%. The determinants of breast cancer screening participation were simple low-cost interventions such as invitation letters, basic information on screening, multiple reminders, fixed appointments, prompts from healthcare professionals, and healthcare organizational factors (e.g. close proximity to screening facility). More complex interventions (such as face-to-face counselling or home visits), mass media or improved access to transport should not be encouraged by policy makers unless other information appears. The repeated participation in mammography screening was consistently high, above 62%. Previous positive experience with screening influenced the repeated participation in screening programs. The reviews were inconsistent in the use of terminology related to breast cancer screening participation, which may have contributed to the heterogeneity in the reported outcomes. CONCLUSIONS: This study shows that consistent findings of systematic reviews bring more certainty into the conclusions on the effects of simple invitation techniques, fixed appointments and prompts, as well as healthcare organizational factors on promoting participation rate in screening mammography.

Disutility associated with cancer screening programs: A systematic review.

OBJECTIVES: Disutility allows to identify how much population values intervention-related harms contributing to knowledge on the benefits/harms ratio of cancer screening programs. This systematic review evaluates disutility related to cancer screening applying a utility theory framework. METHODS: Using a predefined protocol, Embase, Medline Ovid, Web of Science, Cochrane, Google scholar and supplementary sources were systematically searched. The framework grouped disutilities associated with breast, cervical, lung, colorectal, and prostate cancer screening programs into the screening, diagnostic work up, and treatment phases. We assessed the quality of included studies according to the relevance to target population, risk of bias, appropriateness of measure and the time frame. RESULTS: Out of 2840 hits, we included 38 studies, of which 27 measured (and others estimated) disutilities. Around 70% of studies had medium to high-level quality. Measured disutilities and Quality Adjusted Life Years loss were 0-0.03 and 0-0.0013 respectively in screening phases. Both disutilities and Quality Adjusted Life Years loss had similar ranges in diagnostic work up (0-0.26), and treatment (0.09-0.27) phases. We found no measured disutilities available for lung cancer screening and-little evidence for disutilities in treatment phase. Almost 40% of the estimated disutility values were above the range of measured ones. CONCLUSIONS: Cancer screening programs led to low disutities related to screening phase, and low to moderate disutilities related to diagnostic work up and treatment phases. These disutility values varied by the measurement instrument applied, and were higher in studies with lower quality. The estimated disutility values comparing to the measured ones tended to overestimate the harms.

Systematic reviews as a 'lens of evidence': Determinants of benefits and harms of breast cancer screening.

This systematic review, stimulated by inconsistency in secondary evidence, reports the benefits and harms of breast cancer (BC) screening and their determinants according to systematic reviews. A systematic search, which identified 9,976 abstracts, led to the inclusion of 58 reviews. BC mortality reduction with screening mammography was 15-25% in trials and 28-56% in observational studies in all age groups, and the risk of stage III+ cancers was reduced for women older than 49 years. Overdiagnosis due to mammography was 1-60% in trials and 1-12% in studies with a low risk of bias, and cumulative false-positive rates were lower with biennial than annual screening (3-17% vs 0.01-41%). There is no consistency in the reviews' conclusions about the magnitude of BC mortality reduction among women younger than 50 years or older than 69 years, or determinants of benefits and harms of mammography, including the type of mammography (digital vs screen-film), the number of views and the screening interval. Similarly, there was no solid evidence on determinants of benefits and harms or BC mortality reduction with screening by ultrasonography or clinical breast examination (sensitivity ranges, 54-84% and 47-69%, respectively), and strong evidence of unfavourable benefit-to-harm ratio with breast self-examination. The reviews' conclusions were not dependent on the quality of the reviews or publication date. Systematic reviews on mammography screening, mainly from high-income countries, systematically disagree on the interpretation of the benefit-to-harm ratio. Future reviews are unlikely to clarify the discrepancies unless new original studies are published.

What determines the effects and costs of breast cancer screening? A protocol of a systematic review of reviews.

BACKGROUND: Multiple reviews demonstrated high variability in effectiveness and cost-effectiveness outcomes among studies on breast cancer screening (BCS) programmes. No study to our knowledge has summarized the current evidence on determinants of effectiveness and cost-effectiveness of the most used BCS approaches or tried to explain differences in conclusions of systematic reviews on this topic. Based on published reviews, this systematic review aims to assess the degree of variability of determinants for (a) effectiveness and (b) cost-effectiveness of BCS programmes using mammography, clinical breast examination, breast self-examination, ultrasonography, or their combinations among the general population. METHODS: We will perform a comprehensive systematic literature search in Cochrane, Scopus, Embase, and Medline (via Pubmed). The search will be supplemented with hand searching of references of the included reviews, with hand searching in the specialized journals, and by contacting prominent experts in the field. Additional search for grey literature will be conducted on the websites of international cancer associations and networks. Two trained research assistants will screen titles and abstracts of publications independently, with at least random 10% of all abstracts being also screened by the principal researcher. The full texts of the systematic reviews will then be screened independently by two authors, and disagreements will be solved by consensus. The included reviews will be grouped by publication year, outcomes, designs of original studies, and quality. Additionally, for reviews published since 2011, transparency in reporting will be assessed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist for the review on determinants of effectiveness and a modified PRISMA checklist for the review on determinants for cost-effectiveness. The study will apply the Assessing the Methodological Quality of Systematic Reviews checklist to assess the methodological quality of systematic reviews. We will report the data extracted from the systematic reviews in a systematic format. Meta-meta-analysis of extracted data will be conducted when feasible. DISCUSSION: This systematic review of reviews will examine the degree of variability in the effectiveness and cost-effectiveness of BCS programmes. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42016050764 and CRD42016050765.

Chemotherapy for ovarian cancer in the Netherlands: a population-based study on treatment patterns and outcomes.

Information on treatment patterns for ovarian cancer (OC) is limited. The aim of this study was to describe current patterns of chemotherapy and other systemic treatments for OC in the Netherlands and evaluate survival outcomes following subsequent lines of treatment. Data from the Eindhoven Cancer Registry, including on newly diagnosed cancer patients, were linked to the PHARMO Database Network, including information on in- and out-patient drug use. Patients diagnosed with OC between January 2000 and December 2010 were selected. An algorithm was used to identify separate lines of treatment. Data were studied descriptively. Detailed data on systemic drug use were available for 261 patients (17%) with OC. In first-line treatment, 87% of the patients (227/261) received platinum-based chemotherapy. Of the 161 patients receiving second-line treatment, 101 patients (63%) received platinum-based chemotherapy. In third line, this was 51% (53/103). The median number of treatment lines received by patients was two (interquartile range 1-3), and eight or more lines of chemotherapy were identified for 12 patients. Median survival from diagnosis onwards was 47 months from the end of first-line treatment, median survival was 32 months, and from the end of second-line treatment, it was 14 months. Predominantly beyond second-line treatment, there is much variety in treatment patterns with chemotherapy for OC. Although uncertainty remains regarding the desirability of this observed treatment variation, there seems a need for detailed clinical guidance, assuring that physicians can properly choose the most suitable treatment for each patient.

Cost-effectiveness analysis of new generation coronary CT scanners for difficult-to-image patients.

AIMS: New generation dual-source coronary CT (NGCCT) scanners with more than 64 slices were evaluated for patients with (known) or suspected of coronary artery disease (CAD) who are difficult to image: obese, coronary calcium score > 400, arrhythmias, previous revascularization, heart rate > 65 beats per minute, and intolerance of betablocker. A cost-effectiveness analysis of NGCCT compared with invasive coronary angiography (ICA) was performed for these difficult-to-image patients for England and Wales. METHODS AND RESULTS: Five models (diagnostic decision model, four Markov models for CAD progression, stroke, radiation and general population) were integrated to estimate the cost-effectiveness of NGCCT for both suspected and known CAD populations. The lifetime costs and effects from the National Health Service perspective were estimated for three strategies: (1) patients diagnosed using ICA, (2) using NGCCT, and (3) patients diagnosed using a combination of NGCCT and, if positive, followed by ICA. In the suspected population, the strategy where patients only undergo a NGCCT is a cost-effective option at accepted cost-effectiveness thresholds. The strategy of using NGCCT in combination with ICA is the most favourable strategy for patients with known CAD. The most influential factors behind these results are the percentage of patients being misclassified (a function of both diagnostic accuracy and the prior likelihood), the complication rates of the procedures, and the cost price of a NGCCT scan. CONCLUSION: The use of NGCCT might be considered cost-effective in both populations since it is cost-saving compared to ICA and generates similar effects.

Economic considerations and patients' preferences affect treatment selection for patients with rheumatoid arthritis: a discrete choice experiment among European rheumatologists.

OBJECTIVE: To compare the value that rheumatologists across Europe attach to patients' preferences and economic aspects when choosing treatments for patients with rheumatoid arthritis. METHODS: In a discrete choice experiment, European rheumatologists chose between two hypothetical drug treatments for a patient with moderate disease activity. Treatments differed in five attributes: efficacy (improvement and achieved state on disease activity), safety (probability of serious adverse events), patient's preference (level of agreement), medication costs and cost-effectiveness (incremental cost-effectiveness ratio (ICER)). A Bayesian efficient design defined 14 choice sets, and a random parameter logit model was used to estimate relative preferences for rheumatologists across countries. Cluster analyses and latent class models were applied to understand preference patterns across countries and among individual rheumatologists. RESULTS: Responses of 559 rheumatologists from 12 European countries were included in the analysis (49% females, mean age 48 years). In all countries, efficacy dominated treatment decisions followed by economic considerations and patients' preferences. Across countries, rheumatologists avoided selecting a treatment that patients disliked. Latent class models revealed four respondent profiles: one traded off all attributes except safety, and the remaining three classes disregarded ICER. Among individual rheumatologists, 57% disregarded ICER and these were more likely from Italy, Romania, Portugal or France, whereas 43% disregarded uncommon/rare side effects and were more likely from Belgium, Germany, Hungary, the Netherlands, Norway, Spain, Sweden or UK. CONCLUSIONS: Overall, European rheumatologists are willing to trade between treatment efficacy, patients' treatment preferences and economic considerations. However, the degree of trade-off differs between countries and among individuals.

Cost-effectiveness of Elective Endovascular Aneurysm Repair Versus Open Surgical Repair of Abdominal Aortic Aneurysms.

OBJECTIVE/BACKGROUND: The aim of this study was to estimate the lifetime cost-effectiveness of endovascular aneurysm repair (EVAR) versus open surgical repair (OSR) in the Netherlands, based on recently published literature. METHODS: A model was developed to simulate a cohort of individuals (age 72 years, 87% men) with an abdominal aortic aneurysm (AAA) diameter of at least 5.5 cm and considered fit for both repairs. The model consisted of two sub-models that estimated the lifetime cost-effectiveness of EVAR versus OSR: (1) a decision tree for the first 30 post-operative days; and (2) a Markov model for the period thereafter (31 days-30 years). RESULTS: In the base case analysis, EVAR was slightly more effective (4.704 vs. 4.669 quality adjusted life years) and less expensive (€24,483 vs. €25,595) than OSR. Improved effectiveness occurs because EVAR can reduce 30 day mortality risk, as well as the risk of events following the procedure, while lower costs are primarily due to a reduction in length of hospital stay. The cost-effectiveness of EVAR is highly dependent on the price of the EVAR device and the reduction in hospital stay, complications, and 30 day mortality. CONCLUSION: EVAR and OSR can be considered equally effective, while EVAR can be cost saving compared with OSR. EVAR can therefore be considered as a cost-effective solution for patients with AAAs.

Treatment variation in stent choice in patients with stable or unstable coronary artery disease.

AIM: Variations in treatment are the result of differences in demographic and clinical factors (e.g. anatomy), but physician and hospital factors may also contribute to treatment variation. The choice of treatment is considered important since it could lead to differences in long-term outcomes. This study explores the associations with stent choice: i.e. drug-eluting stent (DES) versus bare-metal stents (BMS) for Dutch patients diagnosed with stable or unstable coronary artery disease (CAD). METHODS & RESULTS: Associations with treatment decisions were based on a prospective cohort of 692 patients with stable or unstable CAD. Of those patients, 442 patients were treated with BMS or DES. Multiple logistic regression analyses were performed to identify variables associated with stent choice. Bivariate analyses showed that NYHA class, number of diseased vessels, previous percutaneous coronary intervention, smoking, diabetes, and the treating hospital were associated with stent type. After correcting for other associations the treating hospital remained significantly associated with stent type in the stable CAD population. CONCLUSIONS: This study showed that several factors were associated with stent choice. While patients generally appear to receive the most optimal stent given their clinical characteristics, stent choice seems partially determined by the treating hospital, which may lead to differences in long-term outcomes.

Cost comparison of treating chronic hepatitis C genotype one with pegylated interferons in Ukraine.

Based on the pivotal trial showing no clinically relevant differences between pegylated interferon α-2b (Peg-α-2b) and α-2a (Peg-α-2a) combined with ribavirin for treatment of chronic hepatitis C virus (HCV) genotype 1 infection in Ukraine, a cost-minimization analysis was performed using a 1 year time horizon and both a health care and patients' perspective. A decision tree reflects treatment pathways. Drug costs were based on drug labeling and adjusted to the average body mass in Ukraine. Subgroup analysis was applied to deal with heterogeneity of patient's weight causing dose changes. A break-even price of Peg-α-2a and Peg-α-2b (based on the average dose) was calculated. Univariate sensitivity analyses and probabilistic sensitivity analysis were carried out to reflect decision uncertainty. For an average body weight, total medical costs per patient differ from US$9220 for Peg-α-2b to US$9513 for Peg-α-2a from a health care perspective, and from US$15,212 to US$15,696 from a patients' perspective. Sensitivity analyses show these results are robust. With average body weight, the break-even price of Peg-α-2b may be 7.3% higher than Peg-α-2a to have similar total costs.

Real world cost of human epidermal receptor 2-positive metastatic breast cancer patients: a longitudinal incidence-based observational costing study in the Netherlands and Belgium.

Currently, no country-specific metastatic breast cancer (MBC) observational costing data are available for the Netherlands and Belgium. Our aim is to describe country-specific resource use and costs of human epidermal receptor 2 (HER-2)-positive MBC in the Netherlands and Belgium, making use of real-world data. The eligibility period for patient selection was from April 2004 to April 2010. Inclusion and retrospective data collection begins at the time of first diagnosis of HER-2-positive MBC during the eligibility period and ends 24 months post-index diagnosis of MBC or at patient death. We identified 88 eligible patients in the Netherlands and 44 patients in Belgium. The total costs of medical treatment and other resource use utilisation per patient was €48,301 in the Netherlands and €37,431 in Belgium. Majority of costs was related to the use of trastuzumab in both countries, which was 50% of the total costs in the Netherlands and 56% in Belgium respectively. Our study provides estimates of resource use and costs for HER-2-positive MBC in the Netherlands and Belgium. We noticed various differences in resource use patterns between both countries demonstrating caution is needed when transferring cost estimates between countries.

Is it cost-effective to use a test to decide which individuals with an intermediate cardiovascular disease risk would benefit from statin treatment?

BACKGROUND: The 2012 European guidelines recommend statins for intermediate-risk individuals with elevated cholesterol levels. Improved discrimination of intermediate-risk individuals is needed to prevent both cardiovascular disease (CVD) and statin side-effects (e.g. myopathy) efficiently since only 3-15 in every 100 individuals actually experience a cardiovascular event in the next 10 years. We estimated the potential cost-effectiveness of a hypothetical test which helps to determine which individuals will benefit from statins. METHODS AND RESULTS: Prognosis of different age- and gender-specific cohorts with an intermediate risk was simulated with a Markov model to estimate the potential costs and quality-adjusted life-years for four strategies: treat all with statins, treat none with statins, treat according to the European guidelines, or use a test to select individuals for statin treatment. The test-first strategy dominated the other strategies if the hypothetical test was 100% accurate and cost no more than €237. This strategy and the treat-all strategy were equally effective but the test generated lower costs by reducing statin usage and side-effects. The treat-none strategy was the least effective strategy. Threshold analyses show that the test must be highly accurate (especially sensitive) and inexpensive to be the most cost-effective strategy, since myopathy has a negligible impact on cost-effectiveness and statin costs are low. CONCLUSION: Use of a highly accurate prognostic test could reduce overall CVD risk, frequency of drug side-effects and lifetime costs. However, no additional test would add usefully to risk prediction over SCORE when it does not satisfy the costs and accuracy requirements.

How to select the right cost-effectiveness model? : A systematic review and stepwise approach for selecting a transferable health economic evaluation model for rheumatoid arthritis.

OBJECTIVE: In the current study, we propose an approach for selection of a model that is transferable to a specific decision-making context (in this case, the Netherlands), using the case of rheumatoid arthritis (RA). The objectives of this study were (a) to perform a systematic literature review to identify existing health economic evaluation models for economic evaluation of disease-modifying antirheumatic drugs (DMARDs) in RA; and (b) to test the appropriateness of a stepwise model-selection process. METHODS: First, we searched Medline and Embase to identify relevant studies in the English language, published between 1 January 2002 and 31 August 2012. From the included studies, all unique models were identified. Second, we applied a multi-step approach to model selection. Models that did not meet all minimal methodological and structural requirements based on the Outcome Measures in Rheumatology (OMERACT) criteria were excluded. Next, models were assessed on the basis of their fit when transferred to the Dutch health care setting. The criteria for model fit were transferability factors, as published by Welte et al., after exclusion of those that were deemed transferable by simple adaptation. Finally, the remaining models underwent a general quality check using the Philips checklist. Models showing good fit and high quality were considered to be transferable to the Dutch health care setting, using simple adaptation. RESULTS: The systematic literature search identified 498 articles, which included 33 unique health economic evaluation models. Only six models passed the minimal methodological and structural requirements. Two of these models had an imperfect transferability fit to the Dutch health care setting, according to the Welte method. The remaining four models were, according to the Philips method, of good quality and were expected to be transferable by a simple adaptation. CONCLUSION: This study introduces a stepwise approach for selecting health economic evaluation models that are transferable by a simple adaptation. The approach seems feasible and can be applied in various therapeutic areas, provided that the minimal methodological and structural requirements are defined accordingly. Availability of health economic evaluation models coupled with structured model selection could improve the efficiency, quality and comparability of health economic research.

Rapid fetal fibronectin testing to predict preterm birth in women with symptoms of premature labour: a systematic review and cost analysis.

BACKGROUND: Premature birth is defined as birth of before 37 completed weeks' gestation. Not all pregnant women showing symptoms of preterm labour will go on to deliver before 37 weeks' gestation. Hence, addition of fetal fibronectin (fFN) testing to the diagnostic workup of women with suspected preterm labour may help to identify those women who do not require active management, and thus avoid unnecessary interventions, hospitalisations and associated costs. OBJECTIVE: To assess the clinical effectiveness and cost-effectiveness of rapid fFN testing in predicting preterm birth (PTB) in symptomatic women. DATA SOURCES: Bibliographic databases (including EMBASE, Cochrane Database of Systematic Reviews and Cochrane Central Register of Controlled Trials) were searched from 2000 to September/November 2011. Trial registers were also searched. REVIEW METHODS: Systematic review methods followed published guidance; we assessed clinical effectiveness and updated a previous systematic review of test accuracy. Risk of bias was assessed using the Cochrane tool (randomised controlled trials; RCTs) and a modification of QUADAS-2 (diagnostic test accuracy studies; DTAs). Summary risk ratios or weighted mean difference were calculated using random-effects models. Summary sensitivity and specificity used a bivariate summary receiver operating characteristic model. Heterogeneity was investigated using subgroup and sensitivity analyses. Health economic analysis focused on cost consequences. The time horizon was hospital admission for observation. A main structural assumption was that, compared with usual care, fFN testing doesn't increase adverse events or negative pregnancy outcomes. RESULTS: Five RCTs and 15 new DTAs were identified. No RCT reported significant effects of fFN testing on maternal or neonatal outcomes. One study reported a subgroup analysis of women with negative fFN test observed > 6 hours, which showed a reduction in length of hospital stay where results were known to clinicians. Combining data from new studies and the previous systematic review, the pooled estimates of sensitivity and specificity were: 76.7% and 82.7% for delivery within 7-10 days of testing; 69.1% and 84.4% for delivery < 34 weeks' gestation; and 60.8% and 82.3% for delivery < 37 weeks' gestation. Estimates were similar across all subgroups sensitivity analyses. The base-case cost analysis resulted in a cost saving of £23.87 for fFN testing compared with usual care. The fFN testing was cost-neutral at an approximate cost of £45. Probabilistic sensitivity analysis gave an incremental cost (saving) of -£25.59 (97.5% confidence interval -£304.96 to £240.06), indicating substantial uncertainty. Sensitivity analyses indicated that admission rate had the largest impact on results. CONCLUSIONS: Fetal fibronectin testing has moderate accuracy for predicting PTB. The main potential role is likely to be reducing health-care resource usage by identifying women not requiring intervention. Evidence from RCTs suggests that fFN does not increase adverse outcomes and may reduce resource use. The base-case analysis showed a modest cost difference in favour of fFN testing, which is largely dependent on whether or not fFN testing reduces hospital admission. Currently, there are no high-quality studies and the existing trials were generally underpowered. Hence, there is a need for high-quality adequately powered trials using appropriate study designs to confirm the findings presented. STUDY REGISTRATION: PROSPERO 2011:CRD42011001468. Available from www.crd.york.ac.uk/PROSPERO/display_record.asp?ID=CRD42011001468. FUNDING: The National Institute for Health Research Health Technology Assessment programme.