Interventions for primary prevention of cardiovascular disease: umbrella review of systematic reviews.

Background: Cardiovascular diseases are the leading cause of death globally. The aim of this overview of systematic reviews was to compare the effectiveness of different pharmacological and non-pharmacological interventions for the primary prevention of cardiovascular disease. Methods: A structured search of the Cochrane Database of Systematic Reviews, MEDLINE, EMBASE and the Database of Abstracts of Reviews of Effects archive was conducted to find systematic reviews that reported the effect of various pharmacological and non-pharmacological interventions for the primary prevention of cardiovascular disease from inception to March 2021. References of included studies were also checked. The included systematic reviews' methodological quality was assessed using the Assessment of Multiple Systematic Reviews 2 instrument (range, 0-16). The outcomes of each included review's meta-analysis were extracted and described narratively. Results: This study analysed 95 systematic reviews, including 41 on non-pharmacological interventions and 54 on pharmacological interventions for cardiovascular health. The majority of the reviews focused on lipid-lowering interventions (n = 25) and antiplatelet medications (n = 21), followed by nutritional supplements, dietary interventions, physical activity, health promotion and other interventions. Only 1 of the 10 reviews addressing cardiovascular mortality showed a potential benefit, while the others found no effect. Antiplatelets were found to have a beneficial effect on all-cause mortality in 2 out of 12 meta-analyses and on major cardiovascular disease events in 8 out of 17 reviews. Lipid-lowering interventions showed beneficial effects on cardiovascular disease mortality, all-cause mortality and major cardiovascular disease events in varying numbers of the reviews. Glucose-lowering medications demonstrated significant benefits for major cardiovascular events, coronary heart disease events and mortality. However, the combination of dietary interventions, physical activities, nutritional supplements and polypills showed little or no significant benefit for major cardiovascular outcomes or mortality. Future work and limitations: More research is needed to determine whether the effect of treatment varies depending on population characteristics. The findings of this review should be interpreted with caution because the majority of studies of non-pharmacological interventions compare primary prevention with usual care, which may include recommended pharmacological treatment in higher-risk patients (e.g. statins and/or antihypertensive medications, etc.). In addition, randomised controlled trial evidence may be better suited to the study of pharmacological interventions than dietary and lifestyle interventions. Conclusions: This umbrella review captured the variability in different interventions on randomised controlled trial evidence on interventions for primary prevention of cardiovascular disease and identified areas that may benefit from further research. Specifically, this review focused on randomised controlled trial evidence on interventions for primary prevention of cardiovascular disease. Researchers may use these findings as a resource to direct new intervention studies and network meta-analyses to compare the efficacy of various interventions based on these findings. Funding: This article presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment (HTA) programme as award number 17/148/05.

Heart and blood vessel diseases are the top cause of death worldwide. This study aimed to compare the effectiveness of various drug-based and non-drug-based methods in preventing these diseases. We searched databases like Cochrane, MEDLINE, EMBASE and the Database of Abstracts of Reviews of Effects archive to find reviews about different ways to prevent heart and blood vessel diseases up until March 2021. The results showed that only 1 out of 10 reviews found a possible benefit in reducing heart-related deaths, while the other 9 found no effect. Medicines that lower blood sugar levels had a positive impact on reducing major heart events, heart disease and death. However, combining dietary changes, exercise, nutritional supplements and polypills had little or no effect on reducing heart-related events, deaths due to heart disease or deaths from all causes. This review examined the available evidence on ways to prevent heart and blood vessel diseases and identified areas where more research could be beneficial. Future studies could compare the effectiveness of different interventions using new methods and analyses.

Fatigue and vigilance in medical experts detecting breast cancer.

An abundance of laboratory-based experiments has described a vigilance decrement of reducing accuracy to detect targets with time on task, but there are few real-world studies, none of which have previously controlled the environment to control for bias. We describe accuracy in clinical practice for 360 experts who examined >1 million women's mammograms for signs of cancer, whilst controlling for potential biases. The vigilance decrement pattern was not observed. Instead, test accuracy improved over time, through a reduction in false alarms and an increase in speed, with no significant change in sensitivity. The multiple-decision model explains why experts miss targets in low prevalence settings through a change in decision threshold and search quit threshold and propose it should be adapted to explain these observed patterns of accuracy with time on task. What is typically thought of as standard and robust research findings in controlled laboratory settings may not directly apply to real-world environments and instead large, controlled studies in relevant environments are needed.

The potential impact of policies and structural interventions in reducing cardiovascular disease and mortality: a systematic review of simulation-based studies.

Background: The aim of the study was to investigate the potential effect of different structural interventions for preventing cardiovascular disease. Methods: Medline and EMBASE were searched for peer-reviewed simulation-based studies of structural interventions for prevention of cardiovascular disease. We performed a systematic narrative synthesis. Results: A total of 54 studies met the inclusion criteria. Diet, nutrition, tobacco and alcohol control and other programmes are among the policy simulation models explored. Food tax and subsidies, healthy food and lifestyles policies, palm oil tax, processed meat tax, reduction in ultra-processed foods, supplementary nutrition assistance programmes, stricter food policy and subsidised community-supported agriculture were among the diet and nutrition initiatives. Initiatives to reduce tobacco and alcohol use included a smoking ban, a national tobacco control initiative and a tax on alcohol. Others included the NHS Health Check, WHO 25 × 25 and air quality management policy. Future work and limitations: There is significant heterogeneity in simulation models, making comparisons of output data impossible. While policy interventions typically include a variety of strategies, none of the models considered possible interrelationships between multiple policies or potential interactions. Research that investigates dose-response interactions between numerous modifications as well as longer-term clinical outcomes can help us better understand the potential impact of policy-level interventions. Conclusions: The reviewed studies underscore the potential of structural interventions in addressing cardiovascular diseases. Notably, interventions in areas such as diet, tobacco, and alcohol control demonstrate a prospective decrease in cardiovascular incidents. However, to realize the full potential of such interventions, there is a pressing need for models that consider the interplay and cumulative impacts of multiple policies. Rigorous research into holistic and interconnected interventions will pave the way for more effective policy strategies in the future. Study registration: The study is registered as PROSPERO CRD42019154836. Funding: This article presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number 17/148/05.

This study aimed to explore the potential effects of various policy changes on the prevention of heart disease. By searching two large medical databases, we identified studies that employed computer models to estimate the impact of these policies on heart disease rates. In total, 54 studies matched our criteria. These studies considered a diverse range of policy interventions. Some delved into food and nutrition, investigating aspects like unhealthy food taxes, healthy food subsidies, stricter food regulations, and nutritional assistance programs. Others examined the impact of policies targeting tobacco and alcohol, encompassing smoking bans, nationwide tobacco control measures, and alcohol taxation. Further policies assessed included routine health checkups, global health goals, and measures to enhance air quality. One significant challenge lies in the varied approaches and models each study employed, making direct comparisons difficult. Furthermore, there's a gap in understanding how these policies might influence one another, as the studies did not consider potential interactions between them. While these policies show promise in the computer models, more comprehensive research is needed to fully appreciate their combined and long-term effects on heart health in real-world scenarios. As of now, we recognize the potential of these interventions, but further studies will determine their true impact on reducing heart disease rates.

Advancing leadership in surgery: a realist review of interventions and strategies to promote evidence-based leadership in healthcare.

BACKGROUND: Healthcare systems invest in leadership development of surgeons, surgical trainees, and teams. However, there is no agreement on how interventions should be designed, or what components they must contain to be successful. The objective of this realist review was to generate a programme theory explaining in which context and for whom surgical leadership interventions work and why. METHODS: Five databases were systematically searched, and articles screened against inclusion considering their relevance. Context-mechanism-outcome configurations (CMOCs) and fragments of CMOCs were identified. Gaps in the CMOCs were filled through deliberation with the research team and stakeholder feedback. We identified patterns between CMOCs and causal relationships to create a programme theory. RESULTS: Thirty-three studies were included and 19 CMOCs were developed. Findings suggests that interventions for surgeons and surgical teams improve leadership if timely feedback is delivered on multiple occasions and by trusted and respected people. Negative feedback is best provided privately. Feedback from senior-to-junior or peer-to-peer should be delivered directly, whereas feedback from junior-to-senior is preferred when delivered anonymously. Leadership interventions were shown to be most effective for those with awareness of the importance of leadership, those with confidence in their technical surgical skills, and those with identified leadership deficits. For interventions to improve leadership in surgery, they need to be delivered in an intimate learning environment, consider implementing a speak-up culture, provide a variety of interactive learning activities, show a genuine investment in the intervention, and be customised to the needs of surgeons. Leadership of surgical teams can be best developed by enabling surgical teams to train together. CONCLUSIONS: The programme theory provides evidence-based guidance for those who are designing, developing and implementing leadership interventions in surgery. Adopting the recommendations will help to ensure interventions are acceptable to the surgical community and successful in improving surgical leadership. TRIAL REGISTRATION: The review protocol is registered with PROSPERO (CRD42021230709).

Investigating informed choice in screening programmes: a mixed methods analysis.

BACKGROUND: Screening programmes aim to identify individuals at higher risk of developing a disease or condition. While globally, there is agreement that people who attend screening should be fully informed, there is no consensus about how this should be achieved. We conducted a mixed methods study across eight different countries to understand how countries address informed choice across two screening programmes: breast cancer and fetal trisomy anomaly screening. METHODS: Fourteen senior level employees from organisations who produce and deliver decision aids to assist informed choice were interviewed, and their decision aids (n = 15) were evaluated using documentary analysis. RESULTS: We discovered that attempts to achieve informed choice via decision aids generate two key tensions (i) between improving informed choice and increasing uptake and (ii) between improving informed choice and comprehensibility of the information presented. Comprehensibility is fundamentally at tension with an aim of being fully informed. These tensions emerged in both the interviews and documentary analysis. CONCLUSION: We conclude that organisations need to decide whether their overarching aim is ensuring high levels of uptake or maximising informed choice to participate in screening programmes. Consideration must then be given to all levels of development and distribution of information produced to reflect each organisation's aim. The comprehensibility of the DA must also be considered, as this may be reduced when informed choice is prioritised.

Increasing comprehensiveness and reducing workload in a systematic review of complex interventions using automated machine learning.

BACKGROUND: As part of our ongoing systematic review of complex interventions for the primary prevention of cardiovascular diseases, we have developed and evaluated automated machine-learning classifiers for title and abstract screening. The aim was to develop a high-performing algorithm comparable to human screening. METHODS: We followed a three-phase process to develop and test an automated machine learning-based classifier for screening potential studies on interventions for primary prevention of cardiovascular disease. We labelled a total of 16,611 articles during the first phase of the project. In the second phase, we used the labelled articles to develop a machine learning-based classifier. After that, we examined the performance of the classifiers in correctly labelling the papers. We evaluated the performance of the five deep-learning models [i.e. parallel convolutional neural network ( CNN ), stacked CNN , parallel-stacked CNN , recurrent neural network ( RNN ) and CNN-RNN]. The models were evaluated using recall, precision and work saved over sampling at no less than 95% recall. RESULTS: We labelled a total of 16,611 articles, of which 676 (4.0%) were tagged as 'relevant' and 15,935 (96%) were tagged as 'irrelevant'. The recall ranged from 51.9% to 96.6%. The precision ranged from 64.6% to 99.1%. The work saved over sampling ranged from 8.9% to as high as 92.1%. The best-performing model was parallel CNN , yielding a 96.4% recall, as well as 99.1% precision, and a potential workload reduction of 89.9%. FUTURE WORK AND LIMITATIONS: We used words from the title and the abstract only. More work needs to be done to look into possible changes in performance, such as adding features such as full document text. The approach might also not be able to be used for other complex systematic reviews on different topics. CONCLUSION: Our study shows that machine learning has the potential to significantly aid the labour-intensive screening of abstracts in systematic reviews of complex interventions. Future research should concentrate on enhancing the classifier system and determining how it can be integrated into the systematic review workflow. FUNDING: This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in Health Technology Assessment. See the NIHR Journals Library website for further project information.

Paragons, Mavericks and Innovators-A typology of orthopaedic surgeons' professional identities. A comparative case study of evidence-based practice.

Clinical guidelines, as vehicles for evidence-based practice (EBP) attempt to standardize health-care practice, reduce variation and increase quality. However, their use for surgery has been contested, and often resisted. This article examines professional responses to EBP in hip replacement surgery using data from case study observations and interviews in three English orthopaedic departments. A professional identity perspective is adopted to explain how standardization through EBP, represents an empirical phenomenon around which surgeons enact their identities as Paragons, Mavericks or Innovators, to enhance legitimacy and stratify themselves in their response to EBP. Attention is drawn to variation between Paragon surgeons working in university (teaching) hospitals and Maverick and Innovator types located in general hospitals, and the ways this interacts with adoption of EBP. The typology shows how practice variation is related to surgeons' tendencies to align to characteristic types, with distinct social processes, power and prestige, and which are in turn influenced by organizational context. The dynamics of EBP and professional identity continues to limit attempts to standardize surgical practice. The typology contributes to the understanding of failures to follow EBP, as associated with the identities individuals create and negotiate, and with identity narratives used to legitimize differing responses to EBP.

Factors associated with attendance at screening for breast cancer: a systematic review and meta-analysis.

OBJECTIVE: Attendance at population-based breast cancer (mammographic) screening varies. This comprehensive systematic review and meta-analysis assesses all identified patient-level factors associated with routine population breast screening attendance. DESIGN: CINAHL, Cochrane Library, Embase, Medline, OVID, PsycINFO and Web of Science were searched for studies of any design, published January 1987-June 2019, and reporting attendance in relation to at least one patient-level factor. DATA SYNTHESIS: Independent reviewers performed screening, data extraction and quality appraisal. OR and 95% CIs were calculated for attendance for each factor and random-effects meta-analysis was undertaken where possible. RESULTS: Of 19 776 studies, 335 were assessed at full text and 66 studies (n=22 150 922) were included. Risk of bias was generally low. In meta-analysis, increased attendance was associated with higher socioeconomic status (SES) (n=11 studies; OR 1.45, 95% CI: 1.20 to 1.75); higher income (n=5 studies; OR 1.96, 95% CI: 1.68 to 2.29); home ownership (n=3 studies; OR 2.16, 95% CI: 2.08 to 2.23); being non-immigrant (n=7 studies; OR 2.23, 95% CI: 2.00 to 2.48); being married/cohabiting (n=7 studies; OR 1.86, 95% CI: 1.58 to 2.19) and medium (vs low) level of education (n=6 studies; OR 1.24, 95% CI: 1.09 to 1.41). Women with previous false-positive results were less likely to reattend (n=6 studies; OR 0.77, 95% CI: 0.68 to 0.88). There were no differences by age group or by rural versus urban residence. CONCLUSIONS: Attendance was lower in women with lower SES, those who were immigrants, non-homeowners and those with previous false-positive results. Variations in service delivery, screening programmes and study populations may influence findings. Our findings are of univariable associations. Underlying causes of lower uptake such as practical, physical, psychological or financial barriers should be investigated. TRIAL REGISTRATION NUMBER: CRD42016051597.

Use of artificial intelligence for image analysis in breast cancer screening programmes: systematic review of test accuracy.

OBJECTIVE: To examine the accuracy of artificial intelligence (AI) for the detection of breast cancer in mammography screening practice. DESIGN: Systematic review of test accuracy studies. DATA SOURCES: Medline, Embase, Web of Science, and Cochrane Database of Systematic Reviews from 1 January 2010 to 17 May 2021. ELIGIBILITY CRITERIA: Studies reporting test accuracy of AI algorithms, alone or in combination with radiologists, to detect cancer in women's digital mammograms in screening practice, or in test sets. Reference standard was biopsy with histology or follow-up (for screen negative women). Outcomes included test accuracy and cancer type detected. STUDY SELECTION AND SYNTHESIS: Two reviewers independently assessed articles for inclusion and assessed the methodological quality of included studies using the QUality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool. A single reviewer extracted data, which were checked by a second reviewer. Narrative data synthesis was performed. RESULTS: Twelve studies totalling 131 822 screened women were included. No prospective studies measuring test accuracy of AI in screening practice were found. Studies were of poor methodological quality. Three retrospective studies compared AI systems with the clinical decisions of the original radiologist, including 79 910 women, of whom 1878 had screen detected cancer or interval cancer within 12 months of screening. Thirty four (94%) of 36 AI systems evaluated in these studies were less accurate than a single radiologist, and all were less accurate than consensus of two or more radiologists. Five smaller studies (1086 women, 520 cancers) at high risk of bias and low generalisability to the clinical context reported that all five evaluated AI systems (as standalone to replace radiologist or as a reader aid) were more accurate than a single radiologist reading a test set in the laboratory. In three studies, AI used for triage screened out 53%, 45%, and 50% of women at low risk but also 10%, 4%, and 0% of cancers detected by radiologists. CONCLUSIONS: Current evidence for AI does not yet allow judgement of its accuracy in breast cancer screening programmes, and it is unclear where on the clinical pathway AI might be of most benefit. AI systems are not sufficiently specific to replace radiologist double reading in screening programmes. Promising results in smaller studies are not replicated in larger studies. Prospective studies are required to measure the effect of AI in clinical practice. Such studies will require clear stopping rules to ensure that AI does not reduce programme specificity. STUDY REGISTRATION: Protocol registered as PROSPERO CRD42020213590.

Test accuracy of faecal calprotectin for inflammatory bowel disease in UK primary care: a retrospective cohort study of the IMRD-UK data.

OBJECTIVE: To estimate the test accuracy of faecal calprotectin (FC) for inflammatory bowel disease (IBD) in the primary care setting using routine electronic health records. DESIGN: Retrospective cohort test accuracy study. SETTING: UK primary care. PARTICIPANTS: 5970 patients (≥18 years) without a previous IBD diagnosis and with a first FC test between 1 January 2006 and 31 December 2016. We excluded multiple tests and tests without numeric results in units of µg/g. INTERVENTION: FC testing for the diagnosis of IBD. Disease status was confirmed by a recorded diagnostic code and/or a drug code of an IBD-specific medication at three time points after the FC test date. MAIN OUTCOME MEASURES: Sensitivity, specificity, and positive and negative predictive values for the differential of IBD versus non-IBD and IBD versus irritable bowel syndrome (IBS) at the 50 and 100 µg/g thresholds. RESULTS: 5970 patients met the inclusion criteria and had at least 6 months of follow-up data after FC testing. 1897 had an IBS diagnosis, 208 had an IBD diagnosis, 31 had a colorectal cancer diagnosis, 80 had more than one diagnosis and 3754 had no subsequent diagnosis. Sensitivity, specificity, and positive and negative predictive values were 92.9% (88.6% to 95.6%), 61.5% (60.2% to 62.7%), 8.1% (7.1% to 9.2%) and 99.6% (99.3% to 99.7%), respectively, at the threshold of 50 µg/g. Raising the threshold to 100 µg/g missed less than 7% additional IBD cases. Longer follow-up had no effect on test accuracy. Overall, uncertainty was greater for specificity than sensitivity. General practitioners' (GPs') referral decisions did not follow the anticipated clinical pathways in national guidance. CONCLUSIONS: GPs can be confident in excluding IBD on the basis of a negative FC test in a population with low pretest risk but should interpret a positive test with caution. The applicability of national guidance to general practice needs to be improved.

Advancing clinical leadership to improve the implementation of evidence-based practice in surgery: a longitudinal mixed-method study protocol.

BACKGROUND: Clinical leadership is fundamental in facilitating service improvements in healthcare. Few studies have attempted to understand or model the different approaches to leadership which are used when promoting the uptake and implementation of evidence-based interventions. This research aims to uncover and explain how distributed clinical leadership can be developed and improved to enhance the use of evidence in practice. In doing so, this study examines implementation leadership in orthopaedic surgery to explain leadership as a collective endeavour which cannot be separated from the organisational context. METHODS: A mixed-method study consisting of longitudinal and cross-sectional interviews and an embedded social network analysis will be performed in six NHS hospitals. A social network analysis will be undertaken in each hospital to uncover the organisational networks, the focal leadership actors and information flows in each organisation. This will be followed by a series of repeated semi-structured interviews, conducted over 4 years, with orthopaedic surgeons and their professional networks. These longitudinal interviews will be supplemented by cross-sectional interviews with the national established surgical leaders. All qualitative data will be analysed using a constructivist grounded theory approach and integrated with the quantitative data. The participant narratives will enrich the social network to uncover the leadership configurations which exist, and how different configurations of leadership are functioning in practice to influence implementation processes and outcomes. DISCUSSION: The study findings will facilitate understanding about how and why different configurations of leadership develop and under what organisational conditions and circumstances they are able to flourish. The study will guide the development of leadership interventions that are grounded in the data and aimed at advancing leadership for service improvement in orthopaedics. The strength of the study lies in the combination of multi-component, multi-site, multi-agent methods to examine leadership processes in surgery. The findings may be limited by the practical challenges of longitudinal qualitative data collection, such as ensuring participant retention, which need to be balanced against the theoretical and empirical insights generated through this comprehensive exploration of leadership across and within a range of healthcare organisations.

Determining optimal strategies for primary prevention of cardiovascular disease: systematic review, cost-effectiveness review and network meta-analysis protocol.

BACKGROUND: Despite recent improvements in the burden of cardiovascular disease (CVD) in the UK, deaths from CVD are relatively high compared with other high-income countries. An estimated 7 million people in the UK are living with CVD, and the healthcare cost is approximately £11 billion annually. In more than 90% of cases, the risk of a first heart attack is thought to be related to modifiable risk factors including smoking, poor diet, lipidemia, high blood pressure, inactivity, obesity and excess alcohol consumption. The aim of the study is to synthesise evidence for the comparative effectiveness and cost-effectiveness of different interventions for the primary prevention of CVD. METHODS: We will systematically search databases (for example, MEDLINE (Ovid), Embase (Ovid), Cochrane Library) and the reference lists of previous systematic reviews for randomised controlled trials that assess the effectiveness and cost-effectiveness of any form of intervention aimed at adult populations for the primary prevention of CVD, including but not limited to lipid lowering medications, blood pressure lowering medications, antiplatelet agents, nutritional supplements, dietary interventions, health promotion programmes, physical activity interventions or structural and policy interventions. Interventions may or may not be targeted at high-risk groups. Publications from any year will be considered for inclusion. The primary outcome will be all cause mortality. Secondary outcomes will be cardiovascular diseases related mortality, major cardiovascular events, coronary heart disease, incremental costs per quality-adjusted life years gained. If data permits, we will use network meta-analysis to compare and rank effectiveness of different interventions, and test effect modification of intervention effectiveness using subgroup analyses and meta-regression analyses. DISCUSSION: The results will be important for policymakers when making decisions between multiple possible alternative strategies to prevent CVD. Compared to results from existing multiple separate pairwise meta-analyses, this overarching synthesis of all relevant work will enhance decision-making. The findings will be crucial to inform evidence-based priorities and guidelines for policies and planning prevention strategies of CVD. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42019123940.

Comparison of health technology assessment for new medicines in France and England: an example based on ixazomib for patients with relapsed or refractory multiple myeloma.

Introduction: The appraisal of medicines is often a complex and iterative process. We compared the health technology assessment (HTA) process in England and France taking as a case study the example of ixazomib for multiple myeloma. Methods: We undertook an analysis of eight relevant published documents identifed from the websites of the French and English HTA bodies (HAS and NICE, respectively). We analyse patients' availability of ixazomib resulting in the different stages of the appraisal process. Results: We identified differences in the assessment, one of these being the use of an appraisal scope in England allowing the differentiation of populations and comparators according to previously approved treatments. Ixazomib became available earlier in France as part of an early access programme, but the availability was soon discontinued for newly eligible patients following an HAS determination that Ixazomib yielded no additional benefit. This opinion resulted in long pricing discussions. In England, despite the absence of an early access programme and following a process that included cost-effectiveness evaluation combined with pricing discussions, the medicine was fairly rapidly recommended for use. Conclusions: Differences in the HTA process may result in appreciable differences in time from marketing authorisation to health service adoption of newly licensed drugs.

Comparative survival benefit of currently licensed second or third line treatments for epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) negative advanced or metastatic non-small cell lung cancer: a systematic review and secondary analysis of trials.

BACKGROUND: A review of therapies for advanced cancers licenced by the EMA between 2009 and 2013 concluded that for more than half of these drugs there was little evidence of overall survival or quality of life benefit. Recent years have witnessed a growing number of licensed second-line pharmacotherapies for advanced/metastatic non-small cell lung cancer (NSCLC). With the aim of gauging patient survival benefit, we conducted a systematic review of randomised controlled trials (RCT) and compared survival outcomes from available licensed treatments for patients with advanced/metastatic NSCLC. METHODS: RCTs of second/third line treatments in participants with advanced/metastatic NSCLC and negative/low expression of Anaplastic Lymphoma Kinase (ALK) and of Epidermal Growth Factor Receptor (EGFR) were included. We searched electronic databases (MEDLINE; EMBASE; Web of Science) from January, 2000 up to July, 2017. Two or more independent reviewers screened bibliographic records, extracted data, and assessed risk of bias of studies. Published Kaplan Meier plots for OS and PFS along with restricted-mean-survival methods and parametric modelling were used to estimate the survival outcomes as mean number of months of survival. Network meta-analysis was undertaken to rank interventions and to make indirect comparisons. RESULTS: We included 11 RCTs with data for 7581 participants that compared nine different drugs. In studies of patients regardless of histology groups, targeted drugs (ramucirumab and nintedanib) yielded small overall survival gains of < 2.5 months over docetaxel, erlotinib provided no benefit, while immunotherapies (atezolizumab and pembrolizumab) delivered 5 to 6 months gain. Studies with patients stratified by histology confirmed the apparent superiority of immunotherapy (nivolumab and atezolizumab) over targeted treatments (ramucirumab, nintedanib, afatinib) providing between about 4 to 8 months OS gain over docetaxel. In network analysis immunotherapies consistently ranked higher than alternatives irrespective of population histology and outcome measure. CONCLUSION: Our review indicates that nivolumab, pembrolizumab and atezolizumab provide superior survival benefits compared to other licensed drugs for late stage NSCLC. Patient gains from these immunotherapies are substantial compared to the expected average survival with chemotherapy (docetaxel) of < 1 year for people with squamous histology and about 1.25 year for those with non-squamous histology.

Comparative efficacy and safety of licensed treatments for previously treated non-small cell lung cancer: A systematic review and network meta-analysis.

PURPOSE: This systematic review with network meta-analysis compared the efficacy and safety of currently licensed second-line treatments in patients with late stage non-small cell lung cancer (NSCLC). METHODS: Randomised controlled trials (RCTs) of participants with advanced/metastatic NSCLC receiving second/third line treatments were screened. We searched electronic databases (MEDLINE; EMBASE; Web of Science) from January, 2000 to July, 2017. Two reviewers screened bibliographic records, extracted data, and assessed risk of bias of included studies. The outcomes were overall survival (OS), progression-free survival (PFS), and drug-related grade 3-5 adverse-events (AEs). We pooled study-specific hazard ratios (HR; for OS and PFS) and risk ratios (RR; for AEs) using conventional and network-meta-analyses, and ranked interventions by the surface under the cumulative ranking curve. FINDINGS: We included 11 RCTs (7,581 participants) comparing nine drugs. All drugs except for erlotinib significantly improved OS compared to docetaxel. Nivolumab was the highest ranking drug followed by atezolizumab and pembrolizumab. There was no significant difference in OS across these three drugs (HR = 0.98, 95% CI 0.79, 1.21 for nivolumab vs atezolizumab; HR = 0.98, 95% CI 0.77, 1.25 for nivolumab vs pembrolizumab). For PFS, ramucirumab + docetaxel and nivolumab were the drugs with the highest ranking. All interventions except ramucirumab + docetaxel had a reduced risk for severe drug-related AEs vs. docetaxel. Of the drugs with the highest ranking on AEs, nivolumab was significantly safer compared to atezolizumab (RR = 0.55, 95% CI 0.38, 0.79) or pembrolizumab (RR = 0.52, 95% CI 0.34, 0.81). IMPLICATIONS: Nivolumab, pembrolizumab and atezolizumab exhibited superior benefit/risk balance compared to other licensed drugs used late stage NSCLC. Our results indicate that the use of immunotherapies in people diagnosed with non-specific late stage NSCLC should be promoted. The use of docetaxel may now be judged irrelevant as a comparator intervention for approval of new drugs for second line treatment of NSCLC. STUDY REGISTRATION NUMBER: PROSPERO CRD42017065928.

How are evidence and knowledge used in orthopaedic decision-making? Three comparative case studies of different approaches to implementation of clinical guidance in practice.

BACKGROUND: The uptake and use of clinical guidelines is often insufficient to change clinical behaviour and reduce variation in practice. As a consequence of diverse organisational contexts, the simple provision of guidelines cannot ensure fidelity or guarantee their use when making decisions. Implementation research in surgery has focused on understanding what evidence exists for clinical practice decisions but limits understanding to the technical, educational and accessibility issues. This research aims to identify where, when and how evidence and knowledge are used in orthopaedic decision-making and how variation in these factors contributes to different approaches to implementation of clinical guidance in practice. METHODS: We used in-depth case studies to examine guideline implementation in real-life surgical practice. We conducted comparative case studies in three English National Health Service hospitals over a 12-month period. Each in-depth case study consisted of a mix of qualitative methods including interviews, observations and document analysis. Data included field notes from observations of day-to-day practice, 64 interviews with NHS surgeons and staff and the collection of 121 supplementary documents. RESULTS: Case studies identified 17 sources of knowledge and evidence which influenced clinical decisions in elective orthopaedic surgery. A comparative analysis across cases revealed that each hospital had distinct approaches to decision-making. Decision-making is described as occurring as a result of how 17 types of knowledge and evidence were privileged and of how they interacted and changed in context. Guideline implementation was contingent and mediated through four distinct contextual levels. Implementation could be assessed for individual surgeons, groups of surgeons or the organisation as a whole, but it could also differ between these levels. Differences in how evidence and knowledge were used contributed to variations in practice from guidelines. CONCLUSION: A range of complex and competing sources of evidence and knowledge exists which influence the working practices of healthcare professionals. The dynamic selection, combination and use of each type of knowledge and evidence influence the implementation and use of clinical guidance in practice. Clinical guidelines are a fundamental part of practice, but represent only one type of evidence influencing clinical decisions. In the orthopaedic speciality, other distinct sources of evidence and knowledge are selected and used which impact on how guidelines are implemented. New approaches to guideline implementation need to appreciate and incorporate this diverse range of knowledge and evidence which influences clinical decisions and to take account of the changing contexts in which decisions are made.

Double Reading in Breast Cancer Screening: Cohort Evaluation in the CO-OPS Trial.

Purpose To investigate the effect of double readings by a second radiologist on recall rates, cancer detection, and characteristics of cancers detected in the National Health Service Breast Screening Program in England. Materials and Methods In this retrospective analysis, 805 206 women were evaluated through screening and diagnostic test results by extracting 1 year of routine data from 33 English breast screening centers. Centers used double reading of digital mammograms, with arbitration if there were discrepant interpretations. Information on reader decisions, with results of follow-up tests, were used to explore the effect of the second reader. The statistical tests used were the test for equality of proportions, the χ2 test for independence, and the t test. Results The first reader recalled 4.76% of women (38 295 of 805 206 women; 95% confidence interval [CI]: 4.71%, 4.80%). Two readers recalled 6.19% of women in total (49 857 of 805 206 women; 95% CI: 6.14%, 6.24%), but arbitration of discordant readings reduced the recall rate to 4.08% (32 863 of 805 206 women; 95% CI: 4.04%, 4.12%; P < .001). A total of 7055 cancers were detected, of which 627 (8.89%; 95% CI: 8.22%, 9.55%; P < .001) were detected by the second reader only. These additional cancers were more likely to be ductal carcinoma in situ (30.5% [183 of 600] vs 22.0% [1344 of 6114]; P < .001), and additional invasive cancers were smaller (mean size, 14.2 vs 16.7 mm; P < .001), had fewer involved nodes, and were likely to be lower grade. Conclusion Double reading with arbitration reduces recall and increases cancer detection compared with single reading. Cancers detected only by the second reader were smaller, of lower grade, and had less nodal involvement. © RSNA, 2018.

Ixazomib for Relapsed or Refractory Multiple Myeloma: Review from an Evidence Review Group on a NICE Single Technology Appraisal.

Ixazomib is an oral proteasome inhibitor used in combination with lenalidomide plus dexamethasone (IXA-LEN-DEX) and licensed for relapsed or refractory multiple myeloma. As part of a single technology appraisal (ID807) undertaken by the National Institute of Health and Care Excellence, the Evidence Review Group, Warwick Evidence was invited to independently review the evidence submitted by the manufacturer of ixazomib, Takeda UK Ltd. The main source of clinical effectiveness data about IXA-LEN-DEX came from the Tourmaline-MM1 randomized controlled trial in which 771 patients with relapsed or refractory multiple myeloma received either IXA-LEN-DEX or placebo-LEN-DEX as their second-, third-, or fourth-line treatment. Takeda estimated the cost effectiveness of IXA-LEN-DEX using a de-novo partitioned-survival model with three health states (pre-progression, post-progression, and dead). In their first submission, this model was used to estimate the cost effectiveness of IXA-LEN-DEX vs. bortezomib plus dexamethasone (BORT-DEX) in second-line treatment, and of IXA-LEN-DEX vs. LEN-DEX in third-line treatment. To estimate the relative clinical performance of IXA-LEN-DEX vs. BORT-DEX, Takeda conducted network meta-analyses for important outcomes. The network meta-analysis for overall survival was found to be flawed in several respects, but mainly because a hazard ratio input for one of the studies in the network had been inverted, resulting in a large inflation of the claimed superiority of IXA-LEN-DEX over BORT-DEX and a considerable overestimation of its cost effectiveness. In subsequent submissions, Takeda withdrew second-line treatment as an option for IXA-LEN-DEX. The manufacturer's first submission comparing IXA-LEN-DEX with LEN-DEX for third-line therapy employed Tourmaline-MM1 data from third- and fourth-line patients as proxy for a third-line population. The appraisal committee did not consider this reasonable because randomization in Tourmaline-MM1 was stratified according to one previous treatment and two or more previous treatments. A further deficiency was considered to be the manufacturer's use of interim survival data rather than the most mature data available. A second submission from the company focussed on IXA-LEN-DEX vs. LEN-DEX as third- or fourth-line treatment (the two or more previous lines population) and a new patient access scheme was introduced. Covariate modeling of survival outcomes was proposed using the most mature survival data. The Evidence Review Group's main criticisms of the new evidence included: the utility associated with the pre-progression health state was overestimated, treatment costs of ixazomib were underestimated, survival models were still associated with great uncertainty, leading to clinically implausible anomalies and highly variable incremental cost-effectiveness ratio estimates, and the company had not explored a strong assumption that the survival benefit of IXA-LEN-DEX over LEN-DEX would be fully maintained for a further 22 years beyond the observed data, which encompassed only approximately 2.5 years of observation. The appraisal committee remained unconvinced that ixazomib represented a cost-effective use of National Health Service resources. Takeda's third submission offered new base-case parametric models for survival outcomes, a new analysis of utilities, and proposed a commercial access agreement. In a brief critique of the third submission, the Evidence Review Group agreed that the selection of appropriate survival models was problematic and at the request of the National Institute for Health Care and Excellence investigated external sources of evidence regarding survival outcomes. The Evidence Review Group considered that some cost and utility estimates in the submission may have remained biased in favor of ixazomib. As a result of their third appraisal meeting, the committee judged that for the two to three prior therapies population, and at the price agreed in a commercial access agreement, ixazomib had the potential to be cost effective. It was referred to the Cancer Drugs Fund so that further data could accrue with the aim of diminishing the clinical uncertainties.

Cost-Effectiveness of Community-based Human Immunodeficiency Virus Self-Testing in Blantyre, Malawi.

Background: Human immunodeficiency virus self-testing (HIVST) is effective, with scale-up underway in sub-Saharan Africa. We assessed cost-effectiveness of adding HIVST to existing facility-based HIV testing and counseling (HTC) services. Both 2010 (initiate at CD4 <350 cells/µL) and 2015 (initiate all) World Health Organization (WHO) guidelines for antiretroviral treatment (ART) were considered. Methods: A microsimulation model was developed to evaluate cost-effectiveness, from both health provider and societal perspectives, of an HIVST service implemented in a cluster-randomized trial (CRT; ISRCTN02004005) in Malawi. Costs and health outcomes were evaluated over a 20-year time horizon, using a discount rate of 3%. Probabilistic sensitivity analysis was conducted to account for parameter uncertainty. Results: From the health provider perspective and 20-year time horizon, facility HTC using 2010 WHO ART guidelines was the least costly ($294.71 per person; 95% credible interval [CrI], 270.79-318.45) and least effective (11.64 quality-adjusted life-years [QALYs] per person; 95% CrI, 11.43-11.86) strategy. Compared with this strategy, the incremental cost-effectiveness ratio (ICER) for facility HTC using 2015 WHO ART guidelines was $226.85 (95% CrI, 198.79-284.35) per QALY gained. The strategy of facility HTC plus HIVST, using 2010 WHO ART guidelines, was extendedly dominated. The ICER for facility HTC plus HIVST, using 2015 WHO ART guidelines, was $253.90 (95% CrI, 201.71-342.02) per QALY gained compared with facility HTC and using 2015 WHO ART guidelines. Conclusions: HIVST may be cost-effective in a Malawian population with high HIV prevalence. HIVST is suited to an early HIV diagnosis and treatment strategy. Clinical Trials registration: ISRCTN02004005.