Rachel Court

Background: Newborn screening using whole genome sequencing is being evaluated in numerous projects across the world, including Genomics England Limited’s Generation Study. It presents considerable challenges for policy advisors, not least, given the logistics of simultaneously evaluating the evidence for the suggested 200 rare genetic conditions. The ‘genotype-first’ approach has the potential for harms through overdiagnosis, and benefits are uncertain. Objective: To assess different approaches to evaluating whole genome sequencing for newborn screening to inform the development of a robust method of evaluation for informing policy decisions. Methods: We approached the objective with systematic review methods for a sample of five conditions (considering gene penetrance, expressivity, accuracy and effectiveness of whole genome sequencing and effect of earlier treatment) (search inception to November 2023), evaluated the National Institutes of Health [US] Clinical Genome Resource (ClinGen) as an alternative evidence source for the five conditions and we compared this to a review of genomic studies of newborn screening cohorts reporting penetrance for pathogenic variants of any paediatric condition (search inception to February 2024). We undertook a methodological review of economic evaluations of whole genome sequencing/whole exome sequencing (search inception to January 2024) and explored public views on evaluating whole genome sequencing. Data sources: MEDLINE (Ovid), EMBASE (Ovid), Web of Science, Science Citation Index (via Clarivate), the Cochrane Library (via Wiley), cost-effectiveness analysis registry and American Economic Association electronic bibliography. Actionability reports and scores from the Clinical Genome Resource website (downloaded 30 April 2024). Results: The traditional review approach identified 268 studies reporting the genetic spectrum of individuals with the five conditions or benefits of earlier, symptomatic treatment. No evidence on the penetrance and expressivity or the accuracy or effectiveness of whole genome sequencing in newborns was identified. A review of 200 conditions would take a team of five reviewers 23 years to complete. Clinical Genome Resource reviews were available for four or five conditions. All four ‘actionability’ ratings disagreed with the findings of our reviews. Our review of 14 genomic studies of newborn screening cohorts found insufficient information to allow individual highly penetrant pathogenic variants for any condition to be identified. None of the 86 economic evaluations of whole genome sequencing or whole exome sequencing were set in a screening context. Some micro-costing studies are available that could help understand the resource use and costs associated with whole genome sequencing. Following a series of patient and public involvement meetings, attendees appreciated the uncertainties of whole genome sequencing. A wider stakeholder perspective is needed to inform policy decisions. Limitations: Although we only examined five conditions in depth, the consistency in lack of data suggests that our conclusions are robust. Conclusions: The systematic review approach for evaluating whole genome sequencing of newborns identified a paucity of high-quality evidence. Extending the review to all 200 conditions is not feasible. Currently, the use of existing genome resources and review of genomic studies of newborn screening cohorts are not viable alternatives. The cost-effectiveness of whole genome sequencing in a newborn screening context is unknown. Future work: Large-scale collaborative research is required to evaluate the short- and long-term harms, benefits and economic implications of whole genome sequencing for screening newborns. We propose a staged approach to evaluation, considering only conditions with pathogenic variants with high penetrance to minimise harm from overdiagnosis. Study registration: This study is registered as PROSPERO CRD42023475529. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis Programme (NIHR award ref: NIHR159928) and is published in full in Health Technology Assessment ; Vol. 29, No. 65. See the NIHR Funding and Awards website for further award information.

Background: Cardiovascular disease remains a leading cause of morbidity and mortality worldwide. This series of systematic reviews and meta-analyses synthesised evidence on the effectiveness, comparative effectiveness and cost-effectiveness of pharmacological and non-pharmacological interventions for primary cardiovascular disease prevention. Methods: Five systematic reviews and meta-analyses were conducted using rigorous methods, including comprehensive searches, duplicate screening, risk-of-bias assessments and adherence to reporting guidelines. An umbrella review summarised evidence from 95 systematic reviews. A machine learning study developed a parallel Convolutional Neural Network algorithm with 96.4% recall and 99.1% precision for study screening. A network meta-analysis compared preventive strategies across 139 trials (1,053,772 participants). Simulation modelling projected the population impact of policy interventions, and a cost-effectiveness review appraised eight United Kingdom-based economic evaluations. Results: The umbrella review found that antiplatelets reduced major cardiovascular disease events in 8/17 meta-analyses (relative risks 0.85–0.97), while statins reduced cardiovascular disease mortality (relative risks 0.71–0.89), all-cause mortality (relative risks 0.66–0.93) and major cardiovascular disease events (relative risks 0.59–0.90). sodium-glucose transport protein 2 inhibitors reduced major cardiovascular disease events by 8% (relative risk 0.92, 95% confidence interval 0.89 to 0.95) and all-cause mortality by 6% (relative risk 0.94, 95% confidence interval 0.90 to 0.98). Non-pharmacological interventions showed limited evidence, though vitamin D (relative risks 0.93–0.94) and dietary changes (relative risk 0.91, 95% confidence interval 0.85 to 0.97) had some benefits. The network meta-analysis found that antihypertensives (relative risk 0.76, 95% confidence interval 0.64 to 0.90), intensive blood pressure control (relative risk 0.66, 95% confidence interval 0.46 to 0.96), statins (relative risk 0.81, 95% confidence interval 0.71 to 0.91) and multifactorial lifestyle interventions (relative risk 0.75, 95% confidence interval 0.61 to 0.92) significantly reduced composite cardiovascular disease events and mortality. Blood pressure lowering also reduced all-cause mortality (relative risk 0.82, 95% confidence interval 0.71 to 0.94). Simulation modelling projected substantial population-level health gains. National salt reduction programmes could prevent 1900–48,000 cardiovascular disease deaths annually, while tobacco control initiatives could avert 15,500 deaths yearly. In the United Kingdom, salt reduction could prevent 4450 deaths annually, and transfat elimination could prevent 1700–3500 deaths yearly. Cost-effectiveness analyses found most interventions had incremental cost-effectiveness ratio below £20,000–30,000 per quality-adjusted life-year. However, intensive diabetes treatment and enhanced motivational interviewing exceeded £55,000/quality-adjusted life-year, indicating low value for money. Limitations: Limitations included residual confounding, heterogeneity in simulation models and a lack of head-to-head trials for some interventions. More research is needed on non-pharmacological interventions, policy implementation and health economic analyses. Conclusions: This series supports antihypertensives, statins and multifactorial lifestyle interventions as core strategies for primary cardiovascular disease prevention. Policy interventions show potential for large-scale impact, and most approaches are cost-effective. Future research should prioritise head-to-head trials, implementation studies and health economic analyses to optimise prevention efforts. Funding: This synopsis presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number 17/148/05.

Background: Cardiovascular disease accounts for substantial mortality and healthcare costs worldwide. Numerous interventions exist for primary prevention but lack head-to-head comparisons on long-term impacts. Objective: To determine the comparative effectiveness of interventions for primary cardiovascular disease prevention through network meta-analysis of randomised trials. Data sources: MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, conference abstracts and trial registries from inception to March 2021. Review methods: Randomised controlled trials of pharmacologic therapies, nutritional supplements, lifestyle changes, behavioural approaches and health policies with at least 6 months’ follow-up were included. Pairwise and network meta-analyses were conducted for all-cause mortality, cardiovascular disease events, coronary heart disease and cardiovascular disease mortality. Results: Data from 139 randomised trials, including 1,053,772 participants, proved suitable for quantitative synthesis. Blood pressure-lowering medications (risk ratio 0.82, 95% confidence interval 0.71 to 0.94), tight blood pressure control (risk ratio 0.66, 95% confidence interval 0.46 to 0.96), statins (risk ratio 0.81, 95% confidence interval 0.71 to 0.91) and multifactorial lifestyle interventions (risk ratio 0.75, 95% confidence interval 0.61 to 0.92) reduced composite cardiovascular events and mortality. Limitations: Residual confounding may exist. Few direct head-to-head comparisons limited differentiation between some specific modalities. Conclusions: We found evidence that blood pressure treatments, intense blood pressure targets, statins when appropriate and multifactorial lifestyle changes are the most effective strategies for primary prevention of cardiovascular disease, with unclear effects from other interventions. These findings can inform clinical guidelines and health policies prioritising interventions. Funding: This research 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.

Background: This review assessed the clinical- and cost-effectiveness of point-of-care tests to guide the initial management of people presenting with suspected acute respiratory infection. Methods: Searches for systematic reviews, randomised controlled trials and cost–utility studies were conducted in May 2023. Sources included MEDLINE, Epistemonikos, EMBASE, Cochrane Central Register of Controlled Trials, the Cost-effectiveness Analysis Registry and reference checking. Eligible studies included people (≥ 16 years) making initial contact with the health system with symptoms suggestive of acute respiratory infection. Risk of bias in randomised controlled trials was assessed using the Cochrane risk-of-bias tool. The Drummond checklist was used for cost–utility studies. Meta-analyses of clinical outcomes were conducted to estimate summary risk ratios with 95% confidence intervals. Study characteristics and main results were summarised narratively and tabulated. Results: Clinical effectiveness: Fourteen randomised controlled trials were included; all had a high risk of bias. Ten randomised controlled trials analysed point-of-care tests for C-reactive protein. Compared with usual care, the effects on hospital admissions and mortality were highly uncertain due to sparse data. Three randomised controlled trials had heterogeneous findings on the resolution of symptoms/time to full recovery. The risk of re-consultations increased in patients receiving C-reactive protein point-of-care tests (pooled risk ratio 1.61, 95% confidence interval 1.07 to 2.41; four studies). There was a reduction in antibiotics initially prescribed (C-reactive protein point-of-care tests vs. usual care: pooled risk ratio 0.75, 95% confidence interval 0.68 to 0.84; nine studies). The effects of procalcitonin point-of-care tests compared with usual care on hospital admission, escalation of care, and duration of symptoms were very uncertain as only one randomised controlled trial was included. The study found a large reduction in antibiotic prescriptions within 7 days. Two studies revealed a large reduction in initial antibiotic prescriptions for Group A streptococcus point-of-care tests versus usual care. Only one study compared an influenza point-of-care test with usual care. The effect of the antibiotics prescribed was very uncertain. No deaths occurred in either treatment group. Cost-effectiveness: Six of the 17 included cost–utility studies were judged to be directly applicable to our review, 4 of which focused on the C-reactive protein point-of-care test. The results suggested that the C-reactive protein point-of-care test is potentially cost-effective; these studies were generally limited to capturing only short-term costs and consequences. One study evaluated 14 different point-of-care tests for Group A streptococcus; none were cost-effective compared with usual care. A further study evaluated two rapid tests (Quidel for influenza [Quidel Corp, San Diego, CA, USA], and BinaxNOW [Binax, Inc., Portland, ME, USA]) for the pneumococcal antigen) compared to culture/serology and found that they were not cost-effective. Limitations: Rapid synthesis methods were used, so relevant studies may have been missed. No evidence was identified for several review questions. Conclusion: C-reactive protein point-of-care test may reduce the number of patients given an antibiotic prescription but could increase the rate of re-consultations. C-reactive protein point-of-care test may potentially be cost-effective but existing estimates were based on very small and uncertain gains in quality-adjusted life-years and only accounted for short-term costs and consequences. There was very limited or an absence of evidence for other point-of-care tests. Future work: Research is needed to explore the impact of point-of-care tests on triaging decisions across different clinical settings and to quantify the longer-term health and cost consequences. Study registration: This study is registered as PROSPERO CRD42023429515. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis programme (NIHR award ref: NIHR159946) and is published in full in Health Technology Assessment; Vol. 29, No. 13. See the NIHR Funding and Awards website for further award information.

Background There is widespread interest in the use of innovative ventilation technologies to improve clinical outcomes across the 13–20 million people each year globally that receive invasive ventilation on an intensive care unit. This scoping review aims to summarise the volume and nature of evidence underpinning the use of 22 innovative ventilation technologies in adults and children. Methods We searched MEDLINE, EMBASE, Cochrane library and other key databases from 2010 to May 2024 for primary studies and systematic reviews that evaluated the use of 22 innovative ventilation technologies in adults and children requiring, or at risk of requiring, invasive ventilation. We defined an innovative ventilation technology as a ventilation approach not currently recommended by clinical guidelines due to lack of or uncertainty of evidence. We summarise findings as evidence maps. Results Our search identified 22,274 records of which we included 851 studies (564 primary studies; 277 systematic reviews; 10 economic evaluation studies). Over 50% of studies focussed on non-invasive respiratory support strategies to reduce the risk of a primary tracheal intubation (n=319, 37%) or re-intubation (n=130, 15%). We identified ten or fewer studies for seven technologies, including phrenic nerve stimulation, artificial intelligence, and ultra-low tidal volume ventilation. Few studies include children (n=128, 15%) or report patient-focussed outcomes (n=19, 2%). Conclusions For many technologies despite being used in clinical practice, the available evidence is currently inadequate to determine its clinical effectiveness, particularly in children. Key technologies need to be evaluated in high-quality multi-centre clinical trials that report patient-focussed outcomes.

Background: Hybrid closed-loop systems are a new class of technology to manage type 1 diabetes mellitus. The system includes a combination of real-time continuous glucose monitoring from a continuous glucose monitoring device and a control algorithm to direct insulin delivery through an insulin pump. Evidence suggests that such technologies have the potential to improve the lives of people with type 1 diabetes mellitus and their families. Aim: The aim of this appraisal was to assess the clinical effectiveness and cost-effectiveness of hybrid closed-loop systems for managing glucose in people who have type 1 diabetes mellitus and are having difficulty managing their condition despite prior use of at least one of the following technologies: continuous subcutaneous insulin infusion, real-time continuous glucose monitoring or flash glucose monitoring (intermittently scanned continuous glucose monitoring). Methods: A systematic review of clinical effectiveness and cost-effectiveness evidence following predefined inclusion criteria informed by the aim of this review. An independent economic assessment using iQVIA CDM to model cost-effectiveness. Results: The clinical evidence identified 12 randomised controlled trials that compared hybrid closed loop with continuous subcutaneous insulin infusion + continuous glucose monitoring. Hybrid closed-loop arm of randomised controlled trials achieved improvement in glycated haemoglobin per cent [hybrid closed loop decreased glycated haemoglobin per cent by 0.28 (95% confidence interval −0.34 to −0.21), increased per cent of time in range (between 3.9 and 10.0 mmol/l) with a MD of 8.6 (95% confidence interval 7.03 to 10.22), and significantly decreased time in range (per cent above 10.0 mmol/l) with a MD of −7.2 (95% confidence interval −8.89 to −5.51), but did not significantly affect per cent of time below range (< 3.9 mmol/l)]. Comparator arms showed improvements, but these were smaller than in the hybrid closed-loop arm. Outcomes were superior in the hybrid closed-loop arm compared with the comparator arm. The cost-effectiveness search identified six studies that were included in the systematic review. Studies reported subjective cost-effectiveness that was influenced by the willingness-to-pay thresholds. Economic evaluation showed that the published model validation papers suggest that an earlier version of the iQVIA CDM tended to overestimate the incidences of the complications of diabetes, this being particularly important for severe visual loss and end-stage renal disease. Overall survival’s medium-term modelling appeared good, but there was uncertainty about its longer-term modelling. Costs provided by the National Health Service Supply Chain suggest that hybrid closed loop is around an annual average of £1500 more expensive than continuous subcutaneous insulin infusion + continuous glucose monitoring, this being a pooled comparator of 90% continuous subcutaneous insulin infusion + intermittently scanned continuous glucose monitoring and 10% continuous subcutaneous insulin infusion + real-time continuous glucose monitoring due to clinical effectiveness estimates not being differentiated by continuous glucose monitoring type. This net cost may increase by around a further £500 for some systems. The Evidence Assessment Group base case applies the estimate of −0.29% glycated haemoglobin for hybrid closed loop relative to continuous subcutaneous insulin infusion + continuous glucose monitoring. There was no direct evidence of an effect on symptomatic or severe hypoglycaemia events, and therefore the Evidence Assessment Group does not include these in its base case. The change in glycated haemoglobin results in a gain in undiscounted life expectancy of 0.458 years and a gain of 0.160 quality-adjusted life-years. Net lifetime treatment costs are £31,185, with reduced complications leading to a net total cost of £28,628. The cost-effectiveness estimate is £179,000 per quality-adjusted life-year. Conclusions: Randomised controlled trials of hybrid closed-loop interventions in comparison with continuous subcutaneous insulin infusion + continuous glucose monitoring achieved a statistically significant improvement in glycated haemoglobin per cent in time in range between 3.9 and 10 mmol/l, and in hyperglycaemic levels. Study registration: This study is registered as PROSPERO CRD42021248512. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis programme (NIHR award ref: NIHR133547) and is published in full in Health Technology Assessment; Vol. 28, No. 80. See the NIHR Funding and Awards website for further award information.

Background: Assessment of newborn screening using whole genome sequencing (WGS) presents considerable challenges for policy advisors, not least given the logistics of simultaneously evaluating the evidence for 200 rare genetic conditions. The ‘genotype first’ approach has the potential for harms, and benefits are uncertain. Objective: To assess different approaches to evaluating WGS for newborn screening to inform the development of a robust method for informing policy decisions. Methods: We undertook ‘traditional’ reviews of five conditions using standard systematic review methods (considering gene penetrance, expressivity, and prevalence, the accuracy and effectiveness of WGS, and effect of earlier treatment) (search inception to November 2023), evaluated the NIH Clinical Genome Resource (ClinGen) for evidence on the five conditions, reviewed genomic studies of paediatric screening cohorts reporting penetrance for pathogenic variants (search inception to February 2024) and undertook a methodological review of economic evaluations of WGS/ whole exome sequencing (WES) (search inception to January 2024). We explored public views on evaluating WGS. Data sources: MEDLINE (Ovid), Embase (Ovid), Web of Science, Science Citation Index (via Clarivate), the Cochrane Library (via Wiley), CEA registry and Econlit. Actionability reports and scores were downloaded from the ClinGen website on 30 ^th April 2024. Results: The traditional review approach identified 221 studies that either reported on the genetic spectrum of individuals with the five conditions or provided limited evidence about the benefits of earlier treatment. No evidence about penetrance and expressivity or the accuracy or effectiveness of WGS in newborns was identified. ClinGen reviews were available for four of the five conditions. The ClinGen ‘actionability’ ratings for all four conditions disagreed with the findings of our traditional reviews. Our review of 14 genomic studies of newborn screening cohorts found insufficient information to allow individual highly penetrant pathogenic variants for any condition to be identified for consideration in a screening programme. None of the 86 economic evaluations of WGS or WES were set in a screening context. Some micro-costing studies are available that could help understand the resource use and costs associated with WGS. Following a series of PPI meetings, attendees appreciated the uncertainties of WGS and suggested that a wider stakeholder perspective was needed to inform policy decisions. Limitations: Although we only examined five conditions in depth, the consistency in lack of data suggests our conclusions are robust. Conclusions: The traditional systematic review approach for evaluating WGS of newborns identified a paucity of high-quality evidence. Extending the review to all 200 conditions is not feasible and is unlikely to yield the level of evidence required by policy advisors. The use of existing genome resources and review of genomic studies of newborn screening cohorts were not found to be viable alternatives. The cost-effectiveness of WGS in a newborn screening context is unknown. Future work: Large-scale collaborative research is required to evaluate the short- and long-term harms, benefits and economic implications of WGS for screening newborns. We propose a staged approach to evaluation considering only conditions with pathogenic variants with very high penetrance to minimise harm from overdiagnosis. Study registration: The protocol for this study is registered on PROSPERO: CRD42023475529 Funding details: This study/project is funded by the NIHR Evidence Synthesis Programme (ESG_HTA_NIHR159928). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care.

Background: Lung cancer is one of the most common types of cancer in the United Kingdom. It is often diagnosed late. The 5-year survival rate for lung cancer is below 10%. Early diagnosis may improve survival. Software that has an artificial intelligence-developed algorithm might be useful in assisting with the identification of suspected lung cancer. Objectives: This review sought to identify evidence on adjunct artificial intelligence software for analysing chest X-rays for suspected lung cancer, and to develop a conceptual cost-effectiveness model to inform discussion of what would be required to develop a fully executable cost-effectiveness model for future economic evaluation. Data sources: The data sources were MEDLINE All, EMBASE, Cochrane Database of Systematic Reviews, Cochrane CENTRAL, Epistemonikos, ACM Digital Library, World Health Organization International Clinical Trials Registry Platform, clinical experts, Tufts Cost-Effectiveness Analysis Registry, company submissions and clinical experts. Searches were conducted from 25 November 2022 to 18 January 2023. Methods: Rapid evidence synthesis methods were employed. Data from companies were scrutinised. The eligibility criteria were (1) primary care populations referred for chest X-ray due to symptoms suggestive of lung cancer or reasons unrelated to lung cancer; (2) study designs that compared radiology specialist assessing chest X-ray with adjunct artificial intelligence software versus radiology specialists alone and (3) outcomes relating to test accuracy, practical implications of using artificial intelligence software and patient-related outcomes. A conceptual decision-analytic model was developed to inform a potential full cost-effectiveness evaluation of adjunct artificial intelligence software for analysing chest X-ray images to identify suspected lung cancer. Results: None of the studies identified in the searches or submitted by the companies met the inclusion criteria of the review. Contextual information from six studies that did not meet the inclusion criteria provided some evidence that sensitivity for lung cancer detection (but not nodule detection) might be higher when chest X-rays are interpreted by radiology specialists in combination with artificial intelligence software than when they are interpreted by radiology specialists alone. No significant differences were observed for specificity, positive predictive value or number of cancers detected. None of the six studies provided evidence on the clinical effectiveness of adjunct artificial intelligence software. The conceptual model highlighted a paucity of input data along the course of the diagnostic pathway and identified key assumptions required for evidence linkage. Limitations: This review employed rapid evidence synthesis methods. This included only one reviewer conducting all elements of the review, and targeted searches that were conducted in English only. No eligible studies were identified. Conclusions: There is currently no evidence applicable to this review on the use of adjunct artificial intelligence software for the detection of suspected lung cancer on chest X-ray in either people referred from primary care with symptoms of lung cancer or people referred from primary care for other reasons. Future work: Future research is required to understand the accuracy of adjunct artificial intelligence software to detect lung nodules and cancers, as well as its impact on clinical decision-making and patient outcomes. Research generating key input parameters for the conceptual model will enable refinement of the model structure, and conversion to a full working model, to analyse the cost-effectiveness of artificial intelligence software for this indication. Study registration: This study is registered as PROSPERO CRD42023384164. Funding: This award was funded by the National Institute for Health and Care Research (NIHR) Evidence Synthesis programme (NIHR award ref: NIHR135755) and is published in full in Health Technology Assessment; Vol. 28, No. 50. See the NIHR Funding and Awards website for further award information.

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.