What is the effectiveness of systematic population-level screening programmes for reducing the burden of cardiovascular diseases?

IWHO HEALTH EVIDENCE NETWORK SYNTHESIS REPORT 71 What is the effectiveness of systematic population-level screening programmes for reducing the burden of cardiovascular diseases? Christian Ulrich Eriksen | Oxana Rotar | Ulla Toft | Torben Jørgensen The Health Evidence Network The Health Evidence Network (HEN) is an information service for public health decision-makers in the WHO European Region, in action since 2003 and initiated and coordinated by the WHO Regional Office for Europe under the umbrella of the WHO European Health Information Initiative (a multipartner network coordinating all health information activities in the WHO European Region). HEN supports public health decision-makers to use the best available evidence in their own decision- making and aims to ensure links between evidence, health policies and improvements in public health. The HEN synthesis report series provides summaries of what is known about the policy issue, the gaps in the evidence and the areas of debate. Based on the synthesized evidence, HEN proposes policy considerations, not recommendations, for policy-makers to formulate their own recommendations and policies within their national context. The Noncommunicable Diseases Integrated Prevention and Control programme The Noncommunicable Disease Integrated Prevention and Control programme of the WHO Regional Office for Europe has three main functions: leading the integrated response of policies to address noncommunicable diseases (NCDs) at the regional and country levels; managing the major NCDs (cardiovascular diseases, cancer, chronic respiratory diseases and diabetes) across the continuum of care from prevention to early detection, screening, diagnosis, treatment, rehabilitation, secondary prevention and end-of-life/palliative care; and leading the NCD health systems response. It focuses on priority action areas and interventions in order to achieve regional and global targets to reduce premature mortality, reduce the disease burden, improve the quality of life and make healthy life expectancy more equitable, as called for in the WHO strategies and action plans for NCD prevention and control in particular and for sustainable development in general. WHO Health Evidence Network synthesis report 71 What is the effectiveness of systematic population-level screening programmes for reducing the burden of cardiovascular diseases? Christian Ulrich Eriksen | Oxana Rotar | Ulla Toft | Torben Jørgensen Abstract Cardiovascular diseases (CVDs) remain the main cause of death in the WHO European Region. This systematic literature review assesses whether systematic screening programmes for CVD risk factors and preclinical CVDs across general populations can lower the CVD burden in society. Based on several high-quality randomized controlled trials with large numbers of participants, the results clearly showed that screening for CVD risk factors has no effect on lowering CVD morbidity and mortality in society. Studies showed that screening for preclinical CVDs slightly reduces mortality and negative outcomes related to abdominal aortic aneurysm; however, these results may be outdated, as smoking has declined and treatment has improved since the studies were completed. Results on screening for atrial fibrillation and other preclinical CVDs have not yet been published. In summary, the current evidence indicates that screening for CVD risk factors does not reduce the CVD burden. Keywords SYSTEMATIC REVIEW, MASS SCREENING, CARDIOVASCULAR DISEASES, MORTALITY, POPULATION, NATIONAL SCREENING PROGRAMME Address requests about publications of the WHO Regional Office for Europe to: Publications WHO Regional Office for Europe UN City, Marmorvej 51 DK-2100 Copenhagen Ø, Denmark Alternatively, complete an online request form for documentation, health information, or for permission to quote or translate, on the Regional Office website (http://www.euro.who.int/pubrequest). ISSN 2789-9217 ISBN 978 92 890 5537 6 © World Health Organization 2021 Some rights reserved. This work is available under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 IGO licence (CC BY-NC-SA 3.0 IGO; https://creativecommons.org/licenses/by-nc-sa/3.0/igo). Under the terms of this licence, you may copy, redistribute and adapt the work for non-commercial purposes, provided the work is appropriately cited, as indicated below. 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The responsibility for the interpretation and use of the material lies with the reader. In no event shall WHO be liable for damages arising from its use. The named authors alone are responsible for the views expressed in this publication. Printed in Luxembourg iii CONTENTS Abbreviations ..................................................................................................................................iv Acknowledgements ......................................................................................................................v Summary ........................................................................................................................................ viii 1. Introduction ...................................................................................................................................1 1.1 Background ...........................................................................................................................1 1.2 Methodology ......................................................................................................................4 2. Results .............................................................................................................................................5 2.1 Study characteristics .......................................................................................................5 2.2 Population-level screening for CVD risk and CVD risk factors................ 7 2.3 Population-level screening for preclinical CVDs .............................................9 3. Discussion ....................................................................................................................................12 3.1 Strengths and limitations of this review .............................................................12 3.2 Contextual factors in the WHO European Region related to screening programmes for CVD risk and CVD risk factors ............... 13 3.3 Contextual factors in the WHO European Region related to screening programmes for preclinical CVDs ............................................. 16 3.4 Future research ............................................................................................................... 18 3.5 Policy considerations................................................................................................... 18 4. Conclusions ................................................................................................................................20 References .........................................................................................................................................21 Annex 1. Search strategy ........................................................................................................... 31 Annex 2. Studies excluded after full-text review ........................................................ 40 Annex 3. Risk of bias in the included studies ............................................................... 54 Annex 4. Data extraction .........................................................................................................70 Annex 5. Detailed results of the meta-analyses.......................................................... 98 iv ABBREVIATIONS AAA abdominal aortic aneurism AF atrial fibrillation CAC coronary artery calcification CIS Commonwealth of Independent States CP carotid plaque CVD cardiovascular disease ESC European Society of Cardiology IHD ischaemic heart disease NCD noncommunicable disease PAD peripheral arterial disease RCT randomized controlled trial SCORE Systematic Coronary Risk Estimation (tool) vACKNOWLEDGEMENTS WHO would like to thank all the Member State representatives, technical experts and non-state actors who participated in the technical consultation on screening in February 2019, and the WHO European Conference on Screening in February 2020, both of which were organized by the WHO Regional Office for Europe, and acknowledges their valuable contributions to the preliminary discussions, European situation analysis and background paper for this report. WHO would also like to thank Cherian Varghese, Gojka Roglic and Taskeen Khan at WHO headquarters for their review of this report. The authors would also like to acknowledge the support of Carsten Juhl, Associate Professor at the Department of Sports Science and Clinical Biomechanics, University of Southern Denmark, Denmark, and Asiiat Alieva, a researcher at the Laboratory of Noncommunicable Diseases, Almazov National Medical Research Centre, Russian Federation, who assisted with the study selection. This report and related activities to it were made possible with financial support provided by the Government of Denmark, Government of Germany and the Government of the Russian Federation in the context of the WHO Regional Office for Europe. The views expressed herein can in no way be taken to reflect the official opinion of these Member States. Authors Christian Ulrich Eriksen Research Assistant, Section for Health Promotion and Prevention, Centre for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark Oxana Rotar Head of Laboratory of Noncommunicable Diseases, Almazov National Medical Research Centre and WHO Collaborating Centre on Cardiovascular Diseases, eHealth and Value-based Care, St Petersburg, Russian Federation Ulla Toft Clinical Professor of Health Promotion and Prevention, Department of Public Health, Faculty of Health and Medical Sciences, University of Copenhagen and Head of Section, Health Promotion and Prevention, Centre for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark vi Torben Jørgensen Professor Emeritus, University of Copenhagen and Professor, Aalborg University and Centre for Clinical Research and Prevention, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark Peer reviewers Delphine De Smedt Assistant Professor, Department of Public Health and Primary Care, Gent University, Belgium (on behalf of the European Association of Preventive Cardiology) Ian Graham Professor of Cardiovascular Medicine, Trinity College, Dublin (on behalf of the European Society of Cardiology) Pekka Jousilahti Research Professor, Finnish Institute for Health and Welfare, Helsinki, Finland Francesca Romana Pezzella Stroke Neurologist, San Camillo Forlanini Hospital, Rome, Italy and European Stroke Organisation Fellow, European Stroke Organisation Marilena Vrana Manager, Patients and Research, European Heart Network, Brussels, Belgium Editorial team, WHO Regional Office for Europe Noncommunicable Diseases Integrated Prevention and Control programme Nino Berdzuli, Director, Division of Country Health Programmes Bente Mikkelsen, former Director, Division of Noncommunicable Diseases and Promoting Health through the Life-course Jill Farrington, Coordinator, Noncommunicable Diseases María Lasierra Losada, Technical Officer, Noncommunicable Diseases vii Health Evidence Network (HEN) Natasha Azzopardi Muscat, Director, Division of Country Health Policies and Systems Kristina Mauer-Stender, former Acting Director, Division of Information, Evidence, Research and Innovation Marge Reinap, Editor in Chief (ad interim) Tanja Kuchenmüller, Editor in Chief (outgoing) Tarang Sharma, Series Editor (outgoing) Tyrone Reden Sy, Managing Editor Krista Kruja, Managing Editor Ashley Craig, Technical Editor The HEN Secretariat is part of the Division of Country Health Policies and Systems (previously the Division of Information, Evidence, Research and Innovation) at the WHO Regional Office for Europe. HEN synthesis reports are commissioned works that are subjected to international peer review, and the contents are the responsibility of the authors. They do not necessarily reflect the official policies of the Regional Office. viii SUMMARY The issue Cardiovascular diseases (CVDs) are the main cause of death in the WHO European Region, accounting for nearly 4 million deaths (43% of all deaths) in 2016. Population- level screening is a public health strategy to reduce the burden of disease in society by identifying and managing preclinical disease or the risk factors of disease. In the screening pathway, early identification in people who have not sought medical attention for CVD symptoms is followed by appropriate management of positive cases. Several studies that examined systematic screening programmes for reducing the CVD risk in general populations have questioned their effectiveness. Therefore, a comprehensive analysis of the current evidence on the CVD burden and the impact and potential adverse effects of screening for CVD risk factors and preclinical CVDs (including health economic considerations) is needed to inform national and regional decision-makers about feasible interventions for national screening programmes. The synthesis question The objective of this report is to address the question: “What is the effectiveness of systematic population-level screening programmes for reducing the burden of cardiovascular diseases?” Types of evidence A systematic review of peer-reviewed and selected grey literature in English and Russian was conducted between March and May 2020 to identify population-level randomized controlled trials (RCTs) examining the impact of screening for CVD risk factors (both behavioural factors (smoking, harmful use of alcohol, unhealthy nutrition and physical inactivity) and biological factors (high blood pressure, raised blood sugar, dyslipidaemia and raised body mass index)) preclinical CVD conditions (abdominal aortic aneurysm (AAA), atrial fibrillation (AF), peripheral arterial disease (PAD), coronary artery calcification (CAC) and carotid plaques (CPs)) on reducing the CVD burden (mortality, morbidity and costs) in general populations. No geographical or time limits were applied and only RCTs that included randomization, interventions related to CVD risk factors and/or preclinical CVD conditions and impact analysis at a population level were considered. ix Results A total of 33 studies were identified; these related to 22 RCTs, of which 14 focused on screening for CVD risk and CVD risk factors (two ongoing), four on AAA, two on AF (both ongoing) and two on a combination of preclinical CVDs (one ongoing). Following an assessment of methodological quality, all studies were included in a narrative synthesis, and a subset of studies with appropriate outcome data was included in a series of meta-analyses. In addition, one case study from Sweden was selected to illustrate a possible model for a population-level screening programme for AAA. Based on several high-quality RCTs that included a large number of participants, the overall results clearly showed that screening for CVD risk and CVD risk factors has had no impact on lowering CVD morbidity and mortality in the general population. Moreover, serious adverse effects were identified (e.g. increased mortality). These studies were primarily conducted in western European countries, and the evidence can be difficult to transfer to other settings, such as south-eastern Europe and the Commonwealth of Independent States (CIS), owing to differences in national health-care systems and disease burdens. However, no high-quality RCTs have been conducted in these parts of the WHO European Region. There is, therefore, no evidential basis to recommend population-level screening for CVD risk and CVD risk factors in Member States of the Region. At present, the benefit of screening for AAA is uncertain. Although some studies have reported reductions in AAA-related negative outcomes, there was no reduction in total mortality. However, recent changes in risk factors and less traumatic treatment may negate the apparent effects of AAA screening. Similarly, the results of ongoing population-level RCTs are needed to establish whether screening for AF can lower the CVD burden. Although one study on screening for a combination of preclinical CVDs showed promising results for reducing mortality, more evidence is needed to determine the effect of such programmes. Policy considerations Based on the review findings, the main policy considerations for Member States of the WHO European Region are to: • review existing systematic population-level screening programmes for CVD risk and CVD risk factors (if such already exist), avoid initiating new screening programmes for CVD risk and CVD risk factors, and consider xalternative methods to achieve the desired outcomes in reducing the CVD burden; • re-evaluate current systematic population-level programmes for screening for AAA, taking into account the changes in risk factors and improved treatment; and • await the results of population-level RCTs on the effectiveness of screening for AF and other preclinical CVDs before considering the implementation of such programmes. 11. INTRODUCTION 1.1 Background 1.1.1 CVDs in the WHO European Region CVDs are a diverse range of diseases that include cerebrovascular disease, heart failure, heart rhythm disturbances (such as AF), ischaemic heart disease (IHD), PAD and valvular heart disease. CVDs are currently the main cause of death in the WHO European Region: in 2016 they accounted for nearly 4 million deaths (43% of all deaths) (1). Within the Region, CVD mortality increased from 1990 to 1994 and then decreased, with a faster rate of decline from 2003 onwards. The CVD mortality rate has steadily decreased in Member States of the European Union since the 1980s and in south-eastern European countries since the 1990s. In the CIS, the CVD mortality rate increased throughout the 1990s but has been declining since 2003 (2,3). Modelling studies in several European countries have explored the possible causes of the decline in CVD mortality. These have shown that improved treatment explains one third to half of the reduction and an overall decrease in risk factors explains from half to two thirds (3), despite increases in the prevalence of obesity and type 2 diabetes. In the Region, the CVD morbidity rate – measured as hospital discharge with CVD – increased until 2004 and levelled off thereafter (3). By comparison, the CVD morbidity rate continued to increase in south-eastern Europe until 2007 and in the CIS until 2013. This levelling off in CVD morbidity is probably a result of improved health care and a decline in some risk factors, counteracted by increased longevity. However, considerable variations in CVD morbidity and mortality exist across Europe. Disability-adjusted life-years are an aggregate indicator of years lost due to premature death and years of healthy life lost due to disability: in 2017 CVDs accounted for 64 million disability-adjusted life-years (23% of the total) in Europe (4). Sex differences can be observed for CVD morbidity and mortality: men have a higher mortality risk, while women more often experience disability from CVD (3). In 2015 the total costs of CVDs in the Region were €210 billion, of which 53% were direct health costs (4). Over seven decades of research, several modifiable and non-modifiable risk factors for CVD have been identified. Individual modifiable risk factors are smoking, unhealthy nutrition, physical inactivity, harmful use of alcohol, dyslipidaemia, raised body mass index, raised blood sugar and high blood pressure (hypertension); these can explain 75% of IHD (5,6). Non-modifiable risk factors are age, sex, ethnicity, hereditary factors and familial occurrence (including familial hypercholesterolaemia (7)). Preclinical CVDs include AAA, AF, CAC, CPs and PAD. WHAT IS THE EFFECTIVENESS OF SYSTEMATIC POPULATION-LEVEL SCREENING PROGRAMMES FOR REDUCING THE BURDEN OF CARDIOVASCULAR DISEASES? WHO HEALTH EVIDENCE NETWORK SYNTHESIS REPORT 2 Population-level screening is a public health strategy to reduce the burden of diseases in society by identifying preclinical disease or risk factors for disease early among persons who have not sought medical attention for disease symptoms (8) or are not aware of any symptoms. Preventive interventions or treatment can then be applied to reduce mortality and morbidity rates. In a systematic programme of population-level screening and/or health checks, a predefined, apparently healthy population is approached in an organized and quality-assured way. The process starts by identifying people who are eligible for screening and then invites them for screening, refers positive cases for diagnosis, intervention, treatment and follow- up, and ends by reporting the outcomes (9). This should not be confused with case-finding, which is conducted in daily clinical practice and involves assessing patients indicated to be at risk of a condition when they seek help from the health- care system. Case-finding is an integrated part of the health-care system in any country, whereas systematic screening is a specific systematic programme in which the authorities invite citizens to participate (9). This report focuses on the latter. Popular beliefs about systematic screening are that early detection equals better prognosis and that, theoretically, screening can lead to a reduction in the burden of diseases; however, there are also risks because not all screening programmes are beneficial. The task of any public health service is to identify beneficial programmes by appraising the evidence (10). Adverse effects of screening are reported as overdiagnosis, misdiagnosis and causing a false sense of security (11). Therefore, it is important to only initiate systematic screening when specific criteria are met. In 1968 WHO published the first overview of guidelines on the principles and practice of systematic screening for diseases (12). Since then, several more criteria have been suggested; an updated overview of criteria for systematic screening programmes was published in 2008 (Box 1) (13). To be effective on a population level, a systematic screening programme should reduce morbidity and/or mortality of the disease in question without causing unacceptable adverse effects (9). The programme should also be acceptable to citizens and conducted at a reasonable cost. Box 1. Overview of proposed screening criteria, 1968–2008 1. The screening programme should respond to a recognized need. 2. The objectives of screening should be defined at the outset. 3. There should be a defined target population. 4. There should be scientific evidence of screening programme effectiveness. 5. The programme should integrate education, testing, clinical services and programme management. 36. There should be quality assurance, with mechanisms to minimize the potential risks of screening. 7. The programme should ensure informed choice, confidentiality and respect for autonomy. 8. The programme should promote equity and access to screening for the entire target population. 9. Programme evaluation should be planned from the outset. 10. The overall benefits of screening should outweigh the harm. Source: Andermann et al., 2008 (13). 1.1.2 Strategies to promote cardiovascular health WHO Member States have endorsed global and regional strategies and action plans for the prevention and control of noncommunicable diseases (NCDs) (14,15). Their implementation is monitored through the global monitoring framework, which includes a set of nine voluntary NCD targets, including those related to reductions in NCD premature mortality and in the prevalence of diabetes, hypertension and obesity (16). Furthermore, Sustainable Development Goal 3 includes target 3.4.1 to reduce premature mortality (between 30 and 70 years of age) from four major NCDs (cancer, chronic respiratory disease, CVD and diabetes) by a third in 2030 (17). As part of the Global Action Plan for the Prevention and Control of Noncommunicable Diseases 2013–2020 (14), WHO identified a set of cost-effective (NCD “best buys”) and other recommended interventions for the prevention and control of NCDs. These can be implemented in Member States, as appropriate to their national contexts (18). These include an NCD best buy on CVD risk and CVD risk factor assessment and management that recommends drug therapy and counselling for individuals with a history of stroke or heart attack or individuals at high risk of a cardiovascular event within the next 10 years. The Noncommunicable Disease Integrated Prevention and Control programme of the WHO Regional Office for Europe is leading a cross-programmatic initiative to increase the effectiveness, maximize the benefits and minimize the harm of screening. A short guide on screening and a policy brief (9,19) were launched at the 2020 WHO European Conference on Screening (20). Box 1 contd WHAT IS THE EFFECTIVENESS OF SYSTEMATIC POPULATION-LEVEL SCREENING PROGRAMMES FOR REDUCING THE BURDEN OF CARDIOVASCULAR DISEASES? WHO HEALTH EVIDENCE NETWORK SYNTHESIS REPORT 4 1.1.3 Objectives of this report Several studies that examined systematic population-level screening programmes for reducing the CVD risk in populations (e.g. the Inter991 trial (21)) have questioned their effectiveness in reducing the CVD burden in society. They are supported by a 2019 Cochrane review on the effectiveness of systematic offers of health checks (i.e. multiple tests in a non-symptomatic individual) that included studies both on a population level and targeting specific groups (22). The review concluded that these are not likely to reduce the burden of morbidity and mortality and may lead to overtreatment. This report builds on the Cochrane review by including evidence from more recent studies and on studies focusing more specifically on the effect on the CVD burden at population level (including health economic considerations) and assessing potential adverse effects of systematic population-level screening for CVDs. Thus, this systematic review assesses the impact of systematic population- level screening programmes on the CVD burden (mortality, morbidity and costs). It focuses on CVD risk and CVD risk factors, including screening for single and multiple risk factors (e.g. using a risk score) and for preclinical CVD conditions (i.e. AAA, AF, CAC, CPs and PAD). It aims to inform both national and regional decision-makers who are involved in, or considering implementation of, systematic screening to reduce CVDs in the WHO European Region. 1.2 Methodology A systematic review of peer-reviewed and selected grey literature was conducted between March and May 2020 in English and Russian. No language or time restrictions were applied in the study selection. The methodological quality of included studies was appraised and outcomes were analysed narratively or through a meta-analysis of comparable outcomes. The search of peer-reviewed literature retrieved 6191 records in English after removal of duplicates and five records in Russian. The search of grey literature retrieved 682 records. Of these, 93 articles were selected for full-text review, with 10 further studies identified during this process. In all, 33 studies (representing 22 RCTs) fulfilled the criteria for inclusion (21,23–54). Annex 1 provides further details of the search and selection strategy. Annexes 2–5 give the full details of studies examined, selected and excluded. 1. Full title: A Randomised Non-pharmacological Intervention Study for Prevention of Ischaemic Heart Disease Inter99. 52. RESULTS Section 2.1 presents the study characteristics of all included studies. Sections 2.2 and 2.3 present the results from both the narrative analysis and meta-analyses: for outcomes where meta-analysis was possible, the results of the meta-analyses are presented; for outcomes where meta-analysis was not possible, the results are presented narratively. 2.1 Study characteristics 2.1.1 Screening for CVD risk and CVD risk factors Of the 22 included RCTs, 14 concerned the effectiveness of screening for CVD risk and CVD risk factors (reported in 23 studies (21,23–44)). See Annex 4 for a full list of studies with references. No RCTs were identified through the searches in Russian. Follow-up data were available for 12 RCTs: four in Sweden reported in five studies (31,32,38,39,42), four conducted in the United Kingdom (reported in five studies (27,28,30,40,41)), three in Denmark (reported in 10 studies (21,23,24,25,26,33,34, 35,36,37)) and one in the former East Germany (29). Two RCTs are ongoing: one in Denmark (43) and the other in India (44). Age groups ranged from 18 to 65 years, but most RCTs focused on narrower age groups (e.g. 40–59 years). Three RCTs reported follow-up over 20 years; across all RCTs, follow-up ranged from one to 30 years. A total of 174 073 participants were included, with five RCTs including only men (n = 36 396). Baseline data were collected between 1963 and 2001; eight RCTs collected data before 1990. Although the interventions varied, all RCTs comprised a health check (including clinical examinations, laboratory tests and questionnaires), followed by health counselling and initiation of medical treatment when hypertension or hypercholesterolaemia was identified. Two of the RCTs with follow-up used a risk score (21,30), and the remainder assessed several relevant risk factors. No studies focused solely on hypertension and none focused on screening for familial hypercholesterolaemia. For most studies, the risk of bias was judged as “low” or only as raising “some concerns”. See Annex 3 for an assessment of the bias risk and Annex 4 for a description of the data extracted from each study. Two of the 14 RCTs are ongoing (43,44). The Check your Health RCT is designed to investigate the impact of offering preventive health checks (including screening for behavioural and clinical measures) and calculating a risk score to adults aged 30–49 years in Denmark (43). The second RCT is evaluating a community-based intervention on prevention of stroke mortality among individuals aged 50 years WHAT IS THE EFFECTIVENESS OF SYSTEMATIC POPULATION-LEVEL SCREENING PROGRAMMES FOR REDUCING THE BURDEN OF CARDIOVASCULAR DISEASES? WHO HEALTH EVIDENCE NETWORK SYNTHESIS REPORT 6 or older in 32 rural villages in India (44). In the latter, participants will be screened for diabetes, hypertension and stroke, and followed up with treatment and home visits. See Annex 4 for a detailed description of both RCTs. 2.1.2 Screening for preclinical CVDs Of the 22 included RCTs, eight focused on preclinical CVDs (reported in 10 studies (45–54)). See Annex 4 for a full list of studies with references. Of these, four focused on AAA (reported in six studies (45–50)), two on AF (both of these are ongoing) (51,52) and two on combined screening for preclinical CVDs (one is ongoing) (53,54). Screening for AAA. Of the four RCTs on the effectiveness of screening for AAA, two took place in the United Kingdom (the Chichester study (45–47) and the Multicentre Aneurysm Screening Study (48)), one in Australia (50) and one in Denmark (49). All RCTs were initiated in the late 1980s and 1990s, and the interventions consisted of abdominal ultrasonographic screening. Follow-up ranged from five to 15 years. The total number of participants in all four RCTs was 134 271; of these, 9342 were women. The age groups investigated ranged from 64 to 83 years. Most studies had a low risk of bias (see Annex 3). Annex 4 provides additional study details and describes the data extracted from each study. Screening for AF. Both RCTs on the effectiveness of screening for AF are ongoing (51,52). The Swedish STROKESTOP trial,2 initiated in 2012, involves population-level screening in two Swedish regions comprising more than 25 000 individuals aged 75–76 years (51). In the United States of America, the VITAL-AF trial3 will test whether screening for AF results in increased detection of AF after one year and in a reduced stroke incidence after two years (52). Participants are aged 65 years or older. The intention is to include more than 16 000 patients in each study arm. Enrolment was initiated in July 2018. Screening for other preclinical CVDs. Two RCTs were identified on combined screening for preclinical CVDs (53,54), both in Denmark; of these, one is ongoing (54). The RCT with follow-up investigated screening for AAA, hypertension and PAD among 50 156 men aged 65–74 years (53). The ongoing DanCavas trial4 is a study of population-level screening for subclinical CVDs (AAA, AF, CAC and PAD) (54). It was initiated in 2014 and will follow 45 000 men aged 65–74 years over 10 years. 2. Full title: Systematic ECG Screening for Atrial Fibrillation Among 75 Year Old Subjects in the Region of Stockholm and Halland, Sweden. 3. Full title: Screening for Atrial Fibrillation in an Ambulatory Clinic Population: the VITAL-AF Study. 4. Full title: Danish Cardiovascular Screening Trial II. 72.2 Population-level screening for CVD risk and CVD risk factors In the identified studies as a whole, the main outcomes of population-level screening for CVD risk and CVD risk factors were morbidity and mortality, health-care utilization, disability pension and certified sickness absence, and adverse effects. 2.2.1 Morbidity and mortality Findings from the reviewed studies and the meta-analyses show that population- level screening for CVD risk and CVD risk factors does not reduce total mortality or morbidity and mortality from CVDs, IHD and stroke (21,23,24,29,31,32,38,41,42). Table 1 summarizes the findings of the meta-analyses and Annex 5 provides more detailed results. Table 1. Summary of meta-analysis findings Screen/outcome Number of studies Relative risk of disease 95% confidence interval Screening for CVD risk/ risk factors Total mortality 9 1.00 0.97–1.03 CVD morbidity and mortality 2 1.02 0.95–1.10 CVD mortality 5 1.04 0.73–1.49 IHD morbidity and mortality 4 1.00 0.97–1.05 IHD mortality 2 1.00 0.90–1.12 Stroke morbidity and mortality 3 1.05 0.95–1.17 Screening for AAA Total mortality 4 0.99 0.98–1.00 AAA mortality 4 0.63 0.41–0.97 AAA rupture 2 0.66 0.40–1.09 WHAT IS THE EFFECTIVENESS OF SYSTEMATIC POPULATION-LEVEL SCREENING PROGRAMMES FOR REDUCING THE BURDEN OF CARDIOVASCULAR DISEASES? WHO HEALTH EVIDENCE NETWORK SYNTHESIS REPORT 8 2.2.2 Health-care utilization Four studies reported changes in prescribed medications (27,30,35,40). However, there was no indication of increased or decreased use of medication related to CVDs (e.g. antihypertensive or lipid-lowering drugs). Three studies reported on whether screening for CVD risk and CVD risk factors could reduce the total number of hospitalizations (i.e. not only those related to CVDs) (38,40,41): of these, one reported fewer hospitalizations in the screened groups after 18 months (40), whereas the other two showed no reductions in hospitalizations (38,41). In two studies, screening for CVD risk and CVD risk factors did not seem to reduce the number of physician visits (40,41): one of these reported more physical examinations and laboratory investigations among participants in the screened groups compared with the unscreened group, but with no difference in the rates of presumptive diagnoses (40). Finally, one study reported that screening did not increase the number of contacts with the health-care system or reduce the average direct cost of health care per participant (25). Thus, population-level screening for CVD risk factors does not appear to reduce health-care utilization. 2.2.3 Disability pension and certified sickness absence One study reported that screening did not reduce the proportion of participants receiving disability pension after five years (39). Two studies reported the effect on sickness absence (40,41): one reported a higher rate of long-term sickness absence (15 days or over) in the screened group compared with the unscreened group after 18 months, and the other showed no difference between the groups after nine years. Therefore, population-level screening for CVD risk and CVD risk factors does not appear to reduce the proportion of people who receive disability pension or are on certified sickness leave; however, in the short term, it may lead to a higher proportion of people on long-term sickness leave. 2.2.4 Adverse effects One RCT found a higher incidence of deaths among women from diseases associated with behavioural risk factors in areas with high participation rates, indicating that screening may increase the risk of these outcomes (33,34). Another study reported a higher risk of stroke among the screened population compared with the unscreened group (23). These results suggest that a risk of adverse effects may arise from population-level screening for CVD risk. Furthermore, no psychological adverse effects of screening for CVD risk and CVD risk factors have been identified (26,36). One study found no difference in the use 9of selected psychotropic medications or in hospital admissions due to psychiatric diagnoses before and after screening (35). Thus, the available evidence suggests no psychological adverse effects related to introducing systematic population-level screening for CVD risk and CVD risk factors. In addition, one study reported a lower uptake of screening for CVD risk and CVD risk factors among people with a lower socioeconomic status (37). As a consequence, possible preventive measures will be more readily available to people in higher socioeconomic positions. This has raised concerns about whether screening programmes can increase social inequalities. 2.3 Population-level screening for preclinical CVDs Most of the evidence on the effectiveness of screening for preclinical CVDs was related to AAA, and most of the RCTs on AAA were complete. However, most RCTs on AF and other preclinical CVDs were ongoing, thus limiting the amount of available data on these conditions. 2.3.1 Screening for AAA Three countries have published data on population-level screening for AAA: Australia, Denmark and England (United Kingdom) (45–50). Most of the studies on screening for AAA reported the effects on morbidity and mortality related to AAA and to the cost–effectiveness of interventions, as assessed by life-years gained. Morbidity and mortality. The meta-analyses showed that population-level screening for AAA led to reductions in AAA mortality among men (45,48–50), but not to a reduction in AAA ruptures (45,48) or total mortality (45,48–50) among men. A study that included women did not find that screening reduced AAA mortality or AAA rupture in women (46,47). Cost–effectiveness. A study from the United Kingdom reported that the mean incremental (i.e. additional) cost per person offered screening was £100 (range: £82–£118; approximately US$ 133) at 10-year follow-up (48). A comparison of the additional cost with life-years gained (i.e. by the avoidance of AAA mortality) showed a mean incremental cost–effectiveness ratio for AAA mortality of £7600 (around US$ 10 149; range: £5100–£13 000). However, no data were provided on the incremental cost–effectiveness for total mortality. A Danish RCT reported an incremental cost–effectiveness ratio for total mortality of €157 per life-year gained (around US$ 186; WHAT IS THE EFFECTIVENESS OF SYSTEMATIC POPULATION-LEVEL SCREENING PROGRAMMES FOR REDUCING THE BURDEN OF CARDIOVASCULAR DISEASES? WHO HEALTH EVIDENCE NETWORK SYNTHESIS REPORT 10 range: −€3292 to €4401) and an estimated €179 per quality-adjusted life-year gained (around US$ 212; range: €−4083 to €4682) (50). The confidence limits indicated no evidence that screening was cost-effective for reducing total mortality. In addition to these studies, Case study 1 describes a possible model for a population- level screening programme for AAA from Sweden. Case study 1. The Swedish nationwide AAA screening programme Aim of the programme AAA are usually asymptomatic until they rupture, which is fatal in more than 80% of cases. Screening aims to detect AAAs before they rupture. Based on the results of four RCTs (45,48–50) showing that screening led to a reduction in AAA-related mortality, the Swedish AAA screening programme was introduced in 2006 and achieved nationwide coverage in 2015. Content When they reached 65 years of age, all men were invited for a single ultrasound scan of the abdominal aorta. AAA was defined as an aortic diameter of above 29 mm. Follow-up and treatment followed international criteria indicating that men with an AAA of diameter 30–54 mm should be followed up by lifelong ultrasound surveillance, and those with an AAA of diameter greater than 54 mm or growth rate of 10 mm per year should be referred for surgical treatment. Coverage and results Attendance during the first eight years was 84%. Screening was calculated to result in a reduction in AAA-related mortality, but with no reduction in total mortality (55). In 2014 AAA-related mortality was estimated to have been reduced by 39% since 2000 (six years before the screening programme was launched) (55). This corresponded to an annual reduction of 90 premature deaths from AAA. Arguments for and against the programme Arguments for the programme is that it fulfils most of the screening criteria (Box 1) and has a very high attendance rate. The programme appears to reduce AAA-related mortality (55,56), and one study claimed that the programme is cost-effective (55). 11 2.3.2 Screening for AF No evidence was found to determine whether population-level screening for AF can reduce the incidence of stroke. Only two RCTs addressed this question and both are ongoing (51,52). 2.3.3 Screening for other preclinical CVDs One study showed that combined screening for AAA, hypertension and PAD may slightly reduce total mortality, but not CVD mortality or AAA-related mortality (53). The results of another ongoing study are pending (54). Arguments against the programme are that results from the four RCTs, which took place in the 1980s and 1990s, may be outdated. The occurrence of AAA has since declined in most western European and North America countries, as well as in Australia and New Zealand, from 4–9% in the late 1990s and early 2000s to below 2% in the 2010s (56). This decline parallels the decline in smoking in Sweden, which is the major risk factor for AAA. In addition, less traumatic treatment methods for AAA have been introduced. There is a risk that screening may lead to overdiagnosis and overtreatment, as not all AAA continue to grow. Analyses focusing on the first three years of the Swedish national screening programme concluded that AAA screening in Sweden did not substantially contribute to the large observed reduction in AAA mortality and that the most of the reduction was caused by other factors such as reduced rates of smoking (57). Case study 1 contd WHAT IS THE EFFECTIVENESS OF SYSTEMATIC POPULATION-LEVEL SCREENING PROGRAMMES FOR REDUCING THE BURDEN OF CARDIOVASCULAR DISEASES? WHO HEALTH EVIDENCE NETWORK SYNTHESIS REPORT 12 3. DISCUSSION 3.1 Strengths and limitations of this review An important strength of this systematic review is its stringent approach to searching for, selecting, appraising, and analysing studies. Strict inclusion criteria were employed: studies had to be RCTs performed in a geographically well-defined population, randomized at population level before study initiation, and include an intention-to-treat evaluation method. These criteria ensured that only evidence on the outcomes of national screening programmes for CVD risk and CVD risk factors and preclinical CVDs at population level were included. The strength of the evidence was assessed by determining the risk of bias. A limitation of the review methodology is that authors of the studies were not contacted to provide missing information. Compared with previous systematic reviews on CVD risk and CVD risk factors, this review included fewer studies (owing to the requirement for results to be analysed on a population level), but longer follow-up times (22,58). Despite these differences, there was good agreement with the findings of previous reviews. The review included studies initiated between the 1960s and the 2000s (i.e. both older and more recent studies) but, as most studies need at least 10 years of follow-up, more recent studies could not be included. However, older and newer studies had similar results. The evidence originated mainly from western European countries: only one study conducted in an eastern European country was identified (the former East Germany (29)). Therefore, the limited available evidence does not indicate that screening for CVD risk and CVD risk factors would be effective in eastern European settings. However, relevant evidence from eastern European countries is unlikely to be available soon because high-quality population-level RCTs take several years to reach a conclusion. The only completed RCTs on screening for preclinical CVDs were related to AAA. The identified RCTs on AF and combined screening for preclinical CVDs are ongoing, so no data are available on their outcomes. 13 3.2 Contextual factors in the WHO European Region related to screening programmes for CVD risk and CVD risk factors The review found that systematic population-level screening does not reduce total mortality or combined morbidity and mortality from CVDs, IHD and stroke and that screening for CVD risk and CVD risk factors does not reduce the number of new medications, the proportion of the population receiving a disability pension, or the number of physician visits or hospitalizations. These findings are in agreement with those of a Cochrane review of 15 large RCTs (n = 251 891) (22). The review included evidence on systematic population-level screening for CVD risk and CVD risk factors, and not on case-finding in clinical practice. An alternative to population-level screening is the use of more targeted screening programmes, such as workplace interventions. However, studies conducted in factories have consistently shown that screening performed in a work setting does not reduce the CVD burden. An important study of this type was a large WHO trial on the multifactorial prevention of coronary heart disease that was initiated in 1971; took place in 40 pairs of factories in Belgium, Italy, Poland and the United Kingdom; and included 60 000 participants (59). After six years, no significant effects of the intervention on total IHD, IHD mortality, myocardial infarction morbidity and total deaths were observed. Therefore, these more targeted screening programmes do not appear to reduce the CVD burden. The present report found that some risk of serious adverse effects (e.g. increased mortality) may arise from population-level screening for CVD risk, possibly as a result of overdiagnosis and overtreatment (22). It is usually recommended to follow clinical guidelines, such as European Society of Cardiology (ESC) guidelines, when planning a national screening programme; however, these guidelines were mainly developed for patient populations and not for general populations. In a Danish population-level study, the application of ESC clinical guidelines to the general population led to nearly half of the population aged between 40 and 60 years qualifying for medical preventive treatment (60); this finding suggests a considerable risk of overdiagnosis and overtreatment. A 2012 Cochrane review on screening and treatment for mild hypertension reports the possible negative effects of overtreatment (61). It concluded that this type of screening has not been shown to reduce mortality or morbidity, and that 9% of participants discontinued treatment because of its adverse effects. Another concern is that uptake of screening WHAT IS THE EFFECTIVENESS OF SYSTEMATIC POPULATION-LEVEL SCREENING PROGRAMMES FOR REDUCING THE BURDEN OF CARDIOVASCULAR DISEASES? WHO HEALTH EVIDENCE NETWORK SYNTHESIS REPORT 14 programmes is smaller among people with a lower socioeconomic status (37), which may increase social inequality. Although screening for CVD risk and CVD risk factors is not supported by the scientific literature, some countries have introduced such programmes (e.g. Albania, Austria, England (United Kingdom) and the Russian Federation). In some countries, the programmes have been criticized because of a lack of evidence to support systematic screening (62,63), not fulfilling their own goals (e.g. a participation rate of at least 75%) (64,65) and increasing social inequalities (66). In Norway, general screening of men and women aged 40–42 years was introduced in 1985 but abandoned in 1999 (67). It is difficult to get a current overview of the types of screening programmes that have been implemented in Europe and in which countries they exist because systematic information on such programmes is lacking. In summary, the findings of this review correspond with previous research on the impact of systematic population-level screening for CVD risk and CVD risk factors on reducing the CVD burden in society. Consequently, introducing national or regional screening programmes for CVD risk and CVD risk factors seems to have no beneficial effect. 3.2.1 Comparison with current prevention guidelines Most guidelines on CVD prevention relate to case-finding, that is, when a patient is already in contact with the health-care system. In this situation, it is relevant to measure factors such as the patient’s pulse, blood pressure and cholesterol level. However, in systematic population-level screening, health authorities invite citizens to come for screening via a national or regional programme. Therefore, what may benefit a patient seeking help in the health-care system seems not to be beneficial in the context of a population-level screening programme. Guidelines from various organizations on CVD prevention are widely used by health professionals in Europe. The recommendations on screening differ, and very few address systematic screening of the general population. ESC guidelines recommend screening programmes for hypertension to include all adults (68), and that systematic CVD risk assessment “may be considered” in men aged over 40 years and women aged over 50 years (69). The ESC does not recommend systematic screening of blood glucose levels in the general population to determine CVD risk (70). However, as shown in this review, the available evidence does not support the ESC recommendation on systematic population-level screening for hypertension. In accordance with the evidence identified in this review, the guidelines 15 of most organizations do not directly advocate systematic screening. For example, the United Kingdom National Screening Committee does not recommend screening for hypertension among children and young people (71) and does not recommend screening for hypertension and vascular risk among adults (72,73). The World Heart Federation advocates for screening for high-risk patients only (74), and the United Kingdom National Institute for Health and Clinical Excellence, the American Society of Hypertension and the International Society of Hypertension do not make direct recommendations for systematic population-level screening (75,76). Instead of recommending systematic screening, the general tendency is towards advocating for population-level initiatives such as taxation and a healthy environment to reduce the prevalence of CVDs (77). WHO does not recommend population-level screening programmes for CVDs, but instead proposes targeting those in primary care who may be at a higher risk owing to age or the presence of a risk factor (i.e. case-finding). The WHO Package of Essential Noncommunicable Disease Interventions protocol for assessment and management of cardiovascular risk uses diabetes mellitus, hypertension and smoking as entry points to target people at higher risk in primary health care (77). The later HEARTS technical package on risk-based CVD management, which uses updated WHO risk prediction charts, takes a similar approach by using diabetes mellitus, hypertension and smoking as entry points for CVD risk assessment (78). 3.2.2 Social and physical determinants influence CVD risk factors Social and physical determinants (e.g. available resources, infrastructure and social support) impact on the risk of developing CVDs, for example through behavioural risk factors such as high calorie intake, low physical activity, smoking and the harmful use of alcohol. Disease prevention strategies are based on the rationale that a small shift in CVD risk across an entire population could lead to a greater reduction in the disease burden than a large shift among those already at high risk (79). Population-level prevention strategies for NCDs include fiscal measures (i.e. taxation and subsidies); international, national and regional policy and legislation (e.g. smoke-free policies, rules for advertising, and food production); and local environmental changes that are “making the healthy choice the easy choice”, according to the 1986 WHO Ottawa Charter for Health Promotion (80). These strategies were further developed in the WHO Health in All Policies approach (81), which acknowledges that most aspects of health and well-being lie outside the health sector and are socially and economically formed. As literature on the impact of environmental changes on improving cardiovascular health is growing fast, recommendations to change the environment as the primary effort to reducing the WHAT IS THE EFFECTIVENESS OF SYSTEMATIC POPULATION-LEVEL SCREENING PROGRAMMES FOR REDUCING THE BURDEN OF CARDIOVASCULAR DISEASES? WHO HEALTH EVIDENCE NETWORK SYNTHESIS REPORT 16 CVD burden represent a potentially powerful and cost-effective strategy (82–84) instead of population-level screening. 3.3 Contextual factors in the WHO European Region related to screening programmes for preclinical CVDs 3.3.1 Screening for AAA The review found that screening for AAA reduces AAA mortality, but not AAA rupture or total mortality. These results are comparable to those of a 2007 Cochrane review (85), which included the same four RCTs (but with shorter follow-up periods). The Cochrane review concluded that screening of elderly men (aged over 65 years) reduced AAA-specific mortality by 40% after approximately three to five years of follow-up. The same was not found for women, but the studies may have had too few female participants to determine an effect. A previous meta-analysis of the same four studies reported a 2.7% reduction in total mortality after 15 years of follow-up (86), but this was not supported by the present review. The identified studies reported the cost–effectiveness of screening for AAA on reducing AAA mortality, but not on reducing total mortality. A cost–effectiveness analysis of AAA screening in men (which failed to meet the inclusion criteria) estimated an absolute risk reduction of 9.6 men per 10 000 invited for each 1% in AAA prevalence (87). The report concluded that one-time screening was cost- effective for AAA in men aged 65 years in the context of current AAA epidemiology and management. However, it recommended that the budgetary impact should also be considered, as the costs of this type of screening must be taken from other activities. The identified screening programmes for AAA fulfil most of the screening criteria (see Box 1) and have very high attendance rates. However, it is important to note that, besides age, the biggest risk factor for AAA is smoking (accounting for 75% of the AAA cases). However, the decline in smoking combined with less traumatic treatment (endovascular repair) means that the validity of the four RCTs that form the basis of current recommendations is questionable. These studies were initiated from 1988 to 1999; since then, the smoking prevalence in men has declined in many, but not all, European countries. Thus, the gain from screening for AAA is currently uncertain. 17 Based on data from the largest RCT on AAA (the Multicentre Aneurysm Screening Study), an estimated 176 men per 10 000 people invited (95% confidence interval: 150–202) are overdiagnosed (88). Out of 1334 people with screening-detected AAA, only 11.8% would be expected to avoid death, while the others would live longer as AAA patients (88). Moreover, as prevalence lowers, the benefit of screening decreases and overtreatment increases (57). Regarding the psychosocial consequences of AAA screening, having an AAA diagnosis may moderately impact physical health and perceived stress (89). Furthermore, a study that investigated the possibility of increased social inequality as a result of screening found social inequality in uptake, despite a high participation rate: 65.1% in the most deprived areas and 84.1% in the least deprived areas (90). It is unclear why smoking and former smoking is not used as a first-step screening before ultrasound examination is offered, as is routine practice in the United States AAA screening programme (91). An article exploring the ethical issues of AAA screening concluded that population-level screening for AAA is ethically justified because there are more beneficial than harmful effects (92). AAA screening programmes were recently initiated in Monaco, initiated in Sweden in 2006–2015 (55) and implemented in all countries of the United Kingdom in 2009–2013 (93,94). These programmes are all ongoing. The national programmes in Sweden and the United Kingdom are well described, including the age interval, year of initiation, quality assessment of the programmes, participation rate and effect. National programmes have also been debated but not introduced in Denmark, Finland, Italy and Norway (91). Regarding current CVD prevention guidelines, both ESC guidelines and the United Kingdom National Screening Committee recommend systematic screening for AAA by ultrasound for men aged over 65 years (95,96). In contrast, WHO makes no recommendation on population-level screening programmes for AAA, and this is not mentioned in the WHO “best buys” (18). 3.3.2 Screening for AF No evidence was identified on screening programmes for AF. Regarding current CVD prevention guidelines, both the ESC and the European Association of Cardio- Thoracic Surgery recommend that systematic screening for AF may be considered in persons aged over 75 years (97). In contrast, the United Kingdom National Screening Committee (98) does not recommend screening for three primary reasons: (i) different types of AF exist, and they may not have the same risk for WHAT IS THE EFFECTIVENESS OF SYSTEMATIC POPULATION-LEVEL SCREENING PROGRAMMES FOR REDUCING THE BURDEN OF CARDIOVASCULAR DISEASES? WHO HEALTH EVIDENCE NETWORK SYNTHESIS REPORT 18 stroke; (ii) it is unclear whether treatment for AF is effective in people identified through screening; and (iii) it is not known whether screening for AF is superior to the current approach (99). Similarly, WHO does not make any recommendation regarding population-level screening programmes for AF, and this is not mentioned among the WHO “best buys” (18). 3.3.3 Screening for other preclinical CVDs Only two included studies involved screening for other preclinical CVD conditions, and these included different combinations of preclinical CVD conditions (53,54). More studies are therefore needed to establish recommendation on screening for these conditions. 3.4 Future research Studies into screening for CVD risk and CVD risk factors at population level in countries of the WHO European Region have consistently shown no beneficial effect, despite including several high-quality RCTs with large numbers of participants. This means that population-level screening fails to fulfil the most important screening criterion: that there should be scientific evidence of screening programme effectiveness (Box 1, item 4). However, the studies were primarily conducted in western European countries with well-functioning health-care systems, where case-finding and relevant management among high-risk patients is implemented in clinical practice and the population has general access to medicine and health insurance. The findings may not be transferable to other settings (e.g. eastern Europe and the CIS) owing to differences in national health-care systems, disease burdens and societal factors (which may affect the outcomes of screening programmes); it is possible that countries with weaker health-care systems may benefit from population screening. Therefore, to provide an evidential basis for relevant recommendations, high-quality population-level RCTs on screening for CVD risk and CVD risk factors need to be conducted in eastern European and CIS countries. 3.5 Policy considerations Based on the review findings, the main policy considerations for Member States of the WHO European Region are to: • review existing systematic population-level screening programmes for CVD risk and CVD risk factors (if such already exist), avoid initiating new screening 19 programmes for CVD risk and CVD risk factors, and consider alternative methods to achieve the desired outcomes in reducing the CVD burden; • re-evaluate current systematic population-level programmes for screening for AAA, taking into account the changes in risk factors and improved treatment; and • await the results of population-level RCTs on the effectiveness of screening for AF and other preclinical CVDs before considering the implementation of such programmes. WHAT IS THE EFFECTIVENESS OF SYSTEMATIC POPULATION-LEVEL SCREENING PROGRAMMES FOR REDUCING THE BURDEN OF CARDIOVASCULAR DISEASES? WHO HEALTH EVIDENCE NETWORK SYNTHESIS REPORT 20 4. CONCLUSIONS Population-level screening for diseases is a widely accepted health-care strategy, but a systematic review of the literature showed that screening for CVD risk and CVD risk factors does not lower CVD morbidity and mortality at population level. The proposed screening criteria state that before a population-level screening programme is introduced in a country, the effect should be documented. However, most countries have not initiated studies to determine whether population-level screening for CVD risk and CVD risk factors can lower the CVD burden. In countries where high-quality studies have been performed, the lack of effect is evident. Except for one study, these have been performed in western European countries. Given these findings, population-level screening programmes for CVD risk and CVD risk factors cannot be recommended in the WHO European Region, and countries that have introduced such screening programmes should reconsider their efforts. However, it is important to stress that these findings do not concern case-finding among patients who are in contact with the health-care system, according to national and international guidelines. Screening for AAA was found to reduce relevant outcomes for the burden of AAA, but the evidence may be outdated owing to changes in important risk factors (such as smoking) and improved treatment options. Thus, more context-specific evidence is needed before screening for AAA can be recommended. As RCTs of systematic population-level screening for AF and other preclinical CVD conditions are still in progress, it is not yet possible to base any conclusions on them. A more promising option may be to promote societal changes by health promotion, following the 1986 WHO Ottawa Charter and Health in All Policies approach, to ensure that healthy choices are the easy choices. 21 REFERENCES 1. The data repository. In: Global Health Observatory (GHO) data [website]. Geneva: World Health Organization; 2020 (https://www.who.int/gho/database/en/, accessed 6 October 2020). 2. European Health for All database (HFA-DB). Copenhagen: WHO Regional Office for Europe; 2020 (https://gateway.euro.who.int/en/datasets/european-health-for-all- database/, accessed 25 October 2020). 3. Jakab M, Farrington J, Borgermans L, Mantingh F, editors. Health systems respond to noncommunicable diseases: time for ambition. Copenhagen: WHO Regional Office for Europe; 2018 (https://www.euro.who.int/__data/assets/pdf_file/0009/380997/ Book-NCD-HS.pdf, accessed 6 October 2020). 4. Wilkins E, Wilson L, Wickramasinghe K, Bhatnagar P, Leal J, Luengo-Fernandez R et al. European cardiovascular disease statistics 2017. Brussels: European Heart Network; 2017 (http://www.ehnheart.org/component/attachments/attachments. html?task=attachment&id=3115, accessed 6 October 2020). 5. Beaglehole R, Magnus P. The search for new risk factors for coronary heart disease: occupational therapy for epidemiologists? Int J Epidemiol. 2002;31(6):1117–22; author reply 34–5. doi: 10.1093/ije/31.6.1117. 6. O’Flaherty M, Sans-Menendez S, Capewell S, Jørgensen T. Epidemiology of atherosclerotic cardiovascular disease: scope of the problem and its determinants. In: Gielen S, De Backer G, Piepoli M, Wood D, editors. The ESC textbook of preventive cardiology. Oxford: Oxford University Press; 2015. doi: 10.1093/med/9780199656653.003.0001. 7. Mach F, Baigent C, Catapano AL, Koskinas KC, Casula M, Badimon L et al. 2019 ESC/ EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J. 2020;41(1):111–88. doi: 10.1093/eurheartj/ehz455. 8. Wald NJ. The definition of screening. J Med Screen. 2001;8(1):1. doi: 10.1136/jms.8.1.1. 9. Screening programmes: a short guide. Increase effectiveness, maximize benefits and minimize harm. Copenhagen: WHO Regional Office for Europe; 2020 (https://apps.who. int/iris/bitstream/handle/10665/330829/9789289054782-eng.pdf, accessed 6 October 2020). 10. Gray JAM, Patnick J, Blanks RG. Maximising benefit and minimising harm of screening. BMJ. 2008;336(7642):480–3. doi: 10.1136/bmj.39470.643218.94. 11. O’Sullivan JW, Albasri A, Nicholson BD, Perera R, Aronson JK, Roberts N et al. Overtesting and undertesting in primary care: a systematic review and meta-analysis. BMJ Open. 2018;8(2):e018557. doi: 10.1136/bmjopen-2017-018557. WHAT IS THE EFFECTIVENESS OF SYSTEMATIC POPULATION-LEVEL SCREENING PROGRAMMES FOR REDUCING THE BURDEN OF CARDIOVASCULAR DISEASES? WHO HEALTH EVIDENCE NETWORK SYNTHESIS REPORT 22 12. Wilson JMG, Jungner G. Principles and practice of screening for disease. Geneva: World Health Organization; 1968 (Public health papers No. 34; https://apps.who.int/iris/ bitstream/handle/10665/37650/WHO_PHP_34.pdf?sequence=17, accessed 6 October 2020). 13. Andermann A, Blancquaert I, Beauchamp S, Dery V. Revisiting Wilson and Jungner in the genomic age: a review of screening criteria over the past 40 years. Bull World Health Organ. 2008;86(4):317–9. doi: 10.2471/BLT.07.050112. 14. Global action plan for the prevention and control of noncommunicable diseases 2013–2020. Geneva: World Health Organization; 2013 (http://apps.who.int/iris/ bitstream/10665/94384/1/9789241506236_eng.pdf?ua=1, accessed 6 October 2020). 15. Action plan for the prevention and control of noncommunicable diseases in the WHO European Region 2016–2025. Copenhagen: WHO Regional Office for Europe; 2016 (https://www.euro.who.int/__data/assets/pdf_file/0008/346328/NCD-ActionPlan- GB.pdf, accessed 6 October 2020). 16. NCD Global Monitoring Framework. In: Noncommunicable diseases and mental health [website]. Geneva: World Health Organization; 2020 (https://www.who.int/ nmh/global_monitoring_framework/en/, accessed 6 October 2020). 17. Sustainable Development Goal 3: ensure healthy lives and promote well-being for all at all ages. In: Sustainable Development Knowledge Platform. New York: United Nations Department of Economic and Social Affairs; 2020 (https://sustainabledevelopment. un.org/topics/sustainabledevelopmentgoals, accessed 19 October 2020). 18. Tackling NCDs: “best buys” and other recommended interventions for the prevention and control of noncommunicable diseases. Geneva: World Health Organization; 2017 (WHO/NMH/NVI/17.9; https://apps.who.int/iris/bitstream/handle/10665/259232/ WHO-NMH-NVI-17.9-eng.pdf?sequence=1&isAllowed=y, accessed 6 October 2020). 19. Sagan A, McDaid D, Rajan S, Farrington J, McKee M. Screening: when is it appropriate and how can we get it right? Copenhagen: World Health Organization (acting as the host organization for, and secretariat of, the European Observatory on Health Systems and Policies); 2020 (Policy Brief 35; https://apps.who.int/iris/bitstream/ handle/10665/330810/Policy-brief-35-1997-8073-eng.pdf, accessed 6 October 2020). 20. WHO European Conference on Screening. Copenhagen: WHO Regional Office for Europe; 2020 (https://www.euro.who.int/__data/assets/pdf_file/0008/458549/meeting- report-screening-conference.pdf, accessed 19 October 2020). 21. Jørgensen T, Jacobsen RK, Toft U, Aadahl M, Glumer C, Pisinger C. Effect of screening and lifestyle counselling on incidence of ischaemic heart disease in general population: Inter99 randomised trial. BMJ. 2014;348:g3617. doi: 10.1136/bmj.g3617. 22. Krogsbøll LT, Jørgensen KJ, Gøtzsche PC. General health checks in adults for reducing morbidity and mortality from disease. Cochrane Database Syst Rev. 2019;1(1):CD009009. doi: 10.1002/14651858.CD009009.pub3. 23 23. Skaaby T, Jørgensen T, Linneberg A. Effects of invitation to participate in health surveys on the incidence of cardiovascular disease: a randomized general population study. Int J Epidemiol. 2017;46(2):603–11. doi: 10.1093/ije/dyw311. 24. Bernstorff M, Deichgraeber P, Bruun NH, Dalsgaard E-M, Fenger-Gron M, Lauritzen T. A randomised trial examining cardiovascular morbidity and all-cause mortality 24 years following general health checks: the Ebeltoft Health Promotion Project (EHPP). BMJ Open. 2019;9(10):e030400. doi: 10.1136/bmjopen-2019-030400. 25. Lauritzen T, Ager Jensen MS, Thomsen JL, Christensen B, Engberg M. Health tests and health consultations reduced cardiovascular risk without psychological strain, increased healthcare utilization or increased costs. An overview of the results from a 5-year randomized trial in primary care. The Ebeltoft Health Promotion Project (EHPP). Scand J Public Health. 2008;36(6):650–61. doi: 10.1177/1403494807090165. 26. Christensen B, Engberg M, Lauritzen T. No long-term psychological reaction to information about increased risk of coronary heart disease in general practice. Eur J Cardiovasc Prev Rehabil. 2004;11(3):239–43. doi: 10.1097/01.hjr.0000129739.30593.23. 27. Rahman M, Simmons RK, Hennings SH, Wareham NJ, Griffin SJ. Effect of screening for type 2 diabetes on population-level self-rated health outcomes and measures of cardiovascular risk: 13-year follow-up of the Ely cohort. Diabet Med. 2012;29(7):886–92. doi: 10.1111/j.1464-5491.2012.03570.x. 28. Rahman M, Simmons RK, Hennings SH, Wareham NJ, Griffin SJ. How much does screening bring forward the diagnosis of type 2 diabetes and reduce complications? Twelve year follow-up of the Ely cohort. Diabetologia. 2012;55(6):1651–9. doi: 10.1007/ s00125-011-2441-9. 29. Knappe J, Heinrich J, Dück KD, Holtz H, Gräfner L. Zur Wirksamkeit eines Präventionsprogramms gegen Herz-Kreislauf-Krankenheiten [The effectiveness of a prevention program for cardiovascular diseases]. Z Gesamte Inn Med. 1982;37(19):633–41. 30. Wood DA, Kinmonth AL, Daviesa GA, Yarwood J, Thompson SG, Pyke SDM et al. Randomised controlled trial evaluating cardiovascular screening and intervention in general practice: principal results of British family heart study. BMJ. 1994;308(6924):313–20. doi: 10.1136/bmj.308.6924.313. 31. Tibblin G, Welin L, Larsson B, Ljungberg IL, Svärdsudd K. The influence of repeated health examinations on mortality in a prospective cohort study, with a comment on the autopsy frequency. The study of men born in 1913. Scand J Soc Med. 1982;10(1):27–32. doi: 10.1177/140349488201000106. 32. Wilhelmsen L, Berglund G, Elmfeldt D, Tibblin G, Wedel H, Pennert K et al. The multifactor primary prevention trial in Göteborg, Sweden. Eur Heart J. 1986;7(4):279–88. doi: 10.1093/ oxfordjournals.eurheartj.a062065. WHAT IS THE EFFECTIVENESS OF SYSTEMATIC POPULATION-LEVEL SCREENING PROGRAMMES FOR REDUCING THE BURDEN OF CARDIOVASCULAR DISEASES? WHO HEALTH EVIDENCE NETWORK SYNTHESIS REPORT 24 33. Bender AM, Jørgensen T, Pisinger C. Do high participation rates improve effects of population-based general health checks? Prev Med. 2017;100:269–74. doi:  10.1016/j. ypmed.2017.05.008. 34. Bender AM, Jørgensen T, Pisinger C. Higher mortality in women living in high-participation areas of a population-based health check and lifestyle intervention study. Int J Public Health. 2019;64(1):107–14. doi: 10.1007/s00038-018-1179-2. 35. Løkkegaard T, Andersen JS, Jacobsen RK, Badsberg JH, Jørgensen T, Pisinger C. Psychological consequences of screening for cardiovascular risk factors in an un- selected general population: results from the Inter99 randomised intervention study. Scand J Public Health. 2015;43(1):102–10. doi: 10.1177/1403494814557886. 36. Jørgensen T, Ladelund S, Borch-Johnsen K, Pisinger C, Schrader AM, Thomsen T et al. Screening for risk of cardiovascular disease is not associated with mental distress: the Inter99 study. Prev Med. 2009;48(3):242–6. doi: 10.1016/j.ypmed.2008.12.010. 37. Bender AM, Jørgensen T, Helbech B, Linneberg A, Pisinger C. Socioeconomic position and participation in baseline and follow-up visits: the Inter99 study. Eur J Prev Cardiol. 2012;21(7):899–905. doi: 10.1177/2047487312472076. 38. Lannerstad O, Sternby NH, Isacsson SO, Lindgren G, Lindell SE. Effects of a health screening on mortality and causes of death in middle-aged men. A prospective study from 1970 to 1974 of men in Malmö, born 1914. Scand J Soc Med. 1977;5(3):137–40. doi: 10.1177/140349487700500305. 39. Lannerstad O. Morbidity related to smoking and other risk factors: a population study of disability pension, hospital care and sickness benefit days among middle-aged men in Malmö, Sweden. Scand J Soc Med. 1980;8(1):25–31. doi:10.1177/140349488000800104. 40. Bennett AE, Fraser IG. Impact of a screening programme in general practice: a randomized controlled trial. Int J Epidemiol. 1972;1(1):55–60. doi: 10.1093/ije/1.1.55. 41. D’Souza MF, Partridge JRJ, Shannon D, Stone DH, Swan AV, Trevelyan HT et al. A controlled trial of multiphasic screening in middle-age: results of the South-East London Screening Study. Int J Epidemiol. 1977;6(4):357–63. doi: 10.1093/ije/6.4.357. 42. Theobald H, Bygren LO, Carstensen J, Hauffman M, Engfeldt P. Effects of an assessment of needs for medical and social services on long-term mortality: a randomized controlled study. Int J Epidemiol. 1998;27(2):194–8. doi: 10.1093/ije/27.2.194. 43. Maindal HT, Støvring H, Sandbaek A. Effectiveness of the population-based Check your Health preventive programme conducted in primary care with 4 years follow-up [the CORE trial]: study protocol for a randomised controlled trial. Trials. 2014;15:341. doi: 10.1186/1745-6215-15-341. 44. Kalkonde Y, Deshmukh M, Nila S, Jadhao S, Bang A. Effect of a community-based intervention for cardiovascular risk factor control on stroke mortality in rural Gadchiroli, 25 India: study protocol for a cluster randomised controlled trial. Trials. 2019;20(1):764. doi: 10.1186/s13063-019-3870-x. 45. Ashton HA, Gao L, Kim LG, Druce PS, Thompson SG, Scott RA. Fifteen-year follow- up of a randomized clinical trial of ultrasonographic screening for abdominal aortic aneurysms. Br J Surg. 2007;94(6):696–701. doi: 10.1002/bjs.5780. 46. Scott RA, Wilson NM, Ashton HA, Kay DN. Influence of screening on the incidence of ruptured abdominal aortic aneurysm: 5-year results of a randomized controlled study. Br J Surg. 1995;82(8):1066–70. doi: 10.1002/bjs.1800820821. 47. Scott RAP, Bridgewater SG, Ashton HA. Randomized clinical trial of screening for abdominal aortic aneurysm in women. Br J Surg. 2002;89(3):283–5. doi: 10.1046/j.0007- 1323.2001.02014.x. 48. Thompson SG, Ashton HA, Gao L, Scott RA, Multicentre Aneurysm Screening Study Group. Screening men for abdominal aortic aneurysm: 10 year mortality and cost effectiveness results from the randomised Multicentre Aneurysm Screening Study. BMJ. 2009;338:b2307. doi: 10.1136/bmj.b2307. 49. Lindholt JS, Sørensen J, R Søgaard R, Henneberg EW. Long-term benefit and cost- effectiveness analysis of screening for abdominal aortic aneurysms from a randomized controlled trial. Br J Surg. 2010;97(6):826–34. doi: 10.1002/bjs.7001. 50. McCaul KA, Lawrence-Brown M, Dickinson JA, Norman PE. Long-term outcomes of the Western Australian trial of screening for abdominal aortic aneurysms. JAMA Intern Med. 2016;176(12): 1761–7. doi: 10.1001/jamainternmed.2016.6633. 51. Friberg L, Engdahl J, Frykman V, Svennberg E, Levin L, Rosenqvist M. Population screening of 75- and 76-year-old men and women for silent atrial fibrillation (STROKESTOP). EP Europace. 2013;15(1):135–40. doi: https://doi.org/10.1093/europace/eus217. 52. Ashburner JM, Atlas SJ, McManus DD, Chang Y, Trisini Lipsanopoulos AT, Borowsky LH et al. Design and rationale of a pragmatic trial integrating routine screening for atrial fibrillation at primary care visits: the VITAL-AF trial. Am Heart J. 2019;215:147–56. doi: 10.1016/j.ahj.2019.06.011. 53. Lindholt JS, Søgaard R. Population screening and intervention for vascular disease in Danish men (VIVA): a randomised controlled trial. Lancet. 2017;390(10109):2256–65. doi: 10.1016/S0140-6736(17)32250-X. 54. Diederichsen AC, Rasmussen LM, Søgaard R, Lambrechtsen J, Steffensen FH, Frost L et al. The Danish Cardiovascular Screening Trial (DANCAVAS): study protocol for a randomized controlled trial. Trials. 2015;16:554. doi: 10.1186/s13063-015-1082-6. 55. Wanhainen A, Hultgren R, Linné A, Holst J, Gottsäter A, Langenskiöld M et al. Outcome of the Swedish Nationwide Abdominal Aortic Aneurysm Screening Program. Circulation. 2016;134(16):1141–8. doi: 10.1161/CIRCULATIONAHA.116.022305. WHAT IS THE EFFECTIVENESS OF SYSTEMATIC POPULATION-LEVEL SCREENING PROGRAMMES FOR REDUCING THE BURDEN OF CARDIOVASCULAR DISEASES? WHO HEALTH EVIDENCE NETWORK SYNTHESIS REPORT 26 56. Svensjö S, Björck M, Wanhainen A. Update on screening for abdominal aortic aneurysm: a topical review. Eur J Vasc Endovasc Surg. 2014;48(6):659–67. doi: 10.1016/j. ejvs.2014.08.029. 57. Johansson M, Zahl PH, Siersma V, Jørgensen KJ, Marklund B, Brodersen J. Benefits and harms of screening men for abdominal aortic aneurysm in Sweden: a registry-based cohort study. Lancet. 2018;391(10138):2441–7. doi: 10.1016/S0140-6736(18)31031-6. 58. Ebrahim S, Taylor F, Ward K, Beswick A, Burke M, Davey Smith G. Multiple risk factor interventions for primary prevention of coronary heart disease. Cochrane Database Syst Rev. 2011;(1):CD001561. doi: 10.1002/14651858.CD001561.pub3. 59. World Health Organisation European Collaborative Group. European collaborative trial of multifactorial prevention of coronary heart disease: final report on the 6-year results. Lancet. 1986;1(8486):869–72. doi: 10.1016/S0140-6736(86)90984-0. 60. Vinther JL, Jacobsen RK, Jørgensen T. Current European guidelines for management of cardiovascular disease: Is medical treatment in nearly half a population realistic? Eur J Prev Cardiol. 2018;25(2):157–63. doi: 10.1177/2047487317738826. 61. Diao D, Wright JM, Cundiff DK, Gueyffier F. Pharmacotherapy for mild hypertension. Cochrane Database Syst Rev. 2012;(8):CD006742. doi: 10.1002/14651858.CD006742.pub2. 62. Mechili EA, Sifaki-Pistolla D. Universal check-up programme in Albania: is this an effective decision? J Med Screen. 2017;24(4):223–4. doi: 10.1177/0969141316680646. 63. Kypridemos C, Collins B, McHale P, Bromley H, Parvulescu P, Capewell S et al. Future cost-effectiveness and equity of the NHS Health Check cardiovascular disease prevention programme: Microsimulation modelling using data from Liverpool, UK. PLOS Med. 2018;15(5):e1002573. doi: 10.1371/journal.pmed.1002573. 64. Harte E, MacLure C, Martin A, Saunders CL, Meads C, Walter FM et al. Reasons why people do not attend NHS Health Checks: a systematic review and qualitative synthesis. Br J Gen Pract. 2018;68(666):e28-35. doi: 10.3399/bjgp17X693929. 65. NHS Health Check Data [website]. London: Public Health England; 2020 (https:// fingertips.phe.org.uk/profile/nhs-health-check-detailed, accessed 13 November 2020). 66. Krska J, du Plessis R, Chellaswamy H. Implementation of NHS Health Checks in general practice: variation in delivery between practices and practitioners. Prim Health Care Res Dev. 2016;17(4):385–92. doi: 10.1017/S1463423615000493. 67. 40-årsundersøkelsene (1985–1999) [The 40-year surveys (1985-1999)]: Oslo: Folkehelseinstituttet [Norwegian Institute of Public Health]; 2019 (in Norwegian; https://www.fhi.no/div/helseundersokelser/landsomfattende-helseundersokelser-lhu/ helseundersokelser/40-aringsundersokelsene/, accessed 6 October 2020). 68. Williams B, Mancia G, Spiering W, Agabiti Rosei E, Azizi M, Burnier M et al. 2018 ESC/ESH Guidelines for the management of arterial hypertension. Eur Heart J. 2018;39(33):3021–104. doi: 10.1093/eurheartj/ehy339. 27 69. Piepoli MF, Hoes AW, Agewall S, Albus C, Brotons C, Catapano AL et al. 2016 European Guidelines on cardiovascular disease prevention in clinical practice: the Sixth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in Clinical Practice (constituted by representatives of 10 societies and by invited experts). Developed with the special contribution of the European Association for Cardiovascular Prevention & Rehabilitation (EACPR). Eur Heart J. 2016;37(29):2315–81. doi: 10.1093/eurheartj/ehw106. 70. Rydén L, Grant PJ, Anker SD, Berne C, Cosentino F, Danchin N et al. ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD: the Task Force on diabetes, pre-diabetes, and cardiovascular diseases of the European Society of Cardiology (ESC) and developed in collaboration with the European Association for the Study of Diabetes (EASD). Eur Heart J. 2013;34(39):3035–87. doi: 10.1093/eurheartj/eht108. 71. The UK NSC recommendation on hypertension screening in children and young people. London: UK National Screening Committee; 2018 (https://legacyscreening. phe.org.uk/hypertension-child, accessed 6 October 2020). 72. The UK NSC recommendation on vascular risk screening in adults over 40. London: UK National Screening Committee; 2007 (https://legacyscreening.phe.org.uk/vascularrisk, accessed 6 October 2020). 73. The UK NSC recommendation on hypertension screening in adults. London: UK National Screening Committee; 2006 (https://legacyscreening.phe.org.uk/hypertension-adult, accessed 6 October 2020). 74. Driving sustainable action for circulatory health. White paper for circulatory health. Geneva: Global Coalition for Circulatory Health; 2018 https://www.world-heart- federation.org/wp-content/uploads/2018/11/White-Paper-for-Circulatory-Health.pdf, accessed 6 October 2020). 75. Weber MA, Schiffrin EL, White WB, Mann S, Lindholm LH, Kenerson JG et al. Clinical practice guidelines for the management of hypertension in the community: a statement by the American Society of Hypertension and the International Society of Hypertension. J Clin Hypertens (Greenwich). 2014;16(1):14–26. doi: 10.1111/jch.12237. 76. Hypertension in adults: diagnosis and management. NICE guideline. London: National Institute for Health and Care Excellence; 2020 (https://www.nice.org.uk/guidance/ng136/ resources/hypertension-in-adults-diagnosis-and-management-pdf-66141722710213, accessed 18 November 2020). 77. WHO PEN Protocol 1. In: Implementation tools: package of essential noncommunicable (PEN) disease interventions for primary health care in low-resource settings. Geneva: World Health Organization; 2013 (https://apps.who.int/iris/bitstream/ handle/10665/133525/9789241506557_eng.pdf, accessed 18 November 2020). 78. HEARTS technical package for cardiovascular disease management in primary health care: risk-based CVD management. Geneva: World Health Organization; 2020 WHAT IS THE EFFECTIVENESS OF SYSTEMATIC POPULATION-LEVEL SCREENING PROGRAMMES FOR REDUCING THE BURDEN OF CARDIOVASCULAR DISEASES? WHO HEALTH EVIDENCE NETWORK SYNTHESIS REPORT 28 (https://apps.who.int/iris/bitstream/handle/10665/333221/9789240001367-eng.pdf?ua=1, accessed 20 October 2020). 79. Rose G. The strategy of preventive medicine. Oxford: Oxford University Press; 1992. 80. Ottawa Charter for Health Promotion. In: Health promotion [website]. Geneva: World Health Organization; 2020 (https://www.who.int/healthpromotion/conferences/ previous/ottawa/en/, accessed 6 October 2020). 81. Adelaide Statement on Health in All Policies: moving towards a shared governance for health and well-being. Geneva: World Health Organization; 2010 (https://www.who. int/social_determinants/hiap_statement_who_sa_final.pdf, accessed 6 October 2020). 82. Jørgensen T, Capewell S, Prescott E, Allender S, Sans S, Zdrojewski T et al. Population- level changes to promote cardiovascular health. Eur J Prev Cardiol. 2013;20(3):409–21. doi: 10.1177/2047487312441726. 83. Marteau TM, White M, Rutter H, Petticrew M, Mytton OT, McGowan JG et al. Increasing healthy life expectancy equitably in England by 5 years by 2035: could it be achieved? Lancet. 2019;393(10191):2571–3. doi: 10.1016/S0140-6736(19)31510-7. 84. Mozaffarian D, Afshin A, Benowitz NL, Bittner V, Daniels SR, Franch HA et al. Population approaches to improve diet, physical activity, and smoking habits: a scientific statement from the American Heart Association. Circulation. 2012;126(12):1514–63. doi: 10.1161/ CIR.0b013e318260a20b. 85. Cosford PA, Leng GC. Screening for abdominal aortic aneurysm. Cochrane Database Syst Rev. 2007;(2):CD002945. doi: 10.1002/14651858.CD002945.pub2. 86. Takagi H, Niwa M, Mizuno Y, Goto SN, Umemoto T, for the All-Literature Investigation of Cardiovascular Evidence Group. The Last Judgment upon abdominal aortic aneurysm screening. Int J Cardiol. 2013;167(5):P2331–2 [letter to editor]. doi: 10.1016/j.ijcard.2012.11.011. 87. Svensjö S, Mani K, Björck M, Lundkvist J, Wanhainen A. Screening for abdominal aortic aneurysm in 65-year-old men remains cost-effective with contemporary epidemiology and management. Eur J Vasc Endovasc Surg. 2014;47(4):357–65. doi: 10.1016/j.ejvs.2013.12.023. 88. Johansson M, Hansson A, Brodersen J. Estimating overdiagnosis in screening for abdominal aortic aneurysm: could a change in smoking habits and lowered aortic diameter tip the balance of screening towards harm? BMJ. 2015;350:h825. doi: 10.1136/ bmj.h825. 89. Ericsson A, Holst J, Gottsäter A, Zarrouk M, Kumlien C. Psychosocial consequences in men taking part in a national screening program for abdominal aortic aneurysm. J Vasc Nurs. 2017;35(4):211–20. doi: 10.1016/j.jvn.2017.06.001. 90. Jacomelli J, Summers L, Stevenson A, Lees T, Earnshaw JJ. Editor’s choice – Inequalities in abdominal aortic aneurysm screening in England: effects of social deprivation and ethnicity. Eur J Vasc Endovasc Surg. 2017;53(6):837–43. doi: 10.1016/j.ejvs.2017.03.006. 29 91. Stather PW, Dattani N, Bown MJ, Earnshaw JJ, Lees TA. International variations in AAA screening. Eur J Vasc Endovasc Surg. 2013;45(3):231–4. doi: 10.1016/j.ejvs.2012.12.013. 92. Brownsword R, Earnshaw JJ. The ethics of screening for abdominal aortic aneurysm in men. J Med Ethics. 2010;36(12):827–30. doi: 10.1136/jme.2010.035519. 93. Davis M, Harris M, Earnshaw JJ. Implementation of the National Health Service Abdominal Aortic Aneurysm Screening Program in England. J Vasc Surg. 2013;57(5):1440–5. doi: 10.1016/j.jvs.2012.10.114. 94. Jacomelli J, Summers L, Stevenson A, Lees T, Earnshaw JJ. Impact of the first 5 years of a national abdominal aortic aneurysm screening programme. Br J Surg. 2016;103(9):1125–31. doi: 10.1002/bjs.10173. 95. The UK NSC recommendation on abdominal aortic aneurysm screening in men over 65. London: UK National Screening Committee; 2017 (https://legacyscreening.phe.org. uk/AAA, accessed 6 October 2020). 96. Erbel R, Aboyans V, Boileau C, Bossone E, Bartolomeo RD, Eggebrecht H et al. 2014 ESC Guidelines on the diagnosis and treatment of aortic diseases: document covering acute and chronic aortic diseases of the thoracic and abdominal aorta of the adult. The Task Force for the Diagnosis and Treatment of Aortic Diseases of the European Society of Cardiology (ESC). Eur Heart J. 2014;35(41):2873–926. doi: 10.1093/eurheartj/ ehu281. 97. Hindricks G, Potpara T, Dagres N, Arbelo E, Bax JJ, Blomström-Lundqvist C et al. 2020 ESC guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association of Cardio-Thoracic Surgery (EACTS). Eur Heart J. 2020;ehaa612. doi: 10.1093/eurheartj/ehaa612. 98. UK National Screening Committee [website]. London: PHE Screening; 2020 (https:// www.gov.uk/government/groups/uk-national-screening-committee-uk-nsc, accessed 18 November 2020). 99. The UK NSC recommendation on atrial fibrillation screening in adults. London: UK National Screening Committee; 2019 (https://legacyscreening.phe.org.uk/atrialfibrillation, accessed 6 October 2020). 100. Karmali KN, Persell SD, Perel P, Lloyd‐Jones DM, Berendsen MA, Huffman MD. Risk scoring for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev. 2017;(3):CD006887. doi: 10.1002/14651858.CD006887.pub4. 101. 6.4.11.1. The Cochrane highly sensitive search strategies for identifying randomized trials in MEDLINE. In: Higgins JPT, Green S, editors. Cochrane Handbook for Systematic Reviews of Interventions, version 5.1.0. London: Cochrane; 2011 (https://handbook-5-1. cochrane.org/chapter_6/6_4_11_1_the_cochrane_highly_sensitive_search_strategies_for. htm, accessed 21 October 2020). WHAT IS THE EFFECTIVENESS OF SYSTEMATIC POPULATION-LEVEL SCREENING PROGRAMMES FOR REDUCING THE BURDEN OF CARDIOVASCULAR DISEASES? WHO HEALTH EVIDENCE NETWORK SYNTHESIS REPORT 30 102. Sterne J, Savović J, Page M, Elbers R, Blencowe N, Boutron I et al. RoB 2: a revised tool for assessing risk of bias in randomised trials. BMJ. 2019;366: l4898. doi: 10.1136/bmj. l4898. 103. Tunstall-Pedoe H. The Dundee coronary risk-disk for management of change in risk factors. BMJ. 1991;303(6805):744 7. doi: 10.1136/bmj.303.6805.744. 104. Thomsen TF, Davidsen M, Ibsen H, Jørgensen T, Jensen G, Borch-Johnsen K. A new method for CHD prediction and prevention based on regional risk scores and randomized clinical trials; PRECARD and the Copenhagen Risk Score. J Cardiovasc Risk. 2001;8(5):291–7. doi:  10.1177/174182670100800508. Erratum in: J Cardiovasc Risk. 2001;8(6):391. PMID: 11702035. 105. Conroy RM, Pyörälä K, Fitzgerald AP, Sans S, Menotti A, De Backer G et al. Estimation of ten-year risk of fatal cardiovascular disease in Europe: the SCORE project. Eur Heart J. 2003;24(11):987–1003. doi: 10.1016/s0195-668x(03)00114-3. 106. Thompson SG, Ashton HA, Gao L, Buxton MJ, Scott RA, Multicentre Aneurysm Screening Study (MASS) Group. Final follow-up of the Multicentre Aneurysm Screening Study (MASS) randomized trial of abdominal aortic aneurysm screening. Br J Surg. 2012;99(12):1649–56. doi: 10.1002/bjs.8897. 107. Lindholt JS, Juul S, Fasting H, Henneberg EW. Screening for abdominal aortic aneurysms: single centre randomised controlled trial. BMJ. 2005;330(7494):750. doi:  10.1136/ bmj.38369.620162.82. 31 ANNEX 1. SEARCH STRATEGY NB: references are given in the main reference list. Databases Peer-reviewed documents in English and Russian were identified from CINAHL (Cumulative Index to Nursing and Allied Health Literature), Cochrane Central Register of Controlled Trials, Embase, McMaster’s Health Evidence, MEDLINE and Scopus. Further searches for peer-reviewed documents in Russian were performed in the following databases: CyberLeninka, East View, Russian Science Citation Index, Scholar.ru and the Scientific Archive of the Russian Federation. Further documents were obtained by searching clinical databases (the WHO International Clinical Trials Registry Platform and ClinicalTrials.gov) and grey literature databases (OpenGrey and the United Kingdom Screening Programme). All searches were conducted between March and May 2020 and no geographical or time limits were applied. Hand searches were conducted to identify studies on the adverse effects and empirical (i.e. not modelling) studies on the cost–effectiveness of screening, with Web of Science used for citation tracking for eligible studies. Existing reviews on the topic were examined to identify recent primary studies and reference lists of included studies and systematic reviews were examined to identify further records for inclusion in the analysis. Search terms Search terms in English Searches were built on two previous Cochrane reviews, from 2017 and 2019 (22,100). Search terms relevant to CVDs were collected from the first (and supplemented with other relevant CVD search terms) and those relevant to systematic screening programmes (supplemented with other relevant search terms), and used The Cochrane highly sensitive search strategies for identifying randomized trials in MEDLINE (101). The original search terms from both Cochrane reviews had been prepared for MEDLINE through Ovid; these were converted for use in MEDLINE through PubMed (Table A1.1). WHAT IS THE EFFECTIVENESS OF SYSTEMATIC POPULATION-LEVEL SCREENING PROGRAMMES FOR REDUCING THE BURDEN OF CARDIOVASCULAR DISEASES? WHO HEALTH EVIDENCE NETWORK SYNTHESIS REPORT 32 Table A1.1. English search terms and combinations for the search in MEDLINE No. Query Number of hits 1 (((“cardiovascular”[TIAB] OR “cv”[TIAB] OR “cvd”[TIAB] OR “coronary”[TIAB] OR “chd”[TIAB] OR “heart disease”[TIAB]) AND “risk”[TIAB] AND (estimat*[TIAB] OR assessment*[TIAB] OR scor*[TIAB] OR equation*[TIAB] OR calculat*[TIAB]))) 85 197 2 “Cardiovascular Diseases”[MeSH:noexp] 144 586 3 cardiovascular disease*[TIAB] 172 072 4 “coronary disease”[MeSH:noexp] 130 494 5 heart disease*[TIAB] 174 133 6 ((coronary[TIAB] AND disease*[TIAB])) 192 069 7 coronary risk*[TIAB] 5 470 8 cardiovascular risk*[TIAB] 67 063 9 “hypertension”[MeSH:noexp] 231 439 10 (“Hyperlipidemias”[MeSH] OR “Dyslipidemias”[MeSH] OR “Hyperglycemia”[MeSH]) 112 014 11 cholesterol[TIAB] 240 421 12 “Arteriosclerosis”[MeSH] 173 967 13 ((arteriosclerosis[TIAB] OR atherosclerosis[TIAB])) 129 001 14 OR/1–13 1 153 388 15 stroke 330 380 16 “peripheral vascular diseases” 13 390 17 (ischaemic heart disease OR Myocardial Ischemia OR Myocardial infarction) 540 819 18 atrial fibrillation 81 100 19 abdominal aortic aneurism 156 33 No. Query Number of hits 20 (coronary artery calcification OR “Vascular Calcification”[MeSH]) 10 752 21 (“carotid plaques” OR “Carotid Stenosis”) 19 057 22 (“Angioplasty, Balloon”[MeSH] OR “balloon dilation” OR “balloon angioplasty” OR “Stents”[MeSH]) 114 682 23 (“Cerebral Revascularization”[MeSH] OR “Transmyocardial Laser Revascularization”[MeSH] OR “Myocardial Revascularization”[MeSH] OR revascularization OR revascularization) 129 660 24 (apolipoprotein OR “Apolipoproteins”[MeSH]) 61 921 25 (“Thrombolytic Therapy”[MeSH] OR thrombolysis OR alteplase OR “Anticoagulants”[MeSH] OR anticoagulant* OR embolysis OR “Thrombectomy”[MeSH] OR thrombectomy OR “Percutaneous Coronary Intervention”[MeSH] OR PCI OR “Percutaneous Coronary Intervention” OR congenital heart disease OR “Cardiovascular Abnormalities”[MeSH] OR “Cardiomyopathies”[MeSH]) 657 840 26 OR/15–25 1 516 085 27 14 OR 26 2 210 109 28 (“physical examination”[MeSH:noexp] AND ((annual[TI] OR gp[TI] OR periodic[TI] OR yearly[TI] OR routine[TI]) OR ((primary[TIAB] AND (care[TIAB] OR health care[TIAB])) OR primary health*[TIAB] OR general practitioner*[TIAB] OR general practice[TIAB] OR family doctor*[TIAB] OR family practice*[TIAB] OR family physician*[TIAB]))) 2 911 29 (((health check*[TI] OR healthcheck*[TI] OR annual physical*[TI] OR annual medical[TI] OR medical check*[TI] OR primary care check*[TI] OR wellness check*[TI] OR well care[TI] OR wellcare[TI] OR well woman[TI] OR well visit*[TI]))) 5 299 Table A1.1 contd WHAT IS THE EFFECTIVENESS OF SYSTEMATIC POPULATION-LEVEL SCREENING PROGRAMMES FOR REDUCING THE BURDEN OF CARDIOVASCULAR DISEASES? WHO HEALTH EVIDENCE NETWORK SYNTHESIS REPORT 34 No. Query Number of hits 30 (((annual[TI] OR periodic[TI] OR regular[TI] OR routine[TI] OR yearly[TI]) AND (check*[TI] OR health* exam*[TI] OR health evaluation*[TI] OR medical exam*[TI] OR physical exam*[TI] OR wellness check*[TI] OR gp visit*[TI] OR physician visit*[TI] OR doctor visit*[TI] OR doctors* visit*[TI] OR doctor* visit*[TI] OR office visit*[TI]))) 39 31 (((annual[TI] OR yearly) AND (medical*[TI] OR physical*[TI]))) 2 048 32 (((annual[TI] OR yearly[TI]) AND visit*[TI])) 118 33 ((preventive*[TI] AND (care check*[TI] OR checkup*[TI] OR check-up*[TI] OR visit*[TI] OR exam*[TI] OR family doctor*[TI] OR gp[TI] OR family physician*[TI] OR general practitioner*[TI]))) 1 027 34 (((multifactor*[TIAB] OR multifactor*[TIAB]) AND prevent*[TIAB])) 6 766 35 ((multiphasic[TIAB] AND (screening[TIAB] OR test*[TIAB] OR tests[TIAB] OR testing[TIAB] OR check*[TIAB]))) 1 900 36 “general health screening”[TIAB] 133 37 “multiphasic screening”[MeSH:noexp] 1 088 38 ((alcohol[TIAB] OR “Alcohol Drinking”[MeSH] OR diet[TIAB] OR “diet”[MeSH]) OR smoking[TIAB] OR “smoking”[MeSH] OR tobacco[TIAB] OR “Tobacco Use”[MeSH] OR exercise[TIAB] OR “exercise”[MeSH] OR life style[TIAB] OR “life style”[MeSH] OR (weight reduction[TIAB] OR “Weight Reduction Programs”[MeSH] OR obesity[TIAB] OR “Obesity”[MeSH] OR physical activity[TIAB] OR physical inactivity[TIAB] OR “Sedentary Behavior”[MeSH]) AND (screen*[TIAB] OR “Mass Screening”[MeSH] OR check[TIAB] OR check*[TIAB] OR “Physical Examination”[MeSH]) AND (prevention[TIAB] OR preventive[TIAB] OR preventive[TIAB] OR “Primary Prevention”[MeSH])) 31 534 Table A1.1 contd 35 No. Query Number of hits 39 OR/28–38 50 035 40 “mass screening”[MeSH:noexp] 101 313 41 (((general[TIAB] OR organized[TIAB] OR organized[TIAB] OR prevent*[TIAB] OR systematic[TIAB] OR annual[TIAB] OR yearly[TIAB] OR periodic[TIAB] OR regular[TIAB] OR routine[TIAB]) AND (screen*[TIAB] OR check*[TIAB] OR checkup*[TIAB] OR check-up*[TIAB]))) 216 890 42 ((health check*[TIAB] OR health screen*[TIAB])) 10 515 43 OR/40–42 296 591 44 “primary health care”[MeSH] 155 147 45 “family practice”[MeSH:noexp] 65 009 46 “physicians, primary care”[MeSH:noexp] 3 305 47 “general practice”[MeSH:noexp] 13 047 48 “physicians, family”[MeSH:noexp] 16 276 49 “general practitioners”[MeSH:noexp] 7 615 50 “outpatient clinics, hospital”[MeSH] 16 960 51 “ambulatory care”[MeSH:noexp] 42 452 52 “ambulatory care facilities”[MeSH] 54 247 53 “community health services”[MeSH] 299 000 54 “community health centers”[MeSH] 12 201 55 (((primary[TIAB] OR communit*[TIAB]) AND (care[TIAB] OR health*[TIAB]))) 520 266 56 ((family practi*[TIAB] OR family doctor*[TIAB] OR family physician*[TIAB] OR gp*[TIAB] OR gps*[TIAB] OR general practi*[TIAB])) 163 954 Table A1.1 contd WHAT IS THE EFFECTIVENESS OF SYSTEMATIC POPULATION-LEVEL SCREENING PROGRAMMES FOR REDUCING THE BURDEN OF CARDIOVASCULAR DISEASES? WHO HEALTH EVIDENCE NETWORK SYNTHESIS REPORT 36 No. Query Number of hits 57 (((outpatient*[TIAB] OR ambulatory[TIAB]) AND (care[TIAB] OR healthcare[TIAB] OR clinic*[TIAB] OR service*[TIAB] OR facilit*[TIAB]))) 147 361 58 OR/44–57 1 150 868 59 43 AND 58 55 127 60 39 OR 59 100 436 61 “randomized controlled trial”[PT] 501 912 62 “controlled clinical trial”[PT] 590 612 63 randomized[TIAB] 509 706 64 placebo[TIAB] 210 946 65 “clinical trials as topic”[MeSH: noexp] 190 273 66 randomly[TIAB] 328 467 67 trial[TI] 213 392 68 OR/61–67 1 280 253 69 (animals[MeSH] NOT humans[MeSH]) 4 675 327 70 68 NOT 69 1 178 080 71 27 AND 60 AND 70 2 622 Search terms in Russian Сердечно-сосудистые заболевания, ишемическая болезнь сердца, сердечно- сосудистый риск, артериальная гипертензия, атеросклероз, инсульт, нарушение мозгового кровобращения, инфаркт миокарда, гипертония, холестерин, липиды, липидный спектр, фибриляция предсердий, мерцательная аритмия, аневризма абдоминального отдела аорты, кальцификация коронарных артерий, бляшка сонной артерии, каротидная бляшка, субклинический атеросклероз, диспансеризация, ежегодные Table A1.1 contd 37 профилактические осмотры, скрининг, курение, здоровый образ жизни, профилактическое консультирование, терапевт, семейный доктор, диета, снижение веса, измерение аретраильного давления, сравнительные исследования, рандомизированные исследования, сердечно-сосудистые исходы Study selection The titles and abstracts of all studies identified in the searches were independently assessed for relevance by two reviewers (CUE and TJ for searches in English; OR and AA for searches in the Russian) and then the full text of each selected publication was examined to identify documents for final inclusion. Disagreements were resolved through consensus. Inclusion and exclusion criteria were selected to identify studies that could simulate the scenario of a country introducing population-level screening. Inclusion criteria were: • used a pragmatic RCT design; • reported outcomes for CVD burden; • evaluated interventions of systematic population-level screening for CVD risk and CVD risk factors (behavioural factors: smoking, harmful use of alcohol, unhealthy nutrition and physical inactivity; biological factors: high blood pressure, raised blood sugar levels, dyslipidaemia and raised body mass index) or preclinical CVD conditions, followed by counselling and/or medical and surgical treatment (with no limit on the number of risk factors screened for); • included general populations of children and/or adults; • had a geographically well-defined study area, from which a random population sample in relevant age groups was invited for screening (with the remaining population used as the control group); and • was an intention-to-treat analysis (evaluation included the whole group, regardless of whether some individuals failed to attend the screening). Exclusion criteria were: • specifically targeted older people • included populations with known specific risk factors or diseases. WHAT IS THE EFFECTIVENESS OF SYSTEMATIC POPULATION-LEVEL SCREENING PROGRAMMES FOR REDUCING THE BURDEN OF CARDIOVASCULAR DISEASES? WHO HEALTH EVIDENCE NETWORK SYNTHESIS REPORT 38 Of 6878 titles and abstracts screened after removal of duplicates, 6785 records were excluded and full-text assessment was carried out for 93 records. An additional 14 studies were identified during this process, primarily from the studies included in two systematic reviews of the effectiveness of screening for CVD (58,100) and a systematic review on the effectiveness of screening for AAA (85). A final set of 33 studies (representing 22 RCTs) were included in the narrative synthesis and 13 RCTs were included in the meta-analysis (Fig. A1.1). Annex 2 provides a list of the studies that were excluded following full-text screening, along with the reasons for excluding them. A case study was selected to illustrate a possible model for a national screening programme for AAA. Quality appraisal The methodological quality of included studies was appraised using the RoB 2 Cochrane risk-of-bias tool for randomized trials (102), which considers the risk of bias in five domains: (i) the randomization process; (ii) deviation from the intended intervention; (iii) missing outcome data; (iv) measurement of outcomes; and (v) selection of the reported results. Data extraction Based on a published framework (100), the following data were extracted from all included studies: design; geographical setting; country; start date and duration; diagnostic tests used; intervention; age and sex of participants, number of participants allocated to each arm, number of participants lost to follow-up for each outcome, baseline comparability. The following data were extracted from the study results: number of events or rates for mortality; and number of hospitalizations, surgical treatments, new medications and referrals to specialists; number of diagnostic procedures required because of positive screening tests; number of physician visits; and data on outcomes related to costs, morbidity and (long-term) adverse effects of interventions. Data were extracted independently by two authors, and disagreements were resolved by consensus. Data analysis Data were pooled from studies that reported similar outcome measures and used in a series of random-effects meta-analyses. Primary analyses included the number of cases in both the intervention and control groups; if absolute numbers were not reported, hazard ratios or relative risks were imputed. Sensitivity analyses were conducted to assess the effect of the risk of bias in the results. For outcomes where meta-analysis was not possible, data were analysed and presented narratively. 39 Records identified through English-language database searches (n = 8722) Records identified through Russian-language database searches (n = 5) Records identified through additional sources (n = 682) Records after removal of duplicates (n = 6191) Records screened (n = 6878) Records excluded (n = 6785) RCTs included in meta- analyses (n = 13) Studies identified through handsearching, systematic reviews and reference lists of included studies (n = 14) Full-text articles assessed for eligibility (n = 93) Full-text articles excluded (n = 74). Reasons: randomization not community based (n = 41) not randomized (n = 27) clinical study (n = 2) wrong outcomes (n = 2) no results provided (n = 1) conference paper (n = 1) Studies included in the narrative synthesis (n = 33 studies; representing 22 RCTs) RCTs without similar outcome measures (n = 9) Fig. A1.1. Study selection process WHAT IS THE EFFECTIVENESS OF SYSTEMATIC POPULATION-LEVEL SCREENING PROGRAMMES FOR REDUCING THE BURDEN OF CARDIOVASCULAR DISEASES? WHO HEALTH EVIDENCE NETWORK SYNTHESIS REPORT 40 ANNEX 2. STUDIES EXCLUDED AFTER FULL-TEXT REVIEW Seventy-four studies were excluded after full-text review, for the reasons given. Where available, the formal name of each RCT is given; where not, the geographical location is given. 41 St ud ya Re fe re nc e( s) Re as on Sc re en in g fo r C VD ri sk a nd C VD ri sk fa ct or s A D D IT IO N C ha rle s M , B ru un N H , S im m on s R, D al sg aa rd E -M , W itt e D , J or ge ns en M e t a l. (2 02 0) . T he e ffe ct o f t ra in in g G Ps in m ot iv at io na l i nt er vi ew in g on in ci de nt ca rd io va sc ul ar d is ea se a nd m or ta lit y in p eo pl e w ith s cr ee n- de te ct ed d ia be te s. Re su lts fr om th e A D D IT IO N -D en m ar k ra nd om is ed tr ia l. BJ G P O pe n. 4( 1): bj gp op en 20 X1 01 01 2. d oi : 1 0. 33 99 /b jg po pe n2 0X 10 10 12 . Ec ho uff o- Tc he ug ui JB , S im m on s RK , P re vo st A T, W ill ia m s KM , K in m on th A L, W ar eh am N L (2 01 5) . L on g- te rm e ffe ct o f p op ul at io n sc re en in g fo r d ia be te s on c ar di ov as cu la r m or bi di ty , s el f- ra te d he al th , a nd h ea lth b eh av io r. A nn F am M ed . 1 3( 2) :14 9– 57 . d oi : 1 0. 13 70 /a fm .17 37 . G riffi n SJ , B or ch -Jo hn se n K, D av ie s M J, Kh un ti K, R ut te n G EH M , S an db æ k A e t a l. (2 01 1). E ffe ct o f e ar ly in te ns iv e m ul tif ac to ria l t he ra py o n 5- ye ar ca rd io va sc ul ar o ut co m es in in di vi du al s w ith ty pe 2 d ia be te s de te ct ed by s cr ee ni ng (A D D IT IO N -E ur op e) : a c lu st er -r an do m is ed tr ia l. La nc et . 37 8( 97 86 ):1 56 –6 7. do i:  10 .10 16 /S 01 40 -6 73 6( 11) 60 69 8- 3. G riffi n SJ , R ut te n G , K hu nt i K , W itt e D R, L au rit ze n T, S ha rp S J e t a l. (2 01 9) . L on g- te rm e ffe ct s of in te ns iv e m ul tif ac to ria l t he ra py in in di vi du al s w ith s cr ee n- de te ct ed ty pe 2 d ia be te s in p rim ar y ca re : 1 0- ye ar fo llo w -u p of th e A D D IT IO N - Eu ro pe c lu st er -r an do m is ed tr ia l. La nc et D ia be te s En do cr in ol . 7 (12 ):9 25 –3 7. do i:  10 .10 16 /S 22 13 -8 58 7( 19 )3 03 49 -3 . Si m m on s RK , E ch ou ffo -T ch eu gu i J B, S ha rp S J, Sa rg ea nt L A , W ill ia m s KM , Pr ev os t A T et a l. (2 01 2) . S cr ee ni ng fo r t yp e 2 di ab et es a nd p op ul at io n m or ta lit y ov er 10  y ea rs (A D D IT IO N -C am br id ge ): a cl us te r- ra nd om is ed c on tr ol le d tr ia l. La nc et . 3 80 (9 85 5) :17 41 –8 . d oi : 1 0. 10 16 /S 01 40 -6 73 6( 12 )6 14 22 -6 . Si m m on s RK , G riffi n SJ , W itt e D R, B or ch -Jo hn se n K, L au rit ze n T, S an db æ k A (2 01 7) . E ffe ct o f p op ul at io n sc re en in g fo r t yp e 2 di ab et es a nd c ar di ov as cu la r ris k fa ct or s on m or ta lit y ra te a nd c ar di ov as cu la r e ve nt s: a co nt ro lle d tr ia l am on g 1,9 12 ,3 92 D an is h ad ul ts . D ia be to lo gi a. 6 0( 11) :2 18 3– 91 . d oi : 1 0. 10 07 / s0 01 25 -0 17 -4 32 3- 2. Ra nd om iz at io n no t c om m un ity ba se d Ta bl e A 2. S tu di es e xc lu de d af te r f ul l-t ex t r ev ie w WHAT IS THE EFFECTIVENESS OF SYSTEMATIC POPULATION-LEVEL SCREENING PROGRAMMES FOR REDUCING THE BURDEN OF CARDIOVASCULAR DISEASES? WHO HEALTH EVIDENCE NETWORK SYNTHESIS REPORT 42 St ud ya Re fe re nc e( s) Re as on Sc re en in g fo r C VD ri sk a nd C VD ri sk fa ct or s A sh ke lo n H yp er te ns io n D et ec tio n an d C on tr ol Pr og ra m Yo se fy C , D ic ke r D , V is ko pe r J R, T ul ch in sk y TH , G in sb er g G M , L ei bo vi tz E e t a l. (2 00 3) . T he A sh ke lo n H yp er te ns io n D et ec tio n an d C on tr ol P ro gr am (A H D C Pr og ra m ): a co m m un ity a pp ro ac h to re du ci ng c ar di ov as cu la r m or ta lit y. Pr ev M ed . 3 79 6 pt  1) :5 71 –6 . d oi : 1 0. 10 16 /j .y pm ed .2 00 3. 09 .0 03 . N ot ra nd om iz ed Bu ch ar es t D am sa T , S ch io iu -C os ta ch e L, G eo rg es cu M , P op es cu A , T he od or in i S , Te od or es cu S e t a l. (19 90 ). Ev ol ut io n of is ch em ic h ea rt d is ea se ri sk fa ct or s in “T he B uc ha re st M ul tif ac to ria l P re ve nt iv e Tr ia l o f C or on ar y H ea rt D is ea se ” af te r 1 5- ye ar fo llo w -u p. M ed In te rn e. 2 8( 3) :2 29 –3 3. P M ID : 2 09 23 93 . St ei nb ac h M , C on st an tin ea nu M , G eo rg es cu M , H ar na ge a P, T he od or in i S , G al fi L et a l. (19 84 ). Th e Bu ch ar es t M ul tif ac to ria l P re ve nt io n Tr ia l o f C or on ar y H ea rt D is ea se – te n ye ar fo llo w -u p: 19 71 –1 98 2. M ed In te rn e. 2 2( 2) :9 9– 10 6. PM ID : 6 74 01 87 . St ei nb ac h M , C on st an tin ea nu M , H ar na ge a P, T he od or in i S , G eo rg es cu M , M itu S et a l. (19 82 ). Th e Bu ch ar es t m ul tif ac to ria l p re ve nt io n tr ia l o f c or on ar y he ar t di se as e. G en er al m et ho do lo gy a nd ri sk fa ct or c or re ct io n af te r fi ve y ea r f ol lo w - up (1 97 1– 19 77 ). M ed In te rn e. 2 0( 2) :11 7– 36 . P M ID : 7 12 31 11. St ei nb ac h M , C on st an tin ea nu M , H ar na ge a P, T he od or in i S , G eo rg es cu M , M itu S et a l. (19 82 ). Th e Bu ch ar es t m ul tif ac to ria l p re ve nt io n tr ia l. Th e ch an ge s of m or bi di ty a nd o f g en er al a nd s pe ci fic m or ta lit y. M ed In te rn e. 2 0( 3) :19 7– 20 8. PM ID : 7 15 68 15 . N ot ra nd om iz ed Be ha nd la Bl od tr yc k Bä tt re H an ns on L (1 99 4) . T he B BB S tu dy : t he e ffe ct o f i nt en si fie d an tih yp er te ns iv e tr ea tm en t o n th e le ve l o f b lo od p re ss ur e, s id e- eff ec ts , m or bi di ty a nd m or ta lit y in “w el l-t re at ed ” h yp er te ns iv e pa tie nt s. Be ha nd la B lo dt ry ck B ät tr e. B lo od Pr es s. 3( 4) :2 48 –5 4. d oi : 1 0. 31 09 /0 80 37 05 94 09 10 22 65 . C lin ic al s tu dy Ta bl e A 2 co nt d 43 St ud ya Re fe re nc e( s) Re as on Sc re en in g fo r C VD ri sk a nd C VD ri sk fa ct or s D ia be te s In te rv en tio n St ud y H an ef el d M , F is ch er S , S ch m ec he l H , R ot he G , S ch ul ze J, D ud e H e t a l. (19 91 ). D ia be te s In te rv en tio n St ud y. M ul ti- in te rv en tio n tr ia l i n ne w ly d ia gn os ed N ID D M . D ia be te s C ar e. 14 (4 ):3 08 ‐1 7. do i:  10 .2 33 7/ di ac ar e. 14 .4 .3 08 . Ra nd om iz at io n no t c om m un ity ba se d FI N M O N IC A U us itu pa M , P el to ne n M , L in ds tr om J, A un ol a S, Il an ne -P ar ik ka P , K ei nä ne n- Ki uk aa nn ie m i S e t a l. (2 00 9) . T en -y ea r m or ta lit y an d ca rd io va sc ul ar m or bi di ty in th e Fi nn is h D ia be te s Pr ev en tio n St ud y – Se co nd ar y an al ys is o f t he ra nd om iz ed tr ia l. PL O S O N E. 4 (5 ):e 56 56 . d oi : 1 0. 13 71 /j ou rn al .p on e. 00 05 65 6. Ra nd om iz at io n no t c om m un ity ba se d H el si nk i Bu si ne ss m en St ud y M ie tt in en T A , H ut tu ne n JK , N au kk ar in en V , S tr an db er g T, M at til a S, K um lin T et a l. (19 85 ). M ul tif ac to ria l p rim ar y pr ev en tio n of c ar di ov as cu la r d is ea se s in m id dl e- ag ed m en . R is k fa ct or c ha ng es , i nc id en ce , a nd m or ta lit y. JA M A . 25 4( 15 ):2 09 7– 10 2. P M ID : 4 04 61 37 . N au kk ar in en V A , S tr an db er g TE , V an ha ne n H T, S al om aa V V, S ar na S J, M ie tt in en TA e t a l. (19 89 ). M or ta lit y ra te s af te r m ul tif ac to ria l p rim ar y pr ev en tio n of ca rd io va sc ul ar d is ea se s. A nn M ed . 2 1(6 ):4 41 –6 . d oi : 1 0. 31 09 /0 78 53 89 89 09 14 92 36 . St ra nd be rg T E, M ie tt in en T A (1 99 4) . M ul tif ac to ria l p rim ar y pr ev en tio n: e xp lo rin g th e fa ilu re s. J M yo ca rd ia l I sc he m ia . 6 :15 –2 3. St ra nd be rg T E, R ai kk on en K , S al om aa V , S tr an db er g A , K au tia in en H , K iv im äk i M e t a l. (2 01 8) . I nc re as ed m or ta lit y de sp ite s uc ce ss fu l m ul tif ac to ria l ca rd io va sc ul ar ri sk re du ct io n in h ea lth y m en : 40 -y ea r f ol lo w -u p of th e H el si nk i B us in es sm en St ud y in te rv en tio n tr ia l. J N ut r H ea lth A gi ng . 2 2( 8) :8 85 –9 1. do i:  10 .10 07 /s 12 60 3- 01 8- 10 99 -0 . St ra nd be rg T E, S al om aa V V, N au kk ar in en V A , S ar na S J, M ie tt in en T A e t a l. (19 95 ). M or ta lit y in p ar tic ip an ts a nd n on -p ar tic ip an ts o f a m ul tif ac to ria l pr ev en tio n st ud y of c ar di ov as cu la r d is ea se s: a 28  y ea r f ol lo w u p of th e H el si nk i B us in es sm en S tu dy . B r H ea rt J. 74 (4 ):4 49 ‐5 4. d oi : 1 0. 113 6/ hr t.7 4. 4. 44 9. Ra nd om iz at io n no t c om m un ity ba se d Ta bl e A 2 co nt d WHAT IS THE EFFECTIVENESS OF SYSTEMATIC POPULATION-LEVEL SCREENING PROGRAMMES FOR REDUCING THE BURDEN OF CARDIOVASCULAR DISEASES? WHO HEALTH EVIDENCE NETWORK SYNTHESIS REPORT 44 St ud ya Re fe re nc e( s) Re as on Sc re en in g fo r C VD ri sk a nd C VD ri sk fa ct or s St ra nd be rg T E, S al om aa V V, V an ha ne n H T, S ar na S J, M ie tt in en T A e t a l. (19 91 ). Lo ng -t er m m or ta lit y af te r 5 -y ea r m ul tif ac to ria l p rim ar y pr ev en tio n of c ar di ov as cu la r d is ea se s in m id dl e- ag ed m en . J A M A . 2 66 (9 ):1 22 5– 9. PM ID : 1 87 02 47 . Ra nd om iz at io n no t c om m un ity ba se d J-D O IT 3 U ek i K , S as ak o T, O ka za ki Y , K at o M , O ka ha ta S , K at su ya m a H e t a l. (2 01 7) . Eff ec t o f a n in te ns ifi ed m ul tif ac to ria l i nt er ve nt io n on c ar di ov as cu la r ou tc om es a nd m or ta lit y in ty pe 2 d ia be te s (J- D O IT 3) : a n op en -la be l, ra nd om is ed c on tr ol le d tr ia l. La nc et D ia be te s En do cr in ol . 5 (12 ):9 51 –6 4. do i:  10 .10 16 /S 22 13 -8 58 7( 17 )3 03 27 -3 . Ra nd om iz at io n no t co m m un ity - ba se d Ka is er Pe rm an en te 19 65 Fr ie dm an G D , C ol le n M F, F ire m an B H (1 98 6) . M ul tip ha si c H ea lth c he ck up ev al ua tio n: a 16 -y ea r f ol lo w -u p. J C hr on ic D is . 3 9( 6) :4 53 –6 3. d oi : 1 0. 10 16 /0 02 1- 96 81 (8 6) 90 112 -8 . Ra nd om iz at io n no t c om m un ity ba se d M an ka to 19 82 M ur ra y D M , L ue pk er R V, P iri e PL , G rim m R H , B lo om E , D av is M A e t a l. (19 86 ). Sy st em at ic ri sk fa ct or s cr ee ni ng a nd e du ca tio n: a c om m un ity -w id e ap pr oa ch to p re ve nt io n of c or on ar y he ar t d is ea se . P re v M ed . 1 5( 6) :6 61 –7 2. do i:  10 .10 16 /0 09 1- 74 35 (8 6) 90 07 1- x. W ro ng ou tc om es M RF IT M ul tip le R is k Fa ct or In te rv en tio n Tr ia l f or th e Pr ev en tio n of C or on ar y H ea rt D is ea se (M RF IT ). C lin ic al Tr ia ls .g ov Id en tifi er : N C T0 00 00 48 7 (h tt ps :// cl in ic al tr ia ls .g ov /c t2 /s ho w /N C T0 00 00 48 7? te rm =N C T0 00 00 48 7& dr aw =2 &r an k= 1, ac ce ss ed 2 1 O ct ob er 2 02 0) . Ra nd om iz at io n no t c om m un ity ba se d Ta bl e A 2 co nt d 45 St ud ya Re fe re nc e( s) Re as on Sc re en in g fo r C VD ri sk a nd C VD ri sk fa ct or s M ul tip le R is k Fa ct or In te rv en tio n Tr ia l R es ea rc h G ro up (1 99 0) . M or ta lit y ra te s af te r 1 0. 5  ye ar s fo r p ar tic ip an ts in th e M ul tip le R is k Fa ct or In te rv en tio n Tr ia l. Fi nd in gs re la te d to a p rio ri hy po th es es o f t he tr ia l. JA M A . 2 63 (13 ):1 79 5– 80 1. do i:  10 .10 01 /j am a. 19 90 .0 34 40 13 00 83 03 0. Eb er ly L E, S ta m le r J , K ul le r L H , N ea to n JD (2 01 4) . M ul tip le R is k Fa ct or In te rv en tio n Tr ia l. In : B al ak ris hn an N , e di to r. M et ho ds a nd a pp lic at io ns o f st at is tic s in c lin ic al tr ia ls : c on ce pt s, pr in ci pl es , t ria ls , a nd d es ig n, v ol um e 1. H ob ok en (N J): Jo hn W ile y & So ns :5 77 –8 6. Ku lle r L , N ea to n J, C ag gi ul a A , F al vo -G er ar d L (19 80 ). Pr im ar y pr ev en tio n of he ar t a tt ac ks : t he m ul tip le ri sk fa ct or in te rv en tio n tr ia l. A m J Ep id em io l. 112 (2 ): 18 5– 99 . d oi : 1 0. 10 93 /o xf or dj ou rn al s.a je .a 112 98 4. M ul tip le R is k Fa ct or In te rv en tio n Tr ia l R es ea rc h G ro up (1 98 2) . M ul tip le ri sk fa ct or in te rv en tio n tr ia l. Ri sk fa ct or c ha ng es a nd m or ta lit y re su lts . J A M A . 24 8( 12 ):1 46 5– 77 . d oi : 1 0. 10 01 /j am a. 19 82 .0 33 30 12 00 23 02 5. M ul tip le R is k Fa ct or In te rv en tio n Tr ia l R es ea rc h G ro up (1 99 0) . M or ta lit y af te r 1 0 1/ 2  ye ar s fo r h yp er te ns iv e pa rt ic ip an ts in th e M ul tip le R is k Fa ct or In te rv en tio n Tr ia l. C irc ul at io n. 8 2( 5) :16 16 –2 8. d oi : 1 0. 116 1/ 01 .c ir. 82 .5 .16 16 . Sh er w in R , K ae lb er C T, K ez di P , K je ls be rg M O , T ho m as H E Jr (19 81 ). Th e m ul tip le ris k fa ct or in te rv en tio n tr ia l ( M RF IT ) I I. Th e de ve lo pm en t o f t he p ro to co l. Pr ev M ed . 1 0( 4) :4 02 –2 5. d oi : 1 0. 10 16 /0 09 1- 74 35 (8 1)9 00 58 -x . St am le r J , N ea to n JD , C oh en JD , C ut le r J , E be rly L , G ra nd its G e t a l. (2 01 2) . M ul tip le ri sk fa ct or in te rv en tio n tr ia l r ev is ite d: a n ew p er sp ec tiv e ba se d on no nf at al a nd fa ta l c om po si te e nd po in ts , c or on ar y an d ca rd io va sc ul ar , d ur in g th e tr ia l. J A m H ea rt A ss oc . 1 (5 ):e 00 36 40 . d oi : 1 0. 116 1/ JA H A .11 2.0 03 64 0. W H O E ur op ea n C ol la bo ra tiv e G ro up (1 98 3) . M ul tif ac to ria l t ria l i n th e pr ev en tio n of c or on ar y he ar t d is ea se : 3 . I nc id en ce a nd m or ta lit y re su lts . E ur H ea rt J. 4( 3) :14 1– 7. PM ID : 6 34 51 61 . Ra nd om iz at io n no t c om m un ity ba se d Ta bl e A 2 co nt d WHAT IS THE EFFECTIVENESS OF SYSTEMATIC POPULATION-LEVEL SCREENING PROGRAMMES FOR REDUCING THE BURDEN OF CARDIOVASCULAR DISEASES? WHO HEALTH EVIDENCE NETWORK SYNTHESIS REPORT 46 St ud ya Re fe re nc e( s) Re as on Sc re en in g fo r C VD ri sk a nd C VD ri sk fa ct or s M ul tif ac to ria l Pr ev en tio n, Ru ss ia n Fe de ra tio n То ж ие в М С , Н ор бе ко в М С , Ш ес то в Д Б, и д ру ги е, Хв ан Ю Е, В ор об ье в А М , Т ер еб ов А А и д ру ги е (2 00 4) . Р ас пр ос тр ан ен но ст ь иш ем ич ес ко й бо ле зн и се рд ца , о сн ов ны х ф ак то ро в ри ск а ее р аз ви ти я и эф ф ек ти вн ос ть м но го ле тн ей м но го ф ак то рн ой п ро ф ил ак ти ки н а пр ед пр ия ти ях в р яд е ре ги он ов Р ос си и [P re va le nc e of is ch em ic h ea rt di se as e, b as ic ri sk fa ct or s an d effi ca cy o f l on g- te rm m ul tif ac to ria l p ro ph yl ax is at w or k in s om e re gi on s of th e Ru ss ia n Fe de ra tio n] . Т ер ап ев ти че ск ий ар хи в. 7 6( 1): 33 –8 (in R us si an ). PM ID : 1 51 08 43 5. То ж ие в М С , Х ва н Ю Е, Ш ес то в Д Б, Т ад ж ие в Ф С , В ор об ье в А М , О чи ло ва РХ и д ру ги е (2 00 7) . Р ас пр ос тр ан ен но ст ь ар те ри ал ьн ой ги пе рт он ии и эф ф ек ти вн ос ть м но го ле тн ей м но го ф ак то рн ой п ро ф ил ак ти ки в ря де р ег ио но в Ро сс ии . [ Pr ev al en ce o f a rt er ia l h yp er te ns io n an d effi ca cy of lo ng -t er m m ul tif ac to ria l p ro ph yl ax is in s om e re gi on s of R us si a] . Те ра пе вт ич ес ки й ар хи в. 7 9( 1): 27 –3 2 (in R us si an ). PM ID : 1 73 85 46 0. То ж ие в М С , Ш ес то в Д Б, В ор об ье в А М , Т ер еб ов А А , Х оп ти ар В П , Б ы ко в И Н и д ру ги е (2 00 0) . Р ас пр ос тр ан ен но ст ь иш ем ич ес ко й бо ле зн и се рд ца . е е св яз ь с ос но вн ы м и ф ак то ра м и ри ск а и эф ф ек ти вн ос ть м но го ле тн ей м но го ф ак то рн ой п ро ф ил ак ти ки н а пр ом ы ш ле нн ы х пр ед пр ия ти ях [I nc id en ce o f i sc he m ic h ea rt d is ea se : i ts re la tio n w ith th e m ai n ris k fa ct or s an d eff ec tiv en es s of lo ng -t er m m ul tif ac to ria l p re ve nt io n at an in du st ria l e nt er pr is e] . Т ер ап ев ти че ск ий а рх ив . 7 2( 9) :2 3– 6 (in R us si an ). PM ID : 1 10 76 41 1. N ot ra nd om iz ed Ta bl e A 2 co nt d 47 St ud ya Re fe re nc e( s) Re as on Sc re en in g fo r C VD ri sk a nd C VD ri sk fa ct or s M ul tif ac to ria l Pr ev en tio n of Is ch ae m ic H ea rt D is ea se , Ru ss ia n Fe de ra tio n Я ну ш ке ви чи ус З И , Г ла зу но в И С , Б ау би не не А В, Г ра уб ас ка с ВИ , Д ом ар ки ен е С В (19 77 ). М ет од ол ог ич ес ко е ис сл ед ов ан ие м ул ьт иф ак то рн ой п ро ф ил ак ти ки и ш ем ич ес ко й бо ле зн и се рд ца . [M et ho do lo gi ca l s tu dy o f m ul tif ac to ria l p re ve nt io n of is ch em ic h ea rt d is ea se ]. К ар ди ол ог ия . 1 7( 3) :5 2– 8 (in R us si an ). PM ID : 8 86 70 2. Ka lin in a, A (2 01 4) . M ul tif ac to r p rim ar y pr ev en tio n of is ch em ic h ea rt di se as e in m id dl e- ag ed m en a nd it s effi ca cy (1 0- ye ar fo llo w -u p) . R at io na l Ph ar m ac ot he ra py in C ar di ol og y. 10 (1) :6 –1 7. do i:  10 .2 09 96 /1 81 9- 64 46 -2 01 4- 10 -1 -6 -1 7. Ka lin in a A , K on ts ev ay a AV (2 01 4) . M ul tif ac to r p rim ar y pr ev en tio n of is ch em ic he ar t d is ea se in m id dl e- ag ed m en a nd it s effi ca cy (1 5- ye ar fo llo w -u p) . R at io na l Ph ar m ac ot he ra py in C ar di ol og y. 10 (2 ): 13 4– 46 . d oi : 1 0. 20 99 6/ 18 19 -6 44 6- 20 14 -1 0- 2- 13 4- 14 6. N ot ra nd om iz ed M ul tif ac to ria l Pr ev en tio n of Is ch ae m ic H ea rt D is ea se in M en , R us si an Fe de ra tio n М ей м ан ал ие в ТС , Ш ле йф ер Е А , М ад ам ин ов Я К , Ж ил ьф ан ов а ВШ , А йт м ур за ев а ГТ , Ф ин ге р ЕМ и д ру ги е (19 90 ). Э ф ф ек ти вн ос ть 5 -л ет не й пр ог ра м м ы п о м ул ьт иф ак то рн ой п ро ф ил ак ти ке и ш ем ич ес ко й бо ле зн и се рд ца [E ffe ct iv en es s of th e 5- ye ar p ro gr am o f m ul tif ac to ria l p re ve nt io n of is ch ae m ic h ea rt d is ea se in m en ]. С ов ет ск ая м ед иц ин а. (1 2) :5 7– 9 (in Ru ss ia n) . P M ID : 2 15 14 91 . N ot ra nd om iz ed N ew Y or k 19 71 Sh ap iro S , F in k R, R os en be rg C (1 97 2) . A p ro gr am to m ea su re th e im pa ct o f m ul tip ha si c he al th te st in g on h ea lth d iff er en tia ls b et w ee n po ve rt y an d no n- po ve rt y gr ou ps . M ed C ar e. 10 (3 ):2 07 –1 4. d oi : 1 0. 10 97 /0 00 05 65 0- 19 72 05 00 0- 00 00 3. Ra nd om iz at io n no t c om m un ity ba se d Ta bl e A 2 co nt d WHAT IS THE EFFECTIVENESS OF SYSTEMATIC POPULATION-LEVEL SCREENING PROGRAMMES FOR REDUCING THE BURDEN OF CARDIOVASCULAR DISEASES? WHO HEALTH EVIDENCE NETWORK SYNTHESIS REPORT 48 St ud ya Re fe re nc e( s) Re as on Sc re en in g fo r C VD ri sk a nd C VD ri sk fa ct or s N H S H ea lth C he ck C al ey M , C ho ha n P, H oo pe r J , W rig ht N (2 01 4) . T he im pa ct o f N H S H ea lth C he ck s on th e pr ev al en ce o f d is ea se in g en er al p ra ct ic es : a c on tr ol le d st ud y. Br J G en P ra ct . 6 4( 62 5) :e 51 6– 21 . d oi : 1 0. 33 99 /b jg p1 4X 68 10 13 . G eu e C , L ew se y JD , M ac Ka y D F, A nt on y G , F is ch ba ch er C M , M ui rie J et a l. (2 01 6) . Sc ot tis h Ke ep W el l h ea lth c he ck p ro gr am m e: a n in te rr up te d tim e se rie s an al ys is . J E pi de m io l C om m un ity H ea lth . 7 0( 9) :9 24 –9 . d oi : 1 0. 113 6/ je ch -2 01 5- 20 69 26 . N ot ra nd om iz ed O sl o st ud y H je rm an n I, Ve lv e By re K , H ol m e I, Le re n P (19 81 ). Eff ec t o f d ie t a nd s m ok in g in te rv en tio n on th e in ci de nc e of c or on ar y he ar t d is ea se . R ep or t f ro m th e O sl o St ud y G ro up o f a ra nd om is ed tr ia l i n he al th y m en . L an ce t. 2( 82 59 ):1 30 3– 10 . do i:  10 .10 16 /s 01 40 -6 73 6( 81 )9 13 38 -6 . H ol m e I, H je rm an n I, H el ge la nd A , L er en P (1 98 5) . T he O sl o St ud y: d ie t a nd an tis m ok in g ad vi ce . A dd iti on al re su lts fr om a 5 -y ea r p rim ar y pr ev en tiv e tr ia l in m id dl e- ag ed m en . P re v M ed . 1 4( 3) :2 79 –9 2. d oi : 1 0. 10 16 /0 09 1- 74 35 (8 5) 90 05 7- x. H ol m e I, Re tt er st ol K , N or um K R, H je rm an n I ( 20 16 ). Li fe lo ng b en efi ts o n m yo ca rd ia l i nf ar ct io n m or ta lit y: 4 0- ye ar fo llo w -u p of th e ra nd om iz ed O sl o di et a nd a nt is m ok in g st ud y. J I nt er n M ed . 2 80 (2 ):2 21 –7 . d oi : 1 0. 111 1/ jo im .12 48 5. Ra nd om iz at io n no t co m m un ity - ba se d O XC H EC K 19 89 Im pe ria l C an ce r R es ea rc h Fu nd O XC H EC K St ud y G ro up . ( 19 91 ). Pr ev al en ce o f ris k fa ct or s fo r h ea rt d is ea se in O XC H EC K tr ia l: im pl ic at io ns fo r s cr ee ni ng in pr im ar y ca re . B M J. 30 2( 67 84 ):1 05 7– 60 . d oi : 1 0. 113 6/ bm j.3 02 .6 78 4. 10 57 . Ra nd om iz at io n no t c om m un ity ba se d Pr ev en tio n of S tr ok e in U rb an C hi na Fa ng X H , K ro nm al R A , L i S C , L on gs tr et h W T Jr, C he ng X M , W an g W Z et a l. (19 99 ). Pr ev en tio n of s tr ok e in u rb an C hi na : a c om m un ity -b as ed in te rv en tio n tr ia l. St ro ke . 3 0( 3) :4 95 –5 01 . d oi : 1 0. 116 1/ 01 .st r.3 0. 3. 49 5. N ot ra nd om iz ed Ta bl e A 2 co nt d 49 St ud ya Re fe re nc e( s) Re as on Sc re en in g fo r C VD ri sk a nd C VD ri sk fa ct or s Sa lt La ke C ity 19 72 O ls en D M , K an e RL , P ro ct or P H (1 97 6) . A c on tr ol le d tr ia l o f m ul tip ha si c sc re en in g. N E ng l J M ed . 2 94 (17 ):9 25 –3 0. d oi : 1 0. 10 56 /N EJ M 19 76 04 22 29 41 70 5. N ot ra nd om iz ed SH EP SH EP C oo pe ra tiv e Re se ar ch G ro up (1 99 1). P re ve nt io n of s tr ok e by an tih yp er te ns iv e dr ug tr ea tm en t i n ol de r p er so ns w ith is ol at ed sy st ol ic hy pe rt en si on . F in al re su lts o f t he S ys to lic H yp er te ns io n in th e El de rly P ro gr am (S H EP ). JA M A . 2 65 (2 4) :3 25 5– 64 . P M ID : 2 04 61 07 . C lin ic al s tu dy Ti to gr ad Th or ne r R M , D jo rd je vi c D , V uc km an ov ic C , P es ic B , C ul afi c B, M ar k F (19 73 ). A st ud y to e va lu at e th e eff ec tiv en es s of m ul tip ha si c sc re en in g in Y ug os la vi a. Pr ev M ed . 2 (2 ):2 95 –3 01 . d oi : 1 0. 10 16 /0 09 1- 74 35 (7 3) 90 07 2- 8. N o re su lts pr ov id ed U pp sa la Li th el l H , A be rg H , S el in us I, H ed st ra nd H (1 98 4) . T he p rim ar y pr ev en tiv e st ud y in U pp sa la . F at al a nd n on -f at al m yo ca rd ia l i nf ar ct io n du rin g a 10 -y ea r f ol lo w - up o f a m id dl e- ag ed m al e po pu la tio n w ith tr ea tm en t o f h ig h- ris k in di vi du al s. A ct a M ed S ca nd . 2 15 (5 ):4 03 –9 . P M ID : 6 74 16 05 N ot ra nd om iz ed W H O C ol la bo ra tiv e Tr ia l o f M ul tif ac to ria l Pr ev en tio n 19 71 D e Ba ck er G , K or ni tz er M , D ra m ai x M , K itt el F , T hi lly C , M G ra ffa r M e t a l. (19 88 ). Th e Be lg ia n H ea rt D is ea se P re ve nt io n Pr oj ec t: 10 -y ea r m or ta lit y fo llo w - up . E ur H ea rt J. 9 (3 ):2 38 –4 2. d oi : 1 0. 10 93 /o xf or dj ou rn al s.e ur he ar tj. a0 62 49 1. Ko rn itz er M , R os e G (1 98 5) . W H O E ur op ea n C ol la bo ra tiv e Tr ia l o f m ul tif ac to ria l pr ev en tio n of c or on ar y he ar t d is ea se . P re v M ed . 1 4( 3) :2 72 –8 . d oi : 1 0. 10 16 /0 09 1- 74 35 (8 5) 90 05 6- 8. Ko rn itz er M , D e Ba ck er G , D ra m ai x M , K itt el F , T hi lly C , G ra ffa r M e t a l. (19 83 ). Be lg ia n he ar t d is ea se p re ve nt io n pr oj ec t: in ci de nc e an d m or ta lit y re su lts . La nc et . 1 (8 33 3) :10 66 –7 0. d oi : 1 0. 10 16 /s 01 40 -6 73 6( 83 )9 19 08 -6 . Re se ar ch G ro up o f t he R om e Pr oj ec t o f C or on ar y H ea rt D is ea se P re ve nt io n. (19 86 ). Ei gh t- ye ar fo llo w -u p re su lts fr om th e Ro m e Pr oj ec t o f C or on ar y H ea rt D is ea se P re ve nt io n. P re v M ed . 1 5( 2) :17 6– 91 . d oi : 1 0. 10 16 /0 09 1- 74 35 (8 6) 90 08 7- 3. Ro se G , T un st al l-P ed oe H D , H el le r R F (19 83 ). U K he ar t d is ea se p re ve nt io n pr oj ec t: in ci de nc e an d m or ta lit y re su lts . L an ce t. 1(8 33 3) :10 62 –6 . d oi : 1 0. 10 16 / s0 14 0- 67 36 (8 3) 91 90 7- 4. Ra nd om iz at io n no t c om m un ity ba se d Ta bl e A 2 co nt d WHAT IS THE EFFECTIVENESS OF SYSTEMATIC POPULATION-LEVEL SCREENING PROGRAMMES FOR REDUCING THE BURDEN OF CARDIOVASCULAR DISEASES? WHO HEALTH EVIDENCE NETWORK SYNTHESIS REPORT 50 St ud ya Re fe re nc e( s) Re as on Sc re en in g fo r C VD ri sk a nd C VD ri sk fa ct or s Ry w ik S , C ha rz ew sk a J, Sz os ta k W B, W ag ro w sk a H , C ha br os E , S ob ot ow sk a M et a l. (19 80 ). [P ol is h ex pe rim en t w ith re ga rd to c or on ar y di se as e pr ev en tio n. I. C ha ra ct er is tic s of th e m al e po pu la tio n of th e W ar sa w in du st ria l p la nt s pa rt ic ip at in g in th e C or on ar y D is ea se P re ve nt io n Pr og ra m ]. Ka rd io l P ol . 23 (1) :4 1– 9 (in P ol is h) . P M ID : 7 36 60 71 . Sa ns M en en de z S (19 93 ). En sa yo ra nd om iz ad o de p re ve nc io n m ul tif ac to ria l d e la c ar di op at ia is qu em ic a [R an do m iz ed m ul tif ac to ria l p re ve nt io n of is ch ae m ic ca rd io pa th y] [t he si s] . B ar ce lo na : A ut on om ou s U ni ve rs ity o f B ar ce lo na (i n Sp an is h) . W or ld H ea lth O rg an iz at io n Eu ro pe an C ol la bo ra tiv e G ro up (1 97 4) . A n in te rn at io na l c on tr ol le d tr ia l i n th e m ul tif ac to ria l p re ve nt io n of c or on ar y he ar t d is ea se . I nt J Ep id em io l. 3( 3) :2 19 –2 4. d oi : 1 0. 10 93 /i je /3 .3 .2 19 . W or ld H ea lth O rg an iz at io n Eu ro pe an C ol la bo ra tiv e G ro up (1 98 6) . E ur op ea n co lla bo ra tiv e tr ia l o f m ul tif ac to ria l p re ve nt io n of c or on ar y he ar t d is ea se : fi na l re po rt o n th e 6- ye ar re su lts . L an ce t. 1(8 48 6) :8 69 –7 2. P M ID : 2 87 03 51 . W or ld H ea lth O rg an iz at io n Eu ro pe an C ol la bo ra tiv e G ro up (1 99 0) . W H O Eu ro pe an C ol la bo ra tiv e Tr ia l i n th e m ul tif ac to ria l p re ve nt io n of c or on ar y he ar t d is ea se . I A RC S ci P ub l. (10 3) :12 3- 31 . P M ID : 2 27 97 89 .] Ra nd om iz at io n no t c om m un ity ba se d Sc re en in g fo r A A A Sw ed en Jo ha ns so n M , Z ah l P H , S ie rs m a V, Jø rg en se n KJ , M ar kl un d B, B ro de rs en J (2 01 8) . Be ne fit s an d ha rm s of s cr ee ni ng m en fo r a bd om in al a or tic a ne ur ys m in Sw ed en : a re gi st ry -b as ed c oh or t s tu dy . L an ce t. 39 1(1 01 38 ):2 44 1– 7. do i:  10 .10 16 / S0 14 0- 67 36 (18 )3 10 31 -6 . W an ha in en A , H ul tg re n R, L in ne A , H ol st J, G ot ts ät er A , L an ge ns ki öl d M et a l. (2 01 6) . O ut co m e of th e Sw ed is h N at io nw id e A bd om in al A or tic A ne ur ys m S cr ee ni ng P ro gr am . C irc ul at io n. 13 4( 16 ):1 14 1– 8. d oi : 1 0. 116 1/ C IR C U LA TI O N A H A .11 6. 02 23 05 . N ot ra nd om iz ed ; no t R C Ts Ta bl e A 2 co nt d 51 St ud ya Re fe re nc e( s) Re as on Sc re en in g fo r C VD ri sk a nd C VD ri sk fa ct or s Sc re en in g fo r A F U ni te d Ki ng do m b M cC ah on D , F itz m au ric e D A , B ak er J, M ur ra y ET , J ow et t S , S an dh ar H e t a l. (2 01 4) . A tr ia l fi br ill at io n: is s cr ee ni ng e ffe ct iv e in id en tif yi ng p at ie nt s at ri sk o f st ro ke ? B r J H ae m . 2 01 4; 16 5( Su pp l 1 ):1 0– 11. C on fe re nc e pa pe r; pr ob ab ly no t a R C T M is ce lla ne ou s o th er st ud ie s Ru ss ia n Fe de ra tio n К ал ин ин а А М , И па то в П В, К уш ун ин а Д В, Е го ро в ВА , Д ро зд ов а Л Ю , Б ой цо в С А (2 01 6) . Р ез ул ьт ат ы в ы яв ле ни я бо ле зн ей с ис те м ы кр ов оо бр ащ ен ия п ри д ис па нс ер из ац ии в зр ос ло го н ас ел ен ия : оп ы т пе рв ы х 2 ле т [R es ul ts o f c irc ul at or y di se as e de te ct io n du rin g pr op hy la ct ic m ed ic al e xa m in at io n of th e ad ul t p op ul at io n: th e fir st tw o ye ar s’ ex pe rie nc e] . Т ер ап ев ти че ск ий а рх ив . 8 8( 1): 46 –5 2 (in R us si an ). do i:  10 .17 116 / te ra rk h2 01 68 81 46 -5 2. К ал ин ин а А М , К уш ун ин а Д В, Г ор ны й БЭ , А нт он ов К А , Б ет яе ва О В, С ок ол ов Г Е (2 01 9) . П от ен ци ал п ро ф ил ак ти ки с ер де чн о- со су ди ст ы х за бо ле ва ни й по р ез ул ьт ат ам д ис па нс ер из ац ии в зр ос ло го н ас ел ен ия . [T he p ot en tia l o f c ar di ov as cu la r d is ea se s’ pr ev en tio n ac co rd in g to th e re su lts of d is pe ns ar y ex am in at io ns o f t he a du lt po pu la tio n] . К ар ди ов ас ку ля рн ая те ра пи я и пр оф ил ак ти ка . 1 8( 4) :6 9– 76 (i n Ru ss ia n) . d oi : 1 0. 15 82 9/ 17 28 -8 80 0- 20 19 -4 -6 9- 76 . Я ко вл ев а ТВ , В ы ле гж ан ин С В, Б ой цо в С А , К ал ин ин а А М , И па то в П В (2 01 4) . Д ис па нс ер из ац ия в зр ос ло го н ас ел ен ия Р ос си йс ко й Ф ед ер ац ии : п ер вы й го д ре ал из ац ии , о пы т, ре зу ль та ты , п ер сп ек ти вы [R eg ul ar m ed ic al e xa m in at io n of a du lts in th e Ru ss ia n Fe de ra tio n: fi rs t y ea r im pl em en ta tio n: le ss on s le ar nt , r es ul ts a nd p er sp ec tiv es ]. С оц иа ль ны е ас пе кт ы зд ор ов ья н ас ел ен ия . 4 (3 8) : 2 (i n Ru ss ia n) . N ot ra nd om iz ed Ta bl e A 2 co nt d WHAT IS THE EFFECTIVENESS OF SYSTEMATIC POPULATION-LEVEL SCREENING PROGRAMMES FOR REDUCING THE BURDEN OF CARDIOVASCULAR DISEASES? WHO HEALTH EVIDENCE NETWORK SYNTHESIS REPORT 52 St ud ya Re fe re nc e( s) Re as on Sc re en in g fo r C VD ri sk a nd C VD ri sk fa ct or s C an ad a Kh an N A , M cA lis te r F A , C am pb el l N R, F el dm an R D , R ab ki n S, M ah on J et al . ( 20 04 ). Th e 20 04 C an ad ia n re co m m en da tio ns fo r t he m an ag em en t o f hy pe rt en si on : P ar t I I – T he ra py . C an J C ar di ol . 2 0( 1): 41 –5 4. P M ID : 1 49 68 14 2. N ot R C Ts : co m m en ta ry o r re vi ew s U on um a, Ja pa n C om m un ity h ea lth s ur ve y in U on um a- re gi on ; U on um a co ho rt s tu dy . In flu en ce o f d ie t a nd p hy si ca l a ct iv ity o n pr og re ss io n of th e m et ab ol ic do m in o: c om m un ity -b as ed a nd h ea lth c he ck up sy st em -b as ed p ro sp ec tiv e co ho rt -s tu dy (h tt ps :// up lo ad .u m in .a c. jp /c gi -o pe n- bi n/ ic dr _e /c tr _v ie w . cg i?r ec pt no =R 00 00 16 35 1, ac ce ss ed 2 1 O ct ob er 2 02 0) . N ot R C Ts : co m m en ta ry o r re vi ew s Si ng ap or e H ug he s K (19 97 ). Sc re en in g fo r a nd tr ea tm en t o f h yp er ch ol es te ro la em ia : a re vi ew . A nn A ca d M ed S in ga p. 2 6( 2) :2 15 –2 0. P M ID : 9 20 80 77 . Sw ed en Sa m ue lss on O (1 98 5) . H yp er te ns io n in m id dl e- ag ed m en . M an ag em en t, m or bi di ty a nd p ro gn os tic fa ct or s du rin g lo ng -t er m h yp er te ns iv e ca re . A ct a M ed S ca nd S up pl . 7 02 :1– 79 . P M ID : 3 86 64 85 . U ni te d St at es c U pc hu rc h G Jr (2 00 7) . [ C om m en ta ry o n] A s us ta in ed m or ta lit y be ne fit fr om sc re en in g fo r a bd om in al a or tic a ne ur ys m . A CC C ar di os ou rc e Re v J. 16 :6 –7 . C hi na , au to no m ou s re gi on o f Ti be t, an d In di a A ja y VS , T ia n M , C he n H , W u Y, L i X , D un zh u D e t a l. (2 01 4) . A c lu st er - ra nd om iz ed c on tr ol le d tr ia l t o ev al ua te th e eff ec ts o f a s im pl ifi ed ca rd io va sc ul ar m an ag em en t p ro gr am in T ib et , C hi na a nd H ar ya na , I nd ia : st ud y de si gn a nd ra tio na le . B M C P ub lic H ea lth . 1 4: 92 4. d oi : 1 0. 118 6/ 14 71 -2 45 8- 14 -9 24 . Ra nd om iz at io n no t c om m un ity ba se d Ta bl e A 2 co nt d 53 St ud ya Re fe re nc e( s) Re as on Sc re en in g fo r C VD ri sk a nd C VD ri sk fa ct or s SC A LE U P, N ai ro bi , Ke ny a O ti SO , v an d e Vi jv er S J, Ky ob ut un gi C , G om ez G B, C ha rle s A gy em an g C , M ol l va n C ha ra nt e EP e t a l. (2 01 3) . A c om m un ity -b as ed in te rv en tio n fo r p rim ar y pr ev en tio n of c ar di ov as cu la r d is ea se s in th e sl um s of N ai ro bi : t he S C A LE U P st ud y pr ot oc ol fo r a p ro sp ec tiv e qu as i-e xp er im en ta l c om m un ity -b as ed tr ia l. Tr ia ls . 1 4: 40 9. d oi : 1 0. 118 6/ 17 45 -6 21 5- 14 -4 09 . W ro ng ou tc om es A D D IT IO N : A ng lo -D an is h- D ut ch S tu dy o f I nt en si ve T re at m en t I n Pe O pl e W ith s cr ee N D et ec te d D ia be te s in P rim ar y C ar e; J- D O IT 3: Ja pa n D ia be te s O pt im al In te gr at ed T re at m en t S tu dy fo r 3 M aj or R is k Fa ct or s of C ar di ov as cu la r D is ea se s; M RF IT : M ul tip le R is k Fa ct or In te rv en tio n Tr ia l f or th e Pr ev en tio n of C or on ar y H ea rt D is ea se ; O XC H EC K: O xf or d an d C ol la bo ra to rs H ea lth C H EC K Tr ia l; SC A LE U P: S us ta in ab le m od el fo r C ar di ov as cu la r h ea lth b y A dj us tin g Li fe st yl e an d tr ea tm en t w ith E co no m ic p er sp ec tiv e in s et tin gs o f U rb an P ov er ty ; S H EP : S ys to lic H yp er te ns io n in th e El de rly P ro gr am . a F or S cr ee ni ng fo r C VD ri sk a nd C VD ri sk fa ct or s, th e RC T na m e or g eo gr ap hi ca l l oc at io n is g iv en ; f or th e A A A /A F/ m is ce lla ne ou s ot he r s tu di es , ( m ai nl y re vi ew s an d co m m en ta rie s) , t he g eo gr ap hi ca l l oc at io n re la te s to th e au th or a ffi lia tio n. b A ut ho r a ffi lia tio n: U ni ve rs ity o f O xf or d. c A ut ho r a ffi lia tio n: U ni ve rs ity o f F lo rid a H ea lth . Ta bl e A 2 co nt d WHAT IS THE EFFECTIVENESS OF SYSTEMATIC POPULATION-LEVEL SCREENING PROGRAMMES FOR REDUCING THE BURDEN OF CARDIOVASCULAR DISEASES? WHO HEALTH EVIDENCE NETWORK SYNTHESIS REPORT 54 ANNEX 3. RISK OF BIAS IN THE INCLUDED STUDIES The risk of bias was assessed, where possible, in the included studies using the RoB 2 Cochrane risk-of-bias tool for randomized trials (102). Tables A3.1–A3.3 describe the bias risk in 12 RCTs on screening for CVD risk factors, four RCTs on screening for AAA and one RCT on screening for other preclinical CVDs. Where available, the formal name of each RCT is given; where not, the geographical location is given. NB: references are given in the main reference list. 55 Ta bl e A 3. 1. A ss es sm en t o f b ia s r is k in th e in cl ud ed st ud ie s o n sc re en in g fo r C VD ri sk fa ct or s St ud y, st ar t y ea r O ut co m e( s) o f in te re st Bi as ri sk : do m ai n Ju dg em en t o f ris k le ve l Re as on fo r j ud ge m en t D an M O N IC A , 19 82 (2 3) To ta l m or ta lit y, IH D m or bi di ty & m or ta lit y (c om bi ne d) , st ro ke m or bi di ty & m or ta lit y (t ot al ) Ra nd om iz at io n pr oc es s Lo w Ra nd om iz at io n w as d on e by co m pu te r Ba se lin e ch ar ac te ris tic s w er e co m pa ra bl e D ev ia tio n fr om th e in te nd ed in te rv en tio ns Lo w It w as n ot p os si bl e to b lin d th e in te rv en tio n gr ou p, b ut th e co nt ro l gr ou p w as n ev er c on ta ct ed Th e in te rv en tio n ai m ed to c ha ng e pe op le ’s be ha vi ou r, an d kn ow le dg e of be in g pa rt o f a n in te rv en tio n w ou ld pr ob ab ly n ot h av e le d to b ia s A pp ro pr ia te a na ly se s w er e co nd uc te d M iss in g ou tc om e da ta Lo w O ut co m e da ta w er e co lle ct ed th ro ug h re gi st er s co nt ai ni ng c om pl et e fo llo w - up d at a M ea su re m en t o f th e in te rv en tio n Lo w Re le va nt IC D -1 0 co de s w er e de ci de d up on b ef or e co nd uc tin g th e an al ys es Re gi st er d at a w er e ap pr op ria te fo r ou tc om es o n to ta l m or ta lit y an d on C VD m or bi di ty & m or ta lit y Se le ct io n of th e re po rt ed re su lts Lo w Po st h oc a na ly si s, bu t a n an al ys is p la n (in cl ud in g se le ct io n of re le va nt IC D -1 0 co de s) w as m ad e be fo re th e an al ys es w er e co nd uc te d O ve ra ll Lo w – WHAT IS THE EFFECTIVENESS OF SYSTEMATIC POPULATION-LEVEL SCREENING PROGRAMMES FOR REDUCING THE BURDEN OF CARDIOVASCULAR DISEASES? WHO HEALTH EVIDENCE NETWORK SYNTHESIS REPORT 56 St ud y, st ar t y ea r O ut co m e( s) o f in te re st Bi as ri sk : do m ai n Ju dg em en t o f ris k le ve l Re as on fo r j ud ge m en t Eb el to ft , 1 99 1 (2 4– 26 ) To ta l m or ta lit y, C VD m or bi di ty & m or ta lit y (c om bi ne d) Ra nd om iz at io n pr oc es s Lo w Ra nd om iz at io n w as c on du ct ed in de pe nd en tly o f t he in ve st ig at or s Ba se lin e ch ar ac te ris tic s w er e co m pa ra bl e D ev ia tio n fr om th e in te nd ed in te rv en tio ns So m e co nc er ns It w as n ot p os si bl e to b lin d th e in te rv en tio n gr ou p G Ps w er e no t b lin de d, w hi ch c ou ld ha ve h ad s pi ll- ov er e ffe ct s in th e co nt ro l g ro up A pp ro pr ia te a na ly se s w er e co nd uc te d M iss in g ou tc om e da ta Lo w O ut co m e da ta w er e co lle ct ed th ro ug h re gi st er s w ith c om pl et e fo llo w -u p M ea su re m en t o f th e in te rv en tio n Lo w Re le va nt IC D -1 0 co de s w er e de ci de d up on b ef or e co nd uc tin g th e an al ys es Re gi st er d at a w er e ap pr op ria te fo r ou tc om es o n to ta l m or ta lit y, C VD m or bi di ty & m or ta lit y Se le ct io n of th e re po rt ed re su lts Lo w Po st h oc a na ly si s, bu t r el ev an t IC D -c od es w er e se le ct ed b ef or e th e an al ys es w er e co nd uc te d O ve ra ll So m e co nc er ns – Ta bl e A 3. 1 c on td 57 St ud y, st ar t y ea r O ut co m e( s) o f in te re st Bi as ri sk : do m ai n Ju dg em en t o f ris k le ve l Re as on fo r j ud ge m en t El y, 19 90 (2 7,2 8) Se lf- re po rt ed m ed ic at io n us e (n ew m ed ic at io n) Ra nd om iz at io n pr oc es s So m e co nc er ns Th e al lo ca tio n se qu en ce w as ra nd om Th er e w er e ba se lin e di ffe re nc es be tw ee n gr ou ps Ri sk o f b ia s du e to d ev ia tio n fr om th e in te nd ed in te rv en tio ns H ig h Fo llo w -u p da ta w er e on ly a va ila bl e fo r 43 % o f p ar tic ip an ts It w as n ot p os si bl e to b lin d th e in te rv en tio n gr ou p, a nd th e co nt ro l gr ou p w as n ev er c on ta ct ed M iss in g ou tc om e da ta H ig h Fo llo w -u p da ta w er e on ly a va ila bl e fo r 43 % o f p ar tic ip an ts Th e an al ys es d id n ot c or re ct fo r po te nt ia l b ia s ar is in g fr om th e m iss in g ou tc om e da ta M ea su re m en t o f th e in te rv en tio n H ig h Se lf- re po rt ed o ut co m es w er e no t ap pr op ria te , c on si de rin g th e hi gh at tr iti on ra te Se le ct io n of th e re po rt ed re su lts So m e co nc er ns Pr ob ab ly n o pr e- sp ec ifi ed a na ly si s pl an fo r t hi s ou tc om e N o ra tio na le w as p ro vi de d fo r co lle ct in g se lf- re po rt ed d at a on m ed ic at io n us e O ve ra ll H ig h – Ta bl e A 3. 1 c on td WHAT IS THE EFFECTIVENESS OF SYSTEMATIC POPULATION-LEVEL SCREENING PROGRAMMES FOR REDUCING THE BURDEN OF CARDIOVASCULAR DISEASES? WHO HEALTH EVIDENCE NETWORK SYNTHESIS REPORT 58 St ud y, st ar t y ea r O ut co m e( s) o f in te re st Bi as ri sk : do m ai n Ju dg em en t o f ris k le ve l Re as on fo r j ud ge m en t Er fu rt -S üd , 1 96 8 (2 9) To ta l m or ta lit y, C VD m or ta lit y, IH D m or bi di ty & m or ta lit y (c om bi ne d) , I H D m or ta lit y Ra nd om iz at io n pr oc es s Lo w Pa rt ic ip an ts w er e so rt ed al ph ab et ic al ly , b ut th is w as u nl ik el y to re su lt in b ia s Ri sk o f b ia s du e to d ev ia tio n fr om th e in te nd ed in te rv en tio ns Lo w It w as n ot p os si bl e to b lin d th e in te rv en tio n gr ou p, b ut th e co nt ro l gr ou p w as n ot in fo rm ed a bo ut th e tr ia l M iss in g ou tc om e da ta Lo w Fo llo w -u p th ro ug h re gi st rie s, ho sp ita l re co rd s an d au to ps ie s O nl y tw o pa rt ic ip an ts le ft th e st ud y ar ea M ea su re m en t o f th e in te rv en tio n Lo w A pp ro pr ia te m et ho d us ed to m ea su re th e ou tc om e – un lik el y to re su lt in bi as Se le ct io n of th e re po rt ed re su lts Lo w N o in di ca tio n of s el ec tiv e re po rt in g O ve ra ll Lo w – Fa m ily H ea rt a (3 0) Pr es cr ip tio n of m ed ic at io ns (n ew m ed ic at io n) Ra nd om iz at io n pr oc es s Lo w Ra nd om iz at io n pr oc es s no t d es cr ib ed in m uc h de ta il, b ut p ar tic ip an ts w er e as si gn ed to e ith er in te rv en tio n or co nt ro l c on di tio n at th e sa m e tim e Ta bl e A 3. 1 c on td 59 St ud y, st ar t y ea r O ut co m e( s) o f in te re st Bi as ri sk : do m ai n Ju dg em en t o f ris k le ve l Re as on fo r j ud ge m en t D ev ia tio n fr om th e in te nd ed in te rv en tio ns Lo w It w as n ot p os si bl e to b lin d th e in te rv en tio n gr ou p, b ut th e co nt ro l gr ou p w as n ot in fo rm ed a bo ut th e tr ia l Th e in te rv en tio n ai m ed to c ha ng e pe op le ’s be ha vi ou r, an d kn ow le dg e of be in g pa rt o f a n in te rv en tio n w ou ld pr ob ab ly n ot le ad to b ia s C on tr ol g ro up u na w ar e of th e tr ia l C lu st er R C T de si gn re du ce d th e ris k of c on ta m in at io n of th e co nt ro l g ro up M iss in g ou tc om e da ta H ig h Si gn ifi ca nt lo ss to fo llo w -u p M ea su re m en t o f th e in te rv en tio n H ig h La ck o f i nf or m at io n on h ow m ea su re m en t o f p re sc rip tio ns w as m ad e A ss es sm en t c ou ld h av e di ffe re d be tw ee n gr ou ps Se le ct io n of th e re po rt ed re su lts So m e co nc er ns N o in fo rm at io n on a na ly si s pl an co nc er ni ng th is s pe ci fic o ut co m e O ve ra ll H ig h – Ta bl e A 3. 1 c on td WHAT IS THE EFFECTIVENESS OF SYSTEMATIC POPULATION-LEVEL SCREENING PROGRAMMES FOR REDUCING THE BURDEN OF CARDIOVASCULAR DISEASES? WHO HEALTH EVIDENCE NETWORK SYNTHESIS REPORT 60 St ud y, st ar t y ea r O ut co m e( s) o f in te re st Bi as ri sk : do m ai n Ju dg em en t o f ris k le ve l Re as on fo r j ud ge m en t G ot he nb ur g, 19 63 (3 1) To ta l m or ta lit y, C VD m or ta lit y Ra nd om iz at io n pr oc es s Lo w A llo ca tio n w as b as ed o n bi rt h da te bu t i s no t e xp ec te d to c om pr om is e th e ra nd om iz at io n pr oc es s A llo ca tio n to ok p la ce b ef or e th e in te rv en tio n w as g iv en D ev ia tio n fr om th e in te nd ed in te rv en tio ns Lo w It w as n ot p os si bl e to b lin d th e in te rv en tio n gr ou p, b ut th e co nt ro l gr ou p w as n ev er c on ta ct ed a nd th e re gu la r p hy si ci an s of p ar tic ip an ts in th e in te rv en tio n gr ou p w er e no t in vo lv ed M iss in g ou tc om e da ta Lo w Th e st ud y re po rt s ta te d th at “l os s to fo llo w -u p by th e en d of 19 77 w as 0 .3 % in th e ex pe rim en ta l g ro up a nd 1% in th e co nt ro l g ro up ” M ea su re m en t o f th e in te rv en tio n M or ta lit y ou tc om es : lo w C VD m or ta lit y ou tc om es : hi gh D ea th c er tifi ca te s w er e as se ss ed , a nd so m e w er e re cl as si fie d fo r c au se o f de at h O ut co m e as se ss or s w er e no t b lin de d to a llo ca tio n st at us (2 2) Ta bl e A 3. 1 c on td 61 St ud y, st ar t y ea r O ut co m e( s) o f in te re st Bi as ri sk : do m ai n Ju dg em en t o f ris k le ve l Re as on fo r j ud ge m en t Se le ct io n of th e re po rt ed re su lts So m e co nc er ns Pr ob ab ly n o pr e- sp ec ifi ed a na ly si s pl an O ve ra ll To ta l m or ta lit y ou tc om es : so m e co nc er ns – C VD m or ta lit y ou tc om es : hi gh G ot he nb ur g, 19 70 (3 2) To ta l m or ta lit y, IH D m or bi di ty & m or ta lit y (c om bi ne d) , st ro ke m or bi di ty & m or ta lit y (c om bi ne d) , I H D m or ta lit y, st ro ke m or ta lit y Ra nd om iz at io n pr oc es s Lo w A llo ca tio n w as d on e by c om pu te r ( 22 ) D ev ia tio n fr om th e in te nd ed in te rv en tio ns Lo w It w as n ot p os si bl e to b lin d th e in te rv en tio n gr ou p Pa rt ic ip an ts w er e ra nd om iz ed b ef or e co nt ac t N ei th er G Ps n or th e co nt ro l g ro up w er e co nt ac te d M iss in g ou tc om e da ta Lo w C om pl et e fo llo w -u p M ea su re m en t o f th e in te rv en tio n Lo w Re gi st er d at a w er e us ed Se le ct io n of re po rt re su lts Lo w Pr e- sp ec ifi ed a na ly si s pl an O ve ra ll Lo w – Ta bl e A 3. 1 c on td WHAT IS THE EFFECTIVENESS OF SYSTEMATIC POPULATION-LEVEL SCREENING PROGRAMMES FOR REDUCING THE BURDEN OF CARDIOVASCULAR DISEASES? WHO HEALTH EVIDENCE NETWORK SYNTHESIS REPORT 62 St ud y, st ar t y ea r O ut co m e( s) o f in te re st Bi as ri sk : do m ai n Ju dg em en t o f ris k le ve l Re as on fo r j ud ge m en t In te r9 9, 19 99 (2 1,3 3– 37 ) To ta l m or ta lit y, C VD m or bi di ty & m or ta lit y (c om bi ne d) , st ro ke m or bi di ty & m or ta lit y (c om bi ne d) , IH D m or bi di ty & m or ta lit y (c om bi ne d) , n ew m ed ic at io ns , ho sp ita liz at io n Ra nd om iz at io n pr oc es s Lo w Ra nd om iz at io n w as b y co m pu te r be fo re a ny c on ta ct w as m ad e w ith pa rt ic ip an ts Ri sk o f b ia s du e to d ev ia tio n fr om th e in te nd ed in te rv en tio ns Lo w It w as n ot p os si bl e to b lin d th e in te rv en tio n gr ou p, b ut th e co nt ro l gr ou p w as n ot in fo rm ed a bo ut th e tr ia l. Th e in te rv en tio n ai m ed to c ha ng e pe op le ’s be ha vi ou r, an d kn ow le dg e of be in g pa rt o f a n in te rv en tio n gr ou p w ou ld p ro ba bl y no t l ea d to b ia s. A pp ro pr ia te a na ly se s w er e co nd uc te d M iss in g ou tc om e da ta Lo w Re gi st er d at a us ed M ea su re m en t o f th e in te rv en tio n Lo w Pr e- se le ct ed IC D -1 0 co de s w er e us ed to m ea su re th e ou tc om e Se le ct io n of th e re po rt ed re su lts Lo w A na ly se s w er e in a cc or da nc e w ith a pr e- sp ec ifi ed a na ly si s pl an O ve ra ll Lo w – M al m ö, 19 69 (3 8, 39 ) To ta l m or ta lit y, C VD m or ta lit y, ho sp ita liz at io n, di sa bi lit y pe ns io n Ra nd om iz at io n pr oc es s Lo w A llo ca tio n w as b as ed o n bi rt h da te bu t i s no t e xp ec te d to c om pr om is e th e ra nd om iz at io n pr oc es s. It al so to ok p la ce b ef or e de liv er y of th e in te rv en tio n D ev ia tio n fr om th e in te nd ed in te rv en tio ns Lo w It w as n ot p os si bl e to b lin d th e in te rv en tio n gr ou p, b ut th e co nt ro l gr ou p an d th ei r r eg ul ar p hy si ci an s w er e no t i nf or m ed a bo ut th e tr ia l Ta bl e A 3. 1 c on td 63 St ud y, st ar t y ea r O ut co m e( s) o f in te re st Bi as ri sk : do m ai n Ju dg em en t o f ris k le ve l Re as on fo r j ud ge m en t M iss in g ou tc om e da ta Lo w 99 % fo llo w -u p on m or ta lit y M ea su re m en t o f th e in te rv en tio n Lo w Th e ou tc om e as se ss or w as n ot a w ar e of a llo ca tio n (2 2) Se le ct io n of th e re po rt ed re su lts Lo w N o in di ca tio n of s el ec tiv e re po rt in g O ve ra ll Lo w – N or th um be rla nd , 19 69 (4 0) H os pi ta liz at io ns , nu m be r o f ph ys ic ia n vi si ts , ne w m ed ic at io n, di ag no st ic pr oc ed ur es , ce rt ifi ed s ic kn es s Ra nd om iz at io n pr oc es s So m e co nc er ns A llo ca tio n w as b as ed o n bi rt h da te bu t i s no t e xp ec te d to c om pr om is e th e ra nd om iz at io n pr oc es s. Ba se lin e da ta w er e ba se d on G P re co rd s, an d G Ps w er e aw ar e of th e al lo ca tio n st at us D ev ia tio n fr om th e in te nd ed in te rv en tio ns So m e co nc er ns G Ps tr ea te d bo th in te rv en tio n an d co nt ro l p ar tic ip an ts le ad in g to ri sk of c on ta m in at io n. P ro ba bl e th at pa rt ic ip an ts w er e an al ys ed a s pa rt o f th e gr ou p th ey w er e as si gn ed to M iss in g ou tc om e da ta Lo w 90 .2 % o f p ar tic ip an ts c oo pe ra te d fu lly ; 5 .2 % c oo pe ra te d pa rt ia lly M ea su re m en t o f th e in te rv en tio n H ig h O ut co m e as se ss m en t c ou ld h av e be en in flu en ce d by k no w le dg e of a llo ca tio n st at us Se le ct io n of th e re po rt ed re su lts So m e co nc er ns La ck o f i nf or m at io n on a p re -s pe ci fie d an al ys is p la n O ve ra ll H ig h – Ta bl e A 3. 1 c on td WHAT IS THE EFFECTIVENESS OF SYSTEMATIC POPULATION-LEVEL SCREENING PROGRAMMES FOR REDUCING THE BURDEN OF CARDIOVASCULAR DISEASES? WHO HEALTH EVIDENCE NETWORK SYNTHESIS REPORT 64 St ud y, st ar t y ea r O ut co m e( s) o f in te re st Bi as ri sk : do m ai n Ju dg em en t o f ris k le ve l Re as on fo r j ud ge m en t So ut h- Ea st Lo nd on , 1 96 7 (4 1) To ta l m or ta lit y, C VD m or ta lit y, ho sp ita liz at io ns , ph ys ic ia n vi si ts , ce rt ifi ed s ic kn es s Ra nd om iz at io n pr oc es s H ig h U nc le ar d es cr ip tio n of a llo ca tio n pr oc es s. A llo ca tio n to ok p la ce b ef or e de liv er y of th e in te rv en tio n D ev ia tio n fr om th e in te nd ed in te rv en tio ns So m e co nc er ns It w as n ot p os si bl e to b lin d th e in te rv en tio n gr ou p, b ut th is is n ot ex pe ct ed to re su lt in b ia s du e to th e na tu re o f t he in te rv en tio n. D ue to e m ig ra tio n fr om th e st ud y si te , th e co nt ro l g ro up w as in vi te d fo r sc re en in g af te r 4  y ea rs , w hi ch w as n ot pl an ne d M iss in g ou tc om e da ta Lo w D at a w er e av ai la bl e fo r m os t pa rt ic ip an ts M ea su re m en t o f th e in te rv en tio n To ta l m or ta lit y & C VD m or ta lit y: lo w N ot li ke ly to re su lt in b ia s fo r ou tc om es m ea su rin g m or ta lit y an d m or bi di ty Ph ys ic ia n vi si ts & ce rt ifi ed si ck ne ss : h ig h O rig in al ly , d at a w er e co lle ct ed fr om h ea lth -c ar e pr ov id er s. D ue to m ig ra tio n iss ue s, th is w as su pp le m en te d w ith a s ur ve y Se le ct io n of th e re po rt ed re su lts Lo w N o in di ca tio n of s el ec tiv e re po rt in g O ve ra ll H ig h – Ta bl e A 3. 1 c on td 65 St ud y, st ar t y ea r O ut co m e( s) o f in te re st Bi as ri sk : do m ai n Ju dg em en t o f ris k le ve l Re as on fo r j ud ge m en t St oc kh ol m , 1 96 9 (4 2) To ta l m or ta lit y, C VD m or ta lit y Ra nd om iz at io n pr oc es s Lo w Ra nd om iz at io n w as d on e by co m pu te r ( 22 ) D ev ia tio n fr om th e in te nd ed in te rv en tio ns Lo w It is n ot p os si bl e to b lin d th e in te rv en tio n gr ou p, b ut th is is n ot ex pe ct ed to re su lt in b ia s du e to th e na tu re o f t he in te rv en tio n. A pp ro pr ia te a na ly se s w er e co nd uc te d M iss in g ou tc om e da ta Lo w A ll pa rt ic ip an ts w er e fo llo w ed u p th ro ug h re gi st er s M ea su re m en t o f th e in te rv en tio n Lo w Fo llo w -u p th ro ug h re gi st er s Se le ct io n of th e re po rt ed re su lts Lo w N o in di ca tio n of s el ec tiv e re po rt in g O ve ra ll Lo w – G P: g en er al p ra ct iti on er ; I C D -1 0: 10 th re vi si on o f t he In te rn at io na l C la ss ifi ca tio n of D is ea se s; In te r9 9: A R an do m is ed N on -p ha rm ac ol og ic al In te rv en tio n St ud y fo r P re ve nt io n of Is ch ae m ic H ea rt D is ea se In te r9 9. a N o in fo rm at io n gi ve n on w he n th e ba se lin e da ta w er e co lle ct ed . Ta bl e A 3. 1 c on td WHAT IS THE EFFECTIVENESS OF SYSTEMATIC POPULATION-LEVEL SCREENING PROGRAMMES FOR REDUCING THE BURDEN OF CARDIOVASCULAR DISEASES? WHO HEALTH EVIDENCE NETWORK SYNTHESIS REPORT 66 Ta bl e  A 3. 2. A ss es sm en t o f b ia s r is k in th e in cl ud ed st ud ie s o n sc re en in g fo r A A A St ud y, st ar t y ea r O ut co m e( s) o f in te re st Bi as ri sk : do m ai n Ju dg em en t of ri sk le ve l Re as on fo r j ud ge m en t C hi ch es te r, 19 89 (4 5– 47 ) A A A m or ta lit y, in ci de nc e of A A A ru pt ur e, to ta l m or ta lit y Ra nd om iz at io n pr oc es s Lo w Ra nd om iz at io n w as d on e by co m pu te r b y an e xt er na l r es ea rc h un it D ev ia tio n fr om th e in te nd ed in te rv en tio ns Lo w It is n ot p os si bl e to b lin d th e in te rv en tio n gr ou p, b ut th e co nt ro l gr ou p w as n ev er c on ta ct ed . A pp ro pr ia te a na ly se s w er e co nd uc te d M iss in g ou tc om e da ta Lo w O ut co m e da ta w er e co lle ct ed th ro ug h re gi st er s M ea su re m en t o f th e in te rv en tio n Lo w Re gi st er d at a ar e ap pr op ria te fo r ou tc om es o n to ta l m or ta lit y an d in ci de nc e of A A A ru pt ur e & m or ta lit y Se le ct io n of th e re po rt ed re su lts Lo w O ut co m es p re se nt ed in th e st ud y co rr es po nd w ith th os e re po rt ed in th e tr ia l r eg is tr at io n O ve ra ll Lo w – M ul tic en tr e A ne ur ys m Sc re en in g St ud y, 19 97 (4 8) A A A -r el at ed m or ta lit y, A A A ru pt ur e, to ta l m or ta lit y, co st s Ra nd om iz at io n pr oc es s Lo w Ra nd om iz at io n w as d on e ce nt ra lly b y co m pu te r D ev ia tio n fr om th e in te nd ed in te rv en tio ns So m e co nc er ns In co ns is te nc ie s in th e re po rt ed nu m be r o f p ar tic ip an ts in th e 4- an d 10 -y ea r f ol lo w -u p. A pp ro pr ia te an al ys es w er e co nd uc te d M iss in g ou tc om e da ta Lo w C lo se to c om pl et e fo llo w -u p. D at a co lle ct ed th ro ug h re gi st er s 67 St ud y, st ar t y ea r O ut co m e( s) o f in te re st Bi as ri sk : do m ai n Ju dg em en t of ri sk le ve l Re as on fo r j ud ge m en t M ea su re m en t o f th e in te rv en tio n Lo w Re gi st er d at a ar e ap pr op ria te . O ut co m e as se ss or s no t a w ar e of gr ou p al lo ca tio n Se le ct io n of th e re po rt ed re su lts Lo w Re po rt ed o ut co m es c or re sp on d w ith th e tr ia l r eg is tr at io n O ve ra ll So m e co nc er ns – Vi bo rg , 1 99 4 (4 9) A A A m or ta lit y, to ta l m or ta lit y, co st s Ra nd om iz at io n pr oc es s Lo w A llo ca tio n se qu en ce w as ra nd om D ev ia tio n fr om th e in te nd ed in te rv en tio ns Lo w It is n ot p os si bl e to b lin d th e in te rv en tio n gr ou p, b ut th e co nt ro l gr ou p w as n ev er c on ta ct ed . A pp ro pr ia te a na ly se s w er e co nd uc te d M iss in g ou tc om e da ta Lo w C om pl et e fo llo w -u p M ea su re m en t o f th e in te rv en tio n Lo w Re gi st er d at a ar e ap pr op ria te . O ut co m e as se ss or s w er e no t a w ar e of gr ou p al lo ca tio n Se le ct io n of th e re po rt ed re su lts Lo w Re po rt in g co rr es po nd s w ith th e tr ia l re gi st ra tio n, a nd a pp ro pr ia te a na ly se s w er e co nd uc te d O ve ra ll Lo w – Ta bl e A 3. 2 co nt d WHAT IS THE EFFECTIVENESS OF SYSTEMATIC POPULATION-LEVEL SCREENING PROGRAMMES FOR REDUCING THE BURDEN OF CARDIOVASCULAR DISEASES? WHO HEALTH EVIDENCE NETWORK SYNTHESIS REPORT 68 St ud y, st ar t y ea r O ut co m e( s) o f in te re st Bi as ri sk : do m ai n Ju dg em en t of ri sk le ve l Re as on fo r j ud ge m en t W es te rn A us tr al ia , 19 96 (5 0) A A A m or ta lit y, to ta l m or ta lit y Ra nd om iz at io n pr oc es s Lo w Ra nd om iz at io n w as d on e by co m pu te r D ev ia tio n fr om th e in te nd ed in te rv en tio ns Lo w It is n ot p os si bl e to b lin d th e in te rv en tio n gr ou p, b ut th e co nt ro l gr ou p w as n ev er c on ta ct ed . A pp ro pr ia te a na ly se s w er e co nd uc te d M iss in g ou tc om e da ta Lo w Re gi st er d at a. O ut co m e as se ss or w as no t a w ar e of g ro up a llo ca tio n M ea su re m en t o f th e in te rv en tio n Lo w Re gi st er d at a is a pp ro pr ia te . O ut co m e as se ss or w as n ot a w ar e of g ro up al lo ca tio n Se le ct io n of th e re po rt ed re su lts Lo w N o in di ca tio n of s el ec tiv e re po rt in g O ve ra ll Lo w – Ta bl e A 3. 2 co nt d 69 Ta bl e  A 3. 3. A ss es sm en t o f b ia s r is k in th e in cl ud ed st ud y on c om bi ne d sc re en in g fo r p re cl in ic al C VD s St ud y, st ar t y ea r O ut co m e( s) o f in te re st Bi as ri sk : do m ai n Ju dg em en t of ri sk le ve l Re as on fo r j ud ge m en t Vi bo rg V as cu la r, 20 08 (5 3) To ta l d ea th , C VD - re la te d de at h, A A A -r el at ed de at h Ra nd om iz at io n pr oc es s Lo w Ra nd om iz at io n w as d on e by co m pu te r D ev ia tio n fr om th e in te nd ed in te rv en tio ns Lo w It is n ot p os si bl e to b lin d th e in te rv en tio n gr ou p, b ut th e co nt ro l gr ou p w as n ev er c on ta ct ed . A pp ro pr ia te a na ly se s w er e co nd uc te d M iss in g ou tc om e da ta Lo w <  1% w as lo st to fo llo w -u p M ea su re m en t o f th e in te rv en tio n Lo w Re gi st er d at a is a pp ro pr ia te . O ut co m e as se ss or a nd s ta tis tic ia n w er e no t aw ar e of g ro up a llo ca tio n Se le ct io n of th e re po rt ed re su lts So m e co nc er ns O ut co m es re po rt ed in th e st ud y do no t c or re sp on d fu lly to w ha t w as re gi st er ed w ith c lin ic al tr ia ls .g ov O ve ra ll So m e co nc er ns – WHAT IS THE EFFECTIVENESS OF SYSTEMATIC POPULATION-LEVEL SCREENING PROGRAMMES FOR REDUCING THE BURDEN OF CARDIOVASCULAR DISEASES? WHO HEALTH EVIDENCE NETWORK SYNTHESIS REPORT 70 ANNEX 4. DATA EXTRACTION Tables A4.1–A4.4 describe the data extracted from the included studies on screening for CVD risk factors, AAA, AF and other preclinical CVD. Where available, the formal name of each RCT is given; where not, the geographical location is given. NB: references are given in the main reference list. Table A4.1. Data extracted from included studies on screening for CVD risk Study, start year: status Data category Description DanMONICA, 1982 (23): completed Study design Parallel-group RCT Setting 11 municipalities in the western suburbs of Copenhagen Age and sex of participants 30–60 years at baseline; men and women Country Denmark Date of study Baseline data collected in 1982–1984 Diagnostic tests used Questionnaire (smoking, diet, physical activity, alcohol, family history), clinical examination (weight, height, blood pressure, pulse, ECG, lung function, ultrasound tests and other non-invasive tests), serum lipids and urine analysis Intervention The intervention group was invited for three health checks over the 11-year study period; if needed, participants were referred to GPs Total study duration 30 years (mean: 25.2 years) Number of participants allocated to each arm Intervention group, 4789; control group, 12 994 Loss to follow-up 0% 71 Study, start year: status Data category Description Baseline comparability Older men were intentionally oversampled in the intervention group – this was the only difference between groups at baseline. No difference when adjusted for age and sex Relevant outcomes Total mortality, IHD morbidity & mortality (combined), stroke morbidity & mortality (combined) Results Total mortality: HR = 1.03 (95% CI: 0.98–1.09) IHD morbidity & mortality: HR = 0.99 (95% CI: 0.92–1.07) Stroke morbidity & mortality: HR = 1.14 (95% CI: 1.04–1.25) Ebeltoft, 1991 (24–26): completed Study design Parallel-group RCT Setting 9 GPs in Ebeltoft municipality Age and sex of participants 30–49 years on 1 January 1991; men and women Country Denmark Date of study Baseline data collected in 1991 Diagnostic tests used Questionnaire and assessment of blood tests for cholesterol, glucose and liver enzymes, blood pressure, BMI, carbon monoxide concentration in expired air, serum creatinine, ECG, family medical history, physical endurance, smoking, spirometry, and vision and hearing; a urinary dipstick for albumin and blood; and an optional HIV test Table A4.1 contd WHAT IS THE EFFECTIVENESS OF SYSTEMATIC POPULATION-LEVEL SCREENING PROGRAMMES FOR REDUCING THE BURDEN OF CARDIOVASCULAR DISEASES? WHO HEALTH EVIDENCE NETWORK SYNTHESIS REPORT 72 Study, start year: status Data category Description Intervention The 2000 invited people were divided a priori into three groups. Participants in: • group A were offered a general health check at baseline and after 1 and 5 years, followed by mailed feedback in layman’s terms; if necessary, a 10–15 minutes consultation was offered; • group B were offered the same and, irrespective of the general health check results, a 45-min baseline consultation with their GP to discuss health problems and encourage healthy lifestyle changes; and • group C received a questionnaire at baseline and a general health check at year 5. All participants were offered an additional health check at the 15-year follow-up Total study duration 24 years Number of participants allocated to each arm Invitees: 2000 (493 declined); intervention group A + B, 1006; control group, 501 Non-invitees: 1464 (728 participants were censored after 15 years, as they were offered screening) Loss to follow-up 0% Baseline comparability No significant differences between invitees and non-invitees at baseline Relevant outcomes Total mortality, CVD morbidity & mortality (combined) Results Comparing invitees to non-invitees: • CVD morbidity & mortality: HR = 1.11 (95% CI: 0.88–1.41) • total mortality: HR = 0.93 (95% CI: 0.75–1.16) Table A4.1 contd 73 Study, start year: status Data category Description Comments This synthesis review included the latest follow-up, which was a post hoc study after 24 years and the effect was analysed on a population basis. At the start of the study, the authors compared two intervention groups with a control group. As these analyses were not population-based, they were not included in the main analysis The screened and unscreened groups were also compared with an external control group consisting of 1 511 498 Danes living outside the municipality of Ebeltoft. This comparison was not included in this review because the analysis was not based on a randomization Ely, 1990 (27,28): completed Study design Parallel-group RCT Setting 1 GP in Ely Age and sex of participants 40–65 years; men and women Country England, United Kingdom Date of study Baseline data collected in 1990 Diagnostic tests used Blood pressure measurement, a 75-g oral glucose tolerance test, measurement of plasma lipids and HbA1c Intervention No standard intervention package was specified for people found to have type 2 diabetes or elevated CVD risk factors following screening. GPs were informed of the results and advised to take whatever action they thought necessary. Intervention group was screened 4 times Total study duration 13-year follow-up (mean: 12.5 years) Number of participants allocated to each arm Screened group, 1705; unscreened group, 3231 Table A4.1 contd WHAT IS THE EFFECTIVENESS OF SYSTEMATIC POPULATION-LEVEL SCREENING PROGRAMMES FOR REDUCING THE BURDEN OF CARDIOVASCULAR DISEASES? WHO HEALTH EVIDENCE NETWORK SYNTHESIS REPORT 74 Study, start year: status Data category Description Loss to follow-up for each outcome Results based on re-examination after 10 years: 43% attendance rate Baseline comparability No information Relevant outcomes Self-reported medication use (new medication) Results No difference in self-reported intake of antihypertensive drugs (P = 0.98), lipid- lowering drugs (P = 0.2), antiplatelet drugs (P = 0.6), or antidepressant (P = 0.4) and anxiolytic drugs (P = 0.8) Erfurt-Süd, 1968 (29): completed Study design Parallel-group RCT Setting District of Erfurt-Süd Age and sex of participants 50–54 years; men Country Germany Date of study Baseline data collected in 1968–1971 Diagnostic tests used Questionnaire, clinical examination, including standardized blood pressure measurement, ECG registration and chest X-ray, determination of various laboratory parameters (cholesterol and β-lipoprotein concentration and glucose after oral exposure) Intervention 3 repeated medical examinations, including the reporting of findings, clarification of the role of risk factors in CVD development and indications of behaviour change (smoking, high-calorie/high-fat diet, lack of exercise); high-risk individuals had a 5–6-week stay in a special department (to provide support for physical activity, diet, weight reduction, smoking cessation, psychotherapeutic treatment) Total study duration 9–10 years Table A4.1 contd 75 Study, start year: status Data category Description Number of participants allocated to each arm Intervention group, 314; control group, 600 Loss to follow-up for each outcome < 1% Baseline comparability Not assessed: the control group was not contacted at baseline Relevant outcomes Total mortality, CVD mortality, IHD morbidity & mortality (myocardial infarction), IHD mortality (myocardial infarction) Results (intervention group vs control group) Total mortality: 11.2% vs 11.5% CVD mortality: 5.4% vs 4.2% IHD morbidity & mortality: 11.2% vs 8.2% IHD mortality: 3.8% vs 3.5% No differences were statistically significant Comments Outcomes related to myocardial infarction were analysed together with IHD in other studies Two age groups were included in the study, but data were only extracted for the oldest age group owing to a breach of the randomization for the younger age group Family Hearta (30): completed Study design Cluster RCT Setting 26 GPs in 13 towns in the United Kingdom; patients from 1 GP in each town were randomized to the intervention group Age and sex of participants 40–59 years; men and women Country United Kingdom Date of study No information provided Table A4.1 contd WHAT IS THE EFFECTIVENESS OF SYSTEMATIC POPULATION-LEVEL SCREENING PROGRAMMES FOR REDUCING THE BURDEN OF CARDIOVASCULAR DISEASES? WHO HEALTH EVIDENCE NETWORK SYNTHESIS REPORT 76 Study, start year: status Data category Description Diagnostic tests used An interview recorded demographic details, medical history, family history and smoking habit, knowledge of CVD risk factors and perceived health. Measurements included height and weight, waist–hip ratio, exhaled breath carbon monoxide, blood pressure, and random total blood cholesterol and glucose levels in a capillary blood sample. Calculation of the Dundee risk score (103) Intervention Family health checks conducted by nurses, including counselling and referral to GPs Total study duration 1-year follow-up Number of participants allocated to each arm 12 472 men aged 40–59 years and their partners (7460 men and 5012 women): intervention group, 2984; control group (internal and external), 9488 Loss to follow-up for each outcome 73% of the target population participated in the health check; of these, follow-up was available for 85% Baseline comparability No information provided Relevant outcomes Prescription of medications (new medication) Results No difference after 1 year in the prescription of medications (antihypertensive, lipid- lowering and antidiabetic). No numerical results were presented Gothenburg, 1963 (31): completed Study design Parallel-group RCT Setting Gothenburg, Sweden Age and sex of participants 50 years at study initiation; men Country Sweden Date of study Baseline data collected in 1963 Table A4.1 contd 77 Study, start year: status Data category Description Diagnostic tests used Questionnaire and extensive health examination (e.g. blood pressure, BMI, lipid profile). Later examinations also included a physical test at maximum load Intervention Repeated health examinations in 1963, 1967, 1973 and 1980 and referral to relevant treatment Total study duration 15-year follow-up Number of participants allocated to each arm Intervention group, 1013; control group, 1967 Loss to follow-up for each outcome By the end of 1977: intervention group, 0.3%; control group, 1% Baseline comparability Not assessed: the control group was not contacted at baseline Relevant outcomes Total mortality, CVD mortality Results (intervention group vs control group) Total mortality: 14.5% vs 15.6% (χ2 = 0.35) CVD mortality: 7.3% vs 6.7% (χ2 = 0.72) No differences were statistically significant Gothenburg, 1970 (32): completed Study design Parallel-group RCT Setting Gothenburg, Sweden Age and sex of participants 47–55 years at study initiation; men Country Sweden Date of study Baseline data collected between 1970 and 1973 Diagnostic tests used Questionnaire and screening examination collected data on weight, height, total serum cholesterol and blood pressure; and an ECG Table A4.1 contd WHAT IS THE EFFECTIVENESS OF SYSTEMATIC POPULATION-LEVEL SCREENING PROGRAMMES FOR REDUCING THE BURDEN OF CARDIOVASCULAR DISEASES? WHO HEALTH EVIDENCE NETWORK SYNTHESIS REPORT 78 Study, start year: status Data category Description Intervention Screening examination at baseline and after 4 and 10 years. Treatment of risk factors: smoking (smoking cessation course), high blood pressure (medical treatment) and high cholesterol (dietary advice). Organized in special clinics. Individuals with angina were referred to a cardiologist Total study duration Mean: 11.8 years Number of participants allocated to each arm Intervention group, 10 004; control group 1 (some examinations), 10 011; control group 2 (no examinations): 10 007 Loss to follow-up for each outcome 0% Baseline comparability Baseline comparison between the intervention group and 2% of control group 1: the control group had a slightly higher prevalence of chronic diseases and considerably more alcohol problems Relevant outcomes Total mortality, IHD morbidity & mortality (combined), stroke morbidity & mortality (combined), IHD mortality, stroke mortality Results (no. of cases; intervention group vs control group 1 vs control group 2) Total mortality: 1293 vs 1304 vs 1332 IHD morbidity & mortality: 837 vs 836 vs 861 Stroke morbidity & mortality: 211 vs 196 vs 220 IHD mortality: 462 vs 453 vs 470 Stroke mortality: 64 vs 72 vs 82 No differences were statistically significant Comment The two control groups were pooled for the meta-analysis Inter99, 1999 (21,33–37): completed Study design Parallel-group RCT Setting 11 municipalities in the western part of Copenhagen County Age and sex of participants 30–60 years; men and women Table A4.1 contd 79 Study, start year: status Data category Description Country Denmark Date of study Baseline data collected between 1999 and 2001 Diagnostic tests used Comprehensive questionnaire (lifestyle, motivation to change lifestyle, symptoms, history of diseases, family history of diseases, psychosocial factors), physical measurements (ECG, blood pressure, height and weight, waist and hip circumference, spirometry), blood samples (total cholesterol, total lipid profile, HgbA1c) and a 2-hour oral glucose tolerance test. Total CVD risk was assessed with PRECARD (104) Intervention The intervention group was invited for screening, risk assessment and lifestyle counselling. Those at high risk of IHD (according to predefined criteria) were offered 6 sessions of group-based lifestyle counselling on smoking cessation, diet and physical activity. Participants at high risk were re-invited after 1 and 3 years. After 5 years, all participants who were eligible at baseline were re-invited for final screening, individual counselling and a maintenance plan Total study duration 10 years Number of participants allocated to each arm Intervention group, 11 629; control group: 47 987 Loss to follow-up for each outcome 0% Baseline comparability Significantly different age and sex distribution, which was expected because of the sampling procedure. Significantly more people in the control group were cohabiting and had a lower education level Table A4.1 contd WHAT IS THE EFFECTIVENESS OF SYSTEMATIC POPULATION-LEVEL SCREENING PROGRAMMES FOR REDUCING THE BURDEN OF CARDIOVASCULAR DISEASES? WHO HEALTH EVIDENCE NETWORK SYNTHESIS REPORT 80 Study, start year: status Data category Description Relevant outcomes Total mortality, IHD morbidity & mortality (combined), stroke morbidity & mortality (combined), CVD morbidity & mortality (combined) New medication: use of psychotropic medication (at 4 years before and 5 years after the start of the study) Hospitalization due to psychiatric diagnoses (at 4 years before and 5 years after the start of the study) Results Total mortality: HR = 1.00 (95% CI: 0.91–1.09) IHD morbidity & mortality: HR = 1.03 (95% CI: 0.94–1.13) Stroke morbidity & mortality: HR = 0.98 (95% CI: 0.87–1.11) CVD morbidity & mortality: HR = 1.01 (95% CI: 0.93–1.09) Use of antipsychotics, hypnotics/sedatives, antidepressants or anxiolytics: no statistically significant differences Hospital admissions (all psychiatric disorders): • short term: OR = 1.07 (95% CI: 0.88–1.29, SE = 0.10, P = 0.49) • long-term: OR = 1.00 (95% CI: 0.83–1.21, SE = 0.10, P = 0.98) • drift (difference between short- and long- term effects): OR = 0.94 (95% CI: 0.76–1.16, SE = 0.10, P = 0.55) Malmö, 1969 (38,39): completed Study design Parallel-group RCT Setting Malmö Age and sex of participants 55 years; men Country Sweden Date of study Baseline data collected in 1969 Diagnostic tests used Questionnaire and health examination: weight, blood pressure, lipid profile and lung function Table A4.1 contd 81 Study, start year: status Data category Description Intervention Examination focusing on cardiovascular and pulmonary function. If needed, participants were referred to specialists for follow-up Total study duration 1970–1974 (5 years) Number of participants allocated to each arm Intervention group, 809; control group, 804 Loss to follow-up for each outcome 1% Baseline comparability No comparison made: the control group was not contacted at baseline Relevant outcomes Total mortality, CVD mortality, hospitalization, receipt of a disability pension Results Total mortality (participants vs non- participants vs control group): 7.5% vs 5.8% vs 7.5% (NSD) CVD mortality (participants & non- participants vs control group): 14 vs 33 cases, χ2 = 9.09, P < 0.01 Hospitalization (participants vs non- participants vs control group): 37.6% (total days: 6927) vs 29% (total days: 917) vs 35.6% (total days: 8501; NSD) Disability pension (participants vs non- participants vs control group): 6.6% vs 8.8% vs 9% (NSD) Northumberland, 1969 (40): completed Study design Parallel-group RCT Setting 7 GPs in 4 general practices in the north of England Age and sex of participants 50–59 years; men Country England, United Kingdom Date of study Baseline data collected in 1969 Table A4.1 contd WHAT IS THE EFFECTIVENESS OF SYSTEMATIC POPULATION-LEVEL SCREENING PROGRAMMES FOR REDUCING THE BURDEN OF CARDIOVASCULAR DISEASES? WHO HEALTH EVIDENCE NETWORK SYNTHESIS REPORT 82 Study, start year: status Data category Description Diagnostic tests used Questionnaire and clinical examination (limited to the system(s) affected). Not specified in greater detail Intervention Two intervention groups: 1 completed a questionnaire and was subsequently invited to attend their GP for further examination of symptoms declared in their answers; the other completed the questionnaire and underwent a full examination Total study duration 18 months Number of participants allocated to each arm 867 (59 were excluded due to severe illness/ death or could not be traced): control (group 1), 291; less-intensive intervention (group 2), 275; full intervention (group 3), 242 Loss to follow-up for each outcome 9.8% Baseline comparability Group 1 contained a small excess of patients with previously diagnosed conditions; not statistically significant Relevant outcomes Hospitalizations (≥ 1), number of physician visits/consultations, diagnostic procedures (examinations, investigations performed and presumptive diagnoses), new medication and certified sickness Table A4.1 contd 83 Study, start year: status Data category Description Results (group 1 vs group 2 vs group 3) Hospitalizations (≥ 1): 6.1% vs 5.5% vs 4.2%; P ≤ 0.05 Number of physician visits/consultations: • average number of consultations: 5.0 vs 5.2 vs 5.4 (NSD) • average number of new consultations: 1.4 vs 1.4 vs 1.5 (NSD) Diagnostic procedures: • physical examination: 63.7% vs 65.4% vs 68.6% (P ≤ 0.01) • laboratory investigation: 4.5% vs 5.4% vs 8.8% (P ≤ 0.001) • presumptive diagnosis: 80.8% vs 79.8% vs 80.9% (NSD) New medication: 50.9% vs 48.7% vs 53.1% (NSD) Certified sickness: • 1–14 days: 40.4% vs 42.1% vs 36.2% (NSD) • ≥ 15 days: 4.7% vs 5.8% vs 6.9% (P ≤ 0.05; significantly more in group 3) South-East London, 1967 (41): completed Study design Cluster RCT Setting 2 GPs in South-east London Age and sex of participants 40–64 years; men and women plus their families Country England, United Kingdom Date of study Baseline data collected in 1967–1968 Diagnostic tests used Questionnaire and clinical tests (anthropometry, visual testing, audiometry, chest X-ray, lung function test, ECG, blood pressure, blood tests (including cholesterol and blood sugar), stool sample and basic physician examination) Intervention Two screening sessions about 2 years apart. Counselling and referral to GPs Total study duration 9 years Table A4.1 contd WHAT IS THE EFFECTIVENESS OF SYSTEMATIC POPULATION-LEVEL SCREENING PROGRAMMES FOR REDUCING THE BURDEN OF CARDIOVASCULAR DISEASES? WHO HEALTH EVIDENCE NETWORK SYNTHESIS REPORT 84 Study, start year: status Data category Description Number of participants allocated to each arm Intervention group, 3867; control group, 3353 Loss to follow-up for each outcome Varied for different outcomes: 26.6–34.5% Baseline comparability No significant differences between groups Relevant outcomes After 8 years: total mortality, CVD mortality, hospitalizations, physician visits/ consultations, certified sickness Results (intervention group vs control group) Total mortality (per 1000 person-years at risk): 10.0 vs 9.2 CVD mortality (per 1000 person-years at risk): 4.3 vs 2.8 Hospitalizations (total admissions per 1000 person-years at risk): 73.4 vs 70.7 GP visits/consultations (overall consultation rate): • men: 3.2 (SE = 0.09) vs 3.1 (SE = 0.09) • women: 4.0 (SE = 0.09) vs 3.8 (SE = 0.09) Certified sickness: participants in both groups lost 5.5% of their work time to certified sickness absence No differences were statistically significant Stockholm, 1969 (42): completed Study design Parallel-group RCT Setting Stockholm, Sweden Age and sex of participants 18–65 years; men and women Country Sweden Date of study Baseline data collected in 1969–1970 Diagnostic tests used Screening included social, psychiatric and medical interviews; blood pressure and blood tests; physical examinations, ECGs, exercise tests, psychological tests, and eye and dental examinations Table A4.1 contd 85 Study, start year: status Data category Description Intervention Extensive general health and social screening, focusing primarily on function. The examinations were done by social workers, psychiatrists and physicians during a single day. If needed, participants were referred for specialist treatment. Simple health-care services were provided by the intervention providers Total study duration 22 years Number of participants allocated to each arm Intervention group, 3064; control group, 29 122 Loss to follow-up for each outcome 1% Baseline comparability No comparison made: baseline data were not collected for the control group Relevant outcomes Total mortality, CVD mortality Results Total mortality: rate ratio = 1.03 (95% CI: 0.94–1.14) CVD mortality: rate ratio = 1.06 (95% CI: 0.88–1.23) Check your Health, 2013 (43): ongoing Study design Cluster RCT Setting A selected geographical area in the Central Denmark Region Age and sex of participants 30–49 years; men and women Country Denmark Date of study Baseline data collected in 2013–2014 Table A4.1 contd WHAT IS THE EFFECTIVENESS OF SYSTEMATIC POPULATION-LEVEL SCREENING PROGRAMMES FOR REDUCING THE BURDEN OF CARDIOVASCULAR DISEASES? WHO HEALTH EVIDENCE NETWORK SYNTHESIS REPORT 86 Study, start year: status Data category Description Diagnostic tests used Questionnaire and clinical tests: blood pressure; BMI; HbA1c and lipid profile (total cholesterol, HDL, LDL, triglycerides); height, weight and waist measurements; lung function/spirometry; physical fitness. Risk of CVD within 10 years was calculated using SCORE (105) Number of participants Total, 10 505 Intervention Preventive health checks and assignment of individual risk profile. Based on the risk profile, participants are referred to 1 of 3 programmes: health promotion consultation with GP, behavioural programme at local health centre or no need for follow-up Total study duration Primary outcomes at 4-year follow-up Relevant outcomes Risk of cardiovascular event (Heart-SCORE model (105)), sick leave, labour market attachment, cost–effectiveness Gadchiroli, 2016 (44): ongoing Study design Cluster RCT Setting 32 rural villages in Gadchiroli Age and sex of participants ≥ 50 years; men and women Country India Date of study Baseline data collected in 2016 Diagnostic tests used Blood pressure, urine glucose test; measurement of weight, height, and waist and hip circumference Number of participants Not specified Intervention Intervention group will be screened by community health workers for diabetes, hypertension and stroke, followed up with treatment and home visits Table A4.1 contd 87 Study, start year: status Data category Description Total study duration Planned duration of the intervention, 3.5 years; primary outcome collected after 2.5 years Relevant outcomes Stroke mortality, all-cause and cardiovascular mortality, percentage of hypertensive patients taking blood pressure medications, blood pressure control, blood glucose control BMI: body mass index; CI: confidence interval; ECG: electrocardiogram; GP: general practitioner; HbA1c: glycated haemoglobin; HDL: high-density lipoprotein; HR: hazard ratio; Inter99: A Randomised Non-pharmacological Intervention Study for Prevention of Ischaemic Heart Disease Inter99; LDL: low-density lipoprotein; NSD: not significantly different; OR: odds ratio; SE: standard error. a No information given on when the baseline data were collected. Table A4.1 contd WHAT IS THE EFFECTIVENESS OF SYSTEMATIC POPULATION-LEVEL SCREENING PROGRAMMES FOR REDUCING THE BURDEN OF CARDIOVASCULAR DISEASES? WHO HEALTH EVIDENCE NETWORK SYNTHESIS REPORT 88 Table A4.2. Data extracted from included studies on screening for AAA Study, start year: status Data category Description Chichester, 1989 (45–47): completed Study design Parallel-group RCT Setting 9 GPs in the Chichester district Age and sex of participants 65–80 years; men Country England, United Kingdom Date of study Baseline data collected in 1989 Diagnostic tests used Abdominal ultrasonographic screening Intervention AAA was considered present if the aortic diameter was > 3 cm. Participants with an aortic diameter of 3.0–4-4 cm were rescanned annually, and those with an aortic diameter of 4.5–5.9 cm were scanned every 3 months. Participants with an aortic diameter of > 6 cm, rapid expansion of ≥ 1 cm per year or symptoms related to AAA were referred for surgical evaluation Total study duration 15-year follow-up Number of participants allocated to each arm Intervention group, 2995; control group, 3045 Loss to follow-up for each outcome 0% Baseline comparability No comparison made: baseline data were not collected for the control group Relevant outcomes AAA mortality, AAA rupture, total mortality Results AAA mortality: HR = 0.89 (95% CI: 0.60–1.32) AAA rupture: HR = 0.88 (95% CI: 0.61–1.26) Total mortality: HR = 1.01 (95% CI: 0.95–1.07) 89 Study, start year: status Data category Description Chichester, 1989 (45–47): completed Study design Parallel-group RCT Setting 9 GPs in the Chichester district Age and sex of participants 65–80 years; women Country England, United Kingdom Date of study Baseline data collected in 1989 Diagnostic tests used Abdominal ultrasonographic screening Intervention AAA was considered present if the aortic diameter was > 3 cm. Participants with an aortic diameter of 3.0–4-4 cm were rescanned annually, and those with an aortic diameter of 4.5–5.9 cm were scanned every 3 months. Participants with an aortic diameter of > 6cm, rapid expansion of ≥ 1 cm per year or symptoms related to AAA were referred for surgical evaluation Total study duration 5- and 10-year follow-up Number of participants allocated to each arm Intervention group, 4682; control group, 4660 Loss to follow-up for each outcome 0% Baseline comparability No comparison made: baseline data were not collected for the control group Relevant outcomes AAA mortality, AAA rupture, total mortality Results (intervention group vs control group) AAA mortality (5 years): 3 cases vs 2 cases AAA rupture: • incidence at 5 years: 3 cases vs 2 cases • incidence at 10 years: 14 cases vs 9 cases Total mortality (5 years): 10.7% vs 10.2% Table A4.2 contd WHAT IS THE EFFECTIVENESS OF SYSTEMATIC POPULATION-LEVEL SCREENING PROGRAMMES FOR REDUCING THE BURDEN OF CARDIOVASCULAR DISEASES? WHO HEALTH EVIDENCE NETWORK SYNTHESIS REPORT 90 Study, start year: status Data category Description Multicentre Aneurysm Screening Study, 1997 (48): completed Study design Parallel-group RCT Setting 4 centres in the United Kingdom Age and sex of participants 65–74 years; men Country United Kingdom Date of study Baseline data collected in 1997–1999 Diagnostic tests used Abdominal ultrasonographic screening Intervention Patients with AAA (aortic diameter of ≥ 3 cm) were kept under surveillance and offered surgery after predefined criteria had been met. When the aortic diameter reached 5.5 cm, aortic expansion was ≥1 cm in 1 year, or patients reported symptoms attributable to AAA, patients were referred for surgical evaluation Total study duration Follow-up was 8.9–11.2 years (mean: 10.1) Number of participants allocated to each arm Intervention group, 33 883; control group, 33 887 Loss to follow-up for each outcome Mortality at 10 years, 2.7%; for clinical follow-up (e.g. non-fatal AAA rupture), 28% Baseline comparability The randomized groups were well balanced in terms of age, geographical area and socioeconomic status (106) Relevant outcomes AAA mortality, AAA rupture, total mortality, costs Table A4.2 contd 91 Study, start year: status Data category Description Results AAA mortality: HR = 0.52 (95% CI: 0.43– 0.63) AAA rupture: HR = 0.52 (95% CI: 0.44– 0.62) Total mortality: HR = 0.97 (95% CI: 0.95–1.00) Regarding AAA-related mortality, the incremental cost per man invited to screening was £100 (95% CI: 82–118), leading to an incremental cost–effectiveness ratio of £7600 (95% CI: 5100–13 000) per life-year gained. Viborg, 1994 (49): completed Study design Parallel-group RCT Setting Viborg County Age and sex of participants 64–73 years; men Country Denmark Date of study Baseline data collected in 1994. From 1995 to 1998, all men who turned 65 years were included Diagnostic tests used Abdominal ultrasonographic screening Intervention AAA was considered present if the aortic diameter was ≥ 3 cm. Participants with an aortic diameter of ≥ 5 cm were referred to a vascular surgeon. Participants with an aortic diameter of 3–4.99 cm were offered annual ultrasonography Total study duration Mean: 13 years (SD = 1.3) Number of participants allocated to each arm Intervention group, 6333; control group, 6306 Loss to follow-up for each outcome 0% Table A4.2 contd WHAT IS THE EFFECTIVENESS OF SYSTEMATIC POPULATION-LEVEL SCREENING PROGRAMMES FOR REDUCING THE BURDEN OF CARDIOVASCULAR DISEASES? WHO HEALTH EVIDENCE NETWORK SYNTHESIS REPORT 92 Study, start year: status Data category Description Baseline comparability Groups were similar for duration of observation and age (107) Relevant outcomes AAA mortality, total mortality, costs Results AAA mortality: HR = 0.34 (95% CI: 0.20–0.57) Total mortality: HR = 0.98 (95% CI: 0.93–1.03) Regarding total mortality, the ICER was estimated at €157 (95% CI: −3292 to 4401) per life-year gained and €179 (95% CI: −4083 to 4682) per quality-adjusted life-year gained Western Australia, 1996 (50): completed Study design Parallel-group RCT Setting Perth, Western Australia Age and sex of participants 64–83 years; men (planned subgroup analysis of men aged 65–74 years) Country Australia Date of study Baseline data collected in 1996–1999 Diagnostic tests used Abdominal ultrasonographic screening Interventiona Participants were screened for AAA at 5 community-based clinics. Participants and GPs were informed about the results of the scan. GPs arranged follow-up or referred participants to a surgeon. No general guidelines for management were given Total study duration Mean of 12.8 years (range: 11.6–14.2) Number of participants allocated to each arm Intervention group, 19 249; control group, 19 231 Loss to follow-up for each outcome 0% Table A4.2 contd 93 Study, start year: status Data category Description Baseline comparability No comparison made: baseline data were not collected for the control group Relevant outcomes AAA mortality, total mortality Results AAA mortality: • men aged 64–83 years: HR = 0.91 (95% CI: 0.68–1.21) • men aged 65–74 years: HR = 0.92 (95% CI: 0.62–1.36) Total mortality: • men aged 64–83 years: HR = 0.98 (95% CI: 0.96–1.01) • men aged 65–74 years: HR = 0.99 (95% CI: 0.95–1.02) CI: confidence interval; GP: general practitioner; HR: hazard ratio; ICER: incremental cost–effectiveness ratio; SD: standard deviation. a Despite a more uncertain handling of persons with an aortic diameter of > 3 cm, there were no fewer elective surgeries in this study than in the Viborg study (49) and Multicentre Aneurysm Screening Study (48). Table A4.2 contd WHAT IS THE EFFECTIVENESS OF SYSTEMATIC POPULATION-LEVEL SCREENING PROGRAMMES FOR REDUCING THE BURDEN OF CARDIOVASCULAR DISEASES? WHO HEALTH EVIDENCE NETWORK SYNTHESIS REPORT 94 Table A4.3. Data extracted from included studies on screening for AF Study, start year: status Data category Description STROKESTOP, 2012 (51): ongoing Study design Parallel-group RCT Setting Two Swedish regions Age and sex of participants 75–76 years; men and women Country Sweden Date of study 2012 Diagnostic tests used Intermittent ECG recording Number of participants 13 331 have been invited; 7173 have participated Intervention Screening for AF and follow-up with oral anticoagulant treatment Total study duration 5 years of follow-up Relevant outcomes Incidence of ischaemic stroke, thromboembolic event, intracranial bleeding, other major bleeding, first ever diagnosis of dementia, death from any cause, and a composite of all outcomes 95 Table A4.3 contd Study, start year: status Data category Description VITAL-AF, 2018 (52): ongoing Study design Cluster RCT Setting 22 GPs, Massachusetts Age and sex of participants 65 years or older; men and women Country United States of America Date of study Enrolment began in 2018 Diagnostic tests used Single-lead handheld ECG Number of participants Estimated 16 000 participants in each arm Intervention Screening for AF and follow-up at the participant’s GP Total study duration Primary outcomes after 12 months, secondary outcomes after 24 months Relevant outcomes Incident AF (12 months), new oral anticoagulation drug prescriptions (12 months), continued use of oral anticoagulation drugs (24 months), incident ischaemic stroke (24 months), major haemorrhage (24 months) ECG: electrocardiogram; GP: general practitioner; STROKESTOP: Systematic ECG Screening for Atrial Fibrillation Among 75 Year Old Subjects in the Region of Stockholm and Halland, Sweden; VITAL-AF: Full title: Screening for Atrial Fibrillation in an Ambulatory Clinic Population: the VITAL-AF Study. WHAT IS THE EFFECTIVENESS OF SYSTEMATIC POPULATION-LEVEL SCREENING PROGRAMMES FOR REDUCING THE BURDEN OF CARDIOVASCULAR DISEASES? WHO HEALTH EVIDENCE NETWORK SYNTHESIS REPORT 96 Table A4.4. Data extracted from included studies on combined screening for preclinical CVDs Study, start year: status Data category Description Viborg Vascular, 2008 (53): completed Study design RCT Setting Viborg, Central Denmark Region Age and sex of participants 65–74 years, men Country Denmark Date of study Baseline data collected between 2008 and 2011 Diagnostic tests used Portable ultrasound scanner, bedside equipment for cholesterol measurement, portable Doppler, blood pressure measurement Intervention Screening for AAA, hypertension and PAD, followed by pharmacological therapy and surgical repair (only for AAA). Participants with detected hypertension were referred to their GP Total study duration 5-year follow-up (median: 4.4 years) Number of participants allocated to each arm Intervention group, 25 078; control group, 25 078 Loss to follow-up for each outcome 4 participants (<1%) Baseline comparability No differences were noted in baseline characteristics Relevant outcomes Total mortality, CVD mortality, AAA-related mortality, hospital admission due to CVD, AAA progression, adverse effects of cancer, diabetes, intracerebral haemorrhage and renal failure 97 Study, start year: status Data category Description Results Total mortality: HR = 0.93 (95% CI: 0.88–0.98; P = 0.01) CVD mortality: HR = 0.93 (95% CI: 0.86–1.02; NSD) AAA-related mortality: HR = 0.62 (95% CI: 0.38–1.02; NSD) Cancer-related mortality: HR = 0.97 (95% CI: 0.91–1.04; NSD) Other cause-related mortality: HR = 0.93 (95% CI: 0.81–1.06; NSD) Unknown cause mortality: HR = 0.87 (95% CI: 0.73–1.03; NSD) Hospital admission due to CVD (composite outcome): NSD DANCAVAS, 2014 (54): ongoing Study design RCT Setting Island of Funen, or surrounding communities of Vejle and Silkeborg Age and sex of participants 65–74 years, men Country Denmark Date of study Enrolment initiated in 2014 Diagnostic tests used Low-dose non-contrast computed tomography scan, brachial and ankle blood pressure index, telemetric assessment of heart rhythm, and measurements of cholesterol and plasma glucose levels Number of participants 45 000 Intervention Screening followed by cardiovascular preventive treatment in case of positive findings Total study duration 10 years Relevant outcomes Total mortality; costs after 3, 5 and 10 years CI: confidence interval; DANCAVAS: Danish Cardiovascular Screening Trial II; GP: general practitioner; HR: hazard ratio; NSD: not significantly different. Table A4.4 contd WHAT IS THE EFFECTIVENESS OF SYSTEMATIC POPULATION-LEVEL SCREENING PROGRAMMES FOR REDUCING THE BURDEN OF CARDIOVASCULAR DISEASES? WHO HEALTH EVIDENCE NETWORK SYNTHESIS REPORT 98 ANNEX 5. DETAILED RESULTS OF THE META-ANALYSES Meta-analyses were conducted to analyse comparable data on specific outcomes, where available in the included studies. Where available, the formal name of each RCT is given; where not, the geographical location is given. NB: references are given in the main reference list. Screening for CVD risk and CVD risk factors A total of nine studies reported the specific outcomes of RCTs on screening CVD risk and CVD risk factors (21,23,24,29,31,32,38,41,42). Some studies reported a combined outcome for morbidity and mortality, as well as a separate outcome for mortality. Therefore, separate meta-analyses were conducted for the mortality and combined morbidity/mortality outcomes. Total mortality All nine studies reported on total mortality, with follow-up ranging from five to 30 years (21,23,24,29,31,32,38,41,42). All reported no reduction in total mortality following screening for CVD risk and CVD risk factors. This finding was confirmed by the meta-analysis, which determined an overall relative risk for total mortality of 1.00 (95% CI: 0.97–1.03; Table A5.1). A low level of heterogeneity across all nine studies indicated that they had produced similar results. Sensitivity analyses of the risk of bias did not alter the overall results, confirming that the analysis was robust. The inclusion of adjusted results (hazard ratios) instead of the absolute number of cases did not change the results. CVD morbidity and mortality The two studies that reported on CVD morbidity and mortality (combined) had follow-up periods of 10 and 24 years (21,24). Both reported no reductions in CVD morbidity and mortality following screening for CVD risk and CVD risk factors. This finding was confirmed in the meta-analysis, which determined an overall relative risk for CVD morbidity and mortality of 1.02 (95% CI: 0.95–1.10; Table A5.2). A low level of heterogeneity across the two studies indicated that they had produced similar results. Sensitivity analyses of the risk of bias did not alter the overall effect estimate, which strengthened confidence in the meta-analysis. 99 Ta bl e A 5. 1. Sc re en in g fo r C VD ri sk /r is k fa ct or s: m et a- an al ys is o f t ot al m or ta lit y ou tc om es St ud y St ar t ye ar Fo re st p lo t Re la tiv e ris k 95 % c on fid en ce in te rv al W ei gh t (% ) G ot he nb ur g (3 1) 19 63 0. 94 0. 78 –1 .13 3. 31 So ut h- Ea st L on do n (4 1) 19 67 1.1 0 0. 90 –1 .3 5 2. 74 Er fu rt -S üd (2 9) 19 68 0. 97 0. 66 –1 .4 2 0. 75 M al m ö (3 8) 19 69 0. 81 0. 56 –1 .17 0. 82 St oc kh ol m (4 2) 19 69 1.0 3 0. 94 –1 .13 11. 60 G ot he nb ur g (3 2) 19 70 0. 98 0. 92 –1 .0 4 27 .4 1 D an M O N IC A (2 3) 19 82 1.0 3 0. 98 –1 .0 9 36 .8 2 Eb el to ft (2 4) 19 91 0. 93 0. 75 –1 .16 2. 30 In te r9 9 (2 1) 19 99 0. 96 0. 88 –1 .0 4 14 .2 6 O ve ra ll – 1.0 0 0. 97 –1 .0 3 – N ot es : r an do m e ffe ct s re st ric te d m ax im um li ke lih oo d m od el . A re la tiv e ris k of <  1 fa vo ur s sc re en in g; a re la tiv e ris k of >  1 fa vo ur s th e co nt ro l. H et er og en ei ty s ta tis tic s: t2   =  0. 00 , I 2  =  1. 31 % , H 2  =  1. 01 . Te st o f θ i =  θ j: Q (8 ) =  6 .0 0, P  =  0 .6 5. Te st o f θ  =  0 : z  =  − 0. 01 , P  =  0 .9 9. 0. 60 0. 80 1.0 0 1.2 0 1.4 0 WHAT IS THE EFFECTIVENESS OF SYSTEMATIC POPULATION-LEVEL SCREENING PROGRAMMES FOR REDUCING THE BURDEN OF CARDIOVASCULAR DISEASES? WHO HEALTH EVIDENCE NETWORK SYNTHESIS REPORT 100 Ta bl e A 5. 2. S cr ee ni ng fo r C VD ri sk /r is k fa ct or s: m et a- an al ys is o f C VD m or bi di ty a nd m or ta lit y St ud y St ar t ye ar Fo re st p lo t Re la tiv e ris k 95 % c on fid en ce in te rv al W ei gh t (% ) Eb el to ft (2 4) 19 91 1.1 1 0. 88 –1 .4 1 10 .19 In te r9 9 (2 1) 19 99 1.0 1 0. 93 –1 .0 9 89 .8 1 O ve ra ll – 1.0 2 0. 95 –1 .10 – N ot es : r an do m e ffe ct s re st ric te d m ax im um li ke lih oo d m od el . A re la tiv e ris k of <  1 fa vo ur s sc re en in g; a re la tiv e ris k of >  1 fa vo ur s th e co nt ro l. H et er og en ei ty s ta tis tic s: t2   =  0. 00 , I 2  =  1. 01 % , H 2  =  1. 00 . Te st o f θ i =  θ j: Q (1)  =  0 .5 5, P  =  0 .4 6. Te st o f θ  =  0 : z  =  0 .5 1, P  =  0. 61 . 0. 90 1.0 0 1.2 0 1.4 0 101 Table A5.3. Screening for CVD risk/risk factors: meta-analysis of CVD mortality Study Start year Forest plot Relative risk 95% confidence interval Weight (%) Gothenburg (31) 1963 1.09 0.83–1.43 23.11 Erfurt-Süd (29) 1968 1.30 0.71–2.37 15.26 Malmö (38) 1969 0.42 0.23–0.78 14.90 South-East London (41) 1967 1.54 1.09–2.16 21.48 Stockholm (42) 1969 1.06 0.90–1.25 25.25 Overall – 1.04 0.73–1.49 – Notes: random effects restricted maximum likelihood model. A relative risk of < 1 favours screening; a relative risk of > 1 favours the control. Heterogeneity statistics: t2 = 0.13, I2 = 82.20%, H2 = 5.62. Test of θi = θj: Q(4) = 13.39, P = 0.01. Test of θ = 0: z = 0.20, P = 0.84. 0.40 0.70 1.50 2.501.00 CVD mortality The five studies that reported on CVD mortality had follow-up ranging from five to 22 years (29,31,38,41,42). The study with the shortest follow-up reported a reduction in CVD mortality among participants in the screened group after five years (38). The other four studies reported no reductions in CVD mortality (29,31,41,42). The latter finding was confirmed in the meta-analysis, which determined an overall relative risk of CVD mortality of 1.04 (95% CI: 0.73–1.49; Table A5.3). Substantial heterogeneity across the studies indicated that they had not produced similar results. Sensitivity analyses of the risk of bias did not alter the overall effect estimate, which strengthened confidence in the meta-analysis. WHAT IS THE EFFECTIVENESS OF SYSTEMATIC POPULATION-LEVEL SCREENING PROGRAMMES FOR REDUCING THE BURDEN OF CARDIOVASCULAR DISEASES? WHO HEALTH EVIDENCE NETWORK SYNTHESIS REPORT 102 IHD morbidity and mortality A total of four studies reported on IHD morbidity and mortality (combined) (21,23,29,32), with follow-up ranging from around nine to 30 years. All four studies reported no reduction in IHD morbidity and mortality following screening for CVD risk and CVD risk factors. This finding was confirmed by the meta-analysis, which determined an overall relative risk for IHD morbidity and mortality of 1.00 (95% CI: 0.96–1.05; Table A5.4). A low level of heterogeneity across all four studies indicated that they had produced similar results. Sensitivity analyses of the risk of bias did not alter the overall results, which strengthened confidence in the meta-analysis. Table A5.4. Screening for CVD risk/risk factors: meta-analysis of IHD morbidity and mortality Study Start year Forest plot Relative risk 95% confidence interval Weight (%) Erfurt-Süd (29) 1968 1.36 0.90–2.06 1.29 Gothenburg (32) 1970 0.99 0.91–1.07 34.74 DanMONICA (23) 1982 0.99 0.92–1.07 38.23 Inter99 (21) 1999 1.03 0.94–1.13 25.74 Overall – 1.00 0.96–1.05 – Notes: random effects restricted maximum likelihood model. A relative risk of < 1 favours screening; a relative risk of > 1 favours the control. Heterogeneity statistics: t2 = 0.00, I2 = 0.02%, H2 = 1.00. Test of θi = θj: Q(3) = 2.74, P = 0.43. Test of θ = 0: z = 0.13, P = 0.89. 1.00 1.50 2.00 103 IHD mortality In all, two studies reported outcomes for IHD mortality, with follow-up ranging from 9 to 11.8 years (29,32). Both studies reported no reductions in IHD mortality following screening for CVD risk and CVD risk factors. This finding was confirmed in the meta-analysis, which determined an overall relative risk for IHD mortality of 1.00 (95% CI: 0.90–1.12; Table A5.5). A low level of heterogeneity across both studies indicated that they had produced similar results. Sensitivity analyses of the risk of bias did not alter the overall effect estimate, which strengthened confidence in the meta-analysis. Table A5.5. Screening for CVD risk/risk factors: meta-analysis of IHD mortality Study Study year Forest plot Relative risk 95% confidence interval Weight (%) Erfurt-Süd (29) 1968 1.09 0.54–2.19 2.40 Gothenburg (32) 1970 1.00 0.90–1.12 97.60 Overall – 1.00 0.90–1.12 – Notes: random effects restricted maximum likelihood model. A relative risk of < 1 favours screening; a relative risk of > 1 favours the control. Heterogeneity statistics: t2 = 0.00, I2 = 0.00%, H2 = 1.00. Test of θi = θj: Q(1) = 0.06, P = 0.81. Test of θ = 0: z = 0.07, P = 0.95. 0.60 1.00 1.50 2.00 WHAT IS THE EFFECTIVENESS OF SYSTEMATIC POPULATION-LEVEL SCREENING PROGRAMMES FOR REDUCING THE BURDEN OF CARDIOVASCULAR DISEASES? WHO HEALTH EVIDENCE NETWORK SYNTHESIS REPORT 104 Stroke morbidity and mortality Three studies reported on stroke morbidity and mortality (combined) (21,23,32). Two studies, with follow-up of 10 and 11.8 years, reported no reductions in this outcome following screening for CVD risk and CVD risk factors (21,32). The third study, which had follow-up of around 30 years, reported an increased risk of stroke in the screened group (23). The meta-analysis found an overall relative risk for stroke morbidity and mortality of 1.05 (95% CI: 0.95–1.17), indicating no difference in the risk of stroke following screening for CVD risk and CVD risk factors (Table A5.6). Moderate heterogeneity across all three studies indicated that they had not produced similar results. Sensitivity analyses of the risk of bias did not alter the overall effect estimate, which strengthened confidence in the meta-analysis. Table A5.6. Screening for CVD risk/risk factors: meta-analysis of stroke morbidity and mortality Study Study year Forest plot Relative risk 95% confidence interval Weight (%) Gothenburg (32) 1970 1.01 0.86–1.20 24.25 DanMONICA (23) 1982 1.14 1.04–1.25 42.17 Inter99 (21) 1999 0.98 0.87–1.11 33.57 Overall – 1.05 0.95–1.17 – Notes: random effects restricted maximum likelihood model. A relative risk of < 1 favours screening; a relative risk of > 1 favours the control. Heterogeneity statistics: t2 = 0.00, I2 = 52.35%, H2 = 2.10. Test of θi = θj: Q(2) = 4.22, P = 0.12. Test of θ = 0: z = 1.00, P = 0.32. 0.90 1.00 1.20 105 Stroke mortality Only one study reported on screening for CVD risk and CVD risk factors. It found that screening did not lead to a reduction in stroke mortality after 11.8 years of follow-up (32). Screening for AAA A total of four studies reported the specific outcomes of RCTs on screening for AAA (45,48–50). Total mortality All four studies reported total mortality for men, with follow-up ranging from 10 to 15 years (45,48–50). None of the studies reported a reduction in total mortality following screening. This finding was confirmed in the meta-analysis, which determined an overall relative risk for total mortality of 0.99 (95% CI: 0.98–1.00; Table A5.7). Only one study reported total mortality for women: it found no reduction at five years after screening (46). Table A5.7. Screening for AAA: meta-analysis of total mortality Study Start year Forest plot Relative risk 95% confidence interval Weight (%) Chichester (45) 1989 1.00 0.97–1.04 13.79 Viborg (49) 1994 0.98 0.95–1.02 11.91 Western Australia (50) 1996 0.99 0.97–1.01 42.07 MASS (48) 1997 0.98 0.96–1.00 32.23 Overall – 0.99 0.98–1.00 – MASS: Multicentre Aneurysm Screening Study. Notes: random effects restricted maximum likelihood model. A relative risk of < 1 favours screening; a relative risk of > 1 favours the control. Heterogeneity statistics: t2 = 0.00, I2 = 0.04%, H2 = 1.00. Test of θi = θj: Q(3) = 1.12, P = 0.77. Test of θ = 0: z = −1.85, P = 0.07. 0.95 1.00 1.05 WHAT IS THE EFFECTIVENESS OF SYSTEMATIC POPULATION-LEVEL SCREENING PROGRAMMES FOR REDUCING THE BURDEN OF CARDIOVASCULAR DISEASES? WHO HEALTH EVIDENCE NETWORK SYNTHESIS REPORT 106 A low level of heterogeneity across studies indicated that they had produced similar results. Sensitivity analyses of the risk of bias did not alter the overall effect estimate, which strengthened confidence in the meta-analysis. However, the inclusion of adjusted results (hazard ratios) instead of the absolute number of cases showed a 2% reduction in total mortality (relative risk: 0.98; 95% CI: 0.96–0.99; Table A5.8). AAA mortality All four RCTs reported AAA mortality for men, with follow-up ranging from 10 to 15 years (45,48–50). Two of the studies reported reductions in AAA mortality following screening (48,49), whereas the other two reported no reductions (45,50). The meta- analysis showed that screening reduces AAA mortality, with an overall relative risk of 0.63 (95% CI: 0.41–0.97; Table A5.1). The only identified study to report findings for women found no reduction in AAA mortality at five years after screening (46). Substantial heterogeneity across studies indicated that they had not produced similar results. Sensitivity analyses of the risk of bias did not alter the overall effect estimate, which strengthened confidence in the meta-analysis. Furthermore, Table A5.8. Screening for AAA: meta-analysis of AAA mortality Study Start year Forest plot Relative risk 95% confidence interval Weight (%) Chichester (45) 1989 0.88 0.60–1.30 24.16 Viborg (49) 1994 0.34 0.20–0.58 20.83 Western Australia (50) 1996 0.92 0.69–1.22 26.59 MASS (48) 1997 0.52 0.43–0.64 28.42 Overall – 0.63 0.41–0.97 – MASS: Multicentre Aneurysm Screening Study. Notes: random effects restricted maximum likelihood model. A relative risk of < 1 favours screening; a relative risk of > 1 favours the control. Heterogeneity statistics: t2 = 0.16, I2 = 86.00%, H2 = 7.14. Test of θi = θj: Q(3) = 18.30, P = 0.00. Test of θ = 0: z = −2.11, P = 0.04. 0.25 0.40 0.65 1.50 2.501.00 107 the inclusion of adjusted results (hazard ratios) instead of the absolute number of cases did not change the results. AAA rupture Two studies reported AAA rupture for men (45,48): one study reported no reduction in AAA rupture after 15 years (45), whereas the other reported a relative risk reduction of almost 50% in the screened group after 10 years (48). The meta-analysis showed that screening does not reduce AAA rupture, with an overall relative risk of 0.66 (95% CI: 0.40–1.09). The only identified study to report findings for women found no reduction in the AAA rupture rate at five and 10 years after screening (47). Substantial heterogeneity across studies indicated that they had not produced similar results. Sensitivity analyses of the risk of bias did not alter the overall effect estimate, which strengthened confidence in the meta-analysis. Furthermore, the inclusion of adjusted results (hazard ratios) instead of the absolute number of cases did not change the results. Table A5.9. Screening for AAA: meta-analysis of AAA rupture Study Start year Forest plot Relative risk 95% confidence interval Weight (%) Chichester (45) 1989 0.88 0.61–1.26 44.96 MASS (48) 1997 0.53 0.44–0.63 55.04 Overall – 0.66 0.40–1.09 – MASS: Multicentre Aneurysm Screening Study. Notes: random effects restricted maximum likelihood model. A relative risk of < 1 favours screening; a relative risk of > 1 favours the control. Heterogeneity statistics: t2 = 0.11, I2 = 84.07%, H2 = 6.28. Test of θi = θj: Q(1) = 6.28, P = 0.01. Test of θ = 0: z = −1.61, P = 0.11. 0.50 0.70 1.00 1.50

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