Health Technology Assessment

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

  • Type:
    Research Article
  • Authors:
    Olalekan A UthmanOlalekan A Uthman on ORCiD,
    Lena Al-KhudairyLena Al-Khudairy on ORCiD,
    Chidozie NdukaChidozie Nduka on ORCiD,
    Rachel CourtRachel Court on ORCiD,
    Jodie EnderbyJodie Enderby on ORCiD,
    Seun AnjorinSeun Anjorin on ORCiD,
    Hema MistryHema Mistry on ORCiD,
    G J Melendez-TorresG J Melendez-Torres on ORCiD,
    Sian Taylor-PhillipsSian Taylor-Phillips on ORCiD,
    Aileen ClarkeAileen Clarke on ORCiD
    Detailed Author information

    Olalekan A Uthman1,*, Lena Al-Khudairy1, Chidozie Nduka1, Rachel Court1, Jodie Enderby1, Seun Anjorin1, Hema Mistry1,3, G J Melendez-Torres2, Sian Taylor-Phillips1, Aileen Clarke1

    • 1 Warwick Medical School, University of Warwick, Coventry, UK
    • 2 Peninsula Technology Assessment Group (PenTAG), College of Medicine and Health, University of Exeter, Exeter, UK
    • 3 University Hospitals Coventry and Warwickshire NHS Trust, Coventry, UK
    • * Corresponding author email: olalekan.uthman@warwick.ac.uk

    • Disclaimer: This report contains transcripts of interviews conducted in the course of the research and contains language that may offend some readers.

  • Funding:
    Health Technology Assessment programme
  • Journal:
    Health Technology Assessment
  • Published:
  • Citation:
    Uthman OA, Al-Khudairy L, Nduka C, Court R, Enderby J, Anjorin S, et al. Interventions for primary prevention of cardiovascular disease: umbrella review of systematic reviews [published online ahead of print June 26 2024]. Health Technol Assess 2024. https://doi.org/10.3310/GJTR5006
  • DOI:
    https://doi.org/10.3310/GJTR5006
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Background

Cardiovascular diseases are the leading cause of death globally. The aim of this overview of systematic reviews was to compare the effectiveness of different pharmacological and non-pharmacological interventions for the primary prevention of cardiovascular disease.

Methods

A structured search of the Cochrane Database of Systematic Reviews, MEDLINE, EMBASE and the Database of Abstracts of Reviews of Effects archive was conducted to find systematic reviews that reported the effect of various pharmacological and non-pharmacological interventions for the primary prevention of cardiovascular disease from inception to March 2021. References of included studies were also checked. The included systematic reviews’ methodological quality was assessed using the Assessment of Multiple Systematic Reviews 2 instrument (range, 0–16). The outcomes of each included review’s meta-analysis were extracted and described narratively.

Results

This study analysed 95 systematic reviews, including 41 on non-pharmacological interventions and 54 on pharmacological interventions for cardiovascular health. The majority of the reviews focused on lipid-lowering interventions (n = 25) and antiplatelet medications (n = 21), followed by nutritional supplements, dietary interventions, physical activity, health promotion and other interventions. Only 1 of the 10 reviews addressing cardiovascular mortality showed a potential benefit, while the others found no effect. Antiplatelets were found to have a beneficial effect on all-cause mortality in 2 out of 12 meta-analyses and on major cardiovascular disease events in 8 out of 17 reviews. Lipid-lowering interventions showed beneficial effects on cardiovascular disease mortality, all-cause mortality and major cardiovascular disease events in varying numbers of the reviews. Glucose-lowering medications demonstrated significant benefits for major cardiovascular events, coronary heart disease events and mortality. However, the combination of dietary interventions, physical activities, nutritional supplements and polypills showed little or no significant benefit for major cardiovascular outcomes or mortality.

Future work and limitations

More research is needed to determine whether the effect of treatment varies depending on population characteristics. The findings of this review should be interpreted with caution because the majority of studies of non-pharmacological interventions compare primary prevention with usual care, which may include recommended pharmacological treatment in higher-risk patients (e.g. statins and/or antihypertensive medications, etc.). In addition, randomised controlled trial evidence may be better suited to the study of pharmacological interventions than dietary and lifestyle interventions.

Conclusions

This umbrella review captured the variability in different interventions on randomised controlled trial evidence on interventions for primary prevention of cardiovascular disease and identified areas that may benefit from further research. Specifically, this review focused on randomised controlled trial evidence on interventions for primary prevention of cardiovascular disease. Researchers may use these findings as a resource to direct new intervention studies and network meta-analyses to compare the efficacy of various interventions based on these findings.

Funding

This article presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment (HTA) programme as award number 17/148/05.

Notes

Article history

The contractual start date for this research was in February 2019. This article began editorial review in August 2022 and was accepted for publication in July 2023. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The Health Technology Assessment editors and publisher have tried to ensure the accuracy of the authors’ article and would like to thank the reviewers for their constructive comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this article.

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Copyright statement

Copyright © 2024 Uthman et al. This work was produced by Uthman et al. under the terms of a commissioning contract issued by the Secretary of State for Health and Social Care. This is an Open Access publication distributed under the terms of the Creative Commons Attribution CC BY 4.0 licence, which permits unrestricted use, distribution, reproduction and adaptation in any medium and for any purpose provided that it is properly attributed. See: https://creativecommons.org/licenses/by/4.0/. For attribution the title, original author(s), the publication source – NIHR Journals Library, and the DOI of the publication must be cited.

2024 Uthman et al.

Introduction

In high-income countries, such as the UK, cardiovascular disease (CVD) is one of the primary causes of morbidity and mortality. 1 Heart and circulation disorders account for a quarter of all deaths in the UK, or over 160,000 each year – an average of 460 deaths per day, or 1 every 3 minutes. 1 In the UK, around 7.6 million people (4 million men and 3.6 million women) suffer from heart or circulatory disease. The most common type of heart illness is coronary heart disease (CHD). 1 It is the leading cause of heart attack and the leading cause of death for both men and women worldwide in 2019. 1 Heart attacks cause 100,000 hospital admissions in the UK each year, or one every 5 minutes. In the UK today, around 1.4 million people have survived a heart attack and heart failure affects around 900,000 people. Strokes kill about 35,000 people in the UK every year and are the leading cause of severe disability. 1

Many of the risk factors for developing CVD are modifiable, and data suggest that a substantial percentage of the current CVD burden is either entirely or partially preventable. 2–4 Primary prevention of CVD at the community level is ideal, as the aim is to delay or avoiding the start of CVD. Several systematic reviews and meta-analyses have examined strategies for the primary prevention of CVD, but there has been no consensus regarding the strategy with the best overall results. 5,6 Some have concluded that these interventions may be successful in reducing the burden of CVD, whereas others have questioned their efficacy for CVD primary prevention. 5,6 Determining the effectiveness of various strategies for the primary prevention of CVD necessitates a systematic evaluation and synthesis of the available evidence. 7–9 This study seeks to provide such a synthesis giving an overview of existing systematic reviews. This is a relatively new strategy for summing up evidence which can help researchers synthesise evidence across interventions. This is particularly valuable when conflicting evidence has been reported in previous systematic reviews. We aim to produce a comprehensive overview of the current best evidence by identifying, analysing and synthesising the numerous published systematic reviews assessing the comparative effectiveness of different interventions for primary prevention of CVD.

This publication is part of a series of publications on ‘Determining optimal strategies for primary prevention of CVD: systematic review, network meta-analysis and cost-effectiveness review (National Institute for Health and Care Research (NIHR)/Health Technology Assessment (HTA): 17/148/05)’. Other publications in this series include:

  1. Effectiveness of policies and structural interventions in reducing CVD and mortality: a systematic review of simulation-based studies.

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

  3. Determining optimal primary prevention interventions for major CVD events and all-cause mortality – findings from systematic review and hierarchical network meta-analysis of randomised controlled trials (RCTs).

  4. How conclusive is the evidence for interventions in primary prevention of CVD: a trial sequential analysis?

  5. Mind the gap! A multilevel analysis of factors associated with variation in published CVD primary prevention interventions effect estimates within and between countries.

  6. Determining optimal strategies for primary prevention of CVD: systematic review of cost-effectiveness analyses in the UK.

The findings from all the workstreams, including those from the systematic review of modelling studies, will be summarised in a synopsis paper to be published alongside this series.

Methods

This systematic review was registered in the International Prospective Register of Systematic Reviews (PROSPERO) under the following number: CRD42019123940. We adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA). 10

Review eligibility criteria

The review question guiding this overview is presented in PICOTSS format (patient, intervention, comparators, outcomes, timing, setting and study design):

Patients: The review includes adult populations (18 years and older) from population-based studies, which may target moderate/high CVD risk groups such as those with hypertension, obesity, hyperlipidaemia, type 2 diabetes or a combination of these factors. The focus of the review is on primary prevention of CVD, so we excluded trials involving individuals who have had a previous myocardial infarction (MI), stroke, revascularisation procedure coronary artery bypass grafting or percutaneous transluminal coronary angioplasty and those with angina or angiographically defined CHD. Studies with mixed populations, including both individuals with and without CVD, were included if data relevant to primary prevention could be extracted.

Intervention: Any form of intervention aimed at the primary prevention of CVD, including but not limited to drugs [lipid-lowering medications, blood pressure (BP)-lowering medications, antiplatelet agents], diet (nutritional supplements, dietary interventions), physical activity or public health (health promotion programmes, structural and policy interventions).

Comparators: Other forms of intervention (such as a minimal intervention, active intervention, concomitant intervention), placebo, usual care or no intervention control group or waiting list control.

Outcome measures: The primary outcome was all-cause mortality. Secondary outcomes were CVD-related mortality, major cardiovascular events (defined as fatal and non-fatal MI, sudden cardiac death, revascularisation, fatal and non-fatal stroke and fatal and non-fatal heart failure), CHD (fatal and non-fatal MI and sudden cardiac death, excluding silent MI) and incremental costs per quality-adjusted life-years gained reported alongside a randomised trial.

Timing: Studies of any duration.

Setting: Any setting.

Study design: Systematic reviews of RCTs. Units of randomisation could be either individuals or clusters (such as family, workplace).

Search strategy

A sensitive literature search for existing systematic reviews was developed iteratively. The process involved testing each iteration’s effectiveness in retrieving a high proportion of records for a broad cross-section of more than 70 known, relevant systematic reviews of RCTs that had been found in previous work via a variety of sources. After only a few iterations, we found that by adding a few specific medical subject heading (MeSH) and title terms we were able to find all of the known reviews. Searches were based on the concepts of prevention, CVD outcomes and systematic reviews. From inception until March 2021, we searched the Cochrane Database of Systematic Reviews (via Wiley), MEDLINE (via Ovid), EMBASE (via Ovid) and Database of Abstracts of Reviews of Effects (DARE) (via Centre for Reviews and Dissemination) databases. All searches were carried out by one of us (RC), an experienced information specialist. Appendix 1 of the supplement contains detailed search strategies. References of included studies were also checked for relevant reviews. Records were exported to EndAAFnote X9 and systematically de-duplicated.

Study selection and data extraction

All study selection, data extraction, evidence synthesis and quality assessment processes were completed by two authors separately (CN and SA). Any disagreement was handled by consensus or referral to a third investigator (OAU). We independently abstracted key participant and intervention information and reported data on prespecified outcomes using standardised data extraction templates for studies that met the inclusion criteria. For outcomes that were meta-analysed, we also retrieved pooled effect estimates. Risk ratios (RRs) or odds ratios with 95% confidence intervals (CI) were used to report dichotomous data.

Risk of bias

We independently assessed the methodological quality of each systematic review using the Assessment of Multiple SysTemAtic Reviews (AMSTAR) 2 tool. 11

Results

Study characteristics and evidence mapping

Our search identified 10,883 records, of which 111 records were evaluated as full-text articles after title and abstract screening (Figure 1). In total, we selected 95 systematic reviews for inclusion (see Appendix 2). The systematic reviews were published between 1997 and 2020. On average, the systematic reviews included 18 RCTs (range: 2–287). The largest systematic review included 287 RCTs. The number of participants included in the systematic reviews ranged from as few as 47 to as many as 963,829 (mean: 73,937). When reported, final searches for each reported review were performed between August 2014 and September 2019. Table 1 shows results from the most recent and most comprehensive systematic reviews for each intervention for major cardiovascular events, CHD events, CVD mortality and all-cause mortality.

FIGURE 1.

PRISMA study flow and selection.

Intervention Major cardiovascular events CHD events CVD mortality All-cause mortality
Non-pharmacological
Dietary
 Dietary intervention 0.96 (0.92–1.01) 0.91 (0.85–0.97) 0.92 (0.86–0.99) 0.97 (0.93–1.01)
 Folic acid 0.98 (0.95–1.02) 1.03 (0.98–1.08) 1.00 (0.98–1.02)
 Reduced fat 0.84 (0.72–1.07) 0.91 (0.77–1.07) 0.98 (0.86–1.12)
 Reduced salt 0.76 (0.57–1.01) 0.67 (0.45–1.01) 0.96 (0.83–1.10)
Health promotion
 Digital health 1.21 (0.58–2.54)
 Multifactorial 0.99 (0.92–1.07) 1.00 (0.96–1.05)
Multicomponent intervention
 Diet and physical activity advice 0.57 (0.11–3.07)
Nutritional supplements
 Beta-carotene 1.01 (0.93–1.09) 1.04 (0.99–1.09)
 Calcium 1.14 (0.92–1.41) 1.04 (0.96–1.12)
 Folic acid 0.52 (0.24–1.10)
 Homocysteine-Folic 0.90 (0.81–1.00)
 Multivitamin 0.95 (0.85–1.06) 0.91 (0.84–0.98) 0.92 (0.87–0.98) 0.98 (0.94–1.02)
 Niacin 0.66 (0.49–0.89) 0.75 (0.59–0.96)
 Omega 3 0.95 (0.82–1.12) 0.85 (0.68–1.06) 0.87 (0.73–1.03)
 Selenium 1.03 (0.95–1.11) 0.97 (0.79–1.20) 0.97 (0.88–1.08)
 Vitamin A 1.09 (0.77–1.54)
 Vitamin B3 0.95 (0.74–1.22) 0.93 (0.87–1.00) 1.02 (0.93–1.12) 1.05 (0.97–1.12)
 Vitamin C 0.99 (0.89–1.10) 1.06 (0.97–1.16)
 Vitamin D 0.95 (0.95–0.98) 0.93 (0.89–0.96) 0.94 (0.890.99) 0.94 (0.88–1.01)
 Vitamin D + Calcium 1.01 (0.95–1.07) 0.92 (0.83–1.01)
 Vitamin E 0.97 (0.92–1.03) 1.01 (0.98–1.04)
Pharmacological
Antiplatelet
 Antiplatelet 0.97 (0.96–0.99)
 Aspirin 0.90 (0.85–0.94) 0.86 (0.79–0.92) 0.99 (0.87–1.11) 0.96 (0.90–1.03)
BP lowering
 Angiotensin-converting enzyme (ACE) inhibitors 1.03 (1.00–1.06) 0.95 (0.90–1.01) 1.01 (0.97–1.05)
 Alpha-blockers 1.20 (0.85–1.69) 0.84 (0.63–1.14) 1.04 (0.88–1.23)
 Angiotensin receptor blockers 0.98 (0.93–1.02) 1.06 (0.98–1.15) 0.99 (0.94–1.04)
 Antihypertensive 0.64 (0.53–0.76) 0.69 (0.51–0.94)
 Beta-blockers 1.17 (1.11–1.24) 1.03 (0.96–1.10) 1.06 (1.01–1.12)
 Ca channel blockers 0.97 (0.94–0.99) 0.98 (0.94–1.03) 0.97 (0.94–1.00)
 Diuretics 0.97 (0.94–1.00) 1.02 (0.97–1.09) 1.02 (0.97–1.06)
Glucose lowering
 Glucose-lowering drugs 0.92 (0.89–0.95) 0.92 (0.87–0.97) 0.94 (0.90–0.98)
 Sodium-glucose linked transporter (SGLT) -2 inhibitors 0.83 (0.71–0.96) 0.86 (0.79–0.94) 0.74 (0.67–0.81) 0.85 (0.79–0.92)
Lipid lowering
 Fibrates 0.88 (0.73–1.05) 0.84 (0.74–0.96) 0.86 (0.56–1.32) 0.97 (0.074–1.26)
 Homocysteine lowering 0.90 (0.82–0.99) 1.02 (0.95–1.10) 1.01 (0.96–1.06)
 Statins 0.74 (0.61–0.89) 0.80 (0.71–0.90) 0.85 (0.74–0.98) 0.96 (0.88–1.04)
Polypills
 Polypills 1.38 (0.91–2.10) 1.26 (0.67–2.38)

Risk of bias of included reviews

Assessment of Multiple SysTemAtic Reviews 2 rating is summarised in Appendix 3. A majority of the reviews (81 out of 95) addressed research questions and inclusion criteria using the population, intervention, comparison and outcomes (PICO) components. Just under half (42 out of 95) mentioned that the review methods were predetermined and justified any significant deviations from the protocol. Most authors (85 out of 95) clarified the chosen study designs for inclusion in their reviews.

Just over half of the authors employed a comprehensive literature search strategy (55 out of 95), conducted study selection in duplicate (67 out of 95) and performed data extraction in duplicate (68 out of 95). Only about half (51 out of 95) provided a list of excluded studies and justified their exclusions, while most (75 out of 95) described the included studies in adequate detail.

A limited number of authors (47 out of 95) utilised a satisfactory technique to assess the risk of bias (RoB) in the individual studies included in the review, and even fewer (37 out of 95) reported on the funding sources for the included studies. Only 45 authors applied appropriate methods for statistically combining results, while 42 assessed the potential impact of RoB in individual studies on the meta-analysis or other evidence synthesis results and another 42 accounted for RoB in primary studies when interpreting or discussing the review findings.

The majority of authors (84 out of 95) offered a satisfactory explanation and discussion of any observed heterogeneity in their review results. About 58 authors conducted an adequate investigation of publication bias (small study bias) and discussed its probable impact on the review results. Lastly, 75 authors reported any potential sources of conflict of interest, including any funding received for conducting their reviews.

Antiplatelets

Antiplatelets were examined in 21 systematic reviews published between 2000 and 2020. When reported, the last searches ranged from September 1997 to December 2018. Drugs examined in the reviews included antiplatelets (1 review included) and aspirin (20 reviews included). The AMSTAR ratings ranged from a score of 1 to 12 out of a possible 16. Only of 10 meta-analyses reported a beneficial effect of antiplatelets on CVD mortality. Two of 12 meta-analyses reported a beneficial effect of antiplatelets on all-cause mortality. Eight of 17 systematic reviews reported a beneficial effect of antiplatelets on major CVD events (RR ranging from 0.85 to 0.97, 95% CI ranging from 0.78 to 0.99). Five of eight systematic reviews reported a beneficial effect of antiplatelets on CHD events (RR ranging from 0.70 to 0.86, 95% CI ranging from 0.60 to 0.95).

Blood pressure lowering

Blood pressure-lowering medications were examined in three systematic reviews. When reported, the last searches ranged from January 1998 to November 2015; and these reviews were published between 2001 and 2015. The drugs examined in the reviews included angiotensin-converting enzyme (ACE) inhibitors (one review included), antihypertensives (one review included) and diuretics (one review included). The AMSTAR ratings ranged from a score of 2 to 14 out of 16. None of the reviews showed a benefit of BP lowering in primary prevention of cardiovascular events or mortality, apart from calcium channel blockers which demonstrated a reduction in major cardiovascular events (RR = 0.97, 95% CI 0.94 to 0.99).

Dietary interventions

Dietary interventions were examined in 14 systematic reviews. When reported, the last searches ranged from July 1993 to August 2019; and these reviews were published between 1997 and 2020. Interventions included different types of dietary interventions such as reduced salt (two reviews included), dietary intervention (two reviews included), nuts (one review), folic acid (one review included), green tea (one review included), Mediterranean diet (one review included), low-glycaemic-index diets (one review included), reduced fat (one review included), whole grain cereals (one review included), fibre (one review included) and garlic (one review included). The AMSTAR ratings ranged from a score of 5 to 15 of 16. The dietary interventions showed little or no significant beneficial effect of major cardiovascular events, CHD events and mortality.

Glucose-lowering medications

Glucose-lowering medications were examined in the three systematic reviews. When reported, the last searches ranged from May 2019 and January 2020; and these reviews were published between 2019 and 2020. The drugs examined in the reviews included sodium-glucose linked transporter (SGLT)-2 inhibitors (two reviews included) and glucose-lowering drugs (one review included). The AMSTAR ratings ranged from a score of 11 to 13 of 16. All glucose-lowering medications showed a significant beneficial effect on major cardiovascular events (RR = 0.92, 95% CI 0.89 to 0.95), CHD events (RR = 0.92, 95% CI 0.87 to 0.97) and mortality (RR = 0.94, 95% CI 0.90 to 0.98).

Health promotion

Health promotion interventions were examined in four systematic reviews. When reported, the last searches ranged from June 2006 to January 2014; and these reviews were published between 2010 and 2015. There were various health promotion interventions such as multifactorial interventions (two reviews included), telehealth (one review included) and digital health (one review included). The AMSTAR ratings ranged from a score of 8 to 11 of 16. The health promotion interventions showed little or no significant beneficial effect of major cardiovascular events, CHD events and mortality.

Lipid lowering

Lipid-lowering medications were examined in 25 systematic reviews. When reported, the last searches ranged from June 1996 to August 2020; and these reviews were published between 1999 and 2020. The drugs examined in the reviews included statins (20 reviews included), fibrates (4 reviews included) and homocysteine lowering (1 review included). The AMSTAR ratings ranged from a score of 1 to 16 of 16. Three of nine systematic reviews reported a beneficial effect of lipid lowering on CVD mortality (RR ranging from 0.71 to 0.89, 95% CI ranging from 0.56 to 0.98). Five of 18 systematic reviews reported a beneficial effect of lipid lowering on all-cause mortality (RR ranging from 0.66 to 0.93, 95% CI ranging from 0.49 to 0.99). Fifteen of 18 systematic reviews reported a beneficial effect of lipid lowering on major CVD events (RR ranging from 0.59 to 0.90, 95% CI ranging from 0.48 to 0.99). Eight of 10 systematic reviews reported a beneficial effect of lipid lowering on CHD events (RR ranging from 0.55 to 0.84, 95% CI ranging from 0.42 to 0.96).

Multicomponent intervention

Multicomponent interventions were examined in one systematic review. The last searches were conducted in June 2014 and published in 2015. Interventions included different types of nutrition supplements such as diet and physical activity advice (one review included). The AMSTAR rating was a score of 15 of 16. The combination of dietary intervention and physical activities showed little or no significant beneficial effect of major cardiovascular events.

Nutritional supplements

Nutrition supplements were examined in 19 systematic reviews. When reported, the last searches ranged from February 2002 to September 2019; and these reviews were published between 2004 and 2020. Interventions included different types of nutrition supplements such as multivitamin (nine reviews included), vitamin D (three reviews included), vitamin B3 (one review included), omega 3 (one review included,), omega 6 (one review included), homocysteine-folic (one review included), tomato and lycopene supplement (one review included), selenium (one review included), coenzyme q10 (one review included) and niacin (one review included). The AMSTAR ratings ranged from a score of 3 to 16 of 16.

Most of the nutritional supplements showed little or no significant beneficial effect of major cardiovascular events, CHD events and mortality.

Physical activity

Physical activity was examined in five systematic reviews. When reported, the last searches ranged from December 2013 to October 2016; and these reviews were published between 2014 and 2017. Interventions included different types of physical activity interventions such as workplace physical activity (workplace intervention that aims to boost health literacy and encourage the adoption of healthy lifestyles, with a focus on physical activity as the primary outcome) (one review included), yoga (one review included), meditation (one review included), tai chi (one review included) and physical activity (any form of health education intervention that aims to boost health literacy and encourage the adoption of healthy lifestyles, with a focus on physical activity as the primary outcome at any location) (one review included). The AMSTAR ratings ranged from a score of 14 to 16 of 16. None of the included systematic reviews reported effects of physical activities on major cardiovascular events, CHD events, CVD associated mortality or all-cause mortality.

Polypills

Polypills were examined in the two systematic reviews. When reported, the last searches ranged from December 2010 to July 2013; and these reviews were published between 2012 and 2014. There were two reviews (two reviews included). The AMSTAR ratings ranged from a score of 4 to 15 of 16. Polypills showed little or no significant beneficial effect of major cardiovascular events, CHD events and all-cause mortality.

Discussion

Main findings

This umbrella review provides information about diverse interventions for primary prevention of CVD. Our work constitutes the first comprehensive and systematic summary of diverse non-pharmacological and pharmacological interventions based on the umbrella review methodology. We included 95 systematic reviews, 41 were on various non-pharmacological interventions and 54 concerned various pharmacological interventions. Most of the reviews examined lipid-lowering interventions (n = 25) followed by antiplatelet medications (n = 21). Other reviews included nutritional supplements (n = 19), dietary interventions (n = 13) physical activity (n = 5), health promotion interventions (n = 4), BP-lowering medications (n = 3), blood glucose-lowering medications (n = 3), polypills (n = 2) and multicomponent intervention (n = 1). Out of 95 reviews analysed, most addressed research questions and inclusion criteria using PICO components and clarified their chosen study designs. Approximately half employed comprehensive literature search strategies, conducted study selection and performed data extraction in duplicate. Only a limited number of authors assessed the RoB in individual studies, applied appropriate methods for combining results and accounted for bias when interpreting findings. The majority provided explanations for heterogeneity, investigated publication bias and reported potential conflicts of interest.

We found potential promising effects, indicated by statistically significant pooled treatment effects in more than one systematic review reported for SGLT-2 inhibitors, vitamin D, dietary interventions, reduced salt, fibrates and multifactorial interventions. In addition, several systematic reviews provided evidence of the potential lack of effectiveness across more than one systematic review, such as BP-lowering medications and multivitamins.

The most comprehensive and high-quality systematic reviews of aspirin reported a 10% reduction in major cardiovascular events and a 14% reduction in CHD events; SGLT-2 inhibitors reported a 17% reduction in major cardiovascular events, a 14% reduction in CHD, a 26% in CVD associated mortality and a 15% reduction in all-cause mortality; statins reported a 26% reduction in major cardiovascular events, a 20% reduction in CHD events and a 15% in CVD associated mortality; and niacin reported an 34% reduction in major cardiovascular events and a 25% reduction in CHD events.

Results of our overview of systematic reviews can be also compared with those of previous overviews of systematic reviews of both pharmacological5 and non-pharmacological6 interventions for preventing CVD. Karmali and colleagues5 conducted an overview of systematic reviews to compare the efficacy and safety of aspirin, BP-lowering therapy, statins and tobacco cessation drugs for fatal and nonfatal atherosclerotic cardiovascular disease (ASCVD) outcomes in primary ASCVD prevention. There were 35 systematic reviews of RCTs found in a total of 1967 reports, including 15 reviews of aspirin, 4 reviews of BP-lowering medication, 12 reviews of statins and 4 reviews of cigarette cessation drugs. According to the review, high-quality data support the use of aspirin, BP-lowering treatment and statins for primary ASCVD prevention, as well as tobacco cessation medicines for smoking cessation.

Martin Ruiz and colleague6 conducted an umbrella review to determine the effectiveness of non-pharmacological interventions for prevention of CVD events and mortality in healthy adults or those at high risk of CVD. There were 24 reviews in total, with 13 of them reporting results of interest. Vitamin D supplements, increased omega 3 fatty acid consumption, Qigong and counselling or education to modify more than one cardiovascular risk factor were all found to reduce risk in a statistically meaningful way. The authors concluded that these four non-pharmacological interventions have been shown to provide a statistically significant reduction in risk of CVD events or overall mortality.

Strengths and limitations

Our study has numerous strengths. It presents a thorough, complete evaluation of the data from all published meta-analyses regarding pharmacological and non-pharmacological therapies for CVD primary prevention. First, we concentrated this evidence synthesis on systematic reviews and meta-analyses of RCTs, as RCTs provide the highest-quality evidence for determining the benefits of healthcare interventions. Second, we employed a comprehensive, transparent search approach to locate papers and a predefined procedure to guide our evidence synthesis, documenting any protocol deviations. Third, we did all-title screening, data extraction and quality evaluations in duplicate to reduce the possibility of bias during compilation of this summary. Fourth, we employed a validated instrument (the AMSTAR 2 tool) to evaluate the methodological quality of the included systematic reviews, and we used this evaluation to inform our conclusions regarding the effects of pharmacologic therapies. This methodical procedure, which includes the evaluation of study quality using standardised instruments, could serve as a model for the expedited creation of reliable guidelines.

Our umbrella review also has some limitations. We did not retrieve data from primary RCTs; thus we had to rely on the information provided by the authors of the systematic reviews we retrieved. Selection criteria, search methodologies and definitions of main prevention frequently differed across reviews, and authors of included reviews frequently employed different criteria to define primary prevention, resulting in varying numbers of trials for systematic reviews of the same intervention. In addition, primary studies that were not included in any published meta-analyses may have been omitted, and new studies that were published after the publication of each meta-analysis may have altered the results. Finally, we selected the most recent meta-analysis for each intervention that included the greatest number of primary studies. Therefore, it is possible that the chosen meta-analysis may not be that of the highest quality.

Implications for future research and policy

Because the RCTs included in each systematic review may have been undertaken in very diverse populations, the observed results may not be generalisable. More research is needed to determine whether the effect of treatment varies depending on population characteristics. The findings of this review should be interpreted with caution because the majority of studies investigating non-pharmacological interventions for primary prevention compare them to usual care, which may include recommended pharmacological treatment in higher-risk patients (e.g. statins and/or antihypertensive medications, etc.). This means that the combined effect of non-pharmacological interventions and standard pharmacological practise is being measured in these trials, rather than the effect of these interventions as an alternative to pharmacology. More research is also recommended to evaluate different intervention combinations. Identifying the most effective intervention, on the other hand, continues to be a challenge for researchers and policy-makers. There is a need for an up-to-date comprehensive evidence synthesis of all interventions to inform the NHS and UK Health Security Agency’s rational choice of a minimum set of strategies for primary prevention of CVD in order to avoid targeting relatively fewer effective interventions.

While numerous pairwise systematic reviews and meta-analyses have investigated the effectiveness of various interventions for primary prevention of CVD, no systematic review has yet comprehensively synthesised all available evidence to understand the comparative effectiveness of different drug, lifestyle and structural interventions in order to support evidence-based recommendations. Another issue is that most trials use a ‘no intervention’ control group as the comparator, which limits the usefulness of pairwise analyses in informing practical decisions about the most effective interventions. Network meta-analysis methods are designed to address this question and provide more valuable insights for policy-makers, health service commissioners and care providers when choosing between multiple intervention alternatives. Therefore, we recommend conducting an innovative network meta-analysis to better inform decision-making in primary prevention of CVD.

Patient and public involvement

Drawing on INVOLVE guidance and support for best practice, we worked closely with three dedicated patient and public involvement advisors, we welcomed guidance and support from our advisors at the preparatory phase of the project.

Conclusion

In conclusion, this study examined various interventions for the primary prevention of CVD. Antiplatelet medications showed beneficial effects in some reviews on CVD mortality, all-cause mortality and major cardiovascular events. BP-lowering medications had no significant effect on cardiovascular events or mortality, except for calcium channel blockers, which reduced major cardiovascular events. Dietary interventions had little to no significant impact on major cardiovascular events, CHD events and mortality.

Glucose-lowering medications showed a significant beneficial effect on major cardiovascular events, CHD events and mortality. Health promotion interventions had little to no significant impact on major cardiovascular events, CHD events and mortality. Lipid-lowering medications demonstrated beneficial effects on CVD mortality, all-cause mortality, major cardiovascular events and CHD events in various reviews.

Multicomponent interventions, which combined dietary intervention and physical activities, showed little to no significant impact on major cardiovascular events. Most nutritional supplements had little or no significant effect on major cardiovascular events, CHD events and mortality. Physical activity interventions did not report significant effects on major cardiovascular events, CHD events, CVD-associated mortality or all-cause mortality. Polypills had little or no significant impact on major cardiovascular events, CHD events and all-cause mortality.

Additional information

Contributions of authors

Olalekan A Uthman (https://orcid.org/0000-0002-8567-3081) (Professor, Evidence Synthesis) contributed to the protocol, study selection, data extraction, validity assessments and synthesis of the included studies. He developed the classifiers and undertook the analyses. He also contributed to the interpretation of the results and the writing of the report and had overall responsibility for the project.

Lena Al-Khudairy (https://orcid.org/0000-0003-0638-583X) (Associate Professor, Evidence Synthesis) contributed to the protocol, study selection, validity assessments and synthesis of the included studies. She also contributed to the interpretation of the results and the writing of the report.

Chidozie Nduka (https://orcid.org/0000-0001-7031-5444) (Senior Research Fellow, Evidence Synthesis) contributed to the protocol, study selection, validity assessments and synthesis of the included studies. He also contributed to the interpretation of the results and the writing of the report.

Rachel Court (https://orcid.org/0000-0002-4567-2586) (Information Specialist) contributed to the protocol development, developed the search strategies, and wrote the sections of the report relating to the literature searches. She also contributed to the protocol and interpretation of the results and commented on drafts of the report.

Jodie Enderby (https://orcid.org/0000-0002-1446-7512) (Research Associate) contributed to the protocol, study selection, validity assessments and synthesis of the included studies. She also contributed to the interpretation of the results and the writing of the report.

Seun Anjorin (https://orcid.org/0000-0003-0187-6410) (Research Associate) contributed to the protocol, study selection, validity assessments and synthesis of the included studies. He conducted a range of searches to locate studies. He also contributed to the interpretation of the results and the writing of the report.

Hema Mistry (https://orcid.org/0000-0002-5023-1160) (Associate Professor, Health Economics) contributed to the protocol, study selection, validity assessments and synthesis of the included studies. She also contributed to the interpretation of the results and the writing of the report.

GJ Melendez-Torres (https://orcid.org/0000-0002-9823-4790) (Professor, Evidence Synthesis) contributed to the protocol, study selection, validity assessments and synthesis of the included studies. He also contributed to the interpretation of the results and the writing of the report.

Sian Taylor-Phillips (https://orcid.org/0000-0002-1841-4346) (Professor, Evidence Synthesis) contributed to the protocol, study selection, validity assessments and synthesis of the included studies. She also contributed to the interpretation of the results and the writing of the report.

Aileen Clarke (https://orcid.org/0000-0001-8299-3146) (Professor, Evidence Synthesis) contributed to the protocol, study selection, validity assessments and synthesis of the included studies. She also contributed to the interpretation of the results and the writing of the report.

Disclosure of interests

Full disclosure of interests: Completed ICMJE forms for all authors, including all related interests, are available in the toolkit on the NIHR Journals Library report publication page at https://doi.org/10.3310/GJTR5006.

Primary conflicts of interest: Aileen Clarke and Lena Al-Khudairy were supported by the National Institute for Health and Care Research (NIHR) Applied Research Collaboration (ARC) West Midlands (grant number NIHR200165). Sian Taylor-Phillips was supported by a Career Development Fellowship (reference number NIHR-CDF-2016-09-018). Hema Mistry is a member of the HTA General Committee. Aileen Clarke was a member of the SRP – Cochrane Programme Grant Funding Meeting.

Data-sharing statement

No new data have been created in the preparation of this article and therefore there is nothing available for access and further sharing. All queries should be submitted to the corresponding author.

Ethics statement

This work is a systematic review of accessing, processing and analysing data that have already been published and is available to the public. As a result, no patient data were processed; and patient consent and/or registration via human research ethics committees were, therefore, not relevant.

Information governance statement

This project did not involve the handling of personal information.

Study registration details

This study is registered as PROSPERO CRD42019123940.

Funding

This article presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment (HTA) programme as award number 17/148/05. The views and opinions expressed by authors in this publication are those of the authors and do not necessarily reflect those of the NHS, the NIHR, the HTA programme or the Department of Health and Social Care. If there are verbatim quotations included in this publication the views and opinions expressed by the interviewees are those of the interviewees and do not necessarily reflect those of the authors, those of the NHS, the NIHR, the HTA programme or the Department of Health and Social Care.

This article reports on one component of the research award Interventions for primary prevention of cardiovascular disease: umbrella review of systematic reviews. For more information about this research please view the award page (www.fundingawards.nihr.ac.uk/award/17/148/05)

About this article

The contractual start date for this research was in February 2019. This article began editorial review in August 2022 and was accepted for publication in July 2023. The authors have been wholly responsible for all data collection, analysis and interpretation, and for writing up their work. The Health Technology Assessment editors and publisher have tried to ensure the accuracy of the authors’ article and would like to thank the reviewers for their constructive comments on the draft document. However, they do not accept liability for damages or losses arising from material published in this article.

Department of Health and Social Care disclaimer

This publication presents independent research commissioned by the National Institute for Health and Care Research (NIHR). The views and opinions expressed by authors in this publication are those of the authors and do not necessarily reflect those of the NHS, the NIHR, MRC, NIHR Coordinating Centre, the HTA programme or the Department of Health and Social Care.

This article was published based on current knowledge at the time and date of publication. NIHR is committed to being inclusive and will continually monitor best practice and guidance in relation to terminology and language to ensure that we remain relevant to our stakeholders.

Copyright

Copyright © 2024 Uthman et al. This work was produced by Uthman et al. under the terms of a commissioning contract issued by the Secretary of State for Health and Social Care. This is an Open Access publication distributed under the terms of the Creative Commons Attribution CC BY 4.0 licence, which permits unrestricted use, distribution, reproduction and adaption in any medium and for any purpose provided that it is properly attributed. See: https://creativecommons.org/licenses/by/4.0/. For attribution the title, original author(s), the publication source – NIHR Journals Library, and the DOI of the publication must be cited.

List of abbreviations

ASCVD
atherosclerotic cardiovascular disease
CHD
coronary heart disease
CVD
cardiovascular disease
MeSH
medical subject heading
MI
myocardial infarction
RoB
risk of bias

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  76. Wei CY, Quek RGW, Villa G, Gandra SR, Forbes CA, Ryder S, et al. A systematic review of cardiovascular outcomes-based cost-effectiveness analyses of lipid-lowering therapies. PharmacoEconomics 2017;35:297-318. https://doi.org/10.1007/s40273-016-0464-2.
  77. Zou CY, Liu XK, Sang YQ, Wang B, Liang J. Effects of SGLT2 inhibitors on cardiovascular outcomes and mortality in type 2 diabetes: a meta-analysis. Medicine 2019;98. https://doi.org/10.1097/md.0000000000018245.
  78. Giugliano D, Longo M, Maiorino MI, Bellastella G, Chiodini P, Solerte SB, et al. Efficacy of SGLT-2 inhibitors in older adults with diabetes: systematic review with meta-analysis of cardiovascular outcome trials. Diabetes Res Clin Pract 2020;162. https://doi.org/10.1016/j.diabres.2020.108114.
  79. Ghosh-Swaby OR, Goodman SG, Leiter LA, Cheng A, Connelly KA, Fitchett D, et al. Glucose-lowering drugs or strategies, atherosclerotic cardiovascular events, and heart failure in people with or at risk of type 2 diabetes: an updated systematic review and meta-analysis of randomised cardiovascular outcome trials. Lancet Diabetes Endocrinol 2020;8:418-35. https://doi.org/10.1016/s2213-8587(20)30038-3.
  80. Allemann S, Diem P, Egger M, Christ ER, Stettler C. Fibrates in the prevention of cardiovascular disease in patients with type 2 diabetes mellitus: meta-analysis of randomised controlled trials. Curr Med Res Opin 2006;22:617-23. https://doi.org/10.1185/030079906X89865.
  81. Das A, Roy B, Bandyopadhyay D, Dasgupta S, Chakraborty S, Soudant C, et al. Non-statin interventions in the prevention of cardiovascular events: sex-based meta-analysis. Prog Cardiovasc Dis 2020;63:228-32. https://doi.org/10.1016/j.pcad.2020.03.012.
  82. Gencer B, Marston NA, Im K, Cannon CP, Sever P, Keech A, et al. Efficacy and safety of lowering LDL cholesterol in older patients: a systematic review and meta-analysis of randomised controlled trials. Lancet 2020;396:1637-43. https://doi.org/10.1016/s0140-6736(20)32332-1.
  83. Berger JS, Lala A, Krantz MJ, Baker GS, Hiatt WR. Aspirin for the prevention of cardiovascular events in patients without clinical cardiovascular disease: a meta-analysis of randomized trials. Am Heart J 2011;162:115-24.e2. https://doi.org/10.1016/j.ahj.2011.04.006.
  84. Bukkapatnam RN, Gabler NB, Lewis WR. Statins for primary prevention of cardiovascular mortality in women: a systematic review and meta-analysis. Prev Cardiol 2010;13:84-90. https://doi.org/10.1111/j.1751-7141.2009.00059.x.
  85. Chang YH, Hsieh MC, Wang CY, Lin KC, Lee YJ. Reassessing the benefits of statins in the prevention of cardiovascular disease in diabetic patients – a systematic review and meta-analysis. Rev Diabet Stud 2013;10:157-70. https://doi.org/10.1900/rds.2013.10.157.
  86. Chen YH, Feng B, Chen ZW. Statins for primary prevention of cardiovascular and cerebrovascular events in diabetic patients without established cardiovascular diseases: a meta-analysis. Exp Clin Endocrinol Diabetes 2012;120:116-20. https://doi.org/10.1055/s-0031-1297968.
  87. Loomba RS, Arora R. Prevention of cardiovascular disease utilizing fibrates – a pooled meta-analysis. Am J Ther 2010;17:e182-8. https://doi.org/10.1097/MJT.0b013e3181dcf72b.
  88. Major RW, Cheung CK, Gray LJ, Brunskill NJ. Statins and cardiovascular primary prevention in CKD: a meta-analysis. Clin J Am Soc Nephrol 2015;10:732-9. https://doi.org/10.2215/CJN.07460714.
  89. Marti-Carvajal AJ, Solà I, Lathyris D, Dayer M. Homocysteine-lowering interventions for preventing cardiovascular events. Cochrane Database Syst Rev 2017;8. https://doi.org/10.1002/14651858.CD006612.pub5.
  90. Mills EJ, Rachlis B, Wu P, Devereaux PJ, Arora P, Perri D. Primary prevention of cardiovascular mortality and events with statin treatments: a network meta-analysis involving more than 65,000 patients. J Am Coll Cardiol 2008;52:1769-81. https://doi.org/10.1016/j.jacc.2008.08.039.
  91. Mills EJ, O’Regan C, Eyawo O, Wu P, Mills F, Berwanger O, et al. Intensive statin therapy compared with moderate dosing for prevention of cardiovascular events: a meta-analysis of > 40 000 patients. Eur Heart J 2011;32:1409-15. https://doi.org/10.1093/eurheartj/ehr035.
  92. Mora S, Glynn RJ, Hsia J, MacFadyen JG, Genest J, Ridker PM. Statins for the primary prevention of cardiovascular events in women with elevated high-sensitivity C-reactive protein or dyslipidemia: results from the Justification for the Use of Statins in Prevention: an intervention trial evaluating rosuvastatin (JUPITER) and meta-analysis of women from primary prevention trials. Circulation 2010;121:1069-77. https://doi.org/10.1161/CIRCULATIONAHA.109.906479.
  93. Pignone M, Phillips C, Mulrow C. Use of lipid lowering drugs for primary prevention of coronary heart disease: meta-analysis of randomised trials. BMJ 2000;321:983-6.
  94. Saha SA, Kizhakepunnur LG, Bahekar A, Arora RR. The role of fibrates in the prevention of cardiovascular disease – a pooled meta-analysis of long-term randomized placebo-controlled clinical trials. Am Heart J 2007;154:943-53. https://doi.org/10.1016/j.ahj.2007.07.011.
  95. Saha SA, Arora RR. Fibrates in the prevention of cardiovascular disease in patients with type 2 diabetes mellitus – a pooled meta-analysis of randomized placebo-controlled clinical trials. Int J Cardiol 2010;141:157-66. https://doi.org/10.1016/j.ijcard.2008.11.211.
  96. Taylor F, Huffman MD, Macedo AF, Moore THM, Burke M, Davey Smith G, et al. Statins for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev 2013. https://doi.org/10.1002/14651858.cd004816.pub5.
  97. Taylor RS, Ashton KE, Moxham T, Hooper L, Ebrahim S. Reduced dietary salt for the prevention of cardiovascular disease: a meta-analysis of randomized controlled trials (Cochrane review). Am J Hypertens 2011;24:843-53. https://doi.org/10.1038/ajh.2011.115.
  98. Teng M, Lin L, Zhao YJ, Khoo AL, Davis BR, Yong QW, et al. Statins for primary prevention of cardiovascular disease in elderly patients: systematic review and meta-analysis. Drugs Aging 2015;32:649-61. https://doi.org/10.1007/s40266-015-0290-9.
  99. Thavendiranathan P, Bagai A, Brookhart MA, Choudhry NK. Primary prevention of cardiovascular diseases with statin therapy: a meta-analysis of randomized controlled trials. Arch Intern Med 2006;166:2307-13. https://doi.org/10.1001/archinte.166.21.2307.
  100. Tonelli M, Lloyd A, Clement F, Conly J, Husereau D, Hemmelgarn B, et al. Alberta Kidney Disease Network . Efficacy of statins for primary prevention in people at low cardiovascular risk: a meta-analysis. CMAJ 2011;183:E1189-202. https://doi.org/10.1503/cmaj.101280.
  101. Warshafsky S, Packard D, Marks SJ, Sachdeva N, Terashita DM, Kaufman G, et al. Efficacy of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors for prevention of stroke. J Gen Intern Med 1999;14:763-74.
  102. de Vries FM, Kolthof J, Postma MJ, Denig P, Hak E. Efficacy of standard and intensive statin treatment for the secondary prevention of cardiovascular and cerebrovascular events in diabetes patients: a meta-analysis. PLOS ONE 2014;9. https://doi.org/10.1371/journal.pone.0111247.
  103. de Vries FM, Denig P, Pouwels KB, Postma MJ, Hak E. Primary prevention of major cardiovascular and cerebrovascular events with statins in diabetic patients: a meta-analysis. Drugs 2012;72:2365-73. https://doi.org/10.2165/11638240-000000000-00000.
  104. Sepanlou SG, Farzadfar F, Jafari E, Danaei G. Cardiovascular disease prevention using fixed dose pharmacotherapy in Iran: updated meta-analyses and mortality estimation. Arch Iran Med 2012;15:531-7. https://doi.org/012159/AIM.004.
  105. de Cates AN, Farr MRB, Wright N, Jarvis MC, Rees K, Ebrahim S, et al. Fixed-dose combination therapy for the prevention of cardiovascular disease. Cochrane Database Syst Rev 2014;4. https://doi.org/10.1002/14651858.CD009868.pub2.
  106. Hartley L, Mavrodaris A, Flowers N, Ernst E, Rees K. Transcendental meditation for the primary prevention of cardiovascular disease. Cochrane Database Syst Rev 2017;2017. https://doi.org/10.1002/14651858.CD010359.pub3.

Appendix 1 Search strategy

MEDLINE (Ovid)

Search date: 14 March 2019 (note: see below for update searches).

Actual databases searched: Ovid MEDLINE(R) and Epub Ahead of Print, In-Process & Other Non-Indexed Citations, Daily and Versions(R) < 1946 to March 13, 2019>.

Search Strategy:

--------- --------- -------- ---------- ------------- ------- --------

  1. 1 exp Primary Prevention/ (143046)

  2. 2 primary prevention.ti,ab,kf. (17517)

  3. 3 1 or 2 (156409)

  4. 4 exp Cardiovascular Diseases/ or exp Stroke/ (2253958)

  5. 5 (cardiovascular* or coronary* or heart* or myocardial infarction* or cardiac* or stroke* or cerebrovascular accident*).ti,ab,kf. (602893)

  6. 6 4 or 5 (2507942)

  7. 7 3 and 6 (13417)

  8. 8 *Cardiovascular Diseases/pc or exp *Coronary Disease/pc or exp *Myocardial Infarction/pc or exp *Heart Failure/pc or exp *Heart Arrest/pc or exp *Stroke/pc (47349)

  9. 9 ((prevent* or (reduc* adj risk*)) and (cardiovascular* or coronary* or heart* or myocardial infarction* or cardiac* or stroke* or cerebrovascular accident*)).ti. (20124)

  10. 10 7 or 8 or 9 (65565)

  11. 11 (metaanalys* or ‘meta analys*’ or ‘meta-analys*’).mp. (171776)

  12. 12 (systematic* adj2 review*).mp. (161842)

  13. 13 11 or 12 (261344)

  14. 14 10 and 13 (3434)

  15. 15 limit 10 to (meta analysis or ‘systematic review’) (2006)

  16. 16 14 or 15 (3434)

  17. 17 limit 16 to (comment or editorial or letter) (229)

  18. 18 16 not 17 (3205)

Update 23 October 2019

Actual databases searched: Ovid MEDLINE All.

Search strategy:

Re-ran search above plus…

  1. 19 limit 18 to ed = 20190314-20191023 (203)

  2. 20 limit 18 to ep = 20190314-20191023 (66)

  3. 21 (201903* or 201904* or 201905* or 201906* or 201907* or 201908* or 201909* or 201910*).dt,ez. (826293)

  4. 22 18 and 21 (93)

  5. 23 19 or 20 or 22 (276)

Update 3 March 2021

Actual databases searched: Ovid MEDLINE All

Search strategy:

  1. 19 limit 18 to ed = 20191023-20210303 (459)

  2. 20 limit 18 to ep = 20191023-20210303 (233)

  3. 21 (201910* or 201911* or 201912* or 2020* or 2021*).dt,ez. (2085624)

  4. 22 18 and 21 (339)

  5. 23 19 or 20 or 22 (578)

EMBASE (Ovid)

Search date: 14 March 2019 (note: see below for update searches)

Actual databases searched: EMBASE Classic+EMBASE < 1947 to 2019 March 13>

Search Strategy:

--------- ---------- --------- ------------ ----- --------- ----------

  1. 1 primary prevention/ (37798)

  2. 2 primary prevention.ti,ab,kw. (26632)

  3. 3 1 or 2 (50311)

  4. 4 exp cardiovascular disease/ or exp cerebrovascular accident/ (4109044)

  5. 5 (cardiovascular* or coronary* or heart* or myocardial infarction* or cardiac* or stroke* or cerebrovascular accident*).ti,ab,kw. (2609271)

  6. 6 4 or 5 (4920793)

  7. 7 3 and 6 (24747)

  8. 8 *cardiovascular disease/pc or exp *coronary artery disease/pc or exp *heart infarction/pc or *heart failure/pc or exp *heart arrest/pc or exp *cerebrovascular accident/pc (36993)

  9. 9 ((prevent* or (reduc* adj risk*)) and (cardiovascular* or coronary* or heart* or myocardial infarction* or cardiac* or stroke* or cerebrovascular accident*)).ti. (31542)

  10. 10 7 or 8 or 9 (75904)

  11. 11 (metaanalys* or ‘meta analys*’ or ‘meta-analys*’).mp. (252681)

  12. 12 (systematic* adj2 review*).mp. (271759)

  13. 13 11 or 12 (403426)

  14. 14 10 and 13 (5597)

  15. 15 limit 10 to (meta analysis or ‘systematic review’) (3674)

  16. 16 14 or 15 (5597)

  17. 17 limit 16 to (conference abstract or conference paper or ‘conference review’ or editorial or letter) (1043)

  18. 18 16 not 17 (4554)

Update 23 October 2019

Actual databases searched: EMBASE Classic+EMBASE 1947 to 2019 Week 42

Search strategy:

Re-ran search above plus…

  1. 19 limit 18 to dd = 20190314-20191023 (30)

  2. 20 limit 18 to em = 201903-201910 (67)

  3. 21 limit 18 to dc = 20190314-20191023 (220)

  4. 22 19 or 20 or 21 (287)

Update 3 March 2021

Actual databases searched: EMBASE Classic+EMBASE 1947 to 2021 Week 08

Search strategy:

Re-ran search above plus…

  1. 19 limit 18 to dd = 20191023-20210303 (62)

  2. 20 limit 18 to em = 201910-202103 (497)

  3. 21 limit 18 to dc = 20191023-20210303 (450)

  4. 22 19 or 20 or 21 (593)

Cochrane Database of Systematic Reviews (Wiley)

Date Run: 14 March 2019 (note: see below for update search)

ID Search Hits

  1. MeSH descriptor: [Primary Prevention] explode all trees3804

  2. ‘primary prevention’:ti,ab,kw3139

  3. #1 or #26141

  4. MeSH descriptor: [Cardiovascular Diseases] explode all trees95561

  5. MeSH descriptor: [Stroke] explode all trees8034

  6. (cardiovascular* or coronary* or heart* or (myocardial next infarction*) or cardiac* or stroke* or (cerebrovascular next accident*)).ti,ab,kw1318

  7. #4 or #5 or #696699

  8. #3 and #7934

  9. [mh ^‘cardiovascular diseases’[mj]/PC]51

  10. [mh ‘coronary disease’[mj]/PC]1482

  11. [mh ‘myocardial infarction’[mj]/PC]653

  12. [mh ‘heart failure’[mj]/PC]260

  13. [mh ‘heart arrest’[mj]/PC]197

  14. [mh ‘stroke’[mj]/PC]810

  15. #9 or #10 or #11 or #12 or #13 or #143278

  16. ((prevent* or (reduc* near/2 risk)) and (cardiovascular* or coronary* or heart* or (myocardial next infarction*) or cardiac* or stroke* or (cerebrovascular next accident*))):ti5631

  17. #8 or #15 or #168568

Cochrane Reviews: 149

Update 23 October 2019

Re-ran search above plus…

Limits: with Cochrane Library publication date from Mar 2019 to Oct 2019, in Cochrane Reviews9

Update 3 March 2021

Re-ran search above. Noticed an error in line 6 (a full stop rather than a colon before the field codes). As this may have affected the final number of Cochrane Reviews retrieved in the original search and the previous update, we retrieved all Cochrane Reviews found (226) and de-duplicated in EndNote against those already found in previous searches of both the Cochrane Database of Systematic Reviews, MEDLINE and EMBASE.

Cochrane Reviews: 226

DARE (CRD)

Date searched: 14 March 2019

  1. MeSH DESCRIPTOR Primary Prevention EXPLODE ALL TREES914

  2. (primary prevention)1551

  3. #1 OR #22001

  4. MeSH DESCRIPTOR Cardiovascular Diseases EXPLODE ALL TREES10675

  5. MeSH DESCRIPTOR Stroke EXPLODE ALL TREES1354

  6. (cardiovascular* or coronary* or heart* or myocardial infarction* or cardiac* or stroke* or cerebrovascular accident*)11754

  7. #4 OR #5 OR #615077

  8. #3 AND #7602

  9. MeSH DESCRIPTOR Cardiovascular Diseases WITH QUALIFIER PC475

  10. MeSH DESCRIPTOR Myocardial Infarction EXPLODE ALL TREES WITH QUALIFIER PC202

  11. MeSH DESCRIPTOR Heart Failure EXPLODE ALL TREES WITH QUALIFIER PC38

  12. MeSH DESCRIPTOR Heart Arrest EXPLODE ALL TREES WITH QUALIFIER PC90

  13. MeSH DESCRIPTOR Stroke EXPLODE ALL TREES WITH QUALIFIER PC347

  14. MeSH DESCRIPTOR coronary disease EXPLODE ALL TREES WITH QUALIFIER PC286

  15. #9 OR #10 OR #11 OR #12 OR #13 OR #141255

  16. (((prevent* or (reduc* adj2 risk*)) and (cardiovascular* or coronary* or heart* or myocardial infarction* or cardiac* or stroke* or cerebrovascular accident*))):TI733

  17. #8 OR #15 OR #161910

  18. (#17) IN DARE1006

Not updated since 2015.

Appendix 2 Characteristics of included studies

Study Intervention Number of RCTs Number of participants Last searches AMSTAR 2 rating score
Non-pharmacological
Dietary
 Abdelhamid (2020)12 Dietary intervention 82 162,796 August 2019 14
 Adler (2014)13 Reduced salt 8 7284 May 2013 14
 Brunner (1997)14 Dietary intervention 17 7141 July 1993 5
 Clar (2017)15 Low glycaemic index diets 21 2538 July 2016 16
 Hartley (2013)16 Green tea 11 821 October 2012 15
 Hartley (2016)17 Fibre 23 1513 January 2015 16
 Hooper (2001)18 Reduced fat 27 30,902 May 1999 8
 Kelly (2017)19 Whole grain cereals 9 1414 July 2017 16
 Martin (2015)20 Nuts 7 435 July 2015 16
 Rees (2013)21 Mediterranean diet 11 52,044 September 2012 14
 Stabler (2012)22 Garlic 1 47 November 2011 16
 Taylor (2013)23 Reduced salt 6 6489 October 2008 13
 Yang (2012)24 Folic acid 26 58,804 May 2012 9
Health promotion
 Angermayr (2010)25 Multifactorial 25 7703 July 2007 16
 Ebrahim (2011)26 Multifactorial 55 163,471 June 2006 11
 Merriel (2014)27 Telehealth 8 5106 June 2013 16
 Widmer (2015)28 Digital health 2 1055 January 2014 8
 Uthman (2015)29 Diet and physical activity advice 11 7310 June 2014 15
Nutritional supplements
 Al-Khudairy (2015)30 Omega 6 4 660 September 2014 16
 Al-Khudairy (2017)31 Multivitamin 8 11,445 May 2016 15
 Bjelakovic (2011)32 Multivitamin 50 94,148 January 2011 16
 Cheng (2017)33 Tomato and lycopene supplement 15 1197 16
 Flowers (2014)34 Coenzyme Q10 6 102 December 2013 16
 Fortmann (2013)35 Multivitamin 26 27,955 January 2013 16
 Hartley (2015)36 Multivitamin 1 60 September 2014 16
 Hooper (2004)37 Omega 3 48 36,913 February 2002 15
 Lavigine (2013)38 Niacin 11 9959 December 2011 5
 Mahmoud (2019)39 Multivitamin 21 83,291 December 2018 10
 Marco (2020)40 Multivitamin 14 125,763 February 2019 13
 Maria Cabiddu (2020)41 Vitamin D 11 100,609 September 2019 7
 Myung (2013)42 Multivitamin 50 294,478 November 2012 8
 Pham (2005)43 Multivitamin 8 104,221 July 2005 3
 Qin (2012)44 Homocysteine-Folic 9 8234 July 2012 11
 Rees (2013)45 Selenium 12 19,715 October 2012 15
 Schandelmaier (2017)46 Vitamin B3 23 39,195 August 2016 14
 Wang (2010)47 Vitamin D 17 2988 July 2009 9
 Yang (2019)48 Vitamin D 13 127,477 9
Physical activity
 Castro (2016)49 Physical activity 15 6727 October 2016 14
 Hartley (2014)50 Tai chi 13 1520 December 2013 16
 Hartley (2014)51 Meditation 4 430 January 2014 16
 Hartley (2014) Yoga 11 800 December 2013 16
 Reed (2017)52 Workplace physical activity 20 4074 October 2014 16
Pharmacological
Antiplatelet
 ATC (2002)53 Antiplatelet 287 212,000 September 1997 4
 Bartolucci (2011)54 Aspirin 9 90,000 1
 Berger (2006)55 Aspirin 6 95 March 2005 7
 Calvin (2009)56 Aspirin 9 89,392 November 2008 12
 Campbell (2007)57 Aspirin 8 10,067 February 2007 3
 Daniel Caldeira (2020)58 Aspirin 10 34,058 November 2018 11
 De Berardis (2009)59 Aspirin 6 10,117 November 2008 6
 Desai (2015)60 Aspirin 8 121,850 December 2014 3
 Eidelman (2003)61 Aspirin 5 55,580 January 2003 2
 Georg (2019)62 Aspirin 13 164,225 November 2018 7
 Gerardo (2020)63 Aspirin 13 164,225 December 2018 10
 Hart (2000)64 Aspirin 5 52,251 1
 Hayden (2002)65 Aspirin 5 53,035 January 2001 3
 Matthew (2020)66 Aspirin 12 963,829 January 2018 12
 Raju (2011)67 Aspirin 9 100,076 May 2010 12
 Sanmuganathan (2001)68 Aspirin 4 48,540 January 2001 2
 Stavrakis (2011)69 Aspirin 7 7384 November 2009 8
 Sutcliffe (2013)70 Aspirin 27 102,594 September 2012 9
 Xie (2014)71 Aspirin 14 107,686 December 2012 11
 Younis (2010)72 Aspirin 6 7374 5
 Zhang (2009)73 Aspirin 7 11,618 June 2009 5
BP lowering
 Ettehad (2015)74 ACE inhibitors 124 613,815 November 2015 14
 Fretheim (2012)75 Diuretics 25 10,881 February 2011 9
 Wei (2001)76 Antihypertensive 4 10,400 January 1998 2
Glucose lowering
 Cai-Yan (2019)77 SGLT-2 inhibitors 41 61,076 May 2019 11
 Dario (2020)78 SGLT-2 inhibitors 5 34,323 January 2020 11
 Olivia (2020)79 Glucose-lowering drugs 30 225,305 November 2019 13
Lipid lowering
 Allemann (2006)80 Fibrates 8 12,249 November 05 9
 Avash (2020)81 Statins 7 122,164 November 2019 10
 Baris (2020)82 Statins 6 244,090 August 2020 12
 Berger (2011)83 Statins 9 102,621 January 2005 7
 Bukkapatnam (2009)84 Statins 6 21,963 January 2009 6
 Chang (2013)85 Statins 22 137,441 7
 Chen (2012)86 Statins 7 12,711 January 2011 6
 Loomba (2010)87 Fibrates 10 125,763 5
 Major (2015)88 Statins 6 8834 September 2013 10
 Marti-Carvajal (2017)89 Homocysteine-lowering 15 71,422 June 2017 16
 Mills (2008)90 Statins 19 63,899 May 2008 8
 Mills (2011)91 Statins 10 41,778 December 2010 8
 Mora (2010)92 Statins 5 13,154 July 2009 3
 Pignone (2000)93 Statins 4 21,087 June 1999 5
 Saha (2007)94 Fibrates 10 36,489 July 2006 5
 Saha (2010)95 Fibrates 6 11,590 December 2007 7
 Taylor (2013)96 Statins 18 56,934 January 2012 14
 Taylor (2013)97 Statins 18 56,934 May 2013 1
 Teng (2015)98 Statins 8 25,952 August 2014 14
 Thavendiranathan (2006)99 Statins 7 42,848 June 2005 6
 Tonelli (2011)100 Statins 29 80,711 January 2011 11
 Warshafsky (1999)101 Statins 4 7808 June 1996 7
 de Vries (2014)102 Statins 9 9156 September 2013 8
 de Vries (2012)103 Statins 4 10,187 November 2011 9
Polypills
 Sepanlou (2012)104 Polypills 11 64,639 December 2010 4
 de Cates (2014)105 Polypills 9 7047 July 2013 15

Appendix 3 Assessment of multiple systematic reviews 2 rating of including studies

Author Did the research questions and inclusion criteria use PICO? Explicit statement that the review methods? Explain their selection of the study designs? Use a comprehensive literature search strategy? Perform study selection in duplicate? Perform data extraction in duplicate? Provide a list of excluded studies – reason? Describe the included studies in adequate detail? Assess the RoB (RoB)? Sources of funding Meta-analysis – use appropriate methods? Meta-analysis – potential impact of RoB? Account for RoB in individual studies? Provide explanation for heterogeneity? Publication bias likely impact? Potential sources of conflict of interest?
Adler (2014)13 Yes Yes Yes Partial Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes No Yes
Al-Khudairy (2015)30 Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes
Al-Khudairy (2017)31 Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes
Allemann (2006)80 Yes No Yes Yes Yes Yes Yes Yes No No No No Yes No Yes
Angermayr (2010)25 Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes
Abdelhamid (2020)12 Yes Partial Yes Yes Yes Yes Yes Partial Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes
ATC (2002)53 Yes No Yes No No No No Partial Yes No No No No Yes No Yes
Avash Das (2020)81 Yes Yes No Yes No No No Yes Yes No Yes Yes Yes No Yes Yes
Baris Gencer (2020)82 Yes No Yes Yes Yes Yes Partial Yes Partial Yes Yes No Yes Yes Yes Yes Yes Yes
Bartolucci AA (2011)54 No No No No No No No Partial Yes No No No No Yes No No
Berger JS (2006)55 Yes No Yes No No No No Yes No Yes No No Yes Yes Yes
Berger JS (2011)83 Yes No Yes No No No Yes Yes No No No No Yes Yes Yes
Bjelakovic (2011)32 Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes
Brunner (1997)14 Yes Yes Yes Yes Yes
Bukkapatnam RN (2009)84 Yes No Yes Partial Yes No No No Yes No Yes No No Yes Yes No
Cai-Yan (2019)77 Yes Partial Yes Yes Yes Yes Yes No Yes Yes No Yes Yes Yes Yes No No
Calvin (2009)56 Yes Partial Yes Yes Yes Yes Yes No Yes Yes Yes Yes Yes No Yes Yes
Campbell (2007)57 Yes No Yes Partial Yes No No No Yes No No No meta-analysis No meta-analysis No No No meta-analysis No
Castro (2016)49 Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes No No Yes Yes Yes Yes
Chang (2013)85 Yes No Yes Partial Yes Yes Yes No Yes No No No No Yes Yes
Chen (2012)86 Yes No Yes Partial Yes No No No Partial Yes No No Yes No No Yes Yes Yes
Cheng (2017)33 Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes
Clar (2017)15 Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes
Daniel (2020)58 Yes No Yes Yes Yes Yes Partial Yes Yes Yes Yes Yes No No Yes No;Yes Yes
Dario (2020)78 Yes Yes Yes Yes Yes Yes No No Yes No Yes Yes No Yes Yes
De Berardis (2009)59 Yes No Yes Partial Yes Yes No No Partial Yes No Yes No No Yes No Yes
de Cates (2014)105 Yes Yes Yes Yes Yes Yes Yes Yes Yes No Yes Yes Yes Yes Yes Yes
de Vries (2012)103 Yes No Yes Partial Yes Yes Yes Yes Yes No No No No Yes Yes Yes
de Vries (2014)102 Yes No Yes No Yes Yes Yes Partial Yes No No No No Yes Yes Yes
Desai (2015)60 Yes Yes Yes Partial Yes No No No Partial Yes No No No meta-analysis No meta-analysis No No No meta-analysis
Ebrahim (2011)26 Yes Yes Yes Partial Yes Yes Yes Yes Yes Partial Yes No No Yes Yes Yes Yes
Eidelman (2003)61 No No Yes No No No No Partial Yes No No No No Yes No No
Ettehad (2015)74 Yes Yes Yes Partial Yes Yes Yes Yes Yes Yes No Yes Yes Yes Yes Yes Yes
Flowers (2014)34 Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes
Fortmann (2013)35 Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes
Fretheim (2012)75 Yes Partial Yes Yes Partial Yes Yes Yes Yes Yes No No Yes No No Yes Yes
George (2019)62 Yes Yes Yes Yes No No Partial Yes Yes No No No No No Yes No Yes
Gerardo (2020)63 Yes No Yes Yes Yes Yes Partial Yes Yes No No Yes No Yes Yes Yes
Hart (2000)64 No No Yes No No No No No No No No No No No No
Hartley (2013)16 Yes Yes Yes Yes Yes Yes Yes Yes Yes No Yes Yes Yes Yes Yes Yes
Hartley (2014)50 Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes
Hartley (2015)36 Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes
Hartley (2016)17 Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes
Hartley (2014)51 Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes
Hartley L (2014)106 Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes
Hayden (2002)65 No No No No No No Yes Partial Yes No No No No Yes No Yes
Hooper (2001)18 Yes No Yes Yes Yes Yes Yes Yes No No No No No No Yes
Hooper (2004)37 Yes Yes Yes Yes Yes Yes Yes Yes Yes No Yes Yes Yes Yes Yes Yes
Kelly (2017)19 Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes
Lavigine PM (2013)38 Yes No Yes No No No Yes Partial Yes No No No No Yes Yes No
Loomba RS (2010)87 Yes No Yes No No No No Yes No No No No Yes Yes No
Mahmoud Barbarawi (2019)39 No Yes Yes Yes Yes Yes No Yes Yes No No No Yes Yes Yes
Major RW (2015)88 Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes
Marco Lombardi (2020)40 Yes Yes Yes Yes Yes Yes Yes Yes No Yes No Yes Yes Yes Yes
Maria Francesca Cabiddu (2020)41 Yes No No Yes Yes Yes Partial Yes Partial Yes Partial Yes No Yes No No Yes No Yes
Marti-Carvajal (2017)89 Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes
Martin N (2015)20 Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes
Matthew Nudy (2020)66 Yes No Yes Yes Yes Yes Yes Yes Yes No Yes Yes Yes Yes No No
Merriel S (2014)27 Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes
Mills E (2008)90 Yes No Yes Yes Yes Yes Yes Yes No No No No Yes No No
Mills EJ (2011)91 Yes No Yes Yes Yes Yes Yes Yes No No No No No No Yes
Mora S (2010)92 No No No No No No No Yes No No No No Yes No Yes
Myung SK (2013)42 Yes No Yes Partial Yes Yes No Partial Yes Yes Partial Yes Yes No No Yes Yes Yes
Olivia R Ghosh-Swaby (2020)79 Yes Partial Yes Yes Yes Yes Yes Yes Yes Yes No Yes Yes Yes Yes Yes
Pham DQ (2005)43 No No Yes No No No No Yes No No No meta-analysis No meta-analysis No Yes No meta-analysis No
Pignone (2000)93 No No Yes No Yes Yes No Partial Yes No No No No Yes No Yes
Qin X (2012)44 Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes
Raju N (2011)67 Yes No Yes Yes Yes Yes Yes Yes No No Yes Yes Yes Yes Yes
Reed (2017)52 Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes
Rees K (2013)45 Yes Yes Yes Yes Yes Yes Yes Yes Yes No Yes Yes Yes Yes Yes Yes
Rees K et al. (2013)21 Yes Yes Yes Yes Yes Yes Yes Yes Yes No Yes Yes Yes Yes No Yes
Saha SA (2007)94 No No No Partial Yes Yes Yes No Yes No No No No Yes Yes No
Saha SA (2010)95 Yes No Yes No No Yes No Yes No No No No Yes Yes Yes
Sanmuganathan (2001)68 No No Yes No No No No Partial Yes No No No No Yes No No
Schandelmaier (2017)46 Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes No Yes
Sepanlou SG (2012)104 No No No No Yes Yes No Partial Yes No No No No Yes Yes No
Stabler SN (2012)22 Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes
Stavrakis S (2011)69 Yes No Yes Yes Yes Yes Yes Yes No No No No Yes No No
Sutcliffe P (2013)70 Yes No Yes Yes Yes Yes No Yes Yes No No No Yes No Yes
Taylor F (2013)96 Yes Yes Yes No Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes No Yes
Taylor RS (2013)23 Yes Yes Yes No Yes Yes Yes Yes Yes Yes Yes Yes Yes No Yes
Taylor F (2013)97 No No No No No No No No No No No meta-analysis No meta-analysis No No No meta-analysis Yes
Teng M (2015)98 Yes Yes Yes Yes Yes Yes Partial Yes Yes Yes Yes Yes Yes Yes Yes Yes
Thavendiranathan P (2006)99 Yes No Yes Partial Yes No Yes No Yes No No No No Yes No Yes
Tonelli (2011)100 Yes Yes Yes Yes Yes Yes Partial Yes Yes Partial Yes No Yes No Yes Yes Yes
Uthman OA (2015)29 Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes Yes
Wang L (2010)47 Yes No Yes Partial Yes Yes Yes No Yes Yes No No No Yes Yes Yes
Warshafsky (1999)101 Yes No Yes No Yes Yes Yes Yes No No No No Yes No No
Wei (2001)76 No No Yes No No No No Partial Yes No No No No Yes No No
Widmer R (2015)28 No No Yes Partial Yes Yes No No Partial Yes Yes Yes Yes No Yes Yes No Yes
Xie M (2014)71 Yes Partial Yes Yes Partial Yes Yes Yes Yes Yes Yes No No Yes Yes Yes Yes
Yang HT (2012)24 Yes No Yes Partial Yes Yes Yes Yes Yes No No No No Yes Yes Yes
Yang Hu (2019)48 Yes No Yes Yes No No No Yes No No Yes Yes Yes Yes No Yes
Younis N (2010)72 Yes No Yes Partial Yes No No No Yes No No No No Yes No Yes
Zhang C (2009)73 Yes Partial Yes Yes No No No No Yes No No No No Yes No Yes

Heart and blood vessel diseases are the top cause of death worldwide. This study aimed to compare the effectiveness of various drug-based and non-drug-based methods in preventing these diseases. We searched databases like Cochrane, MEDLINE, EMBASE and the Database of Abstracts of Reviews of Effects archive to find reviews about different ways to prevent heart and blood vessel diseases up until March 2021.

The results showed that only 1 out of 10 reviews found a possible benefit in reducing heart-related deaths, while the other 9 found no effect. Medicines that lower blood sugar levels had a positive impact on reducing major heart events, heart disease and death. However, combining dietary changes, exercise, nutritional supplements and polypills had little or no effect on reducing heart-related events, deaths due to heart disease or deaths from all causes.

This review examined the available evidence on ways to prevent heart and blood vessel diseases and identified areas where more research could be beneficial. Future studies could compare the effectiveness of different interventions using new methods and analyses.

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