Large-scale evidence to influence international cardiovascular guidelines-Danesh
Submitting InstitutionUniversity of Cambridge
Unit of AssessmentPublic Health, Health Services and Primary Care
Summary Impact TypeHealth
Research Subject Area(s)
Mathematical Sciences: Statistics
Medical and Health Sciences: Public Health and Health Services
Economics: Applied Economics
Summary of the impact
The Cambridge-led Emerging Risk Factors Collaboration (ERFC) is a global
consortium involving individual-participant data on 2.5 million
participants from 130 cohort studies. The ERFC has helped optimise
approaches to cardiovascular disease (CVD) risk assessment by: 1)
quantifying the incremental predictive value provided by assessment of
risk factors 2) evaluating the independence of associations between risk
factors and CVD and 3) addressing uncertainties related to the
implementation of screening. ERFC publications on lipids, lipoproteins,
and inflammation biomarkers have been cited by 9 guidelines published
since 2010, including those of the European Society of Cardiology and the
American Heart Association.
To help target scarce preventive resources, promote behavioural change,
and monitor risk, CVD risk is assessed in primary prevention settings in
most high-income countries. There is, however, substantial debate about
what constitutes an optimum approach to risk assessment.
Researchers and outputs The ERFC was conceived and established by
Professor John Danesh (Professor since 2001), together with colleagues at
the Department of Public Health and Primary Care, including Dr Emanuele Di
Angelantonio (UL since 2010) and Dr Stephen Kaptoge (SRA since 2007).
Under the direction of Professor Danesh, the Cambridge coordinating centre
has since 2003 led all aspects of this consortium, including: choice of
hypotheses to study, collation and harmonisation of data, statistical
analyses, interpretation of data, reporting and dissemination of findings.
The ERFC has also given rise to other closely-related consortia led by the
same Cambridge investigators, such as the LpPLA2 Studies Collaboration.
Research Refs #1-5 provide examples of substantive findings. Professor
Danesh has been the key senior scientific leader in all the substantive
reports, exemplified by his role as the senior author and/or corresponding
Underpinning data and methods About 130 long-term prospective
cohort studies based in 25 different countries have shared extensive
individual-level data with the Cambridge coordinating centre of the ERFC.
This effort has yielded one of the largest and most detailed central
databases in CVD epidemiology worldwide (i.e., up to ~500 covariates for
each of 2.5 million participants). More than 100,000 incident CVD outcomes
have been recorded during 15 million person-years at risk. More than
300,000 people have provided serial measurements of risk factors.
In addition to its size and detail, several additional features have
distinguished this consortium's approach that have enhanced its power,
generalisability, and validity. First, cohorts contributing data to the
consortium have typically shared more extensive individual-level data
(e.g., additional types of disease endpoints and extended follow-up) than
have been reported in their own cohort-specific publications, thereby
enhancing power and enabling comparison of different types of CVD
outcomes. Second, the coordinating centre has iteratively checked,
cleaned, re-coded, and harmonised all data shared in this consortium in
close liaison with the investigators of contributing studies, thereby
enhancing the validity of the underlying data analysed.
Third, analyses have focused on a uniform and appropriate subset of
participants (e.g., people without a history of CVD at the baseline
examination who have complete information on relevant risk factors), in
contrast with inconsistent inclusion/exclusion criteria used in previous
studies. Fourth, the ERFC has used methods specifically appropriate for
the evaluation of incremental risk prediction, such as measures of
discrimination and reclassification that require time-to-event data.
Results have also been expressed in a manner to help enhance understanding
by clinicians and policy makers, such as the numbers needed to screen to
avoid 1 additional CVD outcome over 10 years of preventive treatment.
Fifth, under the leadership of Professor Simon Thompson (MRC
Biostatistics Unit Director until 2011 and Professor since 2002) and Dr
Angela Wood (University Lecturer in Biostatistics, Department of Public
Health and Primary Care since 2006), the coordinating centre has developed
methods to optimise such analyses, including measures of discrimination
and reclassification for the multi-study situation [Research Ref #6
provides an example].
References to the research
1. ERFC: (writing committee: Di Angelantonio E, Sarwar N, Perry
P, Kaptoge S, Ray KK, Thompson A, Wood AM, Lewington S,
Sattar N, Packard CJ, Collins R, Thompson SG, Danesh J).
Major lipids, apolipoproteins, and risk of vascular disease. JAMA
2. The Triglyceride Coronary Disease Genetics Consortium and ERFC:
(writing committee: Sarwar N, Sandhu MS, Ricketts SL, Butterworth AS, Di
Angelantonio E, Boekholdt SM, Ouwehand W, Watkins H, Samani NJ,
Saleheen D, Lawlor D, Reilly MP, Hingorani AD, Talmud PJ, Danesh J).
Triglyceride-mediated pathways and coronary disease: collaborative
analysis of 101 studies. Lancet 2010;375:1634-9.
3. ERFC: (writing committee: Erqou S, Kaptoge S, Perry PL, Di
Angelantonio E, Thompson A, White IR, Marcovina SM, Collins R, Thompson
SG, Danesh J). Lipoprotein(a) concentration and the risk of
coronary heart disease, stroke, and nonvascular mortality. JAMA
4. The Lp-PLA2 Studies Collaboration: (writing committee: Thompson A, Gao
P*, Orfei L*, Watson S, Di Angelantonio E, Kaptoge S, Ballantyne
C, Cannon CP, Criqui M, Cushman M, Hofman A, Packard C, Thompson SG,
Collins R, Danesh J). Lipoprotein-associated phospholipase A2 and
risk of coronary disease, stroke and mortality: collaborative analysis of
32 prospective studies. Lancet 2010;375:1536-44.
5. ERFC: (writing committee: Kaptoge S, Di Angelantonio E,
Lowe G, Pepys MB, Thompson SG, Collins R, Danesh J).
C-reactive protein concentration and risk of coronary heart disease,
stroke, and mortality: an individual participant meta-analysis. Lancet
6. ERFC: (writing committee: Thompson SG, Kaptoge S, White IR, Wood
AM, Perry PL, Danesh J) Statistical methods for the
time-to-event analysis of individual participant data from multiple
epidemiological studies. Int J Epidemiol 2010;39:1345-1359.
Grants Professor Danesh is the PI and holder of grants which have
supported the ERFC:
|Emerging risk factors in CVD
|Pooled analyses of CRP
|Pooled analyses of triglycerides
|Statistical methods for risk prediction
|Emerging risk factors in CVD
|Risk factors in coronary heart disease
Details of the impact
Nature of impact Publications from the ERFC have been cited by 9
2010: European Atherosclerosis Society (EAS) Consensus Panel on
lipoprotein(a) in cardiovascular disease.
2010: American College of Cardiology Foundation / American Heart
Association (ACCF / AHA) guideline for assessment of cardiovascular risk
in asymptomatic adults
2011: European Society of Cardiology and European Atherosclerosis Society
(ESC / EAS) Guidelines for the management of dyslipidaemias
2011: American Heart Association statement on Triglycerides and
2011: American Association of Clinical Endocrinologists Medical
Guidelines for Clinical Practice for developing a diabetes mellitus
comprehensive care plan
2011: US National Lipid Association expert advice
2012: Canadian Cardiovascular Society Guidelines for the Diagnosis and
Treatment of Dyslipidemia for the Prevention of Cardiovascular Disease in
2012: European Society of Cardiology (ESC) and Other Societies Guidelines
on cardiovascular disease prevention in clinical practice
2012: Evaluation and treatment of hypertriglyceridemia: an Endocrine
Society clinical practice guideline.
1. Major lipids [Research Refs #1 and #2]
Findings: The ERFC reported that lipid assessment can be greatly
simplified by measurement of HDL-cholesterol and total cholesterol without
the need to fast and without regard to triglyceride (Research Ref #1),
with major implications for screening millions of adults. The same report
demonstrated that measurement of apolipoproteins A and B provides similar
information about CVD risk as does assessment of conventional lipid
fractions. The ERFC reported that large-scale human biomarker and genetic
evidence is consistent with a causal association of triglyceride-related
pathways in CVD (Research Ref #2).
Impact on guidelines: The ERFC paper on major lipids has been cited
in the 2011 ESC / EAS Guidelines for the management of dyslipidaemias
[Impact Ref #1: footnote number 42], in the 2012 ESC Guidelines [Impact
Ref #2: footnote number 52], the 2011 American Association of Clinical
Endocrinologists Medical Guidelines [Impact Ref #4: footnote number 359],
and the 2011 AHA Statement on triglycerides and CVD [Impact Ref #5:
footnote number 17].
The ERFC publication on the causal relevance of triglyceride-related
pathways to CVD (Research Ref #2) has been cited in the following
guidelines to support diagnosis and treatment of hypertriglyceridaemia:
the 2012 Endocrine Society Clinical Practice Guideline [Impact Ref #3:
footnote number 9], the 2011 ESC / EAS Guidelines for the management of
dyslipidaemias [Impact Ref #1: footnote number 121], and the 2011 AHA
Statement on triglycerides and CVD [Impact Ref #5: footnote number 98].
2. Lipoproteins [Research Refs #3 and #4]
Findings: The ERFC reported that lipoprotein(a) is specifically,
continuously and independently associated with CVD in a manner consistent
with causality (Research Ref #3). The LpPLA2 Studies Collaboration
publication has reported that lipoprotein-associated phospholipase A2 is
log-linearly associated with risk of CVD (independent of established
lipids), with a similar magnitude of association as for LDL-cholesterol
(Research Ref #4).
Impact on guidelines: The ERFC paper on lipoprotein(a) has been
cited in the following four guidelines to support assessment of Lp(a) in
practice: the 2010 EAS Consensus Panel [Impact Ref #6: footnote number 3],
the 2011 ESC / EAS Guidelines for the management of dyslipidaemias [Impact
Ref #1: footnote number 49], the 2012 Canadian Cardiovascular Society
Guidelines [Impact Ref #7: footnote number 71], and the 2012 Endocrine
society [Impact Ref #3: footnote number 44], and the 2010 ACCF / AHA
Guidelines [Impact Ref #8: footnote number 102].
The Lp-PLA2 Studies Collaboration publication has been cited the 2011
National Lipid Association expert advice [Impact Ref #9: footnote number
3. Inflammation biomarkers [Research Ref #5]
Findings: The ERFC reported that assessment of inflammation
biomarkers provides only modest improvement in CVD prediction (Research
Impact on guidelines: The ERFC paper on inflammation biomarkers has
been cited in the following 2 guidelines: the 2011 ESC / EAS Guidelines
[Impact Ref #2: footnote number 126], the 2012 ESC Guidelines [Impact Ref
#2: footnote number 126], and the 2012 Canadian Cardiovascular Society
Guidelines [Impact Ref #7: footnote number 72].
Sources to corroborate the impact
- Reiner Z, Catapano AL, De Backer G, Graham I, Taskinen M-R, Wiklund O,
Agewall S, Alegria E, Chapman MJ, Durrington P, Erdine S, Halcox J,
Hobbs R, Kjekshus J, Filardi PP, Riccardi G, Storey RF, Wood D, ESC
Committee for Practice Guidelines (CPG) 2008-2010 and 2010-2012
Committees. ESC/EAS Guidelines for the management of dyslipidaemias: the
Task Force for the management of dyslipidaemias of the European Society
of Cardiology (ESC) and the European Atherosclerosis Society (EAS). Eur.
Heart J. 2011; 32:1769-1818.
- Perk J, De Backer G, Gohlke H, Graham I, Reiner Z, Verschuren M, Albus
C, Benlian P, Boysen G, Cifkova R, Deaton C, Ebrahim S, Fisher M,
Germano G, Hobbs R, Hoes A, Karadeniz S, Mezzani A, Prescott E, Ryden L,
Scherer M, Syvänne M, Scholte op Reimer WJM, Vrints C, Wood D, Zamorano
JL, Zannad F, European Association for Cardiovascular Prevention &
Rehabilitation (EACPR), ESC Committee for Practice Guidelines (CPG).
European Guidelines on cardiovascular disease prevention in clinical
practice (version 2012). The Fifth Joint Task Force of the European
Society of Cardiology and Other Societies on Cardiovascular Disease
Prevention in Clinical Practice (constituted by representatives of nine
societies and by invited experts). Eur. Heart J. 2012; 33:1635-1701.
- Evaluation and treatment of hypertriglyceridemia: an Endocrine Society
clinical practice guideline. Berglund L, Brunzell JD, Goldberg AC,
Goldberg IJ, Sacks F, Murad MH, Stalenhoef AFH, Endocrine society.
Evaluation and treatment of hypertriglyceridemia: an Endocrine Society
clinical practice guideline. J. Clin. Endocrinol. Metab. 2012;
- Task Force for Developing Diabetes Comprehensive Care Plan. Handelsman
Y, Mechanick JI, Blonde L, Grunberger G, Bloomgarden ZT, Bray GA,
Dagogo-Jack S, Davidson JA, Einhorn D, Ganda O, Garber AJ, Hirsch IB,
Horton ES, Ismail-Beigi F, Jellinger PS, Jones KL, Jovanovič L, Lebovitz
H, Levy P, Moghissi ES, Orzeck EA, Vinik AI, Wyne KL, AACE Task Force
for Developing Diabetes Comprehensive Care Plan. American Association of
Clinical Endocrinologists Medical Guidelines for Clinical Practice for
developing a diabetes mellitus comprehensive care plan. Endocr Pract.
2011; 17 Suppl 2:1-53.
- Triglycerides and cardiovascular disease a scientific statement from
the American Heart Association. Miller M, Stone NJ, Ballantyne C,
Bittner V, Criqui MH, Ginsberg HN, Goldberg AC, Howard WJ, Jacobson MS,
Kris-Etherton PM, Lennie TA, Levi M, Mazzone T, Pennathur S, American
Heart Association Clinical Lipidology, Thrombosis, and Prevention
Committee of the Council on Nutrition, Physical Activity, and
Metabolism, Council on Arteriosclerosis, Thrombosis and Vascular
Biology, Council on Cardiovascular Nursing, Council on the Kidney in
Cardiovascular Disease. Triglycerides and cardiovascular disease: a
scientific statement from the American Heart Association. Circulation.
- Nordestgaard BG, Chapman MJ, Ray KK, Borén J, Andreotti F, Watts GF,
Ginsberg H, Amarenco P, Catapano A, Descamps OS, Fisher E, Kovanen PT,
Kuivenhoven JA, Lesnik P, Masana L, Reiner Z, Taskinen MR, Tokgözoglu L,
Tybjærg-Hansen A, for the European Atherosclerosis Society Consensus
Panel. Lipoprotein(a) as a cardiovascular risk factor: Current status.
Eur Heart J 2010;31:2844-2853.
- Anderson TJ, Grégoire J, Hegele RA, Couture P, Mancini GBJ, McPherson
R, Francis GA, Poirier P, Lau DC, Grover S, Genest J, Carpentier AC,
Dufour R, Gupta M, Ward R, Leiter LA, Lonn E, Ng DS, Pearson GJ, Yates
GM, Stone JA, Ur E. 2012 Update of the Canadian Cardiovascular Society
Guidelines for the Diagnosis and Treatment of Dyslipidemia for the
Prevention of Cardiovascular Disease in the Adult. Can J Cardiol 2013;29
- Greenland P, Alpert JS, Beller GA, Benjamin EJ, Budoff MJ, Fayad ZA,
Foster E, Hlatky MA, Hodgson JM, Kushner FG, Lauer MS, Shaw LJ, Smith Jr
SC, Taylor AJ, Weintraub WS, Wenger NK. ACCF/AHA guideline for
assessment of cardiovascular risk in asymptomatic adults: A report of
the american college of cardiology foundation/american heart association
task force on practice guidelines. Circulation 2010;122:e584-e636.
- Davidson MH, Ballantyne CM, Jacobson TA, Bittner VA, Braun LT, Brown
AS, Brown WV, Cromwell WC, Goldberg RB, McKenney JM, Remaley AT,
Sniderman AD, Toth PP, Tsimikas S, Ziajka PE, Maki KC, Dicklin MR.
Clinical utility of inflammatory markers and advanced lipoprotein
testing: advice from an expert panel of lipid specialists. J Clin