JOURNAL OF THE AMERICAN COLLEGE OF CARDIOLOGY VOL. 77, NO.

24, 2021

ª 2021 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION

PUBLISHED BY ELSEVIER

JACC FOCUS SEMINAR: THE BEST OF POPULATION RESEARCH STUDIES

JACC FOCUS SEMINAR

Systematic Coronary Risk

Evaluation (SCORE)
JACC Focus Seminar 4/8

Ian M. Graham, MD,a Emanuele Di Angelantonio, PHD,b Frank Visseren, PHD,c Dirk De Bacquer, PHD,d
Brian A. Ference, PHD,b Adam Timmis, MD,e,f Martin Halle, MD,g Panos Vardas, PHD,f,h Radu Huculeci, PHD,f
Marie-Therese Cooney, PHD,i for the European Society of Cardiology Cardiovascular Risk Collaboration

ABSTRACT

Clinical estimation of the combined effect of several risk factors is unreliable and this resulted in the development of a
number of risk estimation systems to guide clinical practice. Here, after defining general principles of risk estimation, the
authors describe the evolution of the European Society of Cardiology’s (ESC) Systematic COronary Risk Evaluation
(SCORE) risk estimation system and some learnings from the data. They move on to describe the establishment of the
ESC’s Cardiovascular Risk Collaboration and outline its proposed research directions. First among these is the evolution of
SCORE 2, which provides updated, calibrated risk estimates for total cardiovascular events for low, moderate, high, and
very high-risk regions of Europe. The authors conclude by considering that the future of risk estimation may be to express
risk as years of exposure to a cardiovascular risk factor profile rather than risk over a fixed time period, such as 10 years,
and how advances in genetics may permit individualized lifetime risk estimation from childhood on.
(J Am Coll Cardiol 2021;77:3046–57) © 2021 by the American College of Cardiology Foundation.

A therosclerosis starts in childhood, sometimes

with antecedents in utero, and progresses at
a variable rate over years. It is usually
advanced by the time that symptoms occur, typically
in middle age. Although it may manifest as a symp-
tom such as angina, it may also kill suddenly through
rupture of a plaque in a coronary artery producing an
acute coronary syndrome. Thus, waiting until symp-
toms occur is inappropriate because the disease will
generally be advanced and difficult to reverse, or
the person may die unexpectedly without prior
symptoms.
It is therefore logical to try to find the causes of
atherosclerosis to see if a preventive strategy is
feasible. Many decades of meticulous research iden-
tified low-density lipoprotein cholesterol (LDL-C),
raised blood pressure, and cigarette smoking as the
“big 3” causes. Of late, with the increase in the
prevalence of obesity, diabetes has assumed
increased importance. Other potentially important
risk factors include family history (which may reflect
genetic factors, a shared environment, or both),
inactivity, chronic kidney disease, and certain aspects
of stress. The presence of asymptomatic disease on

Listen to this manuscript’s
audio summary by
Editor-in-Chief
Dr. Valentin Fuster on
JACC.org.
From the aTrinity College, Dublin, Ireland; bDepartment of Public Health and Primary Care, University of Cambridge, Cambridge,
United Kingdom; cDepartment of Vascular Medicine, University Medical Center Utrecht, Utrecht University, Utrecht, the
Netherlands; dDepartment of Public Health and Primary Care, Ghent University, Ghent, Belgium; eQueen Mary University of
London, London, United Kingdom; fEuropean Heart Agency, European Society of Cardiology, Brussels, Belgium; gDepartment of
Prevention and Sports Medicine, University Hospital Klinikum rechts der Isar, Technical University of Munich, Munich, Germany;
h
University Hospital, Crete, Greece; and iUniversity College Dublin, Dublin, Ireland.
The authors attest they are in compliance with human studies committees and animal welfare regulations of the authors’
institutions and Food and Drug Administration guidelines, including patient consent where appropriate. For more information,
visit the Author Center.

Manuscript received November 10, 2020; revised manuscript received April 21, 2021, accepted April 21, 2021.

ISSN 0735-1097/$36.00 https://doi.org/10.1016/j.jacc.2021.04.052

JACC VOL. 77, NO. 24, 2021
JUNE 22, 2021:3046–57
HIGHLIGHTS

Estimating an individual’s risk of devel-
oping cardiovascular disease is a funda-
mental component of preventive
cardiology.

The ESC CRC SCORE system provides
calibrated risk estimates for total CVD
events for low, moderate, high, and very
high-risk populations.

Future challenges include generating
personalized estimates of lifetime risk
early in life.
imaging such as computed tomography calcium
scoring will also signal increased risk, but such im-
aging is a diagnostic documentation of disease and
not a risk factor per se.
In most apparently healthy persons, the risk of a
future cardiovascular disease (CVD) event usually
relates to a combination of several risk factors. Clin-
ical estimation of these combined effects is unreliable
(1) and this resulted in the development of a number
of risk estimation systems. Although often termed
risk prediction, such systems in fact make an estimate
of risk on which predictions may be based.
In this article, we focus specifically on the risk of
developing atherosclerotic cardiovascular disease,
ASCVD, hereafter referred to CVD, and its main
manifestations, coronary heart disease, stroke, pe-
ripheral artery disease, and aneurysm, with particular
reference to the Systematic COronary Risk Evaluation
(SCORE) project. The concepts considered have
informed most current European primary prevention
guidelines, including the 2016 Joint European
Guidelines on CVD Prevention (2), and the 2019 Eu-
ropean Society of Cardiology (ESC)/European
Atherosclerosis Society (EAS) guidelines for the
management of dyslipidemias (3) and, in turn, we
draw from these sources.
Risk estimates are derived from large groups of
persons and then applied to an individual. This is an
uncertain process; one can estimate the percentage
risk in a thousand persons with similar risk factors,
but identifying which individuals will be affected is
less certain. The development of more precise indi-
vidualized risk estimation is still in its infancy and is
discussed under the section on “future directions.”
WHAT IS HIGH RISK?
All guidelines on CVD prevention concur that certain
persons declare themselves to be at high to very high
Graham et al. 3047
SCORE
risk of future CVD events and merit prompt ABBREVIATIONS
AND ACRONYMS
management of all risk factors. These are
people with established CVD, most patients
ASCVD = atherosclerotic
with diabetes (especially with end-organ cardiovascular disease,
damage or other risk factors), subjects with abbreviated in this paper to
renal impairment, and asymptomatic persons CVD
with a particularly high level of a single risk BMI = body mass index
factor such as familial hypercholesterolemia. CRC = The European Society of
Cardiology’s Cardiovascular
For other apparently healthy people, risk will
Risk Collaboration
depend on the number, intensity of their risk
EAS = European
factors, and the duration of exposure. As Atherosclerosis Society
mentioned previously, clinical estimation of
ESC = European Society of
the effects of combinations of risk factors is Cardiology
not reliable (1) and the use of a risk estimation HDL-C = high-density
system is recommended. These categories of lipoprotein cholesterol
risk may be summarized in a simplified LDL-C = low-density
version of the tables in the 2016 ESC joint lipoprotein cholesterol
guidelines on the prevention of CVD in clin- RHR = resting heart rate
ical practice (2) and the 2019 ESC/EAS guide- SBP = systolic blood pressure
lines on the management of dyslipidemias (3) SCORE = Systematic COronary
(Table 1). Risk Evaluation
It should be stressed that risk scores are WHO = World Health
Organization
intended for use in apparently healthy per-
sons. Those with the conditions listed in the high and
very high-risk categories deserve immediate atten-
tion to all risk factors. The term “apparently healthy”
implies no apparent disease on history and/or exam-
ination. Developments in imaging have blurred the
traditional distinction between primary and second-
ary prevention in the sense that many middle-aged
and older persons may have asymptomatic CVD,
emphasizing the early onset and continuous long-
term progression of disease.
A word on age may be appropriate here. Although
the strongest driver of risk, it is not a modifiable risk
factor as such, but rather a measure of exposure time
to true risk factors. The importance of this distinction
will become apparent when we consider newer con-
cepts of risk estimation.
OPTIONS TO CREATE A RISK
ESTIMATION SYSTEM
The classical approach (4,5), pioneered by the Fra-
mingham investigators (6), is to start with a defined,
initially healthy cohort in which risk factors were
measured at a baseline examination and which was
followed up for a period of time, usually 10 years or
more, with ascertainment of all cardiovascular
events. From these data, a survival analysis (usually
Cox or Weibull) is performed, including appropriate
risk factors as explanatory covariables. This results in
the baseline risk and beta coefficients for each of the
risk factors. These are combined with the patient’s
3048 Graham et al.
SCORE
T A B L E 1 Risk Categories: Simplified from References 2 and 3
Very high SCORE risk $10%, documented cardiovascular disease,
risk diabetes with end-organ damage or at least 1 major
risk factor, severe chronic kidney disease
High risk SCORE risk 5%–9%, a very high single risk factor, most
others with diabetes, moderate chronic kidney disease
Moderate SCORE risk 1%–4%, many middle-aged persons
risk
Low risk SCORE risk <1%
EAS ¼ European Atherosclerosis Society; ESC ¼ European Society of Cardiology;
SCORE ¼ Systematic Coronary Risk Evaluation.
risk factor levels to calculate the individual cardio-
vascular risk. In SCORE (7), all fatal atherosclerotic
vascular disease was the outcome used, with coro-
nary heart disease and noncoronary vascular disease
modeled separately. This allowed for the risk factors
to have differing effects on the different vascular
outcomes. This has an advantage when recalibrating
for different regions with varying proportions of
coronary heart disease and noncoronary vascular
disease; for example, proportionately more strokes
occur in low-risk countries. For the same reason, the
models also should be separated by gender. The effect
of each risk factor should be allowed to vary by age as
well; absolute multifactorial risk increases with age
but the relative risk of a given risk factor may weaken
with advancing age so that applying a constant beta-
coefficient to this risk factor may overestimate risk
in older persons (8). This can be done either by
including age interactions for each of the risk factors,
or if enough data are available, by deriving the risk
functions separately by age group. The resulting risk
estimates can be expressed as a scoring system, risk
chart, or risk calculator with varying degrees of
interactivity.
LIMITATIONS
The approach described has limitations. One is that
different combinations of risk factors may interact in
variable and complex ways that are difficult to model.
Risk calculators have the advantage of allowing
incorporation of more risk factors than a paper chart,
which has potential to improve the precision of risk
estimates. However, paper charts can be valuable in
the clinical setting, as the health care practitioner can
demonstrate visually to a patient their current risk
and the level their risk will approach as they modify
their risk factors.
Strictly speaking, as with a drug trial, risk esti-
mates are applicable only to the population from
which they were derived. But if the results cannot
be applied to other populations with different
JACC VOL. 77, NO. 24, 2021
JUNE 22, 2021:3046–57
characteristics, the exercise is futile. In general, risk
estimation systems perform usably well in pop-
ulations that are reasonably similar in terms of age
structure, demographics, time, and background risk.
However, because CVD event rates and average risk
factor levels vary over time and by place, algorithms
developed in one population may not predict the
correct risk in the target population being screened.
In other words, they may not be well “calibrated.” In
most cases, algorithms can be adjusted for use in
different populations by recalibration (9). This
process requires updated information on mortality
rates, average risk factor levels, and, for total event
estimates, incidence rates. These are combined with
the beta coefficients from the original derivation
cohort, with the assumption that the effects of risk
factors on cardiovascular disease outcomes does not
vary appreciably between regions or over time. In
general, the performance of recalibrated risk models
has been robust (9). Recalibration for nonfatal events
is far more challenging and is discussed in the next
section.
Cardiovascular risk age (10) was added
more recently to the interactive version of SCORE
(HeartScore) (11) as a concept that may aid effective
communication to patients about their cardiovascular
risk. It is particularly appropriate for use in younger
persons with multiple risk factors, but only moderate
absolute risk because of their youth. The risk age of a
person with several risk factors is the age of a person
with the same estimated risk but with ideal risk factor
levels. The patient can be advised that as they reduce
their risk factor burden, their risk age will begin to
approach their actual age.
FATAL VERSUS TOTAL (FATALD
NONFATAL) EVENTS?
Most risk estimation systems estimate the risk of
combined fatal and nonfatal cardiovascular events.
This is logical, but the inclusion of nonfatal events
poses certain problems. Nonfatal events are depen-
dent on definition, secular trends, developments in
diagnostic tests, methods of ascertainment, and
verification of events, all of which can vary, resulting
in very variable multipliers to convert fatal to total
events. This also makes the testing of the perfor-
mance of systems using nonfatal events more difficult
unless the test-set has used identical methods of
defining and ascertaining nonfatal events. In addi-
tion, total event charts, in contrast to those based on
mortality, are more difficult to recalibrate because of
the variability in outcome measures outlined previ-
ously. Further, nonfatal event data are sometimes
JACC VOL. 77, NO. 24, 2021
JUNE 22, 2021:3046–57
based on those supplied by the Global Burden of
Diseases group. These rely substantially on estimated
and modeled data and contain some inconsistencies.
In summary, the optimal way to create a risk esti-
mation system is to derive it from high-quality
representative local or regional cohort data,
including the registration of well-defined nonfatal
events. Such data do not exist in most parts of the
world. Recalibration can be performed using updated
World Health Organization (WHO) mortality and risk
factor data, bearing in mind that WHO data for many
countries are estimated. Although recalibration for
total events is possible, the degree of uncertainty is
greater than for fatal events, as indicated previously.
THE ORIGINAL GOALS OF THE STUDY GROUP
IN THE CONTEXT OF CURRENT RISK
ESTIMATION SYSTEMS
Many risk assessment systems are available and have
been comprehensively reviewed, including different
Framingham models (6,12,13), SCORE (7), and the
American Pooled Cohort Equation (14), which is the
US guideline recommended risk estimation model.
Recalibration for higher and lower risk U.S. pop-
ulations might improve applicability. Similarly, its
applicability to various European populations is un-
certain. Other risk estimation systems are also sum-
marized and referenced in 2016 ESC joint prevention
guidelines (2) and include ASSIGN (CV risk estimation
model from the Scottish Intercollegiate Guidelines
Network) (15), the UK Q-Risk (16), PROCAM, Reynolds
(17,18), CUORE, the Pooled Cohort equations, and
Globorisk. Recently, country-specific recalibrated to-
tal event risk charts were published on behalf of WHO
(19). As with Globorisk, nonfatal event data were
based on the Global Burden of Disease (GBD) data-
base. This database contains estimates and consid-
erable modeling and there are some uncertainties
about its use; further evaluation of the applicability of
these charts is needed. Ideally the derivation of risk
models for low- and middle-income countries would
involve nationally representative, large-scale pro-
spective cohort data from several of these countries,
each cohort with long-term follow-up and validated
fatal and nonfatal endpoints. Such data do not yet
exist for most low-income and middle-income coun-
tries, hence the use of GBD data by Globorisk and
WHO.
FRAMINGHAM
Although based on a modest-sized cohort of residents
in a single town, Framingham, Massachusetts, this
project has contributed far more than any other to our
Graham et al. 3049
SCORE
understanding of risk factors in the first place and
hence risk estimation, and is acknowledged as the
landmark study in the field of cardiovascular epide-
miology and prevention, from whom subsequent in-
vestigators have learned (6,12,13).
SCORE
SCORE is the ESC’s risk estimation system (7). It is
based on 200,000 subjects from 10 European cohort
studies and may be reasonably representative for
healthy Europeans. It is the simplest of current risk
estimation systems, estimating 10-year risk of total
CVD mortality. Its simplicity makes country-specific
recalibrations straightforward; however, it has been
criticized for not providing total event risks.
The methods used in SCORE evolved over time. It
was originally based on Weibull (7) modeling and this
was changed to Cox (20) to permit the development of
the electronic, interactive version HeartScore (11). For
the 2019 ESC/EAS lipid guidelines (2), SCORE was
adapted in 3 ways:
1. Age was extended to 70 years.
2. The effect of risk factors was allowed to vary by age
to reduce overestimating the impact of risk factors
in older persons as in the original SCORE. This was
done through the inclusion of age interactions with
the other risk factors.
3. The cholesterol band of 8 mmol/l was removed
because such persons need evaluation for familial
hypercholesterolemia and early management of all
risk factors.
The original SCORE charts are widely available, for
example, in the 2016 joint prevention guidelines (2)
and have been recalibrated for different European
and non-European countries. We present here the
modified 2019 version (2) (Figures 1 and 2).
LEARNINGS FROM SCORE OF CLINICAL
AND/OR PUBLIC HEALTH SIGNIFICANCE
1. Effect of age: Risk estimation in older people is
important as populations age. The original SCORE
project only estimated risk to age 65 years.
Extending this to older age groups was examined in
the SCORE OP project (8). Most conventional risk
factors continue to function in older persons (8);
however, the relative risks associated were gener-
ally lower in older people. The hypothesis that a
risk estimation system derived specifically from
the older age group would function better than the
original function (derived from the entire group)
proved to be correct, with area under the receiver
3050 Graham et al. JACC VOL. 77, NO. 24, 2021

SCORE JUNE 22, 2021:3046–57

F I G U R E 1 Updated SCORE Charts for High-Risk European Countries

SCORE Cardiovascular Risk Chart 10-Year Risk of Fatal CVD

High-Risk Regions of Europe

Women Men

Nonsmoker Smoker Age Nonsmoker Smoker

180 12 13 14 15 17 19 20 21 24 26 30 33 33 36 40 45
160 10 11 12 13 14 15 16 18 20 22 25 28 27 31 34 39
70
140 8 9 10 10 12 13 14 15 16 18 21 24 23 26 29 33
120 7 7 8 9 10 10 11 12 13 15 17 20 19 22 25 28

180 7 8 8 9 11 12 13 15 15 17 20 23 23 26 30 34
160 5 6 6 7 9 9 10 11 12 14 16 18 18 21 24 27
65
140 4 4 5 5 7 7 8 9 9 11 12 14 14 16 19 22
120 3 3 4 4 5 5 6 7 7 8 10 11 11 13 15 17

180 4 4 5 5 7 8 9 10 10 11 13 15 16 19 22 25
Systolic Blood Pressure (mm Hg)

160 3 3 3 4 5 6 6 7 7 8 10 11 12 14 16 19
60
140 2 2 2 3 4 4 4 5 5 6 7 8 9 10 12 14
120 1 1 2 2 3 3 3 3 4 4 5 6 6 7 9 10

180 2 2 3 3 5 5 6 7 6 7 9 10 11 13 16 18
160 1 2 2 2 3 3 4 4 4 5 6 7 8 9 11 13
55
140 1 1 1 1 2 2 2 3 3 3 4 5 5 6 7 9
120 1 1 1 1 1 1 2 2 2 2 3 3 4 4 5 6

180 1 1 2 2 3 3 4 4 4 5 6 7 8 9 11 13
160 1 1 1 1 2 2 2 3 2 3 3 4 5 6 7 9
50
140 0 0 1 1 1 1 1 2 2 2 2 3 3 4 5 6
120 0 0 0 0 1 1 1 1 1 1 1 2 2 2 3 4

180 0 0 1 1 1 1 2 2 2 2 2 3 4 4 5 7
160 0 0 0 0 1 1 1 1 1 1 1 2 2 2 3 4
40
140 0 0 0 0 0 0 0 1 0 1 1 1 1 1 2 2
120 0 0 0 0 0 0 0 0 0 0 0 1 1 1 1 1
4 5 6 7 4 5 6 7 4 5 6 7 4 5 6 7

Total Cholesterol (mmol/l)

<3% 3-4% 5-9% ≥10%

High-risk countries, which include most in the Balkan region, are defined in the 2019 ESC/EAS lipid guidelines (2). EAS ¼ European Atherosclerosis Society;
ESC ¼ European Society of Cardiology; SCORE ¼ Systematic Coronary Risk Evaluation.
JACC VOL. 77, NO. 24, 2021 Graham et al. 3051
JUNE 22, 2021:3046–57 SCORE

F I G U R E 2 Updated SCORE Charts for Low-Risk European Countries

SCORE Cardiovascular Risk Chart 10-Year Risk of Fatal CVD

Low-Risk Regions of Europe

Women Men

Nonsmoker Smoker Age Nonsmoker Smoker

180 7 8 8 9 11 11 12 13 12 14 15 17 18 20 22 24
160 6 6 7 7 9 9 10 11 10 11 13 14 15 16 18 20
70
140 5 5 6 6 7 8 8 9 8 9 10 12 12 13 15 17
120 4 4 5 5 6 6 7 7 7 8 9 10 10 11 12 14

180 4 4 5 5 7 7 8 9 8 9 10 12 12 14 16 18
160 3 3 4 4 5 6 6 7 6 7 8 9 9 11 12 14
65
140 2 3 3 3 4 4 5 5 5 5 6 7 7 8 9 11
120 2 2 2 2 3 3 3 4 3 4 5 5 5 6 7 8

180 2 3 3 3 4 5 5 6 5 6 7 8 8 10 11 13
Systolic Blood Pressure (mm Hg)

160 2 2 2 2 3 3 4 4 4 4 5 5 6 7 8 9
60
140 1 1 1 2 2 2 3 3 3 3 3 4 4 5 6 7
120 1 1 1 1 2 2 2 2 2 2 2 3 3 4 4 5

180 1 1 2 2 3 3 3 4 3 4 4 5 6 7 8 9
160 1 1 1 1 2 2 2 3 2 2 3 3 4 4 5 6
55
140 1 1 1 1 1 1 1 2 1 2 2 2 3 3 3 4
120 0 0 0 1 1 1 1 1 1 1 1 2 2 2 2 3

180 1 1 1 1 2 2 2 3 2 2 3 3 4 5 5 6
160 0 0 1 1 1 1 1 2 1 1 2 2 2 3 3 4
50
140 0 0 0 0 1 1 1 1 1 1 1 1 1 2 2 3
120 0 0 0 0 0 0 0 1 0 1 1 1 1 1 1 2

180 0 0 0 0 1 1 1 1 1 1 1 1 2 2 3 3
160 0 0 0 0 0 0 0 1 0 0 1 1 1 1 1 2
40
140 0 0 0 0 0 0 0 0 0 0 0 0 1 1 1 1
120 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1
4 5 6 7 4 5 6 7 4 5 6 7 4 5 6 7

Total Cholesterol (mmol/l)

<3% 3-4% 5-9% ≥10%

Low-risk countries are defined in the 2019 ESC/EAS lipid guidelines (2). Abbreviations as in Figure 1.
3052 Graham et al.
SCORE
operating characteristic curve improving from 0.68
to 0.70 in men and 0.74 to 0.78 in women. Allowing
the effect of risk factors to vary with age is an
approach to reducing the overestimation of risk in
older persons.
The inclusion of age interactions for each of the
risk factors is another method for allowing for the
differential effect of risk factors with age. This has
been incorporated into the recent version of the
SCORE charts published in the lipid guidelines (3).
This aspect is undergoing further exploration in
SCORE 2.
2. High-density lipoprotein (HDL) cholesterol: The
original SCORE project allowed calculation of CVD
risk based on either total cholesterol or total cho-
lesterol:HDL cholesterol ratio (7). Incorporation of
HDL cholesterol as a separate risk factor demon-
strated improved discrimination and also an
improvement in the net reclassification index
(20,21). This index, developed by Pencina et al.
(22), looks at the correct reclassification based on
the incorporation of an extra variable in those who
do and do not develop the outcome. This suggests
that HDL cholesterol is important to include in risk
estimation, especially in those who are borderline
high risk. Based on these results, HDL cholesterol
is now included as a separate variable in Heart-
Score and paper charts at different levels of HDL
cholesterol are also available (11,21).
3. Body mass index (BMI) (23,24): A BMI of 30 kg/m2
was associated with a 2-fold increase in risk
compared with a BMI of 20 kg/m 2. A strong and
graded J-shaped relationship between BMI and
CVD mortality was noted. This effect was mediated
almost entirely through increases in blood pres-
sure and total cholesterol and a reduction in HDL
cholesterol. After adjustment for age, each 1-unit
increase in BMI was associated with a 1.14 mm Hg
increase in systolic blood pressure (SBP),
0.055 mmol/l increase in total cholesterol, and a
0.024 mmol/l decrease in HDL in men. These re-
lationships were similar but slightly lower in
women (23). As expected, the addition of BMI to
conventional risk factors added little to the
discrimination of the risk estimation system.
However, BMI can be used instead of lipid vari-
ables in non–laboratory-based risk estimation sys-
tems, as discussed later in this article.
4. Diabetes: The current European guidelines on CVD
prevention consider that those with diabetes
should automatically be considered high or very
high risk (depending on the presence of other risk
factors) (2). For this reason, diabetes is not
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JUNE 22, 2021:3046–57
included as a risk factor in SCORE (7). However, the
effect of self-reported diabetes on risk of fatal CVD
in the SCORE dataset has been examined. Self-
reported diabetes was associated with a 3-fold in-
crease in risk of fatal CVD in men, and a 5-fold
increase in women (25).
5. Resting heart rate (RHR): Elevated RHR was found
to be an independent risk factor for CVD, especially
fatal coronary heart disease events (26). Elevated
RHR remained a risk factor after adjustment for all
conventional risk factors and importantly, self-
reported physical activity and comorbidities.
Those with RHR >90 beat per minute had a 2-fold
elevated risk compared with those with lower
RHR (26). Despite the continued effect of elevated
RHR on risk after full adjustment, inclusion as an
additional variable did not result in a measurable
improvement in risk estimation, either in the
entire population or in those at borderline risk, as
demonstrated by the low net reclassification
index (27).
6. Non–laboratory-based risk estimation: Following
on from this exploration of the effect of RHR on
risk, the SCORE group studied the function of a
simplified risk estimation system containing only
RHR, BMI, smoking, and age (27). This could
potentially be self-administered and demonstrated
remarkably good discrimination, with area under
the receiver operating characteristic curve of 0.82
in men and 0.86 in women.
MODIFYING FACTORS
The terms “total” or “global” risk are misleading,
because no system includes all possible risk factors,
nor all possible atherosclerotic end points. SCORE
includes only the major risk factors, but includes all
possible endpoints that can reasonably be judged to
be atherosclerotic.
It is usual to tabulate modifying or qualifying
factors that may increase or decrease risk estimates,
including diabetes, existing CVD, inactivity, over-
weight, social class, family history of premature
CVD, unresolved stress, and inflammatory condi-
tions such as rheumatoid arthritis and renal
insufficiency.
SCORE: THE 10 MOST IMPORTANT FINDINGS
1. Due to the generosity of the original investigators,
it proved possible to assemble data from 10
different European cohort studies. Key findings of
clinical and public health relevance are noted
previously.
JACC VOL. 77, NO. 24, 2021 Graham et al. 3053
JUNE 22, 2021:3046–57 SCORE

2. This may have resulted in a reasonably repre- 2. Develop new, regional total event risk charts
sentative sample of healthy Europeans. (SCORE 2) (Central Illustration) based on a new
3. Nevertheless, it was necessary to adapt the approach and using large-scale data from cohort
SCORE charts for high- and low-risk countries, studies, registries, and surveys.
with a comment that there is also a group of Eu-
As described previously (“Fatal vs total events”),
ropean countries at even much higher risk.
estimating the risk of combined fatal and nonfatal
4. The use of fatal CVD as a clear and well-defined
cardiovascular events comes with several challenges,
endpoint facilitated recalibrations for individual
the main one being the lack of up-to-date standard-
countries: 15 country-specific recalibrations are
ized and validated nonfatal event data even for Eu-
available through the HeartScore Web site (11).
ropean countries, a problem that poses a lesser
SCORE has also been translated into 17 languages.
problem when using fatal CVD as outcome. Because
5. Although the use of fatal CVD as the endpoint
of the inherent limitations of fully modeled incidence
facilitates country-specific recalibrations and
data such as those issued by the GBD group, the pri-
inevitably means a higher risk of total (fatal þ
mary aim of SCORE 2 was to derive reliable risks es-
nonfatal) events, there is a demand for a system
timates of total events based as far as possible on
that estimates risk of total events that the SCORE
“real” observational data; even here, incidence esti-
investigators must respond to.
mates will require some modeling. Given the lack of
6. Risk estimation systems based on total events are
solid contemporary total events cohort data across
harder to recalibrate because nonfatal events are
Europe, SCORE 2 will estimate cardiovascular inci-
less uniformly defined and ascertained. Possibly
dence by adopting a multiplier approach to convert
this explains why the US pooled cohort equation
most recent WHO mortality data to total cardiovas-
has not been recalibrated for different population
cular incidence data through establishing a database
groups within the United States.
of region-specific multiplication factors.
7. Although SCORE is based on only age, gender,
The substantial variation of cardiovascular risk
total cholesterol, SBP, and smoking, the addition
across Europe has been well documented. The orig-
of multiple other biomarkers adds rather little.
inal SCORE model was developed for low- (Western
For risk estimation in patients with other condi-
European countries) and high-risk regions (Central
tions, such as diabetes or established CVD, sepa-
and Eastern European countries). However, several
rate risk algorithms need to be developed.
local validation studies have demonstrated over- and
8. All current risk estimation systems are dominated
underestimation of SCORE risks. SCORE 2 aims to
by the effect of age, which represents exposure
establish the risk model in a way that allows flexible
time rather than a risk factor per se. New ap-
updating with future CVD event rates and population
proaches to address this issue may be required.
risk factor distributions. Finally, ignoring the impact
9. Most current risk estimation systems start at
of non-CVD death in the calculation of nonfatal car-
approximately age 40 and estimates applicable to
diovascular risks estimates is leading to an over-
younger persons are required. In addition, exten-
estimation of risks certainly at higher ages. SCORE 2
sion of risk estimates to older persons is needed.
aims to take competing risk for non-CVD death into
The relation between risk factors and CVD risk de-
account making the estimates better fit for purpose.
clines with increasing age and the competing risk of
No risk estimation system is perfect, but we hope
non-CVD death needs to be taken into account.
that the simplicity of SCORE2, its derivation and
10. All current risk estimation systems apply to pop-
testing using very large data sets, and its recalibration
ulations and personalized risk estimation systems
for 4 risk regions will enhance its utility.
applicable to individuals are needed.
Another question is the applicability of SCORE and
THE FUTURE RESEARCH DIRECTIONS FOR SCORE2 to non-European populations. This could be
THE GROUP readily achieved through further recalibrations. The
same would apply to different ethnic groups, although
In 2019, the Board of the ESC approved the estab- there may be data limitations in achieving this.
lishment of the Cardiovascular Risk Collaboration
3. Develop risk algorithms for special situations:
(CRC), based in the ESC’s European Heart Health
secondary prevention, older persons, diabetes,
Institute in Brussels (Central Illustration).
heart failure, atrial fibrillation. Of these, the
Included in its aims are to
development of risk estimation models in older
1. Classify and compare current risk estimation persons (SCORE2-OP) and refinement of risk in
systems. subjects with known CVD are most advanced.
3054 Graham et al. JACC VOL. 77, NO. 24, 2021

SCORE JUNE 22, 2021:3046–57

C E NT R AL IL L U STR AT IO N Systematic Coronary Risk Evaluation and the European Society of Cardiology’s
Cardiovascular Risk Collaboration

Graham, I.M. et al. J Am Coll Cardiol. 2021;77(24):3046–57.

The CRC is situated in the ESC’s European Heart Health Institute in Brussels. It addresses risk of developing ASCVD and is starting to evaluate risk in other categories of
cardiovascular disease. A multidisciplinary team uses data from many sources, as shown. The immediate outputs are SCORE2 and SCORE2 OP. Additional outputs
include the integration of other risk factors, such as inflammatory markers and diagnostic tests into risk estimation, more sophisticated electronic interactivity, and a
new approach to personalized lifetime risk estimation. ASCVD ¼ atherosclerotic cardiovascular disease; CRC ¼ Cardiovascular Risk Collaboration; EAS ¼ European
Atherosclerosis Society; ESC ¼ European Society of Cardiology; SCORE ¼ Systematic Coronary Risk Evaluation; SCORE2 OP ¼ SCORE2 Older Persons.
JACC VOL. 77, NO. 24, 2021
JUNE 22, 2021:3046–57
Despite the fact that most patients with estab-
lished atherosclerotic CVD should be regarded as at
very high risk, there are several situations in clin-
ical practice where further risk stratification may
be warranted to apply more individually tailored
therapeutic interventions in those at very high
residual risk. The EUROASPIRE (28) and SURF (29)
surveys have clearly demonstrated that the man-
agement of coronary patients regarding control of
established risk factors falls short of the standards
set by the Joint European Societies guidelines on
CVD prevention, leaving a substantial potential for
improvement. A validated risk tool identifying
those at very high residual risk and requiring more
intensive efforts may be warranted. A few residual
risk assessment models have been developed, such
as those from the SMART (Secondary Manifesta-
tions of Arterial Disease study) and REACH
(REduction of Atherothrombosis for Continued
Health) studies, but their applicability to pop-
ulations other than those from which they were
derived is uncertain.
4. Examine the integration of diagnostic tests such as
coronary artery calcification into risk estimation. It
should be appreciated that such tests are not risk
factors per se, but identify subjects in whom dis-
ease, even if asymptomatic, is already present,
indicating a higher-than-expected risk of further
CVD events.
5. Define the role other risk factors, such as inflam-
matory markers.
6. Integration of large data sets into risk estimation.
7. Refine and improve the interactivity of risk esti-
mation systems to improve their practical value. In
2020, a new ESC/European Association of Preven-
tive Cardiology interactive mobile app was
launched as the “ESC CVD risk” (30). This app has
improved functionality but requires further vali-
dation and refinement by the CRC.
8. Support other European Heart Health Institute
initiatives: the Atlas of CVD, the new global burden
of CVD diseases project, clinical trials, public
health, advocacy, mobile health and patient
engagement.
9. Develop a totally new approach to individualized
lifetime risk and treatment benefit estimation.
TOWARD A NEW APPROACH TO RISK
ESTIMATION: TRUE LIFETIME RISK AND THE
IMPORTANCE OF GENETICS
Atherosclerosis is a chronic disease that begins early
in life and progresses slowly over time (31). The
trapping of circulating LDL and other apoB-
Graham et al. 3055
SCORE
containing lipoproteins within the artery wall, and
their subsequent presentation to macrophages, is the
necessary step in the initiation and progression of
atherosclerotic plaque (32). This understanding of the
biology of atherosclerosis leads to the cumulative
exposure hypothesis (33). According to this hypoth-
esis, the size of the underlying plaque burden, and
the corresponding risk of experiencing an acute car-
diovascular event, is proportional to the cumulative
exposure to apoB-containing lipoproteins combined
with other causes of atherosclerosis, such as raised
blood pressure or smoking. As a result, lowering LDL/
apoB-containing particles and other causal risk fac-
tors much earlier in life, and therefore much earlier in
the atherosclerotic disease process than is currently
recommended, has the potential to dramatically
reduce the lifetime risk of cardiovascular disease by
prolonging the threshold to initiation and slowing the
progression of atherosclerosis.
The cumulative exposure hypothesis of athero-
sclerosis is supported by the results of Mendelian
randomization studies. These studies demonstrate
that lifelong exposure to genetically determined LDL
and SBP have a much larger effect on the risk of car-
diovascular disease than the effect of LDL and SBP
observed in either short-term randomized trials, or
intermediate-term observational cohort studies
(31,34). This consistent finding implies that both LDL
and SBP have causal effects on the risk of cardiovas-
cular disease that accumulate over time. Indeed,
recent Mendelian randomization studies suggest that
LDL and SBP have independent and additive causal
effects on the risk of cardiovascular disease that
accumulate over time. These studies suggest that
even small, sustained reductions in LDL and SBP over
a prolonged period can substantially reduce the life-
time risk of cardiovascular disease, and that the
combination of sustained exposure to 1 mmol lower
LDL and 10 mm Hg lower SBP can potentially reduce
lifetime risk by 80% or more (34).
However, current clinical practice guidelines do
not focus on lifetime risk or, when it is estimated, the
calculation usually starts relatively late, often around
40 years of age. Instead, most recommend that both
the decision to treat and the intensity of that treat-
ment should be determined by the risk of having a
cardiovascular event over the next 10 years, calcu-
lated using SCORE or another risk-estimating equa-
tion. However, short-term 10-year risk-estimating
equations are mathematically dominated by age. As a
result, 10-year risk is uniformly low in younger per-
sons. Estimating cardiovascular risk using a risk-
estimating equation that is dominated by age has
the practical effect of inviting us to wait until our
3056 Graham et al. JACC VOL. 77, NO. 24, 2021

SCORE JUNE 22, 2021:3046–57

underlying plaque burden is so advanced that we are
at a high risk of experiencing an acute cardiovascular
event in the near future. This concept ignores our
understanding of how atherosclerosis develops and
discourages efforts to substantially slow its progres-
sion even among young persons with high lifelong
exposure to causal risk factors.
The principal reason that current risk-estimating
equations do not accurately reflect the biology of
atherosclerosis is that they are mathematically
dominated by age. However, age, per se, may not be a
risk factor for CVD. Instead, as noted previously, age
may be a measure of the cumulative exposure to all
risk factors that contribute to the development and
progression of atherosclerosis. Therefore, one way to
overcome the mathematical dominance of age in risk-
estimating equations is to replace age with estimates
of the causal and cumulative effect of LDL measured
in mmol-years, SBP measured in mm Hg-years and
other causal risk factors derived from Mendelian
randomization studies.
Importing effect estimates from
randomization studies into risk-estimating equations
allows powerful genomic information to be used in
risk estimation without the need for genotyping.
Furthermore, using estimates of the cumulative ef-
fect of risk factors that cause atherosclerosis permits a
more accurate individualized assessment of risk. In
particular, this approach promises to avoid under-
estimating risk in young people who already have had
cumulative exposure to these risk factors to be
adjusted for time period of changes induced by diet,
exercise, smoking cessation, or medication.
It should be appreciated that there are several
other approaches to lifetime CVD risk. It can be esti-
mated with a methodology called left truncation and
right censoring (35). Various lifetime CVD risk models
have been developed and externally validated in
large data sets, such as Q-risk and LIFE-CVD for
apparently healthy people (36), DIAL for patients with
diabetes (37), and SMART-REACH for patients with
established CVD (38). By combining the estimated
lifetime CVD risk with the results from meta-analysis
of large, randomized trials, an individual treatment
effect can be estimated for blood pressure lowering
and cholesterol-lowering expressed as gain in CVD-
free life.
In summary, using causal estimate of the cumula-
tive effect of LDL, SBP, and other factors that cause
atherosclerosis introduces a new paradigm in risk
estimation: individualized true lifetime risk. Howev-
Mendelian er, this is an active area of research and much work
remains to be done to personalize prevention.
FUNDING SUPPORT AND AUTHOR DISCLOSURES
The Cardiovascular Risk Collaboration is situated in the European
Society of Cardiology’s European Heart Health Institute in Brussels.
Chairpersons of the Institute are Maddalena Lettino (2018 to 2020)
and Adam Timmis (2020 to 2022).This publication received no specific
grants from any funding agency in the public or commercial sectors.
The authors have reported that they have no relationships relevant to

a high lifetime exposure to the causes of atheroscle- the contents of this paper to disclose.

rosis and avoid overestimating risk among older

people who have had a low cumulative lifetime ADDRESS FOR CORRESPONDENCE: Dr. Ian M. Gra-

exposure to the causes of atherosclerosis. In addition, ham, Woodvale, Rocky Valley Drive, Kilmacanogue,
estimating the causal effect of LDL in mmol-years and Co. Wicklow A98 EV18, Ireland. E-mail: ian@
SBP in mm Hg-years allows the estimates of the total grahams.net. Twitter: @IanGrah31599031.

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KEY WORDS cardiovascular disease, CVD
risk assessment, Heart Score, prevention, risk
assessment