Canadian Journal of Cardiology 27 (2011) 171173

Editorial

Framing Cardiovascular Disease Event Risk Prediction

James A. Stone, MD, PhD, FRCPC, FAACVPR, FACC
University of Calgary, Libin Cardiovascular Institute of Alberta, and Cardiac Wellness Institute of Calgary, Calgary, Alberta, Canada

Prediction is very difficult, especially about the future.

Niels Bohr

Prediction about anything, as so aptly pointed out by the famous

Danish physicist Niels Bohr, is not easy. Without knowledge of all
the variables in an equation, their exact behaviour under all conditions, precisely the way each variable interacts with the others,
and all of the plausible, potential outcomes of those interactions,
predicting the outcomes of a system or (patho)physiological process involves as much art as science. Add to this already heady
mixture of uncertainty the frequently chaotic (ie, nonlinear) behaviour of biological systems,1 and the prediction of clinical outcomes becomes very difficult indeed!
And yet, a thing does not have to be perfect to be quite
useful. Most current cardiovascular disease (CVD) prevention
strategies and therapeutic interventions are far from perfect in
the outcomes they deliver. However, their clinical utility in
substantially reducing (recurrent) events and delaying death
remains undeniably useful.2-4 With any therapeutic intervention, it is axiomatic that the greatest absolute improvements in
outcomes are seen in those at the greatest risk of adverse events.
However, the total number of adverse events prevented will
virtually always accrue in lesser-risk populations, based on the
simple reality of population demographics and the observation
that the number of low-risk persons is usually comparatively
large. Thus, any intervention or treatment aimed at reducing
event rates within these lower-risk populations will require
treating the largest proportion of the population at risk. And
despite the clinical information clearly demonstrating the benefits of preventing individual CVD events in these lesser-risk
populations,5,6 the relatively low overall population risk suggests that the number of individuals who must be treated, and
the costs incurred in order to prevent a single adverse outcome,
may be quite large.7 Furthermore, of critical but often underestimated clinical importance is the reality that in any low-risk
population, the risks (and costs) of preventing an event may
actually exceed the risks of not intervening.8
These clinical and economic realities are precisely the reason
that Canadian CVD prevention guidelines recommend some
Received for publication August 3, 2010. Accepted August 3, 2010.
Corresponding author: Dr James A. Stone, Suite 802, 3031 Hospital Dr
NW, Calgary Alberta, 2N T8, Canada.
E-mail: jastone@shaw.ca
See page 172 for disclosure information.

form of cardiovascular disease event prediction or risk stratification (Framingham,9 SCORE,10 Reynolds Risk Score,11,12
QRISK213) as a critical, arguably first, step in planning an
individuals health maintenance or disease care program.14-16
This process of determining event risk helps to ensure that
those at the greatest risk will receive the highest level of intervention (usually pharmacologic), in addition to the same
health behaviour recommendations (smoking cessation, reduced caloric intake, healthy weight, regular physical activity,
proper sleep hygiene, good mental health) that should be applied to individuals and populations of lesser risk. Indeed, failure to risk stratify individuals when initiating or perpetuating
any form of CVD prevention or treatment simply introduces a
different risk: that of substantially overtreating those at low risk
and undertreating those at the highest risk.
It is important, however, that what CVD event risk prediction systems do not predict is the presence (or absence) of
atherosclerosis. They examine an individuals exposure to the
drivers of atherosclerosis, ie, traditional CVD risk factors, and
based on the level of those drivers, in conjunction with the total
time of exposure, ie, age, they calculate a probable adverse event
rate. However, exposure to the drivers of atherosclerosis is only
half of the event determination equation. The other half of the
equation is event susceptibility.17 If CVD event exposure can be
conceptualized as the cumulative burden of atherosclerosis
drivers, event susceptibility can be conceptualized as the total
predisposition to atherosclerosis (ie, age, gender, family history, and vascular phenotypical expression). It is CVD risk
factor exposure plus risk factor susceptibility that determines
the probability of developing atherosclerosis and suffering an
adverse event. It is not just exposure in isolation, as suggested
by most current equations predicting the risk of CVD events.
The clinical interplay between CVD risk factor exposure and
susceptibility is exemplified by the commonly observed clinical
paradox that not everyone at high risk of a CVD event has an
event in the predicted time frame (most famously perhaps Sir
Winston Churchill), and not everyone at moderate or even low
risk is free from atherosclerosis or events.5,18,19 The inability of
current CVD risk prediction systems to adequately account for
CVD susceptibility may help to explain why they still fail to
identify a significant minority of persons at risk and, potentially, why they still remain underused.20
In this issue of CJC, Armstrong and colleagues21 provide a
unique perspective on how their use of the current Framing-

0828-282X/$ see front matter 2011 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved.
doi:10.1016/j.cjca.2010.12.041

172

ham risk score (FRS) incorporated into the 2009 Canadian

Lipid Guidelines22 changed pharmacologic treatment thresholds within their clinic. In a retrospective analysis of their patient database, they demonstrated that application of the more
comprehensive FRS CVD event prediction tool promoted in
the 2009 Lipid Guidelines resulted in a significant upward
reclassification of patients into moderate- or high-risk groups.
Compared with the previous FRS version in the 2006 Canadian Lipid Guidelines,23 which predicted only death or nonfatal myocardial infarction, use of the more comprehensive FRS
model (coronary artery disease-fatal and non-fatal myocardial
infarction, congestive heart failure, stroke, and peripheral arterial disease) increased the combined percentage of moderateand high-risk patients in their clinic from 24.7% to 52.2%.
The authours correctly point out that this change results in a
more than 2-fold increase in the numbers of patients qualifying
for pharmacologic therapy and that the change to a more comprehensive FRS was, in their view, not well highlighted or promoted and, therefore, was likely missed by many clinicians.
Last, they further highlight that the more comprehensive FRS
version in the 2009 Lipid Guidelines also includes risk points
for diabetes but fewer risk points for age and smoking.
Even a cursory examination of the nuances and numerous
versions of FRS prediction algorithms is far beyond the scope
of this limited discussion, and interested readers are directed
elsewhere.24,25 However, incorporation of a broader system for
predicting CVD event risk into the 2009 Lipid Guidelines is
completely consistent with contemporary thinking within the
world of CVD event prediction.26 Atherosclerosis is a systemic
disease process, and as such, adverse event risk prediction systems should predict events in as many vascular beds as possible.
The apparent downgrading of age and smoking (fewer risk
points) is a simple reflection of the fact that changing the outcomes of risk prediction algorithms also changes the influence
that any particular risk variable will have on those outcomes.
The reinclusion of diabetes as a risk factor (it was present in
pre-1998 Framingham risk models27) is also a reflection of
more contemporary thought suggesting that not all persons
with diabetes are at high or proximate risk of CVD events.28
Therefore, diabetes should properly be considered a CVD risk
factor rather than a CVD equivalent.
These qualifications aside, Armstrong and coworkers are to
be congratulated for highlighting the potential impact of the
2009 Canadian Lipid Guidelines on patient care. Their observations on risk estimation within their own patient practice
provide further evidence of the importance of clearly and consistently highlighting when important changes to clinical practice guidelines (CPGs) are made that carry the potential to
meaningfully impact clinical practice.29 In addition, their analysis serves to emphasize that CPG developers should at least
attempt to provide an estimate of the clinical and economic
impact of their CPGs, as suggested by the AGREE (Appraisal
of Guidelines for Research and Evaluation) instrument,30 recognizing that the data may be poor and that good decisions
(particularly government and public health policy decisions
where millions of people may be impacted) are unlikely to be
derived from poor quality data. Although most CPG developers have shied away from producing this information, usually as
a direct consequence of the dearth of good quality information
already alluded to, when significant changes to CPGs may result in substantive changes in the numbers of patients treated,

Canadian Journal of Cardiology

Volume 27 2011

CPG developers should at least attempt to address this issue

directly. In this manner, health care payers and providers, public policy architects, and patients can enter into a meaningful
dialogue with respect to who should be insured, who should be
treated, and who is unlikely to benefit from, or even potentially
be harmed by, the widespread, clinically indiscriminate application of any CPG or evidence-informed clinical practice recommendation.
The clinically appropriate prevention and treatment of
CVD events demands the establishment of an individuals
baseline risk. The fact that most current CVD risk stratification
or event prediction systems estimate only risk factor exposure
and fail to account for individual susceptibility renders them
less than perfect, but still quite useful. However, inclusion of
CVD susceptibility markers such as coronary artery calcium
scores31 or carotid intima media thickness32 may help to improve adverse event prediction.33 And greater fidelity in adverse event prediction may increase the clinical use of risk prediction tools, increase event riskappropriate interventions,
and, similar to CVD CPG harmonization and integration, may
improve clinical outcomes by reducing barriers to implementation.34 These collective considerations notwithstanding, the
paper by Armstrong and colleagues should remind each of us
that CPGs are the collective responsibility of all health care
professionals, not just CPG developers, and as such should be
discussed, constructively criticized, and then amended in subsequent versions to reflect both the scientific evidence and the
important feedback from stakeholders.
Disclosures
Dr Stone has received consulting and/or presentation honorarium from Astra-Zeneca, Merck, Novartis, Pfizer, Servier,
and Sanofi-Aventis.
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