Opinion
EDITORIAL
USPSTF Recommendations for Assessment
of Cardiovascular Risk With Nontraditional Risk Factors
Finding the Right Tests for the Right Patients
John T. Wilkins, MD, MS; Donald M. Lloyd-Jones, MD, ScM
Cardiovascular disease (CVD) remains the leading cause of
death in the United States and a major source of morbidity.1
Individuals in the United States have a 1 in 3 chance of dying
from CVD and a 2 in 3 chance
of developing CVD before
Related articles death.2 However, control of
risk factors, such as with
cholesterol-lowering statin medications, can substantially re-
duce the likelihood of mortality and morbidity among at-risk
patients. Identifying individuals who will benefit from this
highly efficacious class of medications has been a priority of CVD
prevention. For the purposes of primary prevention, the esti-
mation of absolute risk of developing a CVD event is used to as-
sist clinicians in determining which patients are likely to ben-
efit from statin therapy,3 because net benefit (well in excess of
any potential harms) is clearly seen in patients with estimated
absolute risk of 7.5% or greater over 10 years.4 Estimation of ab-
solute risk is practical, because it can be performed rapidly in
clinical practice with the use of clinical calculators. Further-
more, quantitative risk estimation allows for a direct compari-
son of the risks and benefits of statin therapy so clinicians and
patients can make informed decisions about therapy.
However, estimation of absolute risk has several impor-
tant limitations. First, it is an attempt to predict the future,
which is inherently imperfect and probabilistic, not determin-
istic. Second, event rates can vary substantially across differ-
ent populations, which can limit the accuracy of risk estima-
tion equations in diverse populations. Similarly, the risks within
population subgroups may be quite different from the mean
risk observed in a population. The addition of nontraditional
risk factors to risk estimation equations has been proposed as
a potentially attractive strategy to help clinicians manage this
clinical challenge and identify patients most likely to achieve
net benefit from statin therapy.
In this issue of JAMA, the US Preventive Services Task Force
(USPSTF) provides a Recommendation Statement5 based on
a systematic review of current evidence6 to determine whether
there is sufficient evidence to recommend the routine use of
ankle-brachial index (ABI), high-sensitivity C-reactive pro-
tein (hsCRP), or coronary artery calcium (CAC) score measure-
ment in clinical risk assessment and decision making. The task
force addressed 2 important questions: First, do these mark-
ers improve the performance of risk scores (discrimination and
reclassification)? Second, does the use of these markers im-
prove clinical outcomes? The panel concluded that there is
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insufficient evidence to recommend for or against adding the
ABI, hsCRP level, or CAC score to traditional risk assessment
for CVD in asymptomatic adults to prevent CVD events at this
time (I statement).5 These conclusions are understandable from
the policy perspective but do not fully address the issues faced
by individual patients and clinicians in decisions about the rela-
tive merits of primary preventive therapies.
The main conclusion of the USPSTF—that more research
needs to be performed to develop risk stratification algo-
rithms that better identify individuals at risk who will benefit
from primary prevention therapies (and those at sufficiently
low risk, who will not benefit)—is correct. To date, there is no
high-quality evidence evaluating the morbidity, costs, CVD out-
comes, and total mortality associated with the routine use of
these risk markers in clinical practice. There is also insuffi-
cient evidence to recommend that any of these markers be used
in universal screening strategies for CVD prevention in the over-
all population, and it is unlikely that such data are forthcom-
ing, for both statistical and pragmatic reasons. However, when
CAC score is used in a selective, serial testing approach in ap-
propriate patient subgroups, the evidence is strong that CAC
score effectively reclassifies many patients to high or low risk
and can therefore contribute important information for deci-
sion making in individual patients.
CAC scores quantify the extent of calcification of the
major epicardial coronary arteries. The presence of calcium
in the arteries is a correlate of the degree of atherosclerotic
disease burden. Because atherosclerosis is the underlying
disease that causes most acute CVD events, it is no surprise
that the presence of CAC predicts a higher risk for CVD
events, beyond traditional risk factors.7 CAC score is a con-
tinuous measure, and scores can range from 0 into the thou-
sands. The prevalence of CAC varies with age, so it is often
expressed as an age-specific percentile. The utility of CAC
scoring for identifying individuals at higher and lower risk for
incident CVD events has been evaluated rigorously in the car-
diology literature, and the results have been remarkably con-
sistent: CAC scoring routinely and substantially outperforms
other nontraditional risk-assessment tests in the context of
current risk prediction algorithms.8,9
In middle-aged and older US adults whose estimated
absolute risk of developing CVD events is near a treatment
threshold (eg, 7.5%), the presence of CAC scores greater than
100 or higher than the 75th percentile for a given age accu-
rately reclassifies individuals to a higher category of risk.
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 Opinion Editorial

Even individuals with low estimated 10-year risks and high
CAC scores (>100 Agatston units) have substantially greater
observed risks than those with CAC scores of 0.8,10-14 Thus,
the presence of CAC in these patients effectively identifies
those at higher risk who may benefit from statin therapy.
However, individuals with low predicted risk and high CAC
scores are relatively uncommon,15,16 so routinely screening a
population for these individuals would be of low clinical
yield. Conversely, individuals with a CAC score of 0, even if
they are somewhat above benefit thresholds of estimated risk
(eg, those with >7.5% to 15% estimated 10-year risk), are
accurately classified into lower categories of risk, below ben-
efit thresholds.12,17-19 Reclassification studies report results
that are consistent across sex and race groups. In aggregate,
these data suggest that CAC screening, when applied sequen-
tially and selectively (not universally) to individuals with
estimated risks around treatment thresholds (ie, 5% to 15%),
can be a useful serial testing approach to reclassify individu-
als into accurate risk levels.
Thus, application of CAC testing in such a strategy can re-
sult in improved targeting of statin therapy in primary pre-
vention. In this strategy, patients and clinicians who are un-
certain regarding the net benefits of statin therapy based solely
on a quantitative risk estimate could obtain a CAC score. In-
dividuals reclassified to low risk by a CAC score of 0 could avoid
statin therapy in the near term, whereas those with con-
firmed or reclassified risk levels in the range of net statin ben-
efit would be assured of greater likelihood of benefit.
At present, direct evidence is limited to determine whether
the use of CAC screening to reclassify risk for patients at in-
termediate risk results in overall reductions in mortality and
CVD events, but there is no evidence to suggest that event rates
would be worse with such a strategy. Avoidance of statin
therapy in the majority of intermediate-risk patients who have
a CAC score of 0 also could be desirable. As the USPSTF sug-
gests, answering these questions is of vital importance. Until
a randomized clinical trial tests the clinical strategy of CAC mea-
surement in intermediate-risk patients, clear guidance to cli-
nicians (eg, a USPSTF grade A or B recommendation) will not
be possible.20 Such a trial would require a large sample size and
long follow-up to achieve adequate power. Undoubtedly, it
would be expensive, but it would be a wise investment be-
cause it would help to refine current clinical testing strate-
gies to identify patients who will benefit most from primary
prevention interventions. More accurate targeting of statin
therapy would reduce CVD events and the economic burden
of CVD on the economy, while lowering preventive treatment
costs and adverse drug reactions.
The ABI is a well-validated screening test for peripheral
arterial disease. Because the degree of stenosis necessary to
create a differential blood pressure between the legs and up-
per extremities is considerable, a low ABI (<0.9) represents
an advanced form of atherosclerosis. Clinicians should be aware
of PAD and, if it is present, should strongly consider statin
therapy regardless of estimated CVD risk for such patients.
However, the utility of the ABI for assessment of CVD risk is
more limited. First, it is uncommon for an individual to have
a low ABI without an adverse risk factor profile that would typi-
cally result in estimated CVD risks of 7.5% or greater. Second,
an ABI in the normal range tells clinicians very little about an
individual’s risk and has not been shown to meaningfully re-
classify risk downward in an otherwise at-risk individual.
Thus, use of the ABI in routine clinical practice to screen for
PAD in at-risk patients is reasonable, but its routine use in es-
timation of CVD risk is limited. Moreover, in another recent
Recommendation Statement,21 the USPSTF concluded that
“the current evidence is insufficient to assess the balance of
benefits and harms of screening for PAD and CVD risk with the
ABI in asymptomatic adults (I statement).”
Inflammation is clearly in the causal pathway of athero-
sclerosis. Measurement of subclinical inflammation with hsCRP
has been shown to reclassify some individuals at intermedi-
ate levels of risk. Because hsCRP measurement is a blood test,
the radiation exposure (albeit minimal) associated with CAC
scoring is avoided. However, an elevated hsCRP level is non-
specific, and the effect of hsCRP level on risk reclassification
is modest. Furthermore, as noted by the USPSTF for all 3 non-
traditional markers, there are no data to demonstrate im-
proved outcomes with hsCRP testing. Overall, then, the util-
ity of hsCRP measurement in routine assessment of CVD risk
for primary prevention is limited.
In summary, policy-level recommendations about strate-
gies for assessment of CVD risk are challenging because of
somewhat limited data and variable risks between and within
populations. Furthermore, it is difficult to determine
whether a given clinical strategy will change event rates in
the population as a whole. The current literature demon-
strates that CAC measurement, when used in intermediate-
risk patients, helps refine risk assessment in important ways
that can help identify patients far more correctly for use
(or avoidance) of efficacious risk-reducing statin medica-
tions. These USPSTF recommendations should spur ascer-
tainment of the data needed to turn I statements into more
definitive recommendations, specifically regarding the use of
CAC measurement. If CAC measurement succeeds in an end
points–driven clinical trial, it will be unnecessary to fund
research developing weaker biomarkers. If CAC measure-
ment were to fail as a useful biomarker for CVD risk in an
adequately powered trial, it certainly would not be necessary
to develop weaker biomarkers, but rather, the current
approach to primary prevention of CVD would need to be
fundamentally reconsidered. Clearly, identification of the
right patients for the right therapy requires identification of
the right patients for the right risk-assessment tests.

ARTICLE INFORMATION
Author Affiliations: Department of Medicine,
Northwestern University Feinberg School of
Medicine, Chicago, Illinois (Wilkins, Lloyd-Jones);
Department of Preventive Medicine, Northwestern
University Feinberg School of Medicine, Chicago,
Illinois (Wilkins, Lloyd-Jones).
Corresponding Author: Donald M. Lloyd-Jones,
MD, ScM, Department of Preventive Medicine,
Northwestern University Feinberg School of
Medicine, 680 N Lake Shore Dr, Ste 1400, Chicago,
IL 60611 (dlj@northwestern.edu).
Published Online: July 10, 2018.
doi:10.1001/jama.2018.9346

E2 JAMA Published online July 10, 2018 (Reprinted) jama.com

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Conflict of Interest Disclosures: The authors have
completed and submitted the ICMJE Form for
Disclosure of Potential Conflicts of Interest and
none were reported.
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