J A C C : C A R D I O V A S C U L A R I M A G I N G V O L . 1 0 , N O . 3 , 2 0 1 7

ª 2 0 1 7 B Y T H E A M E R I C A N CO L L E G E O F C A R D I O L O G Y F O U N DA T I O N

P U B L I S H E D B Y E L S E V I E R

I S S N 1 9 3 6 - 8 7 8 X / $ 3 6 . 0 0

h t t p : / / d x . d o i . o r g / 1 0 . 1 0 1 6 / j . j c m g . 2 0 1 7 . 0 1 . 0 0 9

Primary Prevention of CVDThe Role of Imaging Trials

Alan Rozanski, MD,a Joseph B. Muhlestein, MD,b Daniel S. Berman, MDc

ABSTRACT

Fro

Sin

Me

Sin

Me

rel

pa

Ma

The optimal approach for screening for cardiovascular disease remains controversial. A new standard of “thera-

peutic efficacy” requires that screening tests which involve cardiac imaging not only predict events but also

improve clinical outcomes compared with usual care. To date, 5 prospective randomized trials have been con-

ducted to compare outcomes based on imaging-guided screening and prevention versus assignment to usual care

in screening populations. One trial involved cardiac stress imaging, 3 involved coronary artery calcium scanning,

and 1 involved coronary computed tomography angiography. Due to the current very low event risk in asymp-

tomatic populations, these trials have been substantially underpowered to assess the impact of imaging-guided

prevention on hard cardiac events. This review derives lessons learned from these trials relative to the

future design of imaging-based screening trials, including analysis regarding the optimal methods for screening,

and what are the relevant clinical outcomes to assess the efficacy of imaging-based screening for prevention.

(J Am Coll Cardiol Img 2017;10:304–17) © 2017 by the American College of Cardiology Foundation.

D ramatic advances in the prevention andtreatment of cardiovascular disease (CVD)over the last few decades have led to a

marked reduction in age-adjusted mortality fromCVD (1). Nevertheless, atherosclerosis leading tocoronary artery disease (CAD) and stroke remainsthe most common cause of death in the UnitedStates and across most nations (2). Once overtCVD ensues, the options for effectively treatingthis disease are potent and can substantially sustainlongevity compared to a few decades ago. However,the cost of cardiovascular health care is becomingincreasingly daunting. For example, an analysisfrom the American Heart Association noted thatthe direct costs of cardiovascular health care ($273billion in 2010) were projected to triple by 2030 toan estimated cost of $818 billion (3). Accordingly,due to the epidemiology of CVD as well as these ris-ing costs, it has become increasingly imperative todevelop a more effective strategy for preventingCVD.

m the aDivision of Cardiology, Mount Sinai St. Luke’s Hospital, Mount Sin

ai, New York, New York; bIntermountain Medical Center Heart Institu

dicine, Salt Lake City, Utah; and the cDepartments of Imaging and Med

ai Heart Institute, Los Angeles, California. This study was funded, in

dical Research Foundation and the Diane & Guilford Glazer Foundati

ationships relevant to the contents of this paper to disclose. Pamela

per.

nuscript received November 17, 2016; revised manuscript received Janua

Traditionally, the identification of individuals whodeserve more intense prevention efforts has beenmade by assessment of population-based CVD riskfactors. As reviewed here, however, there are well-documented limitations to this approach. In recentdecades, the ability to indirectly or directly image thecoronary arteries for the presence of atherosclerosishas become available through computed tomography(CT) imaging. This opportunity has led to the per-formance of several imaging trials to test whether theconduct of imaging-based preventive care is superiorto usual preventive care (i.e., care based on theassessment and management of CVD risk factors).Accordingly, the present review evaluates thefollowing: the rationale for screening; the applicationof global risk factor algorithms for screening and theircomparison versus screening based on coronary ar-tery calcium (CAC) scanning; the rationale fordeveloping preventive imaging trials; a summary ofthe results from these trials; and the lessonslearned from these trials with respect to the future

ai Heart, and the Icahn School of Medicine at Mount

te, Murray, and the University of Utah School of

icine, Cedars-Sinai Medical Center and the Cedars-

part, by the Dr. Miriam and Sheldon G. Adelson

on. The authors have reported that they have no

Douglas, MD, served as the Guest Editor for this

ry 13, 2017, accepted January 19, 2017.

AB BR E V I A T I O N S

AND ACRONYM S

c-IMT = carotid intima-media

thickness

CAC = coronary artery calcium

CAD = coronary artery disease

CT = computed tomography

CTA = computed tomography

angiography

CVD = cardiovascular disease

FRS = Framingham Risk Score

LDL = low-density lipoprotein

MPI = myocardial perfusion

imaging

SPECT = single-photon

ion computed

J A C C : C A R D I O V A S C U L A R I M A G I N G , V O L . 1 0 , N O . 3 , 2 0 1 7 Rozanski et al.M A R C H 2 0 1 7 : 3 0 4 – 1 7 Primary Prevention of CVD

305

application of cardiac imaging for cardiac diseaseprevention.

THE RATIONALE FOR SCREENING

The imperative to screen for CVD is well recognized.Because the progression of atherosclerosis occursover decades, there is usually a long clinicallatency before cardiac symptoms, such as angina,emerge among individuals who have coronaryatherosclerosis. However, in approximately 40% to60% of cases, the first clinical manifestation ofCVD is either myocardial infarction or suddencardiac death (4). Thus, relying on the emergenceof clinical symptoms is not an effective or safemeans for preventing the morbidity and mortalitydue to CAD.

SEE PAGE 318

graphy

The rationale for applying screening that detectsCVD is based on the assumption that earlier identifi-cation of CVD through such screening methods willpermit the identification of disease in its subclinicalphase, thus providing an opportunity to institute riskfactor modification approaches before the develop-ment of more advanced disease and/or the occur-rence of adverse cardiac events. Risk factormodification includes lifestyle changes, such as indiet, exercise activity, sleep hygiene, and manage-ment of stress, as well as the use of medications tolower cholesterol levels, manage hypertension, andcontrol diabetes.

THE ADVENT OF GLOBAL ALGORITHMS TO

SCREEN FOR CVD

Clinical studies have established the presence of ahigh concentration of CVD risk factors among patientswho develop clinical disease. For instance, in theINTERHEART study, 9 potentially modifiable CVDrisk factors were found to provide >90% of thepopulation-attributable risk for myocardial infarction(5). Thus, interest has focused on developingglobal risk factor algorithms for prediction of CVD.In the 1990s, the Framingham Risk Score (FRS)was introduced as the first validated global algorithmfor predicting risk of CVD based on the CVD risk fac-tors that had been identified in the FraminghamHeart Study (6). This algorithm incorporated consid-eration of age, sex, low-density lipoprotein (LDL) andhigh-density lipoprotein cholesterol levels, bloodpressure measurements, presence/absence of dia-betes, and smoking status. Using this score, an initialstrategy for screening emerged, based on dividingsubjects into “low,” “intermediate,” and “high” risk

according to subjects’ 10-year risk of devel-oping clinical disease. Subjects with ahigh 10-year risk would merit aggressiverisk factor modification, whereas thosewith intermediate risk would require furthertesting to evaluate their risk status, basedon such measures as C-reactive protein,ankle–brachial index, ultrasound to assesscarotid intima-media thickness (c-IMT), orCAC scanning. Subsequently, various otherglobal risk factor algorithms have beendeveloped, such as the Systemic CoronaryRisk Evaluation, PROCAM, QRISK, the Rey-nolds Risk Score, and the Pooled CohortEquations.

LIMITATION OF GLOBAL RISK FACTOR

ALGORITHMS COMPARED WITH

CAC SCANNING

The reliance on global algorithms based on subjects’risk factors is limited because these algorithms do notestablish a diagnosis of CVD but rather provide aprobabilistic assessment of CVD likelihood accordingto group data. Moreover, global algorithms primarilyrely on measurement of current risk factor status anddo not consider magnitude or chronicity. In contrast,presence of CAC is a specific, direct marker for thepresence of coronary atherosclerosis in an individualpatient. CAC reflects the effects of the lifetime effectof all CVD risk factors. Although CAC does not detectall plaque, the magnitude of CAC has been shown tobe highly correlated with actual atheroscleroticplaque area in autopsied hearts (7).

Since the advent of CAC scanning, longitudinalstudies have repeatedly shown that the CAC score is apotent predictor of future cardiac events (8–10). Evenmild increases in the CAC score, in the range of 1 to 10,are sufficient to at least double the risk of adverseclinical events compared with subjects with zero CACscores (11,12). Other atherosclerotic screeningmethods are inferior by comparison. For instance, inan important analysis from the MESA (Multi-EthnicStudy of Atherosclerosis) study, Yeboah et al. (13)assessed 1,330 subjects who had an intermediate FRSand had 6 measurements of cardiac risk, includingankle–brachial index, brachial flow–mediated dila-tion, c-IMT, family history of premature CVD, highsensitivity C-reactive protein, and the CAC score. Thesubjects were followed up for a mean of 7.5 yearsfor the occurrence of incident CVD. Five of the6 screening measures provided no significantdiscrimination for the prediction of incident CVD(Figure 1). CAC, however, provided significant

emiss

tomo

FIGURE 1 Prediction of Incident Coronary Disease

Framingham Risk Score (FRS) alone (reference)

FRS plus coronary artery calcium

FRS plus carotid intima-media thickness

FRS plus brachial flow-mediated dilation

FRS plus C-reactive protein

FRS plus family history

FRS plus ankle-brachial index

Incident Coronary Heart Disease

Specificity

Sen

siti

vity

1-Specificity

1.0

1.0

0.8

0.8

0.6

0.6

0.4

0.4

0.2

0.2

0.0

0

1.0

0.8

0.6

0.4

0.2

0

Receiver-operating characteristic curves, comparing the area under the curve for incident

coronary artery disease among intermediate-risk subjects in the MESA (Multi-Ethnic

Study of Atherosclerosis) study. CAC ¼ coronary artery calcium. Reprinted with permis-

sion from Yeboah et al. (13).

Rozanski et al. J A C C : C A R D I O V A S C U L A R I M A G I N G , V O L . 1 0 , N O . 3 , 2 0 1 7

Primary Prevention of CVD M A R C H 2 0 1 7 : 3 0 4 – 1 7

306

discrimination versus all measures. The CAC scorealso provided a high degree of net reclassificationimprovement for the prediction of incident CAD inthis community cohort, compared with a low netreclassification improvement with the other5 screening modalities.

THE SYNERGISTIC ASSESSMENT OF

CVD RISK FACTORS AND CAC

The assessment of CVD risk factors and CAC scores arecomplementary. For instance, when subjects in theMESA study were assessed according to both their FRSand CAC score, a synergy was manifest between the 2in predicting incident CAD (14). Notably, the CACscore was a potent stratifier of risk among all FRSsubgroups, including the subjects with very low andwith high FRS values (Figure 2). Those subjects whohad a low FRS score but a CAC score $400 had a sub-stantially higher mortality rate versus patients who

had a high FRS but no evidence of CAC. An analysisperformed among a cohort of 44,052 asymptomaticpatients who were followed up for a mean of 5.6 � 2.6years for all-cause mortality had similar results (15).Thus, CAC scanning has the capacity to both comple-ment and substantially improve clinical risk predic-tion compared with assessment of CVD risk by usingrisk factor analysis alone.

THE RATIONALE FOR DEVELOPING IMAGING

TRIALS FOR CVD SCREENING

The diagnostic and prognostic efficacy of CAC scan-ning has now been repeatedly demonstrated over thelast decade (7–15). Had CAC scanning been introducedin an earlier era, such data would have led to its earlyand widespread adoption in clinical practice. How-ever, a reluctance to approve the use of CAC scanningby cardiac imaging bodies and third-party carriers isrooted in 2 important factors. The first factor waspractical in nature. CAC scanning was initially onlyperformed by using electron beam tomography, alimited and expensive modality that resulted in ahigh cost for performance of CAC scanning. Addi-tional barriers included a concern that the test wouldlead to an augmentation in downstream testing andto unnecessary radiation exposure in otherwise wellindividuals who could be assessed by using otherscreening approaches.

The second factor has proven to be more long-lasting. The introduction of CAC scanning coincidedwith the development of a new standard for assessingthe efficacy of cardiac imaging tests in general, asschematized in Figure 3. Until the turn of the century,cardiac imaging tests were largely assessed accordingto only 2 criteria: their ability to predict clinicalevents and their ability to provide incremental in-formation compared with more readily available andinexpensive clinical information—a standard of“prognostic efficacy.” However, in the early 2000s,cardiac imaging bodies and third-party carriers beganto adopt a new standard for emerging technologies:proof that these tests lead to a favorable impacton actual clinical outcomes—a new standard of“therapeutic efficacy.” A large driver of this newstandard was a rising concern for containing thegrowth of medical costs that followed a particularlymarked increase in the use of stress imaging modal-ities between 2000 and 2006 (16). Accordingly, thelast decade has seen the initiation of imagingtrials that attempt to meet this new mandate of“therapeutic” efficacy. These trials endeavor to showthat the use of new technologies lead to better clinicaloutcomes compared with usual care practices.

FIGURE 2 Synergy of Risk Predictors

35

30

25

20

15

10

5

0FRS 0 – 6% FRS 6 –10% FRS 10 – 20% FRS > 20%

CAC = 0 CAC 1-100 CAC 101-300 CAC > 300

Eve

nt

Rat

e P

er 1

000

Per

son

-yea

rs

1.13.8

9.1

20.5

1.6

4.1

11.6

15.3

3.5

8.8

15.2

30.4

2.5

15.4

22.1

33.1

Total cardiac event rates (per 1,000 person-years) according to CAC scores and Framingham Risk Score (FRS) category among 6,698

participants in the MESA study. Adapted with permission from Silverman et al. (14). Abbreviations as in Figure 1.

J A C C : C A R D I O V A S C U L A R I M A G I N G , V O L . 1 0 , N O . 3 , 2 0 1 7 Rozanski et al.M A R C H 2 0 1 7 : 3 0 4 – 1 7 Primary Prevention of CVD

307

THE IMAGING TRIALS FOR PREVENTION

The imaging trials for prevention of CVD have beendesigned to test the hypothesis that combining con-ventional risk factor management with an imaging

FIGURE 3 Old Versus New Standards for Evaluating Test Efficacy

Traditional Perspective

DemonstratePrognostic

Efficacy

Current Perspective

DemonstrateTherapeutic

Efficacy

Traditionally, the efficacy of cardiac tests was assessed solely according t

clinical events). A standard of therapeutic efficacy has now been widely

clinical outcomes.

modality that can directly or indirectly assess thepresence of CVD will lead to better clinical outcomescompared with usual preventive care without imag-ing. To date, only 5 trials have been conducted,varying in their use of imaging modalities and in their

PREDICTS adverseclinical events?

Provides incrementalprognostic information?

REDUCES adverseclinical events?

Provides incrementalcost-effectiveness?

o a test’s prognostic efficacy (i.e., the test’s ability to predict adverse

adopted, which also assesses the impact of a test upon subsequent

TABLE

1Su

mmar

yof

Primar

yEn

dpoint

Find

ingsFr

omIm

agingRCT

sin

Primar

yPre

vent

ion

Ran

domization

No.:To

talan

dby

Arm

Interv

ention

Details

Dur

ationof

Follow

-Up

Major

Endp

oint

Res

ults

DIAD

trial

Stress

MPI

vs.stan

dard

care

inpa

tien

tswithtype

2diab

etes

mellitus

1:1rand

omization(N

¼1,123)

Stress

MPI

(n¼

561)

vs.u

sual

care

(n¼

562)

After

screen

ingMPI,furthe

rcare

perph

ysician

preferen

ce

4.8yrs

Cardiacde

athor

MI

HR:0.88

95%

CI:0.44–

1.88

p¼

0.73

St.Fran

cisHea

rtstud

yRxwithstatinsan

dan

tiox

idan

tsvs.usua

lcare

insubjects

with

CACscore>80th

percen

tile

1:1rand

omization(N

¼1,005)

Rxgrou

p(n

¼49

0)

Usual

care

(n¼

515)

TheRxgrou

preceived

20-m

gatorva

statin

andvitamins

Can

dE

4.3yrs

MI,stroke

,reva

scularization,

andpe

riphe

ral

vascular

surgery

33%

redu

ctionin

total

even

tsp¼

0.07

PACC

trial

CACscreen

ingvs.usua

lcare

insettingof

ICM

orno

t2�

2rand

omization(n

¼45

0)

CACresultsprov

ided

orno

tan

dICM

prov

ided

orno

t

After

CACscan

ning

,on

e-ha

lfreceived

ICM

andon

e-ha

lfha

dusua

lcare

1yr

Chan

gein

CAD

riskprofi

les

Nodifferen

cein

FRSin

scan

grou

p

EISN

ERtrial

CACscreen

ingvs.usua

lcare

2:1rand

omization(N

¼2,137)

CACscreen

ing(n

¼1,42

4)Usual

care

(n¼

713)

After

CACscan

,en

hanc

edco

unselin

gwas

performed

4yrs

Chan

gein

CAD

riskprofi

les

at4yrs

Med

ical

costs

Lower

FRSin

scan

grou

p(p

¼0.003);simila

rco

stsin

both

grou

ps

FACT

OR-6

4trial

Corona

ryCT

Avs.usua

lcare

intype

1or

2diab

etes

mellitus

1:1rand

omization(n

¼900)

Corona

ryCT

A(n

¼45

2)vs.

Usual

care

(n¼

562)

After

screen

ingco

rona

ryCT

A,

furthe

rcare

was

protoc

oldirected

4yrs

All-causede

ath,

MI,or

UAP

HR:0.80

95%

CI:0.49–1.32

p¼

0.38

CAC¼

corona

ryartery

calcium;C

AD¼

corona

ryartery

disease;

CI¼

confi

denc

einterval;C

TA¼

compu

tedtomog

raph

yan

giog

raph

y;DIAD¼

Diagn

osticIm

agingin

Asymptom

atic

Diabe

tics;E

ISNER

¼Ea

rlyIden

tification

ofSu

bclin

ical

Atherosclerosisby

Non

inva

sive

Imag

ingResea

rch;

FRS¼

Fram

ingh

amRiskScore;

HR¼

hazard

ratio;

ICM

¼intensivecase

man

agem

ent;MI¼

myo

cardialinfarction;

MPI

¼myo

cardialp

erfusion

imag

ing;

PACC

¼Prospe

ctiveArm

yCo

rona

ryCa

lcium;R

CT¼

rand

omized

controlle

dtrial;Rx¼

trea

tmen

t;UAP¼

unstab

lean

gina

.

Rozanski et al. J A C C : C A R D I O V A S C U L A R I M A G I N G , V O L . 1 0 , N O . 3 , 2 0 1 7

Primary Prevention of CVD M A R C H 2 0 1 7 : 3 0 4 – 1 7

308

basic study design. Only 1 trial has involved cardiacstress imaging, and the other 4 have involvedanatomic imaging of the coronary arteries, including3 trials that assessed the use of CAC scanning and 1that assessed the use of coronary computed tomog-raphy angiography (CTA). The principal findings ofthese 5 trials are summarized in Table 1 and discussedin the following text.

THE DIAGNOSTIC IMAGING IN ASYMPTOMATIC

DIABETICS TRIAL. The DIAD (Diagnostic Imaging inAsymptomatic Diabetics) trial (17) was designed toevaluate whether the screening of patients with type2 diabetes by using single-photon emission computedtomography (SPECT) myocardial perfusion imaging(MPI) could improve the detection of high-risk pa-tients deserving of more aggressive medical man-agement and thereby lead to a reduction in adversecardiac events among patients with diabetes. Theparticipants were 1,123 individuals with type 2 dia-betes and no symptoms of CVD who were randomizedto undergo screening with SPECT-MPI or to usualmedical management. Participants were followed upfor an average of 4.8 years for the occurrence of car-diac death or nonfatal myocardial infarction. Overall,there was no significant difference in clinical out-comes in the 2 groups. However, the overall eventrates were low: 3.0% in the usual care group and 2.7%in the SPECT-MPI group, with an overall annualizedevent rate of only 0.6% per year for the entire cohort.

Another important limitation of this trial was thelow frequency of ischemia in the population withdiabetes (17). Among the 522 subjects who were ran-domized to undergo SPECT-MPI, only 33 (6%) hadmoderate to large size perfusion defects, and another50 (10%) had small perfusion defects. Of note, thediscriminatory ability of SPECT-MPI to predict eventswas still retained in this low-risk population.Although the cardiac event rate was only 2% in thenormal SPECT-MPI group and in the small defect sizegroup, the event rate was 12% among those withmoderate to severe defects.

THE St. FRANCIS HEART STUDY. The purpose of theSt. Francis Heart Study was to determine if a trialdesigned to assess high clinical risk based on an initialCAC scan, followed by aggressive treatment withlipid-lowering and antioxidant therapy, could retardthe progression of CAC score abnormality during se-rial scanning and reduce the occurrence of CVDevents during follow-up (18). Events for this studyincluded coronary death, nonfatal myocardialinfarction, stroke, myocardial revascularization, andperipheral vascular surgery. The study participantswere initially obtained from the analysis of 5,582 men

FIGURE 4 Outcomes in the St. Francis Heart Study

1.00

0.95

0.90

0.85

0.80

0.750 1 2 3 4 5

Treatment (n) 414734094

Control (n) 714554515

Years of Follow Up

Pro

bab

ility

of

Rem

ain

ing

Eve

nt

Fre

e

Control

p = 0.08

Treatment

Kaplan-Meier survival curves for cardiovascular events in the subjects who underwent treatment with atorvastatin and vitamin E (treatment)

versus those in the control arm of the St. Francis Heart Study. Reprinted with permission from Young et al. (17).

J A C C : C A R D I O V A S C U L A R I M A G I N G , V O L . 1 0 , N O . 3 , 2 0 1 7 Rozanski et al.M A R C H 2 0 1 7 : 3 0 4 – 1 7 Primary Prevention of CVD

309

and women who were free of clinical CVD whounderwent CAC scanning at St. Francis Hospital. In-dividuals with a CAC score above the 80th percentilefor age and sex and who met other eligibility re-quirements were recruited, resulting in a final pool of1,005 subjects. These individuals were then random-ized in double-blind fashion to receive placebo or to atreatment group who received a combination ofatorvastatin (20 mg/day) and vitamins C and E, andthen followed up for a mean of 4.3 years. Within thetreatment group, there was a 43% reduction in LDLcholesterol level and a 17% reduction in triglyceridelevel at 6 weeks. The treatment regimen had no effecton retarding CAC score progression during serialscanning. A reduction in cardiac events was notedduring the follow-up period in the treatment group(Figure 4), but the difference did not reach statisticalsignificance.

In a post hoc analysis, treatment significantlyreduced CVD events among the patients with baselineCAC scores >400. Although interesting, this studywas underpowered for assessing its major hypothe-ses. Moreover, the very design of the study is notrelevant for assessing the central question of whethera strategy of CAC scanning reduces clinical eventscompared with usual medical care without CACscanning.

THE PROSPECTIVE ARMY CORONARY CALCIUM

TRIAL. The PACC (Prospective Army Coronary Cal-cium) trial was designed to assess the impact of CACscanning on the management of CVD risk factors (19).The study was a randomized controlled trial with a2 � 2 factorial design to assess the impact of per-forming CAC scanning (vs. “no scanning”) as well asthe impact of intensive case management (vs. usualcare management). The no-scan group actually didundergo CAC scanning, but the results were withhelduntil the end of the trial. The study included 450recruited active army personnel between the ages of39 and 45 years who had no history of heart disease.The primary clinical endpoint was change in FRS at1 year. Those assigned to active case management hadintense follow-up by a nurse and dietitian, withfollow-up contact through telephone, mail, or clinicalvisit at 2, 4, 8, 12, and 24 weeks. At the end of 1 year,there was no difference in the FRS among the subjectswho had been assigned to knowledge of their CACscan results or not. By contrast, the mean absolutechange in FRS was more favorable in the subjectsassigned to intensive case management versus usualcare (–0.06 vs. 0.74; p ¼ 0.003).

Although the use of CAC alone was not associatedwith improvement in cardiac risk factor status in thisstudy, the study was severely limited in its ability to

FIGURE 5 Design of the EISNER Trial

2,137 volunteers with RFs,but no clinical disease

Scan group(n = 1,424)

No scan group(n = 713)

Randomized in 2:1 ratio

One time risk factorconsultation

One time RF consultationincluding CAC scan result

tisiV cinilC raeY 4tisiV cinilC raeY 4

Summary of randomization and subject disposition in the EISNER (Early Identification of

Subclinical Atherosclerosis by Noninvasive Imaging Research) trial. Subjects were

randomized into no-scan versus coronary artery calcium (CAC) scan groups before

receiving risk factor (RF) consultation at baseline, and they were then reassessed at a

4-year clinic visit.

Rozanski et al. J A C C : C A R D I O V A S C U L A R I M A G I N G , V O L . 1 0 , N O . 3 , 2 0 1 7

Primary Prevention of CVD M A R C H 2 0 1 7 : 3 0 4 – 1 7

310

adequately assess this issue (19). This limitationoccurred because the application of CAC scanning inthis very young, low-risk population (mean age 42years) resulted in 85% having a zero CAC score in thescanning arm subjects. Thus, the very low prevalenceof CAC abnormality in this trial precluded the po-tential to adequately assess the potential motiva-tional influence of CAC scanning on clinicalmanagement. In a subsequent 6-year follow-up ofinitial subjects in the PACC trial, a progressive in-crease in the use of statin therapy and aspirin wasnoted among the subjects who had CAC on baselinescanning (20).

THE EARLY IDENTIFICATION OF SUBCLINICAL

ATHEROSCLEROSIS BY NONINVASIVE IMAGING

RESEARCH TRIAL. The EISNER (Early Identificationof Subclinical Atherosclerosis by Noninvasive Imag-ing Research) trial was also a prospective randomizedimaging study that was designed to determine theimpact of CAC scanning on CVD risk factors (21). Un-like the PACC trial, this study did not involve activecase management, and the follow-up period was 4years rather than 1 year. Importantly, an older pop-ulation with baseline risk factors was recruited,resulting in a study population with a 52% prevalenceof CAC abnormality, which is considerably greaterthan the low prevalence noted in the PACC study (19).The study population of 2,137 middle-aged volunteers

was randomized in a 2:1 fashion into either a groupthat received CAC scanning (scan group) or one thatdid not (no-scan group) (Figure 5). A standard riskfactor counseling session was conducted by a nursepractitioner in both groups, but the scan group wasalso counseled based on the results of their CAC scanresults. Evaluation of cardiac risk factors, includingserum measurements, and analysis of subjects’ FRSwere assessed both at baseline and then at a returnvisit at 4 years. Compared with the no-scan group, thescan group exhibited a net favorable change in sys-tolic blood pressure, LDL cholesterol level, and waistcircumference for those with increased abdominalgirth. Although the FRS rose in the no-scan group, itdid not rise in the scan group at the 4-year follow-up.Within the scan group, increasing baseline CAC scoreswere associated with a dose–response improvementin systolic and diastolic blood pressures, LDLcholesterol level, and FRS driven by a proportionallygreater use of statins and other medications withincreasing baseline CAC scores.

The EISNER trial was not powered to assess theimpact of CAC scanning on cardiac events (21). As inthe other trials reviewed in asymptomatic cohorts,the frequency of cardiac events was very low in thistrial and not significantly different in the scan and no-scan groups. The study had 2 important limitations.First, counseling was limited to just a singleencounter with the nurse practitioner at the start ofthe imaging trial, with no provision for follow-upcounseling or feedback. Second, due to restraintsimposed by the institutional review board, the resultsof the CAC scan were only conveyed to the studyparticipants but not to their physicians. Both limita-tions may have reduced the potential impact of CACscanning on subsequent health behaviors and medi-cal treatment.

THE FACTOR-64 STUDY. As with CAC scanning, thenoninvasive assessment of the extent and severity ofcoronary atherosclerosis on coronary CTA has beenshown to be a proportional predictor of futureadverse cardiovascular events. While primarilypromulgated as a test to be used in clinical patientpopulations, the FACTOR-64 study was designed toevaluate the use of coronary CTA for the primaryprevention of CVD (22). This trial randomized 900patients with type 1 or type 2 diabetes of at least 3 to5 years’ duration and without symptoms of CVD toreceive either standard national guidelines–basedoptimal diabetes care (n ¼ 448) or to initial screeningwith coronary CTA (n ¼ 452). In the latter group,subjects identified as having CAD were recommendedto undergo a protocol of more aggressive medical

FIGURE 6 Diabetes Management in the FACTOR-64 Trial

HbA1c < 7%LDL Chol < 100 mg/dl

Systolic BP < 130 mm Hg

HbA1c < 6%LDL Chol < 70 mg/dl

Systolic BP < 120 mm HgHDL Chol > 40 or 50 mg/dl (F/M)

Triglycerides < 150 mg/dl

Standarddiabetes

management

Aggressivediabetes

management

Medical targets for diabetes management

Patients with diabetes in the FACTOR-64 trial were eligible to receive either proscribed

standard versus proscribed aggressive diabetes management, as shown, based on the

results of baseline coronary computed tomography angiography. BP ¼ blood pressure;

Chol ¼ cholesterol; F ¼ female; HbA1C ¼ glycosylated hemoglobin; HDL ¼ high-density

lipoprotein; LDL ¼ low-density lipoprotein; M ¼ male.

J A C C : C A R D I O V A S C U L A R I M A G I N G , V O L . 1 0 , N O . 3 , 2 0 1 7 Rozanski et al.M A R C H 2 0 1 7 : 3 0 4 – 1 7 Primary Prevention of CVD

311

management (Figure 6) and were considered as can-didates for coronary revascularization if clinicallyjustified according to the results of further noninva-sive or invasive coronary evaluation. Patients werefollowed up for an average of 4 years with a primarycomposite outcome of all-cause mortality, nonfatalmyocardial infarction, or unstable angina requiringhospitalization. Of the 452 patients randomized toscreening, 395 actually underwent coronary CTA. Ofthese, a total of 277 (70.1%) were identified as havingsufficient CAD to recommend aggressive medicaltherapy. Screening with CTA resulted in a significantincrease in the incidence of coronary revasculariza-tion (8.9% vs. 3.1%; p ¼ 0.05). As in the DIAD (17) andSt. Francis (18) trials, the primary outcome eventrates were significantly less than predicted and didnot differ significantly between the CTA and thecontrol groups (6.2% vs. 7.6%; p ¼ 0.38). However, asseen in Figure 7, there was a divergence in the eventcurves after 3 years of follow-up, suggesting thatadditional follow-up might be of interest in this studypopulation.

LESSONS LEARNED

Despite the disparate design and goals of the 5 im-aging trials from prevention, there are common les-sons learned from these trials that could help shapethe future use of imaging for prevention. We nextexamine a number of issues in this regard, includingthe issue of trial size, duration of follow-up, theproblem posed by the growing ubiquity of aggressivemedical management, and insights into the preferredimaging modalities for imaging-guided prevention.

STATISTICAL POWER FOR PREVENTION TRIALS. Theimaging-guided prevention trials for CVD that soughtto assess hard outcomes, such as the DIAD (17) andFACTOR-64 (22) trial, were substantially underpow-ered. This problem has also affected the utility ofother recent trials in even large clinical patient sam-ples, such as the PROMISE (Prospective MulticenterImaging Study for Evaluation of Chest Pain) trial,which compared coronary CTA versus stress imaging–guided medical therapy in 10,003 patients with chestpain (23). A primary cause for this lack of power hasbeen the major “taming” of CVD that has occurredover recent decades. Not only has the CVD mortalityrate dropped by approximately 70% since the 1970s(1) but so have all the major comorbidities associatedwith CVD. These include a decline in the prevalenceand severity of myocardial infarction (24,25), stroke(26), peripheral vascular disease (27), office visitsfor angina (28), and even the frequency ofinducible ischemia among patients being evaluated

for CVD (29). Consequently, future imaging-guidedtrials for CVD prevention must correctly assesssample sizes according to the current low levels ofCVD events in general populations. An illustrativeexample is the MASS (Multicentre AneurysmScreening Study) trial, which was developed to assessthe utility for screening for abdominal aortic aneu-rysm (30). This trial was successful because itcorrectly considered the very low prevalence ofruptured abdominal aortic aneurysm in the generalpopulation and consequently anticipated the need fora large enrollment of subjects. To achieve the trial’sgoal of obtaining a statistical difference with ananticipated 30% reduction in death from rupturedaneurysm in the scanned group, a need to recruit66,000 men was anticipated and then recruited.

DURATION OF FOLLOW-UP. A related issue is theduration of follow-up in trials for primary prevention.In 4 of 5 imaging trials for prevention, the durationof follow-up was <5 years, and in the fifth study,follow-up was only 1 year. Due to the now very lowfrequency of cardiac events in the asymptomaticmiddle-aged individuals in whom screening may bemost pertinent, an effective imaging prevention trialwould likely require considerably longer follow-uptimes than required before now. The latter point isillustrated in a study by Chang et al. (31), whichinvolved the follow-up of patients who were referredfor stress/rest SPECT-MPI and who underwent

FIGURE 7 Results of the FACTOR-64 Trial

14

12

10

8

6

4

2

0

0 1 2 3 4 5 6

Exp

erie

nci

ng

Eve

nt

(%)

Years of Follow-up

Cox P value = 0.38

No Coronary CTA

Coronary CTA

Primary Intention-to-treat Analysis of MACE

Number at riskNo Coronary

CTA 447 440 369 289 203 144 76

Coronary CTA

No Coronary CTACoronary CTA 452 449 374 289 215 151 80

14

12

10

8

6

4

2

0

0 1 2 3 4 5 6

Exp

erie

nci

ng

Eve

nt

(%)

Years of Follow-up

Cox P value = 0.16

No Coronary CTA

As-treated Analysis of MACE

Number at risk

504 496 413 324 231 161 88

395 393 330 254 187 134 68

Coronary CTA

Kaplan-Meier event survival curves for the occurrence of major adverse cardiovascular events (MACE) among the subjects in the coronary computed tomography

angiography (CTA) arm and the no–coronary CTA arm of the FACTOR-64 trial. Reprinted with permission from Muhlestein et al. (22).

Rozanski et al. J A C C : C A R D I O V A S C U L A R I M A G I N G , V O L . 1 0 , N O . 3 , 2 0 1 7

Primary Prevention of CVD M A R C H 2 0 1 7 : 3 0 4 – 1 7

312

concomitant CAC scanning. The inflection point forobserving a separation in clinical events among thosepatients who had a CAC abnormality versus thosepatients who did not was approximately 5.6 years inthis clinical population of patients undergoingradionuclide stress testing. This outcome suggeststhat even a longer follow-up period would berequired in screening populations.

THE GROWING UBIQUITY OF AGGRESSIVE MEDICAL

THERAPY. The ubiquity of cardiac risk factors in thegeneral population, coupled with the growing ten-dency to treat these risk factors aggressively onceindividuals meet physicians, has the potential toblur therapeutic differences in the usual care versusimaging arms of trials for CVD prevention. Forexample, the occurrence of aggressive medicalmanagement within both randomized arms of theDIAD study (17) resulted in a similar increased useof lipid-lowering, antihypertensive, and diabeticmedications, as well as the use of aspirin in botharms of the trial. Similarly, even though a distinctlymore aggressive medical management protocol wasinstituted for the patients with diabetes withabnormal CTA studies in the FACTOR-64 trial (22),the subjects in both arms of the study were

managed aggressively, and the only significant dif-ference in treatment targets reached between theFACTOR-64 subgroups was a modest improvementin high-density lipoprotein cholesterol level amongpatients randomized for CTA screening. This blur-ring of medical therapy represents a major obstacletoward the effective design of future imaging trialsfor prevention.

CHOICE OF IMAGING MODALITIES. The imaging tri-als for prevention used a variety of imagingapproaches, including SPECT-MPI, CAC scanning, andCTA angiography. Because of the potential costsassociated with any further imaging trials, developinga consensus around an optimal imaging strategywould be preferable. Among imaging modalities,cardiac stress tests (whether using stress electrocar-diography or advanced imaging) have the least appealbecause of an important “Achilles heel” with respectto screening: because these tests rely on the presenceof hemodynamically significant coronary stenosis,they are poor tests for detecting subclinical athero-sclerosis. This limitation is well illustrated fromstudies that have examined the presence andmagnitude of CAC abnormalities among patients un-dergoing stress/rest SPECT-MPI. Among patients with

FIGURE 8 CAC Scores Among Nonischemic Patients

lateeHlatenamreBDistribution ofCAC Scores

%1116% 0

1-9

10-99

100-399

400-999

%63%

%3217%

26% 39%

%32%73

Distribution of CAC scores among patients with normal stress-rest myocardial perfusion single-photon emission computed tomography tests

in 2 studies. Only a small percentage of patients had zero coronary artery calcium (CAC) scores. By contrast, moderate to severe CAC scores

were commonplace.

J A C C : C A R D I O V A S C U L A R I M A G I N G , V O L . 1 0 , N O . 3 , 2 0 1 7 Rozanski et al.M A R C H 2 0 1 7 : 3 0 4 – 1 7 Primary Prevention of CVD

313

normal SPECT-MPI findings, the presence of a CACabnormality is not only very common, but inapproximately one-quarter or more of patients, theextent of the CAC abnormality may be severe (scores>400), as illustrated in Figure 8 (32,33).

By contrast, CAC has strong appeal as a screeningmodality for reasons that have been discussed earlierin this review. The presence of CAC is both a sensitiveand specific indicator of atherosclerosis, while thetotal CAC score is a strong predictor of both short- andlong-term clinical outcomes. A zero CAC score hasbecome the most definitive predictor of low risk, mildCAC score elevations are indicators for initiatingoptimal prevention strategies, and high CAC scoresmay indicate the need for more aggressive manage-ment and follow-up. Furthermore, the test hasbecome inexpensive and, with current imaging tech-nologies, is associated with radiation exposure thathas decreased to 1.0 to 1.5 mSv per study and to evenlower radiation exposure with the newer low-doseimaging protocols (34).

A third imaging technique, coronary CTA, wasused in the FACTOR-64 trial (22). This test offers theadvantage of characterizing luminal stenosis andassessing both the presence and extent of calcifiedand noncalcified plaque. However, CAC scanning stillcharacterizes the anatomic burden of atherosclerosisand provides a single integrated global measurement(i.e., the CAC score) that is simple to understand andwhich can be converted into useful percentile scores.These characteristics make this modality easy to use

in clinical practice. Moreover, because CAC scanningis considerably less expensive than coronary CTA,the burden of proof requires efficacy studies todetermine whether coronary CTA would save morelives than the performance of CAC scanning inscreening cohorts. Of note, Cho et al. (35) found noadded incremental prognostic information with cor-onary CTA once the CAC score was consideredamong asymptomatic patients within the CONFIRM(Coronary CT Angiography Evaluation for ClinicalOutcomes International Multicenter) registry.Accordingly, until there is a randomized trialshowing otherwise, CAC scanning seems to be thepreferred screening strategy versus CTA whenapplied for screening populations.

Another potential imaging strategy is the use ofvascular ultrasound. This use is based on the under-standing that atherosclerosis is a systemic diseasethat tends to affect multiple vascular territories. Anindirect ultrasound method for this assessment hasinvolved the measurement of c-IMT. However, theapplication of c-IMT has been associated with mixedclinical results, and the technique has less prognosticefficacy than CAC scanning (36–39). However, newerultrasound approaches offer the potential forenhanced detection of subclinical atherosclerosis.One approach involves the use of 3-dimensional ca-rotid ultrasound to characterize carotid plaqueburden. Findings from the BioImage Study found thatmeasurement of carotid plaque burden was morestrongly correlated with CAC scores than was c-IMT

FIGURE 9 Impact of CAC Scores on Subsequent Cardiac Management

40%

30%

20%

10%

StressTests

CardiacCT

CarotidUltrasound

Cath Revasc

P = ns for all

34 35

7 8

1413

3 32 2

No scan group(n = 713)

Scan group(n = 631)

Comparison of the frequency of downstream testing at 4-year follow-up among the subjects randomized to the scan versus no-scan groups in

the EISNER trial. CT ¼ computed tomography; Cath ¼ catheterization; Revasc ¼ revascularization; other abbreviations as in Figure 5.

FIGURE 10 Impact

$3,6

$10,000

Med

ian

Co

sts

Percent ofCAC Scan Cohort

Median medical cost

scanning in the EISN

particularly in the sub

the median medical

Rozanski et al. J A C C : C A R D I O V A S C U L A R I M A G I N G , V O L . 1 0 , N O . 3 , 2 0 1 7

Primary Prevention of CVD M A R C H 2 0 1 7 : 3 0 4 – 1 7

314

(40), and in a 2.7-year follow-up of 5,808 individualsfrom this study, carotid plaque burden was compa-rable to CAC scanning in predicting adverse cardiacevents (41). Another new ultrasound approach toward

of CAC Scanning on Subsequent Medical Costs

CAC ≤ 0(n = 631)

1 – 99(n = 400)

100 – 399(n = 171)

≥ 400(n = 109)

49

$2,623

$4,394

$4,900

$9,309

48% 31% 13% 8%

s incurred during 4-year follow-up in the subjects undergoing CAC

ER trial. Costs increased among subjects with higher CAC scores,

group with CAC scores >400. The dotted horizontal line represents

costs in the no-scan group. Abbreviations as in Figure 5.

screening involves the use of femoral ultrasound forcharacterizing plaques in this vascular bed. The Ara-gon Workers’ Health Study compared the frequencyof plaques that were detected by using femoral andcarotid ultrasound and by CAC scanning (42). Of these3 assessments, ultrasound of the femoral arteriesrevealed the highest prevalence of plaque detection.Similarly, the Progression of Early AtherosclerosisStudy revealed a higher frequency of plaque detec-tion by femoral versus carotid ultrasound (43). Thus,on the basis of these findings, further study toexamine the clinical efficacy of femoral atheroscle-rosis for screening purposes would seem to beindicated.

ALTERNATIVE MEASURES OF

THERAPEUTIC EFFECTIVENESS

Because of the very low event rate in current imagingpopulations, the long duration of follow-up thatwould be required, and the growing ubiquity ofaggressive medical management in general, devel-oping prospective imaging trials for prevention thatwould be based on hard clinical events may beincreasingly impractical. However, a variety of inter-mediate endpoints may be suitable for study insmaller trials. This approach could include examina-tion of whether imaging-guided medical therapyleads to improved health behaviors, reduced risk

J A C C : C A R D I O V A S C U L A R I M A G I N G , V O L . 1 0 , N O . 3 , 2 0 1 7 Rozanski et al.M A R C H 2 0 1 7 : 3 0 4 – 1 7 Primary Prevention of CVD

315

factor profiles, and more informed decisionsregarding medication use. In this regard, a recentsystematic review found that CAC screeningenhanced medication adherence in nearly 90% ofpublished reports, including 3 randomized trials and12 observational studies. (44).

GUIDING THE INTENSITY OF MEDICAL THERAPIES. Ithas been suggested that the use of CAC scanningmight be studied for its ability to downscale therapy(e.g., aspirin or statin use) in selected patients whenthe risk defined after CAC assessment is seen to belower than the risk determined by using global riskalgorithms (45,46). This proposal is based on therecognition that patients with a zero CAC score havean extremely low risk of cardiovascular events (8–12).However, the development of a clinical trial to testthis point might be problematic due to the largenumber of subjects that may need to be recruited toconduct such a trial with adequate power.

IMPROVING THE COST-EFFECTIVENESS OF PREVENTION

CARE. Another potential endpoint of future trialscould be assessment of the overall cost-effectivenessof preventive management based on usual careversus imaging-guided preventive care. This endpointwould include assessment of incurred downstreammedical resource utilization and medical costs, andtheir relationship to changes in CVD risk factors andother clinical parameters. This endpoint has becomeincreasingly relevant in light of the growing high costsof cardiovascular health care. Notably, the examina-tion of these endpoints was an important secondarygoal of the EISNER trial (21). In contrast to initialconcerns that CAC scanning would lead to increaseddownstream testing, no increase in downstreamtesting was observed in subjects assigned to CACscan–guided management in this trial (Figure 9). Inaddition, overall medical costs at 4 years were com-parable in the CAC scan and no-scan groups of thistrial. The reason for this nondifference is shown inFigure 10. Overall, medical costs increased withincreasing CAC score, rising sharply among those pa-tients with CAC scores >400. However, comparedwith the mean medical costs in the no-scan group($3,649), the incurred medical costs in those scannedpatients with zero CAC scores were approximately$1,000 lower. Because the subjects with zero CACscores constituted 48% of the scan population,whereas the subjects with CAC scores >400 onlyconstituted 8% of the population, the net effect wasno difference in costs compared with the no-scangroup. These results are significant when one con-siders what might be desired for an “ideal” screeningtest: the correct identification of a large group of

low-risk patients in whom subsequent medical costsmight be decreased and the correct identification of asmall group at high risk in whom increased costs arejustified.

CONCLUSIONS

Screening asymptomatic individuals for importantdisease states such as breast, colon, and lung cancerand abdominal aneurysms has gained tractionbecause screening for such occult disease states cansave lives. By comparison, the mortality andmorbidity from CVD dwarf these disease states inprevalence, but a consensus approach towardscreening has remained elusive.

The most commonplace approach towardscreening for CAD has involved the use of global al-gorithms, such as the FRS or, more recently, thePooled Cohort Equations. These algorithms incorpo-rate most of the essential risk information that mustbe addressed for prevention and they provide usefulprognostic information, but ample data have nowshown that these algorithms are limited in theirability to predict the presence of underlying athero-sclerosis. Thus, there is growing interest in usingimaging modalities that assess atherosclerosis forscreening purposes.

Over the last 15 years, a large body of data hasconclusively shown that CAC scanning is superior toglobal risk factor algorithms for predicting adverseclinical outcomes in asymptomatic populations. By astandard of “prognostic efficacy,” this approachshould have led to widespread use of CAC scanningfor screening purposes. However, tests today areevaluated according to a standard of “therapeuticefficacy”: their ability to alter clinical outcomes (forwhich clinical trials are desired).

To date, 5 imaging trials for prevention have beenconducted, but they were underpowered to assesshard clinical events. Developing future imaging trialsto look at hard endpoints are unlikely due to the size,duration, and cost that such trials would require anddue to the complexity that is introduced due to thegrowing ubiquity of aggressive medical therapies insubjects with CVD risk factors. However, smaller tri-als designed to assess the impact of imaging-guidedtherapies on the overall cost-effectiveness of pre-ventive care could be conducted (as was performed inthe EISNER trial [21]).

On a practical basis, both CAC scanning and ultra-sound could be used for screening assessments, butCAC scanning might be particularly attractive in thisregard due to its ease of acquisition, low cost, andradiation exposure; its proven ability to predict both

Rozanski et al. J A C C : C A R D I O V A S C U L A R I M A G I N G , V O L . 1 0 , N O . 3 , 2 0 1 7

Primary Prevention of CVD M A R C H 2 0 1 7 : 3 0 4 – 1 7

316

short- and long-term risk; and the widespread andease of understanding the “CAC score” by clinicians(i.e., a single score that conveniently reflects theoverall burden of coronary atherosclerosis). CACscanning may also be beneficial because of its addi-tional ability to ascertain which asymptomatic pa-tients may benefit from subsequent stress testing dueto the correlation between the magnitude of CAC

abnormality and the likelihood of inducible myocar-dial ischemia.

ADDRESS FOR CORRESPONDENCE: Dr. AlanRozanski, Division of Cardiology, Mount SinaiSt. Luke’s Hospital, 1111 Amsterdam Avenue,New York, New York 10025. E-mail: alan.rozanski@mountsinai.org.

RE F E RENCE S

1. Ma J, Ward EM, Siegel RL, Jemal A. Temporaltrends in mortality in the United States, 1969-2013. JAMA 2015;314:1731–9.

2. Mozaffarian D, Benjamin EJ, Go As, et al. Heartdisease and stroke statistics—2016 update: areport from the American Heart Association.Circulation 2016;133:e38–360.

3. Heidenreich PA, Trogdon JG, Khavjou OA, et al.Forecasting the future of cardiovascular disease inthe United States: a policy statement from theAmerican Heart Association. Circulation 2011;123:933–44.

4. Kannel WB, Schatzkin A. Sudden death: lessonsfrom subsets in population studies. J Am CollCardiol 1985;5:141B–9B.

5. Yusuf S, Hawken S, Ounpuu S, et al. Effect ofpotentially modifiable risk factors associated withmyocardial infarction in 52 countries (the INTER-HEART study): case-control study. Lancet 2004;364:937–52.

6. Wilson PW, D’Agostino RB, Levy D, et al. Pre-diction of coronary heart disease using risk factorcategories. Circulation 1998;97:1837–47.

7. Rumberger JA, Simons DB, Fitzpatrick LA,Sheedy PF, Schwartz RS. Coronary artery calciumarea by electron-beam computed tomography andcoronary atherosclerotic plaque area. A histo-pathologic correlative study. Circulation 1995;92:2157–62.

8. Budoff MJ, Shaw LJ, Liu ST, et al. Long-termprognosis associated with coronary calcification:observations from a registry of 25,253 patients.J Am Coll Cardiol 2007;49:1860–70.

9. Detrano R, Guerci AD, Carr JJ, et al. Coronarycalcium as a predictor of coronary events in fourracial or ethnic groups. N Engl J Med 2008;358:1336–45.

10. Polonsky TS, McClelland RL, Jorgensen NW,et al. Coronary artery calcium score and risk clas-sification for coronary heart disease prediction.JAMA 2010;303:1610–6.

11. Budoff MJ, McClelland R, Nasir K, et al. Car-diovascular events with absent or minimalcoronary calcification: the Multi-Ethnic Study ofAtherosclerosis (MESA). Am Heart J 2009;158:554.

12. Blaha M, Budoff MJ, Shaw LJ, et al. Absence ofcoronary artery calcification and all-cause mor-tality. J Am Coll Cardiol Img 2009;2:692–700.

13. Yeboah J, McClelland RL, Polonsky TS, et al.Comparison of novel risk markers for improvement

in cardiovascular risk assessment in intermediate-risk individuals. JAMA 2012;308:788–95.

14. Silverman MG, Blaha MJ, Krumholz HM, et al.Impact of coronary artery calcium on coronaryheart disease events in individuals at the extremesof traditional risk factor burden: the Multi-EthnicStudy of Atherosclerosis. Eur Heart J 2014;35:2232–41.

15. Nasir K, Rubin J, Blaha MJ, et al. Interplay ofcoronary artery calcification and traditional riskfactors for the prediction of all-cause mortality inasymptomatic individuals. Circ Cardiovasc Imaging2012;5:467–73.

16. Shaw LJ, Marwick TH, Zoghbi WA, et al. Whyall the focus on cardiac imaging? J Am Coll CardiolImg 2010;3:789–94.

17. Young LH, Wackers FJ, Chyun DA, et al. Cardiacoutcomes after screening for asymptomatic coro-nary artery disease in patients with type 2 dia-betes: the DIAD study: a randomized controlledtrial. JAMA 2009;30:1547–55.

18. Arad Y, Spadaro LA, Roth M, Newstein D,Guerci AD. Treatment of asymptomatic adults withelevated coronary calcium scores with atorvasta-tin, vitamin C, and vitamin E: the St. Francis HeartStudy randomized clinical trial. J Am Coll Cardiol2005;46:166–72.

19. O’Malley PG, Feuerstein IM, Taylor AJ. Impactof electron beam tomography, with or withoutcase management, on motivation, behavioralchange, and cardiovascular risk profile: a ran-domized controlled trial. JAMA 2003;289:2215–23.

20. Taylor AJ, Bindeman J, Feuerstein I, et al.Community-based provision of statin and aspirinafter the detection of coronary artery calciumwithin a community-based screening cohort. J AmColl Cardiol 2008;51:1337–41.

21. Rozanski A, Gransar H, Shaw LJ, et al. Impactof coronary artery calcium scanning on coronaryrisk factors and downstream testing the EISNER(Early Identification of Subclinical Atherosclerosisby Noninvasive Imaging Research) prospectiverandomized trial. J Am Coll Cardiol 2011;57:1622–32.

22. Muhlestein JB, Lappe DL, Lima JA, et al. Effectof screening for coronary artery disease using CTangiography on mortality and cardiac events inhigh-risk patients with diabetes: the FACTOR-64randomized clinical trial. JAMA 2014;312:2234–43.

23. Douglas PS, Hoffmann U, Patel MR, et al.Outcomes of anatomical versus functional testing

for coronary artery disease. N Engl J Med 2015;372:1291–300.

24. Yeh RW, Sidney S, Chandra M, et al. Popula-tion trends in the incidence and outcomes of acutemyocardial infarction. N Engl J Med 2010;362:2155–65.

25. Myerson M, Coady S, Taylor H, et al. Decliningseverity of myocardial infarction from 1987 to2002: the Atherosclerosis Risk in Communities(ARIC) Study. Circulation 2009;119:503–14.

26. Carandang R, Seshadri S, Beiser A, et al.Trends in incidence, lifetime risk, severity, and 30-day mortality of stroke over the past 50 years.JAMA 2006;296:2939–46.

27. Murabito JM, Evans JC, D’Agostino RB Sr.,Wilson PW, Kannel WB. Temporal trends in theincidence of intermittent claudication from 1950to 1999. Am J Epidemiol 2005;162:430–7.

28. Will JC, Loustalot F, Hong Y. National trends invisits to physician offices and outpatient clinics forangina 1995 to 2010. Circ Cardiovasc Qual Out-comes 2014;7:110–7.

29. Rozanski A, Gransar H, Hayes SW, et al. Tem-poral trends in the frequency of induciblemyocardial ischemia during cardiac stress testing:1991 to 2009. J Am Coll Cardiol 2013;61:1054–65.

30. Ashton HA, Buxton MJ, Day NE, et al. TheMulticentre Aneurysm Screening Study (MASS)into the effect of abdominal aortic aneurysmscreening on mortality in men: a randomisedcontrolled trial. Lancet 2002;360:1531–9.

31. Chang SM, Nabi F, Xu J, et al. The coronaryartery calcium score and stress myocardial perfu-sion imaging provide independent and comple-mentary prediction of cardiac risk. J Am CollCardiol 2009;54:1872–82.

32. He ZX, Hedrick TD, Pratt CM, et al. Severity ofcoronary artery calcification by electron beamcomputed tomography predicts silent myocardialischemia. Circulation 2000;101:244–51.

33. Berman DS, Wong ND, Gransar H, et al. Rela-tionship between stress-induced myocardialischemia and atherosclerosis measured by coro-nary calcium tomography. J Am Coll Cardiol 2004;44:923–30.

34. Hecht H, Menezes de Siqueira M, Cham M,et al. Low-vs. standard-dose coronary artery cal-cium scanning. Eur Heart J Cardiovasc Imaging2015;16:358.

35. Cho I, Chang HJ, Sung JM, et al. Coronarycomputed tomographic angiography and risk ofall-cause mortality and nonfatal myocardial

J A C C : C A R D I O V A S C U L A R I M A G I N G , V O L . 1 0 , N O . 3 , 2 0 1 7 Rozanski et al.M A R C H 2 0 1 7 : 3 0 4 – 1 7 Primary Prevention of CVD

317

infarction in subjects without chest pain syndromefrom the CONFIRM Registry (Coronary CT Angi-ography Evaluation for Clinical Outcomes: an in-ternational multicenter registry). Circulation 2012;126:304–13.

36. Den Ruijter HM, Peters SA, Anderson TJ, et al.Common carotid intima-media thickness mea-surements in cardiovascular risk prediction: ameta-analysis. JAMA 2012;308:796–803.

37. Nambi V, Chambless L, Folsom AR, et al. Ca-rotid intima-media thickness and presence orabsence of plaque improves prediction of coronaryheart disease risk: the ARIC (Atherosclerosis RiskIn Communities) study. J Am Coll Cardiol 2010;55:1600–7.

38. van den Oord SC, Sijbrands EJ, ten Kate GL,et al. Carotid intima-media thickness for car-diovascular risk assessment: systematic reviewand meta-analysis. Atherosclerosis 2013;228:1–11.

39. Gepner AD, Young R, Delaney JA, et al. Com-parison of coronary artery calcium presence, ca-rotid plaque presence, and carotid intima-mediathickness for cardiovascular disease prediction in

the Multi-ethnic study of Atherosclerosis. CircCardiovasc Imaging 2015;8:E002262.

40. Sillesen H, Muntendam P, Adourian A, et al.Carotid plaque burden as a measure of subclinicalatherosclerosis: comparison with other tests forsubclinical arterial disease in the High Risk PlaqueBioImage study. J Am Coll Cardiol Img 2012;5:681–9.

41. Baber U, Mehran R, Sartori S, et al. Prevalence,impact, and predictive value of detecting sub-clinical coronary and carotid atherosclerosis inasymptomatic adults: the BioImage study. J AmColl Cardiol 2015;65:1065–74.

42. Laclaustra M, Casasnovas JA, Fernández-Ortiz A, et al. Femoral and carotid subclinicalatherosclerosis association with risk factors andcoronary calcium: the AWHS study. J Am CollCardiol 2016;67:1263–74.

43. Fernández-Friera L, Peñalvo JL, Fernández-Ortiz A, et al. Prevalence, vascular distribution,and multiterritorial extent of subclinical athero-sclerosis in a middle-aged cohort: the PESA (Pro-gression of Early Subclinical Atherosclerosis)Study. Circulation 2015;131:2104–13.

44. Mamudu HM, Paul TK, Veeranki SP, et al. Theeffects of coronary artery calcium screening onbehavioral modification, risk perception, andmedication adherence among asymptomaticadults: a systematic review. Atherosclerosis 2014;236:338–50.

45. Nasir K, Bittencourt MS, Blaha MJ, et al. Im-plications of coronary artery calcium testingamong statin candidates according to AmericanCollege of Cardiology/American Heart Associationcholesterol management guidelines: MESA(Multiethnic Study of Atherosclerosis). J Am CollCardiol 2015;66:1657–68.

46. Blaha MJ, Cainzos-Achirica M, Greenland P,et al. Role of coronary artery calcium score ofzero and other negative risk markers for cardio-vascular disease: the Multi-Ethnic Study ofAtherosclerosis (MESA). Circulation 2016;133:849–58.

KEY WORDS atherosclerosis,cardiovascular disease, coronary arterycalcium, screening