Calcium Scores in the Risk Assessment of an Asymptomatic Population: Implications for Airline Pilots.

RESEARCH ARTICLE

Calcium Scores in the Risk Assessment of an
Asymptomatic Population: Implications for
Airline Pilots
I. Made Ady Wirawan, Rodney Wu, Malcolm Abernethy,
Sarah Aldington, and Peter D. Larsen
WIRAWAN IMA, WU R, ABERNETHY M, ALDINGTON S, LARSEN PD.
(NZGG) (4,13). The NZ-CRC yields 5-yr risk estimations
Calcium scores in the risk assessment of an asymptomatic populaof , 2.5%, 2.5–5%, 10–15%, 15–20%, and . 20% (Fig. 1);
tion: implications for airline pilots. Aviat Space Environ Med 2014;
for
the purpose of the CAA medical standards, a 5-yr
85:812–7.
CVD risk of 10% (approximate 10-yr CVD risk of 20%)
Background: This study evaluated whether coronary artery calcium
score (CACS) improved cardiovascular disease risk prediction when
or higher is considered excessive (3). Our previous study
compared to the New Zealand Cardiovascular Risk Charts (NZ-CRC),
found that the current approach to investigate excessive
and describes the potential utilization of CACS in cardiovascular disease

Delivered
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Aerospace
Medical
Association
Member relies heavily on
cardiovascular
risk
in pilots, however,
(CVD) risk assessment of pilots. Methods: A cross-sectional study was
203.97.168.43
On: Mon,
28 Jul electrocardiograms
2014 20:40:23
exercise
as a diagnostic test and may
performed among asymptomatic patientsIP:

who
underwent coronary
Aerospace Medical
Association
computed tomography angiography at PacificCopyright:
Radiology Wellington,
not be optimal
either to detect disease or to protect piNew Zealand, between August 2007 and July 2012 and had their CACS
lots from unnecessary invasive coronary angiography.
and CVD risk score calculated. Receiver-operating characteristics (ROC)
A more comprehensive and accurate cardiac investigaanalyses were used to measure the accuracy of the NZ-CRC and CACS.
tion algorithm to assess excessive CVD risk in pilots is
Reclassification analyses were performed to examine the net reclassification improvement (NRI) of CACS when compared to NZ-CRC. Results:
required (19).
Over a 5-yr study period, 237 male asymptomatic patients with ages
Previous studies have indicated that quantification of
ranging from 30 to 69 yr with a mean (SD) of 53.24 (8.18) yr, were incoronary artery calcium score (CACS) using computed
cluded. The area under the ROC curves (AUC) (95% CI) for CACS and
tomography (CT) is one of the methods that can improve
NZ-CRC were 0.88 (0.83-0.93) and 0.66 (0.59-0.73), respectively. The

NRI (95% CI) of the calcium scores was 0.39 (0.17-0.62). CACS should
risk prediction over conventional risk prediction models
be assessed in pilots with 5-yr CVD risk scores of 5–10% and 10–15%.
such as the Framingham Risk Score. Available guidelines,
Conclusion: CACS has a better accuracy than the NZ-CRC and reclassirecommendations,
systematic reviews, and meta-analyfied a considerable proportion of asymptomatic patients into correct carses relevant to cardiovascular risk assessment in asympdiovascular risk categories. An approach on how the CACS should be
employed in the cardiovascular risk assessment of airline pilots is noted
tomatic adults demonstrated that CACS testing is the
in this paper.
best candidate to be applied for cardiovascular risk asKeywords: assessment tool, CACS, Framingham risk score, occupational
sessment in people at intermediate risk or 10–20%
group, risk stratification.

C

ARDIOVASCULAR disease (CVD) risk stratification has been applied by aviation authorities in
many countries. This encompasses risk prediction models to generate an absolute risk of CVD over a particular
time frame (9). However, previous research showed that
the prediction models based on CVD risk factors are
limited in their ability to discriminate between people

who will or will not experience CVD (8). Our previous
study found that, in spite of seemingly appropriate cutoff points, the risk assessment tool had a low sensitivity
and was unable to predict almost half of CVD events.
More than half (60%) of the CVD events observed occurred as sudden clinical presentations and almost half
(47%) of the cardiovascular events occurred in pilots
whose highest 5-yr CVD risk was in the 5–10% range (20).
The New Zealand Civil Aviation Authority evaluates
the cardiovascular risk of medical certificate applicants
using New Zealand Cardiovascular Risk Charts (NZCRC) published by the New Zealand Guideline Group

812

over 10 yr (5,15,16). A clinical expert consensus also supported that CACS has a progressively higher level of
quality evidence in its role in risk stratification of asymptomatic populations (7).
To the best of our knowledge, however, evidence that
CACS improves cardiovascular disease risk prediction
when compared to the NZ-CRC is still limited. This is
important due to the fact that NZ-CRC has some differentiation from the basic Framingham risk score and other
cardiovascular risk prediction tools applied by different
From the Occupational and Aviation Medicine Unit, University

of Otago, Wellington, New Zealand, and the Occupational Health
Department, Udayana University, Bali, Indonesia.
This manuscript was received for review in November 2013. It was
accepted for publication in April 2014.
Address correspondence and reprint requests to: I. Made Ady
Wirawan, M.D., M.P.H., Occupational Health Department, Udayana
University, Jl PB Sudirman, Denpasar, Bali, Indonesia; ady.wirawan@
otago.ac.nz or ady.wirawan@gmail.com.
Reprint & Copyright © by the Aerospace Medical Association,
Alexandria, VA.
DOI: 10.3357/ASEM.3904.2014

Aviation, Space, and Environmental Medicine x Vol. 85, No. 8 x August 2014

CALCIUM SCORE & AIRLINE PILOTS—WIRAWAN ET AL.

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Copyright: Aerospace Medical Association

Fig. 1. New Zealand cardiovascular risk chart for men. Adapted from the New Zealand Cardiovascular Guidelines Handbook (13).

countries. This study aimed at proving that CACS
also has a better accuracy than the NZ-CRC and more
importantly examined the reclassification improvement
of CACS if it is used as a screening tool in comparison
with the NZ-CRC. Based on the results, potential utilization of CACS in CVD risk assessment of pilots is then
presented.
METHODS
Subjects
Asymptomatic patients who underwent a coronary
computed tomography angiography (CCTA) at Pacific
Radiology Wellington, New Zealand, were included in
this study. The main inclusion criteria were patients,
ages between 30-70 yr old, who were referred for cardiovascular risk assessment and cardiac investigation. The
Aviation, Space, and Environmental Medicine x Vol. 85, No. 8 x August 2014

exclusion criteria included: reasons for referral were unavailable; cardiovascular risk score could not be calculated; or coronary artery calcium scores were unavailable.
Patients with established cardiovascular diseases or
who had experienced one or more previous CVD events,

percutaneous coronary intervention, or coronary artery
bypass graft surgery, were also excluded from this study.
Procedure
This was an observational, cross-sectional diagnostic
accuracy study using data collected between 1 August
2007 and 26 July 2012. The main variables tested were
CVD risk score and CACS. The 5-yr risk of a cardiovascular event was calculated using the NZ-CRC (13) based
on CVD risk factors, including: age, gender, systolic
blood pressure, smoking history, diabetes status, and
total cholesterol-HDL ratio. Risk scores are classified as:
813

CALCIUM SCORE & AIRLINE PILOTS—WIRAWAN ET AL.
, 2.5%, 2.5–5%, 5–10%, 10–15%, 15–20%, 20–25%, 25–30%,
to rapid heart rate, and 2 with age more than 70 yr old.
and . 30%. The CVD risk factors data were retrieved
The study included 237 male asymptomatic patients
from the CT Cardiac Patient Health Questionnaire filled
with ages between 30 and 70 yr old.
out during the CT coronary angiography examination.

Table I shows the characteristics of patients undergoThe technical details used for the CT coronary angioging CCTA at Pacific Radiology Wellington. The patients’
raphy are described as follows. Scans were performed
ages ranged from 30 to 69 yr old with a mean (SD) of 53.24
on a GE 64-slice Discovery VCT and, since January 2011,
(8.18) yr and 77% were in the 35-60 yr category. The CVD
the GE 750HD (GE Healthcare, Little Chalfont, Buckingrisk calculation showed that the number of patients with
hamshire, UK). Patients were beta blocked with 50 or
5-yr CVD risk scores of , 5%, 5–10%, and . 10% were
100 mg metoprolol SR 1 h prior. All scans were ECG
55 (23%), 87 (37%), and 95 (40%), respectively.
gated. Contrast was not given for the calcium scoring
Coronary artery calcium (Agatston) scores of the pa(SmartScore, GE Medical Systems, Waukesha, WI), but
tients ranged from 0 to 1781, with a mean (SD) of 140
between 80–100 ml of Omnique 350 for the contrast car(292) and median (interquartile range) of 11 (142). There
diac angiogram (SnapShot Pulse, GE Healthcare) was
were 20 (8.44%) of them who had calcium scores rangused. Patients were given sublingual glyceryl trinitrate
ing from 400-999 and 6 (2.53%) patients who had calcium
spray immediately prior to the contrast run unless there
scores of ⱖ 1000. Stenosis grading on CCTA indicated
was a contraindication. Technical settings were very

that 52 (22%) patients had a stenosis of 50% or higher
similar for both machines. For the calcium scoring the
(significant disease) and 185 (78%) patients had a stenoparameters were: Cine mode, 2.5 mm slice, 40 mm desis of , 50%.
tector size, 0.35 rotation time, 120 kV tube voltage, and
The reasoning for undergoing cardiac investigation in
200-300 mA tube current; for the cardiac angiogram
the
asymptomatic patients is described in Table II. This
(prospective acquisition), the settings were Cine high
Delivered
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Aerospace
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table
indicates
thatAssociation
the majorityMember

of patients were referred
resolution mode, 0.625mm slice, 35 rotation time, 100IP: 203.97.168.43 On: Mon,
28 to
Julhaving
2014 20:40:23
due
a
family
history
of premature ischemic
120 kV tube voltage, and 500-700 mACopyright:
tube current.
The
Aerospace
Medical
Association
heart
disease
alone
or

in
combination
with the presence
algorithm was HD Soft. Agatston scores were calculated
of
one
or
more
cardiovascular
risk
factors
such as hyperand classified as: 0, 1-9, 10-99, 100-399, 400-999, and ⱖ
tension,
hyperlipidemia,
diabetes,
or
having
an elevated
1000 for the analysis in this study. For the presence of a
cardiovascular
risk.
Approximately
24%
of
the
patients
coronary artery disease, a stenosis of 50% or more was
underwent
investigation
for
screening
or
general
mediconsidered a significant cardiovascular disease.
cal
check
purposes.
Similar
fi
ndings
were
found
beReceiver operating characteristics (ROC) analyses
tween patients with stenosis of or more than 50% and
were used to assess the accuracy of the CVD risk score
those with stenosis less than 50%. Furthermore, six of
and CACS. Reclassification analyses were then performed to examine the net reclassification improvement
(NRI) of CACS when it is used as a screening tool comTABLE I. CHARACTERISTICS OF ASYMPTOMATIC PATIENTS WHO
pared to CVD risk score. For the purpose of the reclasUNDERWENT CCTA.
sification analysis, “low risk” is defined as having a
Sample Characteristics
Frequency (%)
CVD risk of , 5% or a calcium score of 0-99; “intermediate risk” is defined as having a CVD risk of 5–10% or a
Age group
30-34
3 (1.27)
calcium score of 100-399; and “high risk” is defined as
35-60
182 (76.79)
having a CVD risk of . 10% or a calcium score of ⱖ 400.
Statistical Analysis
Statistical analyses were performed using R version
2.15.3 (R: a language and environment for statistical computing. R Foundation for Statistical Computing, Vienna,
Austria). “PredictABEL” R package was employed for
ROC and reclassification analyses (10). This is a low-risk
observational study based on clinically obtained data,
with no intervention other than recording, classifying,
counting, and analyzing of the data. This study was approved by the University of Otago Ethical Committee
(Human Ethics Application: Category B)
RESULTS
There were 260 asymptomatic male patients who
underwent a CCTA from 1 August 2007 to 26 July 2012
at Pacific Radiology Wellington. Of these, 23 were
excluded; 6 due to no calcium score, 14 with no cardiovascular risk score, 1 with an unsatisfactory study due
814

61-65
66-70
5-yr CVD Risk
,2.5%
2.5–5%
5–10%
10–15%
15–20%
20–25%
25–30%
Calcium Score
0
1-9
10-99
100-399
400-999
1000+
Stenosis Grading
0%
, 25%
25–49%
50–69%
70–99%
100%
Total

44 (18.57)
8 (3.38)

10 (4.22)
45 (18.99)
87 (36.71)
60 (25.32)
23 (9.7)
8 (3.38)
4 (1.69)
94 (39.66)
24 (10.13)
48 (20.25)
45 (18.99)
20 (8.44)
6 (2.53)
68 (28.69)
74 (31.22)
43 (18.14)
44 (18.57)
6 (2.53)
2 (0.84)
237 (100.00)

Aviation, Space, and Environmental Medicine x Vol. 85, No. 8 x August 2014

CALCIUM SCORE & AIRLINE PILOTS—WIRAWAN ET AL.
TABLE II. RATIONALE FOR CARDIAC INVESTIGATION.
Frequency (%)*
Risk Factors
FH-PIHD
FH-PIHD and 1 of HT/HL/DM
FH-PIHD and ⱖ 2 of HT/HL/DM
FH-PIHD and elevated CV risk
One of HT/HL/DM
2 or more of HT/HL/DM
Elevated CV risk
Screening/ Medical check-up
Total

Patients with ⱖ 50% Stenosis

Patients with , 50% Stenosis

All Patients

16 (30.8)
10 (19.2)
5 (9.6)
1 (1.9)
5 (9.6)
2 (3.8)
1 (1.9)
12 (23.1)
52 (100.0)

63 (34.1)
33 (17.8)
12 (6.5)
1 (0.5)
24 (13.0)
5 (2.7)
3 (1.6)
44 (23.8)
185 (100.0)

79 (33.3)
43 (18.1)
17 (7.2)
2 (0.8)
29 (12.2)
7 (3.0)
4 (1.7)
56 (23.6)
237 (100.0)

* Results are presented as frequency and proportion within column.
FH-PIHD: family history of premature ischemic heart disease; HT: hypertension; HL: hyperlipidemia; DM: diabetes mellitus; CV: cardiovascular.

the eight patients with quite significant disease (stenosis
The accuracy of CACS was shown in a recent systemof ⱖ 70%) were referred for cardiac investigation due
atic review on the added value of CACS in risk stratifito having a family history of premature ischemic heart
cation for cardiovascular events. This review found that
disease alone or in combination with the presence of one
an increase in AUC was shown by all studies when
or more of cardiovascular risk factors or an elevated
CACS was added to the risk model, ranging from 0.05 to
Delivered by Publishing Technology to: Aerospace Medical Association Member
cardiovascular risk. The two others
underwent
CCTA
(15).2014
Other
studies also found that CACS reclassiIP: 203.97.168.43 On: Mon,0.20
28 Jul
20:40:23
because of having one or more cardiovascular
risk Medical
fied a signifi
cant proportion of people into correct risk
Copyright: Aerospace
Association
factors.
categories. This was shown by a NRI that ranged from
The accuracy of the NZGG risk charts and CACS in
14 to 30%, where the most obvious improvement was
predicting cardiovascular disease is shown by Fig. 2.
found in those at intermediate (10–20% over 10 yr)
The area under the ROC curve or AUC (95% CI) for
Framingham risk (15). It was also estimated from the
CACS and the NZGG risk charts were 0.881 (0.829-0.933)
Multi-Ethnic Study of Atherosclerosis that addition of
and 0.661 (0.587-0.734), respectively. Reclassification
CACS measurement to the traditional risk factors model
analysis for calcium score, when it was used as a substiresulted in NRI in the total population of 25%, with NRI
tute for the NZGG’s cardiovascular chart in determinin intermediate risk individuals of about 55% and an Ining cardiovascular risks, including NRI, is presented in
tegrated Discrimination Improvement of 0.026 (16). The
Table III. The NRI (95% CI) of the calcium scores was
higher result found in our study is mainly due to the dif0.39 (0.17-0.62), with a P-value of , 0.001.
ference in the risk prediction tool used and the direct
comparison between NZ-CRC and CACS instead of
DISCUSSION
adding CACS to the existing risk prediction model. Additionally, both NZ-CRC and CACS were assessed in a
The difference in the AUC between CACS and CVD
high prevalence population. In the present study, the
risk score is 0.22. This clearly indicates that CACS is a
better tool in predicting the presence of a coronary stenosis of greater than 50%. In addition, the NRI shows
TABLE III. RECLASSIFICATION TABLE FOR NZ CARDIOVASCULAR
that calcium score correctly reclassified 39% of asympRISK CHART AND CALCIUM SCORE.
tomatic patients into low, intermediate, and high risk
categories.
Calcium Score

NZGG CVD Risk Score
Patient without CVD
Low
Intermediate
High
Patient with CVD
Low
Intermediate
High
Combined Data
Low
Intermediate
High
Fig. 2. Receiver operating characteristics of the New Zealand Cardiovascular Risk Chart and calcium score.
Aviation, Space, and Environmental Medicine x Vol. 85, No. 8 x August 2014

Low

Intermediate

High

% Reclassified

50
53
51

3
11
12

0
1
4

6
83
94

1
5
6

1
10
8

0
7
14

50
55
50

51
58
57

4
21
20

0
8
18

7
76
81

Net reclassification improvement (categorical) [95% CI]: 0.3939 [0.1662 0.6215]; P-value: 7e-04.
NZGG 5 New Zealand Guideline Group; CVD 5 cardiovascular disease.

815

CALCIUM SCORE & AIRLINE PILOTS—WIRAWAN ET AL.
prevalence of patients with a stenosis of ⱖ 50% on CCTA
described how the current risk assessment has worked
was 22%. Several studies have reported results that indiand concluded that the current approach to investigate
cate that diagnostic test accuracies may vary with disexcessive cardiovascular risk in pilots relies heavily on
ease prevalence (11).
exercise electrocardiograms as a diagnostic test, and
This suggests that the evaluation of coronary calcium
may not be optimal either to detect disease or to protect
is useful in primary prevention, especially in subjects
pilots from unnecessary invasive procedures (19).
classified as intermediate risk based on traditional risk
A new approach in CVD risk assessment of pilots
factors. High calcium scores identify subjects at high
should be focused on the application of CACS in those
risk who will benefit from aggressive prevention apwith 5-yr CVD risk of 5–10% and 10–15% according to
proaches. Ferket et al. (5), who conducted a systematic
the New Zealand cardiovascular risk charts. A stress
review of guidelines on imaging of asymptomatic coromyocardial perfusion imaging (MPI) or coronary CT annary artery disease, supported this conclusion. They
giography can be proposed to further investigate pilots
found that the majority guidelines (10/14) considered
with a calcium score of 400 or greater. The Guideline for
CACS a test for improvement of total coronary risk asAssessment of Cardiovascular Risk in Asymptomatic
sessment based on traditional risk factors.
Adults (6) states that the stress MPI may be considered
This was a cross-sectional study in asymptomatic pafor advanced cardiovascular risk assessment in asymptients who underwent CCTA and also had their CT caltomatic adults when previous risk assessment testing
cium score and CVD risk score calculated. CCTA was
suggests high risk of coronary heart disease, such as a
used as the primary endpoint. While CCTA has consisCAC score of 400 or greater. In an asymptomatic poputently shown high sensitivities and specificities in the
lation that requires a high standard of fitness, such as
majority of the previous studies (2), the use of CCTA reairline pilots, the utilization of stress MPI or CCTA to
sults as the outcome
variablebyand
a stenosis
of ⱖ 50% as
exclude aMedical
significant
coronaryMember
heart disease is reasonDelivered
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timate the real cardiovascular eventsCopyright:
and influence
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Aerospace
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ated. This
is practical due to the high negative predictive
strength of the study. The American Society of Aerovalues of the stress MPI and CCTA.
space Medicine Specialists (1) defined clinically signifiAnother consideration for using stress MPI is that this
cant coronary artery disease as one or more lesions with
test can indicate functional myocardial perfusion. Given
. 50% stenosis by coronary angiography. However, the
the fact that coronary artery calcium scoring does not
cardiovascular event rates encountered by patients with
provide functional evidence of obstruction, the combia stenosis of . 50% in the clinical population may not acnation of CACS and stress MPI can be an ideal approach.
curately predict prognosis in the younger and relatively
The combination of an anatomic approach using CT calhealthier aviator population with asymptomatic disease.
cium score followed by a functional approach using
Another limitation of this study is that the patients
stress MPI will be able to identify pilots who may most
were not pilots or an occupationally matched group.
benefit from invasive coronary angiography and coroHowever, they were men and resembled the age of the
nary revascularization.
commercial pilot group within New Zealand (17). DeCurrent evidence shows that management changes
spite all the above limitations in this study, however, the
can happen after screening using a calcium score in
result furthers our understanding on how calcium
community-based cohorts, showing that the presence of
scores can be used to improve the New Zealand cardiocoronary calcification was associated with an indepenvascular risk chart in the risk assessment of cardiovasdent threefold greater likelihood of statin and aspirin
cular diseases in a group of asymptomatic individuals
usage (6,18). Data from the Multi-Ethnic Study of
of similar characteristics to the pilot population.
Atherosclerosis study also suggest that CACS . 400 was
associated with a higher likelihood of initiation and conImplications for Aviation Medicine Practices
tinuation of preventive medications (12). Furthermore,
coronary artery calcium visualization is useful in motiUsing calcium score as the only routine screening tool
vating patients and increasing interactions with a healthfor all asymptomatic patients is not recommended (6);
care provider to support adherence to the lifestyle and
therefore, adding or combining calcium score into a new
treatment recommendations (6,14).
risk assessment approach is a reasonable way to imThis study implies that a more detailed risk assessprove current cardiovascular risk screening in airline
ment algorithm in asymptomatic pilots is needed, along
pilots. Based on the results of this study and other availwith a more comprehensive analysis of the risks, beneable evidence, a new system for cardiovascular investifits, and the validity period of the cardiovascular tests
gation in pilot populations can be proposed.
involved in the new system. Coronary artery calcium
The present CVD risk assessment states that pilots
score has a better accuracy than the NZGG’s cardiovasexceeding a threshold of 10% (5-yr risk) are required
cular risk charts and properly reclassified a significant
to demonstrate normal myocardial perfusion, generally
proportion of asymptomatic patients into low, intermeby undergoing an exercise stress test. The pilot will be
diate, or high cardiovascular risk categories. This findconsidered for further investigation, commonly through
ing has provided an insight on how coronary artery
an invasive coronary angiography, if the functional test
calcium score could be employed in the cardiovascular
is inconclusive or positive (3,4). Our previous study
816

Aviation, Space, and Environmental Medicine x Vol. 85, No. 8 x August 2014

CALCIUM SCORE & AIRLINE PILOTS—WIRAWAN ET AL.
Force (ACCF/AHA Writing Committee to Update the 2000
Expert Consensus Document on Electron Beam Computed
Tomography) developed in collaboration with the Society of
Atherosclerosis Imaging and Prevention and the Society of
ACKNOWLEDGMENT
Cardiovascular Computed Tomography. J Am Coll Cardiol
Authors and affiliations: I. Made Ady Wirawan, M.D., M.P.H.,
2007; 49:378–402.
Occupational Health Department, Udayana University, Bali, Indonesia;
8. Greenland P, LaBree L, Azen SP, Doherty TM, Detrano RC.
Rodney Wu, M.B., Ch.B., Pacific Radiology Group, Wellington, New
Coronary artery calcium score combined with Framingham
Zealand; Malcolm Abernethy, M.B., Ch.B., Wakefield Heart Center,
Score for risk prediction in asymptomatic individuals. JAMA
Wakefield Hospital, Wellington, New Zealand; and I. Made Ady
2004; 291:210–5.
Wirawan, M.D., M.P.H., Sarah Aldington, M.Av.Med., Ph.D., and Peter
9. Houston S, Mitchell S, Evans S. Application of a cardiovascular
D. Larsen, B.Sc.(Hons.), Ph.D., Occupational and Aviation Medicine
disease risk prediction model among commercial pilots. Aviat
Unit, University of Otago Wellington, Wellington, New Zealand.
Space Environ Med 2010; 81:768–73.
10. Kundu S, Aulchenko Y, Duijn C, Janssens ACW. PredictABEL: an
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risk assessment in a specific occupational group such as
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