- Email: [email protected]
Your Coronary Calcium Scan Is Positive
JACC: CARDIOVASCULAR IMAGING
VOL.
ª 2016 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
-, NO. -, 2016
ISSN 1936-878X/$36.00
PUBLISHED BY ELSEVIER
http://dx.doi.org/10.1016/j.jcmg.2015.12.012
EDITORIAL COMMENT
Your Coronary Calcium Scan is Positive Now What?* Todd D. Miller, MD, Martin Rodriguez-Porcel, MD
C
oronary artery calcium (CAC) scanning by
without ischemia. Applying a CAC cutoff of $400
computed
commonly
versus <400, the corresponding percentages were
performed as a screening test for coronary
53% and 25%, respectively. Perhaps the most clini-
artery disease (CAD) risk assessment in clinical prac-
cally useful data reported in this meta-analysis is the
tice. For asymptomatic individuals without known
prevalence of ischemia according to CAC scores,
CAD who are at intermediate to high risk, CAC scan-
derived from a subset of 6 studies involving 2,123
ning is assigned a “may be appropriate” rating
patients where patients were categorized by all 4 CAC
according to American College of Cardiology appro-
scores. The prevalence increased modestly across the
priate use criteria (1) and a Class IIA indication
first 3 CAC categories and increased substantially for
according to American College of Cardiology practice
the fourth category: CAC ¼ 0, 6.6%; CAC ¼ 1 to 100,
guidelines (2). The results of CAC scanning can be
8.5%; CAC ¼ 100 to 399, 10.5%; CAC $400, 23.6%.
tomography
is
applied to determine the aggressiveness of treating
Another important observation from this meta-
CAD risk factors. Additionally, the detection of a
analysis is the significant variability in results re-
high CAC score can raise concern about prognostically
ported across studies. I 2 is a quantity that reflects the
significant obstructive CAD. Performing stress testing
heterogeneity across studies that are included in a
with single-photon emission computed tomography–
meta-analysis (4). I 2 was >75% for all of the analyses
myocardial perfusion imaging (SPECT-MPI) or echo-
performed in this meta-analysis. I 2 values >75% are
cardiography is considered appropriate in patients
generally considered to indicate high heterogeneity.
with an Agatston score >100 (1).
An example of the heterogeneity between studies is
Over the past 15 years several studies have exam-
the prevalence of stress-induced ischemia, which
ined the association between the results of CAC
ranged from 5.6% to 45.5%. In the subset of 6 studies
scanning and the frequency of myocardial ischemia.
that included all 4 categories of CAC scoring, the
In this issue of iJACC, Bavishi et al. (3) report the re-
prevalence of ischemia for CAC ¼ 0 ranged between
sults of a meta-analysis of this topic. An initial liter-
0.0% and 24.1% and for CAC $400 the prevalence
ature search identified 281 potential studies. Twenty
ranged between 12.4% and 57.1%. Bavishi et al. (3)
of these studies, which enrolled 7,155 patients, met
suggest some potential reasons for the high hetero-
their entry criteria. The authors applied 4 commonly
geneity in their analyses, including the small patient
used CAC cutoff categories: 0, 1 to 100, 101 to 399,
populations in many of the studies; differences in
and $400. Twelve of the studies could be analyzed
symptom status, CAD risk factors, and medication use
for CAC cutoff of 0 and 16 studies for CAC cutoff of
between populations; and technical factors related to
400. As expected there was an association between
imaging.
CAC and the prevalence of ischemia. In the studies
There likely were additional factors related to pa-
that used a CAC cutoff of >0 versus 0, the pooled
tient selection and accuracy of imaging not addressed
frequency of a positive CAC score was 86% for
by the authors. During much of the 15-year time
patients with ischemia versus 72% for patients
period covered by this meta-analysis, there was no general consensus concerning which patients were suitable candidates for CAD scanning. Furthermore,
*Editorials published in JACC: Cardiovascular Imaging reflect the views of the authors and do not necessarily represent the views of JACC: Cardiovascular Imaging or the American College of Cardiology. From the Department of Cardiovascular Diseases, Mayo Clinic, Rochester,
in some regions of the country this technology was heavily marketed and the cost of the test usually was not covered by insurance plans. All of these issues
Minnesota. Both authors have reported that they have no relationships
likely significantly impacted the selection of patients
relevant to the contents of this paper to disclose.
who underwent scanning. Studies examining the
2
Miller and Rodriguez-Porcel
JACC: CARDIOVASCULAR IMAGING, VOL.
-, NO. -, 2016 - 2016:-–-
Editorial Comment
reproducibility of CAD and SPECT-MPI have reported
patients to stress imaging. The individual studies
disappointing results. In MESA (Multi-Ethnic Study of
included in this meta-analysis enrolled both symp-
Atherosclerosis), 2 sequential CAC scans were ob-
tomatic
tained at baseline in 6,814 study participants (5). The
because the results were not stratified by symptom
measurement error between the 2 scans was large and
status, this meta-analysis cannot address this issue.
approximately 100% for an Agatston score of 40. In
Although a CAC threshold above which additional
the
Regadenoson
testing is clearly warranted was not identified in this
Comparative Evaluation for Myocardial Perfusion
study, appropriate use criteria consider stress imag-
Imaging) phase 3 trial, the size of the ischemic defect
ing appropriate for patients with CAC >100 (1). This
was compared in 267 patients who underwent 2
recommendation relates to the current paradigm for
adenosine SPECT-MPI studies performed 1 week apart
managing CAD of identifying patients with severe
(6). The rate of agreement between the 2 studies was
ischemia who are candidates for coronary angiog-
only 64%. These issues of patient selection bias and
raphy and revascularization. This paradigm is based
variability in imaging results undoubtedly also
on a large body of observational literature demon-
contributed to the high heterogeneity.
strating the prognostic value of SPECT-MPI (8) and
ADVANCE
(Adenosine
versus
and
asymptomatic
patients.
However,
The major role of a meta-analysis is its potential
improvement in outcome with revascularization (9).
impact on clinical practice. The finding in this meta-
However, 3 recent large imaging substudies per-
analysis of a relatively low prevalence of ischemia in
formed as part of the COURAGE (10), BARI-2D (11),
patients with a CAC of 0 is consistent with several
and STICH (12) trials reported that ischemia not only
prognostic studies demonstrating that this patient
failed to identify patients with better clinical outcome
subset is at very low risk of experiencing a cardiac
that is treated by revascularization but also that
event (7). Unfortunately, the data from this meta-
ischemia had no value as a stand-alone prognostic
analysis are not robust enough to reliably identify a
variable. The prognostic value of stress imaging in
CAC threshold where stress imaging is clearly war-
patients who are carefully treated with modern
ranted, in part because of the high heterogeneity
medical therapy and the role of revascularization in
already acknowledged. Another factor to consider is
patients with extensive ischemia have come under
that in this study ischemia was analyzed as a simple
question (13). The ongoing ISCHEMIA trial is designed
binary variable (present/absent). However, in clinical
to address this issue (14). The conclusion of Bavishi
practice the most accepted way to determine the
et al. (3) that more research with better designed
subsequent management of the patient is not the
studies is necessary to clarify the role of CAC and
presence of any ischemia but rather the extent and
ischemia seems reasonable. However, a more funda-
severity of ischemia, most commonly measured by
mental issue that should first be clarified is the role of
SPECT-MPI as the summed difference score.
ischemia for outcome prediction and treatment
An important clinical issue that is relevant to this
selection to be certain that ischemia-based testing is
meta-analysis but is not directly addressed by these
the correct approach to further investigate patients
data is the identification of patients suitable for CAC
with an elevated CAC score.
scanning. Currently CAC is appropriate only for asymptomatic patients and is rated “rarely appro-
REPRINT REQUESTS AND CORRESPONDENCE: Dr.
priate” for symptomatic patients (1). Bavishi et al. (3)
Todd D. Miller, Department of Cardiovascular Diseases,
propose that CAC scanning potentially could serve as
Mayo Clinic, Gonda 6-411, 200 First Street, SW, Rochester,
a cost-effective strategy for triaging symptomatic
Minnesota 55905. E-mail: [email protected].
REFERENCES 1. Wolk MJ, Bailey SR, Doherty JU, et al. ACCF/ AHA/ASE/ASNC/HFSA/HRS/SCAI/SCCT/SCMR/STS 2013 multimodality appropriate use criteria for the detection and risk assessment of stable ischemic heart disease: a report of the American College of Cardiology Foundation Appropriate Use Criteria Task Force, American Heart Association, American Society of Echocardiography, American Society of Nuclear Cardiology, Heart Failure Society of America, Heart Rhythm Society, Society for Cardiovascular Angiography and Interventions, Society of Cardiovascular Computed Tomography,
Society for Cardiovascular Magnetic Resonance, and Society of Thoracic Surgeons. J Am Coll Cardiol 2014;63:380–406. 2. Greenland P, Alpert JS, Beller GA, et al. 2010 ACCF/AHA guideline for assessment of cardiovascular risk in asymptomatic adults: a report of the American College of Cardiology Foundation/ American Heart Association Task Force on Practice Guidelines Developed in Collaboration With the American Society of Echocardiography, American Society of Nuclear Cardiology, Society
of Atherosclerosis Imaging and Prevention, Society for Cardiovascular Angiography and Interventions, Society of Cardiovascular Computed Tomography, and Society for Cardiovascular Magnetic Resonance. J Am Coll Cardiol 2010;56: e50–103. 3. Bavishi C, Argulian E, Chatterjee S, Rozanski A. Coronary artery calcium score and the frequency of stress-induced myocardial ischemia during myocardial perfusion imaging: a systematic review and metaanalysis. J Am Coll Cardiol Img 2016;9:XXX–XX.
JACC: CARDIOVASCULAR IMAGING, VOL.
-, NO. -, 2016
Miller and Rodriguez-Porcel
- 2016:-–-
4. Higgins JPT, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in metaanalyses. BMJ 2003;327:557–60. 5. Chung H, McClelland RL, Katz R, Carr JJ, Budoff MJ. Repeatability limits for measurement of coronary artery calcified plaque with cardiac CT in the Multi-Ethnic Study of Atherosclerosis. Am J Roentgenol 2008;190:W87–92. 6. Iskandrian AE, Bateman TM, Belardinelli L, et al. Adenosine versus regadenoson comparative evaluation in myocardial perfusion imaging: results of the ADVANCE phase 3 multicenter international trial. J Nucl Cardiol 2007;14:645–58.
Editorial Comment
9. Hachamovitch R, Hayes SW, Friedman JD, Cohen I, Berman DS. Comparison of the short-term survival benefit associated with revascularization compared with medical therapy in patients with no prior coronary artery disease undergoing stress myocardial perfusion single photon emission computed tomography. Circulation 2003;107: 2900–7. 10. Shaw LJ, Weintraub WS, Maron DJ, et al. Baseline stress myocardial perfusion imaging results and outcomes in patients with stable ischemic heart disease randomized to optimal
artery disease: results from the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial. J Nucl Cardiol 2012;19:658–69. 12. Panza JA, Holly TA, Asch FM, et al. Inducible myocardial ischemia and outcomes in patients with coronary artery disease and left ventricular dysfunction. J Am Coll Cardiol 2013; 61:1860–70. 13. Gibbons RJ, Miller TD. Should extensive myocardial ischemia prompt revascularization to improve outcomes in chronic coronary artery disease? Eur Heart J 2015;2015:2281–7.
medical therapy with or without percutaneous coronary intervention. Am Heart J 2012;164: 243–50.
14. The ISCHEMIA Trial. Available at: https:// ischemiatrial.org. Accessed February 14, 2016.
8. Shaw LJ, Iskandrian AE. Prognostic value of gated myocardial perfusion SPECT. J Nucl Cardiol
11. Shaw L, Cerqueira M, Brooks M, et al. Impact of left ventricular function and the extent of ischemia and scar by stress myocardial perfusion imaging on prognosis and therapeutic risk
KEY WORDS coronary artery calcium score, myocardial ischemia, myocardial perfusion
2004;11:171–85.
reduction in diabetic patients with coronary
imaging
7. Hecht HS. Coronary artery calcium scanning: past, present, and future. J Am Coll Cardiol Img 2015;8:579–96.
3
VOL.
ª 2016 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION
-, NO. -, 2016
ISSN 1936-878X/$36.00
PUBLISHED BY ELSEVIER
http://dx.doi.org/10.1016/j.jcmg.2015.12.012
EDITORIAL COMMENT
Your Coronary Calcium Scan is Positive Now What?* Todd D. Miller, MD, Martin Rodriguez-Porcel, MD
C
oronary artery calcium (CAC) scanning by
without ischemia. Applying a CAC cutoff of $400
computed
commonly
versus <400, the corresponding percentages were
performed as a screening test for coronary
53% and 25%, respectively. Perhaps the most clini-
artery disease (CAD) risk assessment in clinical prac-
cally useful data reported in this meta-analysis is the
tice. For asymptomatic individuals without known
prevalence of ischemia according to CAC scores,
CAD who are at intermediate to high risk, CAC scan-
derived from a subset of 6 studies involving 2,123
ning is assigned a “may be appropriate” rating
patients where patients were categorized by all 4 CAC
according to American College of Cardiology appro-
scores. The prevalence increased modestly across the
priate use criteria (1) and a Class IIA indication
first 3 CAC categories and increased substantially for
according to American College of Cardiology practice
the fourth category: CAC ¼ 0, 6.6%; CAC ¼ 1 to 100,
guidelines (2). The results of CAC scanning can be
8.5%; CAC ¼ 100 to 399, 10.5%; CAC $400, 23.6%.
tomography
is
applied to determine the aggressiveness of treating
Another important observation from this meta-
CAD risk factors. Additionally, the detection of a
analysis is the significant variability in results re-
high CAC score can raise concern about prognostically
ported across studies. I 2 is a quantity that reflects the
significant obstructive CAD. Performing stress testing
heterogeneity across studies that are included in a
with single-photon emission computed tomography–
meta-analysis (4). I 2 was >75% for all of the analyses
myocardial perfusion imaging (SPECT-MPI) or echo-
performed in this meta-analysis. I 2 values >75% are
cardiography is considered appropriate in patients
generally considered to indicate high heterogeneity.
with an Agatston score >100 (1).
An example of the heterogeneity between studies is
Over the past 15 years several studies have exam-
the prevalence of stress-induced ischemia, which
ined the association between the results of CAC
ranged from 5.6% to 45.5%. In the subset of 6 studies
scanning and the frequency of myocardial ischemia.
that included all 4 categories of CAC scoring, the
In this issue of iJACC, Bavishi et al. (3) report the re-
prevalence of ischemia for CAC ¼ 0 ranged between
sults of a meta-analysis of this topic. An initial liter-
0.0% and 24.1% and for CAC $400 the prevalence
ature search identified 281 potential studies. Twenty
ranged between 12.4% and 57.1%. Bavishi et al. (3)
of these studies, which enrolled 7,155 patients, met
suggest some potential reasons for the high hetero-
their entry criteria. The authors applied 4 commonly
geneity in their analyses, including the small patient
used CAC cutoff categories: 0, 1 to 100, 101 to 399,
populations in many of the studies; differences in
and $400. Twelve of the studies could be analyzed
symptom status, CAD risk factors, and medication use
for CAC cutoff of 0 and 16 studies for CAC cutoff of
between populations; and technical factors related to
400. As expected there was an association between
imaging.
CAC and the prevalence of ischemia. In the studies
There likely were additional factors related to pa-
that used a CAC cutoff of >0 versus 0, the pooled
tient selection and accuracy of imaging not addressed
frequency of a positive CAC score was 86% for
by the authors. During much of the 15-year time
patients with ischemia versus 72% for patients
period covered by this meta-analysis, there was no general consensus concerning which patients were suitable candidates for CAD scanning. Furthermore,
*Editorials published in JACC: Cardiovascular Imaging reflect the views of the authors and do not necessarily represent the views of JACC: Cardiovascular Imaging or the American College of Cardiology. From the Department of Cardiovascular Diseases, Mayo Clinic, Rochester,
in some regions of the country this technology was heavily marketed and the cost of the test usually was not covered by insurance plans. All of these issues
Minnesota. Both authors have reported that they have no relationships
likely significantly impacted the selection of patients
relevant to the contents of this paper to disclose.
who underwent scanning. Studies examining the
2
Miller and Rodriguez-Porcel
JACC: CARDIOVASCULAR IMAGING, VOL.
-, NO. -, 2016 - 2016:-–-
Editorial Comment
reproducibility of CAD and SPECT-MPI have reported
patients to stress imaging. The individual studies
disappointing results. In MESA (Multi-Ethnic Study of
included in this meta-analysis enrolled both symp-
Atherosclerosis), 2 sequential CAC scans were ob-
tomatic
tained at baseline in 6,814 study participants (5). The
because the results were not stratified by symptom
measurement error between the 2 scans was large and
status, this meta-analysis cannot address this issue.
approximately 100% for an Agatston score of 40. In
Although a CAC threshold above which additional
the
Regadenoson
testing is clearly warranted was not identified in this
Comparative Evaluation for Myocardial Perfusion
study, appropriate use criteria consider stress imag-
Imaging) phase 3 trial, the size of the ischemic defect
ing appropriate for patients with CAC >100 (1). This
was compared in 267 patients who underwent 2
recommendation relates to the current paradigm for
adenosine SPECT-MPI studies performed 1 week apart
managing CAD of identifying patients with severe
(6). The rate of agreement between the 2 studies was
ischemia who are candidates for coronary angiog-
only 64%. These issues of patient selection bias and
raphy and revascularization. This paradigm is based
variability in imaging results undoubtedly also
on a large body of observational literature demon-
contributed to the high heterogeneity.
strating the prognostic value of SPECT-MPI (8) and
ADVANCE
(Adenosine
versus
and
asymptomatic
patients.
However,
The major role of a meta-analysis is its potential
improvement in outcome with revascularization (9).
impact on clinical practice. The finding in this meta-
However, 3 recent large imaging substudies per-
analysis of a relatively low prevalence of ischemia in
formed as part of the COURAGE (10), BARI-2D (11),
patients with a CAC of 0 is consistent with several
and STICH (12) trials reported that ischemia not only
prognostic studies demonstrating that this patient
failed to identify patients with better clinical outcome
subset is at very low risk of experiencing a cardiac
that is treated by revascularization but also that
event (7). Unfortunately, the data from this meta-
ischemia had no value as a stand-alone prognostic
analysis are not robust enough to reliably identify a
variable. The prognostic value of stress imaging in
CAC threshold where stress imaging is clearly war-
patients who are carefully treated with modern
ranted, in part because of the high heterogeneity
medical therapy and the role of revascularization in
already acknowledged. Another factor to consider is
patients with extensive ischemia have come under
that in this study ischemia was analyzed as a simple
question (13). The ongoing ISCHEMIA trial is designed
binary variable (present/absent). However, in clinical
to address this issue (14). The conclusion of Bavishi
practice the most accepted way to determine the
et al. (3) that more research with better designed
subsequent management of the patient is not the
studies is necessary to clarify the role of CAC and
presence of any ischemia but rather the extent and
ischemia seems reasonable. However, a more funda-
severity of ischemia, most commonly measured by
mental issue that should first be clarified is the role of
SPECT-MPI as the summed difference score.
ischemia for outcome prediction and treatment
An important clinical issue that is relevant to this
selection to be certain that ischemia-based testing is
meta-analysis but is not directly addressed by these
the correct approach to further investigate patients
data is the identification of patients suitable for CAC
with an elevated CAC score.
scanning. Currently CAC is appropriate only for asymptomatic patients and is rated “rarely appro-
REPRINT REQUESTS AND CORRESPONDENCE: Dr.
priate” for symptomatic patients (1). Bavishi et al. (3)
Todd D. Miller, Department of Cardiovascular Diseases,
propose that CAC scanning potentially could serve as
Mayo Clinic, Gonda 6-411, 200 First Street, SW, Rochester,
a cost-effective strategy for triaging symptomatic
Minnesota 55905. E-mail: [email protected].
REFERENCES 1. Wolk MJ, Bailey SR, Doherty JU, et al. ACCF/ AHA/ASE/ASNC/HFSA/HRS/SCAI/SCCT/SCMR/STS 2013 multimodality appropriate use criteria for the detection and risk assessment of stable ischemic heart disease: a report of the American College of Cardiology Foundation Appropriate Use Criteria Task Force, American Heart Association, American Society of Echocardiography, American Society of Nuclear Cardiology, Heart Failure Society of America, Heart Rhythm Society, Society for Cardiovascular Angiography and Interventions, Society of Cardiovascular Computed Tomography,
Society for Cardiovascular Magnetic Resonance, and Society of Thoracic Surgeons. J Am Coll Cardiol 2014;63:380–406. 2. Greenland P, Alpert JS, Beller GA, et al. 2010 ACCF/AHA guideline for assessment of cardiovascular risk in asymptomatic adults: a report of the American College of Cardiology Foundation/ American Heart Association Task Force on Practice Guidelines Developed in Collaboration With the American Society of Echocardiography, American Society of Nuclear Cardiology, Society
of Atherosclerosis Imaging and Prevention, Society for Cardiovascular Angiography and Interventions, Society of Cardiovascular Computed Tomography, and Society for Cardiovascular Magnetic Resonance. J Am Coll Cardiol 2010;56: e50–103. 3. Bavishi C, Argulian E, Chatterjee S, Rozanski A. Coronary artery calcium score and the frequency of stress-induced myocardial ischemia during myocardial perfusion imaging: a systematic review and metaanalysis. J Am Coll Cardiol Img 2016;9:XXX–XX.
JACC: CARDIOVASCULAR IMAGING, VOL.
-, NO. -, 2016
Miller and Rodriguez-Porcel
- 2016:-–-
4. Higgins JPT, Thompson SG, Deeks JJ, Altman DG. Measuring inconsistency in metaanalyses. BMJ 2003;327:557–60. 5. Chung H, McClelland RL, Katz R, Carr JJ, Budoff MJ. Repeatability limits for measurement of coronary artery calcified plaque with cardiac CT in the Multi-Ethnic Study of Atherosclerosis. Am J Roentgenol 2008;190:W87–92. 6. Iskandrian AE, Bateman TM, Belardinelli L, et al. Adenosine versus regadenoson comparative evaluation in myocardial perfusion imaging: results of the ADVANCE phase 3 multicenter international trial. J Nucl Cardiol 2007;14:645–58.
Editorial Comment
9. Hachamovitch R, Hayes SW, Friedman JD, Cohen I, Berman DS. Comparison of the short-term survival benefit associated with revascularization compared with medical therapy in patients with no prior coronary artery disease undergoing stress myocardial perfusion single photon emission computed tomography. Circulation 2003;107: 2900–7. 10. Shaw LJ, Weintraub WS, Maron DJ, et al. Baseline stress myocardial perfusion imaging results and outcomes in patients with stable ischemic heart disease randomized to optimal
artery disease: results from the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial. J Nucl Cardiol 2012;19:658–69. 12. Panza JA, Holly TA, Asch FM, et al. Inducible myocardial ischemia and outcomes in patients with coronary artery disease and left ventricular dysfunction. J Am Coll Cardiol 2013; 61:1860–70. 13. Gibbons RJ, Miller TD. Should extensive myocardial ischemia prompt revascularization to improve outcomes in chronic coronary artery disease? Eur Heart J 2015;2015:2281–7.
medical therapy with or without percutaneous coronary intervention. Am Heart J 2012;164: 243–50.
14. The ISCHEMIA Trial. Available at: https:// ischemiatrial.org. Accessed February 14, 2016.
8. Shaw LJ, Iskandrian AE. Prognostic value of gated myocardial perfusion SPECT. J Nucl Cardiol
11. Shaw L, Cerqueira M, Brooks M, et al. Impact of left ventricular function and the extent of ischemia and scar by stress myocardial perfusion imaging on prognosis and therapeutic risk
KEY WORDS coronary artery calcium score, myocardial ischemia, myocardial perfusion
2004;11:171–85.
reduction in diabetic patients with coronary
imaging
7. Hecht HS. Coronary artery calcium scanning: past, present, and future. J Am Coll Cardiol Img 2015;8:579–96.
3