TAYLOR
ET AL., 34th BETHESDA CONFERENCE: Can Atherosclerosis Imaging Techniques
Improve the Detection of Patients at Risk for Ischemic Heart Disease?
J Am Coll Cardiol 2003;41:11:1855-917
BETHESDA
CONFERENCE REPORT
34th Bethesda Conference: Can Atherosclerosis Imaging Techniques
Improve the Detection of Patients at Risk for Ischemic Heart Disease?1
Allen
J. Taylor, MD, FACC, Conference Co-Chair
C. Noel Bairey Merz, MD, FACC, Conference Co-Chair
James E. Udelson, MD, FACC, Conference Co-Chair
Introduction
This
document presents the summary findings from the 34th Bethesda Conference:
“Can Atherosclerosis Imaging Techniques Improve the Detection
of Patients at Risk for Ischemic Heart Disease?” This conference,
comprised of five writing groups, began the process of formulating
report outlines and documents in January 2002. The conference, held
October 7, 2002, at the Heart House in Bethesda, Maryland, allowed
for open discussion, constructive commentary, and the formulation
of summary comments resulting in the documents presented in this
report. The purpose of Bethesda Conference 34 (BC 34) was to review
the current status and controversies within the integration of atherosclerosis
imaging into clinical cardiovascular medicine. Each Task Force was
also specifically charged with developing recommendations on “Future
Directions” for the field of atherosclerosis imaging, as appropriate
within the scope of issues they considered.
Although
it is recognized that atherosclerosis imaging, including many different
emerging technologies, may enhance the detection and treatment of
patients at risk for coronary heart disease (CHD), much remains
unknown about these modalities despite the fact that many are rapidly
moving into broad clinical use. Further consideration of these tests
as clinical tools extends prior efforts such as the Prevention V
Conference of the American Heart Association, and the National Cholesterol
Education Program, Adult Treatment Panel III guidelines. The latter
treatment guidelines focused particular attention on the relevance
of diagnosing subclinical atherosclerosis for altering lipid treatment
goals by designating that aortic, peripheral, and carotid artery
disease were considered to represent “Coronary Heart Disease
Equivalents” because the level of CHD risk and CHD event rates
associated with these conditions is approximately equivalent to
the level of risk seen in stable CHD. Thus, screening for atherosclerosis
in other vascular regions has been considered for CHD risk evaluation.
The
BC 34 brought together the multidisciplinary expertise of pathologists,
epidemiologists, imaging experts, experts in disease detection and
treatment, clinical trialists, and outcomes researchers to work
together for the common goal of crystallizing the current science,
addressing the many unanswered questions on the appropriate clinical
use of the available imaging modalities, and envisioning the future
of this discipline. For the purpose of this Bethesda Conference,
we adhered to the use of the term “coronary heart disease”
(CHD) defined as cardiac events or symptoms related to myocardial
ischemia and/or injury due, in the vast majority of cases, to atherosclerosis.
Such events include unstable angina, myocardial infarction (MI),
and sudden death due to ischemic heart disease. It is important
to recognize that coronary atherosclerosis, ischemia, and events
exist as a continuum. The former need not necessarily lead to the
latter, while the latter is virtually always preceded by the presence
of the former. Thus, the challenge is not only to “detect”
coronary atherosclerosis, but also to “predict” which
individuals, in whom coronary atherosclerosis is detected, will
progress to develop events. Finally, the use of global risk scores,
such as the Framingham Risk Score, was considered as the most appropriate
initial assessment of all patients undergoing coronary risk screening.
Additional testing, such as imaging, must provide incremental riskprediction
information to the Framingham Risk Score. A modification to this
subgrouping has recently been suggested to improve CHD risk assessment
in asymptomatic people. This approach considers a less than 0.6%
per year (less than 6% over 10 years) risk for coronary events as
“low-risk,” 0.6% to 2.0% per year (6% to 20% over 10
years) risk is termed “intermediate risk,” and individuals
with greater than or equal to 2.0% per year (greater than or equal
to 20% over 10 years) risk are “high-risk.” We have
adopted these risk groupings for this Bethesda Conference.
TASK
FORCE 1: Identification of Coronary Heart Disease Risk: Is There
A Detection Gap?
Task
Force 1 addressed the rationale for new methods to detect cardiovascular
risk based upon limitations of current clinical screening methods
within the context of primary CHD prevention. Current CHD risk-screening
tools are imperfect and imperfectly applied, thus potential opportunities
exist with atherosclerosis imaging for CHD risk assessment refinement.
The “detection gap” may be defined as the difference
between CHD cases or events currently detected and the total burden
of disease or events among the population. Whether this gap may
be due to current testing not optimally detecting disease, or due
to testing not being appropriately applied, is incompletely understood.
Although agreed that a detection gap in CHD prognosis exists, the
precise size of this gap, and thus the potential for atherosclerosis
imaging to reduce cardiovascular morbidity and mortality through
enhanced risk screening, is unknown, but may be substantial. The
application of atherosclerosis imaging to intermediate-risk populations
is theoretically “optimal” based upon the Bayes’
theorem. This assumption, and the potential extension of these tests
to both low- and high-risk populations, is in need of a greater
body of supporting evidence in which incremental management and
prognostic impact is demonstrated. Proper calibration of the results
of atherosclerosis imaging modalities is necessary to avoid systematic
under- or overdetection of patients as being at heightened CHD risk.
In
concert with efforts to improve the accuracy of officebased CHD
risk detection, a need exists for more widespread clinical use of
CHD risk-scoring algorithms. Recognition of such efforts as valid
and valuable clinical assessments in the form of specific reimbursement
codes would further the penetrance of these tools into clinical
practice. The community of cardiologists must champion CHD prevention,
beginning by fully translating existing data on effective risk interventions
into practice.
TASK
FORCE 2: What Is the Pathologic Basis for New Atherosclerosis Imaging
Techniques?
Task
Force 2 addressed the anatomic targets within atherosclerosis that
form the basis for imaging modalities, including the relationship
between plaque burden and the pathology of vulnerable atherosclerosis.
Plaque burden is generally substantial in the majority of patients
with acute coronary events. Ultimately, imaging individual plaque
components might achieve importance in detecting both lesions and
individual patients prone to plaque rupture. However, an incremental
value for imaging atherosclerotic components (above and beyond assessing
plaque burden) in predicting acute coronary events requires validation.
A particularly rich area for exploration of vulnerable plaque detection
is in younger individuals who often have relatively little plaque
burden. In the future, the development of a “vulnerable plaque
scoring system” could be feasible, including the characteristics
of: 1) fibrous-cap thickness, 2) necrotic core size (both percent
of cross-sectional plaque area and length), 3) degree of macrophage
infiltration, and 4) compensatory remodeling. In comparison, coronary
calcification principally reflects overall plaque burden, although
it has pathology relationships to healed plaque ruptures and compensatory
remodeling. Thus, indirectly, calcium measurements may reflect underlying
plaque biology and propensity for future plaque rupture events.
TASK
FORCE 3: What Is the Spectrum of Current and Emerging Techniques
for the Noninvasive Measurement of Atherosclerosis?
Task
Force 3 reviewed the existing and emerging noninvasive technologies
for atherosclerosis imaging. The imaging modalities considered within
the document include carotid ultrasound for assessment of intima-media
thickness (IMT), coronary calcium scanning, cardiovascular magnetic
resonance imaging (CMR) for atherosclerosis, brachial artery reactivity
testing, and the ankle-brachial index (ABI). Development of atherosclerosis
imaging tests must be viewed as a continuum from device validation,
diagnostic accuracy, prognostic accuracy, to demonstrating an independent
and incremental impact on CHD risk management and CHD outcomes.
The currently available atherosclerosis imaging modalities are in
different phases of development. The modalities vary greatly in
important parameters such as their availability, their reproducibility,
and their costs. In general, the available data (although no data
are available for CMR) indicate that abnormal values on atherosclerosis
imaging have been associated with a three-fold or greater risk of
a future CHD event. Although the supporting data for ABI and IMT
most clearly show an independent prognostic impact of the test results,
these technologies are also most static, with little room for further
technical development. None of the available tests have yet been
demonstrated to impact CHD management or outcomes. The diagnostic
and prognostic effectiveness of more mature modalities as CHD risk
screening tools cannot be generalized to newer modalities (e.g.,
plaque burden testing with CMR must be independently validated for
CHD prognosis). Among all modalities, a need exists to move toward
broader standardization of imaging modalities to ensure external
validity of published reports, and enable cross-study comparisons.
Because atherosclerosis imaging test results can be considered continuous,
improved definition of “positive” versus “negative”
results is warranted. There is a need for cross-modality prospective
comparisons recognizing that, among important subgroups (e.g., gender
and race), modalities may perform differently in detecting CHD prognosis.
TASK
FORCE 4: How Do We Select Patients for Atherosclerosis Imaging?
Task
Force 4 addressed the application of atherosclerosis imaging tests
to patients, including the selection of patients within categories
of clinically predicted heart disease risk, matching patients to
specific imaging modalities, and management of the results. A valuable
screening test should: a) identify both high- and low-risk groups
(e.g., a low proportion of false negative and false positives) more
accurately; b) enhance the identification of high-risk individuals,
c) result in a favorable impact on disease outcomes; d) be relatively
free of risk; e) be cost-effective when compared to the current
screening modalities; and f) educate the public concerning atherosclerosis
and vascular disease risk. Selecting intermediate-risk patients
for screening with plaqueburden assessment has potential theoretical
advantages within a Bayesian approach to screening. More study is
needed in low- and high-risk patients. Once a modality is shown
to incrementally and to a clinically important extent
predict cardiovascular risk, then effectiveness studies are appropriate
to establish threshold values (indicating a shift to increased intensity
of risk-factor treatments) and to determine their impact on management
and CHD outcomes. Until such effectiveness studies are complete,
the appropriateness of shifting individual patients to more intense
risk-reduction therapies based on atherosclerosis imaging modalities
requires clinical judgment.
Limitations
of modalities within specific patient populations are beginning
to emerge. Currently, coronary calcium detection and the ABI, abnormal
primarily in the setting of advanced atherosclerosis, have limited
application to young patients. A specific ethnic-based imaging limitation
appears to be present for coronary calcium, particularly in African-Americans.
The outcome of efforts to better detect CHD risk is ultimately dependent
upon the effectiveness of the risk-reduction therapies that ensue.
A policy of self-referral to atherosclerosis imaging tests remains
premature and should be the subject of formal effectiveness study
prior to widespread adoption of this practice.
TASK
FORCE 5: Is Atherosclerosis Imaging Cost-Effective?
Task
Force 5 addressed the role of cost-effectiveness considerations
in atherosclerosis imaging. Cost-effectiveness data are increasingly
being applied to the evaluation of imaging technology, and optimally
it should be considered in parallel with the development of imaging
modalities. The aim of cost-effectiveness analysis is to guide health
care payers and regulators in the evaluation of new therapies and
technology for the setting of standards for use, reimbursement,
and for approving use. A requisite amount of highquality clinical
effectiveness data is necessary for the determination of an added
economic benefit. Thus, an important need exists for high-quality,
long-term outcome data to be developed for all of the newer imaging
modalities so as to inform potential models of cost-effectiveness.
Standards for defining cost-effectiveness include the amount of
resources or costs required to achieve a given clinical benefit.
Such standards, developed from therapeutic intervention data and
models, may not be directly applicable to the use and application
of imaging modalities to detect subclinical atherosclerosis. As
such, professional societies and stakeholder government agencies
as well as senior leaders in health care economic analysis should
convene to create and define standards for evaluating imaging procedures
with regard to costs and outcomes. Current clinical and economic
effectiveness analysis are hampered by a lack of clinical algorithms
with noted inputs for serial testing, post-test treatment strategies,
resultant proportional risk reduction, as well as induced resource
consumption levels with a variety of atherosclerosis imaging modalities.
Future research in the area of atherosclerosis imaging must provide
more definitive data regarding the links between the initial imaging
procedure and results and subsequent downstream testing and treatment
effectiveness. Substantial additional data are needed for virtually
all currently available and developing modalities of atherosclerosis
imaging prior to the support of any techniques being considered
as cost-effective.
Call
for Clinical Trials
Observational data are key to improving management of cardiovascular
disease, but diagnostic imaging utility should also be tested with
randomized clinical trials. Undertaking an experimental design,
including blinding the involved patients and their physicians, would
allow rigorous testing of the utility of the new procedures. Appropriate
exclusion criteria within such an experimental design would be necessary
to address concerns over withholding information for individuals
with very “abnormal” test results. Alternatively, rigorous
analysis of testing strategies in this situation might be undertaken
by randomizing patients to testing or no testing, then prospectively
assessing outcomes. Important design elements include demonstrating
incremental diagnostic and management impact beyond that achieved
with global risk scoring algorithms, and inclusion of emerging markers
of CHD risk. Such studies would also serve the valuable purpose
of determining appropriate thresholds for the results of atherosclerosis
imaging and providing input data for cost-effectiveness models.
Finally,
an important concept worthy of testing is the value of a “negative”
test—for example, toward reducing the post-test probability
of disease and validating therapeutic avoidance. As with all clinical
trials, both the presence and magnitude of clinically relevant results
are important interpretive considerations. Funding support for such
initiatives from both the private and public sector is strongly
encouraged.
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