Evidence Synthesis
Richard T. Meenan, Ph.D., M.P.H.a; Craig Fleming, M.D.a; Evelyn P. Whitlock, M.D., M.P.H.a;
Tracy L. Beil, M.S.a; Paula Smith, B.S.N.a
The authors of this article are responsible for its contents,
including any clinical or treatment recommendations. No statement in this article
should be construed as an official position of the Agency for Healthcare Research
and Quality, the Centers for Disease Control and Prevention, or the U.S. Department
of Health and Human Services.
Address correspondence to: Richard T. Meenan, Ph.D., M.P.H., Oregon Evidence-based Practice Center, Kaiser Permanente Center for Health Research, 3800 North Interstate Avenue, Portland, Oregon 97227. Phone: (503) 335-2400. Fax: (503) 335-2424. E-mail: Richard.Meenan@kpchr.org.
Select for copyright information.
Contents
Background
Methods
Results
Conclusions
Acknowledgments
References
Notes
Background
In 1996, the U.S. Preventive Services Task Force
(USPSTF) found insufficient evidence to recommend
for or against routine screening of asymptomatic
adults for abdominal aortic aneurysm (AAA) either
with abdominal palpation or ultrasonography. The
USPSTF did recognize that selective screening of
high-risk patients might be beneficial, for example,
in men with other risk factors such as peripheral
vascular disease or a family history of AAA. However,
the USPSTF stated clearly that there was no direct
evidence that screening for AAA reduces mortality or
morbidity in any population.
In 2002, the Research Triangle Institute-University of North Carolina (RTI-UNC) Evidence-based
Practice Center (EPC) performed a topic
review of AAA screening. The USPSTF used this
review to prioritize AAA screening as a topic
requiring an update. Two key developments were
cited in prioritizing AAA screening as a topic to be
updated in an evidence synthesis:
- Several population-based clinical trials of mass screening for AAA were completed.
- A new procedure, percutaneous endovascular repair (EVAR), was introduced, which may provide a less invasive alternative to surgical repair for certain individuals.
In 2003-04, the Oregon EPC conducted an
evidence synthesis of AAA screening, which was led
by researchers at the Kaiser Permanente Center for
Health Research in Portland, Oregon. Within the
overall scope of this update, which was to focus
primarily on effectiveness, the Oregon EPC was also
charged with evaluating the feasibility of integrating
published evidence on the cost-effectiveness of AAA
screening. Many factors related to AAA screening will
have differential effects on the costs and yields of
screening asymptomatic adults for AAA. Economic
evaluations and cost-effectiveness analyses (CEA), in
particular, can summarize the expected benefits,
harms, and costs of screening asymptomatic adults.
Therefore, in conjunction with the evidence
synthesis,1 we also conducted a systematic review
of published CEAs to evaluate the costs and benefits
of screening asymptomatic adults for AAA. This
ancillary CEA review was intended to inform the deliberations of the USPSTF regarding the overall
appropriateness of AAA screening.
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Methods
Search Strategies
To guide our search, our first task was to develop
a preliminary set of key questions around the cost-effectiveness
of population-based AAA screening.
Subsequent consultation with members of the
USPSTF helped us refine the key questions into
their final form.
- Compared with usual care—i.e., no screening—what is the cost-effectiveness of population-based screening of asymptomatic adults for AAA to reduce the risk for abdominal aortic rupture and AAA-specific morbidity and mortality?
- What is the cost-effectiveness of selectively screening adults at higher risk for rupture—e.g., those with a family history of AAA, peripheral vascular disease, and tobacco use—compared with routine screening and usual care?
- Among individuals with 3.0 to 5.4 cm AAAs on initial screening exam, what is the cost-effectiveness of periodic surveillance compared with one-time screening?
- Among individuals without AAA on initial screening exam, what is the cost-effectiveness of re-screening at varying intervals compared with one-time screening?
- How will differences in treatment effectiveness affect cost-effectiveness estimates for AAA screening?
Our set of key questions initially included 2
questions on endovascular AAA repair (EVAR).
However, discussions with experts on the USPSTF
led us to conclude that data on the effectiveness
of EVAR were too preliminary to meaningfully
inform the cost-effectiveness issues surrounding
population-based AAA screening.
In our literature search, we sought studies that
reported both costs and health outcomes of
population-based screening programs for AAA.
We searched MEDLINE®, the Cochrane Central
Register of Controlled Trials, and the National
Health Service Economic Evaluation Database; we
limited our search of each database to publication
dates between 1994 and 2004. Search strategies
were organized using a combination of controlled
vocabulary terms, where available, and free text
terms (Appendix 1). These strategies were
subsequently combined with those designed for
identification of effectiveness studies in each
database. The final search was conducted in April
2004. To identify studies not captured in our
database searches, we manually searched reference
lists of retrieved articles and solicited input from
experts on the USPSTF.
One author (Meenan) reviewed identified
abstracts for potentially eligible articles, which were
then retrieved for full review. Based on information
within the abstracts, we sought studies that
addressed both the costs and health outcomes of
population-based AAA screening.
We excluded
studies that were:
- Not CEA, cost-utility analyses, or cost-benefit analyses.
- Not relevant to any key question.
For each included study, we extracted
and summarized selected elements into 2 evidence
tables (Tables 1 and 2): authors, publication date,
screening intervention, screening interval, study
time horizon, baseline group, AAA size motivating
treatment, prevalence of AAA, AAA-specific
mortality, operative mortality rates (elective and
emergency), AAA rupture rate, analytic approach
(trial-based vs non-trial-based), study perspective,
data sources, utility measures (if any), discount
rate, cost measures, cost-effectiveness results, and
sensitivity analyses.
We abstracted relevant data
from each study into a Microsoft® Access database
developed in 1997 for use by the Committee on
Clinical Prevention Priorities.2,3
We then organized the included studies by key
question (allowing studies to address more than
1 key question) and evaluated the quality of each
against the following 13 criteria based on those
presented in Saha,4 and which themselves are
based on recommendations of the Panel on
Cost-Effectiveness in Health and Medicine.5
Framing
- Are the interventions and populations compared appropriate?
- Is the study conducted from the societal perspective?
- Is the time horizon clinically appropriate and relevant to the study question?
Effects
- Are all important drivers of effectiveness included—e.g., AAA prevalence, AAA rupture
- rates, operative mortality rates (elective and emergency)?
- Are key harms included?
- Is the best available evidence used to estimate effectiveness?
- Are long-term outcomes used?
- Do effect measures capture preferences or utilities?
Costs
- Are all appropriate downstream costs included?
- Are charges converted to costs appropriately?
- Are the best available data used to estimate costs?
Results
- Are incremental cost-effectiveness ratios (ICERs) presented?
- Are appropriate sensitivity analyses performed?
We used these criteria to guide our
categorization of studies as good, fair, or poor.
Quality grades were assigned based on a subjective
assessment of study design and quality of data
inputs. The intent of our review was to focus on
good quality studies, with fair quality studies also
considered as appropriate. Poor quality studies
were excluded from further review. (Our definition
of fatal study flaws that would lead to a poor
quality rating is provided in Appendix 2.) The
goals of our systematic CEA review were to
identify the best available evidence regarding a
particular key question, and to critically review and
synthesize that evidence to answer the question in
an evidence-based way.
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Results
We initially reviewed the abstracts of 241 studies
and identified 25 definite or possible economic
evaluations, for which we reviewed the full articles.
We determined that 4 were relevant to 1 or more
key questions. The other 21 articles were excluded
from further analysis, either because they were not a
CEA (or other form of economic evaluation such as
a cost-benefit analysis) or were not relevant to any
key question. Where necessary, we converted results
reported in non-U.S. currency to U.S. dollars, and
used the Medical Care component of the Consumer
Price Index to convert all results to 2003 dollars.
Key Questions
1. Compared with usual care—i.e.,
no screening—what is the cost-effectiveness
of population-based
screening of asymptomatic adults for
AAA to reduce the risk for abdominal
aortic rupture and AAA-specific
morbidity and mortality?
We determined that 1 good-quality study (the
Multicentre Aneurysm Screening Study6 [MASS])
and 2 fair-quality studies7-8 addressed the primary key
question regarding the overall cost-effectiveness of
population-based AAA screening. MASS6 was trial-based;
the others were based on published literature
and/or data from a single hospital or health system.
As will be discussed further, the superior quality of
its effectiveness data distinguished MASS from "fair"
studies such as those conducted by Lee, et al., and
Frame, et al. In addition, we believe that the detailed
micro-costing approach used in the MASS CEA, as
well as its use of probabilistic sensitivity analysis,
mitigated its being set outside the United States (it
was conducted in the United Kingdom) and justified
a "good" quality rating. "Fair" quality ratings were
assigned to studies based primarily on the uncertain
quality of their effectiveness and/or cost data, even
if most other favorable design characteristics were
present. Poor studies combined lower-quality effectiveness and/or cost data with an absence of
most other favorable design characteristics—e.g., no
downstream costs, no health state utilities. No study
(including MASS) was conducted from the societal
perspective.
Each study considered population-based
screening of adult males by ultrasonography
compared with no screening, although screening
protocols differed:
- MASS6—initial screen of men aged 65 to 74 with quarterly surveillance of 4.5 to 5.4 cm AAAs and annual surveillance of 3.0 to 4.4 cm AAAs.
- Frame, et al.8—screening of men aged 60 to 80 by ultrasonography or physical examination with 1 followup at 5 years.
- Lee, et al.7—one-time "quick screen" by ultrasonography of men aged 70.
The studies also used different time horizons:
- MASS6—4 years (trial length) and 10 years.
- Frame, et al.8—20 years.
- Lee, et al.7—lifetime.
Over 4 years in the MASS6 trial, AAA screening
generated an "incremental" cost-effectiveness ratio
(ICER) of $57,000/life-years (LY), $72,000/QALY
(quality-adjusted life-years) relative to no screening.
(It must be emphasized that these ratios are not
truly "incremental" because no study compared
population-based screening with targeted screening,
a more meaningful comparison, but rather only to
the absence of screening.)
When life savings were projected out 6 years
for a total 10-year time horizon, the ICER for
screening dropped to $16,000/LY (approximately
$20,000/QALY). This latter estimate is similar
to Lee, et al.'s baseline ICER for screening of
$14,000/QALY.7 However, Frame, et al.8 obtained
a significantly higher ICER of $72,000/LY for onetime
ultrasonography screening ($50,000/LY for
physical exam plus ultrasonography for positives).
Each study used a different base case discount
rate:
- MASS6—6 percent for costs, 1.5 percent for benefits.
- Frame, et al.8—5 percent.
- Lee, et al.7—3 percent.
The use of
different discount rates in MASS6 is not currently
recommended practice, although proponents argue
that it is appropriate if one believes that the value of
health increases over time.9 In any case, it introduces
bias in favor of screening—i.e., lower ICERs—by
raising the value of benefits relative to costs. In a
sensitivity analysis, MASS6 applied a 3-percent discount
rate to both costs and benefits, which raised the
ICER for AAA screening over 4 years to
approximately $62,000/LY ($78,000/QALY).
Next, we discuss aspects of each model that we
believe influenced their specific results:
- MASS6: This CEA included few details about
the MASS effectiveness model; however, the MASS
study itself (Ashton, et al.10) was assigned a "good"
quality rating based on USPSTF criteria (Harris, et
al.11) in our associated evidence synthesis (Fleming,
et al.1). Combined with satisfaction of other CEA
quality criteria, we used this rating to support our
assignment of a good quality rating to the MASS
CEA. This model apparently considered reduction
in the intermediate outcome of AAA-related
mortality as the basis for effectiveness (odds ratio
[OR], 0.58; 95% confidence interval [CI],
0.42-0.78), which was then expressed in terms of
life-years-saved. The MASS trial did not show that
screening reduced all-cause mortality (OR, .97;
95% CI, 0.93-1.02).10 Avoiding death from one
cause (e.g., AAA) compared with avoiding death
from another cause (e.g., coronary heart disease)
would be cogent only if a much greater disutility
were attached to AAA-related mortality. There is
no evidence supporting this assertion. Expressed in
terms of mean survival time, free from AAA-related
mortality at 4 years, screening resulted in an
incremental gain of 0.16 to 1.47 days of life for
each man screened.
These authors applied detailed micro-costing to
both the screening process itself and the surgical
procedures, and included downstream costs related
to post-surgical life expectancy. This was also the
only study of those we reviewed to use probabilistic
sensitivity analysis. The authors also acknowledged
that the focus of the MASS trial was AAA-specific
mortality; univariate sensitivity analysis suggested
that focusing on all-cause mortality would lower
the ICER of screening by over half ($26,000/LY)
relative to the 4-year estimate of $57,000/LY.
The authors did not explain their calculations;
we inferred that the lower ICER using all-cause
mortality results from the greater absolute number
of deaths prevented over the 4-year trial period (105
[all-cause mortality] vs 48 [AAA-specific mortality]).
- Lee, et al.7: The screening and management
protocol in this model was reasonable based on
recent trial results. The sources of key parameter
estimates were not presented in the published article,
although the authors offered to make them available
to readers; we were unable to obtain this information
from the authors. Life-expectancy was modeled using
all-cause mortality over the individual's lifetime. In
the base-case analysis, screening compared with no
screening in a cohort of 70-year-old men generated
an expected incremental gain of 0.059 QALY or 22
days for each man screened. Based on our systematic
review, the risk for rupture for 3.0 to 4.0 cm (0.6 percent
per year) and 4.0 to 5.0 cm AAAs (2.3 percent per year)
appear to be overstated. For example, in the UKSAT
and ADAM trials, the annual rupture risk for 4.0 to
5.4 cm AAAs was 0.6 percent and 1.0 percent, respectively. Also
the distribution of AAA size in screened patients was
significantly skewed toward larger size AAAs than
found in population screening studies.12 The analysis
also appears to assume 100 percent compliance with
screening, although this is not stated. Taken together,
these factors create a bias favoring screening that
may lead to overestimation of its effectiveness.
Micro-cost estimates for screening and treatment
(from the health system perspective) came from a
literature review and a single hospital (New York
Presbyterian). Disease-specific long-term cost and
quality-of-life estimates were included for renal
failure, stroke, major amputation (related to
diabetes), and myocardial infarction. Univariate
sensitivity analyses were conducted focusing on
AAA prevalence in the screened population, annual
incidental detection rate in the unscreened group,
and age at initial screening.
- Frame, et al.8: The Frame, et al. model compared
one-time screening with elective repair of AAAs > 4.0
cm with a usual care approach involving elective
repair of incidentally discovered AAAs and emergency
repair of ruptured AAAs. At the time of its 1993
publication, ADAM and UKSAT trial results
comparing immediate repair of 4.0 to 5.4 cm AAAs
vs surveillance with delayed repair of AAAs
expanding to 5.5 cm were not available.13,14 In the
ADAM and UKSAT trials, however, there were no
significant differences in either AAA-related or all cause
mortality between patients undergoing
immediate repair of 4.0 to 5.4 cm AAA vs patients
undergoing surveillance with delayed repair of AAAs
expanding to 5.5 cm. Taking this into account, the
Frame, et al. model would be comparable to clinical
strategies used in the population-based AAA screening
trials, except that 3.0 to 3.9 cm AAAs would receive
no further followup. Life-expectancy was modeled
using all-cause mortality over a 20-year time horizon
for a cohort of 10,000 males aged 60 to 79 years,
adjusted to match the age distribution of the U.S.
population. Screening resulted in an incremental gain
of 57 life years in a cohort of 10,000 men screened,
or approximately 2 days' average improvement in life
expectancy for each man. The authors conclude that
screening was of small benefit.
Cost data came from a systematic review by the
Canadian Task Force on the Periodic Health
Examination, MEDLINE®, and article bibliographies.
Gross-cost values from the health system perspective
for surgery, ultrasonography tests, and followup
office visits were taken from earlier literature. This
study's estimates of surgical costs ($46,000 for
elective and $90,000 for emergency surgery in year
2003 dollars) were significantly larger than estimates
in most subsequent studies. Downstream costs post-treatment
were included. The only sensitivity
analyses presented varied parameters simultaneously
between their most and least favorable values for
screening. Frame, et al.8 also found that for both
screening protocols, a second screen 5 years after the
first generated ICERs that were quite large ($1.5
million/LY relative to a single ultrasonography and
$1.3 million/LY relative to abdominal palpation with
an ultrasonography for positive results).
2. What is the cost-effectiveness of
selectively screening adults at higher
risk for rupture—e.g., those with a
family history of AAA, peripheral
vascular disease, and tobacco use—compared with routine screening and
usual care?
Two fair-quality studies, by Lee, et al.,7 and
Soisalon-Soininen, et al.,15 addressed the cost-effectiveness
of selective screening for patients with
higher rupture risk. Lee, et al.7 examined the effects of age at initial screening and AAA prevalence at
initial screening, which served as a proxy for specific
risk factors: sex (7 percent males, 1 percent females, 4 percent females
> age 60), circulatory disease (9-12 percent), smoking
history (17 percent), or family history of AAA (19 percent).
Soisalon-Soininen, et al.15 examined selective
screening of male relatives > age 50 of AAA patients.
Life-expectancy was modeled using all-cause
mortality over a 17-year time horizon. Both studies
compared targeted screening with no screening;
neither compared routine, but systematic,
population-based screening with targeted screening.
Lee, et al.7 found that screening males beginning at
age 60 (vs age 70 at baseline) lowers the ICER from
$14,000/QALY to approximately $5,000/QALY. In
generating the latter result, Lee, et al.7 maintained the
baseline AAA prevalence estimate of 7 percent. By age 83,
the ICER rises to $60,000/QALY. AAA prevalence at
initial screening of 2 percent or higher generates an ICER
of $10,000/QALY or below—e.g., a 19-percent prevalence
(proxy for family history of AAA) generates an ICER
of $8,460/QALY.
In Soisalon-Soininen, et al.15
screening male relatives > age 50 generates an ICER
of $8,900/LY; note that their denominator does not
include quality adjustments, so their ICER in terms
of QALYs would be somewhat higher than reported.
However, also note that Soisalon-Soininen et al.'s
cohort is younger than Lee, et al.'s (age 50 vs 70),
and has a much lower AAA prevalence than Lee et
al.'s (8.2 percent based on their own data vs 19 percent from the
literature).
One might expect that using comparable
ages would tend to widen the gap between the ICER
estimates, but that using comparable prevalence
values would tend to bring them closer together.
3. Among individuals with 3.0 to 5.4 cm
AAAs on initial screening exam, what
is the cost-effectiveness of periodic
surveillance compared with one-time
screening?
No identified study addressed the specific issue
of periodic surveillance vs one-time screening.
4. Among individuals without AAA on
initial screening exam, what is the
cost-effectiveness of re-screening at
varying intervals compared with one-time
screening?
No identified study addressed the specific issue of
targeting persons without AAA on initial screening
for subsequent re-screening.
5. How will differences in treatment
effectiveness affect cost-effectiveness
estimates for AAA screening?
Only MASS6 addressed differences in treatment
effectiveness on the cost-effectiveness of AAA
screening. MASS6 focused on AAA-specific
mortality—i.e., "survival free from mortality related
to abdominal aortic aneurysms for each individual
up to 4 years," and including 30-day peri-operative
mortality. In sensitivity analyses, the authors
substituted all-cause mortality from the trial for
AAA-related mortality, and found that the ICER
for screening fell by roughly half ($26,000/LY). The authors acknowledged that the trial was not
powered to detect changes in all-cause mortality,
and the difference between screening and no
screening for such mortality was not significant.
Extending the time horizon from 4 to 10 years
lowered the baseline ICER (again, in terms of AAA-specific
mortality) from $57,000/LY to $16,000/LY.
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Conclusions
Existing evidence—e.g., MASS6, Lee, et al.7—
points to a cost-effectiveness ratio for population-based
AAA screening (compared with no screening)
that lies in the range of $14,000 to $20,000/QALY.
The much higher ICER obtained by Frame, et al.8
is explained at least in part because of relatively
higher surgical cost estimates, which are no longer
appropriate. Applying current discounting practice
to the MASS results would raise its estimated ICER
above $20,000/QALY, although how much is
uncertain. In any case, no study compared
population-based screening with targeted screening,
which would be a more appropriate comparison.
These results rely on the quality of the
effectiveness estimates, which is an open question
based on our associated systematic review. Each
effectiveness model review showed, at best, modest gains in life expectancy ranging from 2 days to 4 months favoring screening vs no screening, and
immediate repair vs surveillance for moderate-sized
AAAs. In each case, concerns regarding the structure
or assumptions of the models indicate that even these
modest gains may be overstated. Our assessment is
supported by the results of clinical trials examining
both screening and management of moderate-sized
AAAs that show no differences in all-cause mortality.
In any case, current evidence addressing the cost-effectiveness
of population-based AAA screening is
extremely limited. Although more recent trial data
on mass screening have been generated, to date only
MASS has produced a CEA based on such data. Also,
our evidence synthesis1 concluded that evidence of
the effectiveness of EVAR, especially over the longer
term, did not yet exist; therefore, we chose early on
to exclude EVAR from our review process. Evidence
that addresses important economic dimensions of
screening—e.g., effectiveness (and appropriate targets)
of selective screening, surveillance of small AAAs,
re-screening of individuals without AAA, appropriate
effectiveness measures—is nearly non-existent. The
quality of cost data varies significantly. All analyses
reviewed were conducted from the health system
perspective. None considered patient-incurred
burdens of time and money related to AAA
screening and treatment. It is unknown whether
their inclusion would alter policy implications
about the cost-effectiveness of AAA screening,
but valid measures of them would be helpful.
CEA of AAA screening would benefit considerably
from more extensive sensitivity analyses. A general
limitation across studies is a focus on univariate
sensitivity analysis without consideration of plausible
connections between parameters—e.g., age and
rupture risk. MASS6 provides a framework for the
future application of probabilistic sensitivity analysis,
which could inform CEA users of the likely
robustness of ICER estimates based on changes in
AAA-related mortality.
Also, most studies took the design of the
screening program as given, especially the screening
interval. Future analyses should explore implications
of variations in the interval of screening—e.g.,
semi-annual vs annual vs bi-annual. Furthermore,
as we have noted, comparisons were made between
a screening program and usual care (no screening),
which tends to bias results toward screening. In
cases where a targeted screening program is of
interest, it would be useful to compare the targeted
program with a systematic population-based
program as well as, or in lieu of, usual care.
In conclusion, currently available evidence
suggests that population-based AAA screening may
have the potential to produce a year of life at
reasonable cost, but new CEAs based on recently
completed screening trials are needed before formal
policy recommendations will be appropriate.
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Acknowledgments
Additional members of the Oregon EPC project team include Daphne Plaut, M.L.S., research librarian. Members of the USPSTF who served as leads for this project include Ned Calonge, M.D., M.P.H.; Russell Harris, M.D., M.P.H.; Mark S. Johnson, M.D., M.P.H.;
Diana B. Petitti, M.D., M.P.H.; and Steven M. Teutsch, M.D., M.P.H.. The authors would like to thank David Ballard, M.D., Ph.D., and the other reviewers for their contributions to this project. Finally, the authors thank Joanna Siegel, Sc.D., and Gurvaneet Randhawa, M.D., M.P.H., of AHRQ, for their many cogent observations throughout the course of the project.
This study was conducted by the Oregon Evidence-based Practice Center under AHRQ contract No. 290-97-0018, Task Order No. 2, Rockville, MD.
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Notes
Author Affiliations
[a] Meenan, Fleming, Whitlock, Beil, Smith: Oregon Evidence-based Practice Center, Center for Health Research, Kaiser Permanente, Portland, Oregon.
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Return to Contents
AHRQ Publication No. 05-0569-C
Current as of February 2005
Internet Citation:
Meenan RT, Fleming C, Whitlock EP, et al. Cost-Effectiveness Analyses of Population-Based Screening for Abdominal Aortic Aneurysm. Evidence Synthesis. AHRQ Publication No. 05-0569-C, February 2005. Agency for Healthcare Research and Quality, Rockville, MD. http://www.ahrq.gov/clinic/uspstf05/aaascr/aaacost.htm