Epidemiology of AAA Screening - SD

Introduction

My name is Mark Lockhart.
I am an associate professor of radiology at the University
of Alabama at Birmingham.
My areas of interest are ultrasound,
specifically doppler imaging
and gen urinary imaging, including pelvic floor.

Epidemiology of Abdominal Aortic Aneurysm Screening

The topic of today's lecture will be epidemiology
of screening for the Abdominal Aortic Aneurysm
Epidemiology of Abdominal Aortic Aneurysm Screening.
The objectives of this discussion are
to discuss the concepts associated with screening
for abdominal aortic aneurysm
to describe the non-basic principles of screening.
And to address the role of ultrasound
for aneurysm screening, I'll
rely heavily on three references, one by
Osky talking about the criteria for screening, one
by Philip Cole,
which was one of the earliest
population screening for cancer articles.
And then also a recent
Cochrane database systematic review by Cosford.

Why Should We Screen?

The purpose for screening for cancer is
to reduce the morbidity
and mortality for that cancer among the person screened.
So you can see for any other type of disease process
that would have morbidity
and mortality, this could be applied.
Now to accomplish this, the operational goal
of screening is the application of relatively simple,
inexpensive tests to a large number of persons in order
to classify them as likely
or unlikely to have, in this case, the aneurysm,
that you are trying to screen for.

Key Concepts in Screening

First of all, we need to go over a few concepts.
We need to understand the timeline
of the disease process in general.
We need to understand the epidemiological concepts,
which can either help
or hinder the results of a screening trial.
And we need to consider the nine principles of screening,
as it applies to this.

Timeline of Disease

First of all, the timeline of disease.
At some point, each of us is born,
the cells are working fine,
and at some point things go wrong
and you get the onset of disease.
Sooner or later, the number of cells
or that abnormality becomes large enough
that we can actually detect it by an imaging study.
At some point, we actually decide to do an imaging study
where that we actually detect the disease
and make the diagnosis.
Hopefully this is occurring before any signs
or symptoms such as, collapse or death would occur.
And then no matter what, at some point,
obviously we all die.
I referred to this slide as smoke and mirrors
because a lot of the evaluation of
population based disease has to use epidemiologic
methods that could look better
or worse than in reality they are.
And this is due to bias.

Biases in Screening

Bias is a systematic deviation from the truth.
And the two types of bias that really affect these type
of evaluations are lead time bias.
And in this case, you are finding the disease earlier,
and yet you're not changing the time of your death.
So all it's doing is allowing you to live with the,
disease for a longer time.
Length bias is a little different in that it's related more
to the screening technique.
If you screen once, you're going
to find more indolent disease than,
more severe aggressive disease.
And it's not until you reduce the interval
of your screening tests
that you really find the more aggressive disease.
So just to start with, the clinical phase
of the disease is from the time that you either have signs
and symptoms until you die.
Lead time bias is the
additional time from the diagnosis
until you would've seen those signs or symptoms.
But notice in this example, the time
of death did not change.
So all we did by finding the disease earlier
was allowed the person to live with
that disease for a longer time.
Length bias, is shown here is a, grid with a number
of years, and each of the arrows represents a disease
that has begun until the point of their death.
So you can see that there are some disease processes
that are very short aggressive, and then some are very long.
So if we do a single screening notice
that we will pick up predominantly the slower,
longer lasting disease processes.
If we increase the interval of the screening, say
to every other year, our main survival will go from four
years down to three years.
So if we did a single screen,
it could make our results look a lot
better in terms of survival.
And it's not until we do almost a yearly screen in this
example that we pick up all of the disease process
and notice the additional ones that we found
were very aggressive, disease.

Nine Principles of Screening

So now we'll turn our attention
to the nine principles of screening.
The disease must be important.
There must be a prevalent, detectable, preclinical disease.
There. A disease must not have much pseudo disease.
There has to be a test which is accurate
for the preclinical disease.
It doesn't help if the test detects it
after they're already presenting with symptoms and signs.
There must be a, ability of the test
to detect the disease before a critical point is reached.
Meaning not after the disease has reached such a point
that nothing can help.
The test must be safe,
it must be cheap and widely available.
There must be a treatment, and then the treatment
before symptoms
or signs should be more effective than if you were to wait
until symptoms and signs were present.

Application to Abdominal Aortic Aneurysm Screening

So looking at each of these individually with regards
to screening for abdominal aortic aneurysm,
we'll first talk about importance of disease.
So do mortality
and morbid justify screening for this disease?
Well, mortality of ruptured aneurysm is 80%.
Mortality of AAA repair is 5%.
So clearly, if we can catch these patients earlier,
there is hope that we would be able
to reduce their mortality In terms of the natural history,
do we understand the disease process?
Is there an adequate time for us to detect the disease
that we can make a difference
before they actually have symptoms?
And is there a low occurrence of pseudo disease?
AAA is present in 5% of men age 65.
So there is quite a bit of disease out there,
and we do understand the disease process
and how it progresses with age
because 10% are prevalent in, men at age 79,
Referring to the disease process.
Clinical phase again is from the onset of symptoms or signs.
Preclinical disease is before this point,
but now I'm gonna add another term to the discussion.
Detectable preclinical phase is when we have detectable
disease, but no symptoms or signs.
Going back to our diagram, you've seen this
before where we have preclinical and clinical,
but now let's bring in the D-D-P-C-P
and you can see that this is a smaller subset.
So it's a shorter time period for us
to hopefully find disease that we can treat
and make a difference before they have signs or symptoms.
Going back to the natural history of disease,
we wanna look at whether or not there is pseudo disease
because pseudo disease can cause us to over diagnose
the disease process for a research trial,
this can actually be good for the results
because if you can find a lot of disease
that really would never have hurt
or killed the patient in the first place,
they'll probably live longer
and it would make the study look art artificially better.
Type one is a pseudo disease where that it looks the same
as the real disease, yet there's no disease progression.
Type two is the actual pathologic process,
but it has such a slow progression
that it will never actually hurt or kill the patient.
This is reflected in,
abdominal aortic aneurysms in the fact that not all patients
with AAA die from rupture.
You can have a fairly good size aortic aneurysm
and not die of it, die from something else.
So moving our attention away from the disease process toward
the test, we're gonna talk about four different areas.
Test characteristics.
We want to know is it sensitive, is it specific?
Is it cost effective?
When we're talking about sensitivity, we're talking about
of those with the disease, how many do we characterize
as a true positive?
So in this, a high sensitivity reduces the number
of false negatives for specificity
of the ones without disease.
How many tests truly negative.
So again, in this,
we're reducing our false positives if further testing
would be dangerous to the patient.
This is quite important for a screening study so
that we're not putting them through the added risk,
when it's not really present.
Abdominal aortic aneurysm threshold value
will definitely affect the sensitivity and specificity.
If you say that three centimeters, if the critical value,
you're going to diagnose a lot higher number
of aneurysms than if you say four.
Program characteristics Deal with how does the prevalence
of disease affect your ability
to characterize the disease with your testing?
Predictive value positive is of those who test positive,
how many are actually true positives in this way?
Abdominal aortic aneurysms are generally hurt
by the low prevalence of disease,
and so it's critical to pick the right population
to screen predictive value.
Negative is of those who do not have the disease,
how many tests negative,
and this is also related to the prevalence of disease.
Switching to cost effectiveness evaluation,
the incremental cost effectness ratio is generally
what is used to determine whether from a population
standpoint the screening is cost effective.
They look at the cost effectiveness in in the format
that I show on the right side of the screen,
the more expensive test subtracted from the next
most expensive test.
And then the qualities of the better test,
which is hopefully higher than the qualities
of the next most effective test
Qualities are quality adjusted life years.
So if you're spending more money,
hopefully you're gaining some years life
because if you're spending more money
and they're actually doing more poorly, then
that's obviously not the best choice.
Just as an example, if the more expensive test was 40,000
and the next was 20,
and yet it increased 0.2 years of life in the population,
this would equate to about a hundred thousand
dollars, per life year.
However, what if
after the repair of the aortic aneurysm, their quality
of life is only half as good as they were before?
Well now 2.6 drops,
2.6 minus 2.5 drops to 0.1.
And so now the cost per quality adjusted life year is
actually $200,000.
Generally, they say
that if less than a hundred thousand dollars per quality
adjusted life year is a pretty good program
for screening for abdominal aortic aneurysm Over four years,
the mass trial showed that there was $71,000
per quality adjusted life year showing that it
is probably reasonable as a screening modality.
Again, we will ask, does the test detect the disease at a
critical point so that we can make a difference
in a 10 year follow up After a single abdominal aortic
aneurysm screen in patients greater than 65 years old,
a three centimeter threshold identified over two thirds
of subsequent repairs or deaths.
These are patients who did have to undergo treatment
or died from their disease.
If you use 2.5 centimeters, it identified 91%.
However, that requires a lot more,
screening
of the population for 2.5 centimeters.
This is the breakdown by size, for the risk.
As you can see, there are a lot more patients
who have smaller aortic calibers.
And as you go to a larger caliber, your risk
of aortic complication goes up significantly.
Safety of the test is important.
This is because people value their current health
more than future health.
When you're calculating this as a,
cost effectiveness trial,
each subsequent year is discounted 5% from the previous
year for this reason.
If you have one death from your test,
this can pretty much wipe out many of the benefits
that you would have from the downstream effects.
However, ultrasound is one of the safest imaging modalities.
So this is not much of a problem. Availability and cost.
Do we have a widespread test access to the test?
Is it cost prohibitive?
And in this case, ultrasound really fares
quite well On both of these.

Treatment of Disease

Switching gears to the treatment of disease, we need
to know whether there is any treatment available
for treatment of aaa.
There are two major options, which is open repair
of the aneurysm versus endovascular stenting,
and it has been shown
that there is improved survival from both
of these if performed as non-emergent surgery.
The survival is greatly impaired.
If this,
is done in the case of a rupturing aneurysm,
does early detection do better than waiting
until there are signs and symptoms?
This is hard to show. And the reason is
that screening benefit,
can be very difficult
because of the biases we've talked to.
And I think this has been shown mainly from the
mammography literature.
There's a lot of trouble with surrogate markers,
stage shift tumor markers, whether
or not you use overall mortality versus disease specific
mortality, and then trying
to show whether there truly is reduced toxicity if
you treat the disease earlier.

Evidence from Trials

So looking at the mammography, trial, just as
as an example, they did seven randomized control trials.
Over 450,000 women were prospectively screened.
The largest trials showed a 31% reduction in
disease specific mortality.
However, complaints were raised
because there was only a 1% decrease in all cause mortality.
Subsequently a meta-analysis throughout
five of the seven trials.
And when what was left was evaluated, they said
that there was no significant difference in screening.
And this set back the, screening process quite a bit
during that time period.
There has been subsequent research that sort of validated
that it did have a positive effect,
but I think it just goes to show
that even the best trials can come under,
Criticism when we're looking at, endpoints.
Most trials do use disease specific mortality.
And the the reference, the reason is pretty good in
that we really shouldn't consider that someone
who died from something completely unrelated should count
against the mortality of that type of trial.
When we're looking at endpoints
for abdominal aortic aneurysm, we look at,
total mortality.
And in a recent article, there was over 40%
higher mortality in those
who were not treated than those who were treated.
The disease specific mortality also increased if they had
aaa, and then there was a higher rate
of cardiovascular events.
Now, if you look at the meta-analysis,
from a similar time period, the meta-analysis showed
that there was no significant reduction in
all cause mortality.
There was a significant reduction in disease specific
mortality, but only in men.
And then no groups of women
actually benefited based on that meta-analysis.
So based on these findings, they suggested
that there is good potential for screening of men.
This is because aaas are present in up to 8% of elderly men.
What's been suggested is a single screening
because if there's no abdominal aortic aneurysm at age 65,
then subsequent death from AAA is extremely low.
And screening results have been shown to work.
They showed that if you screen these patients,
there is 42% reduced disease specific
mortality at four years.
This is all comers.
If you look at only those who accepted the screening,
meaning that some people when they were invited
to be screened turned it down.
If you look at only the ones who said yes,
53% reduced disease specific mortality.
This shows a significant improvement.
And the range of the cost effectiveness analysis was
between 18 and $72,000 per quality adjusted life year.
Very reasonable amounts.

Strengths of AAA Screening

The strengths of screening for AAA are it's a onetime screen
and then you're done.
There are very low number of false positives.
Ultrasound has broad access and is very rapid
and relative to other imaging
modalities as it has low costs.

Conclusion

So in conclusion, screening has the potential
to improve disease outcomes in the proper setting as shown
by the nine different principles we covered.
Many of the benefits of screening are illusory, and this is
because it's important for you
to understand the different biases
that can make such a trial look better
or worse than it actually is.
And then when we apply these concepts to screening
for abdominal aortic aneurysm, this type of process seems
to fulfill many of the criteria
for a good sprinting program.
And this is one of the reasons that Medicare
and governmental programs have suggested
that this would be reimbursed.
Thank you for your attention.