2016 Public Health Grand Rounds 11/18

PUBLIC HEALTH GRAND ROUNDS Linking Research to Community Health Improvement Jointly sponsored by the Department of Public Health Sciences & URMC Center for Community Health

- Try to leave some time for questions and discussions,
certainly at the end.
If anybody has any major questions during the presentation,
you can certainly ask them and I'll try
to go through that topic with you.
What we want to do, well, first of all,
we want you to know a little about what
familial hypercholesterolemia is,
and what some of the treatments are.
This may not be a big medical group here,
medical grand rounds, et cetera,
but basically, I want you to have at least some idea
of what the issues are.
It's really important.
You can't study a population unless you have an idea
of what those issues are.
Have you understand a patient perspective,
or patient perspectives, and have you understand our project
within the Patient-Centered Outcomes Research Institute
sponsored projects.
We've had a couple of them here
at the University of Rochester.
All right, so, what it is basically,
an autosomal dominant genetic disease,
present in all racial and ethnic groups.
It has long been recognized as a cause
of premature atherosclerotic coronary artery disease,
heart attacks, strokes, and don't forget death, OK?
Big problem, most common problem globally
is blood vessel disease globally.
If you add up all the cancers together,
cardiovascular disease in general, stroke included,
kills more people than all the cancers combined.
There's certain ethnicities, particularly French Canadians,
and we know about those people in upstate New York,
than some other places.
People who are from South Africa,
people who are Lebanese Christians, OK,
and also Finns tend to have a little bit higher prevalence
of this disorder than the more general populations.
There are a couple of different forms.
The heterozygous form, as you probably would know,
basically means that you have one genetic,
one chromosome that's affected versus two.
The homozygous form we'll talk about that in a little while.
The homozygous form has the highest prevalence
of genetic defects that cause
significant premature mortality, and it basically affects
about one in 200 to one in 500, depending upon
which group you kind of look at,
and who's publishing their data,
and where they get the data from.
The genetic basis of the disorder, though,
is impaired functioning
of the low-density lipoprotein receptor,
which was first recognized by these two investigators
down in Texas, for which they got the Nobel Prize
a couple of decades ago.
Basically, the LDL receptor is where the LDL cholesterol,
the bad stuff that causes blood vessel disease,
basically attaches to and gets sort of pulled out.
Kind of like your thermostat at home, right?
Your liver doesn't produce as much
if it basically recognizes a lot of it,
and also pulls it out if the receptors don't work,
then the LDL cholesterol kind of just floats around
and doesn't get metabolized properly.
If that happens, then your LDL cholesterol could go way up.
For example, most of us in this room probably have
an LDL cholesterol of maybe 100, 130, something like that,
or even lower.
These folk have ones that are in the 300, 400s,
or potentially 1,000.
Just to give you some idea of what the issues are
for these poor people.
It's not their fault.
It's just they inherited the gene, or genes.
Studies of LDL receptor function have identified
additional mechanisms for the pathogenesis
of familial hypercholesterolemia.
Defects in lipoprotein B, which is basically on the surface
of the LDL cholesterol molecule, that's what attaches
to the LDL receptor in the liver.
So there could be impaired binding with the LDL receptor
because of that.
There's something called PCSK9, and we'll talk a little bit
about that, there's a new class of medications
that basically are inhibitors of PCSK9,
they were approved by the FDA about a year
and three months ago, and we have patients
on these medications.
So basically, these have implications, obviously,
for how we would manage the problem.
It leads to elevated LDL concentrations again,
with levels that can be clearly above 190,
but as I mentioned, many people have more at 300
or so levels on heterozygous form.
Untreated children will be more adults,
and kids have lower LDL cholesterols,
as we all age, our LDL levels tend to go up.
These are sort of minimum thresholds.
Most people, again, have higher levels.
Long term exposure to elevated levels begins in utero,
and that's something that's really important
to understand, is that the disease happens really early.
It doesn't start just when you hit the age 35 automatically.
It starts early.
All of us in this room have some blood vessel disease.
Unless you're really unusual.
You may not have a heart attack or a stroke,
but we all have blood vessel disease,
and LDL is a lot of the reason for that.
So basically, this is the LDL cholesterol floating around
in your blood.
Water does not dissolve in --
or, fats don't dissolve in water, as you know
if you try to make salad dressing at home.
Doesn't work well, they don't mix.
So what you have here is LDL, which is a fat,
encapsulated with a protein core.
Protein dissolves in water,
which is your aqueous environment of plasma in your blood,
and here we have some different receptors,
Apo B 100 on the surface, other things on the surface,
like what we call unesterfied cholesterol.
On the inside we have a cholesterol ester,
also inside we have triglycerides
and that's sort of within that lipoprotein core.
There's also some vitamin E, something called ubiquinol,
which is coenzyme Q10, if anybody's ever heard of that.
Some patients like to take that to help prevent
side effects of taking statin medications.
This is kind of a little bit of a schema
of the metabolism, the normal metabolism.
So your liver basically produces most of your cholesterol.
It's up to basically 60 or 70% of it.
Basically, it makes these different molecules
that are very enriched in cholesterol
but also triglycerides, they're really large,
they do have Apo-B 100 on them,
that protein that attaches to the receptor.
And basically, they're called very low density lipoprotein,
and that basically gets metabolized
by something called lipoprotein lipase,
into intermediate density lipoprotein,
which is a little bit smaller, more cholesterol enriched
than triglyceride rich.
And then you have the LDL, which is metabolized
by something called hepatic lipase,
into that LDL cholesterol molecule,
and then cholesterol floats around.
There's also some receptors in the peripheral cells.
Your muscles, for example.
Not just the liver, but the liver is really the main factor
where the LDL receptors are.
There's also some other receptors that can attach
to a different protein on the surface
called Apo E.
So metabolism is basically pretty straightforward
but there are some ways the body can also complicate things
a little bit, with this E protein.
If we see --
- [Man] Can you turn on your walkabout mic?
- Oh, I'm sorry.
I didn't do that.
OK, hopefully that's better now.
Is that better?
Sorry about that.
So when we think about whether a patient has the problem,
we generally want to think about
some criteria for it, OK?
There are three main criteria that I'll briefly describe
for you, for diagnosing someone
with familial hypercholesterolemia.
So there's something called MEDPED,
which is Make Early Diagnosis, Prevent Early Death.
This is a US-created template for diagnosing people.
This is actually the most simple.
What it does is basically have three columns here
in this one table.
Specificity and sensitivity, this would be 100% specific.
This would be 80% specific.
This would be 80% sensitive.
As many know, sensitivity tends to find, generally,
more people, OK?
But we want to be more specific, so most of us
will kind of use these columns over here.
For example, if you're less than age 20
and your LDL cholesterol is 240 or greater,
then you're 100% chance of having the problem.
As you get older, then those levels tend to simply go up.
This does not require any family history information,
physical examination, history information, et cetera.
It's a commonly used template.
Then there's something that was created
by the people in the United Kingdom,
Simon Broome Diagnostic Criteria,
which is a little different in the sense that
it's a little bit more complicated.
In the sense that, basically, they characterize people
as having definite familial hypercholesterolemia,
or possible familial hypercholesterolemia,
and what they have here is that if you have an adult
with an LDL cholesterol, the total is 290 or greater,
or the LDL, consistent with what I showed you before,
was basically greater than 190,
or a child greater than 155, or greater than that,
plus physical exam findings or DNA-based evidence
of an LDL receptor mutation, particularly like those things
I mentioned before.
The challenge with this issue, with DNA,
is there's over 1,000 single nucleotide polymorphisms
associated with this problem.
So we all think about big data,
but I'm not gonna measure a thousand things
and see what I get.
That's not usually the way we do things these days,
at least in this field,
and that's not what's endorsed
by the National Lipid Association, that I'm a member of.
Normally we'll look at different things,
and I'll show you a picture of what some of these things
look like.
Basically, these are cholesterol buildup in the tendons.
In your body.
I had one patient who came in somewhere
from the Corning area.
She had surgery.
She had these different items removed from her tendons,
her Achilles tendons.
I said, "Did they tell you what was in the tissue?"
They said no.
She has familial hypercholesterolemia
and they were so big that these different buildup
of cholesterol she had to have them removed.
That's part of the reason we're talking about this today,
because oftentimes this problem is not diagnosed.
And then you can kind of see down here,
there's other ways of thinking about someone
possibly having the disease.
If you fit in issues regarding family history,
sometimes it's difficult to know,
particularly if someone's adopted, you don't know
what their family history is, or maybe the accuracy
of the data are not that great.
Or family history of elevated total cholesterol.
This is actually also a fairly common utilized
paradigm for the diagnosis.
This is the last one.
Dutch Lipid Clinic Network criteria.
The one thing I want you to know as FYI
regarding the Dutch is they did a really smart
and very innovative thing.
What they did was, they found patients
who had this problem, then they traveled to personally
talk with them about, do you have kids, sister,
brother, mom and dad?
Let's drill this down, because it's a genetic disorder.
Your child could have this problem.
Have they been diagnosed, et cetera.
Actually, they've been a really great group
to sort of understand some of the implications
of this problem.
In this criteria, you basically add up
specific numbers, like for example,
if you have a first degree relative
with no premature coronary or vascular disease,
and they sort of define these down here,
as less than 55 years of age in a man,
or less than 60 years in a woman,
of basically like a heart attack, for example,
or a stroke, or different LDL levels
that could also be measured in those family members.
Also, things like
the own personal history of that individual.
Do they have premature coronary heart disease?
If they have yes, or the tendonous xanthomas,
which again is a physical examination finding
that we commonly will look for,
and then also LDL cholesterol levels,
and also they add in this issue regarding DNA.
I'm not trying to say that DNA's not important,
they've been sort of measured in many different
research projects, but in the clinical world,
we generally don't use them much at all.
OK, so now we give you an example.
This person is well known.
Her name was Stormy Jones.
She lived in Texas a couple of decades ago, OK?
Just to give you an example,
this is a homozygote with this problem, OK?
The age of six, she has diagnosed
with familial hypercholesterolemia
because her total cholesterol was 1,200
and her low density lipoprotein was over 1,000, OK?
Her triglyceride level, that's actually not bad,
that's certainly not the problem.
Triglycerides tend to be higher in other individuals.
She had receptors looked for in different cells
in her body called fibroblasts,
and she didn't have any existing.
So her LDL was not being metabolized properly.
At the age of six and a half, she had angina
and double coronary bypass.
Two months later, she had a second bypass surgery.
And then a month later, she developed heart failure,
which unfortunately is a complication
of ischemic blood vessel disease in the heart,
particularly after you've had significant major problems.
Then she had combined heart and liver transplant.
They transplanted her liver because then she'd have
some receptors, so then guess what?
Her LDL went down quite nicely
and her total cholesterol dropped quite significantly.
But then at the age of 12, she died
because at that time, years ago,
she had rejection of her transplant.
So we treat a patient with this form of the disease
at U of R cardiology.
She's now age 11.
Because we have treatments and she was diagnosed
fairly early.
Pediatric cardiology, Dr. Roger Vermilion and I
have been taking care of this patient.
She's treated by LDL apheresis, which I'll talk about
in a minute, and a statin medication
to lower her cholesterol.
Both of these work to do that very nicely.
At the age of 11, she was diagnosed
with significant coronary artery disease,
so she was high risk for having a heart attack.
Fortunately, the prevalence of the homozygous form
is about one out of a million,
so you wouldn't expect necessarily more people
in Monroe County.
This is just an example of a patient
with a tendonous xanthoma, so if you feel
the back of your hand,
those tendons, they're nice and smooth,
there are no nodules or no big bumps.
People have cholesterol buildup in those tendons,
and basically, that's particularly
if they have not been treated for long periods of time,
and their LDL levels have remained quite high.
Achilles, down in the back of the ankles,
we also look at those.
Basically, if you treat someone, those tend to disappear,
because the cholesterol goes down,
and then you have implications for the tendons.
So again, I just want to give you a brief idea
of what we do with these patients.
We have oral statin medications, there are seven of them,
and we tend to use those,
because we have great data to support their use.
There's something called Ezetemibe by Zetia,
which also lowers cholesterol through a different mechanism,
by inhibiting the absorption of cholesterol in your stomach.
As I mentioned before, we have PCSK9 inhibitors.
These have to be injected subcutaneously,
because they're antibodies.
If they were in your stomach, they'd be sort of broken down.
They work to lower LDL up to about 70%,
which is a major benefit of them.
There's a couple other medications that basically are
approved for people with the homozygous form.
Obviously, not really large ends in these clinical studies
because it only affects one out of a million people,
but they show major benefits in lowering LDL cholesterol.
Then LDL apheresis, and I'll talk about in a couple minutes.
Also, there's other things that sometimes have been shown
to be used, particularly in the past,
which is ilial bypass surgery in the stomach,
that's where a lot of the LDL is absorbed.
It's rarely used anymore,
because we have these other treatments available.
Port a cable shunt, basically, around the liver
to to basically move the blood so that you can shift
the metabolism some.
Liver transplantation, and an IV plasma exchange,
which basically, that would be called
plasmapheresis, we use apheresis,
which is much more specific to lower the Apo-B 100
containing molecules.
All right, then this is basically,
this is LDL apheresis.
This is made by a company called Kaneka.
And it basically looks a little bit like a dialysis machine
for kidney disease patients.
They come in usually three times a week.
Apheresis is usually every one or two weeks.
It's less frequent.
It takes about two to four hours.
So they come into the hospital and we treat them.
Basically what it uses is these different things.
This separates plasma from the rest of the blood
so the plasma can be treated.
These are filters that basically absorb the cholesterol.
And that's how it works.
Basically it's a simple dual-column system.
Those different filters use dextran sulfate.
That's basically what absorbs the LDL cholesterol molecules.
And it's completely automated.
There's a nurse there the whole time.
I generally go by and see the patient,
make sure they're doing well.
But it's quite well automated.
We've had 360 or so treatments in the last few years
quite successfully.
Specifically, it lowers LDL 73 to about 83%.
It's generally quite well tolerated,
and it requires heparin infusion, which is a blood thinner,
but it's generally, it helps to prevent
the clotting of the blood in the system.
OK, then we have, this sort of drills down
a little bit of what the criteria are for the treatment.
Who can be treated is basically someone who has
an LDL cholesterol equal to 160 milligrams per deciliter,
which is the normal metric for how we measure it,
with coronary heart disease.
So if someone's unsuccessful in getting their LDL down
to less than 160, then basically they might be
a candidate for that.
Other people who do not have a diagnosis yet
of coronary heart disease, they haven't had a heart attack
or stroke or angina, they haven't had a stent placed,
they haven't had some other way of diagnosing it,
then the LDL generally has to be greater than
or equal to 300.
Some patients with high, what's called lipoprotein A,
are also treated and approved.
This is an independent blood vessel mediator
of cardiovascular disease, a little bit like LDL cholesterol
so the benefit is it lowers lipoprotein A also.
We wouldn't use that without evidence,
so this is an example of one study
that was published in Japan some years ago.
Basically, what you can see is, they had
some heterozygous patients with FH
and LDL apheresis, they had 43 people
or 87 who were on medication alone.
The interval was basically every 14 days
for the treatments of LDL apheresis,
and then they had a six year observation
of coronary events, of nonfatal myocardial infarction,
stroke, et cetera.
They had a 72% reduction.
It's endorsed by the Medicare, Medicaid insurers
and other insurers as well.
So I wanted to get into a little bit
of information simply, but not overwhelm you,
about these new drugs.
Partly because I want to make sure that you understand
that we have treatments available.
A lot of the problem is 10% or less
of these patients or less are diagnosed.
Less than 10%.
It's a big problem.
Scott Macintosh and I will talk about that later,
as to what the patients have been telling us about that.
That's where the interest is in our realm
of what PCORI is supporting us to do.
Again, we have treatments.
In 2003, this PCSK9 was discovered
and basically shown to be critically important
in removal of serum LDL cholesterol.
If you have a so-called gainer function of PCSK9,
then you have more problems with very high levels
of LDL cholesterol.
These drugs inhibit them, they're antibodies,
and they have been shown to work very well
in lowering LDL cholesterol.
There are some preliminary data, also strongly suggesting
that they lower heart attacks and strokes.
That's what we have for statin medication,
that's what we have for LDL apheresis.
We don't fully have that information yet
for these new drugs,
but they show a lot of promise in that regard.
So again, people with so called loss of function,
PCSK9 mutations have very low levels of LDL cholesterol
and low risk for cardiovascular disease.
Again, I don't want to bore you with all the details
because this isn't a clinical group,
but basically, we have these antibodies again
that have an effect, and they lower LDL consistently
among a different group of individuals
who have this problem.
One thing that you might want to think about
is if the homozygous person does not have any receptors,
why would this work?
These change the receptor activity.
Turns out that there are some data supporting
that they will be effective in lowering LDL.
It depends a bit on the person.
But the FDA approved one of these drugs,
called Repatha, about nine months or so ago,
to treat also patients with the homozygous form
like Stormy Jones.
That's another promising venue.
Now we're going to kind of shift some gears.
I've told you about the disease.
We work directly with
the Familial Hypercholesterolemia Foundation.
They exist in Southern California.
They were founded by a woman who, in her 30s,
was seeking medical care for some chest discomfort.
She was concerned about it.
She was actually about to have a heart attack.
The doctors didn't think it was possible.
Apparently she went home, had a heart attack.
About 50% of people who have a heart attack don't survive.
So she found that, because she wanted
a patient supportive venue for people to become educated,
to be diagnosed, et cetera.
It's a patient-centered nonprofit organization
dedicated to education advocacy and research
of familial hypercholesterolemia.
It actually has a group of physicians
and other people who do research on their advisory board.
And recently, they had their sort of annual summit
in Texas where they had the Nobel Prize winners
come to their foundation.
They're partners with us,
and they have great things to contribute.
They are a PCORI sponsored project.
Again, its mission is to raise awareness
of FH and save lives
by increasing the rate of early diagnosis
and encouraging proactive treatment.
This guy is the uncle of her.
She's our partner for the FH Foundation.
She has the problem.
She's our outreach coordinator.
She lives in the DC area.
He lives in the Canadaigua area.
We gave a grand rounds talk down there
at the Thompson Medical Center recently,
because he has the problem and she has the problem.
And these are some of his siblings.
They've done quite well.
They like us to show these slides.
So we don't feel bad, there's no conflict
of giving away their information.
Their information is also on the FH Foundation website.
Again, their goal is to show people positive outcomes
of having this problem.
You can be diagnosed and then treated.
This is her cat, Davis Ahmed,
and some of her family members.
So as I was talking about before,
90% of people are not diagnosed.
Big, big problem.
About one out of 200 individuals
could have familial hypercholesterolemia.
When we talk to physicians, let's say
they have 2,000 patients in their practice,
and they haven't diagnosed anyone with it.
I'm like, excuse me.
What's the problem?
You guys gotta be educated.
Let's talk to you.
One out of 200 means you should have a bunch of them, right?
That's part of what we're trying to do.
OK so this kind of gives you some ideas
of again, what's happening in different countries.
As we mentioned before, the Netherlands has sort of been,
Edwin's over there, very positive about
what the Dutch have been doing.
They're better at diagnosing people.
It's not like they have a higher incidence or prevalence
of the problem, but basically
they've been doing a better job.
As you can see,
we're doing poorly.
In the United States, we're doing quite poorly.
And in many other countries, quite poorly
based on the best evidence that we have,
published by some of the people in the Netherlands.
OK, so this is another example of part of the problem.
Published in a pretty good journal here.
Basically, 60% of physicians do not realize
that FH is autosomal dominant,
meaning that you have about a 50% chance
of inheriting it from your parents,
if one of them has it.
They're unaware of the prevalence
of familial hypercholesterolemia.
They think it's much more of a rare disorder.
They don't recognize it when they see an example.
My own primary care doctor told me,
I won't mention names, said,
"Why does it matter?"
Talk to the patients, OK?
You gotta talk to the patients.
That's what PCORI is all about
and what Scott and I will be talking about soon.
Again, it's manageable.
Basically if you take people and put them
on a statin medication, no LDL apheresis,
no PCSK9 inhibitors, no other fancy, expensive drugs,
et cetera, basically you can see
that over the next many years you have a reduction of events
with statin medications versus no statin medications.
So it's not that complicated.
Many of us probably in this room take a statin
and many of them are generic and quite affordable.
This is just another way of thinking about things.
Here you have a threshold for what's diagnosable.
Coronary heart disease, OK,
so thinking about sort of that threshold,
and thinking about the homozygous form,
many of them will develop it around 12 and a half
years of age.
Where people have the heterozygous form,
more in the range of maybe 35 or so,
they have their first heart attack.
But then actually there's a lot of variation
depending upon the gene, how it's functioning,
what's going on metabolically,
there could be some different folk.
Also it depends on other risk factors,
if someone's a smoker, someone's much more physically active
or less physically active, all those things
have to be thought of,
versus the people who don't have FH,
then a lot of people develop the problem
more at the age of 55, but that would still be
the premature group, OK?
We don't like to see anybody have a heart attack
at the age of 55 or less.
Here we have simply what could be recommended
as a safe way at the age of around eight or 10.
Low dose statin medication in a child,
and start higher dose statins,
or higher potency statin medications more in the age
of around 20 or so.
Because the safety data for the adults
tends to be a little bit more robust.
OK, the other thing I wanted to mention to you
that Scott and I are very aware of
is the FH Foundation has a registry
that we're becoming part of.
So we are a clinical site for their national registry,
which is called Cascade.
The reason why they call it Cascade
is it's sort of the way of screening family members,
so you're diagnosed with familial hypercholesterolemia,
does your sister, has she had her cholesterol measured,
your father, your child, et cetera.
So it basically, Duke University is a coordinating center,
so we're working with them to basically try to get people
to be recruited into the registry
so they can be followed longitudinally over time
to see what their outcomes have been.
Also, it's one way of trying to improve the diagnosis
and awareness of the problem.
The way it kind of fits in here is that,
when we have guidelines for screening,
guidelines for treatment,
what we have here is that FH screening
is endorsed here by the American Association of Pediatrics
around the age of two, particularly if you have two parents
with the problem.
This is a controversial topic in the sense
that a lot of people are not really thinking
when they see patients that are the age of two
to ask questions about these types of things.
This is what is being endorsed by a reputable group.
Then we have treatment initiation, to start
around the age of eight and 10.
That's where there are NHLBI guidelines
and other guidelines that support everyone
having their cholesterol measured.
Around this type of age.
And also initiation can be started then.
Adult screening is endorsed by the American College
of Cardiology, American Heart Association guidelines.
And then basically, you then start to move forward,
different treatment options.
Here you have age 39, hyperlipidemia therapy initiated.
That's when things generally in that group,
the registry, hyperlipidemia therapy
has been generally initiated, but it's not until years later
that people through the registry are being diagnosed.
So there's kind of a disconnect between the diagnosis
and the treatment in some ways.
This is their website.
We recommend patients look at their website.
It's a very supportive environment
and it can tell you quite a bit about what it is
that they are doing, and they are our partners,
again, in our PCORI sponsored projects.
A few things I wanted to end on here
before Dr. Scott Macintosh talks for a few minutes,
we can then take some questions,
is that, again, we have this Patient-Centered
Outcomes Research Institute sponsored project.
We had something called Tier One.
Now we're into Tier Two.
They do not give us a million dollars.
They give us a lot less money that that.
However, they're a very supportive environment provided,
very different than the NIH, very different
than the American Heart Association
and many other organizations that sponsor projects.
What we're doing is developing research hypotheses
via patient investigator partnerships.
We ask patients, what's important to you?
Before I applied, I asked patients, what do you want
to focus on?
And they looked at me like I was from Mars.
They said, "I'm not a physician.
"I don't do research.
"What do I know?"
I said, you're a patient.
So they help me.
It's been a partnership all along.
We had a meeting in Chicago a few weekends ago.
I didn't get to go to the Chicago Cubs baseball game,
but basically we had a lot of fun at this meeting.
A patient traveled with me.
And the patient was fully engaged in a day and half
discussion about projects that we and other people have
about having to move them forward to the next step.
The next step will be Tier Three PCORI funded project,
and then we can move on from there.
There, we'll develop hypotheses more drilled down
with the group, and then we'll plan to apply
for maybe an RO1 or some other projects.
That project is what created this project.
The patients had ideas, and we got some funding
through the International Atherosclerosis Society
and Pfizer to focus on developing
electronic health record tools for identifying
and educating patients and physicians about this problem.
It's something that the patients kept saying.
"Why is it that doctors don't know about it?"
so we're trying to figure ways out
through the electronic health record to educate
and motivate people.
Self-determination theory is also part of this.
It actually also mentioned Jeff Williams as a partner
of mine, at the University of Rochester,
and he's part of our team as well.
Then we've had a Kanaka corporation sponsored project
focused on the supportiveness of our LDL apheresis program.
And then, again, we're joining this registry.
Some other things we're sort of considering for PCORI,
they sponsor a comparative effectiveness research project,
so that's something we're moving toward,
is to apply for a larger, more highly funded project
to actually test some research hypotheses
comparing different treatment options.
The thing that we're most focused on
is a supportive environment, because that's what seems
to help patients to kind of move forward and be treated
and know what the options are.
Possible RO1 or RO1s,
and one thing we also are considering
is surveying PCORI sponsored project partners,
so people from other places who are maybe studying
other things like sickle cell disease, et cetera,
using self determination theory based questions
that have already been developed
to basically try to figure out how to move groups forward
by helping them to become autonomously motivated
and feeling connected and feeling competent
at making decisions, because when you start to work
with patients again, they looked at me from Mars,
"I'm not a physician.
"I don't do research.
"What do I have to contribute?"
We want to basically overcome any potential goals.
So Dr. Scott Macintosh will talk with you
about other things.
- Thank you.
To put this in persepctive a little bit,
the PCORI funding is called Pipeline to Proposals.
And so through this pipeline, there's Tier One,
Tier Two, and Tier Three.
Tier One was a nine month project that ended
earlier this year, and the goal was
to establish a patient-centered group
and start establishing potential research partners
and other stakeholders.
We started having these meetings
once a month on a Saturday,
and the patients really found that very supportive.
They kept reiterating how much they enjoyed those meetings.
We started building our research partnerships
and stakeholders.
Other people who came to this group,
there was pharmacist, we got a physician,
a psychologist,
we had family members.
- [Bob] Kat Davis from FH Foundation.
- Yeah, the woman that Dr. Black mentioned,
Kat Davis from the FH Foundation.
We created a governance document
about how this group would function and work.
Then in Tier Two, which we're about three
or four months into now, it's a 12 month project,
and we're refining the research question,
and work toward research ideas,
and increase the research partnership
and overall infrastructure.
Then we'll go for Tier Three
next spring, and that will be a 12 month project
where the goal is to develop an actual proposal
and explore narrowing it down
to one or two research questions.
So the patients, like Dr. Black said,
"We're patients, what do we know about research?"
So we get them to talk about what their needs are,
what they perceive the physician's needs are.
Physicians don't know enough about this.
Through those discussions,
we're trying to generate, that could be a research idea.
We're giving that feedback to the patients
as partners, so they'll be the ones that really lead
what the research questions can be.
They enjoy telling their stories,
it's very complicated.
Obviously the first half of this talk,
there's a lot to this.
Patients who are diagnosed or at high risk,
they have a lot to learn.
After the Tier Three, like Bob mentioned,
then there's going to be funding announcement
from PCORI and maybe other foundations,
like the American Heart Association might have opportunities
that we could go for then.
So the results of our work so far
has been very qualitative in nature.
Hence, that's why I'm here.
Finally, the word can flow off my tongue.
Familial hypercholesterolemia.
That wasn't part of my world before this.
But I do know qualitative approaches,
and we're learning things from the patient center group
so far.
We're still refining these domains, but for example,
knowledge of disease.
They make lots of quotes and comments about
either lack of knowledge or as they gain knowledge,
what the barriers are to gaining knowledge.
The importance of diagnosis.
It's hard to diagnose this and very few people
do get diagnosed, so they make a lot of comments
about that.
Communication between themselves, communication
amongst their family members, to the clinicians,
or even amongst the clinicians.
This has been interesting.
They talk about things they can do as patients
to reach other patients who may be at risk.
So actual outreach.
The use of technology, electronic health records,
MyChart, that can be a way to communicate
between patients and the clinicians.
And treatment, they talk about,
you saw that whole slide on all the different kinds
of treatment, you know, again, a big learning curve,
what is their knowledge of the different treatments,
what is their experiences with each of those?
And so each of those main themes
can turn into research projects.
So again, we'll get feedback to that group
and see what can they help generate
that would be the research project that we go forth?
The Pfizer sponsored project being a direct spinoff
of that has been a terrific growth for us.
Bob mentioned the other potential things we can go for.
Am I going the right direction?
- Yeah, there you go.
- How did I get back that far?
I can answer questions on the last five minutes,
and then Dr. Black will answer questions for the previous.
- We can answer together if you want.
- [Woman] You say that it may run the family,
that you should do a diagnosis at age two.
Is there a kid friendly way to do that
other than to draw blood, or how do you diagnose it?
- It would be via blood, a simple blood test,
a cholesterol blood test.
So generally, genetics could be playing a role,
also, in some people,
and potentially maybe some medical offices,
but generally speaking it's not required.
The person could have a blood test showing the cholesterol
is above a particular threshold,
and say that this all makes sense.
Actually, that's a really good question that relates,
also, to the fact that these guidelines,
basically the templates for how you diagnose someone
are a little bit tricky sometimes.
As you can see, there's different variables
and sometimes you don't have all those variables.
But the folk that I talk with who are colleagues
around the country who do the same kind of clinical work
that Jeff Williams and I do often say
that they see it as sort of a genre of the issues.
The LDL may not reach a specific threshold,
but it's really close
and we sort of put two and two together
regarding family history and what may have happened
where your dad had a heart attack at the age of 30,
and mom at the age of 35,
and then you kind of figure out,
there is something there, this is really unusual,
because dad was not a heavy smoker, and mom either,
and all these other risk factors weren't playing a role.
So I'm glad you asked that question.
- [Woman] It seems striking to me that if somebody walked
into the clinic, even an adult, and had an LDL cholesterol
of 500, that that wouldn't be a huge red flag.
Is it that people are not being diagnosed
because they're not getting tested,
that they don't even have their cholesterol tested,
or is it really that it takes more than just a high
LDL cholesterol count?
- Another really good question.
It does take more, oftentimes,
for people to be aware.
That brings up a really important point,
because physicians are trying to do the right thing,
but when they see a particular group of patients
on a day when they've got much more common things,
it's hard for them to think about,
well, this is a possible problem and I remember that,
because they haven't been diagnosed, many people,
with it, so I think it's part and parcel
of the fact, too, that the National Lipid Association
that Jeff Williams and I are members of
basically specifically stated that if you educate patients,
you'll get more traction than if you educate the physicians.
Physicians can come to a grand rounds,
or something else, or get CME, or read an article,
but if the patient has such stake in the game,
that they will basically be more,
they'll bring this topic up.
Sometimes it's a little bit tricky, though,
for some people.
Even Jeff Williams and I go back and forth sometimes,
saying, does this person really have FH?
Which criteria are you using?
And that type of thing.
Hopefully, it's going to be simplified.
- Just the other day in a focus group,
a couple of the patients who where there
said they always go into MyChart and check their labs.
They want to educate themselves
and find out, OK, this says this is in a normal range
and this is in a high range, this is my number.
And that might trigger that conversation
with the clinician.
Right, and this one patient also said,
basically said, "Look, I have the problem
"and I'm not sure I need to take a stand."
50% of people stop medications after about a year,
particularly in the prevention paradigm,
where people haven't yet had a heart attack.
They haven't had a teachable moment.
But yes, you're high risk, take this medication.
"I feel fine, why do I need to go to the pharmacy, right?"
It's human nature.
But he said because of the supportive environment
of talking with other patients,
he's not gonna stop.
It's kind of like one of the awesome things
about this PCORI project.
I've been following many other projects.
This is really cool stuff,
because you get to partner directly with them
and they give you really important feedback.
- The patients comment on his enthusiasm, too,
and that keeps them coming to the groups. (chuckles)
Other questions?
(audience member speaks inaudibly)
- That's another good question.
We have a specialty pharmacist.
Her name is Dr. Katie Manou, M-A-N-O-U,
at the U or R, she works with us directly.
She'll educate patients about the disease,
treatment with the PCSK9 inhibitors,
they're injectable, so she tells them about how
the drug will be injected.
Usually it's a little pen with a very small needle,
like 26 gauge, which is very tiny,
into the leg, just giving yourself a quick shot.
There are other ways that you can get
the medication as well.
But she also works with the insurance companies.
They cost about $14,000 per year at this time,
so they're quite expensive.
There are certain thresholds that the insurance companies
will need us to meet.
What other medications they've tried.
But the plan would be that they stay on them indefinitely,
unless we see some clinical trial data
that don't show a reduction in heart attacks and strokes.
Those studies are ongoing right now.
I think some of those data should be published
probably in the next year.
Does that answer your questions?
That's OK, great, yes.
- [Woman] I understand that it was in a guideline
for pediatricians to ask kids at two ages,
to check for where the cholesterol is at.
I guess my question is, do you look at particular kids
and if there are motivation interviewing techniques,
or like, is it diabetes type one, when they stop taking
their medication, or anything like that?
- Basically, we don't have any kids at this time.
The one woman who's age 17, she's a high school student,
her brain's in a different place
and she travels back and forth quite a bit.
She doesn't want to be in any projects like this
at this point.
I don't do pediatric work, we don't have any kids.
But we're certainly open.
So family members are invited to these meetings.
Do you want to comment a little bit
about the interviewing technique?
- For like motivation for the kids?
What we're focusing on is what can turn
into a research project.
So if this is coming out of the patient's ideas,
we can certainly prompt for things like that.
That would be an awesome thing to study.
What exactly is the need for this,
how many kids are dropping off medication,
how could we use self determination theory
and other motivational interview strategies
for treatment adherence to be better?
That could be for adults, too.
We'd be open to all ages.
- Yeah?
- [Woman] Since it's familial, couldn't you already
have a ready source of people, some study participants,
on the children?
So if their kids inherited this,
they already have a source for people to have this.
- We have that.
We say to them, please bring in your family members.
I think they all have adult children though.
I don't know anybody with smaller children.
- Right, one of them has a daughter
who clearly seems to have the problem.
We've invited her.
- That one hasn't come yet.
A few spouses have come, and partners.
But that would be an excellent opportunity.
If they brought the kids,
we'd start to get those perspectives and ideas.
- One other thing to consider, too, is the registry
is another tool.
They're basically a group we're working with
and they have a national registry,
so we could use the registry as a control group
in a future study, because those people are being --
I believe there are some kids.
We're not formally part of the registry yet
but I believe some kid information is also collected there.
- So we'll take credit for that idea
and go forth with it, thank you.
- Yes.
- [Woman] How would the old apheresis program
in the area, are there other medical institutions
that have that available?
- Another great question.
The closest place is Pittsburgh.
There's one in Manhattan.
Those are the closest places.
That's part of the reason why we wanted to have one here.
Currently we have I think eight patients
who are being treated,
so we have people come, like,
the furthest person is down near Ithaca.
It usually, sometimes they can't make it every two weeks,
the 17 year old, we like her to come in every week,
but she usually can't.
She's a high school student and mom's busy
and stuff, so she comes in every two weeks.
It's quite accessible if you can get here.
People actually, when we use self determination theory,
there's a guy, Jeff Williams and this guy Chris Niemich,
who's on the river campus in psychology,
worked with us to see whether or not
it was a supportive environment
through the apheresis program
and they were very very positive about it.
(audience member speaks inaudibly)
Good question, we can look that up if you want,
but generally in those four ethnicities,
the Finns and the South Africans,
the French Canadians, the Lebanese Christians,
they have a higher incidence.
More like one out of 150 or so,
where everybody else is more generally
one out of 200, one out of 500.
For example in China or Japan,
yes, the problem certainly exists,
and it's certainly, I think the incidence,
prevalence are similar to what they are
in some of the other countries within that range.
200 to 500 people.
All right, unless there are any other questions,
we can end.
We'll stay here for a couple minutes
if anybody else wants to talk to us.
- Thank you for coming.