- So we know that empathy is important.
That's that's an obvious thing,
that it's associated now with approved patient satisfaction
and compliance with recommended treatments,
and we know that patients who are satisfied
with their communication with their physicians
have improved understanding of their condition,
and less anxiety.
So, if you practice this interval empathy,
along with your communication,
then you actually get improved outcomes as well.
So, let's go back to the beginning of the story
for ulcerative colitis and compliance.
So back in 1990, Stuart Riley published this paper,
"In Gut", and asked basically the simple question,
"Why do patients with ulcerative colitis relapse?"
He followed 92 patients for 48 weeks,
and all of these patients were consented,
so they knew they were in a study,
and he said that there were no difference in relapse rates
based on adherence status.
Well guess what, this was a controlled study, and patients,
whether they had had disease recurrence or not,
had a greater than 95% adherence rate
because they were being followed in a study.
So that wasn't real world, but up until,
when we started looking at this in Chicago,
was the only data that we had looking at adherence
and outcomes in ulcerative colitis,
which was one paper in 1990,
which was why it was easy for me to get into this
and be the expert because there was one paper.
So, we said, well that's not real world.
What happens in the real world?
So in Chicago, as a fellow, that this was
one of my major research projects,
was we built a cohort of 94 patients,
and we just asked the question,
"What are you doing with your medications?"
What we did was we called the pharmacies, three months,
and six months after they were enrolled into this cohort,
and we just followed what they were doing
disease activity wise, and we found
that the daily amount of mesalamine
they were taking didn't matter,
as whether they were compliant or not,
and the regimen didn't matter.
Now this was back in the early 2000s
when it wasn't common for maintenance dosing
to be in a twice daily regimen,
but we were doing it in Chicago
to try to make it easier, and it turns out
that it didn't seem to be of any great import.
What we did find where that demographic variables
like being male and being single
seemed to make a difference.
So, that was the first time that people suggested
that maybe in ulcerative colitis
that gender hadn't had an impact,
and that maybe patients who didn't have support
in their home, were less likely to be adherent.
So, okay, well this is fine,
but where does the rubber hit the road?
Does it matter if you don't take your medicine?
Unless you prove that there's consequences,
you're not gonna get people to change their behavior.
So we took this cohort of patients,
we already knew some of them were adherent and some weren't,
and we just followed them for two years, natural history.
We didn't intervene, they hadn't signed a consent form.
The IRB called this benign neglect,
and said that we didn't have to
actually get their permission.
Nowadays, this would be impossible to do.
You would not be allowed to do this by new IRB rules,
but we just had these patients signed up,
and and I was allowed to call their pharmacies
every three months for two years, and here's what happened.
So after two years, the patients who were nonadherent
were only 30% likely to not have
a flare of their disease or recurrence.
Whereas, the adherent group, 93% of them
were still in remission.
The difference here is five fold.
So the hazard ratio is five.
If you are nonadherent with your medication,
you're five times more likely to have a flare
of your disease after two years
if you don't take your medicine.
I'm not talking about taking 100% of your medicine,
100% of the time, this is taking 80%.
That's the definition of adherence,
it's 80% of your medication.
So, how much were these patients taking?
They were taking somewhere between 50% and 60%
of their medication, and that it really looked like
the key amount that you needed
was somewhere between two, and two and 1/2 grams per day
to not flare.
So, this is a life table that I have laminated,
and I used to carry in my white coat when I was in Chicago,
but at Mayo Clinic, we just wear suits
and don't wear white coats,
so now I just have it posted up in my clinic room
that I use most often, and when my patients ask,
"Well, why do I have to still take this?
"I feel fine."
I say, "Which group do you want to be in?"
This was this was the beginning
of what we thought was important.
So, this was 2003.
We wanted to go back and figure out,
well, where was it that was the key point
of maybe intervening with these patients?
So we did this, looking at 20,000 patients
who were enrolled in a insurance database,
and looked at claims for refills.
This was back before Lialda was on the market,
and so we looked at just
the four different mesalamine products,
5-ASA products that were available at the time.
Thinking ahead of time that we had our suspicions
that one was gonna be better than the others,
and it turns out that they're not.
Look at what happened.
So there's this three month critical window
where suddenly there's this drop off, down to 60%,
and then over time, all of the all of those formulas
were basically equal.
So it didn't matter which one you were taking.
To say, well one gives you a better outcome
because more patients take it, didn't seem to be true.
But what was obvious to us was that suddenly
this three month window became really important,
and you're gonna see this over and over again.
So this is a recurring theme about this three months.
What happened at 12 months?
Again, looking now at 20,000 patients
as opposed to 100, which we had in Chicago,
where we see that there's an increased risk
for nonadherence if you had been hospitalized
in the past year, if you were using
a mail order prescription service.
So again, you're not having contact
with your with a healthcare provider.
They've just given you a prescription for one year,
and you're out the door,
and nobody's saying anything to you.
That if you have comorbid conditions,
well that that seems obvious.
What what was interesting was that increasing age
protected you, and that the use of a rectal 5-ASA
in the past protected you.
So, patients were not interested in being threatened
with topical therapies,
that they were willing to take their oral therapies,
and that if they had been switched to a different 5-ASA.
So, we think that might be explained
by the patient feeling that their doctor
was listening to their complaints
about one not working,
or they were having an adverse event,
and so they were switched over to something else,
and they felt that, that was working better for them.
So, then we said, okay, about the same time
as we were doing this work,
we were trying to figure out
how frequently do you really need to take your medicine,
because we want to intervene with something simple.
Can it be that you can take your medicine less frequently
than what's really, the FDA indicated?
So, we went back to the literature, and if you look,
that the data for active disease,
'cause you think, oh well when you have an active colon
that medicine goes right through,
and that their motility is faster
and that you need to probably take medications
more frequently during the day.
But it turns out that you probably don't have to,
and this is the study from Farup and his group back in 2001,
where they looked at BID versus QID in active disease.
Oh Arden, I just mentioned your research,
but we'll come back to it.
So, it turns out in 2001 there were data
to show that really, you didn't have to dose
an active disease in a QID fashion,
that there was no difference in efficacy,
or in safety of BID versus QID granules.
So that was step one.
Then a few years later, there was another study,
again out of Europe, looking at BID versus TID
in active disease, and again, bottom line,
higher doses could be taken safely
and taken less frequently.
So now, there's the precedent here,
that maybe even when you have active disease
that you don't need to be giving patients 5-ASAs TID or QID,
that BID is going to be safe and effective.
So what about maintenance?
You can do this for eight to 12 weeks.
The patients are now better.
What are you going to do for maintenance?
It turns out that there wasn't a lot of data out there
for maintenance, and how often you really needed to do it,
that the 5-ASAs that were FDA approved,
and the ones that we were using for maintenance,
we were giving BID, we were giving TID,
some community physicians were still doing it QID.
Well, could you do it once a day, maintenance once a day?
That was a novel theory, and it hadn't been proven yet.
So that's where our next step was,
and so we put together a very small pilot study,
and this we published in actually
the very first issue of CGH, which came out in June of 2003.
This was a small pilot trial
where we randomized just 22 patients who were in remission,
to either once daily mesalamine,
or a BID or TID regimen, so conventional therapy,
and we just followed them for six months.