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- This is Lab Medicine Rounds,
a curated podcast for physicians,
laboratory professionals, and students.
I'm your host, Justin Kreuter,
the Bow Tie Bandit of Blood,
a Transfusion Medicine pathologist at Mayo Clinic.
Today, we're rounding with Dr. Meera Sridharan,
Assistant Professor of Medicine and Oncology
and senior associate consultant
in the Department of Hematology
for today's topic on DOAC reversal,
so direct oral anticoagulant reversal.
So thank you for joining us today, Dr. Sridharan.
- Yeah, great.
Thank you so much for having me.
Excited to be here.
- So let's kick us off with, you know,
why is it important for physicians
to understand about the reversal
of these direct oral anticoagulants?
- Yeah, so, you know,
it's been about 10 years since the first approval
of the first direct oral anticoagulant.
And the first FDA approved direct oral anticoagulant
was the direct thrombin inhibitor dabigatran in 2010.
About a year later,
rivaroxaban was the first direct factor 10a inhibitor,
and that was approved
and followed by apixaban in about 2012.
And then there was another one, edoxaban,
that was approved in 2014.
All of these direct oral anticoagulants
are at least as effective as vitamin K antagonists
or warfarin for the prevention of stroke
in patients with atrial fibrillation
or for the treatment of venous thromboembolism.
In addition, these agents are associated
with less life-threatening bleeding,
particularly less intracranial hemorrhage.
So given all of these good things
about direct oral anticoagulants,
since their introduction to the market,
they are increasingly prescribed.
And along with warfarin,
DOACs are among the top 10 drugs contributing to ER visits
in the United States.
So when the DOACs first came out in the market,
one of the fears or barriers
for some providers talking about these medications
with their patients
was the fear of what would we do
if we needed to reverse the medication,
whether that be for reversal of a serious bleed
or for needing to reverse the medication
because someone needed an urgent surgery.
With its counterpart warfarin,
we have a long track record.
Now, because of that long track record,
we have kind of well set guidelines for what to do
if a patient comes in with supratherapeutic INR
and needs to be reversed for bleeding,
or if they come in
because they need a more urgent surgery.
For the direct oral anticoagulants,
it's important that we come up
with a very similar framework
for what to do if someone comes in for bleeding
or needs a more urgent procedure.
- I'm glad you kind of brought this up
because it really kind of gives us a good understanding
of the landscape, this idea that,
so as I'm hearing you,
we have a long background
and experience with Coumadin, warfarin,
and that you're saying that starting in 2010,
this anticoagulation field got a lot more complex,
it sounds like.
You listed off dabigatran, rivaroxaban,
apixaban, edoxaban.
So a lot more complex.
And I think I heard you to say
that the complications
or the bleed rate was a lot less
with these direct oral anticoagulants.
- That is correct.
So compared to warfarin,
the risk of severe bleeding,
so particularly when I think of severe bleeding,
I'm thinking of bleeds like into the head,
they are less with direct oral anticoagulants
than when compared to its counterpart warfarin.
But that brings up other kind of bigger questions
as to because you have less severe bleeding,
who is that best person
that you would consider for a reversal of anticoagulation?
- I see,
'cause that's how you're targeting which direction
or which pathway to follow.
Kind of the traditional warfarin anti-coagulant
or one of these direct oral anticoagulants.
- Correct.
- Oh, fantastic.
And then you were kind of getting at the idea
that although there's less severe bleeding,
there was a concern by patients
and physicians about if it is severe,
what's the plan?
- No, exactly.
So, you know,
when these medications first came out in the market,
we were still learning about how they actually perform
in clinical practice.
So now with 10 years of experience,
I think we're more comfortable saying that yes,
the bleeding rates with direct oral anticoagulants
seem to be less than with its counterpart warfarin.
But back then,
whether we would counsel that for all patients at that time
would not have been as strong of a statement.
So through that experience,
now, when I counsel patients,
I can tell them that yes, compared to warfarin,
we do see decreased bleeding rates.
However, if there is a bleeding episode
where we need to consider reversal,
there are options.
And then that's what we're gonna be talking about today.
- That's awesome.
So then what have we learned new?
I mean, you were talking about
what we now have a decade plus of experience here.
I imagine,
are we learning more about what patient population
to use them in
and as well as the plans to reverse them?
- Yeah.
So in terms of the direct oral anticoagulants itself,
we now have a general idea
of which patient is a good candidate
for a direct oral anticoagulant versus warfarin.
So for example,
a lot of my patients
that come in with acute venous thrombotic events,
I am discussing a direct oral anticoagulant for them.
Oftentimes, they opt to do a direct oral anticoagulant
because there's no need to do the routine INR monitoring,
which is huge for patients.
Some reasons why a patient may consider warfarin
over a direct oral anticoagulant
are the underlying disorder that they have,
warfarin may be better.
And there are still some disorders
where we would want to use warfarin
over a direct oral anticoagulant.
Other considerations are mainly related to cost.
- I see.
We have really kind of a triad of the audience
of this podcast.
We've got physicians,
we've got laboratory professionals,
and we have students.
And I think in the context
of maybe for our laboratory professionals
and for our students,
could you maybe elaborate a little bit
about you brought up the idea
that weekly monitoring for INR is really a huge thing.
That's a big deal.
And I think for some people,
it's just maybe not that obvious on why is that a big deal?
I mean, it's just a simple INR test, right?
- Right.
So it's a simple test, but it's a test.
So for some patients,
particularly when you're first starting warfarin,
that could mean multiple visits to a provider a week.
Our hope is that eventually,
we can get patients on a stable dose of warfarin
where they don't need to be coming in that frequently.
And I have some patients
that often don't need an INR check for a month or so.
But still, that's an additional laboratory test
that they have to leave their house for,
unless they are hooked up with some home INR monitoring,
which all patients are not candidates for.
And so just having that taken off of their to do list
for the day
for a lot of patients makes a huge deal,
especially if they're busy
and don't have time to go to appointments,
or for some of our elderly population
where maybe they don't have people that can help them
take them on a ride or something
to go to a doctor's appointment,
that could be an additional barrier as well.
- Maybe just one follow up question on that.
I was curious,
you mentioned that not everyone's really eligible
for a home INR test.
And I see your point on
if people have difficulty getting rides
why it might be a brilliant option for some folks,
but could you give us an example,
maybe one example where it really wouldn't be ideal
to do home INR monitoring for given patient?
- So I guess the best candidate for someone
who you could do home INR monitoring with is first of all,
you need to make sure that you're dealing with a patient
that reliably can monitor their INR at home
and relay those results to the clinics.
So that would be the first barrier
if you're dealing with a patients that couldn't do that.
The second one is if you have a patient
that is having kind of more fluctuant INRs,
home INR monitoring may be more difficult
because you may be needing to get more frequent checks.
And sometimes, we prefer to use a typical lab assay
rather than using a point of care lab essay type thing
when we have INR values that are very fluctuant.
And so the ideal patient that I think of
for home INR monitoring
is someone that has been on a stable dose of warfarin,
who has kind of very reliable INRs,
is a reliable patient in that they can take their medication
and also report out those results to the nurse team.
- That makes perfect sense.
And thank you for really kind of sharing with us
a little bit on what that clinically looks like.
You know, why that INR testing is a big deal,
why somebody may do home
versus coming into a hospital and getting INR checked.
I had interrupted you.
You were gonna talk about,
I think the kind of updates to the, you know,
what the reversal plans are for direct oral anticoagulants.
How have they changed recently?
- Yeah.
So I guess it depends on what we define as recently,
but at least since the introduction
of direct oral anticoagulants into our treatment algorithm,
we do have two specific reversal agents available.
Each agent is specific to the class of medications.
So in 2018,
idarucizumab was approved as a reversal agent
for the direct thrombin inhibitor dabigatran.
So idarucizumab is a humanized monoclonal antibody fragment
that binds free and thrombin bound dabigatran
and neutralizes its activity.
And then later that year in May 2018,
andexanet alfa was approved for the reversal
of the direct factor 10a inhibitors
apixaban and rivaroxaban.
So andexanet alfa is a recombinantly produced,
catalytically inactive form of factor 10a
that acts as a decoy to bind
and sequester the anticoagulant medication.
So these are the two FDA approved drugs
that are specific for reversal of direct thrombin inhibitors
and direct factor 10a inhibitors.
For idarucizumab,
which is the direct thrombin inhibitor reversal,
the FDA approval is for patients who have severe bleeding
or patients that need a more urgent surgery.
Whereas the FDA approval for Andexxa,
which is the direct factor 10a reversal agent
is only for patients with severe bleeding,
although it's been used on kind of off label uses
for urgent reversal for surgery as well.
In addition to those two specific agents,
prior to the FDA approval
of idarucizumab and andexanet alfa,
we had been using kind of non-specific reversal agents
for the reversal of direct oral anticoagulants.
And so these nonspecific agents,
and what I'm talking about
are prothrombin complex concentrates,
and so there's activated and nonactivated forms of that.
And in reviewing kind of retrospective cohort data,
looking at efficacy of these compounds,
it appears that there may be some clinical efficacy
for use of these agents.
And so in many hospitals where andexanet alfa
or idarucizumab may not be available,
these prothrombin complex concentrates
often work as an alternative medication.
- It's interesting to kind of hear about.
And I think right now,
we're talking about off-label use,
and you're talking about some of the clinical experience
that we've navigated.
Certainly, been an interesting road
since the introduction of these direct oral anticoagulants.
It sounds like now with idarucizumab and andexanet alfa,
we're really having specific reversal agents,
as you mentioned.
And so I think that's kind of what the ideal was
as we had four factor PCC as reversal for warfarin,
and now we've got specific reversal agents
for the other direct oral anticoagulants.
Is it kind of problem solved, check,
and and move on to solve other challenges?
Or are there still some challenges
that remain for reversing these direct oral anticoagulants?
- Yeah, so good question.
So I think there are still challenges
and I think they're mainly challenges to nuances of care.
So I think one of the biggest challenges
is who is the best candidate for DOAC reversal.
So as we spoke about before,
some of the notable differences
of the direct oral anticoagulants compared to warfarin
is that direct oral anticoagulants
often will have decreased life-threatening bleeding risk.
And then the other kind of nuance
is that direct oral anticoagulants
have a shorter half-life than warfarin.
And because of that shorter half-life,
a reversal agent may not be absolutely necessary
for all patients.
And often, managing the patient with supportive care alone
with fluid resuscitation, transfusion support,
while holding the anticoagulant
and waiting for that anticoagulant
to leave the patient's body
may be enough treatment for that specific clinical scenario.
However, there are certain clinical scenarios
where you don't have that time to wait.
And so that's the scenario where we would say, okay,
we really want to use this reversal agent
because I don't think I have that time to wait
for that anticoagulant to leave the patient's system.
The other challenge that I think we face,
more so in hospitals
that maybe don't have kind of an algorithmic approach
for how we deal with reversal of anticoagulants
is that now that we have these approved medications
for reversal of anticoagulation,
we also have our experience
with the prothrombin complex concentrates.
So the question comes, which one do we choose?
Do we go with the FDA approved indicated medications
or do we go with the PCCs
that we may have a little bit more experience with,
and may also be cheaper for some hospitals?
And so I think coming up with good protocols on guidelines
of which patient is the best candidate for which product
is very necessary.
With the prothrombin complex concentrates,
so I'm spending a lot of time talking about that
because it is an option for facilities
that cannot afford andexanet alfa and idarucizumab.
One of the things that needs to happen
is we need to have data that shows
that PCCs are at least equally effective
as these other reversal agents.
And right now, we don't have that.
There are some trials
that are trying to answer these questions.
And so hopefully in the upcoming years,
we'll be able to get a better handle on
is andexanet alfa or idarucizumab
definitely better than PCCs,
or can we not actually say that?
Meta analyses and retrospective cohorts
make me question whether the specific reversal agents
are truly better than PCCs,
but more data is to come on that.
In terms of other questions that still remain.
So the big kind of underlying question
when you're giving a patient one of these reversal agents
is you want to provide benefit
without causing too much harm.
And so when we're giving these reversal agents,
we have to be cautious for potential side effects.
And one of the main side effects
I think about are thrombotic risks.
And when we're looking at the data
for thrombotic risks from these studies,
we have to look at that data in the lens of
you're looking at a population
where they're already at a really high thrombotic risk.
You're taking away a medication,
the anticoagulant
that was supposed to prevent that thrombotic risk.
And then you're adding a medication
that's supposed to help stop bleeding
for an appropriate situation,
but in that, you can also be causing more thrombosis.
And so when you see the data regarding thrombosis rates
and things like that,
it's very important to look at
when was that patient started back on the anticoagulation?
Was the patient started back on anticoagulation?
And that all sometimes is hard to capture
in retrospective cohorts.
So prospective cohorts need to be done
to explore that more,
particularly when we're looking at comparative data
of andexanet alfa, idarucizumab, and PCCs.
And then the last challenge I think of
is more of a challenge
regarding acquisition of these medications
for certain hospitals
who may not have access to specific reversal agents.
There's also problems that hospitals have to deal with
with cost and acquiring these medications.
And then lastly, there's the kind of barrier
that some facilities don't have standardized protocols
to allow for appropriate utilization of these medications,
meaning protocols to ensure that that right patient
is getting the right medication
rather than patients getting over-treated or under-treated.
- Dr. Sridharan,
I asked you for what you were thinking about for challenges
and you gave us four brilliant ones right off the bat there,
which is fantastic.
I think just to summarize for the audience,
you brought the idea of sort of that nuance
and I think your first and your third one,
I kind of linked together with the idea of
who should we be reversing,
thinking about, as I hear you say,
really that big clinical picture
on where are we in the half-life of their dose.
Is it even of value to reverse?
And then the flip side of that,
the third challenge you brought up
was this kind of challenge versus harm.
The idea that if somebody is pro-thrombotic,
that's why they're on the anticoagulant,
and if you reverse them,
we're back to that pro-thrombotic state.
And so I really loved this idea.
And I think particularly
probably for the students listening,
this idea of in clinical medicine,
it's really important to kind of get that,
take that larger viewpoint.
Each one of these are a topic
where there's guidance and stuff out there,
but really, it takes a clinician
in combination with a lab to answer
what's the best thing to do in this situation.
As you said yourself, the nuance of the situation.
I'm really also interested this idea you bring up
about experience versus what's approved.
And that's really a challenging space.
And I think highlights probably to our audience
that this is an interesting topic,
and it's going to remain an interesting topic
as I hear you talk.
And the fourth one about acquisition,
I think that probably highlights probably
for physicians as well as laboratorian listeners
the idea you brought up
that hospitals can develop their protocols
for how are they going to use these medications
or what are they going to do in situations.
And so I think you're highlighting for our audience
the fact of if this is an interesting topic
for you to get engaged,
find out if your hospital has one of these protocols.
If you are a pathologist or hematologist,
look to see if you can participate on these committees
that are making local policies.
I really liked those points that you summarized for us
because they are really wicked challenges.
Next question I got for you,
which really kind of wraps this up.
I'm kind of curious what do you think
that the future looks like for anticoagulant reversal?
- So I think kind of piggybacking
kind of off the last couple of points I mentioned,
I think I've hopefully highlighted
that essential to appropriate
and safe use of anticoagulant reversal agents
is having guidelines from national societies
regarding how to address reversal of DOACs.
So we're already off to a great start.
In 2019, the Anticoagulant Forum,
which is a North American organization
of anticoagulation providers published a manuscript
providing guidance regarding use of DOAC reversal agents.
And this manuscript kind of nicely outlines
how you would approach a patient
coming in with bleeding on a DOAC,
puts patients in categories considering yes,
you would want to reverse,
no, you don't want to reverse,
yes, it's okay to wait,
no, it's not okay to wait.
And I really like guideline statements like that
because it allows for people
who maybe don't have as much time
to go through all the literature to look at one document
and have something to summarize the highlights.
In the near future,
I anticipate other groups will offer similar insights
based off of new data emerging from other trials.
And as someone that works in the coagulation lab currently,
I hope that as more facilities
start having easier access to laboratory assessment,
for example, direct factor 10a inhibitors,
I hope to see utilization of these assays
incorporated into our decision-making for DOAC reversal.
I mean, to be quite honest,
the only way to allow for that though
is for our assays to be resulted in a very quick manner,
which I think one of the barriers right now.
But I think we've already made a lot of progress
in regards to that in the last several years.
So that's something I hope to see improvements on
in the upcoming years.
As I kind of already mentioned,
I would like to see some data comparing prospectively
the specific reversal agents
with the more general prothrombin complex concentrates
because if it's a cost benefit ratio,
and they both work exactly the same,
and they have the same thrombotic risk,
then it's an easy decision, right?
So I would like to see that data.
And hopefully, that'll be coming.
I guess thinking more broadly into the future,
we're always hearing about new medications on the pipeline.
One of the more exciting ones that I've heard about
is a medication called ciraparantag.
Hopefully I didn't butcher that too much.
But it's a small synthetic molecule
that's designed to bind to all DOACs.
So that would be direct thrombin inhibitors,
10a inhibitors.
And then also, it's supposed to have activity
in blocking some heparin medications
like low molecular weight heparin.
So if you think about it,
that's basically a medication
that's like the magic bullet of reversal agents, right?
- It's the skeleton key, come on.
- Yeah.
So I mean, it sounds great.
We need to still see some more data
in clinical practice obviously.
And when you have a medication
that has such broad targeting,
you then also have to worry about the thrombosis risks.
So there's probably pros and cons to this,
but I think it'll be exciting to see
how a medication like this performs in clinical trials.
- Wow.
Thank you so much, Dr. Sridharan.
I think that it really highlights for our audience
the importance of this topic,
the idea that it's a moving, evolving field.
There have been critical advances,
really a lot of opportunities to participate
and to get engaged for our audience listeners.
And really appreciate your expertise
where you really have a strong background
both in clinical medicine and laboratory medicine,
which makes you a brilliant person
for a given this podcast to our listeners.
Thank you.
- Thank you.
- To our listeners, thank you for joining us today.
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