Oral anticoagulation for adults with atrial fibrillation or venous thromboembolism

[Music] Welcome to the Australian Prescriber Podcast. An
independent, no-nonsense podcast for busy health professionals.

Hello and welcome to the Australian Prescriber Podcast. I’m Jo
Cheah, a hospital pharmacist in Melbourne and your host for this episode. In
this episode, I have the pleasure of interviewing Dr Paul Chin. Paul is a
clinical pharmacologist at Christchurch Hospital and a senior lecturer at the
University of Otago in New Zealand. Today, we will be discussing oral
anticoagulation for adults with atrial fibrillation or venous thromboembolism,
which is the title of Paul and co-author Associate Professor Matthew Doogue’s
article in Australian Prescriber. Welcome, Paul.

Thanks very much, Jo. Thanks for having me on.

So Paul, if we go all the way back to the basics, what is atrial
fibrillation, and why are oral anticoagulants indicated?

Yeah, so atrial fibrillation is quite a common cardiac arrhythmia.
Affects something like 1% of the population. And it’s associated with clots
that form in the atria, which then can cause embolic phenomena elsewhere. In
particular, strokes is the big one that people are concerned about.

So anticoagulation reduces that risk, in the order of around about
halving of the risk of clots. Per year, normally would be in the order of 5 to
10% per year. So you’re halving that risk for patients by starting
anticoagulation.

And I’m sure most of our audience would be familiar with venous
thromboembolisms, but do you just want to give us a brief definition?

Yep. So clots within the veins, which importantly can propagate to
the lungs causing pulmonary emboli, and that’s associated with morbidity,
sometimes death. And so anticoagulation can reduce the risk of that as well.

Thanks, Paul. And what are the currently available direct oral
anticoagulants, or DOACs?

Yeah, so the ones that we have available in Australia, apixaban,
rivaroxaban, and dabigatran, are the DOACs. And then we’ve got the
long-standing warfarin.

Do you mind discussing the mechanisms of action of the drugs
you’ve just mentioned and their main differences?

Yeah, sure. Essentially, all of them are anticoagulants, but their
specific action is quite different. Warfarin, in a sense, works upstream of the
anticoagulation as it were in terms of inhibiting the production of clotting
factors.

Whereas the DOACs, they directly inhibit clotting factors in the
bloodstream. So when the DOAC is present in the bloodstream, it’s got some
action; when it’s not, then it hasn’t. Whereas warfarin has got a longer
duration of action because it’s got this downstream effect of inhibiting
production, and then we’re then dependent on how long those clotting factors
are around for as well.

In terms of the DOACs then, we’ve got apixaban, rivaroxaban, that
are both Xa inhibitors, much like enoxaparin and the [other] low molecular
weight heparins. And then the odd one out is dabigatran, which inhibits
thrombin or factor IIa.

And in what clinical scenarios would DOACs be preferred over
warfarin and vice versa?

Yeah, so that comes down to some of the particular characteristics
of the DOACs in comparison to warfarin, and also some of the empiric data we’ve
had from studies looking into particular indications.

If we look at the indications, the empiric data would have us
believe that in the setting of mechanical heart valves, so long-term
anticoagulation for that, warfarin is definitely superior to dabigatran. And I
think after the trial from around about 10 years ago, no one’s really wanted to
revisit that, and so warfarin remains the mainstay there.

The other potential indication for warfarin is that because it is
the only one out of all of our oral anticoagulants that is not renally cleared,
it’s in a sense the simplest one to use when you’ve got a patient with severe
renal impairment. In that sort of setting, you’re wondering, ‘How do I dose
adjust? Do I need to dose adjust the doses of the DOACs?’ which all have some
degree of dependency upon the kidneys for clearance.

The clear marketing advantage of the DOACs over warfarin has
always been that you don’t need to do any INRs, which is what we depend on to
ensure that warfarin is therapeutic and not too much, not too little. And so
this relative freedom from having to have lots of blood tests, but it does also
bring along some potential issues with kidneys, especially in relation to
dabigatran, which is the most dependent upon renal function for its clearance.

Having said that, in terms of some other particular scenarios
then, the DOACs all have got shorter half-lives than warfarin, so half-lives of
between 7, 14 hours or so depending on the DOAC. Whereas warfarin’s got a
half-life of 40 hours, which means that in the, for example, perioperative
setting where you’re wanting a patient to have fairly normal coagulation before
they undergo major surgery, for example, it can, in a sense, be quicker for
patients to commence surgery if they’re withholding DOACs compared with
warfarin. So there’s this sense of agility with the DOACs.

There’s always a trade-off, though. So the trade-off with the
shorter half-life, of course, is that when patients miss a couple of doses of
the DOACs, especially rivaroxaban, for example, so you’ve got a half-life of 7 hours
dosed once a day, missing a couple of doses, you’re basically back to square
one. You’re not anticoagulated at all. Whereas with warfarin, with it’s much
longer half-life, missing one or 2 doses, and as many experienced
clinicians will have observed, not much seems to happen to the INR in many
patients.

And have you found in practise that you’ve had many thrombolic
events with patients missing one dose of rivaroxaban here and there?

No, so that’s much more anecdotal. I think if you spoke of any
stroke physician, they’d have the horror story of a patient who just came off
for a few days and ended up with a stroke as a result of that.

As I was saying earlier on, the annual risk with atrial
fibrillation anyway of a thromboembolic event is 5 to 10% per year.
And so on a daily, weekly basis, the risk should be quite small. But that’s
always a concern, is that it doesn’t take many missed doses for the patient to
essentially be unanticoagulated.

Yep. And I’ll just highlight that there’s a really great table in
your article comparing the characteristics of the oral anticoagulants. So I do
recommend our listeners have a look at that when they can. And do you find that
clinicians are more likely to be prescribing DOACs now in the first instance?

Yeah, totally. I suspect for many clinicians, one just does not
mention warfarin when discussing anticoagulation, just because the notion of
having all of these INR regular tests is expected to be off-putting for people.

So yeah, we’ve certainly seen the DOACs eat warfarin’s lunch as
far as the prevalence anticoagulant use is concerned. The other thing that’s
interesting that’s happened as well is that the rate of anticoagulation for
atrial fibrillation does seem to have improved over the years. And it’s a bit
hard to attribute that to just the onset of the DOACs. Maybe guidelines have
been better implemented and rolled out, but it’s probably reasonable to
attribute some of that increase in anticoagulation rates to the apparent
simplicity of the DOACs.

And are there any major contraindications for DOACs? I know you
mentioned severe renal impairment for dabigatran. Any other contraindications
that we should be aware of if thinking about prescribing DOACs?

Yeah. So a couple of specific scenarios. In the setting of
pregnancy, we just haven’t got the data. So it’s not so much that we’ve got
data that it’s bad, it’s just that we haven’t got data. And we have got plenty
of experience with low molecular weight heparins as being a reasonable option
in pregnancy, so use that.

In the study of breastfeeding, the data for the DOACs are
emerging. Warfarin is still the mainstay there, but we’ve got pharmacological
reasons to expect that rivaroxaban and dabigatran specifically are going to be
okay with breastfeeding. We’ve got data showing that apixaban is not okay, a
bit too much of it gets into breast milk.

Having said that, just coming back to the kidney side of things,
the labels show that below certain renal function limits, DOACs are
contraindicated. Take apixaban, for example. Only a quarter of it is dependent
on kidneys. So even if the kidneys are mostly blanked out, still got the other
three-quarters, which is liver-based. Which supports the notion that apixaban
may well be okay, and there is some data to show that even with severe kidney
disease.

The other burgeoning problem is, of course, the extremes of
weight. So the very large patients give us some concern that the standard doses
of the DOACs are inadequate. And this is where the empirical data have been
quite helpful, at least in terms of rivaroxaban and the apixaban, in assuaging
some of those concerns and showing that standard doses of those 2 seem to be
okay even with the very large patients. At the other extreme, the very small
patients, so 40 kg, that sort of thing, there’s much less data and so
there’s a lot more uncertainty there. That’s the situation where we’re not
sure, so let’s use something that we are more familiar with, warfarin, with
INRs, as a gauge of whether the intensity of anticoagulation is adequate.

Finally, drug interactions, another headache, obviously,
especially when you’ve got drugs that may be expected to either significantly
increase or reduce the concentrations, the levels of the DOACs. Now, this is
nothing new. This was actually one of the problems with warfarin is that if you
open up the standard textbook or table of interactions with warfarin, you’d
have to turn the page because there were so many of them. So yes, the list is
shorter with the DOACs, but the problem is that one is less likely to recognise
them as a routine because of the lack of routine anticoagulation intensity
testing.

So once upon a time, we used to identify when a patient did have
an interaction by, ‘Oh my goodness, the INRs shot up from 2 to 5. Let’s
have a look and see what’s going on. Oh wait, it was the erythromycin that was
prescribed,’ for example. Now you have to be much more on your toes. And big
shout-out to the pharmacists here in supporting safe prescribing of the
anticoagulants and recognising some of these interactions. Because without
routine testing, which is not necessarily something that needs to be done
because in most patients, it’s fine, but without laboratory coagulation indices
being routinely done, you don’t know when a patient’s being over anticoagulated
or not.

In the article, I gave the hyperacute situation, which I just had
in the last few months. So you’ve got a patient who is being treated for an
infection and is requiring rifampicin as part of that, and then that infection
is complicated by a venous thromboembolic event. So now they need to be started
on anticoagulation. Now, rifampicin is a strong inducer of a variety of drug
elimination pathways, and so then the concern is that the concentrations of the
DOACs, if you are going to start that, it’s going to be too low. And we have
got some data showing that it halves or even reduces down to one-third the
concentration of DOACs in the presence of rifampicin.

So in that setting, it would be a ballsy move to double or triple
the dose without getting some sort of feedback from concentration monitoring,
which the turnaround availability of that and also expertise and interpretation
may not be there in some places. In which case, the simplest thing to do, let’s
just go back to tried-and-true enoxaparin and molecular weight heparins that
are relatively free of interactions of this pharmacokinetic nature. Do that
instead in the acute situation until you feel you’re out of the woods a few
weeks down the line, then you can rethink whether to use a DOAC or not.

Yeah, some really interesting points you’ve raised, for example,
where low molecular weight heparins, I know this article is focused on oral
anticoagulants, but there is still a place for low molecular weight injectable
heparins where necessary.

Yeah, yeah.

And with the interactions, you mentioned the rifampicin example.
So for example, in the article, you’ve listed that there are some SIP and PGP
transporter interactions with these drugs. So where’s your favourite reference
that you use for looking at these sorts of interactions?

I think as a general screening tool, it’s quite reasonable to look
up whatever routine drug interaction checker you’ve got. And I’m thinking here
of someone who might be looking up stuff at 9:00 at night in the hospital, for
example. So you’ve got Lexicomp, the AMH, and then obviously during the day on
the wards, get in touch with your ward pharmacist.

Yeah. You mentioned Lexicomp, AMH, I like Stockley’s. The FDA also
have the interactive table that’s freely available that lists these
interactions. And with that rifampicin example, I know you were saying you
could have a third of the efficacy of the anticoagulant. So does the product
information have any advice about, for example, increasing the anticoagulant
dose, or is it really based on expertise and potentially laboratory testing?

Yeah, so it is largely based on expertise. There’s cautionary
stuff like avoid it and proceed with caution, which doesn’t get you very far.
The notion of avoiding it is good if you have got an alternative such as the
low molecular weight heparins. Otherwise, there are data for some particular
combinations.

So it’s with rifampicin, with dabigatran, for example. That’s
where my one-third example comes from. So in theory, instead of 150 mg
twice a day, let’s give 450 mg twice a day. But I think that would be
particularly courageous to do in the absence of actually measuring some
concentrations, because the trouble with the data and the magnitude of
interactions is that what we often see are just the averages. And so some
patients may have a much smaller interaction, other patients have larger. For
that specific patient in front of you, you never really know which one of those
they are.

So tripling the dose on everyone for an anticoagulation just
because they’ve got this other drug there, it’s not necessarily the best thing
to do. This is why warfarin, in a sense, is easier in this sort of setting is
that INRs are ubiquitous in terms of accessibility, and then you can look at
responses there. Whereas trying to get a concentration assay, trying to
interpret what it means, that may be an order of magnitude more difficult than
warfarin with INRs.

Just a small point to make about those patients with severe kidney
disease. While the label would suggest that, say, you’ve got a creatine
clearance GFR of 10 mL/min, it would suggest that the DOACs are more or
less out the window. I think if for whatever reason warfarin wasn’t an option,
then it’s worth getting in touch with your local anticoagulation expert and
having a bit more of a think. Because the fact that, especially with
rivaroxaban and apixaban, where only the minority of those 2 drugs are
dependent on the kidneys for elimination means that there is some possibility
of using smaller doses even with such severe renal impairment if the indication
is worth it.

And in terms of your anticoagulant specialist, do you have an
anticoagulant service at your hospital or even an anticoagulant pharmacist, for
example?

At my particular hospital, it’s managed between pharmacology and
haematology. And pharmacology, we’re mostly involved with the therapeutic drug
monitoring side of things, but also helping out with drug choice type
questions. In a sense, we’re talking about edge cases here. Many general
physicians, cardiologists, geriatricians, et cetera are more than capable of
sorting out the anticoagulation in 80, 90% of patients who need it.

Yes. And as we’ve been mentioning throughout our chat, our
audience is likely familiar with INR testing that we use for warfarin, but may
not be as familiar with the available lab tests for the DOACs. So can you
briefly discuss these tests and how useful they are in clinical practise?

It’s useful to divide up the laboratory testing of anticoagulation
intensity, as it were, into the concentrations [drug concentration assays] as
opposed to the coagulation assays. If we split it up into those 2 things then,
the concentrations, as far as the DOACs are concerned, are useful at least in
so far as if you’re going to do those adjustments are concerned.

However, the problem with the concentrations is that accessibility
to them can be limited, and timing with the DOACs is incredibly important in
interpreting the concentrations. So you can get a several-fold difference
between a sample that’s taken a couple of hours after a dose compared with just
before the next dose. Take rivaroxaban, for example, where you’ve got a
half-life of about 7 hours on average, everything else being equal, and
you’re only dosing it once a day. So in between doses, you’ve got 3 half-lives,
give or take. So knowing when the dose was taken in relation to the sample is
incredibly important, because it’s the difference between [the level being] really
high versus ‘this is fine’ because it was only a couple of hours after the
dose.

We set that to one side because access to that [drug concentration
assays] may be more difficult. The coagulation assays that people will be more
familiar with, so your INR, APTT, thrombin clotting time, screening coagulation
assays. The thrombin time is particularly useful for dabigatran, which I know
in Australia is a bit of a minority player, but it’s in the label as it were.
Dabigatran is a thrombin inhibitor, so no surprises. The thrombin clotting time
is the best test for that. And basically, if that thrombin clotting time is
normal, there more or less is not any dabigatran around. So that’s quite useful
if you’re trying to work out, for example, in the perioperative situation or
indeed a patient is bleeding and you’re trying to work out if idarucizumab is
going to be useful (the reversal agent for dabigatran). [If] The thrombin time
is normal, then you can treat the patient as if they weren’t on any
[dabigatran].

In terms of the other [coagulation] assays for the other DOACs,
essentially the take-home point there is that there is too much either
insensitivity or variability for them to be that useful otherwise and that sort
of variability. And what I mean by that is the relationship even between the
clotting assay result and the concentration, there’s too much variability in
that relationship to hang your hat on in making clinical decisions, including
dose adjustment.

So yeah, if you are going to do any of this for dose adjustment,
you need concentrations. In which case, check with the lab if that is actually
available and if anyone’s going to be around to help you out with the
interpretation.

So are these tests more likely available in major hospitals
compared to a local pathology centre, for example?

Yeah, that would be my expectation. There’s also the question of
turnaround time. So in the hyperacute situation, if your lab can actually get
your concentration back quickly, then that can be useful in that situation
where someone’s bleeding or you’re trying to work out whether to thrombolyse a
patient. But otherwise, ordinarily in the absence of a quick turnaround, it may
be more useful to do a clotting test. But again, that really is dependent on
exactly which DOACs you’re looking at.

And similarly, the audience is probably familiar with the antidote
for warfarin being vitamin K, but can you discuss the available antidotes for
the DOACs and when they would be indicated?

Yeah, sure. So with warfarin, you’ve got reduction of factors II,
VII, IX, and X. So importantly, we’ve got X in there, which also bears some
resemblance to what apixaban and rivaroxaban do.

One of the antidotes for warfarin of course is prothrombin complex
concentrate [Prothrombinex], which contains some of those clotting factors. And
that can be used for the DOACs because if you’ve got an inhibitor of X or an
inhibitor of IIa thrombin, then that can be useful, something to use when you
need that quick reversal.

A useful thing to point out is that because of that relatively
short [DOAC] half-life of 7 to 14 hours, depending on which DOAC
we’re talking about, sometimes all you need is just time, just let it wash out.
But otherwise, if the patient is needing surgery right now, if there is a major
bleed going on, then there can be indications for the antidotes.

So idarucizumab is [an antidote] very specific to dabigatran
because it specifically binds to dabigatran. Whereas the likes of andexanet
alfa that’s an antidote for anything that binds to factor Xa, which includes
rivaroxaban, apixaban, and in fact the likes of enoxaparin as well.

The cloud over the likes of andexanet alfa, as well as
Prothrombinex [prothrombin complex concentrate], is this potential for
clotting, overdoing it as it were. So those antidotes are something to be
wielded if the bleeding is really that severe.

And have you seen them being used much in practise?

Yeah, so I’m based in Christchurch. We haven’t got access to
andexanet alfa, we would use Prothrombinex. Idarucizumab is used as a routine.

One thing to mention about the reversal agents is that because
they’re more or less directly taking out the DOACs from the bloodstream, their
action is actually incredibly quick. So rechecking the coagulation tests even
15 minutes later can often show normalisation. Just a bit different from
what you were mentioning before with vitamin K, which have to go through a long
sequence of events before you replenish the vitamin K-dependent clotting
factors that warfarin is reducing. That’s something that can take 12, 24 hours,
that sort of thing. So the sort of quickness of these reversal agents can be
useful.

But one of the other issues then is, for example, with
idarucizumab, is that we actually have a scenario that’s analogous to the
naloxone-morphine issue, which is that naloxone’s got a much shorter half-life
than morphine. So some of your audience will be familiar with this idea that
sometimes you have to set up a naloxone infusion or give multiple doses because
the patient becomes narcosed again after the naloxone wears off because the
morphine’s still hanging around. That can also happen with idarucizumab and
dabigatran.

Yeah, so in for example, your local practise where the andexanet
alfa is not actually available, you would just watch and wait, you just need
time for the body to clear the drug naturally.

Yeah, that’s right, so time. Otherwise, Prothrombinex complex
concentrate, which has got factor X in it, can be an effective reversal agent.

True. Very interesting to hear your clinical experience in the
area as well.

Paul, that brings us to the end. Thank you so much for your time
for coming onto the podcast today.

Thanks again for having me, Jo.

[Music]

Paul and Matthew’s full article is available on the Australian
Prescriber website. The views of hosts and the guests on the podcast are their
own and may not represent Australian Prescriber or Therapeutic Guidelines. I’m
Jo Cheah, and thanks again for joining us on the Australian Prescriber Podcast.