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.