The role of triple antithrombotic therapy in patients with atrial fibrillation and coronary stent insertion

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Hi, and welcome to this Australian Prescriber podcast on triple antithrombotic therapy. I'm Dr Justin Coleman, a GP in Inala Indigenous Health in Brisbane. And with me I have my fellow Queenslander, Kate Ziser, and Kate is a pharmacist at the Princess Alexandra Hospital in Brisbane and she also teaches at the UQ [University of Queensland] School of Pharmacy, a place where I've given a few lectures in my time. Welcome to the podcast, Kate.

Thanks very much Justin for having me.

Wonderful. You're a lead author in an article called ‘The role of triple antithrombotic therapy in patients with atrial fibrillation and coronary stent insertion.’ So that's what we're going to be talking about. Triple therapy to me used to mean people with Helicobacter pylori, but we're talking here about antithrombotic therapy.

Just for dummies like myself who don't deal with this stuff a whole lot and tend to see the cardiologist start and stop these patients, I'll just run through the very basics to start with as to what this triple stuff really is. So we're really talking about the dual antiplatelet therapy, which we're quite familiar with, DAPT, which is usually for aspirin and clopidogrel. There are probably a few alternatives to that we can run through in a moment. But then for people with atrial fibrillation (AF), they're also going to need warfarin or one of the warfarin substitutes. So that's really what we are going to be talking about and we're going to be talking about your suggested duration of therapy and stepping down therapy. So if you wouldn't mind, Kate, starting us just with the concept of the stents and why people need DAPT and the usual duration of time that people need dual antiplatelet therapy when they have a stent.

Yeah, sure. Thanks Justin for the overview. I think primarily if we just had somebody who didn't have an indication for an anticoagulant who had perhaps a drug-eluting stent put in after a heart attack, normally if we were to give them DAPT or dual antiplatelets, we'd recommend aspirin normally with ticagrelor or prasugrel. So these are more potent P2Y₁₂ inhibitors than clopidogrel and we would normally go with that therapy. But I think it's normally when we use DAPT as part of triple antithrombotic therapy, the P2Y₁₂ inhibitor that we will normally select is actually clopidogrel to minimise bleeding risk.

And with the old metal stents, I think you didn't have to go on the antithrombotics for as long as the newer drug-eluting stents. Is that right?

Originally when coronary artery stents were made, they were bare metal stents and normally they would endothelialise within 6 to 12 weeks. Basically over time though, these stents would restenose, they'd sort of become clogged. So drug-eluting stents were developed and they've demonstrated earlier endothelialisation and lower rates of late stent thrombosis due to the drugs and the scaffolding and the polymers that are used. So we very rarely see bare metal stents in the heart nowadays.

And then looking at the other drug, which is the warfarin or the DOACs [direct-acting oral anticoagulant]. So we're looking here mainly at people with atrial fibrillation, although I guess there are a couple of other indications as well.

Yeah, so it's probably important to note that what we'll be discussing today are patients who have atrial fibrillation as their condition that requires an anticoagulant, but as the audience would know, DOACS, or direct oral anticoagulants, are not indicated for valvular AF or if patients have a left ventricular thrombus. So warfarin, due to its proven efficacy is sort of a reliable anticoagulant in these instances. So if patients who need warfarin for one of those indications are beyond the scope of this article.

Sure. Now the entire concept of the article, the basic take-home message for me seems to be that we should use triple therapy for a shorter amount of time than we used to, and we'll get onto specifics in a moment, but the reason for that is all to do with the bleeding risks. So I suppose any drug we ever use, of course, is a risk versus benefit at that moment in time. And it used to be thought that the thrombus was the big problem, so use triple therapy for a long time, but the bleeding risk, of course, is a problem on the other side. Tell us about the bleeding risk with the triple therapy. What does the evidence say?

Yeah, this is a key part of the article, so thank you for picking up one of those key messages. Initially, the 2018 Australian atrial fibrillation guidelines suggested triple therapy for a minimum of one month extending up to 6 months for patients with high ischaemic risk, but then more evidence was collated in that space and you'd start to see some of the European Society of Cardiology recommendations advocating for only one week of triple therapy and extending up to one month for those at high ischaemic risk. And really that is the key message that the authors behind this piece are advocating for. The key message is that shorter durations of triple therapy, so the one week to one month, they do reduce major or clinically significant bleeding compared to longer durations like 6 months of triple therapy.

So that really is one key benefit and sort of reassuringly the incidence of ischaemic stroke was comparable between dual therapy or triple therapy groups. I did want to highlight that in some of those studies there has been slightly higher rates of heart attacks and stent thrombosis in the dual therapy group, but in some of these studies, they were not statistically significant, and numerous meta-analyses have really concluded that there might be a borderline statistically significant increase in stent thrombosis in dual therapy that have come up in individual trials. But when you pool all the data, the risk versus benefit profile really still does suggest one week to one month.

And certainly the bleeding risk is not insignificant. I noticed one statistic in your article is that people on triple therapy in their first year after a coronary stent, about 44% of them experienced some sort of bleeding event compared to less than 20% of people who were on the dual therapy. So even though the risk of a coronary event is perhaps a bit larger, although, as you say, not statistically significant, certainly statistically significant is a more than doubling of bleeding events if you keep them on the triple therapy.

Yeah, correct.

And you can mitigate to some extent against that risk by putting someone on a PPI, a proton pump inhibitor.

Yeah. So generally if someone's on triple antithrombotic therapy, putting them on a PPI, there's been some work in the literature about some PPIs reducing the efficacy of antiplatelets. But generally pantoprazole is what we'd go for for somebody on triple therapy, and then it's really up to the clinician as to whether they can continue that whilst they're on dual therapy, probably more so if they are at higher bleeding risk, but definitely a PPI for the duration of triple therapy, and also being cognizant for the patient not to use anti-inflammatories or fish oils or other medications that increase bleeding risks or complementary and alternate medicines that may also increase bleeding risk.

That makes a lot of sense. Thanks Kate Ziser. I think we might summarise at this point the take-home messages. So we're really looking at the step-down approach for someone who has atrial fibrillation and has a coronary stent put in and we're trying to protect them from getting a stroke or a heart attack, but at the same time trying not to increase their bleeding risk too much. So there's 3 steps really. For the first week in most patients, but [first] month in some patients, we're looking at triple therapy – that's step one.

Yeah, correct. And that is aspirin, clopidogrel, and NOAC [non–vitamin K antagonist oral anticoagulant, also known as direct-acting oral anticoagulant (DOAC)], and I think it's probably important to highlight that sometimes when you look at the trials, the dose of rivaroxaban that was used was only 15 mg daily, even if the kidneys were fully functioning and they should be indicated for a 20 mg dose. So you might see some cardiologists using a slightly lower dose of rivaroxaban for the duration of triple therapy. The other thing is some cardiologists might, if warfarin is part of the triple therapy, they might have a slightly lower target INR of 2.0 to 2.5 for that first step of triple therapy. So that's probably other things to be aware of. At the end of that first phase, ideally the warfarin INR goes back to 2 to 3 and the dose of rivaroxaban goes back up to 20 mg if that is the normal dose according to their kidney function as well. So I wanted to flag those other changes that can occur in that first phase or step one of triple therapy.

So that covers patients for that first week or for people at particularly high ischaemic risk for the first month. And then the next step is dual therapy?

Yeah. So dual therapy is the combination of one antiplatelet plus the anticoagulant, and normally the cardiologists will recommend to drop the aspirin. So the patient will continue on the clopidogrel with the anticoagulant normally for 1 to 12 months. Some cardiologists might stop the antiplatelet or the clopidogrel at 6 months; however, most times that second phase is continued up to 12 months. So they'll be on the clopidogrel and the NOAC for 12 months.

Thank you. And then finally, of course, they get to stop the clopidogrel, but they will need the ongoing anticoagulant as long as they still have atrial fibrillation because that risk hasn't disappeared.

That is the third phase. Yeah, correct. It's really important for the patient to be cognizant that this rivaroxaban, apixaban, is actually covering both their atrial fibrillation by minimising their ischaemic stroke risk, but also is covering their cardiac stent. I worked in operating theatres for a couple of years and looked after our pre-admission clinic, and we would often have patients come through who were on NOACs or DOACs who were having elective surgery, and the surgeons would stop the DOACs assuming it was for AF, but the patient would have a nice little cardiac stent sitting in there as well. So we'd actually have to put them on aspirin for 48 hours or 72 hours to get them through that elective surgery regime. So I think it's just being cognizant of particularly in the perioperative period, that DOAC is really covering both the AF and the stent, and if it needs to be stopped for any reason, we need to consider that cardiac stent.

Well, thanks so much, Kate Ziser, it's been a pleasure talking to you and thanks for taking us through triple antithrombotic therapy. Listeners, of course, can read the original article in Australian Prescriber. Thanks so much, Kate.

Thanks, Justin.

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My guest's views are their own and don't represent Australian Prescriber and my views are certainly all mine.