And for our fourth lecture, it'll be Dr. Dharam Kumbhani, Triple Therapy, When to Use and How Long. Thank you so much, Dr. Indyk. ACC staff, thank you so much for having me. And I'm gonna try to pull up my slides here. So again, good evening to everybody. I'm gonna be talking a little bit about triple therapy, primarily for patients who have A-fib and also undergo PCI. And so I'll go over some of the details of that, and these are my disclosures, which you already saw. Now, when we think about antithrombotic therapy for patients who have A-fib and PCI, the paradigm that we're kind of dealing with is when you take patients with non-valvular A-fib, we know that anticoagulant therapy is better than antiplatelet therapy. This is a lower shear stress situation in terms of thrombosis risk in the left atrium, and as I said, multiple trials have shown that anticoagulation is superior to antiplatelet therapy. When you have patients that undergo PCI at the same time, you also know that this is a high shear stress situation, particularly when you think about stem thrombosis, because it's platelet-mediated in the arteries, and dual antiplatelet therapy has been shown multiple times to be superior to aspirin alone, and also warfarin is not felt to be as good as DAP for this indication. So the question is, when you have patients who have both non-valvular A-fib and who have also undergone a PCI, what really should be the treatment choice? Would you really treat these patients with both anticoagulant and dual antiplatelet therapy? Now, the issue, of course, is bleeding, and this is true for pretty much everything that we have studied. As you stack on more blood thinning agents, you have a higher risk of bleeding, and so these are some of the data from the RELI trial, which was a dobigatran trial in AF, but when you add even one agent, whether they were studying a NOAC or warfarin, the risk of bleeding increased. When you added one antiplatelet agent to warfarin, the bleeding risk increased by about 60%, and when you added dual antiplatelet therapy to warfarin, the bleeding risk increased two to three-fold. So this is a pretty dramatic increase in the risk of bleeding. Now, the first trial to really assess this was from Europe, the WUS trial, where they took about 573 patients who had an indication for anticoagulation based on AFib, and who had then undergone PCI, and they decided to drop aspirin, which at that time was sort of a dogma that you could never drop aspirin in patients undergoing PCI. And so when they dropped aspirin, they noted that there was a significant reduction in any bleeding in the arm that got what we call now dual antithrombotic therapy, which is the P2Y12 inhibitor plus warfarin compared with triple therapy, which would be aspirin, the P2Y12 inhibitor, and the oral anticoagulant. Interestingly, they also saw a signal for an improvement in ischemic endpoints, but again, remember, this was a smaller study. Now, there have been subsequently many other studies that have looked to assess this question. Primarily, and the rest of them have all been done with NOACs. So Pioneer AF-PCI was one of those trials. Now, one thing that's very important when you're considering this dual antithrombotic therapy paradigm is understanding the doses of the medicines, of the NOACs particularly, that were tested in these trials. So Pioneer AF-PCI, again, the same sort of clinical scenario, a patient who has an indication for anticoagulation for AFib, and then now they undergo PCI. So the dual therapy, now instead of staying with Rivaroxaban 20 milligrams, which in patients with normal renal function is the usual AFib strobe prophylaxis dose, they dropped it down to 15 milligrams, and then they also had an arm where they received sort of what is now, we call the compass dosing, two and a half milligrams BID. But I think just focusing on the Rivaroxaban 15 milligrams a day, dual therapy with Rivaroxaban 15 and Clopidogrel, there was a significant reduction in the bleeding endpoint which sort of transcend for across the board with no difference in ischemic endpoints. Redual PCI was an analogous trial that was done with Dabigatran. And again, there were two doses of Dabigatran, as you know, the 110 BID and the 150, which is what we use in the US. And then again, it was the same construct. It was Dabigatran plus Clopidogrel compared with triple therapy, which included warfarin. And there was a significant reduction in bleeding, a 28% reduction. This met criteria for non-inferiority, but also for superiority of this regimen with no difference in ischemic endpoints. And then there's Augustus, which is, I think actually just from a pure strategy standpoint, a very helpful trial. So they had 4,600 patients with the same sort of paradigm who were randomized in a two by two factorial design. So they had a randomization to a Pixaban five milligrams BID, which is, again, the treatment dose for stroke prophylaxis for AFib. And they were compared to warfarin. And then in a factorial fashion, there was also a randomization to low-dose aspirin versus placebo in both arms. And so this, in my mind, really tests the question, is it two versus three? And if you're doing two, which is better? And so that's sort of really something we understand from this trial. So the highest bleeding risk was with triple therapy, which involved warfarin. So aspirin plus VKA had the highest bleeding risk here at six months. Lower than that was a Pixaban plus aspirin. So again, triple therapy came out worse no matter which way you did it. VKA plus placebo was lower than that, but the best strategy was a Pixaban plus placebo. So this, again, to me, this is a very important trial from a strategy standpoint, really tells you that dual antithrombotic therapy is the way to go, including a NOAC and clopidogrel. Now, this trial also really answered the question about any ischemic benefit with aspirin. So again, we saw that there was no difference for a Pixaban versus placebo. But further in the, you say, okay, well, maybe I'm gonna take a higher risk of bleeding if I have an ischemic benefit with aspirin. But we can see over here that across the board, you only got the downside, which was bleeding, but you didn't really have an improvement in ischemic endpoints. So this is a summary of all the trials. It also includes Entrust-AF-PCI, which was done with Edoxaban 60. And it sort of summarizes what the randomization was. I went through that with the slides. The primary outcome for all these trials, these were all trials that were really powered for the bleeding endpoint, and to a large extent, they were all successful in showing that. And then they really weren't powered for ischemic endpoints, but there was no significant difference. And importantly, there was also no signal that was seen for stent thrombosis. So this was put together in a really elegant meta-analysis by Renato Lopez and colleagues from Duke. And they really, again, show that when you have this paradigm of the highest bleeding risk is gonna be with a VKA plus DAPT, or so-called triple therapy. And so when you look at timi-major bleeding, bleeding as defined by the trial, and also, importantly, intracranial hemorrhage, the NOAC plus P2Y12 inhibitor is gonna come out on top, and you're not really gonna see, or we're not really seeing a signal in terms of ischemic issues. Now, one thing I will point out, these trials did use aspirin. So it wasn't that they didn't have aspirin, even in the trial that had, or even in the arm that had dual antithrombotic drugs used. And so this is the duration. So if you really wanna look at this from an evidence standpoint. So again, the paradigm is somebody has AFib, they've been on anticoagulation, now they get a PCI, obviously, typically with a drug eluting stent, and then what is, how would you deal with that? And so during the procedure, they all get aspirin, and so that's a given. And then you can see there was a sort of difference between the different trials in terms of how many days. The highest was actually with Augustus, where aspirin could be used for up to one week, post-PCI, and that was sort of the average in the trial. Now one interesting sub-study from Augustus, I mentioned that aspirin use did not have a benefit in ischemic endpoints. This was one of the important sub-analyses where they took patients who received, all of these patients were patients who got apixaban plus clopidogrel. When they looked at the first 30 days, there was, again, just like the primary results, a higher risk of bleeding with aspirin, which you are kind of seeing up here, but also up to, for the first 30 days, there was actually a benefit in CV death, stroke, MI, or stent thrombosis. So perhaps in patients who truly have a higher risk and a low bleeding risk, this is something that you might consider. Then when you look at 30 days to six months, there's really, you're just seeing the bleeding issue, but you're not really seeing any ischemic benefit. So this is, again, a sub-analysis, but of a very important trial. So these were the trials that resulted in the expert consensus decision pathway that we put together. And this sort of walks through a lot of these issues, both from a strategy standpoint as well as patient selection standpoint. But basically the scenario is you have somebody with AFib, they are indefinite, they have a need for indefinite anticoagulation, they now undergo PCI. So one of the first things is, even if they come in on a VKA versus a DOAC, you really want to try to steer them towards, based on what you've seen, NOAC or DOAC, as we heard, you really want to try to steer them towards using one of the NOACs, even if they came in on warfarin. And then the next question is how long you would do this. Now, so I think what we've done is we kind of partitioned that based on whether they had PCI for stable ischemic heart disease, like angina, versus if they had it for ACS, like a STEMI or non-STEMI. Now, if you'll see in this diagram, you would continue OAC sort of indefinitely on the other side. Now, when you're looking at what you would do on the antiplatelet side, if it's ACS, it's actually easy. You would just continue clopidogrel, a P2Y12 inhibitor, but really clopidogrel for 12 months. If you do it for stable ischemic heart disease, you really want to do clopidogrel for at least six months. Now, there's a big gap in sort of a knowledge base. We don't have trials that have randomized patients off antiplatelet agent within six months of PCI. There are studies that look at stopping antiplatelet agents after 12 months, but there really haven't been any between six and 12 months. So in general, it is believed that you should continue some kind of antiplatelet agent during that time as well. So again, to summarize, the need for this sort of so-called triple therapy is a common clinical dilemma. NOACs or DOACs are definitely better than warfarin, but the dosing considerations are very important. Double antithrombotic therapy will result in less bleeding than triple therapy long-term, and we don't see a penalty in terms of ischemia or ischemic or thrombotic risk. Clopidogrel is really the P2Y12 inhibitor of choice. So if somebody is getting on this regimen, you really want to switch them away from ticagrel and prasogrel to clopidogrel, although there are some very limited data for ticagrel use as well. And then aspirin 81 low-dose can be considered if high stent thrombosis risk and low bleeding risk based on the Augusta sub-study that I showed. So thank you again for your attention and happy to take any questions. Thank you.

triple therapy

anticoagulant

antiplatelet

aspirin therapy

A-fib