COMMENTARY

Antithrombotics in ACS and TAVR: New Choices, Same Trade-offs

Neil E. Moat, MBBS, FRCS; Michelle L. O'Donoghue, MD, MPH

Disclosures

October 13, 2014

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ATLANTIC: Did Fast Ambulances Erase Benefit?

Neil E. Moat, MBBS, FRCS: Welcome to the European Society of Cardiology (ESC) Congress in Barcelona. I am Neil Moat. I'm a cardiac surgeon from London, in England. It's a pleasure to be joined by Michelle O'Donoghue, who is from Brigham and Women's Hospital in Boston. We are going to talk about novel antiplatelet agents and anticoagulant strategies in a variety of fields.

I would like to start with the ATLANTIC trial,[1,2] which was one of the late-breakers here in Barcelona. What were your thoughts about that study?

Michelle L. O'Donoghue, MD, MPH: The ATLANTIC trial was based on an interesting question that has a very important premise. In the setting of ST-segment elevation myocardial infarction (STEMI), it appears that with clopidogrel and such novel antiplatelet therapies as ticagrelor or prasugrel, the pharmacodynamic effects are delayed. When we are hoping that patients are adequately covered, right around the time of their percutaneous coronary intervention (PCI), we are finding that even with these rapid agents, it may take a few hours for them to have significant pharmacodynamic effects.

With that in mind, the ATLANTIC study aimed to address an important question: Should we be trying to load patients with ticagrelor (Brillinta®) as early as possible in the settling of STEMI, or is it fair to wait until they arrive in the hospital closer to the time of being in the cath lab? The study was conducted in France, and they have a very organized ambulance system that is able to effectively conduct this type of trial. The gap in time from when patients were given ticagrelor or placebo in the ambulance vs in the hospital was a relatively short window. So, the investigators had their work cut out for them in terms of being able to show a benefit.

Dr Moat: The ambulance service was too good.

Dr O'Donoghue: Exactly—too quick for its own good. It was challenging to try to achieve their primary endpoints. They had co-primary endpoints in the trial. The upstream administration of ticagrelor did not modify the incidence of either of those primary endpoints. However, they also looked at prespecified secondary endpoints, one of those being stent thrombosis. They did find that patients who had received ticagrelor in the ambulance had a lower risk for stent thrombosis.

That being said, we need to pause because obviously, once a trial doesn't meet its primary endpoint and you are looking at secondary endpoints, there is always the possibility that these are explained by chance. Furthermore, there were very few events—approximately 13 stent thrombosis events—but there was a very dramatic gap in the incidence of stent thrombosis events. Biologically, it is certainly plausible, considering the pharmacodynamic effects around the time of STEMI. At least on the basis of what we know from those studies, it makes sense to administer ticagrelor as early as possible if that is your drug of choice.

Potential Morphine Interaction

Dr Moat: One issue that was raised was the possibilities of delayed absorption, particularly in patients who had been given morphine. Is that another confounding factor?

Dr O'Donoghue: Exactly. That was one of the interactions that they looked at in this particular study. The interaction with morphine is not completely understood, but you are right. The feeling is that there is a delay in absorption for the anticoagulant medication in patients who receive morphine. They showed that in the patients who did not receive morphine, the prehospital administration of ticagrelor appeared to be even more efficacious. Perhaps it's just because of minimizing that delay of the pharmacodynamic effect and making sure that you are covered around the time of the PCI itself.

Dr Moat: It is an interesting concept, with no clear answer from the study.

Dr O'Donoghue: The STEMI and non-STEMI populations could be different. We previously had the results looking at prasugrel (Effient®) in non-STEMI,[3] which suggested that preloading in the setting of a non-STEMI probably is not a good way to go. There was no clinical efficacy, and just a signal toward more bleeding. STEMI might be a different story because of that delay in the pharmacodynamic effects, and the guidelines do endorse administering whichever P2Y12 inhibitor you plan to use before you get that patient to the cath lab.

Dr Moat: We could maybe hypothesize that if your healthcare system is not quite as quick at getting the patients to the lab, that you may even have more benefits.

Dr O'Donoghue: Right. Unfortunately, that may well be true.

Vorapaxar and Rivaroxaban After ACS

Dr Moat: What else has been going on in terms of novel antiplatelet therapy at ESC or elsewhere?

Dr O'Donoghue: It's an exciting time because clinicians now have many different therapeutics to choose from, but that also makes it a very confusing time. We are becoming more familiar and comfortable with using these novel P2Y12 inhibitors, ticagrelor and prasugrel. Overall, we know that they are efficacious. Both drugs appear to increase the risk for non-coronary artery bypass graft-related bleeding. Nonetheless, the mortality benefit with ticagrelor is quite compelling when you compare it with clopidogrel (Plavix®).

At the same time, other therapeutics have been developed in tandem. We now have vorapaxar (Zontivity™), which is a PAR-1 receptor antagonist. There is probably a little less familiarity with the PAR-1 class. People usually think about thrombin and the coagulation cascade, but in fact, thrombin is the most potent platelet activator. So the agonist for the PAR-1 receptor on the platelet surface is thrombin. Vorapaxar blocks the PAR-1 receptor.

Initially, there was hope that the PAR-1 receptor antagonists would lead to a reduction in clinical outcomes without a clear increase in bleeding. That did not prove to be the case, however. Such drugs as vorapaxar increase the risk for bleeding, but they also have clinical benefit.

The TRA 2P TIMI 50 trial[4] evaluated vorapaxar in patients with stable coronary artery disease. This is a slightly different space than patients who are immediately post-acute coronary syndrome (ACS), but a large proportion of patients in that trial were on a background of dual-antiplatelet therapy. It raises the question about patients who are on dual-antiplatelet therapy with clopidogrel and aspirin, and whether there is value in adding vorapaxar as a third agent. The fact that the TRA 2P trial demonstrated clinical efficacy for that strategy speaks to a possible benefit for continuing antiplatelet therapies long-term.

Obviously, there is much discussion right now about when to stop dual-antiplatelet therapy. In Europe, there is a shift toward stopping it earlier, whereas in North America, the practice has been generally to treat for at least 12 months after stenting. Between those agents, clinicians already have their hands full in terms of making decisions.

The final therapeutic agent that I will mention is rivaroxaban (Xarelto®). Many people think of rivaroxaban as an anticoagulant that is used primarily for deep vein thrombosis or pulmonary embolism treatment, or within the atrial fibrillation realm. In Europe, rivaroxaban is also approved for treatment of patients after ACS. That was based on the results of the ATLAS ACS 2 study.[5]

The ATLAS ACS 2 study evaluated a very different dose of rivaroxaban. It was not the dose that we are most familiar with for treating atrial fibrillation. It was a very low dose—2.5 mg or 5 mg twice daily. In that trial, most patients were being treated with both aspirin and clopidogrel, and they showed that adding this low dose of rivaroxaban on top of dual-antiplatelet therapy led to a very dramatic mortality benefit, with the same trade-off in bleeding events.

That is always where the push/pull is for these agents is: At what point do we accept the efficacy signal in exchange for perhaps a bit of a bleeding signal? I would love to get your thoughts on that as well because, obviously, as a surgeon you are thinking even more about the bleeding.

Dr Moat: Let's change from coronary disease to valvular heart disease. In many of our patients after surgery, we want to use a combination of an antiplatelet agent and anticoagulant. Do you have any thoughts as to whether these new agents offer benefits there? Certainly, in the United Kingdom we have problems having people on aspirin and warfarin, with the interaction and risk for gastrointestinal bleeding. If you have a patient population in whom you want to have an antiplatelet and an anticoagulant effect, what would your thoughts be in the current era?

Post-TAVR Anticoagulation

Dr O'Donoghue: It is an important topic, especially in patients who require dual-antiplatelet therapy with an anticoagulant. Do you treat them with all three drugs? If so, for how long? The WOEST trial[6] created a lot of discussion about the idea of dropping aspirin. Some trials are starting to look at the question of whether taking away the aspirin is the way to go rather than dropping the P2Y12 inhibitor.

It has been very pertinent recently when thinking about the patients who are undergoing transcatheter aortic valve replacement (TAVR). The recommendations are for dual-antiplatelet therapy for a period of time unless those patients need to be on an anticoagulant, in which case the anticoagulant is the drug of choice. That is still an untested domain.

Dr Moat: It's an evidence-free zone. But it is important, because one of the concerns with transcatheter aortic valve implantation or TAVR is stroke. Most series are demonstrating an increased risk for stroke, not just procedurally, but in the first 10 days afterward. It is difficult to know what combination to use.

In our experience, we have only used single-antiplatelet therapy, but we put all the patients on a therapeutic dose of subcutaneous enoxaparin (Lovenox®/Clexane®) for their hospital stay and for about 10 days afterward. Do you have any thoughts—I don't think there is a lot of evidence out there—as to would be a sensible combination, bearing in mind that these patients are often a fairly elderly population who are at risk for hemorrhagic complications?

Dr O'Donoghue: It's an untested area. We are probably going to see a randomized trial emerge soon, but at the Brigham and Women's Hospital, the current practice is typically to use the combination of aspirin and clopidogrel. I have often wondered whether this is really a platelet-driven thrombotic event that occurs with a stroke, or is it coagulation cascade-mediated, so it's hard to know which direction to go. Should we be putting patients on one of the novel anticoagulants, or should we be thinking about one of the novel P2Y12 inhibitors or just old-fashioned clopidogrel? Do we need aspirin on top of it? I don't know. We could come up with many different combinations.

Dr Moat: There are plenty of studies for people to do to provide some evidence of what combination we should be using in the valvular setting and in the TAVI setting.

Thank you for these very interesting insights on the world of novel antiplatelet agents and anticoagulant agents. Thank you for joining us here in Barcelona. I have certainly been educated and appreciated our discussion.

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