COMMENTARY

Dual vs Triple Antithrombotic Therapy? The Debate Continues

Christopher P. Cannon, MD, FACC; C. Michael Gibson, MD, MS, FACC; Christian T. Ruff, MD, MPH

Disclosures

December 18, 2018

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Christian T. Ruff, MD, MPH: Hello. I am Christian Ruff, cardiologist and director of general cardiology at Brigham and Women's Hospital, Harvard Medical School, in Boston, Massachusetts. I am delighted to be joined by two close colleagues and friends. Mike Gibson is a professor of medicine at the Harvard Medical School and also CEO of Baim/PERFUSE Research Institute at Harvard; and Chris Cannon is director of education, clinical cardiovascular innovation, at Brigham and Women's Hospital, and also a professor at Harvard Medical School. Welcome.

We are here to discuss the challenging topic of combination antithrombotic therapy. Obviously, we run into this issue quite a bit. Atrial fibrillation and coronary artery disease are two of the most common conditions we see in all of cardiology, if not medicine. What to do about the patient's anticoagulant and antiplatelet therapy has always been a vexing problem. Obviously, we want to prevent strokes and heart attacks, but we know that combination anticoagulant/antiplatelet therapy leads to a lot of bleeding, some of it potentially serious.

Chris, what have we learned since the warfarin days? Is triple therapy in general still standard of care, or have we moved on from there?

Christopher P. Cannon, MD, FACC: I would say that it is still standard, although I hope we have seen that there are other options with better balance. The anticoagulant is needed for stroke prevention in the setting of atrial fibrillation; we saw in the ACTIVE-W[1] and AVERROES[2] trials that antiplatelet therapy was insufficient. Conversely, a patient with a stent needs a P2Y12 inhibitor at a minimum, and that has always been tested as part of a dual antiplatelet therapy (DAPT) [that includes aspirin]. That has become the standard, but we are tip-toeing our way to dropping aspirin to try to reduce triple therapy to dual therapy, and now [we have] a few trials to support this approach.

Ruff: Mike, you have done a lot of work across the spectrum of atrial fibrillation and coronary disease, whether it is acute coronary syndrome (ACS) or stable coronary artery disease. The novel oral anticoagulants (NOACs) have become entrenched as the real preference for anticoagulation. You led the PIONEER AF-PCI trial,[3] looking at this whole concept of triple therapy with warfarin versus moving to dual therapy with a NOAC and a P2Y12 inhibitor. Can you tell us about the trial, specifically about the critical elements of the trial? Is it the dual therapy or is it selecting modified doses of the NOAC? How do we protect against stent events and stroke from atrial fibrillation, as well as mitigate bleeding?

C. Michael Gibson, MD, MS, FACC: First, we have to give credit to the team from the Netherlands and the WOEST trial,[4] which showed that if you drop an antiplatelet from triple therapy, you get just as good efficacy but better safety. In fact, bleeding was cut in half. That was the genesis of the trials that Chris and I led. We struggled quite a lot with finding the right dose, which is the key to getting all of this right. We had to balance, as do all physicians, the risk for a thrombotic event and the risk for a bleeding event. We knew that, using rivaroxaban, if you go to a higher dose on top of DAPT, you will get excess bleeding. From the ATLAS trial,[5] we knew that if you go from rivaroxaban 2.5 mg twice a day to 5 mg twice a day, you increase the risk for fatal bleeding. Thus, we were hesitant to use high doses of a NOAC—in this case, rivaroxaban—on top of DAPT.

We looked at a couple of approaches. One was to use a very low dose: 2.5 mg twice a day plus DAPT—a kind of ATLAS 2 dose. We also tried a different dose, of 15 mg of rivaroxaban once daily—not the full 20-mg dose for atrial fibrillation, but a 15-mg dose—along with the thienopyridine. As you know, we did see a reduction in bleeding, as expected. You only need to treat 10 to 12 patients to prevent a bleeding event. No real surprise when compared with triple therapy with warfarin.

The big issue is efficacy. The trial was underpowered to look at efficacy, as are all of the trials in this space. The event rates were clearly very similar, and when you look at an expanded endpoint of cardiovascular rehospitalization, we actually saw less cardiovascular rehospitalization with the rivaroxaban strategies versus the conventional triple therapy with warfarin. Thus, we did not think we were doing harm in terms of cardiovascular events.

But I do want to emphasize two things. The 2.5-mg dose of rivaroxaban is not, at this time, approved by the US Food and Drug Administration. That is something worth revisiting. I also want to indicate that, while the 15-mg dose of rivaroxaban is approved for patients with renal insufficiency, it is currently not a labeled dose for this indication. I was simply presenting our research findings. I want to make that very clear to our audience.

Ruff: Thank you. The trial is very interesting because it involved modifying the dose of the NOAC to mitigate bleeding, but certainly in combination with antiplatelet therapy, you may preserve efficacy. In addition, this concept of triple therapy of almost any kind is mostly intolerable in a large majority of patients. Unfortunately, as we learned from WOEST and ISAR-TRIPLE,[6] bleeding tends to occur very early.

When patients have a bleed, they often stop all of their therapy. Chris, obviously showing that this is not just a class effect, you led the RE-DUAL PCI [percutaneous coronary intervention] study[7] with dabigatran, and that had some similarities to PIONEER but some nuances as well. You studied two different doses—sort of higher-intensity/lower-intensity antithrombotic regimens.

Cannon: Very true. Both of the new strategies were with dual therapy, using a novel anticoagulant plus the P2Y12 inhibitor, and dropping aspirin. Again, the WOEST folks get the credit for daring to do this first. We tried to look at a larger experience. The two doses (110 mg twice daily and 150 mg twice daily) used worldwide are approved for stroke prevention, although only the 150-mg dose is approved in the United States. The notion of full-dose anticoagulant but no aspirin was what we tested. The control arm was triple therapy, although the field was already moving on after WOEST, and we shortened the duration of triple therapy to 3 months if it was a drug-eluting stent or 1 month if it was not; and then it was dual therapy, with the aspirin discontinued. We found that the dual-therapy approach resulted in a huge reduction in major bleeding and clinically relevant nonmajor bleeding, and also no increase overall in thrombotic events. It looked safe to use dual therapy, with much improved bleeding profiles.

Ruff: We are seeing a lot of supportive evidence for this approach. Mike, as the only interventionalist among us, are there any patients who maybe have a heart attack after getting a stent, who should be on triple therapy? And, if we are using dual therapy, should we use aspirin or should we just drop the aspirin and use the P2Y12 inhibitor, or is it sort of dealer's choice?

Gibson: Great question. There are some patients who should probably be on triple therapy with warfarin; those would be the patients who have bad renal insufficiency. Very important point. Some patients in Europe get triple therapy. Higher-risk patients get triple therapy in those scenarios, sometimes with the 2.5-mg dose of rivaroxaban plus DAPT. That is a regimen that is approved in Europe.

For the most part, most of the world seems to have embraced this approach of dropping one of the antiplatelet medications early. It is important to note that everyone gets aspirin and clopidogrel for the procedure. We are not saying to drop aspirin for the procedure.

Ruff: Important point.

Gibson: I do think more and more people are stopping the aspirin and not the thienopyridine. Aspirin causes gastrointestinal bleeding and the thienopyridines do not. I would say that we live mostly in a world that uses a NOAC plus one of the thienopyridines, largely clopidogrel; there is not as much data to support ticagrelor or prasugrel.

Cannon: In speaking with other colleagues, I find that, conceptually, people like seeing the data and they are sort of hedging their bets, so they still often use 1 month of triple therapy. As you just indicated, that is when a lot of the bleeding occurs. At the 2018 American Heart Association annual meeting, Deepak Bhatt and Benjamin Peterson, a fellow, presented the landmark analyses from RE-DUAL PCI.[8] They looked at those first 1 to 3 months, where the big difference is aspirin, and when a large amount of the bleeding prevention is related to the dual therapy approach. Beyond 1 to 3 months, when it is dual versus dual, the bleeding with the 150-mg dabigatran dose is the same as warfarin; the 110-mg dose is better, very similar to what was seen in RE-LY.[9]

When the aspirin is removed in that early 1 to 3 months, you see a lot of this benefit on bleeding. One has to turn to the trial data and say, "Three trials in a row have shown the same thing, that it is safe to do this," but people have to get comfortable with it. I hope that talking through the data and seeing all of these analyses will help people shift from what practice has been over the past several years.

Ruff: That is a very important point. To end, I want to go to the other side of the spectrum. We have talked about acute management, but now, many of the guidance documents in Europe and the United States are moving—whether with ACS or elective PCI, once the patient is stable (say, at a year)—to actually transition to monotherapy with the anticoagulant alone. Is this something you both endorse? How do you make that decision about whether your patient should be on a single-agent anticoagulant? Or do you think most cardiologists will probably continue the P2Y12 inhibitor for some indefinite period of time?

Gibson: This is tough. I think we have to say, for all of this conversation, that one size does not fit all. Having been drawn into medicolegal debates, I believe that it is very important for us to give physicians leeway to do what they think is right and in the best interests of their patients in balancing bleeding versus efficacy. As someone who is both an interventional cardiologist but who also very much believes in secondary prevention, I think we have to move the dial a bit in terms of getting away from just treating the stent. You have to treat the patient, and that patient is at risk for a lot of later events. Most of them, 54% of the time,[10] come back [after they have received a stent], and we know that the problems are not going to be in the artery that was stented.

In general and not for all patients, you have to balance bleeding and effectiveness. I would tend to want to [continue dual therapy] in some who have had an ACS event in the past, but that may not be the right scenario for people who are at high bleeding risk. We are developing machine-learning techniques to help guide physicians with this—not for populations of patients but for this individual patient right here, right now, right in front of you. The answer will vary.

Ruff: I think you are right. This is an ideal field for personalized medicine. That is where all of the promise is, because it is very hard, as you said, to sort out the balance of ischemic and bleeding risk in these individual patients. Chris, I know you have spent a lot of your time in preventive cardiology, including secondary prevention. Do you have similar thoughts? It sounds as though, in general, we are moving towards less-is-more, but there is no blanket statement regarding the advantages of antithrombotic regimens in these patients. Would you say that is accurate?

Cannon: I agree. We considered whether we could study this time period of a year post-stenting. The thought of withdrawing all antiplatelet agents is a bit daunting in someone who is just 1 year post-stent, and yet that is what the European guidelines have emphasized. One factor to consider is whether the patient has had any bleeding. If someone had lots of minor bleeding during that first year, then that might be a good person to treat with only an anticoagulant. If the patient is tolerating the P2Y12 inhibitor plus an anticoagulant, continuing it longer may be the right answer. Certainly, beyond atrial fibrillation, recent data from COMPASS[11] showed that the low-dose rivaroxaban plus aspirin [resulted in better cardiovascular outcomes]. Thus, the notion that a little bit of anticoagulant and antiplatelet is a very potent and helpful secondary preventive strategy sort of makes me lean toward considering it for the longer term.

Ruff: This has been a very robust discussion. Thanks for all of your work in this field. Sometimes these studies result in more questions than answers, but that is the whole point of science. We want to further optimize patient outcomes. It is never as easy as we would like it to be, but we have made some important advances in these fields to protect patients. I want to thank both of you for joining us today. There will be lots more data coming, and I hope we will have an opportunity to debate again in the future.

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