COMMENTARY

Antiplatelet Therapy: Where Do We Stand Now?

Sripal Bangalore, MD, MHA; Usman Baber, MD, MS

Disclosures

January 27, 2021

Editorial Collaboration

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This transcript has been edited for clarity.

Sripal Bangalore, MD, MHA: Welcome to this session, "Antiplatelet Therapy: Where Do We Stand Now?" This is Sripal Bangalore, interventional cardiologist and professor of medicine at New York University School of Medicine. I'm joined by my friend and colleague, Usman Baber.

Usman Baber, MD, MS: Hi, Sripal. It's wonderful to be with all of you to discuss this important topic. My name is Usman Baber and I'm an interventional cardiologist at the University of Oklahoma Health Sciences Center, where I serve as a director of the cath lab and interventional cardiology. I look forward to this conversation.

As mentioned, we are going to talk about antiplatelet agents. Sripal, when you and I were in residency and medical school, after you did a coronary stent, patients got aspirin and then one additional drug — clopidogrel — and you usually kept it on for about a year. Now, in the past 20 years or so, there have been a lot of studies and a lot of evidence has been generated. Why are we now revisiting this topic that seems to never be put to rest?

Why Revisit Antiplatelet Therapy?

Bangalore: Great questions. It's interesting that over the past couple of decades, the paradigm has changed. We started by saying "the longer the better" because of all of the stent thrombosis events we used to see 1 year after stent implantation. I think the question obviously is, has anything changed? Should we revisit this? Our understanding of the balance between ischemic and bleeding risk in a patient is critically important to evaluate. Of course, if you look at ischemic risk for a patient who is undergoing stent implantation, we have come a long way. Design changes have significantly improved the safety of these stents. There is much faster healing and less inflammation, etc. No longer are we seeing high rates of stent thrombosis. Nowadays the rate of stent thrombosis in the first year is 0.5%-0.6%, and after that it's like 0.1%. It's very rare to have stent thrombosis these days. Of course, the risk depends on the individual ischemic risk.

We also made significant progress in reducing other ischemic events. For example, we have more potent antiplatelet therapy. We have better, more potent lipid-lowering PCSK9 inhibitors. We have the COMPASS trial data studying the addition of an anticoagulant. We have SGLT2 inhibitors, etc. We are really making an impact on reducing a patient's ischemic events. But if you look at the bleeding side of the equation, our patients are getting older so the risk of bleeding is higher. Once they get older they also get atrial fibrillation (AF), so they get on anticoagulant therapy. The more potent antiplatelet agents also increase the risk of bleeding. So if I have to weigh the risks and benefits of ischemic vs bleeding risk, over the past two decades we have reduced the ischemic risk, but I would say that we have not done much in terms of reducing the bleeding risk. The bleeding risk, if anything, has increased. I think this is the context that we have to look at.

Both the American College of Cardiology (ACC)/American Heart Association (AHA) and European Society of Cardiology (ESC) guidelines recommend a 6-month minimum of dual antiplatelet therapy (DAPT) for a stable patient after stent implantation. No longer is it 1 year. This is supported by a number of randomized trials showing that if you go lower in stable coronary artery disease patients, your risk of bleeding is lower, but you don't pay as much price in increasing the ischemic events.

Extending Duration of DAPT?

Bangalore: There is still a lot of confusion which seems to be based on a couple of these longer DAPT trials, like PEGASUS and the DAPT study, where we saw that extending DAPT beyond 1 year not only may reduce stent-related events but also potentially non-stent-related MI. What are your thoughts? Why is there a lingering confusion?

Baber: You hit the nail on the head, which is this nuanced understanding of ischemic and bleeding risk that set the foundation for all of these conversations. With trials like DAPT, PEGASUS, and THEMIS, you are seeing ongoing benefit with longer durations, going out to several years of DAPT, but one has to reconcile that with guidelines telling us we can just go up to 3 or 6 months in stable patients. The first question is, what is the obligatory minimum duration of DAPT? What is the minimum duration you need to give a patient with these newer stents that heal in a more rapid fashion, in a complete fashion? The evidence clearly supports that that number is probably around 3-6 months, and that is what our guidelines say. The second question still being addressed and evolving is, once we get beyond that obligatory phase, who are the patients in whom we can we give additional ongoing antithrombotic therapy and still get a benefit? I think we are seeing some answers to that. We saw COMPASS-like patients who had prior MI in the DAPT trial and in the PEGASUS trial. There are certain patient phenotypes, usually based on clinical criteria, where we will get ongoing benefit if you extend antithrombotic therapy. But at the end of the day, you have to balance that benefit with the underlying risk of bleeding.

Bangalore: Those are great points. I think the key take-home is to individualize decision-making. For stable coronary artery disease, it's clear that the minimum obligatory DAPT duration is 6 months. If there is a high bleeding risk and you have to stop earlier than 3 months, there are now emerging data on a duration of 1 month of DAPT in these patients.

What Is the Optimal Duration of DAPT in ACS Patients?

Bangalore: Let's just switch briefly to acute coronary syndrome (ACS) patients. We have been talking about changing ACS guidelines for two decades. ACS duration has always been 12 months. ACC/AHA and ESC would say that the obligatory minimum is 12 months. If you have a patient with high bleeding risk, you can go down to 6 months. You did the landmark TWILIGHT trial with Roxana Mehran and you presented the ACS subset as a late-breaker. Can you share some insight into the ACS subset? Can we actually reduce the DAPT duration to shorter than 12 months in ACS patients?

Baber: That is a great point, Sripal. The one area that has not really been pushed until very recently is in patients with ACS. The question around shortening the duration becomes, how do you do it? You can drop the P2Y12 inhibitor, which has been investigated in some studies like SMART-DATE and found to be potentially harmful. The alternative is that maybe we can shorten DAPT duration by getting rid of aspirin, and that is precisely what we looked at in TWILIGHT. About two thirds of our patient population, a little over 4000, actually had non–ST segment ACS. TWILIGHT was a cohort where we took patients who were at high risk, so they had either clinical or angiographic features — namely diabetes, a long stent length implantation. All the patients got 3 months of DAPT with aspirin and ticagrelor. After 3 months, we randomized them to ticagrelor alone or continuing ticagrelor plus aspirin. In the ACS subset we found that you could significantly reduce bleeding and you didn't pay a penalty on the ischemic side. So it suggested that in fact this could be a safe strategy. This hypothesis has really been corroborated by the TICO trial, which focused exclusively on acute MI patients. They had STEMI patients and found essentially the same results that we found in TWILIGHT. I do think there is an evolving paradigm change that might be happening, even in acute MI patients, wherein we can withdraw the aspirin, lessen the bleeding, and keep patients safe by giving them a potent P2Y12 inhibitor.

You have done a lot of work in pooled analyses and network analyses. Maybe you can say what your findings were when you and your team kind of looked at the aggregate data in this area.

Bangalore: We recently published a network meta-analysis looking at all of the ACS groups and asking exactly this question. I think all of us by now are comfortable with the shorter, minimal obligatory DAPT for stable patients, but what about ACS patients? We looked at 14 trials, over 31,000 patients, and the results are very consistent. Shorter DAPT duration of 3-6 months reduced bleeding and there was no increase in ischemic endpoints. More and more emerging data are supporting shorter DAPT even in ACS patients. Of course, the question is always, what do you drop? We published an analysis in the American Heart Journal looking at what should be your treatment after a short duration of DAPT. Should it be aspirin or a P2Y12 inhibitor? There is no head-to-head comparison as to which one is better; trials either dropped aspirin or the P2Y12 inhibitor. We found in our indirect comparison that if your intent for a given patient is to reduce the risk of bleeding (ie, a high–bleeding risk patient), potentially just continuing aspirin after dropping the P2Y12 inhibitor is a better strategy. But if a patient is at high ischemic risk, potentially you should continue the P2Y12 inhibitor and drop aspirin, which makes intuitive sense. Of course, this needs to be tested in head-to-head randomized trials.

Is Single Antiplatelet Therapy a Viable Option?

Bangalore: We have been talking about dropping aspirin in multiple different settings. If you have patients on triple therapy, we recommend a minimum duration of triple therapy, drop aspirin. There is this growing notion that aspirin as part of DAPT may not be needed as previously assumed. What are your thoughts on single antiplatelet therapy?

Baber: It's interesting. Whenever we have a new strategy in medicine, we always start off with high-risk patients and then go to lower and lower–risk patients. We have seen that over and over. This idea of an aspirin-free strategy started off in the highest-risk patients, namely AF needing triple therapy. And it's clear that in those very high-risk patients, you can withdraw aspirin and patients do fine. We have now pushed the envelope with studies like TWILIGHT, GLOBAL LEADERS, and others to take patients without AF and dropping aspirin. And we're seeing consistent themes with or without ACS. The question then is, can we even get to the low-risk patients? Studies have been published and are ongoing, and we're asking the very provocative question which is, at the time of the stent implantation you give aspirin, but then right after that can you just stop it and just go on a P2Y12 inhibitor alone? Now, those are very low-risk patients and we'll have to see what the data show. I think we're going to need some aspirin for at least a few weeks before we want to withdraw. I think people have a hard time, but this is how science moves forward. I think we have learned a lot and are learning a lot. But this field stays exciting. It's moving, and a lot more is to come in the very near future.

Bangalore: Those are great points. And specifically, if you have a patient who is at high ischemic risk and high bleeding risk, I think the emerging data would suggest that the bleeding risk kind of trumps ischemic risk and we should try to do everything possible, like using proton pump inhibitors, to try to reduce the risk of bleeding and reduce the duration of therapy. In terms of single antiplatelet therapy upfront, I will only use that in patients who have aspirin allergies, and I use a more potent P2Y12 inhibitor, but there are no data on that. High-risk guidance is key for those patients. Those are definitely important considerations.

Platelet Function Studies

Bangalore: If you have a patient on triple therapy and, for whatever reason, you are using clopidogrel and you want to drop aspirin, are you doing a platelet function study? It's not a potent antiplatelet but you just want to make sure that it's actually working. What do you do?

Baber: That is a great question. There was a time not too long ago when I was doing a lot of platelet function testing, but because of a lot of data that have come out, I've kind of gone away from that. As long as they are on a direct oral anticoagulant, I'm okay with them being on clopidogrel and getting rid of aspirin without any platelet function testing. In the absence of a direct oral anticoagulant, thus far, I really have not done clopidogrel monotherapy. I have done ticagrelor monotherapy, but I would be concerned about clopidogrel alone without either aspirin or a direct oral anticoagulant. In that context, if I had to make that decision, I would want a platelet function test. That is a very nuanced point. And I agree with you: At least in my practice, I have not dropped aspirin at time zero unless there is some type of allergy or a really compelling indication where I cannot give aspirin at all.

Bangalore: These are things that we discuss. I routinely do test. I get nervous with clopidogrel, the rate of nonresponse. Although you are absolutely right that there is just no evidence for routine testing. But I only routinely test if I'm dropping aspirin, just to make sure. If there is one antiplatelet, let's make sure it works.

This was a great discussion. We packed in a lot of important points. To summarize, there are emerging data to support shorter obligatory minimum DAPT duration, not only in stable patients but also in ACS patients. But we do have to individualize. The challenge is, how do we do this? We have so many other therapies. When do we add anticoagulation therapy? How do we follow a complex regimen? Those are all important discussions to be had. There are more and more emerging data on potentially going with a single antiplatelet therapy, potentially a more potent P2Y12 inhibitor monotherapy, just like what TWILIGHT did. That landmark trial will have a significant impact on how we manage our patients. Any closing remarks?

Baber: Thank you. This was a great discussion. There was a lot to pack in and a lot of different concepts to put into one. But this is an exciting time. It's exciting when we have newer approaches, newer strategies, newer therapies with evidence to help our patients. It's good for us as clinicians and investigators, and good for our patients, to have newer ways to give them an overall clinical benefit. I very much look forward to more data coming out and more discussions. It's been a pleasure having this conversation with you.

Bangalore: Thank you. And thanks, everybody. Thanks for joining us on this important discussion.

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