This transcript has been edited for clarity.
Michelle L. O'Donoghue, MD, MPH: Hi. This is Dr Michelle O'Donoghue, reporting for Medscape. Joining me today is Dr Marco Valgimigli, who is an extraordinary leader in the field of antiplatelet therapy. He's from Lugano, Switzerland.
We are just wrapping up the ESC Congress, and one of the big topics of conversation was the results of a trial that he led, the MASTER DAPT trial, which was an investigator-initiated study and his passion for several years. We're going to talk about that trial and its practice implications. There's been a large amount of chat about that. Welcome, Marco.
Marco Valgimigli, MD, PhD: Thank you very much, Michelle, for having me.
O'Donoghue: Perhaps as a first step, would you like to walk people through the study design? I know that the results have also just been published in The New England Journal of Medicine, so again, congratulations.
Valgimigli: Thank you very much. We set up this study a few years ago to focus on patients who are at high risk for bleeding (HBR) complications who are undergoing PCI for either chronic or acute coronary syndrome. The key question in our mind was how long we should use DAPT. There have been many retrospective studies showing that perhaps, specifically in HBR patients, the DAPT duration could be shortened without compromising safety and gaining with respect to bleeding liability. However, no prospective study had ever tested that.
Therefore, we enrolled roughly 4500 patients. They were all treated with a specific stent, which is a bioresorbable sirolimus-eluting stent, the Ultimaster. [Editor's note: This stent is not available in the United States.] If they were free from recurrent ischemic events 30 days after PCI, they were eligible to get into the study where they either stopped DAPT immediately and continued with single antiplatelet therapy or they continued DAPT for at least 2 or 5 months, depending on whether they had a concomitant indication for oral anticoagulation.
The upper limit of DAPT duration in the control group was basically at the discretion of the treating physician; we simply provided the lower limit, and afterwards, they continued with single antiplatelet therapy as well. Perhaps it's important to state upfront that the single antiplatelet agent in our study was either aspirin or a P2Y12 inhibitor, and the type of P2Y12 inhibitor was completely up to the investigators to choose. In fact, we had quite an interesting mix of different agents.
O'Donoghue: I was going to emphasize some of the points that you just made. I think that one of the important things was that this was a very large-scale study, with more than 4000 patients enrolled. Certainly, it was a huge contribution in that regard. Building upon the earlier results of, for instance, the DAPT trial that we had a few years ago, this was more modern stent technology.
We can talk a little bit about whether we think that the findings are generalizable to other stent types afterwards. Nonetheless, it's a more updated trial that is very relevant. Also, this was specific to patients with HBR.
Valgimigli: That's an important feature. We wanted to have an all-comer HBR population, but we didn't include patients without any HBR features. I think that's very important to emphasize.
O'Donoghue: I think that you had an interesting approach in terms of allowing sites to manage the antiplatelet therapy as they wanted when they were dropping an agent. As you pointed out, you had a mix of people who were going to be on aspirin monotherapy or P2Y12 inhibitor monotherapy, and there was also a mix of people who were or were not on an oral anticoagulant as background as well.
Valgimigli: That is correct. Oral anticoagulation was 1 of 10 HBR features listed. If a patient had an indication for oral anticoagulation, they could be part of this study. In fact, the mean HBR score per patient was 2.1, meaning that the majority of patients had more than one HBR criteria.
O'Donoghue: Let's walk through the top-line findings. What did you find?
Valgimigli: We had three co-primary endpoints, which we prespecified to test in the following order. First, noninferiority for NACE, which was the composite of death, MI, stroke, and major bleeding, which was met. Therefore, we could go forward to test noninferiority for MACE: death, MI, stroke, which was also met, and in both cases with a highly significant P value.
I think the noninferiority endpoint is always a bit tricky, but I think the MASTER DAPT study is particularly robust. That's at least the way I see it, acknowledging my own bias. Therefore, we were allowed to test for superiority for major or nonmajor clinical bleeding complications, which was met. We had a highly significant P value and a difference in cumulative incidence close to 3%, and a number needed to treat for benefit of 35.
It's probably fair to acknowledge, though, that, unlike our expectation, the bleeding benefit came from BARC 2 — not much for BARC 3. There was a trend favoring abbreviated DAPT, but not quite reaching statistical significance. We had two fatal bleeding events with abbreviated DAPT and eight in the standard DAPT group. The bleeding benefits really came from BARC 2, which was unexpected, I have to say.
O'Donoghue: That was an observation that was made when you did the presentation as well. I think it is interesting because everyone expected that, of course, abbreviated DAPT would be associated with less bleeding. Perhaps people would have thought that major bleeds, the BARC 3-5, the most severe ones, would have been significantly reduced as well.
Valgimigli: That was our expectation. I think the explanation is coming from the fact that in the control group, first we gave lower limit of DAPT duration to create some sort of contrast between the two arms, but at the end we left the investigators free to prolong DAPT as much as they wanted. On average, in the control group, DAPT was 5-6 months after stent implantation. It was not 12 months, which probably explains the finding.
O'Donoghue: Overall, you saw with abbreviated DAPT that there was less bleeding, and that it was very reassuring, in terms of MACE. We didn't see any clear uptick in the incidence of MACE for an abbreviated DAPT regimen. I know that you also have the publication that just came out simultaneously in Circulation as well, looking at background use of an oral anticoagulant. Overall it looks like, irrespective of whether or not people were on an oral anticoagulant, the results were, again, grossly similar. There was no clear uptick in MACE.
Valgimigli: That's a great summary. I think that the results are mainly consistent for all three co-primary endpoints. Irrespective of whether the patient did or did not have an indication for oral anticoagulation, the results were quite solid.
I also would like to point out that beyond MACE, acknowledging that is a secondary point, we were quite surprised to see the CVA rates being lower with the abbreviated DAPT. That was due to both lower ischemic and hemorrhagic cerebral events. I think that the latter was perhaps to be expected but the former was a bit of a surprise.
O'Donoghue: Yeah, I saw that as well. That was interesting. Let's take a step back and think about the clinical implications for those who are watching. I know that you had the different strategies for abbreviated DAPT and what that actually meant in practice. The majority of patients were on clopidogrel monotherapy, so the aspirin was being discontinued.
Do you think that is the preferred strategy or does it depend on the patient? Is this only for a patient with HBR where you think clopidogrel monotherapy should be considered? When should it be ticagrelor monotherapy and when should it be aspirin?
Valgimigli: I have to say that I was a bit surprised when I saw the breakdown of the type of P2Y12 inhibitor. Probably my practice would be more clopidogrel monotherapy if a patient is stable, and perhaps ticagrelor or prasugrel therapy if the patient has an ACS.
The investigators gave us different feedback. There was clear domination of clopidogrel as both monotherapy in the experimental arm and on DAPT in the control arm, probably reflecting the fact that we targeted HBR patients. Despite the theoretical concern that clopidogrel is an inconsistent P2Y12 inhibitor as a monotherapy, the study actually proved that this concern was not solid.
There was no clear excess of ischemic events. We had an excess of 11 MIs in the abbreviated DAPT arm but also a gain of 11 strokes in the abbreviated DAPT, which explained the fact that the MACE are pretty much neutral.
O'Donoghue: We also had presented at ESC the results of the ACS subgroup from STOPDAPT, which was a trial looking at a strategy of clopidogrel monotherapy as compared with standard DAPT. There did appear to be an excess in MI events. Overall, the trial was neutral, but within the ACS subgroup there was that uptick.
Perhaps to your point, we know that there exists significant interpatient variability in response to clopidogrel, so perhaps clopidogrel monotherapy would not be a preferred strategy for an ACS patient. Maybe ticagrelor monotherapy would be more appropriate. Is that your thought as well?
Valgimigli: That's completely my thought, yes. I think you did a great summary. At the end of the day, we need to simplify treatment and try to be as short as possible, but perhaps not too short and not be too simplistic in the approach. We already knew in the ACS population that both ticagrelor and prasugrel on top of aspirin are much better off than aspirin and clopidogrel. If you leave aspirin out of the picture, thinking that you can get away without any amount of ischemic repercussions just with clopidogrel monotherapy, I think it's a bit too much.
If you're not concerned about bleeding risk, I don't think clopidogrel should be there. I don't see that treatment option completely justified. Perhaps the sweet spot is really ticagrelor monotherapy, for which we have robust data. Theoretically, even prasugrel monotherapy will be a great choice. It's a QD; it has a very long half-life. The problem is that we have hardly any data on prasugrel monotherapy. There are many studies that are running with prasugrel monotherapy.
I think the future for ACS patients is monotherapy with the potent, and most importantly, reliable P2Y12 inhibitors. Clopidogrel to me is justified only if the risk of bleeding is far greater than the risk of ischemic events, which, in an unselected ACS population, is not clearly the case.
O'Donoghue: Do you think this extends beyond the stent type that you studied within MASTER DAPT? Do you think this would be broadly applicable to all patients who are stented?
Valgimigli: That is difficult to say. For sure, newer-generation drug-eluting stents (DES) are much safer than the stent types that have been tested in the DAPT study. When I think about TAXUS stents and Cypher stents, we are speaking about two different stent types whose safety profiles are completely different. Whether there are minor differences among the latest-generation DES, which perhaps pop up when you are decreasing DAPT, is completely unknown.
The only number I can share with you is that we have 99.8% of stents being Ultimaster, so it's pretty much uniform. We had something like 15 non-Ultimaster stents implanted. Of these 15 stents, we had two stent thromboses. We had 18 stent thromboses overall in the study, and actually two occurred in non-Ultimaster stents. The study cannot really answer whether these results are reproducible with other stent platforms, acknowledging that all of them seem quite safe.
O'Donoghue: I think that the trial builds importantly upon prior research, and as you indicated, this landscape is continuing to evolve so quickly. Who would have thought a few years ago that aspirin would be the drug we'd be routinely discontinuing for patients when we think about abbreviate DAPT regimens? I think we're headed in that direction.
Ultimately, we'll need to think about long-term therapy, too. How do we treat a patient who is now a couple of years post-ACS? Are we going to continue them on P2Y12 inhibitor monotherapy indefinitely?
Valgimigli: That is also my preference. I have to say, acknowledging that the data are much more limited, but the HOST-EXAM study, for example — recently presented and published — is really supportive of clopidogrel monotherapy better than aspirin monotherapy. In that context, I ask myself whether this sweet spot could be prasugrel 5 mg or ticagrelor 60 mg as long-term monotherapy, but unfortunately, we don't have data there.
O'Donoghue: Well, that could be your next investigator-initiated trial, Marco.
Valgimigli: I'll take 1 month off and then I'll start thinking about it.
O'Donoghue: Thank you very much for joining me today. I think it's been a great discussion. Certainly, we will stay tuned for more analyses coming from MASTER DAPT.
Valgimigli: Thank you very much.
O'Donoghue: Signing off for Medscape, this is Dr Michelle O'Donoghue.
Michelle O'Donoghue is a cardiologist at Brigham and Women's Hospital and senior investigator with the TIMI Study Group. A strong believer in evidence-based medicine, she relishes discussions about the published literature. A native Canadian, Michelle loves spending time outdoors with her family but admits with shame that she's never strapped on hockey skates.
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Cite this: Michelle L. O'Donoghue, Marco Valgimigli. Is 1-Month Dual Antiplatelet Therapy Safe? Reconciling MASTER DAPT and STOPDAPT-2 - Medscape - Sep 13, 2021.