Should Aspirin Be the Second-Line Antiplatelet in CAD?

The PANTHER Meta-analysis

Michelle L. O'Donoghue, MD, MPH; Marco Valgimigli, MD, PhD


August 31, 2022

This transcript has been edited for clarity.

Michelle L. O'Donoghue, MD, MPH: Hi. I'm Dr Michelle O'Donoghue. I'm here at ESC Congress 2022, which is now back in person here in Barcelona. It's been very hot. I'm joined by Dr Marco Valgimigli, who almost needs no introduction at this point as he's been a leader in the field of antiplatelet therapy. I'm really specifically thinking about duration.

One of the pieces of science that he presented here at ESC is a meta-analysis asking the question, how does aspirin monotherapy compare to P2Y12 inhibitor monotherapy? This is a very hot topic.

Marco Valgimigli, MD, PhD: Thank you, Michelle. It's wonderful to be here and to be interviewed in person. Last year, we did that remotely. You're correct. We put together individual patient data in a dataset, comparing aspirin vs any P2Y12 inhibitor. I think it's a more relevant question than DAPT duration because, at the end of the day, you will have a DAPT phase, which can be short or less short, and at the end, then you have to decide which of the two components to continue. That was the purpose of pulling this dataset together.

We have seven studies and more than 25,000 patients. We decided to limit ourselves to established CAD, which is very important because some historical studies, such as CAPRIE, did show a greater benefit in a PAD patient compared with a CAD patient. We wanted to answer a specific CAD question, so out of CAPRIE, we excluded the patients who were included because of stroke or PAD. We only focused on CAD patients.

That gave us 25,000 patients where the comparison took place in a randomized manner. For the P2Y12 inhibitor, we have both ticagrelor and clopidogrel, but unfortunately, there is no study comparing prasugrel vs aspirin. Perhaps there will be in the future.

O'Donoghue: It's such an important question because, as you say, people are moving toward wanting to discontinue DAPT on the earlier side. Traditionally, many of the studies have looked at the idea of dropping the P2Y12 inhibitor, but now there's a growing amount of evidence to suggest that maybe we could stop the aspirin and continue people on P2Y12 inhibitor monotherapy. It's important to look at all the trials that have really compared that strategy head-to-head.

Valgimigli: You're completely right. We did include some studies in which there was an early DAPT phase, but that phase was then excluded from the analysis, so it's a really pure comparison of aspirin vs P2Y12 inhibitor. The key question that we had is, which drug should be maintained long term? Should we go for aspirin, which has a Class IA recommendation in the guidelines, or should we go for a P2Y12 inhibitor, which is always recommended second line if the patient cannot tolerate aspirin?

O'Donoghue: When you ask most clinicians which one causes more bleeding, a P2Y12 inhibitor or aspirin, certainly among surgeons the feeling is that the P2Y12 inhibitor probably causes more bleeding.

Valgimigli: You're entirely correct. You can never convince any surgeon to do surgery in a patient on a P2Y12 inhibitor.

O'Donoghue: Which is part of why your research is very important. Tell us about the results.

Valgimigli: The primary endpoint that we prespecified was a composite of cardiovascular death, MI, and stroke, which is a classic endpoint, that was significantly reduced by 12% with a significant P value and a number needed to treat in the range of 120. There was some benefit but not a massive benefit. You will need to treat 120 patients to prevent one component of that endpoint with a P2Y12 inhibitor instead of aspirin.

We had the key safety endpoint of any major bleeding. There was a trend favoring the P2Y12 inhibitor arm but that did not reach statistical significance. As a key secondary point, we looked at a MACE endpoint, the combination of the two, which also statistically favored the P2Y12 inhibitor.

There are some very interesting findings among the secondary endpoints. There was absolutely no difference with respect to death or CV death. There was a trend toward the reduction of stroke that did not reach statistical significance; the P value was .078. The rate of ischemic stroke was pretty much equal, but hemorrhagic stroke was reduced by almost 70%. Finally, we did see a more than 50% reduction for stent thrombosis and a 25% reduction for GI bleeding, perhaps as expected, in favor of the P2Y12 inhibitor.

O'Donoghue: Those are tremendous results because, based on data from CAPRIE and HOST-EXAM more recently, I thought that there was less gastrointestinal bleeding with clopidogrel monotherapy compared with aspirin monotherapy. The part about the hemorrhagic stroke — if that had been known, then that escaped my attention. It's quite striking that you're seeing that much of a lower rate of stroke for people on clopidogrel monotherapy.

Valgimigli: We have two different P2Y12 inhibitors and there was a consistent effect. We can actually, at this stage, call it a class effect for either clopidogrel or ticagrelor. Interestingly, that hemorrhagic stroke finding caught my attention as well. I was honestly not expecting that result. When we looked into the studies that were pulled together, there was a small signal that did not reach statistical significance in all of them — in fact, there was no heterogeneity — for intracranial hemorrhage.

When I saw the results, I remembered the MATCH study; that was a post-stroke or TIA, where patients were randomly allocated to receive aspirin and clopidogrel or clopidogrel monotherapy. There was a massive difference for intracranial bleeding disfavoring DAPT. I think now, with these pieces of evidence coming together, we probably can explain that finding that it is not the combination of DAPT that makes the patient bleed more intracranially, but perhaps it's more aspirin than clopidogrel, per se, which is very interesting.

O'Donoghue: Very interesting. Between clopidogrel and ticagrelor (as you mentioned, prasugrel has not yet been studied as a monotherapy strategy), do you think it is fair to say that ticagrelor monotherapy has a trend toward less bleeding than aspirin or do we not have enough of an evidence base yet to say that explicitly?

Valgimigli: We cannot actually state that because the only comparison between ticagrelor and aspirin comes from the second year of the GLOBAL LEADERS study, where aspirin was compared with ticagrelor 90 mg. In that large study of 18,000 patients, the rate of major bleeding did not differ, yet there was a trend for minor bleeding to be slightly higher with ticagrelor. I don't think we can say that ticagrelor makes the patient bleed less than aspirin. I think clopidogrel makes a patient bleed less than aspirin.

O'Donoghue: As a final thought, in your practice, what are you now doing for a patient who is perhaps a few months post PCI? Are you dropping the aspirin? Are you dropping the P2Y12 inhibitor? If you drop the aspirin, which P2Y12 inhibitor do you pick?

Valgimigli: That's a great question. I started dropping aspirin many years ago, so the results are, in a way, confirmatory of my practice, but I also believe that P2Y12 inhibitor selection depends upon the patient presentation. If a patient has an ACS, I always use ticagrelor and then I try to deescalate to 60 mg as soon as I can and certainly by the second year. If the patient is stable, then I rarely use ticagrelor. I use clopidogrel, and if I am dropping aspirin early on in that stable patient, then I test clopidogrel responsiveness.

O'Donoghue: Very interesting. Thank you again for sharing these exciting results. I look forward to seeing more research from you soon.

Valgimigli: Thank you.

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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