Treating Peripheral Arterial Disease After Revascularization - Episode 5

Advances in PAD Management: CAPRIE and DAPT Trials

December 2, 2021

Manesh Patel, MD, and Marc Bonaca, MD, MPH, review the data from the CAPRIE and DAPT trials that studied therapeutic options for PAD.

Manesh Patel, MD: We’ve had this conversation about the burden and the risk of our patients. Maybe we think a little about the therapeutic options, and we’re going to talk about that shortly. I’ll start by saying that we have a conversation about how things that work for coronary artery disease must work for peripheral artery disease [PAD]. The first trial in the antiplatelet and antithrombotic space to tackle this is 20 years old. The CAPRIE trial still gets mentioned because it was a broad population, around 19,000 patients, who had vascular disease, which is broadly defined as patients who might have coronary disease, cerebrovascular disease, and peripheral artery disease. It randomized patients to aspirin vs clopidogrel, which at that time what was a new therapy. In fact, the CAPRIE trial demonstrated for cardiovascular events that there was a reduction with clopidogrel monotherapy compared with aspirin monotherapy. At that time, to put it in perspective, the event rates over several years were 5.5 vs 5.8 or so. The absolute risk reduction wasn’t that large. The relative risk reduction was about 8%, but it was statistically significant and meaningful. I don’t think it was adopted as monotherapy just because of clopidogrel and the relative difference in efficacy in clinicians’ minds.

Before I go beyond the monotherapy conversation, because we’re going to think about other antiplatelet therapies and other antithrombotic therapies, I want to get your take on CAPRIE and see if it’s changed the way you think about things. Sonia, I’ll start with you. I think it’s a well-done study, and it did move the field forward, right?

Sonia Anand, MD, PhD: Yeah. It was done out of McMaster [University in Hamilton, Ontario], so of course I’m proud of it—I was a resident at the time it came out. I agree with you. We all believe the slight benefit of clopidogrel over aspirin, but then we always have to put it into context: the real gains for our patients. That’s a calculation we make with respect to their baseline risk, that 8.7% relative-risk reduction will translate into a tangible absolute-risk reduction for our patients. We do that. It was important to highlight PAD, Manesh, because the CAPRIE investigators tried to enroll prior MI [myocardial infarction], prior stroke, prior or existing PAD.

It helped put PAD on the map. The relative-risk reduction was greater in the PAD population, so the high-risk nature came from CAPRIE. Also, it was the first trial looking at a more potent antiplatelet compared with aspirin, and that set up a number of large trials that have also asked a similar question. There’s certainly a role. We’ve learned a lot from CAPRIE. We still see patients with their guideline 1A evidence level on clopidogrel, a single antiplatelet agent, which is completely appropriate. That started a series of trials, and we pick and choose from that antithrombotic toolbox which single, combination, or dual-pathway therapy [DAPT] might we choose. Many of our decisions were set by the CAPRIE trial.

Manesh Patel, MD: Great summary. Marc, you can tell us where we went from CAPRIE, and thinking about at least dual-antiplatelet therapy and other antiplatelet therapy potentially. Then we’ll go to dual pathway back with Sonia, and you can think about how we evolved from there.

Marc P. Bonaca, MD, MPH: Thanks, Manesh. CAPRIE was a landmark trial because in many ways, for at least antithrombotic therapies, it wanted to show this broad atherosclerotic population, with prior MI, stroke, and PAD. That was recapitulated in a series of trials later, including the CHARISMA trial, which we’ll talk about. It was a different time. Most patients were getting statins and other things. There are a couple of other things from CAPRIE. One is P2Y12 monotherapy is a hot topic now in coronary disease that followed us from CAPRIE; that’s probably a good option. Is it much better in PAD vs MI [myocardial infarction] after trials like TWILIGHT and others? I’m not sure whether that heterogeneity is as broad the trial showed, but it definitely put it on the map.

One limitation is that there wasn’t a limb vascular benefit, right? We do have to remind ourselves why we’re prescribing, and it was focused on MACE [major adverse cardiovascular event] reduction. Nonetheless, that data put PAD on the map and did a lot of activity. That set up the CHARISMA trial, which looked at the combination of aspirin and clopidogrel vs aspirin alone. It was like CAPRIE, but it went a bit beyond that because it included patients with risk factors alone, without atherosclerosis. Although there was a 7% or 8% relative-risk reduction, it wasn’t statistically significant in CHARISMA. Some of the post hoc subgroups showed that in patients with prior MI, there may have been a benefit to prolonged DAPT, unclear in PAD. That notion of DAPT didn’t hold for PAD, at least in the guidelines. It’s not the same level of evidence as antiplatelet monotherapy.

Then there were other trials looking at DAPT that were looking at PAD subgroups. There were trials like PEGASUS, where it was a post-MI subgroup. If you had comorbid PAD, lo and behold you had a benefit. But that’s different from the PAD alone population. There’s been a lot of push toward potent antiplatelet therapies, but as you know—and maybe you want to comment on EUCLID because you led it—it’s not so straightforward in the PAD-alone patients vs those who were post-MI or CAD plus PAD.

This transcript has been edited for clarity.