Advances in the Management of Peripheral Arterial Disease - Episode 7
Transcript: Deepak L. Bhatt, MD, MPH: Marc, maybe I can ask you to review the data for different classes of therapy for PAD [peripheral artery disease]. Let’s start with one of the basics, antiplatelet therapy, and monotherapy as a beginning.
Marc P. Bonaca, MD, MPH: This is a cornerstone of therapy for atherosclerosis and PAD. Data are less robust in dedicated PAD populations than they are for coronary disease. But it starts with the Antithrombotic Treatment Trialists’ Collaboration, which shows there’s benefit in symptomatic PAD, for claudicants or those having revascularization, with aspirin use. It reduces ischemic risk but increases GI [gastrointestinal] bleeding, mostly.
Then there was a trial called CAPRIE, which compared clopidogrel monotherapy versus aspirin and showed that clopidogrel is better than aspirin, overall. Though the benefit was modest, it seemed to be particularly good in patients with peripheral artery disease. There was some heterogeneity there. Our guidelines tell us antiplatelet monotherapy with aspirin or clopidogrel is a class I indication.
Deepak L. Bhatt, MD, MPH: That’s really good. How about dual antiplatelet therapy [DAPT]? Maybe you could review the old data, and then the new data. You presented, as a matter of fact, a meta-analysis looking at two trials: PEGASUS-TIMI 54 and THEMIS. You just presented that at the American College of Cardiology a few days ago.
Marc P. Bonaca, MD, MPH: This is such an important area in peripheral artery disease, and it’s an area where practice has really gone beyond the data because of the absence of data. There are very few dedicated trials evaluating DAPT in PAD. There’s one called CASPAR, which evaluated patients after bypass surgery using DAPT with clopidogrel versus aspirin alone. It was a broad composite of limb outcomes, systemic outcomes, and mortality. There was no benefit; there was more bleeding. A trial in endovascular revascularization was attempted called CAMPER, but they couldn’t recruit because everyone was using it and thought there was no equipoise. The guidelines do, as a low-level recommendation, say you can use DAPT after intervention as class IIb recommendation. But there are no rigorous data in those PAD cohorts.
What’s interesting, as you mentioned, is that when looking at very carefully adjudicated limb outcomes in some larger datasets with broader populations, we’re seeing limb benefit with the combination of aspirin and ticagrelor. Ticagrelor is a newer, more potent, and less variable P2Y12 inhibitor. It appears from the THEMIS trial, which included coronary disease with diabetes, as well as from PEGASUS-TIMI 54, which included a post-MI [myocardial infarction] cohort, that if you look at acute limb ischemia and major amputation—the worst outcomes in these populations—the combination of ticagrelor and aspirin versus aspirin alone results in pretty marked reductions in those limb outcomes of around 40% to 50%.
It’s an interesting setting in PAD now, where we have this combination of aspirin/ticagrelor. It clearly reduces limb outcomes. We don’t have a dedicated PAD study to really understand how to apply that and its use, but I think the data are promising.
Deepak L. Bhatt, MD, MPH: You are quite right in that summary. It’s a challenge. Of course, there’s the EUCLID trial that Dr. Manesh Patel played a pivotal role in. He will hopefully be joining us depending on how things go with his catheterization laboratory emergency. But that trial wasn’t positive, so it really didn’t establish a role for ticagrelor monotherapy. It seemed like clopidogrel monotherapy—if one is discussing single antiplatelet agents—remains king because of cheaper price, once-a-day dosing, and no superiority with ticagrelor monotherapy. If I can just mention the CHARISMA trial data: within the PAD subgroup data and subgroup analysis, we did see consistent benefits in those with prior MI, ischemic stroke, large vessel stroke, or peripheral artery disease that was symptomatic.
I think there are several lines of evidence that support more than just aspirin alone. But there hasn’t been a single trial specifically looking at PAD and dual antiplatelet therapy that’s nailed it. There are provocative signals from CHARISMA and significant findings from PEGASUS-TIMI 54 and THEMIS as well, albeit not specifically PAD trials but looking at PAD endpoints. This is provocative information.
Transcript Edited for Clarity