Advances in the Management of Peripheral Arterial Disease - Episode 11

Considerations for Adding Novel Agents to Antiplatelet Therapy

April 28, 2020

Transcript: Deepak L. Bhatt, MD, MPH: Marc, let me just pivot back to you now. We talked a bit about antithrombotic therapy. One other agent to at least consider would be vorapaxar, where you’ve done a lot of work. To my knowledge, I don’t know anyone who’s using it now because there’s really no company that’s pushing it. As far as I can tell, that’s the reason why it’s not being used. But the data were actually quite strong. Do you want to summarize those data?

Marc P. Bonaca, MD, MPH: Vorapaxar is an interesting agent because it gets to the core role of thrombin and thrombosis, something that Mike Gibson taught us a lot about. Rather than interrupting thrombin generation, vorapaxar was an attempt to block thrombin’s role in activating platelets. It was a PAR-1 antagonist, and it was included in a large, positive pivotal trial called TRA 2°P—TIMI 50 with a very broad population of MI [myocardial infarction], stroke, and PAD [peripheral artery disease] patients. There was a benefit. There was a bleeding cost that got people’s attention, particularly in the patients with stroke.

For PAD, what was novel was that there were these big reductions in acute limb ischemia, which hadn’t been seen before with prospective trial-adjudicated outcomes. It looked quite promising for that. I think it does support the notion that more potent antithrombotic therapy and targeting thrombin are very efficacious in PAD. There are big benefits there. This particular agent has a long half-life and some bleeding risks. As you said, there isn’t an active ability to market it. I actually don’t know if it’s available. It has fallen out of use, but scientifically, it supports thrombin and antithrombin therapy for PAD.

Deepak L. Bhatt, MD, MPH: That’s the real contribution, because I don’t even know if the drug is available anymore. I haven’t seen it used locally at all, but the concepts are still really important. In fact, it was even broader than patients with PAD, it included patients with prior MI as well. Intensifying their regimen beyond being on aspirin alone provides incremental benefit. That’s an important concept. It’s 1 that you mentioned, Mike Gibson, speaking more broadly in this area. In ATLAS ACS 2 as well, the concept was really established that we can do better than aspirin—or in some cases, aspirin and clopidogrel—by antagonizing thrombin. Obviously, ATLAS ACS 2 was an ACS trial. It studied rivaroxaban at low doses. It wasn’t a PAD trial, per se. Mike, how do you think ATLAS ACS 2 informs our understanding of treating high-risk thrombosis patients with respect to thrombotic therapy and using more than just aspirin alone?

C. Michael Gibson, MS, MD: The platelet is often very activated in the acute setting, and then it calms down a bit over time. But as I say, thrombin is the gift that keeps giving. When you look 2 years out, ACS incurs elevated levels of thrombin precursors compared with control patients without acute syndromes. This puts them at long-term risk. Those levels are related to risk. It makes it a viable biological target.

One thing I want to clarify is that we sometimes call studies chronic studies and other studies acute studies, but I do want to point out that people in a chronic study, such as COMPASS, had an acute event roughly 70% of the time. Many of these people are late survivors after acute event. I also want to point out that in the acute setting, in ATLAS ACS 2, and in the setting of chronic disease after ACS, in COMPASS, the relative risk reduction was constant. It didn’t matter when you started rivaroxaban, whether it was in the midst of the ACS event or years later in the chronic setting: the magnitude of the risk reduction was constant. Those lines were pretty parallel. That’s something people don’t realize, that the acute and chronic syndromes are related in many cases.

Deepak L. Bhatt, MD, MPH: Those are really terrific points, Mike.

Transcript Edited for Clarity