Advances in PAD Management: EUCLID and COMPASS Trials

Manesh Patel, MD: I’ll take a moment and talk about EUCLID, and then we’ll get to COMPASS and VOYAGER because it’s an evolving story. Actually, with you 2 here, we have a lot of the field covered with a few other great colleagues that have helped us. EUCLID was similar, with our great friend and departed colleague Will Hiatt, we studied ticagrelor vs clopidogrel. At that time, our thought was pretty clear. I remember having pretty heated arguments with Will around whether we should have an aspirin arm. We all wanted 1 but it’s hard to conduct them. I’m a revascularization doctor, so I was a big fan of getting people in who had revascularization. Will was a strong proponent of the patients with reduced ABI [ankle-brachial index] getting in.

But we took a broad population of patients in the outpatient arena with PAD [peripheral artery disease]. They hadn’t had a revascularization within 30 days, but they could have had it greater than 30 days—maybe not the acute revascularization population, but a vascular population nonetheless. The average ABI was probably in the 0.7 range. We’re going to talk about some average ABIs in a second: 0.68 to 0.75—about half of them patients with claudication and half with a prior history of revascularization.

At that time, our thought was that stronger antiplatelet therapy prevents events—limb, heart, and others. Just to remind everyone, this PAD population was lower-extremity PAD, and 30% of them had known coronary artery disease [CAD] if you asked if they had a history of MI [myocardial infarction], a coronary revascularization, or a CABG [coronary artery bypass graft], but most of them did not, at least not a clinical 1. It doesn’t mean they didn’t have atherosclerosis in their coronaries. We don’t know. We just know that the clinical presence was evident in 30% of the patients.

We were fairly dumbfounded when we unblinded the trial and found that KM [Kaplan-Meier] curves showed no difference between the 2 therapies. Clopidogrel was obviously effective but had a lot of the antiplatelet effect of ticagrelor, which is a stronger antiplatelet. It did not lead to a difference in cardiovascular [CV] events: CV death, MI, or stroke. We looked at limb events and didn’t see a difference in this population. This was a stable outpatient population, but we didn’t see a substantial difference. Our conclusion from that time period was that more potent antiplatelet therapy in patients with PAD who are outpatients, without known coronary disease not undergoing a recent intervention, certainly didn’t seem to change the profile.

That evolved our thinking to think about 1) what about people broadly undergoing peripheral revascularization, 2) what about people who had both coronary and peripheral disease, and finally the most important, 3) more antiplatelet therapy may not always lead to better substantial gains. That’s a concept that, to an interventional cardiologist, was hearsay a few years ago. We had always thought—and some parts of our field still think—that white clot, more antiplatelet therapy, important stop. It’s always in the perspective of that.

That’s where we were with the data from EUCLID. Sonia, I’ll kick it to you next to talk to us a little about how we went from EUCLID and this antiplatelet story to dual-pathway inhibition with low-dose Xa inhibition with rivaroxaban. Certainly, 1 can think about some of the work you’ve all done in other ways to get to that. Maybe you can tell us how we went from the antiplatelet PAD therapeutic arena to low-dose anticoagulant with antiplatelet.

Sonia Anand, MD, PhD: I’ll take a quick second to mention that we had, prior to COMPASS, worked on another large trial in PAD that tested moderate-intensity oral anticoagulation with warfarin together. That trial, called the WAVE trial, didn’t show a reduction in MACEs [major adverse cardiovascular events] and was associated with an increase of life-threatening bleeding. That put the brakes on testing a full-dose anticoagulant with aspirin, for example, in PAD. Along comes the ATLAS-ACS-2-TIMI trial in ACS [acute coronary syndrome], showing that a half dose of the factor Xa inhibitor rivaroxaban or one-quarter of a full dose, used together with antiplatelet agents, seemed to be effective in patients with ACS, including a more totality in reduction.

That looked very attractive, so our research group had a number of debates and said could we do a CAPRIE-like trial, enrolling patients with established vascular disease and testing some of these dual-pathway inhibitors. This led to the COMPASS trial, and we said from the outset, let’s recruit at least 25% of the patient population to have PAD. That led us to COMPASS, and I’m sure many of our listeners are familiar with the results.

In brief, with patients with either coronary disease or PAD enrolled into COMPASS, there was a clear benefit of using low-dosage rivaroxaban, 2.5 mg twice daily, together with aspirin compared with aspirin alone in the reduction of MACEs. Overall, there was a reduction in morality and what was important and intriguing for our patients with PAD is we saw clear reduction in what we called major adverse limb events, or MALEs, which includes acute limb ischemia and major vascular amputation. For the patients with PAD, there was a clear reduction in MACEs as well as MALEs, and we haven’t had a therapy that had these reductions without a significant excess in serious bleeds prior to COMPASS.

Manesh Patel, MD: It’s a landmark movement in a trial. I’ve been honest, so it won’t shock you to find that I’ve said in the past that when the COMPASS trial was planned, I wasn’t sure if it was going to be positive, much less stopped early for mortality reduction just because it was such an ambitious undertaking: a broad population of patients treated well on aspirin therapy. It’s not easy to beat a broad population of patients with coronary and peripheral disease who did have a substantial risk, so it speaks to just how powerful the therapy was. As you stated, patients with CAD and certainly PAD had limb benefits. Congratulations to you all for conceiving and taking the lessons from the WAVE trial, thinking a little more about how to do it better, and moving the field forward.

This transcript has been edited for clarity.