Marc Bonaca, MD, MPH, explains the VOYAGER trial results and how they compare to the PAD trials that came before.
Manesh Patel, MD: From COMPASS, I turn to Marc and think about VOYAGER. What were the lessons that we take from COMPASS? How did we think about conceiving VOYAGER? Because COMPASS told us about patients with chronically vascular disease, with CAD [coronary artery disease] and PAD [peripheral artery disease], and broadly showed a benefit. But the patients with PAD, as we’ve highlighted, have always had an extended benefit assumed from a broad population, although COMPASS was so large. How did you go from there to VOYAGER?
Marc P. Bonaca, MD, MPH: Thanks, Manesh. Both of you were involved with leading VOYAGER, so you know it well. In retrospect, it may seem obvious that this would be a beneficial therapy, but at the time the trial was designed, it was quite different. EUCLID was a surprise, as you said. The PLATO trial showed a mortality benefit in ACS [acute coronary syndrome]. Ticagrelor vs clopidogrel alone didn’t work in PAD, and it didn’t modify limb outcomes. The ATLAS-ACS-2-TIMI trial, when that was done with Jess Mega and Mike Gibson, I remember thinking, “Boy, that’s really going to work.” Lo and behold, there was mortality benefit there, so there were all sorts of surprises. In the background, too, there was vorapaxar, a drug not widely used now but that was thrombin mediated, which reduced acute limb ischemia [ALI]. There’s this notion of different ways of modulating the thrombotic risk. Is it just about platelets, or is thrombin a key mediator? COMPASS was a landmark trial because it showed it’s not a number of agents but how you modulate the system.
Regardless, at the time VOYAGER was designed, COMPASS hadn’t been unblinded, and many of us were unsure what the effect was going to be for MACEs [major adverse cardiovascular events] and PAD given what happened with the EUCLID trial. We know that’s only part of the equation. We know these limb outcomes are really bad. Although a lot of people who take care of patients with PAD know that ALI is bad, they hadn’t been put in trials before, at least not for primary outcome. The FDA and the trial sponsors had to be convinced that this is something that matters in the postrevascularization setting.
When the trial was designed, it leveraged that low-dose rivaroxaban from the large phase 2 program in ATLAS and ATLAS-2. It was also being used in COMPASS and then changed the primary end point to 1 that included limb outcomes. At the time, had we known the COMPASS results, it wouldn’t have been as much of a risk. But at the time, it was relatively courageous for the group to do and then looked at the postprocedural setting in short- and long-term outcomes. When Sonia talked about risk—atherothrombosis plaque rupture, embolization—what’s driving these limb events are probably different from what’s happening in coronary patients. There is atherosclerosis.
But in the postprocedural setting, a lot of this is grafts going down because of low flow, and you’ve got prosthetic materials and other things. Manesh, you know that if you do these procedures, it may be different. How modifiable are they early on? The other issue is that we know from the WAVE trial and others that this is a very fragile population for bleeding. What’s the safety going to be in a postprocedural setting? As we talk about extrapolating different vascular territories and 1 of the issues, we may talk about is gaps, but what is the CHD [coronary heart disease] in this fragile population? These were all considerations when the trial was deigned.
As you mentioned, our colleague Will Hiatt was at the helm with many of us contributing. It was a pragmatic trial, a dedicated symptomatic PAD without additional enrichment. You didn’t have to have coronary disease, and that was deliberate to distinguish from COMPASS. Then in the postprocedural setting for a primary outcome, that included a composite of limb and cardiovascular events. As you know, that trial ended up being positive. It was probably the first medical therapy shown in a rigorous way to be efficacious after revascularization and that led to a label that included limb outcomes. It was the first time for any drug, at least that I’m aware of. That story from ATLAS to COMPASS to VOYAGER is 1 that’s unique in antithrombotic therapies.
Manesh Patel, MD: It was truly an effort of many over many years to get therapies to patients that hopefully improve their outcomes.
This transcript has been edited for clarity.