Paul Dobesh, PharmD, and James Groce, PharmD, provide an overview of the phase 3 double-blind COMPASS trial, with consideration of the regimen’s safety and efficacy end points.
James Groce III, PharmD: In terms of the study design, let’s talk about the COMPASS trial. If you could, could you review the study design and the safety and efficacy end points of this phase 3, double-blind trial that we collectively refer to as the COMPASS trial, evaluating the role of rivaroxaban when compared with aspirin.
Paul Dobesh, PharmD: Sure. The COMPASS trial—if you’re not familiar with it, you really just need to pull out the New England Journal of Medicine and read it. We discuss landmark trials in many places in medicine and vascular medicine, and there’s not a doubt in my mind that COMPASS is what we would call a landmark trial. A landmark trial is something that I think makes us pivot to do something, that this is something now we have to do. Lots of studies are out there that might help us tweak things. COMPASS is a study that really makes us pivot.
COMPASS is a study of over 20,000 patients, done over 40 countries, more than 300 sites—so, a big study. Patients in the study had to have basically stable coronary disease. When I say stable, this means that they were not within their first year of dual antiplatelet therapy. If you’re on dual antiplatelet therapy, you’re not in this study. That’s important for us to realize. This is not a competition in that first year, OK? So, you had to be outside that. So when I say stable, I mean that these aren’t ACS [acute cardiac syndrome] patients, right? They’re at least outside of a year of their ACS event. So, you had to have coronary disease or peripheral artery disease, and I think 91% had coronary disease, 27% had peripheral arterial disease. So if you can do math as well as I can, those add up to more than 100, so there’s about 17% or so that had both.
In this setting, patients were well managed. Their blood pressures at the time the study was done were pretty well controlled. Over 90% of patients had lipid-lowering therapy, most patients were beta-blocked, most patients had ACE [angiotensin converting enzyme] inhibition therapy. So, the patients were then randomized to aspirin, which was the standard of care. Sometimes we’re like, “Well, why not dual antiplatelet therapy?” Because remember, this is not the first year. You’re outside of that year, right? The question with this is “What are you doing?” This study is answering the question “What do you do after dual antiplatelet therapy?” really; I think that is part of it. After that year, what are you doing to do? Today, the standard of care, like we talked about in the guidelines portion, is aspirin in those patients. They used 100 mg of aspirin. Once again, we don’t have 100 mg; we have 81. It doesn’t matter, right? Low-dose aspirin—just matters what continent you’re on. If you go to Europe, that’s 100. If you go to North America, that’s 81. You go to many parts of Asia, it’s 75. It doesn’t, you know it’s low-dose aspirin. That was the standard of care, which is an appropriate standard of care. Then they wrote about rivaroxaban, 2.5 mg twice daily, very low-dose rivaroxaban compared with the dose we use in other areas, with that low-dose aspirin. There was also a rivaroxaban by itself arm, and that really didn’t make it. So, we’re going to focus on the discussion of the parts of therapy.
The primary outcome, as it is in many types of arterial types of studies, its CV [cardiovascular] death, MI [myocardial infarction], and stroke, and they used a modified definition of the ISTH [International Society on Thrombosis and Haemostasis] major bleeding. I’ll talk a little bit about that because, I’ll tell you, when I read the word modified, I rolled my eyes and thought, “Oh boy, here we go.”
It’s interesting. This was an outcome-based study. They were supposed to have 2200 outcomes to stop, you know, and then the study would be over. With any study, obviously, when you’ve got 27,000 patients, multiple countries, hundreds of sites, you have a data and safety monitoring board, and periodically they look at the data. When 50% of the outcomes were accrued, they said, “OK, after 1100 outcomes, let’s look at the data.” The data and safety monitoring board at that time said, “You have to stop this study. It is unethical to continue with the standard of care.”
Now, for our people, let that sink in. The standard of care was beaten so bad that the study had to be stopped early by the data and safety monitoring board. There was a 24% relative reduction in CV death, MI, and stroke, favoring aspirin with low-dose rivaroxaban as opposed to aspirin by itself. You get into that data a little bit deeper, right, and you start talking about CV death, MI, and stroke, and every single one of those individual outcomes was reduced. The aspirin bar was always bigger than the low-dose rivaroxaban and aspirin arm. So always there was a benefit in each one of those. What’s interesting is that MI was the one that was reduced by 14%; that was probably the one that was affected the least. But there was a 22% significant reduction in cardiovascular death; that was statistically significant by itself.
James Groce III, PharmD: Wow.
Paul Dobesh, PharmD: I mean, there is nothing beyond a year that reduces CV death like that. Nothing, right? And over 40% reduction in stroke. There’s nothing that reduces stroke like that that we do in these patients, OK? So, it’s really a profound reduction in these cardiovascular events. And regarding cardiovascular events, most of the time, like when you look at dual antiplatelet therapy, really, almost all dual antiplatelet therapy ever does, almost always, is reduce MI, right? Like I said earlier, long-term dual antiplatelet therapy has a very modest reduction in MI. There’s no benefit in cardiovascular death with this, nothing with dual antiplatelet therapy beyond a year, and, like I said, dual antiplatelet therapy has never reduced stroke. Now we’re seeing a significant reduction in both of these that is not able to be reproduced by anything else.
So, I think the efficacy is very profound, especially when you look at the PADs, as well. So, that’s in everybody. The benefits were almost identical; it didn’t matter if you had coronary disease or peripheral disease, both groups had the same magnitude of reduction in these outcomes. But in PAD patients, acute limb ischemia was reduced by over 40%.
James Groce III, PharmD: Wow.
Paul Dobesh, PharmD: Remember that acute limb ischemia meant that something had to happen. You had to go get an intervention, whether that be peripheral bypass, peripheral intervention, peripheral stenting, lytic drip, something like that—so, a major outcome. And then major amputation, right, was reduced by 70%. Now, the absolute numbers are small; it was like 0.7 versus 0.2. But think of this: Really, besides maybe a stroke, can you think of something that [affects] a patient’s quality of life more than cutting off their foot?
James Groce III, PharmD: Right.
Paul Dobesh, PharmD: Right? And that’s being able to be reduced by 70% when we’re using low-dose aspirin with the low-dose rivaroxaban versus just the aspirin by itself. So the efficacy was very clear, and hence that’s why the study was stopped.