VOYAGER PAD Trial

Manesh Patel, MD: It’s good to have evidence but not always do we have it. The evidence we now have, I’ll sort of briefly give the top line VOYAGER PAD results which is just out to three years for that combined endpoint of CV [cardiovascular] death, MI, stroke, acute limb ischemia, and amputation from a vascular etiology. There’s a significant reduction. What’s first the take home was that the control arm, which was aspirin and then placebo, the other arm was of course aspirin plus rivaroxaban 2.5 BID [twice daily], the control arm rate was 19.9%, roughly 20%. One in five patients that you’re doing a procedure on, endovascular surgical, at three years is going to have one of those endpoints in 2018. No, so just putting that into context for us, that’s still a significantly large event rate for our patients that maybe we’re not telling them about when we go into these procedures but we certainly would love to figure out ways to reduce.

In fact, the interventional arm reduced that to 17.3% with an absolute risk reduction of 2.6% or number needed to treat of 39, even sort of continuing to spread, just the idea that you would have a benefit. First and foremost, I think that was a powerful finding that obviously all of you all were involved with us to do that. You guys led. And then the TIMI major bleeding because everybody also wants to know about bleeding when you talk about the efficacy. Again, it was more. It wasn’t statistical for TIMI major, but ISTH was increased and that was 2.7% versus 1.9%. There is some general increase in bleeding.

Maybe the first message for us is to say, Marc, how would you put sort of the relatives of this; because people always want to think about this in a way of saying how many of those sorts of what I’ll call strokes, limb event, etcetera, do I prevent for a bleeding event? And you’ve done some nice sort of demonstrations of what I’ll call the thousand person or the hundred person way of thinking of this.

Marc P. Bonaca, MD, MPH: Yeah, risk-benefit is tough, right? And net outcomes, how do you way things. So maybe you’re right, it’s just the best way is in terms of what’s prevented versus caused. We did an analysis which really just to distill it down to the simplest concept was that there was a 6:1 benefit-risk ratio. The number that you said, number needed to treat at 39, very low number, what’s the risk, 6:1 benefit-risk ratio. When we looked at 10,000 patients treated for a year, come out to be about 181 events prevented. But that doesn’t really talk about total events. It just talks about first events. Actually, when we talk about the 6:1 benefit-risk ratio, we’re talking about first events and that’s only about 18% of the benefit that we saw in VOYAGER because there were so many recurrent events and all of them were modified with rivaroxaban. I’d say that’s actually a gross underestimate.

Another way to think about risk is there was more TIMI major bleeding, as you said, Manesh, and this is 6500 patients randomized over three years. The difference between the two treatment arms in terms of bleeding was 18. There were 18 bleeds. These hazard ratios you have to be cautious with because yes, they talk about the relative differences. But, from a clinician’s perspective, you ought to know, if I get 1,000 patients in my practice, what am I likely to see, a couple thousand or whatever it is. And I think those numbers probably give you more information.

Manesh Patel, MD: That’s absolutely really great. By the way, if you have a couple thousand patients in your practice, we’re happy to have you here at Duke at any point. We’re happy to get(?) you there. This speaks to some of the busy practitioners that are doing it. I guess, Sonia, now having been on VOYAGER and COMPASS, you led a nice analysis of the patients that were VOYAGER like or the PAD patients, both in VOYAGER and COMPASS. Maybe you could summarize a little bit for us the consistency across those groups. Because I think the other thing that’s nice is now, we have a spectrum of acute treated patients, revascularization, and we have what I’ll call the more chronic PAD patients. Maybe you tell us a little bit about what you all found with that analysis.

Sonia Anand, MD, PhD: Sure. Thanks, Manesh and we were all part of it. But we’re often asked the question about the COMPASS findings versus VOYAGER and how are these trials different. Both trials would be what we call positive trials, but by combining all of the data from these two large datasets, we can look, as you say, for those consistent effects. Because consistency helps us believe the results even more, that it wasn’t a one-off fluke that one trial found something, and another showed something different. And, in this case, we were able to meta-analyze COMPASS PAD with VOYAGER.

So, if you add up all of those patients, it’s over 10,000 patients that we put together and we also harmonized to the primary outcome to use what we call the VOYAGER 5-point primary outcome of cardiovascular death, ischemic stroke, MI, acute limb ischemia, and major vascular amputation. So, with the two large trials testing and comparing the same therapies, we’d look at the effects on this composite outcome, and we observed overall a 15% relative risk reduction which was highly significant. And that’s with a 5-point primary. And then when we go into some of the nuances of different composites, I’m looking just at the limb with acute limb ischemia and major vascular amp, it’s even more significant, substantial for PAD patients who are getting into the 35% relative risk reduction realm.

Across the primary outcome, across the limb outcomes, we’re seeing a great consistency between our VOYAGER and COMPASS. There are some differences. We’ve mentioned that COMPASS was an outpatient PAD population. About 60% of those patients had concomitant coronary artery disease. Whereas, in VOYAGER, fewer patients had coronary artery disease and more had critical limb ischemia and more supports of post-revascularization population. In spite of all of those differences, the bottom line is we see a very consistent effect. We see that over time the net clinical benefit increases, and so it really should be reassuring to the cardiologist or the vascular specialist to be able to initiate this therapy and know that you’re doing good by all vascular territories, essentially, in being able to prevent MACE as well.

Manesh Patel, MD: Yeah, that’s really well stated, Sonia. Thanks. It sorts of highlights just something that we all look for which is whether it’s consistency or reproducibility, it’s very valuable.

This transcript has been edited for clarity.