VOYAGER Trial and DPI in Clinical Practice

Deepak Bhatt, MD, MPH: Well, we've spoken a bit about the COMPASS [Cardiovascular Outcomes for People Using Anticoagulation Strategies] trial, Manesh, maybe you can help us pivot now to talk about the VOYAGER PAD [Vascular Outcomes Study of ASA Along With Rivaroxaban in Endovascular or Surgical Limb Revascularization] trial. This was another trial that looked at the same dual pathway inhibition strategy.

Manesh Patel, MD: Thanks, Deepak. And again, I'd say it's been great to work on VOYAGER with Marc and others. And just to remind everyone, we talk a lot about coronary, we think about stents. And in my sort of analogy, actually with VOYAGER now, it gets easier in the periphery. I say that because we don't have a history or an evidence-base, where dual antiplatelet therapy chronically either helps the highway or the pothole. We’ve talked about COMPASS, and I just want to highlight a point you made about COMPASS. I want to be clear. I, like Amy, believe in a sort of scale of justice. When you have all-cause mortality improvement, I don't need to look at the scale that much. And thus, since there are so few therapies, that's why we need a scale of justice because usually there's a risk benefit to everything and there still is with using any therapy including low dose in patients. Once I start to get that level of data I start to go, that's the kind of push I need to move my therapy sometimes from where I am. In PAD, what we said is if we have data in COMPASS that shows chronic vascular improvement, can we do it when you're at the procedure? This was actually what I think, including Marc and others, we've been talking about how approving the procedure is important but what are the downstream events? Not just the cardiovascular events, the limb events.

One thing we've been sort of changing our mind about or at least describing better is acute limb ischemia is an emergency of the lower extremity where you have to go and you have limb loss, amputation, cardiovascular death, MI [myocardial infarction] stroke; these are things that matter. Hence, when you go to the peripheral interventional lab, which we do, and you're using whatever device because you're so focused on trying to get that limb blood flow you spend sometimes 3, 4 hours, and boy, if that patient has to come back in a month, in 6 months, that's really devastating to the patient and to you sometimes. What can you do to prevent long term improvement in that patient so their VOYAGER PAD just roughly 6500 patients randomized too? Again, same thing as COMPASS, aspirin plus whatever else you were going to do versus aspiring plus low dose vascular dose rivaroxaban 2.5 and there was a placebo in the other arm. We’ve looked at all those patients out to 3 years, saw their really high rate of events, and these specific 5 coronary vascular events; cardiovascular MI death, stroke and then limb events, amputation or acute limb ischemia. 19% or so, 3 years, 17% if you got to therapy, sounds like not 2.6 percent absolute risk reduction. 33 patents every 30-so patients, I'm going to reduce 1 of these pretty devastating events. How do I translate that for people? In PAD [peripheral artery disease], whether you're treating the pothole or the highway it works in both. Now, I don't have to be thinking about do I need to do DAPT [dual antiplatelet therapy] …. It's both the pothole when I put a stent in and it's chronically there, so we’ve simplified it a little bit for PAD. Now, you've still got to choose your patient, you’ve got to make sure they're there for the right reasons and do all the other things but that's the way.

Deepak Bhatt, MD, MPH: That's really good. Sahil, you do a lot of peripheral procedures. How have you integrated, if you have the VOYAGER data into our actual daily practice?

Sahil Parikh, MD: It comes in 2 phases so I mean most of the patients that I treat are generally chronic patients who we've been caring for and eventually they get to a point where they need something done because they have lifestyle limiting claudication that's refractory to medical therapy. In that patient population, they're sort of more of COMPASS patient. As long as they have not had a recent coronary intervention or acute coronary syndrome [ACS], we are now especially in the higher burden patients moving those patients to dual pathway inhibition in the ambulatory setting. Patients coming in on the other hand either with critical limb ischemia who are the ACS of the legs, if you will that come as quickly as possible to revascularization; those patients upfront we often don't even have time to get the treated medically with adequate therapy but on the flip side after the procedure we're generally sending those patients home with a prescription for dual pathway inhibition.

There are occasional patients, and this is where there's a little bit of gray area where they're on DAPT; let's say it's particularly when I use stents, the platelet as we've talked about already is potentially the bad guy in those patients. With drug eluding stents in the legs as well, there is pretty good evidence that particularly for small caliber along segment of stent therapy, antiplatelet treatment is really important to prevent stent thrombosis in the relatively early phase. Thus, in those patients they wind up getting triple therapy, but we don't think of it in the same way as we do for our Afib [atrial fibrillation] patients where triple therapy is a no-no in so far as possible. Here, they'll get maybe a month of DAPT and then we'll drop to clopidogrel. The study I'd need to see though, is where you drop the aspirin and now, I guess to what we’re doing now with Afib but that’s a conversation for another day.

Usually now, we’re going back to aspirin with low dose rivaroxaban twice daily and I think my threshold for using that in the CLI [claudication/critical limb ischemia] patient is really low. We’ve seen really good response with those patients. In the patients where there’s high bleeding risk, the jury is still out a little bit. We have to sort of titrate to effect and some of those patients certainly early on after their index procedure we'll get them as much antithrombotic therapy as we can and then if they have a bleeding event or if there's concern about bleeding then we'll go back to aspirin monotherapy after a few months’ time. I think those first 6 months are critical in the minimum for even the high bleeding risk patient and if they can manage it, we keep them on maintenance dual pathway inhibition so that's a huge paradigm shift for us.

Deepak Bhatt, MD, MPH: Yes, that is a big shift. How about in your own practice, Eric?

Eric Secemsky, MD: I agree, I mean it's interesting. As I was speaking about earlier, we now have, just to Sahil's point, a big population of patients we've been following for some time and we've already put them on rivaroxaban and then they need a procedure. It makes our decision making a lot easier. We bring them in, they're already on their therapy, they get their procedure done and I usually state keep them on the rivaroxaban and aspiring consistent with VOYAGER PAD. After we do the lower extremity procedure and again stenting being a little bit more of a higher risk, we like at least some period of antiplatelet therapy with aspiring and Plavix, but I usually don't give them a refill. In coronary we make sure they have a year's worth if that's their indicated therapy or 6 months’ worth. Here I'll say, “OK, we're going to do 30 days. If clopidogrel runs out, you're staying on your aspirin and use Xarelto 2.5 twice a day” and so that's really, again to Sahil's point, a shift. Again, we needed that kind of encouragement to say, “all right we know COMPASS, but we don't know exactly when we should pull the trigger.” You get these quick visits, or the patient doesn't follow up routinely but now they're in front of us in the procedure lab, it's time to do something different. Let's use that as impetus to make a change. It's going to benefit them short term and long term.

Deepak Bhatt, MD, MPH: That's interesting to hear that both your practices have been so changed by this trial. It must make you happy to hear that this trial that you led was so influential. Maybe I'll give you, Marc, the final word on VOYAGER and what its implication should be to clinical practice. I mean obviously, it's already changedclinical practice but for our audience, what do you think they should do with these data?

Marc P. Bonaca, MD, MPH: Well, thank you, Deepak, and great comments. I do think that it was an important trial to do, because as Manesh said, we've extrapolated a lot from coronary trials for a long time in terms of how to treat our PAD patients but we know from trials like CASPAR [Clopidogrel and Acetylsalicylic acid in bypass Surgery for Peripheral Arterial disease] that just applying the same DAPT strategy to peripheral patients actually didn't show any benefit for DAPT. That was bypass not endo but it does show you the heterogeneity that we have to test these strategies in our patients and I think particularly for safety too because there was a lot of concern when we started VOYAGER about periprocedural bleeding and actually it was very modest if any. It told us that physicians are good about knowing when to start antithrombotics. I have a couple of comments – I mean one difference between VOYAGER and COMPASS was that actually you could use clopidogrel in the background and so about half of the VOYAGER patients received DAPT for their primarily endovascular procedures.

Manesh presented the endovascular data as an abstract and what we saw was that it didn't modify the scales of justice at all, that the net benefit for rivaroxaban was completely the same. In fact, the overall absolute benefit versus the absolute risk, it was about a 6 to 1 benefit risk ratio. Clopidogrel had no effect on what rivaroxaban was doing. It really taught us that they're doing different things and that clopidogrel does not modify that sort of thrombin mediated risk. The only thing we saw was that long durations of DAPT as you would expect, led to more bleeding so that the strategy that was talked about, a month or so seemed to be safe but longer durations may lead to more bleeding. I think that also helped to sort of hallucinate a strategy should you want to use a triple therapy approach.

The last thing I'll say about the trial, and we talked about high bleeding risk, but we've seen, I think in a lot of disease states, that we overestimate bleeding risk when it comes to medical therapies and we've seen this a lot in Afib when we're using low doses when we probably shouldn't be or we're not treating people. We've done a bunch of analyses out of COMPASS, out of VOYAGER where we've looked at older patients, frail patients, chronic kidney disease, all these things that make you worry about bleeding, but the scales of justice are the same. There's still a clear net benefit and so I think a lot of the work that went into selecting that low dose to be combined with aspirin has shown consistent net benefit in all of these higher risk populations. That's not to say we disregard bleeding risk and there truly are high bleeding risk patients, but you don't want to turn down a therapy that's beneficial for those patients that could benefit just because you overestimate bleeding risk.

Deepak Bhatt, MD, MPH: We sort of got burned by that as a community in atrial fibrillation with the fall risk; you might say “oh this person is 80. They might fall. I guess we won't anticoagulate them.” Obviously, those are the patients at highest risk of thromboembolic stroke from Afib so sometimes the fear of doing harm keeps us from doing what's actually in the patient's best interest. This has been a really terrific discussion. I hope the audience enjoyed it about the details of DAPT and dual pathway inhibition and antiplatelet monotherapy so there's a role in the universe for all 3 of these different types of therapies. It's just a matter of identifying the right patient and there's lots of new data to suggest. We went through it rather quickly but hopefully some of what we mentioned will be useful as you're trying to figure out which therapy is best for which patient.

Transcript Edited for Clarity