Rationale and Study Design of the VOYAGER PAD Trial



Deepak Bhatt, MD, MPH: Marc Bonaca, I can turn back to you to tell us about the VOYAGER PAD trial. What was the purpose, the design and the main result?

Marc Bonaca, MD, MPH: Thank you, Deepak. When we talk about rivaroxaban, I believe it’s 1 of the largest cardiovascular development programs ever. When we talk about arterial vascular disease, it began with the ATLAS trial establishing the low dose and showing a mortality benefit, and that was in a specific acute coronary syndrome population. We heard from Manesh about translating that in the consistent benefits for mortality that were seen in stable or chronic vascular disease, CAD [coronary artery disease] or PAD [peripheral artery disease].

The VOYAGER PAD trial was designed to be complementary. It was not designed to overlap with the other trials, but it took components of both the ATLAS trial and the COMPASS trial, and it said, “What about patients who have peripheral artery disease who are in the acute setting of their illness?” This is when they become sick enough to need peripheral intervention or revascularization, either for severe limiting claudication or critical limb ischemia, of which there were a large number in the trial.

The question for the VOYAGER PAD trial, then, was different from the other trials with what the relevant primary end point for this population in this setting is. It was also noting that, unlike the COMPASS trial, which was enriched for polyvascular disease, patients in the clinic with symptomatic PAD, only about a third of them had symptomatic coronary disease. Although you did angiograms in all of them, of course they’d have atherosclerosis. It’s a distinct population.

The VOYAGER PAD trial asked what the benefit is of this dual-pathway strategy of low-dose rivaroxaban plus aspirin vs aspirin alone in patients with symptomatic PAD requiring revascularization. It was a pragmatic trial in that it allowed people who were getting endovascular revascularization, surgical revascularization, critical limb ischemia—the more modern term for that—or claudication to see clopidogrel in the background. It was a distinguishing feature from the COMPASS trial, although it was also allowed in the ATLAS trial. That was the general design. I can go into some of the results, Deepak, if you’d like.

Deepak Bhatt, MD, MPH: Yes, that would be useful if you could share the main results.

Marc Bonaca, MD, MPH: One thing that caught my attention is this: Manesh mentioned that the background care was good in the COMPASS trial, but the event rates were high. That was particularly notable in this population. For the event rate in the placebo group, meaning they got aspirin, 80% got statins, about half of them got clopidogrel, and the event rate was about 20% at 3 years, which was extremely high. It shows the illness of this population. If you look at some of the subgroups like those with critical limb ischemia or prior revascularization, the event rates are almost 30% at 3 years, so they are at extremely high risk.

We then saw consistency with what we’ve seen for this dual-pathway approach in the other trials. We see that there’s an early separation of the curves with rivaroxaban and that the curves continue to diverge over time with a number needed to treat of less than 40 at 3 years. A lot of that benefit was apparent early on, so there was consistency in terms of a beneficial effect of the strategy in this very different population in different settings. What might get people’s attention is that the pattern of benefit looks a bit different from other populations. It’s driven by limb vascular outcomes, which are frequent in this population. That doesn’t mean that the trials are discordant at all because, if you look at the subgroups, for example polyvascular disease in the VOYAGER PAD trial, it looks just like the COMPASS trial in terms of the spectrum of benefit. What it tells us for this population in this setting is that the risk is driven by limb outcomes, and there was a remarkable benefit particularly for acute limb ischemia in this setting.

The other surprise was that Manesh said he had been surprised that the strategy was efficacious in the COMPASS trial. I wasn’t surprised knowing the results of ATLAS and COMPASS. What I was surprised about was the safety: This is a frail and fragile population with a lot of comorbidities, like renal dysfunction, and a lot of the patients were over 75 years old. I was worried, and a lot of people were worried in the procedural setting that the bleeding risk would be intolerable when in fact we observed no difference in take-back bleeding because patients were started after they achieved hemostasis. The risk for TIMI [thrombolysis in myocardial infarction] major bleeding and ISTH [International Society on Thrombosis and Haemostasis bleeding scale] major bleeding was around the scale of what we saw in the COMPASS trial, if not less, and there was no trend for intracranial hemorrhage or fatal bleeding. The notion that this is consistently efficacious but also safe, even when you give it on top of clopidogrel for a short period, was reassuring.

Deepak Bhatt, MD, MPH: That’s terrific. I want to stick with you, Marc, for 1 other thing that you presented, I believe at AHA [American Heart Association Scientific Sessions], and it had to do with the incidence and the cost of major atherothrombotic vascular events among patients who need lower-extremity revascularization. I thought it was an interesting and insightful analysis. It was out of the Optum database. It showed that there was a pretty high cost associated with these events, but do you want to quickly summarize what that work showed?

Marc Bonaca, MD, MPH: That’s a great question, Deepak. Beyond that, the morbidity and the cost in this population are extremely high, and they’re driven primarily by limb outcomes and by repeat revascularization. It turns out that acute limb ischemia is 1 of the most costly things that can occur in this population. When we applied the VOYAGER PAD trial strategy in concept to real-world prices, there was a cost savings of over $2000 per patient when treated with rivaroxaban because of the prevention, primarily of those limb events that are so costly.

Deepak Bhatt, MD, MPH: There were many things in there in which the cost range was up to $100,000 for lower-limb amputations, so there are a lot of health care costs generated by ischemic events. In general, everyone realizes stroke and the disability and costs associated with that, but amputation is a horrible thing beyond the morbidity as well as the health care cost implications.

Transcript Edited for Clarity

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