What Does VOYAGER PAD Mean for Antithrombotic Therapy?

This transcript has been edited for clarity.

Michelle L. O'Donoghue, MD, MPH: Hi. This is Dr Michelle O'Donoghue, reporting for Medscape. Unfortunately we're in the midst of the pandemic, so I will be interviewing Dr Marc Bonaca remotely through the Zoom interface. As you all know, American College of Cardiology (ACC) live scientific sessions were canceled. But one of the hottest topics being presented at the virtual ACC are the results of the VOYAGER PAD trial. I'd like to introduce Dr Marc Bonaca, who is a cardiologist as well as a vascular medicine specialist at University of Colorado. Welcome, Marc.

Marc Bonaca, MD, MPH: Thank you, Michelle. It's a pleasure to join you virtually. These are very challenging times for all of us with the pandemic, but we're very grateful to you and to the ACC for making all the science move forward through this virtual platform. Thank you.

O'Donoghue: People are really excited about this topic, I think in part because we don't have a lot of options to offer our patients who have peripheral artery disease (PAD). A lot of trials have not been done in the past, and thus far we have not had a lot of great options to turn to reliably. What are the data to date in terms of what we've done so far and what we know?

Very Little Data in PAD to Date

Bonaca: Largely what we know about medical therapies and PAD has been derived from subgroup studies from large cardiology trials—a high-risk subgroup, if you will, showing consistency of benefit for things like statins or aspirin in terms of reducing major adverse cardiovascular events (MACE). But patients with PAD really are a different group of patients, and they are different both in how they respond to therapy in terms of its safety, but also that their lower-extremity disease puts them at very high risk for major adverse limb events.

In the interventional setting, there have only been two previous trials. CASPAR looked at aspirin and clopidogrel versus aspirin alone after below-the-knee bypass surgery. That trial was neutral, but there was over 2.5-fold excess in GUSTO bleeding with dual therapy. The Dutch BOA trial with warfarin was also a neutral trial, but there was a 3.5-fold excess in hemorrhagic stroke. We have very little data in this disease state, particularly in the interventional setting, which is the highest-risk setting.

O'Donoghue: How do you factor in the results of EUCLID as we think about differences between antiplatelet therapies for patients with PAD versus more of an antithrombotic approach?

Bonaca: EUCLID was one of the few dedicated PAD trials with over 12,000 patients looking at ticagrelor versus clopidogrel. They asked the same question that PLATO asked in acute coronary syndrome: Is a more potent, less variable P2Y12 inhibitor superior to clopidogrel? In the coronary patients in PLATO, we saw that it was superior and there was a mortality benefit. In patients with PAD, the therapies were no different. There was no superiority for ticagrelor.

EUCLID really tells us that the biology is a bit different in this population. About a third of patients in EUCLID had coronary disease; about 10% had a prior myocardial infarction (MI) in spite of a lot of risk factors and comorbid disease. So the antiplatelet therapy we use is largely aspirin and clopidogrel, but again, this is based on observations and coronary trials and for stent protection largely.

VOYAGER PAD vs COMPASS

O'Donoghue: It's a very interesting topic, and we'll circle back to it because the question of whether the biology is different is something worth delving into a little bit more. Can you walk us through the study design of VOYAGER PAD?

Bonaca: People familiar with the COMPASS trial may say, "Didn't COMPASS look at low-dose rivaroxaban in patients with PAD?" It's important to understand that VOYAGER PAD is a very different trial. VOYAGER PAD was designed to enroll a very typical lower-extremity symptomatic PAD population needing intervention. In contrast to COMPASS, which was polyvascular disease (over 90% had coronary disease and there were enrichment factors for risk), in VOYAGER PAD, you just had to have lower-extremity symptomatic PAD needing intervention and there were no enrichment criteria for MACE risk or for limb risk. It was a very typical population.

The only exclusions were around being unstable or needing anticoagulant therapy or something that would increase your bleeding risk. It was also designed to look at rivaroxaban on top of standard of care. The standard of care in PAD intervention is aspirin, and for patients getting endovascular therapies it's dual antiplatelet therapy. In contrast to COMPASS, clopidogrel was allowed in VOYAGER PAD. So the population is different, the post-intervention setting is different, and the background therapy is different. Maybe the most important distinction is that the primary endpoint for VOYAGER PAD was designed specifically for this population, where it is a composite of limb events and cardiovascular events—the irreversible harm events, if you will, like acute limb ischemia and amputation, which are an equal weighting to the cardiovascular events and actually the highest risk in this post-intervention period.

O'Donoghue: That seemed to work out quite well for this particular trial. In the past, there had been concerns about combining the MACE outcomes with the peripheral outcomes. But as you walk us through the results, it actually worked quite well to the advantage of the trial.

Bonaca: I think it speaks to the setting as well as the outcome. COMPASS, for example, had a very broad population, mostly coronary with some concomitant PAD. Limb risk was relatively low. But as you point out, VOYAGER PAD trial is real lower-extremity symptomatic PAD post intervention. The majority of the risk profile is really dominated by limb outcomes. Having the right composite endpoint for this population is critical for the outcome of the trial.

Benefits for Rivaroxaban

Bonaca: We reported Kaplan-Meier rates at 3 years. It was sobering to see for the patients receiving aspirin—about half of them also received clopidogrel and 80% were on statins—that at 3 years, 1 of 5, or about 20%, of patients in the placebo group had one of these bad outcome events. This is a very high event rate, even in spite of optimal treatment. We saw that randomized treatment rivaroxaban reduced that risk by 15% (P = .0084). It was a significant result and a positive trial. Beyond the 15% relative risk reduction, the absolute risk reduction probably tells a more compelling story because of the background risk of the population. There was a 1.5% absolute risk reduction significant at 6 months (number needed to treat [NNT] < 70), and at 3 years the absolute risk reduction was about 2.6% (NNT = 39). That is not for some high-risk subgroup of the trial; that is for the overall trial.

O'Donoghue: There certainly was a very large benefit in terms of reducing the risk for acute limb ischemia, which is very exciting for people in the vascular medicine field. It's interesting when we think about EUCLID, where you have a PAD population, and intensification of antiplatelet therapy didn't appear to offer a benefit. Overall, even when you looked at the coronary outcomes, there appears to be a fairly consistent benefit toward reducing acute limb ischemia, MI, and stroke with rivaroxaban. That sort of had me thinking about whether there is something different about this particular disease state and whether antithrombotic therapies may offer more bang for the buck in terms of reducing ischemic risk, both for limbs as well as the coronaries, without a tremendous excess in bleeding.

Bonaca: That will be a lot of the data that comes out of this trial. The risk/benefit and the risk profile for PAD patients, like in EUCLID, is different from what we see for coronary patients, and the spectrum of benefit looks different as well. That is going to be something that emerges from the trial and in the field.

Bleeding Risk

O'Donoghue: Unfortunately, there is never a "free lunch," as we've heard many times. How much excess bleeding did you observe and how do we weigh that against the apparent efficacy?

Bonaca: Major bleeding was the principal safety outcome and it was higher with rivaroxaban (hazard ratio 1.43; P = .069). The events were low so you have to be cautious with the P value. Importantly, there was no excess of take-back bleeds or procedural bleeds, no excess in intracranial or fatal bleeds. There was more International Society on Thrombosis and Haemostasis (ISTH) major bleeding but the hazard ratio is around 1.4, so it's actually less than what we saw in COMPASS. Overall, when we put it together as an on-treatment for events prevented versus caused for 10,000 patients treated per year, you prevented 181 ischemic events at the cost of 29 bleeds, but no excess in fatal bleeding or intracranial hemorrhage. Net benefits are complicated, but overall it seemed to favor benefit.

O'Donoghue: Right. Did the overall benefit appear to be consistent regardless of background antiplatelet therapies too?

Bonaca: About half the patients got clopidogrel (at physician discretion) and there was no attenuation or effect modification for the benefit with clopidogrel. Overall, there was no greater increase in bleeding with rivaroxaban. The safety was consistent. When you look at rates particularly early on, when people use clopidogrel in this setting, there was more "nuisance" and moderate bleeding. We know that that can have a downstream effect like discontinuation of therapy. Although I think the benefit/risk of rivaroxaban is not modified clopidogrel (it works the same either way), there probably is a price to pay for longer durations of background clopidogrel as we see in other studies. I would expect that many will take that as advice to minimize the exposure to that kind of triple therapy, if you will.

O'Donoghue: That is an interesting takeaway point as well. Thank you, again, for taking the time to speak with me, Marc, and best of luck. I know that the results are going to be online in the New England Journal of Medicine. Congratulations.

Bonaca: Thanks very much. I appreciate it, Michelle. And thanks for making time for this interview. I know there is a lot going on in the background right now, but we do recognize that this is a high-risk population and we hope these results help to change practice.

O'Donoghue: That is great. Signing off for Medscape, this is Dr Michelle O'Donoghue.

Michelle O'Donoghue is a cardiologist at Brigham and Women's Hospital and senior investigator with the TIMI Study Group. A strong believer in evidence-based medicine, she relishes discussions about the published literature. A native Canadian, Michelle loves spending time outdoors with her family but admits with shame that she's never strapped on hockey skates.

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