Deepak Bhatt, MD, MPH: Marc, Manesh mentioned the drug coatings, whether they’re drug-coated balloons or drug-coated stents in PAD [peripheral artery disease]. What are your thoughts from the VOYAGER-PAD trial and the work of Connie Hess, who is another of your collaborators, with respect to what insights we can gain from the VOYAGER-PAD trial and the optimal antithrombotic regimen, realizing that not everything was randomized there? Only the rivaroxaban part was randomized. The drug-coated balloon or stent wasn’t a randomized part of the trial, and neither was clopidogrel, but they are still the best data we’ve got. How do you integrate all that?
Marc Bonaca, MD, MPH: That’s a great question. Part of the question here is about the safety of the drug-coated products. There has been a lot of debate around that. Connie Hess presented nice data of over 400 deaths with only 3 missing patients, so there was a small number of missing cases, which is a little number of missing data there. After careful inverse probability weighting, it showed that there was no mortality difference, benefit or harm, of these drug-coated products. It’s a large data set. In fact, the upper confidence interval excluded the lower confidence interval that was seen in the prior meta-analyses. Although it was not randomized, there was certainly no signal for mortality and no trend over time.
What is interesting is that these devices were designed to improve long-term patency and reduce the need for index limb revascularization. What we see is there is a benefit for that, and the benefit is reasonable and durable through 3 years. These devices improve patency, and when you layer them on top of rivaroxaban, you see that the benefits are consistent respective to whether it’s a drug-coated product or a non-drug-coated product. There’s a further reduction in the need for index limb revascularization as well as acute limb ischemia and other things that the devices don’t modify.
One take-home message might be that you obviously have to personalize for each patient, but this combination of device and drug—a pharmaco-invasive approach—may be optimal for some patients in reducing the need to come back to the lab and reducing those hard outcomes in MACEs [major adverse cardiovascular events] and MALEs [major adverse limb events] that we’ve seen both in the VOYAGER-PAD trial and the COMPASS trial.
Deepak Bhatt, MD, MPH: Those are great comments. Manesh, I’ll turn back to you for your quick thoughts on the whole issue of paclitaxel and lower-extremity intervention. It is always important to investigate safety signals when they are displayed, and I would never want to diminish any concern. Likewise, in general, a lot of the PAD interventional literature is not as robust as the pharmacotherapy trial that you and Marc were involved with. The trials like the VOYAGER-PAD trial are oftentimes relatively modest trials or registries that get peripheral devices approved. I was underwhelmed by the safety signal with paclitaxel all along. Sure, with first-generation drug-eluting stents [DESs], there was coronary stent thrombosis concerns with DAPT [dual antiplatelet therapy] duration; it made sense. Yes, you could have stent thrombosis and an MI [myocardial infarction] perhaps, but it seemed odd. Why would paclitaxel in the leg be killing people? It seemed that there was the question of how that could be causal. I have been suspicious of that all along. What is your take on this whole issue? It’s been controversial. Some health care systems have even said, “These things are more expensive. We’re going to pull them.” What are your thoughts?
Manesh Patel, MD: Deepak, that is a great point, and this is an area where, unfortunately, the science and our emotions—what I call the nonrational brain—kicks in. The FDA and clinicians had PTSD [post-traumatic stress disorder] from paclitaxel in the coronary time. With first-generation DESs, we embraced them, and we then saw leg stent thrombosis. We said, “Oh my gosh, we’ve got to use DAPT longer.” In fact, one could argue that we learned a lot of our prolonged DAPT lessons from there.
There was then a meta-analysis, published in the Journal of the American Heart Association, that demonstrated a statistically significant increase in mortality from the drug-coated products, but there was no limb risk and no causal identification of how you would have an increase in mortality. It was several small device trials with differential follow-up, as best we could tell.
From the VOYAGER-PAD trial with the work of Marc, Connie Hess, and many others, I feel fairly comfortable that we do not see that risk with drug-coated products in a much larger study. Patients were not randomized to get it or not, but it was certainly following patients who got drug-coated devices with these thrombotic therapies. We see a reduction in reintervention, which is almost like a positive control.
We see the effects of the drug-coated products in that it reduced reintervention, but there was no mortality signal. And in an adjudicated trial, there was no limb signal. That should make people feel comfortable about the use of drug-coated products. We’re on to generation 2 and 3 now, so that may help us too. The entire story is important because it tells us that we should commit to getting long-term follow-up in our patients even in small device trials. That would be 1 of the lessons because that would help us avoid these kinds of concerns.
Deepak Bhatt, MD, MPH: Yes. That’s useful for our audience because it has been a controversial point. There has been a lot of media coverage of that issue.
Transcript Edited for Clarity