At the 2014 VEITHsymposium, Thomas Zeller, MD, presented on the multicenter randomized controlled IN.PACT DEEP trial, which compared paclitaxel-coated balloons with uncoated balloons and which failed to show benefit for the drug-eluting balloon. Vascular Disease Management spoke with Dr. Zeller about the study’s results.  

Q: Could you describe for us the impact deep study objectives and the outcomes?

A: The aim of the study was to evaluate the technical and clinical outcomes comparing the first commercially available drug-eluting balloon for below-the-knee application to plain balloon treatment in CLI patients. Patients with Rutherford IV, V, and VI disease were enrolled, and the study was designed so that all the patients that had been included in the study went into the clinical endpoint analysis. A subcohort of patients with a lesion length of less than 10 cm treated was analyzed in an angiographic cohort in which the technical success, meaning late lumen loss at 12 months, was the primary endpoint. 

Q: And could you describe the study results?

A: Very unexpectedly, the study results were negative in that there was no technical benefit. Late lumen loss and restenosis rates were identical in both cohorts. This resulted in the equivalent relatively low target lesion revascularization rates in the range of 10% to 15% in both study cohorts and this was disappointing due to the former experience communicated and published in two single-center studies in Italy and in Germany in Leipzig where the benefit of the drug-coated balloon angioplasty had been shown treating lesions either with the drug-eluting Amphirion balloon (Medtronic) or with the bare balloon, and essentially the same drug-eluting balloon was also used with the IN.PACT DEEP trial, so at the end we had seen no biological effect of the release of the drug into the vessel wall, which could mean that the drug was not effectively released. 

The second finding was that even though the cohorts did not significantly differ in terms of safety endpoint, which was a noninferiority endpoint, there was a trend toward more major amputations in the DEB cohort as compared to the plain balloon cohort and this raised the safety issue, obviously, and resulted in withdrawal of the technology from the market in Europe by Medtronic as a consequence. 

Regarding what the message is from this trend toward major amputations, I personally believe that in looking at the old data coming from my side where we have seen more amputations with DEB that, except for 1 patient, the other 4 that had major amputations are easily explained by the initial condition of the patient that was randomized into the study. So, it remains unanswered whether the drug caused this trend toward major amputation or if this was just by chance. It’s worth it to mention that the study was not powered to such an endpoint analysis regarding major amputation.

Q: Are there any other reasons you think that the results were negative?

A: If you compare two different treatments and they end up with the same technical outcome, you cannot expect that there is a difference in terms of clinical efficacy. So the key question is basically, why did we get those completely different outcome results regarding efficacy with the DEB below-the knee? On one hand, we had the single-center studies, the one from Leipzig and the other one was a single-center randomized trial, both clearly showing that there was a difference in favor of DEB. On the other hand we saw no difference in the global study and this is something that is hard to explain. No one has done it so far. What we do know is that the coating technology with the Amphirion DEB is different from the Medtronic In.Pact balloons offered for above-the-knee application. Those balloons are coated in an expanded state and then the balloon is re-folded so that at least about 60% to 70% of the drug is within the balloon folds, and the Amphirion balloon was covered in a deflated state, meaning that all the drug was located on the outside of the balloon folds, but this does not explain the different outcomes between the single-center trials and the global study.

Q: What could this tell us for future studies? Should something be done differently?

A: Definitely. I believe that in the future we will not go directly into a clinical endpoint-driven study to explore the efficacy of drug-eluting devices in CLI patients, simply based on the trend toward a higher amputation rate in the DEB cohort in IN.PACT DEEP. We need to perform a stepwise approach to explore these new technologies. First you do an independently controlled feasibility study to look at the technical efficacy of the new technology in a patient cohort without wounds, meaning claudication or patients with rest pain, and this should be powered to a technical endpoint like late lumen loss or restenosis. If this study does confirm that the DEB or whatever kind of device is superior to the test device, then you move into a large-scale clinical endpoint study, which is then always easier to run because you do not need to ask those patients to come back for angiography. 

Q: So in your opinion, what do you think the most important take-away message is from the results of this study?

A: This individual balloon that was tested in the IN.PACT DEEP trial did not perform as expected, resulting in the lack of clinical benefit in this particular study. But this taught us that every single new device needs to be evaluated specifically so that there is definitely no device or class effect. So each individual drug-eluting balloon needs to be evaluated in this indication independently and you cannot assume that outcomes from one study will translate to another. 

Thomas Zeller, MD, is professor of angiology at Albert-Ludwigs University of Freiburg and head of the Department of Angiology at Universitäts-Herzzentrum Freiburg in Bad Krozingen, Germany. Dr. Zeller reports advisory board membership with and grant funding from Medtronic as well as grant funding from Abbott, Cook, Bard, Gore, St. Jude Medical, Biotronik, B. Braun, and Spectranetics.