More Real-world Data Support Safety of Paclitaxel-Based Devices in PAD

NEW YORK, NY—Six-year follow-up data from Italy show no increased risk of death in patients with femoropopliteal artery disease treated with paclitaxel-based devices compared with those who received plain old balloon angioplasty (POBA), a researcher said here at VEITHsymposium 2019. A second presentation, from a Japanese registry, refuted the suggestion that paclitaxel-treated patients are at higher risk for amputations.

It has been nearly 1 year since the meta-analysis by Konstantinos Katsanos, MD, PhD (Patras University Hospital, Rion, Greece), sent the endovascular community into a tailspin by suggesting increased long-term mortality with paclitaxel-based balloons and stents. Since then, most major medical meetings have devoted sessions to the paclitaxel safety question. VEITHsymposium 2019 was no exception, with a dozen presentations addressing a variety of issues from unexplained toxicity to regulatory concerns and future research needs.

"Our data did not show any signal of increased mortality in patients treated with paclitaxel eluting device for lower limb atherosclerotic disease in a real-life patient-level analysis," said Francesco Liistro, MD (San Donato Hospital, Arezzo, Italy).

From Italy

Liistro’s group performed a propensity-score-matched analysis in 440 patients who received POBA and 414 who received a paclitaxel device (35% DES in each group). The majority of patients in both groups were Rutherford class 5. There was no difference between groups in the use of anticoagulants, beta-blockers, statins, or ACE inhibitors/angiotensin-receptor blockers.

As Liistro showed, there was no difference in mortality at 6 years, with 73.9% survival in the paclitaxel group and 71.6% in the POBA group  (log-rank P = 0.146). Looking only at patients with claudication, 6-year survival again was the same in the paclitaxel and POBA groups (90.7% vs 84.6%; log-rank P = 0.246).

I would be really careful about questioning the validity of randomization as a whole concept. Konstantinos Katsanos

Among the main causes of death, the most common was cardiac followed by cancer and sepsis, all of which occurred at similar rates in both treatment groups. Interestingly, in an analysis of survival free from new neoplasia, the paclitaxel group appeared to have a significant advantage relative to the POBA group (95.5% vs 91.4; log-rank P = 0.001).

Liistro said he believes the anticancer properties of paclitaxel may account for the lower risk of neoplasia. However, he said further dedicated studies looking at this issue may be warranted.

The Italian analysis also included the death rate by cumulative paclitaxel dose in order to account for patients who may have had additional paclitaxel-based treatments in the same or the other leg. Survival at 6 years was approximately 72% whether patients were in the lowest (30.9 ± 17.66 mg) versus the highest percentile of paclitaxel dose (343.8 ± 200.39 mg; log-rank P = 0.88).

The 6-year data are in agreement with recently published findings from the large BARMER database analysis from Germany, which has the longest follow-up to-date, a median of 7.6 years.

From Japan

The Japanese analysis, presented by Osamu Iida, MD (Kansai Rosai Hospital, Hyogo, Japan), addressed concerns raised by Katsanos in a presentation at TCT 2019 that paclitaxel-based devices were associated with higher rates of leg amputation as compared with POBA in randomized trials. Fewer than 10 trials involving paclitaxel-based devices, however, have reported amputation data. In a presentation at VEITHsymposium, Katsanos reiterated that while the number of events is small, there is a “consistent trend towards more major and minor amputations in the case of paclitaxel,” adding that this should be taken “with a grain of salt, of course, because those are very, very rare events and the statistical finding is a little bit unstable.” His analysis for major amputations was based on data from LEVANT 2, IN.PACT SFA, ZILVER PTX, LEVANT 1, and THUNDER. For minor amputations, his data were from ILLUMENATE EU, ILLUMENATE Pivotal, and CONSEQUENT.

Iida presented data from the ongoing RADISH study, which included 281 patients with chronic limb-threatening ischemia treated at one of five Japanese hospitals with or without a drug-coated balloon (DCB). In an interim analysis at 6 months, rates of wound healing and amputation-free survival were similar in the DCB and non-DCB groups. While some researchers paused recruitment of trials involving paclitaxel-based devices after publication of the Katsanos meta-analysis, Japan did not follow suit and its regulatory agency has made no specific announcement regarding concern over the use of paclitaxel-based devices, Iida noted.

Real-world Data in the Hotseat

The emphasis on mining real-world data in an effort to understand whether the mortality signal from the randomized data is real has been an ongoing effort for months, but also a point of contention because of the myriad of differences between RCT and observational populations. Speaking here, Katsanos said the signal in the randomized data from his original meta-analysis remains undisputed, even if the relative risk has decreased slightly as more data have been recovered, and he cautioned against trying to explain the signal away with uneven comparisons.

“We have to be really careful here because we are going to end up undermining the foundation of evidence-based medicine, which is randomization. Randomization by design in a prospective way will take out most of the confounding,” he observed. “I would be really careful about questioning the validity of randomization as a whole concept.”

"We're not doing that at all,” responded Andrew Holden, MBChB (Auckland Hospital, New Zealand). “I would never challenge the patency results that those trials showed. But I do challenge the fact that they were totally underdesigned for mortality,” he said. “That is where the populations studies are real. Because the one thing they are powered for is mortality.” It also would be inappropriate, added Holden, to “undermine” the importance of population studies involving “ thousands of patients with very high sensitivity that have failed to show a [mortality] signal.”