The Vascular Leaders forum 2019, a special consortium organized by VIVA Physicians, featured experts who addressed questions raised by the meta-analysis of paclitaxel-eluting devices by Katsanos and colleagues. An afternoon session delved into mortality outcomes, CEC, and internal evaluation of trial data, with Michael Dake, MD, beginning the session by addressing errors in the Zilver PTX data published in Circulation.
Dr. Dake explained that after reviewing data in the wake of the Katsanos meta-analysis, researchers identified errors in the 5-year Zilver PTX publication. Due to a clerical error, there was an incorrect patient flow diagram submitted during the final stages of the publication process, and mortality numbers were transposed in the overall primary randomization comparison in the narrative text.
Corrections were published in Circulation on February 19, 2019, but Dr. Dake assured the audience that the correct data were used in all global regulatory submissions and presentations, with the incorrect data only present in the 5-year Zilver PTX publication. Dr. Dake then further analyzed the Katsanos study, pointing out that its conclusions were not based on patient-level data.
He described how patient-level analysis of randomized control trial and Japan data reveal no increase in long-term mortality risk with Zilver PTX compared with PTA and bare-metal stent. Additionally, the conclusion of no significant difference is supported by covariate analysis. “These rates were consistent with the rates reported in the literature for PAD patients,” said Dr. Dake. He added, “Cook continues to be committed to working with regulatory authorities and independent physician-led groups to evaluate safety using patient-level data.”
William Gray, MD, continued the discussion with an analysis of patient safety in the Eluvia drug-eluting stent and Ranger drug-coated balloon, though he noted that the data available at this point in time are more limited than those shown by Dr. Dake.
Dr. Gray explained that mortality rates with Eluvia were not greater than contemporary rates observed with non-drug-coated devices. Regarding Ranger, he stated that 3-year mortality in the randomized RANGER SFA study did not differ between the paclitaxel and non-paclitaxel-treated arms. An analysis of patient-level data showed similar causes of mortality for both paclitaxel and non-paclitaxel-treated patients.
Following Dr. Gray, Kenneth Rosenfield, MD, discussed the Lutonix DCB Clinical Program, which includes over 200,000 patients worldwide and approximately 5,000 patients in clinical trials. The program has an established track record of safety, and there are been no mortality signals identified thus far, Dr. Rosenfield noted.
He summarized the safety findings by stating that the plasma paclitaxel is rapidly cleared with no detectable drug at 24 hours. “Clinical studies show no difference in mortality between DCB and PTA,” Dr. Rosenfield said. “The other studies performed elsewhere (Levant, Japan, and in-stent restenosis randomized studies) also confirm that there was no statistical significance in deaths at 24 months. Finally, the global registry and the longer lesions…showed pretty low death rates, comparable at 24 months as compared to the literature,” he said.
Next, Peter Schneider, MD, discussed the IN.PACT Admiral DCB, which is a large, independently adjudicated cohort of patients treated with the same device for femoropopliteal disease. “Mortality rates across the IN.PACT studies are in line with reported rates from other endovascular device trials of similar patient populations,” he stated. He explained that deaths in the IN.PACT SFA trial were adjudicated as not being device or procedure related. He concluded, “The results, I think personally, demonstrate long-term safety. And I also think there was no relationship between the dose and mortality, another helpful piece of information.”
Sean Lyden, MD, described a similar organizational structure for the Stellarex Clinical program, with all studies featuring an independent CEC adjudication of adverse events in which no death was determined to be related to the device or procedure.
In their analysis confirming safety, Dr. Lyden and colleagues found that Stellarex RCT data demonstrate low mortality rates through three years, with the DCB group comparable to one of the largest PTA cohorts. In the 2,274 patients treated in the Stellarex clinical trials, there were no device-related deaths. “This independent, third-party, pooled analysis of patient-level data confirms and reinforces the safety profile of the Stellarex DCB,” said Dr. Lyden.
Robert Lookstein, MD, closed out the session with an examination of DCB usage in arteriovenous (AV) fistula. AV access typically has poor rates of patency and a variety of technologies, including DCBs, have been used to improve outcomes. Reviewing the literature, Dr. Lookstein noted that the field is early in the global experience of evaluating DCBs for this purpose, with only two studies with outcomes out to 24 months.
Dr. Lookstein was the principal investigator for the IN.PACT AV Access trial, and he pointed out that there is high incidence of hypertension, diabetes mellitus, and congestive heart failure among the patient population. “This is likely the sickest demographic that we will study this technology in as we move this science forward,” he said.
He further elaborated on considerations for AV access, including that it is normal for patients to have repeat interventions in one year, that the drug is delivered directly to the pulmonary circulation, and that it is unknown how the drug behaves in the setting of venous hypertension and right heart failure.
Overall, epidemiologic data suggests a control mortality rate of over 30% at 24 months. The only safety data from the first independently adjudicated trial does not demonstrate concerns, noted, and the second trial will also record safety data out to 24 months. “This particular population demands a very different perspective, not the least of which is where the drug is being delivered, out of concern about safety for this very different target circulation, and this very different demographic,” concluded Dr. Lookstein.