Year in Review: Endovascular Saw Paclitaxel Storm Rage, CLI Care Advance in 2019
A widely-criticized meta-analysis led to town halls and FDA advisory meetings, with no resolution of the mortality signal.
The meta-analysis suggesting a higher long-term risk of death for patients with PAD treated with paclitaxel-based balloons and stents, which exploded on the scene late last year, continued to dominate in 2019. Twelve months later, the issue remains far from resolved despite a year full of in-depth poking and prodding at the safety signal, as well as reassuring analyses from observational data across the globe.
“My team and I have to admit that we have been overwhelmed by the response, and by the sort of crisis that has developed over this whole story,” Konstantinos Katsanos, MD, PhD (Patras University Hospital, Rion, Greece) told TCTMD. “One thing that has come out of this is that the quality and the depth and the breadth of the randomized evidence that we have in peripheral vascular disease has been very shallow compared to cardiology or other fields of medicine. So, we had to grow up very quickly in our field, that's for sure. I think everybody has had a crash course in modern evidence-based medicine.”
In mid-January, the US Food and Drug Administration issued the first of three letters to physicians referencing the meta-analysis and updating their efforts to evaluate the mortality signal. Soon after that, a Medicare analysis of 16,560 patients who underwent femoropopliteal artery revascularization showed no evidence of increased mortality compared with non-drug-coated devices through about 20 months of follow-up. A second Medicare analysis with a heavily critical limb ischemia (CLI) population also found no increased mortality out to 2 years.
In June, an FDA advisory committee held a 2-day meeting that debated all aspects of the controversy including the potential for paclitaxel to be toxic, what role the dose of paclitaxel on the device may play, and how the controversy should be addressed with patients. They also heard from the individual sponsors of the RCTs about efforts to reconcile missing and incomplete data, an ongoing theme in the paclitaxel story. In August, the agency said it was working with the device manufacturers to change labeling to include information about the mortality signal.
“Regardless of whether someone believes or not in the toxic effect of paclitaxel, if anything, we should become more open and more transparent with the current evidence and I still think that this has not really happened,” Katsanos observed. He added that by keeping the RCT data under protected silos, “nobody from the public and no independent scientists have access to all the numbers and data.” To date, only Cook Medical has offered its de-identified patient-level data from the Zilver PTX trial to researchers and others who wish to review it. To TCTMD, Katsanos contended that if other companies had followed their lead, it “would have been a major precedent for the level of science and academia in peripheral vascular disease.”
In addition to the Medicare analyses, more real-world data from the German BARMER health insurance database, which found no evidence of a mortality signal in nearly 65,000 patients treated with paclitaxel-based devices compared with plain old balloon angioplasty (POBA) or uncoated stents.
Looking toward what the future may hold for the paclitaxel debate, Katsanos said while he does not think that data from the administrative databases are of high enough quality to convincingly change opinions on paclitaxel, important information could come from the two trials that were briefly halted in the immediate aftermath of the publication of his meta-analysis. They have since resumed.
“I think the major next step is going to be the Basil-3 and the SWEDEPAD studies, because those are very large randomized studies that have a vested interest, by design, in paclitaxel,” Katsanos said.
Sahil A. Parikh, MD (NewYork-Presbyterian/Columbia University Irving Medical Center, New York, NY), agreed that there were some positives in the paclitaxel story. One of those, he said, was the coming together of researchers, industry, and regulatory authorities to identify as many of the patients lost to follow-up as possible. “The percentage of patients now lost to follow-up is in the low single digits, down from as high as 25% at this time last year,” he said. “If there is any silver lining, it's that there's been much cross collaboration, which hopefully will herald a new era in endovascular therapy.”
While paclitaxel was by far the biggest story of the year in the endovascular field, Parikh pointed to some other notable news, including the publication of global vascular guidelines for managing patients with chronic limb-threatening ischemia (CLTI).
“It identified a few different pathways for how we should take care of these patients,” he noted. “Specifically, there is a planning stratification, a vascular anatomy assessment based on angiographic parameters, and there's a planning algorithm for which target vessel you're going to try to open or bypass. It's quite comprehensive.”
Also on Parikh’s list:
- A study showing high safety and low complications in a large series of patients undergoing retrograde tibioperoneal access for peripheral chronic total occlusions. “I think it’s the definitive clinical data set to date on that approach,” he said.
- A case series on the tibiopedal arterial minimally invasive (TAMI) technique for patients with advanced PAD who cannot tolerate standard femoral artery access.
- A substudy of the COMPASS trial looking at major bleeding associated with rivaroxaban and aspirin in patients with CAD or PAD that found most of the bleeding occurred early and was not severe.