The safety of paclitaxel eluting stents and drug-coated balloon catheter was first brought into question by a meta-analysis published in Journal of the American Heart Association in December 2018. That analysis showed a higher mortality rate at two years post-procedure and prompted the U.S. Food and Drug Administration (FDA) to release its first warning letter on the subject. At that time, the agency asserted that the benefits of paclitaxel-coated devices outweighed the possible risks when used as indicated, but more data was needed. In August 2019, the FDA released an updated MedWatch Alert after reviewing long-term follow-up clinical data. The agency said five-year results from three randomized trials showed an increased mortality rate in patients treated with these devices compared to those treated with uncoated devices. While these data provide reason for caution, the FDA noted that the devices still provide documented short-term benefits.
A whole day of discussion at the Transcatheter Cardiovascular Therapeutics (TCT) 2019 conference FDA town hall meeting was devoted to presentations and debate about the safety of paclitaxel. Discussion centered on the clinical data to date, what is being done to gather more clinical information to prove or disprove any safety signals, and what hypothesis could be agreed on for how this signal appeared in the first place. No agreement could be found by the panel because there is no single issue identified as to what might be causing increased mortality.
Several experts on the panel discussion raised questions if this was an anomaly in the data caused by chance. Some suggested the data may be skewed by up to 25 percent of trial participants being lost to long-term follow-up and only the sickest patients remaining in the study cohorts.
Cardiovascular Research Foundation (CRF) CEO Juan F. Granada, M.D., who was heavily involved in DCB development, said he questions if there is an actual safety concern because there is no smoking gun connecting deaths across several trials to any particular cause. He said paclitaxel from the device does not appear to be causing any specific issues elsewhere in the body.
Others said the cause could be related to factors such as the combination of other drugs patients are taking and possible reactions with the paclitaxel. Others said it appears to be just a random coincidence, since there are no specific factors linking any of the deaths.
However, efforts are underway to gather additional data from Medicare to see if there are any patterns in care or drugs used in the patients who died. Also, questions have been added to new and ongoing trials for other paclitaxel-eluting devices that should offer more information from at least 16,000 patients in the next couple years.
One of the late-breaking trial presentations at TCT shed additional light on the issue. It was an independent analysis of Lutonix 035 DCB patient-level data showed no statistically significant mortality increase. This was one of the first major reviews of trial data for patients who were treated with a paclitaxel coated device used in peripheral vessels since the safety issue was first raised.
“As a peripheral operator that has greatly enjoyed the revolution in technology and the reduction in stenosis with the use of drug-eluting balloons in the lower extremities, a lot of us were ver saddened to here that drug-eluting balloons might be related to some type of systemic mortality risk, But mechanistically, it has never made sense to me that a lower-dose elution of paclitaxel from a balloon could somehow systemically cause some sort of mortality signal, explained  Chandan Devireddy, M.D., cath lab director at Emory University Hospital Midtown, associate professor of medicine of interventional cardiology at Emory University, and chairperson for the Society of Cardiovascular Angiography and Interventions (SCAI) Communications Committee.
“But, looking at the LEVANT data for the Lutonix balloon, there does not appear to be that mortality signal, and that data goes out five years, hopefully this will bring that whole armamentarium of drug-eluting balloons back onboard with a new degree of comfort. This study shows there is data supporting the safe use of these devices,” Devireddy said.