FDA to investigate safety of stents, balloons coated with paclitaxel

The U.S. Food and Drug Administration is investigating the safety of certain stents and medical balloons coated with the drug paclitaxel following publication of a wide-ranging study that documented a surprising increase in the risk of death two years after the devices were used above the knee.

Paclitaxel acts as an anti-inflammatory agent when applied to medical devices for reopening clogged blood vessels. These "drug-eluting" devices are intended to prevent vessels from reclosing, which is a risk when using the same devices without drug coatings.

But a systematic review of past randomized controlled trials of paclitaxel devices to open blocked vessels in the legs found that after two years, the death rates were markedly higher in the paclitaxel patient cohorts as compared to control groups that got the same treatments for peripheral artery disease without paclitaxel.

The review, published in the Journal of the American Heart Association in December, found that in 12 clinical trials with two full years of data, the paclitaxel group had a 7.2 percent risk of death from any cause, while the non-paclitaxel patients had a 3.8 percent risk of death from any cause. In three studies with five-year outcomes, there was a 14.7 percent risk of death following paclitaxel-device use vs. 8.1 percent in the control patients.

No definitive explanation has been offered about potential biological causes of the phenomenon. Paclitaxel has long been used as a chemotherapy agent, and no similar finding has been reported in oncology literature.

On Thursday, amid the longest federal government shutdown in U.S. history, the FDA announced that it was opening an investigation into paclitaxel devices used to treat peripheral artery disease in the femoropopliteal artery in the leg. The investigation will consider data from a wide array of sources and will look at factors like doses and individual patient characteristics to see if there are differences in clinical outcomes.

The FDA's letter to physicians does not recommend doctors and patients stop using paclitaxel-containing devices in the legs. Rather, the agency says the benefits of using approved devices continues to outweigh the risks when used in accordance with their labeled indications.

In total, the study in the American Heart Association journal examined 28 randomized controlled trials of paclitaxel-containing devices published between 2008 and 2018. The studies were conducted on devices made by Cook Medical, C.R. Bard, Spectranetics, B. Braun, Biotronik, Medtronic, Boston Scientific and others.

Two ongoing clinical trials of drug-coated balloons have been stopped because of the study's findings. The BASIL-3 trial, testing paclitaxel peripheral-artery devices in the United Kingdom, was halted last month and remained on hold Thursday. Also, the SWEDEPAD study of paclitaxel vascular devices in Sweden was halted because of the study and remained on hold Thursday.

Medical device executives told investors at a health care conference earlier this month that they have already examined their internal data, and they have not found support for the conclusion offered in the journal article. Medtronic officials said they plan to publish their data and discuss their findings at medical meetings in coming weeks.

Boston Scientific spokeswoman Timette Nevala said via e-mail that the company, which employs thousands of Minnesotans, welcomes research and analysis intended to improve patient care.

But the study, she said in her e-mail, "is a meta-analysis that looked at top-level mortality rates across studies featuring paclitaxel-eluting drug-coated balloons and stents. While thought provoking, this meta-analysis did not take into account patient-level data and pathology results that directly link paclitaxel to all-cause mortality. We remain committed to our drug-eluting technologies and believe that endovascular treatment using paclitaxel is safe and effective and represents a substantial improvement for patients over non-drug-eluting technologies."

"At Medtronic, we are the only commercialized drug-coated balloon that has data presented out to five years, and we have been very transparent in reporting our safety and efficacy," Dougherty said. "This meta-analysis includes our previously published findings on the all-cause mortality rate across our trials, which have gone through independent clinical events committee analyses that determined that no deaths were related to IN.PACT DCB or paclitaxel" studied out to one year."

Dr. Konstantinos Katsanos, lead author of the journal article, said via e-mail Thursday that the FDA's investigation was a welcome development for public trust and patient safety.

"I and my team have been in touch with regulatory authorities early on," he said. "I also take the opportunity to implore the industry to provide open, transparent and unrestricted access to anonymized patient-level data of the randomized controlled trials and relevant post-market patient registries so that interested scientists and health care professionals can take a deep dive into the data sets."

Dougherty said Medtronic has been in touch with the FDA and will continue to provide the agency with additional information. The FDA has access to Medtronic's patient-level safety data.

Both Medtronic and Boston Scientific plan to present their patient safety data at the LINC meeting next week in Leipzig, Germany.

In the meantime, the FDA's letter reminded doctors and device makers to report any adverse events with the devices to the FDA's public MAUDE database of medical device problems and to discuss with patients the potential risks and benefits of paclitaxel devices and other treatments during clinical decisionmaking.