Medical device makers Medtronic PLC and Boston Scientific Corp. said this week that they are not backing away from drug-eluting devices used in blood vessels in the legs, despite an analysis in a respected publication linking the devices to a significantly increased risk of death.
The Journal of the American Heart Association (JAHA) published a study-of-studies last month that found a higher risk of death after devices to open vessels above the knees in the legs were coated with a specific anti-inflammatory drug called paclitaxel.
"Further investigations are urgently warranted," the study authors concluded after synthesizing the results of 28 randomized controlled trials of stents and drug-coated balloons used above the knee in the legs.
The devices studied in the data review, called a meta-analysis, include some of the most talked-about new vascular products offered by major Minnesota device makers, including Medtronic's IN.PACT Admiral drug-coated medical balloon and Boston Scientific's Ranger drug-coated balloon. Boston Scientific's Eluvia drug-eluting stent also contains paclitaxel.
In presentations to investors this week at the J.P. Morgan Healthcare Conference in San Francisco, executives with Medtronic and Boston Scientific said they have looked deeply at their own internal data and cannot find support for the higher death rates documented in the JAHA article.
"We've generated a ton of clinical evidence: 1,800 patients, we have data out to five years, randomized controlled study for the U.S., randomized controlled clinical study for Japan, global registry data. And all of these data have been analyzed. We have not seen this safety signal in our data," Medtronic Cardiac and Vascular Group President Mike Coyle told investors Monday. (Those data are likely to be published in coming months, he said.)
On Tuesday, Boston Scientific Global Chief Medical Officer Ian Meredith said meta-analyses like the paclitaxel-device study in JAHA sometimes reach findings that are not borne out in later studies.
Meredith also noted that the broad, study population-level data offered no explanation for the potential mechanism behind the deaths.
"I think at this stage, good clinical studies are appropriate," Meredith said. "There does not seem to be a plausible mechanism to understand how a dose that is imperceptible in plasma or tissue at 30 days could actually really affect mortality two years and beyond."
Reached via e-mail Wednesday, lead study author Dr. Konstantinos Katsanos of Rion, Greece, stood by the findings of the analysis.
"I do understand the skepticism of the industry, but at the end of the day, the statistical signal is too strong to be ignored by reasonable doubt," Katsanos wrote.
Doctors have used skinny balloons and metal tubes to open blood vessels around the heart for decades. When early studies showed these devices allowed quick re-closure of the vessels, drugmakers applied the chemotherapy drug paclitaxel to the devices to tamp down inflammation and reduce re-closure.
More recently, these same types of devices are being used on blocked vessels in the legs to treat conditions like peripheral artery disease (PAD), which can lead to limb amputation if severe enough.
Sometimes doctors use only a tiny balloon to open the femoropopliteal artery in the leg and coat it with paclitaxel. In other cases, a springlike metal stent coated with the drug is left inside the vessel permanently. These devices for the leg are often coated with paclitaxel.
The JAHA study looked at randomized controlled trials published since 2011 that included the experiences of 4,663 patients in studies of devices made by Medtronic, Boston Scientific, Cook Medical, C.R. Bard, Spectranetics, Biotronik, and others.
For the 12 studies that had at least two years of data, the meta-analysis found rates of death were the same between device and non-device patients for the first year after implant, but a "dramatically" higher rate of death among the paclitaxel-device group at two years post-implant.
The all-cause death rate was 7.2 percent for the paclitaxel-device group, vs. 3.8 percent for the control group at two years. The handful of studies with five years of data found the same enhanced risk among the paclitaxel-device patients.
"The authors consider the herein reported findings of particular concern because most of the interrogated devices have already received clearance by regulatory authorities and are currently under routine clinical use," the report in JAHA said.
Boston Scientific's Meredith noted that oncologists have more than two decades of experience with paclitaxel as a chemo agent, at much higher doses than is present on a stent or balloon, and have found no similar increased risk of death.
The JAHA report notes that whereas paclitaxel for chemo is solvent-based and has a half-life of about six hours, the paclitaxel on medical devices has a half life of weeks to months.
New Jersey vascular surgeon Dr. David O'Connor, who has done research and promotional talks for device makers, said he doesn't see the medical community moving away from these paclitaxel-containing devices. That's because proven risks like vessel closure and amputation still outweigh the long-term theoretical risks described in the JAHA study.
"With the alternative of not using these drug-eluting technologies, the trade-off would be a higher incidence of the vessel re-blocking over time," O'Connor said, "which can lead to amputation, or a need for another procedure, or a more complicated procedure."
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