Catheter Kerfuffle: How Concerning Is Off-Label Use in Stroke Interventions?
The FDA sent a reminder to doctors clarifying that not all catheters are cleared for aspiration. But experts say comfort and safety should be considered.
Amid growing interest in interventional stroke treatments, some questions have recently emerged regarding the use of various catheters for aspiration thrombectomy that aren’t approved for that purpose. But is it really a big deal clinically, or is it simply an issue generated by a battle over market share in this booming area?
Only one company makes catheters that are cleared by the US Food and Drug Administration (FDA) for thrombus aspiration in acute stroke—Penumbra—but other manufacturers make similar devices that have been cleared as guide catheters (also called intermediate or distal access catheters) for the purpose of delivering additional devices into the vasculature of the brain.
Neurointerventionalists, who have become accustomed to using devices in an off-label fashion due to the lack of dedicated devices in their field, tend to use what they feel comfortable with. That means some of these other catheters get used for aspiration.
“It’s a balance between patient safety and outcomes versus allowing people to practice the way they feel is in the best interest of the patient,” Ashutosh Jadhav, MD, PhD (University of Pittsburgh, PA), told TCTMD. “We, as a community, need to be pretty protective of operator autonomy, assuming it’s within the constraints of patient outcomes and safety.”
Manufacturers, on the other hand, are allowed to promote their products for approved indications only. In March, after receiving a “complaint alleging regulatory misconduct,” the FDA sent a letter to healthcare providers clarifying that even though both aspiration and guide catheters are cleared through the 510(k) premarket notification program, there are different review processes and intended uses for the two types of devices.
Neurovascular thrombus retrieval catheters are indicated for “restoring blood flow or removal of thrombus within a blood vessel in the brain during an acute ischemic stroke within 8 hours of symptom onset in patients who are ineligible for or fail intravenous tissue plasminogen activator [tPA] therapy.” By contrast, neurovascular guide catheters are indicated for “introducing interventional devices into the neurovasculature or as a conduit for retrievers.” A higher bar in terms of evidence is typically required for the approval of a thrombus retrieval catheter, specifically “clinical performance data” as needed, in addition to bench and animal testing. On the other hand, neurovascular guide catheters are often cleared primarily on the basis of bench performance data, with animal or clinical data typically not required.
The complaint “made the agency aware that marketing materials from multiple companies imply a new intended use for some neurovascular guide catheters for neurovascular thrombus removal in patients with acute ischemic stroke,” FDA spokesperson Stephanie Caccomo told TCTMD in an email.
In its “dear doctor” letter, the FDA noted that it has received a “small number of adverse event reports” stemming from use of a guide catheter for removing a clot, including one case involving vessel perforation that ultimately led to death from a large subarachnoid hemorrhage.
But some neurointerventionalists interviewed by TCTMD said that this is not really a clinical issue, as there is not much difference in performance between the catheters—regardless of labeled indication—when it comes to using them for aspiration either alone or in conjunction with stent retrievers. Instead, the issue is seen more as an attempt for Penumbra to protect its market share in an increasingly competitive stroke market.
Much of the recent evidence supporting endovascular stroke therapy has been centered on use of stent retrievers, but aspiration thrombectomy has been used for years and there is some evidence—from the ASTER trial reported earlier this year, for instance—showing that aspiration as a first-line approach provides similar rates of successful reperfusion when compared with stent retrievers.
Penumbra has positioned itself as the leader in the aspiration field. In an equity research note, Wells Fargo analysts estimated that Penumbra controls 90% of the aspiration segment of the US stroke market, with off-label use of other catheters making up the remaining 10%. They projected that Penumbra’s share could drop to 84% this year and 75% by 2020, although they predicted that the FDA’s letter would slow that “erosion.”
Penumbra’s CEO and President Adam Elsesser declined to say in an interview with TCTMD whether his company was behind the complaint filed with the FDA—“I don’t know how to specifically answer that question,” he said—and stated that the FDA letter has not had a major impact on business. “What is, obviously, best for the company and, more importantly, best for patients is just continuing to make better and better products,” Elsesser said.
One neurointerventionalist interviewed by TCTMD, Aquilla Turk, DO (Medical University of South Carolina, Charleston), suggested that companies may be purposely getting catheters cleared through the less-rigorous review process for guide catheters with the intention of later having them used in an off-label fashion for aspiration thrombectomy.
“I’m not aware of the FDA ever putting a letter out like this before, that was quite so direct, so clearly there’s a big issue at hand,” said Turk, principal investigator of the Penumbra-sponsored COMPASS trial comparing the ADAPT strategy (direct aspiration first pass technique) with stent retrievers. “I think that the FDA is trying to slow the tide of everybody trying to rush to market with guide catheters through a fast approval process and then using them in an off-label fashion as aspiration catheters.”
TCTMD contacted three major manufacturers of guide catheters—MicroVention, Stryker, and Medtronic—for reaction to the FDA letter, and, as expected, representatives of each company said that they only market their products in the United States for indications that have the green light from the FDA.
The agency would not disclose which companies were being referenced in the letter, but at least some of the marketing materials mentioned came from Medtronic. In an email, company spokesperson Andrew Cormack told TCTMD that marketing materials that included comparisons between their Arc intracranial support catheter and one of Penumbra’s Ace catheters “were in the context of delivering intravascular devices, which is the cleared indication for Medtronic's Arc catheter. However, Medtronic has voluntarily discontinued use of those materials to avoid any confusion about the cleared indication for the device.”
What’s the Difference?
Physicians interviewed by TCTMD indicated that there might not be much of a difference in terms of performance between Penumbra’s catheters and guide catheters from the other companies.
“Penumbra makes great catheters, and they’re effective for intracranial work for doing thrombectomy as a standalone device or as an adjuvant device,” Donald Heck, MD (Novant Health, Winston-Salem, NC), said.
But he pointed out that the catheters manufactured by the other companies are constructed similarly, can be delivered intracranially, and have been shown to maintain their integrity under aspiration. “So in that sense they would at least in theory perform similarly to a device that has been shown to be safe for that purpose,” Heck said, adding that he tends to use other companies’ catheters for aspiration adjunctively with a stent retriever.
“Obviously there’s proprietary differences in how the catheters are constructed,” Heck said, adding that “they’re very similar from a performance perspective.”
Turk said the guide catheters in question have physical characteristics that show they are clearly made for the purpose of performing aspiration—ie, there’s very minimal support and the catheters are made to track easily to the distal vasculature.
“So the quick easy way for some of these companies to kind of short circuit the system is to [say] we’re going to get a very quick, easy approval for a guide catheter, but it’s really an aspiration catheter if you look at . . . what its physical constraints are,” Turk said.
Penumbra’s catheters are “very good,” said Mary E. (Lee) Jensen, MD (University of Virginia, Charlottesville), who added, however, that the devices from the other manufacturers are similar. “They’ll all tell you why theirs is better than the others,” she told TCTMD, “but the practical matter is, you hand me any of these catheters and I can get the job done.”
Indeed, both Jadhav and Turk pointed out that published series indicate that it’s safe and effective to use these non-Penumbra devices for aspiration.
In its letter, the FDA raised the possibility that guide versus aspiration catheters could differ in terms of safety and performance, noting that the devices have differences in length, diameter, and material stiffness. Thus, the agency said, use of a catheter without an indication for aspiration could potentially result in device failure and serious adverse events like vessel damage, perforation, or dissection.
Jadhav acknowledged those potential complications, but said that he’s not aware of any data showing that aspiration-related events are more frequent with catheters used in an off-label fashion. “At least with the [catheters] that are commonly being used right now, there’s been no data that they’re unsafe in that scenario,” he said. “There are theoretical complications with any of these catheters whether they’re indicated for aspiration or not.”
And Jensen said, “I am unaware either in the literature or through what I hear from my colleagues that there is one system that is consistently causing higher complication rates than other systems.”
Comfort and Cost Come Into Play
With little difference in performance, physician preference and cost seem to be main drivers of the choice of one catheter over another.
“In this space, people end up using what they’re comfortable with,” Jadhav commented, noting that there is a roughly equal split between Penumbra and other catheters used for aspiration in his practice.
Jensen agreed that physician comfort was the main determinant of catheter choice, saying that she has a go-to system that she uses for nearly all cases, which allows her to perform the procedures as quickly as possible. “It’s good to know what’s available to you, but if you don’t get comfortable with one system, I think then you really never get comfortable,” she said.
But cost may influence the decision, as well. Turk confirmed that the Penumbra catheters are currently more expensive than catheters from other companies.
One particular way cost could become a consideration is if companies package their intermediate or guide catheters together with their stent retrievers and then charge less than if the devices are purchased separately, Heck said. That might cause operators to choose products available packaged together over others, assuming they perform similarly, he added. On the other hand, if the operator believes one device is better than another, then he or she will choose that one, even if there is a higher cost.
Jadhav pointed out that a lot of physicians don’t directly interact with the cost of the devices they’re using, making it hard to quantify how much that is affecting catheter choice. But, he said he thinks cost will start becoming more of a consideration in the future.
When asked about the impact of cost on decision-making, Jensen said that no one system has such a low cost as to be clearly better than another.
“What I tell the reps is, if I have a system that I’m comfortable with and you want me to switch, one of two things has to happen: either it has to work as well as the current system and be cheaper or it has to substantially outperform the current system,” she said. Otherwise, she said, “I usually just stick with what I’m using.”
Heck noted that in addition to physician comfort and cost, catheter size is also involved in decisions about which device to use. Penumbra’s catheters, he said, come in a wider variety of sizes, whereas the other companies’ devices might come in just one size.
Off-Label Use and the Practice of Medicine
All of the neurointerventionalists interviewed by TCTMD said that they use or have used non-Penumbra catheters for aspiration in an off-label fashion in at least a proportion of their cases.
“The FDA does not regulate the practice of medicine, which is why we are allowed to use devices off-label,” Heck said. “I think the FDA understands that physicians have wide latitude in choosing which devices they wish to use to [provide] the best care for the patient that they can. I don’t think there’s any problem with that. If there were safety concerns, then yeah, [but] people use off-label devices all the time.”
Turk put it in a historical perspective, pointing out that physicians in the neurovascular field have often had to use devices designed for cardiology in an off-label fashion because nothing else was available.
Heck noted a similar phenomenon in the field of peripheral interventions. “Almost all the stents that we used for stenting iliac arteries and superficial femoral arteries and things like that were approved for biliary disease,” he said.
Jadhav said off-label use of devices can also be a source of innovation as physicians try new things. “This is a field that’s relied on innovation,” he said. “If you limited what people use for what purpose, probably the field wouldn’t advance very well.”
He argued for the need for flexibility when making decisions about patient care, using indications for aspiration catheters and stent retrievers to illustrate his point. Although both types of devices are approved for removing clots in patients with ischemic strokes, some stent retrievers also have indications for reducing disability.
“It raises the question, should we only use stent retrievers because they’re the only devices that FDA has given on-label indication for reducing disability? Or should we allow operators to have more flexibility in the tools that they use,” assuming they’re getting good results without any safety concerns? he said. Innovation can be stifled if physicians are constrained too much, but it makes sense to take a step back if safety issues arise, he added.
Jadhav gave another example—tPA for acute stroke—to support flexibility in physician decision-making. The therapy is indicated for use within 3 hours of stroke onset, but it is commonly used up to 4-and-a-half hours after symptom onset because of data and guidelines supporting that approach.
“We like the flexibility of being able to use tPA in the 3- to 4-and-a-half-hour time window if we think it’s appropriate for the patient. We like the flexibility of being able to use an aspiration catheter over a stent retriever. And similarly, I think many people in their practice enjoy being able to use some of these guide catheters for aspiration,” he said. “These are all situations that are debatable, but I think that there’s good rationale to avoid being too constrained.”
FDA. Neurovascular thrombus retrieval catheters and guide catheters used during neurological interventional procedures: differences in FDA review and intended use—letter to health care providers. Published on: March 1, 2017. Accessed on: June 15, 2017.
- Turk reports consulting for and owning stock in Penumbra; serving as the chief medical advisor for and owning stock in The Stroke Project; and serving as principal investigator of the Penumbra-sponsored COMPASS trial, which compares aspiration with stent retrievers.
- Heck reports consulting for Stryker and receiving investigator payments from Penumbra for the Separator 3D trial.
- Jadhav and Jensen report no relevant conflicts of interest.