New Stroke Prevention Device May Not Prevent Strokes

–There’s no hard evidence the Sentinel Cerebral Protection System reduces stroke in TAVR.

Here’s how to get a second generation medical product or add-on product approved: show that the original device isn’t nearly as safe and effective as believed back in, you know, the dark ages before the new product showed up. Until now proponents of TAVR have sought to emphasize the benefits of TAVR and have downplayed its negative aspects, including stroke.

Now, with the approval of an add-on device for TAVR that may help prevent some strokes, these same TAVR supporters are emphasizing the stroke risk. Martin Leon (Columbia University), a top TAVR advocate, said in a press release for the new device that “anything we can do as clinicians to reduce the risk of brain injury is extremely meaningful.”

On Monday the FDA approved the Sentinel Cerebral Protection System. In a press release the manufacturer of the device, Claret Medical, said it is “the first and only embolic protection device shown to reduce TAVR procedural strokes by 63%.” The device is designed to reduce the incidence of stroke in the aftermath of a TAVR procedure.

But there are a few big problems the company did not exactly highlight in its press release. The device has not been proven effective and, although stroke is certainly a serious complication of TAVR, until now the actual rate of stroke associated with TAVR has been reported to be much lower than the company stated in its press release.

Sentinel therefore joins the growing list of cardiac devices that have been approved but for which there is no or extremely limited evidence showing that they work. These include the Watchman, the Absorb bioresorbable stent, the Impella heart pump, PFO closure devices, and catheters to open chronic totally obstructed arteries.

TAVR and Stroke

The Claret Medical press release exaggerated the significance of stroke in TAVR patients. “Recent studies have found that almost one in 10 patients experience a clinically-apparent stroke due to the procedure.” But the source for this statistic is their own clinical trial, in which they went looking for evidence of stroke. Like a baseball field of dreams, in the field of medical devices if you build it they will come. But outside their own field of dreams, in the real world, the numbers are quite different. As Sanjay Kaul (Cedars Sinai) observes, the stroke rate is much lower in real life: “The 30-day stroke rate of 9.1% in the control arm appears to be much higher than what is observed with contemporary newer-generation TAVR devices such as SAPIEN 3 (2.7%).” Of course no one would want to discount stroke as an adverse event, but a rate of one in 10 is a lot worse than a rate of one in 37.

Robert Yeh (Beth Israel Deaconess) thinks the high rate is reasonable, though it includes minor strokes that might not be caught in normal clinical practice. He said that the high stroke rate in the control arm was a result of the trial’s design, which included detailed stroke assessments. “This is a very sensitive (albeit probably accurate) definition of stroke.”

Questions About Effectiveness

More importantly, there’s no solid evidence that the device actually reduces the risk of stroke.

In the press release Leon broadly endorsed the benefits of the device: “The 63 percent reduction in clinical strokes in the first 72 hours after TAVR, combined with the fact that one in four patients had an average of 25 particles of debris collected that were visible to the naked eye, is striking. The device was delivered safely, added minimal time to the procedure, and performed as intended with capture of embolic material and reduction in ischemic brain injury.”

But Leon neglected to mention the single most important fact about the trial: it failed to meet its primary effectiveness endpoint. There was no significant difference in the size of new lesions in the brain. Instead Leon focused exclusively on the secondary or post-hoc endpoints.

A major problem is that the small number of strokes in the trial means that it is impossible to draw any firm conclusions about the effectiveness of Sentinel. There were only 23 strokes in the trial, only 3 of which were disabling.

Here are the details: The overall stroke rate was 9.1% in the control group versus 5.6% in the Sentinel group. But this was based on 10 events in 110 patients in the control group versus 13 events in 231 treated patients. These numbers are very small and did not come close to statistical significance (p=0.25). Even worse, the numbers are driven almost entirely by nondisabling strokes. There were 9 nondisabling strokes in 110 control patients versus 11 nondisabling strokes in 231 treated patients. For disabling strokes— the most important thing you want to prevent— there were only 3 events, 1 (out of 109) in the control group versus 2 (out of 231) in the treatment group. No difference whatsoever.

‘Reasonable People Will Argue’

Given the clinical importance of stroke, the absence of any other available treatment, and the lack of any safety concerns, FDA approval was not unreasonable, said two cardiologists who were asked to comment. Sanjay Kaul (Cedars Sinai) said that “reasonable people will argue” whether the results provide “the ‘reasonable assurance’ statute for device approvals, even for a Class II device.”

Yeh said that approval of the device “looks fair to me based on biological plausibility, direction of effect of the major endpoints (namely stroke), the fact this is not a long term therapy or a permanent implant, but just a device that supports another procedure, and the low risk of harm.”

Yeh concluded that “1) there probably are a fair amount of minor strokes after TAVR. This is probably true for SAVR as well. 2) Using a sensitive definition of stroke helps the company. 3) It’s probably fair to use the sensitive definition of stroke here since it is considered the gold standard, and also, going full circle, if it were me, I would want to avoid those very minor strokes in addition to the larger clinically obvious ones.”

The good news, in my opinion, is that the device appears to be safe. It’s unlikely that patients will be directly harmed by the device (except for the added cost, of course), and it is for this reason that the FDA went ahead and approved the device. But there’s a very dangerous and very steep and slippery slope here. Now that the device is on the market it may well be impossible to prove whether or not it is effective. Next generation devices will only need to prove that they are equivalent to Sentinel. An entire industry could develop based on a safe but ineffective device.

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