Penumbra Aspiration Device Safe, Effective for Recanalization in Stroke

Susan Jeffrey

February 28, 2008

February 28, 2008 (New Orleans, Louisiana) -- Results of a prospective, single-cohort, phase 2 study show safety and effectiveness for recanalization of the Penumbra System aspiration catheter in patients with acute stroke due to large vessel occlusion.

Results were presented here at the American Stroke Association International Stroke Conference 2008. The study was funded by Penumbra Inc, maker of the system, and designed by the company in collaboration with the Food and Drug Administration (FDA) to support an approval application; FDA approval for the aspiration device was received by the company in January 2008, when it was judged to be "substantially equivalent" to another currently approved mechanical device, the Concentric Balloon Guide Catheter (Concentric Medical Inc) for the indication of revascularization of patients with acute ischemic stroke secondary to large vessel occlusive disease within 8 hours of symptom onset.

"The device was able to achieve a higher-than-usual rate of recanalization (82%) with a low complication rate, with a range of intracerebral hemorrhages seen after stroke that are compatible with previous studies," said Cameron MacDougall, MD, chief of endovascular surgery at Barrow Neurological Institute, in Phoenix, Arizona, who presented the results here.

Phase 2 Study

The Penumbra System comprises a series of devices, primarily an aspiration catheter, with a distal wire to keep the catheter clear, and a grasping device designed to remove harder thrombus if the aspiration device fails to recanalize the vessel, Dr. MacDougall said.

In this phase 2 trial, 125 patients from 24 international centers with acute large vessel stroke were enrolled if they had failed treatment with intravenous tissue plasminogen activator (tPA) or were not candidates for treatment. Main entry criteria were an National Institutes of Health Stroke Scale (NIHSS) score of 8 or higher, presentation within 8 hours of symptom onset, and an occlusion (TIMI 0 or 1) of a treatable intracranial vessel.

Primary end points were revascularization of the target vessel, defined as TIMI 2 or 3 flow, and the incidence of procedural serious adverse events. Angiographic results were adjudicated by an independent core laboratory.

Mean age of the cohort was 64 years, with a baseline NIHSS score of 17.6 (range, 8 to 34), and a baseline modified Rankin Scale (mRS) of 4.5.

Revascularization of the target vessel was achieved in 82% of patients, all using the aspiration device only, Dr. MacDougall said. In fact, the grasping device was not approved because it was not effectively tested in enough patients in this study, he said.

There were 4 serious adverse events that were deemed to be procedure-related, but not device-related. Of these, 2 events occurred in the same patient; after failure of recanalization with the aspiration device, the investigator followed up with an angioplasty balloon that resulted in a perforation of the vessel and a subarachnoid hemorrhage and a parenchymal hemorrhage.

A third event, a parenchymal hemorrhage, occurred immediately after recanalization and was deemed a reperfusion hemorrhage that again was procedure- but not device-related. The fourth event was a small subarachnoid hemorrhage without hematoma that was felt to be a wire perforation, Dr. MacDougall said.

At 24 hours, intracranial hemorrhage (ICH) was seen in 35 patients (28%), 14 (11.2%) defined by computed tomography (CT) evidence of a bleed and deterioration of 4 points or more on the NIHSS. All-cause mortality was 26.4% at 30 days and 32.8% at 90 days.

Although the trial was not powered to look at clinical outcomes, the researchers reported that a favorable outcome at 30 days, defined as a 4-point improvement on the NIHSS at discharge or a 30-day mRS of 2 or less, was seen in 41.6% of patients. At 90 days, 25% of patients had an mRS of 2 or less. "The trend for a better outcome when vessels were opened was consistently seen across all neurological and functional measures," the authors write.

It is of note that Dr. MacDougall, while he presented the results here, was not the principal investigator for this trial; the trial actually did not have a principal investigator, a situation that he agreed was "odd."

"This was a company-sponsored, company-designed trial, in which the local principal investigators, including myself, did not control the design," he said. Instead, the design was defined through meetings of the company with the FDA, and end points were set comparing outcomes with the original Mechanical Embolus Removal in Cerebral Ischemia (MERCI) trial of the Merci retriever device.

Does Recanalization Equal Better Outcomes?

The approval of another device for revascularization of large vessels on the basis of recanalization in a single-cohort trial, rather than on improved clinical outcomes in controlled clinical trials, again raises the controversial issue of disparate approval processes by the FDA for drugs vs devices in the setting of stroke treatment.

Devices must be shown to be safe and to be effective in what they purport to do — in this setting, recanalizing the stroke-related vessel. Drug approval generally requires 2 studies showing safety and efficacy in phase 3 trials, comparing the drug with a control and looking at hard clinical outcomes.

"This is a prospective, phase 2 single-arm trial, so that's the beginning and end of the story," said Larry Goldstein, MD, from Duke University Medical Center, in Durham, North Carolina, who has written at length on this issue and was not involved in this trial. "The device can apparently remove clots. Whether that leads to better patient outcomes is not proven by this study," he told Medscape Neurology & Neurosurgery .

Although it would seem intuitive that an open vessel is better than a closed one, to date none of the approved devices have been shown in a randomized trial to actually improve outcomes. In the field of cardiology, for example, studies have begun to suggest that late revascularization of established clots may provide no ultimate benefit to the patient. At least 2 ongoing studies have incorporated mechanical clot removal in their trial design — the Interventional Management of Stroke Trial III (IMS III), and the Magnetic Resonance and Recanalization of Stroke Clots Using Embolectomy (MR-RESCUE). .

At a press conference here, Dr. MacDougall agreed there is an imperative for these types of devices, and this device in particular, to be tested in a randomized controlled trial powered to look at clinical outcomes. "That's what we care about, that the outcomes are better. Whether it's through the IMS III or some other mechanism, I think it's very important to get this into randomized trials where we can demonstrate that."

Although his involvement in the development of the Penumbra System is limited to this trial, he noted, "It's my understanding that plans are under way to move toward a mechanism for a randomized trial."

In the meantime, however, session moderator and American Stroke Association program committee chair Philip Gorelick, MD, from the University of Illinois College of Medicine, in Chicago, emphasized the importance of informed consent on this issue.

"Right now, it's exceedingly important that those who are potentially deploying the device have this very frank discussion with family and patients — if they are competent at the time of the stroke — so that they understand there is safety, that stroke is a bad disease that could lead to mortality, and there are potential risks here of using the device. But in terms of definitively showing [whether] the hard stroke outcomes in terms of stroke severity and poststroke function down the road will be improved, we don't really know."

The study was designed and funded by Penumbra Inc. Dr. MacDougall reports no financial disclosure relevant to this presentation.

American Stroke Association International Stroke Conference 2008: Abstract LB 4. Presented February 22, 2008.

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