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Ischemic stroke devices offer hope amidst more failed clinical trials


By Larry Haimovitch

Medical Device Daily Contributing Writer

February 21, 2014

SAN DIEGO – The French say that “plus ca change, plus c’est la meme chose” which translates to “the more it changes, the more it is the same.” This may be the best way to characterize the seemingly unending disappointing progress that is endemic in the world of stroke.

After attending this year’s International Stroke Conference, which is sponsored by the American Stroke Association (ASA; Dallas) this expression seems to be especially apt, with several more failed clinical trials. Indeed, this statement could have been said for each of the past several stroke meetings with failed trials dominating the news.

The most visible trial failure reported here was the Field Administration of Stroke Therapy—Magnesium Phase 3 Clinical Trial (FAST-MAG). This trial, which enrolled 1700 patients between 2005 and 2012, tested whether intravenously administered magnesium, which is believed to be a neuroprotective agent, could be delivered in a timely manner (i.e., within two hours of stroke symptom onset) and could impact the neurological outcome of acute ischemic stroke (AIS) patients.

The FAST-MAG trial results revealed that administration of IV magnesium was safe but did not confer any benefit in neurological outcome, as measured by the 90 day modified Rankin Score.

The “silver lining” of this study is that it demonstrated that up to 75% of stroke patients calling emergency services early can be started on treatment in the first "golden hour" after their stroke symptoms emerge. The median time for receiving treatment in this study was 45 minutes, with 74% of the patients being treated in one hour.

At an ASA press conference, Bruce Ovbiagele, MD, Medical University of South Carolina (Charleston) said that "This opens up a whole new arena for us to test other promising new therapies in the pre-hospital setting. The FAST-MAG study shows it is feasible — it can be done. This is the big message from this study."

The ability to get patients treated quickly is certainly encouraging to the stroke community, where today, 18 years after its FDA approval, the thrombolytic clot-busting drug tissue plasminogen activator (tPA) is still very underutilized. A study presented here, based on 370,000 Medicare stroke claims in 2011, found that only 4% of patients receive tPA and a miniscule 0.5% had endovascular therapy. This dismal treatment rate is occurring despite the fact the number of stroke centers in the U.S. has doubled in the past five years (now approaching 1000 in total) and that 80% of the U.S. population lives within an hour’s drive of a stroke center.

With each passing year, the stroke community is increasingly recognizes that “time is brain” and that reperfusion therapy has to be delivered in a timely way. Indeed, a detailed analysis of the large International Management of Stroke III (IMS III), trial, which failed to meet its primary endpoint, showed that for every 30 minutes that pass until angiographic reperfusion, the probability of good recovery after an ischemic stroke is decreased by about 10%. Moreover, there is a 5% increase in mortality for every hour that treatment is delayed.

Although acute ischemic stroke accounts for roughly 85% of all strokes and represents an enormous opportunity, the current market size of the AIS endovascular device market is paltry compared to the hemorrhagic stroke market. Specifically, the more mature hemorrhagic stroke devices market (coils, stents, flow diverters, liquid embolics and access catheters) generates approximately $1.1 billion in annual global revenue while the embryonic but faster growing AIS device market, generates global sales of only about $200-250 million annually.

One of the key advantages of endovascular devices over tPA is that tPA’s efficacy diminishes rapidly with time. In addition, its FDA label requires that it be used within 4.5 hours of stroke onset. Conversely endovascular techniques often can provide benefits far beyond that 4.5 hour window. Most devices are labeled for use of up to eight hours and some neuro-interventionalists have reported that they have achieved reperfusion in certain AIS patients for up to as much as 24 hours.

The enormous market opportunity for acute stroke therapy has not gone unnoticed, with several large device companies actively involved. Stryker Corp. (Kalamazoo, Michigan) has gained the number one position in the global market with three key acquisitions, the $1.5 billion purchase of the Boston Scientific (Natick, Massachusetts) Neurovascular division in 2010, the $135 million purchase of Concentric Medical (Mountain View, California) in 2011 and the $135 million acquisition of Surpass Medical (Tel Aviv)

Medical Device Daily estimates that the Stryker Neurovascular division currently generates annual global revenue of approximately $475 million, giving it a market share of about 35%.

Stryker Neurovascular is actively involved in several AIS device trials and hopes to begin a large global trial dubbed DAWN by mid-year, randomizing its Trevo XP thrombus removal device to tPA alone. DAWN is a global trial that will enroll up to 500 patients at 50 sites.

Stryker introduced the Trevo XP clot retriever at this meeting, highlighting its ease of placement and delivery and excellent visualization. It also claims to have larger clot capture area than competing clot retrievers.

The Vascular Therapies division of Covidien PLC (Dublin, Ireland) is also a very active player in the neurovascular market, growing both internally and from an aggressive acquisition program. In July 2010, it acquired ev3 Inc. (Plymouth, Minnesota) for approximately $2.6 billion. Prior to that, ev3 Inc. had acquired Chestnut Medical (Menlo Park, California) for $150 million in June 2009. In January 2012, Covidien purchased the distal access guide catheter product line from Reverse Medical (Irvine, California) for an estimated $35 million and in July 2012 it acquired MindFrame Medical (Irvine, California) for $75 million.

Medical Device Daily estimates that Covidien’s neurovascular business generates annual global revenue of about $450 million, giving it a market share of about 33%.

Covidien is actively involved in the ischemic stroke market, with several studies underway. The company claims to be investing over $30 million annually to fund its various endovascular clinical trials. The most notable is the SWIFT PRIME study, which is a randomized multicenter prospective trial that will compare AIS patients with large vessel occlusions treated with either tPA alone or in combination with Covidien’s Solitaire 2, Solitaire FR,  and/or Solitaire RD clot retrievers. This trial will enroll up to 833 patients at up to 90 sites around the world and will assess how these two approaches affect stroke disability, mortality and functional independence.

Impressive results for Solitaire FR in Covidien’s STAR study were reported in the August 1, 2013 issue of Stroke. This trial enrolled 202 patients at 14 centers in Europe, Canada and Australia and demonstrated excellent neurological outcomes. The trial was not randomized but is purported to be the largest multicenter trial of mechanical thrombectomy devices to date.

In addition to the SWIFT PRIME trial, which addresses the need for a randomized, prospective and multi-center trials for ultimate credibility, privately-owned Penumbra (Alameda, California) is engaged in the THERAPY trial which began enrollment about one year ago. Approximately 300 patients will be enrolled in each arm and the trial is expected to take about take about three years to complete. This trial is designed to assess the safety and effectiveness of the Penumbra mechanical thrombectomy catheter system as an adjunctive treatment to tPA in patients with an acute ischemic stroke from a large vessel occlusion (LVO).

At last year’s meeting, Pooja Khatri, MD, associate professor of neurology at the University of Cincinnati, stated that tPA alone is ineffective when the stroke is caused by an LVO, specifically clots in excess of 8 millimeters long. The hypothesis of THERAPY is that the addition of a mechanical thrombectomy device in patients with a large clot burden (i.e., clot length in excess of 8 mm) can improve the clinical outcome of the patient over using tPA alone.

The THERAPY trial is using Penumbra’s recently introduced ACE  “next generation” reperfusion catheter, which uses direct aspiration alone to extract the clot. ACE is the latest addition to Penumbra’s line of mechanical thrombectomy devices and has a much larger lumen size than previous devices, which allows the neuro-interventionalist to engage the clot quickly, aspirate and remove it without the need for any other adjunctive devices.

Blaise Baxter, MD, from the Erlanger Health System (Chattanooga, Tennessee) reported here on a study using direct aspiration at six U.S. centers.  There were 43 patients treated with ACE and adjunctive therapy, 97% of these patients achieved an impressive thrombolysis in cerebral infarction (TICI) score of 2b/3, In addition, 81% achieved TICI 2b/3 with aspiration with ACE alone and no other adjunctive products. The rate of perfect revascularization (TICI 3) in the ACE sole therapy patients was 62%. Most importantly, 55% of the ACE treated patients had a good to excellent neurological outcome (mRS 0-2) at 90 days.

The ACE device is also showing that it achieves its reperfusion success much faster than competing clot retrievers, saving precious time for the neuro-interventionalist and their team.

As a final note, it is crucial that these aforementioned prospective randomized clinical trials are completed in a timely way and demonstrate both safety and efficacy. At a Covidien well-attended evening symposium titled “The SWIFT PRIME and Clot 3 Studies: Advancing Systems of Care and Treatment of Acute Ischemic Stroke,” Hans Christian Diener MD, a noted stroke specialist from the Department of Neurology, University of Duisburg-Essen (Essen, Germany) reviewed some of the failed stroke trials, provided his thoughts on the lessons learned and a roadmap to future success. This is summarized in the following table.

Lessons Learned from Recent Endovascular Stroke Trials

•Patient selection is critical--Randomize all eligible patients, confirm presence of large vessel occlusion with CT or MR angiography

•Revascularization is necessary--Treat with the latest generation devices (i.e., stentrievers)

•Time to reperfusion is crucial

                                                                    Source: Hans Christian Diener MD

2014 International Stroke Conference

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