Conference spotlights treatment options for acute ischemic stroke

By Larry Haimovitch

Medical Device Daily Contributing Writer

March 3, 2010

SAN ANTONIO – The annual International Stroke Conference, sponsored by the American Heart Association (AHA; Dallas) was held here last week. One of the key topics here was the ongoing issue of how and when to treat an acute ischemic stroke (AIS). This remains an extraordinary challenge to the stroke community.

According to the AHA's "Heart & Stroke Statistics 2010 Update" AIS accounts for 691,000 (87%) of the estimated 795,000 new or recurrent annual strokes in the U.S. While there is a plethora of crucial and unanswered AIS treatment questions, two of the most pressing ones are: (1) What is the appropriate time "window of opportunity" to treat a stricken patient; (2) What approach (drugs, device or combination) should be employed?

When the thrombolytic agent tPA was first approved for intravenous (IV) use by the FDA in 1996, it was cleared for use only within the first three hours after first onset of the AIS. With myriad challenges, too many to detail here, the number of patients actually receiving the drug is abysmally low.

At last year's meeting, Peter Sandercock, MD, of the University of Edinburgh Western General Hospital (Edinburgh, Scotland), presented data from an analysis of 600,000 stroke patients in the U.S., showing that a paltry 2% of these patients received tPA within the three-hour time window.

At an evening symposium here titled "The Stroke Circle: When Does the Window Close," moderator and highly-regarded stroke neurologist Anthony Furlan, MD, of Case Western Reserve Medical Center (Cleveland) estimated that despite "overwhelming success" with the 600 accredited primary stroke centers in 49 states in the U.S., less than 5% of stroke patients today are receiving tPA.

The results of the European ECASS III trial showed that tPA administered between three and 4.5 hours after the onset of symptoms provided significantly improved clinical outcomes. These data, which were published in an article in the Sept. 25, 2008 issue of the New England Journal of Medicine, have resulted in important new AIS treatment guidelines.

The European Stroke Organization (ESC; Heidelberg, Germany) now recommends that tPA can be given up to 4.5 hours after stroke onset, even though the drug's European label still prescribes a three-hour limit. Boehringer Ingelheim (Ingelheim, Germany), the distributor of tPA in Europe, has initiated a process to get the drug's label updated to reflect the ESC's recommendations.

In the U.S., the AHA has altered its guidelines to mirror the ESC's. However, it is important to note that the "official" FDA labeling for tPA yet remains at 3 hours.

The ongoing issue persists – what to do when the patient is beyond the 4.5 hour window, particularly given that time to treatment is a critical variable in the patient's outcome. According to Furlan, the other key considerations are age (less than 70 year-olds do far better), a relatively normal CT scan with modest neurological deficit when treated and the absence of other serious co-morbidities such as hypertension, diabetes and heart failure.

In recent years, the search for safe and effective AIS therapies beyond tPA's efficacy slot has evolved rapidly toward endovascular, intra-arterial (IA) approaches. According to Osama Zaidat, MD, an interventional neuroradiologist from The Medical College of Wisconsin (Milwaukee) who spoke at the evening symposium, device-based approaches can be categorized into two broad categories: (1) Mechanical clot retrievers and aspirators; (2) Mechanical clot disrupters, such as stents and balloons, which restore blood flow by widening the vessel.

The former category includes the Merci Retrieval System developed by Concentric Medical (Mountain View, California) and Penumbra (Alameda, California), which markets the Penumbra System. Both companies have attained both FDA and CE mark approvals and appear to be enjoying robust growth. Furlan estimated that about 7,200 IA interventions were performed in the U.S. in 2009 and he pegged the market potential at more than 40,000 procedures per year.

An informal survey by Medical Device Daily suggests that this number may be conservative. Indeed, a poster discussing hospital AIS practice patterns concluded that IA procedures are "higher than expected" and that they may be "entering broader practice, perhaps ahead of available evidence."

Both companies clot retrieval catheter-based devices have been approved to restore blood flow in large vessel occlusions but their efficacy in improving stroke outcome has been less obvious. For example, while the pivotal Penumbra trial demonstrated a solid 81% target vessel recanalization rate and a good safety profile (less than a 3% procedural serious adverse event rate), its benefit in improving the functional outcome (indicated by the mRS or modified Rankin scale at 90 days) was surprisingly low at 25% (29% in patients with successful recanalization). This raises a fundamental question: does successful recanalization lead to a positive functional recovery?

In response to this issue, Penumbra management wisely undertook a post-marketing trial aptly called POST, a multi-center "real world" look at the use of their system. These results were initially presented in July 2009 at the Society of Neurointerventional Surgery (Fairfax, Virginia) annual meeting.

Data was collected on 157 consecutively treated patients at seven academic and community-based international stroke centers, with 90-day follow-up data collected on a forward looking basis. The primary endpoints were the achievement of improved revascularization (as measured by the TIMI score) and serious adverse events, with the key secondary endpoint of an improved mRS score.

Excellent revascularization, as measured by TIMI scores was achieved in 87% of patients, versus 81% in the pivotal trial, with 41% (vs. 25% in the pivotal) showing a better mRS score. The safety profile was fairly comparable in both trials.

According to Penumbra literature, POST showed that "there appears to be a link between high revascularization rates and a high rate of good clinical outcomes, perhaps driven by improved patient selection."

In an effort to further understand which acute stroke patients will benefit most from interventional therapeutic procedures Penumbra launched the START (Stroke Treatment And Revascularization Therapy) trial in October 2009. Patients in this open-label, prospective, single arm, multi-center outcome trial of severe, large vessel ischemic stroke must be enrolled less than eight hours from symptom onset. To date, 19 patients have been treated.

One session at the meeting, titled "Intravenous vs. Intra-Arterial Therapy for Acute Ischemic Stroke" discussed the pros and cons of both approaches and exemplified the divergent views within the stroke community.

The differing results of IA therapy may be due to several factors, including the device's actual performance capabilities, operator skill and experience, size and location of the clot, the patient's neurological condition at the time of intervention, time to treatment etc.

Another example of discrepancies was seen in a poster titled "Failure of Mechanical Clot Retrieval to Affect Poor Outcome Associated with Large Thrombus Burden." This fairly small trial, which used the Merci clot retriever in some patients, concluded that using Merci worsened their outcomes.

Conversely, other posters and presentations strongly supported its use. For example, an analysis of the results in over 600 patients in the still ongoing Merci post-approval registry, which also intends to reveal "real world" experience post-approval, were impressive with recanalization rates and favorable neurological functional improvements.

Important information on this topic was shown at a late breaking poster called "Untangling The Mystery Of Poor Clinical Outcomes Despite Excellent Recanalization: Analysis Of Data From The Penumbra Pivotal Stroke Trial." This poster provided a subset analysis of the data and helps to explain why its 81% recanalization rate produced a mediocre 25% neurological improvement.

Carefully analyzing the data, the authors from the Calgary Stroke Center (Calgary, Alberta,) showed that if patients were carefully selected, as measured by their pre-treatment CT assessment and treated relatively quickly (under five hours), they had dramatically better neurological outcomes.

Specifically, for patients who were treated within five hours and had a good ASPECTS score, which assesses early ischemic changes, they achieved a very impressive 77% improvement in their mRS score. The authors concluded that "proper patient selection based on initial NCCT (i.e., minimal/modest ischemic damage) and faster recanalization are essential in achieving good clinical outcomes . . ."

Speaking to MDD at the poster, Arani Bose, MD, Penembra's founder and chief medical officer, remarked that the message from this analysis is that "we need to treat the living [brain], treat the sick [severe strokes] and treat them quickly."

By far the most important IA trial underway is the Interventional Management of Stroke Study Part III (IMS III), a huge multi-center, randomized 900-patient study, sponsored by the National Institutes of Health (Bethesda, Maryland).

The study, which began in August 2006, is randomizing patients to one of two treatment arms – IV tPA or a combination of IA and IV tPA. The latter arm will be using various FDA-approved clot aspiration or disrupter devices, including Penumbra and Merci.

Its primary endpoint is neurological function at 90 days, with several secondary endpoints evaluating both safety and efficacy. Begun over three years, IMS-III has enrolled about 350 patients to date at 43 sites in three countries.

The results of this landmark trial, which are not expected to be released for at least three more years, are eagerly awaited by the stroke community. Perhaps it will finally resolve or mitigate some controversy in the stroke community about how best to manage AIS patients.

2010 International Stroke Conference

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