Recent disappointing stroke studies are sapping sector’s momentum

By Larry Haimovitch

Medical Device Daily Contributing Writer

February 19, 2013

HONOLULU — In the sports world, the term “wait ‘til next year” is frequently used to describe a team that has had a disappointing outcome and yet is optimistic that things will be better in the future.

After attending this year’s International Stroke Conference, this expression seems to be especially apt. Indeed, this could have been said for each of the past several years, as the field of stroke at times has seemed to be doomed to disappointment and failure.

Ischemic stroke – typically defined as an obstruction of blood flow in the brain – accounts for over 85% of all U.S strokes or about 700,000 per year. Prior to the FDA’s approval of the thrombolytic clot-busting drug tissue plasminogen activator (tPA) in 1996, there was virtually nothing that could rescue the patient from severe neurological damage typically caused by an acute ischemic attack.

tPA’s approval was hailed a watershed event for the treatment of ischemic stroke. Despite an attractive therapeutic profile (solid efficacy and a good safety profile) and a tremendous effort by the stroke community to increase its usage, a paltry 5% of domestic patients who suffer from an ischemic stroke today receive tPA.

The major but not sole contributor to this dismal fact is that for maximum efficacy, tPA must be administered within three hours of stroke onset. Many stroke patients either do not arrive at a stroke center quickly enough or are not treated once they arrive in an expeditious manner. Although tPA is now labeled for use up to 4.5 hours its efficacy diminishes with time and this has had minimal impact on its usage. In addition, despite the fact that the number of U.S. stroke has doubled to more than 900 in the past five years, the percentage of patients receiving tPA has barely increased.

Over a decade ago, significant resources were allocated to develop neuro-protective drugs, agents that would minimize the neurological damage caused by the cascade of chemical changes in the brain post-ischemic stroke. Numerous compounds initially displayed very promising animal data and even some hopeful early human data but then failed in larger trials.

There has also been a concerted quest to develop better thrombolytics but this also has been a miserable failure, with several drugs initially demonstrating promising results then stumbling in either a large feasibility trial or pivotal trial.

Fast-forward to the advent of catheter-based endovascular therapy, which initially included mechanical thrombectomy products and then later stent-like clot catcher devices called stent retrievers. This family of products, all FDA-approved under 510(k) protocol, offers a major advantage by extending the therapeutic window to as long as eight hours with acceptable risks and higher rates of efficacy. They often work very well in combination with tPA administered either intravenously or intra-arterially. Several modest-sized trials, albeit non-randomized (without a sham arm), have been encouraging.

A prime example is the Solitaire FR Thrombectomy for Acute Revascularization (STAR) study, whose results were released here last week. The two-year study evaluated the safety and efficacy of the Covidien (Dublin, Ireland) Solitaire FR revascularization device in the treatment of acute ischemic stroke. STAR was a prospective, multi-center, single arm clinical study started with an enrollment of 202 patients at 14 centers across Europe, Australia and Canada.

This device, based on advanced overlapping stent technology, mechanically removes blood clots from blocked vessels and restores blood flow in patients experiencing ischemic stroke. The results were impressive, with excellent neurological outcomes (Modified Rankin Score of 2 or less) and a low level of adverse events. However, this trial was not randomized.

The results of the first ever randomized, multi-center study-evaluating patients with moderate to severe ischemic strokes were reported here last week. This landmark pivotal trial, called the International Management of Stroke III (IMS III), sought to enroll up to 900 patients at more than 50 centers in the U.S., Canada, and Australia. It was funded by the National Institute of Neurological Disorders and Stroke, a part of the National Institutes of Health (Bethesda, Maryland)

Patients were randomized in a 2:1 ratio to receive either intravenous tPA, combined (if necessary) with a choice of a mechanical clot remover, or intravenous tPA alone. If a patient was not successfully recanalized with tPA, the physician could then choose device-based endovascular therapy. Endovascular therapy included a choice of catheters and devices or intra-arterial tPA based on the lesion characteristics, the experience and training of the investigator, and specified the use of only FDA-approved devices.

The trial was halted by the Data and Safety Monitoring Board nine months ago for futility or “a low likelihood of demonstrating the pre-specified clinically significant difference in benefit between treatment arms of the study,” after the enrollment of 656 patients.

At a session here, the principal investigator Joseph Broderick, MD, of the University of Cincinnati said that “. . . we didn’t see a signal of efficacy or better functional outcomes between the two groups.”

The key takeaway message from this trial, which was heavily discussed at this meeting as well as published online by the New England Journal of Medicine concurrent with the meeting, is that it strongly affirms the crucial role of time to reperfusion. While this concept has been well understood with tPA (“time is brain”) for many years, it has now been clearly demonstrated to be equally true for endovascular treatment.

Specifically, a detailed analysis of the trial 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%.

At a press conference, Pooja Khatri, MD, associate professor of neurology at the University of Cincinnati said “I think the big picture is we have to emphasize speed . . . (in) reperfusion therapies.” She went on to say that “It’s clear that the time from stroke onset to the time that thrombolysis begins is critical but what’s not clear is how this time window for tPA relates to the actual restoration of blood flow, or how it applies to endovascular therapies that typically recanalize vessels more frequently than intravenous tPA.”

Another setback reported here was the failure of the Mechanical Retrieval and Recanalization of Stroke Clots Using Embolectomy (MR RESCUE) trial. This study’s primary goal was to show that advanced multimodal penumbral imaging could help select which patients are most likely to benefit from late endovascular therapy

The final results were doubly negative. First, a favorable penumbral pattern did not identify stroke patients who would benefit preferentially from endovascular treatment for up to eight hours after symptom onset. Second, endovascular therapy did not prove to be superior to standard medical care in these patients.

These ongoing trial failures have heightened the hunger in the stroke community for truly randomized endovascular device clinical trials. Two important randomized trials are now in their embryonic phases. The THERAPY trial, sponsored by privately-owned Penumbra (Alameda, California) 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.

Recent clinical research, which was presented here by Khatri, has shown that tPA alone is ineffective when the stroke is caused by a large vessel occlusion, specifically clots in excess of 8 millimeters long. The hypothesis of THERAPY is that the addition of a mechanical thrombectomy device like the Penumbra system 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 just using tPA alone.

Enrollment of this trial, which just recently began, will include both domestic and international sites. According to company officials, there will be approximately 200 patients enrolled in each arm with the trial is expected to take about take approximately three years to fully enroll.

The second randomized trial, called Solitaire FR With the Intention For Thrombectomy as Primary Endovascular Treatment for Acute Ischemic Stroke (SWIFT PRIME), is sponsored by the ev3 Endovascular (Plymouth Minnesota) division of Covidien. Like THERAPY, it will randomize patients to either the Solitaire FR (a stent retriever) or to tPA followed by the Solitaire FR.

Whereas one of the key inclusion criteria in the THERAPY trial is a large clot burden, patients in this trial will be enrolled partially based on their status as suggested by advanced multimodal penumbral imaging. As noted above, the MR RESCUE trial showed that advanced multimodal penumbral imaging was not accurate in identifying patients who could benefit from endovascular therapy.

Enrollment in these randomized trials could prove to be a huge challenge, as these devices are already FDA- approved and patients and their families would rather not be randomized and possibly receive only tPA. The sponsors of the SWIFT PRIME trial, as indicated on the ClinicalTrials.gov website, believe that it could take as long as six years for this trial to be fully enrolled.

In an editorial in the online edition of the New England Journal of Medicine, Marc Chimowitz, MD, a neurologist from the Medical University of South Carolina (Charleston, South Carolina) proposed a solution that the medical device industry will be not happy to accept, a moratorium on reimbursement for endovascular treatment of acute ischemic stroke outside of randomized trials. Chimowitz said that this “. . . would facilitate recruitment in these urgently needed trials. Once the new trials are completed, endovascular treatment will have been given ample opportunity to prove itself.”

2013 International Stroke Conference

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