Medical Device Daily Contributing Writer

NEW ORLEANS — We know that a strong cup of coffee or two will provide us with a temporary surge of energy. And, we know that a glass or two of wine or beer or a shot of spirits will provide a feeling of relaxation for a time. So, what effect would be produced by an intravenous infusion of the caffeine equivalent of four to six cups of strong coffee, combined with the ethanol equivalent of two drinks?

It is safe to say that you probably did not guess "neuroprotection." If you did, you must have attended last week's International Stroke Conference at the Ernest N. Morial Convention Center here.

In the world of stroke, the term neuroprotection, which is derived from the Greek and Latin roots that means "saving nerve cells," has been one of the Holy Grails in this field.

There has been a longstanding notion that neuroprotection, administered within hours after the onset of an acute ischemic stroke (AIS), could preserve precious brain tissue until adequate blood supply could be re-established, either through spontaneous or therapeutic recanalization or via collateral blood flow. While great in theory, the concept has failed miserably under clinical investigation.

According to an article titled "Acute Ischemic Stroke Treatment in 2007," published in the Sept. 25, 2007, issue of Circulation, "There have been published reports of more than 1,000 experimental neuroprotective treatments for acute stroke … with more than 100 coming to clinical trials. To date, none has proved efficacious."

At this meeting, Sheryl Martin-Schild, MD, a neurovascular fellow at the University of Texas Health Science Center (Houston), presented a small human study that showed that the combination of caffeine and alcohol, called caffeinol, in intravenous combination with tissue plasminogen activator (tPA), reduced brain damage, enhanced neurological recovery and proved to be safe to use. In this feasibility trial, only 10 patients received the combination therapy, compared to 90 patients who received just tPA.

Responding to a question at a press conference, Martin-Schild admitted that "we have no idea why this regimen worked" and said that a larger, randomized controlled trial would be necessary to firmly establish safety and efficacy. She indicated that researchers at the University of California San Diego were in the midst of designing such a trial but no starting date was indicated. Patients will be randomized prospectively into two arms, tPA alone or tPA in combination with caffeinol.

Showing that caffeinol is versatile, Martin-Schild also presented data on a trial for a combination of caffeinol and mild hypothermia, which showed that there is a positive benefit of combining the two modalities. A prospective, multi-center placebo-controlled Phase II trial had been designed to test the efficacy of caffeinol, hypothermia or both within three hours after an AIS.

Another drug trial discussed at a news conference here was Genentech's (South San Francisco, California) TNKase, generically tenecteplase. This agent is a bioengineered variant of tPA, remaining in the blood stream longer and attaching itself to fibrin, a protein that is involved in the clotting process. It was FDA-approved in June 2000 for the treatment of an acute myocardial infarction.

Researchers from Spain compared tPA to TNKase and concluded that the latter "did a faster and more complete job of re-opening blocked brain arteries and is associated with better short and long term neurological outcomes." The trial directly compared the two drugs in reopening the middle cerebral artery, one of the three key arteries that supplies blood to the brain and showed a similar safety profile as tPA.

Commenting on this trial, which enrolled 122 patients in a 2:1 ratio favoring tPA, Jeffrey Saver, MD, director of the University of California Stroke Center (Los Angeles) said that TNKase could represent "the next generation of clot-lysing drugs" but that a larger trial would be required to establish its role in treating an acute ischemic stroke.

As the developer of the first and only FDA-approved drug to treat an AIS, Genentech has both prospered from its commercial success but also been frustrated that it is being used in only about 3% of AIS patients. There were numerous presentations throughout the conference that addressed this issue.

One poster, titled "Use of Tissue Plasminogen Activator: Have we Improved," analyzed data from four hospitals in Ssoutheastern Michigan from January 1996 to January 2005.into three distinct time frames. Its discouraging conclusion was that from both the onset of an AIS to delivery to the emergency room to arrival at the hospital to actual treatment had not improved over the nine-year period studied in that geographic area.

Conversely, a more positive poster titled "The Impact of Improved Hospital Reimbursement on National Rates of tPA Use," noted that in 2006 reimbursement for tPA infusion was doubled and a new DRG code 559 was introduced. National tPA use increased 60% over a two-year period, although the rate of utilization was still a paltry 3% of potential cases.

Even more dramatic results were shown in a poster titled "Increasing Thrombolytic Treatment Rates: Results Utilizing Revised Treatment Criteria and a Multidisciplinary Stroke Education Program," with data generated at California Pacific Medical Center (San Francisco).

The authors hypothesized that a comprehensive education program, coupled with a rapid stroke triage system, would permit safe thrombolysis and therefore substantially boost the current "dismally low" level of tPA use.

Indeed, this hypothesis was borne out, as nearly 24% of all patients were treated after implementation of these initiatives. Note that the patients treated included both IV and intra-arterial therapy. The authors proudly noted that despite treating a very elderly population, safety outcomes were equal to other centers.

Another successful approach to increasing tPA use was presented in a poster titled "Safety and Feasibility of 'Drip & Ship' Paradigm in Patients Transferred to a Tertiary Care Center with Acute Ischemic Stroke." The drip and ship strategy essentially initiates tPA therapy during the patient's initial visit to their local hospital and continues it through to a transfer to the tertiary care center. The authors, from the University of Minnesota (Minneapolis), concluded that transport to a tertiary care center should not delay the initiation of intravenous tPA and was a safe and effective protocol.