CDU Contributing Editor

FORT LAUDERDALE, Florida – It has been recognized for many years that stroke, which is widely acknowledged in both the lay and medical world as a "brain attack," is a costly and devastating disease. With each passing year, more and more research suggests that stroke is even more calamitous than previously realized. With this as the backdrop, the 26th International Stroke Conference, sponsored by the American Stroke Association, a division of the American Heart Association (Dallas, Texas) was held here earlier this year. Although a wide variety of important topics relevant to stroke were presented, it was easy to come away from the meeting with the notion that temperature management has emerged as the hot topic in the stroke field.

One of the enduring issues in the stroke field, in addition to the ongoing battles to reduce the number of stroke occurrences through preventive measures (e.g., diet, exercise, not smoking), is to slash the morbidity after the onset of the stroke. As reported by Cardiovascular Device Update in previous articles on this topic, the availability of "clot-busters" such as Genentech's (South San Francisco, California) FDA-approved, intravenously-delivered recombinant thrombolytic agent, t-PA, has tremendously mitigated the damage from an ischemic stroke. This type of stroke is the most common type (roughly 600,000 of the annual U.S. total of 750,000) and is caused when blood flow in the brain decreases or fails, robbing cells of vital supplies of oxygen and nutrients. However, numerous landmark clinical trials have demonstrated that t-PA and other experimental, intravenously-delivered compounds are only efficacious if administered within three hours after the onset of acute ischemic stroke symptoms. Unfortunately, the vast majority of patients arrive at the hospital too late to be treated within that narrow time frame.

A couple of years ago, favorable results were reported with Abbott Laboratories' (Abbott Park, Illinois) Prolyse (recombinant pro-urokinase or r-pro-UK) delivered with a catheter intra-arterially by a neuro-interventionalist in the cath lab for up to six hours after ischemic stroke onset. These two studies, Prolyse in Acute Cerebral Thrombosis (PROACT-I) and Prolyse in Acute Cerebral Thrombosis-II (PROACT-II), concluded that r-pro-UK treatment administered intra-arterially within six hours of acute ischemic stroke onset significantly improved clinical outcome at 90 days. The first PROACT study randomized patients to either Prolyse or saline, while in PROACT-II patients were randomized to either Prolyse plus intravenous heparin or IV heparin alone.

Unfortunately, Prolyse's debut on the U.S. market has been significantly delayed because the FDA has insisted upon another randomized, blinded, multicenter trial to substantiate the results of the earlier PROACT trials. According to CDU's industry sources, the protocol for the confirmatory trial was recently agreed upon and this trial will shortly begin.

Minimizing brain damage after onset

Along with the narrow therapeutic window of opportunity of thrombolysis, there has been increasing recognition in recent years of the "ischemic penumbra." This is a region in the brain where a "cascade" of biochemical reactions due to reduced cerebral blood flow causes brain cell death. As this information has become more widely appreciated, the battle to reduce ischemic stroke morbidity and mortality therapy has been directed toward protecting cells downstream from the site of an ischemic blockage. This has focused attention on treatment modalities that might minimize or reverse brain damage after stroke onset.

One such approach is the use of neuroprotective drugs, which in animal models have been shown to interfere with this "cascade," thereby reducing the damage from inadequate blood flow and potentially limiting the otherwise lethal impact from ischemia. Amidst great hope that this approach could make a significant contribution to limiting brain injury, many clinical trials were initiated, using a wide variety of neuroprotective compounds. Plainly stated, the results have been very disappointing. According to an article in the November 1999 issue of Trends in Neurosciences, titled "Clinical Trials in Acute Ischemic Stroke: Are We Doing the Right Thing," all 22 agents that had completed Phase III trials failed to show good clinical outcomes. More recently, the April 4, 2001 issue of the Journal of the American Medical Association contained an article on the Glycine Antagonist in Neuroprotection (GAIN) trial, which showed that acute stroke patients did not gain any functional benefits at three months.

At last year's International Stroke Conference, James Grotta, MD, of the University of Texas Medical School (Houston, Texas), said that "effective neuroprotection and the means to achieve it remain an elusive goal." In two different posters at this year's meeting, researchers speculated as to why neuroprotective drug trials have failed, citing faulty drug selection, inadequate patients' traits or whether these trials were statistically underpowered to attain their primary endpoints. Whatever the reason, this approach to post-acute ischemic stroke management has produced dismal results.

With the disappointment of pharmacologic neuroprotection and the very narrow "therapeutic window of opportunity" afforded by thrombolytic therapy, stroke researchers have intensified their efforts toward other approaches to mitigate ischemic stroke morbidity and mortality. It has been increasingly recognized by clinicians over the past several years that maintaining a normal body temperature can be crucial to a patient's well-being. Normothermia, defined as a core body temperature of 37 C, provides the most habitable environment for the body to regulate metabolism and vital body functions. Conversely, the deleterious impact of either hypothermia (body temperature below 37 C) or hyperthermia (body temperature above 37 C), whether triggered by illness, trauma, surgery or other factors, has become widely recognized in the medical community. As body temperature decreases, vasoconstriction and shivering responses occur. As body temperature increases, heart rate, respiration, perspiration and metabolism accelerate. Hyperthermia is detrimental to the brain and vital organs, while hypothermia may cause decreased metabolism and cardiac arrhythmias. With any extremes in body temperature, death can occur.

One of the most promising areas of acute ischemic stroke therapy is temperature management. Several stroke models have shown that hypothermia decreases the final infarct volume and, very significantly, extends the duration or therapeutic window that the brain can tolerate ischemia before permanent damage occurs. In a paper titled "Profound Reduction of Myocardial Infarct Size and Preservation of Microvascular Flow by Mild Hypothermia," presented at the November 2000 scientific sessions of the American Heart Association, researchers showed that mild endovascular hypothermia (34 C) resulted in a "striking reduction" in infarct size in a swine model. The authors concluded by saying that "this therapy may be a useful adjunctive therapy to reperfusion in patients with acute coronary syndromes."

Temperature management a key

While the exact mechanism of elevated temperature and stroke damage may still not be completely understood, stroke researchers have gained tremendous insight in the past few years. In a talk at this year's stroke meeting, Myron Ginsberg, MD, director of the Cerebral Vascular Disease Research Center at the University of Miami School of Medicine (Miami, Florida), provided an excellent discussion of the possible mechanisms of hypothermic neuroprotection and a concise summary and recommendations for temperature management. This information is provided in Tables 1 and 2.

At the same time, the impact of hypothermia on surgical patients undergoing highly-invasive and lengthy procedures in the immediate post-operative phase has become more appreciated as well. In the surgical setting, the body's self-regulating mechanisms are inactive and a certain degree of hypothermia naturally occurs. If the surgery is highly invasive, such as in cardiovascular, thoracic, gastrointestinal or major orthopedic procedures, body temperature may further decrease from physical exposure of the body to the cool environmental conditions of the surgical suite. An article in the April 1999 issue of the American Association of Nurse Anesthetists Journal (Park Ridge, Illinois), titled "Maintaining Intraoperative Normothermia: A Meta-Analysis of Outcomes with Costs," found that hypothermia averaging only 1.5 C resulted in cumulative adverse outcomes, adding between $2,500 and $7,000 per surgical patient to hospitalization costs across a variety of surgical procedures.

The need for neuroprotection was highlighted in an article titled "Longitudinal Assessment of Neurocognitive Function after Coronary-Artery Bypass Surgery" that appeared in the Feb. 8, 2001, issue of the New England Journal of Medicine. The authors from the Duke University Medical Center (Durham, North Carolina) noted that 53% of patients at discharge following their CABG procedure were suffering from neurocognitive decline, while at five years 42% continued to suffer from such problems. In an accompanying editorial in the same issue, it was stated that "these various forms of neurologic and cognitive change after CABG have therapeutic implications. There is great interest in agents that may have neuroprotective effects against a variety of insults to the brain, such as stroke, head trauma, and anoxic injury." It is these articles and new clinical information that is stoking the fires of temperature management for CABG and other surgical procedures that require general anesthesia

While recognition of temperature management has surged in recent years, the traditional methods of warming or cooling patients are surprisingly primitive. Heating methods include forced air warmers, warmed intravenous solutions, warm blankets and warmer room temperatures. While these treatments have a cumulative effect, and over a period of time will eventually warm the patient, they are inexact solutions that have other disadvantages such as bulkiness, interference with the surgical site, and excessive room temperatures, which provide a distraction. Traditional methods of cooling patients include ice baths, alcohol baths, cold-water blankets and fans blowing on the patient. As with the re-warming techniques, these cooling methods are inefficient, require patient sedation or anesthesia, and are clumsy to use and ineffective at maintaining lower temperatures.

Market opportunity draws participants

This huge market need, detailed in Table 3 has not gone unnoticed. Several privately-held device companies are working diligently to address this opportunity.

While most companies are initially targeting just one sector of the market, most intend to pursue several different opportunities. One of the industry leaders is privately held, venture-capital-backed Medivance (Louisville, Colorado), which recently launched its Arctic Sun Temperature Management System. This device features a thermo-regulatory feedback system that combines an exclusive, non-invasive, highly conductive energy transfer material with a control module that monitors and automatically controls temperature to achieve normothermia or mild hypothermia. This externally worn, disposable device provides for energy transfer that is much more efficient than traditional cooling techniques, and the control system uses a closed loop feedback approach to precisely control and monitor temperature. The company's first model, the Arctic Sun Model 100, has received FDA 510(k) approval and will be targeted toward maintaining normothermia in surgical applications.

The company reported in mid-February that its second product, the Arctic Sun Model 200, which also has attained FDA approval, has been selected as the exclusive temperature management system for the Nordic Cooling Stroke Study. This study, which will commence shortly, will enroll 1,000 patients, half randomized to a treatment arm and half to a control arm. It is the first pivotal, randomized multicenter study designed to evaluate the effects of inducing mild hypothermia in stroke victims.

A previous pilot study, conducted by researchers from two hospitals in Copenhagen, Denmark, found that it is feasible and safe to induce mild hypothermia in awake stroke patients and showed trends toward improved patient outcomes. This study was published in an article titled "Feasibility and Safety of Inducing Modest Hypothermia in Awake Patients With Acute Stroke Through Surface Cooling: A Case-Control Study" that appeared in the September 2000 issue of Stroke. Unlike previous pilot studies involving hypothermia, the Nordic Cooling Stroke Study will cool patients without the use of anesthesia. If the hypothermia treatment proves effective, the lack of general anesthesia, in combination with a non-invasive treatment, will make the therapy safer, easier to administer and therefore applicable to the majority of stroke victims.

Whereas the Arctic Sun Temperature Management System is a noninvasive approach to temperature management, other companies are employing more invasive approaches. For example, privately held Radiant Medical (Redwood City, California) has developed the Setpoint Endovascular Temperature Management System, which uses a catheter placed in the inferior vena cava via the femoral vein. Cool or warm saline is circulated over the catheter, thereby either warming or cooling the blood. A microprocessor-controlled redundant safety system, which allows for precise achievement of the target temperature, is critical to the success of the entire system. The company, which completed a $30 million venture capital financing in 4Q00, is now involved in three different temperature regulation studies, one for cardiovascular surgery, another for post acute myocardial infarction and a third for acute ischemic stroke.

COOL AID trials study induced hypothermia

The latter trial, dubbed Cooling for Acute Ischemic Brain Damage (COOL AID), was discussed at this year's stroke meeting by Drs. Derk Krieger and Michael DeGeorgia of the Cerebrovascular Center of the Cleveland Clinic Foundation (Cleveland, Ohio). This pilot study, which explored the feasibility, safety and efficacy of moderate hypothermia with surface cooling, determined that induced moderate hypothermia (32 C) is feasible and safe for patients with severe acute ischemic stroke. As a result, a larger safety study (called COOL AID Phase II) with 40 patients, an expanded number of clinical sites and using endovascular cooling, was recently initiated. The principal investigator will be Krieger, who said that "we hope that hypothermia can improve the outcomes of patients with severe strokes and we conclude that we need a randomized, controlled trial to confirm this benefit." He added that he believes that endovascular cooling is faster, allows more precise control of targeted temperature and can be achieved in awake and non-intubated patients. In combination with endovascular cooling, surface warming of the head and chest and pharmacological suppression of shivering will be used in this trial, with the hope of keeping patients comfortably awake and alert during hypothermia. This technique would also allow hypothermia to be used in a step-down stroke unit, rather than the ICU, "which is the goal of the future," Krieger said. An expansion of COOL AID Phase II will likely occur in late 2001, after safety has been firmly established.

There are two other notable trials in the area of temperature regulation. The first is the Hypothermia After Cardiac Arrest (HACA) study, a four-year randomized trial investigating whether mild hypothermia (target temperature 34 to 36 C) will improve neurologic outcome after resuscitated cardiac arrest. The study includes 225 patients from 10 European centers. While no final data was presented at this year's International Stroke Conference, Dr. Fritz Sterz of the University Clinic of Emergency Medicine (Vienna, Austria) reported on findings from his own center in 83 patients, 38 in the hypothermia group and 45 controls. While he did not give precise data, he indicated that the neurological outcome was "much better in the cooling group."

The Intraoperative Hypothermia for Aneurysm Surgery Trial (IHAST) is studying the use of moderate hypothermia in patients undergoing surgery for subarachnoid hemorrhage following a ruptured cerebral aneurysm. The primary endpoint is the Glasgow Outcome Scale score at three months after the surgery. The principal investigator, Christopher Loftus , MD, of the University of Oklahoma Medical Center (Oklahoma City, Oklahoma) indicated at this year's stroke conference that about 300 of a target 900 patients have been enrolled, and a pre-specified interim analysis will occur shortly.

Another privately held, venture-capital-backed company in this arena is Innercool Therapies (San Diego, California), which also uses a control console and either a venous or arterial catheter to affect blood temperatures, which in turn warms or cools the downstream organs. The company is active on several fronts in temperature management. First, it is in the midst of a pivotal study of temperature management in aneurysm surgery at eight U.S. centers of excellence. Early results show that its product can rapidly and safely induce hypothermia in this setting. Second, Innercool has an approved IDE for a fever therapy study that was to commence in May at one or two U.S. centers. Third, the company will initiate its stroke study in July, led by noted neurologist Dr. Pat Lyden of the University of California San Diego Medical Center (San Diego, California).

Two areas of opportunity eyed

Yet another privately held, venture-capital-backed contender in this arena is Alsius (Irvine, California). The company sees two broad areas of opportunity within temperature management – the maintenance of normothermia and induced therapeutic hypothermia. The former market includes fever reduction in the neuro intensive care unit and the maintenance of normothermia during cardiovascular and general surgery. The latter market includes ischemic stroke, hemorrhagic stroke, sudden cardiac arrest, aneurysm surgery, acute myocardial infarction and brain trauma.

Alsius' products include the Cool Line catheter, which resides in the superior vena cava. It is designed to function exactly like standard central venous catheters, with the exception of two proprietary MicroTherm balloons that are incorporated on the shaft of the catheter that have sterile, temperature controlled saline flowing within. As the blood from the superior vena cava passes by each balloon, heat exchange occurs, thereby altering core body temperature. Another key product is the Icy catheter, a higher power catheter designed to be inserted in the femoral vein and reside in the inferior vena cava. It will be used if time to target temperature is the goal. Both catheters are connected into the CoolGard temperature control system. The CoolGard system uses the company's proprietary Proportional Power Control technology that remotely senses changes in patient temperature and automatically adjusts the temperature of the circulating saline supplied to either the Cool Line or Icy catheter in a closed loop design.

Alsius has received the CE mark for Cool Line, Icy and CoolGard products and has distribution in place in major European markets. The company has a clinical trial under way in the U.S. with the Cool Line for the reduction of fever in the neuro ICU, with a projected completion date of early 2002. In addition, Alsius is investigating the effects of induced therapeutic hypothermia in patients who survive sudden cardiac arrest. This trial is aptly called the HART (Hypothermia After Cardiac Resuscitation Therapy) study. Alsius also is supporting research in Europe in severe ischemic stroke, hemorrhagic stroke and brain trauma. The company notes that it has treated approximately 200 patients worldwide.

Another privately held, venture-capital-backed participant is Cardeon (Sunnyvale, California), whose initial focus at this juncture is in cardiovascular surgery neuroprotection. Its approach is called Targeted Circulatory Management, enabling the surgeon to tailor the optimal cerebral, corporeal and cardiac environments through individualized temperature, flow and perfusate composition. Cardeon's goal is to provide clinicians with a technology platform that provides them with greater control over the procedure, allowing them to select the clinical strategy that they believe is most appropriate and will result in the best outcomes.

Its proprietary first device, called the Cobra, divides the aorta into upper and lower sections, which allows for the simultaneous cooling of the brain and warming of the rest of the body. In addition, the Cobra provides protection from micro-emboli via a blocking membrane built into the device. Cardeon has successfully completed two feasibility studies in 50 patients undergoing cardiovascular surgery and plans to start a larger randomized trial by mid-year. In the stroke and acute MI area, it has developed prototype devices, completed limited animal studies and will initiate human clinicals trials in these areas by late 2002.

Inducing hypothermia locally

The most recent entrant into this embryonic field is Seacoast Technologies (Hampton Falls, New Hampshire) a privately held, venture-capital-backed medical device company that evolved from initial experiments performed at Massachusetts General Hospital (Boston, Massachusetts). It is developing products which induce hypothermia in brain tissue locally, either intraoperatively or through a neurosurgical burr hole in the skull. The company's initial experiments have proven the feasibility of inducing hypothermia in a canine stroke model directly on the surface of the brain using a simplified prototype, circulating chilled saline through a closed-loop system. More recently, the device has shown feasibility in the non-human primate stroke model. This novel technique involves neurosurgical placement of the device, thus providing the only local method of cooling available, allowing for rapid and reliable cooling. It may overcome the complications associated with systemic body cooling. Seacoast Technologies expects to commence human trials near the end of 2001.

It is interesting to note that the larger, cardiovascular medical device companies do not appear to be currently involved in clinical trials for any temperature management devices. Guidant (Indianapolis, IN) has made investments in both Alsius and Cardeon, indicating that at some point they might acquire one or both. Cardiovascular Device Update industry sources have recently noted a surge in interest in this area, suggesting that industry consolidation might occur sometime in thefuture.