UNITED STATES OF AMERICA

P-R-O-C-E-E-D-I-N-G-S

8:06 a.m.

CHAIRMAN MAISEL: Good morning.

I'd like to call to order this meeting of the Circulatory System Devices Panel. Today's topic is discussion of a premarket notification for the Alsius Corporation CoolGard 3000/Icy Catheter system, K040429.

Geretta?

EXECUTIVE SECRETARY WOOD: Before we begin this morning, I have a couple of announcements.

Due to an emergency, Dr. Hallstrom was not able to join us today. We have Dr. Brent Blumenstein on the phone filling in for this morning.

Now I would like to read the conflict of interest.

The following announcement addresses Conflict of Interest issues associated with this meeting and is made part of the record to preclude even the appearance of an impropriety.

To determine if any conflict existed, the Agency reviewed the submitted agenda for this meeting and all financial interest reported by the Committee participants. The Conflict of Interest statutes prohibit special Government employees from participating in matters that could affect their or their employer's financial interests.

However, the Agency has determined that participation of certain members and consultants, the need for whose services outweighs the potential conflict of interest involved is in the best interest of the Government. Therefore, a limited waiver has been granted for Mr. Halperin for his interests related to the issues before the Panel that could potentially be affected by the Panel's recommendations. The limited waiver allows him to participate in the review and discussion, but excludes him from voting. Copies of this waiver may be obtained from the Agency's Freedom of Information Office, Room 12A-15 of the Parklawn Building.

In the event that the discussions involve any other products or firms not already on the agenda for which an FDA participant has a financial interest, the participant should excuse him or herself from such involvement and the exclusion will be noted for the record.

With respect to all other participants, we ask in the interest of fairness that all persons making statements or presentations disclose any current or previous financial involvement with any firm whose products they may wish to comment upon.

ACTING CHAIR MAISEL: Thank you.

At this point I'd like to have the Panel members introduce themselves. I am William Maisel, cardiologist at Brigham and Women's Hospital in Boston.

And why don't we start on my right with Dr. Yustein?

DR. YUSTEIN: I'm Ron Yustein. I'm the Acting Critical Deputy Director for FDA's Office of Device Evaluation.

MS. MOTTLE: Linda Mottle, Director of Clinical Research at GateWay in Phoenix. Consumer rep.

DR. MARLER: John Marler, a neurologist with the National Institute of Neurological Disorders and Stroke.

DR. BRINKER: Jeff Brinker, Interventional cardiologist, Johns Hopkins.

DR. PAGE: Rick Page, cardiologist, University of Washington.

EXECUTIVE SECRETARY WOOD: Geretta Wood, Exec Sec.

DR. BROTT: Thomas Brott, neurologist, Mayo Clinic.

DR. SOMBERG: John Somberg, Professor of Medicine and Pharmacology, Rush University, Chicago.

DR. HALPERIN: Henry Halperin, I'm an electrophysiologist at Johns Hopkins Hospital.

DR. KATO: Norman Kato, cardiothoracic surgery, private practice, Encino, California.

DR. WEISFELDT: Myron Weisfeldt. I'm Chair of the Department of Medicine at Johns Hopkins. My background is in cardiology.

MR. MORTON: I'm Michael Morton. I'm employed by Medtronic. And I'm the industry representative.

CHAIRMAN MAISEL: Dr. Blumenstein? Dr. Blumenstein, can you hear us okay? I'll take that as a no.

DR. BLUMENSTEIN: I'm having a very hard time hearing. I heard some better than others.

CHAIRMAN MAISEL: Can you introduce yourself, please?

DR. BLUMENSTEIN: I'm sorry. Was I asked a question?

CHAIRMAN MAISEL: Can you introduce yourself?

DR. BLUMENSTEIN: Yes. My name is Blumenstein. I'm a consultant working independently living in Seattle, Washington.

CHAIRMAN MAISEL: Thank you.

At this point I'd like to open the public hearing session of today's meeting. Both the Food and Drug Administration and the public believe in a transparent process for information gathering and decision making. To assure such transparency at the open public hearing session of the advisory committee meeting, FDA believes that it is important to understand to understand the context of an individual's presentation. For this reason FDA encourages you, the open public hearing speaker, at the beginning of your written or oral statement to advise the Committee of any financial relationship that you may have with the sponsor, it's product, or if know its direct competitors.

For example, this financial information may include the sponsor's payment of your travel, lodging or other expenses in connection with your attendance at the meeting.

Likewise, FDA encourages you at the beginning of your statement to advise the Committee if you do not have any such financial relationships. If you choose not to address this issue of financial relationships at the beginning of your statement, it will not preclude you from speaking.

Is there anyone in the audience who wishes to address the Panel this morning? Yes, sir?

DR. VANDEN HOEK: Hi. Good morning. My name is Dr. Terry Vanden Hoek. I'm an Associate Professor of Medicine at University of Chicago and in practice as an emergency medicine attending there.

My conflicts of interests that I should declare today is Alsius is paying for my expenses today. I get no other salary support from Alsius or any other cooling device funding.

My research funding is from the NIH and Department of Defense for study of mechanism of post-resuscitation injury after cardiac arrest and hemorrhagic shock.

I was asked to speak today regarding the ILCOR recommendations that were published in 2003 in Circulation. And these recommendations were the result of consensus meetings by professionals from six continents, seven professional organizations that included cardiologist, neurologist, critical care, anesthesiologists, emergency medicine, physicians as well as nursing staff that practice in the critical care and emergency medicine setting.

And what's remarkable is that there were worksheet presentations that were done and a number of forums represented. All of the weight of the evidence for the use of therapeutic hypothermia for selected patients after cardiac arrest.

And what the conclusion was that the American Heart Association had already recognized that hypothermia may play some role after cardiac arrest. And if you read the guidelines in 2000 what they say is that hemodynamically stable patients who develop a degree of hypothermia spontaneously after cardiac arrest should not be actively warmed. And there was already a recognition back then that hypothermia could be tolerated and, in fact, may be beneficial but at that time we didn't have the evidence to suggest that they should be actively cooled in certain groups of patients.

After the evidence had been presented at multiple forums in which specialists could participate, critique the evidence, the decision was made to issue an advisory statement between the guidelines, which were published in 2000 and will be coming out this year, which is an unusual event and I think reflects the consensus among the specialists that we needed to say something because the weight of the evidence suggested that there was actually something we could do for cardiac arrest patients that improved survival. And that was to cool subsets of patients to 32 to 34 degrees for 12 to 24 hours.

And we issued that advisory statement in the summer of 2003.

The thing I want to emphasize to the Panel is how remarkable it is that we actually have anything that can improve survival from cardiac arrest. It's an extremely lethal disease. The mortality rate is 95 percent. It is remarkable that we have even one randomized controlled trial that shows any evidence of improved survival benefit, not only to hospital discharge but actually to six months survival.

The fact that those patients can actually go back and work at last part time and live independently is extraordinary.

I think that the fact that you can develop a consensus amount that many physicians from that many continents is also quite remarkable.

The other thing I want to emphasize is that we think there is great promise in the use of hypothermia but we have a long ways to go. Surface cooling has its own limitations. It could take eight hours to cool a patient. Based on the animal data that's available and some human trials, we think that if we can cool faster, the benefit may be even more profound. And certainly we don't have all the answers yet. Cooling studies such as has been done by Clifton in the study of traumatic brain injury, the onset of cooling was much longer, took longer to cool his patients than it did in the HACA trial.

The Cool MI trials, the cooling certainly was not done for 12 to 24 hours. And those are actually what would be considered Level 7 studies when we present our worksheet. Because those were studies of cooling for other diseases.

So I would like to take any questions. Right now I have to get back to a study section for the NIH.

CHAIRMAN MAISEL: We're going to go through all the public speakers and we'll do a question session at the end if any of the Panel members have questions.

Thank you very much.

DR. VANDEN HOEK: Okay. Thank you.

CHAIRMAN MAISEL: Is there anyone else who wishes to address the Panel this morning?

DR. PEBERDY: Good morning. My name is Mary Ann Peberdy. I'm an Associate Professor of Medicine and Emergency Medicine at Virginia Commonwealth University in Richmond. And I'm a cardiologist by background.

I receive grant support from Medivance for the participation in the RESCUE trial. And my expenses to attend today's meeting will be paid by Alsius.

Intellectual disclosures are that I am an unpaid volunteer for the American Heart Association and a member and past char of the Science Advisory Board for its National Registry of Cardiopulmonary Resuscitation, which is an in-hospital database that currently houses data on over 60,000 in-hospital cardiac arrest resuscitation events. As the current vice chair Research for NRCPR, I am responsible for developing a dataset for post resuscitation care that will include the induction of mild hypothermia in that dataset.

The purpose of my comments today is to provide this Panel with a description of the current practice of providing mild hypothermia to survivors of cardiac arrest. My comments are based, in part, from the data on NRCPR o n information obtained from its participants, from users groups and focus groups, on communications with other clinicians and scientists both individually and as part of the Guidelines 2005 Conference, and on my personal experience as Chairperson of my hospital's Resuscitation Committee, and the primary physician responsible for providing this therapy at my hospital.

The national and international scientific community strongly recommend treatment with mild hypothermia for subsets of comatose survivors of out-of-hospital cardiac arrest. Despite the science and the current guidelines, hypothermia is under utilized in the United States.

Dr. Abella and his colleagues at the University of Chicago recently published an article in Resuscitation citing the survey results of the practice of providing post-resuscitation hypothermia. Out of 265 responders, only 13 percent had admitted to using hypothermia following a cardiac arrest.

While some of this may be due to the fact that it often takes a decade or more to translate science into clinical practice, a third of the responders stated that the reason for not using hypothermia was that the current cooling methods were technically too difficult or too slow and imprecise. Less than five percent of U.S. hospitals participating in NRCPR currently provide hypothermia. Many admit to believing that the therapy should be provided, but find the current protocols to burdensome to perform.

A few hospitals have even reported that after developing their protocols and implementing the hypothermia system, that after doing their first patient the case was so difficult, messy and burdensome that they abandoned this therapy completely.

My personal experience mirrors that of others. Our hospital has been performing hypothermia for over a year, and I am intimately familiar with our cases.

The induction, maintenance and reversal of mild hypothermia is not only difficult to perform accurately and consistently, but is tremendously time and resource consuming. Without a device specifically to provide and control mild hypothermia clinicians are currently left with whatever is cold and available to them for quickly decreasing body temperature. This may include infusing large amounts of icy saline, lavaging gastric contents with ice, packing the patient in ice bags which can range anything from traditional ice packs to large hefty trash bags filled with ice cubes and placing the patient on a cooling blanket traditionally used for the purposes of reducing fever rather than the induction and maintenance of mild hypothermia.

Although these methods of treatment are quite basic and without need for regulation, that does not necessarily equate with them being safe and the quickest and a most effective way to provide this therapy.

Clinicians often use a combination of these methods to induce the quickest time to target temperature. Thus, cooling from inside out and outside in.

Almost all of the patients are packed in ice that moves and leaks and creates an inconsistent temperature control and winds up with the patient being in a soaking wet bed. The inability to control the depth of hypothermia within a reasonable degree of predictability leads to overshoot with respect to the target temperature. Well over half of the patients with induced hypothermia in our institution, a place where that pays particular attention to how we deliver this therapy, have patients with temperatures that fall below 33 to 34 degrees at sometime during their therapy, which could place the patient at risk for further complications from imprecise treatment. The resulting actions to try and rewarm the patient to a more acceptable level of mild hypothermia leads to a ping-pong effect with the patient having temperature curves that swing up and down requiring cooling and reheating for almost the entire duration of the protocol. Rather than a consistent predictable temperature curve for cooling, maintenance and reversal, the typical patient is subject to jagged fluctuations in body temperature.

In addition to this, the ice packs or cooling blankets invariably leak leading to a very electrical unstable patient lying in a puddle of water. Many of us have commented that we have been quite lucky to not have patients refibrillate and require defibrillation in this setting. The dangers of defibrillation are obvious.

The multiple staff carrying for these critically ill patients often have their hands full in providing immediately necessary medical therapies and appropriately find it unreasonable to be expected to change a bed one, two or even times during duration of this protocol.

Attempting to provide this therapy by these means is, for lack of a better term, a thermalregulatory nightmare and potentially even electrically dangerous.

As both scientists and clinicians we can all agree that there is still much to be learned about how to best deliver this therapy, the time frame to initiate cooling, the depth and duration of hypothermia, the optimal use of sedative and paralytics, the different methods of cooling and need for CNS monitoring, just to name a few, are all areas that will clearly benefit from further experience and evaluation. But despite these unknowns post-resuscitation hypothermia makes a difference.

Our hospital has seen noticeable improvements in survival to discharge from out-of-hospital cardiac arrest since starting our program. Other programs also anecdotally report similar results.

In both Europe and the United many EMS systems are now seeing striking differences in survival to discharge after initial ROSC when delivering patients to hospitals performing aggressive hypothermia compared to hospitals that do not.

There was a frank discussion at a recent EMS Director's meeting specifically talking about whether or not it is unethical to deliver patients with out-of-hospital cardiac arrest to hospitals that do not provide hypothermia and whether or not appropriate patients should be diverted to those hospitals known to provide this therapy.

The future focus of survival from cardiac arrest will clearly have post-resuscitation care as a prominent feature. To help spotlight the importance of this currently missing link in the chain of survival, the NRCPR is developing a dataset specifically geared for delivery of care after ROSC and collection of data in this area. Specific attention will be paid to the delivery of mild hypothermia so that many of the current unknowns will be able to be evaluated and tweaked and cared for most carefully. Data on this resuscitation outcomes module will be used by individual hospitals to improve their process of resuscitation as well as by the scientific community as a longitudinal mechanism to track trends in treatment and outcome variables. So a mechanism is already in place for patients who receive hypothermia to be tracked by an independent board of scientists and clinicians.

In summary, I have three roles pertinent to the therapy being discussed today. I care for patients who have suffered a cardiac arrest. I teach others to care for patients who have suffered a cardiac arrest. And I do research to find better ways to care for these patients.

Everything that I know indicates that this therapy should be applied to certain comatose survivors of sudden death. During the time that we are in this room meeting today over 400 people will die from cardiac arrest and only 20 of them will ultimately survive without improve post-resuscitation therapies such as hypothermia.

We are dealing with a disease that carries with it an almost certain death. And although we acknowledge that we do not yet know all the intricacies of how to best deliver this therapy, we do know that despite this hypothermia makes a difference.

Please don't sacrifice better for best in considering devices that may help improve the delivery of this therapy. Clinicians need choices and better options to deliver mild hypothermia and patients need a better chance to survive.

Thank you.

CHAIRMAN MAISEL: Thank you.

Is there anyone else who wishes to address the Panel this morning?

Is there anyone on the Panel that has a question for either of our speakers? Jeff?

DR. BRINKER: I'd just like the last speaker, who is very impassioned, to tell me about whether she uses this device now to do away with all the hassle of leaking ice bags and things?

DR. PEBERDY: No.

DR. BRINKER: Why?

EXECUTIVE SECRETARY WOOD: Please come back to the podium.

DR. PEBERDY: The device is currently not FDA approved for this indication and our hospital was quite reluctant to use devices off label.

DR. BRINKER: There is no device, including ice bags, approved for this indication.

DR. PEBERDY: That is correct.

DR. BRINKER: But you use ice bags?

DR. PEBERDY: But we don't have to purchase them and they are not regulated.

DR. BRINKER: Okay.

DR. PEBERDY: This device is approved for hypothermia for other indications. So to our hospital that makes a difference to them.

DR. BRINKER: Okay.

CHAIRMAN MAISEL: Dr. Vanden Hoek, you can have a seat. No one from the Panel has asked a question to you.

DR. VANDEN HOEK: It is possible that, because we do use the catheter in our institution, we also use cooling blankets and ice bags. Our intensive care unit made a decision a year ago to try to implement a cooling pathway as well. And because of the cooling blanket issues with temperature drops, our ICE had decided to implement a cooling catheter and try to control that temperature better.

CHAIRMAN MAISEL: Okay. Thank you for your comments.

Anyone else on the Panel have a question? John?

DR. MARLER: Well, I was just curious if this second speaker could say why in her hospital it wouldn't be possible. I don't know what numbers were involved, but it sounded from the energy of her presentation like there were quite a few patients in the registry. Why would it be so difficult to do a comparison of ice bags to cooling catheters?

DR. PEBERDY: I don't think that we have said that there would be a difficulty to do that. There are literally just a handful of hospitals now that are performing this therapy. Many are in the stages of developing protocols to implement hypothermia programs which, in a typical hospital, takes almost a year to work through the entire process and do the education and get the protocol development. So there are not really enough hospitals with patients that we would be able to get a meaning comparison at this particular time, although we are continuing to look at data that gets entered on hypothermia patients.

CHAIRMAN MAISEL: Mike?

DR. WEISFELDT: To either of the speakers.

Were you involved in the recent deliberations of American Heart and ILCOR CBR standards dealing with cooling? And if you were, was there any significant effort to vacate the ILCOR statement that was previously adopted?

DR. VANDEN HOEK: In answer to your question, the therapeutic hypothermia worksheets were presented at a plenary session in Dallas at the end of January. And I think that the consensus was that those guidelines will stand.

CHAIRMAN MAISEL: Any other speakers that wish to address the Panel this morning?

At this point I'd like to close the open public hearing and we will move onto the sponsor's presentation.

I'd like to remind the speakers to introduce themselves, to state their conflict of interest as well. Thank you.

DR. BLUMENSTEIN: This is Brent Blumenstein. I'm not hearing anything speaking. Is there a reason for that?

CHAIRMAN MAISEL: Nor are we. We're just getting started here in a moment.

DR. COLLINS: It's the sound of one hand clapping. We will start now.

Good morning. Thank you. My name is Dr. Ken Collins.

CHAIRMAN MAISEL: Could you speak into the microphone a little more.

DR. COLLINS: Is that better?

CHAIRMAN MAISEL: Yes.

DR. COLLINS: My name is Dr. Ken Collins.

Welcome here on St. Patrick's Day.

I'm Executive Vice President of Alsius Corporation. Clearly, my conflicts of interests are that I'm a full time employee of Alsius Corporation.

Speaking also today will be Dr. Sterz from Vienna. Dr. Sterz is the Associate Professor of Internal Medicine, University of Vienna.

And Dr. Risto Roine, he's the Associate Professor of Neurology at the University of Helsinki.

Because the order of slides will change if I don't now delete that slide since I've introduced everybody. And now your slide numbers will match.

Why we are here. Alsius submitted a 510(k) for the CoolGard/Icy catheter system for the induction of hypothermia after cardiac arrest in certain patients. The FDA requested that we conduct a randomized controlled trial for this 510(k). And we appealed this request to the FDA.

In response to our appeal, the FDA offered this Panel. Alsius would like to thank the FDA for this flexibility. And for the purposes of this presentation, we will constrict ourselves to the analysis from the 510(k) dataset.

This is a 510(k) notification.

Next slide.

Substantial equivalence to a predicate device is the standard for FDA clearance of a 510(k). The statutory provisions for 510(k)s refers to clinical and scientific data, and there is no specific requirement for an randomized controlled trial. Alsius believes that it has provided the FDA with the data to support substantial equivalence, and therefore clearance of this 510(k).

For the purpose of determining substantial equivalence for a device, the 510(k) should include according to the statute as quoted "appropriate clinical or scientific data." And the intent is to show that the device is as safe and effective as a legally marketed device.

You previously heard from Dr. Vanden Hoek, who is as you'll see, one of the primary authors on the ILCOR recommendations. ILCOR is the International Liaison Committee on Resuscitation. It is made up of multiple representatives from multiple countries. Typically, for example, in Dr. Vanden Hoek's position in representing the AHA or the European Resuscitation Council, or the Australian Resuscitation Council, the appropriate medical bodies.

The recommendations were first reached in October of 2002 and then published as per the reference at the bottom of the slide in 2003.

Of note, "unconscious adult patients with spontaneous circulation after out-of-hospital cardiac arrest should be cooled to 32 to 34 degrees for 12 to 24 hours with the initial rhythm has been ventricular fibrillation." They also commented that such cooling may be beneficial for other reasons or in-hospital cardiac arrest.

It was the statement that was bolded in that slide that became the indication for use for the Alsius 510(k).

In terms of predicate devices, the Alsius CoolGard system is cleared for marketing. I will give you a description of the device in following slides.

It is cleared for the induction, maintenance and reversal of mild hypothermia in neurosurgery, for rewarming in cardiac surgery and for fever control in the cerebral infarction/intracerebral hemorrhage. The other predicate device was a blanket system, the Thermorite Model HC-83.

The device provides controlled hypothermia. This device is already approved and widely used in the European Union and now approved in Canada.

In terms of the clinical data that was submitted, and which we will review in subsequent slides, Alsius provided in the 510(k) a review of the literature including summaries of some of the compelling animal models demonstrating the mechanism of the benefits of hypothermia, a meta-analysis, Alsius IDE Feasibility Study and an analysis of cardiac arrest patient registry at the Allegemeines Krankenhaus in Vienna, the university hospital in Vienna. To avoid me stumbling that, I will call it the university hospital in Vienna.

Cardiac arrest is one of the most complicated clinical environments. It is an intensive care environment with multiple interventions required simultaneously. Providing hypothermia via a central line is efficient.

The existing cooling methods, there are several. Fluids, limited by the amount of volume you can infuse. Ice/lavage, a nurse intensive and the wet surfaces pose risk. Surface cooling limits access to the body and patient and can increase shivering. As you heard today, it's associated with less control of the desired patient temperature.

Due to these disadvantages, and as explained by Dr. Peberdy, there is a need for better tool to provide hypothermia. The Alsius' device is a tool that allows controlled convenient hypothermia.

The CoolGard 3000 system, it's the picture of the external unit pictured here. It's a heat exchange system. It pumps saline to and from the catheter in a closed loop with temperature control. It cools in a controlled manner at rates between 0.05 to 1.5 degree C per hour.

On the projection now is a picture of the icy catheter in situ. It's a femoral vein insertion. It's a 8.2 French catheter that ends up with the cooling elements predominately in the inferior vena cava.

The close up picture shows the balloons axially mounted on the shaft of the catheter. And I do have and we'll pass it around later, catheters for you to play with, to look at.

Cardiac arrest has significant implications for public health. It effects a large number of people with a terrible outcome. Rhea et al reviewed 35 U.S. community hospitals. In terms of the survival for any rhythm it was 8.4 percent overall, and for primary VT/VF it was 17.7 percent. And larger cities, depending upon the emergency care available, the rates varied enormously. Annually in the United States, at least 155,000 people experience EMS-treated cardiac arrest of any rhythm recorded, and 60,000 experience EMS-treated ventricular fibrillation-rhythm as a cardiac arrest. It's a significant public health issue.

In the 510(k) we presented a meta-analysis. This is subsequently being published as a peer reviewed article in the well respected Critical Care Medicine. I believe you received a copy of that in your Panel pack.

Three studies were looked at to establish an expected result. The HACA study, which you've heard about before and which Mr. Sterz and Dr. Roine were both intimately involved, the Bernard study by my countrymen and the Hachimi-Idrissi study. The end result is a clear benefit of hypothermia in the comatose survivors of cardiac arrest.

This graph shows survival. It is a meta-analysis presenting the risk difference. You can see the three trials, the HACA, Bernard and Idrissi. And overall -- I'm going to use the lethal-looking laser pointer -- there's a clear benefit in terms of the risk difference and its confidence intervals.

Similarly, in terms of survival with good outcome, the three trials are presented. The overall 95 percent confidence intervals and the risk difference is significant.

Included in our 510(k) were the results of the feasibility IDE. Let me put this in historic context for you. We started with a view to understanding a perspective randomized controlled trial. We experienced very slow enroll despite our best efforts. We started in 2001 in March.

In February of 2002 the New England Journal of Medicine articles, the HACA study, the Bernard study were published. ILCOR met in October of 2002 and published its recommendations in the mid-2003.

At this stage we believed that there was established of hypothermia in cardiac arrest. The feasibility study enrolled 13 patients with inclusion criteria that were tied in line with what we expected would be required in a randomized trial. The 30 day survival was 69 percent and the adverse event profile was consistent with the published studies that I've just mentioned.

At the Allegemeines Krankenhaus in Vienna university hospital there is an ongoing data collection activity. They're interested in the use of mild hypothermia and the post-resuscitative care of the comatose survivors in cardiac arrest. It contains data from the randomized controlled trial, patient registry data and includes information on this device and several others. Because of confidentiality, Alsius does not have access to the measurement on other devices.

From this dataset selected controls and device data was analyzed and submitted in our original 510(k) notification. Over the past year there has been ongoing data collection in the registry. This includes additional patients in both the control and device cohorts. And the analysis that I present today are from the 510(k) dataset.

The selection criteria the patients had to be the comatose survivors of cardiac arrest with primary successful cardiac pulmonary resuscitation resulting in return of spontaneous circulation on arrival to the emergency department. This was consecutive series of adults who had survived at least 24 hours and who had had non-trivial resuscitation times.

This table presents the baseline data. There are differences between the device and control groups, as is made clear in this slide. I would like to point out that the GSC score on admission being equal to three is more common in the device group. And that the average ROSC time is also longer.

The imbalance would suggest that the device group where a patient population would grow to risk difference.

This is a crude survival analysis. The hypothermia group, 43 of 62 patients survived. And the controlled group 695 out of approximately 1200.

The risk difference unadjusted was 11 percent with a confidence interval being near significant.

Further analyses were done. This is a 30 day survival multivariate model with values related to outcome. The univariate analysis that I previously showed you, the survival is on the top line. They present results to both survival and survival with good neurological outcome.

If you look at the confidence intervals, you'll see the risk differences at 11 percent for survival unadjusted, 17.7 percent for survival adjusted. Approximately 11 percent for univariate survival with good neurological outcome and 23 percent for adjusted. The confidence intervals are significant.

Of clinical relevance, the number needed to treat the patients using hypothermia for the survival is between 6 and 9. And for survival with good neurological outcome is between 4 and 9.

It's a remarkable benefit, and it implies that for every six or so patients treated with the Alsius device, a life will be saved.

This analysis included propensity scores, and we did do a Hosmer-Lemeshow model of fit for this.

In addition, we did other analyses of propensity scores. Propensity scores are a method to attempt to create better match comparisons between cohorts.

This slide shows the distribution propensity scores of the device an the control cohorts. The lack of good overlap could suggest the groups are not well matched. However, the model which includes the scores and other based on variable that's displayed in this slide, provides an odds ratio I would suggest significant benefit to the device.

On this slide, the dataset, that's the internal code for the CoolGard system. We are looking at all baseline variables.

For the code variate set, set number one is the treatment group and the propensity score. Set number two is the treatment group, the propensity score and all other variables used in the propensity score analysis.

I draw your attention to the odds ratio. Note the highly significant confidence intervals.

In addition, we present logistic regressions of survival with good neurological outcome for both the unadjusted and adjusted and death -- I'm sorry for switching axis for you, less than discharge. And, again, looking at the confidence intervals around the odds ratios, these are significant results.

In summary, may I first of all point out that the efficacy outcome is also the primary safety outcome. Efficacy is survival.

Vienna registry data shows significant improvement in survival and survival with good neurological outcome with the Alsius CoolGard system.

Dr. Roine will later discuss the meaning of the term "good neurological outcome" and the use of the CPC scale.

The effect as seen is consistent across all the different analyses with that reported in the New England Journal of Medicine published randomized controlled trial and the meta-analysis based upon them. These data are appropriate and adequate to demonstrate that the device is as safe and effective as the legally marketed predicate.

I will now hand you to or hand over the microphone to Dr. Fritz Sterz.

DR. STERZ: Good morning, ladies and gentlemen. I hope you will understand my Viennese English. My teacher, whom I want to give credit to, always said it's Vienglish. My teacher was Peter Safar at the University of Pittsburgh. And without him, I wouldn't have been able to stay here and talk to you, which I am very proud about.

So Peter Safar 15 years ago in his lab has taught me how to apply hypothermia in animals.

For this meeting I am paid Alsius with regards to the travel expenses. And with regards to the soldiers working at home, I get both paid a fellow by Alsius.<