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

9:18 a.m.

CHAIRMAN LASKEY: Good morning. I'd like to call this meeting to order. My name is Warren Laskey and pleased to chair this morning's session. Our topic this morning is a discussion of the pre-market application for the Revelation_ Tx Microcatheter with NavAblator^TM RF Ablation System P020039. Geretta, if you could please read the Conflict of Interest statement.

MS. WOOD: 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 interests reported by the Committee participants.

The Conflict of Interest statutes prohibit special Government employee from participating in matters that could affect their or their employers' financial interests. The Agency has determined, however, that the 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, waivers have been granted for Drs. David Schwartzman and Albert Waldo for their interests in firms that could be affected by the Panel's recommendations.

Dr. Schwartzman's waiver involves consulting on a competitor's unrelated product for which he receives an annual fee of less than $10,001. Dr. Waldo's waiver involves consulting on a competitor's unrelated product for which he receives an annual fee of less than $10,001 and also consulting with a competitor on unrelated matters for which he receives an annual fee of less than $10,001. The waivers allow these individuals to participate fully in today's deliberations. Copies of these waivers may be obtained from the Agency's Freedom of Information Office, Room 12A-15 of the Parklawn Building.

We would like to note for the record that the Agency took into consideration other matters involving Drs. Waldo, Schwartzman, Cynthia Tracy and F. Roosevelt Gilliam. Each of these panelists reported past or current interests involving firms at issue but in matters not related to today's agenda. The Agency has determined therefore that they may participate fully in all discussions. We would also like to note that Michael Morton, the Industry Representative for the Panel, has reported interests in firms at issue.

In the event that the discussions involve any other products or firms not already on the agenda for which an FDA participate has a financial interest, the participant should excuse himself/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.

CHAIRMAN LASKEY: Thank you, Geretta. I would like to have the table up front introduce themselves beginning to my right please.

DR. ZUCKERMAN: Okay, Dr. Waldo, can you introduce yourself please?

DR. WALDO: Yes, I'm Dr. Albert Waldo from Case Western Reserve University.

DR. ZUCKERMAN: And please tell us if you can't hear any of these hearings and we'll adjust your phone.

DR. WALDO: Thank you. I hear very well. I guess I'm supposed to say I'm a Clinical Exphysiologist.

DR. ZUCKERMAN: Correct. I'm Bram Zuckerman, Director, Division of Cardiovascular Devices at Food and Drug Administration.

DR. SCHWARTZMAN: David Schwartzman, Electrophysiologist, University of Pittsburgh.

DR. NORMAND: I'm Sharon-Lise Normand, Associate Professor of Biostatistics, Department of Biostatistics, Harvard School of Public Health and also in the Harvard Medical School.

DR. GILLIAM: Roosevelt Gilliam. I'm at Duke University as a Clinical Exphysiologist.

DR. WHITE: I'm Chris White. I'm an Interventional Cardiologist from Ochsner Clinic in New Orleans.

MS. WOOD: I'm Geretta Wood, Executive Secretary.

CHAIRMAN LASKEY: Warren Laskey, I'm an Interventional Cardiologist at the National Naval Medical Center.

DR. MAISEL: William Maisel, I'm a Clinical Electrophysiologist at Bringham and Women's Hospital.

DR. TRACY: Cindy Tracy, Peds, Georgetown University Hospital.

DR. HUGHES: Allen Hughes, Associate Professor of Decision Sciences and Management Information Systems, George Mason University. I'm the Consumer Representative.

MR. MORTON: Michael Morton, I'm an employee of Sorin-COBE and I'm the Industry Representative.

CHAIRMAN LASKEY: Thank you, Members. I understand that there will be some additional folks showing up. There's been an accident outside so we'll have some more people coming in later. We can introduce them at that point. Geretta, if you could read the voting status statement please.

MS. WOOD: Pursuant to the authority granted under the Medical Devices Advisory Charter dated October 27, 1990 and as amended, August 18, 1999, I appoint the following individuals as voting members of the Circulatory System Devices Panel for this meeting on May 29, 2003: Sharon-Lise Normand, Ph.D.; Christopher J. White, M.D.; Alberto L. Waldo, M.D.; Francis R. Gilliam III, M.D.; David S. Schwartzman, M.D.; Thomas Ferguson, M.D.; William Maisel, M.D. M.P.H. For the record, these individuals are special Government employees and are consultants to this Panel under the Medical Devices Advisory Committee. They have undergone the customary conflict of interest review and have received the material to be considered at this meeting.

In addition, I appoint Warren K. Laskey, M.D. to act as temporary Chairperson for the duration of this meeting. This is signed by David W. Feigal Jr., M.D. M.Ph., Director, Center for Devices in Radiological Health and dated May 27, 2003.

CHAIRMAN LASKEY: Thank you. Before we commence with the topic of the day, there will be a brief presentation from the Office of Surveillance and Biometrics on the topic of "Diathermy Interactions with Implanted Leads and Implanted Systems with Leads". So if we can have Marian Kroen.

MS. KROEN: Good morning. I'm Marian Kroen with the Issues Management Staff. The Staff was charged with among other things facilitating centered discussions and evaluations of high profile public health issues through our center wide expert committee meetings. As part of a new initiative to periodically brief panels on important topics, I was asked to make this presentation to you on "Diathermy Interactions with Implanted Leads and Implanted Systems with Leads".

FDA learned of two adverse events. Both of these were interactions of diathermy therapy in patients with deep brain stimulators. Two patients had received shortwave diathermy, one patient treated after oral surgery for a pulled tooth and another patient was treated at the middle back region. Both patients went into a coma and subsequently died.

So what is deep brain stimulation? Basically there's a stimulator or pulse generator implanted around the clavicle and leads snake up through the neck and go to an electrode which is implanted in the brain. It's typically used to treat Parkinson's disease and other conditions.

What is diathermy? Diathermy can be thought of as an electromagnetic heating pad. But while a heating pad heats just the skin, this heats inside the body. Diathermy means deep heat but it can be used in both heating and non-heating modes. It's used for relief from pain with strains, sprains, bursitis and muscle spasms.

Here is a picture of a diathermy unit and a patient receiving diathermy. Diathermy units can come with one or two applicator heads which can be positioned over the patient in appropriate positions.

Who uses this? Diathermy is used by physical therapists, occupational therapists, sports trainers and others.

There are three kinds of diathermy: shortwave which is also called radio frequency, microwave and ultrasound.

When FDA learned of these two adverse events, an expert committee was formed. In parallel to this, Medtronic performed some testing. Medtronic was the manufacturer of the deep brain stimulators. They did some in vitro testing using their deep brain stimulator and the model of diathermy that was used in one of the adverse events.

The result was that there was a temperature rise of 55 degrees Centigrade ("C")at the DBS lead during a 15 minute diathermy exposure at maximum diathermy settings. As you all know, cardiac ablation happens around 50 to 55 degrees C. There was a temperature rise at 27 degrees C at the settings for the adverse event. Again this is a temperature rise from ambient temperature.

So the expert committee sat around and said "What kind of information do we need". And we decided that we really needed to find out how big this problem is and what's the scope. We needed more testing to determine this. Are all implants affected? Are all metal implants affected? Is the problem with only active implants and does the shape of the metal implants matter?

We had OST test active implants. OST is the Center's Office of Science and Technology. They do testing and stimulations in support of FDA's missions. They tested a spinal cord stimulator and a cardiac pacemaker system using a test set up which is similar to Medtronics. They found that the temperature rise at the lead electrode is high. The temperature rise occurs whether or not a pacemaker is connected. So really it's just the lead that's causing this temperature rise.

The cardiac lead in pacemaker systems showed the highest temperature rise of 48.8 degrees Centigrade. The spinal cord stimulator had the second highest temperature rise of 27 degrees C and the temperature rise was highest where a shallowly implanted lead was simulated. It's interesting to note that while Medtronics tested a 15 minute diathermy session, OST tested for a minute or two. They plotted the temperature rise and they tested until the rise flattened out. So this would encompass around 90 percent of the temperature rise. If you did 100 percent of the temperature rise, the temperature at the lead tip for the pacemaker would be around 54 degrees Centigrade.

OST also tested non-active implants to see whether they had an effect. We really found that there was minimal heating of one to four degrees C. We tested mainly orthopedic implants of various shapes and sizes to see if they had any effects. This included screws and plates and titanium and stainless steel rods. We concluded that diathermy interactions with dangerously high temperatures were limited to implantable systems with metallic leads and the implanted leads themselves.

The theory is that the implanted lead acts like an antenna to receive the radiated energy from the diathermy. The power is dissipated. It's collected all along the lead but it's only dissipated where there isn't any insulation which is the electrodes. So the current density and thus the temperature at the lead electrodes can be very high due to the small surface area of the electrodes.

Can all types of diathermy cause this interaction? Both the shortwave and microwave diathermy produce an electromagnetic field which can interact with implanted leads. But ultrasound diathermy would have a different mode of interaction. It has a mechanical vibration rather than an electromagnetic field.

So what did FDA do? We reached into our toolbox and took some actions. We recommend that the labeling on metallic leads and lead systems have a warning against patients with implanted leads. Pacemakers had this warning for eons. Labeling on diathermy equipment had a contraindication against use on patients with implanted leads.

The FDA issued a public health notification which was distributed both to implanting physicians and diathermy endusers. A journal article is in the process of being processed. An issue of "Patient Safety News" was devoted to this. "Patient Safety News" is a televised series that satellite broadcasts to hospitals and other healthcare facilities.

But there's an interesting question here. Why are there no injuries from pacemakers? We have testing that shows that the pace lead electrode temperatures are high, high enough to cause tissue damage. There had certainly been a long enough history of pacemakers and leads for this interaction to have shown up. There have been two reports of damage to the pacemaker but not to the heart with diathermy use.

So we have some possible reasons why we haven't seen any of this. First is the warning may be adequate but as we all know, who reads the labeling? Another thing might be that the blood flow in the heart carries away the heat. This is true but blood flow in the heart also carries away the heat in cardiac ablation and that seems to kill tissues so why would it not kill tissue in this instance.

Next is the distance. Maybe the distance is sufficient to stop damage but we believe the distance of the patient who got diathermy in his mid back is greater than the distance from a pacemaker to a diathermy unit.

What I think really happens is damage but nobody had really put two and two together. A patient might go to the doctor and present with loss of sensing or failure to capture and the physician might reposition the leads. The physician didn't know since this hadn't been publicized to ask the patient whether they had diathermy and the patient didn't volunteer that they had diathermy so they just repositioned the lead and went on.

Another theory is that the brain has no pain receptors and other parts of the body do. If a patient has pain receptors, they can tell the diathermy administrator to lower the settings or stop the diathermy unit. Your thoughts and comments are welcome. Thank you.

CHAIRMAN LASKEY: Thank you, Marian. I guess we will spend a couple of minutes responding. For openers, I don't know if any of those explanations make sense other than the conductive capacity of the heart within the ventricle but it's not a trivial exercise to reposition a lead. I think you would have heard more about that if this was really more than a curiosity. Do my colleagues have any thoughts?

DR. SCHWARTZMAN: Can you tell us more about the nature of the brain injuries that were associated with those deaths?

MS. KROEN: I'm not really that familiar with it. There was an autopsy and it showed edema and necrotic tissue around the lead electrodes but that's all I know. Some representatives from Medtronic are here and they don't know anything more about it either.

DR. TRACY: Was there disruption of the lead or is there thought that the diathermy is causing damage at the tip of the electrode?

MS. KROEN: There was no disruption of the lead. It is at the lead electrode.

DR. TRACY: So you might not know if an ablation took place at the tip of a pacemaker lead as long as it didn't damage things enough so that you lost capture. You might never know.

MS. KROEN: That's correct.

DR. TRACY: And not everybody feels pain with an ablation. Most do but everybody does. It depends on the location of the energy delivery so you might have something that you can't really detect.

MS. KROEN: That's true.

DR. GILLIAM: Short of the dysfunction of the pacemaker, I'm not sure how you'd even know that in pacing just because we ablate with the threshold safety margins we have. It probably could go undetected unless you really created a major lesion. So I wouldn't take shelter in the safety that we haven't had the complaints. It concerns me greatly actually.

CHAIRMAN LASKEY: Do you have any idea what the average number of diathermy sessions per individual is?

MS. KROEN: We don't know. We do that there are chronic pain institutions. They use diathermy quite a lot. I don't know how many pacemaker patients they have but they told me that they've been advocating that pacemakers patients not have this for a long time and had no evidence to back it up. They say they get thousands of hits a day on their site.

DR. GILLIAM: Did they do any work with the defibrillator patients at all? Was there any suggestion along that line? We have mentioned pacemaker but it would seem to me that the defibrillator may have a bigger antenna.

MS. KROEN: They may have a bigger antenna but I think the critical issue is how big the electrode is. I believe the electrode is bigger so it would have a larger area to dissipate the energy. Therefore it wouldn't be as intense and not as hot as the pacemaker lead electrode.

DR. GILLIAM: I guess there are multiple electrodes on a defibrillator. There are some very large ones but they are also smaller points. I'm just looking at a lot of the measurement data that we have. It's a bit more interactive in a defibrillator. We may be able to evaluate other parameters such R-waves or atrial waves and P-waves.

MS. KROEN: Paul, would you know if there are multiple electrodes would the temperature be dissipated among all of the electrodes?

PAUL (tan jacket): I'm Paul Rejaric (PH) of OST. I did the in vitro studies. What we saw with the spinal cord stimulator which is four leads, four electrodes, is that it was distributed among the leads. The report that she gave you today was that the temperature was at the lead at the tip. Then as you went down, the temperature progressively actually got less.

We did find that the area is very definitely a problem. The reason why we saw higher pacemaker one was because the electrode itself was very small compared to the spine cord stimulator lead actually. So it's a surface area energy deposition problem.

CHAIRMAN LASKEY: Well, I'm not sure you're getting a lot of comments from the panel. I guess if you're interested in an inquiry, you go where the money is which is some of these centers where they do a lot of diathermy and do an observational study looking specifically for people with pacemakers which shouldn't be hard.

DR. GILLIAM: Is there a distance from the electrode that you have to be? What's the fall off? If you are within two or three inches, is there a greater amount than as opposed to 15 or 20 inches? Is there a safe distance to be away from it that you wouldn't get this even in a pacemaker lead?

PAUL (Tan coat): We did all of our tests very close. The only reason we did it close was because we were looking at the brain stimulator simulation where they put the thing very close. Ours basically were a half centimeter away which is very close. As we dropped, we dropped down to five centimeters at one point and virtually that knocked away all the heating.

It's a question of how well do you couple. How is the thing oriented? We find for example if you oriented a certain way, you actually get no coupling at all which is true with any antenna. It's all a problem of probability. Had the person turned the lead the other way he still would have gotten the heating but probably not even bother the patient. It's just one of those things.

MS. KROEN: I would also add here that again one of the patients had diathermy to the mid back and the electrodes were in the brain. That's quite a fair distance. So we really don't know what a safe distance would be.

CHAIRMAN LASKEY: All right. Thank you. We're puzzled as well. I would like to move on to the topic at hand and begin with the open public hearing. I would like to invite anyone from the audience who wishes to address the panel on today's topic to please approach the podium and identify yourself. If not, then I will close the open public hearing and we'll move to the sponsor's presentation. Geretta.

MS. WOOD: I would just like to remind the speakers to introduce themselves and state their conflict of interest before presenting.

MS. BALDWIN: Good morning, ladies and gentlemen, members of the Panel. My name is Marianne Baldwin. I'm with Cardima. I'm here today to present to you the results of a very complex study of a very complex disease, Atrial Fibrillation.

I'm going to start just by introducing the people who will be speaking for Cardima today on the Treatment Options of Atrial Fibrillation, Dr. Neal Kay, on the Preclinical Studies and the Protocol Development for the Clinical Studies, Dr. Hugh Calkins, the Results of the Clinical Studies, Dr. Abraham Kocheril, our primary investigator, and the Conclusions and wrap-up again by Dr. Kay.

Just as a brief background since 1993, Cardima has been developing, manufacturing and marketing catheter-based systems for the Electrophysiological field exclusively. The catheters include the PATHFINDER^TM family of mapping devices, the VENAPORT_, VUEPORT_ and NAVIPORT_ guiding catheters and the REVELATION_ family of mapping and ablation systems which represent the system under review today.

Currently the company is marketing its diagnostic and guiding catheters in the U.S.A., Canada and the European Union and Japan. The REVELATION_ family of mapping and ablation devices are marketed in Canada and the European Union.

This is a listing of our currently available products in the U.S. The initial strategic plan for Cardima was to introduce the mapping and guiding systems before the therapeutic devices to allow time for the physicians get comfortable with the smaller devices. 510k clearance was obtained for the diagnostic and guiding catheters being in 1995 with the VENAPORT_. Four years later this entire list was cleared.

These are illustrations of our catheters. This is the guiding catheter of the NAVIPORT_ an 8.0 French device. This device is used to deliver the REVELATION Tx the device we'll be studying today as part of the investigational system although this device has been cleared. It was the first deflectable guiding catheter on the market. The VUEPORT_, its predecessor on the right is practical to obtain good venagrams. We've had 20,000 of these units distributed.

This is the NavAblator^TM, Cardima's four millimeter hot tip developed specifically for this study to create lesions at the isthmus line.

This is the PATHFINDER^TM, examples of the catheters that have designed to access coronary sinus and its feeders. The 1.5 mini PATHFINDER^TM is useful for mapping small vessels such as Vein of Marshall. Our standard PATHFINDER^TM on the right, the 2.5 French, maps the coronary sinus and the feeders. Physicians have been using it lately for the placement of pacemaker leads. Cardima performed a clinical study for the PATHFINDER^TM to demonstrate its ability to map effectively. We have distributed 20,000 units of these devices.

The REVELATION_ Tx, the device shown on the left there, is a 3.7 French device to map and ablate. Its sister device for pulmonary veins is distributed in Europe and that's a 4 French. The AD-deflectable of the 3.7 French device is also distributed in Europe.

This is a description of the differences and the unique features of Cardima's core technology. The principal distinguishing feature is that it incorporates a guide wire technology that was developed for angioplasty permitting a variable stiffness of the guide wire that allows construction of a very flexible and compliant distal segment. It's a composite shaft that includes conductors tightly braided over the core wire and the structure is encapsulated in polyethylene before being coated with a hydrophilic lubricant.

The other really key feature is the fine wire coiled electrode located along the distal segment. We have eight electrodes on this catheter arranged in linear array allowing the catheter to maintain good contact with the wall of the beating heart. It also permits these small electrodes the catheter to ablate with greater current density and requiring less power.

Just to illustrate and compare the lesion shape of this catheter to a hot tip catheter, you'll see that there is similar depth but a significant difference in the width. Preservation of myocardium is a result of this and was one of the features of this design.

Here we have a segment of the linear array with three electrodes shown and four thermocouples in the middle. You'll see that the lesion formation overlaps the thermocouples. You have a continuous lesion there. We can ablate with between seven to 35 watts of power.

Last but not least, Cardima's indications for use are treatment of atrial fibrillation in patients with drug refractory paroxysmal atrial fibrillation by mapping, pacing and ablating with a set of lesions in the right atrium.

Now Dr. Kay will present to you Treatment Options on Atrial Fibrillation. Thank you.

DR. KAY: Thank you very much. My name is Neal Kay. I'm from the University of Alabama. I have no financial interests in Cardima. I'm not an investigator and I'm not a consultant. I'm being paid for my time today however.

Atrial fibrillation as we all know is a huge problem and there probably are as many treatments for this problem as there are patients who have it. This slide just shows the magnitude of the problem as it relates to age. As the population ages, you see that the absolute number of patients with Atrial fibrillation is increasing and both the incidence and prevalence go up with age. So this is becoming more and more of a problem

It's a complex rhythm and not every kind of atrial fibrillation is the same as every other kind. The ACC/AHA have recognized this and have proposed the following classification scheme. Patients may present with their first episode of detected atrial fibrillation in which case the subsequent course is not known. Then they may go on to have paroxysmal atrial fibrillation which are those that terminate spontaneously or have persistent atrial fibrillation, those episodes that require cardioversion or some drug intervention to terminate and do not terminate spontaneously.

Then finally there is this permanent atrial fibrillation which atrial fibrillation that is refractory to cardioversion or atrial fibrillation that in the opinion of the patient and their physician where it's just hopeless to try to maintain sinus rhythm. So it's a complex problem.

There are significant limitations with drug therapy. Shown here in this slide is just the results of one prospective trial looking at different doses of Sotalol vs. Placebo in the recurrence of atrial fibrillation. As you can see, there is a high risk of recurrence even on fairly large doses of Sotalol to maintain sinus rhythm. At six months, less than half the patients will have persistence of sinus rhythm.

Similarly the Canadian Trial of Atrial Fibrillation ("CTAF") look at different drugs after cardioversion as you can see. I think we all know that Amiodarone is more effective than other antiarrhythmic medications. It's more effective than Propafenone or Sotalol. But even so, many patients will have recurrence of atrial fibrillation.

The drugs that we use have limitations. The limitations are largely a function of the kind of underlying heart disease. These are the ACC/AHA guidelines. For example, patients who have congestive heart failure, it's recommended by the ACC/AHA that probably Amiodarone and Dofetilide may be the only drugs that may be used safety.

For patients with coronary artery disease, there's a significant limitation in the use of Type 1C drugs. So this scheme has been proposed that we perhaps start with Sotalol and then perhaps go to Amiodarone or Dofetilide and finally non-pharmacologic options can be considered.

Hypertension and specifically Left Ventricular Hypertrophy present problems with drugs that prolong the QT interval. When there is significant Left Ventricular Hypertrophy, we may be limited to the use of Amiodarone. For patients who don't have significant structural heart disease and just have hypertension, the Type 1C probably are reasonably safe to use followed by Amiodarone, Sotalol or Dofetilide.

This slide is presented to highlight the importance of the pulmonary veins in the initiation of atrial fibrillation. Here is our surface intercardioelectrograms from a patient with the spontaneous onset of atrial fibrillation that arises in this case from a pulmonary vein In this case it's the right superior pulmonary vein. You see an arrow here indicating the first onset of electrical activity in the pulmonary vein. It comes from the pulmonary vein to the left atrium and then subsequently to the right atrium. So the pulmonary veins appear to be important in the initiation at least of atrial fibrillation.

Arial fibrillation ablation is currently being practiced around the world in relatively limited of centers. The most common technique is shown here with a circular mapping catheter place at the ostium of the pulmonary vein to guide recognition of sites of early activation between the pulmonary vein and the left atrium. A radio-frequency catheter is placed just proximal to that mapping catheter and radio-frequency current is delivered with the goal being to electrically isolate the pulmonary vein.

This just shows an example of that. On the bottom tracings in green, you see pulmonary vein potentials and radio-frequency current applied. Finally after the onset of RF, we see that there is disappearance of pulmonary vein potentials. That is how this technique is being applied most commonly to ablate atrial fibrillation now throughout the world.

There are some significant limitations to pulmonary vein ablation that I want to highlight. One of these is the occurrence of this complication which is pulmonary vein stenosis. This is a right superior pulmonary vein. There is significant narrowing of the pulmonary vein just at the ostium as it joins the left atrium. This is an important and potentially devastating complication of ablation in the left atrium.

These results here published about a year ago are fairly typical of those that are seen in most of the large centers doing this procedure. You see that for patients who have paroxysmal atrial fibrillation about 70 percent of the patients can be rendered free of reoccurrence at least in the immediate term.

On the dotted line, you will see that the results for persistent atrial fibrillation really are not as good with only a small minority of the patients having control of their atrial fibrillation with a pulmonary vein isolation procedure if they have persistent AF.

AF ablation does have significant limitations. I just want to highlight them. Pulmonary vein isolation is only effective in about two-thirds of patients with paroxysmal AF. It's less effective in patients with more advanced forms of atrial fibrillation.

There are significant risks and these are likely to be operator dependent. Pulmonary vein stenosis has been reported to occur anywhere from one percent to eight percent and clearly seems to have a relationship to the experience of the operator. There's a risk of stroke that ranges from about one percent to four percent.

Pericardial tamponade again in the same range. Major bleeding complications can and do occur and they are related to the large amounts of anti-coagulation that are generally required to required to ablate on the left side. Importantly, it's limited to physicians who feel competent to perform transeptal catherization. Therefore it presently is not widely applicable.

I would like to highlight that there really have been no multi-center prospective trials of pulmonary vein isolation to this point. So it is likely that the complications that have been reported in single center series probably are actually higher when we finally start to do multi-center prospective trials.

This slide just shows the results of four surgical strategies to treat atrial fibrillation. Here in the top left is what is called the Cox-Maze operation which is bi-atrial operation involving incisions around the pulmonary veins and also incisions in the left atrium and importantly in the right atrium. The percentages are the percentage of patients who are rendered free of atrial fibrillation by the surgery. You can see that this probably is the best results that have been achieved which is with this bi-atrial surgery.

The other tracings show the results from different investigators looking at purely left atrial ablation procedures at surgery. As you can see, the results aren't as good. So it does appear that if you surgery ablate in both atriums the outcome appears to be better than in just the left atrium alone.

How does surgery work? It probably works by at least two different mechanisms. One of those is that it probably prevents pulmonary vein triggers by encircling the pulmonary veins but the incisions in the atrium probably interrupt macroreentry. We know that most atrial fibrillation is maintained by relatively large macroreentry circuits at least in our studies on the size of about nine centimeters. Surgery may help to prevent these by preventing the real estate that's available to maintain macroreentry circuits.

Now I've shown you some reasons why the pulmonary veins are probably very important. I've also shown you some reasons why operations involving both atria may be better than just the left atrium. Here are some results reported from Japan looking at their results with the Cox Maze 3 operation which again these first two columns are bi-atrial operations and just the right atrial Maze operation along. As you can see, the results are clearly better when two atria are operated on.

But there is at least a moderate degree of success with just a right atrial Maze operation done surgically. So it does raise the possibility that a right atrial operation may have some role to play in the prevention of atrial fibrillation.

As I've shown you the results at least from surgery, these results demonstrates that there may be a place for a right atrial ablation alone and I think Cardima will now presents some results showing that there is indeed a role for this approach in a prospective clinical trial. Thank you.

DR. CALKINS: Good morning. My name is Hugh Calkins and I would like to present some of the animal work that has been done with this system as well as the study design.

MS. WOOD: Dr. Calkins, please state your relationship to the sponsor.

DR. CALKINS: I've been involved with animal studies with Cardima about three or four years ago. I also was a clinical investigator in this clinical trial and I've been paid for my time for being here today. I'm not an equity owner in the company.

The Pre-Clinical Studies have been performed which have demonstrated that the Cardima REVELATION_ system is biocompatible. It's compliant with applicable ISO requirements. It also has been demonstrated that this is a reliable catheter be it again compliant with the mechanical and electrical performance requirements of the Massi guidelines.

Now a large number of animal studies have been performed with the Cardima REVELATION_ ablation system and they are summarized on this slide. The system has been worked at the Massachusetts General by David Kean, M.D.

Other animal studies have been performed by Dr. Mauricio Arruda at the University of Oklahoma in both a thigh muscle preparation and the dog preparation. Then additional studies were performed at the Mayo Clinical by Drs. Asirvatham and Doug Packer and also at Johns Hopkins. I would like to highlight the results of some of these for you today.

The study that was done by David Keane who was really first to work with this catheter was performed in an AF goat model where they demonstrated that AF could be induced at baseline and then delivered the four lesions that are part of this study design today and showed that AF was no longer inducible after delivery of these linear lesions. They also showed that these lesions were frequently transmural in nature.

The studies done at the Mayo Clinic were interesting. They look at 14 dogs. Their objection was to compare the linear microcatheter system with the linear standard ablation system where you have standard 4 millimeter 7 French electrodes lined up along a multipolar catheter. They created 30 lesions with the Cardima system and 36 linear lesions with the alternate catheter system.

The results are summarized here that the lesions were slightly narrower with the Cardima microcatheter system with a standard 7 French system. The lesions had similar depth. The volume was less with the Cardima system as you would expect given that it had smaller width. Importantly the presence of lesion formation was the same, 98 versus 95 percent. Lesion was transmural in a similar portion, 89 percent and 85 percent.

Dr. Arruda looked at the NavAblator system, the hot tip, flutter line catheter in six dogs and showed that this indeed was able to ablate the isthmus. Isthmus block was achieved in five of six dogs. The typical lesions were created with this 4 millimeter standard ablation catheter.

The study I'm most familiar with is the study we performed at Hopkins in 10 dogs. When I heard about this ablation system, I was somewhat skeptical that a small 3.7 French catheter could really create linear lesions and it could create deep lesions. I said "Why don't you let me do a little study in our own animal laboratory where we can compare head to head with standard ablation technology using a 4 millimeter catheter with a drag and pullback approach versus the Cardima system".

I set out about to do this again creating four linear lesions in the right atrium of these dogs. The dogs were survived one month and then they were sacrificed and the lesion characteristics were compared. This slide shows what we found with the standard 4 millimeter catheters using the sheath and pulling it back point by point trying to make linear lesions. What you can see on the left side of this screen is what happens on a good day where here's one lesion and here's a second lesion and here's a third lesion. We all would agree that this is a linear lesion as far as we can see.

But what we saw more commonly was this kind of thing where you have one lesion here, one lesion here, a third lesion here and then you had a clear gap between the lines. Then we also commonly saw what you see in the third which looks like a gunshot blast where you have one lesion here, one lesion here, one lesion here, one lesion here, nothing continuous or linear about it. Whether these lesions are in fact pro-rhythmic, anti-arrhythmic, who really knows.

Now you compare that with what we saw with the Cardima system and there was a striking difference. Here's a linear lesion created with a system that is thin and linear and this is on the free wall of the atrium. Here's a line along the septum going through the coronary sinus os going down to the inferior vena cava. Here's a flutter line from the tricuspid valve back to the inferior vena cava again a thin linear lesion.

Now when