UNITED STATES OF AMERICA

P R O C E E D I N G S

(8:04 a.m.)

CHAIRPERSON MAISEL: Good morning. My name is William Maisel. I'd like to call to order this meeting of the Circulatory System Devices Panel.

Today's topic is discussion of a premarket application for the Acorn cardiovascular CorCap, CSDP040049.

Geretta, would you please read the conflict of interest statement?

MS. WOOD: The following announcement addresses conflict of interest issues associated with this meeting and is made a part of the record to preclude even the appearance of an impropriety. To determine if any conflict existed, the agency reviewed the submitted agenda and all financial interests reported by the committee participants. The conflict of interest statutes prohibit special government employees from participating in matters that could affect their or their employers' 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, waivers have been granted for Drs. Eugene Blackstone, Robert Califf, Judah Weinberger, and Christopher White for their employers' interest in the sponsor's study. The waivers involve a grant to their institution for which they had no involvement and have no knowledge of the total funding.

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.

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.

I would also like to note for the record that Cynthia Tracy was unable to attend the meeting today.

CHAIRPERSON MAISEL: Thank you, Geretta.

At this point I'd like to have the panel members introduce themselves.

I'm William Maisel, a cardiologist at Brigham and Women's Hospital, and why don't we start with our industry rep., Michael?

MR. MORTON: I'm Michael Morton. I'm the industry rep., and I'm employed by Medtronic.

DR. KATO: Norman Kato, cardiothoracic surgery, Los Angeles California.

DR. NETROVEC: George Vetrovec, Chief of Cardiology, Virginia Commonwealth University, Richmond.

DR. BLACKSTONE: Eugene Blackstone, Director of Clinical Research in the Department of Thoracic-Cardiovascular Surgery, Cleveland Clinic.

DR. WHITE: Chris White, cardiologist, New Orleans, Louisiana.

DR. NORMAND: Sharon-Lise Normand. I'm Professor of Health Care Policy and Biostatistics at Harvard Medical School and Harvard School of Public Health.

DR. FERGUSON: Tom Ferguson, cardiothoracic surgery, Washington University School of Medicine, St. Louis.

DR. YANCY: Clyde Yancy, heart failure and heart transplantation, UT Southwestern Medical Center in Dallas.

MS. WOOD: Geretta Wood, Executive Secretary.

DR. SOMBERG: John Somberg, Rush University, Chicago.

DR. CALIFF: Rob Califf, Duke University.

DR. BORER: I'm Jeff Borer from Wile Medical College, Cornell University.

MS. MOTTLE: Linda Mottle, Gateway Community College, Phoenix.

DR. VASSILIADES: I'm Tom Vassiliades, cardiovascular surgery at Emory University in Atlanta.

DR. ZUCKERMAN: Bram Zuckerman, Director, FDA, Division of Cardiovascular Devices.

CHAIRPERSON MAISEL: Thank you.

Geretta, would you please read the voting status statement?

MS. WOOD: Pursuant to the authority granted under the Medical Devices Advisory Committee charter dated October 27th, 1990, and as amended August 18th, 1999, I appoint the following individuals as voting members of the Circulatory System Devices Panel for this meeting on June 22nd, 2005:

Eugene Herbert Blackstone, M.D.

Thomas T. Ferguson, M.D.

Norman S. Kato, M.D.

Thomas A. Vassiliades, Jr., M.D.

George W. Vetrovec, M.D.

Judah Z. Weinberger, M.D., Ph.D.

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 reviewed the material to be considered at this meeting.

The agency also would like to note that Dr. William Maisel has consented to serve as Chair for the duration of this meeting.

Please strike that last statement. Dr. Maisel is our permanent Chair.

And that's signed by Daniel G. Schultz, M.D., Director of Center for Devices and Radiological Health.

I also have a separate temporary voting status. Pursuant to the authority granted under the Medical Devices Advisory Committee charter for the Center for Devices and Radiological Health, dated October 27th, 1990, and as amended August 18th, 1999, I appoint Dr. Califf and Dr. Borer as voting members of the Circulatory System Devices Panel for the June 22nd, 2005, session of the meeting.

For the record, Dr. Borer is consultant to the Cardiovascular and Renal Devices Advisory Committee of the Center for Drug Research and Development.

They are special government employees who have undergone the customary conflict of interest review and have reviewed the material to be considered for this meeting.

And this is signed by Sheila Derryberry Walcoff, Esquire, Associate Commissioner for External Relations, and dated June 13th, 2005.

CHAIRPERSON MAISEL: Thank you.

At this point I'd like to begin the open public hearing session of the meeting. Both the Food and Drug Administration and the public believe in a transparent process for information gathering and decision making. To insure such transparency at the open public hearing session of the Advisory Committee meeting, FDA believes that it is important 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, its product, and 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.

At this point I'd like to invite Mr. George Hawkins to address the panel.

At the podium, please.

MR. HAWKINS: Good morning. I'm George Hawkins, and I am a congestive heart failure survivor and would like to thank the Advisory Panel for the opportunity to speak about my experience with the Acorn device.

Before taking a few minutes to share information about myself, my heart condition, and my recovery, I would like to assure the panel that I am not paid by Acorn or anyone else. They did not pay $155 for me to stay at the Hampton Inn last night, and I have not spoken to anyone at the Acorn company regarding my statements here today.

I'm a 49 year old native Washingtonian and received congestive heart failure notice in '97, probably due to family history. Both my father and brother have heart murmurs.

I enjoyed a satisfying professional career in human resources training and traveled a great deal. Unfortunately, I had to retire in 2000 due to congestive heart failure.

My physical activities have included jogging, walking, tennis, weight training, and during the early summer of 2001, my physical condition worsened so much that I was unable to climb the steps in my house without resting to catch my breath.

My heart surgery was successfully completed at the Washington Hospital Center by Dr. Mercedes Dullums. In July 2002, to repair a leaky valve and to insert the Acorn device, the medical team informed me at that time that my heart was one of the largest that the doctor has operated on.

The success of my recovery can be attributed to the Washington Hospital Center staff, which includes Dr. Carlos Ross Cooke and Janice Richey, who is here with me. My recovery involved physical therapies, diligent medical follow-up, effective medications, and assistance from special people in my life.

Fortunately, I have not experienced any returns to the hospital for heart related issues at all. One year after surgery I was walking at least several miles a week and allowed a low impact tennis and weight training. Also, several months ago, in 2004, I worked part time as an HR consultant. Almost three years after surgery, my heart has not gotten any larger, and as a matter of fact, it has gotten a little smaller.

On my pre-op exercise bike test in 2001, I scored 8.6. In January 2005, I scored 15.4. So to sum up, my cardiologist, my surgeon, Dr. Dullums and the Washington Hospital heart center team took a big risk with my surgery because I am surviving two other chronic illnesses, and I'm just hopeful that my experience will help to underscore that the Acorn device is a major factor in enhancing the quality of my continued life.

Thank you very much.

CHAIRPERSON MAISEL: Thank you for your comments, Mr. Hawkins.

Are there any other members of the public who wish to address the panel this morning?

(No response.)

CHAIRPERSON MAISEL: Seeing none, we will close the open public hearing at this point.

At this point I would like to invite the sponsor to give their presentation. I will remind each of the speakers to introduce themselves and state their conflict of interest statements.

DR. KUBO: Good morning. My name is Spencer Kubo. I'm the Senior Vice President, Global Medical Director, and a full-time employee of Acorn Cardiovascular.

We very much appreciate this opportunity to discuss the cardiac support device with you this morning, a new technology for patients with dilated cardiomyopathy and heart failure.

The work summarized today includes extensive animal testing in three different animal models that prove the concept that the cardiac support device would, in fact, work. This animal work, as well, defined the mechanisms, histologic, biochemical, molecular as to why it works.

There is also extensive patient testing that's culminating in one of the largest randomized, prospective, controlled trials ever conducted for a permanent device implant that requires cardiac surgery, and we all feel that this work is potentially important because it fills an unmet need for patients with heart failure.

We're pleased today to have three outstanding speakers who will be sharing the data with you and discussing their results. All three were part of a five-person steering committee who were critical in the design, execution and recording of this trial, and they include Dr. Douglas Mann who recently accepted the position as Chief of Cardiology of

Baylor College of Medicine; Mary L. Jessup, who is Professor of Medicine and Director of the Heart Transplant Program at the University of Pennsylvania; and Dr. Michael Acker, who is Chief of Cardiac Surgery, also at the University of Pennsylvania.

I also want to acknowledge that the Steering Committee represents an extraordinary group of investigators, cardiologists, surgeons, and study coordinators from the 23 centers who participated in this trial. This trial today reflects their dedication and commitment to patient care, and we are delighted that many of them could take time out of their very busy schedules to attend this important meeting as our invited guests.

And I would ask the investigators and study coordinators to stand at this time and be recognized for their extraordinary contributions.

Thank you very much.

Our presentation today is divided into four parts. After a few introductory comments from myself, Dr. Mann will discuss the core concept, the preclinical studies, and the trial design, followed by Dr. Jessup, who will present the results of the trial to you, and I will come back for some final summary comments.

Our presentation today is meant to support an intended use statement which we had proposed and summarized here in this slide that the CorCap cardiac support device provides beneficial changes in cardiac structure associated with a reverse remodeling effect as defined by a reduction of left ventricular size, an increase in left ventricular ejection fraction, and a change to a more elliptical shape.

The CorCap cardiac support device also provides a decrease in the need for additional major cardiac procedures that are associated with the progression of heart failure and in an improvement in quality of life.

Our bases for this intended use statement comes from the demonstration of safety and efficacy, which is based on the four following points:

First, that the randomized trial performed achieved its primary endpoint at a P level of 0.024;

Two, that a number of secondary endpoints, including those that measure cardiac structure, such as the LV end diastolic volume, the end systolic volume, and the sphericity index, as well as secondary endpoints that deal with patient functional status, such as the Minnesota Living with Heart Failure questionnaire and the SF-36. All demonstrated significant clinical benefit of the CorCap cardiac support device.

Third, there were no safety issues identified, indicating that the device was safe.

And, four, based on all of this information, that the CorCap provides an effective therapy for patients with LV dilation and heart failure.

With that as a short background, I'd like to introduce Dr. Douglas Mann, who will introduce the CorCap concept and the preclinical studies.

DR. MANN: Good morning. My name is Doug Mann. I'm a paid consultant for Acorn Cardiovascular. I have no financial interest in the company.

My charge this morning is to briefly review the following three areas. We're going to focus on left ventricular dilation and the importance of that to the syndrome of heart failure. We will briefly mention that there's currently an unmet clinical need for patients who have large hearts and who have progressive symptoms despite optimum medical therapy, and then lastly, we'll review the scientific foundation for the CorCap, including three proof o concept studies which will briefly touch on the cellular and molecular mechanisms. We'll review some of the safety studies, and then we'll present the basics for the clinical trial, which my colleague, Dr. Jessup, will show to you shortly.

Progressive left ventricular dilatation produces a number of adverse consequences for the ventricle which are reviewed on this slide. First of all, as the ventricle begins to dilate and the walls begin to thin, there's an increase in wall stress. This, in turn, directly translates into an increase in after load for the ventricle, which can, in turn, lead to increased oxygen consumption and episodic subendocardial ischemia.

Furthermore, the progressive increase in left ventricular size can leave to stretch activation of a variety of maladaptive genes which are sufficient to activate the fecal gene program.

And finally, there's increasing evidence now that this progressive left ventricular dilatation can pull the papillary muscles apart and lead to progressive mitral regurgitation, which leads to a sustained volume overload on the ventricle.

It has been recognized now for a number of years that progressive LV dilatation heralds a worse prognosis for patients with heart failure. Shown on this slide are two studies, one by Hammermeister in Circulation in 1979, and the second by White and colleagues in Circulation in 1997.

As shown on the left-hand panel on this slide, adverse outcomes following an acute infarction were directly related to changes in left ventricular end diastolic volume and changes in end systolic volume.

Very similar findings were reported by White in Circulation, and as shown here, the relative risk of dying after an infarct is directly related to the end systolic volume of the patient following the infarct.

In addition to changes in left ventricular size, we now recognize the changes in left ventricular shape are also important in terms of determining patient outcomes.

Shown on the left-hand portion of the slide is the normal prolate ellipse shape of the ventricle, and you can see here that we break wall stress down into a circumferential wall stress, which is dependent on the length of the ventricle, and a meridional wall stress which is dependent on the diameter of the ventricle.

One of the things that we recognize now is as the ventricle remodels, the heart undergoes a transition from a prolate ellipse to a more spherical ventricle, and as it does this, there's an increase in the diameter of the ventricle such that meridional wall stress directly increases.

The reason why this is important is most ventricular shortening occurs in the short axis dimension. Very little shortening of the ventricle occurs in the long axis such that the increasing wall stress, meridional wall stress here directly impacts the amount of fractional shortening of the ventricle and can directly create a mechanical burden for the ventricle that didn't exist before.

The concept that ventricular size and shape is important is also borne out by the study by Douglas, et al., shown in the left-hand portion of this slide. They looked at left ventricular dimensions. As shown here the patients who have the larger hearts have the worst outcomes. Seven out of seven patients died who had ventricles greater than 7.6 centimeters, and then, again, in terms of the shape of the ventricle, you can see here the people who had the more spherically shaped ventricles, who had an increase in the ratio of the diameter to the length, also had the worst outcomes.

So both shape and size matter in terms of patient outcomes.

So what I've tried to show you over the last several slides is that patients with left ventricular dilation and progressive symptoms are at a high risk for limitations in the quality of life. They have frequent hospitalizations. They often need transplant and left ventricular assist devices, and as I've shown you there, an increased risk for high mortality.

Unfortunately, we have limited treatment options for this subset of patients. We know that cardiac resynchronization therapy is effective and will induce reverse remodeling, but it's effective really for only 20 to 30 percent of the patients.

We know that both mitral valve repair or replacement is effective, and that coronary bypass surgery is effective, but it's important to emphasize that neither of these two modalities have ever been tested or proven in clinical trials.

And lastly, we know that left ventricular assist devices and transplants are the last option for patients with advanced heart failure. So, in summary, we have limited treatment options for patients with progressive symptoms and large ventricles.

The CorCap cardiac support device is a fabric mesh device that's surgically implanted around the ventricle. It's intended to provide end diastolic ventricular support to reduce left ventricular wall stress and, hence, myocardial stress. It reduces the stimulus for ventricular modeling, and as we'll show you in preclinical studies, it also induces reverse modeling.

It is intended to improve cardiac structure and patient functional status in patients with moderate to advanced heart failure.

The CorCap cardiac support device looks like a very simple device, and yet it's a very complex device that has a number of key features which I'd like to review for you.

First of all, it's a multi-filament yarn, a knit fabric. It has four key design features. It has optimal compliance. It stretches enough so that it doesn't compress the ventricle, and yet it doesn't stretch too much so that it doesn't provide end diastolic support.

It has bidirectional properties, that is, it stretches more in the longitudinal direction than it does in the interior/posterior direction, and this tends to urge the ventricle back into a more elliptical shape.

It has a 31 microfiber construction so that it allows a smooth fit or a conformal fit under the surface of the heart, and last but not least, it has long-term biocompatibility. The polyester material that has been used has been used in other implantable devices.

How does the CorCap cardiac support device work? Most people in heart failure believe that the syndrome begins after some initial index event or injury to the heart that produces a decline in the pumping capacity of the heart. This decline in pumping capacity can lead to an increase in left ventricular wall stress and increase in myocardial stretch. Both of these components are then thought to lead to ventricular remodeling.

As I articulated on the previous slides, ventricular remodeling is sufficient to beget worsening cardiac functioning and worsening remodeling so that you end up with a vicious downward spiral.

The CorCap cardiac support device is intended to prevent the increase in wall stress and prevent the increase in dilatation, thereby preventing further cardiac remodeling, which we believe leads to an improvement in heart failure symptoms and better outcomes with patients with heart failure.

What I'd like to do now is to review a number of preclinical studies that have been compiled, and this is really an extensive preclinical database that shows the safety and efficacy of this device in experimental models, and it will provide some basis for examining the biochemical, cellular, and molecular mechanisms that underlie this unique device.

This slide is from a study by Tony Sabbah, and what they did was to use his microsphere injection model of heart failure. This, in my opinion, is the best model for studying heart failure. What they do is to progressively embolize the coronary artery with small microspheres. This, in turn, leads to microinfarcts and the injury which I mentioned previously. This, in turn, leads to progressive ventricular remodeling, and that's shown here in the control slides. There's a progressive increase in end diastolic volume, and these dogs will undergo the microsphere injection method.

Three months after implantation of the cardiac support device, you can see that there's a decrease in ventricular volume. If the device was just constraining the ventricle, the volumes would be unchanged, but what we see here is actually reverse remodeling.

This, in turn, translates to an improvement in overall pump performance for the ventricle, particularly in comparison to the control hearts, where there's a progressive decline in ejection fraction.

This slides shows the histologic findings of the CorCap cardiac support device. As shown here, it elicits a mild fibrotic response that covers the device. Importantly, there's no invasion of this fibrous tissue into the myocardium, and that's shown in the upper panel here. You can see here's the cardiac support device shown here. This green material is actually fibrous tissue, and you can see that there's really no invasion of the myocardium.

Furthermore, there's no compression of the arteries of the veins. This is the cardiac support device shown here, and you can see there's no compression of the artery and the vein. So it's really safe in preclinical models.

What are the components of reverse remodeling? This is, again, a study by Dr. Sabbah, and what he's done here is to look at a number of key signal transduction molecules that are involved in cardiac growth beginning with the p21ras, which is linked into endocrine signaling. You can see that there's actually up regulation of the amount of protein in heart failure. This is down regulated with the CSD device.

P21ras can activate a variety of signal transduction pathways shown here as the p38 pathway which has been linked into hypertrophic growth and signaling. You can see that the protein amount is increase in heart failure and then downregulated with the CorCap CSD.

And lastly, c-fos is a transcription factor that has been implicated in cardiac hypertrophic growth. Again, the amount of protein is increased in heart failure and then down regulated with the CorCap CSD.

So a variety of signal transduction pathways that we think are important for cardiac growth are up regulated in heart failure and are down regulated by reducing wall stress.

This not surprisingly translates into a decrease in myocyte size. Shown here are normal cardiac myocytes from the canine model. These are canine myocytes from a heart failure model showing an increase in width and length of the cells, and then three months following implantation of the CorCap CSD you can see that the myocyte size, both the length and the width, are both decreased.

In addition to the changes in myocyte size there are also changes in myocyte function, and that's illustrated on this slide. These are cell shortening curves as shown here. This is the cell at rest. This is the cell at the end of shortening. The amount of shortening is shown by the length of this line.

In heart failure we know that there's a decrease in the amount of shortening of the myocyte, and as you can see here, implantation of the CorCap CSD partially returns myocyte function towards a more normal shortening.

What I've done now is to provide the preclinical basis for the human safety studies which I'll show you on the next several slides.

This is a slide from one of the early safety studies done in Charite Hospital, and it has really two important features which we've found to be consistent in the large clinical trial, which my colleague, Dr. Jessup, will show you.

First, you can see that there's a progressive decrease in left ventricular end diastolic volume in these patients who had the CorCap CSD implanted. Furthermore, this change in end diastolic volume is durable.

Secondly, there's an improvement in ejection performance of the ventricle, and again, this improvement in the ejection performance is durable over time.

This slide shows pressure volume loops from a single patient that was enrolled in the Charite safety study, and it has several important features which I'd like to direct your attention to.

Shown on the vertical panel here is left ventricular pressure and on the horizontal panel is left ventricular volume. These are pressure volume loops of the ventricle and for the patient before the CorCap CSD was implanted. If there was cardiac compression, one would expect that the pressure volume, of course, would have been shifted upward and to the left. That doesn't occur with the CorCap CSD.

What we see instead is a reverse remodeling, a true reverse remodeling with a decrease in the pressure volume curve and the ventricles operating on a much more favorable pressure volume curve here.

Also note that the area of the pressure volume loop increases, which implies that there's an increase in cardiac work. So the ventricle is operating more efficiently. There's more work at less pressure.

In addition to reductions in the volumes in the ventricles and the pressures in the ventricles. there's a reverse remodeling in terms of cardiac mass. Shown here is a decrease in cardiac mass with the CorCap only, and a decrease in cardiac mass with the CorCap on top of mitral valve repair.

So in summary, what I've tried to show you over the last series of slides is that left ventricular dilatation is directly related to adverse patient outcomes. We've shown you briefly a series of animal studies that demonstrate proof of concept of reduction of wall stress leads to reverse remodeling of the cellular and molecular level.

And lastly, we've provided some safety studies that confirm the findings of the animal studies. The final step, of course, is the proof in a randomized trial.

What I want to do now briefly is review the trial design for the CorCap CSD. This slide shows the inclusion and exclusion criteria for the trial. We enrolled men and women age 18 to 80 years. They could be New York Heart Class III or IV heart failure of ischemic or nonischemic etiology. They had to have had a left ventricular ejection fraction of less than 35 percent and a large ventricle with a left ventricular end diastolic dimension of greater than 60 millimeters.

The two exceptions to these previous statements are that patients who are enrolled in the mitral valve stratum could have New York Heart Class II and/or an ejection fraction of less than 45 percent was allowed. The patients had to be functionally limited. They had to have had a six minute walk test of less than 450 meters, and they had to be on stable optimal medical therapy defined as ACE inhibitors and beta blockers plus or minus an aldosterone antagonist.

The exclusion criteria shown below, the patients could not have had a CABG, nor could they be on an active transplant list.

This slide shows the randomized trial design. We enrolled 300 patients who, as I said, were on optimal medical management. If, depending on the site investigator, the patient required mitral surgery, they were entered into a mitral surgery stratum and then randomized in a one-to-one fashion to either a control arm, which consisted of mitral surgery alone, or mitral surgery plus the CorCap, which we just referred to the treatment arm.

If, on the other hand, the site investigator deemed that they did not require mitral surgery, they were randomized in a one-to-one fashion to the control arm, which was optimal medical therapy, no surgery here, or optimal medical therapy plus the CSD.

The trial was designed according to an intention to treat analysis. It wa powered for 300 patients. The data analysis plan prespecified pooling of both strata and reporting as one cohort, and we felt that that was justified because the inclusion criteria in both strata were virtually identical, and the endpoints for both strata were identical.

This slide shows the primary endpoint at the trial, the clinical composite. It's important to emphasize that each component was clinically relevant and was detectable by the patient. The three components that comprised the worsening category could account for every clinical outcome for a patient with heart failure. For example, patients who were considered worsened could either have died during the study, could have had a major cardiac procedure that was adjudicated by a blinded committee to be because of worsening heart failure, or could have had worsening New York Heart Association class as assessed by a blinded New York Heart assessor.

If the patient was improved, they had to have had an improvement in New York Heart Association as assessed by a blinded assessor, and they couldn't have had anything that would have categorized them as worsening during the trial.

We underwent a number of careful measurements to assure safety of the device, which my colleague, Dr. Jessup, will review for you. I just briefly want to touch on them. As mentioned, we looked at cardiac mortality. We looked at major cardiac procedures that we felt were indicative of worsening heart failure. We catalogued a variety of serious adverse events, and then finally we looked at the combination of serious adverse events or death.

So we've undergone extensive analysis to prove safety in the device.

This slide summarizes the secondary endpoints for the trial, including cardiac structure and function and changes in patient functional status. So we examined left ventricular end diastolic volume and systolic volume, ejection fraction, sphericity index as a measurement of left ventricular shape. We looked at left ventricular mass and the amount of micro regurgitation severity.

We also looked at patient functional status in terms of the Minnesota Living with Heart Failure questionnaire, SF-36, as the generic functional status measurement, New York Heart Association class, all cause hospitalization, peak VO₂, and finally six minute walk.

We recognized going into this trial that it was a device trial, and as such was unblinded. So we went through a number of careful steps to try to reduce study bias in the trial to maximize the scientific integrity of the trial.

First of all, the design of the primary endpoint included what most people would consider as a hard endpoint, mortality. We also designed the three components that went into worsening to be interdependent. So that, for example, if one didn't undergo cardiac transplantation, they would show up a worsening heart failure. So there's really no way to hide with the way that we designed the primary endpoint.

All core labs were blinded to a treatment allocation, and these were the core labs that made the important measurements of both the primary and secondary endpoints, and the sponsor and the investigators were kept blinded to the aggregate data.

A second implementation that was made was the development of a clinical events review committee that was blinded to the patient treatment allocation with respect to a number of important outcomes.

So shown here, patients who underwent mitral valve surgery, tricuspid valve surgery, biventricular pacing, the CERC committee had to adjudicate whether these were done because of worsening heart failure, and they were blinded to treatment allocation, both VADs and cardiac transplants, the CERC was not blinded as to outcome. We considered that these were indicative of worsening heart failure.

And the third final element that was really implemented at the behest of the FDA was the development of a blinded New York Heart Association core laboratory assessment. This was implemented to reduce a potential bias. It utilized a questionnaire that was administered to the patient by the blinded site clinician. The questionnaire was validated prior to implementation. The questionnaire was then sent to a cardiologist who was blinded to treatment allocation, who then assigned a New York Heart Association class.

The core New York Heart Association class was used in all of the analysis of the primary endpoint. Unfortunately this was implemented as the trial was rolling forward. So they were missing baseline core values that were -- they were missing patients because the analysis was implemented as the trial rolled on.

It's important to emphasize that there are really two types of data in this trial because it can be a little confusing, and I wanted to walk you through these briefly. First of all, there are data that are driven by the common closing date, and this includes deaths, all adverse events, and major cardiac procedures. So all of thee events were captured within the trial.

There were also data that were collected at follow-up visits, including three, six, 12 and every six months thereafter, and this included the echocardiographic assessment of LV structure and function, the New York Heart Association class, the quality of life data, and finally the exercise testing data.

What I'd like to do now is to introduce my colleague, Dr. Mariell Jessup, who will review the main trial results with you. Dr. Jessup is the head of heart failure transplant at the University of Pennsylvania.

DR. JESSUP: My name is Mariell Jessup. I'm a member of the steering committee for the Acorn CorCap randomized trial and was also a co-principal investigator at our clinical site at the University of Pennsylvania. I have no financial interest in the company.

I'm very pleased to present the results of this randomized trial. As reviewed by Dr. Mann, there were 300 patients who had already undergone optimal medical management with standard heart failure therapy. One hundred and ninety-three patients were placed in the mitral surgery stratum, patients in whom the site investigators determined that mitral surgery was required.

These 193 patients were then randomized in a permuted block design for each stratum, into mitral valve repair replacement alone in 102 patients and mitral valve surgery plus the CorCap cardiac support device, CSD, in 91 patients.

The remaining 107 patients were in the no mitral surgery stratum and were randomized to continue on optimal medical therapy as the control group in 50 patients or the optimized medical therapy with the CSD in 57 patients.

Data was collected from the beginning of the study in June of 2000 until the common closing date, July 4th, 2004, so that each patient contributed different amounts of follow-up data by the end of the study.

Specifically, there was a minimum plan follow-up of one year, but there were only 37 percent of patients who were followed for this minimum time of 12 months. Twenty-one percent were followed for 18 months; 23 percent were followed for 24 months; and 19 percent were followed for 30 months or greater. Therefore, the median follow-up was 23 months.

In general, these patients were similar to multiple other low EF heart failure trials with a few notable exceptions. The patients enrolled were slightly younger, with a mean age of 52.5 years. There was a higher percentage of females enrolled. There was a higher number of non-white patients in this study compared to most other trials, and the most common heart failure etiology was idiopathic as compared to ischemic in other trials.

This study does, indeed, however, represent a population of chronic heart failure patients, since the mean duration of heart failure in this group was at least five years.

This slide shows the baseline structural and functional characteristics of our study population. The mean left ventricular end difolic (phonetic) diameter was enlarged at 69.8 millimeters. Peak V dot O₂ in this patient population was 15 mLs per kg per minute. The mean left ventricular ejection fraction was 23 percent. The Minnesota Living with Heart Failure score was elevated at 59.3, and the six minute walk distance achieved was only 340 meters.

A small group of patients were designated as NYH Class II by the site investigators.

You will remember that the study design allowed these patients to be entered if they were going to undergo mitral valve surgery. The majority of the patients, however, were in NYH Class III.

The patients' baseline medications were to include optimal medical management. The investigators of the study adhered to these instructions, and I think the high percentage of concomitant medical therapy in this trial should be taken into account as I present the results to you.

Fully 90 percent of all patients were either on ACE inhibitors or angiotensin receptor blocker, or ARBs. Eighty-five percent of all patients were on a stable beta blocker dose for at least three months. Almost all patients were on a diuretic and almost half of the patients were on aldosterone antagonists.

This represents a concomitant medical therapy or optimal medical management that really is noteworthy in contrast to many other earlier heart failure trials.

Randomization in the study yielded comparable groups between treatment and control, except for three baseline covariates. These included gender. As more women were randomized to the treatment arm, the core lab peak V dot O₂ as the treatment arm in this study had a lower value for V dot O₂, and diastolic blood pressure, especially in the MVR stratum. There was no identifiable cause for this imbalance, and as specified in the data analysis plan, therefore, covariate adjustment of the primary endpoint was necessary for these variables.