• If you live in Minnesota the program provides a 25-percent individual income tax credit.  If you do not generate enough tax liability the difference will be provided as a cash payment.
• If you are not a Minnesota resident, or even a resident of the United States, the entire credit will be given as a cash rebate equivalent to 25% of your investment.
• The program allows a maximum credit or grant of $125,000 per year per individual ($500,000 investment) or $250,000 for those married and filing jointly ($1,000,000 investment).
• The program has allocated $11 million dollars in tax credits for the rest of this year.  So far, about 30 companies have qualified to participate.  It is a first come/ first serve process until the funds are distributed.

Although any prudent investor would not invest in a company only because the investment risk is hedged by government participation, I think the State of Minnesota should be commended in their effort to stimulate the investment process.

Currently, Cardious is looking for qualified investors to invest $1.4MM  to support the next phase of product development resulting in human implantation.  Please contact me if you are interested in learning more.

• We believe all cardiac surgeons in all operating rooms around the world should be able to confidently provide most patients an “off pump” procedure.

• We believe an “off pump” aortic valve procedure should not be constrained by native valve anatomy, limited to “centers of excellence”, carry a high risk profile, or require an extremely high, perhaps unsustainable, selling price to be profitable.

Download this graphic as a PDF File

What I found to be even more interesting is the response Dr. Vliek gave to a question from Dr. John Kern in the Discussion section.  He asks what is the future of AVBG in light of “…soon to be widespread acceptance of transcatheter heart valves”.   I thought her answer  provides a great summary of why AVBG should be considered as a safer, more practical  way for surgeons to provide an off pump, less invasive aortic valve procedure.  I have reprinted her response below.

What is the future of this procedure going to be, seen 5 years from now and 10 years from now, given the transcatheter valve replacements? We feel there are some key differences between aortic valve bypass surgery and transcatheter valve replacements that may favor an aortic valve bypass approach.

Number one, our incision is the same size as is used in a transapical approach for a stent-mounted valve. Aggressive balloon aortic valvuloplasty is mandatory before implantation of a stent-mounted valve, and we know that there is a significant incidence of cerebral embolic injury associated with this maneuver; in contradistinction, the native aortic valve is never manipulated during aortic valve bypass surgery.

There is a clear risk of stroke associated with transcatheter and transapical stent-mounted aortic valve implantation, related to balloon aortic valvuloplasty as well as to manipulation of wires in the arch. In the longer term, we don’t know the embolic risk of a large stent in the ascending aorta. We do know that after conventional AVR, there is a 1% to 2% per year risk of stroke attributable to the presence of a prosthetic valve in the native position. We have shown that all cerebral blood flow after AVB surgery is supplied across the native valve; no blood traversing the prosthesis in the conduit reaches the brain; that may accrue a long-term benefit in terms of stroke prevention.

There is a significant risk of heart block requiring pacemaker implantation after stent-mounted aortic valve implantation; this is as high as 30% in some series. Since the native aortic valve is never manipulated in aortic valve bypass surgery, we have never seen heart block after this operation.

With aortic valve bypass surgery, there is no risk of damage (dissection, rupture) to the ascending aorta, nor a risk of obstruction of the coronary ostia. There is no risk of prosthesis malposition or embolization. There is no risk of peripheral vascular injuries. Although the incidence of paravalvular leak is significant after stent-mounted aortic valve implantation, we have, for obvious reasons, never seen paravalvular leak after aortic valve bypass surgery.

Clinical follow-up after stent-mounted valve implantation is limited to a few years; in contrast, there are a number of patients walking around today who have had an aortic valve bypass in place for more than a quarter of a century.

Aortic valve bypass surgery has not been widely performed because it has largely been under the radar screen, and in addition there is a certain “fear factor” associated with the insertion of a conduit in the apex of the left ventricle, particularly while the heart is beating. There are currently several surgical tools in development that will automate this process, making it rapid, bloodless, and reproducible. So we feel that this approach is very competitive with, and in many ways superior to, transcatheter (or transapical) stentmounted valve implantation.

We would suggest that future prospective studies comparing conventional AVR, medical therapy, and transcatheter valve implantation include an aortic valve bypass arm at a center experienced in this approach.

• We believe a successful aortic valve surgery business should revolve around experienced surgeons safely implanting proven, state of the art heart valves – even if the procedure is done “off pump”.
• We believe all cardiac surgeons in all operating rooms around the world should be able to confidently provide patients an “off pump” procedure.
• We believe an “off pump” aortic valve procedure should not be constrained by native valve anatomy, limited to “centers of excellence”, carry a high risk profile, or require an extremely high, perhaps unsustainable, selling price to be profitable.

Are we basing our business on the right fundamentals?  What do you think?

At the recent TCT conference in San Francisco, the midterm results of the PARTNER EU transcatheter valve study were presented.  This study followed 120 patients implanted with the Edwards Sapien Valve.

Heartwire ran a story on the study results reporting that the patients in the study had dramatic improvements in NYHA classification one year post implant.

Functionally, at one year, 89% of patients had NYHA class 1 or 2 heart failure, with 81% improving by at least one heart-failure class over this period.

I was so impressed with these results that I wanted to look at the actual data.  I went to the TCTMD website and downloaded the 18 mo PARTNER EU results.  Below are the PowerPoint slides showing the basis for the 89% and  81% improvements.

The data looks great upon first inspection  but, after further review, it looks less than great.  Let me summarize the data shown on the charts.

Slide 1 – NYHA Group at One Year

Slide 1 - Click to Enlarge

• About 53% of the patients enrolled in the study are in NYHA class I or II
• About 7 % are in NYHA Class III or V
• About 38 % are dead (there is no NYHA Class for death)
• 2 % are lost to followup

Slide 2 – NYHA Improvement at One Year

Slide 2 - Click to Enlarge

• At one year follow-up, 60 pts of the 118 (2 lost to follow-up) improved at least one NYHA class – this equates to 51% of all patients, not 81% as reported.
• The remaining 58 pts. saw no improvement or got worse, with 46 being dead by year end.

I summarize this data as follows:

Of the patients that received a Sapien valve, about 50% felt better after one year.  About 80% of the pts. that did not feel better died.  This equates to about a 40%  overall death rate at one year.

Why did the study report 89% in Class I or II and  81% improvement in heart class?  It is because the results are based on analyzing only the patients that survived to year one.  The results do not include the significant number that died and are not in a NY heart class.

Although this might be how the PARTNER study investigators have agreed to analyze the data, it does not seem to be a very fair statistical representation, especially when the death rate is so high.   Using this statistical logic to an extreme, if only one patient survived after one year and this lucky patient also improved one heart class, the dismal study results could be optimistically reported as:

“At year one, 100% of patients improved at least one NYHA class”.

There are other slides in this PARTNER presentation that also eliminate the accumulating dead patients from the success calculations as time moves forward.   Even if this is considered standard practice, isn’t it misleading.  Or is my interpretation wrong?

Maybe it would it be helpful if  death was added as NYHA Class V?   What do you think?

AVBG Human Implant

surgeons willing and able to source needed components (off label)  and build the implant on the back table, to a predictable, easy to perform  procedure using an approved device and tool.  We will be successful when all surgeons have access to the implant and tools needed to  perform this procedure off-pump safely and with confidence.   But, until then, surgeons will, out of necessity, continue to perform this procedure using the best available but suboptimal materials and methods.

Recently, at the TCT convention in San Francisco amongst  interventional cardiologists promoting transcatheter valves as the “final solution” in AVR, Dr, James Gammie presented the  state of the art in aortic valve bypass grafting. His presentation did an excellent job explaining the features and benefits of AVBG along with his clinical results.

Compared to Standard AVR, Dr. Gammie points out that AVBG needs:

• No Aortic Cross Clamping
• No Debridement/Removal of Diseased Valve
• No Aortic Cannulation
• No CPB

Together, these all minimize embolic risk.  Also, AVBG has the following features:

• No Sternotomy
• No Cardioplegic Arrest
• No Patient-Prosthesis Mismatch
• No Heart Block

Dr. Gammie reported on his series of 31 patients, representing 7 % of his isolated AVR procedures.  Pre-op STS scores were 9.3 +/- 4.5.  Operative mortality was 26% in his first 15 pts. and 0% in his last 16 patients.  Side effects have been minimal.

Along with Dr. John Brown, Dr. Gammie has become a leading proponent of bypass grafts in the United States and has done an excellent job promoting the procedure to his colleagues.

Dr. Gammie and group at the University of Maryland have a good paper summarizing the current state of the art.

Dr.  Kerut and his colleagues in Louisiana have a good paper analyzing flow post implantation using TTE and TEE.

Dr. Speziali and group from Pittsburgh have a good paper showing the current “On Pump” technique in detail

and..

Dr.   Nishimura and his group from Japan have a great picture of an implanted graft.

Even though these papers, and many others from around the world, report on the success of the basic procedure, we at Cardious think the current clinical use is only the “tip of the iceberg”.  What is needed is a specifically engineered implant device and insertion tool to allow a surgeon to repeatedly and confidently perform the procedure, using a valve of choice, on a beating heart.

Our goal is to deliver exactly that.

How significant is concomitant coronary artery disease and why would it be contraindicated?

Again, based on research done by Dr. William Roberts, a cardiac pathologist who has studied aortic valves for over 40 years, over 65% of stenotic tricuspid patients also present with CAD so severe that at least one bypass graft was necessary at the time of valve surgery.  I have again taken the liberty to graph the data Dr. Roberts presented  in table format only.

This data is significant because the PARTNER Trial specifically excludes patients with CAD.  Here is the specific exclusion statement:

7. Untreated clinically significant coronary artery disease requiring revascularization.

And if a coronary stent procedure is done beforehand to alleviate a coronary obstruction, the patient is excluded from a transcatheter procedure for 6 months, effectively eliminating transcatheter as an option for most of these patients.  Here is the exclusion statement in the PARTNER Trial.

4. Any therapeutic invasive cardiac procedure performed within 30 days of the index procedure, (or 6 months if the procedure was a drug eluting coronary stent implantation)

Why are CAD patients being excluded?  Below are a few pictures that might explain the reason.  Careful examination of angiograms post implant of both a balllon expandable and a self expanding transcatheter valve show the distinct possibility of the implant obstructing the coronary ostia, not from blood flow, but from subsequent guide catheter insertion.   The last photo clearly shows an ostium with an obstructed entrance.  By implanting a transcatheter valve, the patient’s coronaries may become predictably inaccessible in the future.  I assume most cardiologists would agree this is a good reason to exclude transcatheter procedures in patients presenting with CAD.  By providing an immediate less invasive procedure, a future less invasive procedure may be forfeited.

Graphic Source, Anatomy of the Aortic Valve Complex and Its Implications

Graphic Source, Anatomy of the Aortic Valve Complex and Its Implications

In summary – if only 60% of patients over age 70 present with a stenotic tricuspid valve and 65% of these have severe CAD, that leaves only 21% of all stenotic AVR patients over age 70 eleigible for a transcatheter procedure (did I do the math right?).

My point – Transcatheter procedures will not dominate the market due to fundamental clinical restraints.  AVBG, which is agnostic to valve shape or concomitant coronary artery disease, is a logical less invasive choice for many patients.

Bicuspids Do Not Qualify

AVR (Aortic Valve Replacement) have a bicuspid shaped valve and that a bicuspid shaped aortic valve is a major contraindication to transcatheter valve implantation (reference PARTNER Trial and European Guidelines).  Rationale for this contraindication can be found in a paper by Dr. Zegdi.

Actually, when you take into account all age catagories, over 55 percent of current surgical patients have a bicuspid (or unicuspid) valve.  These findings are based on a detailed review of 932 consecutive AVR patients performed at Bayor University Medical Center by Dr. William Roberts, a veteran cardiac pathologist.  Dr. Roberts’ paper clearly defines the morphology of unicuspid, bicuspid, and tricuspid aortic valves and in table form presents the breakdown of valve type by age (in decades) and by sex.  Unfortunately, Dr. Roberts did not present his data in graphical form.  I took the liberty to graph his data and it is shown below.

The literature states about 98% of the population is born with a normal tricuspid aortic valve and that unfortunately, about 2% of the population is born with either a bicuspid or a unicuspid aortic valve.  Obviously (at least to biomedical engineers) a bicuspid valve is prone to early and severe calcification due to the unnaturally high stress levels required in a two leaflet design.  That is how only 2% of the population can deliver over 50% of  the stenotic AVR surgeries and why younger stenotic patients predominantly present with a bicuspid valve.

With this data in hand, it is clear that transcatheter valves, contraindicated for bicuspid valves, will not be applicable to a large percentage of patients  If Roberts’ data published in 2005 is representative, 55% of all stenotic aortic valve patients and more specifically  40% of patients over age 70 that need a less invasive “off pump” procedure will present with a bicuspid valve and will necessarily look to AVBG as their best “off pump” solution.

If 98% of us who have a tricuspid valve  acquire a calcified stenotic valve, it will most likely be due to the typical atherosclerotic aging process similar to that seen in CAD (coronary artery disease).  My next post will talk about the correlation between stenotic aortic valves, transcatheter implants, and concomitant CAD in more detail.

Our device can be viewed as both complementary and directly competitive to the new class of transcatheter valves being developed by Edwards, Medtronic, and others.

It is complementary because it can be implanted in patients that present with a bicuspid shaped valve – a condition strictly contraindicated for transcatheter valve devices.  Even though only 2% of the population is born with a bicuspid shaped valve, over 40% of stenotic aortic valve patients over the age of 70 present with a bicuspid valve!

Our device is also directly competitive because, frankly, it is a better “off pump” solution even for patients presenting with a tricuspid valve.  Unlike transcatheter devices, our device:

1. Is combined with a surgeon selected “off the shelf” prosthetic heart valve with a proven long term implant history and therefore does not require substantial investment into a new class of heart valve.
2. Does not require the implantation of a pacemaker – 30% of transcatheter patients do.
3. Will not inhibit future coronary artery interventions – most transcatheter valves do.
4. Is safe, relying on minimally invasive “line of site” implant management techniques already fully established by skilled cardiac surgeons.
5. Is substantially less expensive, positioned to compete in the current healthcare environment.