• 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.

In an earlier post, I mentioned that a few years back my design consulting firm was involved in the development of a transcatheter valve device.  Like my cartoon friend to the left, when I started the project I  asked my client what were the design guidelines.  Basically, the answer I received, which I think would apply to most all the transcatheter start-ups firms back then, can be summarized as follows:

• Eliminate the use of the heart lung machine
• Perform the procedure thru a small hole.

Given these two parameters, I would agree that a transcatheter valve is a logical design output.

But it wasn’t long into the development program that I soon realized that to be truly successful against the gold standard put forth by traditional valve replacement surgery, these two design parameters were critical, but alone not sufficient for long term success.  I now realize four more guidelines should have been given to me  to meet real market expectations.

• The valve must be as good as current valves on the market
• The procedure should be applicable to a broad range of patients, doctors, and hospitals.
• In this risk adverse marketplace, the new product should present a reasonable risk/reward ratio to investors
• And, the new valve should meet a rule I know all doctors follow – do no harm.

Of course, I believe our AvA device meets this full palate of design guidelines and transcatheter designs fall a bit short.  I hypothesize that transcatheter valve designers were not directly asked to meet all of these additional design requirements so, if they didn’t meet them, that would neither be surprising nor a criticism of their design skills.

Let me quickly go through and review  these design guidelines in more detail.  You can then be the judge as to their validity and importance in the marketplace.  Email me your opinion.

Eliminate use of the heart lung machine

A major drawback of a conventional aortic valve replacement procedure is that the patient must be placed on a heart-lung bypass machine wherein the heart and lungs are stopped.  The risks and complications associated with this highly invasive procedure are well known. These include:

• Increased risk of blood clots / debilitating stroke
• Organ failures post surgery
• Excessive bleeding
• Inability to restart the heart / death

The AvA procedure (and a transcatheter procedure) is performed on a beating heart, thereby eliminating all of the above risks.

Perform the procedure thru a small hole

The AvA procedure does not require a large sternal chest incision like that required to install a traditional heart valve. Similar to an apically place transcatheter valve, our procedure can be performed through a small incision made between the ribs.   Performing the AvA procedure provides the following benefits compared to traditional surgery.

• Shorter hospital stay
• Less pain and scarring
• Less risk of infection
• Less blood loss and fewer transfusions
• Faster recovery
• Quicker return to normal activities

I think we can all agree, when compared to traditional valve surgery, both the AvA Valve Bypass Graft and transcatheter designs currently in development meet these two fundamental guidelines.   Now let’s move on to the remaining four guidelines that I think are equally important to clinical success leading ultimately to business success in the marketplace.

The valve must be as good as current valves on the market

At the operating table, our AvA device is combined with a conventional, FDA approved heart valve selected by the surgeon.  The valve selected  will no doubt already have a long history of excellent performance and be expected to last a minimum of 15 years.

Transcatheter valve products must rely on radically new designs that are unproven in long term clinical trials.  In practice, these designs will need 5+ years of human implant data before even preliminary valve durability and performance can be clinically assessed.   Risk of failure is not insignificant – an implanted heart valve needs to open and close 40,000,000 cycles per year (over 100,000 times per day!).  A valve failure can mean sudden death.

Be applicable to a broad range of patients, doctors, and hospitals

Except for patients presenting with moderate to severe aortic insufficiency, the Cardious device is agnostic to the annulus size, calcific structure, or leaflet configuration of the native aortic valve.

Transcatheter valves, on the other hand, are restricted to implantation into only tricuspid shaped valves.  Patients with bicuspid valves are excluded from the Edward’s FDA human trial and are also excluded in guidelines jointly established by the European Association of Cardio-Thoracic Surgery and the European Society of Cardiology.  The reason is that the elliptically shaped opening of a stenotic bicuspid valve is not conducive to maintaining the necessary blood tight seal around the cylindrically shaped transcatheter valve.   This anatomical restriction is not insignificant with regard to market opportunity.  Published studies suggest up to 40 % of patients over the age of 70 that have valve replacement surgery have a bicuspid shaped aortic valve.

Also, guide catheter access to the coronary ostia will most likely be blocked by the implanted transcatheter valve, thereby preventing future coronary stent interventions.  This is important since a majority of patients presenting with a calcific tricuspid shaped aortic valve also have coronary artery disease.   This “coronary jail” side effect seems likely to be a serious inhibitor of broad clinical use, especially in younger patients (less than 80), but as yet I have not seen it discussed in the literature with one exception.  Upon careful reading of the Edwards PARTNER trial protocol, patients with significant untreated coronary artery disease are excluded from participating in the study.  Is that why – because future coronary intervention may not be possible?

Unlike transcatheter valve products, extensive training, additional personnel, and a hybrid surgical suite are not required to use our device.  The AvA procedure can be easily adopting by all cardiac surgeons working in standard operating rooms anywhere in the world.

In this risk adverse marketplace, develop a product with a a reasonable risk/reward ratio to investors

Our device does not require the large capital investment required to development of a new class of heart valve.  We do not need to design, test, redesign, retest, redesign … our valve stent or tissue selection until we meet the significant performance requirements promulgated by both European and perhaps, as evidenced by Corevale’s no show in the US,  more onerous  FDA regulators.  Our device is a hybrid textile graft with no moving parts.  Although we will need to demonstrate implant quality design and compatibility within a blood flow environment, the risk and related time and money to market is substantially less than that of our transcatheter brethren.

Also, once design and regulatory hurdles are met, customer clinical adoption of our device could be rapid based on surgeon confidence in the procedure (based on prior experience) and limited competition from transcatheter devices in the large cohort of patients presenting with a bicuspid valve or severe CAD.  Also, since our product does not obsolete current valves on the market, we believe current valve companies will be supportive of our device.   These factors should all contribute to reduced investment risk.

Do no harm.

An AVBG procedure is fundamentally a safe procedure.  Throughout the procedure, the surgeon has line of sight control.  If an inevitable “situation” occurs, the surgeon has multiple bail out options not afforded cardiologists performing a percutaneous transcatheter procedure.  Also, because the AVBG graft is connected to the descending aorta, most blood flow will be away from the brain.  Based on prior published papers, embolic stroke events attributed to either the procedure or the implanted valve are not likely.  On the other hand, transcatheter procedures have the following inherent concerns already demonstrated in initial human trials:

• Aortic root disturbance due to valvuloplasty and stent implanatation can lead  to emboli generation leading to stroke.
• Significant infection and/or vessel damage can occur at the catheter insertion site.
• Permanent pacemaker implantation has been necessary in a significant numer of patients.  (This seems more prevelent in nitinol designs compared to stainless)

Of course, you all realize that my critique of the design requirements might be biased.  What do you think?  Which approach – transcatheter or valve bypass – do you think best meets the design requirments, and why?

My short answer:

Superior risk management profile

Now for the longer answer.

When compared to emerging stent valve technologies, I believe our bypass graft device will provide an equivalent less invasive “off pump” aortic valve therapy but with lower short term and long term risks for the patient, the surgeon, and our company.

Prosthetic Heart Valve Risk
In our approach to “off pump” valve surgery, we do not have to accept the historically predictable high development and product liability risks associated with the design, manufacture, and implantation of a new class of heart valves.  One only needs to review the “Shiley Experience” to realize how much risk can be imbedded in a heart valve implant.  Contrary to a defective angioplasty catheter that can be discovered and corrected on the table within a few minutes, a defective heart valve can remain in remission only to emerge years later possibly as a life threatening failure affecting thousands of patients (and implanting physicians) and the financial stability of the valve company.

With our valve bypass graft system, the surgeon will not need to worry about valve quality or valve implantation risks.  Our device employs an already commercially available, already clinically proven heart valve selected by the surgeon at the time of implant.  Our implantable graft device is a low risk design with essentially no chance of peri-valvular leak.  It is composed of well characterized blood compatible materials and has no moving parts.

Implantation Risk
Unlike stent valves, we will not ask our customers to implant a historically unproven valve using a technique outside of their normal surgical skill set.  Based on initial animal studies, we believe all surgeons, not just those fortunate to work in a hybrid OR surrounded by a large support team, can perform our bypass graft procedure off-pump safely with minimal additional training.   With our off-pump approach, through a mini-thoracotomy the surgeon has complete line of sight visual and tactile control of the operation.  If any problem occurs, the surgeon has multiple options to control the situation.  Prior clinical work performed by surgeons around the world has already established  human feasibility of the general procedure, including multi-year follow-ups.

Compare the bypass graft risk scenario with the stent valve procedure (percutaneous or apical) that relies on extensive pre-op work-ups and calculations, a large support staff, real time fluoroscopic and ultrasound vision, remote manipulation, and allows for few bail-out options when, inevitably, a life-threatening mistake is made.  Our device does not rely on “good” stenotic morphology at the implant site for procedure success, does not have a propensity to generate emboli, and will not damage conduction pathways.   Unlike conventional valves where long term durability risk resides exclusively with the manufactuer, stent valve durability relies in large part on the procedure technique.  The implanter must now accept a large portion of the risk for future device failure.  Was the valve damaged during crimping?  Was it placed too high or too low.  Was a native leaflet inverted so that calcific excrescences can wear away a leaflet?  Is the stent so oval that the leaflets do not coapt without exerting undue stress on the tissue?

We all know that in either technology, the patient will benefit short term from a successful “off pump” procedure.  But only with our procedure can the patient benefit long term by knowing that the implanted prosthetic valve (required to open and close 40 million times per year) is an already clinically proven and highly reliable device.   Stent valve supporters openly admit that collapsible stent valves may not be as durable as traditional valves.  They want the patient (and market) to accept the inevitable higher risks associated with a radical new valve design in return for the life saving benefits of an “off pump” procedure.  With our device, this tradeoff is not required.   Patient, surgeon, and Cardious will all sleep well, knowing that the implant will be as safe and reliable as the “gold standard” traditional heart valve because it will contain that same “gold standard” heart valve within a “gold standard” textile graft.

At the End of the Day
In summary, at the end of the day, we believe our customer, the cardiac surgeon, will continue to judge the success of heart valve surgery based on the long term performance of the valve, not the short term convenience of the procedure.  Stent valves have opened the door to allow surgeons to consider “off pump” options for their large pool of “no option” and “high risk surgical” patients.  We believe when we advance our technology into human use,  a proper risk/benefit analysis will drive the market, in particular the cardiac surgeon, to see that our approach is the obvious next step in aortic valve therapy.

What do you think?  I look forward to reader response, especially from surgeons.