Does the Blood Flow Up?

I can’t tell you how many times I have been asked that question when I present our aortic valve bypass concept to non-surgeons.

I no longer need to answer by referring the doubting Thomas’ only to the substantial body of clinical evidence published over the past 40 years demonstrating that apex to aorta valve bypass works just fine perfusing the coronaries, upper extremities, and the brain.  I can now  say – ask the Mayo Clinic.

Through collaboration with cardiac surgeons at the Mayo Clinic we recently completed a ten swine animal study – elegantly simple in design but technically challenging in implementation.  Using ultrasonic flow probes supplied by Medi-Stim, we measured blood flow simultaneously in eight arteries around the heart both before and after the graft was installed and with the native aortic valve completely occluded (simulating a worst case stenotic valve condition).  Flows were simultaneously measured in the:

  • LAD
  • Circumflex
  • RCA
  • Right Common Carotid Artery
  • Right Internal Mammary Artery
  • Ascending Aorta (above graft anastomosis)
  • Descending Aorta 9 below AVBG anastomosis
  • Pulmonary Artery

The bottom-line result:  none of the flows significantly changed after the native aortic valve was totally occluded except flow in the descending aorta above the graft anastomosis immediately reversed from downward to upward.   Also, a key finding was that there was no change in coronary flows.

Although surgeons know this procedure works, the effect on nearby and systemic circulation due to the altered outflow path has never been carefully measured.  Some researchers have performed theoretical flow calculations predicting acceptable retrograde flows to the coronaries and carotids, but to my knowledge no one until now had ever directly measured blood flow in all the major arteries surrounding the heart immediately pre and post graft implantation.

The study results were reported at the ISMICS annual conference in Washington on June 9.   Click to read the paper’s abstract.  Based on this work, lead investigator Dr. Nikolaos Tsirinkos-Karapanos was awarded the prestigious Robert Emery Young Investigator Award.

Congratulations to Dr.  Tsirinkos-Karapanos and the entire team at Mayo.  Through their scientific inquiry, a fundamental question about AVBG has been answered.  No doubt, the now widely accepted Coronary Artery Bypass Graft (CABG) procedure, having similar non-physiological flow, had to answer a similar question early in its path to broad clinical acceptance.

PARTNER Exclusion #23 – Bulky calcified aortic valve leaflets in close proximity to coronary ostia

In prior posts I have argued in support of the clinical need for the AVBG procedure because transcatheter heart valves, even if proven safe and effective, will have significant limitations with regard to broad clinical use.  The recently published Partner Study evaluating the Sapien transcatheter valve in non-operable patients seems to support my argument.  The study lists 23 exclusion criteria limiting the use of the Sapien valve.  In  past posts I have discussed in some detail two of the major exclusion criteria.

Exclusion Criterion # 2 – Aortic valve was a congenital unicuspid or congenital bicuspid valve, or was non-calcified.

(I posted that bicuspid valves are present in 40% of surgical valve patients over the age of 70)

Exclusion Criterion # 7 – Untreated clinically significant coronary artery disease requiring revascularization

(I posted  that CAD is present in 65% of surgical valve patients over the age of 70)

After the PARTNER study was published, I reviewed the entire list of exclusion criteria published in the paper supplement.   I noticed an additional exclusion criterion was added that was not included in the original protocol :

Exclusion Criterion #23 – Bulky calcified aortic valve leaflets in close proximity to coronary ostia.

Bulky Leaflet

I did a little research on “bulky leaflets” and found a good paper by Dr. Masson and colleagues describing a transcatheter patient who had this type of calcific leaflet.   The authors report that when the Sapien valve was expanded into place the “bulky leaflet” was pushed up and positioned in front of the entrance to the coronary artery causing a deadly limitation in the amount of blood flowing to the heart muscle.

It is unclear how many potential transcatheter patients present with a bulky calcified leaflet.  There is no data in the PARTNER study results stating how many patients were excluded for this or any other condition.  All we know is that in aggregate, only 35 % of the patients that cardiologists and surgeons nominated  (1,079 of 3,105) were included in the study.

My point is, with 23 exclusion criteria it is not unreasonable to expect that the majority of  patients presenting with severe aortic stenosis needing an off pump/beating heart procedure will not qualify for a transcatheter implant.   For these patients, an alternative less “excluding” less invasive procedure will be needed.


How Invasive?

Less invasive is a term that is hard to define.  One simple way is by size of scar.

Scar Comparison

Transcatheter Heart Valve Procedures Generate Embolic Brain Lesions in Most Patients

Recently, clinical investigators using both the Edwards and Medtronic transcatheter heart valves reported that in the majority of patients undergoing a transcatheter valve implantatioclick to enlargen, one or more embolic induced lesions are created in the brain, presumably from calcific embolic material breaking loose during the procedure. Emboli could be created while traversing the arch, performing the balloon valvuloplasty (common to all procedures), or during  the actual stent implantation.  In both the Medtronic / Corevalve Emboli Study (22 pts) and the Edwards / Sapien Emboli Study (29 pts femoral / 31 apical), the investigators reported that over 65% of patients undergoing a transcatheter procedure had at least one measurable new brain lesion post procedure identified by MRI (diffusion weighted imaging, 1.5 Tesla). In patients identified with atleast one new lesion, the average number of new lesions ranged from 3.4 to 3.7  per patient for femoral procedures to 7.6 lesions per patient for transapical procedures. Lesion volumes were as big as 5,000 cubic millimeters (if spherical, over 2 cm in diameter). For comparison, I included in the charts shown at the right similar data from a recent study by Bonati, et. al in Lancet/Neurology measuring new brain lesions identified after surgical carotid endarterectomy (MRI, diffusion weighted imaging, 1.5 or 3.0 Tesla).

In the transcatheter studies, there were 3 strokes (3.4%) observed immediately post procedure (one in each group).  Simple neurological work-ups performed 30 days later in both studies showed no long term effects in the remaining patients.  What is the significance of the study results?  Is it business as usual, with patients accepting a reasonable “neural deficit” potential?  Or, is it an early warning sign of potential long term unwanted neurological consequences inherent in the procedure.

In closing, I would like to echo a quote from Dr Stephan Windecker (University Hospital, Bern, Switzerland), a leading expert in transcatheter procedures, after he reviewed the Edwards data.

“You wonder, do they matter? I’m not an expert . . . but my question would be, are these reversible, and what do they mean?”

Dr Stephan Windecker, HeartWire, May 27, 2010

Post Implant MRI Images

Cardious Qualifies for 25% Investment Rebate

I am excited to announce that Cardious has recently qualified to participate in Minnesota’s Angel Tax Credit program. This program provides a 25% tax credit or a direct grant in lieu of credit to investors or investment funds that put money into a Minnesota based startup or emerging company (like Cardious) focused on high technology or new proprietary technology.

  • 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.

All Surgeons / All Operating Rooms / Most Patients

  • We believe a logical aortic valve surgery business should revolve around highly skilled 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 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.

Incremental AVR Paradigm_Page_1

Download this graphic as a PDF File

Data and Common Sense – Powerful Predictors of the Future of AVBG

Dr. Gammie and his colleagues at the University of Maryland continue to present impressive data with regard to the clinical effectiveness of the AVBG procedure in high risk patients.  In a recent publication in the Annals of Thoracic Surgery (Ann Thor Surg 2010;90:136-43), lead author Dr. Crystal Vliek reviews hemodynamic data from 47 very high risk patients who underwent an AVBG procedure at Maryland between 2003 and 2009.  The conclusion is that the AVBG procedure effectively relieves the outflow obstruction created by aortic valve stenosis and that placement of the bypass graft halts the biologic progression of aortic stenosis.  The data is very convincing.

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. Read More »

What We Believe

Recently, I was asked why I thought our aortic valve bypass graft product is competitive compared to transcatheter products that are already in human studies.  After some thought, below are the fundamental reasons why we think we have a good chance for success.

  • 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?

Death is not a New York Heart Class

Is data emanating from human transcatheter aortic valve trials showing clinical strength or weakness?  Here is an example – you be the judge.

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 - NYHA Class at Year 1

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

Click to Enlarge

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?

The State of the Art

At Cardious, our goal is to move the aortic valve bypass graft procedure from a  procedure performed only by

AVBG Human Implant

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.

AVBG References

I just added a new section to our website called Reference Materials.  I have posted a few of the hundreds of references I have collected over the past few years on AVBG.

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.

Will Transcatheter Implants Send Coronaries to Stent Jail?

In my last post, I argued that 40% of patients over age 70 presenting for AVR surgery  with a stenotic aortic valve will Stent Jailhave a bicuspid shaped valve and therefore will not be eligible for a transcatheter device.  What about the 60% that have a tricuspid valve?  Are all of these candidates for a transcatheter procedure?  I don’t think so.  As it turns out,  “significant coronary artery disease” is another major contraindication/exclusion in the PARTNERS Trial and is also contraindicated in the European Guidelines.

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.

Robert's CAD Data

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.

Guide Cath obstrut BalloonGraphic Source, Anatomy of the Aortic Valve Complex and Its Implications

Guide Cath obstrut SelfGraphic Source, Anatomy of the Aortic Valve Complex and Its Implications

Ventor Position

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.

When does 2% equal 55%?

In my last post, I said that 40% of patients over age 70 presenting for stenotic

Bicuspids Do Not Qualify

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.

Roberts Bicuspid Data

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.

Are We Complementary or Competitive to Transcatheter?

The answer is yes.

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.

I’ll be happy to give you innovative thinking. What are the guidelines?

I’ll be happy to give you innovative thinking.  What are the guidelines?

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. Read More »

120 Day Explant

Last week we explanted the AVBG device we installed in a pig in October – approximately 120 day implant duration.    The valve (25 mm Hancock II) inserted into the housing looked fully functional.  We got some terrific echo data.  A quick look at the internal housing via a boroscope indicated a normal pannus response. We did not open it.   At this time we’re fixing the device in formalin.  We’ll let it crosslink and then open it sometime later this week.  Externally the device demonstrated a normal capsular response.   Our first impression is that this implant was a success.

Risky Business

I am always asked – Why do you think the AvA Bypass Graft is a superior off-pump aortic valve procedure compared to stent valve procedures being developed by Edwards LifeScience , CoreValve, and probably a dozen smaller companies?

My short answer:

Superior risk management profile

Now for the longer answer. Read More »

Cardious presentation to LifeScience Alley Conference & Expo

LifeScience Alley, Minnestota’s medical device trade association, held its annual conference in Minneapolis on Dec. 10.  We were fortunate to be selected as one of three New Technology Showcase Award Winners to present our story to the 1.500 attendees.  Here’s the PDF of our 10-page PowerPoint presentation given by our Chief Technology Officer Kem Schankereli.

“How Does It Work” Animation

With the help of Master communications group, we recently produced an animation of the implant procedure.  Click play to watch this 1 minute, 20 second animation, or download the Flash animation file.

Any questions or comments – please contact me.  Remember, even though this general procedure has been performed in humans many times, our particular procedure is not yet approved for use in humans.

First Long Term Animal Implant

On  October 23, 2008, we successfully implanted our AvA™ Bypass Graft into a 100 kg pig.  The graft was implanted by Dr. Lyle Joyce at the University of Minnesota, ESS animal research facility.  Without any cardiopulmonary support, the device was installed through the 6th intercostal space into the left ventricle of a normally beating heart and then attached to the descending aorta.  A standard, commercially available Medtronic Hall 25 mm bioprosthetic valve was suturelessly inserted into the bypass graft valve housing.

As of December 1, the pig is 39 days post op and doing well.  We expect to maintain the pig for a minimum of 45 days before explanting to observe the healing process.

This is our first chronic implant study.  In coming months, we expect to perform a series of long term animal studies to fine-tune our proprietary off pump implantation technique and to demonstrate that the device heals well into the apex and aorta and also to confirm that the bioprosthetic valve performs normally in our valve housing.