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.

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.

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.

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

• 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.

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.

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.