The aim was to replace a defective aortic valve (*) with a prosthesis without invasive surgery. That is, without opening the sternum or using extracorporeal circulation (ECC) during the intervention.
The TAVR has several advantages:
- It is less invasive than conventional surgery,
- And therefore means a shorter period of hospitalisation for patients and avoids the transition to resuscitation.
As with conventional surgery, TAVR provides symptom relief by immediately restoring valve function, also improving patient life expectancy and quality of life.
Today, in the framework of the trainings proposed by Invivox, Professor Alain Cribier shares his pioneering experience: “We only have what we share”, as he pointed out in a recent forum in Le Figaro.
(*) The function of an aortic valve is to allow blood flow from the left ventricle into the aorta, while preventing it's reflux.
Invivox: How did TAVR come to life?
Pr. Cribier: I had observed that many patients with aortic narrowing were abandoned, without any therapeutic option, because of an 80% risk mortality within 2 years. In the 1980s, more than 1/3 of these patients were recused because of their age-related risks. In Rouen, after 75 years, only 1% of patients were accepted for aortic valve replacement, and all other patients died. For these patients, we proposed a cardiac catheterization treatment that consisted of a balloon dilatation of the aortic ring (aortic valvuloplasty). This procedure took place in Rouen in 1985 and quickly, this technique became worldwide known.
In the 1990s, there were many limitations to this method, early restenosis, and this technique rapidly declined. I then wondered what could be done to avoid restenosis and
TAVR was the only possible solution. I had the idea of replacing the damaged aortic valve with an artificial valve, using the same technique (catheterization under local anesthesia) by passing through the femoral artery.
Indeed, we had to find a way to overcome the limitations of the first technique.
Invivox: What device did you come up with?
Pr. Cribier: The only way to implant a valve through the femoral artery was to have one that could be compressed on a balloon, so as to reduce the diameter, allow then its insertion through the femoral artery, and then drop the device inside the damaged valve by inflating the balloon.
For this, the valve was placed on a balloon catheter, which was inserted into the vessels, initially the femoral vein, initially into the femoral artery, ascended to the heart. Once placed, the valve would recover its size by inflating the balloon. At that time, there was only one valve size: 23 mm diameter in full expansion. It is held in place by the calcifications of the aortic valve. The process was ingenious, but it had to be demonstrated by an autopsy study of people who had died as a result of aortic narrowing that it was anatomically feasible. From there, we were able to move on.
The valve was originally made of polymer. Before moving on to humans, we opted for a biological valve of bovine origin that resembles a normal aortic valve of 3 sheets. The bovine pericardium is registered worldwide and is used in surgical bioprotheses.
Many prototypes were manufactured before obtaining the ideal valve, the one ready to be implanted in animals and humans.
Invivox: 12 years of research before the “day” !
Pr. Cribier: The day on which the TAVR technique was first tried was not foreseen in the programme.
We had tested developed prototypes in the laboratory with my start-up (PVT - Percutaneous Valve Technologies Inc.) that I had created in 1999 in the United States, with an American colleague and two engineers. That day, we received a rare patient from Lille. He was a 57-year-old male, with very severe aortic narrowing, terminal, and numerous surgical contraindications. That’s why he was sent to Rouen, not to plant the valve in him, but to give him an emergency balloon aortic valve dilation, which was still used in extreme cases.
We performed an emergency aortic dilatation, without success, with several cardiac arrests during the procedure. We found ourselves in a situation where we could no longer perform aortic dilation. The vital prognosis was engaged within hours. We spoke with the patient and his family, with the teams of PVT to consider a first implantation in this desperate situation. The conditions were not ideal to implant our device for the first time in human! This first aortic valve implantation was therefore carried out in absolute urgency. The conditions of this case were set up for our first attempt to fail. The valve was made in emergency during the weekend. The response went well and the results were spectacular. The technology was ready as studies predicted. The immediate outcome on cardiac function was a success.
Invivox: What was the atmosphere like in the ward?
Pr. Cribier: We were quite stressed because this patient came very tired. We were far from what we had envisioned for a first patient! It was the worst case we could ever have imagined.
He displayed all the contraindications to the TAVR procedure. We didn’t know that yet! He had a clot inside his heart, his femoral arteries were plugged. It was necessary to improvise a new method to put in place the valve which which was not at all planned. This first TAVR was carried out transeptally (passing through the femoral vein and not through the femoral artery). Now, this patient had both femoral arteries plugged. So we had to find another way: the femoral vein.
So it was a real challenge for this first valve because we didn’t know if we could overcome all of these obstacles. The heart was practically inert; the ejection fraction was 10% whereas it is normally 70%. It was terribly tense. Moreover, the valve was implanted practically in cardiac arrest; it had to be put at full speed. Once the valve was placed, the patient regained colour, a real resurrection with immediate recovery of blood pressure.
The next day, the press relayed this world premiere. The patient, who was dying three days before, was able to give interviews. Something really incredible had happened. It was the starting point of the adventure.
Invivox: What happened after that first patient case?
Pr. Cribier: After this first success, the French Health Authorities allowed us to make a series of patients in purely compassionate conditions. The Rouen Hospital Center was the only center to make this intervention in the world.
The patients were referred to us from all over France, but many died either during the journey or upon arrival in the service, because they had serious co-morbidities (cancer, renal failure or respiratory failure at terminal stages, etc.). However, the valve was successfully applied in 85% of cases.
These results have been reported in reference scientific journals and the reaction of the medical community has been good. The news spread like wildfire. Some of these patients survived several years, up to 6 years and more, fully recovered with a fully functional valve. No cases of valve deterioration were observed. The impact of the recognition of this technique has been immense.
Invivox: From the shadows to the light, is it time to transfer the TAVR technology?
Pr. Cribier: Following this series of desperate patients, Edwards Lifesciences, a world leader in surgical bioprotheses (including the Carpentier valve), who had initially not shown interest in supporting this project, finally acquired PVT Inc.
Indeed, during the period of developing the method, I had no choice but to create this start-up, PVT Inc. I had contacted all the biomedical companies to support me in this development. Not only Edwards Lifesciences, but also Medtronic, which developed a competing valve in parallel. Nobody believed in my project.
Creating a start-up was the only way to develop this technology. We were fortunate to find a partner in Israel (Aran Research and Development Ltd.) who agreed to work and invest with/on our team. The engineers were passionate about the subject. We were able to design a prototype valve that was implanted in the animal before it went to humans. An immense amount of research and development work has been carried out thanks to these teams.
Invivox: Is it easier now to develop this type of medical device?
Pr. Cribier: The prosthesis I developed was intended to replace the aortic valve which is the most common acquired valvar disease. Aortic narrowing affects 5-7% of individuals over the age of 65, the other valves are less frequently affected.
TAVR has paved the way for the development of other types of transcutaneous implantable valve stents. Interventional cardiology, limited to cardiac catheterization, has evolved into areas previously reserved for thoracic surgeons. It has become a catalyst for plenty of innovations in the cardiovascular field.
"Today, more than 400,000 patients have been treated by TAVR. In France, around 50 centre practice TAVR. About 15,000 valves are laid per year. In our service in Rouen, we plant 5 to 7 valves per week."
Invivox : What obstacles did you face ?
Pr. Cribier : There was a real conflict with cardiac surgeons who thought TAVR was impossible and dangerous for patients. These conflicts resumed even after making the implantations in humans.
Until the miracle in 2005. Edwards Lifesciences had acquired the valve from already a year and a half. We had the idea to develop a system allowing the valve to be installed by a mini-surgery (transapically, by a small opening of the chest, then by letting the heart beat under general anaesthesia). The first transapical valve was therefore installed in my presence in Leibzig, Germany. There was then a superb live broadcast of TAVR via transapical channel at a cardiac surgery conference in the United States, it was held in front of 2,000 cardiac surgeons. From that moment, the acknowledgement of the teams took place.
In fact, with the prototype I had developed, only 50% of patients had an enough wide femoral artery that can accept the material. The development of the transapical route allowed those who could not benefit from the transfemoral route to take advantage from the technique. All needs were covered.
nvivox: What are the possible available evolutions?
Pr. Cribier : Not only will there be many more to come, but we have already seen so many developments!
Since 2002, Edwards Lifesciences has developed several generations of valves, which are increasingly efficient and perfectly adapted to the different diameters of the aortic ring. The choice of sizes covers all clinical needs. The advances in valve implantation technologies are stunning and unimaginable when we started! Today, valves can be introduced in 92% of cases by transfemoral and percutaneous routes under simple local anaesthesia.
There have also been very important investigations in the field of patient selection and in diagnostic methods that make it possible to understand how to choose the valve, what type of valve to use etc. The medical imaging industry has been completely associated with this innovation. Scanner methods have developed.
Random studies on thousands of patients have confirmed and expanded the indications. And it doesn't stop there. For example, new original and different valves outbound from the initial one will be released this year at Edwards’. Around twenty companies have also developed or are in the process of evaluating implantable cardiac valves by cardiac catheterization to treat aortic stenosis, but also other valves such as mitral insufficiency, for example.
The improvement of the valve operation seems limitless. We are constantly making progress!
Invivox : What is the importance of training to the TAVR ?
Pr. Cribier: Valve implementation training is very important. In 1992, a training program began in Rouen. We trained over 2,000 surgeons from all over the world. This time during the training, We were able to make huge innovative progress, thanks to the use of electronic simulators that allowed us to train in conditions that were extremely life-like.
This training was then carried out directly at the Edwards Lifesciences training centre in Switzerland. It is compulsory for the Institution to be authorized to start implantations in humans. Once authorized, a “proctoring” program is still required. This means that specialists, like myself who have spent my time doing this, come to the institutions to guide cardiologists and surgeons when the first valves are applied. It is a very rigorous training programme and it is essential that it is carried out at an accredited training centre. The other competing valve of Medtronic, the CoreValve, followed the same path: training is therefore considered essential by all of us.
Invivox: The results of the study «PARTNER 3» have just been revealed, what is your reaction as the inventor?
Pr. Cribier : It is a crucial event that marks, in a way, the apotheosis of TAVR.
This is the first random study in TAVR versus surgery, in patients with low cardiovascular risk: in 1,000 patients with low cardiovascular risk, recruited by 71 centres, monitored for 1 year and with annual control planned for 10 years. Results of the “PARTNER 3” study, sponsored by Edwards Lifesciences, were presented at the American College of Cardiology (ACC.19 New Orleans March 2019) and published simultaneously in the New England Journal of Medicine in mid-March.
These results confirm the superiority and effectiveness of TAVR compared to conventional surgeries. As a result of this study, it is expected that TAVR will be validated by various health authorities and will be recommended by many health societies as an alternative to conventional surgery. This will greatly increase the number of patients concerned with this treatment. In less than 20 years we have gone from patients being "high-risk" then being classed as "intermediate risk" and finally to where we are to today with patients being low risk. It is the full recognition of TAVR. In Rouen, the procedure of TAVR carried out by femoral arterial route under local anaesthesia takes 30 to 40 minutes, in 92% of cases. Patients come out of the procedure in good health and 70% of patients are able to leave and return home before the 3rd day after the procedure, without the need of rehabilitation. This is obviously a major advantage over conventional surgery.
The future is rather bright. With the study «PARTNER 3», we could not hope for better recognition of this technique.
"Always persevere, never be discouraged and face criticism, which can sometimes be very difficult!"
