Melody valve

A bare metal stent was positioned in a patient with conduit stenosis. The procedure was successful but the patient presented a clinical deterioration. The idea of the valved stent arose from this clinical failure.

In the late 90ties Philipp Bonhoeffer was invited to join a procedure in Glasgow. The plan was to treat a patient with a leaking conduit after a modified Fontan procedure. The patient was severely blue and a procedure was carried to cover the leaks between the conduit and the left atrium with a large covered stent. The stent was fabricated during the procedure and the procedure was cumbersome but successful.  Shortly after, in Paris he treated a patient with a degenerated valved conduit. The valve was narrowed and had also lost its closing function and was insufficient.

Stenting of such conduits had recently become popular with the intention of opening the narrowed valved segment. Valve closure was then obviously entirely impossible but this was not considered important because the valve was insufficient even before the procedure. The patient of Philipp Bonhoeffer in Paris had an excellent procedural result. The narrowing was perfectly opened.

However, shortly after the patient was released back home, the family came back saying that the patient was significantly more fatigued. In other words this patient now suffered more from the increased insufficiency than he gained from alleviating the obstruction. The patient had to go for surgery to have a new valved conduit implanted just the way one would have traditionally handled these patients before stenting of conduits was introduced in clinical practice only few years before.

The combination of these 2 clinical experiences ultimately led Philipp Bonhoeffer to have the idea of the valved stent. From the first patient he thought that if it was possible to put something around stents to create covered stents it should be equally possible to place a foldable structure inside a stent. From the second patient he was considering that valve leaflets are truly very fine structures in normal heart valves and should not be ticker than the membrane around a stent used for covered stent. He therefore set out to expand a stent to its intended diameter and then to suture a valve inside it. He then folded the stent and measured whether the crimped down stent would have proportions small enough to be introduced in a peripheral vessel in order to be applicable in clinical practice. He then re-expanded the stent to see whether valve function would be preserved when it was brought back to its intended diameter after implantation. He intended to anchor such a valved stent in the narrow segment of the degenerated valve as it was present in his patient in Paris.

The first prototype of a valved stent. This device did not function

His first attempts to find the appropriate valve tissue were with bovine, porcine or homograft valve tissue and failed. Prof. Pascal Vouhé at the time was involved in a CE mark study with the bovine jugular venous valve which was being introduced as a new surgical conduit by the company VenPro. Philipp Bonhoeffer engaged to make contacts with slaughterhouses to get access to this tissue. Out of  rough pieces of cow-necks he dissected jugular venous valves which led him to make the proof of concept of the validity of his idea. He could perform his first animal experiments which became  successful. The difficulties of the valve implants were tied to the lacking catheter technology  to introduce the valved stent whereas the valved stent itself did not pose significant problems.

With NuMed he went through many catheter iterations in order to overcome the technical problems of the catheter implants. However the animal model was not very predictive for the future applications in the human because of a totally different vascular anatomy in the animal as compared to the human.

The first important step to reach human application was the obtain a validated valve for human implant. This presented a major challenge in this project. The catheter company  NuMed was obviously not equipped for the handling of biological tissues. It also had no expertise nor equipment to carry out functional valve testing for the acute bench testing and the long-term tests for durability of the valve. The only way to overcome this hurdle was by involving the company VenPro trying to make a joint venture between NuMed and VenPro.

Eventually an agreement could be reached and now conditions turned out to be favourable for the planning of a first in man procedure. The stent provided by the company NuMed had been in clinical practice in Europe and had previously obtained regulatory approval with CE mark. The valve had also recently gone through CE mark approval in a European study for surgical implantation. Philipp Bonhoeffer travelled to California to show how to reduce the wall of the vein to appropriate thickness and how to suture the valved venous segment in the stent. With both components of the valved stent having gone through separate approval processes the further regulatory challenges appeared to be surmountable. It needed to be demonstrated that the sterilisation process for the venous tissue could safely be performed when it was already mounted on the stent and that the stent would not be affected by the liquid sterilisation. Further a demonstration had to be made that the crimping of the valve and the subsequent balloon dilatation would not alter the function of the valve. A rational had to be made why the delivery system could not be reasonably tested in animals and that the catheter approach needed to be based on comparisons to the most similar procedures already in clinical practice. A clinical rational for the use of this new procedure was also set out.

In early 2000 NuMed, with the help of Philipp Bonhoeffer submitted to the CCPPRB, the French National Ethical committee for approval of a clinical study. The aim of the procedure was to prolong the life of a degenerated conduit between the right ventricle and the pulmonary artery, which was previously positioned in  surgical procedure. Approval was given in August 2000 for a study of 30 patients. The first implant was carried out at the Hopital Necker on the 12th of September 2000 and was successful.

The first 10 patients had valve implantations in France. During his early experience Philipp Bonhoeffer still made numerous modifications to the delivery system and only one modification to the valved stent. In 2001 Philipp Bonhoeffer moved to Great Ormond Street Hospital in London where he performed many procedures. For the first 6 years (>100 cases) of implants Philipp Bonhoeffer was the only person allowed to perform implants. This delay was due to the very complex regulatory realities in Europe and the United States.

The Medtronic Melody® Transcatheter Pulmonary Valve

The valved stent was considered to be a disruptive innovation. Vast regulatory guidelines were written for the requirements of surgical valves. These could not be applied to this new technology.

18 months after the first pulmonary valve implant Prof. Alain Cribier introduced the same concept for aortic valve implantation. This was a procedure with significantly higher risk than the pulmonary valve implantation but needed to be approached with similar regulatory strategies.

Consenting for the early procedures was based on very little practical knowledge. Philipp Bonhoeffer adopted a methodical approach to give informed consent to patients and their families. He informed them about the state of his knowledge and more importantly about the questions which were still open to him. He informed them that unforeseen events were to be expected.

Later in his experience, when such events had happened he told patients how he had modified his approach related to these events. He also informed them that he believed more such events would come with more experience. With this careful approach he was able to manage the complications when they occurred and to bring the valved stent all the way to regulatory approval without procedural death.

After regulatory approval Philipp Bonhoeffer trained operators from around the world who were starting to perform the procedures. His teaching was almost entirely based on discussing the complications he had encountered.

He published a paper about his learning curve (Lurz.et al.) in which he demonstrated that after is initial learning curve of 50 patients results were significantly better. His aim was to avoid that anybody would repeat any of the experiences which he retrospectively interpreted as his mistakes. This open attitude lead to a safe transfer of technology into the hands of new operators and produced very successful clinical results around the world.

 

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