Translational Pathway for Percutaneous Aortic Valve Replacement
On April 16th, 2002, we performed in our institution the audacious first clinical percutaneous implantation of an aortic valve bioprosthesis in an inoperable and desperately ill man with critical calcific aortic stenosis. Ten years later, in May 2012, we celebrated in Rouen the 10th anniversary of this first case in the presence of 600 cardiologists and surgeons of 50 countries. Such an impressive attendance at this event demonstrates the interest of the medical community for a new therapeutic option that has transformed the field of cardiovascular medicine. Transcatheter aortic valve replacement (TAVR) can now be recognized as a medical breakthrough. It is a disruptive technology addressing an unmet clinical need for a common disease, validated by rigorous evidence-based studies, and able to be largely applied worldwide.
In 2013, with more than 80 000 patients treated, TAVR which was so strongly criticized by all the experts throughout the early years, continues to grow in parallel with constant technological improvements. This progress would not have been possible without the remarkable partnership established since the earliest phase between engineers and clinicians, which represents one of the most striking examples of a successful translational collaboration.
Degenerative Aortic Stenosis: Addressing an Unmet Clinical Need
The high prevalence of degenerative aortic stenosis (AS) is well documented. Approximately 5% of people above the age of 75 have moderate to severe AS, and the prevalence of the disease increases with age (1,2). With the aging population, the optimal treatment of AS has turned into an important healthcare concern. In the absence of any effective medical option, open heart surgical valve replacement (SAVR) has been the standard of care for decades. Considering the natural course of the disease, with a survival not exceeding 3 years after the onset of symptoms, SAVR has been recommended since 1968 to be performed promptly once even minor symptoms occur (3). However, for many reasons headed by advanced age and comorbid diseases elevating the perceived surgical risk, more than one third of patients eligible for SAVR are denied surgery and left untreated as shown in several surveys including the well known EuroHeart Survey in 2003 (4,5). Of note that in the 1980s, age per se, above 75 years, was a sufficient condition to consider SAVR unsuitable and this pushed us to consider a less invasive option than open-heart surgery for the management of a large population of patients with inoperable AS.
Balloon aortic valvuloplasty (BAV), a catheter based procedure, was developed by our group in 1985 with the hope of offering a solution for such patients (6). After initial enthusiasm and thousands of patients treated worldwide, it became clear that the results of BAV were insufficient to alter the natural evolution of AS in spite of marked mid-term improvement in quality of life (7). The main limitation of BAV was a high rate of restenosis, reaching 80% at one year (8,9). For these reasons, BAV was progressively discarded. In the early nineties, finding a solution to this issue became for us an obsession.
Birth of the Idea of TAVR
The concept of TAVR emerged from the regular observation that during BAV, high pressure balloon inflation (4 to 5 Atmospheres) was able to circularly open all diseased aortic valves regardless of the amount of valvular calcification. A balloon expandable stent with a high radial force might thus be expanded within the native valve to keep it open and prevent restenosis. A valvular structure would have to be inserted within the stent to prevent massive aortic regurgitation and replace the native valve function. This combination of stent frame and valvular structure might make possible the replacement of the aortic valve using mini-invasive catheterization techniques, even though the idea was intellectually and technologically highly challenging.
Over the last 50 years, several animal studies had already explored the concept of non-surgical heart valves (10-14). In 1992, Andersen et al (15) using a hand-made device, a metallic mesh containing a porcine valve, first reported in the pig model successful implantations of a stented-valve at various cardiac sites. However, none of these animal studies reached human application. The first human implantation of a percutaneous stented-valve (a bovine jugular valve sewn within a large balloon expandable stent) was performed in 2000 by Bonhoeffer et al in a pediatric patient with degenerated right ventricle to pulmonary artery conduit (16). He proved the feasibility of transcatheter valve implantation in humans.
Validation of the Concept of Intra-Valvular Stenting
In 1993-94, we could confirm by an autopsy study in 12 fresh human calcific aortic valve specimens the efficacy of a large (23mm in diameter) balloon expandable peripheral Palmaz stent to circularly open all calcific aortic valves (Fig. 1-A). The optimal dimensions of the stent were set at 14–16 mm in height, in order to minimize interference with adjoining cardiac anatomy (e.g. coronary ostia, intraventricular septum, and anterior mitral valve leaflet) and 23mm in diameter (Fig. 1-B). A high traction force (later quantified to 2kg in an additional cadaver study performed in the USA by R. Virmani, non published data) was necessary to dislodge the stent, thus clearly limiting the risk of device dislocation. This milestone experimentation confirmed the concept of valvular stenting in AS and for us started a phase of drawings and model makings (Fig. 2).
During the next four years, the search for a biomedical company interested in supporting the project failed completely. Our concept was clearly specified: “Implanting a valve prosthesis within the diseased calcific aortic valve, on the beating heart, using percutaneous catheter based techniques, with local anesthesia”. This concept was regularly considered impossible and dangerous. All experts made negative comments including a long list of engineering issues and potential fatal complications pushing the companies to reject the project. Among multiple negative arguments were the impossibility of stenting open a heavily calcific valve, the risks of stroke by emboli of calcium and debris, of device dislocation, coronary occlusion, mitral valve injury, permanent heart block, aortic regurgitation and endocarditis, the foreseeable low hemodynamic performance of the device, its lack of durability, and finally the lack of experience of the cardiologists on valve prosthesis. The project was even considered the “most stupid ever heard”.
End of the Tunnel: Launching “Percutaneous Valve Technologies”
A start-up company, Percutaneous Valve Technologies (PVT, NJ, USA) was eventually launched in 1999 with the goal of making prototypes. The founders were two clinicians, A. Cribier, M. Leon and two R&D engineers, S. Rabinovich and S. Rowe. A development partner was identified, a small company based in Caesarea, Israel (ARAN, R&D, Ltd) which became our long lasting outstanding partner in this venture.
The engineers had to integrate several challenging technologies: a balloon expandable stent, a balloon for predilatation and stent expansion, a valvular structure, and a delivery system. They had to address the following highly challenging goals: 1) making a prosthesis made of a highly resistant frame containing a valve structure, able to be homogeneously compressed to 7-9mm over a high pressure balloon (transfemoral insertion) and expanded to a diameter of 23mm by balloon inflation without damaging the frame and leaflets; 2) Selecting the valve material, its attachment to the frame, and the valve design (uni-, bi- or tri-leaflet) to provide sufficient strength, low profile and durability. The way of delivering the valve accurately, within the calcified valve, on the beating heart, was another issue.
This was the start of a strong, durable and successful collaboration between engineers and clinicians. As shown in Fig. 3, the translational pathway to TAVR was rapidly set by PVT, and would remain unchanged in the future for all companies working on the development of such a procedure.
A Remarkable Preclinical Engineering Output
Different valve configuration, frame material and design, leaflet design, material and attachments were intensively investigated. This concerned the two elements of the bioprosthetic heart valve, the support structure (stent frame) and the valvular structure (leaflets, sealing skirt, attachment posts, sutures, function), but also the loading system (atraumatic, user-friendly), and the delivery catheter system (valve housing, shaft, working handle, recapture, reposition, retrieve, profile, ergonomics). Each of these elements required a specific work on design-geometry, material selection, material manufacturing and processing.
The valve design criteria were based on hemodynamics, durability, and safety. Satisfactory hemodynamics meant high effective orifice area and low gradient, proper leaflets coaptation, and minimized leak. Durability required resistant tissue, uniform stress distribution on leaflets, and leaflets resisting calcification. Safety required minimal interference with adjoining structures (height of frame), low crimped profile, predictable positioning and anchoring capabilities. The requirements on frame design concerned the suspension for the valve leaflets and skirt, the crimping process and expansion, the fatigue and resistance, and the need for circular and consistent deployed diameter. Geometry optimization used the Finite Element Analysis (FEA) method. The goal was to maintain the durability constraints while reducing the crimping profile.
The company also had to design its own testing equipment and crimping tools for a new technology (Fig. 4). Testing included pulse duplicator, accelerated wear tester (durability testers verify 200 million cycles of valve mechanical integrity and leaflet coaptation), test of calcification for the leaflets; FEA, radial force tester, oval crushing and fatigue tester for the frame, and extensive hydrodynamic testing of the device.
This huge development work defined the future of the Transcatheter Heart Valve (THV). The first “finalized” device consisted in a stainless steel stent, 23mm in diameter, 17 mm in height, containing a tri-leaflet valve initially made of polyurethane and soon changed to a bovine pericardium valve. Bovine pericardial tissue is a clinically proven tissue in surgical aortic valves with more than 25 years of follow-up (no other material with such proven history). The device was compatible with a 24F (8mm) introducer sheath.
2000-2004: Animal Evaluation
Animal experimentation on the sheep model started on September 2000 at the CERA (Centre d’Expérimentation et de Recherche Appliquée, Montsouris Institute, Paris). With my collaborator Helene Eltchaninoff, the first implantation was successfully achieved within the native aortic valve, the device being advanced to the heart through the brachio-cephalic trunk. The report of this single case in various meetings aroused memorable enthusiasm. This was the tipping point at which the medical community began to take notice and to show enthusiasm. Over 100 THV implantations at various cardiac sites were subsequently performed by us (Fig. 5). In spite of the clear-cut limitations of this animal model (healthy valves leading to high rate of THV dislocation, THV/annulus size mismatch, coronary occlusion), the experimentation contributed to the optimization of bioprosthesis, delivery systems, and implantation techniques. The lessons concerned the safety of access with the use of large sheath sizes (24F), the delivery system (trackability, catheter shaft, balloon material, burst pressure, quality of crimping), the guidewire and the procedural aspects (assessment of annulus size, accuracy of valve positioning, optimal X-Ray projection, technique of valve delivery, methods of cardiac standstill, evaluation of results by angiography and echocardiography, anticoagulant strategy). Chronic (5 month) evaluation in the systemic circulation was obtained using an original method of THV implantation in the descending aorta (17). This was mandatory before being committed to FIM trial as post-durability testing and a test of biocompatibility. The persistence of an excellent valve function and the integrity of the THV on pathological examination were demonstrated.
Moving to Human Implantation
On April 16TH 2002, we performed the first-in-human transcatheter implantation in a 57-year old patient with severe AS with multiple comorbidities contraindicating SAVR (18). TAVR was offered as a compassionate last-resort option in this man who, as one can admit today, cumulated most of all current contra-indications for the procedure. He was in cardiogenic shock, with major left ventricular dysfunction (ejection fraction: 12%) and no myocardial contractility reserve, no arterial access (occlusion of bilateral aorto-femoral by-passes), and a large left intraventricular floating thrombus. Furthermore, an unplanned technique had to be used for TAVR due to the lack of arterial access, the antegrade transseptal approach (Fig. 6) using the femoral vein as the entry site. Amazingly, each step of the procedure was straightforward and without complications. The THV could be accurately deployed in the middle of the valvular calcification. After deployment, the patient’s hemodynamic and echocardiographic status improved remarkably. From a single case, the feasibility of THV implantation on the beating heart using transcatheter techniques was confirmed. There was no coronary occlusion, no mitral dysfunction, no atrio-ventricular block and only a mild paravalvular aortic regurgitation, thus translating well our 1994 post-mortem study. The patient unfortunately died four months after the procedure, due to complications unrelated to TAVR. This first-in-man case can be considered a milestone in interventional cardiology.
Following three other human cases, two successive feasibility trials on a total of 38 patients (19, 20) restricted to compassionate use (imminent death) were initiated in our center, using for industrial reasons a modified valve structure (equine pericardium). These studies did confirm the feasibility of TAVR using the transseptal approach with elevated success rates (85%) and durable post-procedural hemodynamic and functional improvements. However, a high (25%) incidence of > grade 2 paravalvular regurgitation was noted, indicating an insufficient coverage of the annulus in a number of patients and the need to develop larger size bioprosthesis (> 23mm). Although some patients died shortly after implantation from their severe comorbidities, others survived several years, up to 6.5 years, without any cardiac failure or prosthesis dysfunction. As a striking example of such amazing result is the story of an 84-year lady in whom TAVR was performed as a last resort option. One year later, she was able to travel from Paris to Washington DC to appear on the stage at the 2004 Transcatheter Cardiovascular Therapeutics (TCT) meeting for the highlight celebration of the first 1-year post-TAVR patient. Protocol extension to other centers in Europe, USA and Canada was started but demonstrated a significant degree of technical complexity and adverse outcomes associated with the antegrade delivery. In our series, TAVR was also attempted in 7 patients using the initially planned and technically simpler transfemoral retrograde approach. The procedure was carried out successfully in 4 in spite of the lack of any specific delivery system adapted to this route. Obviously, further expansion of TAVR required technical improvements, procedure simplification, more friendly approaches and larger valve sizes.
Edwards Lifesciences Acquires Percutaneous Valve Technologies: TAVR Takes Flight
When Edwards Lifesciences Corporation (Irvine, CA, USA) acquired PVT in 2004, TAVR entered a new era. Several improvements were rapidly made by the company to the bioprosthesis and the delivery system and new approaches were developed (Fig 7). The Edwards-SAPIEN (originally Cribier-Edwards) valve prosthesis became available in two diameters: 23 mm and 26 mm. This model of bioprosthesis consisted of a tri-leaflet bovine pericardium valve pretreated to decrease calcification, mounted within a stainless steel stent externally covered by a longer pet cuff (50% versus 33% of the frame height). A specific delivery system was conceived for facilitating the retrograde transfemoral approach, the steerable RetroFlex catheter, evaluated by Webb et al in Vancouver, Canada (21). Simultaneously, a new approach was developed, the minimally invasive transapical approach using the Ascendra delivery system, evaluated by Walther et al in Leipzig, Germany (22). The onset of these two approaches made possible the use of TAVR in the vast majority of patients, regardless the suitability of the femoral access. For regulatory reasons, our team was delayed by one year to participate in the evaluation of these new approaches, but was included in the setting of several European feasibility studies including hundreds of patients. These studies led to a growing acknowledgement of TAVR (in particular by cardiac surgeons) and a fast expansion of the procedure.
Since 2004, a concurrent device, the CoreValve, a self-expandable nitinol frame containing a porcine pericardial valve (Medtronic, Irvine, CA, USA) had also been in development (23). This device could be inserted via a transfemoral approach through smaller sheath sizes (21F then 18F) than those required for Edwards devices (22F and 24F). As an alternative to the femoral delivery, the subclavian access was proposed with the CoreValve. Feasibility studies on the Edwards-SAPIEN and the CoreValve (the two aortic valve devices from which the majority of clinical data arise) resulted in both valve models obtaining the CE (Conformité Européenne ) mark in 2007.
From Feasibility Trials to Real Life: A 20 Years Odyssey
Over the last 6 years, acceptance and expansion of TAVR has been amazing with an annual 40% increase in the number of procedures. Post-marketing national and international registries with the two models of bioprosthesis enrolled several thousand of elderly patients, all inoperable or at high-risk, in line with the recommendations of the European Societies of Cardiology (ESC) and Cardiothoracic Surgery (EACT) (24). These registries included single valve evaluation as in the SAPIEN Aortic Bioprosthesis European Outcome (SOURCE) registry (25) which enrolled since 2007, 1123 patients receiving transfemoral or trans-apical TAVR, the Evaluation of the Medtronic CoreValve System in a “Real-World” (ADVANCE) Registry (presented at the EuroPCR meeting, Paris, 21-24 May 2013) including 1015 patients enrolled at 44 centers, and two valves evaluation as in the French Aortic National CoreValve and Edwards (FRANCE) registry (26) followed by the FRANCE 2 registry (27) reporting the French experience on a series of 3500 patients, reflecting the largest exhaustive overview of TAVR in the real life.
These registries contributed to a better appraisal of patient screening, technical modalities and complications. The procedural success rate increased to over 95% whereas with advanced technologies, immediate and long term results kept improving. The hemodynamic results were shown to compare favorably with surgical valve replacement in similarly ill patients. The results of TAVR became more predictable and the mortality rate decreased to 6% – 10% at 1 month and 20% at 1 year as in the SOURCE registry (25) after transfemoral implantation. A dramatic and long lasting improvement in the quality of life (28) was observed in all registries and further confirmed in the remarkable pivotal PARTNER trial.
The only evidence-based evaluation of TAVR was obtained with the Edwards SAPIEN valve in the multicentre pivotal randomized trial “Placement of Aortic Transcatheter Valves” (PARTNER) in the USA. From 2007, 1056 high surgical risk patients were enrolled in 26 centers in USA. Patients were assigned into two arms, a non-surgical arm (Cohort B) in which TAVR was compared with medical therapy (including BAV), and a surgical arm (Cohort A) in which transfemoral or transapical TAVR was compared to traditional SAVR. Briefly, the results confirmed the high superiority of TAVR over medical treatment in non-operable patients with an absolute increase in survival of 20% at 1 year, and the non-inferiority of TAVR versus SAVR in high risk operable patients in terms of all cause mortality and repeat hospitalization at 1-year (29-33). Similar results were observed at 2 and 3 years (32, 33). In view of these results TAVR was approved by the Food and Drug Administration (FDA) in these indications. Subsequent to FDA approval, many centers were certified to apply TAVR in USA, the number reaching currently about 250 centers.
For any new medical technology, to obtain the agreement of the FDA represents an almost inaccessible objective. This was eventually achieved for this innovation after a long and bumpy road, 20 years after the concept of TAVR, 10 years after the first human implantation. A summary of the balloon expandable TAVR pathway is summarized on Fig. 8.
The Essential Role of Translational Pathway for Expanding TAVR
After several years of experience and the report of many post-marketing studies, the task of the engineers was to deal with several clinical requests. They had to improve both the technological aspects of TAVR while reducing the complications. Severe vascular complications (3-16%), stroke (2-7%), paravalvular aortic regurgitation (AR: 5% > grade 2), and complete heart block requiring pacemaker (PM: Edwards 3-12%, CoreValve 16-35%) were the leading complications (34). Improvements were achieved by creating new models of bioprosthesis and delivery systems (Fig. 9-10), decreasing sheath sizes, offering a better coverage of the annulus (additional valve sizes), and facilitating sealing and positioning of the bioprosthesis. In parallel, additional technologies were developed regarding patient screening and procedures (new multimodality imaging technologies), vascular complications (improved vascular closure devices), stroke (embolic protection devices). Even the procedural “milieu” was modified with the development of a “hybrid environment” allowing to integrate in the same setting interventional and surgical therapies. This testifies to a considerable impact of TAVR on the world of industry.
In 2013, innovations in valves and delivery system are ongoing. The Edwards SAPIEN bioprosthesis has been replaced in Europe by the SAPIEN-XT (Fig 9), comprising a highly resistant Cobalt-Chromium stent frame, improved valve and leaflets design, additional size of 29mm, implantable with a new NovaFlex delivery system, compatible with much smaller sheath sizes (16 to 20F). This leads to a potential increase of transfemoral access to about 80% (85% in our centre). Subsequently, transfemoral TAVR is now increasingly performed using a pure percutaneous minimal strategy, with local anesthesia (which fits with our initial concept), leading to improved patient comfort and early discharge after 2 to 3 days. This device has been evaluated in the large (2166 patients) multicenter SOURCE-XT registry (presented at the EuroPCR meeting, Paris, 21-24 May 2013) which reported a decrease in all-cause mortality and cardiac mortality at one year to respectively 19.5% and 10.8%, among the highest reported survival rates for TAVR. Reduction of sheath size has significantly reduced the rate of vascular complications (presented at the EuroPCR meeting, Paris, 21-24 May 2013). New models of Edwards bioprosthesis, the SAPIEN 3 and the CENTERA are being investigated in Europe and will be launched at early 2014. The SAPIEN 3 which shows highly promising results has been specifically designed to reduce paravalvular AR (new sealing cuff) and vascular complications (reduced sheath size to14F). Simultaneously the CENTERA will be available as a self-expanding device requiring also a small 14F introducer sheath. The new EVOLUT device from Medtronic CoreValve has been designed to improve anatomical fit and sealing with modified height and shape. There is no doubt that these advanced technologies will contribute to further expansion of TAVR in the near future.
The field of TAVR is considerably evolving. A number of next-generation THVs markedly different to existing devices are in their early clinical evaluation phase (Fig. 11). They incorporate features to reduce delivery catheter profile, facilitate positioning (repositionability), retrieval, and reduce paravalvular AR. However, it is too early to say whether these new bioprosthesis will represent the future of TAVR, but these advances create an active and stimulating competition which is by essence positive.
The Growing Place of TAVR in the Treatment of Aortic Stenosis
Thanks to technological advancement, greater clinical experience, and the excellent results of post-market registries and evidence-based trials, TAVR has been brought to the fore as a treatment for AS and now appears in the guidelines of the European Society of Cardiology (ESC) and the European Association for Thoracic Surgery (EATCS) (35). TAVR is indicated in patients with severe symptomatic AS who are not suitable for surgery, as assessed by a multidisciplinary heart team (Heart Valve Team) comprising cardiologists, cardiac surgeons, imaging specialists, anesthetists and other specialists including geriatricians. TAVR should also be considered in high-risk patients who may still be candidates for surgery, but in whom a less invasive approach is favored, based on individual risk profile. In the USA, TAVR is similarly recommended in patients with prohibitive surgical risk, based on estimated risk of mortality or irreversible morbidity, or other factors, including frailty (36).
Beside the beneficial effect on clinical outcome, one of the important contributions of TAVR has certainly been the rise of a unique medical culture, the collaborative work of subspecialties in a disease-state model, highlighted by the Heart Valve Team.
In the near future, TAVR may be extended to younger lower-risk patients as reflected by recent observational data reports (37). More evidence-based clinical data are needed in this subset of patients and should be soon provided by the ongoing Surgical Valve Replacement versus Transcatheter Aortic Valve Implantation (SURTAVI) trial with the CoreValve in Europe, and the PARTNER II valve trial with the Sapien-XT device in the USA. Other indications for TAVI may also come such as the use of TAVR for failing surgical bioprosthetic valves (valve-in-valve). In this indication, TAVR is particularly appealing to achieve adequate valvular function for symptom relief without prolonged recovery. Off-label valve-in-valve implantation has already been reported (38, 39) and is being evaluated in an ongoing global multicentre registry (40) including several hundreds of patients. Indeed, the Medtronic CoreValve® system recently gained approval for transcatheter valve-in-valve procedures in Europe.
For the time being, the durability of THV remains unknown and has to be confirmed over the long-term. Our knowledge on long-term clinical follow-up is currently limited, but results are very encouraging. Normal valve function has been reported more than five years after TAVI (41) and as an anecdote, one of our patient has reached the longest clinical follow-up so far (8 years) without any change in hemodynamics and no device deterioration.
The development of TAVR has been a 20-year long inspiring and successful journey from concept to real world. TAVR appears today a breakthrough technology, challenging the foundations of medical practice, enabling thousands of patients with severe AS to receive a life-saving effective alternative treatment to SAVR. This would not have been possible without the excellent and unequalled collaborative spirit between clinicians and engineers who have provided their expertise with the unique goal of making this procedure possible, safe and successful. We are not reaching the end of the story. The continuous translational work promises further technological innovations that will soon make TAVR simpler and safer. Within 10 years, it is likely that TAVR will become the treatment of choice for a majority of patients with symptomatic AS.
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