O P E N A C C E S S
`
`Pioneer series
`The development of transcatheter
`aortic valve replacement (TAVR)
`
`Dept. of Cardiology, University of
`Rouen, France
`*Email: Alain.cribier@chu-rouen.fr
`
`Alain Cribier*
`
`INTRODUCTION
`The development of transcatheter aortic valve replacement (TAVR) can certainly be
`considered one of the most fascinating examples of successful translational research in
`medicine. Thanks to an outstanding partnership between multidisciplinary clinicians and
`engineers, we could move from concept to bench, bench to bedside, bedside to clinical
`feasibility trials, then on to larger clinical registries and evidence based trials, leading
`ultimately to a breakthrough technology with durable impact on the pattern of medical
`practice.
`This disruptive technology evoked scepticism and criticism in the beginning, but
`thanks to innumerable clinical trials and evidence based investigations, it is now widely
`accepted by the medical community and its acceptance is continuing to grow. In the last
`fourteen years, TAVR has been performed in around 300,000 patients in 65 countries and
`adoption is increasing by 40% year on year.
`The field of TAVR is rapidly evolving, with major refinements in technology, procedural
`techniques, patient selection and biomedical engineering. With the development of
`better devices, new approaches and new implantation strategies, TAVI has become much
`simpler and safer. The indications were initially limited to elderly aortic stenosis patients
`with multiple co-morbidities. The same are now cautiously and appropriately growing to
`include a broader population of patients with lower surgical risk, degenerated surgical
`bioprosthesis, and even patients with other valvular diseases such as pure aortic or even
`mitral insufficiency. There are few examples of clinical fields in medicine that match the
`rapid and careful evolution of TAVI.
`
`BACKGROUND
`Calcific aortic stenosis (AS) is the most frequently acquired valvular heart disease in
`developed countries, and its prevalence increases with an ageing population.1 The
`natural history of symptomatic aortic stenosis carries a poor prognosis2 with a survival
`rate of 60% and 32% at one and five years respectively.3 The only effective treatment for
`decades was surgical aortic valve replacement (SAVR) with remarkable results in ideal
`candidates, but which required invasive heart surgery with extracorporeal circulation.
`Operative mortality of SAVR is low, <5%4 and alleviation of symptoms and a return
`to normal life expectancy are observed. However, the operative risks, including post-
`operative complications and mortality, significantly increase in very old patients and/or
`
`Cite this article as: Cribier A. The development of transcatheter aortic valve replacement (TAVR),
`Global Cardiology Science and Practice 2016:32 http://dx.doi.org/10.21542/gcsp.2016.32
`
`http://dx.doi.org/
`10.21542/gcsp.2016.32
`
`Received: 30 November 2016
`Accepted: 12 December 2016
`c(cid:13) 2016 The Author(s), licensee
`Magdi Yacoub Institute. This is an
`open access article distributed un-
`der the terms of the Creative Com-
`mons Attribution license CC BY-4.0,
`which permits unrestricted use, dis-
`tribution and reproduction in any
`medium, provided the original work
`is properly cited.
`
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`in the presence of associated cardiac or non-cardiac comorbidities.5,6 These factors
`are considered one of the main reason for which at least one-third of patients with
`symptomatic AS are not referred for SAVR7 (Fig. 1).
`In the 1980s, age of over 75 years was considered a contraindication of SAVR, and this
`stimulated our group to develop a less invasive therapy, balloon aortic valvuloplasty
`(BAV), consisting of enlarging the calcified native valve with a balloon catheter using
`standard catheterization techniques.8 This technology was adopted with enthusiasm by
`the medical community, as highlighted by the thousands of patients included in broad
`European and US registries and the 1,300 indexed articles dedicated to the procedure.
`However, the enthusiasm progressively declined following the recognition of important
`limitations, headed by early valve restenosis. BAV appeared to provide only temporary
`relief of symptoms with a modest survival benefit9,10, its role remaining controversial in
`US guidelines.11 Interest in BAV resurged with the development of TAVR and its frequent
`integration in the procedure. BAV is also used today as a palliative option in patients with
`contra-indication to TAVR or SAVR, as a bridge to those procedures in severely depressed
`left ventricular function, or when urgent non-cardiac surgery is indicated. Even though
`age is no longer considered a surgical contraindication, large numbers of severe AS
`patients are not offered valve replacement in Europe or the United States.12,13
`
`FROM BALLOON VALVULOPLASTY TO THE CONCEPT OF PERCUTANEOUS
`AORTIC VALVE
`For those of us who had been pioneering BAV, addressing the issue of post-BAV valvular
`restenosis became an obsession in the early 1990s. Placing a balloon expandable
`stent frame containing a valvular structure (stented-valve) within the calcified native
`valve appeared a possible option (Fig. 2). The project had the advantage of requiring
`similar approaches and techniques to those used for BAV. Among several visions of
`endovascular valve implantation, with initial animal investigation performed by Davies,14
`H. R. Andersen’s project was the most elaborated. In 1992 he developed and patented15
`a hand-made ‘‘stented valve’’ for the treatment of various cardiovascular diseases,
`
`Figure 1. Rational for developing interventional
`technologies for severe AS: An Unmet Clinical Need.
`
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`Figure 2. Birth of the idea of ‘‘stented-valve’’ in AS. Left panel: A stent crimped over a high-pressure
`valvuloplasty balloon might keep the valve open and prevent restenosis. A valve structure should be
`added within the stent. Right panel: Validation of the concept of intra-valvular stenting and optimal
`height of the frame to respect adjoining structures.
`
`but the project remained at the experimental stage. In 2000, Bonhoeffer first used a
`stented-valve in a human, a bovine jugular vein in a metallic stent to treat degenerative
`ventriculo-pulmonary conduits in children.16
`Our goal to implant a stented valve in calcific AS, on the beating heart, was very
`original but posed specific, difficult and at first sight insurmountable issues. These issues
`came from the calcified nature of the diseased native valve, and the immediate proximity
`of essential anatomical structures: coronary ostia, mitral valve, and interventricular
`septum (seat of the conduction system).
`
`VALIDATION OF INTRA-AORTIC VALVE STENTING AND FEEDBACK OF EXPERTS
`To validate the concept of intravalvular stenting in aortic stenosis, an autopsy study was
`conducted in Rouen in 1994 on 12 cases of calcific AS (Fig. 2). The study demonstrated
`that a balloon-expandable peripheral artery stent of 23 mm in diameter (Palmaz stent)
`was able to maintain a circular opening in all calcified aortic valves. The study also made
`it possible to establish the optimal dimensions of the stent height, avoiding any contact
`with the neighboring structures. Furthermore, the stent required a high traction force to
`be dislodged from the annulus, thus lowering the potential risk of device embolization.
`This study was a fundamental milestone and validated the concept of aortic valvular
`stenting in a model of human calcific AS. At that stage, the type of valve prosthesis and
`its physical properties were still limited to drawings, however they were still used to file a
`European patent (Fig. 3).
`Getting biomedical companies interested in this concept was a total failure with
`unanimously unfavorable opinions from all experts with regard to the design of the
`prosthesis, the potential risks of the procedure and the medical indication itself. Major
`clinical issues were constantly brought up: coronary occlusion, mitral valve injury, stroke,
`aortic regurgitation, prosthesis migration, permanent auriculo-ventricular block, bleeding,
`endocarditis, and non-lasting results. The project was looking like the ‘‘most stupid ever
`proposed’’.
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`Figure 3. 1994: Drawings and model prefiguring a balloon expandable transcatheter
`bioprosthesis. A: specific stent frame design allowing to attach a tricuspid valvular structure. Partial
`external coverage would limit the risk of aortic regurgitation through the struts. B: Hand made model of
`stented-valve before and after crimping over a balloon catheter (external diameter: 8 mm). C: Drawing of
`the different phases of transcatheter aortic valve implantation.
`
`FROM CONCEPT TO PROTOTYPES: PRE-CLINICAL EVALUATION
`Creation of the start-up: Percutaneous Valve Technologies
`To accomplish this venture, a start-up company, ‘Percutaneous Valve Technologies’ (PVT,
`NJ, USA) was finally formed in 1999 (Alain Cribier, MD, Martin Leon, MD, Stan Rabinovich
`and Stanton Rowe, PhDs). A development and first investment partner was found in Israel
`(ARAN, R&D, Ltd, Caesarea) a small biomedical company with great engineers which
`became our long-lasting partner in this venture. This was the start of a strong, durable
`and successful collaboration between engineers and clinicians. The translational pathway
`to TAVR, set by PVT and ARAN, would remain unchanged in the future for all companies
`working on the development of such a procedure (Fig. 4).
`
`Preclinical engineering output: From concept to finalized prototype
`Indications given to the engineers for the development of a transcatheter heart valve
`(THV) were particularly challenging. They had to integrate many innovative technologies:
`a balloon-expandable stent, a high-pressure balloon for stent expansion, a valvular
`structure and a delivery system. According to the ‘‘philosophy’’ of the THV, they had
`to create a prosthesis made of a highly resistant frame containing a valve structure,
`able to be homogeneously compressed to 7-9 mm over a high pressure balloon (trans-
`femoral artery insertion) and expanded to a diameter of 23 mm by balloon inflation,
`without damaging the frame and leaflets. Selection of the valve material, conceiving its
`attachment to the frame, and the valve design to provide sufficient strength, low profile
`and durability were other issues. The question of how to deliver the valve accurately,
`within the calcified valve, on the beating heart, would come later.
`Many different valve configurations were investigated. Valve design was dependent
`on:
`1. Frame material and design (profile, dimensions, skirt, crimping process and
`expansion, fatigue, resistance).
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`Figure 4. The translational pathway of transcatheter aortic valve replacement: driving for
`superior outcomes.
`
`2. Leaflets design (material, attachments, cooptation, stress distribution, leak,
`hemodynamics, fatigue and durability, calcification).
`3. Loading and delivery catheter system.
`Each of these elements required specific work on design-geometry, material selection,
`manufacturing and processing. Geometry optimization used the Finite Element Analysis
`(FEA) method. The goal was to maintain the durability constraints while reducing the
`crimping profile. For laboratory testing (Fig. 5), the company had to design its own
`equipment for a new technology: crimping tools, pulse duplicators, accelerated wear and
`durability testers, various frame testers, hydrodynamic testers, and a leaflet calcification
`tester.
`The first ‘‘finalized’’ device (Fig. 6) consisted of a stainless steel stent, 23 mm in
`diameter, 17 mm in height, containing a tri-leaflet valve initially made of polyurethane
`(later changed to a bovine pericardium valve), which had been proven for more than 25
`
`Figure 5. New testing equipment designed by PVT for the evaluation of valve structure and frame.
`
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`Figure 6. A: Various prototypes and finalized device (B) created by PVT. C: Crimped device over a
`23 mm Numed balloon catheter, and 24F introducer for implantation in the sheep model. Angiographic
`evaluation post-implantation within the native aortic valve, and transesophageal echocardiography
`evaluation of valvular function.
`
`years in surgical bioprosthesis to have excellent properties. The device was compatible
`with a 24F (8 mm) introducer sheath.
`
`FROM PROTOTYPES TO ANIMAL MODEL
`In the year 2000, we started animal experimentation on the sheep model (Fig. 5). Over
`100 THV implantations at various cardiac sites (pulmonary artery, aorta, aortic valve)
`were performed by myself and my collaborator, Helene Eltchaninoff. In spite of the clear
`limitations of this animal model, the experimentation contributed to the optimization of
`bioprosthesis, delivery systems, and implantation techniques, guidewires and 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 as a test of
`biocompatibility. The persistence of an excellent valve function and the integrity of the
`THV on pathological examination were thus demonstrated.
`
`FROM BENCH TO BEDSIDE
`On 16th April 2002, we performed the first-in-human TAVR (Fig. 7) on a 57-year-old
`patient with severe AS who presented in cardiogenic shock with major left-ventricular
`dysfunction (ejection fraction 12%) with multiple comorbidities contraindicating SAVR.18
`After failed emergent BAV, TAVI appeared to be the last-resort option for this young
`patient. The indication was particularly challenging in this patient, who also had
`subacute leg ischaemia related to an aorto-femoral bypass occlusion and severe
`contralateral atherosclerosis preventing the use of the planned transfemoral retrograde
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`Figure 7. First-in-Man implantation (Rouen, April 16th, 2002). A—The complex antegrade
`transseptal route used for TAVR. B—View of the transcatheter valve in place within the native calcified
`valve and hemodynamic result (no gradient). C—The patient immediately after valve implantation and D,
`8 days later.
`
`access. The procedure was successfully performed using a challenging approach, the
`antegrade transseptal approach via the femoral vein. 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 (leg amputation
`consecutive to his pre-hospitalization leg ischemia). This first-in-man case confirmed
`the feasibility of implanting a THV in a human on the beating heart using transcatheter
`techniques, with perfect subcoronary position and no interference with the surrounding
`structures. In that, it can be considered an important milestone in interventional
`cardiology. The international reaction to this spectacular case defied imagination.
`Two successive feasibility trials on a total of 38 patients19–21 restricted to
`compassionate use (imminent death) were thereafter initiated in our center. These
`studies confirmed the feasibility of TAVI (80% procedural success) using the transseptal
`approach and the lasting haemodynamic and functional improvement after implantation.
`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 ( > 23 mm).
`As expected, several of these critically ill patients died of their comorbidities within
`weeks or months but, amazingly, some survived beyond 2–5 years and even as long
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`as 6.5 years in our most striking case, without any prosthesis dysfunction. 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 patients 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.
`
`FROM BEDSIDE TO FEASIBILITY TRIALS
`When Edwards Lifesciences Corporation (Irvine, CA, USA) acquired PVT in 2004, TAVR
`entered a new era. The prosthesis underwent several iterations and an easier delivery
`system and new approaches were developed (Fig. 8).
`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 deflectable RetroFlex catheter, evaluated by Webb et al. in Vancouver,
`Canada.22 Simultaneously, a new approach was developed, the minimally invasive
`transapical approach using the Ascendra delivery system, evaluated by Walther et al. in
`Leipzig, Germany.23 The onset of these two approaches made TAVR available to the vast
`majority of patients, regardless of the suitability of the femoral access. Our team in Rouen
`was included in the setting of several European feasibility studies (REVIVE, PARTNER
`Europe, TRAVERSE) including hundreds of patients. The satisfactory results of these trials,
`despite specific complications with the two approaches, led to a fast expansion and
`acknowledgement (in particular by cardiac surgeons) of TAVR.
`In 2004, a concurrent THV, the CoreValve (later commercialized by Medtronic, Irvine,
`CA, USA), an auto-expandable nitinol frame containing a porcine pericardial valve,
`was launched and evaluated in feasibility studies.24 This device could be inserted
`
`Figure 8. Edwards Lifesciences input after acquisition of Percutaneous Valve Technologies
`(2004): development of the SAPIEN valve and of new approaches for TAVR: transfemoral
`retrograde and transapical antegrade.
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`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. The Conformité Européenne (CE)
`mark was obtained for both models of transcatheter valves in 2007.
`
`FROM FEASIBILITY TRIALS TO LARGER CLINICAL REGISTRIES AND EVIDENCE-BASED
`TRIALS
`Thereafter, acceptance and expansion of TAVR was amazing, with an annual 40%
`increase in the number of procedures. In line with the recommendations of the European
`Societies of Cardiology (ESC) and Cardiothoracic Surgery (EACTS),25 thousands of
`inoperable or high-risk elderly patients were enrolled in post-marketing national (France,
`Germany, Italy, UK, Canada etc.) and international registries with the two models of THV.
`These registries included:
`• Single valve evaluation as in the SAPIEN Aortic Bioprosthesis European
`Outcome (SOURCE) registry,26 which has enrolled 1,123 patients since 2007 receiving
`transfemoral or transapical TAVR.
`• The Evaluation of the Medtronic CoreValve System in a ‘‘Real-World’’ (ADVANCE)
`Registry, presented at the EuroPCR meeting in Paris, in May 2013, including 1,015
`patients enrolled at 44 centers.
`• Two valve evaluations: the French Aortic National CoreValve and Edwards (FRANCE)
`registry,27 followed by the FRANCE 2 registry,28 reporting the French experience on a
`series of 3,500 patients, making it the largest exhaustive overview of TAVR in the real
`life.
`These registries contributed to a better appraisal of patient screening, technical
`modalities, prevention, and management of complications. The procedural success
`rate increased to over 95%, and 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 10% at 1 month and 20% at 1
`year, as in the SOURCE registry,26 after transfemoral implantation. A dramatic and long
`lasting improvement in the quality of life29 was observed in all registries, and was further
`confirmed in the pivotal PARTNER trial.
`The first evidence-based evaluation of TAVR was obtained with the Edwards SAPIEN
`valve in the multicenter pivotal randomized trial ‘‘Placement of Aortic Transcatheter
`Valves’’ (PARTNER) in the USA. From 2007, 1,056 high surgical risk patients were enrolled
`in 26 centers in USA. Patients were divided into two cohorts, 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, with equal improvement of quality of
`life30,31.
`Similar results were observed at 2, 3 and 5 years.32–34 In view of these results, TAVR
`was approved by the Food and Drug Administration (FDA) in these indications in 2011
`and 2012 respectively. The pivotal CoreValve high-risk trial also randomized TAVR vs
`SAVR in symptomatic high-risk patients with severe AS, with a primary end point of
`all-cause mortality at 1 year. This trial was the first and so far the only randomized trial to
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`ever show superiority for TAVR vs SAVR (14.2 vs 19.1% respectively), results confirmed at 2
`years.35,36 In these trials, the similarity or superiority of transcatheter over surgical valves
`on hemodynamic flow parameters, but the superiority of surgical valve on paravalvular
`leak and the need for a permanent pacemaker were observed.
`
`SOLVING THE PROBLEMS: THE ESSENTIAL ROLE OF TRANSLATIONAL RESEARCH
`After several years of experience, the task of the engineers was 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.37
`Improvements were achieved by creating new models of bioprosthesis and
`delivery systems (Figs. 9 and 10), decreasing sheath sizes, offering a better coverage
`of the annulus (additional valve sizes), and facilitating sealing and positioning of the
`bioprosthesis. Technical advances are demonstrated on the successive generations of
`the balloon expandable and self-expandable transcatheter valves (Fig. 9).
`The SAPIEN XT featured a lower profile delivery system, compatible with the new
`18-20F e-Sheath designed to treat a broader population of patients and to reduce
`vascular complications. The valve consisted of an enhanced designed trileaflet bovine
`
`Figure 9. Advanced valve and delivery systems have changed the world of TAVI overtime. Several
`generations of Edwards and Medtronic CoreValve led to decreased crimped sizes and launch additional
`valve sizes for a better coverage of the aortic annulus.
`
`Figure 10. New models of bioprosthesis approved in Europe.
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`pericardial valve with a polyethylene terephlalate (PET) fabric cuff, sutured into a cobalt-
`chromium balloon-expandable stent with a modified geometry. Valves sizes were 23 mm,
`26 mm and 29 mm. A 20 mm size was later available. Enhanced delivery systems were
`conceived for both transfemoral and mini-surgical approaches.
`As evaluated in the SOURCE-XT registry (2688 patients in 99 European centers),
`the results confirmed important clinical benefits with a marked decrease of vascular
`complications and bleeding, and a decrease of all causes of mortality and cardiovascular
`mortality to 19.8% and 10.8% respectively at one year.38
`The most important data came from the results of the randomized PARTNER 2 trial
`reported early this year.39 The trial enrolled 2,032 intermediate-risk patients at 57 centers,
`to undergo either TAVR or SAVR. At 2 years, non-inferiority of TAVR versus SAVR on rate
`of death or disabling stroke was demonstrated. Furthermore, in the transfemoral-access
`cohort, TAVR resulted in a significantly lower rate of death or disabling stroke than
`surgery. TAVR resulted in larger aortic-valve areas and lower rates of acute kidney injury,
`severe bleeding, and new-onset atrial fibrillation - whereas surgery resulted in fewer
`major vascular complications and less paravalvular aortic regurgitation. This led the FDA
`to extend approval of TAVR to intermediate risk patients.
`Further progress came with the launch of the SAPIEN 3, the newest member of the
`SAPIEN family. The main improved features were a lower profile (compatible with 14-16F
`e-Sheath) allowing us to perform TAVR in about 90% of cases, an improved delivery
`system for more accurate positioning, and an external skirt to reduce paravalvular
`regurgitation. The SAPIEN 3 was approved in Europe in 2014 and in the US in 2015 for the
`treatment of high-risk and inoperable patients. Outcomes for high- and intermediate-risk
`patients treated with the SAPIEN 3 have been evaluated in the PARTNER II S3 trial,40 a
`nested registry of the PARTNER II Trial.
`It reported 1-year follow-up in 1,077 intermediate risk patients implanted with SAPIEN 3
`and compared outcomes using propensity score analysis, to the 747 patients treated with
`SAVR in the PARTNER 2A trial. For the primary endpoint of mortality, stroke, and moderate
`to severe aortic regurgitation, TAVR was superior to SAVR at one year (p < 0.001). The
`study showed the lowest rate of mortality, stroke and aortic regurgitation at 1 year of
`all SAPIEN trials and a superiority of TAVR over SAVR for these composite endpoints
`(p < 0.001). The conclusions suggested that TAVR might become the preferred treatment
`alternative in intermediate risk patients.
`The Medtronic Evolut R is the new generation of the CoreValve self-expanding THV.
`The valve has been re-engineered to improve anatomic fit and sealing, to provide a more
`consistent radial force, to facilitate repositioning and retrieval, and reduce paravalvular
`leak. On a limited series of patients, the 30-day data showed a low rate of moderate to
`severe PVL and pacemaker implantation in comparison to previous Medtronic CoreValve
`series (3.4% and 12.4% respectively).41 This valve is currently approved in the United
`States for high- and extreme-risk patients with symptomatic severe AS.
`The field of TAVR is constantly evolving. A number of next-generation devices,
`markedly different to existing devices, are in clinical evaluation and already CE accredited
`(Fig. 10). 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. As examples, the LOTUS (Boston
`Scientific Marlbourough, MA, USA), comprises a nitinol frame with bovine pericardium
`valve released by an original mechanism offering optimal recapture, the DIRECT FLOW
`MEDICAL (Direct Flow medical, Lake Forest, CA, USA), comprises a rigid scaffold with a
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`bovine pericardium valve and two inflatable aortic and ventricular rings, which almost
`eliminate paravalvular regurgitation.
`
`FROM TRIALS TO DAY-TO-DAY PRACTICE: THE GROWING PLACE OF TAVR AS A
`BREAKTHROUGH TECHNOLOGY
`In parallel to the advances in technologies, additional tools were developed regarding
`patient screening and procedures (new multimodality imaging technologies leaded by
`Multislice Computed Tomography), vascular complications (improved vascular closure
`devices), and stroke (embolic protection devices). Even the procedural ‘‘milieu’’ was
`modified with the development of a hybrid environment allowing integration, in the same
`setting, of interventional and surgical therapies. This testifies to the considerable impact
`of TAVR on the world of industry.
`Thanks to these technological advancements, 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 US and European
`guidelines. 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,
`including frailty. New guidelines in 2017 are expected to approve TAVI in intermediate
`risk patients. Another approved indication of TAVI is the treatment of failing surgical
`bioprosthetic heart valves (valve-in-valve). In this indication, TAVR is particularly
`appealing to achieve adequate valvular function for symptom relief without prolonged
`recovery. This indication is being evaluated in an ongoing global multicentre registry -
`Transcatheter Aortic Valve Implantation in Failed Bioprosthetic Surgical Valves.42 This
`new, less invasive therapeutic option for degenerated cardiac valve is pushing surgeons
`to increasingly select bioprosthetic instead of mechanical valves for primary valve
`replacement.
`Subsequent to FDA approval, many centers were certified to apply TAVR in USA,
`currently nearly 500 centers, with around 26,000 patients included in the Society of
`Thoracic Surgery / American College of Cardiology Transcatheter Valve Therapy (TVT)
`registry.43 An equivalent number of centers are certified in Europe, with Germany being
`leader with 160 TAVR/million of inhabitants, followed by Switzerland, Austria and France.
`The cost-effective ‘‘minimalist strategy’’ (Fig. 11) for transfemoral TAVR that we
`pioneered,44,45 plays an important role in the worldwide expansion of TAVR. It
`includes percutaneous transfemoral access, no general anaesthesia, no periprocedural
`transesophageal echocardiography, reduced operators in the room, and early discharge
`programs. This strategy can be applied in 90% of all TAVR patients, shows equivalent
`clinical outcomes compared to the standard transfemoral approaches, and is cost-
`effective.46
`In the near future, TAVR will be extended to younger, lower-risk patients as reflected
`by the results of the PARTNER 2 and PARTNER 2 S3 studies. Using TAVR in ‘‘all comers’’
`is already being evaluated. The Nordic Aortic Valve Intervention Trial (NOTION) first
`randomized almost 300 patients older than 70 years with severe aortic-valve stenosis
`but deemed low risk for surgery at