European Journal of Cardio-thoracic Surgery 34 (2008) 1—8
`
`www.elsevier.com/locate/ejcts
`
`Transcatheter valve implantation for patients with aortic stenosis:
`a position statement from the European Association of
`Cardio-Thoracic Surgery (EACTS) and the European Society of
`Cardiology (ESC), in collaboration with the European Association
`of Percutaneous Cardiovascular Interventions (EAPCI)§
`
`Alec Vahanian a,*, Ottavio R. Alfieri b,**, Nawwar Al-Attar a, Manuel J. Antunes c,
`Jeroen Bax d, Bertrand Cormier e, Alain Cribier f, Peter De Jaegere g, Gerard Fournial h,
`Arie Pieter Kappetein g, Jan Kovac i, Susanne Ludgate j, Francesco Maisano b, Neil Moat k,
`Friedrich-Wilhelm Mohr l, Patrick Nataf a, Luc Pierard m, Jose´ Luis Pomar n,
`Joachim Schofer o, Pilar Tornos p, Murat Tuzcu q, Ben van Hout r,
`Ludwig K. von Segesser s, Thomas Walther l
`
`a Hoˆpital Bichat, Paris, France
`b Ospedale San Raffaele, Milan, Italy
`c University Hospital, Coimbra, Portugal
`d Leiden University Medical Center, Leiden, The Netherlands
`e Institut Hospitalier Jacques Cartier, Massy, France
`f CHU de Rouen, Hoˆpitaux de Rouen, Hoˆpital Charles Nicolle, Rouen Cedex, France
`g Thoraxcenter, Erasmus Medical Center, Rotterdam, The Netherlands
`h CHU, Centre Hospitalier de Rangueil, Toulouse, France
`i University Hospitals of Leicester, Leicester, UK
`j Department of Health, Medicines and Healthcare Products Regulatory Agency, London, UK
`k Royal Brompton Hospital, London, UK
`l Heart Center Leipzig, University of Leipzig, Leipzig, Germany
`m University Hospital Sart Tilman, Liege, Belgium
`n Hospital Clinico de Barcelona, University of Barcelona, Barcelona, Spain
`o Hamburg University Cardiovascular Center, Hamburg, Germany
`p Hospital Universitari Vall d’Hebron, Barcelona, Spain
`q Cleveland Clinic, Cleveland, OH, USA
`r Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands
`s CHUV, Lausanne, Switzerland
`
`Received 3 April 2008; received in revised form 3 April 2008; accepted 15 April 2008; Available online 27 May 2008
`
`Abstract
`
`Aims: To critically review the available transcatheter aortic valve implantation techniques and their results, as well as propose recommenda-
`tions for their use and development. Methods and results: A committee of experts including European Association of Cardio-Thoracic Surgery and
`European Society of Cardiology representatives met to reach a consensus based on the analysis of the available data obtained with transcatheter
`aortic valve implantation and their own experience. The evidence suggests that this technique is feasible and provides haemodynamic and clinical
`improvement for up to 2 years in patients with severe symptomatic aortic stenosis at high risk or with contraindications for surgery. Questions
`remain mainly concerning safety and long-term durability, which have to be assessed. Surgeons and cardiologists working as a team should select
`
`§ The following authors declared the following conflicts of interest: J.B., research grants from GE Healthcare, BMS Medical Imaging, St Jude, Medtronic, Boston
`Scientific; A.C., consultant for Edwards Lifesciences; J.K., consultant for Medtronic; F.M., consultant for Edwards Lifesciences and Medtronic, consultant and
`stockholder for Micardia; P.N., consultant for Sorin; J.L.P., consultant for Edwards Lifesciences and Boston Scientific; A.V., consultant for Edwards Lifesciences;
`B.v.H., scientific director on a cost effectiveness study concerning PVR sponsored by Edwards Lifesciences; L.K.v.S., founder and shareholder of Smartcanula LLC,
`Lausanne, Switzerland. All other authors have no conflicts of interest to declare. Funding: Edwards Lifesciences provided an unrestricted grant for the practical
`organization of the meeting. No representatives of Edwards Lifesciences attended the meeting or were involved in the elaboration of the document.
`
`1010-7940/$ — see front matter # 2008 The European Society of Cardiology, European Association for Cardio-Thoracic Surgery, and Europa Edition. All rights reserved.
`doi:10.1016/j.ejcts.2008.04.039
`
`Page 1 of 8
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`2
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`A. Vahanian et al. / European Journal of Cardio-thoracic Surgery 34 (2008) 1—8
`
`candidates, perform the procedure, and assess the results. Today, the use of this technique should be restricted to high-risk patients or those with
`contraindications for surgery. However, this may be extended to lower risk patients if the initial promise holds to be true after careful evaluation.
`Conclusion: Transcatheter aortic valve implantation is a promising technique, which may offer an alternative to conventional surgery for high-
`risk patients with aortic stenosis. Today, careful evaluation is needed to avoid the risk of uncontrolled diffusion.
`# 2008 The European Society of Cardiology, European Association for Cardio-Thoracic Surgery, and Europa Edition. All rights reserved.
`
`Keywords: Aortic stenosis; Valve disease; Percutaneous valve interventions
`
`1. Preamble
`
`Valve disease is an important public health problem, as it
`carries a poor prognosis and its prevalence is strongly linked
`to the phenomenon of population ageing [1]. The most
`frequent native valve disease in Europe is currently aortic
`stenosis (AS), which is most often seen in elderly patients
`with comorbidities [2]. Valve replacement is the definitive
`therapy for patients with severe AS who have symptoms or
`objective consequences such as left ventricular (LV) dysfunc-
`tion [3,4]. Operative mortality is quite low, even in elderly
`patients when properly selected, and long-term results have
`been shown to be satisfactory [5,6]. However, the risk of
`surgery may be higher in elderly patients with significant
`comorbidities. In addition, several registries show that
`referring physicians often do not propose surgery, as was
`the case in the Euro Heart Survey with 33% of patients with
`severe valve disease and severe symptoms not being
`considered for surgery [7]. Thus, despite the good results
`of valve surgery, there may well be a role for less invasive
`alternatives.
`Balloon aortic valvuloplasty (BAV) is now rarely used,
`mainly due to its limited long-term efficacy [2].
`Six years after the first-in-man [8], transcatheter aortic
`valve implantation (TAVI) for the treatment of AS currently
`represents a dynamic field of research and development: two
`devices have been CE-marked and are being commercialized.
`At this point in time, it is important for professional
`societies to critically review the available TAVI techniques
`and their results, as well as propose recommendations for
`their use, development in clinical practice, and further
`research [9,10]. On the 18—19th of November 2007, a
`committee of experts, including EACTS and ESC representa-
`tives, met. The consensus reached is summarized in the
`current document, which was approved first by the
`committee members and subsequently by the board of both
`professional societies involved.
`The Committee acknowledges that the conclusions in this
`document rely on limited data reported mostly in oral
`communications and few in peer-reviewed journals and are
`temporally limited by the very nature of the document.
`
`2. Current techniques and results
`
`Two devices are under clinical investigation for TAVI. One
`device is the Edwards—Sapien valve (Edwards Lifesciences
`Inc., CA, USA), which consists of three pericardial leaflets,
`initially equine and currently bovine, mounted within a
`tubular, slotted, stainless steel, balloon-expandable stent. It
`is currently available in 23 and 26 mm sizes, necessitating,
`
`for the transfemoral approach, respectively, 22 and 24F
`introducer sheaths, and for the transapical approach, this
`measurement was 33F and is now 26F. The other device is the
`CoreValve Revalving System (CRS TM, CoreValve Inc., Irvine,
`CA, USA), which has three pericardial leaflets, initially bovine
`and currently porcine, mounted in a self-expanding, nitinol
`frame. It is available in 26 and 29 mm sizes, which go through
`an 18F introducer for transfemoral use, or very recently 21F for
`the transapical route. (NB: the measurements of prosthesis
`size quoted by the manufacturers do not correspond exactly
`to those of surgically implanted prostheses.)
`
`2.1. Techniques of implantation
`
`is currently carried out using two different
`TAVI
`approaches (retrograde transfemoral and anterograde trans-
`apical), which share the same main principles.
` Most teams perform the procedure under general anaes-
`thesia, although sedation and analgesia may suffice for the
`transfemoral approach.
` Peri-procedural transoesophageal echocardiography (TEE)
`monitoring is desirable to correctly position the valve as
`well as to detect complications.
` After crossing the aortic valve, BAV is performed to pre-
`dilate the native valve and serve as a rehearsal for TAVI.
`Simultaneous rapid pacing decreases cardiac output,
`stabilizing the balloon during inflation. Normal blood
`pressure must be completely
`recovered between
`sequences of rapid pacing.
` The following imaging methods can be used to position the
`prosthesis at the aortic valve:
` Fluoroscopy to assess the level of valve calcification.
` Aortography, using different views, performed at the
`beginning of the procedure and eventually repeated
`with the undeployed prosthesis in place, to determine
`the position of the valve and the plane of alignment of
`the aortic cusps.
` Echocardiography: TEE is helpful, in particular, in cases
`with moderate calcification. The additional value of
`three-dimensional real-time TEE is currently being
`evaluated. According to the limited current experience
`with intracardiac echography, it does not seem to add to
`TEE in this setting.
` When positioning is considered correct, the prosthesis is
`released. Rapid pacing is used at this stage in balloon
`expandable but not in self-expanding devices.
` Immediately after TAVI, aortography and, whenever
`available, TEE or, in the absence of TEE, eventually
`Transthoracic echo-cardiogram (TTE) are performed to
`assess the location and degree of aortic regurgitation and
`the patency of the coronary arteries and to rule out
`
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`3
`
`complications such as haemopericardium, and aortic
`dissection. The haemodynamic results are assessed using
`pressure recordings and/or echocardiography.
` After the procedure, the patients should stay in intensive
`care for at least 24 h and be closely monitored for several
`days especially as
`regards haemodynamics, vascular
`access, rhythm disturbances (especially late atrioventri-
`cular block), and renal function.
`
`The following are the specific issues related to the
`different approaches.
`In the transfemoral approach, close attention should be
`paid to the vascular access.
`The common femoral artery can be either prepared
`surgically or approached percutaneously. Echo-guided
`femoral access could be useful. Manipulation of
`the
`introductory sheaths should be careful and fluoroscopically
`guided. Depending on the size of the device, closure of the
`vascular access can be effected surgically or using a
`percutaneous closure device [11].
`femoral access and
`For
`the transapical approach,
`cardiopulmonary bypass should be on standby in patients
`in whom surgical conversion is an option in case of
`complications. The technique requires an antero-lateral
`mini-thoracotomy, pericardiotomy,
`identification of
`the
`apex, and then puncture of the left ventricle using a needle
`through purse-string sutures. Subsequently, an introductory
`sheath is positioned in the LV, and the prosthesis is implanted
`using the anterograde route.
`
`2.2. Results
`
`Vascular complications, with an incidence ranging from
`10% to 15%, remain a significant cause of mortality and
`morbidity. Stroke ranges from 3% to 9%. Finally, atrioven-
`tricular block occurs in 4—8%, necessitating pacemaker
`implantation in up to 24% with self-expandable devices.
`Long-term results up to 2 years (though only 1 year in most
`studies) are reported in a limited number of patients. They
`show a survival rate of 70—80% with a significant improve-
`ment in clinical condition in most cases. The majority of late
`deaths are due to comorbidities.
`Serial echocardiographic studies have consistently shown
`good prosthetic valve function with no structural deteriora-
`tion of valve tissue.
`
`2.2.2. Transapical approach
`The total experience with transapical aortic valve
`implantation comprises over 300 patients, also at high risk
`for conventional surgery, even more so because of con-
`comitant peripheral arterial disease in most cases. Experi-
`ence currently reported only relates
`to the balloon-
`expandable prosthesis [18—21], although, the first-in-man
`has been recently performed with the self-expandable
`device.
`The implantation success rate of the transapical proce-
`dure is 90%. Over 70% of cases are done off pump, the figure
`being 90% in experienced centres, and the rate of peri-
`operative conversion is 9—12%. Mortality rates range from 9%
`to 18%. The incidence-of stroke is 0—6%. The quality of the
`results seems closely related to experience as well as the
`availability of high-quality imaging in the operating theatre
`[19].
`There are currently no direct comparative studies
`available for the two approaches.
`
`Since the first-in-man TAVI by Alain Cribier in 2002, well
`over 1000 high-risk patients with severe symptomatic AS have
`been treated using TAVI (as of January 2008).
`
`2.3. Perspectives
`
`2.2.1. Transfemoral approach
`Over 400 cases have been performed using the balloon-
`expandable and another 500 using the self-expandable
`prosthesis (Company sources January 2008). Reports origi-
`nate from a limited number of centres worldwide [12—17].
`The patients treated were mostly >80 years old, at high risk
`(e.g. Logistic EuroScore >20% in most cases), or with
`contraindications for surgery.
`The overall results can be summarized as follows:
`Procedural success is closely linked to experience and is
`90% in experienced centres. A learning curve can also be
`observed resulting in better patient selection and outcomes.
`Valve function is good with a final valve area ranging from 1.5
`to 1.8 cm2.
`Mortality at 30 days ranges from 5% to 18%. Acute
`myocardial infarction occurs in 2—11%. Coronary obstruc-
`tion is rare (<1%). Mild-to-moderate aortic regurgitation,
`is observed in 50% of cases.
`mostly paravalvular,
`However, the availability of larger prostheses and their
`more careful matching with the size of
`the aortic
`annulus led to the decrease in the incidence of severe
`aortic regurgitation to 5%. Prosthesis embolisation is
`rare, 1%.
`
`Progress in delivery systems and valve manufacturing
`could lead to lower profile, repositionable, retrievable, and
`more durable devices, as well as a wider range of prosthetic
`valve dimensions. Furthermore, improved imaging, such as
`online three-dimensional reconstruction and stereotaxis,
`could facilitate valve placement.
`
`2.4. Pending questions
`
`In the light of the current experience, bearing in mind the
`previously mentioned, inherent limitations of any conclu-
`sions, TAVI using both balloon- and self-expandable devices
`can be said to be feasible. Short- and mid-term haemody-
`namic results are good up to 2 years. However, the technique
`remains challenging, in particular, as regards vascular access,
`device sizing, and positioning. The major concerns as regards
`to safety are as follows:
` Vascular complications with the transfemoral approach,
`which should decrease with smaller devices.
` Stroke rate, in particular, when using the transfemoral
`approach.
` Long-term consequences of paravalvular leaks, even if
`mild-to-moderate regurgitation is considered not to have
`significant clinical consequences in the short-term.
`
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`A. Vahanian et al. / European Journal of Cardio-thoracic Surgery 34 (2008) 1—8
`
` Atrioventricular block, the incidence, timing, and pre-
`dictors of which have to be identified more precisely.
`
`Mid (short)-term clinical outcome is encouraging, how-
`ever, long-term durability of these bioprostheses and the
`incidence of endocarditis or thrombo-embolic events remain
`key questions, especially if considering lowering the thresh-
`old for indication.
`The feasibility of subsequent aortic valve intervention is
`not known.
`
`3. Recommendations for the development of
`transcatheter aortic valve implantation
`
`3.1. Patient selection
`
`Selection of candidates for TAVI, especially risk assess-
`ment,
`should
`involve multi-disciplinary
`consultation
`between cardiologists, surgeons, imaging specialists, anaes-
`thesiologists, and possibly other specialists if necessary.
`TAVI
`is indicated in patients with calcified pure or
`predominant AS. It is unlikely that it will be used in patients
`with pure aortic regurgitation.
`Degeneration of an implanted aortic bioprosthesis (valve-
`in-valve implantation) is an attractive potential indication
`because of the high risk of re-operation in elderly patients.
`However, the current experience is too limited to make any
`recommendations.
`The following are the four steps of patient selection:
` confirmation the severity of AS;
` evaluation of symptoms;
` analysis of the risk of surgery and evaluation of life
`expectancy and quality of life; and
` assessment of the feasibility and exclusion of contra-
`indications for TAVI.
`
`3.1.1. Confirmation of the severity of aortic stenosis
`TAVI should be performed only in severe AS. Echocardio-
`graphy is the preferred tool to assess the severity of AS
`according to a combination of measurements of valve area
`and flow-dependent indices. Low-dose dobutamine echocar-
`diography is useful to differentiate between severe and the
`rare ‘pseudo severe’ AS in patients with low LV ejection
`fraction and low gradient [3,4].
`
`3.1.2. Evaluation of symptoms
`At the present stage, TAVI should only be proposed in
`patients with severe symptoms that can definitely be
`attributed to valve disease because of pending questions
`on safety and valve durability.
`
`3.1.3. Analysis of the risks of surgery, and evaluation of
`life expectancy and quality of life
`Decision-making is particularly complex in these elderly
`patients who represent a heterogeneous population and
`require balanced and individualized analysis.
`The evaluation of the risk of surgery is based on the
`assessment of cardiac and extra cardiac factors [22]. Risk
`scores, such as the EuroScore [23], the STS predicted risk of
`
`mortality score [24], or the Ambler score [25], are of interest.
`However, they all share similar limitations: predictive ability
`is reduced in these high-risk patients who represent only a
`small proportion of the population from which the scores
`were elaborated; and high-risk patients form a particularly
`heterogeneous group in which it is difficult to capture all the
`comorbidities. The value of individual scores in this high-risk
`population has yet to be specifically established [26]. The
`predictive value of these scores for morbidity and long-term
`results is also unknown.
`TAVI should currently be restricted to patients at high-
`risk or with contraindications for surgery. It is premature
`to consider using it in patients who are good surgical
`candidates.
`For the Committee, the key element to establish
`whether patients are at high risk for surgery is clinical
`judgement, which should be used in association with a more
`quantitative assessment, based on the combination of
`several scores (for example expected mortality >20% with
`the Logistic EuroScore and >10% with STS score). This
`approach allows the team to take into account risk factors
`that are not covered in scores but often seen in practice
`such as chest radiation, previous aorto-coronary bypass with
`patent grafts, porcelain aorta, liver cirrhosis, etc. Surgical
`risk estimation should also bear in mind results in the given
`institution [27].
`At this stage, TAVI is not recommended for patients who
`simply refuse surgery on the basis of personal preference.
`Life expectancy is most significantly influenced by
`comorbidities, which should be carefully looked for. In
`addition to clinical evaluation, semi-quantitative scoring
`systems, such as those used in geriatrics, may be helpful
`[28]. Today, TAVI is seldom considered in patients <70,
`however, age alone is not sufficient for its use instead
`of surgery. TAVI should not be performed in patients
`whose life expectancy is <1 year, who should be managed
`conservatively.
`
`3.1.4. Assessment of feasibility and exclusion of
`contraindications of transcatheter aortic valve
`implantation
`The following steps should be taken to assess the
`feasibility of TAVI.
`
`3.1.4.1. Assessment of the coronary anatomy. Coronary
`angiography should be performed to this end. If associated
`coronary artery disease requires revascularization, whether
`to proceed surgically, percutaneously, or in a hybrid manner,
`as well as the chronology of interventions, should be the
`subject of individualized discussion based on the patient’s
`clinical condition and anatomy. TAVI
`is probably not
`recommended in patients with severe proximal coronary
`stenoses not amenable to percutaneous coronary interven-
`tions.
`The position of the coronary arteries relative to the aortic
`cusps can be assessed using aortography or multislice
`computed tomography [29].
`
`3.1.4.2. Measurement of the aortic annulus. Correct sizing
`of the valve is critical to minimize the potential for
`paravalvular leakage and to avoid prosthesis migration
`
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`5
`
`after placement; however, a gold standard method of
`measurement has yet to be established. TEE has been
`found to show larger values than transthoracic echocardio-
`graphy, thus, it should be performed if borderline values
`lead to doubt the feasibility of the procedure [30].
`Multislice computed tomography [29] or magnetic reso-
`nance imaging could also be used for this purpose. Finally,
`aortography measurements performed during BAV are also
`useful.
`Echocardiography is the preferred tool for the assessment
`of the morphology of the LV outflow tract and, before
`implanting self-expandable devices, the dimensions of the
`aortic root.
`
`3.1.4.3. Evaluation of size, tortuosity, and calcification of
`peripheral arteries. Angiography is the reference; however,
`multislice computed tomography can also be used. Finally,
`magnetic resonance imaging is helpful in patients with renal
`insufficiency.
`Some contraindications are general, whereas others are
`approach- or device-specific.
`General contraindications for TAVI are as follows:
` Aortic annulus <18 or >25 mm for balloon-expandable and
`<20 or >27 for self-expandable devices.
` Bicuspid valves because of
`the risk of
`incomplete
`deployment of the prosthesis [31].
` Presence of asymmetric heavy valvular calcification, which
`may compress the coronary arteries during TAVI [15]. The
`bulk and distribution of calcification in the valve may be
`assessed by fluoroscopy and multislice computed tomo-
`graphy. Finally, the risk of coronary compression can be
`anticipated during BAV.
` Aortic root dimension >45 mm at the aorto-tubular
`junction for self-expandable prostheses.
` Presence of apical LV thrombus.
`
`The specific indications for transfemoral and transapical
`approaches are not fully established and should be discussed
`according to patient condition and local expertise.
`Contraindications of the transfemoral approach are as
`follows:
` Iliac arteries:
`small
`tortuosity,
`severe calcification,
`diameter (<6—9 mm according to the device used),
`previous aorto-femoral bypass.
` Aorta: severe angulation, severe atheroma of the arch,
`coarctation, aneurysm of the abdominal aorta with
`protruding mural thrombus.
` Presence of bulky atherosclerosis of the ascending aorta
`and arch detected by TEE.
` Transverse ascending aorta (balloon-expandable device).
`
`for
`
`the transapical approach are as
`
`Contraindications
`follows:
` previous surgery of the LV using a patch, such as the Dor
`procedure;
` calcified pericardium;
` severe respiratory insufficiency; and
` non-reachable LV apex.
`
`3.2. Performance of transcatheter aortic valve
`implantation
`
`The performance of TAVI, even more so ab initio, should
`be restricted to a limited number of high-volume centres,
`which have both cardiology and cardiac surgery departments,
`with expertise in structural heart disease intervention and
`high-risk valvular surgery.
`The procedure requires the close cooperation of a team of
`specialists in valve disease, including clinical cardiologists,
`echocardiographists, interventional cardiologists, cardiac
`surgeons, and anaesthesiologists.
`Interventional cardiologists should be experienced in
`catheter-based valvular interventions, and peripheral access
`using large devices.
`Cardiac surgeons should be experienced in valve surgery
`and the management of complex cases.
`The final organization may vary from centre to centre and
`according to the type of procedure.
`A multidisciplinary team approach and cross-fertilization
`will be fundamental in the development of these procedures.
`Because of the severe clinical condition of these patients,
`the presence of anaesthesiologists with specific expertise in
`cardiology is mandatory for peri- and post-operative care in
`collaboration with cardiologists and cardiovascular surgeons.
`A close collaboration with surgeons skilled in vascular
`access repair and endo-vascular procedures is recommended
`for transfemoral aortic valve implantation.
`The aim of TAVI training is to acquire basic, then
`advanced, and finally device-specific skills. It will concen-
`trate on knowledge of valve disease (clinical assessment,
`catheterization techniques, imaging), working in a sterile
`environment, access management, understanding the equip-
`ment, and anticipation and treatment of complications.
`Training will be through didactic sessions, bench and/or
`computer simulators, animal laboratories, hands-on training,
`participation in established workshops, and proctoring during
`the first cases.
`The field of teaching and certification needs to be
`significantly developed. A new subspecialization may be
`necessary with a common training pathway for cardiologists
`and surgeons wishing to practice TAVI.
`At this early stage, data are insufficient to define a
`minimum number of procedures required for competency.
`Furthermore, individual experience must be continued in
`order to conserve skills.
`As regards the logistics, it is agreed that the operating
`room and the catheterization laboratory should be as close
`as possible to guarantee optimum patient safety. The
`optimal environment for TAVI should be spacious and sterile,
`and feature high-quality imaging equipment, and haemo-
`dynamic monitoring and recording capabilities. However,
`where to find such an environment is still under debate, as
`both current surgical and interventional suites are sub-
`optimal. Catheterization laboratories have good quality
`imaging but may not be sterile and may induce delay in
`rescue surgery. The opposite is often the case for operating
`rooms.
`A hybrid suite is ideal as it fulfils the role of both an
`operating room and a catheterization laboratory. However,
`most institutions do not have a hybrid room available, thus,
`
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`
`the organizational and financial implications of acquiring
`one, which is highly desirable, cannot be overlooked.
`It is the role of professional organizations such as the
`EACTS and the ESC and their national equivalents to set
`the standards for performance of the procedure and train-
`ing and accreditation on an individual and institutional
`level.
`
`3.3. Evaluation of the results
`
`Evaluation of the results of TAVI will present a significant
`challenge because of the unique characteristics of this
`patient population. Thus, comparison with current outcome
`standards may not be appropriate. Close collaboration
`between investigators, regulators, and the industry should
`be assured early on.
`The evaluation of new devices or techniques should be
`performed in accordance with the stipulations of the
`regulating authorities [32,33]. In Europe, TAVI devices are
`classified in the highest risk group (class 3) as regards the
`requirements for the putting of new devices on the market
`[32]. Evaluation should adhere to the following pattern:
`bench testing, in vitro, and animal implantation studies
`(including bio-compatibility studies),
`then, only when
`sufficient data are available, clinical investigation.
`Clinical
`investigation should begin with the proof of
`concept feasibility studies, followed by prospective clinical
`investigations to determine safety and performance [34].
`Randomized trials are the most rigorous design to evaluate
`safety and efficacy in relation to other treatment modalities.
`However, this is difficult with TAVI in relation to the most
`high-risk patients, many of whom are currently not operated
`on mostly due to non-referral
`[7]. Furthermore,
`the
`contemporary natural history of unoperated patients is
`incompletely known.
`The Committee believes that randomized trials are highly
`desirable once greater experience has been acquired, and
`only small modifications in the technology used are to be
`expected. The necessary clear definition of entry criteria for
`these trials may be hindered by the inadequacy of risk scores
`in these high-risk patients (see Section 3.1.3 for more
`details).
`In high-risk operable patients, TAVI should be compared
`with valve replacement, in particular with the perspective of
`patients who are in better clinical condition in the future. In
`these patients, efficacy could be tested as non-inferiority vs
`surgery, avoiding a too large delta, whereas safety can be
`tested as superiority to surgery. In non-operable patients,
`TAVI can be compared with the best available medical
`treatment using the superiority design for efficacy; however,
`this is more debatable and probably more difficult to run. A
`randomized trial, PARTNER US, is currently ongoing where
`the primary endpoint is all-cause mortality at 1 year. In the
`future, the extension of TAVI to a lower risk patient
`population should occur only in the setting of a randomized
`trial.
`As well as enrolment in randomized controlled trials, data
`should be accumulated in registries. Such registries, which
`may be regional, national, or international, are mandatory in
`the evaluation of TAVI before its release in the general
`medical community. Completeness of the data is essential
`
`here. The duration of follow-up to assess safety should be at
`least 1 year in the pre-market phase and ideally 5 years for
`post-marketing surveillance. Retrieval studies should also be
`carried out if appropriate.
`Irrespective of the study design, safety and efficacy
`endpoints must be carefully defined.
`Analysis will include the standard major adverse cardiac
`events: mortality (30 day, in hospital, 1 year), stroke,
`myocardial
`infarction,
`re-hospitalization,
`reoperation,
`arrhythmias, and conduction disturbances. All adverse
`events, anticipated and non-anticipated, should also be
`reported to the health authority. Quality of life is paramount,
`in particular, in these populations; thus, improvement should
`be recorded using quality of life metrics, which should be
`combined with cost effectiveness parameters. Endpoints
`assessing valve function should follow the guidelines devel-
`oped for valve surgery and include structural and non-
`structural valve dysfunction, endocarditis, thrombo-embolism
`and bleeding events.
`Secondary endpoints, particular to TAVI, should also
`include valve area and transvalvular gradient measurement,
`paravalvular leaks, device migration, emergency valve-in-
`valve implantation, conversion to conventional surgery, and
`vascular complications.
`These trials should be performed according to the
`standards for clinical trials, i.e. central data collection
`and analysis, data and safety monitoring board, core
`laboratory analysis, and auditing and quality control, all
`respecting the rules of independence from sponsors.
`TAVI should currently be performed only in clinical studies
`or as part of post-marketing registries. Clinical trials should
`be limited to centres with experience in TAVI and trials, and
`which actively participate in internal evaluation.
`In centres performing TAVI, multi-disciplinary meetings
`should be held on a regular basis to discuss indications,
`procedural techniques, and case outcomes. Hospitals should
`keep proof of close medico-surgical collaboration and
`maintain a log of all patients referred for TAVI, regardless
`of final treatment strategy, for continuous evaluation of the
`programme [35]. Furthermore, a series of thorough quality
`assurance measures should be included.
`
`4. Conclusion
`
`The currently available results obtained with TAVI suggest
`that these techniques are feasible and provide haemody-
`namic and clinical improvement for up to 2 year