REVIEWS New devices for TAVI: technologies and initial clinical experiences Maurizio Taramasso, Alberto Pozzoli, Azeem Latib, Giovanni La Canna, Antonio Colombo, Francesco Maisano and Ottavio Alfieri Abstract | Treatment of aortic stenosis in high-risk surgical patients has been modified in the past 10 years owing to the introduction of transcatheter aortic valve implantation (TAVI). Several issues affecting outcomes with implantation of the first-generation TAVI devices remain unresolved, including haemorrhagic and vascular complications, neurological events, rhythm disturbances, and paravalvular leakage. Further technological improvements are, therefore, required before the indications for TAVI can be extended to young and low-risk patients with aortic stenosis. Many new-generation TAVI devices are currently in the early stages of clinical evaluation. Modifications in the new devices include the ability to reposition the valve before final deployment, features to reduce paravalvular leakage, and the introduction of low-profile delivery systems. The aim of this Review is to provide an overview of the new-generation transcatheter valvular technologies, including initial clinical reports. Taramasso, M. et al. Nat. Rev. Cardiol. 11, 157–167 (2014); published online 21 January 2014; doi:10.1038/nrcardio.2013.221

Introduction

Cardiothoracic Department, San Raffaele University Hospital, Via Olgettina 60, 20122 Milan, Italy (M. Taramasso, A. Pozzoli, A. Latib, G. La Canna, A. Colombo, O. Alfieri). Cardiac Surgery Department, University Hospital of Zurich, Rämistrasse 100, 8006 Zurich, Switzerland (F. Maisano). Correspondence to: M. Taramasso taramasso.maurizio@ hsr.it

The treatment of aortic stenosis in patients at high sur­ gical risk has been modified in the past 10 years because of the introduction of transcatheter aortic valve implant­ ation (TAVI). Only 10 years after the first-in-human TAVI procedure,1 this technology has expanded throughout the world, and is one of the most impressive breakthroughs in the past decade of medical history. The key role of TAVI in the treatment of aortic stenosis in these patients has been recognized by its inclusion in the 2012 European Society of Cardiology and European Association for Cardio-Thoracic Surgery Guidelines for the management of heart valve disease.2 TAVI is considered a Class I rec­ ommendation in patients with severe symptomatic aortic sten­osis who are, according to the ‘heart team’, unsuitable for conventional surgery and have >1 year of life expec­ tancy, a metric that also depends on associated comor­ bidities (Class I, level of evidence B). Moreover, among high-risk patients who are surgical candidates, TAVI should be considered as an alternative to surgery in those patients for whom TAVI is favoured by the ‘heart team’ (Class IIa, level of evidence B). Current guidelines do not recommend TAVI in patients at intermediate surgical risk. Reducing the incidence of major adverse events associated with TAVI is crucial, as these risks are not acceptable to a standard-risk surgical population. However, innovations in devices and delivery system technologies are rapid and unceasing, and these patients could be treated with TAVI in the near future. Several thousands of patients worldwide were treated with the first-generation TAVI devices: the Edwards Competing interests The authors declare no competing interests.

SAPIEN®(and, from 2010, the SAPIEN® XT; Edwards LifeSciences, USA) and the Medtronic CoreValve® (Medtronic, USA). However, several issues affecting mid-term and long-term outcomes remain with the first-generatio­n TAVI devices, such as haemorrhagic and vascular complications, neurological events, rhythm disturbances, and paravalvular leakage. Several newgeneratio­n TAVI devices are currently in early clinical evaluation. Although these new devices could be the future of TAVI, limited information is available on their safety and efficacy. The aim of this Review is to provide an overview of the new-generation transcatheter valvular technologies, including initial clinical reports, focusing on the unique characteristics of each available device.

First-generation devices In 2007, both of the first-generation TAVI devices, the Edwards SAPIEN®balloon-expandable prosthesis and the self-expandable CoreValve®device, obtained the CE (Conformité Européenne) mark; thereafter, the accept­ ance and expansion of TAVI occurred with unprec­ edented speed. Several hundred patients at high surgical risk were included in post-marketing registries with dif­ ferent devices and different approaches. The results of TAVI became increasingly predictable, with a procedural success rate of >90%.3–7 In the multicentre, randomized PARTNER trial,8 conducted with the Edwards SAPIEN®device, patients considere­d not suitable for aortic valve replacement clearly benefitted from TAVI, compared with conserva­ tive treatment including balloon valvuloplasty (1-year mortality was 31% and 51% with TAVI and conserva­ tive treatment, respectively, and individuals treated with

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REVIEWS Key points ■■ The introduction of transcatheter aortic valve implantation (TAVI) has substantially changed the treatment of aortic stenosis in high-risk surgical patients in the past 10 years ■■ Problems with the first-generation TAVI devices include increased rates of vascular complications, neurological events, rhythm disturbances, and paravalvular leakage ■■ The extension of TAVI to young and low-risk patients with aortic stenosis requires further technological improvements ■■ New-generation TAVI devices specifically designed to overcome the limitations of the first-generation devices are currently in the early stages of clinical evaluation

TAVI had significantly greater symptomatic improve­ ment and fewer repeated hospitalizations than those who received conservative treatment).8 In another cohort of the same trial,9 the first randomized study comparing TAVI and surgical aortic valve replacement in high-risk but operable patients, TAVI was noninferior to surgery for all-cause mortality at 1 year (24.2% and 26.8%, respectively), with marked functional improvement in both groups. In an analysis of secondary end points, however, patients who received TAVI had an increased number of cerebrovascular events and vascular com­ plications and a higher incidence of paravalvular leaks (mostly less-than-moderate) than those treated with surgery.9 As a consequence of the PARTNER trial, in November 2011 TAVI was approved by the FDA for the treatment of nonsurgical patients; in 2012 FDA approval was extended to high-risk surgical patients.

Devices with a CE mark JenaValve® Device characteristics The safety and efficacy of transapical implantation of the JenaValve®(JenaValve Technology GmbH, Germany) were evaluated in a multicentre, prospective trial and the valve obtained a CE mark in September 2011. The JenaValve® consists of a porcine valve mounted on a low-profile, self-expanding nitinol stent (Table 1). The valve used in this device is commercially available as either a stentless (ElanTM valve; Vascutek, UK) or stented (AspireTM valve; Vascutek, UK) surgical bioprosthesis, both of which perform well in long-term studies.10,11 The porcine root leaflets are connected to flexible stent posts to reduce leaflet stress during the diastolic phase. Three different sizes are available (23 mm, 25 mm, and 27 mm) for implantation in aortic annuli that are 21–27 mm in diameter. A sheathless 32 French (Fr) delivery system is used for a three-step deployment procedure through the transapical route. Rapid pacing is not required during the procedure, and the JenaValve®implantation procedur­e has been described elsewhere.12 In preclinical animal models of acute and chronic aortic stenosis, JenaValve®transfemoral implant­ation was feasable if dedicated technology was used. Enrolment in a first-in-man clinical trial was planned to start in 2013.13 The unique characteristic of this prosthesis is that the implant relies on active clip fixation of the native aortic leaflets, thus eliminating the radial forces on cardiac and aortic structures that cause embolization of the device. 158  |  MARCH 2014  |  VOLUME 11

The unique clip fixation mechanism of the JenaValve® to the native aortic valve leaflets could provide secure anchorage even in the absence of calcifications. This device, therefore, is likely to be appropriate in patients with noncalcified, pure aortic regurgitation, although the clinical experience is still very limited in these patients. The short stent design and fixation to the native aortic leaflets prevent coronary ostia occlusion, thereby a­llowing future coronary artery interventions. Initial clinical results A pivotal study for CE mark approval was conducted in seven German centres14 (Table 1). Between October 2010 and July 2011, 73 patients at high surgical risk were enroled (mean age 83.1 ± 3.9 years, mean logis­ tic EuroSCORE 28.4 ± 6.5%). Elective TAVI was per­ formed on 67 of these patients. The procedural success rate was 89.6% (60 of 67 patients). The duration of the procedure (from insertion until removal of the deliv­ ery system) was 8.5 ± 6.6 minutes. The overall mortal­ ity at 30 days was 7.6%, and conversion to surgery was necessary in four patients (6%). Perioperative stroke occurred in two patients (3%). Permanent pacemaker implant­ation for new-onset atrioventricular block or left bundle branch block was necessary in six patients (9.1%). No ostial coronary obstructions were observed. After the procedure, patients who received TAVI had a reduc­ tion in mean transvalvular gradient (40.6 ± 15.9 mmHg and 10.0 ± 7.2 mmHg before and after the procedure, respectively) and an increase in valve opening area (0.7 ± 0.2 cm² and 1.7 ± 0.6 cm², respectively). The majority of successfully treated patients (86.4%) had no or minimal para­valvular aortic regurgitation; none had moderate to severe (>grade 2+) postprocedural aortic regurgitation. At 6 months, transvalvular gradients, sys­ tolic function, the paravalvular leak rate, and the effective orifice area remained comparable to early postprocedural measurements. Freedom from cardiac death was 86.6% at 6 months.14 Acute and 30-day interim results for the first half of the patients (88 patients; mean age 80.8 ± 6.1 years; mean logistic EuroSCORE 24.9 ± 13.5%) enroled in the JUPITER registry (a real-world, postmarket registry to evaluate 5 year safety and efficacy outcomes of the JenaValve®in 180 consecutive, elderly patients at high surgical risk) were reported at the EuroPCR meeting in 2013. 15 According to Valve Academic Research Consortium (VARC) definitions,16 procedural success was achieved in 84 of 88 patients (95.5%); conversion to open heart surgery was required in two individuals (2.3%). A permanent pacemaker was implanted in 11 of 88 patients (12.5%). Overall survival was 85.1% at 30 days; ~75% of the survivors were in NYHA class I–II. No major strokes were observed; in one patient (1.3%) an acute myocardial infarction occurred within 30 days. Similarly to the CE mark study, excellent changes in haemodynamic characteristics were documented, with a significant reduction in mean transvalvular gradients (40.4 mmHg and 8.1 mmHg before and after the proce­ dure, respectively) and an increase in valve opening area



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REVIEWS (0.8 cm2 and 1.7 cm2, respectively). Perivalvular aortic regurgitation was absent or trace in 80.2% of the patients, and in 97.6% of patients perivalvular leakage was mild or less than mild.

The first clinical evidence that the JenaValve®prosthe­ sis might be a reasonable option in selected patients with severe noncalcified aortic regurgitation and at high surgi­ cal risk was presented in 2013.17 Promising early results

Table 1 | Characteristics of new-generation valves Device name and valve sizes

Valve structure

CE mark

Delivery system and access routes

Clinical evaluation studies

JenaValve®(JenaValve Technology GmbH, Germany); 23 mm, 25 mm, and 27 mm (for 21–27 mm aortic annuli)

Porcine pericardial tissue valve Self-expanding nitinol stent

September 2011 for aortic stenosis September 2013 for aortic regurgitation

Sheathless 32 Fr Transapical (transfemoral is under clinical evaluation)

JUPITER registry15 (180 patients): 85% overall survival (30 days); 12.5% pacemaker implantation; no major strokes; 1.3% acute MI (30 days); 97.6% mild or absent perivalvular leakage

ACURATE® (Symetis SA, Switzerland) Small (20–23 mm aortic annuli), medium (23–25 mm), and large (25–27 mm)

Porcine pericardial tissue valve Self-expandable nitinol alloy stent

September 2011 for aortic stenosis

Sheathless 28 Fr Transapical (transfemoral is under clinical evaluation)

ACCURATE TA®20 (40 patients): 92.5% device success rate; 82.5% survival (6 months); 7.5% pacemaker implantation; 97.5% ≤mild perivalvular leakage ACCURATE TF®21 (20 patients): 95.6% procedural success; 13% pacemaker implantation; 95% mild or absent perivalvular leakage

Portico® (St Jude Medical, USA) 23 mm (commercial use) and 25 mm (under clinical evaluation)

Bovine pericardial tissue valve Self-expanding nitinol frame Porcine pericardial cuff

November 2012 (23 mm) for aortic stenosis

Transfemoral, transaortic, or subclavian: 18 Fr Transapical: sheathless 24 Fr (Only transfemoral is currently approved)

Feasibility and procedural studies23 (50 patients): no major stroke; six patients with new left bundle branch; 0% pacemaker implantation; 95% mild or absent perivalvular leakage (30 days)

Direct Flow Medical® (Direct Flow Medical, USA) valve 25 mm and 27 mm

Bovine pericardial tissue valve Two polyester rings filled with polymer solution

January 2013 for aortic stenosis

18 Fr outer diameter Transfemoral

DISCOVER trial27 (75 patients): 99% overall survival (30 days); 2.7% major strokes; 4% life-threatening bleeding; 16% pacemaker implantation; 99% mild or absent perivalvular leakage (30 days)

Engager® (Medtronic, USA) 23 mm and 26 mm (for 21.0–26.5 mm aortic annuli)

Bovine pericardial tissue valve Self-expanding nitinol frame and a polyester skirt

February 2013 for aortic stenosis

29 Fr inner diameter Transapical, transaortic

Engager® CE pivotal trial30 (125 patients): 95% device success rate; 13.1 mmHg mean aortic gradient (30 days); 8.1% mortality; 6.5% lifethreatening bleeding (30 days); 1.7% strokes; 28% pacemaker implantation; 100% mild or absent perivalvular leakage (30 days)

CoreValve Evolut® (Medtronic) 23 mm

Porcine pericardial tissue valve Self-expanding nitinol frame

May 2013 for valve-in-valve

AccuTrak® stability layer (18 Fr outer diameter) Transfemoral, transaortic, and subclavian

Valve-in-valve study33 (126 patients): 100% procedural success rate; no deaths or adverse events related to the procedure or the device (30 days); 0% pacemaker implantation

Lotus® valve (Boston Scientific, USA) 23 mm and 27 mm

Bovine pericardial tissue valve Self-expanding, braided nitinol frame

October 2013 for aortic stenosis

18 Fr Transfemoral (minimum vascular access diameter 6.0 mm [23 mm valve] or 6.5 mm [27 mm valve])

REPRISE II trial35 (60 patients): 100% procedural success rate; 11.2 ± 5.2 mmHg mean aortic gradient (30 days); 1.7% cardiovascular mortality; 8.7% ischaemic stroke; 100% mild or absent perivalvular leakage (30 days)

SAPIEN® 3 (Edwards Lifesciences, USA) 26 mm (20 mm, 23 mm, and 29 mm sizes are anticipated)

Bovine pericardial tissue valve Balloon-expandable cobalt chromium frame

Under evaluation

Edwards eSheath® 14 Fr with dynamic expansion mechanism Transfemoral (transapical and transaortic are under clinical evaluation)

First-in-human feasibility SAPIEN 3 study38 (15 patients): 100% procedural success rate; 11.9 ± 5.3 mmHg mean transaortic gradient after procedure; 6.7% pacemaker implantation; no deaths, strokes, or cardiovascular complications (30 days); 100% mild or absent perivalvular leakage (30 days) Transapical implantation39 (two patients): 100% procedural success rate; no neurological events or major vascular complications

CENTERA® (Edwards Lifesciences) 23 mm, 26 mm, and 29 mm

Bovine pericardial tissue valve Self-expanding nitinol frame with polyethylene terephthalate skirt

Under evaluation

Edwards eSheath® 14 Fr with dynamic expansion mechanism and motorized handle Transfemoral and subclavian

First device41 (15 patients): 100% procedural success rate; 10.8 ± 4.1 mmHg mean transaortic gradient (1 year); 27% pacemaker implantation; no neurological or major vascular complications; 92% mild or absent perivalvular leakage (30 days) New configuration device42 (14 patients): 100% implantation success; 0% pacemaker implantation; 100% mild or absent perivalvular leakage

Helio® transcatheter aortic dock (Edwards Lifesciences) 25 mm (for 29 mm Sapien® XT)

Self-expanding nitinol stent encased in polyethylene terephthalate

Under evaluation

Edwards eSheath® 16 Fr Transfemoral

Helio feasibility trial44 (four patients, combined transfemoral and transapical approach): 100% implantation success; 100% freedom from all-cause mortality (30 days); two patients reached 12 month follow-up with no residual aortic regurgitation

Abbreviations: Fr, French; MI, myocardial infarction.

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REVIEWS were observed in a small series of five patients consid­ ered to be at high risk for surgical aortic valve replace­ ment after evaluation by an interdisciplinary heart team. Implantation was successful in all cases with no relevant remaining aortic regurgitation or signs of stenosis in any of the patients. No major device-related or procedure-related adverse events occurred, and all five patients were alive with improved exercise tolerance at 3-months f­ollowup. Although clinical experience is still very limited, the JenaValve®is the only device to have obtained a CE mark for noncalcified aortic regurgitation in 2013.

Symetis ACURATE TA® Device characteristics The ACURATE TA®device (Symetis SA, Switzerland) has been specifically developed for the antegrade transapical approach, focusing on an intuitive implant­ ation technique. This device obtained a CE mark at the end of 2011. The self-expanding nitinol frame is designed for a single-operator, two-step implantation procedure (Table 1). Three features of this device should be high­ lighted. Firstly, at the distal edge of the stent body, three ‘stabilization arches’ are mounted to prevent tilting of the prosthesis during final deployment. Secondly, the upper crown is formed by the most-distal part of the stent body and is designed to embrace the native calcified leaflets and provide tactile feedback during final deployment. Thirdly, the stent commissures are radiopaque and visible with fluoroscopy, facilitating anatomical rota­ tion of the prosthesis for the commissural alignment.18 A biological tissue valve is mounted within the nitinol stent, and has a similar leaflet thickness to conventional surgical porcine tissue valves. The transapical design does not require excessive ‘crimping’ of the leaflets. Various available sizes allow the treatment of annuli with diam­ eters of 20–27 mm, with small (20–23 mm), medium (23–25 mm) and large (25–27 mm) valves available. A polyethylene terephthalate skirt is used and the native calcified leaflet tissue is compressed between the upper crown and the annular level to create a seal and prevent paravalvular leaks at the proximal (intra-annular) part of the stent body. Furthermore, the stent has been designed with minimal protrusion into the left ventricular outflow tract to avoid compression of conduction fibres as much as possible. The delivery system is based on the sheathless catheter design, and is similar in size to a 28 Fr sheath system. The system allows for resheathing and repositioning until the final release of the valve. Access to the left ventricular apex is established surgically in a fashion similar to other transapical TAVI procedures.19 In order to prevent dilata­ tion after the valve has been deployed, valvuloplasty with a balloon fully matching the annulus diameter is recom­ mended prior to valve implantation. Once the valve has been inserted into the ventricle and the annular plane has been matched, the anatomical commissural align­ ment should be adjusted such that the leaflets are physio­ logically oriented and no device commissures exist in front of the coronary ostia (alignment can be guided by clear radiopaque markers). The valve can be implanted in 160  |  MARCH 2014  |  VOLUME 11

few minutes using a two-step procedure and rapid ven­ tricular pacing. In the rare event that the prosthesis is accidentally pulled into the left ventricle (owing to exces­ sive force, minimal calcification, or a borderline large annulus), the delivery system allows for resheathing and subsequent repositioning until full deployment.18 The access site and procedural approach that is best-suited to the patient should always be used. Most centres follow a ‘transfemoral first’ strategy; there­ fore patients who undergo a transapical procedure are usually at higher risk than those who undergo trans­ femoral procedures, either as indicated by risk scores or simply bec­ause they carry a high calcium burden. The trans­apica­l approach has several advantages over the t­ransfemoral approach, especially for early generations of TAVI devices, including a short catheter length and a rel­ atively straight catheter. For the ACURATE TA®device, a relatively simple, unique implantation technique, in which the upper crown compresses the calcified tissue, provides tactile feedback. A conventional surgical porcine valve can be incorporated without reducing the leaflet thickness or tight crimping. These factors have a key role in determining device durability. The short distance over the wire using a transapical approach enables easy device control, and the radiopaque markers allow for anatomi­ cal rotation and commissural alignment of the device. The design of the valve (with a polyethylene terephthalate skirt) and the specific implantation technique (in which the upper crown compresses the calcified tissue) prevent paravalvular leaks and are key features of the ACURATE TA®device. A transfemoral version of the ACURATE TA®, called the ACURATE TF®, has also been developed, and is very similar to the ACURATE TA®device. ACURATE TF® comes in four different sizes: extra small (for a 19–21 mm aortic annulus, available at the end of 2013), small (21–23 mm aortic annulus), medium (23–25 mm aortic annulus) and large (25–27 mm aortic annulus). Initial clinical results A first-in-human trial of 40 patients (mean age 83 ± 4 years, mean logistic EuroSCORE 21.2%) was con­ ducted20 (Table 1). According to the VARC criteria,16 the device success rate (92.5%) and the rate of the combined 30-day safety end point was comparable to data for wellestablished­devices. The results after 6 months confirmed this finding; survival was 82.5%, and 7.5% of patients underwent pacemaker implantation. Only one patient had a moderate (grade 2+) paravalvular leak, the other patients had only mild or trace regurgitation.20 The ACURATE TF®prosthesis has been investigated in a multicentre first-in-human trial.21 A total of 20 patients (95.6% procedural success and 13% with new pacemakers implanted) were treated. At 30 days after implantation, only one patient had a paravalvular leak with a score of 2+, suggesting that good outcomes can be obtained with this device.21 The ACURATE TF®device is expected to receive a CE mark in early 2014. The clinical programme includes premarket and postmarket studies (SAVI 2 registry; 250 patients).



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REVIEWS St Jude Medical Portico® Device characteristics The Portico® TAVI system (St Jude Medical, USA) is designed to be resheathable, repositionable, and retriev­ able. The system is composed of a triple leaflet, bovine peri­ cardial valve mounted inside a radiopaque self-expanding nitinol stent (Table 1). The valve is designed to function at the annular level after transfemoral deployment. The cuff of the valve (inflow portion or annular segment) is made from porcine pericardium and functions as a sealing zone. The large cell area and the annular positioning allow easy engagement of the coronary ostia after implantation. The large cell area also minimizes the risk of paravalvular leakage by allowing valve tissue to conform around cal­ cific nodules at the annulus. The valve uses Linx®anti­ calcification technology (as used on Trifecta®and Epic® surgical valves; St Jude Medical, USA). The delivery cath­ eter has radiopaque tip, and an outer diameter of 18 Fr at the distal end and 12 Fr at the proximal end.22 Currently, only the 23 mm device is available for commercial use (to treat annular diameters of 19–21 mm). The 25 mm device is being evaluated for a CE mark and should be available soon. The system is designed to deliver the valve gradually, releasing the annular end first. Rapid ventricular pacing is not required during deployment. If the desired posi­ tion of the valve is not obtained, it can be resheathed and r­edeployed, provided the stent has not been fully released. Initial clinical results The transfemoral 23 mm Portico® device has been approved for a CE mark. It has been evaluated in two feasibility and procedural outcome studies (a total of 50 patients) performed in Canada and in the UK 23 (Table 1). No major strokes, no moderate or severe para­ valvular leaks, and no deaths occurred within 12 months. Although new left bundle branch blocks developed in six patients, none required pacemaker implantation. At 30 days, paravalvular regurgitation was trivial or non­ existent in 12 patients (60%), mild in seven (35%), and moderate in one (5%). Haemodynamic characteris­ tics were similar at 3 and 12 months. The feasibility of transapical implantation of the small profile 23 mm Portico®valve has been investigated.24 The 24 Fr delivery system used for the transapical approach is composed of a tapered nose cone and a capsule containing the com­ pressed valve.24 Notably, the sheathless Portico®delivery system is one of the smallest used for TAVI by transapical access, which could be particularly useful in patients with frail apexes. Despite the encouraging initial experience, future studies are needed to assess the safety and feasi­ bility of this device. Portico®transaortic and subclavian delivery systems will be also available, with designs similar to the transfemoral system. These systems are compatible with the 18 Fr introducer sheath and are also completely repositionable and re­trievable until fully deployed.

Direct Flow Medical® valve Device characteristics The Direct Flow Medical® aortic valve (Direct Flow Medical, USA) is a nonmetallic, percutaneous valve with

Figure 1 | Aortogram of a Direct Flow Medical®valve (Direct Flow Medical, USA). The system is composed of an upper (aortic) and lower (ventricular) ring balloon interconnected by a tubular bridging system. Permission obtained from J. Schofer, Hamburg University Cardiovascular Center, Germany.

an inflatable ring cuff frame designed to encircle and capture the native valve annulus, thereby anchoring the bioprosthesis and minimizing potential paravalvular leaks (Table 1). The Direct Flow Medical®valve received a CE mark at the beginning of 2013. The biological tissue of the valve is composed of a tricuspid bovine pericardial valve attached to a polyester fabric cuff. The upper (aortic) and lower (ventricular) ring balloons are connected by a tubular bridging system and can be inflated independently through two of the three position-fill lumens (Figure 1). The device is fully reposition­able and retrievable through the introducer prior to final deployment. The delivery system is configured with multi­axial tubes. The ring b­alloons are inflated by injecting a mixture of saline and contrast agent. Balloon valvuloplasty is required and immediately after balloon inflation the valve is functional without interrupting blood flow and without the need for rapid pacing. To place the prosthesis in the desired position, the aortic ring balloon is deflated and the ven­ tricular ring balloon is aligned with the aortic annulus. To fix the valve, the aortic ring balloon is reinflated. If the valve is not in the optimal location, the balloons can be deflated and the prosthesis can then be repositioned or completely retrieved. Once the optimal alignment is achieved, the saline contrast mixture is replaced with a polymer that solidifies within 90 min and maintains the implant p ­ ermanently in position.25 The Direct Flow Medical®valve has several advan­ tages over first-generation devices. The delivery system is very flexible, owing to the nonmetallic valve design. Interruption of blood flow and rapid pacing are not needed during positioning and deployment. The inflat­ able polyester cuff conforms to the native aortic annulus,

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REVIEWS treated. These low rates are at least partially attributable to the ability to retrieve and reposition the device.27

Medtronic Engager®

Figure 2 | Model of an Engager®valve (Medtronic, USA) in situ. The side arms of Engager®valve are fixed to the main frame of the prosthesis, and are placed into the sinuses of the aortic root for best anchorage. The Engager® transcatheter aortic valve implantation system is not commercially available in all countries, such as the USA, and is an investigational device in other countries. Engager®is a registered trademark of Medtronic CV Luxembourg S.a.r.l. Permission obtained from Medtronic.

thereby minimizing paravalvular leaks. The valve can be repositioned and retrieved even after final deployment, allowing for the management of potential complications. Notably, this device might not be useful for patients with extensive calcification of the left ventricular outflow tract, in whom positioning of the Direct Flow Medical® valve could be difficult. Initial clinical results The first-generation Direct Flow Medical®aortic valve, which can be introduced using a 22 Fr system, has been carefully evaluated, particularly because of its non­metallic design, which caused concern about valve durability and recoil over time.26 The long-term performance was evalu­ ated by the assessment of sequential dual-source, multi­ slice CT images and echocardiograms over 2 years, and the position, shape, and haemodynamic performance were found to be stable (Table 1).27 The new Direct Flow Medical®valve (delivered through an 18 Fr catheter) has been notably redesigned to increase efficacy and safety. Specifically, the radial force has been increased and improvements have been made to the positioning by using stiffer position-fill lumens that allow better advancement and retraction than the first iteration of this device. The modified valve was examined in the DISCOVER multicentre, nonrandomized trial.27 The overall freedom from mortality at 30 days was 99%, with only one death at 12 months owing to complications from pneumonia. The mean procedural time (skin to skin) was 57.7 min, and the mean time for valve positioning and assessment by echocardiography or angiography was 14 min. In the DISCOVER trial,27 the combined safety end point was reached by 89% of patients (67 of 75). Of the remaining patients, 2.7% had major strokes, 4% had life-threatening bleeding, and 16% needed a newly implanted pacemaker. Final aortic regurgitation jets were mild or nonexistent in 99% of patients and were absent or trace in 73% of patients 162  |  MARCH 2014  |  VOLUME 11

Device characteristics The Engager®aortic valve bioprosthesis (Medtronic), for­ merly known as the Ventor Embracer, was developed for use through the transapical approach and obtained a CE mark in February 2013. The valve is composed of three bovine pericardium leaflets sewn to a polyester sleeve and mounted on a compressible and self-expanding­nitinol frame (Table 1). The stent assembly consists of a shaped main frame and a support frame, coupled together to form the commissural posts of the valve. Two sizes are available: 23 mm and 26 mm. The height of implant­ation is defined in order to place the valve in the anatomic­ ally correct position. To minimize the risk of coronary obstruction, the side arms are fixed to the main frame of the prosthesis and are designed to be placed into the sinuses of the aortic root (Figure 2). The valve can be repositioned before final deployment.28 Initial clinical results In a multicentre study of the first generation of the Medtronic Engager®aortic valve prosthesis, the feasibil­ ity of implanting this device into the correct anatomical position through the transapical route was investigated29 (Table 1). However, as aortic dissections, caused by non­ covered commissural posts and a rigid, straight deliv­ ery catheter, occurred in four of 30 patients, the delivery system was completely redesigned. The feasibility study with the new Engager® system was conducted in 10 patients at high risk for surgery (mean age 82.5 ± 3.6 years, mean logistic EuroSCORE 24.6 ± 13.6%).28 Implantation was successful in all 10 patients, and no complications related to the device itself or the delivery system were observed. One patient died from multi-organ failure not related to the device at post­operative day 23. The inva­ sively measured peak-to-peak gradient after valve implant­ ation was 7.1 ± 3.5 mmHg. Aortic regurgitation due to paravalvular leakage was absent or trivial (≤grade 1) in 90% of patients. In 10% of the patients, aortic regurgi­ tation of grade 1 or 2 was observed. Two of the 10 patients with valvular implants required permanent pacemaker i­mplantation for complete atrioventricular block. The results from the multicentre Engager®CE pivotal trial,30 in 125 patients (mean age 82 ± 4.7 years, mean logistic EuroSCORE 18.4 ± 9%) 30 days after implant­ ation of the device, were presented at the EuroPCR 2013 meeting. Overall device success was 94.8%, and the prosthesis was successfully implanted in 100% of patients. Mortality at 30 days was 8.1% and the stroke rate was 1.7%; life-threatening bleeding was observed in 6.5% of patients. In ~28% of patients, permanent pace­ maker implantation was required. The incidence of peri­ prosthetic leak was extremely low: in 95.5% of patients periprosthetic leakage was absent or trivial and was mild in 4.2%; moderate to severe periprosthetic aortic regurgi­ tation was not observed in any patient. The mean aortic gradient improved from 41.5 mmHg to 13.1 mmHg at



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REVIEWS 30 days, and the effective orifice area increased from 0.8 cm2 to 1.4 cm2.30

Medtronic CoreValve Evolut® Device characteristics The Evolut®(Medtronic) 23 mm valve is the first nextgeneration CoreValve®device. This device is indicated for small (18–20 mm) aortic annuli. The Evolut®23 mm system acquired a CE mark for valve-in-valve procedures at the end of May 2013. Additional Evolut®devices are being developed to treat annular sizes of 21–30 mm. All the valves are delivered through a catheter with and outer diameter of 18 Fr (equivalent to a 14 Fr inner diameter). The Evolut® has several technical refinements and is designed to be fully repositionable, resheathable, and recapturable. The new-generation Evolut®retains the cell design of the first-generation CoreValve®device, with the large cell design facilitating coronary artery access and preserving conformability in order to fit noncircular and heavily calcified annuli (Table 1). The overall height of the Evolut® is about 10 mm shorter than the firstgeneratio­n CoreValve®in order to optimize the fit, espe­ cially in patients with angulated aortic anatomy. However, the height of the pericardial skirt (12 mm) is preserved to provide a seal and reduce paravalvular leaks.31 The device was developed specifically to optimize valve deployment within small native aortic roots. Initial clinical results Clinical experience with the CoreValve Evolut®is still very limited. The device has been implanted in two patients with degenerated, regurgitant, bioprosthetic aortic valves.32 In one of these patients the surgical bio­ prosthesis was a 21 mm Toronto Stentless Porcine Valve (SPV®, St Jude Medical) and in the other one the bio­ prosthesis was a 23 mm Carpentier–Edwards Perimount® (Edwards Lifesciences). In both cases, the procedure was uneventful and patients with the new CoreValve Evolut® had improved haemodynamics with normal echocardio­ graphic parameters and no measured peak-to-peak valve gradient. The 30 day results of a series of 16 patients with small, degenerated surgical bioprostheses who underwent valvein-valve implantation with the 23 mm CoreValve Evolut® have been reported (Table 1).33 Successful implantation was achieved in all patients, and no device-related or ­procedure-related adverse events were observed (Figure 3). All 16 patients were alive and had improved exercise t­olerance at 30 days.33 No new pacemakers were implanted.

Boston Scientific Lotus® Device characteristics The Lotus®valve system (Boston Scientific, USA) has several features to facilitate safe and accurate device placement using an intuitive design and user control. The Lotus®valve system is comprised of a bio­prosthetic aortic valve and a catheter-based delivery system for transfemoral introduction and delivery (Table 1). Boston Scientific received a CE mark for the Lotus®valve system in October 2013. The valve is preattached to the delivery

Figure 3 | Aortogram of a Medtronic Corevalve Evolut®(Medtronic, USA) valve implanted within a degenerated stented aortic bioprosthesis (valve in valve procedure). Permission obtained from Dr Patrick Diemert, Department of General and Interventional Cardiology, University Heart Center, Hamburg, Germany.

system to simplify the procedure. The design of the delivery handle enables accurate deployment via two controls—a control knob and a release collar. If the initial deployment is suboptimal the device can be advanced or even retracted completely at any time prior to final release. The valve is released under ventricular rapid pacing by sliding the release collar forward and turning the control knob. The biological tissue of the prosthe­ sis is made up of three bovine pericardial leaflets and is supported on a braided nitinol frame. A radiopaque marker is located at the vertical centre to aid positioning (Figure 4). Furthermore, an adaptive seal surrounding the ventricular portion of the device should conform to irregular surfaces and calcified aortic annulus, thereby reducing p­aravalvular aortic regurgitation.34 Initial clinical results The 23 mm and 27 mm Lotus® valves were evaluated in the REPRISE clinical programme (Table 1). The REPRISE II trial35 is one of the first trials to report out­ comes based on VARC-236 metrics. In independent core lab assessments of paravalvular aortic regurgitation, 76.1% of patients had no paravalvular regurgitation and there were no cases of moderate or severe regurgitation. Device success and performance rates were approxi­ mately 100%. Safe valve repositioning and retrieval was performed in 16 and four patients, respectively (as defined by VARC-2 criteria). Consequently, no cases of incorrect valve positioning or other major compli­ cations occurred. At 30 days, the mean aortic gradient (primary efficacy end point) was 11.2 ± 5.2 mmHg (per­ formance goal = 18 mmHg, P = 0.001), and the mean effective orifice area was 1.7 ± 0.4.28 One patient (1.7%) died of cardiovascular causes and five patients (8.6%)

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REVIEWS tereph­t halate skirt. Unlike the SAPIEN®  XT, the SAPIEN® 3 has an additional outer polyethylene tereph­ thalate sealing cuff to reduce perivalvular regurgitation. The SAPIEN® 3 was only available in a 26 mm size for the first-in-human implantations described below, but addi­ tional sizes (20 mm, 23 mm, and 29 mm) are anticipated, and will allow implantation of the device into aortic rings 16–27 mm in diameter. The low-profile SAPIEN® 3 trans­ catheter valve and delivery system might facilitate fully percutaneous implantation in a broad range of patients with the potential for more-accurate positioning and less paravalvular regurgitation than the SAPIEN® XT.

Figure 4 | Aortogram of Lotus®(Boston Scientific, USA) valve after final release. A radiopaque marker is located at the vertical centre to aid the correct positioning (white arrow). Permission obtained from Boston Scientific.

had ischaemic strokes. The high rate of implantation of new pacemakers (17 of 58 patients, 29.3%) could be due to a certain degree of oversizing of the prosthesis, as it was only available in two sizes. Notably, paced rhythms were also observed in 11 of 17 patients (64%).35

Devices not yet CE mark approved Edwards Lifesciences SAPIEN® 3 Device characteristics The SAPIEN® 3 valve (Edwards Lifesciences) is the newest balloon-expandable valve developed by Edwards Lifesciences and can be implanted using the trans­femoral, transapical, and direct transaortic approaches. This valve evolved from the currently used SAPIEN® XT device. The SAPIEN® 3 has some features specifically intended to reduce the risk of vascular complications, mini­ mize paravalvular leaks, and simplify the i­mplantation pr­ocedure (Table 1).37 The Edwards Commander®(Edwards Lifesciences) transfemoral delivery system is a modification of the currently used NovaFlex®(Edwards Lifesciences) system. The profile of the Edwards Commander®is lower and its flexibility is higher than the NovaFlex®. The handle of the new delivery system contains an adjustment wheel that allows precise positioning of the crimped valve, moving millimetre by millimetre in the aortic annulus, without pushing or pulling. The Commander®incorpor­ ates a three-dimensional coaxial positioning catheter and is compatible with a 14 Fr expandable sheath, such as the eSheath® (Edwards Lifesciences). The expand­ able sheath reduces the stress on the access vessel during transfemoral implantation by transiently expanding as the crimped prosthesis passes through the sheath. The sheath then recoils, which could reduce the incidence of vascular injuries during introduction.37 The stent and leaflet design allows for crimping of the valve to a smaller profile than the previous Edwards balloon-expandable prostheses, such as the SAPIEN® XT valve. The inflow of the SAPIEN® 3 is covered by an internal polyethylene 164  |  MARCH 2014  |  VOLUME 11

Initial clinical results In the first-in-human experience with the new SAPIEN® 3 valve, implantation was feasible and the short-term clini­ cal outcomes were good (Table 1).38 The 26 mm device was implanted via the femoral artery in 15 patients with symptomatic, severe aortic stenosis. All the devices were successfully implanted. The aortic valve area increased from 0.7 ± 0.2 cm2 to 1.5 ± 0.2 cm2 (P 10,000 patients undergoing TAVI, the risk of stroke was 3.3% at 30 days and 5.2% at 1 year, with a more than threefold increased risk of impaired clinical outcomes and increased all-cause mortality in patients with neuro­logical events compared with event-free patients.51 Several cerebral protection devices with different mechanisms of action (deflection or filtration of the embolized debris) have been introduced and are currently being investigated in the clinic. The clinical introduction of cerebral protection devices should further decrease the incidence of neurological events. Vascular complications have been associated with mor­ bidity, reduced quality of life, and increased costs, and in

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REVIEWS several studies mortality is higher in patients with vas­ cular complications than in those without.4–6 The reduc­ tion in the delivery catheter profile is crucial to decrease the incidence of major vascular complications. In the PARTNER IIB trial,49 inoperable patients undergoing TAVI with the SAPIEN® XT and NovaFlex®delivery systems (18 Fr and 19 Fr) had a significantly lower rate of major vas­ cular complications than those undergoing TAVI with the earlier generation SAPIEN®and RetroFlex® 3 (Edwards Lifesciences) delivery systems (22 Fr and 24 Fr; 9.6% and 15.5% respectively, P = 0.04). Similarly, in the SOURCE XT registry,50 a reduced major vascular complication rate (7.5%) was observed compared with those reported in the original SOURCE registry (10.6%).52 The incidence of major vascular complications seems to be extremely low with the new ultra-low profile delivery systems; this aspect, together with the availability of different access options, allows clinicians to perform a truly patient-tailore­d pro­ cedure with very low rates of access-related complica­ tions. The high rate of pacemaker implantation, up to 29% with some of the new devices, cannot be accepted in patients with low risk for surgical complications. This issue will probably be overcome with improvements in the delivery systems that allow improved positioning, thereby preventing the device from being implanted too low in the left ventricle. Pacemaker implant­ation is rare with some prostheses, such as the Portico®valve and the new configuration of the CENTERA® valve. The inci­ dence of pacemaker implantation after surgical aortic valve replacement is 3–8%.53–55 The rate of pacemaker implant­ation with the first-generation TAVI devices was higher with the self-expandable CoreValve® device (26.4% at 30 days and 29.3% at 1 year)51 than with the balloonexpandable SAPIEN® XT (3–12%).5–9 The rate of rhythm disturbances with the new-generation devices should be further e­valuated outside of formal clinical trials.

1.

2.

3.

4.

5.

6.

Cribier, A. et al. Percutaneous transcatheter implantation of an aortic valve prosthesis for calcific aortic stenosis: first human case description. Circulation 106, 3006–3008 (2002). Vahanian, A. et al. Guidelines on the management of valvular heart disease (version 2012). Eur. Heart J. 33, 2451–2496 (2012). Piazza, N. et al. Procedural and 30-day outcomes following transcatheter aortic valve implantation using the third generation (18 Fr) corevalve revalving system: results from the multicentre, expanded evaluation registry 1‑year following CE marking approval. EuroIntervention 4, 242–249 (2008). Tamburino, C. et al. Incidence and predictors of early and late mortality after transcatheter aortic valve implantation in 663 patients with severe aortic stenosis. Circulation 123, 299–308 (2011). Thomas, M. et al. One-year outcomes of cohort 1 in the Edwards SAPIEN Aortic Bioprosthesis European Outcome (SOURCE) registry: the European registry of transcatheter aortic valve implantation using the Edwards SAPIEN valve. Circulation 124, 425–433 (2011). Thomas, M. et al. Thirty-day results of the SAPIEN aortic Bioprosthesis European Outcome (SOURCE) Registry: a European registry of

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In the past 3 years, patients at intermediate surgical risk have received TAVI in Europe and have had better out­ comes than the high-risk population.56 Trials conducted specifically in intermediate-risk populations, such as the SURTAVI trial57 in Europe and the PARTNER II trial58 in the USA, are ongoing and will evaluate the potential expansion of TAVI indications. Simplified techniques and devices with improved safety will soon be available in clinical practice, and techno­ logical improvements are likely to continue rapidly and consistently. Although preliminary data with the new devices and technologies seem very promising, the clini­ cal experience is still limited, and more long-term data are required. Although conventional surgical aortic valve replacement is still the gold-standard treatment for the majority of the patients with aortic stenosis, future gen­ erations of devices for TAVI will be able to offer to an ever-increasing number of patients an alternative option to surgery to improve health-related outcomes and quality of life. In this scenario, clinicians, interventional cardio­ logists, and cardiac surgeons must be confident in these new t­reatment options. Review criteria The bibliographic research was conducted using the MEDLINE (PubMed) database. Key words used for the research included: “transcatheter aortic valve implantation”, “TAVI”, “TAVI registries”,” new-generation TAVI”, “complications following TAVI”, and along and in combination. Only information from full-text articles in English from international medical journals was considered. To ensure that the clinical information was as current as possible, abstracts from the most-recent and important international interventional cardiology meetings were considered (www.pcronline.com; www.tctmd.com; www.cardiosource.org).

transcatheter aortic valve implantation using the Edwards SAPIEN valve. Circulation 122, 62–69 (2010). Gilard, M. et al. Registry of transcatheter aorticvalve implantation in high-risk patients. N. Engl. J. Med. 366, 1705–1715 (2012). Leon, M. B. et al. Transcatheter aortic-valve implantation for aortic stenosis in patients who cannot undergo surgery. N. Engl. J. Med. 363, 1597–1607 (2010). Smith, C. R. et al. Transcatheter versus surgical aortic-valve replacement in high-risk patients. N. Engl. J. Med. 364, 2187–2198 (2011). Hadjinikolaou, L. et al. Aspire porcine bioprosthesis: ten years’ experience. J. Heart Valve Dis. 14, 47–53 (2005). Flynn, M. et al. The aortic Elan stentless aortic valve: excellent hemodynamics and ease of implantation. Semin. Thorac. Cardiovasc. Surg. 13, 48–54 (2001). Treede, H. et al. JenaValve. EuroIntervention 8 (Suppl. Q), Q88–Q93 (2012). Rudolph, T. K. & Baldus, S. JenaValve— transfemoral technology. EuroIntervention 9 (Suppl. S), S101–S102 (2013). Treede, H. et al. Transapical transcatheter aortic valve implantation using the JenaValve™ system: acute and 30-day results of the



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multicentre CE‑mark study. Eur. J. Cardiothorac. Surg. 41, e131–e138 (2012). Ensminger, S. First results of the JUPITER Registry on long-term performance and safety of the transapical JenaValve. Presented at EuroPCR 2013. Leon, M. B. et al. Standardized endpoint definitions for Transcatheter Aortic Valve Implantation clinical trials: a consensus report from the Valve Academic Research Consortium. J. Am. Coll. Cardiol. 57, 253–269 (2011). Seiffert, M. et al. Transapical implantation of a second-generation transcatheter heart valve in patients with noncalcified aortic regurgitation. JACC Cardiovasc. Interv. 6, 590–597 (2013). Kempfert, J., Möllmann, H. & Walther, T. Symetis ACURATE TA valve. EuroIntervention 8 (Suppl. Q), Q102–Q109 (2012). Walther, T., Möllmann, H., van Linden, A. & Kempfert, J. Transcatheter aortic valve implantation transapical: step by step. Semin. Thorac. Cardiovasc. Surg. 23, 55–61 (2011). Kempfert, J. et al. Transapical aortic valve implantation using a new self-expandable bioprosthesis (ACURATE TA™): 6‑month outcomes. Eur. J. Cardiothorac. Surg. 43, 52–56 (2013). Abizaid, A. Symetis Transfemoral Technology. Presented at EuroPCR 2013.

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REVIEWS 22. Manoharan, G., Spence, M. S., Rodés-Cabau, J. & Webb, J. G. St Jude Medical Portico valve. EuroIntervention 8 (Suppl. Q), Q97–Q101 (2012). 23. Willson, A. B. et al. Transcatheter aortic valve replacement with the St. Jude Medical Portico valve: first‑in‑human experience. J. Am. Coll. Cardiol. 60, 581–586 (2012). 24. Urena, M., Doyle, D., Rodés-Cabau, J. & Dumont, E. Initial experience of transcatheter aortic valve replacement with the St Jude Medical Portico valve inserted through the transapical approach. J. Thorac. Cardiovasc. Surg. 146, e24–e27 (2013). 25. Bijuklic, K., Tübler, T., Low, R. I., Grube, E. & Schofer, J. Direct Flow Medical valve. EuroIntervention 8 (Suppl. Q), Q75–Q78 (2012). 26. Bijuklic, K. et al. Midterm stability and hemodynamic performance of a transfemorally implantable nonmetallic, retrievable, and repositionable aortic valve in patients with severe aortic stenosis. Up to 2‑year follow-up of the direct-flow medical valve: a pilot study. Circ. Cardiovasc. Interv. 4, 595–601 (2011). 27. Schofer, J. Prospective, multicenter evaluation of the 18 Fr Direct Flow transcatheter aortic valve: the DISCOVER trial – final study enrollment. Presented at EuroPCR 2013. 28. Sündermann, S. H. et al. Feasibility of the Engager™ aortic transcatheter valve system using a flexible over‑the‑wire design. Eur. J. Cardiothorac. Surg. 42, e48–e52 (2012). 20. Falk, V. et al. Transapical aortic valve implantation with a self-expanding anatomically oriented valve. Eur. Heart J. 32, 878–887 (2011). 30. Holzhey, D. Thirty-day outcomes from the multicenter European pivotal trial for transapical transcatheter aortic valve implantation with a self-expanding prosthesis. Presented at EuroPCR 2013. 31. Sinning, J. M., Werner, N., Nickenig, G. & Grube, E. Medtronic CoreValve Evolut valve. EuroIntervention 8 (Suppl. Q), Q94–Q96 (2012). 32. Fairley, S. L., Jeganathan, R., Manoharan, G. & Spence, M. S. Early experience of implantation of the new CoreValve®Evolut™ in degenerated bioprosthetic aortic valves. Catheter. Cardiovasc. Interv. http://dx.doi.org/10.1002/ccd.25125. 33. Diemert, P. Valve‑in‑valve implantation of a novel and small self-expandable transcatheter heart valve in degenerated surgical bioprosthesis. The Hamburg experience. Presented at EuroPCR 2013. 34. Meredith, I. T., Hood, K. L., Haratani, N., Allocco, D. J. & Dawkins, K. D. Boston Scientific Lotus valve. EuroIntervention 8 (Suppl. Q), Q70–Q74 (2012).

35. Meredith, I. T. Thirty day outcome for the first 60 patients in the REPRISE II study. Presented at EuroPCR 2013. 36. Kappetein, A. P. et al. Updated standardized endpoint definitions for transcatheter aortic valve implantation: the Valve Academic Research Consortium‑2 consensus document. Eur. Heart J. 33, 2403–2418 (2012). 37. Binder, R. K., Rodés-Cabau, J., Wood, D. A. & Webb, J. G. Edwards SAPIEN 3 valve. EuroIntervention 8 (Suppl. Q), Q83–Q87 (2012). 38. Binder, R. K. et al. Transcatheter aortic valve replacement with the SAPIEN 3: a new balloonexpandable transcatheter heart valve. JACC Cardiovasc. Interv. 6, 293–300 (2013). 39. Ribeiro, H. B. et al. Transapical Implantation of the SAPIEN 3 Valve. J. Card. Surg. 28, 506–509 (2013). 40. Ribeiro, H. B., Urena, M., Kuck, K. H., Webb, J. G. & Rodés-Cabau, J. Edwards CENTERA valve. EuroIntervention 8 (Suppl. Q), Q79–Q82 (2012). 41. Binder, R. K. et al. Transcatheter aortic valve replacement with a new self-expanding transcatheter heart valve and motorized delivery system. JACC Cardiovasc. Interv. 6, 301–307 (2013). 42. Schäfer, U. Edwards CENTERA transcatheter heart valve. Presented at EuroPCR 2013. 43. Barbanti, M., Ye, J., Pasupati, S., El-Gamel, A. & Webb, J. G. The Helio transcatheter aortic dock for patients with aortic regurgitation. EuroIntervention 9 (Suppl. S), S91–S94 (2013). 44. Pasupati, S. A novel approach to aortic insufficiency: Edwards Helio System—feasibility trial. Presented at EuroPCR 2013. 45. Webb, J. Helio (Giovani): a dedicated transcatheter valve system for aortic insufficiency. Presented at EuroPCR 2013. 46. Abdel-Wahab, M. et al. German transcatheter aortic valve interventions registry investigators. Aortic regurgitation after transcatheter aortic valve implantation: incidence and early outcome. Results from the German transcatheter aortic valve interventions registry. Heart 97, 899–906 (2011). 47. Gotzmann, M. et al. Transcatheter aortic valve implantation in patients with severe symptomatic aortic valve stenosis-predictors of mortality and poor treatment response. Am. Heart J. 162, 238–245.e1 (2011). 48. Linke, A. One year outcome in real world patients treated with transcatheter aortic valve implantation: the ADVANCE study. Presented at EuroPCR 2013. 49. Leon, M. A randomized evaluation of the SAPIEN XT transcatheter valve system in patients with

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aortic stenosis who are not candidates for surgery: PARTNER II, inoperable cohort. Presented at the American College of Cardiology Scientific Sessions (2013). Treede, H. One year outcomes from the SOURCE XT Registry: propensity score matching for transfemoral versus transapical approach. Presented at EuroPCR 2013. Eggebrecht, H. et al. Risk of stroke after transcatheter aortic valve implantation (TAVI): a meta-analysis of 10,037 published patients. EuroIntervention 8, 129–138 (2012). Windecker, S. One-year outcomes from the SOURCE XT post-approval study. Presented at EuroPCR 2013. Emlein, G. et al. Prolonged bradyarrhythmias after isolated coronary artery bypass graft surgery. Am. Heart J. 126, 1084–1090 (1993). Glikson, M. et al. Indications, effectiveness, and long-term dependency in permanent pacing after cardiac surgery. Am. J. Cardiol. 80, 1309–1313 (1997). Van Mieghem, N. M. et al. Persistent annual permanent pacemaker implantation rate after surgical aortic valve replacement in patients with severe aortic stenosis. Ann. Thorac. Surg. 94, 1143–1149 (2012). Wenaweser, P. et al. Clinical outcomes of patients with estimated low or intermediate surgical risk undergoing transcatheter aortic valve implantation. Eur. Heart J. 34, 1894–1905 (2013). US National Library of Medicine. ClinicalTrials.gov [online], http://clinicaltrials.gov/ct2/show/ NCT01586910?term=SURTAVI&rank=1 (2013). US National Library of Medicine. ClinicalTrials.gov [online], http://clinicaltrials.gov/ct2/show/ NCT01314313?term=PARTNER+2+tavi&rank=1 (2013).

Acknowledgements We would like to thank the other members of the TAVI team at San Raffaele University Hospital—Dr Paolo Denti, Dr Micaela Cioni, and Dr Nicola Buzzatti—for their support. Author contributions M. Taramasso researched data for the article, discussed its content, and wrote, reviewed, and edited the manuscript. A. Pozzoli researched data for the article, and wrote, reviewed, and edited the manuscript. A. Latib, G. La Canna, A. Colombo, F. Maisano, and O. Alfieri discussed the content and reviewed and edited the manuscript before submission.

VOLUME 11  |  MARCH 2014  |  167 © 2014 Macmillan Publishers Limited. All rights reserved