P R O G R E S S I N C A R D I O V A S C U L A R D I S E A S E S 5 6 ( 2 0 1 4 ) 6 3 5 – 6 4 5

Ava i l ab l e on l i ne a t www.sc i enced i rec t . com

ScienceDirect

www.on l i nepcd .com

Challenges and Future Opportunities for

Transcatheter Aortic Valve Therapy

Martin B. Leona,⁎, Hemal Gadaa, Gregory P. Fontanab

aCenter for Interventional Vascular Therapy, Columbia University Medical Center, New York Presbyterian Hospital, New York, NYbLenox Hill Heart & Vascular Institute of New York, Lennox Hill Hospital, North Shore – LIJ Health Care System, Manhasset, NY

A R T I C L E I N F O

Statement of Conflict of Interest: see pag⁎ Address reprint requests to Martin B. Le

Pavilion, 6th Floor, New York, NY 10032.E-mail address: ml2398@columbia.edu (M

0033-0620/$ – see front matter © 2014 Elseviehttp://dx.doi.org/10.1016/j.pcad.2014.03.004

A B S T R A C T

Keywords:

Background: Transcatheter aortic valve replacement (TAVR) is a novel less-invasive therapyfor high-risk patients with severe aortic stenosis (AS). Despite the impressive clinicalgrowth of TAVR, there are many challenges as well as future opportunities.Results: The heart valve team serves as the central vehicle for determining appropriate caseselection. Considerations which impact clinical therapy decisions include frailtyassessments and defining clinical “futility”. There are many controversial proceduralissues; choice of vascular access site, valve sizing, adjunctive imaging, and post-dilatationstrategies. Complications associated with TAVR (strokes, vascular and bleeding events,para-valvular regurgitation, and conduction abnormalities) must be improved and willrequire procedural and/or technology enhancements. TAVR site training mandates arigorous commitment to established society and sponsor guidelines. In the future, TAVRclinical indications should extend to bioprosthetic valve failure, intermediate risk patients,and other clinical scenarios, based upon well conducted clinical trials. New TAVR systemshave been developed which should further optimize clinical outcomes, by reducing deviceprofile, providing retrievable features, and preventing para-valvular regurgitation. Otheraccessory devices, such as cerebral protection to prevent strokes, are also being developedand evaluated in clinical studies.Summary: TAVR is a worthwhile addition to the armamentarium of therapies for patientswith AS. Current limitations are important to recognize and future opportunities to improveclinical outcomes are being explored.

© 2014 Elsevier Inc. All rights reserved.

Transcatheter aortic valve replacementAortic stenosisAortic valve replacement

Background

In the past decade, after initial proof-of-concept and subse-quent feasibility studies, the application of less-invasivecatheter-based approaches to functionally replace diseasedaortic valves has been incorporated into the clinical treatmentarmamentarium in symptomatic high-risk patients with

e 643.on, MD, Columbia Unive

.B. Leon).

r Inc. All rights reserved

severe aortic stenosis (AS). Since 2007, in more than 50countries, over 750 cardiovascular centers have treatedalmost 100,000 aortic stenosis patients using transcatheteraortic valve replacement (TAVR) technologies. Despite therapid acceptance and clinical appeal of TAVR, as with anynew and novel medical therapy, there are still manychallenges to be addressed and future opportunities to be

rsity Medical Center, 161 Ft. Washington Avenue, Herbert Irving

.

Abbreviations and Acronyms

AS = aortic stenosis

CT = computerized tomography

ICE = intra-cardiacechocardiography

LBBB = left bundle branch block

LV = left ventricular

PARTNER = Placement of AorticTranscatheter Valves

PVR = para-valvularregurgitation

RV = right ventricular

STS = Society for ThoracicSurgeons

TA = transapical

TAo = transaortic

TAVR = transcatheter aorticvalve replacement

TEE = transesophagealechocardiography

TF = transfemoral

TVT = transcatheter valvetherapy

US = United States

VARC = Valve AcademicResearch Consortium

636 P R O G R E S S I N C A R D I O V A S C U L A R D I S E A S E S 5 6 ( 2 0 1 4 ) 6 3 5 – 6 4 5

explored. The purposeof this manuscript is toselectively highlight thecrucial challenges ofTAVRwhich are present-ly under investigationand to direct attentiontowards expanding clini-cal applications and newtechnologies which con-stitute important futureopportunities.

Challenges

Case selection

Identifying “high-risk”patientsPatient selection underthe auspices of amulti-disciplinary “Heart Team”is crucial to achieve opti-mal clinical outcomesafter TAVR. The differen-tiation between high-risk,“inoperable” (or extremerisk), and prohibitive riskAS patients has been ac-tively debated since regu-latory approval of TAVRand especially during

the formulation of the Placement of Aortic TranscatheterValves (PARTNER) clinical trial.1 Risk assessment has oftenbeen guidedby standard surgical scoring systems, including theSociety of Thoracic Surgery (STS) and EuroSCORE models,which were not fully validated in this high-risk patientpopulation. These on-line risk scores, as designed for everydayuse, do not include important co-morbidities such as severepulmonary hypertension, right ventricular (RV) dysfunction,severe liver disease, home supplemental oxygen, prohibitiveanatomy (such as chest deformity or severe aortic calcification),disability, or frailty. Characterization of surgical risk requiresdirect involvement of experienced surgeons who usuallyinclude a number of important co-morbidities when consider-ing the highest risk patients for TAVR: malnutrition andcachexia, physical deconditioning or wheelchair bound, chron-ic kidney disease on dialysis, history of particular solid tumormalignancies, neurological disorders such as dementia andstroke, and other debilitating conditions that preclude patientsfrom returning to a reasonable functional status. One of thebiggest challenges in assessment of patient risk status isdeveloping a validated quantitative algorithm that best definespatient risk from the standpoint of predicting early and latemortality as well as functional recovery in the setting of TAVR.The combined analyses of the PARTNER trials or the new

United States (US) Transcatheter Valve Therapies (TVT)National Registry will hopefully provide sufficient patient datato offer the possibility of a TAVR specific risk algorithm at somepoint in the future.2

Frailty and futilityNot entirely captured in current risk stratification metrics isthe attribute of frailty, which has been associated with worseTAVR outcomes. The concept of frailty is crudely definedas an impairment in multiple systems that leads to a declinein resiliency and homeostatic reserve. It is influenced byphysical disability and medical co-morbidities, but is notadequately described by just these attributes.3 Green et alhave devised a frailty score for TAVR patients, based looselyon criteria established by Fried et al.4 The frailty phenotype,including impairments in gait speed and grip strength,reduced serum albumin, and diminished Katz activities ofdaily living, was associated with a longer post-TAVR hospitalstay, as well as increased 1-year mortality.5 The multicenterFRAILTY-AVR study will compare outcomes of surgical aorticvalve replacement (SAVR) and TAVR using several frailtyassessment tools in the effort to define which factors are themost predictive of mortality andmorbidity in elderly patients.The results of the US CoreValve Pivotal Trial Extreme Riskcohort highlight the need to define and quantify the signifi-cance of this interaction, as the only two significant predic-tors of all-cause mortality or major stroke (the primaryendpoint), were STS score of >15% (p = 0.02) and residencein an assisted living facility (p < 0.01).6

A careful frailty assessment plays a key role in thedifferentiation of “futility” (“no hope” patients) and high-riskutility patients and should be incorporated into all TAVR riskstratification analyses. The term “Cohort C” describes thissubset of futile inoperable patients who have both poorsurvival (i.e. less than 1 year) and poor quality of life, despitesuccessful TAVR. Simply stated, “Cohort C” or futile patientsrepresent those patients who are dying with aortic stenosisbut not from AS. Common clinical characteristics mostassociated with futile risk patients include extreme co-morbidities (e.g. STS score >15%), extreme frailty usuallywith a dependent social status, severe pulmonary or liverdisease, severe dementia, chronic kidney disease (e.g. dialysisdependent), and hemodynamic instability (especially requir-ing vasopressors). What remains to be defined is thequantitative interplay of frailty metrics and existing riskstratification models based on age and co-morbid conditions,in accurately determining a “Cohort C” patient.

Procedural considerations

Access alternativesFactors whichmay determine preferred TAVR vascular accessinclude peripheral arterial disease (inadequate vessel diame-ter, severe calcification or extreme tortuosity of theiliofemoral vessels), the presence of extensive calcificationof the ascending aorta (i.e. porcelain aorta), hostile chest wallanatomy (either due to ortho-voltage radiation exposure orchest wall deformities), previous coronary bypass graftsurgery with mammary conduits adherent to the chest wall,

637P R O G R E S S I N C A R D I O V A S C U L A R D I S E A S E S 5 6 ( 2 0 1 4 ) 6 3 5 – 6 4 5

and severe lung disease. The four most common techniquesfor TAVR access are the retrograde transfemoral (TF),antegrade transapical (TA), and the more recently developeddirect or trans-aortic (TAo) and subclavian approaches. In thePARTNER trial, using the larger profile SAPIEN transcathetervalve system (outer sheath diameter 9.2 mm for the 26 mmvalve) there were frequent major vascular complicationsassociated with TF–TAVR procedures.1 In the PARTNER II trial,the first-generation SAPIEN systemwas compared to the lowerprofile SAPIEN XT system (33% lower cross-sectional area) andmajor vascular complications were reduced from 15.5% to 9.6%(p = 0.04).7 This highlights the importance of lower profiledelivery systems inmaximally utilizing safe fully percutaneousTF-TAVR as a primary default access strategy.

The TA approach avoids peripheral access issues, but alsohas limitations; increased length of hospitalization, andincreased risk of 30-day and 1-year all-cause mortality.8,9

These adverse TA outcomes may have been influenced bydifferences in underlying baseline co-morbidities between thetwo populations, given the “TF-first” approach often adoptedby clinicians, which relegated only patients with significantperipheral vascular disease to TA-TAVR. Other adverseoutcomes associated with the TA approach include a higherlikelihood of peri-procedural bleeding, increased risk ofhemodynamic instability, and greater patient discomfort,due to pain related to the antero-lateral thoracotomy.10,11

TAo and subclavian access sites for TAVR have beenintroduced more recently. The largest series of TAo cases12

indicated that compared to a contemporary group of TApatients, there was a lower combined bleeding and vascularevent rate (27% vs 46%; p = 0.05), shorter median intensive careunit length of stay (3 vs 6 days; p = 0.01), and a favorablelearning curve. Transcarotid access and antegrade transseptalaccess via the femoral vein have also been described13,14 butthere are scant clinical outcome data. The choice of vascularaccess site for TAVR is an individualized patient-based decisiondetermined by clinical factors, anatomic considerations aswell as the experiences and preferences of the Heart Team.Considering the less-invasive nature of fully percutaneous TFaccess and the increasing availability of lower profile TAVRsystems, it is likely that TF–TAVR will be the preferred optionfor the majority of patients in the foreseeable future.

Valve sizing and positioningMultimodality imaging is essential for patient screening andprocedural guidance during TAVR, and has been incorporatedinto consensus statements, reviews, and guidelines.15,16

Correct valve sizing for either the balloon-expandable or theself-expandable TAVR system requires meticulous attentionto three-dimensional imaging, including multi-slice CT andtrans-esophageal echocardiography (TEE). Optimal TAVRimplantation requires: (1) correct valve sizing based uponestablished criteria for measuring the annulus dimensionsmatched to the specific valve type; (2) accurate valvepositioning (axial height and alignment) within the annularvalve plane. Different TAVR systems mandate specific proce-dural techniques to determine co-planar implantation viewsand optimal height and alignment of valve implantation,which can be facilitated by rapid pacing with cine-

fluoroscopic and/or TEE guidance. The challenge of valvesizing and positioning cannot be underestimated and re-quires an intimate understanding of the anatomy of the aorticvalvar complex. Ideally, correct sizing and placement of TAVRwill result in excellent valve hemodynamics, none or tracepara-valvular regurgitation (PVR), low requirements for newpacemakers due to conduction abnormalities, and no evi-dence of coronary obstruction or annulus injury.

Trans-esophageal echocardiographyIntraprocedural TEE can provide a real-time biplaneassessment of the annulus before and during deployment,thus fostering more precise valve positioning. TEE can alsohelp to predict and is the gold standard to detect PVR aftervalve implantation, as well as other complications such ascoronary artery obstruction, annulus rupture, pericardialtamponade (e.g. due to chamber perforation), severe mitralregurgitation, aortic dissection (or hematoma), and leftventricular (LV) dysfunction. However, the routine use ofTEE during TAVR procedures has become controversial, asTEE usually is associated with general anesthesia andendotracheal intubation, which may introduce additionalrisks in patients who are hemodynamically unstable orhave underlying severe pulmonary disease. Moreover, TEErequires specialized imaging expertise which may not bereadily available for all cases and the additional sedationmay delay recovery. Therefore, a strong trend in TAVRprocedures has been to selectively or systematically favormonitored anesthesia control without intubation, com-bined with transthoracic echocardiography, as needed. Thevirtues and drawbacks of routine TEE have been hotlydebated and the decision to utilize TEE on a case or site-specific basis is presently determined by resource avail-ability, perceived clinical need, and personal preferences.The motivation to eliminate the need for general anesthesiahas led to an increasing interest in intracardiac echocardiogra-phy (ICE) imaging for TAVR procedures. However, single-planeICE imaging cannot accurately visualize the oval annulus forsizing purposes, measure the coronary artery height, or reliablyassess post-implantation PVR.17 New three-dimensional ICEcatheters may overcome some of these limitations in thefuture, thus permitting on-line echo guidance and assessmentwithout the need for general anesthesia.

Pre- and post-dilationBalloon aortic valvuloplasty (BAV) prior to valve deploymenthas been traditionally performed, especially prior to balloon-expandable transcatheter valve deployment. Pre-dilation BAVallows easier crossing of the valve through the annulus andpotentially avoids mechanical complications related to theforce and contour of the delivery system. However, BAVcarries independent risks of atrioventricular block requiringpermanent pacemakers, increased aortic regurgitation, andembolic neurologic events. Recent trends have favoredreduced or no pre-dilation with low profile self-expandingvalve platforms. Grube et al treated 60 consecutivepatients with the Medtronic CoreValve prosthesis withoutballoon pre-dilation and good hemodynamic performance

638 P R O G R E S S I N C A R D I O V A S C U L A R D I S E A S E S 5 6 ( 2 0 1 4 ) 6 3 5 – 6 4 5

(post-procedural mean gradients and effective orifice areas).18

In addition, in-hospital major adverse cardiovascular eventsand need for permanent pacemakers were far less than thosereported in the US CoreValve Pivotal Trial Extreme Riskcohort.6 Garcia et al reported the results of no pre-dilationwith the SAPIEN XT valve in 10 patients with moderatecalcification, homogenous distribution of calcium, and sym-metric opening of the valve.19 No important complicationswere observed and the patients did not require post-dilationfor significant PVR which was none or trivial in all patients.Thus, the growing trend of TAVRwithout pre-dilation appearsto be a feasible technique with potential benefits and will be atarget for further study in the future.

Post-BAV after TAVR has been selectively applied usuallyin situations of significant PVR, which has been associatedwith increased late mortality.20 The benefits and risks ofpost-BAV after TAVR have been hotly debated. TEE dataclearly indicate that post-dilation in carefully selectedpatients importantly reduces PVR.21 However, post-dilationhas been associated with increased complications includingembolic neurologic events,22 conduction abnormalities, andthe risk of annular rupture. Barbanti et al reported 31 patientsreceiving balloon-expandable TAVR with annular rupturefrom a large multicenter TAVR experience23 and the predic-tors of annular rupture were subannuluar/LV outflow tractcalcification, a higher frequency of ≥20% annular areaoversizing, and balloon post-dilation. In the future, withimproved valve sizing and new technology to prevent PVR,there will be a reduced need for selective post-dilationafter TAVR.

TAVR complications – brief updates, current andfuture management

StrokesStrokes in the setting of TAVR remains amajor peri- and post-procedural complication manifesting with a significant deteriorationin quality-of-life and increased mortality. Several diffusion weightedMRI studies have shown that the rate of silent cerebralembolism after TAVR approaches 80% of patients.24–26 VanMieghem et al confirmed these neuro-imaging findings, noting75% of TAVR procedures producing debris captured in a filter-based cerebral embolic protection device.27 However, a recentmeta-analysis of >10,000 patients in 53 studies confirmed thatTAVR is associated with in a reasonable peri-procedural strokerate of 1.5% and a 30-day stroke/transient ischemic attack rateof 3.3%.28 Thus, the discordance between detection of neuro-embolic activity with TAVR and subsequent clinical neurologicevents requires further resolution. Risk stratification for strokebased on patient characteristics is essential in defining whowould likely benefit from cerebral embolic protectiondevices, as well as tailoring post-procedural management(e.g. surveillance for post-procedural atrial fibrillation andadjunctive pharmacotherapy).

Paravalvular regurgitationThe 2-year follow-up of PARTNER Cohort A patients demonstrat-ed that TAVR resulted in significantly worse PVR than SAVRwith >50% of TAVR patients had at least mild PVR.20 Moreover,

even mild PVR post-TAVR was associated with 10–15% highermortality at 2 years than patients with none or trace PVR, asdetermined by a core echocardiography laboratory. Multipleother studies have shown similar associations between varyingdegrees of significant PVR and increased late mortality afterTAVR.29–31 Accurate diagnosis and clinical impact require acombined assessment of hemodynamics, angiography, andespecially echocardiography, which remains the gold standard.The treatment of PVR is based on an understanding of theseverity and specific etiology. Valve undersizing or under-expansion, valve mal-alignment (either too high or too low),and severe global and focal aortic valvar complex calcificationwith mal-apposition are the main causes of PVR and treatmentoptions include strategic post-dilatation, placement of additionalTAVR to extend the “seal zone”, or implantation of peri-valvevascular plugs.32 New TAVR systems (see below) have beendesigned to reduce or eliminate PVR after TAVR in the futureby improving sub-annular fixation or with peri-valve space-filling technology.

Vascular events and bleedingFrom PARTNER, Genereux et al reported that the 15.3% ofinoperable and high-risk A and B patients experiencing ValveAcademic Research Consortium (VARC) major vascular compli-cations had significantly higher rates of 30-day and 1-yearmortality.33 In this analysis, the only identifiable independentpredictor of major vascular complications was female gender(HR 2.31, p = 0.03). Major vascular complications are an indepen-dent predictor of major bleeding events, which were found to bethe strongest independent predictor of 1-year mortality inPARTNER high-risk patients, although there was a greaterprognostic impact in the SAVR arm.34 Hayashida et al,also showed that VARC major vascular complications increased30-day mortality and were predicted by low procedural experi-ence, femoral calcification, and high sheath-to-femoral arteryratio.35 Asmentioned previously, one-year randomized data fromPARTNER comparing SAPIEN vs. the lower profile SAPIEN XT7

show a reduction in major vascular complications. Reductionin vascular and bleeding events is dependent on appropriatemulti-slice CT screening of vascular anatomy and developmentof lower profile TAVR systems, in addition to implementationof advanced percutaneous closure techniques.36

Conduction abnormalitiesThere are important differences in the need for permanentpacemakers after TAVR between the balloon-expandable SAPIENvalve and self-expanding CoreValve; 6.5% with SAPIEN vs. 25.8%with CoreValve (p < 0.001) in a large meta-analysis.37 Similarly,the frequency of new-onset left bundle branch block (LBBB) isincreased with CoreValve compared with the SAPIEN valve. In acombined analysis of all PARTNER data, Nazif et al showedthat persistent, new-onset LBBB occurred in 10.5% of balloon-expandable TAVR patients with normal baseline conduction.38

This finding did not result in increased all-causemortality, aswasindicated in another retrospective study,39 but was associatedwith a higher rate of subsequent pacemaker implantation andfailure of improvement in LV ejection fraction. Device-relatedfactors, such as the depth of the device implant in the LV outflowtract and the continuous radial force exerted by the self-

639P R O G R E S S I N C A R D I O V A S C U L A R D I S E A S E S 5 6 ( 2 0 1 4 ) 6 3 5 – 6 4 5

expanding CoreValve upon deployment (perhaps causingedema or inflammation of the conduction system in themembranous septum), appear to predispose TAVR patients toconduction abnormalities.

TAVR training and site access issues

A four-society expert consensus statement published in 2012elaborates the recommended criteria for new and existingTAVR programs, pertaining to practitioner (interventionalistor surgeon) and programmatic requirements.40 These guide-lines serve as a foundation to maximize the opportunity toprovide safe and effective adoption of TAVR into newcenters, while maintaining access to care for patients inneed of this worthwhile therapy. It has been estimated thatapproximately 400 of the 1,150 cardiac centers in the USthat are currently performing SAVR would meet theseinitial criteria.2 Currently, approximately 300 centers areperforming TAVR in the US. An expert consensus document,incorporating input from 12 professional societies, detailedall aspects of TAVR and its integration into current clinicalpractice, highlighting critical published data, includingclinical results from the PARTNER trial.16 These consensusdocuments will become increasingly valuable as more trial-based evidence becomes available and as new deviceplatforms and newer generations of existing device plat-forms gather clinical data. The expectations regardingtraining, procedural volume requirements, and anticipatedreferral patterns appear to be more conservative amongstTAVR trialists than practicing clinical interventionalists.41

Formal sponsor required and society-based training pro-grams including hands-on exposure to TAVR equipment,simulation training, didactic sessions, imaging workshops,and case presentations are the current foundation forintegrating future TAVR practitioners and sites. Thereafter,careful in-person proctoring experiences, maintaining rea-sonable case volumes to support the maturation of the HeartValve Team and to reduce “learning curve” concerns, andongoing advanced training symposia are required to insureoptimal clinical outcomes in these high-risk AS patients.

Future opportunities

Expanded TAVR clinical indications

Surgical bio-prosthetic valve failure (valve-in-valve)Management of patients with acute or chronic structural valvedeterioration after surgically implanted bioprosthetic valves isoften problematic and can only be successfully treated byrepeat SAVR. The availability of a transcatheter less-invasiveprocedure is an attractive option especially in older patients withco-morbidities or other high-risk characteristics. Early successfulcases of TAVR for SAVR failure (called “valve-in-valve”) demon-strated the feasibility of both balloon-expandable and self-expanding platforms for SAVR failures and the TA balloon-expandable platform for surgical mitral valve failures.42,43 Perhapsmost important in TAVR valve-in-valve procedures is a completeknowledge of the subtleties and differences among surgical valve

prostheses, as described in recent manuscripts and in a widelyused internet application based on the work of Vinayak Bapat.44

The true inner diameter of the surgical valve, the location of thesewing ring, fluoroscopic landmarks, and the placement ofthe valve relative to the frame (inside or outside) are some of thecritical featureswhich impact TAVR placement. Clinical data froma large global TAVR valve-in-valve registry reported by Dvir et al45

indicate that: (1) valve hemodynamics are good, although not asgood as TAVR in native valves, especially in small bioprostheses(≤21 mm), wherein the supra-annular CoreValve may have anadvantage; (2) PVR is rarely observed; (3) clinical outcomes aregenerally similar to native valve TAVR accounting for relativedifferences in patient co-morbidities; (4) both hemodynamics andclinical outcomes are better when the mode of SAVR failure isPVR vs. AS; (5) there is a prohibitively higher frequency of coronaryartery obstruction in surgical prostheseswith the valve external tothe frame. Most thoughtful TAVR specialists (surgeons andcardiologists) agree thatTAVRwill become the treatment of choicefor bioprosthetic SAVR failure inmost patients in the future.

Intermediate risk AS patientsAlthough categorical risk profiling appears contrived insituations where surgical risk is a continuous occurrence, forregulatory and other purposes, the SAVR population has beenpartitioned into low, intermediate, and high risk subgroups.Based upon current data in high-risk AS patients andevidence suggesting improved clinical outcomes with recentmodifications in procedural factors and technology, interme-diate risk AS patients would be the next logical use extensionfor TAVR. The intermediate risk surgical cohort representsbetween one-quarter and one-third of surgically eligiblepatients, and using the STS quantitative risk scoring systemas a guidepost, an STS score between 3 or 4% and 8%approximates intermediate risk for most AS patients. Amulticenter propensity risk adjustment study in intermediaterisk patients comparing TAVR and SAVR has indicated similarearly and late mortality.46 Similarly, among the initial 7,710TAVR patients enrolled in the US Transcatheter ValveTherapy registry,2 the median baseline STS score was only7%, suggesting that a significant subgroup was likely inter-mediate risk. The overall observed in-hospital mortality andstroke rates were 5.5% and 2.0% respectively, both veryacceptable outcomes for recently trained centers. Two impor-tant large randomized clinical trials, PARTNER 2A (SAPIEN XTvalve) and SURTAVI (CoreValve), in intermediate risk ASpatients (STS score ~4–8%) comparing TAVR vs. SAVR areongoing and future analyses of the more than 4,000 random-ized patients from these studies should help to clarifyquestions regarding advisability of TAVR in this risk strata.Nevertheless, clinical practice around the world has alreadyevolved, as elderly AS patients (>80 years old) with none orone co-morbidity are often treated with TAVR strategies.

Other possible clinical indicationsAlthough, several other patient subgroups and clinicalindications would seem reasonable candidates for TAVRtherapy, ultimate decisions await careful assessments ofclinical need and evaluations of results from rigorous clinicaltrials. For instance, subset analyses from PARTNER47 indicate

640 P R O G R E S S I N C A R D I O V A S C U L A R D I S E A S E S 5 6 ( 2 0 1 4 ) 6 3 5 – 6 4 5

that patients with low flow–low gradient AS may benefitfrom TAVR and could be an alternative to SAVR, especially inhigh-risk patients. Patients with AS and concomitantcoronary disease, mandating combined AVR and coronaryrevascularization, may do as well or better with the combi-nation of TAVR and percutaneous coronary angioplasty.Asymptomatic “very severe” AS (peak velocity >5 liters/sec)patients may be well suited for preemptive TAVR rather thanwatchful waiting strategies and there are already some earlydata in selected patients with predominant aortic regurgita-tion who were successfully treated using self-expandingTAVR systems.48,49 Clearly, the temptation to generalizeTAVR to all current SAVR situations must be resisted untilconfirmation of transcatheter valve durability and compel-ling clinical evidence dictates a change in clinical practice.

New TAVR systems

Important features of new TAVR systemsDespite the success of “first generation” TAVR systems,several device design limitations have been identifiedwhich have contributed to suboptimal clinical outcomes(Table 1). The major limitation of early TAVR technologieswas the requirement of excessively large diameter TAVRdelivery sheaths. The overall outer diameter profile of theSAPIEN balloon-expandable FDA-approved TAVR systemis >8 mm for the 23 mm valve size and >9 mm for the26 mm valve. This creates a significant femoral artery–sheath size mismatch in many patients resulting in bothfrequent vascular complications and the frequent use of non-TF access sites. In the future, to support successful TF accessin the vast majority of TAVR-eligible patients (especiallywomen), an outer sheath diameter of less than 18 Frenchfor all valve sizes is advisable. Smaller TAVR system profilesare also important to negotiate tortuous vascular anatomy,facilitate native valve crossing, minimize trauma to the aortaand the native valve, allow the option of no pre-dilationbefore deployment, and improve alignment and positioningaccuracy during implantation. Another important limitationof early and current TAVR systems is the lack of consistentand precise positioning during deployment whichmay resultin valve embolization (or “pull through”), obstruction of the

Table 1 – Design limitationsof first generationTAVRsystems.

1. Large diameter delivery sheaths and catheters resulting infrequent vascular complications and non-transfemoral accessalternatives2. Imprecise valve positioning during deployment which may causepara-valvular regurgitation or interfere with aortic valvar complexstructures (aortic root, coronary arteries, conduction system, andmitral valve)3. Absence of valve retrieval and repositioning features4. Definitive approach to reduce or eliminate para-valvularregurgitation (either improved sub-annular fixation or externalspace-filling materials. or both)5. Unknown durability of the frame and valves (material compositionand thickness, valve geometry, and effects of crimping)

coronary arteries (too high placement), interference with theconduction system or the mitral valve (too low placement),and increased PVR (either too high or too low placement).Ideally, a slow and controlled valve deployment, allowing forpositioning adjustments before final implantation is pre-ferred. This may be limited by the need for transient rapid RVpacing during deployment of balloon-expandable valves. Theavailability of partial or complete valve retrieval is beingincorporated into many of the newer TAVR systems, whichprovides the operator a “second chance” if the initialattempts at precise positioning were suboptimal. The majordifference between SAVR and TAVR has been the greaterfrequency and severity of PVR in most currently availableTAVR systems. To address this issue, newer devices haveexplored improvements in sub-annular fixation and coaxialalignment, as well as the addition of external space-fillingmaterials to reduce or eliminate incomplete circumferentialapposition of the valve frame against the aortic annulus.Finally, durability of the frame and valve itself remains aconcern, especially if long-term implants in younger patientsare being contemplated.

NewTAVR systemswith significant clinical data (and CE-approval)Most of the new TAVR systems in early stages of clinicalpractice have creatively attempted to incorporate designchangeswhich reducemanyof the aforementioned limitations.Importantly, both Edwards SAPIEN and Medtronic CoreValveTAVR technologies have similarly evolved and current iterationsof these landmark devices should be compared with other newTAVR systems.

The version of the balloon-expandable TAVR system mostcommonly used around theworld is the SAPIEN XT (Fig 1A). Thisdevicewas completely redesignedwith important changes in theframe (reduced metal, different geometry, and cobalt alloymaterial), the valve itself (geometry allowing partially closedconfiguration and 29 mm size) and enhanced tissue processingto improve durability. The delivery system is much lower inprofile (18 and20 French),which represents a 33% cross-sectionalarea reduction, in part due to in situ docking of the stent valve onthe balloon. A large multicenter European registry (SOURCE XT)and a randomized multicenter US trial comparing SAPIEN withSAPIEN XT (PARTNER 2B) have confirmed improved ease-of-useand reduced complications with SAPIEN XT in high-risk ASpatients.7,50 The newest version of the balloon expandableplatform, SAPIEN 3 (Fig 1B), has just received CE-approval andhas been studied in an early US registry. This TAVR systemincorporates a further refinement in frame strut pattern,additional changes in valve geometry, even lower profile deliverysystems (all valves delivered via 14 and 16 French expandablesheaths), more precise positioning features prior to deployment,and an external fabric (polyethylene terephthalate) skirt whichprevents PVR.51 The new Edwards self-expanding TAVR system,Centera (Fig 1C), has just initiated clinical trials.52 The contouredshort frame height, treated bovine pericardial valve, and 14French motorized delivery catheter allowing the valve to befully retrieved and redeployed before final implantation aredistinguishing characteristics.

The CoreValve Evolut R (Fig 2) is a next generation self-expanding TAVR systemwith several enhancements, including

A B C D

Fig 1 – Edwards balloon-expandable and self-expandingTAVR systems:A – balloon expandable SAPIEN. B – balloon expandableSAPIEN XT. C – balloon expandable SAPIEN 3. D – self-expanding Centera.

641P R O G R E S S I N C A R D I O V A S C U L A R D I S E A S E S 5 6 ( 2 0 1 4 ) 6 3 5 – 6 4 5

a redesigned and shortened outflow section, more consistentradial force, an extended inflow skirt to elongate the landingzone (should reducePVR), a lower profile in-line sheath, and fullretrievability during deployment.53 Presently, clinical datausing the Evolut R TAVR system are being obtained in Europe.The Medtronic Engager TAVR system (Fig 3) is a TA device(29 French) with a self-expanding short nitinol frame andpolyester skirt, control arms which are placed outside thenative leaflets, a supra-annular bovine pericardial tissue valve,and commissural alignment features. A 125 patient registry inhigh-risk AS patients indicated good clinical outcomes withvery low (<5%) mild, moderate or severe PVR, but frequent newpacemakers (~30%) due to conduction system abnormalities.54

Another recent “long frame” self-expanding TAVR system isthe St. Jude Medical Portico device (Fig 3). Although similar insome respects to CoreValve, differentiating features include anintra-annular bovine pericardial valve with a porcine pericardialsealing cuff, larger stent cells to improve anatomic conformationand coronary access, and complete retrievability of the valve. Atotal of 83 patients were studied in 6 European centers using the

Fig 2 –ThenewMedtronic Evolut R self-expandingTAVRsystem.

TF system with favorable clinical outcomes, good valve hemo-dynamics and lower than expected new pacemakers (10.8%) andmoderate or severe PVR (5%).55 Access alternatives for the PorticoTAVR system include TF, subclavian, direct TAo, and a soon tobe tested TA version.

The Symetis Acurate TAVR (Fig 3) consists of stabilizingarches to maintain coaxial alignment, a supra-annular valvewithin a self-expanding upper crown and a contoured lowercrown encircled by a fabric skirt which can be partiallyresheathed. The 28 French TA Acurate TAVR was studied in40 patients with excellent results; lowmortality, low PVR andinfrequent need for new pacemakers.56 The TF version of theAcurate device was evaluated in 5 centers in Brazil andGermany in 80 patients with similar favorable outcomes.57

The Direct Flow medical TAVR (Fig 3) is the only non-metallic system with polymer-filled ventricular and aorticrings, surrounding a bovine pericardial intra-annular valvewhich is accurately located at the annulus via positioningwiresand is fully retrievable. The DISCOVER trial was conducted at10 European centers in 100 patients and revealed lowmortalityand strokes, rare moderate or severe PVR (2%), infrequent newpacemakers, and slightly higher transvalvular gradients com-pared with other TAVR systems.58

The JenaValve is a short self-expanding nitinol framehousing a valve derived from native porcine valve material,with a porcine pericardial skirt, and an upper crown forstabilization. Arms or “feelers” are positioned behind thenative valve leaflets allowing “clipping” of the valve againstthe lower stent. When ideally positioned, there is correctcommissural alignment, sparing of the coronary arteries,and an intra-annular position which avoids the conductionsystem. The Jupitermulticenter study in 126 patients, all with TAaccess, showedvery lowmortality and strokes, rare PVR, and rarenew pacemakers. This device has also been used for patientswith predominant aortic regurgitation in a small registry.59 A TFversion of the JenaValve has begun clinical evaluation.

The Boston Scientific SADRA Lotus TAVR system is awoven nitinol frame housing an intra-annular bovine peri-cardial valve which shortens and locks into position (Fig 3).The device is fully retrievable and has an exterior adaptivemembrane to reduce PVR. The Reprise II clinical trial enrolled120 patients at 14 centers in Australia and Europe using thetransfemoral SADRA Lotus TAVR system.60 Clinical out-comes at thirty days revealed all-cause mortality in 4.2%,strokes in 5.9%, moderate or severe PVR in 1%, and newpacemakers in 28.6%.

D

A B C

E F

Fig 3 – New TAVR systems approved for clinical use in Europe (and elsewhere). A – Medtronic Engager. B – St. Jude Portico.C – Symetis Acurate. D – Direct Flow Medical. E – Jena Valve. F – Boston Scientific SADRA Lotus.

642 P R O G R E S S I N C A R D I O V A S C U L A R D I S E A S E S 5 6 ( 2 0 1 4 ) 6 3 5 – 6 4 5

TAVR “accessory” devices

Cerebral protection devicesFrom the earliest TAVR experiences, significant concerns wereraised concerning the frequency of clinical neurologic eventsand the presence of new perfusion abnormalities on neuroim-aging studies in as many as 80% of TAVR patients.24–26

Therefore, efforts to develop catheter-based embolic protectiondevices to reduce strokes have been a high priority. Thesedevices fall into two categories; microporous filters whichcapture and retrieve embolic debris liberated into the cerebralcirculation and microporous deflectors which redirect embolicdebris away from the cerebral circulation. Early feasibilityclinical studies have demonstrated bulk material retrieval infilters placed in the cerebral vasculature from 75% of TAVRpatients.27 Similarly, there is evidence of reduced diffusionweighted MRI perfusion deficit volume after placement of bothfilters and deflectors after TAVR. Rigorous randomized trials arenecessary to determine if routine or selective use of these novelcerebral embolic protection devices will significantly improveneuro-imaging and clinical endpoints after TAVR.

New aortic valvuloplasty systemsThe emergence of TAVR as a viable treatment alternative hascreated increased therapy awareness for high-risk AS patientsin general. As a result, many new BAV systems have beenintroduced for the following clinical scenarios: (1) as stand-alone devices in those patients not candidates for TAVR; (2) asa possible “bridge” to TAVR in selected patients requiring

acute stabilization and/or further diagnostic evaluation inanticipation of a staged TAVR; (3) as pre-treatment beforeTAVR to facilitate optimal valve implantation. For example, anew balloon with an hourglass or “figure-eight” geometricshape that locks into the native valve may improve the safetyand effectiveness of BAV. Similarly, balloons constructedfrom high-pressure composite materials or encircled by anitinol frame may further increase effective orifice areascompared with traditional compliant balloons. A particularlycreative device delivers mechanical shock waves via ametallic catheter frame to fracture calcium within the nativediseased valve and improve leaflet compliance. Clearly, thesenovel technologies require further clinical validation beforeclaiming incremental benefit for specific indications.

Miscellaneous other devicesOther potentially worthwhile devices which can improve thesafety or efficacy of TAVR fall into the general categories ofadjunctive imaging systems, large caliber access and/or closuretechnologies (for TF andTAapplications), dedicated sheaths, andpre-shaped guidewires. A variety of innovative imaging systemsincluding echocardiography and multi-slice CT integrated or co-registeredwith fluoroscopy are in various stages of developmentwhich should improve diagnostic accuracy and precision ofTAVR device placement in the future. In similar stages of earlydevelopment are several large caliber access/closure technolo-gies which may improve the consistency of percutaneous TFprocedures and markedly reduce the complexity and invasive-ness of TA procedures.

643P R O G R E S S I N C A R D I O V A S C U L A R D I S E A S E S 5 6 ( 2 0 1 4 ) 6 3 5 – 6 4 5

Summary

TAVR is a worthwhile addition to the armamentarium oftherapies for patients with AS. Despite the impressive clinicalgrowth of TAVR, there are many challenges as well as futureopportunities for improving clinical outcomes. The heart valveteam serves as the central vehicle for determining appropriatecase selection. Important considerations which impact clinicaltherapy decisions include frailty assessments and definingclinical “futility”. Many procedural issues are controversial;choice of vascular access site, valve sizing, adjunctive imaging,and post-dilatation strategies. Improving complications associ-ated with TAVR (strokes, vascular and bleeding events, PVR, andconduction abnormalities) will require procedural and/or tech-nology enhancements. TAVR site training mandates a rigorouscommitment to established society and sponsor guidelines. Inthe future, TAVR clinical indications should extend tobioprosthetic valve failure, intermediate risk patients, and otherclinical scenarios, based uponwell conducted clinical trials. NewTAVR systems have been developed which should furtheroptimize clinical outcomes, by reducing device profile, providingretrievable features, and preventing PVR. Other accessorydevices, such as cerebral protection to prevent strokes, are alsobeing developed and evaluated in clinical studies.

Statement of Conflict of Interest

All authors declare that there are no conflicts of interest.

R E F E R E N C E S

1. Leon MB, Smith CR, Mack M, Miller DC, Moses JW, SvenssonLG, et al. Transcatheter aortic-valve implantation for aorticstenosis in patients who cannot undergo surgery. N Engl J Med.2010;363(17):1597-1607.

2. Mack MJ, Holmes DR, Webb J, Cribier A, Kodali SK, WilliamsMR, et al. Patient selection for transcatheter aortic valvereplacement. J Am Coll Cardiol. 2013;62(Suppl 17):S1-S10.

3. Afilalo J, Eisenberg MJ, Morin JF, Bergman H, Monette J,Noiseux N, et al. Gait speed as an incremental predictor ofmortality and major morbidity in elderly patients undergoingcardiac surgery. J Am Coll Cardiol. 2010;56(20):1668-1676.

4. Fried LP, Tangen CM, Walston J, Newman AB, Hirsch C,Gottdiener J, et al. Frailty in older adults: evidence for aphenotype. J Gerontol A Biol Sci Med Sci. 2001;56(3):M146-M156.

5. Green P, Woglom AE, Genereux P, Daneault B, Paradis JM,Schnell S, et al. The impact of frailty status on survival aftertranscatheter aortic valve replacement in older adults withsevere aortic stenosis: a single-center experience. JACCCardiovasc Interv. 2012;5(9):974-981.

6. Popma JJ, CoreValve US. Pivotal Trial Extreme Risk IliofemoralStudy Results. San Francisco, CA: Transcatheter CardiovascularTherapeutics. 2013.

7. Leon MB. A Randomized Evaluation of the SAPIEN XTTranscatheterValve System in PatientswithAortic StenosisWhoAre Not Candidates for Surgery: PARTNER II, Inoperable Cohort.San Francisco, CA: American College of Cardiology. 2013.

8. Gaasch WH, D'Agostino RS. Transcatheter aortic valveimplantation: The transfemoral versus the transapicalapproach. Ann Cardiothorac Surg. 2012;1(12):200-205.

9. van der Boon RM, Marcheix B, Tchetche D, Chieffo A, VanMieghem NM, Dumonteil N, et al. Transapical versustransfemoral aortic valve implantation: a multicentercollaborative study. Ann Thorac Surg. 2014;97(1):22-28.

10. Al Kindi AH, Salhab KF, Roselli EE, Kapadia S, Tuzcu EM,Svensson LG. Alternative access options for transcatheteraortic valve replacement in patients with no conventionalaccess and chest pathology. J Thorac Cardiovasc Surg. 2014;147(2):644-651.

11. Zierer A, Wimmer-Greinecker G, Martens S, Moritz A, Doss M.The transapical approach for aortic valve implantation. JThorac Cardiovasc Surg. 2008;136(4):948-953.

12. Lardizabal JA, O'Neill BP, Desai HV, Macon CJ, Rodriguez AP,Martinez CA, et al. The transaortic approach for transcatheteraortic valve replacement: initial clinical experience in theUnited States. J Am Coll Cardiol. 2013;61(23):2341-2345.

13. Cohen MG, Singh V, Martinez CA, O'Neill BP, Alfonso CE,Martinezclark PO, et al. Transseptal antegrade transcatheteraortic valve replacement for patients with no other accessapproach – A contemporary experience. Catheter CardiovascInterv. 2013;82(6):987-993.

14. Modine T, Sudre A, Amr G, Delhaye C, Koussa M. Implantationof a Sapien XT Aortic Bioprosthesis through the Left CarotidArtery. J Card Surg. 2014. (Epub ahead of print).

15. Bloomfield GS, Gillam LD, Hahn RT, Kapadia S, Leipsic J,Lerakis S, et al. A practical guide to multimodality imagingof transcatheter aortic valve replacement. JACC CardiovascImaging. 2012;5(4):441-455.

16. Holmes Jr DR, Mack MJ, Kaul S, Agnihotri A, Alexander KP,Bailey SR, et al. 2012 ACCF/AATS/SCAI/STS expert consensusdocument on transcatheter aortic valve replacement. J AmColl Cardiol. 2012;59(13):1200-1254.

17. Hahn RT. Use of imaging for procedural guidance duringtranscatheter aortic valve replacement. Curr Opin Cardiol.2013;28(5):512-517.

18. Grube E, Naber C, Abizaid A, Sousa E, Mendiz O, Lemos P, et al.Feasibility of transcatheter aortic valve implantation withoutballoon pre-dilation: a pilot study. JACC Cardiovasc Interv.2011;4(7):751-757.

19. Garcia E, Martin P, Hernandez R, Rodriguez V, Fernandez A,Gama V, et al. Feasibility and safety of transfemoralimplantation of Edwards SAPIEN XT prosthesis withoutballoon valvuloplasty in severe stenosis of native aortic valve.Catheter Cardiovasc Interv. 2013. (Epub ahead of print).

20. Kodali SK, Williams MR, Smith CR, Svensson LG, Webb JG,Makkar RR, et al. Two-year outcomes after transcatheter orsurgical aortic-valve replacement. N Engl J Med.2012;366(18):1686-1695.

21. Ussia GP, Barbanti M, Imme S, Scarabelli M, Mule M,Cammalleri V, et al. Management of implant failure duringtranscatheter aortic valve implantation.Catheter Cardiovasc Interv. 2010;76(3):440-449.

22. Nombela-Franco L, Rodes-Cabau J, DeLarochelliere R, Larose E,Doyle D, Villeneuve J, et al. Predictive factors, efficacy, and safetyof balloon post-dilation after transcatheter aortic valveimplantation with a balloon-expandable valve. JACC CardiovascInterv. 2012;5(5):499-512.

23. Barbanti M, Yang TH, Rodes Cabau J, Tamburino C, Wood DA,Jilaihawi H, et al. Anatomical and procedural featuresassociated with aortic root rupture during balloon-expandabletranscatheter aortic valve replacement. Circulation.2013;128(3):244-253.

24. Fairbairn TA, Mather AN, Bijsterveld P, Worthy G, Currie S,Goddard AJ, et al. Diffusion-weighted MRI determined cerebral

644 P R O G R E S S I N C A R D I O V A S C U L A R D I S E A S E S 5 6 ( 2 0 1 4 ) 6 3 5 – 6 4 5

embolic infarction following transcatheter aortic valveimplantation: assessment of predictive risk factors and therelationship to subsequent health status. Heart.2012;98(1):18-23.

25. Kahlert P, Knipp SC, Schlamann M, Thielmann M, Al-Rashid F,Weber M, et al. Silent and apparent cerebral ischemia afterpercutaneous transfemoral aortic valve implantation: adiffusion-weighted magnetic resonance imaging study.Circulation. 2010;121(7):870-878.

26. Rodes-Cabau J, Dumont E, Boone RH, Larose E, Bagur R,Gurvitch R, et al. Cerebral embolism following transcatheteraortic valve implantation: comparison of transfemoral andtransapical approaches. J Am Coll Cardiol. 2011;57(1):18-28.

27. VanMieghemNM, SchipperME, Ladich E, Faqiri E, van der BoonR, Randjgari A, et al. Histopathology of embolic debris capturedduring transcatheter aortic valve replacement. Circulation.2013;127(22):2194-2201.

28. Eggebrecht H, Schmermund A, Voigtlander T, Kahlert P, Erbel R,Mehta RH. Risk of stroke after transcatheter aortic valveimplantation (TAVI): a meta-analysis of 10,037 published patients.EuroIntervention. 2012;8(1):129-138.

29. Moat NE, Ludman P, de Belder MA, Bridgewater B,Cunningham AD, Young CP, et al. Long-term outcomes aftertranscatheter aortic valve implantation in high-risk patientswith severe aortic stenosis: the U.K. TAVI (United KingdomTranscatheter Aortic Valve Implantation) Registry. J Am CollCardiol. 2011;58(20):2130-2138.

30. Sinning JM, Hammerstingl C, Vasa-Nicotera M, Adenauer V, LemaCachiguango SJ, ScheerAC, et al. Aortic regurgitation indexdefinesseverity of peri-prosthetic regurgitation and predicts outcome inpatients after transcatheter aortic valve implantation. J Am CollCardiol. 2012;59(13):1134-1141.

31. Tamburino C, Capodanno D, Ramondo A, Petronio AS, Ettori F,Santoro G, et al. Incidence and predictors of early and latemortality after transcatheter aortic valve implantation in 663patients with severe aortic stenosis. Circulation. 2011;123(3):299-308.

32. Genereux P, Head SJ, Hahn R, Daneault B, Kodali S, WilliamsMR, et al. Paravalvular leak after transcatheter aortic valvereplacement: the new Achilles' heel? A comprehensivereview of the literature. J Am Coll Cardiol.2013;61(11):1125-1136.

33. Genereux P, Webb JG, Svensson LG, Kodali SK, Satler LF,Fearon WF, et al. Vascular complications after transcatheteraortic valve replacement: insights from the PARTNER(Placement of AoRTic TraNscathetER Valve) trial.J Am Coll Cardiol. 2012;60(12):1043-1052.

34. Genereux P, Cohen DJ, Williams MR, Mack M, Kodali SK,Svensson L, et al. BleedingComplications after Surgical Aortic Valve Replacement (SAVR)Comparedwith Transcatheter Aortic Valve Replacement (TAVR):Insights from the PARTNER I Trial. J Am Coll Cardiol. 2013.

35. Hayashida K, Lefevre T, Chevalier B, Hovasse T, Romano M,Garot P, et al. Transfemoral aortic valve implantation newcriteria to predict vascular complications. JACC CardiovascInterv. 2011;4(8):851-858.

36. Genereux P, Kodali S, Leon MB, Smith CR, Ben-Gal Y, KirtaneAJ, et al. Clinical outcomes using a new crossover balloonocclusion technique for percutaneous closure aftertransfemoral aortic valve implantation. JACC Cardiovasc Interv.2011;4(8):861-867.

37. Erkapic D, De Rosa S, Kelava A, Lehmann R, Fichtlscherer S,Hohnloser SH. Risk for permanent pacemaker after transcatheteraortic valve implantation: a comprehensive analysis of theliterature. J Cardiovasc Electrophysiol. 2012;23(4):391-397.

38. Nazif TM, Williams MR, Hahn RT, Kapadia S, Babaliaros V,Rodes-Cabau J, et al. Clinical implications of new-onset left

bundle branch block after transcatheter aortic valvereplacement: analysis of the PARTNER experience. Eur Heart J.2013. [Epub ahead of print].

39. HouthuizenP,VanGarsse LA, PoelsTT, de JaegereP, vanderBoonRM, Swinkels BM, et al. Left bundle-branch block induced bytranscatheter aortic valve implantationincreases risk of death. Circulation. 2012;126(6):720-728.

40. Tommaso CL, Bolman III RM, Feldman T, Bavaria J, Acker MA,Aldea G, et al. Multisociety (AATS, ACCF, SCAI, and STS)expert consensus statement: operator and institutionalrequirements for transcatheter valve repair and replacement,part 1: transcatheter aortic valve replacement. J Am CollCardiol. 2012;59(22):2028-2042.

41. Stolker JM, Patel AY, Lim MJ, Hauptman PJ. Estimating theAdoption of Transcatheter Aortic Valve Replacement By USInterventional Cardiologists and Clinical Trialists. Clin Cardiol.2013;36(11):691-697.

42. Webb JG, Wood DA, Ye J, Gurvitch R, Masson JB, Rodes-CabauJ, et al. Transcatheter valve-in-valve implantation for failedbioprosthetic heart valves. Circulation. 2010;121(16):1848-1857.

43. Wenaweser P, Buellesfeld L, Gerckens U, Grube E.Percutaneous aortic valve replacement for severe aorticregurgitation in degenerated bioprosthesis: the first valve invalve procedure using the Corevalve Revalving system.Catheter Cardiovasc Interv. 2007;70(5):760-764.

44. Bapat VN, Attia R, Thomas M. Effect of Valve Design on the StentInternal Diameter of a Bioprosthetic Valve: A Concept of TrueInternal Diameter and Its Implications for the Valve-in-ValveProcedure. JACC Cardiovasc Interv. 2014;7(2):115-127.

45. Dvir D, Webb J, Brecker S, Bleiziffer S, Hildick-Smith D,Colombo A, et al. Transcatheter aortic valve replacement fordegenerative bioprosthetic surgical valves: results from theglobal valve-in-valve registry. Circulation.2012;126(19):2335-2344.

46. Latib A, Maisano F, Bertoldi L, Giacomini A, Shannon J, Cioni M,et al. Transcatheter vs surgical aortic valve replacement inintermediate-surgical-risk patients with aortic stenosis: apropensity score-matched case-control study. AmHeart J.2012;164(6):910-917.

47. Herrmann HC, Pibarot P, Hueter I, Gertz ZM, Stewart WJ,Kapadia S, et al. Predictors of mortality and outcomes oftherapy in low-flow severe aortic stenosis: a Placement ofAortic Transcatheter Valves (PARTNER) trial analysis.Circulation. 2013;127(3):2316-2326.

48. Chandola R, Cusimano R, Osten M, Horlick E. Postcardiactransplant transcatheter core valve implantation for aorticinsufficiency secondary to Impella device placement. AnnThorac Surg. 2012;93(6):e155-e157.

49. Dumonteil N, Marcheix B, Lairez O, Laborde JC. Transcatheteraortic valve implantation for severe, non-calcified aorticregurgitation and narrow aortic root: description from a casereport of a new approach to potentially avoid coronary arteryobstruction. Catheter Cardiovasc Interv. 2013;82(2):E124-E127.

50. Windecker S. One-year outcomes from the SOURCE XTpost-approval study. Paris, France: EuroPCR. 2013.

51. Binder RK, Rodes-Cabau J, Wood DA, Mok M, Leipsic J, DeLarochelliere R, et al. Transcatheter aortic valve replacementwith the SAPIEN 3: a new balloon-expandable transcatheterheart valve. JACC Cardiovasc Interv. 2013;6(3):293-300.

52. Ribeiro HB, Urena M, Kuck KH, Webb JG, Rodes-Cabau J. EdwardsCENTERA valve. EuroIntervention. 2012;8(Suppl Q):Q79-Q82.

53. Sinning JM,Werner N, Nickenig G, Grube E. Medtronic CoreValveEvolut valve. EuroIntervention. 2012;8(Suppl Q):Q94-Q96.

54. Holzhey D, Linke A, Treede H, Baldus S, Bleiziffer S, Wagner A,et al. Intermediate follow-up results from the multicenterengager European pivotal trial. Ann Thorac Surg. 2013;96(6):2095-2100.

645P R O G R E S S I N C A R D I O V A S C U L A R D I S E A S E S 5 6 ( 2 0 1 4 ) 6 3 5 – 6 4 5

55. Urena M, Doyle D, Rodes-Cabau J, Dumont E. Initialexperience of transcatheter aortic valve replacement with theSt Jude Medical Portico valve inserted through the transapicalapproach. J Thorac Cardiovasc Surg. 2013;146(4):e24-e27.

56. Kempfert J, Treede H, Rastan AJ, SchonburgM, ThielmannM, SorgS, et al. Transapical aortic valve implantation using a newself-expandable bioprosthesis (ACURATE TA): 6-month outcomes.Eur J Cardiothorac Surg. 2013;43(1):52-56. [discussion 57].

57. Mollmann H, Diemert P, Grube E, Baldus S, Kempfert J, AbizaidA. Symetis ACURATE TF aortic bioprosthesis. EuroIntervention.2013;9:S107-S110. [Suppl].

58. Schofer J, Colombo A, Klugmann S, Fajadet J, Demarco F,Tchetche D, et al. Prospective Multicenter Evaluation of theDirect Flow Medical(R) Transcatheter Aortic Valve. J Am CollCardiol. 2013;63(8):763-768.

59. Seiffert M, Diemert P, Koschyk D, Schirmer J, Conradi L,Schnabel R, et al. Transapical implantation of asecond-generation transcatheter heart valve in patientswith noncalcified aortic regurgitation. JACC CardiovascInterv. 2013;6(6):590-597.

60. Tofield A. The Lotus valve for transcatheter aortic valveimplantation. Eur Heart J. 2013;34(30):2335.