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STRUCTURAL

Transcatheter Aortic Valve Replacementfor the Treatment of Pure NativeAortic Valve RegurgitationA Systematic Review

Anna Franzone, MD,a Raffaele Piccolo, MD,a George C.M. Siontis, MD,a Jonas Lanz, MD,a Stefan Stortecky, MD,a

Fabien Praz, MD,a Eva Roost, MD,b René Vollenbroich, MD, MPP,a Stephan Windecker, MD,a Thomas Pilgrim, MDa

ABSTRACT

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OBJECTIVES This study sought to summarize available evidence on transcatheter aortic valve replacement (TAVR) for

the treatment of native pure aortic regurgitation (AR).

BACKGROUND Surgical aortic valve replacement (SAVR) is the gold standard for the treatment of AR. However, case

series of high-risk patients undergoing TAVR for native pure AR were reported.

METHODS We systematically searched Medline, Embase, and Scopus for reports of at least 5 patients with native pure

AR undergoing TAVR. Patients’ and procedural characteristics were summarized. The primary outcome of interest was

all-cause mortality. Pooled estimates were calculated using a random-effects meta-analysis. The study protocol was

registered in PROSPERO (CRD42016038422).

RESULTS Thirteen reports including 237 patients were included in the analysis. Self-expandable prostheses were used

in 79% of patients, whereas 21% of the patients were treated with a balloon-expandable valve. Device success ranged

between 74% and 100%. Seventeen patients (7%) required the implantation of a second valve. Conversion to SAVR

was reported in 6 (2.5%) cases. The rate of all-cause mortality at 30 days amounted to 7% (95% confidence interval [CI]:

3% to 13%; I2 ¼ 37%). Cerebrovascular events were rare (0%, 95% CI: 0% to 1%; I2 ¼ 0); major bleeding and vascular

complications occurred in 2% (95% CI: 0% to 7%; I2 ¼ 41%), and 3% (95% CI: 1% to 7%; I2 ¼ 0%), respectively.

Permanent pacemaker implantation was required in 11% of patients (95% CI: 5% to 19%; I2 ¼ 50%). The rate of

moderate or severe post-procedural AR amounted to 9% (95% CI: 0% to 28%; I2 ¼ 90%).

CONCLUSIONS Among selected patients with native pure AR deemed at high risk for SAVR, TAVR is technically

feasible and associated with an acceptable risk of early mortality. (J Am Coll Cardiol Intv 2016;9:2308–17)

© 2016 by the American College of Cardiology Foundation.

m the aDepartment of Cardiology, Swiss Cardiovascular Center, University Hospital, Bern, Switzerland; and the bDepartment of

rdiovascular Surgery, University Hospital, Bern, Switzerland. Dr. Piccolo has received research grant support from the Veronesi

undation. Dr. Windecker has received research grants to the institution from Abbott, Biotronik, Boston Scientific, Edwards

esciences, Medtronic, The Medicines Company, and St. Jude Medical; and speaker fees from AstraZeneca, Eli Lilly, Abbott

scular, Biotronik, Boston Scientific, Bayer, and Biosensors. Dr. Pilgrim has received speaker fees from Biotronik and Medtronic;

d travel honoraria from Biotronik and Edwards Lifesciences. All other authors have reported that they have no relationships

evant to the contents of this paper to disclose.

nuscript received May 26, 2016; revised manuscript received August 14, 2016, accepted August 14, 2016.

AB BR E V I A T I O N S

AND ACRONYM S

AR = aortic regurgitation

SAVR = surgical aortic valve

replacement

TAVR = transcatheter aortic

valve replacement

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S urgical aortic valve replacement (SAVR) is thetreatment of choice for patients with aorticregurgitation (AR) in combination with clinical

symptoms, left ventricular dilation, or decreasingleft ventricular function (1). Transcatheter aorticvalve replacement (TAVR) emerged as a treatmentalternative for intermediate and high-risk patientswith symptomatic severe aortic stenosis, owing toits favorable safety and efficacy profile (1–3). Thebroad implementation of TAVR in patients with awide range of anatomic diversity (4,5) is paralleledby the exploration of the feasibility of transcathetervalve replacement in off-label indications such asbicuspid valvular anatomy, degenerated surgical bio-prostheses, and selected cases of pulmonary, mitral,or tricuspid valve disease (6).

SEE PAGE 2318

Among the off-label uses of TAVR, the treatment ofnative pure AR imposes some unique challenges interms of technical feasibility. In contrast to aorticstenosis, the absence of valvular calcification in themajority of patients with native pure AR complicatesanchoring of the transcatheter valve prosthesiswithin the annular plane (7). In addition, hyper-contractility of the left ventricle in view of theexcessive stroke volume and the dynamic regurgitantjet limits device control during positioning andrelease. Moreover, the annulus width is typicallyincreased and may exceed the range of commerciallyavailable transcatheter valve prostheses.

Reports of inoperable patients with native pure ARundergoing TAVR have recently accumulated. Wetherefore undertook a systematic literature reviewand meta-analysis of studies examining the clinicaloutcomes of patients with native pure AR undergoingTAVR.

METHODS

SEARCH STRATEGY. A search for studies concerninghuman subjects was conducted through Medline,Embase, and Scopus on February 15, 2016. Medicalsubject headings and text words used for thesearch strategy are reported in Online Table 1.The study protocol was registered in PROSPERO(CRD42016038422). Citations were screened on titleand abstract level by 2 independent reviewers (A.F.,R.P.); potentially eligible reports were retrieved andscrutinized for eligibility in full text. The reference listsof the eligible reports were reviewed for any eligiblereports not captured initially.

STUDY SELECTION. We deemed reports eligible ifthey fulfilled the following pre-specified criteria:

1) patients with pure degenerative AR (norelevant aortic stenosis); 2) reports of a mini-mum of 5 patients; 3) studies including pa-tients with pure degenerative AR within alarger cohort of patients undergoing TAVRbecause of severe aortic stenosis; 4) abstractsor conference presentations reporting clinicalfeatures, procedural characteristics, and 30-

day mortality rates of patients with pure native ARundergoing TAVR; and 5) reports written in Englishlanguage. Case reports were excluded as well as seriesincluding patients with regurgitation of bioprosthesesor AR secondary to other conditions such as endo-carditis or aortic dissection. If duplicate studies wereidentified, only the most exhaustive and recent re-ports were retained.

DATA EXTRACTION. Data were gathered through apre-defined extraction sheet including first author,year and journal of publication, number of subjectsincluded, and type of device used. The followingitems were extracted from each study whereveravailable: patients’ characteristics (age, sex, NewYork Heart Association functional class, left ventric-ular ejection fraction, logistic European System forCardiac Operative Risk Evaluation score, the Societyof Thoracic Surgeons score, comorbidities), vascularaccess used, duration of follow-up, and the safety andefficacy outcomes according to the respective defini-tions. Accuracy and validity were assessed by the 2aforementioned reviewers and any disagreements injudgment resolved through consensus.

STUDY ENDPOINTS. In our meta-analysis, we consid-ered all-cause mortality at 30 days as the primaryoutcome of interest. Secondary outcomes of interestwere myocardial infarction, cerebrovascular events,major bleeding, major vascular complications,acute kidney injury (stage 3), moderate to severe re-sidual AR, and permanent pacemaker implantation at30 days.

DATA SYNTHESIS AND ANALYSIS. Categorical variablesare reported as numbers and percentage, and contin-uous variables are reported as mean � SD. Random-effects meta-analysis was conducted using theMetaprop command, which allows computation of 95%confidence intervals (CIs) using the score statistic andthe exact binomial method and incorporates theFreeman-Tukey double arcsine transformation ofproportions (8). Heterogeneity among studies wasassessed with the I2 statistic. The effect of study-levelcovariates (sample size, use of dedicated prosthesis,and annulus size) on the rate of all-cause death, post-procedural aortic moderate or severe AR, and theneed for permanent pacemaker implantation was

FIGURE 1 Flow Diagram of Manuscript Selection According to PRISMA Statement

PRISMA ¼ Preferred Reporting Items for Systematic Reviews and Meta-Analyses. Adapted from Moher et al. (9).

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explored with a meta-regression analysis by usingthe metareg command. All analyses were performedwith Stata statistical software version 13 (StataCorp LP,College Station, Texas).

RESULTS

INCLUDED STUDIES. The electronic searches yielded5,086 references; after exclusion of duplicates, 3,996potentially relevant reports were retrieved for furtherevaluation. After assessment at title and abstract level,65 studies were selected for full-text evaluation.Finally, 13 reports were deemed eligible and includedin our systematic review (9–22) (Figure 1). A summaryof the main characteristics of included studies is pro-vided in Online Table 2. All studies reported data on30-day clinical outcomes and 10 studies reported dataof longer-term follow-up.

PATIENT AND PROCEDURAL CHARACTERISTICS.

A total of 237 patients with native pure AR underwentTAVR across 13 selected reports. Main clinical andprocedural characteristics of patients are summarizedin Table 1. Mean age ranged from 68 to 84 years; thelogistic European System for Cardiac Operative RiskEvaluation score ranged from 15.3 � 8% to 34.0 �8.4%; Society of Thoracic Surgeons score was avail-able for 6 studies, with a mean of 5.4% to 13.1% acrossthe studies. Overall, self-expandable prostheses wereused in 79% of patients whereas 21% of the patientswere treated with a balloon-expandable valve.Fifty-one patients were treated with the only bio-prosthesis with a Conformité Européenne markfor the treatment of aortic regurgitation (JenaValve,JenaValve Technology, Munich, Germany) (12,18,21)Vascular access was specified for 199 patients (83%),and included transapical access in 109 patients (55%),

TABLE 1 Main Clinical and Procedural Characteristics of Patients in Included Studies

First Author, Year (Ref. #) n Male Age (yrs) Logistic EuroSCORE (%) STS Score (%) Access DeviceValve

Post-DilationSecond Valve

RequiredConversion to

SAVR Device Success

Frerker et al., 2015 (10) 22 12 (55) 80.0 � 5.6 25.0 � 18.0 — — CoreValve RevalvingSystem95.5%Sapien/Sapien XT 4.5%

— — — 18 (77)

Guo et al., 2015 (22) 33 26 (79) 74.2 � 5.2 24.4 � 5.1 — Apical J-Valve — 0 1 32 (97)

Koschyk et al., 2014 (21) 10 7 (70) 68.0 26.1 — Apical JenaValve — 1 (10) 0 —

Munoz-Garcia et al., 2015 (20) 10 5 (50) 79.2 � 4.9 15.3 � 8.0 — Femoral CoreValve RevalvingSystem

4 (40) 1 (10) — —

Rossi et al., 2014 (19) 16 9 (56) 84 � 2.6 33.0 — — CoreValve RevalvingSystem

— 1 (6) 2 (13) —

Roy et al., 2013 (11) 43 20 (47) 75.3 � 8.8 26.9 � 17.9 10.2 � 5.3 Femoral (81.4)Subclavian (9.3)Direct aortic (7.0)Carotid (2.3)

CoreValve RevalvingSystem

4 (9) 8 (19) 1 (2) 32 (74)

Schlingloff et al., 2014 (18) 10 6 (60) 79.1 � 9.5 28.3 � 16.8 6.74 � 5.5 Apical JenaValve — 0 0 —

Schofer et al., 2015 (13) 11 4 (36) 74.7 � 12.9 19.8 � 6.9 6.5 � 2.4 Femoral Direct Flow Valve — 0 1 (9) 11 (100)

Seiffert et al., 2014 (12) 31 20 (65) 73.8 � 9.1 23.6 � 14.5 5.4 � 3.6 Apical JenaValve 2 (6) 1 (3) 0 30 (97)

Testa et al., 2014 (14) 26 16 (63) 73.0 � 10.0 24.0 � 8.0 13.1 � 2.0 Femoral (81)Subclavian (15)Aortic (4)

CoreValve RevalvingSystem

3 (10) 5 (19) 0 20 (77)

Wei et al., 2015 (15) 6 4 (67) 75.5 � 8.1 29.3 � 7.7 — Apical J-Valve 0 0 0 —

Wendt et al., 2014 (16) 8 5 (63) 72.5 � 8.4 34.0 � 8.4 7.9 � 3.3 Apical ACURATE TA 2 (25) 0 0 8 (100)

Zhu et al., 2015 (17) 11 — — — — Apical J-Valve 0 0 1 (9) —

Values are n (%) or mean � SD.

EuroSCORE ¼ European System for Cardiac Operative Risk Evaluation; SAVR ¼ surgical aortic valve replacement; STS ¼ Society of Thoracic Surgeons.

JACC:CARDIO

VASCULAR

INTERVENTIO

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FIGURE 2 Forest Plot Showing the Individual and Pooled Event Rates for the Primary Endpoint, 30-Day Mortality After TAVR

For each individual study, the forest plot shows the event rate and respective 95% confidence interval (CI) (horizontal lines). The size of the

black squares is proportional to the weight assigned to the study in the pooled estimate using a random-effects model. The diamond below the

studies represents the effect estimate derived from the meta-analysis, with the center and the vertical line (red) indicating the pooled event

rate and the left and the right ends showing the 95% CI. The central vertical line (blue) represents the event rate of 0%. I2 statistics describe the

percentage of the variability in effect estimates that is due to heterogeneity rather than chance. A value of 0% indicates no observed hetero-

geneity, and larger values show increasing heterogeneity. Phet ¼ p value for heterogeneity; TAVR ¼ transcatheter aortic valve replacement.

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transfemoral access in 77 patients (39%), and trans-carotid, trans-subclavian, or direct aortic access in 13patients (7%). Device success was reported in 7studies and ranged from 74% to 100%. Seventeenpatients (7%) required the implantation of a secondvalve. Conversion to SAVR was reported in 6 patients(2.5%). Other clinical features and baseline echocar-diographic parameters are listed in Online Tables 3and 4, respectively.OUTCOMESAT 30DAYS. Rates of the primary endpoint,all-cause mortality at 30 days, ranged from 0% to 30%with a summary estimate rate of 7% (95%CI: 3% to 13%;I2¼ 37%) (Figure 2). As displayed in Figure 3, there wereno events of myocardial infarction at 30 days; stroke ortransient ischemic attack ranged from 0% to 5% witha summary estimate of 0% (95% CI: 0% to 1%); majorbleeding and vascular complications occurred in 2%

(95% CI: 0% to 7%; I2 ¼ 41%) and 3% (95% CI: 1% to 7%;I2 ¼ 0) of patients, respectively. Reported rates forpermanent pacemaker implantation after TAVRranged from 0% to 44% with a summary estimate rateof 11% (95% CI: 5% to 19%; I2 ¼ 50%). Moderate or se-vere post-procedural AR was reported in up to 88%(range 0% to 88%) of patients with a summary estimaterate of 9% (95% CI: 0% to 28%; I2 ¼ 90%).

In the subgroup of patients treated with the Jena-Valve (n ¼ 51) 30-day mortality amounted to 11%(95% CI: 0% to 30%; I2 ¼ 52%), major bleeding to 4%(95% CI: 0% to 13%; I2 ¼ 0%), major vascular com-plications to 4% (95% CI: 0% to 13%; I2 ¼ 0%), andpermanent pacemaker implantation to 6% (95% CI:0% to 18%; I2 ¼ 21%). Residual moderate to severeresidual AR was exceedingly rare (0%, 95% CI: 0% to3%; I2 ¼ 0%). As shown in Online Table 5, sample size,

FIGURE 3 Meta-Analysis of Secondary Endpoints

Bar graphs show the pooled event rate and relative 95% confidence interval (CI) (horizontal lines) for the secondary study endpoints.

Explanation of the I2 statistic is reported in the legend of Figure 2. AR ¼ aortic regurgitation; PPM ¼ permanent pacemaker;

TIA ¼ transient ischemic attack.

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the use of a dedicated prosthesis, and annulus sizedid not significantly modify the rate of all-causedeath, post-procedural AR or the need for perma-nent pacemaker implantation.

DISCUSSION

To the best of our knowledge, the current analysisincluding 237 patients from 13 studies is the firstsystematic review on the use of TAVR in patients withnative pure AR. Almost 4 of 5 patients were treatedwith self-expandable rather than balloon-expandabledevices, and less than one-quarter of patients weretreated with devices approved for the treatment of AR.Despite considerable heterogeneity across studies interms of devices and techniques, our results show thatTAVR is technically feasible in selected high-risk pa-tients with native pure AR with acceptable earlymorbidity and mortality. Overall, the occurrence ofcomplications such as the need for a second valveimplantation and the rate of residual moderate or se-vere ARwere relatively low. Specific anatomic featureschallenge the proper positioning and stability of cur-rent transcatheter devices in patients with pure nativeAR in comparison with patients with aortic valve ste-nosis, as depicted in panel A of the Central Illustration.Although the use of first-generation devices has been

reported in a considerable number of patients withpure native AR, new-generation valve designs usingleaflet “pinning” or aortic “docking” have the poten-tial to demonstrate greater efficacy for this indication(Central Illustration, panel B).

RATIONALE FOR TAVR IN PATIENTS WITH NATIVE

PURE AR. SAVR is the therapeutic standard for pa-tients with AR (1,23). Low rates of perioperative mor-tality and a substantial reduction of clinical symptomshave been reported after valvular replacement, evenfor advanced stages of disease with compromised leftventricular ejection fraction (7,24). Nevertheless, theEuro Heart Survey on Valvular Heart Disease showedthat only 1 in 5 patients with severe AR and a left ven-tricular ejection fraction between 30% and 50% wasreferred to surgery. In patients with a left ventricularejection fraction below 30%, the proportion of patientsundergoing surgery was as low as 3%. Advanced ageand multiple comorbidities were frequent reasonsfor conservative rather than surgical management,resulting in an annualmortality rate of 10% to 20% (25).The sobering findings of the Euro Heart Survey open aniche for TAVR for the treatment of pure AR. Encour-aging clinical outcomes in patients with mixed aorticvalve disease, featuring up to 40% of patients referredto TAVR lend further support to expansion of TAVR toinoperable patients with pure AR (26–29).

CENTRAL ILLUSTRATION Schematic Representation of Anatomic Features of Aortic ValveStenosis and Regurgitation

Franzone, A. et al. J Am Coll Cardiol Intv. 2016;9(22):2308–17.

(A) Factors challenging the performance of current transcatheter devices are listed. (B) Main characteristics of devices employed in the

treatment of patients with pure native aortic regurgitation. *Conformité Européenne marked for implantation in patients with pure native

aortic regurgitation. **Their use has been reported in anecdotal single case reports, not included in the present analysis. TAVR ¼ transcatheter

aortic valve replacement.

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CHALLENGES FOR TAVR IN PATIENTS WITH NATIVE

PURE AR. Transcatheter treatment of AR is chal-lenged by several clinical and anatomic factors.Chronic aortic regurgitation is characterized by aprolonged silent clinical course followed by thedevelopment of congestive heart failure owing tovolume overload, increased wall stress, and leftventricular dysfunction. However, patients with ARare usually referred for intervention at a younger ageas compared with patients with calcific aortic stenosisdue to different underlying physiopathologicalmechanisms for AR such as degenerative causes,congenital or infectious diseases, vasculitis, andradiotherapy (1). Advanced symptom status andsevere pulmonary hypertension often render patientswith native AR more vulnerable and complex relativeto high-risk patients with aortic stenosis.

Among technical issues, the frequent coexistenceof severe AR and pathological dilation of the aorticroot and ascending aorta often mandate open surgicalrepair. Currently available transcatheter devices arenot approved for annulus dimensions exceeding28 mm in diameter. Furthermore, the peculiar anat-omy of the aortic root in patients with AR counteractsthe basic mechanism of action of transcatheter aorticvalves. First-generation TAVR devices were designedto dilate the stenotic aortic valve while sealing withinits extensively calcified annulus; large aortic annuli,dilation of the left ventricle, and absence of calcifi-cation among patients with native pure AR challengeadequate anchoring of TAVR devices. Malpositioning,migration, or significant paravalvular regurgitationcan be prevented with generous oversizing at theexpense of an increased risk of annulus rupture orvalve dislocation.

The Medtronic CoreValve (Medtronic, Minneapolis,Minnesota) was preferentially chosen in most of theearly reports of TAVR in patients with native pure AR(14,19–21,30–33). Its self-expandable properties wereconsidered to offer stability during device posi-tioning, and ensure anchoring of the prosthesis evenin the absence of heavy calcification. However, thefrequent need for valve-in-valve implantation (19%)and moderate to high rates of moderate to severepost-procedural AR (21%) resulted in modest ValveAcademic Research Consortium–defined device suc-cess in the largest cohort of patients to date (11). Inaddition, the absence of valvular calcification showeda strong correlation with the need for a second valve.Along the same line, rates of valve-in-valve implan-tation and residual AR were 30% and 88%, respec-tively, in the cohort reported by Testa et al. (14),pointing to the limitations of this device for the use inthe setting of this specific off-label indication.

SECOND GENERATION TRANSCATHETER AORTIC

VALVES. Novel devices featuring repositionability,self-positioning geometry, and specific fixationmechanisms have the potential to improve the per-formance of TAVR in patients with native pure AR. TheJenaValve is currently the only device with Con-formité Européenne mark for the treatment of AR. It ismade of a nitinol stent housing a trileaflet porcinevalve, 3 feelers allowing anatomically correct orien-tation of the prosthesis, and a special clipping mech-anism fixing the device onto the native leaflets. Thefirst report of TAVR using the JenaValve included 5patients with moderate or severe AR and high surgicalrisk; procedural success was achieved in all cases andno death or stroke was reported at 30 days (34). Similarperformance was observed in subsequent case seriesincluding a total of 51 patients (12,18,21).

Among the other devices requiring transapicalaccess, the ACURATE TA (Symetis, Ecublens,Switzerland) features a self-positioning mechanism,ensuring the release of the lower crown of the stentonly when the upper crown is in proper position, anda fixation mechanism (waistlike shape) suitable forlarger annuli. In a pilot experience, 8 patients withnative AR were successfully treated with oversizeddevices (1 to 2 mm) (16).

The Direct Flow Valve System (Direct Flow Medi-cal, Santa Rosa, California) can be implanted eithervia transfemoral, subclavian, or direct aortic access; itconsists of 2 systems of rings (ventricular and aortic)that are independently inflated with a contrast-salinemixture during the deployment phase and with apolymer that solidifies to offer support and fix thedevice in the final position. Schofer et al. (13) reportedtheir experience with this device in 11 high-risk pa-tients: device success and the early safety endpointaccording to Valve Academic Research Consortiumcriteria were reached in 100% and 91% of subjects,respectively.

Other new generation devices such as the Engagervalve (Medtronic) and the Lotus valve (Boston Sci-entific, Natick, Massachusetts), featuring some of thecharacteristics described for the above mentionedvalves, and the dedicated Helio transcatheter aorticdock (Edwards Lifesciences, Irvine, California) havebeen used in isolated case reports of patients with AR,not included in the present analysis (35,36).

STUDY LIMITATIONS. First, the number of studies andincluded patients was modest, hence limiting the val-idity of our findings. Second, included studies wereheterogeneous in terms of TAVR devices used, access,technique, and outcome definition, rendering a com-parison across reports impossible. Third, publication

PERSPECTIVES

WHAT IS KNOWN? SAVR is the treatment of choice

for native pure aortic regurgitation. However, trans-

catheter aortic valve replacement is emerging as a

novel treatment option for high-risk patients.

WHAT IS NEW? We performed a systematic review

including 237 high-risk patients with pure native aortic

regurgitation undergoing transcatheter aortic valve

replacement across 13 studies. The 30-day rate of

mortality amounted to 7%; post-procedural AR was

moderate or severe in 9% of patients.

WHAT IS NEXT? Despite encouraging initial data,

expanding the indication of transcatheter aortic valve

replacement to high-risk patients with pure severe

aortic regurgitation requires further studies with

longer-term follow-up data.

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bias may have affected the findings of our meta-analysis of published reports. Fourth, incompletedata reporting was frequent across studies, particu-larly for baseline and anatomic patient characteristics.Fifth, outcome data are predominantly limited toperiprocedural events; longer-term follow-up will beneeded to evaluate efficacy of TAVR for AR. Specifi-cally, akin to patients receiving TAVR for severe aorticstenosis, a detrimental impact of residual more thanmild AR on long-term survival can be expected.Finally, although we explored the effect of covariateson the effect size, the results of the metaregressionshould be carefully interpreted in view of the useof study-level covariates and overall low statisticalpower.

CONCLUSIONS

Although SAVR remains the preferred therapeuticoption for patients with native pure AR, the results ofthis study support the technical feasibility of TAVRfor the treatment of high-risk patients with a rela-tively low rate of early adverse events. However,despite initial encouraging data, larger studies,longer follow-up and further development in devicetechnology are necessary to advance the expansion ofTAVR to patients with pure native AR.

REPRINT REQUESTS AND CORRESPONDENCE: Dr.Thomas Pilgrim, Department of Cardiology, BernUniversity Hospital, Bern 3010, Switzerland. E-mail:thomas.pilgrim@insel.ch.

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KEY WORDS meta-analysis, pure nativeaortic regurgitation, systematic review,transcatheter aortic valve replacement

APPENDIX For supplemental tables, pleasesee the online version of this article.