J A C C : C A R D I O V A S C U L A R I N T E R V E N T I O N S V O L . 1 1 , N O . 1 2 , 2 0 1 8

ª 2 0 1 8 B Y T H E AM E R I C A N C O L L E G E O F C A R D I O L O G Y F O UN DA T I O N

P U B L I S H E D B Y E L S E V I E R

FOCUS ON TRICUSPID, MITRAL, AND AORTIC VALVE INTERVENTIONS

Predictors of Procedural and ClinicalOutcomes in Patients With SymptomaticTricuspid Regurgitation UndergoingTranscatheter Edge-to-Edge Repair

Christian Besler, MD,a,* Mathias Orban, MD,b,c,* Karl-Philipp Rommel, MD,a,* Daniel Braun, MD,b Mehul Patel, MD,d

Christian Hagl, MD,e Michael Borger, MD, PHD,f Michael Nabauer, MD,b Steffen Massberg, MD,b,c Holger Thiele, MD,a

Jörg Hausleiter, MD,b,c,y Philipp Lurz, MD, PHDa,y

ABSTRACT

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OBJECTIVES This study sought to investigate predictors of procedural success and clinical outcomes in patients with

tricuspid regurgitation (TR) at increased surgical risk undergoing transcatheter tricuspid valve edge-to-edge repair

(TTVR).

BACKGROUND Recent data suggest TTVR using the edge-to-edge repair technique in patients at high surgical risk is

feasible and improves functional status at short-term follow-up.

METHODS TTVR was carried out in 117 patients with symptomatic TR (median age 79.0 years [interquartile range (IQR):

75.5 to 83.0 years], EuroSCORE II 6.3% [IQR: 4.1% to 10.8%], STS mortality score 5.3% [IQR: 2.9% to 7.1%]) at 2 centers

in Germany between March 2016 and November 2017. Seventy-four patients had concomitant severe mitral regurgitation

and underwent transcatheter edge-to-edge repair of both valves.

RESULTS During TTVR, 185 and 34 clips were implanted at the anteroseptal and posteroseptal commissures, respec-

tively. Procedural success (TR reduction$1) was achieved in 81% of patients. Median TR effective regurgitant orifice area

was reduced from 0.5 to 0.2 cm2. After a median follow-up of 184 days (IQR: 106 to 363 days), 24 patients died and 21

patients were readmitted for heart failure. TTVR procedural success independently predicted the time free of death and

admission for heart failure (hazard ratio: 0.20 [95% confidence interval: 0.08 to 0.48]; p < 0.01), irrespective of

concomitant mitral regurgitation. Small TR coaptation gap size and a central/anteroseptal TR jet location independently

predicted procedural success on multivariate analysis.

CONCLUSIONS Successful TR reduction by TTVR serves as a predictor for reduced mortality and heart failure

hospitalization. TR coaptation gap and jet location may assist in decision making whether a patient is anatomically

suited for TTVR. (J Am Coll Cardiol Intv 2018;11:1119–28) © 2018 by the American College of Cardiology Foundation.

N 1936-8798/$36.00 https://doi.org/10.1016/j.jcin.2018.05.002

m the aDepartment of Cardiology, Heart Center Leipzig – University Hospital, Leipzig, Germany; bMedizinische Klinik und

liklinik I, Klinikum der Universität München, Munich, Germany; cMunich Heart Alliance, Partner Site German Center for Car-

vascular Disease (DZHK), Munich, Germany; dDepartment of Cardiology, East Carolina University, Greenville, North Carolina;

erzchirurgische Klinik und Poliklinik, Klinikum der Universität München, Munich, Germany; and the fDepartment of Cardiac

rgery, Heart Center Leipzig – University Hospital, Leipzig, Germany. Dr. Braun has received speakers honoraria from

bott Vascular. Dr. Hausleiter has been a consultant to and received speakers honoraria from Abbott Vascular and speakers

noraria from Edwards Lifesciences. Drs. Nabauer and Lurz have been consultants to and received speakers honoraria from

bott Vascular. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

rs. Besler, Orban, and Rommel contributed equally to this work and are joint first authors. yDrs. Hausleiter and Lurz contributed

ually to this work and are joint senior authors.

nuscript received February 1, 2018; revised manuscript received April 23, 2018, accepted May 1, 2018.

ABBR EV I A T I ON S

AND ACRONYMS

CI = confidence interval

EROA = effective regurgitant

orifice area

HF = heart failure

HR = hazard ratio

IQR = interquartile range

LV = left ventricle/ventricular

LVEF = left ventricular ejection

fraction

MR = mitral regurgitation

NT-proBNP = N-terminal

pro–B-type natriuretic peptide

NYHA = New York Heart

Association

RV = right ventricle/ventricular

TAPSE = tricuspid annular

plane systolic excursion

TMTVR = combined

transcatheter mitral and

tricuspid valve edge-to-edge

repair

TOE = transesophageal

echocardiography

TR = tricuspid regurgitation

TTVR = transcatheter tricuspid

valve edge-to-edge repair

TV = tricuspid valve

VC = vena contracta

Besler et al. J A C C : C A R D I O V A S C U L A R I N T E R V E N T I O N S V O L . 1 1 , N O . 1 2 , 2 0 1 8

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T ricuspid regurgitation (TR) eitherisolated or in combination with left-sided valvular heart disease is asso-

ciated with an increased risk of heart failure(HF) hospitalization and cardiovascular mor-tality (1–3). Recent studies in elderly patientsat high surgical risk undergoing transcatheteraortic valve replacement or interventionalmitral valve repair have suggested that resid-ual TR following repair of left-sided valvularheart disease remains associated with poorclinical outcome at mid-term follow-up(4–6). Several transcatheter devices arecurrently in pre-clinical and early clinicalevaluation as potential novel treatment op-tions for symptomatic TR in patients atincreased risk for surgery (7). According torecent data from 106 patients enrolled inthe multicenter TriValve registry, transcath-eter tricuspid valve edge-to-edge repair(TTVR) (MitraClip, Abbott Vascular, SantaClara, California) is so far the most commontechnique applied for interventional TRtreatment (8). Preliminary evidence suggeststhat TTVR is safe and feasible, and associatedwith an improvement in New York Heart As-sociation (NYHA) functional class and 6-minwalking distance at short-term follow-up(9,10). Whether transcatheter treatment ofTR translates to a reduction in objective clin-

ical endpoints is not proven. In addition, clinical andechocardiographic characteristics of patientscurrently treated by interventional TR repair arerather heterogeneous, and predictors of proceduralor clinical outcome remain to be elucidated. There-fore, the aim of the present study was to investigatewhether reduction of TR by TTVR improves clinicaloutcome in terms of HF hospitalizations and mortal-ity in patients deemed unsuitable for surgical treat-ment. In addition, the present study sought toidentify potential predictors of TR reduction duringthe procedure and thereby address the question ofwhich patients benefit the most from TTVR.

SEE PAGE 1129

METHODS

PATIENTS. The retrospective analysis was conductedin 117 consecutive patients with symptomatic TRtreated by TTVR at 2 tertiary care centers in Germany(Heart Center Leipzig–University Hospital, Leipzig,Germany, and the University Hospital of the Ludwig-Maximilians University, Munich, Germany) betweenMarch 2016 and November 2017. Seventy-four

patients had concomitant severe mitral regurgitation(MR) and underwent combined transcatheter mitraland tricuspid valve edge-to-edge repair (TMTVR). Allpatients were referred with symptoms of right HF andwere in NYHA functional class II to IV despite optimalmedical therapy. Pre-procedural assessment includeda comprehensive transthoracic and transesophagealechocardiography (TOE), evaluation of N-terminalpro–B-type natriuretic peptide (NT-proBNP) levels(Cobas, Elecsys NT-proBNP II, Roche, Basel,Switzerland) and a 6-min walk test. Patients werediscussed at the local heart team meeting andconsidered to be at high or prohibitive risk for sur-gery. Therefore, an interventional approach fortreatment of TR on a compassionate use basis with orwithout MR treatment was suggested. Patients withpoor echocardiographic visualization of the tricuspidvalve on screening TOE, with any degree of mitral ortricuspid valve (TV) stenosis, with severe aortic ste-nosis and with tricuspid or mitral anatomy deemedunsuitable for edge-to-edge repair were excluded.Characteristics of anatomic unsuitability of the TVwere not pre-specified but evolved during experienceand included mainly conditions that were thought tomake leaflet grasping unlikely: an effective regur-gitant orifice area (EROA) of >1.5 cm2, a TV coaptationdefect >15 mm, and markedly restricted leafletmobility due to pacemaker or implantable car-dioverter defibrillator leads across the TV. Advancedage, severely impaired left or right ventricular (RV)ejection fraction, and pulmonary hypertension didnot serve as exclusion criteria for intervention. Allpatients gave written informed consent, and theanalysis was approved by the local ethics committee.

ECHOCARDIOGRAPHY ANALYSIS. All echocardio-grams were performed on a GE Vivid E9 (GeneralElectric Healthcare, Chicago, Illinois) or Epiq7 system(Philips Healthcare, Andover, Massachusetts) andanalyzed from stored images by an experiencedoperator in the local echocardiography lab blinded toprocedural details. The imaging protocol has beendescribed previously (11) and is detailed in the OnlineAppendix.

TRANSCATHETER MITRAL AND TRICUSPID EDGE-TO-EDGE

REPAIR. TTVR and TMTVR were performed undergeneral anesthesia with interventional guidance byTOE and fluoroscopy, as described previously (9–12).Please review the Online Appendix for further details.

FOLLOW-UP EXAMINATIONS AND STUDY ENDPOINTS.

All patients underwent echocardiography assessmentbefore discharge (i.e., 2 to 5 days after procedure),and follow-up examinations were carried out 1 month

TABLE 1 Baseline Characteristics of the Study Cohort

All(N ¼ 117)

No Event(n ¼ 79)*

Death/HFHospitalization

(n ¼ 35)* p Value

Age, yrs 79.0 (75.5–83.0) 78.0 (74.0–83.0) 81.0 (76.0–84.0) 0.11

Female 51 (44) 30 (38) 20 (57) 0.07

BMI, kg/m2 25.5 (23.0–27.8) 26.0 (23.5–28.3) 24.1 (22.3–27.1) 0.04

EuroSCORE II, % 6.3 (4.1–10.8) 6.3 (4.1–10.7) 6.2 (4.1–11.6) 0.98

STS mortality score, % 5.3 (2.9–7.1) 4.0 (2.7–7.2) 4.6 (3.0–6.6) 0.56

NYHA functional class

II 4 (3) 4 (5) 0 (0) 0.25

III 68 (58) 48 (61) 19 (53)

IV 45 (39) 27 (34) 16 (46)

NT-proBNP, pg/ml 3,876(2,094–6,608)

3,686(2,074–6,430)

3,481(2,060–8,060)

0.90

Log NT-proBNP – eGFR 84.7 (64.4–118.9) 80.8 (66.7–119.5) 103.5 (63.2–117.9) 0.57

eGFR, ml/min 41.9 � 17.7 41.9 � 17.4 41.7 � 18.4 0.58

Lead across tricuspidvalve

38 (33) 26 (33) 11 (31) 1.00

Previous PCI 37 (32) 26 (33) 10 (29) 0.83

Previous CABG 19 (16) 14 (18) 4 (11) 0.58

HFrEF 39 (33) 25 (32) 13 (37) 0.67

Chronic pulmonarydisease

23 (20) 17 (22) 5 (14) 0.45

ACE inhibitor/ARB 86 (74) 63 (80) 22 (63) 0.07

Beta-blocker 106 (91) 70 (89) 33 (94) 0.50

Aldosterone antagonist 39 (33) 28 (35) 11 (31) 0.83

Diuretic agent 111 (95) 75 (95) 33 (94) 1.00

6MWD, m 187 (120–309) 203 (125–330) 165 (106–263) 0.13

MR grade

0–1 29 (25) 23 (28) 6 (17) 0.392 17 (15) 9 (11) 8 (23)$3 71 (61) 47 (60) 21 (60)

TR grade

2 7 (6) 6 (7) 1 (3) 0.10

3 81 (69) 58 (73) 21 (60)

4 29 (25) 15 (19) 13 (37)

Values aremedian (interquartile range), n (%), ormean� SD. LogNT-proBNP – eGFR¼ 1,000� log(NT-proBNP) / eGFR.*Three patients were lost to follow-up. Results are presented for 114 patients with outcome assessment in thesecolumns.

6MWD ¼ 6-min walk distance; ACE ¼ angiotensin-converting enzyme; ARB ¼ angiotensin receptor blocker;BMI ¼ body mass index; CABG ¼ coronary artery bypass grafting; eGFR ¼ estimated glomerular filtration rate;HF ¼ heart failure; HFrEF ¼ heart failure with reduced ejection fraction (left ventricular ejection fraction <40%);MR ¼ mitral regurgitation; NT-proBNP ¼ N-terminal pro–B-type natriuretic peptide; NYHA ¼ New York HeartAssociation; PCI ¼ percutaneous coronary intervention; STS ¼ Society of Thoracic Surgeons; TR ¼ tricuspidregurgitation.

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and 6 months after treatment. On each visit, symp-toms were recorded and a physical examination wasperformed. In addition, patients underwent echocar-diography and a 6-min walk test. After 6 months,patients were regularly contacted by telephone if nofurther outpatient appointments were scheduled.Three patients who were discharged alive were lost tofollow up. As such, they were excluded from theoutcome analysis.

Procedural success of TTVR was defined as suc-cessful clip placement and reduction of TR $1 gradeassessed on transthoracic echocardiography within30 days after the procedure. Procedural success ofinterventional mitral valve repair was defined as areduction of MR to grade #2 on echocardiographywithin 30 days after clip deployment.

The primary study endpoint was defined as com-posite endpoint including all-cause mortality andneed for repeat hospitalization during follow-up.Secondary endpoints included changes in NYHAfunctional class and 6-min walk test distance.

STATISTICAL ANALYSIS. A detailed description onthe statistical analysis is provided in the OnlineAppendix.

RESULTS

BASELINE CHARACTERISTICS. Baseline demographicdata of the 117 patients enrolled in the present anal-ysis are shown in Table 1 and Online Table 1. Themedian age of the patient sample was 79.0 years([interquartile range (IQR): 75.5 to 83.0 years) with44% of patients being female. Patients were atincreased risk for surgery (EuroSCORE II 6.3% IQR:4.1% to 10.8%], STS Predicted Risk of Mortality scorefor mitral valve repair 5.3% [IQR: 2.9% to 7.1%]) andhighly symptomatic with 97% of subjects presentingin NYHA functional class III or IV in both groups.Exercise capacity was markedly impaired (6-min walkdistance 187 m [IQR: 120 to 309 m]). Nearly all pa-tients were on diuretic therapy (Table 1). NT-proBNPlevels were elevated in all patients, and 39 of 117 pa-tients (33%) presented with HF with reduced leftventricular (LV) ejection fraction (LVEF), according torecent European Society of Cardiology guidelines (13).A pacemaker or defibrillator lead was present in 38 of117 patients (33%). Nineteen patients (16%) had un-dergone prior coronary artery bypass grafting, 37 pa-tients (32%) had prior percutaneous coronaryinterventions, and 9 patients (8%) had undergoneprior aortic valve implantation.

ECHO PARAMETERS. Results of echocardiographiccharacterization are displayed in Table 2 and Online

Table 2. Median LVEF was 50% (IQR: 35% to 61%)with LV end-diastolic diameter being within the uppernormal range (51 mm [IQR: 45 to 58 mm]). Patientsdemonstrated dilated right-sided heart chambers (RVmid cavity diameter 42� 8mm, right atrial area 34 cm2

[IQR: 29 to 44 cm2]) with enlarged tricuspid annulardiameter (49 � 7 mm). RV function was impaired in58% of patients, as defined by tricuspid annular planesystolic excursion (TAPSE) <17 mm (Table 2). All pa-tients displayed severe-to-torrential TR on pre-procedural echocardiography, and the etiology of TRwas functional in all but 4 patients (97%).

TABLE 2 Pre-Procedural Echocardiographic Parameters of the Study Cohort

All(N ¼ 117)

TTVRSuccess(n ¼ 95)

TTVRFailure(n ¼ 22) p Value

LVEF, % 50.0 (34.5–60.5) 50.0 (34.0–60.0) 50.0 (35.0–64.3) 0.49

LVEDD, mm 51.0 (45.0–58.0) 51.0 (45.0–58.0) 50.0 (45.0–55.8) 0.68

RA area, cm2 34.0 (28.7–43.8) 34.0 (28.0–43.3) 36.9 (29.8–45.3) 0.42

RV mid cavitydiameter, mm

41.5 � 7.8 41.4 � 7.9 41.8 � 7.1 0.87

TAPSE, mm 16.1 � 4.5 15.9 � 4.6 16.7 � 4.0 0.52

TAPSE <17 mm 67 (58) 54 (57) 13 (59) 1.00

RV-FAC, % 40.0 (32.0–44.0) 40.0 (31.5–44.0) 38.0 (31.5–42.0) 0.30

RV-FAC <35% 36 (31) 27 (29) 9 (41) 0.31

TV EROA (PISA), cm2 0.50 (0.30–0.70) 0.5 (0.3–0.6) 0.7 (0.4–1.0) 0.02

TR vena contracta, mm 9.0 (7.0–11.0) 8.5 (7.0–10.8) 10.5 (7.8–13.3) 0.06

TV annulus diameter, mm 48.7 � 6.6 48.3 � 6.2 50.5 � 7.9 0.28

TV tenting area, cm2 2.0 (1.4–3.2) 1.9 (1.4–2.9) 2.7 (1.4–4.1) 0.10

TV tenting distance, mm 9.0 (7.0–11.0) 8.9 (7.0–11.0) 9.0 (7.6–13.0) 0.19

TV coaptation gap, mm 5.0 (3.1–7.0) 4.8 (3.0–6.0) 7.5 (4.0–11.3) <0.01

TR dPmax, mm Hg 38.5 (28.0–49.0) 39.0 (30.0–51.0) 31.0 (21.3–44.0) 0.06

TR jet non-central/non-anteroseptal

22 (19) 10 (46) 12 (13) <0.01

Values are median (interquartile range), mean � SD, or n (%).

EROA ¼ effective regurgitation orifice area; LVEDD ¼ left ventricular end-diastolic diameter; LVEF ¼ leftventricular ejection fraction; PISA¼ proximal isovelocity surface area; RA¼ right atrium; RV¼ right ventricle; RV-FAC ¼ right ventricular fractional area change; TAPSE ¼ tricuspid annular plane systolic excursion; TR dPmax ¼TR jet maximal pressure gradient; TTVR ¼ transcatheter tricuspid valve repair; TV ¼ tricuspid valve; other ab-breviations as in Table 1.

TABLE 3 Procedural

Concomitant TMTVR

TTVR success

TV clips, n

Clipping anteroseptal

Clipping posteroseptal

MR grade 0–I post-inteMR grade 2 post-intervMR grade 3 post-interv

TR grade 1–2 post-inteTR grade 3 post-intervTR grade 4 post-interv

Values are n (%) or medianreduction $1 grade post ipatients with an outcome

TMTVR ¼ transcatheter

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In patients undergoing TMTVR, MR was functionalin 69% of patients. Patients with TMTVR showed amore pronounced left-sided heart disease with lowerLVEF (p < 0.01) and more pronounced LV dilatation(p < 0.01) when compared with patients with isolatedTTVR. Although RV and right atrial dimensions

Data and MR/TR Grades on Post-Intervention Echocardiography

All(N ¼ 117)

No Event(n ¼ 79)*

Death/HFHospitalization

(n ¼ 35)* p Value

74 (63) 49 (62) 22 (63) 1.00

95 (81) 71 (89) 21 (60) <0.01

2.0 (1.0–2.0) 2.0 (1.0–2.0) 2.0 (2.0–2.0) 0.23

107 (92) 73 (92) 31 (89) 0.49

31 (27) 20 (25) 11 (31) 0.50

rvention 101 (86) 69 (88) 29 (83) 0.37ention 13 (11) 9 (11) 4 (11)ention 3 (3) 1 (1) 2 (6)

rvention 92 (78) 72 (91) 17 (48) <0.01ention 23 (20) 7 (9) 16 (46)ention 2 (2) 0 (0) 2 (6)

(interquartile range). TTVR success is defined by a successful clip placement and TRntervention. *3 patients were lost-to follow-up. Results are presented for the 114assessment in these columns.

mitral and tricuspid valve repair; other abbreviations as in Tables 1 and 2.

were comparable between both groups, patients un-dergoing isolated TTVR had more frequently animpaired TAPSE (p ¼ 0.02), slightly higher functionalTR parameters, and more often a central/anteroseptaljet location (p ¼ 0.01) (Online Table 2).

PROCEDURAL RESULTS. TV clip implantation failedin 5 of 117 patients (4%) due to insufficient echo view(n ¼ 1), excessive rete chiari (n ¼ 1), chordal clipentrapment (n ¼ 1), or inability to reduce TR despitesuccessful clip placement between the anterior andposterior TV leaflets (n ¼ 2). In the remaining pa-tients, a total of 185 clips were implanted at theanteroseptal commissure in 107 of 117 patients (92%)and a total of 34 clips at the posteroseptal commis-sure in 31 of 117 patients (27%) (Table 3, OnlineTable 3). Overall cohort procedural success of trans-catheter TR repair could be achieved in 81% of pa-tients with 25 of 117 patients (22%) demonstratingresidual TR grade 3þ and 4þ (Table 3, Online Table 3).Median vena contracta (VC) of TR was reduced from 9mm (IQR: 7 to 11mm) to 5mm (IQR: 3 to 7mm) (p<0.01)and median TR EROA from 0.5 cm2 (IQR: 0.3 to 0.7cm2) to 0.2 cm2 (IQR: 0.1 to 0.3 cm2) (p < 0.01),whereas median TAPSE (16 mm [IQR: 13 to 20 mm] vs.16 mm [IQR: 13 to 20 mm]; p ¼ 0.79) and median TRjet maximal pressure gradients (39 mm Hg [IQR: 28 to49 mm Hg] vs. 35 mm Hg [IQR: 28 to 40 mm Hg]; p ¼0.63) were unchanged. Three of 74 patients (4%)showed residual MR grade 3þ despite successfulmitral clip implantation before discharge. Hence,overall MR improvement was achieved in 96% ofTMTVR cases (Online Table 3).

SYMPTOMS AND CLINICAL OUTCOMES DURING

FOLLOW-UP. During a median of 184 days of follow-up, 24 of 114 patients (21%) died, and 21 of 114 pa-tients (18%) were readmitted to hospital for decom-pensated HF, whereas the combined endpoint wasreached in 35 of 114 patients (31%) (Online Table 4).Cardiac death occurred in 10 of 24 patients (42%).Causes of cardiac death were progressive HF (n ¼ 8),ST-segment elevation myocardial infarction (n ¼ 1),and endocarditis (n ¼ 1). A noncardiac cause of deathwas identified in 6 patients (sepsis in 4 patients, andstroke and gastrointestinal bleeding in 1 patienteach). Cause of death remained unknown in 8 pa-tients. Two patients died in-hospital (in-hospitalmortality 1.7%) with 1 patient experiencing malignantstroke 7 days after successful isolated TTVR, andanother patient experiencing progressive HFfollowing combined TMTVR without reduction in MRand TR because of massive annular dilatation.Another 2 patients died within 30 days after hospitaldischarge: 1 patient died for unknown reason 15 days

FIGURE 1 Kaplan-Meier Estimates According to Transcatheter TV Repair Success

Kaplan-Meier estimates according to transcatheter TV repair success for the time to (A)

death/heart failure hospitalization (B) to death and (C) to heart failure hospitalization.

TTVR ¼ transcatheter tricuspid valve edge-to-edge repair; TV ¼ tricuspid valve.

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after successful combined TMTVR, and 1 patient withseverely impaired LV function died from progressiveHF 24 days after combined TMTVR with successfulMR reduction from severe to mild but without TRreduction (30-day mortality 3.4%).

Patients reaching the combined clinical endpointdid not differ in baseline characteristics from patientsnot experiencing an event (n¼82), except for a slightlylower body mass index (p ¼ 0.04) (Table 1). Echocar-diographic parameters did not differ between patientswith andwithout a clinical event. Patients reaching thecombined clinical endpoint were less likely to experi-ence successful transcatheter TR repair (60% vs. 89%;p < 0.01) and demonstrated more severe residual TR(p < 0.01) (Table 3). No differences were observed be-tween the clinical endpoint rates in patients with iso-lated TTVR (n ¼ 43) and TMTVR (n ¼ 74) (OnlineTable 4). When compared with patients with isolatedTTVR, patients with TMTVR were less likely to be fe-male (34% vs. 61%; p¼0.01), weremore likely to be in ahigher NYHA functional class (p ¼ 0.03), had moreoften HF with reduced ejection fraction (41% vs. 21%;p ¼ 0.04) and displayed more severe MR (p < 0.01)(Online Table 1). Improvement of NYHA functionalclass was observed in 76% of patients at their lastfollow-up with patients experiencing a clinical eventbeing significantly more often in NYHA functionalclass III to IV (57% vs. 25%; p<0.01). Although a higherpercentage of patients with TMTVR experienced animprovement in NYHA functional class (84% vs. 64%;p ¼ 0.02), overall improvement in NYHA grades wasindependent from concomitant mitral valve repair (pfor interaction¼0.16). In patients with 6-min walk testat baseline and at least 1 follow-up visit (n ¼ 89),covered median distance improved significantly by29% (from 189 m [IQR: 119 to 311 m] to 244 m [IQR: 164to 374 m]; p < 0.01), and 72% of patients experiencedan improvement of at least 25 m. No impact ofconcomitant mitral valve repair was observed (p forinteraction ¼ 0.52).

PREDICTORS OF CLINICAL OUTCOMES. Rates of thecombined clinical endpoints as well as rates formortality and readmission for HF alone were signifi-cantly higher in patients with unsuccessful trans-catheter TR repair (death/HF hospitalization 64% vs.23%; death 46% vs. 15%, and HF hospitalization 50%vs. 11%; p < 0.01 for all). Kaplan-Meier estimatesdemonstrated a significant longer event-free survival(p < 0.01), a longer mortality-free survival (p ¼ 0.02)and longer freedom from HF readmission (p < 0.01) inpatients with successful transcatheter TR repair(Figure 1). Successful transcatheter TR repair was theonly predictor for freedom from clinical outcomes

TABLE 4 Predictors of Procedural Transcatheter TV Repair Success

Univariate Multivariate

Odds Ratio p Value Odds Ratio p Value

TR EROA (PISA) 0.21 (0.06–0.73) 0.01 — —

TV tenting area 0.65 (0.45–0.94) 0.02 — —

TR vena contracta 0.87 (0.77–0.99) 0.04 — —

TV coaptation gap 0.74 (0.63–0.87) <0.01 0.73 (0.62–0.88) <0.01

TR jet non-central/non-anteroseptal

0.22 (0.08–0.62) <0.01 0.18 (0.06–0.56) <0.01

Univariate and multivariate logistic regression for procedural TTVR success, displaying only sig-nificant univariate predictors. Univariate predictors were subsequently tested in a multivariatestepwise model.

Abbreviations as in Tables 1, 2, and 3.

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and independently predicted freedom from thecombined endpoint (hazard ratio [HR]: 0.20 [95%confidence interval (CI): 0.08 to 0.48]; p < 0.01),freedom from death (HR: 0.40 [95% CI: 0.18 to 0.91];p ¼ 0.03), and freedom from hospitalization for HF(HR: 0.15 [95% CI: 0.06 to 0.36]; p < 0.01). Trans-catheter mitral valve repair success failed to signifi-cantly predict outcomes in the regression models.

PREDICTORS OF PROCEDURAL SUCCESS. Fiveechocardiographic parameters were univariate pre-dictors for procedural success; these included asmaller TR EROA, a smaller TR tenting area, TR VC, asmaller TV coaptation gap and a central/anteroseptalTR jet location (Table 4). In the multivariate model, asmaller TV coaptation gap and a central/anteroseptalTR jet location independently predicted transcatheterTR repair success. Receiver-operating characteristiccurve analysis demonstrated a cutoff value for acoaptation gap of 7.2 mm as the best discriminator forsuccessful transcatheter TR repair. Combining the 2independent predictors as binary variables, patientscould be further stratified according to proceduralsuccess. Notably, none of the patients with a TVcoaptation gap larger than 7.2 mm and a non-central/non-anteroseptal TR jet location could be treatedsuccessfully (Figures 2 and 3). Treatment successdeclined linearly with the magnitude of TV coapta-tion gap, yielding a success rate of <30% with a gap ofmore than 10 mm. Youden index-based cutoff valuesfor the other univariate predictors were 0.6 cm2 forTR EROA, 2.1 cm2 for TV tenting area, and 11 mm forTR VC.

DISCUSSION

The key findings of our bicentric study suggest thatsuccessful interventional TR edge-to-edge repairtranslates into lower mortality and reduced

hospitalization for HF when performed as an isolatedprocedure or combined with MR treatment. Smallcoaptation gap size and a central/anteroseptal locationof the TR jet noted on pre-procedural echocardiogra-phy are important anatomic predictors of proceduralsuccess of transcatheter tricuspid valve repair.

PROGNOSTIC VALUE OF TR TREATMENT. A growingbody of evidence indicates that patients with isolatedTR or residual TR following treatment of left-sidedvalvular pathologies face an inferior clinicaloutcome (1–6,14–16). Based on data from the Fra-mingham Study, estimates suggest that as many as 1.6million Americans may have relevant TR (17,18), andthis population is estimated to grow further (19). Thishigh prevalence together with the low incidence ofsurgery for severe TR and stagnant, but relevantoperative mortality (20) has created a large popula-tion of patients in need of percutaneous, innovativetherapies to improve clinical outcome of TR.

However, data on the impact of TR on clinicaloutcome are not uniform, and some studies have evenquestioned the incremental prognostic value of TRafter adjustment for comorbidities and RV dysfunc-tion in patients with advanced HF, late after left-sidedheart valve surgery and following transcatheter aorticvalve replacement (21–23). These findings, amongothers, have raised concern about the pathophysio-logical and therapeutic relevance of TR in thesesituations, and there is an ongoing debate whether TRrather reflects a surrogate marker for other cardiac orsystemic comorbidities, which ultimately determineclinical outcome. The debate is further complicated bythe lack of adequately powered clinical trials.

Hitherto, data on transcatheter TR repair havebeen limited by short clinical follow-up and use ofsurrogate clinical endpoints to assess the procedure’sefficacy (9,10). The present study is the first to ourknowledge to analyze outcomes in the largest cohortof patients undergoing TTVR/TMTVR by use of hardclinical endpoints over an extended follow-up period.In keeping with a previous report on a cohort un-dergoing transcatheter TR repair by various devices(8), patients in the present study were at an advancedage, highly symptomatic despite optimal medicaltherapy and presented with many comorbidities.Despite this high rate of comorbidities, successfultranscatheter TR repair emerged as the only inde-pendent predictor for death and rehospitalization forHF during follow-up. The strong association oftranscatheter TR repair success with superioroutcome suggests that TR is causative for an inferioroutcome and that transcatheter TR reduction couldindeed improve the natural history of these patients.

FIGURE 2 TOE of Patients Undergoing Transcatheter TV Repair

Patient A:Mid-esophageal biplane imaging of commissural and 4-chamber view demonstratesmedium-to-large TV coaptation gap (Patient A 1)

with significant tricuspid regurgitation in color Doppler imaging (Patient A 2). Transgastric en-face view of the TV verifies the coaptation defect

mainly between anterior and septal leaflet, and visualizes the central regurgitant jet (Patient A 3). The patient went on to have successful

transcatheter TV repairwith implantationof 2 clips (redX) in the anteroseptal commissure, andmarked reduction of tricuspid regurgitation from

pre- (Patient A 4) to post-intervention (Patient A 5) was visible on mid-esophageal 4-chamber views. Patient B: Deep-esophageal biplane

imaging demonstrates huge TV coaptation gap (Patient B 1) with significant tricuspid regurgitation in color Doppler imaging (Patient B 2).

Transgastric en-face view of the TV verifies the enormous coaptation defect and visualizes the regurgitant jet extending from the anteroseptal to

the posteroseptal commissure (Patient B 3). Despite successful deployment of 1 clip (red X) at the anteroseptal and 1 at the posteroseptal

commissure, no reduction of tricuspid regurgitation could be achieved as visualized by mid-esophageal 4-chamber views before (Patient B 4)

and after the procedure (Patient B 5). TOE ¼ transesophageal echocardiography; TV ¼ tricuspid valve.

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OUTCOME IN TMTVR. Because of the pathophysio-logical link between functional TR and left-sidedvalvular heart disease (in particular MR), a signifi-cant proportion of patients evaluated for TTVR havemultivalvular disease (7). In the present study, 63% ofpatients underwent TMTVR. Interestingly, clinicaloutcome in patients with TMTVR did not differ when

compared with patients with isolated TTVR. In fact,effective TR reduction predicted survival in bothhigh-risk groups, those with isolated severe TR andthose successfully treated for combined MR and TR.In patients with TMTVR, effective TR reduction wasthe only predictor for survival and freedom from HFhospitalization. Together, these data support the

FIGURE 3 Patient Stratification According to Procedural Success

Proposed scheme for patient stratification for transcatheter tricuspid valve edge-to-edge repair according to the determined cut-off value of

7.2 mm for tricuspid valve coaptation gap and main tricuspid regurgitant jet orientation. TR ¼ tricuspid regurgitation.

Besler et al. J A C C : C A R D I O V A S C U L A R I N T E R V E N T I O N S V O L . 1 1 , N O . 1 2 , 2 0 1 8

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concept that TR is not just a bystander in coexistingmitral valve disease, but is rather of prognosticimportance and, above all, a valuable target topotentially change the course of the disease.

PREDICTORS OF SUCCESS IN TTVR. Given thevarious mode of action of available transcatheterdevices, one might assume that predictors of successmay vary depending on the transcatheter procedureperformed. Severe leaflet tenting and very largetricuspid annular diameter are considered as pre-dictors of inferior outcome in patients undergoingsurgical tricuspid valve repair (24,25), and one mightspeculate that transcatheter tricuspid annuloplastydevices (such as Trialign [Mitralign Inc., Tewksbury,Massachusetts], Cardioband [Edwards Lifesciences,Irvine, California], or TriCinch [4TECH, Galway,Ireland]) would have the same predictors of success.By contrast, predictors of procedural success fortranscatheter leaflet repair devices such as MitraClipare still lacking despite the increasing use of thetechnique (8). The findings of the present studysuggest that 2 echocardiographically derived param-eters may assist to determine suitability ofTTVR, namely coaptation gap and non-central/non-anteroseptal location of the TR jet. The coapta-tion gap observed in patients with severe TR is likelya result of tricuspid annular dilatation and leaflettethering. Larger coaptation gaps are associated with

more severe TR and consequently increase the like-lihood of residual TR. In addition, a larger coaptationgap will either prevent successful clip placement orwill lead to clip placement away from the region ofmain TR, both resulting in inefficient TR reduction.This may provide an explanation for the predictiverole of the coaptation gap. It should be mentionedthat iterations of the current MitraClip device withlarger clip arms or the Pascal system (Edwards Life-sciences, Irvine, California) might overcome somecurrent technical limitations in large TV gaps. Theassociation of a non-central/non-anteroseptal TR jetwith procedural failure might be less obvious. Fromour experience, clip placement in a posteroseptalposition and even more so in anteroposterior positionis more challenging. Therefore, a non-central/non-anteroseptal TR jet might reflect a technicallymore challenging situation or less suitable substrate.Apart from technical considerations, recent experi-mental work demonstrated less favorable outcome ofclip placement in the posteroseptal and in particularthe anteroposterior positions (26), supporting ourclinical observation.

On the basis of these findings, we propose asequential evaluation approach, considering the TVcoaptation gap followed by TR jet location (Figure 3).The varying success rate stratified according to these2 echocardiographic parameters could aid consentingof patients and physicians at present, but certainly

PERSPECTIVES

WHAT IS KNOWN? Recent evidence suggests that transcath-

eter TTVR is safe and feasible in patients with symptomatic TR at

high surgical risk, and associated with functional improvement

early after the procedure.

WHAT IS NEW? The present analysis suggests that successful

TR reduction by TTVR is an independent predictor of survival and

freedom from heart failure hospitalization. Moreover, the pre-

sent study is the first to demonstrate that small TR coaptation

gap size and a central/anteroseptal TR jet location are major

predictors for TTVR success.

WHAT IS NEXT? The present findings will need confirmation in

larger prospective studies to validate the impact of TTVR on

clinical outcomes and the value of TR coaptation gap and jet

location in decision making for TTVR.

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requires confirmation in larger cohorts before wide-spread use of TTVR outside of clinical trials can berecommended. Also, given the complex anatomy ofthe tricuspid valve apparatus, it appears likely thatthere are other, not-yet-identified imaging charac-teristics that may help to plan for type of repair anddevice selection.

STUDY LIMITATIONS. Although the present cohort ofpatients undergoing TTVR or TMTVR is the largestpublished thus far, the number of patients included isstill small with a follow-up limited to a median of6 months. On the basis of the present data, it istempting to speculate that TTVR or TMTVR may pro-vide prognostic benefit over and above optimal medi-cal therapy alone; however, the present study did notinclude a control group on optimal medical therapy,and therefore, no definite conclusions can be drawn.Also, the high success rate of MR correctionmight limitthe analysis of MR reduction as a predictor for morefavorable outcome in patients with TMTVR. Finally,although echocardiographic data were analyzed byexperienced institutional echocardiographers, therewas no echocardiographic core lab analysis performed.

CONCLUSIONS

Successful TR reduction by means of TTVR in patientsat increased surgical risk serves as a major predictorfor reduced mortality and HF hospitalization duringfollow-up, suggesting that TTVR provides prognosticbenefit in these patients. Small TV coaptation gap sizeand a central/anteroseptal jet location are major

anatomic determinants of procedural success andmay provide a means for patient selection for TTVR inthe future.

ACKNOWLEDGMENTS The authors thank MartinPetzold, Andrea Englmaier, and Diana Rösler forexcellent technical support in study organization.

ADDRESS FOR CORRESPONDENCE: Dr. Philipp Lurz,Department of Internal Medicine/Cardiology, Universityof Leipzig – Heart Center, Strümpellstraße 39, 04289Leipzig, Germany. E-mail: Philipp.Lurz@gmx.de.

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KEY WORDS edge-to-edge repair,heart failure, MitraClip, right ventricle,transcatheter therapy, tricuspidregurgitation, tricuspid valve

APPENDIX For an expanded Methods sectionand supplemental tables, please see the onlineversion of this paper.