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 3 , N O . 1 3 , 2 0 2 0

ª 2 0 2 0 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

STATE-OF-THE-ART REVIEW

Transcatheter Aortic ValveReplacement in Patients WithMultivalvular Heart Disease

Faisal Khan, MBBS,* Taishi Okuno, MD,* Daniel Malebranche, MD, Jonas Lanz, MD, Fabien Praz, MD,Stefan Stortecky, MD, Stephan Windecker, MD, Thomas Pilgrim, MD

ABSTRACT

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As transcatheter aortic valve replacement becomes a more dominant treatment option across all risk profiles, the fre-

quency of encountering patients with multivalvular disease will increase. Furthermore, percutaneous interventions to

treat other valvular lesions are also evolving. Understanding the clinical implications and treatment options for a second

valvular lesion is becoming increasingly important to guide heart team decisions, and this paper aims to review the

evidence around these situations. Diagnosis of multivalvular disease can be challenging because of changes in physiology.

There are little randomized data to guide therapy in multivalvular disease. Multidisciplinary heart team decisions can be

invaluable in integrating the plethora of clinical, hemodynamic, and imaging data on which an optimal management

strategy can be planned. Prospective studies to assess the role of structural valve interventions in the transcatheter aortic

valve replacement era would greatly help improve outcomes for structural heart patients.

(J Am Coll Cardiol Intv 2020;13:1503–14) © 2020 by the American College of Cardiology Foundation.

M ultivalvular heart disease presents achallenge in terms of diagnosis andtreatment. Although the prevalence of

rheumatic heart disease has declined in the Westernworld as the traditional cause of multivalvular dis-ease, the prevalence of degenerative valve diseaseis increasing as a result of the demographic transi-tion (1). For example, in a population-based studyof elderly patients in the United Kingdom, multiplevalve involvement was detected in more thanone-half of all patients with valvular lesions (2).An increase in primary valvular lesions with

N 1936-8798/$36.00

m the Department of Cardiology, Inselspital, Bern University Hospital, U

uno contributed equally to this work. Dr. Okuno has received speaker fee

earch grant support fromEdwards Lifesciences,Medtronic, Abbott Vascular, an

eived consulting fees fromBoston Scientific, British TechnologyGroup, andTe

nt support from Abbott, Amgen, Bristol-Myers Squibb, Bayer, Biotronik, Bo

dicines Company, St. Jude Medical, and Terumo. Dr. Pilgrim has received in

ences, Symetis, and Biotronik; has received speaker fees from Biotronik and

hLife SAS. All other authors have reported that they have no relationships rel

e authors attest they are in compliancewith human studies committees and an

od and Drug Administration guidelines, including patient consent where app

cular Interventions author instructions page.

nuscript received November 8, 2019; revised manuscript received Februa

advancing age is paralleled by a growing interestin secondary valvular lesions resulting fromchanges of ventricular geometry and dimension inpatients with heart failure.

Treatment of multivalvular disease is associatedwith an increased risk of adverse outcome. Therefore,the number of patients undergoing multivalvularsurgery may underestimate the true burden of dis-ease due to a positive selection of surgical candidates.In the Euro Heart Survey, 1 in 10 surgical valve pro-cedures involved multiple valves, more than half ofwhich included the aortic and the mitral valves (3).

https://doi.org/10.1016/j.jcin.2020.03.052

niversity of Bern, Bern, Switzerland. *Drs. Khan and

s from Abbott. Dr. Stortecky has received institutional

d Boston Scientific; and has served as a speaker for and

leflex. Dr.Windecker has received institutional research

ston Scientific, Edwards Lifesciences, Medtronic, The

stitutional research grant support from Edwards Life-

Boston Scientific; and has served as a consultant for

evant to the contents of this paper to disclose.

imalwelfare regulations of the authors’ institutions and

ropriate. For more information, visit the JACC: Cardio-

ry 7, 2020, accepted March 13, 2020.

HIGHLIGHTS

� MR is the most common valvulopathy inTAVR patients, followed by TR, MS, andAR.

� Both coexistent MR and MS may result inunderestimation of AS and portends aworse outcome after TAVR.

� AR at baseline may be protective againstthe deleterious effects of post-TAVRparavalvular leak.

� Further research is needed to define thetiming and role of tricuspid intervention.

ABBR EV I A T I ON S

AND ACRONYMS

AR = aortic regurgitation

AS = aortic stenosis

CI = confidence interval

HR = hazard ratio

LV = left ventricle/ventricular

PAR = paravalvular aortic

regurgitation

MR = mitral regurgitation

MS = mitral stenosis

MVA = mitral valve area

RV = right ventricle/ventricular

TAVR = transcatheter aortic

valve replacement

TR = tricuspid regurgitatio

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Transcatheter aortic valve replacement(TAVR) is becoming a dominant treatmentmodality for symptomatic severe aortic ste-nosis (AS) after iterative advances in bothevidence and technology. Treatment ofmultivalvular disease becomes increasinglycomplex as a wider range of patients may bepotentially eligible for transcatheter in-terventions. The recommendation for a heartteam discussion to decide the most appro-priate treatment plan on an individual basiswill take into account a wide range ofanatomical and clinical factors. This reviewaims to lay out the evidence for variousstrategies when managing symptomatic se-vere AS and additional valvular lesions.

TAVR IN PATIENTS WITH COMBINED AORTIC

STENOSIS AND AORTIC REGURGITATION

PATHOPHYSIOLOGICAL CONSIDERATIONS. Mixed ASand regurgitation represents a complex pathophysi-ology and diagnosis of this entity using conventionalmethods may have caveats. The stenotic componentincreases afterload, causing concentric LV hypertro-phy, while the regurgitant component creates a stateof volume overload, resulting in LV enlargement.Both pathologic remodeling processes, namely LVhypertrophy and LV enlargement, are frequentlyobserved and are associated with increases in LVfilling pressures. The summative hemodynamicsequalae may not be accurately represented by thetraditional thresholds for severe AS such as aorticvalve area <1 cm2 or severe AR (regurgitant volume>60 ml). Furthermore, the AR pressure halftimemethod, which is conventionally used to quantify theseverity of AR, is not reliable in the context of mixedaortic disease. Therefore, a peak aortic jet velocity>4 m/s and a Doppler mean gradient $40 mm Hghave been proposed as important hemodynamic cut-offs in mixed AS and AR as they not only indicate anincreased flow state of both lesions but have alsobeen shown to correlate with outcomes (4,5). At thisjuncture, patients with both moderate AS and mod-erate aortic regurgitation (AR) should be referred forintervention if the criteria for increased flow are met,namely peak aortic jet velocity >4 m/s and Dopplermean gradient $40 mm Hg, even if the aortic valvearea is >1 cm2 and pressure half-time is >200 ms.

Concomitant AR increases the end-diastolic vol-ume and stroke volume, potentially overestimating

n

the transvalvular gradient. Chronic volume overloadof the left ventricle (LV) ultimately enlarges ventric-ular size, which preconditions the LV and may have aprotective effect in patients with paravalvularAR (PAR) after TAVR (6). Additionally, the presence ofbaseline AR increases the rate of PAR afterTAVR, although the latter risk is lower with theadvent of newer-generation transcatheter heartvalves (Table 1).

PREVALENCE OF CONCOMITANT AR IN PATIENTS

UNDERGOING TAVR. Although trivial and mild ARfrequently accompany severe degenerative AS, datafrom observational studies documented a prevalenceof more than mild AR at baseline in 17% to 47% ofpatients (Table 1). Concomitant AR is frequentlyobserved in patients with bicuspid anatomy and pa-tients with rheumatic heart disease.

PERI-PROCEDURAL CHALLENGES OF CONCOMITANT AR

IN PATIENTS UNDERGOING TAVR. Relevant concomi-tant AR may complicate visualization and positioningof the transcatheter heart valve, while calcification ofthe aortic cusps facilitates anchoring within theannulus. In cases of a hyperdynamic jet, rapid ven-tricular stimulation may also be required for self-expanding valves to stabilize the prosthesis for posi-tioning and deployment.

CLINICAL IMPACT OF CONCOMITANT AR. Although theeffect of moderate or severe PAR post TAVR is wellestablished, data regarding the effect of concomitantbaseline AR on outcomes in patients undergoingTAVR for AS are limited (Table 1). A retrospectivestudy by Egbe et al. (5) found that patients withcombined moderate AR and moderate AS had worseoutcomes than did those with a single isolated

TABLE 1 Prevalence of Pre- or Post-Procedural AR in Patients Undergoing TAVR and Impact on Mortality

First Author, Year(Ref. #) n Baseline AR Post-Procedural AR Valve

Post-Procedural AR

Durationof

Follow-Up All-Cause Mortality

Baseline AR

IncreasesPAR Rate

ProtectiveEffect

Hayashida et al.,2012 (7)

400 NR Grade 2 ¼ 22.2% SAPIEN 2 yrs 28.0% (grade 0–1) vs. 40.4%(grade 2) vs. 75.0% (grade 3–4)

NR Yes

Grade 3–4 ¼ 3.0% CoreValve Median297 days

Grade $2: HR: 1.68 (95% CI: 1.21–1.44; p < 0.01)

Jerez-Valero et al.,2014 (8)

1,735 NR Grade 2 ¼ 43.9% SEV,BEV

30 days 4.3%(grade0–1)vs.4.6%(grade2)vs. 11.7% (grade 3–4)

Grade $3: OR: 2.69 (95% CI:1.34–5.38; p: 0.005)

NR Yes

Grade 3–4 ¼ 14.2% Mean 21 �17 months

21.0% (grade 0–1) vs. 27.9%(grade 2) vs. 36.0% (grade 3–4)Grade $3: HR: 1.81 (95% CI:

1.32–2.48; p < 0.001)

Van Belle et al.,2014 (9)

2,769 Grade $2 ¼ 17.1% Grade 2 ¼ 14.7%Grade 3–4 ¼ 1.1%

SAPIENCoreValve

Median306 days

Grade $2: HR: 2.43 (95% CI:1.83–3.24; p < 0.0001)

Yes Yes

Chieffo et al.,2015 (11)

1,062 Grade 2 ¼ 28.4%Grade 3 ¼ 8.9%Grade 4 ¼ 2.2%

Grade 2 ¼ 30.6%Grade 3 ¼ 2%

Grade 4 ¼ 0.3%

SAPIENCoreValve

30 days 6.1% (grade 0–1) vs. 5.7% (grade2–4); p: 0.820

Yes No

2 yrs 12.3% (grade 0–1) vs. 18.1%(grade 2–4); p: 0.032

Grade $2: HR: 2.224 (95% CI:1.517–3.259; p < 0.001)

Colli et al.,2017 (12)

1,708 Grade 2 ¼ 42%Grade 3–4 ¼ 18%

Grade 2 ¼ 31.6%Grade 3–4 ¼ 5%

SAPIEN Median821 days

23% (grade 0–1) vs. 29%(grade 2–4); p: 0.05

Grade 2: HR: 1.33 (95% CI:1.09–1.63; p: 0.012)

Grade $3: HR: 1.36 (95% CI:0.90–2.05; p < 0.001)

Yes No

Grayburn et al.,2018 (10)

386 Grade $1 ¼ 47.2% Grade $1 ¼ 42.2% CoreValve 1 yr 18.6% (grade 0) vs. 9.4%(grade $1); p: 0.008

No Yes

AR grade: 0 ¼ none, 1 ¼ trace, 2 ¼ mild, 3 ¼ moderate, 4 ¼ severe.

AR ¼ aortic regurgitation; BAR ¼ baseline aortic regurgitation; BEV ¼ balloon-expandable valve; CI ¼ confidence interval; HR ¼ hazard ratio; NR ¼ not reported; OR ¼ odds ratio; PAR ¼ post-proceduralaortic regurgitation; SEV ¼ self-expandable valve; TAVR ¼ transcatheter aortic valve replacement.

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moderate lesion, and in fact, had similar adverseoutcomes to patients with asymptomatic severe AS.

In patients with PAR after TAVR, Hayashida et al.(7) reported increased mortality among thosewithout baseline AR compared with patients withpre-existent AR. Similarly, Jerez-Valero et al. (8)reported that any worsening of the severity of AR(even by 1 grade) relative to baseline with a finalseverity of moderate to severe was a strong inde-pendent predictor of mortality. Moreover, theyshowed patients with chronic moderate or severeAR (no severity changes compared with baselineAR) had a similar mortality as compared with pa-tients with none or trace PAR at 2-year follow-up(41.0% [acute moderate-to-severe AR] vs. 26.7%[chronic moderate-to-severe AR] vs. 24.5% [none tomild AR]; hazard ratio [HR] comparing none to mildAR: 2.37; 95% confidence interval [CI]: 1.53 to 3.66;HR comparing chronic moderate-to-severe AR: 2.24;95% CI: 1.17 to 4.30) (8). Van Belle et al. (9)demonstrated that PAR $mild was associated with a

3-fold increase in mortality in patients withoutbaseline AR (HR: 2.94; 95% CI: 2.25 to 3.82) but wasnot associated with an increased mortality in pa-tients with baseline AR $mild (HR: 0.60; 95% CI:0.25 to 1.41) at 1-year follow-up. Grayburn et al. (10)reported that patients with $mild baseline AR hadimproved survival at 1 year as compared with pa-tients without baseline AR in the CoreValve USPivotal High Risk Trial (9.4% vs. 18.6%; p ¼ 0.008),and this advantage disappeared when excludingpatients with $mild PAR (12.4% vs. 18.2%;p ¼ 0.300). In contrast, Chieffo et al. (11) did notdocument a beneficial effect of $mild baseline ARin patients with $mild PAR (p ¼ 0.270). Colli et al.(12) also showed no survival advantage of baselineAR in patients with mild or moderate PAR, whereasthey demonstrated that LV dilatation in patientswith $moderate baseline AR had a protective effecton long-term survival.

Further studies are needed to investigate the pos-sibility of the protective effect of baseline AR and

TABLE 2 Prevalence of MR, Rate of Functional MR, Type of Implanted Valve, and the Association of MR and Short- and Long-Term Mortality

First Author,Year (Ref. #) n

MR($Moderate)

FunctionalMR Valve

Short-Term Mortality Long-Term Mortality

Durationof

Follow-Up

Mortality Rate(No/Mild vs.

Moderate/Severe)

Rate of MRImprovement($1 Grade)

Duration ofFollow-Up

Mortality Rate(No/Mild vs.

Moderate/Severe)

Rate of MRImprovement($1 Grade)

Leon et al.,2010(68)

179 22.2% NA SAPIEN NA NA NA 1 yr 32.3% vs. 23.7% (p ¼ NA) NA

D’Onofrioet al.,2012(69)

176 24.4% NA SAPIENCoreValve

In-hospital

3.0% vs. 9.3%(p ¼ 0.10)

18.6%(to #mild

MR)

10.4 �7.7 months

15.5% vs. 20.5% (p ¼ 0.46) 27.9%(to #mild

MR)

Toggweileret al.,2012 (26)

451 30% NA SAPIEN 30 days 7.5% vs. 14.4%(p ¼ 0.02)

61% 2 yrs 33.8% vs. 35.2% (p ¼ 0.42) 55%

Bedogniet al.,2013 (27)

1,007 33.4% 50%(approximate)

CoreValve 30 days 5.1% vs. 9.2%(p ¼ 0.01)

NA 1 yr 14.8% vs. 21.4% (p ¼ 0.01) 47%

Barbantiet al.,2013 (70)

331 19.6% NA SAPIEN 30 days 5.6% vs. 4.6%(p ¼ 0.76)

57.7% 2 yrs 32.7% vs. 37.0% (p ¼ 0.58) NA

Hutter et al.,2013 (28)

268 22.4% NA SAPIENCoreValve

30 days 9.6% vs. 13.3%(p ¼ NA)

NA 1 yr 21.2% vs. 30.2%(p ¼ 0.068)

67.7%(at 6 months)

Khawajaet al.,2014 (23)

316 19.0% 16.7%–27.6% SAPIEN 30 days NA 52.9% 1 yr 20.2% vs. 28.3% (p ¼ 0.023) NA

Kiramijyanet al.,2016 (71)

589 11.5% NA SAPIEN,CoreValve

30 days 6.5% vs. 14.7%(adjustedp ¼ 0.031)

62.5%(to #mild

MR)

1 yr 20.0% vs. 22.1% (adjusted p ¼ 0.331) 77.7%(to #mild

MR)

Boerlage-vanDijket al.,2016 (25)

375 46% ($mildMR)

92% SAPIEN,CoreValve,

30 days 5% vs. 8%(p ¼ 0.30)*

29%(to <mild

MR)

2 yrs 26% vs. 37% (p ¼ 0.003)† NA

Cortés et al.,2016 (34)

1,110 16% 37.3% SEV, BEV In-hospital

4.6% vs. 9.0%(p ¼ 0.016)†

58.2% 6 months 10.2% vs. 35.0% (p < 0.001)† NA

Mavromatiset al.,2017 (24)

11,104 36.8% NA NA 30 days 6.3% vs. 6.1% vs.7.9% vs. 11.3%(p < 0.0001)‡

79% (ofsevere MR),66% (ofmoderate

MR)

1 yr 21.0% vs. 21.5% vs. 26.3% vs. 28.0%(p < 0.001)‡

NA

Vollenbroichet al.,2017 (15)

603 24.7% 36% SEV, BEV 2 yrs 30.2% (FMR) and 32.4% (DMR) ascompared with patients with 14.6% (no

MR) (p ¼ 0.003 and < 0.001)

56% (FMR)59% (DMR)

at 1 yr

*Comparison between none or trace MR and $mild MR. †Comparison between #nonsignificant moderate MR and $significant moderate MR. ‡Comparison among no MR, mild MR, moderate MR, and severeMR.

DMR ¼ degenerative mitral regurgitation; FMR ¼ functional mitral regurgitation; MR ¼ mitral regurgitation; NA ¼ not available; other abbreviations as in Table 1.

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compensatory LV changes to better understand theircomplex interplay.

TAVR IN PATIENTS WITH AS AND

MITRAL REGURGITATION

PATHOPHYSIOLOGICAL CONSIDERATIONS. Aortic ste-nosis increases afterload, resulting in LV hypertrophyand remodeling. As the disease progresses, increasingfibrosis causes worsening LV function and cavitydilatation resulting in mitral annular dilation, leaflettethering and secondary mitral regurgitation (MR).Coexistent coronary artery disease or alternative

pathologies including primary leaflet abnormalitiescan also contribute to MR.

Elevated LV afterload in the setting of AS exacer-bates the transmitral pressure gradient for a giveneffective orifice area and increases the mitral regur-gitant volume. On transthoracic echocardiography,this may manifest with an increased area of MR jetusing color flow mapping. Therefore, adjunctive im-aging modalities such as cardiac magnetic resonance(CMR) may be used to corroborate the severity of MR.Another important consequence of an increasedregurgitant volume across the mitral valve is adecrease in forward flow across the aortic valve. This

TABLE 3 Mechanisms of MR

Functional MR Organic MR

� Ischemic heart disease� Cardiomyopathy� Myocarditis

� Degenerative change(calcification, flail leaflets)

� Rheumatic change� Endocarditis� Iatrogenic (drugs, radiation,

intracardiac intervention)� Traumatic change (raptured

papillary muscle or chord)

MR ¼ mitral regurgitation.

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low-flow state that can underestimate the degree of ASmay manifest as classical low-flow, low-gradient AS orparadoxical low-flow, low-gradient AS in the case ofpreserved LV systolic function. Dobutamine stressechocardiography might not be an effective means ofuncovering the true severity of AS in this clinicalcontext, and computed tomography determination ofaortic valve calcium may be a useful way to differen-tiate pseudosevere AS with severe MR and truly severeAS with low-flow and low-gradient (13,14).

PREVALENCE OF CONCOMITANT MR IN PATIENTS

UNDERGOING TAVR. The prevalence of concomitantsignificant MR (moderate or severe) in TAVR re-cipients ranges between 11.5% and 36.8% (Table 2).Observational data suggest that the etiology ofconcomitant MR is degenerative in two-thirds ofpatients undergoing TAVR (15).

CLINICAL IMPACT OF CONCOMITANT MR. ConcomitantMR in patients undergoing TAVR has been wellstudied, mainly focusing on the prognostic impactand the changes of severity after TAVR. Althoughconcomitant MR has been suggested to increasemortality in patients undergoing TAVR, the data areconflicting (Table 2). Recently, 2 different meta-analyses demonstrated increased short- and long-term mortality in TAVR patients with significant MR(16,17). However, there are several underlying limi-tations that make it difficult to reach a defini-tive conclusion.

First, the major limitation is the difficulty of reli-able assessment of MR by echocardiography, espe-cially in AS patients (as described previously).Although echocardiographic assessment is the goldstandard for MR, any single parameter is insufficientto grade MR, and multiple quantitative and qualita-tive parameters are recommended. Moreover, theassessment can be more difficult when AS coexistsbecause the color Doppler jet size tends to be largerand overestimates MR severity because of theincreased LV pressure in AS patients. Furthermore,

temporary changes of MR severity because of pa-tients’ hemodynamics makes this assessment morechallenging (13,18–20). For these reasons, multiplediagnostic modalities such as CMR cardiac catheteri-zation, and transesophageal echocardiographyshould be utilized in patients with AS and MR, withparticular attention given to the hemodynamic con-sequences of these valvular lesions, such as chamberenlargement and LV systolic dysfunction.

Second, the prognosis, evaluation, and manage-ment are known to be different between primary andsecondary MR (21). In most studies, etiology of MRand the effects on outcomes have not been wellstudied (Table 2). Although Kiramijyan et al. (22) re-ported similar short- and long-term survival betweensecondary and primary MR, Vollenbroich et al. (15)reported increased mortality at 30 days and at 2 yearsin primary MR as compared with secondary MR incohorts that were considerably larger than the formerstudy. Primary and secondary etiologies of MR arefurther subdivided into multiple mechanisms(Table 3), which could also contribute to a variety ofclinical courses. Moreover, in some cases, multiplemechanisms are mixed.

Third, dynamic changes of MR severity after TAVRhave also been reported and this might affect theimpact on mortality. Khawaja et al. (23) reported thatpatients who had MR deteriorated had a pooreroutcome than those with an improvement in MR (log-rank p ¼ 0.005). Furthermore, Mavromatis et al. (24)reported that patients with improved MR had similaroutcomes as patients with no or mild MR at baseline(HR: 0.98; p ¼ 0.71). There are limited data regardingthe association of incremental severity of post-procedural MR with mortality. Boerlage-van Dijket al. (25) showed numerically increased risk of mor-tality in post-procedural MR ($mild) as comparedwith none or trace MR (25% vs. 18%; p ¼ 0.07). Inprevious studies, 47% to 78% of significant MR im-proves more than 1 grade after TAVR (Table 2). On theother hand, 1% to 6.5% of significant MR and 8% to17% of #mild MR were reported to worsen after TAVR(25–28). Resolution of AS immediately reduces LVpressure, which directly improves MR severity. Sub-sequent reversed LV remodeling or regression of LVhypertrophy might also improve MR severity espe-cially in functional MR. Although several factors havebeen related to the improvement of MR (Table 4),there are conflicting results; therefore, prediction ofMR improvement is still challenging.

INTERVENTIONS FOR CONCOMITANT MR. Whensurgical aortic valve replacement is performed,concomitant mitral valve repair or replacement is

TABLE 4 Suggested Risk Factors of Persistent or Worsening MR

� Low baseline aortic gradient (24,26)� Pulmonary hypertension (26,27)� Atrial fibrillation/flutter (24–27,34)� Mitral leaflet calcification (34)� Mitral annular calcification (34)� Mitral annular diameter

(>35.5 mm) (34)

� Unenlarged left ventricularend-diastolic diameter (24,72)

� Unenlarged left ventricularend-systolic diameter (72)

� Preserved ejection fraction (73)� Self-expandable valve (74)� Organic MR (26,71)� Moderate or severe residual AR

after TAVR (25)� Deep positioning of implanted valve (75)

Abbreviations as in Tables 1 and 2.

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recommended in the presence of severe MR. If theseverity is moderate, the decision becomes case-dependent (29). There is limited evidence support-ing this strategy, and data are required to evaluatewhether double valve intervention, which is knownto be associated with increased operative mortality(30,31), is justifiable, considering the clinical impactand possibility of MR improvement after isolatedaortic valve intervention. Furthermore, in light ofemerging transcatheter interventions for mitral valverepair or replacement, surgical candidates with se-vere AS and concomitant moderate MR may be wellserved with isolated surgical aortic valve replacementand the option of future transcatheter treatmentof MR. A list of available devices for transcathetermitral repair or replacement is provided inSupplemental Table 1.

In surgical high-risk patients, it might be optimal toundergo isolated TAVR and subsequently considertranscatheter treatment of MR depending on the re-sidual severity and anatomical features. Given theshift toward TAVR, a more detailed assessment of thepossibility of MR improvement, clinical impact of MR,and anatomical features are required to decidewhether double valve intervention should be per-formed simultaneously or whether subsequentpercutaneous or surgical treatment after TAVR can beconsidered. Although open surgery may be preferablefor concomitant primary MR in operable candidates, atranscatheter approach may be favorable in thesetting of concomitant secondary MR. Moreover, thetiming of the procedure should be carefully deter-mined because the data regarding subsequent treat-ment of MR after TAVR is limited (32,33). Cortés et al.(34) reported that 14 of 1,110 patients who underwentTAVR were deemed to be potentially suitable forpercutaneous mitral valve intervention at 1 monthfollow-up. However, 12 (86%) of them had died at6 months after TAVR (34). Another study by Abdel-ghani et al. (35) found that moderate-to-severe MR atbaseline ameliorated at 30 days post-TAVR in 60% ofcases, although etiology of MR (i.e., primary vs.

functional) was not specifically assessed. Neverthe-less, additional MR improvement after 30 days wasobserved, particularly in patients who underwentcardiac remodeling. A prospective study with corelaboratory assessment of MR is required to investi-gate the optimal strategy for severe AS concomitantwith significant MR.

TAVR IN PATIENTS WITH AS AND

MITRAL STENOSIS

PATHOPHYSIOLOGICAL CONSIDERATIONS. AS andMS is generally poorly tolerated due to the signifi-cantly reduced cardiac output that frequently ac-companies these lesions. This low-flow state mayresult in an underestimation of gradients across boththe mitral and aortic valve. Akin to AS with MR,reduced flow across the aortic valve may result in anunderestimation of aortic valve stenosis and patientsmay be diagnosed with a paradoxical low-flow low-gradient AS (or classical low-flow low-gradient AS inpatients with LV systolic dysfunction). To clarify thelikelihood of severe AS in these clinical contexts,calcium scoring with MSCT should be employed. Withrespect to the concomitant mitral stenosis (MS),quantification using pressure half-time may beunreliable, and MS severity should be corroboratedusing 3-dimensional MV planimetry or a multi-parametric approach (4). It is important to note thatfrom a procedural perspective, correction of MS mayresult in pulmonary edema if the AS is not addresseddue to the sudden increase in preload in a small andhypertrophied LV.

PREVALENCE OF CONCOMITANT MS IN PATIENTS

UNDERGOING TAVR. In patients undergoing TAVR,the prevalence of concomitant MS ranges between11% and 18% (Table 5). The combination of severe MSand AS is typically a sequela of rheumatic heart dis-ease. Conversely, data from central Europe docu-mented degenerative MS in two-thirds of patientswith combined AS and MS (36).

CLINICAL IMPACT OF CONCOMITANT MS. Recently, asmall number of studies reported the prevalence ofMS and its effect on clinical outcomes in patientsundergoing TAVR (Table 5). Joseph et al. (37) re-ported that one-tenth of patients have concomitantMS, and severe MS was independently associatedwith increased mortality at 1 year, whereas nonsevereMS was not included in the Society of Thoracic Sur-geons/American College of Cardiology TranscatheterValve Therapy Registry. Similarly, a retrospectiveanalysis by Sannino et al. (38) of 928 patients whounderwent TAVR in 2 institutions demonstrated that

TABLE 5 Prevalence of MS, Etiology of MS, and the Association of MS and Short- and Long-Term Mortality

First Author,Year ((Ref. #) n MS MS Etiology

Short-Term Mortality Long-Term Mortality

Duration ofFollow-Up Mortality Rate Time Mortality Rate

Joseph et al.,2018 (37)

44,755 11.6%(severe: 2.7%)

NA In-hospital 3.9% (no) vs. 4.1% (nonsevere) vs.5.6% (severe); p ¼ 0.02

Severe MS vs. no MS: adjusted OR: 1.3(95% CI: 1.0–1.7; p ¼ 0.15)

1 yr 21.3% (no) vs. 21.0% (nonsevere) vs.24.5% (severe); p ¼ 0.093

Severe MS vs. no MS: adjusted HR: 1.2(95% CI: 1.0–1.4; p ¼ 0.046)

Asami et al.,2019 (36)

971 18.1%(moderate/severe 2.9%)

Degenerative62.5%

Rheumatic37.5%

30 days 3.5% (no MS) vs. 9.7% (any MS)Adjusted HR: 3.84 (95% CI:

2.05–7.22); p < 0.001

1 yr 12.3% (no MS) vs. 28.8% (any MS)Adjusted HR: 3.27 (95% CI:

2.28–4.68); p < 0.001

Sannino et al.,2019 (38)

928 18.2%(severe 1.9%)

NA 30 days 3.1% (no) vs. 1.4% (nonsevere) vs.5.9% (severe); p ¼ 0.390

1 yr 8.1% (no MS) vs. 8.2% (nonsevere)vs. 17.6% (severe); p ¼ 0.573

Mean follow-up ¼ 40.8� 13.9 months

Severe MS vs. no MS: adjustedHR: 2.91

(95% CI: 1.17–7.20; p ¼ 0.02)

MS ¼ mitral stenosis; other abbreviations as in Table 2.

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patients with severe MS had a 3-fold increased risk ofmortality, with no effect on mortality in those withnonsevere MS at a mean follow-up of 40.8 �13.9 months. Conversely, Asami et al. (36) reportedthat one-fifth of patients with any degree of MS wasassociated with increased risks of mortality anddisabling stroke at 1 year, despite MS being mild inthe majority of cases. The incremental risk in patientswith MS compared with patients without MS wasparticularly driven by patients with rheumatic MS.

Of note, there is an important difference inassessment methodology of MS among thesestudies. Joseph et al. (37) defined MS severity basedon site-reported mitral valve area (MVA) using var-iable methodologies potentially affecting assess-ment. Sannino et al. (38) stratified MS consistentlybased on mean mitral gradient. Moreover, theydemonstrated that severe MS failed to show anincreased risk of mortality when applying MVA forthe assessment. By contrast, Asami et al. (36) used amultiparametric approach with prioritizing planim-etry MVA over calculated MVA when assessable andthe assessment was performed in a core lab. Thisdifference in methodology might explain thestronger prognostic impact of MS in the latterstudy.

The diagnosis of MS is challenging, especially inthe presence of AS and its potential effect onpressure half-time because of impaired LV relaxa-tion. Therefore, planimetry is generally consideredas the most reliable parameter especially in rheu-matic MS assessment (13). However, when themitral valve is calcified, planimetry is limited byacoustic shadow and blooming artifact of the

calcification. Therefore, in clinical practice, a mul-tiparametric assessment is most appropriate for theassessment of MS (39).

INTERVENTION FOR CONCOMITANT MS. Concomitantmitral valve surgery is indicated for patients withMVA #1.5 cm2 when undergoing surgical aortic valvereplacement for severe AS (39). In current and futurepractice, transcatheter mitral valve interventioncombined with TAVR may also be considered asTAVR expands to lower-risk populations (40,41).Mitral balloon valvuloplasty may be appropriate inpatients with rheumatic valvular disease. Conversely,excessive calcification of the valvular apparatus andconcomitant MR may mitigate reasonable chances ofsuccess of mitral balloon valvuloplasty in patientswith degenerative mitral valve disease. Transcathetermitral valve implantation has recently evolved as analternative option when the anatomical features arenot suitable for percutaneous mitral balloon com-missurotomy (42,43), and it is already being appliedat the same time as TAVR or as a subsequent pro-cedure after TAVR (44–46). Okuno et al. (47) reportedthat mitral annular calcification is associated withsignificant mitral valve disease in half of all patients.Off-label use of transcatheter aortic valve devices inthe mitral position have been evaluated in a pooledanalysis of selected cases from 40 centers. Yoon et al.(48) showed that transcatheter heart valve implan-tation in mitral annular calcification was associatedwith a significantly increased risk of valve emboli-zation and conversion to surgery as compared withvalve-in-mitral valve (valve in valve) or valve-in-mitral ring interventions (valve-in-ring). In addition,

TABLE 6 Prevalence of TR, Change of TR Severity Over Time and Prognostic Impact of TR Following TAVR

FirstAuthor,

Year (Ref. #) nTR

($Moderate)RV

Dysfunction PHT

Changes FollowingTAVR Short-Term Long-Term Mortality Multivariate Analysis

Durationof

Follow-Up Change

Durationof

Follow-Up

Mortality(None/Trace vs.

Moderate/Severe)

Durationof

Follow-Up

Mortality(None/Trace vs.

Moderate/Severe)

Durationof

Follow-Up Results

Hutteret al.,2013(28)

268 22.4% 18.5% 34.5% (PAP>60 mm Hg)

6 months Improve:50%

Worsen:13.6%

30 days 9.6% vs. 11.2% (log-rank p ¼ 0.028)

1 yr 20.9% vs. 33.9%(log-rank p ¼ 0.028)

1 yr Not anindependentpredictor*

Barbantiet al.,2015(55)

518 15.2% NA 37.9% (PAP>60 mm Hg)

30 days Improve:15.2%Worsen:8.9%

30 days 5.7% vs. 10.1% (log-rank p ¼ 0.001)

1 yr 13.9% vs. 36.4%(log-rank p ¼ 0.001)

2 yrs Not anindependentpredictor†

Lindmanet al.,2015(49)

507 26.6% 54% Mean PAP31 mm Hg

30 days Improve:30.6%

NA NA 1 yr 16.9% vs. 17.2% vs.32.6% vs. 61.1% (none/

trace vs. mild vs.moderate vs. severe)

(p < 0.001)

1 yr Severe TR:HR: 3.20(95% CI:

1.50–6.82)‡Moderate

TR: HR: 1.60(95% CI:

1.02–2.52)‡

Schwartzet al.,2017(56)

519 11% 50% Mean systolicpulmonarypressure61.2 �

14 mm Hg

6 months Improve:58.5%

NA NA 3 yrs 30% vs. 49%(log-rank p ¼ 0.01)

Longterm

Not anindependentpredictor§

McCarthyet al.,2018(57)

34,576 24% NA Mean RVSP53.0 �

16 mm Hg

NA NA 30 days 6.5% vs. 5.4% vs.7.0% vs. 11.3% (none/

trace vs. mild vs.moderate vs. severe)

(p < 0.001)

1 yr 22.1% vs. 20.0% vs.26.5% vs. 34.2%

(none/trace vs. mild vs.moderate vs. severe)

(p < 0.001)

1 yr Severe TR:HR: 1.29(95% CI:1.11–1.50)in LVEF>30%||

Covariates included in each multivariate analysis: *Sex, age, implanted valve type, logistic EuroSCORE (European System for Cardiac Operative Risk Evaluation) and Society of Thoracic Surgeons score,moderate or greater MR, previous cardiac operation, coronary artery disease or cerebral infarction, LVEF #35%, atrial fibrillation, renal failure (creatinine >1.5 mg/dl), restrictive or obstructive pulmonarydisease, systolic PAP $60 mm Hg. †Prior pacemaker implantation, atrial fibrillation, mean transaortic gradient #40 mm Hg, renal insufficiency, age, moderate or greater MR, New York Heart Associationfunctional class III/Ⅳ, LVEF #40%, systolic PAP >60 mm Hg. ‡Age, sex, body mass index, Society of Thoracic Surgeons score, prior myocardial infarction (MI), prior coronary artery bypass grafting surgery,frailty, permanent pacemaker implantation, atrial arrhythmia, aortic valve mean gradient, LVEF, MR. §Age, sex, pacemaker and atrial fibrillation, EuroSCORE, stroke volume index, deceleration time, systolicPAP, tricuspid annular plane systolic excursion/TR grade, MR. ||Age, sex, sex-specific body surface area, hemoglobin, platelet count, estimated glomerular filtration rate, bilirubin, procedure date, race (non-Hispanic white vs. other), current dialysis, left main stenosis $50%, proximal LAD $70%, prior MI, endocarditis, prior stroke or transient ischemic attack, carotid stenosis, prior peripheral artery disease,current/recent smoker, diabetes, New York Heart Association functional class III/IV, atrial fibrillation/flutter, conduction defect, moderate/severe chronic lung disease, home oxygen, hostile chest, porcelainaorta, access site (femoral vs. other), pacemaker, previous implantable cardiac defibrillator, prior percutaneous coronary intervention, prior coronary artery bypass grafting, prior cardiac operations, prioraortic valve replacement/repair, prior mitral valve replacement/repair, valve morphology (tricuspid vs. other), aortic insufficiency (moderate/severe vs. other), acuity (elective vs. urgent vs. shock or inotropesor assist device vs. emergency or salvage or cardiac arrest), right ventricular systolic pressure >40 mm Hg, moderate or severe MR, mitral stenosis, LVEF #30%.

LAD ¼ left anterior descending coronary artery; LVEF ¼ left ventricular ejection fraction; PAP ¼ pulmonary artery pressure; RVSP ¼ right ventricular systolic pressure; TR ¼tricuspid regurgitation; otherabbreviations as in Tables 1 and 2.

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all-cause mortality was 3- to 5-fold higher in pa-tients undergoing transcatheter heart valve im-plantation in mitral annular calcification ascompared with those undergoing valve in ring orvalve-in-valve implantation, respectively (48).Because there are no data comparing these strate-gies, the decision should be case-dependent, with acomprehensive assessment of surgical risk andanatomical features.

Even mild MS might have an increased risk ofmortality, as demonstrated in the study by Asamiet al. (36), and worsened MS was reported as a rarecomplication after TAVR in patients with pre-existingimpaired transmitral flow. Therefore, careful assess-ment and follow-up of MS is required in patients withmild MS.

TAVR IN PATIENTS WITH AS AND

TRICUSPID REGURGITATION

PATHOPHYSIOLOGICAL CONSIDERATIONS. Theinterplay among tricuspid regurgitation (TR), pul-monary hypertension, and right ventricular (RV)function has been investigated in several studies(49,50). Secondary TR accounts for 90% of all severeTR and occurs predominantly as a result of LVdysfunction, MR, atrial fibrillation, and pulmonarydisease. The subsequent pulmonary hypertensionresults in a cascade of progressive sequelae on theright side of the heart, including RV dysfunction anddilation (51), annular dilatation toward the RV freewall, tricuspid leaflet tethering, and right atrialenlargement (4). In patients with severe AS,

CENTRAL ILLUSTRATION Proposed Pathway for the Treatment of Severe AS With CoexistentSecond Valvular Disease

Khan, F. et al. J Am Coll Cardiol Intv. 2020;13(13):1503–14.

(A) Patients with severe aortic stenosis (AS) with moderate or severe mitral regurgitation (MR) should be assessed for the presence of

reduced systolic function, presence of functional MR, absence of atrial fibrillation (AF), and absence of pulmonary hypertension. If this group

of criteria is fulfilled, then there is a 50% chance that the functional MR will improve post–transcatheter aortic valve replacement (TAVR), and

thus, this approach is recommended in this clinical context. In patients in whom symptomatic severe MR still persists post-TAVR, then a

subsequent percutaneous or surgical mitral intervention should be considered. In patients in whom the aforementioned group of 4 criteria

is not fulfilled, a double valve procedure is recommended (i.e., open surgical treatment in appropriate candidates or double transcatheter

intervention in nonsurgical patients). (B) In patients with severe AS with moderate or severe mitral stenosis (MS), surgical candidates should

be considered for surgical treatment of both valves, as per clinical practice guidelines, whereas nonsurgical candidates should undergo TAVR

first, followed by mitral balloon valvuloplasty or transcatheter mitral valve replacement (TMVR), depending on the anatomic features of

the MS. It should be noted that there is a 3-fold increased risk of cardiovascular death or disabling stroke at 1 year in TAVR patients with MS.

(C) Patients with severe AS and TR should be referred for TAVR provided that: 1) there is no history of AF; 2) concomitant functional MR is

present; and 3) there is preserved right ventricular (RV) function. Should there be worsening of tricuspid regurgitation (TR) with symptoms

or reduced RV function post-TAVR, then transcatheter tricuspid valve (TV) intervention or TV surgery should be considered. In cases in

which there is severe AS with greater than mild TR with: 1) right atrial dilation; 2) RV failure; and 3) AF, then the patient should be assessed

for surgical candidacy. Open treatment of both valves should be considered in surgical candidates, while a strategy of TAVR first followed by

tricuspid intervention should be considered in nonsurgical candidates. LVEF ¼ left ventricular ejection fraction.

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secondary TR may represent an advanced stage withmyocardial fibrosis and stiffness, affecting mortality(52). It should be noted that from a diagnosticperspective, thermodilution derived cardiac outputcan be erroneously low, which ultimately can resultin an underestimation of aortic valve area and over-estimation of AS severity (53).

PREVALENCE OF CONCOMITANT TR IN PATIENTS

UNDERGOING TAVR. Moderate or more TR has beendocumented in 11% to 27% of patients in observa-tional registries. Relevant TR has been associatedwith RV dysfunction in 18% to 54% of patients andwith pulmonary hypertension in 34% to 38% of pa-tients (Table 6).

CLINICAL IMPACT OF CONCOMITANT TR. Severalstudies have investigated the clinical impact ofconcomitant TR in TAVR patients (Table 6). Thesestudies, as well as a meta-analysis (54), suggest thatconcomitant TR is associated with an increased mor-tality in an unadjusted analysis. However, whenmultivariate adjustment with clinical or echocardio-graphic variables was performed, concomitant TR didnot emerge as an independent predictor of mortalityin most of the studies (28,55,56). Two studiesdemonstrated concomitant TR as an independentpredictor of mortality despite multivariable adjust-ment; however, the significance was limited in pa-tients without MR or reduced LV ejection fraction(49,57). TR may not be a direct factor of increasedmortality, but rather an important marker of under-lying disease that results in higher mortality. Thereare limited data demonstrating the efficacy of inter-vention for functional TR as a result of other cardiacconditions, and it is still unknown whether inter-vention improves clinical outcomes (58).

INTERVENTION FOR CONCOMITANT TR. When per-forming left heart valve surgery, current guidelines(13,39) recommend additional tricuspid valve surgeryfor concomitant TR because it has been shown toprevent worsening of TR and facilitates reverseremodeling of the RV and improvement of functionalstatus without increasing operative risk (59–62).Concomitant tricuspid valve surgery is indicated evenfor mild TR in the presence of tricuspid annulardilation or signs of right heart failure, as it mayworsen later after left heart valve surgery andpossibly cause poor clinical outcomes. Moreover,there is a high mortality after redo surgery for

progressive TR (63–65), thus supporting early inter-vention for concomitant mild or moderate TR. Withthe rise of TAVR, it may be reasonable to consider anadditional intervention for TR depending on theprogress of RV function and TR after TAVR. In fact, ithas been suggested that TR improves in 15% to 60%(Table 6), and normalization of RV function wasobserved in more than one-half of the patients afterTAVR (50), which seems to be better than in patientsundergoing surgical aortic valve replacement (66).

Various devices are now under preclinical andclinical evaluation for transcatheter tricuspid repair(Supplemental Table 2) (67). Further investigation isrequired to determine the efficacy and the optimaltiming of the additional intervention for concomitantTR in the TAVR patient.

CONCLUSIONS

Diagnosis of multiple valvular lesions can be chal-lenging due to changes in physiology and echocar-diographic parameters, which have been validatedfor isolated lesions. When tackling multivalvularheart disease, it is important to recognize the sumeffect of 2 or more moderate valvular lesions. LVimpairment, pulmonary hypertension, and exertionalsymptoms are clues to the cumulative effect of mul-tivalvular disease and should trigger discussionsaround earlier intervention (Central Illustration). Theuse of subtle markers of deteriorating LV functionsuch as LV strain or rising natriuretic peptides andfunctional assessments with exercise testing can allcontribute to deciphering the hemodynamic sequelaefrom multivalvular lesions. Multidisciplinary heartteam decisions can be invaluable in integrating theplethora of clinical, echocardiographic, hemody-namic, and anatomical data, upon which an optimalmanagement strategy can be planned. Prospectivestudies to assess the role of tricuspid intervention arerequired. Given the significant prevalence of coexis-tent MR with severe AS, studies to elucidate theoptimal approach to this pair of lesions in the TAVRera would also greatly help improve outcomes for ourstructural heart patients.

ADDRESS FOR CORRESPONDENCE: Dr. Thomas Pil-grim, Department of Cardiology, Inselspital, BernUniversity Hospital, University of Bern, CH-3010Bern, Switzerland. E-mail: thomas.pilgrim@insel.ch.

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KEY WORDS aortic regurgitation, mitralregurgitation, mitral stenosis, transcatheteraortic valve replacement, tricuspidregurgitation

APPENDIX For an expanded Referencessection and supplemental tables, please see theonline version of this paper.

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