Transcatheter Approaches to Pulmonary Valve Replacement

Journal Pre-proof

Transcatheter Approaches to Pulmonary Valve Replacement in

Congenital Heart Disease: Revolutionizing the Management of RVOT
Dysfunction?

Ari J. Gartenberg MD , Matthew J. Gillespie MD ,

Andrew C. Glatz MD, MSCE

PII: S1043-0679(22)00048-X
DOI: https://doi.org/10.1053/j.semtcvs.2022.02.009
Reference: YSTCS 2152

To appear in: Seminars in Thoracic and Cardiovascular Surgery

Please cite this article as: Ari J. Gartenberg MD , Matthew J. Gillespie MD ,

Andrew C. Glatz MD, MSCE , Transcatheter Approaches to Pulmonary Valve Replacement in
Congenital Heart Disease: Revolutionizing the Management of RVOT Dysfunction?, Seminars in
Thoracic and Cardiovascular Surgery (2022), doi: https://doi.org/10.1053/j.semtcvs.2022.02.009

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Transcatheter Approaches to Pulmonary Valve Replacement in Congenital Heart Disease:
Revolutionizing the Management of RVOT Dysfunction?

Short Title: Transcatheter Approaches to Pulmonary Valve Replacement

Authorship Block:
Ari J. Gartenberg, MD1, Matthew J. Gillespie, MD1, Andrew C. Glatz, MD, MSCE1
1
Division of Cardiology, Children’s Hospital of Philadelphia, Philadelphia, PA

COI Statement: Dr. Gillespie is a proctor and consultant for both Medtronic and Edwards Life
Sciences. The other authors have no conflicts of interest to declare.

Corresponding Author:
Andrew C. Glatz, MD, MSCE
Children’s Hospital of Philadelphia
3401 Civic Center Boulevard
Philadelphia, PA 19104
Phone: 215-590-1790
Email: glatz@chop.edu

1
Central Message (200 characters)

Transcatheter pulmonary valve replacement (TPVR) in congenital heart disease has rapidly

evolved over the last two decades. We present a review of current approaches to TPVR in the

native right ventricular outflow tract.

Central Picture (Legend: 90 characters): Timeline illustrating the introduction of transcatheter

pulmonary valve technologies.

2
Abstract

Transcatheter pulmonary valve (TPV) replacement has become in recent years an increasingly

utilized strategy for patients with congenital heart disease. TPVs were originally designed for

implantation only within surgically placed conduits and bioprosthetic valves (BPVs), but their

use has since expanded to include deployment within the native right ventricular outflow tract

(RVOT). In this article, we review approaches to TPV replacement in the dysfunctional native

RVOT as well as describe the spectrum of available devices and their clinical outcomes.

Advances in TPV technology have produced promising short-term clinical results, and it is

anticipated that TPV replacement will prove to be both a safe and efficacious minimally invasive

alterative to surgical therapy in a burgeoning subset of this population. Longer term studies are

needed to define the durability of this approach and the scope of its applicability in patients with

variable forms of congenital heart disease.

Introduction

Patients with congenital heart disease affecting the right ventricular outflow tract

(RVOT), such as tetralogy of Fallot, truncus arteriosus, and other conotruncal malformations

typically undergo surgical palliative procedures early in life that involve RVOT reconstruction.

Depending on the surgical approach, this often leads to severe pulmonary regurgitation or RVOT

obstruction that is detrimental to right ventricular hemodynamics by the imposition of a volume

load, pressure load, or mix of both.1 These issues were historically managed through repeat

surgical interventions to treat RVOT dysfunction, with attendant risks of associated morbidities.

The first human implant of a transcatheter pulmonary valve (TPV) was performed by Phillip

Bonhoeffer in 2000 in a 12 year old boy with a dysfunctional right ventricle to pulmonary artery

3
(RV-PA) conduit.2 Over the ensuing two decades, transcatheter approaches have become

increasingly utilized as a minimally invasive alternative to surgery for treating postoperative

RVOT dysfunction. While the original TPVs were designed to be implanted only within

surgically-placed circumferential conduits and bioprosthetic valves (BPVs), in recent years

several dedicated valves have been developed specifically for the native or surgically repaired

RVOT. In the following review, we discuss procedural considerations, techniques, and outcomes

for implantation of the available devices in the native RVOT as well as potential challenges that

this emerging technology may face as it continues to evolve. TPV replacement in circumferential

RV-PA conduits and BPVs has already been well summarized and so is not the primary focus of

this review.3-12

Preimplantation Planning

A thorough understanding and assessment of the geometry of the RVOT is necessary

prior to patient and device selection in order to optimize the chances of a successful TPV

implantation. This is especially true when considering implantation in the native RVOT, as the

radial force and compliance of the RVOT following a transannular patch repair may be markedly

different than that of a calcified homograft RV-PA conduit.12 A thorough history should be

reviewed, with attention to any potential history of infective endocarditis.

Standard echocardiography assesses ventricular function, tricuspid valve regurgitation,

the degree of right ventricular dilation and hypertrophy, and outflow tract dysfunction. Cross-

sectional imaging is essential for predicting the interactions of the deployed valve with

surrounding structures, as there is significant heterogeneity of the “landing zone” in this patient

population. This is typically accomplished through either ECG-gated computed tomography

4
angiography (CTA) or cardiac magnetic resonance imaging (CMR), with consideration of 3D

reconstructive modeling to augment the multimodality imaging review. Careful measurements of

the RVOT and branch pulmonary artery dimensions are critical components of preimplantation

screening, as an oversized RVOT or branch pulmonary artery stenosis can preclude successful

valve deployment. A pre-catheterization ultrasound assessment of vascular patency can also be

helpful to plan vascular access, although it is possible to deliver and implant the current

generation of TPVs through a variety of different venous access points.

Preprocedural evaluation for the newer self-expanding TPVs has utilized a more

extensive screening process to identify the optimal patient candidacy. The Medtronic Harmony

TPV, for example, requires an initial review of RVOT anatomy by CMR (when possible),

followed by further cross-sectional imaging by retrospectively gated CT angiography. Given the

dynamic nature of the RVOT, a perimeter plot and 3D model of the RVOT are generated in

systole and diastole to ensure adequate interference of the proximal and distal aspects of the

Harmony valve frame within the landing zone throughout the entirety of the cardiac cycle.

Finally, 3D stereolithographic models of the RVOT facilitate direct anatomic visualization and

can be used for test implantation. A similar series of preimplantation modeling procedures is

performed prior to patient selection for the Edwards Alterra Adaptive Prestent.13 With careful

pre-procedural planning, appropriate anatomic candidates can be selected prior to catheterization,

so anatomic decision-making typically does not need to be made during the procedure.

The relationship of the coronary arteries to the intended TPV implant site should be

delineated in all patients. When considering balloon expandable valves, aortic root and/or

selective coronary angiography must also be performed prior to implantation. Several risk factors

for coronary artery compression have been identified including anomalous coronary origins, a

5
measured distance of <3 mm between the coronary and the TPV landing zone, and a distance <8

mm between the valve landing zone and the chest wall.14, 15 When the coronary arteries are felt to

be potentially at risk for external compression, intraprocedural testing can be performed, which

is typically accomplished by inflating a balloon of comparable size to the anticipated final

diameter of the device while simultaneously conducting selective coronary angiography. Self-

expanding devices are thought to be less likely to cause coronary compression; however, this is

speculation at this point. Coronary compression is considered an absolute contraindication to

TPV replacement and is one prevailing reason to pursue a surgical alternative.16

In addition to delineating coronary anatomy, the proximity of other adjacent structures

including the airway and the aortic root must be defined, particularly in any patient who has

previously undergone an arterial switch or Ross operation, as there have been case reports of

iatrogenic aortopulmonary windows following transcatheter RVOT or pulmonary artery

interventions in these subpopulations.17

Transcatheter Valve Options

Medtronic Melody

The Melody valve (Medtronic, Minneapolis, MN) is a balloon expandable bovine jugular

venous valve, which was designed specifically for use in the pulmonic position and was the first

commercially available transcatheter valve for patients with congenital heart disease. Following

the initial reports of its use in 2000,2, 18 the Melody valve was subsequently studied through an

investigational device exemption (IDE) trial from 2007-2010.3 It received FDA approval under a

humanitarian device exemption (HDE) in 2010 and later premarket approval (PMA) in 2015 for

use in dysfunctional surgically placed RV-PA conduits of ≥16 mm original implant diameter.4-8,

6
19
Despite this highly specific indication for its approval, use of the Melody valve has expanded

off label to include implantation in both dysfunctional bioprosthetic pulmonary valves as well as

in the native RVOT.9, 20-22

The valve is available in two sizes: a 16 mm that can be expanded to ≤20 mm and an 18

mm that can be expanded to ≤22 mm, so larger RVOT sizes are suboptimal candidates for the

standard delivery of the Melody valve. The Melody valve is mounted by hand crimping it on to

the Ensemble delivery system (a balloon-in-balloon catheter with a retractable

polytetrafluoroethylene (PTFE) sheath) and deployed by advancing the delivery system to its

intended position in the RVOT. The delivery system has a 22 Fr crossing profile, which may be a

limiting factor in smaller children who may otherwise be candidates for this TPV system.

The safety and feasibility of deploying the Melody valve in the native RVOT was

published by Martin et al. in 2018 who reported 132 successful deployments across 11 centers,

with only 5 major complications including pre-stent embolization requiring surgery and

arrhythmia. Valve implantation was deferred most commonly either due to a prohibitively large

RVOT size or coronary compression. Most notably, the study found that although the Melody

valve was safe, screening to identify anatomically appropriate patients proved challenging, as

42% of patients were found to be poor candidates at the time of catheterization. The Melody

valve has the longest and most comprehensive follow-up of any TPV. Between the IDE, post-

approval (PAS), and post-market surveillance studies, over 300 patients were prospectively

enrolled and have since been followed.8 A comparison of the complete 5-year post-implant

follow-up data for the IDE and PAS cohorts revealed generally similar hemodynamic and time-

related outcomes.23 Ten-year follow-up data of the 150 patients in the IDE cohort were presented

in May 2020 at the annual Scientific Sessions of the Society for Cardiovascular Angiography and

7
Interventions (SCAI).24 The study demonstrated sustained long-term function of the Melody

valve with strong valve efficacy (97% with none/trace/mild pulmonary insufficiency at 10

years). 54% of patients were free from TPV dysfunction, which was defined as reoperation,

catheter reintervention, or hemodynamic dysfunction (moderate or greater pulmonary

insufficiency and/or mean RVOT gradient >40 mmHg). Importantly, when freedom from TPV

dysfunction was stratified by age, a significant difference was observed. While 65% of adults

were free of TPV dysfunction, only 47% of pediatric age patients (≤18 years) met the endpoint.

Freedom from any reintervention (surgical or transcatheter) was 61%, and freedom from all-

cause mortality was 90%. The rate of stent fracture, a notable finding on previously published

Melody valve follow-up data,8, 25 remained stable at 16% at 10 years. Long-term follow-up

outcomes of the Melody valve specific to implantation in the native RVOT have not yet been

published.

The association of the Melody valve with infective endocarditis (IE), a potentially lethal

complication of intracardiac devices, has been the subject of some debate. In a pooled analysis of

data from the three major prospective Melody valve trials in the U.S., Canada, and Europe, the

annualized rate of a first episode of IE was 2.4% per patient-year and of TPV-related IE was

0.88% per patient-year. Most cases did not involve the TPV and responded to antibiotics.26 A

more recent review of the prospective Melody valve trials in 2018 found a slightly higher

annualized incidence rate of 3.1% per patient-year and of TPV-related endocarditis of 2.4% per

patient-year.27 The 10-year Melody follow-up data reported similar annualized incidence rates of

3% for any IE and 2% TPV-related IE.24 A subsequent multicenter analysis, however, has called

into question whether these findings are intrinsically linked to the Melody valve.28 In an analysis

of an international registry of all TPVR procedures performed with the Melody valve or any

8
generation of Sapien valve, the annualized incidence of IE was 2.2% per patient-year. While a

multivariable analysis found younger age, a previous history of IE, and a higher residual gradient

to be risk factors for IE, the type of TPV interestingly was not.28 Ongoing efforts to better

understand and mitigate the potential risk of IE with TPVs will be critical to optimizing long-

term management of this growing patient population.29

Edwards Sapien

The Sapien valve (Edwards Lifesciences, Irvine, CA) is a balloon expandable bovine

pericardial tissue valve, which was initially designed for aortic valve replacement but has been

utilized off label in the pulmonary circulation since 2006.30 The initial Sapien valve (no longer

commercially available) suffered from a high incidence of para-valvular leak, which was

addressed in the S3 through the addition of a polyethylene terephthalate skirt at the base of the

valve. Currently available Sapien valves include the second generation XT, which is FDA

approved for use in dysfunctional RV-PA conduits, and the third generation S3, which is

approved for use in the aortic position. Both have been used off label in the native RVOT.12, 31-33

Currently available Sapien valves range in size from 20-29 mm diameters, which allows

for use in more dilated RVOTs not amenable to treatment with the Melody valve. Sapien valves

are deployed through transvenous access via an expandable introducer sheath (XT/NovaFlex,

S3/Commander), which has a lower profile than the Melody’s Ensemble delivery system.

Published follow-up data for the Sapien TPV are far more limited compared to available

follow-up data for the Melody valve. In 2020, Shahanavaz et al. published the largest multicenter

study to date of short-term outcomes in patients undergoing TPV replacement using either

Sapien XT or S3, noting a high technical success rate (97%) that was independent of the

9
underlying RVOT anatomy (native RVOT, conduit, and stented BPVs).33 Major adverse events

occurred in 10% of patients, most commonly valve embolization or malposition and tricuspid

valve injury. Valve embolization that warranted surgical intervention was more common

following larger-sized valve deployment in particularly dilated native RVOTs. Given the

incidence of tricuspid valve injury with the Sapien valve, several centers have adopted a

modified deployment approach with the use of a long DrySeal sheath (WL Gore and Associates,

Flagstaff, AZ) in an attempt to better protect the tricuspid valve apparatus.34

The COMPASSION trial (Clinical Trial NCT02987387) prospectively follows patients

with a dysfunctional RVOT conduit that was treated with the Sapien XT TPV. Three-year

follow-up data were reported in a total of 57 patients and demonstrated a device success rate

(defined as deployment of the valve to the target area and removal of the delivery catheter with

improvement in pulmonary insufficiency to mild or less) of 95.2%.11 Through three years of

follow-up, freedom from any reintervention was 93.7%, and freedom from all-cause mortality

was 98.4%. Two early (<30 day) valve failures were reported, one with significant valve stenosis

on the second post-procedural day thought to be due to a stuck leaflet and the other with

significant pulmonary regurgitation noted 28 days after valve implantation. Both patients

underwent successful valve-in-valve implantation. Freedom from IE was 97.1%, with an

annualized rate of 1.04% per patient year and a TPV-specific rate of 0.5% per patient year.11

The ongoing COMPASSION S3 trial (Clinical Trial NCT02744677) prospectively

follows patients with an S3 valve implanted in a dysfunctional RVOT conduit or previously

implanted valve in the pulmonic position. The one-year COMPASSION S3 results were reported

in May 2020 at the annual SCAI Scientific Sessions but have not been formally published.35 In a

total of 58 patients, the primary composite endpoint of valve dysfunction (consisting of RVOT

10
reintervention, moderate or greater pulmonary insufficiency, and mean RVOT gradient >40

mmHg) was 4.3%. At 1 year, no mortality, IE, tricuspid injury, or valve malposition was

reported. A multicenter European registry reported similar findings in 82 patients after S3

implant, with acute hemodynamic improvement and competent valve function.36 There were no

frame fractures, reinterventions, or valve-associated IE with up to 2 years of follow-up.36 Of

note, valve thrombosis was observed in two patients, which resolved with adequate

anticoagulation.

Long-term follow-up outcomes of the Sapien valve specific to implantation in the native

RVOT have not yet been published.

Medtronic Harmony

The Harmony valve (Medtronic, Minneapolis, MN), is a porcine pericardial valve housed

within a self-expanding nitinol stent. First reported by Schievano in 2010, the Harmony system

features an hourglass-shaped profile with the valve seated in the central waist, designed

explicitly to reduce the effective size of the dilated native or surgically patched RVOT.37 The

Harmony valve has evolved over three iterations with modifications implemented to allow the

device to accommodate a wider range of RVOT geometries as well as to improve frame

performance during valve implantation.13 In March 2021, the Harmony valve became the first

FDA approved device for treating the dysfunctional native RVOT in patients with congenital

heart disease.38

Currently available in two sizes (TPV 22 and TPV 25), the Harmony valve is intended to

be implanted via transvenous access through a 25 Fr delivery system with the waist seated in the

MPA between the RVOT and pulmonary artery bifurcation. As such, the device can

11
accommodate a range of RVOT and pulmonary artery dimensions. This flexibility renders the

Harmony valve potentially more suitable for patients with a dilated native RVOT in whom a

balloon expandable valve may not be feasible.

The Harmony TPV was studied in a prospective, nonrandomized, multicenter study

consisting of several phases: an early feasibility study (EFS), Pivotal trial, and continued access

study (CAS; Clinical Trial NCT02979587). The EFS included 20 patients, the Pivotal trial

included 31 patients, and the CAS included 37 patients.

Three-year follow-up data from the EFS demonstrated hemodynamic improvement

(mean RVOT gradient 15.7 ± 5.5 mmHg) and competent valve function (1 patient had a mild

paravalvular leak, 1 patient had mild pulmonary insufficiency).39 Two patients developed

significant neointimal proliferation within the stent frame requiring valve-in-valve treatment. No

stent frame fractures were identified.

The most recent publicly available outcomes for the Pivotal and CAS cohorts were

presented at the Pediatric and Congenital Interventional Cardiovascular Society Symposium in

September 2021.40 Complete 6 month data were available for 66 patients, 34 of which were

followed for over 1 year. At 6 months (n=66), 92% of patients had none/trace pulmonary

insufficiency; by 1 year of follow-up (n=31), pulmonary insufficiency was none/trace in all

patients. Paravalvular leak was similarly reported as none/trace in 93% of patients at 6 months

(n=60) and 100% at 1 year (n=30). Through 1 year, no patients required surgical RVOT repair or

device explant. There were 6 unplanned catheter reinterventions performed in 5 patients, two of

which were Melody valve-in-valve implants due to RVOT obstruction and/or severe pulmonary

insufficiency. The most commonly reported adverse events were periprocedural non-sustained

ventricular tachycardia (19%) and premature ventricular contractions (10%), although there were

12
no post-discharge ventricular arrhythmias. One patient was found to have valve thrombosis at 6

months, which was treated medically. There have been no reported cases of IE, major stent

fracture, or embolization.

Longer term results for this cohort are not yet available, but follow-up of the Pivotal and

CAS study cohorts is planned through 10 years. An additional post-approval study is also

underway with a planned 10-year follow-up period. We speculate that similar longevity will be

seen from the Harmony device on par with the Melody and Sapien valves.

Edwards Alterra Adaptive Prestent

The Alterra Adaptive Prestent (Edwards Life Sciences, Irvine, CA) is a self-expanding,

partially covered nitinol device that is designed to be used as a docking adaptor for the 29 mm

Sapien 3 transcatheter valve. It is also hourglass-shaped to function as an RVOT reducer,

comprised of covered cell inflow and open cell outflow sections that flare out to stabilize the

central waist, which serves as a rigid landing zone for the Sapien valve.41

The device is symmetrical, with inflow and outflow diameters of 40 mm. The open cell

outflow design is intended to preserve blood flow to the branch pulmonary arteries should the

device need to extend more distally. Both the Alterra prestent and valve are deployed via

transvenous access. The prestent is positioned in a proximal branch pulmonary artery through a

16 Fr Edwards eSheath then withdrawn until properly situated in the intended landing zone. The

Sapien 3 valve is then implanted via the Commander delivery system.13

The Alterra early feasibility study demonstrated that this novel two-stage approach of

prestenting followed by valve placement in the same setting was both safe and effective, with a

100% acute success rate in the prescreened subset of enrolled patients. There was no significant

13
valve dysfunction nor need for RVOT reinterventions at 6 months follow-up.42 A nonrandomized

multicenter study is ongoing to further study this device (Clinical Trial NCT03130777), but there

are no medium- or long-term outcome data available at present.

MedTech Venus P-valve

The Venus P-valve (Venus MedTech, Shanghai, China) consists of porcine pericardium

leaflets sutured on to the middle segment of a nitinol self-expanding stent, which also features

flared proximal and distal sections in an hourglass configuration designed specifically for the

dilated native RVOT. Similar to the Alterra design, the distal end of the stent features an open

cell wire frame to minimize the risk of obstructing flow to the branch pulmonary arteries.13 The

initial implantations of the Venus P-valve were performed on a compassionate use basis, as the

device was not developed or manufactured in either the FDA or CE jurisdictions.43

The diameter of the central waist that houses the valve leaflets ranges from 22 to 36 mm

(in 2 mm increments) allowing for deployment in a potentially broad range of RVOT sizes. The

valve is hand crimped to a proprietary delivery system, which varies from 19-24 Fr depending on

the size of the valve, which is advanced through transvenous access.

There have been multiple small series that have reported favorable outcomes for the

Venus P-valve with a high acute success rate. Adverse events have been relatively rare and

include a single case of infective endocarditis that was treated conservatively as well as a

relatively high rate of frame fractures (27% in the European experience), although the clinical

significance of the latter remains to be determined. Longer term outcome studies are ongoing in

Europe but results have not yet been made available.44-46

14
Future Directions

Despite significant evolutionary advances in TPV technology, challenges remain in

implementing this strategy in a widespread fashion. Within the significant heterogeneity inherent

to congenital heart disease and the range of associated surgical repairs, there exists marked

variability in the shape, size, and geometry of the RVOT. Although newer devices targeted at

reducing the effective RVOT have shown promise, relatively strict device-specific criteria must

still be fulfilled to meet eligibility for TPV replacement. Further innovation is needed to expand

the existing selection of TPV devices to accommodate a wider range of patient profiles. Smaller

sized patients who meet criteria for valve replacement are still mostly excluded from a TPV

option due to the size of their vasculature being inadequate for the relatively large delivery

systems required to deploy the transcatheter valve. As miniaturization technology continues to

advance, so does the prospect of deploying TPV devices in even smaller patients. Lower profile

devices may also be able to ameliorate other anatomic issues external to the RVOT that preclude

safe TPV deployment, such as coronary artery compression. Hybrid approaches involving

collaboration between a surgeon and interventionalist have also been described and may be able

to overcome certain limitations of an exclusively percutaneous approach.47 Short- and medium-

term outcomes data of TPV replacement, where available, have certainly shown much promise

with respect to feasibility, safety, and efficacy, but these findings are purely observational. There

are no randomized trials comparing transcatheter and surgical pulmonary valve replacements.

With the long-term durability and function of TPVs yet to be proven, larger studies with longer

follow-up are needed to confirm these preliminary findings.

15
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