Harmony Feasibility Trial - JACC: Cardiovascular Interventions

JACC: CARDIOVASCULAR INTERVENTIONS

VOL. 10, NO. 17, 2017

ª 2017 BY THE AMERICAN COLLEGE OF CARDIOLOGY FOUNDATION PUBLISHED BY ELSEVIER

ISSN 1936-8798/$36.00 http://dx.doi.org/10.1016/j.jcin.2017.05.034

Harmony Feasibility Trial Acute and Short-Term Outcomes With a Self-Expanding Transcatheter Pulmonary Valve Lisa Bergersen, MD, MPH,a Lee N. Benson, MD,b Matthew J. Gillespie, MD,c Sharon L. Cheatham, PHD,d Andrew M. Crean, MD,e,f Kan N. Hor, MD,d Eric M. Horlick, MD,e Te-Hsin Lung, PHD,g Brian T. McHenry, MS,h Mark D. Osten, MD,e Andrew J. Powell, MD,a John P. Cheatham, MDd

ABSTRACT OBJECTIVES This study sought to obtain in vivo data to confirm assumptions on device loading conditions and assess procedural feasibility, safety, and valve performance. BACKGROUND The Harmony transcatheter pulmonary valve (Medtronic, Minneapolis, Minnesota) was designed for patients with severe pulmonary regurgitation who require pulmonary valve replacement. METHODS Three sites participated in this first Food and Drug Administration–approved early feasibility study using an innovative device design to accommodate the complex anatomy of the right ventricular outflow tract. Potentially eligible patients underwent review by a screening committee to determine implant eligibility. Six-month outcomes are reported. RESULTS Between May 2013 and May 2015, 66 subjects were enrolled, and 21 were approved for implant and underwent catheterization; 20 were implanted. Catheterized patients had a median age of 25 years, were predominantly diagnosed with tetralogy of Fallot (95%), had severe pulmonary regurgitation (95%), and had trivial or mild stenosis. The device was delivered in the desired location in 19 of 20 (95%) patients. Proximal migration occurred in 1 patient during delivery system removal. Two devices were surgically explanted. Premature ventricular contractions related to the procedure were reported in 3 patients; 2 were resolved without treatment. One patient had ventricular arrhythmias that required treatment and later were resolved. At 1 month, echocardiography revealed none or trivial pulmonary regurgitation in all and a mean right ventricular outflow tract gradient of 16 8 mm Hg (range 6 to 31 mm Hg). CONCLUSIONS In this feasibility study of the Harmony transcatheter pulmonary valve device, there was high procedural success and safety, and favorable acute device performance. (J Am Coll Cardiol Intv 2017;10:1763–73) © 2017 by the American College of Cardiology Foundation.

From the aDepartment of Cardiology, Boston Children’s Hospital, Boston, Massachusetts; bDivision of Cardiology, Labatt Family Heart Center, Hospital for Sick Children, Toronto, Ontario, Canada; cDepartment of Cardiology, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania; dDepartment of Cardiology, Nationwide Children’s Hospital, Columbus, Ohio; ePeter Munk Cardiac Centre, University Health Network, Toronto General Hospital, Toronto, Ontario, Canada; fJoint Department of Medical Imaging, Toronto General Hospital, Toronto, Ontario, Canada; gCoronary and Structural Heart Clinical Department, Medtronic, Santa Rosa, California; and the hCoronary and Structural Heart Research and Innovation Department, Medtronic, Mounds View, Minnesota. The study was designed and funded by the sponsor, Medtronic (Minneapolis, Minnesota). Dr. Bergersen has served as a consultant for 480 Biomedical. Drs. Benson and Gillespie have served as consultants for Medtronic. Dr. S.L. Cheatham reports that her spouse is a consultant, proctor, and principal investigator for Medtronic. Dr. Hor has served as a consultant for Pfizer (no honoraria received in 2016), Myocardial Solution (honoraria received in 2016), Marathon Pharma (no honoraria received in 2016), and Bristol-Myers Squibb (no honoraria received in 2016). Dr. Horlick has served as a proctor and consultant for Medtronic; has served on the North American advisory board for Medtronic; and has served as a consultant for Edwards Lifesciences and St. Jude Medical. Dr. Lung and Mr. McHenry are employees and shareholders of Medtronic. Dr. Osten has served as a proctor for Medtronic. Dr. J.P. Cheatham has served as a consultant, proctor, and principal investigator for Medtronic. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Manuscript received December 19, 2016; revised manuscript received April 17, 2017, accepted May 21, 2017.

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JACC: CARDIOVASCULAR INTERVENTIONS VOL. 10, NO. 17, 2017 SEPTEMBER 11, 2017:1763–73

Harmony TPV 6-Month Outcomes

P

ABBREVIATIONS AND ACRONYMS CMR = cardiac magnetic resonance

CT = computed tomography PA = pulmonary artery PR = pulmonary regurgitation RV = right ventricle/ventricular RVOT = right ventricular outflow tract

TOF = tetralogy of Fallot TPV = transcatheter pulmonary valve

TPVR = transcatheter pulmonary valve replacement

atients with congenital heart defects

RV end-diastolic volume index $150 ml/m2 were

such as tetralogy of Fallot (TOF) often

screened for anatomic suitability. Those who met all

are left with pulmonary regurgitation

inclusion criteria and no exclusion criteria (Online

(PR) after their initial surgical repair. This

Table 1) were consented and proceeded to the next

may progress over time, requiring additional

steps of the screening process (6).

interventions to establish the pulmonary

Potentially eligible subjects underwent cardiac CT

competence necessary for improved long-

angiography to evaluate the anatomic fit and to create

term quality of life (1). Transcatheter pulmo-

a stereolithographic model of the RVOT in systole and

nary valve replacement (TPVR) is a new, less

diastole. A screening committee met bimonthly with

invasive alternative to surgery for pulmonary

the study investigators to discuss patient suitability

valve replacement (2). Recently the U.S.

for

Food and Drug Administration approved 2

informed consent (1 patient was enrolled into the

transcatheter pulmonary valves (TPVs) for

study twice, as the patient was exited following

TPVR in dysfunctional right ventricle-to-

initial screening, and subsequently re-enrolled over

pulmonary artery (RV-to-PA) conduits: the

1 year later for rescreening), and 21 were approved

Melody TPV (Medtronic, Minneapolis, Min-

for implantation of the Harmony TPV device.

nesota) and the Edwards SAPIEN XT transcatheter heart valve (Edwards Lifesciences, Irvine, California). However, these devices have limited application in off-label use within nonconduit, native right ventricular outflow tracts (RVOTs) due to the heterogeneity in anatomic shapes and sizes, leading to a need for TPV options with novel designs (3,4). The Harmony TPV (Medtronic) is a self-expandable device designed to accommodate the larger RVOTs typical in patients with native RVOTs. This device (currently available in 1 size) is being evaluated in the Study of the Native Outflow Tract Transcatheter Pulmonary Valve (NCT01762124), a Food and Drug Administration– approved early feasibility study (5) with limited enrollment. This article reports 6-month outcomes from this feasibility study.

implantation.

DEVICE

Sixty-six

DESCRIPTION. The

patients

Harmony

provided

TPV

is

a

porcine pericardial tissue valve mounted on a selfexpanding nitinol frame. The device has an outer diameter of 23.5 mm at the valved section and is approximately 55 mm in length. The TPV is treated with an alpha amino oleic acid antimineralization process to mitigate leaflet calcification, and a 0.2% glutaraldehyde sterilant (Figure 1A). The delivery system is a 25-F coil-loading catheter with an integrated sheath. The loading funnel collapses the valve to facilitate mounting on the delivery system, and the retractable sheath helps to control self-expansion of the TPV during deployment (Figure 1B). CLINICAL DATA COLLECTION. Patients will be fol-

lowed for 5 years after implantation. Data are collected by the primary investigator at each site and

SEE PAGE 1785

include transthoracic echocardiography, fluoroscopy,

METHODS

and CMR imaging assessments. These data are

STUDY DESIGN. This nonrandomized, prospective,

tronic, and all procedure-related and follow-up

multicenter, early feasibility study was conducted at 3 centers (Boston Children’s Hospital, Boston, Massachusetts; Nationwide Children’s Hospital, Colum-

entered into an online database managed by Medimaging data are mailed to the sponsor for review. A detailed schedule for pre-implant data collection and follow-up visits can be found in Online Table 2.

bus, Ohio; and the Hospital for Sick Children,

IMPLANT PROCEDURE. All selected patients under-

Toronto, Canada). The primary goal was to evaluate

went cardiac catheterization with general anesthesia

in vivo loading conditions, as demonstrated by radial

using access from the femoral vein and in most cases,

compression, linear compression, axial compression,

an additional femoral vein or right internal jugular

bending, and torsion, using post-implant computed

vein for angiographic imaging during implantation.

tomography (CT) angiography assessment. Addition-

Angiography of the RV and RVOT was performed, as

ally, clinical assessments were collected at baseline

was coronary artery imaging (aortography or selec-

and at follow-up periods of 1 month, 3 months, and 6

tive) if required.

months, and will be collected annually to 5 years.

Early in the implant experience, it was noted that

Patients with native or patch-repaired RVOTs, with

cannulating the left PA was the most stable approach

PR (classified as severe either by echocardiography or

for delivery system placement and valve deployment.

with a PR fraction $30% as measured by cardiac

Once a stable wire position was secured in the distal

magnetic resonance [CMR] imaging), and who were

left lower lobe PA with a Lunderquist wire (Cook

either symptomatic secondary to the PR or who had a

Medical, Bloomington, Indiana), the delivery system

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was advanced to the PA. Deployment of the valve began in the proximal left PA by retracting the sheath

F I G U R E 1 Harmony Transcatheter Pulmonary Valve Device and Delivery System

and gradually exposing each strut until the valve was fully deployed in the main PA, whereas the most proximal strut was deployed into the distal RVOT. Once fully unsheathed in the RVOT, the valve was released from the delivery system with counterclockwise rotation of the delivery handle, allowing the coil loading system to release the frame. The delivery system was then withdrawn carefully to minimize the potential for entanglement with and dislodgement of the implant. This process was more difficult than originally expected, which will be discussed more thoroughly in the Discussion section. ECHOCARDIOGRAPHY. For 2-dimensional imaging of

the Harmony TPV, images were obtained from the parasternal long and short axis views of the RVOT or, if not feasible, the apical or subcostal positions. PR was assessed with color Doppler as none, trace or trivial, mild, moderate, or severe. Continuous wave and color Doppler were used to measure Doppler velocities across the RVOT and tricuspid regurgitation, which was graded as none, trace or trivial, mild, moderate, or severe (Online Table 3). In 1 implanting center, intracardiac echocardiography was used after implant for assessment of PR and the presence of a paravalvular leak. CMR. All CMR studies were performed as part of

routine clinical care using standard CMR imaging protocol for TOF patients, which includes balanced steady-state free precession cine images, phase contrast of the aorta and PA, and post-contrast 3-dimensional

magnetic

resonance

angiography

(A) This porcine pericardial tissue valve is mounted on a self-expanding nitinol frame. It has an outer diameter of 23.5 mm at the valved section and is approximately 55 mm long. The outflow diameter is 34 mm and the inflow diameter is 42 mm. The valve is treated with an alpha amino oleic acid antimineralization process to mitigate leaflet calcification and is

images. The end-diastolic volume, end-systolic vol-

sterilized with a 0.2% glutaraldehyde sterilant. ªMedtronic 2017 (B) The delivery system is

ume, and ejection fraction were obtained from cine

a 25-F coil-loading catheter with an integrated sheath. The loading funnel collapses the valve

images. Aortic and pulmonary regurgitant fractions were calculated from phase contrast flow curves. Pre-

to facilitate mounting on the delivery system, and the retractable sheath helps to control selfexpansion of the valve during deployment.

implant cross-sectional measurements were obtained from 3-dimensional post-contrast magnetic resonance angiography images at multiple levels (RVOT, subvalve, midvalve, supravalve, midtrunk and pre-

radial, linear, and axial compression) for primary

bifurcation) as well as length of the RVOT (from the

endpoint assessment of device performance. The

RVOT to the pre-bifurcation) to determine enrollment

loading conditions data will be used as inputs to

eligibility and before performance of CT angiography

further testing of the current Harmony TPV, and for

scans.

further device development.

CT ANGIOGRAPHY. All baseline CT images were ob-

RADIOGRAPHY. Biplane cinefluoroscopy was used as

tained using a dual-source, multidetector CT scanner

the imaging modality in follow-up. Satisfactory views

(SOMATOM

Malvern,

of the valve included those at implant and a “down-

Pennsylvania). Pre-implant scans were used to char-

the-barrel” view (from the proximal opening to the

acterize

stereolithographic

distal opening of the implant). Radiographic assess-

models (6). A CT scan following the same protocol

ment of potential stent fractures were classified as

was performed within 4 days after implant to assess

type I, II, or III following the Nordmeyer et al. (7)

device loading conditions (bending, torsion, and

classification system used for the Melody TPV.

Definition

anatomy

and

Flash, create

Siemens,

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T A B L E 1 Baseline Characteristics in Catheterized Patients

(N ¼ 21)

Male

11 (52)

Age, yrs

CLINICAL EVENTS COMMITTEE AND DATA SAFETY AND MONITORING BOARD. A joint Clinical Events

Committee and Data Safety and Monitoring Board consisted of 2 cardiologists and 1 cardiothoracic sur-

10–19 yrs

9 (43)

geon, independent of Medtronic, and the study in-

20–29 yrs

2 (10)

vestigators. The Clinical Events Committee and Data

30þ yrs

10 (48)

Safety

Weight, kg

72 24

adverse events and conducted periodic reviews of

Height, cm

166 12

Calculated BSA, m2

1.8 0.3

data related to safety, data integrity, and the overall

Original diagnosis TOF with pulmonary stenosis Dysplastic pulmonary valve

reviewed

serious

conduct of the trial. STATISTICAL ANALYSIS. Categorical variables are

summarized by frequency, and continuous variables

19 (91)

Non-TAP

2 (10)

PR by echocardiography

Mean RVOT gradient by echocardiography, mm Hg

Board

1 (5)

Augmented RVOT/TAP

Severe

Monitoring

20 (95)

RVOT type

Moderate

and

1 (5) 20 (95)

are presented as mean SD. Outcome results are reported only for the patients who underwent implantation.

RESULTS

11 5

Sixty-six subjects underwent CT angiography evalu-

CMR (n ¼ 15) 46 8 (32, 59)

ation and 21 patients were approved for implant of the

159 34 (107, 241)

Harmony TPV device. Of 21 patients, 52% were men

RV ejection fraction, %

51 7 (41, 66) 54 11 (30, 69)

with a mean age of 28 14 years. Most were diagnosed

LV ejection fraction, %

PR, % RV end-diastolic volume index, ml/m2

Values are n (%) or mean SD (minimum, maximum). BSA ¼ body surface area; CMR ¼ cardiac magnetic resonance; LV ¼ left ventricular; PR ¼ pulmonary regurgitation; RV ¼ right ventricular; RVOT ¼ right ventricular outflow tract; TAP ¼ transannular patch; TOF ¼ tetralogy of Fallot.

with TOF (n ¼ 20) and had augmented RVOTs or transannular patch repairs (n ¼ 19). Twenty patients had severe PR by echocardiography with minimal RVOT

obstruction

(mean

RVOT

gradient

11

5 mm Hg). Baseline CMR images showed all patients

F I G U R E 2 Patient Disposition

Twenty-one patients were approved for attempted implant of the study device, and 20 received the Harmony transcatheter pulmonary valve. Mean age was 28 years, and most were diagnosed with tetralogy of Fallot and had augmented right ventricular outflow tracts or transannular patch repairs. 1One patient was enrolled into the study twice, as the patient was exited following initial screening and subsequently re-enrolled over 1 year later for rescreening.

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T A B L E 3 Hemodynamic Pressure Data at Catheterization

F I G U R E 3 Average RVOT/MPA Perimeter

Pre-Implant (mm Hg)

Hemodynamics

RA mean (n ¼ 16) RV systolic (n ¼ 20)

Post-Implant (mm Hg)

Change Between Pre- and Post-Implant (mm Hg)

9 2 (6, 15)

10 3 (4, 16)

1 2 (3, 4)

33 7 (22, 50)

39 9 (24, 57)

6 8 (8, 24)

PA systolic (n ¼ 19)

26 6 (20, 39)

31 8 (21, 52)

5 5 (2, 18)

PA diastolic (n ¼ 19)

8.2 1.9 (5, 12)

15.7 4.3 (8, 25)

7.5 4.4 (0, 17)

PA mean (n ¼ 19) LV systolic (n ¼ 12) LV end-diastolic (n ¼ 12) AO systolic (n ¼ 19) RV to aortic pressure ratio (n ¼ 19)

15 3 (9, 24)

22 6 (13, 38)

7 4 (2, 14)

94 10 (82, 111)

104 14 (88, 129)

10 10 (5, 27)

12 2 (10, 15)

18 7 (10, 29)

6 6 (0, 16)

91 8 (80, 109)

101 17 (76, 143)

10 15 (12, 57)

0.37 0.08 (0.27, 0.56)

0.39 0.07 (0.26, 0.52)

0.02 0.07 (0.14, 0.15)

Values are mean SD (minimum, maximum). AO ¼ aortic; LV ¼ left ventricular; PA ¼ pulmonary arterial; RA ¼ right atrial; RV ¼ right ventricular.

of the Melody TPV) due to investigator concerns about severe PA hypertension observed at catheterization. This patient’s PA systolic pressure was 94 mm Hg compared with a mean of 33 7 mm Hg for the other 20 patients. In the 20 implanted patients, the Harmony TPV was implanted in the intended location within the RVOT. However, in 1 patient the device migrated proximally toward the RV after This plot shows perimeters at several levels along the right ventricular outflow tract (RVOT) or MPA in diastole and sys-

release and during delivery system removal. The device position was lower than desired but func-

tole, average of n ¼ 19 subject datasets. Error bars are SD at

tioned adequately (no significant PR per the primary

each level. MPA ¼ main pulmonary artery.

investigator) and was left in place. One patient had a concomitant left PA stent redilation. Before implant, angiographic data demonstrated a mean pulmonary

with reported values had a pulmonary regurgitant fraction >30%; the mean indexed RV end-diastolic volume was 159 34 ml/m 2 (range 107 to 241 ml/m2 ). Table 1 summarizes baseline characteristics for catheterized patients. Figure 2 shows a study overview flow diagram. Figure 3 shows the dynamic behavior of the RVOT anatomy before implant. Twenty of the 21 patients who underwent catheterization received a Harmony TPV. One patient, a 50-year-old patient with TOF and absent left PA, received a Melody TPV in the right PA (off-label use

annulus diameter of 25 4 mm and a mean length (RV to branch PA) of 48 9 mm (Table 2). Two patients were noted to have paravalvular leak (1 mild, 1 moderate) by intracardiac echocardiography that could not be seen on the discharge echocardiogram. Hemodynamic data before and after implantation are summarized in Table 3 and Figure 4. As expected, there was an increase in PA diastolic and mean pressure after valve placement. The mean procedural time was 129 46 min. All patients were free of device explant at 24 h, but in 1 patient the device migrated distally within 24 h. In this patient, the TPV was surgically explanted during the same hospitalization and within 48 h of

T A B L E 2 Angiographic Catheterization Data

the catheterization, and the patient was discharged 2

Narrowest dimension at intended site of implantation, mm (n ¼ 20)

22 3 (18, 29)

Narrowest dimension at distal PA, mm (n ¼ 19)

24 3 (18, 29)

tients, 17 were discharged the day after the proced-

Widest dimension at proximal PA, mm (n ¼ 18)

29 4 (22, 37)

ure, and 1 was discharged on day 3 with episodes of

Length of native RVOT from RV to branch PA, mm (n ¼ 19)

48 9 (27, 64)

Pulmonary annulus diameter, mm (n ¼ 17)

25 4 (18, 32)

days after the explant surgery. Of the remaining pa-

nonsustained ventricular tachycardia that began during the catheterization procedure and continued after the implant. This patient was transferred to the

Values are mean SD (minimum, maximum).

step-down unit, and an implantable loop recorder

PA ¼ pulmonary artery; RV ¼ right ventricle; RVOT ¼ right ventricular outflow tract.

was placed on day 2. Ventricular tachycardia was not present in follow-up. This patient did have a history

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F I G U R E 4 Pressure Gradients Before and After Implantation

As expected, there was an increase in pulmonary artery (PA) diastolic and mean pressures after valve placement. n ¼ 19 in all panels. Ao ¼ aortic; RV ¼ right ventricular.

of ventricular ectopy before referral. In the remaining

dimensional changes from 1% to 37%. Deformation of

patients only minor events related to the procedure

the TPV inflow, positioned near the native pulmonary

were noted during the implant hospitalization,

annulus, was roughly twice the deformation seen in

including bleeding controlled with manual compres-

the TPV outflow and valve-housing sections, which

sion, nausea, and musculoskeletal discomfort.

are typically within the main PA. Compared to pre-

DEVICE ASSESSMENT AFTER IMPLANT BY CT. After

implant, CT data were collected in 19 patients and demonstrated device conformation to the RVOT anatomy, with good apposition at the distal and proximal ends of the device, providing sealing and preventing migration. The central valve-housing region was generally unconstrained and not compressed

by

the

anatomy.

There

was

minimal

clinical animal evaluations, the device cyclic deformation was on average much lower in human subjects. The cyclic deformation of the implanted TPV was also significantly lower than the native anatomy deformation. Example images showing the device and its interaction with the anatomy are shown in Figure 5. FOLLOW-UP

EVALUATION. After

discharge

and

elongation or shortening of the device, with all de-

before the 1-month evaluation, 2 patients were eval-

vices having length change less than 3%. TPV cyclic

uated for mildly elevated temperatures. Both patients

deformation (change in dimensions over cardiac cy-

had normal blood work and negative blood cultures

cle) showed wide patient-to-patient variation, with

and did not require readmission.

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F I G U R E 5 Rendered Images of Anatomy and Device From Computed Tomography Images

Post-implant imaging demonstrated device conformation to the right ventricular outflow tract anatomy with the distal and proximal ends of the device providing sealing, thus preventing migration. The central valve-housing region was generally unconstrained and not compressed by the anatomy.

F I G U R E 6 Angiogram of Explanted Device

At the 1-month follow-up visit, 18 of the remaining 19 patients were asymptomatic. One patient complained of persistent fatigue and exercise intolerance. Transthoracic

echocardiography

indicated

an

increased RVOT gradient, and fluoroscopy demonstrated a type II stent fracture with associated partial frame collapse. These findings were confirmed at cardiac catheterization (Figure 6). The device was surgically explanted during the same visit, and the patient recovered without complications. Of the remaining 18 patients at the 1-month follow-up, PR was either not present or trace or trivial, and the average peak or mean RVOT gradient was 28 14 mm Hg or 16 8 mm Hg, respectively. There was 1 case of mild paravalvular leak, but the remaining

Noninvasive echocardiography of 1 patient who reported persistent fatigue and exercise intolerance at the 1-month follow-up visit indicated an increased right ventricular outflow

patients had trace to no paravalvular leak. All pa-

tract gradient, and fluoroscopy demonstrated a type II stent fracture with associated partial

tients had trivial or mild tricuspid regurgitation, with

frame collapse. These findings were confirmed at cardiac catheterization.

the exception of 1 patient with moderate tricuspid

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F I G U R E 7 Pulmonary Regurgitation Over Time

regurgitation that was stable from pre-implant findings and then graded as mild at 3- and 6-month assessment. Follow-up fluoroscopy was performed on all 18 patients. Two patients had a type I fracture (stent fracture without loss of stent integrity) identified on screening fluoroscopic imaging. All remaining 18 patients returned for both the 3- and 6-month follow-up assessments. Echocardiographic data remained consistent with those observed at the 1-month visit. Of seventeen patients with evaluable PR data, 16 continued to have none to trace or trivial PR, and 1 patient had mild PR at the 6-month visit (Figure 7). At 6 months, mean RVOT gradient was 15 6 mm Hg (Figure 8). There were 2 patients with mild paravalvular leak. Subsequent 3- and 6-month fluoroscopy demonstrated 1 new case of type I stent fracture, detected on a 6-month fluoroscopy exam. There was no change in stent fracture severity for the

Pulmonary regurgitation improved substantially after implantation; at the 6-month visit,

patient identified with a type I device fracture at the 1-

of 17 patients with evaluable PR data, 16 continued to have none to trace or trivial

month visit. Follow-up echocardiography and fluo-

pulmonary regurgitation, and 1 patient had mild pulmonary regurgitation.

roscopy data are summarized in Table 4. Based on the data collected during the 6-month visit, overall device integrity and functionality appeared to be well maintained in the 18 patients.

F I G U R E 8 RVOT Gradient Characterization

EXPLANTS AND DATA MONITORING. There were 2

explants, 1 after the implant procedure during the same hospitalization stay for nonemergent removal secondary to device migration and the other due to a type II stent fracture with loss of device structural integrity and RVOT obstruction at 1-month follow-up. The second event was classified as a serious unanticipated device-related event, leading to a halt in enrollment during Clinical Events Committee and Data Safety and Monitoring Board review. Bench testing and root cause analysis were conducted and submitted to the Food and Drug Administration for review. Screening committee evaluations thereafter included more detailed analysis and consideration of device position. However, a primary causative etiology was not determined, the device frame was not altered,

and

no

new

inclusion

criteria

were

introduced.

DISCUSSION The significance of pulmonary valve replacement procedures was not recognized until recent years, as PR is often well tolerated early after TOF repairs (8). However, severe RV dilation and PR can develop Mean RVOT gradient (mm Hg) over time depicted as mean SD (A) and the distribution

slowly over time, leading to further complications

of mean gradients (patient level) at each follow-up (B). RVOT ¼ right ventricular

later in patients’ lives (9). With this understanding,

outflow tract.

the prevalence of surgical pulmonary valve replacement has increased over the last decade, coincident

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T A B L E 4 Echocardiography and Fluoroscopy Follow-Up Data

Pre-Implant (n ¼ 20)

Discharge (n ¼ 20)

1 Month (n ¼ 18)

3 Month (n ¼ 18)

6 Month (n ¼ 18)

None

—

12 (60)

13 (72)

14 (78)

12 (71)*

Trace/trivial

—

4 (20)

5 (28)

4 (22)

4 (24)*

Mild

—

4 (20)

—

—

1 (6)*

1 (5)

—

—

—

—

19 (95)

—

—

—

— 14 (82)§

Measurement

Echocardiography Pulmonary regurgitation

Moderate Severe Paravalvular leak None

—

12 (67)†

11 (69)‡

15 (83)

Trace/trivial

—

4 (22)†

4 (25)‡

3 (17)

1 (6)§

Mild

—

1 (6)†

1 (6)‡

—

2 (12)§

Moderate

—

1 (6)†

—

—

—

Severe

—

—

—

—

—

Mean RVOT gradient, mm Hg

10 5 (4, 22)

13 5 (6, 25)

16 8 (6, 31)

15 7 (7, 32)

15 6 (9, 28)

Calculated maximum RVOT gradient by continuous wave Doppler data, mm Hg

19 8 (7, 41)

24 8 (13, 44)

28 14 (10, 61)

25 9 (12, 49)

28 9 (18, 49)

Tricuspid regurgitation —

1 (5)

—

1 (6)

—

Trace/trivial

6 (32)k

7 (35)

9 (50)

5 (28)

6 (33)

Mild

11 (58)k

12 (60)

8 (44)

12 (67)

12 (67)

2 (11)k

—

1 (6)

—

—

—

—

—

—

—

None

Moderate Severe Fluoroscopy Stent fractures Yes

—

—

2 (11)¶

1 (9)#

2 (12)**

No

—

—

17 (90)¶

10 (91)#

14 (88)**

Values are n (%) or mean SD (minimum, maximum). *n ¼ 17. †n ¼ 18. ‡n ¼ 16. §n ¼ 17. kn ¼ 19. ¶n ¼ 19 fluoroscopy with 1 patient missing echo at visit. #n ¼ 11. **n ¼ 16. RVOT ¼ right ventricular outflow tract.

with the development of alternative, less invasive

ongoing clinical trials in China and Europe and have

options such as TPVR. Currently a few patients

shown promising short-term valve performance (10).

receive off-label application of various TPVs for use in

The early clinical outcomes of the Harmony TPV

native RVOTs. Unfortunately, heterogeneity in the

demonstrate promising device performance and

morphologic characteristics of the RVOT leads to a

preservation of stent integrity in the majority

gap between patient needs and available percuta-

of cases. Compared with baseline, patients had sig-

neous technologies.

nificant improvements in PR. By the 6-month follow-

Given the need for such devices, development of

up, there were minimal changes in paravalvular leak

TPVR products is a clinical necessity. At present the

incidence, mean RVOT gradient, or tricuspid regur-

patient who requires PVR but has a large native RVOT

gitation, demonstrating preserved device function.

that is not anatomically appropriate for existing

Two patients had the Harmony TPV explanted,

commercially available percutaneous valves has

1 because of device migration within 24 h post-

limited options aside from surgery. The Harmony TPV

delivery and another because of a type II stent frac-

was developed to accommodate the TPVR needs of

ture at 1-month follow-up. In the first patient, the

this patient population. This is the only TPV device

perimeter plot analysis suggested a “borderline fit”

designed specifically for the native RVOT that has

with a small amount of interference contact in the

undergone an early feasibility clinical trial in the

RVOT during systole only, similar to the interference

United States and Canada.

contact in the distal PA during diastole only. The

The early feasibility pathway is a new and unique

Screening Committee and the implanters agreed that

opportunity to bring the Harmony TPV and other

this anatomy would provide a “learning experience.”

design concepts into clinical trial sooner. Outside the

After embolization, the importance of a larger inter-

United States, similar devices are being studied in

ference contact area of the frame in both systole and

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Bergersen et al.



diastole was recognized and was incorporated into

novel transcatheter therapy for the dysfunctional

the screening process. In the second patient, the

native RVOT.

frame fracture and infolding was unanticipated by the earlier animal studies and bench testing. After a

CONCLUSIONS

stop in implanting, the Data Safety and Monitoring Board, Clinical Events Committee, and engineers

This is the first report presenting early clinical out-

analyzed the frame and recommended a larger

comes of the early feasibility study for the Medtronic

“circumferential” contact area in the dynamic RVOT.

Harmony

An additional screening assessment was added going

valvular function at 6 months. The device was limited

forward. Two additional patients exhibited a type I

to a small group of patients due to anatomical con-

stent fracture with no significant associated symp-

straints; however, with the development of more

toms. Because of observations during removal of the

implant sizes, the Harmony TPV has the potential to

delivery system after deployment of the TPV device,

serve a larger patient population that currently lacks

a design change addressing the length and configu-

TPVR technology.

ration of the distal “carrot” tip should be considered to allow for easier removal. Furthermore, the frame of the current device has suboptimal visibility on fluoroscopy,

making

precise

positioning

more

difficult. The results of the Harmony TPV study will be analyzed for product improvement and development of additional sizes to address the broad range of RVOT anatomies and of ways to maintain or improve device integrity. In this regard, Medtronic has begun a pivotal study to further examine the safety and efficacy of the Harmony TPV (NCT02979587).

TPV,

and

results

ACKNOWLEDGMENTS Overall

indicate

study

preserved

management

for the Native Outflow Tract TPV Research Clinical Study was provided by Kristin Smith, MBA, and Kristin Boulware. Jessica Dries-Devlin, PhD, CMPP, assisted with tables and figures and ensured technical accuracy of the manuscript. All are employees of the sponsor, Medtronic. ADDRESS

FOR

CORRESPONDENCE:

Dr.

diology, Boston Children’s Hospital, Mail Code BCH 3215, 300 Longwood Avenue, Boston, Massachu-

STUDY LIMITATIONS. This early feasibility study was

limited by its small patient cohort size. A rigorous, multidisciplinary screening process was used to

setts 02115. E-mail: [email protected]. PERSPECTIVES

determine device-patient suitability, and only a small percentage of screened patients were ultimately

WHAT IS KNOWN? RVOT surgery is common in

selected for implant. This limits the generalizability

babies with congenital heart disease, with nearly 75%

population.

of patients left with severe residual PR. A specifically

Furthermore, it is not feasible for all patients to be

designed nonsurgical, transcatheter option to restore

screened with CT angiography and the creation of a

pulmonary valve competence is needed to offer

stereolithographic 3-dimensional model, as this pro-

patients an alternative to surgical pulmonary valve

cess is time consuming, costly, and increases overall

replacement.

of

the

results

to

a

wider

patient

radiation exposure. Additionally, patient enrollment was limited to 3 sites, each with an experienced catheterization cardiologist performing the procedure. This might have skewed results and led to an unrealistically high procedural success rate that may not be reflective of procedural success within the Despite these limitations, this study presents the current application of the Harmony TPV for the native after

transannular

patch

WHAT IS NEW? This first Food and Drug Administration–approved early feasibility study allowed an innovative valve design to be tested in these patients with complex right ventricular outflow tract anatomy and succeeded in restoring pulmonary valve function.

general physician population.

RVOT

repair

of

Lisa

Bergersen, Harvard Medical School, Department of Car-

TOF,

demonstrating high rates of procedural success and promising early clinical outcomes. Continual followup and a larger patient population will be needed to assess longer-term durability, function, and safety of this device design to determine its feasibility as a

WHAT IS NEXT? The important data derived from the engineering analysis, perimeter plots, and stereolithographic models in these 66 patients will allow more valves and frame designs to be manufactured to treat the majority of patients with severe PR after surgical repair of complex congenital heart disease.


Bergersen et al. Harmony TPV 6-Month Outcomes

REFERENCES 1. Frigiola A, Redington AN, Cullen S, Vogel M. Pulmonary regurgitation is an important determinant of right ventricular contractile dysfunction in patients with surgically repaired tetralogy of Fallot. Circulation 2004;110:II153–7. 2. Rosengart TK, Feldman T, Borger MA, et al. Percutaneous and minimally invasive valve procedures: a scientific statement from the American Heart Association Council on Cardiovascular Surgery and Anesthesia, Council on Clinical Cardiology, Functional Genomics and Translational Biology Interdisciplinary Working Group, and Quality of Care and Outcomes Research Interdisciplinary Working Group. Circulation 2008;117: 1750–67. 3. Malekzadeh-Milani S, Ladouceur M, Cohen S, Iserin L, Boudjemline Y. Results of transcatheter pulmonary valvulation in native or patched right ventricular outflow tracts. Arch Cardiovasc Dis 2014;107:592–8. 4. Meadows JJ, Moore PM, Berman DP, et al. Use and performance of the Melody Transcatheter

Pulmonary Valve in native and postsurgical, nonconduit right ventricular outflow tracts. Circ Cardiovasc Interv 2014;7:374–80.

8. Discigil B, Dearani JA, Puga FJ, et al. Late pulmonary valve replacement after repair of tetralogy of Fallot. J Thorac Cardiovasc Surg 2001;121:344–51.

5. Farb A, Abel D. Investigational Device Exemptions (IDEs) for Early Feasibility Medical Device Clinical Studies, Including Certain First in Human (FIH) Studies: Guidance for Industry and Food and Drug Administration Staff. 2013. Available at:

9. de Ruijter FTH, Weenink I, Hitchcock FJ, Meijboom EJ, Bennink GBWE. Right ventricular

https://www.fda.gov/downloads/medicaldevices/ deviceregulationandguidance/guidancedocuments/ ucm279103. Accessed June 28, 2016. 6. Gillespie MJ, Benson LN, Bergersen L, et al. Patient selection process for the Harmony Transcatheter Pulmonary Valve Early Feasibility Study. Am J Cardiol 2017. In press. 7. Nordmeyer J, Khambadkone S, Coats L, et al. Risk stratification, systematic classification, and anticipatory management strategies for stent fracture after percutaneous pulmonary valve implantation. Circulation 2007;115: 1392–7.

dysfunction and pulmonary valve replacement after correction of tetralogy of Fallot. Ann Thorac Surg 2002;73:1794–800. 10. Cao QL, Kenny D, Zhou D, et al. Early clinical experience with a novel self-expanding percutaneous stent-valve in the native right ventricular outflow tract. Catheter Cardiovasc Interv 2014;84: 1131–7.

KEY WORDS Harmony TPV, RVOT conduit, tetralogy of Fallot, transcatheter pulmonary valve A PP END IX For supplemental tables, please see the online version of this article.

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