DOI: 10.1161/CIRCULATIONAHA.114.013588
Clinical and Hemodynamic Outcomes Up to 7 Years After Transcatheter Pulmonary Valve Replacement in the US Melody Valve Investigational Device Exemption Trial Running title: Cheatham et al.; Transcatheter PVR Outcomes to 7 Years John P. Cheatham, MD1; William E. Hellenbrand, MD2; Evan M. Zahn, MD3; Thomas K. Jones, MD4; Darren P. Berman, MD1,5; Julie A. Vincent, MD6; Doff B. McElhinney, MD7
1
Division of Cardiology, Nationwide Children's Hospital, Ohio State University Universit ityy Sc it Scho School hool ho ol of of Medicine, Columbus, OH; 2Division of Pediatric Cardiology, Yale University, New Haven, CT; 3 Division of Cardiology, Cedars-Sinai Medical Center, Los Angeles, CA; 4Division of Card Cardiology, dio iolo logy lo gy,, Seat gy Seattle attl at tle Children’s Hospital, Univers tl University rssit ityy of Washington Sc School cho hool of Medicine, Seattle, 5 6 WA; WA; Divi Division isi sioon off Cardiology, Miami Children's Hospital, Hospital, FL; Di Division of Pediatric Cardiology Cardiology, Columbia Colu lumbia University lu Uni n ve vers rsityy Medical Medi Me dica di c l Center, ca Cent Ce nter nt er, New er N w York, Ne Yo NY; NY;; 7De Dept pt off Ca Card Cardiothoracic rdio rd ioth io thoraccic S th Surgery, urge ur g ry ry, St Stan Stanford anfo an ford fo University Un niv versiity ty Sch School chool off Med Medicine, ed dicin ne, P Palo alo A alo Alto, lto o, CA A Address Ad ddr dres esss for es for Correspondence: Coorr rres espo es pond ndence nd ce:: ce John P. Cheatham, MD Professor, Pediatrics & Internal Medicine, The Ohio State University Nationwide Children’s Hospital 700 Children’s Drive Columbus, OH 43205 Tel: 614-722-2459 Fax: 614-722-5030 E-mail: [email protected] Journal Subject Codes: Hypertension:[18] Pulmonary circulation and disease, Hypertension:[19] Valvular heart disease, Treatment:[23] Catheter-based coronary and valvular interventions:other, Cardiovascular (CV) surgery:[41] Pediatric and congenital heart disease, including cardiovascular surgery
1 Downloaded from http://circ.ahajournals.org/ at UNIVERSITY OF LEEDSPERIODICA on May 21, 2015
DOI: 10.1161/CIRCULATIONAHA.114.013588
Abstract
Background—Studies of transcatheter pulmonary valve replacement (TPVR) with the Melody valve have demonstrated good short-term outcomes, but there are no published long-term followup data. Methods and Results—The US Investigational Device Exemption trial prospectively enrolled 171 pediatric and adult patients (median 19 years) with right ventricular outflow tract (RVOT) conduit obstruction and/or regurgitation (PR). The 148 patients who received and were discharged with a TPV were followed annually according to a standardized protocol. During a median follow-up of 4.5 years (0.4-7 years), 32 patients underwent RVOT reintervention for obstruction (n=27, with stent fracture in 22), endocarditis (n=3, 2 with stenosis, 1 with PR), or RV dysfunction (n 2). Eleven patients had the TPV explanted as an initial or secondd (n=2). eintervention. Five-year freedom from reintervention and explant were 76±4% and and 92±3%. 922±3 ±3%. %. A reintervention. conduit pre-stent and lower discharge RVOT gradient were associated with longer freedom from eintervention. In tthe he 113 patients who were alive and and reintervention-free, reintervention-free ee, the follow-up gradient reintervention. med edia i n 4.55 years years after implant) impl p ant)) was unchanged from froom earlyy post-T -TPVR, and all but 1 had mild or -T (median post-TPVR, esss PR. Almost all alll patients paatiients t w ere in NYH YHA cl las a s I oorr II. II. More More or severely seeveerely y impaired imp mp pair aired baseline baseline bas se ne less were NYHA class pir i om ometry w as aassociated sssociiatted with wi h low wer llikelihood ik kelih hood ood ooff im mprrov vem emen e t in en in eexercise xeerccisee fu functi ion af fteer spirometry was lower improvement function after TPVR. Conclusions—TPVR with the Melody valve provided good hemodynamic and clinical outcomes up to 7 years after implant. Primary valve failure was rare. The main cause of TPV dysfunction was stenosis related to stent fracture, which was uncommon once pre-stenting became more widely adopted. Clinical Trial Registration Information—Clinicaltrials.gov. Identifier: NCT00740870.
Key words: pediatrics, congenital heart disease, pulmonary heart disease, tetralogy of Fallot, percutaneous pulmonary valve implantation, Melody valve
2 Downloaded from http://circ.ahajournals.org/ at UNIVERSITY OF LEEDSPERIODICA on May 21, 2015
DOI: 10.1161/CIRCULATIONAHA.114.013588
Introduction Transcatheter pulmonary valve replacement (TPVR) with the Melody valve was first performed by Bonhoeffer et al. in 2000,1 and was introduced in the US in 2007 through a prospective, multicenter Investigational Device Exemption (IDE) trial.2-4 A number of single and multicenter reports have confirmed that TPVR is technically reproducible and results in excellent acute and short-term outcomes, with reduction of right ventricular outflow tract (RVOT) obstruction, elimination of pulmonary regurgitation (PR), and clinical improvement.2-9 At a functional level, TPVR is followed by improved circulatory efficiency and ventricular strain, enhanced cardiopulmonary exercise function in some patients, and better quality of life.10-18 Although these hese and other reports helped substantiate TPVR as a valuable tool in the manag management gem emen entt of en patients with postoperative RVOT dysfunction, the lack of longer-term follow-up data remains an important imp mpor mp orta or tant ta nt limitation lim mit itat a ion in the Melody valve literature. litera ratu ra turre. To date, the studies tu studi diees with the longest di follow-up report patients Bonhoeffer’s group, series folllow-up weree a 22008 fo 0008 re repo portt ooff 15 po 1555 pa pati ients ts ffrom rom mB onnho hoef effe ef fer’’s gr fe rou oup, p, aand nd a 663-patient 3-pa pati pa t en ti nt se seri ries ri e collected which reported outcomes co oll l ec ected through th hro roughh an an Italian Ita talian registry reg egiistry ry that tha haat was waas published pu lishhedd in publ in 2013, 20113, 3 w hic re hich eporrteed ou utc tcoomess a median years post-TPVR, medi me dian di an ooff 22.3 .33 an andd 22.5 .55 year ye ear arss po post st-TPV TPV PVR R, rrespectively. espe es pect pe ctiv ct ivel ely.5,6, To aaddress el ddre dd ress re ss tthis hiss de hi defi deficiency, fici fi cien ci ency en cy, wee aanalyzed naly na lyze zed ed mid-term hemodynamic and clinical outcomes in the IDE trial patients, who were all at least 4 years out from Melody valve implant.
Methods Patients and Study Protocol The US Melody valve IDE trial was a non-randomized, prospective study sponsored by Medtronic, Inc. (Minneapolis, MN) that enrolled patients at 5 sites. The study was conducted under IDE# G050186 and was registered in ClinicalTrials.gov (Identifier: NCT00740870). The
3 Downloaded from http://circ.ahajournals.org/ at UNIVERSITY OF LEEDSPERIODICA on May 21, 2015
DOI: 10.1161/CIRCULATIONAHA.114.013588
protocol was approved by the Food and Drug Administration, and by the Institutional Review Board at each institution. The trial was initially designed to follow patients for 5 years after implant, or until explant, but was modified in 2011 to allow follow-up out to 10 years in patients who provided supplemental written informed consent. The trial design, protocols, and procedural and short-term results were described previously.2-4,14,15 Follow-up Evaluation Follow-up consisting of echocardiography, cardiopulmonary exercise testing, chest radiography, and a clinical history and exam were conducted annually, within pre-determined windows, at the implanting center, or elsewhere after 5 years if more convenient for the patient. Details of follow-up evaluation protocols were summarized previously.2-4,14,15 Radiographic icc sstudies tudi tu dies di es w were eree er performed to assess for Melody valve stent fractures (MSF), which were classified according to a previously prev vio ious usly us ly rreported e orrte ep tedd system19; stent fracture asses assessment esssm sment did not include ex examination xamination of conduit stents ten nts (i.e., pre-stents) pre--st sten ntss) placed plac pl aced ac ed at at a prior prio pr iorr procedure procced cedure (existing) (eexissti ting ng)) or ng or during dur uriing ing the the TPVR TP PVR procedure pro roceedure dure (new). testing new ew). ) The protocol ). proto oco ol for fo or coronary coro ona nary ry artery art rterry compression comprressio io on te estin st ng wa wass disc ddiscussed isccussseed in ddetail etaiil iin n a pprior riorr report. epo port rt.20 Endocarditis rt Endo En doca do card ca rdit rd itis it is was as defined def efin ined in ed and and reported rep epor orte or tedd as described te des escr crib cr ibed ib ed iin n a pr prio prior iorr re io repo report. port po rt.21 Al rt Alll data, data da ta, ta including findings on non-protocol evaluations, reinterventions, and adverse events were recorded on pre-specified case report forms and entered into the web-based data collection system maintained by the sponsor. The database was locked for this analysis on May 16, 2014. Statistical Analysis Procedural results were described previously, but, given the reported relationships between residual obstruction and adverse outcomes,4,18,21,22 a new analysis was conducted of factors associated with a higher early post-implant gradient, which included all patients in whom TPVR was attempted. Follow-up analyses only included patients discharged with a Melody valve in
4 Downloaded from http://circ.ahajournals.org/ at UNIVERSITY OF LEEDSPERIODICA on May 21, 2015
DOI: 10.1161/CIRCULATIONAHA.114.013588
place. The primary outcome was TPVR reintervention over time; secondary outcomes included Melody valve obstruction or regurgitation, functional status, exercise function, MSF (any MSF or a type II MSF, defined as compromise of stent integrity4,19), endocarditis, and any other TPVrelated adverse events. RVOT gradients were presented as the mean Doppler gradient across the conduit or valve. TPV reinterventions were categorized as dilation (angioplasty without placement of an additional stent or a new valve), TPV-in-TPV implant (placement of a second TPV within the original Melody valve),22 or explant (surgical removal of the TPV with placement of a new conduit or valve). According to the protocol, patients were removed from the trial at the time of death, TPV explant, or designation as lost to follow-up. Freedom-from-event estimates and curves were generated using the Kapla ann-Me Meie Me ierr ie Kaplan-Meier method, and were presented as rate ± standardd error, which was determined by Greenwood’s meth hod od.. Fa Fact ctor ct o s as ssociated with shorter freedom m fr fro om events were asse esssed by Cox regression, method. Factors associated from assessed w ith h variables ssignificant ignnifi ig fica fi c nt tto ca o pp0.05 0.05 05 onn univariable univ ivar ariiablee analysis ar anal alyysis al ysis considered con onsi s der si ered ed for foor inclusion inc nclu nc lusi lu sion si on inn a fo forw rwar rw ard ar with forward tep epw wise multivariable mul ulti ul t vaariiablee model. modeel. Additional A di Ad diti t onnal details deetaails concerning conceern rnin ng these thesse analyses th an nalys yses aare ys ree pre eseenteed in th he stepwise presented the Su S upp pple pp leme le ment me ntar nt ary Ma ar Mate teri te rial ri al. To iillustrate al llus ll ustr str trat atee a hy at hhypothetical ypo poth po thet th etiica et call sc scen enar en ario ar io iin n whic wh hic ichh te tech chno ch nolo no logy lo gy aand nd ppractices ract ra ctic ct ices ic es Supplementary Material. scenario which technology allow prevention of major MSF, freedom from TPV reintervention was also estimated for the cohort of patients who did not develop a type II MSF. Hazard ratios (HR) were presented with 95% confidence intervals (CI). The Wilcoxon rank sum test was used to compare continuous data between groups and the signed-rank test was used to evaluate the change in continuous paired data. For selected analyses, continuous variable (e.g., RVOT gradients and the angiographic:nominal conduit diameter ratio) were dichotomized, with threshold values within a reasonable clinical range were determined using receiver operating characteristic curves. Categorical variables were compared
5 Downloaded from http://circ.ahajournals.org/ at UNIVERSITY OF LEEDSPERIODICA on May 21, 2015
DOI: 10.1161/CIRCULATIONAHA.114.013588
between groups using chi-square analysis or Fisher’s exact test. Exploratory multiple linear regression analysis was performed to evaluate factors associated with a higher post-TPVR RVOT gradient. Data were presented as median (minimum-maximum) or frequency (%). The authors had full access to and take full responsibility for the integrity of the data. All authors read and agreed to the manuscript as written.
Results Patients and Procedural Outcomes The US IDE trial enrolled 171 patients with postoperative right ventricular outflow tract (RVOT) conduit dysfunction from January 2007 through January 2010. Of these, 167 und der erwe went we nt underwent catheterization, and 150 had a Melody valve implanted (Figure 1), which was deployed in the ntend nded nd ed location loc ocat a ionn in i all cases. The cohort was almost alm lm mos ost evenly divided between bet etw et ween pediatric patients intended agee 18 years)) an aand d ad adul ults ul ts,, an ts nd th ther erre we w ere sseveral ev verall nnotable otab able ab le ddiagnostic iagn ia gnos osti os ticc di ti diff feren en nce cess be betw twee tw eenn th ee thes esee es (age adults, and there were differences between these po opu pula l tionss (Table (Ta T ble 1) ). populations 1). As ddescribed escr es crib cr ibed ib ed ppreviously, revi re viou iousl sly,2,3, 1 ppatient sl atie at ient ie nt hhad ad eemergent merg me rgen rg entt pu en ppulmonary ulm lmon lm onar on ary valv ar va valve alvee re repl replacement plac pl acem ac emen em entt fo en forr conduit rupture after TPVR and 1 died of cerebral hemorrhage after a course complicated by coronary artery dissection before Melody valve implant and subsequent mechanical circulatory support. The remaining 148 patients were discharged with the valve in place and constitute the study cohort. Acute Hemodynamic Results TPVR provided a competent pulmonary valve in all patients: on the discharge echocardiogram, PR was absent or trivial in 140 patients and mild in 5 (valve not visualized in 3), which was a significant improvement from pre-implant, when 79% of patients had moderate (n=45) or severe
6 Downloaded from http://circ.ahajournals.org/ at UNIVERSITY OF LEEDSPERIODICA on May 21, 2015
DOI: 10.1161/CIRCULATIONAHA.114.013588
(n=69) PR and 9% (n=14) had trivial or no PR (p25mmHg (n=17, 12%). Diagnostic and procedural factors associated with a higher discharge gradient are summarized in Table 2. On multivariable linear regression, a pre-implant mean RVOT gradient >35mmHg and absence of a new pre-stent were associated with higher discharge gradient, but provided only modest explanatory power (model R2=0.08, p25mmHg, and preimplant moderate/severe TR (Table 4). There were several notable interactions between conduit stenting and pre-- an andd po post st-st postTPVR RVOT gradients. The longest freedom from Melody valve reintervention was in patients whoo re rece ceiv ce ived iv ed a nnew ew w pre-stent or who did not rece ceiv ce ivee a new pre-stent bu iv ut ha hhad d a pre-implant mean received receive but D opppler gradient grad dieent 20mmHg shortest ein inte terv te rven enti en tion ti on ((HR HR 33.8 .88 [[1.7-8.7], 1.77-88.7] 7], pp=0.002). 7] =00.00 002) 00 2). Pa 2) Pati tien ti ents en ts wit ithh no nnew it ew ppre-stent, ew re-st sten st entt, a ppre-implant en re-imp imp mpla lant la nt ggradient radi ra dien di en n reintervention Patients with 35 mmHg, and a discharge gradient 20mmHg were intermediate (HR 2.6 [1.1-6.5], p=0.035 vs new pre-stent group). Freedom from RVOT reintervention in the cohort of patients who did not develop a type II MSF was 98±1% at 3 years and 91±3% at 5 years, and was shorter in those with a higher discharge RVOT gradient (HR 2.6 per 10mmHg [1.1-6.3], p=0.03). Transcatheter Melody Valve Reintervention Twenty-five patients underwent transcatheter TPV reintervention, only 3 of whom had a new pre-stent placed before the original Melody valve implant. In 6 of these patients, the initial
8 Downloaded from http://circ.ahajournals.org/ at UNIVERSITY OF LEEDSPERIODICA on May 21, 2015
DOI: 10.1161/CIRCULATIONAHA.114.013588
reintervention was redilation of the Melody valve. Five of these patients had the valve implanted on the smallest size (18mm) delivery system, 14 were among the first 50 implants overall and the first 10 at a given center, and all had relatively high residual gradients early after TPVR, with a mean Doppler gradient on the discharge echocardiogram >20 mmHg in all but 1. A MSF was diagnosed before the redilation in only 2 of these 6 patients. The initial reintervention was a TPV-in-TPV implant in 19 patients. Including 1 other patient whose first reintervention was TPV dilation, 20 patients ultimately underwent implantation of a second Melody valve for TPV dysfunction, which consisted of RVOT obstruction associated with MSF in all cases. All patients who underwent TPV-in-TPV implant had 1 (n=1) or more (2 in 14, 3 in 5) pre-stents placed prior to implantation of thee ssecond econ ec ondd Me on Melo lody lo Melody valve. After the second TPVR, the mean Doppler gradient fell in all patients, from 40mmHg (2072mm mmHg mm Hg)) to 17mmHg Hg 17m mmH m g (8-37mmHg) (p
Clinical and Hemodynamic Outcomes Up to 7 Years After Transcatheter Pulmonary Valve Replacement in the US Melody Valve Investigational Device Exemption Trial Running title: Cheatham et al.; Transcatheter PVR Outcomes to 7 Years John P. Cheatham, MD1; William E. Hellenbrand, MD2; Evan M. Zahn, MD3; Thomas K. Jones, MD4; Darren P. Berman, MD1,5; Julie A. Vincent, MD6; Doff B. McElhinney, MD7
1
Division of Cardiology, Nationwide Children's Hospital, Ohio State University Universit ityy Sc it Scho School hool ho ol of of Medicine, Columbus, OH; 2Division of Pediatric Cardiology, Yale University, New Haven, CT; 3 Division of Cardiology, Cedars-Sinai Medical Center, Los Angeles, CA; 4Division of Card Cardiology, dio iolo logy lo gy,, Seat gy Seattle attl at tle Children’s Hospital, Univers tl University rssit ityy of Washington Sc School cho hool of Medicine, Seattle, 5 6 WA; WA; Divi Division isi sioon off Cardiology, Miami Children's Hospital, Hospital, FL; Di Division of Pediatric Cardiology Cardiology, Columbia Colu lumbia University lu Uni n ve vers rsityy Medical Medi Me dica di c l Center, ca Cent Ce nter nt er, New er N w York, Ne Yo NY; NY;; 7De Dept pt off Ca Card Cardiothoracic rdio rd ioth io thoraccic S th Surgery, urge ur g ry ry, St Stan Stanford anfo an ford fo University Un niv versiity ty Sch School chool off Med Medicine, ed dicin ne, P Palo alo A alo Alto, lto o, CA A Address Ad ddr dres esss for es for Correspondence: Coorr rres espo es pond ndence nd ce:: ce John P. Cheatham, MD Professor, Pediatrics & Internal Medicine, The Ohio State University Nationwide Children’s Hospital 700 Children’s Drive Columbus, OH 43205 Tel: 614-722-2459 Fax: 614-722-5030 E-mail: [email protected] Journal Subject Codes: Hypertension:[18] Pulmonary circulation and disease, Hypertension:[19] Valvular heart disease, Treatment:[23] Catheter-based coronary and valvular interventions:other, Cardiovascular (CV) surgery:[41] Pediatric and congenital heart disease, including cardiovascular surgery
1 Downloaded from http://circ.ahajournals.org/ at UNIVERSITY OF LEEDSPERIODICA on May 21, 2015
DOI: 10.1161/CIRCULATIONAHA.114.013588
Abstract
Background—Studies of transcatheter pulmonary valve replacement (TPVR) with the Melody valve have demonstrated good short-term outcomes, but there are no published long-term followup data. Methods and Results—The US Investigational Device Exemption trial prospectively enrolled 171 pediatric and adult patients (median 19 years) with right ventricular outflow tract (RVOT) conduit obstruction and/or regurgitation (PR). The 148 patients who received and were discharged with a TPV were followed annually according to a standardized protocol. During a median follow-up of 4.5 years (0.4-7 years), 32 patients underwent RVOT reintervention for obstruction (n=27, with stent fracture in 22), endocarditis (n=3, 2 with stenosis, 1 with PR), or RV dysfunction (n 2). Eleven patients had the TPV explanted as an initial or secondd (n=2). eintervention. Five-year freedom from reintervention and explant were 76±4% and and 92±3%. 922±3 ±3%. %. A reintervention. conduit pre-stent and lower discharge RVOT gradient were associated with longer freedom from eintervention. In tthe he 113 patients who were alive and and reintervention-free, reintervention-free ee, the follow-up gradient reintervention. med edia i n 4.55 years years after implant) impl p ant)) was unchanged from froom earlyy post-T -TPVR, and all but 1 had mild or -T (median post-TPVR, esss PR. Almost all alll patients paatiients t w ere in NYH YHA cl las a s I oorr II. II. More More or severely seeveerely y impaired imp mp pair aired baseline baseline bas se ne less were NYHA class pir i om ometry w as aassociated sssociiatted with wi h low wer llikelihood ik kelih hood ood ooff im mprrov vem emen e t in en in eexercise xeerccisee fu functi ion af fteer spirometry was lower improvement function after TPVR. Conclusions—TPVR with the Melody valve provided good hemodynamic and clinical outcomes up to 7 years after implant. Primary valve failure was rare. The main cause of TPV dysfunction was stenosis related to stent fracture, which was uncommon once pre-stenting became more widely adopted. Clinical Trial Registration Information—Clinicaltrials.gov. Identifier: NCT00740870.
Key words: pediatrics, congenital heart disease, pulmonary heart disease, tetralogy of Fallot, percutaneous pulmonary valve implantation, Melody valve
2 Downloaded from http://circ.ahajournals.org/ at UNIVERSITY OF LEEDSPERIODICA on May 21, 2015
DOI: 10.1161/CIRCULATIONAHA.114.013588
Introduction Transcatheter pulmonary valve replacement (TPVR) with the Melody valve was first performed by Bonhoeffer et al. in 2000,1 and was introduced in the US in 2007 through a prospective, multicenter Investigational Device Exemption (IDE) trial.2-4 A number of single and multicenter reports have confirmed that TPVR is technically reproducible and results in excellent acute and short-term outcomes, with reduction of right ventricular outflow tract (RVOT) obstruction, elimination of pulmonary regurgitation (PR), and clinical improvement.2-9 At a functional level, TPVR is followed by improved circulatory efficiency and ventricular strain, enhanced cardiopulmonary exercise function in some patients, and better quality of life.10-18 Although these hese and other reports helped substantiate TPVR as a valuable tool in the manag management gem emen entt of en patients with postoperative RVOT dysfunction, the lack of longer-term follow-up data remains an important imp mpor mp orta or tant ta nt limitation lim mit itat a ion in the Melody valve literature. litera ratu ra turre. To date, the studies tu studi diees with the longest di follow-up report patients Bonhoeffer’s group, series folllow-up weree a 22008 fo 0008 re repo portt ooff 15 po 1555 pa pati ients ts ffrom rom mB onnho hoef effe ef fer’’s gr fe rou oup, p, aand nd a 663-patient 3-pa pati pa t en ti nt se seri ries ri e collected which reported outcomes co oll l ec ected through th hro roughh an an Italian Ita talian registry reg egiistry ry that tha haat was waas published pu lishhedd in publ in 2013, 20113, 3 w hic re hich eporrteed ou utc tcoomess a median years post-TPVR, medi me dian di an ooff 22.3 .33 an andd 22.5 .55 year ye ear arss po post st-TPV TPV PVR R, rrespectively. espe es pect pe ctiv ct ivel ely.5,6, To aaddress el ddre dd ress re ss tthis hiss de hi defi deficiency, fici fi cien ci ency en cy, wee aanalyzed naly na lyze zed ed mid-term hemodynamic and clinical outcomes in the IDE trial patients, who were all at least 4 years out from Melody valve implant.
Methods Patients and Study Protocol The US Melody valve IDE trial was a non-randomized, prospective study sponsored by Medtronic, Inc. (Minneapolis, MN) that enrolled patients at 5 sites. The study was conducted under IDE# G050186 and was registered in ClinicalTrials.gov (Identifier: NCT00740870). The
3 Downloaded from http://circ.ahajournals.org/ at UNIVERSITY OF LEEDSPERIODICA on May 21, 2015
DOI: 10.1161/CIRCULATIONAHA.114.013588
protocol was approved by the Food and Drug Administration, and by the Institutional Review Board at each institution. The trial was initially designed to follow patients for 5 years after implant, or until explant, but was modified in 2011 to allow follow-up out to 10 years in patients who provided supplemental written informed consent. The trial design, protocols, and procedural and short-term results were described previously.2-4,14,15 Follow-up Evaluation Follow-up consisting of echocardiography, cardiopulmonary exercise testing, chest radiography, and a clinical history and exam were conducted annually, within pre-determined windows, at the implanting center, or elsewhere after 5 years if more convenient for the patient. Details of follow-up evaluation protocols were summarized previously.2-4,14,15 Radiographic icc sstudies tudi tu dies di es w were eree er performed to assess for Melody valve stent fractures (MSF), which were classified according to a previously prev vio ious usly us ly rreported e orrte ep tedd system19; stent fracture asses assessment esssm sment did not include ex examination xamination of conduit stents ten nts (i.e., pre-stents) pre--st sten ntss) placed plac pl aced ac ed at at a prior prio pr iorr procedure procced cedure (existing) (eexissti ting ng)) or ng or during dur uriing ing the the TPVR TP PVR procedure pro roceedure dure (new). testing new ew). ) The protocol ). proto oco ol for fo or coronary coro ona nary ry artery art rterry compression comprressio io on te estin st ng wa wass disc ddiscussed isccussseed in ddetail etaiil iin n a pprior riorr report. epo port rt.20 Endocarditis rt Endo En doca do card ca rdit rd itis it is was as defined def efin ined in ed and and reported rep epor orte or tedd as described te des escr crib cr ibed ib ed iin n a pr prio prior iorr re io repo report. port po rt.21 Al rt Alll data, data da ta, ta including findings on non-protocol evaluations, reinterventions, and adverse events were recorded on pre-specified case report forms and entered into the web-based data collection system maintained by the sponsor. The database was locked for this analysis on May 16, 2014. Statistical Analysis Procedural results were described previously, but, given the reported relationships between residual obstruction and adverse outcomes,4,18,21,22 a new analysis was conducted of factors associated with a higher early post-implant gradient, which included all patients in whom TPVR was attempted. Follow-up analyses only included patients discharged with a Melody valve in
4 Downloaded from http://circ.ahajournals.org/ at UNIVERSITY OF LEEDSPERIODICA on May 21, 2015
DOI: 10.1161/CIRCULATIONAHA.114.013588
place. The primary outcome was TPVR reintervention over time; secondary outcomes included Melody valve obstruction or regurgitation, functional status, exercise function, MSF (any MSF or a type II MSF, defined as compromise of stent integrity4,19), endocarditis, and any other TPVrelated adverse events. RVOT gradients were presented as the mean Doppler gradient across the conduit or valve. TPV reinterventions were categorized as dilation (angioplasty without placement of an additional stent or a new valve), TPV-in-TPV implant (placement of a second TPV within the original Melody valve),22 or explant (surgical removal of the TPV with placement of a new conduit or valve). According to the protocol, patients were removed from the trial at the time of death, TPV explant, or designation as lost to follow-up. Freedom-from-event estimates and curves were generated using the Kapla ann-Me Meie Me ierr ie Kaplan-Meier method, and were presented as rate ± standardd error, which was determined by Greenwood’s meth hod od.. Fa Fact ctor ct o s as ssociated with shorter freedom m fr fro om events were asse esssed by Cox regression, method. Factors associated from assessed w ith h variables ssignificant ignnifi ig fica fi c nt tto ca o pp0.05 0.05 05 onn univariable univ ivar ariiablee analysis ar anal alyysis al ysis considered con onsi s der si ered ed for foor inclusion inc nclu nc lusi lu sion si on inn a fo forw rwar rw ard ar with forward tep epw wise multivariable mul ulti ul t vaariiablee model. modeel. Additional A di Ad diti t onnal details deetaails concerning conceern rnin ng these thesse analyses th an nalys yses aare ys ree pre eseenteed in th he stepwise presented the Su S upp pple pp leme le ment me ntar nt ary Ma ar Mate teri te rial ri al. To iillustrate al llus ll ustr str trat atee a hy at hhypothetical ypo poth po thet th etiica et call sc scen enar en ario ar io iin n whic wh hic ichh te tech chno ch nolo no logy lo gy aand nd ppractices ract ra ctic ct ices ic es Supplementary Material. scenario which technology allow prevention of major MSF, freedom from TPV reintervention was also estimated for the cohort of patients who did not develop a type II MSF. Hazard ratios (HR) were presented with 95% confidence intervals (CI). The Wilcoxon rank sum test was used to compare continuous data between groups and the signed-rank test was used to evaluate the change in continuous paired data. For selected analyses, continuous variable (e.g., RVOT gradients and the angiographic:nominal conduit diameter ratio) were dichotomized, with threshold values within a reasonable clinical range were determined using receiver operating characteristic curves. Categorical variables were compared
5 Downloaded from http://circ.ahajournals.org/ at UNIVERSITY OF LEEDSPERIODICA on May 21, 2015
DOI: 10.1161/CIRCULATIONAHA.114.013588
between groups using chi-square analysis or Fisher’s exact test. Exploratory multiple linear regression analysis was performed to evaluate factors associated with a higher post-TPVR RVOT gradient. Data were presented as median (minimum-maximum) or frequency (%). The authors had full access to and take full responsibility for the integrity of the data. All authors read and agreed to the manuscript as written.
Results Patients and Procedural Outcomes The US IDE trial enrolled 171 patients with postoperative right ventricular outflow tract (RVOT) conduit dysfunction from January 2007 through January 2010. Of these, 167 und der erwe went we nt underwent catheterization, and 150 had a Melody valve implanted (Figure 1), which was deployed in the ntend nded nd ed location loc ocat a ionn in i all cases. The cohort was almost alm lm mos ost evenly divided between bet etw et ween pediatric patients intended agee 18 years)) an aand d ad adul ults ul ts,, an ts nd th ther erre we w ere sseveral ev verall nnotable otab able ab le ddiagnostic iagn ia gnos osti os ticc di ti diff feren en nce cess be betw twee tw eenn th ee thes esee es (age adults, and there were differences between these po opu pula l tionss (Table (Ta T ble 1) ). populations 1). As ddescribed escr es crib cr ibed ib ed ppreviously, revi re viou iousl sly,2,3, 1 ppatient sl atie at ient ie nt hhad ad eemergent merg me rgen rg entt pu en ppulmonary ulm lmon lm onar on ary valv ar va valve alvee re repl replacement plac pl acem ac emen em entt fo en forr conduit rupture after TPVR and 1 died of cerebral hemorrhage after a course complicated by coronary artery dissection before Melody valve implant and subsequent mechanical circulatory support. The remaining 148 patients were discharged with the valve in place and constitute the study cohort. Acute Hemodynamic Results TPVR provided a competent pulmonary valve in all patients: on the discharge echocardiogram, PR was absent or trivial in 140 patients and mild in 5 (valve not visualized in 3), which was a significant improvement from pre-implant, when 79% of patients had moderate (n=45) or severe
6 Downloaded from http://circ.ahajournals.org/ at UNIVERSITY OF LEEDSPERIODICA on May 21, 2015
DOI: 10.1161/CIRCULATIONAHA.114.013588
(n=69) PR and 9% (n=14) had trivial or no PR (p25mmHg (n=17, 12%). Diagnostic and procedural factors associated with a higher discharge gradient are summarized in Table 2. On multivariable linear regression, a pre-implant mean RVOT gradient >35mmHg and absence of a new pre-stent were associated with higher discharge gradient, but provided only modest explanatory power (model R2=0.08, p25mmHg, and preimplant moderate/severe TR (Table 4). There were several notable interactions between conduit stenting and pre-- an andd po post st-st postTPVR RVOT gradients. The longest freedom from Melody valve reintervention was in patients whoo re rece ceiv ce ived iv ed a nnew ew w pre-stent or who did not rece ceiv ce ivee a new pre-stent bu iv ut ha hhad d a pre-implant mean received receive but D opppler gradient grad dieent 20mmHg shortest ein inte terv te rven enti en tion ti on ((HR HR 33.8 .88 [[1.7-8.7], 1.77-88.7] 7], pp=0.002). 7] =00.00 002) 00 2). Pa 2) Pati tien ti ents en ts wit ithh no nnew it ew ppre-stent, ew re-st sten st entt, a ppre-implant en re-imp imp mpla lant la nt ggradient radi ra dien di en n reintervention Patients with 35 mmHg, and a discharge gradient 20mmHg were intermediate (HR 2.6 [1.1-6.5], p=0.035 vs new pre-stent group). Freedom from RVOT reintervention in the cohort of patients who did not develop a type II MSF was 98±1% at 3 years and 91±3% at 5 years, and was shorter in those with a higher discharge RVOT gradient (HR 2.6 per 10mmHg [1.1-6.3], p=0.03). Transcatheter Melody Valve Reintervention Twenty-five patients underwent transcatheter TPV reintervention, only 3 of whom had a new pre-stent placed before the original Melody valve implant. In 6 of these patients, the initial
8 Downloaded from http://circ.ahajournals.org/ at UNIVERSITY OF LEEDSPERIODICA on May 21, 2015
DOI: 10.1161/CIRCULATIONAHA.114.013588
reintervention was redilation of the Melody valve. Five of these patients had the valve implanted on the smallest size (18mm) delivery system, 14 were among the first 50 implants overall and the first 10 at a given center, and all had relatively high residual gradients early after TPVR, with a mean Doppler gradient on the discharge echocardiogram >20 mmHg in all but 1. A MSF was diagnosed before the redilation in only 2 of these 6 patients. The initial reintervention was a TPV-in-TPV implant in 19 patients. Including 1 other patient whose first reintervention was TPV dilation, 20 patients ultimately underwent implantation of a second Melody valve for TPV dysfunction, which consisted of RVOT obstruction associated with MSF in all cases. All patients who underwent TPV-in-TPV implant had 1 (n=1) or more (2 in 14, 3 in 5) pre-stents placed prior to implantation of thee ssecond econ ec ondd Me on Melo lody lo Melody valve. After the second TPVR, the mean Doppler gradient fell in all patients, from 40mmHg (2072mm mmHg mm Hg)) to 17mmHg Hg 17m mmH m g (8-37mmHg) (p
