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Background
The pulmonary valve (PV), located between the right ventricle and the pulmonary artery, opens upon contraction of the right ventricle to release oxygen-depleted blood from the right ventricle into the pulmonary artery for delivery to the lungs. Congenital defects cause the great majority of cases of PV insufficiency or stenosis. Patients with severe PV dysfunction require surgical reconstruction of the right ventricular outflow tract (RVOT) between the heart and the pulmonary artery in order to re-establish blood flow to the lungs and mitigate right ventricular strain. In general, RVOT reconstruction entails implantation of a valved conduit through the defective native valve. Most infants with congenital PV defects undergo successful RVOT conduit implantation. However, as RVOT conduits age, valves begin to leak or fail, and adults successfully treated for PV dysfunction as children require surgery to replace failing conduits. Although uncommon, some patients may develop PV dysfunction as adults. Surgical implantation of RVOT conduits for acquired stenosis or insufficiency is rare.
Percutaneous pulmonary valve implantation (PPVI) is a new treatment option in patients with RVOT conduit regurgitation or stenosis. The objective of PPVI is to prolong the lifespan of right ventricle to pulmonary artery conduits; thus postponing open-heart surgery. Early results following PPVI have shown a significant reduction in right ventricular pressure and RVOT gradient. The most common complication during follow-up is stent fractures. Although clinically silent in the majority of cases, stent fractures led to re-intervention in the form of implantation of a second device (valve-in-valve). Significant pulmonary regurgitation (PR) was only seen in the context of endocarditis. Percutaneous pulmonary valve implantation has the potential to become the standard procedure in the treatment of dysfunctional conduits.
Neyt and associates (2009) evaluated current evidence supporting the use of percutaneous heart valves in degenerative aortic valve and congenital pulmonary outflow tract disease, as compared to conservative medical therapy or traditional surgical valve replacement. A systematic review of the literature on percutaneous heart valve was performed. No randomized controlled trials on percutaneous heart valves have been published so far. Only observational data from series and data presented at cardiology meetings are available. Both percutaneous aortic valve as well as percutaneous pulmonary valve seem feasible in the hands of an experienced team. The authors concluded that PPVI appears to be a safe and promising technology for which reimbursement under strict conditions may be recommended.
Oosterhof et al (2009) stated that PR is the most important residual lesion after initial surgical correction for pulmonary sub-valvular stenosis in the early life of patients with tetralogy of Fallot or isolated pulmonary stenosis. Symptomatic or asymptomatic patients with severe right ventricular dilatation due to pulmonary regurgitation may benefit from pulmonary valve replacement. Surgery is ideally performed before the right ventricle becomes irreversibly damaged as a result of long-standing volume overload. However, the beneficial effects must be weighed up against the problems associated with degradation of the allograft, which often result in re-operations. Owing to the higher risk of thrombo-embolic events in mechanical prosthesis and the lifetime need for anti-coagulation, allografts are the most widely used prosthesis. Degradation of the allograft often leads to re-operation, mostly 10 to 20 years after initial implantation. For a patient receiving his first allograft at 20 years of age, several re-operations will have to be performed later in life. In this regard, PPVI has the potential to decrease the number of surgical re-operations.
Zahn and co-workers (2009) assessed the safety, procedural success, and short-term effectiveness of the Melody/Ensemble transcatheter pulmonary valve (Medtronic, Inc., Minneapolis, MN) in patients with dysfunctional RVOT conduits. The Melody/Ensemble transcatheter pulmonary valve system is a novel, minimally invasive alternative to surgical pulmonary valve replacement in children and adults with significant RVOT conduit regurgitation or stenosis. Standardized entry criteria, implantation, and follow-up protocols were used. Non-implanting core laboratories were used to evaluate results. Between January 2007 and September 2007, a total of 34 patients underwent catheterization for intended Melody valve implantation at 3 centers. Mean age was 19.4 +/- 7.7 years. Initial conduit Doppler mean gradient was 28.8 +/- 10.1 mm Hg, and 94 % of patients had moderate or severe PR. Implantation was successful in 29 of 30 attempts and not attempted in 4 patients. Procedural complications included conduit rupture requiring urgent surgery and device removal (n = 1), wide-complex tachycardia (n = 1), and distal pulmonary artery guide-wire perforation (n = 1). Peak systolic conduit gradient fell acutely from 37.2 +/- 16.3 mm Hg to 17.3 +/- 7.3 mm Hg, and no patient had more than mild PR. There were no deaths or further device explants. At 6-month follow-up, conduit Doppler mean gradient was 22.4 +/- 8.1 mm Hg, and PR fraction by magnetic resonance imaging was significantly improved (3.3 +/- 3.6 % versus 27.6 +/- 13.3 %, p < 0.0001). Stent fracture occurred in 8 of 29 implants; 3 of these were treated with a second Melody valve for recurrent stenosis later in follow-up. The authors concluded that implantation of the Melody valve for RVOT conduit dysfunction can be performed by experienced operators at multiple centers, appears safe, and has encouraging acute and short-term outcomes.
Vezmar et al (2010) examined physiological and clinical consequences of PPVI in patients with chronic RVOT obstruction and volume overload. A total of 28 adolescents (median age of 14.9 years; age range of 10.9 to 19 years) underwent PPVI due to RVOT stenosis and/or PR. Before and after PPVI, echocardiography and magnetic resonance imaging, cardiopulmonary exercise tests were obtained. The RVOT gradient (p < 0.001) and right ventricular systolic pressure decreased (p < 0.001), acutely. Magnetic resonance imaging (median of 6 months) documented reduction in right ventricular end-diastolic (RVED) (149 +/- 49 ml/m(2) versus 114 +/- 35 ml/m(2), p < 0.005) volume, increases in left ventricular end-diastolic (LVED) (p < 0.007) volume and cardiac output (RVED volume: p < 0.04 and LVED volume: p < 0.02), and reduced PR fraction (24 +/- 10 % to 7 +/- 7 %, p < 0.0001). Symptoms, aerobic exercise performance (maximal oxygen consumption: p < 0.0001) and ventilatory response to carbon dioxide production (p < 0.003) improved. After 24 months, echocardiography demonstrated the right ventricle/systemic-pressure ratio, and RVOT peak pressure gradient reductions persisted, and PR was absent in 93 % (n = 12 of 13) of the cohort. Freedom from surgery was 91 %, 83 %, and 83 %, and freedom from transcatheter re-intervention was 91 %, 80 %, and 80 %, at 12, 24, and 36 months, respectively. There were no acute device-related complications, with stent fractures noted in 10.8 %. The authors concluded that PPVI is feasible and safe in the young with dysfunctional RVOT conduits. An improvement in symptoms, hemodynamic status, and objective findings of exercise performance occurs. Early follow-up demonstrates persistent improvement in ventricular parameters, PR, and objective exercise capacity.
McElhinney et al (2010) reported the short-term (6 months to 1 year) and medium-term (2 years) outcomes after PPVI in the expanded multi-center U.S. Melody valve trial. From 1/07 to 8/09, 136 patients (median age of 19 years) underwent catheterization for intended Melody valve implant at 5 centers. Implant was attempted in 124 patients; in the other 12, PPVI was not attempted due to risk of coronary artery compression (n = 6) or other clinical or protocol contraindications. There was 1 death from intra-cranial hemorrhage following coronary artery dissection, and 1 valve was explanted after conduit rupture. The median peak RVOT gradient was 37 mm Hg pre-implant and 12 mm Hg acutely post-implant. Prior to implant, PR was moderate or severe in 92 patients (81 % with data); no patient had more than mild PR early after implant or during follow-up (greater than or equal to 1 year in 65 patients). Freedom from diagnosis of stent fracture was 77.8 +/- 4.3 % at 14 months. Freedom from Melody valve dysfunction or re-intervention was 93.5 +/- 2.4 % at 1 year. A higher RVOT gradient at discharge (p = 0.003) and younger age (p = 0.01) were associated with shorter freedom from dysfunction. The authors concluded that this updated report from the multi-center U.S. Melody valve trial demonstrated an ongoing high rate of procedural success and encouraging short-term valve function. All re-interventions in this series were for RVOT obstruction, high-lighting the importance of patient selection, adequate relief of obstruction, and measures to prevent and manage stent fracture.
Webb and colleagues (2010) stated that transcatheter heart valve implantation within a failed bioprosthesis, a "valve-in-valve" procedure, may offer a less invasive alternative than repeat cardiac surgery. These investigators reported the findings of valve-in-valve implantations in 24 high-risk patients. Failed valves were aortic (n = 10), mitral (n = 7), pulmonary (n = 6), or tricuspid (n = 1) bioprostheses. Implantation was successful with immediate restoration of satisfactory valve function in all but 1 patient. No patient had more than mild regurgitation after implantation. No patients died during the procedure. Thirty-day mortality was 4.2 %. Mortality was related primarily to learning-curve issues early in this high-risk experience. At baseline, 88 % of patients were in New York Heart Association (NYHA) functional class III or IV; at the last follow-up, 88 % of patients were in NYHA functional class I or II. At a median follow-up of 135 days (inter-quartile range of 46 to 254 days) and a maximum follow-up of 1,045 days, 91.7 % of patients remained alive with satisfactory valve function. The authors concluded that transcatheter valve-in-valve implantation is a reproducible option for the management of bioprosthetic valve failure. Aortic, mitral, pulmonary, and tricuspid tissue valves were amenable to this approach.
In January 2010, the Food and Drug Administration (FDA) approved the Medtronic Melody/Ensemble Transcatheter Pulmonary Valve System for the treatment of adults and children with previously implanted, poorly functioning pulmonary valve conduits. The FDA approved the Melody/Ensemble system under the Humanitarian Device Exemption program. It is indicated for the treatment of dysfunctional RVOT conduits whose pulmonary valve has become stenotic or regurgitant (wide open with little or no valve function). Patients indicated for the procedure must have a full circumferential RVOT conduit greater than or equal to 16 mm in diameter when originally implanted. The approval was based on clinical studies of 99 subjects in the United States and 68 subjects in Europe, which showed that the device improved function of the heart, and the majority of participants have noted improvements in their clinical symptoms. The device showed similar, limited durability compared with existing alternative treatments; 21 % of U.S. subjects reported a stent fracture, a rate consistent with stent fractures reported for the bare metal stents presently used to treat congenital heart defects of the pulmonary valve.
As a condition of the FDA’s approval, Medtronic will conduct 2 post-approval studies to evaluate long-term risks and benefits as well as the physician specialization needed to perform the implantation procedure. One study will continue to follow 150 subjects from the initial clinical trial for 5 years, and the second study will enroll more than 100 new subjects to be evaluated over 5 years, in order to assess the training program. Safety and benefit assessments will be part of both studies. The FDA also requires that Medtronic maintain a database of Melody/Ensemble recipients.
In a review on transcatheter valve interventions for heart valve diseases, Schaefer and Bertram (2010) stated that PPVI is an interventional treatment for adolescents and young adults with congenital heart disease. After corrective or palliative operation in infancy or early childhood, some patients regularly need re-operations for RVOT reconstruction. In the last decade, PPVI has evolved as an alternative treatment option with much less morbidity compared to repeated surgery.
Lurz et al (2011) evaluated the potential of late positive functional remodeling after PPVI in RVOT dysfunction. A total of 65 patients with sustained hemodynamic effects of PPVI at 1 year were included in this study. Patients were divided into 2 subgroups based on pre-procedural predominant pulmonary stenosis (PS) (n = 35) or predominant PR (n = 30). Data from magnetic resonance imaging and cardiopulmonary exercise testing were compared at 3 time points: (i) before PPVI, (ii) within 1 month (early), and (iii) at 12 months (late) after PPVI. There was a significant decrease in RVED volume early after PPVI in both subgroups of patients. Right ventricle ejection fraction improved early only in the PS group (51 +/- 11 % versus 58 +/- 11 % and 51 +/- 12 % versus 50 +/- 11 %, p < 0.001 for PS, p = 0.13 for PR). Late after intervention, there were no further changes in magnetic resonance parameters in either group (right ventricle ejection fraction, 58 +/- 11 % in the PS group and 52 +/- 11 % in the PR group, p = 1.00 and p = 0.13, respectively). In the PS group at cardiopulmonary exercise testing, there was a significant improvement in peak oxygen uptake early (24 +/- 8 ml/kg/min versus 27 +/- 9 ml/kg/min, p = 0.008), with no further significant change late (27 +/- 9 ml/kg/min, p = 1.00). In the PR group, no significant changes in peak oxygen uptake from early to late could be demonstrated (25 +/- 8 ml/kg/min versus 25 +/- 8 ml/kg/min versus 26 +/- 9 ml/kg/min, p = 0.48). The authors concluded that in patients with a sustained hemodynamic result 1 year after PPVI, a prolonged phase of maintained cardiac function is observed. However, there is no evidence for further positive functional remodeling beyond the acute effects of PPVI.
Nordmeyer et al (2011) examined the feasibility and safety of pre-stenting with a bare metal stent (BMS) before PPVI, and analyzed if this approach improves hemodynamic outcomes and impacts on the incidence of PPVI stent fractures. A total of 108 consecutive patients with congenital heart disease underwent PPVI (54 with PPVI alone, 54 with BMS pre-stenting before PPVI). There were no significant differences in procedural complication rates. Acutely, there was no difference in hemodynamic outcomes. Serial echocardiography revealed that in the subgroups of "moderate" (26 to 40 mm Hg) and "severe" (greater than 40 mm Hg) RVOT obstruction, patients with pre-stenting showed a tendency towards lower peak RVOT velocities compared to patients after PPVI alone (p = 0.01 and p = 0.045, respectively). The incidence of PPVI stent fractures was not statistically different between treatment groups at 1 year (PPVI 31 % versus BMS+PPVI 18 %; p = 0.16). However, pre-stenting with BMS was associated with a lower risk of developing PPVI stent fractures (hazard ratio: 0.35; 95 % confidence interval: 0.14 to 0.87, p = 0.024). The probability of freedom from serious adverse follow-up events (death, device explantation, repeat PPVI) was not statistically different at 1 year (PPVI 92 % versus BMS+PPVI 94 %; p = 0.44). The authors concluded that pre-stenting with BMS before PPVI is a feasible and safe modification of the established implantation protocol. Pre-stenting is associated with a reduced risk of developing PPVI stent fractures.
Eicken and associates (2011) reported on the combined 2-center experience with PPVI. A total of 102 patients with RVOT dysfunction (median weight of 63 kg; range of 54.2 to 75.9 kg, median age of 21.5 years; range of 16.2 to 30.1 years) were included in this study. Percutaneous pulmonary valve implantation was performed in all patients. Pre-stenting of the RVOT was done in 97 patients (95 %). The median peak systolic RVOT gradient decreased from 37 mm Hg (29 to 46 mm Hg) to 14 mm Hg (9 to 17 mm Hg, p < 0.001) and the ratio RV pressure/aortic blood pressure decreased from 62 % (53 to 76 %) to 36 % (30 to 42 %, p < 0.0001). The median RVED-volume index (MRI) decreased from 106 ml/m(2) (93 to 133 ml/m(2)) to 90 ml/m(2) (71 to 108 ml/m(2), p = 0.001). Pulmonary regurgitation was significantly reduced in all patients. One patient died due to compression of the left coronary artery. The incidence of stent fractures was 5 of 102 (5 %). During follow-up (median of 352 days; range of 99 to 390 days), 1 percutaneous valve had to be removed surgically 6 months after implantation due to bacterial endocarditis. In 8 of 102 patients, a repeated dilatation of the valve was done due to a significant residual systolic pressure gradient, which resulted in a valve-in-valve procedure in 4. The authors concluded that these findings showed that PPVI is feasible and it improves the hemodynamics in a selected patient collective. Apart from 1 coronary compression, the rate of complications at short-term follow-up was low. They stated that PPVI can be performed by experienced interventionalists with similar results as originally published.
Raikou et al (2011) evaluated the cost of PPVI and the cost of surgical pulmonary valve replacement in patients with RVOT dysfunction using a cohort simulation model applied to the United Kingdom population. The model resulted in an estimate of mean cost per patient of £5,791 when PPVI is unavailable as a treatment option and in an estimate of mean cost per patient of £8,734 when PPVI is available over the 25-year period of analysis. After sensitivity analysis was undertaken the results showed that the mean per patient cost difference in implementing PPVI over 25 years as compared to surgical pulmonary valve replacement lies somewhere between £2,041 and £3,913. The authors noted that given the lack of long-term data on treatment progression, the cost estimates derived here are subject to considerable uncertainty, and extensive sensitivity analysis has been used to counter this. Thus, this study is merely indicative of the levels of cost that can be expected in a cohort of 1,000 patients faced with a choice of treatment with PPVI or surgery. It is not a cost-effectiveness study, but it helps place current knowledge on short-term benefits into context. The authors concluded that as this analysis shows PPVI is associated with a relatively small increase in treatment management costs over a long time period. Whether this inferred increase in long-term cost is worthwhile given the known short-term benefits and any personal judgment formed over long-term benefit is left to the reader.
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