Left ventricular assist device (LVAD) therapy is a surgical treatment for end-stage congestive heart failure.1 In recent years, the transition from pulsatile to continuous-flow (CF) LVAD therapy has seen significant prolongation of LVAD usage because of the improved side effect profile.1 Along with that, improvements in engineering have allowed the device to become more compact and implantable.2,3
As a result, the therapeutic usage of CF-LVADs has transitioned from a bridge to heart transplantation toward destination therapy.1,2 The growing usage of destination therapy and lack of donor organ availability have also caused the usage of CF-LVAD therapy to exponentially increase over the last few years.1,2
However, with the growing usage of CF-LVADs, there has been greater recognition of side effects and complications that were not as commonly observed in pulsatile LVADs. De novo progressive aortic insufficiency (AI) is a side effect frequently related to prolonged CF-LVAD support.4,5 There has been a wide range of reports that highlight the prevalence of moderate or greater AI in LVAD.2,4–6 Cowger et al6 showed that 11% of the patients 6 months post-LVAD implantation had moderate to severe AI, which increased to 26% and 51% at 12 and 18 months, respectively. The etiology of the apparent correlation between AI development and duration of CF-LVAD therapy is thought to be a physiologic response to nonpulsatile continuous circulation.4–6 The alterations in blood flow kinetics and sustained high pressure results in aortic root dilatation, commissural fusion, and myxoid degeneration of the aortic valve.4–6
In AI, regurgitant blood can return to the left ventricle via a low-resistance circuit, rendering LVAD output ineffective and reducing device support and durability.5,6 Although small amounts of aortic regurgitation can be tolerated, more severe AI requires treatment as it can lead to end-organ malperfusion and heart failure.5,6 The progression of de novo and pre-existing AI is particularly accelerated in CF-LVAD recipients and can cause recurrent clinical heart failure with reduced functional status, progressive dyspnea, and significantly increased mortality.2,7 Although there is currently no consensus on management strategies for LVAD-associated AI, current methods include the management of device pump settings and medical therapy.2 Surgical intervention is also an option, consisting of aortic valve (AV) replacement, suture repair of the aortic valve, or aortic patch closure.2,8 However, many patients with LVAD and significant AI have decompensated heart failure and comorbidities deeming them unfit candidates for reoperation.2,7
Recently, percutaneous methods of intervention have emerged, such as transcatheter AV replacement (TAVR) and percutaneous occluder devices. Given the very scarce global experience with this approach, evidence in the literature is lacking and limited to case reports and series. We have, therefore, sought to assess the outcomes of CF-LVAD patients who had undergone percutaneous intervention by TAVR or occluder devices for their AI. A systematic review and meta-analysis of the available case reports and case series in the literature were conducted.
Literature Search Strategy
Electronic searches were performed using Ovid Medline, PubMed, Cochrane Central Register of Controlled Trials (CCTR), Cochrane Database of Systematic Reviews (CDSR), and American College of Physicians Journal Club, and Database of Abstracts of Review of Effectiveness (DARE) from their dates of inception to April 2016. To achieve the maximum sensitivity of the search strategy, we combined the terms: “left ventricular assist device,” “LVAD,” “occlusion device,” “Amplatzer,” “transcatheter,” “aortic insufficiency,” “aortic regurgitation,” and “closure” as either key words or MeSH terms. The reference lists of all retrieved articles were reviewed for further identification of potentially relevant studies and assessed using the inclusion and exclusion criteria. Authors of the published studies were contacted to obtain data not included in their publications. In addition, coauthors of this manuscript who had unpublished cases at their respective institutions (F.L., S.M., and A.C.) provided these cases for inclusion in the analysis.9
Eligible studies for the present systematic review and meta-analysis included series or cases where patients had percutaneous transcatheter interventions for AI in CF-LVAD patients. Studies that did not include mortality or complications as end points were excluded. When institutions published duplicate studies with accumulating numbers of patients or increased lengths of follow-up, only the most complete reports were included for quantitative assessment at each time interval. All publications were limited to those involving human subjects and in the English language.
All data were extracted from article texts, tables, and figures. Two investigators independently reviewed each retrieved article (K.P. and J.H.). Discrepancies between the two reviewers were resolved by discussion and consensus. Where data were not available, multiple attempts were made to contact corresponding authors to obtain the relevant data for the current study. Expert cardiac surgeons and interventionists were also contacted to obtain unpublished data on cases pertinent to the current study.
Baseline characteristics and demographics were reported using descriptive statistics, including median and interquartile range (IQR), rounded to the nearest integer. The individual patient survival data from each case report and case series included in the present meta-analysis were combined to produce a Kaplan–Meier survival curve. Subgroup analysis was conducted to compare survival outcomes of patients receiving closure devices versus TAVR. SPSS v17.0 was used for the current study, with p < 0.05 considered as statistically significant.
A total of 2116 studies were identified through the six electronic database searches, and 6 other records were identified through other sources. After the removal of duplicate references, 2102 potentially relevant studies were retrieved. After detailed evaluation of these articles via title and abstract screen 45 studies remained for analysis. After full-text screening and application of the selection criteria, 15 published studies4,10–23 and 3 unpublished records were selected for analysis. The study characteristics are summarized in Table I (see Supplemental Digital Content, http://links.lww.com/ASAIO/A111).
A total of 29 patients were included in this study, with a median age of 56 years (52–66) and 72.4% being of male gender. The etiology of heart failure resulting in LVAD placement was ischemic cardiomyopathy in 17.2% of the patients, and nonischemic cardiomyopathy in 44.8%. The etiology subgroups are summarized in Table 1. The median duration for mechanical circulatory support before intervention was 423.5 days (210–541). The device used for circulatory support was a HeartMate II in 67.9% of the patients, a HeartWare HVAD in 25.0%, and unspecified in the remaining 7.1% of patients.
The two intervention groups were TAVR and occluder devices. There were 8 patients (27.6%) who received TAVR and 21 (72.4%) patients who received an occluder device. For the patients undergoing TAVR, 50.0% received an Edwards Sapien valve, 37.5% received a Medtronic CoreValve, and 12.5% received a Medtronic Melody Valve. For the occluder devices, an Amplatzer Cribriform Septal Occluder was the only reported device, which was used in all patients. The median size of the TAVR devices was 29 (23–29) mm, and for the occluder devices it was 25 (25–30) mm. A transfemoral approach for device implantation was most common and used in 69% of the patients. An apical (10%), brachial (7%), subclavian (3%), and transaortic approaches (3%) were also used. Seven percent of studies did not report the method of approach. The patient characteristics are summarized in Table 1.
The preintervention AI grade was severe with a median grade of 4 (4–4). Postoperatively, the AI grade improved significantly to a median grade of 0 (0–2; Figure 1). At long-term follow-up, the AI grade was still trivial with a median AI grade of 1 (0–1). The mean time period for long-term follow-up, which was used for “AI Later” was 10 months. Subgrouping the treatments into the occluder device and TAVR, it was found that both interventional techniques were similarly effective in reducing the AI grade from severe to trivial (Figure 2).
The percentage of patients discharged was 58.6%. Nine patients (31%) died before discharge with one diagnosed with pulseless electrical activity and right ventricle failure, another seven nonsurvivors having significantly increased right ventricle end-diastolic diameter and reduced tricuspid annular plane systolic excursion, and one patient with the reason for death not mentioned. The outcomes for three patients (10%) were not reported. The median survival rate for all percutaneous devices was 6 months postintervention (Figure 3). Subgroup analysis of TAVR and closure devices did not demonstrate a significant difference between the two groups (p = 0.10) (Figure 4). The cumulative survival of patients with TAVR was approximately 35% at 20 months postintervention, compared with the occluder device group in which no patients survived beyond 20 months. In terms of absolute mortality rates, this was 6.25% at 2 months, 6.67% at 4 months, and 25% at 1-year follow-up.
Device migration into the left ventricular outflow tract was found postoperative in two patients who were treated with the Amplatzer occluder device. Management of this device migration was through a heart transplant in one patient and device replacement with a larger occluder in another. Also from the occluder device group, two patients experienced transient hemolysis, which improved in both cases with conservative management. Two patients experienced device migration postoperatively in the TAVR cohort. One was treated by valve explanation and AV closure, and a valve-in-valve implantation was used to treat the other. One of the TAVR patients had significant postimplant perivalvular leakage, which was also treated with a valve-in-valve implantation. These three TAVR patients who experienced valvular complications all received self-expanding valves (Medtronic CoreValve). The patients who received the balloon expandable valves (Edwards Sapiens and Medtronic Melody) had no valvular complications.
Our results support percutaneous intervention as a viable minimally invasive treatment option for patients with severe LVAD-associated AI, particularly nonsurgical candidates. The preliminary analysis of survival does not indicate a significant difference between TAVR and closure devices (p = 0.10). However, TAVR and closure devices demonstrated similar postoperative AI grades, reducing median AI grades from severe preoperatively to trivial postoperatively (Figure 3).
CF-LVAD therapy has been used increasingly as destination therapy, improving quality of life, extending survival and proving to be more reliable than older pulsatile devices.3,7,24 However, the prolonged duration of CF-LVAD therapies has resulted in a greater prevalence of de novo AI. AI can reduce systemic perfusion and functional status, eventually leading to progressive dyspnea and potential clinical heart failure.2,7 Although the etiology is not fully known, it is believed that AI is associated with reduced rates of AV opening as a result of abnormal collagen production and remodeling at the commissural fusion of the AV leaflet.6,25,26 Ideally, if the AI is not too severe, medical treatment is preferred.27,28 This is most commonly done via the management of hypertension, which can decrease LVAD afterload.27,28 This has been achieved in patients with trivial to mild AI through angiotensin converting enzyme inhibitors or volume management via diuretics.2,7 The progression of AI severity could potentially also be reduced or prevented by lowering LVAD pump speed and transvalvular pressure gradient to allow the AV to open intermittently.29–31
Although trivial to mild AI can be tolerated or treated medically, guidelines from the International Society for Heart and Lung Transplantation (ISHLT) recommend that more than mild AI should prompt consideration for surgical intervention in order to prevent progressive worsening of LVAD efficacy and potential clinical heart failure.32 The surgical methods of treatment include replacement of the native AV with a bioprosthetic valve, creation of a bicuspid orifice, repair of the AV via partial stitching of the leaflets (Park stitch), or an aortic patch.8,33 Complete over-sewing of the outflow tract can also be used to completely eliminate AI, but presents the risk of decompression or fatality with device malfunction.2 Thus, patients with the possibility of myocardial recovery are not recommended to have their AV over sewn and should instead consider AV replacement or repair.2 Nevertheless, all the surgical approaches via a redo sternotomy introduce major risks, including right ventricular damage and hemorrhage.7,34,35 Open surgical approaches also have an operative mortality risk of up to 18% with a late mortality of 7%.33
Patients with severe AI commonly have accompanying risk factors against surgery, prompting the need for minimally invasive percutaneous approaches. Percutaneous intervention in nonsurgical patients also minimizes the requirement for accompanying general anesthesia, intensified anticoagulation, extracorporeal circulation, or risks associated with surgery.2 The use of percutaneous left ventricular outflow tract occluders, such as the Amplatzer, has been shown to reduce LVAD demand and systemic flow. This approach has been shown to successfully reduce AI from severe to trivial, without any major changes to pump parameters.35 However, the long-term consequences of AV occlusion via an occluder device are yet to be observed, with potential complications, such as device migration, hemolysis from regurgitant flow, erosion in the aortomitral curtain, coronary ostia obstruction, and complete dependency on LVAD.2,11,23,35 Also, closure of the aortic valve via a septal occluder device is essentially the same as over-sewing the aortic valve, and as such occluder devices have similar inherent disadvantages. The higher mortality in our analysis for occluder device survival may be because of this as device malfunction can potentially cause hemodynamic collapse and death.2,35
TAVR has also been shown as an effective minimally invasive method for treating LVAD-acquired AI. A major advantage of TAVR is that the patients are not fully dependent on the device, unlike AV occlusion via a occluder device. While pump failure via thrombosis or technical malfunction will cause immediate death in occluder device patients, a functioning replacement valve will allow even minimal baseline heart function in LVAD patients to eject blood into the aorta, sustaining life until the issue is addressed. In the conventional use of TAVR in patients with aortic stenosis, perivalvular leakage can result from an incomplete seal or malpositioning.36–38 Thus, for the more unconventional use of TAVR in LVAD-acquired AI patients, there are similar potential complications. Of more concern is that anchoring of the valve prosthesis may be hampered if leaflet and annular calcification is absent, especially in the setting of continuous suction from the CF-LVAD.12,19 Another disadvantage of TAVR is that it is an expensive procedure that has a higher cost than intervention via occluder devices.39,40 This may account for the less TAVR cases than occluder device cases in our analysis (27.6% vs. 72.4%). Another reason may be the limitations of sizes available, particularly in the cases of patients who have dilated annulus.
The present review is constrained by several limitations. We have conducted a meta-analysis of the available limited case report and case series data reported in the literature about the percutaneous intervention for LVAD-acquired AI. There is heterogeneity in patient selection and intervention. However, this is bypassed, as all selected studies are consistent with percutaneous procedure inclusion and scarce reporting in the literature. Strengths of the current study are that it is the first pooled analysis assessing the use of percutaneous intervention to treat de novo AI post-LVAD implantation, and a first attempt to compare outcomes between TAVR and septal occlusion devices. However, it is important to note that a direct comparison of surgical AVR to the results of percutaneous approach should be interpreted with caution, given that percutaneous patients are more likely to be complicated with higher comorbidities. Overall, this study addresses an innovative minimally invasive approach to an increasingly prevalent issue and provides a thorough overview of its efficacy and potential viability in future practice.
As the therapeutic use of CF-LVAD increases so will the adverse consequence of AI. Currently, there are no unanimous guidelines for the treatment of severe AI in this context. The results of our meta-analysis indicate that percutaneous interventions, such as TAVR and AV closure, demonstrate similar efficacy in significantly reducing severe AI. Current results are encouraging, potentiating viability as a treatment option, particularly in nonsurgical candidates. Future research with larger patient cohorts and comparative controls is required to sufficiently evaluate the efficacy of this technique and promote its widespread acceptance as a mainstay treatment.
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