Approximately 2% of people between the ages of 70 and 83 suffer from moderate or greater aortic regurgitation (AR) in the United States. Left untreated, this disease is progressive and fatal; however, up to 8% of patients with AR, who meet the criteria for surgical intervention, do not receive treatment. As such, there is a pressing need to address the lack of treatment options for the thousands of patients with AR who meet a class I indication for aortic valve replacement but who still do not receive surgery. The advent of transcatheter aortic valve implantation (TAVI) has significantly altered the paradigm of treatment for valvular heart disease and is now a well-established therapeutic option for patients with severe aortic stenosis. While transcatheter devices dedicated for the treatment of AR are under investigation, they are not commercially available at this time. Nevertheless, there is a growing body of data that demonstrate acceptable safety and efficacy for the off-label use of current TAVI devices for the treatment of severe AR. Given the dearth of treatment options for inoperable patients with severe AR, available TAVI devices should be considered for this patient population.
- aortic regurgitation
- transcatheter aortic valve replacement
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While less common than aortic stenosis (AS), pure aortic regurgitation (AR) has been estimated to affect approximately 2% of men and women between the ages of 70 and 83,1 which roughly translates to over one million patients a year in the United States.2 When a patient develops symptomatic severe AR or severe AR associated with left ventricular dysfunction, surgical aortic valve replacement (SAVR) is recommended3 and has been shown to be associated with improved cardiovascular mortality and left ventricular remodelling.4 5 Despite the benefits of SAVR in this population, studies have shown that up to 8% of eligible patients with AR do not receive SAVR, usually due to advanced age or other comorbidities.6 Left untreated, the mortality rate in symptomatic patients with severe AR has been reported to be between 10% and 20% per year.7 Transcatheter aortic valve implantation (TAVI) has been shown to be both safe and effective in patients with severe AS when compared with SAVR8–10 and is markedly superior to medical therapy in the inoperable patient population.11 Given the lack of treatment options for the thousands of patients with AR, who do not receive SAVR despite meeting a class I indication for surgery, the question arises as to whether transcatheter aortic valve therapy can be expanded to treat patients with severe AR.
Transcatheter devices for treatment of AR
There are two transcatheter devices specifically designed for the treatment of AR that have been studied in humans. The JenaValve is a self-expanding nitinol valve with supra-annular pericardial leaflets and three locators on the exterior part of the valve, which are used to align the implant with the coronary ostia and clip onto the native leaflets for stabilisation. The first-generation JenaValve was delivered transapically via a 32F sheath, and early studies demonstrated high rates of successful implantation and low rates of residual AR,12 leading to a CE mark approval of the device in 2013 for the treatment of severe AR. However, as data emerged regarding the superiority of a femoral approach for transcatheter aortic valve therapy, manufacturing of the transapical JenaValve was halted in 2016. While evaluation of a transfemoral version of the device is underway, the JenaValve is not currently commercially available.
The J-Valve is another transcatheter device that is designed for the treatment of pure AR. Similar to the JenaValve, this implant consists of bioprosthetic pericardial leaflets mounted onto a self-expanding nitinol stent frame with three U-shaped anchors, which are used to grasp the native valve leaflets. Small single-arm studies using a transapical delivery system have demonstrated excellent device success (>90%) with low rates of residual AR,13 14 and first-in-man studies of a transfemoral J-Valve system15 are in progress. Nevertheless, the J-Valve remains investigational at this time.
Without a commercially available, dedicated device to treat AR, researchers have considered repurposing devices, originally constructed to treat AS, to treat AR as well. However, due to the aetiological and anatomical differences of a stenotic versus a regurgitant aortic valve, valid concerns have been raised that a device designed to treat AS may not perform as well in AR. First, the current TAVI devices rely on annular and leaflet calcification for positioning and anchoring of the implant. Since AR often results from annular dilation or leaflet incompetence in the absence of calcification, there is a risk of device embolisation from insufficient fixation or improper placement of the implant. Additionally, patients with chronic AR develop a hypercontractile left ventricle, resulting in an enhanced stroke volume during systole. Together with significant regurgitation during diastole, these haemodynamic changes could affect the positioning and stability of the valve implant.
To address these fears, implanters have developed innovative strategies when using a current TAVI device to treat AR (table 1). In order to optimise device anchoring, careful assessment of the aortic annulus size using three-dimensional CT along with 15%–20% oversizing of the device has been recommended.16 17 Due to diminished visibility of the non-calcified annulus on fluoroscopy, intraprocedural transoesophageal echocardiogram, CT fusion-guided imaging and/or a two-pigtail technique (pigtails placed in the left and non-coronary cusps) may be useful to aid in the appropriate positioning of the device.16 17 Additionally, rapid pacing during valve deployment (even with self-expanding valves) is suggested to reduce device motion, which can be caused by the increased left ventricular stroke volume and regurgitant flow of AR.16 17
Safety and efficacy of off-label use of currently available transcatheter aortic valve devices for treatment of AR
Although no randomised controlled trials have been performed to evaluate the outcomes in patients with AR treated off-label with available TAVI implants, observational data have demonstrated reassuring trends towards safety and efficacy. De Backer and colleagues18 analysed a multicentre cohort of 254 patients with severe native AR and an average Society of Thoracic Surgeons risk score of >6% who were treated with TAVI. While initial device success according to the Valve Academic Research Consortium-2 definitions was sobering (67%), when analyses were limited to the 145 patients treated with a variety of dedicated and second-generation non-dedicated implants, including the JenaValve, Direct Flow, Evolut R, SAPIEN-3, Lotus valve and ACURATE neo implants, overall outcomes were more promising.18 Of the patients in this cohort, 82% achieved device success and 30-day mortality rate and rate of repeat aortic valve intervention were 8% and 4%, respectively.18 Similar findings were seen in another multicentre registry of 41 patients with severe AR treated with new-generation valve implants (85% device success; 8% 30-day mortality; 3% residual moderate/severe AR).19 Nevertheless, since the majority of patients in the new-generation cohorts in both of these studies were treated with dedicated devices (eg, JenaValve, Direct Flow), it is difficult to ascertain whether these outcomes were due solely to a device specifically designed to treat AR.
The Pure Native AR TAVR registry aimed to address the question of the comparable efficacy of the JenaValve compared with non-dedicated valve implants. In this multicentre registry, 331 non-operable patients with severe AR were treated with TAVI between 2007 and 2017.20 In analyses restricted to patients treated with new-generation devices (n=212), outcomes were similar to what was seen in prior studies, with an 81% device success rate and a 9.4% mortality rate at 30 days.20 When results were further parsed out by device type, device success was similar with the JenaValve (n=64) when compared with the SAPIEN-3 (n=41) device and slightly better when compared with the Evolut R (n=50) (82.8% vs 85.4% vs 76.0%, respectively).20 It is important to note that the majority of device failures for the Evolut R and SAPIEN-3 implants were related to the need for a second valve implant (18.0% and 12.2%, respectively) and not to intraprocedural mortality.20 In fact, numerically lower 30-day mortality rates were noted with the Evolut R and SAPIEN-3 devices when compared with the JenaValve (6.0% vs 4.9% vs 12.5%, respectively) and the rates of postprocedural moderate/severe AR were numerically low with all devices (4.0% vs 0.0% vs 1.6%, respectively).20 These findings of comparable safety and efficacy of treatment with dedicated AR devices versus off-label new-generation TAVI implants were confirmed in a meta-analysis of 640 patients with AR treated with transcatheter therapy, which demonstrated no significant differences in 30-day mortality, stroke or substantial residual AR between the two groups.21
Analyses of real-world registry data are also limited, but have found similar results to the above-mentioned studies (table 2). A small study of 24 non-operable patients with AR treated with the ACURATE neo device demonstrated 87.5% device success and only one death at 30 days.22 Using data derived from the Society of Thoracic Surgeons/American College of Cardiology Transcatheter Valve Therapies (STS/ACC TVT) Registry, researchers found that patients treated with the Evolut R device for a primary indication of AR had low rates of aortic reintervention (4.0%) and moderate/severe paravalvular leak (6.2%) at 30 days.23 Rates of in-hospital mortality, stroke and 30-day cardiovascular readmissions were also noted to be low (2.4%, 1.7% and 4.8%, respectively) in a recent analysis from the Nationwide Readmissions Database (NRD) of 1222 patients who received TAVI for pure AR between 2016 and 2017.24 While these are promising findings, it is important to note that the limitations of the STS/ACC TVT Registry and the NRD (particularly with regard to the reliance on claims data and International Classification of Diseases-10 codes) likely resulted in patients with mixed aortic valve disease being included in these analyses and thus limits the generalisability of these findings to patients with pure AR. Nevertheless, these data suggest that off-label use of current TAVI implants to treat severe AR results in comparable short-term outcomes with those achieved with dedicated AR devices, although data on longer term outcomes for both dedicated and non-dedicated devices are lacking.
In conclusion, while a dedicated transcatheter device for the treatment of AR is ideal, there is a clear need now for percutaneous aortic valve treatment in the subset of patients with AR who cannot undergo SAVR. With appropriate patient selection, careful device sizing and optimal intraprocedural imaging and techniques, TAVI using currently available devices off-label has demonstrated reasonable outcomes and offers a viable therapeutic option for this previously untreated patient population.
Patient consent for publication
Contributors Both authors have contributed substantially to this article.
Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.
Competing interests SJB reports the following conflicts of interest over the past 12 months: consulting/advisory board income: Boston Scientific Corporation, Abiomed, Abbott, Edwards Lifesciences and Mitra Labs; and research support: Abiomed.
Patient and public involvement Patients and/or the public were not involved in the design, or conduct, or reporting, or dissemination plans of this research.
Provenance and peer review Not commissioned; externally peer reviewed.
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