Transcatheter aortic valve implantation (TAVI) has emerged as an effective treatment for degenerated surgical aortic bioprostheses [1, 2, 3, 4]. In particular, valve-in-valve (ViV) TAVI has been recognized as a safer alternative to re-do surgical aortic valve replacement in patients at high surgical risk [5]. ViV-TAVI currently accounts for approximately 5% of all TAVI procedures performed in the United States [6].

While ViV-TAVI can restore valve function and improve symptoms, the currently limited available data suggest that there may be a higher incidence of certain complications, including transcatheter heart valve (THV) malposition, coronary occlusion, and severe patient prosthesis mismatch (PPM). Further, there may be a higher residual gradient, and post-procedure coronary access is complicated [7, 8, 9, 10, 11, 12, 13].

Given the scarcity of currently published data on ViV-TAVI, the aims of the present investigation were to (1) compare clinical and hemodynamic outcomes of TAVI for aortic stenosis in native valves (NV) with corresponding outcomes in ViV-TAVI procedures; (2) evaluate complication rates for ViV-TAVI and compare the same to NV procedures; and (3) correlate the results with the current literature on the topic to help further define the role of ViV-TAVI in comparison to repeat surgical aortic valve implantation.

The majority of the degenerated BHVs (21 patients, 61.76%) were stented-type surgical aortic valves (SAV). The remaining ViV cases consisted of stentless SAV (14.75%), aortic homograft (2.94%), sutureless SAV (14.75%), and THV (5.88%) prostheses. Functionally, 15 patients (44.11%) had stenosis of their bioprosthesis, 7 (20.58%) had significant regurgitation, and 12 (35.29%) presented with both [36, 37, 38] 18 patients (52.95%) had an aortic BHV with a true ID of 19 mm or less. The mean time from surgery to aortic ViV intervention was 8.65 $\pm$ 5.35 years.

Among ViV-TAVI patients, significantly more had moderate or severe pre-procedure AR [19 (55.88%) vs. 3 (4.41%), p 0.0001.] ViV and NV-TAVI groups were both at moderate surgical risk (STS-PROM score 5.58% and 4.96%, respectively).

Baseline data on ViV patients (n = 34) and patients with native aortic stenosis (n = 68) after PSM are summarized in Table 1.

In-hospital clinical and hemodynamic outcomes are presented in Table 2.

Following hospital discharge, five patients (15.62%) in the ViV-TAVI group and 11 patients (16.92%) in the NV-TAVI group were rehospitalized for cardiac causes (p = 1.000), most commonly for cardiac decompensation due to permanent atrial fibrillation (AF) (60.0%) in the ViV group and acute coronary syndrome (36.36%) in the non-ViV group. Infective endocarditis incidence [2 patients (6.25%) vs. 3 patients (4.61%), p = 1.000] and NYHA stage III or IV at 12 months [6 patients (23.07%) vs. 8 patients (15.09%), p = 0.3578] did not differ. 12-month mortality was comparable [ACM (all-cause mortality): 4 patients (11.76%) vs. 6 patients (8.82%), p = 0.588; CVM (cardiovascular mortality): 4 patients (11.72%) vs. 5 patients (7.35%), p = 0.441].

ViV patients had a significantly higher residual MAVG at 6 and 12 months [6 months: 14.83 $\pm$ 8.81 mm Hg vs. 6.96 $\pm$ 4.36 mm Hg, p 0.0001; 12 months: 14.00 $\pm$ 7.76 mm Hg vs. 6.60 $\pm$ 4.19 mm Hg, p 0.0001], whereas the post procedure presence of moderate or severe AR did not differ [6 months: 1 patient (3.44%) vs. 3 patients (5.17%), p = 1.000; 12 months: 1 patient (3.84%) vs. 4 patients (7.54%), p = 1.000].

Clinical and hemodynamic outcomes of the 12-month follow-up are presented in Table 3.

Functional status (NYHA stage) improved significantly (p 0.0001) and equally between the two groups (p = 0.613) (Fig. 2). MAVG was significantly reduced in both groups post procedure (p 0.0001), in the ViV-TAVI group, this reduction was significantly lower (p = 0.036) (Fig. 3).

There was no difference in 30-month survival between the groups [ACM: 8 patients (23.52%) vs. 19 patients (27.94%), p = 0.948; CVM: 8 patients (23.52%) vs. 11 patients (16.17%), p = 0.239] (Fig. 4). For patients undergoing ViV intervention, only cardiovascular cause of death was recorded.

For the SVG subgroup, we found only numerically higher MAVG compared to LVG before interventions (40.22 $\pm$ 11.61 mm Hg vs. 32.13 $\pm$ 20.64 mm Hg, p = 0.261). However, a significantly higher MAVG was observed for SVG after ViV interventions compared to LVG at 6 months follow up [immediate: 17.2 $\pm$ 10. 2 mm Hg vs. 11.6 $\pm$ 4.7 mm Hg, p = 0.119; 6 months: 18.7 $\pm$ 10.1 mm Hg vs. 10.6 $\pm$ 4.5 mm Hg, p = 0.027; 12 months: 16.8 $\pm$ 8.8 mm Hg vs. 10.6 $\pm$ 4.7 mm Hg, p = 0.0502]. MAVG was significantly reduced in SVG and LVG post procedure (p = 0.001), equal between the two subgroups (p = 0.948) (Fig. 5). The number of patients with moderate or severe AR also decreased significantly in SVG and LVG (p = 0.004), equal between the two subgroups (p = 0.252). There was no difference in CVM between the two subgroups based on true ID (SVG and LVG) at 1 year and 30 months [11.11% vs. 12.50%, p = 0.889; 22.22% vs. 25.0%, p = 0.742] (Fig. 6).

Our study groups had comparable risk profiles, allowing the outcome differences between ViV and NV to be attributed with reasonable certainty to the ViV vs. NV aspect of the procedure. We did find that the mean residual aortic pressure gradient was significantly higher at 6 months and 12 months in patients undergoing ViV implantation at 6 months and 12 months, but the degree of aortic insufficiency noted was comparable.

While our total number of ViV-TAVI procedures in this single center study was, of course, limited,ViV-TAVI was a feasible and safe strategy for the treatment of degenerated BHVs in terms of in-hospital, 6-month and 12-month clinical outcomes. These results comport with the findings of a recently published meta-analysis involving 1442 patients undergoing ViV-TAVI and 6986 patients undergoing NV-TAVI interventions [7].

In-hospital and 1-year mortality rates following ViV-TAVI were 8.8% and 11.8%, comparable to those observed in the NV-TAVI group. In our patients, there were no major strokes or TIAs observed immediately or during the hospital stay, and our device success rate was comparable between ViV and NV-TAVI groups (88.23% vs. 91.17%), findings also in agreement with the literature [1, 38, 39, 40, 41, 42, 43, 44, 45].

A direct comparison of survival rates between our ViV-TAVI patient group and reported survival rates of patients undergoing redo-surgical valve replacement is difficult, since TAVI patients in general, and ViV-TAVI patients in particular, are selected for TAVI since they have a lower life expectancy and higher operative risk then surgical candidates. A recent series of contemporary outcomes in repeat aortic valve surgery patients showed short term mortality data similar to our ViV-TAVI group (9.5%), but long-term outcomes far superior (74% survival at 5 years in the published surgical patient series) [46]. This is in accordance with a recent review and meta analysis of ViV-TAVI versus surgical redo aortic valve replacement publications, showing a reduction in mortality of 30%for ViV-TAVI, but, inter alia, less severe patient-prosthesis mismatch in the surgical group, and higher post-operative aortic valve gradients in the ViV-TAVI group [47].

As expected, our patient groups were older (77 years on average for both groups). Further, BMI was 29.69 for the ViV group and 29.51 for the NV group. Malnutrition and frailty have recently emerged as important factors (possibly amenable to corrective intervention) for long-term outcomes after TAVI [48, 49]. While the degree of patients’ frailty was not comprehensively assessed in our patient database, judging by their similar age and BMI values, a significant difference in this important marker was not likely present between groups.

Our subgroup analysis, as expected, shows that the presence of small BHVs (true ID $\le$19 mm) is associated with significantly higher gradients after ViV intervention, a factor to be considered when selecting the appropriate treatment mode for patients with degenerated small surgically placed aortic valves [50, 51, 52, 53, 54]. In fact, the higher MAVG that was (predictably) noted post-procedure in our ViV group reemphasizes the need to consider annulus enlargement techniques in small native annulus patients at the time of primary surgical valve placement, and to strongly consider redo-surgery in patients presenting with degenerated surgically placed aortic valve prostheses [55].

Bioprosthetic valve fracture techniques have recently emerged as a possible solution to the small annulus size of surgically implanted valves [56]. In our series of 34 ViV-TAVI procedures, only two valves were fracturable. Further, our patient series begins in 2012, whereas the procedure gained popularity only at the end of the last decade. Looking forward, however, fracturing of suitable valves now is accepted as an adjunct procedure to ViV that may have a key role in improving hemodynamics. Lastly, following NV-TAVI, coronary occlusion is a rare (1%) but life-threatening complication [57, 58]. While initial data had suggested that this might be up to four times more common (~3.5%) during ViV-TAVI [59], such a difference in the cohorts was not noted, in keeping with newer data reported by others [2, 3, 7, 60].

Our study has several limitations. Despite the application of propensity score matching and the use of appropriate exclusion criteria, the possible influence of other potentially confounding factors cannot be excluded. Furthermore, although the data analysis included all patients undergoing ViV-TAVI in this single-center study, the number of patients undergoing ViV implantation was relatively low.

In summary, our data, obtained over a span of 15 years from a single, large cardiovascular center, suggest that ViV-TAVI is a reasonable treatment option with a risk profile comparable to NV-TAVI procedures. A higher MAVG, especially for SVG, was noted, but it was not associated with a short- or medium- term survival disadvantage.

ACM, all-cause mortality; AF, atrial fibrillation; AKI, acute kidney injury; AMI, acute myocardial infarction; BAV, balloon aortic valvuloplasty; BHV, bioprosthetic heart valve; BMI, body mass index; BVF, bioprosthetic valve failure; CABG, coronary artery bypass grafting; CAD, coronary artery disease; CKD, chronic kidney disease; COPD, chronic obstructive pulmonary disease; CPR, cardiopulmonary resuscitation; CVM, cardiovascular mortality; DM, diabetes mellitus; HLP, hyperlipoproteinaemia; HT, hypertension; ICD, implantable cardioverter defibrillator; ID, internal diameter; LVEF, left ventricular ejection fraction; LVG, large valve group; MACCE, major adverse cardiac and cerebrovascular events; MAVG, mean aortic valve gradient; MR, mitral regurgitation; NV, native valve; NYHA, new york heart association; PAD, peripheral arterial disease; PCI, percutaneous coronary intervention; PE, pulmonary embolism; PP, permanent pacemaker; PPM, patient prosthesis mismatch; PSM, propensity score matching; SAV, surgical aortic valve; SD, standard deviation; SE, self-expanding; sPAP, systolic pulmonary artery pressure; STS-PROM, society of thoracic surgeons predicted risk of mortality; SVG, small valve group; TAVI, transcatheter aortic valve implantation; THV, transcatheter heart valve; TIA, transient ischemic attack; TR, tricuspid regurgitation; TTE, transthoracic echocardiography; ViV, valve-in-valve.

The anonymized data that support the findings of this study are available from the first author (PVB) upon request following institutional patient privacy guidelines.

PVB: Designed the research study, performed the research wrote the manuscript. BM: Wrote the manuscript, analyzed the data. ZH: Analyzed the data. GD: Performed the research, wrote the manuscript. ZP: Performed the research. GH: Performed the research. AA: Performed the research. CMH: Performed the research, wrote the manuscript, provided help and advice on English spelling and grammar. NRC: Performed the research. SS: Performed the research. TP: Performed the research. GF: Performed the research. PA: Performed the research, supervision. All authors contributed to editorial changes in the manuscript. All authors read and approved the final manuscript. All authors have participated sufficiently in the work and agreed to be accountable for all aspects of the work.

The study was conducted in accordance with the Declaration of Helsinki, and approved by the Medical Research Council Scientific and Research Ethics Committee (ETT TUKEB) (IV 1562/2022/EKU), and written consent was obtained from participants enrolled to the study.

The authors appreciate the ability to use the REDCap Data Base in the process of this research project.

This research received no external funding.

The authors declare no conflict of interest.