INTRODUCTION

Over the past decade, the self-expandable CoreValve (Medtronic Ltd, United States) and the balloon-expandable SAPIEN valve (Edwards Lifesciences Ltd, United States) were the valves most commonly used for transcatheter aortic valve implantation (TAVI).1

There are few studies comparing Evolut PRO (Medtronic Ldt, United States) vs SAPIEN 3 (Edwards Lifesciences Ltd, United States), like the SMART trial for small aortic annuli2 and the ALSTER-TAVI all-comers registry.3 However, comparative randomized clinical trials are lacking. Therefore, we designed the present randomized study to provide a head-to-head comparison between these 2 valves regarding procedural data and in-hospital outcomes especially paravalvular leak (PVL). Although the transcatheter heart valves used in this trial are not the latest generation valves of the CoreValve and SAPIEN families (currently, the Evolut-Pro plus and the SAPIEN Ultra), this is the first randomized clinical trial to compare a self-expanding valve with an outer skirt to a balloon expandable valve (with an outer skirt too).

METHODS

Study population

A total of 110 consecutive patients with severe symptomatic aortic stenosis eligible for TAVI were randomly assigned to receive the Evolut PRO valve (51 patients) or the SAPIEN 3 valve (59 patients) at Duisburg Heart Center, Duisburg, Germany, from December 2019 through May 2020. All patients undergoing TAVI for severe aortic stenosis with the SAPIEN 3 and the Evolut PRO via femoral access were included. Patients who underwent TAVI with other valve types like transapically implanted aortic valves, bicuspid aortic valves, and valve-in-surgical-bioprosthesis implantation were excluded. All procedures were performed after obtaining the patients’ written informed consent and in compliance with the national research committee ethical standards.

Procedural aspects

TAVIs were performed under local anesthesia and conscious sedation. Femoral cutdown was used in all the patients. Annular dimensions were obtained by transesophageal echocardiography-guided balloon sizing during the procedure. With this technique we were able to measure annuli with transesophageal echocardiography and then choose a balloon equal to annular size. Balloon inflation during rapid pacing and aortic angiography were performed with 3 different possibilities in mind a) the balloon completely fills the annulus with no para-balloon leak or waisting indicative that annular size equals the balloon size; b) para-balloon leak is indicative that the annulus is 1 mm to 2 mm larger than balloon size; c) balloon waisting is indicative that the annulus is 1 mm to 2 mm smaller than balloon size.4 Valve type (SAPIEN 3 or Evolut PRO) was randomly selected (using simple randomization method; Monday cases for Evolut and Thursday cases for SAPIEN). Valve size was based on the annular dimensions as suggested by the manufacturers. Based on annular diameter and the diameter of the valve finally selected, a so-called cover index was calculated.5

Endpoints

Our primary endpoints were PVL, in-hospital mortality, and the rate of permanent pacemaker implantation (PPI). The study secondary endpoints were valve embolization, need for a second valve, aortic rupture or dissection, stroke or transient ischemic attack, major vascular complications, and acute kidney injury. Endpoints were defined according to the Valve Academic Research Consortium-2 (VARC-2) definitions.6

PVL assessment

Immediate PVL was semi-quantitatively assessed using Seller’s criteria 7: 0/4 (absent); 1/4 (mild); 2/4 (moderate); 3/4 (moderate-to-severe); and 4/4 (severe).7 Transvalvular pressure gradients were obtained invasively using the pullback method. Aortic regurgitation index (AR index) was calculated.8

In case of significant PVL ≥ grade II, if needed, balloon postdilatation using the VACS III or NUCLEUS balloon (NuMED, United States) or else implantation of second valve was used. TTE was performed at discharge to quantify PVL according to the main VARC-2 criteria.9

Assessment of anatomical factors possibly associated with PVL

The following measurements were supported by Philips software (Philips Medical, The Netherlands): the left ventricular outflow tract/ascending aorta (LVOT/AAo) angle was defined as the angle between the axis of the first 4 cm of the ascending aorta (contact surface with the upper part of the prosthesis), and the LVOT axis (the valve landing zone) indicated by a line perpendicular to the plane of the aortic valve annulus).10

Aortic angulation (AA) angle was defined as the angle between the horizontal plane and the plane of aortic annulus.11 We categorized it into < 48° and ≥ 48°.12

Both angles were measured in the optimal fluoroscopic deployment position with all 3 coronary cusps in the same plane (figure 1). Valve implantation depth was assessed in the deployment position on the fluoroscopy from the native aortic annular margin on the side of both the non-coronary cusp (NCC) and left coronary cusp to the proximal edge of the deployed valve on the corresponding side13 (figure 2). Aortic root calcification was fluoroscopically assessed as inexistent, mild (small, isolated calcification spots), moderate (multiple large calcification spots) or severe (extensive calcification).13 Presence or absence of LVOT and mitral annular calcification were also noted.

Figure 1. Measurement of different angles. AA, aortic angulation (49.62º). B: LVOT/AAo angle (18.74º). AAo, ascending aorta; LVOT, left ventricular outflow tract.

Figure 2. Measurement of implantation depth in the Evolut PRO value. A: [A = 1.17 mm associated with the NCC, and B = 4.91 mm associated with the LCC], and SAPIEN 3. B: [A = 5.65 mm associated with the NCC, and B = 7.31 mm associated with the LCC]. Note high implantation associated with the NCC due to increased LVOT/AAo angle in the Evolut PRO (A) but not in the SAPIEN 3 valve (B). AAo, ascending aorta; LCC, left coronary cusp; LVOT, left ventricular outflow tract; NCC, non-coronary cusp.

Statistical analysis

Data was collected and analyzed using the SPSS (Statistical Software Package for the Social Sciences, version 20, IBM, and Armonk, United States). Continuous data was expressed as mean ± SD or median (range). Nominal data was expressed as frequency (percentage). For the comparison of nominal and continuous data, the chi-square test and the Student’s t test were used, respectively. Pearson correlation was used to assess the correlation between implantation depth with LVOT and AA angles based on the type of valve. The level of confidence was kept at 95% and hence, P values < .05 were considered statistically significant. Univariable logistic regression analysis was performed for predictors of significant PVL. ROC analysis was performed for the optimum cut-off value of the LVOT/AAo angle for the outcome of significant PVL.

Regarding sample size, assuming a 1:1 ratio in treatment assignments and an estimated rate of a composite primary endpoint (PVL, in-hospital mortality and rate of pacemaker implantation) of 8% in each study group, we estimated that a total of 52 patients were required in each group for the study to reach an 80% statistical power % at a 1-sided alpha level of 0.05

RESULTS

Baseline characteristics

A total of 110 consecutive patients with severe symptomatic aortic stenosis eligible for TAVI were randomly assigned to receive the Evolut PRO (51 patients) or the SAPIEN 3 valve (59 patients). There was no crossover between both study arms. Baseline clinical characteristics were comparable between both types of valves apart from a significantly higher body mass index among SAPIEN 3 patients and a significantly high baseline right bundle branch block in the SAPIEN group (table 1).

Table 1. Patient characteristics associated with the type of valve implanted

Echocardiographic and fluoroscopic findings

The baseline echocardiographic and fluoroscopic findings of both groups were comparable (table 2).

Table 2. Echocardiographic and fluoroscopic data among the different study groups

Procedural data in relation to the type of valve used

There were few differences in procedural data related to valve design and sheath size as shown on table 3.

Table 3. Procedural data associated with each type of valve

Outcomes in association with the type of valve used

There was a significant difference in PVL (both immediate and at hospital discharge) and consequently more balloon postdilatation in the Evolute compared to the SAPIEN 3 group. The use of significantly larger amounts of contrast with the Evolut PRO valves may explain the increased number of acute kidney injury described in this group compared to the SAPIEN valve group. Results were favorable to the SAPIEN 3 valve regarding the endpoints of stroke or in-hospital mortality. However, no statistically significant differences were reported. The rates of device success (absence of a significant PVL (≥ grade II) at hospital discharge, need for second valve implantation, valve embolization, the performance of the prosthetic heart valve, and mortality) were 86% and 98% with the Evolut PRO and SAPIEN 3 valves, respectively; P = .01 (table 4).

Table 4. In-hospital outcomes in patients treated with the Evolut PRO vs the SAPIEN 3 valve

Impact of anatomical factors on PVL

Calcification and the LVOT/AAo angle had a greater impact on PVL in the Evolut PRO compared to the SAPIEN 3 valve. The LVOT/AAo angle was categorized based on the receiver operating characteristic (ROC)-derived cut-off value for the endpoint of significant PVL ≥ grade II: cut-off value = 11º, 80% sensitivity, and 35.8% specificity, area under the curve (0.57; 95% confidence interval, 0.474-0.666; P = .37.) On the other hand, the AA angle did not seem to be very relevant to PVL within the groups (table 5).

Table 5. Association between anatomical factors and PVL in patients treated with the Evolut PRO vs the SAPIEN 3 valves

Table 6 shows the univariate analysis of predictors of ≥ grade II PVL immediately after the procedure. As demonstrated, moderate and severe valvular calcification, LVOT calcification, and the LVOT/AAo angle contribute to PVL significantly.

Table 6. Univariate analysis of predictors of significant immediate postoperative PVL (grade ≥ 2)

Impact of LVOT/AAo and AA angles on implantation depth

There was a significant negative correlation between the implantation depth of the Evolut PRO valve at the NCC and LVOT/AAo angles (r = -0.38; P = .01). There was no such correlation with the SAPIEN 3 valve (table 7).

Table 7. Correlation of implantation depth (in both valves) with the LVOT/AAo and AA angles

DISCUSSION

In this study 2 important findings were made. First, implantation of the Evolut PRO valve was associated with a higher risk of significant PVL compared to the SAPIEN 3 valve. Secondly, the rate of PPI was equal in both groups. Otherwise, both types of valves yielded similar outcomes.

Reducing PVL is an important challenge regarding TAVI as it is associated with worse outcomes especially with the current use of these devices in lower-risk patients.14

A randomized comparison between the CoreValve and SAPIEN XT valves in the CHOICE trial revealed a lower rate of moderate-to-severe PVL in the SAPIEN XT group.15 In the SOLVE-TAVI trial, the non-inferiority of 2 devices (SAPIEN 3 and Evolut R) was reported in terms of their primary efficacy composite endpoint (death, stroke, paravalvular regurgitation, and new pacemaker implantation).16 Currently, the SAPIEN 3 Ultra and Evolut PRO+ have been developed with early favorable outcomes.17

In our study, relevant PVL (≥ grade II) was more common in patients who received the Evolut PRO compared to the SAPIEN 3 valve (9.6% vs 6.8%, respectively). Enríquez-Rodríguez et al. reported a lower rate (2.5%) of moderate to severe PVL with the SAPIEN 3 valves possibly due to the presence of an external sealing cuff.18

Obviously, anatomical factors are important for the occurrence of PVL. We observed that larger LVOT/AAo angles were associated with a higher rate of PVL, particularly with the Evolut PRO valve. Sherif et al. demonstrated that the risk of PVL increases with larger LVOT/AAo angles.10 We also observed that the LVOT/AAo angle affects implantation depth in association with the NCC with the Evolut PRO, but not with the SAPIEN 3 valves. It is quite conceivable that implantation depth impacts the rate of PVL.

Sherif et al. were the first ones to report on the association between increased AA angles and postoperative PVL with self-expanding valves.10 A subsequent retrospective study conducted by Abramowitz et al. described a higher rate of complications (eg, postoperative PVL in patients with horizontal aortas (defined by an AA ≥ 48º as seen on the cardiac CT scan) who received self-expanding valves.11 We observed that AA angles impacted PVL in patients who received Evolut PRO valves even if these angles were < 48º with no significant differences in the rate of PVL for AA angles < 48^º or ≥ 48^º.

In this study we also observed 6 patients with AA angles ≤ 30º (3 patients with Evolut PRO and 3 patients with SAPIEN 3). All of them were free of PVL immediately after valve deployment. One could speculate that AA angles ≤ 30º are the best for Evolut PRO valve implantation, but the small size of the sample prevents us from drawing any definitive conclusions.

In our study, the rates of device success determined by the absence of a significant PVL (≥ grade II) at hospital discharge, need for a second valve, valve embolization, the performance of the prosthetic heart valve, and the mortality rate according to VARC definition9 were 86% and 98% with the Evolut PRO and SAPIEN 3 valve, respectively. Similarly, Li et. al found a high device success rate for both the SAPIEN 3 and the Evolut R valve (94% and 96%, respectively).19

We found similar rates of postoperative conduction defects and PPI for both Evolut PRO and SAPIEN 3 valve types (7.8% and 5.1%, respectively). Popma et al.20 and Vlastra et al.21 reported lower rates of PPI with new generation balloon expandable valves compared to new-generation self-expanding valves. The comparable rates of conduction defects and PPI with either valve in our study was probably due to the lower implantation depth of Evolut PRO valves.

Li et al. reported higher rates of postdilatation of up to 30% with the Evolut R compared to the SAPIEN 3 valve.19 This was not seen in our study (15.7% and 5.1%, respectively; P = .35). This was probably so thanks to the proper positioning of the Evolut PRO valve and routine predilatation in all our cases.

In this study, in-hospital mortality was similar in both valve groups. Li et al. also reported that mortality was not associated with the type of valve implanted.19 The CHOICE trial also showed a comparable mortality rate with the use of older-generation valves (CoreValve and SAPIEN XT).15

The rates of stroke were similar for both the Evolut PRO and the SAPIEN 3 valve and lower compared to those seen with older generation devices.15,19,22,23 The operators’ experience and improved delivery systems are likely to account for the reduced risk of thromboembolic complications.

Regardless of the type of valve used, acute kidney injury seemed to be slightly more common in our study (5.9% and 3.5% for the Evolut PRO and the SAPIEN 3, respectively) than previously reported. Husser et al.24 noted a rate of 2.7% in SAPIEN 3 valves while Kodali et al.25 reported rates of 1.7%. However, large multicenter studies usually have stricter inclusion criteria so the baseline kidney function of the patients included was better.19

Despite increased sheath/femoral artery ratios with the Evolut PRO valve, the rate of bleeding or vascular complications was similar compared to the SAPIEN 3 valve. Similar results were reported by Li et al.19 and Panchal et al.26

Limitations

This was a single-center study with a small sample size and limited statistical power. As routine computed tomography scan was not part of our study, specific information on the anatomy of the aortic root was not available and no adjustment was performed based on the annular dimensions or degree/distribution of aortic annular calcification. Also, angiography-based measurements of the LVOT/AAo and AA angles may be inaccurate. However, this may have helped exclude selection bias as some operators are reluctant to use self-expanding valves in view of heavy calcifications or severe angulation.

Follow-up was limited to the length of stay (average 1 week). However, this seems reasonable since we focused on procedural aspects. Furthermore, in comparable studies, in-hospital outcome and 30-day follow-up results were quite similar.

CONCLUSIONS

This randomized study demonstrated comparable procedural and in-hospital outcomes for the Evolut PRO and SAPIEN 3 valves except for a significantly higher rate of PVL associated with the Evolut PRO valves. The PVL reported was associated with the LVOT/AAo angle in Evolut PRO group, which also impacted negatively the implantation depth of this type of valve.

FUNDING

None whatsoever.

AUTHORS’ CONTRIBUTIONS

Idea and design: H. M. Elnaggar, M. S. Mahmoud, W. Schoels, and Y. T. Kishk. Administrative support: W. Schoels, M. Kullmer, and M. Dia. Provision of study materials or patients: M. S. Mahmoud, M. Algowhary, and H. M. Elnaggar. Data collection and assembly: M. S. Mahmoud, M. Kullmer, and M. Dia. Data analysis and interpretation: M. S. Mahmoud, Y. T. Kishk, M. Algowhary, and H. M. Elnaggar. Manuscript drafting and final approval: all authors.

CONFLICTS OF INTEREST

None reported.

REFERENCES

INTRODUCTION

Aortic stenosis affects nearly 3% of adults aged > 65 years.1 It often has an initial asymptomatic latent period, but as the disease becomes worse, signs of heart failure, angina, or syncope become evident.1,2 Aortic valve replacement is recommended for most symptomatic patients with echocardiographic evidence of significant aortic stenosis as well as for some asymptomatic patients.1,2

Since the first transcatheter aortic valve implantation (TAVI) was used as a treatment option for severe symptomatic aortic stenosis (sSAS) almost 20 years ago, clinical trial evidence has further increased and continued to validate its use.3 In 2013, TAVI became the treatment of choice for inoperable patients with sSAS, and high surgical mortality risk patients. More recently, this treatment choice has expanded to include patients of intermediate/low surgical mortality risk.4,5

The very recent Placement of aortic transcatheter valve study (PARTNER 3) is among the growing body of robust clinical trial evidence. This is a pivotal, multicenter, randomized, and controlled study in patients with sSAS of low surgical mortality risk.6,7 In PARTNER 3, treatment outcomes with surgical aortic valve replacement (SAVR) were compared to TAVI with the SAPIEN 3 transcatheter heart valve via transfemoral access.6,7 Compared to SAVR, TAVI with the SAPIEN 3 valve reduced the composite endpoint of death, stroke or rehospitalization after 1 and 2 years.6,7 In view of these positive clinical developments, the European Society of Cardiology (ESC)/European Association for Cardio-Thoracic Surgery (EACTS) guidelines now recommend SAVR in younger, low-risk patients, while TAVI is now the treatment of choice in older patients. Also, it can be considered in all other patients with sSAS following careful evaluation of individual clinical, anatomical, and procedural characteristics by the heart team.5

There are no treatment guidelines specific to Spain describing the use of TAVI, but the Spanish Society of Cardiology, as a member of the ESC, endorses the ESC guidelines, and healthcare professionals in Spain follow these ESC guidelines.5 Irrespective of these guidelines, TAVI adoption in Spain remains low compared to other European countries. Despite a higher level of infrastructure available,8 defined as the number of TAVI centres available per million population, there is still significant variability among regions regarding TAVI implantation rates in Spain.9 In 2021, nearly 5000 patients benefited from this transformative minimally invasive technology in Spain. In a recent publication,10 the annual number of TAVI candidates for Spain was estimated at 15 783 patients including low-risk patients. Considering this together with the increasingly evident clinical benefits of TAVI in patients with sSAS, it is important to evaluate the cost-effectiveness ratio of using TAVI vs SAVR for the low surgical risk sSAS patient group for whom TAVI is now advised in recent guidelines.5 Furthermore, compared to SAVR, transfemoral TAVI with the SAPIEN 3 valve has proven cost-effective in the high-and-intermediate-risk population in Spain.11 This further accentuates the need for evidence on the cost-effectiveness ratio of TAVI with the SAPIEN 3 valve in the low surgical risk population of patients with sSAS in Spain. Therefore, the objective of this article is to review the PARTNER 3 data and the economic data from Spain to assess the cost-effectiveness ratio of using TAVI vs SAVR in patients with sSAS and low surgical mortality risk.

METHODS

A cost-utility analysis was developed using methodology validated for the French12 and Italian13 population to estimate changes in both direct healthcare costs and health-related quality of life with the use of TAVI with the SAPIEN 3 valve compared to SAVR in patients with sSAS and low surgical mortality risk (Society of Thoracic Surgeons < 4%) from the perspective of the Spanish National Health System. Costs were measured in 2021 euros and benefits in quality-adjusted life years (QALYs) gained. The incremental cost-effectiveness ratio (ICER) was calculated by dividing the difference in costs between the 2 treatment groups by the difference in QALYs. Consistent with previous studies,11,14 an incremental cost-effectiveness ratio of < €30 000 per QALY gained was used as the willingness-to-pay (WTP) threshold of acceptable cost-effectiveness.

Model structure

Details of the 2-stage model structure have been previously described for the French population.12 In brief, early adverse events associated with TAVI were first captured using the 30-day early adverse events dataset from the PARTNER 3 study6 in a decision tree (figure 1A); subsequently, these data were fed into a Markov model that included 4 distinct health states (‘alive and well’, ‘treated atrial fibrillation [AF]’, ‘disabling stroke’, and ‘dead’) to capture longer-term outcomes of patients after TAVI or SAVR (figure 1B). The model was considered appropriate for the Spanish setting by all authors based on their clinical and health-economic expertise.

Figure 1. Central illustration. The cost-effectiveness model had 2 stages: a) early AEs from the PARTNER 3 trial were captured in a decision tree, which fed into b) a Markov model that captured longer-term outcomes of patients categorized into 4 different health states: ‘Alive and well’= patients who have undergone the procedure and survived with only short-term or no AEs; patients in this health state can transition to ‘disabling stroke’, ‘AF’ or ‘dead’ at any time during the model timespan. ‘Treated AF’= patients who have undergone the procedure and survived, but developed AF requiring specific treatment; this can either occur within the first 30 days or during the rest of the model timespan, and patients in this health state can transition to ‘disabling stroke’ or ‘dead’ at any time during the model timespan. ‘Disabling stroke’ = patients who have undergone the procedure and survived, but had a disabling stroke; this can either occur within the first 30 days or during the rest of the timespan of the model, and patients in this health state can only transition into the ‘dead’ state at any time during the model timespan. ‘Dead’ = this is the absorbing state in the model: all patients in the model are at risk of dying due to general all-cause mortality; patients with treated AF and stroke are at an increased risk of dying.

Reproduced from Gilard M, et al. Value Health 202112 under the terms of the creative commons licence.44 AE, adverse event; AF, atrial fibrillation; SAVR, surgical aortic valve replacement; TAVI, transcatheter aortic valve implantation.

Given that sSAS requires life-long valve replacement, a lifetime timespan of 50 years was selected for the cost-utility analysis with a discounting factor per year of 3% applied for both future costs and benefits following the recommendations set for Spain.15 This timespan was chosen to reflect all potential consequences to individuals with sSAS over their lifetime. Healthcare costs and health-related quality of life was measured using QALYs.

Model inputs

Study overview

The model was informed by the PARTNER 3 study population, which excluded patients with clinical frailty, bicuspid aortic valves or other anatomical features that increased the risk of complications associated with either surgery or TAVI. In the PARTNER 3, 1000 patients were enrolled, 503 of whom were randomized to TAVI and 497 to SAVR, with ‘as treated’ groups of 496 and 454 patients, respectively.6 The primary endpoint was a composite of all-cause mortality, stroke or rehospitalization 1 year after the procedure.

Clinical events

Probabilities of clinical events used in the model (table 1 of the supplementary data) were based on a decision tree that captured all early adverse events experienced up to 30 days after the procedure as reported in the PARTNER 3. Monthly transition probabilities among the Markov model health states were estimated. Regarding the transition from ‘alive and well’ to ‘treated AF’, data from the PARTNER 3 on new-onset treated AF between 30 days and 1 year were used.6 Other literature sources provided a more realistic estimate of the remaining 2 transitions due to the scarcity of these events reported in the PARTNER 3. Burden of stroke data in Spain (Stroke Alliance for Europe)16 were used for the transition from ‘alive and well’ to ‘disabling stroke’, and data from a systematic review/meta-analysis involving 104 eligible cohort studies were used for the transition from ‘treated AF’ to ‘disabling stroke’.17 Myocardial infarction, transient ischemic attack, and severe or life-threatening bleeding were captured as intercurrent events between 30 days and 1 year from PARTNER 3 data.6 Other relevant events like rehospitalization rates using data from the PARTNER 3,6 and reintervention rates due to valve deterioration (data up to 2 years from the PARTNER 3)6,7 and from 3 years onwards from a study on 20-year outcomes of pericardial aortic tissue valve bioprosthesis18 were also considered (table 1 of the supplementary data). In the base case, the same reintervention rate was used for both the TAVI and SAVR arms; this simplifying assumption allowed better use of the available data. In scenario #1, higher reintervention rates were assumed for TAVI with the SAPIEN 3 valve compared to SAVR based on data from the PARTNER 2 at 5 years19 while in scenario #2, an increased risk of stroke was assumed, which was consistent with the PARTNER 3 outcomes.

Table 1. Base case results with acute and lifetime costs

Survival extrapolation

There were 2 options regarding survival extrapolation. In option #1, transition probabilities were taken from the literature (relative risk of death with AF of 1.517; and relative risk of death with disabling stroke of 2.0520). In option #2, parametric survival fitting was performed based on Kaplan-Meier data from the PARTNER 3. A total of 3 parametric distributions were used (Weibull, Exponential, Gompertz) and adjusted to the survival of the overall Spanish population. Therefore, in the base case, survival estimates were based on transition probabilities due to immaturity of survival data from the trial. Annual mortality risk for ‘alive and well’, and other relative risks for other health states are shown on table 2 of the supplementary data. Option #2 (parametric survival analysis) was explored using alternative hazard ratios (HR) in scenario #3: HR, 0.75 from the PARTNER 3 at 2 years adjusted to Spanish population overall mortality. An additional scenario #4 removed any survival benefit with the SAPIEN 3 valve (HR, 1).

Health utilities

There were 2 options for determining utility decrement: option #1 used utility decrements by health state from the literature adjusted by age and Spanish population standards.21 This was the preferred option because there were very few corresponding events in the PARTNER 3, and estimates from the literature were deemed realistic. The age and population standards adjusted utility decrements were 0.16 for AF22 and 0.42 for disabling stroke.23 Option #2 used treatment options from the PARTNER 3 and was explored within scenario #5. The utility decrement for option #2 was individually extracted from the PARTNER 3 at baseline, after 30 days, 6 months and 1 year, and then converted to Spanish health utilities.24

Cost inputs

Costs associated with TAVI and SAVR (procedure, complications, and long-term) are shown on table 3 of the supplementary data. Base case procedure cost information was drawn from the SERGAS.25 We should mention that the SERGAS fee includes market valve and ancillary material price. Also, personnel costs were additionally estimated on a per hour price basis for different professionals. Costs corresponding to complications and health states were drawn from the literature and diagnosis-related groups (DRG). The breakdown of TAVI and SAVR procedure costs are shown on table 4 of the supplementary data. The micro-cost elements are informed from the study conducted by Bayón et al.26 and updated to reflect current TAVI practice in Spanish low-risk patients with sSAS. As costs vary depending on the Spanish region at stake, 3 additional scenarios: 6A, 6B, and 6C were explored using cost information adjusted to reflect current clinical practice in Murcia, Huelva, and Basque regions. Furthermore, a scenario #7 was included to account for early adverse events costs at 30 days.

Model outputs

Key outputs of the model were the overall per-patient costs and QALYs in each arm and ICER.

Sensitivity analyses

To evaluate uncertainty, 1-way deterministic sensitivity analyses were performed by varying inputs using confidence intervals and ranges from the literature when available, and plausible ranges when data were unavailable (table 5 of the supplementary data). Multiple parameters were changed and the impact on the results explored. Overall parameter uncertainty was addressed using a probabilistic sensitivity analysis (PSA) (table 6 of the supplementary data). Several scenario analyses were conducted to explore the impact of major structural assumptions as shown on table 7 of the supplementary data. All analyses were performed using Microsoft Excel (Microsoft Corporation, United States).

RESULTS

Base case

TAVI with SAPIEN 3 improved QALYs per patient (+ 1.0) with higher costs compared to SAVR of approximately €6971 per patient. This represented an ICER of €6952 per QALY, which is lower compared to the WTP threshold of €30 000/QALY that is commonly referenced in the Spanish setting. Base case results over a 50-year timespan are shown on table 1. Further examination of the breakdown of costs for TAVI vs SAVR revealed that although initial procedural costs in the model were higher with TAVI, costs associated with ‘disabling stroke’ and ‘treated AF’ were somehow lower (table 1, and figure 1 of the supplementary data).

Deterministic sensitivity analyses

Univariate sensitivity analyses are displayed in the Tornado diagram (figure 2). SAPIEN 3 TAVI remained cost-effective regardless of any plausible changes to individual model parameters (note: the 20 parameters with the greatest influence on the model are shown on the diagram). The model was most sensitive to age, SAVR procedural costs, and risk of disabling stroke at 30 days with TAVI.

Figure 2. Tornado diagram showing the 20 parameters with greatest influence on the model (deterministic sensitivity analysis).

Probabilistic sensitivity analysis

The results of the PSA confirm the results of the base case analysis. At the conventional WTP threshold of €30 000/QALY, TAVI with SAPIEN 3 remains cost-effective compared to SAVR in 100% of the simulations run in the model (figure 3A). In addition, the cost-effectiveness acceptability curve indicates that SAPIEN 3 TAVI has a 99.9% probability of treatment being cost-effective with a €30 000/QALY WTP threshold (figure 3B). PSA assumptions are shown on table 5 of the supplementary data.

Figure 3. Probabilistic sensitivity analysis: A: cost-effectiveness scatter plot; and B: cost-effectiveness acceptability curve. PSA, probabilistic sensitivity analysis; QALY, quality-adjusted life years.

Scenario analysis

A series of different scenario analyses were conducted to assess the impact of changing various assumptions on the results of the model and the model robustness. TAVI with the SAPIEN 3 valve remains cost-effective compared to SAVR across most of the tested scenarios (table 6 of the supplementary data) including those with different timespans (10, 15, 20, and 30 years). The results from the scenario analyses demonstrate the comparative robustness of the model reported.

DISCUSSION

This analysis suggests that TAVI with the SAPIEN 3 vavle is likely to be a cost-effective valve replacement option for patients with sSAS and low surgical mortality risk in Spain. TAVI with the SAPIEN 3 valve showed an improvement in QALYs (+ 1.0) associated with slightly increased costs compared to SAVR (approximately €6971 per patient). The ICER benefits for TAVI with the SAPIEN 3 shown in this model represent a highly cost-effective intervention (ICER/QALY €6 952) in the Spanish system with a WTP threshold of €30 000/QALY. Uncertainty was assessed using various sensitivity analyses, and the results appeared robust.

The findings of the current study are supported by other cost-effectiveness studies that show that TAVI with SAPIEN 3 is either dominant or cost-effective in patients of low risk surgical mortality risk.27-31 The Spanish findings are also consistent with cost-effectiveness analyses of TAVI with SAPIEN 3 vs SAVR in France12 and Italy13 using the same model structure.

The current analysis is important because TAVI provides patients with a minimally invasive treatment option and a lower risk of complications and/or rehospitalization plus improved recovery rates and quality of life gains. From a provider perspective, TAVI also brings efficiencies by limiting healthcare resource use, reducing postoperative complications, and shortening hospital stays (including Intensive care unit [ICU] beds).32 Shortening the hospital stay allows more patients to be treated in the same hospital, an important element for a health system in high demand and with long waiting lists. These efficiencies also lead to a reduced risk of infections and contamination,33 which was much welcomed during the recent COVID-19 pandemic. Finally, TAVI reduces the recovery period to normal activity that may not be accounted for in this analysis. Indirect benefits like volunteering, grandchild support or less caregiving support most likely would increase even further the overall benefits of this technology.34

The results of this analysis could also enable greater access to TAVI for Spanish patients with sSAS. Recent studies demonstrate the efficacy and safety profile of transfemoral TAVI in Spain.9 This together with the recent European guidelines suggests that the number of TAVIs will increase, thus rendering many low surgical risk patients with sSAS eligible for TAVI. Moreover, with time, TAVI will likely become simplified even further with shorter admission times;35 this should lead to lower TAVI costs in the future. In this regard, the results of this study could inform policy makers on the management of patients with sSAS in Spain.

Limitations

This study comes with certain limitations. The first pertains to certain model inputs and assumptions made. In this model, hospitalization data were based on 1- and 2-year data from the PARTNER 3 study with the assumption that this rate remained constant over the model timespan after 2 years. The impact of this assumption is unknown because individuals from both treatment arms in the model remained at risk of hospitalization. The rate of reinterventions was assumed to remain constant after 22 years; the impact of this assumption on modelled outcomes was deemed minimal based on the expectation that nearly 11% of patients would still be alive in the model after this point in time with limited need for reintervention. Despite of this, uncertainty on the longer-term durability of the TAVI device and subsequent reintervention rates in younger patients cannot be disregarded. Disutilities were not included for any intercurrent events because you can run the risk of counting them twice with the health state utilities being applied to patients in the ‘treated AF’ and ‘disabling stroke’ states. This was a conservative assumption because, apart from pacemaker complications, the rates of intercurrent events are generally lower for TAVI with SAPIEN 3 compared to SAVR.6

A second limitation of this study is the generalizability of the results. Conclusions cannot be generalised to the overall population with aortic stenosis because, among others, patients with unfavourable coronary anatomy were excluded from the PARTNER 3 study. Moreover, caution should be observed when trying to generalize any findings from this model to populations outside Spain.

Finally, we should mention that procedural costs across different regions of Spain are heterogenous. In this study, we use publicly available cost data from a region in Spain and our approach is conservative as we additionally account for current practice. We also conducted multiple scenario analyses with other available cost data sets.

CONCLUSIONS

Data from the PARTNER 3 suggested that the use of TAVI with the SAPIEN 3 valve was more favorable, on the clinical level, compared to SAVR in patients with sSAS and low surgical mortality risk. The results of this cost-effectiveness model indicate that, in Spain, TAVI could provide a cost-effective option over SAVR for this population with an estimated ICER/QALY value well below the national threshold. The model appeared to be robust with uncertainty assessed by various sensitivity analyses. The results of this cost-effectiveness analysis can support policy makers and healthcare budget holders to optimize the management of Spanish patients with sSAS.

FUNDING

Edwards Lifesciences SA, Switzerland provided funding for the economic assessment and was involved in the analysis as well as in the drafting of this manuscript.

AUTHORS’ CONTRIBUTIONS

J.M. Vázquez participated in economic data mining, model validation, and manuscript review. E Pinar in economic data mining, and model validation. J. Zamorano participated in data mining, and model validation. J. Burgos participated in data mining and model validation. J. Díaz participated in data mining, and model validation. B. García del Blanco participated in data mining, and model validation. A. Sarmah in data collection and analysis, result preparation, and manuscript drafting and review. P. Candolfi participated in cost analysis and manuscript drafting. J Shore was involved in model development and manuscript review. M. Green participated in model development, and manuscript drafting.

CONFLICTS OF INTEREST

J.M. Vázquez Rodríguez declared department research or training grants from Edwards Lifesciences, Medtronic, and Boston Scientific, and personal advisory fees from Medtronic, and Boston Scientific. J.L. Zamorano declared research grants from Abbott, and Medtronic to the Institution, and speaker fees from Edwards Lifesciences, Bayer, Novo Nordisk, and Daiichi Sankyo. J. Moreu Burgos declared having received fees from Biosensors, Boston Scientific, Cardiva, Edwards Lifesciences, and Medtronic. A. Sarmah declared to be an employee of Edwards Lifesciences and hold stock options. P. Candolfi declared to be an employee of Edwards Lifesciences and hold stock option. J. Shore declared consultancy fees to the employer for developing the economic model. M. Green declared consultancy fees to the employer for developing the economic model. E. Pinar, J.F. Díaz-Fernández, and B. García del Blanco declared no conflicts of interest whatsoever.

ACKNOWLEDGEMENTS

Writing support was provided by Zenith Healthcare Communications Ltd (Chester, United Kingdom), and funded by Edwards Lifesciences.

SUPPLEMENTARY DATA

REFERENCES

INTRODUCTION

Aortic stenosis is the most common acquired valvular heart disease whose prevalence is around 3% in the population ≥ 65 years up to 7.4% in older ages (≥ 85 years).1 It is also the leading cause of valvular surgery in the adult population.2 Age and sex are among the risk factors (higher incidence rate in men).3,4 After symptom onset, mortality rate is high (up to 50%) during the following years.5,6 Due to the continuing growth of the elderly population in our country,7 a significant burden of disease associated with aortic stenosis is expected8 with the corresponding challenge that this poses to the healthcare system.

Until 14-15 years ago the only therapeutic option was surgical aortic valve replacement. In patients considered inoperable due to their age or comorbidities, the therapeutic alternative was only aimed at symptom control. Transcatheter aortic valve implantation (TAVI) created a new option of therapeutic opportunity for inoperable or high-risk patients at the beginning followed by intermediate-risk patients, and eventually for low-risk patients.9-13 Despite this, the rate of treatment with TAVI in Spain is significantly lower compared to other European countries.14 Although there are numerous reports and registries in Europe on the clinical results of TAVI, the evidence available in Spain on the local results from public ownership sources is scarce although 10 years have already gone by since the first TAVI was performed back in April 2007.14

This study presents the current evidence on the real-world clinical practice available in our country on the use of TAVI including a description of the profile of cases treated, the results obtained in terms of mortality, complications, and length of stay (LoS). Also, the main factors associated are analyzed from the perspective of the Spanish National Health System using the Activity Registry of Specialized Health Care (RAE-CMBD) as the main source of information.

METHODS

Minimum Data Set

This study is based on information included in the RAE-CMBD of the Spanish Ministry of Health, Consumer Affairs, and Social Welfare. It provides detailed information on the demographic characteristics of hospitalized patients, administrative variables, and clinical variables associated with the diagnoses and procedures of both the patient and type of healthcare received. The diagnoses and procedures registered are coded according to the International Classification of Diseases, Ninth Revision – Clinical Modification (ICM-9-CM) for 2014-2015, and the International Classification of Diseases, Tenth Revision – Clinical Modification (ICM-10-CM) for 2016-2017 that is more specific with diagnoses.

This analysis included all episodes registered from 2014 through 2017 of patients > 50 years of age hospitalized in centers of public or public-private partnership after performing the following procedures: “Endovascular replacement of aortic valve” (ICM-9-CM code: 35.05), and “Replacement of aortic valve with zooplastic tissue, percutaneous approach” (ICM-10-CM code: 02RF38Z). Cases treated with extracorporeal circulation were excluded (ICM-9-CM code: 39.61, and ICM-10-CM code: 5A1221Z) for considering that TAVI does not need this technique, which would, therefore, be a coding mistake of the episode. Similarly, episodes of rehospitalization were excluded to complete the patient’s recovery.

The safety analysis included all complications coded in chapter 17 of ICM-9-CM, and in particular, with codes from category 996: “Complications peculiar to certain specified procedures” including complications not classified under other concepts, and in the use of artificial substitutes involving internal device implantation, among others. On the other hand, in the most recent ICM-10-CM classification, this type of complications can be found under category T82 “Complications of cardiac and vascular prosthetic devices, implants, and grafts”. Also, due to their potential association with TAVI and great interest from the clinical standpoint events such as acute kidney injury, acute myocardial infarction, aortic dissection, stroke, sepsis, and permanent pacemaker implantation (PPI) were considered as well.

Statistical analysis

A descriptive analysis of the study variables was conducted. Continuous variables were expressed as means and standard deviations. The categorical ones as absolute and relative frequencies. The differences between 2 independent groups were compared using the Student t test or the U Mann-Whitney-Wilcoxon test based on their distribution (parametric or nonparametric, respectively). The chi-square test or Fisher’s exact test were used with the categorical variables. Multivariate models were implemented to identify factors associated with the risk of in-hospital mortality, significant complications (logistic regression), and LoS (negative binomial regression). Demographic and clinical variables were examined as explanatory variables: age, sex, rate of implantation in the autonomous community where the procedure was performed, complications, and level of severity of each case based on the RAE-CMBD classification (stratified depending on the characteristics of each patient, diagnoses, and procedures) and categorized into a 4-level scale:15,16 mild, moderate, major or extreme according to the severity-adjusted Diagnosis Related Groups (DRG).

To analyze the possible differences among autonomous communities in the volume of TAVIs performed, the rates of implantation standardized per 100 000 inhabitants (×10⁵) were estimated. The seasonal population of each region in the period adjusted by age group (50-74, 75-84, ≥ 85), and sex was taken as the reference point.17 Discrimination between high- and low-volume regions was made by categorizing the rates of implantation. Rates above the national average during the study period were considered high-volume regions (37 procedures × 10⁵ inhabitants). Differences in the baseline characteristics of patients treated in high- and low-volume autonomous communities were taken into consideration during the adjustment of multivariate models.

The independent variables of all logistic regression and negative binomial models were reviewed by clinical experts to guarantee their clinical sense and then selected in such a way that the resulting model would minimize the Akaike information criterion.18 Once the best model was determined in each case, the odds ratios (OR) and their 95% confidence intervals (95%CI) were estimated to determine whether a certain factor was associated with a higher risk (OR > 1) in the presence of a given result and then compare the size of several factors.

Regarding the multivariate analysis of complications, when the number of cases registered was low and statistical power of contrast was limited, all major complications were grouped following the clinical criterion once again. This is how factors associated with the risk of bleeding and accidental puncture or laceration (ICM-9-CM: 998.11, and 998.2 | ICM-10-CM: I97.4, I97.6, and I97.5*), acute myocardial infarction (ICM-9-CM: 410.*1 | ICM-10-CM: I21*), PPI (ICM-9-CM: 37.8 | ICM-10-CM: 5A1223Z), sepsis, and infections (ICM-9-CM: 995.91, 995.92, and 998.5 | ICM-10-CM: T81.4XXA, and A41*); acute kidney injury (ICM-9-CM: 584 | ICM-10-CM: N17*); and stroke (ICM-9-CM: 997.02, 434, and 435 | ICM-10-CM: I97.8*0, I66, I63.3, I63.4, I63.5, G45*, and I67.82) were identified and assessed.

All statistical contrasts were bilateral, and differences with P values > .05 were considered statistically significant. Statistical analysis was conducted using the statistical software package R (version 3.6.1).

RESULTS

A total of 5454 cases with transcatheter aortic valve implantation via transfemoral access were accounted for: 763 cases reported in 2014, 1171 in 2015, 1477 in 2016, and 2043 back in 2017. Implantation was more common in women (52.2%), mostly in patients between 81 and 85 years of age, both men (37%) and women (44%). Mean age was 81.12 ± 6.43 years during the entire period. Overall, the most common diagnoses that triggered the patients’ hospitalization were aortic valve disease (79.7%, ICM-9-CM, and ICM-10-CM codes: 424.1, and I35, respectively) followed by mitral valve regurgitation, and rheumatic stenosis (3.1%, ICM-9-CM, and ICM-10-CM codes: 396.2, and T82.0*XA, respectively), and congestive heart failure (2.9%, ICM-9-CM, and ICM-10-CM codes: 428.0, and I08.0, respectively).

Rates of transfemoral TAVI, mortality, and hospital stay

The number of TAVIs performed remained variable across the years, and grew gradually with significant increases reported between 2014 and 2017 both in the number of centers where this procedure was conducted and in the overall number of TAVIs performed. Therefore, the national implantation rate (× 10⁵ inhabitants) doubled, and the mean during the study period was 33 procedures × 10⁵ inhabitants (table 1).

Table 1. Implantation rate per 100 000 inhabitants, mean hospital stay, and in-hospital mortality rate per autonomous community

The overall mortality rate during the entire period was 3.6% with an obvious decrease from 2014 (4.8%) through 2017 (2.7%) despite the fact that the severity profile assigned to the patients remained constant across the 4 years studied (in 70% of the patients the severity-adjusted DRG score was extreme).

Regarding the length of hospital stay associated with the procedure, the LoS reported in 2014 was 13.1 ± 12.5 days dropping gradually down to 11.3 ± 10.6 days in 2017 with great variability among the different autonomous communities (table 1). When extreme cases were eliminated (defined as cases with stays > 2 standard deviations with respect to the mean), the mean national hospital stay was 8.9 ± 4.69 days, and differences among autonomous communities were reduced from 6.07 ± 4.8 to 11.35 ± 4.31 days; see table 1.

Complications associated with TAVI

Table 2 describes the complications associated with TAVI. Same as it happened with mortality, a gradual reduction in the rate of the most significant complications was reported from 2014 through 2017. The need for PPI was 12.2%, also with great variability of this complication among the different autonomous communities.

Table 2. Complications associated with TAVI

Factors associated with mortality risk, hospital stay, and complications associated with TAVI

Table 3 describes the profile of cases treated, and the results of the procedures performed in high- and low-volume regions. High-volume autonomous communities treated older patients (80.47 vs 81.91, P < .001) with a rate of extreme risk that was slightly lower (70.3% in low-volume autonomous communities vs 67.1% in high-volume autonomous communities; P = .013). In these autonomous communities, it was reported that the population treated had a lower rate of comorbidities such as diabetes, arterial hypertension, heart failure, chronic obstructive pulmonary disease or smoking (table 3).

Table 3. Comparative analysis between high- and low-volume autonomous communities regarding TAVI

Procedural results also varied between high- and low-volume autonomous communities: in high-volume regions, the duration of the LoS was shorter and the risk of certain complications like need for PPI, sepsis or infections was lower too. However, these regions reported a higher risk of acute kidney injury in the bivariate analysis (table 3).

Due to these differences, age, sex, and the level of severity of each case were included in the programmed multivariate models to adjust the analyses of the explanatory variables associated with the in-hospital mortality rate. Figure 1 shows that aortic dissection (OR, 20.58; 95%CI, 6.27-62.40; P < .01), and postoperative shock (OR, 18.16; 95%CI, 9.43-35.16; P < .01) were significantly associated with the postoperative mortality rate. The explanatory weight of other complications like acute myocardial infarction, acute kidney injury, cerebral artery occlusion or heart complications was significantly lower. Mortality differences between high- and low-risk autonomous communities did not reach statistical significance in the overall period studied (figure 1).

Figure 1. Mortality and hospital stay registered based on the rate of implantation and occurrence of procedural complications. Figures represent the impact that the independent variables selected in the logistic multivariate (mortality) or negative binomial models (hospital stay) have on every complication. The following were always among the candidate variables considered: sex, age, region-adjusted volume of TAVIs performed, and level of severity (RAE-CMBD). Axes in the coordinate plane vary based on the sizes of the odds ratio presented. AMI, acute myocardial infarction.

On the other hand, the higher severity of the cases, and the appearance of some complications contributed to a significant increase in the duration of the LoS (figure 1). The level of severity was also the factor that kept a stronger correlation with the occurrence of complications such as bleeding and accidental puncture or laceration, acute myocardial infarction, PPI, acute kidney injury, and stroke (figure 2). In high-volume autonomous communities, the risk of sepsis or infections and need for PPI was significantly lower compared to low-volume autonomous communities (OR, 0.77; 95%CI, 0.65-0.91; P < .01, and OR, 0.54; 95%CI, 0.32-0.9; P = .02, respectively). Finally, we should mention that high-volume autonomous communities also had a significantly shorter LoS that was 12% shorter compared to low-volume autonomous communities (OR, 0.88; 95%CI, 0.86-0.91; P < .01) as shown on figure 1.

Figure 2. Results of the logistic regression analysis on the risk of clinical complications. Figures represent the impact that the independent variables selected in the multivariate models (genetic algorithm selection following the Akaike information criterion) have on every complication. The following were always among the candidate variables considered: sex, age, region-adjusted volume of TAVIs performed, and level of severity (RAE-CMBD). Axes in the coordinate plane vary based on the sizes of the odds ratio presented.

DISCUSSION

Our study main finding was that transcatheter aortic valve implantation via transfemoral access is safe and effective in Spain. Secondly, with the growing number of procedures performed each year and the experience gained, the rates of non-lethal complications, and mortality (2.7% over the last year studied) have reduced gradually.

It is undeniable that TAVI is a safe and effective procedure according to the scientific evidence available from clinical trials,12,13,19 and meta-analyses.20,21 That is why its indication has probably widened from inoperable high-risk patients to intermediate and low-risk patients. This study includes evidence from sources from the Spanish Ministry of Health, Consumer Affairs, and Social Welfare including data from the real-world routine clinical practice in our country.

In Spain, data from the National Registry of Activities in Interventional Cardiology of the Spanish Society of Cardiology Working Group on Hemodynamics and Interventional Cardiology22 and from RAE-CMBD show a considerable increase in the number of cases treated in the 2014-2017 period22 in all autonomous communities. Even so, in our country, the rate of TAVI is still significantly lower compared to other countries.14 We should mention the ongoing improvement reported in the rates of mortality (56.25% reduction in the study period), non-lethal complications, and LoS despite the high rates (around 70%) of cases reported of extreme severity according to the codification of cases in the RAE-CMBD.

Unlike previous studies that showed a worse prognosis in men after implantation data do not show any significant differences based on sex.23 Indeed, the factors that seem to be associated with a higher mortality rate are postoperative shock, sepsis, aortic dissection, and myocardial infarction. In this case, the patient’s risk ratio and the volume of implantation are clearly associated with a different mortality rate, which may have to do with the fact that more experience has been gained with this procedure in the entire country. Consistent with this, data from the CMBD have shown a better mortality rate after conventional surgical aortic valve replacement of 3.3% in 2017 (3.6% in patients between 70 and 80 years of age, and 4.3% in patients > 80 years of age).24

The rate of PPI found was similar to the one reported by other authors in our country.22 In this case, coding the severity of the cases treated was actually associated with a higher risk. The need for PPI after TAVI has been associated, above all, with the type of valve used (this need is greater with self-expanding valves).25 In our analysis, it is impossible to distinguish the type of valve used because this information is not on the data provided by the RAE-CMBD. Both the need for postoperative PPI and the appearance of infectious processes and sepsis after the procedure were inversely associated with a higher number of procedures being performed. This association between the volume of procedures performed and fewer complications has already been described in different settings such as after coronary revascularization26 or after conventional surgical aortic valve replacement,24 among others.

Added to its clinical benefits, TAVI has consolidated as a cost-effective alternative to conventional surgical aortic valve replacement. The fact that the procedural results of TAVI have become safer and more effective gradually with lower mortality and morbidity rates and shorter LOSs is probably associated with the experience gained by the surgeons, the volume of procedures performed, and the technical and technological advances made.24

The growing elderly population in our country and the growing number of indications are the reason why the number of TAVI-eligible patients has been growing.1,11 In this sense, it is important to add new evidence to contribute to the assessment of the health outcomes of these procedures27 to guarantee homogeneous quality services in our National Health System. Also, to provide assessment mechanisms to the strategic lines defined in cardiovascular health28 since TAVI has consolidated a cost-effective option compared to conventional surgical aortic valve replacement.29,30

Limitations

The use of an administrative database to obtain information has obvious pros and cons. On the one hand, it allows us to draw a great deal of information from the national census thanks to the obligatory nature of this registry. Also one of its strengths is the high data standardization.27 However, the administrative nature of the RAE-CMBD whose clinical variables are based on the discharge summary, the thoroughness of coding, and the possible inconsistencies among centers when implementing the codes can impact the accuracy of the results. However, since the period analyzed is a 4-year period, we could say that there are no substantial changes in coding capable of impacting the results significantly. Still, we should mention that the specific codes of complications of ICM-9-CM may not include all the complications that can occur during TAVI. Despite of this, all major clinical complications for the analysis of procedural results were studied. On the other hand, the analysis conducted took into consideration data from the RAE-CMBD until 2017, the most recent ones collected to this date. Also, it would be good to analyze data collected over the last years to see how results evolved. We should expect these results to be even better given the increased number of TAVIs performed, the surgeons’ greater experience, and the improved technology available. This should be analyzed by future studies.

Added to this, we should mention that the information collected in this analysis comes from procedures registered in public or public centers with shared activity. Therefore, discrepancies can be found with the data published by the National Registry of Activities in Interventional Cardiology of the Spanish Society of Cardiology Working Group on Hemodynamics and Interventional Cardiology in absolute terms.22 Still, both sources barely differ in the percentage of cases seen that require PPI (overall difference of 2% in 2016, and 0.1% in 2017 being the data from the Registry of the Spanish Society of Cardiology Working Group on Hemodynamics and Interventional Cardiology) greater.

One of the last limitations of this study is that only the episode that triggered the implantation was analyzed, and no long-term results were obtained, which would provide quality information to assess the extent and cost of healthcare. However, the results from this study are interesting to the extent that they provide key information on aspects to go deeper in the generation of arguments for quality healthcare management.

CONCLUSIONS

TAVI is a safe and effective procedure whose implantation rate is on the rise. Still, there is a huge variability between different autonomous communities and hospitals in Spain. This procedure is mostly performed in patients > 75 years of age with low morbidity and mortality rates that can be compared absolutely to those of conventional surgery. Rates have been going down over the 4 years studied (2014-2017) with gradual reductions in the postoperative LoS, especially in autonomous communities with higher implantation rates.

FUNDING

This study has been funded by Edwards Lifesciences S.L.

AUTHORS’ CONTRIBUTIONS

M. Álvarez-Bartolomé, and J. Cuervo conducted both the validation and statistical management of data. All authors contributed to the study design, conducted the critical review of the manuscript, and gave their final approval. Also, they take full responsibility in all aspects of the study by guaranteeing its integrity and accuracy.

CONFLICT OF INTERESTS

B. Martí-Sánchez is a member of Edwards Lifesciences S.L., the sponsor of this study. J. Cuervo is a member of Axentiva Solutions and received fees for his scientific consulting work for Edwards Lifesciences S.L.

BIBLIOGRAFÍA

INTRODUCTION

Despite growing experience and the development of new closure devices, the rates of vascular complications after transcatheter aortic valve implantation (TAVI) remain high (between 5% and 18%).1-6 Recently, a new collagen plug-based device was recently introduced. Favorable results have been reported regarding the rate of vascular complications associated with this new collagen plug-based MANTA vascular closure device (Essential Medical Inc., United States) compared to suture-based devices.7-9 However, due to several potential disadvantages (including major bleeding events with rates that go from 1% to 16%), limited data on future vessel accessibility, and significantly higher costs, the routine use of the new device has been put into question compared to suture-based devices.7,10,11 Since puncture sites can safely be closed using suture-based devices, the new generation of plug-based systems may, therefore, be a valuable alternative as a bail-out strategy in case of failed suture-based devices.

However, one drawback of the MANTA system as a bail-out device is that it requires to know exactly the distance between the skin incision and the vessel for safe deployment and functionality purposes before inserting the large introducer sheath. Unfortunately, the vendor-specific measuring tool is not wrapped separately. Therefore, we aimed to validate 2 alternative measuring techniques including the preoperative multidetector computer tomography (MDCT), and the Angio-Seal device before inserting the large introducer sheath to get significant information of the depth of the vessel without having to unwrap the device.

METHODS

Patient and procedural characteristics

Patients agreed to the data retrospective anonymized analysis. A total of 168 consecutive patients with severe aortic stenosis scheduled for TAVI were included. All patients were evaluated by interdisciplinary heart teams. As a standard procedure all patients received MDCT to plan TAVI. All procedures were performed under local anesthesia. In all the cases both femoral arteries were used. One side for the TAVI sheath and the other for the pigtail catheter for the angiography plus a 7-Fr arterial line for hemodynamic monitoring. Routine closure follows with a Proglide closure device and a 6-Fr Angio-Seal device for the TAVI side plus a 6-Fr Angio-Seal for the contralateral side.

Measuring the depth of the vessel

Preoperatively, the depth of the vessel was measured using preoperative MDCT. The depth of the vessel was measured on a split screen using the Picture Archiving and Communication System imaging modality. In all the patients the measurements were obtained perpendicularly at skin level towards the femoral artery at mid-femoral head level (figure 1).

Figure 1. Measuring technique of the vessel depth at mid-hip head level (25 mm + 10 mm = 35 mm MANTA depth).

Perioperatively, measurements were obtained using the introducer sheath of a 6-Fr Angio-Seal device as follows. The introducer sheath reaches the vessel when bleeding through the indicator channel of the introducer sheath starts (figure 2A). In this position the letter or dot on the outside of the introducer sheath is noted and translated into distance using the schematic representation shown on figure 2B and table 1. According to the instructions for use of the MANTA vascular closure device, 1 cm had to be added. Then, the deployment depth of the MANTA device was noticed.12

Figure 2. A: Measurement of the vessel depth equal to ‘O’. B: Translation into distance using the scheme shown on table 1 eventually ending in a MANTA depth of 5.5 cm.

Following these precautionary measures, 1 suture-based Proglide closure device was inserted and TAVI was performed as usual.

Table 1. Vessel depth measured using the Angio-Seal device. Eventually, 1 cm had to be added to be able to use the MANTA bail-out device

Vascular closure

During closure, operators aimed for systolic blood pressures < 160 mmHg. Heparin, and protamine were used at the operator’s discretion. The delivery sheath was removed with a standard on-site wire while the access site was closed using the prepared Proglide system plus an additional 6-Fr Angio-Seal device. If the prepared suture-based system ruptures or in the presence of remaining severe bleeding following the insertion of the 8-Fr Angio-Seal introducer sheath, the introducer of the Angio-Seal was removed without implanting the plug, a MANTA vascular closure device was inserted, and then released based on the predefined vessel depth. The wire was removed after the final angiography to identify all possible access site-related complications. The contralateral side was closed using a 6-Fr Angio-Seal device.

A 300 mg clopidogrel loading dose was administered postoperatively, but not in patients already on clopidogrel. In patients on oral anticoagulants, therapy was interrupted prior to the procedure. All operators were familiar with all the vascular closure devices used.

Postoperative follow up

All patients received compression bandage at the puncture site for 6 hours and were monitored on an intermediate care unit for, at least, 24 hours. All the medical attention provided to the puncture site due to residual bleeding, and all postoperative imaging such as MDCT scan or duplex sonography were documented until hospital discharge.

Statistical analysis

The categorical variables were expressed as counts (percentages) while the continuous variables were expressed as median [interquartile range]. The correlation between measurements was estimated using Spearman’s rank correlation coefficient.

The data supporting this study findings are available from the corresponding author upon reasonable request.

RESULTS

A total of 168 patients treated with transfemoral TAVI were included. Patients were typical TAVI patients. The patients’ baseline characteristics are shown on table 2.

Table 2. Baseline characteristics

Measurements from preoperative MDCTs were obtained from all patients revealing a moderate correlation compared to perioperative measurements obtained using the vendor-specific MANTA mea- suring tool (r = 0.64; P < .001; figure 3).

Figure 3. Correlation between the depth of the vessel measured on the previous multidetector computer tomography and on the vendor-specific measuring tool. CT, computed tomography.

Measurements using the Angio-Seal device were also successfully obtained from all patients revealing a high correlation with the vendor-specific MANTA measuring tool (r=0.99; P < .001).

Successful vascular closure was achieved in 158 cases using as a standard closure including the suture-based Proglide and the 6-Fr Angio-Seal device. The bail-out MANTA device was required in 10 patients (5.9%) due to Proglide suture rupture (n = 5) or remaining severe bleeding after insertion of the Angio-Seal introducer sheath (n = 5). The MANTA closure device was successfully inserted thanks to the measurements obtained with the Angio-Seal device before large sheath insertion. A total of 40 patients (23%) needed medical attention on the puncture site including prolonged pressure bandage or CT scan or duplex sonography. A total of 7 patients (4.1%) required postoperative surgery at the puncture site. One patient already carried a previous MANTA bail-out device that eventually led to a complete vascular occlusion due to known arterial occlusive disease. A total of 4 patients suffered a pseudoaneurysm after the routine use of the Proglide and the Angio-Seal that could not be treated by thrombin injection.

DISCUSSION

Although the rate of access site-related vascular complications after TAVI has decreased over the last few years, these complications are still associated with higher mortality and morbidity rates.2,3,6,13 In this context, suture-based closure devices such as the Prostar or the Proglide are safe and effective widely used tools.14 Although the use of the Prostar is associated with a lower risk of vascular stenosis, the use of the Proglide device has led to lower rates of adverse events such as device malfunction or residual bleeding.2,13,15,16 However, both systems rely on a similar suture-based technique that demands careful preparation before the large delivery sheath can be inserted. The safe use of these closure devices after the insertion of large delivery sheaths is not possible anymore. Therefore, in case of closure device failure and severe bleeding, covered stent implantation using the cross-over technique or surgery to achieve hemostasis may be the only option left. Although the implantation of a covered stent graft is an effective treatment option for bleeding control, implanting covered stents using the cross-over technique can be challenging. Also, the external iliac and common femoral arteries are exposed to flexion of the hip joint, which may be associated with higher stent compression and fractures.17-19 Additionally, the costs of covered stents are high.

Surgery should be spared as the last resort option only as it often needs to be performed under general anesthesia and the loss of blood is high until the surgical cut-down is prepared. Furthermore, wound infection or lymphatic fistulae may occur, thus delaying the patient’s mobilization after TAVI, which may be associated with pneumonia or thrombosis.

Recently, a new plug-based closure device, the MANTA vascular closure device, has entered the clinical arena, and proved its efficacy and safety profile after TAVI. The first reports show rapid hemostasis and low rates of complications after implantation of the MANTA device, even lower compared to the Prostar and the Proglide vascular closure devices.9 In contrast with this, a recently published randomized clinical trial showed similar results regarding access site bleedings compared to the Proglide system. However, while suture-based closure required additional closure devices more often like the Proglide or the Angio-Seal, the MANTA closure device numerically required complex maneuvers more often like covered stents or surgical bail-out strategies. The reason behind this may be the crossing of the wire through the toggle, which cannot be re-accessed using additional devices like the Angio-Seal or the Proglide.20

The considerably higher costs involved, 4 times more expensive compared to the Proglide, the unknown influence on the femoral artery wall, and re-access after device implantation have delayed the quick market penetration of this device as well as its routine use.

However, when using the MANTA vascular closure device, it is of utmost importance to measure the distance between the skin and the vessel accurately to ensure the precise placement of the anchor. During a scheduled MANTA procedure, this measurement is routinely obtained before the insertion of the large delivery sheath using a dedicated 8-Fr device that comes together with the MANTA device in the sterile package. This measurement may be cumbersome and yield inaccurate values if performed after the large sheath has been inserted given the degree of device-related bleeding. Therefore, we evaluated 2 different techniques to obtain this important data before the insertion of a large introducer device without having to unwrap the device to be prepared for a potential bail-out use. Compared with previous data we proved that a moderate correlation exists in the measurements obtained from preoperative MDCT only that were not good enough to allow the use of the MANTA device safely.21 An inaccurate release of the system could lead to malapposition with persistent major bleeding especially in small or heavily calcified vessels or even to the vessel total occlusion. This inaccuracy may be explained by a smaller angle in the direction of the stitches compared to the perpendicular measurements obtained on the MDCT or to a different distribution or position of a skin flap in very obese patients during the MDCT and the procedure.

In contrast, the measurements obtained with the Angio-Seal device followed by an imaging-based predefinition of the corresponding MANTA implantation depth kept a close association with the measurements of the MANTA device. With this information, the femoral artery can be safely closed after a failed Proglide system. Unsolvable failed suture-based device with an additional Angio-Seal or Proglide due to severe bleeding or suture rupture occurred in 5.9% of the patients. Bail-out with MANTA insertion was successful in all patients. Only 1 patient required surgery due to a complete vascular occlusion (Thrombolysis in Myocardial Infarction grade-0 flow) associated with the MANTA device. In retrospect, a prior MDCT had revealed a very small vessel diameter and wall calcification at the puncture site. In these patients, a surgical cut-down would have been the access of choice.

The method presented here is also helpful in other clinical settings without prior MDCT in which large bore sheath are used such as delayed closures after emergency extracorporeal membrane oxygenation or Impella device placement (Abiomed Inc., United States). In these cases, a wire can be inserted through the arterial cannula or Impella CP introducer, and late vascular closure can then be safely achieved using a MANTA vascular closure device. To avoid the unpacking of the sterile device before the simple measuring method the use of an Angio-Seal is cost-effective, not time consuming, and provides information for future reference in case it is needed.

Limitations

The lack of randomization, and the small number of patients are obvious limitations of this study that should be taken into consideration when analyzing the data presented here.

CONCLUSIONS

Compared to MDCT measurements, the routine measurement of vessel depth using the Angio-Seal device stands as a simple option to obtain exact values to allow the bail-out use of the MANTA device in cases of failed suture-based closure device after TAVI. This method can also be used effectively in cases of delayed vascular closures of late explantations of the Impella device or emergency cannulations for venoarterial extracorporeal membrane oxygenation.

FUNDING

None whatsoever.

AUTHORS’ CONTRIBUTIONS

J. Blumenstein, T. Maruskin, O. Husser, and H. Möllmann contributed to the design, analysis, and writing of this manuscript. D. Sötemann, C. Eckel, C. Grothusen, G. Dohmen, C. Tesche, and H. Al.Terki contributed to both the writing and supervision of the manuscript.

CONFLICTS OF INTEREST

Neither one of the authors have made any disclosures regarding this manuscript, and they have all met all the requirements defined by the International Committee of Medical Journal Editors regarding the criteria for authorship of scientific articles.

REFERENCES