Changes in mitral annular morphology following transcatheter mitral valve repair. Clinical repercussion and importance of etiology

INTRODUCTION

During transcatheter aortic valve implantation (TAVI), coronary computed tomography angiography (CCTA) remains the key factor to determine the characteristics of the aortic valve and predefine the size of annular valve prior to the selection of specific transcatheter heart valves (THV).1,2 Several CCTA protocols were described to achieve reproducible and reliable aortic annulus measurements.3,4 At the same time, transthoracic and transesophageal echocardiographic measurements were used to determine the aortic valve annular size showing good correlation with the gold standard of direct surgical and CCTA-based measurements.5,6 However, CCTA showed better image quality acquisition, detailed evaluation of the aortic annulus, and other useful anatomies for transfemoral TAVI (aorto-iliac-femoral vessels)7 making CCTA the default strategy for preoperative planning.

Adequate THV size selection is an important factor to prevent patient-prosthesis mismatch and reduce the risk of over- and under-sizing and, hence, the increased risk of all cause-mortality and unplanned repeat reintervention.6,8,9 While CCTA has been established as the gold standard method for annular sizing pre-TAVI implantation,4 an associated risk between radiation exposure and cancer, and contrast media and nephropathy has also been described.10,11 Furthermore, in selected cases, CCTA may not be feasible prior to TAVI following emergency clinical indications and/or the patients’ unstable conditions.

Aortography-only annular measurement was described as an efficient technique to determine the size of aortic annulus and select the size of the THV.12,13 Based on the standard 3-cusp view, the angiographic determination of anatomical dimensions with contrast media (and/or balloon-sizing) can facilitate the identification of proper annular size when CCTA-based sizing is not available.14-17 Aortography-based measurements have been shown to correlate with direct anatomical preoperative aortic annulus measurements.13

Against this background, we sought to investigate whether angiographic aortic valve annular measurements between the non-coronary (NCC) and left coronary cusp (LCC) correlate with CCTA-based measurements to facilitate proper size selection of the THV in a retrospective, all-comers, single-center cohort of patients undergoing TAVI.

METHODS

Study population

This retrospective, observational analysis evaluated all consecutive patients undergoing transfemoral TAVI following heart team evaluation at the German Heart Center cardiovascular disease unit in Munich, Germany. Transfemoral TAVI was performed using a minimalistic approach18 in all cases, while THV size selection was left to the operator’s discretion based on size chart, CCTA measurements, anatomical factors including calcium distribution and severity, aortic valve annular size, coronary height, and disease.

All patients with native tricuspid calcified aortic valve disease, and available high-quality CCTA for TAVI were included in this study. Procedural information was obtained from a customized database and screened for all patients treated from January 2014 through December 2021 at the German Heart Center in Munich, Germany. During this period, a total of 2500 transfemoral TAVI cases were performed using commercially available balloon-expandable (1865) and self-expanding (635) THVs. Only those who received the SAPIEN 3 or the SAPIEN 3 Ultra (Edwards Lifesciences, United States) balloon-expandable valves (BEV) were included in this analysis.

The study was performed in full compliance with the principles set forth in the Declaration of Helsinki, and all patients gave their written informed consent to undergo the procedure. Ethical approval was obtained from the Technical University of Munich ethical committee under registry no. OBSERVTAVI (#525/17). CCTA measurements were performed before THV implantation. Angiographic aortic valve annular measurements between the NCC and LCC were performed offline and documented in the database. The baseline clinical and procedural characteristics (including size of the implanted THV and angiographic aortic regurgitation after implantation), and test lab results were obtained from registry data or the clinical records, as appropriate. Regarding the Valve Academic Research Consortium 3 (VARC-3) defined safety and efficacy profile, in-hospital and discharge follow-up was monitored and registered. A 30-day follow-up was established via telephone call, hospital visits or follow-up letter.

Coronary computed tomography angiography measurements

CCTA was analyzed by 1 experienced cardiologist (HA) while a second experienced cardiologist (JM) analyzed a sample of 40 cases to determine inter-observer variability. Using multi-slice computed tomography reconstruction, quantitative measures of the aortic valve annular size (minimum, maximum and mean diameter, perimeter, and area) were obtained based on predefined protocols2 using 3-Mensio software (Pie Medical Imaging, The Netherlands). In summary, the 3 hinge points of the aortic cusps were detected and selected. After proper identification of the 3 hinge points, the aortic annulus was seen in automatic multiplanar reconstruction. Annular measurements were obtained 0.5 mm below the hinge points, and the aortic valve annular contour was traced to calculate the perimeter-derived area and diameter (figure 1A). To define the direct one-planar measurement between the NCC and the LCC on the CCTA, a straight line between the red (LCC) and yellow (NCC) hinge points was used to determine length (figure 1B,C). The most appropriate THV size was selected based on size chart recommendations and anatomical considerations (figure 1D). CCTA-based measurements and calculations were used to determine the proper THV size according to commercial size charts supplied by the manufacturer. The mean diameter and area of the aortic annulus were used to select the THV size (23 mm, 26 mm, and 29 mm) and then coded as a binary variable for each size category; when only 1 measurement was within the proposed range for a specific THV size based on the manufacturer’s size chart (within the gray zone), the area was used to decide the final THV size.

Figure 1. Central illustration. A: aortic annulus CCTA measurements determining the minimum (19.6 mm), maximum (25.9 mm), and mean (22.8 mm) diameter, perimeter (73 mm), and area (394 mm²). B: CCTA measurement from the lowest point between the left coronary cusp (red dot) and the non-coronary cusp (yellow dot) with a 23.0 mm distance. C: CCTA prediction of angiographic angulation to obtain the standard 3-cusp view (cranial right anterior oblique view of first and seventh nerves) with the left-coronary cusp from 1 side (red dot) and the non-coronary cusp on the other side (yellow dot), and the distance between them (23.0 mm). D: angiographic result after balloon-expandable valve implantation based on the tomographic measurements shown on figure 1 A (SAPIEN 3 Ultra 23 mm).

Aortographic measurements

All procedures were performed by experienced TAVI operators using a monoplane digital flat panel detector X-ray system (Allura Xper FD 10 C, Royal Philips, The Netherlands) in a dedicated hybrid cath lab. All fluoroscopic 3-cusp view images were analyzed after completion of the procedure and images with distance measurements saved. Angiographic measurements were obtained offline from the angiographic aortic root injection (native annulus without the implanted THV) using a 5-Fr pigtail catheter placed in the right coronary cusp in the standard 3-cusp view.14,15 The distance between the NCC and LCC hinge points was measured by experienced cardiologists (HA and JM) using dedicated Phillips software (figure 2A-H). Angiographic measurements were performed after automatic (based on calibration factor determined by the software) and manual (using the 5-Fr catheter as reference calibration factor) calibration to determine the distance in millimeters.

Figure 2. A: standard 3-cusp cranial right anterior oblique view of first and seventh nerves (red circle) to determine longitudinal measurement (yellow arow) in the best contrasted image (green circle). B: calibration option based on the best image available (yellow arrow). C: measurement option (red arrow) to determine the distance on the aortic annulus (yellow size) on the images saved (green circle). D: saved image (red arrow) to “start analysis” (yellow arrow). E: manual calibration based on the 5-Fr catheter (red arrow and arrowhead) drawing 2 lines over the catheter (red circle) comparing the calibration factor given by the software (0.1451 mm/pixels, yellow arrow) to the one obtained through manual calibration (0.1486 mm/pixels, yellow arrowhead). F: “longitudinal measurement” option should be selected (red arrow) drawing a line at the hinge point of the left and non-coronary cusp (red circle). G: for automatic calibration, select “accept automatic calibration” (yellow arrow); the calibration factor given by the software (0.1451 mm/pixels) will be used for measurement purpose (yellow arrowhead, calibration factor of 0.1451 mm/pixels). H: aortic valve annulus measurement using automatic calibration selecting “longitudinal measurement” (red arrow) and drawing a line between the hinge points of the left and non-coronary cusp (red circle).

Endpoints

Endpoints were the correlation between angiographic and CCTA measurements of the distance between the NCC and the LCC. The rates of the VARC-3-defined efficacy (technical success, correct position, and intended performance using VARC-319 definitions) and safety profile (multiple valves, valve embolization, pacemaker implantation, and more than moderate valvular regurgitation using VARC-3 definitions) in patients with concordant and discordant measurements between angiographic and CT-based measurements were also analyzed.

Rates of in-hospital complications defined as conversion to surgery, perioperative death, life-threating bleeding, major and minor bleeding, major and minor vascular complications, and in-hospital mortality in patients with concordant and discordant measurements were reported. The 30-day mortality rate, chronic heart failure, stroke, valve dysfunction, aortic mean gradient, and aortic regurgitation were reported too.

Statistical analysis

Categorical variables were expressed as frequencies and proportions and compared using the chi-square test or Fisher’s exact test, as appropriate. Continuous data were tested for normality with the Shapiro-Wilk test and expressed as mean (± standard deviation) or median (interquartile range [IQR]) as appropriate, and then compared, respectively, using the unpaired t test or the Mann-Whitney U test.

The study population was divided into derivation (n = 1256), and validation cohort (n = 40 cases). The study group of interest was obtained from the derivation cohort (n = 393). In the derivation cohort, selection of specific THV sizes (23 mm, 26 mm, and 29mm) based on the gold standard CCTA assessment was categorized as a binary variable and then compared to the THV size selection derived from aortography. Subsequently, logistic regression analysis was performed using the binary variable from the CCTA-based THV selection as a dependent variable while aortographic distance measurements were considered an independent variable. Afterwards, the receiver operating characteristic (ROC) curve was analyzed to identify optimal cut-off criteria (distance in mm, Youden’s index) and determine individual diameter ranges based on aortographic distance measurements of each category of THV sizes. The lowest value from the smallest THV and the highest value from the largest THV was determined using the 25^th and 75^th IQR, respectively, taken from the distribution of the derivation population. The suggested THV size was derived using aortography with manual or automatic calibration. Sensitivity, specificity, positive, and negative predictive values, as well as positive and negative likelihood were used to determine diagnostic accuracy index. Bland-Altman plots were used to test correlation between the CT NCC-LCC and the NCC-LCC aortography with manual calibration and NCC-LCC aortography with automatic calibration.

Inter- and intra-observer analysis using intraclass correlation coefficient (with absolute agreement) and Pearson correlation coefficient for dichotomized data were performed in a sample of 40 cases between the 2 independent cardiologists.

To perform internal validation, previously established cut-off values to determine THV size by aortography were applied in a separate cohort of 40 patients (validation cohort) and compared using the gold standard CCTA-based sizing determination.

Pairs of sizing results based on angiography and CCTA were generated as a study group of interest and classified as concordant or discordant after comparison using the chi square test or Fischer’s exact test, unpaired t test or the Mann-Whitney U test, as appropriate. Statistical analysis was performed using IBM SPSS Statistics software package (version 27, IBM Corporation, United States). All tests were 2-sided at the 0.05 significance level.

RESULTS

After exclusion, 1256/2500 (50.2%) patients who received a BEV were evaluated in the validation cohort (figure 3). Aortography-based diameter measurements were feasible in 393 of these patients (15.7%) (study group of interest).

Figure 3. Study enrollment flow diagram.

Baseline and CCTA characteristics are shown on table 1. The median age of the entire population was 81 (77-85) years, 34.3% female, with a left ventricular function of 60% [47-60], and a median EuroScore II of 3.74 (2.14-6.24).

Table 1. Baseline characteristics

Procedural characteristics are shown on table 2. Procedural time, fluoroscopic dose, and fluoroscopic time were 48 min [38-59], 919 [444-1712] cGys/cm², and 10.9 min [8.2-14.7], respectively. Technical success was achieved in 95.4% of the cases. Regarding in-hospital complications (table 3), there rates of major bleeding events, major vascular complication, and in-hospital mortality were 16.1%, 14.6%, and 1.5%, respectively.

Table 2. Procedural characteristics

Table 3. In-hospital complications

No differences were reported regarding the efficacy (94.2% vs 96%; P = .60) and safety profile (90.9% vs 91.9%; P = .84) between discordant and concordant pairs of tomographic and angiographic measurements using aortography with manual calibration, respectively (table 4).

Table 4. Procedural complications in concordant and discordant valve sizes using manual and automatic calibration in aortography vs CCTA (N = 393)

A moderate correlation was seen between CCTA-based assessment and aortographic THV size determination: 23 mm, 26 mm, and 29 mm THV sizes were associated with Spearman’s correlation coefficients of 0.528 (P < .01), 0.451 (P < .01), and 0.579 (P < .01), respectively. For more details, see tables 1-3 of the supplementary data.

The suggested angiographic cut-off values for each THV size are shown on table 5. In brief, the best diameter range for selecting 23 mm BEVs was 18.46 mm to 22.55 mm; for 26 mm THVs the best diameter range was 21.55 mm to 24.55 mm while for 29 mm THVs the best diameter range was ≥ 24.25 mm to < 28.50 mm. The intra- and inter-observer intraclass correlation coefficients were 0.931 (95%CI, 0.869-0.963; P < .01), and 0.902 (95%CI, 0.814-0.948; P < .01), respectively (see table 4 of the supplementary data). The CT NCC-LCC distance and NCC-LCC showed an intraclass correlation coefficient of 0.885 (95%CI, 0.834-0.920; P < .01) (figure 4).

Table 5. Suggested angiographic size chart for the Sapien balloon-expandable valve

Figure 4. Bland-Altman plots: A: CCTA vs AOMC; B: CCTA vs AOAC. AOAC, aortography with automatic calibration; AOMC, aortography with manual calibration; CCTA, coronary computed tomography angiography; CI, confidence interval; ICC, intraclass correlation coefficient; SD, standard deviation.

The values obtained were tested and compared with the validation cohort (n = 40) showing moderate-to-good diagnostic test analysis with a good Spearman’s correlation coefficient [0.711 (95%CI, 0.506-0.840; P = < .01)], and moderate diagnostic accuracy (table 5 of the supplementary data). The validation cohort of 40 patients is shown on tables 6 to 10 of the supplementary data.

The 30-day follow-up is shown on table 6. There was no difference in 30-day mortality between discordant and concordant tomographic and angiographic measurements (1.7% vs 2.6%; P = .73). There was no difference at 30 days regarding the mean gradient (11 [10-16] vs 12 [10-15] mmHg; P = .76), and more than moderate aortic regurgitation (3.2% vs 1.1%; P = .34) using aortography with manual calibration between discordant and concordant tomographic and angiographic measurements, respectively.

Table 6. 30-day follow-up comparing concordant vs discordant measurements using balloon-expandable valve

Discussion

This single-center, retrospective, observational study investigated the correlation and diagnostic accuracy between angiographic and tomographic measurements to determine THV size according to 1 single angiographic measurement between the NCC and the LCC in patients treated with BEV.

Regarding this objective, the most salient findings are a) angiographic aortic valve annular size determination based on distance measurements between the NCC and LCC is reproducible; b) diagnostic accuracy between CCTA-based and angiography-based aortic valve annular size determination is of moderate strength (table 5 of the supplementary data); and c) internal validation of previously established diameter ranges for angiography-based aortic valve annular size determination revealed moderate diagnostic accuracy.

We found a moderate overall diagnostic accuracy and correlation between angiographic and CCTA measurements to determine aortic valve annular size for THV selection. The use of angiography only measurements may expand the minimalistic TAVI approach in scenarios where CCTA is not an option or is unavailable.

The gold standard method to size the aortic annulus is direct surgical measurement, which is impossible in the TAVI setting. Hereby, several non-invasive reproducible methods have been used to determine the aortic valve annular size.3,5-7,20 However, the CCTA has been established as the gold standard diagnostic tool to determine aortic valve annular size dimensions4 due to its outstanding reproducibility. Before CCTA was established as the actual gold standard method, angiographic measurements were used demonstrating good correlation with direct perioperative measurements in patients undergoing surgical aortic valve replacement (r = 0.93).13 The comparison of transesophageal echocardiography and CCTA and direct perioperative measurements reported by Wang et al.20 showed a moderate correlation. Our study showed moderate diagnostic accuracy and correlation between angiographic and tomographic measurements to determine THV size. Similar results were previously tested in a small sample size of 50 patients where 60% of the valves were properly sized with fair-to-moderate agreement between angiography- and CCTA-guided selections.12 This provides evidence that angiography measurements could potentially be used in scenarios where CCTA is not available or its application is of increased risk.

Radiation exposure during CCTA assessment

It has been shown that TAVI-related imaging studies can potentially increase radiation exposure by some 15.4 to 79 mSv (millisieverts) with the TAVI procedure alone accounting for an effective dose of 26.9 ± 8 mSv and a dose-area product of 2006.3 ± 1152.2 cGys/cm² (centiGrays/cm²). This radiation exposure is associated with a 70% and 50% increased risk of lung cancer-related death in women and men, respectively, and a 12% to 21%, and 23% to 33% risk of leukemia in women and men, respectively.10 We should mention that our study population experienced lower procedural radiation exposure (919 [444-1712] cGys/cm²) during TAVI including aortic valve annular sizing that may reduce radiation-associated risk of cancer. Using intraoperative low-dose radiation protocols can achieve equal efficacy in TAVI patients same as standard protocols without compromising safety,21 thus reducing radiation exposure and its associated risk. Additionally, the use of balloon-sizing combined with our proposed angiographic measurements may increase accuracy when determining the necessary THV size. Specifically, when the aortography annular measurement falls near the cut-off value between 2 different THV sizes, balloon-sizing can be used to confirm the use of the larger or smaller device.15 Although the additional use of balloon-sizing could increase radiation exposure due to additional imaging acquisition, the use of low-dose radiation protocol can reduce this risk without impacting the final result.21

Contrast media-associated nephropathy

Besides the benefits of mitigating radiation-associated risks, contrast media-associated nephropathy remains a critical concern in patients undergoing TAVI. Chronic kidney disease is present in around 38% of patients with aortic valve stenosis, 55%, 30%, and 15% of whom show mild, moderate, and severe chronic kidney disease.22 The use of contrast media can exacerbate acute kidney injury after its administration in patients with moderate-to-severe chronic kidney disease (from 2% to 17%)11 with a higher estimated 5-year mortality rate.22

Previous studies have demonstrated the safety and efficacy profile of TAVI compared to surgical aortic valve replacement across all ranges of surgical risk.23-28 Against this background, our data suggest that using aortography is safe to facilitate THV size selection in selected indications. In cases where aortography THV sizing was concordant with CCTA determined THV size, the safety and efficacy outcomes reported compared favorably to studies published in similar risk categories of patients.

Study limitations

This study is limited by its single-center observational nature. A randomized or prospective study may be needed to confirm our results. Furthermore, the use of 1 type of fluoroscopy equipment may limit the applicability of the findings to fluoroscopy equipment from alternative manufacturers. Additionally, due to data storage limitations, angiography was not always available to determine the aortic valve annular size through manual or automatic calibration. Upper and lower values of the suggested size chart were determined based on 75^th and 25^th interquartile range, respectively, due to the lack of upper or lower outliers that would allow us to determine these values.

CONCLUSIONS

Angiographic aortic valve annular measurements are reproducible and show moderate correlations and diagnostic accuracy compared to CCTA measurements when selecting the proper BEV THV size. This technique may be appropriate in situations when CCTA is not available, when high radiation exposure needs to be avoided, for patients in critical condition, and to reduce the risk of contrast-induced nephropathy. This strategy could potentially advance the minimalistic TAVI approach in selected patients.

FUNDING

None whatsoever.

AUTHORS’ CONTRIBUTIONS

H. A. Alvarez-Covarrubias: conceptualization, methodology, formal analysis, investigation, resources, and original drafting of the manuscript. M. Kasel: conceptualization, original drafting of the manuscript, and editing. J.M. Michel: original drafting of the manuscript, and formal analysis. S. Cassese: visualization, investigation: S. Kufner: supervision, and data curation. C. Duesmann, C. Pellegrini, T. Rheude, and N. P. Mayr: resources, and data curation. H. Schunkert: supervision, drafting and revision of the manuscript, and visualization editing. A. Kastrati: supervision, visualization, drafting and revision of the manuscript, and editing. E. Xhepa: drafting of the manuscript, supervision, and formal analysis. G. Borrayo-Sánchez, and M. Joner: conceptualization, drafting and revision of the manuscript, and project administration.

CONFLICTS OF INTEREST

M. Kasel reports being a proctor and consultant for Edwards Lifesciences, but totally unrelated to this study; J. M. Michel reports a being proctor for Boston Scientific, but totally unrelated to this study; S. Cassese reports having received grants from Abbott Vascular, Boston Scientific, and SIS Medical AG, consulting fees from SIS Medical AG, and speaker fees from Abiomed, Astra Zeneca, SIS Medical AG, and Teleflex, but totally unrelated to this study; S. Kufner reports having received speaker and consultant fees from AstraZeneca, Bristol Myers Squibb, Bentley, and Translumina, but totally unrelated to this study; C. Pellegrini reports having received a grant from Else-Kröner Fresenius Memorial Stipendium, but totally unrelated to this study; T. Rheude reports having received lecturer fees from SIS Medical AG, and Astra Zeneca, but totally unrelated to this study; H. Schunkert reports having received consulting, honoraria, and speaker fees from AMGEN, Daiichi-Sankyo, MSD SHARP&DOHME, Astra Zeneca, Bayer Vital, Boehring-Ingelheim, Novartis, Servier, and Synlab, but totally unrelated to this study; A. Kastrati reports a patent number PCT/EP2021/053116, and participation on the Data Safety Monitoring Board of the DSMB-TARGET Trial, but totally unrelated to this study; E. Xhepa reports having received lecturer and speaker fees from Astra Zeneca, Boston Scientific, and SIS Medical AG, and support for attending meetings from Abbott Vascular, but totally unrelated to this study; G. Borrayo reports being former president of the Asociación Nacional de Cardiólogos de México from 2020 through 2022; M. Joner reports having received grants from Boston Scientific, Cardiac Dimensions, Edwards Lifesciences, Infraredx, consulting fees from Biotronik, TriCares, Veryan and Shockwave, and lecturer and speaker fees from Abbott Vascular, Biotronik, Boston Scientific, Edwards Lifesciences, Cardiac Dimensions, Astra Zeneca, Recor Medical, and Shockwave, but unrelated to this study; the remaining authors declared no conflicts of interest whatsoever. This manuscript is part of the Masters and PhD program in medical sciences of Universidad Nacional Autónoma de México (UNAM).

SUPPLEMENTARY DATA

REFERENCES

INTRODUCTION

Aortic stenosis (AS) is the most common cause of valvular heart disease1 with an estimated prevalence of 3%-5% in people ≥ 65 years to 7.4% in people > 85 years.2,3 Severe AS is the leading cause of valvular surgery among adults. AS typically has a variable but long latent period (asymptomatic) followed by a rapid progression stage after symptom onset (eg, dyspnea, angina or syncope), and has a poor prognosis if aortic valve replacement is not performed in a timely manner.4,5

Although open heart surgery has been the gold standard treatment for many years, aortic valve procedures have progressively become less invasive. Transcatheter aortic valve implantation (TAVI) has become the treatment of choice for inoperable patients with symptomatic, severe AS,6 and a valid alternative for high- and intermediate-surgical risk patients with improved clinical results regarding survival and functional capacity.7,8 Similarly, with new evidence from recent clinical trials, the indication for TAVI was extended to low-risk patients.9,10

According to current clinical guidelines,11 the multidisciplinary decision regarding procedures to solve AS requires an individualized and appropriate assessment of the candidates to optimize the benefits achieved in these patients (eg, regarding survival and symptom amelioration). To this end, significant factors impact the patients’ surgical risk (eg, surgeon-specific risk-adjusted composite according to the Society of Thoracic Surgeons [STS] score), the patient’s quality-adjusted life expectancy, baseline characteristics like frailty (eg, ≥ 2 score in the Katz scale), modifiable risk factors, and comorbidities (eg, chronic obstructive pulmonary disease, pulmonary hypertension, liver disease, previous stroke, anemia, and other systemic conditions). In Europe, recent guidelines recommend TAVI for patients > 75 years. Also, that all patients with AS between 70 and 75 years should be referred for TAVI assessment regardless of their surgical risk.12

Due to the wider indication for TAVI and the ageing demographic factor seen in Western countries,3 TAVI is increasingly used in the routine clinical practice across Europe. This underscores the importance of monitoring TAVI outcomes, particularly among elderly patients to better characterize performance in the real-world practice.

Therefore, our objective was to prospectively assess TAVI (SAPIEN 3, Edwards Lifesciences, United States) outcomes regarding the patient’s health-related quality of life (HRQoL), and the clinical outcomes considering their surgical risk. Also, as secondary endpoint, a description of healthcare resource utilization adjusted for surgical risk (STS score) was intended.

METHODS

Study design

This was a prospective, observational study of all consecutive patients with severe, symptomatic AS treated with elective TAVI via transfemoral access with SAPIEN 3 at the regional Hospital Universitario Virgen de la Arrixaca, a tertiary hospital and a regional referral center for cardiothoracic surgery and interventional cardiology located in Murcia, Spain. Patients received TAVI regardless of the study as part of the routine clinical practice. The recruitment stage was during the calendar year of 2018. In this study we present the observed results from the systematic djustent conducted 1 year after TAVI.

According to the ESC/EACTS guidelines,6 implantation decision was made by the heart team and all procedures followed the recommendations established by the manufacturer’s SAPIEN 3 valve instructions for use. All patients were followed for, at least, 12 months after TAVI and systematically assessed according to the hospital clinical protocol. Written patient information was provided to each participant, and the patient’s consent on data collection was signed before being included in the study that was conducted in full compliance with the recommendations guiding biomedical research in human subjects adopted by the 18^th World Medical Assembly, Helsinki, Finland back in 1964. The study protocol was approved by the assigned ethics Committee (Murcia, SARU Study; code: 2017-01. Effective date, 02/06/2017).

Clinical assessment was conducted at baseline (preoperative), post-intervention (perioperative), and 30 days, 6 months, and 1 year after the procedure. The main objective clinical variables included echocardiographic measurements (eg, paravalvular and total aortic regurgitation, left ventricular ejection fraction, mean and maximum aortic valve gradient, effective orifice area), and major clinical events automatically available in the medical records (eg, all-cause and cardiovascular mortality, stroke, bleeding complications, myocardial infarction, new-onset atrial fibrillation, major vascular complications, permanent pacemaker implantation, rehospitalization and acute kidney injury). In addition, the patients’ New York Heart Association (NYHA) functional class IV was systematically registered. The patients’ risk profile was characterized based on the STS risk score which was validated for the in-hospital and 30-day mortality rates following surgical aortic valve replacement.13 Additionally, postoperative complications were defined based on a modified version of the Valve Academic Research Consortium criteria,14 and this score was routinely applied based on the clinical protocols of our referral hospital.

Finally, length of stay (LOS)–at the hospital and the intensive care unit (ICU) settings–associated with the TAVI procedure was automatically registered for each patient based on hospital medical records and described as a secondary endpoint in this research.

Measurement of patient’s health-related quality of life

A comprehensive assessment was implemented by combining a patient-reported disease-specific tool that has a higher ability to capture changes in the patient’s health status during the observation period, and 2 generic tools to establish comparisons with findings from other procedures or diseases and with the Spanish normal population. Patients’ health-related quality of life was evaluated at baseline and during per protocol medical visits for health management (6 months and 1 year after TAVI).

Disease-specific tools

The Kansas City Cardiomyopathy Questionnaire (KCCQ)15 is a 23-item self-administered disease-specific questionnaire originally developed for patients with heart failure to monitor their reported symptoms and evaluate how and to what extent their heart failure impacts their quality of life (QoL) within a 2-week recall period. The KCCQ includes 6 distinct domains (physical function, symptoms, symptom stability, social limitation, self-efficacy, and quality of life) added to 2 summary scores: the clinical summary score (CSS) and the overall summary score (OSS). Summary scores can be transformed into 0–100 scales with higher scores being indicative of better levels of wellbeing to facilitate score interpretation. This tool has been recently revised and qualified for its use in heart failure by the United States Food and Drug Administration16 with minimal clinically important differences defined as 5-point changes in summary scales.17 Also, the KCCQ has a sound psychometrical performance when measuring functional status and HRQoL in patients with severe, symptomatic AS.18

Generic tools to measure health-related quality of life

The EQ-5D-519—a patient-reported measure—includes a descriptive system and the EQ visual analogue scale (EQ-5D-5L VAS). The former includes 5 different domains: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Responses to the EQ-5D-5L descriptive system were assigned preference-based (utility) weights from the Spanish population. The EQ-5D-5L VAS reflects the patient’s self-rated health on a vertical visual analogue scale (from 0, ‘the worst health you can imagine’ up to 100, ‘the best health you can imagine’).20,21

The Medical Outcomes Study Short Form-36 (SF-36)22 is one of the most widely used and evaluated generic HRQoL questionnaires. It includes 8 dimensions and 2 summary scores (physical component summary [PCS] and mental component summary [MCS]). In this study we used a standardization of summary scores based on age and gender using the Spanish population normative data.23

Statistical approach

First, an exploratory analysis was performed to characterise the analytic cohort presented in this manuscript. Descriptive statistics were used for continuous variables (eg, mean, standard error of measurement) and frequency tables or proportions for discrete variables. McNemar’s test for dependent samples was used to compare NYHA health states at follow-up. Regarding the objective of this study, multivariate models (linear general models with repeated measures at different time points —baseline, 6M, and 12M— as intra-subject factors) were computed to better assess the potential benefits of both regarding clinical endpoints and the patients’ HRQoL at follow-up (baseline, 6M, and 12M) while considering the patients’ comorbidities and risk profile at baseline. To this end, the STS predicted risk of mortality score was included because it is a weighted index of the patients’ risk robustly estimated using a Bayesian hierarchical model for both mortality and major complication events. This model considers 24 meaningful preoperative variables like age, sex, body surface area, atrial fibrillation, chronic heart failure, NYHA functional classification, chronic obstructive pulmonary disease, diabetes mellitus, need for insulin use, arterial hypertension, previous cardiac surgeries, concomitant mitral stenosis, unstable angina, previous percutaneous coronary intervention, and other variables. Based on the estimated STS score, patients were classified into 3 risk groups: high (≥ 8%), intermediate (≥ 4%), and low mortality risk (< 4%).13 Importantly, this score was also considered in the secondary endpoint associated with the description of the LOS (at both the hospital and ICU settings) related to TAVI procedures.

Regarding the size of the sample required to conduct the adjusted analyses described above, the estimated minimal sample size was set at 60 TAVI patients to compare within and between subject differences at 3 different time points of evaluation, effect size (f) was 0.25, statistical power (1-β), 0.9, and risk of type-I error (1-α), 0.95 assuming a weak correlation among repeated measures (0.3).

The software statistical package SPSS 27.0 for Windows (IBM Corp., United States) and the R software (The R Project for Statistical Computing, Institute for Statistics and Mathematics, Austria) were used for analysis.

RESULTS

A total of 76 consecutive patients, 50% female, with a mean age of 82.05 ± 4.76 years underwent elective TAVI during the study period comprising the analytical cohort. STS (surgical risk) score was 5.4 ± 3.41 while 42.5%, 43.8%, and 13.7% of the cases were classified as low-, intermediate-, and high-risk patients, respectively. A complete description of comorbidities is shown on Table 1. Previous coronary artery bypass graft was reported in 1 patient. A total of 6 cases (7.9%) were valve-in-valve procedures, and in 71 cases (93.4%) vascular access was via right femoral artery. Only 1 patient required general anaesthesia before TAVI (table 1 of the supplementary data). The patients’ functional status (NYHA classification) at baseline was remarkably impaired in most cases with 61.84%, and 19.74% of the patients having NYHA functional class III and IV, respectively.

Table 1. Preoperative characteristics of TAVI patients (N = 76)

Clinical outcomes

Successful implantation was achieved in 74 cases (97.37%), and 2 patients (2.63%) died within the first 30 days after the procedure (both cardiovascular causes). In this period, the observed rates of major complications or rehospitalizations were low (Table 2), and permanent pacemaker implantation was required for 5 patients. One year after TAVI, no additional cardiovascular deaths were reported. However, 7 patients died of other causes (Table 2). We should mention that the sample mortality rate was similar to that of a comparable general population (figure 1 of the supplementary data). According to echocardiographic measurements, significant benefits in mean and maximum gradients, and aortic regurgitation were achieved and maintained at follow-up (figure 2 of the supplementary data). Notably, among survivors, 78.4% of patients had a NYHA functional class I-II at 1 month, a benefit that was maintained at 1 year with 77.3% of patients in these functional levels.

Table 2. Clinical outcomes seen at 30 days and 1 year (N = 76)

HRQoL assessment

The patients’ HRQoL across the observational period according to STS risk score at baseline is shown on figure 1. In both summary scores of the KCCQ (OSS and CSS), statistically and clinically significant improvements after TAVI were seen. In OSS cases, the mean differences reported between baseline and 6 months ranged between 18.94 points (low risk) and 29.97 points (intermediate risk) indicative of a meaningful benefit (all P < .001). Similarly, the mean differences regarding the CSS ranged between 13.03 points and 27.3 points (low and intermediate, respectively). In addition, in both scales the observed benefit was maintained at follow-up with no differences being reported at 6 months and 1 year (P > .8 in both summary scales). Remarkably, these improvements were repeated across the 3 risk groups (figure 2).

Figure 1. New York Heart Association (NYHA) functional class at follow-up.

Figure 2. Changes in patient’s health-related quality of life at follow-up (n = 55, out of 67 survivors at 1 year; 82.1% of the sample). No differences in mean/median baseline values were seen in any of the health-related quality of life (HRQoL) measures taken between the patients who completed all the measurements and those with missing values at study period. EQ-5D-5 VAS, EQ visual analogue scale; KCCQ, Kansas City Cardiomyopathy Questionnaire; KCCQ CSS, KCCQ clinical summary score; KCCQ OSS, KCCQ overall summary score; SF-36 MCS, Medical Outcomes Study Short Form-36 Mental Component Summary; SF-36 PCS, SF-36 Physical Component Summary.

Regarding generic questionnaires, a positive impact was also seen in EQ-5D-5L VAS scores and the SF-36 Physical Component Summary, postoperatively, in all patients (P < .006 and P < .004, respectively). However, the size of detected differences was smaller considering the respective scales. No statistically significant differences were seen in the mental component summary (P = .395). In addition, values in all groups were comparable to normative population based on age and sex since baseline (mean—95% confidence interval [95%CI]—at baseline: 47.44, 44.70, and 50.18; 6 months: 49.77, 47.36, and 52.17; and 1 year: 48.64, 46.04, and 50.83-; P = .52). Finally, EQ-5D-5L index values were fairly similar across all time points with a slight increase observed at 6 months (P = .054 compared to baseline) and a mild drop at 1 year, not reaching statistical significance compared to baseline values (mean—95%CI—at baseline: 0.77, 0.71, and 0.83; 6 months: 0.80, 0.75, and 0.85; and1 year: 0.74, 0.68, and 0.80; P = .499).

Secondary endpoint: description of the procedure-related length of stay

Mean LOS at the hospital setting was limited with a mean stay of 5.26 days (± 4.05), and only 10 patients (13.2%) required intensive care, 5 of whom (6.6% of the overall sample) remained at the ICU setting ≤ 1 day, 3 (3.9%) for 2 days, and 2 (2.6%) for 3 days. In figure 3, the ICU and hospital stays are shown based on the patients’ baseline risk (very low in all subgroups).

Figure 3. Length of stay (the hospital and the ICU settings) according to STS PROM score; n = 76 for LOS at the hospital setting, and n = 73 for LOS at the ICU setting. ICU, intensive care unit; LOS, length of stay; STS, Society of Thoracic Surgeons.

DISCUSSION

Ideally, severe, and symptomatic AS should be treated with a valve implanted via minimally invasive procedures while securing minimal perioperative and long-term risks, optimizing hemodynamic response, avoiding patients’ dependency on lifelong anticoagulation therapy, and maximizing their ability to do activities of daily living, and wellbeing. Insights from clinical trials indicate that the management of AS is moving in this direction.7,9 However it is still important to evaluate each innovation in real practice. This study provides new evidence on the performance of TAVI in elderly patients—mean age > 80 years—under real-world practice through a systematic prospective assessment of clinical outcomes, LOS, and patients’ reported outcomes 1 year after the procedure.

In our study, a noticeable positive clinical effect of TAVI was seen in all STS subgroups. Mean and maximum aortic gradients along with valve regurgitation improved significantly after the procedure, and major complications were kept at very reasonable rates. These outcomes were very similar to those recently published on SAPIEN 3.24 Also, regarding the NYHA scale, the percentage of patients with satisfactory functional status increased immediately after the procedure and was maintained at 1 year among survivors.

Importantly, these clinical benefits translated into meaningful improvements in the patients’ HRQoL. Particularly, the OSS of the KCCQ showed a mean change from baseline from 18.9 points in low-risk patients up to near 30 points in intermediate risk 6 months after treatment). Also, this benefit was preserved at 1 year with ranges between 21.9 points in low risk to 26.7 points in intermediate risk. These increments reported in the KCCQ were clearly over the minimal clinically important differences described in the medical literature for this tool.17 Actually, these results are especially important considering than a 10 points drop in KCCQ OSS scores turned out to be a prognostic factor for patients with AS associated with 34% more chances of dying at 12 months.18 Therefore, the HRQoL of older patients who survived 1 year improved significantly. Our results are similar to those from a former research that studied clinical outcomes from TAVI in clinical trials and registries including the SAPIEN 3. For instance, Baron et al.24—according to data from the SAPIEN 3 intermediate-risk registry—found changes at 1 year from TAVI in OS of 23.1 points (21.8-24.9; P > .001) among intermediate-risk patients. Their cohort had similar baseline characteristics and underwent TAVI with the same device (they did, however, include transfemoral and transapical access). In our study, we saw that this enhanced self-perceived health is also maintained in elderly patients classified as low- and high-risk patients.

Regarding generic tools, a positive trend was also detected in the EQ-5D-5L VAS and the PCS of the SF-36 (a summary component more focused on the overall functional performance of patients) with significant differences at 6 months and 1 year. We should mention that no differences were found at follow-up regarding the mental component summary. Also, the patients’ mental health was slightly lower compared to that reported in their reference population since baseline. Similarly, regarding the estimated utilities from the EQ-5D-5L, a global positive trend was seen at 6 months from baseline and a slight drop after 1 year. Nevertheless, all changes detected with this tool were minimal. This finding was surprising considering the great benefit demonstrated with both the OSS and the CSS of the KCCQ. However, as the EQ-5D-5L captures health-related quality of life more globally together with the mean age of the patients included, the slight decline seen could reflect general deterioration of health accumulated over the 1-year observational period (mean age of the sample > 80 years).

Furthermore, consistent with recent experiences in centers of excellence regarding TAVI in Italy, the Netherlands, and the UK, where authors tested novel standardized clinical care pathways to optimize the process with early discharge while reducing complications and LOS,25 we saw a very limited hospital stay with only 13% of patients requiring ICU admission (6.5% of the patients needed 3 days at the ICU). In our center, following an individualized protocol for candidates eligible for TAVI, we saw very high-quality outcomes in elderly patients while minimizing the procedure-related LOS.

Limitations

Inherently to the nature of this observational study, our findings are subject to a few limitations. First, our findings come from the experience of a single center in a tertiary referral hospital very familiar with the procedure so the extrapolation of these results might be affected by the experience of the heart team. Importantly, sample size, especially in the high-risk group, was limited and subject to high dispersion of values and missing data at follow-up. Therefore, further research with a larger number of patients stratified by risk should confirm our findings. Despite this limitation, we should mention that our results observed in the intermediate-risk group are similar to those reported with larger samples allowing for extensive propensity score cohort adjustment.24

Also, in this analysis, we decided to use the STS score as a measure of patient-risk characterization because, even when we acknowledge that this was originally developed for surgical aortic valve replacement, it is a valid prognostic measure of mortality and occurrence of major complications in TAVI making up a comprehensive assessment of the patients’ health status.13,26 However, as it has been described in recent research,27,28 it would also be helpful to include a measure of frailty to complete thedjusttments. Unfortunately, this information was not routinely collected through a standard form as part of the standard clinical management when this study was conducted. Nevertheless, we should mention that in our center, the heart team involved in the decision-making process regarding the individualized management of the patients’ clinical condition, always considers frailty as a key parameter to better adjust the provision of care. Also, precisely due to this preoperative assessment most patients classified as low risk by the STS score (42.5%) were treated with TAVI instead of open surgery. Hence, frailty is a core aspect of this process, always among other important factors like patient preference, history of chest radiation, previous coronary artery bypass graft or porcelain aorta, and others. Although through the comprehensive analysis of clinical and patient-reported outcomes a consistent and positive tendency in outcomes has been shown, we should mention that our results come from a cohort of patients treated in 2018. Consequently, it would be interesting to conduct a new study in multiple centers to obtain data to compare the evolution of the current clinical practice outcomes to those from 2018. Therefore, further research is warranted to continue this monitorization of outcomes in larger samples of patients.

CONCLUSIONS

In conclusion, this research provides clinical and patient-reported evidence on the performance of TAVI in elderly patients with clinical benefits maintained 1 year after the intervention. Furthermore, the short hospital stay observed provides exploratory insights into the benefits of standardized protocols created to manage low- to high-risk patients safely and efficiently.

FUNDING

Edwards Lifesciences provided funds for the analysis of this study that was conducted and interpreted independently by clinicians and methodological experts.

AUTHORS’ CONTRIBUTIONS

E. Pinar, J. García de Lara, J. Hurtado, B. Martí-Sánchez, G. Leithold, and J. Cuervo were involved in the study idea and design, and in the analysis of the study data. All authors were involved in the interpretation of the results and in the critical revision of the paper regarding its intellectual content and agree on the final version of the manuscript to be published.

CONFLICTS OF INTEREST

J. Cuervo, who works for Axentiva Solutions, disclosed that Axentiva Solutions has received financial support in the form of consultancy payments from Edwards Lifesciences towards the design and analysis of the study, and for medical writing support. B. Martí-Sánchez, and P. González work for Edwards Lifesciences. E. Pinar, J. García de Lara, J. Hurtado, M. Robles, G. Leithold, and K. Rand declared no conflicts of interest whatsoever.

SUPPLEMANTARY DATA

REFERENCES

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