Transcatheter aortic valve implantation with SAPIEN 3 versus surgical aortic valve replacement in patients with symptomatic severe aortic stenosis at low risk of surgical mortality: a cost-utility analysis for Switzerland

DOI: https://doi.org/https://doi.org/10.57187/s.3558

Introduction

Severe aortic stenosis is a common valvular disease [1] with survival probabilities as low as 50% at two years and 20% at five years [2] without valve replacement. Since its introduction in 2002, transcatheter aortic valve implantation (TAVI) has become the treatment of choice for the treatment of symptomatic severe aortic stenosis in elderly and high-risk surgical patients [3, 4]. Continuous development of the technology improved patients’ outcomes, patients’ quality of life and reduced complication rates, leading to an unprecedented expansion towards lower-risk patient populations, namely intermediate-risk and low-risk patients [5–8].

The Placement of Aortic Transcatheter Valve Study (PARTNER) 3 trial was a multicentre randomised controlled study in patients with symptomatic severe aortic stenosis considered at low risk of surgical mortality [9–11]. In this study, transfemoral TAVI using the SAPIEN 3 transcatheter heart valve (Edwards Lifesciences) was compared to surgical aortic valve replacement (SAVR) [9–11]. TAVI reduced the composite outcome of death, stroke or rehospitalisation compared with SAVR after 2 years (11.5% vs 17.4%; hazard ratio [HR]: 0.63; 95% confidence interval: 0.45–0.88; p = 0.007) [9, 10] and after 5 years (22.8% vs 27.2%; HR: 0.79; 95% confidence interval: 0.61–1.02; p = 0.07) [11] but slightly short of statistical significance. TAVI also resulted in significantly lower rates of stroke and new-onset atrial fibrillation (AF), shorter index hospitalisation, higher functional status and improved quality of life, at 30 days. Last, there were no significant between-group differences in major vascular complications, new permanent pacemaker insertions, or moderate or severe paravalvular regurgitation [9–11].

Based on the clinical benefits of TAVI versus SAVR in patients with symptomatic severe aortic stenosis across all risk groups, the latest European Society of Cardiology (ESC)/European Association for Cardio-Thoracic Surgery (EACTS) guidelines on valvular heart disease recommend TAVI in all patients aged 75 years or older who are suitable for a transfemoral approach, regardless of the degree of surgical risk (recommendation class IA) [5, 12].

ESC guidelines were endorsed by the Swiss Society of Cardiology, and the Swiss compulsory health insurance scheme (on the legal basis of the Federal Health Insurance Act [13]) recently added coverage for the TAVI procedures in patients with symptomatic severe aortic stenosis at low surgical risk in their latest policy – effective from 1 July 2023. The regulations state that there should be mandatory coverage for inoperable, high- and intermediate- surgical risk patients, and provisional coverage regarding evidence development for those at low risk. Criteria for reimbursement in Switzerland are based on efficacy, effectiveness, expediency and economic efficiency. While both efficacy and expediency were convincingly shown in previous randomised controlled trials, cost-effectiveness largely depends on national tariffs and prosthesis prices, and thus requires a dedicated cost-utility analysis.

Such evaluations have already been performed in various countries, with publications in France [14], Italy [15], Spain [16], Germany [17], Belgium [18] and the Netherlands [19] all showing the cost-effectiveness of TAVI with SAPIEN 3 compared with SAVR; however data for Switzerland is lacking.

We thus aimed to conduct a cost-utility analysis comparing TAVI with SAPIEN 3 with SAVR in symptomatic severe aortic stenosis patients at low risk of surgical mortality from the perspective of Swiss compulsory health insurance, using data from the PARTNER 3 trial and other relevant sources.

Methods

A cost-utility analysis was built using methodology validated for the French [14], Italian [15], Spanish [16], German [17], Belgian [18] and Dutch [19] populations to estimate changes in both direct healthcare costs and health-related quality of life with the use of TAVI with SAPIEN 3 versus SAVR in symptomatic severe aortic stenosis patients at low risk of surgical mortality (<4% as defined by the Society of Thoracic Surgeons [STS]) from the perspective of the Swiss compulsory health insurance system. Ethical approval of research was not required as this cost-utility analysis was based on data from previously conducted studies and did not include any new studies with human participants.

Model structure

Details of the two-stage model structure and the rationale of the four distinct health states have been described previously [14]. In brief, survival, quality of life, costs and early adverse events (AEs) linked to the TAVI procedure were captured using the 30-day AEs dataset from the PARTNER 3 study [10] in a decision tree (figure 1A). This data was then fed into a Markov model that included four distinct health states (“alive and well”, “treated AF”, “disabling stroke” and “dead”) to capture longer-term outcomes of patients, post-TAVI or post-SAVR intervention (figure 1B). The model was considered appropriate for the Swiss context by the authors, based on their clinical and health economics expertise.

Figure 1The cost-effectiveness model had two stages: (A) early adverse events (AE) 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, with four distinct health states: “Alive and well” = patients have undergone the procedure and survived with only short-term or no AEs; patients in this health state can transition to “disabling stroke”, “treated AF” or “dead” at any point during the model time horizon. “Treated AF” = patients have undergone the procedure and survived but developed atrial fibrillation (AF) requiring specific treatment; this can either occur within the first 30 days or during the rest of the time horizon of the model, and patients in this health state can transition to “disabling stroke” or “dead” at any point during the model time horizon. “Disabling stroke” = patients 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 time horizon of the model, and patients in this health state can only transition to the “dead” state at any point during the model time horizon. “Dead” 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 “disabling stroke” are at an increased risk of dying. SAVR: surgical aortic valve replacement; TAVI: transcatheter aortic valve implantation. Reproduced from Gilard M, et al. [14]. Value Health 2021doi: https://doi.org/10.1016/j.jval.2021.10.003, under the terms of the Creative Commons licence “Attribution 4.0 International”.

Considering that the initial treatment decision has long-term consequences and that symptomatic severe aortic stenosis requires life-long valve replacement, a lifetime horizon (50 years) was selected for the cost-utility analysis. This time horizon was chosen to reflect all possible consequences in individuals with symptomatic severe aortic stenosis over their lifetime.

A discounting factor per year of 3% was applied for both future costs and benefits. Such a discount rate is frequently used in Health Technology Assessment (HTA) reports for the Federal Office of Public Health (FOPH) and is thus accepted by the FOPH [20]. Details for input variable definitions have been published previously [10, 14] and are summarised in the sections below.

The cost-utility model generated total per-patient costs and quality-adjusted life years for each intervention and the incremental cost-effectiveness ratio for TAVI compared with SAVR. Output definitions can be found at www.yhec.co.uk/glossary/. For non-experts of economic evaluation, a reader’s guide to facilitate reading and interpretation is recommended [21].

Study overview

The model was informed by the study population of PARTNER 3 (ClinicalTrials.gov number: NCT02675114), a multicentre randomised clinical trial that compared TAVI with transfemoral placement of a third-generation balloon-expandable valve with standard SAVR in patients with symptomatic severe aortic stenosis who were considered at low risk of mortality from surgery (STS-Predicted Risk of Mortality [STS-PROM] score <4%). The trial protocol was designed by the trial sponsor (Edwards Lifesciences) and the steering committee, with guidance from the Food and Drug Administration (FDA). The sponsor funded all trial-related activities and participated in site selection, data collection and monitoring, and statistical analyses. Patients with clinical frailty, bicuspid aortic valves or other anatomical features that increased the risk of complications associated with either surgery or transcatheter aortic valve implantation were excluded. In PARTNER 3, 1000 patients were enrolled, of whom 503 were randomised to TAVI and 497 to SAVR, with “as treated” groups of 496 and 454 patients, respectively [10]. The trial comprised patients with an average age of 73 years and 69% of patients were male.

All-cause mortality was determined from general population normal mortality risk, with relative risks applied from published literature corresponding to each health state. Costs and resources used were based on costing information from Swiss Diagnosis-Related Groups (DRGs), regional tariffs, literature and expert interviews. Utility values used age-adjusted population norms from Germany in the absence of robust Swiss population norms [22], with decrements (disutilities) applied from published literature corresponding to each health state.

Clinical events

Probabilities of clinical events, such as health state transition probabilities, rehospitalisation rates, aortic reintervention rates and intercurrent events (such as myocardial infarction, bleeding and transient ischaemic attack), used in the model were sourced from the PARTNER 3 trial and from Swiss-specific literature sources when available and relevant (table S1 in the appendix). Monthly transition probabilities between health states for the Markov model were estimated based on data from PARTNER 3 (up to 5-year outcomes) or other literature sources where there were too few events in PARTNER 3 for reliable estimates (table S1). Input data for permanent pacemaker insertion at 30 days was based on PARTNER 3 data for SAVR [10] and estimates from the Swiss TAVI Registry [23] to reflect more recently available SAPIEN 3 TAVI data specific to the Swiss population. Rehospitalisation rates were based on data from the PARTNER 3 study up to 5 years [9–11] and assumed to remain constant over the time horizon of the model thereafter. Reintervention rates were also based on data from the PARTNER 3 study up to 5 years [9–11] and by competing risk estimates for the 73-year-old cohort from a study by Bourguignon et al. from Year 6 onwards [24]. The same reintervention rate was used for both TAVI with SAPIEN 3 and SAVR in the base case; this simplifying assumption allowed best use of the available data.

Survival extrapolation

All-cause mortality was determined from general population normal mortality risk, with relative risks applied from published literature corresponding to each health state. In the base case, transition probabilities were taken from the literature (compared to the general population, relative risks of death with “treated AF” and “disabling stroke” are 1.46 and 2.30, respectively) due to immaturity of survival data from the PARTNER 3 trial producing clinically implausible estimates (because of the very low rate of death in the study [9–11]). Annual mortality risk for “alive and well” and other relative risks for other health states are shown in table S2 in the appendix.

Health utilities

The PARTNER 3 trial collected EQ-5D-based utilities; however, given that few clinical events were observed, we decided it was more appropriate to consider estimates from the literature. We used age-specific utility values representing population norms from Germany in the absence of Swiss population norms covering all language regions [22]. Disutilities by health state were calculated as weighted averages of disutilities in neighbouring countries, namely Germany [17], France [14] and Italy [15], with weights based on the distribution of main languages in Switzerland, as reported in the Structural Survey of the Federal Statistical Office (FSO). The resulting disutilities were 0.14 for “treated AF” and 0.38 for “disabling stroke” (table S3 in the appendix).

Cost inputs

Costs were based on costing information from Swiss Diagnosis Related Groups (DRGs), regional tariffs and literature. Costs associated with TAVI and SAVR (procedure, complications and long-term) are shown in table 1. Base case procedure cost information was drawn from a composite of SwissDRG version 13.0 AG 2024 [25]: F98B and F98C (TAVI); F03C and F03E (SAVR). The breakdown of TAVI and SAVR procedure costs is shown in table S4 in the appendix. For pacemaker complication costs, in the absence of Swiss-specific data we used data from a German study [31]. To adjust the costs to the Swiss price level, we used purchasing power parity corrections (Germany: 1.544 for 2020 and 1.490 for 2021 [32]). All costs were adjusted to 2022 Swiss franc (CHF) using the Consumer Price Index.

Cost-effectiveness threshold per quality-adjusted life year

In the absence of an official willingness-to-pay threshold for Switzerland, we assumed the cost-effectiveness threshold to be CHF 50,000 per quality-adjusted life year gained.

Sensitivity and scenario 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 was unavailable (appendix table S5). All parameters were changed and the impact on the results explored. Overall parameter uncertainty was addressed using a probabilistic sensitivity analysis (PSA). Probability distributions for all input parameters were specified and 1000 Monte Carlo simulations were run using random draws of all parameters from within their assigned distributions (appendix table S6).

Finally, several scenario analyses were performed to account for uncertainties not captured by the standard sensitivity analyses. The impact of increased risk of reintervention was explored in Scenario 1, based on data at 5 years from the PARTNER 2 trial [7]. Scenarios 2 and 3 considered parametric survival fitting based on Kaplan-Meier data from the PARTNER 3 trial, utilising various HRs. Among the three parametric distributions considered (Weibull, Exponential, Gompertz), the Weibull was best in terms of goodness-of-fit statistics, minimising the Akaike information criterion (AIC) and the Bayesian information criterion (BIC), and was adjusted to the survival of the overall Swiss population. In Scenario 2, the HR from the PARTNER 3 trial at two years (HR = 0.75) was used and adjusted to the Swiss population overall mortality. Scenario 3 removed any survival benefit with the SAPIEN 3 valve (HR = 1). Scenario 4 considered utility decrements for each treatment arm from the PARTNER 3 trial – individually extracted at baseline, after 30 days, 6 months and 1 year [33]. Scenarios 5 and 6 considered various costing estimates (SAVR based on minimal invasive tariff and assuming inpatient rehabilitation only). Lastly, Scenarios 7 to 11 looked at various model time horizons (from 5 to 30 years). All analyses were performed using Microsoft Excel (Microsoft Corporation, Redmond, WA, USA).

Results

Base case

Compared with SAVR, TAVI is estimated to offer significant benefits by increasing quality-adjusted life years (incremental improvement of +0.68 per patient) at a slightly increased cost (+CHF 2643 per patient) over a lifetime horizon. This represents an incremental cost-effectiveness ratio of CHF 3866 per quality-adjusted life year gained. Overall, TAVI with SAPIEN 3 resulted in lifetime costs per patient of CHF 79,534 and lifetime quality-adjusted life year per patient of 9.64; SAVR in CHF 76,891 and 8.96 quality-adjusted life years respectively.

The estimated incremental cost-effectiveness ratio is much lower than the considered highly-cost-effectiveness threshold of CHF 50,000 per quality-adjusted life year gained (table 2). Further examination of the breakdown of costs for TAVI with SAPIEN 3 versus SAVR revealed that, despite initial higher procedural costs in the model with TAVI, costs with respect to “disabling stroke”, “treated AF” and “rehospitalisation” were lower (figure 2).

Figure 2Cost breakdown for transcatheter aortic valve implantation (TAVI) with SAPIEN 3 and for surgical aortic valve replacement (SAVR). AF: atrial fibrillation; CHF: Swiss franc; MI: myocardial infarction; TIA: transient ischaemic attack.

Probabilistic sensitivity analyses

The findings of the PSA corroborate those of the base case analysis. At the considered highly-cost-effectiveness threshold of CHF 50,000/quality-adjusted life year, TAVI with SAPIEN 3 remained cost-effective compared with SAVR in 99.9% of simulations (figure 3). Even at a lower threshold of CHF 30,000/quality-adjusted life year, TAVI with SAPIEN 3 still had a high probability (97.7%) of being cost-effective (figure 4).

Figure 3Probabilistic sensitivity analysis (PSA): Cost-effectiveness scatter plot. “Assumed threshold” is the willingness-to-pay threshold that corresponds to Swiss francs (CHF) 50,000 per quality-adjusted life year (QALY) gained. The scatter plot is shown on a cost-effectiveness plane. The cost-effectiveness plane plots incremental QALYs against incremental costs for each probabilistic simulation. As an example, simulations in the top-right quadrant represent simulations in which transcatheter aortic valve implantation (TAVI) is more costly and more effective than surgical aortic valve replacement (SAVR).

Figure 4Probabilistic sensitivity analysis: Cost-effectiveness acceptability curve. CHF: Swiss franc; QALYs: quality-adjusted life years; TAVI: transcatheter aortic valve implantation.

Deterministic sensitivity analyses

Univariate sensitivity analyses showed that TAVI remained cost-effective irrespective of plausible changes in individual model parameters (figure 5). The model was most sensitive to the procedure and the reintervention costs of both strategies, the risk of new onset of AF at 30 days for SAVR, and the starting age of patients entering the model (only those 10 parameters with the greatest influence on the model’s results are displayed).

Figure 5Deterministic sensitivity analysis: Tornado diagram showing the 10 parameters with greatest influence on the model. CHF: Swiss franc; ICER: incremental cost-effectiveness ratio; SAVR: surgical aortic valve replacement; TAVI: transcatheter aortic valve implantation. Interpretation note: This chart presents the results of the 10 univariate sensitivity analyses that had the greatest influence on the model ICER. Each analysis is summarised using a horizontal bar which represents the variation in the ICER around a central value corresponding to the base case analysis as the relevant parameter is varied between two plausible but extreme values. The horizontal bars are ordered so that those with the greatest spread (i.e. parameters to which the model output is most sensitive) are at the top of the diagram, and those with the lowest spread at the bottom.

Scenario analyses

The results from the various scenario analyses demonstrated the comparative robustness of the model reported (table 3).

Discussion

This analysis indicates that TAVI with SAPIEN 3 is expected to be a cost-effective valve replacement choice for patients with symptomatic severe aortic stenosis at low risk of surgical mortality in Switzerland. Incremental cost-effectiveness ratio benefits shown in this analysis suggest a cost-effective intervention in the Swiss system, even with a considered cost-effectiveness threshold of CHF 50,000 per quality-adjusted life year. Sensitivity analyses were used to assess uncertainty and the results appeared robust.

The findings of the current analyses are reinforced by other cost-effectiveness studies which show that TAVI with SAPIEN 3 is either dominant or cost-effective in patients at low risk of surgical mortality [34–38]. The Swiss findings are also consistent with cost-effectiveness analyses of TAVI with SAPIEN 3 versus SAVR in France [14], Italy [15], Spain [16], Germany [17], Belgium [18] and the Netherlands [19] using the same model structure.

The cost-effectiveness of TAVI in low-risk patients in Switzerland appears to be driven by lower long-term management costs, particularly those costs related to “treated AF” and “disabling stroke”; cost savings in these areas were also seen in France, Italy, Spain, Germany, Belgium and the Netherlands [13–19]. Our analysis showed that initial procedure costs for TAVI with SAPIEN 3 were higher than for SAVR in Switzerland; this was also the case in Italy and Spain, whereas the initial cost for performing TAVI was lower than for SAVR in France, mainly driven by the higher rehabilitation costs that SAVR patients experience.

The results of this cost-effectiveness study in Switzerland are valuable for supporting the use of TAVI as a minimally invasive treatment option in patients with symptomatic severe aortic stenosis at low risk of surgical mortality. Data suggests that, with TAVI, rehospitalisation risk is reduced, there is a lower risk of procedural complications and recovery rates improve, resulting in overall quality of life gains. There are also many societal benefits associated with the use of TAVI. Reducing hospital stays as well as resource use (e.g. lower general anaesthesia, less intensive care/ICU stays, improvement in efficiencies during the index hospitalisation) allows for more patients to be treated in the same hospital. The former is an important element as long waiting lists after the COVID-19 pandemic occurred in some countries and an expected increase in number of TAVI procedures due to demographic changes have put health systems, already in high demand, under even further stress [39].

Following the update to the European guidelines [5, 12] and the potential update to the Swiss guidelines, it would be expected that the number of TAVIs will increase in the coming months and years, as large numbers of symptomatic severe aortic stenosis patients at low surgical risk become eligible to benefit from this treatment. It is likely that the TAVI procedure will be further simplified, with shorter admission times and lengths of stay post-procedure, leading to decreasing costs. In this regard, the results of this analysis could inform policymakers on the management of patients with symptomatic severe aortic stenosis in Switzerland and improve access to TAVI for these patients.

Limitations

Some limitations relate to those of any cost-effectiveness analysis and include assumptions made where there is “best fit” data or paucity of data, extrapolations modelled for time horizons beyond the scope of existing input data, and potential for under- and over-estimations due to differences in healthcare systems or by the intervention/treatment selection criteria within a specific system. First, neither utilities nor estimates for annual mortality rates were derived from aortic stenosis patients. Both are likely different in an aortic stenosis population than the average normal population.

Second, the reintervention rate was assumed to stay constant after 22 years; the effect of this assumption on modelled outcomes was thought to be minimal based on an expectation that around 15% of patients would still be alive in the model after this time point, with limited need for reintervention. Nevertheless, uncertainty about the longer-term durability of the TAVI device and consequent reintervention rates in younger patients cannot be disregarded. Third, disutilities were not included for intercurrent events because it would risk them being counted 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, rates of intercurrent events were generally lower for TAVI with SAPIEN 3 compared with SAVR [10]. Fourth, the literature data used to calculate the utility decrements for “treated AF” and “disabling stroke” could imply a limitation. The disutilities were calculated through an average weighting of disutilities in neighbouring countries, namely Germany, France and Italy. Although the best available option and methodologically sound, further investigation into disutilities specific to the Swiss population on these conditions may be valuable. Moreover, utilities were taken from population norms in Germany that were recorded 20 years ago; hence, they may not be applicable to current times. Fifth, additional charges (Zusatzentgelte), which would have a greater impact on SAVR costs (transfusion, haemofiltration in acute kidney injury) were not taken into consideration. Sixth, to calculate some costs, such as the rehabilitation costs following a TAVI and SAVR procedure, the “treated AF” cost, the “alive and well” cost and the pacemaker cost, expert interviews were partially relied upon. This was seen as the best available option to localise the cost. The generalisability of the PARTNER 3 results was a limitation. Patients with unfavourable coronary anatomy were excluded from PARTNER 3, so any conclusions cannot be generalised to the overall population with aortic stenosis. In addition, findings from this model cannot be generalised to populations outside of Switzerland. Seventh, variations may occur across regions of Switzerland. Finally, the employment of some of the authors by Edwards Lifesciences could be considered a limitation.

Conclusions

This analysis suggests that TAVI using the SAPIEN 3 device is likely to be a cost-effective alternative for symptomatic severe aortic stenosis patients at a low risk of surgical mortality, treated in the contemporary Swiss setting. The findings are consistent with cost-effectiveness analyses of TAVI with SAPIEN 3 versus SAVR in other European countries using the same model structure. While the initial procedure costs for TAVI with SAPIEN 3 are higher than those of SAVR in Switzerland, the overall cost-effectiveness of TAVI is driven by lower long-term management costs. TAVI with SAPIEN 3 offers efficiency gains by limiting healthcare resource use, reducing postoperative complications and shortening hospital length of stay compared with SAVR, while also meeting patients’ preference for a minimally invasive option and improving patients’ quality of life. We propose that this analysis is valuable for clinical decision-making and for policymakers specifically considering the 2021 European Society of Cardiology / European Association for Cardio-Thoracic Surgery guidelines that recommend TAVI in all patients ≥75 years who are suitable for a transfemoral approach regardless of the degree of surgical risk.

Data availability statement

Input parameters values used and data generated during this cost-utility study are wholly included within this published article and the associated supplementary material in the appendix.

Acknowledgments

This work was funded by Edwards Lifesciences (Nyon, Switzerland). We would like to thank Prof. Lorenz Räber and Christophe Alain Wyss who were part of the scientific committee that provided guidance regarding the clinical outcomes and costs specific to Switzerland. The original model was developed by Michelle Green and Judith Short from York Health Economics Consortium (YHEC) (University of York, United Kingdom) [14]. Tom Bromilow, Daniela Afonso and Karin Butler from YHEC also contributed to this adaptation for Switzerland. Polynomics AG (Olten, Switzerland) provided support to structure the local data in the report that can be found in the appendix. Writing support was provided by Zenith Healthcare Communications Ltd (Chester, United Kingdom) and was funded by Edwards Lifesciences.

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Appendix

The appendix is available in the pdf version of the article at https://doi.org/10.57187/s.3558.