Methods

This was a prospective multi-center study registered at National Institute for Health Research (Study ID 16043) performed across 5 hospitals in the United Kingdom between February 2016, and December 2018. Patients included in this study were those identified to be eligible for TAVI following a Heart Team meeting carried out locally at each participating center. Exclusion criteria included patients who were unable to comprehend English or provide written informed consent. The flow chart for the study is summarized in Supplementary Figure 1 . All patients underwent a comprehensive assessment of feasibility for the procedure using a standardized protocol including transthoracic echocardiography, evaluation of the coronary anatomy, and computed tomography scan. All patients were deemed inoperable or at high risk for SAVR. The protocol of the study was reviewed and approved by each participating center review board and ethical committee. The final version of the protocol was approved by the national health research authority and research ethics committee (reference:12/NW/0384). All patients provided written informed consent.

TAVI was performed using either self-expandable (Medtronic CoreValve / Evolut R, Portico valve, Acurate Neo valve [Medtronic, Minnesota]) or balloon expandable (Edwards Sapien XT or S3 [Edwards Lifesciences Corp. California]) valves. The size and choice of the valve types were based on computed tomography assessment as well as clinical and anatomical considerations by the operators. The transfemoral route was the preferred route unless anatomical consideration mandated alternative approaches.

HRQoL was assessed using MacNew, EQ-5D-5L, and SF-36 questionnaires. The primary endpoint was the change in MacNew global score at 3 months after the procedure, with a change of 0.5 points deemed clinically relevant. The MacNew instrument is a self-administered questionnaire which is a modification of the original QoL after MI questionnaire. The SF-36 and the EQ-5D-5L questionnaires are widely accepted instruments that have been previously used in TAVI QoL studies. Full descriptions of these questionnaires are detailed in the Supplementary material. The initial questionnaires were carried out at baseline and then at 3-, 6- and 12 months after the procedure through self-administration. All the preprocedural and postprocedural data were collected according to the Valve Academic Research Consortium (VARC-2) criteria from the National Institute for Cardiovascular Outcomes Research database at each participating site after being anonymized.

Descriptive statistics were summarized as mean ± SD for normally distributed continuous variables or otherwise as median (Q1–Q3), and compared using Wilcoxon signed-rank test or paired Student t test as appropriate. Categorical variables were described by frequencies and percentages. The minimum important difference for the MacNew instrument for a moderate change in QoL was estimated as an effect size of 0.5 point. Based on 80% power to detect a difference of 0.5 and an SD of 1, 175 patients were needed to detect this difference between the baseline and follow-up. Kruskal-Wallis tests were used to compare the scores at 3 different time points. Post hoc testing of each pair was conducted using a Dunn test with the p values corrected for multiple pairwise comparisons using the Bonferroni adjustment. Scores from the EQ-5D-5L tool were converted to a utility index for comparison.

Analysis of covariance (ANCOVA) change score models were fitted to determine the predictors for change in the MacNew scores at 3 months, with the baseline score included as a covariate. Backward selection methods were performed to retain only variables that were (a) significant, (b) clinically relevant and/or (c) improved model fit. Change in scores was calculated by subtracting the baseline from 3-month scores, such that a positive change score indicates an increase in QoL over this period, and positive parameter estimates mean that the variable has an improving effect in QoL, and vice versa.

Linear mixed models were fitted to the scores recorded at each time point to determine the factors affecting the score over time, allowing a random intercept and slope per patient. Selection of variables was performed as for the ANCOVA models; here a positive parameter coefficient corresponds to a variable whose presence leads to higher QoL scores, and vice versa. All statistical analyses were performed using R software version 4.0.2 (The R Foundation for Statistical Computing, Vienna, Austria). A 2-sided significance level of p <0.05 was considered statistically significant.

Results

From February 2016 to December 2018, 225 patients were recruited. Of these patients, 19 did not go on to have the TAVI procedure and 4 patients withdrew consent for their data to be used. Therefore, the final study included 202 patients. The longitudinal analysis for HRQoL included 181, 161, and 147 patients at 3, 6, and 12 months respectively ( Supplementary Table 1 ). The baseline demographic, procedural characteristics, and clinical outcomes are listed in Table 1 . Five patients required a further TAVI procedure during their index episode because of mal-positioned valves. All-cause mortality was 5.4% at 30 days, 6.4% at 3 months, and 9.9% at 1-year after the procedure.

The distribution of the individual domain score for MacNew, EQ-5D, and the 2 components SF-36 across each time point are depicted in Figure 1. There is an initial increase in all the domains of MacNew score that is maintained across the 12 months follow-up period. Similar changes were observed in the 2 broad summary scales of the SF-36 with an initial rise at 3 months, although the physical component score began to decline again by 1 year. Using the visual analog scale and the EQ-5D utility index there were slight upward changes over time ( Supplementary Figure 2 ). Combining evidence from all tools, it is apparent that physical activity was the major limitation for these TAVI patients.

Boxplot graph illustrating the distribution of different scores across time point . (A) MacNew score. (B) EQ5D score. (C) Two components SF-36 summary score. Boxes represents median and IQRs, whereas whiskers display the smallest and largest nonoutlie.

There was a significant increase in all 4 domains of MacNew score at 3 months ( Table 2 ). None of the MacNew domains demonstrated any floor or ceiling effect. The tests were repeated for the patients who have completed 12 months of follow-up and it demonstrated that the improvements made after the TAVI procedure are maintained at 1 year ( Table 3 ). The percentage of patients achieving this primary endpoint at 3- and 12-months was 74.6% and 71.7% respectively. To rule out any potential “healthy patient bias”, whereby mean score increases are falsely inflated by the absence of more severely unwell patients who died before this time-point, we have performed further analysis by comparing baseline GD MacNew score between those who were in their last year of life (died within 12 months of TAVI) and those who survived to the end of the follow-up, and found no statistically significant difference in baseline QoL (died: 4.15 ± 1.16 vs survived: 4.48 ± 1.02, p = 0.25). This indicates that baseline QoL was similar for the 2 groups, and hence absent data in samples at later time points did not affect our finding. Results for the 2-components SF-36 and the EQ-5D utility index are listed in Tables 2 and 3 .

Table 2

HRQoL scores at baseline, 3 and 6 months for the questionnaires

HRQOL Measure	Time Points and Post hoc Pairwise Comparisons						p Trend
	Baseline n = 147	3 mo n = 147	p *	6 mo n = 147	p †	p ‡
Global MacNew	4.6 [3.7, 5.2]	5.5 [4.6, 6.0]	<0.001	5.6 [4.9, 6.2]	<0.001	0.28	<0.001
Physical MacNew	4.0 [3.2, 4.8]	5.3 [4.5, 5.9]	<0.001	5.5 [4.8, 6.0]	<0.001	0.19	<0.001
Emotional MacNew	5.0 [4.0, 6.9]	5.6 [4.7, 6.1]	<0.001	5.6 [4.9, 6.4]	<0.001	0.72	<0.001
Social MacNew	4.3 [3.5, 5.1]	5.4 [4.4, 6.1]	<0.001	5.6 [4.9, 6.3]	<0.001	0.14	<0.001
EQ-5D utility index	0.71 [0.52, 0.83]	0.78 [0.62, 0.86]	0.01	0.79 [0.61, 0.88]	0.006	>0.99	0.01
SF-36 PCS	33.2 [28.7, 39.5]	36.8 [31.8, 44.0]	<0.001	37.9 [30.1, 44.6]	<0.001	>0.99	<0.001
SF-36 MCS	45.4 [39.2, 56.5]	42.1 [42.5, 58.8]	0.015	52.7 [43.0, 58.5]	0.014	>0.99	0.01

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