Abstract
We sought to evaluate survival of patients with mixed aortic valve disease (MAVD) versus predominant aortic stenosis (AS) undergoing transcatheter aortic valve replacement (TAVR). This was a study-level meta-analysis of reconstructed time-to-event data from nonrandomized studies published by October 2024. Electronic databases were searched for studies with Kaplan-Meier data for overall survival. Individual patient data were reconstructed from published graphs and merged for analysis. Conventional random-effects meta-analysis was conducted for secondary post-TAVR outcomes. Ten studies (5 propensity-matched, 5 unmatched) met inclusion criteria with a total of 7340 patients (4263 AS, 3077 MAVD). MAVD was defined as severe AS with ≥ mild or ≥ moderate concomitant aortic regurgitation in the included studies. At 5 years, there was no difference in survival between patients in the AS group and MAVD group ([hazard ratio (HR) 1.03, 95% confidence interval (CI) 0.94–1.14, p = 0.51]). Sensitivity analysis restricted to studies defining MAVD as ≥ moderate concomitant aortic regurgitation (62% of population) also determined no difference between groups (HR 0.97, 95% CI 0.84–1.12, p = 0.67). When including only propensity-matched studies (35% of population), we observed a significant survival benefit in patients with MAVD (HR 0.79, 95% CI 0.65–0.94, p = 0.01). Patients with MAVD had higher post-TAVR paravalvular leak (RR 1.64, 95% CI 1.15–2.33, p < 0.01). In conclusion, transcatheter aortic valve replacement appears to be safe in patients with MAVD, with similar survival as patients with predominant AS despite higher post-TAVR paravalvular leak. A survival benefit of MAVD is observed after 1 year in propensity-matched studies.
Mixed aortic valve disease (MAVD) is defined as aortic stenosis (AS) with concomitant aortic regurgitation. Patients with MAVD have a poor prognosis, however, a significant improvement in survival is seen with aortic valve replacement. , Transcatheter aortic valve replacement (TAVR), which is a standard treatment for severe, symptomatic isolated AS, is also a common intervention in patients with MAVD. An analysis of the STS/ACC TVT registry including 54,000 patients found that 78% of patients had severe AS with mild or greater aortic regurgitation and 19% with moderate or greater aortic regurgitation, suggesting that patients undergoing TAVR commonly have MAVD.
Current guidelines suggest that the treatment of MAVD should be based on the dominant valvular lesion. To date, no randomized trials have been conducted focused on this population, however. Multiple observational studies have provided conflicting results on how MAVD impacts survival after TAVR compared to those with predominant AS. ,,,,,,,,, Prior meta-analyses have only evaluated 30-day and 1-year mortality in patients with MAVD undergoing TAVR. , Additionally, more recently published studies from 2022 to 2024 were not included in these meta-analyses. Therefore, we performed a meta-analysis using reconstructed Kaplan-Meier data from available observational studies to compare overall survival between patients with MAVD and predominant AS. Conventional meta-analysis was also conducted on post-TAVR outcomes using dichotomous data from the included studies.
Methods
Eligibility criteria, databases, and search strategy
This study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines. All data supporting the findings of this study are available from the corresponding author upon reasonable request. Using the Population, Interventions, Comparison, Outcome, and Study design (PICOS) strategy, studies were included based on the following criteria:
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(1)
The population comprised of patients who underwent TAVR. Patients with pure native aortic regurgitation were excluded.
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(2)
There was a group which had preoperative MAVD defined as severe AS with concomitant aortic regurgitation of at least mild severity.
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(3)
There was a second group which had predominant AS.
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(4)
The primary outcome studied was survival or all-cause mortality. Secondary outcomes included post-TAVR ≥ moderate paravalvular leak (PVL), stroke, total bleeding, major or life-threatening bleeding, major vascular complication, pacemaker implantation, and acute kidney injury.
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(5)
The studies included were prospective/retrospective, monocentric/multicentric, with matched/unmatched populations.
PubMed/MEDLINE and EMBASE were searched for articles meeting our inclusion criteria and published by October 30 th, 2024. Exclusion criteria included studies with overlapping samples and studies without Kaplan-Meier curves. There were no language restrictions.
The following steps were taken for study selection: (1) identification of titles and records through database search; (2) removal of duplicates; (3) screening and selection of abstracts; (4) assessment for eligibility through full-text articles; and (5) final inclusion in the study. Studies were selected by 2 independent reviewers. When there was a disagreement, a third reviewer decided to exclude or include the study. Ethical approval was not applicable for this study, as it consisted of a study level meta-analysis.
Assessment of risk of bias
The Cochrane tool Risk of Bias in Nonrandomized Studies of Interventions (ROBINS-I) was used to assess included studies for risk of bias. Two independent reviewers made assessments, and a third reviewer made the final decision if there was a disagreement.
Statistical analysis
Individual patient data was reconstructed from published Kaplan-Meier graphs of all included studies using the “curve approach.” We used the 2-stage approach as described by Liu et al. based on the R package “IPDfromKM” (version 1.2.3.0). For the first stage, raw coordinates (time, survival/event probability) were extracted from each subgroup in each of the respective Kaplan-Meier curves. In the second stage, the raw coordinates from the first stage and the numbers at risk at given time points were used to generate individual patient data (time-to-event or time-to-last-follow-up for each individual patient). The individual patient data was then merged to create a final data set for each outcome.
Overall survival was assessed visually using Kaplan-Meier estimates. Hazard ratios (HRs) with 95% CIs for the difference between the MAVD and AS groups were calculated using a cox regression model. In this model, study groups (MAVD vs AS) were included as a fixed effect. Between-study heterogeneity was assessed by inclusion of a γ frailty term, where individual studies modeled as a random effect using random intercepts. A likelihood ratio test was used to test the significance of the γ frailty term. A robust variance estimator was used to account for violations of the assumption of homoscedasticity. A HR > 1 indicated a higher risk of an outcome in the MAVD group compared to the AS group. The Grambsch-Therneau test and Schoenfield residual plots were used to assess the proportional hazards assumption. Meta-regression analyses were conducted to explore whether baseline covariates, each modeled alongside a moderator for propensity-matched study design, had a modulating effect on survival outcomes.
Meta-analysis of secondary outcomes was conducted using dichotomous data. Data was extracted independently by 2 reviewers as absolute numbers along with total denominators as reported in the original publication. Random-effects modeling was used for all outcomes using a DerSimonian-Laird estimator to determine relative risks (RRs). All tests were completed as 2-sided with an alpha level of 0.05 to determine statistical significance. All analyses were completed with R Statistical Software (version 4.3.2, Foundation for Statistical Computing, Vienna, Austria).
Results
Study selection and characteristics
After excluding duplicates and noneligible studies, 10 studies ,,,,,,,,, met our eligibility criteria ( Supplementary Figure 1 ). All studies were nonrandomized observational studies. Wang et al., Pepe et al., Heidari et al., Chahine et al., and Seeger et al., included propensity matched cohorts. Study characteristics can be seen in Table 1 . A total of 7340 patients were included (4263 AS, 3077 MAVD). Patients’ baseline characteristics are displayed in Table 2 . The mean age in the AS group ranged from 72 to 83 years while the mean age in the MAVD group ranged from 71 to 83 years. Across studies, the percentage of female patients in the AS group ranged from 40.4% to 60.8% while it ranged from 38.6% to 57.1% in the MAVD group. Supplementary Figure 2 shows the qualitative assessment of the studies with the ROBINS-I tool, and we found moderate-to-serious risk of bias. The main concerns were regarding differences in baseline variables, selection bias, and missing data.
Table 1
Characteristics of the study
| Study | Study design | Total sample (N) | AS (N) | MAVD (N) | Adjustment of possible confounders and/or multivariate analysis | MAVD defined as ≥ moderate AR |
|---|---|---|---|---|---|---|
| Wang et al. | NR, NP, SC | 156 | 78 | 78 | Yes | Yes |
| Demirel et al. | NR, NP/P, SC | 880 | 233 | 647 | Yes | No |
| Yousef et al. | NR, NP, SC | 1118 | 595 | 523 | Yes | Yes |
| Guddeti et al. | NR, NP, MC | 973 | 769 | 204 | Yes | Yes |
| Pepe et al. | NR, NP, MC | 1026 | 513 | 513 | Yes | Yes |
| Heidari et al. | NR, NP, SC | 369 | 274 | 95 | Yes | Yes |
| Chahine et al. | NR, NP, SC | 852 | 426 | 426 | Yes | No |
| Seeger et al. | NR, P, SC | 138 | 69 | 69 | Yes | Yes |
| Abdelghani et al. | NR, P, MC | 766 | 663 | 103 | Yes | Yes |
| Chieffo et al. | NR, NP, MC | 1062 | 643 | 419 | Yes | No |
Abbreviations: NR = nonrandomized; P = prospective; NP = nonprospective; MC = multicentric; SC = single-center.
Table 2
Baseline characteristics
| Study | Age (mean/median) | Female Sex (%) | HTN (%) | DM (%) | PVD (%) | Ejection fraction (%) | Prior CABG (%) | AF (%) | NYHA III/IV (%) | CAD (%) | Pulmonary disease (%) | CKD (%) | Prior stroke (%) | STS risk score (%) | SEV (%) | |||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| AS | M | AS | M | AS | M | AS | M | AS | M | AS | M | AS | M | AS | M | AS | M | AS | M | AS | M | AS | M | AS | M | AS | M | AS | M | |
| Wang et al. | 72 | 71 | 46.9 | 38.6 | 45.3 | 41.0 | 24.6 | 16.9 | 9.5 | 7.2 | 62 | 48 | 0 | 0 | 12.3 | 8.4 | 54.2 | 59.0 | 28.5 | 24.1 | NA | NA | 28.5 | 24.1 | 4.5 | 7.2 | 1.97 | 2.04 | 96.1 | 98.8 |
| Demirel et al. | 81.0 | 82.0 | 44.6 | 55.8 | 89.3 | 89.5 | 30.0 | 29.2 | 11.6 | 10.2 | 53.8 | 53.5 | NA | NA | 45.1 | 40.0 | NA | NA | 67.0 | 56.4 | NA | NA | NA | NA | NA | NA | NA | NA | 53.2 | 38.3 |
| Yousef et al. | 83.1 | 83.3 | 50.1 | 42.9 | 91.2 | 89.6 | 45.6 | 32.9 | 26.5 | 27.8 | 55.6 | 53.0 | NA | NA | NA | NA | 56.7 | 73.0 | 42.3 | 40.6 | 26.5 | 33.3 | 2.5 | 5.1 | 10.1 | 12.3 | 5.13 | 6.23 | 47.2 | 38.2 |
| Guddeti et al. | 80.0 | 81.7 | 44.5 | 53.6 | 93.9 | 89.9 | 43.7 | 30.9 | NA | NA | 59 | 55 | 22.4 | 24.6 | 40.3 | 38.8 | NA | NA | 70.7 | 71.5 | NA | NA | NA | NA | 12.4 | 14.5 | 5.0 | 6.0 | 34.9 | 38.1 |
| Pepe et al. | 83.4 | 82.1 | 60.8 | 57.1 | 85.2 | 82.1 | 27.9 | 22.8 | 21.6 | 20.1 | 51.0 | 51.0 | 9.7 | 7.0 | NA | NA | 76.4 | 76.8 | 30.8 | 28.5 | 18.3 | 17.9 | 40.4 | 38.8 | 7.4 | 7.6 | 7.2 | 6.1 | 56.7 | 65.3 |
| Heidari et al. | 80.8 | 79.9 | 47.8 | 49.5 | 85.8 | 81.1 | 31.0 | 24.2 | 69.0 | 65.3 | 54.8 | 53.8 | 28.5 | 31.6 | 40.5 | 49.5 | 83.2 | 85.3 | NA | NA | 43.1 | 44.2 | 1.8 | 1.1 | 8.4 | 11.6 | 8.2 | 7.4 | 26.6 | 32.6 |
| Chahine et al. | 82 | 83 | 40.4 | 44.5 | 92.1 | 92.0 | 43.6 | 35.9 | 35.3 | 33.9 | 58.7 | 57.1 | 30.1 | 26.0 | 47.2 | 41.0 | NA | NA | NA | NA | NA | NA | 4.9 | 3.3 | 16.6 | 21.9 | NA | NA | NA | NA |
| Seeger et al. | 81.0 | 79.9 | 55.1 | 55.1 | NA | NA | 30.3 | 30.4 | NA | NA | NA | NA | 8.7 | 5.8 | 47.8 | 36.2 | 81.2 | 73.9 | 72.5 | 76.8 | NA | NA | 37.7 | 33.3 | 18.8 | 18.8 | 7.2 | 7.4 | NA | NA |
| Abdelghani et al. | 81.8 | 79.7 | 51.5 | 48.1 | 76.1 | 73.6 | 32.2 | 29.2 | 17.2 | 16.0 | 59.0 | 57.1 | 17.8 | 27.4 | 14.9 | 12.1 | 80.3 | 88.7 | 57.6 | 62.3 | 18.2 | 19.8 | 15.7 | 25.0 | 7.9 | 9.4 | NA | NA | 75.5 | 73.6 |
| Chieffo et al. | 81.1 | 80.8 | 44.6 | 51.6 | 72.6 | 68.5 | 29.4 | 27.9 | 27.9 | 21.3 | 51.3 | 51.4 | 23.2 | 19.3 | 22.0 | 25.4 | 79.4 | 82.8 | NA | NA | 32.0 | 32.9 | 39.6 | 36.8 | 15.2 | 14.6 | 9.1 | 7.9 | NA | NA |
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