Transcatheter aortic valve implantation (TAVI) has become a first-line therapy for severe aortic stenosis in patients aged ≥ 75 years.1 Despite the widespread use of this technique, there is still a need for strategies to help in patient selection and risk stratification. Circulating biomarkers have emerged as potentially valuable tools for improving risk stratification and patient selection. Natriuretic peptides have been evaluated for this purpose with conflicting results.2–4

Circulating levels of carbohydrate antigen 125 (CA125) have shown clinical usefulness in heart failure (HF).5 Plasma CA125 concentrations correlate with clinical, hemodynamic, and echocardiographic parameters related to disease severity and fluid overload.5,6 As a marker of fluid overload, higher levels of CA125 identify patients with greater extravascular congestion.7 In acute HF, high levels of this glycoprotein are associated with a higher risk of mortality and readmission.5,8 Changes in this biomarker after the first months following HF decompensation are also associated with prognosis.8–10 Additionally, 2 randomized clinical trials have shown that this biomarker seems helpful in tailoring the intensity of diuretic therapy in patients after an episode of acute HF.11,12

CA125 is upregulated in a significant percentage of patients with symptomatic aortic stenosis, which is associated with the severity of symptoms and risk of adverse outcomes.13 Moreover, it has been suggested that higher baseline and follow-up levels are independently associated with adverse clinical outcomes after TAVI.14–16 We hypothesized persistently elevated CA125 levels despite pre-TAVI diuretic up-titration would identify patients with a poor prognosis. Conversely, we also hypothesized that a reduction in CA125 after optimization would improve clinical results.

The aim of the present study was to evaluate whether pre-TAVI medical optimization guided by CA125 levels influences TAVI clinical outcomes.

From May 2018 to June 2021, 184 patients were included from a total of 258 TAVI performed in this period (figure 1). Baseline characteristics are summarized in table 1. Furosemide daily dose in patients with baseline CA125≥20 U/mL was titrated following protocol recommendations, resulting in a change from 21.75mg±19.15 before inclusion to 63.5mg±38.3mg; there were no significant differences in diuretic dose between groups IIa and IIb (70mg±32.9 and 63.4mg±41.2 respectively; P=.58). After a median of 13 [IQR, 8.5] days, with no significant differences between groups (P=.187), CA125 levels were re-evaluated immediately before the TAVI procedure, with a median decrease of 6 [IQR, 18] U/mL from 40 U/mL to 33 U/mL, P=.005, representing a 18% reduction [IQR, 34]. Based on both the baseline and preprocedural CA125 levels, patients were categorized into 3 distinct groups. Group I consisted of 115 patients with baseline CA125 <20 U/mL. Group II was divided into 2 subcategories: Group IIa with 46 patients who had baseline CA125 levels≥20 U/mL and demonstrated a decrease following diuretic treatment, and group IIb with 23 patients who had baseline CA125 levels≥20 U/mL but showed no subsequent decrease. Table 2 shows baseline and preprocedural CA125 levels in each group; of note, no statistical difference was found in baseline CA125 levels between groups IIa and IIb. Procedural data are summarized in table 1 of the supplementary data. NT-proBNP changes are shown in table 2 of the supplementary data.

Figure 1.

Flow Chart. CA125, carbohydrate antigen 125; QoL, quality of life; TAVI, transcatheter aortic valve implantation.

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Quality of life change according to CA125 group

The baseline QoL measurements were statistically different across the 3 study groups, with better QoL in those belonging to group I and worse QoL in group IIb (group I median KCCQ 51 [IQR, 29], group IIa 45 [IQR, 27] and group IIb 43 [IQR, 18]; P=.029).

After TAVI, patients in groups I and IIa experienced early and sustained improvements in KCCQ compared with its baseline values. Specifically, in group I, a median gain of 18.9 points was observed at 90 days (95%CI, 15.7-22.1; P <.001), which was maintained at 1 year with an increase of 18.1 points (95%CI, 14.9-21.4; P <.001). In group IIa, an elevation by a median of 21.1 points was noted at 90 days (95%CI, 15.4-26.7; P <.001), and this trend persisted at 1 year, registering a median increase of 19.5 points (95%CI, 13.9-25.1; P <.001) (figure 2). In contrast, patients in group IIb did not experience a significant improvement in KCCQ at 90 days (increase of 8.9 points, 95%CI, −2.3-20.1; P=.12); however, a notable improvement was observed at the 1-year evaluation, with an increase in KCCQ score to 17.8 points relative to baseline (95%CI, 5.9-29.6; P=.003) (figure 2).

Figure 2.

Central illustration. Study overview and findings. The left panel outlines the study protocol, interventions, and groups. The upper right displays quality of life changes (KCCQ) in CA125 groups at baseline, 90 days, and 1 year, with P values indicating intragroup baseline comparisons. Group definitions are as follows: group I: baseline CA125 <20 U/mL; IIa: baseline CA125 ≥ 20 U/mL with significant diuretic therapy improvement; IIb: baseline CA125 ≥ 20 U/mL without significant improvement posttherapy. The lower right shows Kaplan-Meier curves for mortality and heart failure admissions during follow-up. CA125, carbohydrate antigen 125; HF, heart failure; KCCQ, Kansas City Cardiomyopathy Questionnaire.

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At 90 days, between-group comparisons showed higher KCCQ in group I (11.9 points; 95%CI, 1.9-22; P=.019) and group IIa (12.1 points; 95%CI, 1.7-22.6; P=.022) compared with group IIb. However, between-group differences were no longer significant at 1 year (I vs IIb: 4.4; 95%CI, -5.8-14.8; P=.396, and IIa vs IIb: 3.44; 95%CI, −7.2-14.1; P=.529) (figure 3). Figure 4 illustrates changes in QoL categorized as an ordinal variable.

Figure 3.

Comparative analysis of variation in KCCQ scores at 90 days and 1 year. Each bar delineates the differential change in KCCQ between group I and group IIb, as well as between group IIa and group IIb. Corresponding P values are specified for each comparison. The left panel represents the evaluation at the 90-day mark, while the right panel corresponds to 1-year assessment. KCCQ, Kansas City Cardiomyopathy Questionnaire.

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Figure 4.

Quality of life change as an ordinal variable, categorized into the following groups: dead; worse (decrease from baseline of 5 points in the KCCQ); unchanged (change between 5 and 5 points); slightly improved (increase between 5 and 10 points); moderately improved (increase between 10 and 20 points); and substantially improved (increase 20 points). A: at the 90-day evaluation. B: At the 1-year evaluation. KCCQ, Kansas City Cardiomyopathy Questionnaire.

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The present study represents a step further in risk stratification, and optimal management of patients with symptomatic aortic stenosis referred for TAVI. The novelty of this research lies in demonstrating that a CA125-diuretic guided strategy may be useful for optimizing the TAVI results in terms of QoL and adverse clinical events. Patients with CA125 levels below 20 U/mL (no overt fluid overload) and those with levels above 20 U/mL that decreased following diuretic up-titration displayed (adequate decongestion) showed a similar pattern of early and sustained increase in KCCQ scores. In contrast, patients with CA125 levels above 20 U/mL that did not decrease after enhanced diuretic therapy exhibited no significant improvement in KCCQ scores at the 90-day follow-up, although survivors within this group demonstrated a significant improvement in QoL at the end of 1 year. Regarding clinical events, nonresponders showed a higher incidence of the combined event of death and HF admission.

Risk stratification in candidates for TAVI has been an issue of the utmost interest since the beginning of this technique when only high-risk patients were considered for this procedure and futility was a major concern.26 The widespread use of TAVI throughout the risk spectrum has increased even further the need for tools for this purpose to optimize results and resources. Multiple scores have been proposed, but there is no clear gold-standard or validated thresholds to guide therapeutic decisions.27–30 Biomarkers may help in this process, as they offer an objective and reproducible evaluation of patient status and are widely available.

CA125 has emerged as a useful biomarker in acute HF by showing a close relationship with the severity of fluid overload and prognosis.6,8–10,31,32 CA125 plasma levels are also elevated in a significant percentage of patients with symptomatic aortic stenosis and they have shown a correlation with symptoms and prognosis.13–16 In a series of 363 TAVI patients, Rheude et al.16 found that both CA125 and NT-proBNP are related to death and readmission at 1 year of follow-up after the procedure, but the predictive capacity of the former was superior when combined. In that article, the optimal threshold to predict clinical events was 18.4 U/mL. Based on these data, we used a similar cutoff (20 U/mL) for the design of our study. The novelty of the present work is the prospective design and the evaluation of the response to diuretic therapy. We found that not only baseline levels but also changes after diuretic treatment are useful to determine the probability of clinical benefit after TAVI.

Some data suggest that patients with severe aortic stenosis treated with diuretics have a worse prognosis.30,33 However, in the present study, only nonresponders (ie, those with no decrease in CA125 levels despite diuretic up-titration) were less prone to clinical improvement in QoL and clinical events. Of note, the impact of CA125 response was independent of left ventricular function, mitral disease, atrial fibrillation and systolic pulmonary pressure, which are all determinants for aortic stenosis cardiac damage staging, as well as STS score frailty (assessed by Fried) and other relevant comorbidities.34,35 Importantly, patients in group IIb who survived 1 year after TAVI significantly increased their KCCQ score and there were no longer statistically significant differences with the other groups. This observation suggests that within this high-risk group, certain individuals could potentially benefit from TAVI in terms of QoL, albeit at a more gradual pace of improvement. Conversely, patients presenting with initially elevated CA125 levels that dropped following diuretic intensification exhibited comparable outcomes to those patients with low baseline levels, suggesting a high probability of clinical benefit after TAVI.

Recent data support the potential role of CA125 levels for treatment titration in HF. The CHANCE-HF trial randomized 380 patients discharged for acute HF with persistent high CA125 levels to a biomarker-guided strategy (aimed to reduce CA125 to ≤ 35 U/mL) vs standard of care.11 The CA125 strategy resulted in a significant reduction in the primary combined endpoint (death or readmission for HF), mainly driven by a reduction in HF readmissions. Another randomized trial showed that a CA125-guided diuretic strategy was associated with a significant improvement in glomerular filtration rate at 72hours in patients with acute HF and renal dysfunction.12 The results of our study support the use of CA125-guided therapy in TAVI patients. Adding CA125 assessment in the clinical pathway before and after TAVI may be helpful in 3 ways: up-titrating diuretic therapy before the procedure in patients with high baseline CA125 levels, including CA125 response to diuretics as a part of a multimodal assessment for clinical futility, and performing a close clinical follow-up after TAVI in nonresponders.

Our results raise the dilemma of futility of TAVI in patients with higher levels of CA125 that do not decrease after diuretic up-titration. Although this subgroup represents a minority (12.5% of our sample), it is characterized by an exceedingly adverse prognosis. However, the potential benefits of TAVI should not be entirely dismissed without thorough assessment. Patients unresponsive to therapy may require either a more prolonged or intensified diuretic regimen prior to TAVI, and/or may need to sustain high-dose diuretic treatment or other HF medications postprocedure. It is doubtful that a longer diuretic treatment before the procedure could be warranted because delays in the intervention are related to fatal events. Therefore, a strategy based on continued intensive treatment and close follow-up after TAVI in this subgroup of patients seems more reasonable. Further investigation is warranted to evaluate the clinical benefit of this approach.

CA125 assessment may be helpful for risk stratification and guiding diuretic therapy before TAVI. Our results suggest that diuretic optimization in patients with CA125 ≥ 20 U/mL with subsequent CA125 reduction may identify patients with favorable outcomes early after TAVI. Conversely, those without CA125 reduction after diuretic intensification may belong to a higher risk group, susceptible to adverse outcomes after TAVI. Whether CA125 may help guide the timing of TAVI or identify futility requires larger controlled studies.

This work was supported by grants from Spain's Ministry of Science and Innovation through the Carlos III Health Institute and FEDER founds: FIS18/01138; Exp. JR/21/00041; CIBER-CV 16/11/00420, Madrid, Spain.

The study was approved by the Clinical Research Ethics Committee of the University Hospital Clinic in Valencia. Written informed consent was obtained from all included patients and was adequately archived. Sex was included in statistical analysis.

None.

Study concept and design: J. Sanchis and J. Núñez. Analysis and interpretation of data: S. García-Blas, J. Núñez, J. Sanchis, C. Bonanad, A. Fernández-Cisnal. Drafting of the manuscript: S. García-Blas, A. Fernández-Cisnal, J. Núñez, V. Pernias. Critical review of the manuscript for important intellectual content: J. González D’Gregorio, C. Sastre, C. Bonanad, E. Valero, G. Miñana, G. Zaharia, J. Núñez, J. Sanchis.

J. Sanchis is editor-in-chief of Rev Esp Cardiol. The journal's editorial procedure to ensure impartial handling of the manuscript has been followed.

The remaining authors report that they have no relationships with industry relevant to the contents of this article to disclose.