Figure 1. Cumulative incidence curve for all-cause mortality based on plasma albumin levels.

Figure 2. ROC curve of plasma albumin concentration to discriminate all-cause mortality.

Table 1. Baseline characteristics.

Table 2. Therapeutic strategy, anatomical-functional, and chemical characteristics

Introduction

Over the last few decades, transcatheter aortic valve implantation (TAVI) has been proposed as a therapeutic strategy that should be taken into consideration in patients with symptomatic severe aortic stenosis (AS) from a wide age range and with a different degree of surgical risk. (1)(2)(3) Therefore, it is of paramount importance to stratify risk for the proper selection of TAVI eligible patients. In this sense, heart teams are multidisciplinary groups including clinical cardiologists, interventional cardiologists, cardiovascular surgeons, and gerontologists in charge of the comprehensive assessment of the patient to determine the feasibility of the percutaneous procedure and discuss each case individually from different perspectives while considering clinical, geriatric, and social parameters with an important role in the entire decision-making process. (4)(5)

The surgical risk parameters we use today to assess TAVI eligible patients like the Society of Thoracic Surgeons (STS) score and the European System for Cardiac Operative Risk Evaluation (EuroSCORE) score were developed from cohorts of non-comparable characteristics. (6)(7) Also, there is a mounting concern surrounding the fact that these scores do not include conditions that are often present in this subgroup of patients like chronic kidney damage, need for additional oxygen, and parameters associated with frailty that can all negatively impact clinical progression. In this context, the Valve Academic Research Consortium (VARC-2) stressed out the importance of parameters associated with frailty in the risk stratification of patients assessed before performing TAVI. Based on these criteria, plasma albumin levels < 3.5 g/dL are a new frailty surrogate risk factor that can be associated with unfavorable clinical progression. (8)

Currently, in our setting, there is little information on the prevalence and long-term clinical impact of low plasma albumin levels in patients with severe AS treated with TAVI.

Endpoints

Primary endpoint

To determine the prevalence and clinical impact of hypoalbuminemia regarding all-cause mortality in patients with severe AS treated with TAVI.

Co-primary endpoint

To determine the feasibility of using plasma albumin levels as a predictor of all-cause mortality, and its plasma value of improved discrimination and calibration abilities.

Material and methods

This was a single-center, retrospective cohort that included patients with severe AS treated by a heart team from Hospital Italiano de Buenos Aires, Argentina who underwent TAVI and with data available on their plasma albumin levels. The baseline characteristics, anatomical-functional, biochemical data, and adverse clinical events at 2-year follow-up of the overall cohort were studied and followed by stratification based on the presence or lack of hypoalbuminemia.

Term definition

• Hypoalbuminemia: it was defined as plasma albumin levels < 3.5 g/dL. (8)
• Pre-frailty/Frailty: defined based on Fried Frailty Index where the presence of 1 or more factors is considered “pre-frailty” while the presence of 3 or more factors is considered “frailty”. In sum, this index considers 5 different domains: unintentional weight loss; weakness or poor handgrip strength; self-reported exhaustion; slow walking speed; and low physical activity. (9)

  Statistical analysis

  The statistical software package SPSS version 25.0 was used (IBM, Armonk, United States). To assess normality, the Kolmogorov-Smirnov test or the Shapiro-Wilk test were used, when appropriate. Quantitative variables were expressed as mean and standard deviation or median and interquartile range and compared using the Student t test or the Mann-Whitney U test based on their distribution. Categorical variables were expressed as frequency and percentage and analyzed using the chi-square test or Fisher’s exact test. The overall survival rate associated with the presence or lack of hypoalbuminemia was assessed using the Kaplan-Meier estimator and expressed using the log-rank test.

  The discrimination abilities of plasma albumin levels were analyzed (g/dL). The all-cause mortality prediction at 2-year follow-up was studied using the receiver operating characteristics (ROC) curves and the area under the curve (AUC) was measured. The cut-off value of better discrimination abilities was determined (Youden index) for the primary clinical endpoint.

  Error type I < 5% was considered statistically significant (2-tailed P < .05).

  Follow-up

  The follow-up period was 24 months since the heart team early assessment.

  Ethical considerations

  This study was approved by the Hospital Italiano de Buenos Aires Research Ethics Committee (#5834) and is registered under the Buenos Aires Computer Registry Platform of Health Research (PRIISA BA, #3030). Given its retrospective nature, no informed consent was required.

  Results

  A total of 132 patients were included. The population sample mean age was 83.44 ± 5.85 years; 53.8% of the patients were women. The median of follow-up was 13.05 months (IQR, 5.96-24.50). The prevalence of hypoalbuminemia was 18.3% (N = 24). Table 1.

  The subgroup of patients with hypoalbuminemia was of a higher surgical risk as seen on the STS score, the prevalence of heart failure was 3 times higher while the prevalence of atrial fibrillation and chronic kidney disease was 2 times higher compared to patients with normal albumin levels. No statistically significant differences were reported regarding body mass index with a tendency towards a greater presence of pre-frailty/frailty. Table 1.

  Regarding the anatomical-functional and biochemical characteristics, a higher prevalence of moderate/severe tricuspid failure was seen in the subgroup of patients with hypoalbuminemia compared to those with normal albumin levels. The subgroup of patients with hypoalbuminemia had a lower-than-normal hematocrit, fewer platelet count, less plasma creatinine clearance, and higher cancer antigen 125 concentrations (CA-125), high-sensitivity cardiac troponin T, and b-type natriuretic peptide compared to the subgroup of patients with normal albumin levels (Table 2).

  The event-free analysis showed a higher cumulative rate of all-cause mortality in the subgroup of patients with hypoalbuminemia at 2-year follow-up (25.5% vs 6.0%; log-rank test; P = .002) (Figure 1).

  The plasma albumin concentration revealed the feasibility and significant discrimination abilities for all-cause mortality with an AUC of 0.715 (P = .004), and a cut-off value of improved discrimination of 3.81 g/dL, 70.6% sensitivity, 69.3% specificity, a 25.5% positive predictive value, and a 94.0% negative predictive value (Figure 2).

  Discussion

  As far as we know, this is the first trial ever conducted in our setting that analyzed the prevalence, long-term clinical impact, feasibility, and discrimination abilities of hypoalbuminemia to predict all-cause mortality in patients with severe AS treated with TAVI following indication from the heart team.

  In patients with severe AS treated with TAVI, there was a significant prevalence of hypoalbuminemia that was consistent with the findings reported in previous studies. (10) We should expect patients assessed by a heart team to have higher degrees of frailty before deciding on the indication for TAVI. In this context, plasma albumin levels are an independent marker of frailty since they keep a positive correlation with the degree of associated comorbidities, disability, and states of vulnerability, all surrogate components of plasma albumin. (11)

  It was confirmed that the subgroup of patients with hypoalbuminemia had a higher burden of associated comorbidities. Albumin is an acute phase reactant associated with a higher cardiovascular mortality rate in different clinical settings analyzed. (12)(13) The baseline characteristics of patients with hypoalbuminemia can be associated with the function of plasma albumin as an effector of intravascular oncotic pressure, thus generating reduced effective actual volemia and renal failure due to hypovolemia. Also, albumin is a surrogate marker of the baseline nutritional status capable of showing disorders in the process of liver protein synthesis and an underlying state of malnutrition. (14)(15) A retrospective study that included patients with severe AS treated with TAVI (N = 464) demonstrated that patients with hypoalbuminemia are more comorbid, have a higher prevalence of diabetes mellitus (45% vs 30%; P = .038), chronic kidney disease requiring dialysis (12% vs 3%; P = .009), chronic obstructive pulmonary disease (39% vs 25%; P = .042), and a higher left ventricular ejection fraction < 45% (39% vs 22%; P = .010) compared to patients with normal albumin levels. Similarly, patients with hypoalbuminemia had lower hemoglobin concentrations (11 ± 2 vs 12 ± 2 g/dL; P < .001), and higher plasma creatinine concentrations (1.3 vs 1.1 mg/dL; P = .01). (10)

  Hypoalbuminemia was associated with a higher overall mortality rate at the long-term follow-up. In this context, it has been demonstrated that plasma albumin levels keep a close correlation with the levels of circulating cytokines, controls the electrolyte plasma levels, keeps an interaction with plasma-free fatty acids and steroid hormones, and has antioxidant effects. (16) Similarly, it is a marker of kidney and liver failure, subclinical systemic inflammation, and endothelial dysfunction. (17) Therefore, it is hard to understand what the exact mechanism is through which low plasma albumin concentrations are associated with a higher TAVI related mortality rate. A Japanese study that included patients treated with TAVI (N = 1215) demonstrated that the presence of hypoalbuminemia was associated with higher all-cause and cardiovascular mortality rates compared to patients with normal albumin levels at a median follow-up of 330 days (25.3% vs 7.7%; log-rank test; P < .001) even after matching the groups per propensity score.(18) This impact hypoalbuminemia had on the higher mortality rate reported is consistent with what former studies have reported on this regard. (19) Therefore, a systematic review and a meta-analysis of the medical literature available that analyzed patients treated with TAVI (N = 8236) demonstrated that low plasma albumin concentrations were associated with higher 30-day overall mortality rates (HR, 2.09 [95%CI, 1.53-2.86]), and at 1-year follow-up (HR, 1.61 [95%CI, 1.31-1.98]). (20)

  Finally, it is feasible to use plasma albumin concentration as a parameter to predict mortality with a modest discrimination power. This study had a cut-off value of greater discrimination for all-cause mortality of 3.81 g/dL of plasma albumin, a value that is close to the one accepted for the definition of hypoalbuminemia, which is associated with a great clinical utility regarding risk stratification using this biomarker. We should mention that despite the importance of obtaining a single value that is also easy to use in the routine clinical practice, the plasma albumin concentration as a continuous quantitative variable can be inversely associated with a higher rate of adverse events. (11)

  This study has some limitations that have to do with observational studies and their inherent biases. No echocardiographic data at follow-up were reported, which may have explained the causes that led to mortality. No data associated with the pharmacological medical therapy prescribed were reported either.

  Conclusions

  A significant prevalence of hypoalbuminemia was described in patients with severe AS treated with TAVI that was associated with a greater burden of concomitant comorbidities and a higher mortality rate at follow-up. The plasma albumin value obtained of improved discrimination for the overall mortality rate is similar to the one used for the definition of hypoalbuminemia.

  Conflicts of interest

  None whatsoever.

  Keypoints

• Proper risk stratification is of paramount importance to implement individualized therapeutic approaches.
• The risk scores commonly used do not include highly prevalent clinical comorbidities.
• Therefore, hypoalbuminemia is considered a surrogate marker of frailty, a finding commonly seen in patients with severe aortic stenosis (AS) treated with transcatheter aortic valve implantation (TAVI).
• The presence of hypoalbuminemia is associated with a lower survival rate in patients with AS treated with TAVI.
• Determining the plasma albumin concentrations has modest discrimination abilities to predict mortality in this subgroup of patients.

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