The impact of subclinical congestion on the outcome of patients undergoing transcatheter aortic valve implantation

Abstract Background We investigated the impact of an elevated plasma volume status (PVS) in patients undergoing TAVI on early clinical safety and mortality and assessed the prognostic utility of PVS for outcome prediction. Materials and methods We retrospectively calculated the PVS in 652 patients undergoing TAVI between 2009 and 2018 at two centres. They were then categorized into two groups depending on their preoperative PVS (PVS ≤−4; n = 257 vs PVS>−4; n = 379). Relative PVS was derived by subtracting calculated ideal (iPVS = c × weight) from actual plasma volume (aPVS = (1 − haematocrit) × (a + (b × weight in kg)). Results The need for renal replacement therapy (1 (0.4%) vs 17 (4.5%); P = .001), re‐operation for noncardiac reasons (9 (3.5%) vs 32 (8.4%); P = .003), re‐operation for bleeding (9 (3.5%) vs 27 (7.1%); P = .037) and major bleeding (14 (5.4%) vs 37 (9.8%); P = .033) were significantly higher in patients with a PVS>−4. The composite 30‐day early safety endpoint (234 (91.1%) vs 314 (82.8%); P = .002) confirms that an increased preoperative PVS is associated with a worse overall outcome after TAVI. Conclusions An elevated PVS (>−4) as a marker for congestion is associated with significantly worse outcome after TAVI and therefore should be incorporated in preprocedural risk stratification.


| INTRODUCTION
Chronic heart failure (CHF) has a significant impact on the outcome after transcatheter aortic valve implantation (TAVI), yet is widely underestimated in the daily clinical practice. 1 Since contemporary risk models are based exclusively on left ventricular pump function, newly developed CHF scores represent a decisive decision-making aid in the preoperative risk assessment.
CHF is a syndrome of a very heterogeneous group of patients with cardiac pathologies. A common feature in all patients with CHF is the extremely poor long-term prognosis, with mortality curves found to be steeper than in some patients harbouring malignant diseases. 2 Individuals undergoing TAVI procedure are at great risk of adverse procedural events related to heart failure. 3 The reason for this is mainly based on two factors: patient selection and the underlying disease. TAVI patients are in general older and suffer from more comorbidities than patients suitable for conventional surgical aortic valve replacement (SAVR). 4 Aortic stenosis (AS) also inherently leads to left ventricular hypertrophy via increased filling pressures, which ultimately results in heart failure. 5 Refractory volume overload and congestion, often accelerated by impaired renal function, is one of the biggest concerns in the progression of CHF. 6 An increase of plasma volume in patients with CHF can lead to acute decompensated heart failure (ADHF) with known adverse effects on prognosis. 2,7 A recently published score to calculate plasma volume status (PVS) was able to show a correlation between elevated PVS and cardiovascular mortality in patients with stable CHF and PVS greater than −4. In this study, PVS was calculated using only haematocrit, body weight and gender, information easily available for all patients. 8 Every invasive procedure can trigger ADHF and thereby increase the periprocedural mortality. 9 As a new tool for risk stratification, calculated PVS was able to show significant results in patients with CHF and patients undergoing coronary bypass graft surgery. 10 The goal of this study was to determine the impact of preprocedural (often subclinical) cardiac decompensation on early mortality and clinical safety in patients undergoing a TAVI procedure and to assess the predictive power of PVS as a prognostic parameter in preprocedural risk assessment.

| MATERIALS AND METHODS
The study investigated 652 patients who underwent TAVI either via transfemoral (n = 365), transapical (n = 266) or via alternative access (n = 5). Complete data from 532 consecutive patients from the prospectively maintained VICTORY treated between June 2009 and December 2018 at the Heart Center Hietzing/Vienna as well as from 120 consecutive patients of the TAVI Registry from the Johns Hopkins Hospital treated between January and August 2018. The preprocedural assessment and the procedure were performed in a standard fashion by a multidisciplinary heart team and have been previously described in detail. 11,12 The patient selection process followed the same principles and guidelines at both institutions. As the procedural steps are standardized, comparability of the Austrian and American patient collective can be assumed.
A total of 636 patients had both their weight measured and a complete preprocedural haematologic workup done one day prior to the procedure, and PVS was calculated accordingly. Sixteen patients had to be excluded due to their haematocrit levels having been measured in an extramural setting before the admission for TAVI.
All patients included were educated about the procedure and the associated risks and gave written informed consent. Following approval of the study by the local ethics committees, a retrospective analysis of the patient's baseline characteristics, as well as clinical and procedural data were carried out. Long-term mortality data including the cause of death were obtained by examination of hospital records and by inquiry to the Federal Institute for Statistics Austria.
Patients were diagnosed with (subclinical) cardiac decompensation when their PVS exceeded threshold levels greater than −4. This cut-off value derived from the Valsartan in Heart Failure Trial (Val-HeFT) has proven to be associated with death-and morbidity-related events in its 5248 patient strong analysis. 8

| Plasma volume equations
An equation derived from curve-fitting techniques using the patients' haematocrit (Hct) and weight compared to scores of measurements taken from radioisotope assays has been used to calculate the actual plasma volume 13 : Two constants are included in the equation to account for gender differences: a = 1530 in males and 864 in females; b = 41 in males and 47.9 in females.
The ideal plasma volume was calculated using the following formula described by Longo et al 14 where c is a constant accounting for gender differences, equivalent to 39 in males and 40 in females.
Subsequently, the relative plasma volume describing the patients percentual deviation from their ideal plasma volume was calculated using the following Equation 8 : The clinical outcome and the occurrence of related periand postprocedural complications were classified as per the updated Valve Academic Research Consortium (VARC)-II criteria. 15 The primary study endpoint was defined as 30-day mortality; the composite secondary endpoint was defined as early safety at 30-days incorporating the freedom of allcause mortality, stroke, life-threatening bleeding, acute kidney injury stage 2 or 3, coronary artery obstruction requiring intervention, major vascular complication and valve-related dysfunction requiring repeat procedure. Long-term survival was assessed between the two groups.

| Statistical analysis
The study population was separated into two cohorts: those who presented with a relative PVS > −4 prior to TAVI and those who had a relative PVS score ≤−4. Continuous variables were-based on their distribution-expressed as either a median and interquartile range (IQR) or a mean and standard deviation (±SD) and compared using the Student's t test or the Mann-Whitney U test, respectively. Categorical variables were expressed as absolute numbers and percentage and compared with a Chi 2 test or the Fisher's exact test.
To examine the association between the PVS and the overall long-term mortality, a Cox proportional hazards model was used to estimate hazard ratios and 95% confidence intervals. The date of the implantation to either death or the last available follow-up was used to calculate the individual person-time interval. The hazard ratio was stratified by the PVS score and adjusted for baseline characteristics including the STS score, and both the logistic EuroSCORE and the EuroSCORE II in a stepwise fashion.
All reported p-values are two-sided, and results were categorized as statistically significant with an alpha level set at <0.05; the analyses were performed using spss, version 24.0 (IBM Corp).

| RESULTS
In total, the study investigated 636 patients. The preprocedural medical history and the patients' risk profile are outlined in Table 1. According to the PVS, almost twothirds of all patients referred for TAVI were in (subclinical) cardiac decompensation (PVS > −4: n = 379; 59.6%).
The preoperative echocardiographic investigation demonstrated that patients with a PVS higher than −4 had a significantly higher systolic pulmonary artery pressure (39.1 ± 23.6 vs 33.7 ± 23.5 mm Hg; P = .018). Importantly, no significant difference in preoperative left ventricular ejection fraction was observed between the two PVS cohorts.

| Procedural and postinterventional characteristics
The procedural and postinterventional characteristics are outlined in Table 2. In our study, patients with a higher PVS were generally smaller in stature and consequently also received smaller sized prosthetic valves (27 ± 2.9 mm vs 26.3 ± 2.6 mm; P = .007). The significantly increased requirement for predilatation (53.3% vs 64.9%; P = .002) and reduced amount of radiation exposure (9794 cGy vs 7199 cGy; P < .001) may be indicative of a higher calcific burden in these patients. Furthermore, patients with a higher PVS score demonstrated a longer stay at both the intensive care unit and the general ward (20 ± 44 hours vs 21 ± 50 hours; P = .001 and 8 ± 11 vs 10 ± 9 days; P = .001, respectively) and showed a strong trend towards prolonged postprocedural ventilation (0 ± 6.0 hours vs 2.5 ± 6.0 hours; P = .053).

| Adverse events and survival
Significantly more patients in the PVS > −4 cohort were in need of postoperative renal replacement therapy (0.4% vs 4.5%; P = .001) and of reoperation/reintervention for noncardiac reasons (3.5% vs 9.2%; P = .003). The latter comprise mostly the need for pleural drainage placement. Moreover, patients with an elevated PVS score were more prone to major bleeding events (5.4% vs 9.8%; P = .033) resulting in an increased requirement for red blood cell transfusions (0.4 vs 1.6 units; P = .001). Although no difference in 30-day all-cause mortality (3.5% vs 5.8%; P = .127) was demonstrated between the two groups, patients with a higher PVS at baseline reached the procedural safety endpoint at 30-days less frequently (82.3% vs 88.9%; P = .042), thus confirming the notion that an elevated PVS increases the overall risk for patients undergoing TAVI procedure (Table 3).
Adjusting the Cox proportional hazards model for the STS score, as well as the EuroSCORE II, the treatment centre, the access site and the investigation period tertiles (2009-2011; 2012-2014; 2015-2018), a significantly lower long-term survival of patients with a higher PVS was demonstrated (adjusted hazard ratio: 1.5; 95% CI: 1.11-2.02; P = .009; Figure 1).

| DISCUSSION
We assessed the association of (sub-) clinical decompensation determined by PVS and outcomes in patients with severe, symptomatic AS undergoing TAVI.
Every TAVI procedure has an impending risk for adverse events related to heart failure. 3 Patients in need of TAVI are frequently at advanced age with symptomatic AS, and multiple preexisting conditions and comorbidities. Generally, in hospital admissions for ADHF, increased congestion is associated with morbidity and mortality. 7 In line with these findings, our data show that cardiac decompensation defined by the PVS status was associated with worse short-and long-term outcomes. The potential implications of this become evident when considering that about two-thirds (59.6%) of the patients in our study admitted for TAVI were in cardiac decompensation. These patients were not necessarily clinically decompensated but defined by an elevated PVS rather subclinically.
These patients had a significantly lower BMI presumably underlining the overall impaired health and advanced disease progression of this population. Taking comorbidities into account, iron deficiency represents a plausible pathophysiological link, as decongestion according to the PVS could be achieved by intravenous iron repletion in CHF patients with iron deficiency. 18 Considering anaemia is a well-established predictor unfavourable outcome in CHF, iron deficiency along with several other factors such as haemodilution may be involved in the underlying mechanism. 19 In the present study, we were able to show that the calculated PVS may help identify patients at risk for adverse outcomes. Patients with a high PVS were not only at increased risk for periprocedural death but also demonstrated a substantially impaired long-term survival during the follow-up